A Review on Ethnopharmacological Applications, Pharmacological Activities, and Bioactive Compounds of Mangifera indica (Mango)

Mangifera indica (family Anacardiaceae), commonly known as mango, is a pharmacologically, ethnomedically, and phytochemically diverse plant. Various parts of M. indica tree have been used in traditional medicine for the treatment of different ailments, and a number of bioactive phytochemical constituents of M. indica have been reported, namely, polyphenols, terpenes, sterols, carotenoids, vitamins, and amino acids, and so forth. Several studies have proven the pharmacological potential of different parts of mango trees such as leaves, bark, fruit peel and flesh, roots, and flowers as anticancer, anti-inflammatory, antidiabetic, antioxidant, antibacterial, antifungal, anthelmintic, gastroprotective, hepatoprotective, immunomodulatory, antiplasmodial, and antihyperlipemic. In the present review, a comprehensive study on ethnopharmacological applications, pharmacological activities, and bioactive compounds of M. indica has been described.


Introduction
M. indica L. is considered as one of the main tropical fruits in the world believed to be originated from Asia [1]. It has been reported that China, India, Brazil, Nigeria, Pakistan, Mexico, Thailand, and Philippine are well-known for mango cultivation with India being the highest mango cultivating country [2]. World production of mango is approximately 42 million tons per year which is second only to banana production. There are about 1000 mango varieties grown all over the world [2][3][4]. Mango is known by various names around the world, for example, Manja in Arabic, Mannko in Greek, Am or Ambi in Hindi, Amba in Sinhala, Mangue in French, Mango in Finnish, Mango in Dutch, Mangue in German, Mángguǒin in Chinese, and Mampalam in Tamil [5]. Both ripe or unripe mango fruits are in human use as pickles, juice, oils, nectar, powder, sauce, cereal flakes, and jam [6]. Mango fruit peel and flesh are reported to be a rich source of fiber, vitamin C and A, essential amino acids, and polyphenols [7]. Mango seed has also been reported as a rich source of polyphenols [8]. Despites the common use of mango fruit as a food item, various parts of mango trees have also been used for medical purposes since ancient times, mostly in Southeast Asian and African countries [9]. Much evidence is found in literature on pharmacological and ethnomedicinal uses of M. indica; however, there is no complete review on phytochemicals, biological effects of phytochemicals, and pharmacological and ethnomedicinal properties of M. indica. Therefore, we present this review as an up-to-date and comprehensive evaluation which mainly includes phytochemicals, some reported bioactivities of phytochemicals, and pharmacological and ethnomedicinal properties of M. indica. with M. indica being the most common species in the same genus [10,11]. M. indica plant is an evergreen broad canopy tree which grows to a height of 8-40 m [12]. M. indica bark is a thick brown-gray colour and is superficially cracked [13]. Leaves are 15-45 cm in length with variable sizes [13]. Leaf petiole has a variable length from 1-10 cm [13]. M. indica leaves (Figure 1) possess different shapes (lanceolate, ovate-lanceolate, linear-oblong, roundish-oblong, oval, and oblong) [13]. Green, red, and yellow leaves are seen in some mango varieties and upper leaf surfaces are normally shiny [13,14]. In case of M. indica flowers, male and hermaphrodite flowers are produced in the same panicle; its size can vary from 6-8 mm in diameter. There are about 4000-5000 small flowers in panicles with red/purple spots on petals [13,14]. Even though a large number of flowers present in panicles, very few will be developed as fruits. Flowering season is mainly from January to April and most of the flowers are subsessile and have a sweet smell. M. indica fruit ( Figure 1) is drupe with different sizes, shapes, and colours. Fruit peel is green, yellow, red, or orange. Seeds are ovoid-or oblongshaped covered with a hard endocarp having a woody fiber covering [15].

Ethnomedicinal Use
Various parts of M. indica (bark, leaves, roots, fruits, and flowers) have been used in traditional medicine for the treatment of various diseases and conditions. Ethnomedicinal uses of various parts of M. indica in different countries in the world have been summarized in Table 1.

