WGX50 mitigates doxorubicin-induced cardiotoxicity through inhibition of mitochondrial ROS and ferroptosis DOI Creative Commons

Panpan Tai,

Xinyu Chen, Guihua Jia

et al.

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Nov. 17, 2023

Abstract Background Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major impediment to its clinical application. It indispensable explore alternative treatment molecules or drugs for mitigating DIC. WGX50, an organic extract derived from Zanthoxylum bungeanum Maxim, has anti-inflammatory and antioxidant biological activity, however, function mechanism in DIC remain unclear. Methods We established DOX-induced models both vitro vivo. Echocardiography histological analyses were used determine the severity of cardiac injury mice. The myocardial damage markers cTnT, CK-MB, ANP, BNP, ferroptosis associated indicators Fe 2+ , MDA, GPX4 measured using ELISA, RT-qPCR, western blot assays. morphology mitochondria was investigated with transmission electron microscope. levels mitochondrial membrane potential, ROS, lipid ROS detected JC-1, MitoSOX™, C11-BODIPY 581/591 probes. Results Our findings demonstrate that WGX50 protects via restraining ferroptosis. In vivo, effectively relieves doxorubicin-induced dysfunction, injury, fibrosis, damage, redox imbalance. vitro, preserves by reducing level potential increasing ATP production. Furthermore, reduces iron accumulation increases expression, regulates metabolism inhibit Conclusion Taken together, pathway, which provides novel insights as promising drug candidate cardioprotection. Graphic abstract

Language: Английский

Copper homeostasis and cuproptosis in health and disease DOI Creative Commons
Liyun Chen, Junxia Min, Fudi Wang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Nov. 23, 2022

As an essential micronutrient, copper is required for a wide range of physiological processes in virtually all cell types. Because the accumulation intracellular can induce oxidative stress and perturbing cellular function, homeostasis tightly regulated. Recent studies identified novel copper-dependent form death called cuproptosis, which distinct from other known pathways underlying death. Cuproptosis occurs via binding to lipoylated enzymes tricarboxylic acid (TCA) cycle, leads subsequent protein aggregation, proteotoxic stress, ultimately Here, we summarize our current knowledge regarding metabolism, copper-related disease, characteristics mechanisms that regulate cuproptosis. In addition, discuss implications cuproptosis pathogenesis various disease conditions, including Wilson's neurodegenerative diseases, cancer, therapeutic potential targeting

Language: Английский

Citations

751
Inflammation and aging: signaling pathways and intervention therapies DOI Creative Commons
Xia Li, Chentao Li, Wanying Zhang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: June 8, 2023

Abstract Aging is characterized by systemic chronic inflammation, which accompanied cellular senescence, immunosenescence, organ dysfunction, and age-related diseases. Given the multidimensional complexity of aging, there an urgent need for a systematic organization inflammaging through dimensionality reduction. Factors secreted senescent cells, known as senescence-associated secretory phenotype (SASP), promote inflammation can induce senescence in normal cells. At same time, accelerates immune resulting weakened function inability to clear cells inflammatory factors, creates vicious cycle senescence. Persistently elevated levels organs such bone marrow, liver, lungs cannot be eliminated leading damage aging-related Therefore, has been recognized endogenous factor elimination could potential strategy anti-aging. Here we discuss at molecular, cellular, organ, disease levels, review current aging models, implications cutting-edge single cell technologies, well anti-aging strategies. Since preventing alleviating diseases improving overall quality life are ultimate goals research, our highlights critical features mechanisms along with latest developments future directions providing theoretical foundation novel practical

Language: Английский

Citations

524
Targeting ferroptosis opens new avenues for the development of novel therapeutics DOI Creative Commons

Shumin Sun,

Jie Shen, Jianwei Jiang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 21, 2023

