Antioxidants & redox signaling最新文献

Aims: Radioresistance in non-small cell lung cancer (NSCLC) presents a major barrier to effective treatment. This study explores the molecular mechanisms underlying this resistance, focusing on the heterogeneous nuclear ribonucleoprotein A2B1/hepatoma-derived growth factor/pleiotrophin (HNRNPA2B1/HDGF/PTN) signaling pathway and its role in autophagy-dependent ferroptosis regulation. Our aim is to uncover how this pathway contributes to tumor cell survival under radiotherapy stress, thereby identifying potential therapeutic targets to overcome radioresistance. Results: We developed radiotherapy-resistant lung cancer cell lines and assessed their proliferation and migration capabilities through Cell Counting Kit-8 and Transwell assays, respectively. Single-cell RNA sequencing revealed significant differences in gene expression profiles between radioresistance and radiation-sensitive cells. Functional studies, including immunofluorescence, flow cytometry, and biochemical staining, confirmed that radioresistance was associated with enhanced autophagy and altered ferroptosis. Furthermore, HNRNPA2B1 knockdown reduced the expression of Ki67 and proliferating cell nuclear antigen, markers of proliferation, in a mouse tumor model. In addition, modulation of HNRNPA2B1 affected protein interactions and N6-methyladenosine RNA modifications, as demonstrated by reverse transcription-quantitative polymerase chain reaction, Western blot, and methylation RNA immunoprecipitation-quantitative PCR. Innovation: This study provides new insights into how the HNRNPA2B1/HDGF/PTN pathway promotes radioresistance by influencing autophagy-dependent ferroptosis. This mechanism represents a potential vulnerability that could be therapeutically targeted to improve radiotherapy efficacy in lung cancer. Conclusion: Our findings demonstrate that the HNRNPA2B1/HDGF/PTN signaling pathway plays a crucial role in sustaining radioresistant phenotypes by modulating autophagy and ferroptosis. Targeting this pathway may enhance the therapeutic response in NSCLC, offering a novel strategy to combat treatment resistance. Antioxid. Redox Signal. 43, 189-214.

Aims: In Friedreich ataxia (FRDA), early motor discoordination stems from dysfunctional sensory neurons in the spinal cord driven by epigenetic dysregulation, frataxin (FXN) deficiency, oxidative stress, and inflammation. Omaveloxolone, a nuclear factor erythroid 2-related factor-2 (NRF2) inducer, is the only treatment available. In various chronic disease models, sulforaphane (SF) can target NRF2 and the above processes. This study compared the effects of SF with omaveloxolone and dimethyl fumarate (DMF) in sensory neurons generated from FRDA patient-induced pluripotent stem cells and their isogenic control. Results: The successful generation of the FRDA and isogenic control sensory neurons was confirmed by the positive expression of β-III TUBULIN, BRN3A, ISLET1, PERIPHERIN, and tropomyosin receptor kinase C. In comparison with the isogenic control, FRDA sensory neurons displayed an aberrant gene expression profile alike to that reported in patients. None of the drugs affected the viability of the isogenic control sensory neurons. SF treatment improved the viability of FRDA sensory neurons by up to 61% versus the untreated control. DMF treatment showed a modest 35% increase, while omaveloxolone lacked an effect. SF-treated FRDA sensory neurons demonstrated increased reduced glutathione/oxidized glutathione ratio and expression of FXN and redox markers, and a reduced expression of selected epigenetic enzymes and inflammatory cytokines, at the respective gene and protein levels. DMF and omaveloxolone treatments only modulated some of these biomarkers. Innovation: We revealed the therapeutic potential of SF and how it performs in comparison with omaveloxolone and DMF, in a physiologically and genetically relevant in vitro FRDA model. Conclusion: SF offers a multipronged approach to alleviating the different cellular events underlying FRDA. Antioxid. Redox Signal. 43, 308-327.