Phytochemicals in M. indica.
A large variety of chemical compounds have been reported in M. indica [30]. Among these, polyphenols (flavonoids, xanthones, and phenolic acids) are the most abundant compound types in M. indica [31]. Mangiferin, gallic acid, catechins, quercetin, kaempferol, protocatechuic acid, ellagic acids, propyl and methyl gallate, rhamnetin, and anthocyanins are the major polyphenolic compounds found in M. indica [32]. Mangiferin is a wellknown polyphenolic compound which has been extensively studied for its numerous biological properties [33]. The quantities of different polyphenols in mango depend on the part and variety of mango [34]. Antioxidant properties have been shown to be the main biological property of almost all the M. indica polyphenols [35]. Ascorbic acid and dehydroascorbic acid (oxidized form of ascorbic acid) are two other common polyphenols found in M. indica [36]. The amount of polyphenols is high in many parts of M. indica. Thus, a pure compound alone has been proven to be less effective than crude drugs, implying that the synergism of many M. indica polyphenols is essential for optimum biological activities [37,38]. Carotenoids are another class of natural compounds found in plants. They are considered as natural organic pigments [39]. The bright yellow colour of M. indica fruit peel and flesh is due to the presence of carotenoids [39]. Biologically they are very good free radical scavengers [40]. It has been reported that carotenoids in M. indica are biosynthesized in the fruit and carotenoid concentration rises upon ripening [41]. -carotene, luteoxanthin, violaxanthin, neoxanthin, zeaxanthin, and cryptoxanthin are the main carotenoids found in M. indica fruit flesh and peel [42]. Among these, -carotene is the most abundant [42].
Terpenoids are a class of lipids, similar to terpenes, commonly found in the plant kingdom [43]. M. indica is reported to contain several terpenoids, including careen, ocimene, terpinolene, myrcene, or limonene [44]. These terpenoids are volatile and responsible for aroma in M. indica [45]. Lupeol and lupeollinoleate are two other common triterpenoids found in mango [46]. Gallotannins (hydrolyzable tannins) are another class of chemical compounds found in M. indica bark, leaves, kernel, and fruit pulp [47]. The presence of tocopherols in M. indica has also been reported. Alpha-tocopherol, betatocopherol, and gamma-tocopherol are commonly found tocopherols in M. indica fruit peel and flesh [48]. Resorcinolic Evidence-Based Complementary and Alternative Medicine 3  [49]. The isolation of a wide range of resorcinolic lipids with different biological properties has been reported from M. indica fruit peels, flesh, and bark [49]. The isolation of a novel resorcinolic lipid from the bark of Mangifera zeylanica (endemic Sri Lankan mango) with anticancer effects has been presented in a study carried out by us [50]. It was thought that halogenated compounds are limited only to marine plants and microorganisms. However, occurrence of halogenated compounds in the bark of M. indica has been reported in a study conducted in India [51].
A recent study carried out by us also reported the isolation of two novel halogenated compounds (chloromangiferamide and bromomangiferic acid) from the bark of M. zeylanica [52]. Structures of some common compounds present in M. indica are shown in Figures 2(a) and 2(b). Quercetin and mangiferin are most commonly found in M. indica. As these two compounds containing food items (including mango fruits) are very common in human diet, studies on their safety and toxicity have been well-documented [17,[53][54][55]. Moreover, kaempferol, another well-known mango compound, has also been subjected to various safety and toxicity studies in order to validate its uses in human diet [56][57][58]. In most of the studies it has been mentioned that quercetin mangiferin and kaempferol are less toxic in studied animal models.  It has been reported that reactive oxygen species (ROS) and some other oxidants cause various disorders and diseases to human [71]. Humans possess antioxidative mechanisms which fight against reactive oxygen species (ROS) and some other oxidants by deactivating free radicals before they attack targets in human body [72]. Naturally occurring antioxidants have gained much attention recently as they possess a remarkable ability to fight against free radicals and reactive 6 Evidence-Based Complementary and Alternative Medicine oxygen species [72]. As almost all the parts of the mango tree are reported to possess polyphenols, which are wellknown antioxidants, most of the pharmacological studies have proven that antioxidant properties with extract(s) of various parts of the M. indica tree are related to polyphenolic content. The following section will summarize some selected studies which illustrate antioxidant effects of different parts of M. indica. A recent study carried out by Thambi et al. 2016 [73] evaluated antioxidant effects of mango peel powder and proved that the acetone extract of the M. indica peel exerts strong radical scavenging effects. A research carried out by Abbasi et al. 2017 [74] with nine mango varieties (Royal mango, Thai mango, Egg mango, Luzon, Narcissus, Big Tainong, Keitt, Australian mango, and Small Tainong) found in China found that the peel of Small Tainong (Xiao Tainong) variety exerts the highest antioxidant potential among the tested varieties. Another study conducted by Sultana et al. 2012 [75] measured the antioxidant potential of water-methanol extracts of the peels of two mango varieties (Langra and Chaunsa) grown in Pakistan. Among these two peel extracts, water-methanol extract of Chaunsa exhibited strong antioxidant effects than Langra. Kim et al. 2010 [76] who studied antioxidant effects of ethanolic extracts of mango peel and flesh showed potent antioxidant effects of mango peel extracts compared to flesh extracts. Effect of temperature on the antioxidant activity of mango peel extracts (a variety found in Spain) was studied by Dorta et al. 2012 [77]. Methanol, ethanol, acetone, water, methanol-water, acetone-water, and ethanol-water extracts were subjected to radical scavenging activity and methanol-water, acetonewater and ethanol-water extracts were found to possess high antioxidant capacity when the temperature is increased from 50−70 ∘ C. A number of studies around the world have evaluated the antioxidant effects of mango fruit flesh. A study conducted with methanol extracts of fruit flesh of two mango varieties (Americana and Jose) grown in France by Septembre-Malaterre et al. 2016 [78] has shown that methanol extracts of both these varieties exert antioxidant effects. A comparative study has been carried out with fruit flesh of five mango varieties (Langara, Fazli, Amrupali, Himsagor, and Ashwina) grown in Bangaladesh [79]. Methanolic extracts of all the tested mango varieties exerted considerable antioxidant effects and the fruit flesh extract of Langra exerted the highest effect. Another comparative study carried out with methanol/dichloromethane and aqueous extracts of fruit flesh of four Egyptian mango varieties (Zebdia, Sukkari, Taimor, and Hindi) showed that methanol/dichloromethane extracts of all the varieties have prominent antioxidant effects than the aqueous extracts [80]. Antioxidant potential of ethanolic extract of the seed of an M. indica variety grown in Malaysia has been reported by Norshazila et al. 2010 [81]. Pitchaon, 2011 [82], has demonstrated antioxidant capacity of seed kernel obtained from a mango variety (Chok-Anan) grown in Thailand. Two kernel extracts have been prepared by acid hydrolysis and shaking in ethanol. The results of this study showed that the extract prepared by acid hydrolysis has a high antioxidant potential than the extract prepared by shaking in ethanol. Sultana et al. 2012 [75] have presented antioxidant potential of water-methanol extracts of the bark of two M. indica varieties (Langra and Chaunsa) grown in Pakistan. The bark of the variety Chaunsa exerted a higher antioxidant potential than Langra. Antioxidant effects of methanolic extract of M. indica leaves have been reported by Mohan et al. 2013 [83]. They showed that ethyl acetate and butanol fractions obtained after solvent partition of the crude methanol extract have antioxidant effects.

