Phytochemistry and Ethnopharmacology of Ficus carica

Ficus carica L. (Moraceae) is a plant of great importance in the traditional Arab medicine thanks to its therapeutic properties. This work was carried out in order to contribute to the ethnopharmacological knowledge of this medicinal species. We describe phytochemical compounds and ethnopharmacological properties of F. carica, species that has been used in traditional medicine for many decades. Possible trends and perspectives for future research of this plant are discussed, as well. F. carica has been found to contain several chemical constituents, mostly polyphenols and flavonoids. With its bioactive compounds, F. carica possesses a wild range of biological activities. In traditional medicine, It was reported that F. carica was applied mainly as the remedy for ulcers, indigestion and diarrhea. Some published studies have shown a broad spectrum of pharmacological activities, including antibacterial, antioxidant, antitumor, as well as anti-inflammatory activities. This paper reviews the main medicinal uses, phytochemistry and pharmacology of this plant in order to summarize its therapeutic potential and to shed light on gaps necessitating for prospected research works. Review Article Bouyahya et al.; IJBCRR, 14(1): 1-12, 2016; Article no.IJBCRR.29029 2


INTRODUCTION
The fig tree is called Kerma in Arabic and figuier in French, it belongs to the Moraceae family and Ficus genus that includes 750 species, all growing in warm regions of the globe, whose Ficus carica L. (Syn: F. sycomorous), typically Mediterranean species, is the most studied. This is a very suitable fruit for extensive farming with its crop hardiness, adaptability to various situations and its easy multiplication [1,2], as he reached the age fruit in one to two years and has a long life [3].
The figs are eaten fresh as well as dried in Mediterranean regions [4]. The fruit is widely used in archaic medicine through its diverse beneficial effects such as antipyretic, tonic, purgative, alexiterique, aphrodisiac, lithontriptique, diuretic, astringent and carminative. It is also used against inflammation, weakness, paralysis, thirst, diseases of the liver and spleen, chest pain, batteries cures, diseases of the head and blood, leprosy, nosebleeds, it also stimulates hair growth [4,2].
It is also known for its antitumor activity against certain types of cancer such as stomach cancer, prostate, colon, liver and testis [5]. By their potential as a functional food, common figs possess nutritional properties, phytochemicals, antioxidant and antibacterial, they are used in traditional medicine for their therapeutic benefit against various disorders. These properties may be due to the presence of different bioactive compounds [6]. Through Moroccan regions, F. carica is cultivated species with its various varieties (Kuhlan, Homran, Ghodan, Lkouti ...). It is widely used in Moroccan traditional medicine because of their different pharmacological properties argued by the empirical studies. Based on these considerations, we gathered the information and made a bibliographical synthesis of chemical compounds and ethnopharmacological properties F. carica.

METHODOLOGY
The current review was achieved using a designed search of the scientific data published about medicinal use, phytochemistry and pharmacological activities of F. carica. The searches were carried out using various databases, including PubMed

TRADITIONAL USE
Figs have been traditionally used for its medicinal benefits as laxative, cardiovascular, respiratory, antispasmodic and anti-inflammatory remedies [7]. Its fruit is generally referred as figs which have been used as food and medicine for several centuries [8,9]. Its fruit, root and leaves are used in the native system of medicine in different disorders, such as colic, indigestion, diarrhea, sore throats, coughs, bronchial problems, inflammatory, cardiovascular disorders, ulcerative diseases, and cancers [8][9][10][11][12].

