Bing Sun , Jing-dong Wang , Meng-yao Wu , Hua-yong Chen , Si-qin Yang , Yi-min Chen , Yu Fu , Zhao-hong Chen , Yong-ming Yao
{"title":"Sestrin2 alleviates sepsis-induced immunosuppression of dendritic cells by regulating mitochondrial dynamics","authors":"Bing Sun , Jing-dong Wang , Meng-yao Wu , Hua-yong Chen , Si-qin Yang , Yi-min Chen , Yu Fu , Zhao-hong Chen , Yong-ming Yao","doi":"10.1016/j.freeradbiomed.2025.08.050","DOIUrl":"10.1016/j.freeradbiomed.2025.08.050","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondrial dynamics and mitophagy are key mechanisms maintaining mitochondrial quality and homeostasis in inflammatory diseases, though their activation pathways in inflammatory regulation remain unclear. Sestrin2 (Sesn2), a stress-responsive protein critical for cellular homeostasis, was investigated in this study for its regulatory role in mitochondrial dynamics during sepsis and its potential mechanism in dendritic cell (DC) necroptosis.</div></div><div><h3>Methods</h3><div>This study evaluated Sesn2-regulated mitochondrial dynamics proteins such as dynamin-related protein 1 (DRP1), mitochondrial fission factor (MFF), and mitofusin 2 (MFN2) in DCs during sepsis using Western blotting, laser confocal microscopy, and transmission electron microscopy. Lentiviral-transfected cell lines and Sesn2-knockout mouse models were developed to assess Sesn2 deletion's role in DC necroptosis and its impact on immune response signaling pathways post-septic challenge.</div></div><div><h3>Results</h3><div>Both cecal ligation and perforation (CLP)-induced sepsis and lipopolysaccharide (LPS) stimulation elicited significant alterations in mitochondrial dynamics, and Sesn2 expression peaked at 24 h. When Sesn2 was knocked down, necroptosis and mitochondrial fission of DCs were noticeably increased, while mitochondrial fusion was decreased. Conversely, the overexpression of Sesn2 exerted a significant protective impact on DCs. Consistently, the necroptosis and immunosuppression of DCs and 7-days mortality rate in Sesn2 gene-deficient mice were significantly increased compared with those in wild-type (WT) mice. Furthermore, Sesn2-mediated mitochondrial fusion and division on DCs was identified to be closely associated with the necroptosis pathway, and DRP1-ROS-ZBP1 signaling was obviously involved in down-regulating necroptosis of DCs in the setting of sepsis.</div></div><div><h3>Conclusions</h3><div>Sesn2-mediated mitochondrial fusion and division can be significantly activated to alleviate the necroptosis of DCs <em>via</em> the DRP1-ROS-ZBP1 pathway in the context of sepsis. Thus, it is of importance that Sesn2 stabilized mitochondrial dynamics might be beneficial for reversing immunosuppression associated with septic complications.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 583-596"},"PeriodicalIF":8.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144948620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Allison Janak , Abhishek Jain , Rolando Garcia-Milian , Oladimeji Aladelokun , Xiaomei Ma , Philip B. Paty , Sajid A. Khan , Caroline H. Johnson
{"title":"Distinct metabolic and genetic alterations in tumors from early-onset versus late-onset colorectal cancer","authors":"Allison Janak , Abhishek Jain , Rolando Garcia-Milian , Oladimeji Aladelokun , Xiaomei Ma , Philip B. Paty , Sajid A. Khan , Caroline H. Johnson","doi":"10.1016/j.freeradbiomed.2025.08.052","DOIUrl":"10.1016/j.freeradbiomed.2025.08.052","url":null,"abstract":"<div><div>Early-onset colorectal cancer (EO-CRC) occurring in individuals under age 50 is rapidly increasing globally, while the incidence of late-onset colorectal cancer (LO-CRC) has decreased over recent years. Previous studies have identified metabolites linked to CRC biology, however tumor-specific differences between EO-CRC and LO-CRC have not been explored. This study aimed to compare the tumor metabolome of EO-CRC and LO-CRC patients to reveal the unique biochemical state of EO-CRC. Mass spectrometry-based untargeted metabolomics was performed on tumor and patient-matched normal tissues from EO-CRC (n = 53) and LO-CRC (n = 314) patients to identify