首页 > 最新文献

Journal of Clinical Investigation最新文献

英文 中文
SH3BP5L triggers the RAB11A-regulated integrin recycling network implicated in breast cancer metastasis. SH3BP5L触发rab11a调控的整合素循环网络,参与乳腺癌转移。
IF 13.6 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-02 DOI: 10.1172/JCI192705
Huayi Li, Maria Chiara De Santis, Francesco A Tucci, Daniela Tosoni, Ping Zhang, Meredith L Jenkins, Giulia Villari, Maria Grazia Filippone, Elisa Guerrera, Simone Tealdi, Luca Gozzelino, Federico Gulluni, Lorenzo Prever, Cristina Zanini, Marco Forni, Irene Franco, Miriam Martini, John E Burke, Guido Serini, Carlo Cosimo Campa, Salvatore Pece, Jean Piero Margaria, Emilio Hirsch

Metastatic progression in aggressive breast cancer (BC) depends on a tightly controlled vesicular recycling network regulated by RAB11, a small guanosine triphosphate enzyme (GTPase). In a cohort of more than 1,000 patients with BC, we identified SH3BP5L as the most highly expressed guanine nucleotide exchange factor (GEF) for RAB11A. High SH3BP5L expression marked an advanced tumor stage, distant metastasis, and poor prognosis, with significant associations in human epidermal growth factor receptor 2-positive (HER2+) and triple-negative breast cancer (TNBC). Using Förster resonance energy transfer (FRET) sensors and artificial intelligence- (AI-assisted) microscopy, we showed that cargo delivery to the plasma membrane required SH3BP5L-dependent activation of RAB11A and assembly of a complex with the anterograde motor KIF5B. This trafficking governed key metastatic features of TNBC, including β1 integrin recycling and α3β1 integrin surface exposure. Inhibition of SH3BP5L or its GEF activity reduced cell spreading in zebrafish and lung metastasis in mouse models, revealing a previously unidentified driver of BC dissemination and a potential therapeutic vulnerability.

侵袭性乳腺癌(BC)的转移进展取决于由RAB11(一种小鸟苷三磷酸酶(GTPase))调节的严格控制的囊泡再循环网络。在1000多名BC患者的队列中,我们发现SH3BP5L是RAB11A最高表达的鸟嘌呤核苷酸交换因子(GEF)。SH3BP5L高表达标志着肿瘤分期晚期、远处转移、预后差,在人表皮生长因子受体2阳性(HER2+)和三阴性乳腺癌(TNBC)中有显著相关性。利用Förster共振能量转移(FRET)传感器和人工智能(ai辅助)显微镜,研究人员发现,将货物运送到质膜需要依赖sh3bp5l的RAB11A激活,并与顺行马达KIF5B组装复合物。这种转运控制了TNBC的关键转移特征,包括β1整合素循环和α3β1整合素表面暴露。抑制SH3BP5L或其GEF活性可减少斑马鱼中的细胞扩散和小鼠模型中的肺转移,揭示了先前未被发现的BC传播驱动因素和潜在的治疗脆弱性。
{"title":"SH3BP5L triggers the RAB11A-regulated integrin recycling network implicated in breast cancer metastasis.","authors":"Huayi Li, Maria Chiara De Santis, Francesco A Tucci, Daniela Tosoni, Ping Zhang, Meredith L Jenkins, Giulia Villari, Maria Grazia Filippone, Elisa Guerrera, Simone Tealdi, Luca Gozzelino, Federico Gulluni, Lorenzo Prever, Cristina Zanini, Marco Forni, Irene Franco, Miriam Martini, John E Burke, Guido Serini, Carlo Cosimo Campa, Salvatore Pece, Jean Piero Margaria, Emilio Hirsch","doi":"10.1172/JCI192705","DOIUrl":"10.1172/JCI192705","url":null,"abstract":"<p><p>Metastatic progression in aggressive breast cancer (BC) depends on a tightly controlled vesicular recycling network regulated by RAB11, a small guanosine triphosphate enzyme (GTPase). In a cohort of more than 1,000 patients with BC, we identified SH3BP5L as the most highly expressed guanine nucleotide exchange factor (GEF) for RAB11A. High SH3BP5L expression marked an advanced tumor stage, distant metastasis, and poor prognosis, with significant associations in human epidermal growth factor receptor 2-positive (HER2+) and triple-negative breast cancer (TNBC). Using Förster resonance energy transfer (FRET) sensors and artificial intelligence- (AI-assisted) microscopy, we showed that cargo delivery to the plasma membrane required SH3BP5L-dependent activation of RAB11A and assembly of a complex with the anterograde motor KIF5B. This trafficking governed key metastatic features of TNBC, including β1 integrin recycling and α3β1 integrin surface exposure. Inhibition of SH3BP5L or its GEF activity reduced cell spreading in zebrafish and lung metastasis in mouse models, revealing a previously unidentified driver of BC dissemination and a potential therapeutic vulnerability.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"136 3","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12867135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146105564","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
Exploring the biology of metastatic hormone-sensitive prostate cancer: on the road to precision medicine. 探索转移性激素敏感前列腺癌的生物学:在精准医学的道路上。
IF 13.6 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-02 DOI: 10.1172/JCI200920
Alice Bernard-Tessier, Himisha Beltran

