{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T02:01:29Z","timestamp":1784599289874,"version":"3.55.0"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":63,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Stress can elevate plasma homocysteine (Hcy) levels, a key factor in the development of various diseases, leading to hyperhomocysteinemia (HHcy). The enzyme Cystathionine \u03b2-synthase (CBS) functions in the trans-sulfuration pathway, which links the methionine cycle to glutathione synthesis. This pathway is essential for the metabolism of homocysteine. However, the precise mechanism by which stress regulates hepatic CBS expression remains unclear. The present study aimed to elucidate the molecular mechanism by which CBS expression is regulated in the livers of restraint-stressed rats. Our results showed that stress-induced over-secretion of epinephrine and norepinephrine (E\/NE) activated the \u03b2-adrenergic receptor, leading to elevated serum IL-6 levels. Treatment of rat primary hepatocytes with IL-6 for 1\u00a0h suppressed both CBS activity and\n                    <jats:italic>Cbs<\/jats:italic>\n                    mRNA expression, concomitant with an enhancement of Sp3-mediated transcriptional repression. Furthermore, we found that IL-6 activates NF-\u03baB via the tyrosine phosphorylation pathway, which in turn potentiates Sp3-mediated repression of\n                    <jats:italic>Cbs<\/jats:italic>\n                    transcription. These findings suggest that E\/NE contributes to stress-induced HHcy by inhibiting\n                    <jats:italic>Cbs<\/jats:italic>\n                    transcription through the upregulation of Sp3, and that the IL-6\/NF-\u03baB axis plays a critical role in the dysregulation of Hcy metabolism.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-52669-3","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T13:10:05Z","timestamp":1779196205000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cystathionine \u03b2-synthase is inhibited by epinephrine and norepinephrine over-secretion via NF-\u03baB activation in stress-induced hyperhomocysteinemia"],"prefix":"10.1038","volume":"16","author":[{"given":"Ling","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaowei","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingjia","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"52669_CR1","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/j.neubiorev.2020.05.010","volume":"115","author":"CE Lyons","year":"2020","unstructured":"Lyons, C. E. & Bartolomucci, A. Stress and Alzheimer\u2019s disease: A senescence link? [J]. Neurosci. Biobehav. Rev. 115, 285\u2013298 (2020).","journal-title":"Neurosci. Biobehav. Rev."},{"issue":"4","key":"52669_CR2","doi-asserted-by":"publisher","first-page":"436","DOI":"10.4103\/RPS.RPS_24_23","volume":"19","author":"N Forghani","year":"2024","unstructured":"Forghani, N. et al. Effect of acute and chronic stress on memory impairment and hippocampal oxidative stress following global cerebral ischemia in adult male rats [J]. Res. Pharm. Sci. 19 (4), 436\u2013446 (2024).","journal-title":"Res. Pharm. Sci."},{"key":"52669_CR3","doi-asserted-by":"crossref","unstructured":"Sic, A. et al. Neurobiological Implications of Chronic Stress and Metabolic Dysregulation in Inflammatory Bowel Diseases [J]. Diseases (Basel, Switzerland), 12(9). (2024).","DOI":"10.3390\/diseases12090220"},{"key":"52669_CR4","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.yfrne.2018.02.001","volume":"49","author":"SJ Lupien","year":"2018","unstructured":"Lupien, S. J. et al. The effects of chronic stress on the human brain: From neurotoxicity, to vulnerability, to opportunity [J]. Front. Neuroendocr. 