{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:06:21Z","timestamp":1790831181855,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2015,6,4]],"date-time":"2015-06-04T00:00:00Z","timestamp":1433376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Human cytomegalovirus (HCMV) is a major risk factor in transplantation and AIDS patients, which induces high morbidity and mortality. These patients infected with HCMV experience an imbalance of redox homeostasis that cause accumulation of reactive oxygen species (ROS) at the cellular level. H2O2, the most common reactive oxygen species, is the main byproduct of oxidative metabolism. However, the function of H2O2 on HCMV infection is not yet fully understood and the effect and mechanism of N-acetylcysteine (NAC) on H2O2-stimulated HCMV replication is unclear. We, therefore, examined the effect of NAC on H2O2-induced HCMV production in human foreskin fibroblast cells. In the present study, we found that H2O2 enhanced HCMV lytic replication through promoting major immediate early (MIE) promoter activity and immediate early (IE) gene transcription. Conversely, NAC inhibited H2O2-upregulated viral IE gene expression and viral replication. The suppressive effect of NAC on CMV in an acute CMV-infected mouse model also showed a relationship between antioxidants and viral lytic replication. Intriguingly, the enhancement of HCMV replication via supplementation with H2O2 was accompanied with the activation of the p38 mitogen-activated protein kinase pathway. Similar to NAC, the p38 inhibitor SB203580 inhibited H2O2-induced p38 phosphorylation and HCMV upregulation, while upregulation of inducible ROS was unaffected. These results directly relate HCMV replication to H2O2, suggesting that treatment with antioxidants may be an attractive preventive and therapeutic strategy for HCMV.<\/jats:p>","DOI":"10.3390\/v7062748","type":"journal-article","created":{"date-parts":[[2015,6,4]],"date-time":"2015-06-04T11:54:59Z","timestamp":1433418899000},"page":"2816-2833","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Hydrogen Peroxide Induce Human Cytomegalovirus Replication through the Activation of p38-MAPK Signaling Pathway"],"prefix":"10.3390","volume":"7","author":[{"given":"Jun","family":"Xiao","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing 100850, China"},{"name":"Beijing Institute of Transfusion Medicine, 27 (9) Taiping Road, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Deng","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing 100850, China"},{"name":"Beijing Institute of Transfusion Medicine, 27 (9) Taiping Road, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Lv","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing 100850, China"},{"name":"Beijing Institute of Transfusion Medicine, 27 (9) Taiping Road, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Kang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing 100850, China"},{"name":"Beijing Institute of Transfusion Medicine, 27 (9) Taiping Road, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Ma","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing 100850, China"},{"name":"Beijing Institute of Transfusion Medicine, 27 (9) Taiping Road, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Yan","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing 100850, China"},{"name":"Beijing Institute of Transfusion Medicine, 27 (9) Taiping Road, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Song","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing 100850, China"},{"name":"Beijing Institute of Transfusion Medicine, 27 (9) Taiping Road, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Gao","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing 100850, China"},{"name":"Beijing Institute of Transfusion Medicine, 27 (9) Taiping Road, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing 100850, China"},{"name":"Beijing Institute of Transfusion Medicine, 27 (9) Taiping Road, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinbo","family":"Xu","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing 100850, China"},{"name":"Beijing Institute of Transfusion Medicine, 27 (9) Taiping Road, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.humimm.2004.02.009","article-title":"Pathogenesis of human cytomegalovirus infection and cellular targets","volume":"65","author":"Gerna","year":"2004","journal-title":"Hum. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S754","DOI":"10.1093\/clinids\/12.Supplement_7.S754","article-title":"Impact of cytomegalovirus infection on organ transplant recipients","volume":"12","author":"Rubin","year":"1990","journal-title":"Rev. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1097\/00007890-199605150-00001","article-title":"Cytomegalovirus prophylaxis in solid organ transplant recipients","volume":"61","author":"Patel","year":"1996","journal-title":"Transplantation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1182\/blood.V99.6.1943","article-title":"Unrelated donor marrow transplantation for myelodysplastic syndromes: Outcome analysis in 510 transplants facilitated by the National Marrow Donor Program","volume":"99","author":"Harris","year":"2002","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jcv.2006.03.005","article-title":"Cytomegalovirus disease in the era of highly active antiretroviral therapy (HAART)","volume":"37","author":"Steininger","year":"2006","journal-title":"J. Clin. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1161\/01.CIR.0000109692.16004.AF","article-title":"Cytomegalovirus infection impairs the nitric oxide synthase pathway: Role of asymmetric dimethylarginine in transplant arteriosclerosis","volume":"109","author":"Weis","year":"2004","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2657","DOI":"10.1161\/CIRCULATIONAHA.107.718874","article-title":"Endothelial dysfunction and cytomegalovirus replication in pediatric heart transplantation","volume":"117","author":"Simmonds","year":"2008","journal-title":"Circulation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1093\/infdis\/jit325","article-title":"Cytomegalovirus and cardiovascular disease--the importance of covariates","volume":"208","author":"Arasaratnam","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1097\/00054725-200305000-00002","article-title":"Evidence of active cytomegalovirus infection and increased production of IL-6 in tissue specimens obtained from patients with inflammatory bowel diseases","volume":"9","author":"Rahbar","year":"2003","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4140","DOI":"10.1073\/pnas.0408994102","article-title":"Latency, chromatin remodeling, and reactivation of human cytomegalovirus in the dendritic cells of healthy carriers","volume":"102","author":"Reeves","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"12750","DOI":"10.1128\/JVI.05878-11","article-title":"Inhibition of inflammatory interleukin-6 activity via extracellular signal-regulated kinase-mitogen-activated protein kinase signaling antagonizes human cytomegalovirus reactivation from dendritic cells","volume":"85","author":"Reeves","year":"2011","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1073\/pnas.1114966108","article-title":"Human cytomegalovirus activation of ERK and myeloid cell leukemia-1 protein correlates with survival of latently infected cells","volume":"109","author":"Reeves","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9173","DOI":"10.1128\/JVI.72.11.9173-9180.1998","article-title":"Extracellular signal-regulated kinase activity is sustained early during human cytomegalovirus infection","volume":"72","author":"Rodems","year":"1998","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1099\/0022-1317-82-3-493","article-title":"The role of MKK1\/2 kinase activity in human cytomegalovirus infection","volume":"82","author":"Johnson","year":"2001","journal-title":"J. Gen. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1097\/00007890-200202270-00001","article-title":"The role of mitochondria in ischemia\/reperfusion injury","volume":"73","author":"Jassem","year":"2002","journal-title":"Transplantation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3939","DOI":"10.1016\/j.transproceed.2011.09.021","article-title":"Oxidative stress indices in rats under immunosuppression","volume":"43","author":"Kedzierska","year":"2011","journal-title":"Transplant. Proc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.jprot.2011.09.005","article-title":"Quantitative proteomic analysis of cyclosporine-induced toxicity in a human kidney cell line and comparison with tacrolimus","volume":"75","author":"Lamoureux","year":"2011","journal-title":"J. Proteomics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"13","DOI":"10.2174\/1570162X12666140402100959","article-title":"Oxidative stress in HIV patients receiving antiretroviral therapy","volume":"12","author":"Sharma","year":"2014","journal-title":"Curr. HIV Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s11739-013-0999-6","article-title":"Is there a clinical role for oxidative stress biomarkers in atherosclerotic diseases?","volume":"9","author":"Pastori","year":"2014","journal-title":"Intern. Emerg. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.atherosclerosis.2014.09.001","article-title":"Vascular oxidative stress, nitric oxide and atherosclerosis","volume":"237","author":"Li","year":"2014","journal-title":"Atherosclerosis"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.3748\/wjg.15.1702","article-title":"Reactive oxygen species: A double-edged sword in oncogenesis","volume":"15","author":"Pan","year":"2009","journal-title":"World J. Gastroenterol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.bbagrm.2009.08.001","article-title":"Chromatin structure regulates human cytomegalovirus gene expression during latency, reactivation and lytic infection","volume":"1799","author":"Sinclair","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1016\/j.cellsig.2006.02.001","article-title":"Involvement of JNKs and p38-MAPK\/MSK1 pathways in H2O2-induced upregulation of heme oxygenase-1 mRNA in H9c2 cells","volume":"18","author":"Aggeli","year":"2006","journal-title":"Cell. Signal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.1016\/j.cellsig.2006.05.004","article-title":"ERK1\/2 and p38-MAPK signalling pathways, through MSK1, are involved in NF-kappaB transactivation during oxidative stress in skeletal myoblasts","volume":"18","author":"Kefaloyianni","year":"2006","journal-title":"Cell. Signal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1080\/10799890903178141","article-title":"Human cytomegalovirus-encoded chemokine receptor homolog US28 stimulates the major immediate early gene promoter\/enhancer via the induction of CREB","volume":"29","author":"Wen","year":"2009","journal-title":"J. Recept. Signal Transduct. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1099\/vir.0.037309-0","article-title":"Cyclophilin A is required for efficient human cytomegalovirus DNA replication and reactivation","volume":"93","author":"Keyes","year":"2012","journal-title":"J. Gen. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/nm.1958","article-title":"Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms","volume":"15","author":"Satoh","year":"2009","journal-title":"Nat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8833","DOI":"10.1128\/jvi.70.12.8833-8849.1996","article-title":"Analysis of the complete DNA sequence of murine cytomegalovirus","volume":"70","author":"Rawlinson","year":"1996","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.micinf.2003.09.007","article-title":"Pathogenesis of murine cytomegalovirus infection","volume":"5","author":"Krmpotic","year":"2003","journal-title":"Microbes Infect.\/Inst. Pasteur"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.3892\/ijmm.2014.1972","article-title":"Detoxifying effect of fermented black ginseng on H2O2-induced oxidative stress in HepG2 cells","volume":"34","author":"Bak","year":"2014","journal-title":"Int. J. Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1097\/00007890-199606270-00017","article-title":"Impact of oxidative stress on human cytomegalovirus replication and on cytokine-mediated stimulation of endothelial cells","volume":"61","author":"Scholz","year":"1996","journal-title":"Transplantation"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1161\/01.RES.79.6.1143","article-title":"Role of reactive oxygen intermediates in cytomegalovirus gene expression and in the response of human smooth muscle cells to viral infection","volume":"79","author":"Speir","year":"1996","journal-title":"Circ. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1128\/JVI.01742-10","article-title":"Oxidative stress induces reactivation of Kaposi\u2019s sarcoma-associated herpesvirus and death of primary effusion lymphoma cells","volume":"85","author":"Li","year":"2011","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e1002054","DOI":"10.1371\/journal.ppat.1002054","article-title":"Reactive oxygen species hydrogen peroxide mediates Kaposi's sarcoma-associated herpesvirus reactivation from latency","volume":"7","author":"Ye","year":"2011","journal-title":"PLoS Pathog."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/S0891-5849(03)00023-6","article-title":"Inhibition of influenza infection by glutathione","volume":"34","author":"Cai","year":"2003","journal-title":"Free Radic. Biol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9943","DOI":"10.1073\/pnas.87.24.9943","article-title":"Intracellular thiols regulate activation of nuclear factor kappa B and transcription of human immunodeficiency virus","volume":"87","author":"Staal","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10806","DOI":"10.1128\/JVI.00675-11","article-title":"Adenovirus type 5 rupture of lysosomes leads to cathepsin B-dependent mitochondrial stress and production of reactive oxygen species","volume":"85","author":"McGuire","year":"2011","journal-title":"J. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1128\/JVI.01265-10","article-title":"Adenovirus membrane penetration activates the NLRP3 inflammasome","volume":"85","author":"Barlan","year":"2011","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3316","DOI":"10.1002\/jcp.22677","article-title":"Enterovirus 71 induces integrin beta1\/EGFR-Rac1-dependent oxidative stress in SK-N-SH cells: Role of HO-1\/CO in viral replication","volume":"226","author":"Tung","year":"2011","journal-title":"J. Cell. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1080\/13550280701460573","article-title":"Herpes simplex virus type 1 infection induces oxidative stress and the release of bioactive lipid peroxidation by-products in mouse P19N neural cell cultures","volume":"13","author":"Kavouras","year":"2007","journal-title":"J. Neurovirol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1128\/JVI.01341-07","article-title":"The antiapoptotic herpes simplex virus glycoprotein J localizes to multiple cellular organelles and induces reactive oxygen species formation","volume":"82","author":"Aubert","year":"2008","journal-title":"J. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2779","DOI":"10.1016\/j.febslet.2006.04.041","article-title":"HCMV infection attenuates hydrogen peroxide induced endothelial apoptosis-involvement of ERK pathway","volume":"580","author":"Wang","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"12585","DOI":"10.1128\/JVI.05572-11","article-title":"Human cytomegalovirus induces multiple means to combat reactive oxygen species","volume":"85","author":"Tilton","year":"2011","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1099\/vir.0.81891-0","article-title":"Latency and reactivation of human cytomegalovirus","volume":"87","author":"Sinclair","year":"2006","journal-title":"J. Gen. Virol."},{"key":"ref_45","first-page":"409","article-title":"The effect of reactive oxygen species on the synthesis of prostanoids from arachidonic acid","volume":"64","author":"Korbecki","year":"2013","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"16045","DOI":"10.1074\/jbc.M011766200","article-title":"c-Jun N-terminal kinase activation by hydrogen peroxide in endothelial cells involves SRC-dependent epidermal growth factor receptor transactivation","volume":"276","author":"Chen","year":"2001","journal-title":"J. Biol. Chem."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/7\/6\/2748\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:47:27Z","timestamp":1760215647000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/7\/6\/2748"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,6,4]]},"references-count":46,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2015,6]]}},"alternative-id":["v7062748"],"URL":"https:\/\/doi.org\/10.3390\/v7062748","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,6,4]]}}}