Romain Haudecoeur

Marine Peuchmaur

Basile Pérès

Maxime Rome

Germain Sotoing Taïwe

Ahcène Boumendjel

Benjamin Boucherle
email: benjamin.boucherle@univ-grenoble-alpes.fr

Traditional uses, phytochemistry and pharmacological properties of African Nauclea species: A review

Keywords: Genus Nauclea, N. latifolia, N. diderrichii, N. pobeguinii, traditional medicine, malaria, pain, digestive ailments, infection, phytochemistry, indoloquinolizidines

Ethnopharmacological relevance: The genus Nauclea in Africa comprises seven species.

Among them, N. latifolia, N. diderrichii and N. pobeguinii are widely used by local population as traditional remedies. Preparation of various parts of plants (e.g. roots, bark, leaves) are indicated by traditional healers for a wide range of diseases including malaria, pain, digestive ailments or metabolic diseases.

Materials and methods:

A literature search was conducted on African species of the genus Nauclea using scientific databases such as Google Scholar, Pubmed or SciFinder. Every document of ethnopharmacological, phytochemical or pharmacological relevance and written in English or French were analyzed.

Results and discussion:

The Nauclea genus is used as ethnomedicine all along sub-Saharan Africa. Several local populations consider Nauclea species as a major source of remedies for malaria. In this regard, two improved traditional medicines are currently under development using extracts from N. latifolia and N. pobeguinii. Regarding the chemical composition of the Nauclea genus, indoloquinolizidines could be considered as the major class of compounds as they are reported in every analysed Nauclea species, with numerous structures identified. Based on traditional indications a considerable amount of pharmacological studies were conducted to ensure activity and attempt to link them to the presence of particular compounds in plant extracts.

Conclusion:

Many experimental studies using plant extracts of the African species of the genus Nauclea validate traditional indications (e.g. malaria and pain). However, bioactive compounds are rarely identified and therefore, there is a clear need for further evaluations as well as for toxicity experiments. The sustainability of these plants, especially of N. diderrichii, a threatened species, should be kept in mind to adapt local uses and preparation mode of traditional remedies.

Introduction

For centuries, medicinal plants of tropical sub-Saharan Africa have been extensively used by local communities for preparing traditional remedies, and still provide an important therapeutic option for a large part of the population (Moyo et al., 2015a). This fact is in line with the presence of higher number of traditional healers -1 for 500 patients (WHO, 2013)as compared with that of physicians -1 for 6,700 patients (WHO, 2010) in this region.

Additionally, these practices are linked to one of the richest and most diverse ecosystems across the world (Moyo et al., 2015b), with rain forests offering very specific environments that comprise 40% of plant species worldwide, whereas representing only 7-8% of the emerged land surface [START_REF] Vlietinck | The value of central-African traditional medicine for lead finding: Some case studies[END_REF]. In aerial part arena, Rubiaceae is the largest family of woody plants with about 13,100 species spread in 611 genera in the wet tropics [START_REF] Govaerts | World Checklist of Rubiaceae. The Board of Trustees of the Royal Botanic Gardens[END_REF], where their known high alkaloid content correlates with an impressive body of reported past and present ethnopharmacological uses. The sub-Saharan traditional medicine indeed includes more than 60 Rubiaceae species for a wide portfolio of therapeutic indications, and these long-standing practices is still practiced to date [START_REF] Karou | Sub-Saharan Rubiaceae: a review of their traditional uses, phytochemistry and biological activities[END_REF].

From a botanical point of view, the Rubiaceae family is divided into three subfamilies [START_REF] Rydin | Deep divergences in the coffee family and the systematic position of Acranthera[END_REF] including the Cinchonoideae with 220 species in 28 genera. It contains the tribe Naucleeae with 17 genera [START_REF] Löfstrand | Phylogeny and generic delimitations in the sister tribes Hymenodictyeae and Naucleeae (Rubiaceae)[END_REF]. This group can be easily distinguished from those of other tribe by its spherical inflorescences and its epigynous floral nectaries deeply embedded in the hypanthia [START_REF] Verellen | Pollen morphology of the tribes Naucleeae and Hymenodictyeae (Rubiaceae -Cinchonoideae) and its phylogenetic significance[END_REF]. It includes the genus Nauclea whose range is limited to the tropical areas of Africa and Asia. These trees have flattened terminal buds, and adpressed stipules deciduous or subpersistent, ovate to elliptic. Their leaves are lustrous, green, opposite and pinnately nerved. Hypanthia and fruitlets can be free or connate into a syncarp.

Flowers include corolla with imbricate lobes and fusiform stigma. Inflorescences contain 2locular ovary with Y-shaped placentas (when they are attached to the upper third of the septum) or discoidal (when they are attached to the middle of the septum). Ovules are generally pendulous or spreading in all directions. Seeds are ovoidal to ellipsoidal and pitted [START_REF] Löfstrand | Phylogeny and generic delimitations in the sister tribes Hymenodictyeae and Naucleeae (Rubiaceae)[END_REF][START_REF] Ridsdale | A revision of the tribe Naucleeae s.s. (Rubiaceae)[END_REF]. In Africa, the genus Nauclea contains seven species which can be distinguished by a combination of criteria (Figure 2), like their placentas, stipules shapes, and fruit type [START_REF] Ridsdale | A synopsis of the African and Madagascan Rubiaceae -Naucleeae[END_REF], leaves shape, seeds margin and petiole length [START_REF] Pellegrin | Les bois d'or » d'Afrique occidentale[END_REF], calyx and corolla pubescence, diameter of flowering heads, leaves pubescence [START_REF] Ridsdale | A revision of the tribe Naucleeae s.s. (Rubiaceae)[END_REF]. Nauclea latifolia Smith, Nauclea pobeguinii (Hua ex Pobég.) Merr. and Nauclea diderrichii (De Wild.) Merr. seem to be most widely distributed in an area that extends from the center to the west of tropical Africa whereas Nauclea vanderguchtii (De wild.) Petit., Nauclea gilleti (De Wild.) Merr. and Nauclea xanthoxylon (Chev.) Aubr. [START_REF] Löfstrand | Phylogeny and generic delimitations in the sister tribes Hymenodictyeae and Naucleeae (Rubiaceae)[END_REF], appear to be far less common taxa. The exception is N. nyasica which occurs in Tanzania, Mozambique and Malawi (Figure 3). This genus is well represented in several pharmacopoeias from West Africa (e.g. Benin, Central African Republic, Senegal, Ivory Coast), especially through the emblematic species Nauclea latifolia, whose alkaloid content and biological activities have been reviewed recently [START_REF] Boucherle | Nauclea latifolia: biological activity and alkaloid phytochemistry of a West African tree[END_REF]. Ethnopharmacological uses of Nauclea pobeguinii and Nauclea diderrichii are also heavily documented whereas others species were largely left behind.

Medicinal indications of these species often match the specific needs of the regional health context in their occurring area. Indeed, as viral diseases, respiratory infections, diarrheas and malaria are the leading causes of death in sub-Saharan Africa [START_REF] Who | Mortality and global health estimates. Causes of death. Estimates for 2000-2012[END_REF], Nauclea-based corresponding remedies have been developed by local population and numerous antiplasmodial, antimicrobial or antidiarrheal uses have been reported. Besides, these ethnopharmacological data are widely supported by validated biological activities from both extracts and phytochemicals. The very recent clinical development of two antimalarial phytomedicinal preparations from N. latifolia (NIPRD-AM1; [START_REF] Gamaniel | A comparative randomized clinical trial of NIPRD AM1 against a chloroquine and sulphadoxine/pyrimethamine combination in symptomatic but uncomplicated malaria[END_REF] and N. pobeguinii (PR 259 CT1; [START_REF] Mesia | Assessment of the short-term safety and tolerability of a quantified 80% ethanol extract from the stem bark of Nauclea pobeguinii (PR 259 CT1) in healthy volunteers: a clinical phase I study[END_REF]Mesia et al., , 2012aMesia et al., , 2012b) ) in Nigeria and Democratic Republic of Congo respectively, is a perfect illustration of the potential of confronting traditional uses with objective biological assays and phytochemical analyses. Additionally, the extraction of the synthetic analgesic tramadol from N. latifolia roots by [START_REF] Boumendjel | Occurrence of the synthetic analgesic tramadol in an African medicinal plant[END_REF], albeit still controversial, contributed to put the genus under the spotlights during the past few years [START_REF] Kusari | Tramadol-A True Natural Product?[END_REF][START_REF] Kusari | Synthetic Origin of Tramadol in the Environment[END_REF][START_REF] Lecerf-Schmidt | Biomimetic synthesis of Tramadol[END_REF][START_REF] Nature | Natural products: African tree gets to the root of pain[END_REF][START_REF] Romek | A retro-biosynthetic approach to the prediction of biosynthetic pathways from position-specific isotope analysis as shown for tramadol[END_REF].

Therefore, the aim of this review is to document the present knowledge about the traditional medicinal uses, the phytochemical composition, and the validated pharmacological activities of the Nauclea members from sub-Saharan Africa, and to highlight potential high-value connections between all these research fields.

Figure 2.

Identification key of Nauclea species in Africa adapted from [START_REF] Ridsdale | A synopsis of the African and Madagascan Rubiaceae -Naucleeae[END_REF][START_REF] Ridsdale | A revision of the tribe Naucleeae s.s. (Rubiaceae)[END_REF] and [START_REF] Pellegrin | Les bois d'or » d'Afrique occidentale[END_REF] with their distribution [START_REF] Govaerts | World Checklist of Rubiaceae. The Board of Trustees of the Royal Botanic Gardens[END_REF].

Non-medical ethnobotanical uses

Apart from therapeutic and healthcare considerations, some other ethnobotanical applications of African Nauclea species are described and reported in Table 1. Nauclea diderrichii wood is used as high-value primary material in building industries of West Africa, due to the high quality of timber (strength and durability) and its resistance to termites (Towns, 2014a). A survey conducted with 200 aboriginals showed the wide applications of N.

diderrichii trunk for crafts, mortar for building housing, energy wood and canoe construction (Siribina et al., 2014). The bark is also used as an aphrodisiac (Towns, 2014a), and as a substitute for hops as bittering substance in the brewing of local beers [START_REF] Desobgo | Caractérisation des moûts et bières du sorgho Safrari houblonnés avec Vernonia amygdalina et Nauclea diderrichii[END_REF].

As a result, due to heavy exploitation and uncontrolled harvest [START_REF] Jusu | Medicinal plant trade in Sierra Leone: threats and opportunities for conservation[END_REF], N.

diderrichii has been placed in 1998 on the IUCN Red List of Threatened Species, with a "vulnerable" status (IUCN, 2016). The plant also displays detoxifying property. Indeed, a recent research publication has described the ability of seeds to absorb the chromium (III) in aqueous solution [START_REF] Omorogie | Efficient chromium abstraction from aqueous solution using a low-cost biosorbent: Nauclea diderrichii seed biomass waste[END_REF]. This property is of particular interest, as N. diderrichi seeds are abundant and considered as waste in the plantations where the tree is produced as timber.

Moreover, a study realized in the Apra Hills Forest Reserve in Ghana described the use of N. latifolia as primary materials for roofing and as heating source [START_REF] Adeniyi | Diversity and ethnobotanical uses of plants in proposed Apra Hills Forest Reserve in Southern Ghana[END_REF]. Similarly, N.

xanthoxylon has been reported as energy wood and lumber for framework constructions in the swamp forest of Agonvè in Benin [START_REF] Dossou | Etude ethnobotanique des ressources forestières ligneuses de la forêt marécageuse d'Agonvè et terroirs connexes au Bénin[END_REF]. N. vanderguchtii was also described in Nigeria with applications for timber and furniture [START_REF] Obute | Ethnobotanical applications of some floral species in Bayelsa state, Nigeria[END_REF]. Finally, the nutritional use of fruits of Nauclea species is reported. N. latifolia fruits, an excellent source of ascorbic acid, are for example used in Guinea by the Malinké ethnic group [START_REF] Adeniyi | Diversity and ethnobotanical uses of plants in proposed Apra Hills Forest Reserve in Southern Ghana[END_REF]. In addition, a study on mammals conducted in Congo revealed that N. pobeguinii fruits are a feeding source for Gorillas [START_REF] Breuer | Mbeli Bai Study -report Annuel[END_REF].

Ethnopharmacological uses

3.1.Anti-infective

Anti-malarial

As mentioned above, the recent clinical assays undertaken for two Nauclea-based antimalarial preparations in two different countries endorse a widespread traditional use of the genus in African communities against malaria. Indeed, the indication of N. latifolia, N. diderrichii and N. pobeguinii extracts have been often mentioned, sometimes with high citation frequency among the traditional healers (Table 2). The Nauclea genus especially appears among the most cited plants traditionally used for treating malaria in the Sélingué subdistrict of Mali (N.

latifolia, 66% and N. pobeguinii, 55%; [START_REF] Diarra | Ethnobotanical study of plants used against malaria in Selingue subdistrict, Mali[END_REF], in the Sierra Leone city Bo (N. latifolia, 50%; [START_REF] Ranasinghe | Herbs and herbal combinations used to treat suspected malaria in Bo, Sierra Leone[END_REF], in the plateau of Allada in Benin (N. latifolia, 86% and N. diderrichii, 52%; [START_REF] Yetein | Ethnobotanical study of medicinal plants used for the treatment of malaria in plateau of Allada, Benin (West Africa)[END_REF], and in Southern Nigeria (N. latifolia, 46%; [START_REF] Iyamah | Ethnomedicinal survey of plants used in the treatment of malaria in Southern Nigeria[END_REF]. If the use of N. latifolia and N. diderrichii is heavily documented in the Southern Nigeria [START_REF] Gbile | Nigerian flora and its pharmaceutical potential[END_REF][START_REF] Odugbemi | Medicinal plants useful for malaria therapy in Okeigbo, Ondo State, Southwest Nigeria[END_REF][START_REF] Ajibesin | Ethnobotanical survey of Akwa Ibom State of Nigeria[END_REF][START_REF] Adebayo | Potential antimalarials from Nigerian plants: A review[END_REF][START_REF] Dike | Ethnobotanical survey for potential antimalarial plants in south-western Nigeria[END_REF][START_REF] Olorunnisola | Ethnobotanical survey of medicinal plants used in the treatment of malarial in Ogbomoso, Southwest Nigeria[END_REF][START_REF] Iyamah | Ethnomedicinal survey of plants used in the treatment of malaria in Southern Nigeria[END_REF][START_REF] Chukwuma | Traditional medicine and the future of medicinal Plants in Nigeria[END_REF], antimalarial ethnopharmacological data about the genus have been recorded in neighboring countries such as Cameroon [START_REF] Betti | Impact of forest logging in the dja biosphere reserve, Cameroon[END_REF][START_REF] Ndenecho | Herbalism and resources for the development of ethnopharmacology in Mount Cameroon region[END_REF][START_REF] Tsabang | Ethnopharmacological survey of Annonaceae medicinal plants used to treat malaria in four areas of Cameroon[END_REF],

Benin [START_REF] Yetein | Ethnobotanical study of medicinal plants used for the treatment of malaria in plateau of Allada, Benin (West Africa)[END_REF], Togo [START_REF] Koudouvo | An ethnobotanical study of antimalarial plants in Togo Maritime Region[END_REF] or Ghana [START_REF] Asase | Ethnobotanical study of some Ghanaian anti-malarial plants[END_REF][START_REF] Asase | Traditional antimalarial phytotherapy remedies in herbal markets in southern Ghana[END_REF][START_REF] Asase | Ethnopharmacological use of herbal remedies for the treatment of malaria in the Dangme West District of Ghana[END_REF], and more generally over a wide geographical area from Senegal to the Democratic Republic of Congo (Table 2). Interestingly, if the active extracts are most often prepared as decoctions, various plant parts (leaves, roots, bark) are used, even within the same region.

Anti-helminthic

From Sierra Leone to Angola, extracts of N. latifolia are used as anti-helminthic agents [START_REF] Göhre | Plants from disturbed savannah vegetation and their usage by Bakongo tribes in Uíge, Northern Angola[END_REF] (Table 5). The roots, bark, stem or leaves are prepared, often through decoction, and consumed as vermifuge [START_REF] Lebbie | Ethnobotanical value and conservation of sacred groves of the Kpaa Mende in Sierra Leone[END_REF][START_REF] El-Ghani | Traditional medicinal plants of Nigeria: an overview[END_REF][START_REF] Ahombo | Investigating on related diabetes therapeutic plants used in traditional medicine at Brazzaville[END_REF][START_REF] Kanteh | Diversity of plants with pesticidal and medicinal properties in southern Sierra Leone[END_REF][START_REF] Tittikpina | Togo to go: products and compounds derived from local plants for the treatment of diseases endemic in Sub-Saharan Africa[END_REF] and for the management of helminthiasis of humans and animals [START_REF] Agyare | An ethnopharmacological survey and in vitro confirmation of the ethnopharmacological use of medicinal plants as anthelmintic remedies in the Ashanti region, in the central part of Ghana[END_REF]. The stem bark decoctions of N. diderrichii and N. pobeguinii have also been described as traditional anti-helminthic remedies in D.R. Congo [START_REF] Mesia | Antimalarial activities and toxicities of three plants used as traditional remedies for malaria in the Democratic Republic of Congo: Croton mubango, Nauclea pobeguinii and Pyrenacantha staudtii[END_REF][START_REF] Mbuta | Plantes médicinales de traditions Province de l'Equateur -R.D.C[END_REF]Lusakibanza Manzo, 2012). [START_REF] Gbile | Nigerian flora and its pharmaceutical potential[END_REF]) (Table 3). N. latifolia is also consumed in Sierra Leone for its effect against yellow fever, flu and measles [START_REF] Lebbie | Ethnobotanical value and conservation of sacred groves of the Kpaa Mende in Sierra Leone[END_REF]. Interestingly, it was also cited among the most frequently used herbal medicine for the management of HIV/AIDS in Uganda [START_REF] Lamorde | Medicinal plants used by traditional medicine practitioners for the treatment of HIV/AIDS and related conditions in Uganda[END_REF]. The use of N. diderrichii, although far less mentioned, has been reported in Gabon [START_REF] Betti | An ethnobotanical and floristical study of medicinal plants among the Baka Pygmies in the periphery of the Ipassa-Biosphere reserve, Gabon[END_REF] and Democratic Republic of Congo [START_REF] Mbuta | Plantes médicinales de traditions Province de l'Equateur -R.D.C[END_REF] for treating jaundice and hepatitis respectively.

