Elephantorrhiza elephantina: Traditional Uses, Phytochemistry, and Pharmacology of an Important Medicinal Plant Species in Southern Africa

Elephantorrhiza elephantina is used in southern Africa as traditional remedy for a wide range of human diseases and ailments including dermatological diseases, gastrointestinal system disorders, sexual dysfunction, sexually transmitted infections, and wounds. The rhizome decoction of E. elephantina is widely used by small-scale farmers in Botswana and South Africa as ethnoveterinary medicine for cattle, goats, horses, pigs, poultry, and sheep. Several classes of phytochemical compounds including anthocyanidins, anthraquinones, esters, fatty acids, phenolic compounds, flavonoids, glycosides, polysterols, saponins, sugars, tannins, and triterpenoids have been isolated from E. elephantina. Scientific studies on E. elephantina indicate that it has a wide range of biological activities including anthelmintic, antibacterial, antifungal, anti-inflammatory and antinociceptive, antiplasmodial, antioxidant, antibabesial, and antirickettsial activities. Elephantorrhiza elephantina is a valuable source of traditional medicine in southern Africa that it is worth additional research attention because of its wide ethnomedicinal applications and promising biological activities. However, the current health-related information on E. elephantina is not sufficiently explored as diverse studies on its chemical and pharmacological activities are required to understand its mechanism of action and to characterize the metabolites responsible for these activities.


Introduction
Elephantorrhiza elephantina (Burch.) Skeels is a member of a small and purely African genus represented by nine species on the continent [1]. Elephantorrhiza elephantina is the type species of the genus, where the generic name "Elephantorrhiza" means "elephant root" and is based, most descriptively, on the large underground stem common to most members of the genus [2]. Four species in this genus, namely, E. burkei Benth., E. elephantina, E. goetzei (Harms) Harms, and E. suffruticosa Schinz, are highly regarded as medicinal plants in southern Africa [3][4][5]. Elephantorrhiza elephantina is an important plant resource in southern Africa, where it provides food and medicine for the indigenous people and the bark of its tuberous rhizome is a popular source of tanning and dyeing materials [6]. The underground rhizomes, often referred to as roots, are one of the primary herbal medicines in southern Africa. Due to its popularity as herbal medicine, E. elephantina is sold as herbal medicine in the herbal medicine (muthi) markets in Botswana and Zimbabwe [7], the Eastern Cape province of South Africa [8,9], Gauteng province [10], Limpopo province [11], and the Northern Cape province [12]. According to Dold and Cocks [8], the average price of E. elephantina per kg in the Eastern Cape province is R30.80 (US$3.60) and 108.80 kg is the mean quantity sold per trader per year. Due to high demand of the species as herbal medicine and also because harvesters mainly target the rhizomes, E. elephantina is recorded in the Red Data List of Lesotho as data deficient by Talukdar [13] based on the utilization of the species as herbal medicine for stopping bleeding, treating syphilis and intestinal disorders. van Wyk [14] listed E. elephantina as a plant species of high importance with its roots having potential in the formulation of commercial herbal medicines as antioxidant, skin ailments, diarrhoea, perforated ulcers, prostrate hypertrophy, and male pattern baldness in South 2 Evidence-Based Complementary and Alternative Medicine Africa. In South Africa, E. elephantina is used as a traditional remedy for a wide range of ailments, including diarrhoea and dysentery, stomach disorders, skin diseases and acne, haemorrhoids, and perforated peptic ulcers and as emetics [15]. Rhizomes or bark of E. elephantina is crushed with some water added; the resulting paste is applied to hides to tan and dye them a reddish colour [16]. The young shoots of E. elephantina are eaten by livestock and its seeds have a sweetish taste followed by a burning sensation and are often roasted in southern Africa as a coffee substitute [16].
