Redox BiologyPub Date : 2025-05-30DOI: 10.1016/j.redox.2025.103707
Laura Bragagna , Lina Maqboul , Ricarda Baron , Muriel Harloff , Monika Spasova , Sahar Noori , Agnes Draxler , Bernhard Franzke , Eva-Maria Strasser , Patrick A. Zöhrer , Sandra Unterberger , Rudolf Aschauer , Barbara Wessner , Karl-Heinz Wagner
{"title":"A high-protein diet with and without strength training shows no negative effects on oxidative stress markers in older adults","authors":"Laura Bragagna , Lina Maqboul , Ricarda Baron , Muriel Harloff , Monika Spasova , Sahar Noori , Agnes Draxler , Bernhard Franzke , Eva-Maria Strasser , Patrick A. Zöhrer , Sandra Unterberger , Rudolf Aschauer , Barbara Wessner , Karl-Heinz Wagner","doi":"10.1016/j.redox.2025.103707","DOIUrl":"10.1016/j.redox.2025.103707","url":null,"abstract":"<div><div>A long, healthy and pain-free life is the goal of an aging society. However, people become increasingly less active in old age, which can lead to sarcopenia. To counteract this development, strength training and a sufficient protein supply are essential. To investigate the effects of a high-protein diet in combination with strength training on oxidative stress markers in older adults, 116 men and women underwent a 17-week single-blind randomized control trial with 3 groups (Control CON, Recommended Protein RP and High Protein HP) as part of the NutriAging Study.</div><div>After finishing a 6-week dietary intervention, a strength training program was additionally implemented for RP and HP for the remaining study period. CON continued with their habitual protein intake throughout the study. Blood was drawn at three time points (baseline T1, week 8 T2, and after study completion T3) and analyzed for chemical blood parameters and the oxidative stress markers superoxide dismutase (SOD), glutathione-peroxidase (GSH-Px), catalase (CAT), ferric reducing ability potential (FRAP); γ-glutamyl-cysteinyl-glycine (GSH), glutathione disulfide (GSSG), unconjugated bilirubin (UCB), and malondialdehyde (MDA). The results showed a significant time effect of certain blood parameters and all measured oxidative stress markers independent of group allocation. This can be explained by seasonal changes over the study period. Urea and blood urea nitrogen (BUN) were significantly increased in HP, which could be attributed to the high protein intake, however they remained in the normal range. UCB and FRAP were significantly lower in HP, which could be due to the metabolization of the additional protein. Women in particular showed more altered oxidative stress markers as well as reduced uric acid (UA) in the HP group, suggesting lower estrogen secretion during menopause, possibly due to decreased nuclear factor erythroid 2-related factor 2 (NrF2) synthesis and subsequently impaired antioxidant defense. The strength training intervention alone showed no negative effects on blood or oxidative stress parameters. In summary, a high-protein diet along with strength training showed no major impact on oxidative stress in older adults.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103707"},"PeriodicalIF":10.7,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144312893","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}
Redox BiologyPub Date : 2025-05-29DOI: 10.1016/j.redox.2025.103672
Jieyou Li , Guibing Wu , Hairou Su , Manfeng Liang , Shengpei Cen , Yandan Liao , Xiangjun Zhou , Guantai Xie , Zihao Deng , Wenchong Tan , Yan Li , Wang Xiao , Lixia Liu , Jinxin Zhang , Zhenming Zheng , Yaotang Deng , Yaling Huang , Xiongjie Shi , Yilin Liu , Guowei Zhang , Xuemei Chen
{"title":"Hsp90 C-terminal domain inhibition enhances ferroptosis by disrupting GPX4-VDAC1 interaction to increase HMOX1 release from oligomerized VDAC1 channels","authors":"Jieyou Li , Guibing Wu , Hairou Su , Manfeng Liang , Shengpei Cen , Yandan Liao , Xiangjun Zhou , Guantai Xie , Zihao Deng , Wenchong Tan , Yan Li , Wang Xiao , Lixia Liu , Jinxin Zhang , Zhenming Zheng , Yaotang Deng , Yaling Huang , Xiongjie Shi , Yilin Liu , Guowei Zhang , Xuemei Chen","doi":"10.1016/j.redox.2025.103672","DOIUrl":"10.1016/j.redox.2025.103672","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies worldwide. Given the critical role of liver in iron storage and metabolism, ferroptosis, characterized by iron-dependent lipid peroxidation and oxidative damage, has become a potential therapy for HCC. Recent research indicated that Voltage-dependent anion-selective channel protein 1 (VDAC1), a key gatekeeper on the outer mitochondrial membrane (OMM), promotes ferroptosis in its oligomeric form. While oxidative stress is known to promote VDAC1 oligomerization, the relationship between oxidative modifications such as carbonylation and VDAC1 oligomerization remains poorly understood. Additionally, it is uncertain whether oligomerized VDAC1 channels facilitate the release of ferroptosis-related molecules. Our research discovered that the inhibition of the C-terminal domain of Heat shock protein 90 (Hsp90) reduced the protein level of Glutathione peroxidase 4 (GPX4) and decreased the interaction between GPX4 and VDAC1, consequently activating the carbonylation and oligomerization of VDAC1 through VDAC1-K274 site in a redox-dependent manner. The VDAC1 oligomerization promotes the release of Heme oxygenase-1 (HMOX1) from mitochondria into the cytoplasm, leading to iron overload and ultimately promoting ferroptosis. Thus, VDAC1 oligomerization is a critical factor in the pathway linking mitochondrial dysfunction to ferroptosis, highlighting the potential therapeutic interventions for HCC associated with iron dysregulation.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103672"},"PeriodicalIF":10.7,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204776","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}
Redox BiologyPub Date : 2025-05-29DOI: 10.1016/j.redox.2025.103705
Changhao Hu , Siying Gao , Xinyi Li , Kaiqing Yang , Ye Cheng, Wei Guo, Huijun Wu, Xueqin Cheng, Weiwen Zhao, Yuxuan Kong, Haoyuan Hu, Songyun Wang
{"title":"Crosstalk of autophagy and ferroptosis in cardiovascular diseases: from pathophysiology to novel therapy","authors":"Changhao Hu , Siying Gao , Xinyi Li , Kaiqing Yang , Ye Cheng, Wei Guo, Huijun Wu, Xueqin Cheng, Weiwen Zhao, Yuxuan Kong, Haoyuan Hu, Songyun Wang","doi":"10.1016/j.redox.2025.103705","DOIUrl":"10.1016/j.redox.2025.103705","url":null,"abstract":"<div><div>Cardiovascular diseases (CVDs) are characterized by high morbidity and mortality rates, imposing substantial epidemiological and economic burdens worldwide. Among the multifaceted mechanisms implicated in CVDs, autophagy and ferroptosis, two intimately linked cellular processes, emerge as pivotal pathophysiological contributors. Autophagy, as an evolutionary conserved process that mediates the degradation and recycling of intracellular components, including proteins and organelles, exerts critical regulatory effects on iron metabolism and lipid homeostasis through various specialized forms, including ferritinophagy and lipophagy. Conversely, ferroptosis, an iron dependent form of cell death, involves oxidative stress and the accumulation of lipid peroxides, often triggered by iron overload and the dysfunction of glutathione peroxidase 4 (GPX4). The intricate crosstalk between these two processes, particularly ferritinophagy-mediated iron regulation influencing ferroptosis, plays a crucial role in diverse CVDs contexts. Key regulatory molecules, such as Beclin-1 and nuclear factor E2-related factor 2 (Nrf2), function as central hubs, orchestrating the intricate interplay between autophagy and ferroptosis. Through a comprehensive examination of these mechanisms across various CVDs pathologies, we summarize the latest findings and outline potential therapeutic strategies targeting the crosstalk between autophagy and ferroptosis. As the inaugural review focusing on autophagy-ferroptosis interactions in CVDs, this work significantly enriches our understanding of the pathophysiology of CVDs and identifies novel therapeutic targets with potential for precision medicine interventions in managing CVDs.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103705"},"PeriodicalIF":10.7,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144185308","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}
Redox BiologyPub Date : 2025-05-29DOI: 10.1016/j.redox.2025.103685
Muhammad Arif Asghar , Bing Wan , Lu Li , Jie Zhang , Shixin Tang , Hang Han , Yuanyuan Yang , Long Chu , Qian Zhang , Xiao Zhang , Qinjian Zhao
