{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T10:55:56Z","timestamp":1784717756198,"version":"3.55.0"},"reference-count":92,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,1,25]],"date-time":"2020-01-25T00:00:00Z","timestamp":1579910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["NFP0075515"],"award-info":[{"award-number":["NFP0075515"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Italian Ministry of Health Research Program 2018","award":["RC: 2635256"],"award-info":[{"award-number":["RC: 2635256"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Carnosine is a natural endogenous dipeptide widely distributed in mammalian tissues, existing at particularly high concentrations in the muscles and brain and possesses well-characterized antioxidant and anti-inflammatory activities. In an in vitro model of macrophage activation, induced by lipopolysaccharide + interferon-gamma (LPS + IFN-\u03b3), we here report the ability of carnosine to modulate pro-oxidant and pro-inflammatory activities of macrophages, representing the primary cell type that is activated as a part of the immune response. An ample set of parameters aimed to evaluate cytotoxicity (MTT assay), energy metabolism (HPLC), gene expressions (high-throughput real-time PCR (qRT-PCR)), protein expressions (western blot) and nitric oxide production (qRT-PCR and HPLC), was used to assess the effects of carnosine on activated macrophages challenged with a non cytotoxic LPS (100 ng\/mL) + IFN-\u03b3 (600 U\/mL) concentration. In our experimental model, main carnosine beneficial effects were: (1) the modulation of nitric oxide production and metabolism; (2) the amelioration of the macrophage energy state; (3) the decrease of the expressions of pro-oxidant enzymes (Nox-2, Cox-2) and of the lipid peroxidation product malondialdehyde; (4) the restoration and\/or increase of the expressions of antioxidant enzymes (Gpx1, SOD-2 and Cat); (5) the increase of the transforming growth factor-\u03b21 (TGF-\u03b21) and the down-regulation of the expressions of interleukins 1\u03b2 and 6 (IL-1\u03b2 and IL-6) and 6) the increase of the expressions of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1). According to these results carnosine is worth being tested in the treatment of diseases characterized by elevated levels of oxidative stress and inflammation (atherosclerosis, cancer, depression, metabolic syndrome, and neurodegenerative diseases).<\/jats:p>","DOI":"10.3390\/ijms21030776","type":"journal-article","created":{"date-parts":[[2020,1,27]],"date-time":"2020-01-27T07:41:11Z","timestamp":1580110871000},"page":"776","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":94,"title":["Modulation of Pro-Oxidant and Pro-Inflammatory Activities of M1 Macrophages by the Natural Dipeptide Carnosine"],"prefix":"10.3390","volume":"21","author":[{"given":"Claudia G.","family":"Fresta","sequence":"first","affiliation":[{"name":"Ralph N. Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS 66047-1620, USA"},{"name":"Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047-1620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Fidilio","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Lazzarino","sequence":"additional","affiliation":[{"name":"UniCamillus\u2014Saint Camillus International University of Health Sciences, 00131 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicol\u00f2","family":"Musso","sequence":"additional","affiliation":[{"name":"Bio-nanotech Research and Innovation Tower (BRIT), University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Grasso","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Catania, 95125 Catania, Italy"},{"name":"Oasi Research Institute\u2014IRCCS, 94018 Troina (EN), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6558-9800","authenticated-orcid":false,"given":"Sara","family":"Merlo","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3525-9955","authenticated-orcid":false,"given":"Angela M.","family":"Amorini","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Bucolo","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8743-0895","authenticated-orcid":false,"given":"Barbara","family":"Tavazzi","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Clinical Biochemistry, Catholic University of Rome, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5917-7279","authenticated-orcid":false,"given":"Giuseppe","family":"Lazzarino","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Lunte","sequence":"additional","affiliation":[{"name":"Ralph N. Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS 66047-1620, USA"},{"name":"Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047-1620, USA"},{"name":"Department of Chemistry, University of Kansas, Lawrence, KS 66047-1620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Caraci","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Catania, 95125 Catania, Italy"},{"name":"Oasi Research Institute\u2014IRCCS, 94018 Troina (EN), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1571-5327","authenticated-orcid":false,"given":"Giuseppe","family":"Caruso","sequence":"additional","affiliation":[{"name":"Oasi Research Institute\u2014IRCCS, 94018 Troina (EN), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1146\/annurev.immunol.021908.132532","article-title":"Alternative activation of macrophages: An immunologic functional perspective","volume":"27","author":"Martinez","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1111\/brv.12234","article-title":"Circulating phagocytes: The ancient and conserved interface between immune and neuroendocrine function","volume":"92","author":"Malagoli","year":"2017","journal-title":"Biol. Rev. Camb. Philos. Soc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.imlet.2018.10.013","article-title":"Critical regulation of th17 cell differentiation by serum amyloid-a signalling in behcet\u2019s disease","volume":"201","author":"Lucherini","year":"2018","journal-title":"Immunol. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"200","DOI":"10.3389\/fimmu.2017.00200","article-title":"Cytokine signatures in mucocutaneous and ocular behcet\u2019s disease","volume":"8","author":"Lopalco","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.freeradbiomed.2014.03.019","article-title":"Detection of superoxide production in stimulated and unstimulated living cells using new cyclic nitrone spin traps","volume":"71","author":"Abbas","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Caruso, G., Fresta, C.G., Fidilio, A., O\u2019Donnell, F., Musso, N., Lazzarino, G., Grasso, M., Amorini, A.M., Tascedda, F., and Bucolo, C. (2019). Carnosine decreases pma-induced oxidative stress and inflammation in murine macrophages. Antioxidants (Basel), 8.","DOI":"10.3390\/antiox8080281"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.4161\/cc.6.14.4438","article-title":"Lps\/ifngamma-induced raw 264.7 apoptosis is regulated by both nitric oxide-dependent and -independent pathways involving jnk and the bcl-2 family","volume":"6","author":"Seminara","year":"2007","journal-title":"Cell Cycle"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s12026-012-8291-9","article-title":"Macrophage polarization and plasticity in health and disease","volume":"53","author":"Biswas","year":"2012","journal-title":"Immunol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1016\/S1734-1140(13)71528-7","article-title":"Macrophages and depression\u2014A misalliance or well-arranged marriage?","volume":"65","author":"Roman","year":"2013","journal-title":"Pharmacol. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.bcp.2018.02.010","article-title":"The macrophage heme-heme oxygenase-1 system and its role in inflammation","volume":"153","author":"Vijayan","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.abb.2014.09.005","article-title":"Heme oxygenase-1 and anti-inflammatory m2 macrophages","volume":"564","author":"Naito","year":"2014","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/S0076-6879(05)96035-7","article-title":"Cytotoxic and cytoprotective actions of o2- and no (onoo-) are determined both by cellular gsh level and ho activity in macrophages","volume":"396","author":"Srisook","year":"2005","journal-title":"Methods Enzymol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"131","DOI":"10.4037\/ajcc1998.7.2.131","article-title":"Nitric oxide and regulation of vascular tone: Pharmacological and physiological considerations","volume":"7","author":"McHugh","year":"1998","journal-title":"Am. J. Crit. Care"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1096\/fj.03-1450fje","article-title":"Nitric oxide levels regulate macrophage commitment to apoptosis or necrosis during pneumococcal infection","volume":"18","author":"Marriott","year":"2004","journal-title":"FASEB J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/ni1001-907","article-title":"Nitric oxide and the immune response","volume":"2","author":"Bogdan","year":"2001","journal-title":"Nat. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.lfs.2003.10.042","article-title":"Inos-mediated nitric oxide production and its regulation","volume":"75","author":"Aktan","year":"2004","journal-title":"Life Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1152\/physrev.00029.2006","article-title":"Nitric oxide and peroxynitrite in health and disease","volume":"87","author":"Pacher","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7003","DOI":"10.1007\/s00216-015-8865-1","article-title":"Indirect detection of superoxide in raw 264.7 macrophage cells using microchip electrophoresis coupled to laser-induced fluorescence","volume":"407","author":"Siegel","year":"2015","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1111\/j.1749-6632.2002.tb04069.x","article-title":"Nitric oxide and superoxide, a deadly cocktail","volume":"962","author":"Estevez","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/S0304-4165(99)00189-0","article-title":"Hydrogen peroxide-mediated cu,zn-superoxide dismutase