Ger-Gen-Chyn-Lian-Tang (GGCLT), an officially standardized mixture of Chinese herbal medicines, consists of Puerariae Radix, Scutellariae Radix, Coptidis Rhizoma, and Glycyrrhizae Radix in a ratio of 8:3:3:2.1 In this issue of the Journal of the Chinese Medical Association, Chang and his colleagues1 evaluated the possible effects and mechanism of GGCLT on thioacetamide (TAA)-induced hepatic injury and fibrosis in mice. Incremental doses (30 mg/kg/day, 100 mg/kg/day, and 300 mg/kg/day) of GGCLT were orally administered to mice for as long as 6 weeks, similar to the intraperitoneal TAA injection period as noted in Chang et al's1 study. Conclusively, their study reported that chronic GGCLT treatment effectively ameliorated hepatic fibrosis by decreasing hepatic oxidative stress and modulating transforming growth factor (TGF)-β/TGF-β receptor/smooth muscle α-actin signaling in TAA mice.
Cumulative studies had reported the preventive effects of Chinese medicine in experimental models and patients with chronic hepatitis.2–9 The first active component of GGCLT, pueratin (diadzein 8-C-glucoside) is the major isoflavonoid derived from the Chinese medical herb Radix puerariae (kudzu root). In China, R. puerariae is known as GeGen, and has been used as a traditional medicine for treating various diseases.2–6 The protective mechanisms of puerarin, at least in part, are related to its ability to increase superoxide dismutase activity, decrease lipid peroxidation, and enhance fibronolysis.3 In mice, pretreatment with puerarin prior to administration of carbon tetrachloride (CCl4) substantially prevented the elevation of liver function and hepatic malondialdehyde (oxidants) formation in a dose-dependent manner. In addition, pretreatment with puerarin significantly prevented both the depletion of reduced glutathione (antioxidants) content and the decrease in glutathione S-transferase activity, and histological liver damage severity in the liver of CCl4-intoxicated mice.4 In rats with chronic alcohol-induced liver injury, the liver function test and proinflammatory cytokines were significantly reduced following puerarin treatment. In addition, the endogenous levels of tumor necrosis factor-α (TNF-α) and nuclear factor-κB (NF-κB) proteins in the liver tissue were effectively decreased following the puerarin treatment. Together, these findings demonstrate that puerarin mediates hepatoprotection against alcohol-induced liver injury by the inhibition of inflammatory response and downregulation of the TNFα/NFκB pathway, thereby maintaining metabolic homeostasis in the liver.5 Additionally, chronic puerarin treatment inhibits endotoxin gut leakage, Kupffer cell activation, endotoxin receptors expression, and alleviate chronic alcoholic liver injury in rats.6
The second active component of GGCLT, baicalin is a major bioactive flavonoid isolated from the radix of Scutellaria baicalensis GeorGi, which is widely used in traditional Chinese medicine to treat inflammation.7 In mice, acute baicalin pretreatment protected against lipopolysaccharide/D-galactosamine-induced liver injury, including dose-dependent alleviation of mortality and hepatic pathological damage, decrease of aspartate aminotransferase/alanine aminotransferase release, inhibition of NFκB activity to reduce TNF-α production and increase antioxidants.8 Moreover, baicalin dose-dependently increased heme oxygenase (HO-1) protein expression and activity. Further, inhibition of HO-1 activity significantly reversed the protective effect of baicalin against lipopolysaccharide/D-galactosamine-induced liver injury.8 Furthermore, acute baicalin treatment inhibited the typical CCl4-induced liver damage portal inflammation, centrizonal necrosis, and Kupffer cell hyperplasia, The beneficial effects of baicalin protect hepatocytes by inhibition of the proinflammatory mediators, downregulation of TNF-α/inducible nitric oxide synthase (iNOS) and upregulated HO-1 in mice.9 The antifibrotic effects of baicalin had also been reported to act through the depression of peroxisomal proliferator-activated receptor γ in hepatic stellate cells.10
The third active component of GGCLT, berberine is an active compound in Coptidis Rhizoma (Huanglian) with anti-inflammatory and antioxidative stress effects.11 It had been reported that acute berberine treatment possesses hepatoprotective effects against CCl4-induced hepatotoxicity by increasing the hepatic superoxide dismutase activity.11In vitro study suggested that berberine effectively prevented CCl4-induced liver fibrosis in mice by inducing cell cycle arrest in G1 phase and a decrease in the number of activated hepatic stellate cells.12
Licorice root is an herbal preparation that has been used to reduce liver injury in a number of clinical disorders.13 The forth active component of GGCLT, glycyrrhizin is the principal triterpene component of licorice root that shows beneficial effects for patients with chronic hepatitis C.13 It had been reported that acute administration of glycyrrhizin alleviates CCl4-induced acute liver injury, and this protection is likely to be due to the induction of HO-1 and downregulation of proinflammatory mediators.14 Potenlini is an injectable compound whose active component is glycyrrhizin, which is extracted from licorice. The results suggest that potenlini can inhibit the NFκB binding activity in CCl4 and ethanol-induced chronic liver injury and cirrhosis.15
Taking together, the protective effects of four components, including puerariae, baicalin, berberine, and glycyrrhizin, of GGCLT in acute and chronic liver injury are mainly mediated by the inhibition of hepatic oxidative stress, TNFα/NFκB/iNOS signal pathway, inflammatory mediator release, activated HSCs and upregulation of HO-1. In the Chang et al1 study, chronic GGCLT treatment prevented liver fibrosis by the inhibition of various profibrogenic markers including oxidative stress, NFκB, TGFβ (receptor), and smooth muscle α-actin (maker of the activated HSCs) in a TAA mice model. Notably, the chronic effects of GGCLT in the TNFα/iNOS and HO-1 signal pathway as well as inflammatory mediators release should be further explored in future studies in a TAA mice model. Nonetheless, the additional traditional herbal medicines reported by Chang et al1 are noteworthy as potential agents to treat hepatic fibrosis.
Conflicts of interest
The author declares that there are no conflicts of interest related to the subject matter or materials discussed in this article.
Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
1. Chang ZY, Lee TY, Huang TH, Wen CK, Chien RN, Chang HH. Hepatoprotective effects of Ger-Gen-Chyn-Lian-Tang in thioacetamide-induced fibrosis in mice. J Chin Med Assoc
2. Yeung DKY, Leung SWS, Xu YC, Vanhoutte PM, Man RY. Puerarin, an isoflavonoid derived from Radix puerariae
, potentiates endothelium-independent relaxation via the cyclic AMP pathway in porcine coronary artery. Eur J Pharmacol
3. Gao Q, Yang B, Ye ZG, Wang J, Bruce IC, Xia Q. Opening the calcium-activated channel participates in the cardioprotective effect of puerarin. Eur J Pharmacol
4. Hwang YP, Choi CY, Chung YC, Jeon SS, Jeong HG. Protective effects of puerarin on carbon tetrachloride-induced hepatotoxicity. Arch Pharm Res
5. Li R, Liang T, He Q, Guo C, Xu L, Zhang K, et al. Puerarin, isolated from Kudzu root (Wild.), attenuates hepatocellular cytotoxicity and regulates the GSK-3β/NF-κB pathway for exerting the hepatoprotection against chronic alcohol-induced liver injury in rats. Int Immunopharmacol
6. Peng JH, Cui T, Huang F, Chen L, Zhao Y, Xu L, et al. Puerarin ameliorates experimental alcoholic liver injury by inhibition of endotoxin gut leakage, Kupffer cell activation, and endotoxin receptors expression. J Pharmacol Exp Ther
7. Taira Z, Yabe K, Hamaguchi Y, Hirayama K, Kishimoto M, Ishida S, et al. Effects of Sho-saiko-to extract and its components, baicalin, baicalein, glycyrrhizin and glycyrrhetic acid, on pharmacokinetic behavior of salicylamide in carbon tetrachloride intoxicated rats. Food Chem Toxicol
8. Wan JY, Gong X, Zhang L, Li HZ, Zhou YF, Zhou QX. Protective effect of baicalin against lipopolysaccharide/D-galactosamine-induced liver injury in mice by up-regulation of heme oxygenase-1. Eur J Pharmacol
9. Park SW, Lee CH, Kim YS, Kang SS, Jeon SJ, Son KH, et al. Protective effects of baicalin against carbon tetrachloride-induced acute hepatic injury in mice. J Pharmacol Sci
10. Yang MD, Chiang YM, Higashiyama R, Asahina K, Mann DA, Mann J, et al. Rosmarinic acid and baicalin epigentically depress peroxisomal proliferator-activated receptor γ in hepatic stellate cells for their antifibrotic effect. Hepatology
11. Chao J, Liao JW, Peng WH, Lee MS, Pao LH, Cheng HY. Antioxidant, analgesic, anti-inflammatory and hepotoprotective effects of the ethanol extract of Mahonia oiwakensis
stem. Int J Mol Sci
12. Sun X, Zhang X, Hu H, Lu Y, Chen J, Yasuda K, et al. Berberine inhibits hepatic stellate cell proliferation and prevents experimental liver fibrosis. Biol Pharm Bull
13. Kumada H. Long-term treatment of chronic hepatitis C with glycyrrhizin [stronger neo-minophagen C (SNMC)] for preventing liver cirrhosis and hepatocellular carcinoma. Oncology. 2002;62(Suppl 1):94-100.
14. Lee CH, Park SW, Kim YS, Kang SS, Kim JA, Lee SH, et al. Protective mechanism of glycyrrhizin on acute liver injury induced by carbon tetrachloride in mice. Biol Pharm Bull
15. Wang JY, Guo JS, Li H, Liu SL. Inhibitory effect of glycyrrhizin on NF-κB binding activity in CC14
- plus ethanol-induced liver cirrhosis in rats. Liver