Ahmet Kor , Merve Yalçın , Göktuğ Okyar , Tahire Betül Kor , İsmail Doğan , Ebru Atalar , Hatice Ecem Konak , Pınar Akyüz Dağlı , Dudu Çelik Tam , Sema Işık , Bünyamin Polat , Salim Neşelioğlu , Özcal Erel , Şükran Erten
{"title":"Urinary total superoxide dismutase activity is low in rheumatoid patients, and its low levels are associated with higher DAS28 scores","authors":"Ahmet Kor , Merve Yalçın , Göktuğ Okyar , Tahire Betül Kor , İsmail Doğan , Ebru Atalar , Hatice Ecem Konak , Pınar Akyüz Dağlı , Dudu Çelik Tam , Sema Işık , Bünyamin Polat , Salim Neşelioğlu , Özcal Erel , Şükran Erten","doi":"10.1016/j.freeradbiomed.2025.03.035","DOIUrl":"10.1016/j.freeradbiomed.2025.03.035","url":null,"abstract":"<div><h3>Aim</h3><div>Rheumatoid factor and anti-citrullinated peptide antibodies are generally used to diagnose rheumatoid arthritis (RA). However, these antibodies are negative in 15–20 % of RA cases. This study aimed to investigate new biomarkers that can be used in diagnosing RA and evaluating disease activity.</div></div><div><h3>Methods</h3><div>This study included 99 RA patients and 94 healthy volunteers. Modified Disease Activity Score28 (DAS28) erythrocyte sedimentation rate (ESR) was used for disease activity score. Thiol/disulfide molecules were measured using an automatic spectrophotometric method, and ischemia-modified albumin was measured using an albumin-cobalt binding test. A spectrophotometer calculated urinary and serum total superoxide dismutase (SOD) activities at 420 nm wavelength.</div></div><div><h3>Results</h3><div>In the RA group, serum IMA level was higher (unstandardized beta [B]: 5.552, Odds Ratio [OR]: 250.1, CI 95 %: 1.29–48219.1, p: .040), and urinary total SOD activities were significantly lower (B: 2.640 OR: .071, CI 95 %: .027–.192, p < 0.0001) than in the control group. A cut-off value of 5.06 for urinary total SOD was found to have a sensitivity of 97.9 % and a specificity of 97 % in distinguishing RA patients from healthy controls (AUC [95 %Cl] = .986 [.967–1.000], p < 0.001). Urinary total SOD activity was significantly lower in the RA subgroup with high disease activity compared to the groups with moderate disease activity (B: .954, OR: 2.596, CI 95 %: 1.104–6.103, p: .029) and low disease activity (B: 1.251, OR: 3.494, CI 95 %: 1.143–10.678, p: .028).</div></div><div><h3>Conclusion</h3><div>This study showed that urinary total SOD activity has high sensitivity and specificity in distinguishing RA patients from healthy controls and that RA patients with higher DAS28 ESR activity scores have lower urinary total SOD activity.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 77-85"},"PeriodicalIF":7.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143714263","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}
Stephanie M. Eick , Manuela L. Celia-Sanchez , Tracey J. Woodruff , Dana E. Goin , Amy M. Padula , Lara Cushing , Kaegan Ortlund , Erin DeMicco , Ginger L. Milne , Rachel Morello-Frosch
{"title":"Experiences of multiple psychosocial stressors and associations with oxidative stress biomarkers during pregnancy","authors":"Stephanie M. Eick , Manuela L. Celia-Sanchez , Tracey J. Woodruff , Dana E. Goin , Amy M. Padula , Lara Cushing , Kaegan Ortlund , Erin DeMicco , Ginger L. Milne , Rachel Morello-Frosch","doi":"10.1016/j.freeradbiomed.2025.03.036","DOIUrl":"10.1016/j.freeradbiomed.2025.03.036","url":null,"abstract":"<div><h3>Background</h3><div>Oxidative stress is hypothesized to be one mechanism linking psychosocial stressor exposure to preterm birth and other adverse pregnancy outcomes. However, prior studies have focused solely on singular psychosocial stressors, which may not reflect real world exposures as pregnant women may experience multiple stressors simultaneously.