key: cord-009987-biop7gyd
authors: Ali, Muhammad; Khan, Tariq; Fatima, Kaneez; Ali, Qurat ul Ain; Ovais, Muhammad; Khalil, Ali Talha; Ullah, Ikram; Raza, Abida; Shinwari, Zabta Khan; Idrees, Muhammad
title: Selected hepatoprotective herbal medicines: Evidence from ethnomedicinal applications, animal models, and possible mechanism of actions
date: 2017-10-19
journal: Phytother Res
DOI: 10.1002/ptr.5957
sha: 
doc_id: 9987
cord_uid: biop7gyd

Insight into the hepatoprotective effects of medicinally important plants is important, both for physicians and researchers. Main reasons for the use of herbal medicine include their lesser cost compared with conventional drugs, lesser undesirable drug reactions and thus high safety, and reduced side effects. The present review focuses on the composition, pharmacology, and results of experimental trials of selected medicinal plants: Silybum marianum (L.) Gaertn., Glycyrrhiza glabra, Phyllanthus amarus Schumach. & Thonn., Salvia miltiorrhiza Bunge., Astragalus membranaceus (Fisch.) Bunge, Capparis spinosa (L.), Cichorium intybus (L.), Solanum nigrum (L.), Sapindus mukorossi Gaertn., Ginkgo biloba (L.), Woodfordia fruticosa (L.) Kurz, Vitex trifolia (L.), Schisandra chinensis (Turcz.) Baill., Cuscuta chinensis (Lam.), Lycium barbarum, Angelica sinensis (Oliv.) Diels, and Litsea coreana (H. Lev.). The probable modes of action of these plants include immunomodulation, stimulation of hepatic DNA synthesis, simulation of superoxide dismutase and glutathione reductase to inhibit oxidation in hepatocytes, reduction of intracellular reactive oxygen species by enhancing levels of antioxidants, suppression of ethanol‐induced lipid accumulation, inhibition of nucleic acid polymerases to downregulate viral mRNA transcription and translation, free radical scavenging and reduction of hepatic fibrosis by decreasing the levels of transforming growth factor beta‐1, and collagen synthesis in hepatic cells. However, further research is needed to identify, characterize, and standardize the active ingredients, useful compounds, and their preparations for the treatment of liver diseases.

Liver disorders have been classified in the high priority areas of health care. According to an estimate by the World Health Organization, approximately 500 million people of the world are suffering from a severe form of liver disorders, that is, chronic hepatitis (Al-Asmari et al., 2014) . Medicine of herbal origin may serve as a feasible therapy for the prevailing liver problems because of their safety, easier availability, cost effectiveness, and environment friendliness (Izzo, Hoon-Kim, Radhakrishnan, & Williamson, 2016) . Medicinal plants have acquired importance in healthcare system throughout the world for their proven and effective therapeutic properties (Helmstädter & Staiger, 2014 ). An estimated 80% of the world's population is relying on medicines that contain compounds of herbal origin (Ekor, 2013) .

The International Union for Conservation of Nature has suggested that approximately 50,000 to 80,000 flowering plants are used for medicinal purposes (Chen, Li, Ren, & Hu, 2016) . Many factors regarding these medicines are important. Herbal medicines are claimed to both treat and prevent diseases, which adds to a deep belief that these Abbreviations: ALT, alanine aminotransaminase; ASP, Angelica sinensis polysaccharides; AST, aspartate transaminase; EGF, epidermal growth factor; HBV, Hepatitis B virus; LBPs, Lycium barbarum polysaccharides; WF4, Woodfordia fruticosa flower extract. treatments are safe because they are "natural and gentle" and therefore, a harmless alternative to the conventional medicine. Moreover, the latter may sometimes cause disappointing results and undesirable side effects in patients (Izzo et al., 2016) . In addition, the less expensive herbal products are often not subject to strict regulations and medication prescribed by a physician or other qualified practitioners (Hunter & Hegele, 2017) . Although medicinal plants have been used globally, their wider usage is limited to a few countries like Japan, India, China, Pakistan, Thailand, Iran, and some African countries (Bahmani et al., 2014; Iwu, 2014; Li, 2016; Sivasankari, Anandharaj, & Gunasekaran, 2014) . Other countries are also encouraging the use of plant-based medicinal products in their healthcare systems. For example, Natural Health Product Regulations of Canada for the plant-based product in healthcare encourages usage of modern technology and evidencebased scientific support towards promoting medicinal plants and the associated products (Tomlinson & Akerele, 2015) . A major concern of scientists investigating herbal treatments is that the chemical composition of the plants contributing to their biological effects is mostly undetermined (Ling et al., 2009 ).

