Therapeutic role of Ricinus communis L. and its bioactive compounds in disease prevention and treatment

Waseem Mohammed Abdul, Nahid H. Hajrah, Jamal S.M. Sabir, Saleh M. Al-Garni,Meshaal J. Sabir, Saleh A. Kabli, Kulvinder Singh Saini,3, Roop Singh Bora,3

1Biotechnology Research Group, Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia

2Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia

3Department of Biotechnology, Eternal University, Baru Sahib-173101, HP, India

1. Introduction

Nature has been an excellent source of therapeutic agents since the immemorial time[1]. Traditional and conventional medicines are mostly based on numerous natural resources, including plants which are being used as a primary source in folkloric medicine[2]. Before the discovery of chemical and synthetic compounds, these plants played a significant role as a traditional medicine for curing various diseases throughout the world[3]. However, with the emergence of modern techniques and equipment, synthesis of new classes of synthetic compounds has attracted attention among researchers during recent years. Some of these compounds were first isolated from the natural sources but further modified to improve their efficacy[4]. However, synthetic drugs have several limitations such as poor absorption, low bio-availability and adverse side effects. Thus, there is an urgent need to substitute these synthetic compounds with some excellent alternative sources of therapeutic agents which can be used for curing diseases around the globe.Plant-based biologically active compounds have gained momentum on a large scale in last 3 decades[5]. So, the idea of combining the old and conventional concept of using herbal plants as a primary source of folkloric medicine with the modern and latest technology based application can lead to tremendous development in the field of new drug discovery[6].

Plant-based compounds are of great interest for discovering a drug for the particular disease. Due to varied pharmacological activities of plants as tested by using the plant crude extracts, the screening and selection of lead candidates for drug development from medicinal plants have come into effect. The number of higher plant species estimated is 300 000–400 000. One of the most extensive programs of plant screening was conducted by Smith Kline & French in which about 19 000 plants species were screened using a simple colour test for alkaloid content detection in the 1960s[7].

Out of the 1 073 new chemical entities, that had been approved as drug between 1981 and 2010, the purely synthetic compounds amounts for only 36%, while most of the new drugs were derived from medicinal plants[1]. Many of the lead chemical structures used as a template for synthesis of drugs are derived from natural products which help in designing novel compounds with all the enhanced biological properties against some diseases. The WHO has predicted natural products as an essential resource for emerging therapeutics and future medicines. Based on the statistical estimation, nearly 83 billion USD worth of herbal medicine was used globally in 2008[8].Development of resistance to various antibiotics is also a reason for the pharmaceutical industry to look for the discovery of novel molecules which can fight against various antibiotic-resistant microbes. Moreover, there is an urgent need to combat the menace of resistance developed towards anti-cancer drugs[9]. By deciphering the mechanism of action of various crude extracts and plant-based compounds, there is a excellent possibility for obtaining novel compounds[10]. Biological effects of the plants are determined and represented by various bioactive constituents present in it, which act as a ligand and bind to the protein targets of a particular pathogen,virus or tumour cell and exert their action[11].

Ricinus communisL. (R. communis) is a medicinal plant which grows to a height of about 6 m and is distributed around various continents including Arabian Peninsula. Castor plant has been cultivated as far back as 6 000 years ago[12]. The botanical name ofR. communiswas coined by Swedish naturalist Carlos Linnaeus in the 18thcentury[13]. Some scholars believe its origin to be from Tropical Africa. In Saudi Arabia, it is commonly known as Kherwa[12]. It is an angiosperm shrub which is commonly known as castor oil plant. Castor bean is an oilseed crop which is fast-growing,suckering perennial herb belonging to spurge (Euphorbiaceae)family, comprising of about 6 300 species[14].R. communishas been a therapeutic agent for 4 000 years, used as a herbal medicine for treating many different diseases, disorders and also many infections. Leaves, root, bark and various parts of theR. communishave been used for medicinal purposes. It has been used as a laxative for 2 500 years in Greece and Rome[12]. Due to the large quantity of oil extracted fromR. communisseeds, it has been known as castor oil plant[15]. This oil is of great application in various perspectives[12]. The various phytochemicals which are found inR.communisare steroids, terpenoids, saponins, alkaloids, flavonoids,and glycosides[19,22,30]. Lectins ofR. communisare also used prominently in the treatment of some diseases, especially tumour[16].In the present review, the primary focus is on the pharmacological activities and bioactive compounds ofR. communis, and their applications in targeting of various microbes, infectious diseases and disorders.

2. Traditional uses of R. communis

There are numerous uses ofR. communisplant which utilizes every part of the plant including roots, seeds, bark, leaves, flower, fruit and stem[12]. The leaves are made up of 5–12 deep lobes, which are coarsely toothed segmental, that are palmate and alternate. The powdered leaves are found to be effective in combating mosquitoes,repelling aphids, rust mites and whiteflies. Apart from this, the leaves are found to be responsible for the increase in the yield of milk in cattle which is fed with these leaves. The oil derived from these leaves is used in relieving flatulence in infants. An infusion of leaves is used as an eye lubricant and also for relieving stomach ache. The leaves as such are used as a decoction or poultice and applied to breasts of females for an increase in milk secretion (lactation). Fresh juice obtained from leaves has been reported for its use as an emetic in the poisoning of narcotics like opium. Some have reported that leaves can be useful against jaundice too[18]. Extracts from leaves of the plant are being marketed under the trade name ‘Spra Kast’ in the United States. Antifungal activity of aqueous and alkaline extracts againstMycobacterium tuberculosisand yeast was also reported[17].

