Redox Biology最新文献

{"title":"Particulate matter exposure induces pulmonary TH2 responses and oxidative stress-mediated NRF2 activation in mice","authors":"Yuna Jo ,&nbsp;Bo-Young Kim ,&nbsp;So Min Lee ,&nbsp;Jisu Park ,&nbsp;Wooseok Kim ,&nbsp;Ju A Shim ,&nbsp;Jun Hong Park ,&nbsp;Jong-Eun Park ,&nbsp;Yong-Il Shin ,&nbsp;Ji Hyeon Ryu ,&nbsp;Changwan Hong","doi":"10.1016/j.redox.2025.103632","DOIUrl":"10.1016/j.redox.2025.103632","url":null,"abstract":"<div><h3>Introduction</h3><div>Particulate matter (PM) is a harmful air pollutant associated with respiratory and cardiovascular diseases, but its effects on adaptive immunity are poorly understood.</div></div><div><h3>Objectives</h3><div>This study investigates the role of NRF2 in T cells in mediating immune and pulmonary responses to long-term PM exposure, highlighting its impact on inhalation toxicity.</div></div><div><h3>Methods</h3><div>To establish a mouse model of lung injury induced by PM exposure, C57BL/6 mice were intranasally administered 20 μg/kg PM₁₀ or PM_2.5 daily for 16 weeks. Lung injury parameters were analyzed in bronchoalveolar lavage fluid (BALF), plasma, and lung tissue. Changes in the proportion of immune cells in the lymph nodes and spleen were analyzed.</div></div><div><h3>Results</h3><div>Mice exposed to PM for 16 weeks showed severe lung damage, such as inflammatory cell infiltration, thickened alveolar walls, and increased oxidative stress and apoptosis. PM exposure also increased collagen and fibronectin levels, indicating tissue remodeling. Immune cell analysis revealed reduced B cell expansion, increased IL-4-producing CD4⁺ T cells, and decreased IFN-γ- and TNF-α-producing CD4⁺ T cells, accompanied by higher T_H2 cytokines and plasma IgE and IgG1 levels. PM activated the NRF2 pathway, skewing immune responses toward T_H2 differentiation, which worsened lung inflammation.</div></div><div><h3>Conclusions</h3><div>These findings highlight how PM exposure disrupts immune balance and exacerbates conditions like asthma and chronic obstructive pulmonary disease by promoting T_H2-driven inflammation through NRF2 activation.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"82 ","pages":"Article 103632"},"PeriodicalIF":10.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143815079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sulfhydrated albumin transmits H2S signaling and ameliorates DOX-induced multiorgan injuries","authors":"Yijun Xu ,&nbsp;Yang Sui ,&nbsp;Rui Jiang ,&nbsp;Xin Wang ,&nbsp;Mika Suda ,&nbsp;Manabu Niimi ,&nbsp;Zhimin Mao ,&nbsp;Zhen Zhang ,&nbsp;Shao-Ling Zhang ,&nbsp;Jianglin Fan ,&nbsp;Jian Yao","doi":"10.1016/j.redox.2025.103631","DOIUrl":"10.1016/j.redox.2025.103631","url":null,"abstract":"<div><div>Hydrogen sulfide (H₂S) is a vital signaling molecule involved in various physiological processes; however, the mechanisms underlying its systemic signaling remain poorly understood. We hypothesized that albumin, the predominant plasma protein and a vital sulfhydryl carrier, mediated systemic H₂S signaling, which could potentially treat H₂S-deficient diseases. This study aimed to investigate this hypothesis. Our results showed the presence of sulfhydrated proteins in normal mouse serum, with albumin being particularly enriched. The level of sulfhydration was influenced by H₂S availability and the redox environment. In vitro incubation of albumin with NaHS resulted in an increased number of sulfhydrated groups. Under reductive conditions, this sulfhydrated albumin (–SSH–Alb) released substantial amounts of H₂S. When –SSH–Alb was added to cultured endothelial cells, it activated the cAMP signaling pathway, upregulated cystathionine γ-lyase (CSE) expression, and enhanced intracellular H₂S levels. In an in vitro inflammatory model involving macrophages and endothelial cells, –SSH–Alb inhibited macrophage adhesion, reduced LPS-induced expression of adhesion molecules, and suppressed cytokine production and