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Background: Oxidative stress and chronic inflammation, at both the systemic and the central level, are critical early events in atherosclerosis and Alzheimer's disease (AD). Purpose: To investigate the oxidative stress-, inflammation-, and Tau-phosphorylation-lowering effects of pomegranate polyphenols (PPs) (punicalagin, ellagic acid, peel, and aril extracts). Methods: We used flow cytometry to quantify the protein expression of proinflammatory cytokines (IL-1β) and anti-inflammatory mediators (IL-10) in THP-1 macrophages, as well as M1/M2 cell-specific marker (CD86 and CD163) expression in human microglia HMC3 cells. The IL-10 protein expression was also quantified in U373-MG human astrocytes. The effect of PPs on human amyloid beta 1-42 (Aβ1-42)-induced oxidative stress was assessed in the microglia by measuring ROS generation and lipid peroxidation, using 2′,7′-dichlorofluorescein diacetate (DCFH-DA) and thiobarbituric acid reactive substance (TBARS) tests, respectively. Neuronal viability and cell apoptotic response to Aβ1-42 toxicity were assayed using the MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay and the annexin-V-FITC apoptosis detection kit, respectively. Finally, flow cytometry analysis was also performed to evaluate the ability of PPs to modulate Aβ1-42-induced Tau-181 phosphorylation (pTau-181). Results: Our data indicate that PPs are significantly (p < 0.05) effective in countering Aβ1-42-induced inflammation through increasing the anti-inflammatory cytokines (IL-10) in U373-MG astrocytes and THP1 macrophages and decreasing proinflammatory marker (IL-1β) expression in THP1 macrophages. The PPs were also significantly (p < 0.05) effective in inducing the phenotypic transition of THP-1 macrophages and microglial cells from M1 to M2 by decreasing CD86 and increasing CD163 surface receptor expression. Moreover, our treatments have a significant (p < 0.05) beneficial impact on oxidative stress, illustrated in the reduction in TBARS and ROS generation. Our treatments have significant (p < 0.05) cell viability improvement capacities and anti-apoptotic effects on human H4 neurons. Furthermore, our results suggest that Aβ1-42 significantly (p < 0.05) increases pTau-181. This effect is significantly (p < 0.05) attenuated by arils, peels, and punicalagin and drastically reduced by the ellagic acid treatment. Conclusion: Overall, our results attribute to PPs anti-inflammatory, antioxidant, anti-apoptotic, and anti-Tau-pathology potential. Future studies should aim to extend our knowledge of the potential role of PPs in Aβ1-42-induced neurodegeneration, particularly concerning its association with the tauopathy involved in AD. [ABSTRACT FROM AUTHOR]

Background: Pomegranate is a fruit that contains various phenolic compounds, including punicalagin and ellagic acid, which have been attributed to anti-inflammatory, antioxidant, and anticarcinogenic properties, among others. Objective: To evaluate the effect of punicalagin and ellagic acid on the viability, migration, cell cycle, and antigenic profile of cultured human fibroblasts (CCD-1064Sk). MTT spectrophotometry was carried out to determine cell viability, cell culture inserts were used for migration trials, and flow cytometry was performed for antigenic profile and cell cycle analyses. Cells were treated with each phenolic compound for 24 h at doses of 10−5 to 10−9 M. Results: Cell viability was always significantly higher in treated versus control cells except for punicalagin at 10−9 M. Doses of punicalagin and ellagic acid in subsequent assays were 10−6 M or 10−7 M, which increased the cell migration capacity and upregulated fibronectin and α-actin expression without altering the cell cycle. Conclusions: These in vitro findings indicate that punicalagin and ellagic acid promote fibroblast functions that are involved in epithelial tissue healing. [ABSTRACT FROM AUTHOR]

Diabetic liver injury has received increasing attention as a serious complication of type 2 diabetes. Punicalagin (PU), a major component of pomegranate polyphenols, has various biological activities such as antioxidant, anti-inflammatory, and lipid metabolism regulation. In this study, we observed the protective effect of punicalagin on a high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic liver injury in mice and revealed the underlying mechanism. The results showed that fasting blood glucose (FBG), fasting serum insulin (FINS), and homeostasis model assessment for insulin resistance (HOMA-IR) in diabetic liver injury mice were significantly decreased after punicalagin intervention. Simultaneously, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), free fatty acids (FFA), malondialdehyde (MDA), and total superoxide dismutase (T-SOD) in the serum and liver were significantly decreased, with reductions in fat lesions and inflammatory cells. Mitophagy is a selective autophagy that maintains a balance between the quality and quantity of intracellular mitochondria. Studies have shown that mitophagy is closely related to the occurrence and development of diabetic liver injury. In our study, the mitochondrial membrane potential (MMP) was significantly increased in mice with diabetic liver injury after punicalagin intervention; the protein expression of Pink1, Parkin, Bnip3, LC3b, P62, manganese superoxide dismutase (MnSOD), and catalase (CAT) was significantly increased in the liver; and the activities of MnSOD and CAT in the serum and liver were significantly increased, which is consistent with the results of in vitro experiments. In summary, our study provided evidence that punicalagin could reduce the level of oxidative stress in the liver by upregulating mitophagy and the activities of antioxidant enzymes, thus having a certain protective effect against diabetic liver injury. [ABSTRACT FROM AUTHOR]

