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Background and purpose: Gastric cancer is one of the common gastrointestinal malignancies. FKBP1A has been reported to be involved in the occurrence and development of various tumors, but the biological role and mechanism of it in gastric cancer remain unclear. This study aimed to investigate the expression level and prognostic value of FKBP1A in gastric cancer tissues, and to analyze the possible pathways and mechanisms of its regulation of gastric cancer progression. Methods: The expression of FKBP1A in gastric cancer was observed by immunohistochemistry, and its correlation with poor prognosis was analyzed by combining bioinformatics and clinicopathological parameters. Kaplan-Meier survival curve was used to analyze the effect of FKBP1A on the 5-year survival rate of patients with gastric cancer after surgery, and COX multivariate regression analysis was used to explore the independent prognostic factors affecting the 5-year survival rate of patients with gastric cancer after surgery. The diagnostic value of FKBP1A expression in patients with gastric cancer was analyzed using receiver operating characteristic (ROC) curve. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to enrich and analyze the biological function of FKBP1A and the possible signal pathways involved. We constructed the MGC803 cell model transfected with lentivirus in vitro, explored the influence of FKBP1A on the glucose metabolism and malignant biological behavior of MGC803 cells, and the possible molecular mechanism involved, and established a nude mouse transplantation tumor model in vitro to verify it. Results: Immunohistochemical results showed that FKBP1A was highly expressed in gastric cancer (P

Background and aims: Patients with Crohn's disease (CD) exhibit excessive apoptosis of intestinal epithelial cells (IECs), which contributes to damage to the intestinal barrier structure and function, thereby playing a role in the progression of colitis. Preventing IEC apoptosis and protecting the intestinal barrier are critical to alleviating colitis. Natural plant monomers have been reported to possess multiple pharmacological properties, particularly with the potential to treat CD. This study focuses on Cynaroside (Cyn) to explore its effect on IEC apoptosis and evaluate its pharmacological impact on the intestinal barrier and colitis. Methods: The 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced CD-like colitis mice model was employed in this study. We assessed the therapeutic effect of Cyn on CD-like colitis by evaluating the disease activity index (DAI), body weight changes, intestinal tissue pathological damage, and inflammatory factor levels. Immunofluorescence and Western blotting were used to detect the expression and localization of tight junction (TJ) proteins, allowing us to analyze the intestinal barrier structure. The function of the intestinal barrier was examined using FITC-dextran (FD4), TEER values, and bacterial translocation. Network pharmacology enrichment analysis revealed that Cyn could inhibit cell apoptosis. We also explored the effect and underlying mechanism of Cyn in inhibiting IEC apoptosis on intestinal barrier function and colitis using both the TNF-α-induced colonic organoid model and the TNBS-induced mouse model. Results: Our findings show that Cyn significantly alleviates TNBS-induced colitis symptoms in mice, as evidenced by reduced body weight loss, colon shortening, DAI score, colon histopathology score, and lower levels of inflammatory factors (IL-1β, TNF-α, and IL-6) compared to the model group. Additionally, the Cyn intervention group showed significant improvements in both the intestinal barrier structure (elevated tight junction protein levels and proper localization) and function (reduced serum FD4 levels, increased intestinal TEER, and decreased bacterial translocation rates in mesenteric lymph nodes [MLNs] and livers). Combining network pharmacology prediction analysis with our validation data from animal models and colonic organoids, we demonstrated that Cyn significantly inhibits IEC apoptosis, as indicated by a decrease in the proportion of TUNEL-positive cells and changes in apoptosis-related protein levels. KEGG enrichment analysis and signaling pathway intervention experiments confirmed that Cyn inhibits the activation of PI3K/AKT signaling. Conclusion: Cyn inhibits IEC apoptosis by blocking the PI3K/AKT signaling pathway, which is the primary mechanism underlying its protective effects on the intestinal barrier and its ability to improve CD-like colitis. This study also supports the potential of the Chinese medicine monomer Cyn as a promising therapeutic agent for the treatment of CD. [ABSTRACT FROM AUTHOR]

Background and Aims Intestinal fibrotic stenosis is a major reason for surgery in Crohn's disease [CD], but the mechanism is unknown. Thus, we asked whether intestinal adipocytes contribute to intestinal fibrosis. Adipocytes were found to transdifferentiate into myofibroblasts and confirmed to be involved in mesenteric fibrosis in our recent study. Here, we investigated the role and possible mechanisms of intestinal adipocytes in intestinal fibrosis in CD. Methods The intestinal tissue of patients with CD with or without fibrotic stenosis [CDS or CDN] and normal intestinal tissue from individuals without CD were obtained to assess alterations in submucosal adipocytes in CDS and whether these cells transdifferentiated into myofibroblasts and participated in the fibrotic process. Human primary adipocytes and adipose organoids were used to evaluate whether adipocytes could be induced to transdifferentiate into myofibroblasts and to investigate the fibrotic behaviour of adipocytes. LPS/TLR4/TGF-β signalling was also studied to explore the underlying mechanism. Results Submucosal adipocytes were reduced in number or even absent in CDS tissue, and the extent of the reduction correlated negatively with the degree of submucosal fibrosis. Interestingly, submucosal adipocytes in CDS tissue transdifferentiated into myofibroblast-like cells and expressed collagenous components, possibly due to stimulation by submucosally translocated bacteria. Lipopolysaccharide [LPS]-stimulated human primary adipocytes and adipose organoids also exhibited transdifferentiation and profibrotic behaviour. Mechanistically, TLR4-mediated TGF-β signalling was associated with the transdifferentiation and profibrotic behaviour of intestinal adipocytes in CDS tissue. Conclusions Intestinal adipocytes transdifferentiate into myofibroblasts and participate in the intestinal fibrosis process in CD, possibly through LPS/TLR4/TGF-β signalling. [ABSTRACT FROM AUTHOR]

Excessive apoptosis of intestinal epithelial cells leads to intestinal barrier dysfunction, which is not only one of the pathological features of inflammatory bowel disease (IBD) but also a therapeutic target. A natural plant extract, Ginkgetin (GK), has been reported to have anti‐apoptotic activity, but its role in IBD is unknown. This study aimed to explore whether GK has anti‐colitis effects and related mechanisms. An experimental colitis model induced by dextran sulfate sodium (DSS) was established, and GK was found to relieve colitis in DSS‐induced mice as evidenced by improvements in weight loss, colon shortening, Disease Activity Index (DAI), macroscopic and tissue scores, and proinflammatory mediators. In addition, in DSS mice and TNF‐α‐induced colonic organoids, GK protected the intestinal barrier and inhibited intestinal epithelial cell apoptosis, by improving permeability and inhibiting the number of apoptotic cells and the expression of key apoptotic regulators (cleaved caspase 3, Bax and Bcl‐2). The underlying mechanism of GK's protective effect was explored by bioinformatics, rescue experiments and molecular docking, and it was found that GK might directly target and activate EGFR, thereby interfering with PI3K/AKT signaling to inhibit apoptosis of intestinal epithelial cells in vivo and in vitro. In conclusion, GK inhibited intestinal epithelial apoptosis in mice with experimental colitis, at least in part, by activating EGFR and interfering with PI3K/AKT activation, explaining the underlying mechanism for ameliorating colitis, which may provide new options for the treatment of IBD. [ABSTRACT FROM AUTHOR]