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Ceramide(d18:1/18:1)-NDUFA6 interaction inactivates respiratory complex I to attenuate oxidative-stress-driven pathogenesis in liver ischemia/reperfusion injury. 神经酰胺(d18:1/18:1)-Ndufa6相互作用使呼吸复合体I失活,减轻肝脏缺血/再灌注损伤中氧化应激驱动的发病机制。
IF 6.3 1区 医学
JCI insight Pub Date : 2025-04-17 eCollection Date: 2025-05-22 DOI: 10.1172/jci.insight.187083
Kai Wang, Leyi Liao, Hanbiao Liang, Pengxiang Huang, Qingping Li, Baoxiong Zhuang, Chen Xie, Xiangyue Mo, Xuesong Deng, Jieyuan Li, Yang Lei, Minghui Zeng, Cungui Mao, Ruijuan Xu, Cuiting Liu, Xianqiu Wu, Jie Zhou, Biao Wang, Yiyi Li, Chuanjiang Li
{"title":"Ceramide(d18:1/18:1)-NDUFA6 interaction inactivates respiratory complex I to attenuate oxidative-stress-driven pathogenesis in liver ischemia/reperfusion injury.","authors":"Kai Wang, Leyi Liao, Hanbiao Liang, Pengxiang Huang, Qingping Li, Baoxiong Zhuang, Chen Xie, Xiangyue Mo, Xuesong Deng, Jieyuan Li, Yang Lei, Minghui Zeng, Cungui Mao, Ruijuan Xu, Cuiting Liu, Xianqiu Wu, Jie Zhou, Biao Wang, Yiyi Li, Chuanjiang Li","doi":"10.1172/jci.insight.187083","DOIUrl":"10.1172/jci.insight.187083","url":null,"abstract":"<p><p>Oxidative stress driven by malfunctioning respiratory complex I (RC-I) is a crucial pathogenic factor in liver ischemia/reperfusion (I/R) injury. This study investigated the role of alkaline ceramidase 3 (ACER3) and its unsaturated long-chain ceramide (CER) substrates in regulating liver I/R injury through RC-I. Our findings demonstrated that I/R upregulated ACER3 and decreased unsaturated long-chain CER levels in human and mouse livers. Both global and hepatocyte-specific Acer3 ablation, as well as treatment with CER(d18:1/18:1), led to a significant increase in CER(d18:1/18:1) levels in the liver, which mitigated the I/R-induced hepatocyte damage and inflammation in mice. Mechanistically, ACER3 modulated CER(d18:1/18:1) levels in mitochondria-associated membranes and the endoplasmic reticulum (ER), thereby influencing the transport of CER(d18:1/18:1) from the ER to mitochondria. Acer3 ablation and CER(d18:1/18:1) treatment elevated CER(d18:1/18:1) in mitochondria, where CER(d18:1/18:1) bound to the RC-I subunit NDUFA6 to inactivate RC-I and reduced reactive oxygen species production in the I/R-injured mouse liver. These findings underscore the role of the CER(d18:1/18:1)-NDUFA6 interaction in suppressing RC-I-mediated oxidative-stress-driven pathogenesis in liver I/R injury.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984032","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
METTL14 promotes intimal hyperplasia through m6A-mediated control of vascular smooth muscle dedifferentiation genes. METTL14通过m6a介导的血管平滑肌去分化基因调控促进内膜增生。
IF 6.3 1区 医学
JCI insight Pub Date : 2025-04-17 eCollection Date: 2025-05-22 DOI: 10.1172/jci.insight.184444
Grace Chensee, Bob Sl Lee, Immanuel D Green, Jessica Tieng, Renhua Song, Natalia Pinello, Quintin Lee, Majid Mehravar, David A Robinson, Mian Wang, Mary M Kavurma, Jun Yu, Justin Jl Wong, Renjing Liu
{"title":"METTL14 promotes intimal hyperplasia through m6A-mediated control of vascular smooth muscle dedifferentiation genes.","authors":"Grace Chensee, Bob Sl Lee, Immanuel D Green, Jessica Tieng, Renhua Song, Natalia Pinello, Quintin Lee, Majid Mehravar, David A Robinson, Mian Wang, Mary M Kavurma, Jun Yu, Justin Jl Wong, Renjing Liu","doi":"10.1172/jci.insight.184444","DOIUrl":"10.1172/jci.insight.184444","url":null,"abstract":"<p><p>Vascular smooth muscle cells (VSMCs) possess significant phenotypic plasticity, shifting between a contractile phenotype and a synthetic state for vascular repair/remodeling. Dysregulated VSMC transformation, marked by excessive proliferation and migration, primarily drives intimal