Hydroxytyrosol (HT) and punicalagin (PC) exert cardioprotective and antiatherosclerotic effects. This study evaluated the effect of an oral supplement containing HT and PC (SAx) on dyslipidemia in an adult population. A randomized, double-blind, controlled, crossover trial was conducted over a 20-week period. SAx significantly reduced the plasma levels of triglycerides (TG) in subjects with hypertriglyceridemia (≥150 mg/dL) (from 200.67 ± 51.38 to 155.33 ± 42.44 mg/dL; p < 0.05), while no such effects were observed in these subjects after the placebo. SAx also significantly decreased the plasma levels of low-density lipoprotein cholesterol (LDL-C) in subjects with high plasma levels of LDL-C (≥160 mg/dL) (from 179.13 ± 16.18 to 162.93 ± 27.05 mg/dL; p < 0.01), while no such positive effect was observed with the placebo. In addition, the placebo significantly reduced the plasma levels of high-density lipoprotein cholesterol (HDL-C) in the total population (from 64.49 ± 12.65 to 62.55 ± 11.57 mg/dL; p < 0.05), while SAx significantly increased the plasma levels of HDL-C in subjects with low plasma levels of HDL-C (<50 mg/dL) (from 44.25 ± 3.99 to 48.00 ± 7.27 mg/dL; p < 0.05). In conclusion, the supplement containing HT and PC exerted antiatherosclerotic and cardio-protective effects by considerably improving dyslipidemia in an adult population, without co-adjuvant treatment or adverse effects. [ABSTRACT FROM AUTHOR]

Background: Pomegranate is a fruit that contains various phenolic compounds, including punicalagin and ellagic acid, which have been attributed to anti-inflammatory, antioxidant, and anticarcinogenic properties, among others., Objective: To evaluate the effect of punicalagin and ellagic acid on the viability, migration, cell cycle, and antigenic profile of cultured human fibroblasts (CCD-1064Sk). MTT spectrophotometry was carried out to determine cell viability, cell culture inserts were used for migration trials, and flow cytometry was performed for antigenic profile and cell cycle analyses. Cells were treated with each phenolic compound for 24 h at doses of 10 -5 to 10 -9 M., Results: Cell viability was always significantly higher in treated versus control cells except for punicalagin at 10 -9 M. Doses of punicalagin and ellagic acid in subsequent assays were 10 -6 M or 10 -7 M, which increased the cell migration capacity and upregulated fibronectin and α-actin expression without altering the cell cycle., Conclusions: These in vitro findings indicate that punicalagin and ellagic acid promote fibroblast functions that are involved in epithelial tissue healing.

The extract of pomegranate (Punica granatum) has been applied in medicine since ancient times due to its broad-spectrum health-beneficial properties. It is a rich source of hydrolyzable tannins and anthocyanins, exhibiting strong antioxidative, anti-inflammatory, and antineoplastic properties. Anticancer activities of pomegranate with reference to modulated signaling pathways in various cancer diseases have been recently reviewed. However, less is known about punicalagin (Pug), a prevailing compound in pomegranate, seemingly responsible for its most beneficial properties. In this review, the newest data derived from recent scientific reports addressing Pug impact on neoplastic cells are summarized and discussed. Its attenuating effect on signaling circuits promoting cancer growth and invasion is depicted. The Pug-induced redirection of signal-transduction pathways from survival and proliferation into cell-cycle arrest, apoptosis, senescence, and autophagy (thus compromising neoplastic progression) is delineated. Considerations presented in this review are based mainly on data obtained from in vitro cell line models and concern the influence of Pug on human cervical, ovarian, breast, lung, thyroid, colorectal, central nervous system, bone, as well as other cancer types. [ABSTRACT FROM AUTHOR]

