Redox Biology最新文献

{"title":"Cellular and molecular mechanisms of hepatic ischemia-reperfusion injury: The role of oxidative stress and therapeutic approaches","authors":"Joseph George ,&nbsp;Yongke Lu ,&nbsp;Mutsumi Tsuchishima ,&nbsp;Mikihiro Tsutsumi","doi":"10.1016/j.redox.2024.103258","DOIUrl":"https://doi.org/10.1016/j.redox.2024.103258","url":null,"abstract":"<div><p>Ischemia-reperfusion (IR) or reoxygenation injury is the paradoxical exacerbation of cellular impairment following restoration of blood flow after a period of ischemia during surgical procedures or other conditions. Acute interruption of blood supply to the liver and subsequent reperfusion can result in hepatocyte injury, apoptosis, and necrosis. Since the liver requires a continuous supply of oxygen for many biochemical reactions, any obstruction of blood flow can rapidly lead to hepatic hypoxia, which could quickly progress to absolute anoxia. Reoxygenation results in the increased generation of reactive oxygen species and oxidative stress, which lead to the enhanced production of proinflammatory cytokines, chemokines, and other signaling molecules. Consequent acute inflammatory cascades lead to significant impairment of hepatocytes and nonparenchymal cells. Furthermore, the expression of several vascular growth factors results in the heterogeneous closure of numerous hepatic sinusoids, which leads to reduced oxygen supply in certain areas of the liver even after reperfusion. Therefore, it is vital to identify appropriate therapeutic modalities to mitigate hepatic IR injury and subsequent tissue damage. This review covers all the major aspects of cellular and molecular mechanisms underlying the pathogenesis of hepatic ischemia-reperfusion injury, with special emphasis on oxidative stress, associated inflammation and complications, and prospective therapeutic approaches.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724002362/pdfft?md5=87ce9bfd4d71b14194f5ec9cb23b1118&pid=1-s2.0-S2213231724002362-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141540671","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}

{"title":"NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's disease","authors":"Filippo Pullara ,&nbsp;Madison C. Forsmann ,&nbsp;Ignacio J. General ,&nbsp;Joseph C. Ayoob ,&nbsp;Emily Furbee ,&nbsp;Sandra L. Castro ,&nbsp;Xiaoping Hu ,&nbsp;J. Timothy Greenamyre ,&nbsp;Roberto Di Maio","doi":"10.1016/j.redox.2024.103254","DOIUrl":"10.1016/j.redox.2024.103254","url":null,"abstract":"<div><p>Ca²⁺/calmodulin-dependent protein kinase II α (CaMKIIα) signaling in the brain plays a critical role in regulating neuronal Ca²⁺ homeostasis. Its dysfunctional activity is associated with various neurological and neurodegenerative disorders, including Parkinson's disease (PD). Using computational modeling analysis, we predicted that, two essential cysteine residues contained in CaMKIIα, Cys30 and Cys289, may undergo redox modifications impacting the proper functioning of the CaMKIIα docking site for Ca²⁺/CaM, thus impeding the formation of the CaMKIIα:Ca²⁺/CaM complex, essential for a proper modulation of CaMKIIα kinase activity. Our subsequent <em>in vitro</em> investigations confirmed the computational predictions, specifically implicating Cys30 and Cys289 residues in impairing CaMKIIα:Ca²⁺/CaM interaction. We observed CaMKIIα:Ca²⁺/CaM complex disruption in dopamine (DA) nigrostriatal neurons of post-mortem Parkinson's disease (PD) patients' specimens, addressing the high relevance of this event in the disease. CaMKIIα:Ca²⁺/CaM complex disruption was also observed in both <em>in vitro</em> and <em>in vivo</em> rotenone models of PD, where this phenomenon was associated with CaMKIIα kinase hyperactivity. Moreover, we observed that, NADPH oxidase 2 (NOX2), a major enzymatic generator of superoxide anion (O₂^●-) and hydrogen peroxide (H₂O₂) in the brain with implications in PD pathogenesis, is responsible for CaMKIIα:Ca²⁺/CaM complex disruption associated to a stable Ca²⁺CAM-independent CaMKIIα kinase activity and intracellular Ca²⁺ accumulation. The present study highlights the importance of oxidative stress, in disturbing the delicate balance of CaMKIIα signaling in calcium dysregulation, offering novel insights into PD pathogenesis.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724002325/pdfft?md5=d3df8eed1e481a00998461cbd7d397bd&pid=1-s2.0-S2213231724002325-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141538574","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}