{"title":"Micronutrient antioxidant supplementation alleviates valproic acid-induced oxidative stress and male infertility via the NRF2/HO-1 pathway","authors":"Muhammad Arif Asghar , Bing Wan , Lu Li , Jie Zhang , Shixin Tang , Hang Han , Yuanyuan Yang , Long Chu , Qian Zhang , Xiao Zhang , Qinjian Zhao","doi":"10.1016/j.redox.2025.103685","DOIUrl":"10.1016/j.redox.2025.103685","url":null,"abstract":"<div><h3>Background</h3><div>Valproic Acid (VPA), a widely used anticonvulsant, is known to induce oxidative stress, contributing to male infertility. This study explores the potential of micronutrient antioxidants to improve fertility in VPA-treated individuals.</div></div><div><h3>Methods</h3><div>Six-week-old male mice were treated with VPA and supplemented with antioxidants, including <span>l</span>-Arginine (120 mg/kg), N-Acetylcysteine (NAC) (2 mg/kg), Taurine (200 mg/kg), L-Tryptophan (0.5 mg/kg), Zinc chloride (ZnCl2) (1.5 mg/kg), and Selenium (0.5 mg/kg). The dosing regimen lasted for 34 days. Sperm quality, oxidative stress, and inflammatory biomarkers were assessed through gene expression analysis, western blotting, histological assessments, TUNEL assays, and immunohistochemistry. Additionally, GC-2spd(ts) and HepG2 cell lines were used to examine the testicular and systemic effects of VPA and antioxidants. Network pharmacology was applied to identify key molecular targets and pathways.</div></div><div><h3>Results</h3><div>Antioxidant supplementation significantly improved sperm count, with <span>l</span>-Arginine showing an approximately 296.1 % increase, NAC a 270.7 % increase, and Taurine a 255.9 % increase compared to the VPA-only group. Furthermore, antioxidants enhanced semen volume, testosterone levels, sperm motility, morphology, and viability. Gene expression analysis revealed significant upregulation of key oxidative stress-related proteins such as SOD1, HO-1, NRF2, and NQO1. Western blot and histological analyses showed a reversal of oxidative stress and preservation of seminiferous tubule integrity. TUNEL assays demonstrated a reduction in apoptotic damage, and IHC confirmed an increase in HO-1 and SOD1. In vitro studies with GC-2spd(ts) and HepG2 cells confirmed that antioxidants alleviated VPA-induced oxidative stress. Network pharmacology identified key molecular targets, such as GPX4, SOD1, HO-1, and NRF2, which are involved in oxidative stress, apoptosis, and inflammation pathways, that were modulated by antioxidants.</div></div><div><h3>Conclusion</h3><div>Micronutrient antioxidants effectively reduce VPA-induced oxidative stress and improve male fertility. These results suggest that antioxidant supplementation could be a promising strategy to mitigate oxidative damage and enhance fertility in individuals undergoing VPA therapy.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103685"},"PeriodicalIF":10.7,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144253774","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}
Redox BiologyPub Date : 2025-05-28DOI: 10.1016/j.redox.2025.103703
Rong-Rong Wang , Dan-Lei Chen , Meng Wei , Se-Ruo Li , Peng Zhou , Jing Sun , Qi-Yuan He , Jin Yang , Hui Zhao , Lin Fu
{"title":"Histone lactylation-induced premature senescence contributes to 1-nitropyrene-Induced chronic obstructive pulmonary disease","authors":"Rong-Rong Wang , Dan-Lei Chen , Meng Wei , Se-Ruo Li , Peng Zhou , Jing Sun , Qi-Yuan He , Jin Yang , Hui Zhao , Lin Fu","doi":"10.1016/j.redox.2025.103703","DOIUrl":"10.1016/j.redox.2025.103703","url":null,"abstract":"<div><div>Our previous study revealed that mice exposed to 1-nitropyrene (1-NP) develop pulmonary fibrosis and senescent alveolar cells. However, the impacts of chronic 1-NP on chronic obstructive pulmonary disease (COPD) and the underlying mechanism are unclear. Our research suggested that chronic 1-NP evoked alveolar structure damage, inflammatory cell infiltration, and pulmonary function decline in mice. Moreover, 1-NP increased p53 and p21 expression, the number of β-galactosidase-positive cells, and cell cycle arrest in mouse lungs and MLE-12 cells. Moreover, 1-NP promoted glycolysis and upregulated lactic dehydrogenase A (LDHA) and lactate production in mouse lungs and MLE-12 cells. Elevated glycolysis provoked histone lactylation, but not histone acetylation in pulmonary epithelial cells. Mechanistically, histone H3 lysine 14 lactylation (H3K14la) was upregulated in pulmonary epithelial cells. <em>P53</em> knockdown mitigated 1-NP-induced cell cycle arrest and senescence in MLE-12 cells. CUT&Tag and ChIP-qPCR experiments confirmed that increased H3K14la directly upregulated <em>p53</em> transcription in pulmonary epithelial cells. As expected, <em>LDHA</em> knockdown alleviated 1-NP-triggered cell cycle arrest and senescence in MLE-12 cells. In addition, supplementation with oxamate, an inhibitor of LDH, attenuated 1-NP-incurred premature senescence and the COPD-like phenotype in mice. These data revealed for the first time that histone lactylation-induced the increase in p53 transcription contributes to pulmonary epithelial cell senescence during 1-NP-induced COPD progression. Our results provide a basis for repressing lactate production as a promising therapeutic strategy for COPD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103703"},"PeriodicalIF":10.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144177639","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}
