Free Radical Biology and Medicine最新文献_第6页

TIMP2-mediated mitochondrial fragmentation and glycolytic reprogramming drive renal fibrogenesis following ischemia-reperfusion injury

IF 7.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Free Radical Biology and Medicine

Pub Date : 2025-02-20 DOI: 10.1016/j.freeradbiomed.2025.02.020

Jingjing Pang , Dongxue Xu , Xiaoyu Zhang , Jiacheng Qu , Jun Jiang , Jinmeng Suo , Tianlong Li , Yiming Li , Zhiyong Peng

Acute kidney injury (AKI) triggers renal structural and functional abnormalities through inflammatory and fibrotic signaling pathways, ultimately progressing to chronic kidney disease (CKD). The mechanisms underlying AKI-to-CKD transition are complex, with hypoxia, mitochondrial dysfunction, and metabolic reprogramming as critical contributors.

Public data analysis demonstrated significant upregulation of tissue inhibitors of metalloproteinases (Timp2) in renal biopsy tissues of CKD patients. In both ischemia/reperfusion (I/R) and unilateral ureteral obstruction (UUO) models, Timp2 upregulation was observed. Tubule-specific Timp2 knockout markedly attenuated renal fibrosis. RNA-sequencing revealed Timp2's association with mitochondrial dynamics and glycolysis in I/R mice. Timp2 deletion improved mitochondrial morphology and suppressed glycolytic enzyme expression. In vitro, TGF-β1-treated Timp2-knockdown HK-2 cells exhibited inhibited Drp1 expression, restored Mfn2 levels, alleviated mitochondrial fragmentation, and elevated mitochondrial membrane potential. Additionally, Pfkfb3 and HIF-1α were downregulated, accompanied by reduced extracellular acidification rate (ECAR), PFK activity, and lactate production. Mechanistically, Timp2 interacts with the extracellular domain of Sdc4 in an autocrine manner, activating the Hedgehog (Hh) signaling pathway. Cyclopamine partially rescued Timp2 overexpression-induced mitochondrial dysfunction, suppressed Pfkfb3-mediated glycolysis, and diminished collagen deposition. This study is the first to demonstrate that Timp2 in TECs exacerbates Hh signaling, promoting mitochondrial fragmentation and metabolic reprogramming to accelerate I/R-induced renal fibrosis.

{"title":"TIMP2-mediated mitochondrial fragmentation and glycolytic reprogramming drive renal fibrogenesis following ischemia-reperfusion injury","authors":"Jingjing Pang , Dongxue Xu , Xiaoyu Zhang , Jiacheng Qu , Jun Jiang , Jinmeng Suo , Tianlong Li , Yiming Li , Zhiyong Peng","doi":"10.1016/j.freeradbiomed.2025.02.020","DOIUrl":"10.1016/j.freeradbiomed.2025.02.020","url":null,"abstract":"<div><div>Acute kidney injury (AKI) triggers renal structural and functional abnormalities through inflammatory and fibrotic signaling pathways, ultimately progressing to chronic kidney disease (CKD). The mechanisms underlying AKI-to-CKD transition are complex, with hypoxia, mitochondrial dysfunction, and metabolic reprogramming as critical contributors.</div><div>Public data analysis demonstrated significant upregulation of tissue inhibitors of metalloproteinases (Timp2) in renal biopsy tissues of CKD patients. In both ischemia/reperfusion (I/R) and unilateral ureteral obstruction (UUO) models, Timp2 upregulation was observed. Tubule-specific Timp2 knockout markedly attenuated renal fibrosis. RNA-sequencing revealed Timp2's association with mitochondrial dynamics and glycolysis in I/R mice. Timp2 deletion improved mitochondrial morphology and suppressed glycolytic enzyme expression. In vitro, TGF-β1-treated Timp2-knockdown HK-2 cells exhibited inhibited Drp1 expression, restored Mfn2 levels, alleviated mitochondrial fragmentation, and elevated mitochondrial membrane potential. Additionally, Pfkfb3 and HIF-1α were downregulated, accompanied by reduced extracellular acidification rate (ECAR), PFK activity, and lactate production. Mechanistically, Timp2 interacts with the extracellular domain of Sdc4 in an autocrine manner, activating the Hedgehog (Hh) signaling pathway. Cyclopamine partially rescued Timp2 overexpression-induced mitochondrial dysfunction, suppressed Pfkfb3-mediated glycolysis, and diminished collagen deposition. This study is the first to demonstrate that Timp2 in TECs exacerbates Hh signaling, promoting mitochondrial fragmentation and metabolic reprogramming to accelerate I/R-induced renal fibrosis.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 244-259"},"PeriodicalIF":7.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476427","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}