Antimicrobial

As a treatment for dysentery and diarrhea, N. latifolia, N. diderrichii and N. pobeguinii have been reported in Ivory Coast [START_REF] Zadou | Valeur de la Forêt des Marais Tanoé-Ehy (Sud-Est de la Côte d'Ivoire) pour la conservation: dimension socio-anthropologique[END_REF][START_REF] Ambe | Diversité des plantes médicinales utilisées dans le traitement traditionnel de la diarrhée sur les marchés d'Abidjan (Côte d'Ivoire)[END_REF], Nigeria [START_REF] Chukwuma | Traditional medicine and the future of medicinal Plants in Nigeria[END_REF], Gabon [START_REF] Betti | An ethnobotanical and floristical study of medicinal plants among the Baka Pygmies in the periphery of the Ipassa-Biosphere reserve, Gabon[END_REF], Uganda [START_REF] Lamorde | Medicinal plants used by traditional medicine practitioners for the treatment of HIV/AIDS and related conditions in Uganda[END_REF]), Sierra Leone (Oliver-Bever, 1983;[START_REF] Kanteh | Diversity of plants with pesticidal and medicinal properties in southern Sierra Leone[END_REF], Congo [START_REF] Ahombo | Investigating on related diabetes therapeutic plants used in traditional medicine at Brazzaville[END_REF], Gambia [START_REF] Madge | Therapeutic landscapes of the Jola, The Gambia, West Africa[END_REF] and

Ghana (Sam et al., 2013) (Table 4). The bark of N. latifolia is also used to cure or prevent sexually transmitted infections, especially in Nigeria [START_REF] Uzodimma | Medico-Ethnobotanical inventory of Ogii, Okigwe Imo State, South Eastern Nigeria-I[END_REF][START_REF] Gbadamosi | Ethnobotanical Survey of Plants Used for the Treatment and Management of Sexually Transmitted Infections in Ibadan, Nigeria[END_REF]. Among the reported venereal diseases, gonorrhea was more specifically targeted by Nauclea-based traditional remedies: the use of the roots and stem barks of N. latifolia, N. diderrichii and N. pobeguinii has been described in Nigeria (MacDonald and Olorunfemi, 2000;Ajibesin et al., 2012a;[START_REF] Chukwuma | Traditional medicine and the future of medicinal Plants in Nigeria[END_REF], but also in Congo [START_REF] Ahombo | Investigating on related diabetes therapeutic plants used in traditional medicine at Brazzaville[END_REF] and D.R. Congo [START_REF] Mesia | Antimalarial activities and toxicities of three plants used as traditional remedies for malaria in the Democratic Republic of Congo: Croton mubango, Nauclea pobeguinii and Pyrenacantha staudtii[END_REF]Lusakibanza Manzo, 2012). Besides these indications, extracts of Nauclea species are used by local populations for a variety of infectious diseases [START_REF] Magassouba | Ethnobotanical survey and antibacterial activity of some plants used in Guinean traditional medicine[END_REF][START_REF] Lawal | Ethno medicinal information on collation and identification of some medicinal plants in research institutes of South-West Nigeria[END_REF][START_REF] Badiaga | Etude ethnobotanique, phytochimique et activités biologiques de Nauclea latifolia Smith, une plante médicinale africaine récoltée au Mali[END_REF][START_REF] Sourabié | Ethnobotanical and ethnopharmacognostical survey on medicinal plants of Malon village and surrounding in the Cascades Region (Burkina Faso)[END_REF], including scalp infections and abscess of children [START_REF] Aworinde | Ethnobotanical investigation of indigenous plants used in the management of some infant illnesses in Ibadan, South-Western Nigeria[END_REF], gale [START_REF] Lebbie | Ethnobotanical value and conservation of sacred groves of the Kpaa Mende in Sierra Leone[END_REF][START_REF] Zadou | Valeur de la Forêt des Marais Tanoé-Ehy (Sud-Est de la Côte d'Ivoire) pour la conservation: dimension socio-anthropologique[END_REF], thrush [START_REF] Olowokudejo | An ethnobotanical survey of herbal markets and medicinal plants in Lagos State of Nigeria[END_REF], lepra [START_REF] Nadembega | Medicinal plants in Baskoure, Kourittenga Province, Burkina Faso: An ethnobotanical study[END_REF], typhoid [START_REF] Ndenecho | Herbalism and resources for the development of ethnopharmacology in Mount Cameroon region[END_REF][START_REF] Adeyemi | Traditional anti-fever phytotherapies in Sagamu and Remo north districts in Ogun State, Nigeria[END_REF][START_REF] Göhre | Plants from disturbed savannah vegetation and their usage by Bakongo tribes in Uíge, Northern Angola[END_REF], tuberculosis [START_REF] Mann | An Ethnobotanical survey of indigenous flora for treating tuberculosis and other respiratory diseases in Niger State, Nigeria[END_REF] or ringworm [START_REF] Ibrahim | Medicinal plants used and the perception of plant endangerment by the traditional medicine practitioners of Nasarawa State, Nigeria: A pilot study[END_REF]. However, to date no studies revealed a particularly high frequency of citation of the Nauclea genus for these ailments. Np/N x 100 (Np is the number of informants that claim a use of a plant species to treat a particular disease and, N is the number of informants that use the plant as a medicine to treat any given disease).

Digestive disorders

Among Nauclea species, only N. latifolia and N. diderrichii are used by African population to cure digestive ailments [START_REF] Mathias | Ethnomedical study of plants used as therapy against some digestive system ailments among Takkad people of Kaduna state, Nigeria. Niger[END_REF][START_REF] Jiofack | Ethnobotanical uses of medicinal plants of two ethnoecological regions of Cameroon[END_REF][START_REF] Ubom | Ethnobotany and biodiversity conservation in the Niger Delta, Nigeria[END_REF][START_REF] Eto | Research in clinical phytopharmacology to develop health care in developing countries: State of the art and perspectives[END_REF] (Table 6). Several therapeutic indications are described all along central Africa from Sierra Leone to Uganda. N. diderrichii and N. latifolia are both reported as agents for dental and oral care, the later being used as chewing stick [START_REF] Ndenecho | Herbalism and resources for the development of ethnopharmacology in Mount Cameroon region[END_REF][START_REF] Kayode | Conservation of botanicals used for dental and oral healthcare in Ekiti State, Nigeria[END_REF].

Various parts of the plant (i.e. stem, bark, root and fruit for N. diderrichii and stem, bark, root, leaf, sap and fruit for N. latifolia) are prescribed by traditional healers for stomach problem management [START_REF] Eyong | Indigenous knowledge systems and sustainable development: relevance for Africa[END_REF][START_REF] Ndenecho | Herbalism and resources for the development of ethnopharmacology in Mount Cameroon region[END_REF][START_REF] Sainge | Biodiversity assessment and conservation status of plants in the Mbembe Forest Reserve, Donga-Mantung Division[END_REF][START_REF] Olowokudejo | An ethnobotanical survey of herbal markets and medicinal plants in Lagos State of Nigeria[END_REF][START_REF] Insoll | Substance and materiality? The archaeology of Talensi medicine shrines and medicinal practices[END_REF][START_REF] Taïta | Use of woody plants by locals in Mare aux Hippopotames Biosphere Reserve in western Burkina Faso[END_REF][START_REF] Tchacondo | Herbal remedies and their adverse effects in Tem tribe traditional medicine in Togo[END_REF]. Constipation could also be treated by both species [START_REF] Lebbie | Ethnobotanical value and conservation of sacred groves of the Kpaa Mende in Sierra Leone[END_REF][START_REF] Betti | Medicinal plants sold in Yaoundé markets, Cameroon[END_REF]. Additionally, N. latifolia is reported as emetic [START_REF] Olowokudejo | An ethnobotanical survey of herbal markets and medicinal plants in Lagos State of Nigeria[END_REF] while N. diderrichii is mentioned as purgative [START_REF] Nadembega | Medicinal plants in Baskoure, Kourittenga Province, Burkina Faso: An ethnobotanical study[END_REF]. N. latifolia is finally used for two other digestive system indications, i.e. hernia [START_REF] Nadembega | Medicinal plants in Baskoure, Kourittenga Province, Burkina Faso: An ethnobotanical study[END_REF][START_REF] Tabuti | Traditional herbal drugs of Bulamogi, Uganda: plants, use and administration[END_REF] and haemorrhoids [START_REF] Tchacondo | Herbal remedies and their adverse effects in Tem tribe traditional medicine in Togo[END_REF][START_REF] Taïta | Use of woody plants by locals in Mare aux Hippopotames Biosphere Reserve in western Burkina Faso[END_REF][START_REF] Ngbolua | Ethno-botanical survey of plant species used in traditional medicine in Kinshasa city (Democratic Republic of the Congo)[END_REF].

3.3.Pain management

Pain management by Nauclea genus extract has been widely described. The most frequent indication is abdominal-or stomach-ache for which root, leaf, bark and fruit of N. latifolia are used in several countries along an arc from Senegal to Angola [START_REF] Adamu | An ethnobotanical survey of Bauchi State herbal plants and their antimicrobial activity[END_REF][START_REF] Lekana-Douki | In vitro antiplasmodial activity and cytotoxicity of nine plants traditionally used in Gabon[END_REF][START_REF] Nadembega | Medicinal plants in Baskoure, Kourittenga Province, Burkina Faso: An ethnobotanical study[END_REF][START_REF] Badiaga | Etude ethnobotanique, phytochimique et activités biologiques de Nauclea latifolia Smith, une plante médicinale africaine récoltée au Mali[END_REF]Lusakibanza Manzo, 2012;[START_REF] Gning | Richesse de la pharmacopée malinké: rôle médicinal de l'arbre a Khossanto:(Kédougou, Sénégal oriental)[END_REF][START_REF] Göhre | Plants from disturbed savannah vegetation and their usage by Bakongo tribes in Uíge, Northern Angola[END_REF][START_REF] Madge | Therapeutic landscapes of the Jola, The Gambia, West Africa[END_REF][START_REF] Kristensen | Perceptions, use and availability of woody plants among the Gourounsi in Burkina Faso[END_REF]) (Table 7). N.

pobeguinii stem bark decoction is mentioned for the same symptoms in D.R. Congo [START_REF] Mesia | Antimalarial activities and toxicities of three plants used as traditional remedies for malaria in the Democratic Republic of Congo: Croton mubango, Nauclea pobeguinii and Pyrenacantha staudtii[END_REF]. Root, leaf, and fruit of N. latifolia are consumed to treat backache in Nigeria, D.R.

Congo and Uganda [START_REF] Tabuti | Traditional herbal drugs of Bulamogi, Uganda: plants, use and administration[END_REF][START_REF] Ngbolua | Ethno-botanical survey of plant species used in traditional medicine in Kinshasa city (Democratic Republic of the Congo)[END_REF][START_REF] Amusa | Ethnobotany and conservation of plant resources of Kainji Lake National Park, Nigeria[END_REF] while N.

diderrichii stem bark is indicated for lumbago in Cameroon [START_REF] Betti | Medicinal plants sold in Yaoundé markets, Cameroon[END_REF]. Two additional traditional uses of bark, root or fruit of this plant are described, i.e. toothache and headache (Ndenencho, 2009). N. latifolia leaves are also used for the later indication [START_REF] Badiaga | Etude ethnobotanique, phytochimique et activités biologiques de Nauclea latifolia Smith, une plante médicinale africaine récoltée au Mali[END_REF][START_REF] Lekana-Douki | In vitro antiplasmodial activity and cytotoxicity of nine plants traditionally used in Gabon[END_REF].

3.4.Fever

Many authors reported the use of N. diderrichii or N. latifolia to manage fever (Table 8).

Sometimes this indication is overlapped with antimalarial without any mention of whether these plants act as an etiologic treatment or as antipyretic. For example, in central Africa N.

diderrichii is indicated to treat fever [START_REF] Eyong | Indigenous knowledge systems and sustainable development: relevance for Africa[END_REF][START_REF] Eto | Research in clinical phytopharmacology to develop health care in developing countries: State of the art and perspectives[END_REF] and especially during malaria [START_REF] Betti | Impact of forest logging in the dja biosphere reserve, Cameroon[END_REF]. Same uses of all parts of N. latifolia are described in different states of Nigeria [START_REF] Olowokudejo | An ethnobotanical survey of herbal markets and medicinal plants in Lagos State of Nigeria[END_REF][START_REF] Igoli | Traditional medicine practice amongst the Igede people of Nigeria. Part II[END_REF] especially among Tiv people who placed it as leader plant against fever in their traditional medical system [START_REF] Igoli | A Survey of anti-venomous, toxic and other plants used in some parts of Tivland, Nigeria[END_REF]. The roots and bark of the same species are also exploited in Gambia [START_REF] Madge | Therapeutic landscapes of the Jola, The Gambia, West Africa[END_REF]. Bark (B), Root (R), Root Bark (RB), Stem (S), Leaves (L), Fruit (F), decoction (d).

Respiratory diseases

Fumigations of N. latifolia seeds are prescribed in D.R. Congo against respiratory diseases [START_REF] Disengomoka | Medicinal plants used for child's respiratory diseases in Zaire. Part II[END_REF]) (Table 9), and the bark of this plant is directly consumed for the same indication in Angola [START_REF] Göhre | Plants from disturbed savannah vegetation and their usage by Bakongo tribes in Uíge, Northern Angola[END_REF]. A recipe using N. latifolia in combination with several other plants is used against asthma in Nigeria [START_REF] Fatokun | Medicinal plants used in the management of asthma: a review[END_REF]. Cough management using bark, root or fruit of N. diderrichii [START_REF] Ndenecho | Herbalism and resources for the development of ethnopharmacology in Mount Cameroon region[END_REF] or various part of N. latifolia [START_REF] Olowokudejo | An ethnobotanical survey of herbal markets and medicinal plants in Lagos State of Nigeria[END_REF][START_REF] Lebbie | Ethnobotanical value and conservation of sacred groves of the Kpaa Mende in Sierra Leone[END_REF], is also reported.

Metabolic and cardio-vascular disorders

Many mentions of treatments against metabolic diseases using Nauclea are reported in West African countries (Table 10). Diabetes management is mentioned for three species: N. pobeguinii (leaf and bark) [START_REF] Baldé | Herbal medicine and treatment of diabetes in Africa: an example from Guinea[END_REF], N. latifolia (root, stem bark, leaf and fruit) [START_REF] Fah | Étude ethnobotanique des plantes utilisées dans le traitement du diabète chez les femmes enceintes à Cotonou et Abomey-Calavi (Bénin)[END_REF][START_REF] Muziazia | Plants used for the treatment of diabetes mellitus in the Democratic Republic of Congo: traditional uses in vitro and in vivo[END_REF][START_REF] Ngbolua | Ethno-botanical survey of plant species used in traditional medicine in Kinshasa city (Democratic Republic of the Congo)[END_REF][START_REF] N'guessan | Ethnobotanical Study of Plants Used to Treat Diabetes, in Traditional Medicine, by Abbey and Krobou People of Agboville (Côted'Ivoire)[END_REF]Gigado et al., 2005;[START_REF] Baldé | Herbal medicine and treatment of diabetes in Africa: an example from Guinea[END_REF] and N. diderrichii (bark) [START_REF] Laleye | Diversity, Knowledge, and Use of Plants in Traditional Treatment of Diabetes in the Republic of Benin[END_REF][START_REF] Nole | Ethnomedical and ethnopharmacological study of plants used for potential treatments of diabetes and arterial hypertension by indigenous people in three phytogeographic regions of Cameroon[END_REF]. The two later species are also indicated as diuretics using root, bark or fruit [START_REF] Ahombo | Investigating on related diabetes therapeutic plants used in traditional medicine at Brazzaville[END_REF][START_REF] Nadembega | Medicinal plants in Baskoure, Kourittenga Province, Burkina Faso: An ethnobotanical study[END_REF][START_REF] Nole | Ethnomedical and ethnopharmacological study of plants used for potential treatments of diabetes and arterial hypertension by indigenous people in three phytogeographic regions of Cameroon[END_REF][START_REF] Ndenecho | Herbalism and resources for the development of ethnopharmacology in Mount Cameroon region[END_REF]. Various parts (i.e. leaf, root and stem) of N. latifolia are used as antihypertensive agents [START_REF] Gbolade | Ethnobotanical study of plants used in treating hypertension in Edo State of Nigeria[END_REF][START_REF] Lagnika | Ethnobotanical survey on antihypertensive medicinal plants in municipality of Ouémé, Southern Benin[END_REF] especially roots that have been highly cited for this indication in the Southwestern Nigeria [START_REF] Olorunnisola | An inventory of plants commonly used in the treatment of some disease conditions in Ogbomoso, South West, Nigeria[END_REF]. Fruits are also mentioned as appetite suppressant [START_REF] Pare | Ethnobotanical Study of Medicinal Plants Used as Anti-Obesity Remedies in the Nomad and Hunter Communities of Burkina Faso[END_REF].