Redox BiologyPub Date : 2025-05-28DOI: 10.1016/j.redox.2025.103704
Zheng Xiao , Yucheng Pan , Hong Meng , Zongze Qu , Liang Guo , Bin Kong , Wei Shuai , He Huang
{"title":"Ubiquitin-specific protease 38 exacerbates diabetic cardiomyopathy via post-translational modification of ACAD11","authors":"Zheng Xiao , Yucheng Pan , Hong Meng , Zongze Qu , Liang Guo , Bin Kong , Wei Shuai , He Huang","doi":"10.1016/j.redox.2025.103704","DOIUrl":"10.1016/j.redox.2025.103704","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic cardiomyopathy (DCM) is a prevalent and severe complication of diabetes, for which effective management strategies remain limited. Ubiquitin-specific protease 38 (USP38) has been associated with various cardiovascular diseases. In this study, we investigate the role of USP38 in the pathogenesis of DCM.</div></div><div><h3>Methods</h3><div>Cardiomyocyte-specific transgenic and knockout USP38 mice were generated, and diabetic mouse model was established using streptozotocin injections. Neonatal rat cardiomyocytes exposed to high glucose conditions were utilized for in vitro experiments. Cardiac remodeling was assessed through echocardiography, electrophysiological analysis, histological assessment, and molecular analysis.</div></div><div><h3>Results</h3><div>USP38 expression was significantly upregulated in DCM. Cardiomyocyte-specific USP38 overexpression aggravated cardiac dysfunction, cardiac inflammation and myocardial fibrosis, mitochondrial dysfunction, and increased vulnerability to ventricular arrhythmia in diabetic mice. Conversely, cardiomyocyte-specific USP38 deletion improved cardiac structural and electrical remodeling and attenuated mitochondrial impairment. Similar results were observed in vitro. Mechanistically, RNA-sequencing analysis, immunoprecipitation and mass spectrometry analysis and lipidomic analysis demonstrated that USP38 directly interacts with Acy-CoA dehydrogenase (ACAD11), deubiquitinating and inactivating it. This leads to abnormal fatty acid oxidation and subsequent activation of the receptor for advanced glycation end products (RAGE) pathway in diabetic heart. Pharmacological inhibition of RAGE using FPS-ZM1 hampered cardiac remodeling and dysfunction in cardiomyocyte-specific USP38 overexpressing diabetic mice.</div></div><div><h3>Conclusion</h3><div>The study demonstrates that USP38 exacerbates diabetes-induced cardiac remodeling and DCM via post-translational modification of ACAD11, highlighting a novel therapeutic target for DCM.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103704"},"PeriodicalIF":10.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144196201","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}
Redox BiologyPub Date : 2025-05-27DOI: 10.1016/j.redox.2025.103680
Zhi-Wei Ye , Jie Zhang , Amit Kumar , Xuejian Huang , Theodore L. Mathuram , Andrew D. Mccall , John Culpepper , Leilei Zhang , Anthony D. Curione , Jianqiang Xu , Kenneth D. Tew , Danyelle M. Townsend , Anna Blumental-Perry
{"title":"Redox signaling-mediated S-glutathionylation of protein disulfide isomerase A1 initiates intrinsic apoptosis and contributes to accelerated aging","authors":"Zhi-Wei Ye , Jie Zhang , Amit Kumar , Xuejian Huang , Theodore L. Mathuram , Andrew D. Mccall , John Culpepper , Leilei Zhang , Anthony D. Curione , Jianqiang Xu , Kenneth D. Tew , Danyelle M. Townsend , Anna Blumental-Perry","doi":"10.1016/j.redox.2025.103680","DOIUrl":"10.1016/j.redox.2025.103680","url":null,"abstract":"<div><div>Identifying factors that contribute to the age-related onset of chronic obstructive pulmonary disease (COPD) is crucial for its prevention and treatment. The multifunctional endoplasmic reticulum (ER) chaperone protein disulfide isomerase A1 (PDIA1) shows a protective increase in expression levels in human and mouse non-COPD smokers. However, this increase slows with aging and