Protective effect of Amauroderma rugosum ethanol extract and its primary bioactive compound, ergosterol, against acute gastric ulcers based on LXR-mediated gastric mucus secretions.

BACKGROUND: Amauroderma rugosum (Blume & T. Nees) Torrend (Ganodermataceae) is an edible mushroom with a wide range of medicinal values. Our previous publication demonstrated the therapeutic effects of the water extract of A. rugosum (WEA) against gastric ulcers. However, the protective effects of the ethanol extract of A. rugosum (EEA) on gastric mucosa and its major active constituents have not yet been elucidated. PURPOSE: This study aims to evaluate the gastroprotective effects and underlying mechanisms of EEA and its fat-soluble constituent, ergosterol, in acute gastric ulcers. STUDY DESIGN AND METHOD: SD rats were pre-treated with EEA (50, 100, and 200 mg/kg) or ergosterol (5, 10, and 20 mg/kg), and acute gastric ulcer models were constructed using ethanol, gastric mucus secretion inhibitor (indomethacin) or pyloric-ligation. The gastric ulcer area, histological structure alterations (H&E staining), and mucus secretion (AB-PAS staining) were recorded. Additionally, Q-PCR, western blotting, immunohistochemistry, ELISA, molecular docking, molecular dynamics simulations, MM-GBSA analysis, and surface plasmon resonance assay (SPR) were used to investigate the underlying mechanisms of the gastroprotective effect. RESULT: Compared with WEA, which primarily exerts its anti-ulcer effects by inhibiting inflammation, EEA containing fat-soluble molecules showed more potent gastroprotective effect through the promotion of gastric mucus secretion, as the anti-ulcer activity was partly blocked by indomethacin. Meanwhile, EEA exhibited anti-inflammatory effects by suppressing the production of IL-6, IL-1ß, TNF-α, and NO, thereby inhibiting the MAPK pathway. Significantly, ergosterol (20 mg/kg), the bioactive water-insoluble compound in EEA, exhibited a gastroprotective effect comparable to that of lansoprazole (30 mg/kg). The promotion of gastric mucus secretion contributed to the effects of ergosterol, as indomethacin can completely block it. The upregulations of COX1-PGE2 and C-fos, an activator protein 1 (AP-1) transcription factor, were observed after the ergosterol treatment. Ergosterol acted as an LXRß agonist via van der Waals binding and stabilizing the LXRß protein without compromising its flexibility, thereby inducing the upregulation of AP-1 and COX-1. CONCLUSION: EEA and its primary bioactive compound, ergosterol, exert anti-ulcer effects by promoting gastric mucus secretion through the LXRß/C-fos/COX-1/PGE2 pathway.

Sijunzi Decoction Targets IL1B and TNF to Reduce Neutrophil Extracellular Traps (NETs) in Ulcerative Colitis: Evidence from Silicon Prediction and Experiment Validation.

Purpose: This study was conducted to explore the mechanism of Sijunzi Decoction (SJZ) in the treatment of ulcerative colitis (UC). Methods: The study aimed to investigate the active components and targets of SJZ in the treatment of UC by screening databases such as TCMSP, GeneCards, OMIM, Distinct, TTD, and Drugbank. An online Venn tool, Cytoscape 3.7.2, and Autodock Tools were used to analyze the components and targets. The study also used a mouse model of UC to further investigate the effects of SJZ. HE staining, immunofluorescence, ELISA, qPCR, and Western blot were used to detect various indices. Results: Eighty-three active components and 112 action targets were identified from SJZ, including 67 targets for treating UC-related NETs. The five core targets identified were AKT1, JUN, IL1B, PTGS2, and TNF, and molecular docking studies indicated that the five targets were well-docked with ginsenoside Rh2, isoflavones, and formononetin. Animal experiments demonstrated that SJZ could alleviate various parameters such as weight, colon length, spleen index, disease activity index, and intestinal pathology of the UC mice. Immunofluorescence and Western blot showed that SJZ could reduce the expression of IL1B and TNF in intestinal neutrophils while increasing the expression of Occludin. Cellular immunofluorescence suggests that SJZ can reduce the expression of TNF and IL1B in NETs. The qPCR results also suggested that SJZ could inhibit TNF signal. Furthermore, ELISA results suggested that SJZ could inhibit the expression of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) while promoting the expression of anti-inflammatory cytokines (IL-10, IL-37, TGF-ß). Conclusion: SJZ treats UC by reducing the content of intestinal NETs, with primary targets on the NETs being IL1B and TNFand suppress TNF signal. The practical components of SJZ may be ginsenoside Rh2, isoflavones, and formononetin.

Chinese herbal compound prescriptions combined with Chinese medicine powder based on traditional Chinese medicine syndrome differentiation for treatment of chronic atrophic gastritis with erosion: a multi-center, randomized, positive-controlled clinical trial.

