Vangueria madagascariensis Fruit Tree: Nutritional, Phytochemical, Pharmacological, and Primary Health Care Applications as Herbal Medicine

Vangueria madagascariensis J. F. Gmel. is a plant species regarded as an important fruit tree and medicinal plant in sub-Saharan Africa. This study critically reviewed the nutritional value, phytochemistry, medicinal uses, and pharmacological properties of V. madagascariensis. Relevant information on food and medicinal uses of the species was collected from electronic databases such as ISI Web of Knowledge, ProQuest, ScienceDirect, OATD, Scopus, OpenThesis, PubMed, and Google Scholar, and preelectronic literatures were obtained from the university library covering the period 1966 to 2018. Literature studies revealed that V. madagascariensis has been integrated into farming systems as a fruit tree to support income and nutritional security of households in the region. Vangueria madagascariensis is used as a herbal medicine against diabetes, gastrointestinal problems, malaria, pain, parasitic worms, and skin diseases. Phytochemical compounds identified from the species include alcohols, aldehydes, esters, furanoids, ketones, and terpenoids. Pharmacological studies revealed that V. madagascariensis extracts have antibacterial, anticonvulsant, antidiabetic, antifungal, anti-inﬂammatory, antioxidant, cytotoxicity, antimalarial, and antiplasmodial properties. Vangueria madagascariensis should be subjected to detailed nutritional, pharmacological, and toxicological evaluations aimed at correlating the traditional uses of the species and the scientific evidence as well as establishing the efficacy, clinical relevance, safety, and mechanisms of action of the plant extracts and compounds.


Introduction
Over the last three decades, there has been renewed interest in the phytochemical properties of Vangueria madagascariensis J. F. Gmel. (Figure 1), a plant species with edible fruits and used as a herbal medicine throughout its distributional range. Vangueria madagascariensis belongs to the bedstraw or family Rubiaceae, which is regarded as one of the largest plant groups characterized by about 637 genera and 13000 taxa [1,2]. Vangueria madagascariensis is a type of species of the genus Vangueria Juss., which formed a strongly supported group or clade including V. esculenta S. Moore, V. infausta Burch., and V. proschii Briq. based on the results of chloroplast markers trnT-F and rps16 and nuclear ITS [1]. All these four species are characterized by calyx lobes that are narrow, oblong, and triangular in shape [1].
Vangueria madagascariensis is a multistemmed deciduous shrub or tree growing up to 15 metres in height. e species is native to Réunion, Tanzania, Democratic Republic of Congo, South Sudan, Angola, Cameroon, Ghana, Benin, Central African Republic, Ethiopia, Eritrea, Madagascar, Mauritius, Mozambique, Nigeria, South Africa, Sudan, Swaziland, Togo, Uganda, Seychelles, and Kenya [3] (Figure 2). e species has been recorded on rocky, sandy red clay, or sandy clay soils in riverine bushlands, evergreen forests, bushed grasslands, rocky outcrops, and termite mounds at an altitude ranging from 0 to 2400 metres above the sea level [3]. Vangueria madagascariensis is cultivated in China, Congo, Cuba, India, northern Australia, Singapore, and Trinidad [8][9][10][11][12]. Considering the existing literature focusing on utilization of V. madagascariensis throughout its distributional range, it is evident that different plant parts are used as both food and herbal medicines as these plant parts have several phytochemical compounds and micronutrients required for human nutrition and health [9,[13][14][15][16][17]. Previous research showed that the medicinal and nutritional properties of edible fruits collected from the wild enable local communities to use such plant resources as traditional remedies, at the same time broadening their nutritional options, micronutrients, diet, and vitamins [6,18,19]. Vangueria madagascariensis is regarded as a popular fruit tree and medicinal plant, and the plant species has positive effects on human health and well-being [9,[13][14][15][16][17] which are beyond the provisions of basic nutritional requirements.
ere is no universally accepted definition of functional food and nutraceuticals, but Hailu et al. [20], Shahidi [21], and Wang and Li [22] argued that functional food and nutraceuticals are natural foods that beneficially affect one or several body functions apart from nutritional effects, influencing both the health and well-being of the consumer. e value of pharmaceutical drugs derived from plants, other natural health products, nutraceuticals, and functional foods are being promoted throughout the world as an alternative strategy for disease risk reduction and reduction in health care costs [21]. It is within this background that the nutritional value, chemical properties, medicinal uses, and biological activities of V. madagascariensis were evaluated.

