Inflammation as the Common Biological Link Between Depression and Cardiovascular Diseases: Can Carnosine Exert a Protective Role?

Giuseppe       Caruso; Claudia    G.    Fresta; Margherita       Grasso; Rosa       Santangelo; Giuseppe       Lazzarino; Susan    M.    Lunte; Filippo       Caraci
doi:10.2174/0929867326666190712091515
Abstract

Several epidemiological studies have clearly shown the high co-morbidity between depression and Cardiovascular Diseases (CVD). Different studies have been conducted to identify the common pathophysiological events of these diseases such as the overactivation of the hypothalamic- pituitary-adrenal axis and, most importantly, the dysregulation of immune system which causes a chronic pro-inflammatory status. The biological link between depression, inflammation, and CVD can be related to high levels of pro-inflammatory cytokines, such as IL-1β, TNF-α, and IL-6, released by macrophages which play a central role in the pathophysiology of both depression and CVD. Pro-inflammatory cytokines interfere with many of the pathophysiological mechanisms relevant to depression by upregulating the rate-limiting enzymes in the metabolic pathway of tryptophan and altering serotonin metabolism. These cytokines also increase the risk to develop CVD, because activation of macrophages under this pro-inflammatory status is closely associated with endothelial dysfunction and oxidative stress, a preamble to atherosclerosis and atherothrombosis.
Carnosine (β-alanyl-L-histidine) is an endogenous dipeptide which exerts a strong antiinflammatory activity on macrophages by suppressing reactive species and pro-inflammatory cytokines production and altering pro-inflammatory/anti-inflammatory macrophage polarization. This dipeptide exhibits antioxidant properties scavenging reactive species and preventing oxidative stress-induced pathologies such as CVD.
In the present review we will discuss the role of oxidative stress and chronic inflammation as common pathophysiological events both in depression and CVD and the preclinical and clinical evidence on the protective effect of carnosine in both diseases as well as the therapeutic potential of this dipeptide in depressed patients with a high co-morbidity of cardiovascular diseases.
Keywords: Carnosine, inflammation, oxidative stress, depression, cardiovascular diseases, macrophages.
« Previous Next »
[1] 
Kessler, R.C.; Chiu, W.T.; Demler, O.; Merikangas, K.R.; Walters, E.E. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry,  2005, 62(6), 617-627.
[http://dx.doi.org/10.1001/archpsyc.62.6.617] [PMID: 15939839] 
[2] 
Almeida, O.P. Prevention of depression in older age. Maturitas,  2014, 79(2), 136-141.
[http://dx.doi.org/10.1016/j.maturitas.2014.03.005] [PMID: 24713453] 
[3] 
Stewart, J.; Manmathan, G.; Wilkinson, P. Primary prevention of cardiovascular disease: A review of contemporary guidance and literature. JRSM Cardiovasc. Dis.,  2017, 62048004016687211
[http://dx.doi.org/10.1177/2048004016687211] [PMID: 28286646] 
[4] 
Global Health Estimates 2016: Deaths by Cause, Age, Sex,by Country and by Region, 2000-2016, Geneva, 2018.
[5] 
WHO methods and data sources for global causes of death 2000-2016: Global Health Estimates Technical Paper WHO/HIS/IER/GHE/2018.3, Geneva, 2018.
[6] 
Jiang, W.; Krishnan, R.R.; O’Connor, C.M. Depression and heart disease: evidence of a link, and its therapeutic implications. CNS Drugs,  2002, 16(2), 111-127.
[http://dx.doi.org/10.2165/00023210-200216020-00004] [PMID: 11825102] 
[7] 
Halaris, A. Inflammation-associated co-morbidity between depression and cardiovascular disease. Curr. Top. Behav. Neurosci.,  2017, 31, 45-70.
[http://dx.doi.org/10.1007/7854_2016_28] [PMID: 27830572] 
[8] 
Hare, D.L.; Toukhsati, S.R.; Johansson, P.; Jaarsma, T. Depression and cardiovascular disease: a clinical review. Eur. Heart J.,  2014, 35(21), 1365-1372.
[http://dx.doi.org/10.1093/eurheartj/eht462] [PMID: 24282187] 
[9] 
Dhar, A.K.; Barton, D.A. Depression and the link with cardiovascular disease. Front. Psychiatry,  2016, 7, 33.
[http://dx.doi.org/10.3389/fpsyt.2016.00033] [PMID: 27047396] 
[10] 
Shi, S.; Liang, J.; Liu, T.; Yuan, X.; Ruan, B.; Sun, L.; Tang, Y.; Yang, B.; Hu, D.; Huang, C. Depression increases sympathetic activity and exacerbates myocardial remodeling after myocardial infarction: evidence from an animal experiment. PLoS One,  2014, 9(7)e101734
[http://dx.doi.org/10.1371/journal.pone.0101734] [PMID: 25036781] 
[11] 
Meredith, I.T.; Broughton, A.; Jennings, G.L.; Esler, M.D. Evidence of a selective increase in cardiac sympathetic activity in patients with sustained ventricular arrhythmias. N. Engl. J. Med.,  1991, 325(9), 618-624.
[http://dx.doi.org/10.1056/NEJM199108293250905] [PMID: 1861695] 
[12] 
Kaye, D.M.; Lefkovits, J.; Jennings, G.L.; Bergin, P.; Broughton, A.; Esler, M.D. Adverse consequences of high sympathetic nervous activity in the failing human heart. J. Am. Coll. Cardiol.,  1995, 26(5), 1257-1263.
[http://dx.doi.org/10.1016/0735-1097(95)00332-0] [PMID: 7594040] 
[13] 
Kemp, A.H.; Quintana, D.S.; Gray, M.A.; Felmingham, K.L.; Brown, K.; Gatt, J.M. Impact of depression and antidepressant treatment on heart rate variability: a review and meta-analysis. Biol. Psychiatry,  2010, 67(11), 1067-1074.
[http://dx.doi.org/10.1016/j.biopsych.2009.12.012] [PMID: 20138254] 
[14] 
Shinba, T. Altered autonomic activity and reactivity in depression revealed by heart-rate variability measurement during rest and task conditions. Psychiatry Clin. Neurosci.,  2014, 68(3), 225-233.
[http://dx.doi.org/10.1111/pcn.12123] [PMID: 24313703] 
[15] 
Malik, S.; Wong, N.D.; Franklin, S.S.; Kamath, T.V.; L’Italien, G.J.; Pio, J.R.; Williams, G.R. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation,  2004, 110(10), 1245-1250.
[http://dx.doi.org/10.1161/01.CIR.0000140677.20606.0E] [PMID: 15326067] 
[16] 
Fiedorowicz, J.G. Depression and cardiovascular disease: an update on how course of illness may influence risk. Curr. Psychiatry Rep.,  2014, 16(10), 492.
[http://dx.doi.org/10.1007/s11920-014-0492-6] [PMID: 25163592] 
[17] 
Carroll, B.J.; Curtis, G.C.; Mendels, J. Neuroendocrine regulation in depression. II. Discrimination of depressed from nondepressed patients. Arch. Gen. Psychiatry,  1976, 33(9), 1051-1058.
[http://dx.doi.org/10.1001/archpsyc.1976.01770090041003] [PMID: 962489] 
[18] 
Carroll, ; Curtis, G.C.; Mendels, J. Neuroendocrine regulation in depression. I. Limbic system-adrenocortical dysfunction. Arch. Gen. Psychiatry,  1976, 33(9), 1039-1044.
[http://dx.doi.org/10.1001/archpsyc.1976.01770090029002] [PMID: 962488] 
[19] 
Rosmond, R.; Björntorp, P. The hypothalamic-pituitary-adrenal axis activity as a predictor of cardiovascular disease, type 2 diabetes and stroke. J. Intern. Med.,  2000, 247(2), 188-197.
