Ethnobotanical and Phytopharmacological attributes of Mesua ferrea : A mini review

1 EMAN Testing and Research Laboratory, Department of Pharmacology, School of Pharmaceutical Sciences, Universti Sains Malaysia, Penang 11800, Malaysia. 2 Department of Pharmacology, School of Pharmaceutical Sciences, Universti Sains Malaysia, Penang 11800, Malaysia. 3 Institute for Research in Molecular Medicine (INFORMM), Universti Sains Malaysia, Penang, 11800, Malaysia. 4 Department of Pharmacology, School of Medical Sciences, Quest International University, Perak, Malaysia.


INTRODUCTION
The guttiferae family is a rich source of secondary metabolites and is blessed with a variety of medicinal properties.It is comprised of 47 genera with more than 100 species.The well-known genera of this family are Cratoxylum, Hypericum, Garcinia, Mesua, and Vismia and are widely distributed in the tropical Asia, Africa, Brazil, New Caledonia and Polynesia (Gontijo et al., 2012;Piccinelli et al., 2005).

MATERIAL AND METHODS
The information on Mesua ferrea was collected from the literature available in the books on medicinal plants and the scientific databases like PubMed, Google Scholar, Springer, and ScienceDirect.Different combination of keywords i.e., "Mesua", "Mesua ferrea", "Pharmacological", "Anticancer", "Antioxidant', "Review", Phytopharmacological" and "Phytochemistry" were applied to retrieve information available on the topic.The references of selected articles were also screened manually for additional studies.We also searched key journals which included BMC Complementary and Alternative Medicine, Fitoterapia, Journal of Ethnopharmacology, International Journal of Immunopharmacology, Phytomedicine, Phytochemistry, Phytotherapy Research and Tetrahedron to find some relevant information about the topic.

PLANT DESCRIPTION
Mesua ferrea is an evergreen medium to large-sized ornamental tree that is distributed in most of Asian countries including Burma, Cambodia, Indochina region, Malaysia, Myanmar, Nepal (southern), Philippines, Sri Lanka, Sumatra and Thailand.Young leaves are reddish yellow in colour while mature leaves are blue grey to dark green in appearance and are approximately 7-15 cm long.Flowers are large in size, have four white petals containing numerous yellow coloured stamens in the centre and are fragrant.Fruits are often beaked, lightly woody in appearance containing 1-4 seeds.Bark is reddish brown in colour.Flower, fruit, seeds and leaves of this plant are edible.Flowers are eaten in Thailand by the local people for the cure of a variety of disorders.Ripe fruits have chestnut like taste when eaten.Seeds are edible when cooked but have an unpleasant taste.The leaves are edible in raw form and have a sour astringent taste (Lim, 2012).

