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Pomegranate (Punica granatum L.) peel is a potential source of bioactive phenolic compounds such as ellagic acid and α- and β-punicalagin. This work explores the efficiency of natural deep eutectic solvents combined with ultrasound-assisted extraction (UAE) and pressurized liquid extraction (PLE) for their extraction. Five NaDESs were evaluated by employing UAE (25 °C, for 50 min) to determine their total phenolic content (Folin–Ciocalteu assay) and ellagic acid and α- and β-punicalagin contents (high-performance liquid chromatography (HPLC-DAD)). The NaDES composed of choline chloride (ChCl) and glycerol (Gly) (1:2, molar ratio) was the most efficient in the UAE when compared with the rest of the NaDESs and water extracts. Therefore, ChCl:Gly was further evaluated using PLE at different temperatures (40, 80, 120 and 160 °C). The PLE-NaDES extract obtained at 80 °C for 20 min at 1500 psi exhibited the highest contents of ellagic acid and α- and β-punicalagin compared to the rest of the temperatures and PLE-water extracts obtained under the same extraction conditions. Combining UAE or PLE with a NaDES emerges as a sustainable alternative for extracting ellagic acid and α- and β-punicalagin from pomegranate peel.

Despite its effectiveness in treating inflammatory diseases and various malignancies, methotrexate (MTX) is well known to cause hepatotoxicity, which involves increased oxidative stress and inflammation, limiting its clinical use. Herein, we looked into the effect of punicalagin (PU), a polyphenolic molecule having a variety of health-promoting attributes, on MTX-induced hepatotoxicity in mice. PU (25 and 50 mg/kg/day) was given orally to the mice for 10 days, while a single dose of MTX (20 mg/kg) was injected intraperitoneally (i.p.) at day 7. The MTX-induced liver damage was demonstrated by remarkably higher transaminases (ALT and AST), ALP, and LDH, as well as significant histological alterations in hepatic tissues. MTX-injected mice also demonstrated increases in hepatic oxidative stress markers, including malondialdehyde (MDA) and nitric oxide (NO), with a concordant drop in glutathione (GSH) content and superoxide dismutase (SOD) and catalase (CAT) activities. PU significantly attenuated the MTX-induced serum transaminases, ALP and LDH elevations, and hepatic oxidative stress measures and boosted antioxidant defenses in the liver. Moreover, the liver of MTX-treated mice showed increases in NF-κB p65 expression, pro-inflammatory cytokine (IL-6 and TNF-α) levels, and pro-apoptotic protein (caspase-3 and Bax) expression, whereas Bcl-2 and Nrf2 expressions were reduced, which were all attenuated by PU treatment. Collectively, PU inhibits oxidative damage, inflammation, and apoptosis and upregulates Nrf2 in the liver of MTX-induced mice. Thus, these findings suggest that PU may have great therapeutic potential for the prevention of MTX-induced hepatotoxicity, pending further exploration in upcoming studies.

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.

Punicalagin is the most bioactive pomegranate polyphenol with high antioxidant and free-radical scavenging activity and can potentially cure different ailments related to the cardiovascular system. The current research work was envisioned to predict the targeting efficiency of punicalagin (PG) nanoparticles to the macrophages, more specifically to bone marrow macrophages. For this, we selected mannose-decorated PLGA-punicalagin nanoparticles (Mn-PLGA-PG), and before formulating this nanocarrier in laboratory settings, we predicted the targeting efficiency of this nanocarrier by in silico analysis. The analysis proceeded with macrophage mannose receptors to be acquainted with the binding affinity and punicalagin-based nanocarrier interactions with this receptor. In silico docking studies of macrophage mannose receptors and punicalagin showed binding interactions on its surface. PG interacted with hydrogen bonds to the charged residue ASP668 and GLY666 and polar residue GLN760 of the Mn receptor. Mannose with a docking score of −5.811 Kcal/mol interacted with four hydrogen bonds and the mannose receptor of macrophage, and in PLGA, it showed a −4.334 Kcal/mol docking score. Further, the analysis proceeded with density functional theory analysis (DFT) and HOMO–LUMO analysis, followed by an extensive 100 ns molecular dynamics simulation to analyse the trajectories showing the slightest deviation and fluctuation. While analysing the ligand and protein interaction, a wonderful interaction was found among the atoms of the ligand and protein residues. This computational study confirms that this nanocarrier could be a promising lead molecule to regulate the incidence of drug-induced neutropenia. Furthermore, experimental validation is required before this can be stated with complete confidence or before human use.

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.