Herbs and herbal medicines have been used for the treatment of liver diseases for a long time (Dhiman & Chawla, 2005) . There are many herbs having ingredients that are potential sources of medicine for the treatment of liver diseases having various modes of actions and bioactivities (Babu, Bhuvaneswar, Sandeep, Ramaiah, & Rajendra, 2017; Gnanadesigan, Ravikumar, & Anand, 2017; Pereira, Barros, & Ferreira, 2016) . However, several of them are well-studied for their bioactive components and the mechanism of hepatoprotective activity. In the current review, we have selected some of these compounds for which elaborate detail about hepatoxicity is available in literature in the form of either in vivo studies, study into biochemical parameters and bioactive compounds. This article highlights the possible ways of inducing hepatoxicity in mice models and encompasses the mechanisms in which certain medicinally important plants perform their hepatoprotective activity. The article further aims to summarize studies conducted on the composition, pharmacology, and nature of the selected plants in the light of possible mechanism deduced from experimental trials.

A thorough search was conducted on the electronic literature databases, Google Scholar, PubMed, Scopus, and Web of Science. Literature was retrieved using the key words and phrases "Hepatitis C", "Hepatoprotective activity", "Mechanism of action", "Medicinal plants", "Herbal", and "Treatment". About 100 relevant articles were extracted after a narrow search for a combination of the keywords and subsequent analysis per the inclusion criteria. There were two sets of criteria applied to articles for inclusion in this manuscript. According to the first, "general criteria", articles selected for this manuscript were those which (a) reported plants and their parts that were traditionally applied to hepatitis and liver disorders and any other type of hepatoprotective activity; (b) reported extract or pure compounds important for their hepatoprotective role; and (c) attempted to explain the mechanism of hepatoprotective action of these plants.

The 2nd criteria were used for selecting those plants that are discussed in detail (shown in Figure 3 ). For this purpose, seventeen plants were selected for which recent articles were available that (a) studied in vitro and in vivo hepatoprotective activities of herbal products, (b) reported active compounds from the plant, and (c) described the mechanism of action herbal hepatoprotective products. The plants described in detail were selected if literature available for them fulfilled at least two of the above 3-point criteria.

Each of the selected plants was discussed; mainly focusing its hepatoprotective activities, active compounds, and possible mechanism of action. In addition, featured hepatoprotective herbal combinations have been deliberated. Toxicity and quality control issues associated with these herbs/herbal products have been debated.

Two of the authors independently reviewed all the full-text articles obtained during the electronic search. Data from the eligible articles were extracted; all the disagreements were discussed and were referred to a third reviewer (one of the author) for a final decision.

All the data were extracted in two tables (Tables 1 and 2) , and the mechanisms of action were explained in respective subheadings and demonstrated through four different figures (Figures 1-3, and 4 ).

The figures were constructed in ChemBioDraw Ultra (version 14.0) software package. Furthermore, the Plant Database "Plant list" was used for the taxonomic categorization of all the documented plant species (Theplantlist, 2013) .

The prerequisite to screen/study any medicinal compound for its hepatoprotective activity is to develop a model (animal model or cell culture model) in which hepatic injury is induced (Salehi, Karegar-Borzi, Karimi, & Rahimi, 2016) . Several studies have manipulated mice models to induce hepatotoxicity and then treat those induced liver diseases using herbs and herbal products (Figure 1 ). This approach provides insight into how hepatitis and other liver diseases are caused. However, for many plants, their mechanism of action against hepatotoxic agents is not well-documented. The common prototype applied for hepatoprotective drug screening is the carbon tetrachloride (CCl 4 ) induced hepatic injury (Rodrigues et al., 2016) . As CCl 4 have been reported for its damaging effects on the liver because on metabolism by P450, it produces free radicals (Johnston & Kroening, 1998) . These free radicals cause lipid peroxidation by binding to DNA, proteins, or lipids (Yasuda, Izumi, Shimada, Kobayakawa, & Nakanishi, 1980) . The degree of hepatic injury is evaluated by the higher level of biochemical parameters that is ascribed to the production of trichloromethyl free radicals which eventually causes lipids peroxidation present in cellular (Dusheiko, 1996) Calotropis procera (Aiton) Dryand.

