Arjunolic acid: A new multifunctional therapeutic promise of alternative medicine

Importance of the field

In recent years, a number of studies describing the effective therapeutic strategies of medicinal plants and their active constituents in traditional medicine have been reported. Indeed, tremendous demand for the development and implementation of these plant derived biomolecules in complementary and alternative medicine is increasing and appear to be promising candidates for pharmaceutical industrial research. These new molecules, especially those from natural resources, are considered as potential therapeutic targets, because they are derived from commonly consumed foodstuff and are considered to be safe for humans.

Areas covered in this review

This review highlights the beneficial role of arjunolic acid, a naturally occurring chiral triterpenoid saponin, in various organ pathophysiology and the underlying mechanism of its protective action. Studies on the biochemistry and pharmacology suggest the potential use of arjunolic acid as a novel promising therapeutic strategy.

What the readers will gain

The multifunctional therapeutic application of arjunolic acid has already been documented by its various biological functions including antioxidant, anti-fungal, anti-bacterial, anticholinesterase, antitumor, antiasthmatic, wound healing and insect growth inhibitor activities. The scientific basis behind its therapeutic application as a cardioprotective agent in traditional medicine is justified by its ability to prevent myocardial necrosis and apoptosis, platelet aggregation, coagulation and lowering of blood pressure, heart rate, as well as cholesterol levels. Its antioxidant property coupled with metal chelating property (by its two hydroxyl groups) protects different organs from metal and drug-induced organ pathophysiology. Arjunolic acid also plays a beneficial role in the pathogenesis of diabetes and its associated complications. The mechanism of cytoprotection of arjunolic acid, at least in part, results from the detoxification of reactive oxygen species (ROS) produced in the respective pathophysiology. In addition to its other biological functions, it also possesses vibrant insecticidal properties and it has the potential to be used as a structural molecular framework for the design of molecular receptors in the general area of supramolecular chemistry and nanochemistry. Esters of arjunolic acid function as organogelators which has wide application in designing thermochromic switches and sensor devices. Arjunolic acid derived crown ether is an attractive candidate for the design of molecular receptors, biomimetics and supramolecular systems capable of performing some biological functions.

Home message

This review would provide useful information about the recent progress of natural product research in the domain of clinical science. This review also aims to untie the multifunctional therapeutic application of arjunolic acid, a nanometer-long naturally occurring chiral triterpenoid biomolecule.     

Protection of arsenic-induced testicular oxidative stress by arjunolic acid

Arsenic-induced tissue damage is a major concern to the human population. An impaired antioxidant defense mechanism followed by oxidative stress is the major cause of arsenic-induced toxicity, which can lead to reproductive failure. The present study was carried out to investigate the preventive role of arjunolic acid, a triterpenoid saponin isolated from the bark of Terminalia arjuna, against arsenic-induced testicular damage in mice. Administration of arsenic (in the form of sodium arsenite, NaAsO(2), at a dose of 10 mg/kg body weight) for 2 days significantly decreased the intracellular antioxidant power, the activities of the antioxidant enzymes, as well as the levels of cellular metabolites. In addition, arsenic intoxication enhanced testicular arsenic content, lipid peroxidation, protein carbonylation and the level of glutathione disulfide (GSSG). Exposure to arsenic also caused significant degeneration of the seminiferous tubules with necrosis and defoliation of spermatocytes. Pretreatment with arjunolic acid at a dose of 20 mg/kg body weight for 4 days could prevent the arsenic-induced testicular oxidative stress and injury to the histological structures of the testes. Arjunolic acid had free radical scavenging activity in a cell-free system and antioxidant power in vivo. In summary, the results suggest that the chemopreventive role of arjunolic acid against arsenic-induced testicular toxicity may be due to its intrinsic antioxidant property.     