N. diderrichii bark, root and fruit are reported as blood thinner [START_REF] Ndenecho | Herbalism and resources for the development of ethnopharmacology in Mount Cameroon region[END_REF] and bark decoction is depicted as anti-anaemia [START_REF] Yetein | Ethnobotanical study of medicinal plants used for the treatment of malaria in plateau of Allada, Benin (West Africa)[END_REF].

Reproduction and sexual dysfunctions

The three most ethnopharmacologically relevant species N. latifolia, N. diderrichii and N.

pobeguinii are indicated for treating sexual and reproductive dysfunctions (Table 11). Stem bark of N. pobeguinii in D.R. Congo [START_REF] Mesia | Antimalarial activities and toxicities of three plants used as traditional remedies for malaria in the Democratic Republic of Congo: Croton mubango, Nauclea pobeguinii and Pyrenacantha staudtii[END_REF]Lusakibanza Manzo, 2012) and bark of N. diderrichii in Cameroon and Gabon [START_REF] Nole | Ethnomedical and ethnopharmacological study of plants used for potential treatments of diabetes and arterial hypertension by indigenous people in three phytogeographic regions of Cameroon[END_REF]Towns, 2014a) are reported for managing sexual asthenia. Infusion of N. latifolia root is used in case of premature ejaculation [START_REF] Tabuti | Traditional herbal drugs of Bulamogi, Uganda: plants, use and administration[END_REF] and more generally root or root bark are prescribed for male sexual dysfunction [START_REF] Fasola | Medicinal plants of Ethiope west and Sapele local government areas of delta state, Nigeria[END_REF][START_REF] Göhre | Plants from disturbed savannah vegetation and their usage by Bakongo tribes in Uíge, Northern Angola[END_REF][START_REF] Badiaga | Etude ethnobotanique, phytochimique et activités biologiques de Nauclea latifolia Smith, une plante médicinale africaine récoltée au Mali[END_REF]. N. diderrichii leaves are also consumed for the same indication [START_REF] Betti | An ethnobotanical and floristical study of medicinal plants among the Baka Pygmies in the periphery of the Ipassa-Biosphere reserve, Gabon[END_REF]. Female infertility is also treated by N. latifolia leaf, root or bark preparations [START_REF] Nadembega | Medicinal plants in Baskoure, Kourittenga Province, Burkina Faso: An ethnobotanical study[END_REF][START_REF] Nkounkou-Loumpangou | Inventaire des plantes médicinales utilisées dans le traitement de l'infertilité féminine à Brazzaville[END_REF][START_REF] Makinde | An Ethnomedical and Ethnobotanical survey of Plants Herbal Therapy used for Obesity, Asthma, Diabetes and Fertility by the Badagry people of Lagos State, Nigeria[END_REF][START_REF] Tchacondo | Herbal remedies and their adverse effects in Tem tribe traditional medicine in Togo[END_REF] and by N. diderrichii stem bark extracts [START_REF] Betti | Medicinal plants sold in Yaoundé markets, Cameroon[END_REF]. Other authors also mentioned indication of N. latifolia bark for reproductive health [START_REF] Diame | Ethnobotany and ecological studies of plants used for reproductive health: a case study at Bia biosphere reserve in the western region of Ghana[END_REF] and of root for woman health [START_REF] Quiroz | Do not fear the supernatural!: the relevance of ritual plant use for traditional culture, nature conservation, and human health in western Africa[END_REF] without further precision.

Almost every parts of N. latifolia (except leaves) are reported for addressing menstrual disorders [START_REF] Olowokudejo | An ethnobotanical survey of herbal markets and medicinal plants in Lagos State of Nigeria[END_REF][START_REF] Omobuwajo | Indigenous knowledge and practices of women herb sellers of south-western Nigeria[END_REF]Towns and Van Andel, 2014b).

Anti-abortifacient effects are described for N. pobeguinii bark while N. latifolia root are reported abortifacient [START_REF] Vaughan | Oppression breeds rebellion: herbal contraceptives and abortifacients and the role they fulfilled in allowing African American women to maintain their reproductive autonomy during slavery[END_REF] and useful against uterine fibroids [START_REF] Tabuti | Traditional herbal drugs of Bulamogi, Uganda: plants, use and administration[END_REF].

Skin disorders

Dermatologic indications of the Nauclea genus are reported in five countries of West and central Africa (i.e. Senegal, Gambia, Sierra-Leone, Cameroon and Nigeria) (Table 12). N.

diderrichii (bark, root, fruit and leaf) [START_REF] Ndenecho | Herbalism and resources for the development of ethnopharmacology in Mount Cameroon region[END_REF][START_REF] Mustapha | Plant remedies practiced by Keffi people in the management of dermatosis[END_REF] and N. latifolia (stem and root) [START_REF] Kayode | Stem barks and roots extravitism in ekiti state nigeria: need for conservation as a sustainable innovation in healthcare management in rural areas[END_REF][START_REF] Ajibesin | Ethnobotanical survey of plants used for skin diseases and related ailments in Akwa Ibom State, Nigeria[END_REF][START_REF] Shomkegh | Utilization of wild plants for medicinal purposes in selected Tiv communities of Benue State, Nigeria: An ethnobotanical approach[END_REF] are used in skin diseases management. Itching could be treated by leaf or root extracts of N. latifolia [START_REF] Shomkegh | Utilization of wild plants for medicinal purposes in selected Tiv communities of Benue State, Nigeria: An ethnobotanical approach[END_REF][START_REF] Aniama | Ethnobotanical documentation of some plants among Igala people of Kogi State[END_REF]. This latter extract is also indicated for dermatosis [START_REF] Erinoso | Herbal recipes used for the traditional management of infantile dermatitis in Odeda, southwestern Nigeria[END_REF] whereas leaves and bark of N. vanderguchtii [START_REF] Jiofack | Ethnobotanical uses of medicinal plants of two ethnoecological regions of Cameroon[END_REF] are employed for wound healing. All parts of N. latifolia are also reported as capable of accelerating cicatrisation [START_REF] Olowokudejo | An ethnobotanical survey of herbal markets and medicinal plants in Lagos State of Nigeria[END_REF][START_REF] Lebbie | Ethnobotanical value and conservation of sacred groves of the Kpaa Mende in Sierra Leone[END_REF][START_REF] Madge | Therapeutic landscapes of the Jola, The Gambia, West Africa[END_REF] while leaf infusion is described to stimulate burn recovery [START_REF] Gning | Richesse de la pharmacopée malinké: rôle médicinal de l'arbre a Khossanto:(Kédougou, Sénégal oriental)[END_REF]. specific study on dermatologic indication; FL (%) = Np/N x 100 (Np is the number of informants that claim a use of a plant species to treat a particular disease and, N is the number of informants that use the plant as a medicine to treat any given disease).

Miscellaneous

N. latifolia is also used for ophthalmologic indications. In Sierra-Leone sap oozing from stem is instilled in eyes to improve sight or to cure eye troubles [START_REF] Kanteh | Diversity of plants with pesticidal and medicinal properties in southern Sierra Leone[END_REF][START_REF] Lebbie | Ethnobotanical value and conservation of sacred groves of the Kpaa Mende in Sierra Leone[END_REF]. Leaf decoction is as well used in Ivory Coast for conjunctivitis healing as ocular bath solution [START_REF] Adiko | Phytothérapie traditionnelle des conjonctivites en milieu urbain ivoirien : enquête sur les deux marchés aux plantes médicinales d'Abidjan[END_REF] (Table 13).

Aqueous extract of N. latifolia leaf is indicated in Ethiopia for swollen spots on the head of children [START_REF] Mengesha | Ethnobotanical survey of medicinal plants used in treating human and livestock health problems in Mandura Woreda of Benishangul Gumuz, Ethiopia[END_REF]. Two parts of this plant (i.e. fruit and root) are also used for thin children to restore their appetite [START_REF] Madge | Therapeutic landscapes of the Jola, The Gambia, West Africa[END_REF][START_REF] Kristensen | Perceptions, use and availability of woody plants among the Gourounsi in Burkina Faso[END_REF].

Other sporadic therapeutic indications of the genus Nauclea are mentioned such as cataplasm for fractured bones [START_REF] Thomas | Notes d'ethnobotanique africaine: plantes utilisées dans la région de la Lobaye (Afrique centrale)[END_REF] (Table 13). N. latifolia is also used for rheumatism [START_REF] Madge | Therapeutic landscapes of the Jola, The Gambia, West Africa[END_REF], for traumatic injuries of central nervous system [START_REF] Kantati | Ethnopharmacological survey of plant species used in folk medicine against central nervous system disorders in Togo[END_REF], as anticancer agent [START_REF] Ashidi | Ethnobotanical survey and cytotoxicity testing of plants of South-western Nigeria used to treat cancer, with isolation of cytotoxic constituents from Cajanus cajan Millsp. leaves[END_REF] or more generally for good health [START_REF] Kristensen | Perceptions, use and availability of woody plants among the Gourounsi in Burkina Faso[END_REF]. Finally, N. xanthoxylon root, leaf and bark are reported as a therapeutic plant parts in Angovè forest (Benin) without mention of indications [START_REF] Dossou | Etude ethnobotanique des ressources forestières ligneuses de la forêt marécageuse d'Agonvè et terroirs connexes au Bénin[END_REF].

Furthermore, N. latifolia is reported for veterinary indications which totally overlap human indications (Table 13). Cardinale et al. described the utilization of root or bark to cure horses fever or hernia in Cameroon [START_REF] Cardinale | Le poney musey et les pratiques vétérinaires (région de Gobo, Nord-Cameroun)[END_REF]. Root, leaf or stem bark are mentioned as anti-helminthic [START_REF] Abu | A study of traditional animal health care in Nasarawa state, Nigeria[END_REF][START_REF] Swaleh | Ethnoveterinary Medicine in Ormaland-Kenya[END_REF] and anti-diarrheic [START_REF] Souare | Use of wild trees and shrubs as fodder and traditional veterinary medicine in Cameroon: ecological impacts and conservation[END_REF][START_REF] Offiah | Ethnobotanical survey of medicinal plants used in the treatment of animal diarrhoea in Plateau State, Nigeria[END_REF].

Phytochemistry

4.1.Steroids & saponins

The chemical composition of African Nauclea species have started to be unraveled in 1953, with the discovery of the steroid β-sitosterol and its palmitate ester as the first identified metabolites from N. diderrichii [START_REF] King | The chemistry of extractives from hardwoods. Part XII. The cyclitols and steroids of opepe (Sarcocephalus diderrichii)[END_REF]. Several other triterpene derivatives were discovered during the following decades (Figure 4). A mixture of β-sitosterol fatty esters was reported in N. diderrichii [START_REF] Adeoye | A rapid method for the identification of fatty acid and sterol constituents of complex sterol ester mixtures[END_REF] and β-sitosterol with two related glucosides were isolated from the roots of N. latifolia (Abreu et al., 2001a;[START_REF] Ngnokam | Nauclefolinine: a new alkaloid from the roots of Nauclea latifolia[END_REF].

Nevertheless, quinovic acid derivatives are the most studied family of triterpene compounds in the genus. Indeed, quinovic acid itself, along with eleven glycosides (e.g. glucosyl, fucosyl, rhamnosyl and derivatives) and the 3-oxo analogue, were extracted from the bark of N.

diderrichii (Adeoye and Waigh, 1983a;Lamidi et al., 1995aLamidi et al., , 1995bLamidi et al., , 1995c[START_REF] Lamidi | Revised structures of four saponins from Nauclea diderrichii[END_REF][START_REF] Di Giorgio | Antileishmanial activity of quinovic acid glycosides and cadambine acid isolated from Nauclea diderrichii[END_REF]. These saponins are not specific to one species, as some compounds have also been described in N. pobeguinii [START_REF] Zeches | Constituants des écorces de racine de Nauclea pobeguinii[END_REF][START_REF] Mesia | Antimalarial activity and toxicity evaluation of a quantified Nauclea pobeguinii extract[END_REF] and N. latifolia [START_REF] Ngnokam | Nauclefolinine: a new alkaloid from the roots of Nauclea latifolia[END_REF][START_REF] Ata | Chemical constituents of Nauclea latifolia and their anti-GST and anti-fungal activities[END_REF]. Two additional triterpenes were identified as rotundic acid and 3acetoxy-11-oxo-urs-12-ene, respectively in the roots of N. latifolia [START_REF] Ngnokam | Nauclefolinine: a new alkaloid from the roots of Nauclea latifolia[END_REF] and in the bark of N. pobeguinii [START_REF] Kuete | Cytotoxicity of selected Cameroonian medicinal plants and Nauclea pobeguinii towards multifactorial drug-resistant cancer cells[END_REF]. The general steroid precursor squalene has also been found in N. latifolia [START_REF] Ngnokam | Nauclefolinine: a new alkaloid from the roots of Nauclea latifolia[END_REF].

Alkaloids

A turning point was reached in phytochemical investigations of the Nauclea genus in 1970, with the description of several nicotinate derivatives, terpenoids and β-carbolines in the bark of N. diderrichii (Figures 5 and6; MacLean and [START_REF] Maclean | Isolation of indole (β-carboline), pyridine, and indolepyridine alkaloids from Nauclea diderrichii[END_REF]Murray, , 1972aMurray, , 1972b)). Interestingly, numerous alkaloid derivatives were isolated later as obvious biosynthetic adducts of these three classes of compounds, especially in N. latifolia, N. diderrichii and N. pobeguinii. Naucledine, desoxycordifolinic acid (N. diderrichii; MacLean and [START_REF] Maclean | Isolation of indole (β-carboline), pyridine, and indolepyridine alkaloids from Nauclea diderrichii[END_REF][START_REF] Murray | The constituents of Nauclea diderrichii. Part III. Indole-pyridine alkaloids[END_REF]Adeoye and Waigh, 1983b), strictosidine, desoxycordifoline (N. pobeguinii; [START_REF] Xu | Chromatographic profiling and identification of two new iridoid-indole alkaloids by UPLC-MS and HPLC-SPE-NMR analysis of an antimalarial extract from Nauclea pobeguinii[END_REF] and 3α,5α-tetrahydrodesoxycordifoline (N. pobeguinii, N. latifolia and N. diderrichii; Lamidi et al., 1995c;[START_REF] Shigemori | Naucleamides A-E, new monoterpene indole alkaloids from Nauclea latifolia[END_REF][START_REF] Mesia | Antimalarial activity and toxicity evaluation of a quantified Nauclea pobeguinii extract[END_REF] are five examples of β-carbolines modified through biosynthetic sequences involving either nicotinate (for naucledine) or diderroside (for the four other compounds) derivatives (Figure 6). A number of reported compounds from the class of indolo[2,3-a]quinolizidines are five-rings analogues of the aforementioned β-carbolines. Among them, a large series based on nauclefine contains no less than fourteen different structures (Figure 7). Besides the naked nauclefine, the 20-vinyl analogue angustine was extracted from the roots, stem bark and leaves of N. latifolia, and from the root bark of N. pobeguinii [START_REF] Hotellier | Nauclefine and naucletine, two new indoloquinolizidine alkaloids isolated from Nauclea latifolia[END_REF][START_REF] Hotellier | Alkaloids and glyco-alkaloids from leaves of Nauclea latifolia SM[END_REF][START_REF] Zeches | Constituants des écorces de racine de Nauclea pobeguinii[END_REF]Abreu andPereira, 1998, 2001b;[START_REF] Boumendjel | Occurrence of the synthetic analgesic tramadol in an African medicinal plant[END_REF]. Several derivatives of angustine have also been discovered from Nauclea species: naucletine (N. latifolia; [START_REF] Hotellier | Nauclefine and naucletine, two new indoloquinolizidine alkaloids isolated from Nauclea latifolia[END_REF], angustoline (N. latifolia and N. pobeguinii; [START_REF] Hotellier | Nauclefine and naucletine, two new indoloquinolizidine alkaloids isolated from Nauclea latifolia[END_REF][START_REF] Zeches | Constituants des écorces de racine de Nauclea pobeguinii[END_REF]Abreu andPereira, 1998, 2001b;[START_REF] Agomuoh | Novel indole alkaloids from Nauclea latifolia and their renin-inhibitory activities[END_REF], 19-O-methylangustoline (N. pobeguinii; [START_REF] Mesia | Antimalarial activity and toxicity evaluation of a quantified Nauclea pobeguinii extract[END_REF], 19-O-ethylangustoline (N. latifolia; Abreu andPereira, 1998, 2001b) and 19-O-acetylangustoline (N. pobeguinii; [START_REF] Zeches | Constituants des écorces de racine de Nauclea pobeguinii[END_REF]. Angustidine [START_REF] Phillipson | The Chemotaxonomic Significance of Alkaloids in the Naucleeae S.L. (Rubiaceae)[END_REF]Abreu andPereira, 1998, 2001b) and naulafine [START_REF] Hotellier | Alkaloids and glyco-alkaloids from leaves of Nauclea latifolia SM[END_REF] are particular derivatives from N. latifolia, respectively bearing a 21-methyl group and an additional fused ring. Furthermore, the 3,14-dihydro analogue of angustine has been described in the root bark of N. pobeguinii [START_REF] Zeches | Constituants des écorces de racine de Nauclea pobeguinii[END_REF], and several derivatives are also Nauclea constituents:

3,14-dihydroangustoline, 19-O-methyl-3,14-dihydroangustoline (N. pobeguinii; [START_REF] Xu | Chromatographic profiling and identification of two new iridoid-indole alkaloids by UPLC-MS and HPLC-SPE-NMR analysis of an antimalarial extract from Nauclea pobeguinii[END_REF], and latifoliamides D and E (N. latifolia; [START_REF] Agomuoh | Novel indole alkaloids from Nauclea latifolia and their renin-inhibitory activities[END_REF]. Alternatively, strictosamide-based indolo[2,3-a]quinolizidines can be formed upon cyclization of strictosidine derivatives. Strictosamide itself has been frequently isolated from various parts of N. latifolia [START_REF] Hotellier | Isolation of isovincoside lactam (strictosamide) from the root bark of Nauclea latifolia Sm[END_REF][START_REF] Brown | Isolation of strictosidine (isovincoside) lactam from Nauclea latifolia[END_REF][START_REF] Shigemori | Naucleamides A-E, new monoterpene indole alkaloids from Nauclea latifolia[END_REF][START_REF] Ata | Chemical constituents of Nauclea latifolia and their anti-GST and anti-fungal activities[END_REF][START_REF] Boumendjel | Occurrence of the synthetic analgesic tramadol in an African medicinal plant[END_REF] and N. pobeguinii [START_REF] Zeches | Constituants des écorces de racine de Nauclea pobeguinii[END_REF][START_REF] Xu | Chromatographic profiling and identification of two new iridoid-indole alkaloids by UPLC-MS and HPLC-SPE-NMR analysis of an antimalarial extract from Nauclea pobeguinii[END_REF][START_REF] Kuete | Cytotoxicity of selected Cameroonian medicinal plants and Nauclea pobeguinii towards multifactorial drug-resistant cancer cells[END_REF] through alcoholic extraction, sometimes in very high yields (Figure 8). Indeed, amounts up to 1.7% for N. latifolia (Abreu and Pereira, 2001b) and 0.85% for N. pobeguinii [START_REF] Mesia | Antimalarial activity and toxicity evaluation of a quantified Nauclea pobeguinii extract[END_REF] Besides the two aforementioned subfamilies of indolo[2,3-a]quinolizidines, eight additional analogues with various structures have been described to date (Figure 9): naucleamide A, B, D, E (N. latifolia; [START_REF] Shigemori | Naucleamides A-E, new monoterpene indole alkaloids from Nauclea latifolia[END_REF][START_REF] Ata | Chemical constituents of Nauclea latifolia and their anti-GST and anti-fungal activities[END_REF][START_REF] Boumendjel | Occurrence of the synthetic analgesic tramadol in an African medicinal plant[END_REF], latifoliamide A (N. latifolia; [START_REF] Agomuoh | Novel indole alkaloids from Nauclea latifolia and their renin-inhibitory activities[END_REF], nauclefitine, nauclefidine and nauclequiniine (N.

pobeguinii; [START_REF] Mao | Correction to "Alkaloids of Nauclea officinalis[END_REF][START_REF] Anam | Novel nauclequiniine from the root extract of Nauclea pobequinii (Pob. & Pellegr.) Petit (Rubiaceae)[END_REF]. Several metabolites from African Nauclea were identified as seven-membered ring counterparts to indolo[2,3-a]quinolizidines. Among them, the cadambine and naufoline subclasses appear as closely related to the strictosamide-based and naufoline-based indolo[2,3a]quinolizidines, respectively (Figure 10). Four pyrane-based compounds have been reported so far from African species of genus: cadambine (N. latifolia; [START_REF] Hotellier | Alkaloids and glyco-alkaloids from leaves of Nauclea latifolia SM[END_REF], 3αdihydrocadambine (N. latifolia and N. diderrichii; Dmitrienko et al., 1974a;[START_REF] Maclean | Constituents of Nauclea diderrichii. Part VII. Synthesis of nauclederine, naucleonine, and naucleonidine; spectroscopic evidence for the structures of 3α-dihydrocadambine and two other constituents[END_REF][START_REF] Hotellier | Alkaloids and glyco-alkaloids from leaves of Nauclea latifolia SM[END_REF], cadambine acid (N. diderrichii; [START_REF] Lamidi | Gluco-indole alkaloids from the bark of Nauclea diderrichii. 1 H and 13 C NMR assignments of 3a-5a-tetrahydrodeoxycordifoline lactam and cadambine acid[END_REF] and ND-370 (N. diderrichii; [START_REF] Maclean | Constituents of Nauclea diderrichii. Part VII. Synthesis of nauclederine, naucleonine, and naucleonidine; spectroscopic evidence for the structures of 3α-dihydrocadambine and two other constituents[END_REF]. On the other hand, six pyridine-based molecules are known as Nauclea constituents: naufoline (N. latifolia and N. pobeguinii; [START_REF] Hotellier | Naufoline and decarbomethoxynauclechine, two new indole alkaloids isolated from Nauclea latifolia Sm. (Rubiaceae)[END_REF][START_REF] Hotellier | Alkaloids and glyco-alkaloids from leaves of Nauclea latifolia SM[END_REF][START_REF] Zeches | Constituants des écorces de racine de Nauclea pobeguinii[END_REF], 16-carbomethoxynaufoline, 18,19-dihydro-16carbomethoxynaufoline (N. diderrichii;[START_REF] Richard | Contribution à l'étude de Naucleeae africaines: constituants des feuilles de Nauclea diderrichii[END_REF], nauclechine (N. diderrichii and N. latifolia; [START_REF] Murray | The constituents of Nauclea diderrichii. Part III. Indole-pyridine alkaloids[END_REF][START_REF] Hotellier | Nauclefoline a new alkaloid from Nauclea latifolia Sm. (Rubiaceae)[END_REF], descarbomethoxynauclechine (N.

latifolia; [START_REF] Hotellier | Naufoline and decarbomethoxynauclechine, two new indole alkaloids isolated from Nauclea latifolia Sm. (Rubiaceae)[END_REF][START_REF] Boumendjel | Occurrence of the synthetic analgesic tramadol in an African medicinal plant[END_REF] and nauclefoline (N. latifolia; et al., 1981). Finally, four additional compounds are unusual indole alkaloids isolated from N. diderrichii (Figure 11), such as the oxazole-based naucleonine and naucleonidine, the seven-membered ring nauclederine and the macrocyclic nauclexine [START_REF] Murray | The constituents of Nauclea diderrichii. Part III. Indole-pyridine alkaloids[END_REF]Dmitrienko et al., 1974b;[START_REF] Maclean | Constituents of Nauclea diderrichii. Part VII. Synthesis of nauclederine, naucleonine, and naucleonidine; spectroscopic evidence for the structures of 3α-dihydrocadambine and two other constituents[END_REF]. Finally, tramadol, a synthetic alkaloid known as strong analgesic, has been extracted by Boumendjel et al. from N. latifolia in 2013 (Figure 12). Following this discovery, a controversy emerged about the origin of the presence of tramadol in the plant roots, i.e. natural vs.

Hotellier
anthropologic. After several contradictory studies published these past three years, the debate remains open [START_REF] Kusari | Tramadol-A True Natural Product?[END_REF][START_REF] Kusari | Synthetic Origin of Tramadol in the Environment[END_REF][START_REF] Lecerf-Schmidt | Biomimetic synthesis of Tramadol[END_REF][START_REF] Romek | A retro-biosynthetic approach to the prediction of biosynthetic pathways from position-specific isotope analysis as shown for tramadol[END_REF][START_REF] Boucherle | Nauclea latifolia: biological activity and alkaloid phytochemistry of a West African tree[END_REF].

Phenolic Compounds

Six phenolics have been isolated from the three main species of African Nauclea (Figure 13): antiarol (N. diderrichii; MacLean and Murray, 1972b), kelampayoside A (N. pobeguinii; [START_REF] Xu | Chromatographic profiling and identification of two new iridoid-indole alkaloids by UPLC-MS and HPLC-SPE-NMR analysis of an antimalarial extract from Nauclea pobeguinii[END_REF], p-coumaric acid, resveratrol, resveratrol glucoside (N. pobeguinii; [START_REF] Kuete | Cytotoxicity of selected Cameroonian medicinal plants and Nauclea pobeguinii towards multifactorial drug-resistant cancer cells[END_REF] and scopoletin (N. latifolia; Abreu and Pereira, 2001b).

Pharmacological activities

Anti-infective

Anti-parasite

Based on their traditional uses against malaria N. latifolia and N. pobeguinii have been evaluated as antiplasmodial (Table 14). The first report of antimalarial activity of N. latifolia stem and roots aqueous extracts on Plasmodium falciparum was published in 1998 by Benoit-Vical et al. This activity was later confirmed by other studies using aqueous, alcoholic or hydroalcoholic extracts of stem bark, roots or leaves (Udobre et al., 2013a;2013b;[START_REF] Zirihi | In vitro antiplasmodial activity and cytotoxicity of 33 West African plants used for treatment of malaria[END_REF][START_REF] Ettebong | In vivo antiplasmodial activities of Nauclea latifolia[END_REF][START_REF] Onyesom | Nauclea latifolia aqueous leaf extract eliminates hepatic and cerebral Plasmodium berghei parasite in experimental mice[END_REF][START_REF] Dibua | In vivo and in vitro evaluation of the inhibitory effect of some medicinal plant extracts on haemozoin concentration[END_REF][START_REF] Adebajo | In vivo antiplasmodial potentials of the combinations of four Nigerian antimalarial plants[END_REF]; for a review see [START_REF] Boucherle | Nauclea latifolia: biological activity and alkaloid phytochemistry of a West African tree[END_REF]. Hydro-alcoholic extracts of N. pobeguinii stem bark also presented antiplasmodial activity. These pharmacological activities, as mentioned previously, led to the development of two improved traditional medicines in D.R. Congo and Nigeria using N. pobeguinii and N. latifolia extracts respectively [START_REF] Mesia | Antimalarial activities and toxicities of three plants used as traditional remedies for malaria in the Democratic Republic of Congo: Croton mubango, Nauclea pobeguinii and Pyrenacantha staudtii[END_REF]2010;2012a;[START_REF] Ajibesin | Ethnobotanical survey of plants used for skin diseases and related ailments in Akwa Ibom State, Nigeria[END_REF][START_REF] Pieters | Standardisation of a stem bark extract of Nauclea pobeguinii and its in vivo antiplasmodial activity, in: African Journal of Traditional, Complementary and Alternative Medicines (AJTCAM)[END_REF][START_REF] Gamaniel | A comparative randomized clinical trial of NIPRD AM1 against a chloroquine and sulphadoxine/pyrimethamine combination in symptomatic but uncomplicated malaria[END_REF].

The antihelmintic efficacy of N. latifolia was studied with various approaches and several models (Table 14). In sheep with acute or sub-acute parasitic gastro-enteritis due to infection by mixed nematode species, oral administration of extracts significantly reduced faecal egg counts for both aqueous stem bark and ethanolic leaf extracts at 500 mg/kg compare to untraited control [START_REF] Ademola | Anthelmintic efficacy of Nauclea latifolia extract against gastrointestinal nematodes of sheep: in vitro and in vivo studies[END_REF] or with an efficacity at 1600 mg/kg comparable to albendazole

(5 mg/kg) [START_REF] Onyeyili | Anthelmintic activity of crude aqueous extract of Nauclea latifolia stem bark against ovine nematodes[END_REF]. The larvicidal efficacy of hot, cold water and ethanolic extracts on Heligmosomodes bakeri larvae at 5000 μg/ml was assessed. The mortality rate of L1 larvae was 77, 89 and 74% for hot, cold water and ethanolic extracts respectively while for L2 larvae, 83, 78 and 83% mortality rate were observed [START_REF] Wabo Poné | In vitro ovicidal and larvicidal activities of aqueous and ethanolic extracts of stem bark of Nauclea latifolia (Rubiaceae) on Heligmosomoides bakeri (Nematoda, Heligmosomatidae)[END_REF]. Furthemore, aqueous extracts of N. latifolia leaves paralyzed T. columbriformis L3 larvae with EC50 value of 0.52 mg/ml at 24 h [START_REF] Asuzu | The anthelmintic effect of Alstonia boonei bark and Nauclea latifolia leaf aqueous extracts on Trichostrongylus infective larvae[END_REF]. Helminth glutathione-S-transferases (GSTs) are potential targets for antihelmintic compounds since GST could protect the parasite against an immune response from its host. Stem bark hydro-methanolic extract contained inhibitors against recombinant Ascaris and Onchocerca GSTs with IC50 of 15 and 28 mg/mL respectively [START_REF] Fakae | Inhibition of glutathione S-transferases (GSTs) from parasitic nematodes by extracts from traditional Nigerian medicinal plants[END_REF].

The anti-parasitic activity of N. latifolia on various other parasites (i.e. trypanosome, leishmania and amoeba) was also investigated. Stem bark and wood extracts were evaluated on amastigote and promastigote forms of Leishmania major. A methanolic extract of stem bark was found to be active only on the latter form (17% survival) [START_REF] Ahua | Antileishmanial activities associated with plants used in the Malian traditional medicine[END_REF]. Dichloromethane extract reduced survival of both forms (15% survival for promastigote form and 19% for amastigote form) when the control compound Amphotericin B was about 10 times more potent (1% and 2% survival for promastigote and amastigote forms respectively) but presented a higher toxicity on macrophage survival (60% compare to 88% for N. latifolia extract).

In mice experimentally infected with Trypanosoma brucei brucei, the root bark ethanolic extract was evaluated and found to decrease the level of parasitaemia in a dose dependent manner [START_REF] Madubunyi | Antihepatotoxic and trypanocidal activities of the ethanolic extract of Nauclea latifolia root bark[END_REF]. The trypanosomes were completely eradicated at 6 th day after treatment at a dose range of 40 to 100 mg/kg. Studying methanolic extracts of stem bark and leaves, Olanrewaju et al. were not able to show trypanocidal effect [START_REF] Olanrewaju | Investigation on the trypanocidal effects of aqueous extracts of Vernonia amygdalina and Nauclea latifolia in albino rats[END_REF].

The traditional use of Nauclea latifolia as antidiarrheal led to its evaluation on Entamoeba histolytica growth. The root bark aqueous extract exhibited antiamoebic activity with minimum amoebicidal concentrations ≤ 5 µg/ml [START_REF] Tona | Antiamoebic and spasmolytic activities of extracts from some antidiarrheal traditional preparations used in Kinshasa, Congo[END_REF]2009).

Antimicrobial

Antimicrobial activity of N. latifolia have been extensively described since decades. Both aerial parts (i.e. fruits, leaves and stem bark) and roots were extracted using different organic solvents or water and their antimicrobial activities on various bacteria or fungi strains were tested (Table 15). The available data present few conclusions due to conflicting results by different authors.

However, the key points emerging are: (1) an overall good anti-bacterial activities of alcoholic extracts of all part of the plant against a broad spectrum of pathogens including gram negative or positive bacteria and fungi, (2) a poor efficiency of extracts using nonpolar solvents (e.g.

alkanes), and (3) very contrasted results for aqueous extracts which are the most described mode of intake for traditional uses. A rationalization of the antimicrobial activities is so very difficult and further complicated by the lack of standardization in antimicrobial evaluations and the absence of a common reference as positive control. N. pobeguinii root, bark and leaf methanolic extracts were evaluated as antimicrobial. Both plant parts extracts were found inhibitors of bacterial growth on several pathogen bacteria [START_REF] Njimoh | Antimicrobial activities of a plethora of medicinal plant extracts and hydrolates against human pathogens and their potential to reverse antibiotic resistance[END_REF][START_REF] Seukep | Antibacterial and antibioticresistance modifying activity of the extracts and compounds from Nauclea pobeguinii against Gram-negative multi-drug resistant phenotypes[END_REF].

