The advances of traditional Chinese medicine in the treatment of liver diseases in 2019

Min Cao, Jing Miao, Li Wang, Hai-Zhao Liu, Huan-Tian Cui, Yu-Hong Bian

The advances of traditional Chinese medicine in the treatment of liver diseases in 2019

Min Cao1#, Jing Miao2#, Li Wang3, Hai-Zhao Liu1, Huan-Tian Cui4, Yu-Hong Bian5*

1Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China;2Department of Integrated Traditional and Western Medicine, Tianjin Second People’s Hospital, Tianjin 300192, China;3Department of Pharmacy, Tianjin Second People’s Hospital, Tianjin 300192, China;4Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 250100, China;5College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.

Currently, the treatment of liver diseases remains an unsolved problem due to its complicated etiology and pathogenesis. Traditional Chinese medicine (TCM) has been used for liver disease treatment for thousands of years. Disease treatment using TCM compounds conforms to the concept of “holism”, which coincides with the complicated pathogenic mechanisms of liver diseases. However, the mechanisms have not been clearly explained due to the complex components and multi-targets, which is a big obstacle TCM’s popularity and application. In recent years, studying the mechanisms and identifying the novel ingredients in herbal medicines are becoming a hot spot for many researchers. Therefore, we obtained literature in PubMed and summarized the progress of TCM’s active ingredients and formulas in treating various liver diseases in 2019. Based on the literature, flavonoids, polysaccharides, saponins, and alkaloids, as well as Chinese medicine formulas, such as Ba-Bao pill and Yin-Chen-Hao decoction, have attracted much attention. In addition, we also focused on the application of new omics analysis techniques, such as metabolomics, network pharmacology, and other omics analyses in the study of TCM formulas.

Traditional Chinese medicine, Liver diseases, Mechanism, Metabolomics, Network pharmacology, Omics analysis

This article focuses on introducing the mechanism and application prospect of the active ingredients and formulas of traditional Chinese medicine in the treatment of liver diseases in 2019. Metabolomics, transcriptomics, network pharmacology, 16S rRNA gene sequencing, and other omic analyses have been widely used in many studies in the past year.

This annual review summarizes the hot research mechanisms of traditional Chinese medicine in the treatment of liver disease, especially hepatitis, liver injury, non-alcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma in 2019, which can provide a comprehensive description of the hot spots and ongoing research areas.

Background

Liver diseases, mainly including hepatitis, liver injury, non-alcoholic fatty liver disease (NAFLD), liver fibrosis, and hepatocellular carcinoma (HCC), have become a global threat for human health due to their high global prevalence rate and poor prognosis [1]. Currently, less effective medicines have been developed to control the progression of these liver diseases. Most patients need to receive lifelong medications, increasing the economic burden of the patients and their families. Moreover, long-term medication may cause hepatotoxicity and renal toxicity, which could exacerbate the liver damage and impair renal functions [2]. Therefore, identifying more effective, safer, and cheaper medicines for liver disease treatment is becoming a necessary research focus.

Traditional Chinese medicine (TCM) has been used on liver diseases for thousands of years. However, the mechanisms have not been clearly explained due to the multi-compounds and multi-targets, which is a big obstacle for the wide use of TCM worldwide. Studying the mechanisms and identifying the novel ingredients could promote Chinese herbal medicine application. In addition, novel techniques such as metabolomics, network pharmacology, and other omics analyses have also been applied in this field. In 2019, the accumulated effort of researchers made great advances in studying the possible mechanisms of TCM on liver diseases.

In this review, we summarized the research progress of several studies on the active ingredients and formulas in treating liver diseases. Papers focusing on TCM usage in liver diseases in PubMed were searched, with “liver disease” and “traditional Chinese medicine” as the keywords. Generally, more than 700 articles were obtained from January 1, 2019 to December 31, 2019 in PubMed. We analyzed the number of literature published in different countries in 2019 via PubReMiner (https://hgserver2.amc.nl/cgi-bin/miner/miner2.cgi), a tool enabling the counting of the occurrence of certain search results within PubMed Search [3]. China contributed 679 papers in this field (Figure 1). Then, we summarized the top ten journals according to the number of published articles. Most of the articles were from the, which published 48 papers in 2019 (Figure 2). Moreover, we found that liver injury, NAFLD, liver fibrosis, and HCC were the mainly studied liver diseases (Figure 3).

Figure 1 An analysis of the number of articles regarding the use of TCM in the treatment of liver diseases published in different countries in 2019. We searched in PubReMiner (https://hgserver2.amc.nl/cgi-bin/miner/miner2.cgi) using the keywords “liver disease” and “traditional Chinese medicine” from 2019/01/01 to 2019/12/31 and analyzed the country distribution of the resulted articles.

Figure 2 The top 10 journals with publications of TCM in the treatment of liver diseases in 2019. We searched in the PubReMiner (https://hgserver2.amc.nl/cgi-bin/miner/miner2.cgi) using the keywords “liver disease” and “traditional Chinese medicine” from 2019/01/01 to 2019/12/31 to analyze the journal’s contribution.

Figure 3 The top 12 keywords in TCM on liver disease therapy in 2019. We searched in the PubMed (https://www.ncbi.nlm.nih.gov/pubmed/) database using the keywords “liver disease” and “traditional Chinese medicine” from 2019/01/01 to 2019/12/31 to analyze the keyword contribution.

