Moringa Genus: A Review of Phytochemistry and Pharmacology

Moringa is a genus of medicinal plants that has been used traditionally to cure wounds and various diseases such as colds and diabetes. In addition, the genus is also consumed as a source of nutrients and widely used for purifying water. The genus consists of 13 species that have been widely cultivated throughout Asia and Africa for their multiple uses. The purpose of this review is to provide updated and categorized information on the traditional uses, phytochemistry, biological activities, and toxicological research of Moringa species in order to explore their therapeutic potential and evaluate future research opportunities. The literature reviewed for this paper was obtained from PubMed, ScienceDirect, and Google Scholar journal papers published from 1983 to March 2017. Moringa species are well-known for their antioxidant, anti-inflammatory, anticancer, and antihyperglycemic activities. Most of their biological activity is caused by their high content of flavonoids, glucosides, and glucosinolates. By documenting the traditional uses and biological activities of Moringa species, we hope to support new research on these plants, especially on those species whose biological properties have not been studied to date.


INTRODUCTION
The genus Moringa is one of the genera found in the Moringaceae family along with Anoma and Hyperanthera. It is well-known as the "drumstick" or "horseradish" family. The Moringa genus comprises 13 species distributed through southwest Asia, southwest Africa, northeast Africa, and Madagascar. The species and their distributions are listed in Table 1.
Among the 13 species, current research is limited to Moringa oleifera, Moringa stenopetala, Moringa concanensis, and Moringa peregrina. As the other species are endemic to Madagascar and Northeast Africa, they are being evaluated less as there is less exploration for naturally occurring bioactive substances in these locations. In contrast, M. oleifera, which is native to India, is being studied widely. As a result, the species has been cultivated throughout the world, specifically in Asia, Latin America, Florida, the Caribbean, and the Pacific Islands (Fahey, 2005).
The species in this genus can be categorized into three groups depending on their type of trunk (Olson and Rosell, 2006). M. stenopetala, Moringa drouhardii, Moringa ovalifolia, and Moringa hildebrandtii have bloated water-storing trunks and are known as bottle trees. Meanwhile, M. peregrina, M. concanensis, and M. oleifera have slender trunks. The remaining species are tuberous shrubs endemic to Northeast Africa. Moringa species are also resistant to drought, and can grow fast without needing much care.
The Moringa genus has traditionally been widely used to improve health. Kings and queens used Moringa to improve their alertness and to maintain healthy skin. Indian warriors were fed common flavonoids of the genus are rutin (1), quercetin (3), rhamnetin (6), kaempferol (8), apigenin (9), and myricetin (14). Optimization research has been conducted to discover the best way to extract flavonoids from M. oleifera with highest yield. As a result, subcritical ethanol extraction yielded 26.7% more flavonoid than a reflux method (Wang et al., 2017).
Disruption of plant tissues usually from cutting or chewing caused the release of myrosinase which, when in contact with glucosinolates produces isothiocyanates. The most abundant isothiocyanate found in the genus, 4-[(α-L-rhamnosyloxy) benzyl] isothiocyanate (GMG-ITC) (34), is derived from 4-O-(α-L-rhamnopyranosyloxy)-benzyl glucosinolate (30). Recently, isothiocyanates have become a major research interest of Moringa for their various biological activities such as their anticancer, antidiabetic, antimicrobial, and anti-inflammatory effect (Park et al., 2011;Padla et al., 2012;Waterman et al., 2014Waterman et al., , 2015. The alkylation of isothiocyanates with proteins and DNA contribute to their biological activity (Nibret and Wink, 2010).  Dehshahri et al. (2012a) initiated an in vitro callus culture study of M. peregrina to induce the production of isothiocyanates but the study did not manage to produce any. Isothiocyanate is commonly present as a volatile oil and is not stable at room temperature. In contrast, M. oleifera's isothiocyanate is very stable and present as a solid at room temperature because of the additional sugar moiety on its structure .

