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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Toxic oxygen metabolites may contribute to the development of tissue damage, and play a role in the pathogenesis of malignancies, some acute and chronic pulmonary diseases, and in cell damage by radiomimetic agents, which can be seen in patients with ataxia-telangiectasia (A-T). Oxidative stress resulting from increased free radical production and/or defects in antioxidant defences is also involved in neurodegenerative disorders. Thus, oxidative stress could account for several aspects of the pleiotropic phenotype of A-T patients. The aim of this study was to determine the activities of the enzymes involved in cellular antioxidant metabolism in A-T patients to see if there is any defect which may result in constant oxidative stress. Superoxide dismutase (SOD) and catalase activities of erythrocytes, in contrast to lymphocytes, were found to be significantly higher in patients than in healthy controls. Our results may be another indication for the presence of constant oxidative stress in A-T patients as suggested previously.
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PMID:Antioxidant enzymes in red blood cells and lymphocytes of ataxia-telangiectasia patients. 1550 71

Cyclosporine A (CsA), a fungal undecapeptide, is the most common immunosuppressive drug used in organ transplantation and autoimmune diseases. However, nephrotoxicity is the major adverse effect of CsA use. The molecular mechanisms of CsA nephrotoxicity are not well characterized, but more recent studies suggest an involvement of angiotensin II (ANG II) and reactive oxygen species in the development of cyclosporine nephrotoxicity. Induction of heat shock proteins (HSPs) is one of the best-described cellular responses to heat stress, hypoxia, and exposure to oxidants. HSPs have beneficial roles in protein processing and protection against cell injury. There is emerging evidence that ANG II induces oxidative stress in vitro and in vivo. This study was thus designed to investigate the role of Angiotensin II type I (AT1) receptor antagonist, irbesartan, on CsA-induced nephrotoxicity. Five groups of rats were employed in this study: group 1 served as control, group 2 rats were treated with CsA (20 mg kg(-1), subcutaneously for 21 days), and groups 3, 4, and 5 received CsA along with irbesartan (10, 25, and 50 mg kg(-1), perorally 24 hr before and 21 days concurrently), respectively. Renal function was assessed by measuring serum creatinine, blood urea nitrogen, creatinine, and urea clearance. The renal oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels, and enzymatic activity of catalase, glutathione reductase, and superoxide dismutase. Renal morphological alterations were assessed by histopathological examination. CsA administration for 21 days resulted in a marked renal oxidative stress and significantly deranged the renal functions as well as renal morphology. All these factors were significantly improved by irbesartan (50 mg kg(-1)) treatment. HSP72, HSP47, and HSP25 were clearly induced and expressed in CsA-treated animals. The induction and expression of HSP25 was markedly protected by treatment with irbesartan, whereas the induction and expression of HSP47 and HSP72 remained unaltered with the irbesartan treatment. These results clearly demonstrate the pivotal role of ANG II-induced oxidative stress and therapeutic potential of AT, receptor antagonist in ameliorating CsA-induced nephrotoxicity.
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PMID:Amelioration of cyclosporine nephrotoxicity by irbesartan, A selective AT1 receptor antagonist. 1552 4

The aim of this work was to investigate the production of oxidative damage in homogenized kidney, liver and brain of spontaneously hypertensive rats (SHR), as well as the involvement of angiotensin (Ang) II in this process. Groups of 12-week-old SHR and Wistar Kyoto rats (WKY) were given 10 mg/kg/day losartan in the drinking water during 14 days. Other groups of WKY and SHR without treatment were used as controls. The production of thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and the activity of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (Gpx) were determined. No significant difference in TBARS was observed between untreated SHR or WKY rats; GSH content was lower in the liver but higher in the brain of SHR compared to WKY rats. In tissues from the SHR group, SOD and Gpx activities were reduced, whereas CAT activity was slightly increased in kidney. TBARS levels did not change in WKY rats after losartan administration, but were reduced in SHR liver and brain. Losartan treatment decreased GSH content in WKY kidney, but increased GSH in SHR liver. The activity of the antioxidant enzymes was not modified by losartan in WKY rats; however, their activities increased in tissues from treated SHR. The lower activity of antioxidant enzymes in tissues from hypertensive rats compared to those detected in normotensive controls, indicates oxidative stress production. Ang II seems to play no role in this process in normotensive animals, although AT1 receptor blockade in SHR enhances the enzymatic activity indicating that Ang II is implicated in oxidative stress generation in the hypertensive animals.
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PMID:Effects of angiotensin II type 1 receptor blockade on the oxidative stress in spontaneously hypertensive rat tissues. 1572 81