</div></div><div><h3>Methods</h3><div>Participants included a subset of the Chemicals in Our Bodies cohort, a prospective birth cohort in San Francisco, California (N = 227). Self -reported psychosocial stressors were assessed via questionnaires administered during the second trimester that addressed financial strain, food insecurity, job strain, neighborhood quality, caregiving, stressful life events, unplanned pregnancy, and perceived community status. Oxidative stress biomarkers were measured during the second trimester of pregnancy and included 15-F<sub>2t</sub>-IsoP, and its two major metabolites 2,3-dinor-5,6-dihydro-15-F<sub>2t</sub>-IsoP, and 2,3-dinor-15-F<sub>2t</sub>-IsoP, and PGF<sub>2α</sub>. Linear regression models were used to examine associations between individual and pairwise combinations of psychosocial stressors in relation to each oxidative stress biomarker.</div></div><div><h3>Results</h3><div>15-F<sub>2t</sub>-IsoP, 2,3-dinor-15-F<sub>2t</sub>-IsoP, and 2,3-dinor-5,6-dihydro-15-F<sub>2t</sub>-IsoP were elevated among participants reporting experiences of low perceived community status, job strain, poor neighborhood quality, food insecurity, and stressful life events (e.g., β = 0.36, 95 % CI = 0.00, 0.72 for food insecurity in association with 15-F<sub>2t</sub>-IsoP). In models that included pairwise combinations of stressor exposures, nearly every combination was also associated with an increase in all oxidative stress biomarkers compared to those who experienced one or neither stressor. For example, stressful life events and poor neighborhood quality was associated with statistically significant increases in all biomarkers (e.g., β = 0.94, 95 % CI = 0.17, 1.71 for 2,3-dinor-5,6-dihydro-15-F<sub>2t</sub>-IsoP).</div></div><div><h3>Conclusions</h3><div>Urinary oxidative stress biomarkers were elevated among pregnant women exposed to psychosocial stressors, and exposure to multiple stressors resulted in the strongest associations. These findings support oxidative stress as one potential biological pathway linking prenatal psychosocial stress to preterm birth and other adverse pregnancy outcomes.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 70-76"},"PeriodicalIF":7.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143714353","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":"The clinical-grade CBP/ p300 inhibitor CCS1477 represses the global NRF2-dependent cytoprotective transcription program and re-sensitizes cancer cells to chemotherapeutic drugs","authors":"Ke Wang , Liam Baird , Masayuki Yamamoto","doi":"10.1016/j.freeradbiomed.2025.03.034","DOIUrl":"10.1016/j.freeradbiomed.2025.03.034","url":null,"abstract":"<div><div>Constitutive activation of NRF2 provides a selective advantage to malignant tumour clones through the hijacking of the NRF2-dependent cytoprotective transcriptional program, which allows the cancer cells to survive and thrive in the chemically stressful tumour niche, whilst also providing resistance to anti-cancer drugs due to the upregulation of xenobiotic metabolizing enzymes and drug efflux pumps. Through a small-molecule epigenetic screen carried out in <em>KEAP1</em> mutant lung cancer cells, in this study, we identified CCS1477 (Inobrodib) to be an inhibitor of the global NRF2-dependent transcription program. Mechanistically, CCS1477 is able to repress NRF2’s cytoprotective response through the inhibition of its obligate transcriptional activator partner CBP/p300. Importantly, in addition to repressing NRF2-dependent anti-oxidative stress and xenobiotic metabolizing enzyme gene expression, CCS1477 treatment is also able to reverse the chemoresistance phenotype and re-sensitize NRF2-activated tumour cells to anti-cancer drugs. Furthermore, in co-culture experiments of <em>KEAP1</em> mutant cancer cells with primary human T cells, CCS1477 treatment suppressed the acquisition of the T cell exhaustion transcriptional state, which should function to augment the anti-cancer immune response. Thus, CCS1477-mediated inhibition of CBP/p300 represents a novel therapeutic strategy with which to target the currently untreatable tumours with aberrant NRF2 activation.