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Pomegranate extract (PE) and its polyphenols have been reported to show skin protective effects but their cytoprotective effects against methylglyoxal (MGO)-induced DNA damage and cell dysfunctions are unclear. Herein, we evaluated whether PE, punicalagin (PA), ellagic acid (EA), and urolithin A (UA), can alleviate MGO-induced DNA damage in human keratinocytes. PE (50 µg/mL) and PA (50 µM) protected DNA integrity and reduced the formation of MGO-DNA adducts and tailed DNA by 60.2 and 49.7%, respectively, in HaCaT cells. PE and PA reduced MGO-induced cytotoxicity by increasing the cell viability (by 17.5 and 15.0%) and decreasing reactive oxygen species (by 28.3 and 30.0%), respectively. PE and PA also ameliorated MGO-induced cell dysfunction by restoring cell adhesion, migration, and wound healing capacity. Findings from this study provide insights into the skin protective effects of PE and its polyphenols supporting their applications as potential bioactive ingredients for cosmeceuticals.

To develop a more effective and safer drug for the treatment of type 2 diabetes mellitus (T2DM)-induced liver damage, we investigated the protective effects of punicalagin, a major component in pomegranate peel, on the liver of mice with T2DM. After five weeks of punicalagin treatment, blood and liver samples were obtained for the subsequent analyses. Western blotting, reverse transcription polymerase chain reaction, and immunohistochemical staining were performed to determine the expression of endoplasmic reticulum (ER) stress markers in the liver tissue. The results showed that punicalagin alleviated glucose and insulin resistance, increased insulin sensitivity, and reduced serum free fatty acids levels and hepatic steatosis in the mice with T2DM. Furthermore, punicalagin down-regulated the elevated mRNA expression of the ER stress markers eIF2α, GRP78, ATF4, and CHOP in the liver of mice with T2DM. Our results suggest that punicalagin is a potential natural agent for the prevention of T2DM-induced liver damage.

Ultraviolet (UV)-B is an established etiological cause of skin damage. SIRT1, a mammalian SIR2 homolog localized in the nucleus and cytosol, plays a protective role in UVB-induced DNA damage. In this study, we established a method of screening foods and food ingredients, which augment the SIRT1 promoter in HaCaT cells, where we used recombinant HaCaT cells transduced with the vector expressing EGFP under the control of SIRT1 promoter. We identified four SIRT1-augmenting pomegranate-derived polyphenols (ellagic acid, punicalin, punicalagin, and urolithin A). All of these contributed to the proliferation of UVB-irradiated HaCaT cells. Punicalagin and urolithin A removed UVB-induced cyclobutane pyrimidine dimers (CPD) by activating nucleotide excision repair (NER). Both punicalagin and urolithin A upregulated NER-related XPC expression and XPA deacetylation level in a SIRT1-dependent manner. In the present study, we attempted to elucidate the mechanisms underlying the repair of UVB-damaged HaCaT cells by pomegranate-derived polyphenols.

Inflammatory response remains one of the most common and serious complications of disease in clinical studies. It has been established that some molecules found in pomegranate peel polyphenols (PPPs) are related to inflammatory processes; however, the mechanisms are unclear, leaving a significant unmet medical need. The goal of this study was to analyze the anti-inflammatory effects of PPPs in RAW264.7 macrophages and examine the relationship between certain special components such as - punicalagin (PC) and ellagic acid (EA) and systemic inflammation. The results showed that PPPs and their main components PC and EA, could decrease pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) at the mRNA and protein levels and, down-regulate iNOS and COX-2 expression, which in turn reduced NO and PGE2. The molecular mechanism might be associated with the inhibition of MAPKs activation. Additionally, PPPs and PC performed much better than EA. We highlight the key role of food-derived molecules PPPs and its main components in understanding the mechanism of anti-inflammatory.

