Phytochemical profile and pro-healthy properties of Terminalia chebula: A comprehensive review

ABSTRACT Globalization witnessed changing trends in consumer markets. However, their long-term impacts include lifestyle and dietary changes. Although research in the pharmaceutical and chemical sciences led to the discovery and development of drugs saving millions of lives, their persistent use led to safety and toxicological issues. The plants previously used in Chinese and Ayurveda medicines received attention of the researchers to validate their traditional therapeutic applications. As a result, the reliance of communities on complementary and alternative medicines started to recover in the last few decades. The myrobalan (Terminalia chebula) is one such example that was renowned as the king of medicinal plants in Ayurveda due to its wide range of utilization in herbal decoctions to treat various health disparities. The current review showed phytochemical profile, that includes phenolic acids, casuarinin, chebulagic acid, chebulinic acid, rutin, and corilagin. Phytochemistry is linked with its medicinal applications and several research studies validated its antioxidant, antimicrobial, anti-inflammatory, hypoglycemic, and digestive tonic. The facts presented in the current article are derived from cell culture, animal, and human studies. Moreover, conceptualized framework regarding the effectiveness against cardiovascular disorders, immune dysfunction, cancer insurgence, and neurological disorders is in the limelight of the article. In last, a comprehensive discussion regarding its potential inclusion in the modern-day functional food market and presents its future applications.


Introduction
The health care systems relied on medicinal plants since human inception and various pharmaceutical drugs are derived from them.The scenario changed in the last two centuries due to scientific expedites in pharmaceutical and analytical chemistry that led to the discovery and development of modern drugs. [1]The development of vaccines to treat infectious diseases is another hallmark that decreased mortality thus increasing life expectancy.Moreover, the medical sciences witnessed the development of diagnostic tools and surgical approaches. [2]The industrialization brought many comforts for the human thus changing their lifestyle.Couple with these positive changes, increased burden of diseases i.e. cardiovascular disorders, diabetes mellitus, degenerative diseases, cancer insurgence, gastrointestinal disorders, and neurological problems were posed serious threat to the success of the modern-day health care system. [3]he last few decades infuriated with the increased aged population and adverse lifestyle changes reshaped the science of nutrition.The concept of revolutionized and prevention strategies were developed focusing on the consumption of a balanced diet. [4]The 21 st century shifted the gears from balanced to optimum nutrition and scientists developed novel foods and novel ingredients to improve human health.Amongst, medicinal plants gained a promising place due to their rich phytochemistry. [5]Medicinal plants were a pillar of traditional medicine systems, especially in Chinese and Ayurvedic medicinal systems.Although, they were known to human and intensively used in South Asia, South Africa, and South America due to efficiency and cost-effectiveness, their abusive use can be lethal and harmful to human health. [6]he World Health Organization (WHO) devised a policy on traditional medicine and issued directives with a series of monographs on widely used herbal medicines. [7]In recent years, the utilization of herbal medicines increasing worldwide due to their minimal side effects. [8]The annual global export of several plants with exceptional medicinal properties was approximately 2.2 billion USD in 2012.[11][12] The scientific and evidence base knowledge regarding these plants is deficient and researchers across the globe conducted studies to determine their safe doses.
The myrobalan (Terminalia chebula) is one such example that was renowned as the king of medicinal plants in Ayurveda due to its utilization in herbal decoctions to treat various health disparities. [13]The unripe fruit is most valued for its astringent and aperient properties and useful in dysentery and diarrhea, it should even be utilized in aromatics.The ripened fruit is also used to improve the health of the gastrointestinal tract due to its purgative nature and adsorption ability.The Unani physicians consider it a tonic for the brain, memory, and vision.Furthermore, it was utilized in the treatment of diarrhea, piles, headache, epilepsy, and to purge yellow bile. [14][17] The current review highlighted the phytochemical profile of the Terminalia chebula.In this review, efforts are made to highlight antioxidant activity, anti-microbial activity, anti-inflammatory activity, hypolipidemic, and hypoglycemic potential.These activities are indeed responsible for possible effectiveness against cancer insurgence, liver damage, cardiovascular disorders, and diabetes mellitus.The antiulcer activity and wound healing ability are also pharmacological activities.The conceptualized framework regarding the effectiveness of myrobalan as a functional food is the limelight of the article.

