Paraquat disrupts the anti-inflammatory action of cortisol in human macrophages in vitro: therapeutic implications for paraquat intoxications.

The herbicide paraquat (1,1'-dimethyl-4,4'-bipyridinium dichloride) has been banned in Europe since 2007 due to its high toxicity in humans. However, it is still widely used in Middle/South America and in Asia where it is annually associated with a high incidence of unintentional and intentional poisoning. Human macrophage-like cell lines were used to shed more light on the inflammatory response elicited by paraquat. Paraquat (3-1000 µM) reduced cell viability in a dose- and time-dependent manner. Exposure to 50 or 200 µM paraquat for 24 h elevated the release of interleukin 8 and gene expression of tumor necrosis factor-α. Expression of the 11ß-hydroxysteroid dehydrogenase 1 gene tended to increase, while cellular glutathione concentrations decreased. The anti-inflammatory effect of cortisol was significantly disrupted. The paraquat-induced cortisol resistance could not be prevented by N-acetyl-l-cysteine. However, a polyphenolic extract of grape seeds consisting of monomeric and oligomeric flavan-3-ols (MOF) reduced paraquat-induced inflammation in the presence of cortisol to baseline. In conclusion, the results suggest that an impaired cortisol response may contribute to paraquat-mediated inflammation. Agents with pleiotropic cellular and subcellular effects on redox regulation and inflammation, such as plant-derived polyphenols, may be an effective add-on to the therapy of paraquat intoxications with glucocorticoids.

Is intestinal oxidative stress involved in patients with compensated liver cirrhosis?

BACKGROUND: Liver cirrhosis is associated with intestinal epithelial barrier dysfunction, which may be affected by oxidative stress. Studies in cirrhotic rats provided evidence for intestinal oxidative stress, but studies in cirrhotic patients are scarce. We have shown intestinal barrier dysfunction in patients with compensated cirrhosis. AIM: The present study aimed to investigate whether oxidative stress occurs in the intestinal mucosa of compensated cirrhotic patients and may contribute to barrier dysfunction. MATERIAL AND METHODS: Oxidative stress was studied in duodenal and sigmoid biopsies from 15 cirrhotic patients and 22 controls by analyzing transcription of genes involved in glutathione and uric acid metabolism using quantitative real-time polymerase chain reaction. Protein levels of glutathione and glutathione disulphide were measured and the glutathione/glutathione disulphide ratio was calculated as marker of oxidative stress. In addition, intestinal myeloperoxidase and fecal calprotectin were determined. RESULTS: Gene transcription of glutathione synthetase and glutathione reductase were significantly different in duodenal and sigmoid biopsies of cirrhotic patients vs. controls, but no alterations were found for other genes nor for glutathione, glutathione disulphide, glutathione/glutathione disulphide ratio and intestinal myeloperoxidase and fecal calprotectin concentrations. CONCLUSION: This study did not find indications for oxidative stress and low-grade inflammation in the small and large intestine of stable compensated cirrhotic patients. Although these preliminary findings need further validation, we found intestinal oxidative stress not to be a major mechanism contributing to epithelial barrier dysfunction in patients with compensated cirrhosis.