Review Articles

2022  |  Vol: 7(5)  |  Issue: 5 (September-October) | https://doi.org/10.31024/apj.2022.7.5.1

Medicinal plants with hepatoprotective potential: A brief review

Namrata Patel, Mukesh Kumar Patel*

Sagar Institute of Pharmaceutical Science, Sagar M.P. 470228

*Address for Corresponding Author

Mukesh Kumar Patel

Sagar Institute of Pharmaceutical Science, Sagar M.P. 470228 India

---

Abstract

The liver is a vital organ in the body. It plays a major role in metabolism, including ridding the body of substances that would otherwise be injurious if allowed to accumulate, and excretion of xenobiotics from the body. The endogenous antioxidants defenses from reactive oxygen species are strengthened by natural antioxidants and restore the optimal balance by neutralizing reactive species. Liver diseases have become a major global health challenge and may be triggered by several toxic chemicals, which include chemotherapeutic agents, thioacetamide, carbon tetrachloride, certain antibiotics, excessive alcohol consumption, and pathogenic microbes. Hence, safeguarding a healthy liver is vital for good health and well‑being. Despite advances in pharmacology, the demerits associated with synthetic drugs have outshone the merits. Treatment of liver diseases based on modern medical principles is becoming ineffective and also associated with adverse effects of long‑term use, in addition to prohibitive costs in developing countries. Thus, exploring medicinal plants which are easily available and cheap and do not involve strenuous pharmaceutical production processes appears to have gained worldwide attention as alternative therapeutic agents for the diseases. Consequently, emphasis has been placed on folkloric herbs with high efficacy, low toxicity, and cost‑effectiveness. Medicinal herbs are nature’s gift to humanity, contributing crucially to the preservation, maintenance and improvement of our health. Insight into the hepatoprotective effects of medicinally important plants is important, both for physicians and researchers. Main reasons for the use of herbal medicine include their lesser cost compared with conventional drugs, lesser undesirable drug reactions and thus high safety, and reduced side effects. The available information was critically analyzed to gain new insights and directions for future investigations towards establishing such natural products as potent hepatoprotective agents or dietary supplements.

Keywords: Liver, hepatoprotective, liver diseases, hepatotoxicity, bile acid

---

Introduction

Liver is the most crucial and indispensable organ in the body with multifunctional capabilities. It is involved in the metabolism of nutrients such as lipids, proteins, and carbohydrates, as well as in the excretion of waste metabolites (Abhilash et al., 2014). Bile produced in liver is momentarily stored in the gall bladder which later releases it into the duodenum to assist in lipid digestion. Bile salts, which make up majority of the biliary content, acts as detergent and facilitate the solubilization of highly hydrophobic materials including oils, fats, long chain fatty compounds and fat-soluble vitamins, into the highly hydrophilic and acidied digestive content. Moreover, through similar action, bile salts also enable the elimination of cholesterol and other fat-soluble harmful substances such as environmental toxins, carcinogens drugs, xennobiotics and toxic metabolites (Trauner and Boyer, 2003). It also detoxifies drugs, alcohol, chemicals, heavy metals, infectious organisms, as well as toxin by‑products from the blood (Akinloye and Olaniyi, 2011). It serves as a storage compartment for numerous substances such as glycogen, vitamins, minerals, and iron. Whenever there is depletion in the level of blood sugar in the body and energy is needed, the liver breaks down stored glycogen into glucose that is then utilized by the body (Rane et al., 2016). Therefore, a healthy liver is crucial for maintaining homeostasis and optimum health. However, liver is susceptible to infection by hundreds of etiological events including microorganisms (hepatitis viruses, yellow fever viruses, cytomegalovirus, Epstein-Barr virus), metabolic problems (obesity related liver disease, hemochromatosis, Wilson’s disease), alcohol, drugs, and chemicals (hepatotoxic substances) as well as different autoimmune disease (Lavanchy, 2009). Many hepatotoxic substances precipitate the formation of powerful free radicals leading to an increased oxidative burden which in turn, may potentially translate into hepatic damage, cirrhosis and hepatitis (Valko et al., 2007).

