Pub Date : 2025-03-03DOI: 10.1016/j.freeradbiomed.2025.03.002
Arno R Bourgonje, Tim J Knobbe, Daan Kremer, Marian L C Bulthuis, Frederike J Bemelman, Stefan P Berger, Gerjan J Navis, Stephan J L Bakker, Eva Corpeleijn, Harry van Goor
Background: Oxidative stress is associated with adverse outcomes in kidney transplant recipients (KTR), including graft failure, morbidity, and mortality. Since both exercise training and dietary modifications have the potential to improve redox status, we aimed to investigate the potential mitigating effects of exercise or exercise plus diet intervention on circulating levels of free thiols (R-SH) as marker of systemic redox status in KTR.
Methods: We conducted a post-hoc analysis of the Active Care after Transplantation (ACT) study, a randomized controlled lifestyle intervention trial which proved to enhance physical functioning of KTR. Systemic R-SH levels were quantified at baseline, 3-months, and 15-months (end of study) using a colorimetric detection method. Estimated marginal means (EMM) were reported using general linear mixed models.
Results: KTR were randomized to usual care (n=40), exercise intervention (n=54), or exercise plus diet intervention (n=55). At 3 months post-baseline, systemic R-SH concentrations decreased significantly in the control group, while the intervention groups showed a less pronounced decrease, although the difference compared to control nearly reached statistical significance in either the exercise intervention group (EMM +20.2 μM (95%CI -1.4, +41.9), P=0.067) or the exercise plus diet intervention group (EMM +18.9 μM (95%CI -2.7, +40.4), P=0.086). At 15 months post-baseline, R-SH concentrations further decreased in the exercise intervention group, resulting in a difference compared to control of +9.0 μM (95%CI -14.4, +32.3; P=0.45), whereas R-SH concentrations increased to above baseline in the exercise plus diet intervention group, with a statistically significant difference compared to control of +32.8 μM (95%CI +9.4, +56.2; P=0.006).
Conclusions: Lifestyle changes involving exercise and diet positively impacted systemic R-SH, suggesting that reducing oxidative stress through lifestyle interventions could potentially contribute to clinical benefits in KTR.
{"title":"Effect of Lifestyle Intervention on Systemic Oxidative Stress in Kidney Transplant Recipients: A Post-Hoc Analysis of the Active Care after Transplantation (ACT) Randomized Controlled Trial.","authors":"Arno R Bourgonje, Tim J Knobbe, Daan Kremer, Marian L C Bulthuis, Frederike J Bemelman, Stefan P Berger, Gerjan J Navis, Stephan J L Bakker, Eva Corpeleijn, Harry van Goor","doi":"10.1016/j.freeradbiomed.2025.03.002","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.03.002","url":null,"abstract":"<p><strong>Background: </strong>Oxidative stress is associated with adverse outcomes in kidney transplant recipients (KTR), including graft failure, morbidity, and mortality. Since both exercise training and dietary modifications have the potential to improve redox status, we aimed to investigate the potential mitigating effects of exercise or exercise plus diet intervention on circulating levels of free thiols (R-SH) as marker of systemic redox status in KTR.</p><p><strong>Methods: </strong>We conducted a post-hoc analysis of the Active Care after Transplantation (ACT) study, a randomized controlled lifestyle intervention trial which proved to enhance physical functioning of KTR. Systemic R-SH levels were quantified at baseline, 3-months, and 15-months (end of study) using a colorimetric detection method. Estimated marginal means (EMM) were reported using general linear mixed models.</p><p><strong>Results: </strong>KTR were randomized to usual care (n=40), exercise intervention (n=54), or exercise plus diet intervention (n=55). At 3 months post-baseline, systemic R-SH concentrations decreased significantly in the control group, while the intervention groups showed a less pronounced decrease, although the difference compared to control nearly reached statistical significance in either the exercise intervention group (EMM +20.2 μM (95%CI -1.4, +41.9), P=0.067) or the exercise plus diet intervention group (EMM +18.9 μM (95%CI -2.7, +40.4), P=0.086). At 15 months post-baseline, R-SH concentrations further decreased in the exercise intervention group, resulting in a difference compared to control of +9.0 μM (95%CI -14.4, +32.3; P=0.45), whereas R-SH concentrations increased to above baseline in the exercise plus diet intervention group, with a statistically significant difference compared to control of +32.8 μM (95%CI +9.4, +56.2; P=0.006).</p><p><strong>Conclusions: </strong>Lifestyle changes involving exercise and diet positively impacted systemic R-SH, suggesting that reducing oxidative stress through lifestyle interventions could potentially contribute to clinical benefits in KTR.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566557","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}
Oxidative Stress (OS) is the main cause of damage to the Blood-Testis Barrier (BTB) in cryptorchidism, which seriously endangers male reproductive health. It is well known that the OS induced ferroptosis is an important cause of dysfunction in the body. However, it is still unknown whether BTB damage in cryptorchidism leads to ferroptosis of Sertoli cells. We establishing the cryptorchidism model through surgery to avoid the complex effects of drugs on the model animals, combined with in vitro culture of the primary Sertoli cells for validation, and the methods of immunofluorescence staining, Western blotting and Prussian blue staining were used to study the oxidative stress in cryptorchidism. The effects of ferroptosis of Sertoli cells inducing BTB damage caused by OS in cryptorchidism were analyzed. We found that the inhibition of Nrf-2/keap-1/HO-1 pathway resulted in decreased expression levels of Glutathione Peroxidase 4 (GPX4), Ferroportin 1 (FPN1), and increased expression of Ferritin light chain (FTL) protein. Our research further confirms that inhibiting ferroptosis reduced BTB damage by reflecting a decrease expression of Zonula Occludens protein 1 (ZO-1), Occludin and Claudin-11 protein caused by OS. In addition, we found that the testosterone (T) secretion disorders and the supplementation of T can alleviate the damage of the BTB in cryptorchidism, and this effect is achieved through the Androgen Receptor (AR). In conclusion, our study found that the inhibition of Nrf-2/keap-1/HO-1 pathway in testis and the reduction of Tight junction proteins (TJs) ZO-1, Occludin and Claudin-11 protein expression levels in cryptorchidic mice, indicated that the cryptorchidism triggering a serious reproductive disorder, and one of the important reasons is the OS induced ferroptosis of Sertoli cells, which ultimately leads to the damage of the BTB. This findings may have important implications in the field of male reproductive disorders.