With the increasing realization worldwide that traditional medicines based on indigenous medical systems are potential sources of natural products that can be developed into pharmaceutical drugs and health products [14], substantial efforts have been made to investigate ethnomedicinal uses, chemical constituents, and biological activities of E. elephantina during the last three decades. Unfortunately, no comprehensive review on this important plant species in southern Africa has been published, documenting the species' biology, traditional uses, phytochemistry, and pharmacological properties. Therefore, in this study, the advances in traditional utilization, botany, phytochemistry, pharmacology, and safety aspects of E. elephantina are systematically reviewed. In addition to this, the perspectives for the future research on E. elephantina are also discussed in the hope that the article will provide a better understanding of the plant species.

Methodology of the Review
The literature search was performed from March 2016 to January 2017 using electronic search engines such as Google and Google Scholar and publishing sites such as Elsevier, Science Direct, BioMed Central (BMC), and PubMed. The databases and literature sources were chosen based on the topics covered (i.e., biological activities, ethnobotany, ethnomedicinal uses, ethnopharmacology, pharmacology, phytochemistry, and therapeutic value) and geographical coverage (i.e., southern Africa). The following keywords were used to search literature sources: Acacia elephantina, Elephantorrhiza burchellii and Elephantorrhiza elephantina, dwarf elephant's root, eland's bean, eland's wattle, and elephant's foot. Other literature sources included papers published in international journals, reports from international, regional, and national organizations, conference papers, books, theses, websites, and other grey literature. References were also identified by searching the library collections of the National Herbarium and Botanic Gardens (SRGH), Harare, Zimbabwe, and the University of Fort Hare, South Africa.

Species Description
Elephantorrhiza elephantina has been recorded in southern Africa, that is, Namibia, Botswana, Zimbabwe, Mozambique, Swaziland, Lesotho, and South Africa. Elephantorrhiza elephantina is usually widespread, often gregarious and forming huge patches in hot and dry areas in grasslands and open scrub [6]. Synonyms of E. elephantina are Acacia elephantina Burch. and Elephantorrhiza burchellii Benth. Elephantorrhiza elephantina is a perennial suffrutex or low shrub, producing annual stems up to 90 cm tall at ground level, from the woody end of an elongate, with often thickened rhizome up to 8 m long [16]. Its leaves are alternate, bipinnately compound, almost glabrous with a petiole up to 8 cm long [17]. The leaves consist of 2-4 pairs of pinnae in lower leaves and 7-17 pairs in upper ones, where the axis is up to 10 cm long. The leaflets are up to 55 pairs per pinna, linear to oblong in shape, 4-15 mm long and 0.50-2.50 mm wide with an asymmetric base, apex acute, and usually mucronate [17]. Elephantorrhiza elephantina inflorescence is an axillary raceme, usually confined to the lower part of the stem usually solitary or clustered. The flowers are bisexual with redbrown glands at the base and free petals which are slightly connate at the base. The petals are linear-oblong, 2-4 mm long and about 1 mm wide, and yellow-white in colour [16]. The stamens are 10 which are free, with filaments up to 6.50 mm long [17]. The fruit is a compressed-oblong, straight or slightly curved pod 5-21 cm long and 3-6 cm wide, redbrown in colour, prominently transversely veined, and often swollen over the seeds [16].

Vernacular Names of Elephantorrhiza elephantina
Elephantorrhiza elephantina is known by several vernacular names in its geographical areas of occurrence (Table 1). Literature survey showed no fewer than 41 common or vernacular names for E. elephantina in the seven countries where it is indigenous (Table 1). Local people rarely name plant species that they do not use [18]. This list of common or vernacular names implies that local people in southern Africa have an active interest in E. elephantina. South Africa has the highest number of common or vernacular names (21 in total) followed by Botswana (seven), Namibia (five), and Zimbabwe with four names and the rest of the countries have either one or two names (Table 1). A vernacular name often describes some characteristic feature of the plant species or the plant parts, for example, "eland's bean" (an eland is an indigenous gazelle species); "elandsboontjie"; "eland's wattle"; "elephant's foot"; "elephant-root"; or "dwarf elephant's root" (Table 1). Elephantorrhiza elephantina is commonly referred to as "elandsboontjie" in Afrikaans in South Africa and "eland's bean" and "eland's wattle" in English in Namibia and South Africa because elands feed on the species foliage and pods [19]. The other English common names, "elephant's foot" and "elephant-root," are in reference to large and long rhizomes or roots of the species measuring up to 8 m long [2]. The common name "dwarf elephant's root" is in reference to the height of E. elephantina, which rarely exceeds one metre in height [17,20] in comparison to a closely related species E. goetzei also known as "elephant's root" but averaging seven metres in height [5,6].