[http://dx.doi.org/10.1046/j.1365-2796.2000.00603.x] [PMID: 10692081] 
[20] 
Jokinen, J.; Nordström, P. HPA axis hyperactivity and cardiovascular mortality in mood disorder inpatients. J. Affect. Disord.,  2009, 116(1-2), 88-92.
[http://dx.doi.org/10.1016/j.jad.2008.10.025] [PMID: 19054568] 
[21] 

KT, J.Y; Babic, N.; Hannoush, Z.C. Endocrine Testing Protocols: Hypothalamic Pituitary Adrenal Axis; Endotext, 2000. 
[22] 
Bhattacharya, A.; Drevets, W.C. Role of Neuro-immunological factors in the pathophysiology of mood disorders: implications for novel therapeutics for treatment resistant depression. Curr. Top. Behav. Neurosci.,  2017, 31, 339-356.
[http://dx.doi.org/10.1007/7854_2016_43] [PMID: 27677784] 
[23] 
Remus, J.L.; Dantzer, R. Inflammation models of depression in rodents: relevance to psychotropic drug discovery. Int. J. Neuropsychopharmacol.,  2016, 19(9)pyw028
[http://dx.doi.org/10.1093/ijnp/pyw028] [PMID: 27026361] 
[24] 
Caraci, F.; Copani, A.; Nicoletti, F.; Drago, F. Depression and Alzheimer’s disease: neurobiological links and common pharmacological targets. Eur. J. Pharmacol.,  2010, 626(1), 64-71.
[http://dx.doi.org/10.1016/j.ejphar.2009.10.022] [PMID: 19837057] 
[25] 
Maes, M.; Nowak, G.; Caso, J.R.; Leza, J.C.; Song, C.; Kubera, M.; Klein, H.; Galecki, P.; Noto, C.; Glaab, E.; Balling, R.; Berk, M. Toward omics-based, systems biomedicine, and path and drug discovery methodologies for depression-inflammation research. Mol. Neurobiol.,  2016, 53(5), 2927-2935.
[http://dx.doi.org/10.1007/s12035-015-9183-5] [PMID: 25934103] 
[26] 
Pariante, C.M. Why are depressed patients inflamed? A reflection on 20 years of research on depression, glucocorticoid resistance and inflammation. Eur. Neuropsychopharmacol.,  2017, 27(6), 554-559.
[http://dx.doi.org/10.1016/j.euroneuro.2017.04.001] [PMID: 28479211] 
[27] 
Szczepanska-Sadowska, E.; Cudnoch-Jedrzejewska, A.; Ufnal, M.; Zera, T. Brain and cardiovascular diseases: common neurogenic background of cardiovascular, metabolic and inflammatory diseases. J. Physiol. Pharmacol.,  2010, 61(5), 509-521.
[PMID: 21081794] 
[28] 
Baghai, T.C.; Varallo-Bedarida, G.; Born, C.; Häfner, S.; Schüle, C.; Eser, D.; Zill, P.; Manook, A.; Weigl, J.; Jooyandeh, S.; Nothdurfter, C.; von Schacky, C.; Bondy, B.; Rupprecht, R. Classical risk factors and inflammatory biomarkers: one of the missing biological links between cardiovascular disease and major depressive disorder. Int. J. Mol. Sci.,  2018, 19(6)E1740
[http://dx.doi.org/10.3390/ijms19061740] [PMID: 29895759] 
[29] 
Capuron, L.; Miller, A.H. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol. Ther.,  2011, 130(2), 226-238.
[http://dx.doi.org/10.1016/j.pharmthera.2011.01.014] [PMID: 21334376] 
[30] 
Benatti, C.; Blom, J.M.; Rigillo, G.; Alboni, S.; Zizzi, F.; Torta, R.; Brunello, N.; Tascedda, F. Disease-induced neuroinflammation and depression. CNS Neurol. Disord. Drug Targets,  2016, 15(4), 414-433.
[http://dx.doi.org/10.2174/1871527315666160321104749] [PMID: 26996176] 
[31] 
Maes, M. Major depression and activation of the inflammatory response system. Adv. Exp. Med. Biol.,  1999, 461, 25-46.
[http://dx.doi.org/10.1007/978-0-585-37970-8_2] [PMID: 10442165] 
[32] 
Myint, A.M.; Leonard, B.E.; Steinbusch, H.W.; Kim, Y.K. Th1, Th2, and Th3 cytokine alterations in major depression. J. Affect. Disord.,  2005, 88(2), 167-173.
[http://dx.doi.org/10.1016/j.jad.2005.07.008] [PMID: 16126278] 
[33] 
Musil, R.; Schwarz, M.J.; Riedel, M.; Dehning, S.; Cerovecki, A.; Spellmann, I.; Arolt, V.; Müller, N. Elevated macrophage migration inhibitory factor and decreased transforming growth factor-beta levels in major depression--no influence of celecoxib treatment. J. Affect. Disord.,  2011, 134(1-3), 217-225.
[http://dx.doi.org/10.1016/j.jad.2011.05.047] [PMID: 21684012] 
[34] 
Rush, G.; O’Donovan, A.; Nagle, L.; Conway, C.; McCrohan, A.; O’Farrelly, C.; Lucey, J.V.; Malone, K.M. Alteration of immune markers in a group of melancholic depressed patients and their response to electroconvulsive therapy. J. Affect. Disord.,  2016, 205, 60-68.
[http://dx.doi.org/10.1016/j.jad.2016.06.035] [PMID: 27414954] 
[35] 
Caraci, F.; Spampinato, S.F.; Morgese, M.G.; Tascedda, F.; Salluzzo, M.G.; Giambirtone, M.C.; Caruso, G.; Munafò, A.; Torrisi, S.A.; Leggio, G.M.; Trabace, L.; Nicoletti, F.; Drago, F.; Sortino, M.A.; Copani, A. Neurobiological links between depression and AD: The role of TGF-β1 signaling as a new pharmacological target. Pharmacol. Res.,  2018, 130, 374-384.
[http://dx.doi.org/10.1016/j.phrs.2018.02.007] [PMID: 29438781] 
[36] 
Strawbridge, R.; Arnone, D.; Danese, A.; Papadopoulos, A.; Herane Vives, A.; Cleare, A.J. Inflammation and clinical response to treatment in depression: A meta-analysis. Eur. Neuropsychopharmacol.,  2015, 25(10), 1532-1543.
[http://dx.doi.org/10.1016/j.euroneuro.2015.06.007] [PMID: 26169573] 
[37] 
Caraci, F.; Calabrese, F.; Molteni, R.; Bartova, L.; Dold, M.; Leggio, G.M.; Fabbri, C.; Mendlewicz, J.; Racagni, G.; Kasper, S.; Riva, M.A.; Drago, F. International Union of Basic and Clinical Pharmacology CIV: The neurobiology of treatment-resistant depression: from antidepressant classifications to novel pharmacological targets. Pharmacol. Rev.,  2018, 70(3), 475-504.
[http://dx.doi.org/10.1124/pr.117.014977] [PMID: 29884653] 
[38] 
Dey, A.; Hankey Giblin, P.A. Insights into Macrophage Heterogeneity and cytokine-induced neuroinflammation in major depressive disorder. Pharmaceuticals (Basel),  2018, 11(3)E64
[http://dx.doi.org/10.3390/ph11030064] [PMID: 29941796] 
[39] 
Biswas, S.K.; Chittezhath, M.; Shalova, I.N.; Lim, J.Y. Macrophage polarization and plasticity in health and disease. Immunol. Res.,  2012, 53(1-3), 11-24.
[http://dx.doi.org/10.1007/s12026-012-8291-9] [PMID: 22418728] 
[40] 
Roman, A.; Kreiner, G.; Nalepa, I. Macrophages and depression - a misalliance or well-arranged marriage? Pharmacol. Rep.,  2013, 65(6), 1663-1672.
