Pomegranate, fruit of the desert, a functional food, and a healthy diet

Traditional medicinal plants contain various ranges of chemical contents and they have become popular because of effectiveness, frequently inadequate provision of modern medicine, preferences and cultural beliefs. Pomegranate belongs to the family of Punicaceae, and its various pharmacological activities are due to presence of wide range of bioactive compounds. The current searching was done by the keywords in main indexing systems including PubMed/MEDLINE, Scopus, and Institute for Scientific Web of Science as well as the search engine of Google Scholar. The keywords were traditional medicine, health benefits, pharmaceutical science, pomegranate, punicalin, punicalagin, and ellagitannins. Major polyphenols in peel and juice of pomegranate are flavonoids such as flavonols (catechin, epicatechin, gallocatechin), condensed tannins, phenolic acids such as gallic, ellagic and caffeic, hyrolysable tannins such as ellagitannins and gallotannins. The main organic acids in pomegranate juice are malic and citric, and in seed is fatty acids (punicic). The major alkaloids and lignans in peel are punigratane and isolariciresinol, respectively. Pomegranate fruit has been proven to act against various diseases like cancer, cardiovascular disorders, diabetes, AIDS, Alzheimer’s disease, male infertility, inflammation, coronary heart disease, and aging. The review summarizes the beneficial impacts of pomegranate which is recommended for consumption. Pomegranate is a high potential natural functional food due to its high pharmacological activities as an ancient efficacious natural drug.


Introduction Introduction Introduction Introduction
Pomegranate occurrence and classification Population rise, inadequate supply of drugs, prohibitive cost of treatments, side effects of several synthetic drugs and development of resistance to currently used drugs for infectious diseases have led to increased emphasis on the use of plant materials as a source of medicines (Shahrajabian et al., 2021;Sun et al., 2021a,b,c). Herbal medicines proved to be the major remedy in traditional system of medicine (Shahrajabian et al., 2020a,b,c,d,e). Pomegranate (Punica granatum L.) which is a perennial fruit tree from the Punicaceae native in Iran, has been considered a functional fruit in many countries especially Iran, India, Turkey and China (Sharma et al., 2011;Soloklui et al., 2012). Its name come from the Latin name of the fruit Malum granatum, which means granular apple; and the most important producers are Iran, India, Turkey, China, the USA and  Proximate composition of pomegranate seeds is percentage moisture (8.6%), total lipids (27.2%), crude protein (13.2%), crude fiber (35.3%), pectin (6%), total sugars (4.2%), and ash (2%); trace minerals present in pomegranate seeds are iron (1.3 ppm), sodium (6 ppm), magnesium (12.4 ppm), potassium (45.2 ppm), zinc (1 ppm), and copper (1.2 ppm) (Khan et al., 2017). Nutritional values of pomegranate seeds are shown in Table   3. Fatty acids found in pomegranate seeds are presented in Table 4. The name, peel color, aril color, taste and origin of 31 pomegranate cultivars in Iran are mentioned in Table 5. Table 3. Table 3. Table 3. Table 3. Nutritional values of pomegranate seeds (Khan et al., 2017) Table 5. Table 5. Table 5. Several bioactive compounds were extracted by the pomegranate peels which can be employed for the preparation of nutraceuticals (Turrini et al., 2019). Around 153 different phytochemicals have been found in pomegranate which have ability to fight against various diseases (Karimi et al., 2017). Its fruit peel contains phenolic compounds including ellagic acid, ellagitannins, lignins, catechin, rutin, punicalagin and epicatechin (Fischer et al., 2011;Glazer et al., 2012;Rosas-Burgos et al., 2017), and the peel consists of cellulose, ligning, pectin and proteins (Hasnaoui et al., 2014;Abid et al., 2017). Rowayshed et