{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T17:41:37Z","timestamp":1769276497880,"version":"3.49.0"},"reference-count":40,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["MOST 105-2311-B-039-003-MY2"],"award-info":[{"award-number":["MOST 105-2311-B-039-003-MY2"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["MOST 107-2311-B-039-001-"],"award-info":[{"award-number":["MOST 107-2311-B-039-001-"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["MOST 108-2311-B-039-001-"],"award-info":[{"award-number":["MOST 108-2311-B-039-001-"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["MOST 109-2311-B-039-001"],"award-info":[{"award-number":["MOST 109-2311-B-039-001"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["CMU109-MF-102"],"award-info":[{"award-number":["CMU109-MF-102"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["CMU109-S-11"],"award-info":[{"award-number":["CMU109-S-11"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["CMU-110-S-23"],"award-info":[{"award-number":["CMU-110-S-23"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"publisher","award":["MOST 105-2311-B-039-003-MY2"],"award-info":[{"award-number":["MOST 105-2311-B-039-003-MY2"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"publisher","award":["MOST 107-2311-B-039-001-"],"award-info":[{"award-number":["MOST 107-2311-B-039-001-"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"publisher","award":["MOST 108-2311-B-039-001-"],"award-info":[{"award-number":["MOST 108-2311-B-039-001-"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"publisher","award":["MOST 109-2311-B-039-001"],"award-info":[{"award-number":["MOST 109-2311-B-039-001"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"publisher","award":["CMU109-MF-102"],"award-info":[{"award-number":["CMU109-MF-102"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"publisher","award":["CMU109-S-11"],"award-info":[{"award-number":["CMU109-S-11"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"publisher","award":["CMU-110-S-23"],"award-info":[{"award-number":["CMU-110-S-23"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Because hydrogen sulfide (H2S) is classified as a gaseous signaling molecule, protein S-sulfhydration is known to be one of the mechanisms by which H2S signals are conducted. PTP1B, a negative regulator in insulin signaling, has been found to be S-sulfhydrated at Cys215-SH to form Cys215-SSH in response to endoplasmic reticulum (ER) stress. Therefore, we aimed to understand the change in PTP1B S-sulfhydration and cellular redox homeostasis in response to insulin stimulation. We demonstrated a feasible PEG-switch method to determine the levels of PTP1B S-sulfhydration. According to the results obtained from HEK293T and MDA-MB-231 cells, insulin induced a change in PTP1B S-sulfhydration that was similar to the change in Insulin receptor substrate 1 (IRS1) phosphorylation in both cell lines. However, insulin-induced PTP1B S-sulfhydration and IRS1 phosphorylation were only significantly affected by metformin in HEK293T cells. Insulin also induced an increase in reactive oxygen species (ROS) in both cell lines. However, the level of H2S, GSH, and GSSG was only significantly affected by insulin and metformin in HEK293T cells. HEK293T cells maintained high levels of H2S and cysteine, but low levels of GSSG and GSH in general compared to MDA-MB-231 cells. From these findings, we suggest that PTP1B activity is modulated by H2S and redox-regulated S-sulfhydration during insulin signaling.<\/jats:p>","DOI":"10.3390\/ijms24032898","type":"journal-article","created":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T05:44:45Z","timestamp":1675316685000},"page":"2898","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["H2S- and Redox-State-Mediated PTP1B S-Sulfhydration in Insulin Signaling"],"prefix":"10.3390","volume":"24","author":[{"given":"Yu-Chin","family":"Lin","sequence":"first","affiliation":[{"name":"Ph.D. Program for Health Science and Industry, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wan-Ting","family":"Zeng","sequence":"additional","affiliation":[{"name":"Graduate Institute of Integrated Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3741-8753","authenticated-orcid":false,"given":"Der-Yen","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate Institute of Integrated Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nrm3391","article-title":"H2S signalling through protein sulfhydration and beyond","volume":"13","author":"Paul","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1016\/j.bbapap.2011.02.004","article-title":"PLP-dependent H(2)S biogenesis","volume":"1814","author":"Singh","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"52082","DOI":"10.1074\/jbc.C400481200","article-title":"Production of the neuromodulator H2S by cystathionine beta-synthase via the