[http://dx.doi.org/10.1016/S1734-1140(13)71528-7] [PMID: 24553015] 
[41] 
Haapakoski, R.; Ebmeier, K.P.; Alenius, H.; Kivimäki, M. Innate and adaptive immunity in the development of depression: An update on current knowledge and technological advances. Prog. Neuropsychopharmacol. Biol. Psychiatry,  2016, 66, 63-72.
[http://dx.doi.org/10.1016/j.pnpbp.2015.11.012] [PMID: 26631274] 
[42] 
Torres-Platas, S.G.; Cruceanu, C.; Chen, G.G.; Turecki, G.; Mechawar, N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav. Immun.,  2014, 42, 50-59.
[http://dx.doi.org/10.1016/j.bbi.2014.05.007] [PMID: 24858659] 
[43] 
Haroon, E.; Raison, C.L.; Miller, A.H. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology,  2012, 37(1), 137-162.
[http://dx.doi.org/10.1038/npp.2011.205] [PMID: 21918508] 
[44] 
Pace, T.W.; Mletzko, T.C.; Alagbe, O.; Musselman, D.L.; Nemeroff, C.B.; Miller, A.H.; Heim, C.M. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am. J. Psychiatry,  2006, 163(9), 1630-1633.
[http://dx.doi.org/10.1176/ajp.2006.163.9.1630] [PMID: 16946190] 
[45] 
Campbell, B.M.; Charych, E.; Lee, A.W.; Möller, T. Kynurenines in CNS disease: regulation by inflammatory cytokines. Front. Neurosci.,  2014, 8, 12.
[http://dx.doi.org/10.3389/fnins.2014.00012] [PMID: 24567701] 
[46] 
Leonard, B.E. Inflammation, depression and dementia: are they connected? Neurochem. Res.,  2007, 32(10), 1749-1756.
[http://dx.doi.org/10.1007/s11064-007-9385-y] [PMID: 17705097] 
[47] 
Leonard, B.E. The concept of depression as a dysfunction of the immune system. Curr. Immunol. Rev.,  2010, 6(3), 205-212.
[http://dx.doi.org/10.2174/157339510791823835] [PMID: 21170282] 
[48] 
Bilici, M.; Efe, H.; Köroğlu, M.A.; Uydu, H.A.; Bekaroğlu, M.; Değer, O. Antioxidative enzyme activities and lipid peroxidation in major depression: alterations by antidepressant treatments. J. Affect. Disord.,  2001, 64(1), 43-51.
[http://dx.doi.org/10.1016/S0165-0327(00)00199-3] [PMID: 11292519] 
[49] 
Raedler, T.J. Inflammatory mechanisms in major depressive disorder. Curr. Opin. Psychiatry,  2011, 24(6), 519-525.
[http://dx.doi.org/10.1097/YCO.0b013e32834b9db6] [PMID: 21897249] 
[50] 
Alcocer-Gómez, E.; de Miguel, M.; Casas-Barquero, N.; Núñez-Vasco, J.; Sánchez-Alcazar, J.A.; Fernández-Rodríguez, A.; Cordero, M.D. NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder. Brain Behav. Immun.,  2014, 36, 111-117.
[http://dx.doi.org/10.1016/j.bbi.2013.10.017] [PMID: 24513871] 
[51] 
Blann, A.D.; Lip, G.Y.; McCollum, C.N. Changes in von Willebrand factor and soluble ICAM, but not soluble VCAM, soluble E selectin or soluble thrombomodulin, reflect the natural history of the progression of atherosclerosis. Atherosclerosis,  2002, 165(2), 389-391.
[http://dx.doi.org/10.1016/S0021-9150(02)00184-3] [PMID: 12417293] 
[52] 
Fioranelli, M.; Bottaccioli, A.G.; Bottaccioli, F.; Bianchi, M.; Rovesti, M.; Roccia, M.G. Stress and inflammation in coronary artery disease: a review psychoneuroendocrineimmunology-based. Front. Immunol.,  2018, 9, 2031.
[http://dx.doi.org/10.3389/fimmu.2018.02031] [PMID: 30237802] 
[53] 
Li, Y.Y.; Zhou, Y.H.; Gong, G.; Geng, H.Y.; Yang, X.X. TGF-β1 Gene -509C/T Polymorphism and coronary artery disease: an updated meta-analysis involving 11,701 subjects. Front. Physiol.,  2017, 8, 108.
[http://dx.doi.org/10.3389/fphys.2017.00108] [PMID: 28280469] 
[54] 
Grainger, D.J.; Kemp, P.R.; Metcalfe, J.C.; Liu, A.C.; Lawn, R.M.; Williams, N.R.; Grace, A.A.; Schofield, P.M.; Chauhan, A. The serum concentration of active transforming growth factor-beta is severely depressed in advanced atherosclerosis. Nat. Med.,  1995, 1(1), 74-79.
[http://dx.doi.org/10.1038/nm0195-74] [PMID: 7584958] 
[55] 
McCaffrey, T.A.; Du, B.; Fu, C.; Bray, P.J.; Sanborn, T.A.; Deutsch, E.; Tarazona, N.; Shaknovitch, A.; Newman, G.; Patterson, C.; Bush, H.L., Jr The expression of TGF-beta receptors in human atherosclerosis: evidence for acquired resistance to apoptosis due to receptor imbalance. J. Mol. Cell. Cardiol.,  1999, 31(9), 1627-1642.
[http://dx.doi.org/10.1006/jmcc.1999.0999] [PMID: 10471347] 
[56] 
Papanicolaou, D.A.; Wilder, R.L.; Manolagas, S.C.; Chrousos, G.P. The pathophysiologic roles of interleukin-6 in human disease. Ann. Intern. Med.,  1998, 128(2), 127-137.
[http://dx.doi.org/10.7326/0003-4819-128-2-199801150-00009] [PMID: 9441573] 
[57] 
Empana, J.P.; Jouven, X.; Canouï-Poitrine, F.; Luc, G.; Tafflet, M.; Haas, B.; Arveiler, D.; Ferrieres, J.; Ruidavets, J.B.; Montaye, M.; Yarnell, J.; Morange, P.; Kee, F.; Evans, A.; Amouyel, P.; Ducimetiere, P. C-reactive protein, interleukin 6, fibrinogen and risk of sudden death in European middle-aged men: the PRIME study. Arterioscler. Thromb. Vasc. Biol.,  2010, 30(10), 2047-2052.
[http://dx.doi.org/10.1161/ATVBAHA.110.208785] [PMID: 20651278] 
[58] 
Mainz, E.R.; Gunasekara, D.B.; Caruso, G.; Jensen, D.T.; Hulvey, M.K.; da Silva, J.A.F.; Metto, E.C.; Culbertson, A.H.; Culbertson, C.T.; Lunte, S.M. Monitoring intracellular nitric oxide production using microchip electrophoresis and laser-induced fluorescence detection. Anal. Methods,  2012, 4, 414-420.
[http://dx.doi.org/10.1039/c2ay05542b] 
[59] 
de Campos, R.P.; Siegel, J.M.; Fresta, C.G.; Caruso, G.; da Silva, J.A.; Lunte, S.M. Indirect detection of superoxide in RAW 264.7 macrophage cells using microchip electrophoresis coupled to laser-induced fluorescence. Anal. Bioanal. Chem.,  2015, 407(23), 7003-7012.
[http://dx.doi.org/10.1007/s00216-015-8865-1] [PMID: 26159570] 
[60] 
Birben, E.; Sahiner, U.M.; Sackesen, C.; Erzurum, S.; Kalayci, O. Oxidative stress and antioxidant defense. World Allergy Organ. J.,  2012, 5(1), 9-19.
[http://dx.doi.org/10.1097/WOX.0b013e3182439613] [PMID: 23268465] 
[61] 
Gunasekara, D.B.; Siegel, J.M.; Caruso, G.; Hulvey, M.K.; Lunte, S.M. Microchip electrophoresis with amperometric detection method for profiling cellular nitrosative stress markers. Analyst (Lond.),  2014, 139(13), 3265-3273.
