UMLS:C0011849 - FACTA Search

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The circulatory inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is increased in pathological conditions, such as diabetes, which initiate or exacerbate vascular endothelial injury. Both nitric oxide (NO) and reactive oxygen species may play a dual role (i.e., inhibiting or promoting) in TNF-alpha-induced endothelial cell apoptosis. We investigated the effects of the antioxidant N-acetylcysteine on TNF-alpha-induced apoptosis in human vascular endothelial cell (cell line ECV304) apoptosis, NO production and lipid peroxidation. Cultured vascular endothelial cell (ECV304) were either not treated (control), or treated with TNF-alpha (40 ng/ml) alone or TNF-alpha in the presence of N-acetylcysteine at 30 mmol/l or 1 mmol/l, respectively, for 24 h. Cell viability was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Cell apoptosis was assessed by flow cytometry. TNF-alpha-induced endothelial cell apoptosis was associated with increased inducible NO synthase but reduced endothelial NO synthase (eNOS) protein expression. NO production and the levels of the lipid peroxidation product malondialdehyde were concomitantly increased. Treatment with NAC at 30 mmol/l restored eNOS expression and further increased NO production as compared to TNF-alpha alone, resulting in improved cell viability and reduced apoptosis. This was accompanied by increased superoxide dismutase activity, increased glutathione peroxidase production and reduced malondialdehyde levels. N-acetylcysteine at 1 mmol/l, however, did not have significant effects on TNF-alpha-induced endothelial cell apoptosis and cell viability despite it slightly enhanced glutathione peroxidase production. N-acetylcysteine attenuation of TNF-alpha-induced human vascular endothelial cell apoptosis is associated with the restoration of eNOS expression.
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PMID:N-acetylcysteine attenuates TNF-alpha-induced human vascular endothelial cell apoptosis and restores eNOS expression. 1702 86

Peroxisome proliferator activated-receptor gamma (PPARgamma) binds to peroxisome receptor response elements with its heterodimeric partner, retinoid X receptor, and regulates downstream gene expression. PPARgamma transcriptionally modulates fat metabolism, and receptor agonists have been developed to treat type II diabetes. PPARgamma is also overexpressed in some tumor cell lines and primary tumors, including breast and prostate tumors. Two PPARgamma antagonists, 2-chloro-5-nitro-N-phenylbenzamide (GW9662) and 2-chloro-5-nitro-N-pyridin-4-yl-benzamide (T0070907), represent good lead compounds for radiotracer development. In the current study, four additional halogen substituted analogs were synthesized and evaluated in a whole cell screening assay for PPARgamma binding activity. Two bromine-containing analogs having EC50 values <5 nM were chosen for bromine-76 radiolabeling. Bromine-76-labeled 2-bromo-5-nitro-N-phenyl-benzamide was selected for subsequent in vitro and in vivo studies due to its superior radiolabeling yield (approximately 70%) and the well-characterized pharmacological properties of its analog GW9662. An in vitro stability study showed that 40% of the compound remained intact in plasma and about 25% in whole blood after 30 min. Biodistribution studies in MDA-MB-435 human breast tumor-bearing nude mice were carried out at 5 min, 30 min, 2 h and 24 h post injection of the radiotracer. Although in vivo metabolite studies demonstrated rapid compound degradation, at least 10% of the parent compound was delivered to the tumor. We are currently exploring second generation analogs of these lead compounds for the development of radiolabeled antagonists of the PPARgamma receptor.
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PMID:Synthesis and evaluation of a bromine-76-labeled PPARgamma antagonist 2-bromo-5-nitro-N-phenylbenzamide. 1704 64

The complexity of the human plasma proteome is greatly increased by post-translational modifications. Besides physiological modifications, pathological conditions such as diabetes are responsible for adding to this complexity by producing advanced glycation endproducts (AGEs). When searching for specific biomarkers it is a prerequisite to reduce this complexity prior to analysis. To do this, agarose hydrogel was used to create a high-capacity affinity layer on the modified aluminum surface of MALDI (matrix-assisted laser desorption/ionization) targets. 3-Aminophenylboronic acid was immobilized via cyanogen bromide activation as a ligand for affinity sorption of glycated proteins, followed by their direct detection by MALDI. High protein capacity of prepared MALDI chips, efficient separation and low non-specific protein binding were demonstrated. The results show that phenylboronic acid modified hydrogels are very suitable for creating affinity surfaces for the high-throughput analysis of AGEs.
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PMID:Application of phenylboronic acid modified hydrogel affinity chips for high-throughput mass spectrometric analysis of glycated proteins. 1712 56