Hepatitis

Hepatitis B and C virus (HBV and HCV, respectively) are the major risk factors of liver injury, liver cirrhosis, and HCC. Currently, interferon and nucleoside (acid) analogs are the first-line clinical HBV and HCV treatment medicines. However, the covalently closed circular DNA of HBV could not be eliminated completely, and long-term medication could induce side effects, such as nephrotoxicity, bone toxicity, and medicine resistance [4–5]. Clinical studies also indicated that many patients experienced recurring HBV and HCV infection after medicine withdrawal [6–7]. In 2019, several articles showed that Chinese herbs and formulas could inhibit viral replication and control hepatitis progression. The saponins extracted from Jigucao (Hance) could inhibit the DNA replication of HBV by increasing the CD4+/CD3+T cell ratio and promoting interferon (IFN)-γ secretion [5]. Empirical formulas, especially the Bushen formula, consist of Huangqi (), Nüzhenzi (Lucidi), Yinyanghuo (Maxim), Huhuanglian (), and Qingpi (), which could significantly decrease the levels of Hepatitis B surface antigen in patients with HBV, compared with entecavir treatment alone. It also showed that the regulatory T cell number and the PD-L1 expression in dendritic cells were decreased in HBV-infected patients after the combination treatment with Bushen formula and entecavir[8]. The classical prescription Yin-Chen-Hao decoction, first described in the ancient book of Chinese medicine(), is composed of 18 g of Yinchen (), 12 g of Zhizi (), and 6 g of Dahuang (.), which could improve the clinical effect of patients with HBV [7]. In addition, a survey in Taiwan compared the effects and prognosis of patients with HCV that were treated with or without TCM, such as Danshen () and Huzhang (), and found that Chinese herbal medicine, as an adjuvant treatment, reduced the total mortality of patients and lowered the risk of cirrhosis and hepatoma development [9].

Liver injury

Liver injury is usually caused by exogenous substances, such as alcohol, medicines, and chemicals, which could cause liver metabolism disorders, oxidative stress, and toxification [10]. Nuclear factor 2-related factor 2 (Nrf2) is an important transcription factor of a series of detoxification and antioxidant defense genes in the liver, which plays an important role in protecting the liver against oxidative injury. Several TCMs have been proven to activate Nrf2-related signaling pathways and their downstream key antioxidant enzymes to protect against liver injuries in 2019 [11–12].

Acute liver injury

Quercetin is a naturally occurring polyphenolic flavonoid with a great antioxidant capacity and is commonly found in Huangqi ((Fisch.) Bunge.) [13], tomatoes, and berries [14], which could attenuate toosendanin-induced acute liver injury by promoting the Nrf2-GCL-GSH antioxidant signaling pathway [11]. Magnolol, the main chemical component ofHoupo (), could prevent alcohol-induced acute liver injury by activating the PI3K-Nrf2-peroxisome proliferator-activated receptor (PPAR)γ signaling pathway and inhibiting NOD-like receptor protein 3 inflammasome [15]. Chinese patent drug Ba-Bao pill (SFDA approval number of China: Z10940006) consists of eight constituents, including natural Niuhuang (), Shedan (snake gall), Lingyangjiao (), Shexiang (), and Sanqi (), which protected against acute ethanol-induced liver injury in mice by activating the Nrf2 pathway to decrease hepatocyte oxidative stress [16]. In addition, metabolomics and 16S rRNA gene sequencing indicated that the classical prescription Yin-Chen-Hao decoction, first described in the ancient book of Chinese medicine(), could prevent carbon tetrachloride (CCL4)-induced acute liver injury by regulating 3-hydroxybutyric acid production andandratios in the gut [17].

Chronic liver injury

Hot water extracts of Zhijuzi (), including 1.08% dihydromyricetin, 0.43% dihydroquercetin, and 1.40% quercetin, could alleviate lipid deposition and inflammation response in ethanol-induced chronic liver injury by modulating abnormalities in the gut-liver axis and inhibiting the TLR4 pathway [18]. A set prescription of the Tibetan medicine San-Wei-Gan-Jiang powder, first described in the(–), is composed of three herbs, including Ganjiang (Rosc.), Caodoukou (AHayat), and Roudoukou (), which could protect against CCL4-induced chronic liver injury in rats by dynamically regulating the Nrf2–Bach1 pathway [19]. The empirical formula “Compound T11” contains 14 Chinese medicines, including Huzhang (Sieb. et Zucc.), Sharen (Lour.), Dahuang (L.), Huanglian (Franch.), Huangqin (Georgi), and nine others, which could protect against CCL4-induced liver injury by enhancing matrix metalloproteinase-2 (MMP-2) and CD147 protein expression and reducing matrix metalloproteinase inhibitor-2 expression [20].

Non-alcoholic fatty liver disease

NAFLD is a liver manifestation of metabolic or insulin resistance syndrome. NAFLD pathogenesis, including insulin resistance, lipid metabolic changes, mitochondrial dysfunction, oxidative stress, and other factors, are not fully clear [21]. Currently, no effective therapeutic medicine has been developed for NAFLD treatment, as it is a metabolic disease with multi-systems disorder [22]. A variety of active ingredients and formulas of TCM had been proven effective in treating NAFLD. Triterpenic acid-enriched fractions mainly extracted from Qingqianliu ()could decrease hepatic lipid accumulation and attenuate insulin resistance by upregulating the PI3K-Akt-GSK3β pathway invivoand in vitro models of NAFLD [23]. Resveratrol, a major compound in many traditional Chinese herbs such as Huzhang () [24], could reduce insulin resistance, hepatic steatosis, oxidative stress, and hepatic inflammation in rats with hyperuricemia-induced NAFLD by activating the silent information regulator 1 pathway [25].