[http://dx.doi.org/10.1039/C4AN00185K] [PMID: 24728039] 
[62] 
Weidinger, A.; Kozlov, A.V. Biological activities of reactive oxygen and nitrogen species: oxidative stress versus signal transduction. Biomolecules,  2015, 5(2), 472-484.
[http://dx.doi.org/10.3390/biom5020472] [PMID: 25884116] 
[63] 
Siti, H.N.; Kamisah, Y.; Kamsiah, J. The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review). Vascul. Pharmacol.,  2015, 71, 40-56.
[http://dx.doi.org/10.1016/j.vph.2015.03.005] [PMID: 25869516] 
[64] 
Michel, T.M.; Pülschen, D.; Thome, J. The role of oxidative stress in depressive disorders. Curr. Pharm. Des.,  2012, 18(36), 5890-5899.
[http://dx.doi.org/10.2174/138161212803523554] [PMID: 22681168] 
[65] 
Martinez, F.O.; Helming, L.; Gordon, S. Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol.,  2009, 27, 451-483.
[http://dx.doi.org/10.1146/annurev.immunol.021908.132532] [PMID: 19105661] 
[66] 
Beckman, J.S.; Crow, J.P. Pathological implications of nitric oxide, superoxide and peroxynitrite formation. Biochem. Soc. Trans.,  1993, 21(2), 330-334.
[http://dx.doi.org/10.1042/bst0210330] [PMID: 8395426] 
[67] 
Borutaite, V.; Hope, H.; Brown, G.C. Arachidonate and NADPH oxidase synergise with iNOS to induce death in macrophages: mechanisms of inflammatory degeneration. Pharmacol. Rep.,  2006, 58(Suppl.), 96-102.
[PMID: 17332678] 
[68] 
Elhelu, M.A. The role of macrophages in immunology. J. Natl. Med. Assoc.,  1983, 75(3), 314-317.
[PMID: 6343621] 
[69] 
Liu, Y.C.; Zou, X.B.; Chai, Y.F.; Yao, Y.M. Macrophage polarization in inflammatory diseases. Int. J. Biol. Sci.,  2014, 10(5), 520-529.
[http://dx.doi.org/10.7150/ijbs.8879] [PMID: 24910531] 
[70] 
Wynn, T.A.; Chawla, A.; Pollard, J.W. Macrophage biology in development, homeostasis and disease. Nature,  2013, 496(7446), 445-455.
[http://dx.doi.org/10.1038/nature12034] [PMID: 23619691] 
[71] 
Lucherini, O.M.; Lopalco, G.; Cantarini, L.; Emmi, G.; Lopalco, A.; Venerito, V.; Vitale, A.; Iannone, F. Critical regulation of Th17 cell differentiation by serum amyloid-A signalling in Behcet’s disease. Immunol. Lett.,  2018, 201, 38-44.
[http://dx.doi.org/10.1016/j.imlet.2018.10.013] [PMID: 30385329] 
[72] 
Lopalco, G.; Lucherini, O.M.; Lopalco, A.; Venerito, V.; Fabiani, C.; Frediani, B.; Galeazzi, M.; Lapadula, G.; Cantarini, L.; Iannone, F. Cytokine signatures in mucocutaneous and ocular Behçet’s disease. Front. Immunol.,  2017, 8, 200.
[http://dx.doi.org/10.3389/fimmu.2017.00200] [PMID: 28289419] 
[73] 
Pinto, A.R.; Paolicelli, R.; Salimova, E.; Gospocic, J.; Slonimsky, E.; Bilbao-Cortes, D.; Godwin, J.W.; Rosenthal, N.A. An abundant tissue macrophage population in the adult murine heart with a distinct alternatively-activated macrophage profile. PLoS One,  2012, 7(5)e36814
[http://dx.doi.org/10.1371/journal.pone.0036814] [PMID: 22590615] 
[74] 
Swirski, F.K.; Nahrendorf, M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science,  2013, 339(6116), 161-166.
[http://dx.doi.org/10.1126/science.1230719] [PMID: 23307733] 
[75] 
Nahrendorf, M.; Swirski, F.K.; Aikawa, E.; Stangenberg, L.; Wurdinger, T.; Figueiredo, J.L.; Libby, P.; Weissleder, R.; Pittet, M.J. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med.,  2007, 204(12), 3037-3047.
[http://dx.doi.org/10.1084/jem.20070885] [PMID: 18025128] 
[76] 
Nahrendorf, M.; Swirski, F.K. Monocyte and macrophage heterogeneity in the heart. Circ. Res.,  2013, 112(12), 1624-1633.
[http://dx.doi.org/10.1161/CIRCRESAHA.113.300890] [PMID: 23743228] 
[77] 
Frantz, S.; Nahrendorf, M. Cardiac macrophages and their role in ischaemic heart disease. Cardiovasc. Res.,  2014, 102(2), 240-248.
[http://dx.doi.org/10.1093/cvr/cvu025] [PMID: 24501331] 
[78] 
Balligand, J.L.; Ungureanu-Longrois, D.; Simmons, W.W.; Pimental, D.; Malinski, T.A.; Kapturczak, M.; Taha, Z.; Lowenstein, C.J.; Davidoff, A.J.; Kelly, R.A. Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes. Characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. J. Biol. Chem.,  1994, 269(44), 27580-27588.
[PMID: 7525557] 
[79] 
Balligand, J.L.; Ungureanu, D.; Kelly, R.A.; Kobzik, L.; Pimental, D.; Michel, T.; Smith, T.W. Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage-conditioned medium. J. Clin. Invest.,  1993, 91(5), 2314-2319.
[http://dx.doi.org/10.1172/JCI116461] [PMID: 8486792] 
[80] 
Frostegård, J. Immunity, atherosclerosis and cardiovascular disease. BMC Med.,  2013, 11, 117.
[http://dx.doi.org/10.1186/1741-7015-11-117] [PMID: 23635324] 
[81] 
Gerrity, R.G.; Naito, H.K.; Richardson, M.; Schwartz, C.J. Dietary induced atherogenesis in swine. Morphology of the intima in prelesion stages. Am. J. Pathol.,  1979, 95(3), 775-792.
[PMID: 453335] 
[82] 
Cochain, C.; Zernecke, A. Macrophages in vascular inflammation and atherosclerosis. Pflugers Arch.,  2017, 469(3-4), 485-499.
[http://dx.doi.org/10.1007/s00424-017-1941-y] [PMID: 28168325] 
[83] 
Vogiatzi, G.; Tousoulis, D.; Stefanadis, C. The role of oxidative stress in atherosclerosis. Hellenic J. Cardiol.,  2009, 50(5), 402-409.
[PMID: 19767282] 
[84] 
Antoniades, C.; Tousoulis, D.; Stefanadis, C. Effects of endothelial nitric oxide synthase gene polymorphisms on oxidative stress, inflammatory status, and coronary atherosclerosis: an example of a transient phenotype. J. Am. Coll. Cardiol.,  2007, 49(11), 1226.
[http://dx.doi.org/10.1016/j.jacc.2006.12.029] [PMID: 17367670] 
[85] 
Sugamura, K.; Keaney, J.F., Jr Reactive oxygen species in cardiovascular disease. Free Radic. Biol. Med.,  2011, 51(5), 978-992.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.05.004] [PMID: 21627987] 
[86] 
Demarco, V.G.; Whaley-Connell, A.T.; Sowers, J.R.; Habibi, J.; Dellsperger, K.C. Contribution of oxidative stress to pulmonary arterial hypertension. World J. Cardiol.,  2010, 2(10), 316-324.
[http://dx.doi.org/10.4330/wjc.v2.i10.316] [PMID: 21160609] 
[87] 
DeMarco, V.G.; Habibi, J.; Whaley-Connell, A.T.; Schneider, R.I.; Heller, R.L.; Bosanquet, J.P.; Hayden, M.R.; Delcour, K.; Cooper, S.A.; Andresen, B.T.; Sowers, J.R.; Dellsperger, K.C. Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat. Am. J. Physiol. Heart Circ. Physiol.,  2008, 294(6), H2659-H2668.
