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Int J Mol Sci ; 23(24)2022 Dec 16.
Article in English | MEDLINE | ID: covidwho-2200326


HSV-1 is a typical neurotropic virus that infects the brain and causes keratitis, cold sores, and occasionally, acute herpes simplex encephalitis (HSE). The large amount of proinflammatory cytokines induced by HSV-1 infection is an important cause of neurotoxicity in the central nervous system (CNS). Microglia, as resident macrophages in CNS, are the first line of defense against neurotropic virus infection. Inhibiting the excessive production of inflammatory cytokines in overactivated microglia is a crucial strategy for the treatment of HSE. In the present study, we investigated the effect of nicotinamide n-oxide (NAMO), a metabolite mainly produced by gut microbe, on HSV-1-induced microglial inflammation and HSE. We found that NAMO significantly inhibits the production of cytokines induced by HSV-1 infection of microglia, such as IL-1ß, IL-6, and TNF-α. In addition, NAMO promotes the transition of microglia from the pro-inflammatory M1 type to the anti-inflammatory M2 type. More detailed studies revealed that NAMO enhances the expression of Sirtuin-1 and its deacetylase enzymatic activity, which in turn deacetylates the p65 subunit to inhibit NF-κB signaling, resulting in reduced inflammatory response and ameliorated HSE pathology. Therefore, Sirtuin-1/NF-κB axis may be promising therapeutic targets against HSV-1 infection-related diseases including HSE.

Herpes Simplex , Herpesvirus 1, Human , Humans , NF-kappa B/metabolism , Microglia/metabolism , Herpesvirus 1, Human/metabolism , Sirtuin 1/metabolism , Inflammation/metabolism , Cytokines/metabolism , Herpes Simplex/pathology
Int J Mol Sci ; 22(12)2021 Jun 17.
Article in English | MEDLINE | ID: covidwho-1282513


Novel antiviral nanotherapeutics, which may inactivate the virus and block it from entering host cells, represent an important challenge to face viral global health emergencies around the world. Using a combination of bioorthogonal copper-catalyzed 1,3-dipolar alkyne/azide cycloaddition (CuAAC) and photoinitiated thiol-ene coupling, monofunctional and bifunctional peptidodendrimer conjugates were obtained. The conjugates are biocompatible and demonstrate no toxicity to cells at biologically relevant concentrations. Furthermore, the orthogonal addition of multiple copies of two different antiviral peptides on the surface of a single dendrimer allowed the resulting bioconjugates to inhibit Herpes simplex virus type 1 at both the early and the late stages of the infection process. The presented work builds on further improving this attractive design to obtain a new class of therapeutics.

Antiviral Agents/pharmacology , Dendrimers/pharmacology , Glycoproteins , Herpesvirus 1, Human , Peptides/pharmacology , Viral Proteins , Amino Acid Sequence , Animals , Antiviral Agents/chemistry , CHO Cells , Cell Line , Cell Survival/drug effects , Chemical Phenomena , Chemistry Techniques, Synthetic , Chromatography, High Pressure Liquid , Cricetulus , Dendrimers/chemistry , Glycoproteins/chemistry , Herpesvirus 1, Human/metabolism , Microbial Sensitivity Tests , Molecular Structure , Peptides/chemistry , Spectrum Analysis , Viral Proteins/chemistry