The Genus Terminalia (Combretaceae): An Ethnopharmacological, Phytochemical and Pharmacological Review

Terminalia Linn, a genus of mostly medium or large trees in the family Combretaceae with about 250 species in the world, is distributed mainly in southern Asia, Himalayas, Madagascar, Australia, and the tropical and subtropical regions of Africa. Many species are used widely in many traditional medicinal systems, e.g., traditional Chinese medicine, Tibetan medicine, and Indian Ayurvedic medicine practices. So far, about 39 species have been phytochemically studied, which led to the identification of 368 compounds, including terpenoids, tannins, flavonoids, phenylpropanoids, simple phenolics and so on. Some of the isolates showed various bioactivities, in vitro or in vivo, such as antitumor, anti HIV-1, antifungal, antimicrobial, antimalarial, antioxidant, diarrhea and analgesic. This review covers research articles from 1934 to 2018, retrieved from SciFinder, Wikipedia, Google Scholar, Chinese Knowledge Network and Baidu Scholar by using “Terminalia” as the search term (“all fields”) with no specific time frame setting for the search. Thirty-nine important medicinal and edible Terminalia species were selected and summarized on their geographical distribution, traditional uses, phytochemistry and related pharmacological activities.


Introduction
Terminalia Linn, comprising about 250 species in the world mostly as medium or large trees, is the second largest genus in the family Combretaceae. The name "Terminalia" is derived from Latin word "terminus", which means the leaves are located at the tip of the branch. The bark of Terminalia plants usually has cracks and branches tucked into layers. Most of the Terminalia plants' leaves are large, leathery 1 3 with solitary or clustered small green white flowers. Their fruits are yellow, dark red or black; drupe, usually angular or winged. Some fruits are edible, highly nutritious and possess medicinal values.
Terminalia species are widely distributed in the southern Asia, Himalayas, Madagascar, Australia, and the tropical and subtropical regions of Africa. Terminalia plants in southern Asia have been intensively studied phytochemically due to their wide usage in Asian (India, Tibetan, and Chinese) traditional medicine systems [1]. For example, the fruits of Terminalia bellirica and Terminalia chebula, together with Phyllanthus emblica (Euphorbiaceae) which form the herbal remedy, Triphala, in Tibetan medicine, have received much attention because of its extensive and remarkable effectiveness in the treatment of anticancer, antifungal, antimicrobial, antimalarial, antioxidant.
So far, 39 Terminalia species have been investigated for their phytochemical constituents, which resulted in the identification of terpenes, tannins, flavonoids, lignans and simple phenols, amongst others. Pharmacological studies suggest that they have exhibited activity on liver and kidney protection, antibacterial, antiinflammatory, anticancer, and have displayed a positive effect on immune regulation, cardiovascular disease and diabetes, and acceleration of wound healing.
This paper features 39 important medicinal and edible Terminalia species and summarizes their traditional usage, geographical distribution, structures of isolated chemical constituents and pharmacological activities.

Species' Description, Distribution and Traditional Uses
So far, 50 Terminalia species have been documented, 39 Table 1.
Terminalia species are broadly used in many aspects. Some are employed as drugs, while others can provide high quality wood, tannin or dyes. For example, fruits of T. ferdinandiana, a species largely distributed in Australia, are rich in vitamin C, and possess strong antioxidant activity [25]. T. bellirica and T. chebula are not only recorded in every version of Chinese pharmacopoeia, but are also the important and most commonly applied drugs in Han, Tibetan, Mongolian and many other folk medicinal systems in India, Burma, Thailand, Malaysia, Vietnam and other southeast asian countries. T. catappa is a commonly used medicinal plant for liver protection in China [20].

Phenols and Glycosides
There are 52 phenols and glycosides reported in the Terminalia genus (Fig. 5), in which ellagic acid (268) and gallic acid (289) are present in almost all species. Studies have shown that most of the simple phenolic compounds have antioxidant, antibacterial, hypoglycemic, liver and kidney protection [23].

Other Compounds
Other compounds featured in the Terminalia genus are shown in Fig. 8 and are mostly styrenes. Cao et al. isolated two new cytotoxic xanthones -termicalcicolanone A (365), termicalcicolanone B (366) in T. calcicola, and found an inhibitory effect on ovarian cancer [19]. Hiroko Negishi et al. obtained a new chromone derivative -terminalianone (364) from the barks of Terminalia brownii [98]. Ansari et al. isolated the novel compound, 4′-substituted benzoylβ-d glycoside (368), from the fruits of T. bellirica and illustrated its potential for anticoagulation [160].
Moreover, chlorophyll and various vitamins were reported from the genus Terminalia.

Pharmacological Activities
The pharmacological activities of the genus Terminalia, mainly including antimicrobial, antioxidant, cytotoxicity, anti-inflammatory, hypoglycemic, cardiovascular, mosquitocidal and antiviral, have been extensively studied.
TaB contains various natural antioxidants and has been used to protect animal cells against oxidative stress. The alleviating effect of TaB aqueous extract against Ni toxicity in rice (Oryza sativa L.) suggested that TaB extract considerably alleviated Ni toxicity in rice seedlings by preventing Ni uptake and reducing oxidative stress in the seedlings [162]. Behavioral paradigms and PCR studies of TaB extract against picrotoxin-induced anxiety showed that TaB supplementation increased locomotion towards open arm (EPM), illuminated area (light-dark box test), and increased rearing frequency (open field test) in a dose dependent manner, compared to picrotoxin (P < 0.05). Furthermore, alcoholic extract of TaB showed protective activity against picrotoxin in mice by modulation of genes related to synaptic plasticity, neurotransmitters, and antioxidant enzymes [174].  . 115 and 147 induced a decrease of the human poly (ADP-ribose) polymerase (PARP) cleavagerelated procaspase-3 and elevated activity of caspase-3 in HL-60 cells, but not normal human peripheral blood mononuclear cells, PBMCs [18].
Aqueous and ethanolic extracts of T. citrina fruits were revealed to exhibit significant mutagenicity in tested strains of baby hamster kidney cell line (BHK-21). Ethanolic extract showed higher mutagenicity in TA 100 strain, whereas aqueous extract exhibited higher mutagenicity in TA 102 strain than TA 100. Both extracts showed dose-dependent

