Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have clarified that reactive oxygen species (ROS) are involved in a diversity of biological phenomena including radiation damage, carcinogenesis, ischemia-reperfusion injury, diabetes mellitus and neurodegenerative diseases. The breakthrough of these fruitful accomplishments was the discovery of an enzyme, superoxide dismutase, by McCord and Fridovich in 1968. In the 1970s and 80s, biochemists and radiation biologists were attracted by the role of ROS in its irreversible damage to biological molecules. In the 1990s, ROS were further found to be a reversible modulator of protein structure as well, and this led to a recent rapid data accumulation on the association of ROS and transcription factors. At the same time, methods to localize ROS-induced damage in paraffin-embedded tissues have been established. This owes to a successful production of antibodies against covalently modified structures specific for ROS-induced damage. The epitopes include 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins. The present article reviews histochemical and immunohistochemical methods to localize ROS-induced damage in tissues and cells, further comments on the association of ROS with transcription factors, and shows a prospective view of ROS-induced carcinogenesis.
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PMID:Reactive oxygen species-induced molecular damage and its application in pathology. 1035 61

Free radicals have been implicated in over a hundred disease conditions in humans, including arthritis, hemorrhagic shock, atherosclerosis, advancing age, ischemia and reperfusion injury of many organs, Alzheimer and Parkinson's disease, gastrointestinal dysfunctions, tumor promotion and carcinogenesis, and AIDS. Antioxidants are potent scavengers of free radicals and serve as inhibitors of neoplastic processes. A large number of synthetic and natural antioxidants have been demonstrated to induce beneficial effects on human health and disease prevention. However, the structure-activity relationship, bioavailability and therapeutic efficacy of the antioxidants differ extensively. Oligomeric proanthocyanidins, naturally occurring antioxidants widely available in fruits, vegetables, nuts, seeds, flowers and bark, have been reported to possess a broad spectrum of biological, pharmacological and therapeutic activities against free radicals and oxidative stress. We have assessed the concentration- or dose-dependent free radical scavenging ability of a novel IH636 grape seed proanthocyanidin extract (GSPE) both in vitro and in vivo models, and compared the free radical scavenging ability of GSPE with vitamins C, E and beta-carotene. These experiments demonstrated that GSPE is highly bioavailable and provides significantly greater protection against free radicals and free radical-induced lipid peroxidation and DNA damage than vitamins C, E and beta-carotene. GSPE was also shown to demonstrate cytotoxicity towards human breast, lung and gastric adenocarcinoma cells, while enhancing the growth and viability of normal human gastric mucosal cells. The comparative protective effects of GSPE, vitamins C and E were examined on tobacco-induced oxidative stress and apoptotic cell death in human oral keratinocytes. Oxidative tissue damage was determined by lipid peroxidation and DNA fragmentation, while apoptotic cell death was assessed by flow cytometry. GSPE provided significantly better protection as compared to vitamins C and E, singly and in combination. GSPE also demonstrated excellent protection against acetaminophen overdose-induced liver and kidney damage by regulating bcl-X(L) gene, DNA damage and presumably by reducing oxidative stress. GSPE demonstrated excellent protection against myocardial ischemia-reperfusion injury and myocardial infarction in rats. GSPE was also shown to upregulate bcl(2) gene and downregulate the oncogene c-myc. Topical application of GSPE enhances sun protection factor in human volunteers, as well as supplementation of GSPE ameliorates chronic pancreatitis in humans. These results demonstrate that GSPE provides excellent protection against oxidative stress and free radical-mediated tissue injury.
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PMID:Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention. 1096 38

Vascular endothelial growth factor (VEGF) is known to be linked to retinal ischemia-associated neovascularization. It was recently found that insulin-like growth factor-I (IGF-I) enhances VEGF gene expression. In this study we investigated whether plasma VEGF levels are increased in patients with acromegaly, a disease in which plasma IGF-I levels are elevated, and whether plasma VEGF levels are correlated with plasma IGF-I levels in these patients. We retrospectively analyzed plasma samples from 13 active acromegalic patients (7 males and 6 females) aged 33 to 66 years, with a mean age of 52.3+/-10.8 years. The results were compared with plasma VEGF levels in 16 age- and sex-matched, healthy subjects (9 males and 7 females) aged 22 to 66 years, with a mean age of 52.4+/-11.5 years. Plasma VEGF levels were not higher in the acromegalic patients than in the healthy subjects (253+/-61 vs. 197+/-30 pg/mL, P= 0.39). In 5 patients plasma VEGF levels were rather slightly increased after pituitary adenomectomy while one patient showed a reduced plasma VEGF level. In addition there was no correlation between plasma VEGF and GH or IGF-I levels. These data indicate that plasma VEGF levels are not increased in patients with acromegaly and that serum VEGF may play a less important role in the neovascularization in the carcinogenesis and/or disturbances of the cardiovascular system in patients with acromegaly.
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PMID:Plasma levels of vascular endothelial growth factor in patients with acromegaly. 1098 29