The adenosine monophosphate-activated protein kinase (AMPK) is a heterotrimeric enzyme that plays an important role in maintaining energy metabolism homeostasis [26]. AMPK has been proven to regulate sterol regulatory element-binding protein 1 expression and acetyl-CoA carboxylases (ACC) in the liver. In vivo and in vitro studies showed that Midiexiang (Linn) could alleviate lipid metabolism in rats with orotic acid-induced NAFLD by regulating the AMPK-sterol regulatory element-binding protein 1c signaling pathway [27]. Swertiamarin is a secoiridoid glycoside mainly extracted from Zhangyacai ((Sieb. et Zucc.) Hook. Thoms. ex Clarke rude), which could regulate metabolic alterations in mice with fructose-induced NAFLD by downregulating regulatory SREBP-1, fatty acid synthase, and ACC1 expression [28]. Berberine, a protoberberine isoquinoline alkaloid mainly derived from Huanglian (Franch.), could ameliorate hyperlipidemia in rats with high-fat diet (HFD)-induced NAFLD by activating the SIRT3-AMPK-ACC pathway[29].

In recent years, studying TCM’s mechanisms based on metabolomics, gut microbiota, and bioinformatics analyses aroused widespread concern because of the complex components of TCM. Based on metabolomics, quercetin could protect HFD-induced NAFLD in rats by regulating fatty acid-related metabolites [30]. MDG-1, a β-D-fructan polysaccharide mainly extracted from Maidong (), could modulate the gut-liver axis to regulate lipid metabolism in mice with HFD-induced NAFLD via increasing short-chain fatty acid-producing beneficial bacteria and activating AMPK expression [31]. Ilexhainanoside D and Ilexsaponin A1, the triterpenoid saponins mainly extracted from Dongqing (Merr.), could protect HFD-induced NAFLD in mice by reducing inflammation, regulating gut microbiota, and improving the intestinal barrier function [32]. Classical prescription Shen-Ling-Bai-Zhu powder is a famous formula derived fromthe ancient book of Chinese medicine(1078–1085 C.E.), mainly consists of Renshen (C. A. Mey.), Fuling (), Baizhu (Koidz.), Shanyao (Thunb), and Sharen (Lour.). Bioinformatics analysis showed that Shen-Ling-Bai-Zhu powder could protect HFD-induced NAFLD in rats by regulating hepatic microRNA expression profiles, mainly including miR-155-5p, miR-146b-5p, miR-132-3p, and miR-34a-5p [33]. In addition, Pan et al. proved that Shen-Ling-Bai-Zhu powder could also regulate hepatic lipid metabolism in HFD-fed rats by regulating glycerophospholipid and glycerolipid metabolism [34].

Liver fibrosis

Liver fibrosis is characterized by extracellular matrix (ECM) deposit accumulation with significant collagen fiber buildup, which is largely produced by activated hepatic stellate cells (HSCs)[35]. Several studies proved that HSC activation has been considered as the most important fibrosis-promoting factor [36]. In addition, transforming growth factor-beta1 (TGF-β1) secreted by activated HSCs is the most effective fibroblast, which induces ECM accumulation and collagen production [37]. Therefore, inhibiting HSCs activation, promoting HSC apoptosis, or regulating the TGF-β-related signaling pathways are the major mechanisms for liver fibrosis treatment. Jinyinhua (Flos)could inhibit HSC activation in mice with CCL4-induced liver fibrosis by activating the Nrf2 pathway [38]. Moreover, 4-hydroxy-2 (3H) -benzoxazolone, isolated from Laoshule (), could improve the condition of CCL4-induced liver fibrosis in rats by inhibiting the TGF-β1-Smad signaling pathway to inhibit HSC activation [39].Wenyujin ()could inhibit the activation and proliferation of HSCs in rats with pig-serum-induced hepatic fibrosis and reduce ECM accumulation by regulating the TGF-β-Smad signaling pathway and upregulating the MMP-2-matrix metalloproteinase inhibitor-1 ratio [40]. Salvianolic acid B, an effective water-soluble component of Danshen (.), could inhibit the activation of HSCs isolated from human liver specimens by downregulating the myocyte enhancer factor-2 signaling pathway [41]. Corilagin is a polyphenol mainly extracted from Zhuzicao (L.) [42], which could prevent liver fibrosis by blocking the miR-21-regulated TGF-β1-Smad signaling pathway in vivo and in vitro[43].

In addition, transcriptomic analysis showed that schisandrin B, one of the bioactive components mainly extracted from Wuweizi (), could alleviate CCL4-induced liver fibrosis by regulating oxidation-reduction, endoplasmic reticulum stress, and apoptosis-related biological processes [44]. Based on metabolomics, bear bile powder could attenuate dimethylnitrosamine-induced liver fibrosis in rats by promoting PPARα and PPARγ expressions in the liver [45]. Network pharmacology analysis showed that the empirical formula Danshiliuhao granule, composed of Jinqiancao (), Huzhang (), Dahuang (), Zhizi (), Zhiqiao (), Muxiang (), Yanhusuo (), and Mangxiao (), could inhibit liver fibrosis by regulating multiple targets and multiple pathways, such as the PI3K-Akt-FoxO and Ras signaling pathways [46].

