Pub Date : 2024-10-30DOI: 10.1016/j.redox.2024.103413
Xiao Shan , Zemin Ji , Baochen Wang , Yanan Zhang , Hongyuan Dong , Weijia Jing , Yanzhao Zhou , Penghui Hu , Yan Cui , Zihan Li , Sujun Yu , Jinxue Zhou , Ting Wang , Long Shen , Yuping Liu , Qiujing Yu
Riboflavin kinase (RFK) is essential in riboflavin metabolism, converting riboflavin to flavin mononucleotide (FMN), which is further processed to flavin adenine dinucleotide (FAD). While RFK enhances macrophage phagocytosis of Listeria monocytogenes, its role in macrophage polarization is not well understood. Our study reveals that RFK deficiency impairs M(IFN-γ) and promotes M(IL-4) polarization, both in vitro and in vivo. Mechanistically, RFK interacts with inducible nitric oxide (NO) synthase (iNOS), which requires FMN and FAD as cofactors for activation, leading to increased NO production that alters energy metabolism by inhibiting the tricarboxylic acid cycle and mitochondrial electron transport chain. Exogenous FAD reverses the metabolic and polarization changes caused by RFK deficiency. Furthermore, bone marrow adoptive transfer from high-riboflavin-fed mice into wild-type tumor-bearing mice reprograms tumor-associated macrophage polarization and inhibits tumor growth. These results suggest that targeting RFK-iNOS or modulating riboflavin metabolism could be potential therapies for macrophage-related immune diseases.
{"title":"Riboflavin kinase binds and activates inducible nitric oxide synthase to reprogram macrophage polarization","authors":"Xiao Shan , Zemin Ji , Baochen Wang , Yanan Zhang , Hongyuan Dong , Weijia Jing , Yanzhao Zhou , Penghui Hu , Yan Cui , Zihan Li , Sujun Yu , Jinxue Zhou , Ting Wang , Long Shen , Yuping Liu , Qiujing Yu","doi":"10.1016/j.redox.2024.103413","DOIUrl":"10.1016/j.redox.2024.103413","url":null,"abstract":"<div><div>Riboflavin kinase (RFK) is essential in riboflavin metabolism, converting riboflavin to flavin mononucleotide (FMN), which is further processed to flavin adenine dinucleotide (FAD). While RFK enhances macrophage phagocytosis of <em>Listeria monocytogenes</em>, its role in macrophage polarization is not well understood. Our study reveals that RFK deficiency impairs M(IFN-γ) and promotes M(IL-4) polarization, both <em>in vitro</em> and <em>in vivo</em>. Mechanistically, RFK interacts with inducible nitric oxide (NO) synthase (iNOS), which requires FMN and FAD as cofactors for activation, leading to increased NO production that alters energy metabolism by inhibiting the tricarboxylic acid cycle and mitochondrial electron transport chain. Exogenous FAD reverses the metabolic and polarization changes caused by RFK deficiency. Furthermore, bone marrow adoptive transfer from high-riboflavin-fed mice into wild-type tumor-bearing mice reprograms tumor-associated macrophage polarization and inhibits tumor growth. These results suggest that targeting RFK-iNOS or modulating riboflavin metabolism could be potential therapies for macrophage-related immune diseases.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"78 ","pages":"Article 103413"},"PeriodicalIF":10.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142627157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 : 2024-10-28DOI: 10.1016/j.redox.2024.103412
Tong-sheng Huang , Teng Wu , Xin-lu Fu , Hong-lin Ren , Xiao-dan He , Ding-hao Zheng , Jing Tan , Cong-hui Shen , Shi-jie Xiong , Jiang Qian , Yan Zou , Jun-hong Wan , Yuan-jun Ji , Meng-ying Liu , Yan-di Wu , Xing-hui Li , Hui Li , Kai Zheng , Xiao-feng Yang , Hong Wang , Wei-bin Cai
Statins therapy is efficacious in diminishing the risk of major cardiovascular events in diabetic patients. However, our research has uncovered a correlation between the prolonged administration of statins and an elevated risk of myocardial dysfunction in patients with type II diabetes mellitus (TIIDM). Here, we report the induction of sterol regulatory element-binding protein 1 (SREBP1) activation, associated lipid peroxidation, and the consequent diabetic myocardial dysfunction after statin treatment and explored the underlying mechanisms. In db/db mice, we observed that 40 weeks atorvastatin (5 and 10 mg/kg) and rosuvastatin (20 mg/kg) administration exacerbated diabetic myocardial dysfunction by echocardiography and cardiomyocyte contractility assay, increased myocardial inflammation and fibrosis as shown by CD68, IL-1β, Masson's staining and Collagen1A1 immunohistochemistry (IHC) staining, increased respiratory exchange ratio (RER) by metabolic cage system assessment, exacerbated mitochondrial structural pathological changes by transmission electron microscopy (TEM) examination, increased deposition of lipid and glycogen by TEM, Oil-red and periodic acid-schiff stain (PAS) staining, which were corresponded with augmented levels of myocardial SREBP1 protein and lipid peroxidation marked by 4-hydroxynonenal (4-HNE) staining. Comparable myocardial fibrosis was also observed in KK-ay and low-dose streptozotocin (STZ)-induced TIIDM mice. Elevated SREBP1 levels were observed in the heart tissues from diabetic patients, which was positively correlated with their myocardial dysfunction. To elucidate the role of statin induced SREBP1 in lipid peroxidation and lipid deposition and related mechanism, we cultured neonatal mouse primary cardiomyocytes (NMPCs) and treated them with atorvastatin (10 μM, 24 h), tracing with [U–13C]-glucose and evaluating for SREBP1 expression and localization. We found that statin treatment elevated de novo lipogenesis (DNL) and the levels of SREBP1 cleavage-activating protein (SCAP), reduced the interaction of SCAP with insulin-induced gene 1 (Insig1), and enhance SCAP/SREBP1 translocation to the Golgi, which facilitate SREBP1 cleavage leading to its nuclear trans-localization and activation in NMPCs. Ultimately, SREBP1 knockdown or l-carnitine mitigated long-term statins therapy induced lipid peroxidation and myocardial fibrosis in low-dose STZ treated SREBP1+/− mice and l-carnitine treated db/db mice. In conclusion, we demonstrated that statin therapy may augment DNL by activating SREBP1, resulting in myocardial lipid peroxidation and lipid deposition.
