The Genus Eriosema (Fabaceae): From the Ethnopharmacology to an Evidence-Based Phytotherapeutic Perspective?

The genus Eriosema (Fabaceae) includes approximately 150 species widely distributed across tropical and subtropical regions of the world (Africa, Neotropics, Asia and Australia). Throughout these regions, several species are used since centuries in different traditional medicinal systems, while others are used as food or food supplement. The present review attempts to critically summarize current information concerning the uses, phytochemistry and pharmacology of the Eriosema genus and to evaluate the therapeutic potential. The information published in English and French (up to September 2020) on ethnopharmacology or traditional uses, chemistry, pharmacology and toxicology of Eriosema genus was collected from electronic databases [SciFinder, PubMed, Google, Google Scholar, Scopus, Web of Science, Prelude Medicinal Plants—http://www.ethnopharmacologia.org/recherche-dans-prelude/?plant, The Plant List (http://www.theplantlist.org/), POWO (http://powo.science.kew.org/) and IUCN Red List Categories (https://www.iucnredlist.org/)], conference proceedings, books, M.Sc. and Ph.D. dissertations. The information retrieved on the ethnomedicinal indications of Eriosema genus allowed to list 25 species (∼16.6% of the genus). The majority of uses is recorded from Africa. Phytochemical analyses of 8 species led to the identification and/or isolation of 107 compounds, with flavonoids (69.2%), chromones (7.5%) and benzoic acid derivatives (3.7%) as the main chemical classes. Pharmacological investigations with crude extracts and isolated compounds showed a broad range of activities including aphrodisiac, estrogenic, anti-osteoporosis, hypolipidemic, anti-diabetic, anti-diarrheal, anti-microbial, anti-oxidant, anthelmintic, anti-cancer, and acetylcholinesterase inhibitory activities. Despite the low number of Eriosema species tested, there is convincing evidence in vitro and in vivo studies validating some traditional and ethnobotanical uses. However, the utility of several of the described uses has not yet been confirmed in pharmacological studies. Reviewed data could serve as a reference tool and preliminary information for advanced research on Eriosema species.


INTRODUCTION
Eriosema (Fabaceae), with approximately 150 species of shrubs, shrublets and herbs, is the second-largest genus of the Cajaninae subtribe (Ma et al., 1995;LPWG, 2017). This monophyletic clade originated in the late Miocene and its diversification occurred in parallel with the savanna biome expansion around the world (Cândido et al., 2020). The current centers of diversity and endemism of Eriosema species include the grasslands, wooded savanna and waste places of Africa (West, Central, East and South Africa), Central America (from Mexico to northern Argentina, except for Chile), Southeast Asia and Northern Australia (Wu, 1991;Schrire et al., 2005;Cândido et al., 2019). The African species are most abundant (nearly 110 species) and the first diverging evolution suggests an African origin of the genus (Cândido et al., 2020). The study by Cândido et al. (2019) recorded 35 Eriosema species in Brazil, which encompasses 85% of the diversity of the genus in the Americas (35 out of 41 species).
Throughout this pantropical region, several Eriosema species are intensively used in traditional medicine and for nonmedicinal purposes (e.g. food/vegetables, tooth brush). Based on the traditional uses, phytochemical, pharmacological and toxicological investigations of different Eriosema species have been performed. Nevertheless, till now only few reviews dealing with Eriosema species have been published. The studies by Cândido et al. (2019Cândido et al. ( , 2020, respectively, focused on the taxonomic synopsis of Eriosema in Brazil and molecular phylogenetic insights into the evolution of Eriosema. In 2015, Awouafack et al. demonstrated that Eriosema species represent a rich source of flavonoids with interesting pharmacological activities. In this review, authors compiled a total of 52 flavonoids (isoflavones, dihydroflavanols, isoflavanones, flavanols, flavanones, and dihydrochalcones) isolated from Eriosema species. However, the pharmacological properties are not limited to the flavonoids. In the literature, compounds from other chemical classes as well as plant extracts (more easily available and affordable than isolated compounds) demonstrated pharmacological properties. More recently, the review of Kleynhans et al. (2020) focused on Eriosema kraussianum Meisn. None of these reviews presented the global overview on the traditional uses, phytochemistry, pharmacological properties and toxicological evaluation of this genus. Accordingly, the present review attempts to critically summarize the available information on the traditional uses, phytochemistry, and pharmacological activities as well as safety evaluation of the genus Eriosema and, therefore to evaluate the data for potential phytotherapeutic approaches.

SEARCH STRATEGY AND TERMS USED
The information on the genus Eriosema published up to September 2020 in English and French was collected from different electronic data bases (SciFinder including Chemical Abstracts and Medline, PubMed, Google, Google Scholar, Scopus, Web of Science), conference proceedings, books, M.Sc. and Ph.D. dissertations. The keywords "Eriosema" in conjunction with 'traditional uses' or 'ethnopharmacology,' 'phytochemistry,' 'pharmacology,' and 'toxicology' were used. In addition, Prelude Medicinal Plants (http://www.ethnopharmacologia.org/ recherche-dans-prelude/?plant), The Plant List (http://www. theplantlist.org/) and POWO (http://powo.science.kew.org/) were explored for the plant´s traditional uses and scientific names, while information on the global extinction risk status of Eriosema species was gathered from the IUCN (International Union for Conservation of Nature) Red List Categories (https:// www.iucnredlist.org/).

