Redox Biology最新文献

{"title":"PPARγ drives mitochondrial stress signaling and the loss of atrial cardiomyocytes in newborn mice exposed to hyperoxia","authors":"","doi":"10.1016/j.redox.2024.103351","DOIUrl":"10.1016/j.redox.2024.103351","url":null,"abstract":"<div><p>Diastolic dysfunction is increasingly common in preterm infants exposed to supplemental oxygen (hyperoxia). Previous studies in neonatal mice showed hyperoxia suppresses fatty acid synthesis genes required for proliferation and survival of atrial cardiomyocytes. The loss of atrial cardiomyocytes creates a hypoplastic left atrium that inappropriately fills the left ventricle during diastole. Here, we show that hyperoxia stimulates adenosine monophosphate-activated kinase (AMPK) and peroxisome proliferator activated receptor-gamma (PPARγ) signaling in atrial cardiomyocytes. While both pathways can regulate lipid homeostasis, PPARγ was the primary pathway by which hyperoxia inhibits fatty acid gene expression and inhibits proliferation of mouse atrial HL-1 cells. It also enhanced the toxicity of hyperoxia by increasing expression of activating transcription factor (ATF) 5 and other mitochondrial stress response genes. Silencing PPARγ signaling restored proliferation and survival of HL-1 cells as well as atrial cardiomyocytes in neonatal mice exposed to hyperoxia. Our findings reveal PPARγ enhances the toxicity of hyperoxia on atrial cardiomyocytes, thus suggesting inhibitors of PPARγ signaling may prevent diastolic dysfunction in preterm infants.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221323172400329X/pdfft?md5=25cda8a9cf5613da51752caefef98c1e&pid=1-s2.0-S221323172400329X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142230382","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":"Targeting GPX4-mediated ferroptosis protection sensitizes BRCA1-deficient cancer cells to PARP inhibitors","authors":"","doi":"10.1016/j.redox.2024.103350","DOIUrl":"10.1016/j.redox.2024.103350","url":null,"abstract":"<div><p><em>BRCA1</em> is one of the most frequently-mutated tumor suppressor genes in ovarian and breast cancers. Loss of BRCA1 triggers homologous recombination (HR) repair deficiency, consequently leading to genomic instability and PARP inhibitors (PARPi)-associated synthetic lethality. Although, the roles of BRCA1 in DNA repair and replication have been extensively investigated, its tumor suppressive functions beyond genome safeguard remain poorly understood. Here, we report that BRCA1 promotes ferroptosis susceptibility through catalyzing K6-linked polyubiquitination of GPX4 and subsequently accelerating GPX4 degradation. Depletion of BRCA1 induces ferroptosis resistance in ovarian cancer cells due to elevated GPX4 protein, and silence of GPX4 significantly suppresses the growth of BRCA1-deficient ovarian cancer xenografts. Importantly, we found that PARPi triggers ferroptosis in ovarian cancer cells, inhibition of GPX4 markedly increase PARPi-induced ferroptosis in BRCA1-deficient ovarian cancer cells. Combined treatment of GPX4 inhibitor and PARPi produces synergistic anti-tumor efficacy in BRCA1-deficient ovarian cancer cells, patient derived organoid (PDO) and xenografts. Thus, our study uncovers a novel mechanism via which BRCA1 exerts tumor suppressive function through regulating ferroptosis, and demonstrates the potential of GPX4 as a therapeutic target for BRCA1-mutant cancers.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724003288/pdfft?md5=fcaeb7e4336f550019c4bd1dc27c0c13&pid=1-s2.0-S2213231724003288-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142173228","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":"UBR5 mediates colorectal cancer chemoresistance by attenuating ferroptosis via Lys 11 ubiquitin-dependent stabilization of Smad3-SLC7A11 signaling","authors":"","doi":"10.1016/j.redox.2024.103349","DOIUrl":"10.1016/j.redox.2024.103349","url":null,"abstract":"<div><p>Chemoresistance remains a principal culprit for the treatment failure in colorectal cancer (CRC), especially for patients with recurrent or metastatic disease. Deciphering the molecular basis of chemoresistance may lead to novel therapeutic strategies for this fatal disease. Here, UBR5, an E3 ubiquitin ligase frequently overexpressed in human CRC, is demonstrated to mediate chemoresistance principally by inhibiting ferroptosis. Paradoxically, UBR5 shields oxaliplatin-activated Smad3 from proteasome-dependent degradation via Lys 11-linked polyubiquitination. This novel chemical modification of Smad3 facilitates the transcriptional repression of <em>ATF3</em>, induction of <em>SLC7A11</em> and inhibition of ferroptosis, contributing to chemoresistance. Consequently, targeting UBR5 in combination with a ferroptosis inducer synergistically sensitizes CRC to oxaliplatin-induced cell death and control of tumor growth. This study reveals, for the first time, a major clinically relevant chemoresistance mechanism in CRC mediated by UBR5 in sustaining TGFβ-Smad3 signaling and tuning ferroptosis, unveiling its potential as a viable therapeutic target for chemosensitization.