Inhibition of autophagy improves resistance and enhances sensitivity of gastric cancer cells to cisplatin

Autophagy plays critical roles in tumorigenesis, while the effects of autophagy on chemoresistance of cancer cells had great disparity. This study aims to explore the impacts of autophagy on the sensitivity and resistance of gastric cancer cells to cisplatin (DDP). We firstly demonstrated that there was stronger autophagy activity in gastric cancer SGC-7901 cells than that in DDP-resisting SGC-7901/DDP cells. Then, we discovered that inhibiting autophagy by chloroquine (CQ) significantly enhanced the proliferation-inhibiting and apoptosis-inducing effects of DDP to SGC-7901 and SGC-7901/DDP cells. Moreover, CQ could partially reverse the resistance of SGC-7901/DDP cells to DDP in a concentration-dependent manner. However, the autophagy inducer everolimus (RAD001) had no obvious effects on the sensitivity of gastric cells to DDP. Mechanistically, we demonstrated that CQ might enhance the sensitivity of SGC-7901cells and improve the resistance of SGC-7901/DDP cells to DDP through inhibiting the mTORC1 pathway, especially to SGC-7901/DDP cells. Additionally, we found interfering Beclin-1 using Beclin-1 shRNA also enhanced the proliferation-inhibiting and apoptosis-inducing effects of DDP on gastric cancer cells by inhibiting phosphorylation of Akt. Our study shows that inhibiting autophagy could improve the chemoresistance and enhanced sensitivity of gastric cancer cells to DDP and provide a rationale for the administration of cisplatin combined with CQ for treating patients with gastric cancer.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Efficacy of tenofovir in preventing perinatal transmission of HBV infection in pregnant women with high viral loads

Abstract Mother-to-child transmission is the major cause of chronic hepatitis B virus (HBV) infection. This double-blind trial tested the effect of tenofovir disoproxil fumarate (TDF) in preventing vertical transmission. Pregnant women who were HBsAg/HBeAg-positive with a HBV DNA titer ≥ 2×106 IU/mL were randomly assigned to the control (n = 60) and TDF-treated (n = 60) groups. TDF treatment (oral dose 300 mg/day) was initiated at 24 weeks of gestation and continued to 4 weeks after delivery. The subjects were followed up to 28 weeks postpartum. The effects of TDF on vertical transmission, outcomes of the mothers and infants and virological changes were monitored. TDF dynamically reduced the serum HBV DNA level of the mothers, particularly during the first 4 weeks of treatment. The lower viral loads were maintained in the pregnancies until delivery. Approximately 90% and 33.9% of the TDF-treated mothers had viral loads ≤2000 IU/mL after delivery and at 28 weeks postpartum, respectively. No cervical transmission or adverse effects were observed in the TDF-treated individuals, whereas 13.5% of the infants were infected with HBV in the control group. We conclude that TDF treatment initiated at 24 weeks of gestation in high-viremia, HBsAg/HBeAg-positive mothers efficiently prevents mother-to-child HBV transmission without adverse events in mothers and infants

A Transcriptomic Regulatory Network among miRNAs, lncRNAs, circRNAs, and mRNAs Associated with L-leucine-induced Proliferation of Equine Satellite Cells

In response to muscle injury, muscle stem cells are stimulated by environmental signals to integrate into damaged tissue to mediate regeneration. L-leucine (L-leu), a branched-chain amino acid (BCAA) that belongs to the essential amino acids (AAs) of the animal, has gained global interest on account of its muscle-building and regenerating effects. The present study was designed to investigate the impact of L-leu exposure to promote the proliferation of equine skeletal muscle satellite cells (SCs) on the regulation of RNA networks, including mRNA, long non-coding RNA (lncRNA), covalently closed circular RNA (circRNA), and microRNA (miRNA) in skeletal muscles. Equine SCs were used as a cell model and cultured in different concentrations of L-leu medium. The cell proliferation assay found that the optimal concentration of L-leu was 2 mM, so we selected cells cultured with L-leu concentrations of 0 mM and 2 mM for whole-transcriptiome sequencing, respectively. By high-throughput sequencing analysis, 2470 differentially expressed mRNAs (dif-mRNAs), 363 differentially expressed lncRNAs (dif-lncRNAs), 634 differentially expressed circRNAs (dif-circRNAs), and 49 differentially expressed miRNAs (dif-miRNAs) were significantly altered in equine SCs treated with L-leu. To identify the function of autoimmunity and anti-inflammatory responses after L-leu exposure, enrichment analysis was conducted on those differentially expressed genes (DEGs) related to lncRNA, circRNA, and miRNA. The hub genes were selected from PPI Network, including ACACB, HMGCR, IDI1, HAO1, SHMT2, PSPH, PSAT1, ASS1, PHGDH, MTHFD2, and DPYD, and were further identified as candidate biomarkers to regulate the L-leu-induced proliferation of equine SCs. The up-regulated novel 699_star, down-regulated novel 170_star, and novel 360_mature were significantly involved in the competing endogenous RNA (ceRNA) complex network. The hub genes involved in cell metabolism and dif-miRNAs may play fundamental roles in the L-leu-induced proliferation of equine SCs. Our findings suggested that the potential network regulation of miRNAs, circ-RNAs, lncRNAs, and mRNAs plays an important role in the proliferation of equine SCs, so as to build up new perspectives on improving equine performance and treatment strategies for the muscle injuries of horses

Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model

Abstract Background We previously performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China (ACGC) (phase I). Here, we expand this analysis to a larger cohort of patients (ACGC phase II) to better understand the prevalence, inheritance, and genotype–phenotype correlations of likely gene-disrupting (LGD) mutations for autism candidate genes originally identified in cohorts of European descent. Methods We sequenced 187 autism candidate genes in an additional 784 probands and 85 genes in 599 probands using single-molecule molecular inversion probes. We tested the inheritance of potentially pathogenic mutations, performed a meta-analysis of phase I and phase II data and combined our results with existing exome sequence data to investigate the phenotypes of carrier parents and patients with multiple hits in different autism risk genes. Results We validated recurrent, LGD, de novo mutations (DNMs) in 13 genes. We identified a potential novel risk gene (ZNF292), one novel gene with recurrent LGD DNMs (RALGAPB), as well as genes associated with macrocephaly (GIGYF2 and WDFY3). We identified the transmission of private LGD mutations in genes predominantly associated with DNMs and showed that parental carriers tended to share milder autism-related phenotypes. Patients that carried DNMs in two or more candidate genes show more severe phenotypes. Conclusions We identify new risk genes and transmission of deleterious mutations in genes primarily associated with DNMs. The fact that parental carriers show milder phenotypes and patients with multiple hits are more severe supports a multifactorial model of risk