Introduction

The liver, largest organ in human body, contributes 2% of our body weight, weighing almost 1.5 kg in a fully grown adult [57]. The liver is the site for drug metabolism and biotransformation, thereby having defensive role in the body against toxic foreign chemical agents. Due to these, the liver is exposed to drugs, chemicals, and other xenobiotics in different concentrations which finally results in liver injury. There are over hundreds of etiology causing hepatic diseases. The most profound causes of hepatic disease consist of microbes (hepatitis virus A, B, C,Cytomegalovirus, Epstein-Barr virus, and yellow fever virus); disease related to metabolic syndrome (fatty liver disease caused by obesity, hemochromatosis, and Wilson’s disease); xenobiotics (alcohol, drugs, and chemicals); hereditary-related hepatic diseases; autoimmune diseases (biliary cirrhosis, hepatitis, and sclerosing cholangitis); and liver malignancies [75]. End result of hepatic diseases is disturbance and loss of workdays, compensation in quality of personal life, squeezing in expected life span, and financial burden to the individual as well as to the society, subsequently resulting in mortality and morbidity.

Around the globe, near to 2 million people are fading away each year because of hepatic complexities among which 1 million are due to complication of cirrhosis and another half are cognated to liver carcinoma and viral hepatitis [60, 107]. At present, the most prevalent cause of death is cirrhosis ranking 11 (1.16 million deaths) and liver cancer which ranks 16 (788,000 deaths) for death complication, and in combination, they account for 3.5% of all deaths worldwide [54, 107]. High intake of alcoholic product is the major factor for liver disease in global context [142]. A report published by the World Health Organization showed that among the total alcohol consumer worldwide which is predicted to be around 2 billion, slightly less than half, i.e., 75 million, are diagnosed with disorders related to the alcohol use specifically to several alcohol-associated liver disease [11, 181]. In 2015, more people died with viral hepatitis-related disease (1.34 million deaths) than by human immunodeficiency virus (HIV) (1.06 million deaths) or malaria (0.44 million deaths) and similar to the number caused by tuberculosis (1.37 million) [154, 178]. Among the morbidity cause by viral hepatitis, total of 96% is accounted for hepatitis B virus (66%) and hepatitis C virus (30%) which is mainly due to the cirrhosis complication and profusion of liver cancer [154].

Drug-induced liver injury (DILI) is one of the major problems associated with the treatment for several acute and chronic disease conditions. Research studies revealed that antitubercular drug (isoniazid), antipsychotic (chlorpromazine), penicillin antibiotic (amoxicillin), and histamine antagonist (cimetidine), analgesic and antipyretic (acetaminophen), and HMG-CoA reductase inhibitors (statins) are major drugs causing DILI [15, 143]. In West region of the globe, amoxicillin/clavulanic acid-induced liver injury occurs in 1 in 2350 [17], whereas combined antitubercular drug-induced liver injury is more profound in the east region [22, 198]. Among them, India and Nigeria have highest burden of DILI followed by China and South Korea having herbal and alternative medicine-induced liver injury [34, 156], WHO [179]. Globally, antimicrobial agents are considered as the major cause of idiosyncratic DILI [33, 170, 201]. The above latest figures depict that the worldwide liver disease burden has increased with growing time showing massive influence on the public life around the globe WHO [

Traditional medicine is prevalent all over the world which plays important role for preventive and curative purpose for people in developing countries [31]. According to the definition given by the WHO, “Traditional medicine is regarded as diverse health practices, approaches, knowledge and beliefs incorporating plant, animal, and/or mineral based medicine, spiritual therapies, manual techniques and exercises applied singularly or in combination to maintain well-being, as well as to treat, diagnose or prevent illness” [196].

