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Background and Purpose: Fibrotic lung remodelling after a respiratory viral infection represents a debilitating clinical sequela. Studying or managing viral-fibrotic sequela remains challenging, due to limited therapeutic options and lack of understanding of mechanisms. This study determined whether protein disulfide isomerase A3 (PDIA3) and secreted phosphoprotein 1 (SPP1), which are associated with pulmonary fibrosis, can promote influenza-induced lung fibrotic remodelling and whether inhibition of PDIA3 or SPP1 can resolve viral-mediated fibrotic remodelling., Experimental Approach: A retrospective analysis of TriNetX data sets was conducted. Serum from healthy controls and influenza A virus (IAV)-infected patients was analysed. An inhibitor of PDIA3, punicalagin, and a neutralizing antibody for SPP1 were administered in mice. Macrophage cells treated with macrophage colony-stimulating factor (M-CSF) were used as a cell culture model., Key Results: The TriNetX data set showed an increase in lung fibrosis and decline in lung function in flu-infected acute respiratory distress syndrome (ARDS) patients compared with non-ARDS patients. Serum samples revealed a significant increase in SPP1 and PDIA3 in influenza-infected patients. Lung PDIA3 and SPP1 expression increased following viral infection in mouse models. Punicalagin administration 2 weeks after IAV infection in mice caused a significant decrease in lung fibrosis and improved oxygen saturation. Administration of neutralizing SPP1 antibody decreased lung fibrosis. Inhibition of PDIA3 decreased SPP1secretion from macrophages, in association with diminished disulfide bonds in SPP1., Conclusion and Implications: The PDIA3-SPP1 axis promotes post-influenza lung fibrosis in mice and that pharmacological inhibition of PDIA3 or SPP1 can treat virus-induced lung fibrotic sequela., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The skin acts as a vital barrier, shielding the body from external threats that can trigger dryness, itching, and inflammation. Pilea mongolica, a traditional Chinese medicinal herb, holds promise for various ailments, yet its anti-inflammatory properties remain understudied. This study aimed to explore the potential anti-inflammatory effects of the methanol extract of P. mongolica (MEPM) and its underlying molecular mechanisms and active compounds in LPS-stimulated human keratinocytes. MEPM treatment, at concentrations without cytotoxicity, significantly decreased NO productions and the iNOS, IL-6, IL-1β, and TNF-α levels in LPS-induced HaCaT cells. Moreover, MEPM suppressed IRAK4 expression and phosphorylation of JNK, ERK, p38, p65, and c-Jun, suggesting that the anti-inflammatory effects of MEPM result from the inhibition of IRAK4/MAPK/NF-κB/AP-1 signaling pathway. Through LC/MS/MS analysis, 30 compounds and 24 compounds were estimated in negative and positive modes, respectively, including various anti-inflammatory compounds, such as corilagin and geraniin. Through HPLC analysis, geraniin was found to be present in MEPM at a concentration of 18.87 mg/g. Similar to MEPM, geraniin reduced iNOS mRNA expression and inhibited NO synthesis. It also decreased mRNA and protein levels of inflammatory cytokines, including IL-6 and TNF-α, and inhibited IRAK4 expression and the phosphorylation of MAPKs, NF-κB, and AP-1 pathways. Therefore, it can be inferred that the anti-inflammatory effects of MEPM are attributable to geraniin. Thus, MEPM and its active compound geraniin are potential candidates for use in natural functional cosmetics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is closely associated with the neurotoxic effects of amyloid-β (Aβ), leading to synaptic damage, neuronal loss and cognitive dysfunction. Previous in vitro studies have demonstrated the potential of corilagin to counteract Aβ-induced oxidative stress, inflammatory injury, and β-site amyloid precursor protein cleaving enzyme-1 (BACE1) activity in Aβ production. However, the in vivo protective effects of corilagin on Alzheimer's disease remain unexplored. The purpose of this study was to investigate the protective effects of corilagin on APP/PS1 mice and the underlying mechanisms. The cognitive function of the mice was assessed by step-through passive avoidance and Morris water maze tests. Nissl staining was used to evaluate neuronal damage in the hippocampus. ELISA and Western blotting analyses were used to determine the associated protein expression. Transmission electron microscopy was utilized to observe the synaptic ultrastructure of hippocampal neurons. Golgi staining was applied to assess dendritic morphology and dendritic spine density in hippocampal pyramidal neurons. Immunohistochemistry and Western blotting were performed to examine the expression of synaptic-associated proteins. The results showed that corilagin improves learning and memory in APP/PS1 mice, reduces hippocampal neuron damage, inhibits BACE1 and reduces Aβ generation. It also improves synaptic plasticity and the expression of synaptic-associated proteins. Corilagin effectively reduces Aβ generation by inhibiting BACE1, ultimately reducing neuronal loss and enhancing synaptic plasticity to improve synaptic transmission. This study sheds light on the potential therapeutic role of corilagin in Alzheimer's disease., Competing Interests: Declaration of competing interest No conflicts of interest are declared by the authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Parasitic infections impose a significant burden on public health worldwide. European pharmacopoeia records and ethnopharmacological studies indicate that Hagenia abyssinica (Bruce) J.F. Gmel. has traditionally been used to treat a variety of parasitic infections, while the potential antiparasitic compounds remain ambiguous., Aim of the Study: Acetylcholinesterase (AChE), lactate dehydrogenases (LDH), and glutathione reductase (GR) are the key target enzymes in the survival of parasites. The aim of our work was to screen antiparasitic compounds targeting AChE, LDH, and GR from H. abyssinica., Materials and Methods: Ultrafiltration-liquid chromatography-mass spectrometry (UF-LC-MS) combined with molecular docking was used in this study. Therein, the alamarBlue® and Ellman's methods were employed to reveal the antitrypanosomal effect and AChE inhibitory activity. Meanwhile, the UF-LC-MS was carried out to screen the potential active compounds from H. abyssinica. Subsequently, molecular docking was performed to evaluate the binding mechanisms of these active compounds with AChE, LDH, and GR. Finally, the AChE inhibitory activity of potential inhibitors was detected in vitro., Results: H. abyssinica exhibited significant antitrypanosomal and AChE inhibitory activity. Corilagin, brevifolin carboxylic acid, brevifolin, quercetin, and methyl ellagic acid were recognized as potential AChE inhibitors by UF-LC-MS, while methyl brevifolin carboxylate was identified as AChE, LDH, and GR multi-target inhibitor, with binding degree ranged from 20.96% to 49.81%. Molecular docking showed that these potential inhibitors had a strong affinity with AChE, LDH, and GR, with binding energies ranging from -6.98 to -9.67 kcal/mol. These findings were further supported by the observation that corilagin, quercetin, brevifolin carboxylic acid, and methyl brevifolin carboxylate displayed significant AChE inhibitory activity compared with the positive control (gossypol, 0.42 ± 0.04 mM), with IC 50 values of 0.15 ± 0.05, 0.56 ± 0.03, 0.99 ± 0.01, and 1.02 ± 0.03 mM, respectively., Conclusions: This study confirms the antiparasitic potential of H. abyssinica, supporting the traditional use of H. abyssinica in local ethnopharmacology to treat parasites. At the same time, corilagin, brevifolin carboxylic acid, brevifolin, quercetin, methyl ellagic acid, and methyl brevifolin carboxylate exert their anti-parasitic effects by inhibiting AChE, LDH, and GR, and they are expected to be natural lead compounds for the treatment of parasitic diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aryl hydrocarbon receptor (AhR) plays an important role in inflammation and immunity as a new therapeutic target for infectious disease and sepsis. Punicalagin (PUN) is a Chinese herbal monomer extract of pomegranate peel that has beneficial anti-inflammatory, antioxidant and anti-infective effects. However, whether PUN is a ligand of AhR, its effect on AhR expression, and its signaling pathway remain poorly understood. In this study, we found that PUN was a unique polyphenolic compound that upregulated AhR expression at the transcriptional level, and regulated the AhR nongenomic pathway. AhR expression in lipopolysaccharide-induced macrophages was upregulated by PUN in vitro and in vivo in a time- and dose-dependent manner. Using specific inhibitors and siRNA, induction of AhR by PUN depended on sequential phosphorylation of 90-kDa ribosomal S6 kinase (p90RSK), which was activated by the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and phosphoinositide-dependent protein kinase (PDK)1 pathways. PUN promoted p90RSK-mediated activator protein-1 (AP-1) activation. AhR knockout or inhibitors reversed suppression of interleukin (IL)-6 and IL-1β expression by PUN. PUN decreased Listeria load and increased macrophage survival via AhR upregulation. In conclusion, we identified PUN as a novel selective AhR modulator involved in AhR expression via the MEK/ERK and PDK1 pathways targeting p90RSK/AP-1 in inflammatory macrophages, which inhibited macrophage inflammation and promoted bactericidal activity., (© 2024. The Author(s).)