Anti-Inflammatory Effects of M. indica.
Several naturally found polyphenols are reported to possess anti-inflammatory effects via inhibition of nuclear factor kappa-B (NF-B) [84]. However, anti-inflammatory activities of these compounds depend on their chemical structures and their cellular targets [84]. Production of a large amount of proinflammatory cytokines (IL-1, 2 and 6 and TNF) increase the expression of enzymes such as COX-2 and iNOS which are associated with anti-inflammations [85]. Nuclear factor kappa-B (NF-B), a transcriptional factor, is reported to control expression of proinflammatory cytokines [86]. Ulcerative colitis and inflammatory bowel disease are considered as main diseases that occur due to chronic inflammation [87]. Several studies have shown that mango extracts can exert anti-inflammatory effects in experimental models of ulcerative colitis. In a recent study, treatment with a mango beverage prepared from fruit (Mexican variety) which consists of polyphenols and vitamins has caused attenuation of colitis symptoms by expressing the PI3K/AKT/mTOR pathway [88]. Another study conducted by the same authors showed that the same mango polyphenols-rich beverage can inhibit the IGF-1R/AKT/mTOR pathway in ulcerative colitis [89]. In another study, aqueous extract of stem-bark extract from M. indica rich in polyphenols and flavonoids was found to attenuate colitis symptoms in a model of colitis [90]. Attenuation of symptoms was accompanied by a reduction in COX-2, TNFR-2, TNF-, and iNOS levels in colonic tissue. Gout is considered as one of the most common causes of inflammatory arthritis. Deposition of monosodium urate crystals on local tissue and joints is the major clinical manifestation of gout [91]. Antigouty arthritis effects of ethanol extract of M. indica leaves have been studied by Jiang et al. 2012 [91]. Oral administration of ethanol extract of M. indica leaves has caused reduction in IL-1 and TNF-mRNA levels and ankle swelling in a rat with gouty arthritis induced by monosodium urate [91].
Vimang is an aqueous extract of M. indica (stem-bark) used in Cuba as a natural supplement [92]. A number of in vivo and in vitro studies have been conducted with Vimang to demonstrate its antioxidant effects. A study carried out by Garrido et al., 2004 [92], has shown that administration of Vimang can reduce arachidonic acid (AA) and phorbolmyristate acetate-induced ear edema in mice. Reduction in myeloperoxidase (MPO) activity was observed in phorbolmyristate acetate-induced mice. Inhibition of tumor necrosis factor alpha (TNF) serum levels was also observed in both models of inflammation after administration of Vimang. In vitro evaluations carried out with Vimang have shown that it can inhibit PGE2 (prostaglandin E2) or LTB4 (Leukotriene B4) in macrophage cells (RAW264.7) induced with proinflammatory stimuli. Another study conducted Evidence-Based Complementary and Alternative Medicine 7 by Garrido et al., 2001 [93], has also shown possible anti-inflammatory effects of Vimang. Carrageenan and formalin-induced oedema in mice were used to study antiinflammatory effects in this study. Results of this study have shown that Vimang can significantly inhibit carrageenan-and formalin-induced oedema (in rat, guinea pigs, and mice). Moreover, Garrido et al., 2004 [94], have shown for the first time that Vimang can block TNF (tumor necrosis factor alpha) and inhibit the production of NO (nitric oxide) in macrophages (RAW264.7 and N9) and in mice model of septic shock. Martnez et al., 2000 [95], have evaluated in vitro antioxidant effects of Vimang with the help of some commonly accepted assays. Strong radical scavenging activity and a significant inhibition of peroxidation of rat-brain phospholipids by Vimang were observed in this study.
Neuroprotective efficacy of mangiferin in doxorubicin (DOX)-induced rats has been studied by Siswanto et al., 2016 [96]. Brain damage in male Sprague-Dawley rats has been induced by doxorubicin, and mangiferin has been given to brain damage-induced rats for 7 weeks. Results of this study have shown that mangiferin can effectively reverse the brain damage induced by doxorubicin. Cognitive enhancing effects and improvement in memory impairment by M. indica fruit pulp extract (ethanol) were studied by Wattanathorn et al., 2014 [97]. To determine cognitive enhancing effects and improvement in memory impairment, male Wistar rats have been administered with the neurotoxin AF64A and given the fruit peel extract. Results of the study have shown increased cholinergic neurons density and decreased oxidative stress in rates, which illustrates possible cognitive enhancing effects of M. indica fruit pulp. Neuroprotective activities of methanol and aqueous extracts of M. indica leaf have been studied by Kawpoomhae et al., 2010 [98]. Neuroprotective effects of methanol and aqueous extracts were evaluated by determining protection of neuroblastoma cells from H 2 O 2 -induced oxidative damage and results showed that methanol extract and aqueous extract can effectively protect H 2 O 2 -induced neuroblastoma cells from oxidative damage.
Liver, a vital organ in the human body, mainly regulates metabolism and detoxification of toxic substances [166]. It plays an important role by removing reactive oxygen species (ROS) and helps maintains oxidative balance [167]. A number of chemical substances that cause hepatotoxicity by inducing oxidative damage and lipid peroxidation have been identified [168]. Hepatotoxicity is currently treated with drugs that can activate p450 enzyme mechanism either by stopping or inducing the metabolic activity of enzymes [169]. Investigation of phytochemicals with hepatoprotective effects and their mechanism of action has gained much attention. Many authors have investigated hepatoprotective effects of certain plant extracts/pure compounds including M. indica. Ebeid et al. 2015 [170] have demonstrated hepatoprotective effects of an aqueous extract of leaves of an M. indica variety found in Egypt where they found that the aqueous extract successfully inhibited CCl 4 -induced hepatocellular toxicity in albino rats. Results were further confirmed by analyzing lipid profiles, high-density lipoprotein (HDL), and malondialdehyde (MDA) levels. An in vitro study carried out by Hiraganahalli et al. 2012 [171] has shown that methanol/acetone extract of M. indica bark can exert hepatoprotective effects in tert-butyl hydroperoxide-induced HepG2 cells in a dosedependent manner. Hepatoprotective effects of lupeol and aqueous M. indica pulp extract (collected from Lucknow, India) have been studied in 7,12-Dimethylbenz[a]anthracene (DMBA)-induced Swiss albino mice. Lupeol and mango M. indica extract were found to be effective in the treatment of liver injury caused by oxidative stress [172]. Pourahmad et al. 2010 [173] investigated hepatoprotective effects of an aqueous extract of a mango fruit variety collected from Iran and demonstrated that the extract exerts hepatoprotective effects in cumene hydroperoxide-induced rat hepatocytes. Hepatoprotective effects of an ethanolic extract of kernel of a Thai M. indica variety have been also reported by Nithitanakool et al. 2009 [174]. Significant hepatoprotective effects of the ethanolic extract of kernel have been reported in rats with liver injuries induced by carbon tetrachloride (CCl 4 ).

