{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T06:45:11Z","timestamp":1793169911778,"version":"4.5.0"},"reference-count":38,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T00:00:00Z","timestamp":1732233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jilin Province Science and Technology Department Talent Special","award":["20240601086RC"],"award-info":[{"award-number":["20240601086RC"]}]},{"name":"Jilin Province Science and Technology Department Talent Special","award":["20220304002YY"],"award-info":[{"award-number":["20220304002YY"]}]},{"name":"Jilin Province Science and Technology Department Talent Special","award":["20220304001YY"],"award-info":[{"award-number":["20220304001YY"]}]},{"name":"Jilin Province Science and Technology Department Talent Special","award":["JARS-2024-0801-09"],"award-info":[{"award-number":["JARS-2024-0801-09"]}]},{"name":"Jilin Province Major Science and Technology Special Project","award":["20240601086RC"],"award-info":[{"award-number":["20240601086RC"]}]},{"name":"Jilin Province Major Science and Technology Special Project","award":["20220304002YY"],"award-info":[{"award-number":["20220304002YY"]}]},{"name":"Jilin Province Major Science and Technology Special Project","award":["20220304001YY"],"award-info":[{"award-number":["20220304001YY"]}]},{"name":"Jilin Province Major Science and Technology Special Project","award":["JARS-2024-0801-09"],"award-info":[{"award-number":["JARS-2024-0801-09"]}]},{"name":"Major Science and Technology Project of Sika Deer Industrial Scientific and Technological Innovation","award":["20240601086RC"],"award-info":[{"award-number":["20240601086RC"]}]},{"name":"Major Science and Technology Project of Sika Deer Industrial Scientific and Technological Innovation","award":["20220304002YY"],"award-info":[{"award-number":["20220304002YY"]}]},{"name":"Major Science and Technology Project of Sika Deer Industrial Scientific and Technological Innovation","award":["20220304001YY"],"award-info":[{"award-number":["20220304001YY"]}]},{"name":"Major Science and Technology Project of Sika Deer Industrial Scientific and Technological Innovation","award":["JARS-2024-0801-09"],"award-info":[{"award-number":["JARS-2024-0801-09"]}]},{"name":"Jilin Province Department of Agriculture and Rural Industry Technology system project","award":["20240601086RC"],"award-info":[{"award-number":["20240601086RC"]}]},{"name":"Jilin Province Department of Agriculture and Rural Industry Technology system project","award":["20220304002YY"],"award-info":[{"award-number":["20220304002YY"]}]},{"name":"Jilin Province Department of Agriculture and Rural Industry Technology system project","award":["20220304001YY"],"award-info":[{"award-number":["20220304001YY"]}]},{"name":"Jilin Province Department of Agriculture and Rural Industry Technology system project","award":["JARS-2024-0801-09"],"award-info":[{"award-number":["JARS-2024-0801-09"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Inflammation assumes a vital role in the pathogenesis of depression and in antidepressant treatment. Paeoniflorin (PF), a monoterpene glycoside analog possessing anti-inflammatory attributes, exhibits therapeutic efficacy on depression-like behavior in mice. The objective of this study was to evaluate the antidepressant effects of PF on depression elicited by the chronic unpredictable mild stress (CUMS) model and the precise neural sequence associated with the inflammatory process. In this study, we established an in vivo mouse model induced by CUMS and an in vitro BV2 cell model induced by LPS+ATP. The mechanism of PF for depression was assessed by the SIRT1 selective inhibitor EX-527. The findings demonstrated that PF significantly alleviated the damage of BV2 cells treated with LPS and ATP, inhibited the generation of ROS, up-regulated the expression of SIRT1 mRNA, and down-regulated the expression of nuclear NF-\u03baB, p65, NLRP3, Caspase-1 and GSDMD-N in vitro. In vivo, PF mitigated the depressive-like behavior induced by CUMS, reduced the number of neurons, and decreased the secretion of pro-inflammatory factors IL-1\u03b2, IL-6, and TNF-\u03b1 in the hippocampus. Immunohistochemical results indicated that PF attenuated CUMS-induced hyperactivation of microglia. Moreover, the expression level of SIRT1 in the hippocampus was augmented, while the protein levels of NF-\u03baB, p65, NLRP3, Caspase-1, IL-1\u03b2 and GSDMD-N were diminished after PF treatment. Additionally, the selective inhibition of SIRT1 attenuated the therapeutic effect of PF on depression. These results imply that PF possesses antidepressant properties that rely on SIRT1 signaling to regulate NLRP3 inflammasome inactivation.