Ethnomedicinal Uses of Elephantorrhiza elephantina
The rhizome, roots, leaves, and stems of E. elephantina are reported to possess diverse medicinal properties and are used to treat or manage various human and animal ailments Evidence-Based Complementary and Alternative Medicine 3 Zimbabwe [20,35] and diseases throughout its distributional range in southern Africa (  [3,24] and chest pains in South Africa [42] and applied to open wounds to stop bleeding [39]. In South Africa, roots and rhizomes of E. elephantina are boiled in water for external use to treat acne and other skin diseases [36][37][38] [36,37]. Roots or rhizome decoction of E. elephantina is taken orally as remedy for various ailments and diseases including anemia in Mozambique [25], blood pressure, clearing air canal, erectile dysfunction, haemorrhoids, itching, kidney failure, intestinal disorders, menstrual disorders, peptic ulcers, rheumatic conditions, shingles, sores, syphilis, and tonsillitis in South Africa [4,12,15,31,38,44,47,48,50]. In Botswana, rhizome or root powder of E. elephantina is used to wipe the anus of children with bloody diarrhoea, to clean the womb after abortion, as remedy for early menstruating children, earache, erectile dysfunction, and sexually transmitted infections [21,40,41]. In Lesotho, rhizome decoction of E. elephantina is used to cleanse blood, as remedy for breast cancer, herpes, infertility, intestinal disorders, stomach problems, syphilis, and tuberculosis [24,39]. Leaf, rhizome, and root decoction of E. elephantina are used as remedy for diarrhoea and dysentery in Mozambique [45] and South Africa [15,28,29,32,38,44,46]. In some cases in South Africa, the rhizome of E. elephantina is mixed with Acokanthera oblongifolia Benth. & Hook.f. ex B.D. Jacks root as remedy for diarrhoea and stomach ailments in South Africa [44]. In Mozambique, root decoction of E. elephantina is taken orally as a pain killer [25] and for sexually transmitted infections [45].
Elephantorrhiza elephantina root decoction is taken orally as emetics for fever in Mozambique [25] and South Africa [42]. The rhizome of E. elephantina is mixed with roots of Pentanisia prunelloides and taken orally as remedy for fever and stomach ailments in Zimbabwe [43]. Elephantorrhiza elephantina is an ingredient of a herbal mixture known as "Sejeso" (Ingwe5 brand) made up of Alepidea amatymbica Eckl. & Zeyh., Hypoxis obtusa Burch. ex Ker Gawl., Pentanisia prunelloides, deionized water, and potassium sorbate as preservative used as remedy for constipation, heartburn, indigestion, loss of appetite, stomach ailments, and vomiting [43]. According to Semenya et al. [49], the rhizome of E. elephantina is mixed with roots of Boscia albitrunca (Burch.) Gilg & Gilg-Ben., Peltophorum africanum Sond., and Plectranthus ciliatus E. Mey. as remedy for HIV/AIDS opportunistic infections. Research by de Wet et al. [51] revealed that E. elephantina root decoction is taken orally in combination with Cladostemon kirkii (Oliv.    Sarcophyte sanguinea ssp. piriei, and Senecio serratuloides DC. (leaves) as remedy for sores. Rhizome decoction of E. elephantina is widely used by small-scale farmers in Botswana and South Africa as ethnoveterinary medicine for poultry and retained placenta in cattle and as ethnoveterinary medicine for other animals such as goats, horses, pigs, and sheep and for diseases such as black quarter, appetite stimulant, coughing, diarrhoea, gastrointestinal parasites, gall sickness, heartwater, mange, pneumonia, and ectoparasites [22,23,27,30,33,48,52,53]. The young shoots of E. elephantina are eaten by livestock and wild animals in southern Africa [6]. In Namibia, the pods of E. elephantina are eaten by both people and animals [26].

