Wen-Qing Li1,2†
Wen-Hao Liu3†Die Qian1Jia Liu1Shi-Qiong Zhou4Lei Zhang5
Wei Peng1*Li Su6*
Hong Zhang1,2*- 1School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- 2Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- 3Department of Pharmacy, Tenth People’s Hospital of Tongji University, Shanghai, China
- 4Hospital of Nursing, The Second Affiliated Hospital of Guilin Medical University, Guilin, China
- 5Department of Vascular Surgery, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- 6Institute of Translational Medicine, Shanghai University, Shanghai, China
Hepatic fibrosis (HF) refers to the pathophysiological process of connective tissue dysplasia in the liver caused by various pathogenic factors. Nowadays, HF is becoming a severe threat to the health of human being. However, the drugs available for treating HF are limited. Currently, increasing natural agents derived from traditional Chinese medicines (TCMs) have been found to be beneficial for HF. A systemic literature search was conducted from PubMed, GeenMedical, Sci-Hub, CNKI, Google Scholar and Baidu Scholar, with the keywords of “traditional Chinese medicine,” “herbal medicine,” “natural agents,” “liver diseases,” and “hepatic fibrosis.” So far, more than 76 natural monomers have been isolated and identified from the TCMs with inhibitory effect on HF, including alkaloids, flavones, quinones, terpenoids, saponins, phenylpropanoids, and polysaccharides, etc. The anti-hepatic fibrosis effects of these compounds include hepatoprotection, inhibition of hepatic stellate cells (HSC) activation, regulation of extracellular matrix (ECM) synthesis & secretion, regulation of autophagy, and antioxidant & anti-inflammation, etc. Natural compounds and extracts from TCMs are promising agents for the prevention and treatment of HF, and this review would be of great significance to development of novel drugs for treating HF.
Introduction
Hepatic fibrosis (HF) refers to abnormal hyperplasia of connective tissue in the liver caused by various pathogenic factors, and is a pathophysiological process of the repair of chronic liver injury. HF is a key step in the development of various chronic liver diseases to cirrhosis (Zhang C. Y. et al., 2016; Parola and Pinzani, 2019), and activation of HSCs is the central link in the development of HF, which is characterized by excessive and abnormal deposition of ECM in the liver (Chen S. R. et al., 2015; Povero et al., 2015) (Figure 1). In fact, HF is reversible (Roeb, 2018), and liver injury commonly has a process of HF in the process of liver repair and healing. However, if the injury factors cannot be removed for a long time, HF will develop into irreversible cirrhosis or even liver cancer (Tao et al., 2020). Liver cancer is one of the most commonly ones with high morbidity and mortality, and the epidemic investigations also reported that liver cancer is one of the currently leading causes of cancer-related death in the world (Mehta et al., 2015; Xiao et al., 2017). According to statistical analyses, approximately one million deaths annually were caused by liver cancer (Rawat et al., 2018; Martínez-Chantar et al., 2020). Therefore, it is important to treat HF before it evolves into cirrhosis or even liver cancer. However, nowadays, no specific therapeutic drugs could be used in clinical for treating HF, and western drugs don’t have good curative effects on HF but often result in some adverse reactions (Daniyal et al., 2019; Shan et al., 2019; Ma et al., 2020). Natural products have a general health promoting effect on the prevention and treatment of different diseases, especially liver ones. Polydatin, an active monomer from the Poygonum cuspidatum Sieb.et Zucc. (Polygonaceae), can protect hepatocytes from oxidative injury and ameliorate liver damage induced by carbon tetrachloride in rats (Peng et al., 2013). Hawthorn herbal preparation from Crataegus oxyacantha (Rosaceae) attenuates carbon tetrachloride-induced hepatic fibrosis in vivo via modulating oxidative stress and inflammation (Hamza et al., 2020). TCMs are derived from animals, plants and mineral agents with certain pharmacological activities, and herbal medicines and their formulas are dominant (Shan et al., 2019). TCMs have attracted much attention due to their unique advantages, such as wide sources, lower prices, few side effects, etc. Previous evidence suggests that many agents derived from TCMs could be beneficial for the treatment or prevention of HF (Shan et al., 2019). So far, more than 76 natural compounds with anti-hepatic fibrosis activities have been isolated and identified from TCMs, including alkaloids, flavones, quinones, terpenoids, saponins, phenylpropanoids, and polysaccharides, etc. The anti-hepatic fibrosis effects of these compounds include hepatoprotection, inhibition of hepatic stellate cells (HSC) activation, regulation of extracellular matrix (ECM) synthesis & secretion, regulation of autophagy, and antioxidant & anti-inflammation, etc. (Figure 2). In the present review, we summarized the potential anti-hepatic fibrosis components from TCMs and their possible molecular mechanisms, which would be of great significance to develop novel drugs against hepatic fibrosis.
FIGURE 1. Schematic representation of the pathogenesis of HF.
FIGURE 2. Pharmacological effects of TCMs on HF.
Pathogenesis of hepatic fibrosis
HSCs-mediated hepatic fibrosis
Hepatic stellate cells (HSCs) are a kind of non-parenchymal cells of liver, located in the disse space, accounting for 5–10% of total of hepatocytes, and maintain close interaction with hepatic sinusoidal endothelial cells and hepatocytes (Puche et al., 2013; de Oliveira da Silva et al., 2017). HSCs are the most important source cells of extracellular matrix (ECM) in HF, and activation of HSCs is a key and central step in the development of HF (Cai et al., 2020). In normal liver, HSCs are in a quiescent state without α-smooth muscle actin (α-SMA) secretion, have low proliferative activity and low ability to synthesize collagen, and their main functions are to store and metabolize VitA lipid droplets. When the liver is damaged by inflammation or mechanical stimulation, HSCs could be activated, and their phenotype changes from “quiescent” to “active” (Dewidar et al., 2019).