{"title":"The ferroptosis of sertoli cells inducing blood-testis barrier damage is produced by oxidative stress in cryptorchidism","authors":"Jianlin Zeng , Ligang Yuan , Guojuan Chen , Yumei Qi , Xiaolong Qie , Yajuan Jin , Yulu Chen , Haijun Li","doi":"10.1016/j.freeradbiomed.2025.02.043","DOIUrl":"10.1016/j.freeradbiomed.2025.02.043","url":null,"abstract":"<div><div>Oxidative Stress (OS) is the main cause of damage to the Blood-Testis Barrier (BTB) in cryptorchidism, which seriously endangers male reproductive health. It is well known that the OS induced ferroptosis is an important cause of dysfunction in the body. However, it is still unknown whether BTB damage in cryptorchidism leads to ferroptosis of Sertoli cells. We establishing the cryptorchidism model through surgery to avoid the complex effects of drugs on the model animals, combined with in vitro culture of the primary Sertoli cells for validation, and the methods of immunofluorescence staining, Western blotting and Prussian blue staining were used to study the oxidative stress in cryptorchidism. The effects of ferroptosis of Sertoli cells inducing BTB damage caused by OS in cryptorchidism were analyzed. We found that the inhibition of Nrf-2/keap-1/HO-1 pathway resulted in decreased expression levels of Glutathione Peroxidase 4 (GPX4), Ferroportin 1 (FPN1), and increased expression of Ferritin light chain (FTL) protein. Our research further confirms that inhibiting ferroptosis reduced BTB damage by reflecting a decrease expression of Zonula Occludens protein 1 (ZO-1), Occludin and Claudin-11 protein caused by OS. In addition, we found that the testosterone (T) secretion disorders and the supplementation of T can alleviate the damage of the BTB in cryptorchidism, and this effect is achieved through the Androgen Receptor (AR). In conclusion, our study found that the inhibition of Nrf-2/keap-1/HO-1 pathway in testis and the reduction of Tight junction proteins (TJs) ZO-1, Occludin and Claudin-11 protein expression levels in cryptorchidic mice, indicated that the cryptorchidism triggering a serious reproductive disorder, and one of the important reasons is the OS induced ferroptosis of Sertoli cells, which ultimately leads to the damage of the BTB. This findings may have important implications in the field of male reproductive disorders.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 97-106"},"PeriodicalIF":7.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540728","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}
Pub Date : 2025-03-01DOI: 10.1016/j.freeradbiomed.2025.02.046
Rajitha Gadde, Shrey Shah, Mark Böhlke, Jonghan Kim, Swati Betharia
Wilson's Disease (WD) is a rare autosomal recessive disorder caused by mutations in the ATP7B gene. These mutations lead to defective copper (Cu) transport and to accumulation of Cu in tissues, primarily in the liver and brain. Current treatment options such as D-penicillamine, trientine, and zinc salts focus on increasing Cu excretion or reducing Cu absorption, but often cause debilitating side effects. N,N' bis-(2-mercaptoethyl)isophthalamide (NBMI) is a lipophilic thiol-based compound originally developed for environmental decontamination. It has been shown to chelate toxic metals such as mercury, lead, and cadmium. This study was designed to evaluate the efficacy of NBMI to mitigate Cu overload using both in vitro and in vivo models of WD. HepG2 cells with the ATP7B gene knocked down had increased sensitivity to copper sulfate (CuSO4) compared to wild-type (WT) cells, validating the cell model for WD. Pretreatment with NBMI (2.5-50 μM) improved cell viability, reduced Cu-induced oxidative stress, decreased metallothionein levels, mitigated resulting DNA damage, and reduced overall levels of free intracellular Cu. In an established toxic milk mouse (tx-J) model of WD, 1% dietary NBMI effectively lowered hepatic, cerebral, and renal Cu levels. Treatment with 1% NBMI also improved liver function, as evidenced by reduced ALT levels and normalized hepatocyte morphology. Tx-J mice displayed higher liver-to-body weight ratios compared to WT mice, and treatment with 1% NBMI effectively reduced this ratio. While NBMI did not impact the elevated white blood cell counts and low platelet levels characteristic of tx-J mice, it also did not cause any detrimental effects on red blood cell, hemoglobin, and hematocrit levels. High dose NBMI also restored homeostasis of other dysregulated essential metal ions in tx-J mice. These findings suggest that dietary administration of NBMI effectively chelates excess free Cu, ameliorates WD symptoms and offers a promising alternative to existing chelators.
