{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T08:39:02Z","timestamp":1783672742716,"version":"3.55.0"},"reference-count":51,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T00:00:00Z","timestamp":1741824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PRIAM-based consortium of multiple funders"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Copper functions as a cofactor and antioxidants in a large number of enzymes that are important for cellular respiration and the nervous system. In the last century scholars have explored copper\u2019s relationship with the immune system, with copper deficiency drastically upsetting the overall function of the immune system, as seen in symptoms such as increased susceptibility to pathogens, decreased proliferation of lymphocytes, and impaired function of both cytotoxic T lymphocytes and helper T cells. Among copper\u2019s various forms, copper bis-glycinate (Cbg) has been used as an official EU-approved oral supplement to promote health. In this study, we observed the influence of Cbg on human epithelial cells (HCE-T cells) to determine its cytotoxicity, anti-reactive oxygen (ROS), and wound healing capabilities. We also evaluated Cbg\u2019s anti-inflammatory immune cells like primary human mononuclear cells (PBMCs), monocytic THP-1, and Jurkat cells in the context of anti-inflammation. At all the investigated concentrations of Cbg (0.05\u2013100 \u03bcg\/mL), ther was no considerable impact detected on the epithelial cells. However, the proliferation rate of stimulated PBMCs was affected progressively (3\u201350 \u03bcg\/mL). In CD4+ helper T cells, interleukin (IL)-17 and IL-2 cytokine levels were decreased in a dose-dependent manner, while interferon (IFN)-\u03b3 and IL-2 levels were slightly decreased with no noticeable changes between each treated concentration. Furthermore, stimulated monocytic THP-1 cells treated with Cbg reduced IL-6 and significantly reduced tumor necrosis factor (TNF)-\u03b1 cytokines secretion. Lastly, stimulated Jurkat intracellular Ca2+ influx was significantly inhibited in a dose-dependent manner. Taken together, this study demonstrated that copper possesses modulatory effects on immune cells but not on epithelial cells, but further studies are needed to underline this hypothesis.<\/jats:p>","DOI":"10.3390\/molecules30061282","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T04:18:32Z","timestamp":1741839512000},"page":"1282","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Immunomodulatory Effects of Copper Bis-Glycinate In Vitro"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3908-2582","authenticated-orcid":false,"given":"Alexander","family":"Areesanan","sequence":"first","affiliation":[{"name":"Translational Complementary Medicine, Department of Pharmaceutical Sciences, University of Basel, Campus Rosental\u2014Mattenstrasse 22, CH-4058 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4370-6600","authenticated-orcid":false,"given":"Luise","family":"Wolf","sequence":"additional","affiliation":[{"name":"Translational Complementary Medicine, Department of Pharmaceutical Sciences, University of Basel, Campus Rosental\u2014Mattenstrasse 22, CH-4058 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7924-3364","authenticated-orcid":false,"given":"Sven","family":"Nicolay","sequence":"additional","affiliation":[{"name":"Translational Complementary Medicine, Department of Pharmaceutical Sciences, University of Basel, Campus Rosental\u2014Mattenstrasse 22, CH-4058 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8641-5965","authenticated-orcid":false,"given":"Amy Marisa","family":"Zimmermann-Klemd","sequence":"additional","affiliation":[{"name":"Translational Complementary Medicine, Department of Pharmaceutical Sciences, University of Basel, Campus Rosental\u2014Mattenstrasse 22, CH-4058 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Gr\u00fcndemann","sequence":"additional","affiliation":[{"name":"Translational Complementary Medicine, Department of Pharmaceutical Sciences, University of Basel, Campus Rosental\u2014Mattenstrasse 22, CH-4058 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.jaci.2009.12.980","article-title":"Overview of the immune response","volume":"125","author":"Chaplin","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1111\/joim.12395","article-title":"Human autoimmune diseases: A comprehensive update","volume":"278","author":"Wang","year":"2015","journal-title":"J. Intern. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jaci.2015.10.023","article-title":"Alterations in immune function with biologic therapies for autoimmune disease","volume":"137","author":"Her","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.rdc.2015.08.002","article-title":"Corticosteroids: Mechanisms of Action in Health and Disease","volume":"42","author":"Ramamoorthy","year":"2016","journal-title":"Rheum. Dis. Clin. N. Am."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0162-3109(00)00186-7","article-title":"Immunosuppressive drugs: The first 50 years and a glance forward","volume":"47","author":"Allison","year":"2000","journal-title":"Immunopharmacology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.2174\/1389201019666171226152448","article-title":"Biologics in Inflammatory Immune-mediated Systemic Diseases","volume":"18","author":"Moroncini","year":"2017","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1007\/s00108-019-00676-0","article-title":"Biologika in der Rheumatologie","volume":"60","author":"Wagner","year":"2019","journal-title":"Der Internist"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.jtemb.2016.02.006","article-title":"Dietary copper and human health: Current evidence and unresolved issues","volume":"35","author":"Bost","year":"2016","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/jat.3390","article-title":"Immunomodulatory effects of metal salts at sub-toxic concentrations","volume":"37","author":"Steinborn","year":"2017","journal-title":"J. Appl. Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1146\/annurev-biochem-030409-143539","article-title":"Copper metallochaperones","volume":"79","author":"Robinson","year":"2010","journal-title":"Annu. Rev. Biochem."},{"key":"ref_11","unstructured":"(2025, January 15). National Institutes of Health. Copper\u2014Fact Sheet for Consumers, Available online: https:\/\/ods.od.nih.gov\/factsheets\/Copper-Consumer\/."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1182\/blood.V28.2.280.280","article-title":"Hypocupremia and neutropenia in copper deficiency","volume":"28","author":"Cordano","year":"1966","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/0021-9975(81)90032-3","article-title":"Effects of selenium and copper deficiency on neutrophil function in cattle","volume":"91","author":"Boyne","year":"1981","journal-title":"J. Comp. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1126\/science.7244654","article-title":"Copper deficiency suppresses the immune response of mice","volume":"213","author":"Prohaska","year":"1981","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Cheng, F., Peng, G., Lu, Y., Wang, K., Ju, Q., Ju, Y., and Ouyang, M. (2022). Relationship between copper and immunity: The potential role of copper in tumor immunity. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1019153"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1093\/jn\/111.5.907","article-title":"Mineral deficiency effects on the generation of cytotoxic T-cells and T-helper cell factors in vitro","volume":"111","author":"Flynn","year":"1981","journal-title":"J. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.3181\/00379727-141-36926","article-title":"The effect of leukocytic endogenous mediator (LEM) on serum copper and ceruloplasmin concentrations in the rat","volume":"141","author":"Pekarek","year":"1972","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/BF01972407","article-title":"Copper and inflammation","volume":"8","author":"Whitehouse","year":"1978","journal-title":"Agents Actions"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1007\/BF01983655","article-title":"Copper and inflammation\u2014A possible rationale for the pharmacological manipulation of inflammatory disorders","volume":"16","author":"Milanino","year":"1985","journal-title":"Agents Actions"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1007\/BF01998975","article-title":"Is copper pro- or anti-inflammatory? A reconciling view and a novel approach for the use of copper in the control of inflammation","volume":"39","author":"Berthon","year":"1993","journal-title":"Agents Actions"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1515\/REVEH.2006.21.3.153","article-title":"Copper: Role of the \u2018endogenous\u2019 and \u2018exogenous\u2019 metal on the development and control of inflammatory processes","volume":"21","author":"Milanino","year":"2006","journal-title":"Rev. Environ. Health"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zangiabadi, S., Chamoun, K.P., Nguyen, K., Tang, Y., Sweeney, G., and Abdul-Sater, A.A. (2023). Copper infused fabric attenuates inflammation in macrophages. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0287741"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/0008-8749(90)90330-T","article-title":"Differential effects of copper and zinc on human peripheral blood monocyte cytokine secretion","volume":"126","author":"Scuderi","year":"1990","journal-title":"Cell. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s11010-006-1168-2","article-title":"Evaluation of copper toxicity in isolated human peripheral blood mononuclear cells and it\u2019s attenuation by zinc: Ex vivo","volume":"282","author":"Singh","year":"2006","journal-title":"Mol. Cell. Biochem."},{"key":"ref_25","unstructured":"Akhouri, S., and House, S.A. (2025). Allergic Rhinitis. StatPearls, StatPearls Publishing LLC."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.aller.2010.07.006","article-title":"Oxidative stress status and plasma trace elements in patients with asthma or allergic rhinitis","volume":"39","author":"Sagdic","year":"2011","journal-title":"Allergol. Immunopathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"324","DOI":"10.29271\/jcpsp.2022.03.324","article-title":"Trace Elements (Zn and Cu) and Oxidative Stress in Pediatric Patients with Persistent Allergic Rhinitis","volume":"32","author":"Gunizi","year":"2022","journal-title":"J. Coll. Physicians Surg. Pak."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e19","DOI":"10.2500\/aap.2020.41.190020","article-title":"The role of antioxidants and 25-hydroxyvitamin D during pregnancy in the development of allergic diseases in early school-age children-Polish Mother and Child Cohort Study","volume":"41","author":"Hanke","year":"2020","journal-title":"Allergy Asthma Proc."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Sahoyama, Y., Hamazato, F., Shiozawa, M., Nakagawa, T., Suda, W., Ogata, Y., Hachiya, T., Kawakami, E., and Hattori, M. (2022). Multiple nutritional and gut microbial factors associated with allergic rhinitis: The Hitachi Health Study. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-07398-8"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"718","DOI":"10.2903\/j.efsa.2008.718","article-title":"Opinion on certain bisglycinates as sources of copper, zinc, calcium, magnesium and glycinate nicotinate as source of chromium in foods intended for the general population (including food supplements) and foods for particular nutritional uses-Scientific Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food","volume":"6","year":"2008","journal-title":"EFSA J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.actbio.2023.12.021","article-title":"A tissue-adhesive F127 hydrogel delivers antioxidative copper-selenide nanoparticles for the treatment of dry eye disease","volume":"175","author":"Ou","year":"2024","journal-title":"Acta Biomater."