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)

Patients with diabetic nephropathy have a high rate of cardiovascular events and mortality. Nontraditional cardiovascular risk factors such as oxidative stress and inflammation are thought to be particularly important in mediating these events. Studies suggest that thiazolidinediones (TZDs) can reduce the level of nontraditional cardiovascular risk in people with or without diabetes mellitus. Whether this benefit occurs in patients with diabetic nephropathy is unknown. I hypothesized that the TZD pioglitazone will mitigate oxidative stress and inflammation compared with glipizide in patients with overt diabetic nephropathy. Markers of oxidative stress (plasma and urine albumin carbonyl and total protein carbonyls and malondialdehyde), inflammation [white blood cell (WBC) count, C-reactive protein (CRP), plasma IL-6, TNF-alpha], and plaque stability [matrix metalloproteinase 9 (MMP-9)] were measured in frozen samples obtained from patients with overt diabetic nephropathy participating in a randomized, open-label, blinded end-point, 16-wk trial with glipizide (n = 22) or pioglitazone (n = 22). Pioglitazone therapy in men with advanced diabetic nephropathy reduced WBC count by 1,125/mul (P < 0.001), CRP by 41% (P = 0.042), IL-6 by 38% (P = 0.009), and MMP-9 by 29% (P = 0.016). Specific differential reductions in WBC count of 1,251/mul (P = 0.009) and reduction in IL-6 of 58% with pioglitazone (P = 0.001) were seen compared with glipizide. There were no statistically significant changes observed with plasma TNF-alpha concentrations or markers of oxidative stress with either hypoglycemic agent. In conclusion, pioglitazone reduces proinflammatory markers in patients with overt diabetic nephropathy, which indicates potentially beneficial effects on overall cardiovascular risk. This surrogate end point needs to be confirmed in trials designed to demonstrate cardiovascular protection.
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PMID:Anti-inflammatory effects of short-term pioglitazone therapy in men with advanced diabetic nephropathy. 1615 95

Osteopontin (OPN) is a cytokine upregulated in diabetic vascular disease. To better understand its role in vascular remodeling, we assessed how OPN controls metalloproteinase (MMP) activation in aortic adventitial myofibroblasts (AMFs) and A7r5 vascular smooth muscle cells (VSMCs). By zymography, OPN and tumor necrosis factor (TNF)-alpha preferentially upregulate pro-matrix metalloproteinase 9 (pro-MMP9) activity. TNF-alpha upregulated pro-MMP9 in AMFs isolated from wild-type (OPN(+/+)) mice, but pro-MMP9 induction was abrogated in AMFs from OPN(-/-) mice. OPN treatment of VSMCs enhanced pro-MMP9 activity, and TNF-alpha induction of pro-MMP9 was inhibited by anti-OPN antibody and apocynin. Superoxide and the oxylipid product 8-isoprostaglandin F(2) alpha-isoprostane (8-IsoP) were increased by OPN treatment, and anti-OPN antibody suppressed 8-IsoP production. Like OPN and TNF-alpha, 8-IsoP preferentially activated pro-MMP9. Superoxide, 8-IsoP, and NADPH oxidase 2 (Nox2) subunits were reduced in OPN(-/-) AMFs. Treatment of A7r5 VSMCs with OPN upregulated NADPH oxidase subunit accumulation. OPN structure/function studies mapped these activities to the SVVYGLR heptapeptide motif in the thrombin-liberated human OPN N-terminal domain (SLAYGLR in mouse OPN). Treatment of aortic VSMCs with SVVYGLR upregulated pro-MMP9 activity and restored TNF-alpha activation of pro-MMP9 in OPN(-/-) AMFs. Injection of OPN-deficient OPN(+/-) mice with SVVYGLR peptide upregulated pro-MMP9 activity, 8-IsoP levels, and Nox2 protein levels in aorta and increased panmural superoxide production (dihydroethidium staining). At equivalent hyperglycemia and dyslipidemia, 8-IsoP levels and aortic pro-MMP9 were reduced with complete OPN deficiency in a model of diet-induced diabetes, achieved by comparing OPN(-/-)/LDLR(-/-) versus OPN(+/-)/LDLR(-/-) siblings. Thus, OPN provides a paracrine signal that augments vascular pro-MMP9 activity, mediated in part via superoxide generation and oxylipid formation.
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PMID:An osteopontin-NADPH oxidase signaling cascade promotes pro-matrix metalloproteinase 9 activation in aortic mesenchymal cells. 1679 91

The peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear hormone receptor family, represents a possible new target in glioma therapy. Because PPARgamma plays a crucial role in regulation of insulin sensitivity, synthetic agonists are already in clinical use for type II diabetes treatment. Beyond these metabolic effects, PPARgamma agonists exhibit antineoplastic effects. In this study, we investigated the antineoplastic effects of the PPARgamma agonist pioglitazone in glioma cells. Pioglitazone reduced cellular viability of rat, human, and PPARgamma-overexpressing glioma cells in vitro in a time- and concentration-dependent manner. No antineoplastic effects were induced by pioglitazone in glioma cells overexpressing a PPARgamma mutant. Furthermore, proliferation was reduced by pioglitazone, as measured by Ki-67 immunoreactivity, in vitro. Continuous intracerebral infusion of pioglitazone into gliomas induced by intrastriatal injection of C6 cells reduced tumor volumes by 83%. Oral administration of pioglitazone reduced tumor volumes by 76.9%. Subsequent brain tissue analysis revealed induction of apoptotic cell death. Ki-67 expression and BrdU incorporation revealed a reduction of proliferation in vivo. Reduced invasion of C6 cells and lower matrix metalloproteinase 9 levels in vivo indicate pioglitazone-mediated reduction of invasion. Together, these data indicate that pioglitazone may be of potential use in treatment of malignant gliomas.
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PMID:Inhibition of in vivo glioma growth and invasion by peroxisome proliferator-activated receptor gamma agonist treatment. 1688 36

The aim of this article is to provide methods for the isolation and identification of pancreatic stem cells and cell source for research and therapy of diabetes. ICCs were isolated by collagenase IV digesting and then cultured; epithelial cells were purified from monolayer cultured ICCs. The growth curve of the epithelial cells was measured by MTT. The expression of molecular markers in the cells was identified by immunohistochemical staining. The surface markers in the epithelial cells were analyzed by FACS. Epithelial cells were purified from isolated human fetal ICCs and passaged 40 times, and 10(6) - 10(8) cells were cryopreservated per passage. The growth curve demonstrated that the epithelial cells proliferated rapidly. The epithelial cells expressed PDX-1, PCNA, CK-7, CK-19, Nestin, Glut2, and Vimentin, but Insulin was undetected. The cells expressed CD29, CD44, and CD166, but did not express CD11a, CD14, CD34, CD45, CD90, CD105, and CD117. Taken together, these results indicate that self-renewable epithelial cells can be isolated and purified from human fetal pancreas. These also show that the epithelial cells originate from ducts and have the characteristics of pancreatic stem cells.
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PMID:[Isolation, purification and identification of epithelial cells derived from fetal islet-like cell clusters]. 1746 Aug 96

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the CNS. Metformin is the most widely used drug for diabetes and mediates its action via activating AMP-activated protein kinase (AMPK). We provide evidence that metformin attenuates the induction of EAE by restricting the infiltration of mononuclear cells into the CNS, down-regulating the expression of proinflammatory cytokines (IFN-gamma, TNF-alpha, IL-6, IL-17, and inducible NO synthase (iNOS)), cell adhesion molecules, matrix metalloproteinase 9, and chemokine (RANTES). Furthermore, the AMPK activity and lipids alterations (total phospholipids and in free fatty acids) were restored by metformin treatment in the CNS of treated EAE animals, suggesting the possible involvement of AMPK. Metformin activated AMPK in macrophages and thereby inhibited biosynthesis of phospholipids as well as neutral lipids and also down-regulated the expression of endotoxin (LPS)-induced proinflammatory cytokines and their mediators (iNOS and cyclooxygenase 2). It also attenuated IFN-gamma and IL-17-induced iNOS and cyclooxygenase 2 expression in RAW267.4 cells, further supporting its anti-inflammatory property. Metformin inhibited T cell-mediated immune responses including Ag-specific recall responses and production of Th1 or Th17 cytokines, while it induced the generation of IL-10 in spleen cells of treated EAE animals. Altogether these findings reveal that metformin may have a possible therapeutic value for the treatment of multiple sclerosis and other inflammatory diseases.
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PMID:Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. 1949 26

Many epidemiological studies and animal experiments have shown that individuals with preexisting diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and diabetes mellitus (DM) are more susceptible to particulate matter (PM)-related health problems. However, the mechanisms underlying this susceptibility are still unclear. PM has been shown to affect macrophage functions. We hypothesized that exposure to PM in the setting of DM and high glucose levels would result in enhanced macrophage activation. Rabbits were rendered diabetic with alloxan administered intravenously. Blood glucose concentration was measured daily for the first several weeks and weekly thereafter using a blood glucose meter. After 9 months of diabetes (blood glucose great than 450mg/dl), rabbits were sacrificed and bronchoalveolar lavage was performed to collect alveolar macrophages. Alveolar macrophages were exposed in vitro to urban particulate matter SRM 1648 (U-PM). Our results showed that U-PM caused dose-dependent cytotoxic effects, and these effects were significantly higher in macrophages obtained from DM rabbits than those from normal rabbits. Reactive oxygen species (ROS) generation in macrophages from DM rabbits with exposure to U-PM was also greater than in macrophages from normal rabbits. Our results also showed that exposure of macrophages to U-PM caused an increase in cytokine mRNA expression level and activity of matrix metalloproteinase 9 (MMP-9), but not MMP-2, and that these effects were greater in macrophages from DM rabbits. These results demonstrate that U-PM caused severe oxidative stress in macrophages from DM rabbits and up-regulation of cytokine expression and MMP-9 activity.
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PMID:Diabetes is associated with increased sensitivity of alveolar macrophages to urban particulate matter exposure. 1950 25

