Redox Biology最新文献

{"title":"Microgliosis, neuronal death, minor behavioral abnormalities and reduced endurance performance in alpha-ketoglutarate dehydrogenase complex deficient mice","authors":"Márton Kokas ,&nbsp;András Budai ,&nbsp;Andrea Kádár ,&nbsp;Soroosh Mozaffaritabar ,&nbsp;Lei Zhou ,&nbsp;Tímea Téglás ,&nbsp;Rebeka Sára Orova ,&nbsp;Dániel Gáspár ,&nbsp;Kristóf Németh ,&nbsp;Daniel Marton Toth ,&nbsp;Nabil V. Sayour ,&nbsp;Csenger Kovácsházi ,&nbsp;Andrea Xue ,&nbsp;Réka Zsuzsanna Szatmári ,&nbsp;Beáta Törőcsik ,&nbsp;Domokos Máthé ,&nbsp;Noémi Kovács ,&nbsp;Krisztián Szigeti ,&nbsp;Péter Nagy ,&nbsp;Ildikó Szatmári ,&nbsp;Attila Ambrus","doi":"10.1016/j.redox.2025.103743","DOIUrl":"10.1016/j.redox.2025.103743","url":null,"abstract":"<div><div>The alpha-ketoglutarate dehydrogenase complex (KGDHc), also known as the 2-oxoglutarate dehydrogenase complex, plays a crucial role in oxidative metabolism. It catalyzes a key step in the tricarboxylic acid (TCA) cycle, producing NADH (primarily for oxidative phosphorylation) and succinyl-CoA (for substrate-level phosphorylation, among others). Additionally, KGDHc is also capable of generating reactive oxygen species, which contribute to mitochondrial oxidative stress. Hence, the KGDHc and its dysfunction are implicated in various pathological conditions, including selected neurodegenerative diseases. The pathological roles of KGDHc in these diseases are generally still obscure.</div><div>The aim of this study was to assess whether the mitochondrial malfunctions observed in the dihydrolipoamide succinyltransferase (<em>DLST</em>) and dihydrolipoamide dehydrogenase (<em>DLD</em>) double-heterozygous knockout (DLST^+/−DLD^+/−, DKO) mice are associated with neuronal and/or metabolic abnormalities.</div><div>In the DKO animals, the mitochondrial O₂ consumption and ATP production rates both decreased in a substrate-specific manner. Reduced H₂O₂ production was also observed, either due to Complex I inhibition with α-ketoglutarate or reverse electron transfer with succinate, which is significant in ischaemia-reperfusion injury. Middle-aged DKO mice exhibited minor cognitive decline, associated with microgliosis in the cerebral cortex and neuronal death in the <em>Cornu Ammonis</em> subfield 1 (CA1) of the hippocampus, indicating neuroinflammation. This was supported by increased levels of dynamin-related protein 1 (Drp1) and reduced levels of mitofusin 2 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in DKO mice. Observations on activity, food and oxygen consumption, and blood amino acid and acylcarnitine profiles revealed no significant differences. However, middle-aged DKO animals showed decreased performance in the treadmill fatigue-endurance test as compared to wild-type animals, accompanied by subtle resting cardiac impairment, but not skeletal muscle fibrosis.</div><div>In conclusion, DKO animals compensate well the double-heterozygous knockout condition at the whole-body level with no major phenotypic changes under resting physiological conditions. However, under high energy demand, middle-aged DKO mice exhibited reduced performance, suggesting a decline in metabolic compensation. Additionally, microgliosis, neuronal death, decreased mitochondrial biogenesis, and altered mitochondrial dynamics were observed in DKO animals, resulting in minor cognitive decline. This is the first study to highlight the <em>in vivo</em> changes of this combined genetic modification. It demonstrates that unlike single knockout rodents, double knockout mice exhibit phenotypical alterations that worsen under stress situations.