Food Uses
e fruits of V. madagascariensis which are globose, smooth and shiny, and yellowish brown in colour when ripe are edible and highly sought after throughout the distributional range of the species. Although the fruits are mainly collected from the wild, but in clearing land for agricultural purposes, some farmers leave these trees as future sources of fruits. Teklehaimanot [23] identified V. madagascariensis, Strychnos cocculoides Baker, Balanites aegyptiaca (L.) Delile, Vitex doniana Sweet, Berchemia discolor (Klotzsch) Hemsl., Sclerocarya birrea (A. Rich.) Hochst., Borassus aethiopum Mart., Carissa spinarum L., Cordeauxia edulis Hemsl., and Vitellaria paradoxa C. F. Gaertn. as priority indigenous fruit tree species with domestication potential in Ethiopia, Kenya, South Sudan, Sudan, Tanzania, and Uganda. erefore, V. madagascariensis has been integrated into rural agricultural farming systems in sub-Saharan countries as a strategy to improve food and income security of households in the region. Based on the popularity of its fruits, V. madagascariensis was also introduced in home gardens in Congo, Cuba, India, and the West Indies [8][9][10]. e fruits are marketed in Cuba, Ethiopia, Kenya, Madagascar, Tanzania, and Uganda [8-10, 24, 25]. e fruit pulp of V. madagascariensis has a sweet, pleasant chocolate-like flavour when eaten raw and a somewhat astringent and acidic taste like a blend of apple (Malus pumila Miller) and tamarind (Tamarindus indica L.) [8,26]. e pulp is also stewed, roasted, added to mealie meal porridge and other food to add flavour, and made into juice, jellies, jam, and puddings [26][27][28][29]. In Ethiopia, fruits of V. madagascariensis are an important food resource especially during droughts and in times of food shortages [30]. e pulp is a good source of both macrominerals and trace elements such as potassium, zinc, calcium, magnesium, chromium, phosphorus, copper, manganese, and iron ( Table 1). e nutritional contribution of the pulp is comparable to other well-known fruits with commercial potential such as Mangifera indica L. and Ziziphus mauritiana Lam (Table 1). Mangifera indica and Ziziphus mauritiana are among the top five important fruit species in the dryland agricultural farming systems in tropical Africa that contribute to household incomes, nutritional needs, and food security [38]. Several amino acids and fatty acids ( Table 2) have been identified from the fruit pulp of V. madagascariensis, and these include the essential amino acids such as lysine, threonine, histidine, leucine, phenylalanine, valine, isoleucine, and methionine [39,44]. Research by Mariod et al. [15] revealed that the contribution of conditionally essential amino acids such as tyrosine, arginine, glycine, and cysteine and nonessential amino acids such as glutamic acid, aspartic acid, and serine was close to 50% (5.9 g out of 14.2 g/100 g) of the total amino acids identified from the species (Table 2). e amino acid and fatty acid constituents and other physicochemical properties of V. madagascariensis make the species a valuable source of these nutrients when compared with the nutritional value of Mangifera indica and Ziziphus   (Tables 1 and 2). Pino et al. [9] identified sixty volatile constituents from the fruit pulp of V. madagascariensis (Table 3). e major phytochemical compounds identified include alcohols, aldehydes, esters, furanoids, ketones, and terpenoids (Table 3). Pino et al. [9] argued that the acidic and pungent taste associated with the fruit pulp of V. madagascariensis can be explained by the higher amounts of fatty acids as shown in Table 2.