Crude hydro-ethanol solution extract

Prevents of the depletion of GSH levels. C. procera contains flavonoids thus it also performs the antioxidant activity (McOmish et al., 1994) Clerodendrum abilioi R. Fern.

Ethanol extract decreased the serum enzyme ALT, AST, ALP, TGL, and total cholesterol and considerably increased the glutathione level (Chamberlain, Adams, Saeed, Simmonds, & Elliott, 1997) Ficus carica L. Leaves Crude petroleum ether extract

Reduction in the levels of ALT and AST. The petroleum ether extract of Ficus leaves repair the damaged liver cell (Gond & Khadabadi, 2008) Glycyrrhiza uralensis -Glycyrrhizin Glycyrrhizin administered in PLC/PRF/5 cells suppressed the secretion of HBsAg into the culture medium and concluded that glycyrrhizin modifies the intracellular transport and the surface nature of the hepatocytes (Sato et al., 1996) Momordica dioica Roxb. ex Willd.

Alkaloids, phenolic compounds, glycosides, flavonoids

Oral administration of the extract significantly normalized and restored the elevated serum enzymatic levels of AST, ALT, SALP, and total bilirubin. Its hepatoprotective activity is due to the antioxidant and free radical scavenging activity. (Surai, 2015) Nelumbo nucifera Gaertn. Leaves Catechin glycoside, myricitrin-3-O-glucoside, hyperin, isoquercitrin, quercetin-3-O-rhamnoside, astragalin

Lotus leaf extract possess significant hepatoprotective and antioxidant activity in CCl 4 -induced toxicity rat model. Free radicalscavenging and antioxidant activity due to the presence of some flavonoids and phenolic compounds results in the hepatoprotective activity. (Theplantlist, 2013) Paeonia lactiflora Pall. and A. membranaceus (Fisch.) Bunge.

-Progression of CCl 4 -induced hepatic fibrosis was inhibited in rates by decreasing the level of tumor growth factor-β1 and inhibit collagen synthesis (Sun et al., 2007) S. miltiorrhiza Bunge. Roots -S. miltiorrhiza could reverse the CCl 4 -induced fibrosis treatment by decreasing the levels of transforming growth factor-β1, procollagens I and III, and metalloproteinase-1 and decreasing the levels of metalloproteinase-13 in liver of the affected rates (Wasser et al., 1998) S. miltiorrhiza Bunge. Roots S. miltiorrhiza polysaccharides Protects liver against immunological injury by adjusting the levels of alanine aminotransferase, aspartate aminotransferase, nitric oxide, tumor necrosis factor and interleukin-1 (Zein et al., 1996) Solanum nigrum L. Total decoction Crude aqueous extract Inhibited thioacetamide-induced collagen (α1) and transforming growth factor-β1 mRNA levels in the liver of mice with thioacetamide-induced liver fibrosis (Hsieh et al., 2008) S. nigrum L. and Cichorium intybus L.

Crude plant extract Protect DNA against oxidative damage in the reaction mixture containing calf thymus DNA and free radical generating system (Sultana et al., 1995) (Continues) membrane (Chen, Yu et al., 2016) . Figure 2 shows the different strategies applied for studying the in vivo effects of induced hepatotoxicity in mice models. The leaves are marked by distinct white "milky" veins that give the plant its common name (Theplantlist, 2013) . Historically, S. marianum was used medicinally to treat disorders of the gallbladder, spleen, and liver, but the most important medicinal application of S. marianum is its use as a hepatoprotective herbal treatment and as supportive treatment for chronic inflammatory liver disorders such as hepatitis, cirrhosis, fatty infiltration, and some other forms of liver damages due to toxic chemicals, poisonous mushrooms, and alcohol (Freitag et al., 2015) .

The most important component extracted from S. marianum is silymarin (Lu, Lu, Chen, Zhang, & Wu, 2007; Wu, Wang, & Que, 2006) , which is used to treat a variety of liver disorders, including chronic and acute viral or drug/toxin-induced hepatitis, alcoholic liver disease, and liver cirrhosis (Lu et al., 2007) . Silymarin is a combination of different ingredients with silibinin as the most active among them (Surai, 2015) . Silymarin has been approved for clinical studies in treating the Hepatitis C virus infection (Ferenci et al., 2008) .