condensation of cysteine and homocysteine","volume":"279","author":"Chen","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"22457","DOI":"10.1074\/jbc.M109.010868","article-title":"Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions","volume":"284","author":"Singh","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11601","DOI":"10.1074\/jbc.M808026200","article-title":"H2S biogenesis by human cystathionine gamma-lyase leads to the novel sulfur metabolites lanthionine and homolanthionine and is responsive to the grade of hyperhomocysteinemia","volume":"284","author":"Chiku","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1146\/annurev-pharmtox-010510-100505","article-title":"Hydrogen sulfide and cell signaling","volume":"51","author":"Li","year":"2011","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1089\/ars.2012.5024","article-title":"Hydrogen sulfide treatment promotes glucose uptake by increasing insulin receptor sensitivity and ameliorates kidney lesions in type 2 diabetes","volume":"19","author":"Xue","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4419","DOI":"10.1074\/jbc.R111.275578","article-title":"Analysis and functional prediction of reactive cysteine residues","volume":"287","author":"Marino","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.cbpa.2008.01.021","article-title":"Discovering mechanisms of signaling-mediated cysteine oxidation","volume":"12","author":"Poole","year":"2008","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1089\/ars.2010.3376","article-title":"Cysteine-based redox switches in enzymes","volume":"14","author":"Klomsiri","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"pe10","DOI":"10.1126\/scisignal.2002943","article-title":"From sulfenylation to sulfhydration: What a thiolate needs to tolerate","volume":"5","author":"Finkel","year":"2012","journal-title":"Sci. Signal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"ra86","DOI":"10.1126\/scisignal.2002329","article-title":"H2S-Induced sulfhydration of the phosphatase PTP1B and its role in the endoplasmic reticulum stress response","volume":"4","author":"Krishnan","year":"2011","journal-title":"Sci. Signal."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.tibs.2015.08.007","article-title":"H2S: A Novel Gasotransmitter that Signals by Sulfhydration","volume":"40","author":"Paul","year":"2015","journal-title":"Trends Biochem. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"ra72","DOI":"10.1126\/scisignal.2000464","article-title":"H2S signals through protein S-sulfhydration","volume":"2","author":"Mustafa","year":"2009","journal-title":"Sci. Signal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.molcel.2014.10.019","article-title":"Cytokine-induced GAPDH sulfhydration affects PSD95 degradation and memory","volume":"56","author":"Mir","year":"2014","journal-title":"Mol. Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3511","DOI":"10.1080\/15548627.2021.1876342","article-title":"Hydrogen sulfide-induced GAPDH sulfhydration disrupts the CCAR2-SIRT1 interaction to initiate autophagy","volume":"17","author":"Iqbal","year":"2021","journal-title":"Autophagy"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.molcel.2011.10.021","article-title":"Hydrogen sulfide-linked sulfhydration of NF-kappaB mediates its antiapoptotic actions","volume":"45","author":"Sen","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1074\/jbc.C117.819110","article-title":"A potent, selective, and orally bioavailable inhibitor of the protein-tyrosine phosphatase PTP1B improves insulin and leptin signaling in animal models","volume":"293","author":"Krishnan","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1016\/S0960-894X(03)00257-9","article-title":"5-Aryl thiazolidine-2,4-diones as selective PPARgamma agonists","volume":"13","author":"Koyama","year":"2003","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1021\/jm701260b","article-title":"Prodrugs of phosphates and phosphonates","volume":"51","author":"Hecker","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5258","DOI":"10.1074\/jbc.M511546200","article-title":"Residues distant from the active site influence protein-tyrosine phosphatase 1B inhibitor binding","volume":"281","author":"Montalibet","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.cell.2011.08.036","article-title":"Conformation-sensing antibodies stabilize the oxidized form of PTP1B and inhibit its phosphatase activity","volume":"147","author":"Haque","year":"2011","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/s41467-017-02252-2","article-title":"Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development","volume":"9","author":"Krishnan","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13398","DOI":"10.1073\/pnas.1302891110","article-title":"Selective activation of oxidized PTP1B by the thioredoxin system modulates