BIOLOGICAL ACTIVITIES Antioxidant
The high phenolic content of Moringa species contributes to their high antioxidant activity. Phenolic compounds stabilize radicals produced in cells by donating or accepting electrons, hence acting as antioxidants. A water extract of M. stenopetala leaves had higher DPPH (1,1-di-phenyl-2-picrylhydrazyl) inhibition (IC 50 : 40 µg/mL) than a similar extract of M. oleifera leaves (IC 50 : 215 µg/mL). Rutin (1) also possessed high antioxidant activity (IC 50 : 5 µg/mL) in a DPPH assay. An HPLC analysis showed a higher content of rutin (1) in M. stenopetala, making it a stronger antioxidant than M. oleifera (Habtemariam and Varghese, 2015). A methanol fraction of M. peregrina leaves showed DPPH inhibition (IC 50 : 17.07 µg/mL) which was comparable to ascorbic acid's DPPH inhibition (IC 50 : 13.68 µg/mL) (Al-Owaisi et al., 2014). Based on HPLC results, M. peregrina leaves' hexane fraction did not contain phenolic compounds, but did possess radical scavenging activity. Abd El Baky and El-Baroty (2013) reported that M. peregrina seed oil also had significant antioxidant activity compared to the common antioxidants BHA, α-tocopherol, and BHT. M. ovalifolia, specifically its bark, contained quercetin (3), kaempferol (8), and myricetin (14) that showed antioxidant activity by increasing ferric reducing activity and inhibiting DPPH activity (Ananias, 2015). A study reported that pre-treatment of M. peregrina leaves could prevent the plasma hydrogen peroxide concentration from rising at doses of 200 and 400 mg/kg (Safaeian et al., 2015). It also reduced the elevated hydrogen peroxide concentration in plasma and increased the ferric reducing antioxidant at doses of 400 mg/kg. Santhi and Sengottuvel (2016) reported that a methanol extract of M. concanensis leaves inhibited DPPH activity, hydroxyl radicals, reducing power, and superoxide anion radicals. The hydroxyl radical inhibition of the extract (IC 50 : 45.3 µg/mL) was stronger than that of ascorbic acid (IC 50 : 58.2 µg/mL). Ndhlala et al. (2014) studied the phytochemical properties, and the antioxidant and antimicrobial activities of M. oleifera from 13 different cultivars around the world. It was found that M. oleifera from different cultivars had different antioxidant, phytochemical, and antimicrobial profiles. M. oleifera from one of Thailand's cultivars was five times stronger in inhibiting DPPH radical scavenging activity than ascorbic acid was. Verma et al. (2009) reported that the most active fraction of a M. oleifera leaf hydromethanolic extract was the ethyl acetate fraction. The fraction inhibited DPPH by IC 50 at 0.04 mg/mL, which was comparable with quercetin (3) activity that had inhibited DPPH with an IC 50 -value of 0.02 mg/mL. As well as in-vitro tests, the ethyl acetate fraction of M. oleifera leaves has been tested on CCl 4 intoxicated rats (Verma et al., 2009). The extract increased superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) levels. Pre-treatment of the M. oleifera leaf hydroethanolic extract also counteracted hepatoxicity induced by paracetamol in Sprague-Dawley rats by reducing lipid peroxidation levels and normalizing antioxidant enzyme levels (Uma et al., 2010). A study observed that M. oleifera leaf extract reduced DNA breakage in KB cells in addition to increasing their antioxidant enzymes and inhibiting lipid peroxidation (Sreelatha and Padma, 2011). The antioxidant activity of leaf, oil, and seed ethanolic extracts of M. oleifera have been reported to display renal protective and hepatoprotective activity against gamma radiation, HgCl 2 , acetaminophen, and arsenic Fakurazi et al., 2008;Sinha et al., 2011;Abarikwu et al., 2017). Agrawal et al. (2015) observed that M. oleifera hydro alcoholic root extract acted synergistically with curcumin and with piperine in inhibiting oxidative stress induced by beryllium in rats. By controlling GSH level, M. oleifera ethanol extract reduced glucose-induced cataractogenesis of isolated goat eye lenses (Kurmi et al., 2014). This activity was also observed in the flavonoid fraction of the M. oleifera leaves that reduced seleniteinduced cataractogenesis in rat pups (Sasikala et al., 2010).
A study stated that myricetin (14) from M. oleifera seeds had stronger antioxidant activity than α-tocopherol and BHT (Lalas and Tsaknis, 2002). A leaf extract of M. oleifera contained isoquercetin (4), astragalin (5), and crypto-chlorogenic acid (54). The leaf extract of the plant, together with the compounds, reduced reactive oxygen species in HEK-293 cells that were induced by H 2 O 2 (Vongsak et al., 2015). The compound that had the highest antioxidant activity was determined to be isoquercetin (4) as it increased the mRNA expression levels of CAT, heme oxygenase 1, and SOD. Maiyo et al. (2016) isolated two compounds from M. oleifera seeds and leaves that showed antioxidant activity: quercetin-3-O-glucoside (18) displayed significant antioxidant activity while 4-(β-D-glucopyranosyl-1->4-α-L-rhamnopyranosyloxy) benzylisothiocyanate (43)'s activity was moderate. Ngamukote et al. (2016) conducted a study on the effects of M. oleifera extract on the fasting plasma glucose (FPG) concentrations of healthy volunteers, in addition to its antioxidant activity. The extract reduced plasma malondialdehyde (MDA) levels, increased Trolox equivalent antioxidant activity, increased the ferric reducing ability of the plasma, and did not change the FPG concentration compared with that of healthy volunteers that were fed only warm water.

