Table 4.

Therapeutic potential of Punica granatum on skin and wound

Model	Activity	Plant part/compd.	Study design	Mechanism	Ref.
Bacterial	Antimicrobial and antivirulence activities against Pseudomonas aeruginosa	PPE (Aqueous extract)	P. aeruginosa collected from burn wound cultures	↓Bacterial gelatinase activity by 40.28±2.35%; ↓Lecithinase activity by 53.84±4.89%; MIC= 1.4 mg/ml	(118)
Cellular	Protection against skin photoaging induced by UVB irradiation	Rind, seed, and fruit (methanol extracts)	Normal human dermal fibroblasts; Irradiated with UVB (170 mJ/cm2) for 1 min.	↑Procollagen type I and MMP-1 expression (especially by rind extract); ↑Collagen synthesis	(119)
Cellular	Inhibition of melanin content	Fruit (ethanol extract)	Melan-a melanocyte cells; Melanin inhibition assay; Fruit extract standardized to 20% punicalagin; at concentrations of 50 µg/ml and 100 µg/ml	↓Melanin content by 40% (50 µg/ml) and 60% (100 µg/ml)	(120)
Cellular	Anti-tyrosinase activity	Rind (methanol extract)	Murine melanoma B16 F0 cells; Positive control=Kojic acid (1%); Extract concentrations (200–500 mg/ml)	Tyrosinase inhibition at 500 μg/ml= 82.3±5%	(121)
Cellular	Inhibition of melanin production	Fruit (ethanol extract)	Testing Salvia hispanica (chia) seed extract and P. granatum fruit extract (20% punicalagin), in combination or alone; Melanin inhibition assay: Melan-a cells, positive control=phenylthiourea 60 μg/ml; Tyrosinase enzyme assay: enzyme extracted from B16 melanoma cells, positive control=kojic acid; Melanogenesis-related gene expression (RT-PCR) analysis: Melan-a cells, positive control=ascorbic acid-2-glucoside	↓Melanin content (1:1 ratio of the combination of extracts showed maximum efficacy); Not effectively inhibiting tyrosinase activity; ↓Tyrosine, Tyrp1 and Mc1r expression	(122)
Cellular	Protection against oxidative stress	Pomegranate extract	Human keratinocyte HaCaT cells treated with extract for 24 hr; Methylglyoxal-induced cytotoxicity,	↓Methylglyoxal-DNA adducts, reactive oxygen species; ↑Cell adhesion, migration, and wound healing capacity	(123)
Animal	Chemopreventive agent against skin cancer	Seed oil	Female CD1 mice; Skin cancer initiated with topical exposure of 7,12-dimethylbenzanthracene and with biweekly promotion using 12-O-tetradecanoylphorbol-13-acetate (TPA); Pretreated with 5% pomegranate seed oil	↓Tumor incidence (P=0.05) and multiplicity; ↓TPA-induced ornithine decarboxylase (ODC) activity (17% reduction)	(124)
Animal	Cutaneous wound healing	Pomegranate peel polyphenols (PPP) gel	Adult alloxan-induced diabetic Wistar rats; Polyphenol mass fraction in PPP gel=30%;	↓Wound closure; ↑Fibroblast infiltration, collagen regeneration, vascularization, and epithelialization in the wound area; ↑Hydroxyproline, NO production, and NO synthase activities; ↑Transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) expressions	(119)
Animal	Wound healing activity	PPE (methanol extract)	Wistar rats; Water-soluble gel of extract; Negative control=no gel, positive control=blank gel, commercial preparation=silver sulfadiazine; Treatment with 2.5% and 5.0% gel	↑Wound healing by 55.8% at 2.5% and 59.5% at 5.0% (on day 15); ↑Hydroxyproline content up to 34.5% (2.5%), and 48.5% (5.0%) compared with the negative control; ↑Hydroxyproline 24.1% (2.5%) and 38.0% (5.0%) compared with the positive control	(125)
Animal	Wound healing activity	Male abortive flowers (ethanol extract)	Male Wistar rats; reference standard (nitrofurazone ointment); topical treatment (extract ointment 200 mg/kg/day); Control (simple ointment); 16 days	↓Wound size, inflammation cells, collagen fibers, and re-epithelization	(126)
Animal	Anti-inflammatory activity on the skin	Rind (aqueous extract); Total pomegranate tannins (TPT)	Porcine skin mounted in Franz diffusion cells; Test solutions (1 ml): pomegranate rind extract (PRE) (consisted of 20% w/w punicalagin), PRE + ZnSO4, ZnSO4, TPT, tannin-free fraction (TFF) and control=phthalate buffer pH 4.5; Analysis of COX-2 by SDS PAGE and western blotting and Immunohistochemical (IHC)	TPT and PRE and PRE + ZnSO4: ↓COX-2 expression (after 6 hr and up to 24 hr); No anti-inflammatory activity by ZnSO4 and TFF and control	(127)