There are many studies on the mechanism of hepatoprotective effects of silymarin. Recently, Tunca et al. (2009) showed that silymarin has a protective action on pyridine-induced hepatic injury in Syrian hamsters. The study concluded that it decreases the metabolic activation of pyridine (by decreasing the cytochromes P450 1A1

protein concentration) and control the elevation of inducible nitric oxide synthase expression. All these factors play a protective role in liver injury.

In another study, Farghali, Kamenikova, Hynie, and Kmonickova (2000) concluded that in addition to inhibition of lipid peroxidation, the 

Hepatoprotective activity against thioacetamide-induced hepatotoxicity (Khatri, Garg, & Agrawal, 2009) Tephrosia purpurea (L.) Pers.

Decreased serum aspartate aminotransaminase (35% and 31%), alanine aminotransaminase (50% and 42%), gamma glutamyl transpeptidase (56% and 49%), alkaline phosphatase (46% and 37%), total bilirubin (61% and 48%), and liver MDA levels (65% and 50%), and significant improvement in liver glutathione (73% and 68%) when compared with thioacetamide-damaged rats. (Hosseinzadeh & Nassiri-Asl, 2015) Vitex negundo L.

Administration of ethanol solution extract of Vitex leaf caused a significant decrease in TB, AST, ALT, and ALP levels in rats. (Abdulkarim et al., 1998) Zanthoxylum armatum DC. Bark Berberine Elevated serum enzymatic levels of serum transaminases, alkaline phosphatase. Total bilirubin was considerably restored to a normal level. (Cha et al., 1991) Note. GPX = glutathione peroxidase; MDA = malondialdehyde; AST = aspartate transaminase; ALT = alanine aminotransaminase; CCl 4 = carbon tetrachloride; SOD = superoxide dismutase; GSH = glutathione; TB = Total Bilirubin; ALP = alkaline phosphatase HBsAg = hepatitis B surface antigen; TGL = triglyceride lipase.

inhibition of the increased intracellular Ca 2 i plays a critical role in the hepatoprotective effect of Silymarin. Although, Upadhyay, Kumar, and

Singh (2007) showed that silymarin restores the changes in the expression and activity of Cytochrome P450 (CYP) enzymes (CYP1A1, CYP1A2, and CYP2E1), glutathione-S-transferase, glutathione reductase and glutathione peroxidase, and lipid peroxidation in male Swiss albino mice. Glycyrrhizin administered in PLC/PRF/5 cells suppressed the secretion of HBsAg into the culture medium and concluded that glycyrrhizin modifies the intracellular transport and the surface nature of the hepatocytes Glycyrrhizin administered intraperitoneally inhibits the lipopolysaccharide-and D-galactosamine-induced liver injury by preventing inflammatory responses and IL-18 production in mice Glycyrrhizin inhibited anti-Fas antibody-induced hepatitis in mice by acting upstream of CPP32-like protease Administration of glycyrrhizin or glycyrrhetinic acid, significantly suppressed α2 (I) collagen gene promoter activation and progression of liver fibrosis induced by repeated CCl 4 injections in transgenic mice (Liew, Erali, Page, Hillyard, & Wittwer, 2004; Martell et al., 1992; Ogata, Alter, Miller, & Purcell, 1991; Sato et al., 1996) Phyllanthin Phyllanthus amarus Schum. et Thonn. Phyllanthin help in restoration of antioxidant potential of rat hepatocytes, level of GSH, and SOD and GR activities reduced by ethanol (Chirdchupunseree & Pramyothin, 2010) p-Methoxy benzoic acid Capparis spinosa L. The compound alleviated the enzyme levels increased as result of administration of CCl 4 , and PCL (Gadgoli & Mishra, 1999) Silymarin Silybum marianum (L.) Gaertn. Silymarin attenuated the rifampicinand/or pyrogallol-induced hepatotoxicity by restoring the alterations in the expression and activity of CYP1A2 and CYP2E1, glutathione-S-transferase, glutathione reductase and glutathione peroxidase, and lipid peroxidation in male Swiss albino mice. Silymarin suppresses N-nitrosodiethylamine induced hepatocarcinogenesis by modulating the antioxidant defense status of the animals (Farghali et al., 2000; Upadhyay et al., 2007) Note. HBsAg = hepatitis B surface antigen; CPP32 = 32-kDa putative cysteine protease; CCl 4 = carbon tetrachloride; GSH = glutathione, SOD = superoxide dismutase; GR = glutathione reductase; CYP = Cytochrome P450; PCL = Paracetamol.