{"title":"N,N'bis-(2-mercaptoethyl) isophthalamide (NBMI) as a novel chelator for Wilson's Disease.","authors":"Rajitha Gadde, Shrey Shah, Mark Böhlke, Jonghan Kim, Swati Betharia","doi":"10.1016/j.freeradbiomed.2025.02.046","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.02.046","url":null,"abstract":"<p><p>Wilson's Disease (WD) is a rare autosomal recessive disorder caused by mutations in the ATP7B gene. These mutations lead to defective copper (Cu) transport and to accumulation of Cu in tissues, primarily in the liver and brain. Current treatment options such as D-penicillamine, trientine, and zinc salts focus on increasing Cu excretion or reducing Cu absorption, but often cause debilitating side effects. N,N' bis-(2-mercaptoethyl)isophthalamide (NBMI) is a lipophilic thiol-based compound originally developed for environmental decontamination. It has been shown to chelate toxic metals such as mercury, lead, and cadmium. This study was designed to evaluate the efficacy of NBMI to mitigate Cu overload using both in vitro and in vivo models of WD. HepG2 cells with the ATP7B gene knocked down had increased sensitivity to copper sulfate (CuSO<sub>4</sub>) compared to wild-type (WT) cells, validating the cell model for WD. Pretreatment with NBMI (2.5-50 μM) improved cell viability, reduced Cu-induced oxidative stress, decreased metallothionein levels, mitigated resulting DNA damage, and reduced overall levels of free intracellular Cu. In an established toxic milk mouse (tx-J) model of WD, 1% dietary NBMI effectively lowered hepatic, cerebral, and renal Cu levels. Treatment with 1% NBMI also improved liver function, as evidenced by reduced ALT levels and normalized hepatocyte morphology. Tx-J mice displayed higher liver-to-body weight ratios compared to WT mice, and treatment with 1% NBMI effectively reduced this ratio. While NBMI did not impact the elevated white blood cell counts and low platelet levels characteristic of tx-J mice, it also did not cause any detrimental effects on red blood cell, hemoglobin, and hematocrit levels. High dose NBMI also restored homeostasis of other dysregulated essential metal ions in tx-J mice. These findings suggest that dietary administration of NBMI effectively chelates excess free Cu, ameliorates WD symptoms and offers a promising alternative to existing chelators.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540726","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}
High-fat diet (HFD) is associated with visceral obesity due to disruption in the lipid metabolism and gut dysbiosis. These symptoms may contribute to hepatic steatosis and the formation of oxidized polyunsaturated fatty acids (PUFAs). Alpha-aminobutyric acid (ABA) is an amino-acid derived metabolite, and its concentration has been correlated with several metabolic conditions and gut microbiome diversity while its direct effects on visceral obesity, lipid metabolism and the gut microbiota are not well understood. This study was designed to investigate the effect of physiological dose of ABA on diet-induced visceral obesity and lipid metabolism dysregulation by examining the fatty acids and oxidized PUFAs profile in the liver as well as the gut microbiota.
Results
ABA administration reduced visceral obesity by 28 % and lessened adipocyte hypertrophy. The expression of liver Cd36 was lowered by more than 50 % as well as the saturated and monounsaturated FA concentration. Notably, the desaturation index for C16 and C18 FAs that are correlated with adiposity were reduced. The concentration of several DHA-derived oxidized PUFAs were also enhanced. Faecal metagenomics sequencing revealed enriched abundance of Leptogranulimonas caecicola and Bacteroides sp. ZJ-18 and were positively correlated with several DHA- and ALA-derived oxidized PUFAs in ABA group.
Conclusion
Our study revealed the modulatory effect of physiological dose of ABA on attenuating visceral obesity, reducing hepatic steatosis, and promoting the production of anti-inflammatory oxidized PUFAs that were potentially mediated by the gut microbiota.
