Cellular and Molecular Life Sciences最新文献

{"title":"sTLR9 on maternal Circulating immune cells as a negative regulatory phenotype during pregnancy.","authors":"Hong Wang, Wenting Lu, Mengru Zhu, Yongli Yu, Liying Wang","doi":"10.1007/s00018-025-05858-8","DOIUrl":"https://doi.org/10.1007/s00018-025-05858-8","url":null,"abstract":"<p><p>TLR9 is an intracellular receptor that can also be localized to the cell surface, called sTLR9. sTLR9 is thought to have a negative immunomodulatory effect, which is conductive to the maintenance of immune tolerance. Since pregnancy is a physiological process accompanied with inflammation experienced by pregnant women while maintaining immune tolerance to the fetus, the change in sTLR9 of immune cells during pregnancy are worth studying. In this study, we first found that with the progress of pregnancy, the most significant change in PWBCs of pregnant women was the increasing percentage of neutrophils (Neu%) accompanied by the decreasing sTLR9⁺ Neu%. Then, we found that percentages and sTLR9 levels of sTLR9⁺ Neu were significantly higher in pregnant mice than those in non-pregnant mice, while the latter was obviously elevated in the first and second trimesters than that in third trimester and after delivery. In mice, the TLR9 agonist CpG ODN induced a proinflammatory environment characterized by a significant increase in Neu% and a decrease or no change in sTLR9⁺ Neu%. In this case, the delivery time of pregnant mice was not affected, but their newborn mice showed significant weight loss. These results link sTLR9 as an immune cell phenotype to immune tolerance status during pregnancy, providing a kind of new insights into the mechanisms by which pregnant mother maintain immune tolerance to the fetus.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"324"},"PeriodicalIF":6.2,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12397482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944806","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":"Regulation of antiviral and antimicrobial innate immunity and immune evasion.","authors":"Ling Wang, Dandan He, Naoko Satoh-Takayama, Chunfu Zheng, Junji Xing","doi":"10.1007/s00018-025-05864-w","DOIUrl":"10.1007/s00018-025-05864-w","url":null,"abstract":"<p><p>The interplay between host innate immunity and pathogen evasion is a dynamic battle shaping infection outcomes. The Topical Collection \"Regulation of Antiviral and Antimicrobial Innate Immunity and Immune Evasion\" synthesizes findings from thirteen recent studies to elucidate the molecular mechanisms of innate immune signaling and pathogen countermeasures. Host pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and DNA sensor cyclic GMP-AMP synthase (cGAS), drive type I interferon (IFN-I) and interferon-stimulated genes (ISGs) responses, alongside processes like autophagy and inflammasome activation, to combat viral and bacterial infections. Pathogens, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cytomegalovirus, and porcine reproductive and respiratory syndrome virus, deploy sophisticated strategies to target immune sensors and adaptors, enabling replication and persistence. Novel insights, including the roles of ISG15, autophagy protein ATG7, and host factors such as THAP11 and PSMB4, highlight complex interactions influencing viral replication and host defense. These studies propose targeted therapeutic strategies, such as inflammasome modulation for human immunodeficiency viruses (HIV), and prostaglandin E2 regulation for foot-and-mouth disease virus vaccine production, offering promising avenues to enhance host immunity and counter pathogen evasion.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"326"},"PeriodicalIF":6.2,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12397027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944865","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":"Loss of synaptic Munc13-1 underlies neurotransmission abnormalities in spinal muscular atrophy.","authors":"Mehri Moradi, Chunchu Deng, Michael Sendtner","doi":"10.1007/s00018-025-05859-7","DOIUrl":"https://doi.org/10.1007/s00018-025-05859-7","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is a devastating neurodegenerative disease characterized by degeneration of spinal motoneurons, leading to muscle atrophy and synaptic loss. SMN functions in mRNA splicing, transport, and local translation are crucial for maintaining synaptic integrity. Within the presynaptic membrane, the active zone orchestrates the docking and priming of synaptic vesicles. The Munc13 family proteins are key active zone components that operate precise neurotransmitter release in conjunction with