Anti-convulsant
Experiments to discern the effects of M. concanensis leaf ethanol extract on the maximal electroshock seizure test and the pentylene tetrazole-induced convulsion test were conducted on Swiss albino mice (Joy et al., 2013). For both of the tests, M. concanensis inhibited mortality compared to control group in which deaths resulted. The study reported that the extract might block either calcium channels, sodium channels, or NMDA receptors, or has GABA agonist activity.

Anticancer
The main pathway for the anticancer activity of Moringa species is by inhibiting proliferation through apoptosis. Table 4 summarizes the cancerous cell lines that have been inhibited by Moringa species. Methanol crude extracts of M. concanensis root bark inhibited the proliferation of hepatocellular carcinoma (Hep-G2) cells through intrinsic pathways by regulating caspase 9 and caspase 3 while reducing the mitochondrial membrane potential of the cells (Vijayarajan and Pandian, 2016). (4 ′ -Oacetyl-α-L-rhamnopyranosyloxy)benzyl isothiocyanate (37) and niazimicin (70) were responsible for the regulation of caspase 9 activity (Tiloke et al., 2013). M. oleifera leaf extract decreased the proliferation of B16F10 melanoma cells in addition to causing roughly 22% cancerous cell death (Gismondi et al., 2013). It caused apoptosis at the sub G1-area and induced cell arrest at the G2/M phase. The extract increased the p27 Kip1 , p 53 , and p21 WAF1/Cip1 levels of the cells. Moringin (34) inhibited malignant astrocytoma cells by oxidative stressmediated apoptosis through Bax and p53 activation pathways . Nibret and Wink (2010) reported that seed oil from M. stenopetala inhibited the proliferation of HL-60 cells with IC 50 : 11.63 µg/mL. The bioactive compound reported was benzyl isothiocyanate (42), that had high cytotoxic activity against HL-60 cell with IC 50 : 4.62 µg/mL.
An ethanol extract of M. stenopetala leaves and seeds reduced Hep-G2 activity and increased LDH leakage in a dose and time-dependent manner (Mekonnen et al., 2005). 4-(β-D-glucopyranosyl-1->4-α-rhamnopyranosyloxy)benzylisothiocyanate (43) had stronger anticancer activity than quercetin-3-O-glucoside (18) against Caco-2 and Hep-G2 cells (Maiyo et al., 2016). The presence of eugenol (101)  A water extract of M. oleifera pods exhibited suppressive effects on dextran sodium sulfate-and azoxymethane-induced mouse colon carcinogenesis (Budda et al., 2011). The extract reduced COX-2 proteins and iNOS expression in addition to reducing the PCNA index of the mice. The extract also reduced the multiplicity and incidence of the tumors. The study reported that the high content of omega-9 oleic fatty acid (83) in the extract, that possesses anti-inflammatory activity, could modulate this cell proliferation. Alternately, glucomoringin (30) might also be responsible for this antitumor activity.
A hydro alcoholic extract of M. oleifera also exhibited antitumorigenic activity by balancing xenobiotic metabolism between Phase I and Phase II (Bharali et al., 2003). The extract increased Cyt P450 and Cyt b5 activity in Phase I while increasing glutathione S-transferase, glutathione reductase, and glutathione peroxidase, and reducing the GSH levels that are responsible for Phase II. The study also reported that the extract might act as a "blocking agent" in reducing xenobiotic substrates for Phase II. In addition, the extract increased CAT concentration while reducing mouse skin papilloma genesis and lipid peroxidation.

Antimicrobial
Various research has been conducted on Moringa species for their antimicrobial activity.  activity of each species. Moringa species have been widely used as water purifiers and antiseptics for water treatment because of their high antimicrobial activity. Hexane and methanol seed extracts of both M. oleifera and M. stenopetala showed inhibition against waterborne pathogens, particularly against Salmonella typhii, Vibrio cholera, and Escherichia coli (Walter et al., 2011). Most of the extracts showed better inhibition in lower concentrations. Ethyl acetate, acetone, and ethanol extracts of M. oleifera seeds, roots, leaves, and a mixture, were assessed for their dental antibacterial and antifungal activity (Elgamily et al., 2016). All of the extracts showed inhibition of Streptococcus aureus and Streptococcus mutans with the ethanol extract and leaf extract showing the highest inhibition. In contrast, none of the extracts showed inhibition against Candida albicans. Another study reported that higher concentrations of M. oleifera seeds were needed to inhibit the growth of C. albicans (Saadabi and Abu Zaid, 2011). The ethanolic leaf extract of M. oleifera was formulated into mouthwash and toothpaste (Elgamily et al., 2016). As a result, the toothpaste showed inhibition of Streptococcus aureus, S. mutans, and C. albicans, but the mouthwash only showed antimicrobial activity. The ethanol extracts of the seeds and leaves of M. oleifera also exhibited inhibition against the dermatophytes Trichophyton mentagrophytes, Microsporum canis, Trichophyton rubrum, and Epidermophyton floccosum (Chuang et al., 2007).