Untreated hypertensive patients show increased oxidative stress and decreased antioxidant enzyme activity in mononuclear cells. Therefore, the objective of this study was to determine whether or not the low antioxidant enzyme activity observed in mononuclear cells of hypertensive subjects is in part dependent on a defective activity of antioxidant mechanisms. Activity and mRNA level of antioxidant enzymes, CuZn- and Mn-superoxide dismutases, catalase, glutathione peroxidase type 1, and glutathione reductase were simultaneously measured in mononuclear cells of controls (n = 38) and hypertensive subjects (n = 35), in the absence of and during antihypertensive treatment. An increase in oxidative stress and a decrease in the activity of cytoplasmic enzymes were observed in untreated hypertensive patients. Concurrently, CuZn-superoxide dismutase and glutathione reductase mRNA levels were significantly reduced, and glutathione peroxidase type 1 mRNA was slightly reduced. In contrast, increased activity and mRNA levels of the mitochondrial Mn-superoxide dismutase were observed. Antihypertensive treatment, nonpharmacologic with or without a drug regimen of beta-blocker or angiotensin AT1 receptor blocker was administered for a 3-month period. Afterward, after the improvement in oxidative stress during treatment, a recovery of the cytoplasmic antioxidant enzymatic activity and a more profound decrease in mRNA levels were observed for CuZn-superoxide dismutase, glutathione peroxidase type 1, and glutathione reductase. Meanwhile mitochondrial enzymatic activity decreased, as did the mRNA level. The inadequate response of the main cytoplasmatic antioxidant systems, as well as of the enzymes participating in the maintenance of glutathione levels, may contribute to the vulnerability of hypertensives to oxidative stress.
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PMID:Inadequate cytoplasmic antioxidant enzymes response contributes to the oxidative stress in human hypertension. 1719 13

Androgenetic alopecia (AGA), a hereditary disorder that involves the progressive thinning of hair in a defined pattern, is driven by androgens. The hair follicle dermal papilla (DP) expresses androgen receptors (AR) and plays an important role in the control of normal hair growth. In AGA, it has been proposed that the inhibitory actions of androgens are mediated via the DP although the molecular nature of these interactions is poorly understood. To investigate mechanisms of AGA, we cultured DP cells (DPC) from balding and non-balding scalp and confirmed previous reports that balding DPC grow slower in vitro than non-balding DPC. Loss of proliferative capacity of balding DPC was associated with changes in cell morphology, expression of senescence-associated beta-galactosidase, as well as decreased expression of proliferating cell nuclear antigen and Bmi-1; upregulation of p16(INK4a)/pRb and nuclear expression of markers of oxidative stress and DNA damage including heat shock protein-27, super oxide dismutase catalase, ataxia-telangiectasia-mutated kinase (ATM), and ATM- and Rad3-related protein. Premature senescence of balding DPC in vitro in association with expression of p16(INK4a)/pRB suggests that balding DPC are sensitive to environmental stress and identifies alternative pathways that could lead to novel therapeutic strategies for treatment of AGA.
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PMID:Premature senescence of balding dermal papilla cells in vitro is associated with p16(INK4a) expression. 1798 30

