NAD+ augmentation ameliorates acute pancreatitis through regulation of inflammasome signalling

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.

Overexpression of CYB5R3 and NQO1, two NAD+‐producing enzymes, mimics aspects of caloric restriction

“…Guarente, 2013]. Overall, our findings are in agreement with the role of CYB5R3 and NQO1 as efficient intracellular generators of NAD + for utilization by sirtuins (Ross & Siegel, 2017; Shen et al., 2017), and are consistent with the notion that modulation of SIRT1 and NAD + levels represents a promising approach for the treatment of age‐associated metabolic diseases (Herranz et al., 2010; Imai, 2010; Verdin, 2015). …”

Polyphyllin VI Induces Caspase-1-Mediated Pyroptosis via the Induction of ROS/NF-κB/NLRP3/GSDMD Signal Axis in Non-Small Cell Lung Cancer

“…Therefore, the ROS/NF-κB signaling pathway plays an important role in the activation of the NLRP3 inflammasome. For the NF-κB signaling pathway in the NLRP3 inflammasome, most researchers found that Acetyl-NF-κB p65 (Lys310) was upregulated and the NF-κB signaling pathway was activated, and ultimately activated the NLRP3 inflammasome [74][75][76][77]. Therefore, the Acetyl-NF-κB p65 (Lys310) antibody, which recognizes the overexpressed levels of the NF-κB p65 protein acetylated at Lys310, was also used in this study.…”

Augmentation of NAD+ levels by enzymatic action of NAD(P)H quinone oxidoreductase 1 attenuates adriamycin-induced cardiac dysfunction in mice

“…In addition, NF-κB activity is regulated via post-translational modifications, namely phosphorylation and acetylation. Current studies have suggested that the incapability of reduced SIRT1 activity to deacetylate the NF-κB subunit p65 at lysine-310 aggravates the inflammatory mediators [12,17,28]. Interestingly, the level of acetylated NF-κB p65 was strongly increased in the cardiac tissue of ADR-treated WT mice compared with control, and this effect was significantly suppressed by dunnione (Fig.…”

“…6E-F). As previously demonstrated, ADR induces the activation of acetylated p53 [29], a key mediator and upstream regulator of miR-34a [28]. Therefore, we assessed whether dunnione reduced ADR-induced acetylation of p53 in the cardiac tissue.…”

“…Accumulating studies prove that miR-34a is a negative regulator of SIRT1 as well as downstream effector of p53 [27]. It has also been reported that p53-mediated miR-34a induction downregulates SIRT1 protein expression and activity in an acute pancreatitis model, but increase in cellular NAD + by NQO1 enzymatic action suppresses acute pancreatitis through modulation of the p53-mediated miR-34a pathway [28]. Therefore, we examined whether dunnione Fig.…”