Hepatocellular carcinoma (HCC) is a widespread, common type of cancer in Asian countries, and the need for biomarker-matched molecularly targeted therapy for HCC has been increasingly recognized. However, the effective treatment for HCC is unclear. Therefore, identifying additional hub genes and pathways as novel prognostic biomarkers for HCC is necessary. In this study, the expression profiles of GSE121248, GSE45267 and GSE84402 were obtained from the Gene Expression Omnibus (GEO), including 132 HCC and 90 noncancerous liver tissues. Differentially expressed genes (DEGs) between HCC and noncancerous samples were identified by GEO2 R and Venn diagrams. In total, 109 DEGs were identified in these datasets, including 24 upregulated genes and 85 downregulated genes. Subsequently, Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) preliminary analyses of the DEGs were performed using DAVID. The protein–protein interaction (PPI) network of the DEGs was constructed with the Search Tool for the Retrieval of Interacting Genes (STRING) and visualized in Cytoscape. Module analysis of the PPI network was performed using MCODE to get hub genes. Moreover, the influence of the hub genes on overall survival was determined with Kaplan–Meier plotter. All hub genes were analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) and KEGG. Overall, the hub genes DTL, CDK1, CCNB1, RACGAP1, ECT2, NEK2, BUB1B, PBK, TOP2A, ASPM, HMMR, RRM2, CDKN3, PRC1, and ANLN were upregulated in HCC, and the survival rate was lower for HCC with increased expression of these hub genes. CCNB1, CDK1, and RRM2 were enriched in the p53 signaling pathway, and CCNB1, CDK1, and BUB1B were enriched in the cell cycle. In brief, we screened 15 hub genes and pathways to identify potential prognostic markers for HCC treatment. However, the specific occurrence and development of HCC with expression of the hub genes should be verified in vivo and in vitro.

Objective: The dietary index for gut microbiota (DI-GM) is a newly proposed metric for assessing diet quality, and its relationship with biological age is unclear. We hypothesize that consuming foods conducive to a healthy gut microbiota environment may decelerate aging. Methods: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) spanning the years 2007 to 2018. The DI-GM was calculated by averaging the intakes from two 24-h dietary recall interviews. The biological age indicators were assessed using the Klemera–Doubal Method (KDM), phenotypic age (PA), and homeostasis disorder (HD). Logistic regression, restricted cubic splines (RCS), and mediation analysis were employed to explore the association between DI-GM and KDM, PA, and HD. Results: The study included 20,671 participants. According to the logistic regression model, adjusting for all covariates, a negative association was observed between the DI-GM score and biomarkers of biological aging. Compared to participants in the lowest quartile for DI-GM scores, those in the highest quartile exhibited reduced odds ratio (OR) for all of the biological age indicators, namely biological age assessed via KDM (OR: 0.69, 95% CI: 0.60–0.79), PA (OR: 0.84, 95% CI: 0.73–0.97), and HD (OR: 0.86, 95% CI: 0.76–0.98). Additionally, RCS analysis revealed a nonlinear association between DI-GM and biological age. Mediation analysis showed that the body mass index (BMI) partly mediated the association between DI-GM and biological age. Conclusions: Therefore, we concluded that a higher DI-GM score is associated with a lower risk of accelerated aging, with BMI mediating this association. Future research should validate these findings through the use of longitudinal studies.

Hepatic insulin resistance (IR) plays a crucial role in the development of many metabolic diseases, such as type 2 diabetes. MicroRNAs (miRNAs) are involved in the pathogenesis of IR and related diseases; however, studies of miRNAs in hepatic IR are limited. In this study, we adopted a high-throughput sequencing approach to construct small RNA libraries in the livers of normal mice and high-fat diet-induced hepatic IR mice. Through analysis of data, 107 known and 56 novel miRNAs were identified as differentially expressed miRNAs between the two groups. Additionally, bioinformatics methods were used to predict targets of the differentially expressed miRNAs and to explore the potential downstream Gene Ontology categories and Kyoto Encyclopedia of Genes and Genomes pathways. Meanwhile, some differentially expressed miRNAs (miR-34a-5p, miR-149-5p, miR-335-3p, miR-10b-5p, miR-1a-3p, miR-411-5p, and miR-592-5p) were validated by quantitative-time PCR, and their potential target genes related to IR or glycolipid metabolism were also predicted and presented in this study. Taken together, our results defined miRNA expression signature that may lead to hepatic IR in mice, and the findings provided a foundation for future studies to further explore the effects and underlying mechanisms of the miRNAs and their target genes in the pathogenesis of hepatic IR and related diseases.

The detrimental role of hepatic lipotoxicity has been well-implicated in the pathogenesis of NAFLD. Previously, we reported that inhibiting autophagy aggravated saturated fatty acid (SFA)-induced hepatotoxicity. Insulin, a physiological inhibitor of autophagy, is commonly increased within NAFLD mainly caused by insulin resistance. We therefore hypothesized that insulin augments the sensitivity of hepatocyte to SFA-induced lipotoxicity. The present study was conducted via employing human and mouse hepatocytes, which were exposed to SFAs, insulin, or their combination. Unexpectedly, our results indicated that insulin protected hepatocytes against SFA-induced lipotoxicity, based on the LDH, MTT, and nuclear morphological measurements, and the detection from cleaved-Parp-1 and -caspase-3 expressions. We subsequently clarified that insulin led to a rapid and short-period inhibition of autophagy, which was gradually recovered after 1 h incubation in hepatocytes, and such extent of inhibition was insufficient to aggravate SFA-induced lipotoxicity. The mechanistic study revealed that insulin-induced alleviation of ER stress contributed to its hepatoprotective role. Pre-treating hepatocytes with insulin significantly stimulated phosphorylated-Akt and reversed SFA-induced up-regulation of p53. Chemical inhibition of p53 by pifithrin-α robustly prevented palmitate-induced cell death. The PI3K/Akt pathway blockade by its special antagonist abolished the protective role of insulin against SFA-induced lipotoxicity and p53 up-regulation. Furthermore, we observed that insulin promoted intracellular TG deposits in hepatocytes in the present of palmitate. However, blocking TG accumulation via genetically silencing DGAT-2 did not prevent insulin-protected lipotoxicity. Our study demonstrated that insulin strongly protected against SFA-induced lipotoxicity in hepatocytes mechanistically through alleviating ER stress via a PI3K/Akt/p53 involved pathway but independently from autophagy.