Angiotensin II (Ang II) induces reactive oxygen species (ROS) production by human vascular smooth muscle cells (hVSMCs). ROS have been implicated in the development of both acute stress-induced premature senescence (SIPS) and chronic replicative senescence. Global oxidative DNA damage triggers SIPS and telomere DNA damage accelerates replicative senescence, both mediated via p53. This study tests the hypothesis that DNA is an important target for Ang II-induced ROS leading to senescence via telomere-dependent and independent pathways. DNA damage was quantified using the Comet assay, telomere DNA length by Southern blotting and hVSMC senescence by senescence-associated beta-galactosidase staining. Exposure to Ang II increased DNA damage in hVSMCs within 4 hours. Inhibition by an AT1 receptor antagonist (losartan metabolite: E3174) or catalase, confirmed that Ang II-induced DNA damage was AT1 receptor-mediated, via the induction of ROS. Acute exposure to Ang II resulted in SIPS within 24 hours that was prevented by coincubation with E3174 or catalase. SIPS was associated with increased p53 expression but was not dependent on telomere attrition because overexpression of human telomerase did not prevent Ang II-induced SIPS. Exposure to Ang II over several population doublings accelerated the rate of telomere attrition (by >2-fold) and induced premature replicative senescence of hVSMCs--an effect that was also attenuated by E3174 or catalase. These data demonstrate that Ang II-induced ROS-mediated DNA damage results in accelerated biological aging of hVSMCs via 2 mechanisms: (1) Acute SIPS, which is telomere independent, and (2) accelerated replicative senescence which is associated with accelerated telomere attrition.
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PMID:Angiotensin II-mediated oxidative DNA damage accelerates cellular senescence in cultured human vascular smooth muscle cells via telomere-dependent and independent pathways. 1799 83

Early gestation dexamethasone (dex) administration is an ovine model of fetal programming associated with increased coronary reactivity to angiotensin II (Ang II). NADPH oxidase-dependent superoxide production plays an important role in both Ang II signaling and coronary disease. We sought to determine whether early gestation dex-exposure increases coronary reactivity to Ang II by enhancing endothelial NADPH oxidase-dependent superoxide production. Dex (0.28 mg/kg/d for 48 h) was administered to pregnant ewes at 27-28 d gestation. Dex-exposed and control offspring were studied at 4 mo of age. Coronary superoxide production was measured by lucigenin-enhanced chemiluminescence and dihydroethidium fluorescence. Coronary arteries from dex-exposed sheep had significantly enhanced vasoconstriction to Ang II, an effect abolished by either endothelial removal or preincubation with membrane-permeable superoxide dismutase and catalase. Ang II significantly increased endothelial superoxide production and NADPH oxidase activity in coronaries from dex-exposed offspring, but not controls. This programmed alteration in superoxide production was accentuated by PD123319 (AT2 antagonist), but abolished by losartan (AT1 antagonist). In conclusion, early gestation dex-exposure programs coronary reactivity to Ang II by enhancing Ang II-stimulated endothelial superoxide production. This programming effect may predispose to progressive coronary endothelial dysfunction and coronary artery disease.
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PMID:Coronary constriction to angiotensin II is enhanced by endothelial superoxide production in sheep programmed by dexamethasone. 1835 41

