Antioxidants & redox signaling最新文献

Significance: Oxidative mechanisms contribute to both vascular function and pathogenesis of many diseases, but their role in the microvasculature remains poorly understood. Recent Advances: The role of reactive oxygen and reactive nitrogen species (ROS/RNS) in the vasculature has been well-established for years. Our knowledge of microvascular responses to ROS/RNS has relied on extrapolation of studies performed in large vessels or cultured endothelial cells from large vessels. In healthy tissue, ROS/RNS are implicated in microvascular cell survival and death, angiogenesis, vasodilation, and barrier function, and, in disease, they contribute to increased permeability, leukocyte extravasation, and inflammation. Redox-mediated microvascular dysfunction underlies a multitude of conditions, including cardiovascular diseases, autoimmune diseases, infectious diseases, hemoglobinopathies, inflammatory diseases, vasculitides, and metabolic diseases. Critical Issues: New single-cell RNA sequencing studies reveal that endothelial cells from different vascular beds have unique gene signatures. Moreover, microvessels respond differently than large vessels, yet findings are frequently extrapolated across vascular beds. Technical challenges have limited our ability to reliably link alterations in ROS/RNS levels to microvascular outcomes. Moreover, successful therapeutics targeting redox signaling in general and in the microvasculature in particular are lacking. While numerous associations exist between common diseases and the microvasculature, the precise contribution of redox-mediated microvascular dysfunction to disease pathogenesis has been challenging. Future Directions: Additional research in organ-specific microvasculature focusing on the redox mechanisms underlying microvascular function and dysfunction is needed, as well as the development of new targeted therapeutics that can be locally delivered. Comparison of redox responses between different diseases may uncover general mechanisms to exploit therapeutically. Antioxid. Redox Signal. 43, 566-621.

Significance: Hydrogen sulfide (H₂S) is an important signaling molecule involved in cardiovascular diseases (CVDs). Although it is important, the precise mechanisms underlying the diverse functions of H₂S in CVDs are not known and need to be elucidated. Recent Advances: Studies have shown the importance of different programmed cell death (PCD) modalities, such as NETosis, apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis, in the pathogenesis of CVDs. An overview of the role of H₂S in regulating PCD in diabetic cardiomyopathy (DCM), cardiac hypertrophy and fibrosis, hypertension, heart failure, atherosclerosis and myocardial ischemia/reperfusion injury, might provide a better understanding of the cardiovascular effects of H₂S. Critical Issues: The mechanisms by which H₂S modulates each type of PCD in CVD patients need to be elucidated. The differences in the effects of H₂S on PCD modalities in different cardiovascular cell types, such as cardiomyocytes, endothelial cells, smooth muscle cells, and immune cells, require further evidence. Future Directions: Future studies should focus on the mechanism by which H₂S affects distinct PCD pathways. Whether H₂S acts as a switch between different PCD pathways under stress or disease conditions needs to be determined. H₂S might regulate the temporal and spatial overlapping PCD pathways in CVDs. Single-cell RNA sequences, spatial transcriptomics, and live-cell imaging are needed to map PCD events regulated by H₂S. Innovation: In this review, we summarized the regulatory effects of H₂S on signaling pathways related to PCD in patients with CVDs. Understanding these mechanisms is crucial for elucidating the pathophysiological roles of H₂S in CVDs. Antioxid. Redox Signal. 43, 637-690.

