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REVIEW ON AEGLE MARMELOS (L) CORR: MEDICINAL VALUES, BIOLOGICAL ACTIVITIES, FORMULATIONS, TOXICITY STUDIES

 

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About Authors:
Kambham Venkateswarlu
Graduate Student
Sri Lakshmi Narasimha College of Pharmacy, Palluru,
Gudipala Mandal Chittoor-517132, Andhra Pradesh, India.
k.v.reddy9441701016@gmail.com

ABSTRACT:
In recent times, focus on plant research has increased all over the world and a large body of evidence has collected to show immense potential of medicinal plants used in various traditional systems. Over the last few years, rehears have aimed at identifying and validating plant derived substances for the treatment of various diseases. Similarly it has been already proved that various parts of plants such as Leafs, fruits, seeds etc. provide health and nutrition promoting compounds in human diet. The Bael (Aegle Marmelos) (L) Corr) is another Indian plant, which has enormous traditional uses against various diseases. The present review aims to compile medicinal values of Aegle Marmelos generated through the research activity using modern scientific approaches and innovative scientific tools.
It is called 'Shivadurme', the tree of Shiva, and is one of the sacred trees of the Hindus. Leaves are offered in prayers to Shiva and Parvathi since ancient times.


Reference Id: PHARMATUTOR-ART-1564

I.INTRODUCTION:
Indian Medicinal plants are considered a vast source of several pharmacologically active principles and compounds, which are commonly used in home remedies against multiple ailments.

Bael (Aegle marmelos (L) Corr.) is another Indian medicinal plant, which has enormous traditional values against various diseases and many bioactive compounds have been isolated from this plant.

History:
It is called 'Shivadurme', the tree of Shiva, and is one of the sacred trees of the Hindus. Leaves are offered in prayers to Shiva and Parvathi since ancient times. It has its own place in indigenous systems of medicine. The fruit is the subject of several solar-phallic myths. Hindu physicians regard the unripe or half-ripe fruit as astringent, digestive and stomachic and prescribe it to treat diarrhea and dysentery. The thick sherbet of the ripe fruit has a reputation among Europeans as an agreeable laxative. It is also given for piles; and as a remedy for diarrhea. The root bark is used as a remedy in hypochondrias, melancholia and palpitation of the heart. Fresh leaf juice used as a laxative and febrifuge is used in asthmatic complaints and jaundice. The Chinese used the leaves and young fruits to adulterate Opium. In Bengal it is used for dysentery. In Concur, small and unripe fruits are used for piles. The juice of bark is a remedy for poverty of seminal fluid.

Botanical name: Aegle marmelos (L.) Corr.
Synonym: Crataeva marmelos Linn.
Genus: Aegle
Species: marmelos
Family: Rutaceae

Vernacular Names (Nadkami, 1978):
English: Bengal quince, Beal fruit, Golden apple, Holy fruit, Indian quince, Stone apple.
Tamil: Aluvigam, Iyalbudi, Kuvilam, Mavilangai, Vilwam, Villuvam.
Telugu: Bilvamu, Maluramu, Maredu, Sailushamu, Sandiliyamu, Sriphalamu.
Hindi: Bael, Bili, Sirphal, and Bela,
Sanskrit: Adhararutha, Asholam, Atimangaliya, Bilva, Durarutha, Gandhaptra, Hridyagandha, Kantak adhya, Kapitana, Sriphala, Lakshmiphala, Mahakapitthakya.
Bengal: Bael, Bel,
Gujarat: Billi,
Kannada: Bela, Bilva
Malayalam: Koovalam, Vilwam
Orissa: Belo

Threat status:
Vulnerable (AIC) – K.A & T.N
Not evaluated – K.L

Habit: Tree

Habitat: From coastal plains to most deciduous forests.

Altitude: From Sea level to 1200m.

II. PLANT DESCRIPTION:

Bark: Grey outside, rough, peeling off irregularly to small flakes.

Blaze:Yellow

Wood:  Hard, dull white, branch lets often drooping with straight, start, sharp, solitary of period about 4cm long thorns.

Leaves:Alternative

Spine: Spine is present in the axils of leaves. They are either single, double or absent in some variants. If a pair of spine is present the arms are either equal or unequal. Spine length 2-3cm.

Leaflets:  3(rarely 5), egg shaped or elliptic or oblong. Lanceolate, thin pale green on both surfaces, hairless, base wedge shaped or rounded, apex tapering into a blunt tip, margin toothed with minute rounded teeth, terminal leaflets larger about 13×6.5cm, lateral leaflets smaller about 7×4cm, leaf stalks about 6cm long.

Flowers: Bisexual, 3-6 in axillary racemes, about 1.5cm long greenish white fragrant.

Berries: Ovoid to sub-globes, 5 to 10×4-8cm, Yellow, when nature with woody rind and short neck.

Seeds:Many oblong, flat about 1cm long, embedded in thick orange or flesh colored mucilaginous sweet pulp.

Phrenology:
Leaf fall:   January
New foliage: February onwards

Flowering:  March to April

Fruiting:   September to December

Stem:  Transverse section of the stem reveals the presence of 1) Well developed periderm consisting of cork, phellogen and phelloderm, 2) Distinct patches of stone cells above the phloem region, 3) Several layers of cambium, 4) Conspicuous xylem with large vessels and uniseriate medullary rays and 5) Parenchymatous pith.