TRADITIONAL USES AND ETHNOPHARMACOLOGY OF ERIOSEMA SPECIES
Since centuries, Eriosema species have widely been traditionally used as household remedies against various human ailments. Accordingly, in the pharmaceutical landscape this genus may represent a remarkable source of promising substances. From the literature review, various medicinal and contemporary uses associated with this genus are summarized in Table 1.
According to South African Zulu traditional health practitioners, the roots of several Eriosema species such as Eriosema kraussianum N. E. Br., Eriosema salignum E. Mey. and Eriosema cordatum E. Mey., known under the indigenous umbrella name of uBangalala, are effective to cure or alleviate erectile dysfunction (ED) and/or impotence (Bryant, 1966;Hutchings et al., 1996;Ojewole et al., 2007;Drewes et al., 2013). In Southern and Eastern Africa, they are also used as expectorants and diuretics (Watt and Breyer-Brandwijk, 1962). In case of impotence, hot milk infusions of the plants´roots and/ or pounded boiled root decoctions are taken at small doses twice a day (Hulme, 1954;Bryant, 1966). Studies reported that the roots of E. cordatum are used for male (Hutchings et al., 1996) and female (Bryant, 1966) infertilities and as constituent of Imbiza ephuzwato, a Zulu traditional herbal medicine (Van Wyk et al., 1997). This mixture is used as tonic, against anxiety, for clearing skin conditions, to treat diabetes mellitus, kidney and urinary infections, tonsillitis, pneumonia, constipation, stomach and back pains, for the improvement of high blood pressure, to boost energy, vitality and sexual activity as well as in the prevention of arthritis (Ndhlala et al., 2011).
In Angola, fresh leaves of Eriosema glomeratum (Guill. & Perr.) Hook. f. are eaten as food/vegetables and administered against diarrhea and dysentery (Göhre et al., 2016;Lautenschläger et al., 2018). In Benin, they are used against diabetes (Lawin et al., 2015), while the leafy stem is claimed to promote the closure of fotannel (Adomou et al., 2012). The roots are applied in Burkina Faso against hernia (Ouoba et al., 2006). In the Bakola Pygmy tribe, the whole plant is used for many purposes including pulmonary troubles, nasopharyngeal infections, leprosy and venereal diseases (Verdcourt, 1970).
Indians around Kunana (Venezuela) use the root decoction of Eriosema rufum G. Don. against sterility in women and to accelerate delivery in childbirth (Morton, 1981). Application of juice of fresh leaves on the infection site Ngezahayo et al. (2015) Eriosema montanum Bak. f.
Not specified Democratic

Eye diseases
Eye instillation of fresh leaves´juice Wome (1985) Wound healing Application of pounded dried leaves on the wound Nyakabwa and Gapusi (1990) Abscess, boil, ulcer, acne Local application of pounded fresh leaves Nyakabwa and Gapusi (1990) (Gillett et al., 1971). It is believed to cure coughs in East Africa (Kokwaro, 2009) and skin diseases in Central Africa (Awouafack et al., 2013a).
Eriosema laurentii De Wild. widely dispersed in West and Central Africa is used in this area as food and herbal medicine for many purposes such as nasopharyngeal, brain and nervous system affections, pulmonary troubles and venereal diseases (Burkill, 1985). In Cameroon, the plant is utilized for the treatment of infertility and various gynecological problems (Ateba et al., 2013).
The roots of Eriosema chinense Vogel (syn. Eriosema himalaicum H. Ohashi; Eriosema tuberosum (Ham.) Wang et Tang) are reported to be used as food in Northern Australia, China and North East India and against diarrhea in Meghalaya (India) (Neogi et al., 1989;Martin and Ryan, 2004;Prasad et al., 2013a). In Yunnan Province of China, the roots are used against diarrhea, orchitis, hydrophobia and as detoxifying medicine (Kunming Institute of Botany, 1979). In Thailand, the fresh roots are eaten as a tonic, and decoctions of the seeds are used for wound healing and for their diuretic properties (Thongnest et al., 2013). Such decoctions are also well-known as astringent, diuretic, tonic, against cold sweats and during delivery to promote discharge of the lochia. Decoctions additionally containing powdered pepper are given for diarrhea (Ashraf and Borthakur, 2005;Laloo and Hemalatha, 2011;Prasad et al., 2013c;Thongnest et al., 2013).
Eriosema psoraleoides (Lam.) G. Don. is a species widely used over Africa from Togo to Tanzania. In Tanzania, peeled or unpeeled twigs are used as chewing sticks (Khan et al., 2000), while leaves are used against health problems related to HIV/ AIDS such as chronic diarrhea (Kisangau et al., 2007), impotence, erectile dysfunction, fever and malaria (Moshi et al., 2009(Moshi et al., , 2010. In several countries in Central and West Africa, leaves are applied against eye diseases (Kerharo and Bouquet, 1950;Malzy, 1954;Descoings, 1963;Wome, 1985). The roots are used in Central African Republic against ear problems (Boulesteix and Guinko, 1979), and in Democratic Republic of Congo and Burundi against sexually transmitted diseases (Staner and Boutique, 1937;Baerts and Lehmann, 1989). Eating raw roots is claimed to treat pulmonary problems in Rwanda (Durand, 1960).
Leaves of Eriosema griseum Baker are known as infant cures for treating parasitic diseases and associated discomforts such as stomach ache, dysentery or diarrhea in Northern parts of Ivory Coast (Koné 2005;Koné et al., 2012).
The roots of Eriosema englerianum Harms are traditionally used in Zimbabwe in combination with other plants such as Vigna ungiculata and Terminalia sericea to treat bilharziosis (Mmbengwa et al., 2009).
Globally, the search of information resulted in 25 species (∼16.6% of the genus), for which written evidence of traditional uses is available. Clearly, this list cannot be exhaustive as in many traditional medicine systems a vast knowledge on medicinal plants exists as oral information only. The majority of medicinal plants used over the world are harvested from wild resources in increasing volumes. Given their integral role in basic healthcare in many developing countries, their conservation and sustainable use are a necessity. The information of the IUCN (International Union for Conservation of Nature) Red List Categories, assessing the conservation status of species, was accessed for Eriosema species from https://www.iucnredlist.org/fr/ search?query Eriosema&searchType species. At the moment, only 22 Eriosema species (Table 2) are included in this list. Information for the vast majority of species widely used in traditional medicine such as E. chinense, E. cordatum, E. glomeratum and E. psoraleoides and others depicted in Table 1 is still missing. Only the three traditionally used species Eriosema crinitum (Kunth) G. Don, Eriosema englerianum Harms and Eriosema montanum Baker f. are listed, characterized by a stable population with least concern. Nevertheless, the most popular species with traditional use should be assessed to avoid a negative impact on the size of the populations. Root and whole-plant harvesting is more destructive than collecting leaves and flowers or buds (Chen et al., 2016). Among the 25 species traditionally used and reported in this review, mainly roots are utilized (18 species), followed by leaves (11 species), bark and whole plant (3 species), seeds or fruits (2 species) and twigs (1 species) (Figure 1). Rather to use roots, leaves can be an alternative to avoid the destruction and highspeed disappearing of Eriosema species. In case roots are unavoidable for the use, non-destructive harvest protocols such as partial-root harvest should be applied.

