{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:30:44Z","timestamp":1789579844059,"version":"build-2803163510"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T00:00:00Z","timestamp":1740614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003500","name":"Universit\u00e0 Degli Studi di Padova","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003500","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>We have recently shown that polydatin (PD) prevents calcium pyrophosphate (CPP) crystal-induced arthritis in mice. This study aims to explore potential mechanisms of action associated with this anti-inflammatory effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>Acute arthritis was induced in Balb\/c mice by the injection of crystals into the ankle joint. Animals were randomised to receive PD or colchicine according to a prophylactic protocol. Ankle swelling was measured and both joints and muscles were harvested at sacrifice. Histological evaluations were performed using H&amp;amp;E staining to assess cartilage and muscle damage. Kondziela\u2019s inverted test was used to assess muscle strength. An exploratory protein array was performed on joint tissue to identify relevant inflammatory pathways. Human monocytes pretreated with PD were stimulated with CPP crystals. The use of specific inhibitors was instrumental in demonstrating their anti-inflammatory effects and assessing the role of SIRT1. The chemotaxis assay was performed to test the effect of PD and J-113863 on PBMCs migration in response to plasma and synovial fluids. Cytokine levels were measured by ELISA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CPP crystals injection resulted in swelling, leukocyte infiltration, loss of synovial membrane structure homogeneity. Mice pretreated with PD showed reduced ankle swelling and this was associated with very limited inflammatory damage. Regarding the effect on gastrocnemius muscle, crystals induced leukocyte infiltration and edema. PD and colchicine treatment reduced muscle damage and preserved musculoskeletal structure in mice. The cytokine array revealed the activation of various inflammatory pathways after CPP injection and PD was shown to influence leukocyte migration, angiogenesis and inflammation. <jats:italic>In vitro<\/jats:italic>, PD reduced inflammatory cytokines, chemokines and VEGF levels. CCR-1 inhibition was effective in reducing pro-inflammatory mediator levels in CPP treated monocytes and in reducing PBMCs migration. The anti-inflammatory action of PD also involved SIRT-1 activation, and its inhibition reverted the beneficial effects of PD. Finally, PD reduced the PBMCs migration in response to synovial fluids.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>PD effectively prevents inflammatory responses to CPP crystals in mice, preserving both articular and muscular structures. Its anti-inflammatory effects are primarily mediated through pathways regulating leukocyte migration and the suppression of pro-inflammatory mediators.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmolb.2025.1553912","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T08:14:56Z","timestamp":1740989696000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Multitargeted biological actions of polydatin in preventing pseudogout acute attack"],"prefix":"10.3389","volume":"12","author":[{"given":"Chiara","family":"Baggio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Galozzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Damasco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanni","family":"Lazzarin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giampietro","family":"Ravagnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Sfriso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Ramonda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Punzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianmaria","family":"Pennelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Doria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Luisetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Oliviero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1002\/art.40517","article-title":"Review: unmet needs and the path forward in joint disease associated with calcium pyrophosphate crystal deposition","volume":"70","author":"Abhishek","year":"2018","journal-title":"Arthritis Rheumatol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1038\/sj.bjp.0706912","article-title":"Pharmacological blockade of CCR1 ameliorates murine arthritis and alters cytokine networks in vivo","volume":"149","author":"Amat","year":"","journal-title":"Br. J. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1038\/sj.bjp.0706912","article-title":"Pharmacological blockade of CCR1 ameliorates murine arthritis and alters cytokine networks in vivo","volume":"149","author":"Amat","year":"","journal-title":"Br. J. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/s11926-018-0739-z","article-title":"Therapy for CPPD: options and evidence","volume":"20","author":"Andr\u00e9s","year":"2018","journal-title":"Curr. Rheumatol. Rep."},{"key":"B5","doi-asserted-by":"publisher","first-page":"152245","DOI":"10.1016\/j.imbio.2022.152245","article-title":"CCR1 antagonist J-113863 corrects the imbalance of pro- and anti-inflammatory cytokines in a SJL\/J mouse model of relapsing-remitting multiple sclerosis","volume":"227","author":"Ansari","year":"2022","journal-title":"Immunobiology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"5450","DOI":"10.3390\/ijms24065450","article-title":"Leucocyte abnormalities in synovial fluid of degenerative and inflammatory arthropathies","volume":"13","author":"Baggio","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"7341","DOI":"10.4049\/jimmunol.174.11.7341","article-title":"Proteolytic activation of alternative CCR1 ligands in inflammation","volume":"174","author":"Berahovich","year":"2005","journal-title":"J. Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1038\/s41387-018-0025-1","article-title":"The antioxidant potential of the Mediterranean diet in patients at high cardiovascular risk: an in-depth review of the PREDIMED","volume":"8","author":"Billingsley","year":"2018","journal-title":"Nutr. Diabetes"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1785","DOI":"10.1039\/c6fo01561a","article-title":"Polydatin attenuates potassium oxonate-induced hyperuricemia and kidney inflammation by inhibiting NF-\u03baB\/NLRP3 inflammasome activation via the AMPK\/SIRT1 pathway","volume":"8","author":"Chen","year":"2017","journal-title":"Food Funct."},{"key":"B10","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.brainres.2006.06.065","article-title":"Involvement of cell adhesion molecules in polydatin protection of brain tissues from ischemia-reperfusion injury","volume":"1110","author":"Cheng","year":"2006","journal-title":"Brain Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3389\/fnut.2018.00087","article-title":"The role of polyphenols in human health and food systems: a mini-review","volume":"5","author":"Cory","year":"2018","journal-title":"Front. Nutr."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1264074","DOI":"10.1155\/2018\/1264074","article-title":"Regulation of immune function by polyphenols","volume":"2018","author":"Ding","year":"2018","journal-title":"J. Immunol. Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"121766","DOI":"10.1016\/j.lfs.2023.121766","article-title":"Polydatin ameliorates inflammation and oxidative stress associated with MSU-induced gouty arthritis in mice by regulating PPAR-\u03b3 and ferritin activation","volume":"326","author":"Du","year":"2023","journal-title":"Life Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/s0014-5793(97)00408-0","article-title":"CKbeta8, a novel CC chemokine that predominantly acts on monocytes","volume":"408","author":"Forssmann","year":"1997","journal-title":"FEBS Lett."},{"key":"B15","first-page":"2263","article-title":"Polydatin reduces IL-1 \u03b2-induced chondrocytes apoptosis and inflammatory response via p 38 MAPK signaling pathway in a rat model of osteoarthritis","volume":"10","author":"Guang","year":"2017","journal-title":"Int. J. Clin. Exp. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.bbrc.2009.02.149","article-title":"CCL23 up-regulates expression of KDR\/Flk-1 and potentiates VEGF-induced proliferation and migration of human endothelial cells","volume":"382","author":"Han","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B17","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1136\/annrheumdis-2020-219247","article-title":"SMASH' recommendations for standardised microscopic arthritis scoring of histological sections from inflammatory arthritis animal models","volume":"80","author":"Hayer","year":"2021","journal-title":"Ann. Rheum. Dis."},{"key":"B18","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1096\/fj.201800750R","article-title":"Polydatin suppresses VEGF-induced angiogenesis through binding with VEGF and inhibiting its receptor signaling","volume":"33","author":"Hu","year":"2019","journal-title":"FASEB J."},{"key":"B19","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.cyto.2005.01.018","article-title":"Human CC chemokine CCL23, a ligand for CCR1, induces endothelial cell migration and promotes angiogenesis","volume":"30","author":"Hwang","year":"2005","journal-title":"Cytokine"},{"key":"B20","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1007\/s00011-011-0350-5","article-title":"Potential involvement of CCL23 in atherosclerotic lesion formation\/progression by the enhancement of chemotaxis, adhesion molecule expression, and MMP-2 release from monocytes","volume":"60","author":"Kim","year":"2011","journal-title":"Inflamm. Res."},{"key":"B21","first-page":"277","article-title":"A new method for the measurement of muscle relaxation in white mice","volume":"152","author":"Kondziella","year":"1964","journal-title":"Arch. Int. Pharmacodyn. Ther."},{"key":"B22","doi-asserted-by":"publisher","first-page":"101","DOI":"10.3390\/gucdd2020010","article-title":"Calcium pyrophosphate and basic calcium phosphate crystal arthritis: 2023 in review","volume":"2","author":"Latourte","year":"2024","journal-title":"Gout Urate Cryst. Depos. Dis."},{"key":"B23","doi-asserted-by":"publisher","first-page":"118322","DOI":"10.1016\/j.jep.2024.118322","article-title":"The role of polydatin in inhibiting oxidative stress through SIRT1 activation: a comprehensive review of molecular targets","volume":"15","author":"Liu","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.intimp.2018.09.009","article-title":"Polydatin ameliorates dextran sulfate sodium-induced colitis by decreasing oxidative stress and apoptosis partially via Sonic hedgehog signaling pathway","volume":"64","author":"Lv","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.3389\/fimmu.2018.01145","article-title":"Disease-associated particulates and joint inflammation; mechanistic insights and potential therapeutic targets","volume":"9","author":"Mahon","year":"2018","journal-title":"Front. Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1038\/nature04516","article-title":"Gout-associated uric acid crystals activate the NALP3 inflammasome","volume":"440","author":"Martinon","year":"2006","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1002\/jlb.65.6.822","article-title":"Dendritic cells and MPIF-1: chemotactic activity and inhibition of endogenous chemokine production by IFN-gamma and CD40 ligation","volume":"65","author":"Nardelli","year":"1999","journal-title":"J. Leukoc. Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"4335","DOI":"10.4049\/jimmunol.178.7.4335","article-title":"CCL23 expression is induced by IL-4 in a STAT6-dependent fashion","volume":"178","author":"Novak","year":"2007","journal-title":"J. Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"166","DOI":"10.3389\/fmed.2020.00166","article-title":"Autoinflammatory mechanisms in crystal-induced arthritis","volume":"7","author":"Oliviero","year":"2020","journal-title":"Front. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"929","DOI":"10.3390\/nu13030929","article-title":"Polydatin prevents calcium pyrophosphate crystal-induced arthritis in mice","volume":"13","author":"Oliviero","year":"2021","journal-title":"Nutrients"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1653","DOI":"10.1002\/jsfa.8664","article-title":"Anti-inflammatory effects of polyphenols in arthritis","volume":"98","author":"Oliviero","year":"2018","journal-title":"J. Sci. Food Agric."},{"key":"B32","doi-asserted-by":"publisher","first-page":"560","DOI":"10.3390\/foods8110560","article-title":"Polydatin and resveratrol inhibit the inflammatory process induced by urate and pyrophosphate crystals in THP-1 cells","volume":"8","author":"Oliviero","year":"2019","journal-title":"Foods"},{"key":"B33","doi-asserted-by":"publisher","first-page":"e791","DOI":"10.1016\/S2665-9913(24)00122-X","article-title":"Calcium pyrophosphate deposition disease","volume":"6","author":"Pascart","year":"2024","journal-title":"Lancet Rheumatol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1084\/jem.185.7.1163","article-title":"Molecular and functional characterization of two novel human C-C chemokines as inhibitors of two distinct classes of myeloid progenitors","volume":"185","author":"Patel","year":"1997","journal-title":"J. Exp. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1007\/s10753-012-9516-8","article-title":"Polydatin, a natural precursor of resveratrol, induces \u03b2-defensin production and reduces inflammatory response","volume":"36","author":"Ravagnan","year":"2013","journal-title":"Inflammation"},{"key":"B36","doi-asserted-by":"publisher","first-page":"e0185704","DOI":"10.1371\/journal.pone.0185704","article-title":"The tyrosine kinase inhibitor imatinib mesylate suppresses uric acid crystal-induced acute gouty arthritis in mice","volume":"12","author":"Reber","year":"2017","journal-title":"PLoS One"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2023\/5592455","article-title":"Development and validation of a multiparametric semiquantitative scoring system for the histopathological assessment of ischaemia severity in skeletal muscle","volume":"2023","author":"Sanz-Nogu\u00e9s","year":"2023","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"B38","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1016\/j.bbrc.2005.12.037","article-title":"Human CC chemokine CCL23 enhances expression of matrix metalloproteinase-2 and invasion of vascular endothelial cells","volume":"340","author":"Son","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B39","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1080\/14728214.2018.1527899","article-title":"Expert opinion on emerging urate-lowering therapies","volume":"23","author":"Stamp","year":"2018","journal-title":"Expert Opin. Emerg. Drugs"},{"key":"B40","doi-asserted-by":"publisher","first-page":"111549","DOI":"10.1016\/j.biopha.2021.111549","article-title":"SIRT1 provides new pharmacological targets for polydatin through its role as a metabolic sensor","volume":"139","author":"Sun","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"B41","doi-asserted-by":"publisher","first-page":"10137","DOI":"10.1002\/jcb.28297","article-title":"Polydatin suppresses the development of lung inflammation and fibrosis by inhibiting activation of the NACHT domain-leucine-rich repeat-and pyd-containing protein 3 inflammasome and the nuclear factor-\u03baB pathway after Mycoplasma pneumoniae infection","volume":"120","author":"Tang","year":"2019","journal-title":"J. Cell Biochem."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1039\/c7fo01555k","article-title":"Polydatin inhibits the IL-1\u03b2-induced inflammatory response in human osteoarthritic chondrocytes by activating the Nrf2 signaling pathway and ameliorates murine osteoarthritis","volume":"9","author":"Tang","year":"2018","journal-title":"Food Funct."},{"key":"B43","doi-asserted-by":"publisher","first-page":"2264","DOI":"10.1111\/j.1523-1755.2004.66038.x","article-title":"CCR1 blockade reduces interstitial inflammation and fibrosis in mice with glomerulosclerosis and nephrotic syndrome","volume":"66","author":"Vielhauer","year":"2004","journal-title":"Kidney Int."},{"key":"B44","doi-asserted-by":"publisher","first-page":"110308","DOI":"10.1016\/j.biopha.2020.110308","article-title":"Polydatin for treating atherosclerotic diseases: a functional and mechanistic overview","volume":"128","author":"Wu","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"B45","doi-asserted-by":"publisher","first-page":"105919","DOI":"10.1016\/j.intimp.2019.105919","article-title":"Inhibition of NET formation by polydatin protects against collagen-induced arthritis","volume":"77","author":"Yang","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"3118","DOI":"10.1182\/blood.v91.9.3118.3118_3118_3126","article-title":"Characterization of CK\u03b28 and ck\u03b28-1: two alternatively spliced forms of human \u03b2-chemokine, chemoattractants for neutrophils, monocytes, and lymphocytes, and potent agonists at CC chemokine receptor 1","volume":"91","author":"Youn","year":"1998","journal-title":"Blood"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1007\/s10067-015-2933-y","article-title":"Molecular basis of oxidative stress in gouty arthropathy","volume":"34","author":"Zamudio-Cuevas","year":"2015","journal-title":"Clin. Rheumatol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1136\/ard.2010.139360","article-title":"EULAR recommendations for calcium pyrophosphate deposition. Part II: management","volume":"70","author":"Zhang","year":"2011","journal-title":"Ann. Rheum. Dis."}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2025.1553912\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T08:15:00Z","timestamp":1740989700000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2025.1553912\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,27]]},"references-count":48,"alternative-id":["10.3389\/fmolb.2025.1553912"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2025.1553912","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,27]]},"article-number":"1553912"}}