HSC activation includes two main stages: initiation phase and persistence phase. The priming stage refers to the changes in gene expression in early stage and in cell phenotype caused by stimulating factors such as cytokines. When liver parenchymal cells are injured, cytokines are created by the neighboring hepatocytes, Kupffer cells through paracrine action, such as tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), insulin growth factor (IGF), hepatocyte growth factor (HGF), and platelet-derived growth factor (PDGF), etc. (Tsuchida and Friedman, 2017), which can significantly promote the activation, division, proliferation, transformation of HSCs into myofibroblasts (MFBs) to synthesize ECM. Furthermore, activated HSCs can also secrete cytokines such as TNF, TGF and PDGF to sustain the activation, leading to further aggravation of HF. Persistent phase refers to the maintenance of HSC activation due to the role of above factors, increasing the deposition of ECM, resulting in HF. Thus, HSC activation is regulated by both autocrine and paracrine at this stage (Chen et al., 2008; Wallace et al., 2015; de Oliveira da Silva et al., 2017; Tsuchida and Friedman, 2017; Barcena-Varela et al., 2019). Obviously, activation of HSC is the cytological basis of HF.
ECM-mediated hepatic fibrosis
Extracellular matrix (ECM) is mainly composed of collagen, non-collagen glycoproteins (including fibronectin, laminin, etc.), elastin, proteoglycans and aminoglycans, whose intercellular adhesion structure is interstitial connective tissue. The formation of HF is due to the deposition of large amounts of ECM in the liver, and HSC activation is the main cause of ECM production (Seki and Brenner, 2015; Zhao et al., 2019). In normal liver, the synthesis and degradation of ECM mainly composed of collagens IV and VI maintain a dynamic balance, which regulates cell growth and metabolic activities. When the liver is damaged, the synthesis of ECM is greater than degradation. ECM proliferation leads to a large amount of collagen deposition. The original collagens IV and VI are replaced by collagen I, III and fibronectin to promote the formation of fibrosis. On the other hand, ECM stimulates HSC activation and proliferation. Activated HSCs can produce matrix metalloproteinases (MMP) -9 and -13, breaking the balance mechanism between MMPs and tissue inhibitors of metalloproteinases (TIMPs), which leads to partial hydrolysis of ECM deposited in large amount, reducing the occurrence of fibrosis (Nunes de Carvalho et al., 2013; Motawi et al., 2014; Karsdal et al., 2015). MMPs are the main enzymes degrading ECM and can specifically hydrolyze collagen and other matrix proteins, while TIMPs can prevent ECM degradation and promote the formation of fibrosis by inhibiting the activity of MMPs (Pinlaor et al., 2010; Baig et al., 2016). Therefore, regulating the balance of MMPs/TIMPs is essential for the degradation of ECM.
Autophagy-mediated hepatic fibrosis
Autophagy is a process of degrading excess or damaged organelles or other components in the cell with the participation of lysosomes, is essential for cell survival, differentiation, growth, and homeostasis (Tao et al., 2020). Autophagy not only regulates hepatocyte functions but also impacts on non-parenchymal cells, such as endothelial cells, macrophages and hepatic stellate cells (Allaire et al., 2019). Dysregulation of autophagy has been implicated in many liver diseases, and its modulation has also been suggested as a potential new therapeutic strategy for hepatic fibrosis. Studies have shown that autophagy has important regulatory effects on hepatic stellate cells (HSCs) energy metabolism, and then affects the activation state of HSCs (Hou et al., 2022), and further affects the progression of hepatic fibrosis. It is reported that, on the one hand, autophagy has a direct promoting effect on liver fibrosis because it could participate in the digestion of lipid droplets and provide energy for the activation of HSCs; on the other hand, autophagy could inhibit the emergence of hepatic fibrosis through anti-inflammatory effects (Sun et al., 2021). Undoubtedly, autophagy is seen in both physiological and pathological processes of the organism, and whether the role it plays is positive or negative has not been fully elucidated, and research on hepatic fibrosis, in particular, is of concern.
Oxidative stress-mediated hepatic fibrosis
Oxidative stress refers to a state in which reactive oxygen species (ROS) are produced and/or the antioxidant defense function is weakened in the body or cells during the transition, resulting in a serious imbalance between the two and tissue and cell damage (van der Pol et al., 2019). When the liver is injured, firstly, ROS production increases and clearance decreases in the liver tissue, Kupffer cells are activated to release many inflammatory mediators and cytokines (Gong and Yang, 2020). On the other hand, chemokines secreted by Kupffer cells recruit other immune cells to the site of injury to aggravate inflammatory injury, which can directly stimulate HSCs activation and proliferation (Ghatak et al., 2011) through autocrine and paracrine, resulting in a large deposition of ECM, thereby promoting the formation of hepatic fibrosis (Yang J. J. et al., 2013; Richter et al., 2015).
Hepatic fibrosis mediated by cytokines and signaling pathways
TGF-β signaling pathway
TGF-β, an activator of MFBs, is a central regulator of chronic liver disease and potent profibrotic cytokine (Deng et al., 2012; Fabregat et al., 2016). When the liver is damaged, Kupffer cells produce TGF-β in a paracrine manner, causing HSC activation. Activated HSCs can also secrete a large amount of TGF-β, which continues to stimulate the active expression of TGF-β, forming a step-by-step amplification effect (Dooley and ten Dijke, 2012). When activated TGF-β binds to the membrane receptor in HSC, TGF-β receptor activates and phosphorylates R-smad protein that binds to this receptor. Activated R-smad forms heteropolymers with co-Smad protein shared by the cytoplasm and translocated into the nucleus. Smad protein regulates transcription through target gene, thereby triggering the overexpression of fibrotic genes. Many studies have shown that TGF-β1/Smad-2 and Smad-3 are major downstream regulators promoting TGF-β-mediated HF, while Smad-7 is a negative feedback regulator of the TGF-β1 signaling pathway which has a protective effect on TGF-β-mediated HF (Xu et al., 2016; Hu H. H. et al., 2018; Dewidar et al., 2019).
