Abstract-Metabolic syndrome (MetS) is associated with nephropathy. Along with common risk factors such as hypertension and hyperglycemia, adipocytokines released from perirenal adipose tissue (PRAT) are implicated in the pathogenesis of MetS nephropathy. The study was designed to elucidate the adverse effects of PRAT-derived leptin on nephropathy and to determine whether the angiotensin II type 1 receptor antagonist telmisartan exerts a renoprotective effect by decreasing the PRAT-derived leptin level in the high-fat diet-induced MetS rat. In MetS rats, PRAT-derived leptin expression increased concomitant with dysfunction of adipogenesis, and the activities of the angiotensin II-angiotensin II type 1 receptor and the angiotensin-converting enzyme 2-angiotensin (1-7)-Mas receptor axes were imbalanced in PRAT. PRAT-derived leptin from MetS rats promoted proliferation of rat glomerular endothelial cells (GERs) by activating the p38 MAPK (mitogenactivated protein kinase) pathway, thereby contributing to the development of nephropathy. Long-term telmisartan treatment improved metabolic parameters and renal function, decreased the amount of PRAT, promoted adipogenesis, increased the expression of angiotensin-converting enzyme 2, restored balanced activities of the angiotensin II-AT1R and angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axes, and exerted an indirect renoprotective effect on MetS rats by decreasing PRAT-derived leptin release. Our results demonstrate a novel link between nephropathy and PRAT in MetS and show that telmisartan confers an underlying protective effect on visceral adipose tissue and the kidney, suggesting that it has potential as a therapeutic agent for the treatment of MetS-associated nephropathy. (Hypertension. 2016;68:478-490.

BackgroundThere are limited data about cardiac resynchronization therapy (CRT) in adult congenital heart disease. We aimed to assess early and late outcomes of CRT among patients with adult congenital heart disease.Methods and ResultsWe retrospectively studied 54 patients with adult congenital heart disease (median age, 46 years; range, 18–73 years; 74% men) who received CRT implantation (biventricular paced >90%) between 2004 and 2017. Clinical and echocardiographic data were analyzed at baseline and early (mean±SD: 1.8±0.8 years) and late (4.7±0.8 years) follow‐up after CRT. Compared with baseline, CRT was associated with significant improvement at early follow‐up in New York Heart Association functional class, QRS duration, and cardiothoracic ratio (P<0.05 for all); improvement in New York Heart Association class was sustained at late follow‐up. Among patients with a systemic left ventricle (LV; n=39), there was significant increase in LV ejection fraction and reduction in LV end‐systolic volume at early and late follow‐up (P<0.05 for both). For patients with a systemic right ventricle (n=15), there was a significant early but not late reduction in systemic right ventricular basal and longitudinal diameters. Eleven patients died, and 2 had heart transplantation unrelated to systemic ventricular morphological characteristics. Thirty‐five patients (65%) responded positively to CRT, but only baseline QRS duration was predictive of a positive response.Conclusions CRT results in sustained improvement in functional class, systemic LV size, and function. Patients with a systemic LV and prolonged QRS duration, independent of QRS morphological characteristics, were most likely to respond to CRT.

A proper pH microenvironment is crucial to mobilizing regeneration function of biomaterials. Neutralizing the acidity in bone defects with alkaline substances is a promising strategy to create favorable environments for cell proliferation and bone repair. In this study, to neutralize the acidity and reduce the inflammation caused by the rapid release of citric acid, a novel citrate-based biodegradable elastomeric poly(citric acid-1,8-octanediol-1,4-bis(2-hydroxyethyl)piperazine (BHEp)) (POPC) is synthesized with the introduction of the alkaline fragment BHEp, and then POPC/𝜷-tricalcium phosphate (𝜷-TCP) porous scaffolds are fabricated by 3D printing technique. The results reveal that the alkaline fragment BHEp effectively corrects the acid environment and improves the biocompatibility, cells affinity and promoted cell adhesion, and proliferation of POPC. Furthermore, the improved pH of POPC15/𝜷-TCP (PTCP15) enhances the adhesion and the proliferation of rabbit bone marrow mesenchymal stem cells, and the expression of osteogenesis-related genes. Moreover, PTCP15 scaffolds relieve inflammatory response and switch RAW 264.7 toward a prohealing extreme. The rat femoral defect model further demonstrates good biocompatibility and enhanced bone regeneration of PTCP15. In conclusion, the results offer a promising approach for biodegradable polymers to address the degradation acidity issue. Meanwhile, a positive regulation strategy is provided for biopolymer to enhance cell proliferation, osteogenic differentiation, and bone repair.

Osteoporosis is a reduction in skeletal mass due to the decrease of osteogenic ability and the activation of the osteoclastic function. Inhibiting bone resorption and accelerating the new bone formation is a promising strategy to repair the bone defect of osteoporosis. In this study, we first systematically investigated the roles of Chinese medicine Asperosaponin VI (ASP VI) on osteogenic mineralization of BMSCs and osteoclastogenesis of BMMs, and then explored the synergistic effect of ASP VI and BS (BMP-2 immobilized in 2-N, 6-O-sulfated chitosan) on bone formation. The result showed that ASP VI with the concentration lower than 10 −4 M contributed to the expression of osteogenic gene and inhibited osteoclastic genes RANKL of BMSCs. Simultaneously, ASP VI significantly reduced the differentiation of mononuclear osteoclasts in the process of osteoclast formation induced by M-CSF and RANKL. Furthermore, by stimulating the SMADs, TGF-β1, VEGFA, and OPG/RANKL signaling pathways, ASBS (ASP VI and BS) substantially enhanced osteogenesis, greatly promoted angiogenesis, and suppressed osteoclastogenesis. The findings provide a new perspective on osteoporosis care and prevention.

Context: Allicin is a potential antiarrhythmic agent. The antiarrhythmic properties of allicin rely on its blockade of various cardiac ion channels. The l -type calcium (Cav1.2) channel provides a pivotal substrate for cardiac electrophysiologic activities. The mechanism of allicin on Cav1.2 remains unclear. Objective: This study evaluated the potential of allicin on the synthesis and trafficking of Cav1.2 channels. Materials and methods: Primary cardiomyocytes (CMs) from neonatal Sprague-Dawley (SD) rats were exposed to allicin (0, 0.0001, 0.001, 0.01, 0.1, 1, 10, 100 μg/mL) for 24 and 48 h. The CellTiter-Glo assay was performed to measure CM viability. Western blot with grayscale analysis and confocal laser scanning microscopy were used to evaluate the effects of allicin on the synthesis and trafficking of Cav1.2 channel proteins in primary CMs. Results: There was no significant difference in apoptotic toxicity from the actual cell viability ( p > 0.05) in any group (0, 0.0001, 0.001, 0.01, 0.1, 1, 10, 100 μg/mL allicin), except that viability in the 0.001 and 0.01 μg/mL groups at 24 h were significantly greater (137.37 and 135.96%) ( p < 0.05). Western blot with grayscale analysis revealed no substantial inhibition by allicin of the synthesis of Cav1.2 proteins. Confocal laser scanning microscopy revealed trafficking dysfunction of Cav1.2 channels caused by allicin in primary CMs. Conclusion: This study is the first to demonstrate that allicin inhibits cardiac Cav1.2 channels by disrupting trafficking, possibly mediating its antiarrhythmic benefits. Therefore, allicin might serve as a new antiarrhythmic agent in the future.