Anti-inflammatory
Inflammation has been considered as a major risk factor for various kinds of human diseases. Macrophages play substantial roles in host defense against infection. It can be activated by LPS, the major component of the outer membrane of Gram-negative bacteria. An investigation was carried out to determine anti-inflammatory potential of ethyl acetate fraction isolated from T. bellirica (EFTB) in LPS stimulated RAW 264.7 macrophage cell lines. EFTB (100 μg/mL) inhibited all inflammatory markers in dose dependent manner. Moreover, EFTB down regulated the mRNA expression of TNF-α, IL-6, COX-2 and NF-κB against LPS stimulation. These results demonstrated that EFTB is able to attenuate inflammatory response possibly via suppression of ROS and NO species, inhibiting the production of arachidonic acid metabolites, proinflammatory mediators and cytokines release [165].
Anolignan B (242) isolated from roots of T. sericea was tested for anti-inflammatory activity using the cyclooxygenase enzyme assays (COX-1 and COX-2) It showed activity against both COX-1 (IC 50 = 1.5 mM) and COX-2 (IC 50 = 7.5 mM) enzymes [151]. Termiarjunosides I (47) and II (48) isolated from stem barks of T. arjuna inhibited aggregation of platelets and suppressed the release of NO and superoxide from macrophages [156].

Cardiovascular
A few species of Terminalia have demonstrated cardiovascular activities. It was reported that the barks of T. arjuna possessed significant inotropic and hypotensive effect, mild diuretic, antithrombotic, prostaglandin E2 enhancing and hypolipidaemic activities [66].
Ethanolic extract of T. pallida fruits (TpFE) were studied to determine their cardioprotection against isoproterenol (ISO)-administered rats. The supplementation of TpFE dose-dependently exerts notable protection on myocardium by virtue of its strong antioxidant activity. It could be used as a medicinal food for the treatment of cardiovascular ailments [163].

Mosquitocidal
Insect-borne diseases remain to this day a major source of illness and can cause death worldwide. The resistance to chemical insecticides among mosquito species has been a major problem in vector control. The larvicidal and ovicidal activities of crude benzene, hexane, ethyl acetate, chloroform and methanol extracts of T. chebula were tested for their toxicity against three important vector mosquitoes, viz., Anopheles stephensi, Aedes aegypti and Culex quinquefasciatus. All extracts showed moderate larvicidal effects, the highest larval mortality was found in the methanol extract of T. chebula against the larvae of A. stephensi, A. aegypti, and C. quinquefasciatus with the LC 50 values of 87.13, 93.24 and 111.98 ppm, respectively. Mean percent hatchability of the ovicidal activity was observed 48 h post treatment. All the five solvent extracts showed moderate ovicidal activity. The maximum egg mortality (zero hatchability) was observed in the methanol extract of T. chebula at 200 and 250 ppm against A. stephensi, while A. aegypti and C. quinquefasciatus showed 100% mortality at 300 ppm. No mortality was observed in the control group. The finding of the investigation revealed that the leaf extract of T. chebula possesses remarkable larvicidal and ovicidal activity against medically important vector mosquitoes [167,168].
In vitro anti-HIV-1 activity of acetone and methanol extracts of T. paniculata fruits was studied by Durge A. et al. Cytotoxicity tests were conducted on TZM-bl cells and PBMCs, the CC 50 values of both extracts were ≥ 260 μg/ mL. By using TZM-bl cells, the extracts were tested for their ability to inhibit replication of two primary isolates HIV-1 (X4, Subtype D) and HIV-1 (R5, Subtype C). The activity against HIV-1 primary isolate (R5, Subtype C) was confirmed by using activated PBMC and quantification of HIV-1 p24 antigen. Both the extracts showed anti-HIV-1 activity in a dose-dependent manner. The EC 50 values of the acetone and methanol extracts of T. paniculata were ≤ 10.3 μg/ mL. Furthermore, the enzymatic assays were performed to determine the mechanism of action which indicated that the anti-HIV-1 activity might be due to inhibition of reverse transcriptase (≥ 77.7% inhibition) and protease (≥ 69.9% inhibition) enzymes [172].

Conclusion and Future Prospects
The genus Terminalia contains not only a large number of tannins, simple phenolics, but also a lot of terpenoids, flavonoids, lignans and other compounds. Most tannins, simple phenolics and flavonoids have antioxidation, antibacterial, antiinflammatory and anticancer activities. The plants of the genus Terminalia have exhibited positive effect on immune regulation, cardiovascular disease and diabetes, and can accelerate wound healing [157]. Therefore, the Terminalia genus has great medicinal potential. However, most of the chemical composition of species is still unknown, we should use modern advanced technology such as LC-MS to continue to isolate its compounds, and determine their pharmacological activities and mechanism of action, to explore other possible greater medicinal value.