This upregulation of GRK2 is also accompanied by upregulation and increased production of the enzyme tyrosine hydroxylase, which catalyzes the rate limiting step of catecholamine synthesis.
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BZW2 has been studied to determine its role in multiple cancers. Overall, the studies all showed that upregulation of BZW2 lead to more severe forms of cancer, higher rate of mortality, and increased likeliness of reoccurrence. A 2019 study focused on the effect of BZW2 in colorectal cancer. It found that upregulation of BZW2 promoted tumor growth and had a downstream upregulation effect on c-Myc, a proto-oncogene.
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Resveratrol, a natural phenol and antioxidant, upregulates miR-663 in human THP-1 monocytic cells, human blood monocytes and MCF7 brest cancer cells. Endogenous activator protein-1 (AP-1) activity is decreased by miR-663 and there is additional impaired lipopolysaccharide upregulation. miR-663 directly targets JunD and JunB transcripts, and alters AP-1 upregulation through this. It is further involved in the impaired lipolysaccharide upregulation of miR-155 by resveratrol.
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In the lung parenchyma of smokers, upregulation of FGG transcript levels has been reported.
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However, the use of certain receptor antagonists may also damage receptors Upregulation and downregulation can also happen as a response to toxins or hormones. An example of upregulation in pregnancy is hormones that cause cells in the uterus to become more sensitive to oxytocin.
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This means that any upregulation in PA production can be matched, over time, with a corresponding upregulation in LPPs and in DAG metabolising enzymes. PA is, therefore, essential for lipid synthesis and cell survival, yet, under normal conditions, is maintained at very low levels in the cell.
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Hyperthyroidism, or any other endocrine disturbance which causes upregulation of the LDL receptor, may result in hypocholesterolemia.
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Int Immunopharmacol. 2005 Mar;5(3) 609-18. Antidepressants have also been shown to suppress TH1 upregulation.
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Activation of this pathway can also stimulate presynaptic glutamate release and cause an upregulation of AMPA receptors postsynaptically.
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Activation of c-Src can lead to the so-called hallmarks of cancer: upregulation of angiogenesis, proliferation, and invasion.
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FOXM1 gene is now known as a human proto- oncogene. Abnormal upregulation of FOXM1 is involved in the oncogenesis of basal cell carcinoma, the most common human cancer worldwide. FOXM1 upregulation was subsequently found in the majority of solid human cancers including liver, breast, lung, prostate, cervix of uterus, colon, and brain.
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During early and reperfusion stage of ischemia, there is an upregulation of secondary active cotransporter NKCCl. NKCCl play an important role in modulating loading of sodium and chloride in neurons, glia, endothelial cells and choroid plexus. The upregulation of NKCCl is followed by increased deposition of Sodium(Na) and Chloride in endothelial cells and Na+K+ATPase activity plays a role in expelling Na followed by chloride and water from endothelial cells into extracellular space leading to vasogenic edema. Thus, preventing NKCCl upregulation has the potential to prevent cerebral edema from forming.
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JARID1A has been shown to interact with Estrogen receptor alpha, LMO2 and Retinoblastoma protein. JARID1A is a major component of the circadian clock, the upregulation of which at the end of the sleep phase blocks HDAC1 activity. Blocking HDAC1 activity results in an upregulation of CLOCK and BMAL1 and consequent upregulation of PER proteins. The PSF (polypyrimidine tract-binding protein-associated splicing factor) within the PER complex recruits SIN3A, a scaffold for assembly of transcriptional inhibitory complexes and rhythmically delivers histone deacetylases to the Per1 promoter, which repress Per1 transcription.
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The efficacy of spectral filters in the upregulation of retinohypothalamic drive. Program No. 927.13. 2007. San Diego, CA: Society for Neuroscience, 2007.
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In various cancers, upregulation tends to lead to higher severity and mortality. It has been found to interact with SARS-CoV-2.
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TERC-mediated upregulation of Lin37, Trpg1l, tyrobp, Usp16 stimulates the NF-κB pathway, resulting in increased expression and secretion of inflammatory cytokines.
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Upregulation of the same pathway in the locus coeruleus is also a mechanism responsible for certain aspects of opioid- induced physical dependence.
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Endogenous FOXO3a activation results in marked upregulation of Mmp13 expression which is capable of promoting extracellular matrix degradation and apoptotic cell death.
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Treatment of human cells expressing MCHR2 with MCH resulted in upregulation of IDH3A, PCK1 and PFKFB4 and the downregulation of INSIG2 and ACOT8.
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Practical use of the knowledge of induced-self antigens is in targeting tumors for immune response. As tumors are very often capable of escaping the immune system by many ways, upregulation of specific ligands on the tumor cells could mount effective immune mechanisms able to eliminate these cells. For example, upregulation of NKG2D ligands can stimulate the NK cells triggering cell- mediated cytotoxicity.
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During withdrawal from full or partial agonists, changes occur in benzodiazepine receptor with upregulation of some receptor subtypes and downregulation of other receptor subtypes.
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Male reproductive function declines with increasing age as indicated by decreased sperm quality and fertility. As rats age, undifferentiated spermatogonial cells undergo numerous changes in gene expression. These changes include upregulation of several genes involved in the DNA damage response. This finding suggests that during aging there is an increase in DNA damage leading to an upregulation of DNA damage response proteins to help repair these damages.
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In addition, reduced glutamate release in the dorsal hippocampus has been linked to spatial memory loss. Chronic alcohol users experience an upregulation of NMDA receptors because the brain is attempting to reestablish homeostasis. When a chronic alcohol user stops drinking for more than 10 hours, apoptosis can occur due to excitotoxicity. The seizures experienced during alcohol abstinence are thought to be a result of this NMDA upregulation.
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An example of upregulation is the response of liver cells exposed to such xenobiotic molecules as dioxin. In this situation, the cells increase their production of cytochrome P450 enzymes, which in turn increases degradation of these molecules. Downregulation or upregulation of an RNA or protein may also arise by an epigenetic alteration. An epigenetic alteration can be permanent or semi-permanent in a somatic cell lineage.
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Upregulation of target genes can also render the fungicide ineffective. This is seen in DMI-resistant strains of Venturia inaequalis.Schnabel, G., and Jones, A. L. 2001.
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ERK3/MAPK6 interacts with and phosphorylated steroid receptor coactivator 3 (SRC-3) This coreceptor is an oncogenic protein which when overexpressed at serine 857 leads to cancer. After the phosphorylation of SRC-3 results in the upregulation of MMP activity ERK3-mediated phosphorylation at S857 was essential for interaction of SRC-3 with the ETS transcription factor PEA3, which promotes upregulation of MMP gene expression and proinvasive activity.
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Mutations in this gene have been linked to a subset of autism cases. Mutations in CHD8 could lead to upregulation of β-catenin-regulated genes, in some part of the brain this upregulation can cause brain overgrowth also known as macrocephaly, which occurs in 15-35% of autistic children. Some studies have determined the role of CHD8 in autism spectrum disorder (ASD). CHD8 expression significantly increases during human mid-fetal development.
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C/EBPβ has been found to have a role in the development of osteoporosis. The full-length isoform of the C/EBPβ protein (LAP) activates the MafB gene, whereas the short isoform (LIP) suppresses it. MafB gene activation suppresses the formation of osteoclasts. Thus, upregulation of LAP diminishes the number of osteoclasts, and this weakens the osteoporotic process, whereas upregulation of LIP does the opposite, increasing loss of bone mass.
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Moreover, it is proposed that chronic ethanol exposure results in upregulation of HDAC activity, causing anxiety-like effects that can no longer be alleviated by acute ethanol exposure.
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The exact mechanism of FOXM1 in cancer formation remains unknown. It is thought that upregulation of FOXM1 promotes oncogenesis through abnormal impact on its multiple roles in cell cycle and chromosomal/genomic maintenance. Aberrant upregulation of FOXM1 in primary human skin keratinocytes can directly induce genomic instability in the form of loss of heterozygosity (LOH) and copy number aberrations. FOXM1 overexpression is involved in early events of carcinogenesis in head and neck squamous cell carcinoma.
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FOXO3a also functions as a trigger for apoptosis through upregulation of genes necessary for cell death, such as Bim and PUMA, or downregulation of anti-apoptotic proteins such as FLIP.
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BTG2 binds to the promoter of Id3 and represses its activity. By this mechanism, the upregulation of Id3 in the hippocampus caused by BTG2 ablation prevents terminal differentiation of hippocampal neurons.
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Upregulation of eEF1A has been reported in breast cancer samples. Interestingly, however, this upregulation only occurs at the protein level, because the mRNA level is significantly reduced in breast cancer samples. This paradox has been explained by cell cycle-regulated EEF1A1 mRNA expression and stress-induced increase in eEF1A protein levels in breast cancer cells. Though its role in metastasis remains unclear, the role of eEF1A in cytoskeleton organization may promote tumor cell motility and thus spread.
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This species shares certain behavioral commonalities with Drosophila mettleri. A major difference between these two fly species, however, that serves to limit the amount of competition between them in nesting site selection is more genetically than behaviorally explained. D. mettleri contains an upregulation in the CYP28A1 gene in the P450 gene family. Upregulation in this gene enables D. mettleri to breed in both the toxic soil surrounding rotting cacti and on the tissues of rotting cacti patches.
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The upregulation of BCL-2 after androgen ablation in prostate carcinoma cell lines and in a castrated- male rat model further established a connection between BCL-2 expression and prostate cancer progression.
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Myelodysplastic syndrome and 5q-syndrome have also been linked to an upregulation of ZNF183, an alias of RNF113A. It appears RNF113A may allow for a more stable activated spliceosome and post-catalytic spliceosome.
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The expression of PHOT1 and PHOT2 changes depending on the presence of blue or red light. There was a downregulation of PHOT1 mRNA in the presence of light, but upregulation of PHOT2 transcript.
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Relaxin increases the rate and force of cardiac contraction in rat models. Via upregulation of VEGF, relaxin plays a key role in blood vessel formation (angiogenesis) during pregnancy, tumour development or ischaemic wounds.
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More recently, CLIMP-63 has been related to different types of cancer prognosis. Upregulation of CLIMP-63 is observed in cholangio-cellular and hepatocellular carcinoma and it correlates with lymph node metastasis appearance.
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These transcription factors cause the upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression. The upregulation of these inflammatory mediators by ethanol is also associated with an increase in caspase 3 activity and a corresponding increase in cell apoptosis. The exact mechanism by which various concentrations of ethanol either activates or inhibits TLR4/IL-1RI signaling is not currently known, though it may involve alterations in lipid raft clustering or cell adhesion complexes and actin cytoskeleton organization.
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The role of HDAC2 in various forms of cancer such as osteosarcoma, gastric cancer, and acute myeloid leukemia have been studied. Current research is focused on creating inhibitors that decrease the upregulation of HDAC2.
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Interleukin-4 (IL-4) and granulocyte-macrophage colony stimulating factor (GMCSF) both upregulate PD-L2 expression in DCs in vitro. IFN-α, IFN-β, and IFN-γ induce moderate upregulation of PD-L2 expression.
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Upon tissue damage, there is an upregulation in the activity of many pathways that control tissue growth, including the YAP/TAZ pathway, Wnt signaling pathway, and growth factors that activate the PI3K/AKT/mTOR pathway.
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BRAFP1, the BRAF (gene) pseudogene, has been implicated in the development of cancer, including B-cell lymphoma, by acting as a ceRNA for BRAF. Upregulation of BRAFP1 led to an overexpression of the BRAF oncogene.
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Experimentally, human endometrial stromal cells can be decidualized in culture by using analogs of cAMP and progesterone. The cells will exhibit a decidualized phenotype and display upregulation of common decidualization markers such as prolactin and IGFBP1.
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TGFB is a regulatory molecule involved in proteoglycan production. This production is increased in the presence of bFGF or Interleukin 1. An anti-TGFβ antibody may potentially reduce GFAP upregulation after CNS injuries, promoting axonal regeneration.
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Consistent with these findings is a study demonstrating downregulation of epithelial markers (E-cadherin, occludin, β-catenin) and concurrent upregulation of mesenchymal markers (N-cadherin, vimentin, fibronectin) in response to NEDD9 overexpression in MCF-10 cells.
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ARIA plays a role in synapse development, influencing the upregulation of acetylcholine receptor genes beneath the endplate after mammalian motor neurons have made synaptic contact with muscle fibres, hence its name ARIA = Acetylcholine Receptor Inducing Activity.
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The pattern of high and low expression with the brain is very similar to another widespread gene: beta actin. This is one indication that CHID1 may show normal expression patterning in mammals, despite its general upregulation.
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Without the shield, there is an increased quantity of phospholipid molecules on cell membranes, speeding up coagulation reactions and causing the blood-clotting characteristic of the antiphospholipid antibody syndrome. Annexin A5 showed upregulation in papillary thyroid carcinoma.
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This allows the expression of the X chromosome to be "doubled," or hyperactivated, to match the amount that females have with two X chromosomes. The second dosage compensation that occurs in mammals are the balancing of X’s and autosomes. This regulation occurs by the upregulation of Xa, which is the active X. The upregulation of the active X shows increases in the activation of transcription and elongation. The X chromosome, compared to an autosomal gene, contains more silent genes which influences measuring the amount of influence active genes have.
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Diagnostically, researchers are investigating the role of novel biomarkers to assist in determining which AKs are more likely to develop into cutaneous or metastatic SCC. Upregulation of matrix metalloproteinases (MMP) is seen in many different types of cancers, and the expression and production of MMP-7 in particular has been found to be elevated in SCC specifically. The role of serin peptidase inhibitors (Serpins) is also being investigated. SerpinA1 was found to be elevated in the keratinocytes of SCC cell lines, and SerpinA1 upregulation was correlated with SCC tumor progression in vivo.
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This upregulation implies that peripherin may also play a role in axon regeneration. However, experiments using peripherin depleted PC12 cells and peripherin knockout mice provide proof that the majority of neurons have no requirement of peripherin for axonal guidance and regrowth. PC12 cells lacking peripherin showed no defects in neurite outgrowth and peripherin knockout mice develop normally with no anatomical abnormalities or different phenotypes. In these experiments, peripherin deficiency did produce an upregulation of α-internexin, indicating the possibility that this type IV intermediate filament makes up for the loss of peripherin.
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The theoretical tardive psychosis is distinct from schizophrenia and induced by the use of current (dopaminergic) antipsychotics by the depletion of dopamine and related to the known side effect caused by their long-term use, tardive dyskinesia. > In addition to dopaminergic upregulation in the nigrostriatal tracts, many > investigators have suggested that dopaminergic upregulation may occur in > mesolimbic or mesocortical tracts, leading to a worsening of psychosis > beyond the original level. This phenomenon has been called 'tardive > psychosis' or 'supersensitivity psychosis'. Tardive psychosis was researched in 1978 and 1989, and sporadic research continues.
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Upregulation of this methyl donor through heightened expression of methionine adenosyltransferase 2A leads to increased DNA methylation, which can lead to the down-regulation of target genes. Nicotine found in cigarette smoke binds to nicotinic acetylcholine receptors. This binding leads to an increase in calcium levels which in turn can activate the cAMP response element-binding protein (CREB) transcription factor. The most striking downstream effect of the upregulation of this transcription factor is the downregulation of the DNMT1 gene, which has a cAMP response element in its promoter.
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ECs located in this niche have been found to support new HSCs through the upregulation of factors such as p57 and IGF2. The relocalization of hemogenic endothelium coincides with the migration of distinct endothelial precursors to the AGM.
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Methods of delivering UCP1 to cells by gene transfer therapy or methods of its upregulation have been an important line of enquiry in research into the treatment of obesity, due to their ability to dissipate excess metabolic stores.
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With further research into the role of AQP4, it may be possible to modify the human body's system of upregulation of these channels to help in the reabsorption of CSF without the need to use physically invasive treatments.
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As of 2010, current research indicates DLC1 negatively regulates angiogenesis in a paracrine fashion. This is by upregulation of VEGF mediated through the epidermal growth factor receptor (EGFR)-MAP/ERK Kinase (MEK)- hypoxia inducible factor 1 (HIF1) pathway.
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Ultimately, this leads to the inactivation of transcription. Acetylation is usually linked to the upregulation of genes. This is the case in H3K27ac which is an active enhancer mark. It is found in distal and proximal regions of genes.
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A more serious case of myelin deterioration is called Canavan disease. The immune system may play a role in demyelination associated with such diseases, including inflammation causing demyelination by overproduction of cytokines via upregulation of tumor necrosis factor or interferon.
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Gli2beta is an isoform spliced at the first splicing site which contains a repression domain and consists of an intact activation domain. Overexpression of this Gli2 splice variant may lead to the upregulation of the Shh signalling pathway, thereby inducing BCCs.
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Another long-term adaptation to opioid use can be upregulation of glutamate and other pathways in the brain which can exert an opioid-opposing effect, so reduce the effects of opioid drugs by altering downstream pathways, regardless of MOR activation.
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Upregulation refers to the increase in the number of receptor sites on the membrane. Estrogen and FSH upregulate LHCGR sites in preparation for ovulation. After ovulation, the luteinized ovary maintains LHCGR s that allow activation in case there is an implantation.
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IRAK2 encodes the interleukin-1 receptor-associated kinase 2, one of two putative serine/threonine kinases that become associated with the interleukin-1 receptor (IL1R) upon stimulation. IRAK2 is reported to participate in the IL1-induced upregulation of NF-kappaB.
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Treatment of glioblastoma cells with TPEN showed that upregulation of ZIP9 in glioblastoma cells enhances cell migration in brain cancer by influencing P53 and GSK-3ß, and also ERK and AKT signalling pathways in phosphorylation after activation of B-cell receptors.
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Regarding downstream factors, the Tnmd knockout mouse model suggested correlation to collagen I based on the observed abnormal collagen fibrillogenesis resulting in pathologically thicker fibres. The lower cellular density and proliferation in the mutant tendons, as well as the reduced self-renewal and earlier senescence of Tnmd-deficient tendon stem/progenitor cells was coupled with downregulation of the proliferative marker Cyclin D1 and upregulation of the senescent marker p53. A study analysing ruptures of human chordae tendineae cordis revealed loss of Tnmd expression in the affected area coupled with upregulation of VEGF-A and MMP1, 2 and 13.
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Thus, stress-induced upregulation of avp due to demethylation might alter mood, behavior, and stress responses. Demethylation of this locus can be explained by reduced binding of DNA methyl transferases (DNMT), an enzyme that adds methyl groups to DNA, to this locus. MeCP2 is known to have interactions with several other enzymes that modify chromatin (for example, HDAC-containing complexes and co-repressors) and in turn regulate activity of genes that modulate stress response either by increasing or decreasing stress tolerance. For example, epigenetic upregulation of genes that increase stress response may cause decreased stress tolerance in an organism.
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There appears to be a further increase in programmed enterocyte cell death by Giardia intestinalis, which further damages the intestinal barrier and increases permeability. There is significant upregulation of the programmed cell death cascade by the parasite, and, furthermore, substantial downregulation of the anti-apoptotic protein Bcl-2 and upregulation of the proapoptotic protein Bax. These connections suggest a role of caspase- dependent apoptosis in the pathogenesis of giardiasis. Giardia protects its own growth by reducing the formation of the gas nitric oxide by consuming all local arginine, which is the amino acid necessary to make nitric oxide.
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The symptoms of AGS closely resemble those of congenital viral infection and are associated with inappropriate upregulation of type I interferon. AGS can also be caused by mutations in other genes: TREX1, SAMHD1, ADAR, and MDA5/IFIH1, all of which are involved in nucleic acid processing. Characterization of mutational distribution in an AGS patient population found 5% of all AGS mutations in RNASEH2A, 36% in 2B, and 12% in 2C. Mutations in 2B have been associated with somewhat milder neurological impairment and with an absence of interferon- induced gene upregulation that can be detected in patients with other AGS- associated genotypes.
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During gestation, the cells of the primordial gonad that lie along the urogenital ridge are in a bipotential state, meaning they possess the ability to become either male cells (Sertoli and Leydig cells) or female cells (follicle cells and theca cells). TDF initiates testis differentiation by activating male-specific transcription factors that allow these bipotential cells to differentiate and proliferate. TDF accomplishes this by upregulating SOX9, a transcription factor with a DNA-binding site very similar to TDF's. SOX9 leads to the upregulation of fibroblast growth factor 9 (Fgf9), which in turn leads to further upregulation of SOX9.
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Upon activation, BNIP3 can form heterodimers with BCL2 and BCL-XL and bind to itself. Various conditions have been shown to induce activation and upregulation. Hypoxia has been shown to induce transcriptional upregulation of BNIP3 through an HIF1-dependent pathway in a p53-independent manner in HeLa cells, human skeletal muscle cells, and adult rat cardiomyocytes. Using BNIP3 phosphomimetics in HEK 293 cells, researchers found that phosphorylation of BNIP3’s C-terminus is necessary to prevent mitochondrial damage and promote cell survival by allowing a significant amount of autophagy to occur without the induction of cell death.
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Dopamine Pre- existing cognitive and mood disorders may influence the development and maintenance of nicotine dependence. Nicotine is a parasympathomimetic stimulant that binds to and activates nicotinic acetylcholine receptors in the brain, which subsequently causes the release of dopamine and other neurotransmitters, such as norepinephrine, acetylcholine, serotonin, gamma- aminobutyric acid, glutamate, endorphins, and several neuropeptides. Repeated exposure to nicotine can cause an increase in the number of nicotinic receptors, which is believed to be a result of receptor desensitization and subsequent receptor upregulation. This upregulation or increase in the number of nicotinic receptors significantly alters the functioning of the brain reward system.
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Cross linking antibody induced aggregation of Thy1 cause death of thymocytes and mesangial cells mainly by apoptosis despite Bcl2 upregulation. The death of mesangial cells seems to be apoptosis by TUNEL staining or annexin V staining, but electron microscopy suggest it is necrosis.
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The inflammatory reaction leads to damage of retinal cells and infiltration of cells of the immune system. The inflammatory process including NLRP3 upregulation is one of the causes of age-related macular degeneration and other retinal diseases that lead to vision loss.
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In support of these data, FLCN inactivation was correlated with PGC-1α activation and upregulation of its target genes in BHD-associated renal tumors, and kidney, heart and muscle tissues from genetically engineered mouse models with Flcn inactivation targeted to the respective tissues.
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Additionally, a couple of other antagonists may have no effect on 5-HT2A receptor number. Nevertheless, upregulation is the exception rather than the rule. Neither tolerance nor rebound is observed in humans with regard to the SWS promoting effects of 5-HT2A antagonists.
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Rhododendrol can have a toxic effect via the production of reactive oxygen species (ROS). This will cause an impairment in the further development of melanocytes in the skin. Impairment is caused by upregulation of the GADD45 gene. A study of Kim et al.
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However, ORF3 also interacts with pPirh2 at the same region as p53 and causes an upregulation of p53 expression. This increase in p53 stops the cell division cycle and the result of this is p53 mediated apoptosis, which releases PCV into the extracellular environment.
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Upregulation refers to the increase in the number of receptor sites on the membrane. Estrogen upregulates FSH receptor sites. In turn, FSH stimulates granulosa cells to produce estrogens. This synergistic activity of estrogen and FSH allows for follicle growth and development in the ovary.
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Another mechanism of tumor cells to avoid immune system is upregulation of non- classical MHC I (HLA-E, HLA-F, HLA-G) which prevents NK-mediated immune reaction by interaction with NK cells. The tumor begins to develop and grow after escaping the immune system.
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In the literature, stress is mentioned as a factor and may be implicated via the adrenal axis. This ultimately results in downstream activation of NMDA receptor activation, NFκB activation, and upregulation of iNOS with subsequent production of NO leading to pain as described above.
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Upregulation of the signal transduction pathway in the locus coeruleus by has been implicated as the mechanism responsible for certain aspects of opioid-induced physical dependence. The temporal course of withdrawal correlates with LC firing, and administration of α2 agonists into the locus coeruleus leads to a decrease in LC firing and norepinephrine release during withdrawal. A possible mechanism involves upregulation of NMDA receptors, which is supported by the attenuation of withdraw by NMDA receptor antagonists. Physical dependence on opioids has been observed to produce an elevation of extracellular glutamate, an increase in NMDA receptor subunits NR1 and NR2A, phosphorylated CaMKII, and c-fos.
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These molecules are transported, via specialized amino acid permeases and carbohydrate transporters embedded in the fungal peloton membrane, into the interficial space where they are absorbed into the plant through similar analogous transporters in the plant endoplasmic reticulum membrane which surrounds the peloton. Genes which encode for such transporters experience significant upregulation in both plant and fungi, similar to the upregulation seen in nitrogen and phosphorus compound transporter genes during symbiosis. This active transport of carbon from fungi to plant is an exclusively biotorphic reaction but it is thought that a significant amount of carbon may also be transferred to the plant when the fungal pelotons degrade and are digested.
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Treatment of mice with anti- TCR αβ antibody at the time of Experimental autoimmune encephalomyelitis(EAE) disease induction completely prevented disease onset, while treatment during chronic EAE disease caused disease remission. Anti-TCR αβ antibody treatment induces tolerance through a number of mechanisms including the functional blockade of T cells at the site of inflammation, transient T-cell depletion, upregulation of Th2 cytokines,Claus-Dieter, H., et al. “alpha-beta-T Cell Receptor-Directed Therapy in Rat Allograft Recipients: Long-Term Survival of Cardiac Allografts After Pretreatment with R73 mAb is Associated with Upregulation of Th2-Type Cytokines”, Transplantation 27 March 1996. and an increase in the regulatory NKT cell population.
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BCK2 overexpression leads to CLN3 and SWI4 upregulation. Mutations of ECB elements in CLN3 and SWI4 promoters blocked these effects. Bck2 may also be sensing cell size to promote crossing of START. Budding yeast senses cell size at START in part through sensing Whi5 concentrations in G1.
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Exercise causes acetylation of histone H3 in the exon IV promoter region of the Bdnf gene essential for memory formation. This acetylation contributes to upregulation of Bdnf in the brain hippocampi of rats. Two weeks of treadmill exercise improves memory performance in an inhibitory avoidance task.
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EAAT2 may possess an important role in drug addiction and tolerance to addictive drugs. Upregulation of EAAT2 (GLT-1) causes impairment of prepulse inhibition, a sensory gating deficit present in schizophrenics and schizophrenia animal models. Some antipsychotics have been shown to reduce the expression of EAAT2.
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Upregulation of OGFr and consequent stimulation of the OGF-OGFr system are important for the anti- proliferative effects of imidazoquinoline drugs like imiquimod and resiquimod, which are immune response modifiers with potent antiviral and antitumour effects, used as topical creams for the treatment of skin cancers and warts.
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One case also reported the absence of CD1, a MHC-like glycoprotein involved in the presentation of lipid antigens to T cells, in a CD25 deficient patient. Furthermore, chronic upregulation of anti-apoptotic Bcl-2 in thymocytes was also described possibly allowing autoreactive T cells to escape deletion.
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Near-infrared light, or photobiomodulation, is used for treatment of chemotherapy-induced oral ulceration as well as wound healing. There is some work relating to anti-herpes virus treatment. Research projects include work on central nervous system healing effects via cytochrome c oxidase upregulation and other possible mechanisms.
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Both of these pathways probably involve calcium-mediated phosphorylation of CREB at Ser133, thus allowing it to interact with BDNF's Cre regulatory domain and upregulate transcription. However, NMDA-mediated receptor signaling is probably necessary to trigger the upregulation of BDNF exon IV expression because normally CREB interaction with CRE and the subsequent translation of the BDNF transcript is blocked by of the basic helix-loop-helix transcription factor protein 2 (BHLHB2). NMDA receptor activation triggers the release of the regulatory inhibitor, allowing for BDNF exon IV upregulation to take place in response to the activity-initiated calcium influx. Activation of Dopamine receptor D5 also promotes expression of BDNF in prefrontal cortex neurons.
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Whilst many FANC protein mutations account for only 1% of the total observed cases, they are also stabilized by FANCA within the complex. For example, FANCA stabilises FANCG within the core complex, and hence mutations in FANCG are compensated for as the complex can still catalyse FANCD2-ubiquitination further downstream. FANCA upregulation also increases expression of FANCG in cells, and the fact this transduction is not mutual – FANCG upregulation does not cause increased expression of FANCA – suggests that FANCA is not only the primary stabilizing protein in the core complex, but may act as a natural regulator in patients who would otherwise suffer from mutations in FANC genes other than FANCA or FANCD2.
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The Bonini lab discovered that a conserved microRNA, miR-34, plays a neuroprotective role in the brains of aging Drosophila. The loss of miR-34 resulted in a profile consistent with accelerated aging, late-onset brain neurodegeneration, and reduced survival, whereas upregulation of miR-34 enhanced survival and mitigated neurodegeneration.
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These kinases initiate the DNA damage response pathway which participates in NKG2D ligand upregulation. DNA damage response thus participate in alerting the immune system to the presence of potentially dangerous cells. All NKG2D ligands are homologous to MHC class I molecules and are divided into two families: MIC and RAET1/ULBP.
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Unlike AMPARs, however, NMDARs are permeable to both Na+ and Ca2+. The Ca2+ that enters the cell triggers the upregulation of AMPARs to the membrane, which results in a long-lasting increase in EPSP size underlying LTP. The calcium entry also phosphorylates CaMKII, which phosphorylates AMPARs, increasing their single- channel conductance.
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A generalized response to methylating agents in bacteria is known as the adaptive response and confers a level of resistance to alkylating agents upon sustained exposure by upregulation of alkylation repair enzymes. The third type of DNA damage reversed by cells is certain methylation of the bases cytosine and adenine.
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Functional coupling of p38-induced upregulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells. Cancer Res. 66, 1702–1711. # An idea for a therapeutic strategy is to cause cancer cells to be induced or maintained in a dormant state.
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UBE3A, in normal function, adds ubiquitin chains to proteins to target unnecessary or damaged proteins for degradation by the proteasome. 16 topoisomerase inhibitors unsilence paternal UBE3A. Topoisomerases are enzymes that regulate the unwinding of DNA.(Miller) Of these 16 inhibitors, topotecan was found to induce the strongest upregulation of UBE3A.
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C5a plays a key role in increasing migration and adherence of neutrophils and monocytes to vessel walls. White blood cells are activated by upregulation of integrin avidity, the lipoxygenase pathway and arachidonic acid metabolism. C5a also modulates the balance between activating versus inhibitory IgG Fc receptors on leukocytes, thereby enhancing the autoimmune response.
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The kinase inhibitor blocks serine-threonine kinase RAF-1 as well as FLT-ITD (Kindler, 2010). The drug has been proven to be effective in reducing FLT3-ITD overexpression (Metzelder et al., 2009). In patients with DEK-NUP214, it was found that the fusion oncoprotein caused an upregulation of mTORC1 (Sanden et al.