Terminalia chebula: a brief overview
Terminalia chebula is a prime medicinal plant known as "Harard" in Indian sub-continent.In China, ripen fruit of T. chebula is named "Hezi" and the unripe fruit is named "Xiqingguo." [18]Its fruits are utilized vastly in the preparation of traditional medicine throughout the Asia.It is a native tree of India, Bangladesh, Myanmar, Nepal, Pakistan, Vietnam, and South Western China. [14]In India, it is found in the Sub Himalayan traces from Ravi eastwards to West Bengal and Assam, ascending to the altitude of 1500 m in the Himalayas.This tree is wild in the forest of Northern India, central provinces and Bengal, common in Madras, Mysore, and in the southern part of the Bombay presidency.The taxonomy and nomenclature of Terminalia chebula are shown in Table 1.
It is growing at an altitude of 1800 m.These fruits are collected from wild grown forest plants.Fruits are collected from early stage of ripening to quite yellow and ripe A medium-sized tree, up to 15-25 m tall, with variable appearance, with a usually short cylindrical bole of 5-10 m length, it has spreading branches and round crown.The bark is dark brown in color; leaves are ovate with two large glands at the top of the petiole.It has yellowish white flowers in the terminal spike.The fruit are yellowish brown in color on ripe when unripe the fruit is green, 20 to 25 mm long and 15 to 25 mm wide in size.The fruit is Ovate and wrinkled longitudinally in shape.The fruits are collected from January to April, fruit formation started from November to January. [20]According to Basri Terminalia chebula is of four types; halela-e-zard, halela-e-hindi (smaller and black colored), halela-e-siyah (large size), and hashaf waqaq also known as halaila chini.However, some Unani Physicians described the following three varieties of halela-Halail-e-siyah (choti har): The fruit falls off from tree before seed formation and turns black within a few days.Halaila-e-zard: The fruit doesn't fall off from the tree but is semi-ripe, having a seed within it.Halaila-e-kabuli (kabuli har).The fruit is fully developed, completely ripe and attain full growth. [16]aditional uses Unani physicians extensively described this herb as a medicinal plant to treat different diseases since ancient times.It is a widely used drug in Ayurveda, Siddha, Unani and the Homeopathic systems of medicine in India.It is a top listed herb in Unani Materica Medica for the treatment of asthma, hemorrhoids, sore throat, gastric disorders (vomiting, anorexia, flatulence), diarrhea, dysentery, splenomegaly, epilepsy, leprosy, skin disorders, melancholia, gout and joints pain. [21]Ibn Hubal, a renowned Unani physician, in his famous book "Kitab Al-Mukhtarat Fi-Al-Tib" mentioned that T. chebula acts as an excellent brain tonic, eye tonic, cardiotonic and blood purifier.Hence, the Unani physicians used this herb for the treatment of dementia, conjunctivitis, cataract, zoaf-e-basarat, and palpitation.It is used in Thai traditional medicine as a carminative, astringent, and expectorant.The "Triphala," herbal preparation of "three fruits" from plants T. chebula, T. bellerica, and Emblica officinalis, used as an excellent laxative in chronic constipation, rejuvenator of the body, poor digestion and detoxifying agent of colon. [22]Recent studies have shown that "Triphala" improve appetite and is useful in treating cancer and detoxification.The fruits of halaila are used by Unani physicians both externally and internally for treatment purpose.Externally, the ointment (marham) of halaila (prepared from roghan gul, halaila powder and mom) was used by Unani physicians to cure the piles.The gargle with its decoction gives excellent results in stomatitis, bleeding and ulceration of gums and sore throat.The powder of Triphala can be used externally for hair wash and prevent hair falling and whitening.A fine powder of halaila is used as a tooth powder to strengthen the gums. [23]The paste of fruit with honey also beneficial in conjunctivitis due to its anti-inflammatory property.The paste of fruits effectively decreases swelling, accelerates the healing, and unsoiled the wounds.Halaila also prevents the collection of pus in skin disorders.The oil (roghan) of halaila is extremely helpful in the healing of wound, especially in burns.Internally, halaila is applied to cure a vast variety of diseases.The murabbah of halaila is used as an excellent brain tonic, cardiotonic, stomach tonic and in Source: Akhtar and Husain . [19]roblems of constipation. [24]According to Rhaze's (Rhazi), when halaila powder is consumed regularly, it promotes memory, thinking and reasoning power, boosts the nervous system due to beneficial effects on the nerves of brain and also cure the ascites, spleenomegaly, leprosy, colitis and headache.Gastric disorders (anorexia, vomiting, indigestion, flatulence etc.), piles, enlargement of liver and liver, worms, colitis, epilepsy, diarrhea, dysentery can be treated well with halaila.All the varieties of halaila are beneficial in chronic fever.The decoction of haritaki or triphala is given along with honey in hepatitis.Haritaki powder with honey and ghee is also effective remedy for anemia.In obesity, its decoction with honey reduces the excessive body fats. [19]rminalia chebula: nutritional composition and phytochemistry Terminalia chebula plant contains extraordinary nutritional composition in all its parts like seeds, aerial parts, and roots.The highest percentages of crude fiber were observed in aerial parts followed by roots and seeds with values 48.62 ± 0.01, 40.67 ± 0.01 and 16.45 ± 0.02%.The highest amounts of CH 2 O are present in roots followed by the aerial parts and seeds.Moreover, the amounts of CH 2 O were higher in all parts of T. chebula. [25]Proximate composition of Terminalia chebula is presented in Table 2.The minerals are present in considerable amounts in various parts of T. chebula.Though, its seeds contain higher amounts of Mg, P, S, K, Ca, Rb, Mn, Fe, Cu, and Zn in relevance to other plant parts.Furthermore, the leaves are also rich in K and Ca, which play a key role in blood homeostasis and bones strength. [25,26]Mineral composition of different parts and extracts of Terminalia chebula is shown in Table 3. Source: Malik, Madan, and Dhanda . [25]ble 3 [25] ; Chakradhari et al. [26] ; Gunasekar et al. [8] Phytochemicals are important secondary metabolites that formulate an important category of bioactive compounds.Numerous nutritional and phytochemicals are produced in T. chebula that hold potential biological activities and pharmacological properties.The phenolic acids present in T. chebula were reported effective against ischemic stroke, diabetes, immunodeficiency diseases, neurological diseases, and stomach ulcers. [17]Phenolic compounds like glycosides, anthraquinone glycoside are present in the stem and pericarp of T. chebula. [27][30] Beside phytochemicals, it contains fatty acids Zhang et al. [31] revealed that the T. chebula have fatty acids extracted from seed portion such as stearic-acid, palmitic-acid, behenic acids, linoleic acids, arachidic acids then oleic acid.
Tannins are oligomeric due to being part of phenolic compounds, and also possess multiple structural units along with free phenolic groups having a molecular weight from 500 to 3000D.These are present in both hydrolysable and non-hydrolysable forms.The hydrolysable tannins are present with the percentage of 35-45.Highest amount of tannins is present in the fruit pulp and pericarp of seeds. [32]The fruit pericarp may contain ~32-45% pyrogallol type hydrolysable tannins and their basic components including gallic acid, ellagic acid, ethyl gallate, and methyl gallate are attached with monosaccharides/oligosaccharides e.g., D-fructose and D-glucose. [33][38][39] In research study, Mammen et al. [32] reported that it contains glycosides of triterpenoid such as chebulosides II and I, 2α-hydroxymicromiric acid and 2α-hydroxyursolic acids.Previously, Nollet and Gutierrez-Uribe [40] described that T. chebula contains phenolic acids i.e. vanillic, caffeic, p-coumaric, ferulic, shikimic and quinic acids.

