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)

Proteins constitute the major 'working force' for all forms of biological work. Their exact conformation and pattern of folding are tightly connected to their activity and function. Reactive oxygen and nitrogen species (ROS and RNS) are formed during normal metabolism and in higher fluxes under pathological conditions. They cause cellular damage, an important part of which is the oxidation of amino acid residues on proteins, forming protein carbonyls. Other direct modifications of protein side chains, such as o-tyrosine, chloro-, nitrotyrosine, and dityrosine, have been identified. In addition, carbohydrate and lipid derivatives can react with proteins to form adducts that can be analyzed. Protein carbonyl content (PCC) is the most widely used marker of oxidative modification of proteins. There are several methodologies for the quantitation of PCC; in all of them 2,4-dinitrophenyl hydrazine is allowed to react with the protein carbonyls to form the corresponding hydrazone, which can be analyzed optically by radioactive counting or immunohistochemically. Using PCC as a marker, it could be demonstrated that oxidative damage to proteins correlates well with aging and the severity of some diseases. A critical evaluation of PCC and other markers of protein oxidation is presented, together with examples of protein oxidation in diabetes, neurodegenerative diseases, and aging.
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PMID:Human studies related to protein oxidation: protein carbonyl content as a marker of damage. 1119 Dec 80

Recent experimental findings suggest that overproduction of reactive oxygen and nitrogen species (ROS/RNS), lowered antioxidant defense and alterations of enzymatic pathways in humans with poorly controlled diabetes mellitus can contribute to endothelial, vascular and neurovascular dysfunction. Over the past decade, there has been substantial interest in oxidative stress and its potential role in diabetogenesis, development of diabetic complications, atherosclerosis and associated cardiovascular disease. Consequences of oxidative stress are damage to DNA, lipids, proteins, disruption in cellular homeostasis and accumulation of damaged molecules. This review summarizes recent knowledge on the pathomechanism of ROS/RNS in vascular oxidative stress and Maillard reactions. Evidence suggests that Maillard reactions act as amplifier of oxidative damage in aging and diabetes. Furthermore, results of experimental observations with antioxidant systems and antioxidant pharmacotherapy in the treatment of diabetes mellitus are discussed. These data indicate that the targeting therapy to specific macromolecules, tissues and organs of diabetics by specific antioxidants or combined drug preparates could become a relevant adjuvant pharmacotherapy with improved glycaemic control, blood pressure control and management of dyslipidemia for the treatment or prevention of progression of micro- and macrovascular diabetic complications. Supplementation with antioxidants as a promising complementary treatment can exert beneficial effects in diabetes. Some antidiabetic drugs may have antioxidant properties independently of their main role on glycaemia control. Therapeutic potential of inhibitors of AGEs formation for delaying of diabetic complications is now intensively studied in several laboratories. Furthermore, for functional outcomes of the intervention with antioxidants is also important development of accurate and sensitive methods for early detection of oxidative damage in diabetes. (Tab. 6, Fig. 3, Ref. 117.)
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PMID:The role of free radicals, oxidative stress and antioxidant systems in diabetic vascular disease. 1121 44

The formation of intracellular reactive oxygen and nitrogen species (ROS and RNS) has been implicated in the pathogenesis of a variety of diseases. In excess, ROS and their byproducts may cause oxidative damage and be cytotoxic to cells. Recently, it has been established that these oxidants can also act as subcellular messengers in gene regulatory and signal transduction pathways. Estrogen, on the other hand, is known to offer protection from coronary artery diseases in post-menopausal women and to be involved in various ROS-related diseases, such as Alzheimer's and Parkinson's diseases, diabetes and aging. The existence of estrogen receptors in these tissues lead us to investigate whether ROS can regulate their expression. We demonstrated here, for the first time, that oxidative stress induced by hydrogen peroxide (H(2)O(2)), Fe(2+), 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH) and activated macrophages, affect the expression of estrogen receptors alpha and beta (ERalpha and ERbeta) differently, demonstrating cell-specific response which can be blocked by antioxidants. This data suggest that oxidative stress and the production of ROS/RNS function as physiological regulators of ERalpha and ERbeta expression. This may provide a new insight into the ERbeta-dependent protective action of estrogen and phytoestrogens in inflammation involving diseases, and may contribute to the development of novel therapeutic treatment strategies.
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PMID:The effect of oxidative stress on ERalpha and ERbeta expression. 1236 22

