Ke Fu†
Yunxia Li- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
Liver diseases have been a common challenge for people all over the world, which threatens the quality of life and safety of hundreds of millions of patients. China is a major country with liver diseases. Metabolic associated fatty liver disease, hepatitis B virus and alcoholic liver disease are the three most common liver diseases in our country, and the number of patients with liver cancer is increasing. Therefore, finding effective drugs to treat liver disease has become an urgent task. Chinese medicine (CM) has the advantages of low cost, high safety, and various biological activities, which is an important factor for the prevention and treatment of liver diseases. This review systematically summarizes the potential of CM in the treatment of liver diseases, showing that CM can alleviate liver diseases by regulating lipid metabolism, bile acid metabolism, immune function, and gut microbiota, as well as exerting anti-liver injury, anti-oxidation, and anti-hepatitis virus effects. Among them, Keap1/Nrf2, TGF-β/SMADS, p38 MAPK, NF-κB/IκBα, NF-κB-NLRP3, PI3K/Akt, TLR4-MyD88-NF-κB and IL-6/STAT3 signaling pathways are mainly involved. In conclusion, CM is very likely to be a potential candidate for liver disease treatment based on modern phytochemistry, pharmacology, and genomeproteomics, which needs more clinical trials to further clarify its importance in the treatment of liver diseases.
Introduction
Chinese medicine (CM) is an effective drug treatment system with a history of thousands of years. It is used for disease prevention, treatment and diagnosis. CM is characterized by individualized adjustment of multiple components and multiple targets, which makes the body change from an abnormal state to a normal state (Wang et al., 2018). It has made an indelible contribution to human health and is considered a potential natural source of therapeutic drugs (Hesketh and Zhu, 1997; Chan and Ng, 2020). For example, Tu won the 2015 Nobel Prize for discovering and developing artemisinin in Artemisia annua Linn. It is a clear example to prove the therapeutic potential of CM and is of great significance to the continued development of the field (Tu, 2016). Besides, this field has huge and undeveloped resources. Screening and providing effective monomer chemicals are important means of CM to promote the development of medicine in the world (Wang et al., 2018).
Liver diseases are serious diseases threatening the whole human health, mainly including metabolic associated fatty liver disease (MAFLD), alcoholic liver disease (ALD), chronic viral hepatitis (e.g., hepatitis B virus (HBV) and hepatitis C virus (HCV) infections), autoimmune hepatitis, hepatic schistosomiasis, drug-induced liver injury, liver cirrhosis (LC), hepatocellular carcinoma (HCC), and so on (Li, Q. et al., 2018; Wang et al., 2014). China has the highest incidence of liver diseases in the world, and about 300,000–400,000 people die from various liver diseases each year. According to the data, MAFLD, HBV and ALD are the three most common liver diseases in China, with the incidence of 49.3, 22.9 and 14.8% respectively (Wang et al., 2014).
At present, CM has shown significant efficacy in the treatment of liver diseases, such as Rheum palmatum L. (Jin et al., 2005; Yang et al., 2012; Neyrinck et al., 2017), Silybum marianum (L.) Gaertn. (Alaca et al., 2017; Jindal et al., 2019), and Sophora flavescens Ait. (Yang et al., 2018; Yim et al., 2019). Furthermore, liver diseases are various, and the course of each disease is also different. Fortunately, CM can effectively treat a variety of liver diseases, and it has played an important role in the prevention and treatment of liver diseases. For example, Zingiber officinale and Glycyrrhiza uralensis Fischer can effectively treat ALD and MAFLD (Jung et al., 2016; Kandeil et al., 2019), and Rhizoma Coptidis can be used in the treatment of hepatitis virus (Hung et al., 2018). For more serious liver diseases, such as liver cirrhosis and liver cancer, Salvia offificinalis L. and Portulaca oleracea L. have shown good effects (Guoyin et al., 2017; Jiang, Y. et al., 2017). Besides, according to relevant records, the variety of CM commonly used in the treatment of liver diseases is up to 90 kinds (Wu, 2001). It can be seen that the resources of CM for the treatment of liver diseases are rich and valuable, which is worthy of further research and development.
In this review, we collected relevant literature in recent 6 years (2015–2020) through CNKI, PubMed, ScienceDirect and Google academic, and analyzed the application, toxicology and clinical data of CM and their related compounds, aiming to dig out more CM with potential biological activities for liver diseases, and promote their application value in the treatment of liver diseases, further providing relevant reference for the clinical application CM.
Characteristics of Several Important Liver Diseases
The Three Most Common Liver Diseases in China
MAFLD
MAFLD is a clinical syndrome characterized by hepatocyte steatosis and increased lipid deposition with the exception of alcohol and other clear liver-damaging factors (Mantovani et al., 2019). It is associated with obesity, insulin resistance, type 2 diabetes mellitus, hypertension, hyperlipidemia, and metabolic syndrome (Younossi, 2019). MAFLD is a broad umbrella term for a range of liver disorders, from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). It is called NAFL if it is only steatosis (fatty liver) and NASH if there is severe inflammation and liver cell damage (steatohepatitis). The course of MAFLD is complex and variable, which can lead to cirrhosis and liver cancer in severe cases (Friedman et al., 2018).
The pathogenesis of MAFLD mainly includes abnormal lipid metabolism, oxidative stress, inflammasome activation, insulin resistance, mitochondrial dysfunction, and genetic determinants (Buzzetti et al., 2016). Abnormal lipid metabolism in hepatocytes is the initial factor for MAFLD. When the number of fatty acids entering the liver is greater than their oxidation and secretion, the lipid accumulates in the liver, resulting in hepatic lipid deposition (Onyekwere et al., 2015), which leads directly to MAFLD. Furthermore, excessive lipid deposition further aggravates tissue damage by promoting the production of reactive oxygen species (ROS) and a series of pathological changes, such as the peroxidation of cells themselves, the release of pro-inflammatory factors and the infiltration of inflammatory cells, damaged hepatocytes activate the nuclear factor kappa-B (NF-κB) pathway, thus inducing the production of proinflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-1β/-6 (IL-1β, IL-6) (Buzzetti et al., 2016; Xiao et al., 2020). These inflammatory factors can not only induce the activation of astrocytes and the remodeling of cell matrix, but also accelerate the progression of the disease by promoting insulin resistance. In addition, MAFLD is strongly associated with gut microbes, some of which carry genes that ferment dietary sugars into ethanol. When released into the bloodstream, they will increase oxidative stress and inflammation in the liver. In the liver, alcohol dehydrogenase metabolizes ethanol into toxic acetaldehyde, which forms adducts with proteins and other molecules in the cell because of its electrophilic properties, resulting in the loss of hepatocyte structure and function (Kolodziejczyk et al., 2019).
HBV Infection
HBV, a part of the Hepadnaviridae family, consists of nucleocapsid, envelope, and three complete membrane proteins (Seitz et al., 2007), which is a partially double-stranded and non-cytopathic DNA virus. The virus replicates the DNA by reverse transcription of the pre-RNA genome and has many serological markers such as HBsAg and anti-HBs, HBeAg and anti-HBe, and anti-HBc IgM and IgG (Trépo et al., 2014; Hu and Liu, 2017). HBV is the most common chronic virus in the world. Infected cells produce covalently closed circular DNA intermediates and integrated sequences that act as transcription templates for viral proteins (Fanning et al., 2019). HBV is transmitted through a number of routes, but mainly in the form of blood and body fluids, including perinatal and mother-to-child transmission, as well as sexual and extraintestinal patterns (Yuen et al., 2018).
At present, vaccination is still the most effective tool to prevent HBV infection, but there are also other therapeutic approaches, such as antiviral drugs that directly act on virus replication (interferon) and immune modulators (including reverse-transcriptase inhibitors, primarily a nucleoside or nucleotide analogue) (Yuen et al., 2018). These treatments can effectively inhibit HBV replication, but the disadvantages are the long-term medication and side effects. In addition, HBV infection can lead to chronic hepatitis and a series of complications, and studies have shown that HBV may persist in the body even after the infected person has fully recovered (Rehermann et al., 1996; Shi and Zheng, 2020). If immunosuppression-mediated host immune control is weakened, or several therapies and drugs have a direct effect on HBV replication, HBV may be reactivated (Shi and Zheng, 2020). Therefore, it is urgent to find a more effective HBV therapy to ensure the health of all human beings.
ALD
ALD refers to hepatocyte necrosis and destruction of normal liver function under the action of ethanol for a long time, which is a series of liver diseases including fatty liver, alcoholic hepatitis, cirrhosis, and its complications (such as ascites, portal hypertension-related bleeding, hepatic encephalopathy, and HCC) (Singal et al., 2018). The disease initially presents as alcoholic fatty liver disease, then gradually develops into alcoholic cirrhosis, even extensive hepatocyte necrosis, eventually inducing liver failure (Penny, 2013; Hu et al., 2019).
Sustained large quantity of alcohol stimulation is the primary factor of ALD. The pathogenesis is complicated and varied, mainly related to genetics, oxidative stress, hepatic steatosis, hepatic inflammation, and so on (2018). There is some evidence that aldehyde dehydrogenase2*2 and alcohol dehydrogenase 1B*3 alleles are closely related to alcoholic liver disease, and they can have some kind of chemical reaction with alcohol to achieve rapid metabolism (Agrawal and Bierut, 2012; Dodge et al., 2014); transmembrane 6 superfamily member 2 gene mutation can lead to the accumulation of liver fat, so that the disease will develop into a bad situation (2018); patatinlike phospholipase domain-containing protein 3, which mediates triglyceride hydrolysis in adipocytes, is closely related to lipid metabolism in the liver, but the mechanism of how it affects ALD is unclear (Salameh et al., 2015; BasuRay et al., 2017). At the same time, membrane-bound O-acetyltransferase domain-containing protein 7 is also an important genetic material related to ALD, but its mechanism is not clear (2018).
Oxidative stress plays a crucial role in the pathogenesis of ALD. In biological systems, free radicals include oxygen free radicals and nitrogen free radicals, among which oxygen free radicals and non-free radicals such as hypochlorite and ozone are called ROS. Under normal circumstances, the body contains antioxidants (such as superoxide dismutase (SOD), catalase, glutathione (GSH), glutathione peroxidase, glutathione transferase, heme oxygenase bilirubin etc.) and ROS in a state of balance, which are not harmful to the human body (Li et al., 2015). But in the case of long-term alcohol abuse, the reduction in the level or activity of antioxidants in the body causes oxidative stress. Alcohol may also increase the level of ROS. For example, ROS and nicotinamide adenine dinucleotide (NADH) are produced when ethanol is oxidized to acetaldehyde by alcohol dehydrogenase in the liver. Acetaldehyde is oxidized to acetic acid in mitochondria, which stimulates the body to produce large amounts of ROS (Li et al., 2014). NADH also interferes with the mitochondrial electron transport system and promotes ROS production (Ceni et al., 2014). Alcohol can also activate the NAD (P) H oxidase in hepatocytes, leading to an increase in the production of superoxide (Kalyanaraman, 2013). There is also evidence that another important pathophysiological mechanism of ALD is the interaction between endotoxin and Kupffer cells (KCs). Long-term high alcohol intake can induce low levels of intestinal endotoxemia, and increase intestinal permeability, causing Gram-negative bacteria to enter the hepatic portal circulation to suppress immune function (Mello et al., 2008; Gao and Liu, 2016). KCs recognize and clear gut-derived endotoxins, and promote oxidative stress and inflammatory response through their interaction (Yang and Wei, 2017).
Other Liver Diseases
HCV Infection
Hepatitis C is an infectious disease caused by HCV. HCV is an RNA virus, 45–65 nm in diameter, encapsulated in a lipid bilayer, belonging to the Flaviviridae family (Manns et al., 2017). HCV enters its target cells by a variety of host factors, including CD81, low-density lipoprotein receptor, dendritic cell-specific ICAM-grabbing non-integrin, claudin-1, and occludin. Among the different types of liver diseases, HCV is unique in requiring liver specific microRNA-122 replication (Luna et al., 2015). In addition, the genotypes of HCV are very rich. By the culture, analysis and identification of HCV strains isolated from all parts of the world, seven major HCV genotypes were found, namely 1–7 (Manns et al., 2017). Genotype 1 is the most prevalent in the world, including 83.4 million cases (46.2% of all HCV cases), about a third of which are in East Asia. Genotype 3 ranks second in the world (54.3 million, 30.1%), genotype 2, 4 and 6 account for 22.8% of all cases, and genotype 5 accounts for less than 1% of the remaining cases (Messina et al., 2015).
HCV transmission is most commonly associated with direct percutaneous exposure to blood via blood transfusions, health-care-related injections, and injecting drug use (Spearman et al., 2019). Alcohol is also a common cofactor for HCV infection, and alcohol use is more strongly associated with the progression of liver fibrosis (Poynard et al., 1997). Secondly, HCV infection can induce the abnormal expression of two host microRNAs (miR-208b and miR-499a-5p) encoded by myosin genes in hepatocytes. MiR-208b and miR-499a-5p inhibit type I IFN signal transduction in infected hepatocytes by directly down-regulating type I IFN receptor expression (Jarret et al., 2016). In addition, chronic HCV infection can also lead to liver fibrosis, cirrhosis, hepatocellular carcinoma and other serious complications.
LC
LC is a pathological stage characterized by diffuse fibrosis, pseudolobules formation, and intrahepatic and extrahepatic vascular proliferation (He and Liu, 2021). It is one of the main causes of death in patients with liver diseases all over the world, and also the final result of the development of a variety of acute and chronic liver diseases. LC shows symptoms such as portal hypertension and liver dysfunction. At present, the diagnosis of LC mainly depends on the imaging of irregular nodular liver by ultrasound, CT or MRI and the evaluation of liver synthesis function. In clinical practices, LC is considered as an end-stage manifestation of liver pathology with a high mortality without liver transplantation treatment (Tsochatzis et al., 2014; Zhou et al., 2014). But liver transplantation requires a lot of ligands and money, which is not an easy thing to solve, so CM has become a more effective approach.
The pathological pathway of LC is very complicated, but the research has shown that it is closely related to the expression of some cells on the wall of hepatic sinus. Hepatic sinus walls are composed of three kinds of non-parenchymal cells (liver sinusoidal endothelial cells (LSECs), KCs and hepatic stellate cells (HSCs)), which are involved in the development of LC (Zhou et al., 2014). In non-diseased liver, HSCs are located in the subendothelial space of Disse and are primarily involved in the storage of retinoic acid, but HSC is activated in the area of liver injury (Friedman, 1993; Hernandez-Gea and Friedman, 2011). In this activated phenotype, HSC is the main source of collagen and non-collagen matrix proteins in fibrosis. Related studies have shown that LSECs can secrete the cytokine IL-33 to activate HSCs and promote fibrosis (Marvie et al., 2010). Secondly, the exfoliation and capillarization of LSECs were proved to be the main contributing factors of liver dysfunction in cirrhosis (Yokomori et al., 2012). Finally, KCs can mediate liver inflammation to aggravate liver damage and fibrosis (López-Navarrete et al., 2011). Cytokines such as platelet-derived growth factor, transforming growth factor-β (TGF-β), TNF-α, and Interferon also play a crucial role in the pathogenesis of liver fibrosis and cirrhosis (Zhou et al., 2014). It is worth mentioning that if a patient has been diagnosed with ALD, concomitant chronic hepatitis B or C infection will directly aggravate the liver injury, leading to more frequent and rapid occurrence of cirrhosis (Poynard et al., 1997).
HCC
HCC is the most common form of liver cancer, accounting for 90% of the total cases of liver cancer. Among the various chronic liver diseases, HCC is the final stage of the disease in some patients with LC. About 80% of HCC patients have the pathological basis of LC, and the rate of HCC in patients with cirrhosis disease base in the short-term can be 5–30% (El-Serag, 2012). HBV and HCV are major risk factors for the development of HCC (Llovet et al., 2021). Others include exposure to aflatoxin, excessive drinking, smoking, diabetes, and knowledge of other risk factors such as MAFLD has been gradually recognized (Forner et al., 2012; Forner et al., 2018). The high incidence of HCC is concentrated in developing countries such as China, mainly due to chronic HBV infection (Jemal et al., 2011). Until now, there has been no nationwide cancer screening in China. Once a patient develops HCC, not only does the patient face tremendous pain from radiation therapy, but the improvement in survival rates is very limited, if more potential anti-cancer drugs can be tapped from the CM system, it will be beneficial to HCC patients.
Figure 1 is a map of the major pathogenesis of some important liver diseases.
FIGURE 1. Main pathogenesis of important liver diseases.
Pharmacological Effects of CM for Management of Liver Disease
There are abundant varieties of natural CM resources in China, which is worthy of further development and utilization. For example, Figure 2 only shows the distribution of some CM for liver disease in the main producing area (also named “Daodi” producing area). Among them, many of the common CM have shown anti-liver disease activity, see Table 1. In addition, the pharmacological effects of CM on liver disease are summarized in Figure 3.
FIGURE 2. Distribution of some Chinese medicine for liver diseases in main producing areas (also named “Daodi” producing area). Shaanxi: Rheum palmatum L., Polygonum cuspidatum Sieb.et Zucc.; Sichuan: Salvia miltiorrhiza Bunge., Zingiber officinale Rosc., Ligusticum chuanxiong Hort., Curcuma wenyujin Y. H. Chen et C. Ling, Lysimachia christinae Hance; Gansu: Angelica sinensis (Oliv.) Diels; Tibet: Alisma orientalis (Sam.) Juzep.; Hebei: Prunus persica (L.) Batsch, Forsythia suspensa (Thunb.) Vahl, Isatis indigotica Fort., Scutellaria baicalensis Georgi; Henan: Carthamus tinctorius L., Chrysanthemum morifolium Ramat.; Zhejiang: Gardenia jasminoides Ellis, Corydalis yanhusuo W. T. Wang; Liaoning: Artemisia scoparia Waldst. et Kit.; Guangdong: Alpinia oxyphylla Miq.; Anhui: Chaenomeles speciosa (Sweet) Nakai, Poria cocos (Schw.) Wolf; Xinjiang: Glycyrrhiza uralensis Fisch.; Inner Mongolia: Gentiana scabra Bunge, Isatis indigotica Fort.; Dongbei (Heilongjiang, Jilin, Liaoning): Schisandra chinensis (Turcz.) Baill., Paeonia lactiflora Pall., Sparganium stoloniferum Buch-Ham.
TABLE 1. Some of the Chinese medicine used for the treatment of liver diseases are described in the standard and their biological activities.
FIGURE 3. Pharmacological effects of Chinese medicine on liver diseases.
Regulating Lipid Metabolism
Lipid uptake, esterification, oxidation, and fatty acid secretion all occur in hepatocytes. These processes are regulated by hormones, nuclear receptors, and transcription factors to maintain liver lipid homeostasis (Nguyen et al., 2008). If the balance of liver lipid metabolism is destroyed, the lipid will accumulate abnormally in the liver. Excessive lipid accumulation will lead to liver steatosis, insulin resistance and the development of fatty liver disease, and even induce oxidative stress, causing inflammation, cytotoxicity and aggravating liver injury. Therefore, maintaining normal lipid metabolism is an important function of the liver (Ding, H.-R. et al., 2018; Li, X. et al., 2019).
Many CMs have shown good effects in regulating lipid metabolism, such as Radix Bupleuri, Pericarpium Citri Reticulatae, Rhubarb, Polygonum Multiflorum, Coptis Chinensis, Artemisia Annua, Flos Lonicera and Radix Sophorae Tonkinensis. The results showed that the serum high-density lipoprotein cholesterol (HDL-C), TC and low-density lipoprotein cholesterol (LDL-C) levels of c57BL/6 mice were reduced by Citrus reticulata Blanco peel extract. The author further revealed that 0.2 and 0.5% of the extract could effectively prevent the micro fatty degeneration and excessive accumulation of lipid droplets in the liver (Ke et al., 2020). Rheum Palmatum L. can continuously reduce the accumulation of excess fat and the expression of lipogenic genes in the liver of male Sprague-Dawley rats induced by a high-fat diet. Concomitantly, increased phosphorylation of adenine monophosphate activated protein kinase (AMPK) and acetyl-CoA carboxylaze was observed (Yang, M. et al., 2016). In addition, Sophorae Tonkinensis water extract and Polygonum Multiflorum Thunb. extract alleviate nonalcoholic liver disease by enhancing hepatic carnitine palmitoyltransferase 1A activity to promote fatty acids β-oxidation, and regulating the protein response to lipid metabolism and expression in the liver to reduce lipid accumulation (Jung et al., 2020; Zhao et al., 2020).
It is worth mentioning that relevant studies of hepatic lipid metabolism were also conducted in fish. Addition of 200–400 mg/kg Radix Bupleuri extract to the daily diet of hybrid grouper fish can reduce the expression of lipogenesis-related genes, such as diacylgycerol acyltransferase 2, glucose-6-phosphate dehydrogenase, malic enzyme 1 and diacylglycerol kinase alpha (Zou et al., 2019). Lonicera japonica extract can effectively reduce the levels of LDL-C, triglyceride (TG) and total cholesterol (TC) in the serum of grass carp as well as the expression of lipogenic genes acc1, fas, SREBP1 and PPARγ, and increase the expression of liposoluble genes CPT1, ATGL, LPL and PPARα (Meng et al., 2019).
Liver Injury
Liver Fibrosis
Liver fibrosis belongs to chronic liver injury, mainly manifested as the accumulation of extracellular matrix (Tsuchida and Friedman, 2017), which is a dynamic process. Hepatocytes, activated hepatic stellate cells, endothelial cells, immune cells, and macrophages all participate in its establishment and regression (Campana and Iredale, 2017). Liver fibrosis is a pathological insult mainly caused by chronic liver disease (viral infection, alcoholic liver disease, NASH, etc). If not treated in time, it will continue to deteriorate and eventually progress to cirrhosis and even liver cancer.
The TGF-β/Smads pathway plays an important role in the regulation of liver fibrosis. In the background of liver fibrosis, Smad3 and Smad4 are pro-fibrosis, while Smad2 and Smad7 are anti-fibrosis (Xu et al., 2016). Meanwhile, TGF-β is also activated by the deposits in the fibrous extracellular matrix, and expressed and released from a variety of cells (Dewidar et al., 2019). The evidence has shown that Forsythiae Fructuse water extract (FSE), Curcuma Wenyujin, and Zingiber Officinale can effectively inhibit the development of liver fibrosis through the TGF-β/Smads signaling pathway (Hasan et al., 2016; Hu et al., 2020a; Xie et al., 2020).
