JCI insight最新文献

{"title":"Virologic effects of broadly neutralizing antibodies VRC01LS and VRC07-523LS on chronic HIV-1 infection.","authors":"Myra Happe, Rebecca M Lynch, Carl J Fichtenbaum, Sonya L Heath, Susan L Koletar, Raphael J Landovitz, Rachel M Presti, Jorge L Santana-Bagur, Randall L Tressler, LaSonji A Holman, Laura Novik, Jhoanna C Roa, Ro Shauna Rothwell, Larisa Strom, Jing Wang, Zonghui Hu, Michelle Conan-Cibotti, Anjali M Bhatnagar, Bridget Dwyer, Sung Hee Ko, Frida Belinky, Aryan M Namboodiri, Janardan P Pandey, Robin Carroll, Manjula Basappa, Leonid Serebryannyy, Sandeep R Narpala, Bob C Lin, Adrian B McDermott, Eli A Boritz, Edmund V Capparelli, Emily E Coates, Richard A Koup, Julie E Ledgerwood, John R Mascola, Grace L Chen, Pablo Tebas","doi":"10.1172/jci.insight.181496","DOIUrl":"10.1172/jci.insight.181496","url":null,"abstract":"<p><p>BACKGROUNDHIV-1-specific broadly neutralizing monoclonal antibodies (bNAbs) have emerged as promising interventions with the potential to effectively treat and prevent HIV-1 infections. We conducted a phase I clinical trial evaluating the potent CD4-binding site-specific (CD4bs-specific) bNAbs VRC01LS and VRC07-523LS in people with HIV-1 (PWH) not receiving antiretroviral therapy (ART).METHODSParticipants received a single intravenous 40 mg/kg dose of either VRC01LS (n = 7) or VRC07-523LS (n = 9) and did not initiate ART for a minimum of 14 days. The primary study objective was to evaluate safety and tolerability; the secondary study objectives were to evaluate pharmacokinetics (PK) and the impact of administered bNAbs on viral loads (VL) and CD4+ T cell counts in the absence of ART.RESULTSThis trial enrolled 16 PWH aged 20 to 57 years. Both bNAbs were safe and well tolerated. Mild local reactogenicity was only reported in participants who received VRC07-523LS, while both bNAbs were associated with mild systemic symptoms. Maximum serum concentrations (Cmax) following VRC01LS or VRC07-523LS were 1,566 ± 316 and 1,295 ± 376 μg/mL, respectively. VRC07-523LS administration significantly decreased VL in 8 out of 9 participants, with an average decline of 1.7 ± 0.8 log10 copies/mL within 14 days after administration. In contrast, VRC01LS administration resulted in a smaller average decline (0.8 ± 0.8 log10 copies/mL), and 3 out of 7 participants showedno change in VL. Postinfusion maximum decline in VL correlated with post hoc baseline in vitro viral susceptibility results for both bNAbs.CONCLUSIONThe results of this trial support inclusion of potent CD4bs-specific bNAbs, such as VRC07-523LS, into next-generation treatment regimens for HIV-1.TRIAL REGISTRATIONClinicalTrials.gov NCT02840474.FUNDINGNational Institute of Allergy and Infectious Diseases (NIAID)/NIH (grants UM1 AI068634, UM1 AI068636, UM1 AI106701, UM1AI069424, UM1AI069501, UM1AI69415, UM1AI069534, UM1AI69494); the Intramural Research Program of the NIAID/NIH; National Center for Advancing Translational Sciences/NIH (grants UM1TR004548, UL1TR001881, and UL1TR001878); and the National Cancer Institute/NIH (contract 75N91019D00024).</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 4","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483254","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":"CD103+ dendritic cell-fibroblast crosstalk via TLR9, TDO2, and AHR signaling drives lung fibrogenesis.","authors":"Hannah Carter, Rita Medina Costa, Taylor S Adams, Talon M Gilchrist, Claire E Emch, Monica Bame, Justin M Oldham, Steven K Huang, Angela L Linderholm, Imre Noth, Naftali Kaminski, Bethany B Moore, Stephen J Gurczynski","doi":"10.1172/jci.insight.177072","DOIUrl":"10.1172/jci.insight.177072","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients die from the disease within 2-5 years. The molecular pathogenesis underlying the immunologic changes that occur in IPF is poorly understood. We characterize noncanonical aryl-hydrocarbon receptor (ncAHR) signaling in DCs as playing a role in the production of IL-6 and increased IL-17+ cells, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2, which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing mice harboring a floxed AHR exon 2 deletion (AHRΔex2) with mice harboring a CD11c-Cre. Bleomycin (blm) was used to study fibrotic pathogenesis. Isolated CD11c+ cells and primary fibroblasts were treated ex vivo with relevant TLR agonists and AHR-modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis; however, AHRΔex2 mice treated with blm developed more fibrosis, and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2, and fibrotic fibroblasts activated IL-6 production in CD103+ DCs. Study of human samples corroborated the relevance of these findings in patients with IPF. We also show, for the first time to our knowledge, that AHR exon 2 floxed mice retain the capacity for ncAHR signaling.