{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:20:48Z","timestamp":1790770848255,"version":"4.1.0"},"reference-count":33,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,20]],"date-time":"2021-04-20T00:00:00Z","timestamp":1618876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 107-2311-B-037-005-MY3"],"award-info":[{"award-number":["MOST 107-2311-B-037-005-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chi-Mei Medical Center and Kaohsiung Medical University Research Foundation, Taiwan","award":["105 CM-KMU-05, 107 CM-KMU-03, and 108 CM-KMU-13"],"award-info":[{"award-number":["105 CM-KMU-05, 107 CM-KMU-03, and 108 CM-KMU-13"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Dengue virus (DENV) infection, which causes dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, is a severe global health problem in tropical and subtropical areas. There is no effective vaccine or drug against DENV infection. Thus, the development of anti-DENV agents is imperative. This study aimed to assess the anti-DENV activity of (E)-guggulsterone using a DENV infectious system. A specific inhibitor targeting signal molecules was used to evaluate the molecular mechanisms of action. Western blotting and qRT-PCR were used to determine DENV protein expression and RNA replication, respectively. Finally, an ICR suckling mouse model was used to examine the anti-DENV activity of (E)-guggulsterone in vivo. A dose-dependent inhibitory effect of (E)-guggulsterone on DENV protein synthesis and RNA replication without cytotoxicity was observed. The mechanistic studied revealed that (E)-guggulsterone stimulates Nrf2-mediated heme oxygenase-1 (HO-1) expression, which increases the antiviral interferon responses and downstream antiviral gene expression by blocking DENV NS2B\/3B protease activity. Moreover, (E)-guggulsterone protected ICR suckling mice from life-threatening DENV infection. These results suggest that (E)-guggulsterone can be a potential supplement for controlling DENV replication.<\/jats:p>","DOI":"10.3390\/v13040712","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T00:16:02Z","timestamp":1618964162000},"page":"712","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["(E)-Guggulsterone Inhibits Dengue Virus Replication by Upregulating Antiviral Interferon Responses through the Induction of Heme Oxygenase-1 Expression"],"prefix":"10.3390","volume":"13","author":[{"given":"Wei-Chun","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Biotechnology and PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Ku","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monir","family":"Hossen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medicine in College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao-Chin","family":"Hsu","sequence":"additional","affiliation":[{"name":"Chinese Medical Department, Chi-Mei Medical Center, Tainan 71004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0729-9589","authenticated-orcid":false,"given":"Jin-Ching","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Graduate Institute of Medicine in College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan"},{"name":"Graduate Institute of Natural Products in College of Pharmacy and Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Harapan, H., Michie, A., Sasmono, R.T., and Imrie, A. (2020). Dengue: A minireview. Viruses, 12.","DOI":"10.3390\/v12080829"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"449","DOI":"10.3389\/fcimb.2017.00449","article-title":"Neurological manifestations of dengue infection","volume":"7","author":"Li","year":"2017","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00284-020-02284-w","article-title":"Current understanding of the pathogenesis of dengue virus infection","volume":"78","author":"Bhatt","year":"2021","journal-title":"Curr. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1080\/17460441.2020.1811675","article-title":"An update on dengue vaccine development, challenges, and future perspectives","volume":"16","author":"Idris","year":"2021","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Anasir, M.I., Ramanathan, B., and Poh, C.L. (2020). Structure-based design of antivirals against envelope glycoprotein of dengue virus. Viruses, 12.","DOI":"10.3390\/v12040367"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1016\/j.jmb.2013.11.023","article-title":"Innate immunity to dengue virus infection and subversion of antiviral responses","volume":"426","author":"Green","year":"2014","journal-title":"J. Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Yu, C.Y., Chang, T.H., Liang, J.J., Chiang, R.L., Lee, Y.L., Liao, C.L., and Lin, Y.L. (2012). Dengue virus targets the adaptor protein MITA to subvert host innate immunity. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002780"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ijid.2013.09.022","article-title":"Association between proinflammatory cytokines and lipid peroxidation in patients with severe dengue disease around defervescence","volume":"18","author":"Soundravally","year":"2014","journal-title":"Int. J. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.freeradbiomed.2009.04.035","article-title":"Oxidative damage in dengue fever","volume":"47","author":"Seet","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.coviro.2020.07.015","article-title":"Dengue virus infection and Nrf2 regulation of oxidative stress","volume":"43","author":"Zevini","year":"2020","journal-title":"Curr. Opin. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"32176","DOI":"10.1038\/srep32176","article-title":"Human heme oxygenase 1 is a potential host cell factor against dengue virus replication","volume":"6","author":"Tseng","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1146\/annurev.pharmtox.010909.105600","article-title":"Mechanisms of cell protection by heme oxygenase-1","volume":"50","author":"Gozzelino","year":"2010","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1080\/21505594.2017.1421893","article-title":"Lucidone suppresses dengue viral replication through the induction of heme oxygenase-1","volume":"9","author":"Chen","year":"2018","journal-title":"Virulence"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Olagnier, D., Peri, S., Steel, C., van Montfoort, N., Chiang, C., Beljanski, V., Slifker, M., He, Z., Nichols, C.N., and Lin, R. (2014). Cellular oxidative stress response controls the antiviral and apoptotic programs in dengue virus-infected dendritic cells. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004566"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ferrari, M., Zevini, A., Palermo, E., Muscolini, M., Alexandridi, M., Etna, M.P., Coccia, E.M., Fernandez-Sesma, A., Coyne, C., and Zhang, D.D. (2020). Dengue virus targets Nrf2 for NS2B3-mediated degradation leading to enhanced oxidative stress and viral replication. J. Virol., 94.","DOI":"10.1128\/JVI.01551-20"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1097\/01.mib.0000235830.94057.c6","article-title":"Plant sterol guggulsterone inhibits nuclear factor-kappaB signaling in intestinal epithelial cells by blocking IkappaB kinase and ameliorates acute murine colitis","volume":"12","author":"Cheon","year":"2006","journal-title":"Inflamm. Bowel. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1093\/carcin\/bgr259","article-title":"Guggulsterone induces heme oxygenase-1 expression through activation of Nrf2 in human mammary epithelial cells: PTEN as a putative target","volume":"33","author":"Almazari","year":"2012","journal-title":"Carcinogenesis"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1055\/a-1014-3303","article-title":"Virucidal Effect of guggulsterone isolated from Commiphora gileadensis","volume":"85","author":"Bouslama","year":"2019","journal-title":"Planta Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"44701","DOI":"10.1038\/srep44701","article-title":"Cyclooxygenase-2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents","volume":"7","author":"Lin","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jim.2018.03.004","article-title":"A new background subtraction method for Western blot densitometry band quantification through image analysis software","volume":"457","author":"Ordonez","year":"2018","journal-title":"J. Immunol. Methods"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.ajpath.2016.11.011","article-title":"Modulation of antiviral immunity by heme oxygenase-1","volume":"187","author":"Espinoza","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Aguirre, S., Maestre, A.M., Pagni, S., Patel, J.R., Savage, T., Gutman, D., Maringer, K., Bernal-Rubio, D., Shabman, R.S., and Simon, V. (2012). DENV inhibits type I IFN production in infected cells by cleaving human STING. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002934"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1093\/infdis\/jiv321","article-title":"High anti-dengue virus activity of the OAS gene family is associated with increased severity of dengue","volume":"212","author":"Lin","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7283","DOI":"10.1096\/fj.201902878R","article-title":"MicroRNA-155 inhibits dengue virus replication by inducing heme oxygenase-1-mediated antiviral interferon responses","volume":"34","author":"Su","year":"2020","journal-title":"FASEB J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1128\/AAC.00855-10","article-title":"Novel dengue virus-specific NS2B\/NS3 protease inhibitor, BP2109, discovered by a high-throughput screening assay","volume":"55","author":"Yang","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_26","first-page":"1409582","article-title":"Flaviviridae viruses and oxidative stress: Implications for viral pathogenesis","volume":"2019","author":"Zhang","year":"2019","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/978-3-319-41342-6_15","article-title":"Guggulsterone and its role in chronic diseases","volume":"929","author":"Yamada","year":"2016","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.atherosclerosis.2003.10.008","article-title":"The hypolipidemic natural product Commiphora mukul and its component guggulsterone inhibit oxidative modification of LDL","volume":"172","author":"Wang","year":"2004","journal-title":"Atherosclerosis"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Valero, N., Mosquera, J., Anez, G., Levy, A., Marcucci, R., and de Mon, M.A. (2013). Differential oxidative stress induced by dengue virus in monocytes from human neonates, adult and elderly individuals. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073221"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wang, J., Chen, Y., Gao, N., Wang, Y., Tian, Y., Wu, J., Zhang, J., Zhu, J., Fan, D., and An, J. (2013). Inhibitory effect of glutathione on oxidative liver injury induced by dengue virus serotype 2 infections in mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055407"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1159\/000365750","article-title":"Guggulsterone, a plant-derived inhibitor of NF-TB, suppresses CDX2 and COX-2 expression and reduces the viability of esophageal adenocarcinoma cells","volume":"90","author":"Yamada","year":"2014","journal-title":"Digestion"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5105","DOI":"10.1167\/iovs.09-4873","article-title":"Prevention of endotoxin-induced uveitis in rats by plant sterol guggulsterone","volume":"51","author":"Kalariya","year":"2010","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_33","first-page":"74","article-title":"The effectiveness of Commiphora mukul for osteoarthritis of the knee: An outcomes study","volume":"9","author":"Singh","year":"2003","journal-title":"Altern. Ther. Health Med."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/4\/712\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:50:19Z","timestamp":1760161819000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/4\/712"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,20]]},"references-count":33,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["v13040712"],"URL":"https:\/\/doi.org\/10.3390\/v13040712","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,20]]}}}