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ATN1 and atrophin-2 can be co-immunoprecipitated, indicating that they may carry out some functions together in a molecular complex. Atrophin-1 may be a dispensable or redundant protein as mice bred with a null allele for atrophin-1 produce viable and fertile offspring and show no compensatory upregulation of atrophin-2.
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PD-L1 on the cell surface binds to PD1 on an immune cell surface, which inhibits immune cell activity. Among PD-L1 functions is a key regulatory role on T cell activities. It appears that (cancer-mediated) upregulation of PD-L1 on the cell surface may inhibit T cells that might otherwise attack.
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The HMG-CoA reductase (HMGCR), converts HMG-CoA into mevalonic acid. Thus, when HMGCR activities are reduced, the cell associated cholesterols are also reduced. This results in the activation of SREBP-2-mediated signaling pathways. SREBP-2 activation for cholesterol homeostasis is crucial for the upregulation of low density lipoprotein (LDL) receptor (LDLR).
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Transcripts of MALAT1 are significantly increased in the cerebellum of human alcoholics, as well as in similar regions of rat brains after the withdrawal of ethanol vapours. This alcohol-induced upregulation of MALAT1 may be responsible for differential expression of a number of proteins which contribute to ethanol tolerance and dependency in humans.
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BRAFV600E and Ras are two oncogenes implicated in cellular senescence. BRAFV600E induces senescence through synthesis and secretion of IGFBP7. Ras activates the MAPK cascade which results in increased p53 activation and p16INK4a upregulation. The transition to a state of senescence due to oncogene mutations are irreversible and have been termed oncogene-induced senescence (OIS).
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NCOA3 is a transcriptional coactivator protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA3 is recruited to DNA promotion sites by ligand-activated nuclear receptors. NCOA3, in turn, acylates histones, which makes downstream DNA more accessible to transcription. Hence, NCOA3 assists nuclear receptors in the upregulation of gene expression.
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Sulf2 also upregulated glypican-3, which is commonly overexpressed in HCC, by increasing ERK, AKT activation through enhanced FGF2 signaling. GPC3 is important in Sulf2-enhanced FGF signaling in vitro, so glypican-3 may mediate its own upregulation through Sulf2. Given that Sulf1 and Sulf2 have redundant functions, Sulf2 contrasting function in HCC was unexpected.
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Three phases have been observed during the interplay between ARE and ZPA. Initiation phase involves the Grem1 expression in a fast initiator loop (~2h loop time) due to upregulation by BMP4. The Shh signalling is activated independently of GREM1 and AER-FGFs. Propagation phase involves the control of distal progression during limb bud development.
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However, this putative receptor identity is unknown. One candidate is Annexin A2, identified as being able of binding progastrin and derived peptides. Annexin A2 is a partial mediator of the effect of progastrin/gastrins. In particular, Annexin A2 mediates NF-kappaB upregulation and ß-catenin in response to progastrin in mice and HEK-293 cells.
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GPR64 is significantly overexpressed in the Wnt signaling-dependent subgroup of medulloblastoma, as well as in ewing sarcomas and carcinomas derived from prostate, kidney or lung. Richter et al. demonstrated that GPR64 promotes tumor invasion and metastasis through placental growth factor and MMP1. Upregulation and activation of GPR64 are associated with primary hyperparathyroidism and hypersecretion of parathyroid hormone.
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NCoA-2 is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA2 is recruited to DNA promotion sites by ligand-activated nuclear receptors. NCOA2 in turn acetylates histones, which makes downstream DNA more accessible to transcription. Hence, NCOA2 assists nuclear receptors in the upregulation of DNA expression.
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The resting expression of GPR84 is usually low but it is highly inducible in inflammation. Its expression on neutrophils can be increased with LPS stimulation and reduced with GM-CSF stimulation. The LPS- induced upregulation of GPR84 was not sensitive to dexamathasone pretreatment. There was also a GPR84 downregulation in dentritic cell derived from FcRgamma chain KO mice.
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The mechanism of these changes has been shown to be primarily due to upregulation of a group of cytokines including IL-7 and IL-15 induced by lymphodepletion. Additionally, lymphodepletion is a non-selective method of eliminating several known regulatory, or immunosuppressive, subsets of immune cells, such as regulatory T cells.Ghiringhelli F, Larmonier N, Schmitt E, et al.
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Oct-4 has been implicated in tumorigenesis of adult germ cells. Ectopic expression of the factor in adult mice has been found to cause the formation of dysplastic lesions of the skin and intestine. The intestinal dysplasia resulted from an increase in progenitor cell population and the upregulation of β-catenin transcription through the inhibition of cellular differentiation.
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Transcriptomic profiling also provides crucial information on mechanisms of drug resistance. Analysis of over 1000 isolates of Plasmodium falciparum, a virulent parasite responsible for malaria in humans, identified that upregulation of the unfolded protein response and slower progression through the early stages of the asexual intraerythrocytic developmental cycle were associated with artemisinin resistance in isolates from Southeast Asia.
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In 2012, a research paper showed that when activated CD4+ T cells and monocytes are in close contact, interaction of CD40-CD40L between these two cells and subsequent IFNγ secretion by the T cells causes upregulation and secretion of fusion-related molecule DC-STAMP (dendritic cell-specific transmembrane protein) by the monocytes, which results in LGC formation.
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Greater than 90% of cases contain a clonal rearrangement of the T-cell receptor. Oncogenic potential is conferred by upregulation of a tyrosine kinase gene on chromosome 2. Several different translocations involving this gene have been identified in cases of this lymphoma. The most common is a chromosomal translocation involving the nucleophosmin gene on chromosome 5.
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Theoretically, a decrease in transferrin could additionally be decreased by an upregulation of transferrin receptors, but the latter does not appear to change with inflammation. While the production of C3 (a complement factor) increases in the liver, the plasma concentration often lowers because of an increased turn-over, therefore it is often seen as a negative acute- phase protein.
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Hypertension is one of the most common side effects regarding inhibition of VEGF signalling. VEGF increases synthesis of NO through upregulation of endothelial NO synthase and therefore inhibition of VEGF diminishes NO synthesis. Decrease in NO causes vasoconstriction, increased peripheral resistance and increased blood pressure. Hypertension caused by VEGF inhibition can usually be treated with oral antihypertensive agents.
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J Neurosci, 27, 9054–9067. It is regulated by both BDNF and CREB signaling.Ying, S.W., Futter, M., Rosenblum, K., Webber, M.J., Hunt, S.P., Bliss, T.V., Bramham, C.R. (2002). Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci, 22, 1532–1540.
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This gene product inactivates ERK2, is expressed in a variety of tissues with the highest levels in heart and pancreas and, unlike most other members of this family, is localized in the cytoplasm. Two transcript variants encoding different isoforms have been found for this gene. Upregulation of MKP-3 has been shown to alleviate chronic postoperative pain.
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When GADD45G expression is low, liver cells may be able to bypass the growth arrest stage, leading to cancerous cells. The presence of GADD45G in the urinary system is also related to renal disease. The renal cells expressing the gene were damaged. The upregulation of Gadd45g due to hormones may account for the changes in the mouse uterus.
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These activators can be introduced into the system through attachment to dCas9 or to the sgRNA. Some researchers have noted that the extent of transcriptional upregulation can be modulated by using multiple sites for activator attachment in one experiment and by using different variations and combinations of activators at once in a given experiment or sample.
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Roles of transient receptor potential channels in pain. Brain Res Rev 2009;60(1):2-23 Desensitization involves both tachyphylaxis (short-term desensitization) and long-term, persistent, desensitization. It is suggested that the downregulation of proalgesic substances (such as SP) and upregulation of analgesic peptides are implicated in desensitization.Brederson JD, Kym PR, Szallasi A. Targeting TRP channels for pain relief.
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In the same study administration of proadifen was demonstrated to produce time- and dose-dependent phosphatidylserine externalization, caspase-3 activation and PARP cleavage. Intense upregulation of NAG-1 and ATF3 and downregulation of Mcl-1 and Egr-1 were also observed. Proadifen has been demonstrated to inhibit the nicotinic acetylcholine receptor (NAChR) and muscarinic acetylcholine receptor (MAChR) in rats.
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The AhR may also signal the presence of toxic chemicals in food and cause aversion of such foods. AhR activation seems to be also important for immunological responses and inhibiting inflammation through upregulation of interleukin 22 and downregulation of Th17 response. The Knockdown of AHR mostly downregulates the expression of innate immunity genes in THP-1 cells.
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Tenascin-C has been shown to interact with fibronectin. This interaction is shown to have the potential to modify cell adhesion. A solid-state interaction between fibronectin and TN-C results in cellular upregulation of matrix metalloproteinase expression. TN-C also interacts with one or more TN-C receptors on cells which activate and repress the same signal transduction pathway.
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Notably, RNA affinity purification showed that the La protein interacts with the LamB1 IRES. This interaction and its regulation during EMT were confirmed by ribonucleoprotein immunoprecipitation. In addition, La was able to positively modulate LamB1 IRES translation. In summary, these data indicate that the LamB1 IRES is activated by binding to La which leads to translational upregulation during hepatocellular EMT.
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D5 receptors negatively regulate production of IFNγ by NK cells. The expression of D5 receptors was shown to be upregulated in NK cells in response to prolonged stimulation with recombinant interleukin 2. This upregulation inhibits proliferation of the NK cells and suppresses synthesis of IFNγ. Activation of D5 prevents p50, part of NF-κB protein complex, from repressing the transcription of miRNA 29a.
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Chronic alcohol consumption leads to the overproduction (upregulation) of these receptors. Thereafter, sudden alcohol abstinence causes the excessive numbers of NMDARs to be more active than normal and to contribute to the symptoms of delirium tremens and excitotoxic neuronal death. Withdrawal from alcohol induces a surge in release of excitatory neurotransmitters like glutamate, which activates NMDARs. Acamprosate reduces this glutamate surge.
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Additional uses that have arosen from encapsulation of bacterial cells include protection against challenge from M. Tuberculosis and upregulation of Ig secreting cells from the immune system. The technology is limited by the risk of systemic infections, adverse metabolic activities and the risk of gene transfer. However, the greater challenge remains the delivery of sufficient viable bacteria to the site of interest.
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The nuclear receptor coactivator 1 (NCOA1) is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA1 is recruited to DNA promotion sites by ligand-activated nuclear receptors. NCOA1, in turn, acylates histones, which makes downstream DNA more accessible to transcription. Hence, NCOA1 assists nuclear receptors in the upregulation of DNA expression.
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Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) are homologous peptides that function as neurotransmitters and neuroendocrine hormones. While the receptors for VIP (VIRP 1 and 2) and PACAP (ADCYAP1R1) share homology, they differ in their substrate specificities and expression patterns. VIPR2 transduction results in upregulation of adenylate cyclase activity. Furthermore, VIPR2 mediates the anti-inflammatory effects of VIP.
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The ERK1/2 pathway also phosphorylate NFκB causing an upregulation of cyclin D1, a G1 phase regulator protein. When NNK is present it directly involves cellular survival dependent on NFκB. Further studies are needed to better understand NNK cellular pathyways of NFκB. The phosphoinositide 3-kinase (PI3K/Akt) pathway is also an important contributor to NNK-induced cellular transformations and metastasis.
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Increased extracellular pH levels have been found to increase vesicle formation in Microcytis species. Under increased pH, levels of gvpA and gvpC transcripts increase, allowing more exposure to ribosomes for expression and leading to upregulation of Gvp proteins. It may be attributed to greater transcription of these genes, decreased decay of the synthesized transcripts or the higher stability of the mRNA.
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P2X4 receptors are stored in lysosomes and brought to the cell surface in response to extracellular signals. These signals include IFN-γ, CCL21, CCL2. Fibronectin is also involved in upregulation of P2X4 receptors through interactions with integrins that lead to the activation of SRC-family kinase member, Lyn. Lyn then activates PI3K-AKT and MEK-ERK signaling pathways to stimulate receptor trafficking.
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The P2X4 receptor has been linked to neuropathic pain mediated by microglia in vitro and in vivo. P2X4 receptors are upregulated following injury. This upregulation allows for increased activation of p38 mitogen-activated protein kinases, thereby increasing the release of brain-derived neurotrophic factor (BDNF) from microglia. BDNF released from microglia induces neuronal hyperexcitability through interaction with the TrkB receptor.
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Dynein light chain roadblock-type 1 is a protein that in humans is encoded by the DYNLRB1 gene. This gene is a member of the roadblock dynein light chain family and encodes a cytoplasmic protein that is capable of binding intermediate chain proteins. Upregulation of this gene has been associated with hepatocellular carcinomas, suggesting that this gene may be involved in tumor progression.
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Neurogenesis continues after development well through adulthood. Growth arrest and DNA-damage-inducible, beta (GADD45b) is required for the demethylation of promoters of critical genes responsible for new-born neuron development such as brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (FGF2). As such, upregulation of GADD45b leads to increased demethylation, increased BDNF and FGF2, and ultimately more neural progenitor cells.
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PROW and IWHLDA present the GUIDE on: CD88 Sensitivity of C5aR to C5a stimulation is enhanced by Lipopolysaccharides exposure, yet this is not due to C5aR upregulation. C5L2 is another C5a receptor that is thought to regulate the C5a-C5aR effects. There is apparently contradictory evidence showing decoy receptor activity conferring anti-inflammatory properties and also signalling activity conferring pro-inflammatory properties.
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The parthanatos pathway is activated by DNA damage caused by genotoxic stress or excitotoxicity. This damage is recognized by the PARP-1 enzyme which causes an upregulation in PAR. PAR causes translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus where it induces DNA fragmentation and ultimately cell death. This general pathway has been outlined now for almost a decade.
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This causes endothelial hyperplasia, abnormal junctions, and diabetic retinopathy. A lack of pericytes also causes an upregulation of vascular endothelial growth factor (VEGF), leading to vascular leakage and hemorrhage. Angiopoietin 2 can act as an antagonist to Tie-2, destabilizing the endothelial cells, which results in less endothelial cell and pericyte interaction. This occasionally leads to the formation of tumors.
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In TSC2-null and human LAM cells, Rho GTPase activity is required for cell adhesion, motility, proliferation and survival. Loss of TSC1/TSC2 in LAM induces uncontrolled LAM cell growth and increases LAM cell viability. Upregulation of STAT1 and STAT3 and autophagy are known mediators of LAM cell viability and survival. LAM cells behave, in many ways, like metastatic tumor cells.
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Some natural tolerance to habitual use of ayahuasca (roughly once weekly) may develop through upregulation of the serotonergic system. A phase 1 pharmacokinetic study on ayahuasca (as Hoasca) with 15 volunteers was conducted in 1993, during the Hoasca Project. A review of the Hoasca Project has been published. Several studies have shown the alkaloids in the B. caapi vine promote neurogenesis.
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Exposure to cigarette smoke impacts proteins involved in DNA methylation. These effects come from either hypoxia induced by the cigarette smoke, or the chemical consequences of nicotine. Inhaling cigarette smoke increases blood levels of carbon monoxide which negatively affects oxygenation throughout the body leading to hypoxia. One response to hypoxia is the upregulation in synthesis of the major methyl donor S-adenosylmethionine.
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Micrograph showing a PD-L1 positive lung adenocarcinoma. PD-L1 immunostain. It appears that upregulation of PD-L1 may allow cancers to evade the host immune system. An analysis of 196 tumor specimens from patients with renal cell carcinoma found that high tumor expression of PD-L1 was associated with increased tumor aggressiveness and a 4.5-fold increased risk of death.
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Recently there has been much interest in abnormal levels of expression of microRNAs in cancers. Upregulation of miR-10 has been found in a number of cancers. Increased levels of miR-10a have been found in glioblastoma, anaplastic astrocytomas, primary hepatocellular carcinomas and colon cancer. Increased levels of miR-10b have been found in glioblastoma, anaplastic astrocytomas, pancreatic cancer, and metastatic breast cancer.
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Estrogen binds its ER-β receptor on the cell surface to suppress many miRNAs, including miR-145, thus blocking inhibition of OPG mRNA translation. Estrogen suppresses osteoclastogenesis through the upregulation of OPG expression in osteoblast lineage cells. Androgens such as testosterone and DHT also inhibit osteoclastogenesis, however androgens act directly through androgen receptors on osteoclast precursor cells without affecting OPG expression in osteoblasts.
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Associated with a breakdown in gut barrier function, necrotizing enterocolitis may be mediated by HB-EGF effects on intestinal mucosa. HB-EGF expressed during skeletal muscle contraction facilitates peripheral glucose removal, glucose tolerance and uptake. The upregulation of HB-EGF with exercise may explain the molecular basis for the decrease in metabolic disorders such as obesity and type 2 diabetes with regular exercise.
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Cervical cancer can be caused by human papillomavirus (HPV) infection. AIM2 protein can recognise viral DNA in cytoplasm and form AIM2 inflammasome, which then triggers by a caspase-1 dependent canonical pyroptosis pathway. HPV infection causes the upregulation of sirtuin 1 protein, which disrupts the transcription factor for AIM2, RelB. Knockdown of sirtuin 1 upregulates AIM2 expression and triggers pyroptosis.
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Amiloride is the treatment of choice for Liddle phenotype, which is characterized by high blood pressure, low blood potassium, and metabolic alkalosis in conjunction with a low plasma renin activity and a low aldosterone. Some people with the Liddle phenotype have Liddle syndrome, which involves a genetic mutation resulting in upregulation of the epithelial sodium channel (ENaC), located in the apical membrane of polarized epithelial cells in the late distal tubule and collecting duct of the kidney. Because Liddle phenotype usually involves an upregulation of ENaC channels, leading to retention of sodium and water and to hypokalemia, amiloride is useful as an ENaC channel inhibitor due to its promotion of sodium excretion and its potassium-sparing effects, restoring potassium to normal levels. Amiloride can be used as a monotherapy (single-drug therapy) or an adjunctive therapy alongside other diuretics (e.g.
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Also, evidence shows that increased NEDD8 conjugation in human oral carcinoma cells led to abnormal higher degrees of proliferation. Because NEDD8 conjugation to cullin proteins plays an important role in the regulation of the cell cycle, an upregulation in conjugation causes this proliferation.Chairatvit K, Ngamkitidechakul C. Control of cell proliferation via elevated NEDD8 conjugation in oral squamous cell carcinoma. Mol Cell Biochem. 2007;306(1-2):163-9.
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Counteracting huntingtin toxicity, SGK1 has been found to phosphorylate huntingtin. "Genomic upregulation of SGK1 coincides with the onset of dopaminergic cell death in a model of Parkinson's disease". However, at the current time, it is unclear whether SGK1 prevents or motivates cell death. An excessive expression of SGK1 has also been observed in Rett syndrome (RTT), which is a disorder of severe mental retardation.
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There is a variety of different treatment options for Kaposi sarcoma. The appropriate therapy options may vary depending on the variation of disease and the patients immune status. If the lesion is localised, usually found in classical Kaposi sarcoma, and not systemic treatments can be any from lasers, cryotherapy, non- intervention, chemotherapy and immune upregulation. For generalized and systemic cases chemotherapeutic drugs are used.
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The upregulation of these proteins could increase the carbon uptake during starvation. Another CrfA regulated gene () is thought to encode a proton pump powered by pyrophosphate hydrolysis. Increasing production of this protein could enable the cell to maintain its electrochemical gradient and power ATP synthesis during carbon starvation. σ54 regulates many other proteins involved in the carbon starvation response at the level of transcription.
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ADAMTS 1, 5, 7, 15, and 19 are zinc metalloenzymes responsible for degrading the ECM prior to compaction. Many studies have analyzed the effects of Slc39a8-/- on fetal heart development and have shown a decrease in zinc influx leading to an increase in cardiomyocyte proliferation through BMP10, hypertrabeculation through the upregulation of Notch1, and ventricular non-compaction due to the persistence of the ECM.
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This is likely mediated through upregulation of neuronal specific genes such as the neurogeneic basic helix-loop-helix transcription factors NEUROD, NEUROGENENIN1, and Math1. Conditional loss of HDAC1 and HDAC2 in neural progenitor cells prevented them from differentiating into neurons and their loss in oligodendrytic progenitor cells disrupted oligodendrocyte formations, suggesting that histone deacetlyation plays important but varying roles in different stages of neuronal development.
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Yeast cells respond to low extracellular phosphate levels by activating genes that are involved in the production and upregulation of inorganic phosphate. The PHO pathway is involved in the regulation of phosphate levels. Under normal conditions, the yeast cyclin-dependent kinase complex, Pho80-Pho85, inactivates the Pho4 transcription factor through phosphorylation. However, when phosphate levels drop, Pho81 inhibits Pho80-Pho85, allowing Pho4 to be active.
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An upregulation of aquaporin and H+ - ATPase allows for the rapid flux of water out of these motor cells. Water flux out of the cells results in a decrease in turgor pressure, and the characteristic closing of the leaves of Mimosa pudica. The drop in turgor pressure is reversible but slow. Leaves slowly open to their initial position after 20 minutes of lack of stimulation.
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"...experts on this topic still recommend informing oral contraceptive users of the potential for a rare interaction" (DeRossi, 2002) and this remains current (2006) UK Family Planning Association advice. The traditional medicinal herb St John's Wort has also been implicated due to its upregulation of the P450 system in the liver which could increase the metabolism of ethinyl estradiol and progestin components of some combined oral contraception.
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Loss of function mutations in the TERC genomic locus have been associated with a variety of degenerative diseases. Mutations in TERC have been associated with dyskeratosis congenita, idiopathic pulmonary fibrosis, aplastic anemia, and myelodysplasia. Overexpression and improper regulation of TERC have been associated with a variety of cancers. Upregulation of hTR is widely observed in patients with precancerous cervical phenotype as a result of HPV infection.
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Mesembrine is a major alkaloid present in S. tortuosum. There is about 0.3% mesembrine in the leaves and 0.86% in the leaves, stems, and flowers of the plant. It serves as a serotonin reuptake inhibitor with less prominent inhibitory effects on phosphodiesterase 4 (PDE4). In an in vitro study, a high-mesembrine Sceletium extract showed monoamine releasing activity by upregulation of vesicular monoamine transporter 2 (VMAT2).
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TRIF activation is necessary for the upregulation of pro-caspase-11 (an inactive precursor to active caspase-11) expression and caspase-11-mediated pyroptosis. Once expressed, caspase-11 is only able to bind cytosolic LPS and cannot respond to extracellular LPS. Caspase-11 will only recognize the hexa- and penta-acylated forms of LPS. LPS enters the cytosol through intracellular infection of vacuolar Gram-negative bacteria.
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The second set of experiments that Renthal et al. performed showed that chronic cocaine use induced upregulation of the NK1 receptor protein in HDAC5 knockout mice, which is associated with hyperacetylation of H3 at the NK1R gene promoter. The NK1R gene promoter has been associated with enhanced response to cocaine reward, meaning HDAC5 in normal genomes may decrease cocaine reward with chronic cocaine exposure.
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Aldolase A (ALDOA) is a highly expressed in multiple cancers, including lung squamous cell carcinoma (LSCC), renal cancer, and hepatocellular carcinoma. It is proposed that ALDOA overexpression enhances glycolysis in these tumor cells, promoting their growth. In LSCC, its upregulation correlates with metastasis and poor prognosis, while its downregulation reduces tumor cell motility and tumorigenesis. Thus, ALDOA could be a potential LSCC biomarker and therapeutic drug target.
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Enhanced epithelial Na (+) channel (ENaC) activity in mouse endometrial epithelium by upregulation of gammaENaC subunit. The Japanese journal of physiology, 51(4), 539-543. The increase in claudin-4 prevents the movement of Na+ ions between the cells, and the appearance of ENaC in the apical membrane allows movement of Na+ ions through the cell, from the lumen into the underlying stroma.Orchard, M. D., & Murphy, C. R. (2002).
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Caffeine's widespread appeal is due primarily to its mild psychostimulant properties, which increase alertness and cognitive arousal and diminish fatigue. Caffeine also produces a wide range of other symptoms, including upregulation of the cardiovascular system, increased global cognitive processing, and improved physical functioning. Cardiovascular effects can range from increased heart rate and reactivity to severe cardiac arrhythmia. The cognitive effects of caffeine include increased performance in memory, attention, and text reading.
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These effects cause maintenance of hyperglycemia. Because sodium is absorbed at the same time as glucose via SGLT-2, the upregulation of SGLT-2 probably leads to development or maintenance of hypertension. In study where rats were given either ramipril or losartan, levels of SGLT-2 protein and mRNA were significantly reduced. In patients with diabetes, hypertension is a common problem so this may have relevance in this disease.
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The Cln3-CDK2 complex promotes transcription of S-phase genes by inactivating the transcriptional repressor Whi5. Since upregulation of S-phase genes drive further suppression of Whi5, this pathway creates a positive feedback loop that fully commits cells to S-phase gene expression. A remarkably similar regulatory scheme exists in mammalian cells. Mitogenic signals received throughout G1-phase cause gradual accumulation of cyclin D, which complexes with CDK4/6.
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The increase in receptor production means muscle contractions could cause upregulation of the signaling cascade relating to angiogenesis. As part of the angiogenic signaling cascade, NO is widely considered to be a major contributor to the angiogenic response because inhibition of NO significantly reduces the effects of angiogenic growth factors. However, inhibition of NO during exercise does not inhibit angiogenesis, indicating there are other factors involved in the angiogenic response.
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Cancer cells can also cause defects in the cellular pathways of apoptosis (programmed cell death). As most chemotherapy drugs kill cancer cells in this manner, defective apoptosis allows survival of these cells, making them resistant. Many chemotherapy drugs also cause DNA damage, which can be repaired by enzymes in the cell that carry out DNA repair. Upregulation of these genes can overcome the DNA damage and prevent the induction of apoptosis.
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Following ischemic stroke or traumatic brain injury, angiogenesis supports oxygen and nutrient re-supply to injured tissue, and stimulates neurogenesis and synaptogenesis, particularly in the ischemic penumbra. Neuroangiogenesis is finely regulated and sequential, involving proliferation and migration of endothelial cells to restore blood- brain barrier function, recruitment of pericytes, and stabilization new blood vessels, a process dependent on upregulation of proangiogenic factors, such as VEGF and angiopoietin-1.
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There is an upregulation of this SUR1/ TRPM4 nonselective cation channel followed by brain tumor, ischemic injury, and traumatic brain injury. This channel which is activated by ATP depletion is found on neurons, neuroglia and endothelium. This channel enables the passive transport of water and solute and represents the ATP independent stage of cerebral formation. Opening of these channels result in cellular depolarization and blebbing causing cytotoxic edema.
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However, some C. neoformans cells can survive intracellularly in macrophages. Intracellular survival appears to be the basis for latency, disseminated disease, and resistance to eradication by antifungal agents. One mechanism by which C. neoformans survives the hostile intracellular environment of the macrophage involves upregulation of expression of genes involved in responses to oxidative stress. Traversal of the blood–brain barrier by C. neoformans plays a key role in meningitis pathogenesis.
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Two virus-free isolates were successfully infected by purified TmPV1 using protoplast transfection. Mice challenged with TmPV1-infected T. marneffei isolates showed significantly shortened survival time and higher fungal burden in organs than mice challenged with isogenic TmPV1-free isolates. Transcriptomic analysis showed that TmPV1 causes aberrant expression of various genes in T. marneffei, with upregulation of potential virulence factors and suppression of RNA interference (RNAi)-related genes.
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One of the cardinal features of addiction is its persistence. The persistent behavioral changes appear to be due to long-lasting changes, resulting from epigenetic alterations affecting gene expression, within particular regions of the brain. Drugs of abuse cause three types of epigenetic alteration in the brain. These are (1) histone acetylations and histone methylations, (2) DNA methylation at CpG sites, and (3) epigenetic downregulation or upregulation of microRNAs.
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There is an upregulation of a macroautophagic pathway related to AD that can be related to an actin aggregate thought to be an intermediate in the formation of Hirano bodies. More specifically the actin and actin binding proteins seen in Hirano bodies are a significant feature of an Alzheimer’s disease brain. Additionally, variations in the locational characteristics of β-amyloid precursor proteins seen in Alzheimer’s disease are connected to Hirano bodies.
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In the CNS, activation of the NPSR by NPS promotes arousal and anxiolytic-like effects. In addition, mututations in NPSR have been linked to a susceptibility to asthma (rs3249801, A107I). Hence NPSR has also been called GPRA (G protein-coupled receptor for asthma susceptibility). Activation of NPSR in the airway epithelium has a number of effects including upregulation of matrix metalloproteinases which are involved in the pathogenesis of asthma.
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Endothelial cells possess a large number of OSM receptors. Stimulation of a primary endothelial culture (HUVEC) with hOSM results in delayed but prolonged upregulation of P-selectin, which facilitates leukocyte adhesion and rolling, necessary for their extravasation. OSM also promotes the production of IL-6 from these cells. As mentioned above the action of OSM as a quencher of the inflammatory response is by no means established yet.
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There are multiple studies that link FAM83A overexpression to lung, prostate, and bladder cancers. Researchers believe that this gene might make a good candidate for early detection of these cancers, especially lung cancer. It is unknown why or how FAM83A is upregulated. Studies have shown that arsenic can acetylate the promoter causing upregulation, suggesting this may be a similar mechanism to how this gene becomes unregulated in cancer.
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Hu and her team study the neural circuit mechanisms driving depression in rodent models. They found in 2013 that the lateral habenula (LHb) circuits play a role in depression through neuronal adaptations associated with the enzyme BCamKII upregulation. Increases in BCamKII lead to increased excitatory synaptic transmission and action potential firing through increased expression of a specific subtype of glutamate receptors. Overall habenular hyperactivity was associated with depressive phenotypes.
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Ang has a prominent role in the pathology of cancer due to its functions in angiogenesis and cell survival. Since Ang possesses angiogenic activity, it makes Ang a possible candidate in therapeutic treatments of cancer. Studies of Ang and tumor relationships provide evidence for a connection between the two. The translocation of Ang to the nucleus causes an upregulation of transcriptional rRNA, while knockdown strains of Ang cause downregulation.
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Upregulation results in a decrease in mitochondrial potential, an increase in reactive oxygen species, mitochondrial swelling and fission, and an increase in mitochondrial turnover via autophagy. Sequence similarity with Bcl-2 family members was not detected. Humans and other animals (Drosophila, Caenorhabditis), as well as lower eukaryotes (Dictyostelium, Trypanosoma, Cryptosporidium, Paramecium) encode several BNIP3 paralogues including the human NIP3L, which induces apoptosis by interacting with viral and cellular anti-apoptosis proteins.
