Users Online: 160

Home Print this page Email this page Small font sizeDefault font sizeIncrease font size

Home | About us | Editorial board | Search | Ahead of print | Current issue | Archives | Submit article | Instructions | Subscribe | Contacts | Login 
     

   Table of Contents      
REVIEW ARTICLE
Year : 2012  |  Volume : 2  |  Issue : 3  |  Page : 171-184

Pomegranate (Punica granatum L). Ancient seeds for modern cure? Review of potential therapeutic applications


Department of Pharmacology, S. D. M. College of Medical Sciences and Hospital, Sattur, Dharwad, Karnataka, India

Date of Web Publication8-Aug-2012

Correspondence Address:
Prasan R Bhandari
Department of Pharmacology, S.D.M. College of Medical Sciences and Hospital, Sattur, Dharwad - 580 009, Karnataka
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0738.99469

Rights and Permissions
   Abstract 

Pomegranate (Punica granatum L), in addition to its ancient historical uses, has been used in several systems of medicine for a variety of ailments. Pomegranate juice is a polyphenol-rich juice with high antioxidant capacity. In studies of human and murine models, pomegranate juice has been shown to exert significant antiatherogenic, antioxidant, anti-carcinogenic, and anti-inflammatory effects. In the past decade, numerous studies on the antioxidant, anti-carcinogenic, and anti-inflammatory properties of pomegranate constituents have been published, focusing on the treatment and prevention of cancer, cardiovascular disease, diabetes, dental conditions, and ultraviolet radiation-induced skin damage. Other potential applications include infant brain ischemia, male infertility, Alzheimer's disease, arthritis, and obesity. The aim of the present review is to discuss the cumulative evidence, which suggests that pomegranate consumption possesses a diverse array of biological actions and may be helpful in the prevention of some inflammatory-mediated diseases, including cancer. The search strategy included Pubmed, using terms 'pomegranate' or 'Punica granatum'. Citations relevant to the topic were screened.

Keywords: Anti-carcinogenic, antioxidant, pomegranate, Punica granatum, therapeutic applications


How to cite this article:
Bhandari PR. Pomegranate (Punica granatum L). Ancient seeds for modern cure? Review of potential therapeutic applications. Int J Nutr Pharmacol Neurol Dis 2012;2:171-84

How to cite this URL:
Bhandari PR. Pomegranate (Punica granatum L). Ancient seeds for modern cure? Review of potential therapeutic applications. Int J Nutr Pharmacol Neurol Dis [serial online] 2012 [cited 2017 May 25];2:171-84. Available from: http://www.ijnpnd.com/text.asp?2012/2/3/171/99469


   Introduction Top


Almost 25 centuries ago, Hippocrates, the Father of Medicine, stated, "Let food be thy medicine and let medicine be thy food". Supporting this statement, at present, there has been an enormous interest worldwide in nutraceuticals, which are known to play a pivotal role in health management. Many different studies have shown the beneficial effects of a range of different fruits, vegetables, and spices. Dietary fibers are increasing in importance in chronic diseases, and reinforcing their place in the diet, to face these true 'epidemics'. [1] This is due to their presumed safety and potential nutritional and therapeutic benefit.

Some of the commonly consumed nutraceuticals include glucosamine (for arthritis), lutein (for macular degeneration), ginseng (for cold), Echinechea (immunomodulator), and cod liver oil, on to name a few. [2] In vitro, in vivo, and human clinical studies have all established curcumin's promise and revealed its therapeutic value. [3] In addition, topical capsaicin has been shown to improve the outcome in neuropathic and musculoskeletal pain, post herpetic neuralgia, arthritic pain, burning mouth syndrome, pain due to fibromyalgia, psoriatic disorder, burning mouth syndrome, various allergic disorders, and intranasally for cluster headache. [4]

On reviewing the literature through a Medline search, it was observed that there was a substantial jump in the scientific articles pertaining to the health benefits of pomegranate in the last decade, as compared to the time spanning 1950 to 1999, [5] hence, this review on pomegranate. The aim of the present review is to discuss the cumulative evidence that suggests that pomegranate consumption possesses a diverse array of biological actions and may be helpful in the prevention of some inflammatory-mediated diseases, including cancer.

Historical background

Pomegranate probably originated in Iran and Afghanistan. Before its medicinal properties were defined, the pomegranate was revered by many of the world's main religions. In Greek mythology, the pomegranate represented life, regeneration, and marriage. Besides, being used in Zoroastrian ceremonial and domestic adherences, the pomegranate confined invincibility. Pomegranate seeds, which are stated to be 613 in number, represent each of the Bible's 613 commandments. It also signifies sanctity, fertility, and abundance. In Buddhism, pomegranate is considered to be one of the three sacred fruits, along with citrus and peach, symbolizing the essence of favorable influences. Pomegranate is widely represented in ceramic art in China. Additionally, pomegranate denotes fertility, abundance, posterity, and numerous and virtuous offsprings, with a sanctified future. An icon of renaissance and life eternal in Christian art, the pomegranate is often found in devotional statues and paintings of the Virgin and Child. Islamic legend holds that each pomegranate contains one seed that has come down from paradise. The pomegranate plays a distinct role as a fertility symbol in marriages among the Bedouins of the Middle East. In Hinduism, the pomegranate (Sanskrit: Beejpur, literally; replete with seeds) implies prosperity and fertility and is related with both Bhoomidevi (the earth goddess) and Lord Ganesha (who is also called Bijapuraphalasakta, or the one fond of the many-seeded fruit).

All parts of the plant (roots, bark, flowers, fruits, and leaves) are used for remedial purposes in Ayurveda. The Ayurvedic system of medicine regards pomegranate as a 'pharmacy unto itself'. It is used as an anti-parasitic agent and a blood tonic. It heals aphthae, diarrhea, and ulcers. Pomegranate also functions as a remedy for diabetes in the Unani system of medicine practiced in the Middle East and India.

However, the name pomegranate originates from the genus 'Punica', which was the Roman name for Carthage, where the best pomegranates were known to grow. Pomegranate is known by the French as grenade, the Spanish as Granada, which literally translates to seeded ('granatus') apple ('pomum'). [6],[7]

Description

The pomegranate tree typically grows 12−16 feet and has many spiny branches. It can be extremely long-lived, as evidenced by trees at Versailles, France, known to be over 200 years old. The leaves are glossy and lance shaped. The bark of the tree turns gray as the tree ages. The flowers are large, red, white, or variegated, and have a tubular calyx that eventually becomes the fruit [Figure 1]. The ripe pomegranate fruit can be up to five inches wide with a deep red, leathery skin. It is grenade-shaped, and crowned by the pointed calyx. The fruit contains many seeds (arils) separated by white, membranous pericarp, and each is surrounded by small amounts of tart, red juice [Figure 2]. The pomegranate is native of the Himalayas in northern India to Iran. However, it has been cultivated and naturalized since ancient times over the entire Mediterranean region. It is also found in India, in the more arid regions of Southeast Asia, the East Indies, and tropical Africa. The tree is also cultivated for its fruit in the drier regions of California and Arizona. [8]
Figure 1: Pomegranate tree parts[6]

Click here to view
Figure 2: Pomegranate fruit

Click here to view


Phytochemistry

Alhough all the fruits are known to possess therapeutic properties, some studies report that even the bark, roots, and leaves of these trees have medicinal benefit. Considerable progress has been made in the last decade in establishing the pharmacological mechanisms of pomegranate and its individual constituents.

Pomegranate juice contains anthocyanins, glucose, ascorbic acid, ellagic acid, gallic acid, caffeic acid, catechin, Epigallocatechin gallate (EGCG), querticin, rutin, iron, and amino acids. Pomegranate seed oil is composed primarily of punicic acid and sterols. The pericarp (peel, rind) contains punicalgins, flavones, flavonones, and other flavanols. Tannins, including punicalin and punicafolin, and flavone glycosides like luteolin and apigenin, form important constituents of pomegranate leaves. The flowers of pomegranate are composed of ursolic acid, triterpinoids like maslinic acid, and asiatic acid. Ellagitannins and piperidine alkaloids are present in pomegranate roots and bark. However, current research seems to indicate that the most therapeutically beneficial pomegranate constituents include ellagic acid ellagitannins (including punicalagins), punicic acid, flavonoids, anthocyanidins, anthocyanins, and estrogenic flavones.

Pomegranate aril juice provides about 16% of an adult's daily vitamin C requirement per 100 ml serving, and is a good source of vitamin B 5 (pantothenic acid), potassium, and natural phenols, such as ellagitannins and flavonoids. [9]

Functional components of pomegranate parts

The pomegranate fruit could be considered a functional food because it has valuable compounds in different parts of the fruit that display functional and medicinal effects [Figure 3]. Pomegranate flowers attenuate aging-mediated undesirable skin abnormalities, [10] besides possessing potent antioxidant and hepatoprotective properties. [11] Additionally, they also diminish cardiac toxicity [12] and glucose levels. [13] The pomegranate peel has been shown to have anti-inflammatory, [14] anti-mutagenic, [15] and antifungal activity. [16] Furthermore, the pomegranate peel extracts also prevents liver fibrosis. [17] Pomegranate juice, which is rich in tannins, possesses anti-atherosclerotic, antihypertensive, anti-aging, and potent anti-oxidative characteristics. [18] Hence, it provides cardioprotective benefits. [19] Pomegranate juice may have cancer-chemopreventive as well as cancer-chemotherapeutic effects against prostate cancer, in humans. [20] Pomegranate seed oil exhibits nephroprotective properties. [21] Pomegranate bark has been seen to have molluscicidal activity. [22]
Figure 3: Major functional and medicinal effects of pomegranate

Click here to view


Pharmacokinetics

Ellagitannins (ETs) from pomegranate juice (PJ) are recorded to have several biological properties; yet their absorption and metabolism in humans are poorly understood.

