Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HIV-1 accessory protein Vpr arrests host cells at the G2/M phase of the cell cycle by interacting with members of the protein family 14-3-3, which regulate the activities of "partner" molecules by binding to their phosphorylated serine or threonine residues and changing their intracellular localization and/or stability. Vpr does this by facilitating the association of 14-3-3 to its partner protein Cdc25C, independent of the latter's phosphorylation status. Here we report that the same viral protein interfered with and altered the activity of another 14-3-3 partner molecule, Foxo3a, a subtype of the forkhead transcription factors, by inhibiting its association with 14-3-3. Foxo3a's transcriptional activity is normally suppressed by insulin-induced translocation of this protein from the nucleus into the cytoplasm. Vpr inhibited the ability of insulin or its downstream protein kinase Akt to change the intracellular localization of Foxo3a preferentially to the cytoplasm. This HIV-1 protein also interfered with insulin-induced coprecipitation of 14-3-3 and Foxo3a in vivo and antagonized the negative effect of insulin on Foxo3a-induced transactivation of a FOXO-responsive promoter. Moreover, Vpr antagonized insulin-induced suppression of the mRNA expression of the glucose 6-phosphatase, manganese superoxide dismutase, and sterol carrier protein 2 genes, which are known targets of insulin and FOXO, in HepG2 cells. These findings indicate that Vpr interferes with the suppressive effects of insulin on FOXO-mediated transcription of target genes via 14-3-3. Vpr thus may contribute to the tissue-selective insulin resistance often observed in HIV-1-infected individuals.
Diabetes 2005 Jan
PMID:HIV-1 accessory protein Vpr inhibits the effect of insulin on the Foxo subfamily of forkhead transcription factors by interfering with their binding to 14-3-3 proteins: potential clinical implications regarding the insulin resistance of HIV-1-infected patients. 1561 7

Reactive oxygen species (ROS) and nitric oxide (NO) are proposed mediators of cytokine-induced beta-cell destruction in type 1 diabetes. We produced transgenic mice with increased beta-cell expression of manganese superoxide dismutase (MnSOD) and catalase. Expression of these antioxidants increased beta-cell ROS scavenging and improved beta-cell survival after treatment with different sources of ROS. MnSOD or catalase conferred protection against streptozotocin (STZ)-induced beta-cell injury. Coexpression of MnSOD and catalase provided synergistic protection against peroxynitrite and STZ. To determine the potential effect of these antioxidants on cytokine-induced toxicity, we exposed isolated islets to a cytokine mixture, including interleukin-1beta and interferon-gamma. Cytokine toxicity was measured as reduced metabolic activity after 6 days and reduced insulin secretion after 1 day. Cytokines increased ROS production, and both antioxidants were effective in reducing cytokine-induced ROS. However, MnSOD and/or catalase provided no protection against cytokine-induced injury. To understand this, the nuclear factor-kappaB (NF-kappaB) signaling cascade was investigated. Antioxidants reduced NF-kappaB activation by ROS, but none of the antioxidants altered activation by cytokines, as measured by inhibitor of kappaB phosphorylation, NF-kappaB translocation, inducible NO synthase activation, and NO production. Our data agree with previous reports that antioxidants benefit beta-cell survival against ROS damage, but they are not consistent with reports that antioxidants reduce cytokine toxicity. ROS appear to have no role in cytokine toxicity in primary beta-cells.
Diabetes 2005 May
PMID:MnSOD and catalase transgenes demonstrate that protection of islets from oxidative stress does not alter cytokine toxicity. 1585 31