49, 91\u2013105 (2018).","journal-title":"Front. Neuroendocr."},{"key":"52669_CR5","doi-asserted-by":"crossref","unstructured":"Knezevic, E. et al. The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders [J]. Cells, 12(23). (2023).","DOI":"10.3390\/cells12232726"},{"issue":"1","key":"52669_CR6","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1186\/s12974-024-03306-1","volume":"21","author":"AK Evans","year":"2024","unstructured":"Evans, A. K. et al. Impact of noradrenergic inhibition on neuroinflammation and pathophysiology in mouse models of Alzheimer\u2019s disease [J]. J. Neuroinflamm. 21 (1), 322 (2024).","journal-title":"J. Neuroinflamm."},{"issue":"10","key":"52669_CR7","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1093\/abbs\/gmu076","volume":"46","author":"Y Zhao","year":"2014","unstructured":"Zhao, Y. & Qian, L. Homocysteine-mediated intestinal epithelial barrier dysfunction in the rat model of irritable bowel syndrome caused by maternal separation [J]. Acta Biochim. Biophys. Sin. 46 (10), 917\u2013919 (2014).","journal-title":"Acta Biochim. Biophys. Sin."},{"issue":"8","key":"52669_CR8","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1007\/s12264-022-00852-7","volume":"38","author":"SD Wang","year":"2022","unstructured":"Wang, S. D. et al. Homocysteine-Induced Disturbances in DNA Methylation Contribute to Development of Stress-Associated Cognitive Decline in Rats [J]. Neurosci. Bull. 38 (8), 887\u2013900 (2022).","journal-title":"Neurosci. Bull."},{"key":"52669_CR9","doi-asserted-by":"publisher","first-page":"103668","DOI":"10.1016\/j.redox.2025.103668","volume":"84","author":"L Zhang","year":"2025","unstructured":"Zhang, L. et al. Homocysteine induced N6-methyldeoxyadenosine modification perturbation elicits mitochondria dysfunction contributes to the impairment of learning and memory ability caused by early life stress in rats [J]. Redox Biol. 84, 103668 (2025).","journal-title":"Redox Biol."},{"key":"52669_CR10","doi-asserted-by":"crossref","unstructured":"Hainsworth, A. H. et al. Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID) [J]. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1862(5): 1008\u20131017. (2016).","DOI":"10.1016\/j.bbadis.2015.11.015"},{"key":"52669_CR11","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/s12986-017-0233-z","volume":"14","author":"A Kumar","year":"2017","unstructured":"Kumar, A. et al. The metabolism and significance of homocysteine in nutrition and health [J]. Nutr. metabolism. 14, 78 (2017).","journal-title":"Nutr. metabolism"},{"key":"52669_CR12","doi-asserted-by":"crossref","unstructured":"Zuhra, K. et al. Cystathionine-\u03b2-Synthase: Molecular Regulation and Pharmacological Inhibition [J]. Biomolecules, 10(5). (2020).","DOI":"10.3390\/biom10050697"},{"issue":"Suppl 1","key":"52669_CR13","doi-asserted-by":"publisher","first-page":"2494s","DOI":"10.1093\/jn\/nxaa094","volume":"150","author":"MH Stipanuk","year":"2020","unstructured":"Stipanuk, M. H. Metabolism of Sulfur-Containing Amino Acids: How the Body Copes with Excess Methionine, Cysteine, and Sulfide [J]. J. Nutr. 150 (Suppl 1), 2494s\u2013505s (2020).","journal-title":"J. Nutr."