Hepatic problems are one of the highly pronounced reason for mortality and morbidity in human [109, 114]. Liver damage is usually related to cell necrosis, diminution, and increase of liver biomarkers such as aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin (TB), total protein (TP), an increase in tissue lipid per oxidation, and oxidative damage [36, 100]. Traditional medicine from the natural sources has significant effect in the management of the hepatic diseases. Many natural phytoconstituents have been demonstrated to be effective hepatoprotective agents, while many more are claimed to have hepatoprotective and hepatocurative activity. Natural product-based phytoconstituents are regarded as the best and most validated source for developing novel therapeutic agents, but poor absorption, distribution, metabolism, and elimination followed by few toxicological properties still restrain the wide utilization of them for therapeutic purpose. In the last couple of decades, researcher and scientist are more encouraged for finding out more promising hepatoprotective agents from plant source to develop novel modern medicine for different liver aliments [61, 161].

In view of these facts, this review is effort to evaluate the available proven scientific data on the following:

  1. (i)

    Recently developed modern medicines for liver disorder

  2. (ii)

    Major phytoconstituents from the natural sources with their hepatoprotective activity

  3. (iii)

    Promising hepatoprotective agents from the natural sources with its mechanism of action

  4. (iv)

    Clinical trial data of some promising hepatoprotective leads in patients with different liver diseases

  5. (v)

    Common mechanism of action of natural product-based leads for the protection against different liver diseases

Review method

The information about liver disease, clinical trial of recent hepatoprotective leads, promising hepatoprotective agents, and specific phytoconstituents was gathered by systematic literature survey with reference to the publications published mostly from 2000 to 2022. A comprehensive systematic literature survey was carried out in different scientific search engines such as Google Scholar, Wiley, PubMed, Taylor & Francis, ScienceDirect, and Springer to find required information. Major keywords used to search and to retrieve the related articles are "Liver disease," "Hepatoprotective," "Hepatoprotective AND Plant," "Hepatoprotective AND Herbal," "Hepatoprotective AND Natural Product," "Hepatotoxicity," "Hepatotoxicity AND Ethnopharmacology," and so forth.

Results

Some clinical significance of allopathic drugs for liver disorder

Due to the recent advancement, medication evaluation based on evidence, standard pharmacopeia, and randomized placebo control clinical trial to outline the clinical efficacy of modern medicine is more frequent. Therapies developed with synthetic hit and lead compounds relying in the principle of allopathic medicine have significant risk–benefit ratio, often expensive and less effective [117, 163]. Some liver-protective medicines and their adverse effects are depicted in Table 1 below.

Table 1 Commonly used allopathic medicine for liver protection with clinical application
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Major bioactive phytochemicals with hepatoprotective activity

Active hepatoprotective phytoconstituents discovered in experimental laboratory mouse model during the experiment in mouse with different liver diseases are mentioned in Tables 1 and 2. Their chemical structures are illustrated in Fig. 1.

Table 2 Some major phytoconstituents with hepatoprotective activity
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Fig. 1
figure 1

Chemical structure of some potent bioactive phytochemical with hepatoprotective activity

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Some promising hepatoprotective agents from natural sources

Silymarin (family: Asteraceae)

Silymarin, an active compound of Silybum marianum (L.) Gaertn., commonly known as “milk thistle,” is one of the oldest plant which has been commonly utilized for the treatment of liver diseases [90, 102].

Dried seeds are major sources of active phytoconstituents, which contain four flavonolignans isomer, i.e., silybin, isosilybin, silydianin, and silychristin. The complex mixture of these four flavonolignans isomer is known as silymarin [47, 73].

Silymarin shows hepatoprotection via various underlying mechanisms of which most common are modulation of enzymatic and nonenzymatic liver biochemical markers [170, 173] and induction of nuclear factor-erythroid 2-related factor 2 (Nrf2) expression [70]. In addition, anti-inflammatory properties of silymarin have been proved in several models of liver damage. In rats, with alcoholic fatty liver model, silymarin acted by downregulating the expression of nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), mission mode project-2 (MMP-2), mission mode project-13 (MMP-13), transforming growth factor beta-1 (TGF-β1), tumor-suppressor Krueppel-like factor, collagen α1 expression, and platelet-derived growth factor (PDGF) signaling when tested in hepatotoxic damage animal models [30, 194]. Likewise, silymarin could inhibit cells infected by HCV via TNF-α-induced activation of NF-κB and its nuclear translocation [104, 131]. Silymarin is well tolerated by patients with good safety profile [132]. Poor water solubility of silymarin is being overcame by silymarin-loaded solid nanoparticles which enhance its antioxidant and hepatoprotective activity in comparison with crude silymarin [20].