引用次数: 0

N6-methyladenosine-mediated EIF3H promotes anaplastic thyroid cancer progression and ferroptosis resistance by stabilizing β-catenin

IF 7.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Free Radical Biology and Medicine

Pub Date : 2025-02-19 DOI: 10.1016/j.freeradbiomed.2025.02.025

Zeyu Zhang , Di Zhou , Xiangyuan Qiu , Fada Xia , Xinying Li

Anaplastic thyroid cancer (ATC) patients suffer from a poor prognosis with very limited treatment options. The accumulation of β-catenin and the activation of downstream signaling is one of the main events in ATC, while the role of JAMM family in ATC remains unknown. In this study, we aimed to identify a new deubiquitinating enzyme regulating β-catenin in ATC. We found that EIF3H was positively correlated with β-catenin, and the knockdown of EIF3H deactivated the Wnt/β-catenin signaling pathway in ATC. Further exploration revealed that EIF3H interacted with, deubiquitylated, and stabilized β-catenin by acting as a deubiquitinating enzyme. Mechanistically, EIF3H removed the K48-linked ubiquitin chain on β-catenin by binding the N tails of β-catenin. The knockdown of EIF3H could inhibit ATC cell proliferation, invasion, and ferroptosis resistance by regulating β-catenin. In addition, the dysregulation of EIF3H was associated with m6A modification in the 3′UTR and a m6A reader, IGF2BP2. In summary, the EIF3H/β-catenin axis promotes ATC progression and ferroptosis resistance by activating the Wnt/β-catenin signaling pathway. The EIF3H/β-catenin axis may serve as a potential diagnostic marker and a therapeutic target in ATC.

{"title":"N6-methyladenosine-mediated EIF3H promotes anaplastic thyroid cancer progression and ferroptosis resistance by stabilizing β-catenin","authors":"Zeyu Zhang , Di Zhou , Xiangyuan Qiu , Fada Xia , Xinying Li","doi":"10.1016/j.freeradbiomed.2025.02.025","DOIUrl":"10.1016/j.freeradbiomed.2025.02.025","url":null,"abstract":"<div><div>Anaplastic thyroid cancer (ATC) patients suffer from a poor prognosis with very limited treatment options. The accumulation of β-catenin and the activation of downstream signaling is one of the main events in ATC, while the role of JAMM family in ATC remains unknown. In this study, we aimed to identify a new deubiquitinating enzyme regulating β-catenin in ATC. We found that EIF3H was positively correlated with β-catenin, and the knockdown of EIF3H deactivated the Wnt/β-catenin signaling pathway in ATC. Further exploration revealed that EIF3H interacted with, deubiquitylated, and stabilized β-catenin by acting as a deubiquitinating enzyme. Mechanistically, EIF3H removed the K48-linked ubiquitin chain on β-catenin by binding the N tails of β-catenin. The knockdown of EIF3H could inhibit ATC cell proliferation, invasion, and ferroptosis resistance by regulating β-catenin. In addition, the dysregulation of EIF3H was associated with m6A modification in the 3′UTR and a m6A reader, IGF2BP2. In summary, the EIF3H/β-catenin axis promotes ATC progression and ferroptosis resistance by activating the Wnt/β-catenin signaling pathway. The EIF3H/β-catenin axis may serve as a potential diagnostic marker and a therapeutic target in ATC.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"231 ","pages":"Pages 38-47"},"PeriodicalIF":7.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472363","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}