Roots are used for various purposes such as a powerful purgative,for a toothache, and this can be possible when the roots are administered in the form of decoction and paste respectively. Roots contain Indole-3-acetic acid. Seeds ofR. communisvary in size,shape, and color, and they are compressed and oval with a diameter of 8–18 mm. Castor seeds have a wart appendage called the caruncle.Seeds are the primary source of oil which is in use both as a herbal medicine and as a conventional therapy for various ailments[18].

3. Phytochemical composition of R. communis

R. communisis rich in a diverse variety of phytochemicals, Alugah and Ibraheem have reported the flavonoids and tannins content in the castor plant[19]. Following are the individual studies reporting the isolation of compounds from R.communis plant.R. communiscontain various bioactive phytochemicals such as kaempferol-3-Oand kaempferol-3-O-β-D-glucopyranoside[20], ingenol[21]triterpenoids (lupeol, β- and α-amyrin)[22], quercetin and gallic acid[23], αthujone, camphor and beta thujone[24], ricin[25],epicatechin[26], gentisic acid[27], catechin[28], linoleic acid and ricinoleic acid[29], kaempferol-3-O-β-D-glucopyranoside and quercetin-3-O-β-monoterpenoids[30].

4. Pharmacological applications of R. communis

R. communisis a multipurpose folkloric medicinal plant with some medicinal properties; these properties are associated with either direct application of crude plant extract as a therapeutic agent in various diseases or by inhibition of harmful pathogens, which are known to cause various infections and diseases. Among the various reported activities ofR. communis, a large number of them are attributed to its extract in crude form followed by various fractions which could be ethanolic, methanolic or chloroform, ethyl acetate,toluene, benzene, and butanol solvents.

Numerous studies have been carried out and published on the biological activities ofR. communisplants. These activities are both due to the crude extract and its phytochemical compounds which can be of great interest in future for the development of plant-based complementary medicine. Presently, the properties ofR. communismentioned in this review include antimicrobial, antifungal, anticancer, antidiabetic, anti-inflammatory, antimalarial, antioxidant,central analgesic, anticonvulsant, antinociceptive, anthelminthic,antifertility, laxative, uterine contracting, anti-implantation, antiasthmatic, bone regeneration, molluscicidal, antiulcer, antihistamine,wound-healing, cytotoxic, insecticidal, anti-arthritic, antidandruff and hepatoprotective (Figure 1). Diverse phytochemicals bind to specific molecular targets and hence exhibit several pharmacological activities as shown in Table 1.

Figure 1. Phytochemicals of R. communis and their pharmacological activity.

4.1. Antibacterial activity

Due to the increase in the incidence of infections in human beings with various clinical strains of bacteria and adoption of resistance against the antibiotics, there is a great need to find the reliable alternative sources to combat this so-called life-threatening issue of antibiotic resistance[43].R. communisand its phytochemicals have been found to have antimicrobial properties against various microorganisms. Some of the reported antimicrobial activity of the crude extract includes inhibition of various bacteria such asStaphylococcus aureus,Escherichia coli,Streptococcus mutans,Enterococcus faecalisand methicillin-resistantStaphylococcus aureus[44].

The activity of theR. communishas been tested using various aqueous and solvent-based extracts. The different solvents systems used are ethanolic extract (hot and cold), methanolic extract, ethyl acetate extract, butanolic extract and so forth. The ethanolic extract was found to be most effective in a large number of the cases,and the highest activity was shown againstStaphylococcus aureuswith a MIC of 5 mg/mL[45]. In one study, methanolic extractexhibited maximum activity againstEscherichia coliand lowest activity againstBacillus subtilis[46]. A study, conducted for testing the antibacterial activity indicated thatRicinusaqueous extract had shown the highest activity againstStaphylococcus aureusand lowest activity was shown towardsKlebsiella pneumonia[47]. A randomised clinical study, against bacterial pathogens, has shown theR. communisactivity as a complete cleanser solution. Inhibition of biofilm formation is due to the presence of sodium ricinoleate inR. communisoil, which damages cell wall and leads to cell death by loss of cytoplasmic components[48]. By the above results, it can be concluded thatR. communiscan be a good source for an antibacterial drug against various bacterial pathogens.

Table 1 Biological activity of phytochemicals from R. communis against different potential molecular targets.

4.2. Antifungal activity

Various parts ofR. communisincluding root, leaf and stems are known to have antifungal activity. Both methanolic and aqueous extracts ofR. communisare found to be active against many fungal species. A study was carried out for testing the antifungal activity ofR. communisextract against various fungal species, the maximum antifungal activity was shown againstCandida albicans,and lowest activity was detected againstAlternaria solani[17]. One of the studies, showed that the methanolic extract has prominent inhibitory activity againstAspergillus nigerandAspergillus fumigatusand less activity againstAspergillus flavus[45]. Another study, carried out with aqueousR. communisleaf extract have shown lowest activity againstAspergillus fumigatusandAspergillus flavus[46]. The above-mentioned studies confirm the antifungal activity ofR. communisextract, and it may be a good source for identifying a new drug candidate for inhibiting the fungi.

