Exploration of Berberine Against Ulcerative Colitis via TLR4/NF-κB/HIF-1α Pathway by Bioinformatics and Experimental Validation.

Purpose: This study aimed to delineate the molecular processes underlying the therapeutic effects of berberine on UC by employing network pharmacology tactics, molecular docking, and dynamic simulations supported by empirical validations both in vivo and in vitro. Patients and Methods: We systematically screened potential targets and relevant pathways affected by berberine for UC treatment from comprehensive databases, including GeneCards, DisGeNET, and GEO. Molecular docking and simulation protocols were used to assess the interaction stability between berberine and its principal targets. The predictions were validated using both a DSS-induced UC mouse model and a lipopolysaccharide (LPS)-stimulated NCM460 cellular inflammation model. Results: Network pharmacology analysis revealed the regulatory effect of the TLR4/NF-κB/HIF-1α pathway in the ameliorative action of berberine in UC. Docking and simulation studies predicted the high-affinity interactions of berberine with pivotal targets: TLR4, NF-κB, HIF-1α, and the HIF inhibitor KC7F2. Moreover, in vivo analyses demonstrated that berberine attenuates clinical severity, as reflected by decreased disease activity index (DAI) scores, reduced weight loss, and mitigated intestinal inflammation in DSS-challenged mice. These outcomes include suppression of the proinflammatory cytokines IL-6 and TNF-α and downregulation of TLR4/NF-κB/HIF-1α mRNA and protein levels. Correspondingly, in vitro findings indicate that berberine decreases cellular inflammatory injury and suppresses TLR4/NF-κB/HIF-1α signaling, with notable effectiveness similar to that of the HIF-1α inhibitor KC7F2. Conclusion: Through network pharmacology analysis and experimental substantiation, this study confirmed that berberine enhances UC treatment outcomes by inhibiting the TLR4/NF-κB/HIF-1α axis, thereby mitigating inflammatory reactions and improving colonic pathology.

Different therapies of Chinese herbal medicine for diarrhea-predominant irritable bowel syndrome: A network meta-analysis of double-blinded, placebo-controlled trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Shuganjianpi Therapy (SGJP), Jianpi Therapy (JP), Shugan Therapy (SG), Jianpiwenshen Therapy (JPWS), and Shuganjianpiwenshen Therapy (SGJPWS), consisting of formulas from Chinese herbal medicine (CHM), have been tremendously applied to irritable bowel syndrome (IBS). However, it remains uncertain when exploring the preferable option among different CHM therapies for diarrhea-predominant irritable bowel syndrome (IBS-D). AIM OF THE STUDY: To compare and rank the efficacy and safety of different CHM therapies for IBS-D. MATERIALS AND METHODS: We searched randomized, double-blinded, placebo-controlled trials through mainstream databases from their inception to October 31, 2022. Eligible randomized controlled trials (RCTs) applied one of the CHM therapies as the experimental group and placebo as the control group. Two authors independently extracted data into a form and evaluated the quality of the retrieved articles by the Cochrane Risk of Bias Tool. At least one of the following outcomes was assessed: Serotonin, Neuropeptide Y (NPY), Incidence of Adverse Events (AE), and Irritable Bowel Syndrome-Severity Scoring System (IBS-SSS) with its subscales of Severity of Abdominal Pain (SAP), Frequency of Abdominal Pain (FAP), Severity of Abdominal Distension (SAD), Dissatisfaction with Bowel Habits (DBH), and Interference with Quality of Life (IQOL). A Bayesian network meta-analysis on a random-effect model was conducted using R 4.2.2 software. RESULTS: 1367 records were retrieved from databases in an initial search. Fourteen studies involving six interventions with 2248 participants were identified. Provided pairwise comparisons, the surface under the cumulative ranking curve (SUCRA) ranking, and cluster analysis, JPWS was the best option for ameliorating clinical symptoms simultaneously, which included IBS-SSS, SAP, FAP, SAD, DBH, and IQOL. As for AE, JPWS contributed to fewer adverse events than others as well. In respect of serum indicators, we noticed the dominance of SGJP in regulating both serotonin and NPY. CONCLUSIONS: JPWS and SGJP were the most prominent CHM therapies for IBS-D in terms of clinical symptoms, including abdominal pain, distension, bowel habits, and improvement of quality of life. The effect of JP and SG for IBS-D required further investigation. As a potential candidate, SGJP may well treat IBS-D by mediating dysmotility, visceral hypersensitivity, and the gut-brain axis with an increase of NPY and a reduction of serotonin. For safety, JPWS was ideal for the fewest adverse events in the treatment of IBS-D. On account of a small sample size and possible geographical publication bias, more double-blinded and placebo-controlled trials with larger samples worldwide would be necessary for strengthening current evidence.