Trials performed by Seeram NP et al. 2006, on 18 healthy volunteers, who were administered 180 mL of PJ concentrate, showed that Ellagic acid (EA) was present in the plasma of all subjects, with a maximum concentration of 0.06 ± 0.01 μmol / L, in the area under the concentration time curve of 0.17 ± 0.02 (μmol.h) x L (-1) , time of maximum concentration of 0.98 ± 0.06 hours, and elimination half-life of 0.71 ± 0.08 hours. EA metabolites, including dimethylellagic acid glucuronide (DMEAG) and hydroxy-6H-benzopyran-6-one derivatives (urolithins), were also detected in the plasma and urine, in conjugated and free forms. DMEAG was found in the urine obtained from 15 of 18 subjects on day 0, but was not detected on day -1 or +1, demonstrating its potential as a biomarker of intake. Urolithins, formed by intestinal bacteria, may contribute to the biological effects of PJ, as they may persist in the plasma and tissues and account for some of the health benefits noted after chronic PJ consumption. [23]

Another study investigated the absorption of a standardized extract from pomegranate in healthy human volunteers after the acute consumption of 800 mg of extract. Results indicate that ellagic acid (EA) from the extract is bioavailable, with an observed C(max) of 33 ng / mL at t(max) of one hour. The plasma metabolites urolithin A, urolithin B, hydroxyl-urolithin A, urolithin A-glucuronide, and dimethyl ellagic acid-glucuronide were identified by HPLC-MS. [24]

Pomegranate juice inhibited human CYP2C9 activity and could inhibit CYP3A-mediated drug metabolism. [25],[26]

Pharmacodynamics

The antioxidant, antitumor, and anti-inflammatory properties of pomegranate contribute to its beneficial action as per research.

Animal studies have demonstrated the free-radical scavenging properties of pomegranate juice. It has also been seen to decrease macrophage oxidative stress and lipid peroxidation. Human trials have shown that pomegranate juice increases the plasma antioxidant capacity; whereas in vitro assays have demonstrated that pomegranate juice has two to three times the antioxidant capacity compared to red wine and green tea. [27],[28],[29] Even pomegranate peel extract enhances the free-radical scavenging activity of hepatic enzymes catalase, superoxide dismutase, and peroxidase. [30] There is a significant decrease in the plasma carbonyl content (a biomarker for oxidant / antioxidant barrier impairment in various inflammatory diseases) compared to apple juice. [29]

Pomegranate cold-pressed oil, supercritical CO(2)-extracted seed oil, fermented juice polyphenols, and pericarp polyphenols inhibit prostate cancer cell invasiveness and proliferation causes cell cycle disruption, induces apoptosis, and inhibits tumor growth, as per the in vitro assays utilizing three prostate cancer cell lines (DU-145, LNCAP, and PC-3). [31],[32] Studies in mice implanted with the prostate cancer PC-3 cell line demonstrated that pomegranate fruit extract inhibits cell growth and induces apoptosis via modulation of the proteins regulating apoptosis. [20],[33] Recent research also indicates that pomegranate seed oil and fermented juice polyphenols inhibit angiogenesis via the downregulation of vascular endothelial growth factor in MCF-7 breast cancer and human umbilical vein endothelial cell lines. [34]

Both cyclooxygenase (COX) and lipoxygenase enzymes were inhibited in vitro by the pomegranate seed oil extract. [35]

The pomegranate flower extract has demonstrated improvement in insulin sensitivity, thus reducing glucose levels in rats. It inhibited alpha-glucosidase activity and caused regeneration of pancreatic beta cells. [13],[36]

Pomegranate juice has been seen to inhibit serum angiotensin converting enzyme activity, thus reducing blood pressure and cardiovascular diseases. [37]

Pomegranate juice concentrate decreased cholesterol absorption, increased fecal excretion, and improved cholesterol metabolizing enzymes, thus improving total / HDL and LDL / HDL cholesterol ratio. [38]

Both animal as well as human studies have demonstrated the antimicrobial activity of hydroalcoholic extract (HAE) and gel from pomegranate fruits against Staphylococcus, aureus, Streptococcus pyogenes, Diplococcus pneumoniae,  Escherichia More Details coli, and Candida albicans. [39],[40]

Additionally, another in vitro study has demonstrated that pomegranate fruit extract has a significant and broad inhibitory activity on matrix metalloproteinases (MMP's). These are a subgroup of collagenase enzymes expressed in high levels in arthritic joints which are involved in turnover, degradation, and catabolism of the extracellular joint matrix. Besides, it also inhibits the IL-1 beta-induced destruction of proteoglycan, expression of MMP's at cellular levels, phosphorylation, and activation of mitogen-activated protein kinases (signal transduction molecules involved in MMP expression). All of these suggest that pomegranate fruit extract may prevent collagen destruction and joint degradation in patients with osteoarthritis. [41]

Potential therapeutic applications Cancer

As the use of dietary supplements as alternative treatments or adjuvant remedies in cancer management is rising, a scientific corroboration of their biological activity and the comprehensive mechanisms of their action are essential for the recognition of dietary supplements in conventional cancer treatments.

Studies suggest that pomegranates contain bioactive chemicals with prospects for the treatment and prevention of cancer. Pomegranate juice extracts (PJE) have been shown to inhibit cellular proliferation and tumor growth and induce cell death via apoptosis in a number of cancer cell lines. [42]

Prostate cancer

Prostate cancer is the second leading cause of cancer-related deaths among US males. [43] Epidemiology supports the important role of nutrition in prostate cancer (PCA) prevention. [44] The basic mechanisms responsible for the anti-progression effects of pomegranate juice on prostate cancer remain uncertain. However, it has been observed that besides causing cell death of hormone-refractory prostate cancer cells, pomegranate juice also enhances cell adhesion and reduces cell migration of the cells that do not die. Thus, it has been postulated that pomegranate juice does so by stimulating the expression and / or activation of molecules that modify the cytoskeleton and the adhesion machinery of prostate cancer cells, causing enhanced cell adhesion and lesser cell migration.

Additionally, pomegranate juice significantly decreased the concentration of liberated pro-inflammatory cytokines / chemokines like IL-6, IL-12p40, IL-1β, and RANTES, thus, having the prospect to reduce inflammation and its influence on cancer progression. Pomegranate juice also inhibits the capacity of the chemokine SDF1α to chemoattract these cancer cells. SDF1α and its receptor CXCR4 are vital in the metastasis of cancer cells to the bone.[43] Results suggest that urolithin glucuronides and dimethyl ellagic acid may be the molecules responsible for the beneficial effects of pomegranate juice against PCA. [44]

Pantuck AJ et al., 2006, reported the first clinical trial of pomegranate juice in patients with prostate cancer. Mean PSA doubling time significantly improved with treatment, from a mean of 15 months at baseline to 54 months post treatment (P < 0.001). In vitro assays comparing pretreatment and post treatment patient serum on the growth of LNCaP, demonstrated a 12% reduction in cell proliferation and a 17% elevation in apoptosis (P = 0.0048 and 0.0004, respectively). This study also demonstrated a 23% enhancement in serum nitric oxide (P = 0.0085), a significant (P < 0.02) decrease in the oxidative state, and sensitivity to oxidation of serum lipids, after pomegranate juice consumption. [45]

Breast cancer

Roughly70% of breast cancer is estrogen receptor-alpha (ER-α) positive, signifying better prognosis and determining if tumors will respond to the estrogen-blocking / ER-antagonist drug Tamoxifen (TAM). Yet, a substantial section of ER-positive tumors respond with minimal or no response to TAM. It is unclear why some breast cancer cells resist TAM and how to make these cells respond. However, studies suggest that pomegranate fruit extracts (PFEs) demonstrate an anticancer effect against some cancers, hence, a study was initiated to determine if PFEs could augment / sensitize the TAM's effect in ER-positive MCF-7 breast cancer cells . To test the assumption, the investigators evaluated the effect of PFEs on sensitive and TAM-resistant MCF-7 cell viability and cell death in the presence and absence of TAM, under an estrogenic and non-estrogenic culture environment. The studies demonstrated that PFEs improved the TAM action in both sensitive and TAM-resistant MCF-7 cells through the inhibition of cell viability (regular or estrogen-induced), by stimulating the cell-death machinery. Results showed, for the first time, that pomegranate as an adjunct to TAM could signify a unique and dominant approach to improve and sensitize TAM action. [46]

Punicic acid is an omega-5 long chain polyunsaturated fatty acid present in pomegranate seed oil. A number of long chain fatty acids have been claimed to possess cancer-preventive actions. Studies evaluated the possibility of punicic acid to modify the growth of both the estrogen insensitive breast cancer cell line (MDA-MB-231) and the estrogen sensitive cell line, developed from the MDA-MB-231 cells (MDA-ERalpha7). Proliferation was inhibited by 92 and 96% for MDA-MB-231 and MDA-ERalpha7 cells, respectively, compared to the untreated cells by 40 μM punicic acid. Observations suggested that punicic acid had breast cancer inhibitor properties due to its effect on lipid peroxidation and the PKC pathway. [47]