To clarify the molecular mechanism underlying the transepidermal extrusion of dermal collagen in acquired perforating dermatosis (APD) associated with diabetes mellitus and renal failure, we studied the interaction between advanced glycation end product (AGE)-modified extracellular matrix proteins and keratinocytes (KCs) in a cell culture system. The expression of involucrin (INV) and keratin 10 was significantly enhanced in normal human KCs grown on AGE-modified collagen I or III compared with cells grown on unmodified collagen I or III. Glycated collagens I and III preferentially induced the expression of AGE receptor CD36, but not of other AGE receptors. KCs induced to terminal differentiation demonstrated markedly elevated CD36 expression. Glycated collagen I- and III-induced INV expression was partially blocked by the anti-CD36 antibody (Ab). These substrates also induced epidermal matrix metalloproteinase 9 (MMP-9) expression. Lesional skin from APD patients reacted moderately or strongly with the anti-CD36 Ab as well as the anti-MMP-9 Ab in the epidermal cells surrounding the collagenous materials being eliminated. These results suggest that exposing KCs to AGE-modified interstitial collagen (types I and III) by scratching induces terminal differentiation of KCs via the AGE receptor (CD36), leading to the upward movement of KCs together with glycated collagen.
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PMID:AGE-modified collagens I and III induce keratinocyte terminal differentiation through AGE receptor CD36: epidermal-dermal interaction in acquired perforating dermatosis. 1986 95

Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K(i)=13.2nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.
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PMID:Characterization of a novel non-steroidal glucocorticoid receptor antagonist. 2003 23

Approximately 25% of elderly patients scheduled for carotid endarterectomy (CEA) develop post-operative cognitive dysfunction (CD). We tested the hypothesis that the plasma levels of matrix metalloproteinase 9 (MMP-9) are predictive of moderate to severe CD after CEA. A total of 73 patients were prospectively enrolled in this Institutional Review Board-approved study. Plasma samples were obtained at baseline and day 1 post-surgery. We measured the plasma concentrations of both MMP-9 and its inhibitor, tissue inhibitor of metalloproteinases 1 (TIMP-1). We estimated the MMP-9 activity by calculating the MMP-9:TIMP-1 ratio. The cognitive performance day 1 post-surgery was quantified with z-scores, using a control group who were undergoing spinal surgery. The criteria used to define CD was performance of >or=1.5 standard deviations worse than the control group; approximately 19% of eligible patients developed CD. Compared to patients without CD, this group had both higher total (81.66+/-12.25 ng/mL versus [vs.] 43.18+/-4.44 ng/mL, p=0.005) and activity (0.88+/-0.24 ng/mL vs. 0.54+/-0.06 ng/mL, p=0.003) MMP-9 levels at baseline. All of the results were adjusted for age, diabetes and neurovascular symptoms.
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PMID:MMP-9 levels in elderly patients with cognitive dysfunction after carotid surgery. 2011 Jan 72

The molecular mechanisms underlying the glucose-lowering effects of Isaria sinclairii (Cicada Dongchunghacho), a fungus cultured on silkworm, are not fully elucidated. Thus the glucose-lowering effects of I. sinclairii as potential an antidiabetic agent were investigated in C57BL/6 obese (ob/ob) mice over a 6-mo period. For a period of 26 wk, ob mice were administered either 5 or 10% (w/w) I. sinclairii powder (IS), 10% dry mulberry leaf powder (ML), or 10% silkworm (SW) powder in the standard diet while a control group received only standard diet. The ML and SW preparations served as positive controls. Isaria sinclairii at 10% in the diet was more effective in reducing body weight compared to 10% ML, 10% SW, or 5% I. sinclairii. The fall in blood glucose levels in the groups treated for 26 wk was greater in both IS groups at 1 mo compared to ML or SW but equal in all groups at 6 mo. Microarray analyses were performed with a mouse 7.4K cDNA clone set array to identify the gene-expression profiles for the IS-, ML-, and SW-exposed ob mouse liver. The 10% IS group, compared to control, showed that 15 genes including glucokinase (Gk-rs1) and LDL receptor relating protein 1 were upregulated and 12 genes including cell translocation gene2 (antiproliferative) and hydroxyprostaglandin dehydrogenase (Hpgd 15) were downregulated. Upregulation of Gk-rs 1 and downregulation of Hpgd 15 were previously shown to occur in drug-induced suppression of diabetes. With ML, Lepr (leptin receptor), Pik3cb (phosphatidylinositol 3-kinase), and Prodh (proline dehydrogenase), related to suppression of diabetes, were upregulated. In the case of SW, the enzymes (G2an, alpha glucosidase 2) and Mmp9 (matrix metalloproteinase 9) involved in elevation of blood glucose levels were both downregulated. Data suggest that I. sinclarii is effective in lowering blood glucose due to the upregulation of glucokinase (Gk-rs1) and downregulation of hydroxyprostaglandin dehydrogenase (Hpgd 15), both associated with suppression of diabetes, indicating that microarray analysis is a useful tool to assess pharmacological potency of therapeutic compounds.
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PMID:Antidiabetic effects and gene expression profiling in obese mice treated with Isaria sinclairii over a 6-month period. 2095 77


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