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 102-117"},"PeriodicalIF":7.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Reductive stress and mitochondrial dysfunction: The hidden link in chronic disease","authors":"Joseph Mercola","doi":"10.1016/j.freeradbiomed.2025.03.029","DOIUrl":"10.1016/j.freeradbiomed.2025.03.029","url":null,"abstract":"<div><div>Conventional theories of oxidative stress have long focused on the deleterious consequences of excessive reactive oxygen species (ROS) formation. However, growing evidence reveals that an overload of reducing equivalents—termed <em>reductive stress</em>—may be equally pivotal in driving mitochondrial dysfunction and chronic disease. In this paradigm, abnormally high concentrations of NADH and NADPH create an electron “traffic jam” in the mitochondrial electron transport chain (ETC), leading to partial inhibition or reverse electron flow at upstream complexes. Paradoxically, this hyper-reduced environment promotes ROS generation by increasing electron leakage to molecular oxygen, thereby intensifying oxidative damage to lipids, proteins, and mitochondrial DNA.</div><div>This review explores the intertwined nature of reductive and oxidative stress, showing how a surplus of reducing equivalents can potentiate metabolic derangements in conditions such as type 2 diabetes, nonalcoholic fatty liver disease, and neurodegenerative disorders. The review discusses common drivers of reductive overload, including chronic hyperglycemia, high-fat diets, and specific dietary patterns—particularly those enriched in polyunsaturated omega-6 fatty acids—that inundate mitochondria with electron donors. The review also highlights emerging evidence that targeted assessment of redox biomarkers (e.g., lactate:pyruvate, β-hydroxybutyrate:acetoacetate ratios) can provide clinically relevant indicators of reductive stress.</div><div>Finally, the review examines how novel therapeutic strategies can address the underlying reductive imbalance, from rational nutrient modulation to pharmacologic interventions that restore NAD<sup>+</sup> levels or optimize ETC flux. Recognizing reductive stress as a critical inflection point in mitochondrial pathophysiology underscores the need for a refined redox framework, one that moves beyond conventional oxidative paradigms to embrace the full spectrum of redox dysregulation in chronic degenerative disease.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 118-131"},"PeriodicalIF":7.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rui Yang , Meng-Yan Deng , Lu-Kui Yang, Guan-Zhe Wang, Jun Ma, Qiang Wen, Na Gao, Hai-Ling Qiao
{"title":"Identification of cytochrome P450 2E1 as a novel target in neuroinflammation and development of its inhibitor Q11 as a treatment strategy","authors":"Rui Yang , Meng-Yan Deng , Lu-Kui Yang, Guan-Zhe Wang, Jun Ma, Qiang Wen, Na Gao, Hai-Ling Qiao","doi":"10.1016/j.freeradbiomed.2025.03.032","DOIUrl":"10.1016/j.freeradbiomed.2025.03.032","url":null,"abstract":"<div><div>Neuroinflammation is implicated in nearly all pathological processes of central nervous system (CNS) diseases. However, no medications specifically targeting neuroinflammation are clinically available, and conventional anti-inflammatory drugs exhibit limited efficacy. Here, we identified cytochrome P450 2E1 (CYP2E1) as a novel therapeutic target in neuroinflammation. Elevated CYP2E1 levels were observed in hippocampal tissues of mouse and rat neuroinflammation models, as well as in LPS-stimulated primary microglia. Genetic ablation of <em>Cyp2e1</em> improved spatial learning and memory in neuroinflammatory rats and reduced pro-inflammatory cytokine levels in <em>Cyp2e1</em>-deficient microglia. Furthermore, Q11 (1-(4-methyl-5-thiazolyl) ethanone), a novel CYP2E1 inhibitor developed and synthesized in our laboratory, effectively ameliorated Alzheimer's disease-related spatial learning and memory functions and depression-related anxiety-like behaviors in mice/rats. Mechanistically, Q11 attenuated microglial activation, neuronal damage, oxidative stress, and neuroinflammation by suppressing the PI3K/Akt, STAT1/3, and NF-κB signaling pathways. These findings establish CYP2E1 as a druggable target for neuroinflammation and propose Q11 as a promising candidate for treating neuroinflammation-related diseases.