fragmentation: Protection by carnosine, homocarnosine and anserine","volume":"1472","author":"Choi","year":"1999","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1039\/C6AY03009B","article-title":"Monitoring carnosine uptake by raw 264.7 macrophage cells using microchip electrophoresis with fluorescence detection","volume":"9","author":"Fresta","year":"2017","journal-title":"Anal. Methods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3023","DOI":"10.1161\/STROKEAHA.107.488502","article-title":"Carnosine is neuroprotective against permanent focal cerebral ischemia in mice","volume":"38","author":"Rajanikant","year":"2007","journal-title":"Stroke"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Caruso, G., Fresta, C.G., Musso, N., Giambirtone, M., Grasso, M., Spampinato, S.F., Merlo, S., Drago, F., Lazzarino, G., and Sortino, M.A. (2019). Carnosine prevents abeta-induced oxidative stress and inflammation in microglial cells: A key role of tgf-beta1. Cells, 8.","DOI":"10.3390\/cells8010064"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/0006-3002(59)90437-8","article-title":"Carnosineanserine synthetase of muscle. I. Preparation and properties of soluble enzyme from chick muscle","volume":"31","author":"Winnick","year":"1959","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1249\/MSS.0b013e3181c74e38","article-title":"Role of beta-alanine supplementation on muscle carnosine and exercise performance","volume":"42","author":"Artioli","year":"2010","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/j.1749-6632.1998.tb09890.x","article-title":"Pluripotent protective effects of carnosine, a naturally occurring dipeptide","volume":"854","author":"Hipkiss","year":"1998","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Schon, M., Mousa, A., Berk, M., Chia, W.L., Ukropec, J., Majid, A., Ukropcova, B., and de Courten, B. (2019). The potential of carnosine in brain-related disorders: A comprehensive review of current evidence. Nutrients, 11.","DOI":"10.3390\/nu11061196"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/BF00376439","article-title":"Carnosine and anserine concentrations in the quadriceps femoris muscle of healthy humans","volume":"64","author":"Mannion","year":"1992","journal-title":"Eur. J. Appl. Physiol. Occup. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"44492","DOI":"10.1038\/srep44492","article-title":"Carnosine attenuates the development of both type 2 diabetes and diabetic nephropathy in btbr ob\/ob mice","volume":"7","author":"Albrecht","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Caruso, G., Fresta, C.G., Grasso, M., Santangelo, R., Lazzarino, G., Lunte, S.M., and Caraci, F. (2019). Inflammation as the common biological link between depression and cardiovascular diseases: Can carnosine exert a protective role?. Curr. Med. Chem.","DOI":"10.2174\/0929867326666190712091515"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.ejphar.2011.06.003","article-title":"Carnosine pretreatment protects against hypoxia-ischemia brain damage in the neonatal rat model","volume":"667","author":"Zhang","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"983","DOI":"10.3233\/JAD-2012-121324","article-title":"Beta-alanyl-l-histidine rescues cognitive deficits caused by feeding a high fat diet in a transgenic mouse model of alzheimer\u2019s disease","volume":"33","author":"Herculano","year":"2013","journal-title":"J. Alzheimers Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s11010-017-2991-3","article-title":"Carnosine modulates nitric oxide in stimulated murine raw 264.7 macrophages","volume":"431","author":"Caruso","year":"2017","journal-title":"Mol. Cell. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4529","DOI":"10.1007\/s00216-017-0401-z","article-title":"Microchip electrophoresis with laser-induced fluorescence detection for the determination of the ratio of nitric oxide to superoxide production in macrophages during inflammation","volume":"409","author":"Caruso","year":"2017","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s11010-016-2864-1","article-title":"Receptor-mediated toxicity of human amylin fragment aggregated by short- and long-term incubations with copper ions","volume":"425","author":"Caruso","year":"2017","journal-title":"Mol. Cell. Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Caruso, G., Fresta, C.G., Lazzarino, G., Distefano, D.A., Parlascino, P., Lunte, S.M., Lazzarino, G., and Caraci, F. (2018). Sub-toxic human amylin fragment concentrations promote the survival and proliferation of sh-sy5y cells via the release of vegf and hspb5 from endothelial rbe4 cells. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113659"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ab.2003.07.013","article-title":"Single-sample preparation for simultaneous cellular redox and energy state determination","volume":"322","author":"Lazzarino","year":"2003","journal-title":"Anal. Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1093\/humrep\/dey279","article-title":"Low-molecular weight compounds in human seminal plasma as potential biomarkers of male infertility","volume":"33","author":"Lazzarino","year":"2018","journal-title":"Hum. Reprod."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"11252","DOI":"10.1038\/srep11252","article-title":"A key role for tgf-beta1 in hippocampal synaptic plasticity and memory","volume":"5","author":"Caraci","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative pcr and the 2(-delta delta c(t)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Barresi, V., Ragusa, A., Fichera, M., Musso, N., Castiglia, L., Rappazzo, G., Travali, S., Mattina, T., Romano, C., and Cocchi, G. (2010). Decreased expression of graf1\/ophn-1-l in the x-linked alpha thalassemia mental retardation syndrome. BMC Med. Genom., 3.","DOI":"10.1186\/1755-8794-3-28"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1042\/BJ20110162","article-title":"Assessing mitochondrial dysfunction in cells","volume":"435","author":"Brand","year":"2011","journal-title":"Biochem. J."},{"key":"ref_43","first-page":"145","article-title":"Oxidative stress and inflammatory markers\u2014The future of heart failure diagnostics?","volume":"12","author":"Szczurek","year":"2015","journal-title":"Kardiochir. Torakochirurgia Pol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1016\/j.phytochem.2007.11.012","article-title":"Stimulus (polyphenol, ifn-gamma, lps)-dependent nitric oxide production and antileishmanial effects in raw 264.7 macrophages","volume":"69","author":"Kolodziej","year":"2008","journal-title":"Phytochemistry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1080\/152165400306232","article-title":"Osteopontin is induced by nitric oxide in raw 264.7 cells","volume":"49","author":"Takahashi","year":"2000","journal-title":"IUBMB Life"},{"key":"ref_46","first-page":"264","article-title":"Schisandrin a suppresses lipopolysaccharide-induced inflammation and oxidative stress in raw 264.7 macrophages by suppressing the nf-kappab, mapks and pi3k\/akt pathways and activating nrf2\/ho-1 signaling","volume":"41","author":"Kwon","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1089\/ars.2007.1670","article-title":"Oxidative stress, lipid rafts, and macrophage reprogramming","volume":"9","author":"Cuschieri","year":"2007","journal-title":"Antioxid. Redox Signal."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1007\/s12035-013-8425-7","article-title":"Role of the toll like receptor (tlr) radical cycle in chronic inflammation: Possible treatments targeting the tlr4 pathway","volume":"48","author":"Lucas","year":"2013","journal-title":"Mol. Neurobiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.mito.2014.09.002","article-title":"Atp\/adp ratio, the missed connection between mitochondria and the warburg effect","volume":"19 Pt A","author":"Maldonado","year":"2014","journal-title":"Mitochondrion"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.bbadis.2016.01.023","article-title":"Metabolic, enzymatic and gene involvement in cerebral glucose dysmetabolism after traumatic brain injury","volume":"1862","author":"Amorini","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"41265","DOI":"10.18632\/oncotarget.17172","article-title":"Rewiring carbohydrate catabolism differentially affects survival of pancreatic cancer cell lines with diverse metabolic profiles","volume":"8","author":"Tataranni","year":"2017","journal-title":"Oncotarget"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Hu, L., Zhang, S., Wen, H., Liu, T., Cai, J., Du, D., Zhu, D., Chen, F., and Xia, C. (2019). Melatonin decreases m1 polarization via attenuating mitochondrial oxidative damage depending on ucp2 pathway in prorenin-treated microglia. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0212138"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.freeradbiomed.2018.04.581","article-title":"The proinflammatory effects of macrophage-derived nadph oxidase function in autoimmune diabetes","volume":"125","author":"Feduska","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_54","first-page":"739","article-title":"The biological role of carnosine and its possible applications in medicine","volume":"22","author":"Budzen","year":"2013","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.pneurobio.2018.12.004","article-title":"Pivotal role of carnosine in the modulation of brain cells activity: Multimodal mechanism of action and therapeutic potential in neurodegenerative disorders","volume":"175","author":"Caruso","year":"2019","journal-title":"Prog. Neurobiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1080\/08923973.2017.1344987","article-title":"Zinc l-carnosine suppresses inflammatory responses in lipopolysaccharide-induced raw 264.7 murine macrophages cell line via activation of nrf2\/ho-1 signaling pathway","volume":"39","author":"Ooi","year":"2017","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_57","first-page":"62","article-title":"Neuropeptide carnosine increases stability of