Kai Zhang1, Yongtai Zhang2, Nana Li3, Feng Xing4, Jihui Zhao5, Tao Yang6, Chenghai Liu7, Nianping Feng8. 1. Department of Pharmaceutical Sciences, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China; First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China. Electronic address: kennyfind@sina.com. 2. Department of Pharmaceutical Sciences, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China. 3. Department of Pharmaceutical Sciences, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China. Electronic address: linana0327@163.com. 4. Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, People's Republic of China. Electronic address: 13817568896@163.com. 5. Department of Pharmaceutical Sciences, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China. Electronic address: zhaojihui07168@hotmail.com. 6. Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, People's Republic of China. Electronic address: 13917577668@163.com. 7. Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, People's Republic of China. Electronic address: chenghai.liu@outlook.com. 8. Department of Pharmaceutical Sciences, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China. Electronic address: npfeng@hotmail.com.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine boasts a 440-year-long history of treating refractory ascites via combinations of herbal medicines, called formulae. Xiaozhang Tie (XT) is a proprietary herbal-compound-based formula that has been proven to be very effective in the treatment of cirrhosis-associated ascites in clinical practice, but the mechanism of action of XT remains unknown. AIM OF THE STUDY: In this study, we used a metabolomics-based systematic method to elucidate the mechanism of XT in the treatment of cirrhotic ascites. METHODS: Decompensated liver cirrhosis was induced in rats by intraperitoneal injection of Carbon tetrachloride (CCl4). Ultra performance liquid chromatography-mass spectrometry (UPLC-MS) combined with pattern recognition approaches were used to determine differentiating metabolites relevant to XT treatment. Biomarkers were further validated by a targeted quantitative method and by the results from serum and urine analyses. Pathway analysis and correlation network construction were used to reveal the therapeutic targets associated with XT treatment, and the potential mechanisms were verified by the results from biochemical, histopathological and immunohistochemical assays. RESULTS: XT synergistically mediated the abnormalities of amino acid metabolic pathways in cirrhotic rats. XT significantly elevated the arginine levels, reduced the serum nitric oxide (NO) levels and alleviated the gastrointestinal motility disorder of cirrhotic rats. This effect of XT has been confirmed by the inhibition of the activities of inducible NO synthase and neuronal NO synthase in the small intestine. CONCLUSIONS: These results reveal that XT promotes gastrointestinal motility by acting on multiple targets in multiple pathways, of which the L-arginine/NO pathway is most affected.
ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine boasts a 440-year-long history of treating refractory ascites via combinations of herbal medicines, called formulae. Xiaozhang Tie (XT) is a proprietary herbal-compound-based formula that has been proven to be very effective in the treatment of cirrhosis-associated ascites in clinical practice, but the mechanism of action of XT remains unknown. AIM OF THE STUDY: In this study, we used a metabolomics-based systematic method to elucidate the mechanism of XT in the treatment of cirrhotic ascites. METHODS: Decompensated liver cirrhosis was induced in rats by intraperitoneal injection of Carbon tetrachloride (CCl4). Ultra performance liquid chromatography-mass spectrometry (UPLC-MS) combined with pattern recognition approaches were used to determine differentiating metabolites relevant to XT treatment. Biomarkers were further validated by a targeted quantitative method and by the results from serum and urine analyses. Pathway analysis and correlation network construction were used to reveal the therapeutic targets associated with XT treatment, and the potential mechanisms were verified by the results from biochemical, histopathological and immunohistochemical assays. RESULTS: XT synergistically mediated the abnormalities of amino acid metabolic pathways in cirrhotic rats. XT significantly elevated the arginine levels, reduced the serum nitric oxide (NO) levels and alleviated the gastrointestinal motility disorder of cirrhoticrats. This effect of XT has been confirmed by the inhibition of the activities of inducible NO synthase and neuronal NO synthase in the small intestine. CONCLUSIONS: These results reveal that XT promotes gastrointestinal motility by acting on multiple targets in multiple pathways, of which the L-arginine/NO pathway is most affected.