Recent studies have revealed the cytoprotective roles of microRNAs (miRNAs) miR-21 and miR-146a against ischemic cardiac injuries. While these studies investigated each of these miRNAs as an independent individual factor, our previous study has suggested the possible interaction between these two miRNAs. The present study was designed to investigate this possibility by evaluating the effects of miR-21 and miR-146a combination on cardiac ischemic injuries and the underlying mechanisms. MiR-21 and miR-146a synergistically decreased apoptosis under ischemia/hypoxic conditions in cardiomyocytes compared with either miR-21 or miR-146a alone. Mice coinjected with agomiR-21 and agomiR-146a had decreased infarct size, increased ejection fraction (EF), and fractional shortening (FS). These effects were greater than those induced by either of the two agomiRs. Furthermore, greater decreases in p38 mitogen-associated protein kinase phosphorylation (p-p38 MAPK) were observed with miR-21: miR-146a combination as compared to application of either of the miRNAs. These data suggest that combination of miR-21 and miR-146a has a greater protective effect against cardiac ischemia/hypoxia-induced apoptosis as compared to these miRNAs applied individually. This synergistic action is mediated by enhanced potency of inhibition of cardiomyocyte apoptosis by the miR-21—PTEN/AKT—p-p38—caspase-3 and miR-146a—TRAF6—p-p38—caspase-3 signal pathways.

The genome-wide transcriptome profiling of cancerous and normal tissue samples can provide insights into the molecular mechanisms of cancer initiation and progression. RNA Sequencing (RNA-Seq) is a revolutionary tool that has been used extensively in cancer research. However, no existing RNA-Seq database provides all of the following features: (i) large-scale and comprehensive data archives and analyses, including coding-transcript profiling, long non-coding RNA (lncRNA) profiling and coexpression networks; (ii) phenotype-oriented data organization and searching and (iii) the visualization of expression profiles, differential expression and regulatory networks. We have constructed the first public database that meets these criteria, the Cancer RNA-Seq Nexus (CRN, http://syslab4.nchu.edu.tw/CRN). CRN has a user-friendly web interface designed to facilitate cancer research and personalized medicine. It is an open resource for intuitive data exploration, providing coding-transcript/lncRNA expression profiles to support researchers generating new hypotheses in cancer research and personalized medicine.

Background: Brain-derived neurotrophic factor (BDNF) is associated with coronary artery diseases. However, its role and mechanism in myocardial infarction (MI) is not fully understood.Methods: Wistar rat and Kunming mouse model of MI were induced by the ligation of left coronary artery. Blood samples were collected from MI rats and patients. Plasma BDNF level, protein expression of BDNF, tropomyosin-related kinase B (TrkB) and its downstream transient receptor potential canonical (TRPC)3/6 channels were examined by enzyme-linked immunosorbent assay and Western blot. Infarct size, cardiac function and cardiomyocyte apoptosis were measured after intra-myocardium injection with recombinant human BDNF. Protective role of BDNF against cardiomyocyte apoptosis was confirmed by BDNF scavenger TrkB-Fc. The regulation of TRPC3/6 channels by BDNF was validated by pretreating with TRPC blocker (2-Aminoethyl diphenylborinate, 2-APB) and TRPC3/6 siRNAs.Results: Circulating BDNF was significantly enhanced in MI rats and patients. Protein expression of BDNF, TrkB and TRPC3/6 channels were upregulated in MI. 3 days post-MI, BDNF treatment markedly reduced the infarct size and serum lactate dehydrogenase activity. Meanwhile, echocardiography indicated that BDNF significantly improved cardiac function of MI mice. Furthermore, BDNF markedly inhibited cardiomyocyte apoptosis by upregulating Bcl-2 expression and downregulating caspase-3 expression and activity in ischemic myocardium. In neonatal rat ventricular myocytes, cell viability was dramatically increased by BDNF in hypoxia, which was restored by TrkB-Fc. Furthermore, protective role of BDNF against hypoxia-induced apoptosis was reversed by 2-APB and TRPC3/6 siRNAs.Conclusion: BDNF/TrkB alleviated cardiac ischemic injury and inhibited cardiomyocytes apoptosis by regulating TRPC3/6 channels, which provides a novel potential therapeutic candidate for MI.