},{"key":"52669_CR14","doi-asserted-by":"publisher","unstructured":"Safe, S. Specificity Proteins (Sp) and Cancer [J\/OL] 24(6): (2023). https:\/\/doi.org\/10.3390\/ijms24065164","DOI":"10.3390\/ijms24065164"},{"key":"52669_CR15","doi-asserted-by":"crossref","unstructured":"Yerra, V. G. & Drosatos, K. Specificity Proteins (SP) and Kr\u00fcppel-like Factors (KLF) in Liver Physiology and Pathology [J]. Int. J. Mol. Sci., 24(5). (2023).","DOI":"10.3390\/ijms24054682"},{"issue":"10","key":"52669_CR16","doi-asserted-by":"publisher","first-page":"8558","DOI":"10.1074\/jbc.M310211200","volume":"279","author":"KN Maclean","year":"2004","unstructured":"Maclean, K. N., Kraus, E. & Kraus, J. P. The dominant role of Sp1 in regulating the cystathionine beta-synthase \u2013\u20091a and \u2013\u20091b promoters facilitates potential tissue-specific regulation by Kruppel-like factors [J]. J. Biol. Chem. 279 (10), 8558\u20138566 (2004).","journal-title":"J. Biol. Chem."},{"issue":"8","key":"52669_CR17","doi-asserted-by":"publisher","first-page":"4850","DOI":"10.1074\/jbc.M706387200","volume":"283","author":"B Por\u00e9e","year":"2008","unstructured":"Por\u00e9e, B. et al. Interleukin-6 (IL-6) and\/or soluble IL-6 receptor down-regulation of human type II collagen gene expression in articular chondrocytes requires a decrease of Sp1.Sp3 ratio and of the binding activity of both factors to the COL2A1 promoter [J]. J. Biol. Chem. 283 (8), 4850\u20134865 (2008).","journal-title":"J. Biol. Chem."},{"key":"52669_CR18","doi-asserted-by":"crossref","unstructured":"Zhao, Y. et al. Inhibition of cystathionine \u03b2-synthase is associated with glucocorticoids over-secretion in psychological stress-induced hyperhomocystinemia rat liver [J] Vol. 18, 631\u2013641 (Cell stress & chaperones, 2013). 5.","DOI":"10.1007\/s12192-013-0416-0"},{"issue":"6","key":"52669_CR19","doi-asserted-by":"publisher","first-page":"a001651","DOI":"10.1101\/cshperspect.a001651","volume":"1","author":"T Lawrence","year":"2009","unstructured":"Lawrence, T. The nuclear factor NF-kappaB pathway in inflammation [J]. Cold Spring Harb. Perspect. Biol. 1 (6), a001651 (2009).","journal-title":"Cold Spring Harb. Perspect. Biol."},{"issue":"5","key":"52669_CR20","doi-asserted-by":"publisher","first-page":"3462","DOI":"10.1074\/jbc.M111.286443","volume":"287","author":"G Beauchef","year":"2012","unstructured":"Beauchef, G. et al. The p65 subunit of NF-\u03baB inhibits COL1A1 gene transcription in human dermal and scleroderma fibroblasts through its recruitment on promoter by protein interaction with transcriptional activators (c-Krox, Sp1, and Sp3) [J]. J. Biol. Chem. 287 (5), 3462\u20133478 (2012).","journal-title":"J. Biol. Chem."},{"key":"52669_CR21","doi-asserted-by":"crossref","unstructured":"Zhu, W. et al. Transcriptional activation of CSTB gene expression by transcription factor Sp3 [J] Vol. 649, 71\u201378 (Biochemical and biophysical research communications, 2023).","DOI":"10.1016\/j.bbrc.2023.01.087"},{"issue":"1","key":"52669_CR22","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1007\/s12017-025-08844-2","volume":"27","author":"X Pang","year":"2025","unstructured":"Pang, X. et al. SP3-Mediated Transcriptional Activation of GRIK1 is Involved in Alzheimer\u2019s Disease-Induced Cognitive Decline by Inducing Inflammasome Activation in Microglia [J]. Neuromol. Med. 27 (1), 22 (2025).","journal-title":"Neuromol. Med."