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. In our previous study, the antiarrhythmic drug procainamide inhibits the expression of DNA methyltransferase 1 (DNMT1) and diminishes IL-6 levels in rats with rhabdomyolysis. Thus, we further evaluated the 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) followed by procainamide administration. The changes of hemodynamics, blood glucose, biochemical variables, and plasma nitric oxide (NO) levels were analyzed during the experimental period. At the end of experiments, animal organs were also obtained for examining superoxide production, neutrophil infiltration, and DNA methylation status. Our results showed that LPS induced circulatory failure, multiple organ dysfunction, and high mortality rate 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. Treatment of endotoxemic animals with procainamide not only inhibited the increased levels of DNMT1 and 5-methylcytosine but also ameliorated neutrophil infiltration and superoxide production in the lung. In addition, the anti-inflammatory gene, IL27RA, was down-regulated in the LPS group and up-regulated in the LPS + Procainamide group. Procainamide also diminished IL27RA methylation in the lung of endotoxemic rat. Moreover, both DNMT inhibitors procainamide and hydralazine improved hypotension, hypoglycemia, and multiple organ dysfunction of LPS-treated rats. Thus, we suggest that the beneficial effects of procainamide could be attributed to the suppression of DNA methylation, neutrophil infiltration, superoxide production, and NO formation. It seems that this old drug may have new potential uses in infectious diseases, in particular, associated with endotoxemia.
Septic shock is a syndrome with severe hypotension and multiple organ dysfunction caused by an imbalance between pro-inflammatory and anti-inflammatory response. The most common risk factor of acute lung injury is severe sepsis. Patients with sepsis-related acute respiratory distress syndrome have higher mortality. Recent studies reveal regulatory roles of Wnt3a and Wnt5a signaling in inflammatory processes. Wnt3a signaling has been implicated in anti-inflammatory effects, whereas Wnt5a signaling has been postulated to have pro-inflammatory properties. However, the balance between Wnt3a and Wnt5a signaling pathway in the lung of rats with endotoxic shock has not been determined. Thus, we investigated the major components of Wnt3a and Wnt5a signaling pathway in the lung of endotoxemic rats. Male Wistar rats were intravenously infused with saline or lipopolysaccharide (LPS, 10 mg/kg). The changes of hemodynamics, biochemical variables, and arterial blood gas were examined during the experimental period. At 6 h after saline or LPS, animals were sacrificed, and lungs were obtained for analyzing superoxide production, water accumulation, histologic assessment, and protein expressions of Wnt3a and Wnt5a signaling pathway. Animals that received LPS showed circulatory failure, multiple organ dysfunction, metabolic acidosis, hyperventilation, lung edema, and high mortality. The lung from rats with endotoxic shock exhibited significant decreases in the levels of Wnt3a, Fzd1, Dsh1, phosphorylated GSK-3β at Ser9, and β-catenin. In contrast, the expressions of Wnt5a, Fzd5, and CaMKII were up-regulated in the lung of endotoxemic rats. These findings indicate the major components of Wnt3a and Wnt5a signaling in the lung are disturbed under endotoxic insult.
OBJECTIVESRobotic mitral valve replacement (MVR) emerged in the late 1990s as an alternative approach to conventional sternotomy. With the increased use of bioprosthetic valves worldwide and strong patient desire for minimally invasive procedures, the safety and feasibility of robotic MVRs with bioprosthetic valves require investigation.METHODSBetween January 2013 and May 2017, 52 consecutive patients underwent robotic MVRs using the da Vinci Si surgical system (Intuitive Surgical Inc., Sunnyvale, CA, USA). Their mean age was 55.1 ± 13.8 years, and mean EuroSCORE II was 2.25% ± 1.25%. Among the enrolled patients, 32 (61.5%) patients presented with preoperative atrial fibrillation, 6 (11.5%) patients had experienced embolic stroke and 5 (9.6%) patients had undergone previous cardiac surgery. The operations were performed using cardiopulmonary bypass (CPB) under an arrested heart status.RESULTSFive porcine valves and 47 bovine valves were implanted. A total of 38 (73.1%) patients received concomitant cardiac procedures, including 26 Cox-maze IV procedures, 12 tricuspid valve repairs and 5 atrial septal defect repairs. The mean aortic cross-clamp and CPB times were 141.3 ± 34.3 min and 217.1 ± 42.0 min, respectively. There was no operative mortality. During the mean follow-up of 29 ± 15 months, no prosthesis degeneration was noted. The average left atrial dimension exhibited a significant decrease from 51.4 ± 11.5 mm to 42.6 ± 10.1 mm.CONCLUSIONSRobotic MVR with bioprosthetic valves is safe, feasible and reproducible. Mid-term results are encouraging. Both aortic cross-clamp and CPB times can be improved with experience.
Human parvovirus B19 (B19) and human bocavirus 1 (HBoV) are the only known pathogenic parvoviruses, and are responsible for a variety of diseases in human beings. Mounting evidence indicates a strong association between B19 infection and cardiac disorders including myocarditis, dilated cardiomyopathy and heart failure. However, very limited information about the role of HBoV in cardiac disorders is known. To elucidate the effects of B19 and HBoV on cardiac disorders, we expressed EGFP‑conjugate constructs of B19‑VP1 unique region (VP1u) and HBoV‑VP1u, along with the mutants EGFP‑B19‑VP1uD175A and EGFP‑HBoV‑VP1uV12A, in H9c2 cells by stable transfection. The protein expression levels of EGFP, EGFP‑B19‑VP1u, EGFP‑B19‑VP1uD175A, EGFP‑HBoV‑VP1u and EGFP‑HBoV‑VP1uV12A in H9c2 cells were observed under a fluorescence microscope and confirmed by western blotting. Secreted phospholipase A2 (sPLA2) activity was detected in B19‑VP1u and HBoV‑VP1u but not B19‑VP1uD175A and HBoV‑VP1uV12A recombinant proteins. Significantly higher expression levels of MCP2 and IP‑10 mRNA were detected in H9c2 cells that were transfected with pEGFP‑B19‑VP1u, compared with in those cells transfected with pEGFP‑HBoV‑VP1u, pEGFP‑B19‑VP1uD175A or pEGFP‑HBoV‑VP1uV12A. Significantly higher protein levels of IL‑1β and IL‑6 were detected in H9c2 cells transfected with pEGFP‑B19‑VP1u or pEGFP‑HBoV‑VP1u, compared with in those cells transfected with pEGFP‑B19‑VP1uD175A or pEGFP‑HBoV‑VP1uV12A. Notably, significantly higher expression of both TNF‑α and NF‑κB was observed only in H9c2 cells transfected with pEGFP‑B19‑VP1u, but not in those cells transfected with pEGFP‑HBoV‑VP1u, pEGFP‑B19‑VP1uD175A or pEGFP‑HBoV‑VP1uV12A. These findings, to our knowledge for the first time, reveal the difference between B19‑VP1u and HBoV‑VP1u in H9c2 cells and provide insight into the roles of B19‑VP1u and HBoV‑VP1u in the pathogenesis of cardiac inflammation.
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