Redox Biology最新文献

{"title":"Inhibition of S100A8/A9 ameliorates neuroinflammation by blocking NET formation following traumatic brain injury","authors":"Guihong Shi ,&nbsp;Yiyao Cao ,&nbsp;Jianye Xu ,&nbsp;Bo Chen ,&nbsp;Xu Zhang ,&nbsp;Yanlin Zhu ,&nbsp;Liang Liu ,&nbsp;Xilei Liu ,&nbsp;Luyuan Zhang ,&nbsp;Yuan Zhou ,&nbsp;Shenghui Li ,&nbsp;Guili Yang ,&nbsp;Xiao Liu ,&nbsp;Fanglian Chen ,&nbsp;Xin Chen ,&nbsp;Jianning Zhang ,&nbsp;Shu Zhang","doi":"10.1016/j.redox.2025.103532","DOIUrl":"10.1016/j.redox.2025.103532","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) triggers a robust inflammatory response that is closely linked to worsened clinical outcomes. S100A8/A9, also known as calprotectin or myeloid-related protein-8/14 (MRP8/14), is an alarmin primarily secreted by activated neutrophils with potent pro-inflammatory property. In this study, we explored the roles of S100A8/A9 in modulating neuroinflammation and influencing TBI outcomes, delving into the underlying mechanisms. S100A8/A9-enriched neutrophils were present in the injured brain tissue of TBI patients, and elevated plasma levels of S100A8/A9 were correlated with poorer neurological function. Furthermore, using a TBI mouse model, we demonstrated that treatment with the selective S100A8/A9 inhibitor Paquinimod significantly mitigated neuroinflammation and neuronal death, thereby improving the prognosis of TBI mice. Mechanistically, we found that S100A8/A9, in conjunction with neutrophil activation and infiltration into the brain, enhances reactive oxygen species (ROS) production within neutrophils, accelerating PAD4-mediated neutrophil extracellular trap (NET) formation, which in turn exacerbates neuroinflammation. These findings suggest that S100A8/A9 amplifies neuroinflammatory responses by promoting NET formation in neutrophils. Inhibition of S100A8/A9 effectively attenuated NET-mediated neuroinflammation; however, when PAD4 was overexpressed in the brain using adenovirus, leading to an increased formation of NET in the brain, the anti-inflammatory effects of S100A8/A9 inhibition were markedly diminished. Further experiments with PAD4 knockout mice confirmed that the reduction of NETs could substantially alleviate S100A8/A9-driven neuroinflammation. Finally, we established that the suppression of NET formation by S100A8/A9 inhibition is primarily mediated through the AMPK/Nrf2/HO-1 signaling pathway. These findings underscore the critical pathological role of S100A8/A9 in TBI and emphasize the need for further exploration of S100A8/A9 inhibitor Paquinimod as a potential therapeutic strategy for TBI.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103532"},"PeriodicalIF":10.7,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373070","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":"The nonlinear cysteine redox dynamics in the i-space: A proteoform-centric theory of redox regulation","authors":"James N. Cobley ,&nbsp;Panagiotis N. Chatzinikolaou ,&nbsp;Cameron A. Schmidt","doi":"10.1016/j.redox.2025.103523","DOIUrl":"10.1016/j.redox.2025.103523","url":null,"abstract":"<div><div>The post-translational redox regulation of protein function by cysteine oxidation controls diverse biological processes, from cell division to death. However, most current site-centric paradigms fail to capture the nonlinear and emergent nature of redox regulation in proteins with multiple cysteines. Here, we present a proteoform-centric theory of redox regulation grounded in the <em>i</em>-space. The <em>i</em>-space encapsulates the theoretical landscape of all possible cysteine proteoforms. Using computational approaches, we quantify the vast size of the abstract <em>i</em>-space, revealing its scale-free architecture—elucidating the disproportionate influence of cysteine-rich proteins. We define mathematical rules governing cysteine proteoform dynamics. Their dynamics are inherently nonlinear, context-dependent, and fundamentally constrained by protein copy numbers. Monte Carlo simulations of the human protein PTP1B reveal extensive <em>i</em>-space sampling beyond site-centric models, supporting the “oxiform conjecture”. This conjecture posits that highly oxidised proteoforms, molecules bearing multiple oxidised cysteines, are central to redox regulation. In support, even 90%-reduced proteomes can house vast numbers of unique, potentially functioanlly diverse, oxiforms. This framework offers a transformative lens for understanding the redox biology of proteoforms.