Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pulmonary fibrosis can be observed as an end state in a number of chronic inflammatory pulmonary diseases. Although the mechanisms by which lung fibrosis develops are not fully ascertained, recent findings suggest that oxidative stress may play an important role in the pathogenesis of tissue fibrosis affecting apoptosis of both structural and inflammatory cells and altering the cytokine microenvironment balance. Damage and alteration of alveolar epithelial cells is one of the hallmarks of interstitial lung fibrosis. Recently, it has been demonstrated that the presence of oxidative stress may lead to the damage, activation and/or apoptosis of alveolar epithelial cells either directly, through an imbalanced intracellular redox equilibrium, or indirectly, by activating redox-sensitive effector pathways, such as transcription factors and angiotensin converting enzyme, increasing the conversion of angiotensinogen into angiotensin II that can be considered a mediator of oxidative stress, capable of inducing apoptosis. Furthermore, it has been demonstrated that angiotensin II acts as a proinflammatory cytokine and is effective in activating fibroblasts through the release of transforming growth factor (TGF-beta). As well as activation, differentiation, proliferation and apoptosis of fibroblasts seem related to the oxidant/antioxidant balance, and the maintenance of a high intracellular level of reduced glutathione (GSH) is considered crucial in providing a reducing environment within the cell, able to protect against oxidative stress. In those conditions where oxidants, either inhaled or produced by inflammatory cell, increase, the ratio between GSH and oxidized glutathione (GSSH) may lower, influencing a variety of cellular redox-sensitive signaling processes such as the activation of nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) that lead to a transcriptional up-regulation of a number of genes involved in inflammation and/or fibrogenesis, including cytokines [interleukin (IL)-1,, tumor necrosis factor (TNF-alpha), IL-6] chemokines (IL-8), adhesion molecules (VCAM-1, ICAM-1) and growth factors (GM-CSF). In addition, several studies have shown that oxidative stress may also affect the immune response by inducing an up-regulation of HLA-DR as well as the expression of two costimulatory molecules such as CD40 and CD86, determining a persistent state of immune activation, and affecting the Th1/Th2 balance, modulating the T-cell effector response towards the Th2 phenotype. It is clear that a better understanding of the precise sequence of events that make the difference between normal tissue repair and fibrosis, including the role played by oxidative stress, will certainly improve our therapeutic approach to pulmonary fibrosis.
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PMID:Role of oxidative stress in pulmonary fibrosis. 1261 77

DCP has been utilized as a soil fumigant for more than 45 yr for the control for parasitic plant nematodes. Injected into soil before planting of crops, the instability of DCP in soil and water and its volatility dictate the principal route of human exposure that may occur, inhalation. Extensive data have been accumulated on the toxicity and metabolism of DCP. DCP is moderately toxic via oral or inhalation exposure, is irritating to the skin and eyes, and has potential to produce skin sensitization. It is rapidly and extensively metabolized. It has a half-life in the blood of rats and humans of only 3-7 min and < 10 min, respectively. Rats and mice excrete approximately 80% of even relatively high oral dosages within 24 hr, primarily as breakdown products of a glutathione conjugate or as carbon dioxide. These products reflect the primary routes of metabolism of DCP, via GSH-conjugative and hydrolytic pathways. An additional pathway based upon the epoxidation of DCP has also been proposed, but this does not appear to occur to any toxicologically significant degree in the presence of normally occurring GSTs. Direct evidence of the latter pathway is only been obtained at dosages of DCP in excess of the reported LD50. Humans also appear to rapidly metabolize DCP and excrete its metabolites. Subchronic toxicity studies of relatively pure DCP in rats and mice via oral or inhalation routes have resulted in portal-of-entry tissue effects that reflect the irritant properties of this chemical to nasal and gastric mucosa. At higher exposure levels in mice, however, toxicity was also identified in a remote tissue, the urinary bladder. Toxicity in dogs ingesting DCP was limited to the formation of a regenerative hypochromic, microcytic anemia. No teratological or reproductive effects were observed in rats or rabbits inhaling DCP vapors. Nonneoplastic changes from chronic dosing of DCP were generally similar to those observed in subchronic studies. Somewhat variable responses, however, have been observed for neoplastic effects, depending on the DCP formulation, route, and species used. Inhalation of a recent formulation increased the benign tumor incidence in the lungs of male mice (only) while ingestion of similar test material by rats and mice resulted in a low incidence of benign liver tumors in rats (only). In contrast, an older formulation containing Epi as a stabilizing agent administered to rats and mice via bolus oral dosing induced a number of malignant or benign tumors: in the forestomach and liver in rats and the forestomach, lung, and urinary bladder in mice. An equally complicated database has accumulated for DCP in vitro and in vivo genotoxicity testing. Genotoxicity has been reported in in vitro assays; however, confounding factors such as low-purity formulations, use of a genotoxic stabilizer, or generation of reactive impurities during attempts to purify test material have complicated interpretation. DCP appears to lack direct DNA reactivity, and a general trend toward decreasing activity with increasing complexity of the assay system and the presence of GST is evident. The weight-of-evidence evaluation of the genotoxicity data base suggests a lack of genotoxicity in vivo. Clearly definable treatment-related effects of DCP suggesting a plausible nongenotoxic mechanism of tumorigenic action, for example, enhanced cell proliferation, have not been in evidence in target tissues of treated animals. Thus, the specific mode of tumorigenesis of DCP in test animals remains to be elucidated but appears to involve a non-DNA-reactive mechanism. In conclusion, DCP-based soil fumigants have maintained an important role in agricultural despite the structural similarity of DCP to known genotoxic carcinogens and its own activity in in vitro genotoxicity assays. This role results from a combination of its use on soils before the planting of crops, its limited environmental half-life, rapid metabolism by animals via GSH conjugation and catabolism to CO2, lack of genotoxicity in in vivo assays, and an extensive toxicological database in animals, including several oncogenicity bioassays. These data, when combined with occupational and environmental exposure information, have provided a scientifically sound basis for the continued safe use of DCP-containing products.
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PMID:Mammalian toxicity of 1,3-dichloropropene. 1288 26