<\/jats:p>","DOI":"10.3390\/ijms252312543","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T06:41:48Z","timestamp":1732257708000},"page":"12543","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Paeoniflorin Inhibits the Activation of Microglia and Alleviates Depressive Behavior by Regulating SIRT1-NF-kB-NLRP3\/Pyroptosis Pathway"],"prefix":"10.3390","volume":"25","author":[{"given":"Xue","family":"Wang","sequence":"first","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Su","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silu","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2694-6510","authenticated-orcid":false,"given":"Zhongmei","family":"He","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"},{"name":"Jilin Provincial Engineering Research Center for Efficient Breeding and Product Development of Sika Deer, Changchun 130118, China"},{"name":"Key Laboratory of Animal Production and Product Quality and Security, Ministry of Education, Ministry of National Education, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Li","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"},{"name":"Jilin Provincial Engineering Research Center for Efficient Breeding and Product Development of Sika Deer, Changchun 130118, China"},{"name":"Key Laboratory of Animal Production and Product Quality and Security, Ministry of Education, Ministry of National Education, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zong","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"},{"name":"Jilin Provincial Engineering Research Center for Efficient Breeding and Product Development of Sika Deer, Changchun 130118, China"},{"name":"Key Laboratory of Animal Production and Product Quality and Security, Ministry of Education, Ministry of National Education, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijia","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"},{"name":"Jilin Provincial Engineering Research Center for Efficient Breeding and Product Development of Sika Deer, Changchun 130118, China"},{"name":"Key Laboratory of Animal Production and Product Quality and Security, Ministry of Education, Ministry of National Education, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Du","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"},{"name":"Jilin Provincial Engineering Research Center for Efficient Breeding and Product Development of Sika Deer, Changchun 130118, China"},{"name":"Key Laboratory of Animal Production and Product Quality and Security, Ministry of Education, Ministry of National Education, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Yu, X., Wang, S., Wu, W., Chang, H., Shan, P., Yang, L., Zhang, W., and Wang, X. (2023). Exploring New Mechanism of Depression from the Effects of Virus on Nerve Cells. Cells, 12.","DOI":"10.3390\/cells12131767"},{"key":"ref_2","unstructured":"World Health Organization (2017). Depression and Other Common Mental Disorders: Global Health Estimates, World Health Organization."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3564","DOI":"10.1007\/s12035-022-02780-z","article-title":"Neuroanatomical, Biochemical, and Functional Modifications in Brain Induced by Treatment with Antidepressants","volume":"59","author":"Khushboo","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"16065","DOI":"10.1038\/nrdp.2016.65","article-title":"Major depressive disorder","volume":"2","author":"Otte","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Guzman-Martinez, L., Maccioni, R.B., Andrade, V., Navarrete, L.P., Pastor, M.G., and Ramos-Escobar, N. (2019). Neuroinflammation as a Common Feature of Neurodegenerative Disorders. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.01008"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Sun, X., Zhang, T., Liu, S., Cai, E., and Zhu, H. (2021). Study on the antidepressant effect of panaxynol through the I\u03baB-\u03b1\/NF-\u03baB signaling pathway to inhibit the excessive activation of BV-2 microglia. Biomed. Pharmacother., 138.","DOI":"10.1016\/j.biopha.2021.111387"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.brainresbull.2020.12.003","article-title":"Naringenin improves depressive- and anxiety-like behaviors in mice exposed to repeated hypoxic stress through modulation of oxido-inflammatory mediators and NF-kB\/BDNF expressions","volume":"169","author":"Olugbemide","year":"2021","journal-title":"Brain Res. Bull."