metabolites significantly altered in tumors (q ≤ 0.05). Metabolite set enrichment analysis, metabolic pathway, and network analyses were performed, to identify the relationship between the altered metabolites and biological function. Analysis revealed 155 metabolites significantly altered between normal and tumor tissues. Homovanillic acid , a metabolite of dopamine, was uniquely downregulated in EO-CRC. Despite shared changes to homovanillic acid-metabolizing genes between EO- and LO-CRC the disruption in catecholamine metabolism may be specific to EO-CRC biology. Pathway and network analysis, supported by gene expression validation, showed that PD-L1 was uniquely decreased in EO-CRC suggesting immunosuppression. Additionally, phospholipid signaling was favored in EO-CRC, whereas LO-CRC tumors showed alterations to EGFR signaling and oxidative stress-related genes. In summary, this study reveals the metabolic nuances in tumor tissues from patients with EO-CRC and LO-CRC, indicating catecholamine metabolism, phospholipid signaling and immunosuppression in the biology of EO-CRC. These findings provide new insight into the metabolism of EO-CRCs that may inform new therapeutic strategies for this group of CRC patients.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 773-782"},"PeriodicalIF":8.2,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144948624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiao-Yi Zhang , Yi-Hao Zhang , Nan-Nan Liang , Shan-Shan Xu , Qiang-Sheng Li , Ya-Ping Song , Wei-Wei Zhang , Bo Wang , Hua Wang , Yi-Chao Huang , De-Xiang Xu
{"title":"The m6A modification-mediated upregulation of ETS2 translation drives arsenic-induced spermatogonial senescence","authors":"Xiao-Yi Zhang , Yi-Hao Zhang , Nan-Nan Liang , Shan-Shan Xu , Qiang-Sheng Li , Ya-Ping Song , Wei-Wei Zhang , Bo Wang , Hua Wang , Yi-Chao Huang , De-Xiang Xu","doi":"10.1016/j.freeradbiomed.2025.08.053","DOIUrl":"10.1016/j.freeradbiomed.2025.08.053","url":null,"abstract":"<div><div>Accumulating evidence indicates that arsenic (As) exposure causes a decline in sperm quality. This study aimed to investigate the impact of As exposure on spermatogonial senescence. GC-1 cells were exposed to NaAsO<sub>2</sub> (10 μM). RNA sequencing and ribosome profiling sequencing were performed to identify key regulators of cellular senescence. Methylated RNA immunoprecipitation-qPCR was used to determine N<sup>6</sup>-methyladenosine (m6A) modification. The results revealed that the differentially expressed genes were enriched in pathways related to cellular senescence. Several established senescence markers, β-galactosidase activity, γ-H2AX, and P16, were elevated in As-exposed GC-1 cells. Further analysis revealed that P21 and its transcription factor ETS2 were upregulated. ETS2 knockout prevented As-induced P21 upregulation and cell senescence. The multi-omics joint analysis indicated that As exposure elevated ETS2 translation efficiency by YTHDC2-dependent m6A modification. Mechanistically, As exposure induced mitochondrial dysfunction. Alpha-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate and RNA demethylase cofactor, was reduced in As-exposed GC-1 cells. Additional experiments showed that As exposure induced NAD<sup>+</sup> depletion and suppressed SIRT3 activity. Supplementation with nicotinamide mononucleotide, an NAD<sup>+</sup> precursor, attenuated As-evoked α-KG reduction and ETS2 upregulation. These findings suggest that As induces spermatogonial senescence via m6A modification-mediated upregulation of ETS2 translation and identify NAD<sup>+</sup> replenishment as a potential countermeasure.