Pei Ma

Background: N6‐methyladenosine (m⁶A) RNA modification is known as a common epigenetic regulation form in eukaryotic cells. Emerging studies show that m⁶A in noncoding RNAs makes a difference, and the aberrant expression of m⁶A‐associated enzymes may cause diseases. The demethylase alkB homologue 5 (ALKBH5) plays diverse roles in different cancers, but its role during gastric cancer (GC) progression is not well known.Methods: The quantitative real‐time polymerase chain reaction, immunohistochemistry staining and western blotting assays were used to detect ALKBH5 expression in GC tissues and human GC cell lines. The function assays in vitro and xenograft mouse model in vivo were used to investigate the effects of ALKBH5 during GC progression. RNA sequencing, MeRIP sequencing, RNA stability and luciferase reporter assays were performed to explore the potential molecular mechanisms involved in the function of ALKBH5. RNA binding protein immunoprecipitation sequencing (RIP‐seq), RIP and RNA pull‐down assays were performed to examine the influence of LINC00659 on the ALKBH5–JAK1 interaction.Results: ALKBH5 was highly expressed in GC samples and associated with aggressive clinical features and poor prognosis. ALKBH5 promoted the abilities of GC cell proliferation and metastasis in vitro and in vivo. The m⁶A modification on JAK1 mRNA was removed by ALKBH5, which resulted in the upregulated expression of JAK1. LINC00659 facilitated ALKBH5 binding to and upregulated JAK1 mRNA depending on an m⁶A‐YTHDF2 manner. Silencing of ALKBH5 or LINC00659 disrupted GC tumourigenesis via the JAK1 axis. JAK1 upregulation activated the JAK1/STAT3 pathway in GC.Conclusion: ALKBH5 promoted GC development via upregulated JAK1 mRNA expression mediated by LINC00659 in an m⁶A‐YTHDF2‐dependent manner, and targeting ALKBH5 may be a promising therapeutic method for GC patients.

Background:Coreopsis tinctoria Nutt. (CT), an annual herb in the genus Coreopsis, is an important traditional medicine to be used for antidiabetes and antioxidation.Objective: The antioxidant compounds from CT may affect mitochondrial function and apoptosis, which in turn may affect related diseases. The aim of this study was to explore the potential molecular mechanism and new therapeutic opportunities of CT based on network pharmacology.Methods: A network pharmacology-based method, which combined data collection, drug-likeness filtering, target prediction, disease prediction, and network analysis, was used to decipher the potential targets and new therapeutic opportunities of CT. The potential molecular mechanism and pathway were explored through Gene Ontology (GO) and KEGG analyses. Then MPTP-induced SH-SY5Y cell model was applied to evaluate the neuroprotective effects and key targets.Results: There were 1,011 targets predicted for 110 compounds. Most targets were regulated by flavones, phenylpropanoids, and phenols and had synergistic effects on memory impairment, pancreatic neoplasm, fatty liver disease, and so on. The compounds–targets–diseases network identified TNF, PTGS2, VEGFA, BCL2, HIF1A, MMP9, PIK3CG, ALDH2, AKT1, and EGFR as key targets. The GO and KEGG analyses revealed that the cell death pathway, mitochondrial energy metabolism, and PI3K-AKT signal pathway were the main pathways. CT showed neuroprotective effects via regulating gene and protein expression levels of key targets in an in vitro model.Conclusion: CT had potential neuroprotective effects by targeting multiple targets related with apoptosis, which were affected by the BCL-2 and AKT signaling pathways. This study provided a theoretical basis for the research of neuroprotective effects of CT.

Purpose: Several novel genetic variants for type 2 diabetes mellitus (T2DM) have been identified through genome-wide association studies (GWAS). A case-controll study was performed to investigate the association of five new European or South Asian GWAS-derived susceptibility loci with T2DM in a Chinese population. Methods: Five single nucleotide polymorphisms (SNPs) were genotyped: rs3923113 near GRB14, rs16861329 in ST6GAL1, rs1802295 in VPS26A, rs7178572 in HMG20A, and rs231362 near KCNQ1, by high-resolution melting (HRM) of small amplicons. The association between T2DM and related quantitative traits in a total of 900 Chinese individuals, including 498 type 2 diabetic patients and 402 ethnically matched control subjects, were examined. Results: After adjusting for age and gender, rs1802295 (OR 5.724, P=0.03) and rs231362 (OR=5.683, P=0.016) were found to be associated with T2DM. Triglyceride levels were higher in TT and CT carriers for rs16861329 (1.05 (0.8-1.34) mmol/l) than in CC carriers (0.91 (0.73-1.23) mmol/l) with P=0.008 and that high-density lipoprotein cholesterol (HDL-C) was lower in TT and CT carriers (1.17 (1.02-1.33) mmol/l) than in CC carriers (1.21 (1.05-1.41) mmol/l), with P=0.034. For rs3923113, the HDL-C levels were lower in the GG carriers (1.08 (0.90-1.18) mmol/l) than in the GT+TT carriers (1.21 (1.04-1.38) mmol/l), with P=0.018. Ours is the first report of this association. Conclusion: rs231362-KCNQ1 and rs1802295-VPS26A are associated with T2DM in the Chinese population. The remaining three SNPs are associated with other aspects of lipid metabolism.