Redox Biology最新文献

{"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":"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}

{"title":"Polysulfide and persulfide-mediated activation of the PERK-eIF2α-ATF4 pathway increases Sestrin2 expression and reduces methylglyoxal toxicity","authors":"Shin Koike ,&nbsp;Hideo Kimura ,&nbsp;Yuki Ogasawara","doi":"10.1016/j.redox.2024.103450","DOIUrl":"10.1016/j.redox.2024.103450","url":null,"abstract":"<div><div>Unfolded protein response (UPR) is activated in cells under endoplasmic reticulum (ER) stress. One sensor protein involved in this response is PERK, which is activated through its redox-dependent oligomerization. Prolonged UPR activation is associated with the development and progression of various diseases, making it essential to understanding the redox regulation of PERK. Sulfane sulfur, such as polysulfides and persulfides, can modify the cysteine residues and regulate the function of various proteins. However, the regulatory mechanism and physiological effects of sulfane sulfur on the PERK–eIF2α–ATF4 pathway remain poorly understood. This study focuses on the persulfidation of PERK to elucidate the effects of polysulfides on the PERK–eIF2α–ATF4 pathway and investigate its cytoprotective mechanism. Here, we demonstrated that polysulfide treatment promoted the oligomerization of PERK and PTP1B in neuronal cells using western blotting under nonreducing conditions. We also observed that <span>l</span>-cysteine, a biological source of sulfane sulfur, promoted the oligomerization of PERK and the knockdown of CBS and 3-MST, two sulfane sulfur-producing enzymes, and reduced PERK oligomerization induced by <span>l</span>-cysteine treatment. Furthermore, the band shift assay and LC–MS/MS studies revealed that polysulfides and persulfides induce PTP1B and PERK persulfidation. Additionally, polysulfides promoted eIF2α phosphorylation and ATF4 accumulation in the nucleus, suggesting that polysulfides activate the PERK–eIF2α–ATF4 pathway in neuronal cells. Moreover, polysulfides protected neuronal cells from methylglyoxal-induced toxicity, and this protective effect was reduced when the expression of Sestrin2, regulated by ATF4 activity, was suppressed. This study identified a novel mechanism for the activation of the PERK–eIF2α–ATF4 pathway through persulfidation by polysulfides and persulfides. Interestingly, activation of this pathway overcame the toxicity of methylglyoxal in dependence on Sestrin2 expression. These findings deepen our understanding of neuronal diseases involving ER stress and UPR disturbance and may inspire new therapeutic strategies.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103450"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819085","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":"Sarcopenic obesity is attenuated by E-syt1 inhibition via improving skeletal muscle mitochondrial function","authors":"Chao Song ,&nbsp;Wu Zheng ,&nbsp;Guoming Liu ,&nbsp;Yiyang Xu ,&nbsp;Zhibo Deng ,&nbsp;Yu Xiu ,&nbsp;Rongsheng Zhang ,&nbsp;Linhai Yang ,&nbsp;Yifei Zhang ,&nbsp;Guoyu Yu ,&nbsp;Yibin Su ,&nbsp;Jun Luo ,&nbsp;Bingwei He ,&nbsp;Jie Xu ,&nbsp;Hanhao Dai","doi":"10.1016/j.redox.2024.103467","DOIUrl":"10.1016/j.redox.2024.103467","url":null,"abstract":"<div><div>In aging and metabolic disease, sarcopenic obesity (SO) correlates with intramuscular adipose tissue (IMAT). Using bioinformatics analysis, we found a potential target protein Extended Synaptotagmin 1 (E-syt1) in SO. To investigate the regulatory role of E-syt1 in muscle metabolism, we performed in vivo and in vitro experiments through E-syt1 loss- and gain-of-function on muscle physiology. When E-syt1 is overexpressed in vitro, myoblast proliferation, differentiation, mitochondrial respiration, biogenesis, and mitochondrial dynamics are impaired, which were alleviated by the silence of E-syt1. Furthermore, overexpression of E-syt1 inhibited mitophagic flux. Mechanistically, E-syt1 overexpression leads to mitochondrial calcium overload and mitochondrial ROS burst, inhibits the fusion of mitophagosomes with lysosomes, and impedes the acidification of lysosomes. Animal experiments demonstrated the inhibition of E-syt1 increased the capacity of endurance exercise, muscle mass, mitochondrial function, and oxidative capacity of the muscle fibers in OVX mice. These findings establish E-syt1 as a novel contributor to the pathogenesis of skeletal muscle metabolic disorders in SO. Consequently, targeting E-syt1-induced dysfunction may serve as a viable strategy for attenuating SO.