Free Radical Biology and Medicine最新文献

{"title":"GATAD1 is involved in sphingosylphosphorylcholine-attenuated myocardial ischemia-reperfusion injury by modulating myocardial fatty acid oxidation and glucose oxidation","authors":"Yuqing Cai,&nbsp;Yifan Yu,&nbsp;Tianliang Zhang,&nbsp;Baoshuo Qian,&nbsp;Benlong Wang,&nbsp;Wenxiu Yan,&nbsp;Jing Zhao","doi":"10.1016/j.freeradbiomed.2024.11.054","DOIUrl":"10.1016/j.freeradbiomed.2024.11.054","url":null,"abstract":"<div><div>Modulating the equilibrium between glucose metabolism and fatty acid metabolism represents highly promising novel strategies for therapy of myocardial ischemia/reperfusion (I/R) injury. Sphingosylphosphorylcholine (SPC), an intermediate metabolite of sphingolipids, has shown cardioprotective roles during myocardial infarction by regulating the activities of various transcript factors. Gene microarray revealed that SPC significantly upregulated the expression of GATA zinc finger domain protein 1 (GATAD1), which is a vital transcript factor affecting heart development and various heart diseases. However, it remains unclear whether SPC is involved in the regulation of cardiac fatty acid and glucose metabolism via GATAD1. In this study, we found that myocardium-specific <em>Gatad1</em> knockout (<em>Gatad1</em> CKO) significantly increased the myocardial infarct size, impaired cardiac function in I/R mice, and disrupted the protective effect of SPC on the hearts of I/R mice. Immunofluorescence experiment and Western blot evaluation of the nuclear-cytoplasmic fractionation sample showed that GATAD1 acted as a transcription factor and was regulated by SPC. Double fluorescence reporting experiment and quantitative polymerase chain reaction (qPCR) revealed that GATAD1 could inhibit the expression of genes involved in fatty acid oxidation (FAO), i.e., <em>acetyl-coenzyme A acyltransferase 2</em> (<em>Acaa2</em>) and <em>medium-chain acyl-CoA dehydrogenase</em> (<em>Acadm</em>), and promoted the expression of genes involved in glucose oxidation<em>,</em> i.e., <em>pyruvate dehydrogenase E1 α subunit</em> (<em>Pdha1</em>). Small interfering RNA (SiRNA) or overexpression strategies confirmed the pro-apoptotic roles of <em>Acaa2</em> and <em>Acadm</em> and anti-apoptotic role of <em>Pdha1</em> in cardiac myocytes challenged with I/R treatment. In summary, our findings suggest that SPC can be used as a candidate to prevent I/R injury by reshaping fatty acid and glucose metabolism. Transcription factor GATAD1 plays a crucial role in regulating fatty acid oxidation and glucose oxidation homeostasis and is involved in SPC-mediated cardioprotection during I/R of the heart. Our study identifies GATAD1 as a new therapeutic target for clinical treatment of myocardial I/R injury.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"227 ","pages":"Pages 166-178"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular evolution of ovothiol biosynthesis in animal life reveals diversity of the natural antioxidant ovothiols in Cnidaria","authors":"Annalisa Zuccarotto ,&nbsp;Marco Sollitto ,&nbsp;Lucas Leclère ,&nbsp;Lucia Panzella ,&nbsp;Marco Gerdol ,&nbsp;Serena Leone ,&nbsp;Immacolata Castellano","doi":"10.1016/j.freeradbiomed.2024.11.037","DOIUrl":"10.1016/j.freeradbiomed.2024.11.037","url":null,"abstract":"<div><div>Sulfoxide synthase OvoA is the key enzyme involved in the biosynthesis of ovothiols (OSHs), secondary metabolites endowed with unique antioxidant properties. Understanding the evolution of such enzymes and the diversity of their metabolites should reveal fundamental mechanisms governing redox signaling and environmental adaptation. “Early-branching” animals such as Cnidaria display unique molecular diversity and symbiotic relationships responsible for the biosynthesis of natural products, however, they have been neglected in previous research on antioxidants and OSHs.</div><div>In this work, we have integrated genome and transcriptome mining with biochemical analyses to study the evolution and diversification of OSHs biosynthesis in cnidarians. By tracing the history of the <em>ovoA</em> gene, we inferred its loss in the latest common ancestor of Medusozoa, followed by the acquisition of a unique <em>ovoB/ovoA</em> chimaeric gene in Hydrozoa, likely through a horizontal gene transfer from dinoflagellate donors. While Anthozoa (corals and anemones), bearing canonical <em>ovoA</em> genes, produced a striking variety of OSHs (A, B, and C), the multifunctional enzyme in Hydrozoa was related to OSH B biosynthesis, as shown in <em>Clytia hemisphaerica.