JCI insight最新文献_第2页

Transplantation of endothelial progenitor cells attenuates pulmonary fibrosis via IFITM3-containing exosomes. 内皮祖细胞移植通过含ifitm3的外泌体减轻肺纤维化。

IF 6.8 1区医学

JCI insight Pub Date : 2026-10-08 DOI: 10.1172/jci.insight.199743

Ying-Wei Lan, Jonathan Do, Wen Gao, Zicheng Deng, Xiaomei Xia, Enhong Li, Jillian Kash, Gautam Verma, Angara Sureshbabu, Kenneth S Knox, Ross M Bremner, Nicholas E Banovich, Vladimir V Kalinichenko, Tanya V Kalin

{"title":"Transplantation of endothelial progenitor cells attenuates pulmonary fibrosis via IFITM3-containing exosomes.","authors":"Ying-Wei Lan, Jonathan Do, Wen Gao, Zicheng Deng, Xiaomei Xia, Enhong Li, Jillian Kash, Gautam Verma, Angara Sureshbabu, Kenneth S Knox, Ross M Bremner, Nicholas E Banovich, Vladimir V Kalinichenko, Tanya V Kalin","doi":"10.1172/jci.insight.199743","DOIUrl":"https://doi.org/10.1172/jci.insight.199743","url":null,"abstract":"Endothelial progenitor cells (EPCs) are critical for vascular regeneration after injury. However, their role in pulmonary fibrosis (PF) remains unclear. Here, we identified a previously unrecognized population of lung capillary EPCs coexpressing c-KIT and FOXF1 (capEPCs) in adult human and mouse lungs. capEPCs were significantly reduced in lungs from patients with PF and in bleomycin-injured mice, implicating loss of this regenerative endothelial population in disease pathogenesis. Transplantation of donor capEPCs attenuated experimental PF, improved survival, reduced collagen deposition, and restored lung function. Donor capEPCs engrafted into the lung microcirculation of bleomycin-injured mice. Single-cell RNA sequencing identified interferon-induced transmembrane protein 3 as a highly enriched transcript in capEPCs. Conditioned media from IFITM3-overexpressing EPCs or recombinant IFITM3 enhanced endothelial proliferation and angiogenesis while suppressing TGF-β1-induced fibroblast activation in vitro. IFITM3 was found in capEPC-derived exosomes. Treatment with IFITM3-containing exosomes recapitulated the therapeutic effects of capEPC transplantation by improving endothelial function, inhibiting fibroblast activation, increasing animal survival, reducing lung fibrosis, and restoring lung function. Together these findings identified capEPC deficiency as a feature of PF and demonstrated that IFITM3-containing exosomes promoted vascular repair. Restoration of capEPC regenerative function or delivery of IFITM3-enriched exosomes may represent a promising therapeutic strategy for human PF.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 19","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136551","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

Innate allorecognition induces HSP70 in monocytes contributing to renal allograft rejection. 先天同种异体识别诱导单核细胞HSP70参与肾移植排斥反应。

IF 6.8 1区医学

JCI insight Pub Date : 2026-10-08 DOI: 10.1172/jci.insight.197348

Zeping Gui, Neda Feizi, Berkay Demirors, Canxiang Lin, Hehua Dai, Mouhamad Al Moussawy, Andrew Friday, Steven M Sanders, Latha Halesha, Amanda L Williams, Faruk Sacirbegovic, Parmjeet S Randhawa, Khodor I Abou-Daya, Martin H Oberbarnscheidt