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724003276/pdfft?md5=390d859f82866064ac875f87d72c3d72&pid=1-s2.0-S2213231724003276-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142163123","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":"High expression levels of haem oxygenase-1 promote ferroptosis in macrophage-derived foam cells and exacerbate plaque instability","authors":"","doi":"10.1016/j.redox.2024.103345","DOIUrl":"10.1016/j.redox.2024.103345","url":null,"abstract":"<div><p>Plaque rupture with consequent thrombosis is the leading cause of acute cardiovascular events, during which macrophage death is a hallmark. Ferroptosis is a pivotal intermediate link between early and advanced atherosclerosis. Existing evidence indicates the involvement of macrophage ferroptosis in plaque vulnerability; however, the exact mechanism remains elusive. The aim of this study was to explore key ferroptosis-related genes (FRGs) involved in plaque progression and the underlying molecular mechanisms involved. The expression landscape of FRGs was obtained from atherosclerosis-related GEO datasets. Molecular mechanism studies of ferroptosis were performed using bone marrow-derived macrophages (BMDMs) and macrophage-derived foam cells (MDFCs). Bioinformatics analysis and immunohistochemistry revealed that macrophage haem oxygenase-1 (HMOX1) is the key FRG involved in plaque destabilization. Hypoxic conditions induced a significant increase in Hmox1 expression in MDFCs but not in macrophages. In addition, the beneficial or deleterious effects of Hmox1 were dependent on the degree of Hmox1 induction. Hmox1 overexpression drove inflammatory responses and ferroptotic oxidative stress in MDFCs and aggravated the plaque burden in atherosclerotic model mice. Further mechanistic investigations demonstrated that hypoxia-mediated degradation of egl-9 family hypoxia-inducible factor 3 (Egln3) stabilized Hif1a, which subsequently promoted Hmox1 transcription. Our findings suggest that high Hmox1 expression under hypoxia is deleterious to MDFC viability and plaque stability, providing a reference for the management of acute cardiovascular events.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724003239/pdfft?md5=bbb826dd93dd97e2351a02f152e3c007&pid=1-s2.0-S2213231724003239-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142163113","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":"LOX-mediated ECM mechanical stress induces Piezo1 activation in hypoxic-ischemic brain damage and identification of novel inhibitor of LOX","authors":"","doi":"10.1016/j.redox.2024.103346","DOIUrl":"10.1016/j.redox.2024.103346","url":null,"abstract":"<div><p>Hypoxic-ischemic encephalopathy (HIE) poses a significant challenge in neonatal medicine, often resulting in profound and lasting neurological deficits. Current therapeutic strategies for hypoxia-ischemia brain damage (HIBD) remain limited. Ferroptosis has been reported to play a crucial role in HIE and serves as a potential therapeutic target. However, the mechanisms underlying ferroptosis in HIBD remain largely unclear. In this study, we found that elevated lysyl oxidase (LOX) expression correlates closely with the severity of HIE, suggesting LOX as a potential biomarker for HIE. LOX expression levels and enzymatic activity were significantly increased in HI-induced neuronal models both <em>in vitro</em> and <em>in vivo</em>. Notably, we discovered that HI-induced brain tissue injury results in increased stiffness and observed a selective upregulation of the mechanosensitive ion channel Piezo1 in both brain tissue of HIBD and primary cortex neurons. Mechanistically, LOX increases its catalytic substrates, the Collagen I/III components, promoting extracellular matrix (ECM) remodeling and possibly mediating ECM cross-linking, which leads to increased stiffness at the site of injury and subsequent activation of the Piezo1 channel. Piezo1 senses these stiffness stimuli and then induces neuronal ferroptosis in a GPX4-dependent manner. Pharmacological inhibition of LOX or Piezo1 ameliorated brain neuronal ferroptosis and improved learning and memory impairments. Furthermore, we identified traumatic acid (TA) as a novel LOX inhibitor that effectively suppresses LOX enzymatic activity, mitigating neuronal ferroptosis and promoting synaptic plasticity. In conclusion, our findings elucidate a critical role for LOX-mediated ECM mechanical stress-induced Piezo1 activation in regulating ferroptotic cell death in HIBD. This mechanistic insight provides a basis for developing targeted therapies aimed at ameliorating neurological outcomes in neonates affected by HIBD.