voltage-gated Ca²⁺ channels (VGCCs). However, the role of Munc13s in synaptic dysfunction in SMA remains elusive. Our findings reveal that Munc13-1 loss, but not Munc13-2, is closely linked to synaptic aberrations in SMA. Specifically, Munc13-1 mRNA localization in axons is dependent on Smn, and its disruption leads to impaired AZ assembly and VGCC clustering in motoneurons, ultimately reducing neuronal activity. In contrast, Munc13-2 does not appear to be essential for AZ assembly or motoneuron differentiation, as its functions can be compensated by Munc13-1. These findings highlight the pivotal role of Munc13-1 in synapse integrity and point to potential therapeutic targets for mitigating synaptic loss in SMA.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"325"},"PeriodicalIF":6.2,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12397458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944799","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":"Wnt signaling - using the bloodstream to send a message.","authors":"Michal Caspi, Yan Lender, Rina Rosin-Arbesfeld","doi":"10.1007/s00018-025-05863-x","DOIUrl":"https://doi.org/10.1007/s00018-025-05863-x","url":null,"abstract":"<p><p>Wnt signaling is one of the cell's most complex and important signal transduction pathways. This pathway, which is divided into additional sub-pathways, regulates cell growth, motility, polarity, and differentiation during embryonic development as well as stem cell regeneration. In addition, the Wnt cascades are involved in maintaining different aspects of adult homeostasis. The Wnt ligands, which normally initiate this cascade, are secreted glycoproteins that bind specific receptors and co-receptors to execute their intracellular signaling activity. The Wnt pathways have been extensively studied in anchored cells and in tissues. However, recent evidence now shows that the Wnt cascades are functional in the circulation and that these important signals can affect different circulating blood cells by traveling through the bloodstream. Wnt signaling can function in both paracrine and autocrine manner; however, in the current review, we will discuss the exocrine properties of the pathway and address the following topics: the source of Wnt ligands and their ability to travel in the bloodstream; which cell populations express Wnt signaling components; and finally, what are the physiological roles of the Wnt cascade in the different circulating blood cells.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"322"},"PeriodicalIF":6.2,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12397474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944812","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":"Deep learning in chromatin organization: from super-resolution microscopy to clinical applications.","authors":"Mikhail Rotkevich, Carlotta Viana, Maria Victoria Neguembor, Maria Pia Cosma","doi":"10.1007/s00018-025-05837-z","DOIUrl":"https://doi.org/10.1007/s00018-025-05837-z","url":null,"abstract":"<p><p>The 3D organization of the genome plays a critical role in regulating gene expression, maintaining cellular identity, and mediating responses to environmental cues. Advances in super-resolution microscopy and genomic technologies have enabled unprecedented insights into chromatin architecture at nanoscale resolution. However, the complexity and volume of data generated by these techniques necessitate innovative computational strategies for effective analysis and interpretation. In this review, we explore the transformative role of deep learning in the analysis of 3D genome organization, highlighting how deep learning models are being leveraged to enhance image reconstruction, segmentation, and dynamic tracking in chromatin research. We provide an overview of deep learning-enhanced methodologies that significantly improve spatial and temporal resolution of images, with a special focus on single-molecule localization microscopy. Furthermore, we discuss deep learning's contribution to segmentation accuracy, and its application in single-particle tracking for dissecting chromatin dynamics at the single-cell level. These advances are complemented by frameworks that enable multimodal integration and interpretability, pushing the boundaries of chromatin biology into clinical diagnostics and personalized medicine. Finally, we discuss emerging clinical applications where deep learning models, based on chromatin imaging, aid in disease stratification, drug response prediction, and early cancer detection. We also address the challenges of data sparsity, model interpretability and propose future directions to decode genome function with higher precision and impact.