WANG Yan-min;YU Yu-ling;WANG Si-qi;SUN Ya-teng;YAN Yong-huang;YANG Xin-yu;HAN Si-qi;SONG Yu-hong;WANG Yu-han;WANG Yun-he;ZHANG Cai;SU Ze-qi;School of Chinese Materia Medica, Beijing University of Chinese Medicine;School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine;Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine;Key Laboratory of Famous Doctors and Famous Prescriptions of National Administration of Traditional Chinese MedicineThis study aims to explore the mechanism of Shuangshen Yiwei Granules, an empirical prescription developed by Professor LU Zhi-zheng(a master of TCM), in regulating gastric acid secretion and impeding malignant progression of chronic atrophic gastritis with gastric intestinal metaplasia(GIM). Seventy-two specific-pathogen free(SPF) Wistar male rats were randomly divided into a normal group and a modeling group. GIM model rats were established by a four-factor GIM induction protocol involving "N-methyl-N′-nitro-N-nitrosoguanidine(MNNG), ranitidine, irregular feeding, and sodium salicylate". After successful modeling, the rats in the modeling group were further divided into a model group, a positive control(Moluodan), and a Shuangshen Yiwei Granules group, with 12 rats in each group. Each group was continuously intervened for eight weeks. General conditions were observed, and pathological changes in the gastric mucosa were evaluated via hematoxylin-eosin staining. Serum pepsinogen Ⅰ(PGⅠ), pepsinogen Ⅱ(PGⅡ), and gastrin-17(G-17) were quantified by enzyme-linked immunosorbent assay. Parietal cell ultrastructure was analyzed via transmission electron microscopy. The apoptosis of gastric glandular cells was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL) staining. Gastric pH was measured with precision test strips. The expression of apoptosis pathway-related proteins Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3) and tumor necrosis factor receptor 1(TNFR1)/cysteine-aspartic acid protease-8(caspase-8) and acid secretion-related proteins cyclin dependent kinase 5(CDK5)/soluble N-ethylmaleimide sensitive factor attachment protein receptors(SNAREs) in gastric mucosal tissue were detected by Western blot. Compared to the normal group, the model group exhibited lethargy in mental state, pale eyes/ears/claws/tongue, tail desquamation, glandular atrophy of the gastric mucosa with disordered arrangement, and tumor-like structures, significantly reduced PGⅠ, PGⅠ/PGⅡ ratio, and G-17(P<0.01), significantly elevated PGⅡ(P<0.01), parietal cell nuclear condensation, loss and abnormal structures of mitochondria, significantly increased gastric glandular apoptosis(P<0.01), and significantly elevated gastric pH(P<0.01). The levels of p-JAK2/JAK2, p-STAT3/STAT3, B-cell lymphoma-2(Bcl-2)-associated X protein(Bax)/Bcl-2, TNFR1, TNFR1 associated via death domain(TRADD), Fas-associated death domain(FADD), and cleaved caspase-8/caspase-8 significantly increased(P<0.05, P<0.01), while histamine receptor H_2(HRH_2), CDK5, syntaxin 3(STX3), and synaptosome associated protein 25(SNAP25) significantly decreased(P<0.05). Compared with the model group, the Shuangshen Yiwei Granules group exhibited alleviated mental state, general conditions, and pathological features of the gastric mucosa, significantly upregulated PGⅠ, PGⅠ/PGⅡ ratio, and G-17(P<0.05, P<0.01), significantly downregulated PGⅡ(P<0.01), ameliorated parietal cell ultrastructure to varying degrees, significantly reduced gastric glandular apoptosis(P<0.01), significantly lowered gastric pH(P<0.01), significantly decreased expression of p-JAK2/JAK2, p-STAT3/STAT3, Bax/Bcl-2, TNFR1, TRADD, FADD, and cleaved caspase-8/caspase-8(P<0.05, P<0.01), and significantly increased expression of HRH_2, CDK5, STX3, and SNAP25(P<0.05). To sum up, Shuangshen Yiwei Granules potentially inhibit JAK2/STAT3 and TNFR1/caspase-8 signaling pathways to suppress gastric glandular apoptosis while activating CDK5/SNAREs to enhance parietal cell acid secretion, thereby restoring gastric acid homeostasis and blocking GIM progression.
2025 24 v.50 [Abstract][OnlineView][Download 3475K]