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724003240/pdfft?md5=7d54623011afbb65fb14250346f8818c&pid=1-s2.0-S2213231724003240-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142163114","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":"CARM1 phosphorylation at S595 by p38γ MAPK drives ROS-mediated cellular senescence","authors":"","doi":"10.1016/j.redox.2024.103344","DOIUrl":"10.1016/j.redox.2024.103344","url":null,"abstract":"<div><p>CARM1 is predominantly localized in the nucleus and plays a pivotal role in maintaining mitochondrial homeostasis by regulating gene expression. It suppresses mitochondrial biogenesis by downregulating <em>PGC-1α</em> and <em>TFAM</em> expression, while promoting mitochondrial fission through increased <em>DNM1L</em> expression. Under oxidative stress, CARM1 translocates to the cytoplasm, where it directly methylates DRP1 and accelerates mitochondrial fission, enhancing reactive oxygen species (ROS) production. Cytoplasmic localization of CARM1 is facilitated by its phosphorylation at S595 by ROS-activated p38γ MAPK, creating a positive feedback loop. Consequently, cytoplasmic CARM1 contributes to cellular senescence by altering mitochondrial dynamics and increasing ROS levels. This observation was supported by the increased cytoplasmic CARM1 levels and disrupted mitochondrial dynamics in the transformed 10T1/2 cells. Moreover, CARM1 inhibitors not only inhibit the proliferation of cancer cells but also induce apoptotic death in senescent cells. These findings highlight the potential of CARM1 inhibitors, particularly those targeting cytoplasmic functions, as novel strategies for eliminating cancer and senescent cells.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724003227/pdfft?md5=914e1463917126e03a5c48b76b5c9258&pid=1-s2.0-S2213231724003227-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142173229","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":"Comprehensive modulatory effects of whole grain consumption on immune-mediated inflammation in middle-aged and elderly community residents: A real-world randomized controlled trial","authors":"","doi":"10.1016/j.redox.2024.103337","DOIUrl":"10.1016/j.redox.2024.103337","url":null,"abstract":"<div><h3>Background and aims</h3><p>Whole grain consumption is widely recognized as a vital component of a balanced diet. Dietary fiber has been well-documented to play a crucial role in these health benefits attributed to whole grain intake. However, population-based evidence directly linking whole grain consumption to anti-inflammatory effects, especially in the context of immune-mediated inflammation, remains limited. We hypothesized that whole grain consumption promotes health by modulating immune-mediated inflammation.</p></div><div><h3>Methods and results</h3><p>This study was designed as a real-world, population-based randomized controlled trial. We compared the effects of whole grain versus refined grain consumption on immune-mediated inflammation through staple food substitution, while participants maintained their usual dietary practices. The results demonstrated that whole grain consumption significantly reduced circulating levels of pro-inflammatory cytokines IL-22 and IL-23 compared to refined grain consumption. These reductions were associated with optimized short-chain fatty acid profiles and changes in CD4⁺ T cell subset distributions.</p></div><div><h3>Conclusions</h3><p>The findings suggest that the anti-inflammatory effects of whole grain consumption in middle-aged and elderly populations are mediated by targeting specific CD4⁺ T cell subsets, in addition to modulating both upstream short-chain fatty acid composition and downstream expression of the pro-inflammatory cytokines IL-22 and IL-23.