Apigenin Decreases Acinar Cell Damage in Pancreatitis

Abstract

Objective: Chronic pancreatitis is the consequence of multiple episodes of recurrent acute pancreatitis (RAP). We hypothesized that apigenin can minimize the sequelae of RAP by limiting acinar cells' pro-inflammatory signaling pathways. Methods: AR42J acinar cells were treated in vitro with transforming growth factor beta (TGF-β), apigenin, and other inhibitors. Dual luciferase reporter assay measured parathyroid hormone related protein (PTHrP) promoter activity. MAPK/ERK pathway activity was assessed by immunoblotting and in vivo by immunohistochemistry with a cerulein-induced RAP mouse model. Nuclear factor kappa B (NF-κB) nuclear localization was analyzed in vitro in cells stimulated with tumor necrosis factor alpha (TNF-α). Primary acini were isolated and treated with cerulein; interleukin 6 (IL-6) mRNA were measured comparing PTHrP wild-type and knockout mice. Results: Apigenin and PD98059 each downregulated TGF-β stimulation of PTHrP P3 promoter activity. In a RAP mouse model, apigenin reduced pERK nuclear localization in acinar cells and preserved acinar cell architecture. Apigenin suppressed TNF-α mediated signaling by decreasing NF-κB nuclear localization and decreased IL-6 mRNA levels via a PTHrP-dependent mechanism. Conclusions: Apigenin reduced inflammatory responses in experimental models of RAP. The mechanisms mediating the actions of apigenin, in part, are due to attenuation of PTHrP and TGF-β pro-inflammatory signaling.

Emodin attenuates adenosine triphosphate‑induced pancreatic ductal cell injury in vitro via the inhibition of the P2X7/NLRP3 signaling pathway

“…Thus, pancreatic ductal cells play critical roles in injury in AP. However, previous studies on AP have focused on pancreatic acinar cells (13)(14)(15), while studies on pancreatic ductal cells are limited (7).…”

Identification of Novel Ligands for Targeted Antifibrotic Therapy of Chronic Pancreatitis

“…53 The ability to selectively target multiple different cell types in CP can open a new avenue for therapeutic strategies that address the crosstalk between ECM components and aPSCs, which initiates multiple cascades of events in fibrogenesis and inflammation in CP. 12 , 54 Indeed, we demonstrated that targeting apigenin to the ECM demonstrated enhanced pharmacodynamic effects beyond that of targeting macrophages alone with NP liposomes, underscoring the importance of targeting. Apigenin is a small molecule drug that has been shown to have antifibrotic, anti-inflammatory, and proapoptotic effects in cancer and chronic inflammatory diseases in vitro and in vivo.…”

“…Apigenin is a small molecule natural compound, that has been demonstrated preclinically to have antifibrotic and anti-inflammatory properties in CP. 11 , 12 Apigenin, however, suffers from low aqueous solubility, metabolic instability, and off-target effects and there are no approved clinical applications of apigenin available. 21 , 36 , 37 Therefore, we used apigenin as a proof of concept and directly loaded it into the MDLSLKP-conjugated liposomes (ECM liposome).…”

Tricetin Reduces Inflammation and Acinar Cell Injury in Cerulein-Induced Acute Pancreatitis: The Role of Oxidative Stress-Induced DNA Damage Signaling

“…Flavonoids from most subgroups have been evaluated for potential protective effects in AP. For example, genistein (isoflavone) [ 31 ], quercetin (flavonol) [ 32 ], naringenin (flavanone) [ 33 ], apigenin (flavone) [ 34 ], dihydromyricetin (flavanonol) [ 35 ], luteolin (flavone) [ 36 ], and fisetin (flavonol) [ 37 ] either suppressed inflammation, prevented acinar cell damage, or both [ 38 , 39 ]. Tricetin (TCT) ( Supplementary Figure S1B ) is a flavone compound with likely or proven bioactivity in models of neurotoxicity, Parkinson’s disease [ 40 ], diabetes [ 41 , 42 ], and bacterial infections [ 43 ].…”