The effects of in vitro exposure of human erythrocytes to different concentrations of 2,4-dichlorophenoxyacetic acid (2,4-D) and its metabolite 2,4-dichlorophenol (2,4-DCP) were studied. The activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and the level of reduced glutathione (GSH) were determined. The activity of erythrocyte superoxide dismutase SOD decreased with increasing dose of 2,4-D and 2,4-DCP, while glutathione peroxidase activity increased. 2,4-D (500 ppm) decreased the level of reduced glutathione in erythrocytes by 18% and 2,4-DCP (250 ppm) by 32%, respectively, in comparison with the controls. These results lead to the conclusion that in vitro administration of herbicide-2,4-D and its metabolite 2,4-DCP causes a decrease in the level of reduced glutathione in erythrocytes and significant changes in antioxidant enzyme activities. Comparison of the toxicity of 2,4-D and 2,4-DCP revealed that the most prominent changes occurred in human erythrocytes incubated with 2,4-DCP.
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PMID:Effects of 2,4-D and its metabolite 2,4-dichlorophenol on antioxidant enzymes and level of glutathione in human erythrocytes. 1296 88

We reported that melatonin prevents the progression of carbon tetrachloride (CCl4)-induced acute liver injury in rats possibly by attenuating enhanced lipid peroxidation and reduced glutathione depletion. Herein, we examined the effect of melatonin on the changes in hepatic reactive oxygen species (ROS) metabolism in rats with a single intraperitoneal injection of CCl4 (1.6 g/kg body weight); the intent was to clarify the therapeutic mechanism of the indoleamine on CCl4-induced acute liver injury. Rats with and without CCl4 treatment received a single oral dose of melatonin (10, 50 or 100 mg/kg body weight) 6 hr after CCl4 treatment. Hepatic concentrations of ascorbic acid (ASC) and vitamin E (VE) and hepatic activities of superoxide dismutase (SOD), catalase (CAT), Se-glutathione peroxidase (Se-GSH-Px), glutathione reductase (GSSG-R), glucose-6-phosphate dehydrogenase (G-6-PDH), and xanthine oxidase (XO) were determined 6 and 24 hr after CCl4 treatment. The liver of CCl4-treated rats showed reductions in ASC concentrations, and SOD activity and an increase in G-6-PDH activity at 6 hr after treatment and further decreases in ACS concentrations and SOD activity and also further increase in G-6-PDH activity in addition to decreases in CAT and GSSG-R activities and increases in VE concentrations and XO activity at 24 hr after treatment. Melatonin attenuated the reductions in hepatic ASC concentrations and SOD, CAT and GSSG-R activities and the increase in hepatic XO activity in a dose-dependent manner without affecting either hepatic Se-GSH-Px activity or the increased hepatic VE concentration and G-6-PDH activity at 24 hr after CCl4 treatment. No dose of melatonin influenced hepatic ACS and VE concentrations and SOD, CAT, Se-GSH-Px, G-6-PDH, and XO activities in CCl4-untreated rats. These results indicate that melatonin postadministered at pharmacological doses prevents the disruption of hepatic ROS metabolism associated with ASC, SOD, CAT, GSSG-R, and XO, in addition to reduced glutathione, in CCl4-treated rats.
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PMID:Melatonin prevents disruption of hepatic reactive oxygen species metabolism in rats treated with carbon tetrachloride. 1467 25