Purpose/Background In clozapine therapeutic drug monitoring (TDM) studies, Chinese reached the same concentrations using half the dosage Caucasians use. Defining clozapine poor metabolizers (PMs) requires stratification by ethnicity, smoking, and sex. Methods/Procedures After sex and smoking stratification in 129 Chinese inpatients (mean, 8.8 TDM samples per patient), we explored the association between the total concentration-dose (C/D) ratio and CYP1A2 (*1C, *1F, and *7) and CYP2C19 alleles (*2 and *3). A systematic literature review identified 22 clozapine TDM prior studies (13 in Caucasians and 7 in East Asians). Findings/Results In our Chinese sample, the mean total clozapine C/D ratio (ng/mL per mg/d) was 1.96 for 22 male smokers, 2.07 for 5 female smokers, 2.47 for 36 male nonsmokers, and 2.95 for 66 female nonsmokers. CYP1A2 *1C had no significant effects, and CYP1A2 *1F had small effects. Five clozapine PMs (4%) needed low clozapine doses of 75 to 115 mg/d to get therapeutic concentrations. Using the same methodology in a published Italian sample, we found 5 PMs (3.3% of 152). In the systematic review, the clozapine C/D ratio (ng/mL per mg/d) was higher when comparing: (1) weighted mean values of 1.57 in 876 East Asians versus 1.07 in 1147 Caucasians and (2) ranks of 8 East Asians versus 13 Caucasian samples (P < 0.001). Implications/Conclusions Future TDM studies need to further explore the frequency of clozapine PMs after sex and smoking stratification in East Asian and Caucasian patients. Compared with Caucasians, East Asians appear to have a clinically relevant decrease in clozapine clearance.

Acute myocardial infarction (MI) is the leading cause of sudden death worldwide. MicroRNAs (miRs)is a novel class of regulators of cardiovascular diseases such as MI. This study aimed to explore the role of miR-98 in MI and its underlying mechanisms. We found that miR-98 was downregulated both in infarcted and ischemic myocardium of MI mice as well as H 2 O 2 -treated neonatal rat ventricular myocytes (NRVCs). miR-98 overexpression remarkably increased cell viability and inhibited apoptosis of H 2 O 2 -treated NRVCs. Meanwhile, overexpression of miR-98 reversed H 2 O 2 -induced Bcl-2 downregulation and Bax elevation and significantly reduced JC-1 monomeric cells. Meanwhile, miR-98 overexpression attenuated the upregulation of Fas and caspase-3 in H 2 O 2 -treated cardiomyocytes at the mRNA and protein levels. Dual-luciferase reporter assay showed that miR-98 directly targeted to Fas 3′-UTR. Furthermore, MI mice injected with miR-98-agomir had a significant reduction of apoptotic cells, the serum LDH levels, myocardial caspase-3 activity, Fas and caspase-3 expression in heart tissues. Administration of miR-98-agomir also showed decreased infarct size and improved cardiac function. Collectively, miR-98 is downregulated in the MI heart and NRVCs in response to H 2 O 2 stress, and miR-98 overexpression protects cardiomyocytes against apoptosis. Anti-apoptotic effects of miR-98 are associated with regulation of Fas/Caspase-3 apoptotic signal pathway.Acute myocardial infarction (AMI), resulting from coronary artery occlusion, is the most common causes of cardiovascular morbidity and mortality worldwide 1 . Apoptosis, which is triggered by an imbalance between proand anti-apoptotic factors, is frequently detected in ischemic heart tissue 2 . Cardiomyocyte apoptotic death in the border area close to myocardial infarcted area leads to cardiomyocyte loss, aggravates cardiac dysfunction and even causes heart failure and mortality 3,4 . Therefore, targeting inhibition of cardiomyocytes apoptosis during early stage of MI is critical for reducing infarct size and promoting cardiac repair, which is a key approach for treating ischemic heart disease. However, the molecular components regulating AMI-induced apoptosis in cardiomyocytes remain poorly understood.MicroRNAs (miRNAs) are a group of small, endogenous and non-coding RNA molecules, with about 22 nucleotides in length, which has been shown to post-transcriptionally regulate the expression of target genes, leading to the destruction and degeneration of mRNAs 5 . Clinical trials and animal experiments indicate that miRNAs are potential biomarkers and therapeutic targets for cardiac ischemia 6,7 . Moreover, several miRNAs are implicated in playing regulatory roles in cardiomyocytes apoptosis. Recent studies elucidate that miR-21, -24, -133, -210, -494 and -499 prevent myocytes against ischemia/reperfusion-induced apoptosis, while miR-1, -29, -195, -199a, -497 and -320 promote apoptosis [8][9][10] . Our previous study has also shown that combination of miR-21 and miR-146a h...