Abstract
Liver diseases are quite prevalant in many densely populated countries, including Bangladesh. The liver and its hepatocytes are targeted by virus and microbes, as well as by chemical environmental toxicants, causing wide-spread disruption of metabolic fuctions of the human body, leading to death from end-stage liver diseases. The aim of this review is to systematically explore and record the potential of Bangladeshi ethnopharmacological plants to treat liver diseases with focus on their sources, constituents, and therapeutic uses, including mechanisms of actions (MoA). A literature survey was carried out using Pubmed, Google Scholar, ScienceDirect, and Scopus databases with articles reported until July, 2020. A total of 88 Bangladeshi hepatoprotective plants (BHPs) belonging to 47 families were listed in this review, including Euphorbiaceae, Cucurbitaceae, and Compositae families contained 20% of plants, while herbs were the most cited (51%) and leaves were the most consumed parts (23%) as surveyed. The effect of BHPs against different hepatotoxins was observed via upregulation of antioxidant systems and inhibition of lipid peroxidation which subsequently reduced the elevated liver biomarkers. Different active constituents, including phenolics, curcuminoids, cucurbitanes, terpenoids, fatty acids, carotenoids, and polysaccharides, have been reported from these plants. The hepatoameliorative effect of these constituents was mainly involved in the reduction of hepatic oxidative stress and inflammation through activation of Nrf2/HO-1 and inhibition of NF-κB signaling pathways. In summary, BHPs represent a valuable resource for hepatoprotective lead therapeutics which may offer new alternatives to treat liver diseases.
1. Introduction
The liver is one of the vital organs in the human body that is responsible for metabolism, excretion, and regulation of body homeostasis [1]. Therefore, the liver and its hepatocytes are the major targets of various toxicants (i.e., heavy metals, toxins, drugs, and other chemicals), microbes, and viral infections [2]. Harmful effects of the abovementioned factors on the liver and its hepatocytes include inflammatory (i.e., hepatitis) or non-inflammatory (i.e., hepatosis) liver diseases, liver fibrosis (i.e., cirrhosis), jaundice, and alcoholic liver disease. Liver diseases are now considered as one of the major global health problems, particularly in low- and middle-income countries where it gives the highest burden but largely neglected [3]. Liver disease affects millions of people worldwide, with about 2 million dying annually, and the rates of affecting are increasing sharply over the years irrespective of age, sex, region, and race [4, 5]. Liver diseases, including jaundice and chronic viral hepatitis, as well as nonalcoholic fatty liver, are one of the major treatment burdens in Bangladesh. About eight million people are reported to have viral hepatitis, Hep B (HBV) and C (HCV), and also, frequent outbreak of hepatitis A (HAV) and E (HEV) have been reported in Bangladesh [6]. It is estimated that one in five maternal deaths associated with acute jaundice occurred in Bangladesh as well as increasing trend of fatty liver diseases [7]. Drugs that are currently available for the treatment of liver diseases suffer a number of shortcomings including side effects, poor bioavailability, stability, and selectivity [8]; thus, it is necessary to search new drugs with optimum efficacy, stability, selectivity, and safety for the treatment of liver diseases.
Medicinal plants play a key role in human health, and about 80% of the world’s population in developing countries relies on the use of plant-based traditional medicine [9]. The use of medicinal plants for the treatment of liver diseases has a long history. Scientific study has increased with ethnopharmacological plants that possess strong hepatoprotective activity [10]. The term “hepatoprotective” means either to protect or prevent the liver damage. A number of scientific studies on such local plants and their herbal formulations around the world have been recorded as hepatoprotective [8, 10–17]. Numerous phytoconstituents have already proved to protect liver diseases in both in vitro and in vivo settings [18–21]. It is obvious that traditional herbal medicines are a natural treasure because of their chemical diversity, affordability, availability, few side effects, and diverse pharmacological activity [8, 22]. It is established that traditional knowledge on the medicinal plants has indispensable importance on new drug discovery [23], which attracted immense interest by the scientists over many decades.
The use of medicinal plants for the treatment of different diseases by Indo-Aryans has been reported in Rig-veda in 4500–1600 BC [24, 25]. Bangladesh, which belongs to the Indian subcontinent, also possesses a rich heritage of herbal medicines [26]. About 500 species of medicinal plants are growing in Bangladesh, and among these, more than 250 species are currently in use for the preparation of herbal medicines using the traditional approach and about 80% of rural population of Bangladesh depends on traditional herbal medicine for their primary healthcare [25].
Ethnobotanical use of Bangladeshi medicinal plants has a long history of use in the treatment of liver diseases including jaundice, ascites, liver cirrhosis, hepatitis, liver enlargement, inflammatory liver, sclerosis of the liver, and other liver diseases [26]. Traditional healers of Bangladesh have strong believed on alternative natural plant-based medicine that has few side effects than modern synthetic medicine. The traditional medicinal practitioner, Kabiraj, have developed a number of herbal and ayurvedic formulations in Bangladesh for the treatment of liver diseases [27]. This is one of the affordable and accessible treatment options in liver diseases by rural people because of low cost and lack of access to modern treatment [7]. It is well known that plant-derived natural molecules including flavonoids, terpenoids, sterols, and antioxidants possess diverse therapeutic effects including hepatoprotective activity [10]. The presence of these bioactive phytoconstituents has made these traditionally used plants highly effective against liver diseases. However, there is no up-to-date report on ethnopharmacological and phytochemical investigations for active constituents of Bangladeshi medicinal plants used to treat liver diseases. The aim of this review is to summarize the potential of active compounds from plants used traditionally for liver diseases, as well as the underlying proposed mechanisms of action by compiling both in vitro and in vivo studies.
2. Literature Search Strategy and Data Extraction
Plants that are currently used locally to treat liver diseases are listed in two ethnopharmacological books, namely, the Medicinal Plants of Bangladesh with Chemical Constituents and Uses and the Medicinal Plants of Bangladesh [26, 28]. A comprehensive list of such plants (Table 1) was developed from these two book sources. Furthermore, a complete literature survey on each plants was conducted by PubMed, Scopus, Google Scholar, Web of Sciences, and ScienceDirect databases, using keywords “Bangladeshi medicinal plants” and “plant extracts”, and then refined with the additional keywords “hepatoprotective,” “liver diseases,” “hepatoprotective activity,” and “isolated compound.” In this review, the following surveys were conducted, including (a) in vivo, in vitro, and clinical studies of plant extracts and compounds for liver diseases, (b) studies concerning the concentrations, doses, and route of administration of extracts and/compounds, and (c) studies concerning MoA associated with the hepatoprotective activity of extracts and/or constituents.
3. Results and Discussion
3.1. Hepatoprotective Plants
In this review, a total of 88 species belonging to 47 families and more than 75 genera were selected based on various liver diseases including jaundice, ascites, liver cirrhosis, hepatitis, liver enlargement, inflammatory liver, and sclerosis of the liver [26, 28]. Table 1 shows the common names, plant parts, dosage form of extracts, and recommended use for liver diseases of these plants, and the most used form of preparation was juice (21%), hydroalcoholic extract (14%), and the decoction or infusion (5–19%). The distribution of various species with respect to families is shown in Figure 1, while the percentage distribution of various categories of samples, such as herbs, shrubs, and trees with 51%, 28%, and 21%, respectively, is shown in Figure 2. Finally, Figure 3 illustrates that about 43% of the total recorded plants are distributed all over the country, including the districts of Chittagong, Dhaka, Mymensing, Sylhet, and Rajshahi.
