Evidence-Based Complementary and Alternative Medicine

Evidence-Based Complementary and Alternative Medicine / 2020 / Article
Special Issue

Traditional Medicine in Liver Disease and Inflammation

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Review Article | Open Access

Volume 2020 |Article ID 7171498 | https://doi.org/10.1155/2020/7171498

Xiaoqi Pan, Xiao Ma, Yinxiao Jiang, Jianxia Wen, Lian Yang, Dayi Chen, Xiaoyu Cao, Cheng Peng, "A Comprehensive Review of Natural Products against Liver Fibrosis: Flavonoids, Quinones, Lignans, Phenols, and Acids", Evidence-Based Complementary and Alternative Medicine, vol. 2020, Article ID 7171498, 19 pages, 2020. https://doi.org/10.1155/2020/7171498

A Comprehensive Review of Natural Products against Liver Fibrosis: Flavonoids, Quinones, Lignans, Phenols, and Acids

Guest Editor: Hongwei Zhang
Received24 Jun 2020
Revised23 Jul 2020
Accepted25 Jul 2020
Published05 Oct 2020

Abstract

Liver fibrosis resulting from continuous long-term hepatic damage represents a heavy burden worldwide. Liver fibrosis is recognized as a complicated pathogenic mechanism with extracellular matrix (ECM) accumulation and hepatic stellate cell (HSC) activation. A series of drugs demonstrate significant antifibrotic activity in vitro and in vivo. No specific agents with ideally clinical efficacy for liver fibrosis treatment have been developed. In this review, we summarized the antifibrotic effects and molecular mechanisms of 29 kinds of common natural products. The mechanism of these compounds is correlated with anti-inflammatory, antiapoptotic, and antifibrotic activities. Moreover, parenchymal hepatic cell survival, HSC deactivation, and ECM degradation by interfering with multiple targets and signaling pathways are also involved in the antifibrotic effects of these compounds. However, there remain two bottlenecks for clinical breakthroughs. The low bioavailability of natural products should be improved, and the combined application of two or more compounds should be investigated for more prominent pharmacological effects. In summary, exploration on natural products against liver fibrosis is becoming increasingly extensive. Therefore, natural products are potential resources for the development of agents to treat liver fibrosis.

1. Introduction

Liver fibrosis is a progressive liver disease that results from a chronic wound healing response to various pathogenic factors, such as chronic infection with hepatitis B virus (HBV)/hepatitis C virus (HCV), alcohol abuse, nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), autoimmune hepatitis, hemochromatosis, or primary/secondary biliary cholangitis [1, 2]. Liver fibrosis gradually develops into cirrhosis and causes liver dysfunction with liver failure. This progression is estimated to influence approximately 1% to 2% of the population worldwide. Moreover, over 1 million people will suffer death annually worldwide [3]. It is believed that liver fibrosis is characterized by redundant deposition and intrahepatic accumulation of extracellular matrix (ECM). In the fibrotic liver, quiescent hepatic stellate cells (HSCs) differentiate into proliferative and contractile myofibroblasts. This activation of HSCs plays a primary role in ECM accumulation [4]. The hepatic sinusoid is a well-organized structural and biochemical microenvironment for liver cell survival and communication. This microenvironment is a multidirectional interaction complex with multiple signals or targets [5]. Besides injured hepatocytes, hepatic macrophages, endothelial cells, and lymphocytes are also included due to the abundant blood supply in this microenvironment. Thus, the death of hepatocytes is progressively to release cellular contents and reactive oxygen species (ROS) that activate hepatic immune response containing resident macrophages (Kupffer cells) with excessive proinflammatory factors like TNF-α, IL-1β, and IL-6 [6]. On the other hand, after sustained liver injury from this progress, liver sinusoidal endothelial cells (LSECs) lose their phenotype and protective properties, promoting angiogenesis and vasoconstriction. It further contributes to repeating inflammation and triggers fibrosis [7]. All these actions will contribute to HSCs activation. HSCs are one of the vital constituents in liver sinusoidal cells and are located between LSECs and hepatocytes. Thus, HSC activation and fibrogenesis are associated with a series of mechanisms, such as transforming growth factor-β (TGF-β) secretion, autophagy, endoplasmic reticulum stress, oxidative stress, and cholesterol stimulation [4]. Apart from HSC activation, liver fibrosis is widely associated with hepatocyte apoptosis and dysregulation of inflammation. To date, no satisfactory agents for liver fibrosis treatment have been developed due to the complicated progression of liver fibrosis.

In recent years, a number of natural products derived from formulae or composites have drawn much attention as resources for drug discovery [8]. The prevailing natural products involving plants, animals, fungi, and microorganisms are widely used in traditional Chinese medicine (TCM), Ayurveda, Kampo, and Unani. Some natural products have exhibited therapeutic effects on liver diseases for thousands of years. In particular, several kinds of representative natural products, such as flavonoids, quinones, lignans, phenols, and acids, demonstrate potent function in liver protection, cholestasis prevention, NASH inhibition, and hepatocellular carcinoma (HCC) suppression [9, 10]. In addition, natural products that have promising efficacy in preventing fibrosis have been under rapid development [1113]. Hence, this review provides a comprehensive overview of the potential effects and possible mechanisms of several natural products against liver fibrosis.

2. Flavonoids

Flavonoids, a type of compounds with a 2-phenyl flavone structure, are widely distributed in nature, which are characterized by a variety of biological activities, including cardiovascular activity, antibacteria, antivirus, antitumor, antioxidant, anti-inflammatory, and liver protection. Chemical structure of some common flavonoids that have antifibrotic effects is shown in Figure 1.

2.1. Silibinin

Silibinin is one kind of flavonolignans isolated from the plant Silybum marianum (L.) (milk thistle). It is the major bioactive component and accounts for approximately 60% of silymarin. In recent years, silibinin has been widely applied as a hepatoprotective compound for the treatment of a variety of liver diseases [14]. A team of Italian researchers first confirmed that silibinin at a dose of 100 mg/kg alleviated iron-induced liver fibrosis with mitochondrial dysfunction [15, 16]. Then, another chronic CCl4-induced liver fibrosis model was assessed. However, the results indicated that silibinin at 50 mg/kg did not significantly reverse fibrogenic progression [17]. In addition, Wang’s team reported that silibinin at 200 mg/kg inhibited thioacetamide- (TAA-) induced liver injury and fibrosis by decreasing α-SMA and inflammatory cytokines IL-1β, IL-6, and TNF-α levels, which was associated with the upregulation of CYP3A via pregnane X receptor (PXR) [18]. Silibinin at a dose of 105 mg/kg was effective for preventing hepatic steatosis and fibrosis in a NASH mouse model through regulating lipid metabolism-related gene expression, activating Nrf2, and inhibiting the NF-κB signaling pathway [19]. In an in vitro study, 25–50 μmol/L silybin dose-dependently inhibited the activation of HSC proliferation, cell motility, and ECM deposition through anti-inflammatory activities [20]. Moreover, another recent study indicated that silibinin inhibited LX-2 cell proliferation in a dose- and time-dependent manner and arrested HSC cell cycle by enhancing p53/p27 ratio and inhibiting Akt downstream signaling [21].

2.2. Silymarin

Silymarin is a mixture of flavonolignans that mainly contains silybin, silydianin, and silychristin, which are extracted from Silybum marianum (L.) [22]. Silymarin is a well-known complex with antioxidant, anti-inflammatory, and immunomodulatory effects on various liver disorders [23]. Silymarin showed antifibrotic effects in a variety of liver fibrosis models, such as alcohol, CCl4, TAA, and schistosomiasis-induced models [2427]. The antihepatic fibrosis mechanism of silymarin seems to be varied. El-Lakkany reported that silymarin at 750 mg/kg alleviated Schistosoma mansoni-induced liver fibrosis by downregulating MMP-2 and TGF-β1 and upregulating glutathione (GSH) [28]. In a series of CCl4-induced liver fibrosis studies, silymarin significantly decreased connective tissue growth factor (CTGF), regulated Kupffer cells, inhibited inflammation via NF-κB signaling, and suppressed the activation of HSCs [2931]. Moreover, silymarin relieved diet-induced NASH with liver fibrosis by suppressing HSC activation and TNF-α release [32]. The combined application of silymarin with other agents, such as caffeine, lisinopril, and taurine, also displayed remarkable antifibrotic effects through the downregulation of LPAR1 and NF-κB expression [3335].

2.3. Puerarin

Puerarin is an isoflavone that is extracted from the plant Pueraria lobata (Willd.) Ohwi. Puerarin has abundant pharmacological effects, including cardiovascular protection, neuroprotection, and liver injury prevention [36]. In recent years, puerarin was confirmed to be effective for the treatment of liver fibrosis with multiple target hits. A study suggested that puerarin at doses of 40–80 mg/kg significantly increased the activated HSCs apoptosis and downregulated Bcl-2 expression in a CCl4-induced liver fibrosis model [37]. Apart from apoptosis signaling, it is believed that puerarin also alleviates liver fibrosis via inhibition of excessive collagen deposition through peroxisomal proliferator-activated receptor γ (PPAR-γ) expression and the PI3K/Akt pathway, attenuation of inflammatory response through the TNF-α/NF-κB pathway, and suppression of PARP-1 and mitochondrial dysfunction [3840]. Moreover, puerarin also blocked the TGF-β1/Smad signaling pathway in dimethylnitrosamine- (DMN-) induced liver fibrosis and HSC-T6 in a dose-dependent manner [41]. Similarly, puerarin was showed to alleviate TAA-induced liver fibrosis by reducing HSC activation and alleviating ECM expression through the downregulation of the TGF-β/ERK1/2 pathway [42]. In addition, the combined application of puerarin and vitamin D showed a significant effect against liver fibrosis through the Wnt/β-catenin signaling pathway [43].

2.4. Baicalin

Baicalin primarily derived from Scutellaria baicalensis Georgi is an active flavonoid compound and is believed to be a specific TCM for treating liver diseases [44]. In the past 15 years, this compound has been widely suggested to have a therapeutic effect on liver fibrosis. Peng’s research demonstrated that 70 mg/kg baicalin had a significant effect on CCl4-induced liver fibrosis, which was correlated with immunoregulation of the imbalance between profibrotic and anti-fibrotic cytokines, including TGF-β1, TNF-α, IL-6, and IL-10 expression [45]. Another study also confirmed that baicalin could enhance PPAR-γ levels contributing to the downregulation of the TGF-β1 signaling pathway and the suppression of HSC activation to play antifibrotic effect [46]. Baicalin also decreased liver fibrosis progression with marked inhibition of α-SMA, TGF-β1, and Col1A1 expression in a NASH model [47]. Furthermore, baicalin at doses of 50–150 μmol/L inhibited platelet-derived growth factor-B subunit homodimer- (PDGF-BB-) induced HSC-T6 activation via the miR-3595/ACSL4 axis in vitro [48]. Other systematic studies indicated that baicalin combined with rosmarinic acid suppressed fibrotic effects via PPAR-γ in HSCs [49].

2.5. Baicalein

Baicalein is another active flavonoid from Scutellaria baicalensis Georgi. Baicalein possesses hepatoprotective activities via a variety of biological properties [50]. Treatment with 20–80 mg/kg baicalein dose-dependently decreased hydroxyproline and MMPs in CCl4-induced liver fibrosis, which was related to reduction of inflammation, liver structural repair, and protein synthesis inhibition of the PDGF-β receptor [51]. Moreover, 3–30 μmol/L baicalein presented potent antiproliferative effect in HSCs stimulated with PDGF-BB-, indicating that baicalein could be regarded as a potential antifibrotic drug [52].

2.6. Hesperidin

Hesperidin is a flavanone glycoside that is widely found in citrus fruits and has various biological activities, such as neuroprotection, liver protection, anticancer effects, and inflammatory regulation [53, 54]. Hesperidin was found to be effective for liver fibrosis treatment based on a series of liver fibrosis models. Hesperidin at doses of 100 and 200 mg/kg demonstrated antifibrotic effects by reducing HSC activation in DMN-induced fibrosis [55]. In a CCl4-induced liver fibrosis model, hesperidin at 200 mg/kg decreased lipid peroxidation, NF-κB, TGF-β, CTGF, and IL-1β and increased IL-10 expression [56]. Moreover, hesperidin prevented from the progression of BDL-induced liver fibrosis through inhibition of TGF-β1/Smad signaling pathway-mediated ECM deposition and apoptosis [57]. A similar study in vitro indicated that hesperidin inhibited HSC-T6 proliferation and activation by modulating the TGF-β1/Smad signaling pathway [58].

2.7. Quercetin

Quercetin, a well-known flavonoid, is widely found in various vegetables and fruits, including onion, mulberry, tomato, apples, and tea [59]. Quercetin is thought to effectively suppress liver fibrosis involving multiple mechanisms. A study from Lee first reported that administration of quercetin at 10 mg/kg markedly prevented from DMN-induced liver fibrosis by reducing TGF-β1 expression [60]. Quercetin at doses of 5–200 mg/kg significantly alleviated liver fibrosis induced by CCl4 through regulating inflammation involving NF-кB and MAPK signals and protecting from apoptosis via inhibiting proapoptotic gene Bax and improving antiapoptotic gene Bcl-2 expression [61]. Quercetin also reduced autophagy via the TGF-β1/Smad and PI3K/Akt pathways, improving HSC apoptosis and activating MMPs, as well as inhibiting macrophage infiltration and modulating M1 macrophage polarization by regulating the Notch1 signaling pathway [6264]. In addition, quercetin modulated the HMGB1-TLR2/4-NF-κB signaling pathways to inhibit HSC activation in CCl4-induced liver fibrosis [65]. In BDL-induced liver fibrosis rats, quercetin markedly inhibited ROS-associated inflammation and ameliorated insulin resistance via the STAT3/SOCS3/IRS1 signaling pathway [66]. In vitro research also showed that liver steatosis, inflammatory cell accumulation, oxidative stress, and liver fibrosis were totally or partially prevented by treatment with quercetin [67].