inflammasome activation. These effects correlated with improved cellular redox status. Furthermore, in vivo administration of –SSH–Alb protected mice from doxorubicin (DOX)-induced cardiotoxicity and intestinal damage. It improved mouse mortality, and alleviated ferroptotic cardiac injury and gut barrier dysfunction. These therapeutic benefits were associated with rebalanced local and systemic redox status. In summary, our study reveals that –SSH–Alb reserves, transmits, and amplifies H₂S signals and exhibits significant anti-inflammatory and antioxidant properties. This characteristic of –SSH–Alb holds promise for preventing and treating a wide range of diseases.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"83 ","pages":"Article 103631"},"PeriodicalIF":10.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New role for thioredoxins in plants: Implication of TRXo1 in protein depersulfidation","authors":"Sabrina De Brasi-Velasco ,&nbsp;Angeles Aroca ,&nbsp;Luis C. Romero ,&nbsp;Cecilia Gotor ,&nbsp;Francisca Sevilla ,&nbsp;Ana Jiménez","doi":"10.1016/j.redox.2025.103627","DOIUrl":"10.1016/j.redox.2025.103627","url":null,"abstract":"<div><div>Persulfidation, a posttranslational modification of cysteines to persulfides, is the best characterized molecular mechanism of H₂S signaling. This study is focused on new functions for thioredoxins (TRXs) in plants beyond those of thiol disulfide (S–S) exchange, including the regulation of protein persulfidation as it has been described in animal systems. To elucidate the impact of TRX<em>o</em>1 deficiency on the protein persulfidation pattern in plants of <em>Arabidopsis thaliana</em> L. wild type (WT) and two <em>Attrxo1</em> T-DNA insertion mutants grown under non stress conditions, a quantitative proteomic approach was performed. The proteomic analysis revealed a higher number of proteins that were more persulfidated in the mutants compared to WT plants, suggesting a role for TRX<em>o</em>1 in protein depersulfidation. Interestingly, most of the differentially persulfidated proteins were located in the chloroplast, implying a coordination between chloroplast H₂S-dependent persulfidation and mitochondrial TRX<em>o</em>1 depersulfidation. Among the differentially persulfidated proteins located in mitochondria, the antioxidant enzymes sAPX, DHAR1 and MDAR6 were selected for further studies. The effect of H₂S-dependent persulfidation on their enzymatic activities and its reversibility by the NADPH/thioredoxin reductase (NTRB)/TRX<em>o</em>1 system was analyzed, as well as their persulfidation levels were quantified. Sulfide treatment brought about increases in the activity levels of the enzymes, that match with a raise on the persulfidation levels. Interestingly, both activations declining after treatment with the thioredoxin system, indicate the regulation of their persulfidation by TRX<em>o</em>1. These results point to a positive effect of persulfidation on the enzymatic activities and also to a new depersulfidase activity for TRX<em>o</em>1. All together these results give a new insight of the mechanism of elimination of –SSH groups in plants exerted by TRX<em>o</em>1, and the involvement of a redox regulation on the protein persulfidation.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"82 ","pages":"Article 103627"},"PeriodicalIF":10.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143815080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redox signaling modulates axonal microtubule organization and induces a specific phosphorylation signature of microtubule-regulating proteins","authors":"Christian Conze ,&nbsp;Nataliya I. Trushina ,&nbsp;Nanci Monteiro-Abreu ,&nbsp;Lisha Singh ,&nbsp;Daniel Villar Romero ,&nbsp;Eike Wienbeuker ,&nbsp;Anna-Sophie Schwarze ,&nbsp;Michael Holtmannspötter ,&nbsp;Lidia Bakota ,&nbsp;Roland Brandt","doi":"10.1016/j.redox.2025.103626","DOIUrl":"10.1016/j.redox.2025.103626","url":null,"abstract":"<div><div>Many