Journal of Clinical Investigation最新文献

{"title":"Microbial influencers: the airway microbiome's role in asthma.","authors":"Young Jin Kim, Supinda Bunyavanich","doi":"10.1172/JCI184316","DOIUrl":"10.1172/JCI184316","url":null,"abstract":"<p><p>Asthma is a common chronic respiratory disease affecting people of all ages globally. The airway hosts diverse microbial communities increasingly recognized as influential in the development and disease course of asthma. Here, we review recent findings on the airway microbiome in asthma. As relationships between the airway microbiome and respiratory health take root early in life, we first provide an overview of the early-life airway microbiome and asthma development, where multiple cohort studies have identified bacterial genera in the infant airway associated with risk of future wheeze and asthma. We then address current understandings of interactions between environmental factors, the airway microbiome, and asthma, including the effects of rural/urban environments, pet ownership, smoking, viral illness, and antibiotics. Next, we delve into what has been observed about the airway microbiome and asthma phenotypes and endotypes, as airway microbiota have been associated with asthma control, severity, obesity-related asthma, and treatment effects as well as with type 2 high, type 2 low, and more newly described multi-omic asthma endotypes. We then discuss emerging approaches to shape the microbiome for asthma therapy and conclude the Review with perspectives on future research directions.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 4","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441000","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":"Nonclassical action of Ku70 promotes Treg-suppressive function through a FOXP3-dependent mechanism in lung adenocarcinoma.","authors":"Qianru Huang, Na Tian, Jianfeng Zhang, Shiyang Song, Hao Cheng, Xinnan Liu, Wenle Zhang, Youqiong Ye, Yanhua Du, Xueyu Dai, Rui Liang, Dan Li, Sheng-Ming Dai, Chuan Wang, Zhi Chen, Qianjun Zhou, Bin Li","doi":"10.1172/JCI191305","DOIUrl":"10.1172/JCI191305","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 4","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441012","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":"Reinvigorating drug development around NGF signaling for pain.","authors":"Andi Wangzhou, Theodore J Price","doi":"10.1172/JCI189029","DOIUrl":"10.1172/JCI189029","url":null,"abstract":"<p><p>Nerve growth factor (NGF) signaling is a clinically validated target for the treatment of several prevalent types of chronic pain; however, addressing safety concerns remain a key challenge. In this issue of the JCI, Peach et al. take a major step forward in this area by deciphering complexities in the signaling of the NGF receptor TrkA, finding that neuropilin 1 (NRP1) acted as a coreceptor for NGF actions at TrkA and the receptor complex required scaffolding from GIPC1. Using a mix of techniques, including animal behavioral models, electrophysiology on mouse and human dorsal root ganglion (DRG) neurons, and elegant biochemical pharmacology, the authors demonstrated that this therapeutic target might more safely manipulate NGF signaling to achieve pain alleviation. While there are still important questions to answer, the innovative work paves the way for the development of nonopioid pain therapeutics.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 4","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440969","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":"Clinical Research and Public Health in the JCI.","authors":"Elizabeth M McNally","doi":"10.1172/JCI190119","DOIUrl":"10.1172/JCI190119","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 4","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441063","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":"The microbiome as a modulator of neurological health across the maternal-offspring interface.","authors":"Stephanie B Orchanian, Elaine Y Hsiao","doi":"10.1172/JCI184314","DOIUrl":"10.1172/JCI184314","url":null,"abstract":"<p><p>The maternal microbiome is emerging as an important factor that influences the neurological health of mothers and their children. Recent studies highlight how microbial communities in the maternal gut can shape early-life development in ways that inform long-term health trajectories. Research on the neurodevelopmental effects of maternal microbiomes is expanding our understanding of the microbiome-gut-brain axis to include signaling across the maternal-offspring unit during the perinatal period. In this Review, we synthesize existing literature on how the maternal microbiome modulates brain function and behavior in both mothers and their developing offspring. We present evidence from human and animal studies showing that the maternal microbiome interacts with environmental factors to impact risk for neurodevelopmental abnormalities. We further discuss molecular and cellular mechanisms that facilitate maternal-offspring crosstalk for neuromodulation. Finally, we consider how advancing understanding of these complex interactions could lead to microbiome-based interventions for promoting maternal and offspring health.