Background

Liver diseases continue to be a major health concern over the last few years due to chronic alcohol abuse and modern lifestyle, and cause of morbidity and mortality worldwide (Iqbal et al., 2019). Every year, 3 million deaths occur due to alcohol consumption all over the world (WHO, 2019). At the same time, NAFLD is emerging even larger health problem and is considered to be the most common liver disease. A significant number of individuals are developing non-alcoholic steatohepatitis (NASH) which may progress toward hepatic fibrosis, cirrhosis and ultimately hepatocellular carcinoma (Ahmad & Ahmad, 2012; Page & Harrison, 2009). Approximately one-third of the population in developed countries have NAFLD responsible for liver transplantation (Angulo, 2006; Mikolasevic et al., 2018). Hepatitis B and C virus infections, like ALD and NAFLD, cause chronic liver disease (Raimondo et al., 2005). Due to lack of any effective treatment and increase in the number of cases of cirrhosis and in need of liver transplantation, chronic liver diseases are important health and economic concern. Therefore, there is a need of effective and affordable treatment modalities to reduce the morbidity and mortality associated with CLDs.

Herbal remedies are highly valued all over the world as a rich source of pharmaceutical agents for the prevention of infections and diseases (Kayani et al., 2014; Latief & Ahmad, 2018; Zain-ul-Abidin et al., 2018). In India, there are enormous varieties of medicinal plants; thus, our country has often been referred as ‘Medicinal Garden of the world’. These plants have played vital roles in various ancient traditional systems of medication and even today, provide an inexpensive source of drugs for majority of world’s population (Sen & Chakraborty, 2017). Bergenia ciliata (family Saxifragaceae), a highly valuable plant has been used as a medicine for the treatment of different kinds of human diseases since long. It is commonly called ‘Zakhmehayat’ or ‘Pakhanabhed’ and is an evergreen perennial herb, widely distributed in Central and East Asia (Phull et al., 2016; Tiwari et al., 2020). This plant has thick rootstock, and outer surface is dark brown and rough whereas the inner skin is pinkish and smooth. It is covered with dark sheaths of withered leaves. Flowers are arranged in terminal corymbs and may be pink, white or purple. In Himalayan region, people traditionally use B. ciliata for the treatment of various ailments (Chowdhary et al., 2009). Bergenia ciliata is considered as a miracle herb due to its use in treatment of numerous diseases such as gastrointestinal problems, pulmonary infections, heart diseases, ophthalmic, hemorrhoids, kidney and gall bladder stones. (Hussain et al., 2019; Rajkumar et al., 2011). In addition, it is accredited with antifungal, diuretic, antitussive, anticancer, analgesic, antiviral, antibacterial, anti-inflammatory and antimalarial properties (Rajkumar et al., 2011; Ruby et al., 2012; Timalsena & Lamichhane, 2019; Zafar et al., 2019). In India, an Ayurvedic polyherbal formulation ‘Cystone’ contains Bergenia in combination with other plants and is used against urolithiasis (Vidyashankar et al., 2010). These virtues of the plant are attributed directly to its phytochemicals composition and account for its utilization in traditional medicine (Fig. 1).

Fig. 1
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Schematic representation of parts used, phytochemicals and applications of Bergenia ciliata against different ailments

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Phytochemical studies on this plant have revealed the presence of gallic acid (3,4,5 trihydroxybenzoic acid), bergenin (C-glycoside of 4-O-methyl Gallic acid), catechin, gallicin, paashaanolactone, arbutin, β-sitosterol, afzelechin, etc. (Dharmender et al., 2010; Kanth et al., 2019). Tannic acid, mucilage, glucose, albumen, metarbin, mineral salts and wax are also reported to be present (Kanth et al., 2019). Extensive examination of medicinal plants for bioactive compounds and biological activities is the foremost and critical step in development of effective novel medications. In view of this, the present review is the first attempt to gather utmost fragmented literature showing the protective effects of various bioactive compounds of B. ciliata against liver diseases. It will improve the efficacy of this miracle herb against liver infirmities, as well as the active medicinal compounds responsible for them. Furthermore, this article would unfurl logical holes in existing knowledge and make it easier for researchers all over the world to approach studies relating to the discovery of novel compounds and medicines from B. ciliata.