Analgesic Effects.
Analgesic effects of stem-bark aqueous extract of M. indica have been studied by Ojewole, 2005 [175]. Hot-plate and acetic acid test models of pain in mice have been used to study analgesic effects, and results of this study have demonstrated significant analgesic effects in mice with nociceptive pain. Islam et al. 2010 [176], have demonstrated analgesic effects of methanol extract of leaves of M. indica. Results have demonstrated a significant reduction in writhing response in an acetic acid-induced writhing response rat model. Garrido et al., 2001 [93], have shown possible analgesic effects of Vimang. Acetic acid-induced abdominal restriction and formalin-induced licking were used to test analgesia. Results of this study have shown that Vimang can exhibit antinociceptive effects in mice. Moreover, a considerable dose-dependent inhibition in formalin-induced pain was also observed in rats after administration of Vimang.

Immunomodulatory Effects of M. indica.
Immunomodulation is a process that adjusts the immune system of an organism upon any change caused by a foreign agent [177]. Immunomodulation can be of two types, namely immunostimulation and immunosuppression [178]. Immunostimulation includes stimulation of the immune system with immunostimulating agents that activate components of the immune system (macrophages, certain T-lymphocytes and granulocytes) [178]. In immunosuppression, efficiency of the immune system decreases [178]. As clinically used immunomodulating drugs cause serious side effects, it is necessary to discover immunomodulating agents with fewer side effects [179]. Garrido et al. 2005 [180] have shown immunomodulatory activity of bark aqueous extract of a mango variety collected from Cuba. Inhibition of proliferation of Tcells and NF-B transcription factor were reported in this in vitro study suggesting possible immunomodulation. Another study conducted in Cuba with an aqueous extract of mango bark has also shown in vivo immunomodulatory effects, where NOS-2, COX-2, IL-1 , TNF-, and colony-stimulating factor (GM-CSF) mRNA levels were found to decrease in experimental mice model(s) [181]. Makare et al. 2001 [182] have assessed immunomodulatory effects of an ethanolic extract of mango bark rich in mangiferin in Swiss 8 Evidence-Based Complementary and Alternative Medicine albino mice. Administration of the ethanolic bark extract increased delayed type hypersensitivity (DTH) and humoral antibody (HA) titer suggesting possible immunostimulation by the extract. Immunostimulatory effects of a mango kernel powder in a species of fish (Labeo rohita) infected with Aeromonas hydrophila have been studied by Sahu et al. 2007 [183], where increased immunological parameters (lysozyme activity, superoxide anion production, and bactericidal activity) were detected in fish fed with mango kernel powder. Moreover, a recent study has shown that a hexane leaf extract from M. indica collected from Varanasi, India, possesses immunomodulatory effects in RAW 264.7 cells. Immunomodulatory effects were confirmed by analyzing intracellular NO levels, where a significant increase in response to the leaf hexane extract was observed. Furthermore, oral administration of the leaf hexane extract has also caused increased white blood cells, hemoglobin concentration, and temporary increase in the size of spleen and thymus in cyclophosphamide-induced myelosuppressed mice, which indicates immunostimulation in bone marrow hematopoietic cells and white blood cells [184].

