Ghrelin and Its Analogues, BIM-28131 and BIM-28125, Improve Body Weight and Regulate the Expression of MuRF-1 and MAFbx in a Rat Heart Failure Model

Cardiac cachexia is a serious complication of chronic heart failure with a prevalence of 10-16% and poor prognosis. There are no current therapy options for cardiac cachexia. Ghrelin is the natural ligand for the GHS-1a-receptor and a potential target for conditions associated with cachexia. Ghrelin has been shown to increase weight in several species. The GHS-1a-receptor is not only found in the brain, but also in other tissues, including the myocardium. Human clinical trials with native ghrelin in cardiac cachexia demonstrated increases in appetite, weight and cardiac output. Methods: Human ghrelin or one of two analogues BIM-28125 and BIM-28131 (also known as RM-131) were tested at 50 nmole/kg/d and 500 nmole/kg/d versus placebo in a ratmodel of heart failure (myocardial infarction). Animals (SD-rats, approx. 225 g at surgery) received diuretics from day 14 and compounds from day 28 for 4 weeks using osmotic pumps. Weight was monitored and body composition analysed (NMR-scanning). Cardiac function was assessed by echocardiography and hemodynamics. Results: Animals with MI gained less weight compared to sham rats until start of the therapy (311 g vs 324 g, p = 0.0129). Animals treated with BIM-28131 at 50 nmole/kg/d or all compounds at 500 nmole/kg/d displayed stronger weight gain compared to placebo and sham (all p < 0.001). Before treatment, body composition was similar in all groups (average: 36 g fat, 248 g lean). Placebo-treated rats gained no fat, but only lean mass. The active compounds induced both fat and lean mass gain, but to a different extent. The fat-to-muscle-ratio of tissue gain was 0.9 +/- 0.07 for BIM-28131 at 50 nmole/kg/d, whereas at 500 nmole/kg/d it was 0.76 +/- 0.07 for BIM-28131, 0.68 +/- 0.12 for BIM-28125, and 0.48 +/- 0.05 for ghrelin. MuRF-1 and MAFbx were differentially regulated by treatment. Conclusion: Ghrelin is a very promising treatment option for cardiac cachexia, with the analogue BIM-28131 (RM-131) being the most effective compound

Consumption of low-moderate level arsenic contaminated water does not increase spontaneous pregnancy loss: a case control study

BACKGROUND: Previous work suggests an increased risk for spontaneous pregnancy loss linked to high levels of inorganic arsenic (iAs) in drinking water sources (>10 μg/L). However, there has been little focus to date on the impact of low-moderate levels of iAs in drinking water (<10 μg/L). To address this data gap we conducted a hospital-based case–control study in Timis County, Romania. METHODS: We recruited women with incident spontaneous pregnancy loss of 5–20 weeks completed gestation as cases (n = 150), and women with ongoing pregnancies matched by gestational age (±1 week) as controls (n = 150). Participants completed a physician-administered questionnaire and we collected water samples from residential drinking sources. We reconstructed residential drinking water exposure histories using questionnaire data weighted by iAs determined using hydride generation-atomic absorption spectrometry (HG-AAS). Logistic regression models were used to generate odds ratios (OR) and 95% confidence intervals (CI) for associations between iAs exposure and loss, conditioned on gestational age and adjusted for maternal age, cigarette smoking, education and prenatal vitamin use. We explored potential interactions in a second set of models. RESULTS: Drinking water arsenic concentrations ranged from 0.0 to 175.1 μg/L, with median 0.4 μg/L and 90(th)%tile 9.4 μg/L. There were no statistically significant associations between loss and average or peak drinking water iAs concentrations (OR 0.98, 95% CI 0.96-1.01), or for daily iAs intake (OR 1.00, 95% CI 0.98-1.02). We detected modest evidence for an interaction between average iAs concentration and cigarette smoking during pregnancy (P = 0.057) and for daily iAs exposure and prenatal vitamin use (P = 0.085). CONCLUSIONS: These results suggest no increased risk for spontaneous pregnancy loss in association with low to moderate level drinking water iAs exposure. Though imprecise, our data also raise the possibility for increased risk among cigarette smokers. Given the low exposures overall, these data should reassure pregnant women and policy makers with regard to the potential effect of drinking water iAs on early pregnancy, though a larger more definitive study to investigate the potential risk increase in conjunction with cigarette smoking is merited