Methodology

This review article has been designed by compiling and consulting published papers about the protective efficacy and scientific validation of Bergenia ciliata as an anti-hepatotoxic agent. Published papers were retrieved from scientific journals, theses and online bibliographical databases: PubMed, Scopus, Google Scholar and Web of Science. In total, almost 100 research articles on B. ciliata plant and its phytochemicals published in English language were reviewed for this article. Inside the databases, we used the keywords including: liver diseases, hepatoprotective activity, Bergenia ciliata, pharmacology, phytochemicals, bergenin, gallic acid, arbutin, tannic acid, β-sitosterol, limonene and β-caryophyllene. All the obtained data from previous published literature is summarized in three figures and two table.

Phytochemical constituents

Phytochemical studies include identification and isolation of the chemical compounds, determination of their biological effectiveness through in vitro and in vivo studies in experimental models and through epidemiological and clinical trials in humans. The phytochemical constituents of Bergenia species are summarized in Table 1.

Table 1 Phytochemical constituents of Bergenia species
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Therapeutic activities of phytochemicals of Bergenia ciliata against liver diseases

Gallic acid

Gallic acid (GA) is an important phytochemical of B. ciliata and is also found in tea leaves, sumac, oak bark, gallnuts, witch hazel and other kinds of plants (Nabavi et al., 2012). Studies have shown that GA possesses a lot of biological activities such as antiviral antibiotic, anti-inflammatory, antimutagenic and anticancer (Badhani et al., 2015; Kahkeshani et al., 2019). These effects are due to the fact that GA is a potent antioxidant, involved in neutralizing and absorbing free radicals produced by the cells (Badhani et al., 2015).

It is reported that gallic acid has protective activity against hepatotoxicity due to its hydroxyl groups (Anand et al., 1997). Several previous studies have revealed the efficacy of GA on hepatic injury caused by different etiologies, such as cyclophosphamide, paracetamol, diethylnitrosamine, carbon tetrachloride, lindane and methotrexate. (Latief et al., 2016; Oyagbemi et al., 2016; Padma et al., 2011; Safaei et al., 2018; Wang et al., 2014). GA attenuated on hepatic injury and hepatic fibrosis induced by these chemicals in rodent models, which might be due to inhibition of inflammation, oxidative stress and hepatic stellate cell (HSC) activity. The ameliorative effect of GA on hepatic glycoprotein components and lipid peroxidation in the streptozotocin-induced diabetic rats has also been found (Punithavathi et al., 2011). Gallic acid treatment was found to reverse the disturbed metabolism to its normal condition in a mice model with non-alcoholic fatty liver disease (Chao et al., 2014). Results indicated that the potential targets of GA were lipid metabolism and ketogenesis, amino acids metabolism, choline metabolism, glycolysis and gut-microbiota metabolism. GA improved lipid metabolism and glucose tolerance in obese mice, thereby showing evidence of anti-hyperglycemic activity (Bak et al., 2013). This was due to improved triglyceride concentrations and induced PPAR-γ and Akt activations, thus improving the glucose metabolism. Gallic acid was found active on chronic ethanol-induced liver injury in rats by decreasing the serum alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase activities and elevating paraoxonase and arylesterase activity (Kartkaya et al., 2013). GA suppressed ethanol-induced necroptosis in hepatocytes by reducing the expression of distinct necroptotic signals receptor-interacting protein 1 (RIP1) and RIP3, as well as the release of high mobility group box protein 1 (Zhou et al., 2019). It also increased the expression of NrF2, which served as a molecular basis for suppressing ethanol-induced hepatocyte necroptosis. Thus, NrF2, a classical antioxidant protein, is a newly identified crucial suppressor for necroptosis. It has been reported that GA attenuated hepatitis C virus infection in hepatoma cells through its antioxidant and antiviral production (Govea-Salas et al., 2016; Hsu et al., 2015). It was also reported that GA decreased DEN-induced HCC by diminishing expression of proliferative marker PCNA and regulating signal transducer and activator of transcription 3 (STAT 3) signaling pathway (Aglan et al., 2017; Jagan et al., 2008). This was due to its high bioactivity, which included antioxidant, anti-inflammatory, apoptotic and antitumor properties. GA was able to inhibit liver metastasis of mastocytoma cells P-815 (Ohno et al., 2001).