TRADITIONAL USES
Various parts of M. ferrea are used either alone or in combination with other medicinal herbs by the inhabitants of India, Pakistan, Indochina, Malaysia and Thailand for the treatment of various disorders (Ratnamhin et al., 2011).Traditionally, M. ferrea is used as an antipyretic, antimicrobial, anticancer, carminative, cardiotonic, diuretic, and expectorant (Chahar et al., 2012;Rahman et al. 2008).In Malaysia, poultice of seed oils or crushed kernels are used for wound healing while the flowers and root decoction is used by women after child birth (Lim, 2012).In Thailand, seeds are used as aroma, cardiotonic, expectorant and wound healer (Wetwitayaklung et al., 2008).In India, it is used in a variety of Ayurvedic formulations (Brahma Ramayana and Chyawanprash) as an immunity booster agent.It is also used as a herbal supplement for the treatment of a variety of diseases including bleeding piles, cough, cardiovascular disorders, dysentery, excessive thirst, headache, hiccup, itching, sweating, scabies, skin problems, small tumors and vomiting respectively (Joseph et al., 2010;Lim, 2012).Dried flowers have antiinflammatory and stomachic properties (Lim, 2012).Bark is traditionally used for the treatment of cough, dysentery, sore throat and vomiting (Keawsa-ard and Kongtaweelert, 2012).Powder of dried fruits and leaves mixed with ghee is used by the local communities of Bangladesh to get relief from burning sensation in hands and feet, joint pain and cold (Sharkar et al., 2013).M. ferrea is an important ingredient of the Indian Siddha medicine (Yelaathi Churanam) which is used internally to treat chancres, leprosy and ulcers.It is prescribed in combination with butter and sugar in Indian system of herbal medicine for the treatment of bleeding piles.Another herbal formulation (Jawarish-e-Naaremushk) is prescribed in hepatic and intestinal problems (Khare, 2004).An Ayurvedic formulation (Maharisi amrit kalash-4) containing M. ferrea is traditionally used to treat cancer in India and neighbouring countries (Saxena et al., 2008;Asif et al., 2016).
Similarly, M. ferrea is also used for the treatment of inflammation and other cancer associated disorders (Rai et al., 2000).Another polyhebral formulation named Kanakasava containing M. ferrea is traditionally used as an anti-asthmatic agent in India (Arora and Ansari, 2014).
Table 1: Highlights of phytochemical composition of selected parts of M. ferrea.and vanillic acid (Rajesh et al., 2013).Preliminary phytochemical screening of ethanol extract of M. ferrea leaves showed that it contains 14.72 mg/g of dry weight extract of total phenolic contents, 11.25 mg/g of dry weight extract of total tannin contents, 30 mg/g of dry weight extract of total flavonoid contents (rutin equivalent) and 3.60 mg/g of dry weight extract of total flavonol contents (rutin equivalent) respectively (Sahu Alakh et al., 2013b).
From oleo-gum resin, isoledene, a sesquiterpene, has been identified by Asif and colleagues in their recent study (Asif et al., 2016).

PHARMACOLOGICAL STUDIES
Recent scientific studies have highlighted the medicinal importance of different parts of M. ferrea against a variety of human ailments.

Antioxidant activity
70% ethanol extract of M. ferrea leaves have been shown to have better antioxidant activity in DPPH, superoxide and hydroxyl radical scavenging assays as compared with other solvent extracts i.e., hexane, ethyl acetate and methanol.However, the antioxidant activity of 70% ethanol extract was found to be lower when compared with standard antioxidant agent (ascorbic acid) (Prasad et al., 2012).Another study conducted by Sahu Alakh and colleagues showed modest antioxidant activity of methanol extract of flowers in DPPH free radical (IC 50 = 300 µg/mL), superoxide (IC 50 = 273.56µg/mL), and hydrogen peroxide (IC 50 = 21.70 µg/mL) scavenging assays (Sahu Alakh et al., 2013a).Similarly, in another study polar extract (methanol) of M. ferrea roots was found to be more active as compared with less polar and non-polar extracts (Teh et al., 2013).Essential oils obtained from the leaves showed moderate antioxidant activity in the DPPH assay with an IC 50 value of 31.67 mg/mL (Keawsa-ard and Kongtaweelert, 2012).Another study reported the promising antioxidant activities of water and hot water extracts of M. ferrea flowers in the DPPH scavenging assay and effects were shown to be even stronger than standard agent i.e., butylated hydroxytoulene (BHT) with an EC 50 values of 7.49 and 6.95 µg/mL respectively (Makchuchit et al., 2010).Chloroform and methanol extracts of M. ferrea stem bark have been shown to have good antioxidant activity in the in vitro antioxidant models.Both extracts protected erythrocytes, haemoglobin and DNA against oxidative stress-induced damage.The methanol extract showed strong activity (> 90%) as compared with chloroform extract (> 70% < 90%).This was suggested to be due to higher total phenolic and flavonoid contents of methanol extract (Rajesh et al., 2013).In another recent study, n-hexane extract of M. ferrea stamens has been reported to possess good free radical scavenging activity with an IC 50 value of 66.3 µg/mL.However, one major drawback of this study was that no standard drug was used to compare the efficacy of active stamen extract (Barbade and Datar, 2015).

Analgesic activity
In an acetic acid-induced visceral pain mouse model, non-polar (n-hexane) fraction of M. ferrea leaf extract showed better antinociceptive activity in terms of percent reduction in writhing response as compared with polar fractions (methanol and ethyl acetate) (Hassan et al., 2006;Lim, 2012).

