Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thirty-two normal LEW/Sea rats were transplanted a piece of syngeneic pancreas between the peritoneum and abdominal muscle. Among them, 17 (68%) of the 25 rats that received pancreatic transplantation at 41-50 days of age had a surviving beta-cell mass at 5.5-7.1 months after transplantation. Among the 25 rats, 12 rats injected with interleukin-1 receptor (IL-1R) and IL-2Rbeta peptides at post-transplantation showed better surviving grafts at 5.5 months' observation. Only 2 (25%) of the other 7 young rats that received a pancreatic graft at 20 days of age had a small mass at 21 days post-transplantation. Flow cytometer (FCM) analyses showed that thymus OX40(+) (CD134(+)) T-cells were increased up to 37+/-4% at the graft rejection in the 13 old rats without the IL-R peptide injections. The 7 young rats had 99% of thymus OX40(+) T-cells. However, the 12 old rats injected with the IL-R peptides showed suppressed numbers of thymus OX40(+) T-cells (8-13+/-3%). The long-term surviving, but apoptotic, grafted beta-cells were stained positively both with anti-insulin monoclonal antibody (mAb) and with anti-c-erbB-2/human epidermal growth factor receptor (HER)-2/neu mAb. Expression of a c-erb family oncogene was shown on the pancreatic graft surviving for 7.1 months. Electron microscopic analysis of the grafted beta-cells showed abnormally large beta granules and loss of functioning mitochondria in the cytoplasm. In 18 (56%) of the 32 rats, the 220-bp and 380-bp specific products of insulin-degrading enzyme (IDE) gene were amplified using the polymerase chain reaction (PCR) of the liver DNA. Among the 18 rats, 6 rats expressed 2 extra hands of 280-bp and 700-bp in a correlation with the high levels of the transforming growth factor-alpha (TGF-alpha) cDNA of 120-bp which was amplified in the quantitative reverse-transcriptase (RT)-PCR of the liver cDNA. Among the selected 11 rats, 5 rats showed large amounts of the 120-bp TGF-alpha cDNA. Host pancreatic RT-PCR showed 235-bp or 250-bp bcl-2 and 181-bp bcl-xS gene products. The bcl-2 cDNA of the host pancreas was amplified actively when the pancreatic graft was being rejected. Exceptionally, the one female injected with the IL-R peptides showed a low level of the liver TGF-alpha cDNA together with the pancreatic expressions of Bax (140-bp), bcl-2 and like interleukin converting enzyme (LICE) (318-bp) cDNA. Insulin secretion from the grafted beta-cells and IL-1beta-induced Fas-mediated apoptosis of the beta-cells were suspected to be present at the same time in the female with the best graft survival.
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PMID:Oncogene expression on the syngeneic beta-cells of long-term surviving pancreatic grafts and better effects of interleukin-1 receptor (IL-1R) and IL-2Rbeta on the grafted beta-cells in LEW/Sea strain rats. 1272 75

Insulin secretion from pancreatic beta cells is partly regulated by cell membrane potential. Background K+ channels that stabilize the resting membrane potential would suppress excitability and insulin secretion. Recent studies show that members of the two-pore domain K+ (K2P) channel family behave as background K+ channels in many excitable cells. Therefore, the expression of K2P channels was studied in insulin-secreting MIN6 cells. Reverse transcriptase PCR showed that, among nine K2P channels tested, TASK-1, TASK-2, TASK-3, TREK-2, and TRESK-2 were expressed in MIN6 cells. Cell-attached recordings on MIN6 cells revealed five types of K+ channels that were open at rest. Two were ATP-sensitive and Ca2+-activated K+ channels, as judged by their sensitivity to ATP and Ca2+, respectively, and single-channel conductance. Among five K2P channels, only TREK-2 could be clearly identified in MIN6 cells. The molecular identity of two other K+ channels is not yet known. TREK-2 in MIN6 cells was activated by arachidonic acid, membrane stretch, and low pH solution (pH 5.8). Arachidonic acid increased Ba2+-sensitive whole-cell current in MIN6 cell. These results suggest that TREK-2 contributes to the background K+ conductance in MIN6 cells, and may regulate depolarization-induced secretion of insulin.
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PMID:Functional expression of TREK-2 in insulin-secreting MIN6 cells. 1535 40

