Vibrio cholerae , a noninvasive bacterium, colonizes the intestinal epithelium and secretes cholera toxin (CT), a potent enterotoxin that causes the severe fluid loss characteristic of the disease cholera. In this study, we demonstrate that adherence of V. cholerae to the intestinal epithelial cell line INT 407 strongly induces the expression of the major virulence genes ctxAB and tcpA and the virulence regulatory gene toxT . No induction of toxR and tcpP , which encode transcriptional activators of toxT , was observed in adhered bacteria, and the adherence-dependent upregulation of toxT expression was independent of ToxR and TcpP. A sharp increase in the expression of the vieA gene, which encodes a cyclic di-GMP (c-di-GMP) phosphodiesterase, was observed in INT 407-adhered V. cholerae immediately after infection. Induction of toxT , ctxAB , and tcpA in INT 407-adhered vieA mutant strain O395 Δ vieA was consistently lower than in the parent strain, although no effect was observed in unadhered bacteria, suggesting that VieA has a role in the upregulation of toxT expression specifically in host cell-adhered V. cholerae . Furthermore, though VieA has both a DNA binding helix-turn-helix domain and an EAL domain conferring c-di-GMP phosphodiesterase activity, the c-di-GMP phosphodiesterase activity of VieA is necessary and sufficient for the upregulation of toxT expression.

Nutrient surplus and consequent free fatty acid accumulation in the liver cause hepatosteatosis. The exposure of free fatty acids to cultured hepatocyte and hepatocellular carcinoma cell lines induces cellular stress, organelle adaptation, and subsequent cell death. Despite many studies, the mechanism associated with lipotoxicity and subsequent cell death still remains poorly understood. Here, we have used the proteomics approach to circumvent the mechanism for lipotoxicity using hepatocellular carcinoma cells as a model. Our quantitative proteomics data revealed that ectopic lipids accumulation in cells severely affects the ubiquitin-proteasomal system. The palmitic acid (PA) partially lowered the expression of deubiquitinating enzyme USP7 which subsequently destabilizes p53 and promotes mitotic entry of cells. Our global phosphoproteomics analysis also provides strong evidence of an altered cell cycle checkpoint proteins’ expression that abrogates early G2/M checkpoints recovery with damaged DNA and induced mitotic catastrophe leading to hepatocyte death. We observe that palmitic acid prefers apoptosis-inducing factor (AIF) mediated cell death by depolarizing mitochondria and translocating AIF to the nucleus. In summary, the present study provides evidence of PA-induced hepatocellular death mediated by deubiquitinase USP7 downregulation and subsequent mitotic catastrophe.

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease leading to continuous mucosal inflammation in the rectum extending proximally towards the colon. Chronic and/or recurrent UC is one of the critical predisposing mediators of the oncogenesis of human colorectal carcinoma (CRC). Perturbations of the differential expression of the UC-critical genes exert an intense impact on the neoplastic transformation of the affected tissue(s). Herein, a comprehensive exploration of the UC-critical genes from the transcriptomic profiles of UC patients was conducted to study the differential expression, functional enrichment, genomic alterations, signal transduction pathways, and immune infiltration level encountered by these genes concerning the oncogenesis of CRC. The study reveals that WFDC2, TTLL12, THRA, and EPHB3 play crucial roles as UC-CRC critical genes and are positively correlated with the molecular transformation of UC to CRC. Taken together, these genes can be used as potential biomarkers and therapeutic targets for combating UC-induced human CRC.