A comprehensive review and perspectives on pharmacology and toxicology of saikosaponins.

BACKGROUND: Radix Bupleuri (RB) has been widely used in Chinese Traditional Medicine for over 2000 years and is currently marketed in China as Chai-Hu-Shu-Gan tablets and Xiao-Yao-Wan tablets. Saikosaponins (SSs, especially SSa, SSc and SSd), as the major bioactive compounds in RB, represent anti-inflammatory, anti-tumor, anti-oxidant, anti-viral and hepatoprotective effects. PURPOSE: To summarize recent findings regarding to the extraction, detection, biosynthesis, metabolism, pharmacological/toxicological effects of SSs. METHODS: Online academic databases (including PubMed, Google Scholar, Web of Science and CNKI) were searched using search terms of "Saikosaponin", "Radix Bupleuri", "Bupleurum" and combinations to include published studies of SSs primarily from 2003 to 2018. Several critical previous studies beyond this period were also included. RESULTS: 354 papers were found and 165 papers were reviewed. SSs have drawn great attention for their anti-inflammation, anti-viral and anti-cancer effects and contradictory roles in the regulation of cell apoptosis, oxidative stress and liver fibrosis. Meanwhile, increased risks of overdose-induced acute or accumulation-related chronic hepatotoxicity of SSs and RB have also been reported. However, underlying mechanisms of SSs bioactivities, the metabolism of SSs and bioactivities of SSs metabolites are largely unknown. CONCLUSION: This comprehensive review of SSs provides novel insights and perspectives on the limitations of current studies and the importance of metabolism study and the dose-pharmacological/toxic relationship of SSs for the future discovery of SSs-based therapeutic strategies and clinical safe practice.

Toxic polyacetylenes in the genus Bupleurum (Apiaceae) - Distribution, toxicity, molecular mechanism and analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Bupleurum includes approximately 200 species that are widely distributed in the Northern Hemisphere, Eurasia and North Africa. Certain species of this genus have long been used as antiphlogistic, antipyretic and analgesic agents in traditional folk medicine. As described in the Chinese Pharmacopoeia, the roots of Bupleurum chinense DC. and B. scorzonerifolium Willd. are the herbal materials that compose Chaihu (Radix Bupleuri), a well-known TCM herb. AIM OF THE REVIEW: This review aims to provide up-to-date and comprehensive information regarding the distribution, toxicity, molecular mechanism and relatively new methods for the qualitative and quantitative determination of polyacetylenes in different Bupleurum species. METHOD: The information needed for this paper were sourced from publishing sites such as Elsevier, science Direct, PubMed; electronic search engines such as Scopus and Web of Science, Google scholar; other scientific database sites for chemicals such as ChemSpider, PubChem, SciFinder, and also from on line books. RESULTS: Polyacetylenes, which are widely distributed in genus Bupleurum of the Apiaceae family, have high toxicity. Among polyacetylenes, bupleurotoxin, acetylbupleurotoxin and oenanthotoxin have strong neurotoxicity. Through previous research, it was found that the toxicity of Bupleurum polyacetylenes manifested as epileptic seizures, with the target of toxicity being the brain. The neurotoxicity of polyacetylenes exhibits a relationship with the γ-aminobutyric acid (GABA) receptor pathway, and polyacetylenes have been shown to inhibit GABA-induced currents (IGABA) in a competitive manner. CONCLUSIONS: The plants of genus Bupleurum have been used in traditional medicine for thousands of years. However, certain species of this genus are poisonous, and it was attributed to the high content of polyacetylenes. The present review indicates that certain polyacetylenes in the genus Bupleurum have highly neurotoxic effects. The major challenge with regard to toxic polyacetylenes is to test their neurotoxic effects in vivo as well as in further preclinical studies, which will require large amounts of purified polyacetylenes. More reference substances should be prepared, and sophisticated analytical technologies should be developed to comprehensively assess the quality of Radix Bupleuri herbs. These investigations will be helpful for further utilization of the plants of genus Bupleurum.

Activation of Fas death receptor pathway and Bid in hepatocytes is involved in saikosaponin D induction of hepatotoxicity.

Drug-induced liver injury can lead to acute liver failure. Saikosaponin D (SSD) is a major component isolated from the medicinal herb Bupleurum falcatum, which has been linked to hepatotoxicity. We previously reported that SSD disrupted PDGF-ßR pathway leading to mitochondrial apoptosis in human LO2 hepatocytes. The present study was aimed at further exploring the underlying mechanisms in vitro and in vivo. We initially determined the concentration range of SSD at up to 2µM for subsequent apoptosis examinations. SSD significantly upregulated Fas expression, promoted caspase-8 cleavage and activated the pro-apoptotic protein Bid in LO2 cells. Moreover, SSD reduced the abundance of cytochrome c in mitochondria and increased the cleaved-caspase-3 in LO2 cells, but did not apparently affect PI3K/AKT, ERK and STAT3 pathways that are involved in cell fate regulation. Experiments in vivo showed that one-week treatment with SSD at 300 mg/kg significantly elevated the liver/body weight ratio and caused histological injury in mouse liver. Furthermore, SSD treatment induced massive hepatocyte apoptosis, and significantly downregulated Bcl-2 but upregulated Bax in mouse liver. Taken together, these results revealed a specific mechanism of activation of extrinsic apoptosis pathway and Bid by SSD, which was involved in SSD-induced mitochondrial apoptosis in hepatocytes and potential hepatotoxicity.

Herb-induced autoimmune-like hepatitis in C57BL/6J mice.

BACKGROUND & AIMS: Animal model suitable for studying herb-induced experimental autoimmune hepatitis (AIH) remains a challenging problem. A medicinal herb containing Scutellaria baicalensis Georgi (Sb) and Bupleurum chinense DC (Bc) has been sporadically reported to be related to liver fibrosis. The aim of this study was to investigate the effects of Sb and Bc on experimental AIH in mice. METHODS: C57BL/6J mice received intraperitoneal injection of Sb and/or Bc herbal extracts (1 mg/kg) for 4 or 8 weeks. Serum samples were collected to analyse serum transferase (AST, ALT), creatinine, markers for AIH and hepatic cytokine levels such as IFN-γ, IL10 and TGF-ß1. Peripheral mononuclear cell (PBMC) gene expression profiles were analysed to show their effects on immune system. RESULTS: Our results showed that Sb or Bc treatment increased serum AST, ALT, IgG and ANA levels. Prominent necroinflammatory changes were demonstrated in the livers of Sb- or Bc-treated mice while the decrease in IFN-γ and elevation of IL10 and TGF-ß1 levels in liver tissues. Furthermore, the PMBC gene expression profile suggested that Sb or Bc treatment could modulate immune responses. CONCLUSION: We conclude that the presence of AIH in Sb- or Bc-treated mice and C57BL/6J strain mice is a reliable animal model for studying herb-induced AIH-like hepatitis.

Toxicological aspects of Kampo medicines in clinical use.

Among 210 medicinal prescriptions used in present-day Japan, the clinical uses and the acute, chronic and mutagenic toxicity study of 16 Kampo (Japanese herbal) medicines are summarized. These Kampo medicines are classified into two categories; eight prescriptions containing Bupleurum root (Bupleurum falcatum L.) such as Sho-saiko-to and Saiko-keishi-to, and eight prescriptions not containing Bupleurum root such as Juzen-taiho-to and Ninjin-yoei-to. Studies of some potential interaction between herbal medicine and western drugs are also described.