{"title":"Alpha-aminobutyric acid administration suppressed visceral obesity and modulated hepatic oxidized PUFA metabolism via gut microbiota modulation","authors":"Marsena Jasiel Ismaiah , Emily Kwun Kwan Lo , Congjia Chen , Jacob Shing-Jie Tsui , Winifred Audrey Johnson-Hill , Felicianna , Fangfei Zhang , Hoi Kit Matthew Leung , Camille Oger , Thierry Durand , Jetty Chung-Yung Lee , Hani El-Nezami","doi":"10.1016/j.freeradbiomed.2025.02.029","DOIUrl":"10.1016/j.freeradbiomed.2025.02.029","url":null,"abstract":"<div><h3>Background</h3><div>High-fat diet (HFD) is associated with visceral obesity due to disruption in the lipid metabolism and gut dysbiosis. These symptoms may contribute to hepatic steatosis and the formation of oxidized polyunsaturated fatty acids (PUFAs). Alpha-aminobutyric acid (ABA) is an amino-acid derived metabolite, and its concentration has been correlated with several metabolic conditions and gut microbiome diversity while its direct effects on visceral obesity, lipid metabolism and the gut microbiota are not well understood. This study was designed to investigate the effect of physiological dose of ABA on diet-induced visceral obesity and lipid metabolism dysregulation by examining the fatty acids and oxidized PUFAs profile in the liver as well as the gut microbiota.</div></div><div><h3>Results</h3><div>ABA administration reduced visceral obesity by 28 % and lessened adipocyte hypertrophy. The expression of liver <em>Cd36</em> was lowered by more than 50 % as well as the saturated and monounsaturated FA concentration. Notably, the desaturation index for C16 and C18 FAs that are correlated with adiposity were reduced. The concentration of several DHA-derived oxidized PUFAs were also enhanced. Faecal metagenomics sequencing revealed enriched abundance of <em>Leptogranulimonas caecicola</em> and <em>Bacteroides</em> sp. <em>ZJ-18</em> and were positively correlated with several DHA- and ALA-derived oxidized PUFAs in ABA group.</div></div><div><h3>Conclusion</h3><div>Our study revealed the modulatory effect of physiological dose of ABA on attenuating visceral obesity, reducing hepatic steatosis, and promoting the production of anti-inflammatory oxidized PUFAs that were potentially mediated by the gut microbiota.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 86-96"},"PeriodicalIF":7.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540705","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}
Pub Date : 2025-03-01DOI: 10.1016/j.freeradbiomed.2025.02.048
Zirui Zhao , Ruonan Wang , Haitao Ge , Liyan Hou , Taku Hatano , Nobutaka Hattori , Hong Su , Qingshan Wang , Jie Zhao
Background
Parkinson's disease (PD) is the most common neurodegenerative movement disorder with uncleared mechanisms. Short-chain enoyl-CoA hydratase 1 (ECHS1) is a mitochondrial enzyme critical for the β-oxidation of fatty acids and ATP production. This study aims to explore the roles of ECHS1 in PD by using rotenone-induced experimental PD models.
Methods
To evaluate the role of ECHS1 in rotenone-induced dopaminergic neurodegeneration, adeno-associated virus (AAV)-ECHS1 was stereotactically injected into the substantia nigra region of mice to overexpress ECHS1. Motor function of mice among groups was detected by rotarod test and gait analysis. Neurodegeneration, mitochondrial dysfunction and apoptosis were determined by immunohistochemistry, immunofluorescence staining, Western blot or kits, respectively.
Results
The expression and activity of ECHS1 were decreased in PD mice and positive correlations between ECHS1 reduction and dopaminergic neurodegeneration were observed. Overexpression of ECHS1 by AAV delivery attenuated loss of dopaminergic neuron and motor deficits in PD mice. Mechanistically, ECHS1 attenuated rotenone-induced mitochondrial swelling and loss of cristae as well as decrease of ATP production, mitochondrial membrane potential, complex I/IV activities and oxygen consumption rate (OCR). Mitochondrial ROS (mtROS)-targeted antioxidant mito-TEMPO prevented ECHS1 silence-mediated mitochondrial dysfunction. Furthermore, we found that ECHS1 interacted with NADPH oxidase 4 (NOX4), resulting in decrease of NOX4 activation and subsequent reduction of mtROS production and mitochondrial dysfunction. Finally, inhibition of NOX4 by GLX351322 or mtROS production by mito-TEMPO greatly reduced ECHS1 silence-mediated apoptosis in rotenone-treated SH-SY5Y cells.
Conclusions
ECHS1 counteracted dopaminergic neurodegeneration through inhibition of mtROS and restoration of mitochondrial function via interaction with NOX4. Given the central role of mitochondrial dysfunction in PD pathogenesis, elucidating the role of ECHS1 holds great promise for uncovering novel therapeutic targets.