We previously demonstrated a high susceptibility of neonatal red blood cells (RBC) to oxidative stress at birth. The aim of this study was to compare the RBC antioxidant capacity and redox cycle enzyme activities as well as glutathione (GSH) recycling in full-term and preterm infants at birth and in normal adults. GSH and GSH disulfide (GSSG) concentrations, GSH/GSSG ratio, and the activities of glucose-6-phosphate dehydrogenase (G-6-PDH), GSH peroxidase, GSH reductase (GR), catalase (CAT), superoxide dismutase (SOD), and hexokinase (HK) were measured in RBC of 25 healthy adults and 56 newborns (23 term, 33 preterm) at birth. The GSH recycling was measured in adult and newborn RBC exposed to oxidative stress (1 mM tert-butylhydroperoxide). The RBC of term and preterm babies showed higher GSH, GSSG, G-6-PDH, GR, and HK levels/activities and lower GSH/GSSG ratios and higher GSH-recycling rates than those of adults. In preterm babies significant correlations were found between G-6-PDH and CAT, GSH, GSH/GSSG ratio, and GSSG (r = -0.67, r = 0.71, r = -0.66, p < 0.01; r = 0.71, p < 0.05, respectively). In term newborns, statistically significant correlations were observed between G-6-PDH and CAT, SOD, and GSH (r = -0.65, r = -0.65, r = -0.69, p < 0.01, respectively). The results indicate the central role of the G-6-PDH activity in antioxidant defenses. We speculate that preterm babies have prompter involvement of antioxidant defenses than term babies.
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PMID:Glutathione recycling and antioxidant enzyme activities in erythrocytes of term and preterm newborns at birth. 1470 31

Cytochrome P450-dependent oxidation and glutathione (GSH)-dependent conjugation are the primary routes of metabolism of haloalkanes. Using rat liver microsomes and cytosol, we investigated the metabolism of two halopropanes found on the U.S. Environmental Protection Agency Contaminant Candidate List, 1,3-dichloropropane (1,3-DCP) and 2,2-dichloropropane (2,2-DCP). An automated headspace technique using gas chromatography was developed to determine rates of metabolism. Additional dihaloalkanes (1,2-dichloroethane, 1,2-dichloropropane, 1,4-dichlorobutane, 1,2-dibromoethane, 1,2-dibromopropane, 1,4-dibromobutane) were evaluated to assess structure-activity relationships. In general, brominated dihaloalkanes were eliminated from rat cytosol faster than chlorinated dihaloalkanes, reflecting the expected halide order of reactivity (Br > Cl). Furthermore, the rate of GSH conjugation was proportional to alpha,omega-haloalkane chain length. The clearance of 1,3-DCP via the GSH conjugation pathway (1.6 x 10(-4) l/h/mg cytosol protein) was minor relative to the P450 pathway (2.8 x 10(-2) l/h/mg microsomal protein). In contrast, we did not observe metabolism of 2,2-DCP via the GSH-dependent conjugation pathway and observed only a minor level of clearance via the P450 pathway (7 x 10(-4) l/h/mg microsomal protein). Neither compound was mutagenic in various strains of Salmonella, including those containing GSTT1-1, indicating that GSTT1-1 does not metabolize 1,3-DCP or 2,2-DCP to mutagens. Analysis of the reaction products of 1,3-DCP and GSH in cytosol by liquid chromatography/mass spectrometry revealed significant production of S-(3-chloropropyl) glutathione conjugate, indicating that the conjugate half-mustard does not rearrange to form a sulfonium ion, as typically occurs with vicinal dihaloalkanes.
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PMID:Metabolism and mutagenicity of source water contaminants 1,3-dichloropropane and 2,2-dichloropropane. 1470 29