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"234 ","pages":"Pages 220-232"},"PeriodicalIF":7.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691631","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}
Junfeng Shi , Yifeng Cheng , Lixue Wang , Wen Xing , Yudi Li , Xiulin Sun , Yunpeng Lv , Yichuan Zhang , Yanming Li , Wenhua Zhao
{"title":"SR-B1 deficiency suppresses progression in acute myeloid leukemia via ferroptosis and reverses resistance to venetoclax","authors":"Junfeng Shi , Yifeng Cheng , Lixue Wang , Wen Xing , Yudi Li , Xiulin Sun , Yunpeng Lv , Yichuan Zhang , Yanming Li , Wenhua Zhao","doi":"10.1016/j.freeradbiomed.2025.03.031","DOIUrl":"10.1016/j.freeradbiomed.2025.03.031","url":null,"abstract":"<div><div>Increase of immature myeloid cells in the bone marrow drives the development of acute myeloid leukemia (AML). The study aimed to clarify the biological function and regulatory mechanism of scavenger receptor class B type 1 (SR-B1) in AML, mainly its effect on ferroptosis and the influences on leukemogenesis and resistance to venetoclax. In this study, we found that the SR-B1 deficiency directly reduced the invasion and promoted death of malignant cells in AML. Strikingly, SR-B1 deficiency could up-regulated the expression of ferroptosis-related proteins to facilitate the occurrence of ferroptosis <em>in vivo</em>, and could also down-regulated the expression of apoptosis related protein B-cell lymphoma-2 (BCL-2). And then, we confirmed SR-B1 inhibitor block lipid transport-1 (BLT-1) had a superior efficacy in AML cells and AML model mice. The study found that whether SR-B1 deficiency or BLT-1 treatment could cause iron deposition and the accumulation of lipid peroxides <em>in vivo</em>, thereby suppressing leukemogenesis through ferroptosis. Critically, we found that SR-B1 inhibitor BLT-1 could reverse drug-resistance of venetoclax to promote AML cells death <em>via</em> ferroptosis. Our finding identified that SR-B1 as a critical regulator of the proliferation in AML which could provide a promising therapeutic strategy against malignant myeloid leukemia cells and drug-resistance.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 24-38"},"PeriodicalIF":7.1,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691633","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}
Juan Sebastián Reyes , Eduardo Fuentes-Lemus , Angélica Fierro , Karina Rivero-Rodríguez , Felipe Arenas , Michael J. Davies , Camilo López-Alarcón
{"title":"Inactivation of human glucose 6-phosphate dehydrogenase (G6PDH) by peroxyl radicals is strongly modulated by its substrate and cofactor","authors":"Juan Sebastián Reyes , Eduardo Fuentes-Lemus , Angélica Fierro , Karina Rivero-Rodríguez , Felipe Arenas , Michael J. Davies , Camilo López-Alarcón","doi":"10.1016/j.freeradbiomed.2025.03.030","DOIUrl":"10.1016/j.freeradbiomed.2025.03.030","url":null,"abstract":"<div><div>Glucose 6-phosphate dehydrogenase (G6PDH) is the rate-limiting enzyme of the pentose phosphate pathway (PPP). This enzyme catalyzes the oxidation of glucose 6-phosphate (G6P) into 6-phosphogluconolactone with concomitant reduction of NADP<sup>+</sup> to NADPH. Despite the link between the PPP and oxidative stress, the oxidation and consequences on the activity of the human G6PDH (<em>h</em>G6PDH) has not been investigated. In the present work we report the oxidative inactivation of <em>h</em>G6PDH mediated by peroxyl radicals (ROO<sup>•</sup>) generated by AAPH (2,2′-azobis(2-methylpropionamidine) dihydrochloride) thermolysis. <em>h</em>G6PDH (46.4 μM, monomers) was incubated at 37 °C with 10 or 100 mM AAPH. At defined times, enzyme activity was determined (NADPH release followed at 340 nm), mapping of modifications studied by LC-MS, structural changes analyzed by circular dichroism, and results rationalized by <em>in silico</em> analysis of the three-dimensional structure of the enzyme. Analogous experiments were developed in the presence of NADP<sup>+</sup> or G6P at excess or 1:1 (<em>h</em>G6PDH:NADP<sup>+</sup> or G6P) molar ratios. High susceptibility to inactivation by ROO<sup>•</sup> was observed, 3.6 mol of ROO<sup>•</sup> inactivated 1 mol of <em>h</em>G6PDH. This behavior is rationalized, at least in part, by oxidation at Trp349 which is located close to the structural site of NADP<sup>+</sup>. The presence of G6P significantly increased the ROO<sup>•</sup>-mediated inactivation of <em>h</em>G6PDH, while an opposite effect was observed in the presence of NADP<sup>+</sup> where, despite oxidation at different sites, the enzyme activity was practically unaltered by ROO<sup>•</sup>. These results demonstrate that <em>h</em>G6PDH is highly susceptible to inactivation mediated by ROO<sup>•</sup> with these processes strongly modulated by G6P and NADP<sup>+</sup>.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 55-69"},"PeriodicalIF":7.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691632","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}
Qing Yu , Jie Yang , Heyu Chen , Ruishan Liu , Ruomeng Hu , Jiachang Cai , Shikuan Yang , Beiwen Zheng , Peng Guo , Zhijian Cai , Shufang Zhang , Gensheng Zhang
{"title":"Corrigendum to “Macrophages hijack carbapenem-resistance hypervirulent Klebsiella pneumoniae by blocking SLC7A11/GSH-manipulated iron oxidative stress” [Free Radic Biol Med. 230 (2025) 234–247]","authors":"Qing Yu , Jie Yang , Heyu Chen , Ruishan Liu , Ruomeng Hu , Jiachang Cai , Shikuan Yang , Beiwen Zheng , Peng Guo , Zhijian Cai , Shufang Zhang , Gensheng Zhang","doi":"10.1016/j.freeradbiomed.2025.03.015","DOIUrl":"10.1016/j.freeradbiomed.2025.03.015","url":null,"abstract":"","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 453-455"},"PeriodicalIF":7.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhiqun Bian , Yu Zhai , Yuyao Zhang , Tianling Wang , Hao Li , Jian Ouyang , Chao Liu , Siya Wang , Zhilei Hu , Xian Chang , Chao Zhang , Minghan Liu , Changqing Li
{"title":"Senescent cartilage endplate stem cells-derived exosomes induce oxidative stress injury in nucleus pulposus cells and aggravate intervertebral disc degeneration by regulating FOXO3","authors":"Zhiqun Bian , Yu Zhai , Yuyao Zhang , Tianling Wang , Hao Li , Jian Ouyang , Chao Liu , Siya Wang , Zhilei Hu , Xian Chang , Chao Zhang , Minghan Liu , Changqing Li","doi":"10.1016/j.freeradbiomed.2025.03.027","DOIUrl":"10.1016/j.freeradbiomed.2025.03.027","url":null,"abstract":"<div><div>Intervertebral disc degeneration (IVDD) is the leading cause of low back pain and associated disability worldwide. The cartilage endplate (CEP) is a critical structure in maintaining the homeostasis of the intervertebral disc, by exosomes (Exos)-mediated intracellular communication between cartilage endplate stem cells (CESCs) and nucleus pulposus cells (NPCs). However, whether the senescence of CESCs influences the functionality of CESCs-derived Exos (CESCs-Exos) and participates in the progress of IVDD remains unclear. In this study, we explored the role and mechanism of the Exos-based intracellular communication between senescent CESCs and NPCs in IVDD. CESCs isolated from aged individuals (S-CESCs) exhibited high levels of senescence compared with CESCs isolated from young individuals (Y-CESCs). Exos from Y-CESCs (Y-Exos) and from S-CESCs (S-Exos) were extracted and identified. Surprisingly, we found that S-Exos lost the therapeutic effects as the Y-Exos exhibited in mitigating IVDD, and even aggravated IVDD by inducing