Journal of ethnopharmacology · 2026
Tibetan medicine Anzhi Jinghua San alleviates chronic atrophic gastritis: attenuation of LysoPC-induced Bcl-2 suppression and inhibition of pyroptosis and apoptosis.
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Liu Yingying, Tashi Dolma, Ma Yuanan, Sonam Lhamo, Xiao Yuancan, Zhang Ming, Chen Ying, Pema Tsering, Wei Lixin, Zhou Wenbin
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Anzhi Jinghua San (AZJHS), a traditional Tibetan medicine formula officially recorded in the Drug Standards of the Ministry of Health of the People's Republic of China (Tibetan Medicine, Volume 1, 1995 edition), has shown clinical efficacy against chronic atrophic gastritis (CAG), but its molecular mechanism needs further exploration.
AIM OF THE STUDY: To decipher the therapeutic compounds and mechanisms of AZJHS against CAG using an integrative multi-omics approach.
MATERIALS AND METHODS: A CAG rat model was induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), irregular feeding, ranitidine, and sodium salicylate, followed by AZJHS treatment for four weeks. Serum gastric function markers, inflammatory cytokines, gastric mucosal histopathology, ultrastructure, and apoptosis and proliferation were evaluated. Serum pharmacochemistry, network pharmacology, proteomics, and metabolomics were integrated to identify absorbed components, key targets, and differential metabolites. Candidate targets were validated in gastric tissues by western blotting and RT-qPCR. Component-target binding was assessed by molecular docking, surface plasmon resonance (SPR), microscale thermophoresis (MST), and cellular thermal shift assay (CETSA). Cytoprotective effects and underlying mechanisms were further examined in MNNG-exposed GES-1 cells.
RESULTS: AZJHS treatment increased serum pepsinogen I (PG I) and pepsinogen II (PG II), decreased gastrin-17 (GAS-17), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), alleviated histopathological and ultrastructural damage, and restored the proliferation-apoptosis balance. Multi-omics analysis identified Bcl-2 as a candidate target within the NOD-like receptor signaling pathway. AZJHS restored Bcl-2 expression, suppressed the NLRP1/Caspase-1/gasdermin D (GSDMD)/interleukin-18 (IL-18)/interleukin-1β (IL-1β) pyroptotic cascade, and attenuated mitochondrial apoptosis (Bax/Caspase-9/Caspase-3). Metabolomic profiling revealed that AZJHS reversed the glycerophospholipid disturbances associated with CAG, notably reducing lysophosphatidylcholine (LysoPC), and Spearman analysis identified LysoPC 18:1 as the metabolite most negatively correlated with Bcl-2. Apigenin was identified as an active constituent of AZJHS that directly binds Bcl-2 by molecular docking, SPR, MST, and CETSA. In MNNG-exposed GES-1 cells, apigenin reduced TNF-α, IL-6, IL-18, IL-1β, and lactate dehydrogenase (LDH) levels, upregulated Bcl-2, suppressed downstream pyroptotic and apoptotic pathways, and reversed LysoPC 18:1-induced Bcl-2 downregulation and activation of these pathways.
CONCLUSION: AZJHS ameliorates CAG, with restoration of glycerophospholipid homeostasis, upregulation of Bcl-2, and suppression of NLRP1-mediated pyroptosis and mitochondrial apoptosis. Apigenin, a bioactive component of AZJHS, directly binds Bcl-2 and attenuates LysoPC-induced Bcl-2 suppression. These findings suggest that the metabolism-inflammation-cell death axis may be a therapeutic target for CAG in Tibetan medicine.
AIM OF THE STUDY: To decipher the therapeutic compounds and mechanisms of AZJHS against CAG using an integrative multi-omics approach.
MATERIALS AND METHODS: A CAG rat model was induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), irregular feeding, ranitidine, and sodium salicylate, followed by AZJHS treatment for four weeks. Serum gastric function markers, inflammatory cytokines, gastric mucosal histopathology, ultrastructure, and apoptosis and proliferation were evaluated. Serum pharmacochemistry, network pharmacology, proteomics, and metabolomics were integrated to identify absorbed components, key targets, and differential metabolites. Candidate targets were validated in gastric tissues by western blotting and RT-qPCR. Component-target binding was assessed by molecular docking, surface plasmon resonance (SPR), microscale thermophoresis (MST), and cellular thermal shift assay (CETSA). Cytoprotective effects and underlying mechanisms were further examined in MNNG-exposed GES-1 cells.
RESULTS: AZJHS treatment increased serum pepsinogen I (PG I) and pepsinogen II (PG II), decreased gastrin-17 (GAS-17), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), alleviated histopathological and ultrastructural damage, and restored the proliferation-apoptosis balance. Multi-omics analysis identified Bcl-2 as a candidate target within the NOD-like receptor signaling pathway. AZJHS restored Bcl-2 expression, suppressed the NLRP1/Caspase-1/gasdermin D (GSDMD)/interleukin-18 (IL-18)/interleukin-1β (IL-1β) pyroptotic cascade, and attenuated mitochondrial apoptosis (Bax/Caspase-9/Caspase-3). Metabolomic profiling revealed that AZJHS reversed the glycerophospholipid disturbances associated with CAG, notably reducing lysophosphatidylcholine (LysoPC), and Spearman analysis identified LysoPC 18:1 as the metabolite most negatively correlated with Bcl-2. Apigenin was identified as an active constituent of AZJHS that directly binds Bcl-2 by molecular docking, SPR, MST, and CETSA. In MNNG-exposed GES-1 cells, apigenin reduced TNF-α, IL-6, IL-18, IL-1β, and lactate dehydrogenase (LDH) levels, upregulated Bcl-2, suppressed downstream pyroptotic and apoptotic pathways, and reversed LysoPC 18:1-induced Bcl-2 downregulation and activation of these pathways.
CONCLUSION: AZJHS ameliorates CAG, with restoration of glycerophospholipid homeostasis, upregulation of Bcl-2, and suppression of NLRP1-mediated pyroptosis and mitochondrial apoptosis. Apigenin, a bioactive component of AZJHS, directly binds Bcl-2 and attenuates LysoPC-induced Bcl-2 suppression. These findings suggest that the metabolism-inflammation-cell death axis may be a therapeutic target for CAG in Tibetan medicine.