Bergenin

Bergenin (C14H16O9) is a natural secondary metabolite isolated from the herb Bergenia ciliata, and it is reported that rhizome of B. ciliata contains 0.75% bergenin (Ahmad et al., 2018a, 2018b, 2018c). It is an isocoumarin compound extracted from the leaves, roots and bark of many families and genera of plants (Patel et al., 2012). It exhibits anti-inflammatory, antiarrhythmic, antitussive, antifungal, anticancer, antitumor, antiviral, immune enhancement, wound repair, anticoagulant, analgesic, antidiabetic, neuroprotective, antimalarial and antioxidant properties (Aggarwal et al.,; 2016; Ahmed & Urooj, 2012; Bajracharya, 2015; Bessong et al., 2005; Patel et al., 2012). It is reported that there are no side effects of bergenin even in very high dosages (Chauhan et al., 2012).

It was found that liver injury altered the pharmacokinetic behavior of bergenin and enhanced its absorption after given orally (Rong-Hua et al., 2016). These findings provided valuable information for the study of clinical pharmacokinetics of bergenin under hepatic injury condition and guidance for the potential use of bergenin as a hepatoprotective agent. It is reported that bergenin exerted hepatic protection in hepatic ischemia reperfusion (IR) injury model (Xiang et al., 2020). The protective action of bergenin was due to its ability to eliminate reactive oxygen species (ROS), influence the release of inflammatory factors, apoptosis and autophagy-related genes via the PPAR pathway. In a recent study, it was found that bergenin acted as a promising drug candidate for abrogating hepatic fibrosis induced by carbon tetrachloride and bile duct ligation (Xia et al., 2020). Bergenin retarded autophagy and hindered the energy supply required for HSC activation, thereby reducing collagen deposition and hepatocyte damage. Bergenin and metformin helped with hepatic hyperglycemia, insulin sensitivity and glucose uptake (Ambika & Saravanan, 2016). These phytochemicals increased the activity of glycolytic enzymes and significantly decreased the gluconeogenic enzymes in diabetic mice. Under diabetic conditions, this facilitated the release of hepatic glucose into circulation. Bergenin and metformin regulated the activities of these enzymes through metabolic activation or inhibition of glycolysis and gluconeogenesis, respectively. Bergenin improved insulin signalling in the liver of HFD-fed mice by increasing the tyrosine phosphorylation of IR-β and IRS-1, improving PI3K/Akt activation and glucose transporter protein 2 (GLUT 2) translocation. Thus, this phytochemical may be used to treat obesity-related type 2 diabetes mellitus as it enhanced insulin-dependent glucose transport in hepatic tissues by activating and translocating GLUT 2 in a PI3K/phosphorylated protein kinase B (AKT) dependent pathway. Bergenin was also effective against alcohol and tert-butyl hydroperoxide (TBHP)-induced liver injury in hepatoma cells (Sriset et al., 2020). It exhibited hepatoprotective activity via restoration of oxidant-antioxidant system and thus a potential candidate for hepatoprotective treatment.