Radix Salvia Miltiorrhiza (RSM) is the dry root and rhizome of Labiatae plant Salvia Miltiorrhiza Bunge, whose main functions include removing blood stasis, relieving pain, activating blood circulation, clearing the heart, and removing trouble (Commission, 2015). It is widely used in the treatment of liver fibrosis in clinic, but the specific mechanisms are not clear. The recent study of Yuan et al. showed that RSM improved liver fibrosis by increasing the activity of natural killer (NK) cells as well as the effects of NKG2D and NKp46 on NK cells, and inhibiting the activation of HSCs in vivo and in vitro (Peng et al., 2018). Another study showed that the mixture of RSM extract and Astragalus Membranaceus extract at a ratio of 1:1 could regulate the expression of TGF-β1 and Cyclin D1 to improve liver fibrosis and the liver functions, especially having a good effect on reducing the cyclin D1 expression (Cao et al., 2020). In addition, many CM have anti-fibrosis activities. For example, Gentiana Scabra bage inhibits fibrosis by reducing the expression of hepatic type I and type III collagen proteins in rats (Qu et al., 2015). Ginkgo biloba is also a common CM mainly used in coronary heart disease, angina pectoris, and hyperlipidemia (Commission, 2015). Wang et al. found that Ginkgo biloba extract could improve liver fibrosis by inhibiting inflammation, HSC activation, and hepatocyte apoptosis, which may be related to the p38MAPK, NF-κB/IκBα, and Bcl-2/Bax signaling pathway (Wang et al., 2015).
Chemical Liver Injury
Chemical liver injury is mainly caused by alcohol, toxic chemicals, and drugs. As we all know, the liver has dual blood supply of hepatic artery and hepatic vein, which is the main detoxification organ of human body. The liver plays a core role in biotransformation and excretion of foreign compounds, so it is the main target of the adverse reactions of drugs and other heterologous organisms (Holt and Ju, 2010). Secondly, the liver is the initial contact site of alcohol, chemical toxic substances, and the oral drugs absorbed through the intestine, so it is vulnerable to chemical damage. At the same time, electrophilic compounds and free radicals are the intermediate products of many chemical substances after liver metabolism. These substances may change the structure and function of cell macromolecules, and even lead to the occurrence of liver cancer (Gu and Manautou, 2012).
At present, a variety of CM are widely used for chemical injuries. Both Schisandra Sphenanthera extract and Polygonatum Sibiricum water extract can regulate alcoholic liver injury in mice through the nuclear factor-erythroid 2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) signaling pathway (Wang, G. et al., 2021; Zeng et al., 2017). The liver damage caused by CCl4 can be alleviated by Curcuma longa L. extract and Prunus persica Seeds Extract, which is mainly related to inhibiting liver oxidative stress, and increasing the Nrf2 and NQO-1 levels, as well as reducing type Ⅲ collagen mRNA expression (Lee, G.-H. et al., 2017; Rehman et al., 2021). In addition, Hedyotis Diffusa water extract, Ligusticum Chuanxiong Hort, and Panax ginseng can also be used to respectively relieve the chemical damage caused by hydrogen peroxide and D-galactose (Gao et al., 2016; Mo et al., 2017). It is worth mentioning that a large number of CM can also alleviate drug-induced liver injuries. Paracetamol (acetaminophen) is a commonly used drug in clinic, which is mainly used for cold-induced fever, headache, joint pain, neuralgia, migraine, dysmenorrhea, and so on. Lycium Barbarum extract can significantly improve paracetamol-induced apoptosis to protect the liver from chemical damage (Gündüz et al., 2015), and Isatidis Folium can enhance the endogenous antioxidant system and reduce paracetamol-induced liver damage in mice (Ding and Zhu, 2020). Ahmed et al. also found that Panax ginseng could be used as a hepatoprotective agent, which prevented cyclophosphamide (with immunosuppressive and anti-cancer potential)-induced liver injury by reducing the expression of TNF-α, IL-1β and Caspase3 genes, as well as increasing the BCL-2 gene expression, and its liver-protective effect is better than vitamin E (Abdelfattah-Hassan et al., 2019).
Anti-oxidative Stress
Oxidative stress is the main influencing factor of the pathogenesis of ALD and MAFLD. It has been briefly discussed in the previous content. When the level or activity of antioxidants in the human body is reduced, oxidative stress will occur. Due to the stimulation of external factors (such as alcohol), the body will produce a large amount of active oxygen, which is the key to the development of fatty liver into steatohepatitis. GSH is an endogenous antioxidant, which is widely present in animals. Excessive oxidative stress can cause GSH consumption and lead to the accumulation of ROS (Li, X. et al., 2019). In addition, cytochrome P4502E1 (CYP2E1) plays a key role in the generation of ROS, which is also induced by alcohol (Leung and Nieto, 2013). Calculus bovis is a commonly used CM for fever, faintness, stroke and phlegm. The evidence showed that calculus bovis could inhibit oxidative stress in hepatocytes by reducing ROS and increasing SOD content, thereby achieving the liver-protective effect on mice with nonalcoholic fatty liver. And curcuma longa hot water extract and zingiber officinale hydroalcoholic extract can reduce the level of GSH to protect the liver.
Nrf2 is an important redox-sensitive transcription factor, and controls the basic and induced expression of a series of antioxidant response element-dependent genes, which is beneficial to improve the body’s oxidative stress state, thus regulating the physiological and pathological consequences under oxidant exposure (Ma, 2013). Under normal physiological conditions, Nrf2 is locked in the cytoplasm by Keap1. But when the cells are attacked by ROS or electrophiles, Nrf2 will dissociate from Keap1 and quickly translocate into the nucleus, first forming a heterodimer with the small Maf protein, and then combining with the ARE, which finally transcribes and activates the expression of the antioxidant enzyme genes regulated by Nrf2 (Ho et al., 2012; Heiss et al., 2013). In addition, the signal pathways related to Nrf2 (such as Nrf2-Keap1 and Nrf2-ARE) in the oxidative stress system have been widely recognized, especially the Nrf2-Keap1 pathway, which is an anti-stress mechanism inherited from our ancestors, as well as a defense system to maintain the homeostasis of the cells (Buendia et al., 2016; Bellezza et al., 2018). As reported, Polygonum Cuspidatum extract could reduce oxidative stress by targeting the Keap1/Nrf2 pathway, and down-regulate the levels of sterol regulatory element bending protein 1, fatty acid synthase, and stearoyl coenzyme alpha desaturase-1 to prevent hepatic lipid accumulation in fructose-fed rats (Zhao, X.-J. et al., 2019). Paeonia Lactiflora Pall. (PLP) can increase the expression of AKt, Nrf2, HO-1, NQO1 and GCLC, and activate the PI3K/Akt/Nrf2 pathway to enhance the antioxidant system, thereby reducing ANIT-induced liver tissue damage (Ma et al., 2015). In addition, Citrus Reticulata Blanco peel extract, Glycyrrhiza Uralensis ethanol extract, and Polygonum Multiflorum Thunb. ethanolic extract can directly activate the Nrf2 to regulate the redox state of liver injury (Cao et al., 2017; Ke et al., 2020; Lin, E.-Y. et al., 2018). The details are showed in Figure 4.
FIGURE 4. Some CM treat liver disease through Nrf2 and TLR4-MyD88-NF-κB signaling pathway. CBE, Citrus reticulata Blanco peel extract; GUE, Glycyrrhiza uralensis ethanol extract; PTE, Polygonum multiflorum Thunb. ethanolic extract; PLP, Paeonia lactiflflora Pall.; CL, Curcuma longa; CB, Calculus bovis; PCE, Polygonum cuspidatum extract.
Regulation of Bile Acid Metabolism
Bile acids (BAs) are important components of bile, which have the functions of regulating metabolism, endocrine and immune (Chávez-Talavera et al., 2017). The liver is the site of bile acid synthesis. The primary bile acids, such as cholic acid and chenodeoxycholic acid, combine with glycine or taurine to form bound BAs, which are secreted into bile canaliculus through the transport proteins such as bile salt export pump and multidrug resistance associated protein 2, and are temporarily stored in the gallbladder and released through the bile duct. When BAs and other components of bile are discharged into the intestine together, they can promote the emulsification and absorption of dietary fat, cholesterol, and fat-soluble vitamins. About 90–95% of BAs are reabsorbed in the ileum through apical sodium-dependent bile acid transporter and ileal bile acid transporter (IBAT), and the remaining 5–10% of BAs are excreted in feces (Li and Chiang, 2014; Tripathi et al., 2018). BAs are the important physiological basis involved in the regulation of liver function and disease states. According to the data, the metabolism and inflammation related to obesity, type 2 diabetes, dyslipidemia, and MAFLD are all regulated by BAs (Chávez-Talavera et al., 2017). Therefore, BAs’ normal synthesis, transportation and excretion are vital factors for the homeostasis.
Cholestasis means that the bile cannot flow from the liver to the duodenum, and its flow is decreased, which is characterized by the excessive accumulation of bile acids and other toxic compounds (Crocenzi et al., 2012). Excessive accumulation of bile acids in the liver may cause liver damage, liver fibrosis, and eventually liver failure and biliary cirrhosis (Padda et al., 2011). The study has shown that PLP can regulate glycocholic acid, taurocholic acid, glycodeoxycholic acid, L (D)-arginine, and L-tryptophan, and these metabolites are related to bile acid secretion and amino acid metabolism, which is concluded that bile acid metabolism may be involved in the therapeutic effects of PLP on cholestasis (Ma et al., 2016). Ma et al. further demonstrated that PLP could alleviate cholestasis by regulating the NF-κB-NLRP3 inflammasome and the PI3K/Akt-dependent pathways (Ma, X. et al., 2018; Ma et al., 2015). Another study showed that the ethanol extract of Schisandra Chinensis could significantly protect the mice from intrahepatic cholestasis induced by cholic acid (Zeng et al., 2016). In addition, Schisandra Chinensis extract can also enhance the excretion of bile acids from the serum and liver to the intestine and feces, and adjust the intestinal microorganisms disturbed by the external factors to achieve the protective effects on liver injury caused by cholestasis (Li, D.-S. et al., 2020).
Regulating the Immune System
Inhibition of Inflammatory Response
Inflammation is the basis of a variety of physiological and pathological processes, mainly induced by infection and tissue damage (Medzhitov, 2008). When natural antioxidants are out of balance, the free radicals produced by different organisms and environments can further lead to various inflammation-related diseases (Arulselvan et al., 2016). As we all know, there are many kinds of cytokines involved in the inflammatory response. For example, TNF-α, IL-1β, and IL-6 play a pro-inflammatory role, by contrary, TGF-β, IL-4, IL-10, and IL-13 can inhibit the occurrence and progress of inflammation. There is evidence that the inflammatory mechanisms of the liver are essential for maintaining the homeostasis of the tissues and organs. When the inflammatory mechanisms are out of balance, the hepatic pathological process will be drived, such as chronic infection, autoimmunity, and malignant tumor (Robinson et al., 2016). FSE, Gentianae Macrophyllae extract, and Aloe vera can reduce inflammatory liver injury by reducing the serum concentration of TNF-α, IL-1β, IL-6, NF-κB, and other cytokines (Zhao et al., 2017; Cui et al., 2019; Hu et al., 2020a; Klaikeaw et al., 2020). Moreover, Radix Bupleuri extract and Schisandra Sphenanthera extract can directly inhibit the mRNA expression of TNF-α, IL-1β, and IL-6 to protect the liver (Chen et al., 2019; Jia et al., 2019). In addition, Angelica Sinensis Supercritical Fluid CO2 Extract can significantly inhibit D-galactose-mediated expression of inflammatory cytokines, such as iNOS, COX-2, IKBα, p-IκBα, and p65, protecting the liver and kidney tissues (Mo et al., 2018).
Toll-like receptor4 (TLR4)-myeloid differentiation factor 88 (MyD88)-NF-κB signaling pathway is a key pathway in the physiologic and biochemical reactions of diseases. It widely exists in various tissues and cells, which is one of the important signaling pathways that mediate the expression of inflammatory factors (Wu et al., 2017). As one of the important pathways associated with inflammatory response and hepatic fibrosis, its activation can lead to the release of downstream inflammatory factors and induce the production of TNF-α, IL-1β, and IL-6. Hu et al. found that FSE could improve the inflammatory state of liver fibrosis through the TLR4-MyD88-NF-κB pathway (Hu et al., 2020a). Jia et al. found that RBE could inhibit TLR4-MyD88-NF-κB signaling pathway to reduce H2O2-induced liver inflammation in tilapia (Jia et al., 2019). Another study showed that GME could also attenuate ALD by inhibiting the phosphorylation of JNK and p38 to inhibit the initiation of inflammation (Cui et al., 2019).
The molecular mechanisms of the CM alleviating liver diseases through inflammatory pathways are shown in Figure 4.
Enhancing Immune Function
Zou et al. found that adding 200–800 mg/kg RBE to the diet of hybrid grouper could effectively reduce the serum ALP, ALT, AST, and LDH contents. In addition, it could down-regulate the expression of apoptosis-related genes (caspase-9), and up-regulate the antioxidant genes (CAT) and immune-related genes (MHC2, IKKα, and TGF-β1) (Zou et al., 2019). Tan et al. reported that dietary supplementation of Lycium barbarum extract (0.50–2.00 g/kg) could effectively increase IL-10 and TGF-β1 mRNA levels in the liver of HFD-fed hybrid grouper (Tan et al., 2019). In addition, Ginkgo biloba extract not only improves the hepatic antioxidant status of HFD-fed hybrid grouper, and maintains normal liver histology and preserves liver function, but also up-regulates the expression of immune-related genes (MHC2 and TLR3) (Tan et al., 2018).
Hepatitis Virus
Some CM have inhibitory effects on hepatitis virus and can assist the treatment of patients with viral hepatitis. Some studies have shown that most of the terpenoids isolated from Flos Lonicerae can inhibit the secretion of HBsAg and HBeAg, as well as the DNA replication of HBV (Ge et al., 2019). In addition, Yang et al. found that the methanolic extract of Rhizoma Coptidis could block the attachment of HCV and the entry/fusion with host cells, which effectively inhibited the infection of pseudoparticles of HCV in Huh-7.5 cells, and hindered the infection of several HCV genotypes (Hung et al., 2018).
Liver Cancer
Currently, Western medicine and therapies are the main treatment strategies for liver cancer, but the overall prognosis of liver cancer patients is still very poor. Under such circumstances, it is extremely urgent to find a better method for the treatment of liver cancer. CM contains abundant treatment resources and has been used for the prevention of liver cancer for thousands of years. In modern China, CM has also been proven to be an effective method for the treatment of liver cancer. However, the theory of CM prevention and treatment of liver cancer is more widely accepted in China than abroad (Liao et al., 2020). According to relevant data, most CM can show anti-liver cancer effects. Ethanol extract of root of Prunus Persica can significantly inhibit the migration of liver cancer HepG2 cells and the expression of extracellular matrix metalloproteinases, MMP3 and MMP9. It is worth mentioning that it can also inhibit tumor growth in nude mice in vivo (Shen et al., 2017). Artemisia capillaris extract can inhibit the growth, migration and invasion of Huh7 and HepG2 liver cancer cells. This inhibitory effect is closely related to blocking the PI3K/AKT signaling pathway (Yan, Honghua et al., 2018). Jiang et al. further found that the anti-liver cancer effect of Artemisia capillaris extract is also related to the inhibition of the IL-6/STAT3 signal axis (Jang et al., 2017). Futhermore, Zheng et al. found that oral administration of portulaca oleracea extract to male AKR mice for seven consecutive days could contribute to the treatment of liver cancer. The results showed that the serum levels of IL-6, IL-1β, TNF-α and MDA in mice decreased after 7 days of treatment, while the activity of SOD increased. The pathological changes of the liver were significantly alleviated. Meanwhile, portulaca oleracea extract could effectively inhibit PI3K, Akt, mTOR, NF-κB and IκBα, and up regulate the expression of Nrf2 and HO-1. These effects are attributed to the protective effect of Portulaca oleracea extract on liver cancer by regulating PI3K/Akt/mTOR and Nrf2/HO-1/NF-κB pathway (Guoyin et al., 2017).
In addition, some CM can also achieve protection against liver cancer through various other effects. For examples, Astragalus membranaceus and Curcuma wenyujin promote the normalization of blood vessels in liver tumor endothelial cells by increasing the expression of CD34 and reducing the expression of HIF1a (Zang et al., 2019). Artemisia capillaris leaves can achieve pro-apoptotic effects on liver cancer cells by reducing the expression of XIAP and the release of cytochrome C through mitochondrial membrane potential (Kim et al., 2018). Besides, Ligustrum lucidum Ait. fruit extract can induce apoptosis and cell senescence of human liver cancer cell Bel-7402 by up-regulating p21. All in all, there are abundant resources of CM against liver cancer, which are worthy of our further development and utilization.
Other Anti-liver Disease Mechanisms
A large number of studies have shown that the occurrence of liver diseases is also closely related to endoplasmic reticulum stress and insulin resistance. Scutellaria baicalensis Georgi extract can regulate the endoplasmic reticulum stress and protect the liver by reducing the expression of glucose-related protein 78 (Dong et al., 2016). HFD increased the expression of adipose-derived carbohydrate response element binding protein and endoplasmic reticulum stress genes CHOP, x-box binding protein 1, and glucose regulated protein 78 in male wistar rats, and Ginger extract could restore these changes to normal state (Kandeil et al., 2019). Jung et al. reported that Polygonum multiflfluorum thunb. reduced nonalcoholic steatosis and insulin resistance by regulating the expression of the proteins on lipid metabolism and glucose transport in the liver (Jung et al., 2020).
Recently, the evidence has shown that gut microbiota play an important role in metabolism, immune system, and so on. The changes of gut microbiota and their function can promote the development of acute and chronic liver diseases. In addition, the destruction of intestinal barrier can make microorganisms transfer to the blood, and continuously cause inflammatory reaction, thus promoting liver injury, hepatic fibrosis, cirrhosis, and carcinogenic transformation (Shen et al., 2018; Chopyk and Grakoui, 2020). Rhubarb extract can promote some intestinal bacteria (such as Akkermansia muciniphila and Parabacteroides goldsteinii.) to participate in the intestinal barrier function, and alleviate liver inflammation caused by acute alcohol intake (Neyrinck et al., 2017). In addition, Schisandra chinensis bee pollen could inhibit the expression of LXR-α, SREBP-1c, and FAS genes, and regulate the structure of intestinal microflora in obese mice, so as to achieve the protective effect on MAFLD (Cheng et al., 2019).
Natural Agents From CM for Liver Disease Treatment
Polysaccharides and Glycosides
Polysaccharide is one of the active components of CM. The polysaccharides in CM have a wide range of biological activities in enhancing immunity, antiviral, anti-inflammation, anti-oxidation, and anti-tumor (Chen et al., 2016). Ginkgo biloba leaf polysaccharides and Astragalus polysaccharides can effectively inhibit liver steatosis (Yan et al., 2015; Huang et al., 2017). The polysaccharides from roots of Sophora flavescens can significantly inhibit the HBsAg and HBeAg secretion of HepG2.2.15 cells, and have good anti-HBV activity (Yang et al., 2018). In addition, the polysaccharides extracted from many CM have obvious protective effects on acute liver injury, such as Rhizoma Atractylodis Macrocephalae polysaccharides (Han et al., 2016), Angelica sinensis polysaccharides (Wang, K. et al., 2020), Poria Cocos polysaccharides (Wu, K. et al., 2018), Lycium barbarum polysaccharides (Wei et al., 2020), and Schizandra chinensis acidic polysaccharides (Yuan et al., 2018). Wang et al. reported that Paeoniae Radix Alba polysaccharides inhibited the NF-κB signaling pathway (including the liver infiltration of inflammatory CD4+ and CD8+ cells, and the overexpression of inflammatory cytokines IL-2, IL-6, and IL-10) to inhibit the immune inflammatory response in experimental autoimmune hepatitis mice (Wang, S. et al., 2020). Finally, it is also important that APS is the main active component extracted from Astragalus, which has been proved to have a significant inhibitory effect on many types of human solid tumors. A recent study showed that APS could reduce the activity of hepatoma cells and induce the apoptosis of HCC cells in a concentration-dependent manner. The study further showed that the results might be related to inhibiting the expression of Notch 1 in HCC cells (Huang et al., 2016).
Glycosides are a class of compounds formed by linking the sugar or sugar derivative with another non-sugar substance through the terminal carbon atom of the sugar. The studies have shown that most glycosides have good hepatoprotective effects on liver, such as amygdalin, amarogentin, and forsythiaside A (Pan, C.-W. et al., 2015; Tang et al., 2019; Zhang et al., 2017). Chrysophanol 8-o-glucoside, extracted from Rheum palmatum, can significantly inhibit the gene expression of α-SMA and collagen I, and inhibit the phosphorylation of STAT3 by inhibiting the nuclear translocation of p-STAT3, thus alleviating fibrosis and achieving liver protection (Park et al., 2020). What’s more, Gentiopicroside not only protects alcoholic liver disease by improving lipid metabolism imbalance and mitochondrial dysfunction caused by alcohol (Yang, H.-X. et al., 2020; Zhang et al., 2021), but also treats alcoholic liver cancer by regulating the activation of P2x7R-NLRP3 inflammasome (Li, Xia et al., 2018). It is worth mentioning that astragaloside IV can inhibit hepatoma cells by inhibiting multidrug resistance-associated protein 2, and long noncoding RNA ATB (Li, Y. et al., 2018; Qu et al., 2020).
The specific information of polysaccharides and glycosides is shown in Table 2. In addition, the chemical structures of the glycosides with therapeutic effects on liver diseases are shown in Figure 5.
TABLE 2. Summary of polysaccharides and glycosides with significant anti-liver disease activity.
FIGURE 5. The chemical structures of glycosides showing anti-hepatopathy activity.
Phenols and Flavonoids
Phenolic compounds are composed of the aromatic rings with one or more hydroxyl groups. They play an important role on oxidative stress in the human by maintaining the balance between oxidants and antioxidants, which are divided into phenolic acids, flavonoids, coumarins, and tannins (Van Hung, 2016). A large number of phenolic compounds in CM have obvious antioxidant capacity, which can reduce the oxidative damage of the liver, such as Lithospermic acid, Chlorogenic acid, Curcumin, Polydatin, and Salvianolic acid C (Chan and Ho, 2015; Koneru et al., 2017; Shi et al., 2016; Wu, C.-T. et al., 2019; Zhong et al., 2016). Yang et al. further found that Chlorogenic acid could reduce the expression of α-SMA, collagen I in the liver tissue and serum TGF-β1 by increasing the mRNA and protein expression of Smad7 and MMP-9, thus alleviating liver fibrosis (Wu, C. et al., 2019). The studies have shown that Curcumin and Polydatin can inhibit lipid accumulation by regulating endoplasmic reticulum stress and the Keap1/Nrf2 pathway (Lee, H.-Y. et al., 2017; Zhao, X.-J. et al., 2018). In addition, Yan et al. demonstrated that Chlorogenic acid could improve liver injury and insulin resistance by inactivating the JNK pathway and inhibiting the autophagy in MAFLD rats (Yan, Hua et al., 2018).