2.8. Genistein

Genistein is an isoflavone that is found in several soy products and has potential therapeutic effects on a multitude of diseases [68]. Increasing evidence has shown that genistein is specifically hepatoprotective [6971]. Ganai reported that genistein at a dose of 5 mg/kg ameliorated D-GalN-induced liver fibrosis by inhibiting the TGF-β/Smad2/3 signaling pathway [72]. Genistein also significantly attenuated CCl4-induced and BDL-induced liver fibrosis [73, 74]. Schistosomiasis-induced liver fibrosis was also markedly reversed by genistein through the NF-κB signaling pathway [75, 76]. Furthermore, genistein significantly decreased hepatic injury and fibrosis induced by chronic alcohol after treatment with 0.5–2 mg/kg [77]. Genistein inhibited proliferation and activation of HSCs as a tyrosine protein kinase inhibitor in vitro [78]. In addition, several studies conducted by Liao indicated that genistein combined with taurine and epigallocatechin gallate had a significantly preventive effect on liver fibrosis via protein metabolism, as well as glycolysis, gluconeogenesis, and ribosomal regulation [7984].

2.9. Naringenin

Naringenin is a specific flavanone that is distributed in several plants, such as cherries, cocoa, grapes, tangelos, and lemons [85]. Naringenin displays wide preventative properties in liver damage induced by alcohol, CCl4, lipopolysaccharide, and heavy metals [86]. For instance, naringenin at doses of 20 and 50 mg/kg prevented from liver fibrosis induced by DMN [87]. Naringenin at a dose of 100 mg/kg significantly reversed CCl4-induced liver fibrosis by blocking the TGF-β-Smad3 and JNK-Smad3 signaling pathways [88]. In addition, in vitro research revealed that naringenin exerted antifibrotic effects by downregulating Smad3 and TGF-β phosphorylation in activated HSCs [89].

2.10. Hydroxysafflor Yellow A

Hydroxysafflor yellow A, a flavonoid compound extracted from Carthamus tinctorius L., has received extensive attention and possesses broad pharmacological activities [90]. Zhang’s research revealed that 5 mg/kg hydroxysafflor yellow A attenuated liver fibrosis by downregulating TGF-β1, inhibiting phosphorylation of Smad4, and suppressing the ERK5 signaling pathways [91, 92]. The antifibrotic effect of hydroxysafflor yellow A was also correlated with the regulation of the PPAR-γ/p38 MAPK signaling pathway and a reduction in oxidative stress [93, 94]. Hydroxysafflor yellow A was further proven effective in stimulating PPAR activity, reducing cell proliferation, and suppressing ECM synthesis in vivo and in vitro [95]. Apart from these signaling pathways, hydroxysafflor yellow A also induced apoptosis by blocking ERK1/2 kinase in primary HSCs [96].

2.11. Oroxylin A

Oroxylin A is the main bioactive flavonoid extracted from Scutellaria baicalensis Georgi. Many studies have shown that oroxylin A demonstrates a variety of pharmacological properties against oxidative stress, inflammation, metastasis, and hepatosteatosis [97100]. A series of studies showed that oroxylin A ameliorated hepatic fibrosis by inhibiting HSC activation. Zheng revealed that continuous treatment with oroxylin A at 20 mg/kg reduced CCl4-induced liver fibrosis. Oroxylin A significantly inhibited the reversion of lipid droplets by reducing ROS-dependent adipose triglyceride lipase in activated HSCs [101]. Angiogenesis of liver sinusoidal endothelial cells is closely related to liver fibrosis. Oroxylin A prevented from angiogenesis of LSECs in liver fibrosis via inhibition of the YAP/HIF-1α signaling pathway [102]. Moreover, inhibition of glycolysis-dependent contraction via suppression of lactate dehydrogenase-A (LDH-A) and induction of apoptosis via endoplasmic reticulum (ER) stress in HSCs were involved in antihepatic fibrosis effects of oroxylin A [103, 104]. Apart from these signaling pathways, oroxylin A also alleviated CCl4-induced liver fibrosis by activating autophagy signaling [105].

2.12. Anthocyanins

Anthocyanins are compounds that are widely isolated from fruits and dietary supplements, such as grapes, blueberries, purple-fleshed sweet potatoes, and peanuts. Anthocyanins are believed to have many health-promoting benefits with prominent anti-inflammatory, antioxidant, and immunomodulatory effects [106]. Choi reported that treatment with 50–200 mg/kg anthocyanins significantly decreased DMN-induced enhancement of α-SMA and collagen types I and III levels in a liver fibrosis model, as well as TNF-α and TGF-β [107]. Another study further indicated that anthocyanins were efficient in attenuating HSC-T6 proliferation, which was associated with blocking the PDGFRβ signaling pathway and suppressing Akt and ERK1/2 activation and α-SMA expression [108]. Anthocyanins alleviated HSC activation and liver fibrosis in both HSCs-T6 cells and CCl4-treated rats. Anthocyanins from blueberries improved liver function and liver fibrosis by regulating histone acetylation in rats with hepatic fibrosis [109]. In addition, a study revealed that anthocyanins ameliorated liver fibrosis in a network manner by manipulating oxidative stress, inflammation, and HSC activation to remodel ECM deposition [110]. Cyanidin-3-O-β-glucoside is a classical anthocyanin with potent antifibrotic activity. A series of studies from Ling’s team suggested that 800 mg/kg dietary cyanidin-3-O-β-glucoside alleviated liver fibrosis by suppressing inflammatory factors, such as TNF-α, IL-6, and IL-10. The progression of HSC activation was also blocked by cyanidin-3-O-β-glucoside through significant inhibition of HSC proliferation and migration [111, 112].

2.13. Other Flavonoids

There are other flavonoid compounds that improve liver fibrosis, such as breviscapine, galangin, and skullcapflavone I. A study from Liu indicated that 15–30 mg/kg breviscapine dose-dependently reduced collagen deposition and narrowed fibrotic area induced by CCl4, which was partially related to inhibition of inflammatory apoptotic response and ROS generation [113]. Treatment with 20–80 mg/kg galangin also significantly reversed CCl4-induced rat liver fibrosis by inhibiting HSC activation and proliferation [114]. In early research, skullcapflavone I could induce apoptosis of HSCs to exert antifibrotic effects by activating caspase-3 and caspase-9 [115].

3. Quinones

Quinones belong to aromatic organic compounds with cyclic diketone structure of six-carbon atom containing two double bonds, including emodin and rhein, tanshinone IIA, and thymoquinone (Figures 2(a)–2(d)). Anthraquinone and its derivatives are particularly important in TCM. These quinones have various physiological activities, such as excretion promotion, diuretic effect, antibacteria and antivirus, hemostasis, and spasmolysis.

3.1. Emodin and Rhein

Emodin and rhein are the main bioactive anthraquinones derived from the rhizome of Rheum palmatum L. . Treatment with 20–80 mg/kg emodin significantly alleviated hepatic fibrosis [116]. Zhao’s research indicated that the mechanism of emodin against liver fibrosis was partially related to a reduction in the infiltration of Gr1hi monocytes [117]. Moreover, emodin also protected against liver fibrosis and HSC activation by reducing TGF-β1 and Smad4 expression and inhibiting tissue inhibitor of metalloproteinases-1 (TIMP-1) expression, and epithelial-mesenchymal transition [118120]. In addition, 25 and 100 mg/kg rhein inhibited liver fibrosis induced by CCl4/ethanol in rats, which possibly benefited from antioxidant and anti-inflammatory activities of rhein. The antifibrotic effect of rhein was also related to inhibition of TGF-β1 [121].

3.2. Tanshinone IIA

Tanshinone IIA is the main active diterpene quinone phytochemical extracted from Salvia miltiorrhiza Bunge (Labiatae). Tanshinone IIA has been commonly used for the treatment of liver diseases, such as hepatic injury, NASH, hepatic fibrosis, and HCC in recent years [122]. A systematic review summarized that tanshinone IIA at doses of 2–200 mg/kg significantly improved liver function in CCl4, DMN, TAA, and pig serum-induced liver fibrosis. Various mechanisms, such as reduction of inflammation, inhibition of immunity and antiapoptotic processes, and induction of apoptosis to inhibit HSC activation, are involved in antifibrosis effects of tanshinone IIA [123]. For example, tanshinone IIA enhanced apoptosis of HSCs by promoting the ERK-Bax-caspase signaling pathway via the C-Raf/prohibition complex [124]. Tanshinone IIA also inhibited cell proliferation by arresting the cell cycle in S phase in activated rat HSCs [125]. Moreover, the antifibrotic effect of tanshinone IIA was proved by the team’s further research. Su and Zhang found that tanshinone IIA was able to significantly alleviate ECM accumulation HSC proliferation as well as activation. The molecular mechanism involved MAPK, Wnt, and PI3K/Akt signaling pathways via inhibiting c-Jun, p-c-Jun, c-Myc, CCND1, MMP9, P65, p-P65, PI3K, and P38 [126]. In addition, tanshinone IIA could also work effectively in combination application such as Fuzheng Huayu formula, a well-known Chinese patent medicine used for liver fibrosis, according to a series of high-quality studies [127129].

3.3. Thymoquinone

Thymoquinone is the active ingredient from Nigella sativa plants. This compound has a protective effect against various types of liver diseases primarily due to its anti-inflammatory and antioxidant properties [130]. A study from Bai demonstrated that 20 and 40 mg/kg thymoquinone significantly enhanced the phosphorylation of AMPK and LKB-1. Thus, regulation of the AMPK signaling pathway might be involved in the inhibitory effect of thymoquinone on ECM accumulation and TAA-induced liver fibrosis [131]. Another study indicated that thymoquinone at 25 mg/kg alleviated CCl4-induced liver fibrosis through markedly suppressing activated rat HSCs and LX2 cells by inhibiting the proinflammatory response [132]. Furthermore, the antifibrosis mechanism of thymoquinone was correlated with blocking TLR4 expression and inhibiting the phosphorylation of PI3K in activated HSCs [133]. The combination of thymoquinone and vitamin D exhibited marked antifibrotic effects by downregulating TGF-β1, IL-6, and IL-22 and upregulating MMP-9 and IL-10 [134].

4. Lignans

Lignans are a kind of natural compounds synthesized by the polymerization of two phenylpropanol derivatives (C6–C3 monomer), such as schisandrin B, honokiol and magnolol, and sauchinone (Figures 2(e)–2(h)). Most of them are free, while a few glycosides are combined with sugar and exist in the wood and resin of plants. Lignans have the functions of antitumor, liver protection, antioxidation, antivirus, and neuromodulation.

4.1. Schisandrin B

Schisandrin B is an important bioactive lignan derived from a well-known herbal medicine named Schisandra chinensis that has been used for liver protection in recent years. Schisandrin B at 25 and 50 mg/kg significantly attenuated liver damage and liver fibrosis progression in CCl4-treated rats. Schisandrin B also markedly suppressed HSC-T6 activation. Schisandrin B could exert antifibrotic effects by increasing the Nrf2-ARE signaling pathway and decreasing the TGF-β/Smad signaling pathway [135]. Schisandrin B at 2.5 and 5 μmol/L also attenuated lipopolysaccharide- (LPS-) induced HSCs activation by upregulating Nrf-2 expression [136]. Moreover, transcriptomic analyses were also applied for mechanistic investigation. The results indicated that metabolic pathways, CYP450 enzymes, and the PPAR signaling pathway were the major target pathways of schisandrin B [137].

4.2. Honokiol and Magnolol

Honokiol and magnolol are the main bioactive lignans isolated from Magnolia officinalis Rehd. et Wils [138]. In recent years, a number of studies have focused extensive attention on the hepatoprotective effect of honokiol and magnolol. Treatment with honokiol at 10 mg/kg alleviated ConA-induced liver fibrosis by downregulating hydroxyproline, α-SMA, and collagen fiber deposition, which was associated with restoring antioxidant defense, regulating inflammatory cascades, and inhibiting the TGF-β/Smad/MAPK signaling pathway [139]. In vitro research showed that 12.5–50 μmol/L honokiol induced apoptotic death in activated rat HSCs through the release of mitochondrial cytochrome C [140]. Magnolol also attenuated ConA-induced liver fibrosis and suppressed human LX2 HSC activation, which was closely related to inhibiting Th17 cell differentiation by suppressing IL-17A generation [141]. In addition, other honokiol derivatives, such as 4′-O-methylhonokiol, also prevented from HSC activation and induced apoptosis via regulation of Bak1 and Bcl-2 expression [142].

4.3. Sauchinone

Sauchinone is a bioactive lignan that is mainly extracted from Saururus chinensis and has been widely used for treating fever, edema, jaundice, and several inflammatory diseases [143]. A team from Korea investigated the effect of sauchinone on liver fibrosis. The results showed that sauchinone at 10 and 20 mg/kg alleviated CCl4-induced liver fibrosis and inhibited TGF-β1-induced HSC activation, which might be associated with suppressing autophagy and oxidative stress in HSCs [144]. Sauchinone also has liver protection effect to resist liver fibrosis. For instance, sauchinone protected the liver from toxicity induced by iron accumulation by regulating LKB1-dependent AMPK activation [145].

5. Phenols and Acids

One or more hydroxyl groups are directly connected to the benzene ring in the chemical structure of phenolic compounds with weak acid, which is easy to be oxidized in the environment. Chemical structure of several representative phenols and acids is shown in Figure 3. Phenols always have the functions of antioxidation, anti-inflammatory, antiviral, and antitumor.

5.1. Salvianolic Acid B

Salvianolic acid B (SA-B) is a water-soluble phenolic acid isolated from Salvia miltiorrhiza Bunge. SA-B is a promising compound for the treatment of liver fibrosis according to reports in vivo and in vitro. Previous studies showed that SA-B significantly inhibited HSC activation by modulating the MAPK and Smad3 signaling pathways and ROS accumulation to reduce matrix collagen deposition and TGF-β1 expression [146148]. Inhibition of ERK, MEF2, and p38 MAPK-MKK3/6 signaling was also involved in the antifibrotic effect of SA-B both in vivo and in vitro [149, 150]. SA-B prevented from liver fibrosis in CCl4- and DMN-treated models, which were probably related to downregulating the Ang II signaling pathway by AT1R, ERK, and c-Jun phosphorylation and by regulating the NF-κB/IkBα signaling pathway [151, 152]. Yu reported that SA-B also inhibited the microRNA-17-5p-activated Wnt/β-catenin pathway and modulated lincRNA-p21 expression in HSC activation [153, 154]. In addition, a series of studies testified that the regulation of TGF-β/Smad, MAPK, TbR-I kinase, and microRNA-152 targets contributed to the antifibrotic effect of SA-B [155157].

