Betulinic Acid Ameliorates the Severity of Acute Pancreatitis via Inhibition of the NF-κB Signaling Pathway in Mice.

Ziqi Zhou,Sung-Joo Park,Gi-Sang Bae,Dong-Uk Kim,Youn-Chul Kim,Ji-Won Choi,Hyuncheol Oh,Bitna Kweon,Ho-Joon Song,Joon Yeon Shin

doi:10.3390/ijms22136871

Ziqi Zhou, Sung-Joo Park + Show 8 more

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https://doi.org/10.3390/ijms22136871

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Abstract

Acute pancreatitis (AP) is an inflammatory disorder, involving acinar cell death and the release of inflammatory cytokines. Currently, there are limited effective therapeutic agents for AP. Betulinic acid (BA) is a pentacyclic triterpenoid extracted from Betula platyphylla that has been shown to have anti-inflammatory effects. In this study, we aimed to investigate the effects of BA on AP and elucidate the potential underlying mechanisms. AP was induced in mice through six intraperitoneal injections of cerulein. After the last cerulein injection, the mice were sacrificed. Our results revealed that pre- and post-treatment with BA significantly reduced the severity of pancreatitis, as evidenced by a decrease in histological damage in the pancreas and lung, serum amylase and lipase activity and pancreatic myeloperoxidase activity. Furthermore, BA pretreatment reduced proinflammatory cytokine production, augmentation of chemokines, and infiltration of macrophages and neutrophils in the pancreas of AP mice. In addition, mice that were pretreated with BA showed a reduction in Iκ-Bα degradation and nuclear factor-kappa B (NF-κB) binding activity in the pancreas. Moreover, BA reduced the production of proinflammatory cytokines and NF-κB activation in pancreatic acinar cells (PACs). These findings suggest that BA may have prophylactic and therapeutic effects on AP via inhibition of the NF-κB signaling pathway.

Highlights

Acute pancreatitis (AP) is a complex disease, caused by the release of active pancreatic enzymes and the invasion of inflammatory cells [1]
Nuclear factor-κB (NF-κB) heterodimers consist of p50 and RelA in complex with the inhibitory κ-Bα (Iκ-Bα), which sequesters them in the cytoplasm under a steady state [5]
We provided evidence that Betulinic acid (BA) ameliorates the severity of AP in a mouse model with cerulein-induced AP and pancreatic acinar cells (PACs), in addition to elucidating the potential mechanism underlying this effect

Summary

Introduction

Acute pancreatitis (AP) is a complex disease, caused by the release of active pancreatic enzymes and the invasion of inflammatory cells [1]. The pathogenesis of AP remains unclear, pancreatic damage is initiated by acinar cell injury followed by the production of proinflammatory cytokines and mediators, leading to the activation of immune cells [3]. These cells escalate the inflammatory response, resulting in increased damage to the pancreas [4]. Iκ-Bα protein is phosphorylated via activation of the IκB kinase (IKK) complex IKKα/IKKβ, which allows proteasomemediated degradation of Iκ-Bα [6]. Pharmacological inhibition of NF-κB activation would be beneficial for pancreatitis treatment

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