EMBO Molecular Medicine最新文献_第10页

Immune-enhancing neutrophils reprogrammed by subclinical low-dose endotoxin in cancer treatment. 亚临床低剂量内毒素在癌症治疗中重塑的免疫增强中性粒细胞

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-08-01 Epub Date: 2024-07-15 DOI: 10.1038/s44321-024-00100-7

Yao Zhang, Christina Lee, Shuo Geng, Jing Wang, Udipta Bohara, Jacqueline Hou, Ziyue Yi, Liwu Li

{"title":"Immune-enhancing neutrophils reprogrammed by subclinical low-dose endotoxin in cancer treatment.","authors":"Yao Zhang, Christina Lee, Shuo Geng, Jing Wang, Udipta Bohara, Jacqueline Hou, Ziyue Yi, Liwu Li","doi":"10.1038/s44321-024-00100-7","DOIUrl":"10.1038/s44321-024-00100-7","url":null,"abstract":"Despite the re-emergence of the pioneering \"Coley's toxin\" concept in anti-cancer immune therapies highlighted by check-point inhibitors and CAR-T approaches, fundamental mechanisms responsible for the immune-enhancing efficacy of low-dose \"Coley's toxin\" remain poorly understood. This study examines the novel reprogramming of immune-enhancing neutrophils by super-low dose endotoxin conducive for anti-cancer therapies. Through integrated analyses including scRNAseq and functional characterizations, we examined the efficacy of reprogrammed neutrophils in treating experimental cancer. We observed that neutrophils trained by super-low dose endotoxin adopt a potent immune-enhancing phenotype characterized by CD177loCD11bloCD80hiCD40hiDectin2hi. Both murine and human neutrophils trained by super-low dose endotoxin exhibit relieved suppression of adaptive T cells as compared to un-trained neutrophils. Functionally, neutrophils trained by super-low dose endotoxin can potently reduce tumor burden when transfused into recipient tumor-bearing mice. Mechanistically, Super-low dose endotoxin enables the generation of immune-enhancing neutrophils through activating STAT5 and reducing innate suppressor IRAK-M. Together, our data clarify the long-held mystery of \"Coley's toxin\" in rejuvenating anti-tumor immune defense, and provide a proof-of-concept in developing innate neutrophil-based anti-tumor therapeutics.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1886-1900"},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619638","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}

引用次数: 0

PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets. PD-1/LAG-3协同信号分析发现CBL泛素连接酶是关键的免疫疗法靶点。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-08-01 Epub Date: 2024-07-19 DOI: 10.1038/s44321-024-00098-y

Luisa Chocarro, Ester Blanco, Leticia Fernandez-Rubio, Maider Garnica, Miren Zuazo, Maria Jesus Garcia, Ana Bocanegra, Miriam Echaide, Colette Johnston, Carolyn J Edwards, James Legg, Andrew J Pierce, Hugo Arasanz, Gonzalo Fernandez-Hinojal, Ruth Vera, Karina Ausin, Enrique Santamaria, Joaquin Fernandez-Irigoyen, Grazyna Kochan, David Escors

{"title":"PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets.","authors":"Luisa Chocarro, Ester Blanco, Leticia Fernandez-Rubio, Maider Garnica, Miren Zuazo, Maria Jesus Garcia, Ana Bocanegra, Miriam Echaide, Colette Johnston, Carolyn J Edwards, James Legg, Andrew J Pierce, Hugo Arasanz, Gonzalo Fernandez-Hinojal, Ruth Vera, Karina Ausin, Enrique Santamaria, Joaquin Fernandez-Irigoyen, Grazyna Kochan, David Escors","doi":"10.1038/s44321-024-00098-y","DOIUrl":"10.1038/s44321-024-00098-y","url":null,"abstract":"Many cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD-1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers immune infiltrates. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic, and epigenetic pathways, but especially a reinforced negative regulation of the TCR signalosome. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. A differential analysis of the proteome of PD-1/LAG-3 T-cells showed a specific enrichment in ubiquitin ligases participating in E3 ubiquitination pathways. PD-1/LAG-3 co-blockade inhibited CBL-B expression, while the use of a bispecific drug in clinical development also repressed C-CBL expression, which reverted T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD-1 blockade. The combination of CBL-B-specific small molecule inhibitors with anti-PD-1/anti-LAG-3 immunotherapies demonstrated notable therapeutic efficacy in models of lung cancer refractory to immunotherapies, overcoming PD-1/LAG-3 mediated resistance.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1791-1816"},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727062","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}