Colon cancer

Pomegranate juice derived ellagitannins and their intestinal bacterial metabolites, urolithins, inhibited TCDD-induced CYP1-mediated EROD activity in vitro with IC (50) concentrations ranging from 56.7 μM for urolithin A to 74.8 μM for urolithin C. These compounds demonstrated dose- and time-dependent reduction in cell proliferation and clonogenic efficiency of HT-29 cells. Inhibition of cell proliferation was facilitated through cell cycle arrest in the G (0) / G (1) and G (2) / M stages of the cell cycle followed by induction of apoptosis. These results suggest that the ellagitannins and urolithins liberated in the colon, upon administration of pomegranate juice, in considerable amounts, could potentially reduce the risk of colon cancer progress, by inhibiting cell proliferation and inducing apoptosis. [48]

Hepatocellular carcinoma

Hepatocellular carcinoma (HCC), one of the most widespread and fatal cancers, has shown an alarming rise in the USA. In the absence of the effective treatment for HCC, innovative chemopreventive approaches may efficiently reduce the prevailing morbidity and mortality. Oxidative stress predisposes to hepatocarcinogenesis and is the foremost driving force of HCC. As the pomegranate has powerful antioxidant properties, investigators have examined the chemopreventive potential of pomegranate emulsion (PE) against dietary carcinogen in diethylnitrosamine (DENA)-induced rat hepatocarcinogenesis that mimics human HCC.

Results showed that PE significantly reduced the number and area of î³-glutamyl transpeptidase-positive hepatic foci compared to the DENA control. PE also inhibited DENA-induced hepatic lipid peroxidation and protein oxidation. Mechanistic studies demonstrated that PE elevated the gene expression of a range of hepatic antioxidant and carcinogen detoxifying enzymes in DENA-exposed animals. PE increased protein and messenger RNA expression of the hepatic nuclear factor E2-related factor 2 (Nrf2). Thus, studies validate that pomegranate constituents provide chemoprevention of hepatocarcinogenesis, probably through potent antioxidant activity obtained by the upregulation of an array of housekeeping genes under the control of Nrf2, without toxicity. This study, thus substantiates the development of pomegranate-derived products in the prevention and treatment of human HCC, which remains a shattering disease. [49]

Leukemias

To date, few studies have investigated the potential of PJE in the treatment of leukemia. Dahlawi H et al., 2012, tested the potential effect of PJE on the induction of apoptosis and inhibition of cellular proliferation in eight leukemia cell lines (four lymphoid and four myeloid) and non-tumor hematopoietic stem cells (control cells).

Pomegranate juice extracts induced apoptosis considerably in all cell lines, including non-tumor control cells, although lymphoid cells and two of the myeloid cell lines were more sensitive. Additionally, PJE stimulated cell cycle arrest. DAPI analysis and viable cell counts, using the trypan blue exclusion assay, confirmed these observations. Thus, studies have provided proof that PJE contains bioactive compounds that can be used in the treatment of leukemia. [42]

Chemotherapy-induced toxicity

Cisplatin (CDDP), one of the most active cytotoxic agents against cancer, is frequently associated with nephrotoxicity and hepatotoxicity. Investigators evaluated the potential protective effect of pomegranate seed extract (PSE) against oxidative stress caused by CDDP injury of the kidneys and liver, by measuring tissue biochemical and antioxidant variables and immunohistochemically testing caspase-3-positive cells.

It was observed that PSE provided a significant protective effect toward the liver and kidney by reducing the level of lipid peroxidation. Additionally, it enhanced the concentrations of glutathione S-transferase, improved activities of glutathione peroxidase, glutathione S-transferase, and superoxide dismutase. Supporting the claim were the immunohistochemical findings, thus, corroborating that PSE significantly diminished nephrotoxicity and hepatotoxicity due to its antioxidant, radical-scavenging, and anti-apoptotic effects. Thus, investigators suggest that PSE extract could be used as a dietary supplement in patients receiving chemotherapy medications. [50]

Cardioprotective

Pomegranate juice contains antioxidants like soluble polyphenols, tannins, and anthocyanins possessing anti-atherosclerotic properties. Sumner et al., 2005, investigated whether daily intake of pomegranate juice for three months would improve myocardial perfusion in 45 patients who had Coronary Heart Disease (CHD) and myocardial ischemia, in a randomized, placebo-controlled, double-blind study.

After three months, the amount of stress-induced ischemia reduced in the pomegranate group, but increased in the control group Thus, the investigators concluded that daily consumption of pomegranate juice improves stress-induced myocardial ischemia in patients who have CHD. [51]

Another randomized, double-blind, parallel trial, evaluated the effect of pomegranate juice consumption on the progression rates of anterior and posterior carotid intima-media thickness (CIMT), in subjects at moderate risk for coronary heart disease. Results suggested that in subjects who were at risk for moderate coronary heart disease, pomegranate juice consumption had no significant effect on the overall CIMT progression rate, but may have slowed CIMT progression in subjects with increased oxidative stress and disturbances in the TG-rich lipoprotein / HDL axis. [52]

Pomegranate juice consumption caused a significant decrease in serum lipid peroxides and TBARS levels by 56 and 28%, respectively. Serum SH groups and PON1 activity significantly increased by 12 and 24%, respectively. It significantly reduced cellular peroxides (by 71%) and increased glutathione levels (by 141%). Furthermore, PJ consumption significantly decreased the extent of Ox-LDL cellular uptake (by 39%). Thus, PJ consumption by diabetic patients did not worsen the diabetic parameters, but rather resulted in anti-oxidative effects on the serum and macrophages, which could contribute to the attenuation of atherosclerosis development in these patients. [53]

The diabetic heart shows increased fibrosis, which impairs cardiac function. Endothelin (ET)-1 and nuclear factor-kappaB (NF-kappaB) interactively regulate fibroblast growth. Pomegranate flower extract reduced the upregulated cardiac mRNA expression of ET-1, ETA, inhibitor-kappa B beta, and c-Jun. It also normalized the downregulated mRNA expression of inhibitor-kappa B alpha in Zucker diabetic fatty rats. In vitro, pomegranate flower extract and its components, oleanolic acid, ursolic acid, and gallic acid, inhibited lipopolysaccharide-induced NF-kappaB activation in macrophages. These findings indicate that the pomegranate flower extract diminishes cardiac fibrosis in Zucker diabetic fatty rats, at least in part, by modulating cardiac ET-1 and NF-kappaB signaling. [54]

De Nigris et al., 2006, observed a significant dose-dependent reduction in nitric oxide bioactivity, represented by both basal and bradykinin-stimulated cellular cGMP accumulation. These phenomena were corrected significantly by concomitant treatment with PJ. These data suggest that PJ can exert beneficial effects on the evolution of clinical vascular complications, coronary heart disease, and atherogenesis in humans, by enhancing the NOSIII bioactivity. [55]

Antidiabetic

The hyperglycemia-induced oxidative stress in diabetes mellitus (DM) is the main factor in the pathogenesis of cardiovascular complications. The phenolic compounds are potent antioxidants that can reverse the factors leading to cardiovascular complications in DM. A study was conducted to determine the antagonizing effects of a polyphenol-rich antioxidant supplement containing pomegranate extract, green tea extract, and ascorbic acid, on oxidative stress in Type 2 diabetic patients.

Observations indicated that the polyphenol-rich antioxidant supplement containing pomegranate extract, green tea extract, and ascorbic acid, had significant antagonizing effects on oxidative stress and lipid peroxidation in patients with Type 2 DM, thus preventing cardiovascular complications. [56]

Peroxisome proliferator-activated receptor (PPAR)-gamma activators are widely used in the treatment of type-2 diabetes, because they improve the sensitivity of insulin receptors. From the in vitro studies, it has been demonstrated that the PGF extract enhances PPAR-gamma mRNA and protein expression. It also increases the activity of the lipoprotein lipase in human THP-1-differentiated macrophage cells. A phytochemical investigation has demonstrated that the gallic acid in the PGF extract is mostly responsible for this activity. Results suggest that the anti-diabetic activity of the PGF extract may result from improved sensitivity of the insulin receptor. Thus, these findings provide a better understanding of the potential mechanism of the anti-diabetic action of PGF. [13]

Lipid-Lowering

In vitro and in vivo studies have shown that punicic acid, a type of conjugated fatty acid, and the main constituent of pomegranate seed oil (PSO), has anti-atherogenic effects. A study was designed for evaluating the effect of PSO treatment on serum lipid profiles. Although serum cholesterol, LDL cholesterol, glucose concentrations, and body composition levels remained unaltered, administration of PSO for four weeks in hyperlipidemic subjects had encouraging effects on lipid profiles, including TAG and the TAG : HDL-C ratio. [57]

Another study was undertaken to determine the effect of concentrated pomegranate juice consumption on the lipid profiles of type II diabetic patients with hyperlipidemia (total cholesterol or triglycerides > or = 200 mg / dL). Following the consumption of concentrated pomegranate juice, a significant decrease was seen in total cholesterol (P < 0.006), low-density lipoprotein-cholesterol (LDL-c) (P < 0.006), LDL-c / high-density lipoprotein-cholesterol (HDL-c) (P < 0.001), and total cholesterol / HDL-c (P < 0.001). Thus, CPJ consumption could modify heart disease risk factors in these hyperlipidemic patients. Therefore, its inclusion in their diets could be beneficial. [38]

Dermatology

Clinical and epidemiological studies suggest that exposure of the skin to environmental factors / pollutants, such as solar ultraviolet (UV) radiation, produces injurious effects causing various skin diseases like sunburn, edema, hyperplasia, immunosuppression, photoaging, melanoma, and non-melanoma skin cancers. The incidence of non-melanoma skin cancer, including squamous cell carcinoma and basal cell carcinoma, is a substantial public health concern worldwide. Exposure of the skin to solar UV radiation results in inflammation, oxidative stress, DNA damage, dysregulation of cellular signaling pathways, and immunosuppression, leading to skin cancer. The regular consumption of natural plant products containing polyphenols, which are widely present in fruits, vegetables, dry legumes, and beverages, have become popular as protective agents, against the adverse effects of UV radiation.