Phytochemistry
Multiple classes of phytochemicals including anthocyanidins, anthraquinones, esters, fatty acids, phenolic compounds, flavonoids, glycosides, polysterols, saponins, sugars, tannins, and triterpenoids have been isolated from rhizome extracts of E. elephantina [41,[54][55][56][57]. Considerable pharmacological potential of E. elephantina has been documented through detection, isolation and purification of its natural products via advances in spectrometric techniques such as attenuated total reflection (ATR), Fourier transform infrared (FTIR) spectroscopy, liquid chromatography electron spray ionization mass spectroscopy (LC-ESI-MS), gas chromatographymass spectrometry (GC-MS), and nuclear magnetic resonance (NMR) for structural elucidation of new and complex compounds (Table 3). Advanced research through ATR, LC-ESI-MS, FTIR, GC-MS, and NMR spectroscopy enabled researchers to have a better understanding of the correlations between molecular conformation and biological activities of the natural compounds of E. elephantina and its importance as herbal medicine. The compounds isolated from E. elephantina are documented and listed in Table 3 and their structures are displayed in Figure 1. Aaku et al. [41] isolated the following compounds from n-butanol Evidence-Based Complementary and Alternative Medicine 7      Recently, Msimanga et al. [55]  13% of all known compounds isolated from the species), followed by phenolic compounds (26.09%) and esters (13.04%) and the contribution of the rest of the compounds is less than 10% each; see Table 3.  [28] used ten microliters of dimethyl sulfoxide (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. MIC activities against the pathogens ranged between 0.08 and 0.63 mg/mL, and the highest inhibition was exhibited against Shigella flexneri with MIC values ranging from 0.08 to 0.16 mg/mL [28], and these findings somehow confirm the species' antibacterial potential and its usefulness in the treatment and management of gastrointestinal infections. Mukanganyama et al. [21] evaluated antibacterial activities of ethanol root extracts of E. elephantina against Bacillus cereus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus using the agar diffusion assay. The species exhibited antibacterial properties against all microorganisms tested and the authors assessed the minimal inhibitory concentrations (MICs) against Mycobacterium aurum, where E. elephantina showed some activity with MIC value of 1.25 mg/mL [21].

Pharmacological Activities
Mabona et al. [61] evaluated antibacterial activities of aqueous and dichlomethane/methanol (1 : 1) leaf, root, and rhizome extracts of E. elephantina using the micro-titre plate dilution technique against dermatologically relevant pathogens such as Brevibacillus agri, Propionibacterium acnes, Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus epidermidis with ciprofloxacin as positive control and acetone and dimethyl sulfoxide (DMSO) as negative controls. Mabona et al. [61] found varied antibacterial activities of the aqueous and dichlomethane/methanol (1 : 1) leaf, root and rhizome extracts with minimum inhibition concentration (MIC) ranging from 0.05 to >16.00 mg/mL. Antibacterial activities were displayed by dichlomethane/methanol leaf, root and rhizome extracts against Propionibacterium acnes (MIC values ranging from 0.05 to 1.00 mg/mL), Staphylococcus aureus (0.50 mg/mL) and Staphylococcus epidermis (0.38 to 1.00 mg/mL) as well as aqueous and dichlomethane/methanol root and rhizome extracts against Brevibacillus agri with MIC value of 0.50 mg/mL. The leaf, root and rhizome extracts of E. elephantina are reported to be traditionally used to treat acne vulgaris and pimples and such usage was corroborated by noteworthy activity against Propionibacterium acnes with MIC values between 0.05 and 2.0 mg/mL [61]. Propionibacterium acnes is an important skin pathogen responsible for the chronic inflammatory disease of the sebaceous glands and hair follicles of the skin [ [50]. Nciki et al. [50] and Mabona et al. [61] obtained similar results in terms of overall antibacterial activities displayed against Brevibacillus agri, Propionibacterium acnes and Pseudomonas aeruginosa although Nciki et al. [50] also assessed the antibacterial activities of E. elephantina against Escherichia coli. Nciki et al. [50] assessed antibacterial activities of aqueous and dichlomethane/methanol (1 : 1) root extracts of E. elephantina while Mabona et al. [61] assessed antibacterial activities of other plant parts which included leaves and rhizomes. Therefore, the results obtained by both Nciki et al. [50] and Mabona et al. [61] provide a scientific rational for the traditional use of E. elephantina as herbal medicine against several skin infections in South Africa such as acne [15,[36][37][38], eczema [36,37], itching [12], sores [50,51] and sunburn [15,38].