Stem bark:   Grey in color more warty and less number of cracks and fissures. Thickness 4-8mm; cork zone showing 5-8 stratification. Stone cells present in more number of groups in the phelloderm and also present in groups in the phloem fibers present in groups arranged in concentric rings (Anonymous, 1976).

Roots:
The T.S. of root shows the presence of
1. Outer zone of cork which gets peeled off consequent on secondary growth.
2. This is followed by phellogen and secondary cortex whose cells contain abundance of starch grains.
3. Interior to the cortex is the characteristic concentric patches of sclerenchyma.
4. Phloem is concentrically arranged; phloem cells alternating with narrow strip of sclerenchyma.
5. Medullary rays, distinct ring of cambium, wood consisting of large vessels, tracheids and fibers, uniseriate and biseriate medullary rays filled with starch grains, and pent arch primary xylem are other features (Krishnan Nambiar et al., 2000).

Seed Germination:
Among the various treatment given to seed of Bael (Aegle marmelos), water  soaking result in highest percentage of germination (80%) which was closely followed by concentrated sulfuric acid treatment for 20 min. (76%) and least percent of germination occurred with concentrated sulfuric acid (10min) + thiourea 1 percent (20%). Although water soaking resulted in highest percentage of germination, it took longer time for initiation and completion of germination as compared to concentrated sulfuric acid, which resulted in quicker germination (Nayak and Sen, 1999).

Floral Vasculature:
Floral vasculature of A.marmelos was worked out by Krishnan (Nambiar et al., 2000).

Calyx lobe:
Each lobe is supplied by a single vascular strand, which gets divided into three branches, from the base itself. These branches in-turn go on branching and re-branching irregularly and from a net work.

Petal:
Each petal is supplied with five vascular strands of these, the middle one gets branched into two, near about the centre of the petal. The two laterals on either sides of the median, branch into three from the base itself. Each branch again gets abruptly branched. The two peripheral ones get simply branched into four from base itself giving rise to laterals.

Stamen:
Each stamen is supplied with a single vascular strand, which traverse through the connective and reaches up to the rip without any branching.

Gynoecium:
Eleven bundles enter into the ovary. Each one branches into two. Peripheral traverse through the ovary wall and the central one form the ventral bundle and supplies the ovules. So eleven peripheral bundles and eleven central bundles which supply the ovules are seen in cross section of the ovary. The two branches of each bundle again join at the top of the ovary and enter into the stigma. Thus eleven bundles are seen in the stigma. Thus eleven bundles are seen in the stigma. Further each bundle gets feebly branched.

Gums and Resins:
One of the sources of gum in Asia is Asiatic tropic gum from Aegle marmelos (Bengal quince). These are distinct plant products insoluble inwater but dissolve in alcohol, ether, carbondi-sulfide and certain othersolvents with heat they first soften and then melt to a more or less clear,sticky fluid. They burn with a smoky flame and are resistant to mostreagents and to decay. Resin is generally secreted in plant tissue in speciallayer of secretary cells which secret the resin into the cavity through a thincuticular skin (Sambamurty and Subramanyam, 1989).

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ETHNOBOTANICAL INFORMATION:
The term “Ethno botany” was first used by Harshberger (1985) and its scope was much elaborated later (Faulks, 1958 and Ford, 1978). Since then there has been a growing interest in this field (Jain, 1985). Ethnobotany in the wilder context denotes the entire realm of useful relationship between plant and man. Ethnobotany studies assume great importance in enhancing our knowledge about the plants grown and used by native / tribal communities (Arora, 1997).

Ethno medical information on Aegle marmelos is available from many parts of India and other countries. Available ethno medical literatures reveal that entire plant; leaf, fruit, stem bark, root and essential oil of fruits of this plant are used in various diseases. Decoction of dried leaf of Aegle mamelos and entire plants of Borreria hispida, Cardiospermum helicacabum, Evolvulu alsinoides is used as medicine for curing jaundice, inflammationpiles, asthma, malarial fever, dysentery, skin disease etc., (Jayabarathi,1998).

The plant has been already reported for eye complaints from the district of kamrup in Assam. It reduces heat in abdomen used by the tribals from Ranchi and Hazaribug district of Bihar and Mirzapur district of Uttarpradesh (Maheswari et al., 1996). It is given the honor by saying it as sriphala and by associating it with Lord Shiva who is fond of its leaves. Bilva is one of the members of dasmula in which its root is used (Jain, 1989).

Aegle marmelos was used as a stick by the Babylonian slam 7000 years ago. Puppetries and dental oral health have been discussed (Alimas, et al., 1996). In Srivilliputhur T.K., of Tamilnadu ethnobotanical study reported that, 40 plants including A. marmelos wers found to be commonly used as medicine for curing jaundice , piles , dysentery , malarial fever (Jayabarathi et al., 1999). Dhanapandi et al., (2007) observed ethanoveterinary herbel practices in Thanjavur district; some of ethanoveterinary plants used from the study area include Aegle marmelos, Casia auriculata, Mukia scarbrella and Lippia nudifloea.

Applying of leaf paste on head has been reported as remedy for premature graying of hair. The leaf juice of A.marmelos is used in diabetsoema; the Leaves along with the seed of Foeniculam vulgare are used for chronic diarrhea and dysentery (Jain, 1989).

