Cimifugin improves intestinal barrier dysfunction by upregulating SIRT1 to regulate the NRF2/HO-1 signaling pathway.

Irritable bowel syndrome (IBS) is a prevalent gastrointestinal dysfunction. Cimifugin is an active component of Radix saposhnikoviae which is effective for maintaining intestinal barrier integrity and intestinal function. This study aimed to investigate the treatment efficacy of Cimifugin on intestinal barrier dysfunction and to unveil the relevant mechanism through network pharmacology and experimental verification as well as molecular docking. Through SuperPred and Pubchem databases, the targets of Cimifugin were obtained. The disease targets were screened using Disgenet and GEO databases. With STRING database and Cytoscape software, the analysis of PPI network was performed. In DAVID database, the hub genes of Cimifugin were analyzed using GO and Pathway enrichment analyses. To validate the binding of Cimifugin with core targets, molecular docking was performed. The in vitro cellular model of intestinal barrier was established via the induction of Caco2 cells with LPS. TEER was used to detect epithelial barrier function and permeability was measured using FITC-dextran (FD4). Western blotting was used to measure the expressions of SIRT1, tight junction proteins, and NRF2/HO-1 signaling pathway-related proteins. The fluorescence intensity of ZO-1, Occludin, and Claudin-1 was detected using immunofluorescence staining. ELISA was used to detect the expression levels of inflammatory cytokines. Through the integration of all targets of IBS and Cimifugin, 94 frequent drug-disease-related targets were identified. These targets were enriched in some signaling pathways, like cellular responses to stress, cellular responses to stimuli, and VEGFA-VEGFR2. Ten hub genes including PTGS2, ANPRP, TGFB1, ACACA, SIRT1, NEF2L2, APEX1, IL6, AKT1, and HSP90AB1 were obtained. Cimifugin showed strong affinity with four key genes, including AKT1, SIRT1, IL6, and NFE2L2 (NRF2), which were obtained through the intersection of hug genes with cellular responses to stimuli. In vitro experiments showed that Cimifugin ameliorated LPS-induced intestinal barrier injury in Caco2 cells via upregulating SIRT1 to modulate NRF2/HO-1 signaling pathway. Cimifugin could alleviate intestinal barrier dysfunction in IBS by upregulating SIRT1 to regulate the NRF2/HO-1 signaling pathway.

Clinical efficacy of lenvatinib, trans-arterial chemoembolization, and PD-1/L1 inhibitors in advanced hepatocellular carcinoma: a systematic review and network meta-analysis.

BACKGROUND: Currently, the effectiveness of TACE, Lenvatinib, and PD-1/L1 inhibitors used alone or in combination has been thoroughly reported. However, the differences in effectiveness between these treatment protocols require further verification. To this end, this study employs a Bayesian network meta-analysis to compare the efficacy and safety of TACE, Lenvatinib, and PD-1/L1 inhibitors, whether administered by monotherapy or in combination, providing evidence-based medicine for the treatment of unresectable HCC. PURPOSE: This study employed a network meta-analysis to evaluate the efficacy and safety of trans-arterial chemoembolization (TACE), Programmed Cell Death Protein/Ligand 1 (PD-1/L1) inhibitors, and Lenvatinib in the treatment of advanced HCC. METHODS: Literature on the treatment of advanced HCC with TACE, PD-1/L1 inhibitors, and Lenvatinib was searched for in both Chinese and English databases, including PubMed, EMBASE, ClinicalTrials.gov, Cochrane Library, CNKI, and Wanfang. Two researchers conducted independent screening and data extraction, and the meta-analysis was performed using R language with the gemtc package. RESULTS: After retrieval and screening, a total of 21 articles were included, involving 2052 participants and six treatment modalities: Lenvatinib (L), TACE (T), TACE + Lenvatinib (TL), Lenvatinib + PD-1/L1 inhibitors (LP), TACE + Lenvatinib + PD-1/L1 inhibitors (TLP), and TACE + PD-1/L1 inhibitors (TP). In terms of objective response rate (ORR), the TLP regimen provided the optimal effect. In predicting the best ORR, TLP had the highest (75.5%) probability. In terms of disease control rate (DCR), the TLP regimen showed the best effect. In predicting the best DCR, the TLP again offered the highest (76.1%) probability. In terms of overall survival (OS), the best outcome was observed in the TLP protocol. In predicting the best OS, the TLP holds the highest (86.00%) probability. Furthermore, the best outcome in progression-free survival (PFS) was found in the TLP regimen. In predicting the best PFS, the TLP still holds the highest (97.0%) result. CONCLUSION: The combination of TACE, Lenvatinib, and PD-1/L1 inhibitors appears to provide the maximum benefit for inoperable HCC patients.

Ursolic acid targets secreted phosphoprotein 1 to regulate Th17 cells against metabolic dysfunction-associated steatotic liver disease.

BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become an increasingly important health challenge, with a substantial rise linked to changing lifestyles and global obesity. Ursolic acid, a natural pentacyclic triterpenoid, has been explored for its potential therapeutic effects. Given its multifunctional bioactive properties, this research further revealed the pharmacological mechanisms of ursolic acid on MASLD. METHODS: Drug target chips and bioinformatics analysis were combined in this study to explore the potential therapeutic effects of ursolic acid on MASLD. Molecular docking simulations, surface plasmon resonance analyses, pull-down experiments, and co-immunoprecipitation assays were used to verify the direct interactions. Gene knockdown mice were generated, and high-fat diets were used to validate drug efficacy. Furthermore, initial CD4+ T cells were isolated and stimulated to demonstrate our findings. RESULTS: In this study, the multifunctional extracellular matrix phosphorylated glycoprotein secreted phosphoprotein 1 (SPP1) was investigated, highlighting its capability to induce Th17 cell differentiation, amplifying inflammatory cascades, and subsequently promoting the evolution of MASLD. In addition, this study revealed that in addition to the canonical TGF-ß/IL-6 cytokine pathway, SPP1 can directly interact with ITGB1 and CD44, orchestrating Th17 cell differentiation via their joint downstream ERK signaling pathway. Remarkably, ursolic acid intervention notably suppressed the protein activity of SPP1, suggesting a promising avenue for ameliorating the immunoinflammatory trajectory in MASLD progression. CONCLUSION: Ursolic acid could improve immune inflammation in MASLD by modulating SPP1-mediated Th17 cell differentiation via the ERK signaling pathway, which is orchestrated jointly by ITGB1 and CD44, emerging as a linchpin in this molecular cascade.