Aims: Reactive oxygen species (ROS) are considered to play a key damaging role in brain during the development of ischemic stroke. To clarify how different ROS contribute to ischemic pathogenesis, innovative approaches for real-time in vivo detection of redox parameters are necessary. Results: Using highly sensitive genetically encoded biosensor HyPer7 and a fiber-optic neurointerface technology, we demonstrated that the level of hydrogen peroxide (H₂O₂) slowly increases in neurons and astrocytes of the ischemic area of the rat brain after middle cerebral artery occlusion during next 40 h; notably, in astrocytes the level is somewhat higher. Raman microspectroscopy in awake mice also revealed redox differences between mitochondria of neurons and astrocytes during acute ischemia caused by photothrombosis. Astrocytes demonstrated the overloading of the electron transport chain (ETC) with electrons after 1 h of ischemia, whereas neurons do not demonstrate changes in the amount of reduced electron carries. Innovation and Conclusion: The combination of novel in vivo approaches allows to detail redox events with spatiotemporal resolution. We demonstrated redox difference between neurons and astrocytes in damaged brain areas in vivo. An elevated loading of astrocytic ETC with electrons during the acute ischemia phase provides basis for the increased generation of superoxide anion radical (O₂^•-) with its following conversion to other reactive species. However, we observed increased H₂O₂ concentrations in astrocytes and neurons at later pathogenesis stages. During this period, ETC did not demonstrate an elevated loading with electrons, and therefore, increased H₂O₂ generation may be a phenomenon of secondary redox events. Antioxid. Redox Signal. 43, 272-287.

Ferroptosis, a distinct form of regulated cell death (RCD), has emerged as a promising approach for cancer treatment owing to its potential to inhibit tumor malignancy. Research indicates that non-coding RNAs (ncRNAs) regulate ferroptosis susceptibility in cancer cells through epigenetic modifications. ncRNAs play essential roles in cancer initiation, metastasis, and drug resistance. Findings indicate that small-molecule compounds (SMCs) target ncRNAs to regulate ferroptosis, providing new opportunities for precision cancer therapy. Therefore, this review aims to elucidate current molecular mechanisms underlying ncRNA-mediated ferroptosis regulation in cancer and investigate the potential of SMCs as therapeutic agents to modulate this process, offering a new strategy for precision in cancer treatment. This review also summarizes the innovative strategy of targeting ncRNAs with SMCs, a therapeutic approach for regulating ferroptosis and transforming the landscape of cancer treatment. Overall, it highlights a novel strategy for cancer therapy by pharmacologically targeting the ncRNA-ferroptosis axis with SMCs. Antioxid. Redox Signal. 43, 345-362.

Aims: NADPH oxidase (NOX)-derived reactive oxygen species (ROS) are critical for platelet activation and thrombus formation. We hypothesized that inhibiting NOX-mediated ROS production with a pan-NOX inhibitor, APX-115, could effectively suppress platelet activation and thrombus formation, potentially serving as a novel antiplatelet therapeutic. This study aimed to explore the effects of APX-115 on human platelet functional responses and ROS-mediated signaling pathways. Results: APX-115 inhibited intracellular and extracellular ROS production in collagen-stimulated platelets, suppressing aggregation, P-selectin exposure, and ATP release. By preserving protein tyrosine phosphatase activity, APX-115 reduced tyrosine phosphorylation-dependent pathways inhibition, including spleen tyrosine kinase, LAT, Vav1, Bruton's tyrosine kinase, and phospholipase Cγ2, leading to decreased PKC activation and calcium mobilization. APX-115 also suppressed collagen-induced integrin αIIbβ3 activation, accompanied by elevated cGMP and vasodilator-stimulated phosphoprotein phosphorylation levels. In addition, APX-115 reduced p38 MAPK and ERK5 activation, leading to diminished phospholipase A2 phosphorylation, thromboxane production, and the exposure of procoagulant phosphatidylserine. These inhibitory effects extended to thrombus development caused by platelet adherence under shear and arterial thrombosis without prolonging bleeding time in murine models. Innovation: This study is the first to demonstrate that APX-115 inhibits NOX-mediated ROS production, platelet activation, and thrombus formation. By uncovering its effects on collagen receptor glycoprotein VI-mediated pathways, the work highlights the promise of APX-115 as an antiplatelet and antithrombotic agent. Conclusion: Our findings highlight the therapeutic potential of APX-115 in treating thrombotic and cardiovascular disorders by targeting NOX-mediated ROS production to mitigate platelet hyperreactivity and thrombus formation. Antioxid. Redox Signal. 43, 288-307.

