Genus Terminalia: A phytochemical and Biological Review

Abbreviations:A549: Human lung epithelial cancer; AChE: Acetylcholinesterase; ACP: Acid phosphatase; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Bw: Body weight ; COLO-205: Human colon cancer ; COX-2: Cyclooxygenase-2 enzyme; DPPH•: 2;2-diphenyl-1-picrylhydrazyl radical; DU-145: Human prostate cancer; FRAP: Ferric reducing ability of plasma; GSH: Glutathione; HbA1c: Glycated hemoglobin; HCT-15: Human colorectal cancer; HL-60: Human promyelocytic leukemia ; IMR: Ischemic mitral regurgitation; iNOS: inducible nitric oxide synthase ; K562: Human immortalised myelogenous leukemia; MBC: Minimum bactericidal concentration; MDA-MB-231:M.D.anderson-metastatic breast cancer; MIC: Minimum inhibitory concentration; ORAC: Oxygen radical absorbance capacity; PPARα / PPARγ: Peroxisome proliferator-activated receptor alpha/ gamma ; STZ: Streptozotocin; T: Terminalia


Introduction
The genus Terminalia is the second largest genus of the Combretaceae after Combretum, with about 200 species. These plants are distributed in tropical regions of the world with the greatest genetic diversity in Southeast Asia [1]. Genus Terminalia gets its name from Latin terminus, since the leaves appear at the tips of the shoots [2]. Terminalia species range from shrubs to large deciduous forest trees. Mostly they are very large trees reaching in height up to 75 m tall [3]. Members of the genus Terminalia are widely used in traditional medicine in several continents in the world for the treatment of numerous diseases including, abdominal disorders, bacterial infections, colds, sore throats, conjunctivitis, diarrhea, dysentery, fever, gastric ulcers, headaches, heart diseases, hookworm, hypertension, jaundice, leprosy, nosebleed, edema, pneumonia and skin diseases [4]. The fruits of both T. bellerica and T. chebula are important components of triphala, a popular Ayurvedic formulation that possess numerous activities in the Indian traditional medicine [5]. T. chebula fruit possess an extraordinary power of healing and is called the "King of Medicine" in Tibet as it's used for the treatment of various diseases [6,7]. The Bark of T. arjuna are used as cardioprotective and anti-hyperlipidemic in folklore medicine [8]. In Africa, T. mollis is used to treat diarrhea, gonorrhea, malaria, and in HIV treatment, while T. brachystemma is used for the treatment of shistosomiasis and gastrointestinal disorders [9]. The diverse phytochemical constituents and various biological activities attracted us to perform a comprehensive literature survey of different Terminalia species regarding their phytochemical constituents, their ability to exert biological activities and the evidence-based information regarding the phytochemistry and biological activities of this genus. The present review is divided into two main sections, the first include a phytochemical review of various chemical constituents and their occurrence within the Terminalia species, the second comprises the numerous biological studies conducted for different species of the genus Terminalia.

Phytochemical Studies
Phytochemical studies performed on different Terminalia species have demonstrated the occurrence of several classes of active constituents, such as tannins, pentacyclic triterpenes and their glycoside derivatives, flavonoids and other phenolic compounds [10].
Literature survey has revealed that genus Terminalia is a rich source of tannins and pseudotannins, including gallic acid and its simple gallate esters, chebulic and non-chebulic ellagitannins, ellagic acid derivatives and ellagic acid glycosides (Table 1 and Figure 1). 1 Gallic acid  Figure 2), flavonoids (Table 3 and Figure  3), triterpenes and triterpenoidal glycosides (Table 4 and Figure 4) are also present in high amounts in various Terminalia species, few lignan and lignan derivatives have been isolated from genus Terminalia ( Table  5 and Figure 5).

Biological Studies
Screening of available literature on genus Terminalia revealed numerous biological activities in various in vivo and in vitro models. Biological activities included anti-diabetic, anti-hyperlipidemic, antioxidant, anti-bacterial, anti-fungal, anti-viral, anti-inflammatory, anti-cancer, anti-ulcer, anti-parasitic, hepatoprotective and cardioprotective activities.