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448815","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":"Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome-associated MSH2-deficient endometrial cancer.","authors":"Mikayla Borthwick Bowen, Brenda Melendez, Qian Zhang, Diana Moreno, Leah Peralta, Wai Kin Chan, Collene Jeter, Lin Tan, M Anna Zal, Philip L Lorenzi, Kenneth Dunner, Richard K Yang, Russell R Broaddus, Joseph Celestino, Nisha Gokul, Elizabeth Whitley, Deena M Scoville, Tae Hoon Kim, Jae-Wook Jeong, Rosemarie Schmandt, Karen Lu, Hyun-Eui Kim, Melinda S Yates","doi":"10.1172/jci.insight.185946","DOIUrl":"10.1172/jci.insight.185946","url":null,"abstract":"<p><p>Lynch syndrome (LS), caused by inherited mutations in DNA mismatch repair genes, including MSH2, carries a 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, mechanisms driving LS-associated EC (LS-EC) remain unclear. We investigated MSH2 loss in EC pathogenesis using a mouse model (PR-Cre Msh2LoxP/LoxP, abbreviated Msh2KO), primary cell lines, human tissues, and human EC cells with isogenic MSH2 knockdown. By 8 months, 58% of Msh2KO mice developed endometrial atypical hyperplasia (AH), a precancerous lesion. At 12-16 months, 50% of Msh2KO mice exhibited either AH or ECs with histologic similarities to human LS-ECs. Transcriptomic profiling of EC from Msh2KO mice revealed mitochondrial dysfunction-related pathway changes. Subsequent studies in vitro and in vivo revealed mitochondrial dysfunction based on 2 mechanisms: mitochondrial content reduction and structural disruptions in retained mitochondria. Human LS-ECs also exhibited mitochondrial content reduction compared with non-LS-ECs. Functional studies demonstrated metabolic reprogramming of MSH2-deficient EC, including reduced oxidative phosphorylation and increased susceptibility to glycolysis suppression. These findings identified mitochondrial dysfunction and metabolic disruption as consequences of MSH2 deficiency in EC. Mitochondrial and metabolic aberrations should be evaluated as biomarkers for endometrial carcinogenesis or risk stratification and represent potential targets for cancer interception in women with LS.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448842","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":"Complement activation at the interface between adipocytes and cancer cells drives tumor progression.","authors":"Andres Valdivia, Ana Maria Isac, Horacio Cardenas, Guangyuan Zhao, Yaqi Zhang, Hao Huang, Jian-Jun Wei, Mauricio Cuello-Fredes, Sumie Kato, Fernán Gómez-Valenzuela, Francoise Gourronc, Aloysius Klingelhutz, Daniela Matei","doi":"10.1172/jci.insight.184935","DOIUrl":"10.1172/jci.insight.184935","url":null,"abstract":"<p><p>The omentum is the primary site of metastasis for ovarian cancer (OC). Interactions between cancer cells and adipocytes drive an invasive and prometastatic phenotype. Here we studied cancer cell-adipocyte crosstalk by using a direct coculture model with immortalized human visceral nondiabetic pre-adipocytes (VNPADs) and OC cells. We demonstrated increased proliferation, invasiveness, and resistance to cisplatin of cocultured compared with monocultured OC cells. RNA sequencing of OC cells from coculture versus monoculture revealed significant transcriptomic changes, identifying over 200 differentially expressed genes common to OVCAR5 and OVCAR8 cell lines. Enriched pathways included PI3K/AKT and complement activation. Lipid transfer into OC cells from adipocytes induced upregulation of complement C3 and C5 proteins. Inhibiting C3 or C5 reversed the invasive phenotype and C3 knockdown reduced tumor progression in vivo. Increased C3 expression was observed in omental implants compared with primary ovarian tumors and C3 secretion was higher in OC ascites from high-BMI versus low-BMI patients. C3 upregulation in OC cells involved activation of the ATF4-mediated integrated stress response (ISR). Overall, adipocyte-cancer cell interactions promoted invasiveness and tumorigenesis via lipid transfer, activating the ISR, and upregulating complement proteins C3 and C5.