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103467"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823233","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":"Adipocyte-derived small extracellular vesicles exacerbate diabetic ischemic heart injury by promoting oxidative stress and mitochondrial-mediated cardiomyocyte apoptosis","authors":"Lu Gan ,&nbsp;Jianli Zhao ,&nbsp;Peng Yao ,&nbsp;Theodore A. Christopher ,&nbsp;Bernard Lopez ,&nbsp;Wayne B. Lau ,&nbsp;Walter Koch ,&nbsp;Erhe Gao ,&nbsp;Xinliang Ma ,&nbsp;Yajing Wang","doi":"10.1016/j.redox.2024.103443","DOIUrl":"10.1016/j.redox.2024.103443","url":null,"abstract":"<div><h3>Background</h3><div>Diabetes increases ischemic heart injury via incompletely understood mechanisms. We recently reported that diabetic adipocytes-derived small extracellular vesicles (sEV) exacerbate myocardial reperfusion (MI/R) injury by promoting cardiomyocyte apoptosis. Combining <em>in vitro</em> mechanistic investigation and <em>in vivo</em> proof-concept demonstration, we determined the underlying molecular mechanism responsible for diabetic sEV-induced cardiomyocyte apoptosis after MI/R.</div></div><div><h3>Methods and results</h3><div>Adult mice were fed a high-fat diet (HFD) for 12 weeks. sEV were isolated from plasma or epididymal adipose tissue. HFD significantly increased the number and size of plasma- and adipocyte-derived sEV. Intramyocardial injection of an equal number of diabetic plasma sEV in nondiabetic hearts significantly increased cardiac apoptosis and exacerbated MI/R-induced cardiac dysfunction. Diabetic plasma sEV significantly activated cardiac caspase 9 but not caspase 8, suggesting that diabetic sEV induces cardiac apoptosis via the mitochondrial pathway. These pathologic alterations were phenotyped by intramyocardial injection of sEV isolated from diabetic adipocytes or HGHL-challenged 3T3L1 adipocytes. To obtain direct evidence that diabetic sEV promotes cardiomyocyte apoptotic cell death, isolated neonatal rat ventricular cardiomyocytes (NRVMs) were treated with sEV and subjected to simulated ischemia/reperfusion (SI/R). Treatment of cardiomyocytes with sEV from diabetic plasma, diabetic adipocytes, or HGHL-challenged 3T3L1 adipocytes significantly enhanced SI/R-induced apoptosis and reduced cell viability. These pathologic effects were replicated by a miR-130b-3p (a molecule increased dramatically in diabetic sEV) mimic and blocked by a miRb-130b-3p inhibitor. Molecular studies identified PGC-1α (i.e. PGC-1α1/-a) as the direct downstream target of miR-130b-3p, whose downregulation causes mitochondrial dysfunction and apoptosis. Finally, treatment with diabetic adipocyte-derived sEV or a miR-130b-3p mimic significantly enhanced mitochondrial reactive oxygen species (ROS) production in SI/R cardiomyocytes. Conversely, treatment with a miR-130b-3p inhibitor or overexpression of PGC-1α extremely attenuated diabetic sEV-induced ROS production.</div></div><div><h3>Conclusion</h3><div>We obtained the first evidence that diabetic sEV promotes oxidative stress and mitochondrial-mediated cardiomyocyte apoptotic cell death, exacerbating MI/R injury. These pathological phenotypes were mediated by miR-130b-3p-induced suppression of PGC-1α expression and subsequent mitochondrial ROS production. Targeting miR-130b-3p mediated cardiomyocyte apoptosis may be a novel strategy for attenuating diabetic exacerbation of MI/R injury.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103443"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11750569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142910418","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 ABC transporter Opp imports reduced glutathione, while Gsi imports glutathione disulfide in Escherichia coli","authors":"Lisa R. Knoke,&nbsp;Maik Muskietorz,&nbsp;Lena Kühn,&nbsp;Lars I. Leichert","doi":"10.1016/j.redox.2024.103453","DOIUrl":"10.1016/j.redox.2024.103453","url":null,"abstract":"<div><div>Glutathione is the major thiol-based antioxidant in a wide variety of biological systems, ranging from bacteria to eukaryotes. As a redox couple, consisting of reduced glutathione (GSH) and its oxidized form, glutathione disulfide (GSSG), it is crucial for the maintenance of the cellular redox balance. Glutathione transport out of and into cellular compartments and the extracellular space is a determinant of the thiol-disulfide redox state of the organelles and bodily fluids in question, but is currently not well understood. Here we use the genetically-encoded, glutathione-measuring redox probe Grx1-roGFP2 to comprehensively elucidate the import of extracellular glutathione into the cytoplasm of the model organism <em>Escherichia coli</em>. The elimination of only two ATP-Binding Cassette (ABC) transporter systems, Gsi and Opp, completely abrogates glutathione import into <em>E. coli</em>'s cytoplasm, both in its reduced and oxidized form. The lack of only one of them, Gsi, completely prevents import of GSSG, while the lack of the other, Opp, substantially retards the uptake of reduced glutathione (GSH).