Antioxidants & redox signaling最新文献

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.

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. 43, 1-13.

Aims: Duchenne muscular dystrophy (DMD) is a severe, incurable X-linked genetic disorder caused by mutations in the DMD gene, leading to a deficiency of the muscle structural protein, dystrophin, which results in damage to skeletal and cardiac muscles. Altered expression of enzymes that generate hydrogen sulfide (H₂S) has been demonstrated in dystrophic muscles, however, the exact role of this gasotransmitter in DMD remains elusive. Here, we investigated the effect of the slow-releasing H₂S donor (GYY4137) on the skeletal muscles of the dystrophin-deficient mdx mice. Methods and Results: Grip strength assay and the treadmill exhaustion test showed that administering the GYY4137 donor to mdx mice improved DMD-related decline in motor functions. Additionally, the H₂S donor decreased the level of muscle damage markers such as lactate dehydrogenase, creatine kinase, and osteopontin (OPN). Histological, gene, and protein analyses of the dystrophic gastrocnemius and diaphragm muscles revealed reduced inflammation and fibrosis after treatment with the H₂S donor. Moreover, we showed decreased necrosis with improved muscle regeneration and angiogenesis. We demonstrated that GYY4137 upregulates the levels of phosphorylated AMPKα, as well as the cytoprotective and antioxidant heme oxygenase-1, mitochondrial superoxide dismutase, and glutamate-cysteine ligase modifier subunit (Gclm). Finally, it exerted an anti-apoptotic effect by reducing cleaved caspase-3 and caspase-3 and increasing AKT phosphorylation. Innovation and Conclusion: The administration of GYY4137 improves exercise capacity and ameliorates the markers of inflammation, fibrosis, oxidative stress, apoptosis, and necrosis in the skeletal muscles of mdx animals pointing out its possible therapeutic use in DMD pathology. Antioxid. Redox Signal. 43, 115-137.

Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent hepatic disorder worldwide. Arachidonic acid 15-lipoxygenase (ALOX15), an enzyme catalyzing the peroxidation of polyunsaturated fatty acids, plays a crucial role in various diseases. Here, we sought to investigate the involvement of ALOX15 in MASLD. Results: In this study, we observed upregulation of ALOX15 in the liver of high-fat diet (HFD)- and streptozotocin (STZ)-induced mice. Metabolomic analysis revealed elevated levels of ALOX15 metabolites, 12(S)-hydroperoxyeicosatetraenoic acid and 15(S)-hydroperoxyeicosatetraenoic acid. Transcriptomic analysis showed that the increased fatty acid uptake regulated by the PPARγ/CD36 pathway predominated in lipid accumulation. To elucidate the mechanism underlying ALOX15-induced lipid accumulation, HepG2 cells were transfected with a lentivirus expressing ALOX15 or small interfering RNA targeting ALOX15 and exposed to palmitic acid (PA). Both ALOX15 overexpression and PA exposure led to increased intracellular free fatty acid and triglyceride, resulting in lipotoxicity. ALOX15 overexpression aggravated the effect of PA, while the knockdown of ALOX15 attenuated PA-induced lipotoxicity. Moreover, the treatment with PPARγ antagonist GW9662 or CD36 inhibitor sulfosuccinimidyl oleate sodium effectively reduced lipid accumulation and lipotoxicity resulting from ALOX15 overexpression and PA exposure, indicating the involvement of the PPARγ/CD36 pathway in ALOX15-mediated lipid accumulation. Furthermore, liraglutide, a widely used glucagon-like peptide 1 receptor (GLP-1R) agonist (GLP-1RA), improved hepatic lipid accumulation in HFD/STZ-induced mice by suppressing the ALOX15/PPARγ/CD36 pathway. Innovation and Conclusion: Our study underscores the potential of ALOX15 as an emerging therapeutic target for MASLD. In addition, the GLP-1RA may confer hepatoprotection by regulating ALOX15, enhancing our comprehension of the mechanisms underpinning their protection on MASLD. Antioxid. Redox Signal. 43, 37-55.

Significance: The role of melatonin (MEL) in plants has gained significant relevance due to its involvement in a wide range of physiological functions, particularly in response mechanisms to both abiotic and biotic stresses. Recent Advances: Recent progress highlights the significance of the biosynthetic pathway of MEL in plants, which surpasses that of animals. The discovery of specific plant MEL receptors has revealed new signaling mechanisms. Studies also show that applying exogenous MEL offers benefits under stress conditions and helps maintain the organoleptic qualities of fruits and vegetables during postharvest storage. Critical Issues: This review explores MEL's biochemistry, emphasizing its dual role as both an antioxidant and a signaling molecule. It examines how MEL interacts with phytohormones, its role in regulating the metabolism of reactive oxygen and nitrogen species, and its influence on plant growth and stress tolerance. The potential of MEL-based biotechnological applications for enhancing crop resilience and postharvest quality is also discussed. Future Directions: Future research should prioritize molecular mechanisms, high-throughput approaches, and translational studies to bridge the gap between fundamental science and agricultural practices. MEL's role as a sustainable solution in agriculture offers exciting possibilities for addressing global food security challenges. Antioxid. Redox Signal. 43, 151-188.

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. 43, 75-91.