Aug 2026· Frontiers in Immunology· Vol 17· 0 citations· 29 references
TL;DR
Collectively, AA interrupts the vicious “microbiota–oxidative stress–STING” loop in a STING‑dependent manner and contributes to remodeling the precancerous immune microenvironment, positioning it as a promising chemopreventive candidate targeting the earliest phase of gastric carcinogenesis.
Abstract
Chronic inflammation-driven gastric precancerous lesions (GPL) are characterized by progressive immune remodeling toward an immunosuppressive state, yet effective chemopreventive agents targeting this process remain scarce. Here, we identify asiatic acid (AA), a natural pentacyclic triterpenoid, as a STING‑binding compound that contributes to reshaping the gastric immune microenvironment and interfering with the Correa cascade.
Using a rat model of MNNG‑induced GPL (atrophy, intestinal metaplasia, dysplasia) and MNNG‑treated GES‑1 cells, we assessed histopathological damage, systemic pro‑inflammatory cytokines (TNF, IL‑6, MCP1), and gastric physiological function. STING binding was evaluated by surface plasmon resonance (SPR) with KD measurement and 100 ns molecular dynamics simulations. The cGAS–STING–TBK1–IRF3 axis was examined
in vivo
and
in vitro
. Gut microbiota was analyzed by 16S rRNA sequencing, and the Nrf2–Keap1 antioxidant pathway, mitochondrial membrane potential, and oxidative stress were measured. Rescue experiments were performed using the STING agonist cGAMP.
AA ameliorated histopathological damage, exerted regulatory effects on systemic pro‑inflammatory cytokines with a non‑linear dose‑response pattern, and improved gastric physiological function. Mechanistically, AA directly bound to STING with a KD of 4.0 μM and maintained a stable conformation in simulations, suppressing aberrant activation of the cGAS–STING–TBK1–IRF3 axis. AA also reversed gut microbiota dysbiosis (notably reducing pro‑inflammatory Erysipelotrichales), restored the Nrf2–Keap1 pathway, improved mitochondrial membrane potential, and reduced oxidative stress. Rescue experiments with cGAMP partially abolished AA’s protective effects, supporting the functional involvement of STING signaling in AA’s actions.
Collectively, AA interrupts the vicious “microbiota–oxidative stress–STING” loop in a STING‑dependent manner and contributes to remodeling the precancerous immune microenvironment, positioning it as a promising chemopreventive candidate targeting the earliest phase of gastric carcinogenesis.
Evaluating the preventive and therapeutic effects of RQMJ on CAG and its intervention in the inflammation–cancer transition process highlights the potential pharmacological value and therapeutic prospects of RQMJ in inflammation-driven gastric diseases.
Fengyu Huang, Peiping Chen, Daiyue Ding et al.· Chinese Medicine· 0 citations
Background Chronic atrophic gastritis (CAG) is a precancerous gastric lesion characterized by persistent inflammatory injury, glandular atrophy, and impairment of gastric mucosal barrier-associated integrity. Huangjin Shuangshen Decoction (HJSS) has shown therapeutic potential in gastritis-related disorders, but its effects on CAG and the underlying mechanism remain unclear. This study investigated whether HJSS alleviates CAG by modulating inflammation-associated barrier dysfunction. Methods CAG was induced in mice by MNNG combined with ranitidine and irregular feeding, followed by treatment with different doses of HJSS, with folic acid as a positive control. Histopathology, gastric function indices, inflammatory mediators, apoptosis-related markers, and barrier-associated molecules were assessed in vivo. MNNG-injured GES-1 cells treated with HJSS-medicated serum were used for in vitro validation. Transcriptomic analysis, network pharmacology, and pharmacological inhibition were integrated to explore the underlying mechanisms. Results HJSS alleviated gastric mucosal atrophy and histopathological injury, improved gastric functional impairment, reduced inflammatory burden, and attenuated apoptosis-associated epithelial injury in experimental CAG. HJSS also promoted the recovery of gastric mucosal barrier-associated molecules, including CFTR, ZO-1, MUC5AC, Occludin, and Claudin-1. Integrated transcriptomic and network pharmacology analyses highlighted an inflammation–barrier framework involving TNF-related signaling and CFTR-associated regulation. In vitro, HJSS mitigated MNNG-induced epithelial injury, whereas CFTR inhibition attenuated the HJSS-associated restoration of CFTR and ZO-1. HJSS was further associated with suppression of TNF/NF-κB signaling and reduced p65 nuclear translocation. Conclusion HJSS alleviates MNNG-induced CAG by attenuating inflammatory injury and promoting the recovery of gastric mucosal barrier-associated molecular features. Its protective effects are associated with suppression of TNF/NF-κB signaling and involvement of CFTR-associated regulation, supporting an inflammation–barrier mechanism underlying the action of HJSS in CAG.
Shuo Zhang, Shuya Zhang, Mengyi Wang et al.· Frontiers in Immunology· 0 citations
Colorectal cancer (CRC) linked to colitis is a major cause of cancer-related deaths, highlighting the need for effective treatment options. This study aimed to investigate the effects of berberine (BRR) on gut microbiota and the endocannabinoid system (ECS) in a mouse model of colitis-associated CRC, which was induced using azoxymethane (AOM) and dextran sulfate sodium (DSS). Through a combination of animal experiments, microbial sequencing, and biochemical assays, we discovered that BRR significantly inhibited tumor development. This was demonstrated by a dose-dependent increase in body weight and a notable decrease in both the number and size of tumors. Histopathological examinations showed a reduction in aberrant crypt foci and inflammation. Additionally, BRR treatment led to lower levels of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, while increasing the levels of the anti-inflammatory cytokine IL-10, indicating a modulation of immune responses. Importantly, BRR altered gut microbial communities by promoting beneficial bacteria such as Akkermansia muciniphila, Bacteroides, Lachnoclostridium, Blautia, and Prevotellaceae_UCG-001, while reducing harmful species. We also observed improvements in intestinal barrier integrity, characterized by decreased permeability and lower levels of plasma lipopolysaccharides. Furthermore, BRR restored the expression of cannabinoid receptors CB2 and GPR55, suggesting that the ECS plays a role in mediating its effects. In summary, BRR shows significant promise in alleviating colitis-associated CRC through various mechanisms, including the modulation of gut microbiota, regulation of immune responses, and enhancement of intestinal barrier function. Future studies should aim to validate these findings clinically and further explore the efficacy of BRR in the prevention and treatment of CRC.
