Comparative Efficacy of Drug Interventions on NAFLD Over 24 Weeks: A Traditional and Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD), currently referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), affects approximately 38% of the world's population, yet no pharmacological therapies have been approved for treatment. We conducted a traditional and network meta-analysis to comprehensively assess the effectiveness of drug regimens on NAFLD, and continued to use the old terminology for consistency. METHODS: Randomized, placebo-controlled trials (RCTs) investigating drug therapy in an adult population diagnosed with NAFLD with or without diabetes mellitus were included. We assessed the quality of RCTs via the Risk of Bias 2 (ROB 2) tool. When I2 < 50%, we chose a random-effects model, otherwise a fixed-effects model was selected. A random effects model was applied in the network meta-analysis. The odds ratio (OR), weighted mean difference (WMD) or standard mean difference (SMD) with 95% confidence interval (CI) were used for outcome evaluation. The primary endpoint was the resolution of nonalcoholic steatohepatitis (NASH) without the worsening of liver fibrosis. Other endpoints included histological findings and metabolic changes. The PROSPERO Registration ID was CRD42023404309. RESULTS: Thiazolidinediones (TZDs), vitamin E plus pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists and fibroblast growth factor-21 (FGF-21) analogue had a higher surface under the cumulative ranking curve (SUCRA = 76.6, 73.0, 72.0 and 71.6) regarding NASH resolution. Improvement of liver fibrosis stage (≥ 1) was observed with obeticholic acid 25 mg/day (OR 2.01, 95% CI 1.35-2.98), lanifibranor 1200 mg/day (OR 2.39, 95% CI 1.19-4.82) and silymarin (OR 4.54, 95% CI 1.18-17.43) in traditional meta-analysis. CONCLUSIONS: The results of the comprehensive analysis suggested hypoglycemic drug therapy as an effective intervention for NAFLD, with or without diabetes mellitus. A prioritized selection of TZDs, vitamin E plus pioglitazone, GLP-1 receptor agonists and FGF-21 analogue may be considered for NASH resolution. Obeticholic acid, lanifibranor and silymarin could be considered for the improvement of liver fibrosis. Each medication was relatively safe compared with placebo.

PLGA microspheres carrying miR-20a-5p improved intestinal epithelial barrier function in patients with Crohn's disease through STAT3-mediated inhibition of Th17 differentiation.

BACKGROUND: Recent studies have shown that microRNAs (miRNAs) are aberrantly expressed in patients with Crohn's disease (CD). This suggests that the aberrant expression of miRNAs may contribute to the development of CD. Currently, the specific miRNAs involved in CD development have not been clearly identified. Therefore, we aimed to identify CD-associated miRNAs and explore their functions. METHODS: miRNA microarray analysis was performed to screen for differentially expressed miRNAs in colon tissues from normal controls (NC) and CD patients. The identified miRNAs were validated using quantitative real-time PCR (qPCR). The therapeutic roles of miR-20a-5p mimics via the delivery of poly(lactic-co-glycolic acid) microspheres (PLGA MSs) were further investigated in IL-10-/- mice with spontaneous chronic colitis that were used as a model of CD. The target genes of miR-20a-5p and the associated signaling pathways were identified through bioinformatic analysis and experimental verification of the interactions between the targets predicted by the algorithms and dysregulated mRNAs. RESULTS: The analysis showed that miR-20a-5p was the most significantly downregulated miRNA in patients with CD. Treatment with PLGA MSs carrying miR-20a-5p significantly ameliorated the colitis, decreased mucosal inflammation, and improved epithelial barrier function. Bioinformatic analysis and experimental studies showed that miR-20a-5p inhibition enhanced Th17 differentiation and improved intestinal epithelial barrier function by targeting STAT3. CONCLUSIONS: Downregulation of miR-20a-5p improved the intestinal epithelial barrier function and prevented CD development through the STAT3/IL-17 signaling pathway. Therefore, the delivery of miR-20a-5p by PLGA MSs may serve as a potential therapeutic strategy for CD treatment.

Fibroblastic galectin-1-fostered invasion and metastasis are mediated by TGF-ß1-induced epithelial-mesenchymal transition in gastric cancer.

Background The gastric cancer (GC) microenvironment has important effects on biological behaviors, such as tumor cell invasion and metastasis. However, the mechanism by which the GC microenvironment promotes GC cell invasion and metastasis is unknown. The present study aimed to clarify the effects and mechanism of galectin-1 (GAL-1, encoded by LGALS1) on GC invasion and metastasis in the GC microenvironment. Methods The expression of GAL-1/ LGALS1 was determined using western blotting, immunohistochemistry, and quantitative real-time reverse transcription PCR in GC tissues. Besides, methods including stable transfection, Matrigel invasion and migration assays, and wound-healing assays in vitro; and metastasis assays in vivo, were also conducted. Results GAL-1 from cancer-associated fibroblasts (CAFs) induced the epithelial-mesenchymal transition (EMT) of GC cells though the transforming growth factor beta (TGF-ß1)/ Sma- and mad-related protein (Smad) pathway, and affected the prognosis of patients with GC. The level of GAL-1 was high in CAFs, and treating MGC-803 and SGC -7901 cell line with the conditioned medium from CAFs promoted their invasion and metastasis abilities. Overexpression of LGALS1 promoted the expression of TGF-ß1 and induced EMT of GC cell lines. A TGF-ß1 antagonist inhibited the invasion and migration of GC cells. In vivo, overexpression of LGALS1 promoted GC growth and metastasis, and the TGF-ß1 antagonist dramatically reversed these events. Conclusions These findings suggested that high expression of GAL-1 in the GC microenvironment predicts a poor prognosis in patients with GC by promoting the migration and invasion of GC cells via EMT through the TGF-ß1/Smad signaling pathway. The results might provide new therapeutic targets to treat GC.