{"title":"SREBP1 induction mediates long-term statins therapy related myocardial lipid peroxidation and lipid deposition in TIIDM mice","authors":"Tong-sheng Huang , Teng Wu , Xin-lu Fu , Hong-lin Ren , Xiao-dan He , Ding-hao Zheng , Jing Tan , Cong-hui Shen , Shi-jie Xiong , Jiang Qian , Yan Zou , Jun-hong Wan , Yuan-jun Ji , Meng-ying Liu , Yan-di Wu , Xing-hui Li , Hui Li , Kai Zheng , Xiao-feng Yang , Hong Wang , Wei-bin Cai","doi":"10.1016/j.redox.2024.103412","DOIUrl":"10.1016/j.redox.2024.103412","url":null,"abstract":"<div><div>Statins therapy is efficacious in diminishing the risk of major cardiovascular events in diabetic patients. However, our research has uncovered a correlation between the prolonged administration of statins and an elevated risk of myocardial dysfunction in patients with type II diabetes mellitus (TIIDM). Here, we report the induction of sterol regulatory element-binding protein 1 (SREBP1) activation, associated lipid peroxidation, and the consequent diabetic myocardial dysfunction after statin treatment and explored the underlying mechanisms. In <em>db/db</em> mice, we observed that 40 weeks atorvastatin (5 and 10 mg/kg) and rosuvastatin (20 mg/kg) administration exacerbated diabetic myocardial dysfunction by echocardiography and cardiomyocyte contractility assay, increased myocardial inflammation and fibrosis as shown by CD68, IL-1β, Masson's staining and Collagen1A1 immunohistochemistry (IHC) staining, increased respiratory exchange ratio (RER) by metabolic cage system assessment, exacerbated mitochondrial structural pathological changes by transmission electron microscopy (TEM) examination, increased deposition of lipid and glycogen by TEM, Oil-red and periodic acid-schiff stain (PAS) staining, which were corresponded with augmented levels of myocardial SREBP1 protein and lipid peroxidation marked by 4-hydroxynonenal (4-HNE) staining. Comparable myocardial fibrosis was also observed in KK-ay and low-dose streptozotocin (STZ)-induced TIIDM mice. Elevated SREBP1 levels were observed in the heart tissues from diabetic patients, which was positively correlated with their myocardial dysfunction. To elucidate the role of statin induced SREBP1 in lipid peroxidation and lipid deposition and related mechanism, we cultured neonatal mouse primary cardiomyocytes (NMPCs) and treated them with atorvastatin (10 μM, 24 h), tracing with [U–<sup>13</sup>C]-glucose and evaluating for SREBP1 expression and localization. We found that statin treatment elevated de novo lipogenesis (DNL) and the levels of SREBP1 cleavage-activating protein (SCAP), reduced the interaction of SCAP with insulin-induced gene 1 (Insig1), and enhance SCAP/SREBP1 translocation to the Golgi, which facilitate SREBP1 cleavage leading to its nuclear <em>trans</em>-localization and activation in NMPCs. Ultimately, SREBP1 knockdown or <span>l</span>-carnitine mitigated long-term statins therapy induced lipid peroxidation and myocardial fibrosis in low-dose STZ treated <em>SREBP1</em><sup><em>+/−</em></sup> mice and <span>l</span>-carnitine treated <em>db/db</em> mice. In conclusion, we demonstrated that statin therapy may augment DNL by activating SREBP1, resulting in myocardial lipid peroxidation and lipid deposition.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"78 ","pages":"Article 103412"},"PeriodicalIF":10.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Uterine leiomyoma (UL), commonly referred to as benign tumors, is characterized by excessive cell proliferation, extracellular matrix (ECM) accumulation, and the presence of stem cell-like properties. Nicotinamide adenine dinucleotide (NAD+) metabolism, regulated in part by nicotinamide phosphoribosyltransferase (NAMPT), plays a crucial role in these pathological processes and has emerged as a potential therapeutic target. Additionally, redox signaling pathways are integral to the pathogenesis of UL, influencing the dynamics of NAD+ metabolism. This study sought to elucidate the regulatory functions of NAMPT and NAD+ metabolism, in conjunction with redox signaling, in the progression of UL, and to explore potential therapeutic strategies targeting these pathways. Evaluation of NAMPT expression in human UL tissues revealed a positive correlation between elevated NAMPT levels and increased ECM deposition, as well as the expression of stemness markers. The use of FK866 and nicotinamide (NAM), to inhibit NAMPT significantly suppressed UL cell viability and attenuated stem cell-like characteristics. Redox signaling pathways, including those associated with DNA damage, lysosomal function homeostasis, and redox-sensitive phagophore formation, were implicated in the regulation of ECM dynamics, particularly through ECM-targeted inhibition. This study highlights the pivotal roles of NAMPT, NAD+ metabolism, and redox signaling in the pathophysiology of UL. Targeting NAMPT, particularly through the use of inhibitors FK866 and NAM, represents a promising therapeutic approach for mitigating UL progression by modulating redox and ECM dynamics. These findings offer novel insights into UL pathogenesis and establish NAMPT as a compelling target for future clinical investigation.
