{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:30:36Z","timestamp":1783643436285,"version":"3.55.0"},"reference-count":57,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,3,10]],"date-time":"2020-03-10T00:00:00Z","timestamp":1583798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004396","name":"Thailand Research Fund","doi-asserted-by":"publisher","award":["BRG6080006"],"award-info":[{"award-number":["BRG6080006"]}],"id":[{"id":"10.13039\/501100004396","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004396","name":"Thailand Research Fund","doi-asserted-by":"publisher","award":["IRN58W0002"],"award-info":[{"award-number":["IRN58W0002"]}],"id":[{"id":"10.13039\/501100004396","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004396","name":"Thailand Research Fund","doi-asserted-by":"publisher","award":["IRN5802PHDW04"],"award-info":[{"award-number":["IRN5802PHDW04"]}],"id":[{"id":"10.13039\/501100004396","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004156","name":"Mahidol University","doi-asserted-by":"publisher","award":["A46\/2562"],"award-info":[{"award-number":["A46\/2562"]}],"id":[{"id":"10.13039\/501100004156","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007209","name":"Thailand Graduate Institute of Science and Technology","doi-asserted-by":"publisher","award":["TG-22-14-59-005D"],"award-info":[{"award-number":["TG-22-14-59-005D"]}],"id":[{"id":"10.13039\/501100007209","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Kaempferol, a plant-derived flavonoid, has been reported to have activity against Japanese encephalitis virus (JEV) in BHK-21 cells. To determine the broader utility of this compound, we initially evaluated the activity of kaempferol against JEV and dengue virus (DENV) in HEK293T\/17 cells. Results showed no significant antiviral activity against either virus. We subsequently investigated the activity of kaempferol against both JEV and DENV in BHK-21 cells. Results showed a significant inhibition of JEV infection but, surprisingly, a significant enhancement of DENV infection. The effect of kaempferol on both host protein expression and transcription was investigated and both transcriptional and translational inhibitory effects were observed, although a more marked effect was observed on host cell protein expression. Markedly, while GRP78 was increased in DENV infected cells treated with kaempferol, it was not increased in JEV infected cells treated with kaempferol. These results show that cellular alteration induced by one compound can have opposite effects on viruses from the same family, suggesting the presence of distinct replication strategies for these two viruses.<\/jats:p>","DOI":"10.3390\/molecules25051246","type":"journal-article","created":{"date-parts":[[2020,3,13]],"date-time":"2020-03-13T08:58:59Z","timestamp":1584089939000},"page":"1246","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Discordant Activity of Kaempferol Towards Dengue Virus and Japanese Encephalitis Virus"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5006-733X","authenticated-orcid":false,"given":"Chit","family":"Care","sequence":"first","affiliation":[{"name":"Institute of Molecular Biosciences, Mahidol University, Salaya 73170, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wannapa","family":"Sornjai","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biosciences, Mahidol University, Salaya 73170, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janejira","family":"Jaratsittisin","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biosciences, Mahidol University, Salaya 73170, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3614-2313","authenticated-orcid":false,"given":"Atitaya","family":"Hitakarun","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biosciences, Mahidol University, Salaya 73170, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitwara","family":"Wikan","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biosciences, Mahidol University, Salaya 73170, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanokporn","family":"Triwitayakorn","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biosciences, Mahidol University, Salaya 73170, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6592-9852","authenticated-orcid":false,"given":"Duncan R.","family":"Smith","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biosciences, Mahidol University, Salaya 73170, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1099\/jgv.0.000672","article-title":"ICTV virus taxonomy profile: Flaviviridae","volume":"98","author":"Simmonds","year":"2017","journal-title":"J. Gen. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/nature02165","article-title":"Structure of the dengue virus envelope protein after membrane fusion","volume":"427","author":"Modis","year":"2004","journal-title":"Nature"},{"key":"ref_3","unstructured":"Acheson, N.H. (2011). Introduction to Virology, Kaye Pace: John Wiley & Sons, Inc.. [2nd ed.]."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1099\/0022-1317-70-1-37","article-title":"Antigenic relationships between flaviviruses as determined by cross-neutralization tests with polyclonal antisera","volume":"70 (Pt 1)","author":"Calisher","year":"1989","journal-title":"J. Gen. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/S0140-6736(08)60238-X","article-title":"Pathogenic flaviviruses","volume":"371","author":"Gould","year":"2008","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1128\/CMR.11.3.480","article-title":"Dengue and dengue hemorrhagic fever","volume":"11","author":"Gubler","year":"1998","journal-title":"Clin. Microbiol Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The global distribution and burden of dengue","volume":"496","author":"Bhatt","year":"2013","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1179\/2046904712Z.00000000052","article-title":"The revised WHO dengue case classification: does the system need to be modified?","volume":"32","author":"Hadinegoro","year":"2012","journal-title":"Paediatr Int Child. Health"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6355","DOI":"10.1016\/j.vaccine.2017.09.089","article-title":"Dengvaxia sensitizes seronegatives to vaccine enhanced disease regardless of age","volume":"35","author":"Halstead","year":"2017","journal-title":"Vaccine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1136\/jnnp.68.4.405","article-title":"Japanese encephalitis","volume":"68","author":"Solomon","year":"2000","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"766","DOI":"10.2471\/BLT.10.085233","article-title":"Estimated global incidence of Japanese encephalitis: a systematic review","volume":"89","author":"Campbell","year":"2011","journal-title":"Bull. World Health Organ."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"263","DOI":"10.4161\/hv.26902","article-title":"Japanese encephalitis: the virus and vaccines","volume":"10","author":"Yun","year":"2014","journal-title":"Hum. Vaccin Immunother"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e888","DOI":"10.1016\/j.ijid.2010.03.022","article-title":"Japanese encephalitis virus remains an important cause of encephalitis in Thailand","volume":"14","author":"Olsen","year":"2010","journal-title":"Int J. Infect. Dis"},{"key":"ref_14","first-page":"647","article-title":"A test production of inactivated mouse brain JE vaccine in Thailand","volume":"20","author":"Pongpairoj","year":"1989","journal-title":"The Southeast. Asian J. Trop Med. Public Health"},{"key":"ref_15","unstructured":"Smith, D.R. (2016). Waiting in the wings: The potential of mosquito transmitted flaviviruses to emerge. Crit Rev. Microbiol, 1\u201318."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"298","DOI":"10.2174\/138955711795305335","article-title":"A review on the dietary flavonoid kaempferol","volume":"11","year":"2011","journal-title":"Mini Rev. Med. Chem"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/B978-0-444-53836-9.00026-8","article-title":"Flavonoids as anti-inflammatory and analgesic drugs: Mechanisms of action and perspectives in the development of pharmaceutical forms","volume":"36","author":"Verri","year":"2012","journal-title":"Studies Nat. Prof. Chem"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1017\/jns.2016.41","article-title":"Flavonoids: an overview","volume":"5","author":"Panche","year":"2016","journal-title":"J. Nutr Sci"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6816","DOI":"10.1016\/j.bmc.2009.08.036","article-title":"Neuraminidase inhibitory activities of flavonols isolated from Rhodiola rosea roots and their in vitro anti-influenza viral activities","volume":"17","author":"Jeong","year":"2009","journal-title":"Bioorg Med. Chem."},{"key":"ref_20","first-page":"463","article-title":"In vitro anti-HIV-1 activities of kaempferol and kaempferol-7-Oglucoside isolated from Securigera securidaca","volume":"9","author":"Behbahani","year":"2014","journal-title":"Res. Pharm. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Dai, W., Bi, J., Li, F., Wang, S., Huang, X., Meng, X., Sun, B., Wang, D., Kong, W., and Jiang, C. (2019). Antiviral efficacy of flavonoids against enterovirus 71 infection in vitro and in newborn mice. Viruses, 11.","DOI":"10.3390\/v11070625"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhang, T., Wu, Z., Du, J., Hu, Y., Liu, L., Yang, F., and Jin, Q. (2012). Anti-Japanese-encephalitis-viral effects of kaempferol and daidzin and their RNA-binding characteristics. PLoS One, 7.","DOI":"10.1371\/journal.pone.0030259"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5951","DOI":"10.1016\/j.vaccine.2017.03.032","article-title":"Yellow fever live attenuated vaccine: A very successful live attenuated vaccine but still we have problems controlling the disease","volume":"35","author":"Barrett","year":"2017","journal-title":"Vaccine"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4301","DOI":"10.1016\/j.vaccine.2011.09.114","article-title":"Flaviviruses and flavivirus vaccines","volume":"30","author":"Heinz","year":"2012","journal-title":"Vaccine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3389\/fphar.2013.00177","article-title":"The growing use of herbal medicines: issues relating to adverse reactions and challenges in monitoring safety","volume":"4","author":"Ekor","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1055\/s-2000-8550","article-title":"Evaluation of the antiviral activity of kaempferol and its glycosides against human cytomegalovirus","volume":"66","author":"Mitrocotsa","year":"2000","journal-title":"Planta Medica"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"D125","DOI":"10.1093\/nar\/gkj081","article-title":"IRESite: the database of experimentally verified IRES structures (www.iresite.org)","volume":"34","author":"Mokrejs","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1093\/jmcb\/mjz091","article-title":"IRES-mediated cap-independent translation, a path leading to hidden proteome","volume":"11","author":"Yang","year":"2019","journal-title":"J. Mol. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.1128\/jvi.62.8.2636-2643.1988","article-title":"A segment of the 5\u2019 nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation","volume":"62","author":"Jang","year":"1988","journal-title":"J. Virol"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1038\/334320a0","article-title":"Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA","volume":"334","author":"Pelletier","year":"1988","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Song, Y., Mugavero, J., Stauft, C.B., and Wimmer, E. (2019). Dengue and Zika virus 5\u2019 untranslated regions harbor internal ribosomal entry site functions. mBio, 10.","DOI":"10.1128\/mBio.00459-19"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.foodchem.2011.03.022","article-title":"Kaempferol inhibits enterovirus 71 replication and internal ribosome entry site (IRES) activity through FUBP and HNRP proteins","volume":"128","author":"Tsai","year":"2011","journal-title":"Food Chem"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/S0042-6822(03)00544-0","article-title":"Enterovirus 71 contains a type I IRES element that functions when eukaryotic initiation factor eIF4G is cleaved","volume":"315","author":"Thompson","year":"2003","journal-title":"Virology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12871","DOI":"10.1128\/JVI.01419-09","article-title":"Dengue virus infection induces upregulation of GRP78, which acts to chaperone viral antigen production","volume":"83","author":"Wati","year":"2009","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Nain, M., Mukherjee, S., Karmakar, S.P., Paton, A.W., Paton, J.C., Abdin, M.Z., Basu, A., Kalia, M., and Vrati, S. (2017). GRP78 is an important host factor for Japanese encephalitis virus entry and replication in mammalian cells. J. Virol., 91.","DOI":"10.1128\/JVI.02274-16"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1016\/j.bcp.2010.01.032","article-title":"Bax deficiency mediated drug resistance can be reversed by endoplasmic reticulum stress induced death signaling","volume":"79","author":"Chandrika","year":"2010","journal-title":"Biochem Pharmacol"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.biopha.2018.12.105","article-title":"Kaempferol protects mice from d-GalN\/LPS-induced acute liver failure by regulating the ER stress-Grp78-CHOP signaling pathway","volume":"111","author":"Wang","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Abdullah, A., and Ravanan, P. (2018). Kaempferol mitigates endoplasmic reticulum stress induced cell death by targeting caspase 3\/7. Sci Rep., 8.","DOI":"10.1038\/s41598-018-20499-7"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1080\/08923970701812530","article-title":"Kaempferol protects ischemia\/reperfusion-induced cardiac damage through the regulation of endoplasmic reticulum stress","volume":"30","author":"Kim","year":"2008","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.antiviral.2017.02.015","article-title":"AR-12 suppresses dengue virus