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 384-396"},"PeriodicalIF":8.2,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144904230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Redox reactivities of membrane-bound amyloid-β-Cu complexes and their targeting by metallothionein-3","authors":"Luciano Perez-Medina, Gabriele Meloni","doi":"10.1016/j.freeradbiomed.2025.08.047","DOIUrl":"10.1016/j.freeradbiomed.2025.08.047","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β peptide (Aβ<sub>1-40/42</sub>) in the central nervous system (CNS). Copper coordination to Aβ triggers Aβ<sub>1-40/42</sub> aggregation and promotes the catalytic generation of reactive oxygen species (ROS). Due to its amphiphilic nature, Aβ<sub>1-40/42</sub> can interact with cell membranes and compromise their integrity. In this work, we characterized the insertion of Aβ<sub>1-42</sub> into an artificial lipid bilayer system mimicking cell membranes and demonstrate that the Aβ<sub>1-42</sub>-lipid interaction does not prevent the Cu<sup>2+</sup> coordination to Aβ<sub>1-42</sub>. We performed a comparative analysis of the redox reactivities of membrane-bound Aβ<sub>1-42</sub> (memAβ<sub>1-42</sub>-Cu<sup>2+</sup>) with soluble Aβ<sub>1-42</sub>-Cu<sup>2+</sup> establishing that membrane insertion leads to memAβ<sub>1-42</sub>-Cu<sup>2+</sup> complexes featuring an enhanced detrimental catechol oxidase activity towards the neurotransmitter dopamine. Moreover, memAβ<sub>1-42</sub>-Cu<sup>2+</sup> efficiently catalyzes Aβ di-tyrosine crosslinking and hydroxyl radical production in the presence of ascorbate. In addition, we establish that memAβ<sub>1-42</sub>-Cu<sup>2+</sup> redox reactivity catalyzes polyunsaturated fatty acids (PUFAs) lipid peroxidation, leading to the generation of malondialdehyde (MDA) toxic end-product. This reactivity compromises the structural integrity of the lipid bilayers resulting in membrane leakage.</div><div>Metallothioneins (MTs) are cysteine-rich metalloproteins central to neuronal and astrocytic metal homeostasis. MTs bind d<sup>10</sup> metals (Cu<sup>+</sup> and Zn<sup>2+</sup>) forming two metal thiolate clusters in their structure. In the CNS, the metallothionein-3 (MT-3) isoform possess a neuroprotective role, but it is downregulated in AD patients. MT-3 controls aberrant protein-Cu<sup>2+</sup> interactions and redox reactivities of amyloidogenic protein-Cu<sup>2+</sup> complexes, including soluble Aβ<sub>1-40.</sub> In this work, we unravel that the detrimental memAβ<sub>1-42</sub>-Cu<sup>2+</sup> redox reactivities can also be efficiently silenced by MT-3 via metal swap reactions, by scavenging and reducing Cu<sup>2+</sup> to Cu<sup>+</sup> in its β-domain using thiolates as electron source, forming the redox-inert Cu<sup>+</sup><sub>4</sub>Zn<sup>2+</sup><sub>4</sub>MT-3 species. Consequently, MT-3 efficiently prevents lipid peroxidation and protects membrane structural integrity. New strategies targeting membrane-bound Aβ<sub>1-42</sub>-Cu<sup>2+</sup> complexes as key players in AD etiology could be envisioned.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 472-490"},"PeriodicalIF":8.2,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144917645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"RBMS2 mediates SLC7A11 transcription-translation to regulate ferroptosis in colorectal cancer","authors":"Xiao Wang, Pengfei Liu, Yifan An, Yanting Hu, Hui Qiao, Huihui Miao","doi":"10.1016/j.freeradbiomed.2025.08.051","DOIUrl":"10.1016/j.freeradbiomed.2025.08.051","url":null,"abstract":"<div><div>The incidence of colorectal cancer (CRC) increases yearly. Ferroptosis, a form of regulated cell death, has gained extensive attention in cancer research. RNA-binding motif single-stranded interacting protein 2 (RBMS2) has been implicated in various cancers, but its role in CRC and its involvement with ferroptosis remains poorly understood. This study explores the involvement of RBMS2 in CRC development and its potential as a therapeutic target. Functional assays, including CCK-8, colony formation, Transwell migration, invasion assays, and EMT-related gene determination, were conducted to evaluate the effects of RBMS2 overexpression and knockdown. Ferroptosis, apoptosis, and autophagy were assessed using specific inhibitors, ferroptosis inducers, and apoptosis and proliferation detection. The interaction between RBMS2 and SLC7A11 was explored during the ferroptosis process. In vivo experiments involved xenograft models in nude mice to observe tumor growth, EMT, and metastasis. Overexpression of RBMS2 inhibited CRC cell proliferation, migration, and epithelial-mesenchymal transition (EMT). Furthermore, RBMS2 promoted ferroptosis by downregulating SLC7A11. Mechanistic studies revealed that RBMS2 destabilizes SLC7A11 at the mRNA level. In vivo, RBMS2 overexpression significantly suppressed tumor growth and lung/liver metastasis. Our findings indicate that RBMS2 inhibits CRC progression by promoting ferroptosis and regulating SLC7A11 mRNA stability. Targeting the RBMS2-SLC7A11 axis could provide a novel therapeutic strategy for CRC.