Bangladesh Journal of Pharmacology Mini Review Advances in hepatoprotective me-Advances in hepatoprotective me-Advances in hepatoprotective me- dicinal plants researchdicinal plants researchdicinal plants research BJP D-GalN/ LPS ↓Oxidative stress mark- er enzymes & albumin Lepidium sativum Down-regulate TNF-α IL-6 HO-1 iNOS mRNA Up-regulate Inhibit NF-kβ activi- ty Caspase-3 IL-10 bcl-2 Alleviate MPO content Reduce TBARS level ↓AST, ALP, ALT, ɣ-GT & Bilirubin ↑SOD, GSH&CAT 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, detoxifi- cation 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 12th 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 endothe- lial cells are involved in the pathogenesis of hepatic injury by programmed cell death, necrosis, ischemia and renewal, leading to tainted gene expression. Jaun- dice, 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 A Journal of the Bangladesh Pharmacological Society (BDPS) Bangladesh J Pharmacol 2017; 12: 229-242 Journal homepage: www.banglajol.info Abstracted/indexed in Academic Search Complete, Asia Journals Online, Bangladesh Journals Online, Biological Abstracts, BIOSIS Previews, CAB Abstracts, Current Abstracts, Directory of Open Access Journals, EMBASE/Excerpta Medica, Global Health, Google Scholar, HINARI (WHO), International Pharmaceutical Abstracts, Open J-gate, Science Citation Index Expanded, SCOPUS and Social Sciences Citation Index; ISSN: 1991-0088 Abstract 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 and 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 per- form the work. You must attribute the work in the manner specified by the author or licensor tetrachloride, thioacetamide, diethylenitrosamine, 4-D- glucosamine/lipopolysaccharides) and overdose of alcohol (Khan et al., 2016); leads to the elevation of serum biochemical markers like serum aminotrans- aminases, 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-p- benzoquinoneimine); 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 incom- patibility 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 monoter- penes are present in the plant as well as fruits for liver protection (Madrigal-Santillán et al., 2014). Many fields such as botany, chemistry, biotechnology, pharmacog- nosy 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 above- mentioned restrictions, the researchers are probing some valuable treatments for the liver disorders. Plant- derived natural products and herbs have gained significant considerations in recent years due to their various pharmacological properties; anti-oxidant, anti- inflammatory, 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 stimula- tory 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 anti- inflammatory 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 anti- lipoperoxidative 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 tetrachloride- induced 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 non- significant effect on hematological parameters (Iqbal et 230 Bangladesh J Pharmacol 2017; 12: 