Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the role of glutathione and nitric oxide synthase (NOS) in fiber-induced cell and DNA toxicity using alkaline (pH 13) single-cell gel electrophoresis (the Comet assay). Transformed cultured human pleural mesothelial (MeT-5A) cells and alveolar epithelial cells (A549) were exposed to crocidolite asbestos fibers (1-10 microg/cm(2)) in the presence of buthionine sulfoximine (BSO) or L-arginine-methyl ester (L-NAME). BSO inhibits gamma-glutamylcysteine synthetase (gamma-GCS) and causes glutathione depletion, and L-NAME inhibits nitric oxide generation. Studies were also conducted to assess the expression of the heavy and light subunits of gamma-GCS in human pleural mesothelium and bronchial epithelium in vivo and the induction of inducible NOS (iNOS) by asbestos fibers. Asbestos fibers caused DNA single-strand breaks, and the process was significantly enhanced by BSO (69% compared to the non-treated cells). A549 cells had a 3.5-fold glutathione content compared to MeT-5A cells, which was consistent with the higher resistance of these cells against oxidants and fibers. Flow cytometry of iNOS showed no change of iNOS by the fibers in either cell type in vitro. L-NAME had no effects on the DNA single-strand breaks in the Comet assay, either. Studies on lung biopsies showed that the immunoreactivities of both gamma-GCS subunits were very low in healthy human mesothelium in vivo. We conclude that glutathione may play an essential role in protecting intact cells against fiber-induced oxidative DNA alterations, and low gamma-GCS reactivity in pleural mesothelium may be associated with the high sensitivity of mesothelial cells to fiber-induced toxicity.
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PMID:Modulation of DNA single-strand breaks by intracellular glutathione in human lung cells exposed to asbestos fibers. 1181 40

Recent studies confirmed a critical importance of c-Met signaling for liver regeneration by modulating redox balance. Here we used liver-specific conditional knockout mice (MetKO) and a nutritional model of hepatic steatosis to address the role of c-Met in cholesterol-mediated liver toxicity. Liver injury was assessed by histopathology and plasma enzymes levels. Global transcriptomic changes were examined by gene expression microarray, and key molecules involved in liver damage and lipid homeostasis were evaluated by Western blotting. Loss of c-Met signaling amplified the extent of liver injury in MetKO mice fed with high-cholesterol diet for 30days as evidenced by upregulation of liver enzymes and increased synthesis of total bile acids, aggravated inflammatory response and enhanced intrahepatic lipid deposition. Global transcriptomic changes confirmed the enrichment of networks involved in steatosis and cholestasis. In addition, signaling pathways related to glutathione and lipid metabolism, oxidative stress and mitochondria dysfunction were significantly affected by the loss of c-Met function. Mechanistically, exacerbation of oxidative stress in MetKO livers was corroborated by increased lipid and protein oxidation. Western blot analysis further revealed suppression of Erk, NF-kB and Nrf2 survival pathways and downstream target genes (e.g. cyclin D1, SOD1, gamma-GCS), as well as up-regulation of proapoptotic signaling (e.g. p53, caspase 3). Consistent with the observed steatotic and cholestatic phenotype, nuclear receptors RAR, RXR showed increased activation while expression levels of CAR, FXR and PPAR-alpha were decreased in MetKO. Collectively, our data provide evidence for the critical involvement of c-Met signaling in cholesterol and bile acids toxicity.
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PMID:Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress. 2739 61

Sumatriptan has been among the top choices in the management of migraine headaches. The association between migraine and epilepsy highlights the possible effect of sumatriptan on seizures. In this regard, we investigated sumatriptan effects on PTZ-induced seizures thresholds and delineated the modulatory role of 5-HT1B/D receptors and NOS/NO pathway. Our data revealed the anti-convulsant effects of lower doses of sumatriptan, and pro-convulsant effects of higher doses of sumatriptan. GR 127935, a selective 5-HT1B/D antagonist, could abolish the sumatriptan anti-convulsant effects, but it was ineffective against the sumatriptan pro-convulsant effects. Serotonin depletion by consecutive administration of p-CPA, a selective irreversible inhibitor of tryptophan hydroxylase, could not affect the anti-convulsant effects of sumatriptan. The anti-convulsant effects of sumatriptan was potentiated by L-NAME, a non-selective NOS inhibitor, 7-NI, a selective nNOS inhibitor, but not AG, an iNOS inhibitor. It was also neutralized by L-ARG, a NO precursor. The pro-convulsant effects of sumatriptan were blocked by L-NAME and AG, but not 7-NI. It was also potentiated by L-ARG. Our data revealed that anti-convulsive effects of sumatriptan is mediated by interaction between non-serotonergic 5-HT1B/D receptors and nNOS/NO pathway. Besides, the pro-convulsive effect of sumatriptan is mediated by iNOS/NO pathway independent of 5-HT1B/D receptors. For the first time, this study reported the biphasic effect of sumatriptan on an animal model of GCS and its modulatory pathways.
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PMID:Biphasic effect of sumatriptan on PTZ-induced seizures in mice: Modulation by 5-HT1B/D receptors and NOS/NO pathway. 2941 Feb 49