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 4","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440973","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":"FOXP1 controls mesenchymal stem cell commitment and senescence during skeletal aging.","authors":"Hanjun Li, Pei Liu, Shuqin Xu, Yinghua Li, Joseph D Dekker, Baojie Li, Ying Fan, Zhenlin Zhang, Yang Hong, Gong Yang, Tingting Tang, Yongxin Ren, Haley O Tucker, Zhengju Yao, Xizhi Guo","doi":"10.1172/JCI191424","DOIUrl":"10.1172/JCI191424","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 4","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440993","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":"An FDA-approved drug structurally and phenotypically corrects the K210del mutation in genetic cardiomyopathy models.","authors":"Ping Wang, Mahmoud Salama Ahmed, Ngoc Uyen Nhi Nguyen, Ivan Menendez-Montes, Ching-Cheng Hsu, Ayman B Farag, Suwannee Thet, Nicholas T Lam, Janaka P Wansapura, Eric Crossley, Ning Ma, Shane Rui Zhao, Tiejun Zhang, Sachio Morimoto, Rohit Singh, Waleed Elhelaly, Tara C Tassin, Alisson C Cardoso, Noelle S Williams, Hayley L Pointer, David A Elliott, James W McNamara, Kevin I Watt, Enzo R Porrello, Sakthivel Sadayappan, Hesham A Sadek","doi":"10.1172/JCI174081","DOIUrl":"10.1172/JCI174081","url":null,"abstract":"<p><p>Dilated cardiomyopathy (DCM) due to genetic disorders results in decreased myocardial contractility, leading to high morbidity and mortality rates. There are several therapeutic challenges in treating DCM, including poor understanding of the underlying mechanism of impaired myocardial contractility and the difficulty of developing targeted therapies to reverse mutation-specific pathologies. In this report, we focused on K210del, a DCM-causing mutation, due to 3-nucleotide deletion of sarcomeric troponin T (TnnT), resulting in loss of Lysine210. We resolved the crystal structure of the troponin complex carrying the K210del mutation. K210del induced an allosteric shift in the troponin complex resulting in distortion of activation Ca2+-binding domain of troponin C (TnnC) at S69, resulting in calcium discoordination. Next, we adopted a structure-based drug repurposing approach to identify bisphosphonate risedronate as a potential structural corrector for the mutant troponin complex. Cocrystallization of risedronate with the mutant troponin complex restored the normal configuration of S69 and calcium coordination. Risedronate normalized force generation in K210del patient-induced pluripotent stem cell-derived (iPSC-derived) cardiomyocytes and improved calcium sensitivity in skinned papillary muscles isolated from K210del mice. Systemic administration of risedronate to K210del mice normalized left ventricular ejection fraction. Collectively, these results identify the structural basis for decreased calcium sensitivity in K210del and highlight structural and phenotypic correction as a potential therapeutic strategy in genetic cardiomyopathies.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 4","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441059","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":"Metastatic Tumor Growth in Steatotic Liver is Promoted by HAS2-Mediated Fibrotic Tumor Microenvironment.","authors":"Yoon Mee Yang, Jieun Kim, Zhijun Wang, Jina Kim, So Yeon Kim, Gyu Jeong Cho, Jee Hyung Lee, Sun Myoung Kim, Takashi Tsuchiya, Michitaka Matsuda, Vijay Pandyarajan, Stephen J Pandol, Michael S Lewis, Alexandra Gangi, Paul W Noble, Dianhua Jiang, Akil Merchant, Edwin M Posadas, Neil A Bhowmick, Shelly C Lu, Sungyong You, Alexander M Xu, Ekihiro Seki","doi":"10.1172/JCI180802","DOIUrl":"10.1172/JCI180802","url":null,"abstract":"<p><p>Steatotic liver enhances liver metastasis of colorectal cancer, but this process is not fully understood. Steatotic liver induced by a high-fat diet (HFD) increases cancer-associated fibroblast (CAF) infiltration and collagen and hyaluronic acid (HA) production. We investigated the role of HA synthase 2 (HAS2) in the fibrotic tumor microenvironment in steatotic liver using Has2ΔHSC mice, in which Has2 is deleted from hepatic stellate cells. Has2ΔHSC mice had reduced steatotoic liver-associated metastatic tumor growth of MC38 colorectal cancer cells, collagen and HA deposition, and CAF and M2 macrophage infiltration. We