Moreover a synergistic effect to various usual antibiotics was shown, thereby validating their use during treatment of resistant bacteria strains. [START_REF] Tekwu | Investigations of antimicrobial activity of some Cameroonian medicinal plant extracts against bacteria and yeast with gastrointestinal relevance[END_REF][START_REF] Abiodun | Anti-microbial evaluation of a herbal dental remedy: stem bark of Nauclea latifolia-family Rubiaceae[END_REF][START_REF] Osadebe | Investigation into the folkloric antimicrobial and antiinflammatory properties of Nauclea latifolia leaves and stem bark extracts and fractions[END_REF][START_REF] Maitera | Phytochemical analysis and the chemotherapeutics of leaves and stem-bark of Nauclea latifolia grown in Hong, Adamawa State Nigeria[END_REF][START_REF] Kubmarawa | Preliminary phytochemical and antimicrobial screening of 50 medicinal plants from Nigeria[END_REF][START_REF] El-Mahmood | In vitro antibacterial activities of crude extracts of Nauclea latifolia and Daniella oliveri[END_REF] CHCl3 [START_REF] Okiei | Comparative studies of the antimicrobial activity of components of different polarities from the leaves of Nauclea latifolia[END_REF][START_REF] Maitera | Phytochemical analysis and the chemotherapeutics of leaves and stem-bark of Nauclea latifolia grown in Hong, Adamawa State Nigeria[END_REF][START_REF] Musa | A comparative study of the antibacterial activity of aqueous ethanol and chloroform extracts of some selected medicinal plants used in Igalaland of Nigeria[END_REF][START_REF] Fagbohun | Chemical composition and antibacterial activities of some selected traditional medicinal plants used in the treatment of gastrointestinal infections in Nigeria[END_REF][START_REF] Okwori | The antibacterial potentials of Nauclea latifolia[END_REF][START_REF] Osadebe | Investigation into the folkloric antimicrobial and antiinflammatory properties of Nauclea latifolia leaves and stem bark extracts and fractions[END_REF] Aq (Aqueous); EA (Ethylacetate); +: antimicrobial activity; -: no antimicrobial activity; +/-: Activity is different among the different strains tested.

Miscellaneous

Molluscicidal activity of N. latifolia bark methanol and aqueous extract was assessed using a survival test on Lymnae natalensis (Kela et al., 1989a;1989b), as this snail is the intermediate host of Fasciola hepatica (Table 16). Only the water extract exhibited an activity with a LC50 of 42 mg/L.

The folk medicinal use of N. latifolia against yellow fever and jaundice had conducted Donalisio et al. to evaluate the antiviral activity of a dichloromethane/methanol root bark extracts [START_REF] Donalisio | In vitro anti-Herpes simplex virus activity of crude extract of the roots of Nauclea latifolia Smith (Rubiaceae)[END_REF]). An inhibition was observed for both aciclovir sensitive (IC50 = 5.4 μg/ml) and aciclovir resistant (IC50 = 7.8 μg/ml) strains on the HSV-2 model chosen. Bark (B), Root Bark (RB), Aq (Aqueous), m (maceration).

Digestive

Digestive activities of N. latifolia were reported through antidiarrheal and anti-ulcer evaluations (Table 17). Hydro-alcoholic root bark extract of N. latifolia was found to exert antidiarrheal activity on castor oil-induced diarrhea [START_REF] Owolabi | Antidiarrheal evaluation of the ethanol extract of Nauclea latifolia root bark[END_REF]. Balogun et al. published several studies on gastric protection of N. latifolia extracts using indomethacin-induced ulcer rat model.

A significant augmentation of ulcer protection from 67% at 170 mg/kg to 91% at 510 mg/kg was reported for aqueous leaf extract while cimetidine used as control at 100 mg/kg presented 76% of protection [START_REF] Balogun | Anti-ulcer activity of aqueous leaf extract of Nauclea latifolia (rubiaceae) on indomethacin-induced gastric ulcer in rats[END_REF]. Effects of aqueous and methanolic leaf extracts on gastric acid secretion was also investigated and a significantly and dose dependently decrease was observed. The total gastric acid content was lowered from 9.8 µEq HCl/100g of body weight and 6.1 at 400 mg/kg for methanol and water extract respectively (control: cimetidine 5.6 µEq HCl/100g of body weight at 100 mg/kg) [START_REF] Balogun | Gastric acid anti-secretory effects of aqueous leaf extract of Nauclea latifolia (Rubiaceae) in rats[END_REF]2015). The hydroalcoholic extract did not exhibit any protective effects on aspirin-induced ulcer in rats [START_REF] Orole | Antiulcerogenic Activity of Kigelia africana, Nauclea latifolia and Staudtia stipitata on Induce Ulcer in Albino Rats[END_REF]. Stem bark hydro-methanolic extract anti-ulcer activity was also investigated in histamine and aspirin induced-ulcer models in rats. This extract significantly increased ulcer tolerance rate compared to controls at 50mg/kg but was found ineffective at 100 mg/kg [START_REF] Alaribe | Healing, cytoprotective and anti-Helicobacter pylori activities of stem bark extracts and butanol fraction of Nauclea latifolia[END_REF]. The same extract was found potent on Helicobacter pylori with MIC of 25 mg/mL (amoxicillin: MIC = 3.1 mg/mL) [START_REF] Alaribe | Healing, cytoprotective and anti-Helicobacter pylori activities of stem bark extracts and butanol fraction of Nauclea latifolia[END_REF]. Root Bark (RB), Stem Bark (SB), Leaf (L), Aq (Aqueous), m (maceration), d (decoction), i (infusion).

Pain and other neurologic uses

Many studies have been conducted on neurologic effects of N. latifolia (Table 18). Using animal models, analgesic, anticonvulsivant, anxiolytic, sedative, antidepressant and myorelaxant activities were described. The first analgesic activity of an extract of N. latifolia was reported by Okiemy-Andissa et al. in 2004 on acetic acid-induced writhing and hot plate mice models using aqueous and hydro-ethanolic extracts of aerial parts. Same evaluations were conducted with methanolic extract of stem bark [START_REF] Otimenyin | Acute toxicity studies, anti-inflammatory and analgesic activities of the methanolic extract of the stem bark of Enantia chlorantha and Nauclea latifolia[END_REF] or with aqueous macerate of root bark [START_REF] Abbah | Pharmacological evidence favouring the use of Nauclea latifolia in malaria ethnopharmacy: effects against nociception, inflammation, and pyrexia in rats and mice[END_REF] and also demonstrated analgesic effect. Total alkaloids extracts of root and leaf were found moderately active on acetic acid-induced writhing mice model [START_REF] Badiaga | Etude ethnobotanique, phytochimique et activités biologiques de Nauclea latifolia Smith, une plante médicinale africaine récoltée au Mali[END_REF]. Besides, studies on other neurologic properties of N. latifolia were conducted by Taïwe and colleagues. They first assessed anticonvulsant, anxiolytic and sedative effects on mice of aqueous root extract [START_REF] Ngo Bum | Anticonvulsant, anxiolytic, and sedative properties of the roots of Nauclea latifolia Smith in mice[END_REF]. Other evaluations on the same type of extract on mice confirmed anxiolytic [START_REF] Taïwe | Antidepressant, myorelaxant and anti-anxiety-like effects of Nauclea latifolia smith (Rubiaceae) roots extract in murine models[END_REF] and analgesic [START_REF] Taïwe | Antipyretic and antinociceptive effects of Nauclea latifolia root decoction and possible mechanisms of action[END_REF]2014) effects and also showed myorelaxant and antidepressant [START_REF] Taïwe | Antidepressant, myorelaxant and anti-anxiety-like effects of Nauclea latifolia smith (Rubiaceae) roots extract in murine models[END_REF] activities.

Studying ethanolic extract of fruits in rat model, Shamoun et al. demonstrated sedative, anticonvulsant and anxiolytic properties [START_REF] Shamoun | Anticonvulsant, Anxiolytic, and Sedative Properties of the Fruit of Sarcocephalus latifolius in Rats[END_REF]. However, the anxiolytic effect of the same kind of extract was infirmed using mice model [START_REF] Arome | Absence of anxiolytic activity of Sarcocephalus latifolius fruit extract[END_REF]. Sedative properties of aqueous macerate on mice and rats have also been reported [START_REF] Amos | Neuropharmacological effects of the aqueous extract of Nauclea latifolia root bark in rats and mice[END_REF].

Furthermore, methanolic leaf and root extracts of N. latifolia were evaluated and found to possess interesting pharmacological actions on purinergic neurotransmission using a rat bladder model [START_REF] Udoh | Effects of leaf and root extracts of Nauclea latifolia on purinergic neurotransmission in the rat bladder[END_REF]. Stem Bark (SB), Root (R), Aerial parts (AP), Root Bark (RB), Leaf (L), Fruit (F), Aq (

, Alk (Total alkaloids).

Metabolic disorders

Metabolic disease prevalences are increasing in Africa. In order to rationalize traditional therapeutic uses of Nauclea species for these indications, several authors have conducted studies especially on hypertension-and diabetes-related effects of these plants (Table 19).

Methanolic extracts of leaf and root of N. latifolia presented opposite effects on the cardiovascular systems of rats and rabbits. While leaf extract potently reduced both mean arterial blood pressure in rats from 122 to 95 mm Hg and rabbit heart rate, root extract was found hypertensive via adrenoreceptor stimulation [START_REF] Udoh | Effects of leaf and root extracts of Nauclea latifolia on the cardiovascular system[END_REF]. 10 mg/kg of the ethanolic root extract also reduced the mean arterial pressure from 116 to 100 mm Hg and 157 to 72 mm Hg on normotensive and hypertensive rats respectively while concomitantly reducing the heart rate from 365 to 280 beats/min and from 550 to 120 beats/min respectively [START_REF] Nworgu | Preliminary studies of blood pressure lowering effect of Nauclea latifolia in rats[END_REF]. The hypotensive effect was confirmed on normotensive rabbits using sub-fractions of the ethanolic root extract [START_REF] Nworgu | The effect of active fractions of the roots of Nauclea latifolia Smith (Rubiaceae) on blood pressure of normotensive rabbits[END_REF]. Odey et al. evaluated body and organ weight changes of hypertensive rats fed with ethanolic root or stem bark extracts of N. latifolia. A significant decrease in heart and liver weight of rats treated with 150 mg/kg of any of the extracts was associated with significant increase in the body weight (Odey et al., 2012a). A 40% relaxation on pre-contracted thoracic aorta was elsewhere reported on rats treated with the ethanolic leaf extract (Akpanabiatu et al., 2005a).

Since extracts of N. latifolia are traditionally used for the treatment of diabetes, several studies demonstrated antidiabetic effects using murine models. An aqueous extract of the leaves was found to significantly lower the glucose level in alloxan-induced diabetic rats by 45% [START_REF] Gidado | Effect of Nauclea latifolia leaves aqueous extracts on blood glucose levels of normal and alloxan-induced diabetic rats[END_REF], and the fasting blood glucose (FBG) by 32% of the streptozotocin-induced diabetic rats [START_REF] Gidado | Hypoglycaemic activity of Nauclea latifolia Sm. (Rubiaceae) in experimental animals[END_REF]. In the latter model, hexanic extract was inactive while ethanolic leaf extract presented a similar potency to the aqueous extract [START_REF] Gidado | Hypoglycaemic activity of Nauclea latifolia Sm. (Rubiaceae) in experimental animals[END_REF] and significantly reduced FBG levels in a dose-independent manner [START_REF] Gidado | Antidiabetic effect of Nauclea latifolia leaf ethanolic extract in Streptozotocin-induced diabetic rats[END_REF]. However, other authors reported inactivity of ethanolic extract on blood glucose level using the same model (Effiong et al., 2013a). Ethanolic leaf extract was also evaluated on non-diabetic rats. After both oral and intraperitoneal glucose loads, it inhibited the increase of glucose level and both maltase and sucrase activities in vitro but not in vivo, suggesting a similar mechanism to that of glibenclamide, i.e. an increase of insulin release from pancreatic β-cells [START_REF] Gidado | A preliminary study of the mechanism of hypoglycaemic activity of Nauclea latifolia leaf ethanolic extract[END_REF].

In acute study and prolonged treatment, oral administration of an ethanolic root extract (450 mg/kg) caused a significant reduction in FBG levels with values similar to the reference glibenclamide (10 mg/kg) [START_REF] Antia | Phytochemical composition and antidiabetic activity of ethanol root extract of Nauclea latifolia[END_REF]. Effects of root and stem extracts on diabetic pregnant rats were evaluated. If a butanolic extract decreased glycaemia in streptozotocin-induced diabetic pregnant rats, an ethanolic extract was ineffective and both of them were not active on normal pregnant rats [START_REF] Yessoufou | Anti-hyperglycemic effects of three medicinal plants in diabetic pregnancy: modulation of T cell proliferation[END_REF]. Aqueous root extract of N. latifolia and Daniella oliveri (1:1, w:w) was investigated on normoglycaemic and alloxan-induced diabetic rats and presented a significant lowering of blood sugar level in diabetic rats from 302 mg/dL to 119 mg/dL but did not show any effect in normoglycaemic rats [START_REF] Iwueke | Antihyperglycaemic effect of aqueous extract of Daniella oliveri and Sarcocephalus latifolius roots on key carbohydrate metabolic enzymes and glycogen in experimental diabetes[END_REF]. α-amylase inhibition using methanolic stem bark extract of N. diderrichii was assessed. It was found as a potent inhibitor with IC50 of 248 μg/mL, comparable to reference αamylase inhibitor acarbose (IC50 = 177 μg/mL) [START_REF] Ogbole | Alpha-amylase Inhibition and Brine Shrimp Lethality Activities of Nine Medicinal Plant Extracts from South-West Nigerian Ethnomedicine[END_REF]. Similar results were obtained by Agnaniet et al. on aqueous extracts of bark and leaf [START_REF] Agnaniet | Antidiabetic potential of two medicinal plants used in Gabonese folk medicine[END_REF]. The later showed a 60-fold better potency than acarbose. During the same evaluation aqueous extracts of bark of N. pobeguinii also presented a good inhibition of α-amylase [START_REF] Agnaniet | Antidiabetic potential of two medicinal plants used in Gabonese folk medicine[END_REF].

Otherwise, N. latifolia extracts administration also conducted to changes in lipid metabolism.

Hence, total cholesterol (TC) and high density lipoprotein (HDL) levels significantly decreased and low density lipoprotein (LDL) and triacylglycerol (TG) levels raised after feeding normal rats with an aqueous stem extract [START_REF] Arise | Effects of aqueous extract of Nauclea latifolia stem on lipid profile and some enzymes of rat liver and kidney[END_REF]. Different results were obtained when ethanol leaf extract and its sub-fractions were evaluated on alloxan-induced diabetic rats: for all sub-fraction-treated groups, TC and HDL levels also decreased and no significant change was observed for TG. Very low density lipoprotein (VLDL) level decreased upon treatment with methanol, butanol and ethyl acetate subfraction [START_REF] Edet | Lipid profile of alloxaninduced diabetic albino Wistar rats treated with ethanol whole extract and fractions of Nauclea latifolia leaves[END_REF]. Total cholesterol was lowered to non-hypertensive control values by both stem and root ethanolic extracts after oral administration on hypertensive rats (Odey et al., 2012b). No significant change was observed for the TG, LDL and VLDL levels while treatment increased HDL levels. Ethanolic extract of the leaf re-extracted in cold water did not present significant changes in the lipid profile of the experimental animals fed with 10% coconut oil meal compared to the controls (Akpanabiatu et al., 2005a). Using a Poloxamer 407 induced hypercholesterolemic rat model, root extracts (crude, ethyl acetate and butanol) were evaluated on lipid metabolism [START_REF] Effah | Preventive and curative effect of african peach (Nauclea latifolia) root extracts on poloxamer 407 induced hypercholesterolemic rats[END_REF]. When extracts were administrated before induction of hypercholesterolemia, they provoked a reduction of TC and TG. The groups treated with aqueous and ethyl acetate extracts also presented a decrease of LDL levels. In a curative treatment, all the groups showed significant increase in the HDL level, ethyl acetate and butanol extract were able to lower TG while only the ethyl acetate extract provoked a decrease in TC. N. latifolia methanolic leaf extract was evaluated on rats treated with ciprofloxacine showing a hypolipidaemic effect associated to an anti-lipid peroxidative efficiency [START_REF] Chinedu | Anti lipid peroxidative and hypolipidaemic potentials of Nauclea latifolia leaves extract on ciprofloxacin induced oxidative stress in rats[END_REF]. Cholesterolemia was measured on rats fed with crude fruits of N. latifolia. The supplementation of total alimentation induced hypocholesterolemic effect in a dose-dependent manner [START_REF] James | Hypocholesterolemic effects of Nauclea latifolia (Smith) fruit studied in albino rats[END_REF].

The hormonal effects of N. latifolia roots extracts were explored. An aqueous infusion was evaluated on rats with cyproteron acetate-caused testis failure which is a traditional indication of the plant. Extract administration conducted to an increase of testis weight from 1% for control to 13% and allowed a regeneration of germinal function of testis, unlike the control group [START_REF] Rukundo | Contribution à l'étude de l'activité androgénique de Nauclea latifolia. Sm.(Rubiaceae)[END_REF]. Based on these results, other authors studied the influence of administration of a N. latifolia aqueous extract both on fertility rate of male and female rats, and on body weight gain of young rats from treated parents. The treatment of female rats was ineffective on both parameters while treatment of male rats led to an augmentation of the fertility rate as compared to control (40% and 60% respectively) and an increase of body weight gain of newborn rats perceptible until day 25 after birth [START_REF] Ishimwe | Effets de l'infusé des racines entières de Nauclea latifolia Sm. sur les performances de reproduction: étude expérimentale chez le rat[END_REF].

The use of N. latifolia by traditional healers to stop pre-term labor has been reported. The ethanolic extract of the roots was then evaluated on agonist-induced contractions of uterine smooth muscles in non-pregnant female rats and clearly indicated an anti-abortifacient property since a reduction of oxytocin, acetylcholine and ergometrine-induced uterine contractions was observed [START_REF] Nworgu | Effect of the ethanolic extract of Nauclea latifolia (Family: Rubiaceae) on the isolated uterus of non-pregnant rats[END_REF]. A methanol extract of the roots of N. latifolia was screened in the yeast test-system to evaluate potential estrogenic properties. A promising activity was found and further investigations in vivo on ovariectomized Wistar rats were performed. N. latifolia significantly increased vaginal epithelial height by 16% compared to untreated controls, suggesting an estrogenic activity [START_REF] Njamen | Effects of the extracts of some tropical medicinal plants on estrogen inducible yeast and Ishikawa screens, and on ovariectomized Wistar rats[END_REF].