NF-κB signaling pathway
NF-κB is an important nuclear transcription factor in cells (Robinson and Mann, 2010), and a major regulator of inflammatory response and apoptosis (Sun and Karin, 2008). In HF, NF-κB can be activated by LPS, TNF and IL-1β, leading to enhanced TGF-β signaling and HSC activation, while NF-κB secretion of macrophage recruitment chemokines and its anti-apoptotic effect can promote the formation of fibrosis (Elsharkawy and Mann, 2007; Tacke et al., 2009). On the other hand, NF-κB plays an anti-fibrotic role by inhibiting the transcription of COL1a1 gene (Zhang Y. Z. et al., 2019). Therefore, NF-κB may act as both pro-fibrotic and anti-fibrotic effects.
TLR4 signaling pathway
TLR4 is an important regulator of hepatic inflammatory response in chronic injury (Roy et al., 2016). In the liver, HSC has a complete TLR4 signaling pathway. TLR4 can be activated by LPS and HMGB1, and the activated TLR4 could induce downregulation of TGF-β pseudo receptor BAMBI through the downstream NF-κB signaling pathway, leading to increased activity of TGF-β1 (Roh and Seki, 2013; Li Z. et al., 2019; Nakanishi et al., 2019; Dong Z. et al., 2020). Meanwhile, TLR4 activation in HSCs promotes the recruitment of Kupffer cells, which in turn promotes the release of TGF-β, leading to the activation of HSCs and the formation of fibrosis (Pradere et al., 2010; Gao et al., 2011).
Wnt/β-catenin signaling pathway
The Wnt signaling pathway is a signal transduction one that activates downstream channels by binding of ligand protein Wnt and membrane protein receptors, enabling extracellular signals to be transmitted into cells (Thompson and Monga, 2007). In the classical Wnt signaling pathway, its membrane receptor is β-catenin, so it is also called Wnt/β-catenin signaling pathway (Huang et al., 2018). The canonical Wnt signaling pathway is active in HSCs, which promotes the formation of fibrosis by inducing the activation and survival of HSCs, leading to increased expression of type I collagen and α-SMA (Wang J. N. et al., 2018; Nishikawa et al., 2018; Li L. Y. et al., 2019; Rong et al., 2019).
PDGF signaling pathway
Platelet-derived growth factor (PDGF) is the most effective one to stimulate HSC proliferation, differentiation, and migration (Ying et al., 2017). PDGF also promotes collagen production and deposition, and converts HSCs into MFBs. The receptor of PDGF (PDGFR) belongs to the protein tyrosine kinase receptor family and has the function of protein tyrosine kinase, mainly located in vascular endothelial cells, fibroblasts and Kupffer cells (Borkham-Kamphorst and Weiskirchen, 2016). When liver injury occurs, hepatocytes release excessive PDGF, which binds to and activates PDGFR to initiate a variety of protein cascade phosphorylation signal transduction pathways, thereby causing a cellular response. The main downstream signaling pathways of PDGF include: 1) Ras/ERK/MAPK pathway; 2) AKT/mTOR/p27 pathway; 3) JAK/STAT pathway; 4) Ca2+ pathway (Kocabayoglu et al., 2015; Borkham-Kamphorst and Weiskirchen, 2016; Ying et al., 2017). Collectively, PDGF continuously activates and proliferates through autocrine and paracrine mechanisms, which leads to mitosis of HSCs and excessive deposition of ECM, promoting the formation of fibrosis.
Effects of extracts/monomers from TCMs against hepatic fibrosis
Hepatoprotective
Liver injury can be caused by a variety of reasons, including alcohol, drug poisoning, autoimmune overreaction, etc. In the process of liver injury, activated HSC could produce excessive ECM and promote the formation of fibrosis (Hu et al., 2020a). Therefore, search for effective hepatoprotective agents has attracted extensive attention (Li et al., 2020; Wu et al., 2020). It has been reported that some monomers extracted from TCMs have hepatoprotective effects, such as glycyrrhetinic acid, curcumin, emodin, baicalin and some plant polysaccharides (Stanković et al., 2017), which can reduce the occurrence of fibrosis by protecting the liver. Chen et al. (Chen et al., 2013) found that glycyrrhetinic acid (25, 50, 100 mg/kg) might enhance the expression of its target genes and the activity of antioxidant enzymes by activating the nuclear translocation of Nrf2 to protect the liver of mice from oxidative stress. It can be used as a feasible candidate drug to prevent HF. Kong et al. (Kong et al., 2020) found that curcumin (100, 200, 400 mg/kg) could blunt the epithelial-mesenchymal transition (EMT) of hepatocytes to reduce the occurrence of HF.
Inhibiting activation and promoting apoptosis in HSC
Activation of HSCs is a major event in the pathogenesis of HF (Jin et al., 2016), and inhibiting activation and proliferation of HSC is a possible step in the intervention of HF. Following observing the effect of conophylline (0.9 μg/g) on the expression of α-SMA and collagen I in rat HSCs. Kubo et al. (2014) found that conophylline reduced the expression of α-SMA and collagen-1, thereby inhibiting HSC activation. Ligustrazine (50, 100, 200 mg/kg) inhibited the production, migration, metabolism, and contraction of angiogenic factors in HSCs (Zhang et al., 2018). Artesunate (50, 100, 200 mg/kg) significantly induced apoptosis of activated HSCs in CCl4-induced mouse hepatic fibrosis (Kong et al., 2019). Consistent with the experimental results in vivo, artesunate treatment markedly repressed HSC activity, raised cell mortality, increased lipid peroxides and reduced antioxidant capacity in vitro.
Regulation synthesis, secretion and degradation of ECM
Overaccumulation of ECM is the initial stage of HF, and HSC activation is a central event in the pathogenesis of HF (Xie et al., 2021). Therefore, regulation of the synthesis and degradation of ECM is of great significance for the treatment of HF. Oroxylin A (20, 30, 40 mg/kg) could significantly inhibit the deposition of ECM in CCl4-induced mouse HF model, suggesting the possibility of oroxylin A for the treatment of HF (Chen et al., 2018). In the experiment of CCl4-induced hepatic fibrosis in rats, tanshinone IIA (2.5, 5.0, 10 mg/kg) significantly improved liver function, reduced liver injury, decreased ECM accumulation, inhibited HSC proliferation and activation, thus improving fibrosis (Shi et al., 2020).