PHYTOCHEMISTRY OF THE GENUS
Based on the ethnopharmacological applications, numerous chemical analyses of Eriosema species have been carried out. Compounds identified or isolated are depicted in Table 3 and Figure 2.
Twigs of E. robustum contained orostachyscerebroside A (107) (Awouafack et al., 2013a). Globally the phytochemical investigation of the Eriosema genus led to the isolation and/or identification of 107 compounds from only eight species (5.3% of the genus) out of ca. 150 (E. chinense, E. englerianum, E. glomeratum, E. kraussianum, E. laurentii, E. robustum, E. tuberosum and E. psoraleoides). Isolated and/or identified constituents are mostly isoflavones (26.2%), flavonols (11.2%), flavanonols (11.2%), flavanones (8.4%) and chromones (7.5%) ( Figure 3). Awouafack et al. (2015) documented flavonoids from 5 Eriosema species and concluded that the genus represents a rich source of flavonoids, mostly isoflavones which could be considered as markers for the genus and have chemotaxonomic significance. However, given the low number of species investigated until now, the deduction of a chemotaxonomic significance of some of the components seems premature.

PHARMACOLOGY
Based on their ethnopharmacological use, Eriosema species aroused the interest of the scientific community. In line with this, many studies have been carried out aiming at evaluating or confirming the therapeutic potential of species from this genus. As depicted in Table 4, extracts and constituents from Eriosema species are shown to be responsible for a wide range of pharmacological activities such as aphrodisiac, anti-diarrheal, anti-oxidant, anti-microbial, anti-diabetic/hypoglycemic and estrogenic properties.

Antioxidant Activities
By controlling the formation and scavenging of reactive oxygen and nitrogen species (ROS/RNS) as well as interrupting the related chain reactions and lipid peroxidation, antioxidants constitute the first line of defense against the genesis of various chronic and degenerative diseases. Different in vitro methodologies, including the DPPH (1,1-di-phenyl-2-       picrylhydrazyl), nitric oxide radical and H 2 O 2 scavenging assays, potassium ferricyanide antioxidant power (PFRAP), hydroxyl radical antioxidant capacity (HORAC), thiobarbituric acid reactive substances (TBARS) and the β-carotene bleaching test were used to evaluate the radical scavenging and antioxidant potential of members of the Eriosema genus. Using a β-carotene bleaching assay, essential oil from fresh leaves of E. englerianum containing 3.65% ascaridole (91), 7.86% terpinolene (92) and 88.50% O-cymene (93) showed anti-oxidant activity with a color retention zone of 14.4 mm (Mmbengwa et al., 2009).
The anti-oxidant activity of an ethanol extract of twigs of E. robustum, its fractions and the isolated compounds 16 and 17, 41 and 101 resulted in unphysiological IC 50 values (≥1.13 mg/ml) using a DPPH method (Awouafack et al., 2013b). Using the same assay, compounds 5 and 72 displayed IC 50 values of 340.3 and 524.6 μM, respectively, while that of ascorbic acid was 35.9 μM (Awouafack et al., 2018).
The antioxidant capacity of Eriosema species was evaluated in vitro by different methods addressing different mechanisms of action. Each of them has its strengths and weaknesses (Bibi Sadeer et al., 2020). The plant extracts and products are mixtures of compounds that can display their antioxidant activity through different mechanisms. Therefore, to better estimate the overall antioxidant activity of a sample, at least two (or even all) of these assays must be combined. Tan and Lim (2015) recommended a mix of single electron transfer based (DPPH, ABTS, FRAP, TBARS) and hydrogen atom transfer based (ORAC, HORAC, TRAP, crocin and β-carotene bleaching) assays. Among the six in vitro studies recorded in this review, just two (Prasad et al., 2013a;Prasad et al., 2013b) met with this requirement, while the other ones only used β-carotene bleaching (Mmbengwa et al., 2009) or DPPH (Awouafack et al., 2013b;Thongnest et al., 2013;Awouafack et al., 2018) assays. In vitro models are known to be not always reproducible in respective in vivo assays. Therefore, in vivo studies are necessary for the confirmation of such effects. Interestingly, the weakly active ethanol root extract of E. chinense, its chloroform fraction and the inactive compound 39 using DPPH method, restored the alterations of nitric oxide, TBARS, superoxide dismutase and catalase activities in the castor oil-mediated diarrhea model in rats (Prasad et al., 2013c). Although data at this level seems to be naïve and preliminary for any conclusion, they are indicator of the antioxidant potential of members of the Eriosema genus. However, more species need to be investigated in vitro and in vivo.

Estrogenic and Aryl Hydrocarbon Agonistic Properties
Estrogens deficiency (natural or surgical) is associated with numerous health problems including urogenital atrophy, hot flushes, osteoporosis and increased risk of cardiovascular diseases (Calleja-Agius and Brincat, 2015;Nappi and Cucinella, 2020). Given the adverse outcomes associated with the long-term usage of the hormone replacement therapy e.g. increased risk of endometrial and breast cancer, stroke and pulmonary thromboembolism, phytoestrogens have gained and continue to receive great interest.
The estrogenic properties of E. laurentii, traditionally used against female infertility, gynecological and menopausal complaints have been evaluated in vitro and in vivo. In vitro, a methanol extract of the aerial parts (AEL), its fractions and the predominant secondary metabolites 43, 44 and 73 induced a significant and concentration-dependent β-galactosidase activity in the ERα yeast two-hybrid assay (yERα) (Ateba et al., 2013;Ateba et al., 2014b). At 25 μg/ml, AEL was as potent as 10 nM estradiol (Ateba et al., 2013). Compounds 43, 44 and 73 displayed EC 50 values of 0.32 µM, 6.1 µM and 21.4 nM, respectively, while that of 17β-estradiol (E 2 ) was 0.27 nM. All the three compounds were full ERα agonists as they displayed the maximal efficacy of E 2 although at much higher concentrations (Ateba et al., 2014b). A methanolic extract of the underground parts of E. laurentii (UEL) was also highly active in yERα (Ateba et al., 2016b). The concentration of 10 μg/ml was as potent as 0.5 nM E 2 . However, compounds 22, 62 and 63 from this extract did not show any yERα activity (Ateba et al., 2016b).
In vivo, a 3-days uterotrophic assay and a 9-weeks oral treatment in ovariectomized adult rats were tested. AEL at the doses of 50, 100 and 200 mg/kg p. o. did not induce endometrium proliferation either in the 3-days or the 9weeks treatment regimens, but induced vaginal stratification and cornification (Ateba et al., 2013). This tissue-dependent effect suggests that AEL could prevent vaginal dryness experienced by menopausal women, while not inducing the unwanted uterine proliferation. In the other hand, the decoction of aerial parts of E. laurentii had no significant effect on the uterine and vaginal endpoints at all tested doses following a 3days uterotrophic assay (Ateba et al., 2014c).
Classical, suitable and reproducible systems/models have been used to evaluate estrogenic and aryl hydrocarbon agonistic properties of E. laurentii in vitro (Jungbauer and Beck, 2002;Reiter et al., 2009) andin vivo (OECD, 2007;Mvondo et al., 2011). Accordingly, all data reported in this section demonstrated the potential of E. laurentii for managing various gynecological and menopausal complaints. However, this species is also traditionally used for treating female infertility. Studies in that domain are needed. Similarly, a wide traditional use of E. cordatum in South Africa against female infertility has been recorded. Nevertheless, no published study demonstrates this potential till now.