PDGF-beta receptor tyrosine kinase signaling","volume":"110","author":"Dagnell","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/978-3-319-18144-8_2","article-title":"Persulfidation (S-sulfhydration) and H2S","volume":"Volume 230","author":"Filipovic","year":"2015","journal-title":"Chemistry, Biochemistry and Pharmacology of Hydrogen Sulfide. Handbook of Experimental Pharmacology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1002\/elps.201800335","article-title":"Quantitative display of the redox status of proteins with maleimide-polyethylene glycol tagging","volume":"40","author":"Lee","year":"2019","journal-title":"Electrophoresis"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/S1734-1140(13)71053-3","article-title":"Metformin raises hydrogen sulfide tissue concentrations in various mouse organs","volume":"65","author":"Wilinski","year":"2013","journal-title":"Pharmacol. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2102","DOI":"10.1002\/jcp.29112","article-title":"Administration of metformin alleviates atherosclerosis by promoting H2S production via regulating CSE expression","volume":"235","author":"Ma","year":"2020","journal-title":"J. Cell. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Herman, R., Kravos, N.A., Jensterle, M., Janez, A., and Dolzan, V. (2022). Metformin and Insulin Resistance: A Review of the Underlying Mechanisms behind Changes in GLUT4-Mediated Glucose Transport. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031264"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"117717","DOI":"10.1016\/j.lfs.2020.117717","article-title":"Anticancer mechanisms of metformin: A review of the current evidence","volume":"254","author":"Zhao","year":"2020","journal-title":"Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"102519","DOI":"10.1016\/j.redox.2022.102519","article-title":"Cystathionine gamma lyase S-sulfhydrates Drp1 to ameliorate heart dysfunction","volume":"58","author":"Wu","year":"2022","journal-title":"Redox Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/ars.2021.0029","article-title":"Insufficient S-Sulfhydration of Methylenetetrahydrofolate Reductase Contributes to the Progress of Hyperhomocysteinemia","volume":"36","author":"Ji","year":"2022","journal-title":"Antioxid. Redox Signal."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1021\/acs.chemrev.7b00205","article-title":"Chemical Biology of H(2)S Signaling through Persulfidation","volume":"118","author":"Filipovic","year":"2018","journal-title":"Chem. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.chroma.2018.04.008","article-title":"Quantitative and comparative liquid chromatography-electrospray ionization-mass spectrometry analyses of hydrogen sulfide and thiol metabolites derivaitized with 2-iodoacetanilide isotopologues","volume":"1552","author":"Lee","year":"2018","journal-title":"J. Chromatogr. A"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"294","DOI":"10.3389\/fendo.2019.00294","article-title":"Role of Mitochondria in the Mechanism(s) of Action of Metformin","volume":"10","author":"Vial","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s10863-006-9003-8","article-title":"The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin","volume":"38","author":"Batandier","year":"2006","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"20348","DOI":"10.1074\/jbc.M115.662114","article-title":"Metformin Inhibits the Production of Reactive Oxygen Species from NADH:Ubiquinone Oxidoreductase to Limit Induction of Interleukin-1beta (IL-1beta) and Boosts Interleukin-10 (IL-10) in Lipopolysaccharide (LPS)-activated Macrophages","volume":"290","author":"Kelly","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1089\/ars.2017.7046","article-title":"Hydrogen Sulfide and Glucose Homeostasis: A Tale of Sweet and the Stink","volume":"28","author":"Untereiner","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1210\/en.2012-1658","article-title":"Hydrogen sulfide impairs glucose utilization and increases gluconeogenesis in hepatocytes","volume":"154","author":"Zhang","year":"2013","journal-title":"Endocrinology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4212","DOI":"10.1096\/fj.201801894R","article-title":"Cystathionine gamma-lyase deficiency aggravates obesity-related insulin resistance via FoxO1-dependent hepatic gluconeogenesis","volume":"33","author":"Guo","year":"2019","journal-title":"FASEB J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2898\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:22:13Z","timestamp":1760120533000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2898"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,2]]},"references-count":40,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24032898"],"URL":"https:\/\/doi.org\/10.3390\/ijms24032898","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,2]]}}}