Medicinal Uses of
Vangueria madagascariensis e seeds, bark, leaves, fruits, roots, and stem bark of V. madagascariensis are utilized in monotherapeutic or multitherapeutic applications in Eritrea, Kenya, Madagascar, Mauritius, Sudan, and Tanzania (Table 4). Bark, fruit, leaf, and root maceration of V. madagascariensis is taken by mouth for diabetes in Madagascar [47], Mauritius [14,48], and Sudan [49,50]. Bark, leaf, root bark, and stem bark infusion of V. madagascariensis is taken by mouth for bloody diarrhoea in Tanzania [45], dysentery in Mauritius [47], and stomach problems in Kenya [58]. Root bark and root infusion of V. madagascariensis is taken by mouth for intestinal worms in Eritrea [52] and Tanzania [8,45]. Bark, root bark, and stem bark maceration of V. madagascariensis is taken by mouth for malaria in Kenya [53][54][55][56][57] and Tanzania [8,45,51]. In Tanzania, the leaf, root, root bark, and stem bark maceration of V. madagascariensis is taken by mouth for abdominal pains, asthma, convulsions, gonorrhoea, hepatitis, hernia, and oedema [45,51]. Fruit decoction of V. madagascariensis is taken by mouth for back pain and mouth infections in Kenya [46,58], while root decoction is taken orally as a purgative in Eritrea [52]. In Sudan, the fruit and seed decoction of V. madagascariensis is taken orally as a remedy for hypertension, kidney problems, and tumour [50,59], while bark and leaf decoction is taken orally for palpitations and nausea in Mauritius [47]. Multitherapeutic applications of V. madagascariensis involve mixing leaves of the species with leaves of Jatropha curcas L., Azadirachta indica A. Juss., and Ipomoea pes-caprae (L.) R. Br. as a herbal medicine for abscesses, carbuncle, and scurf in Mauritius [14]. In Mauritius, the leaf decoction of V. madagascariensis is mixed with the leaves of Jatropha curcas, Toddalia asiatica (L.) Lam., and Sporobolus africanus (Poir.) Robyns & Tournay as a mouthwash [48].

Phytochemistry and Pharmacological Properties of Vangueria madagascariensis
Phytochemical screening of the bark, fruits, leaves, kernel oil, seeds, stems, and stem bark has shown the presence of fibre, carbohydrates, proteins, and several classes of phytochemicals such as volatile and nonvolatile metabolites (Table 5), and chemical structures of representative phytochemical compounds are shown in Figure 3. e majority of the phytochemicals were identified using highperformance liquid chromatography (HPLC-DAD) with diode array detection (DAD), mass spectrometry (MS), gas chromatography-mass spectrometry (GC/MS), nuclear magnetic resonance (NMR) spectroscopy, and gas chromatography (GC) ( Table 5). Each fruit of V. madagascariensis has 4 to 5 seeds, and the seed kernel contains considerable amount of oil which is higher than that of conventional oil seeds such as groundnut (Arachis hypogaea L.), cottonseed (Gossypium hirsutum L.), and sunflower (Helianthus annuus L.) [62]. Some of the phytochemical compounds such as flavonoids identified from V. madagascariensis are known to have antiallergic, antiinflammatory, antimicrobial, antiproliferative, antioxidant, enzyme inhibition, and oestrogenic activities, synergism with antibiotics, and suppression of bacterial virulence [63][64][65][66]. Research by Prochazkova et al. [65] revealed that the antioxidant activities of flavonoids involve quenching free radical elements, metal chelation, suppression of enzymes involved in free radical scavenging, and stimulation of enzymes that activate antioxidant activities. Research has also revealed that food resources characterized by high levels of flavonoids and related phenolic compounds may reduce the risk of cardiovascular diseases [67]. Pereira et al. [63] argued that the structural figure of phenolic compounds has the potential to interact with several proteins; mainly, they have a hydrophobic benzenoid ring and hydrogen-binding properties which enhance their capacity to be antioxidants by inhibiting several enzymes that catalyze radical generation, including xanthine oxidase, cytochrome P450 isoforms, cyclooxygenase, and lipoxygenase enzymes. e different parts of V. madagascariensis are associated with several fatty acids [16,60,61], and these compounds are known to have a wide range of physiological effects such as cardiovascular function, immune system regulation, neuronal development, regulation of plasma lipid levels, insulin regulation, and visual function [68]. Several studies done elsewhere demonstrated the importance of dietary intake of fatty acids as they lead to reduced blood pressure, they lower the risk of heart attack and arteriosclerosis risks, and these compounds are associated with antimicrobial properties and synthetic accessibilities [69][70][71]. Desbois and Smith [71] argued that the antimicrobial properties of fatty acids are based on their ability to disturb and distort the oxidative phosphorylation process and the electron transport chain process, thereby disturbing the cellular energy production, leading to reduction of enzymatic activity, reduced nutrient uptake, and production of toxic peroxidation. e phytochemicals detected in various parts of V. madagascariensis may be used to justify some of the medicinal uses of this species recorded in Table 4 and also documented antibacterial [13,60,72], anticonvulsant [60], antidiabetic [13,73], antifungal [60,74], anti-inflammatory [60], antioxidant [13,17], cytotoxicity [17], antimalarial, and antiplasmodial [55,56] activities.

