Fan-Biao Kong

Advanced gastric cancer is frequently refractory to therapy because of multidrug resistance and apoptotic escape. BCL2 and SIVA1 are core apoptosis regulat

The aim of the present study was to investigate the effects of SIVA‑1 silencing on the drug resistance and biological functions of cisplatin (DDP)‑resistant human gastric cancer cells (AGS/DDP), and to explore the mechanism underlying its occurrence. AGS/DDP cells with stable silencing of SIVA‑1 were established by molecular biology techniques. The Cell Counting Kit‑8 assay was used to investigate the effect of SIVA‑1 silencing on drug sensitivity in AGS/DDP cells by measuring the IC₅₀ of Adriamycin, DDP and vincristine. The findings demonstrated that the suppression of SIVA‑1 in AGS/DDP cells markedly augmented the resistance to DDP. In addition, cell proliferation, cell migration, cell invasion and cell apoptosis were assessed using colony formation, cell scratch, Transwell and cell apoptosis assays, respectively. The results of these assays demonstrated that silencing SIVA‑1 notably increased the proliferation, migration and invasion of AGS/DDP cells, while concurrently inhibiting their apoptosis. Furthermore, the effects of SIVA‑1 silencing on drug‑resistant gastric cancer cells in vivo were confirmed using a subcutaneous xenograft model in nude mice. The results demonstrated that silencing SIVA‑1 led to a notable increase in tumor volume, growth rate and weight. The bioinformatics analyses results indicated that SIVA‑1 may have an interactive relationship with Bcl‑2, BAX, X‑linked inhibitor of apoptosis protein (XIAP), MAPK8 and baculoviral inhibitor of apoptosis repeat‑containing 5 (BIRC5), and could participate in the mitochondria‑dependent apoptosis pathway. The results of reverse transcription‑quantitative PCR and western blotting indicated that silencing SIVA‑1 in AGS/DDP cells promoted the expression levels of Bcl‑2, XIAP, MAPK8 and BIRC5, and inhibited the expression levels of BAX. In conclusion, silencing SIVA‑1 has been shown to modify sensitivity to DDP and biological function in drug‑resistant gastric cancer cells, either directly or indirectly. This phenomenon may be associated with the Bcl‑2/BAX‑mediated, mitochondria‑dependent apoptosis pathway.

This research investigates the causal relationships among gut microbiota, inflammatory proteins, and inflammatory bowel disease (IBD), including crohn disease (CD) and ulcerative colitis (UC), and identifies the role of inflammatory proteins as potential mediators. Our study analyzed gut microbiome data from 13,266 samples collected by the MiBioGen alliance, along with inflammatory protein data from recent research by Zhao et al, and genetic data on CD and UC from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). We used Mendelian randomization (MR) to explore the associations, complemented by replication, meta-analysis, and multivariable MR techniques for enhanced accuracy and robustness. Our analysis employed several statistical methods, including inverse-variance weighting, MR-Egger, and the weighted median method, ensuring comprehensive and precise evaluation. After MR analysis, replication and meta-analysis, we revealed significant associations between 11 types of gut microbiota and 17 inflammatory proteins were associated with CD and UC. Mediator MR analysis and multivariable MR analysis showed that in CD, the CD40L receptor mediated the causal effect of Defluviitaleaceae UCG-011 on CD (mediation ratio 8.3%), and the Hepatocyte growth factor mediated the causal effect of Odoribacter on CD (mediation ratio 18%). In UC, the C-C motif chemokine 4 mediated the causal effect of Ruminococcus2 on UC (mediation ratio 4%). This research demonstrates the interactions between specific gut microbiota, inflammatory proteins, and CD and UC. Furthermore, the CD40L receptor may mediate the relationship between Defluviitaleaceae UCG-011 and CD; the Hepatocyte growth factor may mediate the relationship between Odoribacter and CD; and the C-C motif chemokine 4 may mediate the relationship between Ruminococcus2 and UC. The identified associations and mediation effects offer insights into potential therapeutic approaches targeting the gut microbiome for managing CD and UC.