Among the plant parts employed for ethnopharmacological use, leaves were highly utilized with 23%, followed by roots, fruits, whole plants/aerial parts, seeds, bark, rhizomes, and flowers (19%, 18%, 12%, 6%, 5%, 3%, and 2%, respectively) (Figure 4).The methods of preparation of each plant parts showed the unique indigenous knowledge of the traditional healers [25, 29]; thus, different methods of preparation carry different active constituents. Here is a summary of active plants from various plant families.
3.1.1. Plants from Euphorbiaceae
Euphorbiaceae is a large family containing about 300 genera and over 5000 species [30]. The ethnomedicinal significance of this family has a long tradition because of its diverse secondary metabolites [31]. The present review demonstrated that, among the 47 families, Euphorbiaceae possesses eight species, including Baliospermum montanum, Croton caudatus, Croton oblongifolius, Euphorbia tirucalli, Flacourtia jangomas, Phyllanthus acidus, Phyllanthus emblica, and Phyllanthus freternus, that have been traditionally used to treat liver diseases (Table 1). B. montanum, locally known as Dantimul, is a leafy branched undershrub, distributed throughout Bangladesh and India. Decoction of the roots has been used to treat jaundice in Bangladesh [26], as well as in the Ayurvedic system of medicine [32]. A number of in vivo and in vitro hepatoprotective models have been developed for extract or isolated compounds to prevent or cure liver toxicity induced by various hepatotoxins, such as thioacetamide (TAA), carbontetrachloride (CCl4), and paracetamol (APAP) [33]. The liver protective effect of alcoholic and aqueous extract of B. monatum root was reported by restoring the biochemical changes induced by paracetamol (2 mg/kg) in rat, and the results were comparable to the silymarin (Table 2). The dose-dependent hepatoprotective effects of methanolic fraction and its subfractions in either CCl4-, thioacetamide-, or paracetamol-induced liver damage rats were comparable to the protective effect of silymarin at 100 mg/kg, and the protective effect of root extracts was believed to be for their antioxidant effects (Figure 5) [34–37].
3.1.2. Plants from Cucurbitaceae
There are six local species from five genera of the Cucurbitaceae family [38] which have been used to treat liver disease (Table 1). Among these, the fruits of C. colocynthis and C. lanatus are cross compatible and reported to protect hepatic injury induced by different hepatotoxins (Table 2), and the fruit and root of C. colocynthis have been used for the treatment of jaundice [39, 40]. Initial toxicity study of its methanolic extract in mice was found to be safe upto a dose of 2000 mg/kg [40]. A number of in vivo investigations of the crude extract showed dose-dependent hepatoprotective activity induced by hepatotoxins, such as APAP, CCl4, cisplatin, or polluted water, in rats (Table 2). The alcoholic extract of C. colocynthis fruits showed protective activity against APAP-induced hepatotoxicity in rats at 200–300 mg/kg via decreasing the elevated level of liver enzymes, and the results were comparable to the marketed preparation Liv. 52 (1 mL/kg) and silymarin (100 mg/kg), respectively [40, 41]. Pretreatment with chloroform fractions of this fruits has also been reported to reduce the impact of CCl4 and lipopolysaccharide toxicity on the serum liver markers which was comparable to the Chinese drug Bifendate pills (a synthetic intermediate of schisandrin C). The mechanism of the protective effect of C. colocynthis might be involved in the reduction of cellular oxidative stress through increasing antioxidant defense systems as well as upregulating the cellular antioxidant enzymes level [40, 42–45].
The juice of C. lanatus (local name: tarmuj) fruit pulp possesses antioxidant activity and protects liver damage in ethanol-induced liver toxicity in rat via increasing cellular glutathione (GSH) and catalase (CAT) enzymes, which supports the traditional use to treat liver damage [46]. The dose-dependent liver protective effect of MeOH or EtOH seed extracts (200–400 mg/kg) showed a significant reduction of oxidative stress and improved drug metabolizing enzyme activity in the liver [47–49]. The seed extracts also protect liver fibrosis via inhibiting alpha-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) protein expression in CCl4-induced hepatotoxicity in the rat model [47], whereas the EtOH extracts of the leaf of C. lanatus ameliorate and reverse damage of the rat liver tissues induced by CCl4 via reduced congestion and necrosis as well as normalized serum AST, ALT, ALP, and bilirubin concentrations [50].
Momordica charantea has been used for various medicinal values, especially diabetes, which is recommended for jaundice as well (Table 1). In India, the fruit juice or leaf decoction has been used traditionally for hepatitis and jaundice [51, 52]. Mada showed that the extract of M. charantea is quite safe and found the LD50 was more than 5000 mg/kg [53]. A number of reports showed that the hydroalcoholic or aqueous extract of M. charantea leaves dose-dependently (100–400 mg/kg) protect hepatotoxicity induced by CCl4 in the rat model in which the extract supplementation restored the elevated level of different liver toxicity markers, and the results were comparable to marketed liver protective preparation silymarin (50 mg/kg) or Liv 52 (5 mL/kg) [53–55]. The aqueous extract of M. charantea fruit also reported to protect dose dependently liver toxicity in mice or rats by reducing the elevated liver markers as well as attenuating oxidative stress (Table 2) [51, 56, 57].
3.1.3. Plants from Compositae/Asteraceae
Plants from Compositae (Asteraceae) have been used in traditional medicinal practice in Bangladesh to treat liver diseases for a long time. It is a large family of flowing plants which consists of over 32,000 species within over 1,900 genera and 13 subfamilies [58]. Decoction of different plant parts of local species Carthamus tinctorius, Eclipta alba, Elephantopus scaber, Sonchus wightianus, and Wedelia chinensis has been used in the treatment of liver diseases, including jaundice and enlargement of the liver (Table 1). The plant C. tinctorius, known as safflower, has been used as a hepatotonic in Unani medicine of India and Bangladesh, whereas in Jamaica and the Philippines, the flowers are used for jaundice [59].The MeOH extract of C. tinctorius flowers reported to protect CCl4-induced liver injury in rat via the antioxidant and anti-inflammatory mechanism, as well as reduced the level of biochemical markers (Table 2) [60]. The seed oil and leaf extract of C. tinctorius also possess liver protective activity and showed protective effect via reducing the liver toxicity biomarkers in alloxen-induced diabetic rat or CCl4-induced liver toxicity in rat [61, 62].
E. alba is an annual herb that is traditionally used in Bangladesh against jaundice and enlargement of the liver [26]. In India, the plant has been used as a tonic and in the treatment of enlargement of the liver [63]. It has also been reported to be used in Ayurvedic medicine to treat infective hepatitis in adults and children [64]. In Chinese medicine, the palnt has use in liver and kidney problems [65]. Sing showed that E. alba is safe up to 2 g/kg in mice [64], and later, Lal demonstrated the LD50 5 g/kg [66]. The aqueous extract of E. alba leaf showed protection against liver damage induced by either CCl4 or ethanol in rat via reduced oxidative stress on the liver by elevating the antioxidant enzyme level (Table 2) [65, 67]. Another study conducted by Lal showed that the MeOH extract of leaves and CHCl3 extracts of roots reduced the level of lysosomal enzyme and protected from hepatic damage in CCl4-treated rats [66]. The dose-dependent hepatoprotective effect (62.5–500 mg/kg) exhibited by alcoholic aerial part extract of E. alba was found to be due to some protection of hepatic drug-metabolizing enzymes, and it restored the impaired excretory capacity of the liver in CCl4-treated animals [64].