Metastatic hormone-sensitive prostate cancer (mHSPC) is a clinically and molecularly heterogeneous disease. Recent insights into the biology underlying disease presentation, volume of disease, and response to therapies are starting to point toward biomarkers to improve selection for intensified and deintensified treatment strategies. In addition, the therapeutic landscape is rapidly changing, with new biomarker-driven studies targeting genotype (e.g., BRCA or PTEN mutant) and phenotype (e.g., prostate-specific membrane antigen status) in development for mHSPC. A better understanding of tumor heterogeneity, clonal evolution, and metastatic homing in prostate cancer will hopefully inform future strategies for local and systemic disease control, personalized monitoring strategies, and improved patient outcomes.

转移性激素敏感前列腺癌(mHSPC)是一种临床和分子异质性疾病。最近对疾病表现、疾病数量和治疗反应的生物学基础的见解开始指向生物标志物,以改善强化和去强化治疗策略的选择。此外,治疗领域正在迅速变化,针对mHSPC的基因型(如BRCA或PTEN突变)和表型(如前列腺特异性膜抗原状态)的新的生物标志物驱动研究正在开发中。更好地了解前列腺癌的肿瘤异质性、克隆进化和转移归巢,有望为未来的局部和全身疾病控制策略、个性化监测策略和改善患者预后提供信息。
{"title":"Exploring the biology of metastatic hormone-sensitive prostate cancer: on the road to precision medicine.","authors":"Alice Bernard-Tessier, Himisha Beltran","doi":"10.1172/JCI200920","DOIUrl":"10.1172/JCI200920","url":null,"abstract":"<p><p>Metastatic hormone-sensitive prostate cancer (mHSPC) is a clinically and molecularly heterogeneous disease. Recent insights into the biology underlying disease presentation, volume of disease, and response to therapies are starting to point toward biomarkers to improve selection for intensified and deintensified treatment strategies. In addition, the therapeutic landscape is rapidly changing, with new biomarker-driven studies targeting genotype (e.g., BRCA or PTEN mutant) and phenotype (e.g., prostate-specific membrane antigen status) in development for mHSPC. A better understanding of tumor heterogeneity, clonal evolution, and metastatic homing in prostate cancer will hopefully inform future strategies for local and systemic disease control, personalized monitoring strategies, and improved patient outcomes.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"136 3","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12867139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146105732","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
Neurodegeneration biomarkers in Alzheimer's disease: axonal density index expands the "N" in the AT(N) framework. 阿尔茨海默病的神经退行性生物标志物:轴突密度指数扩大了AT(N)框架中的“N”。
IF 13.6 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-02 DOI: 10.1172/JCI202411
Ryn Flaherty, Arjun V Masurkar

Neurodegeneration, along with amyloid and tau, define the AT(N) framework of Alzheimer's disease that has shaped the development of diagnostics and therapeutics. Yet, biomarker development for neurodegeneration has lagged behind that for amyloid and tau, with limited definition of its heterogeneous microstructural aspects that may each serve as critical measures. In this issue of the JCI, Gong et al. leveraged diffusion MRI to derive a unique measure of axonal injury or axonal density index (ADI). Through cross-sectional and longitudinal analyses, they demonstrated that the ADI has superior performance in detecting, tracking, and predicting clinical impairment compared with prior diffusion MRI methods to evaluate axonal health and standard biomarkers of amyloid and tau. As such, the ADI measure may serve as an important expansion of the neurodegeneration biomarker repertoire.