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 504-513"},"PeriodicalIF":8.2,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Runtian Zhou , Xiaonan Wang , Yuanzhang Jin , Binghong Chen , Haifeng Liu, Xiaofeng Zhao, Doudou Jing, Bin Zhao
{"title":"Mechanism of lidocaine-induced ROS generation triggering DNA double-strand breaks and promoting intervertebral disc cell senescence via the MYC-DUSP1-P53 axis","authors":"Runtian Zhou , Xiaonan Wang , Yuanzhang Jin , Binghong Chen , Haifeng Liu, Xiaofeng Zhao, Doudou Jing, Bin Zhao","doi":"10.1016/j.freeradbiomed.2025.08.049","DOIUrl":"10.1016/j.freeradbiomed.2025.08.049","url":null,"abstract":"<div><div>Discogenic lower back pain (DLBP) is a prevalent lumbar disorder. Functional Anesthetic Discography (FAD) is the primary diagnostic method for DLBP, with a high positivity rate. However, the mechanism by which lidocaine, a local anesthetic commonly used in FAD, induces damage to intervertebral disc cells remains unclear. This study aimed to investigate how lidocaine causes intervertebral disc cell damage and exacerbates the process of intervertebral disc degeneration (IVDD). We conducted primary nucleus pulposus cell (NPC) isolation and culture, and divided the cells into groups by lidocaine concentration (2.0 %, 1.0 %, 0.5 %, and 0 %). The cytotoxic effect of lidocaine on NPCs was evaluated using the CCK-8 colorimetric assay. We then created a mouse IVDD model, and conducted X-ray, magnetic resonance imaging (MRI), and mRNA-seq analysis. Assays, immunofluorescence detection, and real-time quantitative polymerase chain reaction (RT-qPCR) analyses were also performed. Lidocaine-induced oxidative stress damage in NPCs, leading to DNA double-strand breaks and triggering the transition of NPCs into a senescent state. Furthermore, treatment with an ROS inhibitor significantly alleviated both DNA damage and senescence. RNA-seq analysis revealed a marked upregulation in the MYC-DUSP1 axis expression. By employing si-RNA to inhibit the MYC-DUSP1 axis, the expression of senescence-related phenotypes was effectively reduced. Additionally, dasatinib (DASA) administration effectively mitigated the lidocaine-induced senescence of NPCs and alleviated the detrimental effects of lidocaine on IVDD. This study demonstrated that lidocaine exacerbates oxidative stress reactions within NPCs, leading to DNA double-strand breaks and promoting cellular senescence, thereby further aggravating IVDD progression. Moreover, an effective anti-senescence drug was identified, suggesting that DASA could be utilized as an intervention during FAD to reduce further pharmacological damage to NPCs. These findings provide an experimental foundation for optimizing the diagnostic approaches for DLBP.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 457-471"},"PeriodicalIF":8.2,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144913967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nikolaus Falb , Robert Warneke , Johannes Stadlmann , Nikola Luca Satrapa , Paul G. Furtmüller , Tim Causon , Jörg Stülke , Stefan Hofbauer