hyperplasia. N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotes, plays a critical role in gene expression regulation; however, its impact on VSMC plasticity is not fully understood. We investigated the changes in m6A modification and its regulatory factors during VSMC phenotypic shifts and their influence on intimal hyperplasia. We demonstrate that METTL14, crucial for m6A deposition, significantly promoted VSMC dedifferentiation. METTL14 expression, initially negligible, was elevated in synthetic VSMC cultures, postinjury neointimal VSMCs, and human restenotic arteries. Reducing Mettl14 levels in mouse primary VSMCs decreased prosynthetic genes, suppressing their proliferation and migration. m6A-RIP-seq profiling showed key VSMC gene networks undergo altered m6A regulation in Mettl14-deficient cells. Mettl14 enhanced Klf4 and Serpine1 expression through increased m6A deposition. Local Mettl14 knockdown significantly curbed neointimal formation after arterial injury, and reducing Mettl14 in hyperplastic arteries halted further neointimal development. We show that Mettl14 is a pivotal regulator of VSMC dedifferentiation, influencing Klf4- and Serpine1-mediated phenotypic conversion. Inhibiting METTL14 is a viable strategy for preventing restenosis and halting restenotic occlusions.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017222","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
Shared roles of immune and stromal cells in the pathogenesis of human bronchiolitis obliterans syndrome. 免疫细胞和基质细胞在人闭塞性细支气管炎综合征发病机制中的共同作用。
IF 6.3 1区 医学
JCI insight Pub Date : 2025-04-15 eCollection Date: 2025-05-22 DOI: 10.1172/jci.insight.176596
Patrick W Mellors, Ana N Lange, Bruno Casino Remondo, Maksim Shestov, Joseph D Planer, Andrew R Peterson, Yun Ying, Su Zhou, Jason D Christie, Joshua M Diamond, Edward Cantu, Maria C Basil, Saar Gill
{"title":"Shared roles of immune and stromal cells in the pathogenesis of human bronchiolitis obliterans syndrome.","authors":"Patrick W Mellors, Ana N Lange, Bruno Casino Remondo, Maksim Shestov, Joseph D Planer, Andrew R Peterson, Yun Ying, Su Zhou, Jason D Christie, Joshua M Diamond, Edward Cantu, Maria C Basil, Saar Gill","doi":"10.1172/jci.insight.176596","DOIUrl":"10.1172/jci.insight.176596","url":null,"abstract":"<p><p>Bronchiolitis obliterans syndrome (BOS) is a progressive, fatal obstructive lung disease that occurs following lung transplant, where it is termed chronic lung allograft dysfunction BOS (CLAD-BOS), or as the primary manifestation of pulmonary chronic graft versus host disease (cGVHD-BOS) following allogeneic hematopoietic stem cell transplant. Disease pathogenesis is poorly understood; however, chronic alloreactivity is common to both conditions, suggesting a shared pathophysiology. We performed single-cell RNA-Seq (scRNA-Seq) on explanted human lungs from 4 patients with CLAD-BOS, 3 patients with cGVHD-BOS, and 3 deceased controls to identify cell types, genes, and pathways enriched in BOS to better understand disease mechanisms. In both forms of BOS, we found an expanded population of CD8+ tissue resident memory T cells (TRM), which was distinct to BOS compared with other chronic lung diseases. In addition, BOS samples expressed genes and pathways associated with macrophage chemotaxis and proliferation, including in nonimmune cell populations. We also identified dysfunctional stromal cells in BOS, characterized by pro- and antifibrotic gene programs. These data suggest substantial cellular and molecular overlap between CLAD- and cGVHD-BOS and, therefore, common pathways for possible therapeutic intervention.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983804","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