PHYTOCHEMISTRY
Ficus carica is rich in compounds belonging to different chemical families. Several studies have revealed the presence of phenolic compounds in the extracts of F. carica [13,14,15]. The phytochemical screening of F. carica leaves methanolic extracts of different Algerian varieties revealed their richness by flavonoids and polyphenols with significant variability between varieties tested [14]. In another recent study, Harzallah et al. [13] showed that the methanol extracts of fruit, pulp peel and pulp are rich on polyphenols, flavonoids, O-diphenols tannins and anthocyanins. This study is focused on three figs of Tunisian varieties and it showed significant difference between these compounds in the tested varieties. On the other hand, the total composition of F. carica differs from one region to another for the same variety.
The latex of the fig has a large amount of polyphenols, flavonoids and anthocyanins [16]. Total phenolics and flavonoids content in fig extracts were estimated and found to be moderated. A large amount of alkaloids was found in the extract of the figs while saponins were present in very small quantities [6]. Figs have the highest global content in minerals and their calcium content comes in second place after oranges, they are also rich in phosphorus. Dried figs are known as a very good source of strontium, magnesium and iron. They are very useful in anemia cases. Figs are a good source of potassium, a mineral that helps control blood pressure. They are rich on fiber compared to all other common fruits and are naturally sweet [3,4,6].

Antibacterial Activity
Infectious diseases represent an important cause of morbidity and mortality among population. Many efforts have been made to discover new antimicrobial compounds from various kinds of sources such as microorganisms and plants. Therefore, pharmaceutical companies have been motivated to develop new antimicrobial drugs in recent years. The drug-resistant bacteria have further complicated the treatment of infectious diseases. Contrary to the synthetic drugs, antimicrobials of plant origin are not associated with many side effects and have an enormous therapeutic potential to heal many infectious diseases [19][20][21][22].
In the scenario of emergence of multiple drug resistance to human pathogenic organisms, this has necessitated a search for new antibacterial substances from other sources as plants.
Medicinal plants, which represent the backbone of traditional medicine, become in the last few decades the subject of very intense pharmacological studies [20][21][22][23][24]. Screening of plant extracts is often done by disk diffusion method and dilution. Many medicinal plants have demonstrated an antibacterial activity against different bacterial strains implicating in almost infectious diseases [25][26][27][28].
Antibacterial activity of F. carica extracts has been widely studied against several bacterial strains [29,30,31] (Table 1). These extracts of the leaves have been shown to be effective in the inhibition of bacterial growth [28,29]. The antibacterial activity of F. carica is certainly depends on polyphenols and flavonoids in the chemical composition of leaves extracts. Indeed, these phenolic compounds have various biological activities including antibacterial activity [29,31]. Lee et Cha, showed that F. carica leaves methanolic extract inhibits the growth of clinical isolates of Staphylococcus aureus resistant to penicillin. In addition, this extract had an additive effect when tested in synergy with antibiotics [30]. Its action was mainly linked to the cell loss of viability that the properties of phenolic compounds to cross the bacterial membrane. The methanol and ethanol extracts of the fruit of F. carica were tested by Jasmine et al., against Escherichia coli, Pseudomonas aeruginosa, Streptococcus sp., Enterobacter sp., Klebsiella pneumonia, Salmonella typhi et Salmonella paratyphi [31]. Weli et al. [32] investigated the antibacterial activity of the extracts of chloroform, hexane, ethyl acetate and alcoholic. Ethyl acetate extract showed a significant zone of inhibition against S. aureus. While in another study carried out by Jeong et al. [29] the ethanol leaves extracts was tested against several bacterial strains and the results have shown an inhibitory activity against Streptococcus anginosus at a concentration of MIC = 0.156 mg / ml (Table 1).