Hexane, ethyl acetate, methanol, and chloroform extracts of M. oleifera leaves were also tested on different diarrhea associated bacteria: Serratia marcescens, Shigella dysenteriae, Enterobacter sp., E. coli, Klebsiella pneumoniae, and Salmonella sp. . All of the extracts exhibited antibacterial activity against the bacteria with minimum inhibitory concentrations ranging from 62.5 to 1,000 µg/mL and zones of inhibition of 8-23.2 mm. Peixoto et al. (2011) reported that aqueous and ethanolic extracts of M. oleifera leaves showed inhibition against Staphylococcus aureus, Vibrio parahaemolyticus, Enterococcus faecalis, and Aeromonas caviae. In contrast, the extracts showed negative result on E. coli, Salmonella enteritidis, and Pseudomonas aeruginosa. Throughout the study it was observed that the extract showed stronger inhibition against gram-positive species than gram-negative species.

Antitrypanosomal
In the Moringa genus, M. stenopetala showed significant antitrypanosomal activity. M. stenopetala leaf acetone extract and root ethanol extract inhibited the infective stages of Trypanosoma brucei (Mekonnen, 2002). A methanol extract of M. stenopetala maintained 100% survival against Trypanosoma congolense (Kifleyohannes et al., 2014). It also minimized PCV which is a method of controlling anemia. Dichloromethane and methane extracts of the seeds had low trypanocidal activity while the essential oils that contain mainly benzyl isothiocyanate (42) and isobutyl isothiocyanate (41) showed potent trypanocidal activity (Nibret and Wink, 2010). Petroleum ether, chloroform, methanol, and aqueous fractions of M. oleifera leaves, stem bark, and roots inhibited Trypanosoma brucei brucei (Ibrahim et al., 2014). Ayyari et al. (2013) reported that 4-[(α-L-rhamnosyloxy) benzyl] isothiocyanate (34) from M. peregrina aerial parts inhibited Trypanosoma brucei rhodesiense with an IC 50 of 0.1 µM. With a dose 10 mg/kg for four consecutive days, the compound reduced parasitemia by 95% but the parasitemia increased again after 10 days of infection. The compound was reported to have the potential to become a high quality antitrypanosomal drug as it inhibited the parasite at specific enzymes and irreversibly inhibited trypanothione reductase. An acetone extract of M. stenopetala leaves and an ethanol extract of M. stenopetala root wood inhibited Trypanosoma brucei trypomastigotes with ED 50 -values of 10 and 9.2 µg/mL, respectively (Mekonnen et al., 1999). Mekonnen and Gessesse (1998) reported that high concentrations of M. stenopetala extract, 600 to 1,500 µg/mL, changed Leishmania donovani promastigotes' shape and resulted in the loss to their flagella in 40-95% of them. A root extract of the plant inhibited Leishmanial aethiopica in mice (Bekele et al., 2013). 1,3-Dilinoleoyl-2-olein (106) and 1,3-dioleoyl-2-linolein (110) from the roots inhibited the promastigotes and amastigotes stages of the parasite. The activity of 1,3-Dilinoleoyl-2-olein (106) in inhibiting the promastigotes stage was comparable to that of the positive control, miltefosine. Kaur et al. (2014) reported that a 70% ethanolic extract of M. oleifera roots and a methanolic extract of M. oleifera leaves displayed antileishmanial activity against L. donovani promastigotes. The ethyl acetate fraction of a methanolic extract inhibited leishmaniasis with an IC 50 of 27.5 µg/mL. Niazinin, isolated from the ethyl acetate fraction, showed the most antileishmanial activity with an IC 50 of 27.5 µg/mL. Singh et al. (2015) observed antileishmanial activity from different parts of M. oleifera, the bark, leaf, stem, flower, and root. The flower, especially from the ethyl acetate fraction, showed the most potent activity against L. donovani promastigotes in infected macrophages by inhibiting parasite viability in a dose-and timedependent manner. The extract also reduced parasite activity in both the spleen and the liver of Balb/c mice.

Antiviral
M. oleifera extract possessed antiviral activity against the herpes simplex virus type 1 (HSV-1) by inhibiting more than 50% of plaque formation at a 100 µg/mL dose (Lipipun et al., 2003). The extract inhibited phosphonoacetate-resistant HSV-1 and kinasedeficient HSV-1 strains in mice. At a dose of 750 mg/kg, the extract reduced the mortality of the infected mice by prolonging their mean survival time and delaying the development of skin lesions. An aqueous extract of M. oleifera leaves activated cellular immunity in mice that were infected with HSV-1 by reducing the virus concentration and limiting herpetic skin lesion development (Kurokawa et al., 2016). M. peregrina seed oil was also reported to have antiviral effects against HSV (Soltan and Zaki, 2009). Murakami et al. (1998) reported that 4-[(4 ′ -Oacetyl-alpha-L-rhamnosyloxy) benzyl] isothiocyanate (37) and niaziminin (76) inhibited Epstein-Barr virus activation. M. oleifera also showed inhibition against the foot and mouth disease virus at concentrations of 1-50 µg/mL (Younus et al., 2016).