Interaction between native and prosthetic visual responses in optogenetic visual restoration. 光遗传视觉恢复中天然和假体视觉反应的相互作用。
IF 6.3 1区 医学
JCI insight Pub Date : 2025-04-15 eCollection Date: 2025-06-09 DOI: 10.1172/jci.insight.190785
Eleonora Carpentiero, Steven Hughes, Jessica Rodgers, Nermina Xhaferri, Sumit Biswas, Michael J Gilhooley, Mark W Hankins, Moritz Lindner
{"title":"Interaction between native and prosthetic visual responses in optogenetic visual restoration.","authors":"Eleonora Carpentiero, Steven Hughes, Jessica Rodgers, Nermina Xhaferri, Sumit Biswas, Michael J Gilhooley, Mark W Hankins, Moritz Lindner","doi":"10.1172/jci.insight.190785","DOIUrl":"10.1172/jci.insight.190785","url":null,"abstract":"<p><p>Degenerative retinal disorders leading to irreversible photoreceptor death are a common cause of blindness. Optogenetic gene therapy aims to restore vision in affected individuals by introducing light-sensitive opsins into the surviving neurons of the inner retina. While up until now, the main focus of optogenetic therapy has been on terminally blind individuals, treating at stages where residual native vision is present could have several advantages. However, it is still unknown how residual native and optogenetic vision would interact if present at the same time. Using transgenic mice expressing the optogenetic tool ReaChR in ON-bipolar cells, we herein examine this interaction through electroretinography (ERG) and visually evoked potentials (VEP). We find that optogenetic responses show a peculiar ERG signature and are enhanced in retinas without photoreceptor loss. Conversely, native responses are dampened in the presence of ReaChR. Moreover, in VEP recordings, we find that optogenetic responses reach the cortex asynchronous to the native response. These findings should be taken into consideration when planning future clinical trials and may direct future preclinical research to optimize optogenetic approaches for visual restoration. The identified ERG signatures, moreover, may serve to track treatment efficiency in clinical trials.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998432","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
The heme scavenger hemopexin protects against lung injury during aspergillosis by mitigating release of neutrophil extracellular traps. 血红素清除剂,血凝素,在曲霉病期间通过减轻中性粒细胞-细胞外陷阱的释放来防止肺损伤。
IF 6.3 1区 医学
JCI insight Pub Date : 2025-04-15 eCollection Date: 2025-05-22 DOI: 10.1172/jci.insight.189151
Ganlin Qu, Henrique Al Ribeiro, Angelica L Solomon, Luis Sordo Vieira, Yana Goddard, Nickolas G Diodati, Arantxa V Lazarte, Matthew Wheeler, Reinhard Laubenbacher, Borna Mehrad
{"title":"The heme scavenger hemopexin protects against lung injury during aspergillosis by mitigating release of neutrophil extracellular traps.","authors":"Ganlin Qu, Henrique Al Ribeiro, Angelica L Solomon, Luis Sordo Vieira, Yana Goddard, Nickolas G Diodati, Arantxa V Lazarte, Matthew Wheeler, Reinhard Laubenbacher, Borna Mehrad","doi":"10.1172/jci.insight.189151","DOIUrl":"10.1172/jci.insight.189151","url":null,"abstract":"<p><p>Invasive aspergillosis is characterized by lung hemorrhage and release of extracellular heme, which promotes fungal growth. Heme can also mediate tissue injury directly, and both fungal growth and lung injury may induce hemorrhage. To assimilate these interdependent processes, we hypothesized that, during aspergillosis, heme mediates direct lung injury independent of fungal growth, leading to worse infection outcomes, and the scavenger protein hemopexin mitigates these effects. Mice with neutropenic aspergillosis developed a time-dependent increase in lung extracellular heme and a corresponding hemopexin induction. Hemopexin deficiency resulted in markedly increased lung