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Ethnopharmacological relevance Tithonia diversifolia (TD) is widely valued in several cultures for its medicinal properties. A comprehensive review of the current understanding of this plant species is required due to emerging concerns over its efficacy, toxicity and allergenic potential. Aim of the review We critically summarized the current evidence on the botany, traditional use, phytochemistry, pharmacology and safety of TD, with the view to provide perspectives for developing more attractive pharmaceuticals of plant origin, but also to lay a new foundation for further investigations on this plant. Materials and methods A preliminary consultation of search engines such as Web of Science, PubMed, ScienceDirect and other published/unpublished resources provided an overview of extant literature on TD. Then, we meticulously screened all titles, abstracts and full-texts to establish consistency in the application of inclusion criteria. Studies were considered for inclusion if they dealt with taxonomy, global distribution, local and traditional knowledge, phytochemistry, toxicity and biological effects. Results 1856 articles were retrieved among which 168 were revised and included. Several studies conducted on cell lines and animals provided supporting evidence for some ethnomedicinal claims of extracts from TD. Short-term use of Tithonia extracts were effective and well-tolerated in animals when taken at lower doses. Both the toxic and therapeutic effects were attributed to bioactive principles naturally occurring in this species including sesquiterpene lactones, chlorogenic acid and flavonoids. Conclusions T. diversifolia is a valuable source of bioactive compounds with significant therapeutic implications and favourable safety index. However, more rigorously designed investigations are needed to recommend the whole plant or its active ingredients as a medication, and should focus on understanding the multi-target network pharmacology of the plant, clarifying the effective doses as well as identifying the potential interactions with prescribed drugs or other chemicals.

Ethnopharmacological relevance Tithonia diversifolia (Helms.) A. Gray, popularly known in Brazil as “margaridao” or “mao-de-Deus” has been used in the folk medicine as anti-inflammatory and against other illnesses in several countries. Indeed, many studies show de effect of T. diversifolia in the inflammatory process, however, any of them have demonstrated the mechanism of cell migration. Aim of the study The aim of this investigation was to show the in vivo and in vitro effects of T. diversifolia leaves ethanol extract on neutrophil trafficking from the blood to the inflamed tissue and on cell-derived secretion of chemical mediators, as well as, the effects on inflammatory resolution and inflammatory pain. Materials and methods Anti-inflammatory activity was investigated using carrageenan-induced inflammation in the subcutaneous tissue of male Swiss mice orally treated with the T. diversifolia extract (0.1, 1 or 3 mg/kg). The leukocyte influx (optical microscopy) and the secretion of chemical mediators (TNF, IL-6, IL-1β and CXCL1, by enzyme-linked immunosorbent assay) were quantified in the inflamed exudate. Histological analysis of the pouches was performed. N-Formyl-methionine-leucine-phenylalanine-induced chemotaxis, lipopolysaccharide-induced TNF, IL-6, IL-1β, CXCL1 and NO production, and adhesion molecule expression (CD62L and CD18, flow cytometry) were in vitro quantified using oyster glycogen recruited peritoneal neutrophils previous treated with the extract (1, 10, or 100 μg/mL). The resolution of inflammation was accessed by efferocytosis assay, and the antinociceptive activity was investigated using carrageenan-induced mechanical hypersensitivity. Results The oral treatment with T. diversifolia promoted reduction in the neutrophil migration as well as the decrease in total protein, TNF, IL-1β and CXCL1 levels in the inflamed exudate. In vitro treatment with T. diversifolia shedding of β2 integrin expressions, without alter CD62L expression. The extract was able to increase the efferocytosis of apoptotic neutrophils, and the increase of the IL-10 and the decrease of TNF secretion. Additionally, the extract reduced the hypersensitivity induced by carrageenan. Conclusions Together, the data herein obtained showed that T. diversifolia extract presented anti-inflammatory activity by inhibiting the cytokine and NO production, and also the leukocyte migration. The mechanisms involved in the extract anti-inflammatory effects include the impairment in the leukocyte migration to the inflamed tissue, the pro-resolution activity, and consequently the anti-hypersensitivity.