The activities of the enzymes NTPDase (EC 3.6.1.5, apyrase, CD39) and 5'-nucleotidase (EC 3.1.3.5, CD73) were analyzed in platelets from rats submitted to demyelination by ethidium bromide (EB) and treated with interferon beta (IFN-beta). The following groups were studied: I - control (saline), II - (saline and IFN-beta), III - (EB) and IV - (EB and IFN-beta). After 7, 15 and 30 days, the animals (n=7) were sacrificed and the platelets were separated by the method of Lunkes et al. [Lunkes, G., Lunkes D., Morsch, V., Mazzanti, C., Morsch, A., Miron, V., Schetinger, M.R.C., 2004. NTPDase and 5'-nucleotidase in rats alloxan- induced diabetes. Diabetes Research and Clinical Practice 65, 1-6]. NTPDase activity for ATP and ADP substrates was significantly lower in groups II and III after seven days, when compared to control (p<0.001). At fifteen days, ATP hydrolysis was significantly lower in group III and IV and higher in group II (p<0.001), while there was an activation of ADP hydrolysis in group II (p<0.001), when compared with the control. 5'-nucleotidase activity was significantly higher in group IV (p<0.001) after seven days, and lower in the groups III and IV (p<0.001) after fifteen days in relation to the control. No significant differences were observed in NTPDase and 5'-nucleotidase activities after thirty days. In conclusion, our study demonstrated that the hydrolysis of adenine nucleotides is modified in platelets of rats demyelinated and treated with IFN-beta.
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PMID:Activities of enzymes that hydrolyze adenine nucleotides in platelets from rats experimentally demyelinated with ethidium bromide and treated with interferon-beta. 1723 2

l-arginine is the substrate used by NO synthase to produce the vasodilator NO. However, in several human diseases, such as hyperhomocysteinemia, diabetes mellitus, and hypertension, there is an increase in serum levels of methylated l-arginines, such as asymmetrical dimethylarginine (ADMA), which cannot be used by NO synthase to produce NO. Yet, the functional consequence of increased levels of ADMA on the vasomotor function of resistance vessels has not been delineated. We hypothesized that elevated levels of exogenous ADMA inhibit NO mediation of flow/shear stress-dependent dilation of isolated arterioles. In the presence of indomethacin, isolated arterioles from rat gracilis muscle (approximately 165 microm at 80 mm Hg) were incubated with ADMA (10(-4) mol/L), which eliminated the dilations to increases in intraluminal flow (control: from 164+/-5.4 to 188+/-3.8 microm versus ADMA: from 171+/-6.1 to 173+/-6.3 microm at 20 microL/min). ADMA did not affect dilations to nifedipine (10(-6) mol/L; control: 63.4+/-2%, ADMA: 65.8+/-3%) or 8-bromo cGMP (10(-4) mol/L; control: 51.2+/-2.1%, ADMA: 49.3+/-3.4%). In addition, ADMA elicited significant constriction of arterioles (from 173+/-17 microm to 138+/-16 microm at 80 mm Hg), which was prevented by previous incubation of arterioles with polyethylene-glycol (PEG) superoxide dismutase (SOD; 120 U/mL, control: 155+/-11 microm versus ADMA: 150+/-14 microm). Correspondingly, ADMA increased PEG-SOD reversible manner the production of vascular superoxide assessed by lucigenin-enhanced chemiluminescence and ethidium bromide fluorescence. Thus, increased levels of ADMA in various diseases could inhibit the regulation of arteriolar resistance by shear stress-induced release of NO and elicit superoxide-mediated increase in basal tone, both of which favor the development of hypertension.
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PMID:Asymmetrical dimethylarginine inhibits shear stress-induced nitric oxide release and dilation and elicits superoxide-mediated increase in arteriolar tone. 1724 3