Flavonoids, a part of phenolic compounds, also have significant hepatoprotective effects. For example, Isorhamnetin suppresses the TGF-β/Smad pathway and reduces oxidative stress to alleviate hepatic fibrosis (Yang, J.H. et al., 2016), and Wogonin reduces hepatic fibrosis by regulating the activation and apoptosis of HSCs (Du et al., 2019). Quercetin can effectively alleviate MAFLD, which depends on its regulation of intestinal microbiota imbalance and related gut-liver axis activation (Porras et al., 2017). Hesperidin and Oxylin A have significant anti-hepatoma activity (Mo'men et al., 2019; Wei et al., 2017). In addition, Licochalcone A can increase the expression of antioxidant enzymes by reducing the apoptosis, mitochondrial dysfunction, and reactive oxygen production stimulated by tert butyl peroxide and Acetaminophen, thus protecting APAP-induced hepatotoxicity, which is largely dependent on the antioxidant Nrf2 pathway (Lv et al., 2018). What’s more, rutin has a good protective effect on various acute liver injury induced by carbon tetrachloride, lipopolysaccharide, and mercury chloride (Caglayan et al., 2019; Elsawy et al., 2019; Rakshit et al., 2021).
Bacalin, a kind of flavonoid extracted from Scutellaria baicalensis, has significant biological activity, which is widely used in the treatment of liver diseases. The study has shown that bacalin suppresses the production of IL-1β, IL-6, and TNF-α, as well as regulates the TLR4 expression and inhibits the NF-κB activation, protecting the inflammation of chicken’s liver induced by LPS through the negative regulation of inflammatory medium (Cheng et al., 2017). Another study showed that the inhibition of the proliferation, apoptosis, invasion, migration, and activation of HSCs induced by platelet derived growth factor-BB through mir-3595/acsl4 axis is one of the mechanisms of bacalin in anti-hepatic fibrosis (Wu, X. et al., 2018).
The specific information of the phenols and flavonoids is shown in Table 3, and the chemical structures of the phenols and flavonoids are shown in Figure 6.
TABLE 3. Summary of phenols and flavonoids with significant anti-liver disease activity.
FIGURE 6. The chemical structures of phenols and flavonoids showing anti-hepatopathy activity.
Terpenoids
Terpenoids (isoprenoids) are the most abundant chemical compounds in plants (Tholl, 2015), which has a wide range of biological activities, such as anti-inflammation (Kim, T. et al., 2020), anti-depressant (Agatonovic-Kustrin et al., 2020), anti-cancer (Ateba et al., 2018), and so on. Many studies have shown that terpenoids are also widely used in the treatment of liver diseases. Leucodin is a sesquiterpene lactone isolated from Artemisia capillaris, which can inhibit the inflammatory response of macrophages, and P2x7R-NLRP3-mediated lipid accumulation in hepatocytes (Shang et al., 2018). Saikosaponin-d is an active component isolated from Radix Bupleuri, which can inhibit the COX2 expression through the p-STAT3/C/EBPβ signaling pathway in HCC (Ren et al., 2019). Oleanolic acid (OA) is a kind of triterpenoid widely existing in fruits, vegetables, and herbs. It is liver-specific and can selectively inhibit adipogenesis (Lin, Y.-N. et al., 2018). In addition, OA can regulate antioxidant status, and induce mitochondria-mediated apoptosis and regulate inflammation, which effectively inhibits 7,12-Dimethylbenz[a]anthracene-induced liver cancer (Hosny et al., 2021).
Rhizoma Alismatis is a kind of common CM, which is often used in clinic for adverse urination, edema, diarrhea, and so on. Modern studies have shown that many compounds extracted from Rhizoma Alismatis have hepatoprotective effects. For example, Alisol A 24-acetate, a natural triterpene extracted from Rhizoma Alismatis, can improve NASH by inhibiting oxidative stress, and stimulating autophagy through the AMPK/mTOR signaling pathway (Wu, C. et al., 2018). Meng et al. found that Alisol A 23-acetate could also improve NASH in the mice, which was achieved by the activation of X-like receptor (Meng et al., 2017). Futhermore, Meng et al. found that Alisol A 23-acetate activated FXR to induced the phosphorylation of STAT3 and the expression of its target genes, Bcl-xl and SOCS3. And it reduced the expression of the liver uptake transporter NTCP, and bile acid synthases CYP7A1 and Cyp8b1, as well as increased the expression of the outflow transporters BSEP and MRP2, reducing the hepatic bile acid deposition, which achieved the protective effect on CCl4-induced hepatotoxicity in the mice (Meng et al., 2015).
The specific information of the terpenoids in the treatment of liver diseases is shown in Table 4, and the chemical structures of the terpenoids with therapeutic effects on liver diseases are shown in Figure 7.
TABLE 4. Summary of terpenoids with significant anti-liver disease activity.
FIGURE 7. The chemical structures of terpenoids showing anti-hepatopathy activity.
Alkaloids
Alkaloids are an important class of natural products, which have a wide range of biological activities, and have been used in folk medicine for many years (Stöckigt et al., 2011). We are surprised to find that alkaloids play an important role in the treatment of liver diseases. Matrine and Oxymatrine are the main active substances extracted from the roots of Sophora flavescens, and are widely used (Yuan et al., 2010). They have significant biological activities against MAFLD, liver injury, and liver cancer (Gao et al., 2018; Shi et al., 2020; Wei et al., 2018; Xu et al., 2018; Zhang, H. et al., 2020). Ligustrazine is an alkaloid extracted from Ligusticum chuanxiong. It not only activates Nrf2 to inhibit hepatic steatosis, but also induces the apoptosis and autophagy of hepatoma cells to exert an anti-hepatoma effect (Cao et al., 2015; Lu et al., 2017). And coptisine exerts an anti-hepatoma effect by activating the 67 kDa laminin receptor/cGMP signal to induce the apoptosis of human hepatoma cells, and the proliferation and migration of HCC cells (Chai et al., 2018a; Zhou et al., 2018).
The specific information of various alkaloids in the treatment of liver diseases is shown in Table 5. In addition, the chemical structure formulas are shown in Figure 8.
TABLE 5. Summary of alkaloids with significant anti-liver disease activity.
FIGURE 8. The chemical structures of alkaloids showing anti-hepatopathy activity.
Other Bioactive Ingredients
In addition to the above compounds, many compounds have the activities of anti-liver diseases, including phenylpropanoids (such as simple phenylpropanoids, coumarins, and lignans), anthraquinones, and volatile oils. Some lignans extracted from CM have been proved to have the effects on improving liver diseases. For example, Gomisin N extracted from Schisandra chinensis not only has protective effects on endoplasmic reticulum stress-induced hepatic steatosis, but also alleviates the liver injury caused by ethanol by improving lipid metabolism and oxidative stress (Jang et al., 2016; Nagappan et al., 2018). Futhermore, Arctigenin can inhibit the proliferation of HepG2 cells and block the autophagy cells that lead to the accumulation of sequestosome 1/p62, so as to achieve the therapeutic effects on liver cancer. It will become a new drug for the autophagy research and cancer chemoprevention. It is worth noting that many anthraquinones in Rhubarb have good activities of anti-liver diseases, including chrysophanol, emodin, rhein, and aloe emodin (Bai et al., 2020; Dong et al., 2017; Kuo et al., 2020; Li, Y. et al., 2019). Cryptotanshinone, the main anthraquinone extracted from Salvia miltiorrhiza Bunge, can protect liver by activating the AMPK/SIRT1 and Nrf2, and inhibiting CYP2E1 to inhibit adipogenesis, oxidative stress, and inflammation (Nagappan et al., 2019). Other bioactive components against liver diseases are shown in Table 6. In addition, the related chemical structures are also shown in Figure 9.
TABLE 6. Summary of other bioactive ingredients with significant anti-liver disease activity.
FIGURE 9. The related chemical structures of other anti-hepatopathy bioactive components.
Toxicity
After the above discussion, it is not difficult to find the important position of CM in the treatment of liver diseases. As we all know, CM is a relatively safe class of drugs, but we can’t ignore its toxic and side effects on the liver when we use CM to treat liver diseases. The studies have found that some CM show certain hepatotoxicity. For example, Rhubarb extract had a certain protective effect on the rats with chronic renal failure, but the incidence of mild hepatotoxicity was also observed in normal rats (Wang et al., 2009). Ginkgo biloba extract induced DNA damage by inhibiting the topoisomerase II activity in human hepatocytes (Zhang et al., 2015). Interestingly, the hepatotoxicity of some CM comes from their own hydrolysates. For example, after the intragastric administration of Sophora flavescens extract to the rats, kurarinone glucosides was hydrolyzed into Kurarinone in liver cells, which eventually led to the lipid accumulation and liver injury through a series of actions (Jiang, P. et al., 2017). In addition, the use of herbal products is also a crucial cause of acute liver injury. It has been reported that a 68-year-old woman suffered from acute liver injury caused by aloe, after stopping taking aloe, her liver functions returned to normal levels (Parlati et al., 2017). It is worth noting that the first case of autoimmune hepatitis caused by turmeric supplements has been reported (Lukefahr et al., 2018).
The dosage of CM is often closely related to hepatotoxicity. In order to study the hepatotoxicity of Cortex Dictamni, fan et al. used its water extract and alcohol extract to carry out the toxicity experiments in vivo and in vitro. The results showed that high dose of water extract and alcohol extract significantly increased the levels of ALT and AST, absolute and relative liver weight, and the liver-to-brain ratio, and the histological examination of the liver showed the cell enlargement and nuclear contraction. In vitro cell experiment also showed that water extract and alcohol extract reduced the cell viability in a dose-dependent manner (Fan et al., 2018). A single oral dose of 60 g/kg Cortex Dictamni ethanol extract for 24 h resulted in severe hepatocyte necrosis in mice, and the induced liver injury showed a dose and time-dependent manner (Huang et al., 2020). Saikosaponins, a major bioactive component extracted from Radix Bupleuri, enhances the CYP2E1 expression in a dose and time-dependent manner, and induces oxidative stress in vivo and in vitro, leading to liver injury in mice (Li et al., 2017). In another study, the rats were fed with 300, 1250 and 2500 mg kg−1·D−1 Radix Scutellariae Baicalensis ethanol extract for 26 weeks. It was found that the liver tissues of the rats in the high-dose group showed some inflammatory changes mainly characterized by leukocyte infiltration. In addition, there were also some changes in the levels of glucose, electrolyte, and lipid (Yi et al., 2018). It can be seen that the hepatotoxicity of many CM are closely related to the dosage.
In addition, the abuse of CM without the guidance of doctors is also the source of toxic reactions. Because traditional Chinese medical science thinks that “toxicity” refers to the biases of drugs, the toxic components of CM are often the effective components for treating diseases. The key to judging whether CM is toxic or non-toxic is to see whether it is used according to the syndrome. As long as the treatment is besed on the syndrome, toxic drugs are also safe. If the treatment is not for the syndrome, non-toxic drugs may be harmful. It is worth noting that there are also some CM products considered non-toxic or low toxic, which have obvious toxicological effects on different organs in animal and human models (Liu, R. et al., 2020). So it is a great problem to control the toxic and non-toxic boundaries reasonably, and every traditional medical scholar should make efforts to do so.
Clinical Trials
Most drugs for anti-liver diseases used in clinic are CM compounds, and less clinical research and application involve only one CM or one compound. Table 7 shows some CM (excluding CM compounds) used in the clinical treatment of liver diseases. The purpose is to improve the richness of clinical medication, so that more CM with potential and significant therapeutic effects can be noticed.
TABLE 7. Some Chinese medicine are used to treat liver diseases in clinic.
Single extract or chemical component of CM showed good activity of anti-liver diseases in clinical research. Artemisia annua L. extract can improve the liver function in the patients with mild to moderate nonalcoholic liver dysfunction, and no obvious adverse reactions were observed in all subjects (Han et al., 2020). Futhermore, Portulaca oleracea extract can improve liver enzyme, blood lipid, and blood glucose in the patients with MAFLD (Darvish Damavandi et al., 2021). It is worth noting that Carcuma longa has a wide range of clinical applications, with a large number of clinical data, suggesting its position in the clinical treatment of liver diseases. To assess the effect of Carcuma longa on MAFLD, 92 MAFLD patients aged 20–60 years were enrolled in a 12-week study. The results showed that Carcuma longa supplement was very useful in controlling MAFLD-related risk factors (Darvish Damavandi et al., 2021). Curcumin, the main active component of Curcuma longa, can increase the serum inflammatory cytokine levels in the patients with MAFLD, which may be partly dependent on the anti-steatosis effect (Saberi-Karimian et al., 2020). In addition, curcumin can improve the quality of life of the patients with liver cirrhosis (Nouri-Vaskeh et al., 2020a). Although the clinical application of Curcuma longa has surpassed other CM against liver diseases, it still fails to solve the problem of its optimal dosage, and the molecular mechanisms on treating liver diseases is unclear. More importantly, in view of the widespread use of Curcuma longa, we need larger, more impartial and high-quality controlled randomized trials to conduct a deeper evaluation.
In the future, more clinical experiments should be studied, which makes more CM into clinical application, and even go to the international stage. There are still many deficiencies in the current clinical research. First, the dosage is single and the sample size is small, which is not good for screening the best treatment dose. Secondly, the existing clinical experiments mainly focus on the study of MAFLD, but there are many kinds of liver diseases. In the future, the research can be expanded to make more patients with liver diseases benefit from CM. Finally, the mechanisms of many CM (especially CM compounds) used in the treatment of liver diseases are not clear. We should further explore the mechanism of action of CM, making its fuzzy mechanism clearer and letting more people accept it.
Conclusion and Perspectives
In conclusion, CM can prevent and treat liver diseases through many ways, including regulating lipid metabolism, anti-liver injury (such as CCl4, H2O2, alcohol, and drug damage), anti-oxidant stress (including reducing ROS, increasing SOD, GSH and CAT content, and regulating Nrf2 and other related pathways), regulating bile acid metabolism (including regulating the excreted and ingested receptors), regulating the immune system, anti-hepatitis virus, and anti-liver cancer. In terms of the current situation, a large number of studies have proved the potential of CM in the treatment of liver diseases. However, the resources of CM are huge, and it is probably known that the effective CM for liver diseases are only one corner of the iceberg. More tasks need the joint efforts of all traditional medicine scholars. In addition, a large part of the current research has not only been focused on the study of efficacy, but also the expression level of genes and proteins. But it is not enough, and more new methods should be explored, such as using multi-group analysis (metabolomics, proteomics), so as to promote the progress of CM in the treatment of liver diseases.
It is worth noting that there is also relevant evidence that the new technology of CM combined with other preparations can greatly enhance the therapeutic effects on liver diseases. For example, due to the characteristics of unstable chemical structure, low bioavailability, easy oxidation, and UV degradation, the toxic effect of curcumin on hepatoma cells is limited. Therefore, Kong et al. used curcumin loaded mesoporous silica nanoparticles, and found that the complex had better antioxidant activity than curcumin alone, as well as significantly enhanced the cytotoxic effect on hepatoma cells (Kong et al., 2019). Another study showed that curcumin liposome had a greater inhibitory effect on the growth and apoptosis of cancer cells (Feng et al., 2017). But these studies are still very few, which should be increased later.
This paper lists and elaborates the active ingredients of some CM against liver diseases, such as polysaccharides, glycosides, phenols, flavonoids, terpenoids, alkaloids, etc. We found the research on the mechanism of action of each ingredient was relatively single, and CM showed the joint action of multi-component and multi-target in the treatment of liver diseases. Therefore, screening more effective components and studying their molecular mechanisms should be greatly strengthened. For example, recent studies have shown that iron is essential for life, but excessive iron may be cytotoxic, which may lead to cell death and some diseases (Bogdan et al., 2016; Nakamura et al., 2019). In addition, in the previous discussion, we also know that the gut microbiota plays an important role in the treatment of liver diseases. Therefore, it is suggested that we can refer to these relevant mechanisms in the future research of CM on treating liver diseases.
CM, including Tibetan medicine, has shown good effects of anti-liver diseases (Li, Qi et al., 2018; Fu et al., 2020), which is indispensable in the treatment of liver diseases. This paper is a comprehensive review of CM and the related compounds, toxicology, and clinical research, which is aimed to provide scientific and effective references for the treatment of liver diseases, and to better use and develop the treasure of CM.
Author Contributions
KF and YL designed this article and established the structure. CW, CM, and HZ assisted in data collection and form establishment. YL helped to revise the manuscript.
Funding
The study was supported by National Natural Science Foundation of China (No: 81891012, 81630101, and U19A2010), Sichuan Science and Technology Program (2021JDRC0041).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
ALD, alcoholic liver disease; AMPK, adenine monophosphate activated protein kinase; ARE, antioxidant responsive element; BAs, bile acids; CM, Chinese medicine; CYP, cytochrome P450; FL, fatty liver; FSE, Forsythiae Fructuse water extract; GSH, glutathione; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HSCs, hepatic stellate cells; IL-1β, interleukin-1β; IL-6, interleukin-6; KCs, kupffer cells; LC, liver cirrhosis; LSECs, liver sinusoidal endothelial cells; MAFLD, metabolic associated fatty liver disease; NAFL, non-alcoholic fatty liver; NASH, non-alcoholic steatohepatitis; NF-κB, nuclear factor kappa-B; NK, natural killer; Nrf2, nuclear factor-erythroid 2-related factor 2; ROS, reactive oxygen species; RSM, Radix Salvia Miltiorrhiza; SOD, superoxide dismutase; TC, total cholesterol; TG, triglyceride; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α.
References
Abdelfattah-Hassan, A., Shalaby, S. I., Khater, S. I., El-Shetry, E. S., Abd El Fadil, H., and Elsayed, S. A. (2019). Panax Ginseng Is superior to Vitamin E as a Hepatoprotector Against Cyclophosphamide-Induced Liver Damage. Complement. Ther. Med. 46, 95–102. doi:10.1016/j.ctim.2019.08.005
Abu Ahmad, N., Raizman, M., Weizmann, N., Wasek, B., Arning, E., Bottiglieri, T., et al. (2019). Betaine Attenuates Pathology by Stimulating Lipid Oxidation in Liver and Regulating Phospholipid Metabolism in Brain of Methionine-Choline-Deficient Rats. FASEB J. 33 (8), 9334–9349. doi:10.1096/fj.201802683R
Agatonovic-Kustrin, S., Kustrin, E., Gegechkori, V., and Morton, D. W. (2020). Anxiolytic Terpenoids and Aromatherapy for Anxiety and Depression. Adv. Exp. Med. Biol. 1260, 283–296. doi:10.1007/978-3-030-42667-5_11
Agrawal, A., and Bierut, L. J. (2012). Identifying Genetic Variation for Alcohol Dependence. Alcohol. Res. 34 (3), 274–281.