al. (2013) also reported catechins, phenol gallic acid, caffeic acid, ellagic acid, p-coumaric acid and resocenol compounds in pomegranate peels powder. Peels and membranes of pomegranate fruits can be recommended as a source of highly and lowly methyl-esterified pectic polysaccharides (Shakhmatov et al., 2019). The most abundant compounds in pomegranate in Mexico were hexanol, (Z)-3-hexen-1-ol, hexanal, 4-terpineol, α-terpineol, and 2-ethyl-1hexanol, and in the peel, high concentration of color, phenols, flavonoids, and antioxidants were observed (Escarcega et al., 2020). Pomegranate exerts antiproliferative, anti-invasive and antimetastatic effects, induces apoptosis through modulation of Bcl-2 proteins, increases p21 and p27, and downregulates cyclin-cdk network (Faria and Calhau, 2011). Pomegranate seed oil is a rich source of rare conjugated fatty acids (punicic acid) (Paul et al., 2020). Ellagic acid (EA) is one of the most important biological molecules found in pomegranate which may induce vasorelaxation, oxygen free radical scavenging, hypolipidemic, anti-inflammatory and anticarcinogenic activities (Usta et al., 2013). Pomegranates have the potential to cause toxicity to ruminants, because large amounts of toxic gallic acid can potentially be produced through rumen fermentation of punicalagin (Read et al., 2019). Concentrated pomegranate peel extract supplementation increases milk antioxidant capacity which have higher benefits in individuals with lower natural productivity capacity (Argov-Argaman et al., 2020). Pomegranate juice powder can replace some or all sucrose in fermentation matrix for the production of functional yogurt (Pan et al., 2019). There are 11 volatile organic compounds namely 1hexanol, [Z]-3-hexen-1-ol, 1-octanol, α-terpineol, β-myrcene, limonene, [E]-α-bergamotene, β-caryophyllene, hexanal, [E]-2-hexenel, and guaiacol are common to pomegranate juices and seeds; hexalin, phenylacetaldehyde, 3-methyl butanal, and methyl-(1-methylethenyl) benzene are found just in seeds (Guler and Gul, 2017). Pomegranate juices has similar or higher sweetness than apple, orange and sour cherry juice (Topalovic et al., 2020). The fruit quality of pomegranate is a balance between taste attributes and nutraceutical compounds (Tozzi et al., 2020). It contains significant amounts of phenolic ingredients, and the antioxidant and anti-inflammatory impacts of pomegranate poly phenols have been confirmed previously (Yan et al., 2017;Pontonio et al., 2019;Morvaridzadeh et al., 2020). Pomegranate peel polysaccharides (PPP) is a good source for dietary supplement application, which has good antioxidant activity in vivo (Wu et al., 2019). A positive correlation between antioxidant activity and total phenolic content was reported (Derakhshanet al., 2018).
The reason of the bright color of pomegranate flowers is a type of the flavonoids, which is anthocyanins (Zhang et al., 2011;Ben-Simhon et al., 2015). The pomegranate peel polysaccharides are composed of rhamnose, glucuronic acid, galacturonic acid, glucose and xylose in the molar percentage of 0.71%, 27.07%, 22.05%, 22.12%, and 28.05%, respectively (Wu et al., 2019). Habibnia et al. (2012) found that the predominant fatty acids in Iranian pomegranate was punicic acid, and beta-sitosterol and γ-tochopherol were the main sterol and tochopherol present in the extracted oil, respectively. The pomegranate peel, seed and whole fruit powder consists of moisture content, ash, protein, crude fiber, fat and minerals such as sodium, calcium, magnesium, potassium, phosphorus and iron (Sharma et al., 2018). Pomegranate seed oil (PSO) nanoemulsion is widely used as a promising delivery system for α-tocopherol (Sahafi et al., 2021). Pomegranate ellagitannins may inhibit α-flucosidase activity in vitro possibly affecting in vivo starch digestion (Bellesia et al., 2015). Its juice could be beneficial as a dietary supplement in patients receiving chemotherapy medications (Bakir et al., 2015).
