The Novel Chinese Medicine JY5 Formula Alleviates Hepatic Fibrosis by Inhibiting the Notch Signaling Pathway

Abstract

Advanced liver fibrosis can lead to cirrhosis, resulting in an accelerated risk of hepatocellular carcinoma and liver failure. Fuzheng Huayu formula (FZHY) is a traditional Chinese medicine formula treated liver fibrosis in China approved by a Chinese State Food and Drug Administration (NO: Z20050546), composed of Salvia Miltiorrhiza bge., Prunus davidiana (Carr.) Franch., cultured Cordyceps sinensis (BerK.) Sacc. Mycelia, Schisandra chinensis (Turcz.) Baill., Pinus massoniana Lamb., and Gynostemma pentaphyllum (Thunb.) Makino. However, the main active substances and mechanism of FZHY are unclear. The aim of this study is to identify a novel anti-fibrotic compound, which consists of the main active ingredients of FZHY, and investigate its mechanism of pharmacological action. The main active ingredients of FZHY were investigated by quantitative analysis of FZHY extracts and FZHY-treated plasma and liver in rats. The anti-fibrotic composition of the main active ingredients was studied through uniform design in vivo, and its mechanism was evaluated in carbon tetrachloride (CCl4)- and bile duct ligation (BDL)-induced liver fibrosis models in rats and mice, and transforming growth factor beta 1-induced LX-2 cell activation model in vitro. A novel Chinese medicine, namely JY5 formula, consisting of salvianolic acid B, schisantherin A, and amygdalin, the main active ingredients of FZHY, significantly alleviated hepatic hydroxyproline content and collagen deposition in CCl4-and BDL-induced fibrotic liver in rats and mice. In addition, JY5 inhibited the activation of hepatic stellate cells (HSCs) by inactivating Notch signaling in vitro and in vivo. In this study, we found a novel JY5 formula, which exerted anti-hepatic fibrotic effects by inhibiting the Notch signaling pathway, consequently suppressing HSCs activation. These results provide an adequate scientific basis for clinical research and application of the JY5 formula, which may be a potential novel therapeutic candidate for liver fibrosis.

Traditional Chinese medicine: An important source for discovering candidate agents against hepatic fibrosis

“…In the CCl 4 -and BDL-induced hepatic fibrosis rat experiment, after treatment with JY5 (salvianolic acid B: 16 mg/kg, schisantherin A: 2 mg/kg, amygdalin: 0.5 mg/kg), significantly alleviated hepatic injury and collagen deposition, the expressions of Jagged1, Notch2, Notch3, Notch4 and recombination signal binding protein-κB (RBP-κB) were significantly decreased. Meanwhile, consistent results were obtained in CCl 4 -induced hepatic fibrosis in mice, after JY5 (salvianolic acid B, 16 mg/kg amygdalin, 0.5 mg/kg schisantherin A, 2 mg/kg) treatment (Fu et al, 2021). These results suggest that JY5 could significantly inhibit the activation of Notch signaling pathway in CCl 4 -and BDL-induced liver fibrosis.…”

“…Moreover, FZHY dramatically elevated the expression of Hexokinase 2 (Hk2) and glutamine synthetase (Gs), regulated the both glucose metabolism and amino acid metabolism as well as reduced dehydrogenase 1 (Adh1), acetyl-CoA synthetase 2 (Acss2) and glutamic-pyruvictransaminase (Gpt) ( Hu et al, 2019 ), suggested FZHY has good anti-hepatic fibrosis effect via altering the metabolic pathways. Fu et al (2021) found a novel Chinese medicine, namely JY5 formula, composed of salvianolic acid B, schisantherin A and amygdalin, the main active ingredients of FZHY, and evaluated its anti-hepatic fibrosis activity both in vitro and in vivo . In the CCl 4 -and BDL-induced hepatic fibrosis rat experiment, after treatment with JY5 (salvianolic acid B: 16 mg/kg, schisantherin A: 2 mg/kg, amygdalin: 0.5 mg/kg), significantly alleviated hepatic injury and collagen deposition, the expressions of Jagged1, Notch2, Notch3, Notch4 and recombination signal binding protein-κB (RBP-κB) were significantly decreased.…”

“…These results suggest that JY5 could significantly inhibit the activation of Notch signaling pathway in CCl 4 -and BDL-induced liver fibrosis. Moreover, in vitro results showed, compared to the TGF-β1-induced activation of hepatic stellate cell line (LX-2) group, after treatment with JY5, at concentrations of 6.587, 13.174 and 26.348 μg/ml, the mRNA levels of α-SMA, Col-I, Jagged1, Notch2, Notch3 and RBP-кB were significantly reduced, the expression above these proteins were significantly reduced in the JY5-treated groups, and the high-dose JY5 group more significantly ( Fu et al, 2021 ). The commonly clinically used TCM formulas against HF were displayed in Table 1 .…”

Potential Therapeutic Strategies for Renal Fibrosis: Cordyceps and Related Products

“…It has nephroprotective effects in both glycerol-induced acute renal failure and adenine-induced chronic renal failure rats (Ngai et al, 2005). Cordyceps-related formulations of Novel JY5 formula (Fu et al, 2021), CGA formula Tian et al, 2019), and Fuzheng Huayu formula (Chen et al, 2019b) all have good effects against liver fibrosis, suggesting that these formulations may also be potential novel therapeutic candidates for RF.…”

Salvianolic acid B from Salvia miltiorrhiza bunge: A potential antitumor agent

“…Recently, the anticancer effects of Sal-B have been demonstrated in human cancer cell lines and in vitro studies have shown that Sal-B induces cell death and promotes apoptosis. Fu et al (2021) found a key factor in the ability of Sal-B to induce cell death is the promotion of autophagy and apoptosis in tumor cells. Moreover, Gong et al showed that Sal-B-induced cell death was associated with AKT/mTOR signaling inhibition (Gong et al, 2016).…”