Yalan Huang, Junhui Zhang, Huiqing Yu et al.· Molecular Nutrition & Food R...· 0 citations
It is demonstrated that HEP exerts gastroprotective effects against CAG through coordinated anti-inflammatory, antioxidant, and structure-dependent NF-κB inhibitory actions, supporting its potential as a promising natural agent for CAG intervention.
Ping Li, Jianran Hu, Yan-juan Yang et al.· International Journal of Bio...· 0 citations
Background Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by hepatic steatosis, inflammation, and fibrosis, yet effective pharmacological therapies remain limited. Melandrii Herba, a traditional East Asian medicinal herb used to improve blood circulation and relieve inflammatory disorders, has reported anti-inflammatory activity. However, its therapeutic potential and active constituents in MASH remain unclear. Purpose This study investigated the hepatoprotective and anti-fibrotic effects of Melandrii Herba ethanol extract (MHE) and its purified constituent melandryoside in MASH and explored the underlying mechanisms. Methods Palmitic acid-challenged HepG2 hepatocytes and TGF-β-stimulated HSC-LX2 cells were used to evaluate metabolic and fibrogenic stress responses. In vivo efficacy was examined in choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-fed mice, with MHE administered therapeutically after disease establishment (weeks 8–12) under continued dietary challenge. Interactome analysis, co-immunoprecipitation, and PPM1A loss-of-function approaches were used to investigate the underlying mechanisms. Results MHE reduced lipid accumulation and oxidative stress in palmitic acid-treated hepatocytes and suppressed TGF-β-induced hepatic stellate cell activation, fibrogenic gene expression, and SMAD2/3 phosphorylation in HSC-LX2 cells. In CDAHFD-fed mice, oral administration of MHE attenuated hepatic steatosis, inflammatory injury, and collagen deposition. Mechanistically, MHE and melandryoside restored PPM1A-SMAD interaction and reduced SMAD2/3 phosphorylation, whereas PPM1A knockdown diminished their anti-fibrotic effects. Conclusion MHE and melandryoside alleviated pathological features of MASH by reducing metabolic stress and suppressing fibrotic signaling. These findings identify melandryoside as a bioactive constituent of Melandrii Herba and suggest that regulation of PPM1A-SMAD signaling may represent a potential therapeutic strategy for MASH.
Yo-Han Lee, Youngsang Nam, Kieun Park et al.· Frontiers in Pharmacology· 0 citations
BACKGROUND
Ulcerative colitis (UC) is a chronic inflammatory disease that seriously endangers human health. Shaoyao Decoction (SYD) has been widely used in clinical practice to treat UC; however, its active components and molecular mechanisms remain unclear.
OBJECTIVE
To elucidate the pharmacological mechanisms by which SYD and its active constituents ameliorate UC using single-cell RNA sequencing (scRNA-seq).
METHODS
We first assessed the therapeutic efficacy of SYD in a dextran sulfate sodium (DSS)-induced UC mouse model. We then applied scRNA-seq to identify the potential cell populations and molecular pathways involved in SYD-mediated protection. Guided by these findings, we verified the inferred mechanisms in vivo and screened potential active compounds from SYD. We further examined their inhibitory effects on formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophil migration and their protective effects on DSS-induced Caco-2 cell injury in vitro. Finally, we validated the underlying mechanisms using inhibitors, agonists, gene silencing, and overexpression approaches in vitro.
RESULTS
SYD markedly alleviated weight loss, reduced disease activity index (DAI) scores, and mitigated colon shortening and histopathological damage in mice with UC. The scRNA-seq analysis revealed alterations in neutrophils and intestinal epithelial cells. Functional pathway analysis indicated that neutrophil migration, epithelial tight junction regulation, and apoptosis were key processes modulated by SYD. In vivo, SYD decreased neutrophil infiltration and downregulated the expression of RAC1, RAC2, S100A8, and S100A9. Concurrently, SYD upregulated the tight junction proteins TJP1 and OCLN and suppressed epithelial apoptosis. In vitro, Ferulic acid emerged as the potential compound responsible for suppressing neutrophil migration. RAC1 inhibition and Ferulic acid treatment produced comparable suppressive effects on neutrophil migration, whereas RAC1 activation effectively antagonized the inhibitory effect of Ferulic acid. Chrysin-7-O-glucuronide was identified as the potential component enhancing tight junction integrity and suppressing apoptosis in intestinal epithelial cells; silencing KLF4 eliminated these protective effects of Chrysin-7-O-glucuronide. Conversely, KLF4 overexpression exerted protective effects comparable to those of Chrysin-7-O-glucuronide treatment.
CONCLUSION
SYD exerts potent therapeutic effects against UC. Mechanistically, Ferulic acid in SYD suppresses RAC1-mediated neutrophil migration, while Chrysin-7-O-glucuronide enhances tight junction integrity and suppresses apoptosis in intestinal epithelial cells through a KLF4-dependent mechanism.
Huantian Cui, Huan Pei, Feitian Min et al.· Phytomedicine· 0 citations
