review on punica granatum

Inventi Impact: Ethnopharmacology Vol. 2012, Issue 4 [E- ISSN 0976-7568, P- ISSN 2229-4155]

2012 pep 700, CCC: $10 © Inventi Journals (P) Ltd Published on Web 15/10/2012, www.inventi.in

REVIEW ARTICLE

INTRODUCTION Traditional medicines, as defined by WHO is the health practices, approaches, knowledge, and beliefs incorporating plant, animal, and mineral based medicines, spiritual therapies, manual techniques and exercises, applied singularly or in the combination to treat , diagnose, and prevent illnesses or maintain well-being. There has been considerable evidence of about 80 % of population residing in Asian and African countries relying on traditional system of medicines.

According to the certain evidences available, the study of herbs dates back to the 5000 years to the ancient Sumerians, describing well established use of medicinal plants. Many herbs and minerals used in Ayurveda were described by ancient Indian herbalists such as Charaka and Sushruta during the 1st millennium BC. [1]

The first pictorial evidence of herbal medicine, on the walls of the Lascaux Caves in France, was radiocarbon dated in between 13000 to 25000 B.C. Paracelsus 1493-1541 physician and botanist, originally known as Philippus Theophrastus von Hohenheim, pioneered the use of chemicals and minerals in medicine as well as plants, starting the first ever use of plants in Medicine and toxicology. Cists and burial sites dated to 1000 and 2000 B.C. have found evidence of medicinal herbs being left with bodies. [2] However, the first written record of herbal medicine use showed up in 2800 B.C. in China (Titled Pen Ts’ao by Shen Nung). It recorded around 252 plants descriptions and describes their medicinal effects, including information about on the places to grow these plants. Another written evidence signals use of herbs in Mesopotamia (now Iraq) and in China dates back to 3000 B.C. [3]

Times have changed now, as more and more people seek to shift towards herbal medicines, the physicians and researchers are again focusing back to traditional plants to look for cure in support of challenging ailments and

1Department of Pharmacology, Kharvel Subharti College of Pharmacy, S. V. Subharti University, Meerut – 250005, Uttar Pradesh, India. E-mail: [email protected] *Corresponding author

diseases developing resistance to existing drugs. [4]

European Union has now put regulations on using herbal medicines as well as upon its testing to find possible cure and develop a potential medicine to be marketed. [2]

There are about 45,000 Medicinal plant species in India, with concentrated spots in the region of Eastern Himalayas, Western Ghats, and Andaman and Nicobar Islands. There are currently about 250000 registered medicinal practitioners of the Ayurvedic system, as compared to 700,000 of the modern medicine system. In rural India, 70 percent of population depends on the traditional type of medicine, the Ayurveda. It is estimated that about 80,000 species of plants are utilized in some form or other by the different systems of Indian medicines. [4]

Punica granatum L. Historical significance of Pomegranates dates back to its evidence available through the 800 year old, Kabbalistic text, Sefera Rimon: The book of Pomegranates giving it an position equivalent to Shekinah, the female aspect of creation, and its creator. [5] Punica granatum commonly known as Pomegranate is a fruit bearing deciduous shrub or small tree growing between five and eight meters tall. The name Pomegranate derives from the Medieval Latin Pomum ‘apple’ and granatum ‘seeded’. The genus name Punica refers to the Phoenicians, who were active in broadening its cultivation, partly for religious reasons.

Punica granatum L. (Punicaceae): Lifeline for Modern Pharmaceutical Research

Devansh Mehta1*, Manish Mehta1

Abstracts: Medicinal plants have been in use for millenniums by human race as potential source for healing and protective actions for our own benefit. For centuries scientists have found synthetic route for rapid and fast relief from the ailments. But somewhere, the danger of adverse reactions haunted many pharmaceutical giants, leading to rejections of potential leads having side effects making them inappropriate for human consumption, causing them huge losses. An Alternative exists in form of Natural route, as a source it provides an advantage of lower rejections and higher productivity with positive feedback from the patients or prospective clients for doctors. Therefore, recent decades, have seen an increase in surge towards natural source, and people preferring traditional system over conventional allopathic system for their respective ailments. The trend seems to shift for pharmaceutical bigwigs, with many pharmaceutical companies setting up their own indigenized Nutraceutical strategic business units, focusing on isolating potential natural drug leads. Punica granatum is boon for such companies having high potential for drug leads in various ailments. Ranging from having antioxidant potential, being antimicrobial, the plant proves to be a positive approach for cancer carcinogenesis and even AIDS (working as immustimulant and developing immune system strength). The present review just portrays a detailed factsheet on the future medicine store house for pharmaceuticals and mankind as a whole.

Figure 1: Punica granatum

185



REVIEW ARTICLE

The Pomegranate is native to the region of Persia (Modern day Iraq) and the western Himalayan range. It has been cultivated in Iran, Iraq, Azerbaijan, Afganistan, Pakistan, India, Russia and the Mediterranean region for several millennia. [6]

In Indian subcontinent, Punica granatum has been in use for several thousand years as a part of Ayurvedic system of medicines. The rind of fruit and the bark of the Pomegranate tree are used as a traditional remedy against diarrhea, dysentery, and intestinal parasites. The seeds and juice are considered a tonic for the heart and throat, and classified as a bitter-astringent (pitta or fire) component in the Indian Ayurvedic system, and considered a healthful counterbalance to a diet high in sweet-fatty (kapha or earth) components. The astringent qualities of the flower juice, rind and tree bark are considered valuable for a variety of purposes, such as stopping bleeding from gums and nose, toning skin firming up sagging breast and treating hemorrhoids. [7-11]

Over 1000 cultivars of Punica granatum L. exists, originating from the Middle east, extending throughout the Mediterranean, east –ward to China and India, and on to the American southwest, California and mexico in the New world. [12]

Morphology Also known as jewel of winter, P.granatum is small deciduous tree found in warm climates throughout the world. The height may vary from five feet to twice of it. It has elongated leaves arranged in alternating pattern. Bright red, orange or white flowers may be clustered or dispersed sporadically near the end of the branches. Fruits on ripening grow up to five inches in diameter. [13]

Leaves, opposite, lanceolate, shining from above, 5.7 cm long, 1.7 cm broad, having entire margin; petiole, thin, 4 cm long; leaves, often clustered on arrested branchlets.

