Isoproterenol induces MD2 activation by ß-AR-cAMP-PKA-ROS signalling axis in cardiomyocytes and macrophages drives inflammatory heart failure.

Cardiac inflammation contributes to heart failure (HF) induced by isoproterenol (ISO) through activating ß-adrenergic receptors (ß-AR). Recent evidence shows that myeloid differentiation factor 2 (MD2), a key protein in endotoxin-induced inflammation, mediates inflammatory heart diseases. In this study, we investigated the role of MD2 in ISO-ß-AR-induced heart injuries and HF. Mice were infused with ISO (30 mg·kg-1·d-1) via osmotic mini-pumps for 2 weeks. We showed that MD2 in cardiomyocytes and cardiac macrophages was significantly increased and activated in the heart tissues of ISO-challenged mice. Either MD2 knockout or administration of MD2 inhibitor L6H21 (10 mg/kg every 2 days, i.g.) could prevent mouse hearts from ISO-induced inflammation, remodelling and dysfunction. Bone marrow transplantation study revealed that both cardiomyocyte MD2 and bone marrow-derived macrophage MD2 contributed to ISO-induced cardiac inflammation and injuries. In ISO-treated H9c2 cardiomyocyte-like cells, neonatal rat primary cardiomyocytes and primary mouse peritoneal macrophages, MD2 knockout or pre-treatment with L6H21 (10 µM) alleviated ISO-induced inflammatory responses, and the conditioned medium from ISO-challenged macrophages promoted the hypertrophy and fibrosis in cardiomyocytes and fibroblasts. We demonstrated that ISO induced MD2 activation in cardiomyocytes via ß1-AR-cAMP-PKA-ROS signalling axis, and induced inflammatory responses in macrophages via ß2-AR-cAMP-PKA-ROS axis. This study identifies MD2 as a key inflammatory mediator and a promising therapeutic target for ISO-induced heart failure.

Identifying susceptibility genes for essential hypertension by transcriptome-wide association study.

Hypertension is a leading risk factor of cardiovascular disease and mortality in the population worldwide. Recently, hundreds of genomic loci were reported for hypertension by GWAS, however, the most SNPs are located in intergenic regions of genome, where a functional cause is difficult to determine. In the current study, a TWAS of hypertension was conducted using 452,264 individuals including 84,640 patients. KEGG and GO enrichment analyses were performed for the hypertension-related genes identified via TWAS. PPI network analysis based on the STRING database was also performed to detect TWAS-identified genes in hypertension. We have identified 18,420 genes from the GWAS summary data, and of those 1010 non-overlapping genes expression were significantly associated with hypertension after FDR correction (PFDR <0.05) in four tissues (left heart ventricle, aorta, whole blood, and peripheral blood). The KEGG and GO terms were mostly related to autoimmune mechanisms, and the autoimmune-related pathways have also been enriched using GO analysis for PPI genes. We further performed Mendelian randomization analysis, and the results supported a significant association between autoimmunity and hypertension. Moreover, 15 novel hypertension-susceptible genes were identified in all tissues, and five of the genes (RBM6, HLA-DRB5, UHRF1BP1, LYZ, and TMEM116) were associated with autoimmune system, which provide further evidence supporting an autoimmune mechanism in hypertension. In summary, our study supports that an autoimmune mechanism plays an important role in the development of hypertension, and these findings will provide new biological insights that will assist in deciphering the molecular etiology of hypertension.

Pharmacokinetic drug interactions of integrase strand transfer inhibitors.