5.2. Resveratrol

Resveratrol is a natural polyphenol that is widely found in grapes, peanuts, berries, and nuts. A variety of studies have focused on the antifibrotic effect of resveratrol in recent years. Treatment with 10–50 mg/kg resveratrol prevented from liver fibrosis induced by CCl4. The reduction in NF-κB activation and Akt/NF-κB signaling pathways might contribute to the antagonistic effect of resveratrol on liver fibrosis [158160]. Another study indicated that resveratrol alleviated fibrosis by producing IL-10 through polarization of macrophages in a CCl4-induced model [161]. Resveratrol also significantly inhibited DMN-induced liver fibrosis at doses of 10–20 mg/kg through improving antioxidant defense and alleviating oxidative stress [162, 163]. In addition, resveratrol was proven to be effective in N′-nitrosodimethylamine- (NDMA-) induced fibrosis via reducing oxidative damage and resisting HSC activation [164]. Resveratrol demonstrated an antifibrotic effect by modulating alpha fetoprotein transcriptional levels and normalization of protein kinase C (PKC) responses in a TAA-treated model [165]. Resveratrol also had a potent effect on fibrosis induced by NASH and Schistosoma japonicum infection [166, 167]. Similar studies in vitro verified that resveratrol inhibited the activation of HSCs by modulating PPAR-γ/SIRT1 signals and blocking NF-κB activation, as well as PI3K/Akt phosphorylation [168, 169]. Resveratrol also induced HSC apoptosis by modulating autophagy/mitophagy and mitochondrial biogenesis [170].

5.3. Epigallocatechin-3-Gallate

Epigallocatechin-3-gallate (EGCG) is a major polyphenol that accounts for 10%–15% of the components in green tea [166]. EGCG is also a well-known antioxidant with potent activity in various diseases [171]. Several studies revealed that 25–300 mg/kg EGCG attenuated CCl4-induced liver fibrosis partially through inhibiting HSC activation and targeting MMP-2 via the modulation of membrane type 1-MMP activity [172]. The reduction in oxidative stress and proinflammatory response may also contribute to the effect of EGCG against liver fibrosis [173]. EGCG effectively altered fibrogenesis by blocking ERK and Smad1/2 phosphorylation, as well as targeting PDGFRβ and IGF-1R [174, 175]. Moreover, EGCG markedly inhibited BDL-induced liver fibrosis and TGF-β1-stimulated LX-2 cells and downregulated profibrotic markers. The antifibrotic effect of EGCG was related to inhibiting the PI3K/Akt/Smad signaling pathway and modulating mitochondrial oxidative stress and inflammation [176, 177]. Arffa reported that EGCG reduced TAA-induced fibrosis and inhibited osteopontin by upregulating miR-221 [178]. Furthermore, EGCG treatment counteracted the activated effects of the TGF/Smad, PI3K/Akt/FoxO1, and NF-κB signaling pathways to alter hepatic fibrosis in NAFLD models [179]. Studies have revealed that EGCG inhibits HSC activation in primary rat HSCs, TWNT-4 cells, and LI90 cells. A study by Sakata revealed that EGCG inhibited PDGF-BB-induced cell proliferation of LI90 cells by blocking PDGF-BB binding to its receptor in a noncompetitive manner [180]. Moreover, Nakamuta found a similar antifibrotic effect of EGCG in TWNT-4 human HSCs by regulating ERK1/2, c-Jun kinase, and p38 via the suppression of Rho signaling pathways [181, 182]. Further studies also suggested that EGCG suppressed MMP-2 activation and HSC invasiveness and induced de novo synthesis of GSH [183, 184]. In addition, the combination therapy of EGCG with taurine, genistein, or atorvastatin also demonstrated a significant antifibrotic effect [78, 185].

5.4. Curcumin

Curcumin is a well-known polyphenolic compound that is mainly isolated from Curcuma longa [186]. In the past 20 years, accumulating evidence in vivo and in vitro has shown that curcumin is a promising agent for liver fibrosis treatment. Studies indicated that curcumin exerted antifibrotic effect via networks and multiple signals. For example, curcumin suppressed HSCs by targeting PPAR-γ signaling in vitro [187, 188]. The increase in PPAR-γ might inhibit the gene expression of receptor for advanced glycation end-products (RAGE) and attenuate oxidative stress in HSCs [189]. Moreover, inhibition of srebp-2 by modulating specificity protein-1 and suppressing inflammatory cytokines, including IL-6, TNF-α, and INF-γ, also contributed to antihepatic fibrosis effect of curcumin [190, 191]. Other studies revealed that curcumin could promote apoptosis of activated HSCs by upregulating caspase-3, Bax, and p53 and downregulating Bcl-2 to alleviate liver fibrosis [192195]. Wu’s team suggested that curcumin primarily attenuated liver fibrosis by modulating immune system by blocking Gr1hi monocytes via MCP-1 and reducing Ly6Chi monocyte infiltration via Kupffer cell activation [196, 197]. In addition, curcumin also reversed aberrant methylation in liver fibrosis in vivo and in vitro [198]. Several studies from Zhou’s group indicated that curcumin inhibited HSCs by affecting the β-catenin signaling pathway and regulating the Shh-associated delta-like homolog 1 (DLK1) signaling pathway [199, 200]. Furthermore, curcumin could exert antifibrotic activity through regulating the AMPK/PGC-1α axis to inhibit HSC activation [200]. Another team found that the core mechanism by which curcumin affected liver fibrosis was inhibiting the TGF-β1/Smad signaling pathway and CTGF expression [201]. The inhibition of the TGF-β/Smad signaling pathway was also observed in alcohol-induced hepatic fibrosis [202]. In addition to the above signals, curcumin also reduced HMGB1, TLR4, and TLR2 expression in fibrogenesis, while ameliorating intrahepatic angiogenesis and capillarization of the sinusoids during liver fibrosis [203, 204]. A series of studies revealed that curcumin alleviated ECM deposition and regulated HSC senescence by suppressing cannabinoid receptor type-1 (CBR1) signaling, activating the PPAR-γ/p53 signaling pathway, inhibiting sinusoidal angiogenesis, and activating Nrf2 to induce the lipocyte phenotype in HSCs [205, 206]. Furthermore, NK cells and Hedgehog signaling are also regulated by curcumin to inhibit fibrotic progression [207, 208]. A study initially verified that curcumin protected against CCl4-induced hepatic fibrosis by suppressing HIF-1α via the ERK-dependent signaling pathway [209]. Another study further showed that curcumin prevented from the activation of HSCs by blocking the succinate/HIF-1α signaling pathway [210]. Several other signals, including the modulation of CB1 receptors, IRS1, SOCS3, and STAT3 targets, MyD88 pathway, CXCL12/CXCR4 biological axis, Plin5 gene expression, and LD formation, were also involved in various mechanisms underlying antihepatic fibrosis effect of curcumin [211215].

5.5. Rosmarinic Acid

Rosmarinic acid is a natural polyphenolic antioxidant derived from a variety of common herbal plants [216]. Studies indicated that rosmarinic acid might have a therapeutic effect on liver fibrosis. For instance, a study from Li revealed that 2.5–10 mg/kg rosmarinic acid significantly suppressed TGF-β1 and CTGF expression in CCl4-induced liver fibrosis. Rosmarinic acid markedly inhibited HSC proliferation and activation by decreasing α-SMA, TGF-β1, and CTGF levels in HSC-T6 cell line [217]. Similarly, El-Lakkany reported that rosmarinic acid inhibited liver fibrosis progression by inhibiting HSC activation and proliferation by initiating apoptosis-related signals in a TAA-induced model and HSC-T6 cells [218]. Furthermore, rosmarinic acid stimulated the activity of ARE promoter through enhancing GSH level and removing ROS by stimulating Nrf2 translocation into the nucleus, GSH enhancement, and subsequent GCLC upregulation. Thus, ROS elimination by rosmarinic acid directly inhibited NF-κB-dependent MMP-2 expression and suppressed HSC activation [219]. In addition, rosmarinic acid is also the active ingredient in a potent antifibrotic herbal medicine named Yang-Gan-Wan. Rosmarinic acid and Yang-Gan-Wan are effective against liver fibrosis by suppressing the canonical Wnt signaling pathway and reducing PPAR-γ in HSCs [47].

5.6. Chlorogenic Acid

Chlorogenic acid is one of most plentiful phenolic acids and is widely distributed in various fruits, plants, and vegetables [220]. Many studies have confirmed that chlorogenic acid is specifically potent in liver protection. A series of studies indicated that 30 and 60 mg/kg chlorogenic acid significantly repressed liver fibrosis induced by CCl4 by inhibiting HSC activation and downregulating fibrogenetic factors [221]. Moreover, chlorogenic acid could present the hepatoprotective effect through inhibiting the TLR4/MyD88/NF-κB signaling pathway by downregulating several cytokines, such as IL-1β, IL-6, TNF-α, iNOS, and COX-2 [222]. In addition, a study reported that NOX subunits expression, ROS generation, and the phosphorylated levels of p38 and ERK1/2 decreased in HSCs, while Nrf2 and Nrf2-regulated antioxidant genes (HO-1, GCLC, and NQO-1) increased in liver tissues after chlorogenic acid intervention. Therefore, chlorogenic acid could prevent from liver fibrosis by activation of Nrf2 pathway and inhibition of NOX/ROS/MAPK pathway [223]. Another research group revealed that chlorogenic acid displayed significant antifibrotic effects on the hepatic stellate LX2 cell line and Schistosome-infected mice mainly through IL-13/miR-21/Smad7 signaling interaction [224]. Chlorogenic acid also blocked the miR-21-regulated TGF-β1/Smad7 signaling pathway by decreasing the expression of α-SMA, TGF-β1, and collagen I in CCl4-induced liver fibrosis and LX2 cells [225].

5.7. Other Phenols and Acids

Apart from the above compounds, there are several other phenols and acids used for liver fibrosis treatment, such as chicoric acid, syringic acid, vanillic acid, and sinapic acid. Chicoric acid is a natural phenolic acid that is mainly isolated from chicory and Echinacea plants [226]. A study from Kim suggested that 10–30 mg/kg chicoric acid significantly reduced liver fibrosis through downregulating α-SMA, TGF-β1, and collagen expression in NASH mice. Inhibition of NF-κB-regulated inflammatory response, suppression of AMPK-mediated lipid/triglyceride accumulation, and enhancement of Nrf2 antioxidant defense system might contribute to the effect of chicoric acid against NASH and fibrosis [227]. Syringic acid and vanillic acid are two phenolic compounds found in fruits and vegetables, which markedly suppressed collagen accumulation and decreased the hepatic hydroxyproline content in CCl4-induced liver fibrosis [228, 229]. Moreover, these compounds inhibited the activation of cultured HSCs but did not influence hepatocyte viability [230]. Thus, treatment with syringic acid and vanillic acid could suppress the progression of fibrosis during chronic liver injury. Sinapic acid is an orally bioavailable phenolic acid from spices, citrus and berry fruits, and vegetables with wide pharmacological effects [231]. Shin revealed that 10 and 20 mg/kg sinapic acid significantly ameliorated of α-SMA, TGF-β1, and col I expression in DMN-induced liver fibrosis, which might be relevant to antioxidant effect and suppression of NF-κB and TGF-β1 signals [232].

6. Outlook and Conclusions

6.1. Limitations and Outlook

Growing evidence suggests that liver fibrosis is a complicated process involving multiple dysfunctions of sinusoidal cells [5]. HSC activation and ECM deposition are thought to be the key markers of fibrogenesis. Recently, many attempts have been made to explore the antifibrotic effects of some natural products to promote drug discovery. Previous study by us reviewed the risk components of TCM-induced liver injury, including alkaloids, glycosides, toxic proteins, terpenoids and lactones, anthraquinones, and heavy metals [233]. In this review, we summarized only four kinds of natural compounds that exert potential antifibrotic function, especially their biological activities and potential mechanisms against liver fibrosis. However, three aspects should be noted. First, the transition from bench to bedside is limited for most natural products. Silymarin and silybin are currently used in the clinic for liver protection during fibrosis in China [234, 235]. However, other promising compounds, such as genistein, quercetin, resveratrol, and curcumin, are still waiting for further clinical confirmation or more evidence of efficacy. Secondly, most of these compounds show antifibrotic effects via multiple targets or signaling pathways (Figure 4). For instance, curcumin inhibits HSC proliferation and activation and modulates the immune microenvironment. The protection of hepatocytes by reducing oxidative stress and inflammatory responses is also involved in the antifibrotic effects of some natural products, such as silibinin, silymarin, anthocyanins, and emodin and rhein. Finally, the strength of evidence for the antifibrotic effect of several natural products is different based on various liver fibrosis models. Most natural products, including flavonoids, quinones, lignans, and phenols and acids, present excellent antifibrotic function in CCl4, DMN, TAA, Schistosome, and ethanol-treated models. However, a few compounds, such as skullcapflavone I and magnolol, have only been confirmed to have effects on HSCs in vitro. Stronger evidence is needed for the effects of these compounds in liver fibrosis. Despite the rapid growth of studies on antifibrotic natural products, there are still future breakthroughs in two aspects. The potent effects of natural compounds have been presented, but the low bioavailability of several compounds vastly limits their clinical application. Enhancement of pharmacokinetic parameters for these compounds should be investigated. Moreover, the combined application of several natural products seems to be a promising method for liver fibrosis treatment. The combination of silymarin with caffeine, puerarin with vitamin D, baicalin with rosmarinic acid, and genistein with taurine and EGCG has been explored in previous studies. The results also show the potent synergistic effect of these combinations.

7. Conclusions

In summary, exploration on natural products against liver fibrosis is increasingly thorough. Natural products are a potential resource for the development of agents to treat liver fibrosis. Thus, natural products are very valuable when seeking novel therapeutic agents for liver fibrosis.

