Punicalagin

Ann Clin Microbiol Antimicrob. 2014 Sep 5;13(1):32.

Antifungal activity of pomegranate peel extract and isolated compound punicalagin against dermatophytes.[Pubmed: 25260038]

Dermatophyte species infect the epidermis and appendages, often with serious social and health-economic consequences. The hydroalcoholic extract of pomegranate fruit peel showed activity against the dermatophyte fungi Trichophyton mentagrophytes, T. rubrum, Microsporum canis and M. gypseum.
METHODS AND RESULTS:
Hydroalcoholic extract was prepared with pomegranate peels. This crude extract was fractionated and submitted to liquid-liquid partition, resulting in an active fraction which was fractionated in a Sephadex LH-20 column, followed by a Lobar column. The structure of the active compound was established with the use of spectroscopic methods. The crude extract of pomegranate fruit peel showed activity against the dermatophytes Trichophyton mentagrophytes, T. rubrum, Microsporum canis, and M. gypseum, with MICs values of 125 μg/ml and 250 μg/ml, respectively for each genus. Punicalagin was isolated and identified by spectroscopic analysis. The crude extract and Punicalagin showed activity against the conidial and hyphal stages of the fungi. The cytotoxicity assay showed selectivity for fungal cells than for mammalian cells.
CONCLUSIONS:
These results indicated that the crude extract and Punicalagin had a greater antifungal activity against T. rubrum, indicating that the pomegranate is a good target for study to obtain a new antidermatophyte medicine.

Appl Environ Microbiol. 2014 Oct;80(19):6204-11.

Punicalagin inhibits Salmonella virulence factors and has anti-quorum-sensing potential.[Pubmed: 25085489]

Punicalagin, an essential component of pomegranate rind, has been demonstrated to possess antimicrobial activity against several food-borne pathogens, but its activity on the virulence of pathogens and its anti-quorum-sensing (anti-QS) potential have been rarely reported. This study investigated the efficacy of subinhibitory concentrations of Punicalagin on Salmonella virulence factors and QS systems.
METHODS AND RESULTS:
A broth microdilution method was used to determine the MICs of Punicalagin for 10 Salmonella strains. Motility assay and quantitative reverse transcription (RT)-PCR were performed to evaluate the effects of Punicalagin on the virulence attributes and QS-related genes of Salmonella. The MICs of Punicalagin for several Salmonella strains ranged from 250 to 1,000 μg/ml. Motility assays showed that Punicalagin, at 1/16× MIC and 1/32× MIC, significantly decreased bacterial swimming and swarming motility, which corresponded to downregulation of the motility-related genes (fliA, fliY, fljB, flhC, and fimD) in RT-PCR assays. RT-PCR also revealed that Punicalagin downregulated the expression of most of the selected genes involved in Salmonella virulence. Moreover, a QS inhibition assay indicated that Punicalagin dose dependently inhibited the production of violacein by Chromobacterium violaceum and repressed the expression of QS-related genes (sdiA and srgE) in Salmonella. In addition, Punicalagin significantly reduced Salmonella invasion of colonic cells (P<0.01) with no impact on adhesion.
CONCLUSIONS:
These findings suggest that Punicalagin has the potential to be developed as an alternative or supplemental agent for prevention of Salmonella infection.

Antiviral Res . 2021 Jun;190:105075.

Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CL pro[Pubmed: 33872675]

Abstract The emerging SARS-CoV-2 infection is the cause of the global COVID-19 pandemic. To date, there are limited therapeutic options available to fight this disease. Here we examined the inhibitory abilities of two broad-spectrum antiviral natural products chebulagic acid (CHLA) and Punicalagin (PUG) against SARS-CoV-2 viral replication. Both CHLA and PUG reduced virus-induced plaque formation in Vero-E6 monolayer at noncytotoxic concentrations, by targeting the enzymatic activity of viral 3-chymotrypsin-like cysteine protease (3CLpro) as allosteric regulators. Our study demonstrates the potential use of CHLA and PUG as novel COVID-19 therapies. Keywords: 3CLpro; Allosteric inhibitor; Chebulagic acid; Punicalagin; SARS-CoV-2.

Phytother Res. 2001 May;15(3):206-12.

