Pinocembrin's protective effect against acute pancreatitis in a rat model: The correlation between TLR4/NF-κB/NLRP3 and miR-34a-5p/SIRT1/Nrf2/HO-1 pathways

Biomed Pharmacother. 2024 Jul:176:116854. doi: 10.1016/j.biopha.2024.116854. Epub 2024 Jun 1.

Abstract

Background: Acute pancreatitis (APS) is a prevalent acute pancreatic inflammation, where oxidative stress, inflammatory signaling pathways, and apoptosis activation contribute to pancreatic injury.

Methods: Pinocembrin, the predominant flavonoid in propolis, was explored for its likely shielding effect against APS provoked by two intraperitoneal doses of L-arginine (250 mg / 100 g) in a rat model.

Results: Pinocembrin ameliorated the histological and immunohistochemical changes in pancreatic tissues and lowered the activities of pancreatic amylase and lipase that were markedly elevated with L-arginine administration. Moreover, pinocembrin reinstated the oxidant/antioxidant equilibrium, which was perturbed by L-arginine, and boosted the pancreatic levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Pinocembrin markedly reduced the elevation in serum C-reactive protein (CRP) level induced by L-arginine. Additionally, it decreased the expression of high motility group box protein 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and NOD-like receptor (NLR) Family Pyrin Domain Containing 3 (NLRP3) inflammasome in the pancreas. Furthermore, it also reduced myeloperoxidase (MPO) activity. Pinocembrin markedly downregulated miR-34a-5p expression and upregulated the protein levels of peroxisome proliferator-activated receptor alpha (PPAR-α) and Sirtuin 1 (SIRT1) and the gene expression level of the inhibitor protein of NF-κB (IκB-α), along with normalizing the Bax/Bcl-2 ratio.

Conclusions: Pinocembrin notably improved L-arginine-induced APS by its antioxidant, anti-inflammatory, and anti-apoptotic activities. Pinocembrin exhibited a protective role in APS by suppressing inflammatory signaling via the TLR4/NF-κB/NLRP3 pathway and enhancing cytoprotective signaling via the miR-34a-5p/SIRT1/Nrf2/HO-1 pathway.

Keywords: Cytoprotective signaling; HMGB1; Inflammation; PPAR-α; Pancreatitis; Pinocembrin.

MeSH terms

  • Acute Disease
  • Animals
  • Antioxidants / pharmacology
  • Arginine / pharmacology
  • Disease Models, Animal*
  • Flavanones* / pharmacology
  • Heme Oxygenase (Decyclizing)* / metabolism
  • Male
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • NF-E2-Related Factor 2* / metabolism
  • NF-kappa B* / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • Oxidative Stress / drug effects
  • Pancreas / drug effects
  • Pancreas / metabolism
  • Pancreas / pathology
  • Pancreatitis* / chemically induced
  • Pancreatitis* / drug therapy
  • Pancreatitis* / metabolism
  • Pancreatitis* / pathology
  • Pancreatitis* / prevention & control
  • Rats
  • Rats, Sprague-Dawley*
  • Signal Transduction* / drug effects
  • Sirtuin 1* / metabolism
  • Toll-Like Receptor 4* / metabolism

Substances

  • Sirtuin 1
  • NF-kappa B
  • Toll-Like Receptor 4
  • pinocembrin
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • MicroRNAs
  • Tlr4 protein, rat
  • Flavanones
  • Nfe2l2 protein, rat
  • Sirt1 protein, rat
  • Heme Oxygenase (Decyclizing)
  • NF-E2-Related Factor 2
  • Hmox1 protein, rat
  • MIRN34 microRNA, rat
  • Nlrp3 protein, rat
  • Arginine
  • Antioxidants