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Megakaryocytes that were isolated from mice deficient for PSMC1 failed to produce pro platelets. The failure to produce proplatelets in proteasome-inhibited megakaryocytes was due to upregulation and hyperactivation of the small GTPase, RhoA. It appears that proteasome function, through an underlying mechanisms involving PSMC1, is critical for thrombopoiesis. Furthermore, inhibition of RhoA signaling in this process may be a potential strategy to treat thrombocytopenia in bortezomib-treated multiple myeloma patients.
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In the case of all five children, there was consanguinity in their pedigrees. All affected were found to have a functional defect in the upregulation of TNFα production by their blood macrophages in response to stimulation with IFNγ. Furthermore, all lacked expression of IFNγR's on their blood monocytes or lymphocytes, and each was found to have a mutation in the gene on chromosome 6q22-q23 that encodes IFNγR1.
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Lysyl oxidase (LOX), also known as protein-lysine 6-oxidase, is an enzyme that, in humans, is encoded by the LOX gene. It catalyzes the conversion of lysine molecules into highly reactive aldehydes that form cross-links in extracellular matrix proteins. Its inhibition can cause osteolathyrism, but, at the same time, its upregulation by tumor cells may promote metastasis of the existing tumor, causing it to become malignant and cancerous.
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Echinocandin resistance is rare among Candida spp. However, case studies have shown some resistance in C. albicans, C. glabrata, C. lusitaniae, C. tropicalis, and C. parapsilosis. Resistance patterns include alterations in the glucan synthase (Fks1-Fks2 complex), overexpression of efflux pumps, strengthening of cell wall by increased chitin production, upregulation of stress-response pathways, and dysregulation of mismatch repair pathways. In addition a few species and strains of Candida spp.
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The Gfap locus, which codes for the formation and regulation of the cytoskeleton of astrocytes, is one such locus where this activity is observed. The gene is regularly methylated to downregulate glioma related cancers. DNMT inhibition leads to decreased methylation and increased synaptic activity.[2] Several studies show that the methylation-related increase or decrease in synaptic activity occurs due to the upregulation or downregulation of receptors at the neurological synapse.
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Natural antibodies recognize these clusters on senescent erythrocytes. Protection by HbAS involves the enhancement of not only innate but also of acquired immunity to the parasite. Prematurely denatured sickle hemoglobin results in an upregulation of natural antibodies which control erythrocyte adhesion in both malaria and sickle cell disease. Targeting the stimuli that lead to endothelial activation will constitute a promising therapeutic strategy to inhibit sickle red cell adhesion and vaso-occlusion.
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Chronic use of alcohol leads to changes in brain chemistry especially in the GABAergic system. Various adaptations occur such as changes in gene expression and down regulation of GABAA receptors. During acute alcohol withdrawal, changes also occur such as upregulation of alpha4 containing GABAA receptors and downregulation of alpha1 and alpha3 containing GABAA receptors. Neurochemical changes occurring during alcohol withdrawal can be minimized with drugs which are used for acute detoxification.
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The μ-opioid receptor also binds endogenous opioid peptides such as β-endorphin, Leu-enkephalin, and Met-enkephalin. Repeated use of heroin results in a number of physiological changes, including an increase in the production of μ-opioid receptors (upregulation). These physiological alterations lead to tolerance and dependence, so that stopping heroin use results in uncomfortable symptoms including pain, anxiety, muscle spasms, and insomnia called the opioid withdrawal syndrome.
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Atopic dermatitis (AD) is a chronic inflammatory skin disorder, in which patients suffer from eczema, often severe pruritus on the affected skin, as well as complications and secondary infections. AD surfaces from an upregulation of Th2-modified immune responses, therefore a novel AD approach using DNAzymes targeting GATA-3 is a plausible treatment option. The topical DNAzyme SB011 is currently in phase II clinical trials. DNAzyme research for the treatment of cancer is also underway.
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A number of cardiac dysfunctions have been linked to cytosine methylation patterns. DNMT deficient mice show upregulation of inflammatory mediators, which cause increased atherosclerosis and inflammation. Atherosclerotic tissue has increased methylation in the promoter region for the estrogen gene, although any connection between the two is unknown. Hypermethylation of the HSD11B2 gene, which catalyzes conversions between cortisone and cortisol, and is therefore influential in the stress response in mammals, has been correlated with hypertension.
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This gene is expressed predominantly in brain and may play a role in the nervous system. Role in breast cancer The HS3ST2 promoter is hypermethylated in breast cancer tissue compared to normal breast ducts, suggesting a potential involvement in the pathogenesis of the disease. Functional analysis revealed that upregulation of HS3ST2 in human breast cancer cells resulted in altered invasiveness, which was due to changes in Mitogen-activated protein kinase signaling and matrix metalloproteinase expression.
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Upregulation was observed in tumors progressing after anti-PD-1 therapy. This seems to be a form of adaptive resistance to immunotherapy. Multiple phase 1/2 clinical trials with anti- HAVCR2 monoclonal antibodies (LY3321367, Eli Lilly and Company; MBG453, Novartis Pharmaceuticals; TSR-022, Tesaro, Inc.) in combination with anti-PD-1 or anti-PD-L1 therapies are ongoing. The role of HAVCR2 in the T-cell dysfunction has been investigated in chronic viral infections.
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The delayed onset of clinical effects from antidepressants indicates involvement of adaptive changes in antidepressant effects. Rodent studies have consistently shown upregulation of the 3, 5-cyclic adenosine monophosphate (cAMP) system induced by different types of chronic but not acute antidepressant treatment, including serotonin and norepinephrine uptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, lithium and electroconvulsions. cAMP is synthesized from adenosine 5-triphosphate (ATP) by adenylyl cyclase and metabolized by cyclic nucleotide phosphodiesterases (PDEs).
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Heat shock proteins (HSPs) are expressed during exposure to high temperatures and is a characteristic held by most organisms. In some species of nototheniids, this trait is not expressed. The trait is not expressed because of the extreme cold of the Southern Oceans leading to upregulation of Hsp70. HSP expression indicates that regulation of Hsp70 occurred once during speciation, showing that it is a trait of most, if not all Antarctic notothenioids possess.
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When complexed with the SF1 protein, TDF acts as a transcription factor that causes upregulation of other transcription factors, most importantly SOX9. Its expression causes the development of primary sex cords, which later develop into seminiferous tubules. These cords form in the central part of the yet-undifferentiated gonad, turning it into a testis. The now- induced Leydig cells of the testis then start secreting testosterone, while the Sertoli cells produce anti-Müllerian hormone.
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Expression of c-fos is an indirect marker of neuronal activity because c-fos is often expressed when neurons fire action potentials. Upregulation of c-fos mRNA in a neuron indicates recent activity. The c-fos promoter has also been utilised for drug abuse research. Scientists use this promoter to turn on transgenes in rats, allowing them to manipulate specific neuronal ensembles to assess their role in drug-related memories and behavior.
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When exposed to infection, there is an upregulation of sensome genes involved in neuroinflammation and a downregulation of genes that are involved with neuroplasticity. The sensome’s ability to alter neurodevelopment may however be able to combat disease. The deletion of CX3CL1, a highly expressed sensome gene, in rodent models of Rett syndrome resulted in improved health and longer lifespan. The downregulation of Cx3cr1 in humans without Rett syndrome is associated with symptoms similar to schizophrenia.
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"Calcium Upregulation by Percutaneous administration of gene therapy In cardiac Disease (CUPID Trial), a first-in-human phase 1/2 clinical trial". Journal of Cardiac Failure. 15(3):171-181. Using the α-myosin heavy chain gene promoter in the cardiac muscle cells, also called cardiomyocytes, Mydicar is able to direct the gene expression only to the heart muscle.Baker DL, Hashimoto K, Grupp IL, Ji Y, Reed T, Loukianov E, et al. (1998).
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MMP7 is found to potentially involved in tumor metastasis and inflammatory processes. The upregulation of MMP7 is associated with many malignant tumors including esophagus, stomach, colon, liver, pancreas, and renal cell carcinomas. High MMP7 expression facilitates cancer invasion and angiogenesis by degrading extracellular matrix macromolecules and connective tissues. These degradations are associated with many mechanisms including embryogenesis, postpartum uterine involution, tissue repair, angiogenesis, bone remodeling, arthritis, decubitus ulcer, and tumor metastasis/invasion.
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Floppy eyelid syndrome is a disease whose most prominent features often include floppy upper eyelids that can be easily everted, as well as papillary conjunctivitis. It is often associated with patients with high body mass index and obstructive sleep apnea. Floppy eyelid syndrome is thought to revolve around the upregulation of elastin-degrading enzymes, as well as mechanical factors. These can cause instability of the eyelid scaffold, resulting in the malposition of the eyelid.
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This abnormal regulation leads to a decreased level of androgen in the body which, itself, is obesogenic. Finally, if PPARα activation occurs during critical periods of development, the resulting decrease in lipid concentration in the developing fetus is recognized by the fetal brain as undernourishment. In this case, the developing brain makes what will become permanent changes to the body's metabolic control, leading to long-term upregulation of lipid storage and maintenance.
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String/cdc25 is a phosphatase that stimulates mitotic cyclin-CDK complex activity. Upregulation of S-phase CDK activity is accomplished via transcriptional repression of the inhibitory kinase dacapo. Together, these changes allow for the circumvention of mitotic entry, progression through G1, and entry into S-phase. The induction of endomitosis in mammalian megakaryocytes involves activation of the c-mpl receptor by the thrombopoietin (TPO) cytokine and is mediated by ERK1/2 signaling.
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A gain in copy number of the mir-10a gene has been found in melanoma and breast cancer. Upstream of the mir-10b gene is a promoter region containing a binding site for the Twist transcription factor (Twist). Binding of Twist to this promoter region induces miR-10b expression, leading to a reduced translation of the tumour suppressor HOXD10. This results in upregulation of RhoA/RhoC, Rho kinase activation and tumour cell invasion.
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As found by Brooks, et al., while lactate is disposed of mainly through oxidation and only a minor fraction supports gluconeogenesis, lactate is the main gluconeogenic precursor during sustained exercise. Brooks demonstrated in his earlier studies that little difference in lactate production rates were seen in trained and untrained subjects at equivalent power outputs. What was seen, however, was more efficient clearance rates of lactate in the trained subjects suggesting an upregulation of MCT protein.
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Targets of upregulation include c-myc, e-fabp, and cyclins A & E. This has the effect of promoting tumor growth. Additionally, EpEX that has been cleaved can stimulate the cleavage of additional EpCAM molecules resulting in a positive feedback loop. The amount of β-catenin in the nucleus can modulate the expression level of EpCAM. EpCAM may also play a role in epithelial mesenchymal transition (EMT) in tumors, although its exact effects are poorly understood.
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This leads to the increased expression of many genes, some of which are involved in cell proliferation, contributing to the formation of cancer. A common human translocation involving c-myc is critical to the development of most cases of Burkitt lymphoma. Constitutive upregulation of Myc genes have also been observed in carcinoma of the cervix, colon, breast, lung and stomach. Myc is thus viewed as a promising target for anti-cancer drugs.
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A large body of evidence shows that Myc genes and proteins are highly relevant for treating tumors. Except for early response genes, Myc universally upregulates gene expression. Furthermore, the upregulation is nonlinear. Genes for which expression is already significantly upregulated in the absence of Myc are strongly boosted in the presence of Myc, whereas genes for which expression is low in the absence Myc get only a small boost when Myc is present.
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Accessed January 1, 2007. Cancer, especially squamous cell carcinoma, may also form as the result of chronic wounds, probably due to repetitive tissue damage that stimulates rapid cell proliferation. Another factor that may contribute to chronic wounds is old age. The skin of older people is more easily damaged, and older cells do not proliferate as fast and may not have an adequate response to stress in terms of gene upregulation of stress-related proteins.
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DDIT4 acts as a negative regulator of mTOR, a serine/threonine kinase that regulates a variety of cellular functions such as growth, proliferation and autophagy. In particular, upregulation of HIF-1 in response to hypoxia upregulates DDIT4, leading to activation of Tsc1/2 via 14–3–3 shuttling and subsequent downregulation of mTOR via Rheb. In addition to hypoxia, DDIT4 expression has also been shown to be activated by DNA damage and energy stress.
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The expression of various genes in the subfornical organ have been studied. For example, it was seen that water deprivation in rats led to an upregulation of the mRNA that codes for angiotensin II receptors, allowing for a lower angiotensin concentration in the blood that produce the "thirst" response. It also has been observed to be a site of thyroid transcription factor 1 (TTF1) production, a protein generally produced in the hypothalamus.
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For example, major differences in telomere regulation enable murine cells to bypass the requirement for telomerase upregulation, which is a rate-limiting step in human cancer formation. As another example, certain ligand-receptor interactions are incompatible between mice and humans. Additionally, experiments have demonstrated important and significant differences in the ability to transform cells, compared with cells of murine origin. For these reasons, it remains essential to develop models of cancer that employ human cells.
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This is typically seen in animal hormone receptors. Upregulation of receptors, on the other hand, can result in super- sensitized cells especially after repeated exposure to an antagonistic drug or prolonged absence of the ligand. Some receptor agonists may cause downregulation of their respective receptors, while most receptor antagonists temporarily upregulate their respective receptors. The disequilibrium caused by these changes often causes withdrawal when the long-term use of a drug is discontinued.
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Epigenetic upregulation of the DNA repair genes PARP1 and FEN1 occurs in numerous cancers (see Regulation of transcription in cancer). PARP1 and FEN1 are essential genes in the error-prone and mutagenic DNA repair pathway microhomology- mediated end joining. If this pathway is upregulated, the excess mutations it causes can lead to cancer. PARP1 is over-expressed in tyrosine kinase- activated leukemias, in neuroblastoma, in testicular and other germ cell tumors, and in Ewing's sarcoma.
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The enzyme is also thought to act as a safety valve for stress conditions in the photosynthetic apparatus. By providing an electron sink when the plastoquinone pool is over-reduced, the oxidase is thought to protect photosystem II from oxidative damage. Knockouts for Rubisco and photosystem II complexes, which would experience more photodamage than normal, exhibit an upregulation of plastid terminal oxidase. This effect is not universal because it requires plants to have additional PTOX regulation mechanisms.
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Medullary breast carcinoma is a rare type of breast cancer that often can be treated successfully. It is marked by lymphocytes (a type of white blood cell) in and around the tumor that can be seen when viewed under a microscope. This is the only breast cancer associated with a loss of function mutation in BRCA1, and thus the only form associated with a hereditary mutation. It is typically triple-negative and exhibits upregulation of p53.
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Recently, SCF complexes have become an attractive anti-cancer target because of their upregulation in some human cancers and their biochemically distinct active sites. Though many of the aforementioned FBPs have been implicated in cancer, cytotoxicity has been a limiting factor of drug development. Skp2-targeting anti-sense oligonucleotides and siRNAs are in the drug development pipeline. Preliminary studies have shown that Skp2 downregulation can inhibit the growth of melanomas, lung cancer cells, oral cancer cells, and glioblastoma cells.
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CYP7A1 is upregulated by the nuclear receptor LXR (liver X receptor) when cholesterol (to be specific, oxysterol) levels are high. The effect of this upregulation is to increase the production of bile acids and reduce the level of cholesterol in hepatocytes. It is downregulated by Sterol regulatory element- binding proteins (SREBP) when plasma cholesterol levels are low. Bile acids provide feedback inhibition of CYP7A1 by at least two different pathways, both involving the farnesoid X receptor, FXR.
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This resulted in suppression of lytic infection. Ezh1/2 inhibitors also activate cellular antiviral pathways. Specifically, in cells treated with Ezh1/2 inhibitors, greater numbers of promyelocytic leukemia (PML) foci, which are involved with repression of gene expression, were seen, along with upregulation of interferon-alpha (IFN-α) and interleukin-8 (IL-8). These pathways are not specific to HSV; treatment with Ezh1/2 inhibitors reduced infection of multiple viral pathogens, including human cytomegalovirus, adenovirus, and Zika virus.
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Diagram illustrating the interaction between the Wnt and insulin signaling pathways Insulin is a peptide hormone involved in glucose homeostasis within certain organisms. Specifically, it leads to upregulation of glucose transporters in the cell membrane in order to increase glucose uptake from the bloodstream. This process is partially mediated by activation of Wnt/β-catenin signaling, which can increase a cell's insulin sensitivity. In particular, Wnt10b is a Wnt protein that increases this sensitivity in skeletal muscle cells.
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Flies of this species have adapted an upregulation of this gene due to exposure of high levels of alkaloids in host plants. CYPs have been extensively examined in mice, rats, dogs, and less so in zebrafish, in order to facilitate use of these model organisms in drug discovery and toxicology. Recently CYPs have also been discovered in avian species, in particular turkeys, that may turn out to be a useful model for cancer research in humans.
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The first is an agonist conformation which favors the binding of coactivator proteins which in turn favors upregulation of gene transcription. The second is an antagonistic conformation which in contrast favors the binding of corepressors and as a consequence down regulation of gene expression. Full agonists such as progesterone, which display agonist properties in all tissues, strongly shift the conformational equilibrium in the agonist direction. Conversely full antagonists such as aglepristone strongly shift the equilibrium in the antagonist direction.
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In HDAC1 knockout (KO) mice, mice were found to die during embryogenesis and showed a drastic reduction in the production but increased expression of Cyclin-Dependent Kinase Inhibitors (CDKIs) p21 and p27. Not even upregulation of the other Class I HDACs could compensate for the loss of HDAC1. This inability to recover from HDAC1 KO leads researchers to believe that there are both functional uniqueness to each HDAC as well as regulatory cross-talk between factors.
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The authors of this study posit that the results of this RNA transcriptomic study could provide evidence for the mechanisms through which BP oil spill workers experienced respiratory oxidative stress and associated symptoms. Gene regulation was studied for both Corexit EC9500A and EC9527A. The study showed harmful effects and interactions between both types of Corexit as well as the oil. Abnormal regulation was detected in the study and both upregulation and downregulation of genes was found.
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Elevated levels of galectin-3 have been found to be significantly associated with higher risk of death in both acute decompensated heart failure and chronic heart failure populations. In normal human, murine, and rat cells galectin-3 levels are low. However, as heart disease progresses, significant upregulation of galectin-3 occurs in the myocardium. Galectin-3 also may be used as a biomarker to identify at risk individuals, and predict patient response to different drugs and therapies.
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Tumor Biol. 2012, 33(4), 1031-8 ZnPP suppression of heme oxygenase reduces cell viability of cancer cells and increases cytotoxicity in cancer cells. ZnPP works in combination with anticancer drugs to increase cytotoxicity greatly in some cases; results in one study have shown a five-fold increase in treatment efficacy.Yin, H., Fang, J., Liao, L., Maeda, H., & Su, Q. Upregulation of heme oxygenase-1 in colorectal cancer patients with increased circulation carbon monoxide levels, potentially affects chemotherapeutic sensitivity.
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The HIV viral protein gp120 induces apoptosis of neuronal cells by inhibiting levels of furin and tissue plasminogen activator, enzymes responsible for converting pBDNF to mBDNF. gp120 induces mitochondrial-death proteins like caspases which may influence the upregulation of the death receptor Fas leading to apoptosis of neuronal cells, gp120 induces oxidative stress in the neuronal cells, and it is also known to activate STAT1 and induce interleukins IL-6 and IL-8 secretion in neuronal cells.
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These Treg abnormalities likely play a major role in autoimmunity, although some patients with normal Tregs also presented with autoimmunity disorders. Additionally, a partial decrease of STAT1 activation likely participates in immune deficiencies. Data suggest the upregulation of STAT3 transcriptional activity may have consequences for other cytokine signaling pathways as well. Notably, there has been no correlation between STAT3 hyperactivity and the severity of the phenotype, in addition to an absence of any genotype-phenotype correlation.
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Research on the role of TRPC channels in cardiomyopathies is still in progress. An upregulation of TRPC1, TRPC3, and TRPC6 genes are seen in heart disease states including fibroblast formation and cardiovascular disease. The TRPC channels are suspected of responding to an overload of hormonal and mechanical stimulation in cardiovascular disease, contributing to pathological remodelling of the heart. TRPC1 channels are activated by receptors coupled to phospholipase C (PLC), mechanical stimulation, and depletion of intracellular calcium stores.
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HDAC inhibitors have been regarded as a potential treatment of neurodegenerative diseases, such as Parkinson's disease. Parkinson's disease is usually accompanied by an increase in the number of microglial proteins in the substantia nigra of the brain. In vivo evidence has shown a correlation between the number of microglial proteins and the upregulation of HDAC2. It is thought therefore that HDAC2 inhibitors could be effective in treating microglial-initiated loss of dopaminergic neurons in the brain.
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Some actions of HMGB1 are mediated through the toll-like receptors (TLRs). Interaction between HMGB1 and TLR4 results in upregulation of NF-κB, which leads to increased production and release of cytokines. HMGB1 is also able to interact with TLR4 on neutrophils to stimulate the production of reactive oxygen species by NADPH oxidase. HMGB1-LPS complex activates TLR4, and causes the binding of adapter proteins (MyD88 and others), leading to signal transduction and the activation of various signaling cascades.
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Hamster BHK ts11 cells produce an inactive asparagine synthetase enzyme, and this loss of asparagine synthetase activity directly led to cell cycle arrest in the cells as a consequence of a depletion of cellular asparagine. Upregulation of asparagine synthetase mRNA was observed as well in these hamster cells. Other experiments demonstrated that quiescent rat thyroid cells entering S phase as a result of thyroid-stimulating hormone treatment was matched with a concurrent increase in asparagine synthetase mRNA content.
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This high level of TERF2 decreases the ability to recruit and activate natural killer cells in human tumor cells. One study used a dominant negative form of TERF2ΔBΔC, to inhibit TERF2, and found that it could induce a reversion malignant phenotype in human melanoma cells. Therefore, over-expression of TERF2ΔBΔC, causing blocking of TERF2, induced apoptosis and reduced tumourigenicity in certain cell lines. Additionally, upregulation of TERF2 may be the cause of the establishment and maintenance of short telomeres.
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These effects of siRNA-mediated PSMD2 inhibition were associated with changes in the balance between phosphorylated AKT and p38, as well as with the induction of p21. In addition, patients with higher PSMD2 expression indicated a poorer prognosis and a small fraction of lung cancer specimens carried increased copies of PSMD2. Notably, findings illustrate that lung adenocarcinomas can be divided into two main groups; those with and without general upregulation of proteasome pathway genes including PSMD2.
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The Warburg effect, proposed by Otto Warbug in 1956, describes the upregulation of glycolysis in most cancer cells, even in the presence of oxygen. The high rate of glycolysis is accompanied by increased lactic acid fermentation, providing additional nutrients for cancer cell growth and tumorigenesis. PFKFB3 is associated with the Warburg effect because its activity increases the rate of glycolysis. PFKFB3 has been found to be upregulated in numerous cancers, including colon, breast, ovarian, and thyroid.
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Pomalidomide directly inhibits angiogenesis and myeloma cell growth. This dual effect is central to its activity in myeloma, rather than other pathways such as TNF alpha inhibition, since potent TNF inhibitors including rolipram and pentoxifylline do not inhibit myeloma cell growth or angiogenesis. Upregulation of interferon gamma, IL-2 and IL-10 as well as downregulation of IL-6 have been reported for pomalidomide. These changes may contribute to pomalidomide's anti-angiogenic and anti-myeloma activities.
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Downregulation of ATG5 protein and mutations in the Atg5 gene have also been linked with prostate, gastrointestinal and colorectal cancers as ATG5 plays a role in both cell apoptosis and cell cycle arrest. Upregulation of Atg5 on the other hand has been shown to suppress melanoma tumorigenesis through induction of cell senescence. ATG5 also plays a protective role in M. tuberculosis infections by preventing PMN-mediated immunopathology. An Atg5−/− mutation in mice is known to be embryonic lethal.
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The VCAM-1 protein mediates the adhesion of lymphocytes, monocytes, eosinophils, and basophils to vascular endothelium. It also functions in leukocyte-endothelial cell signal transduction, and it may play a role in the development of atherosclerosis and rheumatoid arthritis. Upregulation of VCAM-1 in endothelial cells by cytokines occurs as a result of increased gene transcription (e.g., in response to Tumor necrosis factor-alpha (TNF-α) and Interleukin-1 (IL-1)) and through stabilization of Messenger RNA (mRNA) (e.g.
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The epigenetic effects IL-6 have also been implicated in the pathology of depression. The effects of IL-6 on depression are mediated through the repression of brain-derived neurotrophic factor (BDNF) expression in the brain; DNMT1 hypermethylates the BDNF promoter and reduces BDNF levels. Altered BDNF function has been implicated in depression, which is likely due to epigenetic modification following IL-6 upregulation. BDNF is a neutrophic factor implicated in spine formation, density, and morphology on neurons.
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Recently it has been shown that upregulation of IFRD1 in vivo in injured muscle potentiates muscle regeneration by increasing the production of staminal muscle cells (satellite cells). The underlying molecular mechanism lies in the ability of IFRD1 to cooperate with MyoD at inducing the transcriptional activity of MEF2C. This relies on the ability of IFRD1 to bind selectively MEF2C, thus inhibiting its interaction with HDAC4. Therefore, IFRD1 appears to act as a positive cofactor of MyoD.
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UGT2B4 is mainly involved in the glucuronidation of hyodeoxycholic acid, a bile acid, and catechol-estrogens, such as 17-epiestriol and 4-hydroxy-estrone. The expression of the UGT2B4 enzyme is upregulated by the farnesoid X receptor (FXR), a nuclear receptor which is activated by bile acids. These same bile acids are substrates for the UGT2B4 enzyme. Hence upregulation of UGT2B4 by activated FXR provides a mechanism for the detection, conjugation and subsequent elimination of toxic bile acids.
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Its upregulation through overexpression can induce arrest independent of DNA damage. In addition, overexpression of Chk1 rescues the radiation sensitivity of rad mutants, presumably by allowing DNA repair to take place before entry into mitosis. The presence of DNA damage triggers the ATM (Ataxia telangiectasia mutated) or ATR (Ataxia Telangiectasia and Rad3 related) pathways which activate the Chk2 and Chk1 kinases, respectively. These kinases act upstream of Cdc25 and Wee1, the direct regulators of the CyclinB-Cdc2 complex.
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The upregulation of this gene is an adaptive response to exposure to toxic alkaloids in host plants. Similarly, the Cyp 28A1 gene expression is also upregulated in D. mettleri that are exposed to more alkaloids in host plants. The P450 family of genes have a protein structure that can be highly altered by few mutations and sequence changes. A site in the Cyp 28A1 gene has a single change from a nonpolar to polar amino acid.
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AGR2 is also associated with prostate cancer, though lower levels are associated with higher Gleason grades. In contrast to upregulation of AGR2 in various cancers, downregulation of AGR2 is linked with inflammatory bowel disease and increases in the risk of Crohn's disease and ulcerative colitis. This implies the importance of AGR2 in maintaining epithelial barrier function, which is supported by FOXA1 and FOXA2 molecules (transcription factors for epithelial goblet cells) which can activate the AGR2 promoter.
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The dopamine hypothesis states that the increase in dopamine results in secondary homeostatic downregulation of key system elements and receptors such as lower sensitivity of dopaminergic receptors. This results in decreased dopamine transmission characteristic of the depressive phase. The depressive phase ends with homeostatic upregulation potentially restarting the cycle over again. Glutamate is significantly increased within the left dorsolateral prefrontal cortex during the manic phase of bipolar disorder, and returns to normal levels once the phase is over.
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The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types. Cytokine signals produced by helper T cells enhance the microbicidal function of macrophages and the activity of killer T cells. In addition, helper T cell activation causes an upregulation of molecules expressed on the T cell's surface, such as CD40 ligand (also called CD154), which provide extra stimulatory signals typically required to activate antibody-producing B cells.
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PPARG regulates fatty acid storage and glucose metabolism. The genes activated by PPARG stimulate lipid uptake and adipogenesis by fat cells. PPARG knockout mice are devoid of adipose tissue, establishing PPARG as a master regulator of adipocyte differentiation. PPARG increases insulin sensitivity by enhancing storage of fatty acids in fat cells (reducing lipotoxicity), by enhancing adiponectin release from fat cells, by inducing FGF21, and by enhancing nicotinic acid adenine dinucleotide phosphate production through upregulation of the CD38 enzyme.
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ANGPTL4-deficient mice exhibit delayed wound reepithelialization with impaired keratinocyte migration, angiogenesis and altered inflammatory response. ANGPTL4 induces nitric oxide production through an integrin/JAK/STAT3-mediated upregulation of iNOS expression in wound epithelia, and enhances angiogenesis to accelerate wound healing in diabetic mice. ANGPTL4 induces a β-catenin-mediated upregulation of ID3 in fibroblasts to reduce scar collagen expression. ANGPTL4 is capable of reversing the fibroblast-to-myofibroblast differentiation induced aligned electrospun fibrous substrates. Cyclic stretching of human tendon fibroblasts stimulated the expression and release of ANGPTL4 protein via TGF-β and HIF-1α signalling, and the released ANGPTL4 was pro-angiogenic. ANGPTL4 is also a potent angiogenic factor whose expression is up-regulated in hypoxic retinal Müller cells in vitro and the ischemic retina in vivo. The expression of ANGPTL4 was increased in the aqueous and vitreous of proliferative diabetic retinopathy patients and localized to areas of retinal neovascularization. ANGPTL4 has been established as a potent inhibitor of serum triglyceride (TG) clearance, causing elevation of serum TG levels via inhibition of the enzyme lipoprotein lipase (LPL).
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There is evidence that the change is selective, and DNMT1 is overexpressed in reelin-secreting GABAergic neurons but not in their glutamatergic neighbours. Methylation inhibitors and histone deacetylase inhibitors, such as valproic acid, increase reelin mRNA levels, while L-methionine treatment downregulates the phenotypic expression of reelin. One study indicated the upregulation of histone deacetylase HDAC1 in the hippocampi of patients. Histone deacetylases suppress gene promoters; hyperacetylation of hystones was shown in murine models to demethylate the promoters of both reelin and GAD67.
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VEZT is a gene located on chromosome 12 and encodes for the protein vezatin. Vezatin is a major component of the cadherin-catenin complex that is critical to the formation and maintenance of adherens junctions. The protein is expressed in most epithelial cells and is crucial to the formation of cell- cell contact junctions. Mutations of the gene can lead to upregulation or downregulation of the protein which can have detrimental effects on physiological systems, particularly those involved in development.
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The absence of the Mohawk (Mkx) gene led to significantly lower Tnmd expression as well as collagen I and fibromodulin. A significant loss of Tnmd was noticeable in Mkx knockouts at E16.5, while Scx expression was unchanged [22], suggesting that Mkx can also directly affect Tnmd expression. Activation of the Wnt/β-catenin signalling pathway in bone marrow-derived stem cells resulted in Tnmd upregulation. Scx and Mkx expression were unaffected, suggesting the Wnt/ β-catenin signalling works independent from these transcription factors.