引用次数: 0

Rabbit model of oxidative stress-induced retinal degeneration

IF 7.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Free Radical Biology and Medicine

Pub Date : 2025-02-19 DOI: 10.1016/j.freeradbiomed.2025.02.024

Yogita Kanan , Jingwen Zhang , Alexandra Bernardo-Colón , Subrata Debnath , Mahmood Khan , S. Patricia Becerra , Peter A. Campochiaro

Retinitis pigmentosa (RP) is a disorder that results in the death of rod photoreceptors in the retina, caused by several different mutations. As rods are 95 % of the photoreceptors in the eye and consume the most oxygen, their death causes tissue hyperoxia resulting in oxidative stress in the retina. Oxidative stress is implicated in the pathogenesis of photoreceptor death in RP. Therefore, oxidative stress models are very relevant to identifying drugs to prevent photoreceptor death in RP. Rabbits are an excellent model to study retinal degeneration due to their large eyes and therefore larger subretinal and vitreous space, makes it easier for surgical and drug interventions techniques. Herein, we have created a rabbit model of oxidative stress-induced retinal degeneration using paraquat (PQ), a known oxidant. PQ causes oxidative stress in the retina, that results in functional and structural loss of photoreceptors. We also show that using an antioxidant PEDF[H105A], we were able to blunt the damage to photoreceptors caused by PQ. Therefore, this rabbit model of oxidative stress-induced retinal degeneration will serve as an excellent model to test a wide array of surgical and drug interventions techniques.

{"title":"Rabbit model of oxidative stress-induced retinal degeneration","authors":"Yogita Kanan , Jingwen Zhang , Alexandra Bernardo-Colón , Subrata Debnath , Mahmood Khan , S. Patricia Becerra , Peter A. Campochiaro","doi":"10.1016/j.freeradbiomed.2025.02.024","DOIUrl":"10.1016/j.freeradbiomed.2025.02.024","url":null,"abstract":"<div><div>Retinitis pigmentosa (RP) is a disorder that results in the death of rod photoreceptors in the retina, caused by several different mutations. As rods are 95 % of the photoreceptors in the eye and consume the most oxygen, their death causes tissue hyperoxia resulting in oxidative stress in the retina. Oxidative stress is implicated in the pathogenesis of photoreceptor death in RP. Therefore, oxidative stress models are very relevant to identifying drugs to prevent photoreceptor death in RP. Rabbits are an excellent model to study retinal degeneration due to their large eyes and therefore larger subretinal and vitreous space, makes it easier for surgical and drug interventions techniques. Herein, we have created a rabbit model of oxidative stress-induced retinal degeneration using paraquat (PQ), a known oxidant. PQ causes oxidative stress in the retina, that results in functional and structural loss of photoreceptors. We also show that using an antioxidant PEDF[H105A], we were able to blunt the damage to photoreceptors caused by PQ. Therefore, this rabbit model of oxidative stress-induced retinal degeneration will serve as an excellent model to test a wide array of surgical and drug interventions techniques.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"231 ","pages":"Pages 48-56"},"PeriodicalIF":7.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472374","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}

引用次数: 0

Overexpression of hnRNPK and inhibition of cytoplasmic translocation ameliorate lipid disorder in doxorubicin-induced cardiomyopathy via PINK1/Parkin-mediated mitophagy

IF 7.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Free Radical Biology and Medicine

Pub Date : 2025-02-19 DOI: 10.1016/j.freeradbiomed.2025.02.021

Qian Xu , Xuehua Wang , Jing Hu , Ya Wang , Shuai Lu , Jingjie Xiong , Han Li , Ni Xiong , YanLing Huang , Yan Wang , Zhaohui Wang