Stem yields a gum and leaves contain essential oil. Stem and root are used as antipyretic (Nadkarni, 1927). One of the sources of gum in Asia is Asiatic tropic gums from of A.marmelos.

Bark of Beal tree and the roots Andrographis paniculata are made into a paste. The paste is made into small piles after drying in sunlight one tablet is taken thrice daily to cure diarrhea (Maheswari, 1996).

Only ripe fruits are eaten. A delicious drink is prepared by mixing the fruit with sugar and milk medicinally; the pulp of ripe fruit is given for chronic stomach disorders (Manorajan Sharma et al., 2002).

The pulp of fruit is commonly used for preparation if jam, candy, syrup etc, the tribal child use roasted fruit. The mucilaginous substance around seed is used as an adhensive. The tripinnately digital leaves are used for worship by tribal (Maheswari, 2000).

The root infusion has been reported to reduce body ache and indigestion in children.The plant has been already reported for body ache from Kamrup district of Assam. Root is applied externally on snake bite (Samba murty and Subramaniyam, 1980). It is given the honor by saying it as sriphala’ and by associating it with Lord Shiva who is fond of its leaves. Bilva is one of the members of Dasmula in which its root is used (Jain, 1989). The root powder has been reported as remedy for dyspepsia, gastric trouble, jaundice and swellings.The plant has been already reported forgastric trouble from sandal pargana of Bihar. Root decoction helps normal delivery (Rosakuttiy et al., 2000).

Aegle marmelos leaves claimed to be useful in treating pain, fever, inflammation, respiratory disorders, cardiac disorders, dysentery and diarrhea (Dymock William et al., 1890, Kirtikar et al., 1935 and Murugesa Mudaliar, 1988). More than 30 identified compounds from the leaves of Aegle marmelos have been reported (Chatterjee and Bose, 1952, Sharma et al., 1980 and Chatterjee and Satyesh, 1994). Based on the ethnomedical reports, following clinical and pharmacological studies were done.

1. Dried Leaf– Digestive
Hot H2O Ext: Oral: Human Adult

2. Fruit – Antispasmodic activity (unspecified type) ETOH – H2O
(1:1) Ext Guinea pig – conc. used not stated: Active: Ileum:

3. Used as digestive and stomachic – Dried Fruit
Hot H2O Ext: Oral: Human Adult

4. Dried fruit– Stomachic
Hot H2O Ext: Oral: Human Adult

5. Dried fruit – Used for Asthma – Decoction oral human adult,
Antipyretic - Hot H2O Ext: Oral: Human Adult

6. Dried fruit –Smooth muscle relaxant activity – H2O Ext. Rat
Anti histaminic activity ETOH – H2O (1:1) Ext. and anti spasmodic activity (unspecified types) ETOH – H2O (1:1) Ext. were also reported.

The leaf juice of Aegle marmelos used in diabetes and edema (Jain, 1989). The leaves of Aegle marmelos with the seeds of Foeniculam vulgare Mill are used for cure of chronic diarrhoea and dysentery. Root decoction helps in normal delivery (Rosakutty et al., 2000).

Ethnobotanical observation of Kollihills, TamilNadu, reveals 21 plants used in veterinary medicine. Tribes, Kolli-Malayalis of this area depend upon these plants for curing various diseases (Geetha et al., 1996).

Seven leaves of wood apple (Aegle marmelos) and seven seeds of Black pepper (Piper nigrum) are to be chewed like pan with rock salt (Kala namak) for 21 days every morning in empty stomach. It can regress any kind of body tumor they claim (Jain, 1995). Ripe fruits are sweet aromatic, cooling, alternative, and nutritive (Anonymous, 1976). Unripe or half ripe fruit astringent, digestive and stomachic, used for diarrhea, dysentery. The rind of unripe fruit yields a yellow dye (Anonymous, 1986). Only ripe fruits are eaten. A delicious drink is prepared by mixing the fruit with sugar and milk medicinally; the pulp is applied externally on snakebite. Bark of Beal and the roots of Andrographis paniculata are made into a paste. The paste is made in to small pills after drying in sunlight; one tablet is taken thrice daily to cure diarrhea (Mahaswari, 1996).

The yield and physiochemical characters of 13 types of bael fruits (Aegle marmelos) collected from different locations were examined. The results indicated that there are a few types suitable for commercial cultivation and processing in west Bengal (Ghosh et al., 2002). The effect of the Aegle marmelos extract at a dose of 250 mg / kg was more effective than glibenclamide in restring the values of diabetic parameters. (Kamalakkannan and Price, 2004). A number of ethno medicinal plants and herbal preparations are used in traditional system of medicine for the management hepatic disorders .however many of them have not been investigated to valorize the traditional claims. Aegle marmelos is widely used in the treatment of hepatitis in folk medicine. Results indicate that ethanolic aqueous fruit pulp extracts of A.marmelos had moderate to significant activity over ccl4 treatment as compared to the control. Results of the present investigation suggest that CCl4 induced liver damage in rats can substantially be ameliorated by treatment of ethnolic extracts from fruit pulp of A.marmelos .Also the study confirms the claim on this plant as a potential hepatoprotective agent in the traditional medicine (Rajasekaran et al.,2009). Taxonomis description, Distribution, Pharmacognostical studies leading to establishment of correct identity if the raw drugs are to be followed for any herbal drug. Chemical analysis and propagation methods of A.marmelos was reported (Krishnan Nambiar et al., 2000) Pharmacognostical studies in A.marmelos are lacking and on fruit, is completely absent.