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Abstract

Arsenic-induced tissue damage is a major concern to the human population. An impaired antioxidant defense mechanism followed by oxidative stress is the major cause of arsenic-induced toxicity, which can lead to reproductive failure. The present study was carried out to investigate the preventive role of arjunolic acid, a triterpenoid saponin isolated from the bark of Terminalia arjuna, against arsenic-induced testicular damage in mice. Administration of arsenic (in the form of sodium arsenite, NaAsO₂, at a dose of 10 mg/kg body weight) for 2 days significantly decreased the intracellular antioxidant power, the activities of the antioxidant enzymes, as well as the levels of cellular metabolites. In addition, arsenic intoxication enhanced testicular arsenic content, lipid peroxidation, protein carbonylation and the level of glutathione disulfide (GSSG). Exposure to arsenic also caused significant degeneration of the seminiferous tubules with necrosis and defoliation of spermatocytes. Pretreatment with arjunolic acid at a dose of 20 mg/kg body weight for 4 days could prevent the arsenic-induced testicular oxidative stress and injury to the histological structures of the testes. Arjunolic acid had free radical scavenging activity in a cell-free system and antioxidant power in vivo. In summary, the results suggest that the chemopreventive role of arjunolic acid against arsenic-induced testicular toxicity may be due to its intrinsic antioxidant property.     

Experimental myocardial necrosis in rats: Role of arjunolic acid on platelet aggregation,coagulation and antioxidant status

Arjunolic acid, a new triterpene and a potent principle from the bark of Terminalia arjuna, has been shown to provide significant cardiac protection in isoproterenol induced myocardial necrosis in rats. To further explore the mechanism of action of arjunolic acid, antiplatelet activity, anticoagulant assays, electrocardiographic changes, serum marker enzymes, antioxidant status, lipid peroxide and myeloperoxidase (MPO) have been measured and the results are compared with a potent cardioprotective drug, acetyl salicylic acid (ASA). Administration of isoproterenol produces electrocardiographic changes such as decreased R amplitude and increased ST segment elevation and has resulted in an increase in serum marker enzyme levels as well as a decrease in enzymatic and nonenzymatic antioxidant levels. Arjunolic acid at an effective dosage of 15 mg/kg body weight (pre and post treatment),when administered intraperitoneally (i.p.), effects a decrease in serum enzyme levels and the electrocardiographic changes get restored towards normalcy. Arjunolic acid treatment is also shown to prevent the decrease in the levels of superoxide dismutase, catalase, glutathione peroxidase, ceruloplasmin, -tocopherol, reduced glutathione (GSH), ascorbic acid, lipid peroxide, MPO and the cardioprotection is confirmed by the histopathological studies.This study shows that the cardioprotection of arjunolic acid pre and post treatment could possibly be due to the protective effect against the damage caused by myocardial necrosis.     

Protective effect of arjunolic acid against arsenic-induced oxidative stress in mouse brain

Arsenic, a notoriously poisonous metalloid, is ubiquitous in the environment, and it affects nearly all organ systems of animals including humans. The present study was designed to investigate the preventive role of a triterpenoid saponin, arjunolic acid against arsenic-induced oxidative damage in murine brain. Sodium arsenite was selected as a source of arsenic for this study. The free-radical-scavenging activity and the in vivo antioxidant power of arjunolic acid were determined from its 2,2-diphenyl-1-picryl hydrazyl radical scavenging ability and ferric reducing/antioxidant power assay, respectively. Oral administration of sodium arsenite at a dose of 10 mg/kg body weight for 2 days significantly decreased the activities of antioxidant enzymes, superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase and glutathione peroxidase, the level of cellular metabolites, reduced glutathione, total thiols and increased the level of oxidized glutathione. In addition, it enhanced the levels of lipid peroxidation end products and protein carbonyl content. Treatment with arjunolic acid at a dose of 20 mg/kg body weight for 4 days prior to arsenic administration almost normalized above indices. Histological findings due to arsenic intoxication and arjunolic acid treatment supported the other biochemical changes in murine brains. Results of 2,2-diphenyl-1-picryl hydrazyl radical scavenging and ferric reducing/antioxidant power assays clearly showed the in vitro radical scavenging as well as the in vivo antioxidant power of arjunolic acid, respectively. The effect of a well-established antioxidant, vitamin C, has been included in the study as a positive control. Combining all, results suggest that arjunolic acid possessed the ability to ameliorate arsenic-induced oxidative insult in murine brain and is probably due to its antioxidant activity.     

