title: Induction of Osteopontin by Dengue Virus-3 Infection in THP-1 Cells: Inhibition of the Synthesis by Brefelamide and Its Derivative.
abstract: Osteopontin (OPN) is a multifunctional matricellular protein produced by a broad range of cells including osteoclasts, macrophages, T cells, endothelial cells, and vascular smooth muscle cells. OPN modulates various physiological and pathological events such as inflammation, wound healing, and bone formation and remodeling. Dengue virus (DENV) infection causes an increase in plasma OPN levels, which is correlated with the severity of symptoms and coagulation abnormalities. DENV infection also inducesOPNgene expression in human macrophages. This study investigated the inhibitory effects of brefelamide and its methyl ether derivative on DENV-3 by measuring changes in OPN levels in human THP-1 and 293T cell lines infected at different multiplicities of infection and post-infection time points.OPNmRNA expression and viral RNA were detected by reverse transcriptase quantitative real-time PCR, whereas protein level was determined by enzyme-linked immunosorbent assay. We found that viral copy number was higher in 293T than in THP-1 cells. However, THP-1 constitutively expressed higher levels of OPN mRNA and protein, which were enhanced by DENV-3 infection. Brefelamide and its derivative suppressed OPN production in DENV-3 infected THP-1 cells; the effective doses of these compounds had no effect on uninfected cells, indicating low cytotoxicity. These results suggest that brefelamide and its methyl ether derivative have therapeutic effects in preventing inflammation, coagulopathy, and fibrinolysis caused by OPN upregulation induced by DENV-3 infection.
authors.affiliation: Division of International Cooperation for Disaster Medicine, International Research Institute of Disaster Science, Tohoku University Sendai, Japan.
authors.forename: Dyshelly N
authors.initials: DN
authors.lastname: Pascapurnama
authors.affiliation: Division of Emerging Infectious Diseases, Graduate School of Medicine, Tohoku University Sendai, Japan.
authors.forename: Hannah K M
authors.initials: HK
authors.lastname: Labayo
authors.affiliation: Division of Disaster-related Infectious Diseases, International Research Institute of Disaster Science, Tohoku University Sendai, Japan.
authors.forename: Isolde
authors.initials: I
authors.lastname: Dapat
authors.affiliation: Division of Emerging Infectious Diseases, Graduate School of Medicine, Tohoku University Sendai, Japan.
authors.forename: Divya D
authors.initials: DD
authors.lastname: Nagarajegowda
authors.affiliation: Division of Disaster-related Infectious Diseases, International Research Institute of Disaster Science, Tohoku University Sendai, Japan.
authors.forename: Jingge
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Research and Development Center, FUSO Pharmaceutical Industries, Ltd Osaka, Japan.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Research and Development Center, FUSO Pharmaceutical Industries, Ltd Osaka, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamada
authors.affiliation: Laboratory of Natural Product Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University Sendai, Japan.
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: Division of International Cooperation for Disaster Medicine, International Research Institute of Disaster Science, Tohoku University Sendai, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Egawa
authors.affiliation: Laboratory of Natural Product Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University Sendai, Japan.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Oshima
authors.affiliation: Division of Emerging Infectious Diseases, Graduate School of Medicine, Tohoku UniversitySendai, Japan; Division of Disaster-related Infectious Diseases, International Research Institute of Disaster Science, Tohoku UniversitySendai, Japan.
authors.forename: Haorile
authors.initials: H
authors.lastname: Chagan-Yasutan
authors.affiliation: Division of Emerging Infectious Diseases, Graduate School of Medicine, Tohoku UniversitySendai, Japan; Division of Disaster-related Infectious Diseases, International Research Institute of Disaster Science, Tohoku UniversitySendai, Japan; Graduate School of Health Science and Social Welfare, Kibi International UniversityTakahashi, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Hattori
keywords: 293T cell; THP-1 cell; brefelamide; dengue virus-3; osteopontin