子宫肌瘤（UL）通常被称为良性肿瘤，其特点是细胞过度增殖、细胞外基质（ECM）堆积以及具有干细胞样特性。烟酰胺腺嘌呤二核苷酸（NAD+）代谢部分由烟酰胺磷酸核糖转移酶（NAMPT）调节，在这些病理过程中起着至关重要的作用，并已成为潜在的治疗靶点。此外，氧化还原信号通路与 UL 的发病机制密不可分，影响着 NAD+ 代谢的动态变化。本研究旨在阐明 NAMPT 和 NAD+ 代谢以及氧化还原信号在 UL 进展过程中的调控功能，并探索针对这些途径的潜在治疗策略。对人类 UL 组织中 NAMPT 表达的评估显示，NAMPT 水平的升高与 ECM 沉积的增加以及干性标志物的表达呈正相关。使用FK866和烟酰胺（NAM）抑制NAMPT可显著抑制UL细胞的活力，并减弱干细胞样特征。氧化还原信号通路，包括与DNA损伤、溶酶体功能平衡和氧化还原敏感性吞噬体形成相关的通路，都与ECM动态调控有关，特别是通过ECM靶向抑制。这项研究强调了 NAMPT、NAD+ 代谢和氧化还原信号在 UL 病理生理学中的关键作用。以 NAMPT 为靶点，特别是通过使用抑制剂 FK866 和 NAM，是通过调节氧化还原和 ECM 动态来缓解 UL 进展的一种很有前景的治疗方法。这些发现为了解 UL 的发病机制提供了新的视角，并使 NAMPT 成为未来临床研究的一个引人注目的靶点。
{"title":"Regulatory roles of NAMPT and NAD+ metabolism in uterine leiomyoma progression: Implications for ECM accumulation, stemness, and microenvironment","authors":"Yi-Fen Chiang , Ko-Chieh Huang , Tsui-Chin Huang , Hsin-Yuan Chen , Mohamed Ali , Ayman Al-Hendy , Pei-Shen Huang , Shih-Min Hsia","doi":"10.1016/j.redox.2024.103411","DOIUrl":"10.1016/j.redox.2024.103411","url":null,"abstract":"<div><div>Uterine leiomyoma (UL), commonly referred to as benign tumors, is characterized by excessive cell proliferation, extracellular matrix (ECM) accumulation, and the presence of stem cell-like properties. Nicotinamide adenine dinucleotide (NAD<sup>+</sup>) metabolism, regulated in part by nicotinamide phosphoribosyltransferase (NAMPT), plays a crucial role in these pathological processes and has emerged as a potential therapeutic target. Additionally, redox signaling pathways are integral to the pathogenesis of UL, influencing the dynamics of NAD<sup>+</sup> metabolism. This study sought to elucidate the regulatory functions of NAMPT and NAD<sup>+</sup> metabolism, in conjunction with redox signaling, in the progression of UL, and to explore potential therapeutic strategies targeting these pathways. Evaluation of NAMPT expression in human UL tissues revealed a positive correlation between elevated NAMPT levels and increased ECM deposition, as well as the expression of stemness markers. The use of FK866 and nicotinamide (NAM), to inhibit NAMPT significantly suppressed UL cell viability and attenuated stem cell-like characteristics. Redox signaling pathways, including those associated with DNA damage, lysosomal function homeostasis, and redox-sensitive phagophore formation, were implicated in the regulation of ECM dynamics, particularly through ECM-targeted inhibition. This study highlights the pivotal roles of NAMPT, NAD<sup>+</sup> metabolism, and redox signaling in the pathophysiology of UL. Targeting NAMPT, particularly through the use of inhibitors FK866 and NAM, represents a promising therapeutic approach for mitigating UL progression by modulating redox and ECM dynamics. These findings offer novel insights into UL pathogenesis and establish NAMPT as a compelling target for future clinical investigation.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"78 ","pages":"Article 103411"},"PeriodicalIF":10.7,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142561074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 : 2024-10-24DOI: 10.1016/j.redox.2024.103410
Lukas Lang, Philipp Reinert, Cedric Diaz, Marcel Deponte
Class I glutaredoxins reversibly reduce glutathione- and nonglutathione disulfides with the help of reduced glutathione (GSH) using either a monothiol mechanism or a dithiol mechanism. The monothiol mechanism exclusively involves a single glutathionylated active-site cysteinyl residue, whereas the dithiol mechanism requires the additional formation of an intramolecular disulfide bond between the active-site cysteinyl residue and a resolving cysteinyl residue. While the oxidation of glutaredoxins by glutathione disulfide substrates has been extensively characterized, the enzyme-substrate interactions for the reduction of S-glutathionylated glutaredoxins or intramolecular glutaredoxin disulfides are still poorly characterized. Here we compared the thiol-specificity for the reduction of S-glutathionylated glutaredoxins and the intramolecular glutaredoxin disulfide. We show that S-glutathionylated glutaredoxins rapidly react with a plethora of thiols and that the 2nd glutathione-interaction site of class I glutaredoxins lacks specificity for GSH as a reducing agent. In contrast, the slower reduction of the partially strained intramolecular glutaredoxin disulfide involves specific interactions with both carboxylate groups of GSH at the 1st glutathione-interaction site. Thus, the dithiol mechanism of class I glutaredoxins promotes specificity for GSH as a reducing agent, which might explain the prevalence of dithiol glutaredoxins in pro- and eukaryotes.
