Crosstalk of disulfidptosis-related subtypes, establishment of a prognostic signature and immune infiltration characteristics in bladder cancer based on a machine learning survival framework

Frontiers in Endocrinology, Journal Year: 2023, Volume and Issue: 14

Published: April 19, 2023

Background Bladder cancer (BLCA) is the most common malignancy of urinary tract. On other hand, disulfidptosis, a mechanism disulfide stress-induced cell death, closely associated with tumorigenesis and progression. Here, we investigated impact disulfidptosis-related genes (DRGs) on prognosis BLCA, identified various DRG clusters, developed risk model to assess patient prognosis, immunological profile, treatment response. Methods The expression mutational characteristics four DRGs were first analyzed in bulk RNA-Seq single-cell RNA sequencing data, IHC staining role BLCA progression, two clusters by consensus clustering. Using differentially expressed (DEGs) from these transformed ten machine learning algorithms into more than 80 combinations finally selected best algorithm construct prognostic signature (DRPS). We based this selection mean C-index three cohorts. Furthermore, explored differences clinical characteristics, landscape, immune infiltration, predicted efficacy immunotherapy between high low-risk groups. To visually depict value DRPS, employed nomograms. Additionally, verified whether DRPS predicts response patients utilizing Tumour Immune Dysfunction Rejection (TIDE) IMvigor 210 Results In integrated cohort, several gene that differed significantly overall survival (OS) tumor microenvironment. After integration clinicopathological features, showed robust predictive power. Based median score divided (LR) high-risk (HR) groups, LR group having better higher load being sensitive chemotherapy. Conclusion Our study, therefore, provides valuable tool further guide management tailor patients, offering new insights individualized treatment.

Language: Английский

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Glutathione system enhancement for cardiac protection: pharmacological options against oxidative stress and ferroptosis

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

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Ferroptosis in health and disease

Redox Biology, Journal Year: 2024, Volume and Issue: 75, P. 103211 - 103211

Published: May 30, 2024

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark ferroptosis uncontrolled overwhelming peroxidation polyunsaturated fatty acids contained membrane phospholipids, which eventually leads to rupture the plasma membrane. unique that it essentially spontaneous, uncatalyzed chemical process based on perturbed iron redox homeostasis contributing process, but nonetheless modulated by many metabolic nodes impinge cells' susceptibility ferroptosis. Among affecting sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets treatment numerous currently incurable diseases. Herein, current members Germany-wide research consortium focusing research, well key external experts who made seminal contributions this rapidly growing exciting field gathered provide comprehensive, state-of-the-art review Specific topics include: basic mechanisms, vivo relevance, specialized methodologies, tools, potential contribution disease etiopathology progression. We hope article will not only established scientists newcomers with an overview multiple facets ferroptosis, also encourage additional efforts characterize further molecular pathways modulating ultimate goal develop novel pharmacotherapies tackle associated - or caused

Language: Английский

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Targeting Iron Metabolism and Ferroptosis as Novel Therapeutic Approaches in Cardiovascular Diseases

Nutrients, Journal Year: 2023, Volume and Issue: 15(3), P. 591 - 591

Published: Jan. 23, 2023

Iron functions as an essential micronutrient and participates in normal physiological biochemical processes the cardiovascular system. Ferroptosis is a novel type of iron-dependent cell death driven by iron accumulation lipid peroxidation, characterized depletion glutathione suppression peroxidase 4 (GPX4). Dysregulation metabolism ferroptosis have been implicated occurrence development diseases (CVDs), including hypertension, atherosclerosis, pulmonary myocardial ischemia/reperfusion injury, cardiomyopathy, heart failure. chelators deferoxamine dexrazoxane, lipophilic antioxidants ferrostatin-1 liproxstatin-1 revealed to abolish suppress peroxidation other CVDs. Notably, inhibition has demonstrated alleviate cardiac impairments, fibrosis pathological remodeling during hypertension potentiating GPX4 signaling. Administration improved injury inhibiting peroxidation. Several small molecules may be effective treatment ferroptosis-mediated In this article, we summarize regulatory roles underlying mechanisms dysregulation Targeting are potential therapeutic strategies prevention

Language: Английский

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The mechanism of ferroptosis and its related diseases

Molecular Biomedicine, Journal Year: 2023, Volume and Issue: 4(1)

Published: Oct. 16, 2023

Abstract Ferroptosis, a regulated form of cellular death characterized by the iron-mediated accumulation lipid peroxides, provides novel avenue for delving into intersection metabolism, oxidative stress, and disease pathology. We have witnessed mounting fascination with ferroptosis, attributed to its pivotal roles across diverse physiological pathological conditions including developmental processes, metabolic dynamics, oncogenic pathways, neurodegenerative cascades, traumatic tissue injuries. By unraveling intricate underpinnings molecular machinery, contributors, signaling conduits, regulatory networks governing researchers aim bridge gap between intricacies this unique mode multifaceted implications health disease. In light rapidly advancing landscape ferroptosis research, we present comprehensive review aiming at extensive in origins progress human diseases. This concludes careful analysis potential treatment approaches carefully designed either inhibit or promote ferroptosis. Additionally, succinctly summarized therapeutic targets compounds that hold promise targeting within various facet underscores burgeoning possibilities manipulating as strategy. summary, enriched insights both investigators practitioners, while fostering an elevated comprehension latent translational utilities. revealing basic processes investigating possibilities, crucial resource scientists medical aiding deep understanding effects situations.

