The FASEB Journal最新文献

{"title":"Defective Astrocyte Maturation Drives Cerebellar Neuroinflammation and Degeneration","authors":"Karli Mockenhaupt,&nbsp;Masoumeh Zarei-Kheirabadi,&nbsp;Alexandra K. Gonsiewski,&nbsp;Avani Hariprashad,&nbsp;Lauren Dain,&nbsp;Johannes Verheijen,&nbsp;Sandeep K. Singh,&nbsp;Tomasz Kordula","doi":"10.1096/fj.202501225RR","DOIUrl":"https://doi.org/10.1096/fj.202501225RR","url":null,"abstract":"<p>While persistent neuroinflammation and neurodegeneration are hallmarks of many diseases, the exact mechanisms triggering neurodegeneration are not fully established. Neurodegeneration is accompanied by activation of astrocytes that can have both neuroprotective and neurotoxic functions. Much less is known about how intrinsic dysfunction of astrocytes can lead to neuroinflammation and neurodegeneration. To study astrocyte-driven neurodegeneration, we examined aging cerebella of adult astrocyte-specific Yin Yang1 (<i>Yy1</i>) conditional knockout mice that contain improperly matured dysfunctional astrocytes. We found that deletion of <i>Yy1</i> from astrocytes during development results in subsequent cerebellar neurodegeneration in adult mice. The neurodegeneration was accompanied by profound changes in astrocyte morphologies and expression of astrocyte-specific genes, and development of severe neuroinflammation that preceded cerebellar neurodegeneration and Purkinje cell (PC) loss. Mechanistically, we found that sustained β-catenin expression by Bergmann glia (BG) correlated with their decreased adenomatous polyposis coli (APC) expression and diminished expression of synaptic proteins by glutamatergic neurons, suggesting that <i>Yy1</i> supports astrocytic APC expression needed for β-catenin degradation and proper BG morphology. Our findings highlight the critical role of YY1 in sustaining cerebellar astrocyte functions and suggest that dysfunction of astrocytes has widespread consequences for cerebellar integrity, function, and leads to neurodegeneration.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501225RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598457","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":"Acute Exposure of Veterinary Antibiotic Tilmicosin Leads to Idiopathic Scoliosis-Like Vertebral Malformation Development Through Regulating PI3K-Akt Pathway in Zebrafish","authors":"Xianbin Zeng,&nbsp;Zhongxiao Cong,&nbsp;Meng Xu,&nbsp;Yujie Ju,&nbsp;Yong Huang,&nbsp;Mingkai Zuo,&nbsp;Bo Cheng,&nbsp;Guiyou Tian,&nbsp;Xiaoping Xiao,&nbsp;Danmei Zhao,&nbsp;Wei Yuan,&nbsp;Huiqiang Lu,&nbsp;Yiyue Zhang,&nbsp;Yan Zhao","doi":"10.1096/fj.202403204RR","DOIUrl":"https://doi.org/10.1096/fj.202403204RR","url":null,"abstract":"<div>\u0000 \u0000 <p>The widespread use of veterinary antibiotics in animal husbandry, such as tilmicosin (TIL), poses potential threats to environment pollution and human health. In this study, we conducted acute TIL exposure experiment using zebrafish model to explore the toxicological effects. In the concentration range of 20–80 mg/L, TIL did not affect zebrafish body length development but induced idiopathic scoliosis (IS)-like symptoms accompanied by impaired mobility. IS predominantly occurs in adolescents, while the etiology remains unclear. Further studies showed that the combination of quercetin and luteolin effectively alleviated TIL-induced spinal curvature and motor suppression. To explore the underlying mechanism, we performed network pharmacology analysis and enriched the PI3K-Akt pathway. We validated that the expression of key target genes in the PI3K-Akt pathway were significantly activated after TIL exposure, while quercetin and luteolin treatment effectively inhibited the PI3K-Akt pathway activation. Further experiments revealed that TIL exposure decreased brain neural cell apoptosis, thereby causing an increase in neurocytes, interfering with motor ability, and promoting IS-like vertebral malformations, which were especially noticeable during movement. This study expands our understanding that TIL exposure may be a predisposing factor for IS occurrence and progression, while the combination of quercetin and luteolin combination could protect against IS-like symptom by regulating PI3K-Akt pathway.