神经变性,与淀粉样蛋白和tau蛋白一起,定义了阿尔茨海默病的AT(N)框架,这影响了诊断和治疗的发展。然而,神经变性的生物标志物发展落后于淀粉样蛋白和tau蛋白,其异质微观结构方面的定义有限,每个方面都可以作为关键措施。在本期的JCI中,Gong等人利用弥散MRI得出了一种独特的轴突损伤测量方法或轴突密度指数(ADI)。通过横断面和纵向分析,他们证明,与先前的弥散MRI方法相比,ADI在检测、跟踪和预测临床损伤方面具有优越的性能,可以评估轴突健康状况以及淀粉样蛋白和tau蛋白的标准生物标志物。因此,ADI测量可以作为神经退行性疾病生物标志物库的重要扩展。
{"title":"Neurodegeneration biomarkers in Alzheimer's disease: axonal density index expands the \"N\" in the AT(N) framework.","authors":"Ryn Flaherty, Arjun V Masurkar","doi":"10.1172/JCI202411","DOIUrl":"10.1172/JCI202411","url":null,"abstract":"<p><p>Neurodegeneration, along with amyloid and tau, define the AT(N) framework of Alzheimer's disease that has shaped the development of diagnostics and therapeutics. Yet, biomarker development for neurodegeneration has lagged behind that for amyloid and tau, with limited definition of its heterogeneous microstructural aspects that may each serve as critical measures. In this issue of the JCI, Gong et al. leveraged diffusion MRI to derive a unique measure of axonal injury or axonal density index (ADI). Through cross-sectional and longitudinal analyses, they demonstrated that the ADI has superior performance in detecting, tracking, and predicting clinical impairment compared with prior diffusion MRI methods to evaluate axonal health and standard biomarkers of amyloid and tau. As such, the ADI measure may serve as an important expansion of the neurodegeneration biomarker repertoire.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"136 3","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12867143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146105788","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
Posttranscriptional regulation of PD-1 by PRMT5/WDR77 complex shapes T cell effector function and antitumor immunity. PRMT5/WDR77复合物对PD-1的转录后调控影响T细胞效应功能和抗肿瘤免疫。
IF 13.6 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-02 DOI: 10.1172/JCI191469
Yinmin Gu, Yongbo Pan, Chang Pan, Qiang Pang, Zhantong Tang, Yiwen Chen, Haojing Zang, Xiaodong Wang, Chang Huang, Qingqing Zhang, Facai Yang, Xiaofeng Zhu, Yibi Zhang, Xujie Zhao, Shan Gao

The regulation of the programmed cell death protein 1 (PD-1) gene, PDCD1, has been widely explored at transcription and posttranslational levels in T cell function and tumor immune evasion. However, the mechanism for PDCD1 dysregulation at the posttranscriptional level remains largely unknown. Here, we identify protein arginine methyltransferase 5 (PRMT5) as a RNA binding protein in a methyltransferase activity-independent manner, which promotes PDCD1 decay with WD repeat domain 77 protein (WDR77) and Argonaute2. Furthermore, the type-I IFN/STAT1 pathway transcriptionally activates PRMT5 and WDR77, thus enhancing PRMT5/WDR77 binding on a conserved AU-rich element of PDCD1 3' UTR. Functionally, conditional knockout of either PRMT5 or WDR77 in T cells disrupts T cell effector function and sensitizes the tumors to anti-PD-1 therapy. Clinically, PRMT5 and WDR77 expression in tumor-infiltrating T cells are negatively correlated with PDCD1 expression and renders tumors resistant to PD-1-targeted immunotherapy. Moreover, fludarabine targeting STAT1 in combination with anti-PD-1 has a synergetic effect on suppressing tumor growth in mice. Overall, this study reveals that the RNA binding-dependent function of PRMT5 regulates PDCD1 and T cell effector function with WDR77 and identifies potential combinatorial therapeutic strategies for enhancing antitumor efficacy.