Antitumoral Effects of M. indica.
Cancer is considered as one of the major causes of death in the world and any practical solution in fighting this dreadful disease would be very important in public health [185]. It is the main cause of death in economically developed countries and the second leading cause of death in economically developing countries [186]. Cancer is caused by several factors such as chemicals, radiations, tobacco, infectious microorganisms, hormones, gene mutations, and immune conditions [187]. Though, modern surgeries have considerably reduced the cancer death rates, use of radiotherapy, chemotherapy, and hormone therapy treatments cannot completely reduce the number of deaths due to cancer [188]. Plant-based treatments have been used in traditional medicine to treat different diseases including cancer since ancient times and a number of in vitro and in vivo studies have already been reported in literature to validate these uses [189]. Different organic extracts and decoctions prepared from parts of mango trees and compounds isolated from mango trees have shown anticancer effects.
A recent study by Abbasi et al. 2017 [74] demonstrated antiproliferative effects of fruit peel and pulp of several mango varieties (Royal mango, Thai mango, Egg mango, Luzon Narcissus, Big Tainong, Keitt, Australian mango, and Small Tainong) grown in China. They showed that the acetone extracts of mango peel and pulp exerted antiproliferative effects in HepG2 cells. Another study carried out by Kim et al. 2012 [190] has shown that the ethanolic extract of M. indica peel can induce apoptosis in human cervical adenocarcinoma HeLa cells. Apoptotic effects of the peel ethanolic extract have been studied by analyzing expression of apoptosis-related proteins Bax, Bcl-2, Bid, and caspases (3, 8, and 9) in this study. Phytochemical investigation of peel ethanolic extract has revealed that it contains some reported anticancer compounds such as quercetin 3-O-galactoside, gallic acid, linoleic acid, alpha-tocopherol, mangiferin gallate, mangiferin, kaempferol 3-glucoside and quercetin-3-Oarabinopyranoside. Protective effects of ethanolic extracts of mango fruit peel and flesh (a Korean variety) samples in H 2 O 2 -induced cytotoxicity in HepG2 cells have also been studied by this research group [76]. A study carried out by Corrales-Bernal et al. 2014 [191] has shown that aqueous extract of mango fruit flesh possesses antiproliferative effects in human colon adenocarcinoma cell line (SW480) and in mouse model with colorectal cancer. Antiproliferative effects of methanol extracts of peel and flesh of three mango cultivars (Kensington Pride (KP), Nam Doc Mai (NDM), and Irwin (IW)) found in Australia were studied by Taing et al. 2015 [192]. They have demonstrated that peel methanol extract of NDM can only inhibit the proliferation of MCF-7 breast cancer cells. Antitumor effects of mango polyphenols-rich fruit flesh extracts in human breast cancer xenografts mice have been studied by Banerjee et al. 2015 [193]. This study has proven that mango polyphenols rich fruit pulp extract has a potential to target PI3K/AKT pathway in breast cancer. Anticarcinogenic effects of a crude (methanol : acetone : water-1 : 1 : 1) fruit peel extract of some selected mango varieties  [194]. Among the studied mango varieties, two (Ataulfo and Haden) were more sensitive to SW-480 and MOLT-4 cells. Moreover, apoptotic effects of Ataulfo and Haden varieties have also been studied in SW-480 cells in this study. Induction of apoptosis by aqueous extract of mango fruit peel rich in lupeol has been carried out in testosterone-induced mouse prostate and human prostate cancer cells (LNCaP) by Prasad et al. 2007 [195]. Antiproliferative effects of two extracts (pectinase and Soxhlet extracts) of mango flesh found in Australia have shown in oestrogen receptor positive (MCF-7) breast cancer cells by Wilkinson et al. 2011 [196].
Induction of oxidative stress mediated apoptosis by ethanolic extract of M. indica seed in triple negative breast cancer cells (MDA-MB-231) has been reported by Abdullah et al. 2015 [197]. In this study, apoptotic effects of ethanolic extract of M. indica seeds were evaluated by analyzing apoptosis-related marker proteins such as Bax, Bcl-2, cytochrome c, and caspases (3, 8, and 9). Involvement of oxidative stress markers such as reactive oxygen species (ROS), glutathione (GSH), and malondialdehyde (MDA) levels in apoptosis has also been studied. Another study [198] carried out by the same research group reported oxidative stress mediated apoptosis by ethanolic extract of mango seeds in oestrogen receptor positive breast (MCF-7) cancer cells. Nguyen et al. 2016 [199] have demonstrated cytotoxic effects of methanol bark extract of M. indica in pancreatic cancer cells (PANC-1). Isolation of two novel cycloartanetype triterpenes, namely, mangiferolate A and mangiferolate B, has also been reported in the same study. Studies on the anticancer effects of mango leaves are limited. Cytotoxic effects of ethanolic leaf extract of an M. indica variety grown in Thailand were investigated by Ganogpichayagrai et al. 2017 [200], but a very low cytotoxic potential by ethanolic extract has been reported in all the cancer cell lines tested. Hepatoblastoma (HepG2), gastric carcinoma (Kato-III), bronchogenic carcinoma (Chago K1), ductal carcinoma (BT474), and colon adenocarcinoma (SW 620) cell lines were used in this study. Cytotoxic and apoptotic potential of the bark of two mango varieties (Rata Amba and Kartha Kolomban Amba) grown in Sri Lanka in breast (MCF-7 and MDA-MB-231) and ovarian cancer (SKOV-3) cells has been recently reported by us [201]. In this study we found that methanolic extracts of bark of two mango varieties exert cytotoxic and apoptotic potential in breast and ovarian cancer cells. In addition to these findings, our recent findings have demonstrated that the hexane extract of bark and the chloroform extract of the fruit peel of Mangifera zeylanica, a plant endemic to Sri Lanka (Sri Lankan mango), can induce apoptosis in breast and ovarian cancer cells [202,203]. Results of our studies showed that the hexane extract of bark of M. zeylanica has promising cytotoxic effects in breast (MCF-7 and MDA-MB-231) and ovarian cancer (SKOV-3) cells with less cytotoxicity to normal mammary epithelial (MCF-10A) cells [202]. Hexane extract also showed apoptotic effects in these cancer cells. Phytochemical investigation by GC-MS analysis of the active fractions of the hexane extract revealed few unknown compounds and we isolated a new resorcinolic lipid which was cytotoxic to MCF-7 breast cancer cells [50]. Furthermore, we isolated two new halogenated compounds namely chloromangiferamide and bromomangiferic acid from the chloroform extract of M. zeylanica bark [52]. Of these chloromangiferamide was cytotoxic only to MDA-MB-231 cells whereas bromomangiferic acid had no cytotoxic activity. Studies with the M. zeylanica fruit peel and flesh demonstrated that chloroform extract of fruit peel can induce apoptosis in MCF-7 breast cancer cells through an oxidative stress mechanism. Phytochemical identification of the peel chloroform extract of M. zeylanica showed presence of some reported anticancer compounds such as linoleic acid and -tocopherol [203]. Mangiferin is a well-known bioactive xanthonoid found in various parts of the mango tree. A number of studies have been carried out to illustrate antitumoral effects of mangiferin in various cancer cell lines such as breast, lung, ovary, brain, and cervix, and possible antitumoral mechanisms of mangiferin in several cancer cell lines have also been well-documented [204].

