Ximenia caffra Sond. (Ximeniaceae) in sub-Saharan Africa: A synthesis and review of its medicinal potential

Journal of Ethnopharmacology 184 (2016) 81–100

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Review

Ximenia caffra Sond. (Ximeniaceae) in sub-Saharan Africa: A synthesis and review of its medicinal potential Alfred Maroyi Department of Botany, University of Fort Hare, Private Bag X1314, Alice 5700, South Africa

art ic l e i nf o

a b s t r a c t

Article history: Received 26 November 2015 Received in revised form 28 February 2016 Accepted 29 February 2016 Available online 2 March 2016

Ethnopharmacological relevance: Ximenia caffra Sond. (Ximeniaceae), commonly known as “sour plum” is traditionally used, both topically and orally to treat a wide range of human diseases and ailments such as wounds, sexually transmitted infections (STIs), infertility, stomach ache, fever, eye problems, diarrhoea, bilharzia, menorrhagia, malaria, intestinal worms, impotence and coughs. The bark and fruits are used by small-scale farmers as ethnoveterinary medicine to treat dermatophilosis, foot rot, saddle sores and control ectoparasites. Oil from X. caffra seed is traditionally used as a moisturiser, soap and shampoo for dry, fragile and damaged hair. Aim of the review: The aim of this study was to comprehensively summarize the research that has been done on the botany, ethnomedicinal uses, phytochemistry and biological activities of X. caffra in different locations throughout its geographical range in the sub-Saharan African region so as to understand its importance and potential in primary healthcare systems. Materials and methods: This study was carried out using a comprehensive and systematic literature search on the ethnomedicinal uses, phytochemistry and biological activities of the species throughout its distributional range. Literature sources included papers published in international journals, reports from international, regional and national organizations, conference papers, books and theses. PubMed and Scopus, search engines such as Google Scholar and online collection ScienceDirect were used. Results: This study showed that X. caffra is used as traditional medicine in 83.3% of the countries in tropical Africa where it is indigenous. A total of 65 human and animal ailments and diseases are recorded for X. caffra, with a high degree of consensus for wounds, sexually transmitted infections (STIs), infertility, stomach ache, fever, eye problems, diarrhoea, bilharzia, menorrhagia, malaria, intestinal worms and coughs. Phytochemical investigation of X. caffra revealed that the species has various compounds including flavonoids, phenols, phytosterols, tannins and fatty acids. Different plant parts, aqueous and organic extracts exhibited anti-amoebic, antibacterial, antifungal, anti-inflammatory, antioxidant, antiparasitic, antiproliferative, HIV-1 reverse transcriptase (RT) inhibitory, insecticidal, non-mutagenic and toxicity activities. Conclusion: In this review, the ethnomedicinal uses, phytochemistry, biological activities and toxicity of different extracts and compounds of X. caffra have been summarized. Although many of the ethnomedicinal uses of X. caffra have been validated by phytochemical and pharmacological studies, there are still some gaps where current knowledge could be improved. There are very few to nil experimental animal studies, randomized clinical trials and target-organ toxicity studies involving X. caffra and its derivatives that have been carried out so far. At the present moment, there is not sufficient evidence to interpret the specific chemical mechanisms associated with some of the documented biological activities of the species. Therefore, future studies should identify the bioactive components, details of the molecular modes or mechanisms of action, pharmacokinetics and physiological pathways for specific bioactives of X. caffra. & 2016 Elsevier Ireland Ltd. All rights reserved.

Keywords: Ethnopharmacology Primary healthcare Sub-Saharan Africa Traditional uses Ximenia caffra Ximeniaceae

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 Taxonomy, distribution, vernacular names and ethnomedicinal uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 2.1. Taxonomy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

E-mail address: [email protected] http://dx.doi.org/10.1016/j.jep.2016.02.052 0378-8741/& 2016 Elsevier Ireland Ltd. All rights reserved.

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2.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 2.3. Vernacular names of Ximenia caffra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 2.4. Ethnomedicinal uses of Ximenia caffra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 3. Phytochemical constituents and nutritional composition of Ximenia caffra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 3.1. Phytochemical and nutritional constituents of Ximenia caffra oil and fruits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 3.2. Phytochemical constituents of other plant parts of Ximenia caffra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 4. Pharmacological activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 4.1. Anti-amoebic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 4.2. Antimicrobial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 4.2.1. Antibacterial. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 4.2.2. Antifungal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 4.2.3. Antiviral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 4.3. Anti-inflammatory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 4.4. Antioxidant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 4.5. Antiparasitic and insecticidal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 4.6. Antiproliferative. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 4.7. Toxicity and mutagenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

1. Introduction Medicinal plants harvested from the wild have always been the principal sources of medicines used in primary healthcare in developing countries. The World Health Organization estimates that up to 80% of the people in both rural and urban communities in the developing countries still depend on medicinal plants to fulfil their primary healthcare needs (WHO, 2002). Traditional medicines are widely used in sub-Saharan Africa and this practise is generally regarded as part of the African culture. Traditional medicines are now receiving significant attention globally, with a number of international and local herbal medicine practitioners actively exploring the botanical resources of tropical Africa with the intention of screening medicinal plants for pharmaceutically active compounds. Piwowarski et al. (2015) argued that research into underutilized traditional herbs that are presently not incorporated into orthodox medicine is a promising strategy which may lead to the development of future innovative and sustainable pharmaceutical drugs. Evaluation of phytochemistry and pharmacological properties of herbal medicines is important in medicinal plant research and indigenous knowledge systems. Validating the correlations of ethnomedicinal uses, bioactive compounds, biological and pharmacological effects will help to maintain options of using herbal medicines, particularly as their use is growing

because of their moderate costs and also increasing faith in traditional herbal medicines. There has been a major resurgence in interest in the natural products derived from Ximenia caffra Sond. (Ximeniaceae), (Fig. 1), a plant species with multifaceted uses which are recognized commercially, medicinally and culturally throughout its distributional range. The species bear edible and fleshy fruits that have constituted part of the African diet since ancient times (Palmer and Pitman, 1972). Ximenia caffra and a closely related X. americana L. have been identified as some of the few plant species that should be integrated in the domestication process in farming systems in sub-Saharan Africa to support medicinal, nutritional and income security of local communities (Milimo et al., 1994; Vodouhè and Dansi, 2012). Similarly, Ximenia caffra and X. americana are regarded as multipurpose plant species in South Africa and neighbouring countries. These two species were identified by Van Wyk (2011) as candidates for potential commercialization as they are highly valued sources of fruits, nuts and oil. Ximenia oil is used as a moisturiser, for producing anti-ageing skin care products, eye-care and anti-acne products, shampoo for dry, fragile and damaged hair, soap, lipstick and lip balm (UNEP, 2012). Ximenia caffra and X. americana are commercially important plant species for rural communities in Namibia, where 5805 kg of Ximenia were sold in 2008 generating an income of $117152 (UNEP,

Fig. 1. Ximenia caffra: (A) flowers and leaves and (B) fruit and leaves (Photos: BT Wursten).

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2012). While the societal value of X. caffra has received considerable attention throughout its distributional range (Palmer and Pitman, 1972; Milimo et al., 1994; Van Wyk, 2011; Vodouhè and Dansi, 2012; UNEP, 2012), no attempt has been made to review literature on its medicinal potential, pharmacological properties and biological activities. Therefore, the aim of this study was to comprehensively summarize the research that has been done on the botany, ethnomedicinal uses, phytochemistry and biological activities of X. caffra in different locations throughout its geographical range in the sub-Saharan African region so as to understand its importance and potential in primary healthcare systems.

2. Taxonomy, distribution, vernacular names and ethnomedicinal uses 2.1. Taxonomy Ximenia caffra Sond. is a member of the Ximeniaceae family, formerly Olacaceae. The family Ximeniaceae is a monophyletic group (Nickrent et al., 2010) of four genera, Curupira G. A. Black, Douradora Sleumer, Malania Chun & S. K. Lee and Ximenia L. According to Sørensen (1963), seeds of genus Ximenia contain unusual seed glycerides, in the form of ethanoic acids, that is C26 acid cis-hexacos-17-enoic acid and the C30 acid cis-triacont-21-enoic acid. Genus Ximenia consists of ten species, that is X. americana L., X. caffra Sond., X. coriacea Engl., X. glauca (DeFilipps) Bentouil, X. horrida Urb. & Ekman, X. intermedia (Chodat & Hassl.) DeFilipps, X. parviflora Benth., X. perrieri Cavaco & Keraudren, X. pubescens Standl. and X. roigii León (www.theplantlist.org) with a tropical and subtropical distribution. This genus was first described by Linnaeus in 1753. The generic name ‘Ximenia’ is in honour of a Spanish priest Francisco Ximênez who wrote about the plants of Mexico in the 17th century while the specific name ‘caffra’ is from the Hebrew “kafri” meaning “person living on the land”. Ximenia caffra is divided into two varieties, X. caffra Sond. var. caffra and X. caffra Sond. var. natalensis Sond., which can be distinguished by the degree of hairiness of the leaves. Ximenia caffra var. caffra is the most widespread taxon and its leaves remain hairy to maturity, while var. natalensis is restricted in distribution, with entirely hairless leaves and branchlets even when young. Synonyms of X. caffra Sond. var. caffra and X. caffra Sond. var. natalensis Sond. include X. americana L. var. caffra (Sond.) Engl. and X. americana L. var. tomentosa Engl. (www.theplantlist.org). Most published literature, ethnobotany researchers, traditional healers and local communities do not separate X. caffra into specific varieties, but rather to X. caffra sensu lato, and the same approach has been adopted in this study. Ximenia caffra is a dioecious, sparsely-branched shrub or small tree up to 6 m. tall with a shapeless and untidy crown (Setshogo and Venter, 2003). Branches and twigs are armed with stout axillary spines. Bark is greyishbrown to black, rough and longitudinally fissured on older trees (Palgrave, 2002). Sapwood is white and heartwood is hard and reddish brown. Leaves simple, alternate, elliptic to lanceolate, leathery, blue-green, margin entire, apex rounded or notched, base broadly tapering to rounded, often hairy when young and shiny when getting older and clustered on short side branches (Palmer and Pitman, 1972). The flowers are small, sweet-scented, creamy green to creamy white, sometimes tinged pink to red and borne in single stem clusters in the axils of the spines or on the dwarf branchlets (Palgrave, 2002). Fruit ellipsoidal or ovoid drupe, greenish when young, orange to red flesh when ripe with juicy pulps and a smooth skin (Palmer and Pitman, 1972). The seed is smooth, ellipsoid, yellowish-brown to red, thick and hard coated (Palmer and Pitman, 1972; Palgrave, 2002).