Flowers, sessile, ebracteate, complete, actinomorphic, bisexual, solitary or in axillary clusters of 2 to 6; length, 3.7 cm; diameter, 3.6 cm; colour, claret rose 021; calyx, actinomorphic, persistent, thick, fleshy, 3.1 cm in diameter; corolla, polypetalous. with six petals, begonia 619 in colour, caducous, actinomorphic, inserted at the top of the calyx lute; length, 2 to 2.5 cm; androecium, with numerous stamens, inserted at different levels below the petals, polyandrous; filament, 4 mm long, light red; anther-lobes, dorsifixed and light yellow; style and stigma 1 to 1.2 cm long; ovary, inferior, containing numerous ovules, ovary enclosed entirely within the persistent calyx tube.

Fruits, globular, crowned by a persistent calyx, possessing a hard outer rind diameter, 4.2 to 6.6 cm; weight, 80.5 g volume, 78.5 ml colour, yellowish green, with a red tinge.

Seeds, angular, with a fleshy aril which constitutes the edible part; colour, varying from red to pinkish white.

The phylum Magnaliophyta consists of flowering plants termed as Angiosperms.

Following Figure highlights the Pomegranate taxonomical breakdown, [13]

Flower Morphology Pomegranate had been grown as fruit crop since ancient times. Flowering in Pomegranate is characterized as having both hermaphroditic (bisexual) flowers and functionally male flowers on the same plant, a condition referred to as andromonoecy. The hermaphroditic flowers have well-formed female (stigma, style, ovary) and male (filament

Table 1: Classification of Punica granatum

Classification Type Domain Eukarya

Kingdom Plantae Phylum Magnaliophyta

Class Magnoliopsida Order Myrtales Family Punicaceae Genus Punica L.

Species Punica granatum

Table 2: Flower Differentiation [18]

Flower Characteristics Bisexual (mean + sd) Male

Length of pedicel to tip of sepals (mm) 36.0 + 2.7 26.7 + 2.9 Pistil Length (mm) 27.5 + 2.1 19.4 + 2.9

Stigma + style length 17.1 + 2.0 15.9 + 2.5 Ovary Height (mm) 10.5 + 1.8 3.5 + 2.1

Table 3: Phytoconstituents in Flower parts [21]

Pomegranate Flower

Components Wieght

Composition (%) Total Phenolic

ContentEllagic Acid (mg/ 100 g)

Catechin (g/100g)

Epicatechin (g/100g)

Kic ( μ g total Phenolics/ ml

Mesocarp A 36.50 3.17 100.0 15.36 1.28 0.10+0.05 Endocarp 3.88 1.69 50.2 6.28 0.81 0.07+0.03

Aril 59.63 0.32 3.1 ND ND -

186



REVIEW ARTICLE

and anthers) parts and have been referred to as “fertile”, “vase-shaped”, and “bisexual” flowers. The hermaphrodite flowers are the ones which set fruit. Though it’s mistakenly considered as female part, but actually it’s male with suppressed female parts. Under agricultural production conditions, male: female flower ratios in Pomegranate can impact crop productivity and yield. [14-17]

Pomegranate flowers are large, showy flowers with vibrant petals and numerous anthers. Although organogenesis

of both male and female flower parts occurs in all flowers, the degree of development in petals flucatuates.

Temperature during the flowering period can have a pronounced effect on reproductive processes. The effects of temperature on pollen germination have been significantly reduced at 5° and 15°, whereas the highest and similar germination were obtained at 25° and 35°. The timing of flower types can show seasonal and yearly variations. [18-19]

Figure 2: Taxonomic breakdown

Figure 3: Fully grown flower of P. granata

Figure 4: Single near sessile flower, calyx fused at base

Figure 5: Longitudnal section of pomegranate flower

Figure 6: Anthers with filaments inserted in calyx tube

Figure 7: Male flower with devloped stamen & under devploed pistil

Figure 8: Well formed ovule from hermaphrodite flower

Figure 9: Underdeveloped ovule in male flower

187



REVIEW ARTICLE

Phytoconstituents Punica granatum mainly constitutes polyphenols of which are highly concentrated Ellagitannins, which are water soluble phenolic compounds with high molecular weights. [20] (Cuccioloni et al., 2009) carried out analysis of percentage wise presence of monomeric polyphenols, and

total phenolic content, in the different flower components, and came out with following outcomes,

Punica granatum is a rich source of anthocyanins which give red color to fruit and juice, and hydrolysable tannins, which account for the 92 % of total antioxidant activity of the fruit. [22]

Figure 10: Stigma & styles of pomegranate flowers

Figure 11: Stigma & styles

188



REVIEW ARTICLE

(Jain et al., 2011) isolated four main phytoconstituents present in Punica granatum. They are Punicalin,

Punicalagin, Gallic acid and Ellagic acid based on UV, IR, Mass and NMR data, standardized via HPLC.

(Clifford et al., 2000; Hakkinen et al., 2000) reported an important phytoconstituents elligatannins which are water soluble phenolic compounds with high molecular weight. Elligatannins upon hydrolysis produce hexahydroxydiphenic

Figure 12: Morphology of ovules in bisexual flower of pomegranate

Figure 13: Closer look at anthers and pollen grains

189



REVIEW ARTICLE

acid, which spontaneously rearranges to ellagic acid. An U.V. Chromatograph analysis, proved the presence of

Ellagic acid, Gallic acid, Epicatechin, and Catechin, following figure directs the same.