Background: Manganism, a central nervous system dysfunction correlated with neurological deficits such as Parkinsonism, is caused by the substantial collection of manganese chloride (MnCl 2 ) in the brain., Objectives: To explore the neuroprotective effects of natural compounds, namely, micronized zeolite clinoptilolite (ZC) and punicalagin (PUN), either individually or in combination, against MnCl 2 -induced Parkinson's disease (PD)., Methods: Fifty male albino rats were divided into 5 groups (Gps). Gp I was used as the control group, and the remaining animals received MnCl 2 (Gp II-Gp V). Rats in Gps III and IV were treated with ZC and PUN, respectively. Gp V received both ZC and PUN as previously reported for the solo-treated plants., Results: ZC and/or PUN reversed the depletion of monoamines in the brain and decreased acetyl choline esterase activity, which primarily adjusted the animals' behavior and motor coordination. ZC and PUN restored the balance between glutamate/γ-amino butyric acid content and markedly improved the brain levels of brain-derived neurotrophic factor and nuclear factor erythroid 2-related factor 2/heme oxygenase-1 and decreased glycogen synthase kinase-3 beta activity. ZC and PUN also inhibited inflammatory and oxidative markers, including nuclear factor kappa-light-chain-enhancer of activated B cells, Toll-like receptor 4, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 and caspase-1. Bcl-2-associated X-protein and B-cell leukemia/lymphoma 2 protein (Bcl-2) can significantly modify caspase-3 expression. ZC and/or PUN ameliorated PD in rats by decreasing the levels of endoplasmic reticulum (ER) stress markers (p-protein kinase-like ER kinase (PERK), glucose-regulated protein 78, and C/EBP homologous protein (CHOP)) and enhancing the levels of an autophagy marker (Beclin-1)., Discussion and Conclusion: ZC and/or PUN mitigated the progression of PD through their potential neurotrophic, neurogenic, anti-inflammatory, antioxidant, and anti-apoptotic activities and by controlling ER stress through modulation of the PERK/CHOP/Bcl-2 pathway., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background and Purpose: Diabetic retinopathy (DR) is a prevalent complication of diabetes, with a rising global incidence, and can result in significant vision impairment and potential blindness in adults. Corilagin (COR) has been shown to regulate several pathological processes. However, the specific protective role and mechanism of action of COR in DR remain unknown., Experimental Approach: The protective effects and mechanisms of COR in DR were examined using the ARPE-19 cell line and C57BL/6 mice. Intraretinal tissue damage and molecular markers were evaluated to investigate the impact of COR on oxidative stress and cell death pathways., Key Results: In vitro, COR significantly reduced the cytotoxic effects of high glucose (HG) on ARPE-19 cells. Furthermore, COR also effectively decreased HG-induced lipid peroxidation, iron deposition, and ferroptosis and reduced damage to retinal tight junction proteins. Similarly, an in vivo study of streptozotocin (STZ)-induced DM mice showed that the daily gavage of COR for eight weeks notably alleviated DR. Mechanistically, COR activated the Nrf2 antioxidant signaling pathway both in vivo and in vitro, preventing HG-induced alterations in morphological and biochemical parameters. Notably, our study demonstrated that compared with controls, Nrf2 knockout mice and siNrf2-treated cells were more vulnerable to ferroptosis under HG conditions, and the protective effect of COR on DR was substantially diminished in these models., Conclusion and Implications: These data indicate that COR has a protective effect against HG-induced retinal injury via a mechanism associated with the Nrf2-dependent antioxidant pathway and ferroptosis regulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Oenothein B (OeB), a dimeric ellagitannin with a macrocyclic structure, is reported to have beneficial effects, including antioxidant, antitumor, antiviral, and antimutagenic effects, on human health. Despite the remarkable properties of OeB, its role in neovascularization process has not yet been evaluated. Thus, this study aimed to evaluate the angiogenic activity of OeB using a chorioallantoic membrane (CAM) assay at different concentrations (6.25, 12.5, and 25 μg/μL), employing digital imaging and histological analysis. Furthermore, to elucidate the mechanisms by which OeB influences angiogenesis, we assessed the levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) in CAM using immunohistochemical analysis. All concentrations of OeB significantly increased (p < 0.05) the percentage of vascularization as well as the levels of all the angiogenesis-associated parameters evaluated, indicating the pronounced pro-angiogenic activity of OeB. Our results showed that inflammation was one of the most relevant phenomena observed in CAM histology along with angiogenesis. In addition, a significant increase in VEGF and TNF-α levels was observed in all the CAMs compared to the negative control (p < 0.05). We suggest that OeB may induce the presence of inflammatory cells in CAM, leading to increased VEGF and TNF-α levels that result in the induction of angiogenesis. Therefore, OeB presents a favorable profile that could be further explored for the development of drugs for pro-angiogenic and tissue repair therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

PDIA3 is a pleiotropic protein primarily located in the endoplasmic reticulum where it is involved in protein folding, catalyzing the formation, breakage, and rearrangement of disulfide bonds. PDIA3 is implicated in numerous pathologies such as cancer, inflammation, and neurodegeneration. Although punicalagin has been proven to be a highly promising PDIA3 inhibitor and can be used as target protein in glioblastoma, it does not have sufficient selectivity for PDIA3 and is a quite-large molecule. With the aim of finding punicalagin derivatives with a simplified structure, we selected punicalin, which lacks the hexahydroxy-diphenic acid moiety. Previous docking studies suggest that this part of the molecule is not involved in the binding with PDIA3. In this study we compared the ability of punicalin to bind and inhibit PDIA3 and PDIA1. Tryptophan fluorescence quenching and disulfide reductase activity (using both glutathione and insulin as substrates) were evaluated, demonstrating the ability of punicalin to bind and inhibit PDIA3 even to a lesser extent compared to punicalagin. On the other hand, punicalin showed a very low inhibition activity towards PDIA1, demonstrating a higher selectivity for PDIA3. Protein thermal shift assay evidenced that both proteins can be destabilized by punicalin as well as punicalagin, with PDIA3 much more sensitive. Additionally, punicalin showed a higher change in the thermal stability of PDIA3, with a shift up to 8 °C. This result could explain the presence of PDIA3 aggregates, evidenced by immunofluorescence analysis, that accumulate within treated cells and that are more evident in the presence of punicalin. The results here obtained show punicalin is able to bind both proteins but with a higher selectivity for PDIA3, suggesting the possibility of developing new molecules with a simplified structure that are still able to selectively bind and inhibit PDIA3.

Background: The cGAS-STING pathway is an important component of the innate immune system and plays significant role in acetaminophen-induced liver injury (AILI). Pentagalloylglucose (PGG) is a natural polyphenolic compound with various beneficial effects, including anti-cancer, antioxidant, anti-inflammatory, and liver-protective properties; however, whether it can be used for the treatment of AILI and the specific mechanism remain unclear., Materials and Methods: A cell culture model was created to study the effect of PGG on cGAS-STING pathway activation using various techniques including western blotting (WB), real-time quantitative polymerase chain reaction (RT-qPCR), immunofluorescence (IF), and immunoprecipitation (IP). The effect of PGG was investigated in vivo by establishing a dimethylxanthenone acetic acid (DMXAA)-mediated activation model. An AILI model was used to evaluate the hepatoprotective and therapeutic effects of PGG by detecting liver function indicators, liver histopathology, and cGAS-STING pathway-related indicators in mice with AILI., Results: PGG blocked cGAS-STING pathway activation in bone marrow-derived macrophages (BMDMs), THP-1 cells, and peripheral blood mononuclear cells (PBMCs) in vitro. Furthermore, PGG inhibited the generation of type I interferons (IFN-I) and the secretion of inflammatory factors in DMXAA-induced in vivo experiments. In addition, PGG also reduced serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), improved liver tissue damage and apoptosis, and inhibited the cGAS-STING pathway activation caused by acetaminophen. In terms of the mechanism, PGG disrupted the connection between STING and TBK1., Conclusions: PGG exerts a protective effect against AILI by blocking the cGAS-STING pathway, offering a promising treatment strategy., (© 2024. The Author(s).)

