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Phytochemical and Pharmacological Profile of Terminalia chebula

Kumar M1*, Sharma N2 and Singh Ranjan A3 Review Article 1Department of Chemistry, Sri Varshney PG College, India Volume 4 Issue 3 2Department of Chemistry, University of Rajasthan, India Received Date: October 05, 2020 3Department of Zoology, University of Rajasthan, India Published Date: October 23, 2020 DOI: 10.23880/ipcm-16000208 *Corresponding author: Maheep Kumar, Department of Chemistry, Sri Varshney PG College, India, Tel: +91-6396096995; Email: [email protected]

Abstract

Plant secondary metabolites have been of interest to man for a long time due to their pharmacological relevance. In this search Terminalia chebula is widely used to enhance the natural resistance to various diseases. It is called the “king of medicines” and

always listed first in the Ayurvedic meteria medica because of its extraordinary powers of healing. Traditionally it has been andused hypolipidemic as a popular folkagent. medicine The present for homeostatic, review is an attemptantitussive, to highlight laxative, the diuretic various and ethnopharmacological cardio tonic treatments. and traditionalRecent studies uses showed that it has also been used as antidiabetic, antiviral, cardioprotective, anticancer, antioxidant, free radical scavenging as well as phytochemical and pharmacological aspect of Terminalia chebula.

Keywords: Terminalia chebula

; Pharmacological Effect; Gastrointestinal Activity; Anticariogenic Effect; Antidiabetic Effects; Cardiotonic Activity; Phytochemical Constituents Abbreviations: ITM: Iranian Traditional Medicine; STZ: Streptozotocin; IFHP: Isolated Frog Heart Perfusion Terminalia chebula is Technique; LDL: Low Density Lipoprotein; VLDL: Very Low consideredmedicine (ITM) to destroy as halileh all diseasesor halilaj andand eliminatethe fruit isall used waste to Density Lipoprotein; HDL: High Density Lipoprotein; MIC: develop treatments [3]. In Ayurveda

infrom the the treatment body. At of the any same kind time, of gastric it is known infection to promote in any part tissue of Minimum Inhibitory Concentration; HSV:Terminalia Herpes chebula Simplex; thegrowth body. and It ishealth. found It to is be most an effectivepowerful product Ayurvedic for herbinfections used Virus; CA: Chromosomal Aberration; MN: Micronucleus; caused by E. coli and other parasites of the digestive system. HETC: Hydroalcoholic Fruit Extract of Recent studies have demonstrated that T. chebula Tetrazolium;MES: Maximal-Electroshock; MT: Mother Tincture. EPM: Elevated Plus Maze; wide range of biological activities including cardioprotective PI: Phagocytic Index; AI: Avidity Index, NBT: Nitro Blue exhibits a scavenging [7] and hypolipidemic [8]. Its antimicrobial [9], Introduction [4], antispasmodic [5], antioxidant [6], free radical Terminalia chebula is a native to various parts of Southern antidiabetic [14] activities. antiviral [10,11], anticancer [12], antianaphylaxis [13] and Malaysia and Vietnam [1]. It is found all over India from Habitat easternAsia including to western India, region Nepal, and is China commonly (Yunnan), known Sri as Lanka,“black Myroblans” in English and ‘Harad’ in Hindi. It is known as the Terminalia chebula is a deciduous tree growing upto 30 “king” of Mongolian and Tibetan medicines, a drug for a wide mts. tall with a trunk up to 1 mt. diameter. The leaves are range of diseases [2]. This tree is known in Iranian traditional alternate to sub opposite in arrangement, oval, 7-18 cm

Terminalia chebula Int J Pharmacogn Chinese Med

Phytochemical and Pharmacological Profile of 2 International Journal of Pharmacognosy & Chinese Medicine long and 4.5-10 cm broad with a 1-3 cm petiole. The fruit is drupe-like, 2-4.5 cm long, 1.2-2.5 cm broad and blackish with five longitudinal ridges [15] (Figures 1 & 2).

Figure 1: Leaves of T. chebula. Figure 2: Fruits of T. chebula.

Taxonomical Classification Order: Myrtales Family: Combretaceae Kingdom: Plantae Genus: Terminalia Division: Magnoliophyta Species : Terminalia chebula Class: Magnoliopsida

Chemical Constituents Table 1: Phytochemical Constituents Isolated from Terminelia

Plant Pharmacological S. No. Chemical constituent and Their Pharmacological Activity. References part activity

[20] Immuno- suppressive 1. Fruit [39,40,41] effects [46,47]

Chebulagic Acid 2. [10]

Triacontanoic Acid

3. [10]

Terpinolene

Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 3 International Journal of Pharmacognosy & Chinese Medicine

4. [10]

Terpinen-4-ol

5. Fruit [47]

β Sitosterol

6. [47]

Corilagin

[45] 7. Fruit Hepatoprotective [47]

Chebulic Acid

Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 4 International Journal of Pharmacognosy & Chinese Medicine

8. Fruit [49]

Anticancer

Ethyl Gallate

[47] 9. Fruit [49] Anticancer

Gallic Acid 10. [46]

Stearic Acid

[40] 11. Fruit [46][47] [49] Anticancer

(G = Galloyl) Chebulinic acid

12. [47]

Punicalagin

Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 5 International Journal of Pharmacognosy & Chinese Medicine

13. Fruit [48]

Linoleic Acid

[37] 14. Fruit [49] Anticancer, Antioxident

Tannic Acid

15. [9]

Anti HIV

Galloyl Glucose

[9,10] 16. Fruit [47,49] Anticancer, Anti HIV

Ellagic Acid

Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 6 International Journal of Pharmacognosy & Chinese Medicine

17. [40]

(G = Galloyl) 4-O-(4″-O-galloyl-α-l-rhamnopyranosyl)ellagic acid

18. [40]

acid (G = Galloyl) 4-O-(3″,4″-di-O-galloyl-α-l-hamnopyranosyl)ellagic

19. [10]

β Caryophyllene

20. [10]

Behenic acid

Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 7 International Journal of Pharmacognosy & Chinese Medicine

21. [10]

Eugenol

22. [10]

Isoquercetin

[10] 23. Fruit [48] Oleic acid

24. [10]

[Ca]2+ Ca-phellandrene

25. [10]

Alpha terpine

Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 8 International Journal of Pharmacognosy & Chinese Medicine

26. Hepatoprotective [45]

(G = Galloyl) Neochebulic acid

27. Fruit [47]

(G = Galloyl) Chebulanin

28. [47]

Neochebulinic acid

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29. Fruit [47]

1,2,3,4,6-penta-o-galloyl-beta-d-glucose

30. Fruit [48]

Palmitic acid

31. Fruit [49]

Anticancer

2,4-Chebulyl-beta-d-glucopyranose

32. [49]

Anticancer

Luteolin

Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 10 International Journal of Pharmacognosy & Chinese Medicine

[51] 33. [55]

1,3, 6-Tri-O-galloyl-ß-D-glucose

34. [52]

Castalagin

35. [52]

Flavogallonic acid

Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 11 International Journal of Pharmacognosy & Chinese Medicine

36. [52]

(α- R=H, R’=OH) (β- R=OH,R’=H) Terchebulin

37. Fruit [37]

Ascorbic acid

38. Fruit [53]

Casuarinin

Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 12 International Journal of Pharmacognosy & Chinese Medicine