</em> Surprisingly, the <em>ovoA-</em>lacking jellyfish <em>Aurelia aurita</em> and <em>Pelagia noctiluca</em> also displayed OSHs, and we provided evidence of their incorporation from external sources. Finally, transcriptome mining revealed <em>ovoA</em> conserved expression pattern during larval development from Cnidaria to more evolved organisms and its regulation by external stimuli, such as UV exposure. The results of our study shed light on the origin and diversification of OSH biosynthesis in basal animals and highlight the importance of redox-active molecules from ancient metazoans as cnidarians to vertebrates.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"227 ","pages":"Pages 117-128"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lithium Enhances Ferroptosis sensitivity in melanoma cells and promotes CD8+ T Cell infiltration and differentiation","authors":"Bo Zhu ,&nbsp;Chunhao Yang ,&nbsp;Siqi Hua ,&nbsp;Kaiqiang Li ,&nbsp;Pengyou Shang ,&nbsp;Xiao Chen ,&nbsp;Zi-Chun Hua","doi":"10.1016/j.freeradbiomed.2024.12.012","DOIUrl":"10.1016/j.freeradbiomed.2024.12.012","url":null,"abstract":"<div><div>Lithium exposure reduces melanoma incidence and mortality, yet its therapeutic mechanisms are unclear. This study explores the effects of lithium on ferroptosis sensitivity and anti-tumor T cell response in melanoma. We found that lithium significantly enhanced RSL3-induced ferroptosis <em>in vitro</em>, evidenced by increased mitochondrial peroxide, lipid peroxidation, and mitochondrial abnormalities. Lithium also inhibited B16-F10 melanoma cell proliferation and migration in a dose-dependent manner. Cell cycle analysis showed lithium and RSL3 induced distinct perturbations, including G2/M and G0/G1 phase arrests. Mechanistically, lithium influenced intracellular ferrous ion levels by downregulating ferritin heavy chain (Fth1), crucial for iron homeostasis. The combination of lithium and RSL3 significantly suppressed tumor growth in mice, correlating with reduced Fth1 expression and increased iron deposition in the spleen and liver, highlighting a novel interaction between lithium and iron metabolism. Additionally, this combination enhanced CD8⁺ T cell infiltration and IFN-γ expression in the tumor microenvironment, especially among cytotoxic effector CD8⁺ T cells. These findings reveal the pro-ferroptotic and immune regulation roles of lithium, broaden our understanding of its biological roles, and propose new strategies for ferroptosis-targeted therapies in melanoma.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"227 ","pages":"Pages 233-245"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive review of peroxiredoxin 4, a redox protein evolved in oxidative protein folding coupled with hydrogen peroxide detoxification","authors":"Junichi Fujii ,&nbsp;Haruki Ochi ,&nbsp;Sohsuke Yamada","doi":"10.1016/j.freeradbiomed.2024.12.015","DOIUrl":"10.1016/j.freeradbiomed.2024.12.015","url":null,"abstract":"<div><div>Peroxiredoxin (PRDX) primarily employs electrons from thioredoxin in order to reduce peroxides. PRDX4 mainly resides either in the endoplasmic reticulum (ER) lumen or in extracellular spaces. Due to the usage of alternative promoters, a first exon is transcribed from different regions of the Prdx4 gene, which results in two types of mRNAs. The first type is designated as Prdx4. It is translated with a cleavable, hydrophobic signal sequence and is expressed in most cells throughout the body. The second type is designated as Prdx4t. The peroxidase activity of PRDX4 is involved in both the reduction of hydrogen peroxides and in the oxidative folding of nascent proteins in the ER. Prdx4 appears to have evolved from an ancestral gene in <em>Eutherians</em> simultaneously with the evolution of sperm protamine to cysteine-rich peptides, and, therefore, the testis-specific PRDX4t is likely involved in spermatogenesis through the oxidative folding of protamine. The dysfunction of PRDX4 leads to oxidative damage and ER stress, and is related to various diseases including diabetes and cancer. In this review article we refer to the results of biological and medical research in order to unveil the functional consequences of this unique member of the PRDX family.