Pomegranate (Punica granatum) is a heath with abundant hydrolysable tannin in its peel. This study demonstrated that POMx (70% acetone extract of pomegranate peels) significantly reduced interleukin (IL)-1β-induced inducible nitric oxide synthase, cyclooxygenase-2, and matrix metalloproteinase-13 protein expression in primary rat chondrocytes (PRCs). In the type II collagenase-induced osteoarthritis rat model, POMx (150 mg/kg) recovered the weight-bearing ratio changes in experimental animals, suggesting the alleviation of knee-related inflammation and nociception. Therefore, the major compound, punicalagin, was isolated from POMx. Punicalagin also significantly reduced IL-1β-induced inflammatory factors in PRCs and exerted significant antiosteoarthritis effects in the vivo model after 28-d treatment (concentration: 0.50 mg/kg). However, the IC50 values of POMx and punicalagin against prostaglandin E2 production were 83.2 and 36.0 μg/mL, respectively, and the concentration of punicalagin in POMx was 19.1%. Altogether, POMx can be used to develop functional foods for knee-related diseases, and punicalagin can act as an active ingredient.

• Punicalagin suppress the endoplasmic reticulum stress in the liver. • The molecular mechanism is associated with eIF2α–ATF4–CHOP signaling pathway. • Punicalagin is a potential natural agent for the prevention of T2DM liver damage. To develop a more effective and safer drug for the treatment of type 2 diabetes mellitus (T2DM)-induced liver damage, we investigated the protective effects of punicalagin, a major component in pomegranate peel, on the liver of mice with T2DM. After five weeks of punicalagin treatment, blood and liver samples were obtained for the subsequent analyses. Western blotting, reverse transcription polymerase chain reaction, and immunohistochemical staining were performed to determine the expression of endoplasmic reticulum (ER) stress markers in the liver tissue. The results showed that punicalagin alleviated glucose and insulin resistance, increased insulin sensitivity, and reduced serum free fatty acids levels and hepatic steatosis in the mice with T2DM. Furthermore, punicalagin down-regulated the elevated mRNA expression of the ER stress markers eIF2α, GRP78, ATF4, and CHOP in the liver of mice with T2DM. Our results suggest that punicalagin is a potential natural agent for the prevention of T2DM-induced liver damage. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Twenty-two plant-based polyphenols were screened for keratinocyte SIRT1 promotion. • Punicalagin and urolithin A from pomegranate are the strongest SIRT1 inducers. • Punicalagin and urolithin A can rescue UVB-induced DNA damage. Abstract Ultraviolet (UV)-B is an established etiological cause of skin damage. SIRT1, a mammalian SIR2 homolog localized in the nucleus and cytosol, plays a protective role in UVB-induced DNA damage. In this study, we established a method of screening foods and food ingredients, which augment the SIRT1 promoter in HaCaT cells, where we used recombinant HaCaT cells transduced with the vector expressing EGFP under the control of SIRT1 promoter. We identified four SIRT1-augmenting pomegranate-derived polyphenols (ellagic acid, punicalin, punicalagin, and urolithin A). All of these contributed to the proliferation of UVB-irradiated HaCaT cells. Punicalagin and urolithin A removed UVB-induced cyclobutane pyrimidine dimers (CPD) by activating nucleotide excision repair (NER). Both punicalagin and urolithin A upregulated NER-related XPC expression and XPA deacetylation level in a SIRT1-dependent manner. In the present study, we attempted to elucidate the mechanisms underlying the repair of UVB-damaged HaCaT cells by pomegranate-derived polyphenols. [ABSTRACT FROM AUTHOR]

Ellagic acid (EA) is a polyphenol that must be released from the non-bioavailable ellagitannins in pomegranates, walnuts or strawberries to be absorbed. To estimate whether EA bioavailability could be improved after consumption of a high free EA amount, we conducted a crossover pharmacokinetic study in healthy volunteers that consumed two pomegranate extracts providing either 130 mg punicalagin+524 mg EA (PE-1) or 279 mg punicalagin+25 mg EA (PE-2). Targeted metabolomics (UPLC-ESI-qTOF-MS/MS) identified plasma free EA but not phase-II conjugates. EA pharmacokinetics showed high interindividual variability. Cmax ranged from 12 to 360 nM (PE-1: 74.8 ± 54.4 nM; PE-2: 64.1 ± 76.8 nM). In vitro digestion supported in vivo results. EA bioavailability was limited by the ellagitannin, pH and protein environment. A higher free EA intake does not enhance its bioavailability but promotes urolithin production. Bioavailability of EA, as the unchanged fraction that reaches the systemic circulation, is not as low as previously thought.

Punicalagin is a functional ingredient in pomegranate juice, which has various beneficial effects for health and prevention of disease. In this study, the anti-teratogenic effect of punicalagin (1 × 10−5 or 1 × 10−4 µM) was investigated in cultured mouse embryos and yolk sac-placentas exposed to nicotine (1 mM), one of the main toxins in cigarette smoke. Nicotine-treated embryos revealed severe anomalies as well as impaired yolk sac vascularization, reduced labyrinth formation, and developmental arrest of blood islands in the chorioallantoic border. Furthermore, nicotine significantly altered the regulations of hypoxia- and vascularization-related genes in yolk sac-placenta and the levels of oxidative stress, apoptosis, and inflammation in both embryos and yolk sac-placentas. However, these detrimental changes were remarkably improved in response to co-treatment with punicalagins. These findings indicate that punicalagin could be crucial to the development of clinical strategies to attenuate nicotine-induced teratogenesis in embryos.

Inflammatory response remains one of the most common and serious complications of disease in clinical studies. It has been established that some molecules found in pomegranate peel polyphenols (PPPs) are related to inflammatory processes; however, the mechanisms are unclear, leaving a significant unmet medical need. The goal of this study was to analyze the anti-inflammatory effects of PPPs in RAW264.7 macrophages and examine the relationship between certain special components such as - punicalagin (PC) and ellagic acid (EA) and systemic inflammation. The results showed that PPPs and their main components PC and EA, could decrease pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) at the mRNA and protein levels and, down-regulate iNOS and COX-2 expression, which in turn reduced NO and PGE 2 . The molecular mechanism might be associated with the inhibition of MAPKs activation. Additionally, PPPs and PC performed much better than EA. We highlight the key role of food-derived molecules PPPs and its main components in understanding the mechanism of anti-inflammatory. [ABSTRACT FROM AUTHOR]

Pomegranate ( Punica granatum ) is a heath with abundant hydrolysable tannin in its peel. This study demonstrated that POMx (70% acetone extract of pomegranate peels) significantly reduced interleukin (IL)-1β-induced inducible nitric oxide synthase, cyclooxygenase-2, and matrix metalloproteinase-13 protein expression in primary rat chondrocytes (PRCs). In the type II collagenase-induced osteoarthritis rat model, POMx (150 mg/kg) recovered the weight-bearing ratio changes in experimental animals, suggesting the alleviation of knee-related inflammation and nociception. Therefore, the major compound, punicalagin, was isolated from POMx. Punicalagin also significantly reduced IL-1β-induced inflammatory factors in PRCs and exerted significant antiosteoarthritis effects in the vivo model after 28-d treatment (concentration: 0.50 mg/kg). However, the IC 50 values of POMx and punicalagin against prostaglandin E 2 production were 83.2 and 36.0 μg/mL, respectively, and the concentration of punicalagin in POMx was 19.1%. Altogether, POMx can be used to develop functional foods for knee-related diseases, and punicalagin can act as an active ingredient. [ABSTRACT FROM AUTHOR]

Fatty acid synthase (FAS) has been recognized as a potential therapeutic target for obesity. In this study, for the first time, the inhibitory effect of pomegranate husk extract, punicalagin and ellagic acid on FAS was investigated. We found them potently inhibiting the activity of FAS with half-inhibitory concentration values (IC50) of 4.1 μg/ml (pomegranate husk extract), 4.2 μg/ml (4.50 μM, punicalagin) and 1.31 μg/ml (4.34 μM, ellagic acid), respectively. Moreover, they all exhibited time-dependent inactivation of FAS. Punicalagin and ellagic acid inhibited FAS with different mechanisms compared to previously reported inhibitors, through inactivating acetyl/malonyl transferase and β-ketoacyl synthase domains, respectively. Additionally, 100 μg/ml pomegranate husk extract, 5.24 μg/ml (5 μM) punicalagin and 4.5 μg/ml (15 μM) ellagic acid effectively reduced lipid accumulation inside FAS over-expressed 3T3-L1 adipocytes. Since FAS plays a key role in the biosynthesis pathway of fatty acid, these findings suggest that pomegranate husk extract, punicalagin and ellagic acid have potential in the prevention and treatment of obesity.

