Rationale: Over 50% of heart failure patients have preserved, rather than reduced ejection fraction (HFpEF vs. HFrEF). Complexity of its pathophysiology and the lack of animal models hamper the development of effective therapy for HFpEF. Objective: This study was designed to investigate the metabolic mechanisms of HFpEF and test therapeutic interventions using a novel animal model.Methods and Results: By combining the age, long-term high-fat diet and desoxycorticosterone pivalate challenge in a mouse model we were able to recapture the myriad features of HFpEF. In these mice, mitochondrial hyperacetylation exacerbated while increasing ketone body availability rescued the phenotypes. The HFpEF mice exhibited overproduction of interleukin (IL)-1β/IL-18, and tissue fibrosis due to increased assembly of NLPR3 inflammasome on hyperacetylated mitochondria. Increasing β-hydroxybutyrate (β-OHB) level attenuated NLPR3 inflammasome formation and antagonized proinflammatory cytokines-triggered mitochondrial dysfunction and fibrosis. Moreover, β-OHB downregulated the acetyl-CoA pool and mitochondrial acetylation, partially via activation of citrate synthase and inhibition of fatty acid uptake. Conclusions: Therefore, we identify the interplay of mitochondrial hyperacetylation and inflammation as a key driver in HFpEF pathogenesis which can be ameliorated by promoting β-OHB abundance.

The objective of this study was to determine whether the modified Stoppa approach or the ilioinguinal approach is better for the treatment of acetabular fractures by comparing the results of those 2 approaches. A randomized trial was undertaken of 60 consecutive patients with acetabular fractures treated with either the modified Stoppa or the ilioinguinal approach. In addition to the patients' demographics, the assessed preoperative parameters included fracture pattern, associated injuries, time to surgery, and Injury Severity Score; intraoperative parameters included blood loss and operative time for each procedure; and postoperative parameters included wound drainage, blood transfusion, perioperative complications, early operative complications, late operative complications, quality of reduction, radiological results, and clinical outcomes. The study showed no significant differences in all measured preoperative variables between the 2 groups (all P>.05). In addition, no significant differences were found in the intraoperative complication rate, early operative complication rate, late operative complication rate, quality of reduction, radiological results, and clinical outcomes (all P>.05). However, compared with the ilioinguinal approach, the modified Stoppa approach reduced intraoperative blood loss-and in doing so decreased wound drainage and the need for blood transfusion-and shortened operative time (all P<.05). The authors recommend using the modified Stoppa approach rather than the classical ilioinguinal approach to treat acetabular fractures when anterior exposure of the acetabulum is required.

These results suggested that trehalose could be a potential therapeutic drug for the treatment of AD.

Transporters comprise the largest family of membrane proteins in human organism, including members of solute carrier transporter and ATP-binding cassette transporter families. They play pivotal roles in the absorption, distribution and excretion of xenobiotic and endogenous molecules. Transporters are widely expressed in various human tissues and are routinely evaluated during the process of drug development and approval. Over the past decade, increasing evidence shows that drug transporters are important in both normal physiology and disease. Currently, transporters are utilized as therapeutic targets to treat numerous diseases such as diabetes, major depression, hypertension and constipation. Despite the steady growth of the field of transporter biology, more than half of the members in transporter superfamily have little information available about their endogenous substrate(s) or physiological functions. This review outlines current research methods in transporter studies, and summarizes the drug-transporter interactions including drug-drug and drug-endogenous substrate interactions. In the end, we also discuss the therapeutic perspective of transporters based on their physiological and pathophysiological roles.

Ischemia-reperfusion (I/R) injury is detrimental to cardiovascular system. Alteration in glucose metabolism has been recognized as an important adaptive response under hypoxic conditions. However, the biological benefits underlying this metabolic phenotype remain to be elucidated. This study was designed to investigate the impact of hypoxic acclimation (HA) on cardiac I/R injury and the antioxidative mechanism(s). Male adult mice were acclimated in a hypoxic chamber (10% oxygen [O 2 ]) for 8 h/day for 14 days, and then subjected to cardiac I/R injury by ligation of left anterior descending coronary artery for 30 min and reperfusion for 24 h or 7 days. Our results showed that HA attenuated oxidative stress and reduced infarct size in the I/R hearts. This cardioprotective effect is coupled with an elevation of protein O-linked N -acetylglucosamine (O-GlcNAc) modification partially due to inflammatory stimulation. Hyperglycosylation activated glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme in the pentose phosphate pathway, resulting in an upregulation of NADPH/NADP + and GSH/GSSG couples and enhancement of redox homeostasis in the heart. Pharmacological suppression of O-GlcNAcylation totally abolished the influence of HA on the G6PDH activity, redox balance and post-I/R damage in the hearts and cultured cardiomyocytes, whereby augmentation of O-GlcNAcylation further enhanced the benefits, suggesting a central role of O-GlcNAcylation in HA-initiated antioxidative and cardioprotective effects. These findings, therefore, identified HA as a promising anti-I/R strategy for the heart and proposed O-GlcNAc modification of G6PDH as a therapeutic target in ischemic heart disease.