程序性细胞死亡蛋白1 (PD-1)基因PDCD1在T细胞功能和肿瘤免疫逃避的转录和翻译后水平上的调控已被广泛探索。然而,在转录后水平上PDCD1失调的机制在很大程度上仍然未知。在这里,我们发现蛋白精氨酸甲基转移酶5 (PRMT5)是一种与甲基转移酶活性无关的RNA结合蛋白,它促进PDCD1与WD重复结构域77蛋白(WDR77)和Argonaute2的衰变。此外,i型IFN/STAT1通路转录激活PRMT5和WDR77,从而增强PRMT5/WDR77与PDCD1 3' UTR中富含au的保守元件的结合。功能上,T细胞中PRMT5或WDR77的条件敲除会破坏T细胞效应功能,并使肿瘤对抗pd -1治疗敏感。临床上,PRMT5和WDR77在肿瘤浸润T细胞中的表达与PDCD1表达呈负相关,使肿瘤对pd -1靶向免疫治疗产生耐药性。此外,靶向STAT1的氟达拉滨与抗pd -1合用对小鼠肿瘤生长具有协同抑制作用。总的来说,本研究揭示了PRMT5的RNA结合依赖功能通过WDR77调节PDCD1和T细胞效应功能,并确定了增强抗肿瘤疗效的潜在联合治疗策略。
{"title":"Posttranscriptional regulation of PD-1 by PRMT5/WDR77 complex shapes T cell effector function and antitumor immunity.","authors":"Yinmin Gu, Yongbo Pan, Chang Pan, Qiang Pang, Zhantong Tang, Yiwen Chen, Haojing Zang, Xiaodong Wang, Chang Huang, Qingqing Zhang, Facai Yang, Xiaofeng Zhu, Yibi Zhang, Xujie Zhao, Shan Gao","doi":"10.1172/JCI191469","DOIUrl":"10.1172/JCI191469","url":null,"abstract":"<p><p>The regulation of the programmed cell death protein 1 (PD-1) gene, PDCD1, has been widely explored at transcription and posttranslational levels in T cell function and tumor immune evasion. However, the mechanism for PDCD1 dysregulation at the posttranscriptional level remains largely unknown. Here, we identify protein arginine methyltransferase 5 (PRMT5) as a RNA binding protein in a methyltransferase activity-independent manner, which promotes PDCD1 decay with WD repeat domain 77 protein (WDR77) and Argonaute2. Furthermore, the type-I IFN/STAT1 pathway transcriptionally activates PRMT5 and WDR77, thus enhancing PRMT5/WDR77 binding on a conserved AU-rich element of PDCD1 3' UTR. Functionally, conditional knockout of either PRMT5 or WDR77 in T cells disrupts T cell effector function and sensitizes the tumors to anti-PD-1 therapy. Clinically, PRMT5 and WDR77 expression in tumor-infiltrating T cells are negatively correlated with PDCD1 expression and renders tumors resistant to PD-1-targeted immunotherapy. Moreover, fludarabine targeting STAT1 in combination with anti-PD-1 has a synergetic effect on suppressing tumor growth in mice. Overall, this study reveals that the RNA binding-dependent function of PRMT5 regulates PDCD1 and T cell effector function with WDR77 and identifies potential combinatorial therapeutic strategies for enhancing antitumor efficacy.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"136 3","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12867141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146104790","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
ADAMTS7 promotes smooth muscle foam cell expansion in atherosclerosis. ADAMTS7促进动脉粥样硬化中平滑肌泡沫细胞的扩张。
IF 13.6 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-01-29 DOI: 10.1172/JCI187451
Allen Chung, Lauren E Fries, Hyun-Kyung Chang, Huize Pan, Alexander C Bashore, Karissa Shuck, Caio V Matias, Juliana Gomez Pardo, Jordan S Kesner, Hanying Yan, Mingyao Li, Robert C Bauer

Human genetic studies have repeatedly associated ADAMTS7 with atherosclerotic cardiovascular disease. Subsequent investigations in mice demonstrated that ADAMTS7 is proatherogenic and induced in response to vascular injury. However, the cell-specific mechanisms governing ADAMTS7 proatherogenicity remain unclear. To determine which vascular cell types express ADAMTS7, we interrogated single-cell RNA sequencing of human carotid atherosclerosis and found ADAMTS7 expression in smooth muscle cells (SMCs), endothelial cells (ECs), and fibroblasts. We subsequently created SMC- and EC-specific Adamts7 conditional knockout and transgenic mice. Conditional knockout of Adamts7 in either cell type does not reduce atherosclerosis, whereas transgenic induction in either cell type increases atherosclerosis. In SMC transgenic mice, this increase coincides with an expansion of lipid-laden SMC foam cells and a decrease in fibrous cap formation. RNA-sequencing in Adamts7 overexpressing SMCs revealed an upregulation of lipid genes typically assigned to macrophages. Mechanistically, ADAMTS7 increases SMC oxLDL uptake through CD36, whose expression is upregulated by PU.1. ATAC-seq and motif analysis revealed increased chromatin accessibility at AP-1 enriched regions, consistent with AP-1 dependent remodeling of PU.1-regulated lipid-handling loci. In summary, ADAMTS7 promotes atherosclerosis by driving SMC foam cell formation through an AP-1/PU.1/CD36 regulatory axis.