Several single-nucleotide polymorphisms of genes related to oxidative stress have been evaluated because intracellular reactive oxygen species are associated with development of diabetes and its microvascular complications. We performed a case-control study to investigate whether V16A polymorphism of manganese superoxide dismutase (Mn-SOD) gene is related to pathogenesis of diabetes and whether the polymorphism is associated with stages of albuminuria in Korean type 2 diabetic patients. Genotype distributions were studied in 178 nondiabetic subjects and 371 type 2 diabetic patients of 3 groups with a normoalbuminuria group (Normo group, n = 244), a microalbuminuria group (Micro group, n = 86), and an overt albuminuria group (Macro group, n = 41). The albumin/creatinine ratio (ACR) was defined as a urinary albumin/creatinine ratio. V16A genotypes were determined with polymerase chain reaction-restriction fragment length polymorphism method. Between nondiabetic subjects and type 2 diabetic patients, Mn-SOD genotype distribution (VV/VA + AA, 146/32 vs 314/57) and A allele frequency (0.121 vs 0.104) were not different. Patients with nephropathy, Micro and Macro groups, had significantly lower A allele frequency, longer diabetic duration, higher prevalence of hypertension, and greater ACR than those of patients without nephropathy (P < .05). A allele was significantly less frequent with progression of nephropathy (Normo group, 0.119; Micro group, 0.073; Macro group, 0.03; P < .05). In type 2 diabetic patients, A allele carriers had significantly lower prevalence of hypertension and lesser ACR than those of A allele noncarriers (P < .01). In multivariate analysis, hypertension, duration of diabetes, serum total cholesterol level, and A allele of Mn-SOD gene were independently associated with stages of albuminuria. These results suggest that V16A polymorphism of Mn-SOD gene is not related to pathogenesis of diabetes but is associated with stages of albuminuria in Korean type 2 diabetes.
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PMID:Manganese superoxide dismutase gene polymorphism (V16A) is associated with stages of albuminuria in Korean type 2 diabetic patients. 1632 12

Diabetic retinopathy is a sight-threatening complication of diabetes, and loss of pericytes represents early signs of its development. We tested the hypothesis that high glucose levels may induce signs of oxidative stress in cultured bovine retinal pericytes. Pericytes were exposed to either normal (5.5 mM) or high (22 mM) glucose levels for 1, 3, and 5 days. Signs of oxidative stress were measured by expression of copper/zinc superoxide dismutase, manganese superoxide dismutase, catalase, and glutathione peroxidase using real-time RTPCR. To elucidate the role of oxidative stress, we also measured glutathione (GSH) concentration in the cells and investigated the impact of thiol-reactive metal ions and hydrogen peroxide (H(2)O(2)) on intracellular GSH. Despite the stimulation with high glucose, thiol-reactive metal ions, or H(2)O(2), there was no clear increased expression of antioxidant enzymes or influence of GSH levels. Lipid peroxidation (malondialdehyde level) was increased in bovine aortic smooth muscle cells, but not in bovine retinal pericytes. The data indicate that pericytes do not develop oxidative stress in response to hyperglycemia. However, it is not definitively excluded that oxidative stress may occur after longer time periods of glucose stimulation.
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PMID:Bovine retinal pericytes are resistant to glucose-induced oxidative stress in vitro. 1635 12

Arachidonic acid metabolites, some of which may activate thromboxane A(2) receptors (TPr) and contribute to the development of diabetes complications, including nephropathy, are elevated in diabetes. This study determined the effect of blocking TPr with S18886 or inhibiting cyclooxygenase with aspirin on oxidative stress and the early stages of nephropathy in streptozotocin-induced diabetic apolipoprotein E(-/-) mice. Diabetic mice were treated with S18886 (5 mg . kg(-1) . day(-1)) or aspirin (30 mg . kg(-1) . day(-1)) for 6 weeks. Neither S18886 nor aspirin affected hyperglycemia or hypercholesterolemia. There was intense immunohistochemical staining for nitrotyrosine in diabetic mouse kidney. In addition, a decrease in manganese superoxide dismutase (MnSOD) activity was associated with an increase in MnSOD tyrosine-34 nitration. Tyrosine nitration was significantly reduced by S18886 but not by aspirin. Staining for the NADPH oxidase subunit p47(phox), inducible nitric oxide synthase, and 12-lipoxygenase was increased in diabetic mouse kidney, as were urine levels of 12-hydroxyeicosatetraenoic acid and 8-iso-prostaglandin F(2alpha). S18886 attenuated all of these markers of oxidant stress and inflammation. Furthermore, S18886 significantly attenuated microalbuminuria in diabetic mice and ameliorated histological evidence of diabetic nephropathy, including transforming growth factor-beta and extracellular matrix expression. Thus, in contrast to inhibiting cyclooxygenase, blockade of TPr may have therapeutic potential in diabetic nephropathy, in part by attenuating oxidative stress.
Diabetes 2006 Jan
PMID:The thromboxane receptor antagonist S18886 attenuates renal oxidant stress and proteinuria in diabetic apolipoprotein E-deficient mice. 1638 Apr 83