Regulation of autophagy
Numerous studies suggest a key role of autophagy dysbiosis in the progression of hepatic fibrosis. MFBs are considered to be the main products of HSCs, and their massive production and activation are key to the development of hepatic fibrosis (Kisseleva and Brenner, 2021). More recently, in a model of hepatic fibrosis in rats injected intraperitoneally with CCl4, Kong et al. recently provided evidence that curcumin (100, 200, 400 mg/kg) inhibited TGF-β/Smad signaling transmission by activating autophagy, thereby inhibiting EMT, further inhibiting the production of MFBs to protect against hepatic fibrosis (Kong et al., 2020). In addition, in vitro, curcumin (10, 20, 30 μM/L) suppressed levels of ROS and oxidative stress in hepatocytes, and modulated upstream signaling pathways of autophagy AMPK and PI3K/AKT/mTOR, leading to an increase of the autophagic flow in hepatocytes (Kong et al., 2020). Furthermore, studies have also revealed the role of autophagy in CCl4-induced hepatic fibrosis, and to further examine the molecular mechanisms after treatment oroxylin A, at the same time leading to a decrease in the levels of gene expression of the main actors of liver damage, such as ALP, AST, ALT, TGF-β1, TNF-α, α-SMA, and the expression of autophagy makers, such as LC3-B, Atg3, Atg4, Atg5, Atg6, Atg7, Atg9, Atg12, Atg14 Beclin1, and p62, etc. was significantly up-regulated, consequently, oroxylin A is required to activate autophagy to attenuate hepatic fibrosis and HSCs activation (Chen et al., 2018). Hence, based on these studies, we reasonably point to the possibility of using natural drugs to treat hepatic fibrosis by regulating autophagy.
Antioxidant and anti-inflammatory effects
Oxidative stress can create a vicious circle of fibrous deposition, and persistent inflammation is an initiation and maintenance factor of HF (Ruart et al., 2019; Bai et al., 2020). Therefore, antioxidation and inhibition of inflammation can effectively improve HF. The natural compouds exerting antifibrosis effect through antioxidation and anti-inflammation mainly include acanthopanax senticosus alkaloid A, berberine, betaine, astragaloside IV, breviscapine, rhein, oxymatrine, cucurbitacin B, and so on. For example, berberine (50 mg/kg) has antioxidant and anti-inflammatory activities and is a potential drug for the treatment of HF (Eissa et al., 2018). Astragaloside IV (50 mg/kg) inhibited the activation of HSC by inhibiting oxidative stress and p38 MAPK pathway, thus achieving the anti-hepatic fibrosis effect (Li et al., 2013). Breviscapine (15, 30 mg/kg) attenuated CCl4-induced liver injury in mice by inhibiting inflammatory apoptotic response and ROS production (Liu Y. et al., 2018). In addition, nonalcoholic steatohepatitis (NASH) is characterized by histological lobular inflammation and hepatocyte ballooning, the active form of non-alcoholic fatty liver disease NAFLD, and is associated with disease progression, development of fibrosis, eventually, cirrhosis and hepatocellular carcinoma (Castera et al., 2019). A mouse model of NASH was established by feeding a high-fat/high-cholesterol diet, for 16 weeks, and breviscapine (15 and 30 mg/kg) was administered daily by oral gavage after 8 weeks of treatment, significantly reduced lipid accumulation, inflammatory cell infiltration, liver injury, and fibrosis in mice. Further RNA-sequencing and multiomics analyses indicated that breviscapine inhibited TGF-β-activated kinase 1 (TAK1) -dependent signaling to alleviate NASH (Lan et al., 2022). Moreover, in vitro and in vivo results of the experiment showed that gastrodin (25, 50, 100, 200 μg/ml; 10, 20, 50 mg/kg) activated the AMPK/Nrf2 pathway, ameliorated hepatic oxidative stress/proinflammatory response and significantly improved metabolic disorders in NAFLD (Qu et al., 2016). These findings will provide scientific basis for the clinical application of natural botanical compounds to treat HF in the future.
Blockade of receptors and signaling pathways
TGF-β, PDGF and PPARγ are important fibrogenic factors, and blocking the binding of these cytokines to HSC membrane receptors or inactivating their signal transduction pathways can all achieve anti-fibrotic effects (Zhang et al., 2013; Borkham-Kamphorst and Weiskirchen, 2016; Frangogiannis, 2020; Sharma et al., 2020). For example, caffeine (37.5 mg/kg) inhibited the formation of HF by inhibiting the expression of TGF-β-stimulated connective tissue growth factor (CTGF) in hepatocytes through PPARγ and Smad2/3 pathways (Gressner et al., 2008). A rat model of liver injury was established and treated with different doses of baicalin (25, 50, 100 mg/kg). The results showed that baicalin reversed the biochemical indicators of liver injury, inhibited the upregulation of TGF-β1 expression, and enhanced the expression of PPARγ (Qiao et al., 2011).