Lipid metabolism has been identified as a potential target for the treatment of doxorubicin-induced cardiomyopathy (DIC). Mitochondria, as a central regulator of energy production and utilization, plays a crucial role in this process, and enhancing mitophagy holds promise in mitigating myocardial damage in DIC. However, the relationship between mitophagy and lipid metabolism remains unclear, and the key molecules mediating this connection remain to be elucidated. Among these candidates, heterogeneous nuclear ribonucleoprotein K (hnRNPK) emerges as a potential regulator of mitophagy and metabolism. However, its specific role in DIC remains unclear. In this study, we established chronic DIC models both in vivo and in vitro to assess the relationship between hnRNPK levels, mitophagy, and lipid metabolism, as well as to evaluate the impact of hnRNPK on cardiac function. Our findings revealed that hnRNPK expression is significantly reduced in the hearts of doxorubicin (DOX)-treated mice. Notably, hnRNPK overexpression improves cardiac function and effectively reduces lipid accumulation by enhancing mitophagy. Mechanistically, hnRNPK expression was found to be downregulated in DIC, accompanied by its translocation from the nucleus to the cytoplasm, thereby reducing the transcriptional regulation of PINK1. Overexpression of hnRNPK and inhibition of its cytoplasmic translocation alleviates DOX-induced lipid accumulation by regulating the PINK1/Parkin pathway. These findings underscore a previously unrecognized role of hnRNPK in inhibiting lipid accumulation to prevent DIC.

{"title":"Overexpression of hnRNPK and inhibition of cytoplasmic translocation ameliorate lipid disorder in doxorubicin-induced cardiomyopathy via PINK1/Parkin-mediated mitophagy","authors":"Qian Xu , Xuehua Wang , Jing Hu , Ya Wang , Shuai Lu , Jingjie Xiong , Han Li , Ni Xiong , YanLing Huang , Yan Wang , Zhaohui Wang","doi":"10.1016/j.freeradbiomed.2025.02.021","DOIUrl":"10.1016/j.freeradbiomed.2025.02.021","url":null,"abstract":"<div><div>Lipid metabolism has been identified as a potential target for the treatment of doxorubicin-induced cardiomyopathy (DIC). Mitochondria, as a central regulator of energy production and utilization, plays a crucial role in this process, and enhancing mitophagy holds promise in mitigating myocardial damage in DIC. However, the relationship between mitophagy and lipid metabolism remains unclear, and the key molecules mediating this connection remain to be elucidated. Among these candidates, heterogeneous nuclear ribonucleoprotein K (hnRNPK) emerges as a potential regulator of mitophagy and metabolism. However, its specific role in DIC remains unclear. In this study, we established chronic DIC models both <em>in vivo</em> and <em>in vitro</em> to assess the relationship between hnRNPK levels, mitophagy, and lipid metabolism, as well as to evaluate the impact of hnRNPK on cardiac function. Our findings revealed that hnRNPK expression is significantly reduced in the hearts of doxorubicin (DOX)-treated mice. Notably, hnRNPK overexpression improves cardiac function and effectively reduces lipid accumulation by enhancing mitophagy. Mechanistically, hnRNPK expression was found to be downregulated in DIC, accompanied by its translocation from the nucleus to the cytoplasm, thereby reducing the transcriptional regulation of PINK1. Overexpression of hnRNPK and inhibition of its cytoplasmic translocation alleviates DOX-induced lipid accumulation by regulating the PINK1/Parkin pathway. These findings underscore a previously unrecognized role of hnRNPK in inhibiting lipid accumulation to prevent DIC.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"231 ","pages":"Pages 94-108"},"PeriodicalIF":7.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472369","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}

引用次数: 0

Endogenous production of nitric oxide by iNOS in human cells restricts inflammatory activation and cholesterol/fatty acid biosynthesis

IF 7.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Free Radical Biology and Medicine