The aim of this publication is to compile a summary of the findings regarding punicalagin in various tissues described thus far in the literature, with an emphasis on the effect of this substance on immune reactions. Punicalagin (PUN) is an ellagitannin found in the peel of pomegranate (Punica granatum). It is a polyphenol with proven antioxidant, hepatoprotective, anti-atherosclerotic and chemopreventive activities, antiproliferative activity against tumor cells; it inhibits inflammatory pathways and the action of toxic substances, and is highly tolerated. This work describes the source, metabolism, functions and effects of punicalagin, its derivatives and metabolites. Furthermore, its anti-inflammatory and antioxidant effects are described. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is a diabetic complication caused by chronic inflammation. As the primary polyphenol in pomegranate, punicalagin is believed to have significant anti-inflammatory properties. In this study, we established a mice model for diabetes induced by high-fat diet (HFD)/ streptozotocin (STZ) to verify the protective effect of punicalagin in vivo. The results show that the blood urea nitrogen (BUN), serum creatinine (CREA), and the urine albumin to creatinine ratio (UACR) were significantly decreased in diabetic mice after punicalagin intervention, and the symptoms of glomerular interstitial hyperplasia and glomerular hypertrophy were alleviated. Pyroptosis is an essential manner of programmed cell death in the inflammatory response; the expression of pyroptosis-related proteins such as interleukin-1 (IL-1β), cysteinyl aspartate-specific protease-1 (caspase-1), gasdermin D (GSDMD), and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing protein 3 (NLRP3) was decreased in our study, which proved that the administration of punicalagin for eight weeks can significantly inhibit pyroptosis in mice. In addition, punicalagin reduced high glucose-mediated protein expressions of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) and alleviated mitochondria damage. Low expression of NOX4 inhibits the dissociation of thioredoxin (Trx) and thioredoxin-interacting protein (TXNIP) and the suppression of NLRP3 inflammasome activation. To summarize, our study provided evidence that punicalagin can alleviate diabetic nephropathy, and the effect is associated with downregulating the expression of NOX4, inhibiting TXNIP/NLRP3 pathway-mediated pyroptosis, suggesting its therapeutic implications for complications of diabetes. [ABSTRACT FROM AUTHOR]

Punicalagin, a hydrolysable tannin of pomegranate juice, exhibits multiple biological effects, including inhibiting production of pro-inflammatory cytokines in macrophages. Autophagy, an intracellular self-digestion process, has been recently shown to regulate inflammatory responses. In this study, we investigated the anti-inflammatory potential of punicalagin in lipopolysaccharide (LPS) induced RAW264.7 macrophages and uncovered the underlying mechanisms. Punicalagin significantly attenuated, in a concentration-dependent manner, LPS-induced release of NO and decreased pro-inflammatory cytokines TNF-α and IL-6 release at the highest concentration. We found that punicalagin inhibited NF-κB and MAPK activation in LPS-induced RAW264.7 macrophages. Western blot analysis revealed that punicalagin pre-treatment enhanced LC3II, p62 expression, and decreased Beclin1 expression in LPS-induced macrophages. MDC assays were used to determine the autophagic process and the results worked in concert with Western blot analysis. In addition, our observations indicated that LPS-induced releases of NO, TNF-α, and IL-6 were attenuated by treatment with autophagy inhibitor chloroquine, suggesting that autophagy inhibition participated in anti-inflammatory effect. We also found that punicalagin downregulated FoxO3a expression, resulting in autophagy inhibition. Overall these results suggested that punicalagin played an important role in the attenuation of LPS-induced inflammatory responses in RAW264.7 macrophages and that the mechanisms involved downregulation of the FoxO3a/autophagy signaling pathway. [ABSTRACT FROM AUTHOR]

