{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T15:25:53Z","timestamp":1787153153541,"version":"build-2736575974"},"reference-count":37,"publisher":"American Chemical Society (ACS)","issue":"32","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFE0108700"],"award-info":[{"award-number":["2023YFE0108700"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["52573142"],"award-info":[{"award-number":["52573142"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U22A20155"],"award-info":[{"award-number":["U22A20155"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013314","name":"Higher Education Discipline Innovation Project","doi-asserted-by":"publisher","award":["B16042"],"award-info":[{"award-number":["B16042"]}],"id":[{"id":"10.13039\/501100013314","id-type":"DOI","asserted-by":"publisher"}]},{"name":"State Key Laboratory of Transvascular Implantation Devices","award":["012024004"],"award-info":[{"award-number":["012024004"]}]},{"name":"Overseas Academician Joint Lab for Supramolecular Polymeric Biomaterials, Zhejiang University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Although organoselenium compounds offer unique advantages in antioxidant defense and immune regulation, their inherent high reactivity toward biological thiols leads to nonspecific selenium\u2013sulfur exchange reactions in vivo, resulting in off-target biotoxicity and significantly hindering their applications. Herein, we report a novel diselenium ketal diamine (SEK) to address these challenges by integrating biocompatibility, antioxidant activity, and immunomodulatory function into a single molecule. By incorporating a gem-dimethyl group via acetone condensation, SEK suppressed Se\u2013S exchange through steric stabilization, increasing its half maximal inhibitory concentration (IC50) to 75.5 \u03bcM, which was 10-fold higher than that of its diselenide precursor (7.6 \u03bcM). SEK exhibited rapid and reversible redox reactivity toward oxidants and free radicals. It reacted rapidly with H2O2 to form O2SEK, a stable diselenoxide intermediate stabilized by intramolecular Se\u2550O\u00b7\u00b7\u00b7H\u2013N hydrogen bonding, and was reversibly reduced by glutathione, ultimately reducing intracellular H2O2 levels by 40% in inflammatory microenvironments. SEK promoted polarization of immune cells toward an anti-inflammatory phenotype under oxidative stress by upregulating selenoprotein expression, resulting in a 40% decrease in pro-inflammatory M1 cell populations and a concomitant &amp;gt;30% reduction in pro-inflammatory cytokine secretion. This novel diselenium ketal overcomes the limitations of traditional organoselenium compounds by suppressing nonspecific Se\u2013S exchange and exerting synergistic antioxidant-anti-inflammatory regulatory effects, paving the way for advances in bioactive organoselenium chemistry.<\/jats:p>","DOI":"10.1021\/jacs.6c10111","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T17:02:22Z","timestamp":1785862942000},"page":"34730-34747","source":"Crossref","is-referenced-by-count":0,"title":["Gem-Dimethyl\nSelenoketal: Suppressing Sulfur\u2013Selenium\nExchange with Antioxidant and Anti-Inflammatory Activities"],"prefix":"10.1021","volume":"148","author":[{"given":"Kefei","family":"Zhao","sequence":"first","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]},{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoxuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Zheng","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]},{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilong","family":"Zhong","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haijun","family":"Hu","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyuan","family":"Jin","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiping","family":"Chen","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaicheng","family":"Deng","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]},{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinlei","family":"Wu","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6073-4685","authenticated-orcid":true,"given":"Wenxing","family":"Liu","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]},{"name":"Zhejiang University , , ,","place":["Shaoxing, China, 312099"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5084-7208","authenticated-orcid":true,"given":"Changyou","family":"Gao","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]},{"name":"Zhejiang University , , ,","place":["Shaoxing, China, 312099"]},{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310009"]},{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"issue":"45","key":"2026081910244044700_cit1","first-page":"18456","article-title":"Selenium vs. Sulfur: A Comparative Analysis of Electronic Structure\nand Bonding Properties","volume":"143","author":"Jones","year":"2021","journal-title":"J. Am. Chem. Soc."