Alaca, N., Özbeyli, D., Uslu, S., Şahin, H. H., Yiğittürk, G., Kurtel, H., et al. (2017). Treatment with Milk Thistle Extract (Silybum marianum), Ursodeoxycholic Acid, or Their Combination Attenuates Cholestatic Liver Injury in Rats: Role of the Hepatic Stem Cells. Turk J. Gastroenterol. 28 (6), 476–484. doi:10.5152/tjg.2017.16742
Arulselvan, P., Fard, M. T., Tan, W. S., Gothai, S., Fakurazi, S., Norhaizan, M. E., et al. (2016). Role of Antioxidants and Natural Products in Inflammation. Oxid Med. Cel Longev 2016, 5276130. doi:10.1155/2016/5276130
Ateba, S. B., Mvondo, M. A., Ngeu, S. T., Tchoumtchoua, J., Awounfack, C. F., Njamen, D., et al. (2018). Natural Terpenoids Against Female Breast Cancer: A 5-year Recent Research. Curr. Med. Chem. 25 (27), 3162–3213. doi:10.2174/0929867325666180214110932
Auyeung, K. K., and Ko, J. K. (2009). Coptis Chinensis Inhibits Hepatocellular Carcinoma Cell Growth Through Nonsteroidal Anti-inflammatory Drug-Activated Gene Activation. Int. J. Mol. Med. 24 (4), 571–577. doi:10.3892/ijmm_00000267
Bai, J., Wu, J., Tang, R., Sun, C., Ji, J., Yin, Z., et al. (2020). Emodin, A Natural Anthraquinone, Suppresses Liver Cancer In Vitro and In Vivo by Regulating VEGFR2 and miR-34a. Invest. New Drugs 38 (2), 229–245. doi:10.1007/s10637-019-00777-5
Barandeh, B., Amini Mahabadi, J., Azadbakht, M., Gheibi Hayat, S. M., and Amini, A. (2019). The Protective Effects of Curcumin on Cytotoxic and Teratogenic Activity of Retinoic Acid in Mouse Embryonic Liver. J. Cel Biochem 120 (12), 19371–19376. doi:10.1002/jcb.28934
BasuRay, S., Smagris, E., Cohen, J. C., and Hobbs, H. H. (2017). The PNPLA3 Variant Associated with Fatty Liver Disease (I148M) Accumulates on Lipid Droplets by Evading Ubiquitylation. Hepatology 66 (4), 1111–1124. doi:10.1002/hep.29273
Bellezza, I., Giambanco, I., Minelli, A., and Donato, R. (2018). Nrf2-Keap1 Signaling in Oxidative and Reductive Stress. Biochim. Biophys. Acta Mol. Cel Res 1865 (5), 721–733. doi:10.1016/j.bbamcr.2018.02.010
Bogdan, A. R., Miyazawa, M., Hashimoto, K., and Tsuji, Y. (2016). Regulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease. Trends Biochem. Sci. 41 (3), 274–286. doi:10.1016/j.tibs.2015.11.012
Buendia, I., Michalska, P., Navarro, E., Gameiro, I., Egea, J., and León, R. (2016). Nrf2-ARE Pathway: An Emerging Target Against Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases. Pharmacol. Ther. 157, 84–104. doi:10.1016/j.pharmthera.2015.11.003
Buzzetti, E., Pinzani, M., and Tsochatzis, E. A. (2016). The Multiple-Hit Pathogenesis of Non-alcoholic Fatty Liver Disease (NAFLD). Metabolism 65 (8), 1038–1048. doi:10.1016/j.metabol.2015.12.012
Caglayan, C., Kandemir, F. M., Darendelioğlu, E., Yıldırım, S., Kucukler, S., and Dortbudak, M. B. (2019). Rutin Ameliorates Mercuric Chloride-Induced Hepatotoxicity in Rats via Interfering with Oxidative Stress, Inflammation and Apoptosis. J. Trace Elem. Med. Biol. 56, 60–68. doi:10.1016/j.jtemb.2019.07.011
Cai, L., Zou, S., Liang, D., and Luan, L. (2018). Structural Characterization, Antioxidant and Hepatoprotective Activities of Polysaccharides from Sophorae Tonkinensis Radix. Carbohydr. Polym. 184, 354–365. doi:10.1016/j.carbpol.2017.12.083
Campana, L., and Iredale, J. P. (2017). Regression of Liver Fibrosis. Semin. Liver Dis. 37 (1), 1–10. doi:10.1055/s-0036-1597816
Cao, J., Miao, Q., Miao, S., Bi, L., Zhang, S., Yang, Q., et al. (2015). Tetramethylpyrazine (TMP) Exerts Antitumor Effects by Inducing Apoptosis and Autophagy in Hepatocellular Carcinoma. Int. Immunopharmacol 26 (1), 212–220. doi:10.1016/j.intimp.2015.03.028
Cao, L. J., Hou, Z. Y., Li, H. D., Zhang, B. K., Fang, P. F., Xiang, D. X., et al. (2017). The Ethanol Extract of Licorice (Glycyrrhiza Uralensis) Protects Against Triptolide-Induced Oxidative Stress Through Activation of Nrf2. Evid. Based Complement. Alternat Med. 2017, 2752389. doi:10.1155/2017/2752389
Cao, T., Lu, Y., Zhu, M., Cheng, J., Ye, B., Fang, N., et al. (2020). Effects of Salvia Miltiorrhiza and Radix Astragali on the TGF-β/Smad/Wnt Pathway and the Pathological Process of Liver Fibrosis in Rats. Cel Mol Biol (Noisy-le-grand) 66 (6), 46–51. doi:10.14715/cmb/2020.66.6.9
Ceccarini, M. R., Vannini, S., Cataldi, S., Moretti, M., Villarini, M., Fioretti, B., et al. (2016). In Vitro Protective Effects of Lycium Barbarum Berries Cultivated in Umbria (Italy) on Human Hepatocellular Carcinoma Cells. Biomed. Res. Int. 2016, 7529521. doi:10.1155/2016/7529521
Ceni, E., Mello, T., and Galli, A. (2014). Pathogenesis of Alcoholic Liver Disease: Role of Oxidative Metabolism. World J. Gastroenterol. 20 (47), 17756–17772. doi:10.3748/wjg.v20.i47.17756
Chai, F. N., Ma, W. Y., Zhang, J., Xu, H. S., Li, Y. F., Zhou, Q. D., et al. (2018a). Coptisine from Rhizoma Coptidis Exerts an Anti-cancer Effect on Hepatocellular Carcinoma by Up-Regulating miR-122. Biomed. Pharmacother. 103, 1002–1011. doi:10.1016/j.biopha.2018.04.052
Chai, F. N., Zhang, J., Xiang, H. M., Xu, H. S., Li, Y. F., Ma, W. Y., et al. (2018b). Protective Effect of Coptisine from Rhizoma Coptidis on LPS/D-GalN-induced Acute Liver Failure in Mice Through Up-Regulating Expression of miR-122. Biomed. Pharmacother. 98, 180–190. doi:10.1016/j.biopha.2017.11.133
Chan, H. H. L., and Ng, T. (2020). Traditional Chinese Medicine (TCM) and Allergic Diseases. Curr. Allergy Asthma Rep. 20 (11), 67. doi:10.1007/s11882-020-00959-9
Chan, K. W., and Ho, W. S. (2015). Anti-oxidative and Hepatoprotective Effects of Lithospermic Acid Against Carbon Tetrachloride-Induced Liver Oxidative Damage In Vitro and In Vivo. Oncol. Rep. 34 (2), 673–680. doi:10.3892/or.2015.4068
Chávez-Talavera, O., Tailleux, A., Lefebvre, P., and Staels, B. (2017). Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease. Gastroenterology 152 (7), 1679–1694.e3. doi:10.1053/j.gastro.2017.01.055
Chen, Q., Zhang, H., Cao, Y., Li, Y., Sun, S., Zhang, J., et al. (2017). Schisandrin B Attenuates CCl4-Induced Liver Fibrosis in Rats by Regulation of Nrf2-ARE and TGF-β/Smad Signaling Pathways. Drug Des. Devel Ther. 11, 2179–2191. doi:10.2147/DDDT.S137507
Chen, S., Zhao, X., Ran, L., Wan, J., Wang, X., Qin, Y., et al. (2015). Resveratrol Improves Insulin Resistance, Glucose and Lipid Metabolism in Patients with Non-alcoholic Fatty Liver Disease: a Randomized Controlled Trial. Dig. Liver Dis. 47 (3), 226–232. doi:10.1016/j.dld.2014.11.015
Chen, Y., Yao, F., Ming, K., Wang, D., Hu, Y., and Liu, J. (2016). Polysaccharides from Traditional Chinese Medicines: Extraction, Purification, Modification, and Biological Activity. Molecules 21 (12), 1705. doi:10.3390/molecules21121705
Chen, Z., Liu, F., Zheng, N., Guo, M., Bao, L., Zhan, Y., et al. (2019). Wuzhi Capsule (Schisandra Sphenanthera Extract) Attenuates Liver Steatosis and Inflammation During Non-alcoholic Fatty Liver Disease Development. Biomed. Pharmacother. 110, 285–293. doi:10.1016/j.biopha.2018.11.069
Cheng, N., Chen, S., Liu, X., Zhao, H., and Cao, W. (2019). Impact of SchisandraChinensis Bee Pollen on Nonalcoholic Fatty Liver Disease and Gut Microbiota in HighFat Diet Induced Obese Mice. Nutrients 11 (2), 346. doi:10.3390/nu11020346
Cheng, P., Wang, T., Li, W., Muhammad, I., Wang, H., Sun, X., et al. (2017). Baicalin Alleviates Lipopolysaccharide-Induced Liver Inflammation in Chicken by Suppressing TLR4-Mediated NF-Κb Pathway. Front. Pharmacol. 8, 547. doi:10.3389/fphar.2017.00547
Chopyk, D. M., and Grakoui, A. (2020). Contribution of the Intestinal Microbiome and Gut Barrier to Hepatic Disorders. Gastroenterology 159 (3), 849–863. doi:10.1053/j.gastro.2020.04.077
Chuang, H. M., Su, H. L., Li, C., Lin, S. Z., Yen, S. Y., Huang, M. H., et al. (2016). The Role of Butylidenephthalide in Targeting the Microenvironment Which Contributes to Liver Fibrosis Amelioration. Front. Pharmacol. 7, 112. doi:10.3389/fphar.2016.00112
Commission, C.P. (2015). Pharmacopoeia of the People’s republic of China. Beijing: China medical science and technology press.
Crocenzi, F. A., Zucchetti, A. E., Boaglio, A. C., Barosso, I. R., Sanchez Pozzi, E. J., Mottino, A. D., et al. (2012). Localization Status of Hepatocellular Transporters in Cholestasis. Front. Biosci. (Landmark Ed. 17, 1201–1218. doi:10.2741/3981
Cui, Y., Jiang, L., Shao, Y., Mei, L., and Tao, Y. (2019). Anti-alcohol Liver Disease Effect of Gentianae Macrophyllae Extract Through MAPK/JNK/p38 Pathway. J. Pharm. Pharmacol. 71 (2), 240–250. doi:10.1111/jphp.13027
D'Atanasio, E., Trombetta, B., Bonito, M., Finocchio, A., Di Vito, G., Seghizzi, M., et al. (2018). The Peopling of the Last Green Sahara Revealed by High-Coverage Resequencing of Trans-saharan Patrilineages. Genome Biol. 19 (1), 20. doi:10.1186/s13059-018-1393-5
Darvish Damavandi, R., Shidfar, F., Najafi, M., Janani, L., Masoodi, M., Akbari-Fakhrabadi, M., et al. (2021). Effect of Portulaca Oleracea (Purslane) Extract on Liver Enzymes, Lipid Profile, and Glycemic Status in Nonalcoholic Fatty Liver Disease: A Randomized, Double-Blind Clinical Trial. Phytother Res. 35 (6), 3145–3156. doi:10.1002/ptr.6972
Dewidar, B., Meyer, C., Dooley, S., and Meindl-Beinker, A. N. (2019). TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019. Cells 8 (11), 1419. doi:10.3390/cells8111419
Ding, C. H., and Zhu, H. (2020). Isatidis Folium Alleviates Acetaminophen-Induced Liver Injury in Mice by Enhancing the Endogenous Antioxidant System. Environ. Toxicol. 35 (11), 1251–1259. doi:10.1002/tox.22990
Ding, H. R., Wang, J. L., Ren, H. Z., and Shi, X. L. (2018a). Lipometabolism and Glycometabolism in Liver Diseases. Biomed. Res. Int. 2018, 1287127. doi:10.1155/2018/1287127
Ding, Y., Liu, P., Chen, Z. L., Zhang, S. J., Wang, Y. Q., Cai, X., et al. (2018b). Emodin Attenuates Lipopolysaccharide-Induced Acute Liver Injury via Inhibiting the TLR4 Signaling Pathway In Vitro and In Vivo. Front. Pharmacol. 9, 962. doi:10.3389/fphar.2018.00962
Dodge, N. C., Jacobson, J. L., and Jacobson, S. W. (2014). Protective Effects of the Alcohol Dehydrogenase-Adh1b*3 Allele on Attention and Behavior Problems in Adolescents Exposed to Alcohol During Pregnancy. Neurotoxicol Teratol 41, 43–50. doi:10.1016/j.ntt.2013.11.003
Dong, Q., Chu, F., Wu, C., Huo, Q., Gan, H., Li, X., et al. (2016). Scutellaria Baicalensis Georgi Extract Protects Against Alcohol Induced Acute Liver Injury in Mice and Affects the Mechanism of ER Stress. Mol. Med. Rep. 13 (4), 3052–3062. doi:10.3892/mmr.2016.4941
Dong, X., Fu, J., Yin, X., Yang, C., and Ni, J. (2017). Aloe-emodin Induces Apoptosis in Human Liver HL-7702 Cells Through Fas Death Pathway and the Mitochondrial Pathway by Generating Reactive Oxygen Species. Phytother Res. 31 (6), 927–936. doi:10.1002/ptr.5820
Du, X. S., Li, H. D., Yang, X. J., Li, J. J., Xu, J. J., Chen, Y., et al. (2019). Wogonin Attenuates Liver Fibrosis via Regulating Hepatic Stellate Cell Activation and Apoptosis. Int. Immunopharmacol 75, 105671. doi:10.1016/j.intimp.2019.05.056
Duan, X., Meng, Q., Wang, C., Liu, Z., Liu, Q., Sun, H., et al. (2017). Calycosin Attenuates Triglyceride Accumulation and Hepatic Fibrosis in Murine Model of Non-alcoholic Steatohepatitis via Activating Farnesoid X Receptor. Phytomedicine 25, 83–92. doi:10.1016/j.phymed.2016.12.006
Egresi, A., Süle, K., Szentmihályi, K., Blázovics, A., Fehér, E., Hagymási, K., et al. (2020). Impact of Milk Thistle (Silybum marianum) on the Mycotoxin Caused Redox-Homeostasis Imbalance of Ducks Liver. Toxicon 187, 181–187. doi:10.1016/j.toxicon.2020.09.002
El-Saied, M. A., Sobeh, M., Abdo, W., Badr, O. M., Youssif, L. T., Elsayed, I. H., et al. (2018). Rheum Palmatum Root Extract Inhibits Hepatocellular Carcinoma in Rats Treated with Diethylnitrosamine. J. Pharm. Pharmacol. 70 (6), 821–829. doi:10.1111/jphp.12899
El-Serag, H. B. (2012). Epidemiology of Viral Hepatitis and Hepatocellular Carcinoma. Gastroenterology 142 (6), 1264–e1. doi:10.1053/j.gastro.2011.12.061
Elsawy, H., Badr, G. M., Sedky, A., Abdallah, B. M., Alzahrani, A. M., and Abdel-Moneim, A. M. (2019). Rutin Ameliorates Carbon Tetrachloride (CCl4)-Induced Hepatorenal Toxicity and Hypogonadism in Male Rats. PeerJ 7, e7011. doi:10.7717/peerj.7011
Fan, Q., Zhao, B., Wang, C., Zhang, J., Wu, J., Wang, T., et al. (2018). Subchronic Toxicity Studies of Cortex Dictamni Extracts in Mice and its Potential Hepatotoxicity Mechanisms In Vitro. Molecules 23 (10), 2486. doi:10.3390/molecules23102486
Fanning, G. C., Zoulim, F., Hou, J., and Bertoletti, A. (2019). Therapeutic Strategies for Hepatitis B Virus Infection: Towards a Cure. Nat. Rev. Drug Discov. 18 (11), 827–844. doi:10.1038/s41573-019-0037-0
Feng, R., Chen, J. H., Liu, C. H., Xia, F. B., Xiao, Z., Zhang, X., et al. (2019). A Combination of Pueraria Lobata and Silybum marianum Protects Against Alcoholic Liver Disease in Mice. Phytomedicine 58, 152824. doi:10.1016/j.phymed.2019.152824
Feng, T., Wei, Y., Lee, R. J., and Zhao, L. (2017). Liposomal Curcumin and its Application in Cancer. Int. J. Nanomedicine 12, 6027–6044. doi:10.2147/IJN.S132434
Forner, A., Llovet, J. M., and Bruix, J. (2012). Hepatocellular Carcinoma. Lancet 379 (9822), 1245–1255. doi:10.1016/S0140-6736(11)61347-0
Forner, A., Reig, M., and Bruix, J. (2018). Hepatocellular Carcinoma. Lancet 391 (10127), 1301–1314. doi:10.1016/S0140-6736(18)30010-2
Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M., and Sanyal, A. J. (2018). Mechanisms of NAFLD Development and Therapeutic Strategies. Nat. Med. 24 (7), 908–922. doi:10.1038/s41591-018-0104-9
Friedman, S. L. (1993). Seminars in Medicine of the Beth Israel Hospital, Boston. The Cellular Basis of Hepatic Fibrosis. Mechanisms and Treatment Strategies. N. Engl. J. Med. 328 (25), 1828–1835. doi:10.1056/NEJM199306243282508
Fu, K., Xu, M., Zhou, Y., Li, X., Wang, Z., Liu, X., et al. (2020). The Status Quo and Way Forwards on the Development of Tibetan Medicine and the Pharmacological Research of Tibetan Materia Medica. Pharmacol. Res. 155, 104688. doi:10.1016/j.phrs.2020.104688
Gan, D., Zhang, W., Huang, C., Chen, J., He, W., Wang, A., et al. (2018a). Ursolic Acid Ameliorates CCl4-Induced Liver Fibrosis Through the NOXs/ROS Pathway. J. Cel Physiol 233 (10), 6799–6813. doi:10.1002/jcp.26541
Gan, F., Liu, Q., Liu, Y., Huang, D., Pan, C., Song, S., et al. (2018b). Lycium Barbarum Polysaccharides Improve CCl4-Induced Liver Fibrosis, Inflammatory Response and TLRs/NF-kB Signaling Pathway Expression in Wistar Rats. Life Sci. 192, 205–212. doi:10.1016/j.lfs.2017.11.047
Ganbold, M., Owada, Y., Ozawa, Y., Shimamoto, Y., Ferdousi, F., Tominaga, K., et al. (2019). Isorhamnetin Alleviates Steatosis and Fibrosis in Mice with Nonalcoholic Steatohepatitis. Sci. Rep. 9 (1), 16210. doi:10.1038/s41598-019-52736-y
Gao, L. N., Yan, K., Cui, Y. L., Fan, G. W., and Wang, Y. F. (2015). Protective Effect of Salvia Miltiorrhiza and Carthamus tinctorius Extract Against Lipopolysaccharide-Induced Liver Injury. World J. Gastroenterol. 21 (30), 9079–9092. doi:10.3748/wjg.v21.i30.9079
Gao, X., Guo, S., Zhang, S., Liu, A., Shi, L., and Zhang, Y. (2018). Matrine Attenuates Endoplasmic Reticulum Stress and Mitochondrion Dysfunction in Nonalcoholic Fatty Liver Disease by Regulating SERCA Pathway. J. Transl Med. 16 (1), 319. doi:10.1186/s12967-018-1685-2
Gao, X., Li, C., Tang, Y. L., Zhang, H., and Chan, S. W. (2016). Effect of Hedyotis Diffusa Water Extract on Protecting Human Hepatocyte Cells (LO2) from H2O2-Induced Cytotoxicity. Pharm. Biol. 54 (7), 1148–1155. doi:10.3109/13880209.2015.1056310
Gao, X., and Liu, L. (2016). Research Progress on Epidemiology and Pathogenesis of Alcoholic Liver Disease. Chin. J. Gastroenterol. Imaging 6 (02), 62–65.
Gao, Z., Zhang, J., Wei, L., Yang, X., Zhang, Y., Cheng, B., et al. (2020). The Protective Effects of Imperatorin on Acetaminophen Overdose-Induced Acute Liver Injury. Oxid Med. Cel Longev 2020, 8026838. doi:10.1155/2020/8026838
Ge, L., Xiao, L., Wan, H., Li, J., Lv, K., Peng, S., et al. (2019). Chemical Constituents from Lonicera japonica Flower Buds and Their Anti-hepatoma and Anti-HBV Activities. Bioorg. Chem. 92, 103198. doi:10.1016/j.bioorg.2019.103198
Ghaffari, A., Rafraf, M., Navekar, R., Sepehri, B., Asghari-Jafarabadi, M., and Ghavami, S. M. (2019). Turmeric and Chicory Seed Have Beneficial Effects on Obesity Markers and Lipid Profile in Non-alcoholic Fatty Liver Disease (NAFLD). Int. J. Vitam Nutr. Res. 89 (5-6), 293–302. doi:10.1024/0300-9831/a000568
Gheflati, A., Adelnia, E., and Nadjarzadeh, A. (2019). The Clinical Effects of Purslane (Portulaca Oleracea) Seeds on Metabolic Profiles in Patients with Nonalcoholic Fatty Liver Disease: A Randomized Controlled Clinical Trial. Phytother Res. 33 (5), 1501–1509. doi:10.1002/ptr.6342
Goh, Z. H., Tee, J. K., and Ho, H. K. (2020). An Evaluation of the In Vitro Roles and Mechanisms of Silibinin in Reducing Pyrazinamide- and Isoniazid-Induced Hepatocellular Damage. Int. J. Mol. Sci. 21 (10), 3714. doi:10.3390/ijms21103714
Gong, L., Zhou, H., Wang, C., He, L., Guo, C., Peng, C., et al. (2021). Hepatoprotective Effect of Forsythiaside a Against Acetaminophen-Induced Liver Injury in Zebrafish: Coupling Network Pharmacology with Biochemical Pharmacology. J. Ethnopharmacol 271, 113890. doi:10.1016/j.jep.2021.113890
Gu, M., Zhang, S., Zhao, Y., Huang, J., Wang, Y., Li, Y., et al. (2017). Cycloastragenol Improves Hepatic Steatosis by Activating Farnesoid X Receptor Signalling. Pharmacol. Res. 121, 22–32. doi:10.1016/j.phrs.2017.04.021
Gu, X., and Manautou, J. E. (2012). Molecular Mechanisms Underlying Chemical Liver Injury. Expert Rev. Mol. Med. 14, e4. doi:10.1017/S1462399411002110
Gündüz, E., Dursun, R., Zengin, Y., İçer, M., Durgun, H. M., Kanıcı, A., et al. (2015). Lycium Barbarum Extract Provides Effective protection Against Paracetamol-Induced Acute Hepatotoxicity in Rats. Int. J. Clin. Exp. Med. 8 (5), 7898–7905.
Guo, S., Wang, G., and Yang, Z. (2021). Ligustilide Alleviates the Insulin Resistance, Lipid Accumulation, and Pathological Injury with Elevated Phosphorylated AMPK Level in Rats with Diabetes Mellitus. J. Recept Signal. Transduct Res. 41 (1), 85–92. doi:10.1080/10799893.2020.1789877
Guoyin, Z., Hao, P., Min, L., Wei, G., Zhe, C., and Changquan, L. (20172017). Antihepatocarcinoma Effect of Portulaca Oleracea L. In Mice by PI3K/Akt/mTOR and Nrf2/HO-1/nf-Κb Pathway. Evid. Based Complement. Alternat Med. 2017, 8231358. doi:10.1155/2017/8231358
Gupta, V. K., Siddiqi, N. J., Ojha, A. K., and Sharma, B. (2019). Hepatoprotective Effect of Aloe Vera Against Cartap- and Malathion-Induced Toxicity in Wistar Rats. J. Cel Physiol 234 (10), 18329–18343. doi:10.1002/jcp.28466
Hajighasem, A., Farzanegi, P., Mazaheri, Z., Naghizadeh, M., and Salehi, G. (2018). Effects of Resveratrol, Exercises and Their Combination on Farnesoid X Receptor, Liver X Receptor and Sirtuin 1 Gene Expression and Apoptosis in the Liver of Elderly Rats with Nonalcoholic Fatty Liver. PeerJ 6, e5522. doi:10.7717/peerj.5522
Han, B., Gao, Y., Wang, Y., Wang, L., Shang, Z., Wang, S., et al. (2016). Protective Effect of a Polysaccharide from Rhizoma Atractylodis Macrocephalae on Acute Liver Injury in Mice. Int. J. Biol. Macromol 87, 85–91. doi:10.1016/j.ijbiomac.2016.01.086
Han, B., Kim, S. M., Nam, G. E., Kim, S. H., Park, S. J., Park, Y. K., et al. (2020). A Randomized, Double-Blind, Placebo-Controlled, Multi-Centered Clinical Study to Evaluate the Efficacy and Safety of Artemisia Annua L. Extract for Improvement of Liver Function. Clin. Nutr. Res. 9 (4), 258–270. doi:10.7762/cnr.2020.9.4.258
Han, C., Wei, Y., Wang, X., Ba, C., and Shi, W. (2019). Protective Effect of Salvia Miltiorrhiza Polysaccharides on Liver Injury in Chickens. Poult. Sci. 98 (9), 3496–3503. doi:10.3382/ps/pez153
Hasan, I. H., El-Desouky, M. A., Hozayen, W. G., and Abd el Aziz, G. M. (2016). Protective Effect of Zingiber Officinale Against CCl4-Induced Liver Fibrosis Is Mediated Through Downregulating the TGF-β1/Smad3 and NF-ĸb/iĸb Pathways. Pharmacology 97 (1-2), 1–9. doi:10.1159/000441229
He, Y., and Liu, Y. (2021). Research Progress of Intestinal Bacterial Overgrowth in Patients with Liver Cirrhosis. J. integrated Chin. West. Med. Liver Dis. 31 (03), 286–288.