</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103453"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790152","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":"Tetrahydrobiopterin as a rheostat of cell resistance to oxidant injury","authors":"R. Steven Traeger ,&nbsp;James Woodcock ,&nbsp;Sidhartha Tan ,&nbsp;Zhongjie Shi ,&nbsp;Jeannette Vasquez-Vivar","doi":"10.1016/j.redox.2024.103447","DOIUrl":"10.1016/j.redox.2024.103447","url":null,"abstract":"<div><div>Tetrahydrobiopterin (BH4) deficiency is caused by genetic abnormalities that impair its biosynthesis and recycling, which trigger neurochemical, metabolic, and redox imbalances. Low BH4 levels are also associated with hypoxia, reperfusion reoxygenation, endothelial dysfunction, and other conditions that are not genetically determined. The exact cause of changes in BH4 in nongenetic disorders is not entirely understood, but a role for oxidant species has been implicated. The oxidation of BH4 generates several products, including 7,8-dihydrobiopterin (BH2), the accumulation of which is predicted in cells with low dihydrofolate reductase activity. The relative efficiency of oxidant species at causing variations in BH4/BH2 levels in cells furnished with several antioxidant enzymes has not yet been systematically analyzed. This study examined the quantitative changes of BH4/BH2 in cells challenged with several oxidants. We showed that BH2 is not a major product of treatments with hydrogen peroxide or RSL3, as indicated by the moderate effect of dihydrofolate reductase-inhibitor methotrexate on the accumulation of BH2. However, we found a net loss in BH4/BH2, suggesting that products other than BH2 were generated. These reactions were further examined in NOX4-expressing HEK cells producing hydrogen peroxide. These cells showed slightly decreased BH4/BH2 ratios compared with HEK wild-type cells, and, again, methotrexate treatment moderately increased BH2 levels. In contrast, peroxynitrite-producing RAW 264.7 cells showed dramatically decreased BH4 levels without BH2 accumulation. Following the activation of peroxynitrite production with PMA in lipopolysaccharide-treated cells, we also found a significant time-dependent decline in GTPCH-I protein levels. We conclude that hydrogen peroxide is the least effective oxidant species at decreasing intracellular BH4 levels, while peroxynitrite is highly effective by targeting GTPCH-I and BH4 directly. Moreover, we conclude that BH4/BH2 levels are not a determinant of RSL3 cytotoxicity.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103447"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790155","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":"Macropinocytosis enhances foamy macrophage formation and cholesterol crystallization to activate NLRP3 inflammasome after spinal cord injury","authors":"Chenxi Zhang ,&nbsp;Shujie Zhao ,&nbsp;Zhenfei Huang ,&nbsp;Ao Xue ,&nbsp;Hao Liu ,&nbsp;Siming Dai ,&nbsp;Ziyang Zheng ,&nbsp;Yin Li ,&nbsp;Xiaodong Guo ,&nbsp;Jun Gu ,&nbsp;Feng Zhang ,&nbsp;Fubing Wang ,&nbsp;Yongxiang Wang ,&nbsp;Xiaohua Zhou ,&nbsp;Shujun Zhang ,&nbsp;Hanwen Zhang ,&nbsp;Jun Shen ,&nbsp;Jian Chen ,&nbsp;Guoyong Yin","doi":"10.1016/j.redox.2024.103469","DOIUrl":"10.1016/j.redox.2024.103469","url":null,"abstract":"<div><div>After spinal cord injury (SCI), phagocytes endocytose myelin debris to form foam cells, exacerbating the inflammatory response. It has been previously shown that macrophages become foam cells through the phagocytosis of myelin debris via receptor-dependent mechanisms after SCI. Blocking receptor-mediated endocytosis did not completely prevent foam cell formation, so we investigated receptor-independent endocytosis. Here, we revealed that foam cells formed after myelin debris internalization were predominantly macrophages rather than microglia. Receptor-independent macropinocytosis has an important position in foamy macrophage formation through engagement of myelin debris endocytosis after SCI. Mechanistic studies showed that cholesterol crystallization following macropinocytosis-mediated foamy macrophage formation promoted the reactive oxygen species (ROS) production and the NOD-like receptor protein 3 (NLRP3) inflammasome activation, increasing the secretion of interleukin-1β (IL-1β). Inhibition of macropinocytosis might reverse this effect, resulting in enhanced axonal regeneration and reduced neural apoptosis, thereby improving outcomes after SCI. Overall, our study revealed a previously unrecognized role for macropinocytosis in foamy macrophages formation after SCI, and confer a promising therapeutic strategy for SCI through focus on macropinocytosis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103469"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11723182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865187","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}