Hepatocellular carcinoma

Liver cancer is the second leading cause of cancer-related death. About 780,000 people worldwide die of liver cancer annually [47]. HCC accounts for approximately 90% of primary liver cancer[48]. However, most of the patients with HCC were diagnosed at the middle and late stage, which could not reach the standard of surgical operation. Furthermore, major cancer therapies, such as radiotherapy, chemotherapy, targeted therapeutics, and radiofrequency ablation, do not work well on HCC due to the hepatotoxicity and unresponsiveness to radio-chemotherapy [47, 49]. In addition, the first-line medicines for patients with HCC could cause adverse effects, including gastrointestinal reaction, anaphylaxis, myelosuppression, kidney damage, and neurovirulence [50].

TCM has been proven to play an important role in cancer recurrence and metastasis prevention, toxicity reduction, and the prolonged survival of patients with cancer [49]. Several TCM active ingredients have been proven to have therapeutic effects on HCC by inhibiting cell proliferation and migration, and inducing cancer cell apoptosis.The ethanol extract of Nüzhenzi (.), which is rich in total phenylpropanoid glycosides and secoiridoids, could inhibit HCC cell invasion, migration, and tumor growth by regulating the expression of factors related to apoptosis and cell cycle arrestin vivo and in vitro[50]. Theethanol extracts of Mutong ((Thunb.) koidz seed), mainly including Akebia saponin D, Akebia saponin E, and α-hederin, could inhibit human HCC cell adhesion, migration, and invasion [51]. Aloperine, a quinolizidine alkaloid from Kudouzi (L.), could induce human HCC cell apoptosis and G2/M cell cycle arrest by inhibiting the PI3K-Akt signaling pathway [52]. Psoralen is the main active component of Buguzhi (), which could induce cell cycle arrest in the G1 phase and apoptosis, inhibit malignant proliferation of human HCC cells by triggering endoplasmic reticulum stress [53].In vitro and in vivo studies showed that dioscin, a natural steroidal saponin mainly extracted from Shuyu () [54], could inhibit proliferation and migration and induce apoptosis in human HCC cells by adjusting the TP53-inducible glycolysis and apoptosis regulator-mediated signaling pathway [55].

In addition, the structural abnormalities of tumor vessels may reduce anticancer treatment efficacy. Normalizing the disordered tumor vasculature is a novel method for anticancer therapeutics. Huangqi () and Wenyujin () could promote vascular normalization in tumor-derived endothelial cells of human HCC by regulating CD34 and hypoxia-inducible factor-1α expressions [56]. Moreover, combination therapy with astragali polysaccharide and curcumin, the primary active constituents of Huangqi()andWenyujin() respectively, could inhibit tumor growth in orthotopic nude mice with HCC via improving the tumor vascular morphological structure and inducing tumor vascular normalization [57]. Emodin, aloe-emodin, and rhein are the main components of Dahuang (), which could inhibit the proliferation, migration, and angiogenesis and induce apoptosis of liver cancer cells by inhibiting signal transducer and activator of transcription 3 expression and phosphorylation [58].

MiRNAs are generally considered to manage gene expression at the post-transcriptional level and are considered to be important physiologic disease progression regulators. The latest research showed that miRNAs play an important role in liver cancer occurrence and development, and they directly affect cell growth and metastasis by targeting specific protein-coding genes [59]. Luteolin, a natural flavonoid mainly extracted from Shanyao (Thunb.), could inhibit liver cancer cell proliferation by upregulating miR-6809-5p expression and downregulating flotillin 1expression [60]. Hydroxygenkwanin is a natural flavonoid mainly extracted from Yuanhua (), which could inhibit liver cancer cell proliferation and migration by inducing the expression of miR-320a, which, in turn, inhibits the expression of the forkhead box protein M1 transcription factor [48]. Geniposide is mainly extracted from Zhizi (Ellis), which could inhibit hepatoma cell proliferation and migration via inhibiting the Wnt-β-catenin and AKT cascades to target the downregulation of microRNA-224 [59].

In addition, Saikosaponin D, an active ingredient mainly extracted from Chaihu (), could inhibit the growth and enhance the radio sensitivity of hepatoma cells by inducing autophagy [61]. Atractylon is a sesquiterpenoid mainly extracted from Cangzhu ((Thunb.) DC.) and Beicangzhu ((DC.) Koidz.), which could inhibit liver cancer cell migration and invasion by inhibiting epithelial-to-mesenchymal transition and downregulating MMP-2 and MMP-9 expressions to reduce the mitochondrial membrane potential (ΔΨm) and induce cancer cell apoptosis [62]. Chinese patent drug Shaoyao Ruangan formula (SFDA approval number of China: Z20100018) contains 19 Chinese herbal medicines, including Baihuasheshecao (Willd.), Huangqin (Georgi.), Qingyangshen (.), Wenyujin (Y. H. Chen et C. Ling.), Sanleng (Buch. -Ham.), and 14 more components,which could effectively inhibit tumor progression in mice with primary liver cancer by regulating intestinal flora homeostasis[63].

Other liver diseases

Hepatic encephalopathy (HE) is a neuropsychiatric disease caused by serious liver damage or failure. According to the research, 30–45% of patients with cirrhosis will develop into HE. Elevated blood ammonia levels and an abnormal electroencephalograph result are the common manifestations of HE. Hyperammonemia could impair brain metabolism, astrocyte volume regulation, and mitochondrial function, and may develop neuropsychological symptoms. Lycium barbarum polysaccharides, the major active component of Gouqizi (), could improve liver/brain injury and motor dysfunction in mice with HE by regulating the liver and brain MAPK pathways, TNF-α, interleukin-6, and ammonia [64]. Ba-Bao pill could alleviate hepatic encephalopathy in rats by reducing blood and brain ammonia levels and regulating the TLR4-MyD88-NF-κB pathway to induce anti-inflammatory effects [65].