Antibacterial Effects of M. indica.
Resistance to antibiotics has become one of the biggest problems worldwide [205]. Unnecessary use of antibiotics for viral infections, prolong use of antibiotics for diseases, wrong prescriptions given to patients without determining the exact cause of infection, and discontinuation of antibiotics without completing treatments by patients are some of the major causes for occurrence of antibiotic resistance [206]. Approximately half of all deaths in tropical countries are due to bacterial infections [207]. Therefore, discovery of novel antibacterial agents for drug resistant bacteria is essential. A number of studies have proven the antibacterial effects of certain plant crude drugs and natural compounds isolated against drug resistant bacteria [208]. Herbal remedies for bacterial infections have gained much attention recently as they are readily available, cause fewer side effects, and cheap.
Various studies have been conducted with the extracts of roots, leaves, bark, fruit peel and flesh, and kernel of M. indica to investigate antibacterial properties. Among these parts, mango kernel and leaves are the most studied parts for antibacterial effects. A study carried out by Mutua et al. 2017 [209] with four M. indica varieties grown in Kenya (Apple, Ngowe, Sabine, and Kent) found that the methanol extracts of kernels of Apple and Sabine varieties exert strong inhibitory effects against Escherichia coli. Antibacterial effects of hexane, chloroform, benzene, methanol, and water extracts of kernel of an M. indica variety found in Tamil Nadu, India, have been reported by Rajan et al. 2011 [210]. The methanolic extract of the kernel was more potent in inhibiting the growth of Shigella dysenteriae, a causative agent for diarrhoea. Aqueous kernel extracts of two other M. indica varieties (Bagnapalli and Senthura) found in Tamil Nadu (Vellore) were subjected to study antibacterial effects against Staphylococcus aureus and Pseudomonas aeruginosa by Alok et al. 2013 [211]. Aqueous extracts of Bagnapalli variety exerted a higher effect than the Senthura variety. Antibacterial effects of kernels obtained from three mango varieties (Black Gold, Lemak, and Waterlily) grown in Malaysia were studied by Mirghani et al. 2009 [212]. Kernel samples were extracted to ethanol, methanol, acetone, and phosphate buffer saline and were subjected to antibacterial studies against S. aureus, E. coli, P. aeruginosa and Bacillus subtilis. The results of this study showed that the ethanol and methanol extracts of Lemak have the highest antibacterial potential. Inhibitory effects of methanolic kernel extract (rich in polyphenols) of a Japan M. indica variety against 43 bacterial species have been evaluated by Kabuki et al. 2000 [213]. Methanolic kernel extract of this variety was found to be more active against Gram-positive bacteria in tested organisms.
A number of studies have also been carried out to evaluate antibacterial effects of different extracts of M. indica leaves worldwide. A recent study carried out by Diso et al. 2017 [214] showed that chloroform and aqueous extracts of leaves of an M. indica variety collected in Nigeria possess antibacterial effects against isolates of S. aureus. Chloroform extract of leaves was found to be more inhibitive than the aqueous extracts tested. In vitro antibacterial effects of water, methanol, and acetone extracts of leaves of another M. indica variety grown in Nigeria have been tested on Shigella flexneri, E. coli, S. aureus, Streptococcus pyogenes, Bacillus cereus, P. aeruginosa, Streptococcus pneumoniae, Proteus mirabilis, and Salmonella typhi by Doughari and Manzara, 2008 [215]. Islam et al. 2010 [176] showed the antibacterial effects of leaf ethanol extract of a mango variety found in Bangladesh. Growth inhibition of Staphylococcus aureus, Streptococcus agalactiae, B. cereus, Bacillus megaterium, B. subtilis, and Lactobacillus bulgaricus bacterial species by methanolic leaf extract was observed in the study. An acetone extract of the leaves of an M. indica variety grown in Pakistan exerted a strong inhibition of growth of multidrug resistant S. typhi [216].  [223] has proven antibacterial effects. Ethanol extract of roots of studied M. indica variety was found to be more inhibitory against B. subtilis, E. coli, and K. pneumoniae. Silver nanoparticles (loaded onto nonwoven fabrics) prepared from aqueous extract of mango peel have been subjected to antibacterial effects by Yang and Li, 2013 [224]. The results of this study revealed that prepared nanoparticles can effectively inhibit the growth of E. coli, S. aureus, and B. subtilis. A decoction prepared from ripe and unripe mango peel and seeds has been used to study antibacterial effects by Rakholiya et al. 2013 [225]. Among twenty bacterial species used in this study, Micrococcus flavus was found to be more susceptible to the decoctions prepared from ripe seeds, ripe peel, and unripe seeds. In vitro antibacterial effects of four extracts (aqueous, ethanol, methanol, and acetone) prepared from mango flowers have been studied by Verma et al. 2015 [226] against six pathogenic bacterial strains and methanolic and ethanolic extracts of flowers have shown highest inhibition against S. typhi. Singh et al. 2015 [51] have shown antibacterial effects of bark of a mango variety found in India. Hexane and methanol extracts obtained from Soxhlet extraction of bark have exerted promising antibacterial effects against B. subtilis, S. typhi, P. aeruginosa, E. coli, and S. aureus. Results of antibacterial assays have shown that hexane extract was more active against tested bacterial species. Antibacterial potential of aqueous extract of mango bark has also been carried out by Chidozie et al. 2014 [227]. E. coli, P. aeruginosa, Proteus vulgaris, Streptococcus faecalis, S. typhi, and Shigella have been included in this and results of this study have illustrated that aqueous extract of mango bark was inhibitory to all bacterial species tested except S. faecalis.