We have been investigating the potential utility of engineered cell lines as surrogates for primary islet cells in treatment of type 1 diabetes. To this end, two strategies that have emerged for procuring cell lines with resistance to immune-mediated damage are 1) selection of cytokine-resistant cell lines by growth of INS-1 insulinoma cells in iteratively increasing concentrations of interleukin (IL)-1beta + gamma-interferon (IFN-gamma), and 2) stable overexpression of the anti-apoptotic gene bcl-2 in INS-1 cells. Herein, we show that bcl-2-overexpressing cells are resistant to the cytotoxic effects of reactive oxygen and nitrogen species (ROS/RNS), but are only modestly protected against high concentrations of IL-1beta + INF-gamma, whereas the converse is true in cytokine selected cells. We also found that the combination of bcl-2 expression and cytokine selection confers a broader spectrum of resistance than either procedure alone, such that the resultant cells are highly resistant to cytokines and ROS/RNS, with no impairment in glucose-stimulated insulin secretion. INS-1-derived cells with combined bcl-2 expression and cytokine selection are also more resistant to damage induced by coculture with mitogen-activated peripheral blood mononuclear cells. Surprisingly, application of the cytokine selection procedure to bcl-2-overexpressing cells does not result in impairment of nuclear factor-kappaB translocation, iNOS expression, and NO production, as clearly occurs upon application of the selection procedure to cells without bcl-2 overexpression. Further investigation of the diverse pathways involved in the development of cytokine and ROS/RNS resistance may define simplified and specific strategies for preservation of beta-cell mass.
Diabetes 2003 Jun
PMID:Discrete and complementary mechanisms of protection of beta-cells against cytokine-induced and oxidative damage achieved by bcl-2 overexpression and a cytokine selection strategy. 1276 53

Diabetes mellitus is one of the most common chronic diseases affecting millions of people worldwide. Cardiovascular complication including myocardial infarction is one of the major causes of death in diabetic patients. Diabetes mellitus induces abnormal pathological findings including cell hypertrophy, neuropathy, interstitial fibrosis, myocytolysis and apoptosis and lipid deposits in the heart. In addition, the cytoplasmic organelles of cardiomyocytes including the plasma membrane, mitochondrion and sarcoplasmic reticulum are also impaired in both type I and type II diabetes. Hyperglycaemia is a major aetiological factor in the development of diabetic cardiomyopathy in patients suffering from diabetes. Hyperglycaemia promotes the production of reactive oxygen (ROS) and nitrogen species (RNS). The release of ROS and RNS induces oxidative stress leading to abnormal gene expression, faulty signal transduction and apoptosis of cardiomyocytes. Hyperglycaemia also induces apoptosis by p53 and the activation of the cytochrome c-activated caspase-3 pathway. Stimulation of connective tissue growth factor and the formation of advanced glycation end products in extracellular matrix proteins induces collagen cross-linking and contribute to the fibrosis observed in the interstitium of the heart of diabetic subjects. In terms of signal transduction, defects in intracellular Ca2+ signalling due to alteration of expression and function of proteins that regulate intracellular Ca2+ also occur in diabetes. All of these abnormalities result in gross dysfunction of the heart. Beta-adrenoreceptor antagonists, ACE inhibitors, endothelin-receptor antagonist (Bonestan), adrenomedullin, hormones (insulin, IGF-1) and antioxidants (magniferin, metallothionein, vitamins C and E) reduce interstitial fibrosis and improve cardiac function in diabetic cardiomyopathy.
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PMID:Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. 1536 3

