Abstract
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.
Highlights
Acute pancreatitis (AP) is a complicated disease without specific drug therapy
We observed a significant increase in NOD-like receptor pyrin domain containing 3 (NLRP3) and a caspase recruitment domain (ASC) mRNA and protein expression in pancreatic tissues of caerulein-treated mice compared with saline-injected control mice. β-Lap treatment significantly and dose-dependently lowered the expression of these inflammasome components in AP (Fig. 2C and D)
We demonstrated the impact of NAD+ metabolism on a caerulein-induced AP model
Summary
The cofactor nicotinamide adenine dinucleotide (NAD+) is an important regulator of cellular metabolism and homeostasis It remains unclear whether modulation of NAD+ levels has an impact on caerulein-induced AP. We confirmed that the increase of cellular NAD+ by NQO1 enzymatic action using the substrate β-Lapachone suppressed caerulein-induced AP with down-regulating TLR4mediated 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. Recent studies suggest that the inflammasome links pancreatic acinar cell death to inflammation[5, 6]
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