Acute liver failure (ALF) is a rare but life-threatening syndrome, which presents a rapid deterioration of liver function and potential multiorgan failure [66]. In vivo and in vitrostudies showed that the empirical formula Jie-Du-Hua-Yu formula, which consists of six herbs, including Chishao (), Yinchenhao (), Dahuang (), Yujin (), Baihuasheshecao (), and Shichangpu (), could treat lipopolysaccharide/D-galactosamine-induced ALF in rats by inhibiting the NF-κB-mediated inflammatory pathway [66]. Acute-on-chronic liver failure (ACLF) is a type of ALF, which is characterized by early chronic liver disease or cirrhosis combined with organ failure, and is associated with high short-term mortality [67][68]. The empirical formula Jieduan-Niwan formula contains ten Chinese herbs, including Yexiazhu (Linn.), Honghuayanhuangqi (Maxim.), Gualou (Maxim),Jinqiancao(Hance), and Hujisheng (Heyne), which could protect the liver and attenuate hepatocyte apoptosis in rats with ACLF by inhibiting the E2F1-mediated intrinsic apoptosis pathway [69]. The modified classic ancient formula Sini decoction consists of Wutou (), Gancao (), Shengjiang (), Wumei (), Renshen (), and other components, which could improve liver function and prolong the 12-week survival rate of patients with HBV-related ACLF [67].

Conclusion and perspective

Although Western medicine usually adopts symptomatic support to treat various chronic liver diseases, the current status of liver disease treatment is still not optimistic due to its complicated pathogenic factors and mechanisms [1]. TCM has accumulated a lot of experience in the liver disease treatment and achieved unique curative effects with the guiding concept of “holism” and the ideology of syndrome differentiation and treatment. However, the clinical curative effects of most TCM compounds are obvious, but there is lack of further laboratory experiments to prove its complex mechanics. Therefore, we summarized several researches on the active ingredients of traditional Chinese herbs used in liver disease treatment in 2019, which is mainly focused on their antioxidant effects to treat liver injury, lipid metabolism regulation to treat NAFLD, HSC inhibition to treat liver fibrosis, and inhibition of proliferation or promotion of apoptosis of liver cancer cells to treat HCC. In addition, TCM, especially the Chinese medicine formulas, is characterized by target-pathway-faceted integrated regulation because of its complex composition and structural types. Based on these findings, several researchers are committed to investigating more diversified ways to explore the specific mechanisms of TCM in treating various diseases. Therefore, metabolomics, transcriptomics, network pharmacology, 16S rRNA gene sequencing, and other omic analyses have been used in many studies. Metabolomics analysis could reflect the overall dynamic metabolic characteristics of biological systems and metabolic networks affected by pathologic stimulation or drug intervention [45]. Network pharmacology combines systemic biology, multi-directional pharmacology, bioinformatics, and other disciplines. Based on the “disease-gene-target-medicine” interaction network, it systematically observes the intervention and influence of medicines on the disease network, reflecting the new trend of systematic research of compound Chinese medicine in the era of big data [70]. The use of new omics analysis is in accordance with the concept of “holism” and could provide systematic views for future studies on TCM mechanisms [71].

1. Shi MJ, Dong BS, Yang WN, et al. Preventive and therapeutic role of Tanshinone A in hepatology. Biomed Pharmacother 2019, 112: 108676.

2. Sun D, Zhu L, Yao D, et al. Recent progress in potential anti-hepatitis B virus agents: structural and pharmacological perspectives. Eur J Med Chem 2018, 147: 205–217.

3. Holleman F, Uijldert M, Donswijk LF, et al. Productivity of authors in the field of diabetes: bibliographic analysis of trial publications. BMJ 2015, 351: h2638.

4. Wong GL, Seto WK, Wong VW, et al. Review article: long-term safety of oral anti-viral treatment for chronic hepatitis B. Aliment Pharmacol Ther 2018, 47: 730–737.

5. Yao X, Li Z, Gong X, et al. Total saponins extracted from Abrus cantoniensis Hance suppress hepatitis B virus replication in vitro and in rAAV8-1.3HBV transfected mice. J Ethnopharmacol 2020, 249: 112366.

6. Chi H, Li Z, Hansen BE, et al. Serum level of antibodies against hepatitis B core protein is associated with clinical relapse after discontinuation of nucleos(t)ide analogue therapy. Clin Gastroenterol Hepatol 2019, 17: 182–191 e181.

7. Xu L, Xie T, Shen T, et al. Yinchenhao decoction for chronic hepatitis B: protocol for a systematic review and meta-analysis. Medicine (Baltimore) 2019, 98: e14648.

8. Ji LS, Gao QT, Guo RW, et al. Immunomodulatory effects of combination therapy with Bushen formula plus entecavir for chronic hepatitis B patients. J Immunol Res 2019, 2019: 8983903.

9. Tsai FJ, Cheng CF, Chen CJ, et al. Effects of Chinese herbal medicine therapy on survival and hepatic outcomes in patients with hepatitis C virus infection in Taiwan. Phytomedicine 2019, 57: 30–38.

10. Odeyemi S, Dewar J. Repression of Acetaminophen-induced hepatotoxicity in HepG2 cells by polyphenolic compounds from(L.f.) R.H. Archer. Molecules 2019, 24.