人类遗传学研究反复将ADAMTS7与动脉粥样硬化性心血管疾病联系起来。随后在小鼠中进行的研究表明,ADAMTS7具有促动脉粥样硬化作用,可诱导血管损伤。然而,ADAMTS7致动脉粥样硬化的细胞特异性机制尚不清楚。为了确定哪些血管细胞类型表达ADAMTS7,我们查询了人颈动脉粥样硬化的单细胞RNA测序,发现ADAMTS7在平滑肌细胞(SMCs)、内皮细胞(ECs)和成纤维细胞中表达。随后,我们创建了SMC和ec特异性的Adamts7条件敲除和转基因小鼠。在任何一种细胞类型中,条件敲除Adamts7都不会减少动脉粥样硬化,而在任何一种细胞类型中转基因诱导则会增加动脉粥样硬化。在SMC转基因小鼠中,这种增加与脂质SMC泡沫细胞的扩张和纤维帽形成的减少相一致。在Adamts7过表达的SMCs中,rna测序显示巨噬细胞通常具有脂质基因的上调。在机制上,ADAMTS7通过CD36增加SMC oxLDL摄取,而CD36的表达被PU.1上调。ATAC-seq和基序分析显示,AP-1富集区域的染色质可及性增加,与pu .1调节的脂质处理位点的AP-1依赖性重塑一致。综上所述,ADAMTS7通过AP-1/PU驱动SMC泡沫细胞形成,从而促进动脉粥样硬化。1/CD36调节轴。
{"title":"ADAMTS7 promotes smooth muscle foam cell expansion in atherosclerosis.","authors":"Allen Chung, Lauren E Fries, Hyun-Kyung Chang, Huize Pan, Alexander C Bashore, Karissa Shuck, Caio V Matias, Juliana Gomez Pardo, Jordan S Kesner, Hanying Yan, Mingyao Li, Robert C Bauer","doi":"10.1172/JCI187451","DOIUrl":"10.1172/JCI187451","url":null,"abstract":"<p><p>Human genetic studies have repeatedly associated ADAMTS7 with atherosclerotic cardiovascular disease. Subsequent investigations in mice demonstrated that ADAMTS7 is proatherogenic and induced in response to vascular injury. However, the cell-specific mechanisms governing ADAMTS7 proatherogenicity remain unclear. To determine which vascular cell types express ADAMTS7, we interrogated single-cell RNA sequencing of human carotid atherosclerosis and found ADAMTS7 expression in smooth muscle cells (SMCs), endothelial cells (ECs), and fibroblasts. We subsequently created SMC- and EC-specific Adamts7 conditional knockout and transgenic mice. Conditional knockout of Adamts7 in either cell type does not reduce atherosclerosis, whereas transgenic induction in either cell type increases atherosclerosis. In SMC transgenic mice, this increase coincides with an expansion of lipid-laden SMC foam cells and a decrease in fibrous cap formation. RNA-sequencing in Adamts7 overexpressing SMCs revealed an upregulation of lipid genes typically assigned to macrophages. Mechanistically, ADAMTS7 increases SMC oxLDL uptake through CD36, whose expression is upregulated by PU.1. ATAC-seq and motif analysis revealed increased chromatin accessibility at AP-1 enriched regions, consistent with AP-1 dependent remodeling of PU.1-regulated lipid-handling loci. In summary, ADAMTS7 promotes atherosclerosis by driving SMC foam cell formation through an AP-1/PU.1/CD36 regulatory axis.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146085943","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}
引用次数: 0
Rho/ROCK signaling and α-Catenin mediate β-Catenin-driven hyperplasia in the adrenal cortex via adherens junctions. Rho/ROCK信号和α-Catenin通过粘附连接介导肾上腺皮质β- catenin驱动的增生。
IF 13.6 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-01-27 DOI: 10.1172/JCI196271
Mesut Berber, Betul Haykir, Nick A Guagliardo, Vasileios Chortis, Kleiton Silva Borges, Paula Q Barrett, Felix Beuschlein, Diana L Carlone, David T Breault