Hepatotoxicity

These diseases are classified into different categories, namely hepatosis  (noninflammatory), acute or chronic hepatitis (inflammatory), and cirrhosis or fibrosis (degenerative). The heavy metals, toxins, malnutrition, and over‑the‑counter drug use without doctors’ prescription commonly cause them. Consequently, the aforementioned factors destroy and incapacitate the hepatocytes that finally result in hepatitis, jaundice, liver fibrosis, and alcoholic liver disease. The elevation of cholesterol in the bloodstream is one of the indicators of the liver injury/disease. High percentages of low‑density lipoprotein cholesterol (LDL‑C) and triacylglycerols (TAGs) are connected with a high risk of cardiovascular diseases (Dominiczak, 2005).

Liver toxicity inducing agents

Drugs like PCM, Aspirin, Ibuprofen, amiodarone, isoniazid, methotrexate, valproic acid rifampin, Fluconazole, Diclofenac, Oral contraceptives ect. In addition, hepatic cell ;;;;damage can also be caused by excessive alcohol consumption, toxic substances such as thioacetamide (TAA), abuse of certain drugs such as paracetamol (PCM), chemotherapeutic agents such as carbon tetrachloride  (CC1₄ ), and also some organic and inorganic compounds, a flatoxin, microbes, and viral infections  (for example, hepatitis A, B, C, and D), which have been thoroughly investigated. The endoplasmic reticulum and mitochondrial cytochrome P‑450 metabolize CC1₄ that subsequently generates reactive oxygen species (ROS, CCl3 O⁻), which results in a chain reaction and perhaps triggers lipid peroxidation (Okaiyeto et al., 2018).

Herbal plants used as hepatoprotective

Till date available modern drugs have not been able to come up with a satisfactory answer for liver disorders because of high cost and additional adverse effects. It is therefore necessary to search for alternative drugs for the treatment of liver diseases to replace the currently used drugs of doubtful efficacy and safety. There are numerous plants and polyherbal formulations claimed to Hepatoprotective activity. Nearly phytoconstituents from 101 plants have been claimed to possess liver protecting activity. Thus there are some marketed products in india [Silybon (microlabs), LIV 52(Himalaya)] are available as hepatoprotectives. At the same time surprisingly, we do not have readily available plant drugs/formulations to treat liver diseases. However a number of medicinal plants have been advocated in traditional system of medicine, especially in Ayurveda, for treating liver disorders (Sreshta et al., 2018).

The secondary metabolite pool of the plants not only act as the principal source of these bioactive molecules, but also provide humankind with a continuous stream of signicant structural work with secondary metabolites covering major phytochemical classes including alkaloids, favonoids, glycosides, oils and fats, gums, terpenoids, steroids and vitamins. The major bioactive metabolites isolated from these plants with prominent hepatoprotective potentials include schaftoside, echinocystic acid and eclalbasaponin II. Moreover, thirteen polyphenolic and favonoid molecules including catechin, epicatechin, kaempferol, quercetin, quercitrin, isoquercitrin, anthocyanins, procyanidin A2, quercetin-7-O-rhamnoside, pelargonidin-3-O-glucoside, quercetin 3-O-rutinoside-7-O-a-Lrhamnoside, gallic acid and hyperin have been chemically characterized as the major phytoconstituents of different extracts from these plants which have been found to exert noteworthy hepatoprotective activities (Mohammad et al., 2022).

Curcumin (Curcuma longa L)

It represents a class of antiinflammatory and anti-oxidant reported to be a potent inhibitor of reactive oxygen species (ROS) formation. Traditional Indian medicine claims the use of curcumin powder against biliary disorders, anorexia, coryza, diabetic wounds, hepatic disorders, rheumatism, and sinusitis. Curcumin could exert antioxidative effects either directly as a chemical antioxidant due to its ability to scavenge reactive oxygen and nitrogen free radicals or by modulating cellular defenses which themselves exert antioxidant effects (Elsayed and Mohamed, 2018).