{"title":"Innate allorecognition induces HSP70 in monocytes contributing to renal allograft rejection.","authors":"Zeping Gui, Neda Feizi, Berkay Demirors, Canxiang Lin, Hehua Dai, Mouhamad Al Moussawy, Andrew Friday, Steven M Sanders, Latha Halesha, Amanda L Williams, Faruk Sacirbegovic, Parmjeet S Randhawa, Khodor I Abou-Daya, Martin H Oberbarnscheidt","doi":"10.1172/jci.insight.197348","DOIUrl":"10.1172/jci.insight.197348","url":null,"abstract":"After encountering allogeneic nonself, monocytes differentiate to DCs, which in turn activate the adaptive immune system that drives transplant rejection. The downstream mechanisms of allorecognition are largely unknown. We analyzed scRNA-seq data sets to identify transcriptional changes in monocytes occurring after allostimulation. Hspa1a, which encodes HSP70, was upregulated in monocytes after allostimulation in contrast to syngeneic controls in mice lacking T, B, and NK cells. Similar findings were seen in scRNA-seq data derived from kidney biopsies of rejecting transplant patients. To validate the role of HSP70 in innate allorecognition and transplantation, we performed allogeneic bone marrow plug and kidney transplantation into WT, Hspa1a/Hspa1b-/-, and DSG-treated (HSP70 inhibitor) B6 mice and examined the graft immune infiltrate. Histology, T cell infiltration, and survival were assessed in kidney transplanted mice. In both models, DSG-treated or HSP70-KO recipients displayed significantly reduced infiltration by monocyte-derived DCs (mo-DC). Chronic rejection of Balb/c kidney grafts in WT B6 recipients was attenuated in DSG-treated and HSP70-KO recipients as indicated by a reduction in Banff score. Further experiments demonstrated that in vitro allostimulated immature HSP70-KO BMDC showed less maturation compared with WT BMDC. Targeting HSP70 in innate immune cells offers a novel approach to reduce chronic kidney graft rejection.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 19","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136485","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

Disrupted synaptic vacuolar H+-ATPase renders synaptic vulnerability to Alzheimer's disease. 突触空泡H+- atp酶的破坏使突触易患阿尔茨海默病。

IF 6.8 1区医学

JCI insight Pub Date : 2026-10-08 DOI: 10.1172/jci.insight.202983

Yanting Chen, Khloud Ashraf Farouk Emam, Shuwen Yue, Jing Tian, Tienju Wang, Albert Park, Shalini Mishra, Gagan Deep, Zi-Jun Wang, Heng Du, Lan Guo

{"title":"Disrupted synaptic vacuolar H+-ATPase renders synaptic vulnerability to Alzheimer's disease.","authors":"Yanting Chen, Khloud Ashraf Farouk Emam, Shuwen Yue, Jing Tian, Tienju Wang, Albert Park, Shalini Mishra, Gagan Deep, Zi-Jun Wang, Heng Du, Lan Guo","doi":"10.1172/jci.insight.202983","DOIUrl":"10.1172/jci.insight.202983","url":null,"abstract":"Defective synaptic transmission is a prominent pathology that underlies cognitive deficits in Alzheimer's disease (AD), highlighting the need to elucidate molecular mechanisms of synaptic failure. Vacuolar H+-ATPase (V-ATPase), a proton-pumping enzyme, is essential for synaptic vesicle acidification and neurotransmitter loading. However, whether SV-associated V-ATPase is vulnerable to AD remains unclear. Here, using SV-rich fractions from postmortem brain tissues, we identified SV-associated V-ATPase deficits, including decreased enzymatic activity, impaired complex assembly, and altered expression of its key subunits in AD. SV-associated V-ATPase dysfunction was further associated with pathological and clinical characteristics of AD. Genetic downregulation of the V-ATPase V1D subunit, a component reduced in AD brains, disrupted V-ATPase proton transport and impaired SV acidification. Further experiments using 5×FAD mice, which exhibited AD-like SV-associated V-ATPase deficits, demonstrated the deleterious impact of V-ATPase dysfunction on SV acidification and synaptic transmission including presynaptic neurotransmitter release. In addition, ex vivo studies identified amyloid β-induced oxidative stress as a driver of V1D loss and V-ATPase disassembly, linking AD pathology to SV-associated V-ATPase dysfunction. These findings indicate that SV-associated V-ATPase dysfunction contributes to synaptic failure and cognitive deficits in AD. Therapeutic avenues to mitigate V-ATPase dysfunction have the potential to attenuate synaptic failure for the management of AD.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 19","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136498","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

177Lu-labeled DOTA-EB-RGD as a candidate for thyroid cancer therapy. 177lu标记的DOTA-EB-RGD作为甲状腺癌治疗的候选药物。