G. glabra is a member of the Glycyrrhiza genus (Isbrucker & Burdock, 2006) , an ancient genus that contains the most commonly used herbs in Chinese traditional medicine (Hosseinzadeh & Nassiri-Asl, 2015) .

Glycyrrhiza species are considered among the most important herbaceous plants for a diverse array of pharmacological activities (Hosseinzadeh & Nassiri-Asl, 2015) . Chemical structures of (1) cryptotanshinone, (2) phyllanthin, (3) quercetin, (4) glycyrrhizin, (5) silymarin, and (6) p-methoxybenzoic acid, also known as p-Anisic acid. All the images were adopted from NCBI-PubChem with the compound IDs; 160254, 358901, 5280343, 14982, 7073228, and 7478, respectively (Pubchem, 2017) (Mao et al., 2016) . One of the bioactive compounds from P. amarus is phyllanthin, which is a lignan compound and is traditionally applied in the treatment of many liver diseases (Hanh, Sinchaipanid, & Mitrevej, 2014) . It was shown to have hepatoprotective effects on ethanol-induced oxidative damage in primary culture of rat hepatocytes through its antioxidant activity especially the activities of superoxide dismutase (SOD) and glutathione reductase (Chirdchupunseree & Pramyothin, 2010) . Previously, Naaz, Javed, and Abdin (2007) 3.9 | C. intybus L.

C. intybus L., commonly known as chicory, belongs to the Lactuceae family and is typical Mediterranean plant indigenous to Western Asia, Europe, North America, and Egypt, which varies in perianth color from white, red to blue (Norbaek, Nielsen, & Kondo, 2002 3.10 | S. nigrum L.

S. nigrum L., commonly known as "Black Nightshade", is a species in the family Solanaceae ( CCl 4 -induced hepatic necrosis. This hepatoprotective effect might be due to its adjustment of antioxidant activity, detoxification enzymes, and its free radical scavenger effects.

In another study, Hsieh, Fang, and Lina (2008) induced liver fibrosis by administering thioacetamide in mice and treated them with distilled water and S. nigrum extract via oral administration for 12 weeks.

This treatment alleviated the hepatic hydroxyproline and α-smooth muscle actin protein levels in mice and inhibited thioacetamideinduced collagen and transforming growth factor-β1 mRNA levels in the liver. Histological examination of liver also confirmed that this extract reduced the degree of fibrosis caused by thioacetamide treatment which is the probable reason for the reduction of hepatic fibrosis.

3.11 | S. mukorossi Gaertn.

S. mukorossi Gaertn., commonly known as Ritha or Aritha, is abundantly found in India. Its fruit is reported to have expectorant, purgative, antidotal, and abortifacient effects. Additionally, it is used in epilepsy, extreme salivation, and chlorosis (Suhagia, Rathod, & Sindhu, 2011) .

The saponins extracted from this plant are spermicidal (in vitro) and due to this property, it has been used in contraceptive cream (Rastogi & MB, 1999) .

Pharmacological studies of S. mukorossi have shown their potential effect as hepatoprotective agents (Upadhyay & Singh, 2012) . To assess the hepatoprotective activity of the S. mukorossi, Wistar male rats were treated with CCl 4 . Administration of CCl 4 to normal rats increased the serum levels of ALT, AST, ALP, and bilirubin. These enzymes eventually cause damage to the hepatic cells. The CCl 4 -treated liver cells cultured on Petri plates were treated with the extracts of S. mukorossi and were reported to alleviate the levels of these enzymes. When histopathological studies of the CCl 4 -treated rats were performed, they showed that it also causes the demolition of architectural configuration of target cells. However, rats that were treated with S. mukorossi presented normal lobular structural design, which shows its reparative properties and thus its hepatoprotective effects.

3.12 | G. biloba L.

G. biloba L. belongs to family Ginkgoaceae (Theplantlist, 2013) . It is one of the significant herbs of the Chinese traditional medicine. G. biloba leaf extract has been reported to have therapeutic activities against age-related memory deficit problems, including Alzheimer's and dementia; cardioprotective, antiasthmatic, antidiabetic, hepatoprotective, photoprotective effects, DNA repair mechanism, antioxidant, and antiinflammatory activities (Mohanta, Tamboli, & Zubaidha, 2014) .