11. Jin Y, Huang ZL, Li L, et al. Quercetin attenuates toosendanin-induced hepatotoxicity through inducing the Nrf2/GCL/GSH antioxidant signaling pathway. Acta Pharmacol Sin 2019, 40: 75–85.

12. Kwon SH, Lee SR, Park YJ, et al. Suppression of 6-hydroxydopamine-induced oxidative stress by hyperoside via activation of Nrf2/HO-1 signaling in dopaminergic neurons. Int J Mol Sci 2019, 20.

13. Wang Y, Dong B, Xue W, et al. Anticancer effect ofon cholangiocarcinoma in vitro and its mechanism via network pharmacology. Med Sci Monit 2020, 26: e921162.

14. Rauf A, Imran M, Khan IA, et al. Anticancer potential of quercetin: a comprehensive review. Phytother Res 2018, 32: 2109–2130.

15. Liu X, Wang Y, Wu D, et al. Magnolol prevents acute alcoholic liver damage by activating PI3K/Nrf2/PPARgamma and inhibiting NLRP3 signaling pathway. Front Pharmacol 2019, 10: 1459.

16. Yu Y, Tian ZQ, Liang L, et al. Ba-Bao Dan attenuates acute ethanol-induced liver injury via Nrf2 activation and autophagy. Cell Biosci 2019, 9: 80.

17. Liu F, Sun Z, Hu P, et al. Determining the protective effects of Yin-Chen-Hao Tang against acute liver injury induced by carbon tetrachloride using 16S rRNA gene sequencing and LC/MS-based metabolomics. J Pharm Biomed Anal 2019, 174: 567–577.

18. Qiu P, Dong Y, Zhu T, et al. Semen hoveniae extract ameliorates alcohol-induced chronic liver damage in rats via modulation of the abnormalities of gut-liver axis. Phytomedicine 2019, 52: 40–50.

19. Chen Z, Zhao Y, Song C, et al. SanWeiGanJiang San relieves liver injury via Nrf2/Bach1. J Ethnopharmacol 2019, 251: 112445.

20. Xu H, Yang N, Zhang Z, et al. Expression of matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-2 and CD147 in the traditional Chinese medicine “Compound T11” for treatment of chronic liver injury. Pharmacology 2019, 103: 128–135.

21. Deng Y, Tang K, Chen R, et al. Berberine attenuates hepatic oxidative stress in rats with non-alcoholic fatty liver disease via the Nrf2/ARE signalling pathway. Exp Ther Med 2019, 17: 2091–2098.

22. Hossain N, Kanwar P, Mohanty SR. A comprehensive updated review of pharmaceutical and nonpharmaceutical treatment for NAFLD. Gastroenterol Res Pract 2016, 2016: 7109270.

23. Zheng X, Zhao MG, Jiang CH, et al. Triterpenic acids-enriched fraction fromattenuates insulin resistance and hepatic steatosis via PI3K/Akt/GSK3beta pathway. Phytomedicine 2020, 66: 153130.

24. Wang YL, Horng CT, Hsieh MT, et al. Autophagy and apoptotic machinery caused byextract in cisplatinresistant human oral cancer CAR cells. Oncol Rep 2019, 41: 2549–2557.

25. Xu K, Liu S, Zhao X, et al. Treating hyperuricemia related non-alcoholic fatty liver disease in rats with resveratrol. Biomed Pharmacother 2019, 110: 844–849.

26. Park YJ, Lee GS, Cheon SY, et al. The anti-obesity effects of Tongbi-san in a high-fat diet-induced obese mouse model. BMC Complement Altern Med 2019, 19: 1.

27. Wang SJ, Chen Q, Liu MY, et al. Regulation effects of rosemary (Linn.) on hepatic lipid metabolism in OA induced NAFLD rats. Food Funct 2019, 10: 7356–7365.

28. Yang Y, Li J, Wei C, et al. Amelioration of nonalcoholic fatty liver disease by swertiamarin in fructose-fed mice. Phytomedicine 2019, 59: 152782.

29. Zhang YP, Deng YJ, Tang KR, et al. Berberine ameliorates high-fat diet-induced non-alcoholic fatty liver disease in rats via activation of SIRT3/AMPK/ACC pathway. Curr Med Sci 2019, 39: 37–43.

30. Xu Y, Han J, Dong J, et al. Metabolomics characterizes the effects and mechanisms of quercetin in nonalcoholic fatty liver disease development. Int J Mol Sci 2019, 20.

31. Wang X, Shi L, Wang X, et al. MDG-1, anpolysaccharide, restrains process of non-alcoholic fatty liver disease via modulating the gut-liver axis. Int J Biol Macromol 2019, 141: 1013–1021.

32. Zhao W, Xiao M, Yang J, et al. The combination of ilexhainanoside D and ilexsaponin A1 reduces liver inflammation and improves intestinal barrier function in mice with high-fat diet-induced non-alcoholic fatty liver disease. Phytomedicine 2019, 63: 153039.

33. Pan M, Deng Y, Zheng C, et al. Chinese herbal medicine formula Shenling Baizhu San ameliorates high-fat diet-induced NAFLD in rats by modulating hepatic microRNA expression profiles. Evid Based Complement Alternat Med 2019, 2019: 8479680.

34. Deng Y, Pan M, Nie H, et al. Lipidomic analysis of the protective effects of Shenling Baizhu San on non-alcoholic fatty liver disease in rats. Molecules 2019, 24.

