RESUMO
Doxorubicin (DOX) is a powerful and commonly used chemotherapeutic drug, used alone or in combination in a variety of cancers, while it has been found to cause serious cardiac side effects in clinical application. More and more researchers are trying to explore the molecular mechanisms of DOX-induced cardiomyopathy (DIC), in which oxidative stress and inflammation are considered to play a significant role. This review summarizes signaling pathways related to oxidative stress and inflammation in DIC and compounds that exert cardioprotective effects by acting on relevant signaling pathways, including the role of Nrf2/Keap1/ARE, Sirt1/p66Shc, Sirt1/PPAR/PGC-1α signaling pathways and NOS, NOX, Fe2+ signaling in oxidative stress, as well as the role of NLRP3/caspase-1/GSDMD, HMGB1/TLR4/MAPKs/NF-κB, mTOR/TFEB/NF-κB pathways in DOX-induced inflammation. Hence, we attempt to explain the mechanisms of DIC in terms of oxidative stress and inflammation, and to provide a theoretical basis or new idea for further drug research on reducing DIC. Video Abstract.
Assuntos
Cardiomiopatias , NF-kappa B , Humanos , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismo , NF-kappa B/metabolismo , Sirtuína 1/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Transdução de Sinais , Cardiomiopatias/induzido quimicamente , Doxorrubicina/efeitos adversos , Inflamação/induzido quimicamenteRESUMO
AMP-activated protein kinase (5'-adenosine monophosphate-activated protein kinase, AMPK)/mammalian target of rapamycin (mTOR) is an important signaling pathway maintaining normal cell function and homeostasis in vivo. The AMPK/mTOR pathway regulates cellular proliferation, autophagy, and apoptosis. Ischemia-reperfusion injury (IRI) is secondary damage that frequently occurs clinically in various disease processes and treatments, and the exacerbated injury during tissue reperfusion increases disease-associated morbidity and mortality. IRI arises from multiple complex pathological mechanisms, among which cell autophagy is a focus of recent research and a new therapeutic target. The activation of AMPK/mTOR signaling in IRI can modulate cellular metabolism and regulate cell proliferation and immune cell differentiation by adjusting gene transcription and protein synthesis. Thus, the AMPK/mTOR signaling pathway has been intensively investigated in studies focused on IRI prevention and treatment. In recent years, AMPK/mTOR pathway-mediated autophagy has been found to play a crucial role in IRI treatment. This article aims to elaborate the action mechanisms of AMPK/mTOR signaling pathway activation in IRI and summarize the progress of AMPK/mTOR-mediated autophagy research in the field of IRI therapy.