The FASEB Journal最新文献

{"title":"ATP7A Maintains Bactericidal Function of Neutrophils and Macrophages via Regulating the Formation and Activation of Phagolysosomes","authors":"YuanYuan Jing,&nbsp;JiaHao Shi,&nbsp;ZhiJuan Xie,&nbsp;Zheng Shen,&nbsp;Jingjing Zhang,&nbsp;Fudi Wang,&nbsp;Kuanyu Li,&nbsp;Jianguo Su,&nbsp;Jing-Xia Liu","doi":"10.1096/fj.202500056R","DOIUrl":"https://doi.org/10.1096/fj.202500056R","url":null,"abstract":"<div>\u0000 \u0000 <p>Neutrophils and macrophages are indispensable phagocytic immune cells, critically responsible for fish's ability to combat pathogens. Studies unveil that ATP7A is essential for copper trafficking to the lysosome in the cells, a process that is fundamental for their antibacterial functions in vitro. However, its antibacterial role in vivo and the underlying mechanisms have been insufficiently explored. In this study, we have demonstrated that <i>atp7a</i>^{<i>−/−</i>} mutant larvae are significantly more susceptible to <i>Aeromonas hydrophila</i> (AH) infection and possess fewer neutrophils and macrophages compared to their wild-type (WT) counterparts, and these mutants show a pronounced delay in the migration of the cells in response to infection. <i>Atp7a</i> deficiency leads to a marked downregulation of key phagosomal and lysosomal proteins, which impairs the formation of phagolysosomes and impairs lysosomal acidification and reactive oxygen species (ROS) elevation, then results in the ultimately impaired phagocytic activity and the attenuated release of phagolysosomal inflammatory and chemotactic signals such as <i>il-1β</i>/<i>6</i>/<i>8</i>, underscoring the impaired immune function of the mutants. Furthermore, Atp7a is shown to interact with proteins Lamp1 and Ctsb to facilitate copper trafficking and with Rabep1 and Rabgef1, to shield these proteins from degradation. Meanwhile, Atp7a-dependent copper trafficking is essential in Rabgef1 ubiquitination and the consequent activation of Rab5 and Rab7. These thereby enhance phagolysosomal activity and reinforce the immune response of neutrophils and macrophages against AH infection. In conclusion, this study compellingly establishes the pivotal role of Atp7a in sustaining the bactericidal capacities of immune cells in fish, while also illuminating the potential immune-related implications for individuals with ATP7A deficiency.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179307","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 Novel Interaction of Staphylococcal Protein A With Human Fibronectin and Its Implications in Host Cell Adhesion","authors":"S. Camaione,&nbsp;W. Pansegrau,&nbsp;F. Concetti,&nbsp;M. Del Vecchio,&nbsp;L. Dello Iacono,&nbsp;I. Ferlenghi,&nbsp;A. G. O. Manetti,&nbsp;L. Manzi,&nbsp;N. Norais,&nbsp;A. Pellegrini,&nbsp;S. Savino,&nbsp;I. Margarit,&nbsp;G. Pietrocola","doi":"10.1096/fj.202500086R","DOIUrl":"https://doi.org/10.1096/fj.202500086R","url":null,"abstract":"<p><i>Staphylococcus aureus</i> is the causative agent of serious human health conditions, such as sepsis, endocarditis, and necrotizing pneumonia, as well as less severe clinical manifestations including epithelial and mucosal infections. This pathogen expresses a wide range of surface virulence factors, among which fibronectin-binding proteins play a crucial role in both bacterial adhesion and infection of host cells. Fibronectin is utilized by <i>S. aureus</i> during the early stages of infection to form a protective coating that shields the bacterium from host defenses, facilitating adhesion to the extracellular matrix of host cells and promoting immune evasion and subsequent invasion. <i>S. aureus</i> protein A (SpA) is a key multi-domain cell wall-anchored and secreted molecule that functions to evade the human immune response by non-specifically interacting with Fc and the Fab V_H3 domains of immunoglobulins. Other known human ligands of SpA include the von Willebrand factor, the tumor necrosis factor receptor 1, and a platelet surface protein, all of which contribute to immune evasion and pathogenesis. The present study reveals that SpA can also bind human fibronectin with high affinity, adding a new function to this already multifunctional virulence factor. We show that the N-terminus of fibronectin is involved in the interaction and demonstrate by carbene footprinting experiments that the SpA fibronectin binding site spans the interdomain linker region and helix 1 of the domains D, A, B, and C, partially overlapping with the Fc binding site. In the presence of fibronectin, SpA knock-out mutant strains showed reduced adhesion to human endothelial cells compared to wild-type bacteria, suggesting that this interaction may play a significant role in the attachment to host tissues by <i>S. aureus</i>.