Bioactivities of the Genus Combretum (Combretaceae): A Review

The Combretaceae is a large family of herbs, shrubs and trees, comprising about 20 genera and 600 species with tropical distribution around the globe and centers of diversity in Africa and Asia. Some Combretum species are extensively used in traditional medicine against inflammation, infections, diabetes, malaria, bleeding, diarrhea and digestive disorders and others as a diuretic. The present work is a literature survey of Combretum species that have been evaluated for their ability to exert biological activities. A total number of 36 Combretum species are discussed with regard to plant parts used, component tested and bioassay models. This review is of fundamental importance to promoting studies on Combretum species, thereby contributing to the development of new therapeutic alternatives that may improve the health of people suffering from various health problems.


Introduction
Medicinal plants have been used since ancient times in virtually all cultures as a source of medicines [1], and are of great importance to the health of individuals and communities [2]. Traditional medicine is used in all parts of the World and has a rapidly growing economic importance, mainly through the use of medicinal plants, especially in developing countries [3]. The medicinal use of plants of the family Combretaceae is widely described in the scientific literature [4][5][6]. This family is distributed in appoximately 20 genera with 600 species. The largest genera are Combretum and Terminalia, with about 370 and 200 species, respectively [7]. Members of the Combretaceae occur mainly in tropical and subtropical areas, for example, in Africa and Brazil.
As referenced above, there are several studies describing the phytochemistry of the species of this family, and the medicinal value of plants lies in the chemical substances that produce a physiological change in the human body [2]. Therefore, in continuation of our research on bioactive molecules from the various species of different plant families , the aim of this study was to review the literature on the bioactivity of the genus Combretum.

Results and Discussion
In this review, it was possible to list thirty-six species of the genus Combretum. The effectiveness of the plant extracts depended on the type of drug studied and the bioassay models. Thus, it was possible to classify the extracts as active or inactive. In this study, we chose more species referenced in data collected in the NAPRALERT natural products database and the scientific literature databases ScienceDirect and PubMed.
Di Carlo et al. [62] demonstrated immuno-stimulating activity with a suspension of powdered leaf. Chika and Bello [63] demonstrated an antidiabetic effect for the aqueous leaf extract of C. micranthum. A dose of 100 mg/kg of the extract was the most effective, among the doses tested. It produced a significant hypoglycemic and antidiabetic activity comparable to the effect of a standard drug (0.6 mg/kg glibenclamide) ( Table 1). This study demonstrated the potential antidiabetic properties of aqueous leaf extract of C. micranthum for both type 1 and type 2 diabetes, justifying its traditional use in the treatment of this disease in Northwestern Nigeria. All of the above results contribute to justifying the use of the plant in traditional medicine for treating various conditions, particularly infections and diabetes.
C. molle (soft-leaved Combretum, velvet bush willow) is a tree with a larger, straighter trunk compared to most species of Combretum, further distinguished by its rough bark and dense crown. It occurs throughout tropical Africa and in the Arabian Peninsula in areas where woodlands and wooded grasslands predominate, often forming pure stands on hillsides [64].
Toxicity studies have reported the activity of aqueous and acetone extracts against Artemia salina [9]. Furthermore, Asres et al. [78] and Gansané et al. [6] reported antimalarial activity of the methanolic extract against Plasmodium falciparum at different concentrations tested. Molluscicidal effect of aqueous extract against Biomphalaria pfeifferi was also observed [75]. Meanwhile, embryotoxic effects have not been reported [79] (Table 1).
Methanolic extracts of the roots and leaves (25 μg/mL) of C. molle showed strong cytotoxic effects against T-24 bladder cancer cells [15]. In addition, the aqueous and methanol extracts of C. molle were screened for inhibitory effects against HIV-1 reverse transcriptase. These extracts produced relatively strong inhibition of RNA-dependent-DNA polymerase (RDDP) activity. The compounds responsible for these activities in this plant were not sought [80] (Table 1).
In the case of compounds obtained from C. molle, the analgesic and antiinflammatory properties of mollic acid glucoside (MAG) ( Figure 1H), a 1α-hydroxycycloartenoid extracted from Combretum molle leaves, have been investigated in mice and rats [81]. The results of this laboratory animal study indicate that MAG possesses analgesic and antiinflammatory effects in the mammalian models used. The author suggested that MAG possesses both centrally-and peripherally-mediated analgesic effects.
Ojewole also reported on the cardiovascular effects of MAG. The results of this study showed that this compound was capable of causing bradycardia, vasorelaxation and hypotension in the animals evaluated [82]. In addition, hypoglycemic and antidiabetic activity have also been demonstrated [83].
In vitro anti-HIV activity of two isolated tannins from an acetone fraction, punicalgin ( Figure 1F) and CM-A (whose structure has not yet been fully elucidated), was assessed against human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The results displayed selective inhibition of HIV-1 replication with selective indices (ratio of 50% cytotoxic concentration to 50% effective antiviral concentration) of 16 and 25, respectively and afforded complete cell protection against the virus-induced cytopathic effect when compared to control samples. Neither of the tannins was able to inhibit HIV-2 replication [84]. extract significantly attenuated the elevation of serum glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) induced by paracetamol intoxication in rats [95] (Table 1).
Asuzu et al. [94] demonstrated that the methanol and chloroform extracts obtained with dried roots of C. dolichopetalum have antiinflammatory activity in models of carrageenan-induced paw edema and croton oil-induced edema in mice [96]. Udem et al. conducted toxicity studies in rats and found activity in both sexes (LD 50 246.0 mg/kg) [97] (Table 1).
Combretum quadrangulare is a shrub or tree, indigenous to southeast Asia, especially Burma to Laos. The plant is commonly known as "tram bâu" (Vietnam), "kê khao" (Laos) or "sang kaê" (Cambodia), and the seeds are used in Vietnamese traditional medicine as a remedy against round and tapeworm infections in humans [98]. Studies conducted by Somanabandhu et al. [99] revealed the ether and ethanolic extracts of dried root bark or dried seed are effective against earthworms when tested in vitro [99]. Antimicrobial activity was also reported in extracts of dried leaves, which were active against Helicobacter pylori [100] ( Table 1).

Material and Methods
The biological activity of the Combretum species was searched through the NAPRALERT (acronym for Natural Products ALERT) databank of the University of Illinois at Chicago. The data were updated in April 2011, using biological activity of the Combretum species as search term. The plant extracts were selected for this work and the references found in the search were later consulted for details on the models or mechanisms. Furthermore, this data survey was supplemented with searches in the PubMed and ScienceDirect sites. The specific names of the species were used as keywords.

Conclusions
The research papers cited in this review contribute to justifying the traditional use of the genus Combretum for the treatment of various health problems. This genus presents itself as a promising new scientific research topic to investigate the pharmacological potential of the extracts, fractions and compounds isolated from plant species of this genus.
We see that there is a need for further studies on the standardization or chemical characterization of the extracts used and for other more detailed phytochemical studies. With respect to pharmacological studies, there is an increasing need for further in vivo investigations of toxicity and biological activities, as well as for insights into the possible mechanisms involved. Therefore, new research findings could lead to greater safety and benefits to people who use these species to treat diseases, contributing to a better access to health care and thereby a better quality of life.