Jatropha gossypiifolia L. (Euphorbiaceae): A Review of Traditional Uses, Phytochemistry, Pharmacology, and Toxicology of This Medicinal Plant

Jatropha gossypiifolia L. (Euphorbiaceae), widely known as “bellyache bush,” is a medicinal plant largely used throughout Africa and America. Several human and veterinary uses in traditional medicine are described for different parts and preparations based on this plant. However, critical reviews discussing emphatically its medicinal value are missing. This review aims to provide an up-to-date overview of the traditional uses, as well as the phytochemistry, pharmacology, and toxicity data of J. gossypiifolia species, in view of discussing its medicinal value and potential application in complementary and alternative medicine. Pharmacological studies have demonstrated significant action of different extracts and/or isolated compounds as antimicrobial, anti-inflammatory, antidiarrheal, antihypertensive, and anticancer agents, among others, supporting some of its popular uses. No clinical trial has been detected to date. Further studies are necessary to assay important folk uses, as well as to find new bioactive molecules with pharmacological relevance based on the popular claims. Toxicological studies associated with phytochemical analysis are important to understand the eventual toxic effects that could reduce its medicinal value. The present review provides insights for future research aiming for both ethnopharmacological validation of its popular use and its exploration as a new source of herbal drugs and/or bioactive natural products.


Introduction
The Euphorbiaceae family, which is considered one of the largest families of Angiosperms, covers about 7,800 species distributed in approximately 300 genera and 5 subfamilies worldwide. These species occur preferentially in tropical and subtropical environments [1,2].
Among the main genera belonging to this family, there is Jatropha L., which belongs to the subfamily Crotonoideae, Jatropheae tribe and is represented by about 200 species. This genus is widely distributed in tropical and subtropical regions of Africa and the Americas [1]. The name "Jatropha" is derived from the Greek words "jatros," which means "doctor" and "trophe," meaning "food, " which is associated with its medicinal uses [3]. The Jatropha genus is divided into two subgenera, Jatropha and curcas, from which the subgenus Jatropha has the widest distribution, with species found in Africa, India, South America, West Indies, Central America, and the Caribbean [4]. Jatropha species are used in traditional medicine to cure various ailments in Africa, Asia, and Latin America or as ornamental plants and energy crops [3]. Several known species from genus Jatropha have been reported for their medicinal uses, chemical constituents, and biological activities such as Jatropha curcas, Jatropha elliptica,

Botanic Information
Jatropha gossypiifolia Linneus is a Euphorbiaceae plant popularly known worldwide as "bellyache bush" or "black physicnut". It is a pantropical species originating from South America that is cultivated in tropical countries throughout the world [20][21][22].
J. gossypiifolia is a small shrub with dark green or more frequently purplish-red dark leaves, with 16-19 cm of length per 10-12.9 cm of width; they are alternate, palmate, and pubescent, with an acuminate apex, cordate base, and serrated margin. The flowers are unisexual, purple, and in cymose summits, with the calyx having five petals, which in male flowers may form a petaloid tube. The fruit is capsular, with three furrows, containing a dark seed with black spots [5,35,36]. Regarding the microscopic aspect of the plant leaves, some studies have shown key and important features for botanical identification of this species among other Jatropha species [21,[35][36][37].

Chemical Constituents
Various chemical constituents have been detected in extracts from different parts of J. gossypiifolia, the literature having reported, in general, the presence of fatty acids, sugars, alkaloids, amino acids, coumarins, steroids, flavonoids, lignans, proteins, saponins, tannins, and terpenoids, as can be seen in Table 1.
Accordingly reviewed by Zhang et al. [15], the main compounds isolated from Jatropha genus are the terpenoids. In fact, many of them were isolated from different parts of J. gossypiifolia. Another very important class from J. gossypiifolia is the lignoids, since a good number of them was already isolated and identified.
However, it is important to note that most of the phytochemical studies found in literature are not about isolation of compounds, but only about the phytochemical screening of the major classes through chemical qualitative reactions or more sensitive and specific methods such as thin layer chromatography (TLC). Relative to other Jatropha species, few studies have isolated chemical compounds from J. gossypiifolia (Table 2). In addition, up till now it is not clear which are the major bioactive compounds in the plant, since only a few studies were conducted by bioassay-guided isolation.
Additionally, to the best of our knowledge, there are no phytochemical studies regarding the use of water as solvent for the extraction of J. gossypiifolia constituents. This is important to note since popular use occurs more frequently with infusions or decoctions, and little is known about the constitution of this type of extract. In this context, it is important to conduct studies to evaluate the phytochemical constitution of these extracts. More commonly, the studies use solvents or mixtures of solvents with nonpolar characteristics, which could contribute to further characterization of nonpolar compounds, such as terpenoids and lignoids. Polar compounds such as flavonoids, tannins, and sugars are poorly described in the species so far, probably due to this fact.

