{"paper_id":"2a463b94-d5dc-4874-ab2f-4717c1e53e3c","body_text":"Phylogeny, ethnomedicinal use and the distribution \nof phytoestrogens in the Fabaceae  \n \nKongkidakorn Thaweepanyaporna,*, Jamie B. Thompsona, Nandini Vasudevana, Julie A. \nHawkinsa,** \naSchool of Biological Sciences, University of Reading, Whiteknights, Reading RG6 6BX, UK \n \nAbstract \nAim of the study  \nEthnomedicinal knowledge is a critical resource for drug discovery, and when combined with \nphylogenetic analysis, it increases the precision of bioprospecting. Phytoestrogens, compounds \nfrom plants with estrogenic activity, are commonly found across the Fabaceae family and hold \nthe potential for managing menopause-related symptoms. This study focuses on methods to \nidentify novel sources of phytoestrogens from the Fabaceae. \nMaterials and Methods \nWe identified 183 Fabaceae species traditionally used as aphrodisiacs or with application to \ncontrol fertility to create a cross-cultural dataset of ethnomedicinal use. Phylogenetic analysis \nrevealed \"hot nodes\"—lineages with a higher-than-expected number of species with these traits. \nThe known distribution of estrogenic flavonoids was used to test whether the frequency of \nphytoestrogen-containing species was higher in “hot nodes”. Additionally, we examined the \noverlap of aphrodisiac-fertility uses with neurological applications, hypothesising that such \nspecies may have bioactive compounds with estrogenic properties. Lastly, the “hot-node” \nlineages without previously known estrogenic flavonoids were identified. \nResults \nSpecies in hot nodes were more likely to contain estrogenic flavonoids (21% of species), a \nmajor group of phytoestrogens, compared to Fabaceae as a whole (7% of species). Moreover, \naphrodisiac-fertility species with neurological applications showed even higher search efficiency, \nwith 62% of such species confirmed to contain estrogenic flavonoids. Furthermore, we identified \n43 high-priority hot nodes including several notable genera such as Delonix and Indigofera. \nThese lineages might represent promising targets for future studies on phytoestrogens.  \nConclusions \nThe results demonstrated the predictive power of combining phylogenetic and ethnomedicinal \ndata to guide the discovery of novel drugs with therapeutic potential for menopause, fertility, and \nneurological health. \n \nAbbreviations \n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\nAF \nAphrodisiac-fertility \nPEs \nPhytoestrogens \n1. Introduction \nNatural products have been and remain promising candidates for drug discovery \n(Newman & Cragg, 2020). However, whether natural product research is practicable for drug \ndiscovery (Amirkia & Heinrich, 2015), and whether traditional uses in ethnomedicine can guide \nthe discovery of new chemical compounds, remains controversial (Gertsch, 2012; Gurib-Fakim, \n2006; Saslis-Lagoudakis et al., 2011; Skirycz et al., 2016; Sucher, 2013). Verpoorte (1998), \ncited by Verpoorte (2000) and Fabricant & Farnsworth (2001), estimated that 6% of all plant \nspecies had been screened for biological activity, and 15% evaluated phytochemically. More \nrecent global estimates are lacking, but one study suggests as many as 58% of plants used in \nethnomedicine remain uncharacterised (Souza & Hawkins, 2017). Given the size of the \nunscreened species pool, devising strategies to target species for evaluation has become an \narea of research interest (Fabricant & Farnsworth, 2001; Holzmeyer et al., 2020). Of the \ntargeting strategies proposed, ethnobotanically-guided screening has the longest history \n(Fabricant & Farnsworth, 2001). Strategies incorporating phylogenetic or ecological data, or \nexisting phytochemical and pharmacological data are also becoming established (Pellicer et al., \n2018; Saslis-Lagoudakis et al., 2012; Souza et al., 2018). Here we apply phylogenetic methods \nto ethnobotanical use data, exploring whether they can more efficiently target bioactive plant \nnatural products. \nPlant lineages that contain significantly more species with ethnomedicinal use were first \nreferred to as hot nodes for bioprospecting by Saslis-Lagoudakis et al. (2011). Since then, hot \nnodes have been identified for different groups of medicinal plants from other parts of the world, \nand at varying taxonomic levels. At the generic level, hot nodes for potential anti-inflammatory \ncompounds have been described for genus Euphorbia (Ernst et al., 2016), for species of \ninterest to treat malaria in genus Artemisia (Pellicer et al., 2018), and for putative antioxidant \nand antidiabetic bioactivity for genus Allium (Teotia et al., 2024). At a higher taxonomic level, \nhot nodes in the orchid subtribe Coelogyninae that may show antimicrobial properties were \nidentified based on ethnomedicinal uses (Wati et al., 2021). Geographically-focussed studies \nhave examined cross-cultural patterns between Nepal, South Africa and New Zealand (Saslis-\nLagoudakis et al., 2012), whilst others have focussed on the Brazilian Fabaceae (Souza et al., \n2018), the Chinese Lamiaceae (Zaman et al., 2022) of whole medicinal floras (South Africa, \nYessoufou et al., 2015; Ecuador, Atienza-Barthelemy et al., 2025), or pharmacopoeias (China, \nZaman et al, 2021; India, Yao et al., 2023). Global studies include a study of angiosperms to \nidentify hot nodes for psychoactive activity (Halse-Gramkow et al., 2016), for antimalarial \nproperties (Milliken et al., 2021) and cancer treatment (Thompson & Hawkins, 2023). Some of \nthese studies have sought to validate the hot node method, for example, confidence in the hot \nnode method is increased where hot nodes include a higher proportion of plant drugs in clinical \ntrials (Ernst et al., 2016; Pellicer et al., 2018; Souza & Hawkins, 2017), or where there is cross-\ncultural convergence (Saslis-Lagoudakis et al., 2012). At least one study has used a literature \n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\nsearch to show that hot node species have relevant biological activity (Teotia et al., 2024). \nPellicer et al. (2018) screened for artemisinin in fifteen species, finding four of seven species \nfrom hot nodes and five of eight from outside hot nodes contained artemisinin. Their \ninterpretation was that in this case – where a molecule of interest is common throughout the \ngenus - the hot node approach is not effective. Given the increasing application of the hot node \nmethod, further tests of its validity are crucial.   \nPhytoestrogens (PEs) are plant-derived compounds that have similar functions to \nestrogen. By binding at the estrogen receptor, estrogen (estradiol, E2) or PEs can activate \nestrogen-responsive genes, which in turn encode proteins that maintain bone, reproductive \nhealth, cognition, and cardiovascular function, (O'Donnell et al., 2007; West et al., 2009). \nConsuming one common dietary source of PEs, soybean, can offer a range of health benefits \none of which is alleviating the symptoms of menopause (Branca & Lorenzetti, 2005). These \nsymptoms include hot flashes, night sweats, vaginal dryness, mood changes, difficulty sleeping, \nanxiety and decreased libido (Booyens et al., 2022). Several medicinal plant drugs containing \nPEs are also used to reduce hot flashes and night sweats (Hajirahimkhan et al., 2013), vaginal \ndryness (Rosa Lima et al., 2014), and cardiovascular disease (Rossouw et al., 2007). The \nvarying interactions of PEs with estrogen receptors suggest that different PEs may have specific \nfunctions or roles in various tissues (Ceccarelli et al., 2022; Kiyama, 2022). Because PEs can \nhave both therapeutic and cancer risks (Maggiolini et al., 2002; Umehara et al., 2008; Ye & \nShaw, 2019), characterising the diversity of PEs to identify therapeutically optimal molecules is \ndesirable. However, the studies of PEs for postmenopausal symptoms comprise a small number \nof plants. PEs appear to be distributed throughout the Fabaceae, though most plant sources \nremain uncharacterised, suggesting there are molecules yet unknown (Dixon, 2004; Rutz et al., \n2022). Strategies to identify likely sources of novel PEs are therefore needed.  \nHere we propose a strategy for identifying potential sources of therapeutically optimal, \nnovel PEs for estrogen-related symptoms. A lack or excess of phytoestrogens, particularly from \nsoybean-based foods, has been shown to suppress sexual behaviour development in both male \nand female rodents during puberty, suggesting that optimal concentrations of PEs can modulate \nestrogen-driven behaviours (Khan et al., 2008; Kudwa et al., 2007; Sandhu et al., 2020). \nAdditionally, chemically isolated PEs such as genistein and daidzein have been shown to \nproduce an anxiolytic-like effect in mice, indicating their potential role in reducing anxiety-related \nbehaviours (Rodríguez-Landa et al., 2009; Zeng et al., 2010). The effects of PEs on socio-\nsexual behaviour may be mediated through a set of hypothalamic or hypothalamic-linked areas \nin the brain called the social behaviour network (SBN; Newman, 1999), and applications of plant \ndrugs for neurological symptoms might affect in the same regions (O'Donnell et al., 2007; West \net al., 2009). Treatments for menopausal symptoms are very rarely described in ethnobotanical \nliterature, but plants with hormone-modulating properties or those with estrogenic activity may \nbe used as aphrodisiacs or to enhance fertility. Since these applications are directly relevant to \nsexual behaviour and are often well-documented in traditional medicine, we propose that \nexploration of aphrodisiac-fertility (AF) as a therapeutic category in ethnomedicine could \nhighlight high-activity PEs that may act predominantly in the CNS. Additionally, neurological \napplications that regulate CNS activity (Dong & Nao, 2023) may intersect with these therapeutic \nuses, focusing on plants that have specific effects on the CNS. Species with AF use that also \nhave neurological applications could therefore be of particular interest, as candidates for neuro-\nselective estrogens.   \n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\nThe Fabaceae is a large and medicinally important plant family. Widely distributed, the \nfamily comprises approximately 18, 000 species (Lewis, 2005). Fabaceae plants are rich in \nalkaloids, flavonoids, saponins, tannins, glycosides, and other phytochemicals that contribute to \ntheir medicinal properties (Wink, 2013). Several studies show that the family Fabaceae is over-\nrepresented in medicinal floras, indicating that its species are often preferred in traditional \nmedicine (Moerman, 1991; Moutouama & Gaoue, 2024; Saslis-Lagoudakis et al., 2011). The \nimportance of the Fabaceae in traditional medicine is matched by research efforts to \ncharacterise species. Many traditional plants in the Fabaceae family have been studied for their \npharmacological effects. For example, 71% of Fabaceae genera with traditional uses in Brazil \nhave at least one species that has been characterised (Souza et al., 2018). The species \ndiversity, widespread distribution, numerous reported uses (Souza & Hawkins, 2017), \navailability of phylogenetic information (LPWG, 2017), and multiple reports of estrogenic \ncompounds within this family (Kiyama, 2017; Kiyama, 2022) have motivated us to focus on this \nfamily. \nHere we identify species traditionally used for AF purposes and for closely related \napplications to enhance fertility, and that also have neurological applications. We identify hot \nnodes using ethnomedicinal data and validate them by comparing them to the known \ndistribution of PEs. The phylogenetic analyses to harness the predictive value of traditional \nmedicine that we present here highlight poorly characterised but ethnomedicinally important \nlineages that are putative sources of novel PEs.  \n \n2. Methods \n2.1 Data collection \nSpecies-level data for flowering plants used as medicine were gathered from recent and \ncomprehensive systematic reviews for Brazil (Souza et al., 2018), China (Zaman et al., 2021), \nthe Greco-Roman Mediterranean (Leonti et al., 2023), the sub-Saharan region of Africa (Ajao et \nal., 2019) and Thailand (Phumthum et al., 2018).  \nWe compiled a list of aphrodisiac-fertility (AF) species in Fabaceae from these sources \nby using the search terms ‘aphrodisiac’, ‘sexual intercourse’, ‘libido’, ‘fertility’, and ‘sterilisation’. \nAF plants are those that stimulate sexual desire. Aphrodisiac use refers to sexual desire within \nthe psychological category. However, aphrodisiacs have also been used in other categories, \nsuch as fertility, erectile dysfunction, menstrual disorders, and pregnancy, which fall under the \ngenital system and pregnancy categories. For a more extensive search, we included fertility \nproperties in the search terms because sexual desire and fertility are related to each other \n(Berger et al., 2016) and estrogen and PEs affected both of sexual desire and fertility (Najaf \nNajafi & Ghazanfarpour, 2018; Scavello et al., 2019).  \nWhether the species with AF use had other therapeutic uses was recorded from the \noriginal sources and by Google Scholar and PubMed searches. Other uses were classified into \nten therapeutic applications (general, blood, digestive, eye, circulatory, muscular, neurological, \npsychological, respiratory, skin, nutritional, and urinary) according to the ICPC-3 International \nClassification of Primary Care (van Boven & Ten Napel, 2021).  \nThe list of known PEs (Appendix 1), particularly flavonoids, was obtained by referencing \na review on estrogenic flavonoids (Kiyama, 2022). These compounds were then cross-\nreferenced with the LOTUS initiative database (Rutz et al., 2022) using ‘stringdist_left_join’ \n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\nfunction from the ‘fuzzyjoin’ package with a maximum difference of two characters between \nwords in R (Robinson et al., 2020) to extract Angiosperm species containing estrogenic \nflavonoids (Appendix 2). \n2.2 Phylogenetic analysis \nWe utilised a large time-calibrated phylogeny of the rosids comprising nearly 20,000 \nspecies (Sun et al., 2020), and pruned it to retain only the species in Fabaceae from our data \nusing the 'keep.tip' function from the 'ape' package in R (Paradis et al., 2004). The final \nphylogeny included 5,626 (31%)  of approximately 18,000 Fabaceae species and 651 (85%).of \nthe 765  Fabaceae genera  We used this phylogeny, the list of AF species and the list of \nspecies with estrogenic flavonoids in our analyses. \nThe D statistic was calculated as an estimate of the phylogenetic signal of the AF \nspecies. The D statistic was calculated using the 'phylo.d’ function from the 'caper' package in R \n(Fritz & Purvis, 2010). \nThe nodes on the phylogeny of Fabaceae that include significantly more species with AF \napplication, referred to here as \"hot nodes\" (Saslis-Lagoudakis et al., 2012), were identified. We \npredicted the hot nodes for AF use at the species level using the 'hot.nodes' function developed \nby Molina-Venegas et al. (2020). Hot nodes were considered only if they contained fewer than \n100 species, following Halse-Gramkow et al. (2016). \nTo determine whether screening known AF species or species that belong to AF hot \nnodes is an efficient bioprospecting strategy, we calculated the percentage of known estrogenic \nflavonoids that belonged to these groups. We refer to this as “search efficiency” (Souza et al., \n2018). \nWe supposed those AF hot nodes that contained no known estrogenic flavonoids might \nbe the sources of novel estrogenic flavonoids. So, species lists for hot nodes that did not include \nspecies that are known as estrogenic flavonoids were created.  \nThe predicted lineages, hot nodes and the phylogenetic distributions of species \ncontaining estrogenic flavonoids were visualised using the Interactive Tree of Life v5 (Letunic & \nBork, 2021). \n3. Results \n3.1 AF species and species with known estrogenic flavonoid \nAccording to the five sources, 183 species belonging to 64 genera were the source of \nAF medicines. Eight were from Brazil, 122 were from China, seven were from the Graeco-\nRoman Mediterranean, 28 were sub-Saharan and 19 were from Thailand (Supplementary table \n1.) We were able to identify 1317 species that were recorded to produce estrogenic flavonoids, \nshowing approximately 7% of the estimated 18, 000 species of Fabaceae are known to produce \nestrogenic flavonoids (Appendix 3). Fifty-five (30%) of the species used as AFs were known to \nhave estrogenic flavonoids, and these represented 35 genera; we consider screening AF \nspecies to have 30% efficiency (Figure 1).   \n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\nFigure 1. The Comparison of aphrodisiac-fertility species and species that contained \nestrogenic flavonoid. The first column shows the number of species screened, the central \ntable indicates the sample density and the efficiency of the species with known estrogenic \nflavonoids by the number of species screened, and the last column shows the number of \nspecies with known estrogenic flavonoids.  \n \n3.2 Predicting lineages with elevated bioprospecting potential \n Of the 183 AF species, 106 (57%) were included in the phylogeny. The estimated D \nstatistic for these species was 0.70, indicating a weak to moderate phylogenetic signal for the \nAF trait. The 'hot.nodes' function identified 319 hot nodes. Hot nodes are nested, so our \nanalysis identified 43 highest-level hot nodes (Figure 2). These 43 hot nodes comprise 644 \nspecies in 142 genera, of which 139 species were known to contain estrogenic flavonoids (21% \nefficiency; Figure 1) The average number of species in the higher-level hot nodes was 29.86 +/ -\n52.27.  Of the 43 hot nodes, there were 12 that did not include any species known to have \nestrogenic flavonoids according to the LOTUS initiative database; the average number of hot \nnode species known to have estrogenic flavonoids \nwas 11.49 species, with a standard deviation \nof 31.77. \n \n \n- \nn \n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\n \nFigure 2. Phylogenetic distributions of species with aphrodisiac-fertility applications and \nspecies containing estrogenic flavonoids relative to hot nodes for aphrodisiac-fertility \nuse. species with traditional aphrodisiacs (black bars) and species containing estrogenic \nflavonoids (purple bars) are indicated on the phylogeny of Fabaceae plants. Hot node lineages \nfor ‘aphrodisiac-fertility’ (red dots) are identified by the 'hot.nodes' function developed by Molina\n-\nVenegas et al. (Molina-Venegas, Fischer, et al., 2020). \n \n Of the 78 highest-level hot nodes, there were 12 that did not include any species known \nto contain estrogenic flavonoids. Table 1 shows these hot nodes. The number of species in \nthem ranges from two to 25, with two of the smallest hot nodes only including two species and \none node has three species. The first hot node was a sub-family of Dialioideae Legume \nPhylogeny Working Group, and the third cluster contained the genus Delonix Raf. \nThe sixth and \nseventh clusters were in the genera Vachellia Wight & Arn., and the eighth cluster included \nSenegalia Raf. and relatives. The ninth cluster was in the genus Poiretia Sm. The tenth and \neleventh clusters were in the genus Indigofera L., while the last cluster was in the genus \nSesbania Adans.  \n \n \nd \n-\nd \n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\nTable 1 The clusters of hot nodes that include no species recorded as having estrogenic \nflavonoids in the LOTUS initiative database (Rutz et al., 2022). High-level hot nodes were \nnamed by tribe or by most represented genus. If a hot node is repeated in another named node, \nthe descendant node is named alphabetically by the genus appearing first. * Neurological uses \nHigh-level hot \nnodes \nNumber of \nnested \nHot nodes \nSpecies \n1. Dialioideae \nnodes \n4 Apuleia leiocarpa (Vogel) J.F.Macbr., Dialium guineense \nWilld., Dicorynia guianensis Amshoff, Distemonanthus \nbenthamianus Baill., Koompassia excelsa (Becc.) Taub., \nLabichea punctata Benth., Martiodendron parviflorum \n(Amshoff) Köppen, Storckiella australiensis J.H.Ross & \nB.Hyland, Petalostylis labicheoides R.Br., and Zenia insignis \nChun \n2. Clitoria node 1 Chamaecrista acosmifolia (Mart. ex Benth.) H.S.Irwin & \nBarneby, and Clitoria guianensis (Aubl.) Benth. \n3. Delonix nodes 3 Colvillea racemosa Bojer, Delonix boiviniana (Baill.) Capuron, \nD. brachycarpa (R.Vig.) Capuron, D. edulis (H.Perrier) \nBabineau & Bruneau., D. elata (L.) Gamble, D. floribunda \n(Baill.) Capuron, D. pumila Du Puy, Phillipson & R.Rabev., D. \nregia (Bojer ex Hook.) Raf.*, and D. velutina Capuron  \n4. Entada node 1 Entada elephantina (Burch.) S.A.O’Donnell & G.P.Lewis, and \nE. abyssinica Steud. ex A.Rich. \n5. Alantsilodendron \nnode \n1 Alantsilodendron pilosum Villiers,  Dichrostachys spicata \n(F.Muell.) Domin, and Vachellia nilotica (L.) P.J.H.Hurter & \nMabb.  \n6. Vachellia borleae \nnodes \n5 Vachellia borleae (Burtt Davy) Kyal. & Boatwr.,  V. dyeri \n(P.P.Sw. ex Coates Palgr.) Kyal. & Boatwr., V. flava (Forssk.) \nKyal. & Boatwr., V. karroo (Hayne) Banfi & Galasso*,  V. kirkii \n(Oliv.) Kyal. & Boatwr., V. leucophloea (Roxb.) Maslin, Seigler \n& Ebinger, and V. robbertsei (P.P.Sw. ex Coates Palgr.) Kyal. \n& Boatwr. \n7. Vachellia caven \nnodes \n3 Neltuma laevigata (Humb. & Bonpl. ex Willd.) Britton & Rose, \nVachellia caven (Molina) Seigler & Ebinger, V. bravoensis \n(Isely) Seigler & Ebinger, V. etbaica (Schweinf.) Kyal. & \nBoatwr., V. farnesiana (L.) Wight & Arn., and V. schaffneri \n(S.Watson) Seigler & Ebinger.   \n8. Senegalia nodes 7 Acacia pulchella R.Br., A. scleroxyla Tussac, Senegalia burkei \n(Benth.) Kyal. & Boatwr., S. caffra (Thunb.) P.J.H.Hurter & \nMabb., S. dudgeonii (Craib) Kyal. & Boatwr.,  S. erubescens \n(Welw. ex Oliv.) Kyal. & Boatwr., S. ferruginea (DC.) Pedley, \nS. fleckii (Schinz) Boatwr., S. galpinii (Burtt Davy) Seigler & \nEbinger, S. goetzei (Harms) Kyal. & Boatwr., S. hereroensis \n(Engl.) Kyal. & Boatwr., S. laeta (R.Br. ex Benth.) Seigler & \nEbinger, S. macrostachya (Rchb. ex DC.) Kyal. & Boatwr., S. \n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\nmellifera (Vahl) Seigler & Ebinger, S. modesta (Wall.) \nP.J.H.Hurter, S. nigrescens (Oliv.) P.J.H.Hurter,  S.  \npolyacantha (Willd.) Seigler & Ebinger, S. robynsiana (Merxm. \n& A.Schreib.) Kyal. & Boatwr., S. senegal (L.) Britton, S. \nwelwitschii (Oliv.) Kyal. & Boatwr., Parasenegalia muricata \n(L.) Seigler & Ebinger, P. vogeliana (Steud.) Seigler & \nEbinger, Prosopis cineraria (L.) Druce, and Vachellia \nsieberiana (DC.) Kyal. & Boatwr. \n9. Poiretia nodes 1 Poiretia angustifolia Vogel, P. latifolia Vogel, P. punctata \n(Willd.) Desv., and P. tetraphylla (Poir.) Burkart  \n10. Indigofera \namblyantha nodes \n6 Indigofera amblyantha Craib, I. cassioides Rottler ex DC., I. \ncylindracea Graham ex Baker, I. decora Lindl., I. dosua Buch.-\nHam. ex D.Don, I. grandiflora B.H.Choi & S.K.Cho, I. \nhebepetala Benth. ex Baker, I. heterantha Wall. ex Brandis, I. \nhimalayensis Ali, I. kirilowii Palib, I. koreana Ohwi, I. lacei \nCraib, I. nigrescens Kurz ex King & Prain, I. pendula Franch., \nI. thibaudiana DC. and I. venulosa Champ. ex Benth. \n11. Indigofera \nbemarahaensis \nnodes \n5 Indigofera bemarahaensis Du Puy & Labat, I. exellii Torre, I. \nglandulosa J.C.Wendl., I. leucoclada Baker, I. squalida Prain, \nI. prostrata Willd., and I. psoraloides (L.) L.  \n12. Sesbania \nnodes \n4 Sesbania campylocarpa (Domin) N.T.Burb., S. bispinosa \n(Jacq.) W.Wight, S. brachycarpa F.Muell., S. formosa \n(F.Muell.) N.T.Burb., S. grandiflora (L.) Poir., S. microphylla \nHarm., and S. transvaalensis J.B.Gillett \n \n3.2 Neurological applications of AF plants \n There were 18 of the 165 AF species (10.9%) that also had neurological \napplications. Of these 18 species, 13 were found in the hot nodes and of those 13 there were \neight species (62%) that have been shown to contain estrogenic flavonoids. The eight plants \nwere Peltophorum africanum Sond, Senna siamea (Lam.) H.S.Irwin & Barneby, Senna \npetersiana (Bolle) Lock, Mundulea sericea (Willd.) A.Chev., Abrus precatorius L., Glycyrrhiza \nglabra L., Vicia sativa L., and Mimosa pudica L.. In comparison, only 22% of the 165 AF species \nwithout neurological applications found estrogenic flavonoids.  \nThe frequency of other therapeutic applications of the AF medicinal plants is shown in \nFigure 3. 40 AF plants were used to treat ‘general’ disorders, so this was the most common \ncategory of use for AF. The second most common category was ‘digestive’ disorders; the \n‘neurological’ categories were the next most frequently cited, with 19 AF species reported as \nused for disorders in each of these categories.  \n \n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\n \nFigure 3 Therapeutic applications of aphrodisiac-fertility plants of Fabaceae. The ten \ntherapeutic categories follow the ICPC-3 International Classification of Primary Care (van Boven \n& Ten Napel, 2021) \n \n4. Discussion  \n4.1 The efficiency of phylogenetic prediction \nTherapeutic applications in ethnomedicine have been used in screening programmes to \ndiscover new drug leads for many decades (Fabricant & Farnsworth, 2001; Yuan et al., 2016). \nSpecies with aphrodisiac and fertility use appear good candidates for the discovery of novel \nestrogenic flavonoids. A major challenge in drug discovery from plants is the need to select \nstrategically which species to screen, given the impracticality of evaluating all species \n(Verpoorte, 2000). Effective criteria are essential to identify those most likely to yield useful \ncompounds. Optimisation of the screening process could include focusing on ethnomedicinal \nspecies, or plant lineages to which they most frequently belong. This study focused on plants \nwith aphrodisiac and fertility applications in the context of phylogeny to predict lineages with \nestrogenic flavonoids. Even before we incorporated a phylogenetic framework and hot node \nanalysis, we found that 30% of AF species produce estrogenic flavonoids, compared to 7% of \nspecies overall, demonstrating an increased frequency of estrogenic flavonoid-containing \nspecies amongst species with AF applications.  \nOur study reported a D statistic of 0.70, which is a weak to moderate phylogenetic signal \nfor the AF trait (Fritz & Purvis, 2010). However, our community phylogenetic statistics \nhighlighted a pattern of ‘clusters’, since both MPD and MNTP are positive, encouraging us to \nexplore the distribution of estrogenic flavonoids relative to hot nodes for the AF trait. Our finding, \nthat 21% of species in hot nodes have estrogenic flavonoids compared to 7% overall, appears \nto validate the hot node method, even though the D statistic was suggestive of only moderate \npredictive power. The search efficiency of 21% for screening hot node species is lower than the \nsearch efficiency of 30% for direct screening of AF species. However, hot node species \n0\n5\n10\n15\n20\n25\n30\n35\n40\n45\nOther Therapeutic Application in Fabaceae\n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\nrepresent more than three times as many candidates for screening without a correspondingly \nlarge decrease in known estrogenic flavonoids. We propose that, at least in the case of the \nFabaceae, screening hot node species as well as ethnomedicinal species is strategic.  \nIn this study, we show that considering the overlap between a pair of therapeutic \napplications can enhance the effectiveness of phylogenetic search strategies.  The second \napplication we explore here is the application for neurological therapeutic needs. Our data show \nthat when AF applications overlap with neurological uses, these plants are more likely to include \nestrogenic flavonoids, suggesting a potential dual role in both reproductive and neurological \nhealth. We found that 62% of the AF species that are found in hot nodes and that have \nneurological applications are known to contain estrogenic flavonoids. This is markedly higher \nthan the 22% with phytoestrogens found among the 165 AF species alone. Considering the \nother therapeutic applications of the AF species, we show use for neurological disorders is the \nsecond most common specific application, after digestive applications. This appears to be an \nelevated frequency, for example in comparison to a ranking of ninth in a study of all therapeutic \napplications of Brazilian Fabaceae (Souza and Hawkins, 2017), further supporting the view that \nneurological and AF applications highlight plants with similar bioactivity. Here we highlight the \ntwo hot nodes which meet the criteria of hot-node inclusion and neurological use, but which \nhave not been tested for estrogenic flavonoids: Delonix nodes and Vachillia karroo nodes. A \nliterature survey revealed two species, one from each hot node, Delonix regia (Bojer ex Hook.) \nRaf. and Vachellia karroo (Hayne) Banfi & Galasso that did in fact contain estrogenic flavonoids. \nDelonix regia (Bojer ex Hook.) Raf.  contains quercetin and its derivatives (Modi et al., 2016) \nand Vachellia karroo (Hayne) Banfi & Galasso epicatechin (Maroyi, 2017); both are estrogenic \nflavonoids (Kiyama, 2022). Neither species was included in our list of estrogenic flavonoid \nspecies because the natural product database was incomplete (Rutz et al., 2022). It would have \nbeen possible to make a more complete data set to describe the distribution of estrogenic \nflavonoids in the Fabaceae for this study. Our study shows that the database has been to \nsufficient to validate the use of the AF category in hot node analysis. Going forward it is likely \nthat analyses of this kind for other flowering plant families would use the LOTUS initiative \ndatabase as it is a current and freely available resource. \nIn our study, we use knowledge of whether plants have estrogenic flavonoids to show \nthat ethnomedicinal uses have predictive power. The presence of estrogenic-flavonoid \ncompounds (Kiyama, 2022) was determined using the LOTUS initiative database (Rutz et al., \n2022). Other studies which have sought to validate the hot node method have made \ncomparisons to plant drugs in clinical trials (Ernst et al., 2016; Pellicer et al., 2018; Souza & \nHawkins, 2017). Given the increasing application of the hot node method, validation is crucial, \nso a critical consideration of assumptions related to validation is important. The increase in \n‘search efficiency’ we find, from 7% to 30%, is interpreted here as the power of traditional \nmedicine in phytochemical prediction. However, it could also represent a screening bias, \nbecause plants used in traditional medicine are more likely to have been investigated and are \ntherefore known to have estrogenic flavonoids. Many of the 18 000 species of Fabaceae have \nbeen the focus of phytochemical characterisation, perhaps as many as 43% according to a \nstudy of Brazilian Fabaceae that also showed that 52% of the species used in traditional \nmedicine had been the focus of phytochemical or pharmacological study (Souza et al., 2018). \nHowever, whilst we recognise this caveat, we do consider the raised search efficiency to \nvalidate our method. Three factors in addition to the elevated frequency of species with known \nPEs are relevant here. Firstly, there is an elevated frequency of a secondary therapeutic \n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\napplication, neurological application, and we had predicted these two uses would be attributed \nto the same underlying phytochemistry. Secondly, our hot node data are drawn from a cross-\ncultural sample. This is important because it allows us to discover lineages independently, \nwhere cultural beliefs about virility might result in biases in studies of a single culture. Such \nculture-specific beliefs might be expected for aphrodisiac application, for example, it is well \nknown that bitter tonics are attributed aphrodisiac properties specifically in West Africa and the \nCaribbean (van Andel et al., 2012). Thirdly, we did find that there were PEs in species we \npredicted to have them, even when these were not recorded by the LOTUS initiative database. \nUltimately, the strongest test of the method may be to assay the plants. Pellicer et al. (2018) \nscreened for artemisinin in fifteen species but did not find that species from hot nodes were \nsignificantly more likely to have this bioactive molecule. Whether this is an issue specific to \ncongeneric species, where the biosynthetic pathways needed to produce a bioactive are \nshared, will be determined by further tests of this kind.  \nWe show that predictive methods of the kind we carry out here merit further \ninvestigation. However, the search for therapeutically relevant small molecules has ethical \ndimensions. The data we analyse here are publicly available data describing ethnomedicinal \nplant use. Much of these data are available as the result of ethnobotanical research, perhaps \nmotivated by a perceived need to preserve ethnomedicinal knowledge that was experiencing \nrapid erosion (McManis & Ong, 2018; Schultes, 2007). The ethical dimensions of placing data in \nthe digital commons are now under scrutiny (Mulatinho Simoes & Birchfield, 2024). Where \nresearch in this area is carried out by national programmes, in China and India for example, the \ntwin aims of validating and preserving traditional medicine systems can be met, whilst any \ncommercial benefits remain in-country. In our study, the data that we use comes from multiple \ncultures, and species are highlighted that may not have documented, relevant traditional use. \nPellicer et al. (2018) recognise this as an ethical ‘grey area’, as yet not addressed and we \nfurther highlight this issue here.  \nWhether the ethical dimensions of the kind of analysis we present here become the \nspecific focus of rethinking protections for knowledge holders may depend on whether these \nmethods enter the commercial sphere. At present, to the best of our knowledge, work of the \nkind we present here remains in the academic literature. However, the hot node approach has \nthe advantage of highlighting a broader range of species within the same lineage as known \nethnobotanical species. While easily accessible AF plants have been well-characterized in local \nand regional studies (Ajao et al., 2019; Ganie et al., 2019). Other AF plants remain \nunderstudied, perhaps due to the limited availability of plant material. These local and regional \nstudies of local plants could include screening of species that are not used medicinally but that \nare highlighted by phylogenetic studies. In this way, hot node studies use global data to \nhighlight locally available species to incorporate into local and regional research. Hot nodes \nprovide a better way of identifying species that are a random selection, thus reducing \nunproductive screening in national programmes.  \nEven where a wider number of species might be targetted, practical limitations such as \nthe season-dependent chemical composition of plant material, which restrict the time window for \nrecollection, remain. Although many plant-derived natural products have already been isolated \nand characterized, the amounts available were usually insufficient for extensive testing across a \nwide range of biological activities (Atanasov et al., 2015).  In addition to the accessibility of plant \nmaterial, the quality was also important. The available plant material often varied in quality and \n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\ncomposition, which could hinder the accurate assessment of its therapeutic claims. Chemical \ncomposition was influenced not only by species identity and harvest time but also by factors \nsuch as soil composition, altitude, climate, processing, and storage conditions (Atanasov et al., \n2015). Furthermore, during extraction and isolation processes, compounds could transform and \ndegrade, further complicating the evaluation of their potential therapeutic benefits (Kingston, \n2011). These challenges in devising and implementing a screening programme highlight how \nimportant it may be to widen the pool of targeted species.  \n4.2 Ethnobotany and phytochemistry of priority hot nodes \n In this study, we identified hot nodes that did not include any species known to contain \nestrogenic flavonoids according to the LOTUS initiative database. These priority hot nodes were \ninvestigated in more detail, and several were shown to include estrogenic flavonoids.  \n The Dialioideae nodes include Apuleia leiocarpa (Vogel) J.F.Macbr., the bark of this \nspecies was used in Peru as a drug to help expel the placenta during childbirth (Odonne et al., \n2013), and the root bark of Distemonanthus benthamianus Baill. was used for pain relief \n(Ajibesin et al., 2008). Phytochemical studies of Apuleia leiocarpa (Vogel) J.F.Macbr. have \nrevealed the presence of flavones (Braz Filho & Gottlieb, 1971), although their estrogenic \nactivities have not yet been investigated.  \nThe Delonix nodes includes trees native to Madagascar and East Africa. The most well-\nknown species, Delonix regia (Bojer ex Hook.) Raf., has been used in traditional medicine \nglobally and extensively studied for its phytochemical properties (Modi et al., 2016). \nEthnobotanical reports show that its flowers have been used to treat gynaecological disorders \n(Vidyasagar & Prashantkumar, 2007), and studies have identified flavonoids such as \nleucocyanidin, cyanidin, and quercetin and their derivatives in the plant (Adjé et al., 2010). \nAnother species, D. elata (L.) Gamble, has been researched for its mosquito-repellent \nproperties (Govindarajan et al., 2015). While D. regia and D. elata (L.) Gamble have been \nextensively studied, other species within the genus have received less attention. \nThe genera Acacia, Senegalia, and Vachellia are found in the Vachellia borleae