Pomegranates contain a complex mixture of gallotannins, ellagitannins, ellagic acid and anthocyanins. However, label claims on pomegranate supplements (PS) may not correlate with actual content of antioxidants, polyphenols or tannins. Nineteen PS were evaluated for their authenticity by determining ellagitannin composition by RP-HPLC and studying the relationship between total polyphenols as measured by the Folin–Ciocalteau assay and antioxidant capacity by oxygen radical absorbing capacity (ORAC), free radical scavenging properties by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and ferric reducing antioxidant power (FRAP). Only a limited number of pomegranate supplements were authentic. Product labels were inconsistent with polyphenol composition and antioxidant content. A majority of the samples (n = 13) contained disproportionately high amounts of ellagic acid and low or no detectable pomegranate tannins. Only six products had tannin composition that resembled pomegranates (punicalagin, punicalin, ellagitannins and gallotannins). PS-01 (natural pomegranate extract) was the most representative of pomegranate fruit polyphenols with 99% total pomegranate polyphenol and the highest antioxidant capacity across all measures. Correlations between total polyphenols and antioxidant content were high (R2 > 0.87) in products that had polyphenol composition resembling pomegranates. Products that contained high amounts of ellagic acid and low or no detectable pomegranate tannins had poor correlations between total polyphenols and antioxidant content. The results indicate that reliable labeling information, better standardization, improved manufacturing practices and regulation of the market is required to assure consumers of the quality of pomegranate supplements.

Ellagic acid (EA) is a polyphenol that must be released from the non-bioavailable ellagitannins in pomegranates, walnuts or strawberries to be absorbed. To estimate whether EA bioavailability could be improved after consumption of a high free EA amount, we conducted a crossover pharmacokinetic study in healthy volunteers that consumed two pomegranate extracts providing either 130 mg punicalagin+524 mg EA (PE-1) or 279 mg punicalagin+25 mg EA (PE-2). Targeted metabolomics (UPLC-ESI-qTOF-MS/MS) identified plasma free EA but not phase-II conjugates. EA pharmacokinetics showed high interindividual variability. Cmax ranged from 12 to 360 nM (PE-1: 74.8 ± 54.4 nM; PE-2: 64.1 ± 76.8 nM). In vitro digestion supported in vivo results. EA bioavailability was limited by the ellagitannin, pH and protein environment. A higher free EA intake does not enhance its bioavailability but promotes urolithin production. Bioavailability of EA, as the unchanged fraction that reaches the systemic circulation, is not as low as previously thought. [ABSTRACT FROM AUTHOR]

Punicalagin is a functional ingredient in pomegranate juice, which has various beneficial effects for health and prevention of disease. In this study, the anti-teratogenic effect of punicalagin (1 × 10 −5 or 1 × 10 −4   µM) was investigated in cultured mouse embryos and yolk sac-placentas exposed to nicotine (1 mM), one of the main toxins in cigarette smoke. Nicotine-treated embryos revealed severe anomalies as well as impaired yolk sac vascularization, reduced labyrinth formation, and developmental arrest of blood islands in the chorioallantoic border. Furthermore, nicotine significantly altered the regulations of hypoxia- and vascularization-related genes in yolk sac-placenta and the levels of oxidative stress, apoptosis, and inflammation in both embryos and yolk sac-placentas. However, these detrimental changes were remarkably improved in response to co-treatment with punicalagins. These findings indicate that punicalagin could be crucial to the development of clinical strategies to attenuate nicotine-induced teratogenesis in embryos. [ABSTRACT FROM AUTHOR]