Androgenetic alopecia (AGA) is the leading cause of hair loss in adults. Its pathogenesis remains unclear, but studies have shown that the androgen-mediated 5α-reductase-AR receptor pathway and the Wnt/β-catenin signaling pathway play significant roles. Camellia oleifera is an oil plant, and its fruits have been documented in folklore as having a hair cleansing effect and preventing hair loss. In this study, we used UPLC-Q-TOF-MS/MS to identify the structure of the substances contained in the polyphenols of Camellia oleifera seed shell. These polyphenols are mainly used for shampooing and anti-hair loss purposes. Next, we used molecular docking technology to dock 41 polyphenols and steroidal 5 alpha reductase 2 (SRD5A2). We found that the docking scores and docking sites of 1,3,6-tri-O-galloylglucose (TGG) and finasteride were similar. We constructed a mouse model of DHT-induced AGA to evaluate the effects of Camellia oleifera seed shell polyphenols (CSSP) and TGG in vivo. Treatment with CSSP and TGG alleviated alopecia symptoms and reduced DHT levels. Additionally, CSSP and TGG were able to reduce androgen levels by inhibiting the SRD5A2-AR receptor signaling pathway. Furthermore, by regulating the secretion of growth factors and activating the Wnt/β-catenin signaling pathway, CSSP and TGG were able to extend the duration of hair growth. In conclusion, our study showed that CSSP and TGG can improve AGA in C57BL/6 J mice and reduce the effect of androgen on hair follicle through the two signaling pathways mentioned above. This provides new insights into the material basis and mechanism of the treatment of AGA by CSSP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cancer remains a global health challenge, necessitating the exploration of novel therapeutic agents. Current treatment options are unable to overwhelm and cure the cancer burden. Hence, identifying new bioactive molecular entities with potent anticancer activity is the need of the hour. Ellagitannin Geraniin (GN) is one such evidence-based novel bioactive molecular entity (BME) available from different natural sources that can effectively combat cancer. This narrative review attempts to investigate the potential of BME-GN from 2005 to 2023 as an efficient molecular anti-cancer therapeutic against diverse cancers. We provide information on GN's pharmacological advantages, metabolite profile, and capacity to modulate multiple molecular targets involved in the hallmarks of cancer. Using the search terms "Geraniin," "Gallic acid," "Ellagitannin," "pharmacological properties," "health," "antioxidant," "apoptosis," "disease management," "anti-proliferative," "in vitro," "anti-inflammatory," "anti-angiogenic," "in vivo," and "clinical trials," We searched the scientific literature using Scopus, Web of Science, Google Scholar, and PubMed. We removed publications that included overlap or equivalent content and used the most recent review on each issue as our primary reference. From an initial pool of 430 articles, 52 studies met the search criteria. These studies collectively provide substantial in vitro, in vivo, and clinical evidence of GN's potential to combat diverse cancers. Mechanistic insights revealed its involvement in fostering apoptosis, anti-inflammatory, and modulation of key signalling pathways implicated in the hallmarks of cancer. GN's pleiotropic pharmacological and molecular therapeutic properties strongly suggest its potential as a promising anticancer agent., Competing Interests: Declaration of competing interest The authors report no financial or other conflicts of interest in this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The current study aimed to evaluate the preventive effects of urolithin C (Uro C), a gut microbial metabolite of ellagitannins on D-galactose (D-gal)-induced brain damage during the aging process and to elucidate the underlying mechanisms. In our study, the protective effect of Uro C on D-gal-induced BV2 microglia cell-mediated neuroinflammation damage in primary cortical neurons in vitro was confirmed. The results in an aging model in vivo induced by D-gal demonstrated that Uro C prevented D-gal-induced memory impairment, long-term potentiation (LTP) damage, and synaptic dysfunction through behavioral, electrophysiological, and histological examinations. Additionally, amyloidogenesis was observed in the central nervous system. The findings indicated that Uro C exhibited a preventive effect on the D-gal-induced elevation of β-amyloid (1-42 specific) (Aβ 1-42 ) accumulation, APP levels, ABCE1 levels, and the equilibrium of the cholinergic system in the aging mouse brain. Moreover, Uro C demonstrated downregulation of D-gal-induced glial overactivation through inhibition of the MAPK/NF-kB pathway. This resulted in the regulation of inflammatory mediators and cytokines, including iNOS, IL-6, IL-1β, and TNF-ɑ, in the mouse brain and BV2 microglial cells. Taken together, our results suggested that Uro C treatment could effectively mitigate the D-gal-induced memory impairment and amyloidogenesis, and the underlying mechanism might be tightly related to the improvement of neuroinflammation by suppressing the MAPK/NF-kB pathway, indicating Uro C might be an alternative and promising agent for the treatment of aging and age-associated brain diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., (© 2024. The Author(s).)

Castanea sativa Mill. ( C. sativa ) processing and pruning generate several by-products, including leaves, burs, and shells (inner and outer teguments), which are considered an important source of high-value phytochemicals. Ellagitannins from C. sativa leaf extracts have been described to impair H. pylori viability and inflammation in gastric cells. Furthermore, chestnut shells showed an important anti-inflammatory effect in gastric epithelial cells. Dietary polyphenols, including tannins, have been reported to interfere with targets of inflammation, including the nuclear factor κB (NF-κB). A promising role as a further therapeutical target for gut disorders has been recently proposed for the regulatory subunit of hypoxia-inducible factor (HIF-1α), as a potential stabilizer of intestinal barrier integrity. Therefore, the main objective of this work is the chemical characterization of several chestnut by-products (bud, spiny bur, wood, pericarp and episperm), together with the exploitation of their anti-inflammatory properties in intestinal cells, scavenging capacity, and stability following gastrointestinal digestion. The chemical characterization confirmed the presence of bioactive polyphenols in the extracts, including ellagitannins. In CaCo-2 cells stimulated by an IL-1β-IFN-γ cocktail, nearly all chestnut by-products (50 µg/mL) inhibited the release of proinflammatory mediators (CXCL-10, IL-8, MCP-1, ICAM), along with the NF-κB-driven transcription, and induced the HRE-driven transcription. The stability of the most promising extracts, identified through PCA and cluster analysis, was addressed by in vitro gastrointestinal digestion. Despite the significant reduction in total polyphenol index of chestnut bud and wood after gastric and intestinal digestion, the activity of these extracts on both scavenging and anti-inflammatory parameters remained promising. These data contribute to exploit the potential of chestnut by-products as sources of dietary polyphenols with anti-inflammatory properties at the intestinal level. Moreover, this study could represent an important step to encourage the recycling and valorization of chestnut by-products, promoting the circular economy and reducing the environmental impact related to the management of agriculture waste.

Dementia treatment has become a global research priority, driven by the increase in the aging population. Punicalagin, the primary polyphenol found in pomegranate fruit, exhibits a variety of benefits. Today, a growing body of research is showing that punicalagin is a nutraceutical for the prevention of mild cognitive impairment (MCI). However, a comprehensive review is still lacking. The aim of this paper is to provide a comprehensive review of the physicochemical properties, origin and pharmacokinetics of punicalagin, while emphasizing the significance and mechanisms of its potential role in the prevention and treatment of MCI. Preclinical and clinical studies have demonstrated that Punicalagin possesses the potential to effectively target and enhance the treatment of MCI. Potential mechanisms by which punicalagin alleviates MCI include antioxidative damage, anti-neuroinflammation, promotion of neurogenesis, and modulation of neurotransmitter interactions. Overall, punicalagin is safer and shows potential as a therapeutic compound for the prevention and treatment of MCI, although more rigorous randomized controlled trials involving large populations are required., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The pursuit of renewable and eco-friendly raw materials for biobased materials is a growing field. This study utilized ellagitannin and cellulose microfibrils derived from rambutan peel waste alongside gelatin to develop eco-conscious hydrogels. The cellulose/gelatin hydrogels were formulated in two weight ratios (0.5:1 to 1:1), and the influence of gelatin on the chemical composition and rheology was studied. Composite hydrogels, functionalized with an ellagitannin-rich extract, exhibited a remarkable enhancement of up to 14-fold in compressive strength. The hydrogels also demonstrated antimicrobial properties, reducing the Staphylococcus aureus colony count within 24 h. The hydrogel, derived from rambutan peel waste, is biocompatible and could potentially be explored for biomedical applications such as drug delivery systems, and wound dressings. This suggests that it might offer significant value for sustainable materials science, although specific applications have yet to be tested.

Peri-menopausal discomfort can have a detrimental effect on the physical health of women due to physiological and behavioral changes. Estrogen and progesterone-based hormone therapy can alleviate menopausal symptoms, but estrogen supplementation may have negative health effects. The effectiveness of hormone replacement therapy using natural compounds for peri-menopausal disorders is still uncertain. Evidence from in vivo experiments indicates that Ferula L. extract in ovariectomized rats leads to better sexual behavior. The effect seems to be linked to the phytoestrogenic properties of ferutinin, the primary bioactive compound in the extract. The purpose of this study was to assess the clinical impact of Ferula communis L. extract (titrated at 20% ferutinin, and given at doses of 100 mg/die for 90 days) on the quality of life of 64 menopausal women. The clinical trial was randomized, double-blind, and placebo controlled. Our data showed that Ferula communis L. extract reduced by 67 + 9% all symptoms associated to postmenopausal discomfort and enhanced significantly sexual behavior. In addition, the supplement led to a significant improvement of BMI and oxidative stress decrease in the women who received it, while also keeping platelet aggregation within normal levels. Overall, these results could point to the potential use of supplementation with Ferula communis L. extract to revert or mitigate menopause dysfunction.

