Zhang Xiao, Tian Bing, Deng Qin, Cao Jian, Ding Xionghui, Liu Qingshuang, Zhang Yunfei, Ye Cuilian, Deng Chun, Qiu Lin, Guo Chunbao
Department of General and Neonatal Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Burn, Children's Hospital of Chongqing Medical University, Chongqing, China; National Clinical Research Center for Child Health and Disorders, Chongqing, China; Key Laboratory of Children's Development and Disorders, Ministry of Education, Chongqing, China; National International Science and Technology Cooperation Base for Development and Critical Disorders in Children, Chongqing, China; Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China.
Department of Pediatrics, Yongchuan Hospital, Chongqing Medical University, Chongqing, 400054, China; National Clinical Research Center for Child Health and Disorders, Chongqing, China; Key Laboratory of Children's Development and Disorders, Ministry of Education, Chongqing, China; National International Science and Technology Cooperation Base for Development and Critical Disorders in Children, Chongqing, China; Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China.
Free Radic Biol Med. 2022 May 1;184:218-229. doi: 10.1016/j.freeradbiomed.2022.04.008. Epub 2022 Apr 14.
Nicotinamide adenine dinucleotide (NAD+) is involved in regulating oxidative stress. Although NAD+ is associated with various health issues, its role in the intestinal microcirculation in necrotizing enterocolitis (NEC) remains to be confirmed. In the current study, we explored whether nicotinamide riboside (NR), a natural NAD + precursor, ameliorates the severity of NEC through endothelial nitric oxide synthase(eNOS) signaling.
A mouse experimental NEC model was induced by formula gavage and hypoxia in full-term mouse pups. Intestinal endothelial cells (MIMECs) were isolated and subjected to stress using tumor necrosis factor (TNF)-α. NR was administered to assess the intestinal microcirculation and lipid peroxidation levels and to explore the involved signaling pathways.
NAD + levels were reduced after induction of NEC stress, which was associated with intestinal injury. NR administration promoted NAD + levels, attenuated oxidative stress and relieved the symptoms of experimental NEC, which were relevant to increased intestinal microcirculatory perfusion through the sirtuin (SIRT) 1 pathway in experimental NEC mice. However, this improvement was not found in eNOS-knockout mice. Consistently, MIMECs exposed to TNFα showed decreased SIRT1 activity associated with increased eNOS acetylation, which could bring about endothelial dysfunction due to limited nitric oxide production. NR administration increased the NAD + content and repressed the production of reactive oxygen species (ROS) in MIMECs under TNFα stress. NR also promoted SIRT1 activity and accordingly suppressed the eNOS acetylation levels under TNFα stress.
The current data indicate that NR administration improves the survival of experimental NEC mice via SIRT1-associated eNOS acetylation/deacetylation modulation, which is implicated in endothelial dysfunction. Although NR is commonly found in the human diet, it may also be a promising strategy for NEC treatment because of its pathogenic association with NEC.
烟酰胺腺嘌呤二核苷酸（NAD+）参与调节氧化应激。尽管NAD+与多种健康问题相关，但其在坏死性小肠结肠炎（NEC）肠道微循环中的作用仍有待证实。在本研究中，我们探讨了天然NAD+前体烟酰胺核糖（NR）是否通过内皮型一氧化氮合酶（eNOS）信号通路改善NEC的严重程度。
通过对足月幼鼠进行配方灌胃和低氧诱导建立小鼠实验性NEC模型。分离肠道内皮细胞（MIMECs），并用肿瘤坏死因子（TNF）-α对其施加应激。给予NR以评估肠道微循环和脂质过氧化水平，并探索相关的信号通路。
诱导NEC应激后NAD+水平降低，这与肠道损伤相关。给予NR可提高NAD+水平，减轻氧化应激，并缓解实验性NEC的症状，这与通过实验性NEC小鼠的沉默调节蛋白（SIRT）1途径增加肠道微循环灌注有关。然而，在eNOS基因敲除小鼠中未发现这种改善。同样，暴露于TNFα的MIMECs显示SIRT1活性降低，同时eNOS乙酰化增加，这可能由于一氧化氮生成受限而导致内皮功能障碍。给予NR可增加MIMECs在TNFα应激下的NAD+含量并抑制活性氧（ROS）的产生。NR还可促进SIRT1活性，并因此在TNFα应激下抑制eNOS乙酰化水平。
目前的数据表明，给予NR可通过与内皮功能障碍相关的SIRT1介导的eNOS乙酰化/去乙酰化调节来提高实验性NEC小鼠的存活率。尽管NR在人类饮食中普遍存在，但由于其与NEC的发病机制关联，它可能也是一种有前景的NEC治疗策略。