Inflammatory response mediated by activated immune cells is a vital process in host defense system while responding to various stresses. Our previous studies have indicated that pomegranate peel polyphenols (PPPs) and their main components punicalagin (PC) and ellagic acid (EA) decreased pro-inflammatory cytokines and inflammatory mediators by regulating the mitogen-activated protein kinases (MAPKs) pathway, but whether these tested polyphenols play an important role in NF-κB signaling pathway, another crucial pathway of inflammation, remains unclear. In this study, we analyzed the anti-inflammatory effect of these polyphenols via TLR4-NF-κB pathway in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Different concentrations of PPPs, PC, and EA were pre-incubated with RAW264.7 macrophages and then stimulated with LPS (1 μg/mL), and the effects of reactive oxygen species and TLR4 were investigated. Moreover, NF-κB p65 nuclear translocation and phosphorylation, and degradation of IκB were measured by Western blot. Furthermore, the influence of pro-inflammatory cytokines was detected by enzyme-linked immunosorbent assay (ELISA). Our data showed that PPPs, PC, and EA inhibited LPS-induced intracellular ROS production and suppressed the mRNA and protein expression levels of TLR4 in a dose-dependent manner. Moreover, the anti-inflammatory mechanism was involved in blocking LPS-induced phosphorylation, degradation of IκB, and nuclear translocation of p65. Additionally, PPPs and PC exhibited a stronger anti-inflammatory effect than that of EA. The results indicated that PPPs possess potent anti-inflammatory effect, and PC was the main effective component in PPPs, which provided new insights into the utilization of PPPs to prevent inflammation-associated disorders.

Millions of people worldwide are currently afflicted with neurologic conditions like a seizure, depression, stress, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. However, the precise etiopathology of these diseases is still unknown. Substantial studies are being conducted to discover more treatments against these disorders because many patients do not experience the therapeutic benefits that would be expected from using existing pharmaceutical strategies. Herbal medicines which have been used in traditional medicine for millennia to treat various neurological problems are also being investigated and scientifically assessed. Punicalagin is a known polyphenol that has significant antioxidant, anti-inflammatory, anti-viral, anti-proliferative, and anti-cancer properties. Around the world, traditional use of herbal drugs is gaining wider acceptance as a part of complementary and alternative medicine. The scientific community should pay attention to these many neuroprotective pharmacodynamic activities of Punicalagin to create effective pharmacotherapeutic plans, as evidenced by mounting data in pre-clinical research investigations. The current review describes the recent studies on the pharmacological effects of Punicalagin in a variety of neurological illnesses and paves the way for further study in this field.

Background/Aims: Airborne particulate matter with a diameter of < 10 µm (PM10) causes oxidative damage, inflammation, and premature skin aging. In this study, we evaluated whether polyphenolic antioxidants attenuate the inflammatory responses of PM10-exposed keratinocytes. Methods: Primary human epidermal keratinocytes were exposed in vitro to PM10 in the absence or presence of punicalagin and (–)-epigallocatechin-3-gallate (EGCG), which are the major polyphenolic antioxidants found in pomegranate and green tea, respectively. Assays were performed to determine cell viability, production of reactive oxygen species (ROS), and expression of NADPH oxidases (NOX), proinflammatory cytokines, and matrix metalloproteinase (MMP)-1. Results: PM10 decreased cell viability and increased ROS production in a dose-dependent manner. It also increased the expression levels of NOX-1, NOX-2, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-8, and MMP-1. Punicalagin was not cytotoxic up to 300 μM, and (–)-EGCG was cytotoxic above 30 μM, respectively. Further, punicalagin (3–30 μM) and EGCG (3–10 μM) rescued the viability of PM10-exposed cells. They also attenuated ROS production and the expression of NOX-1, NOX-2, TNF-α, IL-1β, IL-6, IL-8, and MMP-1 stimulated by PM10. Conclusions: This study demonstrates that polyphenolic antioxidants, such as punicalagin and (–)-EGCG, rescue keratinocyte viability and attenuate the inflammatory responses of these cells due to airborne particles.

The World Health Organization (WHO) has declared the monkeypox outbreak a public health emergency, as there is no specific therapeutics for monkeypox virus (MPXV) disease. This study focused on docking various commercial drugs and plant-derived compounds against the E8 envelope protein crucial for MPXV attachment and pathogenesis. The target protein structure was modeled based on the vaccinia virus D8L protein. Notably, maraviroc and punicalagin emerged as potential ligands, with punicalagin exhibiting higher binding affinity (− 9.1 kcal/mol) than maraviroc (− 7.8 kcal/mol). Validation through 100 ns molecular dynamics (MD) simulations demonstrated increased stability of the E8-punicalagin complex, with lower RMSD, RMSF, and Rg compared to maraviroc. Enhanced hydrogen bonding, lower solvent accessibility, and compact motions also attributed to higher binding affinity and stability of the complex. MM-PBSA calculations revealed van der Waals, electrostatic, and non-polar solvation as principal stabilizing energies. The binding energy decomposition per residue favored stable interactions between punicalagin and the protein’s active site residues (Arg20, Phe56, Glu228, Tyr232) compared to maraviroc. Overall study suggests that punicalagin can act as a potent inhibitor against MPXV. Further research and experimental investigations are warranted to validate its efficacy and safety.

The search for effective coronavirus disease (COVID-19) therapy has attracted a great deal of scientific interest due to its unprecedented health care system overload worldwide. We have carried out a study to investigate the in silico effects of the most abundant pomegranate peel extract constituents on the multi-step process of serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) internalization in the host cells. Binding affinities and interactions of ellagic acid, gallic acid, punicalagin and punicalin were studied on four selected protein targets with a significant and confirmed role in the process of the entry of virus into a host cell. The protein targets used in this study were: SARS-CoV-2 spike glycoprotein, angiotensin-converting enzyme 2, furin and transmembrane serine protease 2. The results showed that the constituents of pomegranate peel extracts, namely punicalagin and punicalin had very promising potential for significant interactions with the selected protein targets and were therefore deemed good candidates for further in vitro and in vivo evaluation.