Glycyrrhizin (family: Leguminacae)

Glycyrrhizin, a triterpenoid glycoside isolated from the root of Glycyrrhiza glabra L. commonly known as liquorice root, has been used in traditional medicine system of Nepal, India, China, and other countries for the treatment of jaundice [121, 186]. It is a mixture of potassium and calcium salt of glycyrrhizinic acid, and other phytoconstituents involved are glycyrrhetinic acid, beta-sitosterol, hydroxycoumarins, and flavonoids [50, 147].

Glycyrrhizin shows hepatoprotective effect via various mechanisms such as increasing antioxidant defense in hepatic cell and as anti-inflammatory agent [121, 147]. High-mobility group protein box (HMGB1) are either diminished or interrupted for binding to glutathione S-transferase omega-1 (GSTO1) promoter region by glycyrrhizin to show anti-inflammatory effect [74, 93]. Not only glycyrrhizin, its metabolite, and glycyrrhetinic acid inhibited collagen αI(I) gene expression in liver fibrosis caused by CCl4 [110]. Glycyrrhetinic acid also helps in liver cell growth through the mechanism of epithelial growth factor receptor (EGFR) binding, stimulating DNA synthesis in liver cells by extracellular signal-regulated kinases (ERK2)-mediated pathway [25, 71], which helps in liver regeneration. During interferon alpha (IFN-α)-based therapy failure, glycyrrhizin administered through intravenous route dramatically lowered the serum alanine transaminase level after 12 weeks of therapy and improved liver fibrosis and necrosis caused by inflammation after 52-week treatment in patients with hepatic disease [97]. Moreover, it is also effective in prevention of HCV-related liver cirrhosis in older patients [62, 106]. In a study using in vitro cell model and in vivo animal models with hepatic injury, it was revealed that 18β-glycyrrhetinic acid reduces oxidative stress and expression of inflammatory markers which were predicted as a result of the downregulation of NF-κB and upregulation of Nrf2 target genes [59, 87].

Andrographolide and neoandrographolide (family: Acanthaceae)

Andrographolide and neoandrographolide are the active chemical constituents of herbaceous plant of Andrographis paniculata Nees. commonly known as “king of bitters” due to its extremely bitter taste and is well-known for liver diseases [134, 172].

The main active chemical constituent is diterpene lactone class which is obtained from the leaves, i.e., neoandrographolide, 14-deoxy-11-dehydroandrographolide, 14-deoxy-11-oxoandrographolide and deoxy-andrographolide, andrographolide, andrographine, panicoline, paniculide-A, paniculide-B, and paniculide-C [129, 136].

Andrographolide inhibits inflammation, angiogenesis, and fibrosis in chemically induced liver injury animal model via antioxidant and anti-inflammatory mechanisms [26, 77]. Oxidative stress-inducible gene such as hypoxia-inducible factor-1 alpha, superoxide dismutase (SOD-1), heme oxygenase-1 (HO-1), and glutathione S-transferase (GST1) which uprise nuclear Nrf2 content and its DNA-binding activity and other upregulated protein and gene are balanced by andrographolide [26, 187]. It also helps in upregulation of HO-1 via the p38 mitogen-activated protein kinase, MAPK/Nrf2 pathway shows anti-HCV activity [77]. Additionally, andrographolide helps in downregulation of hypoxia-inducible genes such as vascular endothelial growth factor (VEGF) and also diminishes TNF-α and cycloxygenase-2 (COX-2) expression and finally reduces liver hypoxia and attenuates hepatic apoptosis and fibrosis in rats [72, 79]. The compound decreases serum levels of TNF-α and interleukin-1 beta (IL-1β) and hepatic expression of TGF-β, cannabinoid receptor type 1 (CBR1), and Bax. The predicted mechanism for the decrement of serum levels of TNF-α and IL-1β is through the downregulation of JNK and ERK phosphorylation. A study in high-fat diet (HFD) fed mice administering andrographolide showed that cellular lipid accumulation is diminished [37, 79].