Note: 
A sacred tree of ten grown in Hindu temples in India.
The leaves are used for various rituals.

Bael (Aegle Marmelos (Linn), family Rutacae, is also known as Bale fruit tree, is a moderate sized, slender, aromatic tree, 6.0 -7.5 m in height, and 90 to 120 cm in girth, with a somewhat fluted bole of 3.0-4.5 meter growing wild throughout the deciduous forests of India, ascending to an altitude of 1200 meter in the western Himalayas and also occurring in Andaman island.This is generally considered as sacred tree by the Hindus, as its leaves are offered to Lord Shiva during worship. According to Hindu mythology, the tree is another form of Lord Kailashnath. Leaves, fruit, stem and roots of this tree at all stages of maturity are used as ethno medicine against various human ailments.

III. CHEMICAL CONSTITUENTS:
Various phytoconstituents have been isolated from the various parts of Aegle marmelos, which may be categorized as;

Table1: Phytoconstituents isolated from various parts of Aegle marmelos

Sr. No.

Part

Phytoconstituents

1.

Leaf

Skimmianine, Aegeline, Lupeol, Cineol, Citral, Citronella, Cuminaldehyde, Eugenol, Marmesinine

2.

Bark

Skimmianine, Fagarine , Marmin

3.

Fruit

Marmelosin, Luvangetin, Aurapten, Psoralen, Marmelide, Tannin

The different parts of Bael are used for various therapeutic purposes, such as for treatment of Asthma, Anaemia, Fractures, Healing of Wounds, Swollen Joints, High Blood Pressure, Jaundice, Diarrhea Healthy Mind and Brain Typhoid Troubles during Pregnancy.

Aegle marmelos has been used as an herbal medicine for the management of diabetes mellitus in Ayurvedic, Unani and Siddha systems of medicine in India, Bangladesh and SriLanka.The main usage of the parts of this tree is for medicinal purposes. The unripe dried fruit is astringent, digestive, stomachic and used to cure diarrhea and dysentery.Sweet drink prepared from the pulp of fruits produce a soothing effect on the patients who have just recovered from bacillary dysentery.

The ripe fruit is a good and simple cure for dyspepsia. The pulp of unripe fruit is soaked in gingerly oil for a week and this oil is smeared over the body before bathing. This oil is said to be useful in removing the peculiar burning sensation in the soles. The roots and the bark of the tree are used in the treatment of fever by making a decoction of them. The leaves are made into a poultice and used in the treatment of opthalmia. The leaf part of the plants have been claimed to be used for the treatment of inflammation, asthma, hypoglycemia, febrifuge, hepatitis and analgesic. The mucilage of the seed is a cementing material. The wood takes a fine polish and is used in building houses, constructing carts, agricultural implements. A yellow dye is obtained from the rind of the unripe fruits. The dried fruits, after their pulp separated from the rind are used as pill boxes for keeping valuable medicines, sacred ashes and tobacco. In Homeopathic treatments it is largely used for conjunctivitis and styes, rhinitis, coccygodynia, nocturnal seminal emission with amorous dreams, chronic dysentery. Ayurveda prescribes the fruit of the herb for heart, stomach, intestinal tonic, chronic constipation and dysentery; some forms of indigestion, typhoid, debility, cholera, hemorrhoids, intermittent fever, hypochondria, and melancholia and for heart palpitation. The unripe fruit is medicinally better than the ripe fruit. Leaf poultice is applied to inflammation; with black pepper for edema, constipation and jaundice.

PHYTOCHEMICAL STUDIES:
Many biological active compounds were isolated from various parts of Aegle marmelos. Presence of alkaloids, in the roots and leaves of Aegle marmelos, coumarins in the root and stem bark along with others constituents has been reviewed. Medicinal uses of the plant have been discussed (Das and Das, 1995).

The pulp contains mucilage, pectin, sugar, tannin (tannic acid), volatile oil, bitter principle, ash 2% and a balsamic principle resembling balsam of Peru. Fresh leaves yield marmelosin on distillation which is yellowish-green oil with a peculiar aromatic odour.

The dried pulp was exhausted by Henry & Brown, with boiling alcohol, the extract concentrated in vacuum and the thick syrup diluted with water to precipitate fatty acid and resinous matters (Nadkarani, 1927). A sterol Aegelin was isolated from the leaves. It was first described as a steroid by earlier works, but a neutral alkaloid, with one methyl or diethyl groups with degradative studies the structure of Aegelin has been established (Chakravarthi and Dasgupta, 1955). The non-saponifiable fraction of the ether extract of the leaves on chromatography yielded a sterol having melting point 144- 145oC and identified as aegelin from the leaves of Aegle marmelos has also been described (Chakravarthi and Dasgupta, 1956, 1958).

Aegelin on hydrolysis gave trans-cinnamic acid by UV studies of aegelin and comparison with those of trans-cinnamic acid, trans-cinnamide and Trans-N-methyl, trans-emfiguration of the cinnamoyal grouping in aegelin was confirmed (Chakravarthi and Dasgupta, 1958).