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500086R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179414","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":"SR-717, a Non-Nucleotide STING Agonist, Displayed Anti-Radiation Activity in a IL-6 Dependent Manner","authors":"Duo Fang,&nbsp;Wanli Duan,&nbsp;Xuanlu Zhai,&nbsp;Liao Zhang,&nbsp;Jiayan Fang,&nbsp;Keer Jiang,&nbsp;Jianpeng Zhao,&nbsp;Yue Fu,&nbsp;Lan Fang,&nbsp;Lu Pei,&nbsp;Cong Liu,&nbsp;Jicong Du,&nbsp;Jianming Cai,&nbsp;Fu Gao","doi":"10.1096/fj.202403127R","DOIUrl":"https://doi.org/10.1096/fj.202403127R","url":null,"abstract":"<p>Ionizing radiation (IR) induced damages are common complications of radiotherapy for tumors, severely limiting the intensity and therapeutic efficacy of the radiotherapy program. Emerging data indicated that the cGAS-STING pathway has paradoxical effects on IR-induced damage. SR-717, as a non-nucleotide, small-molecule stimulator of interferon genes (STING) agonist, has been proven that it could activate the STING signaling pathway. In this work, we try to explore the radioprotection of the STING signaling pathway and figure out whether SR-717 could be a potential intestinal radioprotective agent. C57BL/6 mice were intraperitoneally treated with SR-717 or normal saline (NS). By analyzing the survival rate, body weight, and the number of peripheral blood cells after IR exposure, we found that SR-717 improved the survival rate and body weight of mice, protected the intestine from IR-induced damage as well as hematopoietic damage, and promoted the regeneration of intestinal stem cells (ISCs). Cell viability and apoptosis after irradiation were detected after stimulation of MODE-K cells with SR-717 or PBS. We found that SR-717 increased cell viability and inhibited apoptosis in vitro. The mechanism of SR-717 in intestinal radiation protection was investigated by RNA-seq. The results of RNA-seq and qRT-PCR suggested that SR-717 significantly activated the immune system via the STING-IL-6 signaling pathway. In addition, we discussed the role of TLR2 in SR-717-mediated anti-radiation activity, and TLR2 deletion significantly reversed the radioprotective effects of SR717. In conclusion, we proved STING signaling activation displayed anti-radiation activity and found SR-717 displayed anti-radiation activity via the STING-IL-6 signaling pathway, suggesting SR-717 could be a potential intestinal radioprotective agent.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202403127R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179192","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":"circ_0005654 as a Sponge of the miR-588 Dual Pathway to Promote α-Synuclein Expression","authors":"Jiang Lei,&nbsp;Jiajia Liao,&nbsp;Yingyao Liu,&nbsp;Yao Liu,&nbsp;Wenxuan He,&nbsp;Qinxin Zhang,&nbsp;Yuefei Shen,&nbsp;Jin Wang,&nbsp;Pingyi Xu,&nbsp;Yulan Tang,&nbsp;Lu Gan,&nbsp;Yousheng Xiao","doi":"10.1096/fj.202500556R","DOIUrl":"https://doi.org/10.1096/fj.202500556R","url":null,"abstract":"<div>\u0000 \u0000 <p>Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons and the abnormal aggregation of α-synuclein (α-Syn), involving complex regulatory networks where the roles and mechanisms of circular RNAs (circRNAs) remain underexplored. Through RNA sequencing analysis, we identified significant upregulation of circ_0005654 (derived from the PRDM5 gene) in PD patients. Functional studies demonstrated that circ_0005654 overexpression promotes α-Syn accumulation through a dual regulatory mechanism: (1) direct enhancement of its transcriptional/translational activation of α-Syn and (2) indirect suppression of autophagic clearance via miR-588 sequestration-mediated inhibition of the p62-dependent autophagy pathway. Specifically, circ_0005654 functions as a molecular sponge for miR-588, thereby coordinately enhancing α-Syn synthesis while impairing its degradation. This study not only establishes the functional role of circRNAs in PD pathogenesis but also elucidates circ_0005654 as a promising therapeutic candidate for targeted modulation of α-Syn aggregation.