{"title":"ECHS1-NOX4 interaction suppresses rotenone-induced dopaminergic neurotoxicity through inhibition of mitochondrial ROS production","authors":"Zirui Zhao , Ruonan Wang , Haitao Ge , Liyan Hou , Taku Hatano , Nobutaka Hattori , Hong Su , Qingshan Wang , Jie Zhao","doi":"10.1016/j.freeradbiomed.2025.02.048","DOIUrl":"10.1016/j.freeradbiomed.2025.02.048","url":null,"abstract":"<div><h3>Background</h3><div>Parkinson's disease (PD) is the most common neurodegenerative movement disorder with uncleared mechanisms. Short-chain enoyl-CoA hydratase 1 (ECHS1) is a mitochondrial enzyme critical for the β-oxidation of fatty acids and ATP production. This study aims to explore the roles of ECHS1 in PD by using rotenone-induced experimental PD models.</div></div><div><h3>Methods</h3><div>To evaluate the role of ECHS1 in rotenone-induced dopaminergic neurodegeneration, adeno-associated virus (AAV)-ECHS1 was stereotactically injected into the substantia nigra region of mice to overexpress ECHS1. Motor function of mice among groups was detected by rotarod test and gait analysis. Neurodegeneration, mitochondrial dysfunction and apoptosis were determined by immunohistochemistry, immunofluorescence staining, Western blot or kits, respectively.</div></div><div><h3>Results</h3><div>The expression and activity of ECHS1 were decreased in PD mice and positive correlations between ECHS1 reduction and dopaminergic neurodegeneration were observed. Overexpression of ECHS1 by AAV delivery attenuated loss of dopaminergic neuron and motor deficits in PD mice. Mechanistically, ECHS1 attenuated rotenone-induced mitochondrial swelling and loss of cristae as well as decrease of ATP production, mitochondrial membrane potential, complex I/IV activities and oxygen consumption rate (OCR). Mitochondrial ROS (mtROS)-targeted antioxidant mito-TEMPO prevented ECHS1 silence-mediated mitochondrial dysfunction. Furthermore, we found that ECHS1 interacted with NADPH oxidase 4 (NOX4), resulting in decrease of NOX4 activation and subsequent reduction of mtROS production and mitochondrial dysfunction. Finally, inhibition of NOX4 by GLX351322 or mtROS production by mito-TEMPO greatly reduced ECHS1 silence-mediated apoptosis in rotenone-treated SH-SY5Y cells.</div></div><div><h3>Conclusions</h3><div>ECHS1 counteracted dopaminergic neurodegeneration through inhibition of mtROS and restoration of mitochondrial function via interaction with NOX4. Given the central role of mitochondrial dysfunction in PD pathogenesis, elucidating the role of ECHS1 holds great promise for uncovering novel therapeutic targets.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 56-71"},"PeriodicalIF":7.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540708","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}
Pub Date : 2025-03-01DOI: 10.1016/j.freeradbiomed.2025.02.044
Yijun Xin , Yong Zhang , Zhaoji Yuan , Siying Li
Doxorubicin (Dox) is a widely used anticancer drug. However, its time- and dose-dependent side effects, particularly severe cardiotoxicity, limit its clinical use. Understanding the molecular mechanisms underlying Dox-induced cardiotoxicity has become a research focus in recent years. Among these, impaired mitophagy which participated in the process of damaged mitochondria clearance, is considered one of the key mechanisms in Dox-induced cardiomyopathy. Methionine (Met) is an essential amino acid that plays a crucial role in various biological processes. This study aims to investigate the role and mechanism of Met in regulating mitophagy in Dox-induced cardiotoxicity. Met deficiency exacerbated Dox-induced cardiotoxicity, primarily by promoting oxidative stress, affecting mitochondria integrity, disrupting autophagy, and thus leading to cardiomyocyte damage and aggravating heart failure. In addition, Met supplementation alleviated Dox-induced cardiotoxicity, via the general control nonderepessible 2 (GCN2) pathway. This study extends our understanding of the relationship between amino acid metabolism and Dox-induced cardiotoxicity, and indicating the Met-GCN2 axis as a promising therapeutic strategy for Dox-induced cardiotoxicity.
{"title":"Methionine is an essential amino acid in doxorubicin-induced cardiotoxicity through modulating mitophagy","authors":"Yijun Xin , Yong Zhang , Zhaoji Yuan , Siying Li","doi":"10.1016/j.freeradbiomed.2025.02.044","DOIUrl":"10.1016/j.freeradbiomed.2025.02.044","url":null,"abstract":"<div><div>Doxorubicin (Dox) is a widely used anticancer drug. However, its time- and dose-dependent side effects, particularly severe cardiotoxicity, limit its clinical use. Understanding the molecular mechanisms underlying Dox-induced cardiotoxicity has become a research focus in recent years. Among these, impaired mitophagy which participated in the process of damaged mitochondria clearance, is considered one of the key mechanisms in Dox-induced cardiomyopathy. Methionine (Met) is an essential amino acid that plays a crucial role in various biological processes. This study aims to investigate the role and mechanism of Met in regulating mitophagy in Dox-induced cardiotoxicity. Met deficiency exacerbated Dox-induced cardiotoxicity, primarily by promoting oxidative stress, affecting mitochondria integrity, disrupting autophagy, and thus leading to cardiomyocyte damage and aggravating heart failure. In addition, Met supplementation alleviated Dox-induced cardiotoxicity, via the general control nonderepessible 2 (GCN2) pathway. This study extends our understanding of the relationship between amino acid metabolism and Dox-induced cardiotoxicity, and indicating the Met-GCN2 axis as a promising therapeutic strategy for Dox-induced cardiotoxicity.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 28-39"},"PeriodicalIF":7.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540724","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}
Pub Date : 2025-03-01DOI: 10.1016/j.freeradbiomed.2025.02.047
Shuhan Wang , Yaqi Yang , Jiahong Lin , Weishan Zhang , Cuizhu Yang , Runheng Zhang , Chang Zhou , Li Zhang , Xin Wang , Jing Liu , Xiaobao Jin , Yuxin Ma
Alzheimer's disease (AD) as a common neurodegenerative disease, which characterized by amyloid Aβ deposition and neurofibrillary tangles. Astragalin (AST), a natural flavonoid, has anti-inflammatory, antioxidant, anti-cancer, and other pharmacological effects. Astrocytes can phagocytize and degrade Aβ in their vicinity. In this study, we used the AD mice model established by injecting the mixture of Aβ1-42 and Aβ25-35 into the CA1 region of the hippocampus, and C8D1A cells injured by Aβ1-42 to explore the neuroprotective effects of AST. Our findings showed that AST enhances learning and cognitive ability of AD mice, reduces Aβ deposition and neurofibrillary tangles in the brain, and improves the structural morphology of hippocampal nerve cells. Furthermore, AST promoted autophagy and suppressed apoptosis of astrocytes in the AD model. Additionally, AST inhibited the expression of proteins associated with the Fas/Fasl-VDAC1 signaling pathway, while autophagy inhibitor chloroquine (CQ) or apoptosis agonist phenoxodiol reversed above change. Interestingly, consistent with the action of pathway Fas inhibitor KR-33493, AST could activate autophagy of Aβ1-42 injured C8D1A cells while inhibit their apoptosis. In conclusion, AST activated autophagy and inhibited apoptosis of hippocampal astrocytes in AD mice, ameliorating animal cognitive deficits by down-regulating Fas/Fasl-VDAC1 signaling pathway. Thus, this study provided a new perspective and experimental foundation for developing AD treatment drugs.