[http://dx.doi.org/10.1152/ajpheart.00953.2007] [PMID: 18424632] 
[88] 
Spiekermann, S.; Schenk, K.; Hoeper, M.M. Increased xanthine oxidase activity in idiopathic pulmonary arterial hypertension. Eur. Respir. J.,  2009, 34(1), 276.
[http://dx.doi.org/10.1183/09031936.00013309] [PMID: 19567609] 
[89] 
Carvajal, K.; El Hafidi, M.; Baños, G. Myocardial damage due to ischemia and reperfusion in hypertriglyceridemic and hypertensive rats: participation of free radicals and calcium overload. J. Hypertens.,  1999, 17(11), 1607-1616.
[http://dx.doi.org/10.1097/00004872-199917110-00015] [PMID: 10608475] 
[90] 
Arroyo, C.M.; Kramer, J.H.; Dickens, B.F.; Weglicki, W.B. Identification of free radicals in myocardial ischemia/reperfusion by spin trapping with nitrone DMPO. FEBS Lett.,  1987, 221(1), 101-104.
[http://dx.doi.org/10.1016/0014-5793(87)80360-5] [PMID: 3040465] 
[91] 
Ozkul, A.; Akyol, A.; Yenisey, C.; Arpaci, E.; Kiylioglu, N.; Tataroglu, C. Oxidative stress in acute ischemic stroke. J. Clin. Neurosci.,  2007, 14(11), 1062-1066.
[http://dx.doi.org/10.1016/j.jocn.2006.11.008] [PMID: 17884504] 
[92] 
Roger, V.L. Epidemiology of myocardial infarction. Med.Clin. North Am.,,  2007, 91(4), 537-552, ix..
[http://dx.doi.org/10.1016/j.mcna.2007.03.007] [PMID: 17640535] 
[93] 
Min, M.; Jie, H.; Xinrong, X.; Min, M. Effects of inflammation, oxidative stress and platelet activation on coronary heart disease and their interactions. Heart,  2012, 98(Suppl. 2), E170-E170.
[http://dx.doi.org/10.1136/heartjnl-2012-302920j.30] 
[94] 
Weinbrenner, T.; Cladellas, M.; Isabel Covas, M.; Fitó, M.; Tomás, M.; Sentí, M.; Bruguera, J.; Marrugat, J. High oxidative stress in patients with stable coronary heart disease. Atherosclerosis,  2003, 168(1), 99-106.
[http://dx.doi.org/10.1016/S0021-9150(03)00053-4] [PMID: 12732392] 
[95] 
Singh, U.N.; Kumar, S.; Dhakal, S. Study of oxidative stress in hypercholesterolemia. Journal of Contemporary Medical Research,  2017, 4(5), 1204-1207.
[96] 
Keith, M.; Geranmayegan, A.; Sole, M.J.; Kurian, R.; Robinson, A.; Omran, A.S.; Jeejeebhoy, K.N. Increased oxidative stress in patients with congestive heart failure. J. Am. Coll. Cardiol.,  1998, 31(6), 1352-1356.
[http://dx.doi.org/10.1016/S0735-1097(98)00101-6] [PMID: 9581732] 
[97] 
Michel, T.M.; Frangou, S.; Thiemeyer, D.; Camara, S.; Jecel, J.; Nara, K.; Brunklaus, A.; Zoechling, R.; Riederer, P. Evidence for oxidative stress in the frontal cortex in patients with recurrent depressive disorder--a postmortem study. Psychiatry Res.,  2007, 151(1-2), 145-150.
[http://dx.doi.org/10.1016/j.psychres.2006.04.013] [PMID: 17296234] 
[98] 
Michel, T.M.; Camara, S.; Tatschner, T.; Frangou, S.; Sheldrick, A.J.; Riederer, P.; Grünblatt, E. Increased xanthine oxidase in the thalamus and putamen in depression. World J. Biol. Psychiatry,  2010, 11(2 Pt 2), 314-320.
[http://dx.doi.org/10.3109/15622970802123695] [PMID: 20218795] 
[99] 
Talarowska, M.; Gałecki, P.; Maes, M.; Gardner, A.; Chamielec, M.; Orzechowska, A.; Bobińska, K.; Kowalczyk, E. Malondialdehyde plasma concentration correlates with declarative and working memory in patients with recurrent depressive disorder. Mol. Biol. Rep.,  2012, 39(5), 5359-5366.
[http://dx.doi.org/10.1007/s11033-011-1335-8] [PMID: 22170602] 
[100] 
Liu, T.; Zhong, S.; Liao, X.; Chen, J.; He, T.; Lai, S.; Jia, Y. A meta-analysis of oxidative stress markers in depression. PLoS One,  2015, 10(10)e0138904
[http://dx.doi.org/10.1371/journal.pone.0138904] [PMID: 26445247] 
[101] 
Hipkiss, A.R.; Preston, J.E.; Himsworth, D.T.; Worthington, V.C.; Keown, M.; Michaelis, J.; Lawrence, J.; Mateen, A.; Allende, L.; Eagles, P.A.; Abbott, N.J. Pluripotent protective effects of carnosine, a naturally occurring dipeptide. Ann. N. Y. Acad. Sci.,  1998, 854, 37-53.
[http://dx.doi.org/10.1111/j.1749-6632.1998.tb09890.x] [PMID: 9928418] 
[102] 
Gariballa, S.E.; Sinclair, A.J. Carnosine: physiological properties and therapeutic potential. Age Ageing,  2000, 29(3), 207-210.
[http://dx.doi.org/10.1093/ageing/29.3.207] [PMID: 10855900] 
[103] 
Kalyankar, G.D.; Meister, A. Enzymatic synthesis of carnosine and related beta-alanyl and gamma-aminobutyryl peptides. J. Biol. Chem.,  1959, 234, 3210-3218.
[PMID: 14404206] 
[104] 
Winnick, R.E.; Winnick, T. Carnosineanserine synthetase of muscle. I. Preparation and properties of soluble enzyme from chick muscle. Biochim. Biophys. Acta,  1959, 31(1), 47-55.
[http://dx.doi.org/10.1016/0006-3002(59)90437-8] [PMID: 13628602] 
[105] 
Lenney, J.F.; George, R.P.; Weiss, A.M.; Kucera, C.M.; Chan, P.W.; Rinzler, G.S. Human serum carnosinase: characterization, distinction from cellular carnosinase, and activation by cadmium. Clin. Chim. Acta,  1982, 123(3), 221-231.
[http://dx.doi.org/10.1016/0009-8981(82)90166-8] [PMID: 7116644] 
[106] 
Teufel, M.; Saudek, V.; Ledig, J.P.; Bernhardt, A.; Boularand, S.; Carreau, A.; Cairns, N.J.; Carter, C.; Cowley, D.J.; Duverger, D.; Ganzhorn, A.J.; Guenet, C.; Heintzelmann, B.; Laucher, V.; Sauvage, C.; Smirnova, T. Sequence identification and characterization of human carnosinase and a closely related non-specific dipeptidase. J. Biol. Chem.,  2003, 278(8), 6521-6531.
[http://dx.doi.org/10.1074/jbc.M209764200] [PMID: 12473676] 
[107] 
McFarland, G.A.; Holliday, R. Further evidence for the rejuvenating effects of the dipeptide L-carnosine on cultured human diploid fibroblasts. Exp. Gerontol.,  1999, 34(1), 35-45.
[http://dx.doi.org/10.1016/S0531-5565(98)00056-4] [PMID: 10197726] 
[108] 
Holliday, R.; McFarland, G.A. Inhibition of the growth of transformed and neoplastic cells by the dipeptide carnosine. Br. J. Cancer,  1996, 73(8), 966-971.
