{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T19:16:10Z","timestamp":1770837370850,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T00:00:00Z","timestamp":1592524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"This work was funded by the National Plan for Science, Technology and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, Kingdom of Saudi Arabia","award":["(Project no. 13-MED920-02)."],"award-info":[{"award-number":["(Project no. 13-MED920-02)."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Thyroid hormones critically modulate body homeostasis and haemostasis by regulating energy and metabolism. Previous studies have focused on individual pathways or proteins that are affected by increases in thyroid hormone levels, while an overall plasma proteomic signature of this increased level is lacking. Herein, an integrated untargeted proteomic approach with network analysis was used to identify changes in circulating proteins in the plasma proteome between hyperthyroid and euthyroid states. Plasma from 10 age-matched subjects at baseline (hyperthyroid) and post treatment with carbimazole (euthyroid) was compared by difference gel electrophoresis (DIGE) and matrix-assisted laser desorption\/ionization time of flight (MALDI TOF) mass spectrometry (MS). A total of 20 proteins were identified with significant difference in abundance (analysis of variance (ANOVA) test, p \u2264 0.05; fold-change \u2265 1.5) between the two states (12 increased and 8 decreased in abundance in the hyperthyroid state). Twelve protein spots corresponding to ten unique proteins were significantly more abundant in the hyperthyroid state compared with the euthyroid state. These increased proteins were haptoglobin (HP), hemopexin (HPX), clusterin (CLU), apolipoprotein L1 (APOL1), alpha-1-B glycoprotein (A1BG), fibrinogen gamma chain (FGG), Ig alpha-1 chain C region (IGHA1), complement C6 (C6), leucine rich alpha 2 glycoprotein (LRG1), and carboxypeptidase N catalytic chain (CPN1). Eight protein spots corresponding to six unique proteins were significantly decreased in abundance in the hyperthyroid samples compared with euthyroid samples. These decreased proteins were apolipoprotein A1 (APOA1), inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), plasminogen (PLG), alpha-1 antitrypsin (SERPINA1), fibrinogen beta chain (FGB), and complement C1r subcomponent (C1R). The differentially abundant proteins were investigated by ingenuity pathway analysis (IPA). The network pathway identified related to infectious disease, inflammatory disease, organismal injury and abnormalities, and the connectivity map focused around two central nodes, namely the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB) and p38 mitogen-activated protein kinase (MAPK) pathways. The plasma proteome of patients with hyperthyroidism revealed differences in the abundance of proteins involved in acute phase response signaling, and development of a hypercoagulable and hypofibrinolytic state. Our findings enhance our existing knowledge of the altered proteins and associated biochemical pathways in hyperthyroidism.<\/jats:p>","DOI":"10.3390\/molecules25122831","type":"journal-article","created":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T12:19:55Z","timestamp":1592569195000},"page":"2831","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Plasma-Based Proteomics Profiling of Patients with Hyperthyroidism after Antithyroid Treatment"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8082-9326","authenticated-orcid":false,"given":"Afshan","family":"Masood","sequence":"first","affiliation":[{"name":"Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925 (98), Riyadh 11461, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9745-2959","authenticated-orcid":false,"given":"Hicham","family":"Benabdelkamel","sequence":"additional","affiliation":[{"name":"Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925 (98), Riyadh 11461, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aishah A.","family":"Ekhzaimy","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine and king Saud Medical City, King Saud University, P.O. Box 2925 (98), Riyadh 11461, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4792-5188","authenticated-orcid":false,"given":"Assim A.","family":"Alfadda","sequence":"additional","affiliation":[{"name":"Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925 (98), Riyadh 11461, Saudi Arabia"},{"name":"Department of Medicine, College of Medicine and king Saud Medical City, King Saud University, P.O. Box 2925 (98), Riyadh 11461, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3035","DOI":"10.1172\/JCI60047","article-title":"Mechanisms of thyroid hormone action","volume":"122","author":"Brent","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1152\/physrev.2001.81.3.1097","article-title":"Physiological and molecular basis of thyroid hormone action","volume":"81","author":"Yen","year":"2001","journal-title":"Physiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1530\/EJE-09-0875","article-title":"Clinical relevance of thyroid dysfunction in human haematopoiesis: Biochemical and molecular studies","volume":"162","author":"Kawa","year":"2010","journal-title":"Eur. J. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.molmed.2013.04.004","article-title":"Energy balance regulation by thyroid hormones at central level","volume":"19","author":"Lopez","year":"2013","journal-title":"Trends Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1152\/physrev.00030.2013","article-title":"Thyroid hormone regulation of metabolism","volume":"94","author":"Mullur","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1152\/physrev.1991.71.3.733","article-title":"Significance of cation transport in control of energy metabolism and thermogenesis","volume":"71","author":"Clausen","year":"1991","journal-title":"Physiol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1677\/joe.0.1790367","article-title":"Plasma protein regulation by thyroid hormone","volume":"179","author":"Lin","year":"2003","journal-title":"J. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.pharmthera.2017.02.012","article-title":"New insights into thyroid hormone action","volume":"173","author":"Mendoza","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Pietzner, M., Engelmann, B., Kacprowski, T., Golchert, J., Dirk, A.L., Hammer, E., Iwen, K.A., Nauck, M., Wallaschofski, H., and Fuhrer, D. (2017). Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model. BMC Med., 15.","DOI":"10.1186\/s12916-016-0770-8"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1159\/000381769","article-title":"Effect of Experimental Thyrotoxicosis onto Blood Coagulation: A Proteomics Study","volume":"4","author":"Engelmann","year":"2015","journal-title":"Eur. Thyroid. J."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Alfadda, A.A., Benabdelkamel, H., Masood, A., Jammah, A.A., and Ekhzaimy, A.A. (2018). Differences in the Plasma Proteome of Patients with Hypothyroidism before and after Thyroid Hormone Replacement: A Proteomic Analysis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010088"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"511","DOI":"10.3389\/fendo.2018.00511","article-title":"A Renewed Focus on the Association Between Thyroid Hormones and Lipid Metabolism","volume":"9","author":"Duntas","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1210\/jcem-55-3-459","article-title":"Serum lipids and apolipoproteins A-I, A-II, and B in hyperthyroidism before and after treatment","volume":"55","author":"Muls","year":"1982","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1089\/105072502320288384","article-title":"High-density lipoprotein-facilitated entry of thyroid hormones into cells: A mechanism different from the low-density lipoprotein-facilitated entry","volume":"12","author":"Benvenga","year":"2002","journal-title":"Thyroid. Off. J. Am. Thyroid Assoc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e92176","DOI":"10.1172\/jci.insight.92176","article-title":"Plasminogen promotes cholesterol efflux by the ABCA1 pathway","volume":"2","author":"Pamir","year":"2017","journal-title":"JCI Insight"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"21540","DOI":"10.1074\/jbc.M800214200","article-title":"Apolipoprotein L1, a novel Bcl-2 homology domain 3-only lipid-binding protein, induces autophagic cell death","volume":"283","author":"Wan","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1194\/jlr.P061598","article-title":"ApoL1 levels in high density lipoprotein and cardiovascular event presentation in patients with familial hypercholesterolemia","volume":"57","author":"Cubedo","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2528","DOI":"10.1161\/ATVBAHA.110.212894","article-title":"Low clusterin levels in high-density lipoprotein associate with insulin resistance, obesity, and dyslipoproteinemia","volume":"30","author":"Hoofnagle","year":"2010","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.freeradbiomed.2004.10.038","article-title":"Differential effects of clusterin\/apolipoprotein J on cellular growth and survival","volume":"38","author":"Trougakos","year":"2005","journal-title":"Free Radic. Biol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S0891-5849(03)00209-0","article-title":"Thyroid hormone-induced oxidative stress triggers nuclear factor-kappaB activation and cytokine gene expression in rat liver","volume":"35","author":"Tapia","year":"2003","journal-title":"Free Radic. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4716","DOI":"10.1016\/S0021-9258(19)43723-X","article-title":"Effects of hypothyroidism, hyperthyroidism, and thyroxine on net synthesis of plasma proteins by the isolated perfused rat liver. Modulation of the response to insulin plus cortisol in the net synthesis of albumin, fibrinogen, 1-acid glycorprotein, 2-(acute phase) globulin, and haptoglobin","volume":"248","author":"Griffin","year":"1973","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"11158","DOI":"10.1021\/bi7006349","article-title":"Haptoglobin binding to apolipoprotein A-I prevents damage from hydroxyl radicals on its stimulatory activity of the enzyme lecithin-cholesterol acyl-transferase","volume":"46","author":"Salvatore","year":"2007","journal-title":"Biochemistry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/prca.201100062","article-title":"Towards clinical applications of selected reaction monitoring for plasma protein biomarker studies","volume":"6","author":"Krisp","year":"2012","journal-title":"Proteomics. Clin. Appl."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ferrari, E., Wittig, A., Basilico, F., Rossi, R., De Palma, A., Di Silvestre, D., Sauerwein, W.A.G., and Mauri, P.L. (2019). Urinary Proteomics Profiles Are Useful for Detection of Cancer Biomarkers and Changes Induced by Therapeutic Procedures. Molecules, 24.","DOI":"10.3390\/molecules24040794"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/cei.12476","article-title":"Acute-phase protein alpha1-anti-trypsin: Diverting injurious innate and adaptive immune responses from non-authentic threats","volume":"179","author":"Guttman","year":"2015","journal-title":"Clin. Exp. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1097\/00000478-199608000-00004","article-title":"Alpha 1-antitrypsin expression in human thyroid papillary carcinoma","volume":"20","author":"Poblete","year":"1996","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_27","first-page":"83","article-title":"Alpha-1 Antitrypsin Blood Levels as Indicator for the Efficacy of Cancer Treatment","volume":"4","author":"Khouri","year":"2013","journal-title":"World J. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1161\/ATVBAHA.109.190058","article-title":"Protective role of clusterin\/apolipoprotein J against neointimal hyperplasia via antiproliferative effect on vascular smooth muscle cells and cytoprotective effect on endothelial cells","volume":"29","author":"Kim","year":"2009","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/1357-2725(95)00027-M","article-title":"Clusterin: Physiologic and pathophysiologic considerations","volume":"27","author":"Rosenberg","year":"1995","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.metabol.2017.09.014","article-title":"Circulating ApoJ is closely associated with insulin resistance in human subjects","volume":"78","author":"Seo","year":"2018","journal-title":"Metab. Clin. Exp."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/ni.1923","article-title":"Complement: A key system for immune surveillance and homeostasis","volume":"11","author":"Ricklin","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/0140-6736(92)92171-B","article-title":"Antithyroid drugs and release of inflammatory mediators by complement-attacked thyroid cells","volume":"340","author":"Weetman","year":"1992","journal-title":"Lancet"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15571","DOI":"10.1074\/jbc.M113.451757","article-title":"Molecular determinants of the substrate specificity of the complement-initiating protease, C1r","volume":"288","author":"Wijeyewickrema","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/j.1365-2265.2006.02464.x","article-title":"Blood coagulation, fibrinolytic activity and lipid profile in subclinical thyroid disease: Subclinical hyperthyroidism increases plasma factor X activity","volume":"64","author":"Erem","year":"2006","journal-title":"Clin. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.thromres.2011.03.009","article-title":"Cerebral vein and sinus thrombosis and hyperthyrodism: A case report and a systematic review of the literature","volume":"128","author":"Bensalah","year":"2011","journal-title":"Thromb. Res."