life processes are regulated by physiological redox signaling, but excessive oxidative stress can damage biomolecules and contribute to disease. Neuronal microtubules are critically involved in axon homeostasis, regulation of axonal transport, and neurodegenerative processes. However, whether and how physiological redox signaling affects axonal microtubules is largely unknown. Using live cell imaging and super-resolution microscopy, we show that subtoxic concentrations of the central redox metabolite hydrogen peroxide increase axonal microtubule dynamics, alter the structure of the axonal microtubule array, and affect the efficiency of axonal transport. We report that the mitochondria-targeting antioxidant SkQ1 and the microtubule stabilizer EpoD abolish the increase in microtubule dynamics. We found that hydrogen peroxide specifically modulates the phosphorylation state of microtubule-regulating proteins, which differs from arsenite as an alternative stress inducer, and induces a largely non-overlapping phosphorylation pattern of MAP1B as a main target. Cell-wide phosphoproteome analysis revealed signaling pathways that are inversely activated by hydrogen peroxide and arsenite. In particular, hydrogen peroxide treatment was associated with kinases that suppress apoptosis and regulate brain metabolism (PRKDC, CK2, PDKs), suggesting that these pathways play a central role in physiological redox signaling and modulation of axonal microtubule organization. The results suggest that the redox metabolite and second messenger hydrogen peroxide induces rapid and local reorganization of the microtubule array in response to mitochondrial activity or as a messenger from neighboring cells by activating specific signaling cascades.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"83 ","pages":"Article 103626"},"PeriodicalIF":10.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143821419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the effects of uric acid on endothelial cells: A global proteomic study","authors":"Bianca Dempsey,&nbsp;Beatriz Pereira da Silva,&nbsp;Litiele Cezar Cruz,&nbsp;Danielle Vileigas,&nbsp;Amanda R.M. Silva,&nbsp;Railmara Pereira da Silva,&nbsp;Flavia Carla Meotti","doi":"10.1016/j.redox.2025.103625","DOIUrl":"10.1016/j.redox.2025.103625","url":null,"abstract":"<div><div>This work aims to understand how normouricemic levels of uric acid can induce endothelial dysfunction seeking global proteomic alterations in Human Umbilical Vein cells (HUVEC). It reveals significant alterations in redox-sensitive and antioxidant proteins, chaperones, and proteins associated with cell migration and adhesion in response to uric acid exposure. Monitoring cellular oxidation with the roGFP2-Grx1 probe proved increased oxidation levels induced by uric acid, which can be attenuated by peroxidasin (PXDN) inhibition, suggesting a regulatory role for PXDN in mitigating oxidative stress induced by uric acid. As a consequence of uric acid oxidation and the formation of reactive intermediate, we identified adducts in proteins (+140 kDa) in a novel post-translation modification named uratylation. Increased misfolded protein levels and p62 aggregation were also found, indicating disturbances in cellular proteostasis. Furthermore, uric acid promoted monocyte adhesion and upregulated ICAM and VCAM protein levels, implicating a pro-inflammatory response in endothelial cells. These findings provide critical insights into the molecular mechanisms underlying vascular damage associated with uric acid.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"82 ","pages":"Article 103625"},"PeriodicalIF":10.