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103523"},"PeriodicalIF":10.7,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373071","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":"ProteotoxomiRs: Diagnostic and pathologic miRNA signatures for reductive stress induced proteotoxic heart disease","authors":"Santhosh Kumar Karthikeyan ,&nbsp;Palanisamy Nallasamy ,&nbsp;Jarrell Matthew Cleveland ,&nbsp;Ahila Arulmani ,&nbsp;Ashvanthi Raveendran ,&nbsp;Mariam Karimi ,&nbsp;Mohammad Owais Ansari ,&nbsp;Anil Kumar Challa ,&nbsp;Moorthy P. Ponnusamy ,&nbsp;Ivor J. Benjamin ,&nbsp;Sooryanarayana Varambally ,&nbsp;Namakkal S. Rajasekaran","doi":"10.1016/j.redox.2025.103525","DOIUrl":"10.1016/j.redox.2025.103525","url":null,"abstract":"<div><div>Proteotoxic stress progressively leads to irreversible cardiac abnormalities. Using a mouse model of reductive stress-induced proteotoxic cardiomyopathy, we identified novel microRNA signatures, termed “ProteotoxomiRs,” which reflect stage-specific and transgene-specific responses to proteotoxic stress. Seven microRNAs were uniquely linked to the human mutant R120G-αB-Crystallin transgene, indicating their direct association with the pathogenic protein. Additionally, we uncovered two distinct microRNA profiles associated with the early (pre-onset) and late (cardiomyopathy/heart failure) stages of disease progression. Early-stage signatures primarily modulate signaling pathways essential for cardiac health, including mTOR and MAPK, while late-stage signatures reveal regulatory disruptions in calcium signaling and autophagy insufficiency, driving irreversible cardiac damage caused by reductive stress (RS) and proteotoxicity in transgenic mice. These findings reveal stage-specific miRNA biomarkers with potential diagnostic and prognostic value, offering new insights into the molecular underpinnings of proteotoxic cardiac disease. Moreover, our miRNA-mRNA interaction analysis uncovered potential targets unique to the transgene-specific, early, and late stages of the disease, including several promising druggable candidates, warranting further validation for translational applications.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103525"},"PeriodicalIF":10.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452945","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":"Genetic interaction between oxidative stress and body mass index in a Spanish population","authors":"Francisco Lara-Hernández ,&nbsp;Rebeca Melero ,&nbsp;María Elena Quiroz-Rodríguez ,&nbsp;Celeste Moya-Valera ,&nbsp;Mariana de Jesús Gallardo-Espinoza ,&nbsp;Luis Álvarez ,&nbsp;Ingrid Lizeth Valarezo-Torres ,&nbsp;Laisa Briongos-Figuero ,&nbsp;Jessica Abadía-Otero ,&nbsp;Francisco Javier Mena-Martin ,&nbsp;Guillermo Saez ,&nbsp;Josep Redon ,&nbsp;Juan-Carlos Martín-Escudero ,&nbsp;Ana-Bárbara García-García ,&nbsp;Guillermo Ayala ,&nbsp;Felipe Javier Chaves","doi":"10.1016/j.redox.2025.103531","DOIUrl":"10.1016/j.redox.2025.103531","url":null,"abstract":"<div><div>Oxidative stress may act as a contributing factor in the development of an elevated body mass index (BMI). Oxidative stress has the potential to modulate genetic activity at various levels, including gene transcription and protein function regulation. Nevertheless, the interplay between genetic variants and oxidative stress in relation to BMI remains to be elucidated. Based on this premise, we studied the potential association between 723 single-nucleotide polymorphisms (SNPs) located within a set of 212 genes and both BMI and oxidative stress parameters in 1502 adults from the general Spanish population (Hortega Study). Oxidative stress parameters measured included malondialdehyde (MDA) levels, 8-oxo-2′-deoxyguanosine (8-oxo-dG) levels and oxidised/reduced glutathione ratio (GSSG/GSH). We also examined the potential impact of the interaction between these SNPs and oxidative stress levels on BMI. The genes selected regulate several key biological processes, including obesity, blood pressure, inflammation, lipid metabolism and redox homeostasis. Our findings indicate a robust association between specific genes and both BMI and oxidative stress parameters. Significant BMI-related interactions between genes and oxidative stress parameters were identified, which have a multifactorial impact on oxidative stress modulation and on BMI. SNPs identified in genes such as <em>NPPA</em>, <em>CPT1A</em>, <em>DDIT3</em>, <em>NOX</em> and <em>IL6ST</em> were significantly associated with all oxidative stress parameters analysed, indicating a substantial influence on BMI modulation. The results provide compelling evidence of a significant relationship between oxidative stress levels and genetic background. Our data provide new insights into BMI modulation by oxidative stress levels, highlighting a role for <em>TNF</em> as a key player in the interrelation of oxidative stress and BMI.