Antiosteoporosis Activity
Osteoporosis is a skeletal disorder characterized by a deterioration of bone tissue and disruption of bone microarchitecture that lead to low bone mass and strength, predisposing to an increased risk of fracture (Pisani et al., 2016). It affects both sexes and is mainly linked with the agerelated decrease of estradiol and testosterone. Therapeutic agents that would not only inhibit bone resorption but also simultaneously stimulate bone formation would be most favorable (Abdelsamie et al., 2019).
Using a well-known postmenopausal-like model of osteoporosis (ovariectomy) in rats, Ateba et al. (2013) evaluated the effects of a 9-weeks oral treatment with a methanolic extract of the aerial parts of E. laurentii. The extract significantly increased the dry femur weight (at 50 and 200 mg/kg), and calcium levels in serum (at 50 and 200 mg/kg) and femur (at all tested doses) compared with ovariectomized animals. The serum levels of inorganic phosphorus decreased, while the femur levels increased in a dose-dependent manner. Although the dose of 200 mg/kg was not able to completely reverse the ovariectomy-increased alkaline phosphatase (a biomarker for osteoblastic activity and bone remodeling), it decreased it by ∼15%. Based on the increased in femur mass, and femur calcium and inorganic phosphorus contents, the authors concluded that bone formation exceeded resorption suggesting the inhibition of bone resorption and activation of bone formation.
There is growing interest in 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2), an enzyme able to regulate the intracellular concentration of estradiol and testosterone by transforming them into the less potent forms estrone and androstenedione (Marchais-Oberwinkler et al., 2011) in tissues where it is expressed, such as bone (Dong et al., 1998;Eyre et al., 1998). Blockade of this enzyme is thought to increase intracellular estradiol and testosterone, which thereby inhibits bone resorption by osteoclasts and stimulates bone formation by osteoblasts (Abdelsamie et al., 2019). In line with this 17β-HSD2 is more and more considered as target for antiosteoporosis treatment. In an in vitro assay using lysates of cells expressing the recombinant human enzyme 17β-HSD2, Vuorinen et al. (2017) tested 36 hit molecules, including 44 and 73 from E. laurentii. These compounds with respective IC 50 values of 1.52 and 2.03 µM were among the most active 17β-HSD2 inhibitors tested. However, they selectively inhibited 17β-HSD1 (that catalyzes the reverse reaction) over 17β-HSD2 and therefore cannot be suitable lead structures for a possible therapeutic use (Vuorinen et al., 2017).

Erectile Dysfunction and Impotence
Erectile dysfunction (ED) as well as impotence is a multifactorial (psychogenic, neurogenic, vasculogenic, endocrine/metabolic, end organ disease and iatrogenic) health issue common in 20-30% of adult men worldwide (McMahon, 2019;Taylor et al., 2019). It negatively impacts patient's sexual satisfaction and psychological well-being, leading to a greater prevalence of anxiety and depression. Lifestyle changes in combination with oral phosphodiesterase type 5 inhibitors (PDE5Is: sildenafil, tadalafil, vardenafil and avanafil) are typically first-line treatments of most etiologies of ED (Hatzimouratidis et al., 2016;Krzastek et al., 2019;Moses et al., 2019). PDE5Is increase arterial blood flow into the penis (via relaxion of the corpus cavernosum and deep penile artery smooth muscles) and reduce the venous outflow leading to the penile erection. Among PED5Is, only sildenafil is cost-effective as it is the only PDE5-I with a generic option. PED5Is are commonly associated with side effects (flushing, hypotension, headache, dyspepsia, back pain, myalgia, dizziness, blurred vision and rhinitis) and a lot of contraindications that contribute to significant treatment dropout rates (Yuan et al., 2013;Yafi et al., 2018). Moreover, up to 40% of ED patients fail to respond sufficiently to the maximum dose of PDE5Is (Porst et al., 2013).
From ancient times, plants have served as a dependable source of medicines for treating ED. In the Eriosema genus, E. cordatum, E. kraussianum and E. salignum are traditionally or locally used as aphrodisiac or against male sexual disorders (ED, impotence). However, only compounds from E. kraussianum were evaluated until now. In 2002, Drewes et al. investigated the capacity of pyrano-isoflavones 64-68 to relax the corpus cavernosum of rabbits. Compounds 64 and 65 displayed a dose-dependent activity, while 66-68 were inactive. At the low concentration of 78 ng/ml, 64 and 65 displayed 85 and 65% of the relaxation found with sildenafil citrate, respectively. Rather to induce relaxation, 66 and 68 caused contraction of corpus cavernosum tissue (Drewes et al., 2004). Accordingly, the authors indicated that the overall effect of the extract as used in traditional medicine is mainly determined by the activities of 64 and 65, present as the major constituents.
Eriosema cordatum, E. kraussianum and E. salignum and the other Eriosema species that come under the isiZulu indigenous umbrella name of "uBangalala" are widely traditionally used mainly in South Africa for curing or alleviating ED and/or impotence (Bryant, 1966;Hutchings et al., 1996). However, despite their high reputation in that domain, the investigation only focused on E. kraussianum with two papers published more than 15 years ago. In line with this, these Eriosema species traditionally used against ED remain underexplored and even seem to be abandoned. Given the burden of this sensitive topic, they require more research attention.