Pub Date : 2025-02-18 DOI: 10.1016/j.freeradbiomed.2025.02.022

Franklin F. Tam, Jenice M. Dumlao, Amy HY. Lee, Jonathan C. Choy

Nitric oxide (NO) is a bioactive gas that is known to control many physiological processes. In human parenchymal cells, the function of iNOS-derived NO is incompletely understood. Here, we used RNA-seq to examine the role of iNOS-derived NO in the control of gene expression in a human lung epithelial cell line treated with inflammatory cytokines. iNOS-derived NO restricted the expression of genes involved in immune signaling, including the immune-related genes CXCL9 and E-selectin that were not previously known to be inhibited by iNOS. We also determined that iNOS-derived NO inhibits the expression of genes needed for cholesterol/fatty acid biosynthesis in response to cytokine stimulation, a process not previously known to be affected by NO. These findings establish the regulation of immune activation and cholesterol/fatty acid biosynthesis as main functions of iNOS in human parenchymal cells.

引用次数: 0

Macrophages hijack carbapenem-resistance hypervirulent Klebsiella pneumoniae by blocking SLC7A11/GSH-manipulated iron oxidative stress 巨噬细胞通过阻断 SLC7A11/GSH 操纵的铁氧化应激，劫持耐碳青霉烯类药物的高病毒性肺炎克雷伯氏菌。

IF 7.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Free Radical Biology and Medicine

Pub Date : 2025-02-16 DOI: 10.1016/j.freeradbiomed.2025.02.019

Qing Yu , Jie Yang , Heyu Chen , Ruishan Liu , Ruomeng Hu , Jiachang Cai , Shikuan Yang , Beiwen Zheng , Peng Guo , Zhijian Cai , Shufang Zhang , Gensheng Zhang

Infection with carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is life-threatening because of its pronounced virulence and antibiotic resistance. Recent studies revealed that iron and ROS enhance the ability of macrophages to eliminate intracellular pathogenic bacteria. However, whether and how iron-related oxygen stress responses in macrophages elicit a protective role against CR-hvKP infection remains largely unknown. In a mouse model of CR-hvKP pulmonary infection, the production of the Solute Carrier Family 7 member 11 (SLC7A11) was increased. Treatment with the ferroptosis agonist Erastin or Sorafenib decreased the SLC7A11 expression and the bacterial load in infected lung tissues, alleviating CR-hvKP-induced acute lung injury, increasing the content of TLR4, ROS and LPO. In vitro experiments showed that CR-hvKP infection resulted in a remarkable time-dependent changes in the expression of SLC7A11, GSH, ferrous iron, ROS and LPO in MH-S cells. Mechanically, blocking the expression of SLC7A11 in CR-hvKP-infected MH-S cells increased iron and ROS, improving the ability of macrophages to clear CR-hvKP in an LPO-dependent manner. Taken together, our study reveals that improving iron-related oxygen stress via blocking the SLC7A11/GSH pathway promoting the macrophages to phagocytose and eliminate CR-hvKP, which provides a new promising strategy against CR-hvKP infection.

{"title":"Macrophages hijack carbapenem-resistance hypervirulent Klebsiella pneumoniae by blocking SLC7A11/GSH-manipulated iron oxidative stress","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.2025.02.019","DOIUrl":"10.1016/j.freeradbiomed.2025.02.019","url":null,"abstract":"<div><div>Infection with carbapenem-resistant hypervirulent <em>Klebsiella pneumoniae</em> (CR-hvKP) is life-threatening because of its pronounced virulence and antibiotic resistance. Recent studies revealed that iron and ROS enhance the ability of macrophages to eliminate intracellular pathogenic bacteria. However, whether and how iron-related oxygen stress responses in macrophages elicit a protective role against CR-hvKP infection remains largely unknown. In a mouse model of CR-hvKP pulmonary infection, the production of the Solute Carrier Family 7 member 11 (SLC7A11) was increased. Treatment with the ferroptosis agonist Erastin or Sorafenib decreased the SLC7A11 expression and the bacterial load in infected lung tissues, alleviating CR-hvKP-induced acute lung injury, increasing the content of TLR4, ROS and LPO. <em>In vitro</em> experiments showed that CR-hvKP infection resulted in a remarkable time-dependent changes in the expression of SLC7A11, GSH, ferrous iron, ROS and LPO in MH-S cells. Mechanically, blocking the expression of SLC7A11 in CR-hvKP-infected MH-S cells increased iron and ROS, improving the ability of macrophages to clear CR-hvKP in an LPO-dependent manner. Taken together, our study reveals that improving iron-related oxygen stress via blocking the SLC7A11/GSH pathway promoting the macrophages to phagocytose and eliminate CR-hvKP, which provides a new promising strategy against CR-hvKP infection.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"230 ","pages":"Pages 234-247"},"PeriodicalIF":7.1,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448731","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}