Pharmaceutical applications of Terminalia chebula
Terminalia chebula is considered as "King of Plants" in Ayurveda, [13] because it is a major ingredient of several ayurvedic medicines and is used for the treatment of various ailments due to its detoxifying and regenerating properties.As mentioned earlier, it is a good therapeutic agent due to the presence of phenolics, tannins, and flavonoids. [17]Antioxidant activity, anti-mutagenic activity, anti-carcinogenic activity, radioprotective activity, hepatoprotective activity, cardioprotective activity, cytoprotective activity, anti-diabetic activity, anti-fungal activity, anti-viral activity, anti-inflammatory activity, hypolipidemic and hypercholesterolemic activity, anticaries activity, anti-ulcerogenic activity, purgative activity and wound healing activity are some pharmacological activities of Terminalia chebula.

Myrobalan and antioxidant potential
Natural antioxidants are important in human health as they retard the oxidative damage induced by higher levels of undesirable free radicals.The excessive and uncontrolled production of free radicals is associated with neuromas metabolic aliments i.e., degenerative disorders, aging, cancer, and vital organs failure.Antioxidants gained vital importance in disease management as they scavenge the free radicals.Antioxidants can be primary or secondary depending upon their functionality.Free radicals are captured directly by the primary antioxidants, whereas the secondary antioxidants hinder the production of these free radicals. [53]Several scientists highlighted the antioxidant activities of T. chebula and its bioactive component rich fractions.The bark of T. chebula holds remarkable antioxidant activity (85.2 ± 1.10%) as compared to leaves and fruits (80.1 ± 0.9% and 79.8 ± 0.5%, respectively) and their antioxidant activity were attributed to phenolic contents of phenolic compounds which block free radicals to avoid oxidative stress. [54]. chebula exhibits anti-superoxide radical formation, anti-lipid peroxidation, and free radical scavenging activities. [55]T. chebula (Fruit) contains the highest antioxidant activities with an inhibition rate 77.98 ± 0.92% as compared with standard ascorbic acid inhibition rate 84.78 ± 0.39% from DPPH assays.The TPC of T. chebula extract was 203.23 ± 0.01 mg GAE/g.Free radical scavenging activities just like nitric oxide scavenging activity and superoxide (SO) scavenging activity with inhibition rate 88.95 ± 2.42%, and 88.56 ± 1.87% from NO and SO assays. [56]Likewise, ethyl acetate extract of T. chebula fruit has inhibitory activity of DPPH radical with range 91.05% and 96.6%, which is lower than positive control e.g., BHT (91.05% and 96.6%).The IC 50 range of control (BHT) and ethyl acetate extract were 70.02 ± 0.02 and 72.54 ± 0.03 μg/ml, respectively.T. chebula extract exhibited a highly reducing ability (absorbance 2.7 ± 0.07) than control (0.053 ± 0.001) and standard BHT (2.42 ± 0.02).The total phenolic contents of the ethyl acetate extract of T. chebula were 596.75 ± 0.35 μg GAEs/mg and higher antioxidant activities are due to electron donating capacity of the polyphenols. [57]In another research study, Chen et al. [58] isolated tri-ethyl-chebulate from fruits and studied its effects against FeSO 4 , induces lipid peroxidation and H 2 O 2 -induced RBC's hemolysis.They demonstrated that tri-ethyl-chebulate is a strong antioxidant and scavenging agent for free radicals.Different scientists highlighted that the phytochemicals like Chebulic acid, ellagitannins, phenolic acids and their derivative, flavonol aglycones and their glycosides are major contributors to its antioxidant property. [59]he optimization of extraction methods is also desirable and ultrasonic-assisted extraction (UAE) can enhance the 68% yield of the extracts with phenolic contents of (447.8 mgGAE/g d.w.)Interestingly, extracts higher extraction yield retained DPPH radical, DPPH, ABTS scavenging activities and reducing power in a dose-dependent manner.The ultrasonic extraction can rupture the membranes and thus releasing the antioxidants especially phenolic acids bound with dietary fiber. [60]The T. chebula and its extracts have great antioxidant potential to fight the metabolic disorders and can be used as a potential source of natural antioxidants. [57]The mechanism of antiinflammatory and antioxidant potential of the secondary metabolites in T. chebula extracts which were effective against lipid and protein peroxidative modifications associated with several metabolic disorders (Figure 1).

