Comparing Medicinal Uses of Cochlospermaceae Throughout Its Geographic Range with Insights from Molecular Phylogenetics

diversity

Article Comparing Medicinal Uses of Cochlospermaceae throughout Its Geographic Range with Insights from Molecular Phylogenetics

Susannah B. Johnson-Fulton 1,* and Linda E. Watson 2 1 Department of Biology, Shasta College, Redding, CA 96003, USA 2 Department of Plant Biology, Ecology, and Evolution, Oklahoma State University, Stillwater, OK 74078, USA; [email protected] * Correspondence: [email protected]

Received: 13 September 2018; Accepted: 8 November 2018; Published: 15 November 2018

Abstract: Species of the Cochlospermaceae, a small mostly pantropical plant family, were evaluated at a continental scale for medicinal uses in traditional medicine. This ethnobotanical information was placed in a phylogenetic framework to make informed predictions in the search for new medicines and bioactive compounds. Medicinal plant-use data were mapped onto a molecular phylogeny based on DNA sequences of nuclear and chloroplast markers. Associations of medicinal uses among closely related species occurring in different geographic regions and among diverse cultures were evaluated. The most common medicinal uses for these species are those used to treat skin ailments, gastro-intestinal problems, malaria, and liver issues. The plant species with the most numerous uses is Cochlospermum tinctorium, which occurs primarily in West Africa. Closely related species being used by cultural groups in different geographic regions to treat the same illnesses suggests the presence of bioactive compounds with potential biomedical value, since they may represent independent discoveries of similar medicinally-active compounds. This leads to the speculation that those closely related species not currently being used to treat these ailments may also contain identical or similar medicinally-active compounds and are worthy of laboratory investigations.

Keywords: Cochlospermaceae; Cochlospermum; Amoreuxia; medicinal plants; comparative ethnobotany; phylogenetics; molecular systematics; biogeography; culture; pharmacology

1. Introduction Humans, like much of life on Earth, depend almost entirely on plants for survival [1–3]. Most of our food comes from plants both directly and indirectly. Much of our clothing and building materials consist of plant material. And although most drugs in western medicine are produced in the laboratory, these synthesized compounds usually mimic bioactive compounds ﬁrst discovered in the plants in which they naturally occur [2,4,5]. According to the World Health Organization (WHO), approximately 80% of developing countries still depend on traditional folk medicines, 85% of which are plant extracts with the other 15% being mineral, fungal, and animal based. Thus, with over 250,000 species of angiosperms alone, and a plethora of plant use knowledge available, the potential for making many new discoveries, making new connections, and ﬁnding new medicinal plants and medicinally-active compounds for drug development is enormous. With the effects of global warming, the increased loss of the world’s biodiversity, and the disappearance of unique human cultures, it has become even more important to discover and conserve Earth’s species, to document and conserve cultural histories, traditions, and languages, and to search for new medicines and new drought tolerant foods [6–9]. Comparing the medicinal uses of closely related plant species throughout their geographic ranges among different cultural groups can offer a new perspective into the search for effective

Diversity 2018, 10, 123; doi:10.3390/d10040123 www.mdpi.com/journal/diversity Diversity 2018, 10, x FOR PEER REVIEW 2 of 20 Diversity 2018, 10, 123 2 of 19 Comparing the medicinal uses of closely related plant species throughout their geographic ranges among different cultural groups can offer a new perspective into the search for effective botanical medicines and and other other plant plant species species with with economic economic value value [10]. [10 ].Cochlospermaceae Cochlospermaceae Planch. Planch. is isa small, a small, ethnobotanically ethnobotanically important important pantropical pantropical plant plant family family with with species species distributed distributed in in west and central Africa,Africa, India,India, Southeast Southeast Asia, Asia, Northern Northern Australia, Australia, Central Central and Southand South America, America, the West the Indies, West Mexico,Indies, Mexico, and Southwestern and Southwestern United United States States (Figure (Figure1). It is 1). composed It is composed of two of genera, two genera,Amoreuxia AmoreuxiaDC., fourDC., herbaceousfour herbaceous species, species, and Cochlospermum and CochlospermumKunth, Kunth, 12 woody 12 woody species species (Figure 2(Figure). Of its 2). 16 Of species, its 16 12species, are known 12 are to known be used to by be many used culturesby many on cultures different on continents different [continents11–19]. The [11–19]. widespread The widespread distribution ofdistribution its species of combined its species with combined its rich ethnobotanical with its rich ethnobotanical use makes Cochlospermaceae use makes Cochlospermaceae an ideal family an to exploreideal family any to tendencies explore any for tendencies closely related for closely species rela toted be species used in to similar be used ways in similar by people ways ofby diverse people culturalof diverse groups. cultural If, groups. for example, If, for example, closely related closely species related are species used are insimilar used in ways similar by ways distantly by distantly related cultures,related cultures, then those then species those may,species in fact,may, provide in fact, moreprovide effective more medicineseffective medicines because they because represent they independentrepresent independent discoveries discoveries of similar medicinally-activeof similar medicinally-ac compounds.tive compounds.

Figure 1.1. Distribution of the twotwo generagenera ofof Cochlospermaceae.Cochlospermaceae. Blue == CochlospermumCochlospermum; OrangeOrange == Amoreuxia;; YellowYellow == overlappingoverlapping rangesranges ofof thethe twotwo genera.genera. Numbers indicate the numbers of species in different geographicgeographic regions.regions. 8—the8—the Americas; 5—Africa; 1—Asia; 2—Australia.2—Australia.