Anti-diabetic activity
T. chebula showed a strong anti-diabetic activity, compounds isolated from the fruits, such as corilagin and ellagic acid acted as α-glucosidase inhibitors [11]. Additionally, chebulanin, chebulagic acid and chebulinic acid possessed a potent intestinal maltase inhibitory activity, with IC 50 values of 690 μM, 97 μM and 36 μM, respectively [12]. In another study, T. chebula fruits and seeds exhibited a dose-dependent reduction in blood glucose in STZ-induced diabetic rats [13]. Furthermore, ellagitannins and gallotannins isolated from T. bellerica and T. chebula fruit extracts enhanced the PPARα and/or PPARγ signaling [5]. The aqueous extract of T. paniculata bark reduced the elevated blood glucose, HbA1c, creatinine, urea, ALT, AST levels and reversed the abnormal status of endogenous antioxidants and the lipid profile levels towards their normal levels in STZ-induced diabetic rats in comparison with the untreated diabetic rats [14]. Nampoothiri [15] reported that the methanolic extract of T. bellerica fruits exhibited a potent α-amylase and α-glucosidase inhibitory activities. Moreover, the anti-diabetic activity of T. bellerica fruit extract is attributed to its gallic acid content, as it induced a dose-dependent reduction in blood glucose level with a simultaneous increase in plasma insulin (62.92%), C-peptide (79.74%), total protein (42.41%) and albumin (51.52%) in STZ-induced diabetic rats when compared to the untreated 41 3

Anti-hyperlipidemic activity
The oral administration of gallic acid isolated from T. bellerica fruit at a dose of 20 mg/kg bw significantly reduced the serum total cholesterol, triglyceride and LDL-cholesterol levels [21]. Moreover, T. chebula fruits possessed anti-hyperlipidemic activity against cholesterolinduced hypercholesterolemia and atherosclerosis in rabbits [22]. In addition, the ethanolic extract of T. arjuna tree bark reduced the serum total cholesterol, LDL, VLDL, triglycerides and raised HDL levels in diet-induced hyperlipidemic rabbits [23]. Also, it was shown that T. bellerica, T. chebula and T.arjuna had anti-hyperlipidemic activities T.
arjuna the most potent one caused an inhibition of rabbit atheroma after oral administration in hyperlipidemic rabbits [24].

Antioxidant activity
Most Terminalia species were reported to possess an antioxidant activity. The antioxidant activity of the T. arjuna bark was studied and the results of DPPH • assay, superoxide radical scavenging activity and lipid peroxidation assay were comparable with the standard antioxidant ascorbic acid [25]. T. chebula fruit extract possessed a potent antioxidant activity and can be used as a radio-protector as it protected from γ-irradiation-induced oxidative stress in rats by the reduction of radiation-induced cellular DNA damage [26].
The antioxidant activities of the methanolic fruit extract of T. bellerica and its isolated compounds was examined using DPPH • , oxygen radical absorbance capacity (ORAC) and ferric reducing ability of plasma (FRAP) in vitro assays. Chebulic ellagitannins showed the highest antioxidant activity [27]. Moreover, the high antioxidant activity of the aqueous methanolic extracts of the leaves, bark and fruits of T. arjuna, T. bellerica, T. chebula and T. muelleri were attributed to their high phenolic contents (72.00-167.20 mg/g) [28]. C. Flavans D. Flavanones     T. arjuna Stem bark [110] 129

Anti-inflammatory activity
The ethanolic extract of T. phanerophlebia stem as well as its isolated compound β-sitosterol selectively inhibited cyclooxygenase enzyme . The aqueous extract of T. paniculata bark significantly reduced the edema volume in carrageenan-induced rat paw edema [37]. Furthermore, the extract at a dose of 400 mg/kg also reduced the carrageenan-induced leukocyte migration and myeloperoxidase activity in air pouch exudates and exhibited anti-rheumatic and analgesic activities at a dose of 200 mg/kg. T. ferdinandiana fruit had a unique anti-inflammatory activities in lipopolysaccharide-activated murine macrophages, by inhibiting the expression of COX-2 and inducible nitric oxide synthase (iNOS), as well as by inhibiting the production of prostaglandin E 2 [38].
Chebulagic acid from T. chebula seeds, significantly suppressed the onset and progression of collagen-induced arthritis in mice [39]. Moreover, anolignan B isolated from the ethyl acetate root extract of T. sericea possessed an inhibitory activity against both COX-1 and COX-2 enzymes [40]. Punicalagin at a dose of 10 mg/kg and punicalin at a dose of 5 mg/kg isolated from the leaves of T. catappa possessed an anti-inflammatory activity against carrageenan-induced hind paw edema in rats [41]. Ursolic acid and 2α,3β,23-trihydroxyurs-12-en-28oic acid isolated from T. catappa leaf ethanolic extract were responsible for its anti-inflammatory activity, as it caused a significant reduction (over 50%) of the edema induced in mice ear at 0.30 mg/ear dose [42].