229-242 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 toxin- induced 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-ᴋ activity, allevi- ating MPO (myeloperoxidase) content, reducing TBARS (thiobarbituric acid reactive substance), down-regulating IL-6 (interleukin -6), TNF- (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- 1 signaling pathway in CCl4 induced liver fibrosis model. The administration of ginseng in combination with CCl4 significantly decreased the expression of TGF- ; its receptors, Smad2, Smad3, Smad4, MMP2, MMP9 and TIMP1 genes expression. It also reduced AST (aspartate aminotransferase), ALT (alanine aminotrans- ferase), TG (triglyceride), TC (total cholesterol), and LDL (low density lipids) levels as well as increased HDL (high density lipids) D-GalN/ LPS ↓Oxidative stress mark- er enzymes & albumin Lepidium sativum Down-regulate TNF-α IL-6 HO-1 iNOS mRNA Up-regulate Inhibit NF-kβ activi- ty Caspase-3 IL-10 bcl-2 Alleviate MPO content Reduce TBARS level ↓AST, ALP, ALT, ɣ-GT & Bilirubin ↑SOD, GSH&CAT TG, TC, LDL &HDL AST & ALT Gene expression TGF-β, TβF-I, TβF-II Smad2, Smad3, Smad4 MMP2, MMP9, TIMP1 CoƖ1α2, CoƖ3α1 IL-10, IL-8 Panax ginseng Panax gin- seng + CCl4 TGF-β1 Pathway CCl4 Anti-fibrosis effect Bangladesh J Pharmacol 2017; 12: 229-242 231 Table I Medicinal plants having hepatoprotective potential Plants with com- mon name Parts used Extract Hepatotoxic agent Model Results References Acantholimon gilli- ati Aerial part Methanol Formaldehyde Mouse ↓AST, ALT, ALP Lashgari et al., 2017 Acrocarpus fraxini- folius (Shingle tree) Leaf n-Hexane Paracetamol Rat ↓AST, ALT, ALP, lipid, bilirubin, LPO ↑body wt, SP, HAC Abd El-Ghffar et al., 2017 Acalypha indica (Indian nettle) and Centella asiatica (Centella) Leaf, whole plant Methanol Hypoxia Rat ↓MDA, prevention from hypoxia Dwijayanti et al., 2015 Adansonia digitata (Baobab tree) Fruit pulp Methanol Paracetamol Rat ↓AST, ALT, ALP, MDA ↑SOD, GSH, CAT, paren- chyma preservation of hepatocytes Hanafy et al., 2016 Aloe vera (Ghee gangwar) Stem Ethanol Paracetamol Rat ↓AST, ALT, SALP, biliru- bin Hena et al., 2016 Ananas comosus (Pineapple) Fruit No extract Paracetamol Male mouse ↓AST, ALT, ALP, TG, restored SOD, SH, LPO, FRAP, ↓NF-k , NO, iNOS and liver p450 protein expression Mohamad et al., 2015 Andographis alata (Justicia alata) Leaf Aqueous Carbon tetra- chloride Rat ↓AST, ALT Prevents histopathological changes Nagaraja and Krishna, 2016 Annona muricata (Soursop) Leaf Ethanol No Rat ↑body wt, ↓AST, ALT, ALP Okoye et al., 2016 Aquilaria agallocha (Agarwood) Leaf Ethanol Paracetamol Rat ↓AST, ALT, ALP, LDH, CHL, bilirubin, relative liver wt, ↑final body wt, SP Alam et al., 2017 Artemisia absinthi- um (Sweet worm- wood) Aerial part Alcohol No Rat ↓AST, ALT, TTG Non-significant ↓ in TAP Mohammadian et al., 2016 Artemisia capillar- ies (Yin Chen Hao) Oil No extract Carbon tetra- chloride Mouse ↓AST, ALT, MDA Prevent decrease in SOD, GSH, GSH-Px Gao et al., 2016 Artemisia dra- cunculus (Tarragon) Leaf Ethanol Carbon tetra- chloride