The alkaloid, crystallized from ethanol as pale yellow solid, melting point. 245°C and analysis of the alkaloid showed a significant peak at m-32 (Chatterjee et al., 1967a). Marmin a new coumarin with mp.123-1240C was isolated from the trunk park of Aegle marmelos (Chatterjee et al., 1967b).

Aegle marmelos has been found to be a phenolic base having an oxazole and a pyridine moiety from UV, IR, NMR and mass spectra and from degradative experiments (Chatterjee and Majunder, 1971).

Skimmianine has been isolated and characterized from the bark (Khaleque, et al., 1978). The seed and seed oil was analysed for proteins and fatty acid components (Banerjee and Maiti, 1980). The leaves yield rutin and marmesinin, ripe fruits yield rutin and marmesinin, ripe fruits yield xanthotoxal and both parts yield _- sitosterol, _-D glycoside (Sharma et al., 1980). Seeds yield glycoprotein (Mandal and Mukherjee, 1981). The fruit pulp yield polysaccharide (Basak et al., 1981). Alkaloides and cumarin from fruits (Sharma and Sharma, 1981), Alkaloids and other components from unripe fruits (Sharma et al., 1981), components from fruits (Tokitomo et al., 1982), and polysaccharides from cambium layer have been isolated and identified (Basak and Mukherjee, 1982). Seed kernel contains proteins, oils, carbohydrate and ash (Banerji et al., 1982). Alkaloids from the dry leaves have been isolated and identified by Govindachari and Premila (1983).

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Alkaloids, coumarins, fatty acid and sterols from the fruit pericarp (Reisch et al., 1985), and amino acid from fruits and seeds have been isolated and identified (Ali and Qadry, 1987). The leaves were analysed for dry matter, crude proteins, fiber, hemicellulose, cellulose, lignin and ash and silica (Chakrabarty et al., 1988). Furanocoumarin obtained from the plant exhibited tyrosinase accelaring and tryptophan inhibiting effects in Bufo melanostictus (Chakrabarty et al, 1978). The Seed-oil showed antibacterial activity (Banerjee and Kumar, 1980). Roots yield marmin which exhibited anti-inflammatory effects in carrageenin induced paw oedema in rats (Pitre and Srivastava, 1987).

Analysis of the leaf oil of Aegle marmelos afforded the identification of eighteen monoterpene hydrocarbons (71.85%), four sesquiterpene hydrocarbons (14.2%) and one oxygenated sesquiterpene (0.78%) (Garg et al., 1995). AC-glycosylated propelargoindin has been isolated from the aqueous extract of the pulp of the unripe fruit of Aegle marmelos. Structure determination was based on chemical degradation and 13C-NMR (Abeyskera et al., 1996).

The major constituents of the leaf extract were identified to be tannins, skimmianine, essential oil ( mainly caryophyllene, cineole, citral, eugenol), sterols and or triterpenoids, including lupeol, β- and γ-sitosterol, α-and β –amyrin, flavanoids (mainly rutin) and coumarins, including aegeline, marmesin and umbelliferone (Karawya et al., 1980).

The structures of marmenol and known constituents were established with the help of NMR spectroscopy from the methanolic extract of Aegle marmelos (Ali and Pervez, 2004).

The different methanolic extracts of Aegle marmelos plant parts like leaves, fruit, bark, pulp, flora parts were prepared and screened phytochemically by standard tests. All parts showed the presence of carbohydrates, aminoacids, proteins, anthocyanins, steroids, glucosides, etc.

These extract were evaluated for antioxidant activity (Kallar et al., 2005). The alkaloidal amides belonging to cinnamide class were isolated from the leaves of Aegle marmelos. Their chemical transformation and 13CNMR has been reported (Shweta and Norender, 2005).

Phytochemicals and their Biological Activities in Aegle marmelos (Duke, 1992):

P – Cymene:
It has an Analgesic, Antiacetylcholinesterase, Antibacterial, Antiflu, Antirheumatalgic, Antiviral, Flavor, Fungicide, Herbicide, Insectifuge, Irritant, Laxative, Pesticide, Sedative, Trichomonicide activities.

Phellandrene:
Hyperthermic, Irritant, Spasmogenic, Tumor-Promoter

Skimmianine:
It has a following activities Abortifacient, Adrenostimulant, Analgesic, Anticonvulsant, Anti diuretic, Antimalarial, Antipyretic, Antispasmodic, CNS – Depressant, CNSStimulant, Ecbolic, Hypertensive, Hypothermic, Myorelaxant, Myotonic, Pesticide, Photo toxic, Sedative, Utero contract and Vasodilator.

Tissue Culture:

Differentiation and Regeneration:
First report of somatic embryogenesis in A. marmelos by using zygotic embryos showed the somatic embryo (18 percent) and the number of smatic embryo per explants (12) was observed in the presence of 2,4-D (1 micro M) and BA (1 micro M) as per the observation after 42 days (Islam et al., 1995). High frequency regeneration system using callus culture from zygotic embryos of A. marmelos maximum number of shoots per explants were obtained from shoots per explants were obtained from 110- 150 days old cotyledons of the seeds of the A.marmelos (Islam et al., 1995).