Anti-inflammatory and anti-arthritis activities
Anti-arthritis activities of M. ferrea seed extracts were evaluated in two different in vivo models i.e., Formaldehydeinduced and Complete Freund's Adjuvant (CFA) -induced arthritis in rats.In formaldehyde-induced model, significant reduction in the swelling of formaldehyde injected paw was observed in the seed extract treated rats compared to the control animals.Similarly, in CFA model, reduction in the arthritis lesions as noted by swelling volume in CFA injected paw was observed in M. ferrea seed extracts treated animals.An increase in body weight of M. ferrea seed extract treated rats was also observed, while in control CFA injected rats a decrease in body weight was observed at the end of treatment (Jalalpure et al., 2011).
In vivo anti-inflammatory activities of xanthones i.e., mesuaxanthone-A, mesuaxanthone-B, calophyllin-B, dehydrocycloguanandin, euxanthone, jacareubin and 6-desoxy jacareubin isolated from M. ferrea were studied using three different rat inflammation models.All the xanthones were revealed to have promising anti-inflammatory activities in carrageenan-induced paw oedema, cotton pellet granuloma and granuloma pouch inflammatory models (Gopalakrishnan et al. 1980).In addition, an ayurvedic formulation (Shirishavaleha) containing M. ferrea in combination with other herbs has been shown to inhibit oedema development in carrageenan-induced paw oedema model (Yadav et al., 2010).Similarly, another recent study, reports the promising anti-inflammatory activity of 80% ethanol extract of stem bark in a variety of in vitro bioassays.The finding of the study revealed that 80% ethanol extract at the concentration of 100, 200 and 500 µg/mL has stronger antiinflammatory activity in all the in vitro bioassays as compared with standard drug i.e., Indomethacin (100 µg/mL) (Ranganathaiah et al., 2016).

Antimicrobial and antifungal activities
Antimicrobial activities of different parts of M. ferrea have been highlighted by various scientific studies.Coumarins (4alkyl and 4-phenyl 5,7-dihydroxycoumarins) isolated from the blossoms showed selective antibacterial activities towards resistant strains of gram positive bacteria (Verotta et al., 2004).Methanol extract of the leaves has been shown to possess broad spectrum antibacterial activities against Bacillus species, Escherichia coli, Staphylococcus aureus, Shigella, Salmonella and Lactobacillus arabinosus bacterial strains respectively (Mazumder et al., 2003).In addition to in vitro antibacterial activity, methanol extract of leaves has shown profound protective effects in the mice against Salmonella typhimurium infection (Mazumder et al., 2004).Narender Prasad and colleagues also reported that methanol extract of M. ferrea leaves at the concentration of 1200 µg/mL has reasonable antibacterial activity (Narender Prasad et al., 2011).
Similarly, polar extract (chloroform) of stem bark has been reported to exert strong antibacterial activity against gram positive Streptococcus aureus as well as gram negative Escherichia coli bacterial strains (Ali et al., 2004;Lim, 2012).Likewise, another research group tested the antibacterial efficacy of flower extract against five different strains of Salmonella spp and was found to be active towards all the strains at the concentration of 50 µg.In addition, flower extract also showed promising in vivo antibacterial activity in S. Typhimurium NCTC 74 challenged mice and caused a statistically significant reduction in viable count of bacterial strain in liver, spleen and heart blood at the dose of 2-4 mg/mouse (Mazumder et al., 2005).Methanol extract of M. ferrea seeds also showed fungicidal activities against different strains of fungus, including Candida albicans, Trichosporon beigelii, Mucor hiemalis and different species of Aspergillus (Lim, 2012).Likewise, a recent study reports the antibacterial activity of M. ferrea seed oil epoxy resin against Klebsiella pneumoniae (gram negative) and Staphylococcus aureus (gram positive) strains of bacteria (Das et al., 2014).A gel formulation containing six different herbs, including M. ferrea was screened for its potential to prevent skin infections associated with the resistant strains of Staphylococcus aureus, Pseudomonas aeruginosa and Corynebacterium spp.Within 2 hours of contact, 100% bactericidal efficacy was observed in herbal gel treated animal group while complete eradication of infection with no rough or dry skin remnants was observed after 20 days of treatment.Moreover, herbal gel formulation showed no toxicity in skin toxicity tests (Deshmukh et al., 2009).
M. ferrea bio-oils extracted from deoiled cakes through the process of pyrolysis has been reported to have broad range of antimicrobial activities against a variety of bacterial and fungal strains, which gives a hint about possible pharmaceutical application of bio-oils (Phukan et al., 2013).