Aims: Hyperammonemia, defined by elevated ammonia levels, may co-occur in various neurological disorders, but its effects on cerebrovascularity are not fully understood. This study aimed to investigate how hyperammonemia affects brain endothelial cells senescence and selected within in silico analysis micro RNA-183-5p in this process. Results: Reduction in cerebrovascular density in hyperammonemia-induced rats, similar to that seen in 12-month-old rats, using von Willebrand factor staining, was observed. MicroRNA (miRNA) profile analysis of the brain cortex and plasma identified miRNA-183-5p contributing to endothelial senescence. In vitro studies of ammonia-treated rat brain endothelial cell line 4 showed senescent features, including increased β-galactosidase activity, higher mRNA levels and fluorescence intensity of p16 and p21, and altered senescence-associated secretory phenotype. Additionally, the transfection of miRNA-183-5p mimic induced similar senescent characteristics in endothelial cells, whereas miRNA-183-5p mimic inhibition reversed some effects. Innovation: This study is the first to link hyperammonemia-induced cerebrovascular dysfunction with miRNA-183-5p, highlighting its role in promoting endothelial senescence. The findings suggest that miRNA-183-5p could be a target for therapeutic interventions, preventing ammonia-induced brain endothelial dysfunction. Conclusion: Hyperammonemia promotes brain endothelial cells senescence through miRNA-183-5p, reducing cerebrovascular density. This may contribute to cerebral dysfunction seen in hyperammonemia-associated neurological disorders. Targeting miRNA-183-5p could offer a novel therapeutic strategy to mitigate endothelial dysfunction and preserve brain health in hyperammonemia. Antioxid. Redox Signal. 43, 254-271.

Aims: While ferroptosis is involved in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury, the exact mechanism underlying the induction of ferroptosis by I/R remains elusive. Since downregulation of Zrt, Irt-like protein 13 (ZIP13) plays a role in I/R injury by targeting mitochondria, we hypothesized that ZIP13 downregulation during I/R leads to ferroptosis through a mitochondria-dependent mechanism. Results: ZIP13 cKO (cardiac-specific conditional knockout) induced ferroptosis and suppressed mitochondrial iron-sulfur cluster (ISC) biosynthesis. ZIP13 cKO also reduced glutathione levels as well as solute carrier family 7 member 11 (SLC7A11) expression. Moreover, cKO increased mitochondrial Fe²⁺ levels. Similar to the action of cKO, I/R led to ZIP13 downregulation, ferroptosis, mitochondrial Fe²⁺ accumulation, and suppression of ISC biosynthesis. In support, cKO of ZIP13 aggravated I/R-induced ferroptosis and mitochondrial Fe²⁺ accumulation. In contrast, ZIP13 overexpression prevented I/R-induced ferroptosis, mitochondrial Fe²⁺ accumulation, and suppression of ISC biosynthesis. Finally, ferrostatin-1, a ferroptosis inhibitor, alleviated I/R-induced ferroptosis as well as cardiac injury in cKO mice. Innovation: This study proposes a previously unknown mechanism by which ZIP13 downregulation contributes to ferroptosis in the setting of myocardial I/R. Conclusions: These findings highlight that ZIP13 downregulation at reperfusion triggers ferroptosis by suppressing the mitochondrial ISC biosynthesis followed by mitochondrial Fe²⁺ accumulation. Downregulation of SLC7A11 may also contribute to the action of ZIP13 downregulation. Antioxid. Redox Signal. 43, 328-344.

Aims: Parkinson's disease (PD) is characterized by dopaminergic (DAergic) neuron degeneration in the substantia nigra pars compacta (SNpc). Thioredoxin-1 (Trx-1) is a redox protein that protects neurons from various injuries. Our study revealed that Trx-1 overexpression improved the learning and memory impairments induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, the role of the specific transmission of signals from the SNpc to the hippocampus regulated by Trx-1 in cognition deficits associated with PD is still unknown. Results: We observed that Trx-1 downregulation in the SNpc aggravated cognitive dysfunction induced by MPTP. Importantly, we observed that the SNpc directly projects to the hippocampus. We found that the loss of DAergic neurons in the SNpc induced by MPTP resulted in a decrease in dopamine D1 receptor (D1R) expression in the hippocampus, which was promoted by Trx-1 downregulation in the SNpc. The levels of phosphorylated extracellular signal-regulated kinase (p-ERK1/2), phosphorylated cAMP-response element binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and postsynaptic density protein 95 (PSD95) in the hippocampus were decreased by MPTP and further decreased by Trx-1 downregulation in the SNpc. Finally, the number of synapses in the hippocampus was decreased by MPTP in the hippocampus and further reduced by Trx-1 downregulation in the SNpc. Innovation: Trx-1 downregulation accelerated the loss of DAergic neurons in the SNpc, leading to a decrease in the number dopaminergic projections to the hippocampus, subsequently inhibiting the D1R-ERK1/2-CREB-BDNF pathway in the hippocampus, and ultimately impairing hippocampus-dependent cognition. Conclusions: These results indicate that a decrease in Trx-1 level in the SNpc plays a critical regulatory role in cognitive dysfunction in individuals with PD by decreasing the hippocampal D1R signaling pathway. Antioxid. Redox Signal. 43, 138-150.

