Abstract：
Cathepsin B (CTSB) and inflammatory cytokines are critical in initiating and developing pancreatitis. Calcineurin, a central calcium (Ca2+)-responsive signaling molecule, mediates acinar cell death and inflammatory responses leading to pancreatitis. However, the detailed mechanisms for regulating CTSB activity and inflammatory cytokine production are unknown. Myricetin (MC) exhibits various biological activities, including anti-inflammatory effects. Here, we aimed to investigate MC effects on pancreatitis and the underlying mechanisms. Prophylactic and therapeutic MC treatment ameliorated the severity of cerulein-, L-arginine-, and PDL-induced acute pancreatitis (AP). The inhibition of CTSB activity by MC was mediated via decreased calcineurin activity and macrophage infiltration, not neutrophils infiltration, into the pancreas. Additionally, calcineurin activity inhibition by MC prevented the phosphorylation of Ca2+/CaM-dependent protein kinase kinase 2 (CaMKK2) during AP, resulting in the inhibition of CaMKIV phosphorylation and adenosine monophosphate-activated protein kinase (AMPK) dephosphorylation. Furthermore, MC reduced nuclear factor-κB activation by modulating the calcineurin-CaMKIV-IKKα/β-Iκ-Bα and calcineurin-AMPK-sirtuin1 axes, resulting in reduced production of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. Our results showed that MC alleviated AP severity by inhibiting acinar cell death and inflammatory responses, suggesting that MC as a calcineurin and CaMKK2 signaling modulator may be a potential treatment for AP.
摘要：
组织蛋白酶B（CTSB）和炎性细胞因子在胰腺炎的发生和发展中至关重要。钙调磷酸酶,中央钙（Ca2+）响应信号分子，介导腺泡细胞死亡和炎症反应导致胰腺炎。然而,调节CTSB活性和炎性细胞因子产生的详细机制尚不清楚.杨梅素(MC)具有多种生物活性,包括抗炎作用。这里,我们旨在研究MC对胰腺炎的影响及其潜在机制.预防性和治疗性MC治疗改善了cerulein-的严重程度，L-精氨酸-,和PDL诱导的急性胰腺炎（AP）。MC对CTSB活性的抑制是通过降低钙调磷酸酶活性和巨噬细胞浸润来介导的，不是中性粒细胞浸润,进入胰腺。此外,MC抑制钙调磷酸酶活性阻止了AP期间Ca2/CaM依赖性蛋白激酶激酶2（CaMKK2）的磷酸化，导致CaMKIV磷酸化和腺苷一磷酸活化蛋白激酶（AMPK）去磷酸化的抑制。此外，MC通过调节钙调磷酸酶-CaMKIV-IKKα/β-Iκ-Bα和钙调磷酸酶-AMPK-sirtuin1轴来减少核因子-κB的激活，导致肿瘤坏死因子-α的产生减少，白细胞介素（IL）-1β，IL-6我们的结果表明，MC通过抑制腺泡细胞死亡和炎症反应来减轻AP的严重程度，提示MC作为钙调磷酸酶和CaMKK2信号调节因子可能是AP的潜在治疗方法。