Hypoglycemic and Anti-diabetic Effects
Diabetes is a major global health threat. This metabolic disorder is caused by a lack (absolute or relative) of insulin and/or resistance to insulin that lead to chronic hyperglycemia.
ED is a common comorbidity of diabetes mellitus. It can be caused by impaired hemodynamic mechanisms in the penile and ischemic vasculature that occur in diabetes mellitus (Rendell et al., 1999). There is a consensus that lifestyle changes and risk factor modification must precede or accompany any pharmacological or psychological ED treatment (Hatzimouratidis et al., 2016;Hackett et al., 2018). In other words, the amelioration of diabetes risk factors may improve erectile function. Acute oral treatment with a E. kraussianum rootstock hydro-alcoholic extract (40-320 mg/kg) dosedependently and significantly reduced fasting blood glucose levels in normoglycemic and streptozotocin-treated diabetic rats from 2 to 8 h after treatment with peak effects after 4 h (Ojewole et al., 2007). Using an oral glucose tolerance test, a pretreatment with the extract 20 min before challenge significantly reduced the peak blood glucose levels. Similar effects were obtained with 80 mg/kg p. o. of kraussianones 1 and 2 in normoglycemic rats (Ojewole et al., 2006).
In alloxan-induced diabetic Wistar rats, both aqueous and ethanolic leaf extracts of E. psoraleoides (at 200 and 400 mg/kg) significantly decreased fasting blood glucose levels from day 6 of a 7-days treatment (Nduka et al., 2018;Nduka et al., 2019). Using the same model, Elechi et al. (2019) investigated the effects of n-hexane, n-hexane/dichloromethane (1:1 v/v), dichloromethane, and dichloromethane/methanol (19:1 v/v) fractions of the n-hexane leaf extract of E. psoraleoides on the fasting blood glucose levels. The n-hexane/ dichloromethane and the dichloromethane fractions at the dose of 200 mg/kg produced a significant decrease in fasting blood glucose levels from day 2-7, the effects of the dichloromethane fraction being higher or very close to that of 4 mg/kg glibenclamide (Elechi et al., 2019).
Eriosema glomeratum claimed to be traditionally used against diabetes (Lawin et al., 2015) is not yet investigated in relation to the metabolic disorder.

Cardiovascular protection: dyslipidemia, vasodilatation and preeclampsia
Cardiovascular disease remains the leading cause of death worldwide (Global Burden of Disease Study 2017; Causes of Death Collaborators, 2018). Managing its modifiable risk factors such as hypertension and dyslipidemia constitutes key targets of public health organizations over the world (Berman et al., 2019;Michos et al., 2019).
Increased risk of cardiovascular diseases such dyslipidemia is well known to be associated with menopause. Using a postmenopause-like model (ovariectomized Wistar rats), a 9weeks oral treatment with a methanol extract of the aerial parts of E. laurentii significantly decreased the total cholesterol (TC) and LDL levels at 200 mg/kg. Increased HDL as well as a nonsignificant decrease of triglycerides (TG) levels were also observed at all tested doses (50, 100 and 200 mg/kg). The extract decreased the ovariectomy-increased TC/HDL and LDL/HDL ratios. A significant decrease of the atherogenic plasma index [AIP: log 10 (TG/HDL)] was determined at all tested doses (Ateba et al., 2013). Individual cholesterol risk factors are not sufficient to assess cardiovascular risk (Michos et al., 2019). A huge body of evidence supports AIP as one of the strongest predictive indicator of cardiovascular disease risk (Dobiášová et al., 2004;Edwards et al., 2017) also in postmenopausal women (Wu et al., 2018;Barua et al., 2019). This parameter has been evaluated in the study by Ateba et al. (2013) indicating the potential of E. laurentii in the management of dyslipidemia in postmenopausal women. Ojewole et al. (2006) investigated the vasodilatory effects of 64 and 65 (100-2,000 μg/ml) from the rootstock of E. kraussianum in isolated portal veins. Both constituents, after provoked initial slight contraction, induced a dose-dependent secondary and pronounced vasorelaxant effect, probably by affecting calcium mobilization and/or sequestration, and possibly also, calcium release from its various tissue stores.
Preeclampsia is the most common pregnancy-related complication worldwide, affecting 5-7% of all pregnancies with estimated 70,000 maternal deaths and 500,000 fetal and neonatal deaths each year (Rana et al., 2019). This incidence probably remains underestimated due to underreporting (Mayrink et al., 2018). The options for prevention and treatment of this hypertensive disorder are extremely limited, especially in resource-limited settings (Lemoine and Thadhani, 2019) where almost all of the deaths occur (Oyston and Baker, 2020). In this context, medicinal plants and herbs are an opportunity. In preeclampsia, the abnormal placentation characterized by impaired spiral artery remodeling lead to an ischemic placenta, which releases factors such as anti-angiogenic factors sFlt-1 (soluble fms-like tyrosine kinase-1) and sEng (soluble Endoglin), responsible for vascular dysfunction, into the maternal circulation (Chang et al., 2018;Eddy et al., 2018;Jena et al., 2020). Based on the vasodilatory properties of 65 (Drewes et al., 2002;Ojewole et al., 2006), Ramesar et al. (2012) investigated its effects in the L-NAME-induced preeclamptic Sprague-Dawley rat model. Subcutaneously administered at 10 mg/kg for 12 consecutive days, the compound decreased fetal mortality, demonstrated a trend toward increasing birth and placental weights by improving placental perfusion, reducing blood pressure amplification through a NO-independent mechanism, and decreasing the plasma levels of sFlt-1and sEng.
Globally, based on the in vivo models used and the results obtained, the investigated Eriosema species display a potential in the management of modifiable risk factors (hypertension, dyslipidemia) of the cardiovascular disease.

Acetylcholinesterase Inhibition
The inflammation-associated cognitive decline is mainly due to degeneration of central cholinergic neurons or cholinergic impairment, making acetylcholinesterase inhibitors the main class of drugs currently used in the treatment of mild cognitive impairment and Alzheimer's disease (Benfante et al., 2019). In a study by Ndhlala et al. (2011), an aqueous extract of the roots of E. cordatum with an IC 50 value of 756.6 μg/ml showed a very low acetyl cholinesterase inhibitory activity.