Mpofu et al. [43] evaluated antibacterial activity of the methanol and aqueous rhizome extracts of E. elephantina using the micro-titre plate dilution technique against Bacillus cereus, Enterococcus faecalis and Escherichia coli with ciprofloxacin as positive control and distilled water and dimethyl sulfoxide (DMSO) as negative controls. The minimum inhibitory concentration (MIC) values for the aqueous (0.50-2.00 mg/mL) and methanol (0.20-4.00 mg/mL) extracts independently demonstrated varied efficacies depending on the pathogen of study. Mpofu et al. [43] also evaluated the antibacterial activity of E. elephantina with Pentanisia prunelloides combined in 1 : 1 ratios, displaying synergistic interactions with sum of the fractional inhibitory concentration (ΣFIC) values ranging from 0.19 to 1.00 mg/mL for aqueous extracts and 0.60 to 0.80 mg/mL for methanol extracts against Bacillus cereus, Enterococcus faecalis and Escherichia coli. The antibacterial activity of E. elephantina in combination with Pentanisia prunelloides were determined as a validation of their combined use in southern African traditional medicine. Mpofu et al. [43] also evaluated the antibacterial activity of epicatechin 14 and hexadecanoic acid 15 isolated from E. elephantina rhizomes using the microtitre plate dilution technique against Bacillus cereus, Enterococcus faecalis and Escherichia coli with ciprofloxacin as positive control and distilled water and dimethyl sulfoxide (DMSO) as negative controls. The efficacy for the two compounds measured via MIC values ranged between 0.13 and 0.63 mg/mL, while synergistic interactions were noted against Escherichia coli and Enterococcus faecalis with (ΣFIC) values of 0.09 mg/mL and 0.50 mg/mL, respectively [43]. Therefore, the two compounds epicatechin 14 and hexadecanoic acid 15 showed synergistically enhanced activity especially against Escherichia coli and Enterococcus faecalis. Furthermore, previous studies have shown that hexadecanoic acid 15 is active against various bacterial strains [67] including Escherichia coli [68] and epicatechin 14 is also active against Escherichia coli and can play an important role in developing pharmaceutical drugs against urinary tract infections [69]. Epicatechin 14 has also been implicated for antibacterial activity against Escherichia coli, Bacillus cereus, Staphylococcus aureus, and Shigella flexneri at minimum inhibition concentration (MIC) values ranging from 12.50 to 100 mg/mL [70,71]. The antibacterial potency of this compound isolated from E. elephantina is noteworthy as the species is administered as a remedy by traditional healers in Botswana [40,41], Mozambique [45], South Africa [15,28,29,32,38,44,46], and Swaziland [34]. These results support the traditional use of E. elephantina in treating bacterial infections such as diarrhoea and sexually transmitted infections.  [50]. It is important to note that Nciki et al. [50] assessed antifungal activities of root extracts only while Mabona et al. [61] evaluated antifungal roots, leaves, and rhizomes of E. elephantina. There are also differences in terms of best antifungal results documented in these two studies. According to Mabona et al. [61] the best antifungal activities were demonstrated by dichlomethane/methanol leaf, root, and rhizome extracts against Microsporum canis with MIC value of 0.50 mg/mL while best antifungal results obtained by Nciki et al. [50] were demonstrated by dichlomethane/methanol extracts against Candida albicans with MIC value of 130 휇g/mL. Overall, results obtained by Nciki et al. [50] and Mabona et al. [61] provide a scientific basis for the traditional use of E. elephantina as herbal medicine against several skin infections in South Africa such as acne [15,[36][37][38], eczema [36,37], itching [12], sores [50,51], and sunburn [15,38].