Four major strategies are generally used in thethe searchsearch forfor medicinally-activemedicinally-active plants:plants: (1) random approach—randomly selecting selecting plants plants to sampleto sample in a particularin a particular area; (2) area; phylogenetic (2) phylogenetic approach— approach— choosing specieschoosing that species are closely that are related closely to other related species to other with species known with medicinally-active known medicinally-active compounds; (3)compounds; ecological approach—selecting(3) ecological approach—selecting plants that live inplants certain that habitats live orin thatcertain exhibit habitats specific or characteristics that exhibit, suchspecific as anti-herbivorycharacteristics, compounds;such as anti-herbivory and (4) ethnobotanical compounds; and approach—choosing (4) ethnobotanical plants approach—choosing that are used by plants local peoplethat areto used treat by illness local people [2]. The to ethnobotanical treat illness [2]. approach The ethnobotanical is currently approach known to is becurrently the most known successful to be ofthe the most major successful strategies of the [10 major,20]. Herestrategies we have [10,20]. combined Here we both have the combined phylogenetic both the and phylogenetic ethnobotanical and approachesethnobotanical by approaches choosing aby geographically-widespread choosing a geographically-widespread plant family, plant reconstructing family, reconstructing a molecular a phylogenymolecular phylogeny for the family, for the mapping family, ethnobotanical mapping ethnobot dataanical onto thedata resulting onto the phylogeny, resulting phylogeny, and evaluating and correlationsevaluating correlations between thebetween evolutionary the evolutionary relatedness relatedness of the speciesof the species and their and ethnobotanicaltheir ethnobotanical uses byuses different by different cultural cultural groups groups who who live live in differentin different geographic geographic regions. regions. Studies Studies such such asas thisthis that utilize phylogenetic phylogenetic patterns patterns of ofme medicinaldicinal properties properties within within plant plant lineages lineages are few are [10,21–29]. few [10, 21Saslis-–29]. Saslis-LagoudakisLagoudakis et al. [10] et al.concluded [10] concluded that phylogenet that phylogeneticic cross-cultural cross-cultural comparisons comparisons can focus canscreening focus screeningefforts on the efforts closest on therelatives closest of relatives medicinal of pl medicinalants already plants in use already as traditional in use as medicines. traditional medicines. Few comparative ethnobotanical studies, in general, have been conducted, and those that have been conducted usually compare the total use of plantsplants among different culturalcultural groups rather than examining the uses of a singlesingle plantplant lineagelineage acrossacross itsits geographicgeographic rangerange [[10,30–32].10,30–32]. This research focuses on a single plantplant familyfamily withwith aa widespreadwidespread distributiondistribution and compares how diversediverse ethnic groups from different geographicgeographic regionsregions useuse thethe closelyclosely relatedrelated speciesspecies medicinally.medicinally.

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(a) (b) (c)

Figure 2. Examples of Cochlospermaceae: (a) herbaceous Amoreuxia wrightii flowering and fruiting in Figure 2. ExamplesNuevo Leon, of Mexico; Cochlospermaceae: (b) Cochlospermum (planchoniia) herbaceous (sub-shrub)Amoreuxia exhibiting ch wrightiiaracteristicﬂowering large yellow and fruiting in Nuevo Leon,flowers Mexico; and palmately (b) Cochlospermum lobed leaves in Senegal, planchonii West (sub-shrub)Africa; (c) Cochlospermum exhibiting tinctorium characteristic (sub-shrub) large yellow ﬂowers andblooming palmately straight lobed from leaves the ground in Senegal,after a savannah West fire Africa; in Senegal, (c) WestCochlospermum Africa. tinctorium (sub-shrub)

blooming straightThrough from the course the ground of this study, after we a savannah aimed to: (1) fire compare in Senegal, how people West of Africa. different geographic regions use the species of Cochlospermaceae as medicines; (2) determine which species are more Throughcommonly the course used; of(3) thisdistinguish study, which we medicinal aimed to: uses (1) are compare most common how among people the different of different plant geographic regions usespecies the species and between of Cochlospermaceae different geographic regions; as medicines;(4) identify which (2) species determine have received which the speciesmost are more attention in pharmacological research, and which are candidates that lack pharmacological research commonly used;attention; (3) and distinguish (5) map ethnomedici whichnal medicinal data onto a uses molecular are mostphylogeny common and evaluate among correlations the different plant species andbetween between the evolutionary different geographicrelatedness of regions;the plant species (4) identify and the medicinal which speciesuses in different have received the most attentiongeographic in pharmacological regions. research, and which are candidates that lack pharmacological research attention;2. Materials and and Methods (5) map ethnomedicinal data onto a molecular phylogeny and evaluate correlations betweenLiterature the related evolutionary to the medicinal relatedness ethnobotany of of thethe geographic plant species regionsand where the species medicinal of uses in different geographicCochlospermaceae regions. grow was examined, as well as all published pharmacological research conducted on its species. Some plant use data was gathered in the field for Amoreuxia wrightii A. Gray in Yucatan, 2. MaterialsMexico and Methods (2006), Cochlospermum orinocense (Kunth) Steud. in the Peruvian Amazon (2005), and C. planchonii Hook.f. ex Planch. and C. tinctorium Perr. in the region of Kedougou, Senegal (2002 & 2017). LiteratureFieldrelated data were to gathered the medicinal through formal ethnobotany and informal interviews of the following geographic the interview regions methods where species of Cochlospermaceaedescribed growby Alexiades was examined,[33] and Martin as [34]. well as all published pharmacological research conducted Medicinal uses were divided into the following categories: Gastro-intestinal, Respiratory, Kidney, on its species.Urinary Some Tract, plant Female use dataHealth, was Male gathered Health, Muscul in thear/Skeletal, field for Infections/Fevers,Amoreuxia wrightii Vascular/Blood,A. Gray in Yucatan, Mexico (2006),Hepatitis/Jaundice,Cochlospermum Skin, orinocense Neurological,(Kunth) Pain, Steud.Snake Bites, in theEyes, Peruvian Malaria, and Amazon Unspecific. (2005), Selected and C. planchonii medicinal uses of Cochlospermaceae were coded as character states and traced onto the previously Hook.f. ex Planch. and C. tinctorium Perr. in the region of Kedougou, Senegal (2002 & 2017). Field data published majority rule consensus tree resulting from a Bayesian inference analysis of the combined were gatherednuclear through (ITS (internal formal transcri andbed informal spacer)) and interviews chloroplast ( followingtrnG and trnL-F the) DNA interview matrix by methodsthe authors described by Alexiades [33of] this and paper, Martin Johnson-Fulton [34]. and Watson [35], using MacClade 4 [36]. Exploration of character trait evolution was conducted using ACCTRAN optimization assuming Fitch parsimony, equal weighting Medicinal uses were divided into the following categories: Gastro-intestinal, Respiratory, Kidney, of all characters, equal transitioning probability among all states, and characters as unordered. Urinary Tract, Female Health, Male Health, Muscular/Skeletal, Infections/Fevers, Vascular/Blood, Hepatitis/Jaundice,3. Results and Skin, Discussion Neurological, Pain, Snake Bites, Eyes, Malaria, and Unspecific. Selected medicinal uses ofOf the Cochlospermaceae 16 species of Cochlospermaceae were coded examined as in character this study, nine states have and documented traced medicinal onto the previously uses. Table 1 lists the medicinal use, general locality, and plant parts used. Of the different uses, many published majority rule consensus tree resulting from a Bayesian inference analysis of the combined are shared by two or more plant species throughout the geographic range of the plant family. Of the nuclear (ITSnine (internal ethnomedicinal transcribed species spacer)) of Cochlospermaceae, and chloroplast we found (trnG thatand CochlospermumtrnL-F) DNA tinctorium matrix, bya the authors of this paper,subshrub Johnson-Fulton from Africa that and usually Watson flowers [35 at], ground using level MacClade after fire (Figure 4 [36 ].2), Explorationand C. religiosum of (L.) character trait Alston, a tree originating in India, far surpass all other species in number of medicinal uses with C. evolution was conducted using ACCTRAN optimization assuming Fitch parsimony, equal weighting inctorium having 54 medicinal uses and C. religiosum with 52 (Figure 3). The next most highly used of all characters,species equal are C. transitioningvitifolium Spreng. probability(19 uses), a tree among with a widespread all states, range and in characters the Americas, as and unordered. C. regium Pilg. (16 uses), a subshrub from South America (Figures 1 and 3). 3. Results and Discussion Of the 16 species of Cochlospermaceae examined in this study, nine have documented medicinal uses. Table1 lists the medicinal use, general locality, and plant parts used. Of the different uses, many are shared by two or more plant species throughout the geographic range of the plant family. Of the nine ethnomedicinal species of Cochlospermaceae, we found that Cochlospermum tinctorium, a subshrub from Africa that usually flowers at ground level after fire (Figure2), and C. religiosum (L.) Alston, a tree originating in India, far surpass all other species in number of medicinal uses with C. inctorium having 54 medicinal uses and C. religiosum with 52 (Figure3). The next most highly used species are C. vitifolium Spreng. (19 uses), a tree with a widespread range in the Americas, and C. regium Pilg. (16 uses), a subshrub from South America (Figures1 and3). Diversity 2018, 10, 123 4 of 19

Table 1. Major medicinal uses of species of Cochlospermaceae, including general geographic regions where uses occur, plant parts used, and references.

Plant Species Geographic Regions Plant Parts Medicinal Uses/Ailments Treated Amoreuxia wrightii A. Gray Mexico Leaves Headache Mexico Bark Snakebites, diarrhea, skin rashes, hepatitis, jaundice, liver issues, hypertension, high blood pressure, hyperglycemia, diabetes, asthma, cleanse vagina, veterinary Panama Bark Liver issues, kidney issues Mexico, Guatemala Wood, leaves Chest issues, jaundice, liver issues, kidney issues, hasten childbirth Costa Rica Wood Jaundice Cochlospermum vitifolium Mexico, Cuba Leaves Ulcers Spreng. Mexico Flowers Chest issues, hepatitis Mexico, Cuba Root Stimulate menstruation, abscesses, intestinal issues Fruit Blood circulation Panama Not specified Eating disorders, anti-hypertensive [11,14,37–45] Inflammation of the intestine, uterus, and ovaries; skin problems (boils, pimples, dermatitis, and blotchy skin), arthritis and rheumatism, acne, infections of the Roots reproductive and urinary systems Brazil Bark Rheumatoid arthritis, and in a compress to help heal abscesses Cochlospermum regium Pilg. Headaches, internal cleansing agent (removing wastes and toxins), heal wounds, cleanse blood, laxative, internal pains, leucorrhea (abnormal vaginal discharge), Not specified inflammation/infection of prostate, gastritis, ulcers [11,46–52] Bark Fevers Cochlospermum orinocense Amazon Not specified Bruises, wounds, promotes formation of scar tissue (Kunth) Steud. [53,54] Burkina Faso Roots Malaria, hepatitis, jaundice, liver issues, constipation Ivory Coast Roots Fevers, malaria Nigeria Roots Jaundice, fevers, and malaria Cochlospermum planchonii Hook.f. ex Planch. Niger Roots Jaundice, malaria, fevers, lactation issues Benin Leaves Edema West Africa Not specified Stomach troubles, burns, indigestion, leprosy, jaundice, testicular inflammation, and urethral discharges [11,55–63] West Africa, including: Ivory Coast, Ghana, Cameroon, Nigeria, Roots Jaundice, liver diseases, yellow fever, and malaria Gambia, Guinea-Bissau, Cochlospermum tinctorium Guinea, Togo, and Perr. Senegal, Epilepsy, schistosomiasis, leprosy and other skin infections, burns, edema, urethral discharge, menstrual cramps, testicular inflammation, pneumonia and other West Africa Not specified lung infections, conjunctivitis, indigestion, stomachache, diarrhea, rickets, intestinal worms, and beriberi, stimulate blood flow in the uterus and pelvic region and aid in childbirth Diversity 2018, 10, 123 5 of 19

Table 1. Cont.

Plant Species Geographic Regions Plant Parts Medicinal Uses/Ailments Treated Urinary issues, schistosomiasis, gastrointestinal problems, such as ulcers, stomachaches, constipation, and flatulence, abdominal pains, wounds, hemorrhoids, Roots intestinal worms, schistosomiasis, and hepatitis, snakebites Mali Leaves Malaria, ulcers, and flatulence Flowers Constipation Rickets, colic, indigestion, ascite, beriberi, hemorrhoids, testicular inflammation, schistosomiasis, syphilis, bronchitis, convulsions, epilepsy, fever, imflammation Senegal Roots of lymph nodes, measles, malaria, blepharitis (inflammation of eyelid), gonorrhea, boils, worms Togo Root Painful menstruation, rectal prolapse, jaundice Root Jaundice, inner hemorrhaging, headache Benin Whole plant Weakness Root Promote general body health Root, stem Veterinary medicine Nigeria Fruit Snakebites Seed (oil) Leprosy Niger Roots Jaundice Bronchial problems (pneumonia, lung inflammation), epileptic convulsions, eye issues (conjunctivitis, trachoma, sore eyes), fevers, hernias, chest pain, leprosy, Cochlospermum tinctorium Ghana Roots absence of menstruation, female sterility, hemorrhoids, sprains, burns, bruises, stomachaches, indigestion, inflammation, venereal diseases, snakebites, bleeding diarrhea, rheumatic muscle and back pain Burkina Faso Root Malaria Inflammation of the testes, schistosomiasis, jaundice, fevers, epilepsy, pneumonia, chest pain, bronchial problems (pneumonia), conjunctivitis, indigestion, Root stomach pain, snakebites, skin diseases Ivory Coast Leaves Abscesses and boils Stems, roots Urinary and genital pain and disorders, kidney pain, chest pain [15,56,63–74] Protect and heal liver, jaundice, hepatitis, prophylaxis and treatment for malaria, stomach, liver, gallbladder, spleen, and urinary tract, and also used externally as Angola Bark, roots Cochlospermum angolense a wash for skin problems, such as herpes and open sores Welw. [11,75,76] Dry cough, tuberculosis, bronchitis, laryngitis, colds, sneezing, mucus inflammation in the nose, throat, and sinuses, varicose veins, malaria, weakness, fever, headache, earache, hard of hearing, optic inflammation, and inflammation of the stomach, liver, kidney, and urinary tract. Other uses include expelling phlegm from the lungs, dissolving bladder and kidney stones, removing warts, relieving and moisturizing sore, irritated, and/or congested eyes, and enhancing Not specified ejaculation while controlling excessive and/or involuntary emissions, stop or slow bleeding by contracting tissues and/or blood vessels, excessive menstrual bleeding, blood in the urine, bleeding hemorrhoids, lower intestinal bleeding, and vomiting blood. Aphrodisiacs, cerebral tonics (relaxes and soothes anxiety and nervous twitches), astringents, diuretics, general anti-inflammatories, internal cooling agents, and assists with opium addictions Cochlospermum religiosum India (L.) Alston Leaves, flowers Stimulant Whole plant Coughs Pain reliever, sedative, and laxative, and is thought to be thermogenic. It is also used to treat cough, diarrhea, dysentery, pharyngitis, gonorrhoea, syphilis, Gum trachoma, and stomach and urinary tract disorders, protection from heat strokes [11,16,18,77–80] Root Treat sores, boils, and cuts Cochlospermum Australia Leaves, bark, flowers Treat fevers fraseri Planch. [81,82] DiversityDiversity 20182018,, 1010,, 123x FOR PEER REVIEW 86 of of 1920 Diversity 2018, 10, x FOR PEER REVIEW 8 of 20

Number of Medicinal Uses Number of Medicinal Uses 54 52 54 52 Number of Supportive NumberPharmaceutical of Supportive Studies Pharmaceutical Studies Number of Studies on NumberSafety of Studies on Safety19 19 16 16 13 13 8 5 7 7 4 3 3 7 8 7 2 4 1 0 004 5 3 3 0 000111 4 0 000 1 1 0 00 0 0002 111 0 000 1

Figure 3.3. Numbers above barsbars indicateindicate medicinalmedicinal usesuses perper speciesspecies andand pharmacologicalpharmacological studiesstudies thatthat Figure 3. Numbers above bars indicate medicinal uses per species and pharmacological studies that supportsupport medicinalmedicinal activityactivity andand safety.safety. support medicinal activity and safety. Of the manymany documented uses, a high number fall into the categories of gastro-intestinal, skin, Of the many documented uses, a high number fall into the categories of gastro-intestinal, skin, and female health afflictions,afflictions, with many of the gastro-intestinalgastro-intestinal uses occurring in Africa (Figure 44).). and female health afflictions, with many of the gastro-intestinal uses occurring in Africa (Figure 4). TheThe highesthighest numbernumber of species (eight species) are used to treat skin related issues, such as abscesses, The highest number of species (eight species) are used to treat skin related issues, such as abscesses, boils, infections, burns, burns, bruises, bruises, and and cuts cuts in inall all four four major major geographic geographic regions, regions, with with many many of the of uses the boils, infections, burns, bruises, and cuts in all four major geographic regions, with many of the uses usesoccurring occurring in Africa in Africa and andthe Americas: the Americas: C. tinctoriumC. tinctorium, C. ,planchoniiC. planchonii, and, andC. angolenseC. angolense in Africa,in Africa, C. occurring in Africa and the Americas: C. tinctorium, C. planchonii, and C. angolense in Africa, C. C.vitifolium vitifolium, C., C.regium regium, and, and C. C.orinocense orinocense in inthe the Americas, Americas, C. C.religiosum religiosum in India,in India, and and C. fraseriC. fraseri Planch.Planch. in vitifolium, C. regium, and C. orinocense in the Americas, C. religiosum in India, and C. fraseri Planch. in inAustralia Australia (Figures (Figures 4–6).4–6 ).Six Six differ differentent species species are are used used to treat gastro-intestinalgastro-intestinal issues,issues, suchsuch asas Australia (Figures 4–6). Six different species are used to treat gastro-intestinal issues, such as indigestion,indigestion, ulcers,ulcers, intestinal intestinal parasites, parasites, and diarrheaand diarrhea in three majorin three geographic major regions:geographicCochlospermum regions: indigestion, ulcers, intestinal parasites, and diarrhea in three major geographic regions: tinctoriumCochlospermum, C. planchonii tinctorium, and, C. C.planchonii angolense, andWelw. C. angolense in Africa, Welw.C. vitifolium in Africa,and C. vitifolium regium in and the Americas,C. regium Cochlospermum tinctorium, C. planchonii, and C. angolense Welw. in Africa, C. vitifolium and C. regium andin theC. Americas, religiosum inand India C. religiosum (Figures4 –in6 ).India The (Figures female affliction 4–6). The category female hasaffliction the same category number has of the uses same in in the Americas, and C. religiosum in India (Figures 4–6). The female affliction category has the same Africanumber as of in uses the Americasin Africa as (Figure in the 4Americas). Five species (Figure are 4). used Five tospecies treat femaleare used afflictions, to treat female such asafflictions, uterine number of uses in Africa as in the Americas (Figure 4). Five species are used to treat female afflictions, andsuchovarian as uterine infections and ovarian and menstruation infections and and menstruation childbirth issues and in childbirth three major issues geographic in three regions: major such as uterine and ovarian infections and menstruation and childbirth issues in three major Cochlospermumgeographic regions: tinctorium Cochlospermumand C. planchonii tinctoriumin and Africa, C. planchoniiC. vitifolium in Africa,and C. C. regium vitifoliumin theand Americas, C. regium geographic regions: Cochlospermum tinctorium and C. planchonii in Africa, C. vitifolium and C. regium andin theC. Americas, religiosum andin India C. religiosum (Figures4 in–6 India). (Figures 4–6). in the Americas, and C. religiosum in India (Figures 4–6).

12 12 Americas Americas 10 Africa 10 Africa 8 India/Southeast Asia 8 India/Southeast Asia 6 Australia 6 Australia 4 4 2 2 0 0

Figure 4. Number of different types of uses (y-axis) per major category of medicinal use (x-axis) for Figure 4. Number of different types of uses (y-axis) per major category of medicinal use (x-axis) for Figurespecies 4.ofNumber Cochlospermaceae of different in types the Americas of uses (y, -axis)Africa, per India/Southeast major category Asia, of medicinal and Australia. use ( x-axis) for species of Cochlospermaceae in the Americas,Americas, Africa,Africa, India/SoutheastIndia/Southeast Asia, Asia, and and Australia. Australia.

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Diversity 2018, 10, x FOR PEER REVIEW 9 of 20 6 8 5555 444 6 5555 33 444 2 33 2

Figure 5. Number of species of Cochlospermaceae (indicated above bar) used for selected medicinal uses. FigureFigure 5. 5.NumberNumber of of species species of of Cochlospermaceae Cochlospermaceae (indicated aboveabove bar) bar) used used for for selected selected medicinal medicinal uses. uses.

Figure 6. Comparing medicinal use throughout the geographic range of Cochlospermaceae. World maps illustrating general geographic regions where species of Cochlospermacea are being used to treat similar ailments: (a) malaria, hepatitis/jaundice/liver ailments, fevers, gastro-intestinal issues, and urinary tract issues; (b) female and male health issues, pain, respiratory ailments, and skin issues. Medicinal uses were divided between two maps to avoid overlapping stars.

FigureFigure 6. ComparingComparing medicinal medicinal use usethroughout throughout the ge theographic geographic range rangeof Cochlospermaceae. of Cochlospermaceae. World Worldmaps illustrating maps illustrating general general geographic geographic regions regions where species where speciesof Cochlospermacea of Cochlospermacea are being are used being to usedtreat tosimilar treat similarailments: ailments: (a) malaria, (a) malaria, hepatitis/jaundice/liver hepatitis/jaundice/liver ailments, ailments, fevers, fevers,gastro-intestinal gastro-intestinal issues, issues,and urinary and urinary tract issues; tract issues;(b) female (b) femaleand male and health male healthissues, issues,pain, respiratory pain, respiratory ailments ailments,, and skin and issues. skin issues.Medicinal Medicinal uses were uses divided were divided between between two maps two to maps avoid to overlapping avoid overlapping stars. stars.

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Diversity 2018, 10, x FOR PEER REVIEW 10 of 20 Cochlospermum vitifolium (Mexico, Central America, South America), C. religiosum (India), C. angolenseCochlospermum(Angola), andvitifoliumC. planchonii (Mexico, Centraland C. tinctoriumAmerica, South(West America), Africa) C. are religiosum all used (India), as treatments C. angolense (Angola), and C. planchonii and C. tinctorium (West Africa) are all used as treatments for for jaundice and hepatitis, and also for general liver health (Figures5 and6). Five species are used to jaundice and hepatitis, and also for general liver health (Figures 5 and 6). Five species are used to treat fevers in all four of the major geographic regions: C. orinocense in South America, C. religiosum in treat fevers in all four of the major geographic regions: C. orinocense in South America, C. religiosum India,inC. India, planchonii C. planchoniiand C. and tinctorium C. tinctoriumin West in West Africa, Africa, and andC. C. fraseri fraseriin in Australia Australia (Figures 55 andand 6).6). As wellAs well as illustrating as illustrating the the number number of of medicinal medicinal us useses per per species, species, Figure Figure 3 also3 also shows shows the number the number of pharmacologicalof pharmacological studies studies conducted conducted whichwhich havehave tested tested the the bioactivity bioactivity of ofmany many of the of species, the species, includingincluding one one species, species,Cochlospermum Cochlospermum gillivraei gillivraei Benth.,Benth., that that doesn’t doesn’t have have any any documented documented medicinal medicinal uses.uses. Many Many of these of these pharmacological pharmacological studies studies found found extracts extracts from from tested tested species species to be to potentially be potentially effective and safeeffective medicines and safe through medicinesin vitrothroughand/or in vitroin vivoand/orlaboratory in vivo laboratory studies [42 studies,48,50 –[42,48,50–52,59–52,59–61,72,83–107]. Cochlospermum61,72,83–107]. tinctorium Cochlospermum, from Westtinctorium Africa,, from was West found Africa, to be was the found species to withbe the the species highest with number the of highest number of medicinal uses and has been the focus of many bioscreening studies (Figures 3 medicinal uses and has been the focus of many bioscreening studies (Figures3 and7). and 7).

Figure 7. Dried tuberous root of Cochlospermum tinctorium being prepared to be sold at a market in Figure 7. Dried tuberous root of Cochlospermum tinctorium being prepared to be sold at a market Bamako, Mali, West Africa. Photo used with permission. Copyright Sergio Giani, Archives d’Aidemet in Bamako, Mali, West Africa. Photo used with permission. Copyright Sergio Giani, Archives Ong. d’Aidemet Ong. Extracts of Cochlospermum tinctorium from West Africa were found to be antimicrobial, antiviral, Extractsantimalarial, of Cochlospermum anti-tumor, anti-ulcer, tinctorium andfrom hepatoprotective West Africa were[52,72,85,87,98,104,107]. found to be antimicrobial, Cochlospermum antiviral, antimalarial,planchonii,anti-tumor, also from West anti-ulcer, Africa, andwas hepatoprotectivealso found to be antimalarial [52,72,85,87 ,and98,104 hepatoprotective,107]. Cochlospermum in planchoniilaboratory, also fromstudies West [60,61,108,109]. Africa, was Another also found African to be species antimalarial exhibiting and positive hepatoprotective laboratory results in laboratory as studiesan [antimalarial60,61,108,109 is ].C. Anotherangolense African, from Angola species [76,90,91]. exhibiting Cochlospermum positive laboratory vitifolium results and C. asregium an antimalarial, from is C.the angolense Americas,, from were Angola both found [76,90 to, 91be]. analgesicCochlospermum and anti-inflammatory. vitifolium and InC. addition, regium, C. from vitifolium the Americas, was werediscovered both found to tobe beantihypertensive analgesic and and anti-inflammatory. antidiabetic and C. Inregium addition, was foundC. vitifolium to be antimicrobialwas discovered and to be antihypertensivetoxic to cancer cells and [97,100–103,110]. antidiabetic and OneC. pharmacological regium was found study to supports be antimicrobial the use of andC. religiosum toxic to as cancer a treatment for eye afflictions. Devi et al. [111] discovered that a bioactive flavonoid (IR3G) isolated cells [97,100–103,110]. One pharmacological study supports the use of C. religiosum as a treatment for from the leaves of C. religiosum protected enucleated rat lenses from sodium selenite-induced cataract eye afflictions.formation Deviin vitro. et al.These [111 pharmacological] discovered that studies a bioactive provide flavonoid substantial (IR3G) evidence isolated that from many the of leavesthe of C. religiosumtraditionalprotected medicines enucleated from Cochlospermum rat lenses species from sodium are effective selenite-induced and may even cataract be moreformation effective thanin vitro. Thesemodern pharmacological treatments due studies to the provide rise of substantialparasite and evidencebacterial resistance that many [112,113]. of the traditional Many species medicines of fromCochlospermaceaeCochlospermum species have yet are to effective be studied and for may pharmacological even be more activity. effective than modern treatments due to the riseIn of this parasite study, and ethnomedicinal bacterial resistance data were [112 ,113mapped]. Many onto species a previously-published of Cochlospermaceae molecular have yet to be studiedphylogeny for pharmacological [35] to be used as activity. a framework to identify and evaluate correlations between the Inevolutionary this study, relatedness ethnomedicinal among species data wereand ethnobotanical mapped onto uses a previously-publishedby multiple ethnic groups molecular in different geographic regions (Figures 8–11). Species sharing a most recent common ancestor generally phylogeny [35] to be used as a framework to identify and evaluate correlations between the evolutionary relatedness among species and ethnobotanical uses by multiple ethnic groups in different geographic regions (Figures8–11). Species sharing a most recent common ancestor generally produce Diversity 2018, 10, 123 9 of 19 Diversity 2018, 10, x FOR PEER REVIEW 11 of 20 similarproduce secondary similar metabolites secondary metabolites (bioactive compounds)(bioactive compounds) because theybecause share they the share same the or same similar or similar metabolic pathways.metabolic This pathways. predictive This nature predictive of phylogenies nature of phylogenies can be used can for be drug used discovery for drug anddiscovery to guide and studies to thatguide provide studies additional that provide support additional of effectiveness support of of effectiveness target species of target [23,28 species,29,114 [23,28,29,114].].

Dialyceras 37 Dialyceras 37 Diegodendron 31 Diegodendron 31 Bixa 14 Bixa 14 Bixa 15 Bixa 15 Bixa 16 Bixa 16 C. vitifolium 5 C. vitifolium 5 C. vitifolium 13 C. vitifolium 13 C. vitifolium 17 C. vitifolium 17 C. regium 24 C. regium 24 C. religiosum 74 C. religiosum 74 C. angolense 72 C. angolense 72 C. fraseri 46 C. fraseri 46 C. gillivraei 62 C. gillivraei 62 C. planchonii 4 C. planchonii 4 C. planchonii 3 C. planchonii 3 C. tinctorium 45 C. tinctorium 45 C. tinctorium 44 C. tinctorium 44 C. wittei 27 C. wittei 27 C. tetraporum 25 C. tetraporum 25 A. palmatifida 7 A. palmatifida 7 A. palmatifida 19 A. palmatifida 19 A. palmatifida 20 A. palmatifida 20 A. malvifolia 10 A. malvifolia 10 A. malvifolia 12 A. malvifolia 12 A. wrightii 11 A. wrightii 11 A. wrightii 50 A. wrightii 50 A. wrightii 52 A. wrightii 52 A. wrightii 42 A. wrightii 42 A. gonzalezii 18 A. gonzalezii 18 A. gonzalezii 21 A. gonzalezii 21 C. orinocense 92 C. orinocense 92 C. orinocense 74 C. orinocense 74 Yellow Fever Fever unordered unordered unknow n unknow n treats yellow fever treats fevers FigureFigure 8. Medicinal 8. Medicinal uses uses (treatments (treatments for for malaria, malaria, hepatitis/jaundice/otherhepatitis/jaundice/other liver liver issues, issues, yellow yellow fever, fever, andand general general fever) fever) shared shared by by two two or or more more speciesspecies mapped (as (as unordered unordered character character states) states) onto onto the the Bayesian inference phylogeny of Cochlospermaceae of the combined nuclear (ITS) and plastid (trnG and trnL-F) regions from Johnson-Fulton and Watson [35]. Diversity 2018, 10, x FOR PEER REVIEW 12 of 20

DiversityBayesian2018, 10 inference, 123 phylogeny of Cochlospermaceae of the combined nuclear (ITS) and plastid (trnG10 of 19 and trnL-F) regions from Johnson-Fulton and Watson [35].

Dialyceras 37 Dialyceras 37 Diegodendron 31 Diegodendron 31 Bixa 14 Bixa 14 Bixa 15 Bixa 15 Bixa 16 Bixa 16 C. vitifolium 5 C. vitifolium 5 C. vitifolium 13 C. vitifolium 13 C. vitifolium 17 C. vitifolium 17 C. regium 24 C. regium 24 C. religiosum 74 C. religiosum 74 C. angolense 72 C. angolense 72 C. fraseri 46 C. fraseri 46 C. gillivraei 62 C. gillivraei 62 C. planchonii 4 C. planchonii 4 C. planchonii 3 C. planchonii 3 C. tinctorium 45 C. tinctorium 45 C. tinctorium 44 C. tinctorium 44 C. wittei 27 C. wittei 27 C. tetraporum 25 C. tetraporum 25 A. palmatifida 7 A. palmatifida 7 A. palmatifida 19 A. palmatifida 19 A. palmatifida 20 A. palmatifida 20 A. malvifolia 10 A. malvifolia 10 A. malvifolia 12 A. malvifolia 12 A. wrightii 11 A. wrightii 11 A. wrightii 50 A. wrightii 50 A. wrightii 52 A. wrightii 52 A. wrightii 42 A. wrightii 42 A. gonzalezii 18 A. gonzalezii 18 A. gonzalezii 21 A. gonzalezii 21 C. orinocense 92 C. orinocense 92 Urin a ry T ra ct Gastro-intestinal C. orinocense 74 C. orinocense 74 unordered unordered unknow n unknow n treats g astro-intestinal issues (indigestion, ulcers, diarrhea, etc.) tre ats urin a ry tra c t infections, dysuria, etc. equivocal

Dialyceras 37 Dialyceras 37 Diegodendron 31 Diegodendron 31 Bixa 14 Bixa 14 Bixa 15 Bixa 15 Bixa 16 Bixa 16 C. vitifolium 5 C. vitifolium 5 C. vitifolium 13 C. vitifolium 13 C. vitifolium 17 C. vitifolium 17 C. regium 24 C. regium 24 C. religiosum 74 C. religiosum 74 C. angolense 72 C. angolense 72 C. fraseri 46 C. fraseri 46 C. gillivraei 62 C. gillivraei 62 C. planchonii 4 C. planchonii 4 C. planchonii 3 C. planchonii 3 C. tinctorium 45 C. tinctorium 45 C. tinctorium 44 C. tinctorium 44 C. wittei 27 C. wittei 27 C. tetraporum 25 C. tetraporum 25 A. palmatifida 7 A. palmatifida 7 A. palmatifida 19 A. palmatifida 19 A. palmatifida 20 A. palmatifida 20 A. malvifolia 10 A. malvifolia 10 A. malvifolia 12 A. malvifolia 12 A. wrightii 11 A. wrightii 11 A. wrightii 50 A. wrightii 50 A. wrightii 52 A. wrightii 52 A. wrightii 42 A. wrightii 42 A. gonzalezii 18 A. gonzalezii 18 A. gonzalezii 21 A. gonzalezii 21 C. orinocense 92 C. orinocense 92 Fem ale Health Male Health C. orinocense 74 unordered C. orinocense 74 unordered Unknown unknow n treats fem ale health issu es (m enstruation, childbirth , u te rine infections, etc.) treats m ale health issu es (prostate and testicular infections, etc.)