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143800112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative damage to lung mitochondrial DNA is a key contributor to the development of chemical lung injury","authors":"Shubham Dubey ,&nbsp;Zhihong Yu ,&nbsp;Emily Morgan Stephens ,&nbsp;Ahmed Lazrak ,&nbsp;Israr Ahmad ,&nbsp;Saurabh Aggarwal ,&nbsp;Shaida Andrabi ,&nbsp;M. Iqbal Hossain ,&nbsp;Tamas Jilling ,&nbsp;Solana R. Fernandez ,&nbsp;Jennifer L. Bartels ,&nbsp;Suzanne E. Lapi ,&nbsp;James A. Mobley ,&nbsp;Viktor M. Pastukh ,&nbsp;Mark N. Gillespie ,&nbsp;Sadis Matalon","doi":"10.1016/j.redox.2025.103624","DOIUrl":"10.1016/j.redox.2025.103624","url":null,"abstract":"<div><div>Humans exposed to chlorine (Cl₂) due to industrial accidents or acts of terrorism may develop lung injury culminating to Acute Respiratory Distress syndrome and death from respiratory failure. Early molecular targets of inhaled oxidant gases suitable for pharmacologic modulation have not been established. Because the mitochondrial genome is highly sensitive to oxidant stress, we tested the hypothesis that mice exposure to Cl₂ gas causes oxidative damage to the mitochondrial DNA (mtDNA) that triggers the development of acute and chronic lung injury. Cl₂ gas-exposed C57BL/6 mice and returned to room air, developed progressive loss of lung DNA glycosylase OGG1, followed by oxidative mtDNA damage. This resulted in activation of inflammatory pathways by circulating DNA, progressive increased airway resistance, alveolar injury and acute pulmonary edema due to loss of epithelial amiloride-sensitive sodium channels. Mice not succumbing acutely displayed a delayed syndrome of progressive increase in airway resistance and emphysematous-like changes in lung morphology. Global proteomics of lungs harvested 24 h post Cl₂ exposure revealed alterations in over 1500 lung proteins, including 14 key mitochondrial proteins. Intranasal instillation of a recombinant protein targeting OGG1 to mitochondria (mitoOGG1) at 1 h post exposure decreased oxidized lung mtDNA, alterations to the lung and mitochondrial proteomes, severity of the acute and delayed lung injury and increased survival. These data show that injury to the mt-genome is a key contributor to the development of acute and chronic lung injury after Cl₂ gas exposure and point to mtDNA oxidation as a target for pharmacologic intervention.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"82 ","pages":"Article 103624"},"PeriodicalIF":10.7,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143800114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut flora-derived succinate exacerbates Allergic Airway Inflammation by promoting protein succinylation","authors":"Chao Wang ,&nbsp;Xin Yu ,&nbsp;Xiao Yu ,&nbsp;Hui Xiao ,&nbsp;Yuemeng Song ,&nbsp;Xinlei Wang ,&nbsp;Haoyu Zheng ,&nbsp;Kai Chen ,&nbsp;Yiming An ,&nbsp;Zhengjie Zhou ,&nbsp;Xiaoping Guo ,&nbsp;Fang Wang","doi":"10.1016/j.redox.2025.103623","DOIUrl":"10.1016/j.redox.2025.103623","url":null,"abstract":"<div><div>Allergic airway inflammation (AAI) is a prevalent respiratory disorder that affects a vast number of individuals globally. There exists a complex interplay among inflammation, immune responses, and metabolic processes, which is of paramount importance in the pathogenesis of AAI. Metabolic dysregulation and protein translational modification (PTM) are well-recognized hallmarks of diseases, playing pivotal roles in the onset and progression of numerous ailments. However, the role of gut microbiota metabolites in the development of AAI, as well as their influence on PTM modifications within this disease context, have not been thoroughly explored and investigated thus far. In AAI patients, succinate was identified as a key metabolite, positively correlated with certain immune parameters and IgE levels, and having good diagnostic value. In AAI mice, gut bacteria were the main source of high succinate levels. Mendelian randomization showed succinate as a risk factor for asthma. Exogenous succinate worsened AAI in mice, increasing airway resistance and inflammatory factor levels. Protein succinylation in AAI mice lungs differed significantly from normal mice, with up-regulated proteins in metabolic pathways. FMT alleviated AAI symptoms by reducing succinate and protein succinylation levels. In vitro, succinate promoted protein succinylation in BEAS-2B cells, and SOD2 was identified as a key succinylated protein, with the K68 site crucial for its modification and enzyme activity regulation. Gut flora-derived succinate exacerbates AAI in mice by increasing lung protein succinylation, and FMT can reverse this. These findings offer new insights into AAI mechanisms and potential therapeutic targets.