{"title":"Iron(III)-salophene catalyzes redox cycles that induce phospholipid peroxidation and deplete cancer cells of ferroptosis-protecting cofactors","authors":"Fengting Su ,&nbsp;Hubert Descher ,&nbsp;Minh Bui-Hoang ,&nbsp;Hermann Stuppner ,&nbsp;Ira Skvortsova ,&nbsp;Ehsan Bonyadi Rad ,&nbsp;Claudia Ascher ,&nbsp;Alexander Weiss ,&nbsp;Zhigang Rao ,&nbsp;Stephan Hohloch ,&nbsp;Solveigh C. Koeberle ,&nbsp;Ronald Gust ,&nbsp;Andreas Koeberle","doi":"10.1016/j.redox.2024.103257","DOIUrl":"https://doi.org/10.1016/j.redox.2024.103257","url":null,"abstract":"<div><p>Ferroptosis, a lipid peroxidation-driven cell death program kept in check by glutathione peroxidase 4 and endogenous redox cycles, promises access to novel strategies for treating therapy-resistant cancers. Chlorido [N,N′-disalicylidene-1,2-phenylenediamine]iron (III) complexes (SCs) have potent anti-cancer properties by inducing ferroptosis, apoptosis, or necroptosis through still poorly understood molecular mechanisms. Here, we show that SCs preferentially induce ferroptosis over other cell death programs in triple-negative breast cancer cells (LC₅₀ ≥ 0.07 μM) and are particularly effective against cell lines with acquired invasiveness, chemo- or radioresistance. Redox lipidomics reveals that initiation of cell death is associated with extensive (hydroper)oxidation of arachidonic acid and adrenic acid in membrane phospholipids, specifically phosphatidylethanolamines and phosphatidylinositols, with SCs outperforming established ferroptosis inducers. Mechanistically, SCs effectively catalyze one-electron transfer reactions, likely via a redox cycle involving the reduction of Fe(III) to Fe(II) species and reversible formation of oxo-bridged dimeric complexes, as supported by cyclic voltammetry. As a result, SCs can use hydrogen peroxide to generate organic radicals but not hydroxyl radicals and oxidize membrane phospholipids and (membrane-)protective factors such as NADPH, which is depleted from cells. We conclude that SCs catalyze specific redox reactions that drive membrane peroxidation while interfering with the ability of cells, including therapy-resistant cancer cells, to detoxify phospholipid hydroperoxides.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724002350/pdfft?md5=ccbcb5564d687de84daffeff71d26a6f&pid=1-s2.0-S2213231724002350-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141478985","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}

{"title":"Inhibition of ferroptosis rescues M2 macrophages and alleviates arthritis by suppressing the HMGB1/TLR4/STAT3 axis in M1 macrophages","authors":"","doi":"10.1016/j.redox.2024.103255","DOIUrl":"10.1016/j.redox.2024.103255","url":null,"abstract":"<div><p>Ferroptosis is a type of programmed cell death driven by iron-dependent lipid peroxidation. The TNF-mediated biosynthesis of glutathione has been shown to protect synovial fibroblasts from ferroptosis in the hyperplastic synovium. Ferroptosis induction provides a novel therapeutic approach for rheumatoid arthritis (RA) by reducing the population of synovial fibroblasts. The beginning and maintenance of synovitis in RA are significantly influenced by macrophages, as they generate cytokines that promote inflammation and contribute to the destruction of cartilage and bone. However, the vulnerability of macrophages to ferroptosis in RA remains unclear. In this study, we found that M2 macrophages are more vulnerable to ferroptosis than M1 macrophages in the environment of the arthritis synovium with a high level of iron, leading to an imbalance in the M1/M2 ratio. During ferroptosis, HMGB1 released by M2 macrophages interacts with TLR4 on M1 macrophages, which in turn triggers the activation of STAT3 signaling in M1 macrophages and contributes to the inflammatory response. Knockdown of TLR4 decreased the level of cytokines induced by HMGB1 in M1 macrophages. The ferroptosis inhibitor liproxstatin-1 (Lip-1) started at the presymptomatic stage in collagen-induced arthritis (CIA) model mice, and GPX4 overexpression in M2 macrophages at the onset of collagen antibody-induced arthritis (CAIA) protected M2 macrophages from ferroptotic cell death and significantly prevented the development of joint inflammation and destruction. Thus, our study demonstrated that M2 macrophages are vulnerable to ferroptosis in the microenvironment of the hyperplastic synovium and revealed that the HMGB1/TLR4/STAT3 axis is critical for the ability of ferroptotic M2 macrophages to contribute to the exacerbation of synovial inflammation in RA. Our findings provide novel insight into the progression and treatment of RA.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724002337/pdfft?md5=d07962a4b17db02dd4707e5b97fd3a71&pid=1-s2.0-S2213231724002337-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141638902","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}