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448821","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":"Inhibition of histone methyltransferase EZH2 for immune interception of colorectal cancer in Lynch syndrome.","authors":"Charles M Bowen, Fahriye Duzagac, Abel Martel-Martel, Laura Reyes-Uribe, Mahira Zaheer, Jacklyn Thompson, Nan Deng, Ria Sinha, Soham Mazumdar, Melissa W Taggart, Abhinav K Jain, Elena Tosti, Winfried Edelmann, Krishna M Sinha, Eduardo Vilar","doi":"10.1172/jci.insight.177545","DOIUrl":"10.1172/jci.insight.177545","url":null,"abstract":"<p><p>Colorectal precancers in Lynch syndrome (LS) exhibit a distinct immune profile, presenting unique opportunities for developing immune-interception strategies to prevent carcinogenesis. Epigenetic modulation by EZH2 of immune-related genes is implicated in the carcinogenesis of different cancer types, including colorectal cancer. This study utilizes a mouse model of LS and ex vivo colonic organoids to assess the effects of the EZH2 inhibitor GSK503 on immune regulatory pathways, tumorigenesis, and epigenetic reprogramming. Our findings revealed that GSK503 significantly increased CD4+ and CD8+ T cells in both splenocytes and colonic mucosa of treated mice compared with controls. Additionally, a preventive dose of GSK503 over 9 weeks notably reduced adenoma multiplicity, demonstrating its efficacy as a preventive modality. Single-cell RNA-Seq and molecular analyses showed activation of immune and apoptotic markers, along with a reduction in H3K27 methylation levels in colonic crypts. ChIP sequencing further revealed decreased levels of H3K27me3 and H3K4me1, while levels of the active enhancer marks H3K4me3 and H3K27Ac increased in treated mice. Collectively, these findings indicate that EZH2 inhibition enhances immune responses through epigenetic reprogramming in the genome of LS mice, establishing a promising framework for the clinical development of EZH2 inhibitors as a cancer prevention strategy for LS carriers.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414191","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 intracellular complement system drives metabolic and proinflammatory reprogramming of vascular fibroblasts in pulmonary hypertension.","authors":"Ram Raj Prasad, Sushil Kumar, Hui Zhang, Min Li, Cheng-Jun Hu, Suzette Riddle, Brittany A McKeon, M G Frid, Konrad Hoetzenecker, Slaven Crnkovic, Grazyna Kwapiszewska, Rubin M Tuder, Kurt R Stenmark","doi":"10.1172/jci.insight.184141","DOIUrl":"10.1172/jci.insight.184141","url":null,"abstract":"<p><p>The complement system is central to the innate immune response, playing a critical role in proinflammatory and autoimmune diseases such as pulmonary hypertension (PH). Recent discoveries highlight the emerging role of intracellular complement, or the \"complosome,\" in regulating cellular processes such as glycolysis, mitochondrial dynamics, and inflammatory gene expression. This study investigated the hypothesis that intracellular complement proteins C3, CFB, and CFD are upregulated in PH fibroblasts (PH-Fibs) and drive their metabolic and inflammatory states, contributing to PH progression. Our results revealed a pronounced upregulation of CFD, CFB, and C3 in PH-Fibs from human samples and bovine models, both in vivo and in vitro. The finding of elevated levels of C3 activation fragments, including C3b, C3d, and C3a, emphasized enhanced C3 activity. PH-Fibs exhibited notable metabolic reprogramming and increased levels of proinflammatory mediators such as MCP1, SDF1, IL-6, IL-13, and IL-33. Silencing CFD via shRNA reduced CFB activation and C3a production, while normalizing glycolysis, tricarboxylic acid (TCA) cycle activity, and fatty acid metabolism. Metabolomic and gene expression analyses of CFD-knockdown PH-Fibs revealed restored metabolic and inflammatory profiles, underscoring CFD's crucial role in these changes. This study emphasizes the crucial role of intracellular complement in PH pathogenesis, highlighting the potential for complement-targeted therapies in PH.