39. Fruit [54]

Chebuloside II

40. Fruit [53]

1,6-di-O-galloyl-β-D-glucose

41. Fruit [55]

Saponin

Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 13 International Journal of Pharmacognosy & Chinese Medicine

42. Leaves [56]

Terflavin B

43. Leaves [56]

Terflavin C

44 Leaves [56]

Terflavin D

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Ethnic Uses chebula reduction between the pre-rinse and post-rinse samples Plants of the genus Terminalia are amongst the most [22]. aganist microbes showed that there was a significant widely used plants for traditional medicinal purposes worldwide [16]. Plant-derived medicines have been a part Activity Against Anaphylactic Shock of our traditional health care system and the antimicrobial properties of plant-derived compounds are well documented. T. Terminalia chebula fruit was tested in an anaphylactic shock model chebula, Terminalia belerica, and Emblica officinalis in vivoThe water soluble fraction of methanol extract of It is one of the main ingredients of the Triphla ( digestive ailments. It is also useful in asthma, mouth). Triphla ulcers, , by the death of Spague-Dawley rats (200-300 g) stomachis an Ayurvedic infections, preparation gastritis, thathepatitis, is used skin for diseases,correcting piles the and ICR mice (20-30 g). Doses of 0.01-1.0 g/kg of the minsextract, after administered decreased the 1 h mortality before the dose experiment dependently. inhibited Oral mucous membrane of mouth. Its paste with water is found the anaphylactic shock with 100 %. Administration 5-10 and cough. It is used as gargle against inflammation of 7.8 %. From the rat mast cells the release of histamine was healing capacity for wounds. Its decoction as a lotion is used hinderedapplication in reduceda dose dependent the cutaneous manner anaphylaxis [13]. with 63.5 +/- into surgicalbe anti-inflammatory, dressing for healing analgesic the andwound having earlier. purifying The dried and ripe fruit of herb has traditionally been used as a popular folk Gastrointestinal Activity cardiotonic treatments [16,17]. Terminalia chebula is a commonly advocated agent in medicine for homeostatic, antitussive, laxative, diuretic and Study of Pharmacological Effects Ayurveda for improving gastrointestinal motility. Charles In recent years, there is an upsurge in the clinical usage Foster rats (150-200 grams of either sex) were divided into four groups as follows - Group 1 (n = 15) normal animals; agentsGroup IIwere (n = 6)injected rats administered intramuscularly, metoclopramide 30 mins before (1.35 mg/the antibioticsof indigenous resistant drugs, strainsbecause and of their various efficacy side andeffects being caused free kg); Group III (n = 8) rats given atropine (0.45 mg/kg). These byfrom the serious synthetic toxic drugs effects. has Moreover prompted constant scientists increase to look in thefor Terminalia chebula herbal immunomodulators to treat various infections [18]. experiment. Rats from Group IV (n = 8) were administered Herbal drugs are believed to enhance the natural resistance (100 mg/kg/day for 15 days orally). All of the body against infection and their immunomodulatory emptyingrats were thenwas givenmeasured a test 20 meal mins of methyllater. Gastric cellulose emptying (1.5%) activities have been reported in numerous plants [19]. Herbs mixed with phenol red (50 mg/100 ml) orally and gastric are selected and combined for their ability to inhibit microbial overgrowth in various parts of the body and support those of normal rats (Group I) was found to be 51.6 +/- 7.79%. organ systems responsible for immune functions [20]. Metoclopramide significantly increased the gastric emptying (76.33Terminalia +/- 12.37%; chebula p < was 0.01) found and to atropine increase inhibited the percent the Anticariogenic Effect motility (% gastric emptying being 7.26 +/- 19.76%; p < study0.01). it appears that Terminalia chebula can serve as a useful T. chebula is used as a mouth alternativegastric emptying to prokinetic (86.57 +/-drugs 6.65%; available p < 0.01). today Thus [23]. from this mouth The rinse aqueous of 10% extract concentration of was prepared by diluting The antimicrobial action of Teminalia chebula especially rinse seems to be a potential anticariogenic mouthwash.T. chebula inA on gastrointestinal tract is considered in supplementation of soothing to mucosal lining. Ellagic acid present in T. assessedthe concentrated by testing aqueous on 50 salivary extract ofsamples. the fruit Salivary of samples chebula has a potent inhibitory action on microorganisms weresterile collected distilled from water. subjects The efficacy assessed of theto be mouth at high rinse risk was for like C. perfringens and E. coli. It is commonly advocated caries. Salivary pH, buffering capacity and microbial activity for increasing the gastrointestinal motility thus relieving were assessed before rinsing, immediately after, and 10 min, the symptoms of gastroparesis for better bioavailability 30 min and 1 h after rinsing. There was an increase in the pH and fast absorption of the micronutrient. The presence and buffering capacity and decrease in microbial count [21]. of anthraquinone and sennoside are responsible for the purgative action. Studies have also shown the additional antibacterial activity of T. chebula on Helicobacter pylori. T. chebula to be effective The total phenol content of aqueous extract was found against a broad spectrum of pathogens comprising of both increaseto be 21.33 in pH ±1.633 till 45 (meanminutes ± post-rinse SD) and totalwhen flavonoids compared asto Reportsgram positive have shownas well theas gram extract negative of microorganisms [24]. found to be 23.17 ± 2.317 (mean ± SD). There wasTerminalia a gradual pre-rinse was observed. Antimicrobial effect of Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 15 International Journal of Pharmacognosy & Chinese Medicine

Immunosuppressive Effects

Gallic acid and chebulagic acid, isolated from fruits of T. glycogenglibenclamide content produced decreased significant to 75 blood% and glucose 62.2 reduction% in the chebula inhibited the killing activity of CD8 and CTL clones at diabeticof 60.10% controls. (p < In 0.01). the in The vitro hepatic investigation and skeletal the pancreatic muscle IC50 islets showed that the insulin release was nearly two times in response to anti-CD3 stimulation was also blocked by both more than that in untreated diabetic animals. The treatment substances values ofat 30the and equivalent 50 µM, concentrationsrespectively. Granule [25]. Chebulagic exocytose did not bring any unfavourable effects on the other blood acid from immature seeds of T. chebula was found as a potent parameters of the liver and the kidney function tests. The