Context The overproduction of reactive oxygen species (ROS) during in vitro culture of ovarian tissues impairs follicular development and survival. Aims To evaluate the effects of punicalagin on the development and survival of primordial follicles, stromal cell and collagen fibres, as well as on the levels of mRNA for nuclear factor erythroid 2-related factor 2 (NRF2 ), superoxide dismutase 1 (SOD1 ), catalase (CAT ), glutathione peroxidase 1 (GPX1 ) and perirredoxin 6 (PRDX6 ), and activity of antioxidant enzymes in cultured bovine ovarian tissues. Methods Bovine ovarian cortical tissues were cultured for 6days in α-MEM+ alone or with 1.0, 10.0, or 100.0μM punicalagin at 38.5°C with 5% CO2 . Follicle morphology and growth, stromal cell density, and collagen fibres were evaluated by classical histology, while the expression of mRNA was evaluated by real-time PCR. The activity of enzymes was analysed by the Bradford method. Key results Punicalagin improved follicle survival and development, reduced mRNA expression for SOD1 and CAT , but did not influence stromal cells or collagen fibres. Punicalagin (10.0μM) increased the levels of thiol and activity of SOD1, CAT , and GPX1 enzymes. Conclusions Punicalagin (10.0μM) promotes follicle survival and development and activates SOD1, CAT , and GPX1 enzymes in bovine ovarian tissues. Implications Punicalagin improves follicle development and survival in cultured ovarian tissues.

Non-alcoholic fatty liver disease (NAFLD), obesity and related chronic diseases are major non-communicable diseases with high mortality rates worldwide. While dietary sugars are known to be responsible for insulin resistance and metabolic syndrome (MetS), the underlying pathophysiological effects of sustained fructose consumption require further elucidation. We hypothesize that certain bioactive compounds ( i.e. punicalagin and ellagic acid) from dietary pomegranate could counteract the harmful effects of sustained fructose consumption in terms of obesity and liver damage. The present study aimed to elucidate both the molecular mechanisms involved in the pathophysiology associated with fructose intake and the effect of a punicalagin-rich commercial pomegranate dietary supplement (P) used as a nutritional strategy to alleviate fructose-induced metabolic impairments. Thus, nineteen Wistar rats fed on a basal commercial feed were supplemented with either 30% (w/v) fructose in drinking water (F; n = 7) or 30% (w/v) fructose solution plus 0.2% (w/v) P (F + P; n = 6) for 10 weeks. The results were compared to those from a control group fed on the basal diet and provided with drinking water (C; n = 6). Body weight and energy intake were registered weekly. P supplementation decreased fat depots, counteracted the dyslipidemia caused by F and improved markers of liver injury including steatosis. The study of the microbiota by metagenomics and urine by untargeted MS-based metabolomics revealed microbial metabolites from P that may be responsible for these health benefits.

Nature has been a rich source of pharmaceutical compounds, producing 80% of our currently prescribed drugs. The feijoa plant, Acca sellowiana, is classified in the family Myrtaceae, native to South America, and currently grown worldwide to produce feijoa fruit. Feijoa is a rich source of bioactive compounds with anticancer, anti-inflammatory, antibacterial, and antifungal activities; however, the mechanism of action of these compounds is largely not known. Here, we used chemical genetic analyses in the model organism Saccharomyces cerevisiae to investigate the mechanism of action of a feijoa-derived ethanol adduct of vescalagin (EtOH-vescalagin). Genome-wide barcode sequencing analysis revealed yeast strains lacking genes in iron metabolism, zinc metabolism, retromer function, or mitochondrial function were hypersensitive to 0.3 µM EtOH-vescalagin. This treatment increased expression of iron uptake proteins at the plasma membrane, which was a compensatory response to reduced intracellular iron. Likewise, EtOH-vescalagin increased expression of the Cot1 protein in the vacuolar membrane that transports zinc into the vacuole to prevent cytoplasmic accumulation of zinc. Each individual subunit in the retromer complex was required for the iron homeostatic mechanism of EtOH-vescalagin, while only the cargo recognition component in the retromer complex was required for the zinc homeostatic mechanism. Overexpression of either retromer subunits or high-affinity iron transporters suppressed EtOH-vescalagin bioactivity in a zinc-replete condition, while overexpression of only retromer subunits increased EtOH-vescalagin bioactivity in a zinc-deficient condition. Together, these results indicate that EtOH-vescalagin bioactivity begins with extracellular iron chelation and proceeds with intracellular transport of zinc via the retromer complex. More broadly, this is the first report of a bioactive compound to further characterize the poorly understood interaction between zinc metabolism and retromer function., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

In this study, we developed punicalagin-loaded antimicrobial films based on soy protein isolate (SPI) and apple pectin (AP). The AP was derived from apple pomace waste while the punicalagin was obtained from pomegranate peel. Punicalagin was identified to exist in both α- and β-isomers, with the β-type being predominant. The composite films were characterized using scanning electron microscopy, Fourier transformed infrared spectroscopy, X-ray diffraction, and thermogravimetric analysis. Our results demonstrated that the incorporation of AP significantly enhanced the mechanical strength, heat resistance, and barrier properties of the films. Moreover, the composite films integrated with punicalagin exhibited excellent antimicrobial activities against Staphylococcus aureus (with a minimum bactericidal concentration value of 0.25 %), Escherichia coli (with a minimum bactericidal concentration value of 0.50 %), and Aspergillus niger. Finally, these antimicrobial film solutions were tested as coatings on strawberries and found to have significantly better effects on reducing weight loss, improving shelf-life, and maintaining the freshness of strawberries compared to coatings without punicalagin. The results indicate that antimicrobial coatings loaded with punicalagin hold great promise as multifunctional active packaging materials for fruit preservation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background : Inflammatory bowel disease (IBD) is an increasing health burden worldwide. Punicalagin, a bioactive component rich in pomegranate rind, has been shown to attenuate chemical or bacteria-induced experimental colitis in mice, but whether punicalagin exerts its function through modulating gut microbiota and metabolites remains unexplored. Results : Punicalagin (100 mg per kg per day) administered orally to mice alleviated dextran-sodium sulfate (DSS)-induced colitis. Gut microbiota analyzed by 16S rRNA sequencing showed that punicalagin altered gut microbiota by increasing the Lachnospiraceae&#95;NK4A136&#95;group and Bifidobacterium abundance. To evaluate the effect of punicalagin-modulated microbiota and its metabolites in colitis mice, we transplanted fecal microbiota and sterile fecal filtrate (SFF) to mice treated with oral antibiotics. The results of fecal microbiota transplantation (FMT) demonstrated that punicalagin's anti-colitic effect is transferable by transplanting punicalagin-modulated gut microbiota and its metabolites. Additionally, we discovered that punicalagin-modulated sterile fecal filtrate also exhibits anti-colitis effects, as evidenced by improved intestinal barrier integrity and decreased inflammation. Subsequently, fecal metabolites were analyzed using liquid chromatography-mass spectrometry (LC-MS). The analysis revealed that punicalagin significantly increased the level of D-ribose. In vitro experiments showed that D-ribose has both anti-inflammatory and antioxidant properties. Furthermore, D-ribose significantly mitigated DSS-induced colitis symptoms in mice. Conclusions : Overall, this study demonstrated that gut microbiota and its metabolites partly mediate the protective effect of punicalagin against DSS-induced colitis in mice. D-ribose is a key metabolite that contributes to the anti-colitic effect of punicalagin in mice.

In this study, we present data on the effects of condensed tannins (CTs) and hydrolysable tannins (HTs), polyphenols extracted from plants, at different concentrations on zebrafish development to identify the range of concentrations with toxic effects. Zebrafish embryos were exposed to CTs and HTs at two different concentration ranges (5.0-20.0 μgL -1 and 5.0-20.0 mgL -1 ) for 72 h. The toxicity parameters were observed up to 72 h of treatment. The uptake of CTs and HTs by the zebrafish larvae was assessed via HPLC analysis. A qRT-PCR analysis was performed to evaluate the expressions of genes cd63 , zhe1 , and klf4 , involved in the hatching process of zebrafish. CTs and HTs at 5.0, 10.0, and 20.0 μgL -1 were not toxic. On the contrary, at 5.0, 10.0, and 20.0 mgL -1 , HTs induced a delay in hatching starting from 48 h of treatment, while CTs showed a delay in hatching mainly at 48 h. The analysis of gene expression showed a downregulation in the group exposed to HTs, confirming the hatching data. We believe that this study is important for defining the optimal doses of CTs and HTs to be employed in different application fields such as the chemical industry, the animal feed industry, and medical science.