Rat ↓AST, ALT, ALP, bilirubin ↑SP Sultana and Ahmed, 2017 Azadiracta indica (Neem) Leaf Aqueous Paracetamol Rat ↓AST, ALT, ALP ↑Vitamin C & E in liver homogenate Nwobodo et al., 2016 Bauhinia purpurea (Purple bauhinia) Leaf Methanol Paracetamol Rat ↓AST, ALT, LDH, ↓liver/ body wt ratio ↑SP Zakaria et al., 2016 Berberis aristata (Chitra) Stem bark Ethanol Carbon tetra- chloride Rat ↓AST, ALT, ALP, bilirubin Rathi et al., 2015 Bidens pilosa (Blackjack) Aerial part Methanol Carbon tetra- chloride D-galactos- amine Mouse ↓ALT, AST, ALP, ↑SP, GSH Abdel-Ghany et al., 2016 Boerhaavia diffusa (Punarnava) Root Aqueous Carbon tetra- chloride Rat ↓AST, ALT, ALP, SB ↑TP Beedimani and Jeevangi, 2015 Brassica oleracea var. capitata f. alba (White cabbage) Aerial part (oil) No extract Carbon tetra- chloride Rat ↓GGTP, ALT, bilirubin Prevents glycogen deple- tion Morales-López et al., 2017 232 Bangladesh J Pharmacol 2017; 12: 229-242 Table I Medicinal plants having hepatoprotective potential (Cont..) Plants with com- mon name Parts used Extract Hepatotoxic agent Model Results References Butea monosperma (Parrot tree) Bark Ethyl ace- tate Thioacetamide Rat Stabilized AST, ALT, ALB, ALP, SOD, CAT, GSH, GR Restored collagen and hy- droxyproline levels ↓expression of p-P13K, p- Akt, p-mTOR Kaur et al., 2017 Caesalpinia bonduc (Grey nicker) Leaf Ethanol Carbon tetra- chloride Rat ↓AST, ALT, ALP, bilirubin, MDA ↑TP, CAT, GSH-Px Ubhenin et al., 2016 Caesalpinia gilliesii (Yellow bird of paradise) Flower Dichloro- methane Carbon tetra- chloride Rat ↓AST, ALT ↑GSH Osman et al., 2016 Canna indica (Achira) Rhi- zome Aqueous Paracetamol Rat Normalized rat behavior, ↓relative liver wt and ALT Longo et al., 2015 Canscorra decussate (Shankhpushpi) Whole plant Methanol Paracetamol Rabbit ↓AST, ALT, ALP, bilirubin Akhtar et al., 2015 Carica papaya (Papaya/pawpaw) Leaf, Unripe fruit Aqueous Carbon tetra- chloride Paracetamol Rat ↓AST, ALT, ALP, bilirubin, UA, MDA ↑GSH, SOD, CAT Awodele et al., 2016 Cassia fistula (Golden shower tree) Fruit seed Methanol No Chick ↓AST, ALT, ALP, urea, CRE ↑plasma protein Iqbal et al., 2016 Cassia tora (Coffee cassia) Leaf Methanol Carbon tetra- chloride Rat ↑TP, ALB, GSH ↓AST, ALT, ACP, ALT, AST, MDA Saravanan and Malarvannan, 2016 Centratherum anthelminticum (Banjira) Seed Ethanol Carbon tetra- chloride Rat ↓AST, ALP ALT, IBR, bili- rubin, UA ↑TP, ALB ↓in %inhibition of SOD, CAT, GSH Qureshi et al., 2016 Ceriopsdecandra (Mangrove plant) Leaf, Bark, Collar, Hypo- cotyl, Flower Petroleum ether, ethanol Carbon tetra- chloride Rat ↓AST, ALT, ALP, BR, CHL, LDH ↑TPN, ALB Gnanadesigan et al., 2016 Citrus macroptera (Satkara/wild orange) Fruit Ethanol Paracetamol Rat ↓ALT, GGT, LDH, AST, ALP, TB, TG, TC Improved serum CRE, urea, UA, Na+, K+, Cl- ↓MDA Paul et al., 2016 Coreopsis tinctoria (Golden tickseed) Flow- ers Ethanol Carbon tetra- chloride Rat ↓ALT, AST, MDA,NO, TNF- , IL-6, IL-1 ↑GRd, SOD, GSH-Px Tsai et al., 2017 Coriandrum sativum (Coriander) Fruit No extract Ibuprofen Rat ↓ALT, AST Baghdadi et al., 2016 Crocus