Antibacterial Activities.
Bishay et al. [60] assessed antibacterial properties of leaf and bark ethyl acetate, chloroform, and n-hexane extracts of V. madagascariensis against Pseudomonas aeruginosa, Bacillus cereus, Escherichia coli, Klebsiella pneumoniae, Micrococcus luteus, and Staphylococcus aureus using the modified diffusion method with dimethylformamide (DMF) and gentamicin (5 µg/ml) as negative and positive controls, respectively (Table 6). e extracts showed activities with the zone of inhibition stretching from 4 mm to 18 mm which was comparable to the zone of inhibition of 10 mm to 14 mm demonstrated by gentamicin, the control. e minimum inhibitory concentration (MIC) values ranged from 6.3 µg/ml to 75 µg/ml [60]. Ramalingum and Mahomoodally [13] evaluated antibacterial properties of methanol and crude fruit, leaf, and seed extracts of V. madagascariensis making use of the disc diffusion and microtitre dilution broth method against Escherichia coli and Staphylococcus aureus with streptomycin sulphate and gentamicin sulphate as positive controls (Table 6). e crude ripe and unripe fruit extracts and methanol leaf and seed extracts exhibited some antibacterial properties with the zone of inhibition ranging 8.3 mm to 12.7 mm and MIC values ranging from 6.3 mg/mL to 25.0 mg/mL [13]. Mahomoodally and Dilmohamed [72] evaluated antibacterial activities of fruit and leaf extracts of V. madagascariensis against Klebsiella spp., Acinetobacter spp., Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus, Proteus spp., Streptococcus spp. and ). e extracts demonstrated antibacterial properties with MIC values ranging from <0.1 mg/mL to 12.5 mg/mL. e authors found that mixing of antiobiotics such as chloramphenicol and gentamicin with V. madagascariensis extracts resulted in significant antibacterial properties by reducing the MICs [72]. ese antibacterial activities exhibited by different extracts of V. madagascariensis corroborate the traditional use of the species as herbal concoction against bacterial and other microbial infections causing bloody diarrhoea and gonorrhoea in Tanzania [45], carbuncle and dysentery in Mauritius [14,48], mouth infections in Kenya and Mauritius [48,58], and stomach problems in Kenya [58].

Anticonvulsant Activities.
e activities of the different fractions and the total ethanolic extracts of both leaves and stem bark of V. madagascariensis on the central nervous system were evaluated by performing assays of their effect on motor coordination (rotarod test) and pentylene tetrazoleinduced convulsion [60]. e total ethanolic extracts as well as the other fractions of both leaves and stem-bark attained a central nervous system depressant activity. e n-butanol and n-hexane extracts of the leaves, n-hexane and chloroform extracts the stem-bark at 400 mg/kg have anticonvulsant properties against pentylene tetrazole induced convulsions in comparison with carbamazepine. e n-butanol and n-hexane extracts of the leaves, n-hexane and chloroform extracts of the stem-bark at 400 mg/kg exhibited anticonvulsant properties against pentylene tetrazole induced convulsions in rats in comparison with carbamazepine [60]. e anticonvulsant properties demonstrated by the extracts of V. madagascariensis corroborate the usage of stem bark of the species as herbal concoction against convulsions in Tanzania [60].