Abbreviations

ECM:Extracellular matrix
HSCs:Hepatic stellate cells
HBV:Hepatitis B virus
NAFLD:Nonalcoholic fatty liver disease
NASH:Nonalcoholic steatohepatitis
ROS:Reactive oxygen species
LSECs:Liver sinusoidal endothelial cells
TGF-β:Transforming growth factor-β
TCM:Traditional Chinese medicine
HCC:Hepatocellular carcinoma
TAA:Thioacetamide
GSH:Glutathione
CTGF:Connective tissue growth factor
PPAR-γ:Peroxisomal proliferator-activated receptor γ
DMN:Dimethylnitrosamine
PDGF-BB:Platelet-derived growth factor-B subunit homodimer
LDH-A:Lactate dehydrogenase-A
ER:Endoplasmic reticulum
TIMP-1:Tissue inhibitor of metalloproteinases-1
LPS:Lipopolysaccharide
NDMA:N′-Nitrosodimethylamine
PKC:Protein kinase C
EGCG:Epigallocatechin-3-gallate
RAGE:Receptor for advanced glycation end-products
DLK1:Delta-like homolog 1
CBR1:Cannabinoid receptor type-1.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Authors’ Contributions

The authors Xiaoqi Pan and Xiao Ma contributed equally to this work.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81891010, 81891012, 81630101, and 81874365), China Postdoctoral Science Foundation (2018M631070), Sichuan Science and Technology Program (2019YJ0492 and 2018JZ0081), Chengdu University of TCM Found Grant (QNXZ2018025), and Xinlin Scholar Research Promotion Project of Chengdu University of Traditional Chinese Medicine.

