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)

Vascular endothelium plays a crucial role in ensuring normal function and morphology of blood vessels, and many risk factors of atherosclerosis act via their effects on endothelial cells. However, endothelial dysfunction is induced by very different pathomechanisms. In principle, it is caused by an impaired bioavailability of nitric oxide (NO) due to an inhibited synthesis (eg, by asymmetric dimethylarginine [ADMA]) or increased consumption of formed NO (by reactive oxygen species [ROS]). ROS can be synthesized in the organism (eg, by different enzymes) or can be administered from the environment (eg, by cigarette smoking), whereas ADMA is the subject of endogenous metabolism only. Many studies have elucidated the system of pathomechanisms and targeted some as potential goals for therapeutic interventions. This review demonstrates roles of ROS, NO, ADMA, endothelin, and estrogen in endothelial function and dysfunction focusing on homocysteinemia and diabetes mellitus and provide examples for the medical treatment of endothelial dysfunction.
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PMID:Roles of oxidants, nitric oxide, and asymmetric dimethylarginine in endothelial function. 1894 74

Total triterpene acids (TTAs) isolated from Cornus officinalis Sieb., one of the herbs contained in Liuwei Dihuang decoction, were aimed at alleviating diabetic cardiomyopathy. We hypothesized that the benefits of TTAs may result from suppressing the endothelin-reactive oxidative species (ET-ROS) pathway in the myocardium. Diabetes was produced by a single injection of streptozotocin (STZ, 60 mg kg(-1), i.p.) in rats. Assessment of cardiac function, calcium handling proteins, endothelin-1 (ET-1) and redox system was conducted 8 weeks after STZ injection. Medication with TTAs (50 mg kg(-1), i.g.) was installed in the last 4 weeks. The compromised cardiac function was characterized by depressed contractility (LVSP and LV+dp/dt(max)) and relaxation (LVEDP and -LVdp/dt(min)) in association with hyperglycaemia (30.2 +/- 2.6 mmol L(-1)) in STZ-injected rats. Down-regulated expression of FKBP12.6 (calstabin 2), sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) and phospholamban (PLB) were also found. These changes occurred in connection with an increased ET-1, up-regulated mRNA of propreET-1 and endothelin converting enzyme (ECE), and a state of oxidant stress was found by increased malondialdehyde (MDA), decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activity, and an enhanced activity and expression of inducible nitric oxide synthase (iNOS) in the diabetic myocardium. After 4 weeks of treatment with TTAs, these changes were alleviated dramatically despite a mild reduction in hyperglycaemia (26.9 +/- 3.4 mmol L(-1)). In conclusion, TTAs, as active ingredients of Liuwei Dihuang decoction, alleviated diabetic cardiomyopathy by normalizing the abnormality of FKBP12.6 and SERCA2a and ET-ROS pathway in the myocardium rather than by hypoglycaemic activity.
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PMID:Total triterpene acids, active ingredients from Fructus Corni, attenuate diabetic cardiomyopathy by normalizing ET pathway and expression of FKBP12.6 and SERCA2a in streptozotocin-rats. 1900 Mar 75

Chronic arsenic exposure causes skin diseases, gastrointestinal and neurological disorders, diabetes and cancer in various organs. Oxidative stress associated with arsenic exposure cause genetic instabilities and may initiate carcinogenesis. Phytochemicals present in vegetables, fruits, spices, tea, and medicinal plants, have shown to suppress experimental carcinogenesis in various organs. The aim of the present study was to elucidate the protective effect of some of the phytochemicals against the arsenite induced DNA damage in normal mammalian V79 cells. Comet assay was used for assessment of DNA damage and 2', 7'-dichlorofluorescein dihydroacetate for estimation of ROS generated by arsenite. The effect of the phytochemicals was observed during simultaneous treatment with arsenic, before arsenite exposure and during repair experiments. Of all the phytochemicals tested against arsenic, curcumin gave better protection during simultaneous treatment and resveratrol during pre treatment, which was evident both from comet assay and ROS generation experiments. During pre treatment a longer duration of treatment with lower dose of phytochemicals proved fruitful in reducing the genotoxicity. During repair experiments the phytochemicals enhanced recovery of DNA damage and ellagic acid gave promising results. The results indicated that natural phytochemicals may have the efficacy in reducing arsenic induced genotoxicity, in scavenging ROS and in enhancing the process of DNA repair in V79 cells.
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PMID:Protective effect of dietary phytochemicals against arsenite induced genotoxicity in mammalian V79 cells. 1902 66