Garlic (Allium sativum)

Allium sativum contains fatty acids, proteins, carbohydrates, fiber, glycolipids, phospholipids, glycosides lectins, saponins, ajoene, allicin, diallyl trisulfide, diallyl disulfide, SAC sulfoxide, B, E, and C vitamins , which may be responsible for protection from various disorders and tissue damage. Aged Allium sativum extract has a high antioxidant content. However, free radical scavenging activity has been suggested as a possible mechanism of hepatoprotective action (Elsayed and Mohamed, 2018).

Fenugreek (Trigonella foenumgraecum)

The hepatoprotective effect of Trigonella foenumgraecum seeds has been elucidated against hepatic disorders induced by ethanol, aluminum chloride, and diabetes (Elsayed and Mohamed, 2018).

Trigonella foenumgraecum- treated irradiated rats received 1g Trigonella foenumgraecum seed powder/kg body weight/day by gavages for 7 days before irradiation. Trigonella foenumgraecum treatment has significantly alleviated hepatic oxidative stress induced by radiation, which was substantiated by the significant amelioration of serum aminotransferases enzymes and ALP activities (Nouira et al., 2013).

Brassica rapa

The protective effect of turnip root ethanolic extract (TREE) on early hepatic injuries was studied in alloxan-induced diabetic rats. TREE treatment groups received TREE (200 mg/kg) daily for 8 weeks through the gavage. TREE significantly decreased the levels of serum biomarkers of hepatic injury. Furthermore, it significantly decreased the lipid peroxidation and elevated the decreased levels of antioxidant enzymes in diabetic rats. The study also showed that histopathological changes were in agreement with biochemical findings (Snafi, 2016).

Mangifera indica L

The aqueous extract of the fruits was capable of reversing cumene hydroperoxide-induced oxidative stress-mediated hepatotoxicity in male Sprague–Dawley rats. Further biochemical characterization illustrated reduced rates of reactive oxygen species (ROS) generation, lipid peroxidation, hepatocyte lysis and intracellular glutathione depletion. Another in-vivo study investigated the aqueous extract of the stem barks of M. indica for hepatoprotective potential at the doses of 125, 250 and 500 mg/kg body weight in male Wistar rats. The hepatoprotective properties were assessed both in pretreatment and post-treatment model (Omotayo et al., 2015).

Alocasia indica (Araceae)

A. indica is conventionally used in the treatment of spleen and abdomen‑related ailments. The edible tuber part of the plant is commonly utilized as vegetable among Indian people although their research focus is on the nonedible leaf part of the plant (Ali and Kumar, 2015).

Coffee (Coffea arabica)

Researches indicate that coffee consumption is inversely related to hepatic cirrhosis. Animal models and cell culture studies indicate that kahweol, diterpenes, and cafestol (some coffee compounds) can function as blocking agents by modulating multiple enzymes involved in carcinogenic detoxification. kahweol, diterpenes, and cafestol alter the xenotoxic metabolism by inhibiting N-acetyltransferase and inducing the enzymes glutathione-S-transferase (Muriel and Arauz, 2010).

Heliotrpium undulatum

The hapatoprotective effect of n-BuOH extract of Heliotrpium undulatum (HUBE) was evaluated in Acetylhydrazide (ACHD) induced hepatotoxicity in rats. Hepatic damage was induced by administration of ACHD (300 mg/Kg op). HUBE (200 mg/Kg op) administered for 14 days before ACHD administration, caused a decrease in LPO levels and in the transaminase and ALP levels and restored the GSH and its related enzymes (GPx, GST, GR) (50-62 %). Simultaneous administration of HUBE afforded a partial protection in hepatic GSH (Snafi, 2018).