References

  1. T. Higashi, S. L. Friedman, and Y. Hoshida, “Hepatic stellate cells as key target in liver fibrosis,” Advanced Drug Delivery Reviews, vol. 121, pp. 27–42, 2017. View at: Publisher Site | Google Scholar
  2. K. Böttcher and M. Pinzani, “Pathophysiology of liver fibrosis and the methodological barriers to the development of anti-fibrogenic agents,” Advanced Drug Delivery Review, vol. 121, pp. 3–8, 2017. View at: Publisher Site | Google Scholar
  3. M. H. Forouzanfar and L. Alexander, “Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013,” The Lancet, vol. 386, pp. 2287–2323, 2015. View at: Publisher Site | Google Scholar
  4. T. Tsuchida and S. L. Friedman, “Mechanisms of hepatic stellate cell activation,” Nature Reviews Gastroenterology & Hepatology, vol. 14, pp. 397–411, 2017. View at: Publisher Site | Google Scholar
  5. G. Marrone, V. H. Shah, and J. Gracia-Sancho, “Sinusoidal communication in liver fibrosis and regeneration,” Journal of Hepatology, vol. 65, pp. 608–617, 2016. View at: Publisher Site | Google Scholar
  6. C. Trautwein, S. L. Friedman, and D. Schuppan, “Hepatic fibrosis: concept to treatment,” Journal of Hepatology, vol. 62, pp. S15–S24, 2015. View at: Publisher Site | Google Scholar
  7. E. Lafoz, M. Ruart, and A. Anton, “The endothelium as a driver of liver fibrosis and regeneration,” Cells, vol. 9, 2020. View at: Publisher Site | Google Scholar
  8. J. M. Luk, X. Wang, and P. Liu, “Traditional Chinese herbal medicines for treatment of liver fibrosis and cancer: from laboratory discovery to clinical evaluation,” Liver International, vol. 27, pp. 879–890, 2007. View at: Publisher Site | Google Scholar
  9. A. Zhang, H. Sun, and X. Wang, “Recent advances in natural products from plants for treatment of liver diseases,” European Journal of Medicinal Chemistry, vol. 63, pp. 570–577, 2013. View at: Publisher Site | Google Scholar
  10. X. Ma, Y. Jiang, and W. Zhang, “Natural products for the prevention and treatment of cholestasis : a review,” Phytotherapy Research, vol. 34, no. 6, pp. 1291–1309, 2020. View at: Publisher Site | Google Scholar
  11. Y. Zhao, X. Ma, and J. Wang, “A system review of anti-fibrogenesis effects of compounds derived from Chinese herbal medicine,” Mini Reviews in Medicinal Chemistry, vol. 16, no. 2, pp. 163–175, 2016. View at: Publisher Site | Google Scholar
  12. X. Lv, S. Liu, and Z. W. Hu, “Autophagy-inducing natural compounds: a treasure resource for developing therapeutics against tissue fibrosis,” Journal of Asian Natural Products Research, vol. 19, pp. 101–108, 2017. View at: Publisher Site | Google Scholar
  13. D. Q. Chen, Y. L. Feng, and G. Cao, “Natural products as a source for antifibrosis therapy,” Trends in Pharmacological Sciences, vol. 39, pp. 937–952, 2018. View at: Publisher Site | Google Scholar
  14. A. Federico, M. Dallio, and C. Loguercio, “Silymarin/silybin and chronic liver disease: a marriage of many years,” Molecules, vol. 22, p. 191, 2017. View at: Publisher Site | Google Scholar
  15. A. Pietrangelo, G. Montosi, and C. Garuti, “Iron-induced oxidant stress in nonparenchymal liver cells: mitochondrial derangement and fibrosis in acutely iron-dosed gerbils and its prevention by silybin,” Journal of Bioenergetics and Biomembranes, vol. 34, pp. 67–79, 2002. View at: Publisher Site | Google Scholar
  16. A. Masini, D. Ceccarelli, and F. Giovannini, “Iron-induced oxidant stress leads to irreversible mitochondrial dysfunctions and fibrosis in the liver of chronic iron-dosed gerbils. the effect of silybin,” Journal of Bioenergetics and Biomembranes, vol. 32, pp. 175–182, 2000. View at: Publisher Site | Google Scholar
  17. P. Muriel, M. G. Moreno, and M. D. C. Hernández, “Resolution of liver fibrosis in chronic CCl4 administration in the rat after discontinuation of treatment: effect of silymarin, silibinin, colchicine and trimethylcolchicinic acid,” Basic & Clinical Pharmacology & Toxicology, vol. 96, pp. 375–380, 2005. View at: Publisher Site | Google Scholar
  18. Y. Xie, H. P. Hao, and H. Wang, “Reversing effects of silybin on TAA-induced hepatic CYP3A dysfunction through PXR regulation,” Chinese Journal of Natural Medicines, vol. 11, pp. 645–652, 2013. View at: Publisher Site | Google Scholar
  19. Q. Ou, Y. Weng, and S. Wang, “Silybin alleviates hepatic steatosis and fibrosis in NASH mice by inhibiting oxidative stress and involvement with the nf-κb pathway,” Digestive Diseases and Sciences, vol. 63, pp. 3398–3408, 2018. View at: Publisher Site | Google Scholar
  20. M. Trappoliere, A. Caligiuri, and M. Schmi, “Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells,” Journal of Hepatology, vol. 50, pp. 1102–1111, 2009. View at: Publisher Site | Google Scholar
  21. D. Ezhilarasan, J. Evraerts, and B. Sid, “Silibinin induces hepatic stellate cell cycle arrest via enhancing p53/p27 and inhibiting Akt downstream signaling protein expression,” Hepatobiliary & Pancreatic Diseases International, vol. 16, pp. 80–87, 2017. View at: Publisher Site | Google Scholar
  22. P. Ferenci, “Silymarin in the treatment of liver diseases: what is the clinical evidence?” Clinical Liver Disease, vol. 7, pp. 8–10, 2016. View at: Publisher Site | Google Scholar
  23. E. Shaker, H. Mahmoud, and S. Mnaa, “Silymarin, the antioxidant component and Silybum marianum extracts prevent liver damage,” Food and Chemical Toxicology, vol. 48, pp. 803–806, 2010. View at: Publisher Site | Google Scholar
  24. I. S. Chen, Y. C. Chen, and C. H. Chou, “Hepatoprotection of silymarin against thioacetamide-induced chronic liver fibrosis,” Journal of the Science of Food and Agriculture, vol. 92, pp. 1441–1447, 2012. View at: Publisher Site | Google Scholar
  25. H. A. Mata-Santos, F. G. Lino, and C. C. Rocha, “Silymarin treatment reduces granuloma and hepatic fibrosis in experimental schistosomiasis,” Parasitology Research, vol. 107, pp. 1429–1434, 2010. View at: Publisher Site | Google Scholar
  26. J. H. Tsai, J. Y. Liu, and T. T. Wu, “Effects of silymarin on the resolution of liver fibrosis induced by carbon tetrachloride in rats,” Journal of Viral Hepatitis, vol. 15, pp. 508–514, 2008. View at: Publisher Site | Google Scholar
  27. C. S. Lieber, M. A. Leo, and Q. Cao, “Silymarin retards the progression of alcohol-induced hepatic fibrosis in baboons,” Journal of Clinical Gastroenterology, vol. 37, pp. 336–339, 2003. View at: Publisher Site | Google Scholar
  28. N. M. El-Lakkany, O. A. Hammam, and W. H. El-Maadawy, “Anti-inflammatory/anti-fibrotic effects of the hepatoprotective silymarin and the schistosomicide praziquantel against Schistosoma mansoni-induced liver fibrosis,” Parasites & Vectors, vol. 5, p. 9, 2012. View at: Publisher Site | Google Scholar
  29. J. I. Tzeng, M. F. Chen, and H. H. Chung, “Silymarin decreases connective tissue growth factor to improve liver fibrosis in rats treated with carbon tetrachloride,” Phytotherapy Research, vol. 27, pp. 1023–1028, 2013. View at: Publisher Site | Google Scholar
  30. S. Clichici, D. Olteanu, and A. L. Nagy, “Silymarin inhibits the progression of fibrosis in the early stages of liver injury in CCl4-treated rats,” Journal of Medicinal Food, vol. 18, pp. 290–298, 2015. View at: Publisher Site | Google Scholar
  31. S. Clichici, D. Olteanu, and A. Filip, “Beneficial effects of silymarin after the discontinuation of CCl4-induced liver fibrosis,” Journal of Medicinal Food, vol. 19, pp. 789–797, 2016. View at: Publisher Site | Google Scholar
  32. M. Kim, S. G. Yang, and J. M. Kim, “Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: analysis of isolated hepatic stellate cells,” International Journal of Molecular Medicine, vol. 30, pp. 473–479, 2012. View at: Publisher Site | Google Scholar
  33. S. Saber, R. Goda, and G. S. El-Tanbouly, “Lisinopril inhibits nuclear transcription factor kappa B and augments sensitivity to silymarin in experimental liver fibrosis,” International Immunopharmacology, vol. 64, pp. 340–349, 2018. View at: Publisher Site | Google Scholar
  34. S. M. Eraky, M. El-Mesery, and A. El-Karef, “Silymarin and caffeine combination ameliorates experimentally-induced hepatic fibrosis through down-regulation of LPAR1 expression,” Biomedicine & Pharmacotherapy, vol. 101, pp. 49–57, 2018. View at: Publisher Site | Google Scholar
  35. A. M. Abdel-Moneim, M. A. Al-Kahtani, and M. A. El-Kersh, “Free radical-scavenging, anti-inflammatory/anti-fibrotic and hepatoprotective actions of taurine and silymarin against CCl4 induced rat liver damage,” PLoS One, vol. 10, Article ID e0144509, 2015. View at: Publisher Site | Google Scholar
  36. Y. X. Zhou, H. Zhang, and C. Peng, “Puerarin: a review of pharmacological effects,” Phytotherapy Research, vol. 28, pp. 961–975, 2014. View at: Publisher Site | Google Scholar
  37. S. Zhang, G. Ji, and J. Liu, “Reversal of chemical-induced liver fibrosis in Wistar rats by puerarin,” Journal of Nutritional Biochemistry, vol. 17, pp. 485–491, 2006. View at: Publisher Site | Google Scholar
  38. C. Guo, L. Xu, and Q. He, “Anti-fibrotic effects of puerarin on CCl4-induced hepatic fibrosis in rats possibly through the regulation of PPAR-γ expression and inhibition of PI3K/Akt pathway,” Food and Chemical Toxicology, vol. 56, pp. 436–442, 2013. View at: Publisher Site | Google Scholar
  39. R. Li, L. Xu, and T. Liang, “Puerarin mediates hepatoprotection against CCl4-induced hepatic fibrosis rats through attenuation of inflammation response and amelioration of metabolic function,” Food and Chemical Toxicology, vol. 52, pp. 69–75, 2013. View at: Publisher Site | Google Scholar
  40. S. Wang, X. L. Shi, and M. Feng, “Puerarin protects against CCl4-induced liver fibrosis in mice: possible role of PARP-1 inhibition,” International Immunopharmacology, vol. 38, pp. 238–245, 2016. View at: Publisher Site | Google Scholar
  41. L. Xu, N. Zheng, and Q. He, “Puerarin, isolated from Pueraria lobata (Willd.), protects against hepatotoxicity via specific inhibition of the TGF-β1/Smad signaling pathway, thereby leading to anti-fibrotic effect,” Phytomedicine, vol. 20, pp. 1172–1179, 2013. View at: Publisher Site | Google Scholar
  42. X. Li, H. Zhang, and L. Pan, “Puerarin alleviates liver fibrosis via inhibition of the ERK1/2 signaling pathway in thioacetamide-induced hepatic fibrosis in rats,” Experimental and Therapeutic Medicine, vol. 18, pp. 133–138, 2019. View at: Google Scholar
  43. G. R. Huang, S. J. Wei, and Y. Q. Huang, “Mechanism of combined use of vitamin D and puerarin in anti-hepatic fibrosis by regulating the Wnt/β-catenin signalling pathway,” World Journal of Gastroenterology, vol. 24, pp. 4178–4185, 2018. View at: Publisher Site | Google Scholar
  44. B. Dinda, S. Dinda, and S. DasSharma, “Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders,” European Journal of Medicinal Chemistry, vol. 131, pp. 68–80, 2017. View at: Publisher Site | Google Scholar
  45. X. D. Peng, L. L. Dai, and C. Q. Huang, “Correlation between anti-fibrotic effect of baicalin and serum cytokines in rat hepatic fibrosis,” World Journal of Gastroenterology, vol. 15, pp. 4720–4725, 2009. View at: Publisher Site | Google Scholar
  46. H. Qiao, H. Han, and D. Hong, “Protective effects of baicalin on carbon tetrachloride induced liver injury by activating PPARγ and inhibiting TGFβ1,” Pharmaceutical Biology, vol. 49, pp. 38–45, 2011. View at: Publisher Site | Google Scholar
  47. J. Zhang, H. Zhang, and X. Deng, “Baicalin attenuates non-alcoholic steatohepatitis by suppressing key regulators of lipid metabolism, inflammation and fibrosis in mice,” Life Sciences, vol. 192, pp. 46–54, 2018. View at: Publisher Site | Google Scholar
  48. X. Wu, F. Zhi, and W. Lun, “Baicalin inhibits PDGF-BB-induced hepatic stellate cell proliferation, apoptosis, invasion, migration and activation via the miR-3595/ACSL4 axis,” International Journal of Molecular Medicine, vol. 41, pp. 1992–2002, 2018. View at: Publisher Site | Google Scholar
  49. M. D. Yang, Y. M. Chiang, and R. Higashiyama, “Rosmarinic acid and baicalin epigenetically derepress peroxisomal proliferator-activated receptor γ in hepatic stellate cells for their antifibrotic effect,” Hepatology, vol. 55, pp. 1271–1281, 2012. View at: Publisher Site | Google Scholar
  50. W. Sun, P. Liu, and T. Wang, “Baicalein reduces hepatic fat accumulation by activating AMPK in oleic acid-induced HepG2 cells and high-fat diet-induced non-insulin-resistant mice,” Food & Function, vol. 11, pp. 711–721, 2020. View at: Publisher Site | Google Scholar
  51. H. Sun, Q. M. Che, and X. Zhao, “Antifibrotic effects of chronic baicalein administration in a CCl4 liver fibrosis model in rats,” European Journal of Pharmacology, vol. 631, pp. 53–60, 2010. View at: Publisher Site | Google Scholar
  52. T. Inoue and E. K. Jackson, “Strong antiproliferative effects of baicalein in cultured rat hepatic stellate cells,” European Journal of Pharmacology, vol. 378, pp. 129–135, 1999. View at: Publisher Site | Google Scholar
  53. M. Hajialyani, M. Hosein Farzaei, and J. Echeverría, “Hesperidin as a neuroprotective agent: a review of animal and clinical evidence,” Molecules, vol. 24, p. 648, 2019. View at: Publisher Site | Google Scholar
  54. Y. S. Wang, C. Y. Shen, and J. G. Jiang, “Antidepressant active ingredients from herbs and nutraceuticals used in TCM: pharmacological mechanisms and prospects for drug discovery,” Pharmacological Research, vol. 150, Article ID 104520, 2019. View at: Publisher Site | Google Scholar
  55. S. M. Elshazly and A. A. A. Mahmoud, “Antifibrotic activity of hesperidin against dimethylnitrosamine-induced liver fibrosis in rats,” Naunyn-Schmiedeberg’s Archives of Pharmacology, vol. 387, pp. 559–567, 2014. View at: Publisher Site | Google Scholar
  56. R. Kong, N. Wang, and H. Luo, “Hesperetin mitigates bile duct ligation-induced liver fibrosis by inhibiting extracellular matrix and cell apoptosis via the TGF-β1/smad pathway,” Current Molecular Medicine, vol. 18, pp. 15–24, 2018. View at: Publisher Site | Google Scholar
  57. J. E. Pérez-Vargas, N. Zarco, and M. Shibayama, “Hesperidin prevents liver fibrosis in rats by decreasing the expression of nuclear factor-κB, transforming growth factor-β and connective tissue growth factor,” Pharmacology, vol. 94, pp. 80–89, 2014. View at: Publisher Site | Google Scholar
  58. F. Wu, L. Jiang, and X. He, “Effect of hesperidin on TGF-beta1/Smad signaling pathway in HSC,” Zhongguo Zhong Yao Za Zhi, vol. 40, pp. 2639–2643, 2015. View at: Google Scholar
  59. Y. J. Kim and W. Park, “Anti-inflammatory effect of quercetin on RAW 264.7 mouse macrophages induced with polyinosinic-polycytidylic acid,” Molecules, vol. 21, p. 450, 2016. View at: Publisher Site | Google Scholar
  60. E. S. Lee, H. E. Lee, and J. Y. Shin, “The flavonoid quercetin inhibits dimethylnitrosamine-induced liver damage in rats,” Journal of Pharmacy and Pharmacology, vol. 55, pp. 1169–1174, 2003. View at: Publisher Site | Google Scholar
  61. R. Wang, H. Zhang, and Y. Wang, “Inhibitory effects of quercetin on the progression of liver fibrosis through the regulation of NF-кB/IкBα, p38 MAPK, and Bcl-2/Bax signaling,” International Immunopharmacology, vol. 47, pp. 126–133, 2017. View at: Publisher Site | Google Scholar
