Dataset Information

Pharmacological stimulation of NQO1 decreases NADPH levels and ameliorates acute pancreatitis in mice.

ABSTRACT: Reactive oxygen species (ROS) regulates the activation of inflammatory cascades and tissue damage in acute pancreatitis. NADPH oxidase (NOX) is upregulated in pancreatitis and is one of the major enzymes involved in ROS production using NADPH as a general rate-limiting substrate. Dunnione, a well-known substrate of NAD(P)H:quinone oxidoreductase 1 (NQO1), reduces the ratio of cellular NADPH/NADP⁺ through the enzymatic action of NQO1. This study assessed whether a reduction in cellular NADPH/NADP⁺ ratio can be used to regulate caerulein-induced pancreatic damage associated with NOX-induced ROS production in animal models. Dunnione treatment significantly reduced the cellular NADPH/NADP⁺ ratio and NOX activity through the enzymatic action of NQO1 in the pancreas of the caerulein-injection group. Similar to these results, total ROS production and expressions of mRNA and protein for NOX subunits Nox1, p27^phox, p47^phox, and p67^phox also decreased in the dunnione-treated group. In addition, caerulein-induced pancreatic inflammation and acinar cell injury were significantly reduced by dunnione treatment. This study is the first to demonstrate that modulation of the cellular NADPH:NADP⁺ ratio by enzymatic action of NQO1 protects acute pancreatitis through the regulation of NOX activity. Furthermore, these results suggest that modulation of the NADPH:NADP⁺ ratio in cells by NQO1 may be a novel therapeutic strategy for acute pancreatitis.

SUBMITTER: Shen A

PROVIDER: S-EPMC6315021 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pharmacological stimulation of NQO1 decreases NADPH levels and ameliorates acute pancreatitis in mice.

Shen AiHua A Kim Hyung-Jin HJ Oh Gi-Su GS Lee Su-Bin SB Lee SeungHoon S Pandit Arpana A Khadka Dipendra D Sharma Subham S Kim Seon Young SY Choe Seong-Kyu SK Yang Sei-Hoon SH Cho Eun-Young EY Shim Hyuk H Park Raekil R Kwak Tae Hwan TH So Hong-Seob HS

Cell death & disease 20181218 1

Reactive oxygen species (ROS) regulates the activation of inflammatory cascades and tissue damage in acute pancreatitis. NADPH oxidase (NOX) is upregulated in pancreatitis and is one of the major enzymes involved in ROS production using NADPH as a general rate-limiting substrate. Dunnione, a well-known substrate of NAD(P)H:quinone oxidoreductase 1 (NQO1), reduces the ratio of cellular NADPH/NADP<sup>+</sup> through the enzymatic action of NQO1. This study assessed whether a reduction in cellular ...[more]

PMID: 30584237

Similar Datasets

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.

Project description:To study the safety of epidural anesthesia (EA), its effect on pancreatic perfusion and the outcome of patients with acute pancreatitis (AP).From 2005 to August 2010, patients with predicted severe AP [Ranson score ? 2, C-reactive protein > 100 or necrosis on computed tomography (CT)] were prospectively randomized to either a group receiving EA or a control group treated by patient controlled intravenous analgesia. Pain management was evaluated in the two groups every eight hours using the visual analog pain scale (VAS). Parameters for clinical severity such as length of hospital stay, use of antibiotics, admission to the intensive care unit, radiological/clinical complications and the need for surgical necrosectomy including biochemical data were recorded. A CT scan using a perfusion protocol was performed on admission and at 72 h to evaluate pancreatic blood flow. A significant variation in blood flow was defined as a 20% difference in pancreatic perfusion between admission and 72 h and was measured in the head, body and tail of the pancreas.We enrolled 35 patients. Thirteen were randomized to the EA group and 22 to the control group. There were no differences in demographic characteristics between the two groups. The Balthazar radiological severity score on admission was higher in the EA group than in the control group (mean score 4.15 ± 2.54 vs 3.38 ± 1.75, respectively, P = 0.347) and the median Ranson scores were 3.4 and 2.7 respectively (P = NS). The median duration of EA was 5.7 d, and no complications of the epidural procedure were reported. An improvement in perfusion of the pancreas was observed in 13/30 (43%) of measurements in the EA group vs 2/27 (7%) in the control group (P = 0.0025). Necrosectomy was performed in 1/13 patients in the EA group vs 4/22 patients in the control group (P = 0.63). The VAS improved during the first ten days in the EA group compared to the control group (0.2 vs 2.33, P = 0.034 at 10 d). Length of stay and mortality were not statistically different between the 2 groups (26 d vs 30 d, P = 0.65, and 0% for both respectively).Our study demonstrates that EA increases arterial perfusion of the pancreas and improves the clinical outcome of patients with AP.

Dataset Information

Pharmacological stimulation of NQO1 decreases NADPH levels and ameliorates acute pancreatitis in mice.

Publications

Pharmacological stimulation of NQO1 decreases NADPH levels and ameliorates acute pancreatitis in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets