Abstract-Since the first description of the anatomical atrioventricular nodes (AVNs), a large number of studies have provided insights into the heterogeneity of the structure as well as a repertoire of ion channel proteins that govern this complex conduction pathway between the atria and ventricles. These studies have revealed the intricate organization of multiple nodal and nodal-like myocytes contributing to the unique electrophysiology of the AVN in health and diseases.On the other hand, information regarding the contribution of specific ion channels to the function of the AVN remains incomplete. We reason that the identification of AVN-specific ion channels may provide a more direct and rational design of therapeutic target in the control of AVN conduction in atrial flutter/fibrillation, one of the most common arrhythmias seen clinically. In this study, we took advantage of 2 genetically altered mouse models with overexpression or null mutation of 1 of a small conductance Ca 2ϩ -activated K ϩ channel isoform, SK2 channel, and demonstrated robust phenotypes of AVN dysfunction in these experimental models. Overexpression of SK2 channels results in the shortening of the spontaneous action potentials of the AVN cells and an increase in the firing frequency. On the other hand, ablation of the SK2 channel results in the opposite effects on the spontaneous action potentials of the AVN. Furthermore, we directly documented the expression of SK2 channel in mouse AVN using multiple techniques. The new insights may have important implications in providing novel drug targets for the modification of AVN conduction in the treatment of atrial arrhythmias. Key Words: K Ca 2.2 channel Ⅲ SK2 channel Ⅲ atrioventricular nodes T he atrioventricular node (AVN) is a highly specialized pacemaking tissue located at the junction of the right atrium and ventricle. Indeed, it is the only electrical connection between atria and ventricles and provides the critical delay between atrial and ventricular contraction to allow for proper atrial emptying before the start of the ventricular contraction. Pharmacological slowing of impulses across AVN is widely used clinically in atrial flutter/fibrillation to ensure physiological ventricular responses in these conditions. Previous studies have identified the roles of several distinct ion channels in the AVN function, 1-5 and recent work has begun to assemble an array of ion channel genes in the pacemaking tissues. 6 On the other hand, information regarding contribution of specific ion channels to the function of the AVN remains incomplete. We reason that the identification of AVN-specific ion channels may provide a more direct and rational design of therapeutic target in the control of AVN conduction in atrial flutter/fibrillation, one of the most common arrhythmias seen clinically.Specifically -activated K ϩ channels (SK or K Ca 2). 9 -13 SK channels are encoded by at least 3 distinct genes, namely KCNN1 (SK1), KCNN2 (SK2), and KCNN3 (SK3). 9,10,13 Here, we directly document the robust expres...

There has been a growing interest in controlling body weight by increasing dietary levels of leucine recently. By contrast, we have focused on studying the effect of deficiency of branched-chain amino acids (BCAAs) leucine on lipid metabolism. We previously have shown that mice fed a leucine-deficient diet for 7 days exhibit significant changes in lipid metabolism as demonstrated by suppressed lipogenesis in the liver and increased fat mobilization in white adipose tissue, the latter of which was found to be caused by increased lipolysis in WAT and uncoupling protein 1 expression in brown adipose tissue. The goal of our current study is to investigate whether the above effects of leucine deficiency can be generalized to the deficiency of other BCAAs including valine and isoleucine. In our current study, we show that valine or isoleucine deficiency has similar effects on reducing fat mass to leucine deprivation, in a similar manner as those observed during leucine deprivation.

Background:Recent studies have indicated that an imbalance of gut microbiota is associated with the development of type 1 diabetes mellitus (T1DM) and there is no literature regarding it in Chinese children yet. The aim of this study was to evaluate the alteration of gut microbiota between children with newly diagnosed T1DM and healthy controls and to determine if gut microbiota could partly explain the etiology of this disease.Methods:A case-control study was carried out with 15 children with T1DM and 15 healthy children. The fecal bacteria composition was investigated by high-throughput sequencing of the V3–V4 region of the 16S rDNA gene and analyzed by the estimators of community richness (Chao) indexes.Results:There was a notable lower richness of fecal bacteria in T1DM group than controls (156.53 ± 36.96 vs. 130.0 ± 32.85, P = 0.047). At the genus level, the composition of Blautia was increased in T1DM group than control group whereas the composition of Haemophilus, Lachnospira, Dialister, and Acidaminococcus was decreased. In addition, we found that the percentage of Blautia was correlated positively with HbA1c (ρ = 0.40, P = 0.031), the numbers of T1DM autoantibodies (ρ = 0.42, P = 0.023), and the titers of tyrosine phosphatase autoantibodies (IA-2) (ρ = 0.82, P = 0.000) in the study.Conclusions:This study showed that gut microbiota was associated with the development of T1DM by affecting the autoimmunity, and the results suggested a potential therapy for T1DM via modulating the gut microbiota.

Obesity is a growing public health problem, which has now been considered as a pandemic non-communicable disease. However, the efficacy of several approaches for weight loss is limited and variable. Thus, alternative anti-obesity treatments are urgently warranted, which should be effective, safe, and widely available. Active compounds isolated from herbs are similar with the practice of Traditional Chinese Medicine, which has a holistic approach that can target to several organs and tissues in the whole body. Capsaicin, a major active compound from chili peppers, has been clearly demonstrated for its numerous beneficial roles in health. In this review, we will focus on the less highlighted aspect, in particular how dietary chili peppers and capsaicin consumption reduce body weight and its potential mechanisms of its anti-obesity effects. With the widespread pandemic of overweight and obesity, the development of more strategies for the treatment of obesity is urgent. Therefore, a better understanding of the role and mechanism of dietary capsaicin consumption and metabolic health can provide critical implications for the early prevention and treatment of obesity.

Berberine is known to improve glucose and lipid metabolism disorders, but the mechanism is still under investigation. In this paper, we explored the effects of berberine on the weight, glucose levels, lipid metabolism, and serum insulin of KKAy mice and investigated its possible glucose and lipid-regulating mechanism. We randomly divided KKAy mice into two groups: berberine group (treated with 250 mg/kg/d berberine) and control group. Fasting blood glucose (FBG), weight, total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c), and fasting serum insulin were measured in both groups. The oral glucose tolerance test (OGTT) was performed. RT2 PCR array gene expression analysis was performed using skeletal muscle of KKAy mice. Our data demonstrated that berberine significantly decreased FBG, area under the curve (AUC), fasting serum insulin (FINS), homeostasis model assessment insulin resistance (HOMA-IR) index, TC, and TG, compared with those of control group. RT2 profiler PCR array analysis showed that berberine upregulated the expression of glucose transporter 4 (GLUT4), mitogen-activated protein kinase 14 (MAPK14), MAPK8(c-jun N-terminal kinase, JNK), peroxisome proliferator-activated receptor α (PPARα), uncoupling protein 2 (UCP2), and hepatic nuclear factor 4α(HNF4α), whereas it downregulated the expression of PPARγ, CCAAT/enhancer-binding protein (CEBP), PPARγ coactivator 1α(PGC 1α), and resistin. These results suggest that berberine moderates glucose and lipid metabolism through a multipathway mechanism that includes AMP-activated protein kinase-(AMPK-) p38 MAPK-GLUT4, JNK pathway, and PPARα pathway.

Sixteen new withanolides, physangulatins A-N (1-14) and withaphysalins Y and Z (15 and 16), as well as 12 known analogues, were isolated from the stems and leaves of Physalis angulata L. Their structures were established using extensive spectroscopic data analyses. The absolute configurations of 1 and 9 were assigned via X-ray crystallography. The isolated compounds were tested for their antiproliferative effects against human prostate cancer cells (C4-2B and 22Rvl), human renal carcinoma cells (786-O, A-498, and ACHN), and human melanoma cells (A375-S2), as well as inhibitory effects on NO production induced by LPS in macrophages. Compounds 9, 17, 20, 21, 25, and 27 showed antiproliferative effects against all tested cancer cells, with IC50 values of 0.18-7.43 μM. Compounds 3-5, 9-11, 17, 20-22, 24, 25, and 27 displayed inhibitory effects against NO production, with IC50 values of 1.36-11.59 μM.

The high prevalence and low awareness of CKD in the studied population suggest that CKD is a severe public health problem in Central China. Effectively preventive and therapeutic interventions are needed.

ObjectivePrecise genetic analyses were conducted with ring finger protein 213 (RNF213) in relation to a particular clinical phenotype in Chinese patients with moyamoya disease (MMD) to determine whether heterozygosity is responsible for the early-onset and severe form of this disease.MethodsA case–control study for RNF213 p.R4810K involving 1,385 Chinese patients with MMD and 2,903 normal control participants was performed. Correlation analyses between genotype and phenotype or different clinical features were also statistically explored.ResultsAn obvious trend was observed: the carrying rate of RNF213 p.R4810K gradually decreased when moving from coastal cities in northeast, north, and east China to southern cities or inland areas. Higher frequencies of p.R4810K were observed in patients with MMD compared with control participants (odds ratio, 48.1; 95% confidence interval, 29.1–79.6; p = 1.6 × 10−141). In addition, the onset age of all patients with the GA and AA genotypes were lower than with the GG genotype, and the median onset age was 40.0, 36.0, and 11.5 years with GG, GA, and AA, respectively, thereby confirming that those with GA or AA could acquire MMD during early life stages. Patients with MMD with the GA genotype were more susceptible to posterior cerebral artery (PCA) involvement compared to those with the GG genotype (38.4% vs 23.3%, p = 8.3 × 10−7).ConclusionsStrong evidence suggests that the carrying rate of RNF213 p.R4810K is closely related MMD risk in China and has given rise to an earlier onset age and more severe PCA involvement.