  62. L. Wu, Q. Zhang, and W. Mo, “Quercetin prevents hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing autophagy via the TGF-β1/Smads and PI3K/Akt pathways,” Science Reports, vol. 7, p. 9289, 2017. View at: Publisher Site | Google Scholar
  63. L. D. Hernández-Ortega, B. E. Alcántar-Díaz, and L. A. Ruiz-Corro, “Quercetin improves hepatic fibrosis reducing hepatic stellate cells and regulating pro-fibrogenic/anti-fibrogenic molecules balance,” Journal of Gastroenterology & Hepatology, vol. 27, pp. 1865–1872, 2012. View at: Publisher Site | Google Scholar
  64. X. Li, Q. Jin, and Q. Yao, “The flavonoid quercetin ameliorates liver inflammation and fibrosis by regulating hepatic macrophages activation and polarization in mice,” Frontiers in Pharmacology, vol. 9, pp. 1–14, 2018. View at: Publisher Site | Google Scholar
  65. X. Li, Q. Jin, and Q. Yao, “Quercetin attenuates the activation of hepatic stellate cells and liver fibrosis in mice through modulation of HMGB1-TLR2/4-NF-κB signaling pathways,” Toxicology Letters, vol. 261, pp. 1–12, 2016. View at: Publisher Site | Google Scholar
  66. A. Khodarahmi, A. Eshaghian, and F. Safari, “Quercetin mitigates hepatic insulin resistance in rats with bile duct ligation through modulation of the STAT3/SOCS3/IRS1 signaling pathway,” Journal of Food Science, vol. 84, pp. 3045–3053, 2019. View at: Publisher Site | Google Scholar
  67. E. Marcolin, B. San-Miguel, and D. Vallejo, “Quercetin treatment ameliorates inflammation and fibrosis in mice with nonalcoholic steatohepatitis1–3,” Journal of Nutrition, vol. 142, pp. 1821–1828, 2012. View at: Publisher Site | Google Scholar
  68. P. Thangavel, A. Puga-Olguín, and J. F. Rodríguez-Landa, “Genistein as potential therapeutic candidate for menopausal symptoms and other related diseases,” Molecules, vol. 24, p. 3892, 2019. View at: Publisher Site | Google Scholar
  69. M. Gan, L. Shen, and Y. Fan, “MicroRNA-451 and genistein ameliorate nonalcoholic steatohepatitis in mice,” International Journal of Molecular Sciences, vol. 20, p. 6084, 2019. View at: Publisher Site | Google Scholar
  70. O. Akinci, V. Durgun, and N. Kepil, “The role of genistein in experimental hepatic ischemia‒reperfusion model in rats,” Bratislavske lekarske listy, vol. 120, pp. 558–562, 2019. View at: Publisher Site | Google Scholar
  71. Q. Zhang, J. Bao, and J. Yang, “Genistein-triggered anticancer activity against liver cancer cell line HepG2 involves ROS generation, mitochondrial apoptosis, G2/M cell cycle arrest and inhibition of cell migration,” Archives of Medical Science, vol. 15, pp. 1001–1009, 2019. View at: Publisher Site | Google Scholar
  72. A. A. Ganai and M. Husain, “Genistein attenuates D-GalN induced liver fibrosis/chronic liver damage in rats by blocking the TGF-β/Smad signaling pathways,” Chemico-Biological Interactions, vol. 261, pp. 80–85, 2017. View at: Publisher Site | Google Scholar
  73. A. Leija Salas, T. Díaz Montezuma, and G. Garrido Fariña, “Genistein modifies liver fibrosis and improves liver function by inducing uPA expression and proteolytic activity in CCl4-treated rats,” Pharmacology, vol. 81, pp. 41–49, 2007. View at: Publisher Site | Google Scholar
  74. A. L. Salas, G. Ocampo, and G. G. Fariña, “Genistein decreases liver fibrosis and cholestasis induced by prolonged biliary obstruction in the rat,” Annals of Hepatology, vol. 6, pp. 41–47, 2007. View at: Google Scholar
  75. M. M. K. Sobhy, S. S. Mahmoud, and S. H. El-Sayed, “Impact of treatment with a protein tyrosine kinase inhibitor (genistein) on acute and chronic experimental schistosoma mansoni infection,” Experimental Parasitology, vol. 185, pp. 115–123, 2018. View at: Publisher Site | Google Scholar
  76. C. Wan, F. Jin, and Y. Du, “Genistein improves schistosomiasis liver granuloma and fibrosis via dampening NF-kB signaling in mice,” Parasitology Research, vol. 116, pp. 1165–1174, 2017. View at: Publisher Site | Google Scholar
  77. X. J. Liu, L. Yang, and Y. Q. Mao, “Effects of the tyrosine protein kinase inhibitor genistein on the proliferation, activation of cultured rat hepatic stellate cells,” World Journal of Gastroenterology, vol. 8, pp. 739–745, 2002. View at: Publisher Site | Google Scholar
  78. Q. Huang, R. Huang, and S. Zhang, “Protective effect of genistein isolated from Hydrocotyle sibthorpioides on hepatic injury and fibrosis induced by chronic alcohol in rats,” Toxicology Letters, vol. 217, pp. 102–110, 2013. View at: Publisher Site | Google Scholar
  79. Y. Luo, Y. Huo, and P. Song, “Validation and functional analysis of the critical proteins in combination with taurine, epigallocatechin gallate and genistein against liver fibrosis in rats,” Biomedicine & Pharmacotherapy, vol. 115, Article ID 108975, 2019. View at: Publisher Site | Google Scholar
  80. Y. Li, M. Zhu, and Y. Huo, “Anti-fibrosis activity of combination therapy with epigallocatechin gallate, taurine and genistein by regulating glycolysis, gluconeogenesis, and ribosomal and lysosomal signaling pathways in HSC-T6 cells,” Experimental and Therapeutic Medicine, vol. 16, pp. 4329–4338, 2018. View at: Publisher Site | Google Scholar
  81. L. Zhuo, M. Liao, and L. Zheng, “Combination therapy with taurine, epigallocatechin gallate and genistein for protection against hepatic fibrosis induced by alcohol in rats,” Biological and Pharmaceutical Bulletin, vol. 35, pp. 1802–1810, 2012. View at: Publisher Site | Google Scholar
  82. Y. Li, Y. Luo, and X. Zhang, “Combined taurine, epigallocatechin gallate and genistein therapy reduces HSC-T6 cell proliferation and modulates the expression of fibrogenic factors,” International Journal of Molecular Sciences, vol. 14, pp. 20543–20554, 2013. View at: Publisher Site | Google Scholar
  83. W. Cao, Y. Li, and M. Li, “Txn1, Ctsd and Cdk4 are key proteins of combination therapy with taurine, epigallocatechin gallate and genistein against liver fibrosis in rats,” Biomedicine & Pharmacotherapy, vol. 85, pp. 611–619, 2017. View at: Publisher Site | Google Scholar
  84. W. Cao, Y. Zhou, and Y. Li, “ITRAQ-based proteomic analysis of combination therapy with taurine, epigallocatechin gallate, and genistein on carbon tetrachloride-induced liver fibrosis in rats,” Toxicology Letters, vol. 232, pp. 233–245, 2015. View at: Publisher Site | Google Scholar
  85. F. L. Yen, T. H. Wu, and L. T. Lin, “Naringenin-loaded nanoparticles improve the physicochemical properties and the hepatoprotective effects of naringenin in orally-administered rats with CCl(4)-induced acute liver failure,” Pharmaceutical Research, vol. 26, pp. 893–902, 2009. View at: Publisher Site | Google Scholar
  86. E. Hernández-Aquino and P. Muriel, “Beneficial effects of naringenin in liver diseases: molecular mechanisms,” World Journal of Gastroenterology, vol. 24, pp. 1679–1707, 2018. View at: Publisher Site | Google Scholar
  87. E. Hernández-Aquino, M. A. Quezada-Ramírez, and A. Silva-Olivares, “Naringenin attenuates the progression of liver fibrosis via inactivation of hepatic stellate cells and profibrogenic pathways,” European Journal of Pharmacology, vol. 865, Article ID 172730, 2019. View at: Publisher Site | Google Scholar
  88. R. Tovar, R. E. Flores-Beltrán, and L. Favari, “Naringenin prevents experimental liver fibrosis by blocking TGFβ-Smad3 and JNK-Smad3 pathways,” World Journal of Gastroenterology, vol. 23, pp. 4354–4368, 2017. View at: Google Scholar
  89. X. Liu, W. Wang, and H. Hu, “Smad3 specific inhibitor, naringenin, decreases the expression of extracellular matrix induced by TGF-beta1 in cultured rat hepatic stellate cells,” Pharmaceutical Research, vol. 23, pp. 82–89, 2006. View at: Publisher Site | Google Scholar
  90. H. Ao, W. Feng, and C. Peng, “Hydroxysafflor yellow A: a promising therapeutic agent for a broad spectrum of diseases,” Evidence-Based Complementary and Alternative Medicine, vol. 2018, Article ID 8259280, 2018. View at: Publisher Site | Google Scholar
  91. Y. Zhang, J. Guo, and H. Dong, “Hydroxysafflor yellow A protects against chronic carbon tetrachloride-induced liver fibrosis,” European Journal of Pharmacology, vol. 660, pp. 438–444, 2011. View at: Publisher Site | Google Scholar
  92. Y. B. Zhang, H. Y. Dong, and X. M. Zhao, “Hydroxysafflor yellow A attenuates carbon tetrachloride-induced hepatic fibrosis in rats by inhibiting Erk5 signaling,” American Journal of Chinese Medicine, vol. 40, pp. 481–494, 2012. View at: Publisher Site | Google Scholar
  93. Y. Li, Y. Shi, and Y. Sun, “Restorative effects of hydroxysafflor yellow A on hepatic function in an experimental regression model of hepatic fibrosis induced by carbon tetrachloride,” Molecular Medicine Reports, vol. 15, pp. 47–56, 2017. View at: Publisher Site | Google Scholar
  94. Q. Liu, C. Y. Wang, and Z. Liu, “Hydroxysafflor yellow A suppresses liver fibrosis induced by carbon tetrachloride with high-fat diet by regulating PPAR-γ/p38 MAPK signaling,” Pharmaceutical Biology, vol. 52, pp. 1085–1093, 2014. View at: Publisher Site | Google Scholar
  95. C. Y. Wang, Q. Liu, and Q. X. Huang, “Activation of PPARγ is required for hydroxysafflor yellow A of Carthamus tinctorius to attenuate hepatic fibrosis induced by oxidative stress,” Phytomedicine, vol. 20, pp. 592–599, 2013. View at: Publisher Site | Google Scholar
  96. C. C. Li, C. Z. Yang, and X. M. Li, “Hydroxysafflor yellow A induces apoptosis in activated hepatic stellate cells through ERK1/2 pathway in vitro,” European Journal of Pharmaceutical Sciences, vol. 46, pp. 397–404, 2012. View at: Publisher Site | Google Scholar
  97. Q. Han, H. Wang, and C. Xiao, “Oroxylin A inhibits H(2)O(2)-induced oxidative stress in PC12 cells,” Natural Product Research, vol. 31, pp. 1339–1342, 2017. View at: Publisher Site | Google Scholar
  98. W. T. Ku, J. J. Tung, and T. J. F. Lee, “Long-term exposure to oroxylin A inhibits metastasis by suppressing CCL2 in oral squamous cell carcinoma cells,” Cancers (Basel), vol. 11, p. 353, 2019. View at: Publisher Site | Google Scholar
  99. H. Jin, N. Lian, and M. Bian, “Oroxylin A prevents alcohol-induced hepatic steatosis through inhibition of hypoxia inducible factor 1alpha,” Chemico-Biological Interactions, vol. 285, pp. 14–20, 2018. View at: Publisher Site | Google Scholar
  100. W. Zhou, X. Liu, and X. Zhang, “Oroxylin A inhibits colitis by inactivating NLRP3 inflammasome,” Oncotarget, vol. 8, pp. 58903–58917, 2017. View at: Publisher Site | Google Scholar
  101. Z. Zhang, M. Guo, and M. Shen, “Oroxylin A regulates the turnover of lipid droplet via downregulating adipose triglyceride lipase (ATGL) in hepatic stellate cells,” Life Sciences, vol. 238, Article ID 116934, 2019. View at: Publisher Site | Google Scholar
  102. C. Zhang, M. Bian, and X. Chen, “Oroxylin A prevents angiogenesis of LSECs in liver fibrosis via inhibition of YAP/HIF-1α signaling,” Journal of Cellular Biochemistry, vol. 119, pp. 2258–2268, 2018. View at: Publisher Site | Google Scholar
  103. F. Wang, Y. Jia, and M. Li, “Blockade of glycolysis-dependent contraction by oroxylin a via inhibition of lactate dehydrogenase-a in hepatic stellate cells,” Cell Communication and Signaling, vol. 17, pp. 1–13, 2019. View at: Publisher Site | Google Scholar
  104. M. Bian, J. He, and H. Jin, “Oroxylin A induces apoptosis of activated hepatic stellate cells through endoplasmic reticulum stress,” Apoptosis, vol. 24, pp. 905–920, 2019. View at: Publisher Site | Google Scholar
  105. W. Chen, Z. Zhang, and Z. Yao, “Activation of autophagy is required for Oroxylin A to alleviate carbon tetrachloride-induced liver fibrosis and hepatic stellate cell activation,” International Immunopharmacology, vol. 56, pp. 148–155, 2018. View at: Publisher Site | Google Scholar
  106. J. He and M. M. Giusti, “Anthocyanins: natural colorants with health-promoting properties,” Annual Review of Food Science and Technology, vol. 1, pp. 163–187, 2010. View at: Publisher Site | Google Scholar
  107. J. H. Choi, Y. P. Hwang, and C. Y. Choi, “Anti-fibrotic effects of the anthocyanins isolated from the purple-fleshed sweet potato on hepatic fibrosis induced by dimethylnitrosamine administration in rats,” Food and Chemical Toxicology, vol. 48, pp. 3137–3143, 2010. View at: Publisher Site | Google Scholar
  108. J. H. Choi, Y. P. Hwang, and B. H. Park, “Anthocyanins isolated from the purple-fleshed sweet potato attenuate the proliferation of hepatic stellate cells by blocking the PDGF receptor,” Environmental Toxicology and Pharmacology, vol. 31, pp. 212–219, 2011. View at: Publisher Site | Google Scholar
  109. W. Zhan, X. Liao, and R. J. Xie, “The effects of blueberry anthocyanins on histone acetylation in rat liver fibrosis,” Oncotarget, vol. 8, pp. 96761–96773, 2017. View at: Publisher Site | Google Scholar
  110. J. Sun, Y. Wu, and C. Long, “Anthocyanins isolated from blueberry ameliorates CCl4 induced liver fibrosis by modulation of oxidative stress, inflammation and stellate cell activation in mice,” Food and Chemical Toxicology, vol. 120, pp. 491–499, 2018. View at: Publisher Site | Google Scholar
  111. X. Jiang, T. Shen, and X. Tang, “Cyanidin-3-O-β-glucoside combined with its metabolite protocatechuic acid attenuated the activation of mice hepatic stellate cells,” Food & Function, vol. 8, pp. 2945–2957, 2017. View at: Publisher Site | Google Scholar
  112. X. Jiang, H. Guo, and T. Shen, “Cyanidin-3-O-β-glucoside purified from black rice protects mice against hepatic fibrosis induced by carbon tetrachloride via inhibiting hepatic stellate cell activation,” Journal of Agricultural and Food Chemistry, vol. 63, pp. 6221–6230, 2015. View at: Publisher Site | Google Scholar
  113. Y. Liu, P. H. Wen, and X. X. Zhang, “Breviscapine ameliorates CCl4-induced liver injury in mice through inhibiting inflammatory apoptotic response and ROS generation,” International Journal of Molecular Medicine, vol. 42, pp. 755–768, 2018. View at: Google Scholar
  114. X. Wang, G. Gong, and W. Yang, “Antifibrotic activity of galangin, a novel function evaluated in animal liver fibrosis model,” Environmental Toxicology and Pharmacology, vol. 36, pp. 288–295, 2013. View at: Publisher Site | Google Scholar
  115. E. J. Park, Y. Z. Zhao, and L. Lian, “Skullcapflavone I from Scutellaria baicalensis induces apoptosis in activated rat hepatic stellate cells,” Planta Medica, vol. 71, pp. 885–887, 2005. View at: Publisher Site | Google Scholar
  116. Y. Zhan, D. Li, and H. Wei, “Emodin on hepatic fibrosis in rats,” Chinese Medical Journal (England), vol. 113, pp. 599–601, 2000. View at: Google Scholar
  117. X. A. Zhao, G. Chen, and Y. Liu, “Emodin alleviates liver fibrosis of mice by reducing infiltration of Gr1 hi monocytes,” Evidence-Based Complementary and Alternative Medicine, vol. 2018, Article ID 5738101, 2018. View at: Publisher Site | Google Scholar
  118. M. X. Dong, Y. Jia, and Y. B. Zhang, “Emodin protects rat liver from CCl(4)-induced fibrogenesis via inhibition of hepatic stellate cells activation,” World Journal of Gastroenterology, vol. 15, pp. 4753–4762, 2009. View at: Publisher Site | Google Scholar
  119. M. Gui, Y. F. Zhang, and Z. Y. Xiao, “Inhibitory effect of emodin on tissue inhibitor of metalloproteinases-1 (TIMP-1) expression in rat hepatic stellate cells,” Digestive Diseases and Sciences, vol. 52, pp. 200–207, 2007. View at: Publisher Site | Google Scholar