Anti-inflammatory and antipyretic

Several anti-inflammatory and antipyretic assays have been performed using N. latifolia samples (Table 20). Anti-inflammatory effects of hydro-alcoholic root or leaf extracts of N.

latifolia were evaluated on carrageenan-induced paw edema in rats. Both extracts significantly reduced inflammation with an effect similar to control (indometacine, 100 mg/kg) at 1000 mg/kg [START_REF] Amouzoun | Activités antipyrétique et anti-inflammatoire d'extraits hydro-alcooliques des racines et feuilles de Nauclea latifolia Smith (Rubiaceae) chez le rat Wistar[END_REF]. Similar anti-inflammatory results were obtained in egg albumine-induced oedema on rodent. A reduction of edema was obtained since 50 mg/kg using an aqueous extract of the root bark [START_REF] Abbah | Pharmacological evidence favouring the use of Nauclea latifolia in malaria ethnopharmacy: effects against nociception, inflammation, and pyrexia in rats and mice[END_REF]2010), while methanolic leaf and stem bark extracts exerted effects at 200 mg/kg and 150 mg/kg respectively [START_REF] Otimenyin | Acute toxicity studies, anti-inflammatory and analgesic activities of the methanolic extract of the stem bark of Enantia chlorantha and Nauclea latifolia[END_REF][START_REF] Osadebe | Investigation into the folkloric antimicrobial and antiinflammatory properties of Nauclea latifolia leaves and stem bark extracts and fractions[END_REF]. Three different studies also presented anti-pyretic activities in yeastinduced pyrexia on murine model. For aqueous extracts of the root bark, the maximal reduction in rectal temperatures was observed at a dose of 200 mg/kg at 90 min [START_REF] Abbah | Pharmacological evidence favouring the use of Nauclea latifolia in malaria ethnopharmacy: effects against nociception, inflammation, and pyrexia in rats and mice[END_REF]. The tested dose for hydro-alcoholic leaf and root extracts was 1500 mg/kg and presented signifant effect during 10 hours [START_REF] Amouzoun | Activités antipyrétique et anti-inflammatoire d'extraits hydro-alcooliques des racines et feuilles de Nauclea latifolia Smith (Rubiaceae) chez le rat Wistar[END_REF]. Fever reduction of the aqueous root extracts (at 4h, 80 mg/kg) was reported comparable to aspirin (300 mg/kg) [START_REF] Taïwe | Antipyretic and antinociceptive effects of Nauclea latifolia root decoction and possible mechanisms of action[END_REF]. Stem Bark (SB), Root (R), Root Bark (RB), Leaf (L), Aq (Aqueous), m (maceration).

Hepato-protective activity

Several authors presented studies on hepatoprotective activities in infective or toxicological liver damages contexts (Table 21). A ten days treatment with leaf decoction of N. pobeguinii

(5 mg/kg) presented a hepatoprotective activity on CCl4 intoxicated rats [START_REF] Kadiri | Effect of Aqueous Nauclea pobeguinii Leaf Extract on Rats Induced with Hepatic Injury[END_REF].

The effects of the root bark ethanolic (100 mg/kg) and methanolic (300 mg/kg) extracts of N. latifolia on liver were also evaluated on the same model and presented hepatoprotective properties as they reduced the toxicity-induced elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (AP) significantly (Madubunyi 1996, Udeh and[START_REF] Udeh | Hepatoprotective activities of methanolic extract of Nauclea latifolia[END_REF], as well as the total and conjugated bilirubin levels for aqueous extract (100 mg/kg) [START_REF] Yesufu | Phytochemical screening and hepatoprotective properties of the aqueous root bark extract of Sarcocephalus latifolius (Smith) Bruce (African Peach)[END_REF]. A similar effect was observed on acetaminophen intoxication of rats on AST, ALT and AP treated with methanolic leaf extract (100 mg/kg) [START_REF] Nwaehujor | Evaluation of the hepato-protective potential of Sarcocephalus latifolius leaf methanol extracts in paracetamolinduced liver damage of mice[END_REF]. Furthermore, ethanolic leaf extract also exerted hepatoprotective effect on rats by (1) reduction of the activity of γ-glutamyl transferase if raised by other factors (at 170 mg/kg) (Akpanabiatu et al., 2005b) (2) AST, ALT levels diminution and restoration of normal proteinaemia in acetaminophen-treated rats (Effiong et al., 2013b;2014).

Miscellaneous

Antioxidant activities on different parts of N. latifolia were described using different models.

Free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl, and superoxide anion radicals of a root methanolic extract was assessed by Awah et al. (Table 22).

Indeed N. latifolia possesses antioxidant activity and lipid peroxidation inhibitory potency probably correlated with its phenolic and flavonoid components [START_REF] Awah | Free radical scavenging activity, phenolic contents and cytotoxicity of selected Nigerian medicinal plants[END_REF]). An aqueous extract of the leaf and fruit also revealed an antioxidant potential with scavenging activity against DPPH with IC50 of 20 mg/mL and 120 mg/mL respectively [START_REF] Ayeleso | In vitro study on the antioxidant potentials of the leaves and fruits of Nauclea latifolia[END_REF]. N. latifolia root and stem ethanolic extracts were tested on red blood cell model and showed a 50% increase of free radical-induced haemolysis time [START_REF] Yessoufou | Anti-hyperglycemic effects of three medicinal plants in diabetic pregnancy: modulation of T cell proliferation[END_REF]. A study of oxidative stress and lipid peroxidation was performed using a model of alloxaninduced diabetic rats treated with an aqueous root extract. The extract (250 mg/kg) significantly reduced catalase activity (CAT), provoked changes in both malondialdehyde (MDA, a plasma and liver lipid peroxidation marker), and glutathione (GSH) but non-significantly reversed the superoxide dismutase (SOD) activity induced by diabetes [START_REF] Iwueke | Modification of lipid peroxidation and oxidative stress in hepatocytes of diabetic rats treated with root extract of Sarcocephalus latifolius and Daniella oliveri[END_REF]. On a ciprofloxacin induced oxidative stress rat model, the methanolic leaf extract (1200 mg/kg) presented antilipid peroxidative potentials [START_REF] Chinedu | Anti lipid peroxidative and hypolipidaemic potentials of Nauclea latifolia leaves extract on ciprofloxacin induced oxidative stress in rats[END_REF]. N. latifolia alcoholic leaf extracts were tested against acetaminophen-induced hepatotoxicity in rats and showed antioxidant properties while the activities of CAT, glutathione peroxidase and SOD were decreased in treated rats vs. non treated ones (Effiong et al., 2013b;[START_REF] Nwaehujor | Evaluation of the hepato-protective potential of Sarcocephalus latifolius leaf methanol extracts in paracetamolinduced liver damage of mice[END_REF].

Using a model of mice infected by P. berghei, antioxidant effects (CAT, SOD and GSH system) of an aqueous extract of N. latifolia leaf were investigated. Not only an elimination of plasmodium was observed, but also an improvement of antioxidant defense even better than chloroquine-treated mice which means that the N. latifolia extract exhibits antioxidant effect on its own [START_REF] Onyesom | Nauclea latifolia aqueous leaf extract eliminates hepatic and cerebral Plasmodium berghei parasite in experimental mice[END_REF]. These results were not confirmed by Edagha et al. however who did not observe, using the same model, significant variations of antioxidant levels in the groups treated with ethanolic leaf extracts compared to control [START_REF] Edagha | Neuroinflammation and Brain Antioxidant Levels in Ethanol Leaf Extract of Nauclea latifolia and Artemisinin-combination Therapy in Swiss mice Infected with Plasmodium berghei ANKA[END_REF].

The methanolic stem bark extract and its sub-fractions (100 mg/mL) were evaluated as cicatricing agent. Both extracts except butanolic presented wound healing properties in tested rabbits with a complete sore recovery in 24 days using ethylacetate extract (30-35 days for control) [START_REF] Udobre | The wound healing activity of methanol extract of the stem bark of Nauclea latifolia[END_REF].

Yessoufou et al. also evaluated the immunomodulatory ability of an ethanolic macerate of root and stem of N. latifolia. Extracts were found as inhibitors of T cell proliferation activated by anti-CD3 antibody in a dose-dependent manner [START_REF] Yessoufou | Anti-hyperglycemic effects of three medicinal plants in diabetic pregnancy: modulation of T cell proliferation[END_REF].

Finally, bark and leaf methanolic macerates of N. pobeguinii led to IC50 values around 30 µg/mL on various cancer cell lines [START_REF] Kuete | Cytotoxicity of selected Cameroonian medicinal plants and Nauclea pobeguinii towards multifactorial drug-resistant cancer cells[END_REF]. Stem Bark (SB), Root (R), Stem (S), Leaf (L), Fruit (F), Aq (Aqueous), m (maceration), d (decoction) 5.8. Toxicity studies Many toxicity studies have been conducted in various models in order to assess safety of plant extracts. A study on hepatic enzymes (γ-glutamyl transferase, AST and ALT) on normal rats treated with an aqueous stem macerate showed a diminution of their liver activities simultaneously to an elevation in the plasma due to hepatotoxicity [START_REF] Arise | Effects of aqueous extract of Nauclea latifolia stem on lipid profile and some enzymes of rat liver and kidney[END_REF]). An extensive toxicity evaluation was performed on rats and mice orally treated with an aqueous extract of N. latifolia stem bark. Single administration on mice allowed the determination of a LD50 > 18 g/kg body weight while sub-acute toxicity on several parameters was evaluated on rats. In blood, an elevation of platelets, erythrocytes and also eosinophils was observed associated with a decrease AST, ALT and creatinine. A high loss of water and depletion in sodium and potassium levels was observed in urine [START_REF] Kouadio | Acute and sub-acute toxicity of aqueous extract of Nauclea latifolia in Swiss mice and in OFA rats[END_REF]. Moreover, neither hepatotoxicity nor nephrotoxicity were measured for rats treated with the same kind of extract at 3.2 g/kg [START_REF] Akinloye | Nephrotoxicity and hepatotoxicity evaluation in wistar albino rats exposed to Nauclea latifolia leaf extracts[END_REF]). An aqueous leaf extract was similarly evaluated and presented an increase of AST, ALT and AP levels in serum associated with histopathological lesions of liver and kidney [START_REF] Magili | Toxicity study of aqueous leaf extracts of Sarcocephalus latifolius (Rubiaceae) in rats[END_REF]. Conducted on Chinchilla rabbit, a study of liver toxicity of an ethanolic crude extract of N. latifolia leaves, fruits, stem and root barks also demonstrated deleterious effects on hepatic functions since significant elevation of AST and ALT activities and hepatic injury were observed [START_REF] Ogenyi | Effect of ethanolic crude extracts of Nauclea latifolia Smith (Rubiaceae) leaves, fruits, stem and root barks on the liver of Chinchilla Rabbit[END_REF]. Liu et al. described genotoxic and clastogenic activity of a hydro-methanolic bark extract of N. latifolia, N.

pobeguinii and N. diderrichii, the later being the most toxic [START_REF] Liu | Genotoxic and clastogenic activity of saponins extracted from Nauclea bark as assessed by the micronucleus and the comet assays in Chinese Hamster Ovary cells[END_REF]. The authors linked this activity to the various saponins found in these extracts. Mesia et al. did not observe toxic effect after acute or prolonged treatment of 4 weeks of N. pobeguinii stem bark extract on mice.

Moreover, no major lesions were found in the considered organs [START_REF] Mesia | Antimalarial activities and toxicities of three plants used as traditional remedies for malaria in the Democratic Republic of Congo: Croton mubango, Nauclea pobeguinii and Pyrenacantha staudtii[END_REF]2010).

Evaluated on brine shrimp lethality assay, a methanolic macerate of stem bark of N. diderrichii showed a LC50 value of 1 µg/mL. Ethanolic leaf extract administrated on gestational rat model created histopathological alterations on neonatal kidneys and livers discouraging its use during pregnancy (Solomon et al., 2014a;2014b). Bark and leaf methanolic macerates of N. pobeguinii led to IC50 values around 30 µg/mL on various cancer cell lines [START_REF] Kuete | Cytotoxicity of selected Cameroonian medicinal plants and Nauclea pobeguinii towards multifactorial drug-resistant cancer cells[END_REF]. An alkaloid rich extract of N. latifolia was able to interact in vitro with DNA of bacteria and mammalian cells as well as creating single-strand breaks in liver, kidney and blood cells in vivo [START_REF] Traore | Toxicity and genotoxicity of antimalarial alkaloid rich extracts derived from Mitragyna inermis O. Kuntze and Nauclea latifolia[END_REF]. Cytotoxicity and growth inhibitory activity were evaluated on tadpoles of Raniceps ranninus and on radicle length of Sorghum bicolor seeds. A root bark methanolic extract induced 100% mortality at a dose of 200 µg/mL, while stem methanolic extract was less toxic with 33% of mortality at 400 µg/mL. Tested at 30 mg/mL, both stem bark and leaf extracts reduced the grow length of radicle by 99% and 95% respectively [START_REF] Oise | Comparative phytochemical, cytotoxic and growth inhibitory effects of the leaf and root barks of Sarcocephalus latifolius (JE Smith) EA Bruce (Rubiaceae)[END_REF]. During anti-inflammatory evaluation in rats, methanolic extracts of the stem bark of N. latifolia were reported to be highly toxic with a LD50 of 850 mg/kg [START_REF] Otimenyin | Acute toxicity studies, anti-inflammatory and analgesic activities of the methanolic extract of the stem bark of Enantia chlorantha and Nauclea latifolia[END_REF].

Cardiotoxicity on isolated frog heart was also described for a hydro-alcoholic stem bark extracts [START_REF] Gueye-Sanokho | Cardiotoxic action of Nauclea latifolia Sm[END_REF].

Conclusion

The these weaknesses and the reports of some divergent results, the analysis of the pharmacological evaluation literature tends to validate traditional uses, as many extracts displayed biological effects initially suggested by local medicinal practices. However, the aqueous macerate, the major preparation mode for oral intake, was not always identified as the more efficient extracting mode.

Phytochemistry of the genus Nauclea has been extensively described and various classes of compounds are reported in several species. Among these, indoloquinolizidines appeared to be characteristic of this genus. However, while some activities of Nauclea extracts have been related to the presence of particular compounds, especially alkaloidse.g. strictosamide -, some others are still away from any molecular rationalization of the observed effects.

Furthermore, some concerns are persisting about the toxicity of Nauclea extracts that could be a source of adverse effects among populations using these traditional ingredients. It is worth noting that traditional utilization of Nauclea species should be structured in the future for maintaining sustainability of these plants, as N. diderrichii is already threatened. A special caution should be observed for certain rare species or for preparations using bark or roots which are more destructive for the trees. In addition, the less studied Nauclea species (i.e. N.

xanthoxylon and N. nyasica) clearly deserve further ethnopharmacological evaluations about their geographical distribution, traditional uses, pharmacological activities and chemical composition.

Figure 1 .

 1 Figure 1. Photographs of six African Nauclea species. A. N. pobeguinii (Gabon, credit: Ehoarn Bidault). B. N. latifolia (Gabon, credit: Nicolas Texier). C. N. diderrichii (Guinea, credit: Ehoarn Bidault). D. N. vanderguchtii (unknown location, credit: David Kenfa). E. N. gilletii (Gabon, credit: Ehoarn Bidault). F. N. nyasica

  b. Seeds pitted, ellipsoids marginedleaves thin, attenuate, acute at base, petiole 4 to 5 cm long ................................................................... Nauclea pobeguinii (Hua ex Pobég.) Merr. [ syn. Sarcocephalus pobeguinii Hua ex Pobég. ] Distribution: W. Trop. Africa to Zambia.5a. Calyx lobes glabrous, sometimes sparsely hairy or ciliate; inside of calyx tube glabrous ................................................................................................................................6 b. Calyx lobes mediumly to densely pubescent, inside of calyx tube pubescent ................................................................... Nauclea diderrichii (De Wild.) Merr. [ syn. Sarcocephalus diderrichii De Wild., Sarcocephalus trillesii Pierre ex De Wild., Nauclea trillesii (Pierre ex De Wild.) Merr., Sarcocephalus badi Aubrév. ] Distribution: W. Trop. Africa to Uganda. 6a. Leaves pubescent below, at least on the veins ..............Nauclea xanthoxylon (Chev.) Aubr. [ syn. Sarcocephalus xanthoxylon A.Chev. ] Distribution: Ivory Coast to Sudan. b. Leaves glabrous below .........................................................................................................7 7a. Diameter of flowering heads across corollas 40-60 mm, corolla lobes glabrous inside ...................................................................... Nauclea vanderguchtii (De wild.) Petit. [ syn. Sarcocephalus vanderguchtii De Wild., Sarcocephalus nervosus Hutch. & Dalziel, Sarcocephalus nervosus var. cordifolia A.Chev. ] Distribution: Liberia, Nigeria to WC. Trop. Africa. b. Diameter of flowering headsacross corollas up to 40 mm, corolla lobes with 1-3 lines of hairs inside .........................................................................Nauclea gilletii (De wild.) Merr. [ syn. Sarcocephalus gilletii De Wild., Sarcocephalus trillesii var. lancifolia A.Chev., Nauclea lancifolia (A.Chev.) Aubrév. ] Distribution: Ivory Coast to WC. Trop. Africa.