Arjunolic acid,a triterpenoid saponin,prevents acetaminophen (APAP)-induced liver and hepatocyte injury via the inhibition of APAP bioactivation and JNK-mediated mitochondrial protection

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug and is safe at therapeutic doses but its overdose frequently causes liver injury. In earlier studies, we demonstrated that arjunolic acid (AA) has a protective effect against chemically induced hepatotoxicity. The purpose of this study was to explore whether AA plays any protective role against APAP-induced acute hepatotoxicity and, if so, what molecular pathways it utilizes for the mechanism of its protective action. Exposure of rats to a hepatotoxic dose of acetaminophen (700 mg/kg, ip) altered a number of biomarkers (related to hepatic oxidative stress), increased reactive oxygen species production, reduced cellular adenosine triphosphate level, and induced necrotic cell death. Arjunolic acid pretreatment (80 mg/kg, orally), on the other hand, afforded significant protection against liver injury. Arjunolic acid also prevented acetaminophen-induced hepatic glutathione depletion and APAP metabolite formation although arjunolic acid itself did not affect hepatic glutathione levels. The results suggest that this preventive action of arjunolic acid is due to the metabolic inhibition of specific forms of cytochrome P450 that activate acetaminophen to N-acetyl-p-benzoquinone imine. In addition, administration of arjunolic acid 4 h after acetaminophen intoxication reduced acetaminophen-induced JNK and downstream Bcl-2 and Bcl-xL phosphorylation, thus protecting against mitochondrial permeabilization, loss of mitochondrial membrane potential, and cytochrome c release. In conclusion, the data suggest that arjunolic acid affords protection against acetaminophen-induced hepatotoxicity through inhibition of P450-mediated APAP bioactivation and inhibition of JNK-mediated activation of mitochondrial permeabilization.     

Arjunolic acid: beneficial role in type 1 diabetes and its associated organ pathophysiology

In this review article, we describe the most recent development of the beneficial effect of arjunolic acid (AA) in reducing type 1 diabetic pathophysiology. Diabetic mellitus is a serious and growing health problem worldwide. Increasing evidence suggest that oxidative stress plays a pivotal role in the pathogenesis of diabetes and its associated complications. Use of antioxidant supplements as a complimentary therapeutic approach in diabetes has, therefore, been seriously considered worldwide. AA, a natural pentacyclic triterpenoid saponin, is well known for various biological functions including antioxidant activity. It could prevent the increased production of ROS, RNS, AGEs, and the 8OHdG/2dG ratio and increase the intracellular antioxidant defence system. Signal transduction studies showed that AA could prevent hyperglycaemia induced activation of MAPKs, PKC, NF-κB signalling cascades and apoptotic cell death. Combining, AA supplements could be regarded as beneficial therapeutics in the treatment of diabetes and its associated complications.     

Renal protective effects of arjunolic acid in a cisplatin-induced nephrotoxicity model