Aims: Iron metabolism disorders are critical in the pathogenesis of acute kidney ischemia-reperfusion injury (IRI). However, the molecular mechanisms driving these disturbances remain poorly understood. Results: In IRI mouse kidneys, pathological alterations, iron metabolism disruptions, and functional impairments were observed. Retinoic acid-inducible gene-I (RIG-I), transcription factor c-Myc, and ferritin heavy chain (FTH) exhibited elevated expression and colocalization in tubular epithelial cells, accompanied by decreased glutathione peroxidase 4 (GPX4) level and evidence of ferroptosis. Further in vitro studies revealed that RIG-I promoted c-Myc activation. The latter demonstrated its positive regulation of FTH transcription by chromatin immunoprecipitation assays and c-Myc siRNA experiments. Interestingly, FTH overexpression resulted in elevated levels of RIG-I, transferrin receptor, ferroportin, and nuclear receptor coactivator 4. Ultimately, the c-Myc inhibitor 10058-F4 reversed all adverse alterations and demonstrated a protective role in IRI mouse kidneys and mouse kidney tubule cells subjected to the ferroptosis inducer erastin, RIG-I agonist, or hypoxia/reoxygenation. This reversal was reflected in improved renal morphology and function, balanced iron metabolism, increased GPX4 level, decreased 4-hydroxynonenal level, reduced inflammatory cell infiltration, interleukin-1 beta release, and kidney injury molecule 1 expression. Innovation: This study proposes a novel mechanism in which c-Myc is activated by elevated RIG-I in IRI kidneys and positively regulates FTH transcription, therefore involving iron metabolism disorders. Conclusions: The RIG-I, c-Myc, and FTH disrupt iron homeostasis, and the c-Myc inhibition stabilizes iron metabolism and mitigates oxidative stress, suggesting a potential therapeutic target in IRI. Antioxid. Redox Signal. 43, 622-636. [Figure: see text].

Aims: Early myocardial ischemia (MI) predisposes to lethal ventricular arrhythmias (LVA) and subsequent sudden cardiac death (SCD). This study aims to elucidate the roles of cross-regulation between oxidative stress, endoplasmic reticulum (ER) stress, and calcium (Ca²⁺) disturbances in the increased risk of LVA-SCD in early MI. Results: Both clinical and animal model data showed a higher incidence of SCD within 30 min of MI. In MI animals, T-wave alternans and conduction slowing were observed prior to LVA onset. Optical mapping revealed spatiotemporal electrophysiological discordances, including conduction slowing and alternans in both action potentials and Ca²⁺ transients before LVA, peaking 5-15 min after ischemia onset, with the ischemic zone most affected. Reentrant cycles were observed in isolated MI hearts that developed LVA. SCD animals exhibited elevated mitochondrial and cytosolic reactive oxygen species and Ca²⁺, mitochondrial damage, ER stressors upregulation, and activation of the Ca²⁺/calmodulin-dependent protein kinases (oxidized)-RyR2, ryanodine receptor 2 (CaMKII-RyR2) pathway. These results were partly validated in hypoxic and undernourished myocytes. Targeted interventions, such as MitoTEMPO to mitigate oxidative stress, 4-phenyl butyric acid to inhibit ER stress, and dantrolene or RyR2-S2814A to suppress Ca²⁺ leakage, attenuated disturbances and reduced SCD incidence. Innovation and Conclusion: We identify a critical 30-min window post-MI, during which redox/ER stress and Ca² imbalance synergistically drive LVA and SCD via the CaMKII-RyR2 pathway. Targeting this pathway could offer a promising strategy to prevent LVA and SCD in early MI. Antioxid. Redox Signal. 43, 547-565.

Significance: Reactive oxygen species (ROS) are a double-edged sword in the context of oncoviruses. The effects of ROS on cells depend on the cellular environment, the stage of the disease, and the specific molecular pathways involved. In general, ROS levels in oncovirus-infected cells are usually increased and produce two distinct outcomes on cancer progression and metastasis through multiple mechanisms. Therefore, identifying the relationship between ROS and tumor viruses at the molecular level is essential for cancer prevention and treatment. Recent Advances: ROS play an important role in oncoviral infection and disease progression. The excessive accumulation of ROS induces ferroptosis, which has an important role in tumor therapy and the immune microenvironment, thus providing a theoretical basis for the development of new anticancer treatment strategies. Critical Issues: This review summarizes the complex relationship between ROS and oncoviral infection, with the aim of providing a deeper understanding of tumor pathogenesis and new therapeutic strategies. Future Directions: The relationship between ROS induced by oncoviral infection and host metabolic pathways, including lipids, lipoproteins, amino acids, and polyamines. Understanding how metabolism is reprogrammed in cancer cells may elucidate the impact of these processes on viral infection and tumor progression and help develop effective treatment strategies. Antioxid. Redox Signal. 43, 528-546.