},{"issue":"18","key":"2026081910244044700_cit2","first-page":"10423","article-title":"Comparative Analysis\nof Selenium and Sulfur in Biological Systems:\nBond Lengths and Reactivity Trends","volume":"120","author":"Johnson","year":"2020","journal-title":"Chem. Rev."},{"issue":"48","key":"2026081910244044700_cit3","first-page":"30356","article-title":"The Role of Selenocysteine\nin Glutathione Peroxidase Catalysis: Kinetic\nand Structural Insights","volume":"117","author":"Brown","year":"2020","journal-title":"Proc. Natl. Acad. Sci.\nU. S. A."},{"issue":"4073","key":"2026081910244044700_cit4","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1126\/science.179.4073.588","article-title":"Selenium: Biochemical Role as a Component of Glutathione\nPeroxidase","volume":"179","author":"Rotruck","year":"1973","journal-title":"Science"},{"issue":"22","key":"2026081910244044700_cit5","first-page":"5689","article-title":"Reactive Oxygen Species\nScavenging by Organoselenium Compounds: Kinetic\nStudies and Mechanistic Models","volume":"14","author":"Zhang","year":"2023","journal-title":"Chem. Sci."},{"issue":"41","key":"2026081910244044700_cit6","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202314508","article-title":"Photoexcitation of\nDistinct Divalent Palladium Complexes in Cross-Coupling Amination\nUnder Air","volume":"136","author":"Kancherla","year":"2024","journal-title":"Angew. Chem."},{"key":"2026081910244044700_cit7","doi-asserted-by":"publisher","first-page":"103217","DOI":"10.1016\/j.redox.2024.103217","article-title":"Microenvironment-triggered\ncascade metal-polyphenolic nanozyme for ROS\/NO synergistic hyperglycemic\nwound healing","volume":"73","author":"Shi","year":"2024","journal-title":"Redox Biol."},{"issue":"8","key":"2026081910244044700_cit8","doi-asserted-by":"publisher","first-page":"494","DOI":"10.4049\/jimmunol.2400123","article-title":"HIF-1\nTranscriptionally Regulates Basal Expression\nof STING to Maintain Cellular Innate Immunity","volume":"213","author":"Gao","year":"2024","journal-title":"J. Immunol."},{"issue":"2","key":"2026081910244044700_cit9","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1021\/ja907523x","article-title":"On the Chalcogenophilicity of Mercury:\nEvidence for a Strong Hg\u2013Se Bond in [Tm Bu t]HgSePh and Its\nRelevance to the Toxicity of Mercury","volume":"132","author":"Melnick","year":"2010","journal-title":"J. Am.\nChem. Soc."},{"issue":"5","key":"2026081910244044700_cit10","first-page":"432","article-title":"Ebselen Mitigates Oxidative\nLung Injury via GPx-Mimetic Activity\nand Lipid Peroxidation Control","volume":"40","author":"Cheng","year":"2024","journal-title":"Antioxid. Redox\nSignal"},{"key":"2026081910244044700_cit11","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.freeradbiomed.2023.06.028","article-title":"Exposure to\nperoxynitrite impacts the ability of anastellin to modulate the structure\nof extracellular matrix","volume":"206","author":"He","year":"2023","journal-title":"Free Rad. Biol. Med."},{"issue":"15","key":"2026081910244044700_cit12","first-page":"6321","article-title":"Nrf2-Keap1 Pathway Activation\nby Selenium-Containing Small Molecules:\nA Systematic Review","volume":"51","author":"Liu","year":"2022","journal-title":"Chem. Soc. Rev."},{"issue":"4","key":"2026081910244044700_cit13","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1007\/s00204-021-03003-5","article-title":"Toxicology and Pharmacology of Synthetic\nOrganoselenium Compounds: An Update","volume":"95","author":"Nogueira","year":"2021","journal-title":"Arch. Toxicol."