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171848","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 Novel Function of NaV Channel β3 Subunit in Endothelial Cell Alignment Through Autophagy Modulation","authors":"Léa Réthoré,&nbsp;Anne-Laure Guihot,&nbsp;Linda Grimaud,&nbsp;Coralyne Proux,&nbsp;Benjamin Barré,&nbsp;François Guillonneau,&nbsp;Catherine Guette,&nbsp;Alice Boissard,&nbsp;Cécile Henry,&nbsp;Jérôme Cayon,&nbsp;Rodolphe Perrot,&nbsp;Daniel Henrion,&nbsp;Christian Legros,&nbsp;Claire Legendre","doi":"10.1096/fj.202401558RR","DOIUrl":"https://doi.org/10.1096/fj.202401558RR","url":null,"abstract":"<p>Endothelial cells (EC) play a pivotal role in vascular homeostasis. By sensing shear stress generated by blood flow, EC endorse vasculoprotection through mechanotransduction signaling pathways. Various ion channels are involved in mechanosignaling, and here, we investigated the endothelial voltage-gated Na⁺ channels (Na_V channels), since their mechanosensitivity has been previously demonstrated in cardiomyocytes. First, we showed that EC from aorta (TeloHAEC) behave as EC from umbilical vein (HUVEC) under laminar shear stress (LSS). For both EC models, cell alignment and elongation occurred with the activation of the KLF2/KLF4 atheroprotective signaling pathways. We found that LSS decreased the expression of <i>SCN5A</i>, encoding Na_V1.5, while LSS increased that of <i>SCN3B</i>, encoding Na_Vβ3. We demonstrated that the KLF4 transcription factor is involved in <i>SCN3B</i> expression under both static and LSS conditions. Interestingly, <i>SCN3B</i> silencing impaired EC alignment induced by LSS. The characterization of Na_Vβ3 interactome by coimmunoprecipitation and proteomic analysis revealed that mTOR, implicated in autophagy, binds to Na_Vβ3. This result was evidenced by the colocalization between Na_Vβ3 and mTOR inside cells. Moreover, we showed that <i>SCN3B</i> silencing led to the decrease in LC3B expression and the number of LC3B positive autophagosomes. Furthermore, we showed that Na_Vβ3 is retained within the cell and colocalized with LAMP1 and LC3B. Finally, we found that resveratrol, a stimulating-autophagy and vasculoprotective molecule, induced KLF4 together with Na_Vβ3 expression. Altogether, our findings highlight a novel role of Na_Vβ3 in endothelial function and cell alignment as an actor in shear stress vasculoprotective intracellular pathway through autophagy modulation.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202401558RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179362","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":"The Gut Microbial Metabolite Butyrate Alleviates IL-1β-Induced Mitochondrial Dysfunction and Oxidative Stress in Pancreatic Islets","authors":"Signe Schultz Pedersen,&nbsp;Richard Denis Maxime De Mets,&nbsp;Joana Mendes Lopes de Melo,&nbsp;Andrea Irazoki,&nbsp;Patrick E. MacDonald,&nbsp;Michala Prause,&nbsp;Nils Billestrup","doi":"10.1096/fj.202403388R","DOIUrl":"https://doi.org/10.1096/fj.202403388R","url":null,"abstract":"<p>Butyrate, a gut microbiota-derived metabolite, supports cellular health. In pancreatic beta cells, inflammation and oxidative stress disrupt mitochondrial function, contributing to dysfunction. This study explores how butyrate influences mitochondrial function and redox balance to protect beta cells from interleukin-1beta (IL-1β)-induced stress. Pancreatic mouse islets were treated with IL-1β and/or butyrate for 10 days to model chronic inflammation in type 2 diabetes, and their effects on mitochondrial health and oxidative stress were studied. Butyrate protected against IL-1β-induced impairment of insulin secretion by enhancing mitochondrial function, as evidenced by an increased glucose-stimulated oxygen consumption rate and a higher mitochondrial membrane potential compared to IL-1β treatment alone. IL-1β increased mitochondrial mass, but the mitochondria appeared smaller and rounded, indicating fragmentation. In contrast, butyrate co-treatment promoted mitochondrial hyperfusion, as