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103743"},"PeriodicalIF":10.7,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515920","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":"Evidence for alcohol-mediated hemolysis and erythrophagocytosis","authors":"Chaowen Zheng ,&nbsp;Siyuan Li ,&nbsp;Johannes Mueller ,&nbsp;Cheng Chen ,&nbsp;Huanran Lyu ,&nbsp;Guandou Yuan ,&nbsp;Ane Zamalloa ,&nbsp;Lissette Adofina ,&nbsp;Parthi Srinivasan ,&nbsp;Krishna Menon ,&nbsp;Nigel Heaton ,&nbsp;Stephan Immenschuh ,&nbsp;Ines Silva ,&nbsp;Vanessa Rausch ,&nbsp;Seddik Hammad ,&nbsp;Steven Dooley ,&nbsp;Shilpa Chokshi ,&nbsp;Antonio Riva ,&nbsp;Songqing He ,&nbsp;Sebastian Mueller","doi":"10.1016/j.redox.2025.103742","DOIUrl":"10.1016/j.redox.2025.103742","url":null,"abstract":"<div><div>Alcohol-related liver disease (ALD) is the most common liver disease worldwide; however, its underlying molecular mechanisms remain poorly understood. Here, we identify ethanol-mediated hemolysis and erythrophagocytosis as major contributors to ALD pathogenesis using both in vitro and in vivo models, as well as surrogate markers such as heme oxygenase-1 (HO-1) and CD163, a scavenger receptor for hemoglobin-haptoglobin complexes.</div><div>A key initial observation was the direct optical evidence of serum hemolysis in heavy drinkers, which diminished after one week of alcohol withdrawal. In parallel, soluble CD163 (sCD163) levels declined during alcohol detoxification correlating with liver damage and fibrosis stages. Moreover, red blood cells (RBCs) from heavy drinkers exhibited increased fragility under hemolytic stress. In ethanol-fed mice, we also observed serum hemolysis. Erythrophagocytosis in liver tissue was visualized by co-localization of CD163 and hemoglobin autofluorescence. In vitro studies confirmed that ethanol – at concentrations transiently present in the upper gastrointestinal tract during alcohol ingestion – directly induces hemolysis and primes RBCs for erythrophagocytosis through eryptosis, marked by externalization of phosphatidylserine. Both heme, released during hemolysis, and bilirubin, its degradation product, further amplified erythrophagocytosis at clinically relevant concentrations, suggesting a self-perpetuating cycle. The antioxidant N-acetylcysteine efficiently blocked ethanol-induced RBC priming for erythrophagocytosis.</div><div>In conclusion, alcohol triggers a cascade of hemolysis, eryptosis, and erythrophagocytosis that may contribute to the pathogenesis of alcoholic hepatitis and end-stage ALD. sCD163 could serve as a noninvasive marker of hemolysis-associated macrophage activation. This mechanism opens new avenues for antioxidant-based therapies and may help to explain typical iron abnormalities, including ferroptosis, and hyperbilirubinemia in ALD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103742"},"PeriodicalIF":10.7,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511025","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":"Gaylussacin, a stilbene glycoside, inhibits chronic obstructive pulmonary disease in mice","authors":"Hye-Young Min ,&nbsp;Jeong Yeon Sim ,&nbsp;Jee Hwan Ahn ,&nbsp;Nae-Won Kang ,&nbsp;Hye-Jin Boo ,&nbsp;Jina Kim ,&nbsp;Na-Young Yu ,&nbsp;Marta Bottacin ,&nbsp;Jungmoo Huh ,&nbsp;Choon-Sik Park ,&nbsp;Jong-Sook Park ,&nbsp;Suckchang Hong ,&nbsp;Sungyong You ,&nbsp;Dae-Duk Kim ,&nbsp;Ho-Young Lee","doi":"10.1016/j.redox.2025.103744","DOIUrl":"10.1016/j.redox.2025.103744","url":null,"abstract":"<div><div>Chronic obstructive pulmonary disease (COPD) is a major cause of human mortality worldwide and is closely associated with chronic inflammation triggered by environmental toxicants such as lead (Pb) and cadmium (Cd). However, the molecular mechanisms linking Pb/Cd exposure to COPD pathogenesis and effective therapeutic strategies remain poorly defined. In this study, we established a mouse model of environmentally induced COPD by exposing mice to Pb/Cd aerosols using a specialized nebulizer system. Pb/Cd exposure led to characteristic COPD-like pathological features, including alveolar damage, mucus hypersecretion, oxidative stress, and apoptosis. Transcriptome analysis of lung tissues revealed upregulation of pro-inflammatory cytokines, chemokines, and lipid metabolism–related genes, with macrophages–particularly those expressing MMP-12–identified as key contributors to pulmonary inflammation. Through a targeted stilbenoid compound screen, we identified gaylussacin as a potent suppressor of Pb/Cd-induced MMP-12 expression in macrophages. Mechanistically, gaylussacin suppressed expression of MMP-12 and inflammatory mediators via activation of SIRT1. In a porcine pancreatic elastase (PPE)-induced emphysema model, oral administration of gaylussacin significantly improved lung function, reduced apoptosis, ROS production, and inflammation. Pharmacokinetic analysis revealed limited oral bioavailability of gaylussacin but efficient conversion to its active metabolite, pinosylvic acid. Toxicological evaluations confirmed negligible toxicity in normal cells derived from various organs and no significant adverse effects in vivo. Collectively, these findings demonstrate that Pb/Cd inhalation promotes COPD pathogenesis through macrophage-driven inflammation mediated by MMP-12 and that gaylussacin mitigates these effects by enhancing SIRT1 activity. This study supports gaylussacin as a promising therapeutic candidate for the treatment of environmentally induced COPD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103744"},"PeriodicalIF":10.7,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515921","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":"Corrigendum to \"Dysregulated lipids homeostasis disrupts CHAC1-mediated ferroptosis driving fibroblast growth factor receptor tyrosine kinase inhibitor AZD4547 resistance in gastric cancer\" [Redox Biol. 84 (2025) 103693].","authors":"Jingwen Chen, Yedi Huang, Daocheng Zuo, Ruimin Shan, Songmao Li, Ran Li, Dong Hua, Qiang Zhan, Xudong Song, Yun Chen, Pei Ma, Ling Ma, Guoquan Tao, Yongqian Shu","doi":"10.1016/j.redox.2025.103728","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103728","url":null,"abstract":"","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":" ","pages":"103728"},"PeriodicalIF":10.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507973","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":"The inhibition of TXNRD1 by methylglyoxal impairs the intracellular control of Mycobacterium tuberculosis","authors":"Hanxiong Li ,&nbsp;Ruining Liu ,&nbsp;Gokul Raj Kathamuthu ,&nbsp;Radosveta Gencheva ,&nbsp;Zhen Gong ,&nbsp;Axel Tobias Scholz ,&nbsp;Mohammad Alzrigat ,&nbsp;Lucia Coppo ,&nbsp;Elias S.J. Arnér ,&nbsp;Martin E. Rottenberg","doi":"10.1016/j.redox.2025.103741","DOIUrl":"10.1016/j.redox.2025.103741","url":null,"abstract":"<div><div>Type 2 diabetes (DM) is a risk factor for development of tuberculosis (TB). Methylglyoxal (MGO), a reactive carbonyl increased during DM targets diverse macromolecules. Here we discovered that MGO converted the mammalian selenoprotein thioredoxin reductase 1 (TXNRD1) to a NADPH oxidase, activating the NRF2 transcription factor in bone marrow macrophages (BMM). NRF2 signaling hampered the production of immune molecules by BMM, thus allowing intracellular growth of <em>M. tuberculosis (Mtb)</em>. The overexpression of NRF2 was sufficient to increase the <em>M</em><em>tb</em> growth. Several inhibitors of TXNRD1 mimicked the effects of MGO on <em>Mtb</em> growth in BMM. MGO and the TXNRD1 inhibitor auranofin also increased the susceptibility of mice to <em>M</em><em>tb</em> infection. Finally, IFN-γ abrogated the MGO-triggered suppression of the protective responses to <em>Mtb</em> in BMM, by epigenetic regulation of immune genes, without impairing NRF2 activation. Thus, metabolic alterations in DM may have a causative role in TB-DM comorbidity, by activating NRF2 responses that impair immune protective responses.