Advances in hepatoprotective medicinal plants research

Hepatic dysfunction is a major catastrophe that challenges the health concern researchers. Multiple factors such as biological, chemical and drug overdose are associated with liver disorders. Man-made pharmaceutical preparations, which are usually used for the treatment, further accelerate the toxification of the liver. In this situation, a great reliance has been evident on natural products which seem promising in dealing with liver diseases effectively. Plants are the basis of innate products, or dynamic constituents named as phytochemicals, which have been analyzed for their hepatoprotective potential and a review article on hepatoprotective plants was published in 2014 in Bangladesh Journal of Pharmacology. After that, a number of researches have been completed to identify new hepatoprotective medicinal plants. The purpose of this review was to update the information until now. Article Info Received: 2 April 2017 Accepted: 1 July 2017 Available Online: 4 July 2017 DOI: 10.3329/bjp.v12i3.32260 Cite this article: Qadir MI, Ahmad Z. Advances in hepatoprotective medicinal plants research. Bangladesh J Pharmacol. 2017; 12: 229-42. Advances in hepatoprotective medicinal plants research Muhammad Imran Qadir and Zara Ahmad Institute of Molecular Biology & Biotechnology, Bahauddin Zakariya University, Multan, Pakistan. This work is licensed under a Creative Commons Attribution 4.0 International License. You are free to copy, distribute and perform the work. You must attribute the work in the manner specified by the author or licensor M in ire v ie w tetrachloride, thioacetamide, diethylenitrosamine, 4-Dglucosamine/lipopolysaccharides) and overdose of alcohol (Khan et al., 2016); leads to the elevation of serum biochemical markers like serum aminotransaminases, alkaline phosphatase and bilirubin (Chaudhari et al., 2009). Tissue thiol depletion, lipid peroxidation, plasma membrane damage are the indicators of reactive species depletion (Shaik et al., 2012). A number of inflammatory and liver diseases are mediating to oxidative stress and oxidative chain reaction inhibitory compounds have been reported against hepatotoxicity (Pithayanukul et al., 2009). By virtue of the severe hepatotoxic effect of chemicals in humans and animals, carbon tetrachloride is one of the well-known xenobiotics (Parmar et al., 2009) which after reductive halogenations ultimately leads to liver damage. An overdose of paracetamol (also known as acetaminophen) causes oxidative stress and glutathione depletion by its activation and then transformed by cytochrome P450 enzymes to NAPQI (N-acetyl-pbenzoquinoneimine); a deadly metabolite (Parmar et al., 2010). Medicinal Plants to Treat Liver Disease It is a challenge to find the ways of treatment for the common liver diseases. Although, there is best incompatibility among effectiveness of treatment such as colchicine, corticosteroid, interferon and penicillamine but the incidence of adverse effect is severe (Jain et al., 2013). For the management of hepatic diseases, there is a need to innovate alternative pharmaceuticals having more effectiveness and less toxicity. Chiefly, about 80% of the world’s population has employed plant material as traditional medication for health care. A variety of chemical compounds such as coumarins, essential oils, glycosides, carotenoids, organic acids, alkaloids, lignin’s, phenols, xanthenes, flavonoids and monoterpenes are present in the plant as well as fruits for liver protection (Madrigal-Santillán et al., 2014). Many fields such as botany, chemistry, biotechnology, pharmacognosy and pharmacology are doing a massive effort on herbal remedies using statistical methods to assess the reliability of claims (Roy et al., 2014). Although numerous herbal medicines have universal status significantly but there are some limiting factors behind their usage including inconsistency of the herbal drugs, lack of recognition of active constituents, randomized controlled tentative trials, and lack of toxicological review (Saleem et al., 2010). Besides all the abovementioned restrictions, the researchers are probing some valuable treatments for the liver disorders. Plantderived natural products and herbs