[http://dx.doi.org/10.1038/bjc.1996.189] [PMID: 8611433] 
[109] 
Yuneva, M.; Bulygina, E.; Gallant, S.; Kramarenko, G.; Stvolinsky, S.; Semyonova, M.; Boldyrev, A. Effect of carnosine on age-induced changes in senescence- accelerated mice. J. Anti Aging Med.,  1999, 2, 337-342.
[http://dx.doi.org/10.1089/rej.1.1999.2.337] 
[110] 
Mal’tseva, V.V.; Sergienko, V.V.; Stvolinskiĭ, S.L. [The effect of carnosine on hematopoietic stem cell activity in irradiated animals]. Biokhimiia,  1992, 57(9), 1378-1382.
[PMID: 1467357] 
[111] 
Caruso, G.; Fresta, C.G.; Martinez-Becerra, F.; Antonio, L.; Johnson, R.T.; de Campos, R.P.S.; Siegel, J.M.; Wijesinghe, M.B.; Lazzarino, G.; Lunte, S.M. Carnosine modulates nitric oxide in stimulated murine RAW 264.7 macrophages. Mol. Cell. Biochem.,  2017, 431(1-2), 197-210.
[http://dx.doi.org/10.1007/s11010-017-2991-3] [PMID: 28290048] 
[112] 
Fresta, C.G.; Hogard, M.L.; Caruso, G.; Melo Costa, E.E.; Lazzarino, G.; Lunte, S.M. Monitoring carnosine uptake by RAW 264.7 macrophage cells using microchip electrophoresis with fluorescence detection. Anal. Methods,  2017, 9(3), 402-408.
[http://dx.doi.org/10.1039/C6AY03009B] [PMID: 29104617] 
[113] 
Nagai, K.; Suda, T.; Kawasaki, K.; Mathuura, S. Action of carnosine and beta-alanine on wound healing. Surgery,  1986, 100(5), 815-821.
[PMID: 3095942] 
[114] 
Abe, H. Role of histidine-related compounds as intracellular proton buffering constituents in vertebrate muscle. Biochemistry (Mosc.),  2000, 65(7), 757-765.
[PMID: 10951092] 
[115] 
Rashid, I.; van Reyk, D.M.; Davies, M.J. Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro. FEBS Lett.,  2007, 581(5), 1067-1070.
[http://dx.doi.org/10.1016/j.febslet.2007.01.082] [PMID: 17316626] 
[116] 
Nicoll, R.A.; Alger, B.E.; Jahr, C.E. Peptides as putative excitatory neurotransmitters: carnosine, enkephalin, substance P and TRH. Proc. R. Soc. Lond. B Biol. Sci.,  1980, 210(1178), 133-149.
[http://dx.doi.org/10.1098/rspb.1980.0124] [PMID: 6159651] 
[117] 
Hasanein, P.; Felegari, Z. Chelating effects of carnosine in ameliorating nickel-induced nephrotoxicity in rats. Can. J. Physiol. Pharmacol.,  2017, 95(12), 1426-1432.
[http://dx.doi.org/10.1139/cjpp-2016-0647] [PMID: 28675793] 
[118] 
Gorbunov, N.V.; Erin, A.N. [Mechanism of antioxidant action of carnosine]. Biull. Eksp. Biol. Med.,  1991, 111(5), 477-478.
[http://dx.doi.org/10.1007/BF00840997] [PMID: 1878559] 
[119] 
Caruso, G.; Fresta, C.G.; Siegel, J.M.; Wijesinghe, M.B.; Lunte, S.M. Microchip electrophoresis with laser-induced fluorescence detection for the determination of the ratio of nitric oxide to superoxide production in macrophages during inflammation. Anal. Bioanal. Chem.,  2017, 409(19), 4529-4538.
[http://dx.doi.org/10.1007/s00216-017-0401-z] [PMID: 28555342] 
[120] 
Chan, W.K.; Decker, E.A.; Chow, C.K.; Boissonneault, G.A. Effect of dietary carnosine on plasma and tissue antioxidant concentrations and on lipid oxidation in rat skeletal muscle. Lipids,  1994, 29(7), 461-466.
[http://dx.doi.org/10.1007/BF02578242] [PMID: 7968266] 
[121] 
Reddy, V.P.; Garrett, M.R.; Perry, G.; Smith, M.A. Carnosine: a versatile antioxidant and antiglycating agent. Sci. SAGE KE,  2005, 2005(18), pe12.
[http://dx.doi.org/10.1126/sageke.2005.18.pe12] [PMID: 15872311] 
[122] 
Fresta, C.G.; Chakraborty, A.; Wijesinghe, M.B.; Amorini, A.M.; Lazzarino, G.; Lazzarino, G.; Tavazzi, B.; Lunte, S.M.; Caraci, F.; Dhar, P.; Caruso, G. Non-toxic engineered carbon nanodiamond concentrations induce oxidative/nitrosative stress, imbalance of energy metabolism, and mitochondrial dysfunction in microglial and alveolar basal epithelial cells. Cell Death Dis.,  2018, 9(2), 245.
[http://dx.doi.org/10.1038/s41419-018-0280-z] [PMID: 29445138] 
[123] 
Tsai, S.J.; Kuo, W.W.; Liu, W.H.; Yin, M.C. Antioxidative and anti-inflammatory protection from carnosine in the striatum of MPTP-treated mice. J. Agric. Food Chem.,  2010, 58(21), 11510-11516.
[http://dx.doi.org/10.1021/jf103258p] [PMID: 20925384] 
[124] 
Suzuki, T.; Nagai, K. Local Antiinflammatory Effect of L-Carnosine (β alanyl 1-histidine) associated with Pains of Post Dental Extraction. J. Nihon Univ. Sch. Dent.,  1974, 16, 18-22.
[http://dx.doi.org/10.2334/josnusd1959.16.18] 
[125] 
Katakura, Y.; Totsuka, M.; Imabayashi, E.; Matsuda, H.; Hisatsune, T. Anserine/carnosine supplementation suppresses the expression of the inflammatory chemokine CCL24 in peripheral blood mononuclear cells from elderly people. Nutrients,  2017, 9(11)E1199
[http://dx.doi.org/10.3390/nu9111199] [PMID: 29088099] 
[126] 
Son, D.O.; Satsu, H.; Kiso, Y.; Totsuka, M.; Shimizu, M. Inhibitory effect of carnosine on interleukin-8 production in intestinal epithelial cells through translational regulation. Cytokine,  2008, 42(2), 265-276.
[http://dx.doi.org/10.1016/j.cyto.2008.02.011] [PMID: 18397832] 
[127] 
Odashima, M.; Otaka, M.; Jin, M.; Wada, I.; Horikawa, Y.; Matsuhashi, T.; Ohba, R.; Hatakeyama, N.; Oyake, J.; Watanabe, S. Zinc L-carnosine protects colonic mucosal injury through induction of heat shock protein 72 and suppression of NF-kappaB activation. Life Sci.,  2006, 79(24), 2245-2250.
[http://dx.doi.org/10.1016/j.lfs.2006.07.032] [PMID: 16949620] 
[128] 
Ma, J.; Chen, J.; Bo, S.; Lu, X.; Zhang, J. Protective effect of carnosine after chronic cerebral hypoperfusion possibly through suppressing astrocyte activation. Am. J. Transl. Res.,  2015, 7(12), 2706-2715.
[PMID: 26885268] 
[129] 
Ooi, T.C.; Chan, K.M.; Sharif, R. Zinc carnosine inhibits lipopolysaccharide-induced inflammatory mediators by suppressing NF-κb activation in raw 264.7 macrophages, independent of the MAPKs signaling pathway. Biol. Trace Elem. Res.,  2016, 172(2), 458-464.