Cisplatin is the first platinum-containing anti-cancer drugs. Cisplatin notable side effect of nephrotoxicity limits its use in clinic. Meanwhile, arjunolic acid possesses anti-inflammatory properties and plays protective roles against chemically induced organ pathophysiology. This study was conducted to find out whether arjunolic acid could attenuate kidney damage in rats, and to elucidate its possible mechanism of action. Fifty rats were treated with cisplatin (10 mg/kg) in the presence/absence of 100 or 250 mg/kg arjunolic acid. Arjunolic acid is given 1 h after cisplatin. Morphological changes were assessed in kidney sections stained with Hematoxylin/Eosin and Masson Trichrome. Kidney samples were used for measurements of transforming growth factor (TGF)-β1 and its type 1 receptor (TGF-βR1), tumor necrosis factor (TNF)-α and interleukin (IL)-1β by ELISA. Gene expression NFκB was determined by real time-PCR. Kidney tissue apoptosis was assessed by measuring the activities of caspase-3/8/9. The renal protective effect of arjunolic acid was confirmed by approximately normal appearance of renal tissue and the relatively unaffected serum creatinine and urea levels. Furthermore, arjunolic acid showed dose dependent reduction in cisplatin-induced elevation in renal levels of TGF-βR1, TGF-β1, TNF-α, IL-1β and caspases. These findings demonstrated that arjunolic acid attenuates cisplatin nephrotoxicity either indirectly by enhancing body antioxidant activity or directly through several mechanisms, including inhibition of pro-inflammatory cytokines, blocking activation of TGF-β1, and anti-apoptotic effects.     

Comparative Proteomics of Chromium-Transformed Beas-2B Cells by 2D-DIGE and MALDI-TOF/TOF MS

Continuation of prolonged treatment against arsenicosis with conventional chelating therapy is a global challenge. The present study was intended to evaluate the defensive effect of arjunolic acid against arsenic-induced oxidative stress and female reproductive dysfunction. Wistar strain adult female rats were given sodium arsenite (10 mg/kg body weight) in combination with arjunolic acid (10 mg/kg body weight) orally for two estrous cycles. Electrozymographic analysis explored that arjunolic acid co-treatment counteracted As³⁺-induced ROS production in uterine tissue by stimulating the activities of endogenous enzymatic antioxidants. Arjunolic acid was able to enhance the protection against mutagenic uterine DNA breakage, necrosis, and ovarian–uterine tissue damages in arsenicated rats by improving the ovarian steroidogenesis. The mechanisms might be coupled with the augmentation of antioxidant defense system, partly through the elimination of arsenic with the involvement of S-adenosyl methionine pool where circulating levels of vitamin B₁₂, folic acid, and homocysteine play critical roles as evidenced from our present investigation.     

Arjunolic acid: beneficial role in type 1 diabetes and its associated organ pathophysiology

Abstract

In this review article, we describe the most recent development of the beneficial effect of arjunolic acid (AA) in reducing type 1 diabetic pathophysiology. Diabetic mellitus is a serious and growing health problem worldwide. Increasing evidence suggest that oxidative stress plays a pivotal role in the pathogenesis of diabetes and its associated complications. Use of antioxidant supplements as a complimentary therapeutic approach in diabetes has, therefore, been seriously considered worldwide. AA, a natural pentacyclic triterpenoid saponin, is well known for various biological functions including antioxidant activity. It could prevent the increased production of ROS, RNS, AGEs, and the 8OHdG/2dG ratio and increase the intracellular antioxidant defence system. Signal transduction studies showed that AA could prevent hyperglycaemia induced activation of MAPKs, PKC, NF-κB signalling cascades and apoptotic cell death. Combining, AA supplements could be regarded as beneficial therapeutics in the treatment of diabetes and its associated complications.     

Molecular docking analysis of arjunolic acid from Terminalia arjuna with a coronary artery disease target APOE4

Apo lipoprotein-E (APOE) encoded by APOE gene, is a plasma glycoprotein of 34.15 kDa and has a significant genetic association in coronary artery disease (CAD) progression. The silent epidemic of different cardiovascular diseases including CAD challenges novel therapeutic alternatives to prevent to treat chronic conditions of the disease and its associated complications. It is believed that natural phyto compounds and extracts have been a potential source of treating health conditions and have been practiced since several decades. The aim of the study is to identify phyto compounds having significant cardio protective activity targeting APOE4. Since protein-ligand interactions play a leading role in structure-based drug design, with the help of molecular docking, we selected 20 phyto chemicals present in different plants and investigated their binding affinity against targeted APOE isoforms. Among all selected phytoc ompounds, arjunolic acid, from Terminalia arjuna plant was found as promising candidate for developing therapeutic against APOE4 activated CAD. Findings from the present work could be further studied for clinical evaluations on human to adopt strategies and reduce the prevalence and mortality. Arjunolic acid derivatives can be used as a source of new medication or development of novel compounds in the treatment of CAD.     

