Signal Transduction and Targeted Therapy最新文献

{"title":"A comprehensive proteomic analysis of umbilical cord blood supports COVID-19 vaccination before pregnancy","authors":"Jianbin Guo, Xiaoyue Tang, Roujie Huang, Jiangfeng Liu, Lan Zhu","doi":"10.1038/s41392-024-02024-7","DOIUrl":"https://doi.org/10.1038/s41392-024-02024-7","url":null,"abstract":"<p><b>Dear Editor,</b></p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"15 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Next-generation mpox vaccines: efficacy of mRNA-1769 compared to modified vaccinia virus Ankara in non-human primates","authors":"Leonie Mayer, Leonie M. Weskamm, Marylyn M. Addo","doi":"10.1038/s41392-024-02058-x","DOIUrl":"https://doi.org/10.1038/s41392-024-02058-x","url":null,"abstract":"<p>In a recent study published in <i>Cell</i>, Mucker et al. demonstrated in a non-human primate (NHP) model of lethal mpox virus (MPXV) infection, that a novel mRNA-based vaccine, as compared to the standard-of-care modified vaccinia virus Ankara (MVA) vaccine, provides similar protective efficacy against lethality but superior efficacy against disease.¹ In the mRNA-vaccinated group, a reduction in the number of lesions and viremia was associated with both neutralizing and Fc-mediated antibody functionality.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"3 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal delivery of a subunit protein vaccine provides protective immunity against JN.1 and XBB-lineage variants","authors":"Hong Lei, Weiqi Hong, Jingyun Yang, Cai He, Yanan Zhou, Yu Zhang, Aqu Alu, Jie Shi, Jian Liu, Furong qin, Danyi Ao, Xiya Huang, Zimin Chen, Hao Yang, Yun Yang, Wenhai Yu, Cong Tang, Junbin Wang, Bai Li, Qing Huang, Hongbo Hu, Wei Cheng, Haohao Dong, Jian Lei, Lu Chen, Xikun Zhou, Jiong Li, Li Yang, Zhenling Wang, Wei Wang, Guobo Shen, Jinliang Yang, Zhiwei Zhao, Xiangrong Song, Guangwen Lu, Qiangming Sun, Youchun Wang, Shuaiyao Lu, Xiawei Wei","doi":"10.1038/s41392-024-02025-6","DOIUrl":"https://doi.org/10.1038/s41392-024-02025-6","url":null,"abstract":"<p>The mucosal immune response plays a crucial role in the prevention of respiratory viruses. Given the risk of recurrent SARS-CoV-2 infections in the population, the rapid development of next-generation intranasal COVID-19 vaccines with high safety and efficacy is paramount. In the current study, we developed a protein-based intranasal vaccine comprising the XBB.1.5 receptor binding domain (RBD)-derived trimeric recombinant protein (RBD_XBB.1.5-HR) and an MF59-like oil-in-water adjuvant. Intranasal administration of RBD_XBB.1.5-HR vaccine elicited robust and sustained humoral immune responses in mice and rats, resulting in high levels of neutralizing antibodies against XBB-lineage subvariants, with protection lasting for at least six months. The intranasal RBD_XBB.1.5-HR vaccine generated potent mucosal immune responses, characterized by the inductions of tissue-resident T (T_RM) cells, local cellular immunity, germinal center, and memory B cell responses in the respiratory tract. The combination of intramuscular and intranasal delivery of the RBD_XBB.1.5-HR vaccine demonstrated exceptional systemic and mucosal protective immunity. Furthermore, intranasal delivery of RBD_XBB.1.5-HR vaccine as a heterologous booster shot showed more effective boosting effects after mRNA administration compared to homologous vaccination, as evidenced by the induction of superior systemic and extra mucosal immune response. Importantly, the intranasal RBD_XBB.1.5-HR vaccine conferred efficient protection against the challenge with authentic EG.5.1 viruses in vivo. These findings identify the intranasal RBD_XBB.1.5-HR vaccine as a potential mucosal vaccine candidate for the prevention of SARS-CoV-2 infection.