4.3. Anti-diabetic activity

Diabetes is a chronic disease that occurs either when the pancreas does not produce insulin required by the body or due to development of insulin resistance. The number of people who have diabetes has risen steeply from 108 million cases to 422 million in 2014 (WHO). In 2012 diabetes was the sole cause of 1.5 million deaths (WHO 2015). A study was conducted to test the antidiabetic activity of ethanolic extract ofR. communisroots and have been found to be effective against hypoglycemic rats. After treating alloxan diabetic rats for 20 d with a single dose of 500 mg/kg body weight (effective dose), lipid profile was observed by collecting blood on day 0, day 10 and day 20 of the experiment.This study demonstrated the significant lowering of fasting blood sugar to almost normal level and an increase in insulin levels,thereby causing improvement in lipid profile and body weight as well. The decrease in blood glucose levels was from (379±72)mg/dL (Diabetic rat) to (149±11) mg/dL (control)[49]. Anotherin vivostudy, on alloxan-induced diabetic rats, had reported that blood glucose levels decreased from 390.0 to 148.5 mg/dL after treatment withRicinusextract, approximately 61.97% reduction in blood glucose for over a period of 7 d[50]. These studies suggest the potential ofR. communisas a therapeutic agent for diabetic control.

4.4. Anti-cancer activity

Some studies have been carried out using fractions with 100%ethanol, methanol and an aqueous phase which have shown activity against specific cancer cell lines such as melanoma, MCF7(Breast cancer), HepG2 (Hepatic cancer), PC3 (Pancreatic cancer),and cervical cancer[51]. Bothin vitroandin vivostudies have confirmed the anti-cancer activity ofR. communisusing various plant parts and ricin lectins[52,53].

Anti-cancer activity ofR. communiswas studied and reported by several researchers. Initial studies revealed the cytotoxic effect of lectins fromR. communison three different cell lines HeLa cells,sarcoma 180 and human erythrocytes[54]. Lin and Liu observed the increase in lifespan of the mice which is treated with ricin A[55]. In one study, the aqueous extracts ofR. communiswas found to exhibit cytotoxic effects on A375 cell lines (human melanoma cancer cell lines) with IC50value of 48 μg/mL[56].According to You and colleagues, the agglutinin 1 fromRicinus,resulted in rapid down-regulation of vascular endothelial growth factor-2 (VEGFR-2) and also caused apoptosis of endothelial cells in tumour blood vessels[39]. Ohishiet al. have analyzed an alkaloid pyridine which was found to be effective against the β-catenin (WNT) signalling pathway, having an essential role in proliferation, differentiation and development of cells leading to cancer[16].

Some otherin vitrostudies were carried out to test the cytotoxic effects ofR. communison various cell lines such as colon cancer, liver cancer, breast cancer, cervix cancer, ovarian cancer(OVCAR-5), skin melanoma (B16F10) and prostate cancer. At lower concentrations of about 100 μg/mL, theR. communisextract was tested against these cancer cell lines and was shown to be effective[51]. The anti-cancer activity ofR. communis, as revealed by several studies, clearly suggests thatR. communismay be a good source for anti-cancer therapeutic compounds.

4.5. Anti-inflammatory activity

R. communishas been shown to possess potent anti-inflammatory activity. Various fractions like ethanolic, methanolic or hexane have been utilised for assessing the anti-inflammatory potential ofR. communis. In one of the studies, the anti-inflammatory action ofR. communisextract was tested by using the hexane, acetone, and methanol fractions. The methanolic extract showed significant antiinflammatory activity which may be due to flavonoids present in it. In this study, Raw 264.7 macrophage cell lines were used to test the anti-inflammatory activity which resulted in 95% scavenging activity at 2.5 g/mL with methanolic extract [57].

Another study by Lindaueret al. demonstrated the antiinflammatory and pro-inflammatory activity upon repeated application, and this was found to be mediated by ricinolein[58].In vivostudies for anti-inflammatory activity were carried out in two animal models, i.e., carrageenan-induced paw edema model and cotton pellet granuloma model. In carrageenan model, the dose of 100 mg/kg was found to inhibit edema by 26.47%[59].Ricinusmethanolic extract reduced edema by 43.28% in cotton pellet granuloma models at a dose of 250 and 500 μg/kg[60]. This activity was due to the activation of the nucleotide-binding domain and leucine-rich protein (NALP3) inflammasome. Anotherin vivostudy, exhibiting the anti-inflammatory activity ofR. communiswas performed in carrageenan or histamine-induced edema in mice or guinea pigs respectively. Topical administration of ricinoleic acid fromR. communisfor 8 d (0.9 mg/mouse) reduced edema by 58%. This confirms that ricinoleic acid has the potential to be a new capsaicin-like substance representing a class of potent antiinflammatory compound[61].

4.6. Antioxidant activity

Antioxidants are the first line of defence towards free radical damage and play a significant role in maintaining cell viability and optimum health. Many of the neurodegenerative diseases are related to free radicals exposure to the cell. The DPDH (1,1-diphenyl-2-picryohydrazyl) mediatedin vitrostudy, reveals the antioxidant activity ofR. communisdue to the presence of compounds such as gallic acid, quercitin, gentisic acid, rutin,epicatechin and ellagic acid in leaves and methanolic extract[62].In another study, the antioxidant activity ofR. communiswas confirmed in the methanolic extract; polar solvents seem to extract compounds responsible for antioxidant activity. This study,suggestsR. communisas a source to scavenge both 2,2’-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals[63]. Another study has shown the scavenging abilities of DPDH, NO, and superoxide radicals to proveR. communisas a novel antioxidant[62]. Highest antioxidant activity was shown by butanol fraction ofRicinus[64].Ethyl acetate extract ofR. communiswas also found to be a potent antioxidant. The antioxidant activity ofR. communisis attributed more to flavonoids as compared to tannins[63, 65].