evidenced by elongated mitochondria, higher levels of fusion proteins Opa1 and Mfn2, and lower levels of fission protein Fis1 compared to IL-1β alone. Furthermore, butyrate reduced IL-1β-induced reactive oxygen species (ROS) production, antioxidant enzyme gene expression, and protein oxidation, indicating protection against oxidative stress. Butyrate co-treatment further enhanced redox balance by increasing reduced glutathione (GSH) levels and the ratio of GSH to oxidized glutathione (GSSG). These findings suggest that butyrate acts as a potent modulator of mitochondrial function and redox balance, counteracting IL-1β-induced dysfunction and providing a potential therapeutic strategy for improving insulin secretion in inflammatory conditions.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202403388R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171780","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":"Inhibition Molecular Mechanism of α2 Adrenergic Receptor Activation by Antagonist","authors":"Yiming Li,&nbsp;Haizhan Jiao,&nbsp;Hongli Hu,&nbsp;Yuyong Tao,&nbsp;Qiong Guo","doi":"10.1096/fj.202403409R","DOIUrl":"https://doi.org/10.1096/fj.202403409R","url":null,"abstract":"<div>\u0000 \u0000 <p>The α_2A adrenergic receptor (α_2AAR) and α_2B adrenergic receptor (α_2BAR) are G protein-coupled receptors (GPCRs) that mediate important physiological functions in response to the endogenous neurotransmitters norepinephrine and epinephrine. Antagonist drugs targeting α₂ARs have been widely used for many years. However, current structural studies of drug-receptor complexes are insufficient to elucidate their interactions. Here, to uncover the molecular mechanisms of antagonist drug actions, we determine the cryo-electron microscopy (cryo-EM) structures of α_2AAR bound to phentolamine and α_2BAR bound to phenoxybenzamine. Together with the mutagenesis data, these results provide insights into the molecular basis of ligand recognition and antagonism at α_2AAR and α_2BAR. Overall, our studies contribute to a deeper understanding of adrenergic receptor modulation and provide some clues for the development of novel antagonists.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171847","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":"MAP2K2 Knockdown Suppresses Phenotypic Transformation of Vascular Smooth Muscle Cells in Aortic Dissection by Inactivating the JAK/STAT Signaling Pathway","authors":"Yaling Li,&nbsp;Shenghui Bi,&nbsp;Bo Yang,&nbsp;Zengyan Huang,&nbsp;Xiaowu Wang,&nbsp;Jing Feng","doi":"10.1096/fj.202500466R","DOIUrl":"https://doi.org/10.1096/fj.202500466R","url":null,"abstract":"<div>\u0000 \u0000 <p>Aortic dissection (AD) is a severe aortic disease characterized by high morbidity and mortality. However, the primary treatments for AD possess limited efficacy. The role and specific mechanisms of mitogen-activated protein kinase kinase 2 (MAP2K2) in AD are not elucidated. Human aortic vascular smooth muscle cells (HAVSMCs) induced by platelet-derived growth factor-BB (PDGF-BB) and C57BL/6 mice treated with β-aminopropionitrile were used as AD models in vitro and in vivo, respectively. RNA-sequencing analysis was conducted to explore the downstream pathway of MAP2K2. The expression of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), IL-8, malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS) was determined by enzyme-linked immunosorbent assay. The protein levels of MAP2K2, alpha-smooth muscle actin (α-SMA), smooth muscle protein 22-alpha (SM22α), Janus kinase 2 (JAK2), p-JAK2, signal transducer and activator of the transcription 3 (STAT3), and p-STAT3 were detected by western blot. We found that MAP2K2 was abnormally increased in AD. MAP2K2 knockdown repressed the expression levels of TNF-α, IL-1β, IL-8, MDA, ROS, α-SMA, and SM22α, and promoted SOD expression in vitro and in vivo. In addition, the JAK/STAT signaling pathway was identified as the downstream pathway of MAP2K2. MAP2K2 knockdown inhibited the expression of p-JAK2/JAK2 and p-STAT3/STAT3. Activating the JAK/STAT pathway by its activator RO8191 reversed the effect of MAP2K2 knockdown on inflammation, oxidative stress, and abnormal phenotypic transformation in HAVSMCs induced by PDGF-BB. In conclusion, MAP2K2 knockdown could alleviate AD by inhibiting the JAK/STAT signaling pathway to repress inflammation, oxidative stress, and abnormal phenotypic transformation of HAVSMCs.