Traditional applications of TCMs against hepatic fibrosis
In traditional Chinese medicine system, the HF belongs to the scopes of “hypochondriac pain,” “jaundice,” “liver impediment” and “tympanites” and commonly induced by “deficiency of Qi and blood stasis,” “liver Qi stagnation,” “moist-heat collecting in the splenetic and stomach systems” and “damp abundance due to splenic asthenia,” etc. (Zhang X. Y. et al., 2019; Xu, 2020). In China, TCMs have been comprehensively used for treating HF for thousands of years based on the functions of “promoting blood circulation and removing blood stasis,” “tonifying Qi,” “soothing liver and strengthening spleen” and “clearing away heat and toxic material,” etc. (Duan et al., 2020; Xu, 2020). The commonly used TCMs include the Danshen (roots of Salvia miltiorrhiza Bge., Lamiaceae), Gancao (roots of Glycyrrhiza uralensis Fisch., Leguminosae), Banxia (roots of Pinellia ternata (Thunb.) Breit., Araceae), Renshen (roots of Panax ginseng C.A.Mey., Araliaceae), Huangqin (roots of Scutellaria baicalensis Georgi, Lamiaceae), Shengjiang (roots of Zingiber officinale Rosc., Zingiberaceae), Baizhu (roots of Atractylodes macrocephala Koidz., Asteraceae), and Yujin (roots of Curcuma wenyujin Y.H. Chen et C. Ling, Zingiberaceae), etc. (Duan and Wang., 2020). TCMs are often applied in clinical to treat diseases in the form of formula, and importantly, TCM formula is also recognized as one of promising therapies against HF due to its feature of “multiple components, multiple targets and multiple pathways” (Li, 2020; Sun, 2020).
The Fufang-Biejia-Ruangan pill (FBRP) is the first clinically approved classic Chinese herbal formula against fibrosis in China (Zhang et al., 2020). In CCl4-induced hepatic fibrosis rat model, daily orally administration with FBRP, at doses of 0.55 g/kg, for 8 weeks, decreased the serum levels of ALT, AST, PCIII, HA, LN and IV-C, alleviated the level of infiltration of leukocytes, necrosis, bile duct proliferationa, and collagen deposition as well as downregulated reduced the protein expression of TGF-β1 and Smad3 in the rat liver (Yang F. R. et al., 2013). Further in vitro investigations demonstrated that FBRP significantly suppressed HSC-LX-2 cell proliferation and reduced hydroxyproline content (Yang F. R. et al., 2013). These results indicated that FBRP shows significant anti-hepatic fibrosis effects via inhibition of TGF-β/Smad signaling pathway may be an underlying mechanism. Moreover, in vivo model of diethylnitrosamine (DEN) induced hepatocellular carcinoma (HCC) in rats, daily orally administrated with FBRP at doses of 1 g/kg, for 18 weeks, effectively reduced the serum levels of ALT, AST, ALP, TP, HA and alpha fetoprotein (AFP), significantly suppressed the liver tissues expression of p-PI3K, p-AKT, p-IKkB, and p-NF-κB, as well as the ratios of p-IKkB/total IKkB and p-NF-κB/total NF-κB, suggested FBRP may be a promising candidate drug for reduction of fibrogenesis and prevention of HCC via blocking PI3K/AKT/NF-κB activation (Zhang et al., 2020). Meanwhile, in vitro, Huh7 cells were treated with 5.0 and 10.0 mg/ml FBRP for 24 h, suppressed HCC cell proliferation and induced cell cycle arrest, obviously downregulated the expression of related factors in the PI3K/AKT/NF-κB signaling pathway (Zhang et al., 2020). Notably, network-based pharmacological strategies, Zhang et al. (2020) also provided a reasonable data for unveiling that FBRP may block PI3K/AKT/NF-κB activation, further highlighting the multi-target anti-HCC. Similarly, in vivo, orally administrated with FBRP, at doses of 0.625 g/kg, once a day during the 7 weeks, detection of biochemical indicators, fibrosis-related index and the MAPK pathway involved factors at the end of experiment. The results showed that FBRP dramatically the serum level of ALT, AST, HA, LN, IV-C and PCIII, significantly reduced the levels of α-SMA, TNF-α, IL-13, p-p38, p-ERK both in serum and liver tissues in rats (Cai et al., 2010).
Besides, in vivo model of CCl4-induced hepatic fibrosis in rats, daily orally administration with FZHY formula, at doses of 4.6 g/kg, for 9 weeks, alleviated the hepatic lobular distortion and collagen fiber accumulation, improved the hepatocellular steatosis and ballooning. 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 CCl4-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 CCl4-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 CCl4-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.
TABLE 1. Traditional Chinese medicine formulas with anti-hepatic fibrosis effect.
TCMs treating hepatic fibrosis
Nowadays, HF becomes a major public health problem with severe consequence (Berumen et al., 2021). Finding and discovering antifibrotic drugs from TCMs has become a hot research field. TCMs have unique advantages and great application prospects in anti-hepatic fibrosis due to their diverse structures, low toxicity, and wide sources (Daniyal et al., 2019; Hamza et al., 2020). Studies have shown that natural products derived from TCMs, such as alkaloids, flavones, quinones, terpenoids, saponins, phenylpropanols and polysaccharides, have promising anti-fibrotic activities (Shan et al., 2019). In addition, some TCMs and their formulas would be also beneficial for treating HF. The anti-fibrotic effects of these natural products were summarized in the following section according to the classification of chemical structure (Figure 3).
FIGURE 3. Chemical structural formula of natural products.
Alkaloids
Alkaloids is a class of basic organic compounds containing nitrogen that mainly exist in plants or herbs. Most of them have complex ring structures, conjugation, and optical rotation. They have alkali like properties and significant biological activities, which are an important class of effective components in TCMs (Mondal et al., 2019). For example, acanthus ilicifolius alkaloid A, berberine and betaine are effective antioxidants with strong free radical scavenging effects, which can reduce the bio-markers’ levels of HF, so significantly improve liver functions (Wai et al., 2015; Eissa et al., 2018; Shedid et al., 2019). In addition, caffeine, capsaicin, evodiamine, matrine, neferine, oxymatrix and tetrandrine exert anti-fibrotic effects through regulating the TGF-β signal transduction pathway (Hsu et al., 2007; Gressner et al., 2008; Yu et al., 2014; Chen M. S. et al., 2015; Zhao et al., 2016; Choi et al., 2017; Yang et al., 2018). Besides, conophylline and ligustrazine can inhibit the activation of HSCs, and reduce the deposition of ECM (Kubo et al., 2014; Zhang et al., 2018). Table 2 summarized the anti-fibrotic effects of alkaloids found in TCMs against HF.