4.7. Mosquitocidal activity

R. communisexhibited larvicidal effects against various mosquito larvae. Studies have been carried out on various species of mosquitoes such asAnopheles gambiae,Anopheles stephens,Anopheles albopictus, andCulex quinquefasciatus, with a mortality of nearly 100%. The lethal concentration of seed extract ofCommunisamong various larval species is as follows:Culex quinque fasciatus(7.10 μg/mL)＞Anopheles stephensi(11.64 μg/mL)＞Anopheles albopictus(16.84 μg/mL)[66,67].

Malaria is a life-threatening disease which is caused by parasites that are transmitted by the bites of certain species of infectedAnophelesmosquitoes to humans. Despite an increase and growth in research to a large extent over the past 2 decades, malaria has been a worldwide epidemic leading to hundreds of thousands of deaths every year. According to WHO global estimate documents,about 2.7 million cases of malaria were reported and an estimated 627 000 deaths were seen in 2012 (WHO 2012).Plasmodium falciparumis known to exhibit resistance to various available antimalarial drugs.R. communisis found to have the highest activity against theAnopheles gambiaewhich is a vector for malaria. Both male and female larvae ofAnopheles gambiaeare susceptible toR. communisextracts. This activity was supposed to be due to the presence of two compounds ricinine and 3-carboxy-4methoxy-N-methyl-2-pyridone[67]. The larvicidal activity of the different extracts was found to be increasing with increase with the larval exposure. Extracts fromR. communishave recorded highest mortality with a lethal concentration 50 (LC50) of 0.18 mg/mL[67].Apart from this, the extract fromRicinuswas found to be effective againstAnopheles arabiensisandCulex quinque fasciatus[68].

4.8. Analgesic activity

R. communiswas found to possess potent central analgesic activity. Various studies have been conducted for demonstrating the analgesic activity ofR. communisextract. It is studied and proved thatR. communisextract has typical central nervous system stimulant and neuroleptic effects. The stimulant effects such as hyperreactivity, memory improvement and clonic seizures are due to the alkaloid ricinine inR. communis. Ricinine is non-anxiogenic as it does not reduce exploratory behaviour of the brain[69].

In another study, the analgesic activity of aqueous extract ofR. communisroot bark was evaluated against a standard drug diclofenac at a dose of 50 mg/kg. The doses ofR. communisextract used are 100 and 200 mg/kg in Albino mice. Two methods were used for determining the analgesic activity, i.e., Eddy’s hot plate method and tail immersion method[69,70]. In one of the studies,the effect of methanolic extract ofRicinusleaves has proved to be having high antinociceptive activity. A dose of 150 mg/kg showed a gradient increase in the tail flick of mice from (2.900±0.194)in control at 0 min to (6.30±0.110) withRicinustreated mice indicating the analgesic activity ofR. communis[71].

4.9. Anticonvulsant activity

Epilepsy is a pervasive disorder with seizure formation due to neuronal discharges of the brain. Some isolated compounds fromR. communishave been tested for anticonvulsant activity and proved to be reliable epileptic. After electric shock treatment, all the animals exhibited convulsions. Animals receiving a dose of 60 mg/kg of a compound fromR. communisseeds exhibited an inhibition of seizure to about 82% compared to a standard drug which exhibited an 8.89% seizure inhibition[72].

4.10. Anti-helminthic activity

R. communiswas studied for its antihelmintic activity in inducing paralysis and time taken to cause the death of worm.Both ethanolic and aqueous extracts were used for evaluating the anthelmintic activity. AqueousRicinusextract showed high activity at 100 mg/mL in less time when compared to ethanolic extract,i.e.,8.50±0.64 (paralysis) and 31.50±1.25 (death) at a concentration of 100 mg/mL was demonstrated for aqueous extract. Thus the aqueous extract ofR. communiswas found to be having more antihelmintic activity[73].

4.11. Anti-fertility activity

The anti-fertility effects ofR. communiswere studied in male rats which revealed a reduction of epididymal sperm counts. Main features observed after treatment with 50% ethanolic extracts ofR.communisinclude alteration in motility and morphology of sperms was also affected[74]. In another study, semen parameters have been observed wherein the suppression of testicular function is reported in male Wistar rats treated withR. communis(10 mg/kg)[65]. Clinical study, carried out by Isichei and colleagues, for antifertility effects in females with a single dose have prevented pregnancy for 12 months[75].

4.12. Laxative and uterine contracting

Castor oil induces laxation and uterus contraction by involving ricinoleic acid activating prostaglandin receptors 2. Castor oil and ricinoleic acid induce contraction of the intestinal smooth muscle.Both gut and uterus motility is affected. Prostaglandin receptors 2 are proved to be potential targets for drugs to induce laxation[76].

4.13. Antiulcer activity

R. communiswas found to possess significant antiulcer properties.A study, carried out with initial dose 500 mg/kg, has demonstrated the anti-ulcer property ofR. communis. The mechanism underlying the anti-ulcer activity ofR. communisis the cytoprotective action and strengthening of gastric mucosa which ultimately results in the enhancement of mucosal defence[77].

