Daporinad

AD is the abbreviation for Alzheimer's Disease, which is a neurodegenerative disorder that features progressive dysfunction in cognition. Previous research has reported that mitophagy impairment and mitochondrial dysfunction have been crucial factors in the AD's pathogenesis. More recently, literature has emerged which offers findings suggesting that the nicotinamide adenine dinucleotide (short for NAD⁺) augmentation eliminates the defective mitochondria and restores mitophagy. Meanwhile, as an enzyme which is rate-limiting, the Nicotinamide phosphoribosyltransferase, or NAMPT, is part of the salvage pathway of NAD⁺ synthesis. Therefore, the aim of the research project has been to produce proof for how the NAMPT-NAD ⁺-silent information-regulated transcription factors1/3 (short for SIRT1/3) axis function in mediating mitophagy in APP/PS1 mice aged six months. The results revealed that the NAMPT-NAD⁺-SIRT1/3 axis in the APP/PS1 mice's hippocampus was considerably declined. Surprisingly, P7C3 (an NAMPT activator) noticeably promoted the NAD⁺-SIRT1/3 axis, improved mitochondrial structure and function, enhanced mitophagy activity along with the ability of learning and memory. While FK866 (an NAMPT inhibitor) reversed the decreased NAD⁺-SIRT1/3 axis, and even exacerbated Aβ plaque deposition level in the APP/PS1 mice's hippocampus. The findings observed in this study indicate two main points: avoiding downregulation of the NAMPT activity can prevent AD-related mitophagy impairment; on the other hand, NAMPT characterizes a potential therapeutic intervention regarding AD pathogenesis.

Vascular endothelial cytoskeletal disruption leads to increased vascular permeability and is involved in the pathogenesis and progression of various diseases. Oxidative stress can increase vascular permeability by weakening endothelial cell-to-cell junctions and decrease intracellular nicotinamide adenine dinucleotide (NAD⁺) levels. However, it remains unclear how intracellular NAD⁺ variations caused by oxidative stress alter the vascular endothelial cytoskeletal organization. In this study, we demonstrated that oxidative stress activates poly (ADP-ribose [ADPr]) polymerase (PARP), which consume large amounts of intracellular NAD⁺, leading to cytoskeletal disruption in vascular endothelial cells. We found that hydrogen peroxide (H₂O₂) could transiently disrupt the cytoskeleton and reduce intracellular total NAD levels in human umbilical vein endothelial cells (HUVECs). H₂O₂ stimulation led to rapid increase in ADPr protein levels in HUVECs. Pharmaceutical PARP inhibition counteracted H₂O₂-induced total NAD depletion and cytoskeletal disruption, suggesting that NAD⁺ consumption by PARP induced cytoskeletal disruption. Additionally, supplementation with nicotinamide mononucleotide (NMN), the NAD⁺ precursor, prevented both intracellular total NAD depletion and cytoskeletal disruption induced by H₂O₂ in HUVECs. Inhibition of the NAD⁺ salvage pathway by FK866, a nicotinamide phosphoribosyltransferase inhibitor, maintained H₂O₂-induced cytoskeletal disruption, suggesting that intracellular NAD⁺ plays a crucial role in recovery from cytoskeletal disruption. Our findings provide further insights into the potential application of PARP inhibition and NMN supplementation for the treatment and prevention of diseases involving vascular hyperpermeability.