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"82 ","pages":"Article 103623"},"PeriodicalIF":10.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accelerating inflammatory resolution in humans to improve endothelial function and vascular health: Targeting the non-canonical pathway for NO","authors":"Clement Lau ,&nbsp;Christopher P. Primus ,&nbsp;Asad Shabbir ,&nbsp;Ismita Chhetri ,&nbsp;Mutsumi Ono ,&nbsp;Michael Masucci ,&nbsp;Muhammad Aadil Bin Noorany Aubdool ,&nbsp;Julie Amarin ,&nbsp;Alexander JP. Hamers ,&nbsp;Zara Khan ,&nbsp;Nitin Ajit Kumar ,&nbsp;Shanik A. Montalvo Moreira ,&nbsp;Gani Nuredini ,&nbsp;Miski Osman ,&nbsp;Charlotte Whitear ,&nbsp;Tom Godec ,&nbsp;Vikas Kapil ,&nbsp;Gianmichele Massimo ,&nbsp;Rayomand S. Khambata ,&nbsp;Krishnaraj S. Rathod ,&nbsp;Amrita Ahluwalia","doi":"10.1016/j.redox.2025.103592","DOIUrl":"10.1016/j.redox.2025.103592","url":null,"abstract":"<div><h3>Background</h3><div>Chronic cardiovascular diseases (CVD) are characterised by low-grade systemic inflammation in part due to reduced nitric oxide (NO) bioavailability associated with endothelial dysfunction. Bioavailability of NO can be enhanced by activation of the non-canonical pathway, through increased dietary inorganic nitrate consumption with the potential to attenuate inflammation.</div></div><div><h3>Methods</h3><div>We sought to determine whether dietary inorganic nitrate influences the inflammatory response in models of localised (cantharidin-induced blisters) and systemic inflammation (typhoid vaccine), in healthy male volunteers and conducted two clinical trials; Blister-NITRATE and Typhoid-NITRATE respectively.</div></div><div><h3>Results</h3><div>We show that dietary nitrate attenuates endothelial dysfunction following typhoid vaccine administration and accelerates resolution of cantharidin-induced blisters. Both phenomena were associated with an increased level of pro-resolving mediators consequent to a reduction in the expression and activity of pro-inflammatory monocytes. Moreover, we show that leukocytes of the monocyte lineage express the nitrite reductase XOR, that may drive localised nitrite reduction to elevate NO (and cGMP) to drive the protective phenotype.</div></div><div><h3>Conclusions</h3><div>Inorganic nitrate improves endothelial function in the setting of systemic inflammation. Whilst the immediate inflammatory response appeared unaffected by inorganic nitrate treatment, during the resolution phase of the acute inflammatory response lower levels of pro-inflammatory classical inflammatory and intermediate monocytes and attenuated levels of inflammatory cytokines and chemokines were evident. We propose that this reflects a pro-resolution phenotype that may be of potential therapeutic benefit in patients with established CVD.</div></div><div><h3>Clinical trial registration</h3><div>URL: <span><span>https://www.clinicaltrials.gov</span><svg><path></path></svg></span>; unique identifiers NCT02715635, NCT03183830.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"82 ","pages":"Article 103592"},"PeriodicalIF":10.