In our study, methanol, dichloromethane and aqueous extracts of 13 Rwandan medicinal plants used in the treatment of malaria were tested for in vitro antiplasmodial activity.The growth inhibition of chloroquine-sensitive Plasmodium falciparum strain (3D7) was evaluated using the measurement of lactate dehydrogenase activity. The active extracts were also tested against the chloroquine-resistant Plasmodium falciparum strain (W2) and for cytotoxicity assay using human normal foetal lung fibroblasts (WI-38).The majority of the plants tested showed an antiplasmodial activity and the best results were observed with dichloromethane leaf and flower extracts of Tithonia diversifolia, leaf extract of Microglossa pyrifolia and root extract of Rumex abyssinicus, methanol leaf extract of Fuerstia africana, root bark extracts of Zanthoxylum chalybeum and methanol bark extract of Terminalia mollis. Those extracts were active (IC(50)15mug/ml) on both chloroquine-sensitive and resistant strains of Plasmodium falciparum. Zanthoxylum chalybeum, Solanecio mannii and Terminalia mollis presented the best selectivity index.The traditional use of most of the plant evaluated was confirmed by the antiplasmodial test. This study revealed for the first time the antiplasmodial activity of two plants: Terminalia mollis and Rumex abyssinicus.

Aim of study We performed an ethnobotanical study of plants used to treat malaria in Nyakayojo sub-county in south western Uganda because malaria in this region, and in Uganda at large, is still the single most important reason for ill health and mortality. Two of the most vulnerable groups affected by malaria are young children and pregnant women and plants are commonly used in their treatment. Materials and methods Twenty-eight traditional birth attendants were interviewed about how they used plants to treat malaria. Review of the literature available on all species identified was undertaken. Results Altogether 56 plant species were used by the informants, 48 of which have been identified to species level. Thirty-two (67%) of the species used by the respondents are documented for antimalarial use in other studies, and nearly half (44%) have documented anti-plasmodial activity. Fifty-five percent of the species were used by 2 or more of the respondents. The most commonly used species were Vernonia amygdalina, the indigenous Aloe species, Justicia betonica, Vernonia adoensis and Tithonia diversifolia. It was common to use more than one plant in a recipe (43%). The respondents had good knowledge of the symptom of malaria, and fairly good understanding of the causes. Conclusion The interviews show that the group of traditional birth attendants has an extensive and diverse knowledge on plants used in the treatment of malaria. The literature survey may indicate a possible explanation for the use of several plants.

Objective To investigate the toxicity of an ethanolic extract of the aerial parts of Tithonia diversifolia , used in Nigeria to treat malaria, in rats. Materials and methods A 70% ethanol extract was administered orally to adult Wistar rats at various dosages (400–1600 mg/kg) and the animals sacrificed and various organs examined at a range of times from 30 min up to 24 h after administration. Results The studies showed a dose- and time-dependent toxic effect, which was reversible on the kidney and liver while there was no noticeable adverse effect on the morphology of the heart, spleen and brain. Conclusion A 70% ethanol extract of the aerial parts of Tithonia diversifolia , which had previously been shown to reduce parasitemia in mice infected with Plasmodium , displayed kidney and liver toxicity at the lowest dose tested. The use of this plant extract against malaria therefore raises concerns over its safety.

A methanol extract of the dried leaves of Tithonia diversifolia was investigated for anti-inflammatory and analgesic activities. The extract (50–200 mg/kg, p.o.) produced dose-related inhibition of carrageenan-induced paw oedema and cotton pellet-induced granuloma in rats. At the same doses, analgesic effect was also observed with hot plate latency assays maintained at (55 °C) as well as on the early and late phases of formalin-induced paw licking in rats. The results of the present study further confirm the use of Tithonia diversifolia traditionally for the treatment of painful inflammatory conditions.

Ethanolic extracts of the aerial part of Tithonia diversifolia and the stem bark of Crossopteryx febrifuga were investigated against early, residual (repository) and established malaria infections in vivo using Swiss albino mice at a dose range of 50-400 mg/kg per day. Chloroquine at 5 mg/kg per day was used as the positive control for the early and established infections while Pyrimethamine at 1.2 3/kg per day was used as the positive control for the residual infection test. Dose dependent chemo suppressive activities were obtained at the different levels of the infection tested. Tithonia diversifolia and Crossopteryx febrifuga gave some level of suppression of parasitaemia in the early and established infection stages. Tithonia diversifolia was active at 200 mg/kg per day in the repository test. The mean survival period of the mice treated with the extract in the established infection test was low, a possible indication of toxicity as a result of sub chronic administration of the extract. Crossopteryx febrifuga was inactive in the repository test. Beside the above limitations, the suppression of parasitaemia by the extracts at the highest dose was similar to chloroquine and pyrimathamine.