Heiss, E. H., Schachner, D., Zimmermann, K., and Dirsch, V. M. (2013). Glucose Availability Is a Decisive Factor for Nrf2-Mediated Gene Expression. Redox Biol. 1, 359–365. doi:10.1016/j.redox.2013.06.001
Hernandez-Gea, V., and Friedman, S. L. (2011). Pathogenesis of Liver Fibrosis. Annu. Rev. Pathol. 6, 425–456. doi:10.1146/annurev-pathol-011110-130246
Hesketh, T., and Zhu, W. X. (1997). Health in China. Traditional Chinese Medicine: One Country, Two Systems. BMJ 315 (7100), 115–117. doi:10.1136/bmj.315.7100.115
Ho, C., Gao, Y., Zheng, D., Liu, Y., Shan, S., Fang, B., et al. (2019). Alisol A Attenuates High-Fat-Diet-Induced Obesity and Metabolic Disorders via the AMPK/ACC/SREBP-1c Pathway. J. Cel Mol Med 23 (8), 5108–5118. doi:10.1111/jcmm.14380
Ho, C. Y., Cheng, Y. T., Chau, C. F., and Yen, G. C. (2012). Effect of Diallyl Sulfide on In Vitro and In Vivo Nrf2-Mediated Pulmonic Antioxidant Enzyme Expression via Activation ERK/p38 Signaling Pathway. J. Agric. Food Chem. 60 (1), 100–107. doi:10.1021/jf203800d
Holt, M., and Ju, C. (2010). “Drug-induced Liver Injury,” in Handb Exp Pharmacol. Editor J. E. Barrett (New York, NY: Springer), 196.
Hosny, S., Sahyon, H., Youssef, M., and Negm, A. (2021). Oleanolic Acid Suppressed DMBA-Induced Liver Carcinogenesis Through Induction of Mitochondrial-Mediated Apoptosis and Autophagy. Nutr. Cancer 73 (6), 968–982. doi:10.1080/01635581.2020.1776887
Hu, B., Gongji, G., Ta, N., and Wuli, J. (2019). Research Progress of Alcoholic Liver Disease. J. inner mongolia Univ. nationalities 34 (06), 535–538.
Hu, J., and Liu, K. (2017). Complete and Incomplete Hepatitis B Virus Particles: Formation, Function, and Application. Viruses 9 (3), 56. doi:10.3390/v9030056
Hu, N., Guo, C., Dai, X., Wang, C., Gong, L., Yu, L., et al. (2020a). Forsythiae Fructuse Water Extract Attenuates Liver Fibrosis via TLR4/MyD88/NF-Κb and TGF-Β/smads Signaling Pathways. J. Ethnopharmacol 262, 113275. doi:10.1016/j.jep.2020.113275
Hu, N., Wang, C., Dai, X., Zhou, M., Gong, L., Yu, L., et al. (2020b). Phillygenin Inhibits LPS-Induced Activation and Inflammation of LX2 Cells by TLR4/MyD88/NF-Κb Signaling Pathway. J. Ethnopharmacol 248, 112361. doi:10.1016/j.jep.2019.112361
Hu, Y., Bi, X., Zhao, P., Zheng, H., and Huang, X. (2015). Cytotoxic Activities, SAR and Anti-invasion Effects of Butylphthalide Derivatives on Human Hepatocellular Carcinoma SMMC7721 Cells. Molecules 20 (11), 20312–20319. doi:10.3390/molecules201119699
Huang, L., Li, Y., Pan, H., Lu, Y., Zhou, X., and Shi, F. (2020). Cortex Dictamni-Induced Liver Injury in Mice: The Role of P450-Mediated Metabolic Activation of Furanoids. Toxicol. Lett. 330, 41–52. doi:10.1016/j.toxlet.2020.05.004
Huang, W. H., Liao, W. R., and Sun, R. X. (2016). Astragalus Polysaccharide Induces the Apoptosis of Human Hepatocellular Carcinoma Cells by Decreasing the Expression of Notch1. Int. J. Mol. Med. 38 (2), 551–557. doi:10.3892/ijmm.2016.2632
Huang, Y. C., Tsay, H. J., Lu, M. K., Lin, C. H., Yeh, C. W., Liu, H. K., et al. (2017). Astragalus Membranaceus-Polysaccharides Ameliorates Obesity, Hepatic Steatosis, Neuroinflammation and Cognition Impairment without Affecting Amyloid Deposition in Metabolically Stressed APPswe/PS1dE9 Mice. Int. J. Mol. Sci. 18 (12), 2746. doi:10.3390/ijms18122746
Hung, T. C., Jassey, A., Lin, C. J., Liu, C. H., Lin, C. C., Yen, M. H., et al. (2018). Methanolic Extract of Rhizoma Coptidis Inhibits the Early Viral Entry Steps of Hepatitis C Virus Infection. Viruses 10 (12), 669. doi:10.3390/v10120669
Jang, E., Kim, S. Y., Lee, N. R., Yi, C. M., Hong, D. R., Lee, W. S., et al. (2017). Evaluation of Antitumor Activity of Artemisia Capillaris Extract Against Hepatocellular Carcinoma Through the Inhibition of IL-6/STAT3 Signaling Axis. Oncol. Rep. 37 (1), 526–532. doi:10.3892/or.2016.5283
Jang, M. K., Yun, Y. R., Kim, S. H., Kim, J. H., and Jung, M. H. (2016). Protective Effect of Gomisin N Against Endoplasmic Reticulum Stress-Induced Hepatic Steatosis. Biol. Pharm. Bull. 39 (5), 832–838. doi:10.1248/bpb.b15-01020
Jarret, A., McFarland, A. P., Horner, S. M., Kell, A., Schwerk, J., Hong, M., et al. (2016). Hepatitis-C-virus-induced microRNAs Dampen Interferon-Mediated Antiviral Signaling. Nat. Med. 22 (12), 1475–1481. doi:10.1038/nm.4211
Jemal, A., Bray, F., Center, M. M., Ferlay, J., Ward, E., and Forman, D. (2011). Global Cancer Statistics. CA Cancer J. Clin. 61 (2), 69–90. doi:10.3322/caac.20107
Jia, R., Gu, Z., He, Q., Du, J., Cao, L., Jeney, G., et al. (2019). Anti-oxidative, Anti-inflammatory and Hepatoprotective Effects of Radix Bupleuri Extract Against Oxidative Damage in Tilapia (Oreochromis niloticus) via Nrf2 and TLRs Signaling Pathway. Fish. Shellfish Immunol. 93, 395–405. doi:10.1016/j.fsi.2019.07.080
Jiang, P., Zhang, X., Huang, Y., Cheng, N., and Ma, Y. (2017a). Hepatotoxicity Induced by Sophora Flavescens and Hepatic Accumulation of Kurarinone, a Major Hepatotoxic Constituent of Sophora Flavescens in Rats. Molecules 22 (11), 1809. doi:10.3390/molecules22111809
Jiang, Y., Fan, X., Wang, Y., Chen, P., Zeng, H., Tan, H., et al. (2015). Schisandrol B Protects Against Acetaminophen-Induced Hepatotoxicity by Inhibition of CYP-Mediated Bioactivation and Regulation of Liver Regeneration. Toxicol. Sci. 143 (1), 107–115. doi:10.1093/toxsci/kfu216
Jiang, Y., Zhang, L., and Rupasinghe, H. P. (2017b). Antiproliferative Effects of Extracts from Salvia Officinalis L. And Saliva Miltiorrhiza Bunge on Hepatocellular Carcinoma Cells. Biomed. Pharmacother. 85, 57–67. doi:10.1016/j.biopha.2016.11.113
Jin, H., Lian, N., Bian, M., Zhang, C., Chen, X., Shao, J., et al. (2018). Oroxylin A Prevents Alcohol-Induced Hepatic Steatosis Through Inhibition of Hypoxia Inducible Factor 1alpha. Chem. Biol. Interact 285, 14–20. doi:10.1016/j.cbi.2018.02.025
Jin, H., Sakaida, I., Tsuchiya, M., and Okita, K. (2005). Herbal Medicine Rhei Rhizome Prevents Liver Fibrosis in Rat Liver Cirrhosis Induced by a Choline-Deficient L-Amino Acid-Defined Diet. Life Sci. 76 (24), 2805–2816. doi:10.1016/j.lfs.2004.09.041
Jin, Q., Jiang, S., Wu, Y. L., Bai, T., Yang, Y., Jin, X., et al. (2014). Hepatoprotective Effect of Cryptotanshinone from Salvia Miltiorrhiza in D-Galactosamine/lipopolysaccharide-Induced Fulminant Hepatic Failure. Phytomedicine 21 (2), 141–147. doi:10.1016/j.phymed.2013.07.016
Jindal, R., Sinha, R., and Brar, P. (2019). Evaluating the Protective Efficacy of Silybum marianum Against Deltamethrin Induced Hepatotoxicity in Piscine Model. Environ. Toxicol. Pharmacol. 66, 62–68. doi:10.1016/j.etap.2018.12.014
Jung, J. C., Lee, Y. H., Kim, S. H., Kim, K. J., Kim, K. M., Oh, S., et al. (2016). Hepatoprotective Effect of Licorice, the Root of Glycyrrhiza Uralensis Fischer, in Alcohol-Induced Fatty Liver Disease. BMC Complement. Altern. Med. 16, 19. doi:10.1186/s12906-016-0997-0
Jung, K. H., Rumman, M., Yan, H., Cheon, M. J., Choi, J. G., Jin, X., et al. (2018). An Ethyl Acetate Fraction of Artemisia Capillaris (ACE-63) Induced Apoptosis and Anti-angiogenesis via Inhibition of PI3K/AKT Signaling in Hepatocellular Carcinoma. Phytother Res. 32 (10), 2034–2046. doi:10.1002/ptr.6135
Jung, S., Son, H., Hwang, C. E., Cho, K. M., Park, S. W., Kim, H., et al. (2020). The Root of Polygonum Multiflorum Thunb. Alleviates Non-alcoholic Steatosis and Insulin Resistance in High Fat Diet-Fed Mice. Nutrients 12 (8), 2353. doi:10.3390/nu12082353
Kalyanaraman, B. (2013). Teaching the Basics of Redox Biology to Medical and Graduate Students: Oxidants, Antioxidants and Disease Mechanisms. Redox Biol. 1, 244–257. doi:10.1016/j.redox.2013.01.014
Kandeil, M. A., Hashem, R. M., Mahmoud, M. O., Hetta, M. H., and Tohamy, M. A. (2019). Zingiber Officinale Extract and omega-3 Fatty Acids Ameliorate Endoplasmic Reticulum Stress in a Nonalcoholic Fatty Liver Rat Model. J. Food Biochem. 43 (12), e13076. doi:10.1111/jfbc.13076
Ke, Z., Zhao, Y., Tan, S., Chen, H., Li, Y., Zhou, Z., et al. (2020). Citrus Reticulata Blanco Peel Extract Ameliorates Hepatic Steatosis, Oxidative Stress and Inflammation in HF and MCD Diet-Induced NASH C57BL/6 J Mice. J. Nutr. Biochem. 83, 108426. doi:10.1016/j.jnutbio.2020.108426
Kim, H. G., Lee, S. B., Lee, J. S., Kim, W. Y., Choi, S. H., and Son, C. G. (2017a). Artemisia Iwayomogi Plus Curcuma Longa Synergistically Ameliorates Nonalcoholic Steatohepatitis in HepG2 Cells. Evid. Based Complement. Alternat Med. 2017, 4390636. doi:10.1155/2017/4390636
Kim, H. J., Park, K. K., Chung, W. Y., Lee, S. K., and Kim, K. R. (2017b). Protective Effect of White-fleshed Peach (Prunus Persica (L.) Batsch) on Chronic Nicotine-Induced Toxicity. J. Cancer Prev. 22 (1), 22–32. doi:10.15430/JCP.2017.22.1.22
Kim, H. Y., Kim, J. K., Choi, J. H., Jung, J. Y., Oh, W. Y., Kim, D. C., et al. (2010). Hepatoprotective Effect of Pinoresinol on Carbon Tetrachloride-Induced Hepatic Damage in Mice. J. Pharmacol. Sci. 112 (1), 105–112. doi:10.1254/jphs.09234fp
Kim, J., Jung, K. H., Yan, H. H., Cheon, M. J., Kang, S., Jin, X., et al. (2018). Artemisia Capillaris Leaves Inhibit Cell Proliferation and Induce Apoptosis in Hepatocellular Carcinoma. BMC Complement. Altern. Med. 18 (1), 147. doi:10.1186/s12906-018-2217-6
Kim, J., Kim, C. S., Jo, K., Lee, I. S., Kim, J. H., and Kim, J. S. (2020a). POCU1b, the n-Butanol Soluble Fraction of Polygoni Cuspidati Rhizoma et Radix, Attenuates Obesity, Non-Alcoholic Fatty Liver, and Insulin Resistance via Inhibitions of Pancreatic Lipase, cAMP-Dependent PDE Activity, AMPK Activation, and SOCS-3 Suppression. Nutrients 12 (12), 3612. doi:10.3390/nu12123612
Kim, T., Song, B., Cho, K. S., and Lee, I. S. (2020b). Therapeutic Potential of Volatile Terpenes and Terpenoids from Forests for Inflammatory Diseases. Int. J. Mol. Sci. 21 (6), 2187. doi:10.3390/ijms21062187
Klaikeaw, N., Wongphoom, J., Werawatganon, D., Chayanupatkul, M., and Siriviriyakul, P. (2020). Anti-inflammatory and Anti-oxidant Effects of Aloe Vera in Rats with Non-alcoholic Steatohepatitis. World J. Hepatol. 12 (7), 363–377. doi:10.4254/wjh.v12.i7.363
Kolodziejczyk, A. A., Zheng, D., Shibolet, O., and Elinav, E. (2019). The Role of the Microbiome in NAFLD and NASH. EMBO Mol. Med. 11 (2), e9302. doi:10.15252/emmm.201809302
Koneru, M., Sahu, B. D., Gudem, S., Kuncha, M., Ravuri, H. G., Kumar, J. M., et al. (2017). Polydatin Alleviates Alcohol-Induced Acute Liver Injury in Mice: Relevance of Matrix Metalloproteinases (MMPs) and Hepatic Antioxidants. Phytomedicine 27, 23–32. doi:10.1016/j.phymed.2017.01.013
Kong, Z. L., Kuo, H. P., Johnson, A., Wu, L. C., and Chang, K. L. B. (2019). Curcumin-Loaded Mesoporous Silica Nanoparticles Markedly Enhanced Cytotoxicity in Hepatocellular Carcinoma Cells. Int. J. Mol. Sci. 20 (12), 2918. doi:10.3390/ijms20122918
Kuo, C. Y., Chiu, V., Hsieh, P. C., Huang, C. Y., Huang, S. J., Tzeng, I. S., et al. (2020). Chrysophanol Attenuates Hepatitis B Virus X Protein-Induced Hepatic Stellate Cell Fibrosis by Regulating Endoplasmic Reticulum Stress and Ferroptosis. J. Pharmacol. Sci. 144 (3), 172–182. doi:10.1016/j.jphs.2020.07.014
Le, J., Fu, Y., Han, Q., Ma, Y., Ji, H., Wei, X., et al. (2020). Transcriptome Analysis of the Inhibitory Effect of Sennoside A on the Metastasis of Hepatocellular Carcinoma Cells. Front. Pharmacol. 11, 566099. doi:10.3389/fphar.2020.566099
Lee, C. K., Park, K. K., Hwang, J. K., Lee, S. K., and Chung, W. Y. (2008). The Pericarp Extract of Prunus Persica Attenuates Chemotherapy-Induced Acute Nephrotoxicity and Hepatotoxicity in Mice. J. Med. Food 11 (2), 302–306. doi:10.1089/jmf.2007.545
Lee, E. H., Baek, S. Y., Park, J. Y., and Kim, Y. W. (2020). Emodin in Rheum Undulatum Inhibits Oxidative Stress in the Liver via AMPK with Hippo/Yap Signalling Pathway. Pharm. Biol. 58 (1), 333–341. doi:10.1080/13880209.2020.1750658
Lee, G. H., Lee, H. Y., Choi, M. K., Chung, H. W., Kim, S. W., and Chae, H. J. (2017a). Protective Effect of Curcuma Longa L. Extract on CCl4-Induced Acute Hepatic Stress. BMC Res. Notes 10 (1), 77. doi:10.1186/s13104-017-2409-z
Lee, H. Y., Kim, S. W., Lee, G. H., Choi, M. K., Chung, H. W., Lee, Y. C., et al. (2017b). Curcumin and Curcuma Longa L. Extract Ameliorate Lipid Accumulation Through the Regulation of the Endoplasmic Reticulum Redox and ER Stress. Sci. Rep. 7 (1), 6513. doi:10.1038/s41598-017-06872-y
Lee, W., Koo, H. R., Choi, Y. J., Choi, J. G., Oh, M. S., Jin, X., et al. (2019). Z-ligustilide and N-Butylidenephthalide Isolated from the Aerial Parts of Angelica Tenuissima Inhibit Lipid Accumulation In Vitro and In Vivo. Planta Med. 85 (9-10), 719–728. doi:10.1055/a-0901-1307
Leung, T. M., and Nieto, N. (2013). CYP2E1 and Oxidant Stress in Alcoholic and Non-alcoholic Fatty Liver Disease. J. Hepatol. 58 (2), 395–398. doi:10.1016/j.jhep.2012.08.018
Li, C. H., Tang, S. C., Wong, C. H., Wang, Y., Jiang, J. D., and Chen, Y. (2018a). Berberine Induces miR-373 Expression in Hepatocytes to Inactivate Hepatic Steatosis Associated AKT-S6 Kinase Pathway. Eur. J. Pharmacol. 825, 107–118. doi:10.1016/j.ejphar.2018.02.035
Li, D. S., Huang, Q. F., Guan, L. H., Zhang, H. Z., Li, X., Fu, K. L., et al. (2020a). Targeted Bile Acids and Gut Microbiome Profiles Reveal the Hepato-Protective Effect of WZ Tablet (Schisandra Sphenanthera Extract) Against LCA-Induced Cholestasis. Chin. J. Nat. Med. 18 (3), 211–218. doi:10.1016/S1875-5364(20)30023-6
Li, J., Duan, B., Guo, Y., Zhou, R., Sun, J., Bie, B., et al. (2018b). Baicalein Sensitizes Hepatocellular Carcinoma Cells to 5-FU and Epirubicin by Activating Apoptosis and Ameliorating P-Glycoprotein Activity. Biomed. Pharmacother. 98, 806–812. doi:10.1016/j.biopha.2018.01.002
Li, J. P., Yuan, Y., Zhang, W. Y., Jiang, Z., Hu, T. J., Feng, Y. T., et al. (2019a). Effect of Radix Isatidis Polysaccharide on Alleviating Insulin Resistance in Type 2 Diabetes Mellitus Cells and Rats. J. Pharm. Pharmacol. 71 (2), 220–229. doi:10.1111/jphp.13023
Li, J., Zhang, L., Gao, H., Song, X., and Wu, X. (2014). Progress in Pathogenesis and Treatment of Alcoholic Cirrhosis. Med. innovation China 11 (35), 147–149.