I 类谷胱甘肽在还原型谷胱甘肽（GSH）的帮助下，通过单硫醇机制或二硫醇机制可逆地还原谷胱甘肽和非谷胱甘肽二硫化物。单硫醇机制只涉及单个谷胱甘肽化的活性位点半胱氨酰残基，而二硫醇机制则需要在活性位点半胱氨酰残基和解析半胱氨酰残基之间额外形成分子内二硫键。虽然谷胱甘肽二硫化物底物对谷胱甘肽的氧化作用已经有了广泛的表征，但 S-谷胱甘肽化谷胱甘肽或分子内谷胱甘肽二硫化物还原过程中酶与底物之间的相互作用仍鲜为人知。在这里，我们比较了还原 S-谷胱甘肽化谷胱甘肽和分子内谷胱甘肽二硫化物的硫醇特异性。我们发现，S-谷胱甘肽化的谷拉糖苷酶能迅速与大量硫醇发生反应，而 I 类谷拉糖苷酶的第二个谷胱甘肽相互作用位点缺乏对 GSH 作为还原剂的特异性。与此相反，部分分子内紧张的谷胱甘肽二硫化物的缓慢还原涉及与第 1 个谷胱甘肽相互作用位点上的 GSH 的两个羧基的特异性相互作用。因此，I类谷胱甘肽的二硫醇机制促进了GSH作为还原剂的特异性，这或许可以解释原核生物和真核生物中普遍存在二硫醇谷胱甘肽的原因。
{"title":"The dithiol mechanism of class I glutaredoxins promotes specificity for glutathione as a reducing agent","authors":"Lukas Lang, Philipp Reinert, Cedric Diaz, Marcel Deponte","doi":"10.1016/j.redox.2024.103410","DOIUrl":"10.1016/j.redox.2024.103410","url":null,"abstract":"<div><div>Class I glutaredoxins reversibly reduce glutathione- and nonglutathione disulfides with the help of reduced glutathione (GSH) using either a monothiol mechanism or a dithiol mechanism. The monothiol mechanism exclusively involves a single glutathionylated active-site cysteinyl residue, whereas the dithiol mechanism requires the additional formation of an intramolecular disulfide bond between the active-site cysteinyl residue and a resolving cysteinyl residue. While the oxidation of glutaredoxins by glutathione disulfide substrates has been extensively characterized, the enzyme-substrate interactions for the reduction of <em>S</em>-glutathionylated glutaredoxins or intramolecular glutaredoxin disulfides are still poorly characterized. Here we compared the thiol-specificity for the reduction of <em>S</em>-glutathionylated glutaredoxins and the intramolecular glutaredoxin disulfide. We show that <em>S</em>-glutathionylated glutaredoxins rapidly react with a plethora of thiols and that the 2nd glutathione-interaction site of class I glutaredoxins lacks specificity for GSH as a reducing agent. In contrast, the slower reduction of the partially strained intramolecular glutaredoxin disulfide involves specific interactions with both carboxylate groups of GSH at the 1st glutathione-interaction site. Thus, the dithiol mechanism of class I glutaredoxins promotes specificity for GSH as a reducing agent, which might explain the prevalence of dithiol glutaredoxins in pro- and eukaryotes.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"78 ","pages":"Article 103410"},"PeriodicalIF":10.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 : 2024-10-22DOI: 10.1016/j.redox.2024.103407
Jiapeng Zhang , Hang Xu , Yirui He , Xiaonan Zheng , Tianhai Lin , Lu Yang , Ping Tan , Qiang Wei
In clinical practice, the limited efficacy of standard comprehensive therapy for advanced bladder cancer and the lack of targeted treatment options are well recognized. Targeting abnormal epigenetic modifications in tumors has shown considerable potential in cancer therapy. Through drug screening in tumor organoids, we identified that ML324, a histone lysine demethylase 4A (KDM4A) inhibitor, exhibits potent antitumor effects in both in vitro and in vivo cancer models. Mechanistically, Kdm4a demethylates H3K9me3, leading to chromatin opening and increased accessibility of Gabpa to the squalene epoxidase (Sqle) gene promoter, resulting in transcriptional activation. Inhibition of Kdm4a downregulates Sqle transcription, blocking cholesterol synthesis and causing squalene (SQA) accumulation. This process induces reactive oxygen species (ROS) clearance and suppresses JNK/c-Jun phosphorylation, ultimately inducing apoptosis. Furthermore, ML324 treatment significantly inhibited tumor growth in bladder cancer patient-derived xenograft (PDX) models. Our findings reveal the presence of a Kdm4a-Sqle-ROS-JNK/c-Jun signaling axis that regulates oxidative stress balance, offering a novel strategy for targeted therapy in bladder cancer.