The integrase strand transfer inhibitor (INSTI)-containing regimens are currently considered as the first-line treatment of human immunodeficiency virus (HIV) infection. Although possessing a common mechanism of action to inhibit HIV integrase irreversibly to stop HIV replication cycle, the INSTIs, including raltegravir, elvitegravir, dolutegravir, and bictegravir, differ in pharmacokinetic characteristics. While raltegravir undergoes biotransformation by the UDP-glucuronosyltransferases (UGTs), elvitegravir is primarily metabolized by cytochrome P450 (CYP) 3A4 and co-formulated with cobicistat to increase its plasma exposure. The metabolism pathways of dolutegravir and bictegravir are similar, both including CYP3A and UGT1A1, and both agents are substrates to different drug transporters. Because of their differences in metabolism, INSTIs interact with other medications differently through CYP enzymes and transporters as inducers or inhibitors. These drug interactions may become an important consideration in the long-term clinical use because the life expectancy of people with HIV (PWH) approaches to that of the general population. Also, common geriatric challenges such as multimorbidity and polypharmacy have been increasingly recognized in PWH. This review provides a summary of pharmacokinetic interactions with INSTIs and future perspectives in implications of INSTI drug interactions.

Discovery of a Potent Grp94 Selective Inhibitor with Anti-Inflammatory Efficacy in a Mouse Model of Ulcerative Colitis.

As the endoplasmic reticulum paralogue of Hsp90, Grp94 chaperones a small set of client proteins associated with some diseases, including cancer, primary open-angle glaucoma, and inflammatory disorders. Grp94-selective inhibition has been a potential therapeutic strategy for these diseases. In this study, inspired by the conclusion that ligand-induced "Phe199 shift" effect is the structural basis of Grp94-selective inhibition, a series of novel Grp94 selective inhibitors incorporating "benzamide" moiety were developed, among which compound 54 manifested the most potent Grp94 inhibitory activity with an IC50 value of 2 nM and over 1000-fold selectivity to Grp94 against Hsp90α. In a DSS-induced mouse model of ulcerative colitis (UC), compound 54 exhibited significant anti-inflammatory efficacy. This work provides a potent Grp94 selective inhibitor as probe compound for the biological study of Grp94 and represents the first study that confirms the potential therapeutic efficacy of Grp94-selective inhibitors against UC.

The Prevalence of Peripheral Arterial Disease and Its Risk Factors among Patients with Type 2 Diabetes in Community / 昆明医科大学学报

Objective To investigate the prevalence and explore the related risk factors for peripheral arterial disease (PAD) among patients with type 2 diabetes so as to provide the evidence and reference to the early intervention in community. Methods A total of 662 patients with type 2 diabetes were selected in the community from June 2014 to June 2015 in Shenzhen province. All patients were divided into two groups according to the values of ankle-brachial index. The prevalence of PAD was calculated. Univariate and logistic regression analysis was applied to explore risk factors associated with the prevalence of PAD. Results 25.83% (171/662) of the diabetic patients suffered from peripheral arterial disease. Univariate analysis results found that age, education level, family history, course of disease, smoking status, physical exercise, dietary habits, body mass index, with hypertension, with hyperlipidemia, tuberculosis were all significantly associated with the prevalence of PAD (P＜0.05) . Logistic regression analysis finally showed that older age, with hypertension, with dyslipidemia, long course of disease,body mass index,with family history, smoking were found to be the valuable risk factors related to PAD (P＜0.05), whereas high education level and regular physical exercise were protective factors against PAD (P＜0.05) . Conclusions Among diabetic patients in community, the prevalence of PAD was higher and there were many risk factors. We suggest that the early screening of PAD and targeted intervention should be given full attention and strengthened. Based on controlling of blood glucose, diabetic patients should not only strictly control blood pressure,but also pay attention to blood lipid regulation, control BMI and ensure smoking cessation, especially for those with advanced age, long course of disease and family history, so that we can effectively reduce the prevalence of PAD.

Global outbreaks of human trichinellosis / 中国人兽共患病学报

Outbreak of trichinellosis belongs to the sudden public health events,with number of hazards and social influence,and is a serious threat to people's health and the social order stability.Through literature search,we collected the global outbreaks of human trichinellosis in recent years,focused on analyzing outbreak areas,cause of the outbreak,kind of infected meat,the number of cases,the genus of Trichinella and migration,diagnostic methods,etc.,in order to further prevent and control trichinellosis and to provide the important theoretical reference basis.