Insulin-like growth factor-1 (IGF-1) is a member of a family of two interacting polypeptide hormone ligands with close homology to proinsulin. IGF-1 can influence mesenchymal cell migration, proliferation, and extracellular matrix deposition, thus implicating it in the progression of fibrotic disorders. Currently, there is limited information about the regulation of IGF-1 expression in areca quid-associated oral submucous fibrosis (OSF). The aim of this study was to compare IGF-1 expression in normal human buccal mucosa and OSF specimens and further explore the potential mechanism that may lead to induce IGF-1 expression. Twenty OSF specimens and 10 normal buccal mucosa were examined by immunohistochemistry. The activity of IGF-1 from cells cultured from OSF and normal buccal mucosa were by using reverse-transcriptase polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Furthermore, the effect of arecoline, the major areca nut alkaloid, was added to explore the potential mechanism that may lead to induce IGF-1 expression. IGF-1 expression was significantly higher in OSF specimens (p<0.05) and expressed mainly by fibroblasts, endothelial cells, and inflammatory cells. OSF demonstrated significantly higher IGF-1 protein expression than normal buccal mucosa fibroblast (BMF) both in mRNA and protein levels (p<0.05). In addition, arecoline was also found to elevate IGF-1 mRNA and protein expression in a dose-dependent manner (p<0.05). Taken together, the data presented here demonstrated that IGF-1 expression is significantly upregulated in OSF from areca quid chewers and arecoline may be responsible for the enhanced IGF-1 expression in vivo.
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PMID:The upregulation of insulin-like growth factor-1 in oral submucous fibrosis. 1605 26

Diabetes is associated with renal calcium and magnesium wasting, but the molecular mechanisms of these defects are unknown. We measured renal calcium and magnesium handling and investigated the effects of diabetes on calcium and magnesium transporters in the thick ascending limb and distal convoluted tubule in streptozotocin (STZ)-induced diabetic rats. Rats were killed 2 weeks after inducing diabetes, gene expression of calcium and magnesium transporters in the kidney was determined by real-time polymerase chain reaction, and the abundance of protein was assessed by immunoblotting. Our results showed that diabetic rats had significant increase in the fractional excretion for calcium and magnesium (both P < 0.01), but not for sodium. Reverse transcriptase-polymerase chain reaction revealed significant increases in messenger RNA abundance of transient potential receptor (TRP) V5 (223 +/- 10%), TRPV6 (177 +/- 9%), calbindin-D28k (231 +/- 8%), and TRPM6 (165 +/- 8%) in diabetic rats. Sodium chloride cotransporter was also increased (207 +/- 10%). No change was found in paracellin-1 (cortex: 108 +/- 8%; medulla: 110 +/- 10%). Immunofluorescent studies of renal sections showed significant increase in calbindin-D28k (238 +/- 10%) and TRPV5 (211 +/- 10%), but no changes in paracellin-1 in Western blotting (cortex: 110 +/- 7%; medulla: 99 +/- 7%). Insulin administration completely corrected the hyperglycemia-associated hypercalciuria and hypermagnesiuria, and reversed the increase of calcium and magnesium transporter abundance. In conclusion, our results demonstrated increased renal calcium and magnesium transporter abundance in STZ-induced diabetic rats, which may represent a compensatory adaptation for the increased load of calcium and magnesium to the distal tubule.
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PMID:Increased renal calcium and magnesium transporter abundance in streptozotocin-induced diabetes mellitus. 1655 23

Insulin represses gluconeogenesis, in part, by inhibiting the transcription of genes that encode rate-determining enzymes, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase). Glucocorticoids stimulate expression of the PEPCK gene but the repressive action of insulin is dominant. Here, we show that treatment of H4IIE hepatoma cells with the synthetic glucocorticoid, dexamethasone (dex), induces the accumulation of glucocorticoid receptor, as well as many transcription factors, coregulators, and RNA polymerase II, on the PEPCK gene promoter. The addition of insulin to dex-treated cells causes the rapid dissociation of glucocorticoid receptor, polymerase II, and several key transcriptional regulators from the PEPCK gene promoter. These changes are temporally related to the reduced rate of PEPCK gene transcription. A similar disruption of the G-6-Pase gene transcription complex was observed. Additionally, insulin causes the rapid demethylation of arginine-17 on histone H3 of both genes. This rapid, insulin-induced, histone demethylation is temporally related to the disruption of the PEPCK and G-6-Pase gene transcription complex, and may be causally related to the mechanism by which insulin represses transcription of these genes.
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PMID:Insulin represses phosphoenolpyruvate carboxykinase gene transcription by causing the rapid disruption of an active transcription complex: a potential epigenetic effect. 1709 78