A buffer extract of M. oleifera fruits exhibited anti-HBV activity and a hydroalcoholic extract of the plant's leaves reduced the ccDNA level of HBV in HepG2 cells (Waiyaput et al., 2012). According to a survey, M. oleifera was being used as a supplement toward antiretroviral therapy for HIV infection, but no further research has been conducted on the efficiency of the plant as an antiviral substance (Monera and Maponga, 2010).

Antihyperglycemic, Antihyperlipidemic, and Hypocholesterolemic
Ethanol and aqueous extracts of the aerial parts of M. peregrina exhibited antihyperglycemic activity against streptozotocin diabetic rats by lowering their blood glucose levels (El-Alfy et al., 2011). The hexane fraction from an ethanol extract of the plant reduced blood glucose levels by 64-77.44% for 3 h after 30 min of administration. The study suggested that this activity might be because the fraction contained the antihyperglycemic compounds lupeol acetate (62) and βsitosterol (77). M. stenopetala leaf hydroalcoholic extract was reported to inhibit certain enzymes that related to hyperglycemia and hyperlipidia, such as maltase, sucrase, pancreatic cholesterol esterase, pancreatic lipase, and pancreatic α-amylase (Toma et al., 2014). The leaf extract also reduced cholesterol, triglycerides, and the glucose lipid profile in fructose-induced rats (Geleta et al., 2016b). Sangkitikomol et al. (2014) evaluated the effects of M. oleifera leaf hydroethanolic extract on advanced glycation end products. Throughout the study, the extract reduced the mRNA expression of PPARα1, PPAR-γ, and HMG-CoAR that are responsible for maintaining lipid homeostasis. The extract inhibited the formation of AGE in HepG2 cells at doses of 2.5-10 mg/mL. M. oleifera aqueous leaf extract also inhibited formation of both nonfluorescent and fluorescent advanced glycation end products by reducing monosaccharides, in addition to reducing the oxidation of thiols and protein carbonyl content (Nunthanawanich et al., 2016).
A study reported that an aqueous extract of M. oleifera leaves increased insulin levels and decreased insulin resistance, helping to combat hyperglycemia in diabetic rats (Tuorkey, 2016). The extract reduced creatinine and urea levels from damaged kidneys and increased the immune tolerance of the diabetic rats by increasing the activity of CD69, INF-γ, and CD44. Insulin-like protein was observed in the seed coat of M. oleifera (Paula et al., 2016). This protein had antigenic epitopes similar to insulin and displayed hypoglycemic activity on oral administration. The same activity was observed by a protein from M. oleifera leaves (Paula et al., 2017). The protein reduced blood glucose levels after single and repeated doses of the extract. It displayed antioxidant activity by increasing CAT levels and reducing MDA levels. It also cross-reacted with anti-insulin antibodies which proved that it might have antigenic epitopes similar to insulin. M. oleifera leaf extract reduced FPG level, post-prandial levels, blood glycated hemoglobin, total cholesterol, non-HDL-C, HDL-C, VLDL-C, and LDL-C in Type 2 diabetic patients (Kumari, 2010;Nambiar et al., 2010;Ghiridhari et al., 2011). Leaf powder capsules (4 g) significantly increased the secretion of insulin in healthy subjects (Anthanont et al., 2016).