Anti-inflammatory potential of T. chebula
Inflammation is an integral part of human defense system and protects the body from harmful undesirable processes.Anti-inflammatory agents block certain pathways that cause inflammation and reduce the signs of inflammation i.e. redness, swelling and pain.The scientists used different models to assess the anti-inflammatory potential of T. chebula.In one study, Bag et al. [32] used carrageenan-induced inflammation (rat paw edema) model and reported that the T. chebula fruit 70% ethanol extract have anti-inflammatory activity and capable of 69.96% reduction.They also exert protective effect on human red blood cell membrane stability.The inhibition of ear swelling and paw edema is dose-dependent i.e. higher concentration yielded higher responses and comparable with dexamethasone. [61]Recently, Ekambaram et al. [62] used collagen-induced arthritis model and reported the effectiveness of T. chebula against inflammatory activity in arthritis paw.The effects are might be due to reduction in pro-inflammatory cytokines and T-cell subpopulations in lymph nodes.Furthermore, chebulanin, an active ingredient of T. chebula, notably ameliorates the severances of arthritis as evident by the downregulation of inflammatory cytokines and inflammation-induced enzymes (MMP-3 and COX-2).It also reduces bone erosion and cartilage destruction and alcoholic extracts decreased initial phase paw licking-in and increased paw licking behavior.The same formulation showed minor analgesic activity through central and peripheral mechanisms. [63]The bioactive components present in T. chebula showed effectiveness against arthritis severity, undesirable histopathological properties and expression of anti-inflammatory mediators e.g.COX-2, PGE-2, IL-1β, TNF-α, IL-6, and MMP-3 in joints and paws significantly. [63,64]Gallic and chebulagic acid are active phyto-constituents of T. chebula and these constituents have an immunosuppressive effect on T-lymphocyte intervened cytotoxicity. [65]T. chebula promoted phagocytosis and growth of macrophages and inhibition of overproduction of NO, iNOS, IL-6 and TNF-α in induced lipopolysaccharide macrophages at 150-18.75 µg/ml. [61]pplication of T. chebula inhibits joint swelling in induced arthritis models and reduced serum levels.T. chebula hydroalcoholic extract (TCHE) has the potential for the treatment of rheumatoid arthritis. [66]The TCHE inhibited swelling of joint and effects were comparable with complete Freund's adjuvant and formaldehyde-induced arthritis.The TCHE treatment also reduced synovial expression of IL-6, TNF-R1 and IL-1β and also decreased TNF-α level in serum.The results also exhibited that oral LD50 of TCHE was >2000 mg kg −1 .Twelve isolated compounds from methanolic extract of T. chebula inhibited cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS) in LPS-stimulated macrophages.The tannins such as 2, 3, 6-tri-O-galloyl-Beta-D-glucose and chebulinic acid and triterpenoids include arjunolic acid and arjunic acid decreased IC 50 value of NO radical 53 to 38 µmol, respectively.The expressions of protein of COX-2 and iNOS were reduced from 54% to 70% and 33% to 37% at 50 µmol.These extracted compounds were found to inhibited COX-2 and iNOS activities at cell level. [67]. chebula with the combination of some other medicinal plants had significant impact on inhibition of edema formation like T. chebula, T. bellirica, Plumbago zeylenica and Cissus quadrangularis were inhibited COX-1 and COX-2 when their ethanol, water and hexane extracts were used and resulted these plant extracts were more inhibited COX-2 activity than COX-1.The extract if T. bellirica was 73.34% and T. chebula had 74.34% inhibition of COX-2.[68] Likewise, triphala (which contain T. bellirica, T. chebula and Emblica officinalis) were significant decreased activities of lipid peroxidation, glycoproteins, lysosomal enzymes and increased antioxidant activity in the paw tissues.Moreover, the inflammatory level in serum and paw tissue were suppressed by Kalaiselvan and  Rasool.[69] The long-term medical treatment using combination of herbs in the form of capsule and tablets can improve the health of individuals suffering from joints disorders.In one such study, daily consumption of two Shallaki capsules (Boswellia serrata, Triana and Planch) and two Jeewya tablets (consist of T. chebula, Emblica officinalis, and Tinospora cordifolia) for a period of 5 months improved the score of movement, pain, stability and function and improved the quality of life in osteoarthritis patients.Similarly, NDI10218 (a composition of ethanol extract of Terminalia chebula) reduced arthritis index, blocked the synovial hyperplasia and also reduction of IL-6, IL-1β and TNF-α in serum.The selected composition did not inhibit immunosuppressive IL-10, while showed inhibition of inflammatory IL-17 in splenocytes.The standard extract was significantly decreased amount of T cells in lymph node region of arthritis-induced mice.That extract reduced number of abdominal contractions in writhing model of acetic acid induced mice showed that the formulation of NDI10218 was better treatment of rheumatoid arthritis.[70] The LI73014F2 (prepared from extracts of Curcuma longa, T. chebula and Boswellia serrata) give the interactive advantage in inhibition of 5-lipoxygenase (5-LOX).The combination was present to significant relief in pain, physical function improvement and improved osteoarthritis quality of life.The subsequent results showed that LI73014F2 herbal formulation is effective and safe treatment for management of discomfort of joint.[71] The decoction and ethanolic extract of Amalakyadi Gana (composition of Plumbago zeylenica, Piper longum, T. chebula and Emblica officinalis) were exhibited inconsequential increased in tail response in formalin induced paw linking model.[72] Similarly, Nanna et al. [73] reported that Tri-samaw recipe (formulation of equal proportion of Terminalia chebula, Terminalia sp. and Terminalia bellirica) extract decreased the ear edema in ethyl phenylpropiolate induced rat but not showed inhibition of acute inflammation in carrageenan-induced paw edema.Although, the extract formulated recipe at 300 to 200 mg kg −1 was able to inhibit writhing response in acetic acid-induced, while not in heat-induced pain.In conclusion these extracts have the great potential of analgesic property and inhibit the biosynthesis of some pain mediators.
In the nutshell, the T. chebula and its components hold potential as anti-inflammatory herbal products; however, their use in decoction showed more effectiveness.The scenario demands attention of researcher to conduct comprehensive studies to get clear insight of the mechanisms thus future clinical applications could be designed accordingly.