LD50 value was above 3 g/kg. There were no deaths of animals induced by subcutaneous immunization with bovine type II even at this dose [31]. collagensuppressor on ofdays the 0 T and cell 21. activity. Chebulagic In DBA/1J acid micewas administered arthritis was afterintraperitoneally disease onset. for In 3 weeks,both the either prophylactic as prophylaxis and either (10 orin reducedOral administrationthe levels of ofblood ethanolic glucose extract and ofglycosylated the fruits the20 mg/kg)therapeutic before model, disease all onsetclinical or scores,as a therapy like serum (20 mg/kg) levels (200 mg/kg body weight/rat/day) for 30 days significantly of total and anticollagen IgG and levels of interleukin-10 diabetes in rats. Electron microscopic studies showed and interleukin-6 were reduced. The serum levels of the hemoglobin in streptozotocin (STZ)-induced experimental transforming growth factor beta were markedly elevated. The number of the granulocytes was reduced, but the proportion significant morphological changes in the mitochondria and of CD4+, CD25+ T cells was greater in the knee joints of the endoplasmic reticulum of pancreatic β cells of STZ- induced chebulagic acid-treated mice. It concludes that chebulagic abnormalitiesdiabetic rats. Also,were a normalized decrease in theafter number treatment of secretory with T. chebulagranules of β-cells was observed and these pathological disease in mice [26]. T. chebula fruit has potential hypoglycemic action acid significantly suppressed the onset and progression the in STZ-induced extract. diabeticThe present rats studyand the shows effect that was the found ethanolic to be The biologically active compounds such as chebulagic moreextract effective of than glibenclamide [32]. acid, gallic acid and ellagic acid make T. chebula highly potent antioxidant, which may be responsible for its immunomodulatory Study was conducted to evaluate the anti-diabetic Terminalia chebula Retz. Fruits activity [17,27,28]. Its extract neutralizes reactive oxygen effects of ethanolic extract of species (ROS) and scavenges free radicals. The free radicals by using alloxan-monohydrate-1 induced diabetic control by stimulateare responsible additional for causingneutrophils inflammation and macrophages by stimulating at site using Wistar-1 Albino rats for 30 days. The effect of this extract release of cytokines such as IL-1, TNF-α and IFN-β, which (200500 mg mg kg kg-1 b.wt.) was compared with the glibenclamide (600samples mg were kg b.wt.).performed This under extract parameters showed nil like toxicity biochemical up to of inflammation [29]. Thus, different antioxidants of the b.wt. After the completion of the study, collected extract exhibit immunosuppressive properties, which help in neutralizingAntidiabetic these important Effects inflammatory mediators [30]. showedand anti-oxidant the granular enzymes cytoplasm, related dilatation, to shrunken diabetes. nuclei The histopathological changes caused after induction of alloxan T. chebula seed powder, -1 ofand epithelium inflammation, in the which pancreas were was reduced observed after in diabetic treatment rats, of in Streptozotocin-induced The chloroform extract diabetic of rats using short term and whichthe ethanolic was reduced. extract From (200 themg evaluationkg b.wt.). Excessof the present proliferation study longproduced term significantstudy protocols. antidiabetic In short effects term withstudies, various T. Chebula doses against the diabetic condition, even though the mechanism has been confirmed that having the pharmacological action atextract 4 h with produced doses aof maximum 100, 200 reductionand 300 mg/kgof blood respectively, glucose of 20.85% (p < 0.01), 28.45% (p < 0.001) and 42.20% (p < 0.001) Terminalia chebula of the action is unknown [33]. The 80%-ethanolic extract of with standard drug, Retz.metformin. Has also The significant effective dose hypoglycemic was 200 group.whereas While glibenclamide the long term (0.04 administration mg/kg) produced of a maximum T. chebula toeffect 400 on mg/kg alloxaninduced [34]. diabetic rats and it been comparable reduction of 50.44% (4 h, p < 0.001) compared to control (300 mg/kg) for four weeks produced significant reduction in Terminalia chebula Retz. Has been evaluated for its antidiabetic activity in blood glucose. The reduction was significant after treatment The aqueous extract of the fruits of endfor one of 4 thweek week, in both the extract and glibenclamide treated T. chebula with a known drug, tolbutamide. Oral administration of 200 groups and continued to increase up to four weeks. At the streptozotocin (STZ) induced mild diabetic rats and compared daily extract produced significant blood T. chebula glucose reduction of 53.09% (p < 0.01). On the other hand, mg / kg body weight of aqueous extract of Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 16 International Journal of Pharmacognosy & Chinese Medicine once for two months reduced the elevated blood glucose a concomitant increase in the activity of the serum. The contentby 43.2% decreased (p < 0.01) byand 75% significantly and 62.9% reduced respectively the increase in myocardial necrosis was confirmed by histopathological diabeticin HbA1c controls, (p<0.01). these Hepatic alterations and skeletal were partly muscle prevented glycogen retainedexamination. the activities Pre-treatment of the diagnosticwith the extract marker ameliorated enzymes [39]. the effect of isoprotenerol on the lipid peroxide formation and compared to the healthy controls. The in vitro studies with The fruits of T. chebula are claimed to be useful against pancreatic(34.9% and islets 21.17%) showed in aqueous that the extract insulin treated release group was nearly when two times more than that in untreated diabetic animals. The treatment did not have any unfavorable effect on other blood heart diseases.+, K+ and Besides Mg2+ the known effects of extracts on parameters of liver and kidney function tests [35]. isolated frog hearts in this investigation, extracts are applied on (Na ) ATP ases of a whole homogenate Chebulagic acid, isolated from T. chebula proved to be a prepared from ventricular portion of frog heart. The extracts reversible and non-competitive inhibitor of maltase with a exerted the following inhibition: Butanolic extract 13.5 % and 57.4 % with doses of 0.5 and 1.0 mg respectively. Aqueous doseextract of 31.221 mg %,is enormous.40.68 %, and It 49.18is higher % with than doses that causedof 0.1, 0.5, by KI value of 6.6 mµM. The inhibitory influence of chebulagic and 1.0 mg. The inhibition of the ATPase system with the theacid inhibition on the maltase-glucoamylase is greatly affected by complex its origin was [36]. more potent than on the sucrase-isomaltase complex. The magnitude of ouabain,Wound which Healing is a specific inhibitor of this ATPase [4]. Cardiotonic Activity T. chebula was T. chebula topically administered on dermal wounds of rats. The cardiotonic activity when tested on isolated frog hearts. treatedThe wounds alcoholic healed extract much of faster, leaves indicated from by improved The different extracts of fruits of exhibited rates of contraction and a decreased period of epithelisation. cardiotonic activity, though at high doses because they were The benzene and chloroform extracts showed a moderate inThe these granulation tissues also tissue increased increased up into 8 total days protein post-wounding. DNA and fairlynot completely potent cardiotonic soluble in theactivities. experimental These Ringerall gave solution. easily collagen content. The levels of hexosamine andStaphylococcus uronic acid dispersibleEthyl acetate, solutions, butanone, producedbutanol and dose-dependent aqueous extracts positive exerted aureus and Klebsiella isotropic effects and an increase in the cardiac output. There effectsIn addition, of T. chebula the extract was active against . These results document the beneficial being tested here stimulated the isolated perfused frog heart extract for the healingT. Chebula process fruit[40]. was withoutwas no appreciableinducing depression change in[37]. the heart rate. The extracts The hydroalcoholic extract of evaluated for its wound healing activity in alloxan induced of Terminalia chebula was studied by using isolated frog wounddiabetic area rats whenusing excisioncompared and to dead controls space which wound was models. 40%. Cardiotonic effect of aqueous extract of stem bark Extract treated animals exhibited 82% reduction in the both normal and hypodynamic hearts. Calcium free Ringer as compare to controls. The wet and dry granulation tissue solutionheart perfusion was used technique as vehicle (IFHP).for administration This was studiedof aqueous on The extract treated wounds were found to epithelize faster Terminalia chebula inweight diabetic content rats was and increased further evaluationsignificantly of whenthis activitycompared in extract of as a test extract and digoxin humansto controls. is suggested This extract [41]. promotes significant wound healing as a standard. A significant increase in height of force of contraction (positive inotropic effect) with increase in dose, Different concentrations of various organic and aqueous producedno change cardiac in heart arrest rate at was 3 mg/ml, observed a higher with testconcentration, extract as T. chebula were tested on fibroblast compared to dose of a standard digoxin. The test extract (L929) and keratinocytes cells to evaluate its biocompatible Terminalia extractsconcentration (solvent-free) by using ofMTT aschebula compared showed to widestandard, therapeutic digoxin window (15μg/ml). [38]. Compared to 2,5-diphenyltetrazolium bromide] and live-dead viability/ digoxin, a drug with narrow therapeutic window, [3-(4,5-dimethylthiazol-2-yl)- T. chebula decreasing the ammonia accumulation in the media, thereby cytotoxic assay. These extracts were found to be effective in An ethanolic extract of fruits (500 mg/kg) was tested in rats with isoprotenerol (200 mg/kg) induced reducing its toxic effect on cells. The cytoskeletal structure activitymyocardial of the damage. myocardial In them marker the levelenzymes of lipiddecreased peroxidase with control.and extracellular In conclusion, matrix we secretion have demonstrated of the cells treatedthe effect with of increased significantly in the serum and the heart. The extracts showed higher cellular activity in comparison to

Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 17 International Journal of Pharmacognosy & Chinese Medicine

T. chebula on both types of skin cells and optimized concentration in which it could be used as a bioactive concentration of 1-2.5 mg/L inhibited the activity of urease componentthese extracts for ofwound healing applications by increasing cell after autoclaving for 30 min atT. 121°C. chebula The strongly water extract inhibited at a proliferation and decreasing free-radical production without the growth, the sucrose induced adherence and the glucan- affecting the normal cellular matrix [42]. induced[9]. The aggregation aqueous extract of Streptococcus of mutans. Mouth rinsing

Hypolipedemic Effect the total bacterial counts and the total streptococcal counts inwith the a saliva 10 % samples. solution It of successfully the extract inhibited significantly glycolysis reduced of Hypercholesteremia is one of the risk factors for salivary bacteria for up to 90 min after rinsing [9,21]. coronary artery disease. The present study highlights the Terminalia chebula fruit was studied for its antibacterial activity against clinically important efficacy of Ayurvedic herbal formulation Triphala on total standardAn ethanol reference extract bacterial of strains. The antimicrobial cholesterol, low density lipoprotein (LDL), very low density susceptibility was screened using the disc diffusion rats.lipoprotein Four groups (VLDL), of high rats density were employedlipoprotein namely (HDL) andcontrol, free fatty acid in experimentally induced hypercholesteremic was determined using the broth micro dilution method. Themethod results and showed the minimum that it inhibitorywas active concentration against both gram- (MIC) Triphala treated, hypercholesterolemia rats (4% Cholesterol positive and gram-negative bacteria. The T. chebula fruit + 1% cholic acid + egg yolk) and Triphala pre-treatment increase in the total cholesterol, LDL, VLDL, and free fatty Salmonella typhi SSFP in hypercholesteremic rats. Results showed significant 4S, Staphylococcus epidermidis MTCC 3615, Staphylococcus in Triphala treated hypercholesteremic rats [43]. aureusextract wasATCC highly 25923, effective Bacillus against subtilis MTCC 441 and acid in hypercholesteremic rats were significantly reduced Pseudomonas aeruginosa In atherogenic diet induced hyperlipidemic model, determined as 1 mg/ml for S. typhi. These results indicate that Terminalia the T. chebula dry fruit possessesATCC a potential 27853. broad The MICspectrum was chebula triglycerides,the rats receiving total protein treatment and withelevation Haritaki of high ( density strong antimicrobial activity against all the test isolates and lipoprotein) showed cholesterol. significant The reduction results inalso total suggest cholesterol, that foundof antimicrobial to be most effective activity over [48]. others. This extract Phytochemical demonstrated analysis a Haritaki at 1.05 and 2.10 mg/kg b.wt. concentrations is an revealed the presence of high concentration of phenolics and dietary management in the prevention of atherosclerosis in hyperlipidemicexcellent lipid-lowering patients agent. [44]. It Treatment can be utilized with for Terminalia providing low concentration of flavonoids and terpenoids. In acute oral in mice at recommended dosage level and 24 h LD50 was chebula ameliorated the biochemical parameters, histological toxicityfound to study, be >4 no g/kg, gross p.o. behavioral in mice. The changes results were provide observed that and histochemical results [45]. Terminalia chebula fruit could be useful for the development of alternative/complementary medicine for multidrug– Antibacterial resistant uropathogens [49]. T. chebula fruit was tested for its activity against methicillin-resistant and methicillin- Antiviral sensitiveThe ethanolicStaphylococcus extract aureus of strains from clinical isolates. pathogen that causes lifelong latent infection of sensory with an inhibition zone size of 11 to 27 mm, against all the neurons.HSV-1 Non-nucleoside (Herpes simplex inhibitors virus) is a that common can humanlimit testThe bacteria.extract showed There wasa broad a synergistic spectrum interaction of antibacterial of the activity crude HSV-1 recurrence are particularly useful in treating immunocompromised individuals or cases of emerging T. extract with tetracycline, too. TLC analysis indicated phenols chebula showed a strong anti-HSV-1activity in combination onand the flavonoids basis of spectroscopicas major active evidence compounds [47]. [46]. In a similar withacyclovir-resistant acyclovir. With strains doses, ofcorresponding herpes virus. to The the extract human of use investigation gallic acid and its ethyl ester could be verified it limited the development of skin lesions and prolonged the T. chebula and black mean survival times of infected mice compared with both Teminalia chebula Retz) were tested against acyclovir and with the mice treated alone with the herbal HelicobacterEther, alcohol pylori and in wateran agar extracts diffusion of test. The water myrobalan ( mg/L. Plant powder, incorporated in agar gave higher MIC strongerextract (p<0.01 anti-HSV-1 and activityp<0.05). in It thereduced brains virus than yields in the in skin, the extract had a MIC value of 125 mg/L and a MBC of 150 inskin contrast and brain to acyclovirstronger thantreatment acyclovir alone. alone. The It combination exhibited a and MBC values (150 and 175 mg/l). The extract was active

Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 18 International Journal of Pharmacognosy & Chinese Medicine