Previously, we found that high intraluminal pressure leads to production of reactive oxygen species (ROS) and also upregulates several components of the renin-angiotensin system in the wall of small arteries. We hypothesized that acute exposure of arterioles to high intraluminal pressure in vitro via increasing ROS production enhances the functional availability of type 1 angiotensin II (Ang II) receptors (AT1 receptors), resulting in sustained constrictions. In arterioles ( approximately 180 mum) isolated from rat skeletal muscle, Ang II elicited dose-dependent constrictions, which decreased significantly by the second application [maximum (max.): from 59% +/- 4% to 26% +/- 5% at 10(-8) M; P < 0.05] in the presence of 80 mmHg of intraluminal pressure. In contrast, if the arterioles were exposed to high intraluminal pressure (160 mmHg for 30 min), Ang II-induced constrictions remained substantial on the second application (max.: 51% +/- 3% at 10(-8) M). In the presence of Tiron and polyethylene glycol (PEG)-catalase, known to reduce the level of superoxide anion and hydrogen peroxide (H(2)O(2)), second applications of Ang II evoked similarly reduced constrictions, even after high-pressure exposure (29% +/- 4% at 10(-8) M). Furthermore, when arterioles were exposed to H(2)O(2) (for 30 min, 10(-7) M, at normal 80 mmHg pressure), Ang II-induced constrictions remained substantial on second applications (59% +/- 5% at 10(-8) M). These findings suggest that high pressure, likely via inducing H(2)O(2) production, increases the functional availability of AT1 receptors and thus enhances Ang II-induced arteriolar constrictions. We propose that in hypertension-regardless of etiology-high intraluminal pressure, via oxidative stress, enhances the functional availability of AT1 receptors augmenting Ang II-induced constrictions.
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PMID:High intraluminal pressure via H2O2 upregulates arteriolar constrictions to angiotensin II by increasing the functional availability of AT1 receptors. 1856 10

The therapeutic usefulness of doxorubicin (DXR), an anthracycline antibiotic, is limited by its cardiotoxicity. The present study investigated the effects of telmisartan, an angiotensin II receptor (AT1) antagonist against doxorubicin-induced cardiotoxicity in rats using biochemical and histopathological approaches. Doxorubicin (20 mg/kg) was injected intraperitoneally (ip) as a single dose and telmisartan (10 mg/kg) was administered orally for 7 days. Rats treated with DXR showed cardiotoxicity as evidenced by elevation of serum lactate dehydrogenase (LDH) activity, tissue malondialdehyde (MDA) level, catalase activity and a decrease in the level of glutathione (GSH). Pre- and post-treatment with telmisartan elicited a significant decrease in the activities of LDH and catalase in comparison with DXR-treated group. Furthermore, pretreatment with telmisartan also decreased lipid peroxidation (MDA level) and increased the GSH content in comparison with DXR group. However, the difference in lipid peroxidation and GSH content were not statistically significant in post-treated group. Histopathological studies showed disruption of cardiac tisuues in DXR groups. Pre- and post-treatment with telmisartan reduced the damage of cardiac tissue in rats. These results suggest that telmisartan treatment provides a significant protective effect against acute-doxorubicin induced cardiotoxicity in rats.
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PMID:Protective effects of telmisartan against acute doxorubicin-induced cardiotoxicity in rats. 1862 63

The adaptive immune response and, in particular, T cells have been shown to be important in the genesis of hypertension. In the present study, we sought to determine how the interplay between ANG II, NADPH oxidase, and reactive oxygen species modulates T cell activation and ultimately causes hypertension. We determined that T cells express angiotensinogen, the angiotensin I-converting enzyme, and renin and produce physiological levels of ANG II. AT1 receptors were primarily expressed intracellularly, and endogenously produced ANG II increased T-cell activation, expression of tissue homing markers, and production of the cytokine TNF-alpha. Inhibition of T-cell ACE reduced TNF-alpha production, indicating endogenously produced ANG II has a regulatory role in this process. Studies with specific antagonists and T cells from AT1R and AT2R-deficient mice indicated that both receptor subtypes contribute to TNF-alpha production. We found that superoxide was a critical mediator of T-cell TNF-alpha production, as this was significantly inhibited by polyethylene glycol (PEG)-SOD, but not PEG-catalase. Thus, T cells contain an endogenous renin-angiotensin system that modulates T-cell function, NADPH oxidase activity, and production of superoxide that, in turn, modulates TNF-alpha production. These findings contribute to our understanding of how ANG II and T cells enhance inflammation in cardiovascular disease.
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PMID:Regulation of T-cell function by endogenously produced angiotensin II. 1907 7


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