[http://dx.doi.org/10.1007/s12011-015-0615-x] [PMID: 26749414] 
[130] 
Fleisher-Berkovich, S.; Abramovitch-Dahan, C.; Ben-Shabat, S.; Apte, R.; Beit-Yannai, E. Inhibitory effect of carnosine and N-acetyl carnosine on LPS-induced microglial oxidative stress and inflammation. Peptides,  2009, 30(7), 1306-1312.
[http://dx.doi.org/10.1016/j.peptides.2009.04.003] [PMID: 19540429] 
[131] 
Spina-Purrello, V.; Giliberto, S.; Barresi, V.; Nicoletti, V.G.; Giuffrida Stella, A.M.; Rizzarelli, E. Modulation of PARP-1 and PARP-2 expression by L-carnosine and trehalose after LPS and INFγ-induced oxidative stress. Neurochem. Res.,  2010, 35(12), 2144-2153.
[http://dx.doi.org/10.1007/s11064-010-0297-x] [PMID: 21053069] 
[132] 
Ponist, S.; Drafi, F.; Kuncirova, V.; Mihalova, D.; Rackova, L.; Danisovic, L.; Ondrejickova, O.; Tumova, I.; Trunova, O.; Fedorova, T.; Bauerova, K. Effect of carnosine in experimental arthritis and on primary culture chondrocytes. Oxid. Med. Cell. Longev.,  2016, 20168470589
[http://dx.doi.org/10.1155/2016/8470589] [PMID: 26885252] 
[133] 
Calabrese, V.; Cornelius, C.; Mancuso, C.; Pennisi, G.; Calafato, S.; Bellia, F.; Bates, T.E.; Giuffrida Stella, A.M.; Schapira, T.; Dinkova Kostova, A.T.; Rizzarelli, E. Cellular stress response: a novel target for chemoprevention and nutritional neuroprotection in aging, neurodegenerative disorders and longevity. Neurochem. Res.,  2008, 33(12), 2444-2471.
[http://dx.doi.org/10.1007/s11064-008-9775-9] [PMID: 18629638] 
[134] 
Corona, C.; Frazzini, V.; Silvestri, E.; Lattanzio, R.; La Sorda, R.; Piantelli, M.; Canzoniero, L.M.; Ciavardelli, D.; Rizzarelli, E.; Sensi, S.L. Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg-AD mice. PLoS One,  2011, 6(3)e17971
[http://dx.doi.org/10.1371/journal.pone.0017971] [PMID: 21423579] 
[135] 
Di Paola, R.; Impellizzeri, D.; Salinaro, A.T.; Mazzon, E.; Bellia, F.; Cavallaro, M.; Cornelius, C.; Vecchio, G.; Calabrese, V.; Rizzarelli, E.; Cuzzocrea, S. Administration of carnosine in the treatment of acute spinal cord injury. Biochem. Pharmacol.,  2011, 82(10), 1478-1489.
[http://dx.doi.org/10.1016/j.bcp.2011.07.074] [PMID: 21787762] 
[136] 
Pizzi, C.; Santarella, L.; Costa, M.G.; Manfrini, O.; Flacco, M.E.; Capasso, L.; Chiarini, S.; Di Baldassarre, A.; Manzoli, L. Pathophysiological mechanisms linking depression and atherosclerosis: an overview. J. Biol. Regul. Homeost. Agents,  2012, 26(4), 775-782.
[PMID: 23241128] 
[137] 
Barski, O.A.; Xie, Z.; Baba, S.P.; Sithu, S.D.; Agarwal, A.; Cai, J.; Bhatnagar, A.; Srivastava, S. Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein E-null mice. Arterioscler. Thromb. Vasc. Biol.,  2013, 33(6), 1162-1170.
[http://dx.doi.org/10.1161/ATVBAHA.112.300572] [PMID: 23559625] 
[138] 
Menini, S.; Iacobini, C.; Ricci, C.; Scipioni, A.; Blasetti Fantauzzi, C.; Giaccari, A.; Salomone, E.; Canevotti, R.; Lapolla, A.; Orioli, M.; Aldini, G.; Pugliese, G. D-Carnosine octylester attenuates atherosclerosis and renal disease in ApoE null mice fed a Western diet through reduction of carbonyl stress and inflammation. Br. J. Pharmacol.,  2012, 166(4), 1344-1356.
[http://dx.doi.org/10.1111/j.1476-5381.2012.01834.x] [PMID: 22229552] 
[139] 
Brown, B.E.; Kim, C.H.; Torpy, F.R.; Bursill, C.A.; McRobb, L.S.; Heather, A.K.; Davies, M.J.; van Reyk, D.M. Supplementation with carnosine decreases plasma triglycerides and modulates atherosclerotic plaque composition in diabetic apo E(-/-) mice. Atherosclerosis,  2014, 232(2), 403-409.
[http://dx.doi.org/10.1016/j.atherosclerosis.2013.11.068] [PMID: 24468155] 
[140] 
Menini, S.; Iacobini, C.; Ricci, C.; Blasetti Fantauzzi, C.; Pugliese, G. Protection from diabetes-induced atherosclerosis and renal disease by D-carnosine-octylester: effects of early vs late inhibition of advanced glycation end-products in Apoe-null mice. Diabetologia,  2015, 58(4), 845-853.
[http://dx.doi.org/10.1007/s00125-014-3467-6] [PMID: 25471794] 
[141] 
Mahmoud, A.H. Comparative study between carnosine and fluvastatin in hypercholesterolemic rabbits. J. Appl. Sci. (Faisalabad),  2006, 6, 1725-1730.
[http://dx.doi.org/10.3923/jas.2006.1725.1730] 
[142] 
Tomonaga, S.; Yamane, H.; Onitsuka, E.; Yamada, S.; Sato, M.; Takahata, Y.; Morimatsu, F.; Furuse, M. Carnosine-induced antidepressant-like activity in rats. Pharmacol. Biochem. Behav.,  2008, 89(4), 627-632.
[http://dx.doi.org/10.1016/j.pbb.2008.02.021] [PMID: 18377967] 
[143] 
Lamberti, C.; Ipponi, A.; Bartolini, A.; Schunack, W.; Malmberg-Aiello, P. Antidepressant-like effects of endogenous histamine and of two histamine H1 receptor agonists in the mouse forced swim test. Br. J. Pharmacol.,  1998, 123(7), 1331-1336.
[http://dx.doi.org/10.1038/sj.bjp.0701740] [PMID: 9579727] 
[144] 
Barth, J.; Schumacher, M.; Herrmann-Lingen, C. Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom. Med.,  2004, 66(6), 802-813.
[http://dx.doi.org/10.1097/01.psy.0000146332.53619.b2] [PMID: 15564343] 
[145] 
Gorska-Ciebiada, M.; Saryusz-Wolska, M.; Borkowska, A.; Ciebiada, M.; Loba, J. Serum levels of inflammatory markers in depressed elderly patients with diabetes and mild cognitive impairment. PLoS One,  2015, 10(3)e0120433
[http://dx.doi.org/10.1371/journal.pone.0120433] [PMID: 25793613] 
[146] 
Peters, V.; Zschocke, J.; Schmitt, C.P. Carnosinase, diabetes mellitus and the potential relevance of carnosinase deficiency. J. Inherit. Metab. Dis.,  2018, 41(1), 39-47.
[http://dx.doi.org/10.1007/s10545-017-0099-2] [PMID: 29027595] 
[147] 
Menon, K.; Mousa, A.; de Courten, B. Effects of supplementation with carnosine and other histidine-containing dipeptides on chronic disease risk factors and outcomes: protocol for a systematic review of randomised controlled trials. BMJ Open,  2018, 8(3)e020623
[http://dx.doi.org/10.1136/bmjopen-2017-020623] [PMID: 29567852] 
[148] 
Houjeghani, S.; Kheirouri, S.; Faraji, E.; Jafarabadi, M.A. l-Carnosine supplementation attenuated fasting glucose, triglycerides, advanced glycation end products, and tumor necrosis factor-α levels in patients with type 2 diabetes: a double-blind placebo-controlled randomized clinical trial. Nutr. Res.,  2018, 49, 96-106.
