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)

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde to which humans are exposed in a variety of environment situations and is also a product of lipid peroxidation. Increased unsaturated aldehyde levels and reduced antioxidant status play an important role in the pathogenesis of a number of human diseases such as Alzheimer's, atherosclerosis, and diabetes. Mammalian thioredoxin reductase (TR), a central antioxidant enzyme, is a selenoprotein that catalyzes the reduction of oxidized thioredoxin. The findings reported here show that low concentrations of acrolein rapidly inactivate TR, both in vitro and in vivo. These data suggest that acrolein may directly inactivate TR, resulting in an increase in oxidative cellular damage. In addition, we also found that the initial inactivation of TR molecules by acrolein triggers a compensatory signal for inducing TR gene expression in human umbilical vein endothelial cells (HUVEC). The results of the present study suggest that HUVEC may have a protective system against cell damage by acrolein via the upregulation of TR, which is an adaptive response to oxidative stress.
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PMID:Induction of thioredoxin reductase as an adaptive response to acrolein in human umbilical vein endothelial cells. 1565 4

Hepatocellular cancer accounts for almost half a million cancer deaths a year, with an escalating incidence in the Western world. Alcohol has long been recognized as a major risk factor for cancer of the liver and of other organs including oropharynx, larynx, esophagus, and possibly the breast and colon. There is compelling epidemiologic data confirming the increased risk of cancer associated with alcohol consumption, which is supported by animal experiments. Cancer of the liver associated with alcohol usually occurs in the setting of cirrhosis. Alcohol may act as a cocarcinogen, and has strong synergistic effects with other carcinogens including hepatitis B and C, aflatoxin, vinyl chloride, obesity, and diabetes mellitus. Acetaldehyde, the main metabolite of alcohol, causes hepatocellular injury, and is an important factor in causing increased oxidant stress, which damages DNA. Alcohol affects nutrition and vitamin metabolism, causing abnormalities of DNA methylation. Abnormalities of DNA methylation, a key pathway of epigenetic gene control, lead to cancer. Other nutritional and metabolic effects, for example on vitamin A metabolism, also play a key role in hepatocarcinogenesis. Alcohol enhances the effects of environmental carcinogens directly and by contributing to nutritional deficiency and impairing immunological tumor surveillance. This review summarizes the epidemiologic evidence for the role of alcohol in hepatocellular cancer, and discusses the mechanisms involved in the promotion of cancer.
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PMID:Alcohol in hepatocellular cancer. 1576 34

Glucagon-like peptide-1-(7-36) (GLP-1) is a hormone derived from the proglucagon molecule, which is considered a highly desirable antidiabetic agent mainly due to its unique glucose-dependent stimulation of insulin secretion profiles. However, the development of a GLP-1-based pharmaceutical agent has a severe limitation due to its very short half-life in plasma, being primarily degraded by dipeptidyl peptidase IV (DPP-IV) enzyme. To overcome this limitation, in this article we propose a novel and potent DPP-IV-resistant form of a poly(ethylene glycol)-conjugated GLP-1 preparation and its pharmacokinetic evaluation in rats. Two series of mono-PEGylated GLP-1, (i) N-terminally modified PEG(2k)-N(ter)-GLP-1 and (ii) isomers of Lys(26), Lys(34) modified PEG(2k)-Lys-GLP-1, were prepared by using mPEG-aldehyde and mPEG-succinimidyl propionate, respectively. To determine the optimized condition for PEGylation, the reactions were monitored at different pH buffer and time intervals by RP-HPLC and MALDI-TOF-MS. The in vitro insulinotropic effect of PEG(2k)-Lys-GLP-1 showed comparable biological activity with native GLP-1 (P = 0.11) in stimulating insulin secretion in isolated rat pancreatic islet and was significantly more potent than the PEG(2k)-N(ter)-GLP-1 (P < 0.05) that showed a marked reduced potency. Furthermore, PEG(2k)-Lys-GLP-1 was clearly resistant to purified DPP-IV in buffer with 50-fold increased half-life compared to unmodified GLP-1. When PEG(2k)-Lys-GLP-1 was administered intravenously and subcutaneously into rats, PEGylation improved the half-life, which resulted in substantial improvement of the mean plasma residence time as a 16-fold increase for iv and a 3.2-fold increase for sc. These preliminary results suggest a site specifically mono-PEGylated GLP-1 greatly improved the pharmacological profiles; thus, we anticipated that it could serve as potential candidate as an antidiabetic agent for the treatment of non-insulin-dependent diabetes patients.
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PMID:Synthesis, characterization, and pharmacokinetic studies of PEGylated glucagon-like peptide-1. 1576 92