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2.2. Distribution Ximenia caffra occurs naturally along the dryland zone in central, eastern and southern Africa, extending eastward to Madagascar (Fig. 2). The species is native to Angola, Botswana, Burundi, Democratic Republic of Congo, Ethiopia, Kenya, Madagascar, Malawi, Mozambique, Namibia, Rwanda, Somalia, South Africa, Swaziland, Tanzania, Uganda, Zambia and Zimbabwe. Ximenia caffra has been recorded in various types of woodland and wooded grassland, often on rocky kopjes and termite mounds. Like most medicinal plants, X. caffra is generally collected from the wild and Raimondo et al. (2009) categorized it as of Least Concern (LC) in South Africa based on IUCN Red List Categories and Criteria of threatened species (http://www.iucnredlist.org) as the species is widespread and abundant in the country. But X. caffra is of conservation concern in Mozambique (Bruschi et al., 2014) and traditional laws in Venda, the Limpopo province, South Africa, prohibit use of the species as a source of firewood (Mabogo, 1990). 2.3. Vernacular names of Ximenia caffra Ximenia caffra is commonly known as sour plum in English (Table 1), a common name also used for X. americana (Orwa et al., 2009). It is known by various vernacular names in different geographical regions (see Table 1). Prefixes such as “hairy large sourplum”, “kaffir plum”, “large sour plum”, “monkey plum” or “Natal sourplum” are added to differentiate X. caffra from X. americana often referred to as “blue sour plum”, “hog plum”, “small sour plum” or “wild plum” (Hutchings et al., 1996; Setshogo and Venter, 2003; Orwa et al., 2009; Nkwanyana, 2013; Hyde et al., 2015). A survey of literature showed no fewer than 105 vernacular names for X. caffra (Table 1). Tanzania, South Africa and Botswana (in their descending order of importance) appear to have the highest number of vernacular names for X. caffra (Table 1). People rarely name plant species that they do not use. This long list of vernacular names for X. caffra indicates that local people in central, eastern and southern Africa have an active interest in the species. More research needs to be carried out in the Democratic Republic of Congo (DRC), Madagascar, Rwanda and Uganda, where documentation of the vernacular names and uses of X. caffra are missing. Given the fact that X. caffra is a common species in central, eastern and southern Africa, the absence of data in DRC, Madagascar, Rwanda and Uganda is probably due to an overall lack of ethnobotanical research in these countries. 2.4. Ethnomedicinal uses of Ximenia caffra The bark, fruits, leaves, roots and seeds of the sour plum are reported to possess diverse medicinal properties and cure various human and animal ailments and diseases throughout its distributional range (Table 2). It is used to treat common or simple human ailments and diseases such as abdominal pain, cough and wounds, to complicated ailments such as sexually transmitted infections (STIs) and tuberculosis. Table 2 provides a summary of ethnomedicinal uses and plant parts used among diverse ethnic groups in sub-Saharan Africa. Leaves and roots of X. caffra are used as pain killer and against abdominal pains in Kenya, South Africa and Zimbabwe (Gelfand et al., 1985; Mulaudzi et al., 2011; de Wet et al., 2012; Gakuya et al., 2013). The roots are used against a variety of ailments and diseases including abscesses, anaemia, blood in faeces, chest pains, dermatitis, dizziness, dysentery, epilepsy, headache, hepatitis, hernia, hypertension, indigestion, respiratory tract infections, scurvy, sickness or lack of foetal movement, skin rashes, sweating, palpitations, swelling; and as purgative (Hedberg et al., 1983; Gelfand et al., 1985; Hedberg and Staugard, 1989; Mabogo, 1990; Von Koenen, 2001; Ruffo et al.,

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Fig. 2. Ximenia caffra naturally occurs along the dryland zone in central, eastern and southern Africa, extending eastward to Madagascar.

2002; Moshi et al., 2003; Nanyingi et al., 2008; Nzigidahera, 2009; Dan et al., 2010; Maroyi, 2011; Mulaudzi et al., 2011; de Wet et al., 2012; Motlhanka and Nthoiwa, 2013; Peter et al., 2014; Chinsembu et al., 2015). In Malawi and Zimbabwe, the leaf or root infusion or decoction of X. caffra is taken orally as aphrodisiac, against abdominal pains, diarrhoea, fever, haematuria, pelvic diseases in women, venereal diseases and to prevent infants being born crippled (Gelfand et al., 1985). Powdered dried leaves, bark, roots and twigs are taken orally for fever in Angola, Kenya, South Africa and Zimbabwe (Gelfand et al., 1985; Bossard, 1996; Nanyingi et al., 2008; Mulaudzi et al., 2011; de Wet et al., 2012; Bapela et al., 2014) and extracts of the leaves are used as a gargle for tonsillitis in South Africa (Mulaudzi et al., 2011). In several countries, including South Africa, Swaziland, Tanzania and Zimbabwe, the leaf and root infusion of X. caffra is dropped into eyes for relief of sore eyes (Gelfand et al., 1985; Mabogo, 1990; Mbuya et al., 1994; Hutchings et al., 1996; Long, 2005; Mulaudzi et al., 2011). Similarly, fruit, leaf, root or seed decoction, infusion or powder of X. caffra is taken orally for internal wounds such as ulcers or applied as an ointment to external wounds in countries such as Botswana, Ethiopia, Kenya, Namibia, South Africa, Tanzania and Zimbabwe (Gelfand et al., 1985; Hedberg and Staugard, 1989; Von Koenen, 2001; Ruffo et al., 2002; van Wyk and Gericke, 2007; Nanyingi et al., 2008; Dan et al.,

2010; Maroyi, 2011; Mulaudzi et al., 2011; Odhiambo et al., 2011; de Wet et al., 2012; Kidane et al., 2014). The use of X. caffra leaves and roots as a remedy for snake and scorpion bites and stings is widespread in Ethiopia and Tanzania (Ruffo et al., 2002; Maregesi et al., 2013; Getaneh and Girma, 2014). The leaves and roots are used in Malawi, Somalia, South Africa, Tanzania and Zimbabwe as remedy for bilharzia, a worm infection of the gut or urinary tract (Table 2). Von Koenen (2001) and Gakuya et al. (2013) confirm the use of X. caffra leaves and roots for helminth infections in Kenya and Namibia. Ximenia caffra leaves and roots are important remedies for treating unspecified intestinal worms in Mozambique, South Africa and Tanzania (Hedberg et al.,1983; Ruffo et al., 2002; Bruschi et al., 2011; Mulaudzi et al., 2011). Infections of the genitourinary tract, particularly gonorrhoea, syphilis and venereal diseases (Table 2) are treated both internally and externally with preparations of the bark, leaves and roots. De Wet et al. (2012) report that in northern Maputaland, KwaZulu-Natal province, South Africa, half a handful of X. caffra roots are chopped with half a handful of Tabernaemontana elegans Stapf roots and boiled in one litre of water for one hour, and one tablespoon of concoction taken three times a day as cure for gonorrhoea. Sexual complaints in both men and women such as infertility, poor libido, impotence and menorrhagia are treated with leaves and roots of X. caffra. For

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Table 1 The different vernacular names of Ximenia caffra in central, eastern and southern Africa. Vernacular name(s), ethnic group OR geographical region in brackets

Country

Reference

Olu meke, ulu meke (Umbundu) Hairy large sourplum, large sour plum, monkey plum (English), moretologa, moretologakgomo, moretologa wa dipudi, moretologa-wa-kgomo, moretonoga, morokolo, motsidi, mwombe, nswanja-ngombe (Setswana) Amasasa, mushereke, umunyonza (Hutu) Atat (central), hurranh-addee, inginkada (Somali), miloa (northern), mukalle (Maale), muulahuwa (southern) I-amai, ledat (Samburu), kumutili (Luhya), muroroma (Meru), olemo (Luo)

Angola Botswana

Bossard, 1996 Hedberg and Staugard, 1989; Roodt, 1998; Setshogo and Venter, 2003; Motlhanka et al., 2008; Motlhanka and Nthoiwa, 2013

Mlewe (Ngonde, Tumbuka) Mutengueni (ChiTewe, chiNdau) G//OE (Kung Bushmen), g║oeh (Ju|'hoan), hambya (Mbukushu), kaffersuurpruim, suurpruim (Afrikaans), large sour plum (English), mupeke (Rundu), ombyupeke, oshipeke, oshimbyupeke (Ndonga), omumbeke (Herero), omuninga (Himba), ompeke (Oshikoto), oshipeke oshimbyu (Kwanyama), rote wildpflaume (German), s sipeke (Kwangali) Madharuug, mandharud, muracood (Somali) Amathunduluka, umGwenya, umalala, umamumbhalo, umatimbolubu, umthunduluka, umThunduluka-obomvu (Zulu), groot suurpruim, kafferpruim, suurpruim, wildepruim (Afrikaans), itsengeni (Ndebele), Kaffir plum, natal sourplum, sour plum (English), morokolo, morotolonga, morotonoga (Tswana), mosidi (northern Sotho), mutanzwa, mutshili (Venda), ndzundzuluka, nhundzuluka, ntsengele (Tsonga), umthundulukwa (Swazi) Bingimbingi, mpingipingi (Ngoni), lama (Maasai), large sour plum (English), maanyangu (Barabaig, Iraqw), maanyangumo (Gorowa), mbingembinge, mpingipingi (Ndendeule), mhingi (Zigua), miengu, mjingu (Rangi), mjingu, mtundwe (Gogo), mnembwa, mtundwa (Nyamwezi), mpingi (Ngindo, Swahili), mpingipingi (Bena, Matengo), msantu (Bende), mseaka (Kerewe), mseka (Zinza), mtundwi (Isanzu), mtundui (Sambaa), mtundwa (Hehe), mtundwi (Zigua), muhingi (Zaramo), mutundwe (Nyaturu), mtundwi (Nyiramba), wandanda, xaya (Sandawe) Ematfundfuluka, emathunduluka, umftundvuluka, umftunvuluka, umthundulukwa (Swazi), large sour plum (English) Mtswanzwa (Tonga) Munhengeni, mutengeni, mutsvanzva (Shona), sour plum (English)

example, in Zimbabwe, root powder of X. caffra is taken orally as a sexual stimulant or aphrodisiac in soup or traditional beer (Gelfand et al., 1985). The bark and fruits are used by small-scale farmers as ethnoveterinary medicine to treat dermatophilosis in Zimbabwe (Ndhlovu and Masika, 2013) and ectoparasites, foot rot and saddle sores in Ethiopia (Gebrezgabiher et al., 2013; Gemeda et al., 2014; Kidane et al., 2014). A total of 65 traditional medicinal uses of X. caffra are registered (Table 2). There is cross-cultural agreement among ethnomedicinal uses of X. caffra throughout its distributional range, and there is a high degree of consensus for wounds, STIs, infertility, stomach ache, fever, eye problems, diarrhoea, bilharzia, menorrhagia, malaria, intestinal worms and cough (Fig. 3). Previous research by Maroyi (2013) revealed that wounds, STIs, sexual dysfunction, ophthalmonological, gastro-intestinal disorders, fever, ear problems, cold, cough and sore throat are a major concern in tropical Africa. Ethnomedicinal information has been found in Angola, Botswana, Burundi, Ethiopia, Kenya, Malawi, Mozambique, Namibia, Somalia, South Africa, Swaziland, Tanzania, Zambia and Zimbabwe, representing 83.3% of the countries where X. caffra is indigenous. The country with the highest ethnomedicinal uses is South Africa (24) based on 11 literature records, followed by Tanzania with 23 uses and seven literature records, Zimbabwe with 13 uses and five literature records, Kenya with 11 uses and five literature records, Mozambique with 11 uses and two literature records, Namibia with 11 uses and seven literature records, Botswana with nine uses and five literature records, and Ethiopia with eight uses and seven literature records. This qualitative and quantitative data gives a perspective on the ethnomedicinal uses of X. caffra throughout its distributional range. This data is not only

Burundi Ethiopia

Nzigidahera, 2009 Getahun, 1976; Agize et al., 2013; Gebrezgabiher et al., 2013; Getaneh and Girma, 2014; Kidane et al., 2014 Kenya Fratkin, 1996; Geissler et al., 2002; Nanyingi et al., 2008; Odhiambo et al., 2011; Gakuya et al., 2013 Malawi Bundschuh et al., 2011 Mozambique Bruschi et al., 2011, 2014 Namibia LE roux, 1971; palmer and pitman, 1972; Von Koenen, 2001; Leffers, 2003; Cheikhyoussef et al., 2011; Chinsembu et al., 2015

Somalia South Africa

Samuelsson et al., 1992 Palmer and pitman, 1972; Liengme, 1981; Mabogo, 1990; Hutchings et al., 1996; Venter and Venter, 1996; Raymond, 2005; DE wet et al., 2012; Nkwanyana, 2013

Tanzania

Hedberg et al., 1983; Hines and Eckman, 1993; Mbuya et al., 1994; Ruffo et al., 2002; Moshi et al., 2003, 2004; Orwa et al., 2009; Peter et al., 2014

Swaziland

Long, 2005; Singwane and Shabangu, 2012

Zambia Zimbabwe

Ndubani and Höjer, 1999 Kambizi and Afolayan, 2001; Palgrave, 2002; Maroyi, 2011; Hyde et al., 2015

of considerable cultural value, but allows comparative studies relating to ethnomedicinal usage of X. caffra in sub-Saharan Africa to be made. Ximenia caffra fruit, nut and/or oil are traded in several countries, including Botswana, Namibia, Rwanda and Zimbabwe (Roodt, 1998; Motlhanka et al., 2008; Bigirimana et al., 2013). Seed oil is traditionally used as soap, to soften skin as a cosmetic in Botswana and Swaziland (Long, 2005; Motlhanka et al., 2008), soften leather, oil bows and bow strings, lubricate farm machinery and preserve dried meat in Botswana, South Africa and Swaziland (Palmer and Pitman, 1972; Mabogo, 1990; Long, 2005; Motlhanka et al., 2008). Fruits are edible, the flesh of the raw fruits is consumed, the skin is discarded or juice sucked from them. The fruits are also made into a drink, jam or jellies or used as food additive in Angola, Botswana, Burundi, Ethiopia, Mozambique, Namibia, Rwanda, South Africa and Swaziland (Getahun, 1976; Liengme, 1981; Mabogo, 1990; Bossard, 1996; Roodt, 1998; Long, 2005; Motlhanka et al., 2008; Nzigidahera, 2009; Singwane and Shabangu, 2012; Bigirimana et al., 2013; Bruschi et al., 2014). Ximenia caffra is used as source of timber for making tool handles, wood carvings, general construction and as firewood throughout its distributional range and as hedge plant in Tanzania (Ruffo et al., 2002). During initiation ceremonies, Venda girls in the Limpopo province, South Africa wear a tassel woven of the bark of X. caffra painted with the juice of Annona spp. (Palmer and Pitman, 1972). According to the same author, the Ndebele people of the Limpopo and Mpumalanga provinces, South Africa grind the roots of X. caffra and mix them with cow dung into a floor polish to ward off witches.