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SGK1 has been shown to inhibit apoptosis. "The antiapoptotic effect of SGK1 and SGK3 has been attributed in part to phosphorylation of forkhead transcription factors". It is suggested that proliferative signals transport SGK1 into the nucleus, and the effect of SGK1 on cell proliferation may be due to its ability to regulate Kv1.3. "The upregulation of Kv1.3 channel activity may be important for the proliferative effect of growth factors, as IGF-I induced cell proliferation is disrupted by several blockers of Kv channels".
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Chemically, arteriogenesis is related to upregulation of cytokines and cell adhesion receptors. More specifically, mechanical stresses cause endothelial cells to produce chemical facilitators that begin the process of increasing diameter. An increase in shear stress causes an increase in the number of monocyte chemoattractant protein-1 (MCP-1) molecules expressed on the surface of vessel walls as well as increased levels of TNF-α, bFGF, and MMP. MCP-1 increases the tendency of monocytes to attach to the cell wall.
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Tetherin is part of IFN-dependent antiviral response pathway. When the presence of virus and viral components is detected by recognition molecules such as (RIG-I), a cascades of interactions happen between signaling molecules, eventually the signal reaches the nucleus to upregulate the expression of interferon- stimulated genes (ISGs), this in turn activates IFN-a pathway to send the signal to neighboring cells, which causes upregulation in the expression of other ISGs and many viral restriction factors, such as tetherin.
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CX-614 is an ampakine drug developed by Cortex Pharmaceuticals. It has been investigated for its effect on AMPA receptors. Chronic CX-614 treatments produce rapid increases in the synthesis of the brain-derived neurotrophic factor BDNF which has very important effects on synaptic plasticity and may have applications in the treatment of neurodegenerative diseases such as Alzheimer's disease. Acute CX-614 treatments activate local mRNA translation (new protein synthesis) within dendrites and this is mediated by a fast upregulation of BDNF release.
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However, at E.10, DNMT3a expression increases significantly from E13.5 and well into adulthood. In the postnatal forebrain, DNMT3a is expressed in the subventricular zone (SVZ) and the hippocampal dentate gyrus, the primary locations for adult neurogenesis. The loss of DNMT3a in post natal neural progenitor cells leads to the down-regulation of neuronic genes such as Dlx2, Neurog2, and Sp8; but upregulation of genes involved in astroglial and oligodendroglial differentiation, indicating a role in the cell-fate switch from neurogenesis to gliogenesis.
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What is the source of the nucleic acid inducing the immune disturbance in AGS? Intriguingly, it has been shown that TREX1 can metabolise reverse-transcribed HIV-1 DNA and that single-stranded DNA derived from endogenous retroelements accumulates in Trex1-deficient cells; however, the upregulation of retroelements in TREX1-null cells has recently been disputed. Similarly, another AGS-related gene product SAMHD1 also presents strong potency against activity of multiple non-LTR retroelements, which is independent from SAMHD1's famous dNTPase activity.
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The ACADVL gene contains 20 exons, and is about 5.4 kb long. VLCAD has interesting gene structure in humans, in that is located in a head-to-head structure with the DLG4 gene on Chromosome 17, and that the transcribed regions of these genes overlap. It has been shown that treatment with DEHP results in upregulation by the minimal promoter. While DLG4 and VLCAD share common regulatory elements, they each have separate and distinct tissue-specific elements that confer their function.
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IL-23 is an important part of the inflammatory response against infection. It promotes upregulation of the matrix metalloprotease MMP9, increases angiogenesis and reduces CD8+ T-cell infiltration into tumours. IL-23 mediates its effects on both innate and adaptive arms of the immune system that express the IL-23 receptor. Th17 cells represent the most prominent T cell subset that responds to IL-23, although IL-23 has been implicated in inhibiting the development of regulatory T cell development in the intestine.
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By inducing upregulation of methyltransferase inhibitors, the effects of the loss-of-function mutation can be mitigated. Development of drugs that target or modify epigenetic signatures of target genes is growing, especially as bioinformatic analysis increases our knowledge of the human genome and speeds up the search for synthetic lethal interactions. Most widely used to assess potential synthetic lethal interactions is using siRNA and CRISPR-Cas9 to modify target genes. CRISPRi and CRISPRa technology allows researchers to activate or inactivate target genes.
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Fibronectin is an extracellular glycoprotein that can bind to integrins and other ECM components like collagen, fibrin and heparan sulphate proteoglycans(HSPGs). Several different integrins bind to fibronectin. Fibronectin-integrin interactions are important in tumor cell migration, invasion, metastasis and cell proliferation by signaling through integrins. Integrin-mediated tumor cell adhesion to ECM proteins can trigger signal transduction and cause upregulation of gene expression, increased tyrosine phosphorylytion of the focal adhesion kinase, and activation and nuclear translocation of mitogen-activated protein (MAP) kinases.
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CRH has also been shown to promote neurodegeneration, suggesting that CRH1 antagonists may have neuroprotective effects. PC12 cells are derived from the rat adrenal medulla and are extensively used to study neural differentiation. PC12 cells treated with CRH (1-10 nM) showed increased numbers of apoptotic cells and upregulation of the Fas ligand via p38 activation, demonstrating the pro- apoptotic effects of CRH. Administration of Antalarmin (10 nM) completely blocked the CRH-induced apoptosis response and inhibited Fas ligand expression.
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The invasive cell phenotype in LAM is associated with TIMP-3 downregulation and TSC2-dependent upregulation of MMPs. Clinical and histopathological evidence demonstrate the lymphatic involvement in LAM. The prevailing hypothesis is that LAM lesions secrete the lymphangiogenic factor VEGF-D, recruit lymphatic endothelial cells (LECs) that form lymphatic vessels and induce lung cysts. VEGF-D serum levels are increased in LAM compared to other cystic lung diseases, including pulmonary Langerhans cell histiocytosis, emphysema, Sjögren's syndrome, or Birt–Hogg–Dubé syndrome.
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This upregulation is associated with the formation of reactive oxidative species that lead to interstitial injury in the kidney. There is also interest in evaluating MIOX expression as a potential biomarker of acute kidney injury. MIOX expression was shown to increase in the serum of animals and plasma of critically ill patients within 24 hours of acute kidney injury specifically. An immunoassay of MIOX expression may potentially predict these life-threatening injuries earlier than the current diagnostic—detection of plasma creatine.
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Bromantane is a stimulant drug with anxiolytic properties developed in Russia during the late 1980s. Bromantane acts mainly by facilitating the biosynthesis of dopamine, through indirect genomic upregulation of relevant enzymes (tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AAAD), a.k.a. DOPA decarboxylase), although at very high doses bromantane also has anticholinergic effects. Study results suggest that the combination of psychostimulant and anxiolytic actions in the spectrum of psychotropic activity of bromantane is effective in treating asthenic disorders compared to placebo.
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This down-regulation of DNMT1 can have serious consequences on DNA methylation, namely a failure to maintain normal methylation patterns during DNA replication and repair. The upregulation of DNMT3b has also been shown to occur as a result of cigarette exposure. DNMT3b is thought to be critical to de novo methylation, or the production of new methylation marks on DNA. This increased expression of DNMT3b and methionine adenosyltransferase 2A, taken together with the down-regulation of DNMT1, results in myriad unintended epigenetic consequences.
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70–78 The capacity for hyperaccumulation is dependent on two major factors: environmental exposure and expression of members of the ZIP gene family. Although experiments have shown that the hyperaccumulation is partially dependent on environmental exposure (i.e. only plants exposed to metal are observed with high concentrations of that metal), hyperaccumulation is ultimately dependent on the presence and upregulation of genes involved with that process. It has been shown that hyperaccumulation capacities can be inherited in Thlaspi caerulescens (Brassicaceae) and others.
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Mouse liver PPARalpha transcriptome Human hepatocyte PPARalpha transcriptome PPAR-alpha is a transcription factor and a major regulator of lipid metabolism in the liver. PPAR-alpha is activated under conditions of energy deprivation and is necessary for the process of ketogenesis, a key adaptive response to prolonged fasting. Activation of PPAR-alpha promotes uptake, utilization, and catabolism of fatty acids by upregulation of genes involved in fatty acid transport, fatty acid binding and activation, and peroxisomal and mitochondrial fatty acid β-oxidation.
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Activation of LT-β receptors is capable of inducing cell death of cancerous cells and suppressing tumor growth. The process of cell death is mediated by the presence of IFN-γ and can involve apoptotic or necrotic pathways. It is seen that LT-β receptors facilitate the upregulation of adhesion molecules and recruit lymphocytes to tumor cells to combat tumor growth. In other words, LT-α interactions with LT-β receptors can increase anti-tumor effects through direct destruction of tumor cells.
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The muscarinic acetylcholine receptor M1, also known as the cholinergic receptor, muscarinic 1, is a muscarinic receptor that in humans is encoded by the CHRM1 gene. It is localized to 11q13. This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve, is common in exocrine glands and in the CNS. It is predominantly found bound to G proteins of class Gq that use upregulation of phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signalling pathway.
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The exact mechanism in which these diseases cause cachexia is poorly understood, and likely is multifactorial with multiple disease pathways involved. Inflammatory cytokines appear to play a central role including TNF (which is also nicknamed 'cachexin' or 'cachectin'), interferon gamma and interleukin 6. TNF has been shown to have direct catabolic effect on skeletal muscle and adipose tissue through the ubiquitin proteasome pathway. This mechanism involves the formation of reactive oxygen species leading to upregulation of the transcription factor NF-κB.
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Xiao et al.. show that ether-a-go-go related gene (ERG) a K+ channel is a target of miR-133. miR-133 directly and negatively regulates NFATc4. RhoA expression is negatively regulated by miR-133a in bronchial smooth muscles (BSM)and miR-133a downregulation causes an upregulation of RhoA, resulting in an augmentation of contraction and BSM hyperresponsiveness. BMP2 downregulates multiple mIRs, of which one, miR-133, directly inhibits Runx2, an early BMP response gene essential for bone formation.
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It has been observed that the level of RPSA transcript is higher in colon carcinoma tissue and lung cancer cell lines than their normal counterparts. Also, there is a correlation between the upregulation of this polypeptide in cancer cells and their invasive and metastatic phenotype. Multiple copies of the RPSA gene exist; however, most of them are pseudogenes thought to have arisen from retropositional events. Two alternatively spliced transcript variants encoding the same protein have been found for this gene.
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GnRH production/release is one of the few confirmed examples of behavior influencing hormones, rather than the other way around. Cichlid fish that become socially dominant in turn experience an upregulation of GnRH secretion whereas cichlid fish that are socially subordinate have a down regulation of GnRH secretion. Besides secretion, the social environment as well as their behavior affects the size of GnRH neurons. Specifically, males that are more territorial have larger GnRH neurons than males that are less territorial.
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RNAa can be generally classified into two categories: exogenous and endogenous. Exogenous RNAa is triggered by artificially designed saRNAs which target non-coding sequences such as the promoter and the 3’ terminus of a gene and these saRNAs can be chemically synthesized or expressed as short hairpin RNA (shRNA). Whereas for endogenous RNAa, upregulation of gene expression is guided by naturally occurring endogenous small RNAs such as miRNA in mammalian cells and C. elegans, and 22G RNA in C. elegans.
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It has been shown that butyrate inhibits activity of HDAC1 that is bound to the Fas gene promoter in T cells, resulting in hyperacetylation of the Fas promoter and upregulation of Fas receptor on the T cell surface. It is thus suggested that butyrate enhances apoptosis of T cells in the colonic tissue and thereby eliminates the source of inflammation (IFN-γ production). Butyrate inhibits angiogenesis by inactivating Sp1 transcription factor activity and downregulating vascular endothelial growth factor gene expression.
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Upregulation of tyrosinase caused by tyrosinase inhibitors. Several skin whitening agents, including tyrosinase inhibitors, have been found to cause an increase in the expression of tyrosinase, which by itself would increase melanin synthesis. Microphthalmia-associated transcription factor (MITF) is the master transcription factor that controls the expression of TYR, TRP1 and TRP2, MART1, PMEL17, and many other important proteins involved in the function of melanocytes. Downregulation of MITF decreases melanogenesis and is a mechanism of action of some skin whitening agents.
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A gene known as UNC13B shows hypermethylation in diabetes patients genomes and is linked to diabetic nephropathy. The National Center for Biotechnology Information claims that hyperglycemia leads to an upregulation of this gene due to the increase in methylation at important CpG sites within the gene. UNC13B produces a protein with a diacylglycerol (DAG) binding domain. Hyperglycemia increases DAG levels in the blood which causes apoptosis in cells upregulating this gene and renal complications when DAG binds to the product of the UNC13B gene.
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Mutations that lead to EGFR overexpression (known as upregulation or amplification) have been associated with a number of cancers, including adenocarcinoma of the lung (40% of cases), anal cancers, glioblastoma (50%) and epithelian tumors of the head and neck (80-100%). These somatic mutations involving EGFR lead to its constant activation, which produces uncontrolled cell division. In glioblastoma a specific mutation of EGFR, called EGFRvIII, is often observed. Mutations, amplifications or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancers.
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The alpha-3 beta-2 nicotinic receptor, also known as the α3β2 receptor, is a type of nicotinic acetylcholine receptor, consisting of α3 and β2 subunits. It occurs alongside the more common α3β4 nicotinic receptor in autonomic ganglia, and as an facilitatory presynaptic autoreceptor at the neuromuscular junction (NMJ). At the NMJ, it is involved in upregulation of ACh release during high- frequency stimulation. Nicotine, a component of tobacco, a common stimulate of the receptor has been found to increase the concentration of this receptor.
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In many cancers, it has been found that various subunits of V-ATPase are upregulated. Upregulation of these subunits appears to be correlated with increased tumor cell metastasis and reduced clinical outcome. Bafilomycin application has been shown to reduce cell growth in various cancer cell lines across multiple cancer types by induction of apoptosis. Additionally, in vitro bafilomycin's anti-proliferative effect appears to be specific to cancer cells over normal cells, which is seen with selective inhibition of hepatoblastoma cell growth compared to healthy hepatocytes.
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Pregnancy-associated hormones such as hCG and sex steroids regulate numerous biological processes in the maternal system prior to and during pregnancy. The embryo orchestrates biological changes that occur in both the embryo and the mother. The embryo upregulates hCG, drives growth of the cell, and upregulates P4 production driving development. hCG and P4 direct changes in the mother to enable successful pregnancy (see below) via upregulation of specific hormones that act to direct both endocrinological and biological changes within the mother for successful pregnancy.
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OECs are similar to Schwann cells in that they provide an upregulation of low-affinity NGF receptor p75 following injury; however, unlike Schwann cells they produce lower levels of neurotrophins. Several studies have shown evidence of OECs being able to support regeneration of lesioned axons, but these results are often unable to be reproduced. Regardless, OECs have been investigated thoroughly in relation to spinal cord injuries, amyotrophic lateral sclerosis, and other neurodegenerative diseases. Researchers suggest that these cells possess a unique ability to remyelinate injured neurons.
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Histone deacetylases, such as HDAC11, control DNA expression by modifying the core histone octamers that package DNA into dense chromatin structures and repress gene expression.[supplied by OMIM] HDAC11 expression is normally found in brain and testis tissue, but upregulation of HDAC11 expression has also been seen in various cancer cells. HDAC11 has been shown to be a negative regulator of IL-10 production in antigen presenting cells. It has also been shown that inhibition of HDAC11 results in increased expression of OX40L in Hodgkin lymphoma cells.
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Furthermore, an absence of ZNF238 results in upregulation of the epithelial- mesenchymal transition process. In tumors such as medulloblastomas, the loss of ZNF238 can disorganize the tumor's cellular divisional processes, resulting in a cellularly diverse neoplasm. This new diversity has been observed to increase the invasiveness of the tumor, yielding proliferation into more areas of the brain than before the loss of ZNF238. C2H2-type zinc finger proteins, such as ZNF238, act on the molecular level as transcriptional activators or repressors and are involved in chromatin assembly.
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Upregulation of AMPARs and/or the increase of presynaptic release are known to contribute to synaptic potentiation and behavioral learning, while postsynaptic NMDA receptors are not significantly affected. Unlike in learning and memory, Zhuo found that cortical synapses and circuits are undergoing dramatic changes after peripheral never injury. In addition to postsynaptic AMPARs, Min found that NMDA receptors are significantly increased in the ACC as well as insular cortex. Inhibiting NMDA NR2B receptors in these brain areas produced significant analgesic effects in animal models of neuropathic pain.
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Additionally, upregulation of the glyoxylate cycle has been seen for pathogens that attack humans. This is the case for fungi such as Candida albicans, which inhabits the skin, mouth, GI tract, gut and vagina of mammals and can lead to systemic infections of immunocompromised patients; as well as for the bacterium Mycobacterium tuberculosis, the major causative agent of tuberculosis. In this latter case, ICL has been found to be essential for survival in the host. Thus, ICL is a current inhibition target for therapeutic treatments of tuberculosis.
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Interferon lambda 4 (gene symbol: IFNL4) is one of the most recently discovered human genes and the newest addition to the interferon lambda protein family. This gene encodes the IFNL4 protein, which is involved in immune response to viral infection. IFNL4 is similar to three neighboring genes (IFNL1, IFNL2 and IFNL3) in that proteins encoded by these genes bind to a shared co-receptor complex. Formation of this complex leads to activation of the JAK-STAT signalling pathway and upregulation of numerous interferon- stimulated genes.
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Cdc14 activity also leads to the stabilization of the transcription factor Swi5, leading to an upregulation of Sic1 transcription. It is possible that Cdc14 acts as a phosphatase on all Clb-Cdk1 targets, acting to reverse the effects of the mitotic cyclins. The targets of Cdc14 are apparently quite diverse. Yeast two-hybrid and affinity capture methods have identified many proteins that potentially interact with ScCdc14, including those known to regulate the cell cycle and DNA replication, or that associate with the spindle or kinetochore.
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During transmission to the mammalian host, when the nymphal tick begins to feed and the spirochetes in the midgut begin to multiply rapidly, most spirochetes cease expressing OspA on their surfaces. Simultaneous with the disappearance of OspA, the spirochete population in the midgut begins to express an OspC and migrates to the salivary gland. Upregulation of OspC begins during the first day of feeding and peaks 48 hours after attachment. The OspA and OspB genes encode the major outer membrane proteins of B. burgdorferi.
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Furthermore, knockout of HDAC2 in mice helps lower alcohol dependence behaviors. The same pattern of HDAC expression is seen in alcohol withdrawal, but acute alcohol exposure has the opposite effect; in vivo, HDAC expression and histone acetylation markers are decreased in the amygdala. Dysregulation of HDACs is significant because it can cause upregulation or downregulation of genes that have important downstream effects both in alcohol dependence and anxiety-like behaviors, and the interaction between the two. A key example is BDNF (see "BDNF" below).
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While the effect of editing on protein function is unknown, the developmental increase in editing does correspond to changes in function of the GABAA receptor. GABA binding leads to chloride channel activation, resulting in rapid increase in concentration of the ion. Initially, the receptor is an excitatory receptor, mediating depolarisation (efflux of Cl− ions) in immature neurons before changing to an inhibitory receptor, mediating hyperpolarisation (influx of Cl− ions) later on. GABAA converts to an inhibitory receptor from an excitatory receptor by the upregulation of KCC2 cotransporter.
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Few of the known signaling molecules and their effects are understood in the context of reactive astrocytes responding to different degrees of insult. Upregulation of GFAP, which is induced by FGF, TGFB, and ciliary neurotrophic factor (CNTF), is a classic marker for reactive gliosis. Axon regeneration does not occur in areas with an increase in GFAP and vimentin. Paradoxically, an increase in GFAP production is also specific to the minimization of the lesion size and reduction in the risk for autoimmune encephalomyelitis and stroke.
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This snail has been studied in relation to human pathology and the epidemiology of schistosomiasis. S. masoni is known to change its host’s (B. glabrata's) behavior via the upregulation/downregulation of neuropeptides such as schistosomin and NPY, and some studies have reported that FMRFamide is aminergic, and may be implicated in the secretion of molecules to respond to infection with parasites. The ganglionic central nervous system (CNS) of B. glabrata consists of paired cerebral, pedal, pleural, parietal, and buccal ganglia, and one unpaired visceral ganglion.
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A second study from 2020 determined this upregulation also had a positive effect on the activation of the ERK/MAPK pathway. In hepatocellular carcinoma, ostersarcoma, lung adenocarcinoma, and muscle- invasive bladder cancer, overexpression of BZW2 lead to overactivation of the AKT/mTOR signaling pathway by increasing phosphorylation of AKT and mTOR. The AKT/mTOR pathway is an important intracellular signaling pathway that regulates the cell cycle. When the pathway activity is increased, cells proliferated at a higher rate and apoptosis decreases, leading to tumor growth.
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Dopamine supersensitivity psychosis may occur due to upregulation of dopamine 2 receptors (D2). The D2 receptor is the primary target of almost all antipsychotics, which oppose the action of the neurotransmitter dopamine at this receptor. The antagonizing or "blockade" of D2 by antipsychotics may cause neurons, a type of cell within the brain, to undergo compensatory changes to make up for the loss of activity at D2 receptors. The D2 signaling pathway within neurons is complex, and involves multiple enzymes and other secondary messengers.
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Alternatively, a proto-oncogene is fused to a strong promoter, and thereby the oncogenic function is set to function by an upregulation caused by the strong promoter of the upstream fusion partner. The latter is common in lymphomas, where oncogenes are juxtaposed to the promoters of the immunoglobulin genes. Oncogenic fusion transcripts may also be caused by trans-splicing or read- through events. Since chromosomal translocations play such a significant role in neoplasia, a specialized database of chromosomal aberrations and gene fusions in cancer has been created.
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The study found that 228 miRNAs were expressed differently relative to normal pancreatic cells. Included in the findings was an association between hepatocellular carcinoma and the upregulation of miR-92a, a member of OncomiR-1. Extracellular microRNAs (exRNAs) may also be useful in clinical cancer detection. For example, in a study of cancer patients with a type of lymphoma called diffuse large B-cell lymphoma (DLBCL), serum levels of three miRNA's, miR-21, miR-155 and miR-210, were higher in cancer patients than in healthy controls.
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Detection of these signals in infected cells leads to an activation of effector-triggered immunity (ETI), a type of innate immune response. Both the pattern recognition immunity (PTI) and effector-triggered immunity (ETI) result from the upregulation of multiple defense mechanisms including defensive chemical signaling compounds. An increase in the production of salicylic acid (SA) has been shown to be induced by pathogenic infection. The increase in SA results in the production of pathogenesis related (PR) genes which ultimately increase plant resistance to biotrophic and hemibiotrophic pathogens.
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Changes in expression of potassium channels and of potassium currents have been described in a model of temporal lobe epilepsy. In this model, there is downregulation of the A-type encoding Kv4.2 channel. This channel is involved in limiting backpropagation of action potentials and in reducing the transfer of excitatory postsynaptic potentials (EPSPs) from apical dendrites into the soma. In the same model, the aforementioned upregulation of t-type calcium channels also has been shown to result in increased burst behavior in neurons in the hippocampus.
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It has been shown that activation of NPSR by NPS affects both gastrointestinal motility and mucosal permeability simultaneously. Aberrant signaling and upregulation of NPSR1 could potentially exacerbate dysmotility and hyperpermeability by local mechanisms in gastrointestinal functional and inflammatory reactions. The very rare NPSR mutation Y206H, which makes the receptor more sensitive to NPS, is found in human families that need less sleep time than normal ones. It has similar effects in transgenic mice, making them resistant to memory impairment caused by lack of sleep.
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Primary research data suggests that cigarette smoke promotes the dysregulation of a number of miRNA's. One such study showed that cigarette smoke downregulates miR-16, miR-21, and miR-146a in the placenta. A downregulation of miR-16 is predicted to inhibit apoptosis via the subsequent upregulation of BCL2L2 and EDA, both of which contribute to anti-apoptotic signaling. Downregulaton of miR-146a is predicted to influence the expression of TRAF6, which has a number of downstream effects, including regulation of inflammatory responses and anti-apoptotic signaling.
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In A. fischeri, there are two primary quorum sensing systems, each of which respond to slightly different environments. The first system is commonly referred to as the lux system, as it is encoded within the lux operon, and uses the autoinducer 3OC6-HSL. The protein LuxI synthesizes this signal, which is subsequently released from the cell. This signal, 3OC6-HSL, then binds to the protein LuxR, which regulates the expression of many different genes, but is most known for upregulation of genes involved in luminescence.
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There is also differences that occur in the signaling pathways of these two pathways that makes them noticeably different. It is well established that insulin-like growth factor (IGF) signaling is important for cell responses such as mitogenesis, cell growth, proliferation, angiogenesis, and differentiation. IGF1 and IGF2 increase the production of ECs in EB. A method that IGF employs to increase vasculogenesis is upregulation of VEGF. Not only is VEGF critical for mesoderm cells to become an EC, but also for EPCs to differentiate into mature endothelium.
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Furthermore, GBM exhibits numerous alterations in genes that encode for ion channels, including upregulation of gBK potassium channels and ClC-3 chloride channels. By upregulating these ion channels, glioblastoma tumor cells are hypothesized to facilitate increased ion movement over the cell membrane, thereby increasing H2O movement through osmosis, which aids glioblastoma cells in changing cellular volume very rapidly. This is helpful in their extremely aggressive invasive behavior because quick adaptations in cellular volume can facilitate movement through the sinuous extracellular matrix of the brain.
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Increasing evidence points to various mental health disorders as a neurophysiological problem which inhibits neuronal plasticity. This is called the neurogenic hypothesis of depression. It promises to explain pharmacological antidepressant action, including the time lag from taking the drug to therapeutic onset, why downregulation (not just upregulation) of neurotransmitters can help depression, why stress often precipitates mood disorders, and why selective modulation of different neurotransmitters can help depression. It may also explain the neurobiological mechanism of other non-drug effects on mood, including exercise, diet and metabolism.
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Genome-wide surveys based on a quadruplex folding rule have been performed, which have identified 376,000 Putative Quadruplex Sequences (PQS) in the human genome, although not all of these probably form in vivo. A similar studies have identified putative G-quadruplexes in prokaryotes. There are several possible models for how quadruplexes could influence gene activity, either by upregulation or downregulation. One model is shown below, with G-quadruplex formation in or near a promoter blocking transcription of the gene, and hence de-activating it.
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This hypoxic environment can be replicated in vitro, resulting in increased expression of ET-2 by breast tumour cells. This increased ET-2 expression provides the tumour with autocrine protection from hypoxia-associated apoptosis allowing growth of the tumour. Further research using mice with breast tumours in hypoxic conditions showed that the addition of ET-2 increased the survival of tumour cells suggesting the upregulation of ET-2 in hypoxic tumours may explain the increased invasive potential and worse prognosis than their well oxygenated counterparts.
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Hybrid male inviability primarily manifests itself during embryonic development and is most pronounced at lower growth temperature. Moreover, surviving C. nigoni/C. briggsae hybrid males are sterile. This sterility is at least partially caused by the presence of either of two X-chromosomal subsequences from C. briggsae, either of which is associated with abnormal transcriptional downregulation of C. nigoni autosomal genes encoding spermatogenic functions; this downregulation may be due to abnormal upregulation in hybrids of a subset of 22G RNAs specifically targeting the down-regulated spermatogenenic genes.
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Cortisol levels were unchanged in the other groups (e.g., orchiectomy, GnRH agonist therapy, and parenteral estrogen therapy) in this study, but increased by 300 to 400% in the oral and synthetic estrogen groups, likely secondary to increases in hepatic corticosteroid-binding globulin (CBG) production and compensatory upregulation of adrenal corticosteroid synthesis. Changes in levels of weak adrenal androgens are of relevance as these androgens serve as circulating reservoir of precursors that are transformed in tissues into potent androgens like testosterone and dihydrotestosterone and into estrogens.
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Brain-derived neurotrophic factor ;ncRNA: ncRNA that is encoded antisense from an intron within the beta-amyloid cleaving enzyme gene, BACE1, is involved in AD. This ncRNA, BACE1-AS (for antisense), which overlaps exon 6 of BACE1, is involved in increasing the stability of the BACE1 mRNA transcript. As that gene's name suggests, BACE1 is an enzymatic protein that cleaves the Amyloid Precursor Protein into the insoluble amyloid beta form, which then aggregates into senile plaques. With increased stability of BACE1 mRNA resulting from BACE1-AS, more BACE1 mRNA is available for translation into BACE1 protein. ;miRNA: factors have not consistently been shown to play a role in progression of AD. miRNAs are involved in post-transcriptional gene silencing via inhibiting translation or involvement in RNAi pathways. Some studies have shown upregulation of miRNA-146a, which differentially regulates neuroimmune- related Interleukin-1R associated kinases IRAK1 and IRAK2 expression, in human AD brain, while other studies have shown upregulation or downregulation of miRNA-9 in brain. ;DNA methylation: In Alzheimer’s disease cases, global DNA hypomethylation and gene-specific hypermethylation has been observed, though findings have varied between studies, especially in studies of human brains.
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Collectively, Pitx2 first acts to prevent the apoptosis of the extraocular muscles followed by acting as the myogenic programmer of the extraocular muscle cells. There have also been studies showing different isoforms of the transcription factor: Pitx2a, Pitx2b, and Pitx2c, each with distinct and non-overlapping functions. Studies have shown that in chick embryos , Pitx2 is a direct regulator of cVg1, a growth factor homologous to mammalian GDF1. cVg1 is a Transforming growth factor beta signal that is expressed posteriorly before the formation of the embryo germ layers. The Pitx2 regulation of cVg1 is essential both during normal embryonic development and during establishment of polarity in twins created by experimental division of a single, original embryo. Pitx2 is shown to be essential for upregulation of cVg1 through the binding of enhancers, and is necessary for the proper expression of cVg1 in the posterior marginal zone. Expression of cVg1 in the PMZ is in turn necessary for the proper development of the primitive streak. Experimental knockouts of the PITX2 gene are associated with the subsequent upregulation of related Pitx1, which is able to partially compensate for the loss of Pitx2.
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The three major myelin-associated inhibitory factors are Nogo, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein which all share this trimolecular receptor complex. The inhibitory action is achieved through RhoA-GTP upregulation in response to the presence of MOG, MAG or Nogo-66 in the central nervous system. LINGO-1 also inhibits oligodendrocyte precursor differentiation and myelination, by a mechanism that also involves activation of RhoA, but which apparently does not require p75 or NgR1. LINGO-1 is involved in the regulation of neural apoptosis by inhibiting WNK3 kinase activity.