{"title":"Astragalin actives autophagy and inhibits apoptosis of astrocytes in AD mice via down-regulating Fas/Fasl-VDAC1 pathway","authors":"Shuhan Wang , Yaqi Yang , Jiahong Lin , Weishan Zhang , Cuizhu Yang , Runheng Zhang , Chang Zhou , Li Zhang , Xin Wang , Jing Liu , Xiaobao Jin , Yuxin Ma","doi":"10.1016/j.freeradbiomed.2025.02.047","DOIUrl":"10.1016/j.freeradbiomed.2025.02.047","url":null,"abstract":"<div><div>Alzheimer's disease (AD) as a common neurodegenerative disease, which characterized by amyloid Aβ deposition and neurofibrillary tangles. Astragalin (AST), a natural flavonoid, has anti-inflammatory, antioxidant, anti-cancer, and other pharmacological effects. Astrocytes can phagocytize and degrade Aβ in their vicinity. In this study, we used the AD mice model established by injecting the mixture of Aβ1-42 and Aβ25-35 into the CA1 region of the hippocampus, and C8D1A cells injured by Aβ1-42 to explore the neuroprotective effects of AST. Our findings showed that AST enhances learning and cognitive ability of AD mice, reduces Aβ deposition and neurofibrillary tangles in the brain, and improves the structural morphology of hippocampal nerve cells. Furthermore, AST promoted autophagy and suppressed apoptosis of astrocytes in the AD model. Additionally, AST inhibited the expression of proteins associated with the Fas/Fasl-VDAC1 signaling pathway, while autophagy inhibitor chloroquine (CQ) or apoptosis agonist phenoxodiol reversed above change. Interestingly, consistent with the action of pathway Fas inhibitor KR-33493, AST could activate autophagy of Aβ1-42 injured C8D1A cells while inhibit their apoptosis. In conclusion, AST activated autophagy and inhibited apoptosis of hippocampal astrocytes in AD mice, ameliorating animal cognitive deficits by down-regulating Fas/Fasl-VDAC1 signaling pathway. Thus, this study provided a new perspective and experimental foundation for developing AD treatment drugs.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 72-85"},"PeriodicalIF":7.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540707","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}
Pub Date : 2025-02-27DOI: 10.1016/j.freeradbiomed.2025.02.042
Xian Zhang , Yuxin Ge , Mengjie Ye , Xiaolu Wang , Yuanyuan Tong , Chihong Liu , Shicheng Xu , Ziquan Zhao , Qidong You , Xiaoke Guo , Zhengyu Jiang
The pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) involves multiple pathophysiological processes, including abnormal lipid metabolism, insulin resistance, oxidative stress, endoplasmic reticulum stress, inflammatory response, and fibrosis. These factors interact to form a complex network and the development of synergistic and pleiotropic drug modalities targeting multiple pathogenesis of MASH may have a better therapeutic effect. Herein, the bifunctional proteolytic targeting chimeras (PROTAC) technology was utilized for developing pleiotropic drugs for MASH treatment. We constructed a Keap1-recruiting degrader KB-3 which stabilizes the natural Keap1 target Nrf2 and degrades BRD4 synergistically, exhibiting combined therapeutic advantages against MASH-related pathologies. Experimental results confirmed that KB-3 could effectively alleviate MASH in mice by improving lipid metabolic disorder, enhancing the defense against oxidative stress, reducing inflammation, and delaying the progression of liver fibrosis. Such Keap1-recruiting degrader offering a single-molecular approach with polypharmacology effects may be an attractive strategy for the treatment of multifactorial disease.