lipoproteins and red blood cells as well as efficiency of immune competent system in patients with chronic discirculatory encephalopathy","volume":"3","author":"Fedorova","year":"2009","journal-title":"Biochem. (Mosc.) Suppl. Ser. A Membr. Cell Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.peptides.2016.10.008","article-title":"Carnosine ameliorates cognitive deficits in streptozotocin-induced diabetic rats: Possible involved mechanisms","volume":"86","author":"Zamani","year":"2016","journal-title":"Peptides"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"28868","DOI":"10.18632\/oncotarget.7563","article-title":"Heme oxygenase-1 nuclear translocation regulates bortezomibinduced cytotoxicity and mediates genomic instability in myeloma cells","volume":"7","author":"Tibullo","year":"2016","journal-title":"Oncotarget"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"69075","DOI":"10.18632\/oncotarget.11923","article-title":"The non-canonical functions of the heme oxygenases","volume":"7","author":"Vanella","year":"2016","journal-title":"Oncotarget"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1089\/ars.2016.6735","article-title":"The heme oxygenase system in hematological malignancies","volume":"27","author":"Tibullo","year":"2017","journal-title":"Antioxid. Redox Signal."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Raffaele, M., Carota, G., Sferrazzo, G., Licari, M., Barbagallo, I., Sorrenti, V., Signorelli, S.S., and Vanella, L. (2019). Inhibition of heme oxygenase antioxidant activity exacerbates hepatic steatosis and fibrosis in vitro. Antioxidants (Basel), 8.","DOI":"10.3390\/antiox8080277"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41419-018-0280-z","article-title":"Non-toxic engineered carbon nanodiamond concentrations induce oxidative\/nitrosative stress, imbalance of energy metabolism, and mitochondrial dysfunction in microglial and alveolar basal epithelial cells","volume":"9","author":"Fresta","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1016\/j.peptides.2009.04.003","article-title":"Inhibitory effect of carnosine and n-acetyl carnosine on lps-induced microglial oxidative stress and inflammation","volume":"30","author":"Apte","year":"2009","journal-title":"Peptides"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1152\/japplphysiol.00879.2015","article-title":"Effects of sodium nitrite supplementation on vascular function and related small metabolite signatures in middle-aged and older adults","volume":"120","author":"DeVan","year":"2016","journal-title":"J. Appl. Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Lee, S., Yu, S., Park, H.J., Jung, J., Go, G.W., and Kim, W. (2019). Rice bran oil ameliorates inflammatory responses by enhancing mitochondrial respiration in murine macrophages. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0222857"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"101147","DOI":"10.1016\/j.redox.2019.101147","article-title":"Human and murine macrophages exhibit differential metabolic responses to lipopolysaccharide\u2014A divergent role for glycolysis","volume":"22","author":"Vijayan","year":"2019","journal-title":"Redox Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1042\/CS20150660","article-title":"Nox2-dependent regulation of inflammation","volume":"130","author":"Singel","year":"2016","journal-title":"Clin. Sci. (Lond.)"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.brainresbull.2016.03.019","article-title":"Carnosine decreased neuronal cell death through targeting glutamate system and astrocyte mitochondrial bioenergetics in cultured neuron\/astrocyte exposed to ogd\/recovery","volume":"124","author":"Ouyang","year":"2016","journal-title":"Brain Res. Bull."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5582","DOI":"10.1007\/s12035-015-9475-9","article-title":"Acute carnosine administration increases respiratory chain complexes and citric acid cycle enzyme activities in cerebral cortex of young rats","volume":"53","author":"Macedo","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/BF02427283","article-title":"Affinity-purified human interleukin i is cytotoxic to isolated islets of langerhans","volume":"29","author":"Bendtzen","year":"1986","journal-title":"Diabetologia"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s42269-018-0016-3","article-title":"Evaluation of pro-inflammatory and anti-inflammatory cytokines in type 1 diabetes mellitus","volume":"42","author":"Gouda","year":"2018","journal-title":"Bull. Natl. Res. Cent."},{"key":"ref_73","doi-asserted-by":"crossref","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":"ref_74","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1742-2094-5-7","article-title":"The role of interleukin-1 in neuroinflammation and alzheimer disease: An evolving perspective","volume":"5","author":"Shaftel","year":"2008","journal-title":"J. Neuroinflamm."