Anti-microbial activity
The knowledge in the domain of microbiology expanded at alarming pace.Albeit, pathogens and their resistance to antibiotics intensified but search for some natural antimicrobial agents to safeguard the human from deleterious infectious diseases gained momentum in the last two decades.Amongst different strategies developed, traditional medicinal plants and their bioactive components are the hot discussion.The researchers highlighted the significance of T. chebula as effective agent against the harmful microorganism.The T. chebula and its extract showed that the antibacterial activity against both Gram-positive and Gram-negative pathogenic micro-organisms. [74]In the study, Nyinoh et al. [75] explicated that the watery and methanol concentrates of plant can reduce the gastroenteritis caused by gram-negative microbes.It showed extensive antibacterial activity against Salmonella epidermis and Bacillus subtilis with minimum bacteriocidal concentration (MBC) and minimum inhibitory concentration (MIC) of 125 and 150 mg/L, correspondingly. [65]Earlier, T. chebula bioactive rich fractions extracted using butanol 1-2.5 mg/mL showed effectiveness against Clostridium perfingens, Escherichia coli and Helicobacter pylori concentration. [76]Later, Mandeville and Cock [77] reported the antimicrobial potential of myrobalan against bacterial triggered auto-immune inflammatory disorders except Klebsiella pneumoniae.Indeed, Minimum inhibitory concentration values were observed in aqueous extract as 195 μg/mL against Pseudomonas aeruginosa.
The methyl gallate level and tetracycline in cells of HeLa (incubated for 24 h) was comparatively higher than nalidixic acid and ciprofloxacin.The viable number of S. dysenteriae in intracellular cells was decreased in presence of methyl gallate (4 × MBC minimal bactericidal concentration) and decreased to 0 within 20 h.The intracellular activities of methyl gallate could great potential be used as active antibacterial agent for curing various infectious disorders caused by Shigella spp.Methyl gallate from T. chebula caused outer and inner membranes disintegration and cytoplasmic content leakage in Shigella dysenteriae. [78]Gallotannin (1, 2, 6-tri-O-galloyl-β-D-Glucopyranose) showed anti-bacterial potential against uropathogenic E. coli.The effects of gallotannin might be due to effluxpump inhibitory activity which should be further explored to validate the antibacterial activity against multidrug uropathogenic E. coli. [32]Similarly, the decoctions containing the T. chebula extracts e.g.hydroalcoholic extracts of Triphala (comprise of Terminalia belerica, Terminalia chebula and Emblica officinalis) showed antibacterial activity against strain-specific multidrug-resistant uropathogenic bacteria.The mode of action of Triphala revolved around nontoxic expression on membrane of erythrocyte at moderate and even greater doses. [32]he microorganisms are also responsible for diseases of oral cavities especially dental caries, periodontal diseases, oral candidiasis and oral infections.The reduction in microbial count can be a good strategy and ripen seeds along with its liquid concentrate slowed the growth of salivary microorganisms especially Streptococcus mutans and Staphylococcus aureus. [79]Some researchers presented array of evidences showing the potential of T. chebula as its significantly reduced S. mutans and Lactobacillus that might be attributed to the lowering of pH and buffering capacity of saliva.Overall salivary bacteria can be decreased by mouth washing with a solution containing T. chebula extract.The effectiveness of T. chebula was enhanced with chlorhexidine and showed greater anti-caries activity after 90 minutes' mouth rinsing. [80]This means that T. chebula can be used for the management of carious teeth especially elimination damage and de-mineralization of the tooth surface. [20]Bleeding gums, sore throat, and muscular problem can be recovered with the help of Gargle along with T. chebula extract. [36]The strong effect of different triphala was noticed in controlling the dental caries and preventing the other oral infections caused by microbes. [81]Furthermore, the dental diseases i.e. periodontal, gingival and tooth decay can be prevented by triphala as well as it might be helpful in anti-oral candida species and root canal irrigation. [82]Likewise, Palit et al. [83] evaluated that T. chebula hot and cold-water extracts were revealed significant response reduction in S. mutans at 10 to 90 mints collected sample.The children with the 8-10 year had acceptable mouth taste which is depicting the strong anticariogenic potential of both T. chebula aqueous extract.Howshigan et al. [84] T. chebula Retz has significant reduction in case of bleeding on probing (BOP) probing pocket depth (PPD), Quigley Hein plaque index (PS) and total salivary anaerobic counts.The T. chebula inactivates the oral bacterial growth and also reduced the inflammatory proteases and cytokines, destruction of the cyclooxygenase-2 and Prostaglandin E2 and matrix damage.The ethanolic extract of T. chebula decreased the osteoclast precursor production as well as receptor activator of kappa nuclear factor kappa-Β ligand in osteoclast and osteoblast respectively by inducing the stimulation of DPB-derived lipopolysaccharide.It can be a best substitute to help prevent DPB-mediated periodontal disease. [36]In conclusion, these pants had no unpleasant effect of toothpaste and beneficial for anti-plaque and antigingivitis activities.
T. chebula holds anti-fungal activities against various types of dermatophytes and yeasts. [85]It reasonably works against the pathogenic yeast e.g.Trichophyton rubrum and Candida albicans.In vitro, anti-candidal action of methanol concentrate of TC was comparable with the effects of clotrimazole. [74,86]The T. chebula can be a good source of molluscicidal against the snail L. acuminate due to presence of tannic acids. [87]According to Venkatesalu et al., [88] T. chebula has anti-plasmodial activity against Plasmodium falciparum.The water extract hinders the use of hypoxanthine into P. falciparum K1 multi-drug safe strain. [89]Anti-viral activity of T. chebula has also being studied by the different researches due to its positive effects.A study suggested that T. chebula extracts can be used as a home therapy for cough and cold.It defends respiratory cells from influenza and reduces some acute pulmonary infections. [90]T. chebula impedes the attachment of virus and further penetration to the host cells, [91] thus could provide protection sexually transmitted Herpes simplex virus-2 (HCV-2).Earlier, Ajala et al. [92] validated that the bioactive components especially hydrolysable tannins present in Terminalia significantly inhibited HCV protease inhibition with different IC 50 (mentioned in parentheses) e.g.chebumeinin A (59.7 μM), chebumeinin B (67.2 μM), casuarinin (9.6 μM), chebulic acid (182.6 μM), 5-O-galloylshikimic acid (214.7 μM), pentagalloyl glucose (10.6 μM), corilagin (31.5 μM), Ellagic acid (56.3 μM), Chebulagic acid (5.2 μM) and Gallic acid (382.4μM).These isolated compounds from T. chebula have great inhibition activity against hepatitis C virus.In this context, Oyuntsetseg et al. [93] prepared decoction (Deva-5) that was composed of T. chebula, Polygonum bistorta, Hypecoum erectum, Momordica cochinchinensis and Gentiana decumbens extracts.The mixture of these three plants contained various substances that direct effect on antiviral activity and great new antiviral drugs source.The same scientists reported that the extract of T. chebula, M. cochinchinensis and H. erectum significantly reduced the influenza A virus H 3 N 8 infectivity at 0.5-1% concentration.T. chebula exhibit inhibitory effects on human immunodeficiency virus-1 reverse transcriptase.It was also observed that the water extract of TC exhibit anti-herpes simplex virus (HSV) activity in-vivo and anti-cytomegalovirus (CMV) activity both in-vitro and in vivo in a study.T. chebula impedes HSV-1 entry at non-cytotoxic doses in A549 human lung cells by preventing secondary infection. [94]The aqueous extract of T. chebula might be used as an effective anti-HBV (hepatitis B virus) drug in the future because it exhibits the prominent activity against HBV as it decreases the level of extracellular HBV virion DNA. [95]Hepatitis may cause the jaundice in later stages, which also be curable by TC consumption. [96]Figure 2 depicts that the mechanism of antimicrobial action by the bioactive compound's presence in T. chebula.
The aforementioned discussion clearly depicts the potential of T. chebula and its extracts against disease causing microorganisms.The decoctions containing T. chebula could be used as antimicrobial agent against multidrug-resistant bacteria.However, randomized trials in a clinical setting should be conducted to validate the findings.