IF 6.8 1区医学

JCI insight Pub Date : 2026-10-08 DOI: 10.1172/jci.insight.200594

Sonam Kumari, Rhitajit Sarkar, Zhantong Wang, Shilpa Thakur, Laura Abaandou, Oksana Gavrilova, Huiyan Lu, Noha Behairy, Lixin Lang, Dale Kiesewetter, Vasyl Vasko, Joanna Klubo-Gwiezdzinska

{"title":"177Lu-labeled DOTA-EB-RGD as a candidate for thyroid cancer therapy.","authors":"Sonam Kumari, Rhitajit Sarkar, Zhantong Wang, Shilpa Thakur, Laura Abaandou, Oksana Gavrilova, Huiyan Lu, Noha Behairy, Lixin Lang, Dale Kiesewetter, Vasyl Vasko, Joanna Klubo-Gwiezdzinska","doi":"10.1172/jci.insight.200594","DOIUrl":"https://doi.org/10.1172/jci.insight.200594","url":null,"abstract":"Integrin αVβ3, a transmembrane receptor involved in tumor growth and metastasis, specifically recognizes and binds proteins with the Arg-Gly-Asp (RGD) peptide sequence. Using mRNA and/or protein expression data from 496 thyroid cancer (TC) samples in The Cancer Genome Atlas, 14 TC cell lines, and 70 TC and 10 normal thyroid tissues, we found that papillary TC exhibits the highest αVβ3 integrin expression. We then evaluated the therapeutic efficacy of a radiolabeled RGD analog, 177Lu-DOTA-EB-cRGDfK, in TC. Genetic knockout and overexpression of αVβ3 in TC cell lines confirmed the target specificity of 177Lu-DOTA-EB-cRGDfK. In mouse xenograft models established from human TC cell lines with high αVβ3 expression, 177Lu-DOTA-EB-cRGDfK demonstrated superior antitumor efficacy compared with standard-of-care lenvatinib and placebo. However, no synergistic benefit was observed with combination therapy. Biodistribution studies identified the kidneys as the dose-limiting organ. RNA-seq analysis of resected tumors demonstrated that 177Lu-DOTA-EB-cRGDfK induced a type I IFN response, characterized by upregulation of IFI6, IFIT1-2, and MX1, compared with both lenvatinib-treated tumors and placebo. These findings identify αVβ3 integrin as a promising therapeutic target in a subset of TCs and demonstrate that 177Lu-DOTA-EB-cRGDfK exhibits superior efficacy to lenvatinib, supporting its potential clinical translation for progressive TC refractory to standard therapies.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 19","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136517","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

Human filarial infection reshapes CD8+ T-cell transcription and function at homeostasis and following viral activation. 人丝虫病感染重塑CD8+ t细胞的转录和功能在稳态和病毒激活后。

IF 6.8 1区医学

JCI insight Pub Date : 2026-10-08 DOI: 10.1172/jci.insight.206042

Camila Queiroz-Glauss, Justin Lack, Daniel E Sturdevant, Thomas B Nutman

{"title":"Human filarial infection reshapes CD8+ T-cell transcription and function at homeostasis and following viral activation.","authors":"Camila Queiroz-Glauss, Justin Lack, Daniel E Sturdevant, Thomas B Nutman","doi":"10.1172/jci.insight.206042","DOIUrl":"https://doi.org/10.1172/jci.insight.206042","url":null,"abstract":"The role of CD8+ T cells in filarial infections remains poorly understood. Given the chronic nature of these infections, individuals living in endemic regions are frequently exposed to other pathogens including viruses. Because CD8 cells are essential for antiviral immunity, understanding how filarial infections shape the cytotoxic compartment is essential to elucidate their impact on bystander immunity. We evaluated the phenotype and function of CD8+ T cells from Loa loa-infected (Fil+) and -uninfected (Fil-) individuals at baseline and following cytomegalovirus (CMV) re-stimulation. Filarial infection was associated with increased activation and proliferation of CD8+ T cells, characterized by elevated expression of Ki-67, CD107a, and production of type 1 and 17 cytokines. Upon CMV re-stimulation, Fil+ individuals showed markedly reduced expansion of antigen-experienced (CD137+) and polyfunctional (CD137+IFN-γ+TNF-α+, CD137+IFN-γ+TNF-α+IL-2+) CD8+ T cells, along with decreased cytotoxic activity. Unbiased clustering analysis revealed markedly reduced frequency of the CD8+CD45RA+CD57+ subset in Fil+ individuals- a population further defined through transcriptomic profiling that showed enrichment for cytolytic gene signatures (GZMB, GNLY, GZMH, CD244, CX3CR1). These results demonstrated that filarial infection is associated with an altered CD8+ T cell profile that is associated with failure to mount effective viral-specific effector responses, including impaired cytokine production and cytotoxic activity.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136447","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

