Downregulation of Cellular c-Jun N-Terminal Protein Kinase and NF-κB Activation by Berberine May Result in Inhibition of Herpes Simplex Virus Replication

Abstract

bBerberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. Some reports show that berberine exhibits anti-inflammatory, antitumor, and antiviral properties by modulating multiple cellular signaling pathways, including p53, nuclear factor B (NF-B), and mitogen-activated protein kinase. In the present study, we investigated the antiviral effect of berberine against herpes simplex virus (HSV) infection. Current antiherpes medicines such as acyclovir can lessen the recurring activation when used early at infection but are unable to prevent or cure infections where treatment has selected for resistant mutants. In searching for new antiviral agents against herpesvirus infection, we found that berberine reduced viral RNA transcription, protein synthesis, and virus titers in a dose-dependent manner. To elucidate the mechanism of its antiviral activity, the effect of berberine on the individual steps of viral replication cycle of HSV was investigated via time-of-drug addition assay. We found that berberine acted at the early stage of HSV replication cycle, between viral attachment/entry and genomic DNA replication, probably at the immediate-early gene expression stage. We further demonstrated that berberine significantly reduced HSV-induced NF-B activation, as well as IB-␣ degradation and p65 nuclear translocation. Moreover, we found that berberine also depressed HSV-induced c-Jun N-terminal kinase (JNK) phosphorylation but had little effect on p38 phosphorylation. Our results suggest that the berberine inhibition of HSV infection may be mediated through modulating cellular JNK and NF-B pathways.

Berberine inhibits enterovirus 71 replication by downregulating the MEK/ERK signaling pathway and autophagy

“…BBR has been reported to have multi pharmacological effects such as antibacterial effect [19], hypotensive effect [33], and antiviral activity [21, 22]. It has been reported that BBR could regulate signaling pathway in vitro, such as, EGFR/MEK/ERK signaling pathway [23], AMPK/mTOR signaling pathway [24].…”

“…1a), an isoquinoline alkaloid isolated from Berberis vulgaris L. , has been reported to have multi pharmacological effects such as antidiarrheal effect [18], antibacterial effect [19], hypotensive effect [20], and antiviral activity [21, 22]. Most of these pharmacological effects is known to be associated with the mechanisms that BBR regulates signaling pathway in vitro, such as, EGFR/MEK/ERK signaling pathway [23], NF-κB pathway [22], AMPK/mTOR signaling pathway [24]. In addition, Deng et al demonstrated that BBR attenuates autophagy in adipocytes by targeting BECN1 [25].…”

“…These findings suggest that BBR can regulate MEK/ERK signaling pathway and autophagy, which implies that BBR might be effective in limiting viral replication. In line with this notion, BBR is shown to inhibit the replication of respiratory syncytial virus (RSV), herpes simplex virus (HSV), human papilomavirus (HPV), and human cytomegalovirus (HCMV) [21, 22, 26, 27]. However, it is unclear that BBR has an inhibitory action against EV71.…”

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

“…Earlier studies have demonstrated that berberine impedes virus repli- cation by modifying the cellular signaling environment (40)(41)(42). To pinpoint the pathways that are altered by berberine in CHIKV infection, we employed a human phosphokinase array that allows for detection of changes in the relative phosphorylation levels of a panel of different cellular kinases and their substrates.…”

Inhibition of respiratory syncytial virus replication and virus-induced p38 kinase activity by berberine

“…Over the past several decades, numerous biological effects of berberine have been discovered, such as its anticancer [6], antilipogenic and hypoglycemic [7], neuroprotective [8], and antimicrobial effects against fungal pathogens [9] and bacterial pathogens [10]. In addition, berberine has been shown to exert antiviral effects against viruses such as herpes simplex virus, human cytomegalovirus, and influenza A virus [11][12][13].…”