Oxidative stress (OS) is linked to the development of human diseases. Early identification of OS-associated diseases is essential in the control of their progression and treatment. Efforts have been undertaken to identify reliable endogenous markers, which correlate with the progression of a disease in an organ undergoing OS. An ideal biomarker must be validated, utilize noninvasive sampling, and have a simple, specific and highly sensitive detection method. Among the currently used markers assessing OS, are those that are nonspecific (peroxide value [PV], conjugated dienes [CD], thiobarbitoric acid reactive substances [TBARS]), and others that measure end-products of oxidized degradation biomolecules (isoprostanes, oxysterols, keto-proteins, 8-oxodeoxyguanosine), whose accumulation is not necessarily correlated with augmented OS. The search for a more reliable marker necessitates new approaches to fulfill such requirements and overcome many of the obstacles associated with the current markers. We suggest a new strategy of using designed exogenous novel reporters, constructed from endogenous subunits, that are sensitive to reactive oxygen and nitrogen species (ROS/RNS) and commonly known to react with them, forming specific oxidized products. These subunits are tyrosine (representing proteins), bonded covalently to linoleic acid (representing polyunsaturated fatty acids) forming an amide bond, which can be further connected through an ester bond to a third unit, either to cholesterol (representing sterols) or to 2'-deoxyguanosine (representing DNA). Oxidation of the designed probe can outline, in real time, the formation of oxidation products and distinguish them from intrinsic biomolecules, provide information about the relative subunit susceptibilities to a specific oxidant challenge, and allow for the assessment of the utility of intervention, such as antioxidant supplementation. By utilizing such markers, it may be possible to correlate between the damaged fingerprints of the marker and the specific pathological conditions. The above markers were tested to characterize OS in in vitro and in in vivo experiments, such as in those carried out in human fluids (blood, serum, saliva), tissues (brain or muscle homogenates), and cells (macrophages, astrocytes, neurons), pertaining to OS-associated diseases, such as atherosclerosis, diabetes, and Alzheimer's disease.
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PMID:Novel designed probes for the characterization of oxidative stress in biological fluids, cells, and tissues. 1908 34

Healthy vascular function is primarily regulated by several factors including EDRF (endothelium-dependent relaxing factor), EDCF (endothelium-dependent contracting factor) and EDHF (endothelium-dependent hyperpolarizing factor). Vascular dysfunction or injury induced by aging, smoking, inflammation, trauma, hyperlipidaemia and hyperglycaemia are among a myriad of risk factors that may contribute to the pathogenesis of many cardiovascular diseases, such as hypertension, diabetes and atherosclerosis. However, the exact mechanisms underlying the impaired vascular activity remain unresolved and there is no current scientific consensus. Accumulating evidence suggests that the inflammatory cytokine TNF (tumour necrosis factor)-alpha plays a pivotal role in the disruption of macrovascular and microvascular circulation both in vivo and in vitro. AGEs (advanced glycation end-products)/RAGE (receptor for AGEs), LOX-1 [lectin-like oxidized low-density lipoprotein receptor-1) and NF-kappaB (nuclear factor kappaB) signalling play key roles in TNF-alpha expression through an increase in circulating and/or local vascular TNF-alpha production. The increase in TNF-alpha expression induces the production of ROS (reactive oxygen species), resulting in endothelial dysfunction in many pathophysiological conditions. Lipid metabolism, dietary supplements and physical activity affect TNF-alpha expression. The interaction between TNF-alpha and stem cells is also important in terms of vascular repair or regeneration. Careful scrutiny of these factors may help elucidate the mechanisms that induce vascular dysfunction. The focus of the present review is to summarize recent evidence showing the role of TNF-alpha in vascular dysfunction in cardiovascular disease. We believe these findings may prompt new directions for targeting inflammation in future therapies.
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PMID:Role of TNF-alpha in vascular dysfunction. 1911 93