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598458","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":"Adipose Mesenchymal Stem Cells Derived Exosomes Ameliorates KOA Cartilage Damage and Inflammation by Activation of PINK1-Mediated Mitochondrial Autophagy","authors":"Junfeng Kang,&nbsp;Lishi Jie,&nbsp;Houyu Fu,&nbsp;Lu Zhang,&nbsp;Guozhen Lu,&nbsp;Likai Yu,&nbsp;Di Tian,&nbsp;Taiyang Liao,&nbsp;Songjiang Yin,&nbsp;Runlin Xin,&nbsp;Peimin Wang","doi":"10.1096/fj.202501185R","DOIUrl":"https://doi.org/10.1096/fj.202501185R","url":null,"abstract":"<div>\u0000 \u0000 <p>Knee osteoarthritis (KOA) is characterized by degenerative destruction of knee cartilage. Adipose tissue-derived mesenchymal stem cells (MSCs) have been widely used in the clinic to treat joint diseases, and the exosomes secreted by adipose tissue-derived MSCs (ADSC-Exos) are more stable and easier to store than stem cell therapy alone. The aim of this study was to investigate whether ADSC-Exos could reduce KOA chondrocyte damage and inflammation by activating mitochondrial autophagy. In vitro, we induced a KOA chondrocyte model with lipopolysaccharide (LPS), and after treatment with ADSC-Exos, we assessed chondrocyte damage and inflammation by using HE, Senna O solid green, and Alcian blue staining and IL-1β immunofluorescence analysis. We also labeled chondrocytes and assessed their intracellular levels of reactive oxygen species (ROS) using the DCFH-DA probe, assessed the mitochondrial membrane potential of chondrocytes using a mitochondrial membrane potential detection kit (JC-1). In vivo, we constructed a KOA rat model by anterior cruciate ligament tenotomy (ACLT) surgery, treated the knee joint with a local injection of ADSC-Exos, reconstructed the knee joint in three dimensions using micro-CT, and evaluated the pathological changes in cartilage tissues by using HE, Senna O solid green, and Alcian blue staining. The in vivo and in vitro results showed that ADSC-Exos upregulated the expression of PINK1/Parkin pathway components, promoted mitochondrial autophagy in chondrocytes, increased the mitochondrial membrane potential, protected mitochondrial function in chondrocytes, and ameliorated the degradation of the cartilage matrix and inflammation during KOA.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598644","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":"Multi-Omics Integration Reveals Gut Microbiota-Bile Acid Crosstalk Underlying Baizhu Shaoyao Decoction's Therapeutic Efficacy in Weaning Stress of Piglets","authors":"Yuanyuan Wei,&nbsp;Chao Han,&nbsp;Zhuo Chen,&nbsp;Cuncai Wang,&nbsp;Mingjie Liu,&nbsp;Yimeng Fan,&nbsp;Jianyu Lv,&nbsp;Zhihui Hao","doi":"10.1096/fj.202500525R","DOIUrl":"https://doi.org/10.1096/fj.202500525R","url":null,"abstract":"<div>\u0000 \u0000 <p>Diarrhea is common in infants, particularly children less than 2 years old. Intractable or protracted infancy diarrhea is typically associated with feeding intolerance and malabsorption that is lethal for newborns. The objective of this study is to explore the regulatory effects of baizhu shaoyao decoction (BSD) on the gut microbiota and associated metabolites in weaned piglets, thereby elucidating the mechanism by which BSD mitigates weaning stress in piglets. Piglets were allocated into five groups, with each group receiving designated medication for a continuous 14-day period: control, zaohu powder, as well as low-, medium-, and high-dose BSD groups (<i>n</i> = 6 piglets per group). To identify diarrhea-related biomarkers, microbial communities, functions, and metabolites were compared between the early-weaned piglets (control group) and those treated with 1.28 g/kg BSD (medium-dose BSD group). Our findings revealed significant shifts in microbial composition, function, and metabolic profiles in piglets from the medium-dose BSD group, intricately associated with the host's diarrhea status. Furthermore, carbohydrate metabolism and biosynthesis, lipid and amino acid metabolism, glycan activity, and carbohydrate digestive enzymes exhibited downregulation in piglets of the medium-dose BSD group compared to those in the control group. Transcriptome analysis highlighted the pivotal role of the FoxO1/3 transcription factor in mitigating weaning stress, particularly through the augmentation of CD4⁺/CD8⁺ T cell proportions. Our findings underscored that therapeutic effects of BSD on weaning stress involve intestinal barrier restoration, modulation of brain–gut peptide expression, and a reduction in mast-cell activity in the ileum. BSD has a significant effect on improving early weaning diarrhea in infants. Its mechanism of action involves improving the abundance of key intestinal microbiota <i>Lachnospiraceae_bacterium</i>, <i>a</i>ffecting changes in intestinal bile acid metabolites (such as, chenodeoxyglycocholic acid, glycochenodeoxycholic acid) and thereby regulating intestinal mucosal immunity and gut-brain peptides, achieving the effect of treating weaning stress.