},{"key":"52669_CR23","doi-asserted-by":"crossref","unstructured":"Xie, F. et al. The involvement of homocysteine in stress-induced A\u03b2 precursor protein misprocessing and related cognitive decline in rats [J] Vol. 21, 915\u2013926 (Cell stress & chaperones, 2016). 5.","DOI":"10.1007\/s12192-016-0718-0"},{"key":"52669_CR24","doi-asserted-by":"crossref","unstructured":"Cordaro, M. et al. Involvements of Hyperhomocysteinemia in Neurological Disorders [J]. Metabolites, 11(1). (2021).","DOI":"10.3390\/metabo11010037"},{"key":"52669_CR25","doi-asserted-by":"crossref","unstructured":"Jakubowski, H. & Witucki, \u0141. Homocysteine Metabolites, Endothelial Dysfunction, and Cardiovascular Disease [J]. Int. J. Mol. Sci., 26(2). (2025).","DOI":"10.3390\/ijms26020746"},{"key":"52669_CR26","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.neuroscience.2024.11.006","volume":"563","author":"C Xue","year":"2024","unstructured":"Xue, C. et al. Chronic stress disturbed the metabolism of homocysteine in mouse hippocampus and prefrontal cortex [J]. Neuroscience 563, 63\u201373 (2024).","journal-title":"Neuroscience"},{"key":"52669_CR27","doi-asserted-by":"publisher","first-page":"109149","DOI":"10.1016\/j.abb.2022.109149","volume":"718","author":"M Omorou","year":"2022","unstructured":"Omorou, M. et al. Cystathionine beta-Synthase in hypoxia and ischemia\/reperfusion: A current overview [J]. Arch. Biochem. Biophys. 718, 109149 (2022).","journal-title":"Arch. Biochem. Biophys."},{"issue":"1","key":"52669_CR28","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1007\/s00401-013-1223-5","volume":"127","author":"PJ Lucassen","year":"2014","unstructured":"Lucassen, P. J. et al. Neuropathology of stress [J]. Acta Neuropathol. 127 (1), 109\u2013135 (2014).","journal-title":"Acta Neuropathol."},{"issue":"8","key":"52669_CR29","first-page":"e67595","volume":"16","author":"PS Vellapandian","year":"2024","unstructured":"Vellapandian, P. S. Hypothalamic-Pituitary-Adrenal (HPA) Axis: Unveiling the Potential Mechanisms Involved in Stress-Induced Alzheimer\u2019s Disease and Depression [J]. Cureus 16 (8), e67595 (2024).","journal-title":"Cureus"},{"key":"52669_CR30","doi-asserted-by":"publisher","first-page":"149112","DOI":"10.1016\/j.brainres.2024.149112","volume":"1842","author":"A Zaman","year":"2024","unstructured":"Zaman, A. et al. Effect of sex on chronic stress induced alterations in hindbrain catecholaminergic system and autonomic dysfunction resulting in gastrointestinal dysmotility [J]. Brain Res. 1842, 149112 (2024).","journal-title":"Brain Res."},{"key":"52669_CR31","doi-asserted-by":"crossref","unstructured":"Zhu, H. et al. Cystathionine \u03b2-Synthase in Physiology and Cancer [J]. BioMed research international, 2018: 3205125. (2018).","DOI":"10.1155\/2018\/3205125"},{"key":"52669_CR32","doi-asserted-by":"crossref","unstructured":"Li, L. et al. Gene regulation by Sp1 and Sp3 [J]. Biochemistry and cell biology\u2009=\u2009Biochimie et biologie cellulaire, 82(4): 460\u2013471. (2004).","DOI":"10.1139\/o04-045"},{"key":"52669_CR33","doi-asserted-by":"crossref","unstructured":"Suske, G. NF-Y and SP transcription factors \u2014 New insights in a long-standing liaison [J]. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1860(5): 590\u2013597. (2017).","DOI":"10.1016\/j.bbagrm.2016.08.011"},{"key":"52669_CR34","doi-asserted-by":"publisher","first-page":"e18820","DOI":"10.7717\/peerj.18820","volume":"13","author":"W Zhou","year":"2025","unstructured":"Zhou, W. et al. Transcription factor specificity protein (SP) family in renal physiology and diseases [J]. PeerJ 13, e18820 (2025).","journal-title":"PeerJ"},{"issue":"Pt 1","key":"52669_CR35","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1042\/bj3570097","volume":"357","author":"Y Ge","year":"2001","unstructured":"Ge, Y. et al. Transcriptional regulation of the human cystathionine beta-synthase \u2013\u20091b basal promoter: synergistic transactivation by transcription factors NF-Y and Sp1\/Sp3 [J]. Biochem. J. 357 (Pt 1), 97\u2013105 (2001).","journal-title":"Biochem. J."},{"issue":"47","key":"52669_CR36","doi-asserted-by":"publisher","first-page":"43570","DOI":"10.1074\/jbc.M104930200","volume":"276","author":"Y Ge","year":"2001","unstructured":"Ge, Y., Matherly, L. H. & Taub, J. W. Transcriptional regulation of cell-specific expression of the human cystathionine beta -synthase gene by differential binding of Sp1\/Sp3 to the \u2013\u20091b promoter [J]. J. Biol. Chem. 276 (47), 43570\u201343579 (2001).","journal-title":"J. Biol. Chem."},{"issue":"24","key":"52669_CR37","doi-asserted-by":"publisher","first-page":"18225","DOI":"10.1074\/jbc.M110.132142","volume":"285","author":"N Wu","year":"2010","unstructured":"Wu, N. & Siow, Y. L. Ischemia\/reperfusion reduces transcription factor Sp1-mediated cystathionine beta-synthase expression in the kidney [J]. J. Biol. Chem. 285 (24), 18225\u201318233 (2010).","journal-title":"J. Biol. Chem."},{"issue":"4","key":"52669_CR38","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1677\/jme.1.02176","volume":"38","author":"M Egea","year":"2007","unstructured":"Egea, M., Met\u00f3n, I. & Baanante, I. V. Sp1 and Sp3 regulate glucokinase gene transcription in the liver of gilthead sea bream (Sparus aurata) [J]. J. Mol. Endocrinol. 38 (4), 481\u2013492 (2007).","journal-title":"J. Mol. Endocrinol."},{"issue":"1","key":"52669_CR39","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1186\/s12885-018-4349-y","volume":"18","author":"X Kong","year":"2018","unstructured":"Kong, X. et al. ZBP-89 and Sp1 contribute to Bak expression in hepatocellular carcinoma cells [J]. BMC cancer. 18 (1), 419 (2018).","journal-title":"BMC cancer"},{"issue":"1","key":"52669_CR40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.gene.2012.07.022","volume":"508","author":"S Chu","year":"2012","unstructured":"Chu, S. Transcriptional regulation by post-transcriptional modification\u2014Role of phosphorylation in Sp1 transcriptional activity [J]. Gene 508 (1), 1\u20138 (2012).","journal-title":"Gene"},{"issue":"5","key":"52669_CR41","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.aanat.2010.07.010","volume":"192","author":"L Li","year":"2010","unstructured":"Li, L. & Davie, J. R. The role of Sp1 and Sp3 in normal and cancer cell biology [J]. Annals Anat. = Anatomischer Anzeiger: official organ. Anatomische Gesellschaft. 192 (5), 275\u2013283 (2010).","journal-title":"Annals Anat. = Anatomischer Anzeiger: official organ. Anatomische Gesellschaft"},{"key":"52669_CR42","doi-asserted-by":"crossref","unstructured":"Chintalapati, C. et al. Differential regulation of G-protein coupled bile acid receptor (Gpbar-1) by Sp1\/KLF5 family transcription factors [J]. Zeitschrift f\u00fcr Gastroenterologie, 53(12): A2_18. (2015).","DOI":"10.1055\/s-0035-1567990"},{"issue":"2","key":"52669_CR43","doi-asserted-by":"publisher","first-page":"e0298295","DOI":"10.1371\/journal.pone.0298295","volume":"19","author":"P Tian","year":"2024","unstructured":"Tian, P. et al. SP3-induced Timeless