The crused roots of E. scaber are used traditionally to treat liver diseases in Bangladesh [26]. In Malaysia, the plant has been used as a liver tonic, whereas in Brazil, root juice has a common use in treating liver troubles and hepatitis [68]. In China, a herbal drink Yi-GanYin containing E. scaber is used to protect the liver against different diseases including liver cancer, cirrhosis, and hepatitis [69]. Teng-Khia-U is another Taiwanease herbal medicine that also contains E. scaber with other plants and claimed to possess hepatoprotective and anti-inflammatory activity [70]. The alcoholic extract of the root and leaves of E. scaber reported to possess antioxidant activity and reduced the oxidative stress in rat treated with CCl4 or ethanol and protect from liver damage dose dependently (Table 2) [68, 70, 71].
3.1.4. Plants from Acanthaceae
Andrographis paniculata Burm. (Acanthaceae) is a common and widely used medicinal plant from South-East Asia, including Bangladesh, that has been used to treat liver diseases [26, 72, 73]. The leaves and aerial parts of this plant have also been used in Chinese medicine against liver problems [74]. In the Ayurveda system, about twenty-six different polyherbal preparations containing this plant have been recorded [75]. A. paniculata extract has also been reported to be effective in ameliorating the chronic hepatitis B virus infection [76]. A number of animal studies were conducted with ethanolic or aqueous extract of leaves of A. paniculata supplementation against different hepatotoxin (TAA, APAP, CCl4, and hexachlorocyclohexane (BHC))-induced liver toxicity in the rat or mice model, and the results demonstrated that supplementation of A. paniculata normalized cellular oxidative stress and dose-dependently protected against liver toxicity as assessed in terms of either reduced serum marker enzymes, as well as restored the liver tissues antioxidant enzymes (Table 2) [77–80]. A. paniculata extract at a dose of 50–200 mg/kg could protect the liver by restoring antioxidant enzymes as well as reduction (appx. 33–48%) of lipid peroxidation in the liver [81]. The plant extract contains different phenolic phytoconstituents and believed to act as antioxidants as a part of its mechanism of lipid peroxidation [82, 83]. The water extract of the plant exhibited greater antioxidant activity than ethanolic extract because of high phenolic contents in water extract than ethanolic extract [84, 85].
3.1.5. Plants from Combretaceae
A number of species of the genus Terminalia belonging to the Combretaceae family have been used to treat liver problems in the traditional medicinal practice of Bangladesh. Terminalia arjuna, Terminalia chebula, and Terminalia belerica are three important medicinal plants that have been used in Ayurvedic medicine for over centuries, primarily as a tonic for the heart and liver [86, 87]. The use of aqueous bark and ethanolic fruit extracts of T. arjuna and T. chebula showed liver-protective activity in antitubercular drug (single INZ or in combination of RIF, INZ, and pyrazinamide (PZA))-induced liver toxicity in rats at a dose of 50–200 mg/kg (Table 2). The hepatoprotective effect of these extracts was due to their prominent antioxidative and membrane-stabilizing activities [88, 89]. Pretreatment of rats with the extract of T. arjuna bark and T. chebula fruit also showed the hepatoprotective potential against paracetamol-/CCl4-induced liver damage through a significant reduction of serum liver marker enzymes, which was comparable to silymarin [90–92]. The hepatoprotective activity of T. belerica fruit extract was observed by shortened hexobarbitone sleeping time and zoxazolamine paralysis time by inducing drug-metabolizing enzyme and dose-dependent elevation of serum transaminases and bilirubin in CCl4-induced liver injury rats [93].
3.1.6. Plants from Papilionaceae
Cajanus cajan (Papilionaceae) is another popular Bangladeshi plant which has been used in local traditional medicinal practice to treat liver diseases [26]. The juice of leaves is used to treat jaundice by the folklore practitioners of Bangladesh and India [26, 52]. A number of investigations were conducted to evaluate C. cajan extract for its liver-protective activity (Table 2). Pretreatment of alcoholic extract of C. cajan leaves or aerial parts showed liver-protective activity via the reduction of elevated liver enzymes in CCl4- or APAP-induced liver injury rats [94, 95], as well as antiperoxidative activity by induction of the antioxidant enzymes, namely, CAT, SOD, GPx, and GST, in hepatitis rats induced by GNH2 [96]. The methanolic aqueous fraction of C. cajan leaves protects from hepatocyte in alcohol-induced liver-damaged rat through normalized UDP-glucuronosyl transferase (UGT) activity and upregulates the expression of UGT-2B with nuclear translocation of nuclear factor erythroid-2-related factor-2 (Nrf2) [97].
3.1.7. Plants from Caesalpiniaceae
The plants Cassia fistula and Caesalpinia bonducella belonging to the family Caesalpiniaceae have been used in the treatment of liver diseases, and a number of reports have been published on their different parts that possess liver-protective activity (Table 2). In vivo data showed that the liver-protective effect by different extracts of C. fistula were observed at doses 200–800 mg/kg (b.w) via decreasing various elevated liver biomarkers in chemical-induced liver toxicity in animals (Table 2) [98–102]. Drug-induced hepatotoxicity was also prevented by the ethanolic extract of leaves of C. fistula by reduced oxidative stress and other liver biomarkers in diethyl nitrosamine or INZ with RIF-induced liver toxicity in rats [103, 104], whereas the alcoholic or AQ extract of leaves of C. bonducella showed hepatoprotective activity observed by decreasing the activity of serum liver biomarkers [105–107] as well as reduced oxidative stress via increasing the levels of antioxidant enzymes [108, 109].
3.1.8. Plants from Liliaceae
Aloe barbadensis (Aloe vera) and Asparagus racemosus are two popular ethnomedicinal plants belonging to the Liliaceae family that have been used to treat liver diseases. Different hepatotoxin-induced liver toxicities in rat models were used to evaluate their liver-protective activity (Table 2). Among these, the fresh AQ extract of A. barbadensis has been studied for its hepatoprotective activity in a various animal models, and the results confirmed its protective activity that could play a therapeutic role against in either CCl4, APAP, alcohol, or drugs (lindane, INZ, or RIF)-induced liver damage by improving liver enzyme activities and improved antioxidant enzymes in intoxicated rat liver tissue [110–114].
A Korean pharmaceutical preparation of A. barbadensis called ACTIValoe®N-931 (mixture of A. barbadensis and Silybum marianum extracts) has been studied interperitoneally in the CCl4-induced hepatotoxicity and liver fibrosis rat model, and the results demonstrated that both acute hepatotoxicity and liver fibrosis were prevented via restoring the serum aminotransferase, lipid peroxidation, and increasing the hepatic glutathione content. The ACTIValoe®N-931 also attenuated the increase in TNF-α and induced nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and mRNA expressions in acute hepatotoxicity induced by CCl4 in rats [115]. Besides the in vivo assays, a clinical study was also conducted using the fresh juice of A. barbadensis among male and female patients of age 15–65 years diagnosed clinically and biochemically with acute viral hepatitis. A number of liver biochemical markers were measured at the end of 2, 4, and 6 weeks, and it was found that the juice extract of the plant has liver-protective activity compared to the control group, which confirmed the traditional uses of A. barbadensis for the treatment of liver diseases [116].