{"title":"Redox-modulated SNX25 as a novel regulator of GPCR-G protein signaling from endosomes","authors":"Yulong Zhang ,&nbsp;Zhijun Yu ,&nbsp;Mingwei Sun ,&nbsp;Ruyue Du ,&nbsp;Hanhan Gao ,&nbsp;Qiankun Dai ,&nbsp;Yan Dong ,&nbsp;Cuicui Liu ,&nbsp;Menghui Yin ,&nbsp;Tingting Xu ,&nbsp;Xiaofei Zhang ,&nbsp;Jinsong Liu ,&nbsp;Jinxin Xu","doi":"10.1016/j.redox.2024.103253","DOIUrl":"10.1016/j.redox.2024.103253","url":null,"abstract":"<div><p>GPCR-G protein signaling from endosomes plays a crucial role in various physiological and pathological processes. However, the mechanism by which endosomal G protein signaling is terminated remains largely unknown. In this study, we aimed to investigate the regulatory mechanisms involved in terminating the signaling of Gα subunits from endosomes. Through structural analysis and cell-based assays, we have discovered that SNX25, a protein that targets endosomes via its PXA or PXC domain, interacts with regulator of G protein signaling (RGS) proteins (including RGS2, RGS4, RGS8, and RGS17) in a redox-regulated manner. The interaction between SNX25 and these RGS proteins enhances their GTPase-accelerating activity towards Gα_i/q and their ability to bind GDP-bound (inactive form) Gα_i/q. As a result, SNX25 recruits these RGS proteins to endosomes, leading to the termination of endosomal Gα_i/q signaling. Furthermore, we have found that the SNX25/RGS complex also exerts a negative regulatory effect on Gα_i/q signaling from the plasma membrane. This is achieved by recruiting Gα_i/q to endosomes and preventing its activation on the plasma membrane. Our findings shed light on the previously unknown role of redox-modulated SNX25 in inhibiting Gα_i/q signaling, thereby uncovering a novel mechanism for terminating Gα_i/q signaling from endosomes. Importantly, this study expands our understanding of the regulation of GPCR-Gα_i/q signaling beyond the plasma membrane.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724002313/pdfft?md5=4ad151a26af45de87cf1adca69499b30&pid=1-s2.0-S2213231724002313-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141463278","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}

{"title":"An active peptide from yak inhibits hypoxia-induced lung injury via suppressing VEGF/MAPK/inflammatory signaling","authors":"Feiyan Yang ,&nbsp;Zeyu He ,&nbsp;Zhongxing Chu ,&nbsp;Wen Li ,&nbsp;Guangfan Qu ,&nbsp;Han Lu ,&nbsp;Yiping Tang ,&nbsp;Shuguo Sun ,&nbsp;Zhang Luo ,&nbsp;Feijun Luo","doi":"10.1016/j.redox.2024.103252","DOIUrl":"10.1016/j.redox.2024.103252","url":null,"abstract":"<div><p>Pulmonary vascular remodeling and inflammation play an important role in the hypoxic-induced lung diseases. Our previous investigations showed that peptide from yak milk residues could alleviate inflammation. In this study, our results suggest that peptide (LV) from yak milk residues peptide had protective effect of lung in the animal models of hypoxic-induced lung injury. LV Gavage could improve pulmonary vascular remodeling in the lung tissues of hypoxic mice. A comprehensive analysis of metabolomics and transcriptomics revealed that 5-KETE, 8,9-EET, and 6-keto-prostaglandin F1a might be potential targets to prevent lung injury in the hypoxic mice. These metabolites can be regulated by MAPK/VEGF and inflammatory pathways. Our data indicated that LV treatment could inhibit apoptosis and inflammation via Nrf2/NF-κB/MAPK/PHD-2 pathway and protected hypoxic-induced lung epithelial cells injury. Taken together, our results suggest that LV provides a novel therapeutic clue for the prevention of hypoxia-induced lung injury and inflammation-related lung diseases.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724002301/pdfft?md5=81da4d43ad2a02c90e34a9c38abec367&pid=1-s2.0-S2213231724002301-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458912","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}