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/s41581-022-00662-0","article-title":"Gasdermins and pyroptosis in the kidney","volume":"19","author":"Elias","year":"2023","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Wen, J., Xuan, B., Liu, Y., Wang, L., He, L., Meng, X., Zhou, T., and Wang, Y. (2023). NLRP3 inflammasome-induced pyroptosis in digestive system tumors. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1074606"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"R568","DOI":"10.1016\/j.cub.2016.02.019","article-title":"Pyroptosis","volume":"26","author":"Lamkanfi","year":"2016","journal-title":"Curr. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/s41392-021-00507-5","article-title":"Pyroptosis: Mechanisms and diseases","volume":"6","author":"Yu","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_12","first-page":"6044","article-title":"NF-\u03baB-Gasdermin D (GSDMD) Axis Couples Oxidative Stress and NACHT, LRR and PYD Domains-Containing Protein 3 (NLRP3) Inflammasome-Mediated Cardiomyocyte Pyroptosis Following Myocardial Infarction","volume":"24","author":"Lei","year":"2018","journal-title":"Med. Sci. Monit. Int. Med. J. Exp. Clin. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"18192","DOI":"10.1002\/jcp.28452","article-title":"Quercetin attenuates oxidative stress-induced apoptosis via SIRT1\/AMPK-mediated inhibition of ER stress in rat chondrocytes and prevents the progression of osteoarthritis in a rat model","volume":"234","author":"Feng","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"14105","DOI":"10.3390\/ijms140714105","article-title":"Resveratrol inhibits ionising irradiation-induced inflammation in MSCs by activating SIRT1 and limiting NLRP-3 inflammasome activation","volume":"14","author":"Fu","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"106625","DOI":"10.1016\/j.phrs.2022.106625","article-title":"The NLRP3 inflammasome in depression: Potential mechanisms and therapies","volume":"187","author":"Xia","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"012015","DOI":"10.1088\/1755-1315\/559\/1\/012015","article-title":"Modern research progress on pharmacological effects of paeoniflorin","volume":"559","author":"Zhao","year":"2020","journal-title":"IOP Conf. Ser. Earth Environ. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Hong, H., Lu, X., Wu, C., Chen, J., Chen, C., Zhang, J., Huang, C., and Cui, Z. (2022). A review for the pharmacological effects of paeoniflorin in the nervous system. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.898955"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Guo, W., Yao, X., Cui, R., Yang, W., and Wang, L. (2023). Mechanisms of paeoniaceae action as an antidepressant. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.934199"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"347","DOI":"10.55782\/ane-2022-033","article-title":"Paeoniflorin exhibits antidepressant activity in rats with postpartum depression via the TSPO and BDNF-mTOR pathways","volume":"82","author":"Chen","year":"2022","journal-title":"Acta Neurobiol. Exp."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11329","DOI":"10.1080\/21655979.2021.2003676","article-title":"Paeoniflorin ameliorates chronic stress-induced depression-like behavior in mice model by affecting ERK1\/2 pathway","volume":"12","author":"Tang","year":"2021","journal-title":"Bioengineered"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"114046","DOI":"10.1016\/j.jep.2021.114046","article-title":"Paeoniflorin exerts antidepressant-like effects through enhancing neuronal FGF-2 by microglial inactivation","volume":"274","author":"Cheng","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1007\/s12035-020-02144-5","article-title":"Antidepressant Effect of Paeoniflorin Is Through Inhibiting Pyroptosis CASP-11\/GSDMD Pathway","volume":"58","author":"Tian","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1002\/jnr.25026","article-title":"Microglia form satellites with different neuronal subtypes in the adult murine central nervous system","volume":"100","author":"Bakina","year":"2022","journal-title":"J. Neurosci. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"00368504211054985","DOI":"10.1177\/00368504211054985","article-title":"Inflammatory cytokines TNF\u03b1, IL-1\u03b2, and IL-6 are induced in endotoxin- stimulated microglia through different signaling cascades","volume":"104","author":"Ishijima","year":"2021","journal-title":"Sci. Prog."