PARP1 inhibition protects mice against Japanese encephalitis virus infection.

Japanese encephalitis (JE) is a vector-borne viral disease that causes acute encephalitis in children. Although vaccines have been developed against the JE virus (JEV), no effective antiviral therapy exists. Our study shows that inhibition of poly(ADP-ribose) polymerase 1 (PARP1), an NAD+-dependent (poly-ADP) ribosyl transferase, protects against JEV infection. Interestingly, PARP1 is critical for JEV pathogenesis in Neuro-2a cells and mice. Small molecular inhibitors of PARP1, olaparib, and 3-aminobenzamide (3-AB) significantly reduce clinical signs and viral load in the serum and brains of mice and improve survival. PARP1 inhibition confers protection against JEV infection by inhibiting autophagy. Mechanistically, upon JEV infection, PARP1 PARylates AKT and negatively affects its phosphorylation. In addition, PARP1 transcriptionally upregulates PTEN, the PIP3 phosphatase, negatively regulating AKT. PARP1-mediated AKT inactivation promotes autophagy and JEV pathogenesis by increasing the FoxO activity. Thus, our findings demonstrate PARP1 as a potential mediator of JEV pathogenesis that can be effectively targeted for treating JE.

Emerging Roles of SIRT3 in Cardiac Metabolism.

The heart is a highly metabolically active organ that predominantly utilizes fatty acids as an energy substrate. The heart also derives some part of its energy by oxidation of other substrates, including glucose, lactose, amino acids and ketones. The critical feature of cardiac pathology is metabolic remodeling and loss of metabolic flexibility. Sirtuin 3 (SIRT3) is one of the seven mammalian sirtuins (SIRT1 to SIRT7), with NAD+ dependent deacetylase activity. SIRT3 is expressed in high levels in healthy hearts but downregulated in the aged or diseased hearts. Experimental evidence shows that increasing SIRT3 levels or activity can ameliorate several cardiac pathologies. The primary deacetylation targets of SIRT3 are mitochondrial proteins, most of which are involved in energy metabolism. Thus, SIRT3 improves cardiac health by modulating cardiac energetics. In this review, we discuss the essential role of SIRT3 in regulating cardiac metabolism in the context of physiology and pathology. Specifically, we summarize the recent advancements that emphasize the critical role of SIRT3 as a master regulator of cardiac metabolism. We also present a comprehensive view of all known activators of SIRT3, and elaborate on their therapeutic potential to ameliorate energetic abnormalities in various cardiac pathologies.