引用次数: 0

Estrogen mitigates ischemia-reperfusion injury by inhibiting cardiomyocyte ferroptosis through the downregulation of PHLDA3 expression

IF 7.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Free Radical Biology and Medicine

Pub Date : 2025-02-16 DOI: 10.1016/j.freeradbiomed.2025.01.051

Lijie Zhu , Qiongjun Zhu , Zhezhe Chen , Yecheng Tao , Jiayi Hu , Dan'an Wang , Yutong Lin , Honghui Yang , Chuanyu Gao , Wenbin Zhang

Ferroptosis represents a significant target for mitigating myocardial ischemia-reperfusion (I/R) injury. Existing literature indicates that estrogen (17β-estradiol, E2) can alleviate such injuries through various pathways. However, the specific mechanisms by which E2 may confer protection against myocardial I/R injury through the inhibition of ferroptosis remain to be fully elucidated. This study employed a mouse model of left anterior descending coronary artery ligation to investigate the protective effects of E2 on myocardial I/R injury, with a particular focus on its inhibitory effects on ferroptosis and PHLDA3 in both hypoxia-reoxygenation (H/R) and I/R models. A bioinformatics analysis was conducted to evaluate the impact of estrogen receptor GPER knockout on PHLDA3 expression and ferroptosis. Loss-of-function approaches were employed to elucidate the role of PHLDA3 in ferroptosis during myocardial I/R injury. Our findings demonstrate that E2 can ameliorate myocardial I/R injury, primarily by inhibiting ferroptosis. Notably, PHLDA3 expression levels were significantly elevated during ischemia-reperfusion events; however, E2 was observed to suppress this expression. Bioinformatics analysis indicated that PHLDA3 levels increased following GPER knockdown, and the inhibitory effect of E2 on PHLDA3 expression could be partially reversed by GPER inhibitors (G15) in animal models. Furthermore, the suppression of PHLDA3 reduced ferroptosis and mitigated the severity of myocardial I/R injury. Utilizing mass spectrometry and co-immunoprecipitation methodologies, we have elucidated a potential mechanism in which PHLDA3 directly binds to and interacts with proteins involved in the process of ferroptosis.

Our findings demonstrate that E2 effectively suppresses ferroptosis and mitigates myocardial I/R injury by downregulating PHLDA3 expression through the activation of the GPER receptor.