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221323172400315X/pdfft?md5=bd4201bb866b2c56dccbe0ef9b0c51b3&pid=1-s2.0-S221323172400315X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142163122","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":"Impaired HDL antioxidant and anti-inflammatory functions are linked to increased mortality in acute heart failure patients","authors":"","doi":"10.1016/j.redox.2024.103341","DOIUrl":"10.1016/j.redox.2024.103341","url":null,"abstract":"<div><h3>Aims</h3><p>Acute heart failure (AHF) is typified by inflammatory and oxidative stress responses, which are associated with unfavorable patient outcomes. Given the anti-inflammatory and antioxidant properties of high-density lipoprotein (HDL), this study sought to examine the relationship between impaired HDL function and mortality in AHF patients. The complex interplay between various HDL-related biomarkers and clinical outcomes remains poorly understood.</p></div><div><h3>Methods</h3><p>HDL subclass distribution was quantified by nuclear magnetic resonance spectroscopy. Lecithin–cholesterol acyltransferase (LCAT) activity, cholesterol ester transfer protein (CETP) activity, and paraoxonase (PON-1) activity were assessed using fluorometric assays. HDL-cholesterol efflux capacity (CEC) was assessed in a validated assay using [3H]-cholesterol-labeled J774 macrophages.</p></div><div><h3>Results</h3><p>Among the study participants, 74 (23.5 %) out of 315 died within three months after hospitalization due to AHF. These patients exhibited lower activities of the anti-oxidant enzymes PON1 and LCAT, impaired CEC, and lower concentration of small HDL subclasses, which remained significant after accounting for potential confounding factors. Smaller HDL particles, particularly HDL3 and HDL4, exhibited a strong association with CEC, PON1 activity, and LCAT activity.</p></div><div><h3>Conclusions</h3><p>In patients with AHF, impaired HDL CEC, HDL antioxidant and anti-inflammatory function, and impaired HDL metabolism are associated with increased mortality. Assessment of HDL function and subclass distribution could provide valuable clinical information and help identify patients at high risk.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724003197/pdfft?md5=aaaaf85952f7387284b7a89aac2f0d7c&pid=1-s2.0-S2213231724003197-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142148359","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":"Corrigendum to \"Dopamine-modified hyaluronic acid (DA-HA) as a novel dopamine-mimetics with minimal autoxidation and cytotoxicity\" [Redox Biol. 76 (2024) 103320].","authors":"Sunpil Kim, Ye-Ji Kim, Kyoung Hwan Park, Kang Moo Huh, Sun-Woong Kang, C Justin Lee, Dong Ho Woo","doi":"10.1016/j.redox.2024.103338","DOIUrl":"https://doi.org/10.1016/j.redox.2024.103338","url":null,"abstract":"","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of mitochondria in reno-cardiac diseases: A study of bioenergetics, biogenesis, and GSH signaling in disease transition","authors":"","doi":"10.1016/j.redox.2024.103340","DOIUrl":"10.1016/j.redox.2024.103340","url":null,"abstract":"<div><p>Acute kidney injury (AKI) and chronic kidney disease (CKD) are global health burdens with rising prevalence. Their bidirectional relationship with cardiovascular dysfunction, manifesting as cardio-renal syndromes (CRS) types 3 and 4, underscores the interconnectedness and interdependence of these vital organ systems. Both the kidney and the heart are critically reliant on mitochondrial function. This organelle is currently recognized as a hub in signaling pathways, with emphasis on the redox regulation mediated by glutathione (GSH). Mitochondrial dysfunction, including impaired bioenergetics, redox, and biogenesis pathways, are central to the progression of AKI to CKD and the development of CRS type 3 and 4. This review delves into the metabolic reprogramming and mitochondrial redox signaling and biogenesis alterations in AKI, CKD, and CRS. We examine the pathophysiological mechanisms involving GSH redox signaling and the AMP-activated protein kinase (AMPK)-sirtuin (SIRT)1/3-peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) axis in these conditions. Additionally, we explore the therapeutic potential of GSH synthesis inducers in mitigating these mitochondrial dysfunctions, as well as their effects on inflammation and the progression of CKD and CRS types 3 and 4.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724003185/pdfft?md5=6aeb0bafa6d6ec0386fe983299fbce5f&pid=1-s2.0-S2213231724003185-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158479","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}