Pomegranate is a rich source of polyphenols. It has been seen to exert anti-inflammatory, antioxidant, and anti-carcinogenic activity in numerous in vivo and in vitro studies. Studies have investigated the potential protective effects of a pomegranate fruit extract, standardized to punicalagins, against UVA- and UVB-induced damage in SKU-1064 human skin fibroblast cells. Pomegranate fruit extract, in a range of 5 to 60 mg / L, is able to protect human skin fibroblasts from cell death on UV exposure, possibly due to a decrease in induction of the pro-inflammatory transcription factor NF-kappaB, a downregulation of pro-apoptotic caspase-3, and an increased G 0 / G 1 phase, associated with DNA repair. Results from this study demonstrate the protective effects of pomegranate fruit extract against UVA- and UVB-induced cell damage and the potential use of pomegranate polyphenolics in topical applications. [58]

A study by Bae JY et al., 2010, examined the photoprotective effects of ellagic acid on collagen breakdown and inflammatory responses in UV (ultraviolet)-B irradiated human skin cells and hairless mice. Ellagic acid reduced the UV-B-induced toxicity of HaCaT keratinocytes and human dermal fibroblasts. Non-toxic ellagic acid markedly prevented collagen degradation by blocking matrix metalloproteinase production in UV-B-exposed fibroblasts. The anti-wrinkle activity of ellagic acid was assessed in hairless mice exposed to UV-B, in which it decreased UV-B-triggered skin wrinkle formation and epidermal thickening. Topical application of 10 μmol / l of ellagic acid attenuated the production of pro-inflammatory cytokines, IL-1beta and IL-6, and blocked the infiltration of inflammatory macrophages in the integuments of SKH-1 hairless mice, exposed to UV-B, for eight weeks. Furthermore, this compound alleviated inflammatory intracellular cell adhesion molecule-1 expression in UV-B-irradiated keratinocytes and photoaged mouse epidermis. These results suggested that ellagic acid prevented collagen destruction and inflammatory responses caused by UV-B. Therefore, dietary and pharmacological interventions with berries rich in ellagic acid might be promising treatment strategies for diminishing skin wrinkles and inflammation, concomitant with chronic UV exposure, leading to photoaging. Thus, ellagic acid-rich pomegranate extract, ingested orally, has an inhibitory effect on pigmentation in the human skin caused by UV irradiation. [59]

In another study, pomegranate extract (PE) from the rind, containing 90% ellagic acid, was assessed for its skin-whitening effect. PE showed inhibitory activity against mushroom tyrosinase in vitro, and the inhibition by the extract was similar to that of arbutin, a known whitening agent. Oral PE also inhibited UV-induced skin pigmentation on the back of brownish guinea pigs. The intensity of the skin-whitening effect was comparable between the guinea pigs who were administered PE and those fed with L-ascorbic acid. PE decreased the concentration of DOPA-positive melanocytes in the epidermis of UV-irradiated guinea pigs, but L-ascorbic acid did not. These results suggested that the skin-whitening effect of PE was probably due to inhibition of the proliferation of melanocytes, and melanin synthesis by tyrosinase in the melanocytes. PE, when taken orally, could be used as an effective whitening agent for the skin. [60]

A study by Hayouni EA et al., 2011, reports for the first time, the in vivo wound healing potential of pomegranate peels. A 5% (w / w) methanolic extract-based ointment was formulated and evaluated for its wound healing in guinea pigs. The ointment significantly increased wound contraction and duration of epithelialization, as determined by the mechanical (contraction rate, tensile strength), biochemical (increasing of collagen, DNA and proteins synthesis), and histopathological characteristics.

Furthermore, the extract exhibited significant antibacterial and antifungal activity against almost all tested organisms: Pseudomonas aeruginosa ATCC 9027, Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Klebsiella pneumoniae,  Salmonella More Details anatum, Salmonella typhimurium, Streptococcus pneumoniae, and fungi Candida albicans, Candida glabrata, Trichopyton rubrum, and Aspergillus niger. Hence, the formulated ointment might be used as a skin repair agent. [61]

Dental

Pomegranate components have properties that could promote oral health, including reducing the risk of gingivitis.

Four weeks of mouth rinsing, thrice daily, with the pomegranate extract dissolved in water, altered salivary measures pertinent to oral health, including gingivitis. The changes were: Decreased total protein (which can correlate with plaque forming bacteria readings), diminished activities of aspartate aminotransferase (a marker of cell injury), attenuated alpha-glucosidase activity (a sucrose degrading enzyme), enhanced activities of the antioxidant enzyme ceruloplasmin (affording superior protection against oral oxidant stress), and augmented radical scavenging capacity (however non-significant). Hence, the use of pomegranate extracts in oral health products such as toothpastes and mouthwashes could be a viable option. [62]

Menezes SM et al., 2006, studied the effect of the hydroalcoholic extract (HAE) from pomegranate fruits on dental plaque microorganisms. The results, expressed as the number of colony forming units per milliliter (CFU / mL), showed that the HAE was very effective against dental plaque microorganisms, decreasing the CFU / ml by 84%. The results were comparable with chlorhexidine used as standard. The HAE had an antibacterial activity against selected microorganisms, and may be a possible substitute for the treatment of dental plaque bacteria. [39]

Even results from the study conducted by Bhadbade SJ et al., 2011, indicate that the pomegranate mouth rinse has an antiplaque effect. It also states that pomegranate extract is efficacious against the Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Prevotella intermedia strains in vitro. The investigators suggest that pomegranate mouth rinse should be explored as a long-term antiplaque rinse, with prophylactic benefits. [63]

Additionally, adjunctive local delivery of extracts from Centella asiatica, in combination with pomegranate, significantly improved the clinical signs of chronic periodontitis and IL-1 beta level in maintenance patients. [64] Furthermore, the use of gel containing pomegranate extract may be used as a topical antifungal agent for the treatment of candidosis associated with denture stomatitis. [65]

Musculoskeletal

Dietary supplementation with polyphenols, particularly ellagitannins, may mitigate muscular damage experienced after eccentric exercise, producing delayed-onset of muscle soreness. Supplementation with ellagitannins significantly improves the recovery of isometric strength two to three days after a damaging eccentric exercise. [66]

Pomegranate fruit consumption reduced composite Disease Activity Index (DAS28) in rheumatoid arthritis patients, and this effect could be related to the anti-oxidative property of pomegranates. Dietary supplementation with pomegranates may be a useful complementary strategy to attenuate clinical symptoms in rheumatoid arthritis patients. [67]

Gastroprotective

Oral administration of an aqueous methanolic extract of pomegranate fruit (AMP) significantly reduced the ulcer lesion index produced by alcohol, indomethacin, and aspirin in rats. Furthermore, in pylorus-ligated rats, AMP significantly reduced the ulcer lesions, gastric volume, and total acidity. It prevented ulceration by increasing the pH and mucus secretion in pylorus-ligated rats. The present study shows the anti-ulcer activity of AMP in experimentally-induced gastric ulcers. [68]

Pomegranate tannins play a protective role against gastric ulcer. Its antiulcer effect is related to the increasing secretion of adherent mucus and free mucus from the stomach wall. This may inhibit generation of oxygen-derived free radicals, decrease the consumption of GSH-PX (glutathione peroxidase) and SOD (superoxide dismutase), and maintain the content of NO (Nitric Oxide) at a normal level. [69]  Helicobacter pylori Scientific Name Search on causes constant chronic gastritis, which can lead to peptic ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. The rising problem of antibiotic resistance by the organism stresses the search for innovative candidates from plant-based sources. In the present study, Hajimahmoodi M et al., 2011, have evaluated the in vitro anti-H. pylori activity of some selected medicinal plants on the clinical isolates of H. pylori. This study demonstrates that the extracts of pomegranate and Juglans regia have remarkable anti-H. pylori activity, with a mean of inhibition zone diameter of 39 and 16mm at 100μg disk 1 , respectively. [70]

Hepatoprotective

Fatty liver is the most common cause of abnormal liver function tests. The investigators have determined the effect and the underlying mechanism of pomegranate flower (PGF), a traditional anti-diabetic medicine, on fatty liver. The findings suggest that this Unani medicine ameliorates diabetes and obesity-associated fatty liver, at least in part, by activating the hepatic expression of genes responsible for fatty acid oxidation. [71]

