Reactive oxygen species (ROS) contribute to the development of interstitial fibrosis and tubular atrophy seen in chronic allograft nephropathy (CAN). As molecular hydrogen gas can act as a scavenger of ROS, we tested the effect of treatment with hydrogen water (HW) in a model of kidney transplantation, in which allografts from Lewis rats were orthotopically transplanted into Brown Norway recipients that had undergone bilateral nephrectomy. Molecular hydrogen was dissolved in water and recipients were given HW from day 0 until day 150. Rats that were treated with regular water (RW) gradually developed proteinuria and their creatinine clearance declined, ultimately leading to graft failure secondary to CAN. In contrast, treatment with HW improved allograft function, slowed the progression of CAN, reduced oxidant injury and inflammatory mediator production, and improved overall survival. Inflammatory signaling pathways, such as mitogen-activated protein kinases, were less activated in renal allografts from HW-treated rats as compared with RW-treated rats. Hence, oral HW is an effective antioxidant and antiinflammatory agent that prevented CAN, improved survival of rat renal allografts, and may be of therapeutic value in the setting of transplantation.
A meta-analysis of prospective cohort studies was conducted to examine the relation between fruit and vegetables (FV) consumption and the risk of cardiovascular disease (CVD). We searched PubMed and EMBASE up to June 2014 for relevant studies. Pooled relative risks (RRs) were calculated and dose-response relationship was assessed. Thirty-eight studies, consisting of 47 independent cohorts, were eligible in this meta-analysis. There were 1,498,909 participants (44,013 CVD events) with a median follow-up of 10.5 years. The pooled RR (95% confidence interval) of CVD for the highest versus lowest category was 0.83 (0.79-0.86) for FV consumption, 0.84 (0.79-0.88) for fruit consumption, and 0.87 (0.83-0.91) for vegetable consumption, respectively. Dose-response analysis showed that those eating 800 g per day of FV consumption had the lowest risk of CVD. Our results indicate that increased FV intake is inversely associated with the risk of CVD. This meta-analysis provides strong support for the current recommendations to consume a high amount of FV to reduce CVD risk.
The
dopamine D3 receptor (D3R) is a promising
target for the development of pharmacotherapeutics to treat substance
use disorders. Several D3R-selective antagonists are effective
in animal models of drug abuse, especially in models of relapse. Nevertheless,
poor bioavailability, metabolic instability, and/or predicted toxicity
have impeded success in translating these drug candidates to clinical
use. Herein, we report a series of D3R-selective 4-phenylpiperazines
with improved metabolic stability. A subset of these compounds was
evaluated for D3R functional efficacy and off-target binding
at selected 5-HT receptor subtypes, where significant overlap in SAR
with D3R has been observed. Several high affinity D3R antagonists, including compounds 16 (Ki = 0.12 nM) and 32 (Ki = 0.35 nM), showed improved metabolic stability
compared to the parent compound, PG648 (6). Notably, 16 and the classic D3R antagonist SB277011A (2) were effective in reducing self-administration of heroin
in wild-type but not D3R knockout mice.
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