Acute altitude hypoxia is a syndrome that manifests at elevations exceeding 2500 m, posing significant health challenges to individuals who travel or work at high altitudes. Uncoupling proteins are integral proteins located within the mitochondrial inner membrane, playing a crucial role in modulating proton leakage across the mitochondrial membrane. This study investigates the potential role of uncoupling protein 4 (Ucp4) overexpression in an intermittent hypobaric hypoxia (IHH) model and its underlying mechanisms in the cerebellar dyskinesia phenotype. An IHH model was developed using a low-pressure hypoxic chamber, exposing mice to 16 h of hypoxia daily for 5 days. Three mouse strains were used: C57BL/6J, Pcp2^Cre; Ucp4^fl/fl, and Pcp2^Cre; Mito-GFP. Behavioral tests, including rotarod, open field, balance beam, and Morris water maze, were conducted. Ucp4-overexpressing virus was administered to cerebellar lobes 4/5. Mitochondrial morphology was assessed via transmission electron microscopy, 3D reconstruction, and network analysis, while function was evaluated through reactive oxygen species, mitochondrial membrane potential (MMP), glutathione/glutathione disulfide ratio, adenosine triphosphate levels, qPCR, and Western blotting. Results showed that IHH induces hypoactivity without affecting spatial cognition. IHH-induced hypoactivity is linked to Ucp4 upregulation and increased mitochondrial fragmentation in Purkinje cells (PCs), though overall mitochondrial dynamics remain balanced. Ucp4 deficiency exacerbates IHH-induced hypoactivity and mitochondrial fragmentation. Conversely, Ucp4 overexpression in PCs significantly alleviates these effects. Mechanistically, Ucp4 protects PCs by stabilizing MMP and regulating oxidative stress, maintaining mitochondrial integrity. This study reveals that Ucp4 protects cerebellar PCs from oxidative stress in IHH, improving motor function and identifying Ucp4 as a potential therapeutic target for intermittent high-altitude syndrome. Antioxid. Redox Signal. 43, 483-508.

Aims: This study aims to investigate whether melatonin (MLT) exerts protective effects against cognitive impairment following exertional heat stroke (EHS) by modulating ferroportin (Fpn) to alleviate hippocampal ferroptosis and neuroinflammation. Results: Following EHS, genes such as Mt1, Mt2, and Trf were notably upregulated in the hippocampal tissue, whereas genes such as Slc40a1 (encoding Fpn 1) and Il33 were downregulated. Kyoto Encyclopedia of Genes and Genomes analysis implicated ferroptosis as a dominant. MLT significantly ameliorated learning and memory deficits observed in EHS mice. This treatment also modulated ferroptosis markers, such as Fpn, xCT, ferritin H, and glutathione peroxidase 4, reduced hippocampal iron overload, and decreased the secretion of proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-α (TNF-α). Furthermore, MLT treatment reduced oxidative stress and lipid peroxidation and mitigated mitochondrial and neuronal damage in the hippocampal tissue. Strikingly, conditional Fpn knockout abolished MLT's benefits: Fpn-cKO + MLT mice showed persistent iron accumulation, elevated IL-6 and TNF-α, and failed cognitive recovery. Innovation: Our study reveals that MLT prevents EHS-induced neurodegeneration by enhancing Fpn-dependent iron efflux, a mechanism that concurrently resolves hippocampal iron overload, suppresses ferroptosis, and dampens neuroinflammation. Conclusion: Our findings indicate that MLT mitigates EHS-related cognitive impairment by restoring hippocampal iron homeostasis and suppressing neuroinflammation, primarily through Fpn-dependent mechanisms. Antioxid. Redox Signal. 43, 509-527.

Aims: Epstein-Barr virus (EBV)-associated gastric cancer (GC) accounts for about 9% of GC patients, but its pathogenesis remains unclear. Glutathione peroxidase 4 (GPX4) is an important antioxidant enzyme that is highly expressed in various tumors and is associated with viral infections. This study aimed to clarify the relationship between EBV and GPX4 and the role of GPX4 in the occurrence and development of EBV-associated GC. Results: EBV infection leads to oxidative stress and excessive generation of reactive oxygen species (ROS) in GC cells. At the same time, EBV upregulates the expression of antioxidant enzyme GPX4 through the latent membrane protein 2A (LMP2A)/p62/Kelch-like ECH-associated protein 1(Keap1)/nuclear factor (erythroid-derived 2)-like 2 (NRF2) axis, eliminating excessive ROS to balance redox homeostasis and maintain its own survival. The high expression of GPX4 in GC inhibits EBV's immediate early lytic gene BZLF1 expression, thereby inhibiting EBV reactivation, and promotes cell migration and proliferation by upregulating lipocalin-2 (LCN2). Innovation: This study is the first to demonstrate that EBV-induced GPX4 expression via the LMP2A/p62/Keap1/NRF2 axis contributes to both viral latency and tumor progression in GC. Conclusion: EBV activates the p62/Keap1/NRF2 signaling pathway through LMP2A to upregulate the expression of GPX4, thereby alleviating oxidative stress caused by viral infection and maintaining the redox homeostasis in GC cells. Such enhanced expression not only maintains the latent infection of EBV but also promotes the malignant transformation of GC cells through LCN2. Antioxid. Redox Signal. 00, 000-000.