Pretreatment with pomegranate flower extract, at a dose regimen of 50-150 mg / kg body weight, for a week, significantly and dose-dependently protected against ferric nitrilotriacetate (Fe-NTA)-induced oxidative stress, as well as hepatic injury. The extract afforded up to 60% protection against hepatic lipid peroxidation. It increased the glutathione (GSH) levels and activities of the antioxidant enzymes, namely, catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GR), and glutathione-S-transferase (GST), by up to 36, 28.5, 28.7, 40.2, and 42.5%, respectively. Protection against Fe-NTA-induced liver injury was apparent, as there was inhibition in the levels of liver markers, namely, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, and albumin, in the serum. The histopathological changes produced by Fe-NTA, such as, ballooning degeneration, fatty changes, and necrosis were also alleviated by the extract. These results indicate that pomegranate flowers possess potent antioxidant and hepatoprotective properties, the former being probably responsible for the latter. [11]

Fertility

Pomegranate fruit is linked with fertility, birth, and eternal life, because of its many seeds. The aim of this study was to investigate the effects of pomegranate juice (PJ) consumption on sperm quality, spermatogenic cell density, antioxidant activity, and the testosterone level of male healthy rats. PJ caused a significant decrease in the malondialdehyde (MDA) level. Additionally, a marked increase in glutathione (GSH), glutathione peroxidase (GSH-Px), catalase (CAT) activities, and the vitamin C level, was observed in rats treated with different doses of PJ. PJ consumption increased the epididymal sperm concentration, sperm motility, spermatogenic cell density, diameter of seminiferous tubules, and germinal cell layer thickness. It also decreased the abnormal sperm rate when compared to the control group. These results suggest that PJ consumption improves the sperm quality and antioxidant activity of rats. [72]

Anti-trichomonial

Trichomoniasis vaginalis is a significant worldwide health problem. Metronidazole has so far been used as the treatment measure, but metronidazole-resistant strains and unpleasant adverse effects have developed. Treatment of patients with metronidazole-refractory vaginal trichomoniasis constitutes a major therapeutic challenge and treatment options are extremely limited. Natural plant extract purified from pomegranate was investigated in vitro for its efficacy against T. vaginalis on Diamond media. Besides, infected women who accepted to be treated with pomegranate juice were completely cured. The anti-trichomoniasis vaginalis activity of pomegranate extract (in-vitro and in-vivo) gave very promising results. [73]

Miscellaneous

Alzheimer's disease


The most common medicinal herbs for the treatment of alzheimer's disease (AD) and those reported in literature are Ginkgo biloba L. (Ginkgoceae), Salvia officinalis L., and Huperzia serrata Thunb. (Lycopodiaceae). Some other medicinal herbs that have a beneficial effect in the treatment of Alzheimer's disease (AD) and its associated symptoms are: Acorus calamus L. (Araceae), Angelica archangelica L. (Umbelliferae), Bacopa monniera Wettst. (Scrophulariaceae), Biota orientalis L. (Coniferae) Cupressaceae, Celastrus paniculatus Willd. (Celastraceae), Centella asiatica L. (Umbelliferae), Clitoria ternatea L. (Leguminosae), Codonopsis pilosula Franch. (Campanulaceae), Convolvulus pluricaulis Chois. (Convolvulaceae), Coptis chinensis Franch. (Ranunculaceae), Crocus sativus L. (Iridaceae), Curcuma longa L. (Zingeberaceae), Evodia rutaecarpa (Juss.) Benth. (Rutaceae), Ginkgo biloba L. (Ginkgoaceae), Hypericum perforatum L. (Clusiaceae) (Hypericaceae) Magnolia officinalis Rehd. and Wils. (Magnoliaceae), Melissa officinalis L. (Lamiaceae), Piper methysticum Frost. (Piperaceae), Polygala tenuifolia Wild. (Polygalaceae), Rheum spp. L. (Polygonaceae), Salvia lavandulaefolia Vahl. (Lamiaceae), Salvia miltiorrhizia Bung. (Lamiaceae), Salvia officinalis L. (Lamiaceae), Terminalia chebula L. (Combretaceae), Withania somnifera L. (Solonaceae), and so on. [74]

Observations suggest that PGF supplementation decreases oxidative stress and ameliorates impairment in learning and memory performances in diabetic rats. Therefore, it is suggested that PGF supplementation may be clinically useful in treating neuronal deficit in diabetic patients. [75]

Obesity

Several infusions or decoctions of plants used in traditional medicine to reduce obesity could be utilized to reduce the clinical side effects of the current chemically formulated anti-obesity agents; the examples include Camellia sinensis (L.) Kuntze (Theaceae), Chlorella pyrenoidosa Chick. (Oocystaceae), Citrus aurantium L. (Rutaceae), Garcinia cambogia L. (Clusiaceae), Lagerstroemia speciosa (L.) Pers. (Lythraceaea), Panax ginseng C.A. Meyer (Araliaceae), Salix matsudana Koidzumi (Salicaceae), Nelumbo nucifera Gaertn. (Nymphaeaceae), and Hibiscus sabdariffa L. (Malvaceae).

More recently, positive effects on fat reduction have been shown using pomegranate and its extracts. Many of the beneficial effects are related to the presence of anthocyanins, tannins, very high levels of antioxidants, including polyphenols and flavonoids. Many studies have explored the effects of pomegranate on obesity, and various mechanisms have been proposed as to how these different extracts help in fat reduction. [76]

Antinociceptive

A study conducted by Ouachrif A et al., 2012, demonstrated that pomegranate contains active constituents, which possess antinociceptive and anti-inflammatory activity. [77]

Antidiarrheal

The anti-diarrhea1 activity of aqueous and alcohol extracts of the fruit rind of pomegranate was investigated in three experimental models, using albino rats. The extracts exhibited significant activity in rats, when compared to loperamide hydrochloride, a standard anti-diarrheal drug. [78]

Erectile dysfunction

A recent well-controlled trial of pomegranate juice for the treatment of mild-to-moderate erectile dysfunction in men, was made by Forest CP et al., 2007. The randomized, placebo-controlled, double-blind, crossover trial, enrolled 53 men with mild-to-moderate impotence. The subjects consumed pomegranate juice, or placebo, for four weeks. After a two-week washout period, they switched treatments. They concluded that the subjects were more likely to have improved scores when pomegranate juice was consumed. [79]

Antiviral properties

Haidari et al., 2009, evaluated the four major polyphenols in pomegranate extracts, EA, caffeic acid, luteolin, and punicalagin. They suggested that punicalagin had an anti-influenza component, because this compound blocked the replication of the virus RNA, inhibited agglutination of chicken RBCs by the virus, and had viricidal effects. Indeed, it inhibited the replication of human influenza A/Hong Kong (H3N2) in vitro.[80] Additionally, pomegranate has been used in phage amplification assays, as a viricidal agent. [81] Furthermore, pomegranate extract has been reported to have microbiocidal effects on HIV-1. [82]

Safety

No adverse effects have been reported on consuming pomegranate and its constituents, since time immemorial. Additionally, animal studies have failed to report any toxicities at doses conventionally used in the conventional system of medicine. [83] Even the histopathological analyses of pomegranate extract punicalagin were devoid of any toxic findings. [84] Human trials using doses of pomegranate fruit extracts up to 1,420 mg / day (870 mg gallic acid equivalents), for 28 days, did not report any adverse changes in blood or urine laboratory values. [85] Another study in 10 patients with carotid artery stenosis demonstrated that PJ consumption (121 mg / L EA equivalents) for up to three years had no toxic effect on the blood chemistry analysis for kidney, liver, and heart function. [86]


   Discussion and Conclusion Top


Natural products, including plants, animals, and minerals have played a significant role in maintaining human health and improving the quality of human life since long, are continuing to do so at present, and shall play a major role in the future as well. [87]

The indigenous or traditional system of medicine has become important in the field of medicine since the past few decades. This is especially so in most of the developing countries, where a substantial part of the populations depend on traditional practitioners. These practitioners in turn are relying on medicinal plants, for their primary healthcare needs. Herbal medicines are still being used primarily for historical and cultural reasons. As usage of herbal medicines has increased, issues regarding their quality, safety, and efficacy in both the developed and developing countries have cropped up. This has led the researcher to scientifically screen various traditional claims, because, everyone is interested in the scientific support, before using traditional drugs. Therefore, at present, both lay people and healthcare professionals pursue updated, scientific documentation, toward the safety and efficacy of any recommended medicinal plant as a drug, prior to its use. [88]

Given their potential to produce a significant therapeutic effect, medicinal plants can be useful as drugs or supplements in the treatment or management of various diseases. A large body of evidence shows the immense potential of medicinal plants to treat cardiovascular, liver, central nervous system, digestive, and metabolic disorders. Additionally, the current accepted modern medicine or allopathy has gradually developed over the years by scientific and observational efforts of scientists. However, the basis of its development remains rooted in traditional medicine and therapies.

