Effects and Mechanisms of DNA Methyltransferase 1 (DNMT1) Inhibitor Procainamide on Endotoxemic Rats
| Autor: | SHIH, CHIH-CHIN, 施志勤 |
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| Rok vydání: | 2016 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 105 Excessive inflammatory and oxidative stress lead to circulatory failure, multiple organ dysfunction, and high mortality in patients with sepsis. Microbial infection-induced DNA hypermethylation is associated with the augmentation of inflammation and oxidative stress. The antiarrhythmic drug procainamide is a non-nucleoside inhibitor of DNA methyltransferase 1 (DNMT1) used to alleviate DNA hypermethylation. Therefore, we evaluated effects of procainamide on the development of circulatory failure and multiple organ dysfunction in rats with endotoxic shock. Male Wistar rats were intravenously infused with saline or lipopolysaccharide (LPS, 5 mg/kg) followed 1 h later by procainamide administration (50 mg/kg for 30 min). During the experimental period, the changes of hemodynamics, biochemical variables, blood gas, blood electrolytes, serum interleukin-6 (IL-6), and serum nitric oxide (NO) levels were examined. At the end of experiments, animal organs were exercised to analyze superoxide production, neutrophil infiltration, DNMTs expression, and DNA methylation status. Our results showed that LPS induced circulatory failure, multiple organ dysfunction, metabolic acidosis, and hyperkalemia in endotoxemic rats. Overt neutrophil infiltration and superoxide production, accompanied by the elevations of DNMT1 and 5-methylcytosine levels in the lung of endotoxemic rats were also observed. In addition, endotoxemic rats exhibited obvious rises in the levels of serum IL-6 and NO. Treatment of endotoxemic animals with procainamide not only inhibited DNMT1 and 5-methylcytosine levels, but also diminished neutrophil infiltration and superoxide production in the lung. The overproduction of IL-6 and NO were ameliorated in endotoxemic rats treated with procainamide. In addition, procainamide improved hypotension, hypoglycemia, multiple organ dysfunction, metabolic acidosis, and electrolytes disturbance in rats with endotoxic shock. Moreover, procainamide reduced interleukin 27 receptor subunit alpha (IL27RA) methylation and restored IL27RA expression in the lung of endotoxemic rat. Thus, we suggest that beneficial effects of procainamide could be attributed to the suppression of DNMT1, pro-inflammatory cytokine, neutrophil infiltration, superoxide production, and NO formation. It seems that procainamide may have new potential uses in sepsis. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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