Multi-omics analyses reveal key immunological and metabolic correlates of mortality in HIV-associated Pneumocystis pneumonia. 多组学分析揭示了hiv相关肺囊虫肺炎死亡率的关键免疫学和代谢相关因素。

IF 6.8 1区医学

JCI insight Pub Date : 2026-10-06 DOI: 10.1172/jci.insight.206942

Peter Rossi-Smith, Ayanda Trevor Mnguni, Dora Pungan, Robert J Samuels, Vaishnavi R Kumaran, Leena Syed, Trevor Ferris, Kamil Skirlo, Joseph N Jarvis, Nelesh P Govender, Graeme Meintjes, Sean Wasserman, Jay K Kolls, Rachel Pj Lai

{"title":"Multi-omics analyses reveal key immunological and metabolic correlates of mortality in HIV-associated Pneumocystis pneumonia.","authors":"Peter Rossi-Smith, Ayanda Trevor Mnguni, Dora Pungan, Robert J Samuels, Vaishnavi R Kumaran, Leena Syed, Trevor Ferris, Kamil Skirlo, Joseph N Jarvis, Nelesh P Govender, Graeme Meintjes, Sean Wasserman, Jay K Kolls, Rachel Pj Lai","doi":"10.1172/jci.insight.206942","DOIUrl":"https://doi.org/10.1172/jci.insight.206942","url":null,"abstract":"Pneumocystis jirovecii pneumonia (PCP) remains a major cause of life-threatening respiratory failure in people with advanced HIV, yet the biological factors associated with mortality are incompletely understood. We performed integrated transcriptomic, proteomic, and metabolomic profiling of bronchoalveolar lavage fluid from 42 adults with HIV-associated PCP, relating molecular signatures to mortality. We found that fungal burden, measured by sputum immunofluorescence, Pneumocystis qPCR, and 1,3-β-D-glucan, did not differ between survivors and non-survivors or correlate with baseline gas exchange. Instead, non-survivors exhibited a bronchoalveolar immunometabolic failure signature characterised by marked depletion of immunoglobulins and complement, reduced pattern recognition receptors and fibroblast growth factor family proteins, and broad disruption of extracellular matrix organisation. Metabolomic profiling revealed enrichment of arginine-urea cycle and tricarboxylic acid pathways, with coordinated accumulation of arginine, citrulline, and TCA cycle intermediates consistent with nitrosative and mitochondrial stress. An integrated proteo-metabolomic score summarising this state was significantly higher in non-survivors and did not correlate with fungal burden or cytomegalovirus co-infection. In an immunodeficient precision-cut lung slice model, antigen-screened intravenous immunoglobulin restored macrophage-mediated Pneumocystis clearance, providing proof-of-concept for opsonic augmentation. Our findings indicate that mortality in HIV-PCP is defined by profound immunometabolic failure, highlighting humoral depletion and impaired alveolar repair as potential targets for host-directed adjunctive therapy.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109912","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

Impaired regulation of nuclear calcium signals is a driver of chronic liver disease. 核钙信号的调节受损是慢性肝病的驱动因素。

IF 6.8 1区医学

JCI insight Pub Date : 2026-10-06 DOI: 10.1172/jci.insight.204059

Jittima Weerachayaphorn, Mateus T Guerra, Naotaka Kugiyama, Emma Kruglov, Dejian Zhao, Piyachat Chansela, Vitoon Saengsirisuwan, Marie E Robert, Teruo Utsumi, Yasuko Iwakiri, Michael H Nathanson

