Compendium of the most significant studies with reference to properties, intake, effects.

Di Sotto A, Locatelli M, Macone A, Toniolo C, Cesa S, Carradori S, Eufemi M, Mazzanti G, Di Giacomo S. Hypoglycemic, Antiglycation, and Cytoprotective Properties of a Phenol-Rich Extract From Waste Peel of Punica granatum L. var. Dente di Cavallo DC2. Molecules. 2019 Aug 27;24(17):3103. doi: 10.3390/molecules24173103. 

Abstract. Pomegranate peel is a natural source of phenolics, claimed to possess healing properties, among which are antioxidant and antidiabetic. In the present study, an ethyl acetate extract, obtained by Soxhlet from the peel of Dente di Cavallo DC2 pomegranate (PGE) and characterized to contain 4% w/w of ellagic acid, has been evaluated for its hypoglycemic, antiglycation, and antioxidative cytoprotective properties, in order to provide possible evidence for future nutraceutical applications. The α-amylase and α-glucosidase enzyme inhibition, interference with advanced glycation end-products (AGE) formation, and metal chelating abilities were studied. Moreover, the possible antioxidant cytoprotective properties of PGE under hyperglycemic conditions were assayed. Phenolic profile of the extract was characterized by integrated chromatographic and spectrophotometric methods. PGE resulted able to strongly inhibit the tested enzymes, especially α-glucosidase, and exerted chelating and antiglycation properties. Also, it counteracted the intracellular oxidative stress under hyperglycemic conditions, by reducing the levels of reactive oxygen species and total glutathione. Among the identified phenolics, rutin was the most abundant flavonoid (about 4 % w/w). Present results suggest PGE to be a possible remedy for hyperglycemia management and encourage further studies to exploit its promising properties.

El Deeb KS, Eid HH, Ali ZY, Shams MM, Elfiky AM. Bioassay-guided fractionation and identification of antidiabetic compounds from the rind of Punica Granatum Var. nana. Nat Prod Res. 2021 Jun;35(12):2103-2106. doi: 10.1080/14786419.2019.1655411. 

Abstract. This study aimed to evaluate the antidiabetic potential of the rind of Punica granatum var. nana. Acute oral toxicity test revealed the safety profile of its ethanolic extract. The extract was administered at 200 mg/kg b.wt to streptozotocin-induced diabetic rats. Serum diagnostic markers of diabetes (insulin, glucose and glycated hemoglobin), inflammatory mediators (tumor necrosis factor-α, interleukin-6, and nitric oxide), and oxidative stress (total antioxidant capacity and reduced glutathione and malondialdehyde) were assayed. The ethanolic extract was further fractionated and assessed for the aforementioned bioactivities at two different doses (100 and 200 mg/kg b.wt). The results revealed that the ethyl acetate fraction of rind exhibited the highest activities. Using different chromatographic techniques, four compounds were isolated and identified as rutin, gallic acid, nictoflorin, and tulipanin. In conclusion: The ethyl acetate fraction of the rind of Punica granatum var. nana may provide a potential therapeutic approach for hyperglycemia.

Gharib E, Montasser Kouhsari S. Study of the Antidiabetic Activity of Punica granatum L. Fruits Aqueous Extract on the Alloxan-Diabetic Wistar Rats. Iran J Pharm Res. 2019 Winter;18(1):358-368. 

Abstract. Pancreatic β-cells dysfunction and impairment of insulin action usually leads to hyperglycemia. Punica granatum L. is a well-known traditional herbal remedy in Iran due to its positive effects on ameliorating blood glucose homeostasis. In this study, Alloxan-diabetic male Wistar rats were administrated with pomegranate fruits aqueous extract (PE) in different doses of 100, 200, and 350 mg/kg bw (PE+Da, PE+Db and PE+Dc, respectively), and the effects of PE polyphenols content on glucose metabolism in treated groups were examined using oral glucose tolerance test (OGTT), short-term and long-term PE consumption periods models followed by evaluation of plasma insulin, free fatty acids, and triglycerides levels and tissues contents of glycogen and triglycerides; compared with diabetic control (DC) and healthy control (NC) groups. By using Real-time PCR, the possibility of modulations of the Insulin receptor substrate 1 (IRS-1), Protein kinase B (Akt), Glucose transporter 2 and 4 (Glut-2, 4) mRNAs expression levels in PE treated rats were investigated. The obtained data showed noticeable reduction in fasting blood glucose (FBG) by 28.1% and 67.9% in short-term and long-term treatment models, respectively, in PE + Dc group. Also, there existed marked increase in the mRNAs expression levels of IRS-1, Akt, Glut-2, and Glut-4, which results in improvement of glucose uptake and promotes its storage. Taking together, it is suggested that PE administration contributes to the modulation of both hyperglycemia and hyperlipidemia in Alloxan-diabetic Wistar rats.