Antioxidant and hepatoprotective effects of punicalagin and punicalin on acetaminophen-induced liver damage in rats.[Pubmed: 11351354]

Punicalagin and punicalin were isolated from the leaves of Terminalia catappa L., a Combretaceous plant distributed throughout tropical and subtropical beaches, which is used for the treatment of dermatitis and hepatitis. Our previous studies showed that both of these compounds exert antioxidative activity.
METHODS AND RESULTS:
In this study, the antihepatotoxic activity of Punicalagin and punicalin on acetaminophen-induced toxicity in the rat liver was evaluated. After evaluating the changes of several biochemical functions in serum, the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were increased by acetaminophen administration and reduced by Punicalagin and punicalin. Histological changes around the hepatic central vein and oxidative damage induced by acetaminophen were also recovered by both compounds. The data show that both Punicalagin and punicalin exert antihepatotoxic activity, but treatment with larger doses enhanced liver damage.
CONCLUSIONS:
These results suggest that even if Punicalagin and punicalin have antioxidant activity at small doses, treatment with larger doses will possibly induce some cell toxicities.

Biochem Biophys Res Commun. 2008 Jul 11;371(4):799-803.

Immune-suppressive activity of punicalagin via inhibition of NFAT activation.[Pubmed: 18466764]

Since T cell activation is central to the development of autoimmune diseases, we screened a natural product library comprising 1400 samples of medicinal herbal extracts, to identify compounds that suppress T cell activity.
METHODS AND RESULTS:
Punicalagin (PCG) isolated from the fruit of Punica granatum was identified as a potent immune suppressant, based on its inhibitory action on the activation of the nuclear factor of activated T cells (NFAT). PCG downregulated the mRNA and soluble protein expression of interleukin-2 from anti-CD3/anti-CD28-stimulated murine splenic CD4+ T cells and suppressed mixed leukocytes reaction (MLR) without exhibiting cytotoxicity to the cells. In vivo, the PCG treatment inhibited phorbol 12-myristate 13-acetate (PMA)-induced chronic ear edema in mice and decreased CD3+ T cell infiltration of the inflamed tissue.
CONCLUSIONS:
These results suggest that PCG could be a potential candidate for the therapeutics of various immune pathologies.

Phytomedicine. 2012 Dec 15;20(1):67-70.

Antiviral activity of punicalagin toward human enterovirus 71 in vitro and in vivo.[Pubmed: 23146421 ]

Human enterovirus 71 is one of the major causative agents of hand, foot and mouth disease in children and has caused mortalities in large-scale outbreaks in the Asia-Pacific region in recent years. No vaccine or antiviral therapy is available currently in the clinic.
METHODS AND RESULTS:
In this work, we investigated the antiviral effect of Punicalagin on enterovirus 71 both in vitro and in vivo. The results showed that Punicalagin reduced the viral cytopathic effect on rhabdomyosarcoma cells with an IC₅₀) value of 15 μg/ml. Moreover, Punicalagin treatment of mice challenged with a lethal dose of enterovirus 71 resulted in a reduction of mortality and relieved clinical symptoms by inhibiting viral replication.
CONCLUSIONS:
Our work suggested that Punicalagin have the potential for further development as antiviral agents against enterovirus 71.

J. Funct. Foods, 2013, 5(2):633-41.

Pomegranate husk extract, punicalagin and ellagic acid inhibit fatty acid synthase and adipogenesis of 3T3-L1 adipocyte[Reference: WebLink]

Fatty acid synthase (FAS) has been recognized as a potential therapeutic target for obesity.
METHODS AND RESULTS:
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 mu g/ml (pomegranate husk extract), 4.2 mu g/ml (4.50 mu M, Punicalagin) and 1.31 mu g/ml (4.34 mu M, 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 beta-ketoacyl synthase domains, respectively. Additionally, 100 mu g/ml pomegranate husk extract, 5.24 mu g/ml (5 mu M) Punicalagin and 4.5 mu g/ml (15 mu M) ellagic acid effectively reduced lipid accumulation inside FAS over-expressed 3T3-L1 adipocytes.
CONCLUSIONS:
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.

Inflammation. 2014 Jun;37(3):956-65.