Hydroxytyrosol (HT) and Punicalagin (PC) exert cardioprotective and anti-atherosclerotic effects. This study evaluates the effect of oral supplementation with HT and PC (SAx) on early atherosclerosis markers in middle-aged, seemingly healthy adults. A randomized, double-blinded, placebo-controlled, crossover trial was performed for 20 weeks. There were two treatment sequences (Placebo/SAx, n = 41; SAx/Placebo, n = 43) for which the intervention periods (Placebo and SAx) were 8 weeks long, followed by a 4-week wash out period. The supplement was composed of 9.9 mg of HT and 195 mg of PC, and the placebo was composed of maltodextrin. SAx increased endothelial function (Flow-mediated dilatation [FMD]: 2.36%; p < 0.001) in the endothelial dysfunction subgroup compared to the placebo (2.36 ± 3.9 vs. 0.76 ± 3.5%, p < 0.05). SAx also reduced oxLDL by −28.74 ng/mL (p < 0.05) in subjects with higher levels of oxLDL, which was an improvement compared with the placebo (−28.74 ± 40.2 vs. 25.64 ± 93.8 ng/mL, p < 0.001). The prehypertension and hypertension subgroups exhibited decreased systolic (−15.75 ± 9.9 mmHg; p < 0.001) and diastolic (−6.36 ± 8.7 mmHg; p < 0.001) blood pressure after SAx consumption. Moreover, the systolic prehypertension and hypertension subgroups presented significant differences in systolic blood pressure compared to the placebo (−15.75 ± 9.9 vs. −2.67 ± 12.0 mmHg, p < 0.05). In conclusion, the supplement exerted anti-atherosclerotic effects by improving endothelial function, blood pressure, and levels of circulating oxLDL, especially for persons in whom these parameters were altered. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the anti-inflammatory potential of pomegranate peel extracts (PPE) prepared from waste material of pomegranate juice production both in vitro on Caco-2 cells and ex vivo using porcine colonic tissue explants. Caco-2 cells were stimulated in vitro by TNF and colonic tissue explants were stimulated ex vivo with lipopolysaccharide (LPS). Both tissues were co-treated with PPE at 0, 1.0, 2.5, 5.0, 10 and 25 μg/mL. The secretion of CXCL8 in the supernatant of both experiments was determined by enzyme linked immunosorbent assay (ELISA) and the relative expression of inflammatory cytokines were evaluated in the colonic tissue by quantitative polymerase chain reaction (QPCR). The 2.5 to 25 μg/mL of PPE suppressed CXCL8 (p < 0.001) in the Caco-2 cells, whereas CXCL8 production was suppressed by only 5 and 25 μg/mL (p < 0.01) of PPE in the colonic explants. The 5 μg/mL of PPE also suppressed the expression of IL1A (p < 0.05), IL6 (p < 0.01) and CXCL8 (p < 0.05) in LPS challenged colonic tissues compared to controls. In conclusion, the 5 μg/mL of PPE consistently elicits strong anti-inflammatory activity. These results support the potential of bioactive compounds from the waste peel of pomegranate in terms of their anti-inflammatory activity in cells and tissues of the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the anti-inflammatory potential of pomegranate peel extracts (PPE) prepared from waste material of pomegranate juice production both in vitro on Caco-2 cells and ex vivo using porcine colonic tissue explants. Caco-2 cells were stimulated in vitro by TNF and colonic tissue explants were stimulated ex vivo with lipopolysaccharide (LPS). Both tissues were co-treated with PPE at 0, 1.0, 2.5, 5.0, 10 and 25 μg/mL. The secretion of CXCL8 in the supernatant of both experiments was determined by enzyme linked immunosorbent assay (ELISA) and the relative expression of inflammatory cytokines were evaluated in the colonic tissue by quantitative polymerase chain reaction (QPCR). The 2.5 to 25 μg/mL of PPE suppressed CXCL8 ( p < 0.001) in the Caco-2 cells, whereas CXCL8 production was suppressed by only 5 and 25 μg/mL ( p < 0.01) of PPE in the colonic explants. The 5 μg/mL of PPE also suppressed the expression of IL1A ( p < 0.05), IL6 ( p < 0.01) and CXCL8 ( p < 0.05) in LPS challenged colonic tissues compared to controls. In conclusion, the 5 μg/mL of PPE consistently elicits strong anti-inflammatory activity. These results support the potential of bioactive compounds from the waste peel of pomegranate in terms of their anti-inflammatory activity in cells and tissues of the gastrointestinal tract.

Pomegranate fruit is a functional food of high interest for human health due to its wide range of phytochemicals with antioxidant properties are implicated in the prevention of inflammation and cancer. Ellagitannins, such as punicalagin and ellagic acid, play a role as anti-atherogenic and neuroprotective molecules in the complex fighting against the degenerative diseases. The aim of this work was to evaluate the composition in punicalagins and ellagic acid of differently obtained extracts from whole fruit, peels and juices, prepared by squeezing or by centrifugation, of pomegranate belonging to different cultivars. Moreover, a wider phenolic fingerprint was also determined. The bioactivity of the extracts was tested on the redox activity of PDIA3 disulfide isomerase, an enzyme involved in the regulation of several cellular functions and associated with different diseases such as cancer, prion disorders, Alzheimer's and Parkinson's diseases. The results demonstrate that the different ratios between punicalagin and ellagic acid modulate the enzyme activity and other ellagitannins could interfere with this activity. [ABSTRACT FROM AUTHOR]