引用次数: 0

In vitro and in vivo inhibition of the host TRPC4 channel attenuates Zika virus infection. 体外和体内抑制宿主 TRPC4 通道可减轻寨卡病毒感染。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-08-01 Epub Date: 2024-07-15 DOI: 10.1038/s44321-024-00103-4

Xingjuan Chen, Yunzheng Yan, Zhiqiang Liu, Shaokang Yang, Wei Li, Zhuang Wang, Mengyuan Wang, Juan Guo, Zhenyang Li, Weiyan Zhu, Jingjing Yang, Jiye Yin, Qingsong Dai, Yuexiang Li, Cui Wang, Lei Zhao, Xiaotong Yang, Xiaojia Guo, Ling Leng, Jiaxi Xu, Alexander G Obukhov, Ruiyuan Cao, Wu Zhong

{"title":"In vitro and in vivo inhibition of the host TRPC4 channel attenuates Zika virus infection.","authors":"Xingjuan Chen, Yunzheng Yan, Zhiqiang Liu, Shaokang Yang, Wei Li, Zhuang Wang, Mengyuan Wang, Juan Guo, Zhenyang Li, Weiyan Zhu, Jingjing Yang, Jiye Yin, Qingsong Dai, Yuexiang Li, Cui Wang, Lei Zhao, Xiaotong Yang, Xiaojia Guo, Ling Leng, Jiaxi Xu, Alexander G Obukhov, Ruiyuan Cao, Wu Zhong","doi":"10.1038/s44321-024-00103-4","DOIUrl":"10.1038/s44321-024-00103-4","url":null,"abstract":"Zika virus (ZIKV) infection may lead to severe neurological consequences, including seizures, and early infancy death. However, the involved mechanisms are still largely unknown. TRPC channels play an important role in regulating nervous system excitability and are implicated in seizure development. We investigated whether TRPCs might be involved in the pathogenesis of ZIKV infection. We found that ZIKV infection increases TRPC4 expression in host cells via the interaction between the ZIKV-NS3 protein and CaMKII, enhancing TRPC4-mediated calcium influx. Pharmacological inhibition of CaMKII decreased both pCREB and TRPC4 protein levels, whereas the suppression of either TRPC4 or CaMKII improved the survival rate of ZIKV-infected cells and reduced viral protein production, likely by impeding the replication phase of the viral life cycle. TRPC4 or CaMKII inhibitors also reduced seizures and increased the survival of ZIKV-infected neonatal mice and blocked the spread of ZIKV in brain organoids derived from human-induced pluripotent stem cells. These findings suggest that targeting CaMKII or TRPC4 may offer a promising approach for developing novel anti-ZIKV therapies, capable of preventing ZIKV-associated seizures and death.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1817-1839"},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619639","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}

引用次数: 0

Platelet transcription factors license the pro-inflammatory cytokine response of human monocytes. 血小板转录因子许可人类单核细胞的促炎细胞因子反应。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-08-01 Epub Date: 2024-07-08 DOI: 10.1038/s44321-024-00093-3

Ibrahim Hawwari, Lukas Rossnagel, Nathalia Rosero, Salie Maasewerd, Matilde B Vasconcelos, Marius Jentzsch, Agnieszka Demczuk, Lino L Teichmann, Lisa Meffert, Damien Bertheloot, Lucas S Ribeiro, Sebastian Kallabis, Felix Meissner, Moshe Arditi, Asli E Atici, Magali Noval Rivas, Bernardo S Franklin

{"title":"Platelet transcription factors license the pro-inflammatory cytokine response of human monocytes.","authors":"Ibrahim Hawwari, Lukas Rossnagel, Nathalia Rosero, Salie Maasewerd, Matilde B Vasconcelos, Marius Jentzsch, Agnieszka Demczuk, Lino L Teichmann, Lisa Meffert, Damien Bertheloot, Lucas S Ribeiro, Sebastian Kallabis, Felix Meissner, Moshe Arditi, Asli E Atici, Magali Noval Rivas, Bernardo S Franklin","doi":"10.1038/s44321-024-00093-3","DOIUrl":"10.1038/s44321-024-00093-3","url":null,"abstract":"In humans, blood Classical CD14+ monocytes contribute to host defense by secreting large amounts of pro-inflammatory cytokines. Their aberrant activity causes hyper-inflammation and life-threatening cytokine storms, while dysfunctional monocytes are associated with 'immunoparalysis', a state of immune hypo responsiveness and reduced pro-inflammatory gene expression, predisposing individuals to opportunistic infections. Understanding how monocyte functions are regulated is critical to prevent these harmful outcomes. We reveal platelets' vital role in the pro-inflammatory cytokine responses of human monocytes. Naturally low platelet counts in patients with immune thrombocytopenia or removal of platelets from healthy monocytes result in monocyte immunoparalysis, marked by impaired cytokine response to immune challenge and weakened host defense transcriptional programs. Remarkably, supplementing monocytes with fresh platelets reverses these conditions. We discovered that platelets serve as reservoirs of key cytokine transcription regulators, such as NF-κB and MAPK p38, and pinpointed the enrichment of platelet NF-κB2 in human monocytes by proteomics. Platelets proportionally restore impaired cytokine production in human monocytes lacking MAPK p38α, NF-κB p65, and NF-κB2. We uncovered a vesicle-mediated platelet-monocyte-propagation of inflammatory transcription regulators, positioning platelets as central checkpoints in monocyte inflammation.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1901-1929"},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558295","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}

