Antioxidants & redox signaling最新文献

Aims: This study aimed to investigate the potential molecular mechanisms of Akkermansia muciniphila (Akk) in the treatment of abdominal aortic aneurysm (AAA) through the use of 16S rRNA sequencing and transcriptome sequencing technologies. Results: 16S rRNA sequencing analysis revealed distinct microbial composition in Sham, AAA, and Akk-treated AAA groups, highlighting the key role of Akk. Akk treatment prevented AAA development, reduced extracellular matrix degradation, and suppressed neutrophil extracellular trap (NET) formation. High mobility group box 1 (HMGB1) promoted AAA formation, antagonizing Akk's effects on NETs. Cell studies showed NET-induced ferroptosis in vascular smooth muscle cells (VSMCs), blocked by ferroptosis inhibitor ferrostatin-1, with HMGB1 overexpression enhancing ferroptosis and AMP-activated protein kinase (AMPK) inhibition reversing it. Akk activated AMPK to inhibit ferroptosis, consistent with in vivo results. Innovation: This study combines molecular analyses, cellular experiments, and animal studies to uncover Akk's mechanisms in AAA treatment. Identification of pathways influencing VSMCs' response to NETs and ferroptosis is a significant advancement in vascular biology. Conclusion: Akk mitigates HMGB1-mediated NET formation, activates AMPK to reduce VSMC ferroptosis, and inhibits AAA progression. These findings offer insights into AAA pathogenesis and propose Akk as a potential therapeutic agent for this condition. Antioxid. Redox Signal. 43, 782-804.

Significance: Sequestosome 1 (SQSTM1/p62, hereafter referred to as p62) is a multifunctional ubiquitin-binding autophagy receptor that acts as a critical bridge between the kelch-like ECH-associated protein 1 and nuclear factor erythroid 2-related factor 2 (KEAP1-NRF2) pathway and selective autophagy through diverse post-translational modifications (PTMs) and their reverse processes. Recent Advances: As a selective autophagy receptor, p62 facilitates the degradation of ubiquitinated substrates while functioning as a signaling hub to orchestrate cellular responses to oxidative stress. Given its central role in multiple signaling pathways, p62 is subject to tight and intricate regulation. Beyond transcriptional control, p62 activity is finely modulated by diverse PTMs and their reverse processes, including phosphorylation, dephosphorylation, ubiquitination, deubiquitination, acetylation, deacetylation, S-Acylation, and deacylation, which collectively fine-tune its roles in selective autophagy and the KEAP1-NRF2 pathway. Mounting evidence underscores that the PTMs and their reverse processes of p62 are implicated in diverse pathologies through both direct and indirect mechanisms, spanning multiple cancer subtypes, neurodegenerative disorders, inflammatory conditions, non-alcoholic fatty liver disease (NAFLD), and metal-induced toxicity, as well as infectious diseases. Critical Issues: This review synthesizes current knowledge on the PTMs and their reverse processes of p62, its functional implications, its disease-associated mechanisms, and molecular regulators, aiming to provide novel insights for targeting the PTMs and their reverse processes of p62 in therapeutic strategies. Future Directions: Targeting p62 PTMs and their reverse processes may be a promising strategy to ameliorate various diseases, including cancer, neurodegenerative disorders, inflammatory conditions, NAFLD, metal-induced toxicity, and infectious diseases. Antioxid. Redox Signal. 43, 745-764.

Aims: Hepatic ischemia/reperfusion (I/R) injury induces liver damage and secondary neuronal injury, particularly in D1-medium spiny neurons (D1-MSNs). This study investigates whether remifentanil exerts neuroprotective effect by regulating oxidative stress and inflammation via fibroblast growth factor 18 (FGF18) upregulation. Results: Remifentanil markedly attenuated liver and striatal injury in a murine I/R model, as indicated by decreased serum levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, along with reduced inflammatory cytokines interleukin 1 beta and interleukin 18. Oxidative stress was mitigated through enhanced activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and reduced reactive oxygen species levels, confirmed by lower dihydroethidium and mitochondrial superoxide indicator red fluorescence. Neuronal injury was alleviated, demonstrated by improved D1-MSN morphology, reduced apoptosis, increased expression of D1-dopamine receptor and Substance P, and fewer c-Fos-positive cells. Transcriptomic and machine learning analyses identified FGF18 as a key mediator of remifentanil's neuroprotective effects. Functional studies further confirmed that FGF18 overexpression reduced neuronal damage, whereas its knockdown abolished the protective effects of remifentanil, highlighting its pivotal role. Innovation: This study is the first to demonstrate that remifentanil exerts neuroprotective effects in hepatic I/R injury by upregulating FGF18, providing new insights into its combined hepatoprotective and neuroprotective mechanisms. Conclusion: Remifentanil mitigates hepatic I/R-induced injury to D1-MSNs by upregulating FGF18, thereby reducing oxidative stress and inflammation while preserving neuronal structure and function. These findings identify FGF18 as a potential therapeutic target for liver I/R-related neurological damage. Antioxid. Redox Signal. 43, 709-726.