injury, fungal growth, and lung hemorrhage. Using a computational model of the interactions of Aspergillus, heme, and the host, we predicted a critical role for heme-mediated generation of neutrophil extracellular traps (NETs) in this infection. We tested this prediction using a fungal strain unable to grow at body temperature and found that extracellular heme and fungal exposure synergized to induce lung injury by promoting NET release, and disruption of NET was sufficient to attenuate lung injury and fungal burden. These data implicate heme-mediated NETosis in both lung injury and fungal growth during aspergillosis, resulting in a detrimental positive feedback cycle that can be interrupted by scavenging heme or disrupting NETs.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144025512","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
A cross-sectional study of the role of epithelial cell injury in kidney transplant outcomes. 上皮细胞损伤在肾移植结果中的作用-一项横断面研究。
IF 6.3 1区 医学
JCI insight Pub Date : 2025-04-15 eCollection Date: 2025-05-22 DOI: 10.1172/jci.insight.188658
Philip F Halloran, Jessica Chang, Martina Mackova, Katelynn S Madill-Thomsen, Enver Akalin, Tarek Alhamad, Sanjiv Anand, Miha Arnol, Rajendra Baliga, Mirosław Banasik, Christopher D Blosser, Georg Böhmig, Daniel Brennan, Jonathan Bromberg, Klemens Budde, Andrzej Chamienia, Kevin Chow, Michał Ciszek, Declan de Freitas, Dominika Dęborska-Materkowska, Alicja Debska-Ślizień, Arjang Djamali, Leszek Domański, Magdalena Durlik, Gunilla Einecke, Farsad Eskandary, Richard Fatica, Iman Francis, Justyna Fryc, John Gill, Jagbir Gill, Maciej Glyda, Sita Gourishankar, Marta Gryczman, Gaurav Gupta, Petra Hruba, Peter Hughes, Arskarapurk Jittirat, Zeljka Jurekovic, Layla Kamal, Mahmoud Kamel, Sam Kant, Nika Kojc, Joanna Konopa, James Lan, Roslyn B Mannon, Arthur Matas, Joanna Mazurkiewicz, Marius Miglinas, Thomas Mueller, Marek Myślak, Seth Narins, Beata Naumnik, Anita Patel, Agnieszka Perkowska-Ptasińska, Michael Picton, Grzegorz Piecha, Emilio Poggio, Silvie Rajnochová Bloudíčkova, Thomas Schachtner, Soroush Shojai, Majid Ln Sikosana, Janka Slatinská, Katarzyna Smykal-Jankowiak, Ashish Solanki, Željka Veceric Haler, Ondrej Viklicky, Ksenija Vucur, Matthew R Weir, Andrzej Wiecek, Zbigniew Włodarczyk, Harold Yang, Ziad Zaky, Patrick T Gauthier, Christian Hinze
{"title":"A cross-sectional study of the role of epithelial cell injury in kidney transplant outcomes.","authors":"Philip F Halloran, Jessica Chang, Martina Mackova, Katelynn S Madill-Thomsen, Enver Akalin, Tarek Alhamad, Sanjiv Anand, Miha Arnol, Rajendra Baliga, Mirosław Banasik, Christopher D Blosser, Georg Böhmig, Daniel Brennan, Jonathan Bromberg, Klemens Budde, Andrzej Chamienia, Kevin Chow, Michał Ciszek, Declan de Freitas, Dominika Dęborska-Materkowska, Alicja Debska-Ślizień, Arjang Djamali, Leszek Domański, Magdalena Durlik, Gunilla Einecke, Farsad Eskandary, Richard Fatica, Iman Francis, Justyna Fryc, John Gill, Jagbir Gill, Maciej Glyda, Sita Gourishankar, Marta Gryczman, Gaurav Gupta, Petra Hruba, Peter Hughes, Arskarapurk Jittirat, Zeljka Jurekovic, Layla Kamal, Mahmoud Kamel, Sam Kant, Nika Kojc, Joanna Konopa, James Lan, Roslyn B Mannon, Arthur Matas, Joanna Mazurkiewicz, Marius Miglinas, Thomas Mueller, Marek Myślak, Seth Narins, Beata Naumnik, Anita Patel, Agnieszka Perkowska-Ptasińska, Michael Picton, Grzegorz Piecha, Emilio Poggio, Silvie Rajnochová Bloudíčkova, Thomas Schachtner, Soroush Shojai, Majid Ln Sikosana, Janka Slatinská, Katarzyna Smykal-Jankowiak, Ashish Solanki, Željka Veceric Haler, Ondrej Viklicky, Ksenija Vucur, Matthew R Weir, Andrzej Wiecek, Zbigniew Włodarczyk, Harold Yang, Ziad Zaky, Patrick T Gauthier, Christian Hinze","doi":"10.1172/jci.insight.188658","DOIUrl":"10.1172/jci.insight.188658","url":null,"abstract":"<p><strong>Background: </strong>Expression of acute kidney injury-associated (AKI-associated) transcripts in kidney transplants may reflect recent injury and accumulation of epithelial cells in \"failed repair\" states. We hypothesized that the phenomenon of failed repair could be associated with deterioration and failure in kidney transplants.