A.marmelos exhibited the changes in fatty acid, phospholipids and glycolipid during cellular and organ differentiation. The manoglaoctosyl, triglyceride the diaglaoctosyl, diglyceride ratio and linolenicc acid level increased with degree of differentiation (Bharatwaj et al., 1995). Shoots of A. marmelos were cultured in M.S. Medium supplemented with BAP (0- 5mg) showed better performance in most of the parameters elongated shoots were rooted on half strength M.S. Medium supplemented with 0.5mg/1, IBA and successfully transferred to soil. The highest shoot number and weight were observed after 8 weeks of culture on a medium supplemented with BAB at 0.5mg/lt (Hazrika et al., 1996).

IV. Various proved therapeutic values of Aegle marmelos:

1. Anti diabetic Activity:
Aqueous extract of Aegle marmelos leaves, was evaluated for hypoglycemic and antioxidant effect by Upadhya S et al (2004), by using alloxon induced diabetes in male albino rats and proposed AML may be useful in the long-term management of diabetes.Similarly, The anti hyperlipidaemic activity of aqueous extract of Aegle marmelos fruits was demonstrated by P.S. Marinzene et al (2005), using the streptozotocin- induced diabetic wistar rats.Sunderam et al, (2009) worked on alcoholic extract of Aegle Marmelos, Momordica Charantia and Eugenia Jambolana separately; against Streptozotocine induced diabetic rats and confirmed their protective activity against laboratory induced cell necrosis,  Whereas, Kuttan & Sabu ( 2004) studied on leaf extract of Aegle Marmelos on Alloxane induced diabetes and reported that used extract was enough capable to reduce oxidative stress by scavenging lipid peroxidation and enhancing certain Anti oxidant levels which causes lowering of elevated blood glucose level.Beside of all above cited work, Hema & Lalithakumari (1999) had presented tremendous results of Aegle Marmelos and documented its hypoglycemic action along with other pharmacological actions on molecular level.

2.Hepatoprotective activity:
Singanan et al, (2007) worked on Aegle Marmelos leaf extract on alcohol induced liver injury in albino rats and presented data of excellent hepatoprotective effects. Similarly, Ramnik S (2008), also demontrated that aqueous extarct of bael fruit pulp and seeds are effective in the treatment and prevention of CCI4 induced hepatic toxicity.

3.Antimicrobial Activity:
Maheshwari et al, (2009) studied on ethnolic ectract of dried fruit pulp of Aegle Marmelos against various intestinal pathogens i.e. Shigella boydii, S. sonnei & S. Flexneri and proposed that certain phytochemicals including Phenols, Tannins and Flavonoids were effective against all.It was also confirmed by Kaur et al, (2009) by getting treat E. coli with Aegle Marmelos fruit extract. In consonance, Citarasu et al, (2003) also experimented Aegle Marmelos on certain pathogenic bacteria like Salmonella typhi, Pseudomonas aeruginosa, Aeromonas hydrophyla & Vibrio sp., and concluded its positive bactericidal effects.

3.1. Antibacterial activity
Fruits and leaves of Aegle marmelos were subjected to antibacterial screening but were found to be inactive (Valsraj et al., 1997; Sasidharan et al., 1998).From the Indian traditional medicines 78 plants were selected on the basis of their use in the treatment of infectious disease. Different concentrations of 80%, ethanol extracts were tested, using the agar dilution method, against four bacteria: Bacillus subtilis, Staphylococcus aureus, Escheritia coli and Pseudomonas aeruginosa. Lowest test concentrations of 1.6mg/ml, 10% of the plant extract were active, 44%in a concentration of 6.25mg/ml (Valsraj et al., 1998). Extract obtained from leaves and fruits of Aegle marmelos showed antibacterial activity (Valsraj et al., 1998), leaf extract of Aegle marmelos showed antibiotic activity against Staphylococcus aureus, Escheritia coli at 0.5% concentration (Sasidharan et al., 1999).

3.2 Anti fungal activity
Antifungal activity of leaves and fruits of Aegle marmelos was screened by (Valasaraj et al., 1997 and Sasidharan et al., 1998). Different concentrations of 80% ethanol extract were tested, using agar-well diffusion method, against two fungi, Candida albicans and Aspergillus niger. The antifungal activity of essential oil isolated from the leaves of Bael has been evaluated using spore germination assay. The most resistant fungus, Fusarium udum was inhibited 8% at 400PPM (Rana et al., 1999). The aqueous extract of Aegle marmelos were screened against two rice fungal pathogens, Magnaporthea grisea and Rhizoctonia solani (Kausik and Aroro, 2003).

Methanol extract of leaves of Aegle marmelos singnificantly reduce the number of sclerotic, at the same time higher concentration used in the study no sclerotic were formed even after 21 days of incubation (Prithiviraj et al., 1995).

3.3 Antiviral activity
The fruit of Aegle marmelos showed antiviral activity against Ranikhet disease virus (Dhar et al., 1968). Aegle marmelos, Ricinus communis, Solanum nigrum and Tinospora cardifolia have been found to be used either singly or in combination with other plants for the treatment of viral Jaundice (Nagarajan and Rajareddey, 1986).