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"80 ","pages":"Article 103531"},"PeriodicalIF":10.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143372982","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":"FNDC5/irisin mitigates the cardiotoxic impacts of cancer chemotherapeutics by modulating ROS-dependent and -independent mechanisms","authors":"Manish Kumar ,&nbsp;Abhishek Singh Sengar ,&nbsp;Anushree Lye ,&nbsp;Pranesh Kumar ,&nbsp;Sukhes Mukherjee ,&nbsp;Dinesh Kumar ,&nbsp;Priyadip Das ,&nbsp;Suvro Chatterjee ,&nbsp;Adele Stewart ,&nbsp;Biswanath Maity","doi":"10.1016/j.redox.2025.103527","DOIUrl":"10.1016/j.redox.2025.103527","url":null,"abstract":"<div><div>Cardiotoxicity remains a major limiting factor in the clinical implementation of anthracycline chemotherapy. Though the etiology of doxorubicin-dependent heart damage has yet to be fully elucidated, the ability of doxorubicin to damage DNA and trigger oxidative stress have been heavily implicated in the pathogenesis of chemotherapy-associated cardiomyopathy. Here, we demonstrate that fibronectin type III domain-containing protein 5 (FNDC5), the precursor protein for myokine irisin, is depleted in the hearts of human cancer patients or mice exposed to chemotherapeutics. In cardiomyocytes, restoration of FNDC5 expression was sufficient to mitigate reactive oxygen species (ROS) accumulation and apoptosis following doxorubicin exposure, effects dependent on the irisin encoding domain of FNDC5 as well as signaling via the putative irisin integrin receptor. Intriguingly, we identified two parallel signaling cascades impacted by FNDC5 in cardiomyocytes: the ROS-driven intrinsic mitochondrial apoptosis pathway and the ROS-independent Ataxia Telangiectasia and Rad3-Related Protein (ATR)/Checkpoint Kinase 1 (Chk1) pathway. In fact, FNDC5 forms a co-precipitable complex with Chk1 alluding to possible intracellular actions for this canonically membrane-associated protein. Whereas FNDC5 overexpression in murine heart was cardioprotective, introduction of FNDC5-targeted shRNA into the myocardium was sufficient to trigger Bax up-regulation, ATR/Chk1 activation, oxidative stress, cardiac fibrosis, loss of ventricular function, and compromised animal survival. The detrimental impact of FNDC5 depletion on heart function could be mitigated via treatment with a Chk1 inhibitor identifying Chk1 hyperactivity as a causative factor in cardiac disease. Though our data point to the potential clinical utility of FNDC5/irisin-targeted agents in the treatment of chemotherapy-induced cardiotoxicity, we also found significant down regulation in FNDC5 expression in the hearts of aged mice that attenuated the cardioprotective impacts of FNDC5 overexpression following doxorubicin exposure. Together our data underscore the importance of FNDC5/irisin in maintenance of cardiac health over the lifespan.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"80 ","pages":"Article 103527"},"PeriodicalIF":10.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350436","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":"Mitochondrial fission produces a Warburg effect via the oxidative inhibition of prolyl hydroxylase domain-2","authors":"Xutong Sun ,&nbsp;Manivannan Yegambaram ,&nbsp;Qing Lu ,&nbsp;Alejandro E. Garcia Flores ,&nbsp;Marissa D. Pokharel ,&nbsp;Jamie Soto ,&nbsp;Saurabh Aggarwal ,&nbsp;Ting Wang ,&nbsp;Jeffrey R. Fineman ,&nbsp;Stephen M. Black","doi":"10.1016/j.redox.2025.103529","DOIUrl":"10.1016/j.redox.2025.103529","url":null,"abstract":"<div><div>Excessive mitochondrial fission and a shift to a Warburg phenotype are hallmarks of pulmonary hypertension (PH), although the mechanistic link between these processes remains unclear. We show that in pulmonary arterial endothelial cells (PAEC), Drp1 overexpression induces mitochondrial fission and increases glycolytic ATP production and glycolysis. This is due to mitochondrial reactive oxygen species (mito-ROS)-mediated activation of hypoxia-inducible factor-1α (HIF-1α) signaling, and this is linked to hydrogen peroxide (H₂O₂)-mediated inhibition of prolyl hydroxylase domain-2 (PHD2) due to its cysteine 326 oxidation and dimerization. Furthermore, these findings are validated in PAEC isolated from a lamb model of PH, which are glycolytic (Shunt PAEC), exhibit increases in both H₂O₂ and PHD2 dimer levels. The overexpression of catalase reversed the PHD2 dimerization, decreased HIF-1α levels, and attenuated glycolysis in Shunt PAEC. Our data suggest that reducing PHD2 dimerization could be a potential therapeutic target for PH.