Water disinfectant properties
M. ferrea seed kernel oil (NSKO) has been reported to have water disinfectant properties and can be used as natural disinfectant alternative to chlorine.The study showed that kernel oil has remarkable disinfection potential and the kinetic studies suggested that NSKO fitted first-order model with a k value of -0.040 (Adewale et al., 2011).

Antivenom activity
Water extract prepared from the leaves of M. ferrea has been shown to have considerable (40%) anti-venom activity against Heterometrus laoticus (scorpion) venom in the in vitro chick embryo fibroblast cell lysis model (Uawonggul et al., 2006).

Diuretic properties
Polyherbal combination (Draksharishta-T and -M) and its marketed formulation comprising of stamens of M. ferrea has been shown to induce significant diuretic, kaliuretic and natriuretic effects in the albino rats at the dose of 2.0 mL/Kg over a period of 5 hours compared to the control group (Tiwari and Patel, 2011).

Anti-hemorrhoid activities
A polyhedral formulation containing M. ferrea was evaluated for its efficacy to treat bleeding piles in a preliminary clinical study using 22 subjects.Finding of the study revealed that out of 22 subjects, 16 patients had improvement in terms of reduced bleeding with no noticeable adverse effects (Paranjpe et al., 2000).Another recent study also highlights the efficacy of standardized herbal preparations (Daflon ® and Roidosanal ® ) containing M. ferrea in terms of improvement of ano-rectal conditions in Grade I and II patients.Both preparations reduced the bleeding and pain in the hemorrhoid patients (Aggrawal et al., 2014).

Wound healing activity
Tannins isolated from the ethanol extract of aerial parts of M. ferrea have been shown to have promising wound healing activity in excision and incision wound healing rat models when applied in the form of an ointment.Increased epithelialization and wound contraction were proposed to be the possible mechanisms responsible for the wound healing activity of aerial parts (Choudhary, 2012).

Antiulcer activity
Xanthones i.e., jacareubin and 6-desoxy jacareubin obtained from M. ferrea prevented ulceration in the rats as compared with control groups where extensive ulceration, perforations and haemorrhagic spots were observed.On the other hand, in xanthones treated rats only hyperaemia and occasional haemorrhage spots were noticed (Gopalakrishnan et al., 1980;Lim, 2012).

Central nervous system (CNS) depressant and anticonvulsant activities
CNS depressant effects of xanthones (mesuaxanthone-A, mesuaxanthone-B, calophyllin-B, dehydrocycloguanandin, euxanthone, jacareubin and 6-desoxy jacareubin) obtained from M. ferrea were evaluated in both mouse and rat models.Typical CNS depressant effects, i.e., ptosis, sedation, loss of muscle tone and reduced spontaneous motor activity were observed in the xanthones treated animals respectively.Similarly, potentiation of anaesthetic effects of ether and phenobarbitone-induced sleeping time was also observed in the xanthone treated animals (Gopalakrishnan et al., 1980;Lim, 2012).Likewise, another research group showed that M. ferrea flower extract caused a significant increase in the pentobarbital-induced sleeping time in mouse model (Chakma et al., 2006).Ethanol extract of M. ferrea also exhibited anticonvulsant effects in the mice when tested in maximum electroshock seizures (MES) assay.The extract was revealed to reduce the duration of hind limb tonic extensions in a concentration-dependent manner (Lim, 2012).