Li, Q., Li, H. J., Xu, T., Du, H., Huan Gang, C. L., Fan, G., et al. (2018c). Natural Medicines Used in the Traditional Tibetan Medical System for the Treatment of Liver Diseases. Front. Pharmacol. 9, 29. doi:10.3389/fphar.2018.00029
Li, S., Qin, Q., Luo, D., Pan, W., Wei, Y., Xu, Y., et al. (2020b). Hesperidin Ameliorates Liver Ischemia/reperfusion Injury via Activation of the Akt Pathway. Mol. Med. Rep. 22 (6), 4519–4530. doi:10.3892/mmr.2020.11561
Li, S., Tan, H. Y., Wang, N., Zhang, Z. J., Lao, L., Wong, C. W., et al. (2015). The Role of Oxidative Stress and Antioxidants in Liver Diseases. Int. J. Mol. Sci. 16 (11), 26087–26124. doi:10.3390/ijms161125942
Li, S., Wang, Q., Tao, Y., and Liu, C. (2016). Swertiamarin Attenuates Experimental Rat Hepatic Fibrosis by Suppressing Angiotensin II-Angiotensin Type 1 Receptor-Extracellular Signal-Regulated Kinase Signaling. J. Pharmacol. Exp. Ther. 359 (2), 247–255. doi:10.1124/jpet.116.234179
Li, T., and Chiang, J. Y. (2014). Bile Acid Signaling in Metabolic Disease and Drug Therapy. Pharmacol. Rev. 66 (4), 948–983. doi:10.1124/pr.113.008201
Li, X., Jin, Q., Yao, Q., Xu, B., Li, L., Zhang, S., et al. (2018d). The Flavonoid Quercetin Ameliorates Liver Inflammation and Fibrosis by Regulating Hepatic Macrophages Activation and Polarization in Mice. Front. Pharmacol. 9, 72. doi:10.3389/fphar.2018.00072
Li, X., Li, X., Lu, J., Huang, Y., Lv, L., Luan, Y., et al. (2017). Saikosaponins Induced Hepatotoxicity in Mice via Lipid Metabolism Dysregulation and Oxidative Stress: A Proteomic Study. BMC Complement. Altern. Med. 17 (1), 219. doi:10.1186/s12906-017-1733-0
Li, X., Sun, R., and Liu, R. (2019b). Natural Products in Licorice for the Therapy of Liver Diseases: Progress and Future Opportunities. Pharmacol. Res. 144, 210–226. doi:10.1016/j.phrs.2019.04.025
Li, X., Zhang, Y., Jin, Q., Xia, K. L., Jiang, M., Cui, B. W., et al. (2018e). Liver Kinase B1/AMP-Activated Protein Kinase-Mediated Regulation by Gentiopicroside Ameliorates P2X7 Receptor-dependent Alcoholic Hepatosteatosis. Br. J. Pharmacol. 175 (9), 1451–1470. doi:10.1111/bph.14145
Li, Y., Shen, F., Bao, Y., Chen, D., and Lu, H. (2019c). Apoptotic Effects of Rhein Through the Mitochondrial Pathways, Two Death Receptor Pathways, and Reducing Autophagy in Human Liver L02 Cells. Environ. Toxicol. 34 (12), 1292–1302. doi:10.1002/tox.22830
Li, Y., Ye, Y., and Chen, H. (2018g). Astragaloside IV Inhibits Cell Migration and Viability of Hepatocellular Carcinoma Cells via Suppressing Long Noncoding RNA ATB. Biomed. Pharmacother. 99, 134–141. doi:10.1016/j.biopha.2017.12.108
Li, Y. C., Qiao, J. Y., Wang, B. Y., Bai, M., Shen, J. D., and Cheng, Y. X. (2018f). Paeoniflorin Ameliorates Fructose-Induced Insulin Resistance and Hepatic Steatosis by Activating LKB1/AMPK and AKT Pathways. Nutrients 10 (8), 1024. doi:10.3390/nu10081024
Liang, W., Zhang, D., Kang, J., Meng, X., Yang, J., Yang, L., et al. (2018). Protective Effects of Rutin on Liver Injury in Type 2 Diabetic Db/db Mice. Biomed. Pharmacother. 107, 721–728. doi:10.1016/j.biopha.2018.08.046
Liao, C. C., Day, Y. J., Lee, H. C., Liou, J. T., Chou, A. H., and Liu, F. C. (2017). ERK Signaling Pathway Plays a Key Role in Baicalin Protection Against Acetaminophen-Induced Liver Injury. Am. J. Chin. Med. 45 (1), 105–121. doi:10.1142/S0192415X17500082
Liao, X., Bu, Y., and Jia, Q. (2020). Traditional Chinese Medicine as Supportive Care for the Management of Liver Cancer: Past, Present, and Future. Genes Dis. 7 (3), 370–379. doi:10.1016/j.gendis.2019.10.016
Lim, J. Y., Lee, J. H., Yun, D. H., Lee, Y. M., and Kim, D. K. (2021). Inhibitory Effects of Nodakenin on Inflammation and Cell Death in Lipopolysaccharide-Induced Liver Injury Mice. Phytomedicine 81, 153411. doi:10.1016/j.phymed.2020.153411
Lin, C. C., Ng, L. T., Hsu, F. F., Shieh, D. E., and Chiang, L. C. (2004). Cytotoxic Effects of Coptis Chinensis and Epimedium Sagittatum Extracts and Their Major Constituents (Berberine, Coptisine and Icariin) on Hepatoma and Leukaemia Cell Growth. Clin. Exp. Pharmacol. Physiol. 31 (1-2), 65–69. doi:10.1111/j.1440-1681.2004.03951.x
Lin, E. Y., Chagnaadorj, A., Huang, S. J., Wang, C. C., Chiang, Y. H., and Cheng, C. W. (2018a2018). Hepatoprotective Activity of the Ethanolic Extract of Polygonum Multiflorum Thunb. Against Oxidative Stress-Induced Liver Injury. Evid. Based Complement. Alternat Med. 2018, 4130307. doi:10.1155/2018/4130307
Lin, W., Zhong, M., Yin, H., Chen, Y., Cao, Q., Wang, C., et al. (2016). Emodin Induces Hepatocellular Carcinoma Cell Apoptosis Through MAPK and PI3K/AKT Signaling Pathways In Vitro and In Vivo. Oncol. Rep. 36 (2), 961–967. doi:10.3892/or.2016.4861
Lin, Y., Kuang, Y., Li, K., Wang, S., Ji, S., Chen, K., et al. (2017). Nrf2 Activators from Glycyrrhiza Inflata and Their Hepatoprotective Activities Against CCl4-Induced Liver Injury in Mice. Bioorg. Med. Chem. 25 (20), 5522–5530. doi:10.1016/j.bmc.2017.08.018
Lin, Y. N., Chang, H. Y., Wang, C. C. N., Chu, F. Y., Shen, H. Y., Chen, C. J., et al. (2018b). Oleanolic Acid Inhibits Liver X Receptor Alpha and Pregnane X Receptor to Attenuate Ligand-Induced Lipogenesis. J. Agric. Food Chem. 66 (42), 10964–10976. doi:10.1021/acs.jafc.8b03372
Liou, C. J., Lee, Y. K., Ting, N. C., Chen, Y. L., Shen, S. C., Wu, S. J., et al. (2019). Protective Effects of Licochalcone A Ameliorates Obesity and Non-alcoholic Fatty Liver Disease via Promotion of the Sirt-1/AMPK Pathway in Mice Fed a High-Fat Diet. Cells 8 (5), 447. doi:10.3390/cells8050447
Liu, B., Deng, X., Jiang, Q., Li, G., Zhang, J., Zhang, N., et al. (2020a). Scoparone Improves Hepatic Inflammation and Autophagy in Mice with Nonalcoholic Steatohepatitis by Regulating the ROS/P38/Nrf2 axis and PI3K/AKT/mTOR Pathway in Macrophages. Biomed. Pharmacother. 125, 109895. doi:10.1016/j.biopha.2020.109895
Liu, C., Chen, J., Li, E., Fan, Q., Wang, D., Li, P., et al. (2015). The Comparison of Antioxidative and Hepatoprotective Activities of Codonopsis Pilosula Polysaccharide (CP) and Sulfated CP. Int. Immunopharmacol 24 (2), 299–305. doi:10.1016/j.intimp.2014.12.023
Liu, D. M., Yang, D., Zhou, C. Y., Wu, J. S., Zhang, G. L., Wang, P., et al. (2020b). Aloe-emodin Induces Hepatotoxicity by the Inhibition of Multidrug Resistance Protein 2. Phytomedicine 68, 153148. doi:10.1016/j.phymed.2019.153148
Liu, F., Zhang, J., Qian, J., Wu, G., and Ma, Z. (2018). Emodin Alleviates CCl4-induced L-iver F-ibrosis by S-uppressing E-pithelial-mesenchymal T-ransition and T-ransforming G-rowth F-actor-β1 in R-ats. Mol. Med. Rep. 18 (3), 3262–3270. doi:10.3892/mmr.2018.9324
Liu, N., Feng, J., Lu, X., Yao, Z., Liu, Q., Lv, Y., et al. (2019a). Isorhamnetin Inhibits Liver Fibrosis by Reducing Autophagy and Inhibiting Extracellular Matrix Formation via the TGF-β1/Smad3 and TGF-Β1/p38 MAPK Pathways. Mediators Inflamm. 2019, 6175091. doi:10.1155/2019/6175091
Liu, Q., Pan, R., Ding, L., Zhang, F., Hu, L., Ding, B., et al. (2017). Rutin Exhibits Hepatoprotective Effects in a Mouse Model of Non-alcoholic Fatty Liver Disease by Reducing Hepatic Lipid Levels and Mitigating Lipid-Induced Oxidative Injuries. Int. Immunopharmacol 49, 132–141. doi:10.1016/j.intimp.2017.05.026
Liu, R., Li, X., Huang, N., Fan, M., and Sun, R. (2020c). Toxicity of Traditional Chinese Medicine Herbal and Mineral Products. Adv. Pharmacol. 87, 301–346. doi:10.1016/bs.apha.2019.08.001
Liu, W., Li, S., Qu, Z., Luo, Y., Chen, R., Wei, S., et al. (2019b). Betulinic Acid Induces Autophagy-Mediated Apoptosis Through Suppression of the PI3K/AKT/mTOR Signaling Pathway and Inhibits Hepatocellular Carcinoma. Am. J. Transl Res. 11 (11), 6952–6964.
Liu, Y., Bi, Y., Mo, C., Zeng, T., Huang, S., Gao, L., et al. (2019c). Betulinic Acid Attenuates Liver Fibrosis by Inducing Autophagy via the Mitogen-Activated Protein Kinase/extracellular Signal-Regulated Kinase Pathway. J. Nat. Med. 73 (1), 179–189. doi:10.1007/s11418-018-1262-2
Llovet, J. M., Kelley, R. K., Villanueva, A., Singal, A. G., Pikarsky, E., Roayaie, S., et al. (2021). Hepatocellular Carcinoma. Nat. Rev. Dis. Primers 7 (1), 6. doi:10.1038/s41572-020-00240-3
López-Navarrete, G., Ramos-Martínez, E., Suárez-Álvarez, K., Aguirre-García, J., Ledezma-Soto, Y., León-Cabrera, S., et al. (2011). Th2-associated Alternative Kupffer Cell Activation Promotes Liver Fibrosis Without Inducing Local Inflammation. Int. J. Biol. Sci. 7 (9), 1273–1286. doi:10.7150/ijbs.7.1273
Lu, C., Xu, W., Shao, J., Zhang, F., Chen, A., and Zheng, S. (2017). Nrf2 Activation Is Required for Ligustrazine to Inhibit Hepatic Steatosis in Alcohol-Preferring Mice and Hepatocytes. Toxicol. Sci. 155 (2), 432–443. doi:10.1093/toxsci/kfw228
Lukefahr, A. L., McEvoy, S., Alfafara, C., and Funk, J. L. (2018). Drug-induced Autoimmune Hepatitis Associated with Turmeric Dietary Supplement Use. BMJ Case Rep. 2018, bcr2018224611. doi:10.1136/bcr-2018-224611
Luna, J. M., Scheel, T. K., Danino, T., Shaw, K. S., Mele, A., Fak, J. J., et al. (2015). Hepatitis C Virus RNA Functionally Sequesters miR-122. Cell 160 (6), 1099–1110. doi:10.1016/j.cell.2015.02.025
Lv, H., Xiao, Q., Zhou, J., Feng, H., Liu, G., and Ci, X. (2018). Licochalcone A Upregulates Nrf2 Antioxidant Pathway and Thereby Alleviates Acetaminophen-Induced Hepatotoxicity. Front. Pharmacol. 9, 147. doi:10.3389/fphar.2018.00147
Ma, B. X., Meng, X. S., Tong, J., Ge, L. L., Zhou, G., and Wang, Y. W. (2018a). Protective Effects of Coptis Chinensis Inflorescence Extract and Linarin Against Carbon Tetrachloride-Induced Damage in HepG2 Cells Through the MAPK/Keap1-Nrf2 Pathway. Food Funct. 9 (4), 2353–2361. doi:10.1039/c8fo00078f
Ma, P., Sun, C., Li, W., Deng, W., Adu-Frimpong, M., Yu, J., et al. (2020). Extraction and Structural Analysis of Angelica Sinensis Polysaccharide with Low Molecular Weight and its Lipid-Lowering Effect on Nonalcoholic Fatty Liver Disease. Food Sci. Nutr. 8 (7), 3212–3224. doi:10.1002/fsn3.1581
Ma, Q. (2013). Role of Nrf2 in Oxidative Stress and Toxicity. Annu. Rev. Pharmacol. Toxicol. 53, 401–426. doi:10.1146/annurev-pharmtox-011112-140320
Ma, X., Chi, Y. H., Niu, M., Zhu, Y., Zhao, Y. L., Chen, Z., et al. (2016). Metabolomics Coupled with Multivariate Data and Pathway Analysis on Potential Biomarkers in Cholestasis and Intervention Effect of Paeonia Lactiflora Pall. Front. Pharmacol. 7, 14. doi:10.3389/fphar.2016.00014
Ma, X., Wen, J. X., Gao, S. J., He, X., Li, P. Y., Yang, Y. X., et al. (2018b). Paeonia Lactiflora Pall. Regulates the NF-Κb-NLRP3 Inflammasome Pathway to Alleviate Cholestasis in Rats. J. Pharm. Pharmacol. 70 (12), 1675–1687. doi:10.1111/jphp.13008
Ma, X., Zhao, Y. L., Zhu, Y., Chen, Z., Wang, J. B., Li, R. Y., et al. (2015). Paeonia Lactiflora Pall. Protects Against ANIT-Induced Cholestasis by Activating Nrf2 via PI3K/Akt Signaling Pathway. Drug Des. Devel Ther. 9, 5061–5074. doi:10.2147/DDDT.S90030
Ma, X. Y., Zhang, M., Fang, G., Cheng, C. J., Wang, M. K., Han, Y. M., et al. (2021). Ursolic Acid Reduces Hepatocellular Apoptosis and Alleviates Alcohol-Induced Liver Injury via Irreversible Inhibition of CASP3 In Vivo. Acta Pharmacol. Sin 42 (7), 1101–1110. doi:10.1038/s41401-020-00534-y
Ma, Y., Chen, K., Lv, L., Wu, S., and Guo, Z. (2019). Ferulic Acid Ameliorates Nonalcoholic Fatty Liver Disease and Modulates the Gut Microbiota Composition in High-Fat Diet Fed ApoE-/- Mice. Biomed. Pharmacother. 113, 108753. doi:10.1016/j.biopha.2019.108753
Mahmoud, A. M., Hussein, O. E., Hozayen, W. G., Bin-Jumah, M., and Abd El-Twab, S. M. (2020). Ferulic Acid Prevents Oxidative Stress, Inflammation, and Liver Injury via Upregulation of Nrf2/HO-1 Signaling in Methotrexate-Induced Rats. Environ. Sci. Pollut. Res. Int. 27 (8), 7910–7921. doi:10.1007/s11356-019-07532-6
Mahmoud, M. F., Gamal, S., and El-Fayoumi, H. M. (2014). Limonin Attenuates Hepatocellular Injury Following Liver Ischemia and Reperfusion in Rats via Toll-like Receptor Dependent Pathway. Eur. J. Pharmacol. 740, 676–682. doi:10.1016/j.ejphar.2014.06.010
Manns, M. P., Buti, M., Gane, E., Pawlotsky, J. M., Razavi, H., Terrault, N., et al. (2017). Hepatitis C Virus Infection. Nat. Rev. Dis. Primers 3, 17006. doi:10.1038/nrdp.2017.6
Mantovani, A., Gatti, D., Zoppini, G., Lippi, G., Bonora, E., Byrne, C. D., et al. (2019). Association Between Nonalcoholic Fatty Liver Disease and Reduced Bone Mineral Density in Children: A Meta-Analysis. Hepatology 70 (3), 812–823. doi:10.1002/hep.30538
Marvie, P., Lisbonne, M., L'Helgoualc'h, A., Rauch, M., Turlin, B., Preisser, L., et al. (2010). Interleukin-33 Overexpression Is Associated with Liver Fibrosis in Mice and Humans. J. Cel Mol Med 14 (6B), 1726–1739. doi:10.1111/j.1582-4934.2009.00801.x
Medzhitov, R. (2008). Origin and Physiological Roles of Inflammation. Nature 454 (7203), 428–435. doi:10.1038/nature07201
Mello, T., Ceni, E., Surrenti, C., and Galli, A. (2008). Alcohol Induced Hepatic Fibrosis: Role of Acetaldehyde. Mol. Aspects Med. 29 (1-2), 17–21. doi:10.1016/j.mam.2007.10.001
Meng, Q., Chen, X., Wang, C., Liu, Q., Sun, H., Sun, P., et al. (2015). Protective Effects of Alisol B 23-acetate from Edible Botanical Rhizoma Alismatis Against Carbon Tetrachloride-Induced Hepatotoxicity in Mice. Food Funct. 6 (4), 1241–1250. doi:10.1039/c5fo00082c
Meng, Q., Duan, X. P., Wang, C. Y., Liu, Z. H., Sun, P. Y., Huo, X. K., et al. (2017). Alisol B 23-acetate Protects Against Non-alcoholic Steatohepatitis in Mice via Farnesoid X Receptor Activation. Acta Pharmacol. Sin 38 (1), 69–79. doi:10.1038/aps.2016.119
Meng, X. L., Zhu, Z. X., Lu, R. H., Li, S., Hu, W. P., Qin, C. B., et al. (2019). Regulation of Growth Performance and Lipid Metabolism in Juvenile Grass Carp (Ctenopharyngodon Idella) with Honeysuckle (Lonicera japonica) Extract. Fish. Physiol. Biochem. 45 (5), 1563–1573. doi:10.1007/s10695-019-00644-3
Messina, J. P., Humphreys, I., Flaxman, A., Brown, A., Cooke, G. S., Pybus, O. G., et al. (2015). Global Distribution and Prevalence of Hepatitis C Virus Genotypes. Hepatology 61 (1), 77–87. doi:10.1002/hep.27259
Mo, Z. Z., Lin, Z. X., Su, Z. R., Zheng, L., Li, H. L., Xie, J. H., et al. (2018). Angelica Sinensis Supercritical Fluid CO2 Extract Attenuates D-Galactose-Induced Liver and Kidney Impairment in Mice by Suppressing Oxidative Stress and Inflammation. J. Med. Food 21 (9), 887–898. doi:10.1089/jmf.2017.4061
Mo, Z. Z., Liu, Y. H., Li, C. L., Xu, L. Q., Wen, L. L., Xian, Y. F., et al. (2017). Protective Effect of SFE-CO2 of Ligusticum Chuanxiong Hort Against D-Galactose-Induced Injury in the Mouse Liver and Kidney. Rejuvenation Res. 20 (3), 231–243. doi:10.1089/rej.2016.1870
Mo'men, Y. S., Hussein, R. M., and Kandeil, M. A. (2019). Involvement of PI3K/Akt Pathway in the Protective Effect of Hesperidin Against a Chemically Induced Liver Cancer in Rats. J. Biochem. Mol. Toxicol. 33 (6), e22305. doi:10.1002/jbt.22305
Moghadam, A. R., Tutunchi, S., Namvaran-Abbas-Abad, A., Yazdi, M., Bonyadi, F., Mohajeri, D., et al. (2015). Pre-administration of Turmeric Prevents Methotrexate-Induced Liver Toxicity and Oxidative Stress. BMC Complement. Altern. Med. 15, 246. doi:10.1186/s12906-015-0773-6
Mu, M., Zuo, S., Wu, R. M., Deng, K. S., Lu, S., Zhu, J. J., et al. (2018). Ferulic Acid Attenuates Liver Fibrosis and Hepatic Stellate Cell Activation via Inhibition of TGF-β/Smad Signaling Pathway. Drug Des. Devel Ther. 12, 4107–4115. doi:10.2147/DDDT.S186726
Mu, Q., Wang, H., Tong, L., Fang, Q., Xiang, M., Han, L., et al. (2020). Betulinic Acid Improves Nonalcoholic Fatty Liver Disease Through YY1/FAS Signaling Pathway. FASEB J. 34 (9), 13033–13048. doi:10.1096/fj.202000546R
Nagappan, A., Jung, D. Y., Kim, J. H., Lee, H., and Jung, M. H. (2018). Gomisin N Alleviates Ethanol-Induced Liver Injury Through Ameliorating Lipid Metabolism and Oxidative Stress. Int. J. Mol. Sci. 19 (9), 2601. doi:10.3390/ijms19092601
Nagappan, A., Kim, J. H., Jung, D. Y., and Jung, M. H. (2019). Cryptotanshinone from the Salvia Miltiorrhiza Bunge Attenuates Ethanol-Induced Liver Injury by Activation of AMPK/SIRT1 and Nrf2 Signaling Pathways. Int. J. Mol. Sci. 21 (1), 265. doi:10.3390/ijms21010265
Nakamura, T., Naguro, I., and Ichijo, H. (2019). Iron Homeostasis and Iron-Regulated ROS in Cell Death, Senescence and Human Diseases. Biochim. Biophys. Acta Gen. Subj 1863 (9), 1398–1409. doi:10.1016/j.bbagen.2019.06.010
Navarro, V. J., Belle, S. H., D'Amato, M., Adfhal, N., Brunt, E. M., Fried, M. W., et al. (2019). Silymarin in Non-cirrhotics with Non-alcoholic Steatohepatitis: A Randomized, Double-Blind, Placebo Controlled Trial. PLoS One 14 (9), e0221683. doi:10.1371/journal.pone.0221683
Neyrinck, A. M., Etxeberria, U., Taminiau, B., Daube, G., Van Hul, M., Everard, A., et al. (2017). Rhubarb Extract Prevents Hepatic Inflammation Induced by Acute Alcohol Intake, an Effect Related to the Modulation of the Gut Microbiota. Mol. Nutr. Food Res. 61 (1), 1–12. doi:10.1002/mnfr.201500899
Nguyen, P., Leray, V., Diez, M., Serisier, S., Le Bloc'h, J., Siliart, B., et al. (2008). Liver Lipid Metabolism. J. Anim. Physiol. Anim. Nutr. (Berl) 92 (3), 272–283. doi:10.1111/j.1439-0396.2007.00752.x
Ning, C., Gao, X., Wang, C., Huo, X., Liu, Z., Sun, H., et al. (2018). Hepatoprotective Effect of Ginsenoside Rg1 from Panax Ginseng on Carbon Tetrachloride-Induced Acute Liver Injury by Activating Nrf2 Signaling Pathway in Mice. Environ. Toxicol. 33 (10), 1050–1060. doi:10.1002/tox.22616
Nouri-Vaskeh, M., Afshan, H., Malek Mahdavi, A., Alizadeh, L., Fan, X., and Zarei, M. (2020a). Curcumin Ameliorates Health-Related Quality of Life in Patients with Liver Cirrhosis: A Randomized, Double-Blind Placebo-Controlled Trial. Complement. Ther. Med. 49, 102351. doi:10.1016/j.ctim.2020.102351
Nouri-Vaskeh, M., Malek Mahdavi, A., Afshan, H., Alizadeh, L., and Zarei, M. (2020b). Effect of Curcumin Supplementation on Disease Severity in Patients with Liver Cirrhosis: A Randomized Controlled Trial. Phytother Res. 34 (6), 1446–1454. doi:10.1002/ptr.6620