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A. Maroyi / Journal of Ethnopharmacology 184 (2016) 81–100

Table 2 Ethnomedicinal uses of Ximenia caffra in central, eastern and southern Africa. Use

Plant part(s) used

Country practised

Reference(s)

Abdominal pain Abscess Anaemia Antihelmintic Aphrodisiac

Leaves, roots Roots Roots Leaves, roots Roots

South Africa, Zimbabwe Tanzania Tanzania Kenya, Namibia Botswana, South Africa, Zimbabwe

Asthma Backache Bilharzia

Bark, roots Leaves Leaves, roots

Kenya, Swaziland Zimbabwe Malawi, Somalia, South Africa, Tanzania, Zimbabwe

Bleeding of the nose

South Africa

Blood in faeces Boils Chest pains Colic Conjuntivitis Constipation Cough Culture bound syndrome Dermatitis Diarrhoea

Smoke from burning root powder Roots Leaves Roots Bark, roots Leaves Leaves, roots Leaves, roots Roots Roots Bark, roots, leaves

Gelfand et al., 1985; Mulaudzi et al., 2011; de wet et al., 2012 Hedberg et al., 1983 Peter et al., 2014 Von Koenen, 2001; Gakuya et al., 2013 Gelfand et al., 1985; Maroyi, 2011; Mulaudzi et al., 2011; de wet et al., 2012; Motlhanka and Nthoiwa, 2013 Long, 2005; Odhiambo et al., 2011 Maroyi, 2011 Gelfand et al., 1985; Samuelsson et al., 1992; Hines and Eckman, 1993; Ruffo et al., 2002; Moshi et al., 2003; Mulaudzi et al., 2011; de wet et al., 2012 Mabogo, 1990; Hutchings et al., 1996

Dizziness Dysentery Ectoparasites Epilepsy Ethnoveterinary medicine

Roots Roots Fruits Roots Bark, fruits

Eye problems

Leaves, roots

Febrifuge Infertility (including prevention of infertility)

Leaves, roots, twigs Leaves, roots

Fever Flu Headache Intestinal worms

Bark, leaves, roots, twigs Bark, roots Roots Leaves, roots

Hepatitis Hernia Hypertension Impetigo Impotence Indigestion Inflammation Leprosy Malaria

Roots Roots Roots Fruits Roots, whole plant Roots Leaves, roots Leaves, roots Fruits, leaves, roots

Menorrhagia Mental disorder Mouth infection Pain killer Pelvic diseases Poultices Propitiatory Purgative Pustules of chicken pox Respiratory tract infections Scabies Scurvy Sickness or lack of foetal movement Skin rashes Snakebite, scorpion stings Stomach ache

Leaves, roots Leaves, roots Bark, roots Leaves, roots Roots Leaves Leaves, roots Roots Fruits Roots Fruits Roots Roots

STIs (gonorrhoea, syphilis, venereal diseases)

Bark, leaves, roots

Roots Leaves, roots Bark, leaves, roots

South Africa Tanzania Namibia, Tanzania Ethiopia, Tanzania Botswana Mozambique Mozambique, South Africa, Tanzania Namibia Kenya Kenya, Namibia, Somalia, South Africa, Zimbabwe

Mabogo, 1990 Ruffo et al., 2002 Hedberg et al., 1983; Ruffo et al., 2002; Dan et al., 2010 Hines and Eckman, 1993; Agize et al., 2013 Motlhanka and Nthoiwa, 2013 Bruschi et al., 2011 Mabogo, 1990; Mbuya et al., 1994; Ruffo et al., 2002; Bruschi et al., 2011 Cheikhyoussef et al., 2011 Nanyingi et al., 2008 Gelfand et al., 1985; Claeson and Samuelsson, 1989; Mabogo, 1990; Von Koenen, 2001; Maroyi, 2011; Mulaudzi et al., 2011; de wet et al., 2012; Gakuya et al., 2013; Chinsembu et al., 2015 Botswana Hedberg and Staugard, 1989 South Africa Mulaudzi et al., 2011; de wet et al., 2012 Ethiopia Gemeda et al., 2014 Tanzania Moshi et al., 2003 Ethiopia, Zimbabwe Gebrezgabiher et al., 2013; Ndhlovu and Masika, 2013; Gemeda et al., 2014; Kidane et al., 2014 South Africa, Swaziland, Tanzania, Gelfand et al., 1985; Mabogo, 1990; Mbuya et al., 1994; Hutchings et al., Zimbabwe 1996; long, 2005; Mulaudzi et al., 2011 South Africa Mabogo, 1990; Bapela et al., 2014 Botswana, Mozambique, South Africa, Gelfand et al. (1985); Hedberg and Staugard, 1989; Mabogo, 1990; Tanzania, Zimbabwe Hines and Eckman, 1993; Bruschi et al., 2011; Maroyi, 2011; Mulaudzi et al., 2011; de wet et al., 2012 Angola, Kenya, South Africa, Zimbabwe Gelfand et al., 1985; Bossard, 1996; Nanyingi et al., 2008; Mulaudzi et al., 2011; de wet et al., 2012; Bapela et al., 2014 Swaziland Long, 2005 South Africa Mabogo, 1990 Mozambique, South Africa, Tanzania Hedberg et al.,1983; Ruffo et al., 2002; Bruschi et al., 2011; Mulaudzi et al., 2011 Burundi Nzigidahera, 2009 Tanzania Ruffo et al., 2002 Tanzania Moshi et al., 2003 South Africa Van Wyk and Gericke, 2007 Namibia Cheikhyoussef et al., 2011 South Africa Mabogo, 1990 Namibia, Tanzania Mbuya et al., 1994; Von Koenen, 2001 Botswana, Mozambique Hedberg and Staugard, 1989; Bruschi et al., 2011 Rwanda, Tanzania, Zambia Hines and Eckman, 1993; Ruffo et al., 2002; fowler, 2006; Bigirimana et al., 2013 Mozambique, South Africa, Tanzania Mabogo, 1990; Ruffo et al., 2002; Bruschi et al., 2011 Tanzania Mbuya et al., 1994; Ruffo et al., 2002 Kenya Geissler et al., 2002 Kenya Gakuya et al., 2013 Zimbabwe Gelfand et al., 1985 Tanzania Ruffo et al., 2002 Mozambique Bruschi et al., 2011 Namibia Von Koenen, 2001 South Africa Van Wyk and Gericke, 2007 Kenya Nanyingi et al., 2008 South Africa Van Wyk and Gericke, 2007 South Africa Mabogo, 1990 Botswana Hedberg and Staugard, 1989 Namibia Ethiopia, Tanzania Ethiopia, Kenya, Mozambique, Tanzania Ethiopia, Mozambique, Namibia, South Africa, Tanzania, Zambia, Zimbabwe

Chinsembu et al., 2015 Ruffo et al., 2002; Maregesi et al., 2013; Getaneh and Girma, 2014 Hines and Eckman, 1993; Fratkin, 1996; Geissler et al., 2002; Ruffo et al., 2002; Bruschi et al., 2011; Agize et al., 2013 Hedberg et al., 1983; Gelfand et al., 1985; Mabogo, 1990; Ndubani and Höjer, 1999; Kambizi and Afolayan, 2001; Von Koenen, 2001; Ruffo et al., 2002; Bruschi et al., 2011; Cheikhyoussef et al., 2011; Maroyi, 2011; de wet et al., 2012; Agize et al., 2013; Chinsembu et al., 2015

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Table 2 (continued ) Use

Plant part(s) used

Country practised

Reference(s)

Sweating and palpitations Swellings To prevent infant being born crippled Tonsillitis Toothache Tuberculosis Vomiting Weakness in children Weight loss Wounds (sores, ulcers)

Roots Roots Roots

Botswana Botswana Zimbabwe

Hedberg and Staugard, 1989 Hedberg and Staugard, 1989 Gelfand et al., 1985

Leaves Bark, leaves, roots Leaves, roots Leaves Leaves, roots Whole plant Fruits, leaves, roots, seeds

South Africa Kenya, Tanzania Mozambique, Namibia Somalia Mozambique Swaziland Botswana, Ethiopia, Kenya, Namibia, South Africa, Tanzania, Zimbabwe

Mulaudzi et al., 2011 Geissler et al., 2002; Ruffo et al., 2002; Gakuya et al., 2013 Bruschi et al., 2011; Chinsembu et al., 2015 Claeson and Samuelsson, 1989 Bruschi et al., 2011 Long, 2005 Gelfand et al., 1985; Hedberg and Staugard, 1989; Von Koenen, 2001; Ruffo et al., 2002; van Wyk and Gericke, 2007; Nanyingi et al., 2008; Dan et al., 2010; Maroyi, 2011; Mulaudzi et al., 2011; Odhiambo et al., 2011; de wet et al., 2012; Kidane et al., 2014

Wounds STI Infertility Stomach ache Fever Eye problems Diarrhoea Bilharzia Menorrhagia Malaria Intestinal worms Cough 0

1

2

3

4

5

6

7

8

Number of countries Fig. 3. Cross-cultural agreement among ethnomedicinal uses of Ximenia caffra in three or more countries in sub-Saharan Africa.

3. Phytochemical constituents and nutritional composition of Ximenia caffra Based on literature records documenting traditional and potential medicinal uses of X. caffra, many researchers have also investigated its phytochemical and pharmacological properties aimed at identifying the compounds responsible for its wide use as traditional medicine. Multiple classes of phytochemicals including phenolic compounds, flavonoids and tannins as well as many other medicinal ingredients and several minerals have been identified in X. caffra leaves, roots, fruits and oil in different investigations (Lighthelm et al., 1954; Chivandi et al., 2008, 2012a, b; Ndhlala et al., 2008; Mitei et al., 2008, 2009; Mulaudzi et al., 2011; Addis et al., 2013; Nair et al., 2013; Zhen et al., 2015). 3.1. Phytochemical and nutritional constituents of Ximenia caffra oil and fruits Fresh edible fruits have a wide variety of so-called classic nutrients, such as carbohydrates, minerals, proteins, fats and vitamins (Lighthelm et al., 1954; Chivandi et al., 2008, 2012a, b; Ndhlala et al., 2008; Mitei et al., 2008; Addis et al., 2013). The nutritional composition of X. caffra fruits, leaves and roots is shown in Table 3. Ximenia caffra fruits are a good source of minerals such as

calcium, copper, iron, magnesium, manganese, phosphorus and zinc (Addis et al., 2013). High acidity of the fruit juice determined to be 8.6% by Lighthelm et al. (1954) is accounted for entirely by citric acid (1) (Table 3). Some of these nutrients are present in low concentrations, but may have significant impact on human health when X. caffra fruits are eaten raw, used as food additive, fruit oil used in cosmetics or when other plant parts are used as herbal medicines. The fruit peel and pulp of X. caffra contain flavonols, phenolics and proanthocyanidin (Ndhlala et al., 2008, Table 3). These polyphenolic compounds usually occur in combination with glycosides (Harborne and Baxter, 1999) and are responsible for the pharmacological properties of many medicinal plant species. Ndhlala et al. (2006) attributed the antibacterial activity of X. caffra fruits to simple phenolic compounds of the species such as p-coumaric (2), ferulic (3) and vanillic (4) acids. The antioxidant activity exhibited by the peels and pulps of X. caffra is attributed to polyphenols contained in these plant parts (Ndhlala et al., 2006). Mitei et al. (2008) provide lipid and phytosterol, tocopherol as well as tocotrienol profiles of X. caffra seed oil, while amino acid profiles are provided by Chivandi et al. (2012b) (Table 3). Phytosterols have been shown to have important bioactive prevention properties such as lowering of cholesterol levels (Piironen et al., 2000), cancer prevention (Awad and Fink, 2000) and other physiological and nutritive properties. Glutamic acid (18) is the most abundant amino acid in X. caffra seed (Table 4) constituting 2.34 70.18 g 100 g
1 (12.8%) of the total crude protein of the seed. Ximenia caffra oil contain saturated fatty acids such as arachidic (32), behenic (33), cerotic (34), lacceroic (35), lignoceric (36), montanic (37), myristic (38), octacos-19-enoic (39), palmitic (40), stearic (41) and ximenynic (42). Monounsaturated fatty acids included erucic (43), gondoic (44), hexadecenoic (45), lumequic (46), myristoleoic (47), nervonic (48), oleic (49) and ximenic (50); while polyunsaturated fatty acids included α-linolenic (51), linoleic (52) and triunsaturated fatty acids represented by β-eleostearic (53) (Fig. 4, Table 4). Some of the fatty acids isolated from X. caffra oil have more than 22 carbon atoms (Table 4), termed very long fatty acids which are rarely found in nature (Rezanka and Sigler, 2007). The relatively high proportion of very long fatty acid chains in X. caffra seed oil makes it a good candidate for use as lubricating oil for machines (Mitei et al., 2008). These long chain unsaturated fatty acids which are characteristic of X. caffra seed oil have potential as non-conventional energy and protein sources for livestock feeds (Chivandi et al., 2012a), domestic biofuel (Venter and Venter, 1996; Van Wyk and Gericke, 2007), skin conditioner used to treat chapped hands and feet as traditionally used by the KhoiSan people in South Africa (Van Wyk et al., 1997). Some of the very long chain saturated fatty acids such as lignoceric (35) are linked to the etiology of adrenoleukodystrophy