Anti-Microbial Activity
Infectious diseases are among the most important cause of morbidity and mortality worldwide. This is worsened by drug resistance, one of the greatest challenges of the 21st century (Hofer, 2019;Tacconelli and Pezzani, 2019). The importance of plants as a source of effective anti-microbial agents is well established. Several reports dealing with the anti-bacterial and anti-fungal effects of Eriosema species have been documented.
Dichloromethane and ethanolic root extracts of E. cordatum exhibited moderate antibacterial activities against S. aureus, B. subtilis, E. coli and K. pneumoniae (Ndhlala et al., 2011). The ethanol extract showed MIC values of 390 μg/ml toward all these microbial species, while that of the dichloromethane extract were 195 μg/ml against S. aureus and B. subtilis, and 390 μg/ml against E. coli and K. pneumoniae. Petroleum ether and water root extracts were not active (MIC ≥1.56 mg/ml) against all the tested microbial species. The MIC of the standard neomycin ranged between 0.8 μg/ml and 1.6 μg/ml (Ndhlala et al., 2011).
Through the broth dilution method, methanol/ dichloromethane (1:1, v/v) extracts of stems and leaves of E. glomeratum showed MIC values ranging between 50 and 1000 μg/ml against S. aureus, K. pneumoniae, Morexella catarrhalis, Mycobacterium smegmatis and Mycobacterium aurum (Fomogne-Fodjoet al., 2014). The stem extract displayed the highest activity with MIC values of 65 and 50 μg/ml against M. smegmatis and M. aurum, respectively, whereas the leaf extract was most active against M. smegmatis (MIC 130 μg/ml). Against these two Mycobacterium species, the standard ciprofloxacin displayed MIC values of 78 and 1.5 ng/ml, respectively. Compounds 1, 2, 13, 47 and 85 from the methanol/ dichloromethane (1:1 v/v) extract of the whole plant of E. glomeratum were tested at a concentration of 1 μg/ml against bacteria (Bacillus megaterium, E. coli), the green alga Chlorella fusca and the fungus Microbotryum violaceum using an agar diffusion assay (Awouafack et al., 2008). Compound 1 displayed IZ of 7 mm toward B. megaterium, C. fusca and M. violaceum, and of 10 mm against E. coli. IZ values of 10, 8, 9 and 13 mm were observed with 2 against B. megaterium, E. coli, C. fusca and M. violaceum, respectively. Compounds 13 and 47 were only active (IZ of 10 mm) against C. fusca, while 85 was inactive against all four microbial species. In this study, the standards were also tested at a concentration of 1 μg/ml. Tetracycline displayed IZ of 18 mm against bacteria, while an IZ of 20 mm was observed with nystatin against M. violaceum. The IZ of the standard actidione was 35 and 50 mm against the alga and fungus, respectively (Awouafack et al., 2008 (Cos et al., 2002b).
Methanolic extracts of the bark and wood of twigs of E. psoraleoides displayed very high MIC values (≥1.25 mg/ml) against Streptococcus mutans HG 982, Actinomyces viscosus HG485 and C. albicans HG392 in the agar dilution method (Khan et al., 2000). MIC values of 8, 32 and 128 μg/ml against these microorganisms were observed with the standard chlorhexidine, respectively. Using a bioautography agar overlay method, Runyoro et al. (2006) reported that a methanolic extract of the stem bark of E. psoraleoides was not active against C. albicans. A methanolic leaf extract as well as its n-hexane and ethyl acetate fractions were tested against E. coli ATCC35219, S. aureus ATCC25923 and clinical isolates of S. aureus, P. vulgaris, Klebsiella aerogenes, P. aeruginosa, and E. coli and displayed MIC >1.26 mg/ml, except the n-hexane fraction with a MIC value of 150 μg/ml toward S. aureus ATCC. The MIC value of the standard gentamicin was not reported (Elechi and Igboh, 2017).
An ethanolic extract from the twigs of E. robustum showed a MIC value of 80 μg/ml against S. aureus, E. faecalis and E. coli and of 310 μg/ml toward P. aeruginosa. Significant differences in the activity were observed against the fungi Aspergillus fumigatus (MIC 160 μg/ml), Cryptococcus neoformans (MIC 630 μg/ml), C. albicans and C. albicans ATCC (MIC 1,250 μg/ml) (Awouafack et al., 2013a). Compounds from this extract showed either moderate or low activity against these microbial species. Moderate antimicrobial activities (MIC 63 or 65 μg/ml) were observed with 16 and 17 against C. albicans ATCC, A. fumigatus and P. aeruginosa. 17 also showed a moderate activity against Cryptococcus neoformans and E. faecalis. A MIC of 63 or 65 μg/ ml was observed with 107 against P. aeruginosa and with 87 against A. fumigatus and P. aeruginosa; 101 against C. albicans ATCC and P. eruginosa; 99 against S. aureus and P. aeruginosa; 88 against A. fumigatus, C. neoformans, P. aeruginosa and E. faecalis; 41 against C. albicans ATCC, S. aureus, P. aeruginosa, E. faecalis and E. coli (Awouafack et al., 2013a). The standard gentamicin showed a MIC <3.91 μg/ml against bacteria, while that of amphotericin B was 30 μg/ml toward C. albicans (isolate) and C. albicans (ATCC), >250 μg/ml against C. neoformans and 125 μg/ml against A. fumigatus. Using a microdilution method, 5 and 72 from the ethanol extract of twigs of E. robustum displayed weak antimicrobial activity (MICs >150 μg/ml) against Bacillus subtilis, S. aureus, K. pneumoniae, E. coli, C. albicans, and Saccharomyces cerevisiae (Awouafack et al., 2018) In this study, the tested concentrations or MIC values of standard antibiotics ampicillin, kanamycin, and cycloheximide were not indicated.
In a study by Sianglum et al. (2019), lupinifolin (39) demonstrated an antimicrobial activity against E. faecalis ATCC29212, S. aureus ATCC25923 as well as susceptible and multidrug-resistant enterococcal clinical isolates (E. faecalis and E. faecium) in the standard broth microdilution method. Although the tested compound was not extracted from an Eriosema species, it has been reported in roots of E. chinense and E. robustum. In that study, 39 displayed activity against all susceptible and resistant strains with MICs and MBCs (minimum bactericidal concentration) ranging between 0.5 and 2 μg/ml and between 2 and 16 μg/ml, respectively. Toward all the strains, compound 39 with MIC values of 0.5-2 μg/ml was more active than vancomycin (MIC of 1-256 μg/ml). It increased membrane permeability and caused loss of salt tolerance. On E. faecalis ATCC29212, E. faecalis HTY0037 (a multidrug resistance isolate) and E. faecium HTY0256 (a strong biofilm-producing vancomycin-resistant enterococci isolate), after 2 h incubation it displayed significant rapid antibacterial activity. Moreover, an antibiofilm-producing activity of 39 against four MDR enterococci was shown.
Eighteen articles dealing with the antimicrobial activity of Eriosema species have been published using disk diffusion, broth dilution and thin layer chromatography (TLC) bioautography methods. The "traditional" inhibitory zone (IZ) determined by the disc diffusion method depends on the coefficient of diffusion of compounds, highly polar substances diffusing more easily in agar and displaying a high IZ and vice versa (Tan and Lim, 2015). Therefore, this assay is only useful for a simple qualitative screening as it does not allow the determination of the real amount of the antimicrobial agent that diffuses into the agar, impeding the determination of MICs and MBCs (Balouiri et al., 2016). Based on the MIC values, extracts (or compounds) display: i) a strong antimicrobial activity in vitro if the MIC ≤100 μg/ml (or 10 μg/ml), ii) moderate if 100 < MIC ≤625 μg/ml (or 10 < MIC ≤100 μg/ml), iii) and low if MIC > 625 μg/ml (or >100 μg/ ml) (Eloff, 2004;Ríos and Recio, 2005;Kuete, 2010). Based on this classification, several extracts and compounds from Eriosema species displayed promising antimicrobial activity. Unfortunately, in several studies positive controls were not included or their concentration was not stated. Although some studies are suggesting the potential of few compounds to act as an antimicrobial drug against several microorganisms, these deficiencies weaken the evidence.
Anti-Viral Activity Cos et al. (2002a) assessed the anti-human immunodeficiency virus type-1 (HIV-1) effects of a polar fraction of an ethanolic leaf extract of Eriosema montanum Baker f. using a tetrazolium-based colorimetric assay in infected MT-4 cells. The polar fraction was obtained suspending the extract in 60% methanol and defatting with petroleum ether. The polar fraction with an EC 50 value >166 μg/ml did not protect the HIV-infected cells.
At the maximal non-toxic concentrations of 375 μg/ml, this polar fraction exhibited a pronounced antiviral activity (reduction factor of the viral titer (RF) of 10 3 -10 4 ) against Herpes simplex virus type 1, Poliomyelitis virus type 1 strain 1A/S3 and Semliki forest virus A7, while at 187.5 μg/ml it displayed a RF of 10 3 against Coxsackie B2 virus. RF values of 10 2 were observed against Vesicular stomatitis virus T2 and measles Edmonston A at 187.5 and 750 μg/ml, respectively (Cos et al., 2002b).