t was not toxic to mice [50]. Chebulagic acid and punicalagin withinfiltration, Fe2+ ascorbate and repaired were 85.5, necrosis 27, 74, induced and 69 byµg/mL -BHP in vitro [17].. andinhibit inactivated HSV-1 entry HSV-1 at noncytotoxicviral particles doses and in could A549 prevent human Triphala extracts inhibit 50 % of lipid peroxidation, induced binding,lung cells. penetration, Experiments and revealed cell-to-cell that both spread, tannins as targetedwell as secondary infection. Results indicated that both blocked continuedThe concentrations daily administration needed for sustained inhibition the of effect the [14]. hydroxyl interactions between cell surface glycosaminoglycans and radical scavenging were 165, 71, 155.5, and 12.5 µg/mL. A HSV-1 glycoproteins [51,52]. T. chebula fruits was tested for its radio protective ability. The free radical neutralizing ability Chebulagic and chebulinic acids have higher direct The water extract of attachment and penetration to the host cells as compared to was comparable to that of ascorbate (100 µM) 93.5 % and acyclovir.antiviral activity Hence, itagainst may be HSV-2 a useful and candidate efficacy to for inhibit developing virus breaks.gallic acid The (100 administration µM) 91.5 %,of 80 respectively. mg/kg prior It to protected whole body the plasmid DNA pBR322 from the radiation-induced strand HSV-2 infection [53]. membrane lipids in the mice liver from radiation-induced alternative therapy for prevention of sexually transmitted irradiation of mice (4 Gray) reduced the peroxidation of Chebulinic acid and chebulagic acid can effectively inhibit in vitro by 2 Gray [56]. It inhibits DNA damages. Human lymphocytes also were protected act as neuraminidase inhibitors and show antiviral potency from DNA damages exposed IAV (The influenza A virus) replication. These compounds xanthine oxidase activity. It is an excellent scavenger of DPPH Chebulagic acid and/or its hydrolysis fragments as new protectradicals. cell A HPLC organelles analysis from showed radioinduced the presence damages of ascorbate, [57]. to both wild-type and oseltamivir-resistant IAV strains [54]. gallic acid and ellagic acid. The extract seems to be able to yeast and inhibits in vitro ofchemical M2 sequence leads to[55]. restores growth of M2(S31N)-expressing found 95.84% at 25µg/mL of Terminalia chebula aqueous influenza A replication regardless The percentage inhibition of CaOx nucleation was T. chebula cytomegalovirus activity in vitro and in vivo. In vitro they extract which remained almost constant with the increasing inhibitedHot water the replication extracts of of human cytomegalovirus. were examined forIn vivoant concentration of the plant extract; however, plant extract they were tested in an infection model on immune suppressed inhibited CaOx crystal growth in a dose dependent pattern. theWhen injury MDCK in and a dose-dependent NRK-52E cells were manner. injured On by treatment exposure treated with 50 mg/kg cyclosporine for one day before the to oxalate for 48 hours, the aqueous extract prevented mice. The herbal extract was orally administered to the mice the cell viability increased and lactate dehydrogenase reduction of the virus yield in the lung. The T. chebula releasewith the decreased different in concentrations a concentration of dependent the plant manner. extract, intraperitoneal infection. The efficacy was evaluated by the This study indicates that T. chebula is a potential candidate treated mice compared with the water treated animals extract [10]. for phytotherapy against urolithiasis as it not only has a significantly suppressed the virus yields in the lungs of the Antioxidant and Cytoprotective Effects crystals but also has a cytoprotective role [58]. potential to inhibit nucleation and the growth of the CaOx Treatment and pretreatment of the hepatocytes with the T. chebula fruits was evaluated T. chebula t The polyphenolic extract of extract significantlyin vitro reversed the -BHP-induced cell for antioxidant activity by determining the reducing power, 50 14 μg/mL), andcytotoxicity 2,2-diphenyl-1-picryhydrazyl and lactate dehydrogenase free leakage. radical-scavenging In addition, total antioxidant capacity, DPPH radical concentration 50 30.51 μg/ activities.extract exhibited The in vivo studyferric-reducing showed that antioxidant pretreatment activity with (IC nitric oxide radical concentration activity (IC50 265.53 μg/ in vitro conditions. (IC mL) and hydrogen peroxide scavenging single dose of t was also measured by mL)determining under the total phenolic, theextract serum (500 levels or 1000 of the mg/kg) hepatic by enzymegavage formarkers 5 days aspartate before a Moreover, the phytochemical characterization of the extract aminotransferase,-BHP alanine (0.1 mmol/kg)aminotransferase significantly and loweredreduced flavonoid, tannin and ascorbic acid contents. It also scavenges hydrogen peroxide-induced radicals. The activity of the the indicators of oxidative stress in the liver, such as the theextract standard may beascorbic due to acid, the and total its polyphenolic activity is concentration- content. The glutathine disulfide content and lipid peroxidation, in a dependent.antioxidant Itactivity is concluded of the extract that a ispolyphenolic-rich significantly higher fraction than dose dependent manner. Histopathologic examination of liver lesions, including hepatocyte swelling and neutrophilic of T. chebula the rat livers showed that extract reduced the incidence of fruits is a potential source of natural antioxidants

Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 19 International Journal of Pharmacognosy & Chinese Medicine

[59].

Antimutagenic i.e. ABTS, DPPH and NO radical scavenging assay was found to be 2.27μg/ml, 6.04μg/ml and 4.37μg/ml respectively. Tannin fractions and gallic acid from the dried pulp of In experimental study, PTZ (pentylenetetrazole) and MES T. chebula were evaluated for their antimutagenic potential. (maximal-electroshock) treated groups exhibited 100% seizures with increased oxidative stress (p < 0.001) and cognitive deficits (p < 0.01) as compared to control group. fractions;They all were the highlymonomeric significant gallic activeacid was against the S9-dependentleast effective HETC at highest dose (1000mg/kg) showed 83.33% mutagen 2AF. The effect correspondsT. chebula with the fruits nature inhibited of the (5/6) protection in MES induced seizures while 66.66% the direct acting mutagens sodium azide and 4-nitro-o- of(4/6) HETC protection with valproate in PTZ inducedand phenytoin seizures. showed However, complete HETC [60]. The water extract of dried protection.(1000mg/kg) In addition,and co-administration it also attenuated of sub-therapeutic the seizure induced dose Salmonella typhi murium and S9-dependent phenylendiamine in the strains TA100, TA1535, TA97a, TA98 of oxidative stress and cognitive impairment as indicated by mutagen 2-aminofluoren in TA97, TA98 and TA100 strains. assignificant compared (p

[63]. different genotoxic compounds in a dose dependent manner alteredadministration lysosomal produced enzyme significant activities. cardiac Results damage showed (as seenthat T.by chebulathe triphenyltetrazolium chloride assay) and significantly Terminalia chebula prevents myocardial damage [66]. To obtain experimental evidence on the therapeutic extract stabilizes the lysosomal membrane and efficacy of the fruit extract, we examined Immune Activation mutagenicits effect on activity. chromosomal In MN aberrationformation (CA)test, singleand micronucleus application of(MN) Terminalia formation chebula in C57BL hybrid mice, to assess the anti- In recent years, much attention is being focused on doses of 50, 100 and 150 mg/kg dry weight 24 hours prior the immunological changes occur during stress. The methanolic fruit extract at different immunomodulatory activities of Triphala were assessed by testing the various neutrophil functions like adherence, to administration of cyclophosphamide (CP) at the dose of 50 mg/kg significantly reduced the frequency of MNCPE and at the same time significantly increased PCE/NCE ratio phagocytosis [phagocytic index (P.I) and avidity index (A.I)] thecompared same time to CP increased alone. Concerning the % degree CA of test, protection fruit extract in dose at alterand nitrothe neutrophil blue tetrazolium functions. (NBT) The reductionneutrophil infunction albino tests rats. dependentall different manner doses in significantly bone marrow reduced cells of themice % as CAcompared and at andNoise corticosterone (100 dB) stress levels for were 4 h/d carried for 15 out d, wasin eight employed different to to CP alone treated group. However Terminalia chebula fruit groups of animals, namely control, Triphala, noise-stress, Triphala noise-stress, and corresponding immunized groups and/or micronucleus formation. The anti-mutagenic activity observedextract alone in this did study not can show be anyattributed chromosomal to the presence aberration of were used. Sheep red blood cells (SRBC 5 x 10(9) cells per to treat cancer without inducing mutations in healthy body ml) were used for immunizing the animals that belongs to cellsflavonoids [64]. and polyphenols. Thus it could be a better choice Triphalaimmunized group, groups. while In the Triphala remaining administration neutrophil functions (1g/kg/d for 48 d), A.I was found to be significantly enhanced in the Protective Drugs against Stress and steroid levels were not altered significantly. However