transcription contributes to cell growth of lung adenocarcinoma cells [J]. PloS one. 19 (2), e0298295 (2024).","journal-title":"PloS one"},{"issue":"16","key":"52669_CR44","doi-asserted-by":"publisher","first-page":"2357","DOI":"10.1038\/s41388-022-02260-7","volume":"41","author":"C Wang","year":"2022","unstructured":"Wang, C. et al. TP53 mutations upregulate RCP expression via Sp1\/3 to drive lung cancer progression [J]. Oncogene 41 (16), 2357\u20132371 (2022).","journal-title":"Oncogene"},{"key":"52669_CR45","doi-asserted-by":"crossref","unstructured":"Liu, P. et al. Role and mechanisms of the NF-\u0138B signaling pathway in various developmental processes [J] Vol. 153, 113513 (Biomedicine & pharmacotherapy\u2009=\u2009Biomedecine & pharmacotherapie, 2022).","DOI":"10.1016\/j.biopha.2022.113513"},{"issue":"21","key":"52669_CR46","doi-asserted-by":"publisher","first-page":"15318","DOI":"10.1074\/jbc.M112.447318","volume":"288","author":"BJ Carver","year":"2013","unstructured":"Carver, B. J. et al. Interactions between NF-\u03baB and SP3 connect inflammatory signaling with reduced FGF-10 expression [J]. J. Biol. Chem. 288 (21), 15318\u201315325 (2013).","journal-title":"J. Biol. Chem."},{"key":"52669_CR47","doi-asserted-by":"publisher","first-page":"156827","DOI":"10.1016\/j.phymed.2025.156827","volume":"143","author":"Y Jia","year":"2025","unstructured":"Jia, Y. et al. Plantamajoside alleviates DSS-induced ulcerative colitis by modulating gut microbiota, upregulating CBS, and inhibiting NF-\u03baB [J]. Phytomedicine: Int. J. phytotherapy phytopharmacology. 143, 156827 (2025).","journal-title":"Phytomedicine: Int. J. phytotherapy phytopharmacology"},{"issue":"3","key":"52669_CR48","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1007\/s10529-019-02782-3","volume":"42","author":"Y Wang","year":"2020","unstructured":"Wang, Y. et al. H(2)S mediates apoptosis in response to inflammation through PI3K\/Akt\/NF\u03baB signaling pathway [J]. Biotechnol. Lett. 42 (3), 375\u2013387 (2020).","journal-title":"Biotechnol. Lett."},{"issue":"28","key":"52669_CR49","doi-asserted-by":"publisher","first-page":"8615","DOI":"10.3748\/wjg.v21.i28.8615","volume":"21","author":"B Yuan","year":"2015","unstructured":"Yuan, B. et al. TLR4 upregulates CBS expression through NF-\u03baB activation in a rat model of irritable bowel syndrome with chronic visceral hypersensitivity [J]. World J. Gastroenterol. 21 (28), 8615\u20138628 (2015).","journal-title":"World J. Gastroenterol."},{"issue":"21","key":"52669_CR50","doi-asserted-by":"publisher","first-page":"9028","DOI":"10.1523\/JNEUROSCI.1068-13.2013","volume":"33","author":"HH Zhang","year":"2013","unstructured":"Zhang, H. H. et al. Promoted interaction of nuclear factor-\u03baB with demethylated cystathionine-\u03b2-synthetase gene contributes to gastric hypersensitivity in diabetic rats [J]. J. neuroscience: official J. Soc. Neurosci. 33 (21), 9028\u20139038 (2013).","journal-title":"J. neuroscience: official J. Soc. Neurosci."},{"key":"52669_CR51","doi-asserted-by":"publisher","first-page":"16109","DOI":"10.1038\/srep16109","volume":"5","author":"L Zhu","year":"2015","unstructured":"Zhu, L. et al. Adrenergic stimulation sensitizes TRPV1 through upregulation of cystathionine \u03b2-synthetase in a rat model of visceral hypersensitivity [J]. Sci. Rep. 5, 16109 (2015).","journal-title":"Sci. Rep."