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1134\/S0026893319050054","article-title":"The Role of Microglia in the Homeostasis of the Central Nervous System and Neuroinflammation","volume":"53","author":"Gogoleva","year":"2019","journal-title":"Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Iwasa, M., Kato, H., Iwashita, K., Yamakage, H., Kato, S., Saito, S.A., Ihara, M.A., Nishimura, H., Kawamoto, A., and Suganami, T. (2023). Taxifolin Suppresses Inflammatory Responses of High-Glucose-Stimulated Mouse Microglia by Attenuating the TXNIP-NLRP3 Axis. Nutrients, 15.","DOI":"10.3390\/nu15122738"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lee, J.W., Chun, W., Lee, H.J., Kim, S.M., Min, J.H., Kim, D.Y., Kim, M.O., Ryu, H.A.-O., and Lee, S.U. (2021). The role of microglia in the development of neurodegenerative diseases. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101449"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Arioz, B.I., Tastan, B., Tarakcioglu, E., Tufekci, K.U., Olcum, M., Ersoy, N., Bagriyanik, A., Genc, K., and Genc, S. (2019). Melatonin Attenuates LPS-Induced Acute Depressive-Like Behaviors and Microglial NLRP3 Inflammasome Activation Through the SIRT1\/Nrf2 Pathway. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01511"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"100889","DOI":"10.1016\/j.mam.2020.100889","article-title":"The NLRP3 inflammasome: Mechanism of action, role in disease and therapies","volume":"76","author":"Wang","year":"2020","journal-title":"Mol. Asp. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1002\/ddr.21995","article-title":"Berberine ameliorates pulmonary inflammation in mice with influenza viral pneumonia by inhibiting NLRP3 inflammasome activation and gasdermin D-mediated pyroptosis","volume":"83","author":"An","year":"2022","journal-title":"Drug Dev. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s12974-017-0865-y","article-title":"Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors","volume":"14","author":"Yue","year":"2017","journal-title":"J. Neuroinflamm."},{"key":"ref_32","first-page":"1065","article-title":"MicroRNA-30a-5p Promotes Chronic Heart Failure in Rats by Targeting Sirtuin-1 to Activate the Nuclear Factor-\u03baB\/NOD-Like Receptor 3 Signaling Pathway","volume":"37","author":"Wu","year":"2022","journal-title":"Drugs Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"105886","DOI":"10.1016\/j.intimp.2019.105886","article-title":"Suppression of NLRP3 and NF-\u03baB signaling pathways by \u03b1-Cyperone via activating SIRT1 contributes to attenuation of LPS-induced acute lung injury in mice","volume":"76","author":"Liu","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"918","DOI":"10.2174\/1570159X18666200207120949","article-title":"Role of Nuclear Factor Kappa B (NF-\u03baB) Signalling in Neurodegenerative Diseases: An mechanistic approach","volume":"18","author":"Singh","year":"2020","journal-title":"Curr. Neuropharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1080\/21505594.2022.2116169","article-title":"caviae infection triggers IL-1\u03b2 secretion through activating NLRP3 inflammasome mediated by NF-\u03baB signaling pathway partly in a TLR2 dependent manner","volume":"13","author":"Yang","year":"2022","journal-title":"Virulence"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"152720","DOI":"10.1016\/j.tox.2021.152720","article-title":"NLRP3 inflammasome mediated pyroptosis is involved in cadmium exposure-induced neuroinflammation through the IL-1\u03b2\/IkB-\u03b1-NF-\u03baB-NLRP3 feedback loop in swine","volume":"453","author":"Cai","year":"2021","journal-title":"Toxicology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/j.biopha.2018.07.040","article-title":"Gypenosides reverses depressive behavior via inhibiting hippocampal neuroinflammation","volume":"106","author":"Dong","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Hu, Y., Zhao, M., Zhao, T., Qi, M., Yao, G., and Dong, Y. (2022). The protective effect of Pilose antler peptide on CUMS-Induced depression through AMPK\/Sirt1\/NF-\u03baB\/NLRP3-mediated pyroptosis. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.815413"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/12543\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:37:23Z","timestamp":1760114243000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/12543"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,22]]},"references-count":38,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252312543"],"URL":"https:\/\/doi.org\/10.3390\/ijms252312543","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,22]]}}}