The dietary supplementation with 200 and 300 mg/kg pomegranate peel extract (PPE) may increase the antioxidant potential and quality indices of broilers breast meat, and the antioxidant potential of PPE was equal to that of α-Toc in refrigerated meat (Saleh et al., 2017). The potentiated virucidal activity of pomegranate rind extract (PRE) by co-administered zinc (II) has potential as a multi-action novel topical therapeutics against pressure and density lipoprotein oxidation (Turk et al., 2008). Rashidi et al. (2013) reported that concentrated pomegranate juice consumption was not effective on blood glucose and lipid profiles concentrations in type 2 diabetic patients. Pomegranate seed oil demonstrated and important therapeutic effect in the treatment of ovarian ischemia and reperfusion injury (Yayla et al., 2018). Pomegranate juice can be recommended as a suitable transport medium for avulsed teeth, and 1% of its juice was as effective as Hank's balanced salt (HBS) for maintaining PDL cell viability (Tavassoli-Hojjati et al., 2014). Pomegranate seed extract exhibited therapeutic potential for avoidance memories, because it is a potent phytoestrogenic and antioxidant which may have compensating effects for peripheral estrogen deficit (Sarkaki et al., 2015). Black pomegranate peel extract could effectively suppress angiogenesis potentially through a vascular endothelial growth factor (VEGF) dependent mechanism (Dana et al., 2015). Natural pomegranate juice is also a potent inflammatory, and anti-thrombocytopenia treatment among elderly population (Achraf et al., 2018). Saleh et al. (2018) reported that the antioxidant potential of pomegranate pomace extract supplementation was equal to that of α-tocopherol acetate in refrigerated meat. Martinez et al. (2019) concluded that natural extracts from pomegranate, rosemary, and hydroxytyrosol delayed the lipid oxidation, and addition of it to fish products contributed to extend the shelf life to fish. The whole fruit extract of pomegranate has cardioprotective effect against Dox-induced cardiotoxicity in rats (HassanpourFardet al., 2011). Pomegranate peel extract was found to have strong anti-inflamatory activity by the reduction in the levels of Interlukin-6 (IL-6) and tumor Necrosis Factor-α (TNF-alfa), and rich in phenolic and flavonoids which may enhance its reducing activity and free radical scavenging ability (Qabaha et al., 2019).
Pomegranate juice has the potential as a nutraceutical to improve health span and lifespan in human ). The fruits of some pomegranate genotypes could be used to obtain extracts very rich in punicalagins and that these substances could be used as an alternative to synthetic products to control plant disease and improve the quality of the plant products, avoiding the impact of synthetic chemicals on the environment (Rongai et al., 2019). The pomegranate peel extract showed anti-herpes simplex virus-1 (HSV) activity, probably by inhibiting the adsorption stage with SI value of 7.7 (Moradi et al., 2015). Pomegranate peel pectin can act as an effective emulsifier, and can be used as a novel polysaccharide emulsifier in the food industry (Yang et al., 2018).
The antimetastatic effect of pomegranate may be attributed to molecular changes of the extracellular matrix (Ahmadiankia, 2019). The most notable pharmaceutical benefits of pomegranate have been shown in Table 7. The higher doses of three fractions (250 and 500 mg/kg for pomegranate freeze-dried power and pomegranate seeds extract and doses of 100, 200 μL/kg for pomegranate seed oil fraction) significantly reduced amylase and lipase activity in serum, pancreatic pancreatic myeloperoxidase activity, edema, leukocyte infiltration and vacuolization in comparison to the control group.

Minaiyan et al. (2014)
Alzheimer Pomegranate extract is more efficacious as a protectant than a therapeutic measure in reducing histopathological hallmarks in Alzheimer's disease.
Almuhayawi et al. (2020) Anti-depressant effects The aqueous extract of pomegranate (AE-PG) administered by intraperitoneal route induced anti-depressant like effects, and the mechanism of action involved the activation of the Estrogen receptor β (ERβ) and the Valdes-Sustaita et al. (2021) serotonergic system.
Anti-diabetes effects a. Pomegranate seed oil (PSO) has a protective effect against diabetes complications in rats, and also significantly reversed streptozotocin (STZ)-induced depletion in thiol content and histological abnormality. Mollazadeh et al. (2016) b. No significant impacts of pomegranate supplementation on metabolic parameters in patients with type 2 diabetes mellitus (T2DM) was found.
Jandari et al. (2020) c. Pomegranate juice consumption as an antioxidant may have a contribution in changing fasting blood sugar, lipid profiles, lipoprotein oxidation and human serum paraoxonase (PON1) activity. Parsaeyan et al. (2012) d. Consumption of 2000 mg pomegranate seed oil (PSO) per day for 8 weeks had no impact on fasting blood sugar (FBS), insulin resistance and lipid profile in diabetic patients.