Badam et al ., (2006) studied in vitro antiviral activity of series of compound from varies parts of Aegle marmelos the inhibition(IC50) for leaves (L1 and L2) stem and stem bark(S1,S2,S3and S4) fruit (F1)and root bark(R1and R2) and pure compound marmelide were 1000μg/m for (S1,S2,S3and S4),100 μg/m for (F1) and 500 μg/m for (R2) and 62.5 μg/m by plaque inhibition.

4.Analgesic anti-inflammatory & antipyretic Activity:
Arul et al, (2005) presented anti-inflammatory, antipyretic & analgesic properties of serial extract of leaves of Aegle Marmelos, and presented that most of the extract caused a significant inhibition of the carrageenan-induced paw oedema and cotton-pellet granuloma in rats. The extracts also produced marked analgesic activity by reduction the early and late phases of paw licking in mice. A significant reduction in hyperpyrexia in rats was also produced by the most of the extracts.Similarly, Ghangale G. R (2008) also evaluated aqueous extract of Aegle mannelos for anti inflammatory activity by using rat paw oedema model and proposed that Aegle mannelos posseses anti-inflammatory activity.Shankharananth V., (2007), demonstrated that methanolic extract of leaves of Aegle marmelos at a dose level of 200 and 300 mg/ kg show significant analgesic activity on acetic acid induced writhing and tail flick test in mice.

5. Antifungal Activity:
Patil R. H (2009) reported the antifungal activity of ethanolic extract of the Aegle marmelos leaves including antidiarrhoeal, and antimicrobial, activities. Rana B. K. (1997) evaluated anti fungal activity of essential oils isolated from the leaves of Bael using spore germination assay. The oil exhibited variable efficacy against different fungal isolates and 100% inhibition of spore germination of all the fungi tested was observed at 500ppm.They proposed that essential oil from bael leaves may interfere with the Ca2+-dipicolonic acid metabolism pathway and possibly inhibit the spore formation.Pitre S and Srivastava S.K., (1987), demonstrate the antifungal activity of ethanolic root extract against Aspergillus fumiganus and Trichphyton mentagrophytes.

6. Anticancer Activity:
Leticia V and Costa L. (2005) evaluated the anticancer potential of folk medicine used in Bangladeshi and used extracts of Aegle marmelos for cytotoxic action using brine shrimp lethality assay; sea urchin eggs assay, and MTT assay using tumor cell lines. The extract of Aegle marmelos was found to exhibited toxicity on all used assays.Similarly, Gagetia G.C. et al (2005) reported the anticancer effect of hydroalcoholic extract of bael leaves in the animal model of Ehrlich ascites carcinoma and proposed that induction of apoptosis may be due the presence of skimmianine in extract.

7. Radioprotective Activity:
Radioprotective effect of Aegle marmelos extact was studied by Jagetia GC and Venkatesh P (2005). By exposing to different doses of gamma-radiation in mice and found that oral administration of extract resulted in an increase in radiation tolerance by 1.6 Gy. Again, Jagetia GC and coworkers (2006), studied effects of plant extract on the peripheral blood and small intestine of Swiss albino mice. They exposed the animals to gamma radiation and data were collected against radiation-induced changes in the peripheral blood, spleen colony forming units, and intestinal mucosa, reported that Aegle marmelos extract significantly reduces the deleterious effect of radiation in intestine and bone marrow of mouse.

8. Antispermatogenic Activity:
Pramanik et al, (1999) reported antispermatogenic acitivity of ethanolic extract of Aegle marmelos leaves in rats.Again, the same workers, including Bhattacharya D. (2002) presented data of anti motility of rat sperms through In Vitro study.  Similarly, Sharma R. C et al (2009) studied the effect of ethanol extracts of leaves of A. marmelos for their in vitro effect on sperm motility and was suggested that the extracts had a considerable effect on the motility of sperm. It was also proposed that an increase in concentration of the extracts decreased the motility of sperms.

9. Antiulcer Activity:
Goel R.K (1997) reported that oral; administration of pyranocoumarin isolated from the seeds of Aegle marmelos Correa, showed significant protection against pylorus-ligated and aspirin-induced gastric ulcers in rats and cold restraint stress-induced gastric ulcers in rats and guinea pigs.Dhuley J. N; (2007) reported that pretreatment of rats with unripe bael fruit extract produce a significant inhibition of absolute ethanol induced gastric mucosal damage.

10. Anti thyroid Activity:
Panda S, and Kar A. (2006), isolated, Scopoletin (7-hydroxy-6-methoxy coumarin) from Aegle marmelos leaves and evaluate for its potential to regulate hyperthyroidism. It was observed that scopoletin (at 1.00 mg / kg, p.o. for 7 days) to levo-thyroxine treated animals, decreased serum thyroid hormones level. It was also proved that the scopoletin have superior therapeutic activity than the standard antithyroid drug, propylthiouracil.

11.Toxicity Studies:
Total alcoholic, total aqueous, whole aqueous and methanolic extracts were collected from the leaves of A. marmelos by the Veerappan A et al (2007) and studied in experimental rats for their toxicity. No histopathological changes were found when extracts of A. marmelos were administered intraperitoneally for 14 days successively at the dose of 50 mg/kg body wt. The collected data demonstrate that the extracts of the leaves of A. marmelos have a high margin of drug safety.