Language: Английский

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GPX4, ferroptosis, and diseases

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 174, P. 116512 - 116512

Published: April 3, 2024

GPX4 (Glutathione peroxidase 4) serves as a crucial intracellular regulatory factor, participating in various physiological processes and playing significant role maintaining the redox homeostasis within body. Ferroptosis, form of iron-dependent non-apoptotic cell death, has gained considerable attention recent years due to its involvement multiple pathological processes. is closely associated with ferroptosis functions primary inhibitor this process. Together, contribute pathophysiology several diseases, including sepsis, nervous system ischemia reperfusion injury, cardiovascular cancer. This review comprehensively explores roles impacts development progression these aim providing insights for identifying potential therapeutic strategies future.

Language: Английский

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Mitochondrial Glutathione in Cellular Redox Homeostasis and Disease Manifestation

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 1314 - 1314

Published: Jan. 21, 2024

Mitochondria are critical for providing energy to maintain cell viability. Oxidative phosphorylation involves the transfer of electrons from substrates oxygen produce adenosine triphosphate. also regulate proliferation, metastasis, and deterioration. The flow in mitochondrial respiratory chain generates reactive species (ROS), which harmful cells at high levels. stress caused by ROS accumulation has been associated with an increased risk cancer, cardiovascular liver diseases. Glutathione (GSH) is abundant cellular antioxidant that primarily synthesized cytoplasm delivered mitochondria. Mitochondrial glutathione (mGSH) metabolizes hydrogen peroxide within A long-term imbalance ratio mGSH can cause dysfunction, apoptosis, necroptosis, ferroptosis, may lead disease. This study aimed review physiological functions, anabolism, variations organ tissue accumulation, delivery GSH mitochondria relationships between levels, GSH/GSH disulfide (GSSG) ratio, programmed death, ferroptosis. We discuss diseases deficiency related therapeutics.

Language: Английский

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Cellular metabolism: A key player in cancer ferroptosis

Cancer Communications, Journal Year: 2024, Volume and Issue: 44(2), P. 185 - 204

Published: Jan. 13, 2024

Abstract Cellular metabolism is the fundamental process by which cells maintain growth and self‐renewal. It produces energy, furnishes raw materials, intermediates for biomolecule synthesis, modulates enzyme activity to sustain normal cellular functions. foundation of life processes plays a regulatory role in various biological functions, including programmed cell death. Ferroptosis recently discovered form iron‐dependent The inhibition ferroptosis crucial tumorigenesis tumor progression. However, metabolism, particularly glucose amino acid cancer not well understood. Here, we reviewed glucose, lipid, acid, iron selenium involvement elucidate impact different metabolic pathways on this process. Additionally, provided detailed overview agents used induce ferroptosis. We explained that maintaining intracellular redox homeostasis disrupting these renders them more susceptible iron‐induced death, resulting enhanced killing. combination inducers inhibitors may be novel approach future therapy an important strategy advance development treatments.

Language: Английский

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Protosappanin A Protects DOX‐Induced Myocardial Injury and Cardiac Dysfunction by Targeting ACSL4/FTH1 Axis‐Dependent Ferroptosis

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: July 10, 2024

Abstract Doxorubicin (DOX) is an effective anticancer agent, but its clinical utility constrained by dose‐dependent cardiotoxicity, partly due to cardiomyocyte ferroptosis. However, the progress of developing cardioprotective medications counteract ferroptosis has encountered obstacles. Protosappanin A (PrA), anti‐inflammatory compound derived from hematoxylin, shows potential against DOX‐induced cardiomyopathy (DIC). Here, it reported that PrA alleviates myocardial damage and dysfunction reducing maintaining mitochondrial homeostasis. Subsequently, molecular target through proteome microarray, docking, dynamics simulation identified. Mechanistically, physically binds with ferroptosis‐related proteins acyl‐CoA synthetase long‐chain family member 4 (ACSL4) ferritin heavy chain 1 (FTH1), ultimately inhibiting ACSL4 phosphorylation subsequent phospholipid peroxidation, while also preventing FTH1 autophagic degradation release ferrous ions (Fe 2+ ) release. Given critical role in pathogenesis ischemia‐reperfusion (IR) injury, this further investigation posits can confer a protective effect IR‐induced cardiac Overall, novel pharmacological inhibitor unveiled targets uncover dual‐regulated mechanism for DIC, highlighting additional therapeutic options chemodrug‐induced cardiotoxicity ferroptosis‐triggered disorders.

Language: Английский

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Pharmacological activation of GPX4 ameliorates doxorubicin-induced cardiomyopathy

Redox Biology, Journal Year: 2024, Volume and Issue: 70, P. 103024 - 103024

Published: Jan. 10, 2024

Due to the cardiotoxicity of doxorubicin (DOX), its clinical application is limited. Lipid peroxidation caused by excessive ferrous iron believed be a key molecular mechanism DOX-induced cardiomyopathy (DIC). Dexrazoxane (DXZ), an chelator, only drug approved FDA for reducing DIC, but it has many side effects and cannot used as preventive in practice. Single-nucleus RNA sequencing (snRNA-seq) analysis identified myocardial epithelial cells that are susceptible ferroptosis. The glutathione peroxidase 4 (GPX4) activator selenomethione (SeMet) significantly reduced polyunsaturated fatty acids (PUFAs) oxidized lipid levels vitro. Consistently, SeMet decreased H9C2 mortality C57BL/6 mice compared DXZ, ferrostatin-1, normal saline. can effectively reduce serum markers cardiac injury breast cancer patients. Depletion GPX4 gene resulted increase acid (PUFA) eliminated protective effect against DIC. Notably, exerted antitumor on models with DOX while providing protection same animal without detectable toxicities. These findings suggest pharmacological activation valuable promising strategy preventing doxorubicin.

Language: Английский

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