{"title":"A Keap1-recruiting BRD4 degrader offers a single-molecular polypharmacology approach for the treatment of metabolic dysfunction-associated steatohepatitis","authors":"Xian Zhang , Yuxin Ge , Mengjie Ye , Xiaolu Wang , Yuanyuan Tong , Chihong Liu , Shicheng Xu , Ziquan Zhao , Qidong You , Xiaoke Guo , Zhengyu Jiang","doi":"10.1016/j.freeradbiomed.2025.02.042","DOIUrl":"10.1016/j.freeradbiomed.2025.02.042","url":null,"abstract":"<div><div>The pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) involves multiple pathophysiological processes, including abnormal lipid metabolism, insulin resistance, oxidative stress, endoplasmic reticulum stress, inflammatory response, and fibrosis. These factors interact to form a complex network and the development of synergistic and pleiotropic drug modalities targeting multiple pathogenesis of MASH may have a better therapeutic effect. Herein, the bifunctional proteolytic targeting chimeras (PROTAC) technology was utilized for developing pleiotropic drugs for MASH treatment. We constructed a Keap1-recruiting degrader <strong>KB-3</strong> which stabilizes the natural Keap1 target Nrf2 and degrades BRD4 synergistically, exhibiting combined therapeutic advantages against MASH-related pathologies. Experimental results confirmed that <strong>KB-3</strong> could effectively alleviate MASH in mice by improving lipid metabolic disorder, enhancing the defense against oxidative stress, reducing inflammation, and delaying the progression of liver fibrosis. Such Keap1-recruiting degrader offering a single-molecular approach with polypharmacology effects may be an attractive strategy for the treatment of multifactorial disease.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 15-27"},"PeriodicalIF":7.1,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537053","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}
The 'dopamine (DA) deficit' theory is pivotal in understanding the pathogenesis of attention deficit hyperactivity disorder (ADHD). However, the relationship betweeen an imbalance in the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) the DA deficit remains poorly understood. Using the internationally recognized spontaneously hypertensive rats (SHRs) models, we investigated how a high oxidative stress (OS) state in vivo disrupts DAT-VMAT2 transport balance, a key factor influencing DA homeostasis. Our findings revealed abnormal levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), catalase (CAT), total antioxidant capacity (T-AOC), glutathione (GSH), and tumor necrosis factor-α (TNF-α) in SHRs. Furthermore, the antioxidative stress-related nuclear factor erythroid 2-related factor (Nrf2)/kelch-like ECH-associated protein 1 (Keap-1)/heme oxygenase-1 (HO-1) pathway was inhibited, leading to excessive DAT activation and functional antagonism of VMAT2. Notably, Baicalin (BA) ameliorated these imbalances. Treatment with the VMAT2 inhibitor tetrabenazine (TBZ) exacerbated VMAT2 inhibition in SHRs brains, further activating DAT and restricting Nrf2 nuclear translocation. These results confirmed the strong link between the Nrf2/Keap-1/HO-1 pathway the DAT-VMAT2 imbalance. Moreover, under high OS conditions, the phosphorylation of nuclear factor-κB P65 (NF-κB P65) was triggered, leading to the upregulation of heat shock cognate protein 70 (HSC70). We aslo identified a potential negative feedback mechanism between HSC70 and VMAT2. In summary, our study uncovered a novel mechanism in ADHD pathogenesis, demonstrating that the DA deficits resulted from an imbalance between DAT and VMAT2. Remarkably, BA significantly reduced high levels of OS and inflammation by activating the Nrf2/Keap-1/HO-1 pathway, thereby restoring DAT-VMAT2 transport balance and enhancing DA homeostasis. This discovery provides a solid foundation for further exploration of ADHD pathogenesis and offers new molecular insights for ADHD treatment.