Faghihimani et al. (2016) Anti-diarrheal activity a. Its extract showed a concentrationdependent inhibition of the spontaneous movement of the isolated rat ileum and attenuated acetylcholine-induced contractions. Qnais et al. (2007) b. Its extract also caused a dose-dependent decrease of gastrointestinal transit and significantly protected rats against castor oiinduced diarrhea enteropooling.

Qnais et al. (20070
Anti-cancer activity a. Pomegranate extracts inhibit the growth of breast, prostate, colon and lung cancer cells in culture. Polyphenols from pomegranate has been used for prevention of prostate cancer. Adhami and Mukhtar (2006) Adhami et al. (2009) Nallanthighal et al. (2016) Boggula and Peddapalli (2017) b. The extracts derived from pomegranates had significant concentration-dependent antiproliferative and pro-apoptotic effects against MCF-7 (ER+) and MD-MBA-231 or MD-MBA-435 (ER-) breast cancer cell lines. Mehta and Lansky (2004) c. Pomegranate extract suppresses the melanocyte and melanin synthesis through inhibiting tyrosinase activity which is important in treatment of skin cancer. Yoshimura et al. (2005) d. The photo chemo preventive effects of pomegranate against UVA and UVB irradiations in normal human epidermal keratinocytes (NHEK) as a test system has been proved. Syed et al. (2006) e. Pomegranate fruit extracts (PFE) dosedependently inhibited NF-κB-dependent reporter gene expression associated with proliferation invasion, and motility in aggressive breast cancer phenotypes while decreasing RhoC and RhoA protein expression. Khan et al. (2009) f. Pomegranate juice gains lots of attractions due to its remedial and preventative roles against prostate cancer because of its ability in inhibiting cell growth and inducing apoptosis. Koyama et al. (2010) g. Pomegranate extract decreased the expressions of genes of the enzyme involved in the synthesizing androgen and at the same time downregulate the hypoxia-inducible factor 1-α (HIF-1α) to constrain angiogenesis in prostate cancer. Sartippour et al. (2008) h. The inhibitory effects of pomegranate juice on progression of prostate cancer as well as its role on increasing adhesion and decreasing migration of the live cells has been confirmed. Wang et al. (2012) i. Pomegranate extract suppresses cancer stem cells characteristics in part due to inhibition of epithelial-to-mesenchymal which can be exploited in the prevention of breast cancer. Nallanthighal et al. (2017) j. Ellagic acid induced a greater effect than luteolin, suggesting that ellagic acid might be a promising candidate for further preclinical testing for treatment of human ovarian cancer. Liu et al. (2017) k. Black peel pomegranate is a worthy bioagent in silver nanoparticle biosynthesis and treatment of cancer.
Khorrami et al. (2019) l. The MTT assay showed 94.53% inhibition on the oral cancer cell lines and clonogenic assay showed decrease in the colonies after treating with the peel extract.
Jesse Joel et al. (2019) m. Pomegranate juice possesses a promising inhibitory effect on bladder cancer (BC) development, probably due to its anti-oxidant and anti-inflammatory properties. It can correct the expression of pro-inflammatory cytokines (interleukin 6 and hypoxia-inducible factor 1), it also press angiogenesis by downregulation of hypoxia-inducible factor and supports apoptosis through reduction of the tumor suppressor gene p53. Mortada et al. (2020) n. Dwarf pomegranate extracts showed potent growth inhibitory activities in human prostate cancer cells (DU145), which appear to be mediated by a pro-apoptotic mechanism.
Amri et al. (2020) o. Nano-pomegranates have great potential in anti-breast cancer treatment, because MCF-7 cells have shown remarkable efficiencies of enhancing cellular uptake, inhibition and necrosis and apoptosis at in vivo rat experiments.  p. The pomegranate fruit fleshy pericarp acts as a natural agent to synthesize silver nanoparticles (AgNPs) which can be considered as an anticancer agent.