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414045","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":"Effect of aging on pulmonary cellular responses during mechanical ventilation.","authors":"Aminmohamed Manji, Lefeng Wang, Cynthia M Pape, Lynda A McCaig, Alexandra Troitskaya, Onon Batnyam, Leah Jj McDonald, C Thomas Appleton, Ruud Aw Veldhuizen, Sean E Gill","doi":"10.1172/jci.insight.185834","DOIUrl":"10.1172/jci.insight.185834","url":null,"abstract":"<p><p>Acute respiratory distress syndrome (ARDS) results in substantial morbidity and mortality, especially in elderly people. Mechanical ventilation, a common supportive treatment for ARDS, is necessary for maintaining gas exchange but can also propagate injury. We hypothesized that aging leads to alterations in surfactant function, inflammatory signaling, and microvascular permeability within the lung during mechanical ventilation. Young and aged male mice were mechanically ventilated, and surfactant function, inflammation, and vascular permeability were assessed. Additionally, single-cell RNA-Seq was used to delineate cell-specific transcriptional changes. The results showed that, in aged mice, surfactant dysfunction and vascular permeability were significantly augmented, while inflammation was less pronounced. Differential gene expression and pathway analyses revealed that alveolar macrophages in aged mice showed a blunted inflammatory response, while aged endothelial cells exhibited altered cell-cell junction formation. In vitro functional analysis revealed that aged endothelial cells had an impaired ability to form a barrier. These results highlight the complex interplay between aging and mechanical ventilation, including an age-related predisposition to endothelial barrier dysfunction, due to altered cell-cell junction formation, and decreased inflammation, potentially due to immune exhaustion. It is concluded that age-related vascular changes may underlie the increased susceptibility to injury during mechanical ventilation in elderly patients.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414187","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":"Antisense oligonucleotides modulate aberrant inclusion of poison exons in SCN1A-related Dravet syndrome.","authors":"Sheng Tang, Hannah Stamberger, Jeffrey D Calhoun, Sarah Weckhuysen, Gemma L Carvill","doi":"10.1172/jci.insight.188014","DOIUrl":"10.1172/jci.insight.188014","url":null,"abstract":"<p><p>Dravet syndrome is a developmental and epileptic encephalopathy associated with pathogenic variants in SCN1A. Most disease-causing variants are located within coding regions, but recent work has shed light on the role of noncoding variants associated with a poison exon in intron 20 of SCN1A. Discovery of the SCN1A poison exon known as 20N has led to the first potential disease-modifying therapy for Dravet syndrome in the form of an antisense oligonucleotide. Here, we demonstrate the existence of 2 additional poison exons in introns 1 and 22 of SCN1A through targeted, deep-coverage long-read sequencing of SCN1A transcripts. We show that inclusion of these poison exons is developmentally regulated in the human brain, and that deep intronic variants associated with these poison exons lead to their aberrant inclusion in vitro in a minigene assay or in iPSC-derived neurons. Additionally, we show that splice-modulating antisense oligonucleotides can ameliorate aberrant inclusion of poison exons. Our findings highlight the role of deep intronic pathogenic variants in disease and provide additional therapeutic targets for precision medicine in Dravet syndrome and other SCN1A-related disorders.