Antioxidant Activity
The antioxidant activity of a product is expressed by its ability to give electrons or protons to substrates oxidized to reduce their. It is wellknown that F. carica products from latex and fruit are rich in phenolic compounds (Polyphenols, Flavonoids, Tannins, etc ...) with an antioxidant power. Using different systems, several organic extracts from F. carica have proved capable of reducing free radicals (Table 1). Indeed, very recently study focused on the evaluation of the antioxidant activity of F. carica methanolic extract showed a significant reduction of DPPH radical at low concentrations [14]. Another work carried out by Crisosto et al. [33] demonstrated that fresh figs cultivarshas a high levels of antioxidants. Latex of F. carica is very rich in polyphenols and flavonoids, which have been widely shown to be potent antioxidants [27]. In a study carried out on polyphenols and flavonoids extracted from F. carica latex and used the radical-scavenging activity in vivo assay system via the determination of the activity of superoxide dismutase and glutathione reductase, Aziz showed a significant reduction in the rate of these two enzymes in liver cells [34]. In vitro antioxidant activity of F. carica leaves methanolic extracts was also evaluated using the scanning technique of the radical DPPH by Eteraf-Oskouei et al. [35] showed that antioxidant capacity (IC 50 ) is 0.0903 mg /mL. While Javed et al. [28] found an inhibition of 10.222 DPPH radical at a concentration of 250 mcg / ml.

Anti-inflammatory Activity
By its high anti-inflammatory compounds, pure products and extracts of F. carica showed potent anti-inflammatory activity whether In vitro and In vivo [36,37,34,35,38,39]. In an animal model, the petroleum ether, chloroform and ethanol extract of F. carica showed significant antiinflammatory effects. These effects are mainly due to the induction reducing cariogenic and granuloma formation. They are correlated with high levels of flavonoids (very molecules recognized for their anti-inflammatory properties) present in these extracts [39].
In other preclinical studies on animal models, the anti-inflammatory activity has been proven. Indeed, the hydroalcoholic extract administered orally has proven effective against induced inflammation in rats. This extract inhibits the inflammatory process in two phases (exudation and granulation) with a dose-dependent response. This dose-dependent response in the inhibition of exudation and granulation was confirmed even with chronic models. Treatment with sodium diclofénaque also sparked inhibitory effects on both phases of inflammation. The effect of sodium diclofénaque was higher than that of the hydroalcoholic extract of F. carica [38].
Free radicals are known to play a role in tissue injury and inflammation. The work of Eteraf-Oskouei et al. [38] showed that treatment with F. carica leaves methanolic extract is greatly reduced induced angiogenesis in rats.
This extract contains a high total phenolic content indicating its high antioxidant properties responsible for anti-inflammatory and anti-angiogenic activities. These results show that the extract inhibits the production of pro-inflammatory cytokines, including TNF and PGE2 that cause joint damage inducing activation and recruitment of leukocytes into inflammatory exudates in the experimental arthritis model.
With the aim to seek a hepatoprotective effect of F. carica latex, Aziz induced in rats oxidative stress using hepatotoxic property lead acetate. The results revealed a significant reduction of histological alterations in animals; this may be due to the high total content of the latex in polyphenols and flavonoids [34]. Aziz has proposed three mechanisms for this reduction: (1) the reduction of oxidative stress, (2) increasing the level of oxidative enzymes and (3) acting as chelators of lead ions. The hepatoprotective effect of F. carica has also been shown by the petroleum ether extract [37]. Induced hepatotoxicity in rats' rifampicin and hepatocytes were comparably reformed to normal people. In a recent study by Allahyari et al. [36] on general toxicity and antioxidant activity of F. carica leaves extract against ischemic heart disease induced in rats, the results showed that this extract had a significant effect on reducing the size and infarct volume. The mechanisms of this protection are probably due to the antioxidant capacity of phenolic compounds present in F. carica extract.

Antitumor Activity
Cancer is the uncontrolled growth and spread of cells. It can affect almost any part of the body. The growths often invade surrounding tissue and can metastasize to distant sites. Chemotherapy and radiotherapy, the conventional cancer treatments used nowadays, are expensive and cause many side effects, including such minor ones as vomiting, alopecia, diarrhea, constipation, and major ones such as myelosuppression, neurological, cardiac, pulmonary and renal toxicity. For these raisons, the seed of natural products for cancer treatment is very important. Therefore, medicinal plants play a role essential. Several researches have showed cytotoxic activity of medicinal plant [40,41,42,43,44]. IFN-γ, IL-6, and IL-23. Moreover, FCPS-treated DCs showed an enhanced capability to stimulate T cells and promote T cell proliferation. Latex and soybeans 6-O-acyl-beta-Dglucosyl-betasitosterols, acyl moeity and linoleyl with minor amounts of stearyl and oleyl,