G. biloba has been associated with a strong hepatoprotective activity through numerous studies (Parimoo et al., 2014) . G. biloba amplifies cellular antioxidant protection system consisting of glutathione peroxidase, glutathione S-transferase, glutathione reductase, nonprotein thiols, catalase, and antioxidant enzymes (SOD). The binding of an individual part of herbal tracks to that of phosphatidylcholine produces phytosome having better efficacy compared with traditional herbal extracts (Naik, Pilgaonkar, & Panda, 2006) .

Rifampicin is an antibiotic widely used in tuberculosis chemotherapy. It has been reported to cause hepatoxicity, the reason of which is unknown as it is always given in combined form with other antibiotics such as isoniazid and ethambutol. Wistar albino rats were treated with rifampicin that caused hepatoxicity in them. Their blood samples were taken, and assays of their blood samples were performed to know the levels of SGPT, SGOT, and ALP. The elevated levels of SGOT, SGPT, and ALP show liver damage as these enzymes escape from the liver into the blood in case of liver damage. With parallel treatment through Ginkoselect Phytosome® and the standard drug Silymarin, the markers enzymes levels in serum were nearly at a normal level or marginally elevated. This suggests the hepatoprotective quality of G. biloba plant.

It also elevates total protein levels and albumin, which shows its hepa- with activities against chronic hepatic fibrosis (Nitha, Prabha, Ansil, & Latha, 2014) . It also shows antiinflammatory, antibiotic, antileprosy, and antihelminthic properties (Arya et al., 2015; Shoaib et al., 2016; Syed & Khan, 2016) .

In an experiment designed to check the hepatoprotective effect of W. fruticosa flower extract (WF4), albino Wistar rats were administered with CCl 4 which resulted in the increased level of ALP, AST, ALT, and lactate dehydrogenase. These enzymes leak from serum into the blood.

Thus, CCl 4 damage causes loss of enzymes which are responsible for drug metabolism (Chandan et al., 2008) . These rats were administered with WF4. The extract reversed the elevated lipid peroxidation and regulated the liver glucose-6-phosphate and GSH levels. These results are in line with former information for other hepatoprotective agents . 3.14 | V. trifolia L.

V. trifolia L., known generally as chaste tree, is a high-value medicinal plant that belongs to the family Verbenaceae. Its leaves are effective as plaster against pains, infections, and fever. Its fruits are used in curing amenorrhea, and the flowers are effective against fever (Chan, Baba, Chan, Kainuma, & Tangah, 2016) . The active constituents of this plant are essential oil (Kvasnicka, Biba, Sevcik, Voldrich, & Kratka, 2003) , viterifolins, and diterpenes. It also possesses some important pharmacological qualities, that is, antipyretic (Rani & Sharma, 2013) , antibacterial (Lawitz et al., 2014) , antiallergic, and antiasthmatic properties (Lawitz & Gane, 2013) . Medical practitioners use this plant in the treatment of acute jaundice. However, literature study suggested that this plant is not well screened for its hepatoprotective activity.

Nonetheless, the tribal groups of Western Ghats use this plant leaf extracts in treating jaundice, and these results give some scientific evidence of hepatoprotective activity. 3.16 | S. chinensis (Turcz.) Baill S. chinensis (Turcz.) Baill is widely used in traditional and modern Chinese medicine for the treatment of many disorders including insomnia, respiratory failure, and weakness. Moreover, mental health improving ability along with fatigue reduction property is also validated for S. chinensis in Russian medicine (Szopa, Ekiert, & Ekiert, 2017) .

In general, dibenzocyclooctadiene lignans found in S. chinensis are known to exhibit potent hepatoprotective activity (Zheng et al., 2017) . In one of the study of individual lignin, Gomisin A was found responsible for the acceleration of hepatocytes proliferation and increase hepatic flow (Panossian & Wikman, 2008) . Furthermore, elevation of mitochondrial glutathione concentration was found to be linked with γ-schisandrin hepatoprotective mechanism. The increase in vitamin C concentration in the liver of test animals upon treatment with γ-schisandrin also validates its hepatoprotective ability. Another individual lignin, Schisandrin B was also found to counter oxidative harm to liver tissues (Thandavarayan et al., 2015; Xin et al., 2017) . In one scientific study, the hepatoprotective mechanism against acetaminophen-induced liver injury of six Schisandra lignans (deoxyschisandrin, Schisantherin A, Schisandrin B, Gomisin A, Schisandrin C, and schisandrin) was elucidated. The hepatoprotective ability of these lignins was found to be associated with inhibition of cytochrome-mediated bioactivation (Jiang et al., 2015) . Furthermore, another mechanistic study investigated the hepatoprotective effect of Schisandra polysaccharide in nonalcoholic fatty liver disease mice models. The results demonstrate potential down regulation of hepatic lipogenesis genes and LXRα/SREBP-1c/ FAS/ACC and SREBP-2/HMGCR signaling pathways in the liver (Wang, Song et al., 2016) .