The IC50 the neutrophil functions were significantly enhanced in the Terminalia chebula in vitro Triphala immunized group with a significant decrease in value of hydroalcoholic fruit extract of corticosterone level was observed. Upon exposure to the (HETC) in antioxidant assays noise stress, the neutrophil functions were significantly Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 20 International Journal of Pharmacognosy & Chinese Medicine

revealed that 2, 3, and 4 inhibited maltose-hydrolyzing corticosterone levels were observed in both the noise-stress andsuppressed the noise-stress and followed immunized by a significantgroups. These increase noise-stress in the byactivity 1, 2 and of intestinal 3 isolated α-glucosidase, from T. chebula noncompetitively. fruits. These results This administration in both the Triphala noise-stress and the is the first report on mammalian T. chebula α-glucosidase fruits for inhibitionmanaging Triphalainduced changesnoise-stress were immunized significantly groups. prevented Hence by study Triphala has Type 2 diabetes [70]. divulged that oral administration of Triphala appears to suggest a use of the extract of stimulate the neutrophil functions in the immunized rats and Chebulagic acid, isolated form Terminalia chebula stress induced suppression in the neutrophil functions [67]. proved to be a reversible and non-competitive inhibitor of

maltase with a Ki T. chebula value of 6.6 µM. The inhibitory influence in mice. Study TCE reports was administered the effect oforally dry for fruit 10 extract consecutive of Theof chebulagic magnitude acid of α on-glucosidase the maltase inhibition glucoamylase by chebulagic complex (TCE) on Th1/Th2-mediated immune responses acidwas morewas greatly potent affected than on by the its sucrase-isomaltase origin. These results complex. show a use for chebulagic acid in managing type-2 diabetes [36]. days, after which mice were immunized with goat RBC Compounds, 23-O 50 21.7 μM (gRBC) or ovalbumin. TCE enhanced the expression of 23-O-galloylarjunolic acid 28-O-β Th1 cytokine, interferon γ, decreased interleukin 4, and -galloylarjunolic acid ( IC ) and immunized mice. The percentage of CD4+ cells and delayed- IC50 64.2 μM Terminelia chebula also showed potent typeincreased hypersensitivity the number response of plaque-forming also increased cells in these in gRBC- mice. -d-glucopyranosylα-glucosidase ester ( ) from Treatment is reported to increase lymphocyte proliferation 50 174.0 μM and macrophage phagocyte response, but decrease nitrite [71].inhibitory activities against Baker’s yeast compared to the positive control, acarbose (IC ) increased in the treated mice. None of the group showed any Anticancer Activity production. The bone marrow cellularity and WBC count also dose-dependent Th1 response [68]. Homeopathic preparations of Terminalia chebula known sign of toxicity. The data indicate that TCE elicits a significant MT Immunomodulatory activity of ripe T. chebula fruits cells.as Mother However, tincture other homeopathic ( ) decreased preparations the viability of Terminalia of breast chebulacancer (MDAMB2313X, 6C and and 30C MCF7) and non-cancerous (HEK 293) playevidenced important by increase roles in in immunity. the concentration This phenomenon of antioxidant also breast cancer cells without affecting the viability of the non- enhancesenzymes, the GSH, concentration T and B cells, of melatonin the proliferation in pineal ofgland which as ( ) decreasedMT, 3X the, 6C and viability 30C, reduced of only which play important roles in immunity [69]. 1:10cancerous dilution cells. at All24, the 48 potencies, and 72 h. Under SEM, MT appeared well as the levels of cytokines, such as IL-2, IL-10 and TNF-α, growthas a mesh-like kinetics structure of breast cancerwhereas cells, under more TEM, specifically it showed at α-Glucosidase Inhibitor presence of nanoclusters. On the other hand, 6C potency contained 20 nm sized nanoparticles. The current study reports the anticancer activity of homeopathic preparations by Terminalia chebula Retz. fruits was investigated. The of Terminalia chebula against breast cancer and reveals their Mammalian α-glucosidase inhibitory activity nano particulate nature. These preliminary results warrant intestinal maltase inhibitory activity, whereas neither further mechanistic studies at both in vitro and in vivo levels intestinalaqueous methanolicsucrase nor extract isomaltase was found activity to have was potentinhibited rat to evaluate the potential as nanomedicine in breast cancer [72]. by this extract. Using bioassay-guided separation, three In several human malignant cell lines a 70 % methanolic toactive possess ellagitannins potent intestinal were maltase identified inhibitory as chebulanin activity, with (1), T. chebula fruits decreased the cell viability, chebulagic acid (2) and chebulinic acid (3) and were shown the IC50 values of 690 μM, 97 μM and 36 μM, respectively. inhibited the cell proliferation and induced the cell death The intestinal maltase inhibitory activities of 2 and 3 were inextract a dose of dependent manner. In lower concentrations some even higher than that of 1,2,3,4,6-penta-O apoptosis was induced, but at higher concentrations necrosis

50 μM was the major mechanism of the cell death. The following -galloyl-β-d- IC50 values could be revealed: Chebulinic acid: 53.2+/-0.16 1,2,3-glucoseO (PGG) (4, IC =140 ), which is a known potent µM, tannic acid 59.0+/-0.19 µM, ellagic acid 78.5+/-0.24 µM, α-glucosidase inhibitor. Comparison of the activities of 1–4, respectively [14]. galloyl -trigalloyl-β-d-glucosegroups mostly affected (5), the neochebulagic potency. Kinetic acid (6)studies and corilagin (7) suggested that the positions of chebulloyl and

Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 21 International Journal of Pharmacognosy & Chinese Medicine

Potent Suppressor of T- Cell Activity Department of Chemistry, Sri Varshney Post Graduate In both the prophylactic and therapeutic Chebulagic acid 09/149(0516)/2008-EMR-I/19/01/2009]. The Head,