MTT assay
Both the natural and the synthetic compounds showed in vitro inhibitory effects on proliferation of various cancer cell lines. [12] Anti-inflammatory activity leaves Methanolic extract Toxicity test was carried out by brine shrimp lethality assay, the cardiac arrhythmias were analyzed and TTC method was used for infarct size determination.
LD 50 value by brine shrimp test was 0.158 mg/ml, the extract decreased number of VEBs, incidence and duration of Rev VF with clear reduction in infarct size and infarct volume. [36] Leaves Petroleum ether Antihepatotoxic activity on rats treated with 50 mg/kg of rifampicin orally. The parameters assessed were serum levels of glutamic oxaloacetate transaminase, glutamic pyruvic transaminase, bilirubin and histological changes in liver.
Petroleum ether extract was significant reversal of biochemical, histological and functional changes induced by rifampicin treatment in rats. [37] Latex Pure extract Determination of superoxide dismutase activity, determination of Liver Reduced Glutathione (GSH), determination of Liver Enzymes, determination of Liver Homogenate Lead Level, and histological analysis using electron microscopy scaning.
This extract has decreased levels of liver reduced glutathione (GSH) and superoxide dismutase (SOD), histologically and ultrastructurally, the liver showed several histological alterations such as degeneration of hepatocytes by necrosis and apoptosis, fatty changes and inflammatory cells infiltration. [34] Leaves Methanolic extract Creation of Air Pouch Type Inflammation by Carrageenan in Rats. The inflammation was induced by injection of carrageenan into pouches and the Angiogenesis of granulation tissues was determined by measuring hemoglobin content. Quantification of cell migration and exudation, determination of TNFα, PGE2, and VEGF concentrations in the pouch fluid. Determination of granulation tissue weight and determination of angiogenesis in granulation tissue.
Treatment of Leukocyte by extract has an effect on accumulation and volume of exudates were significantly inhibited by the extract. Decreases the production of TNFα, PGE 2 , and VEGF. On other hand the angiogenesis was significantly inhibited by all administered doses. The extract has also anti-inflammatory effects and ameliorated cell influx and exudation to the site of the inflammatory response. [35]