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"227 ","pages":"Pages 336-354"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NADPH oxidase 4-SH3 domain-containing YSC84-like 1 complex participates liver inflammation and fibrosis","authors":"Yeo Kyu Hur ,&nbsp;Hye Eun Lee ,&nbsp;Jung-Yeon Yoo ,&nbsp;Young Nyun Park ,&nbsp;In Hye Lee ,&nbsp;Yun Soo Bae","doi":"10.1016/j.freeradbiomed.2024.12.021","DOIUrl":"10.1016/j.freeradbiomed.2024.12.021","url":null,"abstract":"<div><div>There is growing evidence that NADPH oxidase 4 (Nox4) in hepatocytes contributes to liver inflammation and fibrosis during the development of metabolic dysfunction-associated steatohepatitis (MASH). However, how Nox4 is regulated and leads to liver pathogenesis is unclear. Our previous studies showed that the cytosolic protein SH3 domain-containing Ysc84-like 1 (SH3YL1) regulates Nox4 activity. Here, we asked whether SH3YL1 also participates in liver inflammation and fibrosis during MASH development. We generated that whole body SH3YL1 knockout (SH3YL1^−/−), Nox4 knockout (Nox4^−/−) mice, and the hepatocyte-specific SH3YL1 conditional knockout (Alb-Cre/SH3YL1^fl/fl) mice were fed a methionine/choline-deficient (MCD) diet to induce liver inflammation and fibrosis in pathogenesis of MASH. Palmitate-stimulated primary SH3YL1-and Nox4-deficient hepatocytes and hepatic stellate cells (HSCs) did not generate H₂O₂. While the liver of MCD diet-fed wild type (WT) mice demonstrated elevated 3-nitrotyrosine as a protein oxidation and 4-hydroxynonenal adducts as a lipid oxidation and increased liver inflammation, hepatocyte apoptosis, and liver fibrosis, these events were markedly reduced in SH3YL1^−/−, Nox4^−/−, and Alb-Cre/SH3YL1^fl/fl mice. The MCD diet-fed WT mice also showed elevated hepatocyte expression of SH3YL1 protein. Similarly, liver biopsies from MASH patients demonstrated strong hepatocyte SH3YL1 protein expression, whereas hepatocytes from patients with steatosis weakly expressed SH3YL1 and histologically normal patient hepatocytes exhibited very little SH3YL1 expression. The Nox4-SH3YL1 complex in murine hepatocytes elevates their H₂O₂ production, which promotes the liver inflammation, hepatocyte apoptosis, and liver fibrosis that characterize MASH. This axis may also participate in MASH in humans.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"227 ","pages":"Pages 246-259"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective nitric oxide redistribution by phospholipid nanoparticles: A novel strategy to mitigate massive nitric oxide release and prevent reperfusion injury in septic shock","authors":"Ryan Sasse ,&nbsp;Nathan Carpenter ,&nbsp;Cuthbert O. Simpkins","doi":"10.1016/j.freeradbiomed.2024.12.022","DOIUrl":"10.1016/j.freeradbiomed.2024.12.022","url":null,"abstract":"<div><div>Nitric oxide plays a critical role in regulating vascular tone, but excessive nitric oxide release during septic shock results in hypotension due to excessive vasodilation and the formation of toxic free radicals. VBI-S is a phospholipid nanoparticle based fluid composed of lipid bilayers formed primarily by phosphatidylcholine and micelles of soybean oil encapsulated by a monolayer of phosphatidylcholine. These nanoparticles offer a novel solution by absorbing and redistributing nitric oxide and nitrite, potentially mitigating the harmful effects of excessive nitric oxide in sepsis. This paper proposes a mechanism in which VBI-S not only redistributes nitric oxide but also reduces ischemia-reperfusion injury by limiting the production and availability of reactive species. VBI-S captures nitric oxide and nitrite in areas of high concentration and redistributes them in low-nitric oxide environments, primarily within oxygen-deprived tissues. Nitrite then contributes to nitric oxide regeneration in hypoxic microvasculature via various reduction pathways, thereby improving tissue perfusion and minimizing oxidative stress. Preliminary studies suggest that nitrite may also decrease reactive species production, primarily superoxide, through the inhibition of mitochondrial complex I. Additionally, the lipid composition of VBI-S is rich in poly and monounsaturated fatty acids which allows VBI-S to act as a substrate for peroxidation via peroxynitrite. Therefore, VBI-S acts as a decoy target thereby protecting cellular membranes from oxidative damage caused by reactive species. These findings position VBI-S as a promising therapeutic agent, offering both nitric oxide regulation and protection against hypotension and toxic free radicals in septic shock patients. Further research is necessary to fully elucidate the molecular pathways and optimize its clinical application.