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A. Maroyi / Journal of Ethnopharmacology 184 (2016) 81–100

Table 3 Nutritional composition and other phytochemicals isolated from Ximenia caffra fruits and other plant parts. Caloric, nutritional and phytochemicals Fruit (kernel, peel, pulp/oil)

Values

Reference

Acid detergent fibre (ADF) Ascorbic acid (5) ASH (kernel), % of dry weight Ca2 þ Carbohydrate Citric acid (1) (pulp), % of expressed juice Crude fibre Cu Dry matter Energy Ether extract (EE) Fat Fe Fibre (kernel), % of dry weight Flavanols (fruit peel) Flavanols (fruit pulp) Mg2 þ Mn Moisture (fruit pulp) Moisture (kernel) Neutral detergent fibre (NDF) Oil (fruit pulp), % of fresh weight Oil (kernel), % of dry weight Organic matter P Proanthocyanidin (fruit peel) Proanthocyanidin (fruit pulp) Protein (kernel), % of dry weight Total 4-desmethylsterol Total phenolics (fruit peel) Total phenolics (fruit pulp) Total tocopherol and tocotrienol Vitamin C Vitamin E Zn

51.2 7 1.7 g kg
1 27 mg 100 mg
1 1.6% 17.9 mg 100 g
1 39.4 (g 100 g
1) 8.7% 10.4 7 1.4 (g 100 g
1) 0.58 mg % dry matter 955.17 0.78 g kg
1 157.5 kcal 484.5 70.01 23.6 7 1.0 (g 100g
1) 1.9 mg % dry matter 3.7% 27.1 7 1.3 (mg g
1) 20.4 7 0.2 (mg g
1) 207.9 7 5.9 mg 100 g
1 1.1 mg % dry matter 77.6% 26.2% 213.3 7 5.5 g kg
1 0.3% 65.7% 934.7 7 2.0 g kg
1 345.5 7 5.9 mg 100 g
1 1.177 0.05 (% of dry matter) 0.577 0.04 (% of dry matter) 19.9% 109.11 mg g
1 1205 7 23 (mg g
1) 229 74 (mg g
1) 128.0 73.7 mg g
1 27% 0.53 7 0.1 mg g
1 1.3 mg % dry matter

Chivandi et al., 2012a Addis et al., 2013 Lighthelm et al., 1954 Chivandi et al., 2012a Addis et al., 2013 Lighthelm et al., 1954 Addis et al., 2013 Addis et al., 2013 Chivandi et al., 2012a Addis et al., 2013 Chivandi et al., 2012a Addis et al., 2013 Addis et al., 2013 Lighthelm et al., 1954 Ndhlala et al., 2008 Ndhlala et al., 2008 Chivandi et al., 2012a Addis et al., 2013 Lighthelm et al., 1954 Lighthelm et al., 1954 Chivandi et al., 2012a Lighthelm et al., 1954 Lighthelm et al., 1954 Chivandi et al., 2012a Chivandi et al., 2012a Ndhlala et al., 2008 Ndhlala et al., 2008 Lighthelm et al., 1954 Ndhlala et al., 2008 Ndhlala et al., 2008 Ndhlala et al., 2008 Ndhlala et al., 2008 Ndhlala et al., 2008 Chivandi et al., 2012a Addis et al., 2013

Other plant parts Catechin (6) (leaves) Condensed tannins (leaves) Condensed tannins (roots) Flavonoids (leaves) Flavonoids (roots) Gallic acid (7) (leaves) Gallotannin (leaves) Gallotannin (roots) Kaempferol-galactosyl/glucosyl (8) (leaves) Kaempferol-galactosyl-rhamnosyl/kaempferol-glucosyl-rhamnosyl (8) (leaves) Quercetin-galactosyl/glucosyl (8) (leaves) Quercetin-galactosyl-galloyl (8) (leaves) Quercetin-glucosyl-galloyl (8) (leaves) Quercetin-galactosyl-rhamnosyl/quercetin-glucosyl-rhamnosyl (8) (leaves) Quercetin-glucosyl-rhamnosyl (rutin) (8) (leaves) Quercetin-xylosyl (8) (leaves) Total phenolics (leaves) Total phenolics (roots)

1.77 mg g
1 0.15 70.01 (%LCE)a 0.48 70.03 (%LCE)a 11.9 70.04 (mgCAE g
1)b 11.17 0.2 (mgCAE g
1)b 0.96 mg g
1 40.417 1.65 (mgGAE g
1) 26.92 7 4.21 (mgGAE g
1) 0.26 mg g
1 0.82 mg g
1 2.03 mg g
1 1.59 mg g
1 1.70 mg g
1 1.12 mg g
1 9.08 mg g
1 0.11 mg g
1 11.9 70.1 (mgGAE g
1)c 12.0 70.01 (mgGAE g
1)c

Zhen et al., 2015 Mulaudzi et al., 2011 Mulaudzi et al., 2011 Mulaudzi et al., 2011 Mulaudzi et al., 2011 Zhen et al., 2015 Mulaudzi et al., 2011 Mulaudzi et al., 2011 Zhen et al., 2015 Zhen et al., 2015 Zhen et al., 2015 Zhen et al., 2015 Zhen et al., 2015 Zhen et al., 2015 Zhen et al., 2015 Zhen et al., 2015 Mulaudzi et al., 2011 Mulaudzi et al., 2011

a b c

Values expressed as percentage leucocyanidin equivalents (LCE) per gram plant extracts. Values expressed as catechin equivalents (CTE) per gram of plant extracts. Values expressed as gallic acid equivalent (GAE) per gram of plant extracts.

(ALD) and multiple sclerosis (MS) (William et al., 2001). Previous research demonstrated the importance of dietary intake of oleic acid (49), stearic acid (41), tocopherol, polyphenols and other phenolic compounds that have been isolated from X. caffra, as they aid in blood pressure reduction (Terés et al., 2008), lowering heart attack and arteriosclerosis risks. Previous research by Li et al. (2008) also showed that acetylenic metabolites and unsaturated fatty acids have antifungal potencies, low toxicities, synthetic accessibilities and good pharmaceutical properties. The physiological

and pathophysiological efficacy of some fatty acid classes, particularly polyunsaturated fatty acids in inhibiting carcinogenesis, treating major depression, hyperlipidemia, hypertension, diabetes, auto-immune and chronic inflammatory diseases, reducing the risk of cardiovascular diseases and mortality (Fostok et al., 2011). Therefore, X. caffra oil and other plant parts which have demonstrated to be rich in very long chain fatty acids (Table 4) could play an important role in the treatment and management of diseases such as hypertension and inflammation listed in Table 2.

A. Maroyi / Journal of Ethnopharmacology 184 (2016) 81–100

89

Table 4 The lipids, amino acids, phytosterols and fatty acid composition of seed oil of Ximenia caffra Phytochemicals Lipids

Values

Reference

Diacylglycerols Free sterols Glycolipids Hydrocarbons Monoacylglycerols Phospholipids Sterol esters Triacylglycerols and free fatty acids

16.02% 0.96% 0.97% 0.96% 6.32% 3.02% 0.08% 86.51%

Mitei Mitei Mitei Mitei Mitei Mitei Mitei Mitei

et et et et et et et et

al., al., al., al., al., al., al., al.,

2008 2008 2008 2008 2008 2008 2008 2008

Phytosterols β-Amyrin (9) Δ5-Avenasterol (10) Campesterol (11) Lupeol (12) 24-methylene-cycloartenol (13) Sitosterol (14)

25.417 1.12% 4.417 0.23% 9.14 70.10% 5.21 70.16% 5.98 7 0.16% 46.49 70.91%

Mitei Mitei Mitei Mitei Mitei Mitei

et et et et et et

al., al., al., al., al., al.,

2009 2009 2009 2009 2009 2009

Amino acids Alanine (15) Arginine (16) Aspartic acid (17) Glutamic acid (18) Glycine (19) Histidine (20) Hydroxyproline (21) Isoleucine (22) Leucine (23) Lysine (24) Methionine (25) Phenylalanine (26) Proline (27) Serine (28) Threonine (29) Tyrosine (30) Valine (31)

1.177 0.04 g 100 g
1 1.85 70.16 g 100 g
1 1.217 0.11 g 100 g
1 2.34 7 0.18 g 100 g
1 0.58 7 0.05 g 100 g
1 0.47 70.07 g 100 g
1 0.247 0.01 g 100 g
1 0.62 7 0.02 g 100 g
1 1.03 70.05 g 100 g
1 1.03 70.09 g 100 g
1 0.16 70.02 g 100 g
1 0.55 7 0.04 g 100 g
1 0.79 7 0.00 g 100 g
1 0.64 70.04 g 100 g
1 0.737 0.08 g 100 g
1 0.75 7 0.13 g 100 g
1 0.71 7 0.04 g 100 g
1

Chivandi Chivandi Chivandi Chivandi Chivandi Chivandi Chivandi Chivandi Chivandi Chivandi Chivandi Chivandi Chivandi Chivandi Chivandi Chivandi Chivandi

Saturated fatty acids Arachidic (eicosanoic) (C20:0) (32) Behenic (docosanoic) (C22:0) (33) Cerotic (hexacosanoic) (C26:0) (34) Lacceroic (C32:0) (35) Lignoceric (tetracosanoic) (C24:0) (36) Montanic (octacosanoic) (C28:0) (37) Myristic (C14:0) (38) Octacos-19-enoic (C28:0) (39) Palmitic (C16:0) (40) Stearic (C18:0) (41) Ximenynic (C18:0) (42)

3.31 70.03% 0.56 7 0.24% 3.8% 1.0% 17.84 71.46% 1.0% 0.02 7 0.01% 9.6% 0.4% 2.6% 24.3%

Mitei et al., 2008 Chivandi et al., 2012a Lighthelm et al., 1954 Lighthelm et al., 1954 Chivandi et al., 2012a Lighthelm et al., 1954 Chivandi et al., 2012a Lighthelm et al., 1954 Lighthelm et al., 1954 Lighthelm et al., 1954 Lighthelm et al., 1954

Monounsaturated fatty acids Erucic (docos-13-enoic) (C22:1n9) (43) Gondoic (C20:1) (44) Hexadecenoic (C16:1n7) (45) Lumequic (triacont-21-enoic) (C30:1) (46) Myristoleoic (C14:1n7) (47) Nervonic (C24:1n9) (48) Oleic (C18:1n9) (49) Ximenic (hexacos-17-enoic) (C26:1n9) (50)

22.4% 2.5% 1.5% 5.4% 0.03 7 0.01% 8.64 72.76% 32.5% 3.5%

Khumalo et al., 2002 Lighthelm et al., 1954 Lighthelm et al., 1954 Lighthelm et al., 1954 Chivandi et al., 2012a Chivandi et al., 2012a Lighthelm et al., 1954 Lighthelm et al., 1954