nodes, \nVachellia caven nodes, and Senegalia nodes, and were previously grouped as a single genus \nthat was segregated due to its non-monophyly (Kyalangalilwa et al., 2013) These genera are \nfound in Australia, Africa, and other tropical regions (Maslin et al., 2003), and have been widely \nused in traditional medicine across these areas. Phytochemical investigations have identified \nflavonoids such as apigenin, catechin, epicatechin, kaempferol, naringenin, quercetin, and \nmyricetin derivatives in species from both Africa and Australia (Subhan et al., 2018). One \nspecies, Vachellia nilotica (L.) P.J.H.Hurter & Mabb., has been particularly well studied and \nused to treat a range of conditions, including its use as an aphrodisiac. Research on V. nilotica \n(L.) P.J.H.Hurter & Mabb. indicates that it possesses anti-inflammatory, antioxidant, \nantidiarrheal, antihypertensive, and antispasmodic properties, in addition to antibacterial, \nanthelmintic, anticancer, and acetylcholinesterase (AChE) inhibitory activities (Rather et al., \n2015). \nThe Poiretia nodes consist of twelve endemic species to tropical regions of the \nAmericas. Ethnobotanical reports highlight the use of Poiretia species for treating \nmusculoskeletal ailments (Geck et al., 2016). However, some species, such as Poiretia bahiana \nC.Mueller, contain sabinene, a toxic monoterpene (Araújo et al., 2009). On the other hand, P. \n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\nbahiana C.Mueller also contains isoflavonoids with antifungal properties (Araújo et al., 2021). \nAnother species, Poiretia latifolia Vogal, contains monoterpenes such as limonene, trans-\ndihydrocarvone, and carvone, which also exhibit antifungal activities (Nunes Alves Paim et al., \n2018). \nThe Indigofera nodes are found in the genus Indigofera, one of the largest genera \nwithin the Fabaceae family (Schrire, 2013) and widely used for medicinal purposes (Gerometta \net al., 2020). Several species have been employed as aphrodisiacs, including Indigofera \naspalathoides Vahl ex DC. in India (Prabhu et al., 2014), I. cordifolia B.Heyne ex Roth in \nCameroon, Kenya, and Tanzania (Ajao et al., 2019), and I. flavicans Baker in Botswana (Ajao et \nal., 2019). Additionally, I. cordifolia B.Heyne ex Roth has been used as an abortifacient in India \n(Jain et al., 2004) and I. sanguinea N.E.Br. in Swaziland (Amusan et al., 2002). Phytochemical \nstudies of various species in the genus have identified numerous flavonoids and isoflavonoids, \nincluding apigenin, kaempferol, luteolin, quercetin, genistein, coumestrol, formononetin, and \ntheir derivatives (Gerometta et al., 2020). \nFinally, the species from Sesbania nodes are found in tropical and subtropical regions \nworldwide (Govaerts, 2024). This genus has been used in traditional medicine for treating \nmalaria (Budiarti et al., 2020), dermatology (Mutheeswaran et al., 2011), and headaches \n(Chellappandian et al., 2012). Phytochemical studies have shown that Sesbania species contain \nisoflavonoids (Hasan et al., 2012), though much of their potential pharmacological applications \nremain unexplored. \nDespite the documented medicinal uses of many AF species in hot nodes, significant \ngaps remain in the phytochemical and pharmacological study, particularly regarding their \npotential estrogenic activities. The Dialioideae Legume Phylogeny Working Group subfamily, for \ninstance, has shown promising preliminary results in identifying flavones in Apuleia leiocarpa \n(Vogel) J.F.Macbr., yet its estrogenic potential remains untested. Similarly, while Delonix regia \n(Bojer ex Hook.) Raf. has been extensively studied, other species within the genus Delonix Raf. \nhave not received the same attention. This lack of comprehensive research creates a valuable \nopportunity for further exploration, especially given the known pharmacological relevance of \nflavonoids. Investigating underexplored genera like Poiretia Sm., Indigofera L., and Sesbania \nAdams. could yield novel estrogenic flavonoids and other bioactive compounds with potential \ntherapeutic applications.  \nCRediT authorship contribution statement \nKongkidakorn Thaweepanyaporn: Writing – original draft, review & editing, \nMethodology, Formal analysis, Data curation, Visualization. Jamie Thompson: Writing – review \n& editing, Methodology. Nandini Vasudevan: Writing – review & editing, Methodology, \nSupervision.  Julie Hawkins: Writing – original draft, Writing – review & editing, Methodology, \nSupervision\n \nDeclaration of competing interest \nThe authors declare that they have no known competing financial interests or personal \nrelationships that could have influenced the work reported in this paper. \nAcknowledgements \n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\n We are thankful to Assistant Professor Dr. Methee Phumthum, Mahidol University, for \nproviding Thai ethnobotanical data and advising on this literature.  \nData availability \n Data will be made available on request. \nAppendix A. 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It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint \n\n.CC-BY 4.0 International licenseavailable under a \n(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made \nThe copyright holder for this preprintthis version posted January 20, 2025. ; https://doi.org/10.1101/2025.01.17.633163doi: bioRxiv preprint","source_license":"CC-BY-4.0","license_restricted":false}