Antidiabetic Activities.
Ramalingum and Mahomoodally [14] evaluated antidiabetic activities of methanol and crude fruit, leaf and seed extracts of V. madagascariensis using α-amylase, α-glucosidase and a modified glucose based colorimetric and glucose movement assays with acarbose as the control (Table 6). e crude and methanol extracts  6 Scientifica exhibited inhibitory activities against α-amylase with half maximal inhibitory concentration (IC 50 ) values varying from 1.1 mg/mL to 29.6 mg/mL which was comparable to acarbose with IC 50 value of 0.1 mg/mL. e extracts that exhibited activities against α-glucosidase where unripe fruit decoction, ripe fruit methanol, unripe fruit methanol, leaf decoction exhibited IC 50 values stretching from 0.4 mg/mL to 3.3 mg/mL which were significantly lower than IC 50 value of 5.0 mg/mL demonstrated by the control, acarbose. e kinetic evaluations showed a mixed non-competitive type of inhibition. Beidokhti et al. [73] evaluated the inhibition of pancreatic α-amylase and yeast α-glucosidase by ethanolic bark and leaf extracts of V. madagascariensis (Table 6). e showed activities against both α-glucosidase and α-amylase and characterized by IC 50 values of 1.8 µg/mL and 11.6 µg/mL, respectively [73]. e observed antidiabetic activities of V. madagascariensis extracts support the use of the bark, leaves, fruits and roots of the species as herbal medicine against diabetes in Madagascar, Mauritius and Sudan [14,[47][48][49][50].

Antifungal Activities.
Bishay et al. [60] assessed antifungal properties of bark and leaf aqueous, n-hexane, chloroform, ethyl acetate extracts of V. madagascariensis against Candida albicans using the modified diffusion method with clotrimazole (5 µg/ml) as the positive control (Table 6). e bark and leaf extracts showed antifungal properties with zone of inhibition stretching from 9 mm to 20 mm which was comparable to zone of inhibition of 14 mm demonstrated by clotrimazole, the control. e MIC values stretched from 13.0 µg/ml to 55.0 µg/ml and clotrimazole, the control exhibited MIC value of 4.0 µg/ml [60]. Similarly, Karim et al. [74] assessed antifungal properties of chloroform fruit extract of V. madagascariensis against Candida albicans and Aspergillus Niger using agar diffusion assay with ampicillin as positive control (Table 6). e chloroform fruit extract showed activities with zone of inhibition stretching from 14 mm to 15 mm [74]. ese antifungal activities displayed by the different extracts of V. madagascariensis demonstrate the potential of the species in the management of fungal and microbial infections.

Anti-inflammatory Activities.
Bishay et al. [60] assessed anti-inflammatory properties of bark and leaf aqueous, ethyl acetate, chloroform and n-hexane extracts of V. madagascariensis using the carrageenan-induced rat paw oedema model. Potent anti-inflammatory activities were observed after 2 hrs and continued for 4 hrs with all the extracts [60].
ese findings corroborate the traditional use of V. madagascariensis as herbal concoction for abdominal pains in Tanzania [45], back pain in Kenya [46] and other various inflammatory ailments and diseases including skin infections and body injury that may lead to cell damage and death.   8 Scientifica crude fruit, leaf and seed extracts of V. madagascariensis using DPPH (1, 1-Diphenyl-2-picrylhydrazyl) free radical scavenging, hypochlorus acid (HOCl) scavenging, ferric reducing antioxidant power (FRAP), hydroxyl ( · OH) radical scavenging or deoxyribose, nitric oxide radical (NO) scavenging and iron chelating property assays (Table 6). e methanol leaf, unripe and ripe fruit extracts exhibited antioxidant properties with IC 50 values stretching from 9.0 µg/mL to 48.5 µg/mL which was comparable to ascorbic acid with IC 50 value of 0.001 µg/mL. All the extracts exhibited activities in the reduction of Fe 4+ to Fe 2+ , confirming antioxidant properties with leaf methanol being the most active and seed decoction being the least active. e methanol unripe fruit extract exhibited the highest HOCl scavenging properties with IC 50 value of 223.0 µg/mL which was comparable to that of ascorbic acid, the control which exhibited IC 50 value of 46.0 µg/mL. e methanol leaf, unripe and ripe fruit extracts exhibited _OH scavenging properties with IC 50 values stretching from 0.1 µg/mL to 0.3 µg/mL which were lower than that of α-tocopherol, the control which exhibited IC 50 value of 0.5 µg/mL. e leaf and unripe fruit crude extracts as well as methanolic leaf, ripe and unripe fruit extracts exhibited NO scavenging properties with IC 50 values stretching from 43.2 µg/mL to 436.2 µg/mL which were lower than that of ascorbic acid, the control which exhibited IC 50 value of 546.5 µg/mL. All the extracts exhibited considerable iron chelating properties with IC 50 values stretching from 0.0009 µg/mL to 2.5 µg/mL which were comparable to the positive control EDTA which exhibited IC 50 value of 0.001 µg/mL [13]. Mustafa et al. [17] assessed antioxidant properties of bark, leaf and seed extracts of V. madagascariensis using DPPH radical scavenging assay and oxygen radical absorbance capacity (Table 6). e DPPH assay revealed activities of leaf, seed and bark extracts with IC 50 values of 7.8, 31.3 and 62.5 μg/ml, respectively, which were comparable to IC 50 value of 3.1 μg/ml exhibited by ascorbic acid, the control. e oxygen radical absorbance ability findings revealed that the leaf extract demonstrated higher levels of antioxidant properties of 72.7 μM of trolox than the control, quercetin (5 μg/ml) which showed activity of 59.0 μM of trolox), while the bark and seed extracts showed activities of 47.1 μM of trolox and 44.9 μM of trolox, respectively [17]. e documented antioxidant activities of V. madagascariensis extracts are probably due to flavonoids, phenolics and proanthocyanidins detected in fruits, leaves and stems of the species [14,17,60].