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"80 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Renal remodeling by CXCL10-CXCR3 axis-recruited mesenchymal stem cells and subsequent IL4I1 secretion in lupus nephritis","authors":"Qixiang Zhang, Yunlong Shan, Luping Shen, Qi Ni, Dandan Wang, Xin Wen, Huanke Xu, Xiaoyan Liu, Zhu Zeng, Jingwen Yang, Yukai Wang, Jiali Liu, Yueyan Su, Ning Wei, Jing Wang, Lingyun Sun, Guangji Wang, Fang Zhou","doi":"10.1038/s41392-024-02018-5","DOIUrl":"https://doi.org/10.1038/s41392-024-02018-5","url":null,"abstract":"<p>Human umbilical cord mesenchymal stem cells (hUC-MSCs) have shown potential as a therapeutic option for lupus nephritis (LN), particularly in patients refractory to conventional treatments. Despite extensive translational research on MSCs, the precise mechanisms by which MSCs migrate to the kidney and restore renal function remain incompletely understood. Here, we aim to clarify the spatiotemporal characteristics of hUC-MSC migration into LN kidneys and their interactions with host cells in microenvironment. This study elucidates that the migration of hUC-MSCs to the LN kidney is driven by elevated levels of CXCL10, predominantly produced by glomerular vascular endothelial cells through the IFN-γ/IRF1-KPNA4 pathway. Interestingly, the blockade of CXCL10-CXCR3 axis impedes the migration of hUC-MSCs to LN kidney and negatively impacts therapeutic outcomes. Single cell-RNA sequencing analysis underscores the importance of this axis in mediating the regulatory effects of hUC-MSCs on the renal immune environment. Furthermore, hUC-MSCs have been observed to induce and secrete interleukin 4 inducible gene 1 (IL4I1) in response to the microenvironment of LN kidney, thereby suppressing Th1 cells. Genetically ablating IL4I1 in hUC-MSCs abolishes their therapeutic effects and prevents the inhibition of CXCR3⁺ Th1 cell infiltration into LN kidneys. This study provides valuable insights into the significant involvement of CXCL10-CXCR3 axis in hUC-MSC migration to the LN kidneys and the subsequent remodeling of renal immune microenvironment. Regulating the CXCL10-CXCR3 axis and IL4I1 secretion may be developed as a novel therapeutic strategy to improve treatment outcomes of LN.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"248 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Membraneless organelles in health and disease: exploring the molecular basis, physiological roles and pathological implications.","authors":"Yangxin Li, Yuzhe Liu, Xi-Yong Yu, Yan Xu, Xiangbin Pan, Yi Sun, Yanli Wang, Yao-Hua Song, Zhenya Shen","doi":"10.1038/s41392-024-02013-w","DOIUrl":"10.1038/s41392-024-02013-w","url":null,"abstract":"<p><p>Once considered unconventional cellular structures, membraneless organelles (MLOs), cellular substructures involved in biological processes or pathways under physiological conditions, have emerged as central players in cellular dynamics and function. MLOs can be formed through liquid-liquid phase separation (LLPS), resulting in the creation of condensates. From neurodegenerative disorders, cardiovascular diseases, aging, and metabolism to cancer, the influence of MLOs on human health and disease extends widely. This review discusses the underlying mechanisms of LLPS, the biophysical properties that drive MLO formation, and their implications for cellular function. We highlight recent advances in understanding how the physicochemical environment, molecular interactions, and post-translational modifications regulate LLPS and MLO dynamics. This review offers an overview of the discovery and current understanding of MLOs and biomolecular condensate in physiological conditions and diseases. This article aims to deliver the latest insights on MLOs and LLPS by analyzing current research, highlighting their critical role in cellular organization. The discussion also covers the role of membrane-associated condensates in cell signaling, including those involving T-cell receptors, stress granules linked to lysosomes, and biomolecular condensates within the Golgi apparatus. Additionally, the potential of targeting LLPS in clinical settings is explored, highlighting promising avenues for future research and therapeutic interventions.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"9 1","pages":"305"},"PeriodicalIF":40.