</p><p><strong>Methods: </strong>We defined injury-induced transcriptome states in 4,502 kidney transplant biopsies injury-induced gene sets and classifiers previously developed in transplants.</p><p><strong>Results: </strong>In principal component analysis (PCA), PC1 correlated with both acute and chronic kidney injury and related inflammation and PC2 with time posttransplant. Positive PC3 was a dimension that correlated with epithelial remodeling pathways and anticorrelated with inflammation. Both PC1 and PC3 correlated with reduced survival, with PC1 effects strongly increasing over time whereas PC3 effects were independent of time. In this model, we studied the expression of 12 \"new\" gene sets annotated in single-nucleus RNA-sequencing studies of epithelial cells with failed repair in native kidneys. The new gene sets reflecting epithelial-mesenchymal transition correlated with injury PC1 and PC3, lower estimated glomerular filtration rate, higher donor age, and future failure as strongly as any gene sets previously derived in transplants and were independent of nephron segment of origin and graft rejection.</p><p><strong>Conclusion: </strong>These results suggest 2 dimensions in the kidney transplant response to injury: PC1, AKI-induced changes, failed repair, and inflammation; and PC3, a response involving epithelial remodeling without inflammation. Increasing kidney age amplifies PC1 and PC3.</p><p><strong>Trial registration: </strong>INTERCOMEX (ClinicalTrials.gov NCT01299168); Trifecta-Kidney (ClinicalTrials.gov NCT04239703).</p><p><strong>Funding: </strong>Genome Canada; Natera, Inc.; and Thermo Fisher Scientific.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013812","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
Characterization of a pathogenic nonmigratory fibroblast population in systemic sclerosis skin. 系统性硬化症皮肤中致病性非迁移成纤维细胞群的特征。
IF 6.3 1区 医学
JCI insight Pub Date : 2025-04-15 eCollection Date: 2025-05-22 DOI: 10.1172/jci.insight.185618
Kristina En Clark, Shiwen Xu, Moustafa Attar, Voon H Ong, Christopher D Buckley, Christopher P Denton
{"title":"Characterization of a pathogenic nonmigratory fibroblast population in systemic sclerosis skin.","authors":"Kristina En Clark, Shiwen Xu, Moustafa Attar, Voon H Ong, Christopher D Buckley, Christopher P Denton","doi":"10.1172/jci.insight.185618","DOIUrl":"10.1172/jci.insight.185618","url":null,"abstract":"<p><p>Fibroblasts are central to pathogenesis of systemic sclerosis (SSc). However, studies of conventional explant fibroblast cultures incompletely reflect disease biology and treatment response. We isolated a second nonmigratory \"resident\" population of fibroblasts from skin biopsies after outgrowth of explant \"migratory\" cells. These nonmotile resident fibroblasts were compared with migratory cells from the same biopsy, using functional studies, bulk and single-cell RNA-seq, and localized in situ by multichannel immunofluorescence. Migratory and resident fibroblast populations in SSc showed distinct profibrotic characteristics and gene expression for pathogenic pathways differing by stage and autoantibody subgroup. TGF-β signaling was highly active in migratory fibroblasts in early-stage diffuse cutaneous SSc (dcSSc). Conversely, resident fibroblasts had less upregulated TGF-β signaling, especially in late-stage dcSSc. Increased