Saikosaponins ameliorate hyperlipidemia in rats by enhancing hepatic lipid and cholesterol metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyperlipidemia is the systemic manifestation of abnormal lipid metabolism, characterized by elevated circulating levels of cholesterol and triglyceride and a high risk of cardiovascular events. Radix Bupleuri (RB) is a traditional Chinese herbal product used to treat liver diseases. Our previous study demonstrated that Saikosaponins (SSs), the most potent bioactive ingredients in RB, ameliorate hepatic steatosis. However, whether SSs have anti-hyperlipidemia effects and plausible underlying mechanisms remain elusive. AIM OF THE STUDY: To comprehensively evaluate the lipid-lowering potential of SSs against hyperlipidemia in rats. MATERIALS AND METHODS: RNA sequencing and untargeted metabolomics approaches were applied to analyze the changes in the liver transcriptome and serum lipid profile in long-term high-fat diet feeding-induced hyperlipidemia rats in response to SSs or positive drug simvastatin (SIM) intervention. RESULTS: Our data revealed that SSs significantly alleviated HFD-induced hypertriglyceridemia and hypercholesterolemia. Combined with the analysis of gene ontology enrichment analysis and gene set enrichment analysis, we found that SSs remarkably repaired the unbalanced blood lipid metabolic spectrum in a dose-dependent manner by increasing the hepatic uptake of circulating fatty acids and facilitating mitochondrial respiration in fatty acid oxidation, comparable to SIM group. In addition, SSs markedly modulated cholesterol clearance by promoting intracellular cholesterol efflux, HDL remodeling, LDL particle clearance, and bile acid synthesis. SSs also efficiently protected the liver from lipid overload-related oxidative stress and lipid peroxidation, as well as substantially exaggerated inflammatory response. CONCLUSION: Our research not only unraveled the intricate mechanisms underlying the lipid-lowering functions of SSs but also provided novel perspectives on developing an SSs-based therapeutic strategy for the treatment of hyperlipidemia. CLASSIFICATION: Metabolism.

Integrative lipidomic and transcriptomic study unravels the therapeutic effects of saikosaponins A and D on non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has become one of the most prominent causes of chronic liver diseases and malignancies. However, few therapy has been approved. Radix Bupleuri (RB) is the most frequently used herbal medicine for the treatment of liver diseases. In the current study, we aim to systemically evaluate the therapeutic effects of saikosaponin A (SSa) and saikosaponin D (SSd), the major bioactive monomers in RB, against NAFLD and to investigate the underlying mechanisms. Our results demonstrated that both SSa and SSd improved diet-induced NAFLD. Integrative lipidomic and transcriptomic analysis revealed that SSa and SSd modulated glycerolipid metabolism by regulating related genes, like Lipe and Lipg. SSd profoundly suppressed the fatty acid biosynthesis by downregulating Fasn and Acaca expression and promoted fatty acid degradation by inducing Acox1 and Cpt1a expression. Bioinformatic analysis further predicted the implication of master transcription factors, including peroxisome proliferator-activated receptor alpha (PPARα), in the protective effects of SSa and SSd. These results were further confirmed in vitro in mouse primary hepatocytes. In summary, our study uncoded the complicated mechanisms underlying the promising anti-steatosis activities of saikosaponins (SSs), and provided critical evidence inspiring the discovery of innovative therapies based on SSa and SSd for the treatment of NAFLD and related complications.

Mechanisms exploration of Angelicae Sinensis Radix and Ligusticum Chuanxiong Rhizoma herb-pair for liver fibrosis prevention based on network pharmacology and experimental pharmacologylogy.

Angelicae Sinensis Radix (Danggui) and Ligusticum Chuanxiong Rhizoma (Chuan Xiong) herb-pair (DC) have been frequently used in Traditional Chinese medicine (TCM) prescriptions for hundreds of years to prevent vascular diseases and alleviate pain. However, the mechanism of DC herb-pair in the prevention of liver fibrosis development was still unclear. In the present study, the effects and mechanisms of DC herb-pair on liver fibrosis were examined using network pharmacology and mouse fibrotic model. Based on the network pharmacological analysis of 13 bioactive ingredients found in DC, a total of 46 targets and 71 pathways related to anti-fibrosis effects were obtained, which was associated with mitogen-activated protein kinase (MAPK) signal pathway, hepatic inflammation and fibrotic response. Furthermore, this hypothesis was verified using carbon tetrachloride (CCl4)-induced fibrosis model. Measurement of liver functional enzyme activities and histopathological examination showed that DC dramatically reduced bile acid levels, inflammatory cell infiltration and collagen deposition caused by CCl4. The increased expression of liver fibrosis markers, such as collagen 1, fibronectin, α-smooth muscle actin (α-SMA) and transforming growth factor-ß (TGF-ß), and inflammatory factors, such as chemokine (C-C motif) ligand 2 (MCP-1), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and IL-6 in fibrotic mice were significantly downregulated by DC herb-pair through regulation of extracellular signal-regulated kinase 1/2 (ERK1/2)-protein kinase B (AKT) signaling pathways. Collectively, these results suggest that DC prevents the development of liver fibrosis by inhibiting collagen deposition, decreasing inflammatory reactions and bile acid accumulation, which provides insights into the mechanisms of herb-pair in improving liver fibrosis.

Evodiamine and rutaecarpine from Tetradium ruticarpum in the treatment of liver diseases.

BACKGROUND: Liver is the pivotal organ responsible for plasma protein production, biliary secretion, xenobiotic elimination, glucose and lipid homeostasis. Dysregulation of these functions usually leads to liver diseases and further related complications. The incidence of liver diseases is increasing worldwide, with high morbidity and mortality when at advanced stages, and has become significant public health concern and substential economic burden. Thus, novel therapeutic strategies for managing liver diseases progression are urgently required. T. ruticarpum is one of the most famous and frequently used herbal medicine and has been prescribed in traditional Chinese medicine (TCM) formulas for the treatment of various ailments, including liver diseases. A considerable amount of bioactive ingredients have been isolated and identified from the roots of T. ruticarpum, including alkaloids, saponins, phenols, volatile oils and other compounds. Among these compounds, evodiamine (EVO) and rutaecarpine (RUT) are believed to be the most bioactive compounds. PURPOSE: To summarize recent findings regarding to the metabolism, pharmacological/toxicological effects of EVO and RUT and to highlight the potential therapeutic effects of them against liver diseases. METHODS: Online academic databases (including PubMed, Google Scholar, Web of Science and CNKI) were searched using search terms of "T. ruticarpum", "Wu Zhu Yu", "evodiamine", "rutaecarpine", "liver" and combinations to include published studies of EVO and RUT primarily from 2004-2019. Several critical previous studies beyond this period were also included. RESULTS: Evodiamine (EVO) and rutaecarpine (RUT) are believed to be the most bioactive alkaloids in T. ruticarpum, having anti-inflammation, anti-fibrosis, anti-lipotoxicity, anti-cancer activities, and thus having potential to improve liver disorders. In the current review, we comprehensively summarized recent progresses in the studies of EVO- and RUT-mediated promising hepatoprotective effects and also provide novel insights regarding the potential use of EVO and RUT as therapeutic options for the treatment of liver diseases. CONCLUSION: With further in-depth pharmacology and pharmacokinetic studies, we believe that natural products in T. ruticarpum and their derivatives will become promising medicines with improved clinical efficacy for the treatment of liver diseases in the immediate future.