Tanshinone II A Inhibits Tat‐Induced HIV‐1 Transactivation Through Redox‐Regulated AMPK/Nampt Pathway

Abstract

Tat transactivating activity regulated by NAD(+) -dependent histone deacetylase sirtuin1 (SIRT1) connects HIV transcription with the metabolic state of the cell. Nicotinamide phosphoribosyltransferase (Nampt) is a rate-limiting enzyme in the mammalian NAD(+) biosynthesis. Nampt, SIRT1, and AMPK were involved in inhibiting HIV-1 transactivation through redox-regulated pathway. Tanshinone II A is a main lipid-soluble monomer derivative from the root of Salvia miltiorrhiza (Danshen) and tanshinone II A possess a variety of biological activities through redox signaling pathway. Here we investigated the effect of tanshinone II A on Tat-induced HIV-1 transactivation and the redox signaling pathway involved in it. As the results were shown, tanshinone II A reversed Tat-induced reactive oxygen species (ROS) production and down-regulation of glutathione (GSH) levels in TZM-bl cells through up-regulation of Nrf2 expression. Tanshinone II A reversed Tat-induced inhibition of SIRT1 activity but not SIRT1 protein expression. Tanshinone II A reversed Tat-induced inhibition of Nampt protein expression and depletion of NAD(+) levels in TZM-bl cells in a dose-dependent manner. Tanshinone II A-evoked Nampt expression was mediated by AMPK signaling pathway. Tanshinone II A inhibited Tat-induced HIV-1 LTR transactivation dependent on AMPK-Nampt pathway. Collectively, our data provide new insights into understanding of the molecular mechanisms of tanshinone II A inhibited Tat-regulated transcription, suggesting that targeting AMPK/Nampt/SIRT1 pathway could serve as new anti-HIV-1 agents.

Tanshinone II A enhances pyroptosis and represses cell proliferation of HeLa cells by regulating miR-145/GSDMD signaling pathway

“…As a lipophilic pharmacologically active compound extracted from Salvia miltiorrhiza Bunge (Danshen), tanshinone II A shows a variety of biological activities, including anti-inflammatory [11][12][13], antibacterial [14], antitumor [15], antioxidative [16], antimutagenic [17] and antiplatelet aggregation activities [18]. Several researches revealed that tanshinone II A inhibited lipopolysaccharide (LPS)-induced acute lung injury in mice by regulating PI3K/AKT and MAPK signaling, and ameliorated the cardiovascular dysfunction by regulating NADPH oxidase 2-related signaling [19].…”

Examining Relationships between Metabolism and Persistent Inflammation in HIV Patients on Antiretroviral Therapy

“…Conversely, Tat-induced reductions in NAD + levels and SIRT1 activity have been shown to diminish AMPK activity [ 172 ]. Consistent with these findings, restoration of NAD + levels by tanshinone II-induced nicotinamide phosphoribosyltransferase (Nampt) expression and increased AMPK activation resulted in reduced Tat-mediated HIV transactivation and reduced reactive oxygen species production [ 173 ]. Alternatively, AMPK activators such as metformin or AICAR are currently being tested with clinical trials to reactive latent HIV infection.…”

EZH2 phosphorylation regulates Tat‐induced HIV‐1 transactivation via ROS/Akt signaling pathway

“…Luciferase assays were conducted with the Dual luciferase Reporter Kit (Promega). The pRL vector constitutively expressing Renilla luciferase was used to normalize for transfection efficiency [18].…”