TABLE 2. Alkaloids with anti-hepatic fibrosis effect.
Flavonoids
Flavonoids is a class of compounds with 2-phenyl chromogenic ketone structure as the basic parent core, which widely exists in berries and vegetables in nature. Flavonoids have notable antioxidant, anti-inflammatory, and anticancer activities, and can be used to treat a variety of liver diseases (Akhlaghi, 2016). For example, anthocyanins can significantly improve the severity of liver injury and fibrosis by reducing oxidative stress and inflammation (Sun et al., 2018). Epigallocatechin-3-gallate has anti-hepatic fibrosis effect in vitro by inhibiting PI3K/Akt/Smad pathway (Yu et al., 2015). Breviscapine, nobiletin, proanthocyanidin, silybin and wogonoside have anti-inflammatory and antioxidant activities, and these bioactive flavonoids can be used as promising agents for the treatment of HF and related liver diseases (Trappoliere et al., 2009; Li et al., 2012; Wang Q. et al., 2015; Liu Y. et al., 2018; Wu et al., 2020). Previous investigations showed that apigenin could improve CCl4-induced HF by mediating VEGF-mediated FAK phosphorylation through multiple pathways (Qiao et al., 2020). Baicalein, chrysin, icaritin and myricetin can prevent or reverse the progression of HF by inhibiting the activation of HSCs and inducing apoptosis of activated HSCs (Sun et al., 2010; Li et al., 2011; Balta et al., 2015; Geng et al., 2017). Besides, baicalin and diosmin exert anti-fibrotic effects by stimulating the expression of PPAR-γ (Qiao et al., 2011; Hasan et al., 2017). Genistein, hesperetin and luteolin can block the development of HF by decreasing TGF-β and activating TGF-β/Smad signaling (Li et al., 2015; Ganai and Husain, 2017; Kong et al., 2018). Moreover, hesperidin, naringenin, puerarin and quercetin inhibit liver tissue injury, necrosis, and fibrosis by reducing the activity of cytokines and biological receptors such as NF-κB (Pérez-Vargas et al., 2014; Wang et al., 2016; Wang R. et al., 2017; Hernández-Aquino et al., 2017). In addition, hyperoside and morin improve liver function and reduce the occurrence of HF by enhancing the expression of liver Nrf2 (Sang et al., 2017; Zou et al., 2017). Furthermore, oroxylin A can dose-dependently reduce biomarkers of liver injury and HSC activation by activating autophagy (Chen et al., 2018). Table 3 summarized the anti-fibrotic effects of flavonoids from TCMs against HF.
TABLE 3. Flavonoids with anti-hepatic fibrosis effect.
Quinones
Quinones is a kind of chemical constituents with quinone structure, which are mainly divided into four types: benzoquinone, naphthoquinone, phenanthrenequinone and anthraquinone. Quinones are widely distributed in plants and have various biological activities. Studies have shown that quinones have anti-inflammatory, anticancer, anti-viral and hepatoprotective activities, which lay a foundation for the treatment of HF (Dong X. et al., 2020). For example, rhein can significantly reduce alanine aminotransferase (ALT) activity in liver tissue of CCl4/ethanol-injured rats, improve the histological changes of HF, and decrease the expression of α-SMA and TGF-β1 in liver tissue. Therefore, rhein has a protective effect on CCl4/ethanol-induced liver injury in rats, inhibiting HF. Its mechanism of action may be related to antioxidant and anti-inflammatory effects, but can also inhibit TGF-β1 to stop HSC activation (Guo et al., 2002). Emodin is an active ingredient isolated from rhubarb, which has antimicrobial, immunosuppressive and anti-inflammatory effects. CCl4 was used to establish an experimental HF model in rats, and emodin was administered for treatment. The results suggested that Emodin might play an anti-fibrotic role by inhibiting TGF-β1 signal transduction to prevent HSC activation (Dong et al., 2009; Liu F. et al., 2018). Studies have found that tanshinone IIA can significantly improve liver function, alleviate liver injury, reduce ECM accumulation, inhibit HSC proliferation and activation, thereby playing an anti-fibrotic role. Tanshinone IIA may alleviate HF through multi-target and multi-signal pathways (Liu and Huang, 2014; Shi et al., 2020). In addition, sparstolonin B can play an anti-hepatic fibrosis role by inhibiting the TLR4 signal transduction pathway (Dattaroy et al., 2018). Table 4 summarized the anti-fibrotic effects of quinones from TCMs against HF.
TABLE 4. Quinones with anti-hepatic fibrosis effect.
Terpenoids
Terpenoids and their derivatives are the compounds with isoprene units as their basic structures widely existed in nature. Terpenoids have antioxidant, metabolic, immunomodulatory, and anti-inflammatory activities (Sánchez-Crisóstomo et al., 2019), and have promising potentials for the treatment of some hepatic chronic diseases. For example, cucurbitacin B attenuates HF by inhibiting oxidative stress, inflammation, and STAT3 signaling pathways (Sallam et al., 2018). β-Elemene could reduce plasma endotoxin level, serum tumor necrosis factor-alpha level and CD14 mRNA expression in liver of rats with HF rats by CCl4 treatment (Liu et al., 2011). In addition, andrographolide, ginsenoside Rb1 and paeoniflorin could inhibit HF by regulating the TGF-β1/Smads signaling pathway (Lo et al., 2011; Hu Z. et al., 2018; Lin et al., 2018), and artesunate, ergosterol, ginsenoside Rb2, glaucocalyxin A and swertiamarin can exert anti-fibrotic effects by inhibiting the activation of HSCs (Park et al., 2006; Tai et al., 2016a; Li S. et al., 2016; Dong et al., 2018; Kong et al., 2019). Betulinic acid exerts significant anti-fibrotic effects on rats treated with intraperitoneal injection of thioacetamide (TAA) by regulating TLR4/MyD88/NF-κB signaling pathway (Wan et al., 2012). Table 5 summarized the anti-fibrotic effects of terpenoids found in TCMs against HF.
