Cepharanthine Suppresses Herpes Simplex Virus Type 1 Replication Through the Downregulation of the PI3K/Akt and p38 MAPK Signaling Pathways.

Yao Liu,Jiuseng Zeng,Nan Zeng,Qiong Tang,Dan Li,Li Chen,Fei Luan,Wenjun Liu,Yuexin Zhang

doi:10.3389/fmicb.2021.795756

Abstract

Cepharanthine (CEP) is a naturally occurring isoquinoline alkaloid extracted from Stephania cepharantha Hayata. Although its underlying molecular mechanism is not fully understood, this compound is reported as a promising antiviral drug. In the present study, we explore the anti-HSV-1 effects and the underlying molecular mechanisms of CEP in vitro. Our results show that CEP could significantly inhibit the formation of plaque and the expression of viral proteins and exhibit a general suppression of replication-associated genes. Whereas HSV-1 infection increases the expressions of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and p38 mitogen-activated protein kinase (p38 MAPK) in host cells, CEP was effective indirectly inhibiting phosphorylation levels of the targets in PI3K/Akt and p38 MAPK signaling pathways. Moreover, CEP markedly decreased G0/G1 phase and increased G2/M phase cells and decreased the expression of cyclin-dependent kinase1 (CDK1) and cyclinB1 in a dose-dependent manner. Additionally, CEP increased apoptosis in infected cells, reduced B cell lymphoma-2 (Bcl-2) protein levels, and increased the protein levels of Bcl-associated X protein (Bax), cleaved-caspase3, and nuclear IκB kinaseα (IκBα). Collectively, CEP could arrest the cell cycle in the G2/M phase and induce apoptosis in infected cells by inhibiting the PI3K/Akt and p38 MAPK signaling pathways, hence further reducing HSV-1 infection and subsequent reproduction.

Highlights

Herpes simplex virus type-1 (HSV-1) is a double-stranded DNA virus belonging to the α-herpes virus subfamily that replicates in epithelial cells and produces a lifetime incubation period in neurons
These findings indicate that the phosphoinositide 3-kinase (PI3K)/Akt and p38 MAPK pathways were implicated in the suppression of HSV-1 viral multiplication, whereas CEP could significantly decrease the phosphorylation levels of PI3K in a dose-dependent manner (Figures 5A,D), Akt (Figures 5B,E), and p38 MAPK (Figures 5C,F)
The results indicated that the role of CEP in inhibition of HSV-1 replication is closely associated with the Rap1-related signaling pathway, which is activated by binding with GTP, and its activation mainly affects the cell cycle or apoptosis by regulating the PI3K/AKT and p38 MAPK signaling pathways and thereby affecting cell growth and survival (Raza et al, 2018)

Summary

Introduction

Herpes simplex virus type-1 (HSV-1) is a double-stranded DNA virus belonging to the α-herpes virus subfamily that replicates in epithelial cells and produces a lifetime incubation period in neurons. CEP combinations with antitumor medication are suggested to treat immunosuppression and thrombocytopenia induced by chemotherapy and radiation without obvious side effects. Apart from those mentioned above, there is growing evidence that CEP might be a broad-spectrum antiviral drug that can inhibit infections of SARS, HIV, HSV-1, COVID-19, and Ebola and can treat various autoimmune diseases and allergic reactions due to its immunomodulatory effect (Kim et al, 2019; Rogosnitzky et al, 2020; Li et al, 2021). To further correlate the antiviral applications of CEP with its underlying molecular mechanisms, the anti-HSV-1 effects, and mechanisms of CEP are explored in vitro in this study

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Discussion

Conclusion