Figure 3 .

 3 Figure 3. General geographical distribution of the seven African Nauclea species. The dots are compiled observations of specimens from various occurrence datasets (e.g. Naturalis Biodiversity Center, Tropicos Specimen Data, Herbarium of the "Muséum National d'Histoire Naturelle" of Paris, West African Vegetation Database) gathered by the Global Biodiversity Information Facility (http://www.gbif.org).

  Bark (B), Root (R), Root Bark (RB), Stem (S), Leaves (L), Fruit (F), Wood (W), decoction (d), infusion (i), Democratic Republic of Congo (D.R.Congo); a : including other indications, b : specific study on this indication.

  Bark (B), Stem Bark (SB), Root (R), Root Bark (RB), Stem (S), Leaves (L), Fruit (F), decoction (d), maceration (m), infusion (i), Democratic Republic of Congo (D.R.Congo); a : including other indications; b : specific study on this indication.

Figure 4 .

 4 Figure 4. Structure of steroids and saponins isolated from African Nauclea species.

Figure 5 .

 5 Figure 5. Structure of nicotinate and terpenoid derivatives isolated from African Nauclea species.

Figure 6 .

 6 Figure 6. Structure of simple β-carbolines isolated from African Nauclea species.

Figure 7 .

 7 Figure 7. Structure of nauclefine-based indolo[2,3-a]quinolizidine derivatives isolated from African Nauclea species.

Figure 8 .

 8 Figure 8. Structure of strictosamide-based indolo[2,3-a]quinolizidine derivatives isolated from African Nauclea species.

Figure 9 .

 9 Figure 9. Structure of other indolo[2,3-a]quinolizidine derivatives isolated from African Nauclea species.

Figure 10 .

 10 Figure 10. Structure of indolo[2,3-a]pyrido[1,2-a]azepine derivatives isolated from African Nauclea species.

Figure 11 .

 11 Figure 11. Structure of other indole-based derivatives isolated from the genus Nauclea.

Figure 12 .

 12 Figure 12. Structure of tramadol, isolated from the roots of N. latifolia.

Figure 13 .

 13 Figure 13. Structure of phenolic coumponds isolated from African Nauclea species.

  Bark (B), Stem Bark (SB), Root (R), Root Bark (RB), Stem (S), Leaf (L), Fruit (F), Aq (Aqueous), m (maceration), d (decoction).

  genus Nauclea has been used in sub-Saharan Africa since decades in traditional medicine, and is still a center of interest for researchers and local populations, as witnessed by the number of articlesmore than fiftypublished in the last two years on the topic. The Nauclea genus has become even more popular since our recent reports regarding the occurrence of the analgesic tramadol in the roots of Nauclea latifolia. Thus, the consequent amount of bibliographical data clearly needs a compilation and critical analysis because publications are often poorly indexed in databases, their accesses are frequently difficult and numerous papers are not written in English. African Nauclea species are still indicated today in sub-Saharan countries for a very wide range of pathologies among which infections, digestive ailments, pain and metabolic diseases are the most frequently cited, and including regionally specific illnesses such as malaria. N. latifolia, and in a lesser extend N. diderrichii and N. pobeguinii, have been heavily reported and constitute major remedies in some areas. However, very little is known to date about the traditional use of N. nyasica, N. gilletii, N. vandergutchii and N. xanthoxylon in relation to the low abundance of these species. Many of pharmacological evaluations of Nauclea extracts were conducted on different targets clearly overlapping local indications. An important part of these studies are of insufficient quality as they revealed a lack of internal control, standardization and literature comparison as well as low number of samples. Beside

  ..3 3a. Stipules deltoid or short, obtuse, subpersistent. Placenta attached to the middle of the septum, somewhat discoidal, ovules spreading in all directions ..........................................4 b. Stipules ovate, elliptic, or obovate, deciduous or subpersistent. Placenta attached to the upper third of the septum, y-shaped, ovules spreading in all directions but predominantly pendulous .............................................................................................................................5 4-

a. Seeds pitted, ellipsoid non margined; leaves coriaceous, obtuse at base, petiole short, 1 to 2 cm long ......................................................................................... Nauclea latifolia Smith [ syn. Sarcocephalus latifolius (Sm.) E.A.Bruce, Nauclea sambucina T.Winterb., Sarcocephalus esculentus Afzel. ex Sabine, Cephalina esculenta (Afzel. ex Sabine) Schumach. & Thonn., Sarcocephalus russeggeri Kotschy ex Schweinf., Sarcocephalus sambucinus K.Schum., Nauclea esculenta (Afzel. ex Sabine) Merr., Sarcocephalus esculentus var. amarissima A.Chev., Sarcocephalus esculentus var. velutina A.Chev. ] Distribution: W. Trop. Africa to Ethiopia and NW. Angola.

Table

.

  Non-medical ethnobotanical uses of the genus Nauclea in sub-Saharan Africa

		S	Crafts and energy wood	Siribina et al., 2014
	N. latifolia	S	Lumber and energy wood	Adeniyi, 2015
		F	Food for human, source of ascorbic acid	Ambé, 2001a; Ambé and Malaisse, 2001b
	N. pobeguinii	F	Food for gorillas	Breuer, 2003
	N. vanderguchtii	S	Timber and furniture	Obute and Ekiye, 2008
	N. xanthoxylon	W	Lumber and energy wood	Dossou et al., 2012
	Bark (B), Stem (S), Fruit (F), Seed (Sd), Wood (W).
	Species	Plant parts	Uses	Reference
	N. diderrichii	W	Timber for building	Towns, 2014a
		B	Aphrodisiac	Towns, 2014a
		B	Bitter agent in place of hob for local beer fabrication	Desobgo et al., 2013
		Sd	Ground detoxification properties	Omorogie et al., 2012

Table 2 .

 2 Anti-malarial uses of African Nauclea species

	Species	Plant part (extraction mode)	Country	Region	% of citation	Administration mode (Dose)	Reference
	N. diderrichii	B (d)	Benin	Plateau of Allada	52%		Yetein et al., 2013
	N. diderrichii		Cameroo n	Dja Biosphere Reserve			Betti, 2004
	N. diderrichii	B, R, F	Cameroo n	Mount Cameroon			Ndenecho, 2009
	N. diderrichii		Ivory Coast	Tanoé-Ehy Forest			Zadou et al., 2011
	N. diderrichii	R, SB, F	Nigeria				Chukwuma, 2015
	N. diderrichii	SB (d)	Nigeria	South Nigeria	9%		Iyamah and Idu, 2015
	N. diderrichii			Congo basin forests			Eto, 2013
	N. latifolia R, S	Burkina Faso				Kristensen and Balslev 2003
	N. latifolia R, L (d, m)	Burkina Faso	Baskoure, Kourittenga Province	12%		Nadembega et al., 2011
	N. latifolia SB, R (d)	Cameroo n	Yaoundé & Mbalmayo			Tsabang et al., 2012
	N. latifolia R (d)	D.R. Congo	All regions	19%		Lusakibanza Manzo, 2012
				Accra, Central,
	N. latifolia S (m)	Ghana	Eastern & Ashanti	9%		Asase and Oppong-Mensah, 2009
				Regions
				Wechiau
	N. latifolia	R (m), L (d)	Ghana	Community Hippopotamus			Asase et al., 2005
				Sanctuary area
	N. latifolia R (d)	Ghana	Dangme West District	21%		Asase et al., 2010
	N. latifolia RB (i)	Ghana	North West			Asase and Oteng-Yeboah, 2012
	N. latifolia		Ghana				Osei-Djarbeng et al., 2015
	N. latifolia	L, SB, RB (d)	Guinea	All regions	12%		Traore et al., 2013
	N. latifolia R	Guinea	Fuuta Jallon area			Kamsu-Foguem et al., 2013

Table 5 .

 5 Anti-helminthic uses of African Nauclea species

	Species	Plant part (extraction mode)	Country	Region	% of citation	Administration mode (Dose)	Reference
	N. diderrichii	SB (d)	D.R. Congo	Equateur Province	nd	Enema (half a glass intake twice daily), oral	Mbuta et al., 2012
	N. latifolia	R, B (directly consumed, m, d)	Angola	Uige	Most cited plant a	Enema or oral intake	Göhre et al., 2016
	N. latifolia	R (d)	Congo	Brazzaville	11% a	nd	Ahombo et al., 2012

Table 3 .

 3 Anti-viral uses of African Nauclea species

	Traditional use	Species	Plant part (extraction mode)	Country	Region	% of citation	Administration mode (Dose)	Reference
	Jaundice	N. diderrichii	W (d)	Gabon	Ipassa Biosphere Reserve	1%	Oral intake, enema	Betti et al., 2013
		N. latifolia	L, R (i)	Nigeria	All regions	nd	nd	Gbile and Adesina, 1987

Table 4 .

 4 Anti-microbial uses of African Nauclea species

	Traditional use	Species	Plant part (extraction mode)	Country	Region	% of citation	Administration mode (Dose)	Reference
	General antimicrobial use	N. latifolia SB (m)	Guinea	All regions 0.2%	Oral intake	Magassouba et al., 2007
		N. latifolia	L (d), F (m), B (d), R (m)	Mali	All regions nd	nd	Badiaga, 2011
							Oral intake (m in
		N. latifolia R (m)	Uganda	Bulamogi	nd	beer made from Musa × paradisiaca	Tabuti et al., 2003
							L. var. sapientum)
		N. latifolia		Nigeria	SW	nd	nd	Lawal et al. 2010
		N. latifolia R, L	Burkina faso	Malon village	nd	nd	Sourabié et al. 2013
		N. pobeguinii	SB (m)	Guinea	All regions 0.5%	Oral intake	Magassouba et al., 2007

Bark (B), Stem Bark (SB), Root (R), Root Bark (RB), Stem (S), Leaves (L), Fruit (F), decoction (d), maceration (m), Democratic Republic of Congo (D.R.Congo); a : including other indications; FL (%) =

Table 6 .

 6 Uses of African Nauclea species as digestive disorders treatment

	Traditional use	Species	Plant part (extraction mode)	Country	Region	% of citation	Administration mode (Dose)	Reference
	Dental and oral care	N. diderrichii	B, R, F	Cameroon	Mount Cameroon	nd	nd	Ndenecho, 2009
		N. latifolia S	Nigeria	Ekiti state	nd	Chewing stick	Kayode and Omotoyinbo, 2008
	Digestive ailments	N. latifolia		Nigeria	Kaduna state	nd	nd	Mathias et al., 2013
	Facilitate Digestion	N. latifolia F (eating)	Cameroon	Sudano-sahelian	low	nd	Jiofack et al., 2010
		N. diderrichii	B (d)	Nigeria	Niger delta	nd	Enema	Ubom, 2010
		N. diderrichii			Congo basin forests	nd	nd	Eto, 2013
	Emetic	N. latifolia	Inner B, S, sap, R, F, RB	Nigeria	Lagos state	nd	nd	Olowokudejo et al., 2008
	Stomach problems	N. diderrichii	B, R, S		Central Africa nd	nd	Eyong, 2007
		N. diderrichii	B, R, F	Cameroon	Mount Cameroon	nd	nd	Ndenecho, 2009
					Mbembe
		N. latifolia F, B, R	Cameroon	Forest	nd	nd	Sainge et al., 2014
					Reserve
		N. latifolia	Inner B, S, sap, R, F, RB	Nigeria	Lagos state	nd	nd	Olowokudejo et al., 2008
		N. latifolia		Ghana	Northern	nd	Oral intake or bath	Insoll, 2011
		N. latifolia L (i)	Burkina Faso	Western	nd	nd	Taïta, 2003

Bark (B), Stem Bark (SB), Root (R), Root Bark (RB), Stem (S), Leaves (L), Fruit (F), decoction (d), maceration (m); a : including other indications.

Table 7 .

 7 Uses of African Nauclea species as analgesic

	Traditional use	Species	Plant part mode) (extraction	Country	Region	% of citation	Administration mode (Dose)	Reference
	Toothache	N. diderrichii B, R, F	Cameroon	Mount Cameroon	nd	nd	Ndenecho, 2009
	Headache	N. diderrichii B, R, F	Cameroon	Mount Cameroon	nd	nd	Ndenecho, 2009
						nd	Bath or oral
		N. latifolia	L (d)	Mali	All regions		intake (1 glass thrice or 4	Badiaga, 2011
							times daily)
		N. latifolia		Gabon	Haut-Ogooué Province	nd	nd	Lekana-Douki et al., 2011
	Abdominal-					nd	nd
	/ stomach-	N. latifolia	B	Nigeria	Bauchi State			Adamu et al., 2005
	ache
		N. latifolia		Gabon	Haut-Ogooué Province	nd	nd	Lekana-Douki et al., 2011
		N. latifolia	R, L	Burkina Faso	Baskoure, Kourittenga Province	3% a	nd	Nadembega et al., 2011
						nd	Oral intake (1
		N. latifolia	B (d, m), R (d, m)	Mali	All regions		glass twice or thrice daily) or	Badiaga, 2011
							emena
		N. latifolia	R (d)	D.R. Congo	All regions	19% a	nd	Lusakibanza Manzo, 2012
		N. latifolia	L, R (i)	Senegal	Kédougou	2% a	nd	Gning et al., 2014
						Most	Oral intake or
		N. latifolia	R (m, d)	Angola	Uige	cited	emena	Göhre et al., 2016
						plant a
		N. latifolia	R	Gambia		nd	nd	Madge, 1998
		N. latifolia	R, F, L	Burkina Faso		0.7%	nd	Kristensen and Balslev, 2003
		N. pobeguinii SB (d)	D.R. Congo	District of Sankuru	nd	nd	Mesia et al., 2005
	Backache	N. latifolia	R, F (i)	Uganda	Bulamogi	nd	nd	Tabuti et al., 2003
		N. latifolia	R	D.R. Congo	Kinshasa city	medium	nd	Ngbolua et al., 2016

a : including other indications.

Table 8 .

 8 Uses of African Nauclea species as antipyretic

	Species	Plant part (extraction mode)	Country	Region	% of citation	Administration mode (Dose)	Reference
	N. diderrichii		Cameroon	Dja Biosphere Reserve	nd	nd	Betti, 2004
	N. diderrichii	B, R, S		Central Africa	nd	nd	Eyong, 2007
	N. diderrichii			Congo basin forests	nd	nd	Eto, 2013
	N. latifolia	Inner B, S, sap, R, F, RB	Nigeria	Lagos state	nd	nd	Olowokudejo et al., 2008
	N. latifolia	L (d)	Nigeria	Tivland	2%	nd	Igoli et al., 2011
	N. latifolia	L	Nigeria	Igede People	nd	nd	Igoli et al., 2005
	N. latifolia	R, B	Gambia		nd	nd	Madge, 1998

Table 9 .

 9 Uses of African Nauclea species as respiratory diseases treatment

	Traditional use	Species	Plant part (extraction mode)	Country	Region	% of citation	Administration mode (Dose)	Reference
	General use	N. latifolia Seeds	D.R. Congo	All regions	nd	Fumigation (twice daily)	Disengomoka et al., 1983
		N. latifolia B	Angola	Uige	Most cited plant a	Directly consumed	Göhre et al., 2016
	Cough	N. diderrichii	B, R, F	Cameroon	Mount Cameroon	nd	nd	Ndenecho, 2009
		N. latifolia	Inner B, S, sap, R, F, RB	Nigeria	Lagos state	nd	nd	Olowokudejo et al., 2008
		N. latifolia Inner B	Sierra-Leone	Kpaa Mende	nd	nd	Lebbie and Guries, 1995
	Asthma	N. latifolia	multiplant combination (m)	Nigeria	Western	nd	Oral intake (1 glass daily)	Fatokun et al., 2016
	Bark (B), Root (R), Root Bark (RB), Stem (S), Fruit (F), Democratic Republic of Congo (D.R.
	Congo);

a : including other indications.

Table 10 .

 10 Uses of African Nauclea species as metabolic and cardio-vascular disorders treatment

	Traditional use	Species	Plant part (extraction mode)	Country	Region	% of citation	Administration mode (Dose)	Reference
	Anti-diabetic	N. diderrichii		Benin		1%	nd	Laleye et al., 2015
					Coastal		Oral intake (2
		N. diderrichii	B (d)	Cameroon	rain	nd	glasses thrice	Nole et al., 2016
					forest		daily)
					Cotonou,
		N. latifolia	R	Benin	Abomey-	0.5%	nd	Fah et al., 2013
					Calavi
		N. latifolia	R (d)	Congo		nd	nd	Muziazia et al., 2015
		N. latifolia	R	Congo	Kinshasa city	medium	Oral intake (2 glasses daily)	Ngbolua et al., 2016
		N. latifolia	SB (d)	Ivory Cost	Agbovill e	nd	Oral intake	N'Guessan et al., 2009

Bark (B), Stem Bark (SB), Root (R), Stem (S), Leaves (L), Fruit (F), decoction (d); a : percentage of users; b : including other indications; c : specific study on cardiovascular diseases.

Table 11 .