},{"issue":"3","key":"2026081910244044700_cit14","first-page":"481","article-title":"Selenium-Induced\nDisruption of Sulfur Metabolism: Implications\nfor Protein Structure and Function","volume":"35","author":"Belyaeva","year":"2022","journal-title":"BioMetals"},{"issue":"3","key":"2026081910244044700_cit15","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1093\/molbev\/msi007","article-title":"Selenoproteins\nand the Metabolic Features of the Archaeal Ancestor of Eukaryotes","volume":"22","author":"Foster","year":"2005","journal-title":"Mol. Biol. Evol."},{"issue":"8","key":"2026081910244044700_cit16","doi-asserted-by":"publisher","first-page":"P1728","DOI":"10.1016\/j.immuni.2021.07.004","article-title":"Multiomics\nAnalyses Reveal a Critical Role of Selenium in Controlling T Cell\nDifferentiation in Crohn\u2019s Disease","volume":"54","author":"Huang","year":"2021","journal-title":"Immunity"},{"key":"2026081910244044700_cit17","doi-asserted-by":"publisher","first-page":"127235","DOI":"10.1016\/j.jtemb.2023.127235","article-title":"Molecular\nMechanisms of Ebselen-Mediated NF-\u03baB\nInhibition in Inflammatory Models","volume":"79","author":"Hadrup","year":"2023","journal-title":"J. Trace\nElem Med. Biol."},{"issue":"12","key":"2026081910244044700_cit18","first-page":"2689","article-title":"Toxicity Profiling of Organoselenium Compounds: DNA Damage Induced\nby Diphenyl Diselenide in Hepatocytes","volume":"36","author":"Wang","year":"2023","journal-title":"Chem.\nRes. Toxicol."},{"issue":"1","key":"2026081910244044700_cit19","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1111\/iwj.12557","article-title":"Reactive Oxygen Species (ROS) and Wound Healing: The Functional Role\nof ROS and Emerging ROS-Modulating Technologies for Augmentation of\nthe Healing Process","volume":"14","author":"Dunnill","year":"2017","journal-title":"Int. Wound J."},{"issue":"18","key":"2026081910244044700_cit20","first-page":"12943","article-title":"Hemolytic Effects of\nEbselen: Concentration-Dependent Toxicity in\nErythrocyte Models","volume":"66","author":"Xia","year":"2023","journal-title":"J. Med. Chem."},{"issue":"3","key":"2026081910244044700_cit21","first-page":"685","article-title":"NF-\u03baB Inhibition\nby Selenium Compounds: From Molecular Interactions\nto Therapeutic Potential","volume":"73","author":"Gupta","year":"2021","journal-title":"Pharmacol. Rev."},{"issue":"17","key":"2026081910244044700_cit22","doi-asserted-by":"publisher","first-page":"6345","DOI":"10.1021\/jacs.1c02383","article-title":"Modeling the\nCatalytic Cycle of Glutathione Peroxidase by Nuclear Magnetic Resonance\nSpectroscopic Analysis of Selenocysteine Selenenic Acids","volume":"143","author":"Masuda","year":"2021","journal-title":"J. Am. Chem. Soc."},{"issue":"26","key":"2026081910244044700_cit23","doi-asserted-by":"publisher","first-page":"14184","DOI":"10.1021\/jacs.3c03394","article-title":"Modeling Selenoprotein\nSe-Nitrosation:\nSynthesis of a Se-Nitrososelenocysteine with Persistent Stability","volume":"145","author":"Masuda","year":"2023","journal-title":"J. Am. Chem. Soc."},{"key":"2026081910244044700_cit24","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.jconrel.2021.10.030","article-title":"A polymer-calcium\nphosphate nanocapsule for RNAi-induced oxidative stress and cascaded\nchemotherapy","volume":"340","author":"Huang","year":"2021","journal-title":"J. Controlled Release"},{"issue":"14","key":"2026081910244044700_cit25","doi-asserted-by":"publisher","first-page":"4103","DOI":"10.1039\/d2sc00419d","article-title":"Enantioselective [1,2]-Stevens\nRearrangement of Thiosulfonates to Construct Dithio-Substituted Quaternary\nCarbon Centers","volume":"13","author":"Hu","year":"2022","journal-title":"Chem. Sci."},{"issue":"15","key":"2026081910244044700_cit26","doi-asserted-by":"publisher","first-page":"3149","DOI":"10.1021\/ja01069a036","article-title":"Mass Spectrometry\nin Carbohydrate Chemistry. Diethyl Dithioacetal and Dithioketal Peracetates","volume":"86","author":"DeJongh","year":"1964","journal-title":"J. Am. Chem. Soc."},{"key":"2026081910244044700_cit27","doi-asserted-by":"publisher","first-page":"213621","DOI":"10.1016\/j.bioadv.2023.213621","article-title":"Co-Delivery of Azithromycin and Ibuprofen by ROS-Responsive\nPolymer Nanoparticles Synergistically Attenuates Acute Lung Injury","volume":"154","author":"Muhammad","year":"2023","journal-title":"Biomater. Adv."