have gained significant considerations in recent years due to their various pharmacological properties; anti-oxidant, antiinflammatory, etc for hepatoprotective effect. Some examples of medicinal plants with hepatoprotective effect through different mechanisms are explained here briefly: Berberies aristata, belongs to family the Berberidaceae has hepatoprotective activity against carbon tetrachloride-induced hepatic damage by inhibiting lipid peroxidation. Plant bark extract (at a dose of 100 and 300 mg/kg) inhibits the hepatic damage by decreasing the AST, ALT, ALP and bilirubin (total and direct) which increased after carbon tetrachloride administration (Rathi et al., 2015). Boerhaavia diffusa (at a dose of 250 and 500 mg/kg) prevents the hepatic cells death and lipid peroxidation by free radical scavenging activity and has a stimulatory effect on hepatic regeneration against carbon tetrachloride-induced hepatotoxicity. It also decreases the serum levels of alanine transferases, aspartate transferases, alkaline phosphatase, total serum bilirubin and serum proteins which significantly increased after carbon tetrachloride administration (Beedimani and Jeevangi, 2015). Canna indica is effective against hepatic necrosis and NAPI-mediated paracetamol-induced hepatic damage. The plant rhizome extract exerts an inhibitory effect on hepatocytes necrosis by hepatocytes regeneration, decreased serum alanine transaminase and shows antiinflammatory activity against NAPQI mediated paracetamol poisoning (Longo et al., 2015). Mangifera indica (mango) belonging to family Anarcardiaceae and has hepatoprotective action by anti -oxidative and anti-lipoperoxidative mechanisms. Mangifera indica aqueous stem bark extract at dose of 150-500 mg/kg has hepatoprotective activity against carbon tetrachloride-induced hepatic necrosis via inhibiting increased level of serum aminotransferases, alkaline phosphatase, bilirubin (total and conjugated), fasting blood glucose and malondialdehyde and by increasing total protein, albumin, total cholesterol, high -density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), superoxide dismutase, reduced glutathione (GSH) and catalase activity which might attributed to anti-oxidant and antilipoperoxidative potential (Adeneye et al., 2015). The crude powder of Mimosa pudica prevents liver cell necrosis and lysosomal latency by normalizing serum biochemical parameters against carbon tetrachlorideinduced hepatotoxicity (Kumaresan et al., 2015). Juice of Ananas comosus (family Bromeliaceae), commonly known as pineapple, has liver protective action (Mohamad et al., 2015) by controlling different protein expression, anti-oxidant levels and liver marker enzymes against paracetamol-induced toxicity. Fruit seeds of Cassia fistula (golden shower tree of family Fabaceae) have protective potential against hepatotoxins-induced liver damage and have nonsignificant effect on hematological parameters (Iqbal et 230 Bangladesh J Pharmacol 2017; 12: 229-242


Introduction
Different medicinal plants are used for the protection and treatment of liver diseases and a review article on hepatoprotective plants was published in 2014 (Saleem and Naseer, 2014). After that, a number of researches have been completed to identify new hepatoprotective medicinal plants. The purpose of this review was to update the information regarding medicinal plants used in the protection and treatment of liver diseases, until now.

Liver Diseases
The liver is one of the most rudimentary organs that engage in the biotransformation of nutrients; provide protection to the body against foreign agents, detoxification as well as the excretion of drugs and xenobiotics from the body (Sagar et al., 2014). Thus, it is requisite to protract liver strength for overall body's health and safety. Unluckily, environmental toxins, meager eating habits, alcohol and over-the-counter drug use are recurrent ill-treatments which can weaken the liver (Murugaian et al., 2008). National Center for Health Statistics (NCHS) at the Centers for Disease Control and Prevention (CDC) considered chronic liver disease and cirrhosis; as the 12 th foremost basis of death which are asserting 30,000 lives in the United States per year (Gupta et al., 2015).