Antiretroviral therapy for HIV-I-infections is accompanied with the occurrence of several metabolic side effects. An often encountered complication of antiretroviral therapy is the adipose redistribution syndrome characterised by an altered distribution of body fat, and linked with protease inhibitor (PI) and nucleoside-reverse-transcriptase inhibitors (NRTIs). Some NRTIs have lactate acidosis as a side effect in rare cases (0.1%), which is accompanied by a high mortality. The far less serious side effect hyperlactaemia is more frequently observed; this is a symptomatic elevation of the lactate level without acidosis. Insulin resistance is not only ascribed to therapy-induced lipoatrophy and visceral fat accumulation, it is also directly related to the use of some PIs and NRTIs. PIs and abacavir and to a lesser extend didanosine result in a high risk of cardiovascular disease. Moreover, the prevalence of traditional cardiovascular risk factors in HIV-infected subjects is higher than that in HIV-seronegative subjects. Clinically relevant interactions exist between PIs and statins. Pravastatin seems to be accompanied with the lowest chance of interaction and is therefore recommended as cholesterol-lowering therapy. The metabolic side effects are outweighed by the favourable effect of the antiretroviral agents. Counteraction of these side effects may therefore not be at the expense of the antiretroviral therapy.
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PMID:[Metabolic side effects of antiretroviral therapy]. 1859 59

Insulin resistance and type 2 diabetes are major risk factors for vascular complications. Vascular smooth muscle cells (VSMCs) derived from db/db mice, an established mouse model of type 2 diabetes, displayed enhanced inflammatory gene expression and proatherogenic responses. We examined the hypothesis that aberrant epigenetic chromatin events may the underlying mechanism for this persistent dysfunctional behavior and "memory" of the diabetic cells. Chromatin immunoprecipitation assays showed that levels of histone H3 lysine 4 dimethylation (H3K4me2), a key chromatin mark associated with active gene expression, were significantly elevated at the promoters of the inflammatory genes monocyte chemoattractant protein-1 and interleukin-6 in db/db VSMCs relative to db/+ cells. Tumor necrosis factor-alpha-induced inflammatory gene expression, H3K4me2 levels, and recruitment of RNA polymerase II at the gene promoters were also enhanced in db/db VSMCs, demonstrating the formation of open chromatin poised for transcriptional activation in diabetes. On the other hand, protein levels of lysine-specific demethylase1 (LSD1), which negatively regulates H3K4 methylation and its occupancy at these gene promoters, were significantly reduced in db/db VSMCs. High glucose (25 mmol/L) treatment of human VSMCs also increased inflammatory genes with parallel increases in promoter H3K4me2 levels and reduced LSD1 recruitment. LSD1 gene silencing with small interfering RNAs significantly increased inflammatory gene expression and enhanced VSMC-monocyte binding in nondiabetic VSMCs. In contrast, overexpression of LSD1 in diabetic db/db VSMCs inhibited their enhanced inflammatory gene expression. These results demonstrate novel functional roles for LSD1 and H3K4 methylation in VSMCs and inflammation. Dysregulation of their actions may be a major mechanism for vascular inflammation and metabolic memory associated with diabetic complications.
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PMID:Role of the lysine-specific demethylase 1 in the proinflammatory phenotype of vascular smooth muscle cells of diabetic mice. 1974 69