4.14. Antiasthmatic activity

In a study by Dnyaneshwar and Patil,R. communishad shown significant anti-asthmatic activity.R. communisexhibited the mast cell stabilising effect due to saponin content in its roots, whereas flavonoids are responsible for bronchodilation and smooth muscle relaxant activity. The anti-allergic activity was determined byin vivostudies which play a vital role in the treatment of asthma.The ethanolic extract was effective in reducing the milk induced leukocytosis and eosinophilia due to the presence of flavonoids and saponins[78].

4.15. Bone regeneration

Oil ofR. communiswas used in various bone-related diseases in ancient period as a herbal and folkloric medicine. The diseases which used to be treated byR. communisinclude bone deformities, acute osteomyelitis, articular pains, and afflicted limbs[12]. R.communis has the unique capacity of regeneration of bone without the formation of any scar following its damage. Formation of polyurethane resin promotes fibroblastic neoformation progressively replacing the bone from inside and around the porosities of the biomaterial in the absence of delayed inflammatory reaction without any signs of systematic toxic effects, as being observed both in rat alveolus and rabbit skulls[79]. Biological properties ofR. communispolyurethane can be improved by subsequently incubating in the synthetic body fluids.R. communispolyurethane blended with calcium phosphate could promote matrix mineralisation and can be of immense interest in the preparation of biocompatible materials, when compared with demineralised bone. TheR. communispolyurethane has the advantage of slower reabsorption process[79]. The animal study was performed for treatment of osteoarthritis by usingLawsonia inermisandR. communisin rats for 14 d and had shown a significant effect in treatment without any adverse effects A[80].All the above data confirmed the bone reformation activity ofR.communis, and it may be a novel bone reforming substance for treatment of arthritis and osteoarthritis.

5. Toxicological studies of R. communis

R. communishas shown some toxic effects accidentally due to the presence of toxic compounds such as ricin and ricinine.Some of thein vivomouse model studies have shown the ricin toxicity which may vary from hyperactivity to seizure formation and maybe even lead to death at a dose of more than 340 mg/kg intraperitoneally and 3 g/kg orally. However, independent of its uptake, ricin is found to be almost toxic, and there is an increase in the severity of symptoms with an increase in the dose. Symptoms include abdominal pain, emesis, muscular pains, cramps in the limbs, dyspnea, circulatory collapse, dehydration, dysfunction of kidney and liver. Autopsy results in fatal cases have shown the hemorrhagic necrosis in heart, intestine, and edema[43,81].

6. Conclusions and prospects

R. communisis one of the medicinal plants which have multiple pharmacological applications against various diseases and disorders. The anti-cancer, antidiabetic and antimicrobial activities ofR. communisare the shaft of light in treating the death-causing diseases throughout the world. The various biological activities ofR. communisis due to the presence of a varied degree of bioactive phytochemicals. Through this review, it can be justified that both crude form of plant extract and the isolated compounds are responsible for its pharmacological and therapeutic potential.Further studies and utilisation of these plant compounds in an isolated form can be performed to explore their mechanism of action and by deciphering the actual process by which these plant phytochemicals reach the target and exert their action. Novel drugs can be designed by performing variousin vitroand animal studies of these phytoconstituents.R. communiswas used for the synthesis of nanoparticles for testing its activity against both microbial pathogens and cancer cell lines; these nanoparticles will be of keen interest in target drug delivery.

Conflict of interest statement

The authors declare that they have no competing interests.

[1] Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014.J Nat Prod2016; 79(3): 629-661.

[2] Moreira DL, Teixeira SS, Monteiro MHD, De-Oliveira ACAX,Paumgartten FJR. Traditional use and safety of herbal medicines.Rev Bras Farmacogn2014; 24(2): 248-257.

[3] Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P, et al. Discovery and resupply of pharmacologically active plant-derived natural products: A review.Biotechnol Adv2015; 33(8): 1582-1614.

[4] Davies J, Davies D. Origins and evolution of antibiotic resistance.Microbiol Mol Biol Rev2010; 74(3): 417-433.

[5] Bérdy J. Thoughts and facts about antibiotics: Where we are now and where we are heading.J Antibiot2012; 65(8): 441.

[6] Haque MA, Louis VR, Phalkey R, Sauerborn R. Use of traditional medicines to cope with climate-sensitive diseases in a resource poor setting in Bangladesh.BMC Public Health2014; 14: 202.

[7] Koehn FE, Carter GT. The evolving role of natural products in drug discovery.Nat Rev Drug Discov2005; 4(3): 206-220.

[8] Ekor M. The growing use of herbal medicines: Issues relating to adverse reactions and challenges in monitoring safety.Front Neurol2014; 4: 1-10.

[9] Levy SB. Factors impacting on the problem of antibiotic resistance.J Antimicrob Chemother2002; 49(1): 25-30.

[10] Pan SY, Zhou SH, Gao SH, Yu ZL, Zhang FS, Tang MK, et al.New perspectives on how to discover drugs from herbal medicines:CAM’s outstanding contribution to modern therapeutics.Evid Based Complement Alternat Med2013; 2013: 1-25.

[11] Sasidharan S, Chen Y, Saravanan D, Sundram KM, Yoga Latha L.Extraction, isolation and characterization of bioactive compounds from plants’ extracts.Afr J Tradit Complement Altern Med2011; 8(1): 1-10.

[12] Scarpa A, Guerci A. Various uses of the castor oil plant (Ricinus communisL.) a review.J Ethnopharmacol1982; 5(2): 117-137.