Antifungal Effects of M. indica.
Fungal diseases have been identified as an important health problem nowadays [228]. Candida, Aspergillus, and Cryptococcus species are known to causes many fungal diseases worldwide [228]. Candida albicans is reported to be the most common pathogen in fungal infections [229]. Although fungal infections are common, few antifungal drugs are currently used to treat infections [230]. Therefore, the identification of novel drugs as antifungal agents is necessary. Plant-based treatments and natural compounds derived from plants have been identified as ideal drug leads for fungal diseases.  [232] and results showed a moderate inhibition of fungal strain Colletotrichum gloeosporioides by the aqueous extract. A recent study conducted with seed extracts of four M. indica varieties (Keitt, Sensation, Gomera-3, and peel) found in Spain showed that the extracts inhibited growth of all 18-fungal species tested [233]. Among these species Candida parapsilosis, Candida glabrata, and Lodderomyces elongisporus have exhibited a higher sensitivity towards tested extracts. However, authors have not included the extraction method and type of extracts used to determine antifungal effects. Mango kernel has also been reported to possess antifungal effects. A study carried out by Mutua et al. 2017 [209] has reported methanolic kernel extracts of four mango varieties grown in Kenya (Apple, Ngowe, Sabine, and Kent) exert inhibitory effects against C. albicans. Extracts of Apple, Ngowe, and Sabine showed more inhibitory effects than Kent against C. albicans. Antifungal effects of M. indica bark have also been included in previously mentioned studies [231,232]. Moderate antifungal activity has been reported for ethanol and methanol extracts [231] and aqueous extract [232] of M. indica bark.

Anthelmintic Effects of M. indica.
Helminth infections which are caused by parasitic worms are commonly seen in tropical regions [234]. They live either as parasites or in some cases in a free-living form [234]. Intestinal nematodes (IN) or soil-transmitted helminths (STH) are the most common types of nematodes [235]. It has been estimated that approximately 30% of world population is primarily infected with helminth parasites annually [236]. Development of resistance to helminth parasites has become a major problem in the treatment of the helminth infections [236]. Hence, discovery of natural remedies that can target helminth infections is important.

Antiplasmodial Effects of M. indica.
Complete eradication of malaria appears to be a major challenge in the world due to the development of resistance to antimalarial drugs [241]. Many parasites in genus Plasmodium cause malaria and Plasmodium falciparum is the most predominant in genus Plasmodium [242]. It has been estimated that malaria affects approximately 280-290 million people annually [242]. Quinine and artemisinin are naturally derived antimalarial drugs, which have been used for almost 400 years in the treatment of malaria [243]. However, P. falciparum has developed complete resistance to almost all the antimalarial drugs in clinical use [243]. Therefore, it is of paramount importance to investigate novel treatment methods/drugs which can target the malaria parasites. Despite latest inventions of new drugs by pharmaceutical companies, medicinal plants have gained much interest as novel sources for antimalarial drugs. Studies with antiplasmodial effects of mango are limited in literature. A study carried out by Awe et al. 1998 [244] has shown antiplasmodial effects of a bark methanol extract of a mango variety collected from Nigeria. The methanol extract has exhibited significant antiplasmodial effects against malaria parasite, Plasmodium yoelii nigeriensis. Zirihi et al. 2005 [245] have also shown some mild inhibitory effects of an ethanolic extract of mango bark collected from Ivory Coast on P. falciparum. Bidla et al. 2004 [246], on the other hand, have shown that methanol/chloroform extract of leaves of a mango variety collected from India possesses moderate antiplasmodial effects in P. falciparum.

Antihyperlipemic Effects of M. indica.
Hyperlipidemia is considered as a major reason for atherosclerosis and coronary heart disease [247]. Coronary heart disease is the main cause of death in the world [247]. Scientific investigation of herbal remedies for antihyperlipemic effects will give a strong support for the development of drugs for hyperlipidemia. A recent study by Gururaja et al., 2017 [248], reported cholesterol lowering effects of a methanolic extract of M. indica leaves in albino Wistar rats. A significant decrease in plasma cholesterol levels has been observed in rats administrated with cholesterol in this study. Results of the studies conducted with aqueous extracts [249,250] and ethanolic extracts [251,252] of M. indica leaves have shown promising antihyperlipemic effects in hyperlipemic rat models. Another study conducted by Vasant and Narasimhacharya, 2011 [253], has reported that feeding of mango fruit powder to hyperlipemic rats can significantly reduce serum cholesterol levels, very low-density lipoproteins (VLDL), and triglycerides (TG). A study conducted by Dineshkumar et al. 2010 [254] with 828 type 2 diabetes patients with high serum cholesterol levels, living in Gopali, India, has shown that consumption of aqueous extract of mango bark can significantly reduce serum total cholesterol level.