  120. F. Liu, J. Zhang, and J. Qian, “Emodin alleviates CCl4-induced liver fibrosis by suppressing epithelial-mesenchymal transition and transforming growth factor-β1 in rats,” Molecular Medicine Reports, vol. 18, pp. 3262–3270, 2018. View at: Google Scholar
  121. M. Z. Guo, X. S. Li, and H. R. Xu, “Rhein inhibits liver fibrosis induced by carbon tetrachloride in rats,” Acta Pharmaceutica Sinica B, vol. 23, pp. 739–744, 2002. View at: Google Scholar
  122. M. J. Shi, B. S. Dong, and W. N. Yang, “Preventive and therapeutic role of Tanshinone IIA in hepatology,” Biomedicine & Pharmacotherapy, vol. 112, Article ID 108676, 2019. View at: Publisher Site | Google Scholar
  123. Q. Ying, Y. Teng, and J. Zhang, “Therapeutic effect of tanshinone IIA on liver fibrosis and the possible mechanism: a preclinical meta-analysis,” Evidence-Based Complementary and Alternative Medicine, vol. 2019, Article ID 7514046, 2019. View at: Google Scholar
  124. T. L. Pan and P. W. Wang, “Explore the molecular mechanism of apoptosis induced by tanshinone IIA on activated rat hepatic stellate cells,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 734987, 2012. View at: Publisher Site | Google Scholar
  125. X. H. Che, E. J. Park, and Y. Z. Zhao, “Tanshinone II A induces apoptosis and s phase cell cycle arrest in activated rat hepatic stellate cells,” Basic & Clinical Pharmacology & Toxicology, vol. 106, pp. 30–37, 2010. View at: Google Scholar
  126. M. J. Shi, X. L. Yan, and B. S. Dong, “A network pharmacology approach to investigating the mechanism of Tanshinone IIA for the treatment of liver fibrosis,” Journal of Ethnopharmacology, vol. 253, Article ID 112689, 2020. View at: Publisher Site | Google Scholar
  127. R. Wu, S. Dong, and F. F. Cai, “Active compounds derived from Fuzheng Huayu formula protect hepatic parenchymal cells from apoptosis based on network pharmacology and transcriptomic analysis,” Molecules, vol. 24, 2019. View at: Google Scholar
  128. X. Q. Hu, Y. N. Song, and R. Wu, “Metabolic mechanisms of Fuzheng-Huayu formula against liver fibrosis in rats,” Journal of Ethnopharmacology, vol. 238, Article ID 111888, 2019. View at: Publisher Site | Google Scholar
  129. S. Dong, F. F. Cai, and Q. L. Chen, “Chinese herbal formula Fuzheng Huayu alleviates CCl4-induced liver fibrosis in rats: a transcriptomic and proteomic analysis,” Acta Pharmaceutica Sinica B, vol. 39, pp. 930–941, 2018. View at: Publisher Site | Google Scholar
  130. S. Bimonte, V. Albino, and A. Barbieri, “Dissecting the roles of thymoquinone on the prevention and the treatment of hepatocellular carcinoma: an overview on the current state of knowledge,” Infectious Agents and Cancer, vol. 14, p. 10, 2019. View at: Publisher Site | Google Scholar
  131. T. Bai, Y. Yang, and Y. L. Wu, “Thymoquinone alleviates thioacetamide-induced hepatic fibrosis and inflammation by activating LKB1-AMPK signaling pathway in mice,” International Immunopharmacology, vol. 19, pp. 351–357, 2014. View at: Publisher Site | Google Scholar
  132. M. Ghazwani, Y. Zhang, and X. Gao, “Anti-fibrotic effect of thymoquinone on hepatic stellate cells,” Phytomedicine, vol. 21, pp. 254–260, 2014. View at: Publisher Site | Google Scholar
  133. T. Bai, L. H. Lian, and Y. L. Wu, “Thymoquinone attenuates liver fibrosis via PI3K and TLR4 signaling pathways in activated hepatic stellate cells,” International Immunopharmacology, vol. 15, pp. 275–281, 2013. View at: Publisher Site | Google Scholar
  134. A. H. Abdelghany, M. A. BaSalamah, and S. Idris, “The fibrolytic potentials of vitamin D and thymoquinone remedial therapies: insights from liver fibrosis established by CCl4 in rats,” Journal of Translational Medicine, vol. 14, pp. 1–15, 2016. View at: Publisher Site | Google Scholar
  135. Q. Chen, H. Zhang, and Y. Cao, “Schisandrin B attenuates CCl(4)-induced liver fibrosis in rats by regulation of Nrf2-ARE and TGF-β/Smad signaling pathways,” Drug Design, Development and Therapy, vol. 11, pp. 2179–2191, 2017. View at: Publisher Site | Google Scholar
  136. Z. Yao, J. Han, and S. Lou, “Schisandrin B attenuates lipopolysaccharide-induced activation of hepatic stellate cells through Nrf-2-activating anti-oxidative activity,” International Journal of Clinical and Experimental Pathology, vol. 11, pp. 4917–4925, 2018. View at: Google Scholar
  137. H. Zhang, Q. Chen, and A. Dahan, “Transcriptomic analyses reveal the molecular mechanisms of schisandrin B alleviates CCl4-induced liver fibrosis in rats by RNA-sequencing,” Chemico-Biological Interactions, vol. 309, Article ID 108675, 2019. View at: Publisher Site | Google Scholar
  138. Y. Huang, C. Liu, and S. Liu, “In vitro metabolism of magnolol and honokiol in rat liver microsomes and their interactions with seven cytochrome P substrates,” Rapid Communication and Mass Spectrom, vol. 33, pp. 229–238, 2019. View at: Publisher Site | Google Scholar
  139. M. G. Elfeky, E. M. Mantawy, and A. M. Gad, Mechanistic Aspects of Antifibrotic Effects of Honokiol in Con A-Induced Liver Fibrosis in Rats: Emphasis on TGF-β/SMAD/MAPK Signaling Pathways, Elsevier, Amsterdam, Netherlands, 2020.
  140. E. J. Park, Y. Z. Zhao, and Y. H. Kim, “Honokiol induces apoptosis via cytochrome c release and caspase activation in activated rat hepatic stellate cells in vitro,” Planta Medica, vol. 71, pp. 82–84, 2005. View at: Publisher Site | Google Scholar
  141. H. Zhang, B. Ju, and X. Zhang, “Magnolol attenuates concanavalin A-induced hepatic fibrosis, inhibits CD4+ T helper 17 (Th17) cell differentiation and suppresses hepatic stellate cell activation: blockade of smad3/smad4 signalling,” Basic & Clinical Pharmacology & Toxicology, vol. 120, pp. 560–570, 2017. View at: Publisher Site | Google Scholar
  142. E. Patsenker, A. Chicca, and V. Petrucci, “4-O’-methylhonokiol protects from alcohol/carbon tetrachloride-induced liver injury in mice,” ournal of Molecular Medicine (Berlin), vol. 95, pp. 1077–1089, 2017. View at: Publisher Site | Google Scholar
  143. S. H. Sung and Y. C. Kim, “Hepatoprotective diastereomeric lignans from Saururus chinensis herbs,” Journal of Natural Products, vol. 63, pp. 1019–1021, 2000. View at: Publisher Site | Google Scholar
  144. J. H. Lee, E. J. Jang, and H. L. Seo, “Sauchinone attenuates liver fibrosis and hepatic stellate cell activation through TGF-β/Smad signaling pathway,” Chemico-Biological Interactions, vol. 224, pp. 58–67, 2014. View at: Publisher Site | Google Scholar
  145. Y. W. Kim, S. M. Lee, and S. M. Shin, “Efficacy of sauchinone as a novel AMPK-activating lignan for preventing iron-induced oxidative stress and liver injury,” Free Radical Biology and Medicine, vol. 47, pp. 1082–1092, 2009. View at: Publisher Site | Google Scholar
  146. Y. L. Lin, C. H. Wu, and M. H. Luo, “In vitro protective effects of salvianolic acid B on primary hepatocytes and hepatic stellate cells,” Journal of Ethnopharmacology, vol. 105, pp. 215–222, 2006. View at: Publisher Site | Google Scholar
  147. J. F. Zhao, C. H. Liu, and Y. Y. Hu, “Effect of salvianolic acid B on Smad3 expression in hepatic stellate cells,” Hepatobiliary & Pancreatic Diseases International, vol. 3, pp. 102–105, 2004. View at: Google Scholar
  148. P. Liu, C. H. Liu, and H. N. Wang, “Effect of salvianolic acid B on collagen production and mitogen-activated protein kinase activity in rat hepatic stellate cells,” Acta Pharmaceutica Sinica B, vol. 23, pp. 733–738, 2002. View at: Google Scholar
  149. Z. Lv, Y. Song, and D. Xue, “Effect of Salvianolic-acid B on inhibiting MAPK signaling induced by transforming growth factor-β1 in activated rat hepatic stellate cells,” Journal of Ethnopharmacology, vol. 132, pp. 384–392, 2010. View at: Publisher Site | Google Scholar
  150. W. Zhang, J. Ping, and Y. Zhou, “Salvianolic acid B inhibits activation of human primary hepatic stellate cells through downregulation of the myocyte enhancer factor 2 signaling pathway,” Frontiers in Pharmacology, vol. 10, 2019. View at: Publisher Site | Google Scholar
  151. S. Li, L. Wang, and X. Yan, “Salvianolic acid B attenuates rat hepatic fibrosis via downregulating angiotensin II signaling,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 160726, 2012. View at: Publisher Site | Google Scholar
  152. R. Wang, X. Y. Yu, and Z. Y. Guo, “Inhibitory effects of salvianolic acid B on CCl4-induced hepatic fibrosis through regulating NF-κB/IκBα signaling,” Journal of Ethnopharmacology, vol. 144, pp. 592–598, 2012. View at: Publisher Site | Google Scholar
  153. F. Yu, Y. Guo, and B. Chen, “LincRNA-p21 inhibits the Wnt/β-catenin pathway in activated hepatic stellate cells via sponging MicroRNA-17-5p,” Cellular Physiology & Biochemistry, vol. 41, pp. 1970–1980, 2017. View at: Publisher Site | Google Scholar
  154. F. Yu, Z. Lu, and K. Huang, “MicroRNA-17-5p-activated Wnt/β-catenin pathway contributes to the progression of liver fibrosis,” Oncotarget, vol. 7, pp. 81–93, 2016. View at: Publisher Site | Google Scholar
  155. C. Wu, W. Chen, and H. Ding, “Salvianolic acid B exerts anti-liver fibrosis effects via inhibition of MAPK-mediated phospho-Smad2/3 at linker regions in vivo and in vitro,” Life Science, vol. 239, Article ID 116881, 2019. View at: Publisher Site | Google Scholar
  156. F. Yu, Z. Lu, and B. Chen, “Salvianolic acid B-induced microRNA-152 inhibits liver fibrosis by attenuating DNMT1-mediated Patched1 methylation,” Journal of Cellular and Molecular Medicine, vol. 19, pp. 2617–2632, 2015. View at: Publisher Site | Google Scholar
  157. Y. Y. Tao, Q. L. Wang, and L. Shen, “Salvianolic acid B inhibits hepatic stellate cell activation through transforming growth factor beta-1 signal transduction pathway in vivo and in vitro,” Experimental biology and medicine (Maywood), vol. 238, pp. 1284–1296, 2013. View at: Publisher Site | Google Scholar
  158. E. Chávez, K. Reyes-Gordillo, and J. Segovia, “Resveratrol prevents fibrosis, NF-kappaB activation and TGF-beta increases induced by chronic CCl4 treatment in rats,” Journal of Applied Toxicology, vol. 28, pp. 35–43, 2008. View at: Publisher Site | Google Scholar
  159. M. Di Pascoli, M. Diví, and A. Rodríguez-Vilarrupla, “Resveratrol improves intrahepatic endothelial dysfunction and reduces hepatic fibrosis and portal pressure in cirrhotic rats,” Journal of Hepatology, vol. 58, pp. 904–910, 2013. View at: Publisher Site | Google Scholar
  160. H. Zhang, Q. Sun, and T. Xu, “Resveratrol attenuates the progress of liver fibrosis via the Akt/nuclear factor-κB pathways,” Molecular Medicine Reports, vol. 13, pp. 224–230, 2016. View at: Publisher Site | Google Scholar
  161. B. Yu, S. yu Qin, and B. li Hu, “Resveratrol improves CCL4-induced liver fibrosis in mouse by upregulating endogenous IL-10 to reprogramme macrophages phenotype from M(LPS) to M(IL-4),” Biomedicine & Pharmacotherapy, vol. 117, 2019. View at: Publisher Site | Google Scholar
  162. E. S. Lee, M. O. Shin, and S. Yoon, “Resveratrol inhibits dimethylnitrosamine-induced hepatic fibrosis in rats,” Archives of Pharmacal Research, vol. 33, pp. 925–932, 2010. View at: Publisher Site | Google Scholar
  163. S. W. Hong, K. H. Jung, and H. M. Zheng, “The protective effect of resveratrol on dimethylnitrosamine-induced liver fibrosis in rats,” Archives of Pharmacal Research, vol. 33, pp. 601–609, 2010. View at: Publisher Site | Google Scholar
  164. A. Ahmad and R. Ahmad, “Resveratrol mitigate structural changes and hepatic stellate cell activation in N-nitrosodimethylamine-induced liver fibrosis via restraining oxidative damage,” Chemico-Biological Interactions, vol. 221, pp. 1–12, 2014. View at: Publisher Site | Google Scholar
  165. A. F. Hessin, R. R. Hegazy, and A. A. Hassan, “Resveratrol prevents liver fibrosis via two possible pathways: modulation of alpha fetoprotein transcriptional levels and normalization of protein kinase C responses,” Indian Journal of Pharmacology, vol. 49, pp. 282–289, 2017. View at: Publisher Site | Google Scholar
  166. T. T. Chen, S. Peng, and Y. Wang, “Improvement of mitochondrial activity and fibrosis by resveratrol treatment in mice with Schistosoma japonicum infection,” Biomolecules, vol. 9, 2019. View at: Publisher Site | Google Scholar
  167. T. Kessoku, K. Imajo, and Y. Honda, “Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis,” Science Reports, vol. 6, pp. 3–9, 2016. View at: Publisher Site | Google Scholar
  168. I. C. C. de Souza, L. A. M. Martins, and M. de Vasconcelos, “Resveratrol regulates the quiescence-like induction of activated stellate cells by modulating the pparγ/SIRT1 ratio,” Journal of Cellular Biochemistry, vol. 116, pp. 2304–2312, 2015. View at: Publisher Site | Google Scholar
  169. D. Q. Zhang, P. Sun, and Q. Jin, “Resveratrol regulates activated hepatic stellate cells by modulating NF-κB and the PI3K/Akt signaling pathway,” Journal of Food Sciences, vol. 81, pp. H240–H245, 2016. View at: Publisher Site | Google Scholar
  170. L. A. Meira Martins, M. Q. Vieira, and M. Ilha, “The interplay between apoptosis, mitophagy and mitochondrial biogenesis induced by resveratrol can determine activated hepatic stellate cells death or survival,” Cell Biochemistry and Biophysics, vol. 71, pp. 657–672, 2014. View at: Publisher Site | Google Scholar
  171. B. N. Singh, S. Shankar, and R. K. Srivastava, “Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications,” Biochemical Pharmacology, vol. 82, pp. 1807–1821, 2011. View at: Publisher Site | Google Scholar
  172. M. chuan Zhen, Q. Wang, and X. hui Huang, “Green tea polyphenol epigallocatechin-3-gallate inhibits oxidative damage and preventive effects on carbon tetrachloride-induced hepatic fibrosis,” Journal of Nutritional Biochemistry, vol. 18, pp. 795–805, 2007. View at: Publisher Site | Google Scholar
  173. G. L. Tipoe, T. M. Leung, and E. C. Liong, “Epigallocatechin-3-gallate (EGCG) reduces liver inflammation, oxidative stress and fibrosis in carbon tetrachloride (CCl4)-induced liver injury in mice,” Toxicology, vol. 273, pp. 45–52, 2010. View at: Publisher Site | Google Scholar
  174. L. Wang, G. Yang, and L. Yuan, “Green tea catechins effectively altered hepatic fibrogenesis in rats by inhibiting ERK and smad1/2 phosphorylation,” Journal of Agricultural and Food Chemistry, vol. 67, pp. 5437–5445, 2019. View at: Publisher Site | Google Scholar
  175. Y. Yasuda, M. Shimizu, and H. Sakai, “(−)-Epigallocatechin gallate prevents carbon tetrachloride-induced rat hepatic fibrosis by inhibiting the expression of the PDGFRbeta and IGF-1R,” Chemico-Biological Interactions, vol. 182, pp. 159–164, 2009. View at: Publisher Site | Google Scholar
  176. K. Shen, X. Feng, and R. Su, “Epigallocatechin 3-gallate ameliorates bile duct ligation induced liver injury in mice by modulation of mitochondrial oxidative stress and inflammation,” PLoS One, vol. 10, Article ID e0126278, 2015. View at: Publisher Site | Google Scholar
  177. D. K. Yu, C. X. Zhang, and S. S. Zhao, “The anti-fibrotic effects of epigallocatechin-3-gallate in bile duct-ligated cholestatic rats and human hepatic stellate LX-2 cells are mediated by the PI3K/Akt/Smad pathway,” Acta Pharmaceutica Sinica B, vol. 36, pp. 473–482, 2015. View at: Publisher Site | Google Scholar
  178. M. L. Arffa, M. A. Zapf, and A. N. Kothari, “Epigallocatechin-3-Gallate upregulates miR-221 to inhibit osteopontin-dependent hepatic fibrosis,” PLoS One, vol. 11, Article ID e0167435, 2016. View at: Publisher Site | Google Scholar