},{"issue":"3","key":"52669_CR52","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1007\/s00441-010-0955-y","volume":"340","author":"SJ Peters","year":"2010","unstructured":"Peters, S. J. et al. Co-culture of primary rat hepatocytes with rat liver epithelial cells enhances interleukin-6-induced acute-phase protein response [J]. Cell Tissue Res. 340 (3), 451\u2013457 (2010).","journal-title":"Cell Tissue Res."},{"issue":"1","key":"52669_CR53","doi-asserted-by":"publisher","first-page":"11798","DOI":"10.1038\/s41598-019-48171-8","volume":"9","author":"JY Kim","year":"2019","unstructured":"Kim, J. Y. et al. ROR\u03b1 suppresses interleukin-6-mediated hepatic acute phase response [J]. Sci. Rep. 9 (1), 11798 (2019).","journal-title":"Sci. Rep."},{"key":"52669_CR54","doi-asserted-by":"publisher","first-page":"775","DOI":"10.3389\/fphys.2017.00775","volume":"8","author":"S Sobotta","year":"2017","unstructured":"Sobotta, S. et al. Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib [J]. Front. Physiol. 8, 775 (2017).","journal-title":"Front. Physiol."},{"issue":"3","key":"52669_CR55","doi-asserted-by":"publisher","first-page":"475","DOI":"10.2174\/1570159X22666231005090134","volume":"22","author":"GE Hodes","year":"2024","unstructured":"Hodes, G. E. et al. Sex Differences in Stress Response: Classical Mechanisms and Beyond [J]. Curr. Neuropharmacol. 22 (3), 475\u2013494 (2024).","journal-title":"Curr. Neuropharmacol."},{"issue":"5","key":"52669_CR56","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1080\/10253890.2017.1369523","volume":"20","author":"MG Oyola","year":"2017","unstructured":"Oyola, M. G. & Handa, R. J. Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity [J]. Stress (Amsterdam Netherlands). 20 (5), 476\u2013494 (2017).","journal-title":"Stress (Amsterdam Netherlands)"},{"key":"52669_CR57","doi-asserted-by":"publisher","first-page":"707617","DOI":"10.3389\/fimmu.2021.707617","volume":"12","author":"J Hong","year":"2021","unstructured":"Hong, J. et al. Genetic Associations Between IL-6 and the Development of Autoimmune Arthritis Are Gender-Specific [J]. Front. Immunol. 12, 707617 (2021).","journal-title":"Front. Immunol."},{"issue":"8","key":"52669_CR58","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1016\/j.imbio.2016.03.005","volume":"221","author":"K M\u00f6rs","year":"2016","unstructured":"M\u00f6rs, K. et al. Influence of gender on systemic IL-6 levels, complication rates and outcome after major trauma [J]. Immunobiology 221 (8), 904\u2013910 (2016).","journal-title":"Immunobiology"},{"issue":"1","key":"52669_CR59","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s12944-021-01459-z","volume":"20","author":"J Zhao","year":"2021","unstructured":"Zhao, J. et al. Gender differences in risk factors for high plasma homocysteine levels based on a retrospective checkup cohort using a generalized estimating equation analysis [J]. Lipids Health Dis. 20 (1), 31 (2021).","journal-title":"Lipids Health Dis."},{"key":"52669_CR60","doi-asserted-by":"crossref","unstructured":"Zdrojkowski, \u0141. et al. The Role of NF-\u03baB in Endometrial Diseases in Humans and Animals: A Review [J]. Int. J. Mol. Sci., 24(3). (2023).","DOI":"10.3390\/ijms24032901"},{"key":"52669_CR61","doi-asserted-by":"crossref","unstructured":"Jasi\u0144ski, T. et al. Molecular Mechanism of Equine Endometrosis: The NF-\u03baB-Dependent Pathway Underlies the Ovarian Steroid Receptors\u2019 Dysfunction [J]. Int. J. Mol. Sci., 23(13). (2022).","DOI":"10.3390\/ijms23137360"},{"key":"52669_CR62","doi-asserted-by":"publisher","first-page":"114106","DOI":"10.1016\/j.jep.2021.114106","volume":"276","author":"Y Fan","year":"2021","unstructured":"Fan, Y. et al. Anti-inflammatory activity of the Tongmai Yangxin pill in the treatment of coronary heart disease is associated with estrogen receptor and NF-\u03baB signaling pathway [J]. J. Ethnopharmacol. 