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589801","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":"FAM83A Promotes the Progression and Metastasis of Head and Neck Squamous Cell Carcinoma via PKM2-Mediated Aerobic Glycolysis","authors":"Yuyao Zhang,&nbsp;Huan Ji,&nbsp;Xiangyu Liu,&nbsp;Rong Guo,&nbsp;Zhenyuan Zhao,&nbsp;Jing Wang,&nbsp;Min Wu,&nbsp;Yue Jiang,&nbsp;Zhibai Zhao,&nbsp;Yi Zhong,&nbsp;Jinhua Yu","doi":"10.1096/fj.202500989RR","DOIUrl":"https://doi.org/10.1096/fj.202500989RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy that frequently results in mortality due to postoperative recurrence. In our previous study, we identified for the first time that the family with sequence similarity 83, member A (FAM83A), is overexpressed in HNSCC and associated with poor patient prognosis. However, its role in HNSCC metabolism remains unclear. M2-type pyruvate kinase 2 (PKM2) plays a critical role in glucose metabolic reprogramming in cancer cells, but the regulatory network involving PKM2 and its interaction with FAM83A in HNSCC progression remains poorly understood. In this study, we investigate the relationship between FAM83A and PKM2 in HNSCC for the first time. The overexpression of PKM2 correlates with FAM83A upregulation in HNSCC clinical samples. Single-cell RNA sequencing and RNA sequencing analyses demonstrate that FAM83A enhances the glucose metabolism pathway in HNSCC. In vitro, FAM83A promotes glycolytic activity and accelerates lactate production in HNSCC. Inhibition of PKM2 reverses the increased lactate production, migration, invasion, and epithelial-mesenchymal transition (EMT) induced by FAM83A overexpression. Mechanistically, FAM83A promotes the transcriptional activation of PKM2 by activating the Wnt/β-catenin signaling pathway. Furthermore, the integration of FAM83A with casein kinase 1 alpha (CK1α) contributes to the activation of the Wnt/β-catenin signaling pathway. Finally, shikonin, a pharmacological inhibitor of PKM2, protects mice from HNSCC progression and metastasis induced by FAM83A in vivo. Our findings reveal that PKM2-mediated aerobic glycolysis induced by FAM83A promotes the progression and metastasis of HNSCC, presenting a promising therapeutic target for HNSCC patients.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589800","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":"Inside-Out IP3-Mediated G Protein-Coupled Receptor Activation Drives Intercellular Ca2+ Signaling in the Vascular Endothelium","authors":"C. Buckley,&nbsp;X. Zhang,&nbsp;M. D. Lee,&nbsp;C. Wilson,&nbsp;J. G. McCarron","doi":"10.1096/fj.202500370RR","DOIUrl":"https://doi.org/10.1096/fj.202500370RR","url":null,"abstract":"<p>The endothelium's control of nearly all vascular function relies on rapid intercellular communication to coordinate cellular activity across scale. A key form of intercellular communication arises from the regenerative propagation of IP₃-evoked Ca²⁺ signals from cell to cell, which regulate vessel tone, modulate vascular permeability, and determine immune responses. Despite their importance, the mechanisms by which regenerative propagation of IP₃-evoked Ca²⁺ signals occurs are poorly understood. Here, in intact resistance arteries, precision photolysis of IP₃ combined with high-resolution mesoscale imaging, targeted drug application, and advanced analytical techniques was used to determine the mechanisms underlying regenerative propagation of IP₃-evoked Ca²⁺ signals in the endothelium. Elevated IP₃ in the initiating cell triggers a noncanonical inside-out signaling mechanism that leads to transcellular activation of a G_αq/11-coupled receptor in a neighboring (receiving) cell. This, in turn, initiates canonical outside-in signaling via PLC, leading to the hydrolysis of PIP₂ and production of IP₃. This process creates a regenerative, IP₃-dependent signaling cascade operating between adjacent cells. Notably, neither Ca²⁺ nor IP₃ diffusion through gap junctions plays a significant role in intercellular communication. Our findings uncover a previously unrecognized mechanism of endothelial communication, in which noncanonical IP₃-driven transcellular activation of G protein-coupled receptors sustains a regenerative signaling loop, highlighting a novel framework for intercellular coordination in the vascular endothelium.