An increase in oxidizing response above a certain threshold produces, in the absence of a concomitant rise in antioxidant/reducing response, oxidative stress that is associated with complications in diabetes. A simple technique involving reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye has been developed in order to determine quantitatively the antioxidant status of plasma. MTT (50microL; 5.0mg/mL in PBS) was incubated with plasma (100microL) in PBS for 30, 60 or 120min at 37 degrees C, the reaction terminated by addition of 1.0mL of 0.04M hydrochloric acid in isopropanol and the absorbance measured at 570nm. The modulation by plasma of the generation of reactive oxygen species (ROS) in 12,13-phorbol dibutyrate (PDB)-stimulated granulocytes was evaluated using a chemiluminescence luminol-dependent assay. Plasma from healthy subjects (n=15) showed significantly higher antioxidant status (p<0.05) over all time periods studied compared with plasma from diabetic patients (n=27). MTT was directly reduced by plasma although platelets were not involved. Moreover, the reduction of MTT by bovine serum albumin at levels equivalent to the concentration of human serum albumin in plasma was much lower. The antioxidant status of plasma, as evaluated by MTT dye reduction, may reflect an antioxidant response since ROS generation in PDB-stimulated granulocytes was rapidly down-regulated by the presence of plasma (3.3-fold in diabetic patients and 5.8-fold in healthy subjects) confirming the lower antioxidant activity of plasma from diabetic patients. The results demonstrate that extracellular reduction of MTT by plasma may occur via enzymatic and non-enzymatic processes.
Diabetes Res Clin Pract 2007 Aug
PMID:Determination of the antioxidant status of plasma from type 2 diabetic patients. 1727 Mar 9

Hyperglycemia, advanced glycation end products (AGEs), hyperinsulinemia and dyslipidemia may play roles in the development of diabetes-associated atherosclerosis and post-angioplasty restenosis. Clinically, their effects seem to be synergic. However, few studies have focused on the synergistic action of these factors. In the present study, we investigated whether glycated serum albumin (GSA) has a synergistic effect with insulin on the proliferation of vascular smooth muscle cells (VSMCs). VSMCs were isolated from rat thoracic aortas and cultured in fetal bovine serum (FBS)-free medium for 24 h, then exposed to GSA, insulin or GSA + insulin for 48 h with or without pretreatment of mitogen-activated protein kinase (MAPK) inhibitors or the antioxidant N-acetylcysteine (NAC). Cell growth rate was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay or cell counting. The changes of phosphorylated-p38 MAPK and phosphorylated-C-Jun N-terminal kinase 1/2 (JNK1/2) were measured by Western blot analysis. The results showed that only p38 MAPK, but not JNK was activated by GSA and insulin co-incubation. VSMC proliferation was increased by insulin (10-1000 nmol/L) or GSA (10, 100 microg/mL). Co-incubation of insulin (100 nmol/L) and GSA (100 mug/mL) caused a more potent increase in VSMC proliferation than insulin or GSA incubation alone. p38 MAPK inhibitor, SB203580, as well as NAC, could inhibit the VSMC proliferation induced by co-incubation of GSA and insulin. The results show that insulin enhances GSA-induced VSMC proliferation, which may be mediated through a reactive oxygen species (ROS)-p38 MAPK pathway. The synergism of AGEs and insulin may play a detrimental role in the pathogenesis of diabetic atherosclerosis and post-angioplasty restenosis.
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PMID:Synergistic proliferation induced by insulin and glycated serum albumin in rat vascular smooth muscle cells. 1729 35

Advanced glycation endproducts (AGEs) arise in vivo from the reaction of proteins with sugars or dicarbonyl compounds. They are thought to be involved in the pathogenesis of several diseases such as atherosclerosis, diabetes mellitus, renal failure, and Alzheimer's disease (AD). Several binding molecules for AGEs have been described and it is assumed that many of the effects of AGEs are mediated by receptors like the receptor for AGEs (RAGE). AGEs are known to induce the release of inflammatory cytokines from activated glia in the AD brain and thus AGEs affect the cell viability of neurons and glia. In cell culture experiments controversial effects of AGEs on cell growth and viability were reported by different research groups ranging from stimulation to inhibition of the cell viability. In the present study, the effect of in vitro prepared highly modified AGEs on the viability and the membrane integrity of cultured brain cells was investigated. Three different brain cell lines were treated with glucose human serum albumin AGEs (Glc-AGEs) and methyl glyoxal human serum albumin AGEs (MG-AGEs). To investigate the effect of these model AGEs on cell viability the CellTiter Blue (CTB) and the tetrazolium (3-[4,5-dimethylthioazol-2-yl]-2,5-diphenyl tetrazolium bromide) (MTT) were used. The membrane integrity after exposure to AGEs was assayed using the lactate dehydrogenase (LDH) assay. When using the CTB assay for evaluation all AGEs were found to reduce the viability compared with the native protein in all three cell lines. Additionally, all AGEs were found to affect the membrane integrity compared with the native protein in all cell lines. When using the MTT assay for evaluation only MG-AGEs were found to cause a decrease in the viability in all cell lines used. The results of the MTT assay in Glc-AGEs treated cells varied between the cell lines. To gain a deeper understanding of the cellular responses after exposure of cells to AGEs, the present study compares results obtained when using the CTB, the MTT or the LDH assay in identically AGE treated cells.
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PMID:Comparison of results of the CellTiter Blue, the tetrazolium (3-[4,5-dimethylthioazol-2-yl]-2,5-diphenyl tetrazolium bromide), and the lactate dehydrogenase assay applied in brain cells after exposure to advanced glycation endproducts. 1739 10