Background Prior investigations have indicated a link between metabolic disorders and immune-mediated bowel disease (IBD). Nevertheless, a conclusive causal relationship between metabolites and the facilitation or prevention of IBD remains elusive. Therefore, the primary aim of this study is to evaluate the causal association between 486 blood metabolites and IBD using a two-sample multivariable Mendelian randomization analysis. Method This research employed a genome-wide association study (GWAS) of 486 metabolites as the exposure, with inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC) as the outcomes. Causal analysis predominantly utilized the inverse variance-weighted (IVW) method, complemented by MR-Egger and weighted median analysis methods. Rigorous sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, MR-presso, and leave-one-out analysis, were conducted to ensure the robustness of the results. Moreover, reverse MR and LD score regression (LDSC) analyses were performed to address concerns related to reverse causation, genetic correlation, and linkage disequilibrium (LD). To directly assess the impact of metabolites on IBD, a multivariable MR approach was employed. Additionally, metabolic pathway analysis was carried out using the web-based tool MetaboAnalyst 5.0. All statistical analyses were executed using R software, guaranteeing the rigor and accuracy of the study's findings. Result In this comprehensive MR analysis, we identified a total of 45 metabolites showing significant associations with various IBD phenotypes. By conducting complementary and sensitivity analyses, we identified 4, 8, and 4 metabolites that demonstrated noteworthy correlations with IBD, CD, and UC, respectively. Furthermore, our metabolic pathway analysis unveiled 8 essential metabolic pathways shared between IBD and CD phenotypes. These findings offer valuable insights into the potential contribution of specific metabolites and pathways to the development of IBD and its subtypes, providing potential targets for further research and therapeutic interventions. Conclusion Our study findings indicate that the identified metabolites and metabolic pathways hold promise as reliable circulating metabolic biomarkers for clinical screening and prevention of IBD. Additionally, they represent potential candidate molecules for further mechanistic investigations in future research.

Background Inflammation is intricately intertwined with cancer progression; however, the causal link between inflammatory factors and their propensity to either promote or mitigate colorectal cancer (CRC) remains substantively unexplored. In response to this knowledge gap, we undertook a bidirectional Mendelian randomization (MR) analysis, aimed at rigorously evaluating the causal relationship between 41 distinct genetic proxies representing inflammatory factors and the development of colorectal cancer. Method Cytokine levels were analyzed in a cohort of 8,293 individuals using data from a genome-wide association study (GWAS) focusing on exposures. Preliminary analysis made use of GWAS data related to colorectal cancer (CRC) obtained from the GWAS catalog database with accession number GCST012879. Causality analysis primarily employed the random inverse variance weighted (IVW) method, supplemented by MR-Egger and weighted median techniques. To enhance the study's robustness, sensitivity analyses encompassed the Cochran Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis. Employing a comprehensive approach encompassing Mendelian Randomization, Linkage Disequilibrium Score Regression, and Colocalization Analysis, the study examined cytokines that exhibited statistical significance in the IVW analysis. Moreover, a Confounding Analysis was conducted to evaluate the direct impact of cytokines on CRC occurrence. Result The findings of this study demonstrate a significant association between Interferon-gamma (OR = 1.13, 95% CI = 1.01–1.28, p = 0.039), Tumor Necrosis Factor-beta (OR = 1.07, 95% CI = 1.01–1.14, p = 0.032), Interleukin-2 Receptor Alpha Subunit (OR = 0.93, 95% CI = 0.86–0.99, p = 0.035), and Stem Cell Factor (OR = 0.88, 95% CI = 0.79–0.98, p = 0.023) and CRC. Conclusion This study presents compelling evidence regarding the causal interplay between four specific inflammatory factors and colorectal cancer. Furthermore, the multifaceted analyses employed introduce fresh insights into our understanding of the role played by colorectal cancer. These discoveries hold promising implications for enhancing CRC screening, prevention, and therapeutic strategies.

Background: Several studies give a superficial description that HEPACAM family member 2 (HEPACAM2) seems to be a prognostic biomarker in colon adenocarcinoma (COAD). While, systematic and in-depth research about diagnostic and prognostic value of HEPACAM2 in COAD patients is lacked. Besides, relationship between HEPACAM2 gene expression levels and immune cell infiltration is unclear. Methods: Firstly, we analyzed the differential expression levels of HEPACAM2 gene and diagnostic value from different databases. Secondly, a cohort of Guangxi COAD patients was established to verify HEPACAM2 expression pattern and diagnostic value. Thirdly, univariate and multivariate survival analysis of the prognostic value of HEPACAM2 gene in patients with COAD was performed. We also utilized joint-effects analysis and comprehensive prognosis analysis to investigate the prognostic value of HEPACAM2 and related genes. Finally, we explored the relationship between HEPACAM2 gene expression levels and immune cell infiltration.Results: In several biological databases, HEPACAM2 mRNA expression level in COAD tumor tissues was significantly lower than that of adjacent normal tissues. The diagnostic ROC curve results indicated that HEPACAM2 gene had a high diagnostic value in COAD. The qPCR verification results in the Guangxi cohort showed that HEPACAM2 expression level in COAD tumor tissues was significantly lower than that of adjacent normal tissues (PHEPACAM2 gene had a poorer overall survival (OS) in COAD patients when compared with those with high expression ((P = 0.038, HR (95% CI) = 0.635(0.414-0.976)). Joint-effects analysis and comprehensive prognosis analysis showed that high expression of HEPACAM2 combined with high expression of CLCA1, high expression of REP15, and high expression of B3GNT6 were associated with a better overall survival of COAD.Conclusion: This study suggested that the HEPACAM2 may be a diagnostic and prognostic biomarker for COAD. Besides, HEPACAM2 was involved with immune response progress, Chemokine signaling pathway, Ras signaling pathway and Hematopoietic cell lineage.