Antidiabetic Effects of M. indica.
Diabetes mellitus is a metabolic disease resulting from a defect in insulin action or secretion [255]. It has now become a major health problem affecting 442 million people worldwide [256]. 90% of diabetes cases are type 2 and the remainder is type 1 [257]. Blood glucose homeostasis is the key to prevent diabetes associated complications such as cardiovascular diseases, kidney diseases, eye problems, and peripheral neuropathy [258]. Several plant-based remedies have been used to treat type 2 diabetes in traditional medicine and a number of pharmacological studies have been conducted to validate these claims [259,260]. Fruit peel, flesh, seed kernel, leaves, and bark of M. indica have been extensively studied for their antidiabetic properties. Gondi and Prasada Rao, 2015 [261] have showed that an ethanolic extract of mango fruit peel can successfully reduce blood glucose level in streptozotocininduced diabetic rats. Significant decrease in fructosamine and glycated hemoglobin, which are considered as status indicators of diabetes, has also been observed after treatment with the ethanolic extract of mango peel. Another study carried out by Gondi et al. 2015 [262] with M. indica fruit peel powder showed a significant reduction of blood glucose level and diabetes associated complications in rats. Similar results have been obtained in a study carried with a flour prepared from mango fruit pulp [263]. Irondi et al., 2016 [264], showed that flour supplement prepared with mango kernel effectively reduced blood glucose level in diabetes rats. Improvement in liver function, blood glucose level, hepatic glycogen, lipid profile, and hepatic and pancreatic malonaldehyde was observed in diabetic rats supplied with flour supplement.

Gastroprotective Effects of M. indica.
Peptic ulcers are mainly present in the lining of stomach or in the duodenum [275]. Nonsteroidal anti-inflammatory drugs, mental or physical stress, alcohol, diet, life style, and antibiotics are considered as main causes of peptic ulcers [276]. Peptic ulcers are usually treated with proton pump inhibitors that reduce the secretion of gastric HCl [276]. As peptic ulcer cases are rising at an alarming rate worldwide, it is necessary to discover novel methods or drugs that can effectively reduce peptic ulcers. Assessment of gastroprotective effects of different extracts of M. indica has been carried out. A study conducted by Lima et al. 2006 [277] found that a decoction prepared from M. indica flowers can significantly increase gastroprotective properties in an experimental rat model by reducing gastric juice volume and acidity. Furthermore, Severi et al. 2009 [278] have shown that a decoction prepared from leaves of M. indica reduces gastric lesions induced by HCl, ethanol, and nonsteroidal anti-inflammatory drugs in experimental rat models. Antiulcer potential of ethanol and petroleum ether extracts prepared from mango leaves has also been reported by Neelima et al. 2012 [279]. Akindele et al. 2012 [280] who assessed gastroprotective effects of a drug formulation (DAS-77) which comprises M. indica bark and papaya roots showed a significant reduction of gastric ulcers after feeding with DAS-77 in rat models. Antiulcer activity of an ethanolic extract of mango kernels and in combination with vitamin C, ZnSO 4, and menadione in pylorus ligation and ethanol-induced ulcers in rat models was evaluated by Nethravathi K et al. 2015 [281]. Considerable reduction in gastric volume, ulcer score and index, and total acid output was observed after administration of ethanolic extract and the above drug combinations. There is a good agreement that exists between pharmacological properties of crude extracts of different parts of M. indica and biological effects of pure compounds isolated from M. indica. Common compounds found in various parts (bark, leaves, and fruits) of M. indica such as mangiferin, derivatives of mangiferin, gallic acid, catechin, quercetin, -carotene, shikimic acid, and kaempferol have been reported to possess antioxidant effects in several in vitro and in vivo studies [54-58, 61, 62]. Studies that have shown antioxidant effects of crude extracts of M. indica, [73][74][75][76][77][78][79][80][81][82][83], further suggest a striking correlation for the presence of these antioxidant compounds in those tested extracts. Catechin, mangiferin, gallic acid, epigallocatechin gallate, friedelin, humulene, kaempferol, and quercetin are wellknown reported anticancer compounds present in mango [54-58, 61, 62]. Available studies that show anticancer effects of different crude extracts (leaves, bark, and fruits), [190][191][192][193][194][195][196][197][198][199][200][201][202], strongly correlate the presence of these compounds in crude extracts of M. indica. Alkylresorcinols, epigallocatechin gallate, mangiferin, friedelin, gallic acid, and quercetin have been reported to possess anti-inflammatory effects in various in vitro and in vivo studies [54-58, 61, 62]. Occurrence of these anti-inflammatory compounds in M. indica has been well-documented and reported pharmacological studies which illustrate anti-inflammatory effects [88][89][90][91][92][93][94][95][96][97][98][166][167][168][169][170][171][172][173][174] of M. indica's crude extracts strongly correlate pharmacological effects and chemical composition. Apart from the abovementioned compounds, a large number of chemical compounds have been isolated and reported from different parts (fruits, bark, leaves, flowers, and roots) of M. indica. Some major compounds isolated or identified by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) from different parts of mango tree and reported biological effects of those pure compounds have been listed in Table 2. According to the information present in Table 2, it is clear that common mango compounds such as mangiferin, quercetin, catechin, and kaempferol possess a wide range of pharmacological properties.

Conflicts of Interest
The authors have no conflicts of interest.