Androgen-receptor-negative, androgen-independent (AR neg -AI) prostate cancer aggressively proliferates and metastasizes, which makes treatment difficult. Hence, it is necessary to continue exploring cancer-associated markers, such as oncofetal Receptor Tyrosine Kinase like Orphan Receptor 1 (ROR1), which may serve as a form of targeted prostate cancer therapy. In this study, we identify that Penta-O-galloyl-β-D-glucose (PGG), a plant-derived gallotannin small molecule inhibitor, modulates ROR1-mediated oncogenic signaling and mitigates prostate cancer phenotypes. Results indicate that ROR1 protein levels were elevated in the highly aggressive AR neg -AI PC3 cancer cell line. PGG was selectively cytotoxic to PC3 cells and induced apoptosis of PC3 (IC 50 of 31.64 µM) in comparison to normal prostate epithelial RWPE-1 cells (IC 50 of 74.55 µM). PGG was found to suppress ROR1 and downstream oncogenic pathways in PC3 cells. These molecular phenomena were corroborated by reduced migration, invasion, and cell cycle progression of PC3 cells. PGG minimally and moderately affected RWPE-1 and AR neg -AI DU145, respectively, which may be due to these cells having lower levels of ROR1 expression in comparison to PC3 cells. Additionally, PGG acted synergistically with the standard chemotherapeutic agent docetaxel to lower the IC 50 of both compounds about five-fold (combination index = 0.402) in PC3 cells. These results suggest that ROR1 is a key oncogenic driver and a promising target in aggressive prostate cancers that lack a targetable androgen receptor. Furthermore, PGG may be a selective and potent anti-cancer agent capable of treating ROR1-expressing prostate cancers.

We report the first total synthesis of scleropentaside D, a unique C -glycosidic ellagitannin, from the ketal derivative of scleropentaside A employing site-selective O4-protection of C -acyl glycoside and copper-catalyzed oxidative coupling reaction of galloyl groups as the key steps. Our study confirms the proposed structure of this natural product, scleropentaside D, and demonstrates its effectiveness as an inhibitor of α-glycosidase.

The management of gastrointestinal disease in animals represents a significant challenge in veterinary and zootechnic practice. Traditionally, acute symptoms have been treated with antibiotics and high doses of zinc oxide (ZnO). However, concerns have been raised regarding the potential for microbial resistance and ecological detriment due to the excessive application of this compound. These concerns highlight the urgency of minimizing the use of ZnO and exploring sustainable nutritional solutions. Hydrolysable tannins (HTs), which are known for their role in traditional medicine for acute gastrointestinal issues, have emerged as a promising alternative. This study examined the combined effect of food-grade HTs and subtherapeutic ZnO concentration on relevant biological functions of Caco-2 cells, a widely used model of the intestinal epithelial barrier. We found that, when used together, ZnO and HTs (ZnO/HTs) enhanced tissue repair and improved epithelial barrier function, normalizing the expression and functional organization of tight junction proteins. Finally, the ZnO/HTs combination strengthened enterocytes' defense against oxidative stress induced by inflammation stimuli. In conclusion, combining ZnO and HTs may offer a suitable and practical approach for decreasing ZnO levels in veterinary nutritional applications.

Diabetic liver injury (DLI) is one of the complications of diabetes mellitus, which seriously jeopardizes human health. Punicalagin (PU), a polyphenolic compound mainly found in pomegranate peel, has been shown to ameliorate metabolic diseases such as DLI, and the mechanism needs to be further explored. In this study, a HFD/STZ-induced diabetic mouse model is established to investigate the effect and mechanism of PU on DLI. The results show that PU intervention significantly improves liver histology and serum biochemical abnormalities in diabetic mice, significantly inhibits the expression of pyroptosis-related proteins such as NLRP3, Caspase1, IL-1β, and GSDMD in the liver of diabetic mice, and up-regulated the expression of autophagy-related proteins. Meanwhile, PU treatment significantly increases FoxO1 protein expression and inhibits TXNIP protein expression in the liver of diabetic mice. The above results are further verified in the HepG2 cell injury model induced by high glucose. AS1842856 is a FoxO1 specific inhibitor. The intervention of AS1842856 combined with PU reverses the regulatory effects of PU on pyroptosis and autophagy in HepG2 cells. In conclusion, this study demonstrates that PU may inhibit pyroptosis and upregulate autophagy by regulating FoxO1/TXNIP signaling, thereby alleviating DLI., (© 2024 Wiley‐VCH GmbH.)

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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Recently, geraniin has been identified as a potent antiviral agent targeting SARS-CoV-2 main protease (Mpro). Considering the potential of geraniin in COVID-19 treatment, a stringent validation for its Mpro inhibition is necessary. Herein, we rigorously evaluated the in vitro inhibitory effect of geraniin on Mpro using the fluorescence resonance energy transfer (FRET), fluorescence polarization (FP), and dimerization-dependent red fluorescent protein (ddRFP) assays. Our data indicate that geraniin is not a potential inhibitor against Mpro based on the results from a set of in vitro assays. These results suggest a stringent in vitro validation with diverse biochemical assays is essential for the discovery of Mpro inhibitors, and the fluorescence quenching effect caused by natural products should be considered when evaluating Mpro inhibitors.

Residues ASN94 and GLN41 presented the highest frequency in molecular docking tests. The geraniin-glycoprotein D(gD) complexes was stable with RMSD(root mean square deviation)value less than 0.3 nm. The Molecular dynamic (MD) simulations revealed stable hydrogen bonds between gD and geraniin. Root mean square fluctuation (RMSF) values were less than 0.15 nm around the interface of geraniin-gD complex. In virucidal assays showed a much higher anti-HSV-2 inhibition activity of geraniin as compared to acyclovir(ACV).Human immunodeficiency virus transactivator (HIV-TAT) treatment significantly enhanced HSV-2 replication and lethal effect on HaCaT cells. The inhibitory rate of geraniin against HSV-2 coinfected with HIV-TAT was significantly decreased. The immunofluorescence results also revealed that HSV-2 gD expression presented a green fluorescence on HaCaT cells membranes and showed clear downregulation in geraniin-treated cells, but was expressed clearly on cell membranes under geraniin, HSV-2 and HIV-TAT cotreatment. The anti-apoptotic effect from geraniin persisted after 72 h, while the anti-apoptotic effect from geraniin diminished when HIV-TAT and geraniin were combined.

Introduction: Atherosclerosis, a leading cause of global cardiovascular mortality, is characterized by chronic inflammation. Central to this process is the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, which significantly influences atherosclerotic progression. Recent research has identified that the olfactory receptor 2 (Olfr2) in vascular macrophages is instrumental in driving atherosclerosis through NLRP3- dependent IL-1 production., Methods: To investigate the effects of Corilagin, noted for its anti-inflammatory attributes, on atherosclerotic development and the Olfr2 signaling pathway, our study employed an atherosclerosis model in ApoE -/- mice, fed a high-fat, high-cholesterol diet, alongside cellular models in Ana-1 cells and mouse bone marrow-derived macrophages, stimulated with lipopolysaccharides and oxidized low-density lipoprotein., Results: The vivo and vitro experiments indicated that Corilagin could effectively reduce serum lipid levels, alleviate aortic pathological changes, and decrease intimal lipid deposition. Additionally, as results showed, Corilagin was able to cut down expressions of molecules associated with the Olfr2 signaling pathway., Discussion: Our findings indicated that Corilagin effectively inhibited NLRP3 inflammasome activation, consequently diminishing inflammation, macrophage polarization, and pyroptosis in the mouse aorta and cellular models via the Olfr2 pathway. This suggests a novel therapeutic mechanism of Corilagin in the treatment of atherosclerosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mao, Chen, Zong, Liu, Xie, Wang, Fisher, Hien, Pronyuk, Musabaev, Li, Zhao and Dang.)