Methylglyoxal (MG) is a metabolite of glucose. Our previous study demonstrated an elevated MG level with an increased oxidative stress in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats. Whether MG causes the generation of nitric oxide (NO) and superoxide anion (O2*-), leading to peroxynitrite (ONOO-) formation in VSMCs, was investigated in the present study. Cultured rat thoracic aortic SMCs (A-10) were treated with MG or other different agents. Oxidized DCF, reflecting H2O2 and ONOO- production, was significantly increased in a concentration- and time-dependent manner after the treatment of SMCs with MG (3-300 microM) for 45 min-18 h (n = 12). MG-increased oxidized DCF was effectively blocked by reduced glutathione or N-acetyl-l-cysteine, as well as L-NAME (p < 0.05, n = 12). Both O2*- scavenger SOD and NAD(P)H oxidase inhibitor DPI significantly decreased MG-induced oxidized DCF formation. MG significantly and concentration-dependently increased NO and O2*- generation in A-10 cells, which was significantly inhibited by L-NAME and SOD or DPI, respectively. In conclusion, MG induces significant generation of NO and O2*- in rat VSMCs, which in turn causes ONOO- formation. An elevated MG level and the consequential ROS/RNS generation would alter cellular signaling pathways, contributing to the development of different insulin resistance states such as diabetes or hypertension.
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PMID:Methylglyoxal-induced nitric oxide and peroxynitrite production in vascular smooth muscle cells. 1560 12

Cardiovascular disease affects approximately 60% of the adult population over the age of 65 and represents the number one cause of death in the United States. Coronary atherosclerosis is responsible for the vast majority of the cardiovascular events, and a number of cardiovascular risk factors have been identified. In recent years, it has become clear that insulin resistance and endothelial dysfunction play a central role in the pathogenesis of atherosclerosis. Much evidence supports the presence of insulin resistance as the fundamental pathophysiologic disturbance responsible for the cluster of metabolic and cardiovascular disorders, known collectively as the metabolic syndrome. Endothelial dysfunction is an important component of the metabolic or insulin resistance syndrome and this is demonstrated by inadequate vasodilation and/or paradoxical vasoconstriction in coronary and peripheral arteries in response to stimuli that release nitric oxide (NO). Deficiency of endothelial-derived NO is believed to be the primary defect that links insulin resistance and endothelial dysfunction. NO deficiency results from decreased synthesis and/or release, in combination with exaggerated consumption in tissues by high levels of reactive oxygen (ROS) and nitrogen (RNS) species, which are produced by cellular disturbances in glucose and lipid metabolism. Endothelial dysfunction contributes to impaired insulin action, by altering the transcapillary passage of insulin to target tissues. Reduced expansion of the capillary network, with attenuation of microcirculatory blood flow to metabolically active tissues, contributes to the impairment of insulin-stimulated glucose and lipid metabolism. This establishes a reverberating negative feedback cycle in which progressive endothelial dysfunction and disturbances in glucose and lipid metabolism develop secondary to the insulin resistance. Vascular damage, which results from lipid deposition and oxidative stress to the vessel wall, triggers an inflammatory reaction, and the release of chemoattractants and cytokines worsens the insulin resistance and endothelial dysfunction.From the clinical standpoint, much experimental evidence supports the concept that therapies that improve insulin resistance and endothelial dysfunction reduce cardiovascular morbidity and mortality. Moreover, interventional strategies that reduce insulin resistance ameliorate endothelial dysfunction, while interventions that improve tissue sensitivity to insulin enhance vascular endothelial function. There is general agreement that aggressive therapy aimed simultaneously at improving insulin-mediated glucose/lipid metabolism and endothelial dysfunction represents an important strategy in preventing/delaying the appearance of atherosclerosis. Interventions that 1 correct carbohydrate and lipid metabolism, 2 improve insulin resistance, 3 reduce blood pressure and restore vascular reactivity, and 4 attenuate procoagulant and inflammatory responses in adults with a high risk of developing cardiovascular disease reduce cardiovascular morbidity and mortality. Whether these benefits hold when the same prevention strategies are applied to younger, high-risk individuals remains to be determined.
Diabetes Metab Res Rev
PMID:Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases. 1650 74