{"title":"Impaired regulation of nuclear calcium signals is a driver of chronic liver disease.","authors":"Jittima Weerachayaphorn, Mateus T Guerra, Naotaka Kugiyama, Emma Kruglov, Dejian Zhao, Piyachat Chansela, Vitoon Saengsirisuwan, Marie E Robert, Teruo Utsumi, Yasuko Iwakiri, Michael H Nathanson","doi":"10.1172/jci.insight.204059","DOIUrl":"https://doi.org/10.1172/jci.insight.204059","url":null,"abstract":"Chronic liver disease affects over a billion people worldwide. Despite diverse etiologies, a unifying feature of chronic liver disease is the liver's impaired ability to regenerate during progression to cirrhosis, but no common molecular mechanism has been identified. Hepatocyte proliferation and liver regeneration depend on nucleoplasmic calcium (Ca2+) signals, and Ca2+ signals in hepatocytes depend on the type 2 inositol trisphosphate receptor (ITPR2) calcium release channel. Here, we found that ITPR2 was localized in part to the hepatocyte nucleus, and this localization depended on the presence of nucleoporin 62 (NUP62). Loss of either ITPR2 or NUP62 disrupted nuclear Ca2+ signaling, and impaired Ca2+ signals in the nucleus blunted nuclear entry of β-catenin. Remarkably, both ITPR2 and NUP62 are progressively lost from hepatocytes in patients with the four most common types of chronic liver disease. These findings identify a microdomain regulating Ca2+ signaling in the hepatocyte nucleus that becomes progressively disrupted as liver disease progresses. Preservation of this nuclear microdomain may be a novel approach to maintain liver regeneration and slow the progression to cirrhosis in chronic liver disease.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109906","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

Anti-CRF antibody-mediated HPA axis modulation induces selective fat mass loss with lean mass preservation. 抗crf抗体介导的HPA轴调节诱导选择性脂肪质量减少和瘦质量保存。

IF 6.8 1区医学

JCI insight Pub Date : 2026-10-06 DOI: 10.1172/jci.insight.210525

Zachary A Krumm, Tariful Islam, Caroline M Watson, Yong Ran, Yona Levites, Hunter S Futch, Luming Yin, Edgardo Rodriguez-Lebron, Xuefei Liu, Kazi Farhana Afroz, Ariella Goloborodsky, Thomas B Ladd, Kristy D Dillon, Danny Ryu, Jennifer L Bizon, Jada Lewis, Karen A Scott, Annette de Kloet, Nicholas T Seyfried, Eric G Krause, Karen N McFarland, Todd E Golde

{"title":"Anti-CRF antibody-mediated HPA axis modulation induces selective fat mass loss with lean mass preservation.","authors":"Zachary A Krumm, Tariful Islam, Caroline M Watson, Yong Ran, Yona Levites, Hunter S Futch, Luming Yin, Edgardo Rodriguez-Lebron, Xuefei Liu, Kazi Farhana Afroz, Ariella Goloborodsky, Thomas B Ladd, Kristy D Dillon, Danny Ryu, Jennifer L Bizon, Jada Lewis, Karen A Scott, Annette de Kloet, Nicholas T Seyfried, Eric G Krause, Karen N McFarland, Todd E Golde","doi":"10.1172/jci.insight.210525","DOIUrl":"https://doi.org/10.1172/jci.insight.210525","url":null,"abstract":"The hypothalamic-pituitary-adrenal (HPA) axis integrates central neural processing and responses to stress with endocrine and metabolic responses. We utilized a monoclonal antibody binding corticotrophin-releasing factor (anti-CRF) to achieve durable HPA axis modulation. In mice, anti-CRF treatment decreased plasma corticosterone, food-intake, body weight and fat mass, but preserved lean mass and improved metabolic parameters including insulin sensitization. These body composition effects were observed in middle aged mice on normal chow or high fat diet, aged mice, and Mc4r-/- and ob/ob mice. Single-dose studies demonstrated impacts on weight gain and body composition lasting beyond the period of pharmacological target engagement. Multi-organ transcriptomic and proteomic analyses revealed organ-specific effects of anti-CRF and are consistent with altered glucocorticoid receptor (GR) signaling as a mediator of the observed phenotypes. These studies support anti-CRF-mediated HPA-axis modulation as a metabolic and anti-obesity therapeutic approach distinct from incretins.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109743","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