3.17 | C. chinensis Lam.

C. chinensis Lam. also known as Chinese dodder is a parasitic plant having diverse traditional medicinal uses as a tonic, sex enhancer, and abortion preventer (Zheng, Dong, & She, 1998) . Studies also have scientifically validated the hepatoprotective activity of C. chinensis (Donnapee et al., 2014) . Yen, Wu, Lin, and Lin (2007) chinensis seeds ethanol solution extract was found to be more effective in rats with acetaminophen-induced hepatotoxicity (Yen, Wu, Lin, Cham, & Lin, 2008) . The mechanism of hepatoprotective potential as demonstrated by ethanol solution extract of C. chinensis is proposed to be the elevated activities of antioxidant enzymes.

3.18 | L. barbarum L.

L. barbarum L. berries are very famous in traditional Chinese medicine for the treatment of inflammation, cancer, eye disorders, throat infection, and anemia. The use of these berries has been validated as food and also has gained great importance due to its significant antioxidant potential (Cheng et al., 2015) .

The major active components of L. barbarum berries are L. 3.19 | A. sinensis (Oliv.) Diels A. sinensis (Oliv.) Diels is reported in Chinese herbal medicine for the treatment of cardiovascular disease, anemia, and hepatic disorders (Bunel, Antoine, Nortier, Duez, & Stévigny, 2015) . The A. sinensis polysaccharides (ASP) extracted from A. sinensis roots having the average molecular weight of 72,900 Da is regarded as a potential active component of A. sinensis that exhibits a wide range of pharmacognostic properties (Hsu, Tsai, & Tsai, 2014) .

The hepatoprotective potential of ASP in CCl 4 -induced liver injury and via using ischemia/reperfusion rat is widely established (Zhang et al., 2010) . Wang, Wen, Li, Zhang, & Yang (2016) 

The number of hepatoprotective products from plants is ever increasing. In addition to the hepatoprotective role of a general class of phenolics and flavonoids, many studies have defined specific compounds for their preferable role in hepatitis and other liver disorders (Shehab et al., 2015) . Some of the important plants and their products are highlighted in Figure 3 . Among the many different compounds, few are distinguished for their promising role in liver inflammation. We have, therefore, selected six important compounds for their hepatoprotective role (Table 2) .

Quercetin, for instance, a major flavonol commonly found most of the plants, is a potent hepatoprotective agent. The first basis of quercetin-based potency has been attributed to the antioxidant activity of this compound. One of the specific mechanisms of Quercetin supplementation was established through ethanol-induced cytotoxicity which affects the activity of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. For instance, Quercetin supplementation restored the glutathione reductase activity which was affected by ethanol that in turn reduced the glutathione content of liver. Quercetin supplementation has also been attributed to hepatoprotection against metals, pesticides, drugs, toxins, and viruses (Miltonprabu et al., 2016) .

Rhein (4, 5-dihydroxyanthraquinone-2-carboxylic acid) is another important hepatoprotective compound extensively found in medicinal herbs, such as Rheum palmatum L., Cassia tora L., Polygonum multiflorum

Thunb., and Aloe barbadensis Miller. The mechanism of action through which Rhein acts has been described as modulation of CYP enzymes in rat liver, attenuation of total cholesterol and triglyceride levels in serum, and amelioration of glucose and lipid metabolism. Similarly, Rhein downregulated the levels of serum ALT, hyaluronic acid, procollagen type III, and liver malondialdehyde and inhibited the expression of transforming growth factor beta 1 and alpha-smooth muscle actin in tetrachloride/ethanol-induced liver fibrosis rats .

Similarly, flavonoids, lignans, terpenoids, and steroids from Vitex negundo L. have also been shown to demonstrate hepatoprotective activities (Zheng et al., 2015) . Extracts containing these compounds have been shown to improve biochemical and functional parameters and thus alleviate CCl 4 -induced damage in liver rats. Negundoside, for instance, which is a glycoside, has been demonstrated to reduce calcium-mediated toxicity and CCl 4 -induced oxidative stress through regulation of calcium homeostasis and decreasing the production of ROS and lipid peroxidation (Zheng et al., 2015) . Table 2 with their structures given in Figure 4 .