Picroside I and kutkoside (family: Scrophulariaceae)

Picroside and kutkoside are the active chemical constituents of roots and rhizomes of Picrorhiza kurroa Royle, commonly known as “Kutki” or “Kutaki,” and have been used to treat hepatic disorder since long [58, 140].

The major active constituents are kurkoside, apocynin, drosin, cucurbitacin glycoside, and the iridoid glycoside such as picroside 1, 2, and 3. Kutkin is formed when picroside I and kutkoside are mixed in the ratio of 1:2 [141, 152].

Picroside-I and kutkoside show hepatoprotective effect via membrane stabilizing, hypolipidemic and antioxidant properties, and finally liver regenerative effect in rats via stimulation of nucleic acid and protein synthesis [101, 139, 153]. Picroside-I and kutkoside are free radical scavengers (superoxide anion O2•) and inhibit lipid peroxidation in liver tissue [95]. It also showed restoration of bilirubin and activity of serum liver biomarkers level of AST, ALT, ALP, and LDH against acetaminophen-induced liver toxicity animal model by protecting injury hepatocyte proving its hepatoprotective effect [141]. Moreover, picroside also reduces the lipid peroxidation, normalizes glutathione metabolism, and inhibits hepatocarcinogenesis caused by N-nitrosodiethylamine in rats by increasing the life span of tumor bearing rats [24, 195]. It acts against less expression of LDL receptor on cell surface caused by paracetamol and uprises the conjugated dienes in liver cells as well as maintain of oxidation–reduction balance for healthy liver [108, 152].

Curcumin (family: Zingiberaceae)

Curcumin is the principle curcuminoid found in rhizome of Curcuma longa commonly known as “turmeric.” Traditional use of turmeric for the treatment of bilirubin-related liver disease such as jaundice and several other hepatic complication is being documented since long [81].

Structurally, similar phenolic compounds found in the rhizomes of turmeric are known as curcuminoids in their mixed form. Three major curcuminoids present in rhizomes of turmeric are curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Chemically, curcumin is a diferuloylmethane which consists of diferulic acid moiety fused with methylene moiety or other carbon group and exists mainly in keto-enol form [83, 130].

Hepatoprotection mechanism of the curcumin may be due to its antioxidant activity and activation of the phase 2 detoxifying/antioxidant enzymes such as HO-1 and NADPH quinone oxidoreductase-1 (NQO1) and Nrf2/Kelch-like ECH-associated protein 1 (Keap1)/antioxidant-responsive element (ARE) pathway [43, 48]. In addition, its administration in diet reduces oxidative stress, decreases Cytochrome P450 2E1 (CYP2E1) and paired-related homeobox 1 (Prx1) expression, while upregulates paired-related homeobox 6 (Prx6) expression [78]. Oxidative stress caused by hepatotoxins is closely associated with activation of some inflammatory mediators such as MAPKs, NF-κB, and signal transducer and activator of transcription-3 (STAT3) via different pathways [5]. Research reported that curcumin can inhibit the expression of toll-like receptor-2 (TLR2), toll-like receptor-4 (TLR4), and HMGB1 in rat suffered with fibrogenesis expression of ligand molecules. Concanavalin A-induced hepatitis in mice via T-cell-mediated pathway become less severe when administered with curcumin which is mainly due to the inhibition of liver inflammation [167, 168]. Likewise, curcumin could diminish liver toxicity cause by lipopolysaccharide (LPS)/D-galactosamine (D-GalN) through inhibition of hepatic mRNA levels of Sirtuin (silent mating type information regulation 2 homolog)-1 (SIRT1) [190]. It also suppresses expression of gene for receptors which are involved in final product of advanced glycation in hepatic stellate cells (HSCs) by uprising the peroxisome proliferator-activated receptor-gamma (PPARγ) activity and subsiding oxidative stress [86]. Moreover, curcumin could protect against paracetamol-induced hepatocyte apoptosis by reducing the availability of proapoptotic genes Bax and caspase-3 while improving antiapoptotic genes [80]. However, curcumin is able to downregulate Bcl-2 mRNA expression and upregulates p53 protein expression in thioacetamide-induced cytotoxicity, facilitating apoptosis in damaged cells which reduces hepatic inflammatory gene and fibrogenesis [174]. Additionally, antioxidant and anti-inflammatory effect of curcumin could protect mice against human cytomegalovirus infection [92].