Immunomodulatory and hormone balancing activities
Effect of mesuol isolated from the seed oil of M. ferrea on the immune system was studied using both humoral and cellular immune models.In humoral immune response assay, mesuol resulted in a significant increase in the antibody titer values in the rats, which were previously antibody challenged and immunized by the introduction of sheep red blood cells (SRBCs) followed by immunosuppression by cyclophosphamide.Similarly, mesuol also elicited cellular immune responses in cyclophosphamide-induced immunosuppressant rats due to the stimulation of T-cells.An increase in the thickness of foot pad was observed in mesuol treated rats when exposed to SRBCs (used as an irritant) (Chahar et al., 2012).In addition, flower extract of M. ferrea has also been shown to possess estrogen and progesteronelike effects which were proposed to be helpful in the correction of hormonal imbalance during menstrual disorders (Lim, 2012).

Antidiabetic activity
Methanol extract of M. ferrea leaves has been shown to have promising antidiabetic activity in streptozotocin-induced diabetic rats.Extract was suggested to increase the secretion of insulin from pancreatic β-cells.In addition to the insulin secretory effect, the leaf extract also reduced the blood glucose levels and normalized the body weight in the diabetic rats compared to the untreated rats.In vitro studies using mouse insulinoma pancreatic β-cell line (MIN6 β-cells) showed a dose-dependent increase in the levels of insulin as a result of methanol extract treatment and the effects were more prominent in the hyperglycemic conditions compared to normal cell culture conditions (Balekari and Veeresham, 2015).

Hepatoprotective activities
In vivo hepatoprotective effects of methanol extract of M. ferrea flowers were evaluated in Staphylococcus aureus inoculated male Wistar rats.One week treatment with 50, 100 and 200 mg/Kg of methanol extract showed significant improvement in the levels of liver enzymes, namely CAT, SOD, GPx, and GR with concomitant decrease in the levels of AAT and AST enzymes.Profound effects were observed at the dose of 100 mg/Kg of methanol extract (Garg et al., 2009).In another study, hepatoprotective effects of different extracts of stamens were evaluated using in vitro carbon tetrachloride-induced oxidative stress liver slice culture model.Among different extracts, n-hexane and ethanol extracts of stamens protected cultured liver slice cells against carbon tetrachloride-induced oxidative stress.
The active extracts also showed promising antioxidant activities in different in vitro free radical scavenging models i.e., DPPH, ABTS + , SOD and NO respectively (Rajopadhye and Upadhye, 2012).

Cardioprotective activities
A polyherbal formulation (Ashwagandharishta) and its marketed preparation containing stamens of M. ferrea have been shown to protect against isoproterenol-induced myocardial infarction in the albino rat model.Treatment with herbal formulation also significantly prevented the isoproterenol-induced adverse changes in the levels of serum marker enzymes such as alanine aminotransferase, aspartate aminotransferase, creatine kinase and lactate dehydrogenase with concomitant improvement in the serum lipid profile.In addition, herbal formulation pretreated animals also showed significant increase in glutathione (GSH) and reduction in malondialdehyde (MDA) contents.It was proposed that the cardioprotective activity of herbal formulation may be due to increase in in vivo antioxidants levels such as GSH and inhibition of lipid peroxidation of cardiac membranes in the treated rats (Tiwari and Patel, 2012).

Protection against experimentally-induced Chronic Obstructive Pulmonary Disease (COPD)
A study conducted in the rats showed that herbal formulation (Bresol ® ) comprising of M. ferrea flowers has protective effects against cigarette smoke-induced COPD in rats.The rats treated with 250 and 500 mg/Kg for five weeks showed improvement in terms of reduction in tracheal inflammation, decrease in TNF-α and total protein levels in the bronchoalveolar lavage fluid and maintained the normal cellular architecture of the trachea and lungs (Rafiq et al., 2013).

Anticholinesterase and α-amylase inhibitory activities
Teh and colleagues in their recent study highlighted that the secondary metabolites isolated from different species of Mesua including M. ferrea have acetylcholinesterase inhibitory activities and have potential to be used in Alzheimer's disease (Teh et al., 2016).In vitro α-amylase inhibitory assay conducted by Chakrabarti and team revealed that M. ferrea extract has moderate α-amylase inhibitory activity with an IC 50 value of 146.8 µg/mL while standard drug, acarbose, showed strong α-amylase inhibitory activity with an IC 50 value of 14.24 µg/mL (Chakrabarti et al., 2014).