Peppermint (Mentha piperita)

Peppermint is usually used in treatment for disorders of the biliary system, liver problems, irritable bowel syndrome, and inflammatory bowel disease. The effects of peppermint are related to its effect on bile flow and liver function (Taylor, 1984).

Juglans regia

The protective effect of Juglans regia extract was studied in a rat model of Bleomycin (BLM)-induced pulmonary toxicopathy. Methanolic extract 150mg/kg bw was given per os to Wistar rats for 14days prior to BLM exposure. A single intratracheal injection of BLM (10U/kg bw) was administered on the eleventh day of he treatment. BLM caused marked increase in the hydroxyproline level, lipid peroxidation, nitric oxide production, and in the activities of xanthine oxidase and myeloperoxidase in the lung tissue compared to control animals. BLM also decreased the activities of antioxidant enzymes such as glutathione reductase and catalase and increased the lung inflammation and apoptosis by upregulating the NF-κB signaling pathway and caspase-3 expression. Treatment with walnut extract attenuated these changes in a significant manner, it significantly modulated the lung injury as measured by markers of cellular injury such as lactate dehydrogenase and alkaline phosphatase, total cell count, total protein and reduced glutathione in bronchoalveolar lavage fluid. Histological findings supported the protective effects of walnut extract against BLM-induced lung injury (Snafi, 2018).

Olive (Olea europaea)

Olea europaea leaves contain maslinic acid, ursolic, oleanolic, quercetin, apigenin, luteolin, tannins, and caffeic acid (Dekanski et al., 2019). Treatment of experimental animals with Olea europaea leaves extract caused a reduction in blood glucose prevention of hepatotoxicity (Jamai et al., 2019).

Geum urbanum

A-Hepatica is an herbal combination (contained ten herbs included Geum urbanum (Clove root- 6.5 ml) was used for detoxification of the liver and gallbladder. A-Hepatica was said to be regulates secretion and absorption in the digestive system, has anti-inflammatory and antispasmolytic function in the portal vein, stimulates bile flow and increases detoxification of the liver (Khan et al., 2008).

Phoenix dactylifera (Arecaceae)

The hepatoprotective potential of methanolic P. dactylifera fruit extracts (date palm) in TAA‑induced toxicity in male rats. From their results, it was found that the methanolic fruits extract of the plant displayed substantial hepatoprotective capability because of the reduction in the hepatocellular enzymes levels of the test groups as compared to the TAA‑induced group. The potential of the extract to upset the rise in serum bilirubin and ALP induced by TAA suggests it prospect in reversing the plasma membrane damage (Okwuosa et al., 2014).

Aquilaria agallocha (Thymelaeaceae)

The hepatoprotective role of ethanolic extract of A. agallocha (AAE) leaves (400 mg/ml) in PCM‑induced hepatotoxicity in Sprague–Dawley (SD) rats. These results revealed that AAE leaves exert hepatoprotective effect as it exhibited protective effect contrary to PCM‑induced hepatotoxicity in SD rats as shown by a substantial decrease in AST, ALP, ALT, LDH, CHL, and TB, increase in ALB and total protein concentration, and prevention of PCM‑induced histopathological changes in the liver (Alam et al., 2017).

Parsley (Petroselinum crispum)

Parsley leaves were used for the treatment of colic, jaundice, constipation, flatulence edema, and rheumatism. It was used to treat as impotence, a blood pressure regulator, lumbago and nose bleed (Manderfeld et al., 1997). The constituents of parsley which include ascorbic acid, carotenoids, flavonoids, coumarins, apiole, various terpenoic compounds, phenylpropanoids, phthalides, furanocoumarins, and tocopherol, have been chemically investigated (Tunali et al., 1999). It has been exhibited immunosuppressant, antioxidant, antidiabetic, cytoprotective, and hepatoprotective (Farzaei et al., 2013).

Hypericum japonicum Thunb.