{"title":"Inhibition of KDM4A restricts SQLE transcription and induces oxidative stress imbalance to suppress bladder cancer","authors":"Jiapeng Zhang , Hang Xu , Yirui He , Xiaonan Zheng , Tianhai Lin , Lu Yang , Ping Tan , Qiang Wei","doi":"10.1016/j.redox.2024.103407","DOIUrl":"10.1016/j.redox.2024.103407","url":null,"abstract":"<div><div>In clinical practice, the limited efficacy of standard comprehensive therapy for advanced bladder cancer and the lack of targeted treatment options are well recognized. Targeting abnormal epigenetic modifications in tumors has shown considerable potential in cancer therapy. Through drug screening in tumor organoids, we identified that ML324, a histone lysine demethylase 4A (KDM4A) inhibitor, exhibits potent antitumor effects in both in vitro and in vivo cancer models. Mechanistically, Kdm4a demethylates H3K9me3, leading to chromatin opening and increased accessibility of Gabpa to the squalene epoxidase (Sqle) gene promoter, resulting in transcriptional activation. Inhibition of Kdm4a downregulates Sqle transcription, blocking cholesterol synthesis and causing squalene (SQA) accumulation. This process induces reactive oxygen species (ROS) clearance and suppresses JNK/c-Jun phosphorylation, ultimately inducing apoptosis. Furthermore, ML324 treatment significantly inhibited tumor growth in bladder cancer patient-derived xenograft (PDX) models. Our findings reveal the presence of a Kdm4a-Sqle-ROS-JNK/c-Jun signaling axis that regulates oxidative stress balance, offering a novel strategy for targeted therapy in bladder cancer.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"77 ","pages":"Article 103407"},"PeriodicalIF":10.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 : 2024-10-22DOI: 10.1016/j.redox.2024.103406
Xiaobing Lan , Qing Wang , Yue Liu , Qing You , Wei Wei , Chunhao Zhu , Dongmei Hai , Zhenyu Cai , Jianqiang Yu , Jian Zhang , Ning Liu
Cerebral ischemia-reperfusion injury (CIRI) refers to a secondary brain injury that occurs when blood supply is restored to ischemic brain tissue and is one of the leading causes of adult disability and mortality. Multiple pathological mechanisms are involved in the progression of CIRI, including neuronal oxidative stress and mitochondrial dysfunction. Isoliquiritigenin (ISL) has been preliminarily reported to have potential neuroprotective effects on rats subjected to cerebral ischemic insult. However, the protective mechanisms of ISL have not been elucidated. This study aims to further investigate the effects of ISL-mediated neuroprotection and elucidate the underlying molecular mechanism. The findings indicate that ISL treatment significantly alleviated middle cerebral artery occlusion (MCAO)-induced cerebral infarction, neurological deficits, histopathological damage, and neuronal apoptosis in mice. In vitro, ISL effectively mitigated the reduction of cell viability, Na+-K+-ATPase, and MnSOD activities, as well as the degree of DNA damage induced by oxygen-glucose deprivation (OGD) injury in PC12 cells. Mechanistic studies revealed that administration of ISL evidently improved redox homeostasis and restored mitochondrial function via inhibiting oxidative stress injury and ameliorating mitochondrial biogenesis, mitochondrial fusion-fission balance, and mitophagy. Moreover, ISL facilitated the dissociation of Keap1/Nrf2, enhanced the nuclear transfer of Nrf2, and promoted the binding activity of Nrf2 with ARE. Finally, ISL obviously inhibited neuronal apoptosis by activating the Nrf2 pathway and ameliorating mitochondrial dysfunction in mice. Nevertheless, Nrf2 inhibitor brusatol reversed the mitochondrial protective properties and anti-apoptotic effects of ISL both in vivo and in vitro. Overall, our findings revealed that ISL exhibited a profound neuroprotective effect on mice following CIRI insult by reducing oxidative stress and ameliorating mitochondrial dysfunction, which was closely related to the activation of the Nrf2 pathway.
