Antioxidants & redox signaling最新文献

Aims: Radiation-induced pneumonia (RP) is a common complication after radiotherapy for clinical thoracic tumors, and increasing evidence suggests that miRNAs have potential value in regulating radiation-induced lung injury. However, the potential mechanism is still obscure. Here, we evaluated the miRNAs-dependent mechanism involved in the progression of RP. Results: Our data showed that mmu-miR-208a-3p was consistently highly expressed in the lung tissue of irradiated mice. In vitro studies demonstrated that the expression of miR-208a-3p in cells was significantly increased after X-ray irradiation. Further mechanism studies indicated that radiation-induced upregulation of miR-208a-3p promoted inflammatory responses by suppressing the expression of protein phosphatase 6C (PPP6C) and activating the cyclic GMP-AMP synthase/stimulator of interferon genes protein pathway. Overexpression of PPP6C can alleviate radiation-induced DNA damage and excessive accumulation of ROS. It was also observed that PPP6C inhibited ionizing RP in vivo. Innovation and Conclusion: miR-208a-3p/PPP6C represents a potential therapeutic target for RP which needs to be verified by future clinical studies. Antioxid. Redox Signal. 00, 000-000.

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. 00, 000-000. [Figure: see text].

Significance: Damage after stroke is not only limited to the brain but also often occurs in remote organs, including the heart, lung, liver, kidney, digestive tract, and spleen, which are frequently affected by complex pathophysiological changes. The organs in the human body are closely connected, and signals transmitted through various molecular substances could regulate the pathophysiological changes of remote organs. Recent Advances: The latest studies have shown that inflammatory response plays an important role in remote organ damage after stroke, and can aggravate remote organ damage by activating oxidative stress, sympathetic axis, and hypothalamic axis, and disturbing immunological homeostasis. Remote organ damage can also cause damage to the brain, aggravating inflammatory response and oxidative damage. Critical Issues: Therefore, an in-depth exploration of inflammatory and oxidative mechanisms and adopting corresponding comprehensive intervention strategies have become necessary to reduce damage to remote organs and promote brain protection. Future Directions: The comprehensive intervention strategy involves multifaceted treatment methods such as inflammation regulation, antioxidants, and neural stem cell differentiation. It provides a promising treatment alternative for the comprehensive recovery of stroke patients and an inspiration for future research and treatment. The various organs of the human body are interconnected at the molecular level. Only through comprehensive intervention at the molecular and organ levels can we save remote organ damage and protect the brain after stroke to the greatest extent. Antioxid. Redox Signal. 00, 000-000.

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. 00, 000-000.

Aims: Myocardial fibrosis is an important medium for atrial fibrillation (AF). Exosomes have been demonstrated to affect the development of AF. This study explored the molecular mechanism of exosomes from patients with AF (AF-exo) mediating myocardial fibrosis and thus affecting the development of AF. Results: Prolactin-induced protein (PIP) is highly expressed in AF-exo. AF-exo promoted the proliferation and activation of cardiac fibroblasts (CFs) as well as the migration and endothelial-to-mesenchymal transition (EndMT) of human umbilical vein endothelial cells (HUVECs). However, the effect of AF-exo on CFs and HUVECs was mitigated by PIP-specific short hairpin RNA (shPIP). Adeno-associated virus (AAV)-shPIP reduced the incidence and duration of AF in rats, and improved myocardial fibrosis and collagen deposition. ATPase plasma membrane Ca²⁺ transporting 2 (ATP2B2) overexpression or inhibition reverses the role of PIP or shPIP in CFs, HUVECs, and AF rats. Activation of the cyclic guanosine monophosphate/protein kinase G (cGMP/PKG) pathway is beneficial to alleviate myocardial fibrosis, but this effect is mitigated by shATP2B2. Innovation: Our investigation substantiates the pivotal role of the PIP/ATP2B2 axis in both HUVEC myocardial fibrosis and EndMT progression. Our findings suggest that AF-exo can suppress the activation of the cGMP/PKG pathway mediated by ATP2B2 through exosomal PIP, thus promoting myocardial fibrosis, indicating potential targets for novel antifibrotic drug development targeting either PIP or ATP2B2. Conclusion: Exosomal PIP can inhibit the activation of cGMP/PKG pathway mediated by ATP2B2, thus promoting the development of AF. Antioxid. Redox Signal. 00, 000-000.

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. 00, 000-000.