35. Wang A, Zhou F, Li D, et al. Gamma-mangostin alleviates liver fibrosis through sirtuin 3-superoxide-high mobility group box 1 signaling axis. Toxicol Appl Pharmacol 2019, 363: 142–153.

36. Zhang Z, Guo M, Shen M, et al. Oroxylin A regulates the turnover of lipid droplet via downregulating adipose triglyceride lipase (ATGL) in hepatic stellate cells. Life Sci 2019, 238: 116934.

37. Wang R, Song F, Li S, et al. Salvianolic acid A attenuates CCl4-induced liver fibrosis by regulating the PI3K/AKT/mTOR, Bcl-2/Bax and caspase-3/cleaved caspase-3 signaling pathways. Drug Des Devel Ther 2019, 13: 1889–1900.

38. Chang ZY, Chen CC, Liu HM, et al. Positive effects of Ger-Gen-Chyn-Lian-Tang on cholestatic liver fibrosis in bile duct ligation-challenged mice. Int J Mol Sci 2019, 20.

39. Sun X, Huang X, Zhu X, et al. HBOA ameliorates CCl4-incuded liver fibrosis through inhibiting TGF-beta1/Smads, NF-kappaB and ERK signaling pathways. Biomed Pharmacother 2019, 115: 108901.

40. Xie H, Su D, Zhang J, et al. Raw and vinegar processedregulates hepatic fibrosis via bloking TGF-beta/Smad signaling pathways and up-regulation of MMP-2/TIMP-1 ratio. J Ethnopharmacol 2020, 246: 111768.

41. Zhang W, Ping J, Zhou Y, et al. Salvianolic acid B inhibits activation of human primary hepatic stellate cells through downregulation of the myocyte enhancer factor 2 signaling pathway. Front Pharmacol 2019, 10: 322.

42. Li X, Deng Y, Zheng Z, et al. Corilagin, a promising medicinal herbal agent. Biomed Pharmacother 2018, 99: 43–50.

43. Zhou X, Xiong J, Lu S, et al. Inhibitory effect of corilagin on miR-21-regulated hepatic fibrosis signaling pathway. Am J Chin Med 2019, 47: 1541–1569.

44. Zhang H, Chen Q, Dahan A, et al. Transcriptomic analyses reveal the molecular mechanisms of schisandrin B alleviates CCl4-induced liver fibrosis in rats by RNA-sequencing. Chem Biol Interact 2019, 309: 108675.

45. Zheng M, Li YY, Wang GF, et al. Protective effect of cultured bear bile powder against dimethylnitrosamine-induced hepatic fibrosis in rats. Biomed Pharmacother 2019, 112: 108701.

46. Tao Y, Tian K, Chen J, et al. Network pharmacology-based prediction of the active compounds, potential targets, and signaling pathways involved in Danshiliuhao granule for treatment of liver fibrosis. Evid Based Complement Alternat Med 2019, 2019: 2630357.

47. Chou LF, Chen CY, Yang WH, et al. Suppression of hepatocellular carcinoma progression through FOXM1 and EMT inhibition via hydroxygenkwanin-induced miR-320a expression. Biomolecules 2019, 10.

48. Zhang H, Li JC, Luo H, et al. Pseudolaric acid B exhibits anti-cancer activity on human hepatocellular carcinoma through inhibition of multiple carcinogenic signaling pathways. Phytomedicine 2019, 59: 152759.

49. Zhang JH, Zheng C, Zhu XJ, et al. Ganji formulation for patients with hepatocellular carcinoma who have undergone surgery: a multicenter, randomized, double-blind, controlled trial. Evid Based Complement Alternat Med 2019, 2019: 9492034.

50. Tian G, Chen J, Luo Y, et al. Ethanol extract ofait. leaves suppressed hepatocellular carcinoma in vitro and in vivo. Cancer Cell Int 2019, 19: 246.

51. Lu WL, Yang T, Song QJ, et al.(Thunb.) Koidz seed extract inhibits human hepatocellular carcinoma cell migration and invasion in vitro. J Ethnopharmacol 2019, 234: 204–215.

52. Liu JS, Huo CY, Cao HH, et al. Aloperine induces apoptosis and G2/M cell cycle arrest in hepatocellular carcinoma cells through the PI3K/Akt signaling pathway. Phytomedicine 2019, 61: 152843.

53. Wang X, Peng P, Pan Z, et al. Psoralen inhibits malignant proliferation and induces apoptosis through triggering endoplasmic reticulum stress in human SMMC7721 hepatoma cells. Biol Res 2019, 52: 34.

54. Chen B, Zhou S, Zhan Y, et al. Dioscin inhibits the invasion and migration of hepatocellular carcinoma HepG2 cells by reversing TGF-beta1-induced epithelial-mesenchymal transition. Molecules 2019, 24.

55. Mao Z, Han X, Chen D, et al. Potent effects of dioscin against hepatocellular carcinoma through regulating TP53-induced glycolysis and apoptosis regulator (TIGAR)-mediated apoptosis, autophagy, and DNA damage. Br J Pharmacol 2019, 176: 919–937.

56. Zang W, Bian H, Huang X, et al. Traditional Chinese medicine (TCM)andpromote vascular normalization in tumor-derived endothelial cells of human hepatocellular carcinoma. Anticancer Res 2019, 39: 2739–2747.

57. Tang D, Zhang S, Shi X, et al. Combination of astragali polysaccharide and curcumin improves the morphological structure of tumor vessels and induces tumor vascular normalization to inhibit the growth of hepatocellular carcinoma. Integr Cancer Ther 2019, 18: 1534735418824408.