Both the human immunodeficiency (HIV) and hepatitis C (HCV) viruses have been associated with insulin resistance (IR). However, our understanding of the prevalence of IR, the underlying mechanisms and predisposing factors is limited, particularly among minority populations. We conducted a study of 333 Hispanic adults including: 76 HIV monoinfected, 62 HCV monoinfected, 97 HIV/HCV co-infected and 98 uninfected controls with a specific focus on HCV infection and liver injury as possible predictors of IR. IR was measured using the Quantitative Insulin Sensitivity Check Index (QUICKI). The majority (55-69%) of participants in all groups had QUICKI values <0.350. Body mass index was associated with IR in all groups. Triglycerides were associated with IR in the uninfected control group only (-1.83, SE = 0.58, P = 0.0022). HCV was associated with IR in participants infected with HIV (-0.012, SE = 0.0046, P = 0.010). Liver injury, as measured by score to assess liver injury (FIB-4) score, was significantly associated with IR independently of HCV infection (-0.0035, SE = 0.0016, P = 0.027). In the HIV/HCV co-infected group, treatment with nucleoside reverse-transcriptase (RT) inhibitors plus non-nucleoside RT inhibitors (-0.021, SE = 0.080, P = 0.048), but not protease inhibitors (-0.000042, SE = 0.0082, P = 0.96) was associated with IR. HCV infection and antiretroviral agents, including nucleoside RT inhibitor plus non-nucleoside RT inhibitor treatment are contributors to IR in HIV infection. Liver injury, as measured by the FIB-4 score, is a predictor of IR independently of HCV infection.
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PMID:Predictors of insulin resistance among Hispanic adults infected with or at risk of infection with the human immunodeficiency virus and hepatitis C virus. 1908 26

Insulin-like growth factor binding protein-3 (IGFBP-3) is known to induce apoptosis in an insulin-like growth factor (IGF)-dependent and IGF-independent manner, but the mechanism underlying the IGF-independent effects remains unclear. Polypeptide N-acetylgalactosaminyltransferase 14 (GalNAc-T14) is a novel IGFBP-3 binding partner. In this paper, small interference RNA (siRNA) targeting GalNAc-T14 was used to examine whether GalNAc-T14 affects the apoptotic action of IGFBP-3. Using semi-quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and western blot analysis, we determined that GalNAc-T14 expression was downregulated by the siRNA directed against GalNAc-T14. Apoptosis analysis of IGFBP-3-overexpressing cells treated with siRNA against GalNAc-T14 was performed to determine if GalNAc-T14 was specifically involved in IGFBP-3 signalling. The results, as determined by flow cytometric analysis and caspase-3 assay, showed that the extent of apoptosis induced by IGFBP-increased with RNA interference (RNAi) knockdown of GalNAc-T14. Our data suggest that GalNAc-T14 influences the apoptotic action of IGFBP-3 and might mediate the signalling pathway of IGFBP-3. Experiments to determine the role of GalNAc-T14 in the regulation of apoptosis induced by IGFBP-3 are under way.
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PMID:GalNAc-T14 may be involved in regulating the apoptotic action of IGFBP-3. 1980

Insulin resistance with its associated hyperglycemias represents one significant contributor to mortality in burned patients. A variety of cellular stress-signaling pathways are activated as a consequence of burn. A key player in the cellular stress response is the endoplasmic reticulum (ER). Here, we investigated a possible role for ER-stress pathways in the progression of insulin function dysregulation postburn. Rats received a 60% total body surface area thermal injury, and a laparotomy was performed at 24, 72, and 192 h postburn. Liver was harvested before and 1 min after insulin injection (1 IU/kg) into the portal vein, and expression patterns of various proteins known to be involved in insulin and ER-stress signaling were determined by Western blotting. mRNA expression of glucose-6-phosphatase and glucokinase were determined by reverse-transcriptase-polymerase chain reaction and fasting serum glucose and insulin levels by standard enzymatic and enzyme-linked immunosorbent assay techniques, respectively. Insulin resistance indicated by increased glucose and insulin levels occurred starting 24 h postburn. Burn injury resulted in activation of ER stress pathways, reflected by significantly increased accumulation of phospho-PKR-like ER-kinase and phosphorylated inositol requiring enzyme 1, leading to an elevation of phospho-c-Jun N-terminal kinase and serine phosphorylation of insulin receptor substrate (IRS) 1 postburn. Insulin administration caused a significant increase in tyrosine phosphorylation of IRS-1, leading to activation of the phosphatidylinositol 3 kinase/Akt pathway in normal liver. Postburn tyrosine phosphorylation of IRS-1 was significantly impaired, associated with an inactivation of signaling molecules acting downstream of IRS-1, leading to significantly elevated transcription of glucose-6-phosphatase and significantly decreased mRNA expression of glucokinase. Activation of ER-stress signaling cascades may explain metabolic abnormalities involving insulin action after burn.
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PMID:Post-burn hepatic insulin resistance is associated with endoplasmic reticulum (ER) stress. 2201 39


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