It contains substantial amount of other polyphenols, like sugar bound flavanoids, quercetin, kampferol, [23] flavonoid diglycosid, [24] ellagic acid, ellagic tannin,[25] and organic acids. [26]

(Alighourchi et al., 2008; Miguel et al., 2004) reported isolated anthocyanin like, delphinidin, cyaniding, and pelargonidin 3-glucosides and 3, 5-diglucosides. [27]

(Jain et al., 2011) mentioned the stepwise isolation procedure for near to 100 % percentages of Punicalin and Punicalagin via methanolic solvent extraction. [28]

Following Figure outlines the systemic stepwise isolation procedure,

Figure 14: Basic phytoconstituents of P.granatum

Figure 15: UV chromatogram at 278 nm

190



REVIEW ARTICLE

Following are structures of other main constituents, (Balwani et al., 2011) in Biochimie journal, emphasized

a new isolated compound 2-methyl-1pyran-4-one-3-O-β-D-glucopyranoside, in Punica granatum P, [29]

(Zhang et al., 2011) reported two isolated and purified anthocyanins via reverse phase HPLC, namely, Pelargonidin 3,5-diglucoside and pelargonidin – 3- glucoside; analyses of which was carried out by UV-vis spectrophotometry, Mass and NMR spectroscopy. [30]

An upto-date analysis of the phytoconstituents present in Punica granatum reveals presence of Glucose, [31]

Fructose, [31], Sucrose, [32],Citric acid, [33] Mallic acid, [33]Tartaric acid, [33] Fumaric acid, [33] Succinic acid, [33] Ascorbic acid, [34] Gallic acid, [35-36] Ellagic acid, [35,36] 3,3’-Di-O- methyl ellagic acid, [37] 3,3’,4’-Tri-O-methyl ellagic acid, [38] caffeic acid, [35,38] Flavan-3-ol, [39] Catechin, [39] Epicatechin, [39] Kampferol, [40] Luteolin, [40] Apigenin, [41]

Delphinidin, [42] Cyanidin, [42] Punicalin, [42-43] Punicalagin, [44-45] Corilagin, [46-47] Casuarinin, [44] Granatin A, [46] Proline, [47] Valine, [48] Methionine, [48] Tryptamine, [49] Serotonin, [49] Melatonin, [49] Peelletierine, [50-51] Sedridine, [52] Hygrine, [52] Punicic acid, [53] Linoleic acid, [53,54-55] Daucosterol, [37] Cholestrol, [56] Estrone (Sex steroids), [27;56] Testosterone, [56] γ-Tocopherol, [57] Ursolic acid, [58-59] Oleanolic acid, [60] Cerebroside, [61] Coumestrol, [62] Phenethyl rutinoside. [37] PHARMACOLOGY SIGNIFICANCE: SUMMARY Antibacterial Activity (Prashanth et al., 2001) had reported an antibacterial potential in the Petroleum ether, Chloroform, Methanol and Water extracts. The organisms used for testing were Staphylococcus aureus, Escherichia coli, Klebshiella pneumoniae, P.vulgaris, B.subtilis, S.typhi. The findings signified the effectiveness of petroleum ether extract in

Figure 16: Isolation process for punicalin & punicalagin [28]

Figure 17: Punicalin

Figure18: Ellagic acid

191



REVIEW ARTICLE

suppression of all test strains taken, and water extract effective against S.aureus and E.coli. Petroleum ether extract mainly isolates Alkaloids, Terpenoids, Coumarins, and Fatty acids. Thus, confirming the base behind the antibacterial activity due to the presence of terpenoids and alkaloids. [64]

(Rathinamoorthy et al., 2011) studied antibacterial potential in Punica granatum L. leaf, rind; and found the treated fabrics with Pomegranate extract showed high antibacterial resistance against strains like S. aureus, E.coli, K.pneumoniae, P.vulgaris, and S.typhi. Application of herbal

Figure 19: Punicalagin

Figure 20: Gallic acid

Figure 21: MPG

Figure 22: HPLC chromatogram of anthocyanin extract of pomengrate flowers

192



REVIEW ARTICLE

ointments to fabric for commercial production is possible profit earning scope apart from significance in herbal therapy. [65]

Anti-cancer therapy-A Step towards Chemoprevention (Syed et al., 2007) reported the potential chemoprevention activity in Pomegranate in the cases of Skin, Prostate, Lung,

breast, colon cancer. Chemoprevention is a strategy of preventive oncology that focuses on cancer prevention by administration of one or more natural or synthetic compounds to arrest the stages of carcinogenesis. [66] It reported the 92% antioxidant activity due to phenolic compounds, flavanoids (anthocynanins, catechins) and

Figure 23: Punica granatum chemical epitome [20-63]

Figure 24: Invitro anticancer studies using Punica granatum extract [67-74]

193



REVIEW ARTICLE

hydrolysable tannins (Punicalin, Pedunculagin, Punicalagin, gallagic acid, and ellagic acid). The anthocynanins are responsible for preventing lipid peroxidation of cell or liposomal membranes. Also reported the methanolic extraction gave higher antioxidant activity due to majority of phenolic compounds isolated into methanolic solvent. The higher antioxidant activity resulted to high concentration of

polyphenols present in the methanolic extract, indication ellagitannins of which mainly punicalagins, as major antioxidant phytoconstituent. [67-72]

Immunosuppressive Activity (Lee et al., 2008) studied the potential immune suppressive activity in the Punicalagin, isolated from the plant

Figure 25: Punicalagin role in cancer disease [20]

Figure 26: Ellagic acid in crohn's disease [74]