Govindappa et al. (2021) q. Pomegranate extract and tangeretin may be effective in preventing breast cancer development.
Gul et al. (2021) Anti-inflammatory and analgesic effect a. The methanol extract Amrouz (MoEA) and methanol extract Sefri (MoES) have both analgesic and anti-inflammatory properties. Ouachrif et al. (2012) b. Pomegranate juice may have an antiinflammatory effect in patients with type 2 diabetes (T2D), because it may reduce interlukin-6 and hs-CRP concentrations in plasma. Sohrab et al. (2014) c. The phosphorylation of ERK1/2, p38, JNK and translocation of the NF-B p65 subunit into nuclei were inhibited by the pomegranate flower ethanol (PFE) treatment, and PFE produced potential anti-inflammatory effect. reduced hs-CRP, IL-6, and TNF-α. Anti-inflammatory effects of pomegranate poly phenols have been confirmed. e. Pomegranate (200 mg/kg) attenuate pain and inflammation by down-regulating the activation of TNF-R1, TNF-α, lL-1β, lL-6, NF-κB, oxidative stress markers and tissue histology. Karwasra et al. (2019) f. Oral pretreatment with its dried extract produced statistically significant and dose dependent inhibition of edema induced when compared to the control groups.
Bagri et al. (2010) g. Standardized pomegranate rind extract and the equivalent ellagic acid (EA) dosedependently reduced the croton oil-induced mouse ear edema. e. Pomegranate peel because of its high antioxidant activity can be added to yoghurt for the development of freeze-dried yoghurt with functional ingredients on an industrial scale.

Kennas et al. (2020)
Anti-microbial activity a. Fresh pomegranate juice has antimicrobial activity, which might be attributed to its high polyphenol content and antioxidant capacity. c. According to X-ray diffraction, pomegranate peel retained its semi-crystalline structure in the film, which can shown its importance as an edible film and food grade packaging material.

Ali et al. (2019)
Anti-bacterial activity a. The hydro-alcoholic extract (HAE) from pomegranate presents antibacterial activity against selected microorganisms, and maybe a possible alternative for the treatment of dental plaque bacteria. Pomegranate peel extracts enhances immunity Anti-obesity effects a. A significant decrease in feed consumption and body weight of female rats after exposure them to a diet containing 20% of pomegranate extract (6%) for 37 days.
Cerda et al. (2003) b. The pomegranate lead extract in a mouse model of high-fat diet-induced obesity, and the effects appear to be partly mediated by inhibiting pancreatic lipase activity and suppressing energy intake. Lei et al. (2007) Anti-viral effects The crude pomegranate peel extract and its nbutanol and ethyl acetate fractions had the highest inhibitory effect against influenza A virus with IC50 value of 6.45, 6.07 and 5.6 μg/ml in Madin-Darby Canine Kidney (MDCK) cells, respectively.

Moradi et al. (2019)
Anti-ulcer effects The pomegranate peel extract, especially sour summer has curative potential as an antiulcer, possibly via its high antioxidant activity. Moghaddam et al. (2013) Oral health management a. Pomegranate juice is efficacious against dental plaque microorganisms. Kote et al. (2011) b. Hydroalcoholic extract was effectual against dental plaque microorganisms. Menezes et al. (2006) Sexual behavior a. Administration of the pomegranate extract orally at the dose of 1500 mg/kg produced significant augment of sexual activity in male rats. Lydia et al. (2019) b. Pomegranate juice consumption led to an increase in epididymal sperm concentration, Turk et al. (2008) sperm motility, spermatogenic cell density, and the diameter of seminiferous tubules and germinal cell layer thickness; it also decreased the abnormal sperm rate when compared to the control group. c. Ellagic acid has a protective effect against testicular and spermatozoa toxicity induced by cyclosporine A. has the higher amounts of tannins and flavonoids, compounds that are known to be beneficial for wound healing.
