GLUTATHIONE DEPLETION INHIBITS IL-1β-STIMULATED NITRIC OXIDE PRODUCTION BY REDUCING INDUCIBLE NITRIC OXIDE SYNTHASE GENE EXPRESSION

Nikulina, Marina; Andersen, Henrik U; Karlsen, A. E.; Darville, Martine I.; Eizirik, Décio L.; Mandrup-Poulsen, Thomas

doi:10.1006/cyto.2000.0712

Cited by 20 publications

(16 citation statements)

References 14 publications

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“…It has been shown that glutathione depletion caused marked inhibition of cytokine-induced iNOS expression and activity in different cell types, indicating similar mechanisms of cellular redox regulation of cytokine-induced nitric oxide synthesis (Duval et al 1995;Hothersall et al 1997;Nikulina et al 2000). Thus, the reduced nitric oxide and GSH levels we measured in our study lead us to conclude that GSH depletion could account for the inhibition of MIX-stimulated nitric oxide production in nor-cantharidin-and even more in cantharidin-treated cells.…”

Section: Discussionsupporting

confidence: 75%

In vitro Assessment of Renal Toxicity and Inflammatory Events of Two Protein Phosphatase Inhibitors Cantharidin and Nor‐Cantharidin*

Massicot

Dutertre-Catella

Pham‐Huy

et al. 2005

Basic Clin Pharma Tox

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In China, cantharidin has been reported to be active against various human cancers, but with severe side effects such as nephrotoxicity. In order to reduce this toxicity, its demethylated analogue nor-cantharidin has been synthesized and used in cancer therapy, but with only few data regarding safety assessment. The aim of this study was to compare the in vitro effects of cantharidin and nor-cantharidin on renal toxicity and on inflammatory events associated with tumoural process where protein phosphatases could be involved (energy status, prostanoid production, glutathione and nitrite contents) on RAW 264.7 and LLC-PK 1 cells. In macrophages, both cantharidin and nor-cantharidin decreased cell viability, in a concentration-and time-dependent manner. However, IC 50 was lower with cantharidin than with norcantharidin. These two drugs significantly decreased the ATP level after 24 hr incubation. However, ATP decreased much more with cantharidin (up to 4 times) than with nor-cantharidin. When control macrophages were activated with lipopolysaccharideπinterferon-g for 24 hr a significant increase in nitrite content and in prostanoids were observed. Addition of either drug decreased nitrite generation and prostanoids, however these decreases were greater with cantharidin than with nor-cantharidin. In LLC-PK 1 cells, incubated with either cantharidin or nor-cantharidin, our results show significant differences between the two drugs, similar to those observed in peritoneal macrophages, except for GSH content with opposite variations in both cells. We provide a better understanding of the various mechanisms of cantharidin side effects, allowing an easier comparison with nor-cantharidin which could be an attractive therapeutic potential in cancer chemotherapy in western countries.

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Section: Discussionsupporting

confidence: 75%

In vitro Assessment of Renal Toxicity and Inflammatory Events of Two Protein Phosphatase Inhibitors Cantharidin and Nor‐Cantharidin*

Massicot

Dutertre-Catella

Pham‐Huy

et al. 2005

Basic Clin Pharma Tox

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“…The inhibition of NF B activity also reduces, but does not completely abolish, subsequent production of NO in cells treated with high concentrations of glucose. There are conflicting reports on the involvement of glucose, GSH and NF B in the regulation of iNOS (Guo et al 2000, Miralles et al 2000, Nikulina et al 2000, Stockklauser-Färber et al 2000 and this evidence, together with our findings, suggests that the regulation of iNOS by GSH and NF B is species-or cell-specific (or both). The exact mechanism of iNOS regulation in DLD-1 cells remains to be elucidated, but from the findings of the present study it is apparent that the mechanism by which high concentrations of glucose regulate iNOS differs from cytokine-induced activation.…”

Section: Discussionsupporting

confidence: 72%

“…However, in contrast to our observation that high glucose increases iNOS promoter activity in non-cytokine-stimulated cells, it has been reported that, in bovine aortic endothelial cells, high concentrations of glucose (25 mmol/l) inhibit lipopolysaccharide-induced production of NO by decreasing the expression of iNOS and cNOS (Guo et al 2000). GSH has been shown to regulate IL-1 -induced production of NO in islets, purified cells and insulinoma cells by modulation of iNOS gene expression (Nikulina et al 2000). Miralles et al (2000) observed that molecular oxygen was able to regulate expression of iNOS in rat liver at the transcriptional level, through the production of reactive oxygen species and reduction in GSH.…”

Section: Discussionmentioning

confidence: 99%

“…It is now apparent that the mechanisms by which glucose may influence iNOS regulation may be cell-typedependent. In rat pancreatic cells, high concentrations of glucose are believed to enhance IL-1 -induced production of NO via the p38 signalling pathway (Nikulina et al 2000). Chronic treatment with supraphysiological concentrations of insulin (100 nmol/l) and insulin resistance induced by high glucose treatment (25 mmol/l for 12-24 h) are accompanied by marked reductions in iNOS as a result of p38 mitogen-activated protein kinase (MAPK) activation in rat aortic vascular smooth muscle cells (Begum & Ragolia 2000).…”