Aims: Chronic inflammation is a widely acknowledged contributor to the development of atherosclerosis. Gasdermin D (GSDMD) serves as a key executor of pyroptosis in inflammatory diseases. This study aims to determine the role of endothelial GSDMD in lipopolysaccharide (LPS)-accelerated atherosclerosis and elucidate its underlying molecular mechanisms. Results: GSDMD expression was aberrantly activated in both LPS-accelerated atherosclerotic animal models and oxidized low-density lipoprotein plus LPS-treated endothelial cell models. Compared with the control, endothelial GSDMD deficiency attenuated the atherogenesis progression and vascular endothelial inflammation induced by LPS and protected against the progression of mitochondrial damage, the release of mitochondrial ROS and mitochondrial DNA, and the activation of the stimulator of interferon genes (STING) pathway both in vivo and in vitro. Mechanistically, endothelial GSDMD expression mediates mitochondrial membrane permeabilization and mitochondrial damage-associated molecular patterns release and triggers the STING pathway to aggravate atherosclerotic progression. In addition, the STING pathway activation was proved to partially reverse the effects of endothelial GSDMD deficiency both in vivo and in vitro. Moreover, the signal transducer and activator of transcription 3 was identified as a positive regulator of GSDMD expression. Innovation and Conclusion: Our findings elucidate the mechanism by which endothelial GSDMD exerts its atherogenic effects by increasing mitochondrial damage and upregulating the STING pathway in LPS-accelerated atherosclerosis. GSDMD promises to be a critical therapeutic target for atherosclerotic cardiovascular diseases. Antioxid. Redox Signal. 00, 000-000.

Aims: Diabetic cardiomyopathy (DbCM) typically manifests as diastolic dysfunction, and treating heart failure with preserved ejection fraction (HFpEF) is challenging. Empagliflozin (Empa), a sodium-glucose cotransporter 2 inhibitor, reduces hospitalization and mortality in patients with HFpEF and the risk of DbCM. However, the underlying molecular mechanisms and the specific targets remain largely unknown. Results: Glutathione peroxidase 4 (GPX4) is a key enzyme that mitigates ferroptosis. Empa treatment improved cardiac function, upregulated GPX4 expression, and reduced ferroptosis in DbCM mice. The ferroptosis inducer erastin abolished the protective effects of Empa. Through database screening, we found that nuclear factor erythroid 2-related factor 2 (NRF2) plays an important role in ferroptosis in DbCM. NRF2 was expressed at lower levels in DbCM mice, and its expression significantly increased after Empa treatment. In NRF2-knockout mice, Empa failed to improve the cardiac function of DbCM mice, upregulate the expression of GPX4, and reduce ferroptosis. Moreover, Empa increased NRF2 levels by inhibiting ubiquitin-mediated degradation. A database search predicted that the stability of NRF2 may be regulated by ubiquitin-specific protease 7 (USP7). Immunoprecipitation assays demonstrated that USP7 interacted with NRF2 and mediated its deubiquitination, thereby stabilizing NRF2. Administration of the USP7 inhibitor P5091 abolished the effects of Empa, whereas the use of adeno-associated virus serotype 9 (AAV9)-NRF2 reversed the effects of P5091. Innovation and Conclusion: Empa attenuated cardiomyocyte ferroptosis in DbCM by stabilizing NRF2 through the USP7/NRF2/GPX4 signaling pathway. Targeting the USP7/NRF2/GPX4 pathway may represent a novel therapeutic strategy for attenuating ferroptosis in DbCM, which has clinical significance. Antioxid. Redox Signal. 00, 000-000. 2022-SYDWLL-000213.