Isoliquiritigenin Protects Against Pancreatic Injury and Intestinal Dysfunction After Severe Acute Pancreatitis via Nrf2 Signaling

Background Intracerebral hemorrhage (ICH) induces potently oxidative stress responses and inflammatory processes. Isoliquiritigenin (ILG) is a flavonoid with a chalcone structure and can activate nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated antioxidant system, negatively regulate nuclear factor-κB (NF-κB) and nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathways, but its role and potential molecular mechanisms in the pathology following ICH remain unclear. The present study aimed to explore the effects of ILG after ICH and underlying mechanisms. Methods ICH model was induced by collagenase IV (0.2 U in 1 μl sterile normal saline) in male Sprague-Dawley rats weighing 280–320 g. Different doses of ILG (10, 20, or 40 mg/kg) was administrated intraperitoneally at 30 min, 12 h, 24 h, and 48 h after modeling, respectively. Rats were intracerebroventricularly administrated with control scramble small interfering RNA (siRNA) or Nrf2 siRNA at 24 h before ICH induction, and after 24 h, ICH model was established with or without ILG (20 mg/kg) treatment. All rats were dedicated at 24 or 72 h after ICH. Neurological deficits, histological damages, brain water content (BWC), blood-brain barrier (BBB) disruption, and neuronal degeneration were evaluated; quantitative real-time RT-PCR (qRT-PCR), immunohistochemistry/immunofluorescence, western blot, and enzyme-linked immunosorbent assay (ELISA) were carried out; catalase, superoxide dismutase activities and reactive oxygen species (ROS), and glutathione/oxidized glutathione contents were measured. Results ILG (20 and 40 mg/kg) markedly alleviated neurological deficits, histological damages, BBB disruption, brain edema, and neuronal degeneration, but there was no significant difference between two dosages. ILG (20 mg/kg) significantly suppressed the NF-κB and NLRP3 inflammasome pathways and activated Nrf2-mediated antioxidant system. Gene silencing of Nrf2 aggravated the neurological deficits, brain edema, and neuronal degeneration and increased the protein levels of NF-κB p65, NLRP3 inflammasome components, and IL-1β. ILG delivery significantly attenuated the effects of Nrf2 siRNA interference mentioned above. Conclusions Intraperitoneal administration of ILG after ICH reduced early brain impairments and neurological deficits, and the mechanisms were involved in the regulation of ROS and/or NF-κB on the activation of NLRP3 inflammasome pathway by the triggering of Nrf2 activity and Nrf2-induced antioxidant system. In addition, our experimental results may make ILG a potential candidate for a novel therapeutical strategy for ICH. Electronic supplementary material The online version of this article (doi:10.1186/s12974-017-0895-5) contains supplementary material, which is available to authorized users.

Severe acute pancreatitis (SAP), which is the most serious type of this disorder, is associated with high morbidity and mortality. SAP runs a biphasic course. During the first 1-2 wk, a pro-inflammatory response results in systemic inflammatory response syndrome (SIRS). If the SIRS is severe, it can lead to early multisystem organ failure (MOF). After the first 1-2 wk, a transition from a pro-inflammatory response to an anti-inflammatory response occurs; during this transition, the patient is at risk for intestinal flora translocation and the development of secondary infection of the necrotic tissue, which can result in sepsis and late MOF. Many recommendations have been made regarding SAP management and its complications. However, despite the reduction in overall mortality in the last decade, SAP is still associated with high mortality. In the majority of cases, sterile necrosis should be managed conservatively, whereas in infected necrotizing pancreatitis, the infected non-vital solid tissue should be removed to control the sepsis. Intervention should be delayed for as long as possible to allow better demarcation and liquefaction of the necrosis. Currently, the step-up approach (delay, drain, and debride) may be considered as the reference standard intervention for this disorder.

Inflammation and autophagy are cellular defense mechanisms. When these processes are deregulated (deficient or overactivated) they produce pathologic effects, such as oxidative stress, metabolic impairments, and cell death. Unresolved inflammation and disrupted regulation of autophagy are common features of pancreatitis and pancreatic cancer. Furthermore, obesity, a risk factor for pancreatitis and pancreatic cancer, promotes inflammation and inhibits or deregulates autophagy, creating an environment that facilitates the induction and progression of pancreatic diseases. However, little is known about how inflammation, autophagy, and obesity interact to promote exocrine pancreatic disorders. We review the roles of inflammation and autophagy, and their deregulation by obesity, in pancreatic diseases. We discuss the connections among disordered pathways and important areas for future research. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.