Aims: BTB and CNC homology 1 (Bach1) is a transcription factor that mediates oxidative stress and inflammation and participates in the progression of diseases such as atherosclerosis, colitis, and acute lung injury. In this study, we aimed to explore the role of Bach1 in radiation pneumonitis (RP) and elucidate its underlying mechanism. Results: Bach1 expression was significantly elevated in the lung tissues of RP mice. Deletion of the Bach1 gene markedly ameliorated X-ray-induced RP by reducing inflammation and oxidative stress. In vitro experiments demonstrated that Bach1 deficiency mitigated radiation-induced oxidative damage and inflammation in bone marrow-derived macrophages. Conversely, Bach1 overexpression exacerbated oxidative stress and inflammation in radiation-treated macrophages. Mechanistically, using the JASPAR database, electromobility shift assays, and luciferase reporter assays, we revealed that Bach1 inhibited mRNA expression of mitochondrial transcription factor A (TFAM) by directly binding to its promoter region. Innovation and Conclusion: Our findings indicate that silencing of Bach1 protects against RP by upregulating the mRNA expression of TFAM, which, in turn, enhances mitochondrial function and reduces inflammation and oxidative stress. This study provides valuable insights into potential therapeutic strategies for patients with RP through Bach1 inhibition. Antioxid. Redox Signal. 00, 000-000.

Aims: Peroxiredoxins (Prx) are ubiquitous Cys peroxidases regulated by sulfinylation, a modification that occurs when the sulfenic acid generated on the catalytic Cys by peroxide reduction reacts with a second molecule of peroxide. In the Prx1 family, sulfinylation sensitivity is controlled by competition between a structural transition from a fully folded (FF) to locally unfolded (LU) conformation and the chemical step of sulfinylation. The initial peroxide reduction relies on a conserved catalytic hydroxylated residue that allows peroxide optimal activation. This study aimed at investigating the role of this catalytic residue in sulfinylation. Results: Sulfenate attack on peroxide was favored by one order of magnitude when a catalytic Thr was present, for yeast cytosolic Prx1-type enzymes, human Prx1 and yeast mitochondrial Prx, a Prx6-type enzyme. Furthermore, pKa determination supported the notion of electrostatic interaction between the catalytic hydroxyl and sulfenate intermediate. Finally, FF-LU transition kinetics was faster with a catalytic Thr, supporting that the hydroxyl group proximity to the nascent sulfenate group also promotes the FF-LU transition. Innovation: We identify a major mechanism that activates sulfinylation in hyperoxidation-sensitive Prxs from the Prx1 and Prx6 families. Furthermore, we show that the catalytic hydroxylated residue holds a dual role in regulating hyperoxidation sensitivity, by activating the sulfinylation reaction, while also promoting the competing FF to LU transition, thus acting as an important regulatory determinant. Conclusion: The present work sets the basis for investigating other instances of Cys proteins regulated by sulfinylation, a modification increasingly recognized in cell redox regulation and signaling. Antioxid. Redox Signal. 00, 000-000.

Significance: Hydrogen sulfide (H₂S), a ubiquitous small gaseous signaling molecule, plays a critical role in various diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), ischemic stroke, and myocardial infarction (MI) via reducing inflammation, inhibiting oxidative stress, and cell apoptosis. Recent Advances: Uncontrolled inflammation is closely related to pathological process of ischemic stroke, RA, MI, and IBD. Solid evidence has revealed the axes between gut and other organs like joint, brain, and heart, and indicated that H₂S-mediated anti-inflammatory effect against IBD, RA, MI, and ischemic stroke might be related to regulating the functions of axes between gut and other organs. Critical Issues: We reviewed endogenous H₂S biogenesis and the H₂S-releasing donors, and revealed the anti-inflammatory effects of H₂S in IBD, ischemic stroke, RA, and MI. Importantly, this review outlined the potential role of H₂S in the gut-joint axis, gut-brain axis, and gut-heart axis as a gasotransmitter. Future Direction: The rate, location, and timing of H₂S release from its donors determine its potential success or failure as a useful therapeutic agent and should be focused on in the future research. Therefore, there is still a need to explore internal and external sources monitoring and controlling H₂S concentration. Moreover, more efficient H₂S-releasing compounds are needed; a better understanding of their chemistry and properties should be further developed. Antioxid. Redox Signal. 42, 341-360.

Aims: To investigate the role of the RegSR-NifA regulatory cascade in the oxygen control of nitric oxide (NO) reduction in the soybean endosymbiont Bradyrhizobium diazoefficiens. Results: We have performed an integrated study of norCBQD expression and NO reductase activity in regR, regS₁, regS₂, regS_1/2, and nifA mutants in response to microoxia (2% O₂) or anoxia. An activating role of RegR and NifA was observed under anoxia. In contrast, under microaerobic conditions, RegR acts as a repressor by binding to a RegR box located between the -10 and -35 regions within the norCBQD promoter. In addition, both RegS₁ and RegS₂ sensors cooperated with RegR in repressing norCBQD genes. Innovation: NO is a reactive gas that, at high levels, acts as a potent inhibitor of symbiotic nitrogen fixation. In this paper, we report new insights into the regulation of NO reductase, the major enzyme involved in NO removal in rhizobia. This knowledge will be crucial for the development of new strategies and management practices in agriculture, in particular, for improving legume production. Conclusion: Our results demonstrate, for the first time, a dual control of the RegSR two-component regulatory system on norCBQD genes control in response to oxygen levels. Antioxid. Redox Signal. 42, 408-420.