Okubo, S., Ohta, T., Shoyama, Y., and Uto, T. (2020). Arctigenin Suppresses Cell Proliferation via Autophagy Inhibition in Hepatocellular Carcinoma Cells. J. Nat. Med. 74 (3), 525–532. doi:10.1007/s11418-020-01396-8
Onyekwere, C. A., Ogbera, A. O., Samaila, A. A., Balogun, B. O., and Abdulkareem, F. B. (2015). Nonalcoholic Fatty Liver Disease: Synopsis of Current Developments. Niger. J. Clin. Pract. 18 (6), 703–712. doi:10.4103/1119-3077.163288
Ou, Q., Weng, Y., Wang, S., Zhao, Y., Zhang, F., Zhou, J., et al. (2018). Silybin Alleviates Hepatic Steatosis and Fibrosis in NASH Mice by Inhibiting Oxidative Stress and Involvement with the Nf-Κb Pathway. Dig. Dis. Sci. 63 (12), 3398–3408. doi:10.1007/s10620-018-5268-0
Padda, M. S., Sanchez, M., Akhtar, A. J., and Boyer, J. L. (2011). Drug-induced Cholestasis. Hepatology 53 (4), 1377–1387. doi:10.1002/hep.24229
Pan, C. W., Zhou, G. Y., Chen, W. L., Zhuge, L., Jin, L. X., Zheng, Y., et al. (2015a). Protective Effect of Forsythiaside A on Lipopolysaccharide/d-Galactosamine-Induced Liver Injury. Int. Immunopharmacol 26 (1), 80–85. doi:10.1016/j.intimp.2015.03.009
Pan, T. L., Wang, P. W., Huang, C. H., Leu, Y. L., Wu, T. H., Wu, Y. R., et al. (2015b). Herbal Formula, Scutellariae Radix and Rhei Rhizoma Attenuate Dimethylnitrosamine-Induced Liver Fibrosis in a Rat Model. Sci. Rep. 5, 11734. doi:10.1038/srep11734
Park, C. H., Shin, M. R., An, B. K., Joh, H. W., Lee, J. C., Roh, S. S., et al. (2017). Heat-Processed Scutellariae Radix Protects Hepatic Inflammation through the Amelioration of Oxidative Stress in Lipopolysaccharide-Induced Mice. Am. J. Chin. Med. 45 (6), 1233–1252. doi:10.1142/S0192415X17500689
Park, Y. J., Lee, K. H., Jeon, M. S., Lee, Y. H., Ko, Y. J., Pang, C., et al. (2020). Hepatoprotective Potency of Chrysophanol 8-O-Glucoside from Rheum Palmatum L. Against Hepatic Fibrosis via Regulation of the STAT3 Signaling Pathway. Int. J. Mol. Sci. 21 (23), 9044. doi:10.3390/ijms21239044
Parlati, L., Voican, C. S., Perlemuter, K., and Perlemuter, G. (2017). Aloe Vera-Induced Acute Liver Injury: A Case Report and Literature Review. Clin. Res. Hepatol. Gastroenterol. 41 (4), e39–e42. doi:10.1016/j.clinre.2016.10.002
Peng, Y., Yang, T., Huang, K., Shen, L., Tao, Y., and Liu, C. (2018). Salvia Miltiorrhiza Ameliorates Liver Fibrosis by Activating Hepatic Natural Killer Cells In Vivo and In Vitro. Front. Pharmacol. 9, 762. doi:10.3389/fphar.2018.00762
Pérez-Vargas, J. E., Zarco, N., Shibayama, M., Segovia, J., Tsutsumi, V., and Muriel, P. (2014). Hesperidin Prevents Liver Fibrosis in Rats by Decreasing the Expression of Nuclear Factor-Κb, Transforming Growth Factor-β and Connective Tissue Growth Factor. Pharmacology 94 (1-2), 80–89. doi:10.1159/000366206
Porras, D., Nistal, E., Martínez-Flórez, S., Pisonero-Vaquero, S., Olcoz, J. L., Jover, R., et al. (2017). Protective Effect of Quercetin on High-Fat Diet-Induced Non-alcoholic Fatty Liver Disease in Mice Is Mediated by Modulating Intestinal Microbiota Imbalance and Related Gut-Liver Axis Activation. Free Radic. Biol. Med. 102, 188–202. doi:10.1016/j.freeradbiomed.2016.11.037
Poynard, T., Bedossa, P., and Opolon, P. (1997). Natural History of Liver Fibrosis Progression in Patients with Chronic Hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC Groups. Lancet 349 (9055), 825–832. doi:10.1016/s0140-6736(96)07642-8
Qu, X., Gao, H., Zhai, J., Sun, J., Tao, L., Zhang, Y., et al. (2020). Astragaloside IV Enhances Cisplatin Chemosensitivity in Hepatocellular Carcinoma by Suppressing MRP2. Eur. J. Pharm. Sci. 148, 105325. doi:10.1016/j.ejps.2020.105325
Qu, Z. X., Li, F., Ma, C. D., Liu, J., Li, S. D., and Wang, W. L. (2015). Effects of gentiana Scabra Bage on Expression of Hepatic Type I, III Collagen Proteins in Paragonimus Skrjabini Rats with Liver Fibrosis. Asian Pac. J. Trop. Med. 8 (1), 60–63. doi:10.1016/S1995-7645(14)60188-7
Rahmani, S., Asgary, S., Askari, G., Keshvari, M., Hatamipour, M., Feizi, A., et al. (2016). Treatment of Non-alcoholic Fatty Liver Disease with Curcumin: A Randomized Placebo-Controlled Trial. Phytother Res. 30 (9), 1540–1548. doi:10.1002/ptr.5659
Rakshit, S., Shukla, P., Verma, A., Kumar Nirala, S., and Bhadauria, M. (2021). Protective Role of Rutin Against Combined Exposure to Lipopolysaccharide and D-Galactosamine-Induced Dysfunctions in Liver, Kidney, and Brain: Hematological, Biochemical, and Histological Evidences. J. Food Biochem. 45 (2), e13605. doi:10.1111/jfbc.13605
Rehermann, B., Ferrari, C., Pasquinelli, C., and Chisari, F. V. (1996). The Hepatitis B Virus Persists for Decades after Patients' Recovery from Acute Viral Hepatitis Despite Active Maintenance of a Cytotoxic T-Lymphocyte Response. Nat. Med. 2 (10), 1104–1108. doi:10.1038/nm1096-1104
Rehman, S., Nazar, R., Butt, A. M., Ijaz, B., Tasawar, N., Sheikh, A. K., et al. (2021). Phytochemical Screening and Protective Effects of Prunus Persica Seeds Extract on Carbon Tetrachloride-Induced Hepatic Injury in Rats. Curr. Pharm. Biotechnol. doi:10.2174/1389201022666210203142138
Ren, M., McGowan, E., Li, Y., Zhu, X., Lu, X., Zhu, Z., et al. (2019). Saikosaponin-d Suppresses COX2 Through p-STAT3/C/EBPβ Signaling Pathway in Liver Cancer: A Novel Mechanism of Action. Front. Pharmacol. 10, 623. doi:10.3389/fphar.2019.00623
Robinson, M. W., Harmon, C., and O'Farrelly, C. (2016). Liver Immunology and its Role in Inflammation and Homeostasis. Cell Mol Immunol 13 (3), 267–276. doi:10.1038/cmi.2016.3
Roghani, M., Kalantari, H., Khodayar, M. J., Khorsandi, L., Kalantar, M., Goudarzi, M., et al. (2020). Alleviation of Liver Dysfunction, Oxidative Stress and Inflammation Underlies the Protective Effect of Ferulic Acid in Methotrexate-Induced Hepatotoxicity. Drug Des. Devel Ther. 14, 1933–1941. doi:10.2147/DDDT.S237107
Saberi-Karimian, M., Keshvari, M., Ghayour-Mobarhan, M., Salehizadeh, L., Rahmani, S., Behnam, B., et al. (2020). Effects of Curcuminoids on Inflammatory Status in Patients with Non-alcoholic Fatty Liver Disease: A Randomized Controlled Trial. Complement. Ther. Med. 49, 102322. doi:10.1016/j.ctim.2020.102322
Salameh, H., Raff, E., Erwin, A., Seth, D., Nischalke, H. D., Falleti, E., et al. (2015). PNPLA3 Gene Polymorphism Is Associated with Predisposition to and Severity of Alcoholic Liver Disease. Am. J. Gastroenterol. 110 (6), 846–856. doi:10.1038/ajg.2015.137
Seitz, S., Urban, S., Antoni, C., and Böttcher, B. (2007). Cryo-electron Microscopy of Hepatitis B Virions Reveals Variability in Envelope Capsid Interactions. EMBO J. 26 (18), 4160–4167. doi:10.1038/sj.emboj.7601841
Shan, Y., Jiang, B., Yu, J., Wang, J., Wang, X., Li, H., et al. (2019). Protective Effect of Schisandra Chinensis Polysaccharides Against the Immunological Liver Injury in Mice Based on Nrf2/ARE and TLR4/NF-Κb Signaling Pathway. J. Med. Food 22 (9), 885–895. doi:10.1089/jmf.2018.4377
Shang, Y., Li, X. F., Jin, M. J., Li, Y., Wu, Y. L., Jin, Q., et al. (2018). Leucodin Attenuates Inflammatory Response in Macrophages and Lipid Accumulation in Steatotic Hepatocytes via P2x7 Receptor Pathway: A Potential Role in Alcoholic Liver Disease. Biomed. Pharmacother. 107, 374–381. doi:10.1016/j.biopha.2018.08.009
Shen, B., Feng, H., Cheng, J., Li, Z., Jin, M., Zhao, L., et al. (2020). Geniposide Alleviates Non-alcohol Fatty Liver Disease via Regulating Nrf2/AMPK/mTOR Signalling Pathways. J. Cel Mol Med 24 (9), 5097–5108. doi:10.1111/jcmm.15139
Shen, H., Wang, H., Wang, L., Wang, L., Zhu, M., Ming, Y., et al. (2017). Ethanol Extract of Root of Prunus Persica Inhibited the Growth of Liver Cancer Cell HepG2 by Inducing Cell Cycle Arrest and Migration Suppression. Evid. Based Complement. Alternat Med. 2017, 8231936. doi:10.1155/2017/8231936
Shen, T. D., Pyrsopoulos, N., and Rustgi, V. K. (2018). Microbiota and the Liver. Liver Transpl. 24 (4), 539–550. doi:10.1002/lt.25008
Sheu, M. J., Chiu, C. C., Yang, D. J., Hsu, T. C., and Tzang, B. S. (2017). The Root Extract of Gentiana Macrophylla Pall. Alleviates B19-NS1-Exacerbated Liver Injuries in NZB/W F1 Mice. J. Med. Food 20 (1), 56–64. doi:10.1089/jmf.2016.3817
Shi, H., Shi, A., Dong, L., Lu, X., Wang, Y., Zhao, J., et al. (2016). Chlorogenic Acid Protects Against Liver Fibrosis In Vivo and In Vitro Through Inhibition of Oxidative Stress. Clin. Nutr. 35 (6), 1366–1373. doi:10.1016/j.clnu.2016.03.002
Shi, J., Han, G., Wang, J., Han, X., Zhao, M., Duan, X., et al. (2020). Matrine Promotes Hepatic Oval Cells Differentiation into Hepatocytes and Alleviates Liver Injury by Suppression of Notch Signalling Pathway. Life Sci. 261, 118354. doi:10.1016/j.lfs.2020.118354
Shi, Y., and Zheng, M. (2020). Hepatitis B Virus Persistence and Reactivation. BMJ 370, m2200. doi:10.1136/bmj.m2200
Singal, A. K., Bataller, R., Ahn, J., Kamath, P. S., and Shah, V. H. (2018). ACG Clinical Guideline: Alcoholic Liver Disease. Am. J. Gastroenterol. 113 (2), 175–194. doi:10.1038/ajg.2017.469
Spearman, C. W., Dusheiko, G. M., Hellard, M., and Sonderup, M. (2019). Hepatitis C. Lancet 394 (10207), 1451–1466. doi:10.1016/S0140-6736(19)32320-7
Stöckigt, J., Antonchick, A. P., Wu, F., and Waldmann, H. (2011). The Pictet-Spengler Reaction in Nature and in Organic Chemistry. Angew. Chem. Int. Ed. Engl. 50 (37), 8538–8564. doi:10.1002/anie.201008071
Su, C. M., Wang, H. C., Hsu, F. T., Lu, C. H., Lai, C. K., Chung, J. G., et al. (2020). Astragaloside IV Induces Apoptosis, G1-phase Arrest and Inhibits Anti-apoptotic Signaling in Hepatocellular Carcinoma. In Vivo 34 (2), 631–638. doi:10.21873/invivo.11817
Sun, J., Liu, Y., Yu, J., Wu, J., Gao, W., Ran, L., et al. (2019). APS Could Potentially Activate Hepatic Insulin Signaling in HFD-Induced IR Mice. J. Mol. Endocrinol. 63 (1), 77–91. doi:10.1530/JME-19-0035
Tan, X., Sun, Z., Liu, Q., Ye, H., Zou, C., Ye, C., et al. (2018). Effects of Dietary Ginkgo Biloba Leaf Extract on Growth Performance, Plasma Biochemical Parameters, Fish Composition, Immune Responses, Liver Histology, and Immune and Apoptosis-Related Genes Expression of Hybrid Grouper (Epinephelus Lanceolatus♂ × Epinephelus Fuscoguttatus♀) Fed High Lipid Diets. Fish. Shellfish Immunol. 72, 399–409. doi:10.1016/j.fsi.2017.10.022
Tan, X., Sun, Z., Ye, C., and Lin, H. (2019). The Effects of Dietary Lycium Barbarum Extract on Growth Performance, Liver Health and Immune Related Genes Expression in Hybrid Grouper (Epinephelus Lanceolatus♂ × E. Fuscoguttatus♀) Fed High Lipid Diets. Fish. Shellfish Immunol. 87, 847–852. doi:10.1016/j.fsi.2019.02.016
Tang, F., Fan, K., Wang, K., and Bian, C. (2019). Amygdalin Attenuates Acute Liver Injury Induced by D-Galactosamine and Lipopolysaccharide by Regulating the NLRP3, NF-Κb and Nrf2/NQO1 Signalling Pathways. Biomed. Pharmacother. 111, 527–536. doi:10.1016/j.biopha.2018.12.096
Tholl, D. (2015). Biosynthesis and Biological Functions of Terpenoids in Plants. Adv. Biochem. Eng. Biotechnol. 148, 63–106. doi:10.1007/10_2014_295
Trépo, C., Chan, H. L., and Lok, A. (2014). Hepatitis B Virus Infection. Lancet 384 (9959), 2053–2063. doi:10.1016/S0140-6736(14)60220-8
Tripathi, A., Debelius, J., Brenner, D. A., Karin, M., Loomba, R., Schnabl, B., et al. (2018). The Gut-Liver Axis and the Intersection with the Microbiome. Nat. Rev. Gastroenterol. Hepatol. 15 (7), 397–411. doi:10.1038/s41575-018-0011-z
Tsochatzis, E. A., Bosch, J., and Burroughs, A. K. (2014). Liver Cirrhosis. Lancet 383 (9930), 1749–1761. doi:10.1016/S0140-6736(14)60121-5
Tsuchida, T., and Friedman, S. L. (2017). Mechanisms of Hepatic Stellate Cell Activation. Nat. Rev. Gastroenterol. Hepatol. 14 (7), 397–411. doi:10.1038/nrgastro.2017.38
Tu, Y. (2016). Artemisinin-A Gift from Traditional Chinese Medicine to the World (Nobel Lecture). Angew. Chem. Int. Ed. Engl. 55 (35), 10210–10226. doi:10.1002/anie.201601967
Uchio, R., Higashi, Y., Kohama, Y., Kawasaki, K., Hirao, T., Muroyama, K., et al. (2017). A Hot Water Extract of Turmeric (Curcuma Longa) Suppresses Acute Ethanol-Induced Liver Injury in Mice by Inhibiting Hepatic Oxidative Stress and Inflammatory Cytokine Production. J. Nutr. Sci. 6, e3. doi:10.1017/jns.2016.43
Van Hung, P. (2016). Phenolic Compounds of Cereals and Their Antioxidant Capacity. Crit. Rev. Food Sci. Nutr. 56 (1), 25–35. doi:10.1080/10408398.2012.708909
Veskovic, M., Mladenovic, D., Milenkovic, M., Tosic, J., Borozan, S., Gopcevic, K., et al. (2019). Betaine Modulates Oxidative Stress, Inflammation, Apoptosis, Autophagy, and Akt/mTOR Signaling in Methionine-Choline Deficiency-Induced Fatty Liver Disease. Eur. J. Pharmacol. 848, 39–48. doi:10.1016/j.ejphar.2019.01.043
Wah Kheong, C., Nik Mustapha, N. R., and Mahadeva, S. (2017). A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis. Clin. Gastroenterol. Hepatol. 15 (12), 1940–1949.e8. doi:10.1016/j.cgh.2017.04.016
Wan, S., Luo, F., Huang, C., Liu, C., Luo, Q., and Zhu, X. (2020). Ursolic Acid Reverses Liver Fibrosis by Inhibiting Interactive NOX4/ROS and RhoA/ROCK1 Signalling Pathways. Aging (Albany NY) 12 (11), 10614–10632. doi:10.18632/aging.103282
Wan, S. Z., Liu, C., Huang, C. K., Luo, F. Y., and Zhu, X. (2019). Ursolic Acid Improves Intestinal Damage and Bacterial Dysbiosis in Liver Fibrosis Mice. Front. Pharmacol. 10, 1321. doi:10.3389/fphar.2019.01321
Wang, F. S., Fan, J. G., Zhang, Z., Gao, B., and Wang, H. Y. (2014). The Global Burden of Liver Disease: The Major Impact of China. Hepatology 60 (6), 2099–2108. doi:10.1002/hep.27406
Wang, G., Fu, Y., Li, J., Li, Y., Zhao, Q., Hu, A., et al. (2021a). Aqueous Extract of Polygonatum Sibiricum Ameliorates Ethanol-Induced Mice Liver Injury via Regulation of the Nrf2/ARE Pathway. J. Food Biochem. 45 (1), e13537. doi:10.1111/jfbc.13537
Wang, J., Liao, A. M., Thakur, K., Zhang, J. G., Huang, J. H., and Wei, Z. J. (2019a). Licochalcone B Extracted from Glycyrrhiza Uralensis Fisch Induces Apoptotic Effects in Human Hepatoma Cell HepG2. J. Agric. Food Chem. 67 (12), 3341–3353. doi:10.1021/acs.jafc.9b00324
Wang, J., Wong, Y. K., and Liao, F. (2018). What Has Traditional Chinese Medicine Delivered for Modern Medicine? Expert Rev. Mol. Med. 20, e4. doi:10.1017/erm.2018.3
Wang, J., Zhao, Y., Xiao, X., Li, H., Zhao, H., Zhang, P., et al. (2009). Assessment of the Renal protection and Hepatotoxicity of Rhubarb Extract in Rats. J. Ethnopharmacol 124 (1), 18–25. doi:10.1016/j.jep.2009.04.018
Wang, K., Song, Z., Wang, H., Li, Q., Cui, Z., and Zhang, Y. (2016). Angelica Sinensis Polysaccharide Attenuates Concanavalin A-Induced Liver Injury in Mice. Int. Immunopharmacol 31, 140–148. doi:10.1016/j.intimp.2015.12.021
Wang, K., Wang, J., Song, M., Wang, H., Xia, N., and Zhang, Y. (2020a). Angelica Sinensis Polysaccharide Attenuates CCl4-Induced Liver Fibrosis via the IL-22/STAT3 Pathway. Int. J. Biol. Macromol 162, 273–283. doi:10.1016/j.ijbiomac.2020.06.166
Wang, Q., Liang, Y., Peng, C., and Jiang, P. (2020b). Network Pharmacology-Based Study on the Mechanism of Scutellariae Radix for Hepatocellular Carcinoma Treatment. Evid. Based Complement. Alternat Med. 2020, 8897918. doi:10.1155/2020/8897918
Wang, R., Zhang, D., Tang, D., Sun, K., Peng, J., Zhu, W., et al. (2021b). Amygdalin Inhibits TGFβ1-Induced Activation of Hepatic Stellate Cells (HSCs) In Vitro and CCl4-Induced Hepatic Fibrosis in Rats In Vivo. Int. Immunopharmacol 90, 107151. doi:10.1016/j.intimp.2020.107151
Wang, S., Xu, J., Wang, C., Li, J., Wang, Q., Kuang, H., et al. (2020c). Paeoniae Radix alba Polysaccharides Obtained via Optimized Extraction Treat Experimental Autoimmune Hepatitis Effectively. Int. J. Biol. Macromol 164, 1554–1564. doi:10.1016/j.ijbiomac.2020.07.214
Wang, Y., Wang, R., Wang, Y., Peng, R., Wu, Y., and Yuan, Y. (2015). Ginkgo Biloba Extract Mitigates Liver Fibrosis and Apoptosis by Regulating P38 MAPK, NF-Κb/iκbα, and Bcl-2/Bax Signaling. Drug Des. Devel Ther. 9, 6303–6317. doi:10.2147/DDDT.S93732
Wang, Y. X., Du, Y., Liu, X. F., Yang, F. X., Wu, X., Tan, L., et al. (2019b). A Hepatoprotection Study of Radix Bupleuri on Acetaminophen-Induced Liver Injury Based on CYP450 Inhibition. Chin. J. Nat. Med. 17 (7), 517–524. doi:10.1016/S1875-5364(19)30073-1
Wei, J., Zhang, L., Liu, J., Pei, D., Wang, N., Wang, H., et al. (2020). Protective Effect of Lycium Barbarum Polysaccharide on Ethanol-Induced Injury in Human Hepatocyte and its Mechanism. J. Food Biochem., e13412. doi:10.1111/jfbc.13412
Wei, L., Dai, Y., Zhou, Y., He, Z., Yao, J., Zhao, L., et al. (2017). Oroxylin A Activates PKM1/HNF4 Alpha to Induce Hepatoma Differentiation and Block Cancer Progression. Cell Death Dis 8 (7), e2944. doi:10.1038/cddis.2017.335
Wei, R., Cao, J., and Yao, S. (2018). Matrine Promotes Liver Cancer Cell Apoptosis by Inhibiting Mitophagy and PINK1/Parkin Pathways. Cell Stress Chaperones 23 (6), 1295–1309. doi:10.1007/s12192-018-0937-7
Wu, C., Chen, W., Ding, H., Li, D., Wen, G., Zhang, C., et al. (2019b). 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 Sci. 239, 116881. doi:10.1016/j.lfs.2019.116881
Wu, C., Jing, M., Yang, L., Jin, L., Ding, Y., Lu, J., et al. (2018a). Alisol A 24-acetate Ameliorates Nonalcoholic Steatohepatitis by Inhibiting Oxidative Stress and Stimulating Autophagy through the AMPK/mTOR Pathway. Chem. Biol. Interact 291, 111–119. doi:10.1016/j.cbi.2018.06.005
Wu, C. T., Deng, J. S., Huang, W. C., Shieh, P. C., Chung, M. I., and Huang, G. J. (2019a). Salvianolic Acid C Against Acetaminophen-Induced Acute Liver Injury by Attenuating Inflammation, Oxidative Stress, and Apoptosis through Inhibition of the Keap1/Nrf2/HO-1 Signaling. Oxid Med. Cel Longev 2019, 9056845. doi:10.1155/2019/9056845
Wu, K., Fan, J., Huang, X., Wu, X., and Guo, C. (2018b). Hepatoprotective Effects Exerted by Poria Cocos Polysaccharides Against Acetaminophen-Induced Liver Injury in Mice. Int. J. Biol. Macromol 114, 137–142. doi:10.1016/j.ijbiomac.2018.03.107
Wu, K., Guo, C., Yang, B., Wu, X., and Wang, W. (2019c). Antihepatotoxic Benefits of Poria Cocos Polysaccharides on Acetaminophen-Lesioned Livers In Vivo and In Vitro. J. Cel Biochem 120 (5), 7482–7488. doi:10.1002/jcb.28022
Wu, Q. (2001). Traditional Chinese Medicine for Liver Disease. Beijing: China medical science and technology press.
