{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:46:16Z","timestamp":1790693176979,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T00:00:00Z","timestamp":1669766400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010081","name":"Conseil R\u00e9gional de La R\u00e9union","doi-asserted-by":"publisher","award":["(PHYTODENGUE program, N\u00b0 SYNERGIE: RE0028005)"],"award-info":[{"award-number":["(PHYTODENGUE program, N\u00b0 SYNERGIE: RE0028005)"]}],"id":[{"id":"10.13039\/501100010081","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Dengue and Zika viruses are identified as the most medically important arthropod-borne viral pathogens. Over the past 20 years, the global dengue incidence has dramatically increased with epidemics of severe dengue where the case fatality rate can reach up to 20% in untreated patients. The association between Zika virus infection and severe congenital anomalies was first reported in 2015. Today no specific antiviral therapies are available for dengue and Zika virus infections, accentuating the need of adapted antiviral strategies based on medicinal plant drug discovery. Plants are a potential source of antiviral phytocompounds which act primarily by blocking virus entry in the host-cell. In the present study, we evaluated whether crude extracts from Stenocline ericoides DC. and Stenocline inuloides DC., two endemic plants from Madagascar, may have antiviral effects against dengue and Zika viruses. We showed that S. ericoides has virucidal action whereas S. inuloides inhibits the early steps of virus infection with a non-cytotoxic effect in human cells. The administration of S. ericoides and S. inuloides extracts in zebrafish had no effect on the behavior of animals at the active doses against dengue and Zika viruses, suggesting the absence of adverse effects at these doses. LC-HRMS2 and molecular networking analyses revealed the richness of these two plants in polyphenols and flavonoid with the presence of clusters of phytocompounds specific to each Stenocline species. Consequently, S. ericoides and S. inuloides represent potential sources for natural and safe antiviral phytocompounds against flaviviruses of medical concern.<\/jats:p>","DOI":"10.3390\/ph15121500","type":"journal-article","created":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T01:54:31Z","timestamp":1669859671000},"page":"1500","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Antiviral Effect of Stenocline ericoides DC. and Stenocline inuloides DC., Two Flavonoid-Rich Endemic Plants from Madagascar, against Dengue and Zika Viruses"],"prefix":"10.3390","volume":"15","author":[{"given":"Fenia D.","family":"Ramiharimanana","sequence":"first","affiliation":[{"name":"Unit\u00e9 Mixte Processus Infectieux en Milieu Insulaire Tropical, Plateforme Technologique CYROI, INSERM U1187, CNRS UMR 9192, IRD UMR 249, Universit\u00e9 de la R\u00e9union, 94791 Sainte Clotilde, France"},{"name":"International Associated Laboratory, University of Antananarivo-Lyon 1, Antananarivo P.O. Box 906, Madagascar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5035-0162","authenticated-orcid":false,"given":"Juliano G.","family":"Haddad","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Mixte Processus Infectieux en Milieu Insulaire Tropical, Plateforme Technologique CYROI, INSERM U1187, CNRS UMR 9192, IRD UMR 249, Universit\u00e9 de la R\u00e9union, 94791 Sainte Clotilde, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maminiaina A.","family":"Andrianavalonirina","sequence":"additional","affiliation":[{"name":"International Associated Laboratory, University of Antananarivo-Lyon 1, Antananarivo P.O. Box 906, Madagascar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3785-9620","authenticated-orcid":false,"given":"C\u00e9cile","family":"Apel","sequence":"additional","affiliation":[{"name":"Institut de Chimie des Substances Naturelles, CNRS, University of Paris-Saclay, UPR 2301, 91198 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florent","family":"Olivon","sequence":"additional","affiliation":[{"name":"Waters SAS, 78280 Guyancourt, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2032-518X","authenticated-orcid":false,"given":"Nicolas","family":"Diotel","sequence":"additional","affiliation":[{"name":"Diab\u00e8te Ath\u00e9rothrombose Th\u00e9rapies R\u00e9union Oc\u00e9an Indien (D\u00e9TROI), Universit\u00e9 