Since the bioenergetic capacity of skeletal muscle mitochondria is decreased in type 2 diabetes and obesity, the reduction of mitochondrial DNA (mtDNA) content may be involved in the development of insulin resistance in skeletal muscle. To elucidate the association of cellular mtDNA content and insulin resistance, we produced L6 GLUT4myc myocytes depleted of mtDNA by long-term treatment with ethidium bromide (EtBr). L6 GLUT4myc cells cultured with 0.2 microg/ml EtBr (termed depleted cells) revealed a marked decrease in cellular mtDNA, concomitant with a lack of mRNAs encoded by mtDNA. Interestingly, the mtDNA-depleted cells showed a drastic decrease in basal and insulin-stimulated glucose uptake, indicating that L6 GLUT4myc cells develop impaired glucose utilization and insulin resistance. The repletion of mtDNA normalized basal and insulin-stimulated glucose uptake. The plasma membrane (PM) GLUT4 in the basal state was decreased, and the insulin-stimulated GLUT4 translocation to the PM was drastically reduced by mtDNA depletion. Interestingly, the expression of IRS-1 associated with insulin signaling was decreased by 90% in the depleted cells, and the insulin-stimulated phosphorylation of IRS-1 and Akt2/PKB were drastically reduced in the depleted cells. Those changes returned to control levels after mtDNA repletion. Taken together, our data suggest that PM GLUT4 content and insulin signal pathway intermediates are modulated by the alteration of cellular mtDNA content, and the reduction in the expression of IRS-1 and insulin-stimulated phosphorylation of IRS-1 and Akt2/PKB are associated with insulin resistance in the mtDNA-depleted L6 GLUT4myc myocytes.
Diabetes Res Clin Pract 2007 Sep
PMID:The depletion of cellular mitochondrial DNA causes insulin resistance through the alteration of insulin receptor substrate-1 in rat myocytes. 1746 78

Advanced glycation endproducts (AGEs) are unavoidable byproducts of various metabolic pathways. They are formed by reactive metabolic intermediates such as methylglyoxal (MG), glyoxal, and 3-deoxyglucosone. These reactive intermediates bind to proteins, DNA, and other molecules and disrupt their structures and functions, which leads to different diseases such as vascular complications of diabetes, atherosclerosis, hypertension, Alzheimer's disease, and aging. In recent years, more compounds that prevent the formation of AGEs or degrade the existing AGEs have been produced and patented. They include: 1) aminoguanidine, 2) drugs used in the treatment of type 2 diabetes such as metformin and pioglitazone (patented), 3) angiotensin receptor blockers and angiotensin converting enzyme inhibitors, 4) pentoxyfylline (patented), 5) metal ion chelators desferoxamine and penicillamine, 6) antioxidants such as vitamin C or E, 7) amino group capping agents such as aspirin, 8) enzymes that cause deglycation of Amadori products, the Amadoriases, 9) compounds that mostly break alpha-dicarbonyl cross-links such as phenacylthiazolium bromide and its stable derivative ALT-711 (Alagebrium), and 10) derivatives of aryl ureido and aryl carboxaminido phenoxy isobutyric acids (patented). While some of these anti-AGE compounds are being used in clinical practice (such as metformin, pioglitazone, pentoxyfylline and aspirin) or tested in clinical trials (such as aminoguanidine and ALT-711), most of them are commonly used as experimental tools to investigate the role of AGEs in different disease conditions.
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PMID:Methylglyoxal and advanced glycation endproducts: new therapeutic horizons? 1822 Nov 7

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