Search

Enasidenib (AG-221) is the only approved IDH2 inhibitor, clinical study found Enasidenib have some side-effects. In this work, we synthesized series of novel s-triazine derivatives, and the in vitro and in vivo activity of anti-AML has been studied using AM7577 model. The cell activity found Ta and Th showed excellent inhibition to AM7577. We further used the HuKemia Acute Leukemia xenograft model to investigate the in vivo efficacy of compounds Ta and Th, compared with AG-221, although Ta and Th can't reduce the 2-HG level obviously, those two compounds can prolong the survival of rats. The research can expand the structure of novel IDH2 inhibitors and provide useful information for further research of novel AML drugs.

Zinc finger protein 804A (ZNF804A) has been identified by genome-wide association studies as a robust risk gene in schizophrenia, but how ZNF804A contributes to schizophrenia and its upstream regulation remains unknown. Previous studies have indicated that microRNAs (miRs) are key factors that regulate the expression levels of their target genes. The present study revealed significantly increased expression of miR-148b-3p in the peripheral blood of patients with first-onset schizophrenia compared with healthy controls, and bioinformatics analysis predicted that the ZNF804A gene is a target of miR-148b-3p. Therefore, the present study investigated the possible upstream regulation of ZNF804A by miR-148b-3p in the human neuroblastoma SH-SY5Y cell line, and assessed the implications for schizophrenia. The results revealed significantly reversed expression levels of miR-148b-3p (P=0.0051) and ZNF804A (P=0.0218) in the peripheral blood of patients with first-onset schizophrenia compared with healthy individuals. Furthermore, it was demonstrated that miR-148b-3p directly targeted ZNF804A via binding to conserved target sites in the 3′-untranslated region of ZNF804A mRNA, where it inhibited the endogenous expression of ZNF804A at both the mRNA (P=0.048) and protein levels (P=0.013) in SH-SY5Y cells. Furthermore, miR-148b-3p was revealed to regulate the expression levels of catechol-O-methyltransferase (COMT) and serine protease 16 (PRSS16) by targeting ZNF804A in SH-SY5Y cells. Collectively, the present results indicated that there was a direct upstream regulation of the schizophrenia risk gene ZNF804A by miR-148b-3p, which contributed to the regulation of the downstream genes COMT and PRSS16. Thus, the miR-148b-3p/ZNF804A/COMT/PRSS16 pathway may play an important role in the pathophysiology of schizophrenia, and may serve as a potential target in drug discovery and gene therapy for this disorder.

The main treatments for Parkinson's disease (PD) currently include surgery, rehabilitation, and most commonly, drug therapy. However, the drugs that are currently used to treat PD provide only symptomatic relief and delayed disease progression but have no curative effect and cause many adverse reactions. When considering pathogenic factors and metabolic regulation, PD and type 2 diabetes have a high rate of comorbidity; this provides a theoretical basis for the treatment of PD with first-line antidiabetic drugs. Among these agents, metformin reduces neuronal damage in the brains of PD patients via neuroprotection and the inhibition of oxidative stress and inflammatory responses, thus providing a novel strategy for the clinical treatment of PD. Here, we present the current state of knowledge about the use of metformin to treat PD and discuss its clinical prospects.

Accumulating evidence suggests that epigenetics plays an important role in the etiology of schizophrenia. Here, we performed a methylome-wide association study (MWAS) of first-onset schizophrenia patients and controls from the Han Chinese population using microarray technology. The DNA methylation profiles revealed 4494 differentially methylated CpG sites. Gene ontology (GO) analysis showed that the functions of differentially methylated genes were primarily involved in enzymatic activity, cytoskeleton organization and cell adhesion, and the TNIK (encoding TRAF2- and NCK-interacting kinase) gene was enriched in most of these terms. By combining the MWAS results with those of previous genome-wide association studies (GWASs), we identified 72 candidate genes located in 49 human genome loci. Among the overlapping genes, the most significantly methylated CpG sites were in the transcriptional start site (TSS) 200 region (cg21413905, Punadjusted = 3.20 × 10−5) of TNIK. TNIK was listed in the top 50 differentially methylated loci. The results of pyrosequencing and TNIK mRNA expression were consistent with those of the microarray study. Bioinformatics analyses, dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) studies showed that TNIK interacted with genes associated with schizophrenia and NRF1 was identified as a novel transcription factor (TF) that binds to TNIK in its TSS200 region. Thus, the regulatory function of NRF1 may be influenced by the status of the methylated CpG site in this region. In summary, our study provides new insights into the epigenetic mechanisms that regulate schizophrenia. Studies of the functions of TNIK methylation should be performed in vitro and in vivo to provide a better understanding of the pathophysiology of schizophrenia.