Ghaleh Mohammadi and Mirghazanfari (2019) c. 10% standardized pomegranate extract accelerates the healing of deep second-degree burn wound, and pomegranate standardized with 40% ellagic acid is a promising for the healing of burn wound skin. Lukiswanto et al. (2019) The most important biological effects of methanol extract of pomegranate fruits are antiestrogenic in breast, no induction of proliferation in endometrial, ovarian, and cervical cancer cells, suppressed TNFαmediated endothelial cell apoptosis, estrogen inducible gene expression was not altered, reduced LDL cholesterol levels cardioprotective effect, no DNA adduct formation or oxidative DNA damage and has osteoprotective effects (Sreekumar et al., 2014). Fruit peel administration showed a noteworthy amelioration of abnormalities related Cd-nephrotoxicity (El-Habibi, 2013), and flower extract has protective role and ameliorate nephrotoxicity induced by gentamicin (El-Daly, 2016). The methanolic extract of peels was a potent inhibitor for Listeria monocytogenes, S. aureus, Escherichia coli, and Yersinia enterocolitica (Al-Zoreky, 2009;Devatkal et al., 2013). Extracts from fruit skin showed good antibacterial activity against S. aureus and P. aeruginosa (Sadeghian et al., 2011); and tannin from the pericarp is a very effective constituent against genital herpes virus (HSV-2) (Zhang et al., 1995). Acidity of pomegranate juice and concentrated liquid extract (POMxl) solutions contributed to rapid anti-influenza activity (Sundararajan et al., 2010), and treated mice with pomegranate peel significantly showed reduction in parasitemia as compared to untreated control (Mubaraki et al., 2016). Water extracts from arils has shown antibacterial effects against Bacillus megaterium, P. aeruginosa, S. aureus, Corynebacterium xerosis, E. coli, Enterococcus faecalis and Micrococcusluteus (Duman et al., 2009), and the aqueous and methanol extracts from whole fruit showed antibacterial effects on S. typh, Salmonella typhimurium, and Salmonella paratyphi (Pasha et al., 2009). Nascimento et al. (2000) showed antibacterial effects of ethanol extracts of the whole fruit on P. aeruginosa, and B. subtilis; and Salgado et al. (2009)

Conclusions Conclusions Conclusions Conclusions
Pomegranate is native to Persia and Mediterranean zone which has been widely used in many countries and cultures, especially in west and center of Asia. Nutrient content of pomegranate peel is total solid, moisture, total sugars, reducing sugars, protein, crude fiber, fat content and ash. Fatty acids found in pomegranate seeds are caproic acid, punicic acid, capric acid, lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, linoleic acid and oleic acid. Chemical compounds in pomegranate peels are gallic acid, ellagic acid, punicalin, punicalagin, caffeic acid, ellagitannins, pelletierine, alkaloids, luteolin, kaempferol and quercetin. Chemical constituents in pomegranate seeds are 3,3 , -Di-O-methylellagic acid, 3,3 , ,4 , -Tri-Omethylellagic acid, punicic acid, pleic acid, palmitic acid, stearic acid, linoleic acid, sterols, tocopherols and sex steroids. Chemical compounds in pomegranate juice are simple sugars, aliphatic organic acids, gallic acid, ellagic acid, quinic acid, flavonols, amino acids, minerals, EGCG, and ascorbic acid. Pomegranate leave contains carbohydrates, reducing sugars, sterols, saponins, flavanoids, tannins, piperidine alkaloids, flavone, glycoside, and ellagitannins. The main chemical compounds in root and bark are ellagitannins, piperidine alkaloids, pyrrolidine alkaloid, and pelletierine alkaloids. Flower chemical constituents are gallic acids, ursolic acid, triterpenoids, and fatty acids. The most important potential benefits of pomegranate are antioxidant, cancer prevention, Alzheimer , s disease protection, reduce inflammation in the gut and improve digestion, a powerful anti-inflammatory fruit, positive contributes to osteoarthritis and cartilage damage, heart-healthy juice, may lower systolic blood pressure, antiviral effects, improve learning and memory, a good source for potential fertility aid, a traditional remedy for diabetes, rich in different vitamins such as vitamin C, E, K., and a good source of folate and potassium.

Authors' Contributions Authors' Contributions Authors' Contributions Authors' Contributions
All authors contributed equally to literature research, writing manuscript, etc. All authors read and approved the final manuscript. AdhamiVM, Khan N, Mukhtar H (2009