194



REVIEW ARTICLE

P.granatum. Punicalagin is a polyphenolic compound, an isomer of 2, 3-(S)-hexahybroyldiphoyl-4, 6-(S, S)-gallagyl-o-glucose and structurally belongs to ellagitannins (hydrolysable tannins). As ellagitannins have proven antioxidant activity, it was further found to inhibit the proliferation of several human colon cancer cell lines and induce apoptosis of these cells at higher concentrations. It found P.granatum to be potent inhibitor of nuclear factor of activated T-cells (NFAT). Also (Lee et al., 2008) has reported the potential downregulation potential of the mRNA and soluble protein expression of interleukin-2 from anti-CD3/anti-CD28-stimulated murine splenic CD4+ T cells and suppressed mixed leucocytes reaction without exhibiting cytotoxicity to cells. Thus proves to be a potential candidate for targethed-specific therapy and in various immune pathologies. [20]

(Catalan et al., 2010) reported in affirmation the role of ellagitannins as antioxidant, antimicrobial, or cytotoxic. The extracts were taken from Cistus ladanifer and Cistus populifolius. [73]

Effective in Crohn’s Disease Due to the presence of many effective phytoconstituents, of therapeutic importance, (Rosillo et al., 2011), reported the decrease and suppression of various inflammatory precursors due to the presence of P.granatum extract , involved in the pathophysiology of the Inflammatory Bowel Disease and Crohn’s disease. [75]

Fighting Depression (Okomoto et al., 2004) found pomengrate effective in bone mineral density maintenance even after the presence of strong stimulator ovariectomy leading to sudden depression in bone mineral density. The researcher selected Pomegranate for studying menopausal syndrome, on the basis of estrogenic effect proven in the plant earlier. The estrogenic effects were due to the presence of Estradiol, estrone and estriol. Ovariectomy induces sudden increase in body weight; this was inhibited by the constant administration of Pomegranate juice. [76]

Antioxidant Activity There is no doubt about the mentioned activity, as texted earlier the presence of different phytoconstituents, especially phenolic compounds, polyphenols, flavanoids, and hydrolysable tannins, depict 92 % of total antioxidant activity present in the plant Pomegranate.

Another confirmation comes from the experimental report published by (Moneim A.E.A, 2012), who studied the antioxidant properties in Pomegranate on rat brains. Findings gave positive feedback of polyphenols except catechol tannins, since it was absent in the methanolic extract, on the reduction in Reactive oxygen species (ROS), reduction in superoxide dismutase, hydrogen peroxide, and hydroxyl (*OH) generated capable of damaging cell lines, and DNA.

The result proved Pomegranate as a powerful antioxidant lead for medicine development. [77] Probiotic Enhancer (Bialonska et al., 2010) reported the positive effects of Pomegranate on the gut microbial environment. The study found Pomegranate effective in enhancing the growth of probiotics for e.g Bifidobacterium spp., Lactobacillus Enterococcus species. Thus, making it suitable lead to strengthening immune and defense mechanisms of the body. [78]

Osteoarthiritis Treatment (Rasheed et al., 2010) studied the proliferation factor responsible for pathogenesis of Osteoarthiritis and found, p38-MAPK (Mitogen activated protein kinases) as a major signal-transducing pathway in pathogenesis of Osteoarthiritis, activated further via interleukin-1β leading to plethora of generation of mediators for Osteoarthiritis. The researcher experimented the effect of Pomegranate extract on the chondrocyte cells isolated from Osteoarthritis affected cartilage via enzymatic digestion. The pathogenesis of degradation was observed after IL-1β stimulation. Gene expressions of p38-MAPK were observed and measured by RT-PCR. The results showed a promising treatment lead for Osteoarthiritis, as it was observed that

Figure 27: Pomegranate targeting osteoarthiritis inducer (novel target therapy lead) [79]

195



REVIEW ARTICLE

Pomegranate extract suppressed IL-1β induced activation of MKK3(Mitogen activated prtotein kinase kinsase), p38α-MAPK isoform and DNA binding activity of the transcription factor RUNX-2(Runt-related transcriptioin factor 2. [79]

Potential Anti-coagulant Activity (Cuccioloni et al., 2009) in his report highlighted the significance of Pomegranate extracts in regulation of uncontrolled coagulation cascade. [19] Normally, coagulation process is regulated by endogenous mediators such as, tissue factor pathway inhibitor, the protein C and protein S systems and antithrombin, [80] controlling formation of hemostatic plug at the site of injury. During unbalance state, a condition of hypercoagulation results, which controlled via synthetic leads have a tendency to develop hepatotoxicity as a potential side-effect. Natural source leads having potential targeted inhibition of these mediators have an edge in scientific research due to eradication of side-effect, a major hinderance for clearing of many potential leads. In this case, polyphenols from Pomegranate project the exact requirement of natural source to develop a prospective lead targeting inhibition of crucial enzymes responsible for thrombin generation, thus representing a broad-spectrum natural drug. [19]

Cardioprotective Role (Mohan et al., 2012) studied the dose dependent inhibition of Isoprterenol (85 mg/kg, administered subcutaneously twice to rats) induced increase in heart rate, elevation in electrocardiogram, vascular reactivity to catecholamines, increase in levels of cardiac-marker enzymes-lactate dehydrogenase, creatine kinase, reduction in superoxide dismutase. Doses of (100mg/kg and 300mg/kg, p.o) of Pomegranate extract showed significant proof of potential cardiotonic lead. [81]

