Protective Effects of Necrostatin-1 in Acute Pancreatitis: Partial Involvement of Receptor Interacting Protein Kinase 1.
Protective Effects of Necrostatin-1 in Acute Pancreatitis: Partial Involvement of Receptor Interacting Protein Kinase 1.
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Necrostatin-1在急性胰腺炎中的保护作用：受体相互作用蛋白激酶1的部分参与。
DOI：
10.3390/cells10051035
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发表时间：
2021-04-27
期刊：
影响因子：
6
通讯作者：
Criddle DN
中科院分区：
文献类型：
--
作者：
Ouyang Y;Wen L;Armstrong JA;Chvanov M;Latawiec D;Cai W;Awais M;Mukherjee R;Huang W;Gough PJ;Bertin J;Tepikin AV;Sutton R;Criddle DN
急性胰腺炎（AP）是一种严重的潜在致命疾病，主要由酒精过量和胆结石引起，缺乏特异性治疗。受体相互作用蛋白激酶1 （RIPK1）是程序性坏死（坏死性坏死）的关键组成部分，其在AP中的作用尚不清楚。我们评估了RIPK1抑制剂Necrostatin-1 （Nec-1）和RIPK1修饰（RIPK1K45A：激酶死亡）在胆酸（TLCS-AP）、酒精（FAEE-AP）和小糖蛋白过度刺激（er -AP）小鼠模型中的作用。用抑制剂Epacadostat （EPA）探讨了侧支Nec-1靶点吲哚胺2,3-双加氧酶（IDO）的作用。我们还比较了Nec-1和RIPK1K45A在体外对胰腺腺泡细胞（PAC）命运的影响，并探讨了潜在的机制。Nec-1显著改善了所有模型的组织学和生化变化。然而，在RIPK1K45A小鼠中，这些仅部分减少或保持不变。用EPA抑制IDO对TLCS-AP具有保护作用。Nec-1和RIPK1K45A修饰均能抑制TLCS和faee诱导的PAC坏死。Nec-1不影响tlcs诱导的PACs中Ca2+的进入，然而，它抑制了相关的ROS升高。结果表明，Nec-1在多种模型中均有保护作用。然而，ripk1依赖性坏死性上睑下垂仅部分促成了有益效果，对IDO等靶标的作用可能很重要。
Acute pancreatitis (AP) is a severe and potentially fatal disease caused predominantly by alcohol excess and gallstones, which lacks a specific therapy. The role of Receptor-Interacting Protein Kinase 1 (RIPK1), a key component of programmed necrosis (Necroptosis), is unclear in AP. We assessed the effects of RIPK1 inhibitor Necrostatin-1 (Nec-1) and RIPK1 modification (RIPK1K45A: kinase dead) in bile acid (TLCS-AP), alcoholic (FAEE-AP) and caerulein hyperstimulation (CER-AP) mouse models. Involvement of collateral Nec-1 target indoleamine 2,3-dioxygenase (IDO) was probed with the inhibitor Epacadostat (EPA). Effects of Nec-1 and RIPK1K45A were also compared on pancreatic acinar cell (PAC) fate in vitro and underlying mechanisms explored. Nec-1 markedly ameliorated histological and biochemical changes in all models. However, these were only partially reduced or unchanged in RIPK1K45A mice. Inhibition of IDO with EPA was protective in TLCS-AP. Both Nec-1 and RIPK1K45A modification inhibited TLCS- and FAEE-induced PAC necrosis in vitro. Nec-1 did not affect TLCS-induced Ca2+ entry in PACs, however, it inhibited an associated ROS elevation. The results demonstrate protective actions of Nec-1 in multiple models. However, RIPK1-dependent necroptosis only partially contributed to beneficial effects, and actions on targets such as IDO are likely to be important.
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影响因子：
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作者：
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