Traditional Uses
Various medicinal properties for the species J. gossypiifolia are reported by traditional medicine, as shown in Table 3. Some properties related to J. gossypiifolia are also common to other species of the Jatropha genus [3,9,25], where human and veterinary uses are described. Different parts of this plant, such as leaves, stems, roots, seeds, and latex, are used 4 Evidence-Based Complementary and Alternative Medicine -Quantitative analysis showed 0.26% on leaves [51] Phlobotannins -Detected by phytochemical screening reactions of chloroform and methanol extracts [50] Proteins -Identified on leaves by qualitative phytochemical screening reactions [52] -Leaves obtained by micropropagation were macerated in liquid nitrogen and extracted at 4 ∘ C for 6 h with 0.1 M NaCl. The material was centrifuged and the limpid supernatant was dialyzed against water at low temperature in a cellulose membrane to remove nonprotein compound with molecular mass below 3.5 kDa [56] Evidence-Based Complementary and Alternative Medicine 5 Terpenoids -Detected on leaves by qualitative phytochemical screening reactions [52] Triterpenes (2 , 13 , 14 , 20S)-2,24,25-Trihydroxylanost-7-en-3-one Isolated from the ethanol extract after successive partitions procedures and column chromatography on silica gel and preparative TLC [57] (13 , 14 , 20S)-2,24,25-Trihydroxylanosta-1,7-dien-3-one Isolated from the ethanol extract after successive partition procedures and column chromatography on silica gel and preparative TLC [57] Stems Alkaloids -Quantitative analysis showed 2.16% of alkaloid on stems [51] Coumarin-lignoids 4 -O-Demethyl retrochinensin Not specified [58] Cleomiscosin A Compound isolated from ethyl acetate fraction stems after successive column chromatography on silica gel [59] Gossypidien Compound isolated from hexane extract from dried stems after successive column chromatography on silica gel [60] Isogadain Not specified * [61] Jatrodien Compound isolated from petrol ether extract after successive column chromatography on silica gel [62] Prasanthaline Not specified * [63] Flavonoids -Q u a n t i t a t i v e a n a l y s i s s h o w e d 1 . 2 % o n s t e m s [51] Phenols -Quantitative analysis showed 0.13% on stems [51] Saponins -Quantitative analysis showed 2.18% on stems [51] Tannins -Quantitative analysis showed 1.36% on stems [51] Roots Alkaloids -Quantitative analysis showed 1.6% on roots [51] Diterpenes 2 -Hydroxyjatrophone Isolated from petrol ether extract after successive column chromatography on silica gel [64] 2 -Hydroxy-5,6-isojatrophone Isolated from petrol ether extract after successive column chromatography on silica gel [64] 2 -Hydroxyjatrophone Isolated from petrol ether extract after successive column chromatography on silica gel [64] Citlalitrione Isolated from petrol ether fraction from the methanol extract after successive column chromatography on silica gel [13] Falodone Isolated from petrol ether fraction from the methanol extract after successive column chromatography on silica gel [13] Jatropholone A Not specified * [65] Jatropholone B Not specified * [65] Jatrophone Isolated from ethanol extract [66] Flavonoids -Quantitative analysis showed 1.75% on roots [51] Phenols -Quantitative analysis showed 0.24% on roots [51] Saponins -Quantitative analysis showed 2.83% on roots [51] Tannins -Quantitative analysis showed 2.73% on roots [51] 6 Evidence-Based Complementary and Alternative Medicine  [68,70] Caprilic acid Identified in petrol ether extract [68,70] Lauric acid Identified in petrol ether extract [68,70] Lignoceric acid Identified in petrol ether extract [68,70] Linoleic acid Identified in petrol ether extract [68,70] Myristic acid Identified in petrol ether extract [68,70] Oleic acid Identified in petrol ether extract [68,70] Palmitic acid Identified in petrol ether extract [68,70] Palmitoleic acid Identified in petrol ether extract [68,70] Ricinoleic acid Identified in petrol ether extract [68,70] Stearic acid Identified in petrol ether extract [68,70] Vernolic acid Identified in petrol ether extract [68,70] Fibers -Quantitative analysis showed 9.25% on seeds [68] Flavonoids -Quantitative analysis showed 2.26% on seeds [51] Phenols -Quantitative analysis showed 0.18% on seeds [51] Proteins -Quantitative analysis showed 13.40% on seeds [68] Saponins -Quantitative analysis showed 2.37 on seeds [51] Quantitative analysis showed 6 g/kg on seeds [68] Tannins -Quantitative analysis showed 3.52% on seeds The complete version of the paper was not accessible, so the information was obtained from its abstract.
Evidence-Based Complementary and Alternative Medicine 7  Evidence-Based Complementary and Alternative Medicine 9

