Guangliang Hong1, Dong Zheng2, Lulu Zhang3, Rui Ni4, Grace Wang5, Guo-Chang Fan6, Zhongqiu Lu7, Tianqing Peng8. 1. 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. 2. 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; Department of Medicine, Western University, London, Ontario, Canada N6A 4G5; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China. 3. Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China. 4. 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. 5. Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8. 6. Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. 7. Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: lzq640815@163.com. 8. 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; Department of Medicine, Western University, London, Ontario, Canada N6A 4G5; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China. Electronic address: tpeng2@uwo.ca.
Abstract
AIMS: Sepsis-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. METHODS: Mouse 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. RESULTS: Administration 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. CONCLUSIONS: Administration 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.
AIMS: Sepsis-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. METHODS:Mousesepsis 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. RESULTS: Administration 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. CONCLUSIONS: Administration 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.
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