Numerous in vitro, animal, and human experiments have demonstrated the vast potential benefits of pomegranate, such as, its anti-carcinogenic, cardioprotective, antioxidant, anti-diabetic, lipid-lowering, and dermoprotective characteristics. These properties suggest its possible use as a therapy or adjunct for prevention and treatment of several types of cancers and cardiovascular disease. The author suggests that the investigators could initiate studies to evaluate pomegranate in the management of oral cancers, respiratory cancers, stomach cancers, tuberculosis, metabolic syndrome, and as an adjunct to insulin / oral anti-diabetic agents. Although sparse, data is emerging with regard to its potential benefit in several other disorders, including Alzheimer's disease, osteoarthritis, neonatal brain injury, male infertility, and obesity. This necessitates the need for more human trials, to refute or substantiate any clinical effect. Currently, numerous clinical trials are in progress exploring the therapeutic potential of pomegranate extracts. However, prior to their use, such medicinal plants should be compared with the current established pharmacological treatment. Such studies should also include identification of the active principle, in order to improve the validation of a clinical trial. Further large-scale, multicenter studies are necessary to determine the effectiveness of these substances.

Ethnopharmacological studies on such medicinally important plants should continue to interest investigators throughout the world. This review will definitely help researchers as well as practitioners dealing with this plant, to know its proper usage in nature. Finally it is not wrong to state that this plant offers a wide scope in the treatment of serious and chronic diseases.

 
   References Top

1.Asif M. The role of fruits, vegetables, and spices in diabetes. Int J Nutr Pharmacol Neurol Dis 2011;1:27-35.  Back to cited text no. 1
  Medknow Journal  
2.Rajasekaran A, Sivagnanam G, Xavier R. Nutraceuticals as therapeutic agents: A Review. Research J Pharm and Tech 2008;1:328-40 .  Back to cited text no. 2
    
3.Mullaicharam AR, Maheswaran A. Pharmacological effects of curcumin. Int J Nutr Pharmacol Neurol Dis 2012;2:92-9.  Back to cited text no. 3
  Medknow Journal  
4.Chhabra N, Aseri ML, Goyal V, Sankhla S. Capsaicin: A promising therapy - A critical reappraisal. Int J Nutr Pharmacol Neurol Dis 2012;2:8-15.  Back to cited text no. 4
    
5.Lansky EP, Newman RA. Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer. J Ethnopharmacol 2007;109:177-206.  Back to cited text no. 5
[PUBMED]    
6.http: / / en.wikipedia.org / wiki / Pomegranate, [Accessed 2012 April 27].  Back to cited text no. 6
    
7.Langley P. Why a pomegranate? BMJ 2000;321:1153-4.  Back to cited text no. 7
[PUBMED]    
8.Jurenka J. Therapeutic Applications of Pomegranate (Punica granatum L.): A Review. Altern Med Rev 2008;13:128-44.  Back to cited text no. 8
    
9.Tiwari S. Punica granatum - A 'Swiss Army Knife' in the field of ethnomedicines. J Nat Prod 2012;5:4.  Back to cited text no. 9
    
10.Wang J, Rong X, Um IS, Yamahara J, Li Y. 55-week treatment of mice with the unani and ayurvedic medicine pomegranate flower ameliorates ageing-associated insulin resistance and skin abnormalities. Evid Based Complement Alternat Med 2012;2012:350125. Epub 2011 Dec 28.  Back to cited text no. 10
    
11.Kaur G, Jabbar Z, Athar M, Alam MS. Punica granatum (pomegranate) flower extract possesses potent antioxidant activity and abrogates Fe-NTA induced hepatotoxicity in mice. Food Chem Toxicol 2006;44:984-93.  Back to cited text no. 11
[PUBMED]    
12.Mohan M, Patankar P, Ghadi P, Kasture S. Cardioprotective potential of Punica granatum extract in isoproterenol-induced myocardial infarction in Wistar rats. J Pharmacol Pharmacother 2010;1:32-7.  Back to cited text no. 12
[PUBMED]  Medknow Journal  
13.Huang TH, Peng G, Kota BP, Li GQ, Yamahara J, Roufogalis BD, et al. Anti-diabetic action of Punica granatum flower extract: Activation of PPAR-gamma and identification of an active component. Toxicol Appl Pharmacol 2005;207:160-9.  Back to cited text no. 13
[PUBMED]    
14.Bachoual R, Talmoudi W, Boussetta T, Braut F, El-Benna J. An aqueous pomegranate peel extract inhibits neutrophil myeloperoxidase in vitro and attenuates lung inflammation in mice. Food Chem Toxicol 2011;49:1224-8.  Back to cited text no. 14
[PUBMED]    
15.Zahin M, Aqil F, Ahmad I. Broad spectrum antimutagenic activity of antioxidant active fraction of Punica granatum L. peel extracts. Mutat Res 2010;703:99-107.  Back to cited text no. 15
[PUBMED]    
16.Endo EH, Cortez DA, Ueda-Nakamura T, Nakamura CV, Dias Filho BP. Potent antifungal activity of extracts and pure compound isolated from pomegranate peels and synergism with fluconazole against Candida albicans. Res Microbiol 2010;161:534-40.  Back to cited text no. 16
[PUBMED]    
17.Toklu HZ, Dumlu MU, Sehirli O, Ercan F, Gedik N, Gökmen V, et al. Pomegranate peel extract prevents liver fibrosis in biliary-obstructed rats. J Pharm Pharmacol 2007;59:1287-95.  Back to cited text no. 17
    
18.Stowe CB. The effects of pomegranate juice consumption on blood pressure and cardiovascular health. Complement Ther Clin Pract 2011;17:113-5.  Back to cited text no. 18
[PUBMED]    
19.Basu A, Penugonda K. Pomegranate juice: A heart-healthy fruit juice. Nutr Rev 2009;67:49-56.  Back to cited text no. 19
[PUBMED]    
20.Malik A, Afaq F, Sarfaraz S, Adhami VM, Syed DN, Mukhtar H. Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proc Natl Acad Sci U S A 2005;102:14813-8.  Back to cited text no. 20
[PUBMED]    
21.Bouroshaki MT, Sadeghnia HR, Banihasan M, Yavari S. Protective effect of pomegranate seed oil on hexachlorobutadiene-induced nephrotoxicity in rat kidneys. Ren Fail 2010;32:612-7.  Back to cited text no. 21
[PUBMED]    
22.Tripathi SM, Singh DK. Molluscicidal activity of Punica granatum bark and Canna indica root. Braz J Med Biol Res 2000;33:1351-5.  Back to cited text no. 22
[PUBMED]    
23.Seeram NP, Henning SM, Zhang Y, Suchard M, Li Z, Heber D. Pomegranate juice ellagitannin metabolites are present in human plasma and some persist in urine for up to 48 hours. J Nutr 2006;136:2481-5.  Back to cited text no. 23
[PUBMED]    
24.Mertens-Talcott SU, Jilma-Stohlawetz P, Rios J, Hingorani L, Derendorf H. Absorption, metabolism, and antioxidant effects of pomegranate (Punica granatum l.) polyphenols after ingestion of a standardized extract in healthy human volunteers. J Agric Food Chem 2006;54: 8956-61.  Back to cited text no. 24
[PUBMED]    
25.Nagata M, Hidaka M, Sekiya H, Kawano Y, Yamasaki K, Okumura M, et al. Effects of pomegranate juice on human cytochrome P450 2C9 and tolbutamide pharmacokinetics in rats. Drug Metab Dispos 2007;35:302-5.  Back to cited text no. 25
[PUBMED]    
26.Hidaka M, Okumura M, Fujita K, Ogikubo T, Yamasaki K, Iwakiri T, et al. Effects of pomegranate juice on human cytochrome p450 3A (CYP3A) and carbamazepine pharmacokinetics in rats. Drug Metab Dispos 2005;33:644-8.  Back to cited text no. 26
[PUBMED]    
27.Gil MI, Tomás-Barberán FA, Hess-Pierce B, Holcroft DM, Kader AA. Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. J Agric Food Chem 2000;48:4581-9.  Back to cited text no. 27
    
28.Rosenblat M, Volkova N, Coleman R, Aviram M. Pomegranate byproduct administration to apolipoprotein e-deficient mice attenuates atherosclerosis development as a result of decreased macrophage oxidative stress and reduced cellular uptake of oxidized low-density lipoprotein. J Agric Food Chem 2006;54:1928-35.  Back to cited text no. 28
[PUBMED]    
29.Guo C, Wei J, Yang J, Xu J, Pang W, Jiang Y. Pomegranate juice is potentially better than apple juice in improving antioxidant function in elderly subjects. Nutr Res 2008;28:72-7.  Back to cited text no. 29
    
30.Chidambara Murthy KN, Jayaprakasha GK, Singh RP. Studies on antioxidant activity of pomegranate (Punica granatum ) peel extract using in vivo models. J Agric Food Chem 2002;50:4791-5.  Back to cited text no. 30
[PUBMED]    
31.Lansky EP, Jiang W, Mo H, Bravo L, Froom P, Yu W, et al. Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions. Invest New Drugs 2005;23:11-20.  Back to cited text no. 31
[PUBMED]    
32.Albrecht M, Jiang W, Kumi-Diaka J, Lansky EP, Gommersall LM, Patel A, et al. Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. J Med Food 2004;7:274-83.  Back to cited text no. 32
[PUBMED]    
33.Malik A, Mukhtar H. Prostate cancer prevention through pomegranate fruit. Cell Cycle 2006;5:371-3.  Back to cited text no. 33
[PUBMED]    
34.Bando H, Ramachandran C, Melnick SJ, Imai A, Fife RS, Carr RE, et al. Preliminary studies on the anti-angiogenic potential of pomegranate fractions in vitro and in vivo. Angiogenesis 2003;6:121-8.  Back to cited text no. 34
[PUBMED]    
35.Schubert SY, Lansky EP, Neeman I. Antioxidant and eicosanoid enzyme inhibition properties of pomegranate seed oil and fermented juice flavonoids. J Ethnopharmacol 1999;66:11-7.  Back to cited text no. 35
[PUBMED]    
36.Khalil EA. Antidiabetic effect of an aqueous extract of pomegranate (Punica granatum L) peels in normal and alloxan diabetic rats. Egyptian J Hosp Med 2004;16:92-9.  Back to cited text no. 36
    