{"title":"Isoliquiritigenin alleviates cerebral ischemia-reperfusion injury by reducing oxidative stress and ameliorating mitochondrial dysfunction via activating the Nrf2 pathway","authors":"Xiaobing Lan , Qing Wang , Yue Liu , Qing You , Wei Wei , Chunhao Zhu , Dongmei Hai , Zhenyu Cai , Jianqiang Yu , Jian Zhang , Ning Liu","doi":"10.1016/j.redox.2024.103406","DOIUrl":"10.1016/j.redox.2024.103406","url":null,"abstract":"<div><div>Cerebral ischemia-reperfusion injury (CIRI) refers to a secondary brain injury that occurs when blood supply is restored to ischemic brain tissue and is one of the leading causes of adult disability and mortality. Multiple pathological mechanisms are involved in the progression of CIRI, including neuronal oxidative stress and mitochondrial dysfunction. Isoliquiritigenin (ISL) has been preliminarily reported to have potential neuroprotective effects on rats subjected to cerebral ischemic insult. However, the protective mechanisms of ISL have not been elucidated. This study aims to further investigate the effects of ISL-mediated neuroprotection and elucidate the underlying molecular mechanism. The findings indicate that ISL treatment significantly alleviated middle cerebral artery occlusion (MCAO)-induced cerebral infarction, neurological deficits, histopathological damage, and neuronal apoptosis in mice. <em>In vitro</em>, ISL effectively mitigated the reduction of cell viability, Na<sup>+</sup>-K<sup>+</sup>-ATPase, and MnSOD activities, as well as the degree of DNA damage induced by oxygen-glucose deprivation (OGD) injury in PC12 cells. Mechanistic studies revealed that administration of ISL evidently improved redox homeostasis and restored mitochondrial function via inhibiting oxidative stress injury and ameliorating mitochondrial biogenesis, mitochondrial fusion-fission balance, and mitophagy. Moreover, ISL facilitated the dissociation of Keap1/Nrf2, enhanced the nuclear transfer of Nrf2, and promoted the binding activity of Nrf2 with ARE. Finally, ISL obviously inhibited neuronal apoptosis by activating the Nrf2 pathway and ameliorating mitochondrial dysfunction in mice. Nevertheless, Nrf2 inhibitor brusatol reversed the mitochondrial protective properties and anti-apoptotic effects of ISL both <em>in vivo</em> and <em>in vitro</em>. Overall, our findings revealed that ISL exhibited a profound neuroprotective effect on mice following CIRI insult by reducing oxidative stress and ameliorating mitochondrial dysfunction, which was closely related to the activation of the Nrf2 pathway.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"77 ","pages":"Article 103406"},"PeriodicalIF":10.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 : 2024-10-22DOI: 10.1016/j.redox.2024.103405
Karina Orlowska , Rance Nault , Jesmin Ara , John J. LaPres , Jack Harkema , Elena Y. Demireva , Huirong Xie , Rachel H. Wilson , Christopher A. Bradfield , Dianne Yap , Aditya Joshi , Cornelis J. Elferink , Tim Zacharewski
Metabolic reprogramming by the pyruvate kinase M2 isoform is associated with cell proliferation and reactive oxygen species (ROS) defenses. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant that induces ROS and hepatotoxicity, dose-dependently induces pyruvate kinase muscle isoform M2 (PKM2) in the liver. To further investigate its role in combating TCDD hepatotoxicity, a PkmΔDRE mouse was constructed lacking the dioxin response element mediating aryl hydrocarbon receptor (AHR) induction. TCDD failed to induce hepatic PKM2 in PkmΔDRE mice and in primary hepatocytes isolated from an AHR knockout model (AHRV375Afl/flAlb-CreERT2), demonstrating induction is AHR dependent. Both wild-type (WT) and PkmΔDRE mice exhibited dose-dependent increases in liver weight after treatment with TCDD every 4 days for 28 days. Glutathione (GSH) levels increased in WT mice while oxidized glutathione (GSSG) levels increased in both models with a 24-fold decrease in the GSH/GSSG ratio in PkmΔDRE mice suggesting lower antioxidant and recycling capacity. Moreover, TCDD-induced fibrosis was more severe in PkmΔDRE mice while PkmΔDRE hepatocytes exhibited greater cytotoxicity following co-treatment with TCDD and hydrogen peroxide. TCDD also induced PKM2 in human HepaRG™ cells with AHR enrichment at a conserved DRE core within the locus. These results suggest AHR-mediated PKM2 induction is a novel antioxidant response to TCDD.
