Nicotinamide mononucleotide as a therapeutic agent to alleviate multi-organ failure in sepsis

• Published in: Journal of translational medicine Vol. 21; no. 1; p. 883
• Main Authors: Cao, Ting, Ni, Rui, Ding, Weimin, Ji, Xiaoyun, Fan, Guo-Chang, Zhang, Zhuxu, Peng, Tianqing
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 06.12.2023; BioMed Central; BMC
• Subjects: Analysis; Animals; Apoptosis; Bacteria; Bactericidal activity; Biosynthesis; Caspase-3; Complications and side effects; Creatinine; Dosage and administration; Endothelial Cells; Enzymes; Feces; Gene expression; Heart diseases; Inflammation; Inflammation - complications; Inflammation - drug therapy; Intensive care units; Kidney diseases; Kinases; Laboratory animals; Leukocytes (neutrophilic); Lipopolysaccharides; Liver diseases; Macrophages; Mice; Microvasculature; Mitochondrial Diseases; Morbidity; Mortality; Multiple organ failure; NAD; Niacinamide; Nicotinamide Mononucleotide - pharmacology; Nicotinamide Mononucleotide - therapeutic use; Oxidative stress; Peritoneum; Permeability; Phagocytosis; Prevention; Proteins; Risk factors; Sepsis; Sepsis - complications; Sepsis - drug therapy; Sirtuin 3; Survival analysis; Vitamin B; Canada; United States > US; China
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-023-04767-3

Sepsis-caused multi-organ failure remains the major cause of morbidity and mortality in intensive care units with limited therapeutics. Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD ), has been recently reported to be protective in sepsis; however, its therapeutic effects remain to be determined. This study sought to investigate the therapeutic effects of NMN in septic organ failure and its underlying mechanisms. Sepsis was induced by feces-injection-in-peritoneum in mice. NMN was given after an hour of sepsis onset. Cultured neutrophils, macrophages and endothelial cells were incubated with various agents. We demonstrate that administration of NMN elevated NAD levels and reduced serum lactate levels, oxidative stress, inflammation, and caspase-3 activity in multiple organs of septic mice, which correlated with the attenuation of heart dysfunction, pulmonary microvascular permeability, liver injury, and kidney dysfunction, leading to lower mortality. The therapeutic effects of NMN were associated with lower bacterial burden in blood, and less ROS production in septic mice. NMN improved bacterial phagocytosis and bactericidal activity of macrophages and neutrophils while reducing the lipopolysaccharides-induced inflammatory response of macrophages. In cultured endothelial cells, NMN mitigated mitochondrial dysfunction, inflammation, apoptosis, and barrier dysfunction induced by septic conditions, all of which were offset by SIRT3 inhibition. NAD repletion with NMN prevents mitochondrial dysfunction and restrains bacterial dissemination while limiting inflammatory damage through SIRT3 signaling in sepsis. Thus, NMN may represent a therapeutic option for sepsis.