Roots
Antileukemic in vitro and in vivo [64] 10 Evidence-Based Complementary and Alternative Medicine

Roots
Antileukemic in vitro and in vivo [64] Abiodone Not specified Anticancer in vitro [73] Citlalitrione Whole plant - [40] Falodone O OH Roots Anticancer in vitro [13] Evidence-Based Complementary and Alternative Medicine 11  Latex - [15,71] Evidence-Based Complementary and Alternative Medicine 13 14 Evidence-Based Complementary and Alternative Medicine in different forms of preparation (infusion, decoction, and maceration, among others), by different routes and forms (oral, topical, baths, etc.). The most frequent reports refer to its anti-inflammatory, antidiarrheal, antiophidian, analgesic, antipyretic, antimicrobial, healing, antianemic, antidiabetic, and antihemorrhagic activities, among many other examples [3,5,7,9]. Some properties are attributed to specific parts of the plant, while others are assigned to different parts. Interestingly, in some cases certain uses may appear contradictory, such as antidiarrheal and laxative or its use as anticoagulant and antihemorrhagic. One hypothesis is that this difference may be related with the dose used, since, for example, the laxative effect is an effect commonly related with toxic events with this plant.

Pharmacological Activities
Despite the grand variety of popular uses and the data from Jatropha species, J. gossypiifolia has been scarcely studied regarding biological activities (Table 4). Studies showing the biological potential of aqueous extract are rare so far, which is important to be mentioned since the most popular use of this plant is as a tea (decoction or infusion). Among the main activities that have been studied the antihypertensive, anticancer, antimicrobial, healing, anti-inflammatory, and analgesic activities stand out.

Antihypertensive Action.
Based on popular use of teas from J. gossypiifolia roots and aerial parts, the hypotensive and vasorelaxant effects of the ethanolic extract of aerial parts of the plant were tested by Abreu et al. [45]. The study revealed that the extract (125 and 250 mg/kg/day, over 4 weeks, by oral route in rats), in a dose-dependent manner, produced a reduction of systolic blood pressure in conscious normotensive animals. This hypotensive effect could be attributed to its vasorelaxant action, since it produced concentration-dependent relaxant effect in rat isolated endothelium-deprived mesenteric artery precontracted with norepinephrine or calcium. Moreover, it inhibited, in a concentration-dependent and noncompetitive manner, the contractile response induced by norepinephrine or CaCl 2 in the same preparation [45].