Antimalaria (Dell’Agli et al., 2010) carried out an in-vitro analysis of the Pomegranate extract in the treatment of malaria caused by Plasmodium falciparum involved in inflammatory cytokine-driven diseaee associated with upregulation and activity of metalloproteinase-9 and to the increase of TNF production. The methanolic extract enriched in tannins was prepared inhibited the secretion of MMP-9 induced by haemozoin or TNF. The effect occurred at transcriptional level since MMP-9 mRNA levels are lower in the presence of tested compounds. Thus the Pomegranate depicts its anti-malarial effect via anti-parasitic activity and inhibition of pro-inflammatory response in the onset of cerebral malaria. The Methanolic extract of Pomegranate showed inhibition of secretion of MMP-9 (Matrixmetallopeptidase 9), by 61 %. [82]

Antidiabetic Potential (Patil et al., 2011) reported in his survey of antidiabetic activity plants, a special mention of Punica granatum, where it clearly highlights the use of methanolic extract of the plant at dose range of 500 mg/ kg in normalizing the plasma glucose level in alloxan induced diabetic

experimental rats. Moreover aqueous extract at a dose range of 250 mg/kg and 500 mg/kg had resulted in amelioration of blood glucose levels, lipid parameters and oxidative stresses in streptozotocin induced diabetic rats. [83] Antimutagenic Activity (Zahin et al., 2010) experimented the antioxidant and antimutagenic potential in the peel extracts of the plant Punica granatum. The antioxidant activity was tested via DPPH free radical scavenging, phosphomolybednum, Ferric reducing power and Cupric reducing ability assays. The methanolic extract showed the highest antioxidant activity compared to other solvent fractions such as ethanol, acetone, and ethyl acetate fractions. Antimutagenic activity was explored via Ames Salmonella/ microsome assay against sodium azide (NaN3), methyl methane sulphonate (MMS), 2-aminofluorene (2-AF) and benzo(a)pyrene induced mutagenicity in Salmonella typhimurium tester strains. [84]

Memory Enhancing and Learning Potential (Adiga et al., 2010) has reported positive memory enhancing effect in the peel extracts of Punica granatum. The tests were confirmed with the help of T-maze test or passive avoidance test at dose of 50mg.kg and 100 mg.kg dose of peel extracts of plant Punica granatum. [85]

Larvicidal and Adulticidal Potential (Kamaraj et al., 2010) carried out detailed determination of selected medicinal plants, of which Punica granatum too was selected and observed for the targeted activity. The results showed average larvicidal and adulticidal activity shown by the plants selected. The hexane, ethyl acetate and methanol extract of leaf, bark, and fruit rind of M.charantia, M.oleifera, O.gratissium, O.tenuiflorum, P.granatum and T.terrestris were tested against two mosquito species and found interesting facts of potential of Punica granatum. [86] Antifungal Activity (Duraipandiyan et al., 2011) studied forty five medicinal plants collected from different parts of Tamil Nadu. Hexane, ethyl acetate, and methanol extract of the forty five medicinal plant extracts were investigated for potential antifingal activity. Punica granatum was one of the plant which showed positive test results with having broad spectrum antifungal property. [87] Cytochrome P Inhibitory Effect (Usia et al., 2006) analyzed inhibition of in-vitro metabolism by cytochrome P450 3A4 and CYP 2D6. Cytochrome are enzyme involved in metabolism of many drugs, and leading to early offset of drug activity in body of medicines given for treatment. CYP3A4, the major hepatic and intestinal CYP in humans, metabolizes more than 50 % of clinically used drugs such as cyclosporine A, dihydropyridine, ethinylestradiol, midazolam, terfenadine, and triazolam. CYP2D6 catalyzes drugs like amitriptyline, imipramine, haloperidol, propranolol and

196



REVIEW ARTICLE

dextromethorphan. The findings were Punica granatum had Inhibitory Concentration50 or IC50 at 35 (μg/ ml) for CYP3A4 and 32 (μg/ ml) for CYP2D6. Thus the results signify low dose effectiveness of Punica granatum in prolonging action of potential needy drugs in body via natural leads. [88]

CONCLUSION Plants having potential pharmacological significance in comparison to their synthetic counterpart, directs a powerful natural tool to battle against diseases without compromising over the hazardous effects of the plant on the body. Punica granatum is one of such many plants in our nature whose potentiality could overcome many hurdles, which come in line of drug development processes. Majority of leads fail to cross the final approval due to one or another side effects, which rather than working as healing probe, work in exaggerating the problem further. Elligatannins, Phenolic compounds, flavanoids, and alkaloids, are major phytoconstituents responsible for 98 % explored pharmacological potential in the plant.

Looking forward through this insight, potential new plants could be selected on the basis of these phytoconstituents to develop a power generator for natural medicine, a smart way to cure diseases, without bothering about their adverse effects.

REFERENCES AND NOTES 1. World health organization [Online].2012 June [cited 2012 July

8]; Available from: URL: http://www.who.int/ medicines/ areas/traditional/definitions/en/.

2. An Early timeline of Herbal medicine [Online]. 2010 August 14 [cited 2012 July 8]; Available from URL: http://monicawilde. wordpress.com/2010/08/14/an -early - timeline - of - herbal-medicine/.

3. The History of Gardening: A timeline from Ancient times to the Twentieth century [Online]. 2011 March 12 [cited 2012 July 9]; Available from URL: http://www.gardendigest.com/ timegl.htm#Start.

4. The History of herbal medicine [Online]. 2008 [cited 2012 July 9]]; Available from URL: http://www.herbal-supplement-resource.com/history-herbal-medicine.html.

5. Wolfson E.R. The Book of the Pomegranate: Moses de Leon’s Sefer Ha-Rimmon. Scholar’s Press, Atlanta, 1988.

6. Medicinal plants in India [Online]. 2010 Feburary 16 [cited 2012 July 8]]; Available from URL: http://medicinalpltsinindiamp. blogspot.in/.

7. Medieval Latin etmology of pomengranate on etymoline [Online]. 2012 July 6 [cited 2012 July 9]; Available from URL: http://www.etymonline.com/ index. php? term= pomengranate & allowed_in_frame-0.