Activity
Part of plant Type of extract/ compound

Experimental model Effect References
Fruit Hydroalcoholic extract Anti-inflammatory activity in mice induced by sodium diclofenac, Measure of weight granuloma in mice.
Hydroalcoholic extract of fruit of Ficus carica responsible in changing various biochemical parameters such as serum SGOT, SGPT, ALP and total protein which was not that much significant. In hematological parameters, the hydroalcoholic extract of fruit of Ficus carica showed significant decreased in WBCs. [38] Leaves Petroleum ether, chloroform and ethanolic extract Carrageenan-induced rat paw edema and cotton pellet granuloma methods. The extracts were administered orally in doses of 300 and 600 mg/kg/day of body weight to healthy animals. The extracts were administered orally in doses of 300 and 600 mg/kg/day of body weight to healthy animals. The extracts were administered orally in doses of 300 and 600 mg/kg/day of body weight to healthy animals. The extracts were administered orally in doses of 300 and 600 mg/kg/day of body weight to healthy animals The extracts were administered orally in doses of 300 and 600 mg/kg/day of body weight to healthy animals The extracts were administered orally in doses of 300 and 600 mg/kg/day of body weight to healthy animals.
The ethanolic extract, at 600 mg/kg, exhibited maximum anti-inflammatory effect, which is 75.90% in acute inflammation and in chronic study showed 71.66% reduction in granuloma weight. The petroleum ether (PEE), chloroform (CE) and ethanol (EE) extracts significantly reduced carrageenan-induced paw edema and cotton pellet granuloma method in rats. [39] Antipyretic activity Leaves Ethanolic extract Study on normal body temperature induction of yeastinduced pyrexia Ethanolic extract of F. carica, at doses of 100, 200 and 300 mg/kg body wt. p.o., showed significant dose-dependent reduction in normal body. temperature [2] Anti-acne activity Fruit and leaves Petroleum ether, chloroform, methanol and distilled water extract Anti-acne activity was evaluated against Propionibacterium acnes using agar disc diffusion method And the minimum inhibitory concentration was calculated by using serial tube dilution method.
Leaves and fruits of F. carica, their water extracts were found to be most effective against P. acnes with a Minimum Inhibitory Concentration of 10µg/ml.
Several studies revealed the efficacy of the extracts and / or compounds from F. carica in the inhibition of human tumor cells. Indeed, betasisterol (latex isolated molecule F. carica) showed inhibitory activity on the proliferation of tumor cells In vitro [12]. The F. carica extracts containing polysaccharides have showed antioxidant, antitumor and immunomodulatory [45]. Indeed, these molecules activate dendritic cells, partially by Dectin-1/Syk pathway, and promote their maturation which induce the production of inflammatory factors (the production of multiple cytokines), thus increasing the response of T cells Although many other studies have demonstrated the immunostimulatory capacity, mechanistic pathways involved in this activity are far from clear [45]. . This activity is due to its cytotoxic properties that could be related to the induction of apoptosis and / or necrosis.

Antipyretic Activity
Several studies have revealed the antipyretic activity of figs. Indeed, the leaves ethanolic extracts were tested by Vikas et al. [2], and showed a significant reduction in body temperature, their effect is comparable to that of paracetamol. This effect may be related to the inhibitory action of these extracts on heat shock proteins or due to their effect on the thermoregulatory center.

Others Effects
Some compounds found in F. carica such as α and Υ tocopherols have several biological properties. Indeed, the alpha tocopherol (Vitamin E) has been long considered a powerful antioxidant, improves the immune system and metabolism, reduces the risk of cancer and cardiovascular disease and prevent cataract. While Gamma tocopherol was found to reduce inflammation and regulate the factors that protect against some cancers [6]. Fig has also a laxative effect that is probably due to the seeds and fibers of combined with some specific solvent present in juice. For example, the fruit juice with honey is used to stop the bleeding. Figs are also used for diseases of the liver, spleen, kidney calcification and its bark was very useful to soothe ulcers caused by burns when it was boiled in water with Azadirachta indica and mango [4]. On other hand, the fig latex has and anthelmintic activity and especially against Ascaris Tricharus. This effect has been attributed to the presences of laficine in fig latex (enzyme that has been recognized for its anthelmintic activity) [4]. The hypoglycemic effect was also confirmed in patients suffering from diabetes type 1, by associating their treatment of the leaves of the fig tree, the consumption of insulin was reduced by 12% with a significant cholesterol reduction of spleen [49,10].

CONCLUSION
Ficus carica has been broadly used as traditional medicine in several countries. As argued below, all parts of this plant have been used in the treatment and prevention of several complications. Flavonoids are the main bioactive compounds in this plant and different extracts have been found to possess biological activity. Less toxicity of this plant represent the possible uses as therapeutic remedy for several ailments. This review has presented a comprehensive view about the phytochemistry and pharmacology of F. carica. However the research is very limited in some areas and further study on phytochemicals and their mode of actions revealing pharmacological effects are required to fully understand in concern with the traditional uses. In addition majority of medicinal studies were conducted using crude and poorly other solvent extracts. In such case more bioactive compounds should be identified through bioassay guided isolation. More clinical studies on the toxicity of extracts from different parts and the isolated compounds from this plant need to be assessed for ensuring the safe application as modern medicines in Morocco.

COMPETING INTERESTS
Authors have declared that no competing interests exist.