gratefullyCollege, Aligarh acknowledged. and Department of Chemistry, University and(CHE) IL-6 dosing were models, reduced, all whileclinical serum scores, levels serum of levelstransforming of total of Rajasthan, Jaipur for providing research facilities, are and anticollagen IgG, and levels of interleukin-10 (IL-10) References of granulocytes was reduced, but the proportion of CD4+, CD25+growth T factor cells was (TGF) greater were in markedly the knee elevated. joints of TheCHE-treated number 1. and TGF β Cambridge:Perry LM (1980) The MassachusettsMedicinal Plants Institute of East ofand Technology Southeast collagen-induced arthritis (CIA) mice. Expression of Foxp3 PressAsia-Attributed pp: 447-493. Properties and Use. Eds. By Perry LM dosing model.messenger It concludes RNA thatwas also augmented significantly in the knee joints of CHE-treated CIA mice in the therapeutic 2. CHE significantly suppressed activity of Terminalia chebula representthe onset and a new progression strategy of in CIA the in mice.development Immune ofsuppression therapies Zhang XJ, He LJ, Lu Q, Li DY (2016) Pharmacological via the induction of TGF β and CD4+, CD25+ T cells may . Zhongguo Zhong Yao Za diseases [26]. 3. Zhi 41(4): 619-623. for managing rheumatoid arthritis and other inflammatory Jokar A, Masoomi F, Sadeghpour O, Nassiri Toosi M, Study assessed T. chebula extract-dependent protein for Terminalia chebula in Iranian traditional medicine. Hamedi S (2016) Potential therapeutic applications expression changes in 4. Jurkat cells. Matrix-assisted laser Journal of Traditional Chinese Medicine 36(2): 250-254. desorption/ionization–time-of-flight mass spectrometry and Terminalia chebula Suchalatha, S, Devi CSS (2004) Protective effect of Ingenuity Pathways Analysis (IPA) were performed to assess T. chebula extract against experimental myocardial protein expression and networks, respectively. A comparative injury induced by isoproterenol. Indian Journal of proteomic profile was determined in 5. Experimental Biology 42(2): 174-178. 1,(50 μg/mL)-treated and insulin-like growth and control factor cells;1 receptor the expressions kinase were of alpha-amylase inhibitors, lipase inhibitors, foods and β-tubulin, ring finger and CHY zincT. finger chebula domain extract-treated containing Hashimoto M, Nakajima Y (1997) Antiobesity agents, T. chebula extract significantly inhibitedsignificantly nuclear down-regulated factor-κB activity in and affected the proteomic beverages containing plant extracts. Japanese Kokai Jurkat cells. Treatment with the 6. Tokkyo Koho JP 227: 398. profileConclusion of Jurkat cells [73-89]. Kato Y, Nagaoin A, vitro.Terao J, Osawa T (2003) Inhibition of myeloperoxidase-catalyzed tyrosylation by phenolic Terminalia chebula antioxidants Bioscience, Biotechnology, and 7. Biochemistry 67(5): 1136-1139. have extensive medicinal potential to explore. It is called the “king of medicines” and always TerminaliaCheng HY, Linchebula TC, Yu KH, Yang CM, Lin CC (2003) Antioxidant and free radical scavenging activities of thelisted key first bioactive in the Ayurvedic phytochemicals meteria medicaisolate becausefrom it ofand its . Biological and Pharmaceutical theirextraordinary role in various powers system of healing. of traditional This review medicine describes to 8. Bulletin 26(9): 1331-1335. cure various diseases. Phytochemical constituents of this plant show anticariogenic effect, gastrointestinal Shaila HP, Udupa SL, Udupa AL (1998) Hypolipidemic activity, immunosuppressive effects, antidiabetic effects, activity of three indigex`nous drugs in experimentally hypolipedemic effect, antimutagenic, α-glucosidase inhibitor, induced atherosclerosis. International Journal of 9. CardiologyMalekzadeh 67(2): F, Ehsanifar 119-124. H, Shahamat M, Levin M, Colwell summarizes the ethnic use, pharmacological activities of potent suppressor of T- Cell ActivityTerminelia etc. The Chebula present forreview last Terminalia chebula Helicobacter pylori. 40 years. RR (2001) Antibacterial activity of black myrobalan extractsAcknowledgement and phytochemicals of 88.( Retz) against International Journal of Antimicrobial Agents 18(1): 85- 10.

Council of Scientific and Industrial Research, Yukawa TA, Kurokawa M, Sato H, Yoshida Y, Kageyama S, New Dehli for the financial assistance [Grant No. et al. (1996) Prophylactic treatment of cytomegalovirus

Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 22 International Journal of Pharmacognosy & Chinese Medicine

23. Effect of oral administration of Terminalia chebula on infection with traditional herbs. Antiviral Research Tamhane MD, Thorat SP, Rege NN, Dahanukar SA (1997) 11. 32(2): 63-70. Inhibition of HIV-1 integrase by galloyl glucoses from gastric emptying: an experimental study. The Journal of TerminaliaAhn MJ, Kim chebula CY, Lee JS, Kim TG, Kim SH, et al. (2002) 24. Postgraduate Medicine 43(1): 12-13. Terminalia chebula and flavonol glycoside gallates from Mehra R, Makhija R, Vyas N (2012) Role of 12. Euphorbia pekinensis. Planta Medica 68(5): 457-459. on Gastrointestinal Mucosa. Research Journal of 25. Pharmacy and Technology 5(9): 1183-1186. phenolicsSaleem A, of Husheem Terminalia M, Harkonenchebula P, Pihlaja K (2002) Inhibition of cancer cell growth by crude extract and the Hamada S, Kataoka T, Woo JT, Yamada A, Yoshida T, et retz. Fruit. Journal of al. (1997) Immunosuppressive effects of gallic acid and 13. Ethnopharmacology 81(3): 327-336. chebulagic acid on CTL-mediated cytotoxicity. Biological Inhibitory action of water soluble fraction of Terminalia 26. and Pharmaceutical Bulletin 20(9): 1017-1019. chebulaShin TY, Jeong HJ, Kim DK, Kim SH, Lee JK, et al. (2001) Suppression of the onset and progression of collagen- inducedLee SI, Hyun arthritis PM, Kimby chebulagic SH, Lee SK, acid Kim screened BS, et al. from(2005) a on systemic and local Anaphylaxis. Journal of 14. Ethnopharmacology 74(2): 133-140. 345-353. of medicinal plants and its relationship with their natural product library. Arthritis & Rheumatology 52(1): Sabu MC, Kuttan R (2002) Anti-diabetic activity 27. chebulic acid from Terminalia chebula Retz. and its antioxidant property. Journal of Ethnopharmacology Lee HS, Jung SH, Yun BS, Lee KW (2007) Isolation of 15. 81(2): 155-160. erminelia Chebula Retzius. antioxidant effect in isolated rat hepatocytes. Archives of Zi H (1788) Flora of China, T 28. ToxicologyTejesvi MV, 81(3): Kini KR, 211-218. Prakash HS, Subbiah V, Shetty HS 16. Observ Bot 5(31): 311-313. phytochemistry of plants of the genus Terminalia properties of endophytic Pestalotiopsis species from Cock IE (2015) The medicinal properties and (2008) Antioxidant, antihypertensive, and antibacterial 229. (Combretaceae). Inflammopharmacology 23(5): 203- 29. medicinal plants. Can J Microbiol 54(9): 769-780. 17. Terminalia chebula in vivo and in Conforti F, Sosa S, Marrelli M, Menichini F, Statti GA, et al. vitroLee HS, Won NH, Kim KH (2005) Antioxidant effects (2009) The protective ability of Mediterranean dietary of aqueous extract of plants against the oxidative damage: The role of radical 18. Salmonella . Biol Pharm Bull 28(9): 1639-1644. 587-594.oxygen species in inflammation and the polyphenol, typhimurium-induced lymphocyte depletion and flavonoid and sterol contents. Food Chemistry 112(3): Hassan JO, Curtiss R (1994) Virulent 30. 2027-2036. Immunomodulatory Effects of Triphala and its Individual immunosuppression in chickens. Infect Immun 62(5): Belapurkar P, Goyal P, Tiwari Barua P (2014) 19. 475. Immunomodulating agents of plant origin. I: Preliminary Constituents: A Review. Indian J Pharm Sci 76(6): 467- Atal CK, Sharma ML, Kaul A, Khajuria A (1986) 31. 141. Terminalia chebula screening. Journal of Ethnopharmacology 18(2): 133- Retz.Murali on YK, hyperglycemia Anand P, Tandon and associated V, Singh R, hyperlipidemia, Chandra R, et 20. tissueal. (2007) glycogen Long-term content and effects in vitro of release of insulin in lmmunopotentiating and immunoprophylactic activities Pallabi DE, Dasgupta SC, Gomes A (1998) . streptozotocin induced diabetic rats. Exp Clin Endocrinol of lmmue 21, a polyherbal product. Indian Journal of 32. Diabetes 115(10): 641-646. 21. Pharmacology 30(3): 163-168 Terminalia Terminalia chebula Kumar GPS, Arulselvan P, Kumar DS, Subramanian SP Jagtap AG, Karkera SG (1999) Potential of the aqueous chebula (2006) Anti-Diabetic Activity of Fruits of extract of as an anticaries agent. J on Streptozotocin Induced Diabetic Rats. Journal 22. Ethnopharmacol 68(1-3): 299-306. 33. of health science 52(3): 283-291. Terminalia chebula. Rekha V, Jayamathi , Krishnan R, Vijayalakshmi D, Prabu, Kannan VR, Rajasekar GS, Rajesh P, Balasubramanian et al. (2014) Anti cariogenic effect of V, Ramesh N, et al. (2012) Anti- diabetic Activity on J Clin Diagn Res 8(8): 51-54. Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 23 International Journal of Pharmacognosy & Chinese Medicine