58. Tan ZB, Fan HJ, Wu YT, et al. Rheum palmatum extract exerts anti-hepatocellular carcinoma effects by inhibiting signal transducer and activator of transcription 3 signaling. J Ethnopharmacol 2019, 232: 62–72.

59. Yu X, Wang Y, Tao S, et al. Geniposide plays anti-tumor effects by down-regulation of microRNA-224 in HepG2 and Huh7 cell lines. Exp Mol Pathol 2020, 112: 104349.

60. Yang PW, Lu ZY, Pan Q, et al. MicroRNA-6809-5p mediates luteolin-induced anticancer effects against hepatoma by targeting flotillin 1. Phytomedicine 2019, 57: 18–29.

61. Tian YD, Lin S, Yang PT, et al. Saikosaponin-d increases the radiosensitivity of hepatoma cells by adjusting cell autophagy. J Cancer 2019, 10: 4947–4953.

62. Cheng Y, Chen T, Yang X, et al. Atractylon induces apoptosis and suppresses metastasis in hepatic cancer cells and inhibits growth in vivo. Cancer Manag Res 2019, 11: 5883–5894.

63. Zhen H, Qian X, Fu X, et al. Regulation of Shaoyao Ruangan mixture on intestinal flora in mice with primary liver cancer. Integr Cancer Ther 2019, 18: 1534735419843178.

64. Sun X, Lv Y, Huang L, et al. Pro-inflammatory cytokines serve as communicating molecules between the liver and brain for hepatic encephalopathy pathogenesis andpolysaccharides protection. J Ethnopharmacol 2020, 248: 112357.

65. Lu L, Wu C, Lu BJ, et al. Ba-Bao Dan cures hepatic encephalopathy by decreasing ammonia levels and alleviating inflammation in rats. J Ethnopharmacol 2020, 249: 112301.

66. Qiu H, Mao D, Tang N, et al. The underlying mechanisms of Jie-Du-Hua-Yu granule for protecting rat liver failure. Drug Des Devel Ther 2019, 13: 589–600.

67. Luo JX, Zhang Y, Hu XY, et al. The effect of modified Sini decoction on survival rates of patients with hepatitis B virus related acute-on-chronic liver failure. Evid Based Complement Alternat Med 2019, 2019: 2501847.

68. Ramzan M, Iqbal A, Murtaza HG, et al. Comparison of CLIF-C ACLF score and MELD score in predicting ICU mortality in patients with acute-on-chronic liver failure. Cureus 2020, 12: e7087.

69. Yang W, Hao Y, Hou W, et al. Jieduan-Niwan formula reduces liver apoptosis in a rat model of acute-on-chronic liver failure by regulating the E2F1-mediated intrinsic apoptosis pathway. Evid Based Complement Alternat Med 2019, 2019: 8108503.

70. Li S, Qian Y, Xie R, et al. Exploring the protective effect of ShengMai-Yin and Ganmaidazao decoction combination against type 2 diabetes mellitus with nonalcoholic fatty liver disease by network pharmacology and validation in KKAy mice. J Ethnopharmacol 2019, 242: 112029.

71. Liu F, Wang M, Wang Y, et al. Metabonomics study on the hepatoprotective effect of panax notoginseng leaf saponins using UPLC/Q-TOF-MS analysis. Am J Chin Med 2019, 47: 559–575.

:

Yu-Hong Bian conceived of the presented idea; Min Cao and Jing Miao contributed to the manuscript preparation and modification with support from Yu-Hong Bian; Min Cao contributed to the hepatitis, liver injury, non-alcoholic fatty liver disease as well as conclusion and perspective in the manuscript; Jing Miao contributed to the abstract, liver fibrosis, hepatocellular carcinoma and other liver diseases in the manuscript; Li Wang, Hai-Zhao Liu and Huan-Tian Cui were responsible for searching and screening all of the literatures; all authors provided critical feedback and helped revise the final manuscript.

:

The authors declare no conflicts of interest.

:

This study was supported by Science and Technology Projects in Key Fields of Traditional Chinese Medicine of Tianjin Municipal Health Commission (No. 2020006); Tianjin Administration of Traditional Chinese Medicine, Integrated Chinese and Western Medicine Scientific Research Project of Tianjin Municipal Health Commission (No. 2017073).

:

TCM, traditional Chinese medicine; NAFLD, non-alcoholic fatty liver disease; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; Nrf2, nuclear factor 2-related factor 2; MMP-2, matrix metalloproteinase-2; AMPK, adenosine monophosphate-activated protein kinase; ACC, acetyl-CoA carboxylases; HFD, high-fat diet; ECM, extracellular matrix; HSC, hepatic stellate cell; TGF-β1, transforming growth factor-beta1; PPAR, peroxisome proliferator-activated receptor; HE, hepatic encephalopathy; ALF, acute liver failure; ACLF, acute-on-chronic liver failure.

:

Min Cao, Jing Miao, Li Wang, et al. The advances of traditional Chinese medicine in the treatment of liver diseases in 2019. Traditional Medicine Research 2020, 5 (4): 261–271.

: Rui-Wang Zhao.

:13 April 2020,

14 May 2020,

: 25 May 2020.

#These authors are co-first authors on this work.

Yu-Hong Bian. College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, No.10 Poyanghu Road, Jinghai District, Tianjin 301617, China. E-mail: bianyuhong_2012@163.com.

10.12032/TMR20200520182