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Presently there are four known human Piwi proteins—PIWI-like protein 1, PIWI-like protein 2, PIWI-like protein 3 and PIWI-like protein 4. Human Piwi proteins all contain two RNA binding domains, PAZ and Piwi. The four PIWI-like proteins have a spacious binding site within the PAZ domain which allows them to bind the bulky 2’-OCH3 at the 3’ end of piwi-interacting RNA. One of the major human homologues, whose upregulation is implicated in the formation of tumours such as seminomas, is called hiwi (for _h_ uman p _iwi_ ).
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In any case, the levels of most steroid hormones, including testosterone and cortisol, are usually unchanged by spironolactone in humans, which may in part be related to compensatory upregulation of their synthesis. The weak steroidogenesis inhibition of spironolactone might contribute to its antiandrogenic efficacy to some degree and may explain its side effect of menstrual irregularities in women. However, its androgen synthesis inhibition is probably clinically insignificant. Spironolactone has been found in some studies to increase levels of estradiol, an estrogen, although many other studies have found no changes in estradiol levels.
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As an agonist of the GR, MPA has glucocorticoid activity, and as a result can cause symptoms of Cushing's syndrome, steroid diabetes, and adrenal insufficiency at sufficiently high doses. It has been suggested that the glucocorticoid activity of MPA may contribute to bone loss. The glucocorticoid activity of MPA may also result in an upregulation of the thrombin receptor in blood vessel walls, which may contribute to procoagulant effects of MPA and risk of venous thromboembolism and atherosclerosis. The relative glucocorticoid activity of MPA is among the highest of the clinically used progestins.
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Although malignant tumors are known to display extreme heterogeneity, overexpression of SR-B1 is a relatively consistent marker in cancerous tissues. While SR-B1 normally mediates the transfer of cholesterol between high-density lipoproteins (HDL) and healthy cells, it also facilitates the selective uptake of cholesterol by malignant cells. In this way, upregulation of the SR-B1 receptor becomes an enabling factor for self-sufficient proliferation in cancerous tissue. SR-B1 mediated delivery has also been used in the transfection of cancer cells with siRNA, or small interfering RNAs.
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Decreased LINE-1 methylation is a strong predictive indicator of ischemic heart disease and stroke, although the mechanism is unknown. Various impairments in lipid metabolism, leading to clogging of arteries, has been associated with the hypermethylation of GNASAS, IL-10, MEG3, ABCA1, and the hypomethylation of INSIGF and IGF2. Additionally, upregulation of a number of miRNAs has been shown to be associated with acute myocardial infarction, coronary artery disease, and heart failure. Strong research efforts into this area are very recent, with all of the aforementioned discoveries being made since 2009.
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Nerve growth factor levels in inflamed or injured tissues are increased creating an increased sensitivity to pain (hyperalgesia). The increased levels of nerve growth factor and tumour necrosis factor-α (TNF-α) causes the upregulation of Nav1.8 in sensory neurons via the accessory protein p11 (annexin II light chain). It has been shown using the yeast-two hybrid screening method that p11 binds to a 28-amino-acid fragment at the N terminus of Nav1.8 and promotes its translocation to the plasma membrane. This contributes to the hyperexcitability of sensory neurons during pain.
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In the development of tissues in embryos, miRNA can have a role in the upregulation or downregulation of specific muscular development. miRNA-1 plays a role in muscle differentiation between cardiac and skeletal muscle precursor cells. In development, if levels of precursor cells are not properly regulated, it can result in muscular hypoplasia. By creating AMOs for these known miRNAs involved in muscle generation, it is possible to track a miRNA's specific mechanisms throughout the process of muscle generation by essentially using the created AMO to turn off the miRNA.
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SGLT-2 is a member of the glucose transporter family and is a low-affinity, high-capacity glucose transporter. SGLT-2 is mainly expressed in the S-1 and S-2 segments of the proximal renal tubules where the majority of filtered glucose is absorbed. SGLT-2 has a role in regulation of glucose and is responsible for most glucose reabsorption in the kidneys. In diabetes, extracellular glucose concentration increases and this high glucose level leads to upregulation of SGLT-2, leading in turn to more absorption of glucose in the kidneys.
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Bats are the only mammals capable of sustained flight, as opposed to gliding, as in the flying squirrel. The fastest bat, the Mexican free-tailed bat (Tadarida brasiliensis), can achieve a ground speed of . Little brown bat take off and flight The finger bones of bats are much more flexible than those of other mammals, owing to their flattened cross-section and to low levels of calcium near their tips. The elongation of bat digits, a key feature required for wing development, is due to the upregulation of bone morphogenetic proteins (Bmps).
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ClpP protease is a major contributor for mitochondrial protein quality control system and removing damaged or misfolded proteins in mitochondrial matrix. Defects in mitochondrial Clp proteases have been associated with the progression of neurodegenerative diseases while upregulation of ClpP proteases has been implicated in preventing premature aging. Recessive CLPP mutations were recently observed in the human Perrault variant associating with ovarian failure and sensorineural hearing loss, in parallel with growth retardation. The clinical phenotype was accompanied by the accumulation of ClpP associating partner chaperon ClpX, mtRNA, and inflammatory factors.
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Ceruletide upregulates pancreatic acinar cell intercellular adhesion molecule-1 (ICAM-1) proteins through intracellular upregulation of NF-κB. Surface ICAM-1 in turn promotes neutrophil adhesion onto acinar cells enhancing pancreatic inflammation. In addition to promoting the inflammatory cell reaction to acinar cells, ceruletide induces pancreatitis through dysregulation of digestive enzyme production and cytoplasmic vacuolization, leading to acinar cell death and pancreatic edema. Ceruletide also activates NADPH oxidase, a source of reactive oxygen species contributing to inflammation, as well as the Janus kinase/signal transducer, another inflammation inducer.
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For example, neural progenitor cells can be generated from fibroblasts directly through a physical approach without introducing exogenous reprogramming factors. Physical cues, in the form of parallel microgrooves on the surface of cell-adhesive substrates, can replace the effects of small- molecule epigenetic modifiers and significantly improve reprogramming efficiency. The mechanism relies on the mechanomodulation of the cells' epigenetic state. Specifically, "decreased histone deacetylase activity and upregulation of the expression of WD repeat domain 5 (WDR5) – a subunit of H3 methyltranferase – by microgrooved surfaces lead to increased histone H3 acetylation and methylation".
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Wu LJ, Toyoda H, Zhao MG, Lee YS, Tang J, Ko SW, Jia YH, Shum FW, Zerbinatti CV, Bu G, Wei F, Xu TL, Muglia LJ, Chen ZF, Auberson YP, Kaang BK, Zhuo M. (2005). Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation. J Neurosci 25, 11107-11116.Li XY, Ko HG, Chen T, Descalzi G, Koga K, Wang H, Kim SS, Shang Y, Kwak C, Park SW, Shim J, Lee K, Collingridge GL, Kaang BK, Zhuo M. (2010) Alleviating neuropathic pain hypersensitivity by inhibiting PKMzeta in the anterior cingulate cortex.
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As a result, primary breast cancer tumors quickly form metastases in distant sites. Both the epithelial-to-mesenchymal transition (EMT) and the mesenchymal-to-epithelial transition (MET) are key components of driving this metastasis process. As one may expect, BCSCs undergo both of these processes as they escape from the primary tumor site, enter the bloodstream and home to a new organ site to initiate tumor growth. Over the course of this process, there is an upregulation of growth factors, which in turn activate and deactivate mesenchymal and epithelial transcription factors.
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TRPM8 knockout mice not only indicated that TRPM8 is required for cold sensation but also revealed that TRPM8 mediates both cold and mechanical allodynia in rodent models of neuropathic pain. Furthermore, recently it was shown that TRPM8 antagonists are effective in reversing established pain in neuropathic and visceral pain models. TRPM8 upregulation in bladder tissues correlates with pain in patients with painful bladder syndromes. Furthermore, TRPM8 is upregulated in many prostate cancer cell lines and Dendreon/Genentech are pursuing an agonist approach to induce apoptosis and prostate cancer cell death.
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CpG-S sequences induce polyclonal B-cell activation and the upregulation of cytokine expression and secretion. Stimulated macrophages secrete IL-12, IL-18, TNF-α, IFN-α, IFN-β and IFN-γ, while stimulated B-cells secrete IL-6 and some IL-12. Manipulation of CpG-S and CpG-N sequences in the plasmid backbone of DNA vaccines can ensure the success of the immune response to the encoded antigen and drive the immune response toward a TH1 phenotype. This is useful if a pathogen requires a TH response for protection.
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CerS5 sensitizes cells to the chemotherapeutic drugs doxorubicin and vincristine, but not to cisplatin or carboplatin. A splice variant of CerS5 is expressed in lymphoma and other tumor cells and contribute to tumor recognition by the immune system. In response to upregulation of tumor suppressor protein p53, C16-ceramide levels were increased in leukemia and colon cancer cells, as were levels of CerS5 mRNA in the leukemia cells, but not in the colon cancer cells. For this reason, CerS5 looks like a promising target for the regulation of cancer and of cell death pathways.
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As FADD has such an important role in apoptosis, loss of FADD can give cancer cells a proliferative advantage as apoptosis would no longer be induced when the Fas receptors are stimulated. However, there is significant upregulation of FADD in ovarian cancer and head and neck squamous cell carcinoma. It is not yet clear what advantage this has on the cancer cells, but given FADDs roles in cell cycle regulation and cell survival, it likely that it may be related to this. There are also elevated levels of FADD in non small cell lung cancer.
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As a result, a change in supercoiling can result in domain-specific gene expression, depending on the level of supercoiling in each domain. The effect of supercoiling on gene expression can be mediated by NAPs that directly or indirectly influence supercoiling. The effect of HU on gene expression appears to involve a change in supercoiling and perhaps a higher-order DNA organization. A positive correlation between DNA gyrase binding and upregulation of the genes caused by the absence of HU suggests that changes in supercoiling are responsible for differential expression.
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When inactive the progesterone receptor, as for other steroid receptor, forms a complex consisting of itself, heat shock proteins (hsp70, hsp90) and immunophilins. Upon activation, due to hormone binding to ligand binding pocket, the receptor complex has been shown to dissociate, triggering nuclear import and giving the receptor the property of dimerisation (Fig. 3). In the nucleus the dimer interacts with progesterone hormone response element in the DNA causing upregulation or downregulation of the gene. Various studies have demonstrated that it affects expression of up to 100 different genes, depending on receptor isomer.
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In platelets, conditional knockout of talin-1 results in the inability to activate integrins in response to platelet agonists, resulting in mice with severe hemostatic defects and resistance to arterial thrombosis. Conditional knockout of talin-1 in cardiomyocytes shows that mice have normal cardiac function at baseline, but improved function, blunted hypertrophy, and attenuated fibrosis when subjected to pressure overload-induced cardiac hypertrophy, which correlated with blunted ERK1/2, p38, Akt, and glycogen synthase kinase 3 responses. These data suggest that upregulation of talin-1 in cardiac hypertrophy may be detrimental to cardiomyocytes function.
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4-OH-E2, like 2-OH-E2, can be physiologically active as well as tumorigenic. 4-OH-E2 is capable of binding ER with a reduced dissociation rate and prolonged activation, thereby inducing cellular growth and proliferation, adenohypophyseal hormone secretion, and prostaglandin production. Das et al. implicated 4-OH-E2 in the induction of estrogen-responsive genes, a response that exhibited partial or no abrogation by coadministration with an antiestrogen, providing evidence for the ability of 4-OH-E2 to carry out genetic upregulation via a pathway independent of ER signalling.
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Because the blocking procedure is safe and minimally invasive, this treatment is used for a multitude of sympathetic mediated pain disorders, including complex regional pain syndrome (CRPS) that causes dysregulation of the central and autonomic nervous system. This causes an upregulation of pain and temperature control to the extremity that is affected. However, the patient could experience an allergic reaction to the medications given during the procedure if the patient has uncontrolled diabetes, poorly controlled heart problems, or is under other medications. Managing neuropathic pain is another use for a lumbar sympathetic block.
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Upregulation of PDE5 gene expression has been observed in animal models of pulmonary hypertension, and is thought to contribute to vasoconstriction in the lung. Several randomised controlled trials investigating PDE5 inhibitors use in pulmonary arterial hypertension, a subtype of pulmonary hypertension, have demonstrated their potent effects in reducing pulmonary hypertension and vascular remodelling and improving symptoms and mortality in patients with the condition. Long-term treatment with a PDE5 inhibitor has been shown to enhance natriuretic peptide-cGMP pathway, downregulate Ca2+ signaling pathway and alter vascular tone in pulmonary arteries in rat models.
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However, in some settings ILC2s can produce IL-5 promoting a cytotoxic response from eosinophils and therefore an anti-tumor response. ILC3s can also be involved in pro or anti-tumorigenic environments. The production of IL-17 can support the growth of tumors and metastasis since it induces blood vessel permeability, however, the upregulation of MHC Class II on their surface can prime CD4+ T cells, having an anti-tumorigenic effect. In addition, ILC3s have been reported to promote the formation of tertiary lymphoid structures in lung cancer, playing a protective role.
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The frequency of ILC2s is higher in the inflamed skin of patients with atopic dermatitis than in healthy patients. The ILC2s from the skin of the patients had upregulation of the IL-25, IL-33, TSLP and PGD2 receptors, suggesting their role in the activation of ILC2s. Basophils and mast cells are also present in these skin lesions, producing IL-4, and PGD2, further activating ILC2s. The ILCs present in the epidermis of patients with psoriasis, and the effector cytokines and cells involved in causing inflammation/ epidermal thickening.
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Over time, the proteostasis network becomes burdened with proteins modified by reactive oxygen species and metabolites that induce oxidative damage. These byproducts can react with cellular proteins to cause misfolding and aggregation (especially in nondividing cells like neurons). This risk is particularly high for intrinsically disordered proteins. The IGFR-1 pathway has been shown in C. elegans to protect against these harmful aggregates, and some experimental work has suggested that upregulation of insulin growth factor receptor 1 (IGFR-1) may stabilize proteostatic network and prevent detrimental effects of aging.
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Injury to sensory nerves induces neurochemical, physiological, and anatomical modifications to afferent and central neurons, such as afferent terminal sprouting and inhibitory interneuron loss. Following nerve damage, NaCl channel accumulation causes hyperexcitability, and downregulation of the TTX-resistant Nav1.8 (sensory neuron specific, SNS1) channel and upregulation of TTX-sensitive Nav1.3 (brain type III) and TRPV1 channels. These changes contribute to increased NMDA glutamate receptor-dependent excitability of spinal dorsal horn neurons and are restricted to the ipsilateral (injured) side. A combination of these factors could contribute to the neuropathic pain state of postherpetic neuralgia.
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The addition of rate-limiting nutrients promotes the microbe's biodegrading pathways, including upregulation of genes encoding multiple alkane hydroxylases that oxidize various lengths of linear alkanes. These enzymes essentially remove the problematic hydrocarbon constituents of petroleum oil while A. borkumensis simultaneously increases synthesis of anionic glucoproteins, which are used to emulsify hydrocarbons in the environment and increase their bioavailability. The presence of crude oil along with appropriate levels of nitrogen and phosphor catalyzes the removal of petroleum either by mechanisms that enhance the efficiency of substrate uptake or by direct biodegradation of aliphatic chains.
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These three Chlorella-specific hexose-proton symporter (HUP)-like genes, in addition to rapid pyruvate synthesis, fatty acid synthesis enzyme upregulation, and fatty acid degradation enzyme downregulation, contribute to the high lipid content. The algae have also been shown to grow on plethora of media, including glycerol, glucose, and acetate.Gill,Saba Shahid; Mehmood, Muhammad Aamer; Rashid, Umer; Ibrahim, Muhammad; Saqib, Anam and Rizwan, Muhammad "Waste-water treatment coupled with biodiesel production using microalgae: a bio-refinery approach." Pakistan Journal of Life and Social Sciences 11.3 (2013): 179-189.
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Altered expression profiles in beta-catenin have been associated with dilated cardiomyopathy in humans. Beta-catenin upregulation of expression has generally been observed in patients with dilated cardiomyopathy. In a particular study, patients with end-stage dilated cardiomyopathy showed almost doubled estrogen receptor alpha (ER-alpha) mRNA and protein levels, and the ER-alpha/beta-catenin interaction, present at intercalated discs of control, non-diseased human hearts was lost, suggesting that the loss of this interaction at the intercalated disc may play a role in the progression of heart failure.
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The close interaction of mTOR with the PI3K pathway has also led to the development of mTOR/PI3K dual inhibitors. Compared with drugs that inhibit either mTORC1 or PI3K, these drugs have the benefit of inhibiting mTORC1, mTORC2, and all the catalytic isoforms of PI3K. Targeting both kinases at the same time reduces the upregulation of PI3K, which is typically produced with an inhibition on mTORC1. The inhibition of the PI3K/mTOR pathway has been shown to potently block proliferation by inducing G1 arrest in different tumor cell lines.
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As a result of having apoptosis being suppressed, it provides M. tuberculosis with a safe replicative niche, and so the bacteria is able to maintain a latent state for a prolonged period of time.Aberdein, J. D., Cole, J., Bewley, M. A., Marriott, H. M. & Dockrell, D. H. Alveolar macrophages in pulmonary host defence the unrecognized role of apoptosis as a mechanism of intracellular bacterial killing. Clin Exp Immunol 174, 193–202, (2013). Protective granulomas are formed due to the production of cytokines and upregulation of proteins involved in recruitment.
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Another common cause of being intersex is the crossing over of the SRY from the Y chromosome to the X chromosome during meiosis. The SRY is then activated in only certain areas, causing development of testes in some areas by beginning a series of events starting with the upregulation of SOX9, and in other areas not being active (causing the growth of ovarian tissues). Thus, testicular and ovarian tissues will both be present in the same individual. Fetuses before sexual differentiation are sometimes described as female by doctors explaining the process.
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Structure of amiloride, a channel blocker ENaC interaction with CFTR is of important pathophysiological relevance in cystic fibrosis. CFTR is a transmembrane channel responsible for chloride transport and defects in this protein cause cystic fibrosis, partly through upregulation of the ENaC channel in the absence of functional CFTR. In the airways, CFTR allows for the secretion of chloride, and sodium ions and water follow passively. However, in the absence of functional CFTR, the ENaC channel is upregulated, and further decreases salt and water secretion by reabsorbing sodium ions.
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As such, the respiratory complications in cystic fibrosis are not solely caused by the lack of chloride secretion but instead by the increase in sodium and water reabsorption. This results in the deposition of thick, dehydrated mucus, which collects in the respiratory tract, interfering with gas exchange and allowing for the collection of bacteria. Nevertheless, an upregulation of CFTR does not correct the influence of high-activity ENaC. Probably other interacting proteins are necessary to maintain a functional ion homeostasis in epithelial tissue of the lung, like potassium channels, aquaporins or Na/K-ATPase.
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Among PD-L1 functions is a key regulatory role on T cell activities. It appears that (cancer-mediated) upregulation of PD-L1 on the cell surface may inhibit T cells that might otherwise attack. Antibodies that bind to either PD-1 or PD-L1 and therefore block the interaction may allow the T-cells to attack the tumor. The discoveries in basic science allowing checkpoint inhibitor therapies led to James P. Allison and Tasuku Honjo winning the Tang Prize in Biopharmaceutical Science and the Nobel Prize in Physiology or Medicine in 2018.
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An inflammatory cytokine is a type of cytokine (a signaling molecule) that is secreted from immune cells and certain other cell types that promotes inflammation. Inflammatory cytokines are predominantly produced by T helper cells (Th) and macrophages and involved in the upregulation of inflammatory reactions. Therapies to treat inflammatory diseases include monoclonal antibodies that either neutralize inflammatory cytokines or their receptors. Inflammatory cytokines include interleukin-1 (IL-1), IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte- macrophage colony stimulating factor (GM-CSF).
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Lineage commitment occurs at the late stage of positive selection and works by downregulation of both CD4 and CD8 (reducing the signal from the T cell receptor) and then upregulation of CD4 only. Thymocytes that start receiving signal again are those that recognise MHC class II, and they become CD4+ T cells. Thymocytes that do not start receiving signal again are those that recognize MHC class I, and they downregulate CD4 and upregulate CD8, to become CD8+ T cells. Both of these thymocytes types are known as single positive thymocytes.
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Moreover, the enzyme participates in inflammatory and apoptotic processes in extracellular settings. In the presence of reactive oxygen species (ROS), vascular smooth muscle cells (VSMCs), monocytes/macrophages, and endothelial cells (ECs) secrete PPIA to induce an inflammatory response and mitigate tissue injury. PPIA may also activate Akt and NF-κB signaling, resulting in the upregulation of Bcl-2, an antiapoptotic protein, and thus preventing apoptosis in ECs in response to oxidative stress. PPIA may also regulate ERK1/2, JNK, p38 kinase, Akt, and IκB signalling pathways through activating the CD147 receptor.
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Allele frequency of exon 3 and exon 6 splice at an alliance mutation were analyzed to be similar in African American and mende tribe and was absent in Caucasians. Exon 6–splice donor being heterozygotes, fat oxidation rates was reduced by 50%, initiating a role for UCP3 in metabolic fuel partitioning. UCP3 (uncoupling protein) deliberates the hypoxia resistance to the renal epithelial cells and its upregulation in renal cell carcinoma. The energy consumption of modulated and the association of -55CT polymorphism of UCP3 with the body weight and in type 2 diabetic patients.
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The heat shock protein, HSP60 is also known to be a target for post- transcriptional regulation by miR-1 and miR-206. HSP60 is a component of the defence mechanism against diabetic myocardial injury and its level is reduced in the diabetic myocardium. In both in vivo and in vitro experiments increased levels of glucose in myocardiomyctes led to significant upregulation of miR-1 and miR-206 with resulting modulation of HSP60 leading to accelerated glucose- mediated apoptosis in cardiomyocytes. MiR-1 has key roles in the development and differentiation of smooth and skeletal muscles.
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In experiments conducted by Doyle et al., it was found that MCF-7, a breast adenomacarcinoma cell line, did not express the H19 gene; however a subline of MCF-7 with a multidrug resistance phenotype, MCF-7/AdrVp, had upregulation of H19. Curiously, mutant revertant MCF-7/AdrVp cells that lost their multidrug resistance and became drug- sensitive also lost H19 expression. Drug-resistant MCF-AdrVp cells do not overexpress P-glycoprotein, a cell membrane efflux pump commonly found in multidrug resistant cells; instead, they overexpress a 95kD membrane glycoprotein p95.
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Among the many other observed defects, EVI1−/− mouse embryos have been shown to have defects in both the development and proliferation of hematopoietic stem cells (HSCs). It is presumed that this is due to direct interaction with the transcription factor GATA-2, which is crucial for HSC development. It has subsequently been shown many times in vitro that EVI1 upregulation can induce proliferation and differentiation of HSCs and some other cell types such as rat fibroblasts. However, existing data is inconclusive regarding the absolute role of EVI1 in cell cycle progression.
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A recent report by the research group which first found that the over-expression of FOXM1 is associated with human cancer, showed that aberrant upregulation of FOXM1 in adult human epithelial stem cells induces a precancer phenotype in a 3D-organotypic tissue regeneration system - a condition similar to human hyperplasia. The authors showed that excessive expression of FOXM1 exploits the inherent self-renewal proliferation potential of stem cells by interfering with the differentiation pathway, thereby expanding the progenitor cell compartment. It was therefore hypothesized that FOXM1 induces cancer initiation through stem/progenitor cell expansion.
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One study examined the in vitro effects of pressure on global gene transcription using a microarray approach and a cell stretching system meant to simulate intraocular pressure in the lamina cribosa (connective tissue) of the optic nerve head. Their findings were that perlecan and several other proteoglycans were upregulated in response to the stretching stimulus. TGF-β2 and VEGF were induced as well, possibly contributing to the upregulation of the perlecan transcript and protein. It has been shown that autocrine TGF-β signaling is a compensatory result of mechanical stress in vitro in endothelial cells.
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Alzheimer's disease (AD) is a neurodegenerative disease resulting from synaptic plasticity failure. BC200 RNA plays a role in the dendrites of neurons thought to modulate synthesis of proteins that influence this plasticity. Researchers posit that upregulation of BC200 RNA results in an inadequate delivery of RNA to the neuronal synapses, thus resulting in neurodegeneration. In comparing healthy brains with those with AD, it was determined that BC200 RNA is upregulated in the brains of people with AD, most notably in areas of the brain that correspond to the disease.
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Highly Up-regulated in liver cancer (HULC) is one of the most upregulated of all genes in hepatocellular carcinoma. CREB (cAMP response element binding protein) has been implicated in the upregulation of HULC. HULC RNA inhibits miR-372 activity through a ceRNA function, leading to derepression of one of its target genes, PRKACB, which can then induce the phosphorylation and activation of CREB. Overall, HULC lncRNA is part of a self-amplifying autoregulatory loop in which it sponges miR-372 to activate CREB, and in turn upregulates its own expression levels.
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The Notch (N) gene expression precedes an upregulation of Dll in the cells that will become the center of the focus. This makes N the earliest developmental signal, so far studied, that is related with the establishment of the eyespots. Loss of N completely disrupts Dll expression, and eventually eyespot formation, in several butterfly species. A variety of other wing patterns are determined by N and Dll patterns of expression in early development of the wing imaginal disc, suggesting that a single mechanism patterns multiple coloration structures of the wing.
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The molecular basis for LTP has been extensively studied, and AMPARs have been shown to play an integral role in the process. Both GluR1 and GluR2 play an important role in synaptic plasticity. It is now known that the underlying physiological correlate for the increase in EPSP size is a postsynaptic upregulation of AMPARs at the membrane, which is accomplished through the interactions of AMPARs with many cellular proteins. The simplest explanation for LTP is as follows (see the long-term potentiation article for a much more detailed account).
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At infection of an orchid by a mycorrhizal fungus both partners are altered considerably to allow for nutrient transfer and symbiosis. Nutrient transfer mechanisms and the symbiotic mycorrhizal peloton organs start to appear only shortly after infection around 20–36 hours after initial contact. There is significant genetic upregulation and downregulation of many different genes to facilitate the creation of the symbiotic organ, and the pathways with which nutrients travel. As the fungus enters the parenchyma cells of the orchid the plasma membrane invaginates to facilitate fungal infection and growth.
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In cells lacking TGF-β receptors, a deficiency that is characteristic of lung cancer, lysyl oxidase is found in high concentrations. LOX immunostaining has revealed that high LOX expression is associated with high extent of carcinoma invasion in samples obtained from surgically removed lung adenocarcinomas. Additionally, LOX expression is an indicator of 5-year survival in patients, with a 71% chance of survival for patients with low LOX levels, compared to 43% for patients with high LOX levels. Thus, upregulation of lysyl oxidase is a predictor of poor prognosis in early-stage adenocarcinoma patients.
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2013, polyketal nanoparticles were used as a delivery vehicle for siRNA to target and inhibit Nox2 in the infarcted heart. Following intramyocardial injection in vivo, Nox2-siRNA nanoparticles prevented upregulation of Nox2-NADPH oxidase, and improved fractional shortening. When taken up by macrophages in the myocardium following a MI, the nanoparticles degraded in the acidic environment of the endosomes/phagosomes, releasing Nox2-specific siRNA into the cytoplasm. Polyketal nanoparticles have also been used in the infarcted mouse heart to prevent ischemia-reperfusion injury caused by reactive oxygen species (ROS).
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This gene encodes a type II classical cadherin from the cadherin superfamily, integral membrane proteins that mediate calcium-dependent cell- cell adhesion. Mature cadherin proteins are composed of a large N-terminal extracellular domain, a single membrane-spanning domain, and a small, highly conserved C-terminal cytoplasmic domain. Type II (atypical) cadherins are defined based on their lack of a HAV cell adhesion recognition sequence specific to type I cadherins. Expression of this particular cadherin in osteoblastic cell lines, and its upregulation during differentiation, suggests a specific function in bone development and maintenance.
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Upregulation of BiP has been associated with ER stress-induced cardiac dysfunction and dilated cardiomyopathy. BiP also has been proposed to suppress the development of atherosclerosis through alleviating homocysteine-induced ER stress, preventing apoptosis of vascular endothelial cells, inhibiting the activation of genes responsible for cholesterol/triglyceride biosynthesis, and suppressing tissue factor procoagulant activity, all of which can contribute to the buildup of atherosclerotic plaques. Some anticancer drugs, such as proteasome inhibitors, have been associated with heart failure complications. In rat neonatal cardiomyocytes, overexpression of BiP attenuates cardiomyocyte death induced by proteasome inhibition.
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CD32A is known to aid in the activation of clathrin coat-mediated endocytosis on various cell types. On DCs, CD32A plays an important role in maturation and the upregulation of costimulatory molecules on the cell surface, strengthening the DC's ability to present antigen to T cells. CD32A activation is necessary and sufficient to produce T cell anti-tumor cellular immunity. CD32A is also linked to autoimmunity; for example, the production of antibodies against platelet factor 4 (PF4) bound to CD32A is linked to the development of heparin-induced thrombocytopenia.
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Additionally, uptake of IGF-1 stimulates the mTOR pathway, which activates protein synthesis (and therefore growth) through upregulation of the translation-promoting S6K1, and also inhibits autophagy, a process necessary for recycling of damaged cellular products. Decline of autophagy causes neurodegeneration, protein aggregation and premature aging. Lastly, studies have also indicated that the mTOR pathway also alters immune responses and stimulates cyclin-dependent kinase (CDK) inhibitors such as p16 and p21. This leads to alteration of the stem-cell niche and results in stem cell exhaustion, another theorized mechanism of aging.
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The in-growth of new blood vessels is mediated by the upregulation of angiogenic cytokines. The enzyme metalloproteinase degrades the cornea's basement membrane and extracellular matrix, while proteolytic enzymes allow vascular epithelial cells to enter the stromal layer of the cornea. When ocular inflammation occurs, corneal epithelial and endothelial cells, macrophages and certain inflammatory cells produce angiogenic growth factors, namely vascular endothelial growth factor (VEGF) and fibroblast growth factors. VEGF paves the way for new blood vessel formation by upregulating matrix metalloproteinases production by endothelial cells in the limbal vascular plexus.
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Cyclooxygenases blocking by lornoxicam in acute stage of inflammation reduced the frequency of membrane formation by 43% in the dispase model of PVR and by 31% in the concanavalin one. Lornoxicam not only normalized the expression of cyclooxygenases in both models of PVR, but also neutralized the changes of the retina and the choroid thickness caused by the injection of pro-inflammatory agents. These facts underline the importance of cyclooxygenases and prostaglandins in the development of PVR. PTGS2 gene upregulation has also been linked with multiple stages of human reproduction.
