Abstract
Introduction. According to modern concepts, the inflammatory process is one of the key links in the development of cardiovascular, autoimmune, neurological, oncological diseases, as well as metabolic syndrome, complications of diabetes mellitus, and pathologies of the respiratory system. The implementation of a normal inflammatory response requires metabolic and cellular resources, the functionality of enzymatic and antioxidant systems, which, in turn, depends on the body’s supply of macro- and microelements. Research has shown that zinc and copper are some of the main elements associated with inflammation.
Purpose of the study. The purpose of the study was to examine the relationship between serum copper and zinc concentrations and markers of inflammation.
Material and methods. The study examined correlations between serum copper and zinc concentrations and various measures of inflammation in 1,153 people aged 18 to 86 years. The concentrations of CRP, ESR, ferritin, ceruloplasmin, leukocytes, neutrophils, fibrinogen, uric acid, copper, and zinc were determined in those examined. Serum microelements were measured by ICP-MS; other indicators were determined by standard methods. Correlation analysis was carried out using the Spearman coefficient.
Results. The strongest statistically significant correlations (p 0.05) were found between copper and ceruloplasmin (r=0.612), as well as between copper and CRP (r=0.474) and ESR (r=0.421). Serum copper and zinc showed statistically significant but weak correlations with most inflammatory markers.
Conclusion. The study showed the presence of statistically significant moderate, medium and weak correlations of serum copper and zinc concentrations with inflammation markers, which is due to many intermediate processes and intermediary metabolic reactions between these indicators.
Authors and affiliations
G.D. Morozova(1), E.D. Namiot(1), E.V. Rylina(1, 2), T.V. Korobeinikova(1, 2), A.A. Tsibulina(1), A.R. Sadykov(3), V.V. Yurasov(2), 3, A.V. Skalny(1, 2)
1-First Moscow State Medical University named after. THEM. Sechenov, (Sechenov University),
Trubetskaya st., 8, building 2, Moscow, 119991, Russian Federation;
2-Federal State Autonomous Educational Institution of Higher Education "Russian Peoples' Friendship University",
Miklouho-Maklaya st., 6, Moscow, 117198, Russian Federation;
3-Laboratory of Metabolomic Diagnostics, Starokaluzhskoe Shosse, 63, Moscow, 117630, Russia
References
Barbu E., Popescu M.R., Popescu A.C., Balanescu S.M. Inflammation as A Precursor of Atherothrombosis, Diabetes and Early Vascular Aging. Int J. Mol. Sci. 2022; 23 (2): 963. DOI: 10.3390/ijms23020963.
Xie J., Van Hoecke L., Vandenbroucke R.E. The Impact of Systemic Inflammation on Alzheimer's Disease Pathology. Front Immunol. 2022; 12: 796867. DOI: 10.3389/fimmu.2021.796867.
Nelson D.L., Michael M.C. Lehninger Principles of Biochemistry. 7th ed., W.H. Freeman. 2017.
Максимчук Т.П., Скальный А.В., Радыш И.В. Бионеорганическая химия с основами медицинской элементологии: учебник. М.: Российский ун-т дружбы народов. 2019; 624.
[Maksimchuk T.P., Skalnyj A.V., Radysh I.V. Bioinorganic chemistry with the basics of medical elementology: a textbook. Rossijskij un-t druzhby narodov. 2019; 624 (in Russian)]
Meng H., Ruan J., Yan Z., Chen Y., Liu J., Li X., Meng F. New Progress in Early Diagnosis of Atherosclerosis. Int J. Mol. Sci. 2022; 23 (16): 8939. DOI: 10.3390/ijms23168939.
Gardner D.S., Allen J.C., Goodson D., Harvey D., Sharman A., Skinner H., Szafranek A., Young J.S. Bailey E.H., Devonald M.A. Urinary Trace Elements Are Biomarkers for Early Detection of Acute Kidney Injury. Kidney Int Rep. 2022; 7 (7): 1524–38. DOI: 10.1016/j.ekir.2022.04.085.
Vorotnikov A.V., Stafeev I.S., Menshikov M.Y., Shestakova M.V., Parfyonova Y.V. Latent Inflammation and Defect in Adipocyte Renewal as a Mechanism of Obesity-Associated Insulin Resistance. Biochemistry (Mosc). 2019; 84 (11): 1329–45. DOI: 10.1134/S0006297919110099.
Al-Saleh I., Alrushud N., Alnuwaysir H., Elkhatib R., Shoukri M., Aldayel F., Bakheet R., Almozaini M. Essential metals, vitamins and antioxidant enzyme activities in COVID-19 patients and their potential associations with the disease severity. Biometals. 2022; 35 (1): 125–45. DOI: 10.1007/s10534-021-00355-4.