Abstract Ferroptosis is an iron-dependent form of regulated cell death with distinct characteristics, including altered iron homeostasis, reduced defense against oxidative stress, and abnormal lipid peroxidation. Recent studies have provided compelling evidence supporting the notion that ferroptosis plays a key pathogenic role in many diseases such as various cancer types, neurodegenerative disease, involving tissue and/or organ injury, inflammatory infectious diseases. Although precise regulatory networks underlie are largely unknown, particularly respect to initiation progression diseases, recognized bona fide target for further development treatment prevention strategies. Over past decade, considerable progress has been made developing pharmacological agonists antagonists these ferroptosis-related conditions. Here, we provide detailed overview our current knowledge regarding ferroptosis, its pathological roles, regulation during disease progression. Focusing on use chemical tools preclinical studies, also summarize recent advances targeting across growing spectrum ferroptosis-associated Finally, discuss new challenges opportunities potential strategy treating

Language: Английский

Citations

235
Alox15/15-HpETE Aggravates Myocardial Ischemia-Reperfusion Injury by Promoting Cardiomyocyte Ferroptosis DOI Open Access
Wenbin Cai, Le Liu,

Xuelian Shi

et al.

Circulation, Journal Year: 2023, Volume and Issue: 147(19), P. 1444 - 1460

Published: March 29, 2023

Myocardial ischemia-reperfusion (I/R) injury causes cardiac dysfunction to myocardial cell loss and fibrosis. Prevention of death is important protect function after I/R injury. The process reperfusion can lead multiple types cardiomyocyte death, including necrosis, apoptosis, autophagy, ferroptosis. However, the time point at which various modes occur mechanisms underlying ferroptosis regulation in cardiomyocytes are still unclear.Using a left anterior descending coronary artery ligation mouse model, we sought investigate To discover key molecules involved ferroptosis, performed metabolomics study. Loss/gain-of-function approaches were used understand role 15-lipoxygenase (Alox15) peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α) injury.We found that apoptosis necrosis occurred early phase injury, was predominant form during prolonged reperfusion. Metabolomic profiling eicosanoids revealed Alox15 metabolites accumulated ferroptotic cardiomyocytes. We demonstrated expression specifically increased injured area ventricle below suture colocalized with Furthermore, myocardial-specific knockout mice alleviated restored function. 15-Hydroperoxyeicosatetraenoic acid (15-HpETE), an intermediate metabolite derived from arachidonic by Alox15, identified as trigger for explored mechanism its effects 15-HpETE promoted binding Pgc1α ubiquitin ligase ring finger protein 34, leading ubiquitin-dependent degradation. Consequently, attenuated mitochondrial biogenesis abnormal morphology observed. ML351, specific inhibitor level Pgc1α, inhibited protected myocardium, caused recovery.Together, our results established Alox15/15-HpETE-mediated plays

Language: Английский

Citations

179
Ferroptotic mechanisms and therapeutic targeting of iron metabolism and lipid peroxidation in the kidney DOI
Hülya Bayır, Scott J. Dixon, Yulia Y. Tyurina

et al.

Nature Reviews Nephrology, Journal Year: 2023, Volume and Issue: 19(5), P. 315 - 336

Published: March 15, 2023

Language: Английский

Citations

161
SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism DOI Open Access
Milton Packer

Nature Reviews Cardiology, Journal Year: 2023, Volume and Issue: 20(7), P. 443 - 462

Published: Jan. 6, 2023

Language: Английский

Citations

103
Molecular Mechanisms of Ferroptosis and Relevance to Cardiovascular Disease DOI Creative Commons
Lai‐Hua Xie, Nadezhda Fefelova,

Sri Harika Pamarthi

et al.