Polyunsaturated fatty acids α-linolenic (C18:3n3) (51) Linoleic (C18:2n6) (52)

7.80 70.84% 1.7%

Chivandi et al., 2012a Khumalo et al., 2002

Triunsaturated fatty acid β-Eleostearic (C18:0) (53)

0.4%

Lighthelm et al., 1954

3.2. Phytochemical constituents of other plant parts of Ximenia caffra Multiple classes of flavonoid compounds and polyphenols have recently been isolated, identified and quantified in X. caffra leaves by Zhen et al. (2015), using HPLC/UV/MS analyses, which included catechin (6), gallic acid (7), quercetin (8), kaempferol (8) and other

et et et et et et et et et et et et et et et et et

al., al., al., al., al., al., al., al., al., al., al., al., al., al., al., al., al.,

2012b 2012b 2012b 2012b 2012b 2012b 2012b 2012b 2012b 2012b 2012b 2012b 2012b 2012b 2012b 2012b 2012b

derivatives (Table 3). The total content of these compounds was found to be 19.45 mg/g in the leaf and the most abundant polyphenol was quercetin-rutinoside weighing 9.08 mg/g (Zhen et al. (2015). The same authors quantified the total phenolic content using the Folic-Ciocaltec assay as 261.8777.11 mg GAE/g and the total antioxidant capacity as measured in vitro as 1.4670.01 mmol. Trolox/g. Nair et al. (2013) isolated and identified bisnorsesquiterpen

90

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vomifoliol (54) from the EtOH and DCM leaf extracts of X. caffra. These authors subjected both the EtOH and DCM leaf extracts to bioassay-guided fractionation leading to the identification of the bisnorsesquiterpen vomifoliol (54), also referred to as a megastigmane. It comprises of a polyfunctionalized α, β-unsaturated hexyl ring system together with a 1.3-disubstituted butylidene side chain (Fig. 4). According to Nair et al. (2013), leaf ethanolic extract exhibited 43.9% inhibition and DCM partition exhibited significant activity of 63.1% against gonorrhoeal pathogen, Neisseria gonorrhoeae, thus accounting for the ethnomedicinal applications of X.

caffra against gonorrhoea and allied sexually transmitted infections (STIs) is several countries in sub-Saharan Africa such as Ethiopia, Mozambique, Namibia, South Africa, Tanzania, Zambia and Zimbabwe (see Table 2). Although the compounds contained in the plant's leaves and roots have not been well studied, some of the isolated compounds include p-coumarins (2) isolated from X. caffra roots (Okemo, 1996; Munodawafa, 2012), condensed tannins, flavonoids, gallotannins and phenolics isolated from both the leaves and roots (Zhen et al., 2015). Mulaudzi et al. (2011) determined total

Fig. 4. Chemical structures of major compounds isolated from leaves, roots, fruit peel, pulp and oil of Ximenia caffra.

A. Maroyi / Journal of Ethnopharmacology 184 (2016) 81–100

Fig. 4. (continued)

91

92

A. Maroyi / Journal of Ethnopharmacology 184 (2016) 81–100

phenolics of X. caffra leaves and roots, which amounted to more than 5 mg/ml or 4.5% in dry matter of plant extracts (Table 3), an amount considered to be significantly high and likely to have beneficial effects such as antioxidant properties (Makkar et al., 2007). Ndhlala et al. (2008) argued that some of the phenolic compounds are used to treat inflammatory diseases and they also play an important role in the wound healing process. Mulaudzi et al. (2011) also determined the flavonoid concentrations of X. caffra leaves and roots, which were determined to be at least 11.1 mg/g (Table 3). The roots and leaves of X. caffra were found to have gallotannins of 26.9 and 40.4 mg/g respectively and at least 0.15% condensed tannins by Mulaudzi et al. (2011). Some of these polyphenols such as flavonoids, tannins and phenolic acids possess an ideal structural chemistry for free radical scavenging activity (Bhandare et al., 2010). These secondary metabolites have antioxidant, antiallergenic, anti-inflammatory, antimicrobial and antiproliferative properties (Muchuweti et al., 2007) that make plant extracts and products successful in the treatment of a wide range of human diseases and ailments. These diverse biological activities affect a range of physiological processes in the human body, thus providing protection against both free radicals and growth of undesirable bacterial, fungal and viral organisms. Gallotannins detected in X. caffra are known to have an effect on bioactivities such as antioxidant, antimicrobial, anticancer and antiviral activities (Hagerman et al., 1999; Feldman et al., 2001). Research done by Bruneton (1995) revealed that tannins enhance tissue regeneration in superficial wounds and have also antimicrobial effects. Flavonoid compound is known to have an effect on bioactivities such as anti-inflammatory, enzyme inhibition and antimicrobial activities (Havsteen, 1983; Harborne and Baxter, 1999). The high levels of phenolics, flavonoids, gallotannins and condensed tannins detected in the leaves and roots of X. caffra could be responsible for some of the ethnomedicinal uses of the species listed in Table 2 such as gastro-intestinal disorders, STIs and wounds.

4. Pharmacological activities A number of pharmacological activities of X. caffra have been reported in literature justifying some of its ethnomedicinal uses. Some of the listed pharmacological activities (Table 5) may not relate directly to the ethnomedicinal uses of X. caffra, but may provide some insight into its potential therapeutic value and bioactive properties. A wide range of biological activities have been reported including anti-amoebic (Samie et al., 2009), antibacterial (Fabry et al., 1998; Samie et al., 2005; Mathabe et al., 2006; Steenkamp et al., 2007; Mulaudzi et al., 2011; Munodawafa, 2012; Naidoo et al., 2013; Nair et al., 2013), antifungal (Fabry et al., 1996; Okemo, 1996; Samie et al., 2010; Mulaudzi et al., 2011; Munodawafa, 2012; Naidoo et al., 2013; Samie and Mashau, 2013), antiviral (Klos et al., 2009; Mulaudzi et al., 2011), anti-inflammatory (Mulaudzi et al., 2011; Zhen et al., 2015), antioxidant (Ndhlala et al., 2006; Munodawafa, 2012), antiparasitic and insecticidal (Sparg et al., 2000; Mølgaard et al., 2001; Clarkson et al., 2004; Ojewole, 2004; Maharaj et al., 2012; Bapela et al., 2014; Gemeda et al., 2014), antiproliferative (Chivandi et al., 2012b; Zhen et al., 2015), non-mutagenic and toxicity (Kamuhabwa et al., 2000; Moshi et al., 2003, 2004; Samie et al., 2009; Munodawafa, 2012; Mulaudzi et al., 2013; Naidoo et al., 2013; Bapela et al., 2014) (Table 5). 4.1. Anti-amoebic Samie et al. (2009) report that X. caffra had some anti-amoebic activity against Entamoeba histolytica for acetone leaf extract with IC50 410 mg/ml and IC90 410 mg/ml.

4.2. Antimicrobial 4.2.1. Antibacterial Bark, leaves and roots of X. caffra have been used as herbal medicines for bacterial infections for generations and seem to have potential as antibacterial agents. Steenkamp et al. (2007) showed that aqueous and methanol extracts of X. caffra roots exhibited antibacterial activities against Staphylococcus aureus and Staphylococcus epidermidis, where ampicillin was used as a positive control. These observations are supported by previous reports on the antibacterial activity of leaves and roots acetone extracts of X. caffra against fifteen clinical bacterial species conducted by Samie et al. (2005) together with early studies conducted by Fabry et al. (1998). Antibacterial evaluation carried out by Samie et al. (2005) used 10 ml of a 50 mg/ml gentamycin as a positive control and 15 ml (6%) of dimethyl sulfoxide (DMSO) as negative control while no positive control was mentioned by Fabry et al. (1998). Mathabe et al. (2006), Mulaudzi et al. (2011) and Naidoo et al. (2013) investigated the antibacterial effects of aqueous extract as well as acetone, dichloromethane, ethanol, methanol and petroleum ether extracts of X. caffra against bacteria associated with diarrhoea and urogenital or sexually transmitted infections (Table 5). Mathabe et al. (2006) used ten microliters of DMSO per well as negative control while discs (5 mm in diameter) of nalidixic acid (30 mg), erythromycin (15 mg) and cotrimoxazole (25 mg) were used as positive controls. These authors tested acetone, ethanol, methanol and aqueous extracts of X. caffra against four bacteria that cause gastro-intestinal infections, namely Shigella dysenterae, Staphylococcus aureus, Shigella flexneri and Vibrio cholerae. The obtained antibacterial activity determined using the micro-plate dilution assay in terms of minimum inhibition concentration (MIC) showed values ranging from 0.156 to 0.625 mg/ml (Mathabe et al., 2006, see Table 5), and these findings somehow confirm the species' antibacterial potential and its usefulness in the treatment of diarrhoea. The antibacterial MIC values of aqueous extracts as well as dichloromethane, ethanol and petroleum ether extracts of leaves and roots of X. caffra against Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus ranged from 0.025 to 6.25 mg/ml (Table 5), justifying the use of the species in traditional medicine. Mulaudzi et al. (2011) used two-fold serial dilution of neomycin (Sigma) 0.1 mg/ml as a positive control against each bacterium. High levels of phenolic compounds such as p-coumaric (2), ferulic (3) and vanillic (4) acids were detected in X. caffra (Fig. 4). Naidoo et al. (2013) used 0.01 mg/ml ciprofloxacin as positive control. Naidoo et al. (2013) found that aqueous and methanolic/dichloromethane (1:1) leaf extracts of X. caffra showed moderate to good activity of 0.25–8 mg/ml against Gardnerella vaginalis, Neisseria gonorrhoea, Oligella ureolytica, Trichomonas vaginalis and Ureaplasma urealyticum. Similarly, Munodawafa (2012) investigated the antibacterial activities of methanol extracts of X. caffra leaves and roots against Escherichia coli, Pantoea agglomerans, Staphylococcus aureus and Streptcoccus spp. This investigation revealed good to moderate antibacterial activity with MIC values ranging from 0.625 to 4 10 mg/ml (Table 5). Detailed summary of literature data on antibacterial activities of X. caffra are presented in Table 5. Based on widespread ethnomedicinal uses of X. caffra leaves and roots as remedy for sexually transmitted infections (STIs), particularly gonorrhoea, a number of studies evaluating the antigonococcal effect of the species on Neisseria gonorrhoeae (Mulaudzi et al., 2011; Nair et al., 2013), a bacterium known to cause gonorrhoea in humans have been carried out. Dichloromethane and petroleum ether leaf and root extracts of X. caffra produced good activity against the bacterium with inhibition ranging from 73.3 7 4.3% to 8774.3% (Table 5). The obtained antigonococcal activity determined using the disc diffusion method and

Table 5 Summary of pharmacological activities of the extracts isolated from different parts of Ximenia caffra Extract

Plant part

Model

Effect

Reference

Antiamoebic Antigonococcal

Acetone DCM

Leaves Leaves

Growth inhibition Disc diffusion

EtOH

Leaves

Disc diffusion

PE DCM EtOH PE Water

Leaves Roots Roots Roots Leaves, stem Bark, roots Fruits Leaves Leaves

Disc diffusion Disc diffusion Disc diffusion Disc diffusion Cestode model Cestode model Adult immersion test [3H]-hypoxanthine incorporation assay -

Showed activity against Eh with IC50 410 mg/ml and IC90 410 mg/ml Showed good activity of 79 7 3.2% inhibition of Ng Showed good activity of 78.8% inhibition of Ng at 10 mg/disc Not active with 44 7 0.0% inhibition of Ng Not active with 43.9% inhibition of Ng at 10 mg/disc Showed good activity of 73 74.3% inhibition of Ng Not active with 44 7 0.0% inhibition of Ng Showed moderate activity of 56 71.0% inhibition of Ng Showed good activity of 87 7 4.3% inhibition of Ng Active against cestodes of Hd, lethal concentration varying from 17.3–0.5 mg/ml Active against cestodes of Hd, lethal concentration varying from 50.3–0.8 mg/ml 60% efficacy recorded at 200 mg/mL within 3 h of Mo parasite exposure Active with IC50 value of 43.5 mg/ml against Pf Active with IC50 value of 55 mg/ml against Pf Active with IC50 value of 3.01 mg/ml and therapeutic index of 4 50 against Pf