Antimicrobial Action.
The antibiotic activity of different extracts from J. gossypiifolia is frequently reported, as observed in Table 4. In general, some extent of antibacterial, antifungal, antiparasitic, and antiviral activity was observed. The only report of J. gossypiifolia isolated compound with antimicrobial activity is of the macrocyclic diterpene jatrophenone, which presented significant in vitro antibacterial activity against Staphylococcus aureus [41].
6.3. Anti-Inflammatory and/or Analgesic Action. Many important popular uses of J. gossypiifolia are related to inflammatory process. Bhagat et al. [28] showed that the methanolic extract of leaves of this species has significant systemic acute and chronic anti-inflammatory activity. The extract, at 500 and 1000 mg/kg oral doses, was able to inhibit the acute carrageenan-induced paw edema in rats and at 50 and 100 mg/kg oral doses inhibited the chronic cotton pelletinduced granuloma formation in rats. Additionally, the J. gossypiifolia leaf paste (0.5 and 1 mg/ear) showed significant reduction in TPA-induced local inflammatory changes in mouse ear edema model [28].
In another study, the anti-inflammatory and analgesic properties of the methanol and petrol ether extracts of aerial parts of J. gossypiifolia were demonstrated in mice [92]. At 100 and 200 mg/kg/day, during 7 days, by oral route, only the methanol extract presented significant analgesic activity in Eddy's hot plate and tail-flick models and antiinflammatory activity in carrageenan-induced paw edema [92]. The anti-inflammatory activity of the bark from J. gossypiifolia (methanol and petrol ether extracts) was also demonstrated in carrageenan-induced paw edema in rats [115].
In a recent study, using the in vitro human red blood cell membrane stabilization method, Nagaharika et al. [118] suggested that ethanol and water extracts from J. gossypiifolia leaves have anti-inflammatory activity. According to the authors, since human red blood cell membranes are similar to the lysosomal membrane components, the prevention of hypotonicity-induced membrane lysis of these cells could be taken as a measure in estimating the anti-inflammatory property of compounds [118].
The analgesic activity of the methanol extract from the leaves of J. gossypiifolia was evaluated in acetic acid-induced writhing test in mice, where highly significant inhibition was seen of 67.56 and 65.14% at 200 and 400 mg/kg oral doses, respectively [111]. Similar results were observed in the methanolic extract from fruits [110].
6.4. Healing Action. The healing action of the ethanol crude extract of J. gossypiifolia (plant part not specified) was evaluated in suture healing of ventral abdominal wall of rats, through tensiometric measurement and macro-and microscopic aspect of postoperative period. The extract, which was administered by an intraperitoneal instillation of 100 mg/kg single dose in the peritoneal cavity, presented more intense adhesion on macroscopic examination and greater strain evaluation and vascular neoformation. However, a greater inflammatory process was also observed, and other histological parameters were similar to the control group, indicating that, in general, the extract presented poor wound healing properties in the used model [124].

Aqueous extract
The extract was inactive in bronchodilator activity in guinea pigs [120] Contraceptive Leaves Ethanol extract At 450 mg/kg/day, over 21 days, by oral route, caused an antifertility activity in female mice [121] Healing Aerial parts Ethanol 70% extract At 1 mL/kg dose, by intraperitoneal route in rats, presented beneficial activity in healing process of colonic anastomosis [122] Aerial parts Ethanol 70% extract At 200 mg/kg, by intraperitoneal route in rats, favored the healing process of gastrorrhaphies and reduced the acute inflammatory reaction in vivo [123] Leaves Hydroethanol extract At 200 mg/kg, by intraperitoneal route, decreased the inflammation and increased vascular neoformation and collagen deposition when compared to the control group in healing process of sutures performed on the bladder of rats. However, in general, no favorable healing effect was observed. [108] Not specified Ethanolic extract Although some improvement could be observed in suture healing of ventral abdominal wall of rats treated with 100 mg/kg of extract (intraperitoneal instillation intraperitoneal cavity), in general, only a poor healing activity was observed. [124] Not specified At 0.1 mL volume, by topical application, the crude extract presented significant differences concerning the macroscopic and microscopic aspects of healing process occurring in open skin lesions in rats [125] Hemostatic Latex Crude fresh latex Decreased clotting and bleeding time in healthy subjects [101] Hepatoprotective Aerial parts Petrol ether, methanol, and water extracts At 200 mg/kg/day, over 7 days, by oral route in rats, both extracts presented hepatoprotective activity in carbon tetrachloride induced liver damage, with the petrol ether being the most active and the methanol being the least [126] Hypotensive and vasorelaxant

Aerial parts
Ethanolic extract At 125 and 250 mg/kg/day, over 4 weeks, by oral route in rats, in a dose-dependent manner, reduced the systolic blood pressure and produced a concentration-dependent relaxant effect in rat isolated (ex vivo) endothelium-deprived mesenteric artery precontracted with norepinephrine or CaCl 2 [45] Immunomodulatory Whole plant Petrol ether extract At 100, 200, and 400 g/mL increased the proliferation of mouse spleen cell in vitro [127] Local anesthetic

Not specified
Methanol and aqueous extracts Both extracts presented significant local anesthetic activity by plexus anesthesia in frogs * [128] 24 Evidence-Based Complementary and Alternative Medicine The complete version of the paper was not accessible, so the information was obtained from its abstract. IC 50 : concentration that inhibits 50% of the referred activity.
about extract preparation and plant part not specified), the authors also observed an absence of healing action, although some histological improvement was shown [125]. However, studying the influence of J. gossypiifolia on the healing process of colonic anastomosis in rats, Servin et al. showed that the administration of 1 mL/kg single dose of the hydro alcoholic extract from aerial parts has beneficial effect on the healing process [122]. However, according to these authors, on the seventh day of the experiment, there was a decrease in the action of the extract, suggesting that the extract, in this experiment, was less active in later stages of healing process [122]. A plausible hypothesis, not raised by the authors, could be the fact that the extract was administered in a single dose, which may not have been sufficient to maintain the effect throughout the time of the experiment. Additionally, Vale et al. showed that the ethanolic extract from aerial parts of J. gossypiifolia, at single intraperitoneal dose of 200 mg/kg, favored the healing process of gastrorrhaphies and reduced the acute inflammatory reaction in vivo [123].

Hemostatic
Action. The use of J. gossypiifolia, especially the latex, is widespread as a hemostatic agent for preventing bleeding disorders. The results of whole blood clotting time using Lee and White method and bleeding time using Ivy's method were significantly reduced when stem latex was introduced, suggesting procoagulant activity [101]. Regarding the possible mechanism of action, based on experiments that show the precipitating action of the latex upon bovine albumin, the authors suggest that the latex precipitates clotting factors thereby bringing the coagulation factors into close contact, and then the activation of coagulation cascade leads to the generation of thrombin and formation of a clot takes place in a matter of seconds when compared to the control experiment, which took minutes to complete coagulation [101]. It is important to emphasize that, to the best of our knowledge, this is the only study performed on human subjects. 6.6. Anticholinesterase Action. Based on the cholinergic hypothesis, acetylcholinesterase inhibitors are widely used to treat Alzheimer's disease. J. gossypiifolia presented an important anticholinesterase activity since the methanolic extract from leaves showed an IC 50 of 0.05 mg/mL [117]. Another study showed that the lyophilized latex of the plant was able to inhibit time-and dose-dependently the acetylcholinesterase enzyme in nervous tissue of freshwater air breathing fish Channa marulius [116]. 6.7. Antioxidant Action. The antioxidant activity of extracts from J. gossypiifolia was evaluated by Kharat et al. [55]. In this work the high content of phenols, tannins, and flavonoids in the leaves prompted the authors to evaluate the antioxidant activity of the leaves. DPPH free radical, ferric thiocyanate, and nitric oxide scavenging methods were used to analyze the antioxidant activity in vitro of methanol, ethyl acetate, and aqueous extracts, demonstrating positive results. The authors attributed the free radical scavenging activity to the presence of flavonoids [55]. On the other hand, a study showed that different extracts (petrol ether, chloroform, ethyl acetate, and n-butanol) from whole plant of J. gossypiifolia had only partial antioxidant activity in DPPH scavenging, total antioxidant capacity, and lipid peroxidation tests [48]. Among them, the ethyl acetate extract was the most active, which correlates positively with its higher content of phenolic compounds in comparison with the other extracts [48].
6.8. Contraceptive Action. Based on its popular use, J. gossypiifolia was assessed for its antifertility activity, as an alternative to oral contraceptive agents. J. gossypiifolia leaf extract, by oral route, altered the major hormones involved in estrous cycle regulation, indicating its antifertility effect on mice [121]. Evaluating other parameters (estrogenic and early abortifacient activities) the anti-infertility effect of the extract was once more demonstrated later [130].
6.9. Tocolytic Action. Based on the ethnopharmacological application of the plant as tocolytic remedy, the effects on calcium-evoked uterine smooth muscle contraction of the ethanolic extract and fractions were evaluated [129]. The crude extract and, to a higher extent, the chloroformic fraction reduced the calcium-evoked contractile response of the uterine smooth muscle, promoting a rightward displacement of calcium cumulative curves, as well as reducing the maximal contractions [129].
6.10. Antineoplasic Action. One of the most well-known pharmacological activities of J. gossypiifolia is its antineoplasic action, which is frequently associated with the content of lignoids and terpenoids. One of the first reports was made by Kupchan et al. [66], when the authors found that the ethanolic extract from roots, as well as the isolated diterpene jatrophone, exhibited significant inhibitory activity in vitro against cells derived from human carcinoma of the nasopharynx and lymphocytic leukemia P-388 and in vivo against four standard animal tumor systems, such as sarcoma 180, Lewis lung carcinoma, P-388 lymphocytic leukemia, and Walker 256 intramuscular carcinosarcoma [66]. Later, three new antitumor derivatives of jatrophone were isolated from petrol ether extracts from roots of J. gossypiifolia: 2hydroxyjatrophone, 2 -hydroxy-5,6-isojatrophone, and 2hydroxyjatrophone [64]. Recently, two other diterpenes with potent antineoplasic activity were isolated from J. gossypiifolia: falodone and abiodone. Falodone was isolated from methanol extract from roots and showed potent proliferation inhibitory activity against A-549 human cancer cell line [13]. Abiodone, a lathyrane diterpenoid compound, was isolated from J. gossypiifolia and presented potent anticancer activity [73].
6.11. Local Anesthetic Action. The local anesthetic action of J. gossypiifolia was evaluated by plexus anaesthesia in frogs [128]. The authors observed that the aqueous and methanol extract (plant part not specified) presented significant anesthetic action when compared to control group.

26
Evidence-Based Complementary and Alternative Medicine 6.12. Neuropharmacological Action. The neuropharmacological action of the methanol extract of the leaves of J. gossypiifolia was evaluated by Apu et al. [111]. The authors observed that in hole cross test the extract at 200 and 400 mg/kg, by oral route, showed significant sedative effect in mice. In hole board test, the extract showed highly significant anxiolytic activity at a dose of 200 mg/kg, whereas the same activity was observed at 400 mg/kg dose in elevated plus-maze test [111]. Similar results were observed in the methanolic extract from fruits [110].
6.13. Antidiarrheal Action. Although it may seem contradictory as shown in Table 3, J. gossypiifolia species is popularly used both as purgative and as antidiarrheal remedy. However, in literature, there are interesting results about the antidiarrheal properties of different extracts of this species.
At 200 and 400 mg/kg oral doses in mice, the methanol extract of J. gossypiifolia leaves produced highly significant antidiarrheal activity upon castor oil-induced diarrhea, decreasing the mean number of stool and total weight of fecal output when compared to control group [111]. Similar results were observed in the methanolic extract from fruits [110].
Aiming to determine the possible action mechanism of J. gossypiifolia aerial parts ethanol extract as antidiarrheal agent, Silva et al. [119] have investigated the effect of this extract on intestinal transit velocity and on isolated rat jejunum. At 500, 1000, and 2000 mg/kg, by oral route in mice, the extract showed significant antispasmodic activity in mouse intestinal transit model when compared to control. At 0.5, 1.0, and 2.0 mg/mL, the crude extract inhibited in vitro the acetylcholine and calcium-induced contractions of isolated rat jejunum. The chloroform and aqueous fractions were obtained and it was observed that only the chloroform fraction of the extract had a calcium-antagonist effect, whereas both chloroformic and aqueous fractions had anticholinergic effect, suggesting that the antispasmodic effect of J. gossypiifolia may be due to a combination of anticholinergic and calcium-antagonist mechanisms [119].
6.14. Immunomodulatory Action. The immunomodulatory action of synthetic lignan compounds was evaluated by the assay of proliferation of mouse spleen cell in vitro and compared with petrol ether extract of whole plant of J. gossypiifolia, since it is a natural source of this kind of compound [127]. The authors showed that both synthetic and naturally occurring 1-phenylnaphthalene lignans could positively modulate the immunity of the host, since they significantly increased the proliferation of mouse spleen cell in vitro [127].

Hepatoprotective Action.
Despite some studies having shown the hepatotoxic potential of J. gossypiifolia, a study was performed to analyze the possible hepatoprotective action of extracts of this plant in carbon tetrachloride-induced liver damage in rats [126]. In fact, the petrol ether, methanol, and water extracts from the aerial parts of J. gossypiifolia presented significant hepatoprotective action in this model, substantially restoring towards normalization the serum levels of serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, serum alkaline phosphatase, total bilirubin, superoxide dismutase, and catalase [126]. The authors also discuss the close relationship between the hepatoprotective action observed and the possible antioxidant mechanism present in the extracts.