Phyllanthin and hypophyllanthin (family: Euphorbiaceae)

Phyllanthin is a potent hepatoprotective lignans found in Phyllanthus niruri Linn., commonly known as “gale of the wind,” is a long established herbal remedy for jaundice and other hepatic diseases [50].

The main active chemical constituents include alkaloids, astragalin, brevifolin, ellagitannins, amariin, repandusinic acid, phyllanthusiin D gallocatechins, geraniin, hypophylanthis, lignans, nirutin, phyllanthin, and phyllanthenol. Chemically, phyllanthin and hypophyllanthin are lignans isolated from the hexane extract and have been established as the hepatoprotective agents [58, 83].

Phyllanthus niruri is effective against infective hepatitis and other liver disease [65, 76]. Ethanolic extract of this plant possesses potent hepatoprotective activity both in vitro and in vivo. In India, it was used to treat jaundice in children because of its liver-protective and detoxifying action [38, 52]. A study in the UK revealed that Phyllanthus extract could be effective for treatment of both acute and chronic hepatitis in children [38, 76]. Phyllanthin and hypophyllanthin both can protect rat liver from toxicity induced by carbon tetrachloride and cytotoxicity induced by galactosamine [7, 158].

These lignans also protect against liver damage induced by alcohol and normalize a “fatty liver” condition. The hepatoprotective effects of phyllanthus lignin are achieved with the mechanism of inhibition of superoxide and hydroxyl radicals and lipid peroxidation [16, 67].

Berberine (family: Berberidaceae)

Berberine is an isoquinoline alkaloid which could be isolated from roots, rhizomes, and stem bark of Berberis aristata DC, commonly known as “barberry” and has been used as tonic remedy for liver since long ago [98].

The major active chemical constituents present in Berberis aristata are berberine, oxyberberine, berbamine, aromoline, karachine, and oxycanthine. Berberine is experimentally proved hepatoprotective phytoconstituent [63, 96].

Berberine shows antioxidant activity which could suppress oxidative stress and attenuates apoptosis through the increment of ratio of Bcl-2/Bax in ischemia-/reperfusion-injured rat liver inhibiting caspase-3 cleavage in the liver [123]. Its mechanism of action is upregulation of Akt and inhibition of mTOR expression [146]. Furthermore, hepatocyte nuclear factor-4 alpha and PPARα/peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) could be restored with berberine showing hepatoprotective effect in liver ischemia. Experiment in mice with steatosis induced by ethanol showed that berberine protects the liver from ethanol-induced oxidative stress [193]. Berberine even reduces the expression of hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9), a cholesterol homeostasis regulator, and decreases IFN-γ, TNF-α, IL-1α and 8-isoprostane levels in LPS-induced hepatoxicity mouse model [180]. Carbon tetrachloride-induced liver injury is attenuated by berberine via suppression of TNF-α, COX-2, and iNOS expression and oxidative stress [39]. Berberine could diminish liver fibrosis through the activation of AMPK and decreasing the expression of NOX4 and phosphorylated Akt [82].

Embelin (family: Myrsinaceae)

Embelin, chemically known as “2,5-dihydroxy-3-undecyl-1,4-benzoquinone,” is an active chemical constituent of leaves of Embelia ribes Burm.f. commonly known as “false black pepper” and is known for free radical scavenging and liver protective function [66]. The active constituents are embelin, christembine, quercitol, and resin. Embelin shows its hepatoprotective effect mainly through its free radical scavenging and lipid peroxidation pathway. Embelin can control the liver biomarkers: AST, ALT, ALP, LDH, bilirubin γ-glutamyl transpeptidase, and total protein levels in carbon tetrachloride-treated rats [150]. Study in mitochondria of rat liver showed that embelin could inhibit lipid peroxidation, and impaired superoxide dismutase level was restored with embelin administration. Furthermore, to extraplot mechanism and rate of reactions of embelin with hydroxyl, way of oxidizing single electron and radical called “organo-haloperoxyl” with the technique known as nanosecond pulse radiolysis was studied. Its redox potential was also evaluated, and the study depicted that embelin is a potent-free radical scavenger in physiological conditions [35, 66].