37.Aviram M, Dornfeld L. Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure. Atherosclerosis 2001;158:195-8.  Back to cited text no. 37
[PUBMED]    
38.Esmaillzadeh A, Tahbaz F, Gaieni I, Alavi-Majd H, Azadbakht L. Cholesterol-lowering effect of concentrated pomegranate juice consumption in type II diabetic patients with hyperlipidemia. Int J Vitam Nutr Res 2006;76:147-51 .  Back to cited text no. 38
[PUBMED]    
39.Menezes SM, Cordeiro LN, Viana GS. Punica granatum (pomegranate) extract is active against dental plaque. J Herb Pharmacother 2006;6:79-92.  Back to cited text no. 39
[PUBMED]    
40.Pai MB, Prashant GM, Murlikrishna KS, Shivakumar KM, Chandu GN. Antifungal efficacy of Punica granatum , Acacia nilotica, Cuminum cyminum and Foeniculum vulgare on Candida albicans: An in vitro study. Indian J Dent Res 2010;21:334-6.  Back to cited text no. 40
[PUBMED]  Medknow Journal  
41.Ahmed S, Wang N, Hafeez BB, Cheruvu VK, Haqqi TM. Punica granatum L. extracts inhibits IL-1Beta-induced expression of matrix metalloproteinases by inhibiting the activation of MAP kinases and NF-kappaB in human chondrocytes in vitro. J Nutr 2005;135:2096-102.  Back to cited text no. 41
[PUBMED]    
42.Dahlawi H, Jordan-Mahy N, Clench MR, Le Maitre CL. Bioactive actions of pomegranate fruit extracts on leukemia cell lines in vitro hold promise for new therapeutic agents for leukemia. Nutr Cancer 2012;64:100-10.  Back to cited text no. 42
[PUBMED]    
43.Wang L, Alcon A, Yuan H, Ho J, Li QJ, Martins-Green M. Cellular and molecular mechanisms of pomegranate juice-induced anti-metastatic effect on prostate cancer cells. Integr Biol (Camb) 2011;3:742-54.  Back to cited text no. 43
    
44.González-Sarrías A, Giménez-Bastida JA, García-Conesa MT, Gómez-Sánchez MB, García-Talavera NV, Gil-Izquierdo A, et al. Occurrence of urolithins, gut microbiota ellagic acid metabolites and proliferation markers expression response in the human prostate gland upon consumption of walnuts and pomegranate juice. Mol Nutr Food Res 2010;54:311-22.  Back to cited text no. 44
    
45.Pantuck AJ, Leppert JT, Zomorodian N, Aronson W, 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. Clin Cancer Res 2006;12:4018-26.  Back to cited text no. 45
    
46.Banerjee S, Kambhampati S, Haque I, Banerjee SK. Pomegranate sensitizes Tamoxifen action in ER-á positive breast cancer cells. J Cell Commun Signal 2011;5:317-24.  Back to cited text no. 46
    
47.Grossmann ME, Mizuno NK, Schuster T, Cleary MP. Punicic acid is an omega-5 fatty acid capable of inhibiting breast cancer proliferation. Int J Oncol 2010;36:421-6.  Back to cited text no. 47
    
48.Kasimsetty SG, Bialonska D, Reddy MK, Ma G, Khan SI, Ferreira D. Colon cancer chemopreventive activities of pomegranate ellagitannins and urolithins. J Agric Food Chem 2010;58:2180-7.  Back to cited text no. 48
    
49.Bishayee A, Bhatia D, Thoppil RJ, Darvesh AS, Nevo E, Lansky EP. Pomegranate-mediated chemoprevention of experimental hepatocarcinogenesis involves Nrf2-regulated antioxidant mechanisms. Carcinogenesis 2011;32:888-96.  Back to cited text no. 49
    
50.Cayýr K, Karadeniz A, Simþek N, Yýldýrým S, Karakuþ E, Kara A, et al . Pomegranate seed extract attenuates chemotherapy-induced acute nephrotoxicity and hepatotoxicity in rats. J Med Food 2011;14:1254-62.  Back to cited text no. 50
    
51.Sumner MD, Elliott-Eller M, Weidner G, Daubenmier JJ, Chew MH, Marlin R, et al. Effects of pomegranate juice consumption on myocardial perfusion in patients with coronary heart disease. Am J Cardiol 2005;96:810-4.  Back to cited text no. 51
    
52.Davidson MH, Maki KC, Dicklin MR, Feinstein SB, Witchger M, Bell M, et al. Effects of consumption of pomegranate juice on carotid intima-media thickness in men and women at moderate risk for coronary heart disease. Am J Cardiol 2009;104:936-42.  Back to cited text no. 52
    
53.Rosenblat M, Hayek T, Aviram M. Anti-oxidative effects of pomegranate juice (PJ) consumption by diabetic patients on serum and on macrophages. Atherosclerosis 2006;187:363-71.  Back to cited text no. 53
    
54.Huang TH, Yang Q, Harada M, Li GQ, Yamahara J, Roufogalis BD, et al. Pomegranate flower extract diminishes cardiac fibrosis in Zucker diabetic fatty rats: Modulation of cardiac endothelin-1 and nuclear factor-kappaB pathways. J Cardiovasc Pharmacol 2005;46:856-62.  Back to cited text no. 54
    
55.de Nigris F, Williams-Ignarro S, Botti C, Sica V, Ignarro LJ, Napoli C. Pomegranate juice reduces oxidized low-density lipoprotein downregulation of endothelial nitric oxide synthase in human coronary endothelial cells. Nitric Oxide 2006;15:259-63.  Back to cited text no. 55
    
56.Fenercioglu AK, Saler T, Genc E, Sabuncu H, Altuntas Y. The effects of polyphenol-containing antioxidants on oxidative stress and lipid peroxidation in Type 2 diabetes mellitus without complications. J Endocrinol Invest 2010;33:118-24.  Back to cited text no. 56
    
57.Mirmiran P, Fazeli MR, Asghari G, Shafiee A, Azizi F. Effect of pomegranate seed oil on hyperlipidaemic subjects: A double-blind placebo-controlled clinical trial. Br J Nutr 2010;104:402-6.  Back to cited text no. 57
    
58.Pacheco-Palencia LA, Noratto G, Hingorani L, Talcott ST, Mertens-Talcott SU. Protective effects of standardized pomegranate (Punica granatum L.) polyphenolic extract in ultraviolet-irradiated human skin fibroblasts. J Agric Food Chem 2008;56:8434-41.  Back to cited text no. 58
    
59.Bae JY, Choi JS, Kang SW, Lee YJ, Park J, Kang YH. Dietary compound ellagic acid alleviates skin wrinkle and inflammation induced by UV-B irradiation. Exp Dermatol 2010;19:e182-90.  Back to cited text no. 59
    
60.Yoshimura M, Watanabe Y, Kasai K, Yamakoshi J, Koga T. Inhibitory effect of an ellagic acid-rich pomegranate extract on tyrosinase activity and ultraviolet-induced pigmentation. Biosci Biotechnol Biochem 2005;69:2368-73.  Back to cited text no. 60
    
61.Hayouni EA, Miled K, Boubaker S, Bellasfar Z, Abedrabba M, Iwaski H, et al. Hydroalcoholic extract based-ointment from Punica granatum L. peels with enhanced in vivo healing potential on dermal wounds. Phytomedicine 2011;18:976-84.  Back to cited text no. 61
    
62.DiSilvestro RA, DiSilvestro DJ, DiSilvestro DJ. Pomegranate extract mouth rinsing effects on saliva measures relevant to gingivitis risk. Phytother Res 2009;23:1123-7.  Back to cited text no. 62
    
63.Bhadbhade SJ, Acharya AB, Rodrigues SV, Thakur SL. The antiplaque efficacy of pomegranate mouthrinse. Quintessence Int 2011;42:29-36.  Back to cited text no. 63
    
64.Sastravaha G, Gassmann G, Sangtherapitikul P, Grimm WD. Adjunctive periodontal treatment with Centella asiatica and Punica granatum extracts in supportive periodontal therapy. J Int Acad Periodontol 2005;7:70-9.  Back to cited text no. 64
    
65.Vasconcelos LC, Sampaio MC, Sampaio FC, Higino JS. Use of Punica granatum as an antifungal agent against candidosis associated with denture stomatitis. Mycoses 2003;46:192-6.  Back to cited text no. 65
    
66.Trombold JR, Barnes JN, Critchley L, Coyle EF. Ellagitannin consumption improves strength recovery 2-3 d after eccentric exercise. Med Sci Sports Exerc 2010;42:493-8.  Back to cited text no. 66
    
67.Balbir-Gurman A, Fuhrman B, Braun-Moscovici Y, Markovits D, Aviram M. Consumption of pomegranate decreases serum oxidative stress and reduces disease activity in patients with active rheumatoid arthritis: A pilot study. Isr Med Assoc J 2011;13:474-9.  Back to cited text no. 67
    