[13] Ogunniyi DS. Castor oil: A vital industrial raw material.Bioresour Technol2006; 97(9): 1086-1091.

[14] Rivarola M, Foster JT, Chan AP, Williams AL, Rice DW, Xinyue L, et al. Castor bean organelle genome sequencing and worldwide genetic diversity analysis.PLoS One2011; 6(7): e21743.

[15] Chan AP, Crabtree J, Zhao Q, Lorenzi H, Orvis J, Puiu D, et al.Draft genome sequence of the oilseed speciesRicinus communis.Nat Biotechnol2010; 28(9): 951-956.

[16] Ohishi K, Toume K, Arai MA, Sadhu SK, Ahmed F, Mizoguchi T, et al. Ricinine: A pyridone alkaloid fromRicinus communisthat activates the Wnt signaling pathway through casein kinase 1.Bioorg Med Chem2014; 22(17): 4597-4601.

[17] Vandita P, Amin N, Khyati P, Monisha K. Effect of phytochemical constituents ofRicinus communis,Pterocarpus santalinus,Terminalia belericaon antibacterial, antifungal and cytotoxic activity.Int J Toxicol Pharmacol Res2013; 5(2): 47-54.

[18] Rana M, Dhamija M.Ricinus communisL. – A Review.Int J Pharmacol Res2012; 4(4): 1706-1711.

[19] Alugah CI, Ibraheem O. Whole plant screenings for flavonoids and tannins contents in castor plant (Ricinus communisL .) and evaluation of their biological activities.Int J Herbal Med2014; 2(2): 68-76.

[20] Khafagy SM, Mahmoud ZF, Salam NAE. Coumarins and flavanoids ofRicinus communisgrowing in Egypt.Planta Medica1979; 37: 191.

[21] Rinner U. Progress in the preparation of jatrophane diterpenes.Eur J Org Chem2015; 15: 3197-3219.

[22] Vermeer CP, Nastold P, Jetter R. Homologous very-long-chain 1,3-alkanediols and 3-hydroxyaldehydes in leaf cuticular waxes ofRicinus communisL.Phytochem2003; 62(3): 433-438.

[23] Ghosh S, Tiwari SS, Srivastava S, Sharma AK, Kumar S, Ray DD,et al. Acaricidal properties ofRicinus communisleaf extracts against organophosphate and pyrethroids resistant Rhipicephalus (Boophilus)microplus.Vet Parasitol2013; 192(1-3): 259-267.

[24] Zarai Z, Chobba IB, Mansour RB, Békir A, Gharsallah N, Kadri A.Essential oil of the leaves ofRicinus communisL.:In vitrocytotoxicity and antimicrobial properties.Lipids Health Dis2012; 11: 102.

[25] Ngo T, Nguyen T, Bui D, Hoang N, Nguyen T. Effects of ricin extracted from seeds of the castor bean (Ricinus communis) on cytotoxicity and tumorigenesis of melanoma cells.Biomed Res Ther2016; 3(5): 633-644.

[26] Zahir AA, Rahuman AA, Bagavan A, Geetha K, Kamaraj C, Elango G. Evaluation of medicinal plant extracts and isolated compound epicatechin fromRicinus communisagainst Paramphistomum cervi.Parasitol Res2011; 111(4): 1629-1635.

[27] Singh PP, Ambika, Chauhan SMS. Activity guided isolation of antioxidants from the leaves ofRicinus communisL.Food Chem2009;114(3): 1069-1072.

[28] Rondon FCM, Bevilaqua CML, Accioly MP, Morais SM, Andrade-Junior HF, Machado LK, et al.In vitroeffect ofAloe vera,Coriandrum sativumandRicinus communisfractions onLeishmania infantumand on murine monocytic cells.Vet Parasitol2011; 178(3-4): 235-240.

[29] Houbairi S, Elmiziani I, Lamiri A, Essahli M. Comparison of the antioxidant activity of aromatic medicinal plants of Moroccan origin.Eur J Med Plants2015; 10(4): 1-10.

[30] Jeyam M, Arangaraj M, Ravikumar P, Shalini G. Computational analysis of phytocompounds with 1,3-β-D-glucan synthase for antidermatophytic activity.Sci Rep2014; 6: 24027.

[31] Sharma S, Ali A, Ali J, Sahni JK, Baboota S. Rutin: Therapeutic potential and recent advances in drug delivery.Expert Opin Investig Drugs2013; 22(8): 1063-1079.

[32] Kyung TW, Lee JE, Shin HH, Choi HS. Rutin inhibits osteoclast formation by decreasing reactive oxygen species and TNF-alpha by inhibiting activation of NF-kappaB.Exp Mol Med2008; 40(1): 52-58.

[33] Nafees S, Ahmad ST, Arjumand W, Rashid S, Ali N, Sultana S. Modulatory effects of gentisic acid against genotoxicity and hepatotoxicity induced by cyclophosphamide in Swiss albino mice.J Pharm Pharmacol2012; 64(2): 259-267.

[34] Ranganathan S, Halagowder D, Sivasithambaram ND. Quercetin suppresses Twist to induce apoptosis in MCF-7 breast cancer cells.PLoS One2015; 10(10): e0141370.

[35] Wang G, Zhang J, Liu L, Sharma S, Dong Q. Quercetin potentiates doxorubicin mediated antitumor effects against liver cancer through p53 / Bcl-xl.PLoS One2012; 7(12): e51764.

