{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T18:42:37Z","timestamp":1777056157306,"version":"3.51.4"},"reference-count":48,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T00:00:00Z","timestamp":1676332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["31602082"],"award-info":[{"award-number":["31602082"]}]},{"name":"National Natural Science Foundation of China","award":["2016YFD0500402"],"award-info":[{"award-number":["2016YFD0500402"]}]},{"name":"National Natural Science Foundation of China","award":["2022ABA002"],"award-info":[{"award-number":["2022ABA002"]}]},{"name":"National Natural Science Foundation of China","award":["2019\u2013620\u2013000-001-017"],"award-info":[{"award-number":["2019\u2013620\u2013000-001-017"]}]},{"name":"National Key Research and Development Program","award":["31602082"],"award-info":[{"award-number":["31602082"]}]},{"name":"National Key Research and Development Program","award":["2016YFD0500402"],"award-info":[{"award-number":["2016YFD0500402"]}]},{"name":"National Key Research and Development Program","award":["2022ABA002"],"award-info":[{"award-number":["2022ABA002"]}]},{"name":"National Key Research and Development Program","award":["2019\u2013620\u2013000-001-017"],"award-info":[{"award-number":["2019\u2013620\u2013000-001-017"]}]},{"name":"Technical Innovation Project of Hubei Province","award":["31602082"],"award-info":[{"award-number":["31602082"]}]},{"name":"Technical Innovation Project of Hubei Province","award":["2016YFD0500402"],"award-info":[{"award-number":["2016YFD0500402"]}]},{"name":"Technical Innovation Project of Hubei Province","award":["2022ABA002"],"award-info":[{"award-number":["2022ABA002"]}]},{"name":"Technical Innovation Project of Hubei Province","award":["2019\u2013620\u2013000-001-017"],"award-info":[{"award-number":["2019\u2013620\u2013000-001-017"]}]},{"name":"Hubei Province Innovation Center of Agricultural Sciences and Technology","award":["31602082"],"award-info":[{"award-number":["31602082"]}]},{"name":"Hubei Province Innovation Center of Agricultural Sciences and Technology","award":["2016YFD0500402"],"award-info":[{"award-number":["2016YFD0500402"]}]},{"name":"Hubei Province Innovation Center of Agricultural Sciences and Technology","award":["2022ABA002"],"award-info":[{"award-number":["2022ABA002"]}]},{"name":"Hubei Province Innovation Center of Agricultural Sciences and Technology","award":["2019\u2013620\u2013000-001-017"],"award-info":[{"award-number":["2019\u2013620\u2013000-001-017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Japanese encephalitis virus (JEV) infection causes host endoplasmic reticulum stress (ERS) reaction, and then induces cell apoptosis through the UPR pathway, invading the central nervous system and causing an inflammation storm. The endoplasmic reticulum stress inhibitor, 4-phenyl-butyric acid (4-PBA), has an inhibitory effect on the replication of flavivirus. Here, we studied the effect of 4-PBA on JEV infection both in vitro and vivo. The results showed that 4-PBA treatment could significantly decrease the titer of JEV, inhibit the expression of the JEV NS3 protein (in vitro, p &lt; 0.01) and reduce the positive rate of the JEV E protein (in vivo, p &lt; 0.001). Compared to the control group, 4-PBA treatment can restore the weight of JEV-infected mice, decrease the level of IL-1\u03b2 in serum and alleviate the abnormalities in brain tissue structure. Endoplasmic reticulum stress test found that the expression level of GRP78 was much lower and activation levels of PERK and IRE1 pathways were reduced in the 4-PBA treatment group. Furthermore, 4-PBA inhibited the UPR pathway activated by NS3, NS4b and NS5 RdRp. The above results indicated that 4-PBA could block JEV replication and inhibit ER stress caused by JEV. Interestingly, 4-PBA could reduce the expression of NS5 by inhibiting transcription (p &lt; 0.001), but had no effect on the expression of NS3 and NS4b. This result may indicate that 4-PBA has antiviral activity independent of the UPR pathway. In summary, the effect of 4-PBA on JEV infection is related to the inhibition of ER stress, and it may be a promising drug for the treatment of Japanese encephalitis.<\/jats:p>","DOI":"10.3390\/v15020534","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T03:09:21Z","timestamp":1676430561000},"page":"534","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["4-Phenyl-butyric Acid Inhibits Japanese Encephalitis Virus Replication via Inhibiting Endoplasmic Reticulum Stress Response"],"prefix":"10.3390","volume":"15","author":[{"given":"Shuangshuang","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Prevention and Control Agents for Animal Bacteriosis (Ministry of Agriculture and Rural Affairs), Hubei Provincial Key Laboratory of Animal Pathogenic Microbiology, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Sciences, Wuhan 430064, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keli","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Prevention and Control Agents for Animal Bacteriosis (Ministry of Agriculture and Rural Affairs), Hubei Provincial Key Laboratory of Animal Pathogenic Microbiology, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Sciences, Wuhan 430064, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3133-2369","authenticated-orcid":false,"given":"Chang","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Prevention and Control Agents for Animal Bacteriosis (Ministry of Agriculture and Rural Affairs), Hubei Provincial Key Laboratory of Animal Pathogenic Microbiology, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Sciences, Wuhan 430064, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Prevention and Control Agents for Animal Bacteriosis (Ministry of Agriculture and Rural Affairs), Hubei Provincial Key Laboratory of Animal Pathogenic Microbiology, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Sciences, Wuhan 430064, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Gao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Prevention and Control Agents for Animal Bacteriosis (Ministry of Agriculture and Rural Affairs), Hubei Provincial Key Laboratory of Animal Pathogenic Microbiology, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Sciences, Wuhan 430064, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fangyan","family":"Yuan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Prevention and Control Agents for Animal Bacteriosis (Ministry of Agriculture and Rural Affairs), Hubei Provincial Key Laboratory of Animal Pathogenic Microbiology, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Sciences, Wuhan 430064, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Guo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Prevention and Control Agents for Animal Bacteriosis (Ministry of Agriculture and Rural Affairs), Hubei Provincial Key Laboratory of Animal Pathogenic Microbiology, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Sciences, Wuhan 430064, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zewen","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Prevention and Control Agents for Animal Bacteriosis (Ministry of Agriculture and Rural Affairs), Hubei Provincial Key Laboratory of Animal Pathogenic Microbiology, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Sciences, Wuhan 430064, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiqing","family":"Tan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Prevention and Control Agents for Animal Bacteriosis (Ministry of Agriculture and Rural Affairs), Hubei Provincial Key Laboratory of Animal Pathogenic Microbiology, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Sciences, Wuhan 430064, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianwang","family":"Hu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Prevention and Control Agents for Animal Bacteriosis (Ministry of Agriculture and Rural Affairs), Hubei Provincial Key Laboratory of Animal Pathogenic Microbiology, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Sciences, Wuhan 430064, 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China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Rothan, H.A., and Kumar, M. 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