H. japonicum is distributed throughout the Asia and some parts of Europe. The plant has an extensive history of being utilized for ethnomedicinal purposes. Phytochemical investigations into this plant have afforded a wide variety of bioactive molecules which have been further characterized with prominent pharmacological potentials through appropriate studies. Eventually, the hepatoprotective properties of the plant have also been traced to individual secondary metabolites (Liu et al., 2014).

Jussiaca repens

Elevated serum levels of both alanine transferase (ALT) and gamma glutamyl transferase (GGT) on infection with Schistosoma mansoni were significantly reversed in comparison to praziquantel, which in turn means the improvement of liver functions. Also, elevation of malondialdehyde (MDA) and glutathione (GSH) levels in liver homogenate (6- and 2-folds, respectively) was significantly reduced by 50% and 41% on treatment with the low dose of EA-extract (100mgkg bw). The percentage of this reduction was increased at the high dose (200mgkg bw) in comparison with silymarin. This was an evidence of the strong antioxidant and consequently hepatoprotective effect of this extract, which could be attributed to its high flavonoids content (Nabavi et al., 2011).

B. vulgaris

B. vulgaris (barberry), a well known medicinal plant in Iran and also a food, belongs to Berberidaceae family. As a shrub with 1 to 3 meters in height, B. vulgaris grows in many regions of the world, including Iran (especially Khorasan) (Parsaee et al., 2006). Fruit, leaves, and stem have medical usages including hepatoprotection. B. vulgaris fruit extract contains various flavonoids that act as antioxidant (Hadaruga et al., 2010). Fruit, leaves, and stem have medical usages including hepatoprotection. B. vulgaris fruit extract contains various flavonoids that act as antioxidant. Berberine, oxyacanthine, and other alkaloids such as berbamine, palmatine, columbamine, malic acid, jatrorrhizine and berberrubine comprise some other compounds (Fatehi et al., 2005). Berberine an isoquinoline alkaloid with a long medicinal history, exists in roots, rhizomes, and stem bark of the plant. Berberine inhibits potassium and calcium currents in isolated rat hepatocytes. It has hepatoprotective effects, both preventive and curative, on CC14-induced liver injury through scavenging the peroxidative products. CC14 significantly increased the serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels in rats. Treatment with the methanolic extract of B. vulgaris fruit significantly helped these changes reach to an almost normal level. In addition, the extract could prevent CC14- induced liver oxidative damage in rats (Feng et al., 2010).

C. officinalis

C. officinalis (marigold), from Asteraceae family, is a medicinal plant and cosmetic herb popularly known in Europe and the USA. The dried flower heads or the dried ligulate flowers of this plant are used for pharmaceutical and/or cosmetic purposes (Hamburger et al., 2003). Antibacterial, anti-inflammatory, antiviral, and antioxidant activities have been already noted for C. officinalis (preethi et al., 2006). It has been taken in order to treat fevers and jaundice and to promote menstruation. Extracts, tinctures, balms, and salves of C. officinalis have been applied directly to heal wounds and soothe inflamed and injured skin. C. officinalis compounds, which are potentially active chemical constituents, are monoterpenes, such as α-thujene and T-muurolol, sesquiterpene and flavonol glycosides, triterpene alcohols, triterpenoid saponins, flavonoids, carotenoides, xanthophylls, phenolic acids, mucilage, bitters, phytosterols, tocophrrols, calendulin, resin, and volatile oil. The anti-inflammatory features of C. officinalis flowers, according to in vivo pharmacological tests, have been associated with the triterpenoid fatty acid esters. In Singh’s study, 80% effect of methanolic extract of leaves (500 mg/kg orally, four doses at 12 hours interval) of C. officinalis was investigated against acetaminophen-induced hepatic damage in albino rats. The potential hepatoprotective effects of C. officinalis extracts against CC1₄- induced oxidative stress and cytotoxicity in isolated primary rat hepatocytes were detected (Singh, 2011).