Punicalagin inhibits inflammation in LPS-induced RAW264.7 macrophages via the suppression of TLR4-mediated MAPKs and NF-κB activation.[Pubmed: 24473904 ]

Punicalagin (2,3,hexahydroxydiphenoyl-gallagyl-D-glucose and referred to as PUN) is a bioactive ellagitannin isolated from pomegranate, which is widely used for the treatment of inflammatory bowel disease (IBD), diarrhea, and ulcers in Chinese traditional medicine.
METHODS AND RESULTS:
In this study, we detected the anti-inflammation potentials of PUN in lipopolysaccharide (LPS)-induced macrophages and tried to uncover the underlying mechanism. Results demonstrated that PUN (25, 50, or 100 μM) treatment could significantly decrease the LPS-induced production of nitric oxide), prostaglandin E2 (PGE2), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in RAW264.7 cells. Molecular research showed that PUN inhibited the activation of upstream mediator nuclear factor-κB by suppressing the phosphorylation of IκBα and p65. Results also indicated that PUN could suppress the phosphorylation of mitogen-activated protein kinase including p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase.
CONCLUSIONS:
In conclusion, we observed that PUN could inhibit LPS-induced inflammation, and it may be a potential choice for the treatment of inflammation diseases.

Mol Cell Biochem. 2015 Apr;402(1-2):141-8.

Punicalagin attenuated cerebral ischemia-reperfusion insult via inhibition of proinflammatory cytokines, up-regulation of Bcl-2, down-regulation of Bax, and caspase-3.[Pubmed: 25555468]

Punicalagin (PG) is a hydrolysable tannin compound found in Punica granatum L. The purpose of the present work is to explore the neuroprotective mechanism of Punicalagin against ischemia-reperfusion (I/R) injury in rat model of middle cerebral artery occlusion (MCAO).
METHODS AND RESULTS:
Rats were randomly divided into sham, MCAO, and PG-treated groups. Punicalagin (15 and 30 mg/kg), the vehicle was administered orally for 7 days prior to MCAO. Rats were anesthetised with ketamine (100 mg/kg/im), xylazine (10 mg/kg/im) and subjected to 2 h occlusion and 22 h reperfusion. The effects of Punicalagin on behavioral deficit and infarct volume, the levels of glutamate and calcium as well as the levels of inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) were evaluated. Moreover, the expressions of caspase-3, Bcl-2, and Bax were detected by Western blotting. As compared with MCAO group, Punicalagin-treated rats showed dose-dependent reduction in infarct volume and substantial improvement in behavioral deficit. The levels of glutamate, calcium, TNF-α, IL-1β, and IL-6 were restored significantly. The Western blotting results revealed that the expression of Bcl-2 was up-regulated and that of caspase-3, Bax were down-regulated when exposed to Punicalagin.
CONCLUSIONS:
From our results, it can be concluded that Punicalagin showed an ameliorative effect against cerebral I/R injury in rats through its anti-inflammatory, antioxidant actions besides it inhibits excitotoxicity. It also suppresses apoptosis through regulating, Bcl-2, caspase-3, and Bax protein expressions, perhaps another mechanism by which Punicalagin employs its neuroprotective action.

J Stroke Cerebrovasc Dis. 2014 Nov-Dec;23(10):2869-78.

Neuroprotective effect of punicalagin against cerebral ischemia reperfusion-induced oxidative brain injury in rats.[Pubmed: 25282190]

Punicalagin (PG) is a hydrolyzable polyphenol in Punica granatum. It has been previously reported that it has a protective effect against hypoxia-induced ischemia brain injury. It is a potent antioxidant. The present study is aimed to evaluate the antioxidant potential of Punicalagin against focal cerebral ischemia-reperfusion injury in rats subjected to middle cerebral artery occlusion (MCAO).
METHODS AND RESULTS:
Rats were randomly divided into sham, MCAO, Punicalagin -treated groups. Punicalagin (15 and 30 mg/kg) vehicle was administered orally for 7 days before MCAO. Rats were anesthetized with ketamine (100 mg/kg), xylazine (10 mg/kg), and subjected to 2 hours occlusion, and 22 hours reperfusion. Neurologic deficit, brain water content (BWC), histopathology changes, and oxidative stress markers were evaluated after 22 hours of reperfusion. In comparison with MCAO model group, treatment with Punicalagin significantly reduced the neurologic deficit scores and BWC. Punicalagin -attenuated neuronal damage occurred by downregulating the levels of malondialdehyde, sodium-potassium adenosine triphosphatase activity, nitric oxide, protein carbonyl content, and mitochondria-generated reactive oxygen species and upregulating the superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, glutathione reductase activities.
CONCLUSIONS:
Taken together, these results suggested that supplementation of Punicalagin treatment effectively ameliorates the cerebral ischemia/reperfusion induced oxidative damage by virtue of its antioxidant potential.