瓦尔堡效应发生在癌细胞和炎症巨噬细胞中。我们工作的目的是证明 PI3K-Akt-mTOR 轴在 HL-60 衍生的大鼠腹膜和人血液巨噬细胞的 Warburg 效应中的作用，并研究该途径的选定抑制剂拮抗该效应的潜力。 NOS2 和炎症细胞因子表达增加支持 HL-60 来源和人血单核细胞来源的巨噬细胞中的 M1 极化。研究的所有 M1 极化和炎症巨噬细胞均表达较高水平的 HIF-1α 和 NOS2，这些水平可被选定的激酶抑制剂降低，支持 PI3K-Akt-mTOR 轴的作用。使用 Seahorse XF 板，我们发现在 HL-60 来源和人血液来源的巨噬细胞中，葡萄糖负荷降低了 M1 极化中的耗氧量 (OCR) 并增加了糖酵解 (ECAR)，而选定的激酶抑制剂和二氯乙酸可拮抗这一作用。在大鼠腹腔巨噬细胞中，氧化和糖酵解代谢的变化不太明显，NOS2抑制剂降低了OCR并增加了ECAR。非线粒体耗氧量和 ROS 产生可能是由于 NADPH 氧化酶所致，该酶在每种巨噬细胞类型中表达，与 PI3K-Akt-mTOR 轴无关。我们的结果表明，炎症改变了每个巨噬细胞模型的代谢，但只有在 HL-60 和人血来源的巨噬细胞中葡萄糖负荷后，极化和 Warburg 效应之间的明确关系才得到证实。激酶抑制剂对 Warburg 效应的影响在不同的细胞类型中是不同的，而二氯乙酸盐则导致氧化代谢的转变。我们的研究结果表明，这些最初的抗癌抑制剂也可能是抗炎治疗的候选药物。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

The Warburg effect occurs both in cancer cells and in inflammatory macrophages. The aim of our work was to demonstrate the role of PI3K-Akt-mTOR axis in the Warburg effect in HL-60 derived, rat peritoneal and human blood macrophages and to investigate the potential of selected inhibitors of this pathway to antagonize it. M1 polarization in HL-60-derived and human blood monocyte-derived macrophages was supported by the increased expression of NOS2 and inflammatory cytokines. All M1 polarized and inflammatory macrophages investigated expressed higher levels of HIF-1α and NOS2, which were reduced by selected kinase inhibitors, supporting the role of PI3K-Akt-mTOR axis. Using Seahorse XF plates, we found that in HL-60-derived and human blood-derived macrophages, glucose loading reduced oxygen consumption (OCR) and increased glycolysis (ECAR) in M1 polarization, which was antagonized by selected kinase inhibitors and by dichloroacetate. In rat peritoneal macrophages, the changes in oxidative and glycolytic metabolism were less marked and the NOS2 inhibitor decreased OCR and increased ECAR. Non-mitochondrial oxygen consumption and ROS production were likely due to NADPH oxidase, expressed in each macrophage type, independently of PI3K-Akt-mTOR axis. Our results suggest that inflammation changed the metabolism in each macrophage model, but a clear relationship between polarization and Warburg effect was confirmed only after glucose loading in HL-60 and human blood derived macrophages. The effect of kinase inhibitors on Warburg effect was variable in different cell types, whereas dichloroacetate caused a shift toward oxidative metabolism. Our findings suggest that these originally anti-cancer inhibitors may also be candidates for anti-inflammatory therapy.Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.