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1007\/s00281-006-0015-6","article-title":"Hereditary auto-inflammatory disorders and biologics","volume":"27","author":"Church","year":"2006","journal-title":"Springer Semin. Immunopathol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/ncprheum0681","article-title":"Primer: Inflammasomes and interleukin 1beta in inflammatory disorders","volume":"4","author":"Church","year":"2008","journal-title":"Nat. Clin. Pract. Rheumatol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1523\/JNEUROSCI.2830-13.2014","article-title":"Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain","volume":"34","author":"Campbell","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1161\/CIRCRESAHA.108.182014","article-title":"Interleukin-6 overexpression induces pulmonary hypertension","volume":"104","author":"Steiner","year":"2009","journal-title":"Circ. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1210\/en.2006-0692","article-title":"Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression","volume":"148","author":"Jager","year":"2007","journal-title":"Endocrinology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1124\/jpet.102.041616","article-title":"The cholinergic hypothesis of age and alzheimer\u2019s disease-related cognitive deficits: Recent challenges and their implications for novel drug development","volume":"306","author":"Terry","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.ccr.2011.03.018","article-title":"The unholy trinity: Inflammation, cytokines, and stat3 shape the cancer microenvironment","volume":"19","author":"Li","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.euroneuro.2011.08.006","article-title":"The cc genotype of transforming growth factor-beta1 increases the risk of late-onset alzheimer\u2019s disease and is associated with ad-related depression","volume":"22","author":"Caraci","year":"2012","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.phrs.2018.02.007","article-title":"Neurobiological links between depression and ad: The role of tgf-beta1 signaling as a new pharmacological target","volume":"130","author":"Caraci","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Chen, J.H., Ke, K.F., Lu, J.H., Qiu, Y.H., and Peng, Y.P. (2015). Protection of tgf-beta1 against neuroinflammation and neurodegeneration in abeta1-42-induced alzheimer\u2019s disease model rats. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0116549"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ejphar.2016.02.002","article-title":"Tgf-beta1 prevents rat retinal insult induced by amyloid-beta (1-42) oligomers","volume":"787","author":"Fisichella","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Platania, C.B.M., Fisichella, V., Fidilio, A., Geraci, F., Lazzara, F., Leggio, G.M., Salomone, S., Drago, F., Pignatello, R., and Caraci, F. (2017). Topical ocular delivery of tgf-beta1 to the back of the eye: Implications in age-related neurodegenerative diseases. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102076"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/359693a0","article-title":"Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease","volume":"359","author":"Shull","year":"1992","journal-title":"Nature"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/S0923-2494(97)82669-7","article-title":"Inflammation and tgf beta 1: Lessons from the tgf beta 1 null mouse","volume":"148","author":"Kulkarni","year":"1997","journal-title":"Res. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"693","DOI":"10.3389\/fphar.2019.00693","article-title":"Fluoxetine and vortioxetine reverse depressive-like phenotype and memory deficits induced by abeta1-42 oligomers in mice: A key role of transforming growth factor-beta1","volume":"10","author":"Torrisi","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1016\/j.jnutbio.2015.08.001","article-title":"The complexity of the nrf2 pathway: Beyond the antioxidant response","volume":"26","author":"Huang","year":"2015","journal-title":"J. Nutr. Biochem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5487\/TR.2017.33.1.001","article-title":"Oxidative stress, nrf2, and epigenetic modification contribute to anticancer drug resistance","volume":"33","author":"Kang","year":"2017","journal-title":"Toxicol. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1089\/ars.2007.2019","article-title":"Nrf2-mediated transcriptional induction of antioxidant response in mouse embryos exposed to ethanol in vivo: Implications for the prevention of fetal alcohol spectrum disorders","volume":"10","author":"Dong","year":"2008","journal-title":"Antioxid. Redox Signal."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/3\/776\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:08:32Z","timestamp":1760364512000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/3\/776"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,25]]},"references-count":92,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["ijms21030776"],"URL":"https:\/\/doi.org\/10.3390\/ijms21030776","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,25]]}}}