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Kv1.3 plays an important role in microglial activation. ShK-223, an analogue of ShK-186, decreased lipopolysaccharide (LPS) induced focal adhesion formation by microglia, reversed LPS-induced inhibition of microglial migration, and inhibited LPS-induced upregulation of EH domain containing protein 1 (EHD1), a protein involved in microglia trafficking. Increased Kv1.3 expression was reported in microglia in Alzheimer plaques. Kv1.3 inhibitors may have use in the management of Alzheimer's disease, as reported in a proof-of-concept study in which a small molecule Kv1.3 blocker (PAP-1) alleviated Alzheimer's disease-like characteristics in a mouse model of AD.
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The peripherin gene is transcriptionally activated in both small and large sized sensory neurons of the dorsal root ganglion at about day E10, and mRNA is present in these cells after postnatal day 2 and throughout adulthood. Post transcriptional mechanisms reduce detectable peripherin to only the small sized cells; however, crushing of the peripheral processes in dorsal root ganglion neurons lead to mRNA and detectable peripherin in the large sized cells. The proinflammatory cytokines, interleukin-6 and leukemia inhibitory factor, can also induce peripherin expression through the JAK-STAT signaling pathway. This specific upregulation is linked to neuronal regeneration.
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Plexin A4 binds to neuropilin 1 (Nrp1) and neuropilin 2 (Nrp2) and transduces signals from Sema3A, Sema6A, and Sema6B. These Nrp-plexin and semaphorin complexes initiate cascades that regulate diverse processes such as axon pruning and repulsion, dendritic attraction and branching, regulation of cell migration, vascular remodeling, and growth cone collapse. Both upregulation and downregulation of Plexin A4 has been observed following neural injury suggesting a dynamic role for Sema3A and Plexin A4 in neural maintenance and regeneration. Additionally, Sema3A and therefore its receptor, Plexin A4, have been implicated as possible components of fast-fatigable muscle fiber denervation in ALS.
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As a prebiotic fermentable fiber, its metabolism by gut flora yields short-chain fatty acids (see below) which increase absorption of calcium, magnesium, and iron, resulting from upregulation of mineral-transporting genes and their membrane transport proteins within the colon wall. Among other potential beneficial effects noted above, inulin promotes an increase in the mass and health of intestinal Lactobacillus and Bifidobacterium populations. Inulin's primary disadvantage is its tolerance. As a soluble fermentable fiber, it is quickly and easily fermented within the intestinal tract, which may cause gas and digestive distress at doses higher than 15 grams/day in most people.
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This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve, is common in exocrine glands and in the CNS. It is predominantly found bound to G proteins of class Gq, which use upregulation of phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway. A receptor so bound would not be susceptible to CTX or PTX. However, Gi (causing a downstream decrease in cAMP) and Gs (causing an increase in cAMP) have also been shown to be involved in interactions in certain tissues, and so would be susceptible to PTX and CTX, respectively.
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It has been observed that the development of hormone resistance in prostate cancer may be due to the upregulation of antiapoptotic genes, one of which is survivin. Zhang et al. hypothesize that, if survivin is a significant contributor to the development of hormonal therapy resistance in prostate cancer cells, targeting survivin and blocking it would enhance prostate cancer cell susceptibility to anti-androgen therapy. (Anti-androgen therapy uses drugs to eliminate the presence of androgens in the cell and cellular environment, since such androgens are known to enhance tumour immortality in prostate cancer cells.) Zhang et al.
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While extracellular amyloid beta (Aβ) plaques, neurofibrillary tangles (NFT), inflammation in the form of reactive astrocytes and microglia, and neuronal loss are all consistent pathological features of Alzheimer's disease (AD), a mechanistic link between these factors is yet to be clarified. Although the majority of past research has focused on fibrillar Aβ, soluble oligomeric Aβ species are now considered to be of major pathological importance in AD. Upregulation of GSH may be protective against the oxidative and neurotoxic effects of oligomeric Aβ. Depletion of the closed form of GSH in the hippocampus may be a potential early diagnostic biomarker for AD.
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The earlier expression response of leptins in common carp likely reflects the higher temperature under which the experiments were conducted, but contrasts the findings of upregulation of lepa1 due to the absence of food. Similarly, in mice, a postprandial increase in hepatic leptin expression has also been reported. However, in grass carp, intraperitoneal injection of recombinant leptin only alters the appetite on the first day, and does not influence food intake during the ensuing 12 days. At present, the data for Atlantic salmon are therefore quite different and suggest that leptin expression in this species may have a complex lipostatic function.
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SS is associated with increased levels in cerebrospinal fluid (CSF) of IL-1RA, an interleukin 1 antagonist. This suggests that the disease begins with increased activity in the interleukin 1 system, followed by an autoregulatory upregulation of IL-1RA to reduce the successful binding of interleukin 1 to its receptors. Interleukin 1 likely is the marker for fatigue, but increased IL-1RA is observed in the CSF and is associated with increased fatigue through cytokine- induced sickness behavior. However, SS is characterized by decreased levels of IL-1ra in saliva, which could be responsible for mouth inflammation and dryness.
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Pluripotent stem cells express transcription factors Nanog, Oct4 and Sox2 that seem to play a role in repressing Xist. In the absence of Tsix in pluripotent cells, Xist is repressed, where a mechanism has been proposed that these transcription factors cause splicing to occur at intron 1 at the binding site of these factors on the Xist gene, which inhibits Xist expression A study was conducted where Nanog or Oct4 transcription factors were depleted in pluripotent cells, which resulted in the upregulation of Xist. From this study, it is proposed that Nanog and Oct4 are involved in the repression of Xist expression.
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KCC2b, on the other hand, is scarcely present during prenatal development and is strongly upregulated during postnatal development. The upregulation of KCC2b expression is thought to be responsible for the “developmental shift” observed in mammals from depolarizing postsynaptic effects of inhibitory synapses in early neural networks to hyperpolarizing effects in mature neural networks. KCC2b knockout mice can survive up to postnatal day 17 (P17) due to the presence of functional KCC2a alone, but they exhibit low body weight, motor deficits and generalized seizures. Complete KCC2 knockouts (both KCC2a and KCC2b absent) die after birth due to respiratory failure.
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Once the fungal hyphae make contact with root cap cells, they must continue to grow inwards to the epidermal cells and multiply to form the layers that will eventually produce the mantle. Production of the fungal mantle involves the upregulation of genes responsible for translation and cell growth, as well as those responsible for membrane synthesis and function, such as hydrophobins. Some polypeptides are only found when the fungus and plant have achieved symbiosis; these symbiosis- related (SR) proteins are termed ectomycorrhizins. Major changes in polypeptide and mRNA synthesis happen rapidly after colonization by the fungus, including the production of ectomycorrhizins.
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Changes include the upregulation of genes that may help new membranes to form at the symbiotic interface. The effect of the mantle on root proliferation, root hair development and dichotomous branching can be partially mimicked by fungal exudates, providing a path to identifying the molecules responsible for communication. The Hartig net initially forms from the fully differentiated inner layer of the mantle, and penetration occurs in a broad front oriented at right angles to the root axis, digesting through the apoplastic space. Some plant cells respond by producing stress- and defense-related proteins including chitinases and peroxidases that could inhibit Hartig net formation.
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However, it is also possible that, under certain conditions, these factors can induce cell cycle re-entry. Under conditions such as DNA damage, oxidative stress, and activity withdrawal these factors have been shown to be upregulated. However the cells usually die in the G1/S checkpoint before DNA has been replicated (Park et al., 1998). The process by which the cell re- enters the cell cycle and dies is called “abortive cell cycle re-entry” and is characterized by the upregulation of cyclin D-cdk4/6 and downregulation of E2F, followed by cell death (Frade and Ovejero-Benito, 2015).
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Foam cell formation is triggered by a number of factors including the uncontrolled uptake of modified low density lipoproteins (LDL), the upregulation of cholesterol esterification and the impairment of mechanisms associated with cholesterol release. Foam cells are formed when circulating monocyte-derived cells are recruited to the atherosclerotic lesion site or fat deposits in the blood vessel walls. Recruitment is facilitated by the molecules P-selectin and E-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). Monocytes are then able to penetrate the arterial wall as a result of impaired endothelial integrity which increases permeability.
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Through recent studies, Apetala 2 is found to have a major role in hormone regulation, specific in flowers and plants, such as the AGAMOUS.Mutual Regulation of Arabidopsis thaliana Ethylene-responsive Element Binding Protein and a Plant Floral Homeotic Gene, APETALA2. Ogawa, T., Uchimiya, H., Kawai-Yamada, M. Ann. Bot. (2007) The study that determined this, done by Ogawa, was created to clarify the relationship between Apetala 2 and AtEBP in gene expression. The results showed that over-expression of AtEBP caused upregulation of AP2 expression in leaves which suggested that the N-terminal region is not required to produce AP2-like phenotypes.
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It may be the case that, in response to antipsychotics, neurons increase the production of D2 receptors (upregulation), thereby sensitizing the neuron to dopamine. However, this is likely an oversimplification, as—despite differences in sensitivity to dopamine of around 3-fold in people that have taken antipsychotics chronically, there is a disproportionately low increase in the amount of D2 receptors in the brain in these people (around 1.4-fold in the striatum of the brain in people with schizophrenia). Other hypotheses include increases in the "active" D2 receptors (termed D2High) relative to the "inactive" conformation (D2Low). The end result is dopamine supersensitivity.
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The transcriptomes of several types of quiescent stem cells, such as hematopoietic, muscle, and hair follicle, have been characterized through high-throughput techniques, such as microarray and RNA sequencing. Although variations exist in their individual transcriptomes, most quiescent tissue stem cells share a common pattern of gene expression that involves downregulation of cell cycle progression genes, such as cyclin A2, cyclin B1, cyclin E2, and survivin, and upregulation of genes involved in the regulation of transcription and stem cell fate, such as FOXO3 and EZH1. Downregulation of mitochondrial cytochrome C also reflects the low metabolic state of quiescent stem cells.
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In schizophrenia, the expression of the mRNA for the NR2A subunit of the NMDA glutamate receptor was found to be decreased in a subset of inhibitory interneurons in the cerebral cortex. This is suggested by upregulation of GABA, an inhibitory neurotransmitter. In schizophrenia, the expression of the NR2A subunit of NDMA receptors in mRNA was experimentally undetectable in 49-73% in GABA neurons that usually express it. These are mainly in GABA cells expressing the calcium-buffering protein parvalbumin (PV), which exhibits fast-spiking firing properties and target the perisomatic (basket cells) and axo-axonic (chandelier cells) compartments of pyramidal neurons.
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Overall, results suggest that an enhanced nuclear localization of beta-catenin may be important in the progression of cardiac hypertrophy. Regarding the mechanistic role of beta-catenin in cardiac hypertrophy, transgenic mouse studies have shown somewhat conflicting results regarding whether upregulation of beta-catenin is beneficial or detrimental. A recent study using a conditional knockout mouse that either lacked beta-catenin altogether or expressed a non-degradable form of beta-catenin in cardiomyocytes reconciled a potential reason for these discrepancies. There appears to be strict control over the subcellular localization of beta-catenin in cardiac muscle.
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The down- regulation of C1orf198 was found to be correlated to lung SCC but was not one of the top DEGs found in the study. A third association was found to be an upregulation of C1orf198 in ginsenoside RH2-treated MCF-7, which is a human breast cancer cell line. When the cell line was treated with RH2, the C1orf198 gene was found to be hypomethylated, which suggested that its function could be involved in cell-mediated immune responses and cancer-related pathways. The results of this study showed a higher survival rate associated with the up- regulation of C1orf198.
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Increases in jasmonic acid (JA) synthesis near the sites of pathogen infection have also been described. This physiological response to increase JA production has been implicated in the ubiquitination of jasmonate ZIM domains (JAZ) proteins, which inhibit JA signaling, leading to their degradation and a subsequent increase in JA activated defense genes. Studies regarding the upregulation of defensive chemicals have confirmed the role of SA and JA in pathogen defense. In studies utilizing Arabidopsis mutants with the bacterial NahG gene, which inhibits the production and accumulation of SA, were shown to be more susceptible to pathogens than the wild-type plants.
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Acupuncture of Zusanli induces local serotonin release. Furthermore, the stimulation of this acupoint is shown to decrease inflammation, as evidenced by decreased cytokines (including interleukin 6) and inhibition of edema in a rat model of inflammation involving carrageenan injection. Zusanli activation also improves insulin sensitivity and cerebral blood flow (an effect mediated by nitric oxide), while it decreases sympathetic nerve activity and arterial pressure. An analgesic effect, mediated in part by nitric oxide as well, through the upregulation of inducible nitric oxide synthase (iNOS), an increase in endogenous opiates, muscarinic cholinergic receptors and serotonin receptors 5-HT1a and 5-HT3, was repeatedly evidenced.
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As a result of the autoimmune disease multiple sclerosis (MS), the myelin sheath of neuronal cells in the brain and spinal cord is degraded, resulting in loss of signal transduction capability. MS patients exhibit upregulation of certain cytokines in the cerebrospinal fluid, particularly tumor necrosis factor alpha. This activates sphingomyelinase, an enzyme that catalyzes the hydrolysis of sphingomyelin to ceramide; sphingomyelinase activity has been observed in conjunction with cellular apoptosis. An excess of sphingomyelin in the red blood cell membrane (as in abetalipoproteinemia) causes excess lipid accumulation in the outer leaflet of the red blood cell plasma membrane.
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Several hypotheses are given about how tolerance develops, including opioid receptor phosphorylation (which would change the receptor conformation), functional decoupling of receptors from G-proteins (leading to receptor desensitization), μ-opioid receptor internalization or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the cAMP pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt.) CCK might mediate some counter- regulatory pathways responsible for opioid tolerance. CCK-antagonist drugs, specifically proglumide, have been shown to slow the development of tolerance to morphine.
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In general after any CNS insult, gliosis begins after the blood brain barrier is disrupted, allowing non-CNS molecules, such as blood and serum components, to enter the brain. These components, along with activated macrophages they carry, are known to have a role in beginning the formation of the glial scar by inducing the disconnection of axons, also called secondary axotomy, and the upregulation of fibrous extracellular matrix components which eventually form the scar tissue. The specific molecular triggers responsible for this action, however, remain unknown. One potential trigger is transforming growth factor β (TGF-β).
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The depressive-like behaviors following prolonged morphine abstinence appear to be mediated by upregulation of the KOR/dynorphin system in the nucleus accumbens, as the local application of a KOR antagonist prevented the behaviors. As such, KOR antagonists might be useful for the treatment of depressive symptoms associated with opioid withdrawal. In a small clinical study, pentazocine, a KOR agonist, was found to rapidly and substantially reduce symptoms of mania in patients with bipolar disorder. It was postulated that the efficacy observed was due to KOR activation-mediated amelioration of excessive dopaminergic signaling in the reward pathways.
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Side effects of chronic cocaine use Chronic cocaine intake causes strong imbalances of transmitter levels in order to compensate extremes. Thus, receptors disappear from the cell surface or reappear on it, resulting more or less in an "off" or "working mode" respectively, or they change their susceptibility for binding partners (ligands)mechanisms called downregulation and upregulation. However, studies suggest cocaine abusers do not show normal age-related loss of striatal dopamine transporter (DAT) sites, suggesting cocaine has neuroprotective properties for dopamine neurons. Possible side effects include insatiable hunger, aches, insomnia/oversleeping, lethargy, and persistent runny nose.
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For instance, when studying carcinogenesis of pancreatic islets in transgenic mice, Bergers et al. showed that MMP-2 and MMP-9 were upregulated in angiogenic lesions and that the upregulation of these MMPs triggered the release of bioactive VEGF, a potent stimulator of angiogenesis. Additionally, the group determined that MMP-2 knockout mice showed decreased rates of tumor growth relative to tumor growth rates in wild type mice. Furthermore, increased expression and activity of MMP-2 has been tied to increased vascularization of lung carcinoma metastases in the central nervous system, which likely increases survival rate of these metastases.
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PD-L1 is notably expressed on macrophages. In the mouse, it has been shown that classically activated macrophages (induced by type I helper T cells or a combination of LPS and interferon-gamma) greatly upregulate PD-L1. Alternatively, macrophages activated by IL-4 (alternative macrophages), slightly upregulate PD-L1, while greatly upregulating PD-L2. It has been shown by STAT1-deficient knock-out mice that STAT1 is mostly responsible for upregulation of PD-L1 on macrophages by LPS or interferon- gamma, but is not at all responsible for its constitutive expression before activation in these mice.
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In addition, activation promotes differentiation of preadipocytes and the conversion of mesenchymal progenitor cells to preadipocytes in adipose tissues. Substances that target and act as agonists of PPARγ/RXR complex typically act to increase overall serum concentrations of lipids. Obesogens that target the PPARγ/RXR complex mimic the metabolic ligands and activate the receptor leading to upregulation of lipid accumulation which explains their obesogenic effects. However, in the case of obesogens that target the PPARα/RXR complex, which when stimulated reduces adipose mass and body weight, there are a few explanations as to how they promote obesity.
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After growth factor stimulation of RTKs, ROS can trigger activation of signaling pathways involved in cell migration and invasion such as members of the mitogen activated protein kinase (MAPK) family – extracellular regulated kinase (ERK), c-jun NH-2 terminal kinase (JNK) and p38 MAPK. ROS can also promote migration by augmenting phosphorylation of the focal adhesion kinase (FAK) p130Cas and paxilin. Both in vitro and in vivo, ROS have been shown to induce transcription factors and modulate signaling molecules involved in angiogenesis (MMP, VEGF) and metastasis (upregulation of AP-1, CXCR4, AKT and downregulation of PTEN).
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Postnatal heart development sees the upregulation of multiple miR-15 family members. In particular, miR-195, when found at higher levels than normal in the developing heart, has been identified as a factor that may cause heart abnormalities in newborns. This has been linked to premature cell cycle arrest, through impaired proliferation of heart muscle fibres and through repressed mitotic gene expression. An accumulation of cardiac muscle fibres sees a consequent block in the transition between the pre-mitotic/G2 phase and mitotic phase of the cell cycle, with postnatal inhibition of the miR-15 family inducing cardiac muscle fibres to enter mitosis.
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Recent studies indicate significant HB-EGF gene expression elevation in a number of human cancers as well as cancer-derived cell lines. Evidence indicates that HB-EGF plays a significant role in the development of malignant phenotypes contributing to the metastatic and invasive behaviors of tumors. The proliferative and chemotactic effects of HB-EGF results from the target influence on particular cells including fibroblasts, smooth muscles cells, and keratinocytes. For numerous cell types such as breast and ovarian tumor cells, human epithelial cells and keratinocytes HB-EGF is a potent mitogen resulting in evidenced upregulation of HB-EGF in such specimens.
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Although the literature is limited on the subject, the well-documented effects on HSCs imply that there is a potential indirect effect of aberrant EVI1 expression on tumoral angiogenesis. HSCs secrete angiopoietin, and its receptor molecule Tie2 has been implicated in angiogenesis of tumors in both humans and mice. Upregulation of Tie2 has been shown to occur under hypoxic conditions, and to increase angiogenesis when coinjected with tumor cells in mice. Observations that EVI1−/− mutants have substantially downregulated Tie2 and Ang-I expression, therefore, hints at an interesting role of high EVI1 expression in tumor progression.
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In humans, upregulation of RASD1 leading to increased apoptosis has been observed in several human cancer cell lines such as DU-154 human prostate cancer cells and in human breast cancer cells MCF-7. In the latter, high concentrations of calycosin significantly suppressed the proliferation of MCF-7 cells, thereby promoting apoptosis of the cells. Moreover, compared with a control group, the expression of Bcl-2 decreased with calycosin while Bax increased, and these changes correlated with an elevated expression of RASD1. Together, it appears that, at relatively high concentrations, calycosin can trigger the mitochondrial apoptotic pathway by upregulating RASD1.
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VEGF165 treatment of human brain microvascular endothelial cells in culture stimulates increased pln transcription. This molecule is a ligand of VEGF Receptor-2 (VGFR2), and it seems that this VEGF165 response is specific for perlecan upregulation, leading to a positive feedback loop involving fibroblastic growth factor (FGF), FGF Receptor (FGFR) and VEGFR2 in response to endothelial damage. This microvascular-specific regulation by VEGF165 raises the possibility that the anti-coagulant function of perlecan is a part of the damage-control process in brain endothelia. Protein Kinase C signaling is putatively responsible for upregulating transcription and translation of certain proteoglycans including perlecan.
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Deformation of VSMC cells in culture leads to perlecan upregulation, with a significant increase in sulfation of the heparan sulfate chains. This is not in contrast to the data shown where perlecan expression is constant beyond e19 in rat VSMC, which suggested that perlecan plays an antiproliferative role for VSMCs. In this case, it seems that the molecule's signaling function is the operative upregulated factor, especially due to the increase in sulfation of the heparan sulfate chains. Chemical damage to organs can affect not only the cell's genetic and mechanical integrity but the extracellular matrix of the tissue.
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Investigation into the anti-tumor properties of DIFs have followed one main line; the disruption of a pathway necessary for the cancer's uncontrolled growth reducing its proliferative ability. As mentioned above, the ability of DIF-1 to decrease movement of proliferating cells toward sources of energy could serve as an anti-tumor property. In another example, DIF-1 has been shown to reduce the proliferation of gastric cancer cells via upregulation of the MEK-ERK-dependent pathway. Other studies have shown how complicated the anti-tumor interactions of DIFs may be, especially when considering the indirect impacts DIFs have on target molecules.
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Alternatively, apoptotic cells may secrete antigens, including eEF1A and other elongation factors, to induce an autoimmune response during cancer. It is postulated that high expression and secretion of elongation factors from tumor tissues, combined with altered levels of eEF1A-derived bacterial peptides in neoplastic disease, may lead to autoimmunity in breast cancer. As with breast cancer, upregulation of eEF1A expression is associated with prostate cancer and worsened metastasis-free and overall patient survival. Moreover, a truncated form of the eEF1A1 protein, prostate tumour inducing gene 1 (PTI-1), has been detected in prostate carcinoma patient-derived blood samples.
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Delirium tremens is a component of alcohol withdrawal hypothesized to be the result of compensatory changes in response to chronic alcohol abuse. Alcohol positively allosterically modulates the binding of GABA, enhancing its effect and resulting in inhibition of neurons projecting into the nucleus accumbens, as well as inhibiting NMDA receptors. This combined with desensitization of alpha-2 adrenergic receptors, results in a homeostatic upregulation of these systems in chronic alcohol use. When alcohol use ceases, the unregulated mechanisms result in hyperexcitability of neurons as natural GABAergic systems are down-regulated and excitatory glutamatergic systems are unregulated.
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The D1–D2 receptor is upregulated in individuals suffering from major depression, and especially the ratio D1–D2 to D1 receptor is markedly shifted towards the heteromer. Counteracting this upregulation decreases depressive symptoms. Disruption of the heteromer can be achieved either directly by ligands interacting with the cytoplasmic interface, less directly by ligands that target the extracellular binding site, or indirectly as a downstream effect of classical antidepressant treatment. One study found negative results regarding a shift from Gs/a coupling to Gq/11 signaling; so such dynamics could be mediated by cAMP-dependent cascades rather from phospholipase C regulation.
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HSF-1 is a transcription factor that, upon increases in unfolded cytosolic proteins, will trimerize and enter the nucleus to upregulate the expression of heat shock proteins (HSPs) that will act as protein folding chaperones. In organelles like the ER and mitochondria, the responses is slightly more complex. Both UPR mechanisms are conceptually similar in that they are activated by the accumulation of misfolded/ unfolded proteins and induce the translational upregulation of molecular chaperones and proteases to process proteins and restore homeostasis. Despite their names, the two pathways possess distinct initiating stimuli and signaling mechanisms that regulate the responses.
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Progesterone, like all progestogens, has antiestrogenic effects in certain tissues such as the uterus, cervix, vagina, and breasts, and possibly also the brain. These effects are mediated by activation of the PR in these tissues. Progesterone does not have antiestrogenic effects in the more conventional sense of binding to and antagonizing the ER or binding to and inhibiting enzymes involved in estrogen biosynthesis. Instead, for instance in the endometrium, progesterone causes downregulation of the ER and upregulation of the estrogen-inactivating enzymes 17β-hydroxysteroid dehydrogenase 2 (converts estradiol into estrone) and estrone sulfotransferase (converts estrone into estrone sulfate).
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Constant levels of estradiol may result in downregulation of the ERs and relatively diminished responses to estradiol, although this has not been assessed clinically. Once bound to estradiol, the ERs are ubiquitinated and degraded by proteasomes, which is a major mechanism of ER downregulation. The unbound ERα has an intracellular half-life of up to 5 days, but this shortens to hours once bound to a ligand such as estradiol. Estrogen deprivation can easily increase sensitivity to estrogens like estradiol by 10,000-fold or more, demonstrating a profound capacity of the ERs for upregulation and downregulation.
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In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary process that involves increases of such components is called upregulation. An example of downregulation is the cellular decrease in the expression of a specific receptor in response to its increased activation by a molecule, such as a hormone or neurotransmitter, which reduces the cell's sensitivity to the molecule. This is an example of a locally acting (negative feedback) mechanism.
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H3K9me2 is present at a subset of cardiovascular disease-associated gene promoters in vascular smooth muscle cells to block binding of NFκB and AP-1 (activator protein-1) transcription factors. Reduced levels of H3K9me2 have been observed in vascular smooth muscle cells from human atherosclerotic lesions compared to healthy aortic tissue in patients. Vascular smooth muscle cells from diabetic patients display reduced levels of H3K9me2 compared to non-diabetic controls; it has therefore been suggested that dysregulation of H3K9me2 might underlie the vascular complications associated with diabetes. Loss of H3K9me2 in vascular smooth muscle cells exacerbates upregulation of a subset of cardiovascular disease-associated genes in vascular disease models.
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CMV encodes a protein, UL16, which is involved in the immune evasion of NK cell responses. It binds to ligands ULBP1, ULBP2 and MICB of NK cell activating receptor NKG2D, which prevents their surface expression. These ligands are normally upregulated in times of cellular stress, such as in viral infection, and by preventing their upregulation, CMV can prevent its host cell from dying due to NK cells A substantial portion of the immune system is involved in continuously controlling CMV, which drains the resources of the immune system. Death rates from infectious disease accelerate with age, and CMV infection correlates with reduced effectiveness of vaccination.
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The Imd pathway is orthologous to human TNF receptor superfamily signalling, and is triggered by Gram-negative bacteria through recognition by peptidoglycan recognition proteins (PGRP) including both soluble receptors and cell surface receptors (PGRP-LE and LC, respectively). Imd signalling culminates in the translocation of the NF-κB transcription factor Relish into the nucleus, leading to the upregulation of Imd-responsive genes including the AMP Diptericin. Consequently, flies deficient for AMPs resemble Imd pathway mutants in terms of susceptibility to bacterial infection. Imd signalling and Relish specifically are also involved in the regulation of immunity at surface epithelia including in the gut and respiratory tracts.
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Recent studies on short-term effects of a meal or the absence of a meal has revealed that lepa1 expression specifically peaks in the peripheral tissues after 6 – 9 hr in the unfed fish. This suggests that the transcript specific response could be associated with the absence of food. Conversely, since the unfed fish had not received food for 33 hr (24 + 9 hr), the peaks could represent an unrelated effect. Each lepa1 peak occurred during a phase of falling plasma Lep, and since this occurred in both fed and unfed fish, the temporal upregulation of lepa1 does not in fact appear to be specifically related to the absence of food.
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This seems to suggest that would be a crucial protein involved with bone metabolism and that retention of bone tissue by a protein as yet unknown. Nck1 expression increased twofold when involved with neurectomy-based unloading osteoporosis. This then follows that in a deficient organism this upregulation would not be possible and thus the body would have increased bone loss due to the lack of expression of Nck1 to deal with the stress, which is what happens in vivo. This acceleration of bone loss leads researchers to believe that the pathway for bone metabolism is highly regulated by several proteins that have yet to be discovered or incorporated into a schema.
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Furthermore, she showed that the heterogeneity of the microenvironment within SCCs with regard to TGF-β signaling resulted in cells rich in TGF-β that were chemotherapy resistant to be cells located close to the perivasculature. She showed the ability of TGF-β to cause upregulation of the glutathione pathway, which allowed the SCCs to counter the radical oxygen species often used in radiotherapy and chemotherapy. Fuchs determined that both the factors internal to the cell and the cell's external surrounding environment have an effect on the stem cells’ niche in both their ability to divide and how they divide.Fuchs E., Tumber T., Guasch G. (2004).
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The ability of neurotrophic factors to influence the sprouting of axons has been seen with electron microscopic images and in multiple studies extensively detailed in a review of the role of neurotrophic factors in regeneration. In addition to the ability of the factors to influence sprouting, Schwann cells in particular show a significant upregulation of a number of trophic factors after undergoing axotomy. One major difference in motor and sensory pathways is the difference in what trophic factors are upregulated by the Schwann cells of those pathways. Denervenated motor Schwann cells upregulate BDNF and p75, whereas sensory pathway Schwann cells upregulate a number of other varied trophic factors.
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Altered epigenetic regulation of gene expression within the brain's reward system plays a significant and complex role in the development of drug addiction. Addictive drugs are associated with three types of epigenetic modifications within neurons. These are (1) histone modifications, (2) epigenetic methylation of DNA at CpG sites at (or adjacent to) particular genes, and (3) epigenetic downregulation or upregulation of microRNAs which have particular target genes. As an example, while hundreds of genes in the cells of the nucleus accumbens (NAc) exhibit histone modifications following drug exposure – particularly, altered acetylation and methylation states of histone residues – most other genes in the NAc cells do not show such changes.
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Studying Polyglutamine repeat diseases (polyQ diseases) in Drosophila neurodegeneration models, Bonini's research group elucidated an important role for molecular chaperones in polyQ diseases, and subsequently Parkinson's disease. In those studies, upregulation of the chaperone Hsp70 suppressed neurodegeneration, and this finding established chaperones as a new therapeutic target for Parkinson's disease and other neurodegenerative disorders. Bonini's research team demonstrated the pharmacologic potential of chaperones in further Drosophila studies; administering geldanamycin (an antitumor antibiotic that acts on Hsp90) to mutant flies before symptoms of neural decline were visible averted the onset of neurodegeneration in the mutant flies, suggesting a new approach for people susceptible to Parkinson's disease and other neurodegenerative conditions.
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The upregulation of Th 2 T cell proteins, like IL-4 and TGF-Beta, are the main focus of some research which aims to minimize the effects seen in the model organism disease EAE (experimental autoimmune encephalomyelitis), studied for its similarities to Multiple Sclerosis.Though this study of gene regulation is observed within murine models, it focuses on MS orthologs to humans and research has shown that it may also help to manage: Rheumatoid Arthritis, Diabetes mellitus type 1, Systemic lupus erythematosus (SLE), cardiovascular disease (CVD), and other chronic inflammatory diseasesDeluca H and Cantorna M. 2001. Vitamin D: Its role and uses in immunology. FASEB Journal 15(14):2579-85.