Wu, X., Zhang, F., Xiong, X., Lu, C., Lian, N., Lu, Y., et al. (2015). Tetramethylpyrazine Reduces Inflammation in Liver Fibrosis and Inhibits Inflammatory Cytokine Expression in Hepatic Stellate Cells by Modulating NLRP3 Inflammasome Pathway. IUBMB Life 67 (4), 312–321. doi:10.1002/iub.1348
Wu, X., Zhi, F., Lun, W., Deng, Q., and Zhang, W. (2018c). Baicalin Inhibits PDGF-BB-Induced Hepatic Stellate Cell Proliferation, Apoptosis, Invasion, Migration and Activation via the miR-3595/ACSL4 axis. Int. J. Mol. Med. 41 (4), 1992–2002. doi:10.3892/ijmm.2018.3427
Wu, Z., Meng, X., Hu, J., Ding, Y., and Peng, Y. (2017). Research Progress on the Relationship between TLR4-MyD88-NF-kB Signaling Pathway and Hepatitis Liver Fibrosis Liver Cancer axis. Int. J. Pharm. Res. 44 (05), 396–401.
Xian, Z., Tian, J., Wang, L., Zhang, Y., Han, J., Deng, N., et al. (2020). Effects of Rhein on Bile Acid Homeostasis in Rats. Biomed. Res. Int. 2020, 8827955. doi:10.1155/2020/8827955
Xiao, Y., Kim, M., and Lazar, M. A. (2020). Nuclear Receptors and Transcriptional Regulation in Non-alcoholic Fatty Liver Disease. Mol. Metab. 50, 101119. doi:10.1016/j.molmet.2020.101119
Xie, H., Su, D., Zhang, J., Ji, D., Mao, J., Hao, M., et al. (2020). Raw and Vinegar Processed Curcuma Wenyujin Regulates Hepatic Fibrosis via Bloking TGF-β/Smad Signaling Pathways and Up-Regulation of MMP-2/TIMP-1 Ratio. J. Ethnopharmacol 246, 111768. doi:10.1016/j.jep.2019.01.045
Xie, T., Li, K., Gong, X., Jiang, R., Huang, W., Chen, X., et al. (2018). Paeoniflorin Protects Against Liver Ischemia/reperfusion Injury in Mice via Inhibiting HMGB1-TLR4 Signaling Pathway. Phytother Res. 32 (11), 2247–2255. doi:10.1002/ptr.6161
Xu, F., Liu, C., Zhou, D., and Zhang, L. (2016). TGF-β/SMAD Pathway and its Regulation in Hepatic Fibrosis. J. Histochem. Cytochem. 64 (3), 157–167. doi:10.1369/0022155415627681
Xu, J., Li, C., Li, Z., Yang, C., Lei, L., Ren, W., et al. (2018). Protective Effects of Oxymatrine Against lipopolysaccharide/D-galactosamine-induced A-cute L-iver F-ailure through O-xidative D-amage, via A-ctivation of Nrf2/HO-1 and M-odulation of I-nflammatory TLR4-signaling P-athways. Mol. Med. Rep. 17 (1), 1907–1912. doi:10.3892/mmr.2017.8060
Yan, H., Gao, Y. Q., Zhang, Y., Wang, H., Liu, G. S., and Lei, J. Y. (2018). Chlorogenic Acid Alleviates Autophagy and Insulin Resistance by Suppressing JNK Pathway in a Rat Model of Nonalcoholic Fatty Liver Disease. J. Biosci. 43 (2), 287–294. doi:10.1007/s12038-018-9746-5
Yan, H., Jung, K. H., Kim, J., Rumman, M., Oh, M. S., and Hong, S. S. (2018). Artemisia Capillaris Extract AC68 Induces Apoptosis of Hepatocellular Carcinoma by Blocking the PI3K/AKT Pathway. Biomed. Pharmacother. 98, 134–141. doi:10.1016/j.biopha.2017.12.043
Yan, Z., Fan, R., Yin, S., Zhao, X., Liu, J., Li, L., et al. (2015). Protective Effects of Ginkgo Biloba Leaf Polysaccharide on Nonalcoholic Fatty Liver Disease and its Mechanisms. Int. J. Biol. Macromol 80, 573–580. doi:10.1016/j.ijbiomac.2015.05.054
Yang, F., Luo, L., Zhu, Z. D., Zhou, X., Wang, Y., Xue, J., et al. (2017). Chlorogenic Acid Inhibits Liver Fibrosis by Blocking the miR-21-Regulated TGF-β1/Smad7 Signaling Pathway In Vitro and In Vivo. Front. Pharmacol. 8, 929. doi:10.3389/fphar.2017.00929
Yang, F., Xu, Y., Xiong, A., He, Y., Yang, L., Wan, Y. J., et al. (2012). Evaluation of the Protective Effect of Rhei Radix et Rhizoma Against α-naphthylisothiocyanate Induced Liver Injury Based on Metabolic Profile of Bile Acids. J. Ethnopharmacol 144 (3), 599–604. doi:10.1016/j.jep.2012.09.049
Yang, G., and Wei, W. (2017). Research Progress on Immune Mechanism of Alcoholic Liver Disease and Prevention and Treatment of Traditional Chinese Medicine. J. southwest Med. Univ. 40 (03), 319–321.
Yang, H., Yang, T., Heng, C., Zhou, Y., Jiang, Z., Qian, X., et al. (2019a). Quercetin Improves Nonalcoholic Fatty Liver by Ameliorating Inflammation, Oxidative Stress, and Lipid Metabolism in Db/db Mice. Phytother Res. 33 (12), 3140–3152. doi:10.1002/ptr.6486
Yang, H., Zhou, Z., He, L., Ma, H., Qu, W., Yin, J., et al. (2018). Hepatoprotective and Inhibiting HBV Effects of Polysaccharides from Roots of Sophora Flavescens. Int. J. Biol. Macromol 108, 744–752. doi:10.1016/j.ijbiomac.2017.10.171
Yang, H. X., Shang, Y., Jin, Q., Wu, Y. L., Liu, J., Qiao, C. Y., et al. (2020a). Gentiopicroside Ameliorates the Progression from Hepatic Steatosis to Fibrosis Induced by Chronic Alcohol Intake. Biomol. Ther. (Seoul) 28 (4), 320–327. doi:10.4062/biomolther.2020.008
Yang, J. H., Kim, S. C., Kim, K. M., Jang, C. H., Cho, S. S., Kim, S. J., et al. (2016a). Isorhamnetin Attenuates Liver Fibrosis by Inhibiting TGF-β/Smad Signaling and Relieving Oxidative Stress. Eur. J. Pharmacol. 783, 92–102. doi:10.1016/j.ejphar.2016.04.042
Yang, M., Li, X., Zeng, X., Ou, Z., Xue, M., Gao, D., et al. (2016b). Rheum Palmatum L. Attenuates High Fat Diet-Induced Hepatosteatosis by Activating AMP-Activated Protein Kinase. Am. J. Chin. Med. 44 (3), 551–564. doi:10.1142/S0192415X16500300
Yang, R., Song, C., Chen, J., Zhou, L., Jiang, X., Cao, X., et al. (2020b). Limonin Ameliorates Acetaminophen-Induced Hepatotoxicity by Activating Nrf2 Antioxidative Pathway and Inhibiting NF-Κb Inflammatory Response via Upregulating Sirt1. Phytomedicine 69, 153211. doi:10.1016/j.phymed.2020.153211
Yang, Y., Zhao, J., Song, X., Li, L., Li, F., Shang, J., et al. (2019b). Amygdalin Reduces Lipopolysaccharide-Induced Chronic Liver Injury in Rats by Down-Regulating PI3K/AKT, JAK2/STAT3 and NF-Κb Signalling Pathways. Artif. Cell Nanomed Biotechnol 47 (1), 2688–2697. doi:10.1080/21691401.2019.1634084
Yari, Z., Cheraghpour, M., Alavian, S. M., Hedayati, M., Eini-Zinab, H., and Hekmatdoost, A. (2021). The Efficacy of Flaxseed and Hesperidin on Non-alcoholic Fatty Liver Disease: An Open-Labeled Randomized Controlled Trial. Eur. J. Clin. Nutr. 75 (1), 99–111. doi:10.1038/s41430-020-0679-3
Yi, Y., Zhao, Y., Li, C., Zhang, Y., Bin, Y., Yuan, Y., et al. (2018). Potential Chronic Liver Toxicity in Rats Orally Administered an Ethanol Extract of Huangqin (Radix Scutellariae Baicalensis). J. Tradit Chin. Med. 38 (2), 242–256.
Yim, D., Kim, M. J., Shin, Y., Lee, S. J., Shin, J. G., and Kim, D. H. (2019). Inhibition of Cytochrome P450 Activities by Sophora Flavescens Extract and its Prenylated Flavonoids in Human Liver Microsomes. Evid. Based Complement. Alternat Med. 2019, 2673769. doi:10.1155/2019/2673769
Yokomori, H., Oda, M., Yoshimura, K., and Hibi, T. (2012). Recent Advances in Liver Sinusoidal Endothelial Ultrastructure and Fine Structure Immunocytochemistry. Micron 43 (2-3), 129–134. doi:10.1016/j.micron.2011.08.002
Younossi, Z. M. (2019). Non-alcoholic Fatty Liver Disease - A Global Public Health Perspective. J. Hepatol. 70 (3), 531–544. doi:10.1016/j.jhep.2018.10.033
Yu, Q., Liu, T., Li, S., Feng, J., Wu, L., Wang, W., et al. (20182018). The Protective Effects of Levo-Tetrahydropalmatine on ConA-Induced Liver Injury Are via TRAF6/JNK Signaling. Mediators Inflamm. 2018, 4032484. doi:10.1155/2018/4032484
Yu, Q., Cheng, P., Wu, J., and Guo, C. (2021). Pparγ/NF-Κb and TGF-β1/Smad Pathway Are Involved in the Anti-fibrotic Effects of Levo-Tetrahydropalmatine on Liver Fibrosis. J. Cel Mol Med 25 (3), 1645–1660. doi:10.1111/jcmm.16267
Yuan, F., Chen, J., Wu, W. J., Chen, S. Z., Wang, X. D., Su, Z., et al. (2010). Effects of Matrine and Oxymatrine on Catalytic Activity of Cytochrome P450s in Rats. Basic Clin. Pharmacol. Toxicol. 107 (5), 906–913. doi:10.1111/j.1742-7843.2010.00596.x
Yuan, R., Tao, X., Liang, S., Pan, Y., He, L., Sun, J., et al. (2018). Protective Effect of Acidic Polysaccharide from Schisandra Chinensis on Acute Ethanol-Induced Liver Injury through Reducing CYP2E1-dependent Oxidative Stress. Biomed. Pharmacother. 99, 537–542. doi:10.1016/j.biopha.2018.01.079
Yuen, M. F., Chen, D. S., Dusheiko, G. M., Janssen, H. L. A., Lau, D. T. Y., Locarnini, S. A., et al. (2018). Hepatitis B Virus Infection. Nat. Rev. Dis. Primers 4, 18035. doi:10.1038/nrdp.2018.35
Yun, Y. R., Kim, J. H., Kim, J. H., and Jung, M. H. (2017). Protective Effects of Gomisin N Against Hepatic Steatosis Through AMPK Activation. Biochem. Biophys. Res. Commun. 482 (4), 1095–1101. doi:10.1016/j.bbrc.2016.11.164
Zang, W., Bian, H., Huang, X., Yin, G., Zhang, C., Han, L. I., et al. (2019). Traditional Chinese Medicine (TCM) Astragalus Membranaceus and Curcuma Wenyujin Promote Vascular Normalization in Tumor-Derived Endothelial Cells of Human Hepatocellular Carcinoma. Anticancer Res. 39 (6), 2739–2747. doi:10.21873/anticanres.13400
Zeng, H., Li, D., Qin, X., Chen, P., Tan, H., Zeng, X., et al. (2016). Hepatoprotective Effects of Schisandra Sphenanthera Extract Against Lithocholic Acid-Induced Cholestasis in Male Mice Are Associated with Activation of the Pregnane X Receptor Pathway and Promotion of Liver Regeneration. Drug Metab. Dispos 44 (3), 337–342. doi:10.1124/dmd.115.066969
Zeng, X., Li, X., Xu, C., Jiang, F., Mo, Y., Fan, X., et al. (2017). Schisandra Sphenanthera Extract (Wuzhi Tablet) Protects Against Chronic-Binge and Acute Alcohol-Induced Liver Injury by Regulating the NRF2-ARE Pathway in Mice. Acta Pharm. Sin B 7 (5), 583–592. doi:10.1016/j.apsb.2017.04.002
Zhang, C. Y., Jiang, Z. M., Ma, X. F., Li, Y., Liu, X. Z., Li, L. L., et al. (2019). Saikosaponin-d Inhibits the Hepatoma Cells and Enhances Chemosensitivity through SENP5-dependent Inhibition of Gli1 SUMOylation Under Hypoxia. Front. Pharmacol. 10, 1039. doi:10.3389/fphar.2019.01039
Zhang, H., Yang, L., Wang, Y., Huang, W., Li, Y., Chen, S., et al. (2020a). Oxymatrine Alleviated Hepatic Lipid Metabolism via Regulating miR-182 in Non-alcoholic Fatty Liver Disease. Life Sci. 257, 118090. doi:10.1016/j.lfs.2020.118090
Zhang, Y., Wang, H., Zhang, L., Yuan, Y., and Yu, D. (2020b). Codonopsis Lanceolata Polysaccharide CLPS Alleviates High Fat/high Sucrose Diet-Induced Insulin Resistance via Anti-oxidative Stress. Int. J. Biol. Macromol 145, 944–949. doi:10.1016/j.ijbiomac.2019.09.185
Zhang, Y., Yang, X., Wang, S., Song, S., and Yang, X. (2021). Gentiopicroside Prevents Alcoholic Liver Damage by Improving Mitochondrial Dysfunction in the Rat Model. Phytother Res. 35 (4), 2230–2251. doi:10.1002/ptr.6981
Zhang, Y., Zhao, H., Li, H., Cao, W., Wang, F., Zhang, T., et al. (2017). Protective Effects of Amarogentin Against Carbon Tetrachloride-Induced Liver Fibrosis in Mice. Molecules 22 (5). doi:10.3390/molecules22050754
Zhang, Z., Chen, S., Mei, H., Xuan, J., Guo, X., Couch, L., et al. (2015). Ginkgo Biloba Leaf Extract Induces DNA Damage by Inhibiting Topoisomerase II Activity in Human Hepatic Cells. Sci. Rep. 5, 14633. doi:10.1038/srep14633
Zhao, H., Zhang, Y., Shu, L., Song, G., and Ma, H. (2019a). Resveratrol Reduces Liver Endoplasmic Reticulum Stress and Improves Insulin Sensitivity In Vivo and In Vitro. Drug Des. Devel Ther. 13, 1473–1485. doi:10.2147/DDDT.S203833
Zhao, H. W., Zhang, Z. F., Chai, X., Li, G. Q., Cui, H. R., Wang, H. B., et al. (2016). Oxymatrine Attenuates CCl4-Induced Hepatic Fibrosis via Modulation of TLR4-dependent Inflammatory and TGF-Β1 Signaling Pathways. Int. Immunopharmacol 36, 249–255. doi:10.1016/j.intimp.2016.04.040
Zhao, P., Piao, X., Pan, L., Zeng, Z., Li, Q., Xu, X., et al. (2017). Forsythia Suspensa Extract Attenuates Lipopolysaccharide-Induced Inflammatory Liver Injury in Rats via Promoting Antioxidant Defense Mechanisms. Anim. Sci. J. 88 (6), 873–881. doi:10.1111/asj.12717
Zhao, Q., Wei, M., Zhang, S., Huang, Z., Lu, B., and Ji, L. (2020). The Water Extract of Sophorae tonkinensis Radix et Rhizoma Alleviates Non-alcoholic Fatty Liver Disease and Its Mechanism. Phytomedicine 77, 153270. doi:10.1016/j.phymed.2020.153270
Zhao, X. J., Chen, L., Zhao, Y., Pan, Y., Yang, Y. Z., Sun, Y., et al. (2019b). Polygonum Cuspidatum Extract Attenuates Fructose-Induced Liver Lipid Accumulation through Inhibiting Keap1 and Activating Nrf2 Antioxidant Pathway. Phytomedicine 63, 152986. doi:10.1016/j.phymed.2019.152986
Zhao, X. J., Yu, H. W., Yang, Y. Z., Wu, W. Y., Chen, T. Y., Jia, K. K., et al. (2018a). Polydatin Prevents Fructose-Induced Liver Inflammation and Lipid Deposition through Increasing miR-200a to Regulate Keap1/Nrf2 Pathway. Redox Biol. 18, 124–137. doi:10.1016/j.redox.2018.07.002
Zhao, Y., Ma, X., Wang, J., Zhu, Y., Li, R., Wang, J., et al. (2014). Paeoniflorin Alleviates Liver Fibrosis by Inhibiting HIF-1α Through mTOR-dependent Pathway. Fitoterapia 99, 318–327. doi:10.1016/j.fitote.2014.10.009
Zhao, Z., Wei, Q., Hua, W., Liu, Y., Liu, X., and Zhu, Y. (2018b). Hepatoprotective Effects of Berberine on Acetaminophen-Induced Hepatotoxicity in Mice. Biomed. Pharmacother. 103, 1319–1326. doi:10.1016/j.biopha.2018.04.175
Zheng, N., Liu, F., Lu, H., Zhan, Y., Zhang, M., Guo, W., et al. (2017). Schisantherin A Protects Against Liver Ischemia-Reperfusion Injury via Inhibition of Mitogen-Activated Protein Kinase Pathway. Int. Immunopharmacol 47, 28–37. doi:10.1016/j.intimp.2017.03.019
Zhong, W., Qian, K., Xiong, J., Ma, K., Wang, A., and Zou, Y. (2016). Curcumin Alleviates Lipopolysaccharide Induced Sepsis and Liver Failure by Suppression of Oxidative Stress-Related Inflammation via PI3K/AKT and NF-Κb Related Signaling. Biomed. Pharmacother. 83, 302–313. doi:10.1016/j.biopha.2016.06.036
Zhou, L., Yang, F., Li, G., Huang, J., Liu, Y., Zhang, Q., et al. (2018). Coptisine Induces Apoptosis in Human Hepatoma Cells Through Activating 67-kDa Laminin Receptor/cGMP Signaling. Front. Pharmacol. 9, 517. doi:10.3389/fphar.2018.00517
Zhou, W. C., Zhang, Q. B., and Qiao, L. (2014). Pathogenesis of Liver Cirrhosis. World J. Gastroenterol. 20 (23), 7312–7324. doi:10.3748/wjg.v20.i23.7312
Zhou, X., Cheung, C. M., Yang, J. M., Or, P. M., Lee, W. Y., and Yeung, J. H. (2015). Danshen (Salvia Miltiorrhiza) Water Extract Inhibits Paracetamol-Induced Toxicity in Primary Rat Hepatocytes via Reducing CYP2E1 Activity and Oxidative Stress. J. Pharm. Pharmacol. 67 (7), 980–989. doi:10.1111/jphp.12381
Zhou, X., Wang, L. L., Tang, W. J., and Tang, B. (2021). Astragaloside IV Inhibits Protein Tyrosine Phosphatase 1B and Improves Insulin Resistance in Insulin-Resistant HepG2 Cells and Triglyceride Accumulation in Oleic Acid (OA)-treated HepG2 Cells. J. Ethnopharmacol 268, 113556. doi:10.1016/j.jep.2020.113556
Zhu, H., He, C., Zhao, H., Jiang, W., Xu, S., Li, J., et al. (2020). Sennoside A Prevents Liver Fibrosis by Binding DNMT1 and Suppressing DNMT1-Mediated PTEN Hypermethylation in HSC Activation and Proliferation. FASEB J. 34 (11), 14558–14571. doi:10.1096/fj.202000494RR
Zhu, S. Y., Jiang, N., Yang, J., Tu, J., Zhou, Y., Xiao, X., et al. (2018a). Silybum marianum Oil Attenuates Hepatic Steatosis and Oxidative Stress in High Fat Diet-Fed Mice. Biomed. Pharmacother. 100, 191–197. doi:10.1016/j.biopha.2018.01.144
Zhu, X., Xiong, T., Liu, P., Guo, X., Xiao, L., Zhou, F., et al. (2018b). Quercetin Ameliorates HFD-Induced NAFLD by Promoting Hepatic VLDL Assembly and Lipophagy via the IRE1a/XBP1s Pathway. Food Chem. Toxicol. 114, 52–60. doi:10.1016/j.fct.2018.02.019
Zou, C., Su, N., Wu, J., Xu, M., Sun, Z., Liu, Q., et al. (2019). Dietary Radix Bupleuri Extracts Improves Hepatic Lipid Accumulation and Immune Response of Hybrid Grouper (Epinephelus Lanceolatus♂ × Epinephelus Fuscoguttatus♀). Fish. Shellfish Immunol. 88, 496–507. doi:10.1016/j.fsi.2019.02.052
Zou, C., Tan, X., Ye, H., Sun, Z., Chen, S., Liu, Q., et al. (2018). The Hepatoprotective Effects of Radix Bupleuri Extracts Against D-Galactosamine/lipopolysaccharide Induced Liver Injury in Hybrid Grouper (Epinephelus Lanceolatus♂ × Epinephelus Fuscoguttatus♀). Fish. Shellfish Immunol. 83, 8–17. doi:10.1016/j.fsi.2018.08.047
Keywords: liver diseases, natural agents, toxicity, clinical trials, potential application, Chinese medicine
Citation: Fu K, Wang C, Ma C, Zhou H and Li Y (2021) The Potential Application of Chinese Medicine in Liver Diseases: A New Opportunity. Front. Pharmacol. 12:771459. doi: 10.3389/fphar.2021.771459
Received: 06 September 2021; Accepted: 19 October 2021;
Published: 04 November 2021.
Edited by:
Annabella Vitalone, Sapienza University of Rome, ItalyReviewed by:
Luis Enrique Gomez-Quiroz, Autonomous Metropolitan University, MexicoMaitane Asensio, University of Salamanca, Spain
Copyright © 2021 Fu, Wang, Ma, Zhou and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yunxia Li, lyxtgyxcdutcm@163.com
†These authors have contributed equally to this work