[36] Buachan P, Chularojmontri L, Wattanapitayakul S. Selected activities ofCitrus maximaMerr. fruits on human endothelial cells: Enhancing cell migration and delaying cellular aging.Nutrients2014; 6(4): 1618-1634.

[37] Zhou XX, Ji F, Zhao JL, Cheng LF, Xu CF. Anti-cancer activity of anti-p185HER-2 ricin A chain immunotoxin on gastric cancer cells.JGastroenterol Hepatol (Australia)2010; 25(7): 1266-1275.

[38] Tyagi N, Rathore SS, Ghosh PC. Efficacy of liposomal monensin on the enhancement of the antitumour activity of liposomal ricin in human epidermoid carcinoma (KB) cells.Indian J Pharm Sci2013; 75: 16-22.

[39] You W, Kasman I, Hu-lowe DD, Mcdonald DM.Ricinus communisagglutinin I leads to rapid down-regulation of VEGFR-2 and endothelial cell apoptosis in tumor blood vessels.Am J Pathol2010;176(4): 1927-1940.

[40] Chen W, Xu B, Mao J, Wei F, Li M, Liu T, et al. Inhibitory effects of α-pinene on hepatoma carcinoma cell proliferation.Asian Pac J Cancer Prev2014; 15: 3293-3297.

[41] Kovac J, Šimunovic K, Wu Z, Klancnik A, Bucar F, Zhang Q, et al.Antibiotic resistance modulation and modes of action of (-)-α-Pinene in Campylobacter jejuni.PLoS One2015; 10(4): e0122871.

[42] Baddar NW, Aburjai TA, Taha MO, Disi AM. Thujone corrects cholesterol and triglyceride profiles in diabetic rat model.Nat Prod Res2011; 25(12): 1180-1184.

[43] Friedman M, Rasooly R. Review of the inhibition of biological activities of food-related selected toxins by natural compounds.Toxins2013; 5(4): 743-775.

[44] Abew B, Sahile S, Moges F.In vitroantibacterial activity of leaf extracts ofZehneria scabraandRicinus communisagainstEscherichia coliand methicillin resistanceStaphylococcus aureus.Asian Pac J Trop Biomed2014; 4(10): 816-820.

[45] Jeyaseelan EC, Jashothan PTJ.In vitrocontrol ofStaphylococcus aureus(NCTC 6571) andEscherichia coli(ATCC 25922) byRicinus communisL.Asian Pac J Trop Biomed2012; 2(9): 717-721.

[46] Abd-Ulgadir KS, Suliman SI, Zakria IA, Hassan NEA. Antimicrobial potential of methanolic extractsHibiscus sabdariffaandRicinus communis.Adv Med Plant Res2015; 3: 18-22.

[47] Naz R, Bano A. Antimicrobial potential ofRicinus communisleaf extracts in different solvents against pathogenic bacterial and fungal strains.Asian Pac J Trop Biomed2012; 2(12): 944-947.

[48] Salles MM, Badaró MM, Arruda CN, Leite VM, Silva CH, Watanabe E, et al. Antimicrobial activity of complete denture cleanser solutions based on sodium hypochlorite andRicinus communis– a randomized clinical study.J Appl Oral Sci2015; 23(6): 637-642.

[49] Shokeen P, Anand P, Murali YK, Tandon V. Antidiabetic activity of 50% ethanolic extract ofRicinus communisand its purified fractions.Food Chem Toxicol2008; 46(11): 3458-3466.

[50] Matthew OO, Olusola L, Matthew OA. Preliminary study of hypoglycaemic and hypolipidemic activity of aqueous root extract ofRicinus communisin alloxan-induced diabetic rats.J Phys Pharm Adv2012; 2(10): 354-359.

[51] Prakash E, Gupta DK.In vitrostudy of extracts ofRicinus communisLinn on human cancer cell lines.J Med Sci Pub Health2014; 2(1): 15-20.

[52] Ravishankar K, Indira K, Vijay Bhaskar R.In vivohepatoprotective activity ofRicinus communisLinn leaf extract against CCl4induced hepatic damage in albino rats.Int J Bio Pharma Res2012; 3(3): 444-449.

[53] Saha S, Ghosh M, Dutta SK. Role of metabolic modulator Bet-CA in altering mitochondrial hyperpolarization to suppress cancer associated angiogenesis and metastasis.Sci Rep2016; 6: e23552.

[54] Endo Y, Tsurugi K. Mechanism of action of ricin and related toxic lectins on eukaryotic ribosomes.Nucleic Acids Symp Ser1986; 17: 187-190.

[55] Lin JY, Liu SY. Studies on the antitumor lectins isolated from the seeds ofRicinus communis(castor bean).Toxicon1986; 24(8): 757-765.

[56] Shah TI, Sharma E, Shah GA. Inhibitory property of aqueous extract ofRicinus communisleaves on proliferation of melanoma treated against A375 cell lines.World J Pharma Sci2015; 3(4): 758-761.

[57] Nemudzivhadi V, Masoko P.In vitroassessment of cytotoxicity,antioxidant and anti-inflammatory activities ofRicinus communis(Euphorbiaceae) leaf extracts.J Evid Comple Altern Med2014; 2014:e625961.

[58] Lindauer M, Wong J, Magun B. Ricin toxin activates the NALP3 Inflammasome.Toxins2010; 2(6): 1500-1514.