{"title":"Baicalin restores dopamine homeostasis in the ADHD model by regulating DAT-VMAT2 transport imbalance through activation of the Nrf2/Keap-1/HO-1 pathway","authors":"Xueying Ding , Bingxiang Ma , Rongyi Zhou , Yongting Zhang , Yuyan Zhang , Xinyue Xie , Mengfei Wang , Chenlei Wu , Jia Jia","doi":"10.1016/j.freeradbiomed.2025.02.032","DOIUrl":"10.1016/j.freeradbiomed.2025.02.032","url":null,"abstract":"<div><div>The 'dopamine (DA) deficit' theory is pivotal in understanding the pathogenesis of attention deficit hyperactivity disorder (ADHD). However, the relationship betweeen an imbalance in the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) the DA deficit remains poorly understood. Using the internationally recognized spontaneously hypertensive rats (SHRs) models, we investigated how a high oxidative stress (OS) state in vivo disrupts DAT-VMAT2 transport balance, a key factor influencing DA homeostasis. Our findings revealed abnormal levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), catalase (CAT), total antioxidant capacity (T-AOC), glutathione (GSH), and tumor necrosis factor-α (TNF-α) in SHRs. Furthermore, the antioxidative stress-related nuclear factor erythroid 2-related factor (Nrf2)/kelch-like ECH-associated protein 1 (Keap-1)/heme oxygenase-1 (HO-1) pathway was inhibited, leading to excessive DAT activation and functional antagonism of VMAT2. Notably, Baicalin (BA) ameliorated these imbalances. Treatment with the VMAT2 inhibitor tetrabenazine (TBZ) exacerbated VMAT2 inhibition in SHRs brains, further activating DAT and restricting Nrf2 nuclear translocation. These results confirmed the strong link between the Nrf2/Keap-1/HO-1 pathway the DAT-VMAT2 imbalance. Moreover, under high OS conditions, the phosphorylation of nuclear factor-κB P65 (NF-κB P65) was triggered, leading to the upregulation of heat shock cognate protein 70 (HSC70). We aslo identified a potential negative feedback mechanism between HSC70 and VMAT2. In summary, our study uncovered a novel mechanism in ADHD pathogenesis, demonstrating that the DA deficits resulted from an imbalance between DAT and VMAT2. Remarkably, BA significantly reduced high levels of OS and inflammation by activating the Nrf2/Keap-1/HO-1 pathway, thereby restoring DAT-VMAT2 transport balance and enhancing DA homeostasis. This discovery provides a solid foundation for further exploration of ADHD pathogenesis and offers new molecular insights for ADHD treatment.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 107-127"},"PeriodicalIF":7.1,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537055","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}
Pub Date : 2025-02-27DOI: 10.1016/j.freeradbiomed.2025.02.035
Margrethe A. Olesen , Francisca Villavicencio-Tejo , Gail V.W. Johnson , George A. Porter , Rodrigo A. Quintanilla
Abnormal tau modifications are one of the main contributors to neurodegenerative processes present during Alzheimer's disease (AD). In this context, truncated tau by caspase-3, a pathological tau form, affects mitochondrial function and antioxidant regulation, contributing to synaptic and cognitive impairment in AD mouse models. We previously showed that the presence of caspase-3 cleaved tau promotes mitochondrial impairment in neuronal cells, where Cyclophilin-D (CypD) protein could be a crucial element. CypD is considered the master regulator of mitochondrial permeability transition pore (mPTP) opening, and its ablation prevents neurodegenerative and cognitive damage induced by β−amyloid in mouse models of AD. However, the possible role of CypD in the neurodegenerative processes mediated by caspase-3-cleaved tau has not been explored. Here, we use tau (−/−) and CypD (−/−) knock-out mice that were subjected to right-side hippocampal stereotaxic injection to induce GFP (AAV-Syn-GFP), full-length (AAV-Syn-GFP-T4) or caspase-3-cleaved (AAV-Syn-GFP-T4C3) tau expression. Then, cognitive performance, synaptic architecture, and hippocampal mitochondrial function were evaluated two months later. We observed that caspase-3 cleaved tau expression inducing cognitive decline, vesicle and synaptic protein deregulation, and mitochondrial impairment generated by the mPTP opening. More interestingly, when caspase-3 cleaved tau was expressed in the hippocampus of CypD (−/−) mice, cognitive decline, synaptic impairment, and mitochondrial damage mediated by mPTP were prevented, demonstrating a novel role of CypD in neurodegenerative changes induced by truncated tau in AD.
{"title":"Cyclophilin D (CypD) ablation prevents neurodegeneration and cognitive damage induced by caspase-3 cleaved tau","authors":"Margrethe A. Olesen , Francisca Villavicencio-Tejo , Gail V.W. Johnson , George A. Porter , Rodrigo A. Quintanilla","doi":"10.1016/j.freeradbiomed.2025.02.035","DOIUrl":"10.1016/j.freeradbiomed.2025.02.035","url":null,"abstract":"<div><div>Abnormal tau modifications are one of the main contributors to neurodegenerative processes present during Alzheimer's disease (AD). In this context, truncated tau by caspase-3, a pathological tau form, affects mitochondrial function and antioxidant regulation, contributing to synaptic and cognitive impairment in AD mouse models. We previously showed that the presence of caspase-3 cleaved tau promotes mitochondrial impairment in neuronal cells, where Cyclophilin-D (CypD) protein could be a crucial element. CypD is considered the master regulator of mitochondrial permeability transition pore (mPTP) opening, and its ablation prevents neurodegenerative and cognitive damage induced by β−amyloid in mouse models of AD. However, the possible role of CypD in the neurodegenerative processes mediated by caspase-3-cleaved tau has not been explored. Here, we use tau (−/−) and CypD (−/−) knock-out mice that were subjected to right-side hippocampal stereotaxic injection to induce GFP (AAV-Syn-GFP), full-length (AAV-Syn-GFP-T4) or caspase-3-cleaved (AAV-Syn-GFP-T4C3) tau expression. Then, cognitive performance, synaptic architecture, and hippocampal mitochondrial function were evaluated two months later. We observed that caspase-3 cleaved tau expression inducing cognitive decline, vesicle and synaptic protein deregulation, and mitochondrial impairment generated by the mPTP opening. More interestingly, when caspase-3 cleaved tau was expressed in the hippocampus of CypD (−/−) mice, cognitive decline, synaptic impairment, and mitochondrial damage mediated by mPTP were prevented, demonstrating a novel role of CypD in neurodegenerative changes induced by truncated tau in AD.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 128-141"},"PeriodicalIF":7.1,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537056","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}
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