276, 114106 (2021).","journal-title":"J. Ethnopharmacol."},{"key":"52669_CR63","doi-asserted-by":"publisher","first-page":"110801","DOI":"10.1016\/j.mce.2020.110801","volume":"510","author":"A Carbajal-Garc\u00eda","year":"2020","unstructured":"Carbajal-Garc\u00eda, A. et al. Testosterone augments \u03b2(2) adrenergic receptor genomic transcription increasing salbutamol relaxation in airway smooth muscle [J]. Mol. Cell. Endocrinol. 510, 110801 (2020).","journal-title":"Mol. Cell. Endocrinol."},{"issue":"2","key":"52669_CR64","doi-asserted-by":"publisher","first-page":"1878","DOI":"10.18632\/oncotarget.6479","volume":"7","author":"PR Braadland","year":"2016","unstructured":"Braadland, P. R. et al. Low \u03b2\u2082-adrenergic receptor level may promote development of castration resistant prostate cancer and altered steroid metabolism [J]. Oncotarget 7 (2), 1878\u20131894 (2016).","journal-title":"Oncotarget"},{"key":"52669_CR65","doi-asserted-by":"crossref","unstructured":"Schmidt, K. T. Restraint to Induce Stress in Mice and Rats [J]. Journal of visualized experiments: JoVE, (214). (2024).","DOI":"10.3791\/67387"},{"issue":"2","key":"52669_CR66","doi-asserted-by":"publisher","first-page":"100086","DOI":"10.1016\/j.xpro.2020.100086","volume":"1","author":"M Charni-Natan","year":"2020","unstructured":"Charni-Natan, M. & Goldstein, I. Protocol for Primary Mouse Hepatocyte Isolation [J]. STAR. Protocols. 1 (2), 100086 (2020).","journal-title":"STAR. Protocols"},{"issue":"1","key":"52669_CR67","first-page":"83","volume":"252","author":"P Durand","year":"1996","unstructured":"Durand, P. et al. Hyperhomocysteinemia induced by folic acid deficiency and methionine load\u2013applications of a modified HPLC method [J]. Int. J. Clin. Chem. 252 (1), 83\u201393 (1996). Clinica chimica acta.","journal-title":"Int. J. Clin. Chem."},{"issue":"22","key":"52669_CR68","doi-asserted-by":"publisher","first-page":"2621","DOI":"10.1016\/j.lfs.2004.12.011","volume":"76","author":"PJ Martins","year":"2005","unstructured":"Martins, P. J. et al. Physiological variation in plasma total homocysteine concentrations in rats [J]. Life Sci. 76 (22), 2621\u20132629 (2005).","journal-title":"Life Sci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-52669-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-52669-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-52669-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T01:02:16Z","timestamp":1784595736000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-52669-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,19]]},"references-count":68,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["52669"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-52669-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,19]]},"assertion":[{"value":"17 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All experiments were approved by the Ethics Committee of the Institutional Animal Care and Use Committee of the Academy of Military Medical Sciences (Permit No: IACUC-DWZX-2022-640) and were in accordance with the ARRIVE guidelines.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"22772"}}