Telmisartan loading thermosensitive hydrogel repairs gut epithelial barrier for alleviating inflammatory bowel disease.

Inflammatory bowel disease (IBD) remains a global health concern with a complex and incompletely understood pathogenesis. In the course of IBD development, damage to intestinal epithelial cells and a reduction in the expression of tight junction (TJ) proteins compromise the integrity of the intestinal barrier, exacerbating inflammation. Notably, the renin-angiotensin system and angiotensin II receptor type 1 (AT1R) play a crucial role in regulating the pathological progression including vascular permeability, and immune microenvironment. Thus, Telmisartan (Tel), an AT1R inhibitor, loading thermosensitive hydrogel was constructed to investigate the potential of alleviating inflammatory bowel disease through rectal administration. The constructed hydrogel exhibits an advantageous property of rapid transformation from a solution to a gel state at 37°C, facilitating prolonged drug retention within the gut while mitigating irritation associated with rectal administration. Results indicate that Tel also exhibits a beneficial effect in ameliorating colon shortening, colon wall thickening, cup cell lacking, crypt disappearance, and inflammatory cell infiltration into the mucosa in colitis mice. Moreover, it significantly upregulates the expression of TJ proteins in colonic tissues thereby repairing the intestinal barrier damage and alleviating the ulcerative colitis (UC) disease process. In conclusion, Tel-loaded hydrogel demonstrates substantial promise as a potential treatment modality for IBD.

Identification of Pyroptosis-Relevant Signature in Tumor Immune Microenvironment and Prognosis in Skin Cutaneous Melanoma Using Network Analysis.

Background: Pyroptosis is closely related to the programmed death of cancer cells as well as the tumor immune microenvironment (TIME) via the host-tumor crosstalk. However, the role of pyroptosis-related genes as prognosis and TIME-related biomarkers in skin cutaneous melanoma (SKCM) patients remains unknown. Methods: We evaluated the expression profiles, copy number variations, and somatic mutations (CNVs) of 27 genes obtained from MSigDB database regulating pyroptosis among TCGA-SKCM patients. Thereafter, we conducted single-sample gene set enrichment analysis (ssGSEA) for evaluating pyroptosis-associated expression patterns among cases and for exploring the associations with clinicopathological factors and prognostic outcome. In addition, a prognostic pyroptosis-related signature (PPRS) model was constructed by performing Cox regression, weighted gene coexpression network analysis (WGCNA), and least absolute shrinkage and selection operator (LASSO) analysis to score SKCM patients. On the other hand, we plotted the ROC and survival curves for model evaluation and verified the robustness of the model through external test sets (GSE22153, GSE54467, and GSE65904). Meanwhile, we examined the relations of clinical characteristics, oncogene mutations, biological processes (BPs), tumor stemness, immune infiltration degrees, immune checkpoints (ICs), and treatment response with PPRS via multiple methods, including immunophenoscore (IPS) analysis, gene set variation analysis (GSVA), ESTIMATE, and CIBERSORT. Finally, we constructed a nomogram incorporating PPRS and clinical characteristics to improve risk evaluation of SKCM. Results: Many pyroptosis-regulated genes showed abnormal expression within SKCM. TP53, TP63, IL1B, IL18, IRF2, CASP5, CHMP4C, CHMP7, CASP1, and GSDME were detected with somatic mutations, among which, a majority displayed CNVs at high frequencies. Pyroptosis-associated profiles established based on pyroptosis-regulated genes showed markedly negative relation to low stage and superior prognostic outcome. Blue module was found to be highly positively correlated with pyroptosis. Later, this study established PPRS based on the expression of 8 PAGs (namely, GBP2, HPDL, FCGR2A, IFITM1, HAPLN3, CCL8, TRIM34, and GRIPAP1), which was highly associated with OS, oncogene mutations, tumor stemness, immune infiltration degrees, IC levels, treatment responses, and multiple biological processes (including cell cycle and immunoinflammatory response) in training and test set samples. Conclusions: Based on our observations, analyzing modification patterns associated with pyroptosis among diverse cancer samples via PPRS is important, which can provide more insights into TIME infiltration features and facilitate immunotherapeutic development as well as prognosis prediction.