Center for Metabolic Function Regulation & Department of Microbiology, Daejeon, Republic of Korea.
Internal Medicine, School of Medicine Wonkwang University School of Medicine, Iksan, Jeonbuk, 54538, Republic of Korea.
Sci Rep. 2017 Jun 7;7(1):3006. doi: 10.1038/s41598-017-03418-0.
Acute pancreatitis (AP) is a complicated disease without specific drug therapy. The cofactor nicotinamide adenine dinucleotide (NAD) is an important regulator of cellular metabolism and homeostasis. However, it remains unclear whether modulation of NAD levels has an impact on caerulein-induced AP. Therefore, in this study, we investigated the effect of increased cellular NAD levels on caerulein-induced AP. We demonstrated for the first time that the activities and expression of SIRT1 were suppressed by reduction of intracellular NAD levels and the p53-microRNA-34a pathway in caerulein-induced AP. Moreover, we confirmed that the increase of cellular NAD by NQO1 enzymatic action using the substrate β-Lapachone suppressed caerulein-induced AP with down-regulating TLR4-mediated inflammasome signalling, and thereby reducing the inflammatory responses and pancreatic cell death. These results suggest that pharmacological stimulation of NQO1 could be a promising therapeutic strategy to protect against pathological tissue damage in AP.
急性胰腺炎（AP）是一种没有特定药物治疗的复杂疾病。辅酶烟酰胺腺嘌呤二核苷酸（NAD）是细胞代谢和内稳态的重要调节剂。然而，NAD 水平的调节是否对鹅膏蕈碱诱导的 AP 有影响仍不清楚。因此，在这项研究中，我们研究了增加细胞 NAD 水平对鹅膏蕈碱诱导的 AP 的影响。我们首次证明，在鹅膏蕈碱诱导的 AP 中，细胞内 NAD 水平的降低和 p53-微小 RNA-34a 通路抑制了 SIRT1 的活性和表达。此外，我们通过使用底物β-拉帕醌证实了 NQO1 酶促作用增加细胞 NAD，从而抑制了 TLR4 介导的炎症小体信号通路，减轻了炎症反应和胰腺细胞死亡。这些结果表明，药理学刺激 NQO1 可能是一种有前途的治疗策略，可防止 AP 中的病理性组织损伤。