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143800113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sphaeropsidin A covalently binds to Cys 151 of Keap1 to attenuate LPS-induced acute pneumonia in mice","authors":"Kang Yang ,&nbsp;Qing-Tong Han ,&nbsp;Rong-Xue Xing ,&nbsp;Zhi-Ying Li ,&nbsp;Lin-Tao Xu ,&nbsp;Lu-Zhou Chen ,&nbsp;Lan Xiang ,&nbsp;Dong-Mei Ren ,&nbsp;Qing-Wen Hu ,&nbsp;Xiao-Ning Wang ,&nbsp;Tao Shen","doi":"10.1016/j.redox.2025.103621","DOIUrl":"10.1016/j.redox.2025.103621","url":null,"abstract":"<div><h3>Introduction</h3><div>Kelch ECH-associating protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2) axis is crucial for regulating oxidative stress and inflammatory responses in acute pneumonia. Sphaeropsidin A (SA) is a antioxidant diterpenoid isolated from <em>Sphaeropsis sapinea</em> f. sp. <em>cupressi,</em> discovered as a novel Nrf2 agonist by our research group previously. However, the accurate function and mechanism of SA in treating acute pneumonia are still unknown.</div></div><div><h3>Methods</h3><div>The therapeutic effect of SA was evaluated in LPS-induced acute pneumonia in mice. The underlying mechanism of action was then analyzed by transcriptomics. The direct target of SA was identified through the synthesis of SA-biotin probe, and the binding amino acid residues were found and verified by LC-MS/MS analysis and site-specific mutation. Finally, knockout mice were employed to verify the mechanism of SA.</div></div><div><h3>Results</h3><div>Our data indicated that SA significantly inhibited LPS-induced acute pneumonia in mice via up-regulating Nrf2, inhibiting NLRP3 inflammasome and NF-κB activation, and identified Keap1 as the direct target of SA. Specifically, the effective dose of SA in mice was only 2 mg/kg. SA selectively covalent bound to Keap1 in cysteine 151 residue (Cys151). SA mediated the activation of Nrf2 and reduced the level of ROS, thereby inhibiting the NF-κB and NLRP3 inflammasome. Besides, SA formed hydrogen bond with ASP48 of ASC, blocking its oligomerization and inhibiting the activation of NLRP3 inflammasome.</div></div><div><h3>Conclusion</h3><div>This study indicates that SA might be a new covalent molecule of Keap1 to activate Nrf2, and is a promising drug candidate or lead molecule for the therapy of acute pneumonia through regulating Nrf2/NF-κB/NLRP3 inflammasome axis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"82 ","pages":"Article 103621"},"PeriodicalIF":10.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding ischemic stroke: Perspectives on the endoplasmic reticulum, mitochondria, and their crosstalk","authors":"Chuxin Zhang ,&nbsp;Xin Lan ,&nbsp;Qingguo Wang ,&nbsp;Yuxiao Zheng,&nbsp;Jialin Cheng,&nbsp;Jinhua Han,&nbsp;Changxiang Li ,&nbsp;Fafeng Cheng ,&nbsp;Xueqian Wang","doi":"10.1016/j.redox.2025.103622","DOIUrl":"10.1016/j.redox.2025.103622","url":null,"abstract":"<div><div>Stroke is known for its high disability and mortality rates. Ischemic stroke (IS), the most prevalent form, imposes a considerable burden on affected individuals. Nevertheless, existing treatment modalities are hindered by limitations, including narrow therapeutic windows, substantial adverse effects, and suboptimal neurological recovery. Clarifying the pathological mechanism of IS is a prerequisite for developing new therapeutic strategies. In this context, the functional disruption of mitochondria, the endoplasmic reticulum (ER), and the crosstalk mechanisms between them have garnered increasing attention for their contributory roles in the progression of IS. Therefore, this review provides a comprehensive summary of the current pathomechanisms associated with the involvement of the ER and mitochondria in IS, emphasising Ca²⁺ destabilization homeostasis, ER stress, oxidative stress, disordered mitochondrial quality control, and mitochondrial transfer. Additionally, this article highlights the functional interaction between the ER and mitochondria, as well as the mitochondrial-ER contacts (MERCs) that structurally connect mitochondria and the ER, aiming to provide ideas and references for the research and treatment of IS.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"82 ","pages":"Article 103622"},"PeriodicalIF":10.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143783830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}