Diabetic cardiomyopathy has become a major contributor to the increased mortality of diabetic patients. Although the development and progression of diabetic cardiomyopathy are considered to be associated with diabetes-derived oxidative stress, the precise mechanisms for and effectively preventive approaches to diabetic cardiomyopathy remain to be explored. Recent studies showed that reactive oxygen or nitrogen species (ROS/RNS) not only play a critical role in the initiation of diabetic cardiomyopathy, but also play an important role in physiological signaling. Therefore, this review will first discuss the dual roles of ROS/RNS in the physiological signaling and pathogenic remodeling leading to cardiomyopathy under diabetic conditions. The significant prevention of diabetic cardiomyopathy by metallothionein (MT) as a potent and nonspecific antioxidant will be also summarized. It is clearly revealed that although dual roles of peroxynitrite-nitrated proteins have been indicated under both physiological and pathogenic conditions, suppression of nitrative damage by MT in the diabetic heart is the major mechanism responsible for its prevention of diabetic cardiomyopathy. Finally the potential for clinical enhancement of the cardiac MT expression to prevent or delay the occurrence of cardiomyopathy in diabetic patients will also be addressed.
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PMID:Suppression of nitrative damage by metallothionein in diabetic heart contributes to the prevention of cardiomyopathy. 1693 65

Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NAD(P)H) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents, in the function of a number of cellular signalling pathways, and the induction of a mitogenic response. Ironically, various ROS-mediated actions in fact protect cells against ROS-induced oxidative stress and re-establish or maintain "redox balance" termed also "redox homeostasis". The "two-faced" character of ROS is clearly substantiated. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. This review will describe the: (i) chemistry and biochemistry of ROS/RNS and sources of free radical generation; (ii) damage to DNA, to proteins, and to lipids by free radicals; (iii) role of antioxidants (e.g. glutathione) in the maintenance of cellular "redox homeostasis"; (iv) overview of ROS-induced signaling pathways; (v) role of ROS in redox regulation of normal physiological functions, as well as (vi) role of ROS in pathophysiological implications of altered redox regulation (human diseases and ageing). Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing. Topics of current debate are also reviewed such as the question whether excessive formation of free radicals is a primary cause or a downstream consequence of tissue injury.
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PMID:Free radicals and antioxidants in normal physiological functions and human disease. 1697 5

1 The present study investigated the effect of streptozotocin-induced diabetes on alpha(1)-adrenoceptor subtypes in rat renal resistance vessels. 2 Studies on renal haemodynamics were carried out 7 days after the last streptozotocin. Changes in renal blood flow were recorded in response to electrical stimulation of the renal nerve (RNS) and a range of adrenergic agonists; noradrenaline (NA), phenylephrine (PE) and methoxamine (MTX), either in the absence or the presence of nitrendipine (Nit), 5-methylurapidil (MEU), chlorethylclonidine (CEC) or BMY 7378. 3 In non-diabetic animals, Nit, MEU and BMY 7378 significantly attenuated renal vasoconstriction induced by adrenergic agonists, while CEC showed a significant accentuation in RNS-induced responses without having a significant effect on responses to adrenergic agonists. In diabetic rats, renal vasoconstriction was also significantly reduced in Nit-, MEU- and BMY 7378-treated groups and CEC potentiated RNS-induced contractions caused a change similar to that observed in non-diabetic rats. BMY 7378 significantly (P < 0.05) attenuated the PE- and MTX-induced vasoconstrictions but did not cause any significant (P > 0.05) alteration in the RNS- and NA-induced responses. 4 The results showed functional co-existence of alpha(1A)- and alpha(1D)-adrenoceptors in the renal vasculature of SD rats irrespective of the presence of diabetes. A possible minor contribution of prejunctional alpha-adrenoceptor subtype has also been suggested in either experimental group, particularly possible functional involvement of alpha(1B)-adrenoceptor subtypes in non-diabetic SD rats.
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PMID:Alpha1A- and alpha1D-adrenoceptors are the major functional subtypes of renal alpha1-adrenoceptors in streptozotocin-induced diabetic and normal Sprague-Dawley rats. 1825 46


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