β-Sitosterol

β-Sitosterol (BSS) is a plant derived natural dietary phytosterol similar to cholesterol. It is present in B. ciliata roots and leaves and in many oils from plants and vegetables (Manjunatha, 2010). β-Sitosterol has a wide spectrum of therapeutic effects against various chronic ailments (Yuan et al., 2019). According to reports, this phytosterol shows various types of health benefits against oxidative stress, obesity, anxiety, diabetes, cancer, sedative and prostatauxe effects (Baskar et al., 2012; Berges et al., 1995; Gumede et al., 2020; Jenkins et al., 2003; López-Rubalcava et al., 2006; Normén et al., 2001).

Treatment with BSS showed dose-dependent hepatoprotective effect against CCl4-induced chronic liver diseases (Devaraj et al., 2020). Its treatment inhibited ROS by causing diminution of intracellular enzymatic antioxidants such as superoxide dismutase and catalase in the rat liver. It also significantly reduced the expression of HSCs activation markers (hydroxyproline, collagen, α-SMA, desmin, vimentin, and MMP 9), thus exhibiting antifibrotic action. BSS has radio-protective effect via regulating the gene expression of PPAR-γ which in turn cause rise in PON-1 and ARE enzymes activities (Moustafa & Thabet, 2017). This action of BSS was due to its antioxidant potential, cholesterol reduction and PPAR-γ agonist properties. Another study indicated that BSS and its derivatives restrained LPS/ GalN-induced liver injury by inhibiting the oxidation and inflammation in mice (Yin et al., 2018). Their treatment regulated antioxidant status through the Nrf2 activation, heme oxygenase-1 (HO-1) promotion and controlling anti-inflammatory pathway through the toll like receptor 4 (TLR4) inhibition. It is reported that β-sitosterol in combination with stigmasterol acted against high-fat Western diet (HFWD)-induced NAFLD (Feng et al., 2018). Lipidomic analyses conducted in liver samples collected after thirty three weeks of the treatment have revealed the potency of these phytochemicals against NAFLD. Thus, these phytosterols serve as future candidates for human NAFLD by reducing plasma cholesterol levels (Table 2).

Table 2 Summary of therapeutic activities of different phytochemicals of Bergenia ciliata
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Other phytochemicals

Other phytochemicals found in B. ciliata are arbutin, tannic acid, fatty acids, terpenes, etc. Arbutin, a glycosylated form of hydroquinone is found in rhizome of B. ciliata and other green plants, is often used in various skin diseases (Khanal et al., 2011; Kunwar et al., 2013). It is also effective in repulsion of kidney stones as it possesses antibacterial properties, and heal cystitis and urinary tract infections (Funayama et al., 1995). It was found that arbutin mitigated tert-butyl hydroperoxide-induced toxicity in Hep-G2 cell line (Seyfizadeh et al., 2012). Reports showed that arbutin may protect the liver against cyclosporine and CCl4-induced oxidative damage in rats (Khadir et al., 2015; Mirshahvalad et al., 2016). This hepatoprotective effect was correlated with the antioxidant, lipoperoxidative and free radical scavenger effects of arbutin. Another finding demonstrated that arbutin is a strong radio-protector for reducing the radiation damage in megavoltage therapeutic x-irradiated mice (Nadi et al., 2019). Thus, arbutin may be used as an antioxidant to protect against oxidative damage induced by toxic chemicals and radiations on liver. Tannic acid (TA) is another polyphenol present in B. ciliata and in several fruits and vegetables (Ahmad et al., 2018a, 2018b, 2018c; Fraga-Corral et al., 2020). This compound possesses strong antimicrobial, antioxidant, antiviral, antibacterial and astringent properties, reduces serum cholesterol and triglycerides, and suppresses lipogenesis (Chung et al., 1998; Kaczmarek, 2020). TA exerted significant liver-protective effects against CCl4- and acetaminophen-induced liver damage and fibrosis in mice (Chu et al., 2016; Zhang et al., 2017). The potential mechanism relied on the inhibition of collagen accumulation, antioxidation, anti-inflammation and antiapoptosis.