Aims: The study aimed to determine if the Kindlin-2/Otub1/Slc7a11 cascade could improve cardiac ischemia reperfusion injury by inhibiting ferroptosis. Results: The cardiac tissues of ischemia - reperfusion (I/R) mice, ischemic cardiomyopathy (ICM) patients, and cardiomyocytes underwent hypoxia/reoxygenation stimulation, and the Kindlin-2 levels decreased. Cardiomyocyte-specific Kindlin-2 overexpression alleviated I/R injury by inhibiting cardiomyocyte ferroptosis in vivo while cardiomyocyte-specific low expression of Kindlin-2 impaired cardiac functions, and this was accompanied by cardiomyocyte ferroptosis and reversed by Fer-1. In addition, in vitro experiments verified that Kindlin-2 prevented ferroptosis in cardiomyocytes treated with hypoxia/reoxygenation. An endogenous Kindlin-2 deficiency in cardiomyocytes was subsequently identified to spontaneously induce ferroptosis without exogenous stimulation, which is also prevented by Fer-1. Mechanistically, Kindlin-2 accelerated the interaction between Otub1 and Slc7a11. Consequently, deubiquitinated Slc7a11 contributed to the activation of glutathione (GSH) and Gpx4 to exert the anti-ferroptosis effect. Slc7a11/GSH/Gpx4 cascades strengthened by Kindlin-2 were abolished by Otub1 knock down. Moreover, Otub1 rescued cardiomyocyte ferroptosis and cardiac injury due to the Kindlin-2 deficiency. Innovation: Kindlin-2 accelerated the interaction between Otub1 and Slc7a11. Therefore, Slc7a11/GSH/GPX4 cascades were reinforced to improve the deteriorated tissues of I/R hearts by ameliorating ferroptosis. Conclusions: Our research revealed that the Kindlin-2/Otub1/Slc7a11 cascade improved cardiac I/R injury by inhibiting ferroptosis; hence, it may be a potential therapeutic target for ICM. Antioxid. Redox Signal. 43, 727-744.

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 aimed to investigate the protective effects of 3'-Methoxypuerarin (3'-MOP) on myocardial ischemia-reperfusion injury (MIRI) and elucidate its underlying mechanisms. Specifically, we examined its role in modulating N6-methyladenosine (m6A) methylation and suppressing cardiomyocyte pyroptosis in both in vivo and in vitro models. Results: In vivo, treatment with 3'-MOP markedly reduced myocardial infarct size, preserved cardiac function, and alleviated histopathological injury following ischemia/reperfusion. Consistently, 3'-MOP suppressed m6A methylation and significantly decreased the expression of pyroptosis-related proteins, including NLRP3, cleaved GSDMD, cleaved Caspase-1, IL-1β, and IL-18. In vitro, 3'-MOP decreased m6A methylation, destabilized NLRP3 mRNA, and inhibited pyroptosis in hypoxia/reoxygenation-induced cardiomyocytes. Mechanistically, 3'-MOP disrupted the interaction between insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) and NLRP3 mRNA, regulated m6A modification at predicted NLRP3 sites, and promoted mRNA degradation, thereby mimicking the effects of si-IGF2BP1 and attenuating pyroptottenuating pyroptosis. Conclusion and Innovation: 3'-MOP exerts cardioprotective effects against MIRI by modulating m6A methylation and inhibiting pyroptosis. This study is the first to demonstrate that 3'-MOP regulates cardiomyocyte pyroptosis via the m6A/IGF2BP1-NLRP3 axis, providing a novel epitranscriptomic mechanism for cardioprotection against MIRI. Antioxid. Redox Signal. 00, 000-000.

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.