Abstract: Fatty acid synthase (FAS) has been recognized as a potential therapeutic target for obesity. In this study, for the first time, the inhibitory effect of pomegranate husk extract, punicalagin and ellagic acid on FAS was investigated. We found them potently inhibiting the activity of FAS with half-inhibitory concentration values (IC50) of 4.1μg/ml (pomegranate husk extract), 4.2μg/ml (4.50μM, punicalagin) and 1.31μg/ml (4.34μM, ellagic acid), respectively. Moreover, they all exhibited time-dependent inactivation of FAS. Punicalagin and ellagic acid inhibited FAS with different mechanisms compared to previously reported inhibitors, through inactivating acetyl/malonyl transferase and β-ketoacyl synthase domains, respectively. Additionally, 100μg/ml pomegranate husk extract, 5.24μg/ml (5μM) punicalagin and 4.5μg/ml (15μM) ellagic acid effectively reduced lipid accumulation inside FAS over-expressed 3T3-L1 adipocytes. Since FAS plays a key role in the biosynthesis pathway of fatty acid, these findings suggest that pomegranate husk extract, punicalagin and ellagic acid have potential in the prevention and treatment of obesity. [Copyright &y& Elsevier]

Abstract: Pomegranates contain a complex mixture of gallotannins, ellagitannins, ellagic acid and anthocyanins. However, label claims on pomegranate supplements (PS) may not correlate with actual content of antioxidants, polyphenols or tannins. Nineteen PS were evaluated for their authenticity by determining ellagitannin composition by RP-HPLC and studying the relationship between total polyphenols as measured by the Folin–Ciocalteau assay and antioxidant capacity by oxygen radical absorbing capacity (ORAC), free radical scavenging properties by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and ferric reducing antioxidant power (FRAP). Only a limited number of pomegranate supplements were authentic. Product labels were inconsistent with polyphenol composition and antioxidant content. A majority of the samples (n =13) contained disproportionately high amounts of ellagic acid and low or no detectable pomegranate tannins. Only six products had tannin composition that resembled pomegranates (punicalagin, punicalin, ellagitannins and gallotannins). PS-01 (natural pomegranate extract) was the most representative of pomegranate fruit polyphenols with 99% total pomegranate polyphenol and the highest antioxidant capacity across all measures. Correlations between total polyphenols and antioxidant content were high (R 2 >0.87) in products that had polyphenol composition resembling pomegranates. Products that contained high amounts of ellagic acid and low or no detectable pomegranate tannins had poor correlations between total polyphenols and antioxidant content. The results indicate that reliable labeling information, better standardization, improved manufacturing practices and regulation of the market is required to assure consumers of the quality of pomegranate supplements. [Copyright &y& Elsevier]

[Display omitted] • Pomegranate extract and punicalagin reduce MGO-induced DNA adducts. • Pomegranate extract and punicalagin reduce MGO-induced cellular DNA damage. • Pomegranate extract and punicalagin alleviate MGO-induced keratinocyte toxicity. • Pomegranate extract and punicalagin promote skin cell adhesion and migration. • Pomegranate extract and punicalagin enhance wound healing rate. Pomegranate extract (PE) and its polyphenols have been reported to show skin protective effects but their cytoprotective effects against methylglyoxal (MGO)-induced DNA damage and cell dysfunctions are unclear. Herein, we evaluated whether PE, punicalagin (PA), ellagic acid (EA), and urolithin A (UA), can alleviate MGO-induced DNA damage in human keratinocytes. PE (50 µg/mL) and PA (50 µM) protected DNA integrity and reduced the formation of MGO-DNA adducts and tailed DNA by 60.2 and 49.7%, respectively, in HaCaT cells. PE and PA reduced MGO-induced cytotoxicity by increasing the cell viability (by 17.5 and 15.0%) and decreasing reactive oxygen species (by 28.3 and 30.0%), respectively. PE and PA also ameliorated MGO-induced cell dysfunction by restoring cell adhesion, migration, and wound healing capacity. Findings from this study provide insights into the skin protective effects of PE and its polyphenols supporting their applications as potential bioactive ingredients for cosmeceuticals. [ABSTRACT FROM AUTHOR]