oxidative stress injury in NPCs. MicroRNA-sequencing revealed significant upregulation of miR-29b-3p expression in S-Exos. Through microRNA target prediction, dual luciferase assays, RNA-sequencing, lentivirus-mediated overexpression and suppression, we demonstrated that miR-29b-3p regulates the expression of FOXO3 and downstream antioxidant enzymes to induce oxidative stress injury in NPCs. In vivo experiments further verified that countering miR-29b-3p by antagomir reversed the detrimental effects of S-Exos in exacerbating IVDD. This work elucidates the role and mechanism of senescent CESCs in disrupting redox homeostasis in the nucleus pulposus and exacerbating IVDD by Exos-mediated intracellular communication and offers an experimental foundation for the selection of proper CESCs-Exos to obtain better therapeutic effects in IVDD.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 39-54"},"PeriodicalIF":7.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhiwei Xiong , Yichao Ou , Rongjun Chen , Mingfeng Zhou , Zijing Wang , Guangsen Wu , Mengjie Che , Kai Li , Haodong Gong , Yihan Wang , Xufan Ling , Hai Wang , Xingqin Wang , Qiancheng Song , Songtao Qi , Zhanpeng Feng , Junxiang Peng
{"title":"Tanycyte proliferation and migration through the sonic hedgehog pathway restores hypothalamic function after ischemic injury","authors":"Zhiwei Xiong , Yichao Ou , Rongjun Chen , Mingfeng Zhou , Zijing Wang , Guangsen Wu , Mengjie Che , Kai Li , Haodong Gong , Yihan Wang , Xufan Ling , Hai Wang , Xingqin Wang , Qiancheng Song , Songtao Qi , Zhanpeng Feng , Junxiang Peng","doi":"10.1016/j.freeradbiomed.2025.03.026","DOIUrl":"10.1016/j.freeradbiomed.2025.03.026","url":null,"abstract":"<div><div>Tanycytes, a distinct type of glial cell within the hypothalamus, will be investigated in this study to elucidate the intrinsic mechanisms by which they facilitate the restoration of hypothalamic function. We injected endothelin 1 (ET-1) into the third ventricle to establish an ischemic hypothalamic injury model. Nestin CreER<sup>T2</sup> and Rosa26R-CAG:tdTomato mice were crossbred, and viral tracing was used to label and track tanycytes. Functional changes in these cells were observed with calcium imaging. Alterations in tanycytes were assessed with single-cell and transcriptomic sequencing analyses. The involvement of specific pathways was confirmed via intraperitoneal injection of <em>N</em>-acetyl cysteine (NAC) and cycloheximide. Following ischemic injury to the hypothalamus in mice, acute weight loss and impaired activity of Agrp neurons were observed, both of which recovered within 7 days. The fate of tanycytes was traced in Nestin-CreER<sup>T2</sup>: Rosa26R-CAG:Tdtomato mice to confirm their proliferation and migration after hypothalamic injury. Calcium imaging indicated that these proliferating and migrating cells participated in signal transduction, thereby reconstructing the regulatory network of tanycytes. The analysis of single-cell data on postnatal days 8 and 45 identified CDK1 as a marker of proliferative tanycytes. The roles of ROS and the Shh pathway in the proliferation and migration of tanycytes were validated via the intraperitoneal injection of NAC and cycloheximide inhibitors. After inducing ischemic injury to the arcuate nucleus of the hypothalamus, Agrp neuronal activity declined, accompanied by ROS fluctuations within tanycytes. Activation of the Shh pathway prompts the transition of tanycytes from a quiescent state to a proliferative state, thereby leading to their migration to the arcuate nucleus. This process re-establishes the regulatory network of tanycytes and restores metabolic balance. This finding may provide an important target for promoting the recovery of hypothalamic function.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 437-449"},"PeriodicalIF":7.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669337","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}