M. oleifera seed extract reduced lipid peroxidation and increased antioxidant enzyme activity in streptozotocin-induced mice (Al-Malki and El Rabey, 2015). It also reduced the immunoglobin IgG and IgA activity of the mice which correlated to the reduction of IL-6 that is responsible for glucose homeostasis and pancreatic beta cell activity. The seed extract normalized the activity of both damaged kidneys and pancreases without changing the pathology of the mice. It was reported that the bioactive compounds involved were quercetin (3), kaempferol (8), glucomoringin (30), and chlorogenic acid (54) and that they had various biological activities such as their anticancer, antioxidant, hypotensive, anti-inflammatory, hypoglycemic, and antidyslipidemic effects. Other than these compounds, isothiocyanates (34-37) had also been reported to show antidiabetic activity . A study reported that benzylamine (108) isolated from M. oleifera reduced the plasma cholesterol, body weight gain, hyperglycemic responses, and fasting blood glucose levels of high fat dietinduced mice (Iffiu-Soltesz et al., 2010). Barbagallo et al. (2016) reported that M. oleifera reduced IL6 expression and had protective effect toward adipocytes by inducing the expression of heme-oxygenase-1. The extract increased IRS-1 gene expression which is responsible for insulin resistance and a shortage of which causes type 2 diabetes. In addition, the extract also induced thermogenesis during the differentiation of adipose tissue by upregulating the activity of mediators of thermogenesis, specifically the uncoupling protein, PPARα, sirtuin 1, and coactivator 1 α. M. oleifera extract (100 µg/mL) showed the same behavior as 0.4 µg/mL pravastatin in inhibiting HMG-CoA reductase and decreasing cholesterol biosynthesis (Duangjai et al., 2011). M. oleifera also displayed synergistic effects with sitagliptin showing antihyperglycemic activity and delaying lenticular opacity in diabetic rats (Olurishe et al., 2016). A different reaction of HDL level was observed between normal rabbits and hypercholesterolemic rabbits fed with M. oleifera. M. oleifera decreased HDL levels in normal rabbits but increased HDL levels in hypercholesterolemic rabbits (Mehta et al., 2003;Nunthanawanich et al., 2016). The lipid profiles of the aorta, heart, and liver were reduced in the hypercholesterolemic rabbits. Mekonnen (2002) reported that an ethanolic extract of M. stenopetala leaves reduced fertility by 73.3%. The extract exhibited oxytocic activity on guinea pig and mouse uteri. The extract also increased the smooth muscle of the mice uteri that might lead to contraction, thus rejecting implantation. M. concanensis stem bark also inhibited implantation by 46% using 400 mg/kg of the extract (Ravichandiran et al., 2007). The reaction was solvent-dependent. The ethyl acetate fraction showed the lowest anti-implantation activity in contrast to chloroform, petroleum ether, and an ethanol extract.

Antifertility
It was reported that M. oleifera leaf extract aborted 100% of implantation in seven rats (Sethi et al., 1988). The extract was administered after 5-10 days after mating. The aqueous root extract of the plant did not promote a favorable condition of the uterus for implantation of the fertilized eggs (Prakash et al., 1987). A high dose of the root extract, 600 mg/kg, had anti-progestational activity, preventing the formation of the deciduoma in rats . It also reduced the protein concentration for the formation of the uterus .

Anti-inflammation
A study reported that an ethanolic extract of the M. concanensis flower and fruit inhibited inflammation by 78.4 and 44.08%, respectively (Rao et al., 2008;Jayabharathi and Chitra, 2011). An extract of the aerial part of M. peregrina decreased the effect of peritorial inflammation and reduced the permeability of small blood vessels (Elbatran et al., 2005). Ethanolic and aqueous extracts of M. peregrina seeds inhibited fresh egg albumininduced acute inflammation in rats at doses of 100-300 mg/kg p.o (Koheil et al., 2011).
A study reported that a methanol extract of M. oleifera leaves reduced the edematogenic effect of carrageenan-induced and histamine-induced paw edema (Adedapo et al., 2015). The extract reduced the number of writhes of mice induced by acetic acid. The analgesic activity of the extract was recorded to be higher than that of the reference drug, indomethacin, at doses of 100 and 200 mg/kg. The inflammatory response after administration of an M. oleifera ethanolic leaf extract was observed on atopic dermatitis mice and human keratinocytes (Choi et al., 2016). The extract reduced mannose receptor mRNA, retinoic acid-related orphan receptor γT, and thymic stromal lymphopoietin expression in ear tissue. From an in vitro assay, it was observed that the extract reduced mitogen-activated protein kinases, CCL17, IL-6 pro-inflammatory cytokine-related mRNA, TNF-α, and IL-1β expression. M. oleifera pod extract also inhibited the elevation of protein levels and mRNA of cyclooxygenease-2, TNF-α, IL-6, and iNOS by inhibiting the phosphorylation of mitogen-activated protein kinases and κB proteins (Muangnoi et al., 2012).
M. oleifera hydroethanolic and methanolic leaf extracts improved the cellular and humoral immunity of normal and immunosuppressed mice in a dose-dependent manner (Gupta et al., 2010;Nfambi et al., 2015). The extract increased the phagocytic index, weight of the thymus and spleen, antibody titer, and white blood cell and neutrophil concentration. An ethanolic extract of M. oleifera seeds inhibited the reaction of delayedtype hypersensitivity by reducing mean foot pad thickness on mice (Mahajan and Mehta, 2010). The immunosuppressive activity of the extract was observed by its ability to downregulate phagocytosis by macrophages. The ethanolic extract of the seeds also reduced white blood cell, and leukocyte concentration which usually leads to an immunity reaction. It increased paw edema which typically resulted in type IV hypersensitivity occurring. Methanolic extracts of M. oleifera leaves exhibited analgesic effects by reducing mechanical allodynia and thermal hyperalgesia in Freund's adjuvant arthritisinduced rats (Manaheji et al., 2011). In contrast, M. oleifera methanolic root extracts only reduced thermal hyperalgesia in the rats. The activity of the root and leaf extracts were comparable with indomethacin activity. In addition, a combination of root and leaf extracts showed higher reduction of thermal hyperalgesia in lower doses. An ethanol extract of M. oleifera leaves and its major compounds, quercetin-3-O-glucoside (18), kaempferol-3-O-glucoside (21), and crypto chlorogenic acid (55), showed antiinflammatory activity, inhibiting the migration and chemotactic oxidation of polymorphonuclear leukocytes (Vongsak et al., 2013).