Acne vulgaris is a prevalent skin disorder affecting many young individuals, marked by keratinization, inflammation, seborrhea, and colonization by Cutibacterium acnes ( C. acnes ). Ellagitannins, known for their antibacterial and anti-inflammatory properties, have not been widely studied for their anti-acne effects. Chestnut ( Castanea sativa Mill., C. sativa ), a rich ellagitannin source, including castalagin whose acne-related bioactivity was previously unexplored, was investigated in this study. The research assessed the effect of C. sativa leaf extract and castalagin on human keratinocytes (HaCaT) infected with C. acnes , finding that both inhibited IL-8 and IL-6 release at concentrations below 25 μg/mL. The action mechanism was linked to NF-κB inhibition, without AP-1 involvement. Furthermore, the extract displayed anti-biofilm properties and reduced CK-10 expression, indicating a potential role in mitigating inflammation, bacterial colonization, and keratosis. Castalagin's bioactivity mirrored the extract's effects, notably in IL-8 inhibition, NF-κB inhibition, and biofilm formation at low μM levels. Other polyphenols, such as flavonol glycosides identified via LC-MS, might also contribute to the extract's biological activities. This study is the first to explore ellagitannins' potential in treating acne, offering insights for developing chestnut-based anti-acne treatments pending future in vivo studies.

Myocardial infarction (MI) is a significant global health issue and the leading cause of death. Myocardial infarction (MI) is characterized by events such as damage to heart cells and stress generated by inflammation. Punicalagin (PCN), a naturally occurring bioactive compound found in pomegranates, exhibits a diverse array of pharmacological effects against many disorders. This study aimed to assess the preventive impact of PCN, with its potential anti-inflammatory and antioxidant properties, on myocardial injury caused by isoproterenol (ISO) in rats and elucidate the possible underlying mechanisms. Experimental rats were randomly categorized into four groups: control group (fed a regular diet for 15 days), PCN group (orally administered PCN at 50 mg/kg body weight (b.w.) for 15 days), ISO group (subcutaneously administered ISO (85 mg/kg b.w.) on days 14 and 15 to induce MI), and PCN+ISO group (orally preadministered PCN (50 mg/kg b.w.) for 15 days and administered ISO (85 mg/kg b.w.) on days 14 and 15). The rat cardiac tissue was then investigated for cardiac marker, oxidative stress marker, and inflammatory marker expression levels. PCN prevented ISO-induced myocardial injury, suppressing the levels of creatine kinase-myocardial band, C-reactive protein, homocysteine, cardiac troponin T, and cardiac troponin I in the rats. Moreover, PCN treatment reversed (P<0.01) the ISO-induced increase in blood pressure, attenuated lipid peroxidation markers, and depleted both enzymatic and nonenzymatic markers in the rats. Additionally, PCN inhibited (P<0.01) ISO-induced overexpression of oxidative stress markers (p-38, p-c-Jun N-terminal kinase, and p-extracellular signal-regulated kinase 1), inflammatory markers (nuclear factor-kappa B, tumor necrosis factor-alpha, and interleukin-6), and matrix metalloproteinases and decreased the levels (P<0.01) of apoptosis proteins in the rats. Nuclear factor erythroid 2-related factor 2/silent information regulator transcript-1 (Nrf2/Sirt1) is a major cellular defense protein that regulates and scavenges oxidative toxic substances through apoptosis. Therefore, overexpression of Nrf2/Sirt1 to inhibit inflammation and oxidative stress is considered a novel target for preventing MI. PCN also significantly enhanced the expression of Nrf2/Sirt1 in ISO-induced rats. Histopathological analyses of cardiac tissue revealed that PCN treatment exhibited a protective effect on the heart tissue, mitigating damage. These findings show that by activating the Nrf2/Sirt1 pathway, PCN regulates oxidative stress, inflammation, and apoptosis, hence providing protection against ISO-induced myocardial ischemia.

Cuphea carthagenensis (Jacq.) J. F. Macbr. is a popular plant in Brazilian folk medicine owing to its hypotensive and central nervous system depressant effects. This study aimed to validate the hypotensive effect of the plant's aqueous extract (AE) in rats and examine the vascular actions of three hydrolyzable tannins, oenothein B, woodfordin C, and eucalbanin B, isolated from AE. Systolic blood pressure in unanesthetized rats was determined using the non-invasive tail-cuff method. Oral treatment of normotensive rats with 0.5 and 1.0 g/kg/day AE induced a dose-related hypotensive effect after 1 week. In rat aortic rings pre-contracted with noradrenaline, all ellagitannins (20 - 180 µM) induced a concentration-related vasorelaxation. This effect was blocked by either removing the endothelium or pre-incubating with N G -nitro-l-arginine methyl ester (10 µM), an inhibitor of nitric oxide (NO) synthase. In KCl-depolarized rat portal vein preparations, the investigated compounds did not affect significantly the maximal contractile responses and pD2 values of the concentration-response curves to CaCl 2 . Our results demonstrated the hypotensive effect of C. carthagenensis AE in unanesthetized rats. All isolated ellagitannins induced vasorelaxation in vitro via activating NO synthesis/NO release from endothelial cells, without altering the Ca 2+ influx in vascular smooth muscle preparations. Considering the low oral bioavailability of ellagitannins, the determined in vitro actions of these compounds are unlikely to account for the hypotensive effect of AE in vivo . It remains to be determined the role of the bioactive ellagitannin-derived metabolites in the hypotensive effect observed after oral treatment of unanesthetized rats with the plant extract., Competing Interests: The authors declare that they have no conflicts of interest., (Thieme. All rights reserved.)

Tellimagrandin-I (TL) and camptothin A (CA) are ellagitannins widely found in diverse plant species. Numerous studies demonstrated their significant biological activities, which include antitumor, antioxidant, and hepatoprotective properties. Despite this protective profile, the effects of TL and CA on DNA have not been comprehensively investigated. Thus, the aim of this study was to determine the mutagenic and antimutagenic effects attributed to TL and CA exposure on Salmonella enterica serovar Typhimurium strains using the Ames test. In addition, the cytotoxic and genotoxic effects were examined on human lymphocytes, employing both trypan blue exclusion and CometChip assay. The antigenotoxic effect was determined following TL and CA exposure in the presence of co-treatment with doxorubicin (DXR). Our results from the Ames test indicated that TL or CA did not display marked mutagenic activity. However, TL or CA demonstrated an ability to protect DNA against the damaging effects of the mutagens 4-nitroquinoline-1-oxide and sodium azide, thereby exhibiting antimutagenic properties. In relation to human lymphocytes, TL or CA did not induce significant cytotoxic or genotoxic actions on these cells. Further, these ellagitannins exhibited an ability to protect DNA from damage induced by DOX during co-treatment, indicating their potential beneficial usefulness as antigenotoxic agents. In conclusion, the protective effects of TL or CA against mutagens, coupled with their absence of genotoxic and cytotoxic effects on human lymphocytes, emphasize their potential therapeutic value in chemopreventive strategies.

Psoriasis, an immune-mediated chronic inflammatory skin disease, imposes a huge mental and physical burden on patients and severely affects their quality of life. Punicalagin (PU), the most abundant ellagitannin in pomegranates, has become a research hotspot owing to its diverse biological activities. However, its effects on psoriasis remain unclear. We explored the impact and molecular mechanism of PU on M5-stimulated keratinocyte cell lines and imiquimod (IMQ)-induced psoriasis-like skin inflammation in BABL/c mice using western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), hematoxylin and eosin (H&E) stain, immunohistochemistry, and immunofluorescent. Administration of PU-enriched pomegranate extract at dosages of 150 and 250 mg/kg/day markedly attenuated psoriatic severity, abrogated splenomegaly, and reduced IMQ-induced abnormal epidermal proliferation, CD4+ T-cell infiltration, and inflammatory factor expression. Moreover, PU could decrease expression levels of pro-inflammatory cytokines, such as IL-1β, IL-1α, IL-6, IL-8, TNF-α, IL-17A, IL-22, IL-23A, and reactive oxygen species (ROS), followed by keratinocyte proliferation inhibition in the M5-stimulated cell line model of inflammation through inhibition of mitogen-activated protein kinases/extracellular regulated protein kinases (MAPK/ERK) and nuclear factor kappaB (NF-κB) signaling pathways. Our results indicate that PU may serve as a promising nutritional intervention for psoriasis by ameliorating cellular oxidative stress and inflammation., (© 2023 John Wiley & Sons Ltd.)

Gut microbiota (GM) is an invisible organ that plays an important role in human health. Increasing evidence suggests that polyphenols in pomegranate (punicalagin, PU) could serve as prebiotics to modulate the composition and function of GM. In turn, GM transform PU into bioactive metabolites such as ellagic acid (EA) and urolithin (Uro). In this review, the interplay between pomegranate and GM is thoroughly described by unveiling a dialog in which both actors seem to affect each other's roles. In a first dialog, the influence of bioactive compounds from pomegranate on GM is described. The second act shows how the GM biotransform pomegranate phenolics into Uro. Finally, the health benefits of Uro and that related molecular mechanism are summarized and discussed. Intake of pomegranate promotes beneficial bacteria in GM (e.g. Lactobacillus spp., Bifidobacterium spp.) while reducing the growth of harmful bacteria (e.g. Bacteroides fragilis group, Clostridia ). Akkermansia muciniphila , and Gordonibacter spp., among others, biotransform PU and EA into Uro. Uro contributes to strengthening intestinal barrier and reducing inflammatory processes. Yet, Uro production varies greatly among individuals and depend on GM composition. Uro-producing bacteria and precise metabolic pathways need to be further elucidated therefore contributing to personalized and precision nutrition.