Anticancer activities
Considerable amount of work has been done to explore the anticancer potential of different parts of M. ferrea.Variety of crude extracts and pure compounds have shown promising anticancer activities in the preliminary in vitro anticancer screening assays.Volatile oils rich methanol extract of M. ferrea flowers showed strong cytotoxic activities against T-lymphocyte leukaemia cells with an IC 50 value of 12.5 µg/mL (Nordin et al., 2004).Ethanol extract of M. ferrea flower was tested against three human cancer cell lines viz., CL-6 (cholangiocarcinoma), Hep-2 (human laryngeal cancer) and Hep G2 (human hepatocarcinoma) cell lines.The finding of the study showed that ethanol extract was selectively toxic towards Hep-2 cell line with an IC 50 value of 19.22 µg/mL (Mahavorasirikul et al., 2010).Essential oils isolated from M. ferrea leaves have also been shown to possess cytotoxic activities against three cancer cell lines viz., KB (oral carcinoma), MCF-7 (breast adenocarcinoma) and NCI-H187 (metastatic lung carcinoma) and the order of cytotoxicity was revealed to be MCF-7 > NCI-H187 > KB respectively.While no toxic effects were observed against African green monkey normal kidney cells (Vero) (Keawsa-ard and Kongtaweelert, 2012).n-hexane and dichloromethane extracts of M. ferrea roots have been reported to possess broad spectrum cytotoxic activities against a panel of human cancer cell lines.The order of sensitivity of cancer cells towards n-hexane extract was Hep G2 (human hepatocellular liver carcinoma) > HeLa (human cervical cells) > NCI-H23 (human lung adenocarcinoma) > SNU-1 (human gastric carcinoma) > IMR-32 (human neuroblastoma) > LS-174T (human colorectal adenocarcinoma) > K-562 (human erythroleukemia cells) > SK-MEL-28 (human malignant melanoma cells) > Raji (human B lymphocyte).On the other hand, order of sensitivity of cancer cells towards the dichloromethane extract was Hep G2 (human hepatocellular liver carcinoma) > K-562 (human erythroleukemia cells) > NCI-H23 (human lung adenocarcinoma) > IMR-32 (human neuroblastoma) > SNU-1 (human gastric carcinoma) > LS-174T (human colorectal adenocarcinoma) > SK-MEL-28 .
(human malignant melanoma cells) > Raji (human B lymphocyte) respectively (Teh et al., 2013).In another study, n-hexane and dichloromethane extract of M. ferrea flowers has also been reported to have cytotoxic effects against CCRF-CEM (human lymphoblast leukaemia cell line).In addition both extracts were also shown to reduce resistance against doxorubicin in resistant CEM/ADR5000 cells by modulating P-glycoprotein function (Noysang et al., 2014).Another recent study also reports the anticancer activities of M. ferrea stem extracts and isolated compounds against three cancer cell lines i.e., KB (oral carcinoma), MCF-7 (breast adenocarcinoma) and NCI-H187 (metastatic lung carcinoma).Among different extracts, n-hexane was found to be inactive in terms of induction of cytotoxicity against all the three cancer cell lines, while dichloromethane and methanol extract was found to be more active against KB than rest of two cell lines.Interestingly, isolated compounds, i.e., β-sitosterol, friedelin and mixture of α-and β-amyrin were either found to be less active or even inactive in terms of cytotoxic effects as compared with active crude extracts.It was proposed in the study that multi-components are responsible for the anticancer properties of M. ferrea stamen extracts (Keawsa-ard et al., 2015).Another recent study conducted by Asif et al shows that oleo-gum resin extract has broad spectrum anticancer activities towards human colon carcinoma cell lines.The oleo-gum resin extract was shown to induce apoptosis in HCT 116 cells through ROS-mediated apoptotic pathways.Interestingly, oleo-gum resin extract did not induce toxicity in the normal colon cells (CCD-18co) (Asif et al., 2016) Similarly, Asif et al. in their recent study showed that terpenes rich stem bark extract has broad spectrum anticancer activities.The order of sensitivity (high to low) of cancer cell lines towards F-3 was HCT 116 > MNK-74 > PC-3 > T-47D > MIA PaCa-2 > HT-29 > PANC-1 > MCF-7 > Capan-1 > EA.hy926 > 3T3-L1 > CCD-18co respectively (Asif et al., 2017).In addition to variety of in vitro anticancer studies, there is also one study that reports the in vivo efficacy of chloroform and ethyl acetate extract of M. ferrea flowers against Ehrlich ascites carcinoma in Swiss albino mice.Percent inhibition of carcinoma in chloroform and ethyl acetate treated animals was 54.8 and 41.7% respectively (Rana et al., 2004).Table 2 highlights the anticancer activities of M. ferrea against different cancer cell lines.