Superoxide is involved in the pathogenesis of various diseases, such as inflammation, ischemia-reperfusion injury and carcinogenesis. Superoxide dismutases (SODs) catalyze the disproportionation reaction of superoxide to produce oxygen and hydrogen peroxide, and can protect living cells against the toxicity of free radicals derived from oxygen. Thus, SODs and their functional mimics have potential value as pharmaceuticals. We have previously reported that Fe(II)tetrakis-N,N,N',N'-(2-pyridylmethyl)ethylenediamine (Fe(II)TPEN) has an excellent SOD activity (IC50 = 0.5 microM) among many iron complexes examined (J. Biol. Chem., 264, 9243-9249 (1989)). Fe(II)TPEN can act like native SOD in living cells, and protect Escherichia coli cells from free radical toxicity caused by paraquat. In order to develop more effective SOD functional mimics, we synthesized Fe(II)TPEN derivatives with electron-donating or electron-withdrawing groups at the 4-position of all pyridines of TPEN, and measured the SOD activities and the redox potentials of these complexes. Fe(II) tetrakis-N,N,N',N'-(4-methoxy-2-pyridylmethyl)ethylenediamine (Fe(II)(4MeO)4TPEN) had the highest SOD activity (IC50 = 0.1 microM) among these iron-based SOD mimics. In addition, a good correlation was found between the redox potential and the SOD activity of 15 Fe(II) complexes, including iron-based SOD mimics reported in the previous paper (J. Organometal. Chem., in press). Iron-based SOD mimics may be clinically applicable, because these complexes are generally tissue-permeable and show low toxicity. Therefore our findings should be significant for the development of clinically useful SOD mimics.
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PMID:Superoxide dismutase activity of iron(II)TPEN complex and its derivatives. 1104 60

Hypoxia-inducible factor-1alpha (HIF-1alpha) transactivates genes required for energy metabolism and tissue perfusion and is necessary for embryonic development and tumor explant growth. HIF-1alpha is overexpressed during carcinogenesis, myocardial infarction, and wound healing; however, the biological consequences of HIF-1alpha overexpression are unknown. Here, transgenic mice expressing constitutively active HIF-1alpha in epidermis displayed a 66% increase in dermal capillaries, a 13-fold elevation of total vascular endothelial growth factor (VEGF) expression, and a six- to ninefold induction of each VEGF isoform. Despite marked induction of hypervascularity, HIF-1alpha did not induce edema, inflammation, or vascular leakage, phenotypes developing in transgenic mice overexpressing VEGF cDNA in skin. Remarkably, blood vessel leakage resistance induced by HIF-1alpha overexpression was not caused by up-regulation of angiopoietin-1 or angiopoietin-2. Hypervascularity induced by HIF-1alpha could improve therapy of tissue ischemia.
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PMID:Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1alpha. 1158 Nov 54

Xanthine oxidase (XO) is a highly versatile flavoprotein enzyme, ubiquitous among species (from bacteria to human) and within the various tissues of mammals. The enzyme catalyses the oxidative hydroxylation of purine substrates at the molybdenum centre (the reductive half-reaction) and subsequent reduction of O(2) at the flavin centre with generation of reactive oxygen species (ROS), either superoxide anion radical or hydrogen peroxide (the oxidative half-reaction). Many diseases, or at least symptoms of diseases, arise from a deficiency or excess of a specific metabolite in the body. For an example of an excess of a particular metabolite that produces a disease state is the excess of uric acid which can led to gout. Inhibition of XO decreases the uric acid levels, and results in an antihyperuricemic effect. Allopurinol, first synthesised as a potential anticancer agent, is nowadays a clinically useful xanthine oxidase inhibitor used in the treatment of gout. There is overwhelming acceptance that xanthine oxidase serum levels are significantly increased in various pathological states like hepatitis, inflammation, ischemia-reperfusion, carcinogenesis and aging and that ROS generated in the enzymatic process are involved in oxidative damage. Thus, it may be possible that the inhibition of this enzymatic pathway would be beneficial. In this review the State of the Art will be presented, which includes a summary of the progress made over the past years in the knowledge of the structure and mechanism of the enzyme, associated pathological states, and in the efforts made towards the development of new xanthine oxidase inhibitors.
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PMID:Progress towards the discovery of xanthine oxidase inhibitors. 1186 Mar 55