Limonene is a monoterpene found in the numerous medicinal plants including rhizome of B. ciliata and citrus fruits (Adhikary et al., 2011; Kumar et al., 2010; Peng et al., 2009). It is a colorless liquid and exists in two optical isomers, d- or l-limonene as well as a racemic mixture (Vieira et al., 2018). d-Limonene is reported to have a variety of pharmaceutical applications such as anticancer, antioxidant and anti-inflammatory (Khan et al., 2013; Roberto et al., 2009). It has been reported that d-Limonene is effective against CCl4-induced hepatic fibrosis in Wistar rats via reducing oxidative stress and inflammation (Ahmad et al., 2018). It boosted the antioxidant status, regulated collagen accumulation and inhibited inflammation through ameliorating NF-κB. Another study demonstrated that d-Limonene reduced the oxidative stress in streptozotocin-induced diabetic rats by decreasing lipid peroxidation and restoring the activities of antioxidant enzymes (Murali et al., 2012). d-Limonene supplementation also ameliorated the NAFLD in rats and thus could serve as a promising complementary therapy against metabolic syndrome associated with NAFLD (Santiago et al., 2012). It is found that limonene inhibited experimental hepatocarcinogenesis in rat model via increased apoptosis and decreased cell proliferation (Kaji et al., 2001). Another terpene found in B. ciliata rhizome is β-caryophyllene, a bicyclic sesquiterpene, also a major component of essential oils of food plants such as cinnamon, cloves, black pepper and rosemary (Calleja et al., 2013; Jayaprakasha et al., 2003; Varga et al., 2018). This terpenoid is found to reduce CCl4-mediated hepatic fibrosis and hepatic cell activation by declining the gene expressions of Collagen-1α1, TGF-β1 and TIMP1 (Calleja et al., 2013). It is reported that β-caryophyllene ameliorated alcoholic and non-alcoholic steatohepatitis in experimental mice by regulating the activities of various inflammatory markers and antioxidant enzymes (Arizuka et al., 2017; Varga et al., 2018) (Fig. 2).

Fig. 2
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Chemical structures of phytochemicals of Bergenia ciliata

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Conclusions

The present review gathers the detailed information about the hepatoprotective potential of Bergenia ciliata for the first time. Almost all parts of the plant are used for curing different ailments; the most frequent part used is rhizome followed by root, leaf, flower and latex. The major phytochemical compounds reported in this species are of wide range phenols, flavonoids, fatty acid, glycosides, terpenoids, etc. These phytochemicals exhibit various biological activities including antibacterial, antioxidants, antifungal, antihemolytic and cytotoxic and had been traditionally used among the various communities particularly across the Himalayan region for urinary, gastrointestinal, skin, respiratory, gynecological, inflammatory, kidney disorders and infectious diseases. The techniques of HPLC, NMR, and FTIR can be used to characterize, isolate, and quantify these phytochemicals (Ahmad et al., 2018a, 2018b, 2018c; Majeed et al., 2021). Bergenin, the most abundant phytochemical, may be isolated and studied further in preclinical and clinical studies, allowing researchers to gain a better understanding of its nature and function in order to develop novel treatments for liver illnesses in near future. The antioxidant and hepatoprotective properties of the crude extract and subfractions can also be investigated. Based on the experimental evidences in the current review, Bergenia ciliata is considered is one of the most important anti-hepatotoxic agent which is attributed to its phytochemical constituents. But there is a dire need for further experimental investigations for its use as an antifibrotic and hepatoprotective agents as deficiency in clinical trials has been observed. Therefore, for the future discovery of it as liver medicine, it is necessary to conduct additional clinical studies on this plant. These clinical trials should be conducted to test the efficiency of this plant for its clinical uses along with its safety profit. The outcome of research in these areas will give convincing support for clinical use of B. ciliata in modern medicine in near future. Moreover, the plant has also lesser side effects on living organisms as compared to modern medicines (Fig. 3).

Fig. 3
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Mechanism of protective action of Bergenia ciliata against liver diseases

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