Moringa species also inhibited ulcers induced by non-steroidal anti-inflammatory drugs. M. oleifera extract reduced gastric lesions from acetylsalicylic acid, serotonin, and indomethacin (Pal et al., 1995), while an extract of the aerial part of M. peregrina reduced gastric lesions from indomethacin (Elbatran et al., 2005). A hydroalcoholic extract of M. oleifera seeds reduced the lesion severity and size of acute colitis induced by aceticacid in rats (Minaiyan et al., 2014). The extract also reduced the activity of TNF-α, IL-4, IL-6, and myeloperoxide which are usually responsible for inflammatory bowel diseases. Debnath and Guha (2007) reported that an M. oleifera aqueous leaf extract reduced the mean ulcer index in addition to increasing 5-HT concentration and enterochromaffin cell concentration. The extract protected against ulcer formation in aspirin-induced rats by stimulating enterochromaffin cells in the gastrointestinal tract via 5-HT 3 receptors (Debnath et al., 2011).
The ethyl acetate fraction of M. oleifera leaves obtained from a hydroethanolic extract of the plant increased normal human dermal fibroblast migration and cell proliferation . It was observed that a higher dose, more than 125 µg/mL, reduced cell proliferation. High concentrations of phenols in the extract might induced caspase and apoptosis. The migration observed also displayed a 9% better activity than the positive control, allantoin. The leaf ethyl acetate extract contained 4-[(2 ′ -O-acetyl-α-L-rhamnosyloxy)benzyl]isothiocyanate (35) and 4-[(3 ′ -O-acetyl-α-L-rhamnosyloxy)benzyl]isothiocyanate (36), both of which have anti-inflammatory activity. Muhammad et al. (2016) reported that a leaf extract of M. oleifera proliferated tissue cells, hence reducing the wound size of diabetic foot ulcers. It downregulated the activity of the inflammatory mediators TNFα, IL-1β, IL-6, iNOS, and COX-2. The extract also increased angiogenesis activity by reducing the time needed for the wound healing phase, in which vascular endothelial growth factor activity occurs. The study reported that the bioactive compound for this activity was vicenin-2 (17). An aqueous fraction of M. oleifera leaves reduced scar areas and increased the closure rates of wounds in addition to increasing the granuloma and skin breaking strength, granuloma dry weight, and hydroxyproline content of albino rats (Rathi et al., 2006). M. oleifera protease activity from leaf and root aqueous extracts exhibited proteolytic, fibrinolytic, and fibrinogenolytic activity on blood clotting (Satish et al., 2012). The protease showed similar activity to plasmin and thrombin. The protease also attenuated apoptosis in addition to suppressing PPAR gamma activation. Bhatnagar et al. (2013) reported that an M. oleifera seed extract, together with Acacia arabica biopolymers, had potential as a wound dressing material. In addition to being good antimicrobial substances, the biopolymers were biodegradable and could absorb water from 415 to 935%. They also shortened the time taken to activate partial prothrombin and thromboplastin.
Antihypertension Safaeian et al. (2015) showed that an M. peregrina leaf extract, administered before and during the administration of dexamethasone to rats, prevented their systolic blood pressure from increased but did not reduce already increased systolic blood pressure. The bioactive dose, 400 mg/kg, showed low but significant antihypertensive activity. The compounds that were reported responsible for this activity were quercetin (3), apigenin (9), and lupeol (82) which had been previously reported to possess antihypertension activity. Safaeian et al. (2015) mentioned that the plants used were obtained during summer and this might affect the concentration of bioactive compounds in the plant. This correlated to a study that observed that the total phenolics in M. oleifera harvested in winter was higher than that in plants harvested in summer (Shih et al., 2011).
The vasodilatory activity of an M. stenopetala leaf crude extract and fraction were reported by Geleta et al. (2016a). The activity was observed in the thoracic aorta of guinea pigs that had been induced by various vascular contraction agents. Aqueous and 70% ethanol crude extracts of the leaves reduced the vascular contraction induced by potassium chloride, methylene blue, epinephrine, and glibenclamide, in addition to inhibiting the increment of fructose-induced blood pressure in rats in a dose-dependent manner. The extract possessed alkaloids and glycosides that might have cause stronger activity than observed with the fractions. In the study, the extract had the greatest activity toward vascular contraction induced by potassium chloride either when the thoracic aorta was attached to the endothelium, or not. Geleta et al. (2016a) suggested that the extract blocked Ca 2+ channels during this activity. The endothelium might have stimulated relaxing factors that increased the extract's activity.