{"title":"Lactate drives epithelial-mesenchymal transition in diabetic kidney disease via the H3K14la/KLF5 pathway","authors":"Xuanxuan Zhang ,&nbsp;Jicong Chen ,&nbsp;Ruohui Lin ,&nbsp;Yaping Huang ,&nbsp;Ziyuan Wang ,&nbsp;Susu Xu ,&nbsp;Lei Wang ,&nbsp;Fang Chen ,&nbsp;Jian Zhang ,&nbsp;Ke Pan ,&nbsp;Zhiqi Yin","doi":"10.1016/j.redox.2024.103246","DOIUrl":"10.1016/j.redox.2024.103246","url":null,"abstract":"<div><p>High levels of urinary lactate are an increased risk of progression in patients with diabetic kidney disease (DKD). However, it is still unveiled how lactate drive DKD. Epithelial-mesenchymal transition (EMT), which is characterized by the loss of epithelial cells polarity and cell-cell adhesion, and the acquisition of mesenchymal-like phenotypes, is widely recognized a critical contributor to DKD. Here, we found a switch from oxidative phosphorylation (OXPHOS) toward glycolysis in AGEs-induced renal tubular epithelial cells, thus leading to elevated levels of renal lactic acid. We demonstrated that reducing the lactate levels markedly delayed EMT progression and improved renal tubular fibrosis in DKD. Mechanically, we observed lactate increased the levels of histone H3 lysine 14 lactylation (H3K14la) in DKD. ChIP-seq &amp; RNA-seq results showed histone lactylation contributed to EMT process by facilitating KLF5 expression. Moreover, KLF5 recognized the promotor of cdh1 and inhibited its transcription, which accelerated EMT of DKD. Additionally, nephro-specific knockdown and pharmacological inhibition of KLF5 diminished EMT development and attenuated DKD fibrosis. Thus, our study provides better understanding of epigenetic regulation of DKD pathogenesis, and new therapeutic strategy for DKD by disruption of the lactate-drived H3K14la/KLF5 pathway.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724002246/pdfft?md5=2328d84588f52c9562c16deba5fec867&pid=1-s2.0-S2213231724002246-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458913","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}

{"title":"NADPH Alters DUOX1 Calcium Responsiveness","authors":"Gregory E. Conner","doi":"10.1016/j.redox.2024.103251","DOIUrl":"10.1016/j.redox.2024.103251","url":null,"abstract":"<div><p>Hydrogen peroxide is a key element in redox signaling and in setting cellular redox tone. DUOX1 and DUOX2, that directly synthesize hydrogen peroxide, are the most abundant NADPH oxidase transcripts in most epithelia. DUOX1 and DUOX2 hydrogen peroxide synthesis is regulated by intracellular calcium transients and thus cells can respond to signals and initiate responses by increasing cellular hydrogen peroxide synthesis. Nevertheless, many details of their enzymatic regulation are still unexplored. DUOX1 and DUOXA1 were expressed in HEK293T cells and activity was studied in homogenates and membrane fractions. When DUOX1 homogenates or membranes were pre-incubated in NADPH and started with addition of Ca²⁺, to mimic intracellular activation, progress curves were distinctly different from those pre-incubated in Ca²⁺ and started with NADPH. The Ca²⁺ EC₅₀ for DUOX1's initial rate when pre-incubated in Ca²⁺, was three orders of magnitude lower (EC₅₀ ∼ 10⁻⁶ M) than with preincubation in NADPH (EC₅₀ ∼ 10⁻³ M). In addition, activity was several fold lower with Ca²⁺ start. Identical results were obtained using homogenates and membrane fractions. The data suggested that DUOX1 Ca²⁺ binding in expected physiological signaling conditions only slowly leads to maximal hydrogen peroxide synthesis and that full hydrogen peroxide synthesis activity <em>in vivo</em> only can occur when encountering extremely high concentration Ca²⁺ signals. Thus, a complex interplay of intracellular NADPH and Ca²⁺ concentrations regulate DUOX1 over a wide extent and may limit DUOX1 activity to a restricted range and spatial distribution.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724002295/pdfft?md5=5422e46303159707a7adb8e6d99dd1d8&pid=1-s2.0-S2213231724002295-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141463304","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}