Gastroprotective activity
Chebulinic acid isolated from T. chebula fruit showed a gastro protective effect against ulcers induced by cold restraint (62.90% gastro protection), aspirin (55.30%), alcohol (80.67%) and pyloric ligation (66.63%) induced ulcer models. Chebulinic acid significantly reduced free acidity (48.82%), total acidity (38.29%) and upregulated mucin secretion (by 59.75%). Additionally, chebulinic acid significantly inhibited H + K + -ATPase activity in vitro with an IC 50 value of 65.01 μg/ml compared to that of Omeprazole 30.24 μg/ml, proving its antisecretory activity [43]. In addition, the methanolic extract of T. arjuna caused a significant reduction in the lesion index in diclofenac-induced ulcer, and a significant increase in pH, non-protein sulfhydryls, reduced glutathione, protein bound carbohydrate complexes, adherent mucus content with a significant decrease in the volume of gastric juice, free and total acidity, pepsin concentration, acid output, lipid peroxidase levels and myeloperoxidase activities [44]. The ethanolic extract of T. pallida exhibited a significant anti-ulcer activity against indomethacin, histamine and ethanol in Swiss albino rats by enhancing the antioxidant state of the gastric mucosa, thereby reducing mucosal damage [45].

Antimicrobial and Antiviral activity
Various Terminalia species were reported to exert a potent antimicrobial effect on different microorganism. T. chebula water extract had a significant antibacterial activity on Helicobactor pylori with MIC and MBC of 125 and 150 μg/ml respectively [46]. Additionally, the acetone extract of T. chebula exhibited a potent antibacterial activity on Enterococcus faecalis, Bacillus sabtilis and Klebsiella pneumoniae bacterias [47]. Casuarinin isolated from the bark of T. arjuna, showed a strong antiviral activity on Herpes simplex type 2 at a concentration of 25 μM and reduced the viral titers up to 100,000-fold by inhibiting the viral attachment and penetration [48]. Recently, Fyhrquist reported that the methanolic root and stem bark extracts of T. sambesiaca showed lower MIC values than its aqueous, butanol and chloroform fractions against mycobacterium [49]. The strong antibacterial activity of T. muelleri ethylacetate leaf extract was attributed to its gallic acid content [50].

Cytotoxic activity
T. chebula methanolic fruit extract showed a reduction in cell viability, inhibition of cell proliferation, and induction of cell death in a dose-dependent manner on many malignant cell lines. In addition, it induced apoptosis at lower concentrations, and necrosis at higher concentrations. Chebulinic acid, tannic acid and ellagic acid, with IC 50 values of 53.20, 59.00 and 78.50 µg/ml respectively, were the most cytotoxic compounds of T. chebula fruit [59]. Furthermore, chebulagic acid isolated from the T. chebula fruit extract possessed an antiproliferative activity against HCT-15, COLO-205, MDA-MB-231, DU-145 and K562 cell lines [60]. T. catappa leaf water extract, along with its isolated component punicalagin were effective against bleomycininduced genotoxicity in Chinese hamster ovary cells [61]. Furthermore, T. catappa leaf extract exerted a dose-dependent inhibitory effect on the invasion and motility of highly metastatic A549 and Lewis lung carcinoma cells [62]. Moreover, the ethanol extract of T. catappa leaves significantly inhibited the cell migration capacity of oral squamous cell carcinoma cells [63]. Luteolin, gallic acid and gallic acid ethyl ester isolated from the bark, stem and leaves of T. arjuna methanolic extract possessed a strong antineoplastic activity [64]. Moreover, ivorenoside C isolated from the bark of T. ivorensis had an antiproliferative activity against MDA-MB-231 and HCT116 human cancer cell lines with IC 50 values of 3.96 and 3.43 μM respectively [65]. Additionally, the acetone extract of T. calamansanai leaves inhibited the viability of HL-60 cells [66].