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103529"},"PeriodicalIF":10.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143445249","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":"ROS regulates circadian rhythms by modulating Ezh2 interactions with clock proteins","authors":"Hao-yi Zhang ,&nbsp;Ke-yun Li ,&nbsp;Yi-li Wang ,&nbsp;Chun-Jiao Wei ,&nbsp;Yu-Xuan Gao ,&nbsp;Ren-Zhou ,&nbsp;Ying-bin Zhong ,&nbsp;Zong-jun Yin ,&nbsp;Da-long Ren","doi":"10.1016/j.redox.2025.103526","DOIUrl":"10.1016/j.redox.2025.103526","url":null,"abstract":"<div><div>Redox imbalance induced by the accumulation of reactive oxygen species (ROS) accelerates age-related processes, often accompanied by a decrease in circadian rhythm amplitude. However, the underlying mechanisms by which ROS modulate circadian rhythms remain poorly understood. In this study, we found that ROS disrupt circadian rhythms in both zebrafish, as indicated by changes in diurnal behavior and clock gene expression, and in a human cell model. Using weighted gene co-expression network analysis (WGCNA) and machine learning approaches (RF, LASSO, SVM), EZH2 was identified as a key gene involved in regulating circadian rhythms under oxidative stress conditions. To further investigate the role of EZH2, we employed <em>ezh2</em>^{<em>−/−</em>} mutants, Morpholino injection, and overexpression treatment and discovered that EZH2 is crucial in mediating the effect of ROS on circadian rhythms. Furthermore, EZH2 interacts with the CLOCK-BMAL1 complex to regulate the transcription of clock genes, as demonstrated through co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. Our study revealed that ROS disrupt circadian rhythms by regulating the interaction between EZH2 and the CLOCK-BMAL1 complex, shedding light on the molecular mechanisms of circadian rhythm disruption under oxidative stress and suggesting potential targets for age-related and circadian disorders.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103526"},"PeriodicalIF":10.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403294","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":"Niraparib restricts intraperitoneal metastases of ovarian cancer by eliciting CD36-dependent ferroptosis","authors":"Ning Jin ,&nbsp;Yi-yu Qian ,&nbsp;Xiao-fei Jiao ,&nbsp;Zhen Wang ,&nbsp;Xin Li ,&nbsp;Wen Pan ,&nbsp;Jin-kai Jiang ,&nbsp;Pu Huang ,&nbsp;Si-yuan Wang ,&nbsp;Ping Jin ,&nbsp;Qing-lei Gao ,&nbsp;Dan Liu ,&nbsp;Yu Xia","doi":"10.1016/j.redox.2025.103528","DOIUrl":"10.1016/j.redox.2025.103528","url":null,"abstract":"<div><div>Ovarian cancer (OC) is prone to peritoneum or omentum dissemination, thus giving rise to the formidable challenge of unresectable surgery and a dismal survival rate. Although niraparib holds a pivotal role in the maintenance treatment of OC, its effect on suppressing metastases during primary intervention remains enigmatic. Recently, we initiated a prospective clinical study (NCT04507841) in order to evaluate the therapeutic efficacy of neoadjuvant niraparib monotherapy for advanced OC with homologous recombination deficiency. An analysis of patient tumor burden before and after the niraparib challenge showed a remarkable vulnerability of OC intraperitoneal metastases to niraparib exposure. This killing capacity of niraparib was closely associated with the accumulation of fatty acids within the abdomen, which was confirmed by the increased susceptibility of tumor cells to niraparib treatment in the presence of fatty acids. In the context of abundant fatty acids, niraparib elevated intracellular levels of fatty acids and lipid peroxidation, leading to subsequent tumor cell ferroptosis in a p53 and BRCA-independent manner. Notably, under niraparib exposure, a critical fatty acid transporter CD36 was dramatically upregulated in tumors, facilitating excessive uptake of fatty acids. Pharmacological inhibition of either ferroptosis or CD36 impaired the anti-tumor activity of niraparib both <em>in vitro</em> and in murine intraperitoneal ID8 tumor models. Our findings demonstrate ferroptosis as a novel mechanism underlying the regression of OC metastases induced by niraparib, thereby offering tantalizing prospects for the frontline application of this agent in the management of OC.