8. Seed storage of horticulture crops. New York. Food Products press [Online]. 2012 July 6 [cited 2012 July 9]; Accessed from URL: http://en.wikipedia.org/wiki/Pomegranate.

9. Recent trends in horticulture in the Himalayas [Online]. 2012 July 6 [cited 2012 July 9]; Accessed from URL: http://en.wikipedia.org/wiki/Pomegranate.

10. Pomengranate: The longevity plant [Online]. 2012 July 6 [cited 2012 July 9]; Accessed from URL: http://en.wikipedia.org/ wiki/Pomegranate.

11. Ayurveda for all [Online]. 2012 July 6 [cited 2012 July 9]; Accessed from URL: http://en.wikipedia.org/ wiki/ Pomegranate.

12. Levin GM. Pomegranate (Punica granatum) plant genetic resources in Turkmenistan. Plant Genetic Resources Newsletter, 97:31–37, 1994.

13. Punica granatum: The pomegranate Tree [Online].2007 [cited 2012 July 11]; Accessed from URL: http://bioweb.uwlax.edu /bio203/2011/kruse_sara/classification.html.

14. Holland D, Hatib K, and Ya’akov-Bar I. Pomegranate: Botany, horticulture, breeding. Horticulture Review. Horticulture Science, 35: 127–191, 2009.

15. Shulman Y, Fainberestein L, and Lavee S. Pomegranate fruit development and maturation. Horticulture Science, 59:265–274, 1984.

16. Chaudhari MS and Desai TU. Effects of plant growth regulators on flower sex in pomegranate (Punica granatum L.). Agriculture Science 63:34–35, 1993.

17. DeMason AD and Stolte WK. Floral development in Phoenix dactylifera. Botanical, 60:1437–1446, 1982.

18. Wetzstein YH, Ravid N, Wilkins E, Martinelli PA. A morphological and histological characterization of bisexual and male flower types in Pomengranate. American social horticulture science, 136(2):83-92, 2011.

19. Cuccioloni M, Mozzicafreddo M, Sparapani L, Spina M, Eleuteri MA, Fioretti E, et al. Pomengranate fruit components modulate human thrombin. Fitoterapia, 80:301-305, 2009.

20. Lee IS, Kim SB, Kim SK, Lee S, Shin SK, Lim SJ. Immune-suppresive activity of punicalagin via inhibition of NFAT activation.Biochemical and Biophysical Research communications, 371: 799-803, 2008.

21. Gil MI, Tomas-Barberan FA, Hess-Pierce B, Holcroft DM, Kader AA. Agriculture Food Chemistry, 48:4581-9, 2000.

22. Clifford NM, Scalbert A. Food agriculture, 118, 2000. 23. Chauhan D, Chauhan SJ, Pharmaceutical Biology, 39:155, 2001. 24. Toumy AS, Rauwald WH.Phytochemistry, 61:971, 2002. 25. Poyrazoglu E, Gokmen V, Aruk N. Food compositaea analysis,

15:567, 2002. 26. Heftmann E, Ko TS, Bennett DR.Phytochemistry, 5:1337, 1966. 27. Alighourchi H, Barzegar M, Abbasi S. Anthocyanins

characterization of 15 Iranian pomegranate (Punica granatum L.) varieties and their variation during cold storage and pasteurization. European Food Research and Technology, 228:881–887, 2008.

28. Jain V, Murugananthan G, Deepak M, Vishwanatha LG, Manohar D. Isolation and standardization of various phytochemical constituents from methanolic extracts of fruit rinds of Punica granatum. Natural medicines, 9(6):0414-0420, 2011.

29. Balwani S, Nandi D, Jaisankar Ghosh B. 2-Methyl-pyran-4-one-3-O-b-D-glucopyranoside isolated from leaves of Punica granatum inhibits the TNFa-induced cell adhesion molecules expression by blocking nuclear transcription factor-kB (NF-kB). Biochimie, 93:921-930, 2011.

30. Zhang L, Fu Q, Zhang Y. Composition of anthocyanins in pomengranate flowers and their antioxidant activities. Food chemistry, 127:1444-1449, 2011.

31. Cui SM, Sasada Y, Sato H, Nii N. Cell structure and sugar and acid contents in the arils of developing pomegranate fruit. Journal of the Japanese Society for Horticultural Science, 73:241–243, 2004.

32. Gabbasova LB, Abdurazakova SK. Chemical composition of pomegranate juice] Izvestiya Vysshikh Uchebnykh Zavedenii. Pischevaya Tekhnologiya: Nauchno-Tekhnicheskii Zhurnal, 4:30–31, 1969.

33. Poyrazoglu E, Goekmen V, Artik N. Organic acids and phenolic compounds in pomegranates (Punica granatum L.) grown in Turkey. Journal of Food Composition and Analysis, 15:567–575, 2002.

197



REVIEW ARTICLE

34. Veres M. Study of the mechanical and chemical composition of cultivated pomegranate. Hrana Ishrana, 17:426–432, 1976.

35. Amakura Y, Okada M, Tsuji S, Tonogai Y. High-performance liquid chromatographic determination with photodiode array detection of ellagic acid in fresh and processed fruits. Journal of Chromatography, A896:87–93, 2000b.

36. Huang HT, HPeng G, Kota BP, Li GQ, Yamahara J, Roufogalis BD, Li Y. 2005b. Anti-diabetic action of Punica granatum flower extract: activation of PPAR-gamma and identification of an active component. Toxicology and Applied Pharmacology, 207:160–169, 2005b.

37. Wang RF, Xie WD, Zhang Z, Xing DM, Ding Y, Wang W, Ma C, Du LJ. Bioactive compounds from the seeds of Punica granatum (Pomegranate). Journal of Natural Products, 67: 2096–2098, 2004.