Toxicity Activities.
Bishay et al. [60] evaluated oral acute toxicity of bark and leaf n-hexane, chloroform, ethyl acetate extracts of V. madagascariensis by administering doses of 10 mg/kg, 100 mg/kg and 1000 mg/kg i.p. to male albino rats (Table 6). e treated animals were monitored for 24 hrs for symptoms of toxicity such as writhing, loss of motor coordination, irritability, hypothermia, sedation followed by deep sleep and finally death. e median lethal dose (LD 50 ) values of 3.8 g/kg for both leaf and stem-bark extracts appear to suggest that the extracts of the species are safe to use as herbal medicines [60]. Muthaura et al. [55] assessed the acute, subacute and chronic toxicity of V. madagascariensis stem bark extracts by oral administration in female Swiss mice. e behaviour of mice was observed for 1 hour, intermittently for 4 hours, 24 hours and 14 days noting for any signs of toxicity and the latency of death. e extracts did not cause any mortality or signs of toxicity at any dose level up to the highest dose tested of 5000 mg/kg [55]. Since V. madagascariensis is widely utilized as both food and herbal medicine, there is need to ascertain toxicological properties of the species using different plant parts against several cell    [60] 12 Scientifica  All extracts appear to be nontoxic with LD 50 values of 3.8 g/kg [60] 14 Scientifica lines using both in vitro toxicological assays and in vivo studies.

Conclusion
Vangueria madagascariensis is an important functional food and source of nutraceutical ingredients in tropical Africa. Significant breakthrough has been made in the last 30 years elucidating the nutritional, phytochemical and pharmacological properties of the species. However, there are still some research gaps regarding correlating the nutritional and phytochemical properties of the species with its food value and medicinal applications. Detailed studies on the phytochemistry, pharmacokinetics, in vivo and clinical research are required. Further research on the antinutritive, enzymatic and molecular effects of V. madagascariensis fruits and kernel oil on human health will be needed to motivate further interest in the use of these products as food sources, additives and health promoting products. Given the situation that V. madagascariensis is used as herbal medicine in combination with other plant species such as Azadirachta indica, Ipomoea pes-caprae, Jatropha curcas, Sporobolus africanus and Toddalia asiatica, there is need to investigate the possibility of synergetic effects of the combined extracts. Since V. madagascariensis is a valuable functional food and nutraceutical plant species in tropical Africa, there is need to establish the toxicity and/or any side effects that can arise when the species and its products are used as functional food and sources of nutraceutical ingredients and/or as herbal medicines.

Conflicts of Interest
e author declares that there are no conflicts of interest regarding the publication of this paper.