Significance: This review investigates how radiation therapy (RT) increases the risk of delayed cardiovascular disease (CVD) in cancer survivors. Understanding the mechanisms underlying radiation-induced CVD is essential for developing targeted therapies to mitigate these effects and improve long-term outcomes for patients with cancer. Recent Advances: Recent studies have primarily focused on metabolic alterations induced by irradiation in various cancer cell types. However, there remains a significant knowledge gap regarding the role of chronic metabolic alterations in normal cells, particularly vascular cells, in the progression of CVD after RT. Critical Issues: This review centers on RT-induced metabolic alterations in vascular cells and their contribution to senescence accumulation and chronic inflammation across the vasculature post-RT. We discuss key metabolic pathways, including glycolysis, the tricarboxylic acid cycle, lipid metabolism, glutamine metabolism, and redox metabolism (nicotinamide adenine dinucleotide/Nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADP⁺)/NADPH). We further explore the roles of regulatory proteins such as p53, adenosine monophosphate-activated protein kinase, and mammalian target of rapamycin in driving these metabolic dysregulations. The review emphasizes the impact of immune-vascular crosstalk mediated by the senescence-associated secretory phenotype, which perpetuates metabolic dysfunction, enhances chronic inflammation, drives senescence accumulation, and causes vascular damage, ultimately contributing to cardiovascular pathogenesis. Future Directions: Future research should prioritize identifying therapeutic targets within these metabolic pathways or the immune-vascular interactions influenced by RT. Correcting metabolic dysfunction and reducing chronic inflammation through targeted therapies could significantly improve cardiovascular outcomes in cancer survivors. Antioxid. Redox Signal. 43, 92-114.

Aims: Hyperuricemic nephropathy (HN) represents a prevalent complication of hyperuricemia, typified by tubular dysfunction, inflammation, and progressive renal fibrosis with unclear mechanisms. Ferroptosis, an iron-dependent regulated cell death, is implicated in multiple diseases, but has rarely been linked to HN. In this study, we aim to explore the possible role of ferroptosis in HN and its underlying mechanisms. Results: We showed that urate oxidase knockout mice, a model of hyperuricemia, exhibited renal impairment with elevated uric acid, creatinine, and blood urea nitrogen levels, accompanied by increased iron deposition and decreased glutathione peroxidase 4 (GPX4) and xCT expressions, suggesting ferroptosis involvement. Ferroptosis inhibitor Ferrostatin-1 (Fer-1) ameliorated renal injury, inflammatory cell infiltration, and fibrosis in these mice. Mechanistically, Fer-1 restored antioxidant protein levels, normalized ferroptosis-associated protein expressions, diminished iron overload and lipid peroxidation, and suppressed inflammatory markers and mitogen-activated protein kinase signaling. In vitro, monosodium urate crystals induced ferroptosis in human kidney 2 cells, characterized by increased lipid peroxidation and iron accumulation. Notably, receptor for advanced glycation end products (RAGE) inhibition alleviated renal injury, inflammation, and fibrosis albeit without directly diminishing ferroptosis. These findings were validated in human hyperuricemia-related kidney disease samples showing increased iron deposition, decreased GPX4, and elevated RAGE expression. Innovation and Conclusion: This study suggests that ferroptosis may play a role in the development of renal injury, inflammation, and fibrosis in HN, potentially mediated through RAGE signaling. While RAGE inhibition improved renal injury, it did not directly affect ferroptosis, indicating a complex and context-dependent role of RAGE in kidney injury. These findings highlight ferroptosis and its associated pathways, including RAGE signaling, as potential therapeutic targets for HN. Antioxid. Redox Signal. 43, 56-74.