Samie et al., 2009 Mulaudzi et al., 2011 Nair et al., 2013 Mulaudzi et al., 2011 Nair et al., 2013 Mulaudzi et al., 2011 Mulaudzi et al., 2011 Mulaudzi et al., 2011 Mulaudzi et al., 2011 Mølgaard et al., 2001 Mølgaard et al., 2001 Gemeda et al. 2014 Clarkson et al., 2004 Clarkson et al., 2004 Bapela et al., 2014

Anthelmintic Antiparasitic Antiplasmodial

Water DCM DCM and MeOH

MeOH Water DCM DCM and MeOH MeOH Water Antischistosomal Water Anti-inflammatory DCM EtOH PE Water DCM EtOH PE Water MeOH

Leaves Leaves Roots Roots Roots Roots Roots Leaves Leaves Leaves Leaves Roots Roots Roots Roots Leaves

Antimicrobial

DCM

Leaves

COX-1 and COX-2 inhibitory COX-1 and COX-2 inhibitory COX-1 and COX-2 inhibitory COX-1 and COX-2 inhibitory COX-1 and COX-2 inhibitory COX-1 and COX-2 inhibitory COX-1 and COX-2 inhibitory COX-1 and COX-2 inhibitory LPS-stimulated expression Luciferae reporter Disc diffusion

EtOH

Leaves

Disc diffusion

PE DCM EtOH PE Acetone

Leaves Roots Roots Roots Leaves

Disc Disc Disc Disc Disc

diffusion diffusion diffusion diffusion diffusion assay

Disc-diffusion

MeOH

Roots

Micro-dilution assay Disc diffusion assay

Active Active Active Active

with with with with

IC50 IC50 IC50 IC50

value value value value

of of of of

100 mg/ml against Pf 4100 mg/ml against Pf 4100 mg/ml against Pf 4100 mg/ml against Pf

Active with IC50 value of 4100 mg/ml against Pf Active with IC50 value of 4100 mg/ml against Pf Active, killing 33.3% of schistosomula worms at 50 mg/ml Moderate inhibition activity towards COX-1 (50%) and 0% for COX-2 High inhibition activity towards COX-1 (100%) and moderate for COX-2 (40%) Moderate inhibition activity towards COX-1 (40%) and COX-2 (55%) High inhibition activity towards COX-1 (100%) and low for COX-2 (30%) High inhibition activity towards COX-1 (100%) and low for COX-2 (30%) High inhibition activity towards COX-1 (90%) and 0% for COX-2 High inhibition activity towards COX-1 (100%) and low for COX-2 (30%) High inhibition activity towards COX-1 (90%) and moderate for COX-2 (55%) Inhibited the release of IL-6, iNOS and TNF-α at 312.5 mg/ml Potent to weak inhibition of NF-кB activation in TNF-α stimulated cells at 312.5 mg/ml Showed good activity of 79 7 3.2% inhibition of Ng Showed good activity of 78.8% inhibition of Ng at 10 mg/disc Not active with 44 7 0.0% inhibition of Ng Not active with 43.9% inhibition of Ng at 10 mg/disc Showed good activity of 73 74.3% inhibition of Ng Not active with 44 7 0.0% inhibition of Ng Showed moderate activity of 56 71.0% inhibition of Ng Showed good activity of 87 7 4.3% inhibition of Ng Exhibited activity against Ah at 6.0 mg/ml), Bc (6.0 mg/ml), Bp (6.0 mg/ml), Bs (6.0 mg/ml), Ef (3.0 mg/ml), Ec (6.0 mg/ml), Es (6.0 mg/ml), Kp (6.0 mg/ml), Pa (6.0 mg/ml), Pm (6.0 mg/ml), Ps (6.0 mg/ml), Sc (6.0 mg/ml), Sm (3.0 mg/ml), Sf (6.0 mg/ml) and Sa (6.0 mg/ml) Extract killed fungal organisms at the following MFCs, 47.5 mg/ml (Fn, Fo, Fp, Fv) and Fg at 7.5 mg/ml

Clarkson Clarkson Clarkson Clarkson

et et et et

al., al., al., al.,

2004 2004 2004 2004

Clarkson et al., 2004 Clarkson et al., 2004 Sparg et al., 2000 Mulaudzi et al., 2013 Mulaudzi et al., 2013 Mulaudzi et al., 2013 Mulaudzi et al., 2013 Mulaudzi et al., 2013 Mulaudzi et al., 2013 Mulaudzi et al., 2013 Mulaudzi et al., 2013 Zhen et al., 2015 Zhen et al., 2015 Mulaudzi et al., 2011 Nair et al., 2013 Mulaudzi et al., 2011 Nair et al., 2013 Mulaudzi et al., 2011 Mulaudzi et al., 2011 Mulaudzi et al., 2011 Mulaudzi et al., 2011 Samie et al., 2005

93

Samie and Mashau, 2013 57% Cj isolates suppressed at 6.0–0.7 mg/ml Samie et al., 2009 Active against As with MIC value of 4–48 mg/ml, Ca (0.06–0.5 mg/ml), Cg (0.5–48 mg/ml), Ci (0.25– 48 mg/ Fabry et al., 1996 ml), Ck (0.13–0.2 mg/ml), Cp (0.5–48 mg/ml) and Ct (0.5–48 mg/ml) Active against As with MFC value of 8– 48 mg/ml, Ca (8–4 8 mg/ml), Cg (4– 48 mg/ml), Ci (4–48 mg/ml), Ck Fabry et al., 1996 (0.13–48 mg/ml), Cp (4– 48 mg/ml) and Ct ( 48 mg/ml) Active against En with MIC value of 0.06–1.0 mg/ml, Es (8.0–4 8.0 mg/ml), Kl ( 48.0 mg/ml), Ps (2.0–8.0 mg/ml), Fabry et al., 1998 Sl (2.0–48.0 mg/ml) and Sa (0.5–2.0 mg/ml) Active against En with MBC value of 1.0–8.0 mg/ml, Es (1.0–8.0 mg/ml), Kl (0.5–8.0 mg/ml), Ps (0.5–4.0 mg/ml), Fabry et al., 1998

A. Maroyi / Journal of Ethnopharmacology 184 (2016) 81–100

Activity tested

94

Table 5 (continued ) Activity tested

Extract

MeOH

Acetone

Plant part

Leaves

Roots

Model

Micro-dilution assay Agar-well diffusion assay Disc diffusion assay

Agar-well diffusion assay Micro-dilution Disc diffusion

EtOH

Roots

Agar-well diffusion assay Micro-dilution assay

Water

Roots

Acetone Hexane DCM

Bark Roots Leaves

Agar-well diffusion assay Micro-dilution assay Micro-dilution assay Micro-dilution assay Micro-dilution assay

EtOH

Leaves

Micro-dilution assay

PE Water

Leaves Leaves

Micro-dilution assay Micro-dilution assay Growth inhibition

Antioxidant

DCM

Roots

Micro-dilution assay

PE

Roots

Micro-dilution assay

Water

Roots

Micro-dilution assay

PE DCM and MeOH MeOH

Leaves Leaves

Micro-dilution assay Growth inhibition

Bark

Disk-diffusion assay

Water

Bark

Disc-diffusion assay

MeOH Water MeOH Water MeOH

Leaves Leaves Roots Roots Fruits

Enzyme inhibition assay Enzyme inhibition assay Enzyme inhibition assay Enzyme inhibition assay DPPH, lipid peroxidation and superoxide DPPH assay DPPH assay

Leaves Roots

Sl (0.5–8.0 mg/ml) and Sa (0.06–0.5 mg/ml) Active against An with MIC value of 3.75 mg/ml, Ca (5.0 mg/ml), Es (0.625 mg/ml), Pa (2.5 mg/ml), Sa (1.25 mg/ ml) and St (1.875 mg/ml) Active against An with MBC/MFC value of 5.0 mg/ml, Ca (10.0 mg/ml), Es (10.0 mg/ml), Pa ( 410.0 mg/ml), Sa (5.0 mg/ml) and St (5.0 mg/ml) Active against Sa with MIC value of 5.66 mg/mL and Se (1.42 mg/mL) Active against Sa with MIC value of 0.156 mg/ml, Sd (0.156 mg/ml) and Vc (0.312 mg/ml) Active against An with MIC value of 5.0 mg/ml, Ca (10.0 mg/ml), Es (10.0 mg/ml), Sa (5.0 mg/ml) and St (5.0 mg/ ml) Active against An with MBC/MFC value of 410.0 mg/ml, Ca ( 410.0 mg/ml), Es ( 410.0 mg/ml), Sa ( 410.0 mg/ ml) and St ( 410.0 mg/ml) Active against Sa with MIC value of 0.312 mg/ml, Sd (0.625 mg/ml), Sf (0.156 mg/ml) and Vc (0.156 mg/ml) Weakly active against Mt with MIC value of 4100 mg/mL Active against Ca with MIC value of 0.94 mg/ml, Ck (0.94 mg/ml) and Cn (3.75 mg/ml) Exhibited activity against Ah (3.0 mg/ml), Bc (1.5 mg/ml), Bp (6.0 mg/ml), Bs (3.0 mg/ml), Ef (1.5 mg/ml), Ec (6.0 mg/ml), Es (3.0 mg/ml), Kp (3.0 mg/ml), Pa (1.5 mg/ml), Pm (6.0 mg/ml), Pa (12.0 mg/ml), Sc (6.0 mg/ml), Sm (3.0 mg/ml), Sf (1.5 mg/ml) and Sa (3.0 mg/ml) Extract killed fungal organisms at the following MFCs, 7.5 mg/ml (Fn, Fo, Fp, Fv) and Fg at 4 7.5 mg/ml

Reference

Munodawafa, 2012 Munodawafa, 2012 Steenkamp et al., 2007 Mathabe et al., 2006 Munodawafa, 2012 Munodawafa, 2012 Mathabe Green et Samie et Samie et

et al., 2006 al., 2010 al., 2010 al., 2005

Samie and Mashau, 2013 Active against Sd with MIC value of 0.156 mg/ml, Sf (0.156 mg/ml) and Vc (0.156 mg/ml) Mathabe et al., 2006 Active against Bs with MIC value of 0.195 mg/ml, Es (1.56 mg/ml), Kp (0.78 mg/ml), Sa (0.195 mg/ml) Mulaudzi et al., 2011 Active against Ca with MIC value of 3.125 mg/ml and MFC value of 3.125 mg/ml Mulaudzi et al., 2011 Active against Sa with MIC value of 0.312 mg/ml, Sd (0.625 mg/ml), Sf (0.312 mg/ml) and Vc (0.156 mg/ml) Mathabe et al., 2006 Active against Sa with MIC value of 1.29 mg/mL and Se (10.30 mg/mL) Steenkamp et al., 2007 44% Cj isolates suppressed at 1.5–0.35 mg/ml Samie et al., 2009 Active against Ca with MIC value of 47.5 mg/ml, Ck (4 7.5 mg/ml), Cn (0.75 mg/ml) Samie et al., 2010 Active against Bs with MIC value of 0.78 mg/ml, Es (0.78 mg/ml), Kp (3.125 mg/ml), Sa (3.125 mg/ml) Mulaudzi et al., 2011 Active against Ca with MIC value of 0.78 mg/ml and MFC value of 1.56 mg/ml Mulaudzi et al., 2011 Active against Bs with MIC value of 0.39 mg/ml, Es (0.195 mg/ml), Kp (0.195 mg/ml), Sa (0.025 mg/ml) Mulaudzi et al., 2011 Active against Ca with MIC value of 1.56 mg/ml and MFC value of 1.56 mg/ml Mulaudzi et al., 2011 Active against Bs with MIC value of 1.56 mg/ml, Es (3.125 mg/ml), Kp (3.125 mg/ml), Sa (6.25 mg/ml) Mulaudzi et al., 2011 Active against Bs with MIC value of 0.39 mg/ml, Es (0.39 mg/ml), Kp (0.78 mg/ml), Sa (0.049 mg/ml) Mulaudzi et al., 2011 Active against Ca with MIC value of 1.56 mg/ml and MFC value of 1.56 mg/ml Mulaudzi et al., 2011 Activity with MIC value of 1 mg/ml against Gv, Ca ( 416 mg/ml), Ng (0.25 mg/ml), Ou (2 mg/ml), Tv (8 mg/ml) Naidoo et al., 2013 and Uu (0.25 mg/ml) Active against Bs with MIC value of 0.39 mg/ml, Es (1.56 mg/ml), Kp (1.56 mg/ml), Sa (0.78 mg/ml) Mulaudzi et al., 2011 Active against Ca with MIC value of 3.125 mg/ml and MFC value of 3.125 mg/ml Mulaudzi et al., 2011 Active against Bs with MIC value of 0.39 mg/ml, Es (1.56 mg/ml), Kp (1.56 mg/ml), Sa (0.78 mg/ml) Mulaudzi et al., 2011 Active against Ca with MIC value of 3.125 mg/ml and MFC value of 6.25 mg/ml Mulaudzi et al., 2011 Active against Bs with MIC value of 0.39 mg/ml, Es (3.125 mg/ml), Kp (6.25 mg/ml) and Sa (3.125 mg/ml) Mulaudzi et al., 2011 Active against Ca with MIC value of 1.56 mg/ml and MFC value of 12.5 mg/ml Mulaudzi et al., 2011 Active against Ca with MIC value of 0.78 mg/ml and MFC value of 1.56 mg/ml Mulaudzi et al., 2011 Activity with MIC value of 4 mg/ml against Ca, Gv (4 mg/ml), Ng (1 mg/ml), Ou (0.75 mg/ml), Tv (2 mg/ml) and Naidoo et al., 2013 Uu (0.5 mg/ml) Exhibited activity Bc (4.00 mg/ml), Ef (4.00 mg/ml), Es (1.5 mg/ml), Pv (1.00 mg/ml), So (2.00 mg/ml), Sf Nkwanyana, 2013 (0.50 mg/ml) and Sa (0.38 mg/ml) Exhibited activity Bc (6.00 mg/ml), Ef (6.00 mg/ml), Es (4.00 mg/ml), Pv (3.00 mg/ml), So (3.00 mg/ml), Sf Nkwanyana, 2013 (2.00 mg/ml) and Sa (4.00 mg/ml) Showed high inhibition percentages with IC50 of 0.417 0.05 mg/ml Mulaudzi et al., 2011 Showed high inhibition percentages with IC50 of 0.4 7 0.02 mg/ml Mulaudzi et al., 2011 Showed high inhibition percentages with IC50 of 0.157 0.01 mg/ml Mulaudzi et al., 2011 Showed high inhibition percentages with IC50 of 0.2 7 0.02 mg/ml Mulaudzi et al., 2011 Peels and pulps of fruits exhibited high activity with IC50 of 80 mg/ml in DPPH assay, reducing power and against Ndhlala et al., 2006 superoxide, and 10.1 mg/ml in lipid peroxidation Exhibited 95.7 70.0707% inhibition Munodawafa, 2012 Exhibited 95.7 70.0707% inhibition Munodawafa, 2012