Gastrointestinal disorder
Terminalia chebula present Triphala Rasayana is very effective against gastrointestinal ailments i.e., Inflammatory bowel disease (IBD), gastric ulcer and constipation etc. and have considerable potential to improve the gastrointestinal tract (GIT) system. [97]he scientists assessed the anti-ulcer activities of methanolic extract of T. chebula and observed recovery from the edematous form of gastric tissue, hemorrhage, and deterioration. [98,99]Chebulinic acid showed anti-secretory and cytoprotective effects on gastric ulcers in cold restraint, alcohol, and aspirin-induced animals. [100]The Aqueous extract of T. chebula (CFAE) doses varied from 200 to 800 mg kg −1 reduced diarrhea by 9% to 58% and also inhibited intestinal transit with 18% to 35%.The CFAE decreased the enter pooling volume by 47% to 64% and lesions were alleviated.Furthermore, the ethyl acetate fraction of CFAE range from 41.7 to 166.8 mg/kg) decreased diarrhea with 9% to 54%.The ethyl acetate fraction components were tannins, included 3, 4, 6-tri-O-galloyl-β-d-Glc, gallic acid and ellagic acids.It was resulted that CFAE influenced anti-diarrheal activity and main active fraction. [101]ri-sa-maw recipe (composed of Terminalia chebula, Terminalia sp. and Terminalia bellirica) exhibited both inhibitory and stimulatory effects on stomach functionality.The extract of Tri-samaw recipe inhibit the time of gastric emptying, while also influence the digestive tract movement by increasing mobility of charcoal.At low concentration, the extract was induced by the isolated Guinea pig ileum contraction.However, the contraction effect of isolated Guinea pig ileum was decreased at higher concentration.In conclusive results showed that the tri-sa-maw recipe was used anti-diarrheal and laxative agent. [102]Later, Lee et al. [103] investigated that KM1608 (compose of Zingiber officinale, T. chebula and Aucklandia lappa) significantly decreased colitis symptoms severity (diarrhea, weight loss and rectal bleeding).The TNF-α and Interleukin levels were also declined in the lysate of colon muscles on the presence of inflammatory mediator such as myeloperoxidase and found that formulation reduced colitis through the parameter's response of inflammation in the colon that indicated KM1608 had great activity for treatment of inflammatory bowel disease.Similarly, Patel et al. [104] estimated that Trisama powder was the combination of Zingiber officinale, T. chebula and Tinospora cordifolia.Trisama dose of 0.65 and 1.3 g/kg shortened the intestinal transit time of kaolin.Trisama powder at higher dose and Trisama decoction at dose 12.48 ml/kg significantly affect the consistency of fecal pellet.Trisama showed significant intestinal motility-enhancing property and useful in gastric problem without affecting the general physiology.The inhibitory effect of KM1608 (Aucklandia lappa, T. chebula and Zingiber officinale Roscoe) was reduced Akt-phosphorylation in lipopolysaccharide treated cells.That combination was expressively improved colon weight as well as colon length and inhibited expression of TNF-α, IL-6 and myeloperoxidase in dextran sulfate sodium-induced colitis tissues.In conclusion, KM1608 decreased colitis through anti-inflammatory responses and has higher therapeutic potential in inflammatory diseases. [105]Tarasiuk et al. [106] estimated that Triphala improved reinstitution of epithelium lining of gastrointestinal tract and also revealing minor laxative activity that facilitates passage of stool in colon.In addition, triphala improved lowers gastrointestinal disease signs and valuable to standard management of irritable bowel syndrome.T. chebula and Gurigumu-7 intragastrically entrances in plasma and results showed that Gurigumu-7 better absorption and increased Cmax and area under the ROC curve values of phenols as compared to T. chebula.The lysates of fecal were exhibited that phenols in Gurigumu-7 had lower bio-transformed rate than T. chebula.The metabolism of intestinal bacteria was slowed down due to increase absorption of phenols in Gurigumu-7. [107]Pre-meal consumption of its fresh fruit accelerates digestion.Consumption with a meal can nurture the senses and disinfects the gastrointestinal and genitourinary tract.The presence of chebulinic acid eliminates toxins and undesirable fat from the body.It also possesses an anti-diarrheal activity. [101]ti-diabetic activity Diabetes mellitus is common all over the world, and patients are increasing with each passing day.Generally, the pathogenesis of the disease is linked with poor regulation of blood glucose.It falters into two broader categories i.e., diabetes type 1 type 2 and first class is linked with genetics that result in body failure to produce enough insulin.In diabetes type 2, the insulin either do not produce in our body completely or produce in insufficient amount to allow the glucose or sugar enters to the cell.The researchers linked type-2 with lifestyle and poor dietary habits.The dietary strategies developed to curtail the menace focus on diet diversification as communities consuming fruits and vegetables as regular part of their diets are less susceptible.
The scientists attempted to find some natural solutions to prevent and manage diabetes mellitus.The foods rich in dietary fiber hold key potential due to their ability to improve the gastrointestinal function.The traditional uses of T. chebula are often linked with gastrointestinal tract e.g., ethanol extract of dried T. chebula, Morus alba, Poria cocos and Zea mays retarded the α-glucosidase activity thus favorably affecting the glucose-stimulated insulin secretion.The ethanol extract of dried T. chebula Retz.Polygonatum odoratum, and Glycyrrhiza uralensis significantly decreased transport of glucose across monolayer cell monolayer. [108]Three new poly-hydroxy-tri-terpenoids derivatives isolated from T. chebula fruits showed inhibitory activities against α-glucosidase. [36]The consumption of herbal capsule contained 200 mg of T. chebula, Commiphora mukul and C. myrrha for a period of 3 weeks improved positively the blood glucose and lipid profile, especially total cholesterol, LDL and HDL. [30]The herbal decoction was safer and improved the glycemic and lipid index in type 2 diabetes. [109]The fractions of different plant such as tannins from Syzygium cumini (ScTF), flavonoid from T. chebula (TcFF), saponins from Trigonella foenumgraecum (FgSF) and flavonoid from Salvadora persica (SpFF) significantly decrease the serum glucose when consumed 100 mg/kg. [110]he consumption of decoction containing Terminalia chebula, Glycyrrhiza glabra, Petroselinum crispum, Swertia chirayita and Boerhavia diffusa improved the anti-glycation and thus had great potential to manage diabetic complications. [111]T. chebula shows activity against the advanced glycation end products (AGEs)-influenced endothelial cell malfunction. [112,113]Figure 3 depicts that the pipeline of events in exhibiting the anti-diabetic property of the T. chebula extracts.
Chebulagic acid from T. chebula enhances peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling less than rosiglitazone.Expression of glucose transporter type 4 and secretion of adiponectin was also increased that clearly depicts the effectiveness of chebulagic acid against diabetes mellitus. [114]Some functions like endothelial dysfunction are a main problem in diabetes type 2, which may affect the cardiovascular functions.About 500 g of T. chebula can reduce the risks of cardiovascular diseases in patients of diabetes. [115]Moreover, Triphala Rasayana containing T. chebula in its recipe showed the beneficiary results against different ailments like obesity and diabetes. [97]ti-cancer activity Cancer is uncontrolled mitosis of the cells that leads to the development of tumors.Terminalia chebula showed some effectiveness against cancer insurgence and discussion in research conducted.The lung cancer is spreading (especially in men) at the extent of 35.50% and ~30.80% death rate worldwide.In females, the incidence of breast cancer occurs in female at the rate of 55.2% and death rate 16.6% globally.T. chebula was proved for its anticancer activities on MCF-7 and A549 cells.It works as a cytotoxic against the MCF-7 and A459 with doses of IC 50 (61.02µg/mL) and IC 50 (359.06µg/ml) correspondingly. [116]In another research study, T. chebula phenolics i.e., ellagic, tannic, chebulinic acid and 2,4-chebulyl-β-D glucopyranose showed inhibitory effects in PC3 and PNT1A cell lines.In this regard, Saleem et al. [42] also observed that TC is effective against five diverse human cell-lines like breast cancer (MCF-7), prostate cancer cell line (PC-3), osteosarcoma (HOS1), mouse (S115) breast cancer cell line, and a normal prostate cell line (PNT1 A).Chebulagic acid was found to impede the development of 5 cell lines like HCT-115, COLO-205 (colon cancer), MDAMB-231 (breast carcinoma), DU-145 (prostate cancer), and K-562 (myeloid leukemia).According to Ahuja et al., [117] T. chebula was found to decrease tumor size in wistar rats engrafted with human pancreatic tumors.The anticancer activities of T. chebula leaf gall extracts on BRL3A, MCF-7, and A-549 cells were also detected. [118]Another study demonstrated the anticancer activity of homeopathic preparations of T. chebula against breast cancer and disclosed their nanoparticulate nature. [119]The formulation of T. chebula with Zingiber officinale is very effective against the different ailments especially in reduction of tumor progression through the prevention of mechanistic target of rapamycin (mTOR) pathway. [120]