{"title":"Estrogen mitigates ischemia-reperfusion injury by inhibiting cardiomyocyte ferroptosis through the downregulation of PHLDA3 expression","authors":"Lijie Zhu , Qiongjun Zhu , Zhezhe Chen , Yecheng Tao , Jiayi Hu , Dan'an Wang , Yutong Lin , Honghui Yang , Chuanyu Gao , Wenbin Zhang","doi":"10.1016/j.freeradbiomed.2025.01.051","DOIUrl":"10.1016/j.freeradbiomed.2025.01.051","url":null,"abstract":"<div><div>Ferroptosis represents a significant target for mitigating myocardial ischemia-reperfusion (I/R) injury. Existing literature indicates that estrogen (17β-estradiol, E2) can alleviate such injuries through various pathways. However, the specific mechanisms by which E2 may confer protection against myocardial I/R injury through the inhibition of ferroptosis remain to be fully elucidated. This study employed a mouse model of left anterior descending coronary artery ligation to investigate the protective effects of E2 on myocardial I/R injury, with a particular focus on its inhibitory effects on ferroptosis and PHLDA3 in both hypoxia-reoxygenation (H/R) and I/R models. A bioinformatics analysis was conducted to evaluate the impact of estrogen receptor GPER knockout on PHLDA3 expression and ferroptosis. Loss-of-function approaches were employed to elucidate the role of PHLDA3 in ferroptosis during myocardial I/R injury. Our findings demonstrate that E2 can ameliorate myocardial I/R injury, primarily by inhibiting ferroptosis. Notably, PHLDA3 expression levels were significantly elevated during ischemia-reperfusion events; however, E2 was observed to suppress this expression. Bioinformatics analysis indicated that PHLDA3 levels increased following GPER knockdown, and the inhibitory effect of E2 on PHLDA3 expression could be partially reversed by GPER inhibitors (G15) in animal models. Furthermore, the suppression of PHLDA3 reduced ferroptosis and mitigated the severity of myocardial I/R injury. Utilizing mass spectrometry and co-immunoprecipitation methodologies, we have elucidated a potential mechanism in which PHLDA3 directly binds to and interacts with proteins involved in the process of ferroptosis.</div><div>Our findings demonstrate that E2 effectively suppresses ferroptosis and mitigates myocardial I/R injury by downregulating PHLDA3 expression through the activation of the GPER receptor.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 1-14"},"PeriodicalIF":7.1,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440179","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}

引用次数: 0

Oxidative modification of extracellular histones by hypochlorous acid modulates their ability to induce β-cell dysfunction

IF 7.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Free Radical Biology and Medicine

Pub Date : 2025-02-15 DOI: 10.1016/j.freeradbiomed.2025.02.018

Clara Skjølberg , Laura Degani , Inga Sileikaite-Morvaközi, Clare L. Hawkins

Histones are nuclear proteins that play a key role in chromatin assembly and regulation of gene expression by their ability to bind to DNA. Histones can also be released from cells owing to necrosis or extracellular trap release from neutrophils (NETs) and other immune cells. The presence of histones in the extracellular environment has implications for many pathologies, including diabetes mellitus, owing to the cytotoxic nature of these proteins, and their ability to promote inflammation. NETs also contain myeloperoxidase, a defensive enzyme that produces hypochlorous acid (HOCl), to kill pathogens, but also readily damages host proteins. In this study, we examined the reactivity of histones with and without HOCl modification, with a pancreatic β-cell model. Exposure of β-cells to histones resulted in a loss of metabolic activity and cell death by a combination of apoptosis and necrosis. This toxicity was increased on pretreatment of the β-cells with tumour necrosis factor α and interleukin 1β. Histones upregulated endoplasmic reticulum (ER) stress genes, including the pro-apoptotic transcription factor CHOP. There was also evidence for alterations to the cellular redox environment and upregulation of antioxidant gene expression. However, downregulation of insulin-associated genes and insulin was observed. Interestingly, modification of the histones with HOCl reduced their toxicity and altered the patterns of gene expression observed, and a further decrease in the expression of insulin-associated genes was observed. These findings could be relevant to the development of Type 2 diabetes, where low-grade inflammation favours NET release, resulting in elevated histones in the circulation.