Scassellati C., Bonvicini C., Benussi L., Ghidoni R., Squitti R. Neurodevelopmental disorders: Metallomics studies for the identification of potential biomarkers associated to diagnosis and treatment. J. Trace Elem Med. Biol. 2020; 60: 126499. DOI: 10.1016/j.jtemb.2020.126499.
Skalny A.V., Aschner M., Tinkov A.A. Zinc. Adv Food Nutr Res. 2021; 96: 251–310. DOI: 10.1016/bs.afnr.2021.01.003.
Kim B., Lee W.W. Regulatory Role of Zinc in Immune Cell Signaling. Mol Cells. 2021; 44 (5): 335–41. DOI: 10.14348/molcells.2021.0061.
Olechnowicz J., Tinkov A., Skalny A., Suliburska J. Zinc status is associated with inflammation, oxidative stress, lipid, and glucose metabolism. J. Physiol Sci. 2018; 68 (1): 19–31. DOI: 10.1007/s12576-017-0571-7.
Scheiber I., Dringen R., Mercer J.F. Copper: effects of deficiency and overload. Met Ions Life Sci. 2013; 13: 359–87. DOI: 10.1007/978-94-007-7500-8_11.
Davalli P., Mitic T., Caporali A., Lauriola A., D'Arca D. ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases. Oxid Med Cell Longev. 2016; 2016: 3565127. DOI: 10.1155/2016/3565127.
Ridker P.M., Silvertown J.D. Inflammation, C-reactive protein, and atherothrombosis. J. of periodontology. 2008; 79: 1544–51. DOI: 10.1902/jop.2008.080249
Pepys M.B., Hirschfield, G.M. C-reactive protein: a critical update. The J. of clinical investigation. 2003; 111 (12): 1805–12. DOI: 10.1172/JCI18921
Shrivastava A.K., Singh H.V., Raizada A., Singh S.K. C-reactive protein, inflammation and coronary heart disease. The Egyptian Heart J. 2015; 67 (2): 89–97. DOI:10.1016/j.ehj.2014.11.005
Dong J., Wang X., Xu C., Gao M., Wang S., Zhang J., Tong H., Wang L., Han Y., Cheng N., Han Y. Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson’s disease. Cell death & disease. 2021; 12 (1): 87. DOI: 10.1038/s41419-021-03397-1
Bui V.Q., Stein A.D., DiGirolamo A.M., Ramakrishnan U., Flores-Ayala R.C., Ramirez-Zea M., Grant F.K., Villalpando S., Martorell R. Associations between serum C-reactive protein and serum zinc, ferritin, and copper in Guatemalan school children. Biological trace element research. 2012; 148: 154–60. DOI: 10.1007/s12011-012-9358-0
Luojus M.K., Lehto S.M., Tolmunen T., Elomaa A.P., Kauhanen J. Serum copper, zinc and high-sensitivity C-reactive protein in short and long sleep duration in ageing men. J of Trace Elements in Medicine and Biology. 2015; 32: 177–82. DOI: 10.1016/j.jtemb.2015.07.008
Devanarayanan S., Nandeesha H., Kattimani S., Sarkar S., Jose J. Elevated copper, hs C-reactive protein and dyslipidemia in drug free schizophrenia: relation with psychopathology score. Asian journal of psychiatry. 2016; 24: 99–102. DOI: 10.1016/j.ajp.2016.08.025
Prasad A.S. Zinc is an antioxidant and anti-inflammatory agent: its role in human health. Frontiers in nutrition. 2014; 1: 14. DOI: 10.3389/fnut.2014.00014
Jarosz M., Olbert M., Wyszogrodzka G., Młyniec K., Librowski T. Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling. Inflammopharmacology. 2017; 25: 11–24. DOI: 10.1007/s10787-017-0309-4
Foster M., Samman S. Zinc and regulation of inflammatory cytokines: implications for cardiometabolic disease. Nutrients. 2012; 4 (7): 676–94. DOI: 10.3390/nu4070676
Haase H., Ober-Blobaum J.L., Engelhardt G., Hebel S., Heit A., Heine H., Rink L. Zinc signals are essential for lipopolysaccharide-induced signal transduction in monocytes. The J. of Immunology. 2008; 181 (9): 6491–502. DOI: 10.4049/jimmunol.181.9.6491
Gammoh N.Z., Rink L. Zinc in infection and inflammation. Nutrients. 2017; 9 (6): 624. DOI: 10.3390/nu9060624
Sharma V.K., Tumbapo A., Pant V., Aryal B., Shrestha S., Yadav B.K., Tuladhar E.T., Bhattarai A., Raut M. Ceruloplasmin, a potential marker for glycemic status and its relationship with lipid profile in Type II diabetes mellitus. Asian J. Med. Sci. 2018; 9 (2): 13–8. DOI: 10.3126/ajms.v9i2.19003
Nobili V., Siotto M., Bedogni G., Ravà L., Pietrobattista A., Panera N., Alisi A., Squitti R. Levels of serum ceruloplasmin associate with pediatric nonalcoholic fatty liver disease. J of pediatric gastroenterology and nutrition. 2013; 56 (4): 370–5. DOI: 10.1097/MPG.0b013e31827aced4.