3.1.9. Plants from Zingiberaceae
Curcuma longa (turmeric; Zingiberaceae) has been used as a herbal medicine owing to its multipharmacological activities [117, 118]. It has been used locally in traditional medicine for the treatment of liver diseases (Table 2). Liver cirrhosis induced by TAA in rats was prevented by the ethanolic extract of turmeric through the inhibition of oxidative stress markers and upregulation of liver antioxidant enzymes and the anti-inflammatory mechanism which restored the elevated cytokines TGF-β1 and TNF-α, as well as enhanced apoptosis of damaged hepatocytes as a protective mechanism and downregulated inflammatory effects and fibrogenesis of the liver [119]. Liver-protective activity through upregulation of hepatic antioxidant enzymes and restoring of various liver biomarkers by the crude extract of C. longa were also supported by other studies of this plant with similar activity in different hepatotoxin (CCl4, GNH2, or tubercular drug)-induced liver damage in the animal model [120–122]. Other reports also showed that alcoholic extract of turmeric alleviate of hepatotoxic effects caused by HgCl2 in rats through a protective effect on drug metabolizing CYP-2E1 enzymes, viz., aniline hydroxylase (AH) and amidopyrine-N-demethylase (AND) [123]. The extract of turmeric also reported to improve liver activity via enhancing its antioxidant activity in alloxan-induced diabetic rat liver toxicity [124].
3.1.10. Plants from Other Families
A number of other traditional plants belonging to various families also have been used in the management of liver diseases. Amaranthus spinosus (Acanthaceae) is a leafy vegetable that has been used to treat jaundice. A number of studies found on its extracts of whole plant showed dose-dependent (100–400 mg/kg) liver-protective activity against various hepatotoxin (CCl4, GNH2, and APAP)-induced liver toxicity in rats via induction of liver antioxidant enzymes and inhibiting oxidant enzyme MDA, as well as restored the elevated level of serum liver biomarkers and cellular architecture [125–127]. The latex and extract of Argenome mexicana (Papaveraceae) have been reported to be used in the herbal medicine to treat jaundice in Bangladesh. Literature study found that the supplementation of leaf extract or dietary leaves of A. mexicana has the ability to reduce the activities of liver marker enzymes and protect against liver injury induced by CCl4 in rat models [128–130]. Similarly, Bixa orellana (Bixaceae) also reported to possess inhibition of elevated liver biomarker enzymes activities of CCl4- or EtOH-included hepatotoxic rats to protect against liver injury (Table 2) [95, 131–133].
The hepatoprotective activity of various parts of Boerhavia diffusa (Nyctaginaceae) has been well studied in different hepatotoxin (TAA, CCl4, EtOH, and IB)-induced rat liver toxicity (Table 2). The MeOH extract of B. diffusa root restored the elevated liver markers and reduced oxidative stress, as well as normalized liver histological changes, to protect against hepatotoxicity in ibuprofen- (IB-) induced liver toxicity in rats [134]. The alcoholic or hydroalcoholic extract of B. diffusa whole plant showed protective activity in CCl4-induced liver injury rat via the protection of drug-metabolizing enzymes and restored the elevated liver biomarkers, as well as increased bile flow of the liver [135, 136].
Carica papaya (Carieaceae) is another common species that has been used extensively in the liver problem, especially its fruit, either as cooking of unripe fruit or raw eating of ripe fruit [26]. The AQ extract of C. papaya leaves and unripe fruit at an oral dose of 100–300 mg/kg showed upregulation of antioxidant enzyme activities in liver tissues and decreased serum liver markers, as well as decreased reduced lipid peroxidation as a protective mechanism in CCl4- or APAP-induced hepatotoxicity in rats [137]. The AQ extract of ripe/unripe seeds or dried fruit or MeOH extract of stalk of C. papaya also has liver-protective potential that can hamper the activity of liver biomarker enzymes in CCl4-induced hepatotoxic rats (Table 2) [138–141]. Daucas carota (carrot; Umbelliferae) is another common functional food that has medicinal uses against liver disease. The AQ extract of tuber of D. carota showed protective activity against LD-, APAP-, INZ-, or EtOH-induced liver toxicity in rats through altering lipid profile, restored depressed antioxidant systems, and decreased levels of serum enzymes (Table 2) [142, 143]. Similar activity was also found for the oil extract and its phenolic rich fraction in CCl4-induced hepatic injury rats where the oil extract showed hepatoprotective activity via reduction of cellular oxidative stress and restored the elevated levels liver markers [144].
3.2. Antioxidative Plants for Hepatoprotection
Hepatotoxicity or hepatic injury or liver damage occurs mainly through oxidative stress, inflammation, or lipid peroxidation which ultimately inhibits liver regeneration, mitochondrial damage, and finally, cell death [145]. As a consequence, a number of biochemical marker alterations and upregulatin of cellular antioxidative defense mechanisms occurred as a reflection of hamper of liver function (Figure 5) [145]. Treatment with antioxidant can prevent and cure liver diseases by balancing oxidative stress. It is reported that antioxidants can enhance dissociation of Nrf2 from the complex by either modifying kelch-like ECH-associated protein-1 (Keap1) or Nrf2 phosphorylation which causes activation of Nrf2 (Figure 6). The activated Nrf2 translocates into the nucleus, binds to antioxidant response element (ARE), and upregulates the gene expression of antioxidant enzymes and phase II detoxifying enzymes, which protects and cures cellular damage [146]. A number of reports also showed that some antioxidants or antioxidant-rich plant extracts protect against hepatotoxin-induced liver damages by upregulation of activation of Nrf2 [147–149].
A number of other indigenous ethnomedicinal plants belonging to different families have also reported its hepatoprotective activity through their antioxidant mechanism (Table 2). However, a number of plants have been used in traditional medicine to treat liver diseases, although no report was found on their selective hepatoprotective activity, including Aloe indica, Allamanda cathartica, Anagallis arvensis, Borassus flabellifer, Caesalpinia pulcherrima, Corchorus capsularis, Corchorus olitorius, Croton caudatus, Croton oblongifolius, Flacourtia jangomas, Ipomoea aquatica Forsk., Justicia gendarass Burm., Lagenaria siceraria, Mussaenda glabrata, Meyna spinosa, Phyllanthus freternus, Piper longum, Pavetta indica, Saccharum officinarum, Sonchus wightianus, Semecarpus anacardium, and Tamarix troupiihole (Table 1). Therefore, these Bangladeshi medicinal plants could be a promising source to explore further to evaluate their liver protective activity and further identify the active principle.
3.3. Hepatoprotective Phytoconstituents
Natural product small molecules (NPSMs) or active fractions containing NPSMs that possess different pharmacological actions, especially antioxidant and anti-inflammatory activity, have recently attracted potential attention to treat liver diseases [150]. A variety of plants and fruits have been used to protect liver function that possess different phytoconstituents including phenolics, flavonoids, coumarins, alkaloids, essential oils, glycosides, xanthenes, carotenoids, organic acids, lignins, and monoterpenes [151]. A number of hepatoprotective phytoconstituents belonging to different chemical classes have been isolated and reported so far from these Bangladeshi plants (Table 3). The various active constituents isolated from these plants were assembled based on the class of compounds as follows.
3.3.1. Flavoinoid and Phenolic Compounds
Flavonoid and phenolic compounds occur ubiquitously in plants and are well-known antioxidant and anti-inflammatory compounds [152]. Several investigations on natural antioxidant, especially flavonoids and phenolics from plants, showed a potential effect in different diseases caused by oxidative stress including liver diseases [153]. A number of previous studies demonstrated that these flavonoids can prevent and cure hepatotoxin-induced liver injury in rodents [154–156].