replication by down-regulation of PI3K\/AKT and GRP78","volume":"142","author":"Chen","year":"2017","journal-title":"Antiviral Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1093\/abbs\/gmv108","article-title":"Effect of modulation of unfolded protein response pathway on dengue virus infection","volume":"47","author":"Diwaker","year":"2015","journal-title":"Acta Biochim Biophys Sin. (Shanghai)"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/srep35753","article-title":"Involvement of voltage-dependent anion channel (VDAC) in dengue infection","volume":"6","author":"Jitobaom","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s12985-015-0269-5","article-title":"Constant up-regulation of BiP\/GRP78 expression prevents virus-induced apoptosis in BHK-21 cells with Japanese encephalitis virus persistent infection","volume":"12","author":"Lyoo","year":"2015","journal-title":"Virol J."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Mukherjee, S., Singh, N., Sengupta, N., Fatima, M., Seth, P., Mahadevan, A., Shankar, S.K., Bhattacharyya, A., and Basu, A. (2017). Japanese encephalitis virus induces human neural stem\/progenitor cell death by elevating GRP78, PHB and hnRNPC through ER stress. Cell Death Dis, 8.","DOI":"10.1038\/cddis.2016.394"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1186\/1743-422X-8-128","article-title":"Japanese encephalitis virus co-opts the ER-stress response protein GRP78 for viral infectivity","volume":"8","author":"Wu","year":"2011","journal-title":"Virol. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.tcb.2003.11.001","article-title":"A trip to the ER: coping with stress","volume":"14","author":"Rutkowski","year":"2004","journal-title":"Trends Cell Biol"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4529","DOI":"10.1128\/MCB.25.11.4529-4540.2005","article-title":"Endoplasmic reticulum stress induction of the Grp78\/BiP promoter: activating mechanisms mediated by YY1 and its interactive chromatin modifiers","volume":"25","author":"Baumeister","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"20915","DOI":"10.1074\/jbc.M212328200","article-title":"Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation","volume":"278","author":"Reddy","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1016\/S1097-2765(01)00265-9","article-title":"Translational control is required for the unfolded protein response and in vivo glucose homeostasis","volume":"7","author":"Scheuner","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/S1097-2765(00)80330-5","article-title":"Perk is essential for translational regulation and cell survival during the unfolded protein response","volume":"5","author":"Harding","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1002\/jmv.10520","article-title":"Behavior of the dengue virus in solution","volume":"71","author":"Sithisarn","year":"2003","journal-title":"J. Med. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1159\/000097394","article-title":"Entry into and production of the Japanese encephalitis virus from C6\/36 cells","volume":"50","author":"Boonsanay","year":"2007","journal-title":"Intervirology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1055\/s-2002-32073","article-title":"Interference of plant extracts, phytoestrogens and antioxidants with the MTT tetrazolium assay","volume":"68","author":"Bruggisser","year":"2002","journal-title":"Planta Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"830","DOI":"10.4269\/ajtmh.1982.31.830","article-title":"Dengue virus-specific and flavivirus group determinants identified with monoclonal antibodies by indirect immunofluorescence","volume":"31","author":"Henchal","year":"1982","journal-title":"Am. J. Trop Med. Hyg."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal. Biochem"},{"key":"ref_56","first-page":"36","article-title":"Image processing with Image","volume":"11","author":"Abramoff","year":"2004","journal-title":"J. Biophotonics Int."},{"key":"ref_57","unstructured":"Vargas, M.H. (2020, March 10). ED50plus v1.0. Instituto Nacional de Enfermedades Respiratorias [Computer software]. Mexico, DF, Mexico. Available online: http:\/\/sciencegateway.org\/protocols\/cellbio\/drug\/data\/ed50v10.xls."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/5\/1246\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:05:41Z","timestamp":1760173541000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/5\/1246"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,10]]},"references-count":57,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["molecules25051246"],"URL":"https:\/\/doi.org\/10.3390\/molecules25051246","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,10]]}}}