A. eupatoria

A. eupatoria (from Rosaceae family) is 35-120 cm high, semiorbicular, and rather thick, with densely hirsute stems, herbaceous stipules, coarsely acutely serrated or lobed margins, and pilose and pubescent petiole. The leaf blade is interrupted imparipinnate with 3-5 pairs of leaflets (Kline and Sorensen, 2008). A. eupatoria grows on clay soils. In popular medicine, it is employed for the treatment of several disorders, e.g. inflammations. The aqueous extract of A. eupatoria is full of several phenolic compounds and its ethyl acetate fraction has exhibited antioxidant activity and lower toxicity (Correia et al., 2007). A. eupatoria is rich in coumarins, flavonoids, tannins, terpenoids, and phenolic compounds including protocatechuic acid, coumaric acid, chlorogenic acid, quercitrin, and gallic acid (Giao et al., 2009). Hepatoprotective effects of aqueous extract of A. eupatoria were investigated in experimental liverdamaged models. Hepatoprotective effects of the plant were monitored by reducing serum AST and ALT levels (Kang et al., 2006).

Opuntia ficus‑indica (Cactaceae)

Opuntia ficus‑indica (Cactaceae) is a species of cactus commonly used for fruit production that has long been a house‑trained crop plant essential in agricultural economies distributed in the arid and semiarid parts of the world. It is probably believed to have originated from Mexico. It is often used livestock feed as a vegetable forage resource during water shortage and shortage of herbaceous plants (Felker et al., 2006). Most scientific medicinal research studies involve the leaves (cladodes) rather than the fruit. The hepatoprotective potential of aqueous extract (2 mL/kg) from cactus cladodes in CCl4 ‑induced toxicity in Wistar male rats was examined (Djerrou et al., 2015).

Conclusion

Herbal medicines have the potential to offer an effective mean towards the treatment of liver diseases. Extensive literature survey of hepatoprotective plants clearly indicates that herbal drugs have an enormous potential for the treatment of liver diseases. We also presented the possible data available in the literature for different plants regarding their phytochemical constituents. We, therefore, conclude that herbs are among the most important sources of hepatoprotective and liver regeneration medicines. However, further research is needed to identify, characterize, and standardize the active ingredients, useful compounds, and their preparations for the treatment of liver diseases. The availability of modern hepatoprotective drugs with realistic clinical utility is still very limited and identification of new molecules with similar potentials will surely advocate the process of novel drug discovery as well as development.

References

Abhilash  G, Maheswari  YJ, Gopal  A, Chanda  D. 2014. Review on some medicinal plants with hepato‑protective activities. Research & Reviews: Journal of Pharmacognosy and Phytochemistry, 22:33.

Akinloye  OA, Olaniyi  MO. 2011. Hepato‑protective effect of Cajanus cajan on tissue defense system in D‑galactosamine‑induced hepatitis in rats. Turkish Journal of Biochemistry, 36:237‑41.

Alam J, Mujahid M, Badruddeen, Jahan Y, Bagga P, Rahman MA. 2017. Hepatoprotective potential of ethanolic extract of Aquilaria agallocha leaves against paracetamol induced hepatotoxicity in SD rats. Journal of Traditional and Complementary Medicine, 7:9‑13.

Ali MI, Kumar M. 2015. A recent update on hepatoprotective potential of herbal plant. International Journal of Environmental Science and Technology, 1:25‑49.

Al-Snafi AE. 2016. Detoxification capacity and protective effects of medicinalplants (part 2): plant based review. IOSR Journal of Pharmacy, 6(7):63-84.

Al-Snafi AE. 2018. Pharmacological and therapeutic importance of Hibiscus sabdariffa- A review. International Journal of Pharmaceutical Research, 10(3):451-475.

Al-Snafi AE. 2018. The pharmacological effects of Helianthus annuus- A review. Indo American Journal of Pharmaceutical Sciences, 5(3):1745- 1756.