chemokine expression was a hallmark of resident fibroblasts at all stages. In vitro studies confirmed differential response to TGF-β1 and CCL2 between migratory and resident cells. We suggest that migratory fibroblasts are especially important in early skin disease, whereas nonmigratory fibroblasts may have a regulatory role and contribute more to fibrosis in later-stage disease. Thus, we have identified a pathogenic fibroblast population in SSc, not isolated by conventional explant culture, that could play an important role in fibrosis and be targeted therapeutically.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009988","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
Potassium supplementation and depletion during development of salt-sensitive hypertension in male and female SS rats. 雌雄SS大鼠盐敏感性高血压发生过程中钾的补充和消耗。
IF 6.3 1区 医学
JCI insight Pub Date : 2025-04-15 eCollection Date: 2025-05-22 DOI: 10.1172/jci.insight.181778
Adrian Zietara, Lashodya V Dissanayake, Melissa Lowe, Biyang Xu, Vladislav Levchenko, Vasundhara Kain, Ganesh V Halade, Christine A Klemens, Oleg Palygin, Alexander Staruschenko
{"title":"Potassium supplementation and depletion during development of salt-sensitive hypertension in male and female SS rats.","authors":"Adrian Zietara, Lashodya V Dissanayake, Melissa Lowe, Biyang Xu, Vladislav Levchenko, Vasundhara Kain, Ganesh V Halade, Christine A Klemens, Oleg Palygin, Alexander Staruschenko","doi":"10.1172/jci.insight.181778","DOIUrl":"10.1172/jci.insight.181778","url":null,"abstract":"<p><p>The dietary sodium/potassium ratio is positively correlated with blood pressure, and understanding this relationship is crucial for improving hypertension treatment. Moreover, few studies have examined these effects in both sexes. In this study, we aimed to investigate how supplementing (1.41% K+; HK) or depleting (DK) dietary potassium affects the development of salt-sensitive (SS) hypertension in male and female Dahl SS rats. Potassium supplementation attenuated blood pressure during 5 weeks of high-salt (4% NaCl) diet in male but not in female rats. In contrast, a potassium-deficient diet prevented the development of salt-induced hypertension in both sexes, though this effect is unlikely to be protective. Both males and females on the DK diet were hypokalemic and had diminished heart rates and reduced weight gain; furthermore, females experienced high mortality. RNA-Seq of kidney cortical tissue revealed a number of genes that may underlie the sex-specific differences in phenotype. Male rats supplemented with potassium exhibited a decreased number and size of WNK4 puncta, whereas in potassium-supplemented females, there was no difference in puncta count and there was an increase in puncta size. Our data indicate there are sex-dependent differences in response to dietary potassium in hypertension and that the distal nephron compensates for severe potassium deficiency.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996597","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
CDK2 inhibition produces a persistent population of polyploid cancer cells. CDK2抑制产生多倍体癌细胞的持久群体。
IF 6.3 1区 医学
JCI insight Pub Date : 2025-04-15 eCollection Date: 2025-05-22 DOI: 10.1172/jci.insight.189901
Liliya Tyutyunyk-Massey, Zibo Chen, Xiuxia Liu, Masanori Kawakami, Adam Harned, Yeap Ng, Brian Luke, Samuel C Okpechi, Blessing Ogunlade, Yair Alfaro, Roberto Weigert, Kedar Narayan, Xi Liu, Ethan Dmitrovsky