引用次数: 0

Author Correction: Platinum-induced upregulation of ITGA6 promotes chemoresistance and spreading in ovarian cancer. 作者更正：铂诱导的ITGA6上调促进卵巢癌的化疗耐药性和扩散

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-08-01 DOI: 10.1038/s44321-024-00099-x

Alice Gambelli, Anna Nespolo, Gian Luca Rampioni Vinciguerra, Eliana Pivetta, Ilenia Pellarin, Milena S Nicoloso, Chiara Scapin, Linda Stefenatti, Ilenia Segatto, Andrea Favero, Sara D'Andrea, Maria Teresa Mucignat, Michele Bartoletti, Emilio Lucia, Monica Schiappacassi, Paola Spessotto, Vincenzo Canzonieri, Giorgio Giorda, Fabio Puglisi, Andrea Vecchione, Barbara Belletti, Maura Sonego, Gustavo Baldassarre

引用次数: 0

Tubular insulin-induced gene 1 deficiency promotes NAD⁺ consumption and exacerbates kidney fibrosis. 肾小管胰岛素诱导基因 1 缺乏会促进 NAD+ 的消耗并加剧肾脏纤维化。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-07-01 Epub Date: 2024-05-28 DOI: 10.1038/s44321-024-00081-7

Shumin Li, Jun Qin, Yingying Zhao, Jiali Wang, Songming Huang, Xiaowen Yu

{"title":"Tubular insulin-induced gene 1 deficiency promotes NAD+ consumption and exacerbates kidney fibrosis.","authors":"Shumin Li, Jun Qin, Yingying Zhao, Jiali Wang, Songming Huang, Xiaowen Yu","doi":"10.1038/s44321-024-00081-7","DOIUrl":"10.1038/s44321-024-00081-7","url":null,"abstract":"Profibrotic proximal tubules (PT) were identified as a unique phenotype of proximal tubule cells (PTCs) in renal fibrosis by single-cell RNA sequencing (scRNA-seq). Controlling the process of renal fibrosis requires understanding how to manage the S1 subset's branch to the S3 subset rather than to the profibrotic PT subset. Insulin-induced gene 1 (Insig1) is one of the branch-dependent genes involved in controlling this process, although its role in renal fibrosis is unknown. Here, we discovered that tubular Insig1 deficiency, rather than fibroblast Insig1 deficiency, plays a detrimental role in the pathogenesis of renal fibrosis in vivo and in vitro. Overexpression of Insig1 profoundly inhibited renal fibrosis. Mechanistically, Insig1 deletion in PTCs boosted SREBP1 nuclear localization, increasing Aldh1a1 transcriptional activity, causing excessive NAD+ consumption and ER enlargement, as well as accelerating renal fibrosis. We also identified nicardipine as a selective inhibitor of Aldh1a1, which could restore NAD+ and maintain ER homeostasis, as well as improve renal fibrosis. Together, our findings support tubular Insig1 as a new therapeutic target for chronic kidney disease (CKD).","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1675-1703"},"PeriodicalIF":9.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11251182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141159875","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}

引用次数: 0

Mutation analysis in individual circulating tumor cells depicts intratumor heterogeneity in melanoma. 对单个循环肿瘤细胞的突变分析显示了黑色素瘤的瘤内异质性。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-07-01 Epub Date: 2024-06-19 DOI: 10.1038/s44321-024-00082-6

Mark Sementsov, Leonie Ott, Julian Kött, Alexander Sartori, Amelie Lusque, Sarah Degenhardt, Bertille Segier, Isabel Heidrich, Beate Volkmer, Rüdiger Greinert, Peter Mohr, Ronald Simon, Julia-Christina Stadler, Darryl Irwin, Claudia Koch, Antje Andreas, Benjamin Deitert, Verena Thewes, Andreas Trumpp, Andreas Schneeweiss, Yassine Belloum, Sven Peine, Harriett Wikman, Sabine Riethdorf, Stefan W Schneider, Christoffer Gebhardt, Klaus Pantel, Laura Keller