How β-Catenin (βCat) mediates tissue hyperplasia is poorly understood. To explore this, we employed the adrenal cortex as a model system given its stereotypical spatial organization and the important role βCat plays in homeostasis and disease. For example, excessive production of aldosterone by the adrenal cortex (primary aldosteronism, PA) constitutes a major cause of cardiovascular morbidity and is associated with βCat gain-of-function (βCat-GOF). Adherens junctions (AJs) connect the actin cytoskeletons of adjacent zona Glomerulosa (zG) cells via a cadherin-βCat-α-Catenin complex and mediate aldosterone production. Whether βCat-GOF drives zG hyperplasia, a key feature of PA, via AJs is unknown. Here, we showed that aldosterone secretagogues (K+, AngII) and βCat-GOF mediated AJ formation via Rho/ROCK/actomyosin signaling. In addition, Rho/ROCK inhibition led to altered zG rosette morphology and decreased aldosterone production. Mice with zG-specific βCat-GOF demonstrated increased AJ formation and zG hyperplasia, which was blunted by Rho/ROCK inhibition and deletion of α-Catenin. βCat also impacted AJ formation independently of its role as a transcription factor. Furthermore, analysis of human aldosterone-producing adenomas revealed high levels of βCat expression were associated with increased membranous expression of K-Cadherin. Together, our findings identified Rho/ROCK signaling and αCat as key mediators of AJ formation and βCat-driven hyperplasia.

β-Catenin (βCat)如何介导组织增生尚不清楚。为了探索这一点,我们采用肾上腺皮质作为模型系统,考虑到其刻板的空间组织和βCat在体内平衡和疾病中发挥的重要作用。例如,肾上腺皮质分泌过多的醛固酮(原发性醛固酮增多症,PA)是心血管疾病的主要原因,并与βCat- gof (βCat- gof)有关。粘附连接(AJs)通过钙粘蛋白-βCat-α-Catenin复合物连接相邻肾小球带(zG)细胞的肌动蛋白细胞骨架,并介导醛固酮的产生。βCat-GOF是否通过AJs驱动zG增生(PA的一个关键特征)尚不清楚。在这里,我们发现醛固酮分泌物(K+, AngII)和βCat-GOF通过Rho/ROCK/ actitomyosin信号介导AJ的形成。此外,Rho/ROCK抑制导致zG莲座形态改变和醛固酮产生减少。zG特异性βCat-GOF小鼠表现出AJ形成增加和zG增生,Rho/ROCK抑制和α-Catenin的缺失使其减弱。βCat也独立于其作为转录因子的作用影响AJ的形成。此外,对人醛固酮生成腺瘤的分析显示,βCat的高水平表达与K-Cadherin的膜表达增加有关。总之,我们的研究结果确定了Rho/ROCK信号和αCat是AJ形成和β cat驱动增生的关键介质。
{"title":"Rho/ROCK signaling and α-Catenin mediate β-Catenin-driven hyperplasia in the adrenal cortex via adherens junctions.","authors":"Mesut Berber, Betul Haykir, Nick A Guagliardo, Vasileios Chortis, Kleiton Silva Borges, Paula Q Barrett, Felix Beuschlein, Diana L Carlone, David T Breault","doi":"10.1172/JCI196271","DOIUrl":"10.1172/JCI196271","url":null,"abstract":"<p><p>How β-Catenin (βCat) mediates tissue hyperplasia is poorly understood. To explore this, we employed the adrenal cortex as a model system given its stereotypical spatial organization and the important role βCat plays in homeostasis and disease. For example, excessive production of aldosterone by the adrenal cortex (primary aldosteronism, PA) constitutes a major cause of cardiovascular morbidity and is associated with βCat gain-of-function (βCat-GOF). Adherens junctions (AJs) connect the actin cytoskeletons of adjacent zona Glomerulosa (zG) cells via a cadherin-βCat-α-Catenin complex and mediate aldosterone production. Whether βCat-GOF drives zG hyperplasia, a key feature of PA, via AJs is unknown. Here, we showed that aldosterone secretagogues (K+, AngII) and βCat-GOF mediated AJ formation via Rho/ROCK/actomyosin signaling. In addition, Rho/ROCK inhibition led to altered zG rosette morphology and decreased aldosterone production. Mice with zG-specific βCat-GOF demonstrated increased AJ formation and zG hyperplasia, which was blunted by Rho/ROCK inhibition and deletion of α-Catenin. βCat also impacted AJ formation independently of its role as a transcription factor. Furthermore, analysis of human aldosterone-producing adenomas revealed high levels of βCat expression were associated with increased membranous expression of K-Cadherin. Together, our findings identified Rho/ROCK signaling and αCat as key mediators of AJ formation and βCat-driven hyperplasia.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146063836","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}
引用次数: 0
Retraction for Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation. 收缩白术内酯I通过激活肿瘤抗原呈递增强对免疫检查点阻断治疗的反应性。
IF 13.6 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-01-16 DOI: 10.1172/JCI202473
Hanchen Xu, Kevin Van der Jeught, Zhuolong Zhou, Lu Zhang, Tao Yu, Yifan Sun, Yujing Li, Changlin Wan, Ka Man So, Degang Liu, Michael Frieden, Yuanzhang Fang, Amber L Mosley, Xiaoming He, Xinna Zhang, George E Sandusky, Yunlong Liu, Samy O Meroueh, Chi Zhang, Aruna B Wijeratne, Cheng Huang, Guang Ji, Xiongbin Lu
{"title":"Retraction for Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation.","authors":"Hanchen Xu, Kevin Van der Jeught, Zhuolong Zhou, Lu Zhang, Tao Yu, Yifan Sun, Yujing Li, Changlin Wan, Ka Man So, Degang Liu, Michael Frieden, Yuanzhang Fang, Amber L Mosley, Xiaoming He, Xinna Zhang, George E Sandusky, Yunlong Liu, Samy O Meroueh, Chi Zhang, Aruna B Wijeratne, Cheng Huang, Guang Ji, Xiongbin Lu","doi":"10.1172/JCI202473","DOIUrl":"10.1172/JCI202473","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"136 2","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12807460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989632","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
Protectin DX resolves fracture-induced postoperative pain in mice via neuronal signaling and GPR37-activated macrophage efferocytosis. Protectin DX通过神经元信号和gpr37激活的巨噬细胞efferocytosis来解决小鼠骨折术后疼痛。
IF 13.6 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-01-16 DOI: 10.1172/JCI190754
Yize Li, Sangsu Bang, Jasmine Ji, Jing Xu, Min Lee, Sharat Chandra, Charles N Serhan, Ru-Rong Ji