Liver diseases possibly classified as inflammatory liver diseases (acute/chronic hepatitis), non-inflammatory diseases (hepatosis) and liver fibrosis (also called cirrhosis) (Asadi-Samani et al., 2015). The main cause of pathogenesis of liver injury is the involvement of a deadly agent or the bio-activation of free radicals that elicits an immune response or protein dysfunction, lipid peroxidation, DNA damage, oxidative stress and depletion of reduced glutathione (Bedi et al., 2016). All liver cells including hepatocytes, kupffer and endothelial cells are involved in the pathogenesis of hepatic injury by programmed cell death, necrosis, ischemia and renewal, leading to tainted gene expression. Jaundice, hepatomegaly, hepatic encephalopathy, cirrhosis and obtrusive jaundice are well-known liver disorders (Saleem and Naseer, 2014). Liver damage can be caused by many factors such as biological, autoimmune diseases, some drugs e.g. high dosage of paracetamol, antitubercular drugs, lethal compounds (such as carbon tetrachloride, thioacetamide, diethylenitrosamine, 4-Dglucosamine/lipopolysaccharides) and overdose of alcohol ; leads to the elevation of serum biochemical markers like serum aminotransaminases, alkaline phosphatase and bilirubin (Chaudhari et al., 2009). Tissue thiol depletion, lipid peroxidation, plasma membrane damage are the indicators of reactive species depletion (Shaik et al., 2012). A number of inflammatory and liver diseases are mediating to oxidative stress and oxidative chain reaction inhibitory compounds have been reported against hepatotoxicity (Pithayanukul et al., 2009). By virtue of the severe hepatotoxic effect of chemicals in humans and animals, carbon tetrachloride is one of the well-known xenobiotics (Parmar et al., 2009) which after reductive halogenations ultimately leads to liver damage. An overdose of paracetamol (also known as acetaminophen) causes oxidative stress and glutathione depletion by its activation and then transformed by cytochrome P450 enzymes to NAPQI (N-acetyl-pbenzoquinoneimine); a deadly metabolite (Parmar et al., 2010).

Medicinal Plants to Treat Liver Disease
It is a challenge to find the ways of treatment for the common liver diseases. Although, there is best incompatibility among effectiveness of treatment such as colchicine, corticosteroid, interferon and penicillamine but the incidence of adverse effect is severe (Jain et al., 2013). For the management of hepatic diseases, there is a need to innovate alternative pharmaceuticals having more effectiveness and less toxicity. Chiefly, about 80% of the world's population has employed plant material as traditional medication for health care. A variety of chemical compounds such as coumarins, essential oils, glycosides, carotenoids, organic acids, alkaloids, lignin's, phenols, xanthenes, flavonoids and monoterpenes are present in the plant as well as fruits for liver protection (Madrigal-Santillán et al., 2014). Many fields such as botany, chemistry, biotechnology, pharmacognosy and pharmacology are doing a massive effort on herbal remedies using statistical methods to assess the reliability of claims (Roy et al., 2014). Although numerous herbal medicines have universal status significantly but there are some limiting factors behind their usage including inconsistency of the herbal drugs, lack of recognition of active constituents, randomized controlled tentative trials, and lack of toxicological review (Saleem et al., 2010). Besides all the abovementioned restrictions, the researchers are probing some valuable treatments for the liver disorders. Plantderived natural products and herbs have gained significant considerations in recent years due to their various pharmacological properties; anti-oxidant, antiinflammatory, etc for hepatoprotective effect. Some examples of medicinal plants with hepatoprotective effect through different mechanisms are explained here briefly: Berberies aristata, belongs to family the Berberidaceae has hepatoprotective activity against carbon tetrachloride-induced hepatic damage by inhibiting lipid peroxidation. Plant bark extract (at a dose of 100 and 300 mg/kg) inhibits the hepatic damage by decreasing the AST, ALT, ALP and bilirubin (total and direct) which increased after carbon tetrachloride administration (Rathi et al., 2015).