 11 Uses of African Nauclea species as reproduction and sexual dysfunctions treatment

	Traditional use	Species	Plant part (extraction mode)	Country	Region	% of citati on	Administration mode (Dose)	Reference
	Sexual asthenia	N. diderrichii B (d)	Cameroon	Coastal rain forest	nd	Oral intake (2 daily) glasses thrice	Nole et al., 2016
		N. diderrichii B, W	Gabon	Mont Bouët and Ngouema	nd	nd	Towns, 2014a
		N. pobeguinii SB (d, m)	D.R. Congo		nd	nd	Mesia et al.,
		N. pobeguinii SB (d, m)	D.R. Congo All regions	nd	nd	Lusakibanza Manzo, 2012
	Premature ejaculation	N. latifolia	R (i)	Uganda	Bulamogi	nd	nd	Tabuti et al., 2003
	Male sexual dysfunction	N. diderrichii L (t)	Gabon	Ipassa Reserve Biosphere	nd	Oral intake	Betti et al., 2013
		N. latifolia	RB (alcohol)	Ethiopia and Nigeria	Ethiope West of Nigeria and Delta state	nd	Oral intake (4-twice daily) 5 tablespoon	Fasola et al.
			R (directly			Most
		N. latifolia	consumed	Angola	Uige	cited	Oral or enema	Göhre et al.,
			or d)			plant a

Table 12 .

 12 Uses of African Nauclea species as skin disorders treatment

	Traditional use	Species	Plant part (extraction mode)	Country	Region	% of citation	Administration mode (Dose)	Reference
	Skin disease	N. diderrichii B, R, F	Cameroon	Mount Cameroon	nd	nd	Ndenecho, 2009
		N. diderrichii L	Nigeria	Keffi	29% a	nd	Mustapha et al., 2013
		N. latifolia	S	Nigeria	Ekiti state FL = 88	nd	Kayode et al., 2015
							Oral intake (1
		N. latifolia	R (d)	Nigeria	Rivers state	FL = 65	glass thrice daily for 5	Ajibesin, 2012b
							days)
	Itching	N. latifolia	R (d)	Nigeria	Benue state	nd	Bath (twice daily for 2 days)	Shomkegh et al., 2016
	Itching & filariasis	N. latifolia	L, R	Nigeria	Kogi state nd	nd	Aniama et al., 2016
							Oral intake in
							combination
	Infantile dermatosis	N. latifolia	R (d)	Nigeria	Odeda	3% a	with other plants (2-3	Erinoso et al. 2016
							teaspoon thrice
							daily)

Table 13 .

 13 Miscellaneous ethnopharmacological uses of African Nauclea species

	Traditional use Species	Plant part (extraction mode)	Country	Region	% of citation	Administration mode (Dose)	Reference
		Ophthalmic
	Improve sight N. latifolia	Sap	Sierra-Leone		nd	Ocular (drop sap in the affected eye	Kanteh and Norman, 2015
	Eye troubles	N. latifolia	Sap	Sierra-Leone	Kpaa Mende	nd	nd	Lebbie and Guries, 1995
	Conjunctivitis N. latifolia	L (d)	Ivory Coast	Abidjan	3% a	Ocular	Adiko et al., 2014
		Infant illness
	Swollen spots on the head	N. latifolia	L (m)	Ethiopia	Mandura Woreda	nd	Oral intake (1 glass)	Mengesha, 2016
	Thin children N. latifolia	F	Gambia		nd	nd	Madge, 1998
		N. latifolia	R	Burkina Faso		0.1%	nd	Kristensen and Balslev, 2003
		Others indications
	For good health	N. latifolia	R, L	Burkina Faso		0.1%	nd	Kristensen and Balslev, 2003
	Rheumatism	N. latifolia	R	Gambia		nd	nd	Madge, 1998
	Fractured bones	Nauclea sp.	L	C.A.R.		nd	nd	Thomas, 1959
	SNC injuries	N. latifolia	L (d, bath) Togo	All regions	19% b	nd	Kantati et al., 2016

Bark (B), Stem Bark (SB), Root (R), Leaves (L), Fruit (F), decoction (d), maceration (m), Central African Republic (C.A.R.); a : specific study on this indication; b : including other indications.

  have been measured, and the compound could thus occupy a key place in the pharmacological properties of traditional preparations. Close analogues were also reported from

	Nauclea species: 21-O-methylstrictosamide, 21-O-ethylstrictosamide (N. latifolia; Abreu and
	Pereira, 2001b), 10-hydroxystrictosamide, naucleamide C (N. latifolia; Shigemori et al., 2003)

and 3α,5α-tetrahydrodeoxycordifoline lactam (N. pobeguinii and N. diderrichii;

[START_REF] Lamidi | Gluco-indole alkaloids from the bark of Nauclea diderrichii. 1 H and 13 C NMR assignments of 3a-5a-tetrahydrodeoxycordifoline lactam and cadambine acid[END_REF][START_REF] Xu | Chromatographic profiling and identification of two new iridoid-indole alkaloids by UPLC-MS and HPLC-SPE-NMR analysis of an antimalarial extract from Nauclea pobeguinii[END_REF]

. Several 16,17-dihydro derivatives were discovered, such as naucleofficine D (N. pobeguinii;

Xu et al., 2012), latifoliamides B and C (N. latifolia;[START_REF] Agomuoh | Novel indole alkaloids from Nauclea latifolia and their renin-inhibitory activities[END_REF]

, or nauclefolinine (N. latifolia;

[START_REF] Ngnokam | Nauclefolinine: a new alkaloid from the roots of Nauclea latifolia[END_REF]

, and a pyridine glucosyl analogue was identified as naucleamide F (N. latifolia;

[START_REF] Kakuguchi | Naucleamide F, a new monoterpene indole alkaloid from Nauclea latifolia[END_REF][START_REF] Ata | Chemical constituents of Nauclea latifolia and their anti-GST and anti-fungal activities[END_REF]

.

Finally, four compounds are carbonyl or carboxyl derivatives of strictosamide: naucleidinal (N. latifolia and N. pobeguinii;

[START_REF] Hotellier | Naucleidinal and epinaucleidinal, alkaloids of Nauclea latifolia[END_REF] Abreu and Pereira, 2001b; Xu et al., 2012), 19-epi-naucleidinal (N. latifolia;[START_REF] Hotellier | Naucleidinal and epinaucleidinal, alkaloids of Nauclea latifolia[END_REF] Abreu and Pereira, 2001b)

, naucleidinic acid and magniflorine (N. pobeguinii;

[START_REF] Xu | Chromatographic profiling and identification of two new iridoid-indole alkaloids by UPLC-MS and HPLC-SPE-NMR analysis of an antimalarial extract from Nauclea pobeguinii[END_REF]

.

Table 14 .

 14 Reported antiparasite activities of African Nauclea species.

	Properties	Species	Plant parts	Extracts	Reference
	Anti-plasmodial	N. latifolia	S, R	Aq (m, d)	Benoit-Vical et al., 1998
		N. latifolia	SB	EtOH (d)	Zirihi et al., 2005
		N. latifolia	SB	MeOH (m)	Udobre et al., 2013a
		N. latifolia	L	MeOH (m)	Udobre et al., 2013b
		N. latifolia	L	Aq (d)	Dibua et al., 2013
		N. latifolia	R	EtOH : H2O (70 : 30) (m)	Adebajo et al., 2014
		N. latifolia	L	EtOH : H2O (70 : 30) (m)	Ettebong et al., 2014
		N. latifolia	L	Aq (d)	Onyesom et al., 2015
		N. pobeguinii	SB	MeOH : H2O (80 : 20) (m)	Mesia et al., 2005; 2010; 2012a; 2012b
		N. pobeguinii	SB	EtOH : H2O (80 : 20)	Pieters, 2008
	Anti-helminthic	N. latifolia	L	Aq	Asuzu and Njoku, 1996
		N. latifolia	L	MeOH : H2O (50 : 50) (m)	Fakae et al., 2000
		N. latifolia	L	Aq (d), EtOH (d)	Ademola et al., 2006
		N. latifolia	SB	Aq (d)	Onyeyili et al., 2001
		N. latifolia	SB	Aq (d and m), EtOH	Wabo Poné et al., 2012
	Anti-leishmanial	N. latifolia	SB	CH2Cl2 (m)	Ahua et al., 2007
	Trypanocidal	N. latifolia	RB	EtOH : H2O (70 : 30) (d)	Madubunyi, 1996
	No trypanocidal effect	N. latifolia	SB, L MeOH (m)	Olanrewaju et al., 2014
	Anti-amoebic	N. latifolia	RB	n-BuOH (soluble fraction)	Tona et al., 2000; 2009
	Bark (B), Stem Bark (SB), Root (R), Root Bark (RB), Stem (S), Leaf (L), Aq (Aqueous), m
	(maceration), d (decoction).

Table 15 .

 15 Reported antimicrobial activities of African Nauclea species.

	Plant parts	Extract	S. aureus	S. pneumoniae	B. cereus	S. dysentariae	B. subtilis	S. varidans	S. sonneri	E. coli	K. pneumonia	P. aeruginosa	S. parathypi	S.flexneri	S. typhi	Salmonella sp	A. niger	C. albicans	P. notatum	References
												N. latifolia
		Alkanes	-	-	+	+/-				-	-	-		-	-			-		Anowi et al., 2012a; 2012b ;
	Stem
	Bark

Table 16 .

 16 Reported miscellaneous anti-infective activities of African Nauclea species.

	Properties	Species	Plant parts	Extracts	Reference
	Molluscicidal	N. latifolia	B	MeOH (m), Aq, (m)	Kela et al., 1989a; 1989b
	Anti-viral	N. latifolia	RB	MeOH : CH2Cl2 (50 : 50) (m)	Donalisio et al., 2013

Table 17 .

 17 Reported digestive activities of African Nauclea species.

	Properties	Species	Plant parts	Extracts	Reference
	Anti-diarrheic	N. latifolia	RB	EtOH : H2O (70 : 30) (m)	Owolabi et al., 2010
	Anti-ulcer	N. latifolia	L	Aq (i)	Balogun et al., 2013; 2014
		N. latifolia	SB	MeOH : H2O (50 : 50) (d)	Alaribe et al., 2014
		N. latifolia	L	MeOH (d)	Balogun et al., 2015
	No anti-ulcer effect	N. latifolia	L	MeOH : H2O (50 : 50) (m) Orole et al., 2013

Table 18 .

 18 Reported neuropharmacological activities of African Nauclea species.

	Properties	Species	Plant parts	Extracts	Reference
	Analgesic	N. latifolia	AP	EtOH : H2O (m), Aq (m)	Okiemy-Andissa et al., 2004
		N. latifolia	SB	MeOH	Otimenyin and Uguru, 2007
		N. latifolia	RB	Aq (m)	Abbah et al., 2010
		N. latifolia	R, L, B	Alk	Badiaga, 2011
		N. latifolia	R	Aq (m)	Taïwe et al., 2011

Table 19 .

 19 Reported activities on metabolic disorders of African Nauclea species.

	Properties	Species	Plant parts	Extracts	Reference
	Anti-hypertensive	N. latifolia	L	MeOH	Udoh and Lot, 1998
		N. latifolia	L, R	EtOH (d)	Akpanabiatu et al., 2005a
		N. latifolia	R	EtOH (d), EtOH : H2O (70 : 30) (d)	Nworgu et al., 2008; Nworgu et al., 2009
		N. latifolia	RB, SB	EtOH : H2O (80 : 20) (m)	Odey et al., 2012a
	Anti-diabetic	N. latifolia	L	Aq (m), EtOH (m)	Gidado et al., 2005; 2008
		N. latifolia	L	Aq (d)	Iwueke and Nwodo, 2008
		N. latifolia	L	EtOH (m)	Gigado et al., 2009; 2012; Effiong, 2013a
		N. latifolia	R, S	EtOH (m)	Yessoufou et al., 2013
		N. latifolia	L	EtOH : H2O (50 : 50) (m)	Antia and Okokon, 2014
		N. pobeguinii	B	Aq (d)	Agnaniet et al., 2016
		N. diderrichii	L, B	Aq (m)	Agnaniet et al., 2016
		N. diderrichii	SB	MeOH (m)	Ogbole et al., 2016
	Lipid metabolism	N. latifolia	L	EtOH (d)	Akpanabiatu et al., 2005a
		N. latifolia	L	EtOH (m)	Edet et al., 2011
		N. latifolia	F	MeOH (m)	James and Ugbede, 2011
		N. latifolia	S	Aq (m)	Arise et al., 2012
		N. latifolia	RB, SB	EtOH : H2O (80 : 20) (d)	Odey et al., 2012b
		N. latifolia	L	MeOH	Chinedu et al., 2013
		N. latifolia	R	Aq (d)	Effah, 2014
	Hormonal activity	N. latifolia	R	Aq (i)	Rukundo, 2007, Ishimwe, 2008
		N. latifolia	R	EtOH, MeOH	Nworgu et al., 2010, Njamen et al., 2008
	Bark (B), Stem Bark (SB), Root (R), Root Bark (RB), Stem (S), Leaf (L), Fruit (F), Aq (Aqueous), m
	(maceration), d (decoction), i (infusion).

Table 20 .

 20 Reported anti-inflammatory and anti-pyretic activities of African Nauclea species.

	Species	Plant parts	Extracts	Reference
	N. latifolia	SB	MeOH	Otimenyin and Uguru, 2007
	N. latifolia	L, R	MeOH : H2O (50 : 50) (m)	Amouzoun et al., 2008
	N. latifolia	L, SB	MeOH	Osadebe et al., 2010
	N. latifolia	RB	Aq (m)	Abbah et al., 2010
	N. latifolia	R	Aq (m)	Taïwe et al., 2011

Table 21 .

 21 Reported hepatoprotective activities of African Nauclea species.

	Species	Plant parts	Extracts	Reference
	N. pobeguinii	B, L	MeOH (m)	Kuete et al., 2015
	N. latifolia	RB	EtOH : H2O (70 : 30) (d)	Madubunyi, 1996
	N. latifolia	RB	MeOH	Udeh and Madubunyi, 2008
	N. latifolia	RB	Aq (d)	Yesufu et al., 2010
	N. latifolia	L	EtOH (m)	Effiong et al., 2013b; 2014
	N. latifolia	L	MeOH (m)	Nwaehujor et al., 2016
	N. pobeguinii	L	Aq (d)	Kadiri et al., 2007
	N. latifolia	L	EtOH (d)	Akpanabiatu et al., 2005b

Bark (B), Stem Bark (SB), Root (R), Root Bark (RB), Stem (S), Leaf (L), Fruit (F), Aq (Aqueous), m (maceration), d (decoction).

Table 22 .

 22 Reported miscellaneous activities of African Nauclea species.

	Properties	Species	Plant parts	Extracts	Reference
	Antioxidant	N. latifolia	R	Aq (d)	Iwueke et al., 2010
		N. latifolia	R	MeOH (m)	Awah et al., 2012
		N. latifolia	R, S	EtOH (m)	Yessoufou et al., 2013
		N. latifolia	L	MeOH	Chinedu et al., 2013
		N. latifolia	L	EtOH (m)	Effiong et al., 2013b
		N. latifolia	L, F	Aq (d)	Ayeleso et al., 2014
		N. latifolia	L	Aq (d)	Onyesom et al., 2015
		N. latifolia	L	EtOH	Edagha , 2015
		N. latifolia	L	MeOH (m)	Nwaehujor et al., 2016
	Wound healing	N. latifolia	SB	MeOH (m)	Udobre et al., 2012
	Immunomodulation	N. latifolia	R, S	EtOH (m)	Yessoufou et al., 2013
	Anti-proliferative	N. pobeguinii	B, L	MeOH (m)	Kuete et al., 2015

Table 22 .

 22 Reported toxic activities of African Nauclea species.

	Species	Plant parts	Extracts	Reference
	N. diderrichii	SB	MeOH : H2O (80 : 80) (m)	Liu et al., 2011
	N. diderrichii	SB	MeOH (m)	Ogbole et al., 2016
	N. latifolia	SB	EtOH : H2O	Gueye-Sanokho et al., 1993
	N. latifolia	nd	CHCl3	Traore et al., 2000
	N. latifolia	L	EtOH (d)	Akpanabiatu et al., 2005b
	N. latifolia	SB	MeOH	Otimenyin and Uguru, 2007
	N. latifolia	SB	MeOH : H2O (80 : 80) (m)	Liu et al., 2011
	N. latifolia	S	Aq (m)	Arise et al., 2012
	N. latifolia	L	MeOH (m)	Akinloye and Olaniyi, 2012
	N. latifolia	SB	Aq (m)	Kouadio et al., 2014
	N. latifolia	L	EtOH : H2O (70 : 30) (d)	Solomon et al., 2014a; 2014b
	N. latifolia	L	Aq (d)	Magili et al., 2014
	N. latifolia	RB, L	MeOH (d)	Oise et al., 2014
	N. latifolia	SB, RB, L, F	EtOH : H2O (70 : 30) (m)	Ogenyi et al., 2015
	N. pobeguinii	SB	MeOH : H2O (80 : 20) (m)	Mesia et al., 2005; 2010
	N. pobeguinii	SB	MeOH : H2O (80 : 80) (m)	Liu et al., 2011

Acknowledgments

We are grateful to ANR (Agence Nationale pour la Recherche) for financial support (Labex Arcane ANR-11-LABX-0003-01 and ANR project NAUTRAM ANR-16-CE20-0005-02).