A. Maroyi / Journal of Ethnopharmacology 184 (2016) 81–100

Disc-diffusion

Effect

Antiproliferative

Mutagenic

DCM

Seed oil Leaves Roots Bark, fruits, leaves Leaves

EtOH

Leaves

PE

Leaves

Water

Leaves

DCM

Roots

EtOH

Roots

PE

Roots

Water

Roots

MeOH

Roots

EtOH

Roots

Cytotoxicity

Acetone

Toxicity

DCM and MeOH Water MeOH

Stem Bark Leaves Leaves Leaves Leaves Roots

Trypan blue dye exclusion MTS assay Growth inhibition -

Seed oil suppressed HEK-293 and Caco-2 cell growth at 80 mg/l Inhibited RAW cell growth, potentially possessing a cytotoxic effect at 194–283.5 mg/mL 100% mortality obtained from Aa, showing potent activity Mild to moderate activity with LD90 values ranging from 100–200 ppm

Non mutagenic towards So with the following number of His þ revertants (50–5000 mg/ml), 12.7 7 1.7–17.3 7 0.7 (S9
) and 22.0 7 2.0–22.5 70.5 (S9 þ ) Ames test Non mutagenic towards So with the following number of His þ revertants (50–5000 mg/ml), 12.3 7 2.2–18.7 7 3.2 (S9
) and 21.0 7 0.0–27.5 7 0.5 (S9 þ ) Ames test Non mutagenic towards So with the following number of His þ revertants (50–5000 mg/ml), 15.3 7 0.7–20.7 7 1.9 (S9
) and 21.0 7 0.0–24.0 7 1.0 (S9 þ ) Ames test Non mutagenic towards So with the following number of His þ revertants (50–5000 mg/ml), 10.7 7 0.3–12.7 7 1.8 (S9
) and 26.0 7 4.0–47.0 7 3.0 (S9 þ ) Ames test Non mutagenic towards So with the following number of His þ revertants (50–5000 mg/ml), 17.3 7 0.3–21.0 7 2.5 (S9-) and 18.5 7 4.5–25.5 7 6.5 (S9 þ ) Ames test Non mutagenic towards So with the following number of His þ revertants (50–5000 mg/ml), 13.0 7 2.5–19.3 7 2.3 (S9
) and 19.5 70.5–37.5 7 5.5 (S9 þ ) Ames test Non mutagenic towards So with the following number of His þ revertants (50–5000 mg/ml), 17.3 7 0.3–21.0 7 2.5 (S9
) and 18.5 7 4.5–25.5 7 6.5 (S9 þ ) Ames test Non mutagenic towards So with the following number of His þ revertants (50–5000 mg/ml), 11.3 7 0.3–15.0 7 2.0 (S9
) and 36.0 7 6.0–42.5 73.5 (S9 þ ) Antiproliferative assay No pronounced cytotoxicity effect recorded ( o 25% cell proliferation) by HeLa, HT29 and A431 cells. HeLa (25–0% cell proliferation) at 100 mg/ml, 100–75% at 10 mg/ml; HT29 (50–25%) at 100 mg/ml, 100–75% at 10 mg/ml; A431 (50–25%) at 100 mg/ml and 100
75% at 10 mg/ml MTT assay on human carcinoma Inactive on three cell lines at 10 and 100 mg/ml, i.e., RT-4, 100 (100 mg/ml) and 91 (10 mg/ml); HT-29, 85 (100 mg/ cell lines ml) and 96 (10 mg/ml), A431, 100 (100 mg/ml) and 83 (10 mg/ml) Brine shrimp lethality test Active with LC50 of 11.25 mg/ml) Vero cells Median inhibitory concentration of 130.8 7 2.86 mg/ml against Vero cells Vero cells Median inhibitory concentration of 102.6 7 4.47 mg/ml against Vero cells Cellular viability toxicity assay No toxicity exhibited as extract resulted in 102.3 7 0.85% cell viability Antiproliferative assay Toxic to rat skeletal myoblast L6 cells, IC50 value of 8.68 mg/ml and therapeutic index of 50 Cellular viability toxicity assay No toxicity exhibited as extract resulted in 108.5 7 0.81% cell viability Brine shrimp lethality test Found to be safe with LC50 of 1020 7 52.7 mg/ml Brine shrimp lethality test Found to be safe with LC50 of 1590 7 752 mg/ml Ames test

Chivandi et al., 2012b Zhen et al., 2015 Maharaj et al., 2012 Ojewole 2004 Mulaudzi et al., 2013 Mulaudzi et al., 2013 Mulaudzi et al., 2013 Mulaudzi et al., 2013 Mulaudzi et al., 2013 Mulaudzi et al., 2013 Mulaudzi et al., 2013 Mulaudzi et al., 2013 Kamuhabwa et al., 2000 Moshi et al., 2003 Moshi et al., 2004 Samie et al., 2009 Samie et al., 2009 Naidoo, 2013 Bapela et al., 2014 Naidoo, 2013 Munodawafa, 2012 Munodawafa, 2012

Aa ¼Anopheles arabiensis; Ah ¼ Aeromonas hydrophilla; An ¼ Aspergillus niger; As¼ Aspergillus spp.; Bc¼ Bacillus cereus; Bp ¼Bacillus pumilis; Bs ¼ Bacillus subtilis; Ca ¼Candida albicans; Cg ¼Candida glabrata; Ci ¼ Candida guilliermondii; Cj ¼ Campylobacter jejumi; Ck¼ Candida krusei; Cn¼ Candida neoformans; Cp ¼ Candida parapsilosis; Ct¼ Candida tropicalis; DCM ¼ dichloromethane; Ec ¼ Enterobacter cloacae; Ef¼ Enterococcus faecalis; Eh ¼ Entamoeba histolytica; En ¼ Enterococci spp.; Es¼ Escherichia coli; EtOH ¼ethanol; Fg ¼ Fusarium graminearum; Fn¼ Fusarium nygamai; Fo¼Fusarium oxysporum; Fp¼ Fusarium proliferatum; Fv¼ Fusarium verticillioides; Gv¼ Gardnerella vaginalis; Hd¼ Hymenolepsis diminuta; Kl ¼Klebsiella spp.; Kp ¼Klebsiella pneumoniae; MBC ¼minimum bactericidal concentration; MFC¼ minimal fungicidal concentration; MIC¼ minimum inhibitory concentration; Mo¼ Melophagus ovinus; Mt¼ Mycobacterium tuberculosis; Ng ¼ Neisseria gonorrhoeae; Ou¼ Oligella ureolytica; Pa¼ Pantoea agglomerans; PE ¼petroleum ether; Pf ¼ Plasmodium falciparum; Pm¼ Proteus mirabilis; Ps¼ Pseudomonas aeruginosa; Pv¼ Proteus vulgaris; Sa ¼ Staphylococcus aureus; Sc ¼ Salmonella cholera-suis; Sd ¼Shigella dysenteriae; Se ¼ Staphylococcus epidermidis; Sf ¼ Shigella flexneri; Sl ¼Salmonella spp.; Sm¼ Serratia marcescens; So ¼Salmonella typhimurium; Ss¼Shigella sonnei; St ¼Streptcoccus spp.; Tv¼ Trichomonas vaginalis; Uu ¼Ureaplasma urealyticum; Vc ¼Vibrio cholera.

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Insecticidal Molluscicidal

EtOH MeOH Water Water

95

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ciprofloxacin (1 mg/disc) as positive control, with water and 80% ethanol as negative and solvent controls respectively, confirm the species’ antigonococcal potential and its usefulness in the treatment of gonorrhoea (Nair et al., 2013). 4.2.2. Antifungal In 1996, Fabry et al. (1996) conducted a study on antifungal effects of methanol extract of X. caffra roots using a microtitre serial dilution technique. Fungal organisms investigated included Aspergillus spp., Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida parapsilosis and Candida tropicalis. Noteworthy anticandidal activities were against Candida albicans with MIC value ranging from 0.25 to 0.5 mg/ml, 0.25 mg/ml against Candida krusei and 0.5 mg/ml against Candida guilliermondii (Fabry et al., 1996). Similar results were obtained by Samie et al. (2010) when they investigated antifungal effects of acetone and hexane root extract of X. caffra against Candida albicans, Candida krusei and Cryptococcus neoformans isolated from AIDs patients using the microdilution method using Nystatin and 5-flourocystosine as positive controls. Noteworthy antifungal activities were recorded from Candida albicans and Candida krusei with MIC value of 0.94 mg/ml and 0.75 mg/ml against Cryptococcus neoformans (Table 5). Mulaudzi et al. (2011) reported that dichloromethane and petroleum ether extracts of X. caffra leaves exhibited good antifungal activity against Candida albicans with MIC value of 0.78 mg/ml. Samie and Mashau (2013) found weak to moderate antifungal activity of acetone and hexane leaves and roots extracts of X. caffra against five Fusarium species, including Fusarium graminearum, Fusarium nygamai, Fusarium oxysporum, Fusarium proliferatum and Fusarium verticillioides which cause cutaneous and a broad spectrum of gastrointestinal tract infections in humans. MIC values ranged between 0.95 to 47.5 mg/ml (Samie and Mashau, 2013). Naidoo et al. (2013) also recorded moderate to poor antifungal activity of aqueous and dichloromethane and methanol (1:1) leaf extract of X. caffra against Candida albicans with MIC value ranging from 4 to 16 mg/ml (Table 5). In a previous investigation, Munodawafa (2012) recorded moderate antifungal activities of methanol extracts of X. caffra leaves and roots against Aspergillus niger and Candida albicans. This investigation revealed moderate antifungal activity with minimal fungicidal concentration (MFC) values ranging from 3.75 to 410 mg/ml (Table 5). 4.2.3. Antiviral Mulaudzi et al. (2011) report that aqueous and methanol extracts of X. caffra roots and leaves showed good HIV-1 reverse transcriptase (RT) inhibition percentages (4 70%) at 1 mg/ml based on COX-assay, with all tested extracts exhibiting dose dependent IC50 values ranging from 0.15 70.01 to 0.41 70.05 mg/ml (Table 5). This study showed that X. caffra could be harbouring potent (RT) inhibitors which could be useful for the development of new pharmaceutical products. Ximenia caffra is traditionally used to treat hepatitis in Burundi (Nzigidahera, 2009) and other HIV/AIDs opportunistic diseases and infections such as diarrhoea, sexually transmitted infections (STIs) and skin rash (Maroyi, 2014; Chinsembu et al., 2015). The aqueous and methanol extracts of X. caffra roots and leaves possibly contain antiviral compounds as medicinal plants are excellent sources of anti-HIV agents (Klos et al., 2009). 4.3. Anti-inflammatory In vitro studies have shown that X. caffra leaves and roots inhibit inflammatory reactions and supresses inflammatory factors including the production of cyclooxygenase-1 and 2 (COX-1 and COX-2), inducible nitric oxide synthase (iNOS), interleukin 6 (IL-6), nuclear kinase kappa B (NF-кB) and tumor necrosis factor- α (TNF-