Cells, Journal Year: 2022, Volume and Issue: 11(17), P. 2726 - 2726

Published: Sept. 1, 2022

Ferroptosis has recently been demonstrated to be a novel regulated non-apoptotic cell death characterized by iron-dependence and the accumulation of lipid peroxidation that results in membrane damage. Excessive iron induces ferroptosis promoting generation both soluble ROS via an iron-dependent Fenton reaction lipoxygenase (LOX) enzyme activity. Cytosolic glutathione peroxidase 4 (cGPX4) pairing with suppressor protein 1 (FSP1) mitochondrial (mGPX4) dihydroorotate dehydrogenase (DHODH) serve as two separate defense systems detoxify cytoplasmic well membrane, thereby defending against cells under normal conditions. However, disruption these may cause ferroptosis. Emerging evidence revealed plays essential role development diverse cardiovascular diseases (CVDs), such hemochromatosis-associated cardiomyopathy, doxorubicin-induced cardiotoxicity, ischemia/reperfusion (I/R) injury, heart failure (HF), atherosclerosis, COVID-19–related arrhythmias. Iron chelators, antioxidants, inhibitors, genetic manipulations alleviate aforementioned CVDs blocking pathways. In conclusion, critical pathogenesis various suppression cardiac is expected become potential therapeutic option. Here, we provide comprehensive review on molecular mechanisms involved its implications disease.

Language: Английский

Citations

101
Fighting age-related orthopedic diseases: focusing on ferroptosis DOI Creative Commons
Qin Ru, Yusheng Li, Wenqing Xie

et al.

Bone Research, Journal Year: 2023, Volume and Issue: 11(1)

Published: March 1, 2023

Abstract Ferroptosis, a unique type of cell death, is characterized by iron-dependent accumulation and lipid peroxidation. It closely related to multiple biological processes, including iron metabolism, polyunsaturated fatty acid the biosynthesis compounds with antioxidant activities, glutathione. In past 10 years, increasing evidence has indicated potentially strong relationship between ferroptosis onset progression age-related orthopedic diseases, such as osteoporosis osteoarthritis. Therefore, in-depth knowledge regulatory mechanisms in diseases may help improve disease treatment prevention. This review provides an overview recent research on its influences bone cartilage homeostasis. begins brief systemic metabolism ferroptosis, particularly potential ferroptosis. presents discussion role promotion loss degradation inhibition osteogenesis. Finally, it focuses future targeting treat intention inspiring further clinical development therapeutic strategies.

Language: Английский

Citations

99
Glutathione system enhancement for cardiac protection: pharmacological options against oxidative stress and ferroptosis DOI Creative Commons
Mingyue Tan,

Yunfei Yin,

Xiao Ma

et al.

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(2)

Published: Feb. 16, 2023

Abstract The glutathione (GSH) system is considered to be one of the most powerful endogenous antioxidant systems in cardiovascular due its key contribution detoxifying xenobiotics and scavenging overreactive oxygen species (ROS). Numerous investigations have suggested that disruption GSH a critical element pathogenesis myocardial injury. Meanwhile, newly proposed type cell death, ferroptosis, has been demonstrated closely related system, which affects process outcome Moreover, facing various pathological challenges, mammalian heart, possesses high levels mitochondria weak capacity, susceptible oxidant production oxidative damage. Therefore, targeted enhancement along with prevention ferroptosis myocardium promising therapeutic strategy. In this review, we first systematically describe physiological functions anabolism as well effects on cardiac Then, discuss relationship between comprehensive summary activation strategies presented, where mainly identify several herbal monomers, may provide valuable guidelines for exploration new approaches.

Language: Английский

Citations

95
Polydopamine Nanoparticles Targeting Ferroptosis Mitigate Intervertebral Disc Degeneration Via Reactive Oxygen Species Depletion, Iron Ions Chelation, and GPX4 Ubiquitination Suppression DOI Creative Commons
Xiao Yang, Yan Chen,

Jiadong Guo

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 10(13)

Published: March 23, 2023

Intervertebral disc degeneration (IVDD)-induced lower back pain (LBP) is a common problem worldwide. The underlying mechanism partially accredited to ferroptosis, based on sequencing analyses of IVDD patients from the gene expression omnibus (GEO) databases. In this study, it shown that polydopamine nanoparticles (PDA NPs) inhibit oxidative stress-induced ferroptosis in nucleus pulposus (NP) cells vitro. PDA NPs scavenge reactive oxygen species (ROS), chelate Fe

Language: Английский

Citations

86