Aldose reductase (AR) is widely expressed aldehyde-metabolizing enzyme. The reduction of glucose by the AR-catalyzed polyol pathway has been linked to the development of secondary diabetic complications. Although treatment with AR inhibitors has been shown to prevent tissue injury in animal models of diabetes, the clinical efficacy of these drugs remains to be established. Recent studies suggest that glucose may be an incidental substrate of AR, which appears to be more adept in catalyzing the reduction of a wide range of aldehydes generated from lipid peroxidation. Moreover, inhibition of the enzyme has been shown to increase inflammation-induced vascular oxidative stress and prevent myocardial protection associated with the late phase of ischemic preconditioning. On the basis of these studies, several investigators have ascribed an important antioxidant role to the enzyme. Additionally, ongoing work indicates that AR is a critical component of intracellular signaling, and inhibition of the enzyme prevents high glucose-, cytokine-, or growth factor-induced activation of protein kinase C and nuclear factor-kappa-binding protein. Thus, treatment with AR inhibitors prevents vascular smooth muscle cell growth and endothelial cell apoptosis in culture and inflammation and restenosis in vivo. Additional studies indicate that the antioxidant and signaling roles of AR are interlinked and that AR regulates protein kinase C and nuclear factor-kappaB via redox-sensitive mechanisms. These data underscore the need for reevaluating anti-AR interventions for the treatment of diabetic complications. Potentially, the development of newer drugs that selectively inhibit AR-mediated glucose metabolism and signaling, without affecting aldehyde detoxification, may be useful in preventing inflammation associated with the development of diabetic complications, particularly micro- and macrovascular diseases.
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PMID:Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options. 1581 47

The pathogenesis of non-alcoholic steatohepatitis (NASH) has not been fully studied yet. At the same time, some key points of its forming are already clear. In this regard, the authors studied disturbances of carbohydrate and lipid metabolism in patients with NASH. This included evaluation of fatty acid (FA) and lipoprotein (LP) spectrum, as well as measurement of triglyceride (TG), malonic aldehyde and glucose blood concentrations. The study found that an important role in the pathogenesis of NASH is played by carbohydrate and lipid dysmetabolism, manifested by hyperglycemia, glucose tolerance disorder, and type II diabetes. Other manifestations include hyperlipoperoxidcholia, high concentrations of chylomicrons, low density lipoproteins, and triglycerides, as well as low concentration of high-density lipoproteins. The spectrum of higher fatty acids is characterized by high concentration of saturated fatty acids and deficit of polyunsaturated fatty acids.
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PMID:[Some parameters of carbohydrate and lipid metabolism in patients with non-alcoholic steatohepatitis]. 1607 45

Nonenzymatic covalent adduction of glucose, or aldehydes derived from glucose or oxidation reactions, to proteins (glycation) has been proposed as a key factor in the vascular complications of diabetes. In conditions of chronic glucose elevation, alpha-dicarbonyl compounds, including glyoxal and methylglyoxal, are also present at elevated levels. These carbonyls react rapidly with nucleophilic groups on Lys and Arg side chains and the N-terminal amino group, to give poorly defined products, often called advanced glycation endproducts. These are present at elevated levels in tissue samples from people with diabetes and have been linked with disease development. As the thiol group of Cys is a powerful nucleophile, we hypothesized that adduction should occur rapidly and efficiently at Cys residues. It is shown here that Cys residues react with dicarbonyl compounds to give thiol-aldehyde adducts, which have been detected by electrospray ionization mass spectrometry. This process is accompanied by loss of the thiol group and formation of stable products. In the case of glyoxal, these reactions give S-(carboxymethyl)cysteine. The percentage conversion of thiol lost to product is substrate-dependent and < or = 32%. S-(Carboxymethyl)cysteine has been quantified by HPLC on thiol-containing, protected amino acids, peptides, and proteins, after exposure to glyoxal. The yield of this product has been shown to increase in a time- and dose-dependent manner with higher glyoxal concentrations and to also be formed on extended incubation of serum albumin with glucose. This novel, stable, advanced glycation endproduct is a potential marker of glycation.
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PMID:Evidence for the formation of adducts and S-(carboxymethyl)cysteine on reaction of alpha-dicarbonyl compounds with thiol groups on amino acids, peptides, and proteins. 1609 96

Mutations in HNF-1 alpha cause maturity-onset diabetes of the young (MODY) type 3, which is the most prevalent MODY subtype in most countries. In the present study, we investigated an oligonucleotide microchip for the detection of the known HNF-1 alpha mutations. We first optimized the coupling chemistries for covalent immobilization of allele-specific oligonucleotides on aldehyde (CHO)- and thiocyanate (NCS)-activated glass slides and compared their hybridization efficiencies. CHO-glass was found to provide a more favorable environment for hybridization than NCS-glass, whereas the binding capacity of NCS-glass for amine-activated oligonucleotide was much greater than with CHO-glass. We also investigated the effects of the length of the capture probes on the hybridized signals. To determine the presence of HNF-1 alpha mutations in a human sample, we prepared an oligonucleotide chip from selected mutation sites of exon2 from HNF-1 alpha. Cy3-labeled RNA target probes were obtained by in vitro transcription of promoter-tagged PCR products from a wild-type blood sample and subsequent fragmentation. Hybridization of the chip with the RNA target probes successfully identified all of the genotypes for the tested sites. This work demonstrates that oligonucleotide chip-based analysis is a good candidate for routine clinical testing for HNF-1 alpha mutations.
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PMID:Oligonucleotide chip for the diagnosis of HNF-1 alpha mutations. 1620 77

We measured the content of lipid peroxides in plasma LDL from patients with chronic CHD not accompanied by hypercholesterolemia; CHD and hypercholesterolemia; type 2 diabetes mellitus and decompensation of carbohydrate metabolism; and CHD, circulatory insufficiency, and type 2 diabetes mellitus (without hypercholesterolemia). The content of lipid peroxides in LDL isolated from blood plasma by differential ultracentrifugation in a density gradient was estimated by a highly specific method with modifications (reagent Fe(2+) xylene orange and triphenylphosphine as a reducing agent for organic peroxides). The content of lipid peroxides in LDL from patients was much higher than in controls (patients without coronary heart disease and diabetes). Hypercholesterolemia and diabetes can be considered as factors promoting LDL oxidation in vivo. Our results suggest that stimulation of lipid peroxidation in low-density lipoproteins during hypercholesterolemia and diabetes is associated with strong autooxidation of cholesterol and glucose during oxidative and carbonyl (aldehyde) stress, respectively. These data illustrate a possible mechanism of the progression of atherosclerosis in patients with diabetes mellitus.
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PMID:Oxidative stress in atherosclerosis and diabetes. 1625 16

The ubiquitin-proteasome pathway plays a crucial role in the regulation of many physiological processes and in the development of a number of major human diseases, such as cancer, Alzheimer's, Parkinson's, diabetes, etc. As a new target, the study on the proteasome inhibitors has received much attention recently. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using comparative molecule field analysis (CoMFA) and comparative molecule similarity indices analysis (CoMSIA) techniques were applied to analyze the binding affinity of a set of tripeptide aldehyde inhibitors of 20S proteasome. The optimal CoMFA and CoMSIA models obtained for the training set were all statistically significant with cross-validated coefficients (q(2)) of 0.615, 0.591 and conventional coefficients (r(2)) of 0.901, 0.894, respectively. These models were validated by a test set of eight molecules that were not included in the training set. The predicted correlation coefficients (r(2)) of CoMFA and CoMSIA are 0.944 and 0.861, respectively. The CoMFA and CoMSIA field contour maps agree well with the structural characteristics of the binding pocket of beta5 subunit of 20S proteasome, which suggests that the 3D-QSAR models built in this paper can be used to guide the development of novel inhibitors of 20S proteasome.
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PMID:3D-QSAR studies on tripeptide aldehyde inhibitors of proteasome using CoMFA and CoMSIA methods. 1625 51

Biological properties of renal-specific oxidoreductase (RSOR), characteristics of its promoter, and underlying mechanisms regulating its expression in diabetes were analyzed. RSOR expression, normally confined to the renal cortex, was markedly increased and extended into the outer medullary tubules in db/db mice, a model of type 2 diabetes. Exposure of LLCPK cells to d-glucose resulted in a dose-dependent increase in RSOR expression and its enzymatic activity. The latter was related to one of the glycolytic enzymes, myo-inositol oxygenase. The increase in activity was in proportion to serum glucose concentration. The RSOR expression also increased in cells treated with various organic osmolytes, e.g., sorbitol, myoinositol, and glycerolphosphoryl-choline and H(2)O(2). Basal promoter activity was confined to -1,252 bp upstream of ATG, and it increased with the treatment of high glucose and osmolytes. EMSAs indicated an increased binding activity with osmotic-, carbohydrate-, and oxidant-response elements in cells treated with high glucose and was abolished by competitors. Supershifts, detected by anti-nuclear factor of activated T cells, and carbohydrate-response-element-binding protein established the binding specificity. Nuclear factor of activated T cells tonicity-enhancer-binding protein and carbohydrate-response-element-binding protein had increased nuclear expression in cells treated with high glucose. The activity of osmotic-response element exhibited a unique alternate binding pattern, as yet unreported in osmoregulatory genes. Data indicate that RSOR activity is modulated by diverse mechanisms, and it is endowed with dual properties to channel glucose intermediaries, characteristic of hepatic aldehyde reductases, and to maintain osmoregulation, a function of renal medullary genes, e.g., aldose reductase, in diabetes.
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PMID:Modulation of renal-specific oxidoreductase/myo-inositol oxygenase by high-glucose ambience. 1633 Jul 53


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