TABLE 5. Terpenoids with anti-hepatic fibrosis effects.
Saponins
Saponins, a class of glycosides whose aglycones are triterpenoids or spirosterols, are complex compounds in the structure, which widely exist in plants and have a wide variety of species. Saponins have antioxidant, anticancer and multi-target activities, which play an important regulatory role in the treatment of HF (Li X. et al., 2018). For example, akebia saponin D and saikosapoin D can reduce HF through anti-inflammatory effects (Dang et al., 2007; Gong et al., 2019), and astragaloside IV, glycyrrhizin acid and ursolic acid could alleviate HF by inhibiting HSC activation and inducing apoptosis of activated HSCs (Wang et al., 2011; Li et al., 2013; Liang et al., 2015). In addition, dioscin can specifically inhibit collagen synthesis by regulating the PI3K/Akt pathway, and can be used as an effective anti-fibrotic drug (Xu et al., 2017). Table 6 summarized the anti-fibrotic effects of saponins found in TCMs against HF.
TABLE 6. Saponins with anti-hepatic fibrosis effect.
Phenylpropanoids
Phenylpropanoids is a kind of natural compounds composed of benzene ring and three straight chain carbon, and have anti-tumor, antioxidant and hepatoprotective effects (Teponno et al., 2016). For example, curcumin can significantly improve the severity of liver injury and fibrosis by reducing oxidative stress and inflammation (Kong et al., 2020). Experimental studies have found that the anti-fibrotic mechanism of salvianolic acid B may be through inhibiting HSC proliferation (Liu et al., 2002). In addition, isochlorogenic acid A could delay the progression of HF by regulating HMGB1/TLR4/NF-κB signaling pathway (Liu et al., 2020). Schizandrin B plays an anti-fibrotic role by regulating Nrf2-ARE and TGF-β/Smad signaling pathways (Chen et al., 2017). Phillygenin is a phenylpropanoid compound isolated from Forsythia and has good anti-inflammatory effects. Phillygenin inhibits LPS induced proinflammatory response and Lx2 cell activation through TLR4/MyD88/NF-κB signaling pathway, thereby inhibiting HF (Hu et al., 2020b). Table 7 summarized the anti-fibrotic effects of phenylpropanoids found in TCMs against HF.
TABLE 7. Phenylpropanoids with anti-hepatic fibrosis effect.
Polysaccharides
Polysaccharides are polysaccharide macromolecular carbohydrates consisting of glycosidic bonded sugar chains with at least 10 monosaccharides. Polysaccharides are widely distributed in nature and have the characteristics of multi-component, multi-target, high efficiency, and low toxicity (Qu et al., 2020). In recent years, increasing investigations reported that polysaccharides possess promising hepatoprotective effects against HF. Table 8 summarized the anti-fibrotic effects of polysaccharides found in TCMs against HF.
TABLE 8. Polysaccharides with anti-hepatic fibrosis effect.
Other natural compounds
Many other compounds extracted from TCMs have therapeutic effects on HF through complex mechanisms. Polyphenols have been reported to have good effects in alleviating oxidative stress, lipid metabolism and inflammation (Luk et al., 2007; Li S. et al., 2018). For example, gastrodin can significantly improve the severity of liver injury and fibrosis by reducing oxidative stress and inflammation (Zhao et al., 2014; Zhao et al., 2015). Glycyrrhetinic acid protects the liver by activating the nuclear translocation of Nrf2 and increasing the activity of antioxidant enzymes. Therefore, glycyrrhetinic acid may be an effective hepatoprotective drug for the treatment of HF (Chen et al., 2013; Lam et al., 2016). Experimental studies have found that the anti-fibrotic mechanism of paeonol may be through inhibiting HSC proliferation (Kong et al., 2013; Tai et al., 2016b). Resveratrol delays the progression of HF by reprogramming macrophage phenotype from LPS to IL-4 by upregulating endogenous IL-10 (Hsu et al., 2019; Yu et al., 2019). The anti-fibrotic mechanism of yangonin may be that it reduces collagen content by regulating HF-related genes Col1-α-1 and TIMP-1 (Cao et al., 2018; Wang X. et al., 2019). In addition, Lan et al. (2021) established the fibrosis model in mice induced by 16 weeks of high-fat/high-cholesterol diet administration. They found that cordycepin (100 and 200 mg/kg) treatment significantly inhibited the expression of fibrogenic genes such as ColIa1, ColIIIa1, α-SMA, and decreased the serum levels of ALT and aspartate aminotransferase (AST). It is revealed that cordycepin plays an important protective role in hepatic fibrosis mice. Furthermore, Wang R. et al. (2021) demonstrated the suppressive effects of amygdalin in TGF-β1-induced HSC activation in vitro and found that amygdalin (3 mg/kg) could reduce the levels of ALT and AST in serum, decrease the levels of α-SMA, collagen I, and TIMP-1 in hepatic tissue samples, improve focal necrosis and collagen fiber accumulation in CCl4-induced hepatic fibrosis rats. Table 9 summarized the anti-fibrotic effects of other compounds found in TCMs against HF.
TABLE 9. Other natural compounds with anti-hepatic fibrosis effect.
Other extracts from TCMs
Besides, some TCM extracts are also beneficial for the treatment of HF via protecting hepatocytes and inhibiting hepatitis and fibrosis (Wang Y. et al., 2015; Wang Y. Y. et al., 2017; Miao et al., 2019). Table 10 summarized the anti-fibrotic effects of these extracts.
TABLE 10. Other extracts from TCM with anti-hepatic fibrosis effect.