Neuro-protective potential
The diseases and disorders of the brain are increasing with aging populations.The degenerative cell changes are continuous in nature that affects tissues and organs.The degeneration of cells or organs involved several mechanisms like aging, inflammation and lifestyle.The introduction of some dietary components e.g., T. chebula can improve the brain health due to presence of antioxidants. [121]Some research studies reported its effectiveness in stress recovery due to decreased level of nitric oxide and higher arginase-1 expressions.As mentioned in the previous sections, T. chebula can be utilized as a potential anti-inflammatory agent to protect the CNS system.In one such study, Shen et al. [122] reported that water and methanolic extracts (0.5-5.0 μg/mL) of T. chebula and ellagic acid possess great potential for protecting pheochromocytoma (PC12) cells.The researchers used beta-amyloid25 -35 (Aβ25-35) induced cell toxicity.The neuro-protective activity of T. chebula was linked to inhibition of ROS production and decreased calcium ion influx.The schematic diagram illustrating the spectrum of anti-neurodegenerative effects against Alzheimer's disease, aging and other neuroprotective effects posed by the bioactive molecules of the T. chebula extracts (Figure 4).
Alzheimer's disease is the leading cause of neuro-degenerative disease in the geriatric population, accounting for approximately 5 million cases of dementia in the USA according to estimates from the Alzheimer's Association in 2015. [123]It is characterized by psychopathological signs such as language deterioration, memory loss, visuospatial impairment, and poor judgment. [124]lzheimer's disease is also linked with acetylcholine (Ach) deficiency in the synaptic cleft of the cerebral cortex that causes memory disturbance.Acetyl cholinesterase, also known as AChE or acetyl hydrolase, hydrolyzes the neurotransmitter acetylcholine.AChE is found at mainly neuromuscular junctions and cholinergic brain synapses where its activity serves to terminate synaptic transmission due to its high catalytic activity i.e. each molecule of AChE degrades about 25000 molecules of Ach per second. [125]It might serve as a good medicinal plant in treating Alzheimer's and other neurodegenerative disorders. [122]T. chebula has remarkable activity against Alzheimer's disease.Haritaki has a supportive effect on brain nerves as it improves memory. [21]Ellagic acid, tannic and gallic acid obtained from T. chebula have been found to impede AChE and butyryl cholinesterase. [17]pilepsy and its related disorders are the main area of research nowadays.Much of the research are being conducted on a daily basis.A protective role of different poly herbal extract was documented by Dhar et al., [126] using the potential of different medicinal plant i.e.T. chebula, Embelia ribes, Asparagus racemosus, Tinospora cordifolia, Acorus calamus, Saussurea lappa, Achyranthes aspera and Convolvulus pluricaulis.Their finding revealed the improvement of endogenous antioxidant enzymes i.e.SOD and GSH that reduced MDA in rat's brain.The poly herbal extract might serve against epilepsy and related disorders. [105]The ethanolic extract of T. chebula fruits delays the latency of maximal electrical shock, pentylenetetrazole, and picrotoxine instigated seizures in Swiss mice model, which provides a hint for the anticonvulsant activity of T. chebula fruits. [127]Combination of valproate and ethanolic extract of T. chebula show 100% protective activity. [128]iu et al. [129] investigated that extract of T. chebula were improved behavioral indicators, infarct volume and pathological changes of penumbra tissues were also improved at the same time.The expression levels of β-catenin and cyclin D1 in signaling pathway were significantly up-regulated.T. chebula extract HZ4 decreased infarct volume, improved the sport ability score and promoted rehabilitation.Due to a certain extent in innovation T. chebula had great potential in neuro-protective effects.Kim et al. [130] proposed that the chebulagic acid has enhancing and modulating impact on autophagy.It showed a protective effect against the cytotoxicity symptom of Parkinson's disease and the degradation from the cells of mis-folded protein was increased.The chebulagic acid was suggested as an attractive and promising agent in preventing the aggregation of abnormal proteins as well as controlling the Parkinson's disease.