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"80 ","pages":"Article 103528"},"PeriodicalIF":10.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143347840","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":"HDAC6 inhibitor-loaded brain-targeted nanocarrier-mediated neuroprotection in methamphetamine-driven Parkinson's disease","authors":"Khang-Yen Pham ,&nbsp;Shristi Khanal ,&nbsp;Ganesh Bohara ,&nbsp;Nikesh Rimal ,&nbsp;Sang-Hoon Song ,&nbsp;Thoa Thi Kim Nguyen ,&nbsp;In-Sun Hong ,&nbsp;Jinkyung Cho ,&nbsp;Jong-Sun Kang ,&nbsp;Sooyeun Lee ,&nbsp;Dong-Young Choi ,&nbsp;Simmyung Yook","doi":"10.1016/j.redox.2024.103457","DOIUrl":"10.1016/j.redox.2024.103457","url":null,"abstract":"<div><div>The dynamic equilibrium between acetylation and deacetylation is vital for cellular homeostasis. Parkinson's disease (PD), a neurodegenerative disorder marked by α-synuclein (α-syn) accumulation and dopaminergic neuron loss in the substantia nigra, is associated with a disruption of this balance. Therefore, correcting this imbalance with histone deacetylase (HDAC) inhibitors represents a promising treatment strategy for PD. CAY10603 (CAY) is a potent and selective HDAC6 inhibitor. However, because of its poor water solubility and short biological half-life, it faces clinical limitations. Herein, we engineered lactoferrin-decorated CAY-loaded poly(lactic-<em>co</em>-glycolic acid) nanoparticles (denoted as PLGA@CAY@Lf NPs) to effectively counter methamphetamine (Meth)-induced PD. PLGA@CAY@Lf NPs showed enhanced blood–brain barrier crossing and significant brain accumulation. Notably, CAY released from PLGA@CAY@Lf NPs restored the disrupted acetylation balance in PD, resulting in neuroprotection by reversing mitochondrial dysfunction, suppressing reactive oxygen species, and inhibiting α-syn accumulation. Additionally, PLGA@CAY@Lf NPs treatment normalized dopamine and tyrosine hydroxylase levels, reduced neuroinflammation, and improved behavioral impairments. These findings underscore the potential of PLGA@CAY@Lf NPs in treating Meth-induced PD and suggest that an innovative HDAC6-inhibitor-based strategy can be used to treat PD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103457"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865172","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":"Nox1/PAK1 is required for angiotensin II-induced vascular inflammation and abdominal aortic aneurysm formation","authors":"Hui He ,&nbsp;Tianyu Jiang ,&nbsp;Meng Ding,&nbsp;Yuan Zhu,&nbsp;Xiaoting Xu,&nbsp;Yashuang Huang,&nbsp;Wenfeng Yu,&nbsp;Hailong Ou","doi":"10.1016/j.redox.2024.103477","DOIUrl":"10.1016/j.redox.2024.103477","url":null,"abstract":"<div><div>NADPH oxidase 1 (Nox1) is a major isoform of Nox in vascular smooth muscle cells (VSMCs). VSMC activation and extracellular matrix (ECM) remodelling induce abdominal aortic aneurysm (AAA). In this study, we aim to determine the role of Nox1 in the progression of AAA and explore the underling mechanism. ApoE^−/−Nox1^SMCko mice in which the Nox1 gene was smooth muscle cell (SMC)-specifically deleted in ApoE^−/− background, were infused with angiotensin II (Ang II) for 28 days. We found the Nox1 deficiency reduced AAA formation and increased survival compared with ApoE^−/−Nox1^y/flox mice. Abdominal aortic ROS and monocyts/macrophages were reduced in the ApoE^−/−Nox1^SMCko mice after Ang II-infusion. The SMC-specific Nox1 deletion caused less elastin fragments and lower matrix metalloproteinase (MMP) activities in the abdominal aorta. Further, we found the Nox1 protein interacted with p21-activated kinase 1 (PAK1) in Ang II-stimulated VSMCs. The PAK1, controlled by Nox1/ROS, promoted VSMC proliferation, migration and differentiation; this is associated with increased activities of vimentin and cofilin, and cytoskeleton modulation. Moreover, we found that the Nox1/PAK1 activated the downstream MAPKs (ERK1/2, p38 and JNKs) and NF-κB, and upregulated Sp1-mediated MMP2 expression upon Ang II-stimulation. Finally, overexpression of PAK1 in the ApoE^−/−Nox1^SMCko mice increased vascular elastic fibre degradation, pro-inflammatory cytokine expression and AAA incidence. Therefore, we conclude that Nox1, together with PAK1, facilitates Ang II-induced VSMC activation, vascular inflammation and ECM remodelling, and thus potentiates the AAA formation.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103477"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887875","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}