MicroRNAs (miRNAs) are a class of endogenous and non-coding single-stranded RNAs with length of about 22 nucleotides, and many are evolutionarily conserved. Although postmortem brain samples provide direct evidence of miRNA dysregulation within the brain, peripheral tissue samples can be obtained from living subjects and have the potential to yield biomarkers that could be used as diagnostic tools. To verify and detect additional miRNAs differentially expressed in peripheral blood and further explore their diagnostic value and function for schizophrenia, we performed a next-generation sequencing approach in combination with a literature search to select appropriate miRNAs. We then used real-time quantitative polymerase chain reaction (RT-qPCR) to identify miRNAs expressed aberrantly in schizophrenia. Binary regression analysis identified miR-22-3p, miR-92a-3p, and miR-137. Analysis of receiver operating characteristics (ROC) indicated that these three miRNAs could be used in combination as a biomarker for schizophrenia. Bioinformatic analyses of these genes and gene ontology (GO) enrichment revealed that the combination of miR-22-3p, miR-92a-3p, and miR-137 was closely associated with synaptic structure and function, which play important roles in the etiology and pathophysiology of schizophrenia.

To identify the candidate chromosomal region for congenital preauricular fistula (CPF) through analysis of an affected Chinese family.Conventional linkage analysis using short tandem repeats (STR) markers was performed to investigate three chromosomal regions 8q11.1-q13.3, 1q32-q34.3 and 14q31.1-q31.3.None of 16 STRs could attain a LOD score of more than -2.0 (theta=0). Therefore, the three regions were all excluded as the candidate region for the disease.CPF features high genetic heterogeneity. The family may have a causative gene elsewhere. Whole-genome-based study is needed to identify its genetic etiology.

Recently, genome-wide association studies (GWAS), meta-analyses, and replication studies focusing on bipolar disorder (BD) have implicated the α-1C subunit of the L-type voltage-dependent calcium channel (CACNA1C) and ankyrin 3 (ANK3) genes in BD. Based on the hypothesis that both schizophrenia (SZ) and BD may share some common genetic risk factors, we investigated the association of CACNA1C and ANK3 with SZ using meta-analytic techniques, combining all published data up to April 2015. Nine teams, including four European decent samples and five Asian samples, contributed 14,141 cases and 30,679 controls for the analysis of CACNA1C rs1006737 and SZ. A significant difference was identified between patients and controls for the A-allele of rs1006737 in combined studies (Z = 6.02, P = 1.74E-09), in European studies (Z = 4.08, P = 4.50E-05), and in Asian studies (Z = 4.60, P = 4.22E-06). Meanwhile, for the T-allele of ANK3 rs10761482 (1,794 cases versus 1,395 controls), a significant association was observed in combined samples (Z = 2.06, P = 0.04) and in Asian samples (Z = 3.10, P = 0.002). In summary, our study provides further evidence for the positive association of CACNA1C and ANK3 with SZ. These results support the hypothesis that both SZ and BD share common genetic risk factors. Further research is needed to examine the functions of CACNA1C and ANK3, and their interacting partners in the molecular, developmental, and pathophysiological processes in SZ. © 2015 Wiley Periodicals, Inc.

MicroRNAs (miRNAs) are a class of endogenous and non-coding single-stranded RNAs of approximately 22 nucleotides, many of which are evolutionarily conserved. Genome-wide association studies have identified a robust statistical association between the MIR137 gene and schizophrenia in Europeans, which was replicated in the Han Chinese population in a case-control study. In the previous study, we provided evidence for a significant association between the EFNB2 gene and schizophrenia in Han Chinese subjects. In the current study, we utilized computational analysis, vector construction of point mutations, luciferase reporter assays and gene expression assays including RT-qPCR and western blotting methods to investigate miR-137 directly targeting EFNB2 gene and explore the reversal effect of a genetic variant of SNP rs550067317 in the putative seed-pair region of EFNB2 3′-UTR. We also found that miR-137 could be detected in the peripheral blood of a cohort of first-onset schizophrenia patients and healthy controls, and the area under curve was 0.795 (95% confidence interval 0.700–0.890), which is a middle diagnostic value for disease, suggesting that it might be valuable for diagnosing schizophrenia. In summary, this study would improve our understanding of the role of miR-137 in schizophrenia-associated signaling pathways and identify the genetic basis of rs550067317 for schizophrenia. Furthermore, we provided new evidence for the involvement of miR-137 in the etiology and diagnosis of schizophrenia, which might contribute to the discovery of new biomarkers and therapeutic targets for the disease., Highlights • We demonstrated that miR-137 inhibiting EFNB2 gene at protein level by using classical methods of dual luciferase report assay, RT-qPCR, and western blotting. • MiR-137 inhibiting EFNB2 gene was affected by a genetic variant of SNP rs550067317 tested by the method of dual luciferase reporter assay through point mutation. • MiR-137 expressed aberrantly in peripheral blood of schizophrenia patients, and the area under curve was 0.795 which is a middle diagnostic value for disease. In this study, we provided evidence that miR-137 targets EFNB2 gene directly and a genetic variant in 3’UTR of the EFNB2 affects the regulation. MiR-137 regulated EFNB2 gene expression at protein level. We further found that miR-137 expressed abnormally in peripheral blood of schizophrenia patients and the area under curve reaches a middle diagnostic value for disease.