{"title":"Disruption of canonical AHR-mediated induction of hepatocyte PKM2 expression compromises antioxidant defenses and increases TCDD-induced hepatotoxicity","authors":"Karina Orlowska , Rance Nault , Jesmin Ara , John J. LaPres , Jack Harkema , Elena Y. Demireva , Huirong Xie , Rachel H. Wilson , Christopher A. Bradfield , Dianne Yap , Aditya Joshi , Cornelis J. Elferink , Tim Zacharewski","doi":"10.1016/j.redox.2024.103405","DOIUrl":"10.1016/j.redox.2024.103405","url":null,"abstract":"<div><div>Metabolic reprogramming by the pyruvate kinase M2 isoform is associated with cell proliferation and reactive oxygen species (ROS) defenses. 2,3,7,8-Tetrachlorodibenzo-<em>p</em>-dioxin (TCDD), an environmental contaminant that induces ROS and hepatotoxicity, dose-dependently induces pyruvate kinase muscle isoform M2 (PKM2) in the liver. To further investigate its role in combating TCDD hepatotoxicity, a Pkm<sup>ΔDRE</sup> mouse was constructed lacking the dioxin response element mediating aryl hydrocarbon receptor (AHR) induction. TCDD failed to induce hepatic PKM2 in Pkm<sup>ΔDRE</sup> mice and in primary hepatocytes isolated from an AHR knockout model (AHR<sup>V375Afl/fl</sup>Alb-Cre<sup>ERT2</sup>), demonstrating induction is AHR dependent. Both wild-type (WT) and Pkm<sup>ΔDRE</sup> mice exhibited dose-dependent increases in liver weight after treatment with TCDD every 4 days for 28 days. Glutathione (GSH) levels increased in WT mice while oxidized glutathione (GSSG) levels increased in both models with a 24-fold decrease in the GSH/GSSG ratio in Pkm<sup>ΔDRE</sup> mice suggesting lower antioxidant and recycling capacity. Moreover, TCDD-induced fibrosis was more severe in Pkm<sup>ΔDRE</sup> mice while Pkm<sup>ΔDRE</sup> hepatocytes exhibited greater cytotoxicity following co-treatment with TCDD and hydrogen peroxide. TCDD also induced PKM2 in human HepaRG™ cells with AHR enrichment at a conserved DRE core within the locus. These results suggest AHR-mediated PKM2 induction is a novel antioxidant response to TCDD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"77 ","pages":"Article 103405"},"PeriodicalIF":10.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142529925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 : 2024-10-22DOI: 10.1016/j.redox.2024.103408
Sem Geertsema , Paul Geertsema , Lyanne M. Kieneker , Amaal E. Abdulle , Sacha la Bastide-van Gemert , Stephan J.L. Bakker , Robin P.F. Dullaart , Gerard Dijkstra , Ron T. Gansevoort , Klaas Nico Faber , Harry van Goor , Arno R. Bourgonje
Background
Chronic Kidney Disease (CKD), is often detected late due to its asymptomatic nature in the early stage of the disease. Overproduction of reactive oxygen species contributes to various pathological processes through oxidative stress (OS), impacting on cellular structures and functions with previous studies suggesting a link between OS and CKD progression. This study investigated the association between serum peroxiredoxin-4 (Prx4), a biomarker of oxidative stress, and the development of CKD in the general population.
Methods
This study featured data from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort, involving 5341 participants without CKD at baseline who underwent extensive prospective health evaluations. Serum Prx4 levels were quantified using an immunoluminometric assay. The primary outcome was new-onset CKD as defined by the composite of urinary albumin excretion (UAE) > 30 mg/24-h, an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, or both.
Results
Baseline median Prx4 level was 0.65 [interquartile range (IQR): 0.42–1.04] U/L, median eGFR was 98 [IQR: 87–108] mL/min/1.73 m2, and median UAE was 8.1 [IQR: 6.0–12.1] mg/L. During a median follow-up of 10.4 [IQR: 6.3–11.4] years, 867 (16.2 %) patients developed new-onset CKD. Higher Prx4 levels were significantly associated with an increased risk of CKD (hazard ratio (HR) per doubling: 1.29 [95 % confidence interval (CI): 1.21–1.37], p < 0.001), also after adjustment for risk factors including sex, smoking status, systolic blood pressure, high-sensitive C-reactive protein, chronic heart failure, diabetes mellitus and dyslipidemia (HR per doubling: 1.16 [1.06–1.24], p < 0.001). Sensitivity analyses confirmed the robustness of these findings.
Conclusions
This study supports the hypothesis that systemic oxidative stress, reflected by higher serum Prx4 levels, is significantly associated with the risk of developing CKD in the general population. These findings suggest that Prx4 could be a valuable biomarker for early risk stratification and prevention strategies in CKD management.