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414110","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":"Genotype-phenotype correlation in multiple endocrine neoplasia type 1.","authors":"Charlita C Worthy, Rana Tora, Chandra N Uttarkar, James M Welch, Lynn Bliss, Craig Cochran, Anisha Ninan, Sheila Kumar, Stephen Wank, Sungyoung Auh, Lee S Weinstein, William F Simonds, Sunita K Agarwal, Jenny E Blau, Smita Jha","doi":"10.1172/jci.insight.176993","DOIUrl":"10.1172/jci.insight.176993","url":null,"abstract":"<p><p>BACKGROUNDAmong patients with multiple endocrine neoplasia type 1 (MEN1), 80% develop duodenopancreatic neuroendocrine tumors (dpNETs), of whom 15%-25% die of metastasis. There is a need to identify biomarkers to predict aggressive disease. MEN1 genotype affords an attractive possibility as a biomarker, as it remains constant during life. Currently, patients are clinically diagnosed with MEN1 by the presence of ≥2 primary endocrine tumors (pituitary, parathyroid, and pancreas) or ≥1 primary endocrine tumor with a positive family history. From 10% to 30% of patients diagnosed clinically with MEN1 have no pathogenic germline MEN1 variants.METHODSThis was a retrospective study of 162 index patients or probands with genotype-positive and 47 with genotype-negative MEN1 enrolled from 1977 to 2022.RESULTSCompared with patients with genotype-negative disease, patients with genotype-positive disease were younger at diagnosis and had an increased frequency of recurrent parathyroid tumors, dpNETs, and angiofibromas or collagenomas. We propose a weighted scoring system to diagnose genotype-positive MEN1 based on clinical characteristics. No evidence of MEN1 mosaicism was seen in 30 tumors from 17 patients with genotype-negative MEN1. Patients with germline MEN1 variants in exons 2 and 3 had a reduced risk of distant metastases.CONCLUSIONThe clinical course of genotype-negative MEN1 is distinct from genotype-positive disease, raising uncertainty about the benefits of lifetime surveillance in patients with genotype-negative disease. MEN1 mosaicism is rare.TRIAL REGISTRATION ClinicalTrials.gov NCT04969926FUNDINGIntramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases, NIH (ZIA DK043006-46).</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414129","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":"Quinolinic acid potentially links kidney injury to brain toxicity.","authors":"Afaf Saliba, Subrata Debnath, Ian Tamayo, Hak Joo Lee, Nagarjunachary Ragi, Falguni Das, Richard Montellano, Jana Tumova, Meyer Maddox, Esmeralda Trevino, Pragya Singh, Caitlyn Fastenau, Soumya Maity, Guanshi Zhang, Leila Hejazi, Manjeri A Venkatachalam, Jason C O'Connor, Bernard Fongang, Sarah C Hopp, Kevin F Bieniek, James D Lechleiter, Kumar Sharma","doi":"10.1172/jci.insight.180229","DOIUrl":"10.1172/jci.insight.180229","url":null,"abstract":"<p><p>Kidney dysfunction often leads to neurological impairment, yet the complex kidney-brain relationship remains elusive. We employed spatial and bulk metabolomics to investigate a mouse model of rapid kidney failure induced by mouse double minute 2 (Mdm2) conditional deletion in the kidney tubules to interrogate kidney and brain metabolism. Pathway enrichment analysis of a focused plasma metabolomics panel pinpointed tryptophan metabolism as the most altered pathway with kidney failure. Spatial metabolomics showed toxic tryptophan metabolites in the kidneys and brains, revealing a connection between advanced kidney disease and accelerated kynurenine degradation. In particular, the excitotoxic metabolite quinolinic acid was localized in ependymal cells in the setting of kidney failure. These findings were associated with brain inflammation and cell death. Separate mouse models of ischemia-induced acute kidney injury and adenine-induced chronic kidney disease also exhibited systemic inflammation and accumulating toxic tryptophan metabolites. Patients with advanced chronic kidney disease (stage 3b-4 and stage 5) similarly demonstrated elevated plasma kynurenine metabolites, and quinolinic acid was uniquely correlated with fatigue and reduced quality of life. Overall, our study identifies the kynurenine pathway as a bridge between kidney decline, systemic inflammation, and brain toxicity, offering potential avenues for diagnosis and treatment of neurological issues in kidney disease.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414196","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}