In this study, we investigated the effect of the xanthine oxidase (XO) inhibitor, allopurinol (ALP), on cardiac dysfunction, oxidative-nitrosative stress, apoptosis, poly(ADP-ribose) polymerase (PARP) activity and fibrosis associated with diabetic cardiomyopathy in mice. Diabetes was induced in C57/BL6 mice by injection of streptozotocin. Control and diabetic animals were treated with ALP or placebo. Left ventricular systolic and diastolic functions were measured by pressure-volume system 10 weeks after established diabetes. Myocardial XO, p22(phox), p40(phox), p47(phox), gp91(phox), iNOS, eNOS mRNA and/or protein levels, ROS and nitrotyrosine (NT) formation, caspase3/7 and PARP activity, chromatin fragmentation and various markers of fibrosis (collagen-1, TGF-beta, CTGF, fibronectin) were measured using molecular biology and biochemistry methods or immunohistochemistry. Diabetes was characterized by increased myocardial, liver and serum XO activity (but not expression), increased myocardial ROS generation, p22(phox), p40(phox), p47(phox), p91(phox) mRNA expression, iNOS (but not eNOS) expression, NT generation, caspase 3/7 and PARP activity/expression, chromatin fragmentation and fibrosis (enhanced accumulation of collagen, TGF-beta, CTGF and fibronectin), and declined systolic and diastolic myocardial performance. ALP attenuated the diabetes-induced increased myocardial, liver and serum XO activity, myocardial ROS, NT generation, iNOS expression, apoptosis, PARP activity and fibrosis, which were accompanied by improved systolic (measured by the evaluation of both load-dependent and independent indices of myocardial contractility) and diastolic performance of the hearts of treated diabetic animals. Thus, XO inhibition with ALP improves type 1 diabetes-induced cardiac dysfunction by decreasing oxidative/nitrosative stress and fibrosis, which may have important clinical implications for the treatment and prevention of diabetic cardiomyopathy and vascular dysfunction.
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PMID:Xanthine oxidase inhibitor allopurinol attenuates the development of diabetic cardiomyopathy. 1917 88

Vascular aging is characterized by increased oxidative stress and proinflammatory phenotypic alterations. Metabolic stress, such as hyperglycemia in diabetes, is known to increase the production of ROS and promote inflammatory gene expression, accelerating vascular aging. The oxidative stress hypothesis of aging predicts that vascular cells of long-lived species exhibit lower steady-state production of ROS and/or superior resistance to the prooxidant effects of metabolic stress. We tested this hypothesis using two taxonomically related rodents, the white-footed mouse (Peromyscus leucopus) and the house mouse (Mus musculus), which show a more than twofold difference in maximum lifespan potential (8.2 and 3.5 yr, respectively). We compared interspecies differences in steady-state and high glucose (HG; 30 mmol/l)-induced production of O(2)(*-) and H(2)O(2), endothelial function, mitochondrial ROS generation, and inflammatory gene expression in cultured aortic segments. In P. leucopus aortas, steady-state endothelial O(2)(*-) and H(2)O(2) production and ROS generation by mitochondria were less than in M. musculus vessels. Furthermore, vessels of P. leucopus were more resistant to the prooxidant effects of HG. Primary fibroblasts from P. leucopus also exhibited less steady-state and HG-induced ROS production than M. musculus cells. In M. musculus arteries, HG elicited significant upregulation of inflammatory markers (TNF-alpha, IL-6, ICAM-1, VCAM, and monocyte chemoattractant protein-1). In contrast, the proinflammatory effects of HG were blunted in P. leucopus vessels. Thus, increased life span potential in P. leucopus is associated with decreased cellular ROS generation and increased resistance to prooxidant and proinflammatory effects of metabolic stress, which accord with predictions of the oxidative stress hypothesis of aging.
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PMID:Longevity is associated with increased vascular resistance to high glucose-induced oxidative stress and inflammatory gene expression in Peromyscus leucopus. 1918 67