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11570651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying genetic targets in clinical subtypes of Parkinson's disease for optimizing pharmacological treatment strategies.","authors":"Dewen Kong, Cao Li, LingYan Ma, Lida Du, Nan Jiang, Xiaoyue Zhao, Sen Zhang, Zhigang Zhao, Lianhua Fang, Guanhua Du","doi":"10.1038/s41392-024-02020-x","DOIUrl":"10.1038/s41392-024-02020-x","url":null,"abstract":"<p><p>The heterogeneity of Parkinson's disease (PD) has been recognized in clinical, with patients categorized into distinct subsets based on motor phenotype, such as tremor-dominant PD (TD), postural instability and gait difficulty-dominant PD (PIGD) and mixed PD (Mix). Despite this categorization, the underlying mechanisms of this heterogeneity remain poorly understood, and there is no personalized effective treatment for each PD subtype. To address this, a rat model for PD subtypes was established by unilateral stereotaxic injection of 6-OHDA, followed by cluster analysis of behavioral data. The serum neurofilament light chain (NfL) and uric acid (UA) levels as well as alterations in brain autonomic activity in rats were consistent with clinical patients, and metabolomics results showed that more than 70% of the metabolites in the serum of different subtypes of PD rats and clinical patients appeared to be consistently altered. Further transcriptomic analysis by RNA-seq has elucidated that the development of PD subtypes is associated with altered gene expression in neurotransmitter, neuronal damage in the central or peripheral nervous system, and lipid metabolism. In addition, based on the subtype-specific differentially expressed genes, 25 potential drug candidates were identified. Notably, the Alox15 inhibitor baicalein showed a greater efficacy on Mix rats, highlighting the possibility of selecting targeted treatments for well-defined individuals.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"9 1","pages":"320"},"PeriodicalIF":40.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11570617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond the classic GPCR: unraveling the role of GPR155 role in cholesterol sensing and signaling","authors":"Torsten Schöneberg","doi":"10.1038/s41392-024-02059-w","DOIUrl":"https://doi.org/10.1038/s41392-024-02059-w","url":null,"abstract":"<p>In a recent cryo-EM study published in <i>Nature</i>, Bayly-Jones and co-workers have provided detailed molecular insights into the dimerization and cholesterol binding of the orphan G protein-coupled receptor GPR155, its potential involvement in gut microbiota-derived tryptophan metabolite interactions, and intracellular signaling pathways.¹ GPR155, a lysosomal protein with a unique 17-transmembrane helix domain structure, integrates auxin transporter and G protein-coupled receptor-like features, playing a key role in lysosomal cholesterol sensing and mTORC1 signaling.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"99 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EphrinB2-mediated CDK5/ISL1 pathway enhances cardiac lymphangiogenesis and alleviates ischemic injury by resolving post-MI inflammation","authors":"Yingnan Bai, Liming Chen, Fanghao Guo, Jinghong Zhang, Jinlin Hu, Xuefei Tao, Qing Lu, Wenyi Li, Xueying Chen, Ting Gong, Nan Qiu, Yawei Jin, Lifan Yang, Yu Lei, Chengchao Ruan, Qing Jing, John P. Cooke, Shijun Wang, Yunzeng Zou, Junbo Ge","doi":"10.1038/s41392-024-02019-4","DOIUrl":"https://doi.org/10.1038/s41392-024-02019-4","url":null,"abstract":"<p>EphrinB2 (erythropoietin-producing hepatoma interactor B2) is a key Eph/ephrin family member, promoting angiogenesis, vasculogenesis, and lymphangiogenesis during embryonic development. However, the role of EphrinB2 in cardiac lymphangiogenesis following myocardial infarction (MI) and the potential molecular mechanism remains to be demonstrated. This study revealed that EphrinB2 prevented ischemic heart post-MI from remodeling and dysfunction by activating the cardiac lymphangiogenesis signaling pathway. Deletion of EphrinB2 impaired cardiac lymphangiogenesis and aggravated adverse cardiac remodeling and ventricular dysfunction post-MI. At the same time, overexpression of EphrinB2 stimulated cardiac lymphangiogenesis which facilitated cardiac infiltrating macrophage drainage and reduced inflammation in the ischemic heart. The beneficial effects of EphrinB2 on improving clearance of inflammatory response and cardiac function were abolished in <i>Lyve1</i> knockout mice. Mechanistically, EphrinB2 accelerated cell cycling and lymphatic endothelial cell proliferation and migration by activating CDK5 and CDK5-dependent ISL1 nuclear translocation. EphrinB2 enhanced the transcriptional activity of ISL1 at the VEGFR3 <i>(FLT4</i>) promoter, and VEGFR3 inhibitor MAZ51 significantly diminished the EphrinB2-mediated lymphangiogenesis and deteriorated the ischemic cardiac function. We uncovered a novel mechanism of EphrinB2-driven cardiac lymphangiogenesis in improving myocardial remodeling and function after MI.