Protectin DX (PDX) is a member of the superfamily of specialized proresolving mediators and exerts anti-inflammatory actions in animal models; however, its signaling mechanism remains unclear. Here, we demonstrate the analgesic actions of PDX in a mouse model of tibial fracture-induced postoperative pain (fPOP). Intravenous early- and late-phase treatment of PDX (100 ng/mouse) effectively alleviated fPOP. Compared with protectin D1 (PD1)/neuroprotectin D1, DHA, steroids, and meloxicam, PDX provided superior pain relief. While dexamethasone and meloxicam prolonged fPOP, PDX shortened the pain duration. The analgesic effects of PDX were abrogated in Gpr37-/- mice, which displayed deficits in fPOP resolution. PDX was shown to bind GPR37 and induce calcium responses in peritoneal macrophages. LC-MS/MS-based lipidomic analysis revealed that endogenous PDX levels were approximately 10-fold higher than those of PD1 in muscle at the fracture site. PDX promoted macrophage polarization via GPR37-dependent phagocytosis and efferocytosis through calcium signaling in vitro, and it further enhanced macrophage viability and efferocytosis in vivo via GPR37. Finally, PDX rapidly modulated nociceptor neuron responses by suppressing C-fiber-induced muscle reflex in vivo and calcium responses in DRG neurons ex vivo and by reducing TRPA1/TRPV1-induced acute pain and neurogenic inflammation in vivo. Our findings highlight multiple benefits of PDX to manage postoperative pain and promote perioperative recovery.