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Hence, both the cell wall-degrading enzymes are synthesized by the host grapevine plant specifically to target and degrade the cell walls of the oomycete pathogen. In addition, the upregulation of the PR-9 gene that encodes for peroxidase, which is a reactive oxygen species is associated with the systemic acquired defense of the grapevine host. The roles of other constitutively expressed PR genes during P.viticola infection such as PR-5, PR-1 and PR-10 genes remain ambiguous. PR-5 is involved in the synthesis of thaumatin-like proteins and osmotins, which are believed to inhibit the spore germination and germ tube growth of Plasmopara viticola by creating transmembrane pores.
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An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include interleukin-1 (IL-1), IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions. Excessive chronic production of inflammatory cytokines contribute to inflammatory diseases, that have been linked to different diseases, such as atherosclerosis and cancer.
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Ets1 knockout mice have aberrant thymic differentiation, reduced peripheral T cell numbers, reduced IL-2 production, a skewing towards a memory/effector phenotype and impairments in the production of Th1 and Th2 cytokines. Although Ets1 knockout mice have an impaired development of Th1, Th2, and Treg cells, they have higher numbers of Th17 cells. In CD4/CD8 double positive thymocytes from Ets knockout mice, both the suppression of gene expression programs corresponding to alternative lineages and upregulation of T-cell specific genes are impaired. There are also partial defects in bone marrow B cell development with reduced cellularity and inefficient transition from pro-B to pre-B cell stages.
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FOXM1 is a key player in the activity of the SMAD3/SMAD4 complex, promoting SMAD3 modulator transcriptional activity, and also plays an important role in the turnover of the activity of SMAD3/SMAD4 complex. Based on the importance of this molecule, studies have found that FOXM1 is overexpressed in highly aggressive human breast cancer tissues. The results from these studies also found that the FOXM1/SMAD3 interaction was required for TGF-β-induced breast cancer invasion, which was the result of SMAD3/SMAD4-dependent upregulation of the transcription factor SLUG. MED15 is a mediator molecule that promotes the activity of the TGF-β/SMAD signaling.
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In vivo anti-tumor activity of thalidomide is believed to be due to the potent anti-angiogenic effect and also through changes in cytokine expression. In vitro assays on apoptosis in MM cells have been shown, when treated with thalidomide and its analogs, to upregulate the activity of caspase-8. This causes cross talking of apoptotic signaling between caspase-8 and caspase-9 leading to indirect upregulation of caspase-9 activity. Further anti-tumor activity is mediated through the inhibition of apoptosis protein-2 and pro- survival effects of IGF-1, increasing sensitivity to FAS mediated cell death and enhancement of TNF-related apoptosis inducing ligand.
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In a following study, Hu and her team further explored the mechanisms of habenular hyperactivity. Using a proteomic analysis, they found evidence of upregulation of an astrocytic potassium channel, Kir4.1, in rat models of depression and the expression profiles of this channel seem to be localized to the synaptic junctions between astrocytes and neuronal somas. Hu found that these channels tightly regulate neuronal bursting and excitability of neurons in the LHb. By manipulating the expression levels of Kir4.1, Hu and her team showed that astrocytic Kir4.1 bidirectionally regulates the hyperexcitability of neurons as well as depressive behavioral symptoms highlighting the role of glia-neuron interactions in psychiatric illnesses such as depression.
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This gene encodes the alpha chain of the interleukin-4 receptor, a type I transmembrane protein that can bind interleukin 4 and interleukin 13 to regulate IgE antibody production in B cells. Among T cells, the encoded protein also can bind interleukin 4 to promote differentiation of Th2 cells. A soluble form of the encoded protein can be produced by an alternate splice variant or by proteolysis of the membrane-bound protein, and this soluble form can inhibit IL4-mediated cell proliferation and IL5 upregulation by T-cells. Allelic variations in this gene have been associated with atopy, a condition that can manifest itself as allergic rhinitis, sinusitis, asthma, or eczema.
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Each cytokine has a matching cell-surface receptor. Subsequent cascades of intracellular signaling then alter cell functions. This may include the upregulation and/or downregulation of several genes and their transcription factors, resulting in the production of other cytokines, an increase in the number of surface receptors for other molecules, or the suppression of their own effect by feedback inhibition. The effect of a particular cytokine on a given cell depends on the cytokine, its extracellular abundance, the presence and abundance of the complementary receptor on the cell surface, and downstream signals activated by receptor binding; these last two factors can vary by cell type.
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Downregulation of miR-10a has also been found in acute myeloid leukemia, the most common acute leukemia affecting adults. Conversely, miR-10a and miR-10b have found to be upregulated in acute myeloid leukemia with NPM1 mutations; these account for approximately a third of adult acute myeloid leukemia cases and contain mutations in the NPM1 gene which result in the relocation of NPM1 from the nucleus to the cytoplasm. Upregulation of miR-10b has also been found in B-cell chronic lymphocytic leukemia, the most common type of leukemia. Genomic copy number abnormalities involving microRNA genes (both increases and decreases in copy number) have been found in cancers.
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HB-EGF binding and activation of EGF receptors plays a critical role during cardiac valve tissue development and the maintenance of normal heart function in adults. During valve tissue development the interaction of HB-EGF with EGF receptors and heparan sulfate proteoglycans is essential for the prevention of malformation of valves due to enlargement. In the vascular system areas of disturbed flow show upregulation of HB-EGF with promotion of vascular lesions, atherogenesis, and hyperplasia of intimal tissue in vessels. The flow disturbance remodeling of the vascular tissues due to HB-EGF expression contributes to aortic valve disease, peripheral vascular disease, and conduit stenosis.
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Better effects on suppression of testosterone levels have been observed in men when ketoconazole is combined with a GnRH agonist to suppress the hypothalamic–pituitary–gonadal axis, which prevents compensatory upregulation of luteinizing hormone secretion and consequent activation of gonadal testosterone production. In premenopausal women with polycystic ovary syndrome, ketoconazole has been found to significantly decrease levels of androstenedione and testosterone and significantly increase levels of 17α-hydroxyprogesterone and estradiol. Studies in postmenopausal women with breast cancer have found that ketoconazole significantly decreases androstenedione levels, slightly decreases estradiol levels, and does not affect estrone levels. This indicates minimal inhibition of aromatase by ketoconazole in vivo in humans.
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In a model of explant growth in vitro using corneal epithelium, Matrix Metalloproteinase (MMP) 2 expression correlates with an initial degradation of the original basement membrane. Reformation of basement membrane in culture was dependent on an initial upregulation followed by a downregulation of MMP-9, in contrast to the constant expression of MMP-2. This is not evidence that MMP-2 and MMP-9 directly cleave perlecan protein in vivo but shows that the proteins clearly modulate some factor in maturation of basement membrane. Another family of metalloproteases, the Bone Morphogenetic Protein 1/Tolloid-like family, releases the c-terminal endorepellin domain of the perlecan core protein.
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Both pregnancy and lactation increase demand for choline dramatically. This demand may be met by upregulation of PEMT via increasing estrogen levels to produce more choline de novo, but even with increased PEMT activity, the demand for choline is still so high that bodily stores are generally depleted. This is exemplified by the observation that Pemt −/− mice (mice lacking functional PEMT) will abort at 9–10 days unless fed supplemental choline. While maternal stores of choline are depleted during pregnancy and lactation, the placenta accumulates choline by pumping choline against the concentration gradient into the tissue, where it is then stored in various forms, mostly as acetylcholine.
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In humans, IL-10 is encoded by the IL10 gene, which is located on chromosome 1 and comprises 5 exons, and is primarily produced by monocytes and, to a lesser extent, lymphocytes, namely type-II T helper cells (TH2), mast cells, CD4+CD25+Foxp3+ regulatory T cells, and in a certain subset of activated T cells and B cells. IL-10 can be produced by monocytes upon PD-1 triggering in these cells. IL-10 upregulation is also mediated by GPCRs, such as beta-2 adrenergic and type 2 cannabinoid receptors. The expression of IL-10 is minimal in unstimulated tissues and seems to require triggering by commensal or pathogenic flora.
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The upregulation of phosphatase genes is significant in that it indicates that a significant portion of the phosphorus obtained by the fungi in some environments may be from organic molecule catabolism. It is important to note that once a mycorrhizal symbiosis is established the only phosphorus obtained by the plant comes through the fungal tissue. Additionally the large scale assisted transport of phosphorus from fungi to plant only occurs when the fungal pelotons are alive, once these structures start to degrade significant flow of phosphorus ceases. This classifies this pathway as biotrophic, meaning transfer of nutrients between two or more organisms that are both alive.
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In some studies, it significantly lowers testosterone levels, whereas in other studies, testosterone and estradiol levels remain unchanged, even at high dosages. It has been suggested that spironolactone may weakly and partially inhibit 17α-hydroxylase, which in turn results in upregulation of the HPG axis such that steroid hormone levels remain normal. Conversely however, inhibition of 17α-hydroxylase in the ovary may disrupt the menstrual cycle and thereby result in menstrual irregularities. Animal studies have found that spironolactone inhibits testicular CYP450-mediated steroidogenesis by 5 to 75% across a dosage range of 1 to 100 mg/kg, with 50% inhibition occurring at a dose of 40 mg/kg.
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Such mutations and epigenetic alterations can give rise to cancer (see malignant neoplasms). Thus, epigenetic downregulation or upregulation of DNA genes that were repaired is likely central to progression to cancer. As described in Regulation of transcription in cancer, epigenetic downregulation of the DNA repair gene MGMT occurs in 93% of bladder cancers, 88% of stomach cancers, 74% of thyroid cancers, 40%-90% of colorectal cancers and 50% of brain cancers. Similarly, epigenetic downregulation of LIG4 occurs in 82% of colorectal cancers and epigenetic downregulation of NEIL1 occurs in 62% of head and neck cancers and in 42% of non-small-cell lung cancers.
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The derivatives can be delivered to the cells by using the functional groups L-phenylalanine, folic acid, and L-arginine among others. Functionalizing the fullerenes aims to increase the solubility of the molecule by the cancer cells. Cancer cells take up these molecules at an increased rate because of an upregulation of transporters in the cancer cell, in this case amino acid transporters will bring in the L-arginine and L-phenylalanine functional groups of the fullerenes. Once absorbed by the cells, the derivatives would react to light radiation by turning molecular oxygen into reactive oxygen which triggers apoptosis in the HeLa cells and other cancer cells that can absorb the fullerene molecule.
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In the adult dentate gyrus, reelin provides guidance cues for new neurons that are constantly arriving to the granule cell layer from subgranular zone, keeping the layer compact. Reelin also plays an important role in the adult brain by modulating cortical pyramidal neuron dendritic spine expression density, the branching of dendrites, and the expression of long-term potentiation as its secretion is continued diffusely by the GABAergic cortical interneurons those origin is traced to the medial ganglionic eminence. In the adult organism the non-neural expression is much less widespread, but goes up sharply when some organs are injured. The exact function of reelin upregulation following an injury is still being researched.
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Regarding upstream regulators of Tnmd expression the description of the scleraxis (Scx) knockout mouse line suggested that Scx can directly drive Tnmd transcription, because Scx deletion led to complete elimination of Tnmd expression. Overexpression of scleraxis in cultured tenocytes or in mesenchymal stem cells significantly upregulated Tnmd expression. The deletion of myostatin in mice resulted in a parallel decrease in Scx and Tnmd mRNA levels, while myostatin stimulation of fibroblasts led to their upregulation, suggesting myostatin as an upstream factor in the Tnmd pathway. Egr1/2 transcription factors can induce Scx and collagen I gene expression, hence it would be interesting to investigate if Egr1 or 2 also can affect Tnmd expression.
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FATE1 is detectable in all cell lines derived from tumors, but is low or undetectable in telomere immortalized, non-tumorigenic fibroblasts and lung epithelial cells. FATE1 is suggested to be essential for survival of tumor cells as depletion of FATE1 results in viability reduction in melanoma, breast, prostate and sarcoma settings. Upregulation of FATE1 by a transcription factor steroidogenic factor-1 (SF-1), involved in adrenal and gonadal development as well as in adrenocortical carcinoma, increases ER-mitochondria distance and is utilized by cancer cell to functionally uncouple ER and mitochondria. Silencing FATE1 gene sensitizes non-small-cell lung cancer cell lines to paclitaxel, a chemotherapeutic drug against many different types of cancers.
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Vascular endothelial growth factor (VEGF) has been demonstrated to be a major contributor to angiogenesis, increasing the number of capillaries in a given network. Initial in vitro studies demonstrated bovine capillary endothelial cells will proliferate and show signs of tube structures upon stimulation by VEGF and bFGF, although the results were more pronounced with VEGF. Upregulation of VEGF is a major component of the physiological response to exercise and its role in angiogenesis is suspected to be a possible treatment in vascular injuries. In vitro studies clearly demonstrate that VEGF is a potent stimulator of angiogenesis because, in the presence of this growth factor, plated endothelial cells will proliferate and migrate, eventually forming tube structures resembling capillaries.
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Hypertension effects of overillumination can lead to aggravation of cardiovascular disease and erectile dysfunction, which impacts are outcomes of long-term cumulative exposure and associated systematic increases in blood pressure. The mechanism of this effect seems to be stress by related upregulation of adrenaline production akin to the fight-or-flight response.Narisada Kohei and Duco Schreude, Light Pollution Handbook, Springer, Netherlands (2004) Biological Effects of Power Frequency Electric and Magnetic Fields, Office of Technology Assessment, U.S. Congress, University Press of the Pacific (2002) Circadian rhythm disruption is primarily caused by the wrong timing of light in reference to the circadian phase. It can also be affected by too much light, too little light, or incorrect spectral composition of light.
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Meanwhile, in the second process, GHITM is responsible for cross-linking cytochrome c to the IMM, and upregulation of GHITM is associated with delayed cytochrome c release, regardless of outer mitochondrial membrane permeabilization. Thus, GHITM controls the release of cytochrome c from the mitochondria and can potentially interfere with the apoptotic process to promote cell survival. Moreover, GHITM may further plays a role in apoptosis through maintaining calcium ion homeostasis in the ER. However, while overexpression of the other TMBIM proteins exhibit antiapoptotic effects by decreasing calcium ion concentrations, and thus preventing mitochondrial calcium ion overload, depolarization, ATP loss, reactive oxygen species production, cytochrome c release, and ultimately, cell death, overexpression of GHITM produces the opposite effect.
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The MRN complex's roles in cancer development are as varied as its biological functions. Double-strand DNA breaks, which it monitors and signals for repair, may themselves be the cause of carcinogenic genetic alteration, suggesting MRN provides a protective effect during normal cell homeostasis. However, upregulation of MRN complex sub-units has been documented in certain cancer cell lines when compared to non-malignant somatic cells, suggesting some cancer cells have developed a reliance on MRN overexpression. Since tumor cells have increased mitotic rates compared to non-malignant cells this is not entirely unexpected, as it is plausible that an increased rate of DNA replication necessitates higher nuclear levels of the MRN complex.
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Growth arrest-specific 5 is a non-protein coding RNA that in humans is encoded by the GAS5 gene. GAS5 noncoding RNA, which accumulates in growth arrested cells, acts as a decoy hormone response element for the glucocorticoid receptor (GR) and hence blocks the upregulation of gene expression by activated GR. A number of studies have linked GAS5 to apoptosis and it may play a role in the progression of some types of cancer. The GAS5 introns host several snoRNA sequences, including SNORD81, SNORD47, SNORD80, SNORD79, SNORD78, SNORD44, SNORD77, SNORD76, SNORD75 and SNORD74. These intronic sequences are more conserved than the exons of the host gene, these sorts of genes are often called "inside-out genes".
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Moreover, to increase their pathogen-killing ability, they produce increased amounts of chemicals called reactive oxygen species (ROS) and nitrogen radicals (caused by upregulation of inducible NO synthase iNOS). Thanks to their ability to fight pathogens, M1 macrophages are present during acute infectious diseases. A number of studies have shown that bacterial infection induces polarization of macrophages toward the M1 phenotype, resulting in phagocytosis and intracellular killing of bacteria in vitro and in vivo. For instance, Listeria monocytogenes, a Gram positive bacteria causing listeriosis is shown to induce an M1 polarization, as well as Salmonella typhi (the agent of typhoid fever) and Salmonella typhimurium (causing gastroenteritis), which are shown to induce the M1 polarization of human and murine macrophages.
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N-cadherin showed no change, and there was no compensatory upregulation of plakoglobin at intercalated discs in the absence of beta-catenin. In a hamster model of cardiomyopathy and heart failure, cell–cell adhesions were irregular and disorganized, and expression levels of adherens junction/intercalated disc and nuclear pools of beta-catenin were decreased. These data suggest that a loss of beta-catenin may play a role in the diseased intercalated discs that have been associated with cardiac muscle hypertrophy and heart failure. In a rat model of myocardial infarction, adenoviral gene transfer of nonphosphorylatable, constitutively-active beta-catenin decreased MI size, activated the cell cycle, and reduced the amount of apoptosis in cardiomyocytes and cardiac myofibroblasts.
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Intestinal organoids have thus far been among the gut organoids to be generated directly from pluripotent stem cells. One way human pluripotent stem cells can be driven to form intestinal organoids is through first the application of activin A to drive the cells into a mesoendodermal identity, followed by the pharmacological upregulation of Wnt3a and Fgf4 signaling pathways as they have been demonstrated to promote posterior gut fate. Intestinal organoids have also been generated from intestinal stem cells, extracted from adult tissue and cultured in 3D media. Intestinal organoids recapitulate the crypt-villus structure of the intestine, by recapitulating its function, physiology and organization, and maintaining all the cell types found normally in the structure including intestinal stem cells.
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The RANK/RANKL/OPG axis is a critical pathway in maintaining the symbiosis between bone resorption by osteoclasts and bone formation by osteoblasts. RANKL is released by osteoblast lineage cells and binds to receptor RANK on the surface of osteoclast progenitor cells RANK- RANKL binding activates the nuclear factor kappa B (NF-κB) pathway resulting in the upregulation of the transcription factor nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). NFATc1 is a master regulator for the expression of essential cytokines during the differentiation of osteoclast precursor cells into mature osteoclasts, known as osteoclastogenesis. Mature osteoclasts then bind to bone through tight junctions and release digestive enzymes to resorb the old bone.
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Kv1.3 channels have been found to be highly expressed by activated and plaque-associated microglia in human Alzheimer’s disease (AD) post-mortem brains as well as in mouse models of AD pathology. Patch-clamp recordings and flow cytometric studies performed on acutely isolated mouse microglia have confirmed upregulation of Kv1.3 channels with disease progression in mouse AD models. The Kv1.3 channel gene has also been found to be a regulator of pro-inflammatory microglial responses. Selective blockade of Kv1.3 channels by the small molecule Pap1 as well as a peptide sea anemone toxin-based peptide ShK-223 have been found to limit amyloid beta plaque burden in mouse AD models, potentially via augmented clearance by microglia.
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Blockade of COX-1 by aspirin apparently results in the upregulation of COX-2 as part of a gastric defense and that taking COX-2 inhibitors concurrently with aspirin increases the gastric mucosal erosion. Therefore, caution should be exercised if combining aspirin with any "natural" supplements with COX-2-inhibiting properties, such as garlic extracts, curcumin, bilberry, pine bark, ginkgo, fish oil, resveratrol, genistein, quercetin, resorcinol, and others. In addition to enteric coating, "buffering" is the other main method companies have used to try to mitigate the problem of gastrointestinal bleeding. Buffering agents are intended to work by preventing the aspirin from concentrating in the walls of the stomach, although the benefits of buffered aspirin are disputed.
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Hepatitis A virus cellular receptor 1 (HAVcr-1) also known as T-cell immunoglobulin and mucin domain 1 (TIM-1) is a protein that in humans is encoded by the HAVCR1 gene. It is also known as KIM-1 Kidney Injury Molecule -1, which is a protein the most highly upregulated in injured kidneys by various types of insults. Its upregulation during renal injury has been found in the kidneys of the vertebrates such as Zebrafish and humans. The hepatitis A virus cellular receptor 1 (HAVCR1/TIM-1), is a member of the TIM (T cell transmembrane, immunoglobulin, and mucin) gene family, which plays critical roles in regulating immune cell activity especially regarding the host response to viral infection.
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Cells can communicate with each other by releasing molecules that produce signaling cascades within another receptive cell. If the signal requires upregulation or downregulation of genes in the recipient cell, often transcription factors will be downstream in the signaling cascade. Estrogen signaling is an example of a fairly short signaling cascade that involves the estrogen receptor transcription factor: Estrogen is secreted by tissues such as the ovaries and placenta, crosses the cell membrane of the recipient cell, and is bound by the estrogen receptor in the cell's cytoplasm. The estrogen receptor then goes to the cell's nucleus and binds to its DNA- binding sites, changing the transcriptional regulation of the associated genes.
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Identification of constitutive and inducible forms of nitric oxide synthase in human platelets. Journal of Laboratory and Clinical Medicine 125:370-377, 1995. #Yang BC, Phillips MI, ..... Mehta JL. Critical role of AT1 receptor expression after ischemia-reperfusion in isolated rat hearts: Beneficial effect of antisense oligodeoxynucleotides directed at AT1 receptor mRNA. Circulation Research 1998; 83:552-559. #Li DY, Mehta JL. Antisense to LOX-1 inhibits ox-LDL- mediated upregulation of MCP-1 expression and monocyte adhesion to human coronary artery endothelial cells. Circulation 2000;101;2889-2895. #Chen J, Liu Y, Liu H, Hermonat PL, Mehta JL. Molecular dissection of angiotensin II- activated human LOX-1 promoter. Arteriosclerosis, Thrombosis and Vascular Biology 2006;26:1163-1168.
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CR3 belongs to a family of cell surface receptors known as integrins (because they share this particular β chain, they are referred to as β2-integrins), which are extremely widely distributed throughout nature and which generally are important in cellular adhesion, migration, phagocytosis and other cell-cell interactions in a variety of cells and circumstances. Upregulation of Mac-1 in the presence of certain factors such as IL-2 may cause a prolongation of the life of the immune cell while the presence of TNF-α induces apoptosis and selective removal of the cell. A fully activated neutrophil may express on its membrane 200,000 or more CR3 molecules. Absence of CR3 results in reduced binding and ingestion of Mycobacterium tuberculosis in mice.
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Decrease in RELN expression with concurrent upregulation of DNMT1 is typical of bipolar disorder with psychosis, but is not characteristic of patients with major depression without psychosis, which could speak of specific association of the change with psychoses. One study suggests that unlike in schizophrenia, such changes are found only in the cortex and do not affect the deeper structures in psychotic bipolar patients, as their basal ganglia were found to have the normal levels of DNMT1 and subsequently both the reelin and GAD67 levels were within the normal range. In a genetic study conducted in 2009, preliminary evidence requiring further DNA replication suggested that variation of the RELN gene (SNP rs362719) may be associated with susceptibility to bipolar disorder in women.
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Type I interferon activity was originally described over 50 years ago as a soluble factor produced by cells treated with inactivated, non-replicating viruses that blocked subsequent infection with live virus. Although the rapid induction and amplification of the type I interferon system is highly adaptive in terms of virus eradication, aberrant stimulation or unregulated control of the system could lead to inappropriate and / or excessive interferon output. Studies of the AGS-related proteins TREX1, the RNase H2 complex, SAMHD1 and ADAR1, suggest that an inappropriate accumulation of self-derived nucleic acids can induce type I interferon signaling. The findings of IFIH1 mutations in the similar context implicates the aberrant sensing of nucleic acids as a cause of immune upregulation.
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Hypoxia also causes the upregulation of hypoxia-inducible factor 1 alpha (HIF1-α), which induces angiogenesis and is associated with poorer prognosis and the activation of genes associated with metastasis, leading, for instance, to increased cell migration and also ECM remodeling. While a lack of oxygen can cause glycolytic behavior in cells, some tumor cells also undergo aerobic glycolysis, in which they preferentially produce lactate from glucose even given abundant oxygen, called the Warburg effect. No matter the cause, this leaves the extracellular microenvironment acidic (pH 6.5–6.9), while the cancer cells themselves are able to remain neutral (ph 7.2–7.4) . It has been shown that this induces greater cell migration in vivo and in vitro, possibly by promoting degradation of the ECM.
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In flies, acetylation of H4K16 on the male X chromosome by MOF in the context of the MSL complex is correlated with transcriptional upregulation as a mechanism for dosage compensation in these organisms. In humans, the MSL complex carries out the majority of genome-wide H4K16 acetylation. In the context of their cognate complexes, Sas2 (SAS) and Esa1 (NuA4) also carry out acetylation of H4K16, in particular in the telomere regions of chromosomes. Sas2 is also observed to acetylate H3K14 in vitro on free histones. Esa1 can also acetylate H3K14 in vitro on free histones as well as H2AK5, H4K5, H4K8, and H4K12 either in vitro or in vivo on nucleosomal histones. H2AK7 and H2BK16 are also observed to be acetylated by Esa1 in vivo.
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Animal studies suggest that RB-101 is also likely to be useful in relieving the symptoms of acute opioid withdrawal and in the management of opioid dependence. A significant advantage of inhibiting the breakdown of endogenous opioid peptides rather than stimulating opioid receptors with exogenous drugs is that the levels of opioid peptides are only increased slightly from natural levels, thus avoiding overstimulation and upregulation of the opioid receptors. This means that even when RB-101 is used in high doses for extended periods of time, there is no development of dependence on the drug or tolerance to its analgesic effects. Consequently, even though RB-101 is able to produce potent analgesic effects via the opioid system, it is unlikely to be addictive.
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Venous gas can be admitted to the systemic circulation and become arteriolised by passing through pulmonary or intracardial shunts, bypassing the pulmonary filter. Unconsciousness or other major changes to the state of consciousness within about 10 minutes of surfacing or completion of a procedure are generally assumed to be gas embolism until proven otherwise. The belief that the gas bubbles themselves formed static emboli which remain in place until recompression has been superseded by the knowledge that the gas emboli are normally transient, and the damage is due to inflammation following endothelial damage and secondary injury from inflammatory mediator upregulation. Hyperbaric oxygen can cause downregulation of the inflammatory response and resolution of oedema by causing hyperoxic arterial vasoconstriction of the supply to capillary beds.
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Though typically associated with heat-induced protein expression, RNA thermometers can also regulate cold-shock proteins. For example, the expression of two 7kDa proteins are regulated by an RNA thermometer in the thermophilic bacterium Thermus thermophilus and a similar mechanism has been identified in Enterobacteriales. RNA thermometers sensitive to temperatures of 37 °C can be used by pathogens to activate infection-specific genes. For example, the upregulation of prfA, encoding a key transcriptional regulator of virulence genes in Listeria monocytogenes, was demonstrated by fusing the 5′ DNA of prfA to the green fluorescent protein gene; the gene fusion was then transcribed from the T7 promoter in E. coli, and fluorescence was observed at 37 °C but not at 30 °C.
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This phase involves the synthesis of new cardioprotective proteins stimulated by nitric oxide (NO), ROS and adenosine acting on kinases such as PKCε and Src, which in turn activate gene transcription and upregulation of late PC molecular players (e.g., antioxidant enzymes, iNOS). A role for PKCε in more contemporary cardioprotection strategies including RIPC, local PostC, and remote PostC have been either demonstrated or suggested. It was shown that PKCε translocates from the cytosolic to the particulate fraction upon RIPC induction and that the protection conferred by RIPC can be inhibited with the PKC inhibitor chelerythrine Similarly, in models of local PostC, phosphorylation and activation of PKCε has been shown to be induced and PKCε inhibition attenuated the beneficial effects of these regimens.
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Pitrakinra (trade name Aerovant) is a 15-kDa human recombinant protein of wild-type human interleukin-4 (IL-4). It is an IL-4 and IL-13 antagonist that has been studied in a phase IIb clinical trial for the treatment of asthma. Two point mutations on pitrakinra (position 121 mutated from arginine to aspartic acid and position 124 mutated from tyrosine to aspartic acid) confer its ability to block signaling of IL-4 and interleukin-13 (IL-13) by preventing assembly of IL-4 receptor alpha (IL-4Rα) with either IL-2Rγ or IL-13Rα. Upregulation of Th2 cytokines, including IL-4 and IL-13, is thought to be critical for the allergic inflammation associated with atopic diseases such as asthma and eczema.
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It is also noted that similar decreases in extracellular HS without a change in staining for the core protein chains occur in diabetic kidneys and in kidney cells in culture treated with high glucose. Atherosclerosis is most often the culprit in coronary heart disease and other cardiovascular conditions, and a large aggregation of perlecan protein is symptomatic of advanced atherosclerotic plaques. VSMCs are the producers of the perlecan in this condition, meaning that a good deal of research has been focused on understanding the means of perlecan upregulation in this condition. In a test of the effect of circulating nonesterified fatty acids (symptomatic of diabetes and atherogenesis) on perlecan expression by VSMCs, expression did not change when compared to control cells.
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Bone lesions are caused by an imbalance of regulatory factors, characterized by an increased depletion and resorption of old bone tissue and a decrease in bone rebuilding, known as bone remodeling. This imbalance is due to a flooding of regulatory factors released by specific tumors, thus overwhelming the tissue repair system and resulting in these lesions. The over-activity of osteoclasts can also cause hypercalcemia, which can cause damage to the kidneys and requires additional medication and monitoring. In multiple myeloma, an increased number of myeloma cells block osteoblasts from creating new bone, while these cancerous cells also release factors that cause an upregulation on osteoclasts, causing an increasing in bone tissue resorption and an overall breakdown of bone integrity.
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Given the ability of p130Cas/BCAR1 scaffold protein to convey and integrate different type of signals and subsequently to regulate key cellular functions such as adhesion, migration, invasion, proliferation and survival, the existence of a strong correlation between deregulated p130Cas/BCAR1 expression and cancer was inferred. Deregulated expression of p130Cas/BCAR1 has been identified in several cancer types. Altered levels of p130Cas/BCAR1 expression in cancers can result from gene amplification, transcription upregulation or changes in protein stability. Overexpression of p130Cas/BCAR1 has been detected in human breast cancer, prostate cancer, ovarian cancer, lung cancer, colorectal cancer, hepatocellular carcinoma, glioma, melanoma, anaplastic large cell lymphoma and chronic myelogenous leukaemia. The presence of aberrant levels of hyperphosphorylated p130Cas/BCAR1 strongly promotes cell proliferation, migration, invasion, survival, angiogenesis and drug resistance.