{"title":"Mutation analysis in individual circulating tumor cells depicts intratumor heterogeneity in melanoma.","authors":"Mark Sementsov, Leonie Ott, Julian Kött, Alexander Sartori, Amelie Lusque, Sarah Degenhardt, Bertille Segier, Isabel Heidrich, Beate Volkmer, Rüdiger Greinert, Peter Mohr, Ronald Simon, Julia-Christina Stadler, Darryl Irwin, Claudia Koch, Antje Andreas, Benjamin Deitert, Verena Thewes, Andreas Trumpp, Andreas Schneeweiss, Yassine Belloum, Sven Peine, Harriett Wikman, Sabine Riethdorf, Stefan W Schneider, Christoffer Gebhardt, Klaus Pantel, Laura Keller","doi":"10.1038/s44321-024-00082-6","DOIUrl":"10.1038/s44321-024-00082-6","url":null,"abstract":"Circulating tumor DNA (ctDNA) is the cornerstone of liquid biopsy diagnostics, revealing clinically relevant genomic aberrations from blood of cancer patients. Genomic analysis of single circulating tumor cells (CTCs) could provide additional insights into intra-patient heterogeneity, but it requires whole-genome amplification (WGA) of DNA, which might introduce bias. Here, we describe a novel approach based on mass spectrometry for mutation detection from individual CTCs not requiring WGA and complex bioinformatics pipelines. After establishment of our protocol on tumor cell line-derived single cells, it was validated on CTCs of 33 metastatic melanoma patients and the mutations were compared to those obtained from tumor tissue and ctDNA. Although concordance with tumor tissue was superior for ctDNA over CTC analysis, a larger number of mutations were found within CTCs compared to ctDNA (p = 0.039), including mutations in melanoma driver genes, or those associated with resistance to therapy or metastasis. Thus, our results demonstrate proof-of-principle data that CTC analysis can provide clinically relevant genomic information that is not redundant to tumor tissue or ctDNA analysis.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1560-1578"},"PeriodicalIF":9.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426595","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}

引用次数: 0

An immunohistochemical atlas of necroptotic pathway expression. 坏死通路表达的免疫组化图谱

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-07-01 Epub Date: 2024-05-15 DOI: 10.1038/s44321-024-00074-6

Shene Chiou, Aysha H Al-Ani, Yi Pan, Komal M Patel, Isabella Y Kong, Lachlan W Whitehead, Amanda Light, Samuel N Young, Marilou Barrios, Callum Sargeant, Pradeep Rajasekhar, Leah Zhu, Anne Hempel, Ann Lin, James A Rickard, Cathrine Hall, Pradnya Gangatirkar, Raymond Kh Yip, Wayne Cawthorne, Annette V Jacobsen, Christopher R Horne, Katherine R Martin, Lisa J Ioannidis, Diana S Hansen, Jessica Day, Ian P Wicks, Charity Law, Matthew E Ritchie, Rory Bowden, Joanne M Hildebrand, Lorraine A O'Reilly, John Silke, Lisa Giulino-Roth, Ellen Tsui, Kelly L Rogers, Edwin D Hawkins, Britt Christensen, James M Murphy, André L Samson

{"title":"An immunohistochemical atlas of necroptotic pathway expression.","authors":"Shene Chiou, Aysha H Al-Ani, Yi Pan, Komal M Patel, Isabella Y Kong, Lachlan W Whitehead, Amanda Light, Samuel N Young, Marilou Barrios, Callum Sargeant, Pradeep Rajasekhar, Leah Zhu, Anne Hempel, Ann Lin, James A Rickard, Cathrine Hall, Pradnya Gangatirkar, Raymond Kh Yip, Wayne Cawthorne, Annette V Jacobsen, Christopher R Horne, Katherine R Martin, Lisa J Ioannidis, Diana S Hansen, Jessica Day, Ian P Wicks, Charity Law, Matthew E Ritchie, Rory Bowden, Joanne M Hildebrand, Lorraine A O'Reilly, John Silke, Lisa Giulino-Roth, Ellen Tsui, Kelly L Rogers, Edwin D Hawkins, Britt Christensen, James M Murphy, André L Samson","doi":"10.1038/s44321-024-00074-6","DOIUrl":"10.1038/s44321-024-00074-6","url":null,"abstract":"Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators - Caspase-8, RIPK1, RIPK3 and MLKL - in formalin-fixed mouse and human tissues. We observed surprising heterogeneity in protein expression within tissues, whereby short-lived immune barrier cells were replete with necroptotic effectors, whereas long-lived cells lacked RIPK3 or MLKL expression. Local changes in the expression of necroptotic effectors occurred in response to insults such as inflammation, dysbiosis or immune challenge, consistent with necroptosis being dysregulated in disease contexts. These methods will facilitate the precise localisation and evaluation of necroptotic signaling in vivo.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1717-1749"},"PeriodicalIF":9.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944436","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}