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1604872","DOI":"10.1002\/adfm.201604872","article-title":"A Cooperative Copper Metal-Organic Framework-Hydrogel System Improves Wound Healing in Diabetes","volume":"27","author":"Xiao","year":"2016","journal-title":"Adv. Funct. Mater."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Nordberg, G., Fowler, B.A., and Nordberg, M. (2015). Handbook on the Toxicology of Metals, Elsevier. [4th ed.].","DOI":"10.1016\/B978-0-444-59453-2.00001-9"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Mendes, C., Thirupathi, A., Correa, M., Gu, Y., and Silveira, P.C.L. (2022). The Use of Metallic Nanoparticles in Wound Healing: New Perspectives. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232315376"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Aschner, M., Skalny, A.V., Lu, R., Martins, A.C., Tizabi, Y., Nekhoroshev, S.V., Santamaria, A., Sinitskiy, A.I., and Tinkov, A.A. (2024). Mitochondrial pathways of copper neurotoxicity: Focus on mitochondrial dynamics and mitophagy. Front. Mol. Neurosci., 17.","DOI":"10.3389\/fnmol.2024.1504802"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/sj.cdd.4401830","article-title":"Reactive oxygen species mediate crosstalk between NF-kappaB and JNK","volume":"13","author":"Nakano","year":"2006","journal-title":"Cell Death Differ."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Vasalou, V., Kotidis, E., Tatsis, D., Boulogeorgou, K., Grivas, I., Koliakos, G., Cheva, A., Ioannidis, O., Tsingotjidou, A., and Angelopoulos, S. (2023). The Effects of Tissue Healing Factors in Wound Repair Involving Absorbable Meshes: A Narrative Review. J. Clin. Med., 12.","DOI":"10.3390\/jcm12175683"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.brainres.2013.10.029","article-title":"Multiple effects of copper on NMDA receptor currents","volume":"1542","author":"Marchetti","year":"2014","journal-title":"Brain Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1016\/j.bbrc.2005.10.164","article-title":"Human T lymphocytes express N-methyl-D-aspartate receptors functionally active in controlling T cell activation","volume":"338","author":"Miglio","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1126\/science.1098845","article-title":"TRPM4 regulates calcium oscillations after T cell activation","volume":"306","author":"Launay","year":"2004","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1146\/annurev.immunol.19.1.497","article-title":"Calcium signaling mechanisms in T lymphocytes","volume":"19","author":"Lewis","year":"2001","journal-title":"Annu. Rev. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1111\/imm.12846","article-title":"Neurotransmitter signalling via NMDA receptors leads to decreased T helper type 1-like and enhanced T helper type 2-like immune balance in humans","volume":"153","author":"Orihara","year":"2018","journal-title":"Immunology"},{"key":"ref_43","first-page":"301","article-title":"Bioavailability of trace elements","volume":"42","year":"1984","journal-title":"Nutr. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/S0271-5317(81)80092-9","article-title":"Chelating agents and biovailability of minerals","volume":"1","author":"Shah","year":"1981","journal-title":"Nutr. Res."},{"key":"ref_45","unstructured":"Barnett, J.B., Brundage, K.M., and Lawrence, D. (2010). Comprehensive Toxicology, Elsevier. [2nd ed.]."},{"key":"ref_46","unstructured":"Tomlin, C. (1997). ; British Crop Protection Council. The Pesticide Manual, British Crop Protection Council. [11th ed.]."},{"key":"ref_47","unstructured":"(2009). US. Environmental Protection Agency. Reregistration Eligibility Decision (RED) for Coppers, U.S. Government Printing Office."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Areesanan, A., Nicolay, S., Keller, M., Zimmermann-Klemd, A.M., Potterat, O., and Grundemann, C. (2023). Potential benefits of Malva sylvestris in dry-eye disease pathology in vitro based on antioxidant, wound-healing and anti-inflammatory properties. Biomed. Pharmacother., 168.","DOI":"10.1016\/j.biopha.2023.115782"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0023-6438(95)80008-5","article-title":"Use of a free radical method to evaluate antioxidant activity","volume":"28","author":"Cuvelier","year":"1995","journal-title":"LWT-Food Sci. Technol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.jep.2019.02.034","article-title":"Influence of traditionally used Nepalese plants on wound healing and immunological properties using primary human cells in vitro","volume":"235","author":"Konradi","year":"2019","journal-title":"J. Ethnopharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Winker, M., Chauveau, A., Smiesko, M., Potterat, O., Areesanan, A., Zimmermann-Klemd, A., and Grundemann, C. (2023). Immunological evaluation of herbal extracts commonly used for treatment of mental diseases during pregnancy. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-35952-5"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/6\/1282\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:52:47Z","timestamp":1760028767000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/6\/1282"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,13]]},"references-count":51,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["molecules30061282"],"URL":"https:\/\/doi.org\/10.3390\/molecules30061282","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,13]]}}}