Association of oral endothelin receptor antagonists with risks of cardiovascular events and mortality: meta-analysis of randomized controlled trials.

BACKGROUND: Endothelin receptor antagonists (ERAs) are widely used in a variety of disorders, including pulmonary artery hypertension, systemic sclerosis, diabetic and kidney diseases, and several tumors. However, reported adverse events, especially increased risks of cardiovascular disease (CVD) morbidity and mortality, have cast doubt on their potential clinical application. Therefore, we conducted this meta-analysis to confirm whether ERAs increased CVD risk and mortality. METHODS: We systematically searched PubMed (1966-2015), EMBASE (1974-2015), ClinicalTrials.gov, and the Cochrane Controlled Clinical Trials Register Database for randomized controlled trials published between Jan 1, 1990 and Mar 18, 2015. Inclusion criteria included a study duration of more than 3 weeks, the use of a randomized control group receiving an oral ERA or placebo, and the availability of outcome data for cardiovascular events and all-cause death. RESULTS: A total of 33 trials met the inclusion criteria. There were 8098 cases in the ERA group and 5074 cases in the placebo group. Compared with the control group, the risk ratio (RR) for all-cause death in the ERA group was 0.983 [95% confidence interval (CI), 0.883 to 1.094, P = 0.754]. The summary RR for cardiovascular events was 1.651 in the ERA group (95% CI, 1.164 to 2.34, P = 0.005). The pooled results showed that ERAs treatment could lead to more edema, anemia, and abnormal transaminase levels. Also, there was an increased proportion of discontinued therapy in the ERA treatment because of side effects (RR = 1.322, 95% CI, 1.036 to 1.686, P = 0.025). There were no significant differences in the experienced episodes of headache and dyspnea between the active therapy and control groups. CONCLUSIONS: ERAs therapy is not significantly associated with increased all-cause death, but there are more cardiovascular events and edema or fluid retention, anemia, and liver enzymes disorder. Large clinical randomized controlled studies are needed to further confirm the safety of the clinical application of ERAs.

Association of lean body mass with nutritional parameters and mortality in hemodialysis patients: A long-term follow-up clinical study.

OBJECTIVE: This study aimed to evaluate the correlation between lean body mass (LBM) and nutritional status in hemodialysis (HD) patients to better predict their long-term prognosis. METHODS: Anthropometric body measurements and biochemical parameters were recorded from 222 patients on maintenance hemodialysis (MHD) at the Shanghai Pudong Hospital Hemodialysis Center. LBM was calculated using the serum creatinine index (LBM-SCR), mid-arm muscle circumference (LBM-MAMC), and dominant-arm hand-grip strength (LBM-HGS). Patient mortality and hospitalization were observed after 24 months. RESULTS: LBMs measured from LBM-SCR and LBM-MAMC were associated with sex, body mass index (BMI), serum albumin, and serum creatinine (SCR) ( p < 0.05). Through three methods of LBM evaluation, low LBM was shown to be associated with a higher mortality in patients undergoing HD ( p < 0.05). In addition, the rate of hospitalization among these patients was significantly increased ( p < 0.05). Performing multivariate regression analysis using mortality and hospitalization as the dependent variable, we found LBM-SCR and LBM-HGS are strongly associated with hospitalization and mortality in HD patients, indicating LBM is an important factor in prediction of outcomes in those patients. CONCLUSION: LBM is associated with nutritional parameters in HD patients, and LBM-SCR, HGS, and MAMC are simple approaches for accurately predicting the patient's risk of hospitalization and/or death.

Antioxidant N-acetylcysteine protects pancreatic ß-cells against aldosterone-induced oxidative stress and apoptosis in female db/db mice and insulin-producing MIN6 cells.

Previous studies have shown that primary aldosteronism is associated with glucose-related metabolic disorders. However, the mechanisms by which aldosterone (ALDO) triggers ß-cell dysfunction remains unclear. This study aimed to investigate whether oxidative stress is involved in and whether the antioxidant N-acetylcysteine (NAC) or the mineralocorticoid receptor antagonist spironolactone (SPL) could prevent or delay ß-cell damage in vivo and in vitro. As expected, 8 weeks after ALDO treatment, 12-week-old female diabetic db/db mice exhibited impaired oral glucose tolerance, decreased ß-cell mass, and heightened levels of oxidative stress marker (urinary 8-hydroxy-2'-deoxyguanosine). NAC reversed these symptoms completely, whereas SPL treatment did so only partially. After exposure to ALDO, the mouse pancreatic ß-cell line MIN6 exhibited decreased viability and increased caspase-3 activity, as well as reduced expression of Bcl-2/Bax and p-AKT, even if mineralocorticoid receptor was completely suppressed with small interfering RNA. NAC, but not SPL, suppressed oxidative stress in MIN6 cells, as revealed by the decrease in inducible NOS levels and expression of the proteins p22-phox and p67-phox. These findings suggest that oxidative stress may be involved in ALDO-induced ß-cell dysfunction and that NAC, but not SPL, may protect pancreatic ß-cells of mice from ALDO-induced oxidative stress and apoptosis in a manner independent of its receptor.

Erythropoietin improves insulin resistance via the regulation of its receptor-mediated signaling pathways in 3T3L1 adipocytes.

Recombinant human erythropoietin (rHuEPO) reduces serum insulin levels, increases insulin sensitivity, and reduces insulin resistance (IR). However, the mechanisms behind these effects are unclear. This study aimed to investigate the mechanism by which rHuEPO effects IR in 3T3L1 adipocytes. After treatment with different concentrations of rHuEPO, glucose consumption, and tumor necrosis factor (TNF-α), adiponectin, and leptin levels were assayed with a commercial enzyme-linked immunosorbent assays. Endogenous erythropoietin receptor (EPOR) expression was inhibited using small interfering RNA (siRNA). EPOR protein and mRNA expression was detected via immunofluorescence and real-time PCR analyses, respectively. The expression of pAKT/AKT and p-STAT5/STAT5 was determined via Western blot analysis. rHuEPO treatment improved glucose uptake, increased adiponectin levels, and reduced TNF-α and leptin levels in 3T3L1 adipocytes with dexamethasone-induced IR. Whereas EPOR protein and gene expression was absent in preadipocytes, it was observed in mature 3T3L1 adipocytes. However, the expression of EPOR in insulin resistant 3T3L1 adipocytes was significantly decreased (p<0.05). rHuEPO increased the expression of EPOR, and upregulated the expression of pAKT/AKT and pSTAT5/STAT5 in 3T3L1 adipocytes (p<0.05), which was blocked by siEPOR, the phosphatidylinositol-3-kinase (PI3K) inhibitor, LY294002, and a STAT5 inhibitor, respectively. In summary, rHuEPO reduced IR in adipocytes by increasing glucose uptake and improving the adipokine profile. rHuEPO-induced EPOR protein expression and subsequent induction of pAKT and pSTAT5 suggest that the EPO-EPOR system may play a role in glucose metabolism within adipocytes.