Arman  Md, Chowdhury Kazi AA, Bari  Md, Sazzadul, Forhad Khan  Md, Ataul H,  M Md, Haque Md. 2022. Areeful Capasso Raffaele Hepatoprotective potential of selected medicinally important herbs: evidence from ethnomedicinal, toxicological and pharmacological evaluations. Phytochemistry Reviews,  21:1863–1886.

Azab E. 2018. Albasha  Mohamed Omar Hepatoprotective EffectofSome Medicinal Plants and Herbs against Hepatic Disorders Induced by Hepatotoxic Agent , Journal of Biotechnology and Bioengineering Volume 2, Issue 1,PP 8-23.

Belaid-Nouira Y, Bakhta H, Haouas Z, FlehiSlim I, Neffati F, Najjar MF, Ben Cheikh H. 2013. Fenugreek seeds, a hepatoprotector forage crop against chronic AlCl3 toxicity. BMC Veterinary Research, 9(22):1-9.

Correia HS, Batista MT, Dinis TC. 2007. The activity of an extract and fraction of Agrimonia eupatoria L. against reactive species. Biofactors, 29:91-104.

Dekanski D, Janicijevic-Hudomal S, Tadic V, Markovic G, Arsic I, Mitrovic DM. 2009. Phytochemical analysis and gastroprotective activity of an olive leaf extract. Journal of the Serbian Chemical Society, 74(4):367-377.

Djerrou Z, Maameri Z, Halmi S, Djaalab H, Riachi F, Benmaiza L.2015. Hepatoprotective effect of Opuntia ficus‑indica aqueous extract against carbon tetrachloride‑induced toxicity in rats. OnLine Journal of Biological Sciences, 15:36‑41.

Dominiczak MH, Lipids Li, Baynes JW, Dominiczak MH. 2005. editors. Medical Biochemistry. Philadephia: Elsevier Mosby, 234‑42.

Farzaei MH, Abbasabadi Z, Ardekani MRS, Rahimi R, Farzaei F. 2013. Parsley: a review of ethnopharmacology, phytochemistry and biological activities. Journal of Traditional Chinese Medicine, 33(6):815-826.

Fatehi M, Saleh TM, Fatehi-Hassanabad Z, Farrokhfal K, Jafarzadeh M, Davodi S. 2005 A pharmacological study on Berberis vulgaris fruit extract. Journal of Ethnopharmacology, 102:46-52.

Felker P, Paterson  A, Jenderek  M. 2006 Forage potential of opuntia clones maintained by the USDA, National Plant Germplasm System (NPGS) collection. Crop Science, 46:2161‑8.

Feng Y, Siu KY, Ye X, Wang N, Yuen MF, Leung CH. 2010 Hepatoprotective effects of berberine on carbon tetrachloride-induced acute hepatotoxicity in rats. Chinese Medical Journal, 5:33.

Gião MS, Pereira CI, Fonseca SC, Pintado ME, Malcata FX. 2009. Effect of particle size upon the extent of extraction of antioxidant power from the plants Agrimonia eupatoria, Salvia sp. and Satureja montana. Food Chemistry; 117:412-416.

Hadaruga DI, Hadaruga NG, Bandur GN, Rivis A, Costescu C, Ordodi VL. 2010 Berberis vulgaris extract/β cyclodextrin nanoparticles synthesis and characterization. REVISTA DE CHIMIE (Bucharest), 61: 669-675.

Hamburger M, Adler S, Baumann D, Förg A, Weinreich B. 2003. Preparative purification of the major anti-inflammatory triterpenoid esters from Marigold (Calendula officinalis). Fitoterapia, 74: 328-338.

Jemai H, El Feki A, Sayadi S. 2009. Antidiabetic and antioxidant effects of hydroxytyrosol and oleuropein from olive leaves in alloxan-diabetic rats. Journal of Agricultural and Food Chemistry, 57: 8798-8804.

Kang S, Lee C, Koo H, Ahn D, Choi H, Lee J. 2006. Hepatoprotective effects of aqueous extract from aerial part of agrimmony. Korean Journal of Pharmacognosy, 37:28-32.