de La R\u00e9union, INSERM, UMR 1188, 97491 Sainte Clotilde, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8926-4050","authenticated-orcid":false,"given":"Philippe","family":"Despr\u00e8s","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Mixte Processus Infectieux en Milieu Insulaire Tropical, Plateforme Technologique CYROI, INSERM U1187, CNRS UMR 9192, IRD UMR 249, Universit\u00e9 de la R\u00e9union, 94791 Sainte Clotilde, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Voahangy Vestalys","family":"Ramanandraibe","sequence":"additional","affiliation":[{"name":"International Associated Laboratory, University of Antananarivo-Lyon 1, Antananarivo P.O. Box 906, Madagascar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4673-6614","authenticated-orcid":false,"given":"Chaker","family":"El Kalamouni","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Mixte Processus Infectieux en Milieu Insulaire Tropical, Plateforme Technologique CYROI, INSERM U1187, CNRS UMR 9192, IRD UMR 249, Universit\u00e9 de la R\u00e9union, 94791 Sainte Clotilde, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: Advances and opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","first-page":"14","article-title":"Viral infectious disease and natural products with antiviral activity","volume":"1","author":"Kitazato","year":"2007","journal-title":"Drug Discov. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1039\/C4NP00085D","article-title":"Antiviral drug discovery: Broad-spectrum drugs from nature","volume":"32","author":"Martinez","year":"2015","journal-title":"Nat. Prod. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"112541","DOI":"10.1016\/j.ejmech.2020.112541","article-title":"Natural and nature-inspired stilbenoids as antiviral agents","volume":"202","author":"Mattio","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Goh, V.S.L., Mok, C.K., and Chu, J.J.H. (2020). Antiviral Natural Products for Arbovirus Infections. Molecules, 25.","DOI":"10.3390\/molecules25122796"},{"key":"ref_6","unstructured":"Martin, C.R., Hollins Martin, C.J., Preedy, V.R., and Rajendram, R. (2021). Chapter 38\u2014Medicinal plants as promising source of natural antiviral substances against Zika virus. Zika Virus Impact, Diagnosis, Control, and Models, Academic Press."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1080\/20477724.2018.1514136","article-title":"Dengue: A growing threat requiring vaccine development for disease prevention","volume":"112","author":"Bos","year":"2018","journal-title":"Pathog. Glob Health"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Hafsia, S., Haramboure, M., Wilkinson, D.A., Baldet, T., Yemadje-Menudier, L., Vincent, M., Tran, A., Atyame, C., and Mavingui, P. (2022). Overview of dengue outbreaks in the southwestern Indian Ocean and analysis of factors involved in the shift toward endemicity in Reunion Island: A systematic review. PLoS Negl. Trop. Dis., 16.","DOI":"10.1371\/journal.pntd.0010547"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.micinf.2019.04.005","article-title":"Zika virus infection: An update","volume":"21","author":"Ferraris","year":"2019","journal-title":"Microbes. Infect."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.micinf.2018.02.009","article-title":"Zika virus: From an obscurity to a priority","volume":"20","author":"Lee","year":"2018","journal-title":"Microbes. Infect."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/S0140-6736(16)00562-6","article-title":"Guillain-Barr\u00e9 Syndrome outbreak associated with Zika virus infection in French Polynesia: A case-control study","volume":"387","author":"Blake","year":"2016","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1016\/S0140-6736(16)00651-6","article-title":"Association between Zika virus and microcephaly in French Polynesia, 2013\u20132015: A retrospective study","volume":"387","author":"Cauchemez","year":"2016","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1016\/j.celrep.2017.01.056","article-title":"Frequent Zika Virus Sexual Transmission and Prolonged Viral RNA Shedding in an Immunodeficient Mouse Model","volume":"18","author":"Duggal","year":"2017","journal-title":"Cell Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3390\/v6010069","article-title":"Flavivirus Entry Receptors: An Update","volume":"6","author":"Meertens","year":"2013","journal-title":"Viruses"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Bibi