Cardioprotective activity
T. arjuna bark has been used widely in traditional medicine as a cardioprotective. The ethanolic extract of T. arjuna bark enhanced the cardiac intracellular antioxidant status in CCl 4 -induced oxidative stress in rats [67]. The protective effect was comparable to that of vitamin C.
In addition, The butanol fraction of T. arjuna bark extract exhibited a protective effect against doxorubicin-induced cardiotoxicity by increasing cardiac antioxidant enzymes, decreasing serum creatine kinase-MB levels and reducing lipid peroxidation [68]. Many clinical trials were also conducted to prove the beneficial effect of T. arjuna bark on the heart. A group of scientists showed that patients with refractory chronic congestive heart failure, when received T. arjuna bark extract as an adjuvant therapy, showed a long lasting improvement in the signs and symptoms of heart failure with an improvement in left ventricular ejection phase indices and quality of life [69]. Moreover, a clinical study was done to evaluate the role of T. arjuna in ischemic mitral regurgitation (IMR) following acute myocardial infarction. Patients receiving adjuvant T. arjuna showed significant decrease in IMR and reduction in anginal frequency [70]. In addition, pretreatment with T. pallida fruit extract ameliorated myocardial injury in isoproterenolinduced myocardial infarction in rats and exhibited cardioprotective activity [71]. Similarly, pretreatment with T. chebula extract ameliorated the effect of isoproterenol on lipid peroxide formation [72].

Anti-hypertensive activity
T. superba bark extract showed a potent antihypertensive activity in spontaneously hypertensive rats, as well as in glucose-induced hypertensive rats due to the withdrawal of sympathetic tone and the improvement of the antioxidant status [73,74].

Antiparasitic and molluscicidal activity
The in vitro nematicidal activity of T. nigrovenulosa bark against Meloidogyne incognita was attributed to 3,4-dihydroxybenzoic acid isolated from it. [75]. The ethyl acetate, acetone and methanol leaf and seed extracts of T. chebula showed in vitro ovicidal and larvicidal activities on Haemonchus contortus [76]. In addition, T. chebula fruit molluscicidal activity was due its tannic acid content that significantly inhibited the AChE, ACP and ALP activity in the nervous tissue of freshwater snail Lymnaea acuminate [77]. Additionally, ethanolic leaf extract of T. catappa possessed a molluscicidal activity against the snail intermediate hosts of schistosomiasis (Biomphalaria pfeifferi and Bulinus globosus) with B. pfeifferi being more susceptible [78].

Wound healing activity
Topical administration of T. chebula alcoholic leaf extract on the rat dermal wounds showed a beneficial effect in the acceleration of the healing process, by increasing the tensile strength of tissues by about 40% and decreasing the period of epithelialization [79]. Moreover, the tannin-rich fraction obtained from T. chebula fruits endorsed wound healing in rats due to the powerful antibacterial and angiogenic activity of the extract [80]. Topical application of T. arjuna hydro-alcholic extract resulted in a significant increase in the tensile strength of the incision wounds and epithelialization of excision wounds. This wound healing property was more pronounced in the tannin-rich fraction compared to the other fractions [81].

Conclusion
An extensive literature survey on genus Terminalia has revealed a variety of chemical constituents produced by this genus. Tannins, flavonoids, phenolic acids, triterpenes, triterpenoidal glycosides, lignan and lignan derivatives constitute the major classes of phytoconstituents of this genus . In addition, the current review showed that most of the biological studies performed on different extracts and isolated compounds from different species of Terminalia were focused on the assessment of the antimicrobial, antioxidant, hepatoprotective, anti- Although many phytochemical and biological investigations were reported from the genus Terminalia, the studies have focused mainly on certain species, with chebula, bellerica, arjuna, catappa, horrida, superba, macroptera, pallida, ivorensis, sericea and alata being the most phytochemically and biologically studied species, leaving a fertile area for further investigations on other species that have not been fully explored yet . The present review provides a comprehensive understanding of the chemistry and biology of different Terminalia species, which may help in the discovery and development of new alternative medications for the treatment of various diseases and health problems.

Declaration of Interest
The authors have declared no conflicts of interest.