{"title":"Coproheme decarboxylase from Bacillus subtilis is required for bacterial growth and heme b biosynthesis under anaerobic conditions","authors":"Nikolaus Falb , Robert Warneke , Johannes Stadlmann , Nikola Luca Satrapa , Paul G. Furtmüller , Tim Causon , Jörg Stülke , Stefan Hofbauer","doi":"10.1016/j.freeradbiomed.2025.08.046","DOIUrl":"10.1016/j.freeradbiomed.2025.08.046","url":null,"abstract":"<div><div>Heme biosynthesis notably does not follow a universal pathway. Instead, different organisms utilize various routes of producing this essential molecule. The coproporphyrin-dependent (CPD) pathway is unique to Gram-positive bacteria. Given the ubiquity of Gram-positive pathogenic organisms, thorough research on its enzymatic steps is a prerequisite for the development of novel antibiotics. Here the focus lies on coproheme decarboxylase (ChdC, formerly HemQ), the terminal step of the pathway, catalyzing the transformation of Fe-coproporphyrin III (coproheme) to heme <em>b</em> by oxidative decarboxylation. In previous studies, hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) has been shown to act as a necessary co-substrate and electron acceptor for ChdC. However, H<sub>2</sub>O<sub>2</sub>, due to its cytotoxic effects, needs tight intracellular control and is a sub-optimal substrate <em>in vivo</em>, especially during anaerobic growth. To investigate a H<sub>2</sub>O<sub>2</sub>-free pathway for heme biosynthesis, knockout studies on Gram-positive model organism <em>Bacillus subtilis</em> have been performed. These reveal that Δ<em>chdC</em> strains exhibit heme auxotrophic behavior during aerobic and anaerobic growth, highlighting that ChdC has likely no anaerobic alternative. Free and protein bound FMN (in the form of flavodoxins YkuN and YkuP from <em>B. subtilis</em>) were subsequently characterized as alternative co-substrates. Their reaction with heterologously expressed ChdC from <em>B. subtilis</em> was characterized in different settings. By polarographic dioxygen level determination, liquid chromatography, mass spectrometry and time-resolved spectroscopy, these reactions were shown to be possible and promoted under anaerobic conditions and at elevated pH-values. Overall, the results presented in this study confirm the necessity and the capability of ChdC to react anaerobically in a Gram-positive model organism.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 364-372"},"PeriodicalIF":8.2,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144904228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ravi A. Kumar , Vinicius Mariani , Chaoran Yang , Leonardo F. Ferreira
{"title":"Skeletal muscle knockout of NAD(P)H oxidase 2 delays the development of isotonic diaphragm fatigue in mice","authors":"Ravi A. Kumar , Vinicius Mariani , Chaoran Yang , Leonardo F. Ferreira","doi":"10.1016/j.freeradbiomed.2025.08.045","DOIUrl":"10.1016/j.freeradbiomed.2025.08.045","url":null,"abstract":"<div><div>Mechanisms of skeletal muscle fatigue are commonly studied under isometric conditions, which exclude muscle shortening and limit physiological relevance. We developed a novel <em>in vitro</em> protocol to examine isotonic fatigue using afterload contractions that permits the study of additional active (velocity, power, work) and passive (stiffness, energy loss) mechanical properties of muscle. During the development of this protocol, we examined the impact of shortening load during afterload contractions on the development of fatigue, and observed a relationship where fatigue onset is more rapid and severe with larger shortening loads (30 % vs. 45 % vs. 60 % maximal isometric force). We then applied this protocol to investigate the contribution of NAD(P)H Oxidase 2 (Nox2) to fatigue development and recovery. Nox2 was deleted from skeletal muscle using the Cre-LoxP system (skmNox2KO), while Cre-negative littermates were used as controls. Knockout of Nox2 attenuated the decline in power and increased total isotonic work performed during repeated contractions compared to controls. Recovery kinetics of power, work, and isometric force were similar between groups. Passive mechanical properties—including stiffness and energy loss— increased with fatigue but were unaffected by Nox2 deletion. These findings highlight the importance of incorporating isotonic contractions to uncover fatigue mechanisms and suggest that Nox2, and presumably reactive oxygen species, contributes to the decline in muscle power during repetitive shortening contractions.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 284-295"},"PeriodicalIF":8.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144893354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tilde Andersson , Shoaib Anwaar , Eduardo Fuentes-Lemus , Maria Allhorn , Lotta Happonen , Margaret Veitch , Hui Yi Chew , Marcela Montes de Oca , Lloyd Tanner , Holger Brüggemann , Pontus Nordenfelt , Michael J. Davies , James W. Wells , Rolf Lood