Anti-Diarrheal Activity
Diarrheal diseases are a leading cause of mortality and morbidity worldwide, mainly among children under-five in low developing countries. Defined as the discharge of 4 or more semisolid or watery feces per day, diarrhea involves an increase in intestinal fluid volume, in the frequency of bowel movement, wet stool and abdominal cramps, leading to loss of electrolytes and water. Its treatment and management depend on the duration and specific etiology which can be infectious or not. Over the world, many people or communities still use traditional herbs to treat a variety of diseases including diarrhea. As depicted in Table 1, several Eriosema species are used traditionally for diarrhea.
Castor oil-induced diarrhea is known as an efficient model for the initial screening for antimotility, antisecretory and antiinflammatory compounds. In the gut, ricinoleic acid (castor oil metabolite) causes irritation and inflammation in bowels leading to diarrhea (stomach cramp, increased peristaltic activity and intestinal fluid volume) (Matias et al., 1978;Racusen and Binder, 1979). An ethanol root extract of E. chinense (EEC; at 400 mg/kg), its chloroform fraction (at 100 mg/kg; CEC), and compounds 39 and 81 (at 10 mg/kg) reduced the normal fecal excretion rate and water content 3, 5 and 7 h after the oral treatment of rats. In castor oil-induced diarrhea, these treatments delayed the onset of diarrhea and decreased the mean defecation in a dosedependent manner. At the same dosages, the extract, the fraction and 39 and 81 significantly reduced the peristaltic index, the intestinal fluid volume and PGE2-induced enteropooling, and demonstrated a significant recovery from intestinal fluid loss of Na + and K + (Prasad et al., 2013c;Prasad et al., 2017).
Enteropathogenic E. coli (EPEC) is a common cause of moderate to severe water diarrhea in children, accompanied with fever, vomiting and a high hazard of death. In an enteropathogenic E. coli-induced diarrhea rat model, EEC (100 and 200 mg/kg), CEC (50 and 100 mg/kg) and 81 (5 and 10 mg/kg) induced a significant recovery from diarrhea characterized by the reduction in total number of stools, total number of diarrheal stools, weight of stools, mean defecation rate and water content of stools 6 h after induction of diarrhea (Parmar et al., 2019a;Parmar et al., 2019b). At the higher tested doses, EEC, CEC and eriosematin E displayed diarrhea scores very close to that of 5.7 mg/kg norfloxacin. They also increased Na + /K + -ATPase activity to a higher level than that observed in the normal rats, resulting in reduced intestinal secretion.
Both infectious and non-infectious (chemically induced) reliable models were used to evaluate the anti-diarrheal potential of Eriosema species in vivo. However, from five species traditionally claimed to be anti-diarrheal (E. affine, E. chinense, E. griseum, E. psoraleoides and E. tuberosum), only the ethanolic root extract of E. chinense and compounds 39 and 81 were investigated, indicating that in the Eriosema genus this domain is underexplored. Given the promising results obtained with one extract, it would be interesting to extend the exploration to the other Eriosema species traditionally used against diarrhea.

Anti-Inflammatory Activity
Intestinal disorders often co-occur with inflammation and dysmotility. In enteropathogenic E. coli-induced diarrhea, 10 mg/kg of 81 from roots of E. chinense for 24 h significantly decreased the expression of pro-inflammatory cytokines IL-1β and TNF-α in colonic tissues (Parmar et al., 2019b).
Frontiers in Pharmacology | www.frontiersin.org May 2021 | Volume 12 | Article 641225 Using peripheral blood mononuclear cells, Santos et al. (2016) investigated the impact of a dichloromethane-ethanol extract of E. campestre (6.25, 12.5 and 25 μg/ml) on pathological processes of chronic inflammatory diseases. In a concentration-dependent manner, the extract inhibited the proliferation of T lymphocytes, including CD4 + and CD8 + cells, and decreased IL-2 levels in the supernatant of the cell cultures, a cytokine essential for the expansion of T lymphocytes.
Cyclooxygenase (COX) inhibitors are known to be a therapeutic target in inflammatory and neuroinflammatory diseases (Grosser et al., 2017;Dhir, 2019). The COX-1 and COX-2 inhibitory activities of extracts of the roots of E. cordatum were investigated by Ndhlala et al. (2011). At 250 μg/ml, petroleum ether, dichloromethane and ethanolic extracts weakly inhibited COX-1 activity by 13, 25 and 34%, respectively. A weak inhibition of COX-2 by 6, 35 and 10%, respectively, with 250 μg/ml of the petroleum ether, dichloromethane and ethanolic extracts was observed. The aqueous extract remained almost without effects on both enzymes at 2 mg/ml.