High-performance liquid chromatography as a tool for the chemical standardisation of Triphala--an Ayurvedic formulation

Triphala is an anti-oxidant-rich herbal formulation containing fruits of Emblica officinalis, Terminalia chebula and T. belerica in equal proportions. The preparation is frequently used in Ayurvedic medicine to treat diseases such as anaemia, jaundice, constipation, asthma, fever and chronic ulcers. Anti-mutagenic effects of the polyphenolic fractions isolated from Triphala have been reported, thus indicating that the phenols present in the formulation might be responsible for its therapeutic efficacy. A simple high-performance liquid chromatography method for the separation and quantitative determination of the major antioxidant polyphenols from Triphala has been developed. The use of an RP18 column with an acidic mobile phase enabled the efficient separation of gallic acid, tannic acid, syringic acid and epicatechin along with ascorbic acid within a 20 min analysis. Validation of the method was performed in order to demonstrate its selectivity, linearity, precision, accuracy and robustness. In addition, optimisation of the complete extraction of phenolic compounds was also studied.     

Cisplatin‐Induced Testicular Toxicity in Rats: The Protective Effect of Arjunolic Acid

In the present study, the effect of arjunolic acid on testicular damage induced by intraperitoneal injection of rats with 7 mg/kg cisplatin was studied. Cisplatin induced a significant reduction in testicular weights, plasma testosterone, and testicular reduced glutathione levels in addition to a significant elevation of testicular malondialdehyde levels and testicular gene expressions of inducible nitric oxide synthase (iNOS), tumor necrosis factor‐α (TNF‐α), and p38 mitogen‐activated protein kinase (MAPK) when compared with the control group (p < 0.05). Lower tubular diameters and depletion of germ cells and irregular small seminiferous tubules with Sertoli cells only were observed in the cisplatin group. Arjunolic acid administration significantly corrected the changes in both biochemical and histopathological parameters. Arjunolic acid plays a significant protective role against cisplatin‐induced testicular injury by attenuating oxidative stress parameters along with downregulation of iNOS, TNF‐α, and p38‐MAPK testicular expressions.     

Arjunolic acid, a triterpenoid saponin, ameliorates arsenic-induced cyto-toxicity in hepatocytes

Arsenic is a well-established environmental toxin, which damages various organs of the body. A triterpenoid saponin, arjunolic acid (AA) has been isolated from the bark of Terminalia arjuna. The present study was conducted to investigate the preventive role of AA against arsenic-induced cytotoxicity in isolated murine hepatocytes. Sodium arsenite (NaAsO₂) was chosen as the source of arsenic. Incubation of the hepatocytes with NaAsO₂ (1mM) for 2 h caused reduction in the cell viability and activities of the intracellular enzymatic as well as non-enzymatic antioxidants. Treatment of NaAsO₂ enhanced lipid peroxidation and also increased the activities of the membrane leakage enzymes. Administration of AA (100 μg/ml) before and with the toxin almost normalized the altered activities of antioxidant indices. AA possesses free radical scavenging activity and could enhance the cellular anti-oxidant capability against NaAsO₂-induced cyto-toxicity. The cytoprotective activity of AA was found to be comparable to that of a known antioxidant, vitamin C. Experimental results, therefore, suggest that AA protects arsenic-induced cytotoxicity in murine hepatocytes.     