  179. J. Xiao, C. T. Ho, and E. C. Liong, “Epigallocatechin gallate attenuates fibrosis, oxidative stress, and inflammation in non-alcoholic fatty liver disease rat model through TGF/SMAD, PI3 K/Akt/FoxO1, and NF-kappa B pathways,” European Journal of Nutrition, vol. 53, pp. 187–199, 2014. View at: Publisher Site | Google Scholar
  180. R. Sakata, T. Ueno, and T. Nakamura, “Green tea polyphenol epigallocatechin-3-gallate inhibits platelet-derived growth factor-induced proliferation of human hepatic stellate cell line LI90,” Journal of Hepatology, vol. 40, pp. 52–59, 2004. View at: Publisher Site | Google Scholar
  181. M. Nakamuta, N. Higashi, and M. Kohjima, “Epigallocatechin-3-gallate, a polyphenol component of green tea, suppresses both collagen production and collagenase activity in hepatic stellate cells,” International Journal of Molecular Medicine, vol. 16, pp. 677–681, 2005. View at: Google Scholar
  182. N. Higashi, M. Kohjima, and M. Fukushima, “Epigallocatechin-3-gallate, a green-tea polyphenol, suppresses Rho signaling in TWNT-4 human hepatic stellate cells,” Journal of Laboratory and Clinical Medicine, vol. 145, pp. 316–322, 2005. View at: Publisher Site | Google Scholar
  183. M. Zhen, X. Huang, and Q. Wang, “Green tea polyphenol epigallocatechin-3-gallate suppresses rat hepatic stellate cell invasion by inhibition of MMP-2 expression and its activation,” Acta Pharmaceutica Sinica B, vol. 27, pp. 1600–1607, 2006. View at: Publisher Site | Google Scholar
  184. F. Yumei, Y. Zhou, and S. Zheng, “The antifibrogenic effect of (−)-epigallocatechin gallate results from the induction of de novo synthesis of glutathione in passaged rat hepatic stellate cells,” Laboratory Investigation, vol. 86, pp. 697–709, 2006. View at: Publisher Site | Google Scholar
  185. L. Ying, F. Yan, and Y. Zhao, “(−)-Epigallocatechin-3-gallate and atorvastatin treatment down-regulates liver fibrosis-related genes in non-alcoholic fatty liver disease,” Clinical and Experimental Pharmacology, vol. 44, pp. 1180–1191, 2017. View at: Publisher Site | Google Scholar
  186. H. Khan, H. Ullah, and S. M. Nabavi, “Mechanistic insights of hepatoprotective effects of curcumin: therapeutic updates and future prospects,” Food and Chemical Toxicology, vol. 124, pp. 182–191, 2019. View at: Publisher Site | Google Scholar
  187. S. Zheng and A. Chen, “Activation of PPARγ is required for curcumin to induce apoptosis and to inhibit the expression of extracellular matrix genes in hepatic stellate cells in vitro,” Biochemical Journal, vol. 384, pp. 149–157, 2004. View at: Publisher Site | Google Scholar
  188. J. Xu, Y. Fu, and A. Chen, “Activation of peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth,” American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 285, pp. G20–G30, 2003. View at: Publisher Site | Google Scholar
  189. J. Lin, Y. Tang, and Q. Kang, “Curcumin inhibits gene expression of receptor for advanced glycation end-products (RAGE) in hepatic stellate cells in vitro by elevating PPARγ activity and attenuating oxidative stress,” British Journal of Pharmacology, vol. 166, pp. 2212–2227, 2012. View at: Publisher Site | Google Scholar
  190. Y. Fu, S. Zheng, and J. Lin, “Curcumin protects the rat liver from CCl4-caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation,” Molecular Pharmacology, vol. 73, pp. 399–409, 2008. View at: Publisher Site | Google Scholar
  191. Q. Kang and A. Chen, “Curcumin inhibits srebp-2 expression in activated hepatic stellate cells in vitro by reducing the activity of specificity protein-1,” Endocrinology, vol. 150, pp. 5384–5394, 2009. View at: Publisher Site | Google Scholar
  192. M. E. Wang, Y. C. Chen, and I. S. Chen, “Curcumin protects against thioacetamide-induced hepatic fibrosis by attenuating the inflammatory response and inducing apoptosis of damaged hepatocytes,” Journal of Nutritional Biochemistry, vol. 23, pp. 1352–1366, 2012. View at: Google Scholar
  193. S. Priya and P. R. Sudhakaran, “Curcumin-induced recovery from hepatic injury involves induction of apoptosis of activated hepatic stellate cells,” Indian Journal of Biochemistry and Biophysics, vol. 45, pp. 317–325, 2008. View at: Google Scholar
  194. J. C. Shu, Y. J. He, and X. Lv, “Curcumin prevents liver fibrosis by inducing apoptosis and suppressing activation of hepatic stellate cells,” Journal of Natural Medicines, vol. 63, pp. 415–420, 2009. View at: Google Scholar
  195. Y. J. He, K. Kuchta, and X. Lv, “Curcumin, the main active constituent of turmeric (Curcuma longa L.), induces apoptosis in hepatic stellate cells by modulating the abundance of apoptosis-related growth factors,” Zeitschrift Fur Naturforsch.-Section C Journal of Biosciences, vol. 70, pp. 281–285, 2015. View at: Publisher Site | Google Scholar
  196. R. Huang, Y. Liu, and Y. Xiong, “Curcumin protects against liver fibrosis by attenuating infiltration of gr1hi monocytes through inhibition of monocyte chemoattractant protein-1,” Discovery medicine, vol. 21, 2016. View at: Google Scholar
  197. X. A. Zhao, G. Chen, and Y. Liu, “Curcumin reduces Ly6Chi monocyte infiltration to protect against liver fibrosis by inhibiting Kupffer cells activation to reduce chemokines secretion,” Biomedicine & Pharmacotherapy, vol. 106, pp. 868–878, 2018. View at: Publisher Site | Google Scholar
  198. P. Wu, R. Huang, and Y. L. Xiong, “Protective effects of curcumin against liver fibrosis through modulating DNA methylation,” Chinese Journal of Natural Medicines, vol. 14, pp. 255–264, 2016. View at: Publisher Site | Google Scholar
  199. L. Cui, X. Jia, and Q. Zhou, “Curcumin affects β-catenin pathway in hepatic stellate cell in vitro and in vivo,” Journal of Pharmacy and Pharmacology, vol. 66, pp. 1615–1622, 2014. View at: Publisher Site | Google Scholar
  200. J. Qiu, Q. Zhou, and X. Zhai, “Curcumin regulates delta-like homolog 1 expression in activated hepatic stellate cell,” European Journal of Pharmacology, vol. 728, pp. 9–15, 2014. View at: Publisher Site | Google Scholar
  201. Q. yan Yao, B. li Xu, and J. yao Wang, “Inhibition by curcumin of multiple sites of the transforming growth factor-beta1 signalling pathway ameliorates the progression of liver fibrosis induced by carbon tetrachloride in rats,” BMC Complementary and Alternative Medicine, vol. 12, 2012. View at: Publisher Site | Google Scholar
  202. N. Chen, Q. Geng, and J. Zheng, “Suppression of the TGF-β/Smad signaling pathway and inhibition of hepatic stellate cell proliferation play a role in the hepatoprotective effects of curcumin against alcohol-induced hepatic fibrosis,” Internatioanl Journal of Molecular Medicine, vol. 34, pp. 1110–1116, 2014. View at: Publisher Site | Google Scholar
  203. C. tao Tu, Q. yan Yao, and B. li Xu, “Protective effects of curcumin against hepatic fibrosis induced by carbon tetrachloride: modulation of high-mobility group box 1, Toll-like receptor 4 and 2 expression,” Food and Chemical Toxicology, vol. 50, pp. 3343–3351, 2012. View at: Publisher Site | Google Scholar
  204. Q. Yao, Y. Lin, and X. Li, “Curcumin ameliorates intrahepatic angiogenesis and capillarization of the sinusoids in carbon tetrachloride-induced rat liver fibrosis,” Toxicology Letters, vol. 222, pp. 72–82, 2013. View at: Publisher Site | Google Scholar
  205. Z. Zhang, Y. Guo, and S. Zhang, “Curcumin modulates cannabinoid receptors in liver fibrosis in vivo and inhibits extracellular matrix expression in hepatic stellate cells by suppressing cannabinoid receptor type-1 in vitro,” European Journal of Pharmacology, vol. 721, pp. 133–140, 2013. View at: Publisher Site | Google Scholar
  206. H. Jin, N. Lian, and F. Zhang, “Activation of PPARγ/p53 signaling is required for curcumin to induce hepatic stellate cell senescence,” Cell Death Disease, vol. 7, pp. 1–11, 2016. View at: Publisher Site | Google Scholar
  207. H. Jin, Y. Jia, and Z. Yao, “Hepatic stellate cell interferes with NK cell regulation of fibrogenesis via curcumin induced senescence of hepatic stellate cell,” Cell Signaling, vol. 33, pp. 79–85, 2017. View at: Publisher Site | Google Scholar
  208. N. Lian, Y. Jiang, and F. Zhang, “Curcumin regulates cell fate and metabolism by inhibiting hedgehog signaling in hepatic stellate cells,” Laboratory Investigation, vol. 95, pp. 790–803, 2015. View at: Publisher Site | Google Scholar
  209. Y. Zhao, X. Ma, and J. Wang, “Curcumin protects against ccl4-induced liver fibrosis in rats by inhibiting HIF-1α through an erk-dependent pathway,” Molecules, vol. 19, pp. 18767–18780, 2014. View at: Publisher Site | Google Scholar
  210. L. She, D. Xu, and Z. Wang, “Curcumin inhibits hepatic stellate cell activation via suppression of succinate-associated HIF-1α induction,” Molecular and Cellular Endocrinology, vol. 476, pp. 129–138, 2018. View at: Publisher Site | Google Scholar
  211. S. El Swefy, R. A. Hasan, and A. Ibrahim, “Curcumin and hemopressin treatment attenuates cholestasis-induced liver fibrosis in rats: role of CB1 receptors,” Naunyn-Schmiedeberg’s Archives of Pharmacology, vol. 389, pp. 103–116, 2016. View at: Publisher Site | Google Scholar
  212. A. Eshaghian, A. Khodarahmi, and F. Safari, “Curcumin attenuates hepatic fibrosis and insulin resistance induced by bile duct ligation in rats,” British Journal of Nutrition, vol. 120, pp. 393–403, 2018. View at: Publisher Site | Google Scholar
  213. Y. J. He, K. Kuchta, and Y. M. Deng, “Curcumin promotes apoptosis of activated hepatic stellate cells by inhibiting protein expression of the MyD88 pathway,” Planta Medica, vol. 83, pp. 1392–1396, 2017. View at: Publisher Site | Google Scholar
  214. L. Qin, J. Qin, and X. Zhen, “Curcumin protects against hepatic stellate cells activation and migration by inhibiting the CXCL12/CXCR4 biological axis in liver fibrosis: A study in vitro and in vivo,” Biomedicine & Pharmacotherapy, vol. 101, pp. 599–607, 2018. View at: Publisher Site | Google Scholar
  215. X. Qun Han, S. Qing Xu, and J. Guo Lin, “Curcumin recovers intracellular lipid droplet formation through increasing perilipin 5 gene expression in activated hepatic stellate cells in vitro,” Current Medical Science, vol. 39, pp. 766–777, 2019. View at: Publisher Site | Google Scholar
  216. S. Nunes, A. R. Madureira, and D. Campos, “Therapeutic and nutraceutical potential of rosmarinic acid-Cytoprotective properties and pharmacokinetic profile,” Critical Reviews in Food Science and Nutrition, vol. 57, pp. 1799–1806, 2017. View at: Publisher Site | Google Scholar
  217. G. S. Li, W. L. Jiang, and J. W. Tian, “In vitro and in vivo antifibrotic effects of rosmarinic acid on experimental liver fibrosis,” Phytomedicine, vol. 17, pp. 282–288, 2010. View at: Publisher Site | Google Scholar
  218. N. M. El-Lakkany, W. H. El-Maadawy, and S. H. Seif el-Din, “Rosmarinic acid attenuates hepatic fibrogenesis via suppression of hepatic stellate cell activation/proliferation and induction of apoptosis,” Asian Pacific Journal of Tropical Medicine, vol. 10, pp. 444–453, 2017. View at: Publisher Site | Google Scholar
  219. C. Lu, Y. Zou, and Y. Liu, “Rosmarinic acid counteracts activation of hepatic stellate cells via inhibiting the ROS-dependent MMP-2 activity: involvement of Nrf2 antioxidant system,” Toxicology and Applied Pharmacology, vol. 318, pp. 69–78, 2017. View at: Publisher Site | Google Scholar
  220. M. N. Clifford, “Chlorogenic acids and other cinnamates–nature, occurrence and dietary burden,” Journal of the Science of Food and Agriculture, vol. 79, pp. 362–372, 1999. View at: Publisher Site | Google Scholar
  221. H. Shi, L. Dong, and Y. Bai, “Chlorogenic acid against carbon tetrachloride-induced liver fibrosis in rats,” European Journal of Pharmacology, vol. 623, pp. 119–124, 2009. View at: Publisher Site | Google Scholar
  222. H. Shi, L. Dong, and J. Jiang, “Chlorogenic acid reduces liver inflammation and fibrosis through inhibition of toll-like receptor 4 signaling pathway,” Toxicology, vol. 303, pp. 107–114, 2013. View at: Publisher Site | Google Scholar
  223. H. Shi, A. Shi, and L. Dong, “Chlorogenic acid protects against liver fibrosis in vivo and in vitro through inhibition of oxidative stress,” Clinical Nutrition, vol. 35, pp. 1366–1373, 2016. View at: Publisher Site | Google Scholar
  224. Y. Wang, F. Yang, and J. Xue, “Antischistosomiasis liver fibrosis effects of chlorogenic acid through IL-13/miR-21/Smad7 signaling interactions in vivo and in vitro,” Antimicrobial Agents and Chemotherapy, vol. 61, Article ID e01347, 2017. View at: Publisher Site | Google Scholar
  225. F. Yang, L. Luo, and Z. De Zhu, “Chlorogenic acid inhibits liver fibrosis by blocking the miR-21-regulated TGF-β1/Smad7 signaling pathway in vitro and in vivo,” Frontiers in Pharmacology, vol. 8, 2017. View at: Publisher Site | Google Scholar
  226. Q. Liu, Y. Chen, and C. Shen, “Chicoric acid supplementation prevents systemic inflammation-induced memory impairment and amyloidogenesis via inhibition of NF-κB,” FASEB Journal, vol. 31, pp. 1494–1507, 2017. View at: Publisher Site | Google Scholar
  227. M. Kim, G. Yoo, and A. Randy, “Chicoric acid attenuate a nonalcoholic steatohepatitis by inhibiting key regulators of lipid metabolism, fibrosis, oxidation, and inflammation in mice with methionine and choline deficiency,” Molecular Nutrition & Food Research, vol. 61, 2017. View at: Publisher Site | Google Scholar
  228. C. Srinivasulu, M. Ramgopal, and G. Ramanjaneyulu, “Syringic acid (SA)‒a review of its occurrence, biosynthesis, pharmacological and industrial importance,” Biomedicine & Pharmacotherapy, vol. 108, pp. 547–557, 2018. View at: Publisher Site | Google Scholar
  229. M. D. Vithana, Z. Singh, and S. K. Johnson, “Regulation of the levels of health promoting compounds: lupeol, mangiferin and phenolic acids in the pulp and peel of mango fruit: a review,” Journal of the Science of Food and Agriculture, vol. 99, pp. 3740–3751, 2019. View at: Publisher Site | Google Scholar
  230. A. Itoh, K. Isoda, and M. Kondoh, “Hepatoprotective effect of syringic acid and vanillic acid on CCl4-induced liver injury,” Biological and Pharmaceutical Bulletin, vol. 33, pp. 983–987, 2010. View at: Publisher Site | Google Scholar
  231. C. Chen, “Sinapic acid and its derivatives as medicine in oxidative stress-induced diseases and aging,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 3571614, 2016. View at: Publisher Site | Google Scholar
  232. D. S. Shin, K. W. Kim, and H. Y. Chung, “Effect of sinapic acid against dimethylnitrosamine-induced hepatic fibrosis in rats,” Archives of Pharmacal Research, vol. 36, pp. 608–618, 2013. View at: Publisher Site | Google Scholar
  233. X. Q. Pan, J. Zhou, and Y. Chen, “Classification, hepatotoxic mechanisms, and targets of the risk ingredients in traditional Chinese medicine-induced liver injury,” oxicology Letters, vol. 323, pp. 48–56, 2020. View at: Publisher Site | Google Scholar
  234. C. Loguercio and D. Festi, “Silybin and the liver: from basic research to clinical practice,” World Journal of Gastroenterology, vol. 17, pp. 2288–2301, 2011. View at: Publisher Site | Google Scholar
  235. M. Zhenzeng and L. Lunge, “New advances in drug therapies for liver fibrosis,” Journal of Clinical Hepatology, vol. 32, pp. 1183–1187, 2016. View at: Google Scholar

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