Resveratrol

Resveratrol chemically known as “trans-3,5,4′-trihydroxystilbene” is a naturally occurring polyphenol compound present in Vitis labrusca commonly known as “grapes,” Vaccinium myrtillus L. commonly known as “blueberries” and Rubus idaeus L. commonly known as “raspberries” with potent antioxidant properties. Resveratrol, a phytoalexin, is generated in plants when bacteria and fungi attacked it [32].

Resveratrol shows liver protection via reduction of oxidative stress during hepatocyte injury by modifying the expression of nuclear transcription factors Nrf2 and NF-κB and downregulating HO-1 and iONS gene expression [1, 144]. This enhances the free radical scavenging properties as well as phase 2 enzymes [21]. Furthermore, it even inhibits proinflammatory cytokines such as IL-2, IL-6, and TNF-α in concanavalin A-induced autoimmune hepatitis [199]. In liver injury cause by high cholesterol, resveratrol shows protective effect which is mediated by the enhancement of autophagy and downregulation of proapoptotic proteins such as Bax and caspase-3 and caspase-8 [23]. Followingly, hepatotoxicity caused by isoniazid and rifampicin is ameliorated by resveratrol by modulating the expression of SIRT1 mRNA hepatic cells of mice, which finally minimize hepatic oxidative stress in the liver, production of cytokine, and expression of gene called PPARγ [119]. Moreover, resveratrol also prevents hepatotoxicity resulted from higher consumption of acetaminophen by upregulating expression of SIRT1 and downregulating p53 signaling, enhancing the expression of cell nuclear antigen, promoting hepatic cell proliferation, enhancing liver regeneration and inducing uprising the level of cyclin D1 and Cdk4 [53, 176].

Clinical trials of some hepatoprotective leads

During the drug development phase of the clinical trials, potent hepatoprotective phytoconstituents are studied in different human liver disease condition with specified period to curing the liver disease. The summary of the reported clinical trials of major hepatoprotective leads is documented in Table 3.

Table 3 Clinical trial with different promising hepatoprotective leads in patients with different liver diseases
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Possible best mechanism of herbal remedy for the protection of liver against variety of toxins and injury

The study revealed that the most profound hepatoprotective mechanisms of the herbal plants are through the free radical scavenging effect and anti-inflammatory pathway. The hepatic injury perpetually involves per oxidation of fatty acid present in hepatocyte membrane leading to the distortion of the cells and their organelles. Recent studies suggested that oxidative stress has a vital role in the commencement and development of hepatic damage. Role of oxidative stress in viral hepatitis and in liver diseases caused by autoimmune syndrome has been studied and reported significantly [42]. Furthermore, xenobiotics and toxic chemicals damage hepatic cells mainly by the generation of reactive free radicals which form covalent bonding interaction with the amino acid residue of the hepatic cell membranes (Fig. 2). Due to widespread contact to harmful chemicals, sometimes the produced free radicals override the defensive system available naturally causing hepatic injury. Natural phytoconstituents such a vitamin E and silymarin are known for their protective role against liver injury caused by hepatotoxic agent [197]. Inflammation which is the major clinical symptom in hepatotoxin-induced liver damage is cause by toxin or through oxidative stress which leads towards the noteworthy increment of proinflammatory cytokines including TNF-α (tumor necrosis factor-α) and IL-6 (interlukin-6) and hepatocyte inflammation [2]. In brief, minimizing the oxidative stress and inflammatory cytokines is the major mechanism by which herbal remedies act as hepatoprotectant.