The hepatoprotective plants A. spinosus, C. tinctorius, C. fistula, S. jambos, and T. purpurea possess flavonoids as a major constituent, and a number of reports showed the hepatoprotective activity of these plants due to their active flavonoids (Table 3). Rutin (1), kaempferol 3-O-rutinoside (2) or -glucoside (3) (336–672 μM/kg), and catechin (4) (69 μM/kg) flavonoids were isolated from A. spinosus, C. tinctorius, and C. fistula, respectively, that exhibited hepatoprotective activity in CCl4- or STZ-induced rat liver toxicity (Table 3 and Figure 7). The study revealed that these flavonoids significantly upregulate enzymatic antioxidant systems and regeneration of hepatocytes and, as a result, reduced the elevated serum liver biomarker suggesting their liver-protective effect (Figure 5) [157–159]. Although these studies did not highlight any molecular mechanism of their liver-protective activity, it is well reported that the hepatoprotective activity of these flavonoids might be due to their free-radical-scavenging activity with their anti-inflammatory and antifibrotic responses as well as induction of the Nrf2 signaling pathway (Figure 6) [155, 160, 161].
The flavonoid-rich fraction of another hepatoprotective plant (HP) T. purpurea containing quercetin (5), coumarins, flavonoids, and flavanones protects against rat hepatotoxicity induced by CCl4 at a dose of 100 mg/kg dose via reduction of the elevated level of serum SGOT, SGPT, ALP, and bilirubin (Figure 5) [162]. The rutin (1), catechin (4), quercetin (5), kamferol (6), and luteolin (7) flavonoids have also been isolated from different crude extracts of A. spinosus, C. tinctorius, C. fistula, and T. purpurea, which further supports their reported and traditional liver-protective activity (Figure 7) [163–166]. Flavonoids and phenolics such as myricetin (8), quercetin 3-O-xylosyl-(1 ⟶ 2) rhamnoside (9), ellagic acid rahmnoside (10), and rosmarinic acid (11) from S. jambos leaf extracts have been identified using HPLC-PDA-MS/MS that showed promising liver-protective activity in CCl4-induced liver injury rats (Figure 8) [167]. The extract at a dose of 200 mg/kg reduced the levels of liver markers and increased antioxidant enzymes GSH and SOD. Furthermore, in vitro assay confirmed that pretreatment with the extract inhibited ROS production via prevention of p38 and its target MAPKAP kinase-2- (MAPKAPK-2-) activated signaling cascade in sodium arsenite-induced oxidative stress of HepG2 hepatocytes [167]. The p38 and MAPKAPK-2 are mitogen-activated protein kinase (MAPK) family proteins that regulate the production of inflammatory cytokines as well as play a vital role in hepatoprotective function by restricting ROS accumulation in the liver during oxidative stress [168]. Interestingly, natural flavonoids have already showed their liver-protective activity against oxidative stress via the MAPK signaling pathway [169].
Gallic acid (12) and its derivative methyl gallate (13) are the common plant phenolics that have been isolated from the BHP of Lawsonia inermis and showed significant hepatoprotective effect at an IP (intraperitoneal) dose of 294 μM/kg gallic acid (GA) in CCl4-intoxicated rats (Figure 9) [170]. The study did not reveal any molecular mechanism of GA but demonstrated that the protective effect was observed by lowered serum biochemical parameters, a significant reduction of hepatic ROS, and an increase in antioxidant enzymes, as well as normalized hepatocellular necrosis, vacuolization, and inflammatory cell infiltration. Another report also demonstrated that GA has the ability to protect against liver toxicity by enhancing enzymatic antioxidant systems and reduce hepatic inflammation via inducing Nrf2-mediated antioxidant enzymes and attenuating the inflammatory mediators COX-2 through the NF-κB inhibition pathway [171]. Another plant hepatoprotective phenol, chebulic acid (14), was isolated (as a mixture with neochebulic acid (15)) from Terminilia chebula that showed reduction of tert-butyl hydroperoxide- (t-BHP-) induced ROS and cell cytotoxicity and the ratio of GSSH with GSH in isolated rat hepatocytes in vitro at a dose of 280 µM/mL (Figure 9) [172]. A recent in vitro study conducted by Jung et al. confirmed that chebulic acid can dose dependently (0.4, 2 and 2 µM) enhance phosphorylation of MAPK and protect hepatocytes against t-BHP-induced oxidative stress via controlling the activation of Nrf2 and its related cytoprotective enzymes including HO-1 and gamma-glutamate cysteine ligase (γ-GCL) [173].
3.3.2. Terpenoids
Among the terpenoid class of NPSMs, a number of diterpene type of compounds have been isolated from BHP that showed potential hepatoprotective activity (Table 3). The diterpene lactone, andrographolide (16), is a well-known natural molecule isolated from A. paniculata Nees. (Kalmegh) that has been used as a key ingredient in a variety of polyherbal formulations to treat hepatitis, hepatic dysfunction, and hepatic regeneration, as well as a liver tonic, in Bangladesh and the Indian subcontinent [174]. Literature study demonstrated that andrographolide isolated from A. paniculata showed liver protection against alcoholic (177–1427 µM/kg, ip)/nonalcoholic (143 µM/kg, p.o) fatty liver or APAP (2–34 µM/kg, p.o)/CCl4 (286 µM/kg, ip)-induced hepatotoxicity (Table 3).
The hepatoprotective activity of andrographolide observed via liver regeneration prevents degradation/necrosis of liver cells, upregulates antioxidant enzymes, and inhibits lipid peroxidation [175–178]. Improvement of hepatic biliary function and insulin secretion in hepatocytes has an impact on liver regeneration, prevention of degradation of hepatocytes, or hepatic dysfunction [179, 180]. Interestingly, the protective effect of andrographolide via liver regeneration or prevention of necrosis of liver cells has a close relation with its choleretic effect as well as stimulation of insulin secretion in hepatocytes [181, 182]. It is also reported that andrographolide normalized the hepatic fatty changes, multifocal mononuclear cell infiltration, and hepatocyte ballooning in high-fat-diet fatty liver as a function of its protective effect [183]. Andrographolide derivatives including isoandrographolide (17), neoandrographolide (18), 3,19-acetonylidene andrographolide (19), and andrographiside (20) have also been reported to possesses liver-protective effects as andrographolide and even sometimes more potent than andrographolide (Figure 10). Another hepatoprotective study confirmed that the glucoside group with andrographolide (i.e., andrographiside (20)) might act as a strong antioxidant than andrographolide itself or neoandrographolide in which andographiside significantly inhibit lipid peroxidation, GSH depletion, and enzymatic leakage of SGPT and ALP compared to andrographolide and neoandrographolide alone [177].
Another new diterpene named portulene (21) along with known compounds lupeol (22), β-sitosterol (23), and daucosterol (24) has been isolated from the extract of Portulaca oleracea that showed a liver-protective effect at a dose 10–50 mg/kg against CCl4-induced hepatic injury in rats via the inhibition of leakage of liver enzymes and biomarkers (Figure 11) [184]. The hepatoprotective activity of these phytoconstituents is supported by a previous study of lupeol and β-sitosterol that showed liver-protective activity via antioxidant and anti-inflammatory mechanisms [185, 186].