A study reported that an ethanol extract of M. oleifera leaves reduced pulmonary arterial blood pressure immediately after administration of monocrotaline to rats (Chen et al., 2012). As pulmonary hypertension is usually related to increased reactive oxygen species in the system, the antioxidant activity of the extract that increased SOD activity might be the largest contribution toward its antihypertension activity on pulmonary hypertension. The bioactive compounds reported in this study were niazirin (97) and niaziridin (98). M. oleifera seeds also exhibited cardioprotective activity in spontaneous hypertensive rats (Randriamboavonjy et al., 2016). The extract increased cardiac diastolic function and reduced nocturnal heart rate without modifying the blood pressure of the rats. It also reduced fibrosis and the thickness of the left ventricular relative, interseptal, and anterior walls, in addition to reducing cardiac triglyceride levels. Plasmatic prostacyclin and PPAR-α and γ , activity was also increased by the extract. The study concluded that the extract exhibited antifibrotic and antihypertrophic activity that helped protect cardiac function in hypertension rats.
In addition, it was reported that the antioxidant activity of an M. oleifera leaf butanolic extract helped to reduce cardiac necrosis and oxidative stress in isoproterenol-induced rats (Panda, 2015).
The extract reduced cardiac lipid peroxidation and increased cardiac antioxidants. The free radicals in the cardiac region were inhibited by the extract with IC 50 -values of 19.92 ± 1.19 µg/mL which was comparable with quercetin (3) activity (IC 50 -value of 19.95 ± 1.17 µg/mL). The extract also reduced inflammation and necrosis to almost normal myofibrillar structure. N,α-Lrhamnopyranosyl vincosamide (67) exhibited cardioprotective activity by reducing the level of serum cardiac markers and myocardial necrosis in addition to normalizing the cardiac histology of isoproterenol-induced rats (Panda et al., 2013).

Others
A study reported that M. oleifera exhibited antidepressant activity (Kaur et al., 2015). The crude extract showed positive results in the forced swim test, tail suspension test, and locomotor activity test. The activity was enhanced with coadministration of the SSRI depression drug, fluoxetine. In addition, high doses of the extract, particularly 2,000 mg/kg, did not exert toxicity on the tested mice. Akanni et al. (2014) reported that an ethanol extract of M. oleifera leaves exhibited antileukemic activity against benzene-induced leukemic Wistar rats. The extract normalized the leukemic condition, increased GSH, and reduced MDA levels in the rats. Galuppo et al. (2015a) reported that isothiocyanate, specifically 4-[(α-Lrhamnosyloxy)-benzyl] isothiocyanate (34), isolated from M. oleifera delayed ALS development. The compound reduced PARP-1 activity in addition to promoting Nrf-2 activity. The study suggested that the isothiocyanate interfered with motor neuron degeneration and ALS development in the SOD1 rats. Upon administration of 125 mg/kg M. oleifera leaf extract, rats' antibody against the Salmonella typhimurium "O" antigen increased to 50%. The extract also increased the concentration of serum immunoglobulins, white blood cells, and neutrophils, hence increasing the humoral immune response of the rats (Jayanthi et al., 2015). Awodele et al. (2012) reported that an aqueous extract of M. oleifera leaves did not produce any mortality in Wistar albino mice at orally administered doses of up to 6,400 mg/kg. Higher doses (3,200 and 6,400 mg/kg) did triggered dullness and reduced locomotion in the rats. There was no significant difference observed on the rats' sperm quality, or on their hematological, histological, and biochemical parameters. The LD 50 -value was determined to be 1,585 mg/kg. In another study, it was reported that high doses of M. oleifera leaves (3,000 mg/kg) caused the presence of micro nucleated polychromatic erythrocytes in the femur bone marrow of Sprague-Dawley rats (Asare et al., 2012). The study reported that doses of more than 3,000 mg/kg caused acute toxicity and increased the urea levels of the rats. The study reported that this was caused by high concentrations of nitrogenous compounds in the M. oleifera, potentially from proteins.

CONCLUSION
Various research has been conducted to evaluate the traditional uses of Moringa species and all of the research supported the traditional claims. However, there are still an abundance of traditional uses that have not been evaluated, especially in species other than M. oleifera and M. stenopetala. Hence, further research is needed to exploit the many uses of Moringa species.

AUTHOR CONTRIBUTIONS
NA obtained the literatures and wrote the manuscript while KH and EK gave ideas and edited the manuscript.