Dystonia in a Timothy syndrome mouse model uncovers an interaction between Ca2+ and metabolism. 蒂莫西综合征小鼠模型中的肌张力障碍揭示了Ca2+与代谢之间的相互作用。

IF 6.8 1区医学

JCI insight Pub Date : 2026-10-06 DOI: 10.1172/jci.insight.207748

Patrick Towers, Hong-Gang Wang, Maiko Matsui, Geoffrey S Pitt

{"title":"Dystonia in a Timothy syndrome mouse model uncovers an interaction between Ca2+ and metabolism.","authors":"Patrick Towers, Hong-Gang Wang, Maiko Matsui, Geoffrey S Pitt","doi":"10.1172/jci.insight.207748","DOIUrl":"https://doi.org/10.1172/jci.insight.207748","url":null,"abstract":"The hypothesized cellular and molecular mechanisms underlying dystonia are broad and include mutations that perturb Ca2+ signaling, including those affecting voltage gated calcium channels (VGCC). In mice, pharmacological activation of neuronal L-type VGCCs induces dystonia in a dose dependent manner. Here we demonstrate that mice expressing a gain-of-function mutation in the L-type VGCC CaV1.2, associated with Timothy syndrome (TS), exhibit motor dysfunction consistent with dystonia. Although CaV1.2 is broadly expressed throughout peripheral tissues and across the brain, we establish that the dystonia-like behavior is driven by neuronal expression of the mutant calcium channel and observe an associated potential excitatory/inhibitory (E/I) imbalance. Because patients with TS have profound metabolic dysregulation, which is associated with some dystonias, we measured changes in circulating metabolites. The dystonia-like events are sensitive to perturbations in pyruvate metabolism, reminiscent of a subset of dystonias associated with pyruvate dysregulation. Our study provides insight into the potential convergence of previously established causes of dystonia, calcium signaling and metabolic homeostasis.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109874","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

Development of insulin resistance in women over the menopause transition. 绝经期妇女胰岛素抵抗的发展。

IF 6.8 1区医学

JCI insight Pub Date : 2026-10-06 DOI: 10.1172/jci.insight.206342

Arun S Karlamangla, Wei Juan Han, Preethi Srikanthan, Albert Shieh, Duncan Thomas, Barbara Sternfeld, Monique M Hedderson, Gail A Greendale

{"title":"Development of insulin resistance in women over the menopause transition.","authors":"Arun S Karlamangla, Wei Juan Han, Preethi Srikanthan, Albert Shieh, Duncan Thomas, Barbara Sternfeld, Monique M Hedderson, Gail A Greendale","doi":"10.1172/jci.insight.206342","DOIUrl":"https://doi.org/10.1172/jci.insight.206342","url":null,"abstract":"Background: Body weight and insulin resistance in women increase in midlife. It is not known whether this is driven by the menopause transition or solely by chronological aging. We aimed to determine the role of the menopause transition and menopause-related BMI changes in the development of insulin resistance in midlife women.Methods: Mixed effects, linear spline modeling of longitudinal data in 1315 women, 42- to 52-years-old, pre- or early perimenopausal in 1995 to 1996 with up to 16 follow up visits by 2018. Homeostatic-model-assessed-insulin-resistance (HOMA-IR) was measured up to 12 times. Date of final menstrual period (FMP) was prospectively determined.Results: HOMA-IR increased faster over a 4-year interval extending from 1.5 years prior to 2.5 years after the FMP, than in the years before or after it; p value for both slope changes < 0.0001. In the referent woman (White, age 52 years at FMP, non-smoker, body mass index [BMI] 25.6 kg/m2 at baseline, and not on sex hormone therapy or statins), the average annualized rate of HOMA-IR increase, adjusted for covariates including changes in BMI, was 1.2%, 4.3%, and 0.9% respectively, before, during, and after the 4-year transition.Conclusion: Consistent with an independent effect of the menopause transition, insulin resistance increased significantly faster during the transition (from 1.5 years before the to 2.5 years after the FMP) than in the years preceding or following the transition. Future studies need to investigate mechanisms underpinning this observed association and determine the impact of lifestyle on dampening menopause-associated increases in insulin resistance.Funding: National Institutes of Health.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109787","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