A number of triterpene acids, namely, betulinic (25), oleanolic (26), ursolic (27), alphitolic (28), 3-epimaslinic (29), and euscaphic acid (30), have been isolated from triterpene-rich CH2Cl2 hairy root extract of Ocumum basilicum L. that showed hepatoprotective activity in CCl4-induced hepatotoxicity in experimental animals (Figure 12) [187]. The isolated triterpene acids also dose-dependently (0.1–5 mg/mL) ameliorate liver oxidative stress by inhibition of lipid peroxidation in iron/ascorbate-induced lipid peroxidation in liver homogenate [187]. Interestingly, it is reported that oleanane- and ursane-type triterpenoids are the two largest groups of phytoconstituents that possess noticeable hepatoprotective activities including oleanolic acid and ursolic acid which have been used to treat liver diseases for years in China [188]. The protective effect of oleanolic acid (26) against acute liver injury involved its anti-inflammatory activity thorough the activation of peroxisome proliferator-activated receptor alpha (PPARα) and downregulation of the c-Jun NH2-terminal kinase (JNK) signaling pathway [189]. The antioxidant effect of ursolic acid (27) in the prevention of liver injury involved the modulation of MAPKs and the NF-κB signaling pathway [190]. On the other hand, betulinic acid (25) has the ability to prevent hepatic inflammation and fibrosis via the suppression of the TLR4/MyD88/NF-κB signaling pathway [191].
Hepatitis virus (HBV, HAV, and HCV) causes a severe and frequently transmittable disease of the liver, and among these, HBV was the most common one that infected millions of people worldwide. The extract of O. basilicum L. was reported to be active against viral hepatitis (HAV) [192]. There was no confirmation about the active principle responsible for the antihepatitis activity of O. basilicum L.; however, the triterpene acids, especially betulinic acid, ursolic acid, and oleanolic acid (Figure 12), have been reported to be active against viral hepatitis. The betulinic acid protects mice liver by inhibiting HBV replication in hepatocytes of HBV‐transgenic mice through downregulation of SOD-2 expression as well as inhibition of ROS production and mitochondrial dysfunction [193]. Betulinic acid also inhibits HCV replication in cultured cells, and the molecular mechanism reported that it might downregulate HCV-induced COX-2 expression through the inhibition of phosphorylation of NF-κB and ERK1/2 of the MAPK signaling pathway [194]. The antihepatitis potential of ursolic acid and oleanolic acid was also reported against HBV and HCV viruses. The anti-HBV activity of ursolic acid might be involved in blocking the pathological effects of HBV which confirmed by the study in which ursolic acid reduced the migratory process and matrix metalloproteinase-3 secretion in HBV-X protein-transactivated cell lineages [195], while the anti-HCV activity of oleanolic acid and ursolic acid was observed via inhibition of of viral NS5B RNA-dependent RNA polymerase (RdRp) activity, an enzyme responsible for HCV RNA replication [196].
Cucurbitane-type triterpene glycosides are another class of hepatoprotective triterpenoids found in Momordica charantea L. which has been used as a popular vegetable and traditional medicine to treat liver diseases. A recent study isolated a number of cucurbitane-type triterpene glycosides from the fruits of M. charantea including three new furpyronecucurbitane A (31), goyaglycoside I (32), and charantagenin F (33) along with ten known cucurbitane (34–43) (Figure 13) [197]. All the isolated compounds were evaluated for antihepatic fibrosis activity against murine hepatic stellate cells (t-HSC/Cl-6) and antihepatoma activity against liver cancer cell lines (HepG2 and Hep3B), and karaviloside III (41) was found as the most potent molecule with an IC50 3.74–17 μM [197]. Previously, two norcucurbitane-type triterpenoids named pentanorcucurbitacin B (44) and 25,26,27-trinorcucurbit-5-ene-3, 7, 23-trione (45) were isolated from the same plant that showed cytoprotective potential against t-BHP-induced injury on HepG2 cells with IC50 5–10 mM and was comparable to silybin (Figure 13) [198].
3.3.3. Curcuminoids
Curcuminoids are diarylheptanoids which belongs to natural phenolic compounds, and curcumin (46) (60–70%), demethoxycurcumin (20–27%) (47), and bisdemethoxycurcumin (10–15%) (48) are the major curcuminoids present in turmeric C. longa (Figure 14) [199]. Curcumin (46), chemically known as (1E-6 E)-1,7-bis (4-hydroxy-3-methoxy phenyl)-1,6-heptadiene-3,5-dione, is the major bioactive compound isolated from turmeric. Curcumin reported to possess various pharmacological actions including hepatoprotective and antioxidant properties [200]. The hepatoprotective effect of curcumin has been well established via a number of in vitro and in vivo investigations (Table 3). The hepatoprotective activity of curcumin was due to its multitarget function. Curcumin (136–544 µM/kg. p.o) ameliorated liver injury in animals induced by APAP/CCl4 or lindane through upregulation of the antioxidant defense mechanism and restored the elevated liver markers via inhibition of hepatic cell degradation and leakage and inhibition of lipid peroxidation [201–203]. Alfatoxin B1-induced hepatotoxicity involved LPO and oxidative DNA damage of liver cells. The antioxidant potential of curcumin protected against aflatoxin B1-induced liver toxicity by restoring the elevated levels of serum marker enzymes and LPO and elevating the antioxidant enzyme levels as well as reduced excretion of DNA adducts [204, 205]. The molecular mechanism of hepatoprotection of curcumin was believed to link with reduction of oxidative stress via the antioxidant activity and activation of the Nrf2/Keap1/ARE pathway and its related phase II detoxifying/antioxidant enzymes including HO-1 and NAD(P)H:quinone oxidoreductase-1 (NQO 1) (Figure 6) [206, 207]. Moreover, curcumin protects CYP 2E1 enzymatic activity against mercuric chloride- (HgCl2-) induced hepatotoxicity and oxidative stress in rats [123], which is supported by a previous study of curcumin that it induces peroxiredoxin-6 (Prx-6) and downregulates CYP2E1 as well as Prx1 expression in diet-induced oxidative stress [208]. It is believed that cross regulation of Prx1 and Prx6 is likely to participate in cellular defense against the development of hepatitis. The anti-inflammatory responses of curcumin that protected liver fibrosis induced by dimethylnitrosamine (DMN) were observed along with the reduction of electrical conductivity and leaking of liver biomarkers [209]. Inhibition of the hepatic NF-κB signaling pathway is reported to be a potential pathway to attenuate the inflammatory process in the liver, and a number of investigations confirmed the downregulatory property of curcumin to hepatic expression of NF-κB and its downstream targets [210, 211]. Other reports also showed that curcumin protects against hepatic fibrogenesis through the inhibition of the expression of toll-like receptor 2 and 4 (TLR2 and TLR4) and their ligand molecule high-mobility group protein box-1 (HMGB1) in CCl4-indcued rat hepatic fibrogenesis [212]. Interestingly, all TLR signaling pathways have a close relation with NF-κB activation which regulate the expression of inflammatory cytokine genes [213]. Furthermore, curcumin could ameliorate hepatic inflammation and fibrosis by enhancing the degradation of damaged hepatic cells via apoptosis through the inhibition of the expression of proapoptotic genes Bax, Bcl-2 mRNA, and caspase-3 as well as inducing antiapoptotic genes Bcl-xL and upregulating p53 protein expression in APAP- or TAA-induced hepatotoxicity (Figure 6) [214–216].