38. Artik N. Determination of phenolic compounds in pomegranate juice by using HPLC. Fruit Processing, 8:492–499, 1998.

39. de Pascual-Teresa S, Santos-Buelga C, Rivas-Gonzalo JC. Quantitative analysis of flavan-3-ols in Spanish foodstuffs and beverages. Journal of Agricultural and Food Chemistry, 48:5331–5337, 2000.

40. Van Elswijk DA, Schobel UP, Lansky EP, Irth H, van der Greef J. Rapid dereplication of estrogenic compounds in pomegranate (Punica granatum) using on-line biochemical detection coupled to mass spectrometry. Phytochemistry, 65:233–241, 2004.

41. Nawwar MAM, Hussein SAM, Merfort L. Leaf phenolics of Punica granatum L. Phytochemistry, 37:1175–1177, 1994a.

42. Tanaka T, Nonaka G, Nishioka I. Tannins and related compounds. XL. Revision of the structures of punicalin and punicalagin, and isolation and characterization of 2-O-galloylpunicalin from the bark of Punica granatum L. Chemical and Pharmaceutical Bulletin, 34:650–655, 1986a.

43. Gil MI, Tomas-Barberan FA, Hess-Pierce B, Holcroft DM, Kader AA. Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. Agricultural and Food Chemistry, 48: 4581–4589, 2000.

44. Satomi H, Umemura K, Ueno A, Hatano T, Okuda T, Noro T. Carbonic anhydrase inhibitors from the pericarps of Punica granatum L. Biological and Pharmaceutical Bulletin, 16:787–790, 1993.

45. Nawwar MAM, Hussein SAH, Merfort I. NMR spectral analysis of polyphenols from Punica granatum. Phytochemistry, 36:793–798, 1994b.

46. Tanaka T, Nonaka GI, Nishioka I. Tannins and related compounds. C. Reaction of dehydrohexahydroxydiphenic acid esters with bases, and its application to the structure determination of pomegranate tannins, granatins a & b. Chemical and Pharmaceutical Bulletin, 38: 9424–9428, 1990.

47. Velioglu S, Unal C, Cemeroglu B, Chemical characterization of pomegranate juice. Fruit Processing, 8:307–310, 1997.

48. Seppi AK Franciosi, A. Chemical composition of pomegranate juice (Punica granatum): amino acid contents. La Revista della Societa Italiana di Scienza dell’alimentazione, 9: 211–212, 1980.

49. Badria, FA. Melatonin, serotonin, and tryptamine in some Egyptian food and medicinal plants. Medicinal Food, 5:153–157, 2002.

50. Neuhofer H, Witte L, Gorunovic M, Czygan FC. Alkaloids in the bark of Punica granatum L. (pomegranate) from Yugoslavia. Pharmazie, 48:389–391, 1993.

51. Vidal A, Fallarero A, Pena BR, Medina ME, Gra B, Rivera F, Gutierrez Y, Vuorela, PM. Studies on the toxicity of Punica granatum L. (Punicaceae) whole fruit extracts. Ethnopharmacology 89, 295–300, 2003.

52. Schubert SY, Lansky EP, Neeman I. Antioxidant and eicosanoid enzyme inhibition properties of pomegranate seed oil and fermented juice flavonoids. Ethnopharmacology, 66:11–17, 1999.

53. Hopkins CY, Chisholm MJ. A survey of the conjugated fatty acids of seed oils. Journal of the American Oil Chemists Society 45:176–182, 1968.

54. Hornung E, Pernstich C, Feussner I. Formation of conjugated _11_13-double bonds by _12-linoleic acid (1,4)-acyl-lipid-desaturase in pomegranate seeds. European Journal of Biochemistry, 269:4852–4859, 2002.

55. Abd ElWahab SM, El Fiki, NM, Mostafa SF, Hassan AEB. Characterization of certain steroid hormones in Punica granatum L. seeds. Bulletin of the Faculty of Pharmacy (Cairo University), 36:11–15, 1998.

56. Dean PDG, Exley D, Goodwin TW. Steroid oestrogens in plants: re-estimation of oestrone in pomegranate seeds. Phytochemistry, 10:2215–2216, 1971.

57. Kim MM, Kim S. Composition for improving oral hygiene containing Punica granatum L. extract. Korean Patent: KR 2002066042. 2000.

58. Ahmed R, Ifzal SM, Saifuddin A, Nazeer M. Studies on Punica granatum. I. Isolation and identification of some constituents from the seeds of Punica granatum. Pakistan Pharmaceutical Sciences, 8:69–71, 1995.

59. Huang TH, HYang Q, Harada M, Li GQ, Yamahara J, Roufogalis BD, Li Y. Pomegranate flower extract diminishes cardiac fibrosis in Zucker diabetic fatty rats: modulation of cardiac endothelin-1 and nuclear factor-kappaB pathways. Journal of Cardiovascular Pharmacology, 46:856–862, 2005c.

60. Huang TH, HPeng G, Kota BP, Li GQ, Yamahara J, Roufogalis BD, Li Y. Pomegranate flower improves cardiac lipid metabolism in a diabetic rat model: role of lowering circulating lipids. British Journal of Pharmacology, 145:767–774, 2005a.

61. Tsuyuki H, Ito S, Nakatsukasa Y. Lipids in pomegranate seeds. Nihon Daigaku No-Juigakubu Gakujutsu Kenkyu Hokoku, 38:141–148, 1981.

62. Moneam NM, el Sharaky AS, Badreldin MM, Oestrogen content of pomegranate seeds. Chromatography, 438:438–442, 1988.

63. Tiwari P, Kumar B, Kaur M, Kaur G, Kaur H. Phytochemical screening and extraction: A Review.International Pharmaceutica Sciencia, 1(1):98-106, 2011.