Anthelmintic Activity
Among human helminth infections, schistosomiasis is the most prevalent with regard to mortality and the third most harmful tropical disease in the world. An ethanol leaf extract of E. griseum was tested in vitro against trematodes (Echinostoma caproni and Schistosoma mansoni) and nematodes (Ancylostom aceylanicum, Heligmosomoides bakeri and Trichuris muris). The extract reduced the motility of third-stage larvae (L3) of H. bakeri by at least 80% at a minimal lethal concentration (MLC) of 20 μg/ml 48 h post-incubation, caused death of newly transformed S. mansoni schistosomula and adults with MLC values of 20 and 40 μg/ml, respectively, exhibited a moderate activity against L3 of A. ceylanicum 48 h post-incubation and no activity on adult E. caproni and T. muris (MLC: 2 mg/ml). In vivo, mice harboring adult S. mansoni, E. caproni and T. muris were used. An oral single dose of the extract (400 mg/kg) 49 days post-infection displayed a moderate activity in chronic S. mansoni infection (reduction of total worm burden 49.5% and of female worm burden 48.9%), whereas no activity was observed against E. caproni and T. muris at 400 and 800 mg/kg, respectively (Koné et al., 2012).

TOXICOLOGICAL EVALUATION
Although medicinal plants are widely used and assumed to be safe, however, they can potentially be toxic (Nasri and Shirzad, 2013;Awounfack et al., 2016). "If herbs have an effect, they are also likely to have a side effect" (Lanini et al., 2012). In line with this, the safety evaluation of medicinal plants-even used since centuries-needs to be performed. In vitro and in vivo studies have been carried out aiming at the evaluation of the safety properties of some Eriosema species.
In the Ames test on Salmonella typhimurium strain TA98 with and without S9 metabolic activation, a water extract of the roots of E. cordatum at concentrations up to 5,000 μg/ml was non-mutagenic as shown by the average His + revertant colonies (Ndhlala et al., 2011).
In vivo, the acute oral toxicity of an ethanol root extract (EEC) of E. chinense and its chloroform fraction (CEC) was evaluated in female rats following the OECD (Organization for Economic Cooperation and Development) guideline 425. Administration of FIGURE 4 | Annual publication rate of Eriosema genus since 1995 (phytochemical, pharmacological and toxicological investigation and reviews).
Frontiers in Pharmacology | www.frontiersin.org May 2021 | Volume 12 | Article 641225 EEC and its subfractions did not cause any signs of toxicity or mortality up to 2 g/kg during the observation period of 14 days (Prasad et al., 2013b). In a study by Ateba et al. (2014a), the toxicity of a methanol extract of the aerial parts of E. laurentii following guidelines for acute (OECD guideline 423) and subchronic (OECD guideline 407) oral administrations was investigated. A single dose of 2 g/kg of the extract as well as the repetition of the experiment, caused neither toxicological symptoms nor mortality and the LD 50 was estimated >5 g/kg. In 28-days repeated oral administration, no signs of toxicity were observed phenotypically and in the main organs of rats. The extract only induced a delayed decrease of relative spleen weight and reduced the white blood cell count in males at the highest dose of 400 mg/kg.
Using the Irwin test, Prasad et al. (2017) showed that the acute oral administration of 81 (from the roots of E. chinense) up to 300 mg/kg did not result in any sign of behavioral/neurological toxicity or mortality during the observation period. The weight of organs was not affected. Some signs of physical toxicity were observed at the dose of 500 mg/kg. Nduka et al. (2018) reported LD 50 values of 3807.9 mg/kg and >5,000 mg/kg for ethanolic and aqueous leaf extracts of E. psoraleoides, respectively, following an acute oral treatment.
Toxicological evaluations are of major importance for medicinal plants and herbal products. Without these studies the estimation of their therapeutic potential is limited when the doses to induce non-fatal as well as fatal adverse effects are unknown. Based on the in vivo acute toxicity studies, the tested extracts of E. chinense, E. laurentii and E. psoraleoides are placed at category 5 (or unclassified) in the Globally Harmonized Classification System for Chemical Substances and Mixtures (GHS) as adopted by OECD (OECD, 2001). Such products with no deaths up to 2000 mg/kg (estimated LD 50 > 5000 mg/kg) are considered practically non-toxic (Hodge and Sterner, 1949;Kennedy et al., 1986).

CONCLUSION
In this paper, we reviewed the available information concerning the traditional uses/ethnopharmacology, phytochemistry, pharmacology and toxicology of the genus Eriosema. Twenty-five species (∼16.6% of the genus) recorded in the review are known as traditional medicines and used for nearly 121 ailments. It is evident from anectodical notes that the investigated numbers of species and traditionally treated health problems are so far lower than the reality. Moreover, around 75% of the traditional indications of these plants have not been studied yet in respective pre-clinical studies, indicating that more scientific investigations are necessary. Apart from data on ethnopharmacology, only 49 papers dealing with the phytochemical, pharmacological and toxicological investigation and reviews on Eriosema species and compounds occurring in this genus have been published in 25 years (Figure 4). The mean rate of approximately 2 publications per year is very low. Despite the high reputation of several species for curing or alleviating ED/impotence, especially in Africa, the investigation is only limited to two papers on E. kraussianum which have been published more than 15 years ago indicating an underexplored aspect that requires more research attention. Concerning phytochemistry, the paper covers a total of 107 compounds mainly belonging to the classes of flavonoids, chromones and terpenoids. The pharmacological activities of extracts and pure compounds from this genus focused on the management of erectile dysfunction, pre-eclamptic complications and anti-diabetic, estrogenic, hypolipidemic, anti-oxidant, anti-microbial, antiosteoporosis, anthelmintic, anti-diarrheal and anti-cancer effects as well as cyclooxygenase and acetylcholinesterase inhibitory properties. However, there is lack of studies dealing with the in-depth mechanisms involved in the observed activities in vitro and in animals. Moreover, no clinical study has been carried out till now. Beyond the pharmacological activities, the toxicity evaluation of medicinal plants is of high importance for their valorization. In vivo, acute toxicity carried out with E. chinense, E. laurentii and E. psoraleoides indicated a low toxicity of investigated extracts.

AUTHOR CONTRIBUTIONS
SA obtained literatures, wrote the first draft, and edited the manuscript; DN gave ideas and critically reviewed the manuscript; LK obtained the literatures, gave ideas, critically reviewed and edited the manuscript. All authors read and approved the manuscript.