68.Alam MS, Alam MA, Ahmad S, Najmi AK, Asif M, Jahangir T. Protective effects of Punica granatum in experimentally-induced gastric ulcers. Toxicol Mech Methods 2010;20:572-8.  Back to cited text no. 68
    
69.Lai S, Zhou Q, Zhang Y, Shang J, Yu T. Effects of pomegranate tannins on experimental gastric damages. Zhongguo Zhong Yao Za Zhi 2009;34:1290-4.  Back to cited text no. 69
    
70.Hajimahmoodi M, Shams-Ardakani M, Saniee P, Siavoshi F, Mehrabani M, Hosseinzadeh H, et al. In vitro antibacterial activity of some Iranian medicinal plant extracts against Helicobacter pylori. Nat Prod Res 2011;25:1059-66.  Back to cited text no. 70
    
71.Xu KZ, Zhu C, Kim MS, Yamahara J, Li Y. Pomegranate flower ameliorates fatty liver in an animal model of type 2 diabetes and obesity. J Ethnopharmacol 2009;123:280-7.  Back to cited text no. 71
    
72.Türk G, Sönmez M, Aydin M, Yüce A, Gür S, Yüksel M, et al. Effects of pomegranate juice consumption on sperm quality, spermatogenic cell density, antioxidant activity and testosterone level in male rats. Clin Nutr 2008;27:289-96.  Back to cited text no. 72
    
73.El-Sherbini GM, Ibrahim KM, El Sherbiny ET, Abdel-Hady NM, Morsy TA. Efficacy of Punica granatum extract on in-vitro and in-vivo control of Trichomonas vaginalis. J Egypt Soc Parasitol 2010;40:229-44.  Back to cited text no. 73
    
74.Singhal AK, Naithani V, Bangar OP. Medicinal plants with a potential to treat Alzheimer and associated symptoms. Int J Nutr Pharmacol Neurol Dis 2012;2:84-91.  Back to cited text no. 74
  Medknow Journal  
75.Cambay Z, Baydas G, Tuzcu M, Bal R. Pomegranate (Punica granatum L.) flower improves learning and memory performances impaired by diabetes mellitus in rats. Acta Physiol Hung 2011;98:409-20.  Back to cited text no. 75
    
76.Al-Muammar MN, Khan F. Obesity: The preventive role of the pomegranate (Punica granatum ). Nutrition 2012;28:595-604.  Back to cited text no. 76
    
77.Ouachrif A, Khalki H, Chaib S, Mountassir M, Aboufatima R, Farouk L, et al. Comparative study of the anti-inflammatory and antinociceptive effects of two varieties of Punica granatum. Pharm Biol 2012;50:429-38.  Back to cited text no. 77
    
78.Pillai NR. Anti-diarrhoeal activity of Punica granatum in experimental animals. Int J Pharmaco 1992;30:201-4.  Back to cited text no. 78
    
79.Forest CP, Padma-Nathan H, Liker HR. Efficacy and safety of pomegranate juice on improvement of erectile dysfunction in male patients with mild to moderate erectile dysfunction: A randomized, placebo-controlled, double-blind crossover study. Int J Impot Res 2007;19:564-7.  Back to cited text no. 79
    
80.Haidari M, Ali M, Casscells SW, Madjid M. Pomegranate (Punica granatum ) purified polyphenol extract inhibits influenza virus and has a synergistic effect with oseltamivir. Phytomed 2009;16:1127-36.  Back to cited text no. 80
    
81.De Siqueira RS, Dodd CE, Rees CE. Evaluation of the natural viricidal activity of teas for use in the phage amplification assay. Int J Food Microbiol 2006;111:259-62.  Back to cited text no. 81
    
82.Neurath AR, Strick N, Li YY, Debnath AK. Punica granatum (pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide. Ann N Y Acad Sci 2005;1056:311-27.  Back to cited text no. 82
    
83.Vidal A, Fallarero A, Peña BR, Medina ME, Gra B, Rivera F, et al. Studies on the toxicity of Punica granatum L. (Punicaceae) whole fruit extracts. J Ethnopharmacol 2003;89:295-300.  Back to cited text no. 83
    
84.Cerda B, Ceron JJ, Tomas-Barberan FA, Espin JC. Repeated oral administration of high doses of the pomegranate ellagitannin punicalagin to rats for 37 days is not toxic. J Agric Food Chem 2003;51:3493-501.  Back to cited text no. 84
    
85.Heber D, Seeram NP, Wyatt H, Henning SM, Zhang Y, Ogden LG, et al. Safety and antioxidant activity of a pomegranate ellagitannin-enriched polyphenol dietary supplement in overweight individuals with increased waist size. J Agric Food Chem 2007;55:10050-4.  Back to cited text no. 85
    
86.Aviram M, Rosenblat M, Gaitini D, Nitecki S, Hoffman A, Dornfeld L, et al. Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure, and LDL oxidation. Clin Nutr 2004;23: 423-33.  Back to cited text no. 86
    
87.Prajapati R, Kalariya M, Umbarkar R, Parmar S, Sheth N. Colocasia esculenta: A potent indigenous plant. Int J Nutr Pharmacol Neurol Dis 2011;1:90-6.  Back to cited text no. 87
  Medknow Journal  
88.Bhat ZA, Kumar D, Shah MY. Angelica archangelica Linn. is an angel on earth for the treatment of diseases. Int J Nutr Pharmacol Neurol Dis 2011;1:36-50.  Back to cited text no. 88
  Medknow Journal  


    Figures

  [Figure 1], [Figure 2], [Figure 3]


This article has been cited by
1 Regain d’intérêt pour la grenade, un fruit majestueux aux multiples propriétés
M. Bidri,P. Choay
Phytothérapie. 2016;
[Pubmed] | [DOI]
2 Inhibitory effect of pomegranate (Punica granatum L.) polyphenol extracts on the bacterial growth and survival of clinical isolates of pathogenic Staphylococcus aureus and Escherichia coli
Caterina Pagliarulo,Valentina De Vito,Gianluca Picariello,Roberta Colicchio,Gabiria Pastore,Paola Salvatore,Maria Grazia Volpe
Food Chemistry. 2016; 190: 824
[Pubmed] | [DOI]
3 Antibacterial Effect of Hydroalcoholic Extract ofPunica granatumLinn. Petal on Common Oral Microorganisms
Farnaz Hajifattahi,Elham Moravej-Salehi,Maryam Taheri,Arash Mahboubi,Mohammad Kamalinejad
International Journal of Biomaterials. 2016; 2016: 1
[Pubmed] | [DOI]
4 Consumers’ changing perceptions of quality: revisiting the science of fruit and vegetable cultivation for improved health benefits
B.S. Patil,R.M. Uckoo,G.K. Jayaprakasha,M.A. Palma
Acta Horticulturae. 2016; (1120): 459
[Pubmed] | [DOI]
5 Bioactive components of pomegranate fruit and their transformation by fermentation processes
Malgorzata Gumienna,Artur Szwengiel,Barbara Górna
European Food Research and Technology. 2015;
[Pubmed] | [DOI]
6 Bioactive properties of commercialised pomegranate (Punica granatum) juice: antioxidant, antiproliferative and enzyme inhibiting activities
Francisco Les,Jose M. Prieto,Jose Miguel Arbonés-Mainar,Marta Sofía Valero,Víctor López
Food Funct.. 2015; 6(6): 2049
[Pubmed] | [DOI]
7 Punica granatum: A review on its potential role in treating periodontal disease
Divyashree Prasad,Ravi Kunnaiah
Journal of Indian Society of Periodontology. 2014; 18(4): 428
[Pubmed] | [DOI]
8 The Therapeutic Potential of Medicinal Foods
Nelvana Ramalingum,M. Fawzi Mahomoodally
Advances in Pharmacological Sciences. 2014; 2014: 1
[Pubmed] | [DOI]
9 Dietary botanicals for chemoprevention of prostate cancer
Prasan Bhandari
Journal of Traditional and Complementary Medicine. 2014; 4(2): 75
[Pubmed] | [DOI]
10 Anti-Ulcerogenic Activity of the Pomegranate Peel (<i>Punica granatum</i>) Methanol Extract
Ghazaleh Moghaddam,Mohammad Sharifzadeh,Gholamreza Hassanzadeh,Mahnaz Khanavi,Mannan Hajimahmoodi
Food and Nutrition Sciences. 2013; 04(10): 43
[Pubmed] | [DOI]
11 Diosgenin prevents hepatic oxidative stress, lipid peroxidation and molecular alterations in chronic renal failure rats
Elumalai Balamurugan,Jeganathan Manivannan,Jeganathan Sivasubramanian,Pandiyan Arunagiri
International Journal of Nutrition, Pharmacology, Neurological Diseases. 2013; 3(3): 289
[Pubmed] | [DOI]
12 Susceptibility of Cronobacter sakazakii to plant products, antibiotics, and to lactic acid bacteria
Alka Prakash,Garima Sharma
International Journal of Nutrition, Pharmacology, Neurological Diseases. 2013; 3(3): 263
[Pubmed] | [DOI]



 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Introduction
    Discussion and C...
    References
    Article Figures

 Article Access Statistics
    Viewed18635    
    Printed268    
    Emailed10    
    PDF Downloaded1441    
    Comments [Add]    
    Cited by others 12    

Recommend this journal