BACKGROUND: In this study, Chinese herbal compound prescriptions combined with Chinese medicine powder were evaluated for the treatment of chronic atrophic gastritis with erosion. METHODS: This multi-center, randomized, positive drug control clinical trial randomly assigned 216 patients with chronic atrophic gastritis with erosion to three groups: (1) control group: aluminum plus magnesium suspension thrice per day for 4 weeks; (2) test group 1: Chinese herbal compound prescriptions twice a day plus Sanqi (Panax notoginseng) powder twice a day for 4 weeks; (3) test group 2: Chinese herbal compound prescriptions twice a day plus Sanqi (Panax notoginseng) powder and Zhebeimu (Fritillaria thunbergii Miq.) powder twice a day for 4 weeks. The primary endpoint (improvement of gastric mucosal erosion; improvement of gastric mucosal pathology) and secondary endpoints (improvement of clinical symptoms scores; improvement of the patient-reported outcome [PRO] instrument for chronic gastrointestinal diseases) were assessed using endoscopy at week 4 following the treatment. Drug-related adverse events (AEs) and adverse drug reactions (ADRs) were also compared. RESULTS: The final analysis included 202 patients (control group, 63; test group 1, 69; test group 2, 70). At week 4, using within-group comparison, gastric mucosal erosion improved in each group following treatment with a significant difference (P < 0.05); there were no statistically significant differences in gastric mucosal erosion scores among the groups after treatment (P > 0.05); in terms of improvement of gastric mucosal erosion, the efficacy rate of the control group was 69.12%, the efficacy rate of the test group 1 was 73.24%, and the efficacy rate of the test group 2 was 69.01% and efficacy rate among the groups was not statistically significant (P > 0.05). As determined by acute inflammation, chronic inflammation, atrophy, intestinal metaplasia, and dysplasia, the pathological score (total score and the highest score) did not differ statistically among groups following treatment (P > 0.05); within the control group, the total scores of acute inflammation, chronic inflammation, atrophy, and intestinal metaplasia were significantly decreased (P < 0.05), but there was no significant improvement in dysplasia (P > 0.05); in the test group 1, chronic inflammation, atrophy, and intestinal metaplasia and dysplasia scores were significantly decreased (P < 0.05), but acute inflammation did not improve (P > 0.05); there was a significant reduction in the atrophy score in test group 2 (P < 0.05), but no improvement in the scores of acute inflammation, chronic inflammation, intestinal metaplasia, and dysplasia was observed (P > 0.05). Similarly, within the control group, the highest scores of acute inflammation, chronic inflammation, atrophy, and intestinal metaplasia were significantly decreased (P < 0.05), but there was no significant improvement in dysplasia (P > 0.05); there was a significant reduction in highest scores of atrophy, intestinal metaplasia, and dysplasia (P < 0.05) in test group 1, but the highest scores didn't not improve with acute inflammation and chronic inflammation (P > 0.05); there was a significant reduction in the highest atrophy score in test group 2 (P < 0.05), but no improvement in the highest scores of acute inflammation, chronic inflammation, intestinal metaplasia, and dysplasia was observed (P > 0.05). Compared to the control group, the main symptom scores and total symptom scores in the test groups were lower following treatment, with a statistically significant difference (P < 0.05); the analysis of covariance with center, erosion type, and group as factors was applied, and the comparison among the groups in dyspepsia, defecation, and total PRO instrument scores were statistically significant (P < 0.05). In the study period, AEs were reported in 3 (4.23%) patients in the test group 1 and 3 (4.41%) patients in the control group; ADRs were confirmed in 3 (4.23%) patients from the test group 1 and 2 (2.94%) from the control group. AEs and ADRs were not statistically significantly different among groups (AE, P = 0.2213; ADR, P = 0.2872). No serious AE or ADR was reported. CONCLUSIONS: This study has shown that both aluminum plus magnesium suspension and Chinese herbal compound prescriptions together with Panax notoginseng powder are capable of improving gastric mucosal erosion and reducing gastric mucosal pathological scores, and there were no statistically significant differences among the groups in primary endpoints, indicating that Chinese herbal therapy can achieve similar efficacy than antacids in terms of primary outcomes. The aluminum plus magnesium suspension is comparable to Chinese herbal therapy in improving atrophy and intestinal metaplasia, and is inferior to Chinese herbal therapy in improving dysplasia. In addition, the Chinese herbal therapy significantly outperforms the aluminum plus magnesium suspension in improving symptoms. Therefore, the overall clinical outcome of Chinese herbal compound prescriptions together with Panax notoginseng powder based on TCM syndrome patterns in the treatment of erosive gastritis is superior to that of antacids. Trial registration ChiCTR, ChiCTR-IPR-15005905. Registered 22 January 2015, https://www.chictr.org.cn/showproj.aspx?proj=10359.

Emodin targeting the colonic metabolism via PPARγ alleviates UC by inhibiting facultative anaerobe.