},{"issue":"12","key":"2026081910244044700_cit28","doi-asserted-by":"publisher","first-page":"122247","DOI":"10.1016\/j.biomaterials.2023.122247","article-title":"Simplified\n\u03b12-Macroglobulin as a TNF-\u03b1\nInhibitor for Inflammation Alleviation in Osteoarthritis and Myocardial\nInfarction Therapy","volume":"301","author":"Zheng","year":"2023","journal-title":"Biomaterials"},{"key":"2026081910244044700_cit29","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1016\/j.bioactmat.2022.04.029","article-title":"A reactive\noxygen species-responsive\nhydrogel encapsulated with bone marrow derived stem cells promotes\nrepair and regeneration of spinal cord injury","volume":"19","author":"Li","year":"2023","journal-title":"Bioact. Mater."},{"issue":"15","key":"2026081910244044700_cit30","doi-asserted-by":"publisher","first-page":"1700254","DOI":"10.1002\/adhm.201700254","article-title":"Clickable Microgel\nScaffolds as Platforms for 3D Cell Encapsulation","volume":"6","author":"Caldwell","year":"2017","journal-title":"Adv. Healthcare Mater."},{"issue":"1","key":"2026081910244044700_cit31","doi-asserted-by":"publisher","first-page":"3061","DOI":"10.1038\/s41467-021-23313-7","article-title":"Inhibition Mechanism of SARS-CoV-2 Main Protease by\nEbselen and Its Derivatives","volume":"12","author":"Amporndanai","year":"2021","journal-title":"Nat. Commun."},{"issue":"3","key":"2026081910244044700_cit32","doi-asserted-by":"publisher","first-page":"P409","DOI":"10.1016\/j.cell.2017.11.048","article-title":"Selenium\nUtilization by GPX4 Is Required to Prevent\nHydroperoxide-Induced Ferroptosis","volume":"172","author":"Gold","year":"2018","journal-title":"Cell"},{"key":"2026081910244044700_cit33","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1146\/annurev.pharmtox.41.1.261","article-title":"Properties and Biological\nActivities of Thioredoxins","volume":"41","author":"Powis","year":"2001","journal-title":"Annu. Rev. Pharmacol.\nToxicol."},{"key":"2026081910244044700_cit34","doi-asserted-by":"publisher","first-page":"103653","DOI":"10.1016\/j.redox.2025.103653","article-title":"Distinct\nRoles for the Thioredoxin and Glutathione Antioxidant Systems in Nrf2-Mediated\nLung Tumor Initiation and Progression","volume":"83","author":"Sherwood","year":"2025","journal-title":"Redox\nBiol."},{"issue":"6","key":"2026081910244044700_cit35","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1016\/j.it.2025.04.001","article-title":"The Microglial\nLineage: Present and\nBeyond","volume":"46","author":"Chen","year":"2025","journal-title":"Trends Immunol."},{"issue":"8","key":"2026081910244044700_cit36","doi-asserted-by":"publisher","first-page":"4436","DOI":"10.1021\/acs.jmedchem.1c01859","article-title":"Incorporating Selenium\ninto Heterocycles and Natural Products\u2500From\nChemical Properties to Pharmacological Activities","volume":"65","author":"Hou","year":"2022","journal-title":"J. Med. Chem."},{"issue":"22","key":"2026081910244044700_cit37","doi-asserted-by":"publisher","first-page":"18626","DOI":"10.1021\/jacs.5c00811","article-title":"Responsive Organoselenium\nDendritic Polymers: From Monodisperse Dendrimers to Self-Assembled\nMicelles for Advanced Therapeutic Applications","volume":"147","author":"Sanz Del Olmo","year":"2025","journal-title":"J. Am. Chem. Soc."}],"container-title":["Journal of the American\nChemical Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jacs.6c10111","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/32\/34730\/66390667\/jacs.6c10111.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/32\/34730\/66390667\/jacs.6c10111.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T14:44:01Z","timestamp":1787150641000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jacsat\/article\/148\/32\/34730\/5243321\/Gem-Dimethyl-Selenoketal-Suppressing-Sulfur"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":37,"journal-issue":{"issue":"32","published-online":{"date-parts":[[2026,8,4]]},"published-print":{"date-parts":[[2026,8,19]]}},"URL":"https:\/\/doi.org\/10.1021\/jacs.6c10111","relation":{},"ISSN":["0002-7863","1520-5126"],"issn-type":[{"value":"0002-7863","type":"print"},{"value":"1520-5126","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]}}}