保护蛋白DX (PDX)是特化促炎介质超家族的成员,在动物模型中发挥抗炎作用;然而,其信号机制尚不清楚。在这里,我们展示了PDX在胫骨骨折术后疼痛(fPOP)小鼠模型中的镇痛作用。早期和晚期静脉注射PDX (100 ng/只)可有效缓解fPOP。与保护素D1 (PD1)/神经保护素D1、DHA、类固醇和美洛昔康相比,PDX具有更好的疼痛缓解效果。地塞米松和美洛昔康延长fPOP,而PDX缩短疼痛持续时间。在Gpr37-/-小鼠中,PDX的镇痛作用被消除,显示出fPOP分辨率的缺陷。PDX被证明可以结合GPR37并诱导腹腔巨噬细胞的钙反应。LC-MS/MS-based脂质组学分析显示,骨折部位肌肉中内源性PDX水平约为PD1水平的10倍。PDX在体外通过钙信号通路通过GPR37依赖性吞噬和efferocytosis促进巨噬细胞极化,在体内通过GPR37进一步增强巨噬细胞活力和efferocytosis。最后,PDX通过在体内抑制c纤维诱导的肌肉反射和DRG神经元的钙反应,以及在体内减少TRPA1/ trpv1诱导的急性疼痛和神经源性炎症,快速调节伤害感受器神经元的反应。我们的研究结果强调了PDX在控制术后疼痛和促进围手术期恢复方面的多重益处。
{"title":"Protectin DX resolves fracture-induced postoperative pain in mice via neuronal signaling and GPR37-activated macrophage efferocytosis.","authors":"Yize Li, Sangsu Bang, Jasmine Ji, Jing Xu, Min Lee, Sharat Chandra, Charles N Serhan, Ru-Rong Ji","doi":"10.1172/JCI190754","DOIUrl":"10.1172/JCI190754","url":null,"abstract":"<p><p>Protectin DX (PDX) is a member of the superfamily of specialized proresolving mediators and exerts anti-inflammatory actions in animal models; however, its signaling mechanism remains unclear. Here, we demonstrate the analgesic actions of PDX in a mouse model of tibial fracture-induced postoperative pain (fPOP). Intravenous early- and late-phase treatment of PDX (100 ng/mouse) effectively alleviated fPOP. Compared with protectin D1 (PD1)/neuroprotectin D1, DHA, steroids, and meloxicam, PDX provided superior pain relief. While dexamethasone and meloxicam prolonged fPOP, PDX shortened the pain duration. The analgesic effects of PDX were abrogated in Gpr37-/- mice, which displayed deficits in fPOP resolution. PDX was shown to bind GPR37 and induce calcium responses in peritoneal macrophages. LC-MS/MS-based lipidomic analysis revealed that endogenous PDX levels were approximately 10-fold higher than those of PD1 in muscle at the fracture site. PDX promoted macrophage polarization via GPR37-dependent phagocytosis and efferocytosis through calcium signaling in vitro, and it further enhanced macrophage viability and efferocytosis in vivo via GPR37. Finally, PDX rapidly modulated nociceptor neuron responses by suppressing C-fiber-induced muscle reflex in vivo and calcium responses in DRG neurons ex vivo and by reducing TRPA1/TRPV1-induced acute pain and neurogenic inflammation in vivo. Our findings highlight multiple benefits of PDX to manage postoperative pain and promote perioperative recovery.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"136 2","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12807480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989655","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
Retraction for Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer. 内聚蛋白复合体亚基体细胞突变的缩回赋予了癌症治疗的脆弱性。
IF 13.6 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-01-16 DOI: 10.1172/JCI202472
Yunhua Liu, Hanchen Xu, Kevin Van der Jeught, Yujing Li, Sheng Liu, Lu Zhang, Yuanzhang Fang, Xinna Zhang, Milan Radovich, Bryan P Schneider, Xiaoming He, Cheng Huang, Chi Zhang, Jun Wan, Guang Ji, Xiongbin Lu
{"title":"Retraction for Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer.","authors":"Yunhua Liu, Hanchen Xu, Kevin Van der Jeught, Yujing Li, Sheng Liu, Lu Zhang, Yuanzhang Fang, Xinna Zhang, Milan Radovich, Bryan P Schneider, Xiaoming He, Cheng Huang, Chi Zhang, Jun Wan, Guang Ji, Xiongbin Lu","doi":"10.1172/JCI202472","DOIUrl":"10.1172/JCI202472","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"136 2","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12807461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989639","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
Corrigendum to Axon guidance cue SLIT2 regulates the murine skeletal stem cell niche through sympathetic innervation. 轴突引导线索的勘误SLIT2通过交感神经支配调节小鼠骨骼干细胞生态位。
IF 13.6 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-01-16 DOI: 10.1172/JCI203674
Zuoxing Wu, Na Li, Zhengqiong Luo, Zihan Chen, Xuemei He, Jie Han, Xixi Lin, Fan Shi, Haitao Huang, Baohong Shi, Yu Li, Xin Wang, Lin Meng, Dachuan Zhang, Lanfen Chen, Dawang Zhou, Weinan Cheng, Matthew B Greenblatt, Ren Xu
{"title":"Corrigendum to Axon guidance cue SLIT2 regulates the murine skeletal stem cell niche through sympathetic innervation.","authors":"Zuoxing Wu, Na Li, Zhengqiong Luo, Zihan Chen, Xuemei He, Jie Han, Xixi Lin, Fan Shi, Haitao Huang, Baohong Shi, Yu Li, Xin Wang, Lin Meng, Dachuan Zhang, Lanfen Chen, Dawang Zhou, Weinan Cheng, Matthew B Greenblatt, Ren Xu","doi":"10.1172/JCI203674","DOIUrl":"10.1172/JCI203674","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"136 2","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12807457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989634","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
期刊
Journal of Clinical Investigation
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1