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"227 ","pages":"Pages 276-281"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of JNK signaling attenuates photoreceptor ferroptosis caused by all-trans-retinal","authors":"Bo Yang ,&nbsp;Kunhuan Yang ,&nbsp;Ruitong Xi ,&nbsp;Shiying Li ,&nbsp;Jingmeng Chen ,&nbsp;Yalin Wu","doi":"10.1016/j.freeradbiomed.2024.12.007","DOIUrl":"10.1016/j.freeradbiomed.2024.12.007","url":null,"abstract":"<div><div>The disruption of the visual cycle leads to the accumulation of all-<em>trans</em>-retinal (atRAL) in the retina, a hallmark of autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (AMD), both of which cause retinal degeneration. Although our previous studies have shown that atRAL induces ferroptosis and activates c-Jun <em>N</em>-terminal kinase (JNK) signaling in the retina, the relationship between JNK signaling and ferroptosis in atRAL-mediated photoreceptor damage remains unclear. Here, we reported that JNK activation by atRAL drove photoreceptor ferroptosis through ferritinophagy. In photoreceptor cells loaded with atRAL, activated JNK phosphorylated c-Jun, which facilitated its nuclear translocation and promoted the expression of the nuclear receptor coactivator 4 (NCOA4). Elevated NCOA4 induced ferritin degradation via lysosomal processing, a process known as ferritinophagy, thereby releasing a large amount of labile iron. Iron overload led to the generation of reactive oxygen species (ROS) and lipid peroxidation, ultimately culminating in ferroptosis. Treatment with the JNK inhibitor JNK-IN-8, as well as the knockout of <em>Jnk1</em> and <em>Jnk2</em> genes, significantly rescued atRAL-loaded photoreceptor cells from ferritinophagy-induced ferroptosis. <em>Abca4</em>^{<em>−/−</em>}<em>Rdh8</em>^{<em>−/−</em>} mice, which exhibit atRAL accumulation in the retina following light exposure, are commonly used to study the pathological processes of STGD1 and dry AMD. In these mice, light exposure activated the JNK/c-Jun/NCOA4 axis, resulting in ferritinophagy in the neural retina. Importantly, intraperitoneal administration of JNK-IN-8 significantly rescued retinal function and photoreceptors from ferritinophagy-induced ferroptosis and effectively mitigated retinal degeneration in light-exposed <em>Abca4</em>^{<em>−/−</em>}<em>Rdh8</em>^{<em>−/−</em>} mice. This study underscores the critical role of the JNK/c-Jun/NCOA4 axis in mediating atRAL-induced ferritinophagy, which drives ferroptosis and retinal atrophy, suggesting that targeting this pathway may offer a potential therapeutic approach for STGD1 and dry AMD.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"227 ","pages":"Pages 179-189"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct roles of ascorbic acid in extracellular vesicles and free form: Implications for metabolism and oxidative stress in presymptomatic Huntington's disease","authors":"Felipe A. Beltrán ,&nbsp;Leandro Torres-Díaz L. ,&nbsp;Paulina Troncoso-Escudero ,&nbsp;Juan Villalobos-González ,&nbsp;Gonzalo Mayorga-Weber ,&nbsp;Marcelo Lara ,&nbsp;Adriana Covarrubias-Pinto ,&nbsp;Sharin Valdivia ,&nbsp;Isidora Vicencio ,&nbsp;Eduardo Papic ,&nbsp;Carolina Paredes-Martínez ,&nbsp;Mara E. Silva-Januàrio ,&nbsp;Alejandro Rojas ,&nbsp;Luis L.P. daSilva ,&nbsp;Felipe Court ,&nbsp;Abraham Rosas-Arellano ,&nbsp;Luis Federico Bátiz ,&nbsp;Patricio Rojas ,&nbsp;Francisco J. Rivera ,&nbsp;Maite A. Castro","doi":"10.1016/j.freeradbiomed.2024.12.001","DOIUrl":"10.1016/j.freeradbiomed.2024.12.001","url":null,"abstract":"<div><div>Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin gene. The huntingtin protein (Htt) is ubiquitously expressed and localized in several organelles, including endosomes, where it plays an essential role in intracellular trafficking. Presymptomatic HD is associated with a failure in energy metabolism and oxidative stress. Ascorbic acid is a potent antioxidant that plays a key role in modulating neuronal metabolism and is highly concentrated in the brain. During synaptic activity, neurons take up ascorbic acid released by glial cells; however, this process is disrupted in HD. In this study, we aim to elucidate the molecular and cellular mechanisms underlying this dysfunction. Using an electrophysiological approach in presymptomatic YAC128 HD slices, we observed decreased ascorbic acid flux from astrocytes to neurons, which altered neuronal metabolic substrate preferences. Ascorbic acid efflux and recycling were also decreased in cultured astrocytes from YAC128 HD mice. We confirmed our findings using GFAP-HD160Q, an HD mice model expressing mutant N-terminal Htt mainly in astrocytes. For the first time, we demonstrated that ascorbic acid is released