[http://dx.doi.org/10.1016/j.nutres.2017.11.003] [PMID: 29420997] 
[149] 
Inan, S.Y.; Yalcin, I.; Aksu, F. Dual effects of nitric oxide in the mouse forced swimming test: possible contribution of nitric oxide-mediated serotonin release and potassium channel modulation. Pharmacol. Biochem. Behav.,  2004, 77(3), 457-464.
[http://dx.doi.org/10.1016/j.pbb.2003.12.024] [PMID: 15006455] 
[150] 
Yamashita, S.; Sato, M.; Matsumoto, T.; Kadooka, K.; Hasegawa, T.; Fujimura, T.; Katakura, Y. Mechanisms of carnosine-induced activation of neuronal cells. Biosci. Biotechnol. Biochem.,  2018, 82(4), 683-688.
[http://dx.doi.org/10.1080/09168451.2017.1413325] [PMID: 29224504] 
[151] 
Kishi, T.; Yoshimura, R.; Ikuta, T.; Iwata, N. Brain-derived neurotrophic factor and major depressive disorder: evidence from meta-analyses. Front. Psychiatry,  2018, 8, 308.
[http://dx.doi.org/10.3389/fpsyt.2017.00308] [PMID: 29387021] 
[152] 
Hipkiss, A.R. Glycation, ageing and carnosine: are carnivorous diets beneficial? Mech. Ageing Dev.,  2005, 126(10), 1034-1039.
[http://dx.doi.org/10.1016/j.mad.2005.05.002] [PMID: 15955546] 
[153] 
Hipkiss, A.R. Possible benefit of dietary carnosine towards depressive disorders. Aging Dis.,  2015, 6(5), 300-303.
[http://dx.doi.org/10.14336/AD.2014.1211] [PMID: 26425385] 
[154] 
Tsoi, B.; He, R.R.; Yang, D.H.; Li, Y.F.; Li, X.D.; Li, W.X.; Abe, K.; Kurihara, H. Carnosine ameliorates stress-induced glucose metabolism disorder in restrained mice. J. Pharmacol. Sci.,  2011, 117(4), 223-229.
[http://dx.doi.org/10.1254/jphs.11131FP] [PMID: 22123261] 
[155] 
Nagai, K.; Suda, T.; Kawasaki, K.; Yamaguchi, Y. [Acceleration of metabolism of stress-related substances by L-carnosine]. Nippon Seirigaku Zasshi,  1990, 52(7), 221-228.
[PMID: 1698224] 
[156] 
Hipkiss, A.R. Depression, diabetes and dementia: formaldehyde may be a common causal agent; could carnosine, a pluripotent peptide, be protective? Aging Dis.,  2017, 8(2), 128-130.
[http://dx.doi.org/10.14336/AD.2017.0120] [PMID: 28400979] 
[157] 
Banerjee, S.; Poddar, M.K. Carnosine: effect on aging-induced increase in brain regional monoamine oxidase-A activity. Neurosci. Res.,  2015, 92, 62-70.
[http://dx.doi.org/10.1016/j.neures.2014.09.009] [PMID: 25450310] 
[158] 
Song, M.S.; Baker, G.B.; Dursun, S.M.; Todd, K.G. The antidepressant phenelzine protects neurons and astrocytes against formaldehyde-induced toxicity. J. Neurochem.,  2010, 114(5), 1405-1413.
[http://dx.doi.org/10.1111/j.1471-4159.2010.06857.x] [PMID: 20557421] 
[159] 
Lee, Y.T.; Hsu, C.C.; Lin, M.H.; Liu, K.S.; Yin, M.C. Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur. J. Pharmacol.,  2005, 513(1-2), 145-150.
[http://dx.doi.org/10.1016/j.ejphar.2005.02.010] [PMID: 15878720] 
[160] 
Mauer, J.; Chaurasia, B.; Goldau, J.; Vogt, M.C.; Ruud, J.; Nguyen, K.D.; Theurich, S.; Hausen, A.C.; Schmitz, J.; Brönneke, H.S.; Estevez, E.; Allen, T.L.; Mesaros, A.; Partridge, L.; Febbraio, M.A.; Chawla, A.; Wunderlich, F.T.; Brüning, J.C. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat. Immunol.,  2014, 15(5), 423-430.
[http://dx.doi.org/10.1038/ni.2865] [PMID: 24681566] 
[161] 
Taylor, W.D.; Aizenstein, H.J.; Alexopoulos, G.S. The vascular depression hypothesis: mechanisms linking vascular disease with depression. Mol. Psychiatry,  2013, 18(9), 963-974.
[http://dx.doi.org/10.1038/mp.2013.20] [PMID: 23439482] 
[162] 
Alexopoulos, G.S.; Morimoto, S.S. The inflammation hypothesis in geriatric depression. Int. J. Geriatr. Psychiatry,  2011, 26(11), 1109-1118.
[PMID: 21370276] 
[163] 
Bay-Richter, C.; Linderholm, K.R.; Lim, C.K.; Samuelsson, M.; Träskman-Bendz, L.; Guillemin, G.J.; Erhardt, S.; Brundin, L. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality. Brain Behav. Immun.,  2015, 43, 110-117.
[http://dx.doi.org/10.1016/j.bbi.2014.07.012] [PMID: 25124710] 
[164] 
Caruso, G.; Benatti, C.; Blom, JMC; Caraci, F.; Tascedda, F. The many faces of mitochondrial dysfunction in depression: from pathology to treatment. Front. Pharmacol.,  2019, 10, 995.
[http://dx.doi.org/10.3389/fphar.2019.00995] [PMID: 31551791] 
[165] 
Khandaker, G.M.; Oltean, B.P.; Kaser, M.; Dibben, C.R.M.; Ramana, R.; Jadon, D.R.; Dantzer, R.; Coles, A.J.; Lewis, G.; Jones, P.B. Protocol for the insight study: a randomised controlled trial of single-dose tocilizumab in patients with depression and low-grade inflammation. BMJ Open,  2018, 8(9)e025333
[http://dx.doi.org/10.1136/bmjopen-2018-025333] [PMID: 30244217] 
[166] 
Caruso, G.; Caraci, F.; Jolivet, R.B. Pivotal role of carnosine in the modulation of brain cells activity: Multimodal mechanism of action and therapeutic potential in neurodegenerative disorders. Prog. Neurobiol.,  2019, 175, 35-53.
[http://dx.doi.org/10.1016/j.pneurobio.2018.12.004] [PMID: 30593839] 
[167] 
Krogh, J.; Benros, M.E.; Jørgensen, M.B.; Vesterager, L.; Elfving, B.; Nordentoft, M. The association between depressive symptoms, cognitive function, and inflammation in major depression. Brain Behav. Immun.,  2014, 35, 70-76.
[http://dx.doi.org/10.1016/j.bbi.2013.08.014] [PMID: 24016864] 
[168] 
Ownby, R.L. Neuroinflammation and cognitive aging. Curr. Psychiatry Rep.,  2010, 12(1), 39-45.
[http://dx.doi.org/10.1007/s11920-009-0082-1] [PMID: 20425309] 
[169] 
Baune, B.T.; Sluth, L.B.; Olsen, C.K. The effects of vortioxetine on cognitive performance in working patients with major depressive disorder: a  short-term, randomized, double-blind, exploratory study. J. Affect. Disord.,  2018, 229, 421-428.
[http://dx.doi.org/10.1016/j.jad.2017.12.056] [PMID: 29331703] 
Rights & Permissions Print Cite
Article Metrics
34
2
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0929867326666190712091515	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
Current Medicinal Chemistry

Inflammation as the Common Biological Link Between Depression and Cardiovascular Diseases: Can Carnosine Exert a Protective Role?

Abstract Play Pause

Related Journals

Related Books

Related Articles

Abstract