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500370RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589740","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":"Therapeutic Effects of Mesenchymal Stem Cell Secretome Derived From Adipose Tissue, Umbilical Cord, and Bone Marrow Against Extended-Spectrum Beta-Lactamase-Producing and Non-Producing Escherichia coli Strains Isolated From Urinary Tract Infections","authors":"Leen Ali,&nbsp;Elie Salem Sokhn,&nbsp;Charbel Khalil,&nbsp;Fatima A. Saleh","doi":"10.1096/fj.202500758R","DOIUrl":"https://doi.org/10.1096/fj.202500758R","url":null,"abstract":"<div>\u0000 \u0000 <p>Urinary tract infections (UTIs) are among the most common and persistent bacterial infections, affecting around 150 million people worldwide each year. The emergence of multidrug-resistant (MDR) strains, particularly those producing extended-spectrum β-lactamases (ESBLs), has further complicated treatment and posed a serious global public health challenge. Hence, this study aimed to investigate the antibacterial potential of mesenchymal stem cell (MSCs) secretomes derived from adipose tissue (AD-MSCs), bone marrow (BM-MSCs), and umbilical cord (UC-MSCs) against the most common cause of bacterial UTI, <i>Escherichia coli</i> (<i>E. coli</i>). The MSCs secretomes were derived from human adipose tissue, umbilical cord, and bone marrow. The antibacterial activity of the secretomes was then assessed using the Kirby-Bauer disk diffusion method. These tests were conducted on 105 <i>E. coli</i> urine clinical isolates, including ESBL-producing strains. Further molecular analysis was performed to identify the resistant genes. Statistical analyses were then performed to test for statistically significant differences between MSCs sources. Our results showed that the stem cell secretome was effective against 63.8% of non-ESBL and 52.7% of ESBL-producing <i>E. coli</i> isolates, with that derived from AD-MSCs showing the largest inhibition zones. Molecular analysis revealed that all ESBL-producing isolates (100%) harbored the CTX-M gene either on its own or in combination with another gene. These results underscore the potential of MSC-derived secretomes as a promising alternative for treating <i>E. coli</i> infections. Nonetheless, further research is required to explore their potential clinical uses as either complementary or standalone therapies for resistant infections.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589898","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":"Nuclear Receptor ERRγ Protects Against Cardiac Ischemic Injury by Suppressing GBP5-Mediated Myocardial Inflammation","authors":"Junhao Qiu,&nbsp;Qianji Che,&nbsp;Yichao Zhang,&nbsp;Mu Chen,&nbsp;Zhixing Wei,&nbsp;Yangjinming Bai,&nbsp;Tingting Zhao,&nbsp;Ji Yan,&nbsp;Zhengyang Wu,&nbsp;Zhentao Fei,&nbsp;Yuepeng Wang,&nbsp;Qian Wang,&nbsp;Yi-Gang Li","doi":"10.1096/fj.202500763R","DOIUrl":"https://doi.org/10.1096/fj.202500763R","url":null,"abstract":"<p>Myocardial inflammation plays a critical role in the progression of injury following myocardial infarction (MI), yet the transcriptional mechanisms regulating cardiomyocyte inflammation to mitigate post-ischemic injury remain poorly understood. This study elucidated the role of Estrogen-Related Receptor Gamma (ERRγ) in modulating the inflammatory response post-MI, demonstrating that ERRγ expression was downregulated in ischemic tissue and hypoxic neonatal mouse ventricular myocytes (NMVMs). Cardiomyocyte-specific overexpression of ERRγ reduced infarct size, improved cardiac function, and suppressed excessive myocardial inflammation and pyroptosis by binding to the GBP5 promoter, thereby inhibiting GBP5 transcription and reducing NLRP3 inflammasome assembly. The protective effects of ERRγ overexpression were reversed by overexpressing GBP5, and the ERRγ agonist DY131 also improved cardiac function after MI. These findings suggest that ERRγ activation reduces myocardial ischemic injury by regulating cardiomyocyte inflammation and pyroptosis, highlighting ERRγ as a potential novel therapeutic target for attenuating post-MI injury.