BACKGROUND: Emodin is an active ingredient of traditional Chinese medicine Rheum palmatum L. and Polygonum cuspidatum, which possesses anti-inflammatory and intestinal mucosal protection effects. Our previous study found that emodin significantly alleviated ulcerative colitis induced by sodium dextran sulfate (DSS). In this study, we found the underlying mechanism of emodin on ulcerative colitis (UC). PURPOSE: We aimed to further explore the mechanism of emodin in the treatment of ulcerative colitis from the perspective of metabolism and intestinal flora. METHODS: Ulcerative colitis was induced by 3% sodium dextran sulfate (DSS) on mice, and the mice were respectively treated with mesalazine, rosiglitazone, emodin, and emodin combined with GW9662 (PPARγ inhibitor) simultaneously. Weight changes, the disease activity index (DAI), colonic length, and pathologic changes in colon were used to evaluate the efficacy of emodin. LC-MS/MS was performed for metabolomics analysis of colon. In addition, intestinal flora was assessed using 16S rDNA sequencing. A vector-based short hairpin RNA (shRNA) method was used to silence PPARγ gene expression in Caco-2 cells. RESULTS: Emodin binds to the active site of PPARγ protein and forms hydrogen bond interaction with ARG288 and CYS285 amino acids. Furthermore, Emodin significantly promotes the protein expression of PPARγ, while inhibiting iNOS and NF-kB p65 in UC mice, however, this effect is hardly shown when it is combined with GW9662 (the inhibitor of PPARγ). Meanwhile, emodin suppresses the expression of iNOS in Caco-2 cells induced with IFNγ and IL-22, but has no effect on its expression in shPPARγ-Caco-2 cells. In addition, through activating PPARγ signal pathway, emodin is capable of regulating colonic metabolism including oxidative phosphorylation and citrulline metabolism and effecting luminal availability of oxygen and nitrate. This promotes the recovery of anoxic environment of colon epithelial cells, which strains the growth and expansion of Enterobacteriaceae. CONCLUSION: The mechanism of Emodin in the treatment of ulcerative colitis relies on its regulation of PPARγ signal pathway, which could modulate colonic metabolism and restore intestinal homeostasis.

Chemical Characterization and Metabolic Profiling of the Compounds in the Chinese Herbal Formula Li Chang Decoction by UPLC-QTOF/MS.

Background: Li Chang decoction (LCD), a Chinese medicine formula, is commonly used to treat ulcerative colitis (UC) in clinics. Purpose: This study aimed to identify the major components in LCD and its prototype and metabolic components in rat biological samples. Methods: The chemical constituents in LCD were identified by establishing a reliable ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF/MS) method. Afterwards, the rats were orally administered with LCD, and the biological samples (plasma, urine, and feces) were collected for further analyzing the effective compounds in the treatment of UC. Result: A total of 104 compounds were discriminated in LCD, including 26 flavonoids, 20 organic acids, 20 saponins, 8 amino acids, 5 oligosaccharides, 5 tannins, 3 lignans, 2 alkaloids, and 15 others (nucleosides, glycosides, esters, etc.). About 50 prototype and 94 metabolic components of LCD were identified in biological samples. In total, 29 prototype components and 22 metabolic types were detected in plasma. About 27 prototypes and 96 metabolites were discriminated in urine, and 34 prototypes and 18 metabolites were identified in feces. Conclusion: The flavonoids, organic acids, and saponins were the major compounds of LCD, and this study promotes the further pharmacokinetic and pharmacological evaluation of LCD.

Exploration in the Mechanism of Kaempferol for the Treatment of Gastric Cancer Based on Network Pharmacology.

BACKGROUND: Kaempferol is a natural polyphenol in lots of Chinese herbs, which has shown promising treatment for gastric cancer (GC). However, the molecular mechanisms of its action have not been systematically revealed yet. In this work, a network pharmacology approach was used to elucidate the potential mechanisms of kaempferol in the treatment of GC. METHODS: The kaempferol was input into the PharmMapper and SwissTargetPrediction database to get its targets, and the targets of GC were obtained by retrieving the Online Mendelian Inheritance in Man (OMIM) database, MalaCards database, Therapeutic Target Database (TTD), and Coolgen database. The molecular docking was performed to assess the interactions between kaempferol and these targets. Next, the overlap targets of kaempferol and GC were identified for GO and KEGG enrichment analyses. Afterward, a protein-protein interaction (PPI) network was constructed to get the hub targets, and the expression and overall survival analysis of the hub target were investigated. Finally, the overall survival (OS) analysis of hub targets was performed using the Kaplan-Meier Plotter online tool. RESULTS: A total of 990 genes related to GC and 10 overlapping genes were determined through matching the 24 potential targets of kaempferol with disease-associated genes. The result of molecular docking indicated that kaempferol can bind with these hub targets with good binding scores. These targets were further mapped to 140 GO biological process terms and 11 remarkable pathways. In the PPI network analysis, 3 key targets were identified, including ESR1, EGFR, and SRC. The mRNA and protein expression levels of EGFR and SRC were obviously higher in GC tissues. High expression of these targets was related to poor OS in GC patients. CONCLUSIONS: This study provided a novel approach to reveal the therapeutic mechanisms of kaempferol on GC, which will ease the future clinical application of kaempferol in the treatment of GC.