Curcumin was also a potential natural hepatoprotectve molecule that is effective in viral hepatitis and proved to be active as a host-targeted therapy for HBV infection. Mouler et al. showed that curcumin protects HepG2215 cells from HBV infection via the inhibition of HBV gene expression and replication. The molecular mechanism of the inhibition of replication involved downregulation of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α), which is a starvation-induced protein that has a role in the initiation of the gluconeogenesis cascade and may robustly coactivate HBV transcription [217].
3.3.4. Aromatic Compounds
A study reported that C. longa yielded aromatic compounds ar-turmerone (49) and its derivatives α-tumerone (50) and β-tumerone (51) which showed liver-protective activity (0.5% with diet) against d-galactosamine-induced liver toxicity in rats via suppressing the increase of LDB, ALT, and AST levels (Figure 14) [218]. However, the liver-protective mechanism of sesquiterpenes in turmeric was not clear and might be different from that of curcuminoids [219].
Aloe emodin (52), chemically known as 1,8-dihydroxy-3-hydroxyl-methylanthraquinone, is an anthraquinone derivative and one of the main bioactive components of Aloe vera (Figure 15). Literature study demonstrated that the anthraquinone derivative aloe emodin possesses hepatoprotective potential both in vivo and in vitro. Arosio et al. showed that pretreatment of aloe emodin (185 µM/kg, i.p.) protects against CCl4-induced acute liver damage via the inhibition of lipid peroxidation subsequently reduced to free-radical production [220]. The treatment of aloe emodin also ameliorated the inflammatory lesions in liver cells and ultimately reduced the leakage of liver markers L-aspartate-2-oxoglutate-aminotransferase in serum via the inhibition of proinflammatory cytokines TNF-α mRNA expression [220]. Later, Woo et al. demonstrated that aloe emodin can also inhibit the activation and proliferation of hepatic stellate in vitro by the reduction of DNA synthesis and inhibition of type I collagen production and sm-α (smooth muscle α-actin) expression (0.004–0.04 µM/mL), a key liver cell that has an essential role in the pathogenesis of liver fibrosis [221].
(a)
(b)
(c)
(d)
Aloin (53) is another anthraquinone glycoside that has been reported to isolate from different Aloe species including A. vera (Figure 15) [222]. Aloin protects against chronic alcoholic liver injury at a dose of 24–72 µM/kg by attenuating lipid accumulation, oxidative stress, and LPS-induced inflammatory response as well as significant reduction of hepatic mRNA expression of CYP2E1 [223]. The molecular mechanism of the reduction of lipid accumulation was observed by the activation of AMP-activated protein kinase-α2 (AMPK-α2) and downregulation of sterol regulatory element-binding protein-1c (SREBP-1c) expression that has a role in the balance between lipid synthesis and fatty acid oxidation/lipolysis. A recent interesting study conducted by Jung et al. reported the protective effect of aloin against retinal injury associated with liver failure by normalization of Kir4.1 and aquaporin-4 channels in TAA-induced hepatic retinopathy [224].
Embelin (54), chemically known as 2,5-dihydroxy-3-undecyl-1,4-benzoquinone, is a natural para-benzoquinone derivative derived from the BHP of Embelia ribes that possesses a wide range of medicinal activities including hepaprotective activity (Figure 15) [225]. Sreepriya and Bali investigated the protective effect of embolin (170 µM/kg) against hepatocarcinogenesis induced by N-nitrosodiethylamine- (DENA-) initiated and phenobarbital- (PB-) promoted hepatocarcinogenesis in the rat model. The results showed that embolin has the ability to prevent leakage of hepatic biomarkers, inhibit lipid peroxidation, upregulate antioxidant defense, and reduce the percentage of hepatic hyper plastic nodule incidence and hypoproteinemia in DENA-/PB-treated hepatocarcinogenesis rats [226, 227]. The antioxidant activity of embelin was further confirmed to involve in the protection of liver toxicity in rats [228]. The molecular mechanism of hepatoprotective activity of embelin was not clear; however, a previous study showed that embelin has the ability to modulate Nrf-2/HO-1, MAPK/NF-κB, p53, and STAT3 signaling pathways to regulate cellular oxidative stress, inflammatory response, and apoptosis that might be responsible for its protective effect against hepatotoxin-induced liver damage [229–231].
3.3.5. Fatty Acids
Natural fatty acids are common phytoconstituents in various functional foods that possess different bioactivities and have been used as a supplement to treat different diseases. trans-Tetracos-15-enoic acid (TCA) (55), a monounsaturated fatty acid, was derived from bioactivity-guided isolation of the dried aerial parts of Indigofera tinctorial Linn. that possess hepatoprotective activity in CCl4- and APAP-induced liver toxicity in the rat and mice model (Figure 15) [232]. The study demonstrated that TCA has both preventive and curative potential (34–273 µM/kg, p.o) as a hepatoprotective agent and it was comparable to that of the known protective agent silymarin. Pre- and posttreatment of TCA showed significant dose-dependent (12.5–100 mg/kg, p.o) restoration of elevated serum level of liver marker enzymes and inhibited lipid peroxidation as well as upregulated antioxidant enzyme GSH.
3.3.6. Carotenoids
A carotenoid derivative apocarotenoid, known as bixin (56), has been isolated from B. orellana L. seeds that possess various pharmacological properties (Figure 15) [233]. Pinzón-García et al. reported that bixin (127 µM/kg) and bixin: β-cyclodextrin combination could ameliorate nonalcoholic fatty liver steatosis and its associated obesity, hyperglycemia, and hyperlipidemic condition in the high-fat-diet C57BL/6 mice model [234]. The molecular mechanism of its hepatoprotective activity was not clear, but the study demonstrated the hepatoprotective effect of bixin involved the improvement of lipid profile and inhibition of fat accumulation in the liver.
3.3.7. Polysaccharide
Polysaccharide (57) is another main bioactive constituent in A. vera gel that has been reported to possess a number of biological activities including liver protective activity [235]. Cui et al. demonstrated the supplementation of polysaccharide extracted from A. vera against alcohol liver disease (ALD) in a chronic alcohol-feeding mouse model [236]. The hepatoprotective effect of polysaccharide involved with its antioxidant activity increased lipolysis and anti-inflammatory response. The molecular mechanism of lipolysis by polysaccharide was observed by significant upregulation of hepatic expression of lipolytic genes AMPK-α2 and PPARα; on the other hand, alcohol-induced inflammation was protected through downregulation of TLR-4 and MyD88 and upregulation of IκB-α (nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor, alpha) [236].
4. Challenges with Bangladeshi Hepatoprotective Plants
Based on ethnomedicinal evidence and practice, plant extracts and their active constituents have the potential to treat liver diseases. This review summarized Bangladeshi plants that have been traditionally used for the treatment of liver diseases, namely, jaundice, ascites, liver cirrhosis, hepatitis, liver enlargement, inflammatory liver, sclerosis of the liver, and other ailments. Literature survey revealed that a number of these plants have been reported to ameliorate liver toxicity or injury induced by various chemicals, drugs, and/or foods, in both in vitro and in vivo settings. Generally, people from rural areas are largely dependent on traditional herbal medicine for their primary healthcare needs, including treatment of liver problem, because of traditional evidence of their effectiveness and safety, as well as lack of access to modern drugs. However, the major challenges of these ethnomedicinal herbal treatments are lack of standardization, quality, efficacy, and taxonomic documentation and toxic effects. A number of BHPs underwent pharmacological and phytochemical analysis in terms of their hepatoprotective activity, although a major portion of these plants is still either underexplored or unexplored. Therefore, there is an urgent need for preclinical and clinical studies of these plants to study their efficacy in the treatment of liver diseases. The resolution for these challenges needs rigorous chemical and clinical research to confirm the potentials of these BHPs and identify their active constituents in the treatment of different liver diseases. Since large percentages of people with liver diseases use botanicals as prophylactics all over the world, a substantial effort is being made in recent years to develop plant-based therapeutics with a novel mechanism of action.