Boerhaavia diffusa (at a dose of 250 and 500 mg/kg) prevents the hepatic cells death and lipid peroxidation by free radical scavenging activity and has a stimulatory effect on hepatic regeneration against carbon tetrachloride-induced hepatotoxicity. It also decreases the serum levels of alanine transferases, aspartate transferases, alkaline phosphatase, total serum bilirubin and serum proteins which significantly increased after carbon tetrachloride administration (Beedimani and Jeevangi, 2015).
Canna indica is effective against hepatic necrosis and NAPI-mediated paracetamol-induced hepatic damage. The plant rhizome extract exerts an inhibitory effect on hepatocytes necrosis by hepatocytes regeneration, decreased serum alanine transaminase and shows antiinflammatory activity against NAPQI mediated paracetamol poisoning (Longo et al., 2015).
Mangifera indica (mango) belonging to family Anarcardiaceae and has hepatoprotective action by anti -oxidative and anti-lipoperoxidative mechanisms. Mangifera indica aqueous stem bark extract at dose of 150-500 mg/kg has hepatoprotective activity against carbon tetrachloride-induced hepatic necrosis via inhibiting increased level of serum aminotransferases, alkaline phosphatase, bilirubin (total and conjugated), fasting blood glucose and malondialdehyde and by increasing total protein, albumin, total cholesterol, high -density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), superoxide dismutase, reduced glutathione (GSH) and catalase activity which might attributed to anti-oxidant and antilipoperoxidative potential (Adeneye et al., 2015).
The crude powder of Mimosa pudica prevents liver cell necrosis and lysosomal latency by normalizing serum biochemical parameters against carbon tetrachlorideinduced hepatotoxicity (Kumaresan et al., 2015).
Juice of Ananas comosus (family Bromeliaceae), commonly known as pineapple, has liver protective action (Mohamad et al., 2015) by controlling different protein expression, anti-oxidant levels and liver marker enzymes against paracetamol-induced toxicity. Fruit seeds of Cassia fistula (golden shower tree of family Fabaceae) have protective potential against hepatotoxins-induced liver damage and have nonsignificant effect on hematological parameters (Iqbal et al., 2016). Figure 1 has presented hepatoprotective action of Lepidium sativum (known as garden cress) belongs to family Crucifereae by up-regulating and down-regulating the enzymes, inflammatory genes expression, serum biochemical markers etc (Raish et al., 2016). Plant seeds extract mitigate hepatic injury and structural damage via inhibiting oxidative stress. Numerous plants have been reported against hepatic damage because of their role in hepatic gene regulation. For example, Panax ginseng belongs to family Araliaceae also named as 'ginseng'. Roots of ginseng inhibit toxininduced hepatic damage by decreasing vital genes expression which is essential for normal liver functions (Hafez et al., 2017) as shown in Figure 2.
In Table I, different medicinal plants, fruits, and herbs, Figure 1: D-GalN/LPS (D-galactosamine/lipopolysaccharides) decrease oxidative stress marker enzymes and albumin. Lepidium sativum ethanolic extract has shown hepatoprotective activity by decreasing AST (aspartate aminotransferase), ALP (alkaline phosphatase), ALT (alanine aminotransferase), ɣ-GT (gamma glutamyl transferase) and bilirubin, inhibiting NF-ᴋβ activity, alleviating MPO (myeloperoxidase) content, reducing TBARS (thiobarbituric acid reactive substance), down-regulating IL-6 (interleukin -6), TNF-α (tumor necrosis factor), caspase-3, iNOS and HO-1, up-regulating IL-10 (interleukin-10) and bcl-2 expression CCl4 Figure 2: Panax ginseng has shown anti-fibrosis effect via TGF-β1 signaling pathway in CCl4 induced liver fibrosis model. The administration of ginseng in combination with CCl4 significantly decreased the expression of TGF-β; its receptors, Smad2, Smad3, Smad4, MMP2, MMP9 and TIMP1 genes expression. It also reduced AST (aspartate aminotransferase), ALT (alanine aminotransferase), TG (triglyceride), TC (total cholesterol), and LDL (low density lipids) levels as well as increased HDL (high density lipids)        Amiodarone causes hepatotoxicity with a characteristic prototype of enzyme turbulence. One study was reported on amiodarone-induced liver toxicity in rabbits. Gentamicin, an aminoglycoside antibiotic is used for treatment of bacterial infections. One of the side effects of gentamicin usage is its potential to induce hepatotoxicity. One study was performed on rat to examine the ameliorative effect of plant extract on gentamicin-mediated hepatotoxicity.