Cardiolipin is a unique phospholipid which is almost exclusively located at the level of the inner mitochondrial membrane where it is biosynthesized. This phospholipid is known to be intimately involved in several mitochondrial bioenergetic processes. In addition, cardiolipin also has active roles in several of the mitochondrial-dependent steps of apoptosis and in mitochondrial membrane dynamics. Alterations in cardiolipin structure, content and acyl chains composition have been associated with mitochondrial dysfunction in multiple tissues in several physiopathological conditions, including ischemia/reperfusion, different thyroid states, diabetes, aging and heart failure. Cardiolipin is particularly susceptible to ROS attack due to its high content of unsaturated fatty acids. Oxidative damage to cardiolipin would negatively impact the biochemical function of the mitochondrial membranes altering membrane fluidity, ion permeability, structure and function of components of the mitochondrial electron transport chain, resulting in reduced mitochondrial oxidative phosphorylation efficiency and apoptosis. Diseases in which mitochondrial dysfunction has been linked to cardiolipin peroxidation are described. Ca(2+), particularly at high concentrations, appears to have several negative effects on mitochondrial function, some of these effects being linked to CL peroxidation. Cardiolipin peroxidation has been shown to participate, together with Ca(2+), in mitochondrial permeability transition. In this review, we provide an overview of the role of CL peroxidation and Ca(2+) in mitochondrial dysfunction and disease.
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PMID:Role of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and disease. 1936 71

Like insulin, muscle contraction (in vitro or in situ) and exercise increase glucose uptake into skeletal muscle. However, the contraction/exercise pathway of glucose uptake in skeletal muscle is an independent pathway to that of insulin. Indeed, skeletal muscle glucose uptake is normal during exercise in those who suffer from insulin resistance and diabetes. Thus, the pathway of contraction-mediated glucose uptake into skeletal muscle provides an attractive potential target for pharmaceutical treatment and prevention of such conditions, especially as skeletal muscle is the major site of impaired glucose disposal in insulin resistance. The mechanisms regulating skeletal muscle glucose uptake during contraction have not been fully elucidated. Potential regulators include Ca(2+) (via CaMK's and/or CaMKK), AMPK, ROS, and NO signaling, with some redundancy likely to be evident within the system. In this review, we attempt to briefly synthesize current evidence regarding the potential mechanisms involved in regulating skeletal muscle glucose uptake during contraction, focusing on ROS and NO signaling. While reading this review, it will become clear that this is an evolving field of research and that much more work is required to elucidate the mechanism(s) regulating skeletal muscle glucose uptake during contraction.
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PMID:Skeletal muscle glucose uptake during exercise: a focus on reactive oxygen species and nitric oxide signaling. 1939 Nov 63

AMPK (AMP-activated protein kinase) is a key regulator of cellular energy because of its capacity to detect changes in the concentration of AMP. Recent evidence, however, indicates the existence of alternative mechanisms of activation of this protein. Mitochondrial ROS (reactive oxygen species), generated as a result of the interaction between nitric oxide and mitochondrial cytochrome c oxidase, activate AMPKalpha1 in HUVECs (human umbilical-vein endothelial cells) at a low oxygen concentration (i.e. 3%). This activation is independent of changes in AMP. In the present study we show, using HUVECs in which AMPKalpha1 has been silenced, that this protein is responsible for the expression of genes involved in antioxidant defence, such as manganese superoxide dismutase, catalase, gamma-glutamylcysteine synthase and thioredoxin. Furthermore, peroxisome proliferator-activated-coactivator-1, cAMP-response-element-binding protein and Foxo3a (forkhead transcription factor 3a) are involved in this signalling pathway. In addition, we show that silencing AMPKalpha1 in cells results in a reduced mitochondrial and eNOS (endothelial NO synthase) content, reduced cell proliferation, increased accumulation of ROS and apoptosis. Thus AMPKalpha1 in HUVECs regulates both their mitochondrial content and their antioxidant defences. Pharmacological activation of AMPKalpha1 in the vascular endothelium may be beneficial in conditions such as metabolic syndrome, Type 2 diabetes and atherosclerosis, not only because of its bioenergetic effects but also because of its ability to counteract oxidative stress.
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PMID:AMPKalpha1 regulates the antioxidant status of vascular endothelial cells. 1944 39


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