α) (Mulaudzi et al., 2011; Zhen et al., 2015). The aqueous, dichloromethane, ethanol and petroleum ether leaf and root extracts of X. caffra yielded high to moderate inhibition activity towards COX-1 (40–100%) and no activity to moderate activity towards COX-2 (0–55%) (Mulaudzi et al., 2011). The methanol leaf extract of X. caffra inhibited the release of IL-6, iNOS and TNF-α at at 312.5 mg/ml and yielded potent to weak inhibition of NF-кB activation in TNF-α stimulated cells at 312.5 mg/ml (Zhen et al., 2015). These results support the traditional use of the species in various inflammatory ailments and diseases ranging from microbial infection to injury that result in cell injury and death. 4.4. Antioxidant The in vitro antioxidant activity of methanol extracts of the fruits, leaves and roots of X. caffra were evaluated using DPPH radical scavenging method, reducing power effects and superoxide anion radical scavenging activity (Ndhlala et al., 2006; Munodawafa, 2012). Fruit peels and pulps exhibited high activity with IC50 of 80 mg/ml in DPPH assay, reducing power and against superoxide, and 10.1 mg/ml in lipid peroxidation (Ndhlala et al., 2006). Similarly, Munodawafa (2012) reported antioxidant activity of 95.77 0.0707% inhibition from both leaves and roots of X. caffra. These antioxidant activities of fruit peels and pulps, leaf and root extracts are probably due to the presence of flavonoids and phenolics (Ndhlala et al., 2006). 4.5. Antiparasitic and insecticidal Fruits, leaves and roots of X. caffra are commonly used to kill parasites, including tapeworms, ectoparasites and schistosomes in many countries including Ethiopia, Kenya, Malawi, Mozambique, Namibia, Somalia, South Africa, Tanzania and Zimbabwe (see Table 3). Mølgaard et al. (2001) investigated the anthelmintic activity of aqueous bark, leaf, root and stem extracts of X. caffra using the cestode model. Mølgaard et al. (2001) recorded noteworthy activity against cestodes of Hymenolepsis diminuta with lethal concentration ranging from 50.3 to 0.5 mg/ml. Earlier studies by Sparg et al. (2000) revealed that aqueous root extract of X. caffra was active, killing 33.3% of schistosomula worms at 50 mg/ml. Investigations by Ojewole (2004) revealed that aqueous bark, fruit and leaf extract of X. caffra has mild to moderate molluscicidal activity with LD90 values ranging from 100–200 ppm, an important attribute which can be used to complement methods for controlling snails which act as intermediate hosts of schistosomes. These pharmacological evaluations are of importance in the traditional uses of X. caffra and future research focusing on control and management of schistosomiasis in the tropics. Clarkson et al. (2004) reported weak antiplasmodial activity of aqueous, dichloromethane, dichloromethane and methanol (1:1) leaf and root extracts of X. caffra against Plasmodium falciparum with IC50 value ranging from 43.5 to 4100 mg/ml (Table 5). Recently, Bapela et al. (2014) investigated antiplasmodial activity of the dichloromethane and methanol (1:1) leaf extract of X. caffra using [3H]-hypoxanthine incorporation assay. Bapela et al. (2014) recorded noteworthy activity with IC50 value of 3.01 mg/ml and therapeutic index of 4 50 against Plasmodium falciparum. Gemeda et al. (2014) investigated insecticidal activity of aqueous fruit extract of X. caffra against Melophagus ovinus sheep ked using the in vitro adult immersion test. The findings showed 60% efficacy at 200 mg/mL within 3 h of M. ovinus exposure. The aqueous root extract of X. caffra showed 100% larval mortality of Anopheles arabiensis within the seven day exposure period, one of the major vectors of malaria in southern Africa (Maharaj et al., 2012). Therefore, the potent insecticidal and larvicidal activities demonstrated by X. caffra implies that the species may have

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bioactive constituents with potential as an insecticide and larvicide useful in controlling parasites and mosquito vectors.

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plant parts of the species should be tested against a wide range of cell lines as well as using other in vitro toxicological assays and in vivo studies.

4.6. Antiproliferative Chivandi et al. (2012b) studied antiproliferative effects of X. caffra seed oil using the trypan blue dye exclusion method, it was concluded that seed oil suppressed human embryonic kidney (HEK-293) and human colon adenocarcinoma (Caco-2) cell growth at 80 mg/l. Similarly, Zhen et al. (2015) assessed antiproliferative effects of X. caffra using the MTS cell proliferation assay, demonstrating that RAW cell growth is inhibited by a methanol leaf extract at 194-283.5 mg/mL. 4.7. Toxicity and mutagenic Considering the widespread use of X. caffra as a herbal medicine and also consumption of its fruits and seed oil, it is important to determine if any toxicological effects can occur from its chronic or sub-chronic usage. Kamuhabwa et al. (2000) reported that methanol extract of X. caffra roots had no pronounced cytotoxicity (Table 5) evaluated on three human cell lines (Hela, cervical carcinoma, HT29, colon adenocarcinoma and A431, skin carcinoma). Moshi et al. (2003) tested in vitro cytotoxic activity of ethanol root extract of X. caffra on human bladder carcinoma (RT-4), colon adenocarcinoma (HT29) and skin carcinoma (A431) cell lines and this study showed that the species is non-toxic (Table 5). The brine shrimp lethality test carried out by Munodawafa (2012) revealed that methanol leaf and root extracts of X. caffra are non-toxic, characterized by the LC50 of 1020 752.7 mg/ml and 1590 7752 mg/ ml respectively. No toxicity was exhibited by aqueous and dichloromethane and methanol (1:1) leaf extract of X. caffra or in combination with bark extract of Tabernaemontana elegans (Naidoo et al., 2013), carried out using the cellular viability toxicity test. This cellular viability toxicity assay revealed cellular viability expressed as a percentage of cell growth at 100 mg/ml 7standard deviation of 108.5 70.81 (aqueous extract) and 102.3 70.85 (organic) for X. caffra alone and 105.4 70.68 (aqueous extract) and 110.0 70.70 (organic) in combination with T. elegans (Naidoo et al., 2013). In this investigation, leaf extract of X. caffra alone or in combination with bark extract of T. elegans caused cell replication and stimulatory effects. However, ethanol stem extract of X. caffra exhibited some degree of toxicity on brine shrimp, the concentration killing 50% (LC50) of the shrimps was 11.25 mg/ml (Moshi et al., 2004). Similarly, acetone bark and leaf extract of X. caffra exhibited little toxicity against Vero cells with the median inhibitory concentrations (IC50) of 130.8 72.86 mg/ml and 102.67 4.47 mg/ml respectively (Samie et al., 2009). Bapela et al. (2014) found dichloromethane and methanol (1:1) leaf extract toxic to rat skeletal myoblast L6 cells with an IC50 value of 8.68 mg/ml and therapeutic index of 50, using podophyllotoxin as control. The Ames test revealed that aqueous, dichloromethane, ethanol and petroleum ether leaf and root extracts of X. caffra were non-mutagenic towards Salmonella typhimurium (Mulaudzi et al., 2013; Table 5), where sterile distilled water was used as a negative control. Toxicological analysis documented in this study evaluated the potential adverse effects which directly relates to the administration of X. caffra as herbal medicine for human and animal diseases and ailments. Results obtained by Moshi et al. (2004), Samie et al. (2009) and Bapela et al. (2014) indicating the possibility that X. caffra may be toxic calls for rigorous toxicological tests as the species may contain useful cytotoxic compounds which have not been reported. Different toxicity levels are expected as various cell lines have different sensitivity patterns to plant compounds. In order to ascertain X. caffra's toxicological properties, the different

5. Conclusion The present review summarizes ethnomedicinal uses, phytochemistry, biological activities and toxicity of different extracts and compounds of X. caffra. Ximenia caffra is closely related to X. americana, both species are deemed as highly potent traditional medicines for various ailments throughout their distributional ranges. The two species have overlapping distributional range in sub-Saharan Africa and are quite similar in appearance, as both species are sparsely-branched shrubs or small trees, characterized by sour, edible fruits with oily kernels and are often confused when growing together (Palgrave, 2002; Setshogo and Venter, 2003). There are similarities and overlaps in terms of ethnomedicinal uses, phytochemistry, biological activities and toxicity of extracts and compounds of the two species. From a phytochemical and pharmacological point of view, no chemical variation studies have been conducted on these two species. Future studies should try to establish whether there are phytochemical compounds and pharmacological properties that could be used to distinguish these two species; and also supplement the currently known ethnomedicinal uses and taxonomical characters used to distinguish X. caffra from X. americana. Ximenia caffra has been traditionally used as herbal medicine throughout its distributional range in sub-Saharan Africa, used for the treatment of wounds, STIs, infertility, stomach ache, fever, eye problems, diarrhoea, bilharzia, menorrhagia, impotence, malaria, intestinal worms and cough. Recent research on X. caffra focused primarily on evaluating the anti-amoebic, antibacterial, antifungal, HIV-1 reverse transcriptase (RT) inhibitory, anti-inflammatory, antioxidant, antiparasitic and insecticidal, antiproliferative, nonmutagenic and toxicity activities of the species. The phenolic, flavonoids, tannins, phytosterols and fatty acids appear to be the major plant derivatives and have been demonstrated to be the main active ingredients in X. caffra seed oil, fruit pulp and peels, leaves and roots. Although contemporary research involving X. caffra is promising, it is too preliminary and sometimes too general to be used to explain and support some of the ethnomedicinal uses. In addition to this, some of the pharmacological activities assessed so far, for example, anti-amoebic, antioxidant and antiproliferative were routine screenings using standard procedures lacking molecular mechanisms of the pharmacological effects of X. caffra. Therefore, the mentioned phytochemical constituents such as phenolic and flavonoids compounds; and pharmacological activities such as antibacterial, antifungal, HIV-1 reverse transcriptase (RT) inhibitory, anti-inflammatory, antioxidant, antiparasitic and insecticidal have provided some suggestive scientific evidence for the various ethnomedicinal uses of X. caffra in the treatment of infectious diseases such as control and management of parasitic diseases, diarrhoea, HIV/AIDs opportunistic diseases and infections, inflammatory ailments and STIs. There is not yet enough systematic data regarding the pharmacokinetics and clinical research of X. caffra products and compounds. There are also very few to nil experimental animal studies, randomized clinical trials and target-organ toxicity studies involving X. caffra and its derivatives that have been carried out so far. Therefore, there is not sufficient evidence to interpret the documented ethnomedicinal uses linking them to specific chemical mechanisms associated with some of the documented biological activities of the species. For example, although X. caffra is used traditionally to treat hepatitis in Burundi (Nzigidahera, 2009) and other HIV/AIDs opportunistic diseases and infections (Maroyi,

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2014; Chinsembu et al., 2015), there are gaps regarding active compounds and the possible mechanisms of action. Therefore, future studies should identify the bioactive components, details of the molecular modes or mechanisms of action, pharmacokinetics and physiological pathways for specific bioactives of X. caffra. Further research should comprise of the models which would more precisely refer to the current knowledge about pathophysiology, extensive phytochemical, pharmacological, preclinical and clinical research on well documented and established ethnomedicinal uses such as wounds, sexually transmitted infections (STIs), infertility, stomach ache, fever, eye problems, diarrhoea, bilharzia, menorrhagia, malaria, intestinal worms, impotence and coughs. This future research should also include the identification of any side effects and/or toxicity, aspects of quality control to ensure safety, quality and efficacy of the X. caffra products.

Acknowledgements This work was financed by the National Research Foundation (NRF), South Africa (Grant no. T398).

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