Background: Pentagalloyl glucose (PGG) is a polyphenol with vasoprotective properties. Targeted delivery of PGG reversed aortic aneurysm growth in several rodent models associated with decreased number of macrophages and transforming growth factor-β (TGF-β) expression. Thus, we sought to determine cellular mechanisms by which PGG reduces macrophage-induced aortic pathogenicity and its relationship to TGF-β. Methods: Using THP-1 cells, primary human aortic cells, and explanted rat aortas, we assessed the anti-inflammatory effect of PGG. Expression of pro/anti-inflammatory macrophage markers was analyzed. Adhesion of monocytes as well as oxidative stress status, viability, and TGF-β expression after primary aortic cell exposure to macrophage-conditioned medium with and without PGG were assessed. The release of TGF-β was also examined in elastase-treated cultured rat aortas. Results: PGG pre-treatment of human aortic cell monolayers reduced the adhesion of THP-1 monocytes. PGG enhanced the expression of anti-inflammatory markers in THP-1-derived macrophages, and increased mitochondrial reactive oxygen species as well as mitochondrial polarization. Conditioned medium from THP-1-derived macrophages induced reactive oxygen species, cell death, and TGF-β release from human aortic cells, which was suppressed by PGG. In explanted rat aortas, PGG reduced elastase mediated TGF-β release. Conclusions: Combining anti-inflammatory, cytotoxic, and oxidative effects, PGG has high cardiovascular therapeutic potential. We confirmed previous in vivo observations whereby PGG suppressed TGF-β response associated with disease resolution., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Hydrolysable tannins (HT) show potential as silage additive for autumn herbage silages, high in (rumen degradable) protein, as they may reduce proteolysis. Additionally, they have abilities to form pH-reversible tannin-protein complexes, non-degradable in the rumen but degradable in the abomasum and intestines of ruminants. Therefore they can improve milk N efficiency and shift N excretions from urine to faeces, possibly mitigating the environmental impact of ruminants. In this study, two small bunker silos were filled with autumn grass. One was treated with 20 g/kg DM HT extract (TAN) (TannoSan-L), the other with 8 mg/kg DM inoculant containing lactic acid bacteria (INO) (Bonsilage Fit G). Secondly, micro-silos (2.75 L) were filled with four treatments; (1) grass without additive (CON) (n = 5); (2) TAN (n = 5); (3) INO (n = 5); and (4) TAN + INO (n = 5). The bunker silos were used in a cross-over feeding experiment with periods of 4 weeks involving 22 lactating Holstein cows (average ± SD: 183 ± 36.3 days in milk, 665 ± 71.0 kg body weight, and 33.8 ± 3.91 kg/day milk yield). The HT dose was insufficient to reduce proteolysis or alter chemical composition and nutritional value in the micro- and bunker silages. Including grass silage added with TAN (3.2 g HT/kg DM) in the diet, did not affect feed intake nor fat and protein corrected milk yield in comparison to feeding the grass silage added with INO in a similar diet. The TAN-fed cows had an increased faecal N excretion and decreased apparent total-tract N and organic matter digestibility, but no improvement in the cows' N utilization could be confirmed in milk and blood urea levels. Overall, feeding an autumn grass silage treated with 20 g/kg chestnut HT extract did not affect the performance of dairy cows in comparison to feeding an autumn grass silage treated with a lactic acid bacteria inoculant., (© 2023 The Authors. Journal of Animal Physiology and Animal Nutrition published by Wiley-VCH GmbH.)

Background: In the search for anti-COVID-19 therapy, 1,2,3,4,6-pentakis-O-galloyl-β- D-glucopyranoside, a natural polyphenolic compound isolated from many traditional medicinal herbs, has been reported as an RBD-ACE2 binding inhibitor and as a broad-spectrum anticoronaviral inhibitor targeting the main protease and RNA-dependent RNA polymerase of SARSCoV- 2. To facilitate the structure-activity relationship studies of 1,2,3,4,6-pentakis-O-galloyl-β-Dglucopyranoside, we describe its chemical synthesis and characterization, as well as its activity towards the SARS-CoV-2 spike interaction with host ACE2 receptor., Methods: 1,2,3,4,6-Pentakis-O-galloyl-β-D-glucopyranoside was synthesized in two quantitative steps from 3,4,5-tribenzyloxybenzoic acid and β-D-glucopyranoside: DCC-mediated esterification and palladium-catalyzed per-debenzylation. The synthesized molecule was evaluated using a SARS-CoV-2 spike trimer (S1 + S2) ACE2 inhibitor screening colorimetric assay kit, SARS-CoV- 2 spike S1 RBD ACE2 inhibitor screening assay kit, and a cellular neutralization assay using the Spike (SARS-CoV-2) Pseudotyped Lentivirus, ACE2-HEK293 recombinant cell line., Results: The chemically synthesized product blocked the binding of the spike trimer of SARSCoV- 2 to the human ACE2 receptor with IC 50 =22±2 μM. It also blocked ACE2: spike RBD binding with IC 50 =27±3 μM. Importantly, it inhibited the infectivity of SARS2-CoV2-Spike pseudotyped lentivirus on the ACE2 HEK293 cell line with IC 50 =20±2 μM., Conclusion: Overall, the chemically synthesized 1,2,3,4,6-pentakis-O-galloyl-β-D-glucopyranoside represents a lead molecule to develop anti-SARS-CoV-2 therapies that block the initial stage of the viral infection by blocking the virus entry to the host cell., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This study aimed to assess the effect of dietary tara (Tara spinosa (Feuillée ex Molina) Britton & Rose) hydrolysable tannins on performance and meat quality of finishing pigs. Twenty barrows (crossbred PIC × Piétrain; age: 125 ± 5 d; bodyweight: 60.8 ± 3.89 kg) were randomly assigned to two groups and fed ad libitum for 7 weeks a control diet (CON) or a diet supplemented with 10 g/kg of tara tannins (TAT), respectively. No differences (P > 0.10) on growth performance and carcass traits were observed between the two groups. Meat fatty acid profile was not affected (P > 0.10) by the diet, but the content of C22:5 n-3 tended to be lower (P = 0.079) in TAT pork. Dietary tannins tended to reduce (P = 0.095) meat cholesterol. The diet had no effect (P > 0.10) on fat-soluble antioxidant vitamins, hydrophilic antioxidant capacity, catalase activity, and glutathione peroxidase activity. Superoxide dismutase activity tended to be lower (P = 0.087) in TAT meat than in CON meat. Dietary tannins did not affect (P > 0.10) backfat and meat color development during 6 days of refrigerated storage, but TAT meat tended to be darker (P = 0.082). Meat from pigs fed tara tannins showed lower (P = 0.028) hydroperoxides content and a tendency toward lower conjugated dienes (P = 0.079) and malondialdehyde (P = 0.084) contents. Also, dietary tannins delayed lipid oxidation in meat subjected to oxidative challenges such as catalysis and cooking (P < 0.05). The positive effect of dietary tara hydrolysable tannins on lipid oxidation was likely due to their antioxidant and anti-inflammatory capacity, but it may have been mitigated by the high α-tocopherol content in meat., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Corilagin possesses a diverse range of pharmacologic bioactivities. However, the specific protective effects and mechanisms of action of corilagin in the context of atherosclerosis remain unclear. In this study, we investigated the impact of corilagin on the toll-like receptor (TLR)4 signaling pathway in a mouse vascular smooth muscle cell line (MOVAS) stimulated by oxidized low-density lipoprotein (ox-LDL). Additionally, we examined the effects of corilagin in Sprague-Dawley rats experiencing atherosclerosis., Methods: The cytotoxicity of corilagin was assessed using the CCK8 assay. MOVAS cells, pre-incubated with ox-LDL, underwent treatment with varying concentrations of corilagin. TLR4 expression was modulated by either downregulation through small interfering (si)RNA or upregulation via lentivirus transfection. Molecular expression within the TLR4 signaling pathway was analyzed using real-time polymerase chain reaction (PCR) and Western blotting. The proliferation capacity of MOVAS cells was determined through cell counting. In a rat model, atherosclerosis was induced in femoral arteries using an improved guidewire injury method, and TLR4 expression in plaque areas was assessed using immunofluorescence. Pathological changes were examined through hematoxylin and eosin staining, as well as Oil-Red-O staining., Results: Corilagin demonstrated inhibitory effects on the TLR4 signaling pathway in MOVAS cells pre-stimulated with ox-LDL, consequently impeding the proliferative impact of ox-LDL. The modulation of TLR4 expression, either through downregulation or upregulation, similarly influenced the expression of downstream molecules. In an in vivo context, corilagin exhibited the ability to suppress TLR4 and MyD88 expression in the plaque lesion areas of rat femoral arteries, thereby alleviating the formation of atherosclerotic plaques., Conclusion: Corilagin can inhibit the TLR4 signaling pathway in VSMCs, possibly by downregulating TLR4 expression and, consequently, relieving atherosclerosis., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Candida glabrata, the second most common cause of invasive fungal infections, exhibits multi-drug resistance to commonly used antifungal drugs. To counter this resistance, there is a critical need for novel antifungals. This study identifies small molecule inhibitors that target a three-helix bundle KIX domain in the Med15a Mediator subunit of Candida glabrata (CgMed15a KIX). This domain plays a crucial role by interacting with the Pleiotropic Drug Resistance transcription factor Pdr1, a key regulator of the multidrug resistance pathway in Candida glabrata. We performed high throughput computational screening of large chemical datasets against the binding sites of the CgMed15a KIX domain to identify novel inhibitors. We selected six potential candidates with high affinity and confirmed their binding with the CgMed15a KIX domain. A phytochemical compound, Chebulinic acid binds to the CgMed15a KIX domain with a KD value of 0.339 μM and shows significant inhibitory effects on the growth of Candida glabrata. Molecular dynamics simulation studies further revealed the structural stability of the CgMed15a KIX-Chebulinic acid complex. Thus, in conclusion, this study highlights Chebulinic acid as a novel potential antifungal compound against Candida glabrata., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Hydrolyzable tannins (HTs) deriving from chestnuts have demonstrated, through numerous studies, the ability to exert multiple beneficial effects, including antioxidant and antimicrobial effects, on the lipid metabolism and cancer cells. The latter effect is very fascinating, since different polyphenols deriving from chestnuts were able to synergistically induce the inhibition of cancerous cells through multiple pathways. Moreover, the main mechanisms by which tannins induce antioxidant functions include: the reduction in oxidative stress, the ability to scavenge free radicals, and the modulation of specific enzymes, such as superoxide dismutase. HTs have also been shown to exert significant antimicrobial activity by suppressing microbial growth. The actions on the lipid metabolism are several, among which is the inhibition of lipid accumulation. Thus, tannins seem to induce a cardioprotective effect. In fact, through various mechanisms, such as the relaxation of the vascular smooth muscle, HTs were proven to be efficient against arterial hypertension. Therefore, the great number of studies in this field prove the growing interest on the utilization of natural bioactive compounds, such as HTs deriving from natural sources or obtained by circular economy models, as potential nutraceuticals or adjuvants therapies.

