ETHNOPHARMACOLOGICAL RELEVANCECurrent treatment options for cholestatic liver diseases are limited, and addressing impaired intestinal barrier has emerged as a promising therapeutic approach. Si-Ni-San (SNS) is a Traditional Chinese Medicine (TCM) formula commonly utilized in the management of chronic liver diseases. Our previous studies have indicated that SNS effectively enhanced intestinal barrier function through the modulation of gut microbiota.AIM OF THE STUDYThis study aims to verify the therapeutic effects of SNS on cholestatic liver injury, focusing on elucidating the underlying mechanism involving the gut-liver axis.MATERIALS AND METHODSThe 16s RNA gene sequencing, non-targeted metabolomics were used to investigate the effects of SNS on the gut microbiota dysbiosis. Fecal microbiota transplantation (FMT) was conducted to identify potential beneficial probiotics underlying the therapeutic effects of SNS.RESULTSOur results demonstrated that SNS significantly ameliorated cholestatic liver injury induced by partial bile duct ligation (pBDL). Additionally, SNS effectively suppressed cholestasis-induced inflammation and barrier dysfunction in both the small intestine and colon. While SNS did not impact the intestinal FXR-FGF15-hepatic CYP7A1 axis, it notably improved gut microbiota dysbiosis and modulated the profile of microbial metabolites, including beneficial secondary bile acids and tryptophan derivatives. Furthermore, gut microbiota depletion experiments and FMT confirmed that the therapeutic benefits of SNS in cholestatic liver disease are dependent on gut microbiota modulation, particularly through the promotion of the growth of potential probiotic P. goldsteinii. Moreover, a synergistic improvement in cholestatic liver injury was observed with the co-administration of P. goldsteinii and SNS.CONCLUSIONOur study underscores that SNS effectively alleviates cholestatic liver injury by addressing gut microbiota dysbiosis and enhancing intestinal barrier function, supporting its rational clinical utilization. Furthermore, we highlight P. goldsteinii as a promising probiotic candidate for the management of cholestatic liver diseases.

01 May 2024·Journal of Ethnopharmacology

Si–Ni-San promotes liver regeneration by maintaining hepatic oxidative equilibrium and glucose/lipid metabolism homeostasis

Article

Author: Ma, Tonghui ; Li, Xiang ; Yang, Xu ; Zhang, Junqi ; Li, Yanghao ; Zhang, Bo ; Hu, Huiting

ETHNOPHARMACOLOGICAL RELEVANCEThe efficacy of clinical treatments for various liver diseases is intricately tied to the liver's regenerative capacity. Insufficient or failed liver regeneration is a direct cause of mortality following fulminant hepatic failure and extensive hepatectomy. Si-Ni-San (SNS), a renowned traditional Chinese medicine prescription for harmonizing liver and spleen functions, has shown clinical efficacy in the alleviation of liver injury for thousands of years. However, the precise molecular pharmacological mechanisms underlying its effects remain unclear.AIMS OF THE STUDYThis study aimed to investigate the effects of SNS on liver regeneration and elucidate the underlying mechanisms.MATERIALS AND METHODSA mouse model of 70% partial hepatectomy (PHx) was used to analyze the effects of SNS on liver regeneration. Aquaporin-9 knockout mice (AQP9^-/-) were used to demonstrate that SNS-mediated enhancement of liver regeneration was AQP9-targeted. A tandem dimer-Tomato-tagged AQP9 transgenic mouse line (AQP9-RFP) was utilized to determine the expression pattern of AQP9 protein in hepatocytes. Immunoblotting, quantitative real-time PCR, staining techniques, and biochemical assays were used to further explore the underlying mechanisms of SNS.RESULTSSNS treatment significantly enhanced liver regeneration and increased AQP9 protein expression in hepatocytes of wild-type mice (AQP9^+/+) post 70% PHx, but had no significant effects on AQP9^-/- mice. Following 70% PHx, SNS helped maintain hepatic oxidative equilibrium by increasing the levels of reactive oxygen species scavengers glutathione and superoxide dismutase and reducing the levels of oxidative stress molecules H₂O₂ and malondialdehyde in liver tissues, thereby preserving this crucial process for hepatocyte proliferation. Simultaneously, SNS augmented glycerol uptake by hepatocytes, stimulated gluconeogenesis, and maintained glucose/lipid metabolism homeostasis, ensuring the energy supply required for liver regeneration.CONCLUSIONSThis study provides the first evidence that SNS maintains liver oxidative equilibrium and glucose/lipid metabolism homeostasis by upregulating AQP9 expression in hepatocytes, thereby promoting liver regeneration. These findings offer novel insights into the molecular pharmacological mechanisms of SNS in promoting liver regeneration and provide guidance for its clinical application and optimization in liver disease treatment.

100 Deals associated with Sini San

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Indication	Country/Location	Organization	Date
Bronchitis	JP	Tsumura & Co.	01 Oct 1986
Cholecystitis	JP	Tsumura & Co.	01 Oct 1986
Cholelithiasis	JP	Tsumura & Co.	01 Oct 1986
Hyperchlorhydria	JP	Tsumura & Co.	01 Oct 1986
Stomach Ulcer	JP	Tsumura & Co.	01 Oct 1986

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