Arenas de Larriva A.P., Limia-Pérez L., Alcalá-Diaz J.F., Alonso A., López-Miranda J., Delgado-Lista J. Ceruloplasmin and coronary heart disease–a systematic review. Nutrients. 2020; 12 (10): 3219. DOI: 10.3390/nu12103219
Louro M.O., Cocho J.A., Mera A., Tutor J.C. Immunochemical and enzymatic study of ceruloplasmin in rheumatoid arthritis. J of trace elements in medicine and biology. 2000; 14 (3): 174–8. DOI: 10.1016/S0946-672X(00)80007-3
Sandstead H.H. Requirements and toxicity of essential trace elements, illustrated by zinc and copper. The Am. J. of clinical nutrition. 1995; 61 (3): 621–4. DOI: 10.1093/ajcn/61.3.621S
32. Jensen T., Kierulf P., Sandset P.M., Klingenberg O., Joø G.B., Godal H.C., Skjønsberg O.H. Fibrinogen and fibrin induce synthesis of proinflammatory cytokines from isolated peripheral blood mononuclear cells. Thrombosis and haemostasis. 2007; 97 (05): 822–9. DOI: 10.1160/TH07-01-0039
Davalos D., Akassoglou K. Fibrinogen as a key regulator of inflammation in disease. Seminars in immunopathology. 2012; 34: 43–62. DOI: 10.1007/s00281-011-0290-8
Lu P.P., Liu J.T., Liu N., Guo F., Ji Y.Y., Pang X. Pro-inflammatory effect of fibrinogen and FDP on vascular smooth muscle cells by IL-6, TNF-α and iNOS. Life sciences. 2011; 88 (19–20): 839–45. DOI: 10.1016/j.lfs.2011.03.003
Sitrin R.G., Pan P.M., Srikanth S., Todd R.F. Fibrinogen activates NF-κB transcription factors in mononuclear phagocytes. The J. of Immunology. 1998; 161 (3): 1462–70.
Malek F., Spacek R., Polasek R., Karel I. Relation between levels of acute phase proteins and copper and the parameters of systolic and diastolic left ventricular function in patients with chronic heart failure. Casopis Lekaru Ceskych. 2002; 141 (14): 456–9.
Zhou S., Zhang F., Chen F., Li P., He Y., Wu J., Dong L., Wang C., Wang X., Zhang W., Sun W. Micronutrient level is negatively correlated with the neutrophil-lymphocyte ratio in patients with severe COVID-19. Int. J. of clinical practice. 2022; 2022. DOI: 10.1155/2022/6498794
Bui V.Q., Stein A.D., DiGirolamo A.M., Ramakrishnan U., Flores-Ayala R.C., Ramirez-Zea M., Grant F.K., Villalpando S., Martorell R. Associations between serum C-reactive protein and serum zinc, ferritin, and copper in Guatemalan school children. Biological trace element research. 2012; 148: 154–60. DOI: 10.1007/s12011-012-9358-0
Elsaadany E., Amin S., Abdel-Hafez M., El Amrousy D., Kasem S., Abd Elaziz D., Shawky D. Study of Serum Ferritin, Zinc, and Copper Levels in Children With Helicobacter pylori Gastritis and the Effect of the Treatment. J of Pediatric Gastroenterology and Nutrition. 2022; 75 (5): 88–93. DOI: 10.1097/MPG.0000000000003585
Jiang T., Xie D., Wu J., He H., Wang H., Wang N., Zhu Z., Wang Y., Yang T. Association between serum copper levels and prevalence of hyperuricemia: a cross-sectional study. Scientific Reports. 2020; 10 (1): 8687. DOI: 10.1038/s41598-020-65639-0.
Li L.Z., Zhou G.X., Li J., Jiang W., Liu B.L., Zhou W. Compounds containing trace element copper or zinc exhibit as potent hyperuricemia inhibitors via xanthine oxidase inactivation. J. of Trace Elements in Medicine and Biology. 2018; 49: 72–8. DOI: 10.1016/j.jtemb.2018.04.019