Sadeer, N., Haddad, J.G., Oday Ezzat, M., Despr\u00e8s, P., Abdallah, H.H., Zengin, G., Uysal, A., El Kalamouni, C., Gallo, M., and Montesano, D. (2021). Bruguiera gymnorhiza (L.) Lam. at the Forefront of Pharma to Confront Zika Virus and Microbial Infections-An In Vitro and In Silico Perspective. Molecules, 26.","DOI":"10.3390\/molecules26195768"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"866452","DOI":"10.3389\/fcimb.2022.866452","article-title":"In Vitro Antiviral Activity of Potential Medicinal Plant Extracts Against Dengue and Chikungunya Viruses","volume":"12","author":"Alagarasu","year":"2022","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Clain, E., Haddad, J.G., Koishi, A.C., Sinigaglia, L., Rachidi, W., Despr\u00e8s, P., Duarte Dos Santos, C.N., Guiraud, P., Jouvenet, N., and El Kalamouni, C. (2019). The Polyphenol-Rich Extract from Psiloxylon mauritianum, an Endemic Medicinal Plant from Reunion Island, Inhibits the Early Stages of Dengue and Zika Virus Infection. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20081860"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10856","DOI":"10.1038\/s41598-018-29183-2","article-title":"Extract from Aphloia theiformis, an edible indigenous plant from Reunion Island, impairs Zika virus attachment to the host cell surface","volume":"8","author":"Clain","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Haddad, J.G., Koishi, A.C., Gaudry, A., Nunes Duarte Dos Santos, C., Viranaicken, W., Despr\u00e8s, P., and El Kalamouni, C. (2019). Doratoxylon apetalum, an Indigenous Medicinal Plant from Mascarene Islands, Is a Potent Inhibitor of Zika and Dengue Virus Infection in Human Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20102382"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gaudry, A., Bos, S., Viranaicken, W., Roche, M., Krejbich-Trotot, P., Gadea, G., Despr\u00e8s, P., and El-Kalamouni, C. (2018). The Flavonoid Isoquercitrin Precludes Initiation of Zika Virus Infection in Human Cells. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19041093"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Haddad, J.G., Picard, M., B\u00e9nard, S., Desvignes, C., Despr\u00e8s, P., Diotel, N., and El Kalamouni, C. (2019). Ayapana triplinervis Essential Oil and Its Main Component Thymohydroquinone Dimethyl Ether Inhibit Zika Virus at Doses Devoid of Toxicity in Zebrafish. Molecules, 24.","DOI":"10.3390\/molecules24193447"},{"key":"ref_22","first-page":"20210957","article-title":"The demographic history of Madagascan micro-endemics: Have rare species always been rare?","volume":"288","author":"Helmstetter","year":"2021","journal-title":"Proc. Biol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.jep.2018.12.002","article-title":"First ethnobotanical inventory and phytochemical analysis of plant species used by indigenous people living in the Maromizaha forest, Madagascar","volume":"232","author":"Riondato","year":"2019","journal-title":"J. Ethnopharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.2174\/092986710790827834","article-title":"New and bioactive natural products isolated from madagascar plants and marine organisms","volume":"17","author":"Hou","year":"2010","journal-title":"Curr. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1080\/13880200902988629","article-title":"Biodiversity conservation and drug discovery: Can they be combined? The Suriname and Madagascar experiences","volume":"47","author":"Cao","year":"2009","journal-title":"Pharm. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1126\/science.1187740","article-title":"Conservation. CITES designation for endangered rosewood in Madagascar","volume":"328","author":"Barrett","year":"2010","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1111\/j.1523-1739.2006.00562.x","article-title":"Deforestation and plant diversity of Madagascar\u2019s littoral forests","volume":"20","author":"Consiglio","year":"2006","journal-title":"Conserv. Biol."},{"key":"ref_28","unstructured":"Jolly, A., Oberl\u00c9, P., and Albignac, R. (1984). CHAPTER 2-The Vegetation: An Extraordinary Diversity. Key Environments: Madagascar, Pergamon."