Section: Discussionmentioning

confidence: 99%

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High glucose decreases intracellular glutathione concentrations and upregulates inducible nitric oxide synthase gene expression in intestinal epithelial cells

Powell¹,

Warpeha²,

Xu³

et al. 2004

Journal of Molecular Endocrinology

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Diabetes is associated with oxidative stress and increased concentrations of inflammatory cytokines. The aim of the study was to assess the effects of inflammatory cytokines and oxidative stress associated with increased glucose concentrations on inducible nitric oxide synthase (iNOS) promoter activity in intestinal epithelial cells. High-glucose (25 mmol/l) conditions reduced glutathione (GSH) concentrations in the human intestinal epithelial cell line, DLD-1. Addition of the antioxidant, α-lipoic acid, resulted in the restoration of GSH concentrations to normal. Upregulation of basal iNOS promoter activity was observed when cells were incubated in high glucose alone. This effect was significantly reduced by the addition of the antioxidant, α-lipoic acid, and completely blocked with inhibition of nuclear factor kappa B (NFκB) activity. Stimulation of cytokines (interleukin-1 beta, tumour necrosis factor-alpha, interferon-gamma) induced iNOS promoter activity in all conditions and this was accompanied by an increase in nitric oxide (NO) production. Inhibition of NFκB activity decreased, but did not completely inhibit, cytokine-induced iNOS promoter activity and subsequent production of NO. In conclusion, iNOS promoter activity induced by high concentrations of glucose is mediated in part through intracellular GSH and NFκB.

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“…This may be related to the action of nitric oxide for the following reasons. Similar changes in renal function were observed after inhibition of nitric oxide synthetase in cirrhotic rats (20), and it has been shown that glutathione depletion inhibits nitric oxide production by reducing inducible nitric oxide synthetase gene expression (24). Interestingly, bile acids induce nitric oxide production in vascular endothelial cells (23).…”

Section: Discussionmentioning

confidence: 58%

Increase in renal glutathione in cholestatic liver disease is due to a direct effect of bile acids

Purucker

Marschall

Geier

et al. 2002

American Journal of Physiology-Renal Physiology

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Hepatic synthesis and plasma levels of glutathione are markedly decreased in chronic liver disease. Because glutathione turnover is highest in kidneys, we examined whether changes in kidney glutathione occur in chronic cholestasis and whether they are related to kidney dysfunction in liver disease. Kidney and plasma GSH and GSSG were measured 1) in bile duct-ligated (BDL) rats; 2) in healthy rats after bile acid loading to mimic cholestasis; and 3) after irreversible inhibition of glutathione synthetase with buthionine-sulfoximine (BSO), where glutathione consumption, urinary volume, and sodium excretion were also estimated. In addition, γ-glutamylcysteine synthetase (γ-GCS) mRNA, protein, and enzymatic specific activity were measured in kidney tissue after BDL. After BDL, kidney GSH and GSSG increased within hours by 67 and 66%, respectively. The increases were not related to plasma glutathione, which decreased below control values. Intravenous bile acid loading caused identical increases in GSH and GSSG as occurred after BDL, when glycine- or taurine-conjugated dihydroxy bile acids were administered. Glutathione consumption, as estimated after blocking of de novo synthesis with BSO, was significantly increased after BDL (127 vs. 44 nmol · g−1 · min−1). γ-GCS mRNA and enzymatic specific activity were significantly reduced 5 days after BDL, whereas protein concentrations did not change. The urinary sodium concentration was 70% lower in BDL than in control rats. Depletion of renal glutathione normalized sodium excretion by increasing urinary sodium concentration and urinary volume. The increase in kidney glutathione after BDL seems to be mediated by an increase in plasma bile acids and is critically related to sodium retention. The increase in GSH consumption despite reduced γ-GCS activity indicates a decreased GSH turnover tentatively due to reduced renal GSH efflux by competition with organic anions at membrane transport proteins.

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GLUTATHIONE DEPLETION INHIBITS IL-1β-STIMULATED NITRIC OXIDE PRODUCTION BY REDUCING INDUCIBLE NITRIC OXIDE SYNTHASE GENE EXPRESSION

Cited by 20 publications

References 14 publications

In vitro Assessment of Renal Toxicity and Inflammatory Events of Two Protein Phosphatase Inhibitors Cantharidin and Nor‐Cantharidin*

In vitro Assessment of Renal Toxicity and Inflammatory Events of Two Protein Phosphatase Inhibitors Cantharidin and Nor‐Cantharidin*

High glucose decreases intracellular glutathione concentrations and upregulates inducible nitric oxide synthase gene expression in intestinal epithelial cells

Increase in renal glutathione in cholestatic liver disease is due to a direct effect of bile acids

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