Other Actions and Biotechnological Applications
In addition to studies demonstrating scientific evidences of the pharmacological properties of J. gossypiifolia, several studies have demonstrated the potential of this species to obtain molecules with various applications, thus showing its multipurpose character. Among the main applications described, the use of J. gossypiifolia seed oil for biodiesel production could be mentioned. Jatropha species has drawn the attention of researchers in recent years due to its emergence as a highly suitable feedstock plant for biodiesel production [11]. Among the species, J. gossypiifolia, J. curcas, and J. pohliana produce seeds with high oil content [11]. In a study investigating the potential of two plants of the Jatropha genus (including J. gossypiifolia), the authors observed that the studied physicochemical properties of the produced biodiesel are in the acceptable range for use as biodiesel in diesel engines, showing a promising economic exploitation of these raw materials [131].
Studies have shown the potential of the species for the development of new tools for biochemical analysis. A recent study showed that the diluted fresh latex J. gossypiifolia can be used as precipitating agent for biochemical determination of proteins in plasma, urine, and cerebrospinal fluid, with values comparable to those obtained from the conventional protein precipitants sodium tungstate and trichloroacetic acid [24]. According to the authors, the precipitating potential could be related to the capacity of the latex to form clots when applied to a bleeding sore or wound when it is used in folk medicine [24]. Another study showed the potentiality of the juice extracted from the fresh leaves of J. gossypiifolia as an anticoagulant for haematological analyses [86]. 0.1 mL of extract per mL of blood proved to be suitable for obtaining plasmas for biochemical analysis comparable with conventional anticoagulants [86]. However, the authors emphasize that the extract must be purified to remove interfering substances for it to be perfectly suitable for biochemical analysis [86].
Some studies have demonstrated the potentiality of J. gossypiifolia as a source of pesticide biomolecules. Bullangpoti et al. [49] isolated ricinine from the ethyl acetate extract from senescent leaves, the main compound responsible for the toxicity of the crude extract in Spodoptera exigua larvae, thus demonstrating that it could be an alternative choice to chemical insecticides. In another study, Bullangpoti et al. [132] showed that the ethanol extract of J. gossypiifolia in association with the ethanol extract of Melia azedarach was toxic and inhibited some enzymes from Spodoptera frugiperda larvae, demonstrating once more the potentiality of the species as insecticide agent. Calatayud et al. [56] showed the presence of proteins of about 100 kDa with toxic activity upon Phenacoccus herreni, another type of insect. In this work, the authors performed a strategy of extraction that eliminated nonprotein compounds, being able to demonstrate the potential of the species to obtain insecticidal proteins [56]. Leaf extract of J. gossypiifolia reduced the fecundity and egg viability against stored product insect pests Tribolium castaneum [133].
The potential molluscicidal activity of J. gossypiifolia has also been evaluated as an alternative mode of prevention of schistosomiasis. Sukumaran et al. [134] showed that the methanol and n-butanol extracts from unripened seeds of J. gossypiifolia was toxic against eggs and adults of two species of freshwater snails, Lymnaea luteola and Indoplanorbis exustus. The results indicated that n-butanol extract was the most effective and that the eggs were more susceptible than adults [134].