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.virol.2016.03.006","article-title":"The South Pacific epidemic strain of Zika virus replicates efficiently in human epithelial A549 cells leading to IFN-\u03b2 production and apoptosis induction","volume":"493","author":"Frumence","year":"2016","journal-title":"Virology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.virol.2016.07.015","article-title":"A robust method for the rapid generation of recombinant Zika virus expressing the GFP reporter gene","volume":"497","author":"Gadea","year":"2016","journal-title":"Virology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.virol.2017.12.003","article-title":"The structural proteins of epidemic and historical strains of Zika virus differ in their ability to initiate viral infection in human host cells","volume":"516","author":"Bos","year":"2018","journal-title":"Virology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"15931","DOI":"10.1038\/s41598-017-16130-w","article-title":"Broad-spectrum antiviral agents: Secreted phospholipase A(2) targets viral envelope lipid bilayers derived from the endoplasmic reticulum membrane","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e01455","DOI":"10.1016\/j.heliyon.2019.e01455","article-title":"The epidemic of Dengue virus type-2 Cosmopolitan genotype on Reunion Island relates to its active circulation in the Southwestern Indian Ocean neighboring islands","volume":"5","author":"Pascalis","year":"2019","journal-title":"Heliyon"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/nbt.3597","article-title":"Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking","volume":"34","author":"Wang","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13900","DOI":"10.1021\/acs.analchem.8b03099","article-title":"MetGem Software for the Generation of Molecular Networks Based on the t-SNE Algorithm","volume":"90","author":"Olivon","year":"2018","journal-title":"Anal. Chem."},{"key":"ref_36","unstructured":"(2022, June 20). Global Natural Products Social Molecular Networking. Available online: https:\/\/gnps.ucsd.edu\/ProteoSAFe\/libraries.jsp."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1093\/toxsci\/kfi110","article-title":"Zebrafish as a model vertebrate for investigating chemical toxicity","volume":"86","author":"Hill","year":"2005","journal-title":"Toxicol. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/nature12111","article-title":"The zebrafish reference genome sequence and its relationship to the human genome","volume":"496","author":"Howe","year":"2013","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Tamkut\u0117, L., Haddad, J.G., Diotel, N., Despr\u00e8s, P., Venskutonis, P.R., and El Kalamouni, C. (2022). Cranberry Pomace Extract Exerts Antiviral Activity against Zika and Dengue Virus at Safe Doses for Adult Zebrafish. Viruses, 14.","DOI":"10.3390\/v14051101"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e0006022","DOI":"10.1128\/jvi.00060-22","article-title":"Perturbation of Alphavirus and Flavivirus Infectivity by Components of the Bacterial Cell Wall","volume":"96","author":"Langendries","year":"2022","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.ijbiomac.2017.06.105","article-title":"Epigallocatechin gallate, an active green tea compound inhibits the Zika virus entry into host cells via binding the envelope protein","volume":"104","author":"Sharma","year":"2017","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.3389\/fmicb.2017.01314","article-title":"Antiviral Properties of the Natural Polyphenols Delphinidin and Epigallocatechin Gallate against the Flaviviruses West Nile Virus, Zika Virus, and Dengue Virus","volume":"8","author":"Saiz","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.antiviral.2018.12.002","article-title":"Inhibition of dengue virus by curcuminoids","volume":"162","author":"Balasubramanian","year":"2019","journal-title":"Antivir. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.jmgm.2016.08.011","article-title":"In-silico screening for anti-Zika virus phytochemicals","volume":"69","author":"Byler","year":"2016","journal-title":"J. Mol. Graph. Model."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/12\/1500\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:30:52Z","timestamp":1760146252000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/12\/1500"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,30]]},"references-count":44,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ph15121500"],"URL":"https:\/\/doi.org\/10.3390\/ph15121500","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,30]]}}}