Animal	Antiaging effect on UVB-induced skin	Pomegranate juice concentrated powder (PCP)	Female SKH‑1 hairless mice; 6 groups: Intact vehicle control‑unexposed; UVB control‑UVB exposed (mice received vehicle control and UVB exposure); PCS 2 ml/kg ‑UVB exposed; PCP 100 mg/kg‑UVB exposed; PCP 200 mg/kg‑UVB exposed; and PCP 400 mg/kg‑UVB exposed; UVB irradiation three times a week for 15 weeks at 0.18 J/cm2; PCS (contained 2.31 mg/g ellagic acid)	Anti-apoptotic effects; Skin matrix metalloproteinase activity inhibition; ↓Wrinkles induced by photoaging; ↑Skin water contents, collagen type I, and hyaluronan contents; ↓IL‑1β; Inhibition of glutathione depletion	(128)
Animal	Wound healing activity	Whole fruit extract standardized with 40% ellagic acid	Male albino rats (Rattus norvegicus); Treatment of incised wounds with topical ointment of pomegranate extract at 2.5, 5, and 7.5% concentrations or Betadine® ointment, twice a day for 7 and 14 days	↑Wound healing in the application of 7.5% pomegranate extract ointment for 14 days; ↑Collagen deposition; ↓Polymorphonuclear neutrophils infiltration in wound area; ↑Angiogenesis	(129)
Animal	Wound healing activity	PPE	Inbred Sprague–Dawley male rats; excision wound model; Control group: petroleum jelly, experimental group: PPE (100 mg/kg) +petroleum jelly, standard group: mupirocin ointment (100 mg/kg); 15 days	Wound contraction of 95% (P<0.01) by day 15 in the experimental group; ↑Hydroxyproline content (P<0.05)	(130)
Animal	Anti-psoriasis activity	Punicalagin	Male BALB/c mice (6–8 weeks of age), imiquimod (IMQ)-induced psoriasis; Five groups: Control group, IMQ group, IMQ + DEX group (DEX, dexamethasone cream, positive drug for psoriasis), IMQ + Vehicle group, IMQ + PUN group (25 mg/kg PUN)	Inhibiting NF-κB-mediated IL-1β transcription and caspase-1-regulated IL-1β secretion	(131)
Clinical	Anti-aging activity	Arils (methanol extract)	12 human volunteers aged from 35 to 60 y/o, divided into 2 groups, 2 times daily topical application for a month, one group received a placebo	↓Free radicals	(132)
Clinical	Anti-aging activity	Fermented pomegranate extract	Double-blind, 35–55y/o, 40 healthy subjects, half on placebo, drink 50 ml daily; Another 40 subjects, half on placebo, apply 3 ml serum over their face 2 times daily for 4 weeks	↓Free radicals; ↑Skin moisture, brightness, and elasticity	(133)
Clinical	Skin lightening activity	PPE	Split-face, randomized, double-blind, placebo-controlled test of 30 subjects divided into 2 groups; Applied the preparation on half of their face	↓Free radicals; Tyrosinase and TRP-2 inhibition	(134)
Clinical	Protection against radiation-induced skin and mucosal changes	Whole fruit extract	Prospective, clinical, double-blind, case-control study; 60 patients (30 cases and 30 controls) undergoing radiotherapy for head and neck cancer; 12 months; 2 capsules/day for 6–7 weeks; each capsule containing 300 mg extract (40% polyphenols and 27% punicalagin)	↓Severity of radiation-induced mucositis and dermatitis (P<0.0001)	(135)
Clinical	Prevention or improvement of skin changes associated with striae	Seed oil	An interventional, nonrandomized study; 20 healthy females; 21–48 years old: 10 with striae albae at the hip level and 10 with no stretchmarks; Measurements of skin hydration level, skin elasticity, and thickness of the dermis at the beginning and after 3 and 6 weeks; Application of oil-in-water cream containing plants once daily	↑Dermis thickness, hydration, and elasticity values.	(136)
Clinical	Reduce photodamage from UVB irradiation	POMx® (Pomegranate extract); PJ	A parallel, three-arm, open-label RCT; n=72, female, 30–45 years, with Fitzpatrick skin type II-IV, 3 groups: 1–1000 mg of pomegranate extract (PomX), 2- oz of PJ, 3- placebo; 12 weeks; determination of minimal erythema dose (MED) and melanin index by cutometer;	↑MED; ↓Melanin formation	(137)
Clinical	Improvements in several biophysical properties, wrinkles, and shifts in the skin microbiome	Pomella® (Pomegranate extract)	Prospective, double-blind placebo-controlled study, healthy males and females aged 25–55 years; 4 weeks; BTBP 3D Clarity Pro® wrinkle assessment, SkinColorCatch® facial erythema index, and melanin index assessment	↓Wrinkle severity (P<0.01), forehead sebum excretion rate (P=0.14), facial transepidermal water loss (P<0.05)	(138)