The present literature is not sufficient to assess the safety of most of the hepatoprotective and liver regenerative herbs and herbal products, as most of the studies focus on their antihepatotoxic effects only.

However, some previous experiments on rats show that no adverse effects were observed by administering intraperitoneal injection of the A. membranaceus extracts at 0.5 g/kg for 30 days, whereas large doses (1 g/kg) of A. membranaceus root extracts resulted in mutagenicity in mice when injected directly into the stomach lining ). In another study, Sato et al. (1996) observed no significant toxicity of various concentrations of glycyrrhizin on PLC/PRF/5 cells in vitro. Gadgoli and Mishra (1999) reported that p-Methoxy benzoic acid extracted from C. spinosa was nontoxic at 1 mg/ml when applied to rat hepatocytes in vitro. This supports the claims made in the traditional system of medicine. Similarly, silymarin is shown to have a lack of toxicity and side effects even at high doses (Upadhyay et al., 2007) . Isbrucker and Burdock (2006) reported that No-Observed-Effect Levels for purified glycyrrhizin are in the range of 15-229 mg/ kg/day and concluded that current levels of consumption of licorice extract products and glycyrrhizinate are safe.

Although, several herbals show potential activity for the treatment of acute and chronic liver diseases premarketing drug-testing, and pharmacovigilance is needed as with any other drug. So far, herbals

to treat chronic liver diseases should not be recommended outside clinical trials as the evidence supporting its use is insufficient (Stickel, Patsenker, & Schuppan, 2005) , and publications relevant to the cytotoxicity of medicinal plants should be encouraged (Mukhtar et al., 2008) . Moreover, there are issues like approval of the plant products/extracts as a drug from regulatory agencies such as the Food and Drug Administration or any other equivalent agencies.

Extensive literature survey of hepatoprotective plants clearly indicates that herbal drugs have an enormous potential for the treatment of liver diseases. In this article, we reviewed the scientific merit of selected plants studied for their hepatoprotective mechanism of action. The major hepatoprotective mechanism identified by the majority of the studies is through combating the oxidative stress that damages the liver. We have summarized the effect of extracts and compounds from different herbs on liver injury considering changes in their biochemical parameters. We also presented the possible data available in the literature for different plants regarding their phytochemical constituents.

We, therefore, conclude that herbs and herbal preparations are among the most important sources of hepatoprotective and liver regeneration medicines. However, further research is needed to identify, characterize, and standardize the active ingredients, useful compounds, and their preparations for the treatment of liver diseases. Moreover, a combination of the traditional herbal medicines with the modern and conventional medicine may be one of the best options for the treatment of liver disorders and other diseases and infections, soon.

The importance of medicinal plants can be determined from World Health Organization's estimates, which states that up to 80% of the world's population fulfill their healthcare needs from medicinal plants (Mukhtar et al., 2008) . There has been a significant rise in using overthe-counter medicinal plant products containing powerful medicinal drugs and are believed to have to produce progressive effects with reduced side effects. However, therapeutic failures or adverse effects have been observed in many cases as pharmacological mechanisms of the herbal mixtures/preparations are not well-studied. The most important concern involving the use of medicinal plants is to identify and standardize the exact method of preparation of an extract, identification of active ingredients and details of administration (Yip & Kwan, 2006) . In this relationship, the screening and characterization of other undiscovered herbal products in traditional medicine is needed. The integration of the therapeutic use of traditional Chinese medicinal knowledge with the synthetic and traditional oriental medicinal knowledge is a key area of research (Cho & Leung, 2007) .

However, medicinal plants cultivated in different geographical regions are believed to differ in therapeutic effects in different diseases and infections. For example, A. membranaceus used in Chinese traditional medicine, from certain locality contains more favorable trace elements and fewer harmful trace elements than those from other localities. In this context, the use of new therapeutic strategies based on natural plants may be useful to provide minimal toxicity, higher effectiveness, and a wider therapeutic background for effective manipulation than existing pharmaceutical products (Panico et al., 2005) .

Authors declare that they have no competing interests.

ANIMALS Not applicable.

The current article is a review article and does not contain any studies with human participants performed by any of the authors. 

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