Among the entire listed plants, only a few severe toxicity studies were carried out. For example, Acrocarpus fraxinifolius did not show any sign of toxicity up to oral dose of 250 and 500 mg/kg in rats (Abd El-Ghffar et al., 2017) and ethanolic extract of Pandanus odoratissimus at a particular dose, LD50 was found to be 3,000 mg/kg when injected in rats (Mishra et al., 2015).
Botanical plants have been used for anticipation and management of hepatic disorders due to the charisma of chemical constituents. For instance, polyphenolic compounds have an imperative function in alleviating lipid oxidation as well as anti-oxidant activity. Sigmasterol, β-sterol and flavonoids from Acalypha indica, phenol and triterpenoids from Centella asiatica have provided defensive consequence in rat liver against hypoxia by means of lipid peroxidation (Dwijayanti et al., 2015). 70% ethanolic extract of Oxalis stricta has shown a higher concentration of polyphenolic components that was beneficial for therapy of liver disease by anti-lipoperoxidative activity (Patel et al., 2016). Phytochemical investigation of Melothria perpusilla extract revealed the presence of flavonoids, tannins and steroids that have a role in ameliorating hepatic damage by anti-oxidant mechanisms (Yengkhom et al., 2017). Citrus species containing flavonoids also play a crucial role in plant defense scheme. Hesperidin, a bioflavonoid present in citrus fruits, has pharmacological properties and control hepatic cholesterol production via inhibiting the 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase activity (Çetin et al., 2016). Fungal species have gained importance in the prevention of liver diseases.
Fruiting bodies of Oudemansiella radicata, an edible mushroom and belong to the family Physalacriaseae has hepatoprotective activity by anti-oxidant mechanisms attributed to heteropolysaccharides (mannose, glucose and galactose) prepared from the mushroom (Liu et al., 2017).
Heteropolysaccharides (arabinose and galactose) from Zizyphus jujube, commonly known as red date belongs to the family Rhamnaceae has been involved in liver protective activity via alleviating liver marker enzymes (Liu et al., 2015). Plants containing volatile or essential oils also are main pharmacological active compounds and confers positive effect from the medicinal point of view.
Essential oils of Artemisia capillaries has been investigated against carbon tetrachloride-induced hepatotoxicity and has approved protective potential on liver histology, hepatic profile and serum profile (Gao et al., 2016). Anti-oxidant compounds play the significant role in liver protection.
Phyllanthus emblica, due to its anti-oxidant compounds like ellagic acid and gallic acid, has approved hepatoprotective activity in alcohol induce toxicity model (Chaphalkar et al., 2017). Liver protection is also associated with control of protein and gene expression.
Fragaria ananassa (commonly called strawberry, family: Rosaceae) has anti-oxidant, anti-apoptotic and antifibrotic properties by gene expression regulation

Conclusion
This study signified the probable hepatoprotective effects of therapeutic plants. It can be concluded that plants have verified hepatoprotective potential which can be utilized in outlook to prepare valuable hepatoprotective drugs. There is still necessitating scrutinizing the hepatoprotective potential of plants on molecular stage so that authentic method of phytochemical action can be explored.

Financial Support
Self-funded