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Dendritic cells (DCs) help macrophages sustain inflammatory processes and participate in the innate immune system response, but can also prime adaptive immunity. Gene expression analyses have shown that DCs can “multi-task” by temporally segregating their different functions. Soon after recognizing an infectious agent, immature DCs transition to a state of early activation via a core response characterized by rapid downregulation of genes involved with pathogen recognition and phagocytosis, upregulation of cytokine and chemokine genes to recruit other immune cells to the side of inflammations; and expression of genes that control migratory capacity. Early activated DCs are enabled to migrate from non-lymphoid tissues to lymph nodes, where they can prime T-cell responses. These early DCs responses are related to innate immunity and consist of the “core transcriptional response” of DCs.
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This latter condition is important for any pharmacological agent to be used in the treatment of addiction—drugs used to treat addiction should be less reinforcing than the drug whose addiction they treat and optimally have no reinforcing effects. 400px A recent study published in Nature showed an upregulation of microRNA-212 in the dorsal striatum of rats previously exposed to cocaine for extended periods. Animals infected with a viral vector overexpressing miR-212 in the dorsal striatum produced the same initial levels of cocaine intake; however, drug consumption progressively decreased as net cocaine exposure increased. The authors of the study noted that viral-infected animals exhibited decreased operant responding during the post-infusion time-out period and proposed that this demonstrated a reduction in compulsive drug-seeking behavior.
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HMGB1 is a major mediator of endotoxin shock and is recognized as a DAMP by certain immune cells, triggering an inflammatory response. It is known to induce inflammation by activating NF-kB pathway by binding to TLR, TLR4, TLR9, and RAGE (receptor for advanced glycation end products). HMGB1 can also induce dendritic cell maturation via upregulation of CD80, CD83, CD86 and CD11c, and the production of other pro-inflammatory cytokines in myeloid cells (IL-1, TNF-a, IL-6, IL-8), and it can lead to increased expression of cell adhesion molecules (ICAM-1, VCAM-1) on endothelial cells. (2) DNA and RNA : The presence of DNA anywhere other than the nucleus or mitochondria is perceived as a DAMP and triggers responses mediated by TLR9 and DAI that drive cellular activation and immunoreactivity.
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C-peptide has been shown to bind to the surface of a number of cell types such as neuronal, endothelial, fibroblast and renal tubular, at nanomolar concentrations to a receptor that is likely G-protein-coupled. The signal activates Ca2+-dependent intracellular signaling pathways such as MAPK, PLCγ, and PKC, leading to upregulation of a range of transcription factors as well as eNOS and Na+K+ATPase activities. The latter two enzymes are known to have reduced activities in patients with type I diabetes and have been implicated in the development of long-term complications of type I diabetes such as peripheral and autonomic neuropathy. In vivo studies in animal models of type 1 diabetes have established that C-peptide administration results in significant improvements in nerve and kidney function.
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This interaction prolonged the splicing of XBP-1 mRNA thereby inducing transcriptional upregulation of targets of spliced XBP-1 like EDEM1, ERdj4 and P58IPK rescuing the cells from apoptosis. Other studies suggest that Hsp70 may play an anti-apoptotic role at other steps, but is not involved in Fas-ligand- mediated apoptosis (although Hsp 27 is). Therefore, Hsp70 not only saves important components of the cell (the proteins) but also directly saves the cell as a whole. Considering that stress-response proteins (like Hsp70) evolved before apoptotic machinery, Hsp70's direct role in inhibiting apoptosis provides an interesting evolutionary picture of how more recent (apoptotic) machinery accommodated previous machinery (Hsps), thus aligning the improved integrity of a cell's proteins with the improved chances of that particular cell's survival.
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However mice lacking both copies of ataxin 1 do not develop progressive neurological symptoms or show signs of atrophy, suggesting that toxicity of the mutated protein, not loss of function, is the main mechanism for SCA1 pathology. A comparison of mRNA between ataxin null mice and mice with ataxin1154Q/+ shows that there are common changes in gene expression, including upregulation of genes known to be repressed by an ataxin 1/CIC complex. This suggest that, while not the primary mechanism, a loss of ataxin 1 function contributes to the pathogenesis of SCA1. While the ataxin 1/CIC complex losses some of its regulatory function with expanded ataxin 1, CIC knockout mice do not show degeneration, suggesting interactions between ataxin 1 and CIC mediate most of the toxic effects.
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Following heart failure, the body increases sympathetic activity to the adrenal medulla as the compensatory mechanism to increase heart rate and cardiac output. This increased sympathetic activity leads to chronically increased synthesis and secretion of catecholamines from the adrenal chromaffin cells. This chronic increase of epinephrine and norepinephrine secretion causes desensitization of the chromaffin cells to catecholamines resulting in a decrease in production and presence of α2 adrenergic receptors on their cell membrane. This desensitization and downregulation of α2 adrenergic receptors is caused by the upregulation of the enzyme Adrenal G protein coupled receptor kinase 2 (GRK2) which effectively eliminates the normal autocrine-type negative feedback that normally prevents the cells from over producing the catecholamines and replaces it with a positive feedback loop in which increased secretion further elicits more secretion.
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Increased brain-derived neurotrophic factor (BDNF) signaling in the ventral tegmental area (VTA) has been shown to mediate opioid-induced withdrawal symptoms via downregulation of insulin receptor substrate 2 (IRS2), protein kinase B (AKT), and mechanistic target of rapamycin complex 2 (mTORC2). As a result of downregulated signaling through these proteins, opiates cause VTA neuronal hyperexcitability and shrinkage (specifically, the size of the neuronal soma is reduced). It has been shown that when an opiate-naive person begins using opiates in concentrations that induce euphoria, BDNF signaling increases in the VTA. Upregulation of the cyclic adenosine monophosphate (cAMP) signal transduction pathway by cAMP response element binding protein (CREB), a gene transcription factor, in the nucleus accumbens is a common mechanism of psychological dependence among several classes of drugs of abuse.
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Micro-nutrient transfer is thought, for the most part, to occur by passive transport across cellular membranes, both during absorption, from soil by fungi, and transfer from fungi to host plants. This is not always the case though and although research on the topic is limited, there is evidence of active transport and allocation of micro-nutrients in certain conditions. The upregulation of cation transporters is observed in orchid D. officinale symbioses, suggesting fungi may assisted in the transfer of nutrients from fungi to plant. Cations, especially iron, are often bound tightly to organic and clay substrates keeping them out of reach of plants, fungi and bacteria, but compounds such as siderophores are often secreted into the soil by fungi and bacteria to aid in the acquisition of these cations.
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Upregulation of PHACTR1 by transforming growth factor (TGF)-β has been described in breast cancer cell lines, potentially pointing to a connection with the TGF-β signaling pathway, which is also implicated in genetic predisposition to migraines and has a key role in Marfan and Loeys-Dietz syndromes, two inherited connective tissue disorders causing aortic dissection. In humans, genome-wide association studies have linked PHACTR1 to coronary artery disease. Considering that arterial calcification is a well-known risk factor for coronary artery disease and myocardial infarction, one study tested ∼2.5 million SNPs for an association with coronary artery calcification and aortic calcification in 2620 male individuals who were current or former heavy smokers and underwent chest CT scans in the NELSON trial. No SNPs were associated with aortic calcification on a genome-wide scale.
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The median age of diagnosis is approximately late thirties to early forties. The estimates of childhood disease vary (8%, 15%, 30%) but it can be seen at any age. The disease usually arises in lymph nodes, particularly the neck, but extranodal involvement, including in the gastrointestinal tract, nasal cavity, ovary and brain, has been described. Morphologically, there are large immunoblast-like cells with large central nucleoli, often cellular clusters, with a predilection for the lymph node sinuses in a cohesive pattern that can suggest carcinoma cells. Upregulation of ALK is mainly due to chromosomal translocation t(2;17), resulting in a fusion gene of CLTC with ALK, but can rarely be due to t(2;5), fusing NPM1 with ALK; the later is the usual finding in anaplastic large cell lymphoma (ALCL).
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Isolated 17,20-lyase deficiency is a rare disorder caused by genetic mutations in the gene CYP17A1, while not affecting 17α-hydroxylase. Isolated 17,20 lyase deficiency is a rare disease with only a small number of confirmed reports due to mutations in the CYP17A1 gene. Observed physiological abnormalities of the condition include markedly elevated serum levels of progestogens such as progesterone and 17α-hydroxyprogesterone (due to upregulation of precursor availability for androgen and estrogen synthesis), very low or fully absent peripheral concentrations of androgens such as dehydroepiandrosterone (DHEA), androstenedione, and testosterone and estrogens such as estradiol (due to the lack of 17,20-lyase activity, which is essential for their production), and high serum concentrations of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (due to a lack of negative feedback on account of the lack of sex hormones).
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Recent studies show pro-inflammatory cytokine processes take place during clinical depression, mania and bipolar disorder, and it is possible that symptoms of these conditions are attenuated by the pharmacological effect of antidepressants on the immune system. Studies also show that the chronic secretion of stress hormones as a result of disease, including somatic infections or autoimmune syndromes, may reduce the effect of neurotransmitters or other receptors in the brain by cell-mediated pro- inflammatory pathways, thereby leading to the dysregulation of neurohormones. SSRIs, SNRIs and tricyclic antidepressants acting on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti- inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of Interferon-gamma (IFN-gamma) and Interleukin-10 (IL-10), as well as TNF-alpha and Interleukin-6 (IL-6). Antidepressants have also been shown to suppress TH1 upregulation.
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In 1988, Pierre Lebon and his colleagues identified the additional feature of raised levels of interferon-alpha in patient CSF in the absence of infection. This observation supported the suggestion that AGS was an inflammatory disease, as did the later finding of increased levels of the inflammatory marker neopterin in CSF, and the demonstration that more than 90% of individuals with a genetic diagnosis of AGS, tested at any age, demonstrate an upregulation of interferon-induced gene transcripts - a so-called interferon signature. All cases of Cree encephalitis (an early-onset progressive encephalopathy in a Cree First Nations community in Canada), and many cases previously described as pseudo-TORCH syndrome, (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus), initially considered to be separate disorders, were later found to be the same as AGS (although other causes of, genetically distinct, ‘pseudo-TORCH’ phenotypes exist).
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This reaction is a redox reaction: vitamin C (ascorbic acid) is oxidized to dehydroascorbic acid, and DCPIP is reduced to the colorless compound DCPIPH2 :DCPIP (blue) + H+ → DCPIPH (pink) :DCPIPH (pink) + vitamin C → DCPIPH2 (colorless) In this titration, when all the ascorbic acid in the solution has been used up, there will not be any electrons available to reduce the DCPIPH and the solution remains pink due to the DCPIPH. The end point is a pink color that persists for 10 seconds or more, if there is not enough ascorbic acid to reduce all of the DCPIPH. Pharmacological experiments suggest that DCPIP may serve as a pro-oxidant chemotherapeutic targeting human cancer cells in an animal model of human melanoma; DCPIP-induced cancer cell death occurs by depletion of intracellular glutathione and upregulation of oxidative stress.
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TLR signaling has been linked to accumulation and function of MDSC at the site of tumor and it also allows mesenchymal stromal cells to counter NK cell-mediated anti-tumor immunity. In HepG2 hepatoblastoma cells LPS increased TLR4 levels, cell proliferation and resistance to chemotherapy, and these phenomena could be reversed by TLR4 gene knockdown. Similarly, LPS stimulation of human liver cancer cell line H7402 resulted in TLR4 upregulation, NF-κB activation, TNF, IL-6 and IL-8 production and increased proliferation that could be reversed by signal transducer and STAT3 inhibition. Besides the successful usage of Bacillus Calmette–Guérin in the therapy of bladder cancer there are reports on the treatment of oral squamous cell carcinoma, gastric cancer and cervical cancer with lyophilized streptococcal preparation OK-432 and utilization of TLR4/TLR2 ligands – derivatives of muramyl dipeptide.
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Experiments in mice have demonstrated that tumor cells preferentially invade into the adjacent stroma along stiff collagen fibers. These stiff collagen alignments can be used to identify focal sites of breast tumor cell microinvasion. Pregnancy, which has various links to breast cancer incidence and prognosis, involves postpartum breast involution that relies on collagen remodeling and inflammation that converts these collagen fibers into stiffer counterparts, thus establishing a potential link between pregnancy and metastatic properties. Though some research shows that stiffer tumors are indicative of increased metastasis and decreased survival (which contradicts the concept that durotactic cells should be more attracted to the tumor and metastasize less), this is not counter intuitive because collagen-dependent integrin signaling has a wide range of consequences beyond durotaxis, including inhibition of the tumor suppressor PTEN via upregulation of the miRNA miR-18a.
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This study took special note of the fact that perlecan upregulation occurred even before that of heparanase, an essential protein involved in the process of extravasation. In ovarian cancer as in other cancers, perlecan expression occurs differently throughout progression of the disease. Perlecan staining is lost in ovarian basement membrane that has been breached by an invasive adenocarcinoma, which is in contrast to perlecan staining in the basement membranes of normal ovaries and those with benign tumors, where basement membrane is homogeneous and very similar in composition to that in other normal tissues. This is consistent with other results showing loss of perlecan in basement membranes affected by invasive cervical cancer spreading to the pelvic lymph nodes, which comes as no surprise due to the correlation of elevated levels of heparanase mRNA expression with invasion of similar cervical carcinoma.
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This is similar to the 5- to 10-fold increase in SHBG levels that occurs during pregnancy. Due to the marked increase in SHBG levels, free testosterone levels become very low during treatment with EE-containing birth control pills. In men, a study found that treatment with a relatively low dosage of 20 μg/day EE for five weeks increased circulating SHBG levels by 150% and, due to the accompanying decrease in free testosterone levels, increased total circulating levels of testosterone by 50% (via upregulation of gonadal testosterone production due to reduced negative feedback by androgens on the hypothalamic–pituitary–gonadal axis). The stimulation of hepatic SHBG production by EE is far stronger than with other estrogens like estradiol, owing to the high resistance of EE to inactivation in the liver and hence its disproportionate effects in this part of the body.
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LCHN is localized to the developing mouse brain LCHN expression has been reported to be unregulated following ischemic stroke, chronic alcoholism, and cell culture responses of immature and mature dendrites to prolonged hypoxia. Additionally, decreased expression as a result of CpG methylation has been implicated to be pathogenic in patients with FTD-ALS. Within the predicted promoter of KIAA1147, there are predicted binding sites for hypoxia response elements that would accompany ischemic stroke, heat shock proteins, factors related to the glucocorticoid mediated stress response, and cAMP responsive factors related to the ER stress response. Due to the reported evidence of LCHN upregulation following ischemic stroke, which often results in neuronal damage or death, as well presence of several binding sites for factors induced by rapid trauma to the brain, it is likely that KIAA1147 plays a role in the brain’s response to sudden stress and injury.
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It thus seems likely that while δ-opioid agonists can produce respiratory depression at very high doses, at lower doses they have the opposite effect, a fact that may make mixed mu/delta agonists such as DPI-3290 potentially very useful drugs that might be much safer than the μ agonists currently used for pain relief. Many delta agonists may also cause seizures at high doses, although not all delta agonists produce this effect. Of additional interest is the potential for delta agonists to be developed for use as a novel class of antidepressant drugs, following robust evidence of both antidepressant effects and also upregulation of BDNF production in the brain in animal models of depression. These antidepressant effects have been linked to endogenous opioid peptides acting at δ- and μ-opioid receptors, and so can also be produced by enkephalinase inhibitors such as RB-101.
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ALL and CML therapies have targeted JAK2 as well as BCR-ABL using nilotinib and ruxolitinib within murine models to downregulate downstream cytokine signaling by silencing STAT3 and STAT5 transcription activation (appelmann et al). The interaction between JAK2 and BCR-ABL within these hematopoietic malignancies implies an important role of JAK-STAT-mediated cytokine signaling in promoting the growth of leukemic cells exhibiting the Ph chromosome and BCR-ABL tyrosine kinase activity. Though the centrality of the JAK2 pathway to direct proliferation in CML has been debated, its role as a downstream effector of the BCR-ABL tyrosine kinase has been maintained. Impacts on the cell cycle via JAK-STAT are largely peripheral, but by directly impacting the maintenance of the hematopoietic niche and its surrounding microenvironment, the BCR-ABL upregulation of JAK-STAT signaling plays an important role in maintaining leukemic cell growth and division.
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CARP was originally identified as a YB-1-associating, cardiac- restricted transcription co-repressor in the homeobox NKX2-5 pathway that is involved in cardiac ventricular chamber specification, maturation and morphogenesis, and whose mRNA levels are exquisitely sensitive to Doxorubicin, mediated through a hydrogen peroxide/ERK/p38MAP kinase-dependent as well as M-CAT cis-element-dependent mechanism. Subsequent studies showed that CARP expression in cardiomyocytes is regulated by alpha-adrenergic signaling, in part via the transcription factor GATA4. An additional study showed that beta- adrenergic signaling via protein kinase A and CaM kinase induces the expression of CARP, and that CARP may have a negative effect on contractile function. CARP has also been identified as a transcriptional co-activator of tumor suppressor protein p53 for stimulating gene expression in muscle; p53 was found to be an upstream effector of CARP via upregulation of the proximal ANKRD1 promoter.
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Their homologs in D. deserti were also among the most highly induced, showing that not only their presence but also their strong upregulation in response to radiation damage is conserved. A common 17-base pair radiation/desiccation response motif (RDRM) has been identified upstream of a set of radiation- induced genes, including various DNA repair genes such as recA, gyrA, uvrB and ssb, strongly suggesting the presence of an RDR regulon that is conserved in Deinococcus species. The irrE gene is essential for radiation resistance and required for the radiation-induced expression of recA and other genes with an RDRM (radiation/desiccation response motif) site in D. radiodurans and D. deserti. DdrO could be the global regulator of the RDR regulon, because it is the only induced and conserved regulator gene preceded by an RDRM site in D. radiodurans, D. geothermalis and D. deserti.
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Unlike conventional dendritic cells (cDCs) that leave the bone marrow as precursors, pDCs leave the bone marrow to go to the lymphoid organs and peripheral blood upon completing development. Plasmacytoid dendritic cells are also distinguished from cDCs because of their ability to produce significant amounts of type-1 interferon. pDC maturation is initiated when the cell comes in contact with a virus, prompting the upregulation of MHC class I and MHC class II, co- stimulatory molecules CD80, CD86, CD83, and c-c chemokine receptor 7 (CCR7) and interferon production gradually decreases. CCR7 expression prompts the matured pDC to migrate to a lymph node where it will be able to stimulate and interact with T cells. In humans, pDCs exhibit plasma cell morphology and express CD4, HLA-DR, CD123, blood-derived dendritic cell antigen-2 (BDCA-2), Toll-like receptor (TLR) 7 and TLR9 within endosomal compartments.
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Although miR-133 is known to promote MEF-2-dependent myogenesis, it also inhibits Runx2-mediated osteogenesis. BMP2 controls bone cell determination by inducing miRNAs that target muscle genes but mainly by down- regulating multiple miRNAs that constitute an osteogenic program, thereby releasing from inhibition pathway components required for cell lineage commitment establish a mechanism for BMP morphogens to selectively induce a tissue-specific phenotype and suppress alternative lineages. Nicotine activates α7-nAChR and downregulates the levels of miR-133 and miR-590 leading to significant upregulation of expression of TGF-β1 and TGF-βRII at the protein level establishing miR-133 and miR-590 as repressors of TGF-β1 and TGF-βRII. miR-133 enhances myoblast proliferation by repressing serum response factor (SRF) mIR-133 suppresses SP1 expression In rats, miR-133b is expressed in retinal dopaminergicamacrine cell, and this expression is significantly increased during early stage during retinal degeneration.
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It is now widely accepted that atherosclerosis is a result of cellular and molecular events characteristic of inflammation. Vascular inflammation can be caused by upregulation of Ang-II, which is produced locally by inflamed vessels and induces synthesis and secretion of IL-6, a cytokine responsible for induction of angiotensinogen synthesis in liver through JAK/STAT3 pathway, which gets activated through high affinity membrane protein receptors on target cells, termed IL-6R-chain recruiting gp-130 that is associated with tyrosine kinases (Jaks 1/2, and Tyk2 kinase). Cytokines IL-4 and IL-13 gets elevated in lungs of chronically suffered asthmatics. Signalling through IL-4/IL-13 complexes is thought to occur through IL-4Rα- chain, which is responsible for activation of JAK-1 and Tyk2 kinases. A role of Tyk2 in rheumatoid arthritis is directly observed in Tyk2-deficient mice that were resistant to experimental arthritis.
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Interestingly enough, researchers at the Dana Farber Institute found that breast cancer cells that developed resistance to palbociclib were able to become resensitized to the drug following a seven-day "treatment holiday". Scientists linked the initial development of resistance to an increase in expression of CDK6 (but not CDK4, the other target of palbociclib), with the specific mechanism of CDK6 upregulation originating from suppression of the TGF-β pathway via the miR-432-5p microRNA. Scientists made this discovery after noticing that, in the lab, all breast cancer cells in the dish were found to acquire resistance at a similar time, a phenomenon contrary to classical models of acquiring resistance in which one or two cells become resistant and then expand to encompass more of the tumor as they divide. These palbociclib-resistance cells were also noted to not contain a particular mutation, but rather became resistant via and continued to spread this resistance to neighboring cells via exosomes.
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In June 2005 the Triebel group showed that antibodies to LAG-3 would result in T cell expansion, through increased rounds of cell division which LAG-3 signalling would otherwise block. In July 2005 scientists at the Institute for Research in Biomedicine in Bellinzona established that LAG3 expression on B cells is induced by T cells In 2006 scientists at the Istituto Superiore di Sanità in Rome showed that LAG could be used as a biomarker to assess the induction of Th-type responses in recipients of acellular pertussis vaccines. In April 2007 scientists working at Edward Jenner Institute for Vaccine Research in the UK demonstrated that LAG-3 participates in Treg-induced upregulation of CCR7 and CXCR4 on dendritic cells, resulting in semi-mature dendritic cells with the ability to migrate into lymphoid organs. Scientists at Sun Yat-sen University in China showed that LAG-3 played a role in immune privilege in the eye.
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The affinity of bicalutamide for the is approximately 30 to 100 times lower than that of ( ≈ 3.8 nM), the main endogenous ligand of the receptor in the prostate gland. However, sufficiently high relative concentrations of bicalutamide (1,000- to 10,000-fold excess) are able to completely prevent activation of the by androgens like and testosterone and subsequent upregulation of the transcription of androgen-responsive genes and associated effects. At steady- state, relative to the normal adult male range for testosterone levels (300–1,000 ng/dL), circulating concentrations of bicalutamide at 50 mg/day are roughly 600 to 2,500 times higher and at 150 mg/day around 1,500 to 8,000 times higher than circulating testosterone levels, while bicalutamide concentrations, relative to the mean testosterone levels present in men who have been surgically castrated (15 ng/dL), are approximately 42,000 times higher than testosterone levels at 50 mg/day. Median reduction (%) with bicalutamide monotherapy at different dosages (mg/day) and with castration monotherapy.
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Presence of gene is found in the chorionic plate, in the amnion epithelium, syncytiotrophoblasts, villous fibroblasts, chorionic trophoblasts, amniotic trophoblasts, as well as the basal plate of the placenta, in the decidual cells and extravillous cytotrophoblasts. During the process of chorioamnionitis/deciduitis, the upregulation of PTGS2 in the amnion and choriodecidua is one of three limited effects of inflammation in the uterus. Increased expression of the PTGS2 gene in the fetal membranes is connected to the presence of inflammation, causing uterine prostaglandin gene expression and immunolocalization of prostaglandin pathway proteins in chorionic trophoblast cells and adjacent decidua, or choriodecidua. PTGS2 is linked with the inflammatory system and has been observed in inflammatory leukocytes. It has been noted that there is a positive correlation with PTGS2 expression in the amnion during spontaneous labour and was discovered to have increased expression with gestational age following the presence of labour with no change observed in amnion and choriodecidua during either preterm or term labour.
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It has yet to be fully understood how ketamine mediates its robust and rapid-onset antidepressant effects. In any case, it has been elucidated that acute blockade of NMDA receptors in the brain results in an activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA receptors), which in turn modulate a variety of downstream signaling pathways to influence neurotransmission in the limbic system and mediate antidepressant effects of NMDA receptor antagonists like ketamine. Such downstream actions of this activation of AMPA receptors include upregulation of brain-derived neurotrophic factor (BDNF) and activation of its signaling receptor tropomyosin receptor kinase B (TrkB), activation of the mammalian target of rapamycin (mTOR) pathway, deactivation of glycogen synthase kinase 3 (GSK-3), and inhibition of the phosphorylation of the eukaryotic elongation factor 2 (eEF2) kinase. In addition to blockade of the NMDA receptor, the active metabolite of ketamine hydroxynorketamine, which does not interact importantly with the NMDA receptor but nonetheless indirectly activates AMPA receptors similarly, may also or alternatively be involved in the rapid-onset antidepressant effects of ketamine.
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CCL2 is implicated in pathogeneses of several diseases characterized by monocytic infiltrates, such as psoriasis, rheumatoid arthritis and atherosclerosis. Administration of anti-CCL2 antibodies in a model of glomerulonephritis reduces infiltration of macrophages and T cells, reduces crescent formation, as well as scarring and renal impairment. CCL2 is involved in the neuroinflammatory processes that takes place in the various diseases of the central nervous system (CNS), which are characterized by neuronal degeneration. CCL2 expression in glial cells is increased in epilepsy, brain ischemia Alzheimer's disease experimental autoimmune encephalomyelitis (EAE), and traumatic brain injury. Hypomethylation of CpG sites within the CCL2 promoter region is affected by high levels of blood glucose and TG, which increase CCL2 levels in the blood serum. The later plays an important role in the vascular complications of type 2 diabetes. CCL2 induces amylin expression through ERK1/ERK2/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. Amylin upregulation by CCL2 contributes to the elevation of the plasma amylin and insulin resistance in obesity.
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This is due in part to the marked increases in the mitochondrial biogenesis, upregulation of GLUT-4, UCP-3, Hexokinase II along with other metabolic and mitochondrial enzymes despite decreases in AMPK activity with training. Questions also arise because skeletal muscle cells which express these decreases in AMPK activity in response to endurance training also seem to be maintaining an oxidative dependent approach to metabolism, which is likewise thought to be regulated to some extent by AMPK activity. If the AMPK response to exercise is responsible in part for biochemical adaptations to training, how then can these adaptations to training be maintained if the AMPK response to exercise is being attenuated with training? It is hypothesized that these adaptive roles to training are maintained by AMPK activity and that the increases in AMPK activity in response to exercise in trained skeletal muscle have not yet been observed due to biochemical adaptations that the training itself stimulated in the muscle tissue to reduce the metabolic need for AMPK activation.
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When in symbiotic relationship with orchid plants the mycorrhizal fungus T. calospora upregulates the expression of SvAAP1 and SvAAP2, these genes encode amino acid permeases, supporting the hypothesis that amino acids are an important molecule involved in nitrogen transport. Amino acids contain a significant amount of carbon as well and the transport of carbon may be the primary driving cause of the observed upregulation of the amino acid transporter genes, nonetheless nitrogen can still be transported to the plant via this pathway. The transport of inorganic nitrogen in the form of ammonium and the transport of organic nitrogen as amino acids most likely will occur simultaneously in the same species and or organism, depending on the abundance of different nitrogenous species in the soil, Fochi 2016 along with Dearnaley 2007 suggest that amino acids may in fact be the primary nitrogen compound transferred to orchids, evidence for this coming from isotopic ratios of enriched C13 and N15 within plants associated with mycorrhizal fungi, but more research is needed to fully understand this transport relationship.
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Receptor activation gives rise to a signal transduction cascade that leads to gene activation and diverse biological responses, including cell differentiation, proliferation, and matrix dissolution, thus initiating a process of mitogenic activity critical for the growth of endothelial cells, fibroblasts, and smooth muscle cells. FGF-1, unique among all 22 members of the FGF family, can bind to all seven FGF-receptor subtypes, making it the broadest-acting member of the FGF family, and a potent mitogen for the diverse cell types needed to mount an angiogenic response in damaged (hypoxic) tissues, where upregulation of FGF-receptors occurs. FGF-1 stimulates the proliferation and differentiation of all cell types necessary for building an arterial vessel, including endothelial cells and smooth muscle cells; this fact distinguishes FGF-1 from other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF), which primarily drives the formation of new capillaries. Besides FGF-1, one of the most important functions of fibroblast growth factor-2 (FGF-2 or bFGF) is the promotion of endothelial cell proliferation and the physical organization of endothelial cells into tube-like structures, thus promoting angiogenesis.
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The ability of the immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of immune receptors called toll-like receptors (TLRs) that are expressed on the membranes of leukocytes including dendritic cells, macrophages, natural killer cells, cells of the adaptive immunity T cells, and B cells, and non immune cells (epithelial and endothelial cells, and fibroblasts). The binding of ligands - either in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infection - to the TLR marks the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity. Upon activation, TLRs recruit adaptor proteins (proteins that mediate other protein-protein interactions) within the cytosol of the immune cell in order to propagate the antigen-induced signal transduction pathway. These recruited proteins are then responsible for the subsequent activation of other downstream proteins, including protein kinases (IKKi, IRAK1, IRAK4, and TBK1) that further amplify the signal and ultimately lead to the upregulation or suppression of genes that orchestrate inflammatory responses and other transcriptional events.
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Targeted deletion of Dicer in the FoxD1-derived renal progenitor cells in a murine model resulted in a complex renal phenotype including expansion of nephron progenitors, fewer renin cells, smooth muscle arterioles, progressive mesangial loss and glomerular aneurysms. High throughput whole transcriptome profiling of the FoxD1-Dicer knockout mouse model revealed ectopic upregulation of pro-apoptotic gene, Bcl2L11 (Bim) and dysregulation of the p53 pathway with increase in p53 effector genes including Bax, Trp53inp1, Jun, Cdkn1a, Mmp2, and Arid3a. p53 protein levels remained unchanged, suggesting that FoxD1 stromal miRNAs directly repress p53-effector genes. Using a lineage tracing approach followed by Fluorescent-activated cell sorting, miRNA profiling of the FoxD1-derived cells not only comprehensively defined the transcriptional landscape of miRNAs that are critical for vascular development, but also identified key miRNAs that are likely to modulate the renal phenotype in its absence. These miRNAs include miRs‐10a, 18a, 19b, 24, 30c, 92a, 106a, 130a, 152, 181a, 214, 222, 302a, 370, and 381 that regulate Bcl2L11 (Bim) and miRs‐15b, 18a, 21, 30c, 92a, 106a, 125b‐5p, 145, 214, 222, 296‐5p and 302a that regulate p53-effector genes.
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