We previously proposed that the production of hyperglycemia-induced mitochondrial reactive oxygen species (mtROS) is a key event in the development of diabetes complications. The association between the pathogenesis of diabetes and its complications and mitochondrial biogenesis has been recently reported. Because metformin has been reported to exert a possible additional benefit in preventing diabetes complications, we investigated the effect of metformin and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on mtROS production and mitochondrial biogenesis in cultured human umbilical vein endothelial cells. Treatment with metformin and AICAR inhibited hyperglycemia-induced intracellular and mtROS production, stimulated AMP-activated protein kinase (AMPK) activity, and increased the expression of peroxisome proliferator-activated response-gamma coactivator-1alpha (PGC-1alpha) and manganese superoxide dismutase (MnSOD) mRNAs. The dominant negative form of AMPKalpha1 diminished the effects of metformin and AICAR on these events, and an overexpression of PGC-1alpha completely blocked the hyperglycemia-induced mtROS production. In addition, metformin and AICAR increased the mRNA expression of nuclear respiratory factor-1 and mitochondrial DNA transcription factor A (mtTFA) and stimulated the mitochondrial proliferation. Dominant negative-AMPK also reduced the effects of metformin and AICAR on these observations. These results suggest that metformin normalizes hyperglycemia-induced mtROS production by induction of MnSOD and promotion of mitochondrial biogenesis through the activation of AMPK-PGC-1alpha pathway.
Diabetes 2006 Jan
PMID:Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. 1638 Apr 84

Oxidized LDL (ox-LDL) is involved in the initiation and progression of atherosclerosis. Many factors can affect the LDL oxidation such as oxidative stress. The present study tested whether ox-LDL levels would be associated with apolipoprotein E (APOE), manganese superoxide dismutase (MnSOD) Ala16Val polymorphisms, and classic cardiovascular risk factors. ox-LDL levels were measured by thiobarbituric acid-reactive substances and both polymorphisms were determined by polymerase chain reaction/restriction fragment length polymorphism in a sample of 252 subjects (70 men, 182 women, mean age, 54-85 years). Subjects with ox-LDL >or=0.5 nmol/mg apoprotein were considered the high level group (HLG, N = 82) and subjects with ox-LDL <0.5 nmol/mg apoprotein were considered the expected level group (ELG, N = 170). Classic risk factors were also evaluated. The results showed that diabetes mellitus was more prevalent in HLG, whereas other cardiovascular risk factors were similar between groups. The APOE genotype frequencies did not differ between HLG and ELG subjects. However, AA genotype from MnSOD polymorphism was more frequent in ELG (chi(2) = 8.48; P = 0.014). AV and VV subjects from ELG present highest ox-LDL levels (OR = 3.61; CI95% = 1.42-9.17) than AA. Additional analysis did not find gene-gene interactions associated with ox-LDL levels. Multivariate analysis showed that diabetes and the MnSOD polymorphism were independent factors associated with higher ox-LDL levels in HLG. The results suggest that an important framework on modulation of the redox status influenced by genetic polymorphisms could affect the cardiovascular homeostasis.
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PMID:Association among oxidized LDL levels, MnSOD, apolipoprotein E polymorphisms, and cardiovascular risk factors in a south Brazilian region population. 1647 14