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103741"},"PeriodicalIF":10.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515922","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":"Iron-catalyzed oxidative stress compromises cancer promotional effect of BRCA2 haploinsufficiency through mitochondria-targeted ferroptosis","authors":"Yuki Maeda ,&nbsp;Yashiro Motooka ,&nbsp;Shinya Akatsuka ,&nbsp;Hideaki Tanaka ,&nbsp;Tomoji Mashimo ,&nbsp;Shinya Toyokuni","doi":"10.1016/j.redox.2025.103739","DOIUrl":"10.1016/j.redox.2025.103739","url":null,"abstract":"<div><div>Pathogenic variants in <em>BRCA2</em> are hereditary risks for various cancers, including breast, ovary, pancreas and prostate. Genomic instability due to insufficient homologous recombination is thought as responsible for carcinogenesis. Reportedly, endogenous or exogenous aldehydes, including formaldehyde and acetaldehyde, suppress BRCA2 function. However, molecular sequences how BRCA2 insufficiency leads to carcinogenesis remains unelucidated. To assess whether Fenton reaction-based oxidative stress is a promotional risk factor of carcinogenesis in BRCA2 haploinsufficiency, we here applied iron-induced renal carcinogenesis to a newly established rat heterozygous mutation model of <em>Brca2</em> (mutant, T1942Kfs<em>/+</em>; MUT). Rat MUT model, despite significant increase in spontaneous malignant tumors, showed no promotional effect on renal carcinogenesis induced by ferric nitrilotriacetate (Fe-NTA) in contrast to our previous study using <em>Brca1</em> mutant rats. Array-based comparative genome hybridization of renal cell carcinoma in MUT revealed significant increase in the frequency of homozygous <em>Cdkn2A</em> deletion. Whereas acute-phase analysis of the kidney after single or 1-week Fe-NTA administration to MUT showed suppressed lipid peroxidation, consistent with ferroptosis-resistance, ferroptosis and regeneration of tubular cells were coexistent with higher cytoplasmic catalytic Fe(II) levels in the subacute phase of MUT after 3-week Fe-NTA administration. Mechanistically, mitochondrial dysfunction with excess iron, promoted by insufficient BRCA2 presumably for maintaining DNA integrity, eventually initiated ferroptotic process. In conclusion, iron-dependent oxidative stress plays double-edged roles either for cell death or proliferation in carcinogenesis and its biological consequences are distinct between BRCA2 and BRCA1 haploinsufficiency. Our results suggest that iron-catalyzed oxidative stress is not a major driving force of carcinogenesis in <em>BRCA2</em> pathogenic variants.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103739"},"PeriodicalIF":10.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515923","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":"Translocation of SIRT6 promotes glycolysis reprogramming to exacerbate diabetic angiopathy","authors":"Kemiao Pang ,&nbsp;Jiayi Huang ,&nbsp;Shiwu Zhang ,&nbsp;Yinghui Guan ,&nbsp;Ning Zou ,&nbsp;Jiaxin Kang ,&nbsp;Haining Du ,&nbsp;Dechao Zhao ,&nbsp;Denis V. Abramochkin ,&nbsp;Heyu Chen ,&nbsp;Nan Zhang ,&nbsp;Yunyan Gu ,&nbsp;Ning Liu ,&nbsp;Yining Niu ,&nbsp;Ziqi Xiong ,&nbsp;Xueya Zhang ,&nbsp;Fanghao Lu ,&nbsp;Huitao Fan ,&nbsp;Jinwei Tian ,&nbsp;Bo Yu ,&nbsp;Weihua Zhang","doi":"10.1016/j.redox.2025.103736","DOIUrl":"10.1016/j.redox.2025.103736","url":null,"abstract":"<div><div>Diabetic angiopathy, a major complication of type 2 diabetes mellitus (T2DM), is driven by vascular dysfunction, metabolic reprogramming, and oxidative stress. NAD⁺-dependent deacetylase SIRT6, located in the nucleus, is recognized for its role in modulating cardiovascular and metabolic homeostasis through histone deacetylation. However, the functions and mechanisms of accumulation of cytoplasmic SIRT6 in T2DM remain