Joshi C, Patel P, Kothari V. Anti-infective potential of hydroalcoholic extract of Punica  granatum peel against gram-negative bacterial pathogens. F1000Res. 2019 Jan 18;8:70. doi: 10.12688/f1000research.17430.2. 

Abstract. Background:Punica granatum extracts have been prescribed in traditional medicine for management of a variety of disease conditions including microbial infections. Generation of scientific evidence for validation of P. granatum peel extract's anti-pathogenic efficacy is required. Methods: Hydroalcoholic extract of P. granatum peel (PGPE), prepared by microwave assisted extraction method was evaluated for its quorum-modulatory potential against two different human-pathogenic bacteria viz. Chromobacterium violaceum and Pseudomonas aeruginosa. Results: This extract was able to modulate in vitro production of quorum sensing-regulated pigments in both these test bacteria at ≥5 μg/ml. Virulence traits of P. aeruginosa like haemolytic activity, and biofilm formation were negatively affected by the test extract, and it also made P. aeruginosa more susceptible to lysis by human serum. Antibiotic susceptibility of both test bacteria was modulated owing to pre-treatment with PGPE. Exposure of these test pathogens to PGPE (≥0.5 μg/ml) effectively reduced their virulence towards the nematode Caenorhabditis elegans. Repeated subculturing of P. aeruginosa on PGPE-supplemented growth medium did not induce resistance to PGPE in this notorious pathogen, and this extract was also found to exert a post-extract effect on P. aeruginosa. Individual constituent phytocompounds of PGPE were found to be less efficacious than the whole extract. PGPE seemed to interfere with the signal-response machinery of P. aeruginosa and C. violaceum. PGPE also exhibited notable prebiotic potential by promoting growth of probiotic strains- Bifidobacterium bifidum and Lactobacillus plantarum at ≤50 μg/ml. Conclusions: This study indicates PGPE to be an effective antipathogenic and prebiotic preparation, and validates its therapeutic use mentioned in traditional medicine. This study also emphasizes the need for testing any bioactive extract at broadest possible concentration range, particularly in vivo, so that an accurate picture of dose-response relationship can emerge.

Lavaee F, Motaghi D, Jassbi AR, Jafarian H, Ghasemi F, Badiee P. Antifungal effect of the bark and root extracts of Punica granatum on oral Candida isolates. Curr Med Mycol. 2018 Dec;4(4):20-24. doi: 10.18502/cmm.4.4.382.

Abstract. Background and purpose: Oral candidiasis is one of the most common fungal infections in humans. The treatment and prophylaxis of the patients suffering from this infection require the identification of new anti-Candida agents with no side effects or toxicity like medicinal plants. The present study was conducted to compare the antifungal activities of the aqueous, ethanolic, and methanolic extracts of the bark and roots of P. granatum with those of two routine antifungal agents (i.e., fluconazole and nystatin) on oral Candida strains isolated from liver transplant recipients....Conclusion: As the findings indicated, the methanolic and ethanolic extracts of the bark and root of Punica granatum had anti-Candida activities. Therefore, they can be considered as mouthwash or toothpaste to prevent and treat Candida infections in the oral cavity.

Rios-Corripio G, Guerrero-Beltrán JÁ. Antioxidant and physicochemical characteristics of unfermented and fermented pomegranate (Punica granatum L.) beverages. J Food Sci Technol. 2019 Jan;56(1):132-139. doi: 10.1007/s13197-018-3466-6. 

Abstract. The aim of this study was to evaluate the physicochemical, antioxidant (antioxidant activity, total phenolic compounds, flavonoids, anthocyanins), and sensory characteristics of fresh (FRJ) and fermented (FEB) pomegranate beverages. Three fermentation conditions were tested based on the total soluble solids (TSS: °Bx) content in pomegranate juice: (a) natural TSS (13.9 °Bx) in fresh juice (FEB1), (b) adjusted to 17.5 °Bx (FEB2) and (c) adjusted to 25 °Bx (FEB3). The antioxidant activity, total phenolic compounds, flavonoids and anthocyanins after fermentation in FEB3 were 262.61 ± 0.12 mg Trolox, 188.60 ± 0.20 mg Gallic acid, 64.35 ± 0.09 mg quercetin and 1.92 ± 0.15 cyanidin-3-O-glucoside (C3OG)/100 mL, respectively. The final amounts of ethanol in FEB1, FEB2, and FEB3 were 6.82 ± 0.01, 9.73 ± 0.01, and 12.88 ± 0.01% (v/v), similar to that in wines. In general, the sensory characteristics of both FRJ and FEB beverages were well sensory accepted by consumers.

Tang D, Liu L, Ajiakber D, Ye J, Xu J, Xin X, Aisa HA. Anti-diabetic Effect of Punica granatum Flower Polyphenols Extract in Type 2 Diabetic Rats: Activation of Akt/GSK-3β and Inhibition of IRE1α-XBP1 Pathways. Front Endocrinol (Lausanne). 2018 Oct 15;9:586. doi: 10.3389/fendo.2018.00586.

Abstract. Type 2 diabetes mellitus (T2DM) is the most common type of diabetes with more than hundreds of millions of patients worldwide. However, the medicines for treatment of T2DM are very limited. In China, Punica granatum L. flower (PGF) has been used as an anti-diabetic herb in the herbal medicine. The activity involves in improvement of insulin sensitivity. However, the underlying mechanism of action is elusive. The current study was designed to address this issue by investigating the effect of polyphenols extract of PGF in diabetic rats. A rat model was orally administrated with PGF polyphenols extract at doses of 50 and 100 mg/kg for 4 weeks. Insulin sensitivity was improved as indicated by oral glucose tolerance test (OGTT), insulin tolerance test (ITT) and homeostasis model assessment of insulin resistance (HOMA-IR). At the molecular level, insulin signaling activity was improved with an elevation in insulin-stimulated phosphorylation of insulin receptor substrate (IRS-1), Akt and GSK-3β. Endoplasmic reticulum (ER) stress signals including phosphorylation of inositol-requiring kinase1 (IRE1) and activation of X box binding protein (XBP-1) splicing were decreased by the PGF treatment. Expressions of IRE1α, XBPs, and CHOP were all decreased by PGF. Blood lipid profile, liver glycogen content and antioxidant status were improved by PGF in the rats. The observations suggest that PGF is able to lower glucose levels in T2DM rats by improving the insulin resistance. The mechanism is likely related to the activation of Akt-GSK3β signaling pathway and inhibition of ER stress.

Devanesan S, AlSalhi MS, Balaji RV, Ranjitsingh AJA, Ahamed A, Alfuraydi AA, AlQahtani FY, Aleanizy FS, Othman AH. Antimicrobial and Cytotoxicity Effects of Synthesized Silver Nanoparticles from Punica granatum Peel Extract. Nanoscale Res Lett. 2018 Oct 4;13(1):315. doi: 10.1186/s11671-018-2731-y. 

Abstract. To address the growing challenges from drug-resistant microbes and tumor incidence, approaches are being undertaken to phytosynthesize metal nanoparticles, particularly silver nanoparticles, to get remedial measure. In this study, an attempt has been made to utilize a major biowaste product, pomegranate fruit peel (Punica granatum), to synthesize silver nanoparticles. The silver nanoparticles (AgNPs) were synthesized using the aqueous extract of pomegranate peel. The formation of synthesized AgNPs was confirmed through UV-Vis spectroscopy, X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDX) as well as through the change of the colorless aqueous solution to a dark brown solution. Using UV-Vis spectroscopy, the dark brown solution showed a Plasmon resonance band peak at 378 nm in UV-Vis spectroscopy after reacting for 24, 48, and 72 h. The XRD report revealed that the AgNPs had a cubic structure. The TEM and SEM report showed the nanoparticles were equally distributed in the solution, with a spherical shape and size ranging from 20 to 40 nm and with an average particle size of 26.95 nm. EDX imaging also confirmed the presence of AgNPs. The synthesized AgNPs were found to exhibit good antimicrobial effects on Gram-negative and Gram-positive bacteria, particularly the pathogens Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27584), Proteus vulgaris (ATCC 8427), Salmonella typhi (ATCC 14028), Staphylococcus aureus (ATCC 29213), Staphylococcus epidermidis (MTCC 3615), and Klebsiella pneumonia. The cytotoxic effects of AgNPs were also tested against a colon cancer cell line (RKO: ATCC® CRL-2577™), and it was observed that the viabilities were 56% and 61% on days 3 and 5, respectively, with exposure to 12.5 μg of AgNPs. This simple, economic, and eco-friendly method suggests that the AgNPs biosynthesized using pomegranate peel extract may be a novel, potent solution for the development of a drug for colon cancer that also has antibacterial activity.