{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T18:16:07Z","timestamp":1788372967552,"version":"build-2803163510"},"reference-count":62,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T00:00:00Z","timestamp":1744243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Padua, Italy","award":["PNRR DM 117\/23"],"award-info":[{"award-number":["PNRR DM 117\/23"]}]},{"name":"Distillerie Bonollo Umberto S.p.A.","award":["PNRR DM 117\/23"],"award-info":[{"award-number":["PNRR DM 117\/23"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: 5-(3\u2032,4\u2032-dihydroxyphenyl)-\u03b3-valerolactone (\u03b3-VL), recently identified as a predominant microbial metabolite derived from proanthocyanidins, offers benefits such as reducing inflammation, oxidative stress, and supporting brain health. Its effects on neuroinflammation and microglial activation remain largely unexplored. Curcumin, a bioactive component isolated from Curcuma longa L., is well known for its ability to reduce microglial activation and pro-inflammatory mediator production and release. While the individual effects of \u03b3-VL and curcumin are well documented, their potential combined effects remain unexplored. This research sought to investigate the possible synergistic effects of \u03b3-VL and curcumin in reducing microglial activation. Methods: Primary rat cortical microglia were pre-treated with \u03b3-VL and curcumin, alone or in combination, before stimulation with LPS. An MTT assay was used to evaluate cell viability, while pro-inflammatory mediators were assessed by real-time PCR and ELISA. Nitric oxide production was evaluated with the Griess assay. SynergyFinder Plus software analyzed potential synergistic effects. Results: The combination of low micromolar concentrations of \u03b3-VL and curcumin synergistically reduced LPS-induced microglial activation. Specifically, the combination exhibited a significantly greater ability to inhibit the production and release of pro-inflammatory factors (such as IL-1\u03b2, TNF-\u03b1, and NO) compared to each compound individually. Mechanistically, the anti-inflammatory activity was attributed to the downregulation of NLRP3 expression, and the reduction in microglial activation was linked to the modulation of the NOX2\/Nrf2 signaling pathway. Conclusions: The combination of low micromolar concentrations of \u03b3-VL and curcumin produces synergistic anti-inflammatory effects in microglia by targeting key inflammatory pathways, indicating its potential utility as a treatment strategy for neurodegenerative diseases involving microglial activation.<\/jats:p>","DOI":"10.3390\/nu17081316","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T07:41:51Z","timestamp":1744270911000},"page":"1316","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["A Combination of 5-(3\u2032,4\u2032-Dihydroxyphenyl)-\u03b3-Valerolactone and Curcumin Synergistically Reduces Neuroinflammation in Cortical Microglia by Targeting the NLRP3 Inflammasome and the NOX2\/Nrf2 Signaling Pathway"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1856-2447","authenticated-orcid":false,"given":"Emma","family":"Marcolin","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Chemello","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Piovan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Barbierato","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Morazzoni","sequence":"additional","affiliation":[{"name":"Nutraceutical Division, Distillerie Umberto Bonollo S.p.A., 35035 Mestrino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0390-6823","authenticated-orcid":false,"given":"Eugenio","family":"Ragazzi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6577-2947","authenticated-orcid":false,"given":"Morena","family":"Zusso","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.jns.2017.06.030","article-title":"Worldwide trends in the prevalence of dementia","volume":"379","author":"Cova","year":"2017","journal-title":"J. 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