Antioxidants & redox signaling最新文献

Aims: This study aimed to elucidate the role of N6-methyladenosine (m6A) methylation in necrotizing enterocolitis (NEC) pathogenesis, focusing on its regulation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) expression, and to evaluate PFKFB3 as a therapeutic target for NEC. Results: We observed a significant reduction in N6-methyladenosine (m6A) methylation within the 3'-untranslated region (3'-UTR) of PFKFB3 mRNA in human NEC tissues. This epigenetic change stabilized PFKFB3 mRNA, increased protein levels, and accelerated glycolytic flux. In both in vivo (lipopolysaccharide-hypoxia-cold stress) and in vitro (THP-1-differentiated macrophage) NEC models, PFKFB3-driven glycolysis was found to promote M1 macrophage polarization through reactive oxygen species (ROS) accumulation, thereby intensifying intestinal inflammation. Importantly, pharmacological inhibition of PFKFB3 using 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one significantly reduced ROS production, limited macrophage infiltration, and mitigated mucosal injury. Innovation and Conclusion: This study identifies a critical metabolic-epigenetic axis in NEC pathogenesis, wherein reduced m6A methylation of PFKFB3 mRNA drives intestinal inflammation. Our results demonstrate that pharmacological inhibition of PFKFB3 effectively reduces inflammation and tissue injury in NEC models, positioning PFKFB3 as a novel therapeutic target. This work provides the first evidence of an m6A-mediated mechanism in NEC and highlights the potential of targeting PFKFB3 for clinical intervention. Antioxid. Redox Signal. 43, 765-781.

Aims: This study aims to elucidate the molecular mechanisms underlying the alleviation of cold-climate-induced diabetic macrovascular disease (DM-MVD) by targeting hsa_circ_0010154 with gold nanoparticles (AuNPs)-mediated antisense oligonucleotides (ASOs) delivery, combined with aerobic exercise, and to explore the therapeutic effects on glucose and lipid metabolism, inflammation, and oxidative stress. Results: Significant upregulation of hsa_circ_0010154 in DM-MVD was confirmed through bioinformatics analysis and qRT-PCR validation. The constructed gold nanoparticles-mediated antisense oligonucleotides delivery (AuNPs@ASO) complex exhibited efficient reactive oxygen species-responsive release and effective cellular uptake. Silencing hsa_circ_0010154 led to improved endothelial cell function, reduced inflammation markers, enhanced lipid metabolism, and reduced oxidative stress responses. In vivo studies demonstrated improved cardiac function, vascular remodeling, and enhanced antioxidant enzyme activity. Innovation: This study introduces a novel approach utilizing AuNPs@ASO targeting hsa_circ_0010154 in conjunction with aerobic exercise to address the complex pathophysiology of cold-climate-induced DM-MVD, presenting a targeted, low-toxicity therapeutic strategy with promising translational potential. Conclusion: The combined treatment of AuNPs@ASO and aerobic exercise, targeting hsa_circ_0010154, effectively modulates critical pathological pathways involved in DM-MVD, offering a precise and innovative approach for tackling this condition, with implications for clinical translation. Antioxid. Redox Signal. 00, 000-000.

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.