64. Prashant D, Asha KM, Amit A. Antibacterial activity of Punica granatum.Short Review.Fitoterapia, 72:171-173, 2001.

65. Rathinamoorthy R, Udayakumar S, Thilagavathi G. Antibacterial efficacy analysis of Punica granatum L. leaf, rind and Terminalia chebule fruit extract treated cotton fabric against five most common human pathogenic bacteria. Pharmacy and Life sciences, 2(10):1147-1153, 2011.

66. Syed DN, Malik A, Hadi N, Sarfaraz S, Afaq F, Mukhtar H. Photochemopreventive effect of pomegranate fruit extract on UVA-mediated activation of cellular pathways in normal human epidermal keratinocytes. Photochemistry Photobiology, 82:398–405, 2007.

67. Pantuck AJ, Leppert JT, Zomorodian N, AronsonW, Hong J, Barnard RJ, et al. Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clinical Cancer Research, 12:4018–26, 2006.

68. Khan N, Afaq F, Kweon M-H, Kim KM, Mukhtar H. Oral consumption of pomegranate fruit extract inhibits growth and progression of primary lung tumors in mice. Cancer Research, 67:3475–82, 2007.

69. Kim ND, Mehta R, Yu W, Neeman I, Livney T, Amichay A, et al. Chemopreventive and adjuvant therapeutic potential of pomegranate (Punica granatum) for human breast cancer. Breast Cancer Research Treatment, 71:203–17, 2002.

198



REVIEW ARTICLE

70. Adams LS, Seeram NP, Aggarwal BB, Takada Y, Sand D, Heber D. Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. Agriculture Food Chemistry, 54:980–5, 2006.

71. Kawaii S, Lansky EP. Differentiation-promoting activity of pomegranate (Punica granatum) fruit extracts in HL-60 human promyelocytic leukemia cells. Medicinal Food, 7:13–8, 2004.

72. Mukhtar H, Ahmad N. Cancer chemoprevention: future holds in multiple agents. Toxicol Applied Pharmacology, 158:207–10, 1998.

73. Catalan BE, Arroyo FS, Saura D, Guillen E, Gutieerre FA, Carretero SA, et al. Cistaceae aqueous extracts containing ellagitannins show antioxidant and antimicrobial capacity, and cytotoxic activity.Food and Chemical toxicology, 48:2273-2282, 2010.

74. Lansky EP, Newman RA. Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer, Ethnopharmacology, 109:177–206, 2007.

75. Rosillo AM, Hidalgo SM, Cardeno A, Lastra ld CA. Protective effect of ellagic acid, a natural polyphenolic compound, in a murine model of Crohn’s disease.Biochemical Pharmacology, 82:737-745, 2011.

76. Okamato MJ, Hamamoto OY, Yamato H, Yoshimura H. Pomengranate extract improves a depressive state and bone properties in menopausal syndrome model ovariectomized mice.Ethnopharmacology,92:93-101, 2004.

77. Monein AEA. Antioxidant activities of Punica granatum (pomengranate) peel extract on brain of rats.Medicinal plants Research, 6(2):195-199, 2012.

78. Bailonska D, Ramnani P, Kasimsetty GS, Muntha RK, Gibson RG, Ferreira D. The influence of pomengranate by –product and punicalagins on selected groups of human intestinal microbiota. Food microbiology, 140:175-182, 2010.

79. Rasheed Z, Akhtar N, Haqqi MT. Pomengranate extract inhibits the interleukin-1β-induced activation of MKK-3, p38α-MAPK, and transcription factor RUNX-2 in human osteoarthiritis chondrocytes.Arthiritis Research & Therapy, 12:R195, 2010.

80. Cuccioloni M, Mozzicafreddo M, Sparagani L, Spina M, Eleuteri MA, Fioretti E, Angeletti M. Pomegranate fruit components modulate human thrombin.Fitoterapia, 80:301-305, 2009.

81. Mohan M, Patankar P, Ghadi P, Kasture S. Cardioprotective potential of Punica granatum in isoproterenol-induced myocardial infarction in wistar rats.Pharmacology and Pharmacotherapeutics, 1(1):32-37, 2010.

82. Dell’Agli M, Galli VG, Bulgari M, Basilico N, Romeo S, Bhattacharya D. Ellagitanins of the fruit rind of pomengranate (Punica granatum) antagonize in vitro the host inflammatory response mechanism involved in the onset of malaria.Malaria Journal, 9:208, 2010.

83. Patil R, Patil R, Ahirwar B, Ahirwar D. Current status of Indian medicinal plants with antidiabetic potential: A Review.Tropical biomedicine, S291-S298, 2011.

84. Zahim M, Aqil F, Ahmad I. Broad spectrum antimutagenic activity of antioxidant active fraction of Punica granatum L. peel extracts.Mutation research/Genetic toxicology and Environmental Mutagenesis, 703:99-107, 2010.

85. Adiga S, Trivedi P, Ravichandra V, Deb D, Mehta F. Effect of Punica granatum peel extract on learning and memory in rats.Tropical Medicine,687-690, 2010.

86. Kamaraj C, Rahuman AA. Larvicidal and adulticidal potential of medicinal plant extracts from south India against vectors.Tropical Medicine, 948-953, 2010.

87. Duraipandiyan V, Ignacimuthu S. Antifungal activity of traditional medicinal plants from Tamil Nadu, India.Tropical Biomedicine, S204-S215, 2011.

88. Usia T, Iwata H, Hiratsuka A,Watabe T, Kadota S, Tezuka Y. CYP3A4 and CYP2D6 inhibitory activites of Indonesian medicinal plants.Phytomedicine,13:67-73, 2006.

Cite this article as: Devansh Mehta, Manish Mehta. Punica granatum L. (Punicaceae): Lifeline for Modern Pharmaceutical Research. Inventi Impact: Ethnopharmacology, 2012(4): 185-199, 2012.

199

review on punica granatum

Documents