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171893","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":"GDF11 Alleviates Vascular Calcification in VitD3-Overloaded Mice Through Inhibition of Inflammatory NF-κB Signal","authors":"Jiali Huang,&nbsp;Qingchun Liang,&nbsp;Yuanzhi Ye,&nbsp;Zirong Lan,&nbsp;An Chen,&nbsp;Jianyun Yan,&nbsp;Lihe Lu","doi":"10.1096/fj.202500029R","DOIUrl":"https://doi.org/10.1096/fj.202500029R","url":null,"abstract":"<div>\u0000 \u0000 <p>Vascular calcification, an age-associated disorder, is a highly regulated biological process similar to bone formation. Growth differentiation factor 11 (GDF11), a secreted member of the transforming growth factor beta (TGF-β) superfamily, has been shown to act as an anti-aging factor in the brain, heart, skin, and skeletal muscle. Nevertheless, whether GDF11 affects vascular calcification and the underlying mechanisms remain unclear. In the present study, beta-glycerophosphate and calcium chloride-induced calcification of vascular smooth muscle cells (VSMCs) and a VitD₃-overloaded mouse model were used to investigate the role of GDF11 in vascular calcification. Our results revealed that the knockdown of GDF11 by siRNA promoted the calcification of rat VSMCs, whereas GDF11 treatment significantly reduced the calcification of human and rat VSMCs in vitro, as detected by alizarin red staining and calcium content assay. Similarly, GDF11 treatment reduced the expression of bone-related molecules including Runt-related transcription factor 2 (Runx2) and bone morphogenetic protein-2 (BMP2). Furthermore, ex vivo and in vivo studies confirmed the inhibitory effect of GDF11 on vascular calcification. Mechanistically, GDF11 treatment reduced the levels of NF-κB signaling molecules including NLRP3, phosphorylated p65, IL-6, and IL-1β in VSMCs. Additionally, GDF11 siRNA-induced VSMC calcification was repressed by NF-κB inhibitor PDTC treatment. Taken together, these findings suggest that GDF11 alleviates vascular calcification through inhibiting the NF-κB signal. Modulation of GDF11 may represent a therapeutic strategy for vascular calcification.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148595","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":"Long Noncoding RNA NONHSAT233728.1 Promotes ROS Accumulation and Granulosa Cell Apoptosis by Regulating the MAPK/ERK1/2 Signaling Pathway","authors":"Yao Chen,&nbsp;Heqi Dai,&nbsp;Fei Mao,&nbsp;Yangbai Li,&nbsp;Ruizhi Feng,&nbsp;Yun Qian","doi":"10.1096/fj.202500964R","DOIUrl":"https://doi.org/10.1096/fj.202500964R","url":null,"abstract":"<p>Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorders in women of reproductive age. However, the underlying molecular mechanism remains unclear. In this study, we employed RNA sequencing analysis to identify differentially expressed protein-coding genes and long noncoding RNA (lncRNA) expression profiles in granulosa cells from women with and without PCOS. It was established that the level of NONHSAT233728.1 was diminished in women with PCOS. The present study demonstrated the role of NONHSAT233728.1 in granulosa cells from patients with PCOS and further investigated the potential mechanism of NONHSAT233728.1 in the KGN cell line. Additionally, the knockdown of NONHSAT233728.1 has been observed to promote cell apoptosis, inhibit cell proliferation, promote mitochondrial dysfunction, and inflammation. Western blot analyses confirmed that phospho-extracellular regulated protein kinases (ERK)1/2 were decreased following lnc-NONHSAT233728.1 knockdown. Consequently, we propose that ROS accumulation activates the endogenous mitochondrial apoptosis pathway, leading to granulosa cell apoptosis via the MEK/ERK1/2 pathway, which contributes to follicular atresia. We observed a negative correlation between NONHSAT233728.1 and both LH levels and the LH/FSH ratio. These findings indicate that lncRNA NONHSAT233728.1 is linked to the pathogenesis of PCOS and offer new insights into its underlying mechanisms.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500964R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148594","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}