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引用次数: 0

Oxidative stress in trauma patients receiving a restrictive or liberal oxygen strategy – A sub-study of the TRAUMOX2 trial

IF 7.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Free Radical Biology and Medicine

Pub Date : 2025-02-15 DOI: 10.1016/j.freeradbiomed.2025.02.016

Tobias Arleth , Josefine Baekgaard , Felicia Dinesen , Andreas Creutzburg , Helene Dalsten , Carl Johan Queitsch , Sarah Sofie Wadland , Oscar Rosenkrantz , Volkert Siersma , Claus Moser , Peter Østrup Jensen , Lars S. Rasmussen , Jacob Steinmetz

Introduction

A liberal supplemental oxygen approach is recommended for all severely injured trauma patients despite limited evidence. Liberal oxygen administration may cause oxidative stress. The aim of this study was to investigate the effect of an early restrictive oxygen strategy versus a liberal oxygen strategy in adult trauma patients on biomarkers of oxidative stress within 48 h of hospital admission.

Materials and methods

This was a single-centre, sub-study of an international, randomised controlled trial TRAUMOX2. In TRAUMOX2, patients were randomised shortly after trauma to a restrictive oxygen strategy (arterial oxygen saturation target of 94 %) or a liberal oxygen strategy (12–15 L of oxygen per minute or fraction of inspired oxygen of 0.6–1.0) for 8 h. Blood samplings were performed at four time points within 48 h after randomisation: upon arrival at the trauma centre, and at eight, 24, and 48 h post-randomisation. The primary outcome was the plasma level of malondialdehyde (MDA) 24 h post-randomisation. Secondary outcomes were numerous, and included the level of MDA at other time points, superoxide dismutase (SOD) at all time points, 30-day mortality, and major respiratory complications.

Results

The sub-study included 90 adult trauma patients. The median MDA levels at 24 h post-randomisation was 60.9 μM (95 % CI 49.5 to 73.4) in the restrictive oxygen group and 56.7 μM (95 % CI 46.9 to 68.2) in the liberal oxygen group, corresponding to a difference of −4.2 μM (95 % CI -19.8 to 10.5; P = 0.35). No significant differences were found in MDA or SOD at the other time points either. Neither did we find a significant difference in 30-day mortality or major respiratory complications.

Conclusions

In this sub-study of the TRAUMOX2 trial, no significant differences were found in biomarkers of oxidative stress between a restrictive oxygen strategy and liberal oxygen strategy in adult trauma patients.

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引用次数: 0

Deuterium-reinforced polyunsaturated fatty acids protect against muscle atrophy by STZ-induced diabetic mice

IF 7.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Free Radical Biology and Medicine

Pub Date : 2025-02-14 DOI: 10.1016/j.freeradbiomed.2025.02.015

Hiroaki Eshima , Tomoaki Ishihara , Ayaka Tabuchi , Yutaka Kano , Kenji Kurokawa , Mikhail S. Shchepinov

Oxidative stress and reactive oxygen species (ROS) have been linked to muscle atrophy and weakness. Diabetes increases the oxidative status in all tissues, including muscle tissues, but the role of lipid ROS on diabetes-induced muscle atrophy is not fully understood. Deuterium reinforced polyunsaturated fatty acids (D-PUFA) are more resistant to ROS-initiated chain reaction of lipid peroxidation than regular hydrogenated PUFA (H-PUFA). In this study, we tested the hypothesis that D-PUFA would protect muscle atrophy induced by diabetes driven by an accumulation of lipid hydroperoxides (LOOH). C57BL/6J mice were dosed with H-PUFA or D-PUFA for four weeks through dietary supplementation (10 mg/day) and then injected with streptozotocin (STZ) to induce insulin-deficient diabetes. After two weeks, muscles tissues were analyzed for individual muscle mass, force generating capacity and cross-sectional area. Skeletal muscle fibers from diabetic mice exhibited increased total ROS and LOOH. This was abolished by the D-PUFA supplementation regardless of accumulated iron. D-PUFA were found to be protective against muscle atrophy and weakness from STZ-induced diabetes. Prevention of muscle atrophy and weakness by D-PUFA might be independent of ACSL4/LPCAT3/15-LOX pathway. These findings provide novel insights into the role of LOOH in the mechanistic link between oxidative stress and diabetic myopathy and suggest a novel therapeutic approach to diabetes-associated muscle weakness.

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引用次数: 0