Clinical trials
To date, there are several clinical trials on the anti-hepatic fibrosis effect of TCMs. Chronic hepatitis B (CHB) can progress to liver fibrosis, leading to cirrhosis with liver-related disease, and ultimately markedly increasing the risk of hepatocellular carcinoma (HCC) (Inoue and Tanaka, 2020). At present, a randomized, double-blind, and placebo-controlled clinical trial was carried out to estimate the antifibrotic activities of Anluo huaxian pill (AHP) on chronic hepatitis B (CHB) patients with advanced fibrosis or cirrhosis. The results found that the rate of histological improvement in patients with liver fibrosis was significantly higher in the AHP group than in the placebo group, the level of liver stiffness measurement (LSM) decreased dramatically from baseline in the AHP group but not in the placebo group, after orally administration with AHP at a dose of 6 g, twice daily for 48 weeks (Xiao et al., 2022), which indicated that AHP could improve liver fibrosis and may be useful as a functional food medicine. Besides, cirrhosis developed in one patient in the placebo group but in none of the patients in the AHP group, and no serious side effects occurred in patients treated with AHP (Xiao et al., 2022). Moreover, a multicenter, randomized, double-blind, placebo-controlled trial, patients with CHB were randomly assigned to receive entecavir (ETV) (0.5 mg/day)+FBRP (2 g three times/day), after 72 weeks of treatment, the rate of regression of fibrosis/cirrhosis was significantly higher in the ETV + BR group than ETV monotherapy in overall patients with CHB and those with liver cirrhosis at baseline, and this combination therapy also showed an excellent safety profile (Rong et al., 2022). To evaluate the efficacy and safety of Chunggan extract (CGX), Joung et al. (2020) conducted a randomized controlled clinical trial of CGX in patients with liver fibrosis diagnosed by Fibroscan. Orally administration with CGX (1 g or 2 g, twice daily) to the subjects for 24 weeks could dramatically decreased the LSM scores compared to the placebo group, and no notable adverse events were present, which firstly demonstrated that the potent pharmacological effects of CGX in restoring early liver fibrosis in patients with chronic liver disease. Based on a collective research report, luteolin, quercetin, ursolic acid and salvianic acid A are the main potential active components of FZHY formula to exert anti-inflammatory and anti-hepatic fibrosis pharmacological effects (Xin et al., 2022). Furthermore, the active components of FBRP to prevent HF mainly include total flavonoids from Astragalus membranaceus, salvianic acid A, notoginseng saponins, cordyceps polysaccharides (Yao et al., 2022). More notably, among these biological compounds from TCMs similarly positively affect fibrosis, as reported in the previous section.
At least, these established evidence indicated that TCMs might be considered as a viable, efficacious supplement for hepatic fibrosis, and can be used in daily life to prevent associated with liver disease. However, there is insufficient evidence to support the optimal dose of TCMs and what kind of hepatic fibrosis it has effect on deserve further research. Besides, the underlying mechanisms for the benefit of these TCMs therapy is unclear, and the specific medicinal components of TCMs responsible for the antifibrotic effects remain unknown. Therefore, it is necessary to investigate the effects of TCMs blockade and reversal of hepatic fibrosis in a larger, more rigorous methodological design and more diverse samples.
Conclusion and prospect
Hepatic fibrosis (HF) is a complex pathological process related to multiple factors, targets, and pathways, which causes serious harm to human health. In recent years, many TCMs and their active ingredients have been found to be effective in treating HF via multiple mechanisms (Figure 4). However, most of them remain at the stage of in vitro and in vivo experimental studies, which require more detailed preclinical and clinical studies.
FIGURE 4. Schematic representation of the possible mechanism of TCMs on HF.
First, clinical studies on anti-hepatic fibrosis ingredients derived from TCMs are lacking, the assessment of pre-clinical safety is rarely documented, and the possible side effects and toxicity are still uncovered. Therefore, more work should be devoted to clinical data mining and experimental research in the future. Second, there is currently insufficient evidence to explain the specific molecular mechanisms of these anti-fibrotic components. Therefore, the pharmacokinetics and pharmacological properties of these natural anti-hepatic fibrosis products from TCMs are needed to be further studied. Third, the current research on anti-hepatic fibrosis drugs mainly focuses on plant medicines, while the research on animal and mineral drugs is less. Therefore, future research on anti-hepatic fibrosis drugs can also involve more animal or mineral drugs.
In conclusion, TCMs have more advantages in the treatment of HF due to its unique theoretical system and long-term practice clinically. This review systematically summarized the potential anti-hepatic fibrosis components from TCMs and their related molecular mechanisms, which would be helpful for further investigations on TCMs derived remedies for HF. In addition, it is hoped that this review will inspire more scholars to make more contributions to the study of TCMs in the treatment of HF.
Author contributions
HZ, WP, and LS designed this manuscript; W-QL, W-HL, JL, S-QZ, DQ and LZ wrote the manuscript; HZ and WP revised the manuscript. All authors collaborated in the writing of the present manuscript and approved its submission.
Funding
This work was supported by funds from the National Natural Science Foundation of China (No. 82174023) and National Key R&D Program for key research project of modernization of traditional Chinese medicine (No. 2019YFC1711602).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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Keywords: natural products, hepatic fibrosis, hepatic stellate cells, extracellular matrix, hepatoprotection, mechanism, traditional Chinese medicines, Fufang-Biejia-Ruangan pill
Citation: Li W-Q, Liu W-H, Qian D, Liu J, Zhou S-Q, Zhang L, Peng W, Su L and Zhang H (2022) Traditional Chinese medicine: An important source for discovering candidate agents against hepatic fibrosis. Front. Pharmacol. 13:962525. doi: 10.3389/fphar.2022.962525
Received: 06 June 2022; Accepted: 28 July 2022;
Published: 23 August 2022.
Edited by:
Menghao Huang, Indiana University Bloomington, United StatesReviewed by:
Hu Li, Chinese Academy of Medical Sciences and Peking Union Medical College, ChinaLili Qu, University of Connecticut Health Center, United States
Copyright © 2022 Li, Liu, Qian, Liu, Zhou, Zhang, Peng, Su and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Wei Peng, pengwei@cdutcm.edu.cn; Li Su, suli1020@shu.edu.cn; Hong Zhang, zhanghong@shutcm.edu.cn
†These authors have contributed equally to this work and share first authorship