12. Other reported medicinal values:
The antidiarrhoeal effect of aqueous extract of Aegle marmelos fruit have been reported by effecting outer membrane protein C of Enteropathogenic Escherichia Coli. Besides these activities, Insecticidal activity, Anti-lipid peroxidative activity, Antioxidant property also have been reported.

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V. CLINICAL STUDIES
Role of Aegle marmelos in managing neonatal jaundice has been discussed (Gupta and Sharma et al., 1999). Shriphal (Aegle marmelos) has been considered as one of the effective medicine for the treatment of nonspecific diarrhoea. Therefore, its efficacy for the treatment was tested in 25 patients. All the patient were treated with powdered unripe fruits of Shriphal (5gm thrice daily for 21 days) (Singh et al., 1993). A.marmelos has been considered as one of the effective medicine for the treatment of non-specific diarrhea. Therefore, its efficacy for the treatment of dysentery was tested in 25 patients; all the patients were treated with powdered unripe fruits of A.marmelos 5gm thrice daily for 21 days (Singh et al., 1993). Drug from A.marmelos plays a vital role in diabetes in pregnant women and nursing mother (Bombarde et al., 1995). A.marmelos used as insertion of foreign body in vagina for reduction of vault in common practice in rural India. It also helps in stopping foul smell discharge from vagina (Kara et al., 1998).

VI. FORMULATIONS
Polyphone extracts (PPES) prepared from the leaves of some medicinal plants like karpuravalli (Coleus aromaticus) tulasi (Ocimum sanctum) and A.marmelos PIPE exhibited significant antitumour and antimutagenic activities. The leaves are cause abortion and sterility in women. The bark is used as a fish poison in Celebes. (Annapurani and Priya, 2000). Aritajat et al., (2000) investigated the toxic effect of aqueous extract A.marmelos (AM), Stevia reboudiana (SR), Pouteria cambodiana (PC) by dominant lethal test for 8-week treatment. From the results testicular weights as well as in cauda epididyma notable changes in sperm morphology and motility were observed.

Y-spur is an Ayurvedic formulation consists of A. marmelos showed increased the sperm count in male (81.3%) (Mathur et al, 1999). Bowl care formulation consists of A. marmelos it cures the chronic constipation and irregular bowl movements with diarrhea also disappeared in most of the cases even in case of 16 years old. (Garg et al, 2003). In taila formulation in sesame oil TLC methods were evolved for the detection of the ingredients (Thangamma et al., 2006).

VII. TOXICITY STUDIES
An aqueous extract of Aegle marmelos leaves exhibited significant hypoglycemic activity in stereptozotocin diabetic rats. It also significantly (0.05%) increased the plasma insulin levels of diabetic rats. The extract did not show any signs of toxicity and the LD50 was greater than 10.0 g/kg when given orally in rat (Sharma et al., 1996). In the liver with Aegle marmelos indicated that the treatment may neutralize H2O2 toxicity by its increased decomposition by CAT (Sabu and Kuttan, 2001). Veerappan et al.,(2007) reported that chronic administration of A.marmelos leaf extract at a dose levels of 50,70,90 and 100 mg/kg b.w for 14 consecutive days to male and female Wistar rats did not induce any short term toxicity collectively and reported that the extracts of the leaves have a high margin of drug safety Latica versa et al.(2005) evaluated the anti cancer potential used in Bangladesh folk medicine, extract of Aegle marmelos were tested for cytotoxicity using brain shrimp lethality eggs assay, and MTT assay using tumor cell lines.

The polyphenol extracts (PPES) from leaves of plants namely Aegle marmelos, Coleus aromaticus and Ocimum santum, were prepared andpolyphenol content in each was estimated. The concentration required for50% inhibition of incorporation, of radioactive tritium labelled thymidineinto DNA of Dalton lamphoma ascetic cell lines was found to be higher thanthat required in the in vitro cytotoxicity assay. The LD50 dose in this casewas 30 µg/l, 60 µ g/l for C. aromaticus, O. santum, and A. Marmelos respectively (Annapurani and Priya, 1999).


Fig. 1. Histopathology of liver tissues (400X). (A) Control showing normal cellular architecture with distinct hepatocyte; (B) CCl4 alone shows deformation in central vein, Enlarged nucleus & Infiltration of cells; (C) CCl4+AMEE treated group shows prominent nucleus, reduced infiltration & mild sinusoidal dilation; (D) CCl4 +Silymarin: Cross section of liver treated with known hepatoprotective drug Silymarin in CCl4 intoxicated mice shows similar pattern of hepatocytes arrangement; (E) AM alone treated group showing normal cellular architecture & there is no abnormalities. Nucleus (N), central vein (CV), hepatocytes (H), damaged central vein (DVC), enlarged nucleus & infiltration of cell (IF).

The biochemical & histological results demonstrated that the ethanolic extract of A. marmelos leaves has hepatoprotective activity against CCl4 induced hepatotoxicity in mice. This needs to be further proved to get a lead compound with hepatoprotective nature.

VIII. CONCLUSION:
It is quite evident from this review that Aegle marmelos contains a number of phytoconstituents which reveals its uses for various therapeutic purposes. The Plant or its individual parts can be used for the treatment of various disorders in human being such as, diabetes, liver toxicity, fungal infection, microbial infection, inflammation, pyrexia and to relieve pain. Still, so much work is required with the Aegle marmelos to investigate the mechanism of actions with other therapeutic activities.

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