{"title":"Heme oxygenase-1 protects cells from replication stress","authors":"","doi":"10.1016/j.redox.2024.103247","DOIUrl":"10.1016/j.redox.2024.103247","url":null,"abstract":"<div><p>Heme oxygenase-1 (HO-1, <em>HMOX1</em>) degrades heme protecting cells from heme-induced oxidative damage. Beyond its well-established cellular functions, heme has emerged as a stabilizer of G-quadruplexes. These secondary DNA structures interfere with DNA replication. We recently revealed that nuclear HO-1 colocalizes with DNA G-quadruplexes and promotes their removal. Here, we investigate whether HO-1 safeguards cells against replication stress.</p><p>Experiments were conducted in control and <em>HMOX1</em>-deficient HEK293T cell lines. Immunostaining unveiled that DNA G-quadruplexes accumulated in the absence of HO-1, the effect that was further enhanced in response to δ-aminolevulinic acid (ALA), a substrate in heme synthesis. This was associated with replication stress, as evidenced by an elevated proportion of stalled forks analyzed by fiber assay. We observed the same effects in hematopoietic stem cells isolated from <em>Hmox1</em> knockout mice and in a lymphoblastoid cell line from an <em>HMOX1</em>-deficient patient. Interestingly, in the absence of HO-1, the speed of fork progression was higher, and the response to DNA conformational hindrance less stringent, indicating dysfunction of the PARP1-p53-p21 axis. PARP1 activity was not decreased in the absence of HO-1. Instead, we observed that HO-1 deficiency impairs the nuclear import and accumulation of p53, an effect dependent on the removal of excess heme. We also demonstrated that administering ALA is a more specific method for increasing intracellular free heme compared to treatment with hemin, which in turn induces strong lipid peroxidation.</p><p>Our results indicate that protection against replication stress is a universal feature of HO-1, presumably contributing to its widely recognized cytoprotective activity.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724002258/pdfft?md5=e97d2439cb56b2200b767b2346a7b762&pid=1-s2.0-S2213231724002258-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760639","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}

{"title":"A detrimental role of endothelial S1PR2 in cardiac ischemia-reperfusion injury via modulating mitochondrial dysfunction, NLRP3 inflammasome activation, and pyroptosis","authors":"Yunhao Duan ,&nbsp;Qinyu Li ,&nbsp;Jinjin Wu ,&nbsp;Caixia Zhou ,&nbsp;Xiuxiang Liu ,&nbsp;Jinnan Yue ,&nbsp;Xiaoli Chen ,&nbsp;Jie Liu ,&nbsp;Qi Zhang ,&nbsp;Yuzhen Zhang ,&nbsp;Lin Zhang","doi":"10.1016/j.redox.2024.103244","DOIUrl":"10.1016/j.redox.2024.103244","url":null,"abstract":"<div><p>Sphingosine 1-phosphate (S1P), a bioactive lipid molecule, exerts multifaceted effects on cardiovascular functions via S1P receptors, but its effects on cardiac I/R injury are not fully understood. Plasma lipidomics analysis by mass spectrometry revealed that sphingosine lipids, including sphingosine 1-phosphate (S1P), were significantly down-regulated following cardiac I/R injury in mice. The reduced S1P levels were also observed in the plasma of coronary heart disease (CHD) patients after percutaneous coronary intervention (PCI) compared with those without PCI. We found that S1P exerted a cardioprotective effect via endothelial cell (EC)-S1PR1, whereas EC-S1PR2 displayed a detrimental effect on cardiac I/R. Our data showed that EC-specific <em>S1pr2</em> loss-of-function significantly lessened inflammatory responses and diminished cardiac I/R injury, while EC-specific <em>S1pr2</em> gain-of-function aggravated cardiac I/R injury. Mechanistically, EC-S1PR2 initiated excessive mitochondrial fission and elevated ROS production via RHO/ROCK1/DRP1 pathway, leading to NLRP3 inflammasome activation and subsequent cell pyroptosis, thereby exacerbating inflammation and I/R injuries. Furthermore, RGD-peptide magnetic nanoparticles packaging <em>S1pr2-siRNA</em> to specifically knockdown S1PR2 in endothelial cells significantly ameliorated cardiac I/R injury. Taken together, our investigations demonstrate that EC-S1PR2 induces excessive mitochondrial fission, which results in NLRP3 inflammasome activation and subsequently triggers cell pyroptosis, ultimately exacerbating inflammatory responses and aggravating heart injuries following I/R.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724002222/pdfft?md5=7de6e0b57ddc62e140ded96d29a6fcf4&pid=1-s2.0-S2213231724002222-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141443255","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}