Miscellaneous activities
T. chebula acts as an analgesic medicine to provide relief from pain and the intensity and time of analgesia were dependent on the dose. [131]Different studies are conducted to check the analgesic effect of T. chebula all over the world.Some human studies also supported the claims that T. chebula can enhance pain tolerance and pain threshold time. [132]Earlier, Sireeratawong et al. [133] used a formalin (0.10%) induced pain model they observed that T. chebula extracts exhibit analgesic activity.In another research study, T. chebula aqueous extract significantly increased in mean tolerance time and pain threshold time.The mean value of pain threshold time increased with a range from 34.06 to 41.00 sec and observed the increased tolerance time from 49.67 to 57.30 sec.The percentage increase in the mean value of pain threshold time and pain tolerance time is 20% and 17% suggesting that T. chebula extract had significant potential for anti-analgesic activity. [134]hebulagic acid possesses antispasmodic activity. [22]This plant is helpful as an antidote against snake bites. [21]Poly-herbal formulation of T. chebula has a strong anti-allergic effect. [135,136]Hydro ethanol extract of T. chebula showed an anti-spasmodic and anti-allergic effect in Guinea pigs.According to another intervention, oral gavage of T. chebula suppresses the histamine discharge from rodent peritoneal mast cells. [121]In Wister rats, the fluid concentrates of said plant decrease the level of oxalate and phosphate.Supplementation of concentrate reduces the serum levels of blood urea nitrogen.The T. chebula is conventionally processed in a sugary solution locally called "Myrobalan Murabba" and same product is used to improve skin health in ophthalmia, skin irritation, and edema type disorders. [137]Interestingly, T. chebula was reported to be effective as a skin glow and complexion agent. [22,137]rminalia chebula: hepatoprotection and safety evaluation Herbal medicines are reportedly associated with hepatotoxicity as per toxicological studies.Several studies reported that apart from inducing toxicological effects in kidney, nervous system, blood, and cardiovascular system, as well as mutagenicity and carcinogenicity. [138]Therefore, numerous advanced biological experimental techniques have been used as standard safety tests prior to the efficacy study.T. chebula in form of Bilvadi agada (anti-venom formulation having T. chebula as one of the herbal ingredients) holds nephron-protective activity mainly attributed to biochemical changes observed in serum creatinine, urine creatinine, and potassium levels. [139]T. chebula administration has been reported to maintain kidney performance from cadmium-induced toxicity as indicated by uric acid, serum urea, and creatinine refurbishment.T. chebula induction at a dose of 125 mg/kg has considerably reversed the alterations of elevated blood urea nitrogen, and serum creatinine and offered better protection in Wistar Kyoto rats. [140]Recently, it has been reported by Kalra et al. [141] that T. chebula supplementation in Wistar rats reduces cisplatin-induced nephrotoxicity via modifying apoptotic signaling and amelioration of oxidative stress as evidenced by inhibition of the elevated blood urea nitrogen, serum creatinine, oxidant stress markers, and cytokines.Chebulic acid along with neo-chebulic acid possesses strong hepatoprotective activity.In the sub-chronic model, ethanol extract of T. chebula prevented hepatotoxicity (Tasduq et al.,  2006; Lee et al., 2007).
T. chebula fruit has a protective effect on tetra-butyl hydroperoxide induced oxidative injury along with hepato-protective activity against carbon tetrachloride-induced toxicity in rat hepatocytes.The plant and its extracts can reverse cell cytotoxicity and lactate dehydrogenase that led to fewer liver lesions. [142]The aqueous extract of T. chebula protects the antioxidant enzymes which are produced by gamma radiation in the rat liver, while T. chebula fruit ethanolic extract decreased the lipid-peroxidase level. [143]T. chebula is present in Ruteng formulation and effective in formulating drugs against diseases related to the liver, ankle joints, and serum. [144]Chebulinic acid, the main bioactive constituent, is responsible for hepatoprotective activity achieved through a reduction in MDA, ALT, and AST levels, while increased SOD action that further prevent histopathological alterations and initiation of stimulation pathways of Nrf 2 /HO 1. [145]

Conclusion
Myrobalan (Terminalia chebula) holds strong antioxidant and anti-inflammatory potential that is correlated with its hepato-protective, cardio-protective, and neuro-protective properties.It is effective against diabetes mellitus, cancer insurgence, and diseases of the gastrointestinal tract.The antimicrobial potential of the plant is also of significant importance to safeguard humans from the deleterious effects of pathogens.The studies focusing on safety assessment showed it a safe appraisal.Numerous nutritional and phytochemicals (proteins, carbohydrates, vitamin C, tannins, flavonoids, triterpenoid, and phenolic compounds) are produced in T. chebula that hold potential biological activities and pharmacological properties.In a nutshell, T. chebula can be considered as a prime herb to improve the health of individuals.However, some observational, longitudinal, and randomized control trials must be conducted before warranting its clinical uses.

Figure 1 .
Figure 1.Anti-inflammatory and antioxidant potential of the secondary metabolites in Terminalia chebula extracts.

Figure 2 .
Figure 2. The schematic representation on the mechanism of antimicrobial action by the bioactives of Terminalia chebula.

Figure 3 .
Figure 3.The anti-diabetic property of the Terminalia chebula extracts.

Figure 4 .
Figure 4.The schematic diagram illustrating the spectrum of anti-neurodegenerative effects of Terminalia chebula.

Table 4 .
Categorization of phytochemicals and their structures.