Anti-Inflammatory and Antinociceptive Activities.
Maphosa et al. [62] evaluated anti-inflammatory and antinociceptive activities of root extract of E. elephantina using Wistar rats. The authors evaluated anti-inflammatory activities using carrageenan and histamine-induced rat paw oedema while antinociceptive activity was evaluated by acetic acid-induced writhing test and formalin test. The aqueous extract of E. elephantina reduced the formation of oedema induced by carrageenan and histamine and caused reduction in writhings in the acetic acid test and licking time in the formalin test [62]. According to Maphosa et al. [62], the root extract of E. elephantina reduced oedema and pain even better than the control, indomethacin, a potent inhibitor of prostaglandins (PG) synthesis, showing that the plant species has strong anti-inflammatory and antinociceptive activities. The anti-inflammatory activity displayed by root extract of E. elephantina could be due to anthraquinone 38, as previous research by Mishchenko et al. [72] showed that cell culture composed of anthraquinone 38 isolated from Rubia cordifolia L. exhibited anti-inflammatory activity, which is manifested by an antiexudative effect and antiproliferative action during the rapid development of a model edema. These results support the traditional use of the species in various inflammatory ailments and diseases ranging from microbial infections to sores and wounds that result in cell injury and pain. 7.5. Antiplasmodial Activity. Clarkson et al. [63] evaluated aqueous, dichloromethane, and dichlomethane/methane (1 : 1) leaf and root extracts of E. elephantina for in vitro activity against Plasmodium falciparum using the parasite lactase dehydrogenase (pLDH) assay and chloroquine diphosphate (Sigma) as the positive control. The dichlomethane/methane (1 : 1) leaf and root extracts showed weak activity with IC 50 values of 26 and 28 휇g/mL, respectively, while aqueous extracts for both leaves and roots showed weak activity with IC 50 values >100 휇g/mL [62]. Although E. elephantina is widely used as traditional remedy for fever in Mozambique [25], South Africa [42], and Zimbabwe [43], the species did not display promising in vitro antiplasmodial activity, to support its traditional usage in the management and treatment of fever. A possible explanation could be that E. elephantina act as antipyretics or immune stimulants to relieve the symptoms of the disease, rather than having direct antiparasitic activity [73]. Alternatively, precursors of the active components may be present in E. elephantina extracts but have to be modified, usually in vivo, before activity is exhibited [63]. 7.6. Antioxidant Properties. Mpofu et al. [54] evaluated antioxidant properties of E. elephantina using DPPH radical scavenging method with the yen and duh percentage inhibition values ranging from 33 to 72% for both methanol and aqueous extracts. This study carried out by Mpofu et al. [54] revealed that there were more extractable antioxidants using methanol compared to water as the solvent. The antioxidant activities demonstrated by E. elephantina rhizome extracts are probably due to the presence of flavonoids and phenolics [74] [3,4,48]. Root infusions of E. elephantina have been reported to have constipating effects [48] while seeds are strongly irritant and have been suspected of causing human death when used as herbal medicine [4]. According to Hutchings et al. [4] an aqueous extract of the seed equivalent to 0,75 g produced extensive necrosis at the point of injection and gastroenteritis and pulmonary oedema when injected subcutaneously in the guinea-pig. Symptoms of poisoning were apathy, loss of appetite, and profuse foetid diarrhoea with death occurring within twenty-four hours with the animal in a state of exhaustion. Postmortem examination revealed acute gastroenteritis with numerous haemorrhages and marked degeneration of the liver [4]. Jansen [16] reported that the seeds of E. elephantina are toxic to sheep with a lethal dose 250 g and rabbits (lethal dose 5-7.50 g/kg) causing gastroenteritis and pulmonary oedema.