to be elucidated. Herein, a previously unrecognized cytoplasmic role for SIRT6 is identified in promoting pathological glycolysis during diabetic vascular remodeling. Vascular smooth muscle cell (VSMC) proliferation is observed, which is correlated with protein deacetylation, especially SIRT6, which translocated to the cytoplasm mediated by Importin 13 (IPO13). Furthermore, the accumulation of cytoplasmic SIRT6 facilitates its interaction with enolase 3 (ENO3), a newly discovered downstream target. This interaction promotes ENO3 deacetylation, enhances downstream phosphoenolpyruvic acid (PEP) levels, and thereby drives glycolysis reprogramming, ultimately leading to the pathological changes associated with diabetic angiopathy. Notably, exogenous hydrogen sulfide (H₂S) restores S-sulfhydration of SIRT6 at cysteine 141, counteracting the SIRT6-ENO3 interaction, suppressing glycolysis, and mitigating VSMC hyperproliferation. This study provides novel insights into the SIRT6-ENO3 pathway through regulating vascular glycolysis reprogramming, highlighting the therapeutic potential of targeting SIRT6 in the management of diabetic angiopathy.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103736"},"PeriodicalIF":10.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144491336","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":"Corrigendum to \"FNDC5/irisin mitigates the cardiotoxic impacts of cancer chemotherapeutics by modulating ROS-dependent and -independent mechanisms\" [Redox Biol. 80 (2025) 103527].","authors":"Manish Kumar,Abhishek Singh Sengar,Anushree Lye,Pranesh Kumar,Sukhes Mukherjee,Dinesh Kumar,Priyadip Das,Suvro Chatterjee,Adele Stewart,Biswanath Maity","doi":"10.1016/j.redox.2025.103734","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103734","url":null,"abstract":"","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"51 1","pages":"103734"},"PeriodicalIF":11.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478637","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":"Discovery of a novel chalcone-derived covalent Keap1 binder for mitigating cisplatin-induced mitochondrial dysfunction and nephrotoxicity","authors":"Yanyan Deng ,&nbsp;Leizhi Xu ,&nbsp;Zhengtao Jiang ,&nbsp;Lin Chen ,&nbsp;Guanghao Zhu ,&nbsp;Chuting Xu ,&nbsp;Xiayan Chu ,&nbsp;Lixin Wang ,&nbsp;Xiaoting Niu ,&nbsp;Ling Chen ,&nbsp;Zhangping Xiao ,&nbsp;Jing Hu ,&nbsp;Guangbo Ge","doi":"10.1016/j.redox.2025.103737","DOIUrl":"10.1016/j.redox.2025.103737","url":null,"abstract":"<div><div>Cisplatin-induced kidney injury (CIKI) is a major adverse effect of this widely used chemotherapy agent. Targeting key events involved in CIKI, such as inflammation, apoptosis, mitochondrial dysfunction and oxidative stress, holds potential for mitigating CIKI and improving patient outcomes. Herein, we report a novel N-containing chalcone derivative as a cysteine-targeting covalent binder of Keap1, which effectively mitigate cisplatin (CDDP)-induced mitochondrial dysfunction (CIMD) and CIKI through activating Keap1-Nrf2-ARE signaling. Initially, a chalcone derivative (<strong>A6</strong>) was identified as a strong Nrf2 agonist through high-throughput luminescence screening of in-house compounds. After two rounds of structural optimization, we developed a novel N-containing chalcone derivative (<strong>C5</strong>), which exhibits enhanced Nrf2 agonist activity, favorable drug-like properties, and improved renal-targeting ability. Cellular and animal studies showed that <strong>C5</strong> significantly ameliorated CIMD and CIKI in CDDP-induced nephrocytes and CIKI mice <em>via</em> activating the Keap1-Nrf2-ARE signaling pathway in both settings. Mechanistically, <strong>C5</strong> covalently modified Keap1 on two critical functional cysteines in Keap1 (Cys288 in the IVR domain and Cys319 in the Kelch domain), synergistically