Biological relevance of host plant-derived terpenoid in the cocoons of the tropical tasar silkworm Antheraea mylitta

We have characterized and studied the biological functions of a terpenoid derivative in the Indian tropical tasar silkworm, Antheraea mylitta reared on the primary host plant Arjun, Terminalia arjuna. The compound from insect cocoon turned out to be a terpenoid derivative which resembled oleanane type triterpene (Arjunolic acid) present in the host plant. The plant and cocoon compounds were anti-oxidative as determined by bleaching of beta carotene in vitro. UV-exposure is the major form of peroxidative insult encountered by this wild tropical silkworm. The life cycle comprising five larval stages and the cocoon stage lasts for about 30–45 days. Hence the sequestration of antioxidant and UV-protectant molecule from the host plant commands great biological significance.     

Oleanolic acid

Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid) is a pentacyclic triterpenoid compound with a widespread occurrence throughout the plant kingdom. In nature, the compound exists either as a free acid or as an aglycone precursor for triterpenoid saponins, in which it can be linked to one or more sugar chains. Oleanolic acid and its derivatives possess several promising pharmacological activities, such as hepatoprotective effects, and anti-inflammatory, antioxidant, or anticancer activities. With the recent elucidation of its biosynthesis and the imminent commercialization of the first oleanolic acid-derived drug, the compound promises to remain important for various studies. In this review, the recent progress in understanding the oleanolic acid biosynthesis and its pharmacology are discussed. Furthermore, the importance and potential application of synthetic oleanolic acid derivatives are highlighted, and research perspectives on oleanolic acid are given.     

Therapeutic properties and pharmacological activities of asiaticoside and madecassoside: A review

Centella asiatica is an ethnomedicinal herbaceous species that grows abundantly in tropical and sub-tropical regions of China, India, South-Eastern Asia and Africa. It is a popular nutraceutical that is employed in various forms of clinical and cosmetic treatments. C. asiatica extracts are reported widely in Ayurvedic and Chinese traditional medicine to boost memory, prevent cognitive deficits and improve brain functions. The major bioactive constituents of C. asiatica are the pentacyclic triterpenoid glycosides, asiaticoside and madecassoside, and their corresponding aglycones, asiatic acid and madecassic acid. Asiaticoside and madecassoside have been identified as the marker compounds of C. asiatica in the Chinese Pharmacopoeia and these triterpene compounds offer a wide range of pharmacological properties, including neuroprotective, cardioprotective, hepatoprotective, wound healing, anti-inflammatory, anti-oxidant, anti-allergic, anti-depressant, anxiolytic, antifibrotic, antibacterial, anti-arthritic, anti-tumour and immunomodulatory activities. Asiaticoside and madecassoside are also used extensively in treating skin abnormalities, burn injuries, ischaemia, ulcers, asthma, lupus, psoriasis and scleroderma. Besides medicinal applications, these phytocompounds are considered cosmetically beneficial for their role in anti-ageing, skin hydration, collagen synthesis, UV protection and curing scars. Existing reports and experimental studies on these compounds between 2005 and 2022 have been selectively reviewed in this article to provide a comprehensive overview of the numerous therapeutic advantages of asiaticoside and madecassoside and their potential roles in the medical future.     

A compilation of Bioactive Compounds from Ayurveda

This review deals with the key bioactive compounds and the role of medicinal plants in Ayurvedic systems of medicine in India and their earlier investigation. There has been an increase in demand for the Phytopharmaceutical products of Ayurvĕda in Western countries, because of the fact that the allopathic drugs have more side effects. Many pharmaceutical companies are now concentrating on manufacturing of Ayurvĕdic Phytopharmaceutical products. Ayurvĕda is the Indian traditional system of medicine, which also deals about pharmaceutical science. Different type of plant parts used for the Ayurvedic formulation; overall out line of those herbal scenario and its future prospects for the scientific evaluation of medicinal plants used by traditional healers are also discussed. In India most of them, where Ayurvedic treatment is frequently used, for their ailments and provides instructions to local people how to prepare medicine from the herbs. As much as possible importance is also given for the taxonomic literature.