Abstract
Dengue virus (DENV) infection, which causes dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, is a severe global health problem in tropical and subtropical areas. There is no effective vaccine or drug against DENV infection. Thus, the development of anti-DENV agents is imperative. This study aimed to assess the anti-DENV activity of (E)-guggulsterone using a DENV infectious system. A specific inhibitor targeting signal molecules was used to evaluate the molecular mechanisms of action. Western blotting and qRT-PCR were used to determine DENV protein expression and RNA replication, respectively. Finally, an ICR suckling mouse model was used to examine the anti-DENV activity of (E)-guggulsterone in vivo. A dose-dependent inhibitory effect of (E)-guggulsterone on DENV protein synthesis and RNA replication without cytotoxicity was observed. The mechanistic studied revealed that (E)-guggulsterone stimulates Nrf2-mediated heme oxygenase-1 (HO-1) expression, which increases the antiviral interferon responses and downstream antiviral gene expression by blocking DENV NS2B/3B protease activity. Moreover, (E)-guggulsterone protected ICR suckling mice from life-threatening DENV infection. These results suggest that (E)-guggulsterone can be a potential supplement for controlling DENV replication.
Highlights
Dengue infection is a severe arthropod-borne disease caused by the dengue virus (DENV) and is prevalent in tropical and subtropical areas [1]
We demonstrated that (E)-guggulsterone suppresses Dengue virus (DENV) replication by upregulating antiviral interferon responses by inducing heme oxygenase-1 expression
Our findings suggested that (E)-guggulsterone is a possible candidate for the treatment of DENV infection
Summary
Dengue infection is a severe arthropod-borne disease caused by the dengue virus (DENV) and is prevalent in tropical and subtropical areas [1]. Several antioxidant enzymes such as heme oxygenase-1 (HO-1), superoxidase dismutase (SOD-2), and glutamate-cysteine ligase (GCLM) are activated through the Nrf (Nuclear factor erythroid 2-related factor 2)/Keap (kelch-like ECHassociated protein 1) pathway to quench DENV-induced oxidative stress as well as suppress DENV replication [10,11]. Degradation of Nrf with DENV NS2B/NS3 leads to increased oxidative stress and facilitates DENV replication [15]. These phenomena suggest that induction of HO-1 enzyme activity will be an effective way to reduce DENV-infected oxidative as well as to control DENV replication. We demonstrated that (E)-guggulsterone suppresses DENV replication by upregulating antiviral interferon responses by inducing heme oxygenase-1 expression. Our findings suggested that (E)-guggulsterone is a possible candidate for the treatment of DENV infection
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