Free Radical Biology and Medicine最新文献

{"title":"Nepetin limits NLRP3 inflammasome activation and alleviates NLRP3-driven inflammatory diseases via PINK1-dependent mitophagy","authors":"Wen-jie Bu ,&nbsp;Si-si Li ,&nbsp;Chang Liu ,&nbsp;Yue-hua Wang ,&nbsp;Jian-rong Lu ,&nbsp;Chao-run Dong ,&nbsp;Dong-jie Zheng ,&nbsp;Zhe-yu Fan ,&nbsp;Yi Yu ,&nbsp;Wei Zhang ,&nbsp;Yun-long Bai","doi":"10.1016/j.freeradbiomed.2024.12.027","DOIUrl":"10.1016/j.freeradbiomed.2024.12.027","url":null,"abstract":"<div><div>The NLRP3 inflammasome plays a pivotal role in the progression of inflammatory diseases. Mitochondrial damage, oxidative stress and mitochondrial DNA (mtDNA) leak are the key upstream factors for NLRP3 inflammasome activation. Nepetin (Nep), a naturally occurring flavonoid found with anti-inflammatory properties; however, whether it can affect the NLRP3 inflammasome activation and its precise anti-inflammatory mechanism remains unclear. In this study, we demonstrated that Nep enhances PINK1-mediated ubiquitin phosphorylation, which promotes mitophagy and subsequently inhibits NLRP3 inflammasome activation and pyroptosis in macrophages. The administration of Nep to macrophages alleviated of mitochondrial damage, reduced mitochondrial superoxide production, restored mitochondrial membrane potential and prevented the mtDNA leakage. These findings provide compelling evidence for the antioxidant effect of Nep. Furthermore, the pivotal function of mitophagy in the NLRP3 inflammasome inhibitory impact of Nep was substantiated through the utilisation of mitophagy inhibitors and siRNA techniques. Notably, Nep increased survival and reduced organ damage in mice with systemic inflammation by inhibiting NLRP3 inflammasome activation. In addition, Nep suppressed NLRP3 inflammasome activation in obese mice, which led to reduced white adipose and liver inflammation, thereby ameliorating insulin resistance. In conclusion, our findings suggest that Nep is a potent NLRP3 inflammasome inhibitor and a promising candidate for the development of anti-inflammatory therapies.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"227 ","pages":"Pages 420-433"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799847","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":"Altered mitochondrial unfolded protein response and protein quality control promote oxidative distress in down syndrome brain","authors":"Simona Lanzillotta ,&nbsp;Daniel Esteve ,&nbsp;Chiara Lanzillotta ,&nbsp;Antonella Tramutola ,&nbsp;Ana Lloret ,&nbsp;Elena Forte ,&nbsp;Vito Pesce ,&nbsp;Anna Picca ,&nbsp;Fabio Di Domenico ,&nbsp;Marzia Perluigi ,&nbsp;Eugenio Barone","doi":"10.1016/j.freeradbiomed.2024.11.043","DOIUrl":"10.1016/j.freeradbiomed.2024.11.043","url":null,"abstract":"<div><div>Down Syndrome (DS) is a genetic disorder caused by the presence of an extra copy of chromosome 21, and leading to various developmental and cognitive defects. A critical feature of DS is the occurrence of oxidative distress particularly in the brain, which exacerbates neurodevelopmental processes. Mitochondria play a crucial role in cell energy metabolism and their impairment is one of the major causes of oxidative distress in several pathologies. Hence, this study investigates mitochondrial proteostasis by the mean of the mitochondrial Unfolded Protein Response (UPRmt) and the mitochondrial protein quality control (MQC) mechanisms in the context of DS, focusing on their implications in redox homeostasis in brain development. We analyzed key UPRmt markers and mitochondrial function in the frontal cortex isolated fromTs2Cje mice, a model for DS, across different developmental stages. Our results demonstrate significant alterations in UPRmt markers, particularly at postnatal day 0 (P0) and 1 month (1M). These changes indicate early UPRmt activation, primarily driven by the ATF5/GRP75 axis, although compromised by reduced levels of other components. Impaired UPRmt correlates with decreased mitochondrial activity, evidenced by reduced oxygen consumption rates and altered expression of OXPHOS complexes. Additionally, elevated oxidative stress markers such as 3-nitrotyrosine (3-NT), 4-hydroxynonenal (HNE), and protein carbonyls (PC) were observed, linking mitochondrial dysfunction to increased oxidative damage. Defects of MQC, including disrupted biogenesis, increased fission, and the activation of mitophagy were evident mostly at P0 and 1M consistent with UPRmt activation.</div><div>Principal Component Analysis revealed distinct phenotypic differences between Ts2Cje and control mice, driven by these molecular alterations. Our findings underscore the critical role of UPRmt and MQC in DS brain development, highlighting potential therapeutic targets to mitigate mitochondrial dysfunction and oxidative distress, thereby alleviating some of the neurodevelopmental and cognitive impairments associated with DS.