{"title":"Sacrificial redox modulation by a secreted bacterial effector molecule mitigates oxidative stress and inflammation in vivo","authors":"Tilde Andersson , Shoaib Anwaar , Eduardo Fuentes-Lemus , Maria Allhorn , Lotta Happonen , Margaret Veitch , Hui Yi Chew , Marcela Montes de Oca , Lloyd Tanner , Holger Brüggemann , Pontus Nordenfelt , Michael J. Davies , James W. Wells , Rolf Lood","doi":"10.1016/j.freeradbiomed.2025.08.038","DOIUrl":"10.1016/j.freeradbiomed.2025.08.038","url":null,"abstract":"<div><div>Human-bacterial interactions play a crucial role in several essential aspects of life. Here, we describe how a secreted protein from the skin commensal <em>Cutibacterium acnes</em>, RoxP, functions as a sacrificial redox effector molecule that facilitates beneficial interactions with its human host by counteracting oxidative stress and reducing stress-induced inflammation. Using a combination of structural mapping, biophysical binding studies, and <em>in vivo</em> experiments, we demonstrate how RoxP contributes to skin homeostasis by serving as a target for oxidative attack and influencing cytokine signaling. To our knowledge, this is the first <em>in vivo</em> mechanistic description of a secreted prokaryotic effector molecule modulating host redox balance through sacrificial oxidation, providing evidence of its role as a health-promoting factor.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 339-346"},"PeriodicalIF":8.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144895260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hongli Zhang , Ziyu Lan , Hui Wang , Haojie Yao , Ruiyan Zheng , Zijing Chen , Xiang Luo , Peng Wu , Yuanyuan Cheng , Zhongqiu Liu
{"title":"Dual Keap1-Dependent actions of pubescenoside A against ulcerative colitis: Promoting DDX5 ubiquitination degradation and Nrf2 nuclear translocation to suppress inflammation","authors":"Hongli Zhang , Ziyu Lan , Hui Wang , Haojie Yao , Ruiyan Zheng , Zijing Chen , Xiang Luo , Peng Wu , Yuanyuan Cheng , Zhongqiu Liu","doi":"10.1016/j.freeradbiomed.2025.08.040","DOIUrl":"10.1016/j.freeradbiomed.2025.08.040","url":null,"abstract":"<div><div>Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon, characterized by a complex clinical syndrome. Pubescenoside A (PBA), a phenylpropanoid derived from <em>Ilex pubescens</em>, exhibits significant anti-inflammatory effects; however, the impact and underlying mechanism of PBA on UC remain unclear. Therefore, the aim of this study is to investigate the potential mechanism of PBA against UC using <em>in vivo</em> and <em>in vitro</em> experiments. Pubescenoside A effectively enhances weight loss in UC mice, decreases the disease activity index (DAI). Regarding colonic morphology, PBA ameliorates colorectal stenosis and shortening, reduces intestinal mucosal ulceration, diminishes inflammatory cell infiltration, and tends to normalize glandular arrangement. Furthermore, PBA effectively suppresses pro-inflammatory factors. Mechanism studies have shown that PBA can directly target Kelch-like ECH associated protein 1 (Keap1), subsequently promoting the interaction between Keap1 and DEAD-box RNA helicase 5 (DDX5) to enhance ubiquitination and degradation of DDX5, leading to a down-regulation of C-C motif chemokine ligand 3 (CCL3) expression. Additionally, PBA disrupts the Keap1/Nrf2 complex, facilitating Nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear entry to inhibit the Nuclear factor-κB (NF-κB) pathway. Importantly, in Gpt-lgr5-creERT2 Keap1<sup>flox/flox</sup> mice, the anti-UC effect of PBA was attenuated. Our results indicated that PBA mitigated UC by targeting Keap1, thereby promoting the ubiquitination degradation of DDX5 and facilitating the nuclear entry of Nrf2.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 426-438"},"PeriodicalIF":8.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144908720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}