There were few reports on the antioxidant response of aquatic organisms exposed to 2,4-dichlorophenol (2,4-DCP). This research explored the hepatic antioxidant responses of fish to long-term exposure of 2,4-DCP for the first time. Freshwater fish Carassius auratus were chosen as experimental animals. The fish were exposed to six different concentrations of 2,4-DCP (0.005-1.0 mg/l) for 40 days and then liver tissues were separated for determination. As shown from the results, 40 days afterwards, the activities of catalase (CAT) and selenium-dependent glutathione peroxidase (Se-GPx) and the content of oxidized glutathione (GSSG) were induced significantly on the whole compared to control group; superoxide dismutase (SOD) responded to 2,4-DCP exposure at only 0.005 mg/l; the content of reduced glutathione (GSH) was suppressed continuously except Group 7; the activity of glutathione reductase was inhibited initially and then restored to control level from Group 4 on; glutathione S-transferase had only slight responses in Groups 3 and 4. Total glutathione (tGSH) and GSH/GSSG ratio were also calculated to analyze the occurrence of oxidative stress. Besides, good dose-effect relations, which cover most of the exposure concentration range, were found between 2,4-DCP level and CAT activity, GSSG content, Se-GPx activity, respectively. In conclusion, SOD and Se-GPx may be potential early biomarkers of 2,4-DCP contamination in aquatic ecosystems, and further studies will be necessary.
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PMID:Effects of chronic exposure of 2,4-dichlorophenol on the antioxidant system in liver of freshwater fish Carassius auratus. 1476 89

Effect of prefeeding dehydrated amaranth (A. gangeticus) leaves at 10 and 20% levels on a chemical toxicant, dimethylhydrazine (DMH)-induced free radical stress in rat liver was evaluated. DMH-induced rise in hepatic malondialdehyde (MDA), was diminished by AL. AL intake resulted in a significant increase in hepatic glutathione (GSH). The feeding of AL at 10% level increased the hepatic glucose-6-phosphate dehydrogenase (G-6-PDH) activity, while that at 20% level increased the hepatic glutathione reductase (GSSGR) as well, in addition to G-6-PDH. Amaranth leaves at 10 and 20% levels of feeding diminished the hepatic superoxide dismutase and glutathione peroxidase (GSH-Px) activities. DMH influenced adversely the hepatic antioxidant enzyme activities. Simultaneous administration of DMH and feeding of AL enhanced the DMH-induced decrease in hepatic GSH-Px. DMH enhanced formation of micronuclei was reverted significantly by AL intake. Hence, it was concluded that the consumption of AL at 20% level reduced DMH-induced impaired antioxidant status in rat liver.
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PMID:Effect of amaranth leaves on dimethylhydrazine-induced changes in multicomponent antioxidant system of rat liver. 1526 Jan 11

Glucocorticoid-remediable aldosteronism (GRA) is a monogenic form of human hypertension that predisposes to cerebral hemorrhage. As a result of a chimeric gene duplication, aldosterone is ectopically synthesized in the cortisol-secreting zona fasciculata of the adrenal gland under the control of adrenocorticotropin (ACTH). Hypertension frequently has its onset during childhood and is usually refractory to standard anti-hypertensives such as ACE inhibitors and beta-blockers. Hypokalemia can develop in those treated with a potassium-wasting diuretic, but random potassium levels are usually normal. Diagnosis has been facilitated by the availability of a genetic test. Suppression of ACTH release with exogenous dexamethasone is a useful diagnostic and therapeutic strategy. Treatment with the mineralocorticoid receptor antagonists spironolactone and epleronone is also efficacious. The diagnosis of GRA facilitates directed therapies and screening of at-risk individuals and kindreds.
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PMID:Glucocorticoid-remediable aldosteronism. 1576 39

The present study was aimed to investigate the effect of ACE inhibition on trinitrobenzene sulphonic acid (TNBS)-induced colonic inflammation in rats by using captopril and lisinopril. In treatment groups, the rats were treated with ACE inhibitors, captopril or lisinopril (0.1 and 1 mg/kg/day; intraperitoneally). The drugs were given 5 min after induction of colitis and the treatment was continued for 3 days. Three days after the induction of colitis, all rats were decapitated. The distal colon was weighed and the mucosal lesions were scored at both macroscopical at microscopic levels. Malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content were assessed in tissue samples. Formation of reactive oxygen species in colonic samples was monitored by using chemiluminescence technique. Serum TNF-alphalevel was assessed in trunk blood. Captopril treatment was found to be beneficial in all parameters, except colonic glutathione content. On the other hand, although stimulation of lipid peroxidation and increase in serum TNF-alpha level were successfully prevented by lisinopril, the morphology of the lesions remained unchanged. In conclusion, sulphydryl and non-sulphydryl ACE inhibitors, captopril and lisinopril do not seem to be similarly effective in TNBS-induced colitis model at least at the doses tested in our study.
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PMID:The effect of angiotensin-converting enzyme inhibitors on experimental colitis in rats. 1590 24


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