Khan MA, Shafiullah J, Malik SA, Shafi M. 2008. Hepatoprotective effects of Berberis lycium, Galium aparine and Pistacia integerrima in carbon tetrachloride (CCl4) treated rats. Journal of Postgraduate Medicine, 22(2):91-94.

Kline GJ, Sorensen PD. 2008. A revision of Agrimonia (Rosaceae) in North and Central America. Brittonia, 60:11-33.

Lavanchy D. 2009. The global burden of hepatitis C. Liver International. 29:74–81.

Liu L-S, Liu M-H, He J-Y. 2014. Hypericum japonicum Thunb. ex Murray: phytochemistry, pharmacology, quality control and pharmacokinetics of an important herbal medicine. Molecules, 19(8):10733–10754.

Manderfeld MM, Schafer HW, Davidson PM, Zottola EA. 1997. Isolation and identification of antimicrobial furocoumarins from parsley. Journal of Food Protection, 60:72–77.

Muriel P, Arauz J. 2010. Coffee and liver diseases. Fitoterapia 81:297–305.

Nabavi SF, Ebrahimzadeh MA, Nabavi SM, Mahmoudi M, Rad SK. 2011. Biological activities of Juglans regia flowers. Revista Brasileira de Farmacognosia, 21(3):465-470.

Okaiyeto  K, Nwodo U, Mabinya  LV, Okoh  AI. 2018. A Review on Some Medicinal Plants with Hepatoprotective Effects, Pharmacognosy Reviews.

Okwuosa  CN, Udeani  TK, Umeifekwem  JE, Onuba  AC, Anioke  IC, Madubueze  RE. 2014. Hepatoprotective effect of methanolic fruit extracts of Phoenix dactylifera (Arecaceae) on thioacetamide induced liver damage in rats. American Journal of Phytomedicine and Clinical Therapeutics, 2:290‑300.

Omotayo MA, Ogundare OC, Oluwafunmilayo A, Longe SA. 2015. Hepatoprotective effect of Mangifera-indica stem bark extracts on paracetamol-induced oxidative stress in albino rats. European Scientific Journal, 11(24).

Parsaee H, Shafel MN, Boskabady MH. 2006. Effects of hydro-ethanolic extractof Berberis vulgaris fruit on rabbit isolated heart. DARU Journal of Pharmaceutical Sciences, 14:208-213.

Preethi KC, Kuttan G, Kuttan R. 2006. Antioxidant potential of an extract of Calendula officinalis flowers in vitro and in vivo. Pharmaceutical Biology, 44:691-697.

Rane J, Jadhao R, Bakal RL.2016. Liver diseases and herbal drugs: A review. Journal of innovations in pharmaceutical & biological sciences, 3:24‑36.

Singh MK, Sahu P, Nagori K, Dewangan D, Kumar T, Alexander A. 2011. Organoleptic properties in-vitro and in-vivo pharmacological activities of Calendula officinalis Linn: an over review. Journal of Chemical and Pharmaceutical Research,3:655-66.

Sreshta B, Babu S. 2018. Ravindra Hepatoprotective effect of Poly herbal formulation containing indigenous medicinalplants against various hepatotoxic agents in rats. Asian Journal of Pharmacy and Pharmacology, 4(2):232-237.

Taylor B. 1984. The mechanism of the inhibitory action of menthol on gut smooth muscle. British Journal of Surgery, 71:902-908.

Trauner M, Boyer JL. 2003. Bile salt transporters: molecular characterization, function, and regulation. Physiological Reviews, 83(2):633–671.

Tunali T, Yarat A, Yanardag R, Ozçelik F, Ozsoy O, Ergenekon G, Emekli N. 1999. Effect of parsley (Petroselinum crispum) on the skin of STZ induced diabetic rats. Phytotherapy Research, 13(2), 138-141.

Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. 2007. Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry & Cell Biology, 39(1):44–84.