Abstract
Severe acute pancreatitis (SAP) is a common and life-threatening clinical acute abdominal disease. C1q/tumor necrosis factor-related protein 3 (CTRP3), a novel paralog of adiponectin, has been identified as a crucial regulator in multiple types of inflammatory disorders. However, the biological role of CTRP3 in SAP remains poorly understood. The present study aimed to characterize the role of CTRP3 in SAP and illuminate the potential mechanisms involved. In the current study, SAP mouse models were induced by seven hourly intraperitoneal injection of cerulein (50 μg/kg) and an immediate intraperitoneal injection of lipopolysaccharide (10 mg/kg) after the last cerulein administration. Histological examination and serological analysis demonstrated that SAP mouse models were successfully established. Herein, we found that CTRP3 expression was significantly decreased in the pancreatic tissues of SAP mice compared with normal control mice. Furthermore, we explored the effects of CTRP3 rescue in SAP mice and discovered that CTRP3 overexpression attenuated pathological lesions, inhibited inflammatory mediator release and repressed acinar cell apoptosis. Notably, mechanistic studies revealed that CTRP3 overexpression suppressed NF-κB p65 phosphorylation and p53 acetylation to alleviate cerulein-induced SAP in mouse models through activation of silent information regulator 1 (SIRT1), a nicotinamide adenine dinucleotide-dependent protein deacetylase. Collectively, our data indicate that CTRP3 may exert its protective effects in SAP mice via regulation of SIRT1-mediated NF-κB and p53 signaling pathways, implying a promising therapeutic strategy against SAP.
Highlights
Acute pancreatitis (AP) is a common acute clinical abdominal disorder that is characterized by acinar cell necrosis and abnormal inflammatory response [1,2,3]
A notable increase in tumor necrosis factor α (TNFα), IL-1β, IL-6 and nitric oxide (NO) levels was found in the serum and pancreatic tissues of Severe AP (SAP) mice in comparison with normal control mice (Figure 1D,E)
Western blotting analysis demonstrated a significant increase in the phosphorylation of NF-κB p65 and acetylation of p53 in the pancreas of SAP mice compared with normal control mice
Summary
Acute pancreatitis (AP) is a common acute clinical abdominal disorder that is characterized by acinar cell necrosis and abnormal inflammatory response [1,2,3]. It is estimated that approximately 250000 patients are diagnosed with AP in the United States annually [4,5]. The incidence of AP in the U.K. is reported to be approximately 30 per 100000 per annum, which is linked to gallstones and excessive alcohol consumption to some extent [6,7,8]. It is well documented that SAP is characterized by a rapid onset and a high mortality [11,12]. Despite the fact that great progress has been achieved regarding the diagnosis and management of SAP, its mortality rate has not declined significantly over the past several decades. It is of critical importance to unveil the potential molecular mechanisms underlying SAP development and develop effective therapeutic strategies for SAP patients
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