Figure 9. Medicinal uses (treatments for gastro-intestinal, urinary tract, female health, and male health Figure 9. Medicinal uses (treatments for gastro-intestinal, urinary tract, female health, and male health issues) shared by two or more species mapped (as unordered character states) onto the Bayesian issues) shared by two or more species mapped (as unordered character states) onto the Bayesian inference phylogeny of Cochlospermaceae of the combined nuclear (ITS) and plastid (trnG and trnL-F) inference phylogeny of Cochlospermaceae of the combined nuclear (ITS) and plastid (trnG and trnL- regions from Johnson-Fulton and Watson [35]. F) regions from Johnson-Fulton and Watson [35].

Diversity 2018, 10, 123 11 of 19 Diversity 2018, 10, x FOR PEER REVIEW 13 of 20

Dialyceras 37 Dialyceras 37 Diegodendron 31 Diegodendron 31 Bixa 14 Bixa 14 Bixa 15 Bixa 15 Bixa 16 Bixa 16 C. vitifolium 5 C. vitifolium 5 C. vitifolium 13 C. vitifolium 13 C. vitifolium 17 C. vitifolium 17 C. regium 24 C. regium 24 C. religiosum 74 C. religiosum 74 C. angolense 72 C. angolense 72 C. fraseri 46 C. fraseri 46 C. gillivraei 62 C. gillivraei 62 C. planchonii 4 C. planchonii 4 C. planchonii 3 C. planchonii 3 C. tinctorium 45 C. tinctorium 45 C. tinctorium 44 C. tinctorium 44 C. wittei 27 C. wittei 27 C. tetraporum 25 C. tetraporum 25 A. palmatifida 7 A. palmatifida 7 A. palmatifida 19 A. palmatifida 19 A. palmatifida 20 A. palmatifida 20 A. malvifolia 10 A. malvifolia 10 A. malvifolia 12 A. malvifolia 12 A. wrightii 11 A. wrightii 11 A. wrightii 50 A. wrightii 50 A. wrightii 52 A. wrightii 52 A. wrightii 42 A. wrightii 42 A. gonzalezii 18 A. gonzalezii 18 A. gonzalezii 21 A. gonzalezii 21 Skin C. orinocense 92 Kidney Health C. orinocense 92 unordered unordered C. orinocense 74 C. orinocense 74 unknow n unknow n treats skin issues (infections, burns, sores, bruises, w orts, etc.) supports kidney health (treats kidney inflam m ation, kidney stones, etc.) equivocal

Figure 10.10. Medicinal uses (treatments for skin, kidney,kidney, and respiratory ailments and general pain) sharedshared byby twotwo oror moremore speciesspecies mappedmapped (as(as unorderedunordered charactercharacter states)states) ontoonto thethe BayesianBayesian inferenceinference phylogenyphylogeny ofof CochlospermaceaeCochlospermaceae ofof thethe combinedcombined nuclear (ITS) and plastid (trnGtrnG andand trnL-FtrnL-F)) regionsregions fromfrom Johnson-FultonJohnson-Fulton andand WatsonWatson [[35].35].

Diversity 2018, 10, 123 12 of 19 Diversity 2018, 10, x FOR PEER REVIEW 14 of 20

31 7 19 20 25 92 74

74 4 3

45 44

72 18 21 10 12 5 13 17 e 62

s 37

11 50 52 42

24 46 s 27 a r

14 15 16 inocen yce r l . o C. fraseri palmatifidaA. Bixa Bixa vitifolium C. C. gillivraei C. A. malvifolia gonzalezii A. orinocense C. C. planchonii planchonii C. C. tetraporum A. palmatifida A. A. malvifolia A. palmatifida A. C. tinctorium tinctorium C. C. wittei A. wrightii A. wrightiiA. wrightii A. gonzaleziiA. C. planchonii planchonii C. C. tinctorium C. vitifolium vitifolium C. Bixa Dia wrightii A. C C. angolense angolense C. Diegodendron Diegodendron C. religiosum religiosum C. C. vitifolium vitifolium C. regium C.

Medicinal U sage unordered unknow n 1-10 medicinal uses 11-20 medicinal uses 50-55 medicinal uses equivocal

Figure 11.11. Number of medicinal uses of each species mapped (as unordered characters) onto thethe Bayesian inference phylogeny of Cochlospermaceae of the combined nuclear (ITS) and plastid (trnGtrnG and trnL-FtrnL-F)) regionsregions fromfrom Johnson-FultonJohnson-Fulton andand WatsonWatson [[35].35].

Based on the results of this study, itit isis apparentapparent thatthat thethe speciesspecies usedused forfor aa medicinalmedicinal use are often closelyclosely related,related, withwith a a strong strong phylogenetic phylogenetic signal signal for for a specifica specific medicinal medicinal property property (Figures (Figures8–10 8–). The10). lineageThe lineage showing showing the most the medicinalmost medicinal uses is theuses small is the clade small (branch) clade of(branch) African of species African including species Cochlospermumincluding Cochlospermum tinctorium ,tinctoriumC. planchonii, C., planchonii and C. wittei, andRobyns C. wittei which Robyns are allwhich suffrutescent are all suffrutescent subshrubs (Figuresubshrubs 11). (Figure Of those 11). three Of species,those threeC. wittei species,is the C. only wittei species is the lacking only species documented lacking medicinal documented uses. Thismedicinal clade inuses. the This phylogeny clade in is the sister phylogeny to another is closelysister to related another group closely of speciesrelated thatgroup includes of species all ‘core’ that speciesincludes of allCochlospermum ‘core’ species of(excluding CochlospermumC. orinocense (excludingand C.C. orinocense tetraporum andHallier C. tetraporum f.), many Hallier of which f.), many share medicinalof which share uses. medicinal uses. This high level of similar medicinal uses among closely related species may be due to the shared presencepresence ofof bioactivebioactive compounds.compounds. In searching forfor new medicines, those species not being used to treattreat aa specificspecific illnessillness whilewhile theirtheir closelyclosely relatedrelated speciesspecies are, suchsuch asas isis thethe casecase forfor C. wittei,, couldcould bebe potentialpotential candidates for bioscreening studies and theythey should be examined for more geographically localizedlocalized medicinalmedicinal use. use. Since Since they they are closely are closely related, related, they likely they share likely medicinally-active share medicinally-active compounds. Similarly,compounds. Rønsted Similarly, et al. Rønsted [21] found et medicinally-activeal. [21] found medicinally-active alkaloids in Narcissus alkaloidsin closelyin Narcissus related in speciesclosely andrelated suggested species thatand phylogeneticsuggested that relatedness phylogenetic could rela betedness used to could make be predictions used to make about predictions the presence about of thosethe presence same compounds of those same in uninvestigated compounds species.in uninve Thus,stigated placing species. medicinal Thus, uses placing and/or medicinal the presence uses ofand/or bioactive the presence compounds of bioactive in a phylogenetic compounds framework in a phylogenetic can make it framework possible to targetcan make species it possible for further to research.target species Species for further that are research. closely Species related that to speciesare closely commonly related to used species as plant commonly medicines used mayas plant be harboringmedicines thosemay samebe harboring medicinal those compounds, same medicinal perhaps compounds, even at higher perhaps levels oreven slightly at higher modified levels with or greaterslightly effectiveness.modified with greater effectiveness. Four speciesspecies inin the the major major core coreCochlospermum Cochlospermumclade clade are are used used to treatto treat malaria malaria with with three three of the of four the havingfour having been positivelybeen positively screened screened for their highfor their level ofhigh antimalarial level of activityantimalarial (Figure activity8)[ 60 ,61(Figure,76,90 ,918), 104[60,61,76,90,91,104,107–109].,107–109]. Since malaria is Since such malaria a problem is such in tropical a problem regions in oftropical the world, regions and of since the Plasmodiumworld, and resistancesince Plasmodium is so prevalent, resistance the is so search prevalent, for new theantimalarials search for new remains antimalarials important. remains The important. other African The subshrubother African species, subshrubC. wittei species,, the two C. wittei core Cochlospermum, the two core Cochlospermumspecies from the species Americas from (theC.vitifolium Americasand (C. C.vitifolium regium), and and C. the regium two), species and the from two Australia species from (C. fraseri Australiaand C.(C. gillivraeifraseri and) may C. gillivraei be strong) may candidates be strong in thecandidates search forin the new search antimalarial for new medicines,antimalarial especially medicines, since especially some havesince alreadysome have exhibited already medicinal exhibited bioactivity.medicinal bioactivity. This method This of method combining of combining phylogenetics, phylogenetics, ethnobotany, ethnobotany, and biogeography and biogeography to discover to newdiscover medicines new medicines appears toappears be much to be more much efficacious more efficacious than random than screeningrandom screening of plants of or plants through or ethnobotanicalthrough ethnobotanical studies alone. studies alone. The use categories with the highest number of documented uses and the highest number of species of Cochlospermaceae being used as treatments are gastro-intestinal complaints and skin

Diversity 2018, 10, 123 13 of 19

The use categories with the highest number of documented uses and the highest number of species of Cochlospermaceae being used as treatments are gastro-intestinal complaints and skin issues (Figures4 and5). In the phylogeny optimized for skin treatments (Figure 10), nearly all of the core Cochlospermum species are used to treat skin ailments, in addition to C. orinocense which is placed outside the core Cochlospermum clade in the phylogeny. This includes eight species across the four major geographic regions of the Americas, Africa, India, and Australia. This global use for these closely related, similar species, and the positive results from anti-microbial, anti-tumor, and anti-ulcer research offer strong support for the effectiveness of these skin related treatments [52,72,85,87,98]. Many of these same studies also support the ethnomedicinal uses related to gastro-intestinal issues.

4. Conclusions Within Cochlospermaceae there are many similar medicinal uses among closely related plant species of different geographic regions among diverse cultural groups. Closely related species of Cochlospermaceae being used by cultural groups of different geographic regions to treat the same illness, suggests that these species and other closely related species may contain bioactive chemical compounds with potential biomedical value because they may represent independent discoveries by different cultural groups of similar medicinally-active compounds. Some of these patterns could be due to cultural exchange, such as similar uses between South America and Africa due to diaspora of African slaves into the Americas. However, because there are so many similar use patterns among the species, and because the geographic scale of this study is so large, we propose that those instances, while possible, are few or unlikely. There is also a small chance that these common ethnobotanical patterns could be due to chance rather than the presence of bioactive properties. Perhaps some of the similarities of use could be due to the plants sharing similar morphological characters, such as yellow ﬂowers and sap which could lead different groups to use similar species to treat illnesses that are connected with the color yellow, such as the treatments for jaundice, hepatitis, liver health, yellow fever, and urinary tract issues. This phenomenon, known as the Doctrine of Signatures, would be challenging to test [115]. This study is one of few to take a multidisciplinary approach to explore cross-cultural ethnobotanical patterns at a large geographic scale in a phylogenetic framework. For such a small family, Cochlospermaceae harbors many species with important ethnobotanical uses. Greater effort should be made to study the pharmacological activity of these species that share medicinal uses throughout their geographic ranges, as well as those closely related species as determined through molecular phylogenetics research. It remains valuable to continue to gather ethnobotanical data in the ﬁeld as well as study the effects of wild harvesting on natural populations and the options for cultivation of those species that are highly used and/or rare in occurrence. More investigation on the distribution patterns, population density and regeneration of these species could help with planning and establishing harvest regulations that assure a sustainable supply of plant materials.

Author Contributions: Conceptualization, Formal Analysis, Investigation, and Writing-Original Draft Preparation, S.B.J.-F.; Writing-Review, Editing, and Supervision, L.E.W. Funding: This research was funded in part by Miami University Academic Challenge Grants, Miami University’s Willard Sherman Turrell Herbarium collection grants, and Shasta College. Acknowledgments: We would like to thank Sergio Giani for the use of his photo of the selling of Cochlospermum tinctorium at a market in Mali. We would like to acknowledge the Willard Sherman Turrell Herbarium at Miami University where the voucher specimens used for the molecular phylogenies in Fulton-Johnson and Watson [35] have been deposited. We would also like to thank those who reviewed this manuscript and the editors of this journal who supplied helpful input. Conﬂicts of Interest: The authors declare no conﬂict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Diversity 2018, 10, 123 14 of 19

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