• Guangliang Hong, Dong Zheng, Lulu Zhang, Rui Ni, Grace Wang, Guo-Chang Fan, Zhongqiu Lu, and Tianqing Peng.
• Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada N6A 4G5; Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada N6A 4G5.
• Free Radic. Biol. Med. 2018 Aug 1; 123: 125-137.

AimsSepsis-caused multiple organ failure remains the major cause of morbidity and mortality in intensive care units. Nicotinamide riboside (NR) is a precursor of nicotinamide adenine dinucleotide (NAD+), which is important in regulating oxidative stress. This study investigated whether administration of NR prevented oxidative stress and organ injury in sepsis.MethodsMouse sepsis models were induced by injection of lipopolysaccharides (LPS) or feces-injection-in-peritoneum. NR was given before sepsis onset. Cultured macrophages and endothelial cells were incubated with various agents.ResultsAdministration of NR elevated the NAD+ levels, and elicited a reduction of oxidative stress, inflammation and caspase-3 activity in lung and heart tissues, which correlated with attenuation of pulmonary microvascular permeability and myocardial dysfunction, leading to less mortality in sepsis models. These protective effects of NR were associated with decreased levels of plasma high mobility group box-1 (HMGB1) in septic mice. Consistently, pre-treatment of macrophages with NR increased NAD+ content and reduced HMGB1 release upon LPS stimulation. NR also prevented reactive oxygen species (ROS) production and apoptosis in endothelial cells induced by a conditioned-medium collected from LPS-treated macrophages. Furthermore, inhibition of SIRT1 by EX527 offset the negative effects of NR on HMGB1 release in macrophages, and ROS and apoptosis in endothelial cells.ConclusionsAdministration of NR prevents lung and heart injury, and improves the survival in sepsis, likely by inhibiting HMGB1 release and oxidative stress via the NAD+/SIRT1 signaling. Given NR has been used as a health supplement, it may be a useful agent to prevent organ injury in sepsis.Copyright © 2018 Elsevier Inc. All rights reserved.

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