{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T22:38:52Z","timestamp":1787611132522,"version":"build-2736575974"},"reference-count":54,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2019,7,15]],"date-time":"2019-07-15T00:00:00Z","timestamp":1563148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lupus nephritis (LN) is a kidney inflammatory disease caused by systemic lupus erythematosus (SLE). NLRP3 inflammasome activation is implicated in LN pathogenesis, suggesting its potential targets for LN treatment. Melatonin, an endogenous indoleamine, is considered an important multitasking molecule that has been reported to have anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-\u03baB)-mediated inflammatory responses in vivo. This molecule has also protective effects against the activation of the inflammasomes and, in particular, the NLRP3 inflammasome. Thus, this work evaluated the effect of melatonin on morphological alteration and NLRP3 inflammasome activation in LN pristane mouse models. To evaluate the melatonin effects in these mice, we studied the renal cytoarchitecture by means of morphological analyses and immunohistochemical expression of specific markers related to oxidative stress, inflammation and inflammasome activation. Our results showed that melatonin attenuates pristane-induced LN through restoring of morphology and attenuation of oxidative stress and inflammation through a pathway that inhibited activation of NLRP3 inflammasome signaling. Our data clearly demonstrate that melatonin has protective activity on lupus nephritis in these mice that is highly associated with its effect on enhancing the Nrf2 antioxidant signaling pathway and decreasing renal NLRP3 inflammasome activation.<\/jats:p>","DOI":"10.3390\/ijms20143466","type":"journal-article","created":{"date-parts":[[2019,7,16]],"date-time":"2019-07-16T02:23:16Z","timestamp":1563243796000},"page":"3466","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["NLRP3 Inflammasome Modulation by Melatonin Supplementation in Chronic Pristane-Induced Lupus Nephritis"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7210-0308","authenticated-orcid":false,"given":"Francesca","family":"Bonomini","sequence":"first","affiliation":[{"name":"Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University o of Brescia, Viale Europa, 25123 Brescia, Italy"},{"name":"Interdipartimental University Center of Research, Adaption and Regeneration of Tissues and Organs (ARTO), University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariane","family":"Dos Santos","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology Applied to Nephrology, Experimental Research Center, Hospital de Cl\u00ednicas de Porto Alegre, 90035-903 Porto Alegre, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Ver\u00edssimo","family":"Veronese","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology Applied to Nephrology, Experimental Research Center, Hospital de Cl\u00ednicas de Porto Alegre, 90035-903 Porto Alegre, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7515-5846","authenticated-orcid":false,"given":"Rita","family":"Rezzani","sequence":"additional","affiliation":[{"name":"Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University o of Brescia, Viale Europa, 25123 Brescia, Italy"},{"name":"Interdipartimental University Center of Research, Adaption and Regeneration of Tissues and Organs (ARTO), University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1093\/rheumatology\/kev311","article-title":"The frequency and outcome of lupus nephritis: Results from an international inception cohort study","volume":"55","author":"Hanly","year":"2016","journal-title":"Rheumatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.clim.2016.08.010","article-title":"Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis","volume":"185","author":"Mistry","year":"2017","journal-title":"Clin. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.imlet.2019.04.002","article-title":"Analysis of interleukin-17 and interleukin-23 for estimating disease activity and predicting the response to treatment in active lupus nephritis patients","volume":"210","author":"Dedong","year":"2019","journal-title":"Immunol. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s13075-019-1876-0","article-title":"Baicalein ameliorates pristane-induced lupus nephritis via activating Nrf2\/HO-1 in myeloid-derived suppressor cells","volume":"21","author":"Li","year":"2019","journal-title":"Arthritis Res. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1084\/jem.20100064","article-title":"IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells","volume":"207","author":"Batten","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1084\/jem.180.6.2341","article-title":"Induction of lupus-associated autoantibodies in BALB\/c mice by intraperitoneal injection of pristane","volume":"180","author":"Satoh","year":"1994","journal-title":"J. Exp. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"230","DOI":"10.2478\/v10042-010-0004-4","article-title":"The endothelial cell markers von Willebrand Factor (vWF), CD31 and CD34 are lost in glomerulonephritis and no longer correlate with the morphological indices of glomerular sclerosis, interstitial fibrosis, activity and chronicity","volume":"48","author":"Gluhovschi","year":"2010","journal-title":"Folia Histochem. Cytobiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"541","DOI":"10.5301\/jn.5000030","article-title":"Angiopoietin-2, endothelial dysfunction and renal involvement in patients with systemic lupus erythematosus","volume":"25","author":"Gaber","year":"2012","journal-title":"J. Nephrol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.clim.2014.06.007","article-title":"Serum autoantibodies in pristane-induced lupus are regulated by neutrophil gelatinase associated lipocalin","volume":"154","author":"Pawar","year":"2014","journal-title":"Clin. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5780903","DOI":"10.1155\/2016\/5780903","article-title":"Angiopoietin-2 Is an Early Indicator of Acute Pancreatic-Renal Syndrome in Patients with Acute Pancreatitis","volume":"2016","author":"Sporek","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1177\/0961203318788167","article-title":"Composite urinary biomarkers to predict pathological tubulointerstitial lesions in lupus nephritis","volume":"27","author":"Ding","year":"2018","journal-title":"Lupus"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6143","DOI":"10.4049\/jimmunol.1101284","article-title":"Inflammasome activation of IL-18 results in endothelial progenitor cell dysfunction in systemic lupus erythematosus","volume":"187","author":"Kahlenberg","year":"2011","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1002\/art.40155","article-title":"Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis","volume":"69","author":"Fu","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s12950-018-0192-9","article-title":"Expression and clinical significance of the NEK7-NLRP3 inflammasome signaling pathway in patients with systemic lupus erythematosus","volume":"15","author":"Ma","year":"2018","journal-title":"J. Inflamm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.4049\/jimmunol.1202388","article-title":"Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages","volume":"190","author":"Kahlenberg","year":"2013","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.lfs.2018.07.009","article-title":"Icariin alleviates murine lupus nephritis via inhibiting NF-\u03baB activation pathway and NLRP3 inflammasome","volume":"208","author":"Su","year":"2018","journal-title":"Life Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.intimp.2019.01.046","article-title":"Curcumin attenuates murine lupus via inhibiting NLRP3 inflammasome","volume":"69","author":"Zhao","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e12410","DOI":"10.1111\/jpi.12410","article-title":"Melatonin administration to wild-type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis","volume":"63","author":"Rahim","year":"2017","journal-title":"J. Pineal Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e12514","DOI":"10.1111\/jpi.12514","article-title":"Melatonin and its metabolites vs. oxidative stress: From individual actions to collective protection","volume":"65","author":"Galano","year":"2018","journal-title":"J. Pineal Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1835195","DOI":"10.1155\/2017\/1835195","article-title":"Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation","volume":"2017","author":"Favero","year":"2017","journal-title":"Int. J. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Jaworek, J., Leja-Szpak, A., Nawrot-Por\u0105bka, K., Szklarczyk, J., Kot, M., Pierzchalski, P., G\u00f3ralska, M., Ceranowicz, P., Warzecha, Z., and Dembinski, A. (2017). Effects of Melatonin and Its Analogues on Pancreatic Inflammation, Enzyme Secretion, and Tumorigenesis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18051014"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Favero, G., Trapletti, V., Bonomini, F., Stacchiotti, A., Lavazza, A., Rodella, L.F., and Rezzani, R. (2017). Oral Supplementation of Melatonin Protects against Fibromyalgia-Related Skeletal Muscle Alterations in Reserpine-Induced Myalgia Rats. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071389"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1080\/08916934.2018.1442828","article-title":"Protective effects of quercetin treatment in a pristane-induced mouse model of lupus nephritis","volume":"51","author":"Poletti","year":"2018","journal-title":"Autoimmunity"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s40659-018-0168-5","article-title":"Melatonin ameliorates H2O2-induced oxidative stress through modulation of Erk\/Akt\/NFkB pathway","volume":"51","author":"Moniruzzaman","year":"2018","journal-title":"Biol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Hardeland, R. (2019). Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051223"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.lfs.2017.10.038","article-title":"Oral supplementation of melatonin protects against lupus nephritis renal injury in a pristane-induced lupus mouse model","volume":"193","author":"Favero","year":"2018","journal-title":"Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gao, R., Chen, J., Hu, Y., Li, Z., Wang, S., Shetty, S., and Fu, J. (2014). Sirt1 deletion leads to enhanced inflammation and aggravates endotoxin-induced acute kidney injury. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098909"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1016\/j.cellsig.2013.06.007","article-title":"Antagonistic crosstalk between NF-\u03baB and SIRT1 in the regulation of inflammation and metabolic disorders","volume":"25","author":"Kauppinen","year":"2013","journal-title":"Cell. Signal."},{"key":"ref_29","first-page":"1041","article-title":"The role of miR-146a in modulating TRAF6-induced inflammation during lupus nephritis","volume":"21","author":"Zheng","year":"2017","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.jaut.2018.11.004","article-title":"NF-kB signaling in myeloid cells mediates the pathogenesis of immune-mediated nephritis","volume":"98","author":"Chalmers","year":"2019","journal-title":"J. Autoimmun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s11154-017-9422-3","article-title":"Novel insights into the pathophysiology and clinical aspects of diabetic nephropathy","volume":"18","author":"Ilyas","year":"2017","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_32","first-page":"7659243","article-title":"Markers of Glomerular and Tubular Damage in the Early Stage of Kidney Disease in Type 2 Diabetic Patients","volume":"2018","author":"Dumnicka","year":"2018","journal-title":"Mediat. Inflamm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.jphs.2018.05.012","article-title":"Lentivirus-mediated knockdown of Fc\u03b3RI (CD64) attenuated lupus nephritis via inhibition of NF-\u03baB regulating NLRP3 inflammasome activation in MRL\/lpr mice","volume":"137","author":"Zhang","year":"2018","journal-title":"J. Pharmacol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"100","DOI":"10.3892\/etm.2014.1718","article-title":"A novel NF-\u03baB inhibitor, DHMEQ, ameliorates pristane-induced lupus in mice","volume":"8","author":"Qu","year":"2014","journal-title":"Exp. Ther. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/cr.2010.178","article-title":"Crosstalk of reactive oxygen species and NF-\u03baB signaling","volume":"21","author":"Morgan","year":"2011","journal-title":"Cell Res."},{"key":"ref_36","first-page":"541","article-title":"The effect of cortisone in glomerulonephritis and the nephropathy of disseminated lupus erythematosus","volume":"34","author":"Jacobson","year":"1951","journal-title":"Minn. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1177\/0961203313476155","article-title":"Minimising steroids in lupus nephritis--will B cell depletion pave the way?","volume":"22","author":"Lightstone","year":"2013","journal-title":"Lupus"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.yexmp.2018.12.001","article-title":"Anti-inflammatory and antioxidant effect of melatonin on recovery from muscular trauma induced in rats","volume":"106","author":"Ostjen","year":"2019","journal-title":"Exp. Mol. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s40261-015-0368-5","article-title":"The Safety of Melatonin in Humans","volume":"36","author":"Andersen","year":"2016","journal-title":"Clin. Drug Investig."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/cns.12588","article-title":"Melatonin Stimulates the SIRT1\/Nrf2 Signaling Pathway Counteracting Lipopolysaccharide (LPS)-Induced Oxidative Stress to Rescue Postnatal Rat Brain","volume":"23","author":"Shah","year":"2017","journal-title":"CNS Neurosci. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"BSR20181614","DOI":"10.1042\/BSR20181614","article-title":"Melatonin attenuates acute kidney ischemia\/reperfusion injury in diabetic rats by activation of the SIRT1\/Nrf2\/HO-1 signaling pathway","volume":"39","author":"Shi","year":"2019","journal-title":"Biosci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7629","DOI":"10.1074\/jbc.M110.208173","article-title":"Acetylation-deacetylation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) regulates its transcriptional activity and nucleocytoplasmic localization","volume":"286","author":"Kawai","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.3892\/mmr.2015.4710","article-title":"Resveratrol protects mice from paraquat-induced lung injury: The important role of SIRT1 and NRF2 antioxidant pathways","volume":"13","author":"Li","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.bbr.2017.06.027","article-title":"Nrf2 inhibits NLRP3 inflammasome activation through regulating Trx1\/TXNIP complex in cerebral ischemia reperfusion injury","volume":"336","author":"Hou","year":"2018","journal-title":"Behav. Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.intimp.2018.06.033","article-title":"Melatonin attenuates airway inflammation via SIRT1 dependent inhibition of NLRP3 inflammasome and IL-1\u03b2 in rats with COPD","volume":"62","author":"Peng","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.amjms.2016.10.014","article-title":"Lupus Hepatitis and Autoimmune Hepatitis (Lupoid Hepatitis)","volume":"353","author":"Adiga","year":"2017","journal-title":"Am. J. Med. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.3389\/fimmu.2018.01457","article-title":"Role of Hepatic Deposited Immunoglobulin G in the Pathogenesis of Liver Damage in Systemic Lupus Erythematosus","volume":"9","author":"Fang","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"10934","DOI":"10.1073\/pnas.92.24.10934","article-title":"Anti-nuclear antibody production and immune-complex glomerulonephritis in BALB\/c mice treated with pristane","volume":"92","author":"Satoh","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1111\/cei.12647","article-title":"Targeted IgA Fc receptor I (Fc\u03b1RI) therapy in the early intervention and treatment of pristane-induced lupus nephritis in mice","volume":"181","author":"Liu","year":"2015","journal-title":"Clin. Exp. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.apsb.2016.07.001","article-title":"Salvianolic acid A alleviates renal injury in systemic lupus erythematosus induced by pristane in BALB\/c mice","volume":"7","author":"Lin","year":"2017","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Stacchiotti, A., Favero, G., Giugno, L., Lavazza, A., Reiter, R.J., Rodella, L.F., and Rezzani, R. (2014). Mitochondrial and metabolic dysfunction in renal convoluted tubules of obese mice: Protective role of melatonin. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0111141"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e13084","DOI":"10.14814\/phy2.13084","article-title":"Effects of N-acetyl-seryl-asparyl-lysyl-proline on blood pressure, renal damage, and mortality in systemic lupus erythematosus","volume":"5","author":"Nakagawa","year":"2017","journal-title":"Physiol. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1093\/ndt\/gfh683","article-title":"C-peptide prevents glomerular hypertrophy and mesangial matrix expansion in diabetic rats","volume":"20","author":"Jacobson","year":"2005","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1159\/000450864","article-title":"Insulin Prevents Hyperfiltration and Proteinuria but Not Glomerular Hypertrophy and Increases Mesangial Matrix Expansion in Diabetic Rats","volume":"26","author":"Malatiali","year":"2017","journal-title":"Med. Princ. Pract."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/14\/3466\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:05:41Z","timestamp":1760187941000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/14\/3466"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,15]]},"references-count":54,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2019,7]]}},"alternative-id":["ijms20143466"],"URL":"https:\/\/doi.org\/10.3390\/ijms20143466","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,15]]}}}