[59] Valderramas AC, Moura SHP, Couto M, Pasetto S, Chierice GO,Guimarães SAC, et al. Antiinflammatory activity ofRicinus communisderived polymer.Brazil J Oral Sci2008; 7(27): 1666-1672.

[60] Srivastava P, Jyotshna, Gupta N, Maurya AK, Shanker K. New antiinflammatory triterpene from the root ofRicinus communis.Nat Prod Res2014; 28(5): 306-311.

[61] Vieira C, Evangelista S, Cirillo R, Lippi A, Maggi CA, Manzini S.Effect of ricinoleic acid in acute and subchronic experimental models of inflammation.Mediators Inflamm2000; 9: 223-228.

[62] Ahmed D, Khan M, Saeed R. Comparative analysis of phenolics,flavonoids, and antioxidant and antibacterial potential of methanolic,hexanic and aqueous extracts fromAdiantum caudatumleaves.Antioxidants2015; 4(2): 394-409.

[63] Singh PP, Ambika, Chauhan SMS. Activity guided isolation of antioxidants from the leaves ofRicinus communisL.Food Chem2009;114(3): 1069-1072.

[64] Iqbal J, Zaib S, Farooq U, Khan A, Bibi I, Suleman S. Antioxidant,antimicrobial, and free radical scavenging potential of aerial parts ofPeriploca aphyllaandRicinus communis.ISRN Pharmacol2012; 2012:563267.

[65] Nath S, Kadasi A, Grossmann R, Sirotkin AV, Kolesarova A, Talukdar AD, et al.Ricinus communisL stem bark extracts regulate ovarian cell functions and secretory activity and their response to luteinising hormone.Int J Impot Res2015; 27(6): 215-220.

[66] Mandal S. Exploration of larvicidal and adult emergence inhibition activities ofRicinus communisseed extract against three potential mosquito vectors in Kolkata, India.Asian Pac J Trop Med2010; 3(8):605-609.

[67] Wachira SW, Omar S, Jacob JW, Wahome M, Alborn HT, Spring DR,et al. Toxicity of six plant extracts and two pyridone alkaloids fromRicinus communisagainst the malaria vectorAnopheles gambiae.Parasit Vectors2014; 7(1): 312.

[68] Elimam AM, Elmalik KH, Ali FS. Larvicidal, adult emergence inhibition and oviposition deterrent effects of foliage extract fromRicinus communisL againstAnopheles arabiensisandCulex quinquefasciatusin Sudan.Trop Biomed2009; 26(2): 130-139.

[69] Ferraz AC, Angelucci MEM, Costa MLD, Batista IR, Oliveira BHDE,Cunha CDA. Pharmacological evaluation of ricinine, a central nervous system stimulant isolated fromRicinus communis.Plant Physiol1999;63(3): 367-375.

[70] Almeida RN, Navarro DS, Barbosa-Filho JM. Plants with central analgesic activity.Phytomedicine2001; 8(4): 310-322.

[71] Taur DJ, Waghmare MG, Bandal RS, Patil RY. Antinociceptive activity ofRicinus communisL. leaves.Asian Pac J Trop Biomed2011; 1(2):139-141.

[72] Tripathi AC, Gupta R, Saraf SK. Phytochemical investigation,characterisation and anticonvulsant activity ofRicinus communisseeds in mice.Nat Prod Res2010; 25: 1881-1884.

[73] Rana M, Kumar H, Parashar B.In vitroanthelmintic activity of bark ofRicinus communisLinn.J Chem Pharma Res2013; 5(6): 40-42.

[74] Sandhyakumary K, Bobby RG, Indira M. Antifertility effects ofRicinus communis(Linn) on rats.Phytothera Res2003; 17(5): 508-511.

[75] Isichei CO, Das SC, Ogunkeye OO, Okwuasaba FK, Uguru VE, Onoruvwe O, et al. Preliminary clinical investigation of the contraceptive efficacy and chemical pathological effects of RICOM-1013-J ofRicinus communisvar minor on women volunteers.Phytother Res2000; 42(1): 40-42.

[76] Tunaru S, Althoff TF, Nusing RM, Diener M, Offermanns S. Castor oil induces laxation and uterus contraction via ricinoleic acid activating prostaglandin EP3 receptors.Proc Natl Acad Sci USA2012; 109(23):9179-9184.

[77] Rachhadiya RM, Prasad KM, Shete RV. Evaluation of antiulcer activity of castor oil in rats.Int J Res Ayur Pharm2011; 2(4): 1349-1353.

[78] Dnyaneshwar JT, Patil RY. Antiasthmatic activity ofRicinus communisL. roots.Asian Pac J Trop Biomed2011; 1: S13-S16.

[79] Beloti MM, Oliveira PT, Tagliani MM, Rosa AL. Bone cell responses to the composite ofRicinus communispolyurethane and alkaline phosphatase.J Biomed Mater Res A2007; 84(2): 435-441.

[80] Ziaei A, Sahranavard S, Gharagozlou MJ, Faizi M. Preliminary investigation of the effects of topical mixture ofLawsonia inermisL.andRicinus communisL. leaves extract in treatment of osteoarthritis using MIA model in rats.DARU J Pharma Sci2016; 24: 12.

[81] Bhaskaran M, Didier PJ, Sivasubramani SK, Doyle LA, Holley J,Roy CJ. Pathology of lethal and sublethal doses of aerosolized ricin inRhesus macaques.Toxicol Pathol2014; 42(3): 573-581.