{"title":"Serum peroxiredoxin-4, a biomarker of oxidative stress, associates with new-onset chronic kidney disease: A population-based cohort study","authors":"Sem Geertsema , Paul Geertsema , Lyanne M. Kieneker , Amaal E. Abdulle , Sacha la Bastide-van Gemert , Stephan J.L. Bakker , Robin P.F. Dullaart , Gerard Dijkstra , Ron T. Gansevoort , Klaas Nico Faber , Harry van Goor , Arno R. Bourgonje","doi":"10.1016/j.redox.2024.103408","DOIUrl":"10.1016/j.redox.2024.103408","url":null,"abstract":"<div><h3>Background</h3><div>Chronic Kidney Disease (CKD), is often detected late due to its asymptomatic nature in the early stage of the disease. Overproduction of reactive oxygen species contributes to various pathological processes through oxidative stress (OS), impacting on cellular structures and functions with previous studies suggesting a link between OS and CKD progression. This study investigated the association between serum peroxiredoxin-4 (Prx4), a biomarker of oxidative stress, and the development of CKD in the general population.</div></div><div><h3>Methods</h3><div>This study featured data from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort, involving 5341 participants without CKD at baseline who underwent extensive prospective health evaluations. Serum Prx4 levels were quantified using an immunoluminometric assay. The primary outcome was new-onset CKD as defined by the composite of urinary albumin excretion (UAE) > 30 mg/24-h, an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m<sup>2</sup>, or both.</div></div><div><h3>Results</h3><div>Baseline median Prx4 level was 0.65 [interquartile range (IQR): 0.42–1.04] U/L, median eGFR was 98 [IQR: 87–108] mL/min/1.73 m<sup>2</sup>, and median UAE was 8.1 [IQR: 6.0–12.1] mg/L. During a median follow-up of 10.4 [IQR: 6.3–11.4] years, 867 (16.2 %) patients developed new-onset CKD. Higher Prx4 levels were significantly associated with an increased risk of CKD (hazard ratio (HR) per doubling: 1.29 [95 % confidence interval (CI): 1.21–1.37], p < 0.001), also after adjustment for risk factors including sex, smoking status, systolic blood pressure, high-sensitive C-reactive protein, chronic heart failure, diabetes mellitus and dyslipidemia (HR per doubling: 1.16 [1.06–1.24], p < 0.001). Sensitivity analyses confirmed the robustness of these findings.</div></div><div><h3>Conclusions</h3><div>This study supports the hypothesis that systemic oxidative stress, reflected by higher serum Prx4 levels, is significantly associated with the risk of developing CKD in the general population. These findings suggest that Prx4 could be a valuable biomarker for early risk stratification and prevention strategies in CKD management.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"77 ","pages":"Article 103408"},"PeriodicalIF":10.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142529979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 : 2024-10-19DOI: 10.1016/j.redox.2024.103404
Christophe Glorieux , Pedro Buc Calderon
Healthy cells have developed a sophisticated network of antioxidant molecules to prevent the toxic accumulation of reactive oxygen species (ROS) generated by diverse environmental stresses. On the opposite, cancer cells often exhibit high levels of ROS and an altered levels of antioxidant molecules compared to normal cells. Among them, the antioxidant enzyme catalase plays an essential role in cell defense against oxidative stress through the dismutation of hydrogen peroxide into water and molecular oxygen, and its expression is often decreased in cancer cells. The elevation of ROS in cancer cells provides them proliferative advantages, and leads to metabolic reprogramming, immune escape and metastasis. In this context, catalase is of critical importance to control these cellular processes in cancer through various mechanisms. In this review, we will discuss the major progresses and challenges in understanding the role of catalase in cancer for this last decade. This review also aims to provide important updates regarding the regulation of catalase expression, subcellular localization and discuss about the potential role of microbial catalases in tumor environment. Finally, we will describe the different catalase-based therapies and address the advantages, disadvantages, and limitations associated with modulating catalase therapeutically in cancer treatment.
{"title":"Targeting catalase in cancer","authors":"Christophe Glorieux , Pedro Buc Calderon","doi":"10.1016/j.redox.2024.103404","DOIUrl":"10.1016/j.redox.2024.103404","url":null,"abstract":"<div><div>Healthy cells have developed a sophisticated network of antioxidant molecules to prevent the toxic accumulation of reactive oxygen species (ROS) generated by diverse environmental stresses. On the opposite, cancer cells often exhibit high levels of ROS and an altered levels of antioxidant molecules compared to normal cells. Among them, the antioxidant enzyme catalase plays an essential role in cell defense against oxidative stress through the dismutation of hydrogen peroxide into water and molecular oxygen, and its expression is often decreased in cancer cells. The elevation of ROS in cancer cells provides them proliferative advantages, and leads to metabolic reprogramming, immune escape and metastasis. In this context, catalase is of critical importance to control these cellular processes in cancer through various mechanisms. In this review, we will discuss the major progresses and challenges in understanding the role of catalase in cancer for this last decade. This review also aims to provide important updates regarding the regulation of catalase expression, subcellular localization and discuss about the potential role of microbial catalases in tumor environment. Finally, we will describe the different catalase-based therapies and address the advantages, disadvantages, and limitations associated with modulating catalase therapeutically in cancer treatment.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"77 ","pages":"Article 103404"},"PeriodicalIF":10.7,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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