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"323"},"PeriodicalIF":6.2,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12397471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944848","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":"APEX1-STAT3 signaling mediates the force-coordinated endothelial regeneration.","authors":"Yueqi Liu, Chuanrong Zhao, Zhenhui Liang, Yiwei Xu, Jiayu Liu, Weijuan Yao, Jing Zhou","doi":"10.1007/s00018-025-05850-2","DOIUrl":"https://doi.org/10.1007/s00018-025-05850-2","url":null,"abstract":"<p><p>Endothelial regeneration is critical for maintaining vascular homeostasis and inhibiting neointimal formation during vascular repair following injury. While extracellular matrix (ECM) stiffness of the vascular wall is known to influence vascular endothelial cell (EC) behavior, its role in post-injury endothelial regeneration remains poorly understood. Here, we demonstrate a dynamic change in vascular wall stiffness post-injury, with an initial transient decrease within 5 days, followed by a subsequent increase. Our findings reveal that ECM stiffness enhances the interaction between Apurinic/apyrimidinic endonuclease 1 (APEX1) and the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3). Their interaction promotes ROCK2-dependent phosphorylation of STAT3, facilitating its nuclear translocation and activation. Activated STAT3 drives EC proliferation, migration, and re-establishment of endothelial junctions. Additionally, we identify that STAT3 forms cytoplasmic condensates that impede its activation. ECM stiffening or APEX1 overexpression suppresses these condensates, enabling STAT3 activation. This study elucidates a novel mechanotransduction mechanism by which ECM stiffness regulates EC function through the APEX1-STAT3 signaling axis, offering insights into the coordination of endothelial regeneration during vascular repair.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"321"},"PeriodicalIF":6.2,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12397025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944845","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":"Immunoregulatory properties of cell free DNA.","authors":"Francesca Ferrera, Tiziana Altosole, Samuele Tardito, Giuseppina Astone, Cinzia Bernardi, Alessia Parodi, Chiara Marini, Giuseppina Conteduca, Elena Cichero, Annalisa Salis, Leonardo Arpesella, Laura Camporesi, Andrea Lagazio, Valentina Rigo, Andrea Pigozzo, Gianluca Damonte, Paola Fossa, Daniela Fenoglio, Raffaele De Palma, Giorgio Inghirami, Gilberto Filaci","doi":"10.1007/s00018-025-05862-y","DOIUrl":"10.1007/s00018-025-05862-y","url":null,"abstract":"<p><p>Cell free DNA (cfDNA) is detectable at low concentrations in the plasma of healthy subjects and at high concentrations in disorders characterized by a high rate of necrotic events, such as tumors and vasculitis, leading to the release of necrotic DNA into the surrounding tissue and the bloodstream. Although cfDNA may act as a danger signal by binding to DNA sensors, triggering inflammation and immune responses, elevated cfDNA concentrations instead may exert immunoregulatory activities. Here, we show that exogenously administered cfDNA mediates immunoregulatory functions in vivo, in particular, it protects lupus-prone mice from disease progression and favors tumor growth in tumor-challenged mice. Our data suggest that cfDNA mediates immune regulatory activities by directly interacting with MHC class II molecules on antigen-presenting cells and through recruitment of regulatory T cells. This study unveils unprecedented biologic functions of cfDNA with significant pathogenic relevance and remarkable implications for the treatment of cancer patients.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"320"},"PeriodicalIF":6.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944839","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":"Correction: Lactic acid promotes nucleus pulposus cell senescence and corresponding intervertebral disc degeneration via interacting with Akt.","authors":"Yuyao Zhang, Libangxi Liu, Yuhan Qi, Jinhui Lou, Yuxuan Chen, Chao Liu, Haiyin Li, Xian Chang, Zhilei Hu, Yueyang Li, Yang Zhang, Chencheng Feng, Yue Zhou, Yu Zhai, Changqing Li","doi":"10.1007/s00018-025-05824-4","DOIUrl":"https://doi.org/10.1007/s00018-025-05824-4","url":null,"abstract":"","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"319"},"PeriodicalIF":6.