Oxidative stress is known to be related to various diseases such as inflammation, carcinogenesis, arteriosclerosis and ischemia-reperfusion injury, and is also a major cause of aging. For the prevention of diseases and control of aging, evaluation and control of oxidative stress in vivo may become essential. We have developed the new Oxidative Stress Profile(OSP), a total diagnostic system which provides information about oxidative stress inside human body. The OSP system consists of a number of biomakers including oxidative damage markers, prooxidant factors, antioxidants and life style-related markers. The result is shown in a two dimensional plot form. We measured a combination of biomarkers for oxidative damage of biological components, serum antioxidants and analyzed oxidative stress. The result show that oxidative stress was elevated in diabetic patients in comparison with normal controls. Oxidative stress is also elevated in smokers in comparison with non-smokers. It is also interesting to find that oxidative stress can be greatly reduced by the improvement of life style such as diet. Oxidative Stress Profile system may become a powerful tool for the evaluation of oxidative stress in vivo, and may be useful in prevention of diseases, "mi-byo"(possible cause of diseases)-diagnosis and the control of aging.
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PMID:[Oxidative stress profile: OSP]. 1269 Jun 28

The original neuroprotective hypothesis of estrogen was based on the gender difference in brain response to the ischemia-reperfusion injury. Additional clinical reports also suggest that estrogen may improve cognition in patients with Alzheimer disease. 17beta-Estradiol is the most potent endogenous ligand of estrogen, which protects against neurodegeneration in both cell and animal models. Estrogen-mediated neuroprotection is probably mediated by both receptor-dependent and -independent mechanisms. Binding of estrogen such as 17beta-estradiol to estrogen receptors (ERs) activates the homodimers of ER-DNA and its binding to estrogen response elements in the promoter region of genes such as neuronal nitric oxide synthase (NOS1) for regulating gene expression in target brain cells. In addition to the induction of NOS1, estrogen increases the expression of antiapoptotic protein such as bcl-2. Furthermore, our recent observations provide new molecular biologic and pharmacologic evidence suggesting that physiologic concentrations of 17beta-estradiol (<10 nM) activate ERs (ERbeta > ERalpha) and upregulate a cyclic guanosine 5'- monophosphate (cGMP)-dependent thioredoxin (Trx) and MnSOD expression following the induction of NOS1 in human brain-derived SH-SY5Y cells. We thus proposed that the estrogen-mediated gene induction of Trx plays a pivotal role in the promotion of neuroprotection because Trx is a multifunctional antioxidative and antiapoptotic protein. For managing progressive neurodegeneration such as Alzheimer dementia, our estrogen proposal of the signaling pathway of cGMP-dependent protein kinase (PKG) in mediating estrogen-induced cytoprotective genes thus fosters research and development of the new estrogen ligands devoid of female hormonal side effects such as carcinogenesis.
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PMID:Induction of antioxidative and antiapoptotic thioredoxin supports neuroprotective hypothesis of estrogen. 1277

Primary sclerosing cholangitis (PSC) is an idiopathic inflammatory disorder of the biliary tract characterized by diffuse biliary tract stricture formation, progressive chronic cholestasis and the development of secondary biliary cirrhosis. Biliary tract ischemia can produce morphological changes identical to PSC. We propose the existence of a localized renin-angiotensin system within the liver and extend the hypothesis that aberrant production of angiotensin II within the portal tract is the critical event contributing to the pathogenesis of PSC. A chronic reparative and proliferative state caused by chronic ischemia may promote carcinogenesis. Proof of this hypothesis will have implications for future therapeutic approaches given that current treatments for PSC aimed at reducing inflammation or the effects of cholestasis have proven ineffective.
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PMID:Aberrant local renin-angiotensin II responses in the pathogenesis of primary sclerosing cholangitis. 1278 43

Diabetes is a multifactorial disease that has now been recognized to involve overproduction of reactive oxygen species and pro-inflammatory cytokines. Peroxisomes are subcellular organelles with several important metabolic functions, and their role in the regulation of cellular oxidative stress is now well established. Despite having their own antioxidant system, peroxisomes undergo functional alterations during various conditions that are associated with free radical production such as inflammation, ischemia-reperfusion, carcinogenesis and diabetes. In this study we investigated the effect of diabetes on peroxisomal functions in rat kidneys and show for the first time that experimental diabetes induces redox-sensitive enhancement of peroxisomal activities. Streptozotocin-induced diabetes significantly increased (p < 0.01) beta-oxidation of lignoceric acid and the enzymic activity of acyl coenzyme A oxidase. Catalase activity was significantly reduced (p < 0.01) in the kidneys of diabetic rats, whereas the enzymic activity of DHAPATase (dihydroxyacetone phosphate acyltransferase) was not markedly affected by diabetes. Treatment of diabetic rats with antioxidants, thiocetic acid and vitamin C attenuated the diabetes-induced modulation of peroxisomal functions. The present study shows that the diabetes-induced effects on kidney peroxisomal functions are redox sensitive, and antioxidants might prove useful tools to alleviate nephropathy in diabetes.
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PMID:Antioxidants attenuate diabetes-induced activation of peroxisomal functions in the rat kidney. 1531 30


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