Terminalia chebula Retz. 44. Terminalia chebula Ethanolic Extracts of Fruits of Maruthappan V, Shree KS (2010) Hypolipidemic activity Alloxan Induced Diabetic Rats. American Journal of Drug of haritaki ( ) in atherogenic diet. 34. Discovery and Development 2(3): 135-142. induced hyperlipidemic rats. Journal of Advanced Hypoglycemic Effect of Terminalia chebula Retz. Fruit on 45. Pharmaceutical Technology & Research 1(2): 229-235 Aung EPP, Lwin SH, Aye NN, Phyu KP (2017) Terminalia chebula, TerminaliaEid FA, Helal belerica EGE, and El Emblica Wahsh officinalis AMSEDAE (2011) Alloxan-Induced Diabetic Rats. Siriraj Medical Journal Hypolipidemic effect of triphala ( 35. 69(2): 80-84. ) on female Terminalia chebula Retz. albino rats. The Egyptian Journal of Hospital Medicine Murali YK, Anand P, Tandon V, Singh R, Chandra R, et al. 46. 43(1): 226-240. Tissue(2007) Glycogen Long-term Content Effects and of in Vitro Release of Insulin on Hyperglycemia and Associated Hyperlipidemia, pathogensSharma A, causing Chandraker complicated S, Patel urinary VK, Ramteke Tract Infections. P (2009) Antibacterial activity of medicinal plants against in Streptozotocin Induced Diabetic Rats. Exp Clin 36. Endocrinol Diabetes 115 (10): 1-6. 47. Indian J Pharm Sci 71(2): 136-139.

Gao H, Huang YN, Gao B, Kawabata J (2008) Chebulagic antimicrobialSato Y, Oketani constituents H, Singyouchi of K,Terminalia Ohtesuro chebula T, Kihara Retz M, Acid is a potent -glucosidase inhibitor. Bioscience, againstet al. (1997) methicillin-resistance Extraction and purificationStaphylococcus of effective aureus. 37. Biotechnology, and Biochemistry 72(2): 601-603.

fruitReddy of Terminalia VRC, Kumari chebula SVR, Reddy BM, Azeem MA, 48. Biol Pharm Bull 20(4): 401-404. Prabhakar MC, et al. (1990) Cardiotonic activity of the activity of Terminalia chebula 38. . Fitoterapia 61(6): 517-525. Kannan P, Ramadevi SR, Waheeta H (2009) Antibacterial fruit extract. African ofRavindra Terminalia BP, Naveen chebula BK, Chandrabark on S,isolated Bhaskar frog’sU, Lakshman heart. 49. Journal of Microbiology Research 3(4): 180-184. G, et al. (2012) Cardiotonic activity of aqueous extract In vitro antimicrobial potential of Terminalia chebulaBag A, Bhattacharyya SK, Pal NK, Chattopadhyay RR International Journal of Research in Pharmaceutical (2012) 39. Sciences 3(1): 24-28. fruit extracts against multidrug–resistant Terminalia chebula uropathogens. Asian Pacific Journal of Tropical Azeem MA, Reddy BM, Appa Rhao AVN, Prabhakar MC, 50. BiomedicineKurokawa M, 2(3): Nagasaka S1883-S1887. K, Hirabayashi T, Uyama S, Sato Prasad MSK (1992) Effect of extracts on frog heart muscle (Na+, K+, Mg++) ATP-ase activity. 40. FitoterapiaSuguna S, Singh 63(4): S, Sivakumar 300-302. P, Sampath P, Chandrakasan virusH, et al.type (1995) 1 infection Efficacy in ofvitro traditional herbal medicines Terminalia chebula on dermal in combination with acyclovir against herpes simplex and in vivo. Antiviral Res 227-231.G (2002) Influence of 51. 27(1-2): 19-37. wound healing in rats. Phytotherapy Research 16(3): 41. Lin LT, Chen TY, Chung CY, Noyce RS, Grindley TB, et Terminalia chebula al. (2011) Hydrolyzable tannins (chebulagic acid and Singh MP, Sharma CS (2009) Wound healing activity of punicalagin) target viral glycoprotein-glycosaminoglycan 1267-1270. in experimentally induced diabetic interactions to inhibit herpes simplex virus 1 entry and rats. International Journal of PharmTech Research 1(4): 52. cell-to-cell spread. J Virol 85(9): 4386-4398. 42. Singh D, Singh D, Choi SM, Zo SM, Painuli RM, et al. Terminalia chebula on punicalaginLin LT , Chen against TY , Lin viruses SC , Chung that CYuse , Linglycosaminoglycans TC , et al. (2013) Broad-spectrum antiviral activity of chebulagic acid and ( 2014) Effect of Extracts of Proliferation of Keratinocytes and Fibroblasts Cells: An 53. for entry. BMC Microbiology 13(1): 187-189. 701-656.Alternative Approach for Wound Healing. Evidence- Terminalia Based Complementary and Alternative Medicine pp: chebulaKesharwani A, Polachira SK, Nair R , Agarwal A, Mishra 43. Saravanan S, Srikumar R, Manikandan S, Parthasarathy NN, et al. (2017) Anti-HSV-2 activity of Retz extract and its constituents, chebulagic and chebulinic acids. BMC Complement and Alternative NJ, Devi RS (2007) Hypolipidemic effect of triphala 54. Medicine 17(1): 110-115. in experimentally induced hypercholesteremic rats. Yakugaku Zasshi 127(2): 385-388. Li P, Du R, Wang Y, Hou X, Wang L, et al. (2020) Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of 24 International Journal of Pharmacognosy & Chinese Medicine

66. Dhanalakshmi S, Devi RS, Srikumar R, Manikandan

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Terminalia chebula. Int J Copyright© Kumar M, et al. Pharmacogn Chinese Med 2020, 4(3): 000208. Kumar M, et al. Phytochemical and Pharmacological Profile of