作者: Cui, Lingwen ; Li, Chun ; Wang, Wei ; Qian, Weina ; Yao, Junkai ; Chen, Xiaoyang ; Liu, Xiangning ; Liu, Yizhou ; Li, Weili ; Wang, Yong ; Wang, Xiaoping

BACKGROUND:

Xingpi Capsule (XP), a commercially available over-the-counter herbal medicine in China, plays a prominent role in treating diarrhea-predominant irritable bowel syndrome (IBS-D). Nevertheless, the potential mechanisms remain unclear.

PURPOSE:

This study aimed to investigate XP efficacy in IBS-D and elucidate the underlying molecular mechanisms.

METHODS:

A rat IBS-D model was established by senna decoction gavage combined with restraint stress and swimming exhaustion. The changes in rat body weight and stool were recorded daily. Colon pathological changes and the number of colonic goblet cells of rats were observed by hematoxylin-eosin (HE) staining and Alcian blue plus periodic acid-Schiff (AB-PAS) staining, respectively. The expression of Occludin, a tight-junction-associated protein, was examined via immunohistochemistry. Images of colonic microvilli were obtained by TEM. Western blotting (WB) was used to analyze the protein expression of the ASK1/P38 MAPK pathway. The composition of the rat intestinal microbiota was detected by 16S rRNA sequencing. Changes in colonic metabolites were evaluated by liquid chromatography-mass spectrometry (LC-MS). Changes in colon RNA expression were assessed by RNA sequencing (RNA-Seq). The nontoxic range of hypoxanthine (HPX) was screened by Cell Counting Kit-8 (CCK8), the cell model of human colonic epithelial cells (NCM460) induced by lipopolysaccharide (LPS) was established, and the effective concentration of HPX was screened by CCK8. After transfection of pcDNA3.1-MAP3K5, Hoechst 33,342 staining, flow cytometry to detect cell apoptosis, and immunofluorescence to detect the fluorescence changes of ASK1 and ZO-1. WB detection of ASK1/P38 MAPK pathway protein expression changes.

RESULTS:

XP increased the body weight of IBS-D patients and reduced the loose stool rate, loose stool index, and Bristo score. In addition, XP mitigated colon lesions, increased the number of goblet cells and the expression of Occludin, and prevented severe distortion and effacement of the microvillous structure. Specifically, 16S rRNA gene sequence analysis showed that XP decreased the abundance of Desulfurium and Prevotella 9 at the phylum and genus levels while increasing the abundance of Bacteroides at the genus level. RNA-Seq combined with WB validation showed that XP exerted antidiarrheal effects by inhibiting the ASK1/P38 MAPK signaling pathway. Additionally, XP also increased the relative expression level of the metabolite HPX, as revealed by untargeted metabolomics analysis. Impressively, the correlation analysis between 16S rRNA sequencing and LC-MS suggested that HPX and Prevotella 9 are negatively correlated, which indicated that XP might increase the content of HPX by reducing the abundance of Prevotella 9. Meanwhile, a negative correlation between HPX and ASK1 was indicated through RNA-Seq and LC-MS, which suggested that the inhibition of ASK1 (Map3k5) may be ascribed to the increase in HPX after XP treatment. In vitro experiments have proven that HPX can alleviate LPS-induced NCM460 damage, specifically manifested as enhancing cell viability, reducing cell apoptosis, increasing ZO-1 expression, reducing the fluorescence intensity of MAP3K5 in the model group, and inhibiting the expression of ASK1/P38 MAPK pathway proteins. The protective effect of HPX was reversed after transfection with pcDNA 3.1-MAP3K5, which fully demonstrated that the protective mechanism of HPX was achieved by inhibiting MAP3K5 and its downstream pathways.

CONCLUSION:

XP displayed multifaceted protection against IBS-D in rats by regulating the intestinal microbiota, increasing the relative expression level of HPX, a metabolite of the microbiota, and inhibiting the ASK1/P38 MAPK signaling pathway.

Frontiers in pharmacology2区 · 医学

The Protective Effects of Ciji-Hua’ai-Baosheng II Formula on Chemotherapy-Treated H22 Hepatocellular Carcinoma Mouse Model by Promoting Tumor Apoptosis

2区 · 医学

ArticleOA

作者: Qiu, Yingkun ; Fu, Biqian ; Wang, Jing ; Xu, Yangxinzi ; Wang, Yanhui ; Huang, Shuqiong ; Lu, Dawei ; Wang, Yanan ; Gong, Yuewen ; Yang, Jiaqi ; Xi, Shengyan ; Zhai, Xiangyang

Ciji-Hua'ai-Baosheng II Formula (CHB-II-F) is a traditional Chinese medical formula that has been shown in clinical practice to relieve side effects of chemotherapy and improve quality of life for cancer patients. In order to understand the mechanism of its protective effects on chemotherapy, mice with transplanted H₂₂ hepatocellular carcinoma were employed in this study. Ninety-two mice were injected subcutaneously with H₂₂ HCC cell suspension into the right anterior armpit. After mice were treated with 5-fluorine pyrimidine (5-FU), they were divided into six groups as untreated group, 5-FU group, 5-FU plus Yangzheng Xiaoji Capsule group and three groups of 5-FU plus different concentrations of CHB-II-F. Twenty mice were euthanized after 7 days of treatment in untreated and medium concentration of CHB-II-F groups and all other mice were euthanized after 14 days of treatment. Herbal components/metabolites were analyzed by UPLC-MS. Tumors were evaluated by weight and volume, morphology of light and electron microscope, and cell cycle. Apoptosis were examined by apoptotic proteins expression by western blot. Four major components/metabolites were identified from serum of mice treated with CHB-II-F and they are β-Sitosterol, Salvianolic acid, isobavachalcone, and bakuchiol. Treatment of CHB-II-F significantly increased body weights of mice and decreased tumor volume compared to untreated group. Moreover, CHB-II-F treatment increased tumor cells in G₀-G₁ transition instead of in S phase. Furthermore, CHB-II-F treatment increased the expression of pro-apoptotic proteins and decreased the expression anti-apoptotic protein. Therefore, CHB-II-F could improve mice general condition and reduce tumor cell malignancy. Moreover, CHB-II-F regulates apoptosis of tumor cells, which could contribute its protective effect on chemotherapy.

100 项与心达康胶囊相关的药物交易

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适应症	国家/地区	公司	日期
心绞痛	中国	四川美大康药业股份有限公司	2020-04-15
冠心病	中国	四川美大康药业股份有限公司	2020-04-15

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适应症	最高研发状态	国家/地区	公司	日期
乳腺增生	临床3期	中国	天士力医药集团股份有限公司	2024-04-26
淋巴结炎	临床3期	中国	天士力医药集团股份有限公司	2024-04-26