amplifying Nrf2 activation. As an extremely potent Nrf2 agonist, <strong>C5</strong> mitigated CIKI by orchestrating antioxidant defenses, boosting mitochondrial energetics, promoting mitochondrial biogenesis, restoring mitochondrial dynamics, and inhibiting subsequent apoptotic cascade activation. Furthermore, Nrf2 knockdown markedly attenuated the nephroprotective effects of <strong>C5</strong> in CIKI mice, confirming the critical role of Keap1-Nrf2 signaling in its nephroprotective mechanism. Collectively, a novel N-containing chalcone derivative was developed as an efficacious and renal-targeting covalent binder of Keap1, offering a promising therapeutic candidate for combating CIKI.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103737"},"PeriodicalIF":10.7,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144337668","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":"Exercise-induced mitochondrial protection in skeletal muscle of ovariectomized mice: A myogenic E2 synthesis-independent mechanism","authors":"Xu Tian,&nbsp;Yi Hu,&nbsp;Tao Li,&nbsp;Fangfang Yu,&nbsp;Tingting Li,&nbsp;Xiangyang Tian,&nbsp;Yiwei Feng,&nbsp;Qiuling Zhong,&nbsp;Yifan Meng,&nbsp;Wei Chen,&nbsp;Rengfei Shi","doi":"10.1016/j.redox.2025.103735","DOIUrl":"10.1016/j.redox.2025.103735","url":null,"abstract":"<div><h3>Background</h3><div>Skeletal muscle, a 17β-estradiol (E₂)-sensitive tissue, is prone to accelerated aging due to postmenopausal E₂ deficiency and subsequent mitochondrial dysfunction. While exogenous E₂ treatment has been shown to protect against mitochondrial damage in ovariectomized rodents, the impact of exercise-induced local E₂ production in skeletal muscle on mitochondrial function remains to be determined. This study investigated exercise-mediated mitochondrial protection in ovariectomized mice and the contribution of myogenic E₂.</div></div><div><h3>Methods</h3><div>Female C57BL/6J mice (8-week-old) were divided into Sham, OVX, and OVX + ET groups (N = 12). OVX mice underwent bilateral ovariectomy, with the OVX + ET group performing 8 weeks of treadmill exercise starting 10 weeks post-surgery. Functional tests (grip strength, fatigue resistance) and gastrocnemius analyses (morphology, mitochondrial function, E2/antioxidant levels, and protein expression) were conducted. Parallel experiments in muscle-specific aromatase knockout (MS-ARO-CKO) mice included E2 supplementation via subdermal pellets.</div></div><div><h3>Results</h3><div>18 weeks after ovariectomy (OVX), C57BL/6J mice exhibited significant reductions in grip strength (∼30 %), rotarod performance (∼57 %), and grid hanging performance (∼92 %). Concomitantly, OVX led to marked decreases in mitochondrial respiration (p &lt; 0.05) and antioxidant capacity (p &lt; 0.05) in the gastrocnemius muscle, accompanied by alterations in mitochondrial quality control and antioxidant signaling proteins (p &lt; 0.05). Exercise intervention effectively attenuated these OVX-induced deficits, accompanied by a 66 % increase in E₂ levels and upregulation of aromatase (ARO) activity and expression (p &lt; 0.05). In MS-ARO-CKO mice model, exercise failed to improve the impaired antioxidant capacity induced by OVX. However, exercise, similar to estrogen supplementation, restored mitochondrial function and related protein expression abnormalities induced by OVX (p &lt; 0.05).</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that the protective effects of exercise on skeletal muscle mitochondria involve multiple mechanisms, independent myogenic E₂ Synthesis, providing novel insights for improving skeletal muscle health in postmenopausal women.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103735"},"PeriodicalIF":10.7,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144337669","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}