sativus (Saffron) Dried red stigmas Ethanol Amiodarone Male rabbit ↓ALT, ALP, AST, LDH, BR, UA, Na+ ↑ALB synthesis Saleem et al., 2016 Bangladesh J Pharmacol 2017; 12: 229-242 233 Table I Medicinal plants having hepatoprotective potential (Cont..) Plants with com- mon name Parts used Extract Hepatotoxic agent Model Results References Cucumis sativus (Cucumber) Juice No extract Lead Rat Pb detoxification, positive effect on RBCs count and food intake Bajpai et al., 2017 Cymbopogon citratus (Lemon grass) Whole plant Aqueous Paracetamol Rat ↓AST, ALT, MDA, BUN, CRE ↑GSH (liver) Saenthaweesuk et al., 2017 Eclipta alba (Bhangra) Leaf Aqueous Carbon tetra- chloride Rat ↓ALT, AST, ALP, SB ↑SP Beedimani and Shetkar, 2015 Elettaria carda- momum (True cardamom) Seed Aqueous Gentamicin Rat ↓AST, ALT, BR, CHL, TG, LDL-C ↑SB, HDL-C Aboubakr and Abdelazem, 2016 Eriocaulon quin- quangulare (Eriocaulonsp Australia Red) Whole plant Aqueous Ethanol Porcine liver slices ↓ALT, AST, LDH ↓Lipid peroxidation Fernando and Soysa, 2016 Ferulago angulata (Chavir) Flower Methanol N-nitroso- dimethylamine Rat ↓SOD, CAT, GSH-Px ↓Liver hyperemic Kiziltas et al., 2017 Ficus religiosa (Peepal tree) Latex Methanol, petroleum ether Cisplatin Rat ↓ALT, AST, ALP Yadav, 2015 Fragaria ananassa (Garden strawber- ry) Juice No extract Carbon tetra- chloride Rat ↓AST,ALT, TBARS, nitrate, ↑GSH, SOD, CAT, GPx expression ↑anti-apoptotic protein Bcl2 ↓pro apoptotic proteins bax, caspase-3 Hamed et al., 2016 Gentianella turke- stanerum Whole plant GPE, GEA, GBA, GW Carbon tetra- chloride Male mouse ↓ALT, AST, ALP, TB, GSH, CAT, SOD, MDA ↑ TP Yang et al., 2017 Helicanthus elastica (Mango Mistletoe) Whole plant Ethanol Paracetamol Mouse ↓AST, ALT ↑ALPase activity ↓Serum TB ↑Serum TP Kumar et al., 2016 Grapefruit Lemon Orange (Hesperidin) No No extract Carbon tetra- chloride Rat ↑GSH, CAT, SOD ↓TBARS synthesis, Reduced caspase-3 activa- tion Çetin et al., 2016 Holostemma ada-kodien (Holostemma creeper) Whole plant Alcohol Paracetamol Rat ↓ALT, ASP, ALP, SB, MDA ↑GSH Sunil et al., 2015 Homalium letestui (Makoli) Stem Ethanol Paracetamol Rat ↓ALT, AST, ALP, bilirubin ↑CAT, SOD, GPx, GSH, TP, ALB, hematological param- eters Okokon et al., 2017 Indocalamus latifoli- us Whole plant Ethanol Carbon tetra- chloride Rat ↓ALT, AST, ALP Tan et al, 2015 234 Bangladesh J Pharmacol 2017; 12: 229-242 Table I Medicinal plants having hepatoprotective potential (Cont..) Plants with com- mon name Parts used Extract Hepatotoxic agent Model Results References Juniperus communis (Juniper) Leaf Ethanol Paracetamol Rat ↓ALT, AST, ALP, bilirubin Ved et al., 2017 Lagerstroemia speciosa (Queen’s flower) Flower Ethanol Carbon tetra- chloride Mouse ↓ACP, ALT, AST, ALP, MDA ↑ in %inhibition of LPO, CAT, GSH Tiwary et al., 2017 Lepidium sativum (Garden cress) Seed Ethanol D-galactos- amine/Lipo- polysaccha- rides Rat Down regulate TNF- , IL- 6,HO-1, iNOS, m-RNA ex- pression Up-regulate IL-10, mitigate MPO, NF-k Raish et al., 2016 Lawsonia inermis (Henna) Leaf Methanol Carbon tetra- chloride Rat ↓AST, ALT, ALP, bilirubin Hepatocytes regeneration Mohamed et al., 2016 Mammea africana (African mammee apple) Stem bark Ethanol Paracetamol Rat ↓AST, ALT, ALP, bilirubin ↑TP, ALB, SOD, CAT, GPx, GSH Okokon et al., 2016 Mangifera indica (Mango) Stem bark Aqueous Carbon tetra- chloride Rat ↓ALT, AST, ALP, FBG, TB, CB, LDL-C, MDA ↑TC, TG, HDL-C, TP, ALB ↑SOD, CAT, GSH (liver) Adeneye et al., 2015 Melothria perpusilla (Lamthabi) Aerial parts Aqueous Carbon tetra- chloride Rat ↓ALT, AST, ALP, bilirubin Yengkhom et al., 2017 Mimosa pudica (Touch-me-not) Whole plant Crude extract Carbon tetra- chloride plus paraffin Rat ↓AST, ALT, SB, MDA (serum and tissue), -GT, ALP, ACP Kumaresan et al., 2015 Monotheca buxifoli Fruit Ethanol Isoniazid plusrifampicin Rat Restored ALT, AST, ALP, SP, bilirubin Ullah et al., 2016 Moringa peregrina (Ben tree) Leaf Ethanol Paracetamol Rat Suppress MDA Normalize G-Px ↑GSH, CAT, SOD ↓DNA fragmentation Azim et al., 2017 Moringa oleifera (Sohanjana) Leaf Gum acasia plus alcohol Cadmium Rat ↓AST, ALT, ALP, LPO ↑SOD Toppo et al., 2015 Morus indica (Mulberry) Leaf Aqueous and dechloro- phyllised Carbon tetra- chloride Rat ↓AST, ALT, ALP, TG, LPO ↑SP, GSH Reddy and Urooj, 2017 Murraya koenigii (Curry tree) Leaf Ethanol Carbon tetra- chloride and paraceta- mol Rat ↓AST, ALP, ALT, LPO ↑SOD, CAT, GSH Sangale and Patil, 2017 Nymphaea lotus (White water lily) Whole plant Methanol Carbon tetra- chloride Rat ↓AST, ALT, bilirubin, TBARS (liver) ↑GSH, GSH-Px Oyeyemi et al., 2017 Opuntia mona- cantha (Chnutarthar) Whole plant Methanol, chloroform Paracetamol Rabbit ↓AST, ALT, ALP, bilirubin Saleem et al., 2015 Bangladesh J Pharmacol 2017; 12: 229-242 235 Table I Medicinal plants having hepatoprotective potential (Cont..) Plants with com- mon name Parts used Extract Hepatotoxic agent Model Results References Opuntia robusta (Wheel cactus) and Opuntia streptacan- tha (Prickly pear cactus) Fruits (juice) No extract Paracetamol Rat ↓AST, ALT, ALP ↓LDH leakage and cell ne- crosis Prevent GSH (liver) deple- tion González-Ponce et al., 2016 Otostegia persica (Goldar) Aerial parts Ethanol Carbon tetra- chloride Rat ↓AST, ALT, ALP, bilirubin, MDA ↑SP Toori et al., 2015 Oudemansiella radicata (Mushroom/ Rooting shank fungus) Dried fruiting bodies Ethanol Carbon tetra- chloride Mouse ↓ALT, AST MDA (liver) suppression, ↑SOD, GSH-Px Prevent ↑ in liver wt, ↓Lipid droplet accumulation Liu et al., 2017 Oxalis stricta (Pickle plant) Whole plant Ethanol Paracetamol Rat Prevent GSH depletion ↓lipid peroxidation, AST, ALT, ALP, bilirubin Patel et al., 2016 Panax ginseng (Ginseng) Root Aqueous Carbon tetra- chloride Rat ↓Hepatic fat, reticular fiber deposition, ↓AST, ALT, LDL, TGF- , Smad2, Smad3, Smad4, MMP2, MMP9, TIMP-1, Col1 2, Col3 1 Restored IL-8, IL-10 Hafez et al., 2017 Pandanus odoratis- simus (Umbrella tree) Root Ethanol Paracetamol Rat ↓AST, ALT, ALP, bilirubin, TG Mishra et al., 2015 Picralima nitida (Abeere) Seed Methanol Carbon tetra- chloride Rat ↑CAT, GSH ↓ALT, AST, ALP, bilirubin MacDonald et al., 2016 Piper