disease progression, while increase in glutathione S-transferase <strong>π</strong>1 (GSTP1) does not. PDI has redox sensitive cysteine residues that can become S-glutathionylated (PDI-SSG) which compromise both isomerase and chaperone activity. Oxidized PDIA1 levels progressively rise with age in the lungs of murine non-smokers, with an even greater increase in smokers. To investigate whether an increased oxidized-to-native PDIA1 ratio (PDI-SSG/PDI-SH) contributes to the depletion of alveolar epithelial type 2 progenitor cells in COPD, we used the type-2-like cell line MLE12. High doses of cigarette smoke (CS) induced elevated oxidized PDIA1 levels, while a redox-refractory PDIA1 variant maintained a lower PDI-SSG/PDI-SH. Upon CS exposure, PDIA1 was S-glutathionylated by GSTP1 and predominantly localized at the ER–mitochondria interface. This mitochondrial proximity was prevented by pharmacological or genetic GSTP1 inhibition. When localized at the ER–mitochondria interface, S-glutathionylated PDIA1 decreased mitochondrial membrane potential (MMP), facilitated mitochondrial permeability transition pore opening, decreased mitochondrial respiration and triggered cytochrome <em>c</em> (<em>Cyt c</em>) release, followed by caspase-3 activation. Isolated mitochondrial studies confirmed that PDI-SSG trigger these apoptotic signals whereas native PDI does not. Our findings indicate that GSTP1-mediated S-glutathionylation of PDIA1 drives pro-apoptotic intraorganellar signaling by altering its ER distribution. Overexpression of a redox-refractory PDIA1 variant restored MMP and reduced <em>Cyt c</em> release, suggesting that a lower S-glutathionylated-to-native PDIA1 ratio is protective. These findings highlight a threshold-dependent regulation of PDIA1-SSG/PDIA1-SH redox signaling. We propose that the simultaneous inability to maintain high PDIA1 levels and the age-associated increase in its S-glutathionylated form in smokers accelerates AEC2 depletion and exhaustion, thereby contributing to emphysema progression.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103680"},"PeriodicalIF":10.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204775","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}
Redox BiologyPub Date : 2025-05-27DOI: 10.1016/j.redox.2025.103700
Xingyun Quan , Yukun Yang , Xiaolong Liu , Britta Kaltwasser , Matthias Pillath-Eilers , Bernd Walkenfort , Sylvia Voortmann , Ayan Mohamud Yusuf , Nina Hagemann , Chen Wang , Mike Hasenberg , Dirk M. Hermann , Ulf Brockmeier
{"title":"Autophagy hub-protein p62 orchestrates oxidative, endoplasmic reticulum stress, and inflammatory responses post-ischemia, exacerbating stroke outcome","authors":"Xingyun Quan , Yukun Yang , Xiaolong Liu , Britta Kaltwasser , Matthias Pillath-Eilers , Bernd Walkenfort , Sylvia Voortmann , Ayan Mohamud Yusuf , Nina Hagemann , Chen Wang , Mike Hasenberg , Dirk M. Hermann , Ulf Brockmeier","doi":"10.1016/j.redox.2025.103700","DOIUrl":"10.1016/j.redox.2025.103700","url":null,"abstract":"<div><div>Autophagy has crucial roles for ischemia/reperfusion (I/R) injury. To define the role of the autophagy hub protein p62/SQSTM1 in I/R injury, we conducted gain-of-function and loss-of-function experiments in a set of cell types, including two neuron-like cell lines, primary neurons, brain endothelial and astroglial-like cells, which we combined with mouse ischemic stroke studies. p62 levels post-I/R increased alongside intracellular ROS changes. p62 overexpression increased and p62 knockdown or pharmacological deactivation reduced I/R injury. Autophagic flux was p62-dependent, but oxygen-independent. Using p62 domain deletion mutants we identified p62's ZZ domain as key factor mediating autophagy and cell death. Death-promoting effects of p62 involved elevated ROS burden. At the same time, p62 activated a broad network of cytoprotective responses, which included NRF2-associated antioxidant signaling and inhibition of the pro-inflammatory NFκB pathway, which were bidirectionally linked with p62, and downregulation of the ER stress sensor BiP/GRP78 with consecutive activation of the UPR PERK branch. Our study establishes p62 as a master regulator of I/R injury, which offers itself as target for stroke therapies.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103700"},"PeriodicalIF":10.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144196117","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}