Fig. 2
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The mechanism by which herbal remedies protect against liver injury from different toxins and injurious stimuli [3]

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Discussion

Global use of herb-based regimen is increasing day by day, and at least one-quarter of patients with liver diseases use natural phytoconstituents for disease therapy. Current research strategies are focused on scientific investigation of herbal-based medicine for their safety and efficacy through huge preclinical studies followed by clinical trials to find the mysteries hidden in medicinal plants [51]. Such approaches ultimately help to find the real potent therapeutic lead and valuable pharmacotherapeutic candidate from the natural sources specially plant origin and standardize the dosage regimen on scientific-based finding [135]. Recently, most of the herbal products are marketed for the purpose of disease prevention, support health, relieve symptoms, and curing of different disease and aliments. Still most of these products lack scientific and pharmacological validation. Most of the experimental model study related to hepatotoxicity using cell culture and animals showed that various plant extracts exert hepatoprotective and curative effects which further assist in clinical testing for discovery of hepatoprotective leads. Due to lack of scientific‑based pharmacological data, most of the herbal-based formulations cannot be recommended for the treatment of liver diseases [155].

This review gives the clear idea that herbal-based therapy could play a significant role against various liver disorder and disease condition occurring in human. Several herbs from natural sources and plant extracts have measurable hepatoprotective effect in several experimental animal models. Secondary metabolites such as alkaloid, flavonoids, phenolic, tannins, lignins, and resin-based compound are the major active phytocontituents for hepatoprotective effect [9]. The significant portion of the study depicts that extracts of different parts of medicinal plants have potentials to subside hepatic disorder Baral et al. [14]. In addition, this study highlighted scientific evidence and mechanism of hepatoprotection by crude extracts of medicinal plants. The most probable mechanism of action of several plant extracts is through the scavenging effect of harmful free radical generated during infirmities. Several experiments in vivo study showed that phenolic and flavonoid constituents of plant extracts help to upsurge the decrease proportion of blood glutathione, to enhance protein secretion, to minimize lipid peroxidation and to enhance free radical scavenging properties. Furthermore, phytoconstituents lower the hepatic enzymes such as AST, ALT, ALP and arginase and enhance the level of total bilirubin in blood plasma,upsurge antioxidative enzymes such as SOD, GPx, CAT and GST,and lower MDA level [41]. In a nutshell, it could be highlighted that herbal drug possesses significant hepatoprotective properties which could be proved by various preclinical and clinical studies.

Conclusion and future perspective

To recapitulate, numerous research in last few decades have clearly established that herbal lead compounds have significant hepatic injury; the major mechanism for protection of liver cells is eradication of free radicals, reducing oxidative stress and decreasing the proinflammatory cytokine mediators in the body. This ample review will be helpful to begin a new way and to explore additional clinical application of bioactive constituents as liver-protective agents. Significant natural availability and economic and minimum side effect as compared to allopathic medicine have encouraged utilization of bioactive compounds for the treatment of liver disease. Followingly, subsequent preclinical investigations have been directed, and such studies have already proved several remedies as hepatoprotective agents, and further clinical trials are on demand for authentication. Several in silico studies and compounds from molecular networking have also suggested active phytoconstituents from natural sources as possible hepatoprotective agents. In addition, it is a proper time to uncover the possibility of hepatoprotection potential of new bioactive compounds for human health either through in silico methods such as molecular docking, machine learning, and deep learning or through biophysical and biochemical experimental techniques. Finally, in this review, an attempt has been made to compile the reported hepatoprotective plants and their active phytoconstituents around the globe. These phytoconstituents are claimed to have proved benefit for health professionals, scientists, and scholars working in the field of pharmacology, therapeutics, and pharmacognosy to develop evidence-based alternative medicines to cure different kinds of liver diseases for mankind. This study paved a marvelous path for further scientific validation, research, and investigation to understand the therapeutic potential of these natural lead constituents to discover novel hepatoprotective therapeutics from natural source.

The point is not that natural products will solve all problems. It is that a lot of problems are not being solved because natural products are not being examined.

S. J. Gould, Chem. Eng. News 13 October 2003, p 103