Finally, Bangladesh is located at the juncture of the Indo-Malayan and Indo-China subregion of tropical South-East Asia. With this unique geographical location, the land of Bangladesh (Figure 3) is very fertile for plant growth. About 2.5 million hectares of land is covered by forest which is approximately 17.5% of the total area. Since Bangladesh is in the forefront of global climate change and very susceptible to natural calamities, pollution, and man-made deforestation, these valuable plant resources are already under threat. It is important for governmental and nongovernmental organizations to come forward and preserve these precious plant resources so that proper scientific evaluation and documentation can be carried out before they perish.
5. Conclusions
This review summarized 88 Bangladeshi ethnomedicinal plants that have been traditionally used in the treatment of different liver problems, and among these, 64 species have been reported to have hepatoprotective activity either in vivo or in vitro, and 17 species underwent further phytochemical analysis to identify active constituents. Literature review revealed that A. vera, A. paniculata, C. fistula, C. longa, and B. diffusa with their active compounds, namely, andrographolide (16), aloe emodin (52), curcumin (46), karaviloside III (41), catechin (4), chebulic acid (14), and gallic acid (12) were the most promising lead molecules, which have the potential for further development for hepatoprotective drug discovery. The hepatoprotective activity of these plants was reported to act through different mechanisms, including enhancing regeneration of hepatocytes or decreasing degradation/necrosis of liver cells and subsequently reducing leakage or restoring elevated level of serum liver biomarkers, as well as inhibiting lipid peroxidation and upregulating hepatic antioxidant enzyme activities. Induction of apoptosis of injured hepatocytes and protection from cytochrome enzymes were also reported by the liver-protective agents. The molecular mechanism of activity of constituents varied from molecule to molecule, but the activation of Nrf2/HO-1 and inhibition of p38 MAPKs and TLR4/MyD88/NF-κB were the most common pathways revealed from literature survey. Although a number of plants with similar phytoconstituents have also been explored, a good number of BHPs are still unexplored in terms of isolation of active principle(s), as well as scientific validation of their traditional claim as a hepatoprotective agent. Finally, Bangladeshi plants represent a valuable resource for the development of therapeutics; therefore, well-designed and controlled clinical trials need to be executed on traditionally used BHPs, together with the chemical profiling of actives or markers which will establish the efficacy and safety of botanical medicine for liver diseases.
Abbreviation
| AH: | Aniline hydroxylase |
| AMPK-α2: | AMP-activated protein kinase-α2 |
| AND: | Amidopyrine-N-demethylase |
| APAP: | Paracetamol |
| ALD: | Alcohol liver disease |
| ALP: | Alkaline phosphatase |
| AQ: | Aqueous |
| ARE: | Antioxidant response element |
| AST: | Aspartate aminotransferase |
| BHPs: | Bangladeshi hepatoprotective plants |
| BHC: | Hexachlorocyclohexane |
| t-BHP: | tert-Butyl hydroperoxide |
| BSP: | Bromosulphalein |
| CAT: | Catalase |
| CCl4: | Carbontetrachloride |
| COX-2: | Cyclooxygenase-2 |
| CYP2E1: | Cytochrome P450-2E1 |
| DEN: | Diethyl nitrosamine |
| DENA: | N-nitrosodiethylamine |
| DMN: | Dimethylnitrosamine |
| EtOH: | Ethanol |
| FeSO4: | Ferrus sulphate |
| GA: | Gallic acid |
| γ-GCL: | Gamma-glutamate cysteine ligase |
| GNH2: | D (+)-galactosamine |
| GSH: | Glutathione |
| GPx: | Glutathione peroxidase |
| GRD: | Glutathione reductase |
| GST: | Glutathione s-transferease |
| γ –GT: | Gamma-glutamyl transferase |
| HAV: | Hepatitis A virus |
| HBV: | Hepatitis B virus |
| HCV: | Hepatitis C virus |
| HEV: | Hepatitis E virus |
| HgCl2: | Mercuric chloride |
| HMGB1: | High-mobility group protein box-1 |
| HO-1: | Heme oxygenase-1 |
| HP: | Hepatoprotective plant |
| t-HSC/Cl-6: | Murine hepatic stellate cells |
| IκB-α: | Nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor, alpha |
| IL-6: | Interleukin -6 |
| INZ: | Isoniazid |
| iNOS: | Nitric oxide synthase |
| JNK: | c-Jun NH2-terminal kinase |
| Kep1: | Kelch-like ECH-associated protein-1 |
| LD: | Lindane |
| LDH: | Lactate dehydrogenase |
| LD50: | Lethal dose 50% |
| LPO: | Lipid peroxidation |
| MAPK: | Mitogen-activated protein kinase |
| MAPKAPK-2: | MAPK protein kinase-2 |
| MDA: | Malondialdehyde |
| MeOH: | Methanol |
| MoA: | Mechanisms of action |
| MyD88: | Myeloid differentiation factor 88 |
| NF-kB: | Nuclear factor-kappa B |
| NOS: | Reactive nitrogen species |
| NPSM: | Natural product small molecules |
| NQO-1: | NAD(P)H:quinone oxidoreductase-1 |
| Nrf2: | Nuclear factor erythroid-2-related factor-2 |
| PB: | Phenobarbital |
| PGC-1α: | Peroxisome proliferator-activated receptor-gamma coactivator-1alpha |
| PPARα: | Peroxisome proliferator-activated receptor alpha |
| Prx-6: | Peroxiredoxin-6 |
| PT: | Prothrombin time |
| PZA: | Pyrazinamide |
| RdRp: | RNA-dependent RNA polymerase |
| RIF: | Rifampicin |
| ROS: | Reactive oxygen species |
| SGOT: | Serum glutamic oxaloacetic transaminase |
| SGPT: | Serum glutamic pyruvic transaminase |
| α-SMA: | Alpha-smooth muscle actin |
| sm-α: | Smooth muscle α-actin |
| Smad4: | Decapentaplegic homolog 4 |
| SOD: | Superoxide dismutase |
| SREBP-1c: | Sterol regulatory element-binding protein-1c |
| TAA: | Thiacetamide |
| TB: | Total bilirubin |
| TC: | Total cholesterol |
| TCA: | trans-Tetracos-15-enoic acid |
| TG: | Tryglyceride |
| TGF-β: | Transforming growth factor-β1 |
| TLR2: | Toll-like receptor 2 |
| TLR4: | Toll-like receptor 4 |
| TNF-α: | Tumor necrosis factor-α |
| TP: | Total protein |
| UGT: | UDP-glucuronosyl transferase. |
Data Availability
All relevant data are available within this manuscript.
Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.
Authors’ Contributions
RR, PG, MRU, and FTZ accumulated the literature and systematically analyzed the data. RR and SJU drafted and revised the manuscript. DKS drew the figures. SJU and IM supervised the project and provided helpful comments and revisions. All authors read and approved the final version of the manuscript.