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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 ?-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.

SUBMITTER: Shen A

PROVIDER: S-EPMC5462749 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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NAD+ augmentation ameliorates acute pancreatitis through regulation of inflammasome signalling.

Shen AiHua A Kim Hyung-Jin HJ Oh Gi-Su GS Lee Su-Bin SB Lee Seung Hoon SH Pandit Arpana A Khadka Dipendra D Choe Seong-Kyu SK Kwak Sung Chul SC Yang Sei-Hoon SH Cho Eun-Young EY Kim Hyun-Seok HS Kim Hail H Park Raekil R Kwak Tae Hwan TH So Hong-Seob HS

Scientific reports 20170607 1

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 ...[more]

PMID: 28592850

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Project description:Kaempferol (KA), an natural antioxidant of traditional Chinese medicine (TCM), is extensively used as the primary treatment for inflammatory digestive diseases with impaired redox homeostasis. Severe acute pancreatitis (SAP) was exacerbated by mitochondrial dysfunction and abundant ROS, which highlights the role of antioxidants in targeting mitochondrial function. However, low bioavailability and high dosage of KA leading to unavoidable side effects limits clinical transformation. The mechanisms of KA with poor bioavailability largely unexplored, hindering development of the efficient strategies to maximizing the medicinal effects of KA. Here, we engineered a novel thioketals (TK)-modified based on DSPE-PEG2000 liposomal codelivery system for improving bioavailability and avoiding side effects (denotes as DSPE-TK-PEG2000-KA, DTM@KA NPs). We demonstrated that the liposome exerts profound impacts on damaging intracellular redox homeostasis by reducing GSH depletion and activating Nrf2, which synergizes with KA to reinforce the inhibition of inadequate fission, excessive mitochondrial fusion and impaired mitophagy resulting in inflammation and apoptosis; and then, the restored mitochondrial homeostasis strengthens ATP supply for PAC renovation and homeostasis. Interestingly, TK bond was proved as the main functional structure to improve the above efficacy of KA compared with the absence of TK bond. Most importantly, DTM@KA NPs obviously suppresses PAC death with negligible side effects in vitro and vivo. Mechanismly, DTM@KA NPs facilitated STAT6-regulated mitochondrial precursor proteins transport via interacting with TOM20 to further promote Drp1-dependent fission and Pink1/Parkin-regulated mitophagy with enhanced lysosomal degradation for removing damaged mitochondria in PAC and then reduce inflammation and apoptosis. Generally, DTM@KA NPs synergistically improved mitochondrial homeostasis, redox homeostasis, energy metabolism and inflammation response via regulating TOM20-STAT6-Drp1 signaling and promoting mitophagy in SAP. Consequently, such a TCM's active ingredients-based nanomedicine strategy is be expected to be an innovative approach for SAP therapy.

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NAD⁺ augmentation ameliorates acute pancreatitis through regulation of inflammasome signalling.

Publications

NAD<sup>+</sup> augmentation ameliorates acute pancreatitis through regulation of inflammasome signalling.

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