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"76 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2D4, a humanized monoclonal antibody targeting CD132, is a promising treatment for systemic lupus erythematosus","authors":"Huiqi Yin, Liming Li, Xiwei Feng, Zijun Wang, Meiling Zheng, Junpeng Zhao, Xinyu Fan, Wei Wu, Lingyu Gao, Yijing Zhan, Ming Zhao, Qianjin Lu","doi":"10.1038/s41392-024-02017-6","DOIUrl":"https://doi.org/10.1038/s41392-024-02017-6","url":null,"abstract":"<p>Current therapies for systemic lupus erythematosus that target a particular factor or cell type exhibit limited effectiveness. To address this limitation, our focus was on CD132, a subunit common to six inflammatory factor receptors implicated in SLE. Our study revealed heightened CD132 expression in SLE patients’ lymphocytes, contributing to the production of pro-inflammatory cytokines and immunoglobulins. We developed a novel humanized anti-CD132 monoclonal antibody, named as 2D4. 2D4 efficiently blocked IL-21 and IL-15, with limited effectiveness against IL-2, thereby suppressing T and B cells without disrupting immune tolerance. In the mouse immunization model, 2D4 virtually inhibited T cell-dependent, antigen-specific B-cell response. In lupus murine models, 2D4 mitigated inflammation by suppressing multiple pro-inflammatory cytokines and anti-dsDNA antibody titers, also diminishing proteinuria and glomerulonephritis. Compared to Belimumab, 2D4 exhibited superior efficacy in ameliorating the inflammatory state and preserving renal function. Moreover, 2D4 exhibited the ability to inhibit the production of pro-inflammatory factors and autoantibodies in PBMCs from individuals with SLE, highlighting its therapeutic potential for SLE individuals. Potent, 2D4 has the potential to significantly improve clinical outcomes in SLE and other complex autoimmune disorders.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"37 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progress and prospects of mRNA-based drugs in pre-clinical and clinical applications","authors":"Yingying Shi, Meixing Shi, Yi Wang, Jian You","doi":"10.1038/s41392-024-02002-z","DOIUrl":"https://doi.org/10.1038/s41392-024-02002-z","url":null,"abstract":"<p>In the last decade, messenger ribonucleic acid (mRNA)-based drugs have gained great interest in both immunotherapy and non-immunogenic applications. This surge in interest can be largely attributed to the demonstration of distinct advantages offered by various mRNA molecules, alongside the rapid advancements in nucleic acid delivery systems. It is noteworthy that the immunogenicity of mRNA drugs presents a double-edged sword. In the context of immunotherapy, extra supplementation of adjuvant is generally required for induction of robust immune responses. Conversely, in non-immunotherapeutic scenarios, immune activation is unwanted considering the host tolerability and high expression demand for mRNA-encoded functional proteins. Herein, mainly focused on the linear non-replicating mRNA, we overview the preclinical and clinical progress and prospects of mRNA medicines encompassing vaccines and other therapeutics. We also highlight the importance of focusing on the host-specific variations, including age, gender, pathological condition, and concurrent medication of individual patient, for maximized efficacy and safety upon mRNA administration. Furthermore, we deliberate on the potential challenges that mRNA drugs may encounter in the realm of disease treatment, the current endeavors of improvement, as well as the application prospects for future advancements. Overall, this review aims to present a comprehensive understanding of mRNA-based therapies while illuminating the prospective development and clinical application of mRNA drugs.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"162 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}