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944861","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":"RCN1 downregulation-driven endoplasmic reticulum stress impairs endothelial function and diabetic foot ulcer healing.","authors":"Zhiyan Weng, Xiaoyan Ren, Wanxin Lin, Lifeng Zheng, Renfu Weng, Liangxiao Xie, Fengying Zhao, Sunjie Yan, Ximei Shen","doi":"10.1007/s00018-025-05814-6","DOIUrl":"10.1007/s00018-025-05814-6","url":null,"abstract":"<p><p>Diabetic foot ulcers (DFUs) are a leading cause of disability and mortality, with endothelial dysfunction playing a key role in the development of non-healing ulcers. A primary driver of endothelial cell impairment in this context is endoplasmic reticulum (ER) stress, triggered by glycolipotoxicity, though the underlying mechanisms are not fully understood. In this study, we observed that diabetic mice displayed poor ulcer healing associated with reduced angiogenesis and downregulated Reticulocalbin 1 (RCN1) expression. Proteomic analysis in human umbilical vein endothelial cells (HUVECs) identified a strong link between RCN1 and the damaging effects of glycolipotoxicity on endothelial cell function, leading to impaired tubule formation, reduced migratory capacity, and increased apoptosis in endothelial cells. Mechanistic RNA sequencing analysis highlighted a significant role for RCN1 in regulating ER function. RCN1 overexpression alleviated ER stress by reducing Protein kinase R-like endoplasmic reticulum kinase (PERK) phosphorylation and C/EBP homologous protein (CHOP) expression, both induced by glycolipotoxicity or Thapsigargin (TG), while RCN1 silencing intensified these effects. Additionally, TRIM11-mediated ubiquitination, influenced by glycolipotoxicity, regulated RCN1 stability, specifically promoting angiogenesis through RCN1 modulation. RCN1 overexpression accelerated ulcer healing in diabetic mice by suppressing ER stress proteins and enhancing angiogenesis, whereas RCN1 inhibition further delayed ulcer healing. In human DFU samples, proteomic analysis revealed that low RCN1 levels were linked to disrupted ER functional proteins, with RCN1 serum levels decreasing as diabetes progressed to DFU. Following surgical debridement treatment, RCN1 levels increased in patients with improved DFU healing outcomes. These findings suggest that ER stress, initiated by RCN1 inhibition in response to glycolipotoxicity, leads to endothelial dysfunction and apoptosis, ultimately contributing to the non-healing of DFUs.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"318"},"PeriodicalIF":6.2,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12378791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944843","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":"Microtubules and mechanosensing: key players in endothelial responses to mechanical stimuli.","authors":"Danahe Mohammed, Ibrahim Hamid, Benoit Vanhollebeke, Maud Martin","doi":"10.1007/s00018-025-05828-0","DOIUrl":"https://doi.org/10.1007/s00018-025-05828-0","url":null,"abstract":"<p><p>The vascular mechanical microenvironment is characterized by dynamic forces such as blood flow, stretch, and matrix stiffness, which profoundly influence endothelial cell (EC) behavior. ECs detect these forces through specialized mechanosensing structures and activate mechanotransduction pathways to adapt their responses and maintain vascular homeostasis. While actin filaments and focal adhesions are well-established mediators of these processes, emerging evidence highlights microtubules as critical players in endothelial mechanotransduction. Composed of α- and β-tubulin, microtubules are stiff elements forming a dynamic and adjustable network that regulates cell polarity, migration, and signaling. Their characteristics make them interesting candidates as essential regulators in force sensing, modulating cellular stiffness and adaptation to mechanical constraints. In this Review, we discuss the role of microtubules in endothelial mechanosensing, emphasizing their contribution to force perception and cellular adaptation. Specifically, we describe their involvement in shear stress sensing, curvature and matrix stiffness detection, pressure response, and topographical sensing. Furthermore, we highlight how microtubules are dynamically modified upon mechanical cues and explore the role of post-translational modifications, particularly acetylation, in regulating their mechanical properties. These insights provide a new perspective on endothelial responses to mechanical stimuli, offering potential therapeutic avenues in the context of pathological angiogenesis, where microtubule regulation may play a crucial role.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"317"},"PeriodicalIF":6.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12370616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944739","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}