引用次数: 0

Disrupting TSLP-TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases. 通过假定的小分子抑制剂破坏 TSLP-TSLP 受体之间的相互作用，可为特应性疾病提供一种新型、高效的治疗方案。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-07-01 Epub Date: 2024-06-14 DOI: 10.1038/s44321-024-00085-3

Partho Protim Adhikary, Temilolu Idowu, Zheng Tan, Christopher Hoang, Selina Shanta, Malti Dumbani, Leah Mappalakayil, Bhuwan Awasthi, Marcel Bermudez, January Weiner, Dieter Beule, Gerhard Wolber, Brent Dg Page, Sarah Hedtrich

{"title":"Disrupting TSLP-TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases.","authors":"Partho Protim Adhikary, Temilolu Idowu, Zheng Tan, Christopher Hoang, Selina Shanta, Malti Dumbani, Leah Mappalakayil, Bhuwan Awasthi, Marcel Bermudez, January Weiner, Dieter Beule, Gerhard Wolber, Brent Dg Page, Sarah Hedtrich","doi":"10.1038/s44321-024-00085-3","DOIUrl":"10.1038/s44321-024-00085-3","url":null,"abstract":"Thymic stromal lymphopoietin (TSLP) is a key player in atopic diseases, which has sparked great interest in therapeutically targeting TSLP. Yet, no small-molecule TSLP inhibitors exist due to the challenges of disrupting the protein-protein interaction between TSLP and its receptor. Here, we report the development of small-molecule TSLP receptor inhibitors using virtual screening and docking of >1,000,000 compounds followed by iterative chemical synthesis. BP79 emerged as our lead compound that effectively abrogates TSLP-triggered cytokines at low micromolar concentrations. For in-depth analysis, we developed a human atopic disease drug discovery platform using multi-organ chips. Here, topical application of BP79 onto atopic skin models that were co-cultivated with lung models and Th2 cells effectively suppressed immune cell infiltration and IL-13, IL-4, TSLP, and periostin secretion, while upregulating skin barrier proteins. RNA-Seq analysis corroborate these findings and indicate protective downstream effects on the lungs. To the best of our knowledge, this represents the first report of a potent putative small molecule TSLPR inhibitor which has the potential to expand the therapeutic and preventive options in atopic diseases.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1630-1656"},"PeriodicalIF":9.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141320709","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}

引用次数: 0

Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson's patients. 帕金森病患者血液中抗聚集的α-突触核蛋白四聚体减少。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-07-01 Epub Date: 2024-06-05 DOI: 10.1038/s44321-024-00083-5

Laura de Boni, Amber Wallis, Aurelia Hays Watson, Alejandro Ruiz-Riquelme, Louise-Ann Leyland, Thomas Bourinaris, Naomi Hannaway, Ullrich Wüllner, Oliver Peters, Josef Priller, Björn H Falkenburger, Jens Wiltfang, Mathias Bähr, Inga Zerr, Katharina Bürger, Robert Perneczky, Stefan Teipel, Matthias Löhle, Wiebke Hermann, Björn-Hendrik Schott, Kathrin Brockmann, Annika Spottke, Katrin Haustein, Peter Breuer, Henry Houlden, Rimona S Weil, Tim Bartels

{"title":"Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson's patients.","authors":"Laura de Boni, Amber Wallis, Aurelia Hays Watson, Alejandro Ruiz-Riquelme, Louise-Ann Leyland, Thomas Bourinaris, Naomi Hannaway, Ullrich Wüllner, Oliver Peters, Josef Priller, Björn H Falkenburger, Jens Wiltfang, Mathias Bähr, Inga Zerr, Katharina Bürger, Robert Perneczky, Stefan Teipel, Matthias Löhle, Wiebke Hermann, Björn-Hendrik Schott, Kathrin Brockmann, Annika Spottke, Katrin Haustein, Peter Breuer, Henry Houlden, Rimona S Weil, Tim Bartels","doi":"10.1038/s44321-024-00083-5","DOIUrl":"10.1038/s44321-024-00083-5","url":null,"abstract":"Synucleinopathies such as Parkinson's disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1657-1674"},"PeriodicalIF":9.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261573","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}

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