Preliminary acute toxicity evaluation of root extract of E. elephantina using Wistar rats showed no physiological and behavioural changes in the animals and also no mortalities were recorded [62]. In another study, Maphosa et al. [76] evaluated the acute, subacute, and chronic toxicity of E. elephantina root extracts by oral route in male and female Wistar rats. The authors recorded no mortalities but changes in body weight and haematological and serum biochemical parameters between the control and treated animals were observed. In acute tests, Maphosa et al. [76] observed decreased respiratory rate at higher doses of 1600 mg/kg, and, in subacute tests, the root extract of E. elephantina caused an increase in white blood cells, monocytes, and serum levels of creatinine at higher doses of 400 and 800 mg/kg. In chronic toxicity, E. elephantina extracts caused increase in lymphocytes and platelets and changes were also noted in the body and organ weights in both subacute and chronic toxicities. Maphosa et al. [76] observed acute hepatitis, intracrystal deposition (reminiscent of oxalate crystals) with renal crystals and secondary ascending pyelonephritis in animals receiving 800 mg/kg in subacute toxicity tests while pulmonary granulomas were noted in animals which received 400 mg/kg. In chronic toxicity tests, Maphosa et al. [76] observed mild to moderate splenic siderosis, pulmonary granulomas, refractile crystal deposits, and associated ascending pyelonephritis. Mpofu et al. [54] evaluated cytotoxicity activity of E. elephantina using the brine shrimp lethality test. Chloroform rhizome extract of E. elephantina exhibited some degree of biological activity with LC 50 value of 0.80 [54]. Based on toxicity evaluations done so far [54,62,76], it can be inferred that E. elephantina has some potential toxicity at certain dose levels and should be taken with caution when used as herbal medicine.

Conclusion
The present review summarizes the ethnomedicinal uses and recent findings on traditional uses, phytochemistry, pharmacology, and toxicity of different extracts and compounds of E. elephantina. Anthocyanidins, anthraquinones, esters, fatty acids, phenolic compounds, flavonoids, glycosides, polysterols, saponins, sugars, tannins, and triterpenoids (1) Since E. elephantina is widely used in combination with other plant species in various herbal concoctions, there is need for extensive research to evaluate synergistic effects of the different extracts or pure isolates to evaluate their ability to enhance the efficiency of the additive mixtures, (2) Future research should also focus on aerial parts of the species in order to ensure full utilization of the possible medicinal potential of E. elephantina. There is need to investigate the chemical constituents and pharmacological effects of the bark, leaves, flowers, fruits, and seeds of E. elephantina.
(3) Literature studies show that the major phytochemical compounds isolated from E. elephantina so far are mainly fatty acids, phenolic compounds, and esters, but very little attempt has been made to correlate the activities of these compounds with the ethnomedicinal uses of the species. Therefore, there is need for further research on different compounds isolated from E. elephantina; examples include fatty acids and esters. Detailed phytochemical studies of E. elephantina and its pharmacological properties especially the mechanism of action of its bioactive constituents to illustrate the correlation between its ethnomedicinal uses and pharmacological activities should be the focus of future research studies.
(4) Extensive in vivo experiments are required to validate the existing pharmacological activities.
(5) Since E. elephantina contain potentially toxic compounds, future studies should include the identification of toxic compounds, possible side effects caused by taking E. elephantina as herbal medicine, and mechanisms of how potential toxic components of the species can be managed.

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