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"227 ","pages":"Pages 80-93"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715720","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":"Pink1-dependent mitophagy in vascular smooth muscle cells: Implications for arterial constriction","authors":"Dongliang Li ,&nbsp;Jingqi Nie ,&nbsp;Shi Zhang ,&nbsp;Shengmiao Yu ,&nbsp;Yang Li ,&nbsp;Feifei Zheng ,&nbsp;Shipeng Bo ,&nbsp;Nan Wang ,&nbsp;Yanqiu Zhang","doi":"10.1016/j.freeradbiomed.2024.10.306","DOIUrl":"10.1016/j.freeradbiomed.2024.10.306","url":null,"abstract":"<div><div>Hypertension is a major global health issue, contributing to significant cardiovascular morbidity and mortality. Mitochondrial dysfunction, particularly through dysregulated mitophagy, has been implicated in the pathogenesis of hypertension. We wanted to find out the relationship between mitochondrial autophagy and changes in arterial smooth muscle cell tension and the molecular mechanism. Using RNA-seq analysis, we identified significant upregulation of autophagy-related genes, including Pink1, in the aortas of spontaneously hypertensive rats (SHR) compared to normotensive Wistar-Kyoto (WKY) rats. Further in vivo and in vitro studies revealed enhanced mitophagy, characterized by increased expression of Pink1 protein. Our experiments showed that knockdown of Pink1 expression by shRNA attenuated KPSS-induced vascular smooth muscle cells (VSMCs) contraction, suggesting that excessive mitophagy contributes to vascular dysfunction in hypertension. These findings highlight Pink1-mediated mitophagy as a crucial player in hypertensive vascular remodeling and present a potential therapeutic target for managing hypertension.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"227 ","pages":"Pages 608-618"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557524","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":"The RNA chaperone Hfq is a novel regulator of catalase expression and hydrogen peroxide-induced oxidative stress response in Listeria monocytogenes EGD-e","authors":"André Filipe Seixas,&nbsp;Alda Filipa Queirós Silva,&nbsp;João Pedro Sousa,&nbsp;Cecília Maria Arraiano,&nbsp;José Marques Andrade","doi":"10.1016/j.freeradbiomed.2024.11.038","DOIUrl":"10.1016/j.freeradbiomed.2024.11.038","url":null,"abstract":"<div><div>The RNA chaperone Hfq plays a pivotal role in many bacteria, acting as a regulator of gene expression and promoting interaction between mRNA-sRNA pairs in Gram-negative bacteria. However, in Gram-positive bacteria this protein is expendable for riboregulation, and the main function of Hfq remains elusive. This work unveils a novel function for Hfq in the oxidative stress response of the human pathogen <em>Listeria monocytogenes</em>, a Gram-positive bacterium responsible for the infectious disease listeriosis. Disruption of <em>hfq</em> gene (Δ<em>hfq</em>) results in a hypersensitive phenotype towards hydrogen peroxide (H₂O₂), in which sub-inhibitory concentrations of this reactive oxygen species (ROS) severely impair growth and viability of <em>L. monocytogenes</em> EGD-e. A Δ<em>hfq-</em>complemented strain does not show this phenotype. This Hfq-dependent regulation of oxidative stress seems specific for H₂O₂, as exposure to superoxides caused no differences. We demonstrate that Hfq has a dual regulatory role in the expression of catalase (<em>kat</em>), the key enzyme involved in H₂O₂ detoxification. Hfq influences <em>kat</em> transcription under non-stress conditions by modulating the levels of the transcriptional repressor PerR, and also acts post-transcriptionally by stabilizing <em>kat</em> mRNA under H₂O₂-induced stress. Indeed, enzymatic assays revealed reduced catalase activity in Δ<em>hfq</em> cell extracts, a result unrelated to differences in cellular iron content. Bacterial infection triggers immune cells to produce massive amounts of ROS, like H₂O₂. We show that inactivation of Hfq increases susceptibility to macrophage killing, connecting Hfq with the stress resistance and virulence of <em>L. monocytogenes</em> EGD-e. Overall, these findings advance the understanding of Hfq function within Gram-positive bacteria, revealing for the first time that Hfq is a novel regulator of catalase expression. This paves the way for the study of yet unknown oxidative stress response pathways regulated by Hfq in other pathogens.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"227 ","pages":"Pages 103-116"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750341","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":"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}