Danggui-Shaoyao-San protects against non-alcoholic steatohepatitis via modulation of hepatic APP protein, Lysosomal CTSB release, and NF-κB activation
Siting Gao,
Ziming An,
Qian Zhang,
Qinmei Sun,
Qian Huang,
Lei Shi,
Wei Liu,
Xiaojun Gou,
Yajuan Li,
Xin Xin,
Qin Feng
Affiliations
Siting Gao
Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
Ziming An
Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
Qian Zhang
Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
Qinmei Sun
Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
Qian Huang
Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
Lei Shi
Department of Clinical Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
Wei Liu
Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine, Ministry of Education, Shanghai, China
Xiaojun Gou
Central Laboratory, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai, Shanghai, China
Yajuan Li
Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Corresponding author. 1200 Cailun Road, Pudong New Area, Shanghai, 201203, China.
Xin Xin
Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine, Ministry of Education, Shanghai, China; Corresponding author. 528 Zhangheng Road, Pudong New Area, Shanghai, 201210, China.
Qin Feng
Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine, Ministry of Education, Shanghai, China; Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China; Corresponding author. 528 Zhangheng Road, Pudong New Area, Shanghai, 201210, China.
Background: Non-alcoholic steatohepatitis (NASH), an escalating global health concern, is a primary factor behind cirrhosis, liver transplantation, and hepatocellular carcinoma. Effective treatments remain elusive. Danggui-Shaoyao-San (DGSY), a classic famous prescription employed in treating NASH, could hold promise, although its molecular underpinnings are still under investigation. This study undertakes an exploration of the impacts of DGSY on NASH and seeks to illuminate the mechanisms at play. Methods: UHPLC-Q-Orbitrap HRMS was employed to identify compounds within DGSY. Mice underwent a 25-week regimen of HFHC diet and high-sugar water, with 4 weeks of DGSY treatment for efficacy and pathogenic mechanism exploration in vivo. L02 cells were cultured with 0.2 mM FFA for 24 h, exposed to DGSY at 1 mg/ml and 2 mg/ml for efficacy and pathogenic mechanism exploration in vitro. Using online databases, we sought potential targets for NASH treatment, and through PPI networks, identified key targets. Expression levels of genes and proteins were examined by western blotting, RT-PCR, and immunofluorescence staining. Results: Thirty-four compounds were identified within DGSY. DGSY brought about marked reductions in biochemical indicators and yielded significant improvements in NASH mice histological features. Additionally, it mitigated hepatic steatosis and inflammation both in vivo and in vitro. The top 10 targets from two network pharmacology analyses, one focusing on structural prediction and the other on literature mining, identified APOE and APP as potential therapeutic targets for DGSY in NASH treatment. PCR validation confirmed that DGSY reduced APP expression after treatment, and further investigation revealed that DGSY significantly suppressed hepatic APP and Aβ expression, indicating its effectiveness in treating NASH. Furthermore, it inhibited Aβ-induced Cathepsin B lysosomal release, reducing hepatic inflammation. Conclusion: Danggui-Shaoyao-San has anti-steatohepatitis effects in ameliorating hepatic APP protein expression, reducing hepatic lysosomal CTSB release, and suppressing hepatic NF-κB activation. The study provided a more theoretical basis for the future clinical application of DGSY.