Toxicology
Species of Jatropha are notably known for their toxic potential [135,136]. This toxicity is related primarily to latex and seeds. The latex is released from the aerial parts of the plant by mechanical injury and it is extremely caustic and irritating to skin and mucous membranes. The seeds are rich in toxalbumins that cause agglutination and hemolysis to erythrocytes as well as damage to other cell types and contain a lipoid resin complex that can cause dermatitis [3,12,135]. The symptomatology consists, in general, of gastrointestinal disorders (abdominal pain, nausea, vomiting, and diarrhea). Additionally, the clinical course can bring cardiovascular, neurological, and renal complications [136]. Cases of poisoning in humans usually occur by eating fruit and seeds because of its similarity to edible chestnuts [136].
Some toxicological studies have demonstrated the toxic properties of J. gossypiifolia, while others show the absence of toxicity. However, it is important to observe the models used, doses administrated, and types of extract employed (solvent and plant part), among other aspects, to make the proper conclusions about the toxicity.
The study of experimental poisoning in sheep showed that the intake of fresh plant leaves in a single dose of 40 g/kg was lethal to these animals [137]. The clinical and pathological picture in the experimental sheep was characterized by digestive, lung, and heart disturbances and also by slight regressive changes evidenced in hepatic and renal histological examinations [137]. However, as observed by Mariz et al. [7], it is important to note that the medicinal use of the plant is rarely in natura, but instead by different preparations, such as infusions or decoctions, sometimes of the dried material, which could inactivate the possible toxic components. However, this is only a hypothesis, and so the toxicity of extracts from leaves cannot be discarded.
One of the first studies relating the identification of the constituents responsible for the toxic effects of the Jatropha species was published by Adolf et al. [69]. In this work, by a bioguided isolation, the irritant polyunsaturated ester 12-deoxy-16-hydroxylphorbol was isolated from the ether extract from the seeds of J. gossypiifolia by countercurrent chromatography [69]. The irritant activity was visualized in mouse ear after 24 h of the application of the fractions and isolated compounds [69].
The in vitro cytotoxicity assay using brine shrimp larvae test revealed that ethanol and methanol extracts (plant organ unspecified) showed low toxicity [138]. An earlier study showed that the water and ethyl acetate fraction of a methanol extract from aerial parts of J. gossypiifolia did not present toxicity against the same organisms [114].
A study performed in Wistar rats evaluated the toxicity of the ethanolic root extract of J. gossypiifolia at 10, 20, and 30 mg/kg by oral route [139]. The authors observed that the extract was toxic to the kidney and caused increased urea retention in the blood, as observed by histological studies and biochemical analysis of blood [139].
A preclinical toxicological assessment of the crude ethanol extract from J. gossypiifolia leaves showed that the extract presents relatively low oral acute toxicity in Wistar rats [18,19]. Rats treated with single doses of 1.2-5.0 g/kg by oral route were observed for 14 days, and the most important signs of toxicity were ptosis, reduction of body weight, and hind limb paralysis. Other significant alterations occurred only in males treated with 5.0 g/kg dose: increase in creatinine, aspartate aminotransferase, sodium and potassium seric levels, reduction of urea and albumin, leucopenia and small alteration in color, and consistency of viscera. The median lethal dose (LD 50 ) was higher than 4.0 g/kg for males and higher than 5.0 g/kg for females [19]. In the histopathological evaluation some alteration was observed in liver and lung only at 5.0 g/kg, suggesting the relatively low toxicity of the extract [18]. However, in the chronic toxicological study (thirteen weeks of treatment), this extract showed significant oral chronic toxicity in rats [17]. The most significant toxic signs indicated a reduction of the activity in the central nervous system and digestive disturbances. The histopathological analysis revealed hepatotoxicity and pulmonary damages. The lethality was 46.6% and 13.3% among males and females under the higher tested dose (405 mg/kg), respectively [17]. Based on this, Mariz et al. [7] discussed that the development of herbal medicine based on this species needs to prioritize the chemical refinement of the crude extracts to obtain less toxic fractions, which should be tested for their safety and therapeutic efficacy.
Another study, on the other hand, evaluating the oral acute toxicity of the aqueous and ethanol extracts from leaves of J. gossypiifolia, did not show any sign of toxicity in up to 2 g/kg in rats, enabling the authors to conclude that this extract could be considered safe [118]. This is an interesting result since in most cases the plant is used popularly as tea (aqueous extract).
The toxicity of the stem latex of J. gossypiifolia was studied in Wistar rats by applying different doses of crude latex on incised skin daily for 18 days, based on the popular use of the latex as hemostatic agent in skin lesions [140]. The authors observed that the application of the latex did not produce any significant difference in results of biochemical 28 Evidence-Based Complementary and Alternative Medicine and hematological parameters obtained from the control and experimental animals, leading to the conclusion that the stem latex has no harmful effects [140].

Conclusions
As demonstrated by this review, J. gossypiifolia presents an important potential for the generation of pharmacological and/or biotechnological products, based on popular uses and biological studies scientifically showing its properties. However, regarding specifically its medicinal properties, further studies are still necessary to assay important folk uses of the species and characterize the major compounds responsible for the bioactivity. Thus, studies of bioprospecting could prioritize this species, since many popular uses for various medical purposes are reported, demonstrating a great potential to originate bioactive molecules with pharmacological relevance. Furthermore, future phytochemical studies of this plant are important to obtain the best knowledge of the chemical composition of different extracts of the plant, in order to recognize the really important compounds in the pharmacological actions, aspiring to the chemical refinement of the products to eliminate the eventual toxic effects that could reduce the medicinal value of the species. In conclusion, the data presented in this review could provide insights for future research aimed at both ethnopharmacological validation of the popular use of J. gossypiifolia and its exploration as a new source of bioactive molecules for herbal drugs and/or bioactive natural products for potential application in complementary and alternative medicine.