found low-molecular-weight HA activates yes-associated protein (YAP) in cancer cells, which then releases connective tissue growth factor to further activate CAFs for HAS2 expression. Single-cell analyses revealed a link between CAF-derived HAS2 with M2 macrophages and colorectal cancer cells through CD44; these cells associated with exhausted CD8 T cells via programmed death-ligand 1 and programmed cell death protein 1. The HA synthesis inhibitors reduced steatotic liver-associated metastasis of colorectal cancer, YAP expression, CAF and M2 macrophage infiltration. In conclusion, steatotic liver modulates a fibrotic tumor microenvironment to enhance metastatic cancer activity through a bidirectional regulation between CAFs and metastatic tumors, enhancing the metastatic potential of colorectal cancer in the liver.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414393","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":"PGLYRP2 drives hepatocyte-intrinsic innate immunity by trapping and clearing hepatitis B virus.","authors":"Ying Li, Huihui Ma, Yongjian Zhang, Tinghui He, Binyang Li, Haoran Ren, Jia Feng, Jie Sheng, Kai Li, Yu Qian, Yunfeng Wang, Haoran Zhao, Jie He, Huicheng Li, Hongjin Wu, Yuanfei Yao, Ming Shi","doi":"10.1172/JCI188083","DOIUrl":"https://doi.org/10.1172/JCI188083","url":null,"abstract":"<p><p>Spontaneous clearance of hepatitis B virus (HBV) is frequent in adults (95%) but rare in infants (5%), emphasizing the critical role of age-related hepatic immunocompetence. However, the underlying mechanisms of hepatocyte-specific immunosurveillance and age-dependent HBV clearance remain unclear. Here, we identified PGLYRP2 as a hepatocyte-specific pattern recognition receptor with age-dependent expression, and demonstrated that phase separation of PGLYRP2 was a critical driver of spontaneous HBV clearance in hepatocytes. Mechanistically, PGLYRP2 recognized and potentially eliminated covalently closed circular DNA (cccDNA) via phase separation, coordinated by its intrinsically disordered region and HBV DNA-binding domain (PGLYRP2IDR/209-377) in the nucleus. Additionally, PGLYRP2 suppressed HBV capsid assembly by directly interacting with the viral capsid, mediated by its PGRP domain. This interaction promoted the nucleocytoplasmic translocation of PGLYRP2 and subsequent secretion of the PGLYRP2-HBV capsid complex, thereby bolstering the hepatic antiviral response. Pathogenic variants or deletions in PGLYRP2 impaired its ability to inhibit HBV replication, highlighting its essential role in hepatocyte-intrinsic immunity. These findings suggest that targeting the PGLYRP2-mediated host-virus interaction may offer a potential therapeutic strategy for the development of anti-HBV treatments, representing a promising avenue for achieving a functional cure for HBV infection.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414395","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":"Ablating VHL in Rod Photoreceptors Modulates RPE Glycolysis and Improves Preclinical Model of Retinitis Pigmentosa.","authors":"Salvatore Marco Caruso, Xuan Cui, Brian M Robbings, Noah Heaps, Aykut Demikrol, Bruna Lopes da Costa, Daniel T Hass, Peter Mj Quinn, Jianhai Du, James B Hurley, Stephen H Tsang","doi":"10.1172/JCI185796","DOIUrl":"https://doi.org/10.1172/JCI185796","url":null,"abstract":"<p><p>Neuroretinal degenerations including retinitis pigmentosa (RP) comprise a heterogeneous collection of pathogenic mutations that ultimately result in blindness. Despite recent advances in precision medicine, therapies for rarer mutations are hindered by burdensome developmental costs. To this end, Von Hippel-Lindau (VHL) is an attractive therapeutic target to treat RP. By ablating VHL in rod photoreceptors and elevating hypoxia-inducible factor (HIF) levels, we demonstrate a path to therapeutically enhancing glycolysis independent of the underlying genetic variant that slows degeneration of both rod and cone photoreceptors in a preclinical model of retinitis pigmentosa. This rod-specific intervention also resulted in reciprocal, decreased glycolytic activity within the retinal pigment epithelium (RPE) cells despite no direct genetic modifications to the RPE. Suppressing glycolysis in the RPE provided notable, non-cell-autonomous therapeutic benefits to the photoreceptors, indicative of metabolically sensitive crosstalk between different cellular compartments of the retina. Surprisingly, targeting HIF2A in RPE cells did not impact RPE glycolysis, potentially implicating HIF1A as a major regulator in mouse RPE and providing a rationale for future therapeutic efforts aimed at modulating RPE metabolism.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399323","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}