from astrocytes via extracellular vesicles (EVs). Decreased number of particles and exosomal markers were observed in EV fractions from cultured YAC128 HD astrocytes and Htt-KD cells. We observed reduced number of multivesicular bodies (MVBs) in YAC128 HD striatum via electron microscopy, suggesting mutant Htt alters MVB biogenesis. EVs containing ascorbic acid effectively reduced reactive oxygen species, whereas “free” ascorbic acid played a role in modulating neuronal metabolic substrate preferences. These findings suggest that the early redox imbalance observed in HD arises from a reduced release of ascorbic acid-containing EVs by astrocytes. Meanwhile, a decrease in \"free\" ascorbic acid likely contributes to presymptomatic metabolic impairment.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"227 ","pages":"Pages 521-535"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selenoproteome depletion enhances oxidative stress and alters neutrophil functions in Citrobacter rodentium infection leading to gastrointestinal inflammation","authors":"Tai-Jung Lee ,&nbsp;Hsiao-Chi Liao ,&nbsp;Agus Salim ,&nbsp;Shaneice K. Nettleford ,&nbsp;Kendall L. Kleinman ,&nbsp;Bradley A. Carlson ,&nbsp;K. Sandeep Prabhu","doi":"10.1016/j.freeradbiomed.2024.12.025","DOIUrl":"10.1016/j.freeradbiomed.2024.12.025","url":null,"abstract":"<div><div>Reactive oxygen species (ROS) play a critical role in modulating a range of proinflammatory functions in neutrophils, as well as regulating neutrophil apoptosis and facilitating the resolution of an inflammatory response. Selenoproteins with the 21st amino acid, selenocysteine (Sec), regulate immune mechanisms through the modulation of redox homeostasis aiding in the efficient resolution of inflammation, while their role in neutrophil functions during diseases remains unclear. To study the role of selenoproteins in neutrophils during infection, we challenged the granulocyte-specific tRNA^Sec (Trsp) knockout mice (Trsp^N) with <em>Citrobacter rodentium</em> (<em>C. rodentium</em>), a murine pathogenic bacterium. Reduced bacterial shedding during the disease-clearing phase and increased tissue damage and neutrophil accumulation in the colon of the Trsp^N mice were observed following infection. Trsp^N neutrophils showed increased intracellular ROS accumulation during <em>ex vivo C. rodentium</em> stimulation and upregulated fMLP or Cx3cl1-induced chemotaxis. We also observed delayed neutrophil apoptosis, reduced efferocytosis of Trsp^N neutrophils, and increased abundance of apoptotic cells in the colon of Trsp^N mice. Together, these studies indicate that selenoprotein depletion results in increased neutrophil migration to the gut accompanied by ROS accumulation, while downregulating neutrophil apoptosis and subsequent efferocytosis by macrophages. Such an increase in inflammation followed by impaired resolution culminates in decreased bacterial load but with exacerbated host tissue damage.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"227 ","pages":"Pages 499-507"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multifunctional peptide-drug conjugate CORM-401@R9: A novel approach to combat oxidative stress in cataracts","authors":"Yilin Chen ,&nbsp;Haixu Chen ,&nbsp;Zhaohui Li","doi":"10.1016/j.freeradbiomed.2024.12.031","DOIUrl":"10.1016/j.freeradbiomed.2024.12.031","url":null,"abstract":"<div><div>Cataracts, the leading cause of blindness globally, are primarily driven by oxidative stress and protein aggregation in the lens. Effective pharmacological treatments for cataracts are still elusive. This study developed a novel multifunctional peptide-drug conjugate, CORM-401@R9 (CO-R9), which activates in response to reactive oxygen species (ROS) and releases carbon monoxide (CO). The conjugate combines poly-arginine-9 peptide (R9) with CORM-401 to improve cellular uptake and CO delivery, targeting the elevated ROS levels characteristic of cataract pathology. In vitro, CO-R9 effectively reduced ROS levels and prevented senescence and apoptosis induced by oxidative stress. Further investigation into the molecular mechanisms reveals that CO-R9 restored redox homeostasis by modulating the expression of key genes and proteins involved in antioxidant defense, anti-apoptotic responses, and molecular chaperoning. This study highlights CO-R9 as a promising therapeutic agent with potential for cataract prevention and treatment.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"227 ","pages":"Pages 570-581"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}