Grape Seed Proanthocyanidins Inhibit Replication of the Dengue Virus by Targeting NF-kB and MAPK-Mediated Cyclooxygenase-2 Expression

Wei-Chun Chen; Monir Hossen; Wangta Liu; Chia-Hung Yen; Chung-Hao Huang; Yao-Chin Hsu; Jin-Ching Lee

doi:10.3390/v15040884

Grape Seed Proanthocyanidins Inhibit Replication of the Dengue Virus by Targeting NF-kB and MAPK-Mediated Cyclooxygenase-2 Expression

Viruses. 2023 Mar 30;15(4):884. doi: 10.3390/v15040884.

Authors

Wei-Chun Chen^{1

2}, Monir Hossen³, Wangta Liu², Chia-Hung Yen⁴, Chung-Hao Huang^{5

6

7}, Yao-Chin Hsu⁸, Jin-Ching Lee^{1

2

4}

Affiliations

¹ Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
² Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
³ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁴ Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁵ Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁶ School of Medicine, Graduate Institute of Medicine, College of Medicine, Sepsis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁷ Center for Tropical Medicine and Infectious Disease, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁸ Department of Chinese Medicine, Chi Mei Medical Center, Tainan 71004, Taiwan.

Abstract

Dengue virus (DENV) infection is a serious global health issue as it causes severe dengue hemorrhagic fever and dengue shock syndrome. Since no approved therapies are available to treat DENV infection, it is necessary to develop new agents or supplements that can do this. In this study, grape seed proanthocyanidins extract (GSPE), which is widely consumed as a dietary supplement, dose-dependently suppressed the replication of four DENV serotypes. The inhibitory mechanism demonstrated that GSPE downregulated DENV-induced aberrant cyclooxygenase-2 (COX-2) expression, revealing that the inhibitory effect of the GSPE on DENV replication involved targeting DENV-induced COX-2 expression. Mechanistic studies on signaling regulation have demonstrated that GSPE significantly reduced COX-2 expression by inactivating NF-κB and ERK/P38 MAPK signaling activities. Administrating GSPE to DENV-infected suckling mice reduced virus replication, mortality, and monocyte infiltration of the brain. In addition, GSPE substantially reduced the expression of DENV-induced inflammatory cytokines associated with severe dengue disease, including tumor necrosis factor-α, nitric oxide synthase, interleukin (IL)-1, IL-6, and IL-8, suggesting that GSPE has potential as a dietary supplement to attenuate DENV infection and severe dengue.

Keywords: cyclooxygenase; dengue virus; grape seed extract; inflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cyclooxygenase 2 / genetics
Dengue Virus* / physiology
Dengue*
Mice
NF-kappa B / metabolism
Severe Dengue* / drug therapy
Virus Replication

Substances

Grape Seed Proanthocyanidins
NF-kappa B
Cyclooxygenase 2

Grants and funding

This research was funded by the Ministry of Science and Technology of Taiwan (under grant numbers MOST111-2311-B-110-001 and MOST110-2314-B-037-117-MY2), the NSYSU-KMU Joint Research Project (#NSYSYKMU 111-I06), and the Chi-Mei Medical Center and Kaohsiung Medical University Research Foundation, Taiwan (grant number 109 CM-KMU-006).