We previously reported damage and elevated biogenesis in cardiac mitochondria of a type 1 diabetic mouse model and proposed that mitochondria are one of the major targets of oxidative stress. In this study, we targeted overexpression of the mitochondrial antioxidant protein manganese superoxide dismutase (MnSOD) to the heart to protect cardiac mitochondria from oxidative damage. Transgenic hearts had a 10- to 20-fold increase in superoxide dismutase (SOD) activity, and the transgenic SOD was located in mitochondria. The transgene caused a twofold increase in cardiac catalase activity. MnSOD transgenic mice demonstrated normal cardiac morphology, contractility, and mitochondria, and their cardiomyocytes were protected from exogenous oxidants. Crossing MnSOD transgenic mice with our type 1 model tested the benefit of eliminating mitochondrial reactive oxygen species. Overexpression of MnSOD improved respiration and normalized mass in diabetic mitochondria. MnSOD also protected the morphology of diabetic hearts and completely normalized contractility in diabetic cardiomyocytes. These results showed that elevating MnSOD provided extensive protection to diabetic mitochondria and provided overall protection to the diabetic heart.
Diabetes 2006 Mar
PMID:Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy. 1650 46

Chronic exposure to elevated levels of free fatty acids (FFAs) impairs pancreatic beta-cell function and contributes to the decline of insulin secretion in type 2 diabetes. Previously, we reported that FFAs caused increased nitric oxide (NO) production, which damaged mitochondrial DNA (mtDNA) and ultimately led to apoptosis in INS-1 cells. To firmly establish the link between FFA-generated mtDNA damage and apoptosis, we stably transfected INS-1 cells with an expression vector containing the gene for the DNA repair enzyme human 8-oxoguanine DNA glycosylase/apurinic lyase (hOGG1) downstream of the mitochondrial targeting sequence (MTS) from manganese superoxide dismutase. Successful integration of MTS-OGG1 into the INS-1 cellular genome was confirmed by Southern blot analysis. Western blots and enzyme activity assays revealed that hOGG1 was targeted to mitochondria and the recombinant enzyme was active. MTS-OGG1 cells showed a significant decrease in FFA-induced mtDNA damage compared with vector-only transfectants. Additionally, hOGG1 overexpression in mitochondria decreased FFA-induced inhibition of ATP production and protected INS-1 cells from apoptosis. These results indicate that mtDNA damage plays a pivotal role in FFA-induced beta-cell dysfunction and apoptosis. Therefore, targeting DNA repair enzymes into beta-cell mitochondria could be a potential therapeutic strategy for preventing or delaying the onset of type 2 diabetes symptoms.
Diabetes 2006 Apr
PMID:Protection of INS-1 cells from free fatty acid-induced apoptosis by targeting hOGG1 to mitochondria. 1656 24

Tumor necrosis factor (TNF)-alpha inhibits insulin action; however, the precise mechanisms are unknown. It was reported that TNF-alpha could increase mitochondrial reactive oxygen species (ROS) production, and apoptosis signal-regulating kinase 1 (ASK1) was reported to be required for TNF-alpha-induced apoptosis. Here, we examined roles of mitochondrial ROS and ASK1 in TNF-alpha-induced impaired insulin signaling in cultured human hepatoma (Huh7) cells. Using reduced MitoTracker Red probe, we confirmed that TNF-alpha increased mitochondrial ROS production, which was suppressed by overexpression of either uncoupling protein-1 (UCP)-1 or manganese superoxide dismutase (MnSOD). TNF-alpha significantly activated ASK1, increased serine phosphorylation of insulin receptor substrate (IRS)-1, and decreased insulin-stimulated tyrosine phosphorylation of IRS-1 and serine phosphorylation of Akt, and all of these effects were inhibited by overexpression of either UCP-1 or MnSOD. Similar to TNF-alpha, overexpression of wild-type ASK1 increased serine phosphorylation of IRS-1 and decreased insulin-stimulated tyrosine phosphorylation of IRS-1, whereas overexpression of dominant-negative ASK1 ameliorated these TNF-alpha-induced events. In addition, TNF-alpha activated c-jun NH(2)-terminal kinases (JNKs), and this observation was partially inhibited by overexpression of UCP-1, MnSOD, or dominant-negative ASK1. These results suggest that TNF-alpha increases mitochondrial ROS and activates ASK1 in Huh7 cells and that these TNF-alpha-induced phenomena contribute, at least in part, to impaired insulin signaling.
Diabetes 2006 May
PMID:Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling. 1664 73


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