Restoration of mRNA Expression of Solute Carrier Proteins in Liver of Diet-Induced Obese Mice by Metformin.

Metformin (MET), the most common medicine for type 2 diabetes (T2DM), improves insulin sensitivity by targeting the liver, intestine and other organs. Its impact on expression of the solute carrier (Slc) transporter genes have not been reported in the mechanism of insulin sensitization. In this study, we examined Slc gene expression in the liver and colon of diet-induced obese (DIO) mice treated with MET by transcriptomic analysis. There were 939 differentially expressed genes (DEGs) in the liver of DIO mice vs lean mice, which included 34 Slc genes. MET altered 489 DEGs in the liver of DIO mice, in which 23 were Slc genes. Expression of 20 MET-responsive Slc DEGs was confirmed by qRT-PCR, in which 15 Slc genes were altered in DIO mice and their expressions were restored by MET, including Slc2a10, Slc2a13, Slc5a9, Slc6a14, Slc7a9, Slc9a2, Slc9a3, Slc13a2, Slc15a2, Slc26a3, Slc34a2, Slc37a1, Slc44a4, Slc51b and Slc52a3. While, there were only 97 DEGs in the colon of DIO mice with 5 Slc genes, whose expression was not restored by MET. The data suggest that more genes were altered in the liver over the colon by the high fat diet (HFD). There were 20 Slc genes with alteration confirmed in the liver of DIO mice and 15 of them were restored by MET, which was associated with improvement of insulin sensitivity and obesity. The restoration may improve the uptake of glucose, amino acids, mannose, fructose, 1,5-anhydro-D-glucitol and bumetanide in hepatocytes of the liver of DIO mice. The study provides new insight into the mechanism of metformin action in insulin sensitization and obesity.

Uncovering and quantifying the subduction zone sulfur cycle from the slab perspective.

Sulfur belongs among H2O, CO2, and Cl as one of the key volatiles in Earth's chemical cycles. High oxygen fugacity, sulfur concentration, and δ34S values in volcanic arc rocks have been attributed to significant sulfate addition by slab fluids. However, sulfur speciation, flux, and isotope composition in slab-dehydrated fluids remain unclear. Here, we use high-pressure rocks and enclosed veins to provide direct constraints on subduction zone sulfur recycling for a typical oceanic lithosphere. Textural and thermodynamic evidence indicates the predominance of reduced sulfur species in slab fluids; those derived from metasediments, altered oceanic crust, and serpentinite have δ34S values of approximately -8‰, -1‰, and +8‰, respectively. Mass-balance calculations demonstrate that 6.4% (up to 20% maximum) of total subducted sulfur is released between 30-230 km depth, and the predominant sulfur loss takes place at 70-100 km with a net δ34S composition of -2.5 ± 3‰. We conclude that modest slab-to-wedge sulfur transport occurs, but that slab-derived fluids provide negligible sulfate to oxidize the sub-arc mantle and cannot deliver 34S-enriched sulfur to produce the positive δ34S signature in arc settings. Most sulfur has negative δ34S and is subducted into the deep mantle, which could cause a long-term increase in the δ34S of Earth surface reservoirs.