trioicum Aerial part Ethanol Carbon tetra- chloride Rat ↓AST , ALT, bilirubin, MDA ↑TP, SOD, CAT, GPx Lakshmi et al., 2016 Phyllanthus emblica (Amla) Bark Alcohol Ethanol Rat Restored ALT, AST, ALP, SP Chaphalkar et al., 2017 Prunus armeniaca (Apricot) Leaf Methanol Paracetamol Rat ↓AST, ALT, SALP, TBARS, GGT, LDH, SP, SB, ALB Raj et al., 2016 Pongamia pinnata (Indian beech tree) Leaf Ethanol Paracetamol Rat ↓ALT, AST, ALP, GT, SP, bilirubin ↑SOD, CAT, GPx Rajeshkumar and Kayalvizhi, 2015 Pterospermum aceri- folium (Karnikara tree) Leaf Petroleum ether, alcohol Paracetamol Rat ↓ALP, AST, ALT, LPO ↑GSH, SOD, CAT George et al., 2016 Randia dumetorum (Emetic nut) Leaf Bark Methanol Carbon tetra- chloride Rat ↓AST, ALT, ALP, LDH, ALB, TB, DB, TBARS, TNF- , IL-1 ↑SP, SOD, CAT, GSH Kandimalla et al., 2016 Rosa canina (Dog-rose) Fruit Ethanol Carbon tetra- chloride Rat ↓AST, ALT, ALP, MDA ↑SP Sadeghi et al., 2016 Salix subserrata (Flute willow) Flower Ethanol Carbon tetra- chloride Rat ↓AST, ALT, ALP, LDH, S- chol, TG, MDA, bilirubin, expression of TNF- , NF-k ↑SP, GSH Wahid et al., 2016 Sapium sebiferum Leaf Methanol Paracetamol Mouse ↓AST, ALT, ALP, bilirubin Hussain et al., 2015 236 Bangladesh J Pharmacol 2017; 12: 229-242 Abbreviations: AST: Aspartate aminotransferase, ALT: Alanine aminotransferase, ALP: Alkaline phosphatase, GSH: Reduced glutathione, GSH-Px: Glutathione peroxidase, CAT: Catalase, SOD: Superoxide dismutase, ROS: Reactive oxygen species, STP: Total protein, TB: Total bilirubin, CB: Con- jugate bilirubin, SB: Serum bilirubin, DB: Direct bilirubin, TG: Triglyceride, MDA: Malondialdehyde, LDH: Lactate dehydrogenase, CCl4: Tetra chloromethane/carbon tetrachloride, GGT: Gamma glutamyl transferase, LPO: Lipid peroxide, TC: Total cholesterol, TP: Total protein, ALB: Albu- min, FBS: Fasting blood sugar, BUN: Blood urea nitrogen, UA: Uric acid, TBARS: Thiobarbituric acid reactive substance, LDL-c: Low density lipopro- tein cholesterol, HDL-c: High density lipoprotein cholesterol, TNF- : Tumor necrosis factor- , IL-6: Interleukin-6, NO: Nitric oxide, FRAP: Ferric reducing ability plasma, NF-k : Nuclear factor kappa , HO-1: Heme oxygenase-1, iNOS: Inhibitory nitric oxide synthase, ACP: Acid phosphatase, CHL: Cholesterol, CRE: Creatinine, MPO: Myeloperoxidase, TPN: Total protein, MCV: Mean corpuscular volume, MCH: Mean corpuscular hemo- globin, TLC: Total leukocyte count, DLC: Differential leukocyte count, TAP: Total antioxidant power, TTG: Total thiol groups, GGPT: Gamma glu- tamyl transpeptidase, IBR: Indirect bilirubin, MMPT: Matrix metalloproteinase, TGF- : Transforming growth factor beta, TIMP: Tissue inhibitor matrix metalloproteinase, Col1 2: Collagen 1a2, Col3 1: Collagen 3a1, Smad2: Mothers against decapentaplegic homologue 2, B.wt: Body weight, SP: Serum protein, HAC: Hepatic anti-oxidant capacity Table I Medicinal plants having hepatoprotective potential (Cont..) Plants with com- mon name Parts used Extract Hepatotoxic agent Model Results References Simaroua glauca (Paradise tree) Leaf Ethanol and chlo- roform