{"title":"CDK2 inhibition produces a persistent population of polyploid cancer cells.","authors":"Liliya Tyutyunyk-Massey, Zibo Chen, Xiuxia Liu, Masanori Kawakami, Adam Harned, Yeap Ng, Brian Luke, Samuel C Okpechi, Blessing Ogunlade, Yair Alfaro, Roberto Weigert, Kedar Narayan, Xi Liu, Ethan Dmitrovsky","doi":"10.1172/jci.insight.189901","DOIUrl":"10.1172/jci.insight.189901","url":null,"abstract":"<p><p>Aneuploidy, a cancer hallmark, drives chromosomal instability, drug resistance, and clinically aggressive tumors. Cyclin-dependent kinase 2 (CDK2) antagonism with independent inhibitors or CDK2 knockdown triggered anaphase catastrophe. This disrupts supernumerary centrosome clustering, causing multipolar division and apoptosis. Time-lapse fluorescence microscopy of fluorescent ubiquitination-based cell cycle indicator (FUCCI) cell cycle probes transduced into aneuploid lung cancer cells revealed distinct fates of bipolar and polyploid cells after CDK2 inhibition. Apoptosis occurred in multipolar progeny but was repressed in persistent polyploid cancer cells. RNA-Seq analyses after CDK2 inhibition of 4N versus 2N lung cancer cells were enriched for CDK1 pathway and KIF family members. The Cancer Genome Atlas (TCGA) analysis of lung cancers indicated that CDK1 and KIF family member overexpression was associated with an unfavorable survival. Intravital microscopy of transplanted lung cancer cells in mice extended findings from the in vitro to in vivo settings. CDK2 inhibition of tumor-bearing mice produced polyploid cancer cells in vivo. These cancer cells were resistant to apoptosis and proliferated despite CDK2 inhibition. In contrast, polyploid populations were rarely detected in CDK2-inhibited human alveolar epithelial cells. These findings are translationally relevant. Combined targeting of CDK2 with CDK1 or kinesin family member antagonists should eliminate polyploid cancer cells, promote apoptosis, and augment antineoplastic effects.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013193","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
The PERK/ATF4 pathway is required for metabolic reprogramming and progressive lung fibrosis. PERK-ATF4通路是代谢重编程和进行性肺纤维化所必需的。
IF 6.3 1区 医学
JCI insight Pub Date : 2025-04-10 eCollection Date: 2025-05-22 DOI: 10.1172/jci.insight.189330
Jyotsana Pandey, Jennifer L Larson-Casey, Mallikarjun H Patil, Chao He, Nisarat Pinthong, A Brent Carter
{"title":"The PERK/ATF4 pathway is required for metabolic reprogramming and progressive lung fibrosis.","authors":"Jyotsana Pandey, Jennifer L Larson-Casey, Mallikarjun H Patil, Chao He, Nisarat Pinthong, A Brent Carter","doi":"10.1172/jci.insight.189330","DOIUrl":"10.1172/jci.insight.189330","url":null,"abstract":"<p><p>Asbestosis is a prototypical type of fibrosis that is progressive and does not resolve. ER stress is increased in multiple cell types that contribute to fibrosis; however, the mechanism(s) by which ER stress in lung macrophages contributes to fibrosis is poorly understood. Here, we show that ER stress resulted in protein kinase RNA-like ER kinase (PERK; Eif2ak3) activation in humans with asbestosis. Similar results were seen in asbestos-injured mice. Mice harboring a conditional deletion of Eif2ak3 were protected from fibrosis. Lung macrophages from asbestosis individuals had evidence of metabolic reprogramming to fatty acid oxidation (FAO). Eif2ak3fl/fl mice had increased oxygen consumption rate (OCR), whereas OCR in Eif2ak3-/- Lyz2-cre mice was reduced to control levels. PERK increased activating transcription factor 4 (Atf4) expression, and ATF4 bound to the Ppargc1a promoter to increase its expression. GSK2656157, a PERK-specific inhibitor, reduced FAO, Ppargc1a, and Aft4 in lung macrophages and reversed established fibrosis in mice. These observations suggest that PERK is a therapeutic target to reverse established fibrosis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981722","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
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