},{"key":"ref_36","first-page":"981638","article-title":"The changes in the endothelial function and haemostatic and inflammatory parameters in subclinical and overt hyperthyroidism","volume":"2013","author":"Siewko","year":"2013","journal-title":"Int. J. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/1465-9921-11-173","article-title":"Cardiovascular and musculskeletal co-morbidities in patients with alpha 1 antitrypsin deficiency","volume":"11","author":"Duckers","year":"2010","journal-title":"Respir. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1177\/1076029609348315","article-title":"Human platelet aggregation and degranulation is induced in vitro by L-thyroxine, but not by 3,5,3\u2019-triiodo-L-thyronine or diiodothyropropionic acid (DITPA)","volume":"16","author":"Mousa","year":"2010","journal-title":"Clin. Appl. Thromb. Hemost. Off. J. Int. Acad. Clin. Appl. Thromb. Hemost."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1177\/1076029618774150","article-title":"New Interfaces of Thyroid Hormone Actions With Blood Coagulation and Thrombosis","volume":"24","author":"Davis","year":"2018","journal-title":"Clin. Appl. Thromb. Hemost. Off. J. Int. Acad. Clin. Appl. Thromb. Hemost."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1007\/BF03350928","article-title":"Fibrinogen and fibrinolytic activity in hyperthyroidism before and after antithyroid treatment","volume":"11","author":"Marongiu","year":"1988","journal-title":"J. Endocrinol. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"30193","DOI":"10.1074\/jbc.M803659200","article-title":"Fibrinogen-elongated gamma chain inhibits thrombin-induced platelet response, hindering the interaction with different receptors","volume":"283","author":"Lancellotti","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/bs.vh.2017.05.003","article-title":"The NF-kappaB Family of Transcription Factors and Its Role in Thyroid Physiology","volume":"106","author":"Reale","year":"2018","journal-title":"Vitam. Horm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.imbio.2007.10.005","article-title":"Activation of NF-kappaB in lymphocytes and increase in serum immunoglobulin in hyperthyroidism: Possible role of oxidative stress","volume":"213","author":"Nandakumar","year":"2008","journal-title":"Immunobiology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1186\/1756-6614-4-S1-S6","article-title":"Transcriptional regulation by nonclassical action of thyroid hormone","volume":"4","author":"Moeller","year":"2011","journal-title":"Thyroid. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"352","DOI":"10.11613\/BM.2012.037","article-title":"Investigation of unusual high serum indices for lipemia in clear serum samples on siemens analysers dimension","volume":"22","author":"Fliser","year":"2012","journal-title":"Biochem. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.clinbiochem.2004.03.008","article-title":"Validation of the Friedewald formula for the determination of low-density lipoprotein cholesterol compared with beta-quantification in a large population","volume":"37","author":"Tremblay","year":"2004","journal-title":"Clin. Biochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"48A","DOI":"10.1021\/ac002709u","article-title":"Detecting proteins separated by 2-D gel electrophoresis","volume":"72","author":"Rabilloud","year":"2000","journal-title":"Anal. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.exger.2013.07.008","article-title":"Proteomic analysis of mature adipocytes from obese patients in relation to aging","volume":"48","author":"Alfadda","year":"2013","journal-title":"Exp. Gerontol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1021\/ac950914h","article-title":"Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels","volume":"68","author":"Shevchenko","year":"1996","journal-title":"Anal. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"W147","DOI":"10.1093\/nar\/gkw419","article-title":"Heatmapper: Web-enabled heat mapping for all","volume":"44","author":"Babicki","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1038\/227680a0","article-title":"Cleavage of structural proteins during the assembly of the head of bacteriophage T4","volume":"227","author":"Laemmli","year":"1970","journal-title":"Nature"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/12\/2831\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:40:47Z","timestamp":1760175647000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/12\/2831"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,19]]},"references-count":51,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["molecules25122831"],"URL":"https:\/\/doi.org\/10.3390\/molecules25122831","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,19]]}}}