Paracetamol Rat ↓AST, ALT, ALP John et al., 2016 Solanum melongena (Eggplant) Ripe fruit Methanol Carbon tetra- chloride Rat ↓ALT, AST, ALP, MDA ↑SOD, CAT Hamzah et al., 2016 Solanum nigrum (Black nightshade) Aerial parts Aqueous Carbon tetra- chloride Rat ↓ALT, ALP, bilirubin Goyal and Shar- ma, 2016 Sonchus asper Whole plant - Paracetamol Rabbit ↓ALT, ALP, bilirubin Aftab-Ullah et al., 2015 Sphaeranthus ama- ranth ides (Sivakaranthai) and Oldenlandia umbellate (Chay root) Whole plant Methanol Carbon tetra- chloride Rat ↓AST, ALT, ALP, bilirubin, necrosis De et al., 2017 Syzygium cumini (Jamun) Seed Methanol Carbon tetra- chloride Rat ↓AST, ALT, BiT, ALP ↑SP Islam et al., 2015 Terminalia catappa (Sea almond tree) Bark Alcohol Isoniazid Rat ↓AST, ALT, ALP, bilirubin ↑SP Vahab and Harin- dran, 2016 Tinospora cordifolia (Heart-leaved moonseed) Aerial part Aqueous Carbon tetra- chloride Rat ↓ALT, ALP, bilirubin Goyal and Ku- mar, 2016 Valeriana wallichii (Mushkbala) Root Aqueous Carbon tetra- chloride Rat ↑CAT, GSH ↓AST, ALT, ALP, MDA Syed et al., 2017 Vernonia amygda- lina (African bitter leaf) Leaf Ethanol Dimethyl- nitrosamine Rat ↓AST, ALT, ALP, GGT Improved TG, MDA, necro- sis ↑SOD, CAT, GSH Usunobun et al. 2015 Veronica ciliata (Dongdongchi) Whole plant Ethanol, petroleum ether Paracetamol Mouse ↑SOD, GSH ↓ALT, AST, MDA, TNF- , NF-k Tan et al., 2017 Viola canescens (Banafsha) Whole plant Methanol, Ethyl acetate Carbon tetra- chloride Mouse ↓ALT, ALP, bilirubin, MDA ↑CAT, SOD Restored SP Khan et al., 2017 Zizyphus jujube cv. Huanghetanzao (Red date) Whole plant Ethanol Paracetamol, carbon tetra- chloride Mouse ↓AST, ALT, LDH, MDA ↑SOD, GSH-Px Liu et al., 2015 Bangladesh J Pharmacol 2017; 12: 229-242 237 etc are compiled which have been reported for their hepatoprotective activity against various hepatotoxins. 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 toxi- city 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. Sigmas- terol, -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 com- ponents 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 bioflavo- noid 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 preven- tion of liver diseases. Fruiting bodies of Oudemansiella radicata, an edible mushroom and belong to the family Physalacriaseae has hepatoprotective activity by anti-oxidant mecha- nisms 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 investiga- ted 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 anti- fibrotic properties by gene expression regulation (Hamed et al., 2016) 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. More studies to find out the scientific basis of herbal treatment can open the new era in developing the drugs which are not only effective but also free from side effects. Conflict of Interest All authors have completed the ICMJE uniform disclosure form and declare no support from any organization for the submitted work. References Abd El-Ghffar EA, El-Nashar HA, Eldahshan OA, Singab ANB. 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