Toxicological studies
Acute toxicity studies on different extracts of M. ferrea were conducted using albino mouse and rat models.In rat model, 5g/Kg doses of three different seed extracts i.e., petroleum ether, ethyl acetate and alcoholic did not provoke any signs of toxicity during the first 24 hours and no mortality in any of the test groups was observed (Jalalpure et al., 2011).Similarly, acute toxicity studies of methanol extract of M. ferrea flowers were performed in Swiss albino mice using three different doses i.e., 50, 500 and 2000 mg/Kg.In all the treated groups, none of the mice showed any visible signs of toxicity with zero mortality rates.there was no differences in haematological and biochemical profiles of M. ferrea flowers feed and control mice, respectively (Udayabhanu et al., 2014).In another recent study, n-hexane extract of M. ferrea stamens has been reported to be safe in the acute toxicity mouse model, however, the doses used and safety level was not mentioned in the study (Barbade and Datar, 2015).

INDUSTRIAL APPLICATIONS
Apart from pharmacological attributes, numerous studies have highlighted the industrial applications of M. ferrea seed oils as an alternative biofuel in the diesel and compression ignition engines, in paint industry, as a multi-purpose industrial coating preparation and as biomaterials (nanocomposites etc.).Stamens are used as a fragrant stuffing for cushions and pillows.Wood is considered suitable for all types of heavy construction including railway sleepers, transmission posts, heavy-duty furniture, posts and tool handles (Lim, 2012).

PROPOSED PHARMACEUTICAL APPLICATIONS
Based on scientific studies reported above, we hereby propose that M. ferrea has potential to be developed as a herbal pharmaceutical product in the form of topical antibacterial gel/cream, as a standardised extract for internal bleeding disorders i.e., ulcers and hemorrhoids and as a chemopreventive and chemotherapeutic agent respectively.However, further studies are still needed in this aspect.

CONCLUSION
Recent scientific studies have highlighted that M. ferrea is a rich source of secondary metabolites which are having multiple health promoting benefits including antioxidant, antiinflammatory, antimicrobial, anticancer and others.Several studies have recurrently highlighted the antioxidant, antimicrobial and anticancer effects of whole extracts, active fractions and pure compounds isolated from different parts of M. ferrea.However, there are some problems which need to be addressed, (i) conclusion of majority of studies are based on preliminary in vitro screening assays.Still further research is needed to confirm these activities by employing proper experimental tools.(ii) In majority of the studies no standard marketed drug was used as positive control and where positive control is used the efficacy of the active extract/ compound was not compared.The efficacy of active extract/ compound must be compared with standard drug as well.(iii) None of the study has reported the pharmacokinetic profile of active extract and isolated compounds.Further research is needed in this regard to estimate the feasibility of active samples for commercial drug formulation.(iv) Stamens are most commonly used in the polyherbal formulations, however, efficacy of other parts such as seeds, flowers, stems, bark and oleo-gum resin are also needed to be evaluated for the effective pharmaceutical product development.(v) Only few studies have reported the toxicity profile of selected parts, however, further studies are highly recommended in this regards before commencement of clinical studies.(vi) Standardization of active extracts is highly recommended in order to develop product of uniform composition and biological activity.(vii) Majority of studies did not identify molecular targets responsible for the biological activity; further studies to identify the molecular targets responsible for these medicinal properties especially anticancer, can help in the development of cost-effective and natural remedies against this chronic disorder.

Table 2 :
Highlights of anticancer activities of M. ferrea.
(Asif et al., 2016)Values shown in brackets are expressed in µg/mL