Redox BiologyPub Date : 2025-05-27DOI: 10.1016/j.redox.2025.103702
Christian Lindermayr , Ali Önder Yildirim
{"title":"Redox-signaling in innate immune memory: Similar mechanisms in animals/humans and plants","authors":"Christian Lindermayr , Ali Önder Yildirim","doi":"10.1016/j.redox.2025.103702","DOIUrl":"10.1016/j.redox.2025.103702","url":null,"abstract":"<div><div>Plants and animals/humans have evolved sophisticated innate immune systems to cope with microbial attack. Innate immunity implies the presence of membrane-located and intracellular receptors to recognize compounds released by damage or by invading pathogens. After detection the receptor molecules initiate intracellular defense signaling, resulting in cell death and/or production of defense molecules. Interestingly, the defense response includes also memory mechanisms, which allow the organisms to better cope with future microbial attacks. Redox mechanisms play an important role in defense signaling. In this review article, we compare the innate immune memory of animals/humans and plants and describe how reversible nitric oxide- and reactive oxygen species-dependent protein modifications enable the activation of defense signaling proteins and transcription factors and regulate the activity of chromatin modifying enzymes to establish innate immune memory. We hope to encourage efforts to characterize further molecular redox mechanisms of the innate immune memory, which might enable the development of new immunotherapies.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103702"},"PeriodicalIF":10.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144169913","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}
Redox BiologyPub Date : 2025-05-24DOI: 10.1016/j.redox.2025.103691
Ting Zhang , Kaiyu Jin , Shaoxue Zeng , Penghui Yang , Meidong Zhu , Jialing Zhang , Yingying Chen , Sora Lee , Michelle Yam , Yue Zeng , Xiaoyan Lu , Lipin Loo , G. Gregory Neely , Andrew Chang , Fanfan Zhou , Jianhai Du , Xiaohui Fan , Ling Zhu , Mark C. Gillies
{"title":"Divergent redox responses of macular and peripheral Müller Glia: Implications for retinal vulnerability","authors":"Ting Zhang , Kaiyu Jin , Shaoxue Zeng , Penghui Yang , Meidong Zhu , Jialing Zhang , Yingying Chen , Sora Lee , Michelle Yam , Yue Zeng , Xiaoyan Lu , Lipin Loo , G. Gregory Neely , Andrew Chang , Fanfan Zhou , Jianhai Du , Xiaohui Fan , Ling Zhu , Mark C. Gillies","doi":"10.1016/j.redox.2025.103691","DOIUrl":"10.1016/j.redox.2025.103691","url":null,"abstract":"<div><div>The macula is preferentially affected in some common retinal diseases (such as age-related macular degeneration, diabetic retinopathy and macular telangiectasia type 2), whereas most inherited retinal degenerations (e.g., retinitis pigmentosa) tend to initially affect the peripheral retina. This pattern suggests the macula may have intrinsic vulnerabilities in its oxidative stress defences, compared to the periphery. Profiling of single-cell level transcriptional changes found that the peripheral retina exhibited greater transcriptional alterations than the macula in response to stress. One pronounced change was in a subgroup of Müller glia (MG) that was dominant in the peripheral retina. Genes more abundantly expressed in peripheral MG were mainly associated with redox regulation, oxidative stress responses and cellular detoxification and were more influenced by oxidative insults, such as light-induced stress. In contrast, genes highly expressed in macular MG were primarily involved in cellular homeostasis and neuroprotection, showing less responsiveness to oxidative challenges. Notably, Metallothionein 1 (MT1), A-Kinase Anchor Protein 12 (AKAP12) and MAF BZIP Transcription Factor F (MAFF) were significantly more expressed in peripheral MG than in macular MG, indicating a region-specific redox regulatory mechanism. Knockdown of these genes in primary MG led to decreased viability under oxidative stress, suggesting their role in antioxidant defence. Our findings indicate that macular MG prioritise retinal function over redox adaptation, which may contribute to their vulnerability to degenerative diseases associated with oxidative damage. These insights underscore the importance of region-specific redox homeostasis in retinal health and disease.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103691"},"PeriodicalIF":10.7,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144239637","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}