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.

Ulcerative colitis, an immune-mediated inflammatory disease of the gastrointestinal tract, places a significant financial burden on patients and the healthcare system. Recently, reviews of the pomegranate and the abundant medicinal applications of its ellagitannins, as well as its pharmacological action, phytochemicals, metabolism, and pharmacokinetics, have been completed. However, summaries on their anti-ulcerative colitis effects are lacking. Numerous preclinical animal investigations and clinical human trial reports demonstrated the specific therapeutic effects of pomegranate and the effect of its ellagitannins against ulcerative colitis. According to the literature collected by Sci-finder and PubMed databases over the past 20 years, this is the first review that has compiled references regarding how the rich ellagitannins found in pomegranate have altered the ulcerative colitis. It was suggested that the various parts of pomegranates and their rich ellagitannins (especially their primary components, punicalagin, and ellagic acid) can inhibit oxidant and inflammatory processes, regulate the intestinal barrier and flora, and provide an anti-ulcerative colitis resource through dietary management.

Urolithin A (Uro-A), an intestinal microbiota metabolite of ellagitannin, has anti-aging properties. Through the direct intake of ellagitannin (or ellagic acid) and strains capable of producing Uro-A, the transformation of Uro-A in vivo is a potential method to develop anti-aging preparations. Therefore, this study aimed to investigate the dose-response relationship between the colonic infusion of Uro-A and its anti-aging effects. Results indicated that Uro-A exhibited a dose-dependent anti-aging effect in the colon, and the minimum effective dose might be 3.0 mg kg -1 day -1 . The main manifestations were that, compared with the model group, 3.0 mg kg -1 day -1 and 15.0 mg kg -1 day -1 of Uro-A can increase forelimb grip strength by 11.87% and 16.72%, respectively, and increase the discrimination index by 92.14% and 238.11%, respectively. Both doses effectively inhibited the D-galactose-induced increase in oxidative stress levels in the body, muscle atrophy, and neuronal apoptosis. Additionally, Uro-A released through the colon could alleviate D-galactose-induced aging in mice by inhibiting NF-κB and mTOR targets, providing significant protection for motor and cognitive functions. These findings provide a theoretical basis for future application and development of ellagitannin (or ellagic acid) in combination with strains capable of producing Uro-A.

Modern research achievements support the health-promoting effects of natural products and diets rich in polyphenols. Pomegranate (PG) ( Punica granatum L.) contains a considerable number of bioactive compounds that exert a broad spectrum of beneficial biological activities, including antimicrobial, antidiabetic, antiobesity, and atheroprotective properties. In this context, the reviewed literature shows that PG intake might reduce insulin resistance, cytokine levels, redox gene expression, blood pressure elevation, vascular injuries, and lipoprotein oxidative modifications. The lipid parameter corrective capabilities of PG-ellagitannins have also been extensively reported to be significantly effective in reducing hyperlipidemia (TC, LDL-C, VLDL-C, and TAGs), while increasing plasma HDL-C concentrations and improving the TC/HDL-C and LDL-C/HDL-C ratios. The health benefits of pomegranate consumption seem to be acheived through the amelioration of adipose tissue endocrine function, fatty acid utilization, GLUT receptor expression, paraoxonase activity enhancement, and the modulation of PPAR and NF-κB. While the results from animal experiments are promising, human findings published in this field are inconsistent and are still limited in several aspects. The present review aims to discuss and provide a critical analysis of PG's bioeffects on the components of metabolic syndrome, type-2 diabetes, obesity, and dyslipidemia, as well as on certain cardiovascular-related diseases. Additionally, a brief overview of the pharmacokinetic properties, safety, and bioavailability of PG-ellagitannins is included.

Background: α-Glucosidase inhibitors could effectively reduce postprandial blood glucose (PBG) levels and control the occurrence of complications of diabetes. Gallotannins (GTs) in plants have attracted much attention due to their significant α-glucosidase inhibitory activities in vitro. However, there is still a lack of systematic comparative studies to further elucidate inhibitory activities in vivo and in vitro of these compounds against α-glucosidase, especially for mammalian sucrase and maltase, and analyze their structure-activity relationship., Purpose: Determine the in vitro and in vivo inhibitory activities of five GTs with different number of galloyl moieties (GMs) on sucrase, maltase and α-amylase, and elucidate the relationship between α-glucosidase inhibitory activities and the number and connection mode of GMs., Methods: Molecular docking and dynamics were used to study the binding mode and binding ability of five GTs against sucrase, maltase and α-amylase. Then, the inhibitory activities and inhibitory mechanisms of these compounds on sucrase, maltase and α-amylase in vitro were studied using inhibitory assay and enzyme inhibition kinetics. Further, the hypoglycemic effects in vivo of these compounds were demonstrated by three polysaccharides tolerance experiments on diabetes model mice., Results: The results of molecular docking showed that these compounds could bind to enzymes through hydrogen bonds, hydrophobic interactions, etc. In addition, the α-glucosidase inhibition comparative studies in vitro and in vivo demonstrated that the inhibitory activities of these compounds on all three sucrase, maltase and α-amylase were ranked as TA ≈ PGG > TeGG > TGG > 1GG, and their inhibitory activities increases with the increase in the number of GMs. Moreover, the hypoglycemic effects of 1,2,3,4,6-pentagalloylglucose (PGG) and tannic acid (TA) in vitro and in vivo were also confirmed to be equivalent to or even stronger than that of acarbose., Conclusion: α-Glucosidase inhibitory activities in vitro and in vivo of GTs were positively correlated with the number of GTs, and the more the number, the stronger the activity. However, PGG with five GTs and TA with ten GTs showed almost identical α-glucosidase inhibitory activities, possibly due to the reduced binding force with the enzyme caused by spatial hindrance., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest., (Copyright © 2023 Elsevier GmbH. All rights reserved.)