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500763R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589794","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":"Identification of New Key Players for Ferrous Iron Export in the Asymmetric Inner Gate of Human Ferroportin 1","authors":"Marlène Le Tertre,&nbsp;Ahmad Elbahnsi,&nbsp;Cécile Ged,&nbsp;Kevin Uguen,&nbsp;Isabelle Gourlaouen,&nbsp;Claude Férec,&nbsp;Chandran Ka,&nbsp;Gérald Le Gac,&nbsp;Isabelle Callebaut","doi":"10.1096/fj.202500790RR","DOIUrl":"https://doi.org/10.1096/fj.202500790RR","url":null,"abstract":"<p>The Major Facilitator Superfamily (MFS) is the largest known family of secondary transporters. These proteins share a common architecture comprising two lobes, each including 6 transmembrane (TM) helices, related by twofold pseudosymmetry. They transport a wide range of substrates through large conformational changes relying on the opening and closing of gates located on either side of biological membranes. Human ferroportin 1 (HsFPN1), the sole characterized mammalian iron exporter, follows this pattern. It is, however, characterized by an unusual intracellular gate, formed by two asymmetric networks of non-covalent bonds linking the two lobes. We studied the behavior of these networks in all-atom molecular dynamics simulations and functionally assessed the effect of alanine substitutions on HsFPN1 plasma membrane expression and iron export activity. We identified two new critical residues, Arg156 and Tyr318, connecting the networks to each other and to one of two metal-coordinating sites, located in an unwound region of TM7. We extended the analysis to a previously unreported missense variation, p.Gln478Arg, which was found to have a very strong impact on one of the two inter-lobe connection networks, and to result in a significant HsFPN1 loss-of-function. This led us to present the p.Gln478Arg substitution as a new pathogenic variation causing ferroportin disease. Together, our results provide new insights into the structure and dynamics of the human FPN1 inner gate and its asymmetry, shedding light on its potential role in the mechanism of iron export while offering a framework to better understand previously unexplained clinical observations.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500790RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598666","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":"Lycium barbarum Polysaccharide Ameliorates Hindlimb Unloading-Induced Bone Loss by Targeting Noggin","authors":"Chuanxin Sun,&nbsp;Yuke He,&nbsp;Xia Chen,&nbsp;Kan Ding,&nbsp;Chang Chen","doi":"10.1096/fj.202403082R","DOIUrl":"https://doi.org/10.1096/fj.202403082R","url":null,"abstract":"<div>\u0000 \u0000 <p>Disuse bone loss is a common metabolic bone disease with limited effective, safe treatments. <i>Lycium barbarum</i> (<i>L. barbarum</i>), a traditional Chinese medicine and popular health food, has been historically noted in Ben Cao Gang Mu (Compendium of Materia Medica) for its bone-strengthening properties. However, the effects of <i>L. barbarum</i> on disuse bone loss and the underlying mechanisms remain unclear. This study used a hindlimb-unloading mouse model and a simulated microgravity model of MC3T3-E1 cells in a rotary cell culture system to investigate the role of <i>L. barbarum</i> water extract (LBE) and polysaccharide (LBP). LBE and LBP significantly enhanced bone mass and strength in hindlimb-unloaded mice. Further analysis identified a polysaccharide component, LBPP, as the active ingredient mediating these effects. LBPP enhanced osteoblast differentiation and ossification under normal conditions and promoted osteoblast activity under simulated microgravity. Mechanistic studies revealed that LBPP directly binds to noggin, a potent inhibitor of BMPs, facilitating phosphorylation of downstream Smads to stimulate bone formation. These findings demonstrate the potential of <i>L. barbarum</i> as a functional food for preventing disuse bone loss and provide a theoretical basis for its therapeutic applications.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589899","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}