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The muscle stem cell case of Benjamin Button: rejuvenating muscle regenerative capacity through nutraceuticals.
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-12-16 DOI: 10.1172/JCI185054
Taylor Peach, Mattia Quattrocelli
{"title":"The muscle stem cell case of Benjamin Button: rejuvenating muscle regenerative capacity through nutraceuticals.","authors":"Taylor Peach, Mattia Quattrocelli","doi":"10.1172/JCI185054","DOIUrl":"10.1172/JCI185054","url":null,"abstract":"<p><p>Aging negatively affects the capacity of muscle stem cells (MuSCs) to regenerate muscle. In this issue of the JCI, Ancel, Michaud, and colleagues used a high-content imaging screen to identify nicotinamide and pyridoxine as promoters of MuSC function. The combination of the two compounds promoted MuSC function in vivo in aged mice and in primary cells isolated from older individuals. Furthermore, the two compounds were lower in the circulation of older men, paralleling decreases in lean mass and gait speed. These results advance the translational perspective of rejuvenating MuSC function through nutraceuticals.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 24","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836564","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 paradox of eGFR trends and kidney failure incidence in patients without monogenic kidney disorders.
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-12-16 DOI: 10.1172/JCI187470
Xiaona Wang, Dongyan Wang
{"title":"The paradox of eGFR trends and kidney failure incidence in patients without monogenic kidney disorders.","authors":"Xiaona Wang, Dongyan Wang","doi":"10.1172/JCI187470","DOIUrl":"10.1172/JCI187470","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 24","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836568","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
Beyond ketosis: the search for the mechanism underlying SGLT2-inhibitor benefit continues.
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-12-16 DOI: 10.1172/JCI187097
Justin H Berger, Brian N Finck
{"title":"Beyond ketosis: the search for the mechanism underlying SGLT2-inhibitor benefit continues.","authors":"Justin H Berger, Brian N Finck","doi":"10.1172/JCI187097","DOIUrl":"10.1172/JCI187097","url":null,"abstract":"<p><p>Despite the impressive clinical benefits and widespread adoption of sodium glucose cotransporter 2 inhibitors (SGLT2i) to treat all classes of heart failure, their cardiovascular mechanisms of action are poorly understood. Proposed mechanisms range broadly and include enhanced ketogenesis, where the mild ketosis associated with SGLT2i use is presumed to be beneficial. However, in this issue of the JCI, carefully conducted metabolic flux studies by Goedeke et al. comparing the effects of SGLT2i and exogenous ketones suggest differential effects. Thus, the mechanisms of action for SGLT2i are likely pleiotropic, and further work is needed to fully understand their beneficial effects.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 24","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836504","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
CRISPR/Cas13d targeting suppresses repeat-associated non-AUG translation of C9orf72 hexanucleotide repeat RNA.
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-12-16 DOI: 10.1172/JCI189439
Honghe Liu, Xiao-Feng Zhao, Yu-Ning Lu, Lindsey R Hayes, Jiou Wang
{"title":"CRISPR/Cas13d targeting suppresses repeat-associated non-AUG translation of C9orf72 hexanucleotide repeat RNA.","authors":"Honghe Liu, Xiao-Feng Zhao, Yu-Ning Lu, Lindsey R Hayes, Jiou Wang","doi":"10.1172/JCI189439","DOIUrl":"10.1172/JCI189439","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 24","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836519","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 paradox of eGFR trends and kidney failure incidence in patients without monogenic kidney disorders. Reply.
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-12-16 DOI: 10.1172/JCI187783
Mark Elliott, Krzysztof Kiryluk, Ali Gharavi
{"title":"The paradox of eGFR trends and kidney failure incidence in patients without monogenic kidney disorders. Reply.","authors":"Mark Elliott, Krzysztof Kiryluk, Ali Gharavi","doi":"10.1172/JCI187783","DOIUrl":"10.1172/JCI187783","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 24","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836571","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
Evi1 governs Kdm6b-mediated histone demethylation to regulate the Laptm4b-driven mTOR pathway in hematopoietic progenitor cells. Evi1 可调控 Kdm6b 介导的组蛋白去甲基化，从而调节造血祖细胞中 Laptm4b 驱动的 mTOR 通路。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-12-16 DOI: 10.1172/JCI173403
Qiong Wu, Chunjie Yu, Fang Yu, Yiran Guo, Yue Sheng, Liping Li, Yafang Li, Yutao Zhang, Chao Hu, Jue Wang, Tong-Chuan He, Yong Huang, Hongyu Ni, Zhiguang Huo, Wenshu Wu, Gang Greg Wang, Jianxin Lyu, Zhijian Qian
{"title":"Evi1 governs Kdm6b-mediated histone demethylation to regulate the Laptm4b-driven mTOR pathway in hematopoietic progenitor cells.","authors":"Qiong Wu, Chunjie Yu, Fang Yu, Yiran Guo, Yue Sheng, Liping Li, Yafang Li, Yutao Zhang, Chao Hu, Jue Wang, Tong-Chuan He, Yong Huang, Hongyu Ni, Zhiguang Huo, Wenshu Wu, Gang Greg Wang, Jianxin Lyu, Zhijian Qian","doi":"10.1172/JCI173403","DOIUrl":"10.1172/JCI173403","url":null,"abstract":"<p><p>Ecotropic viral integration site 1 (EVI1/MECOM) is frequently upregulated in myeloid malignancies. Here, we present an Evi1-transgenic mouse model with inducible expression in hematopoietic stem/progenitor cells (HSPCs). Upon induction of Evi1 expression, mice displayed anemia, thrombocytopenia, lymphopenia, and erythroid and megakaryocyte dysplasia with a significant expansion of committed myeloid progenitor cells, resembling human myelodysplastic syndrome/myeloproliferative neoplasm-like (MDS/MPN-like) disease. Evi1 overexpression prompted HSPCs to exit quiescence and accelerated their proliferation, leading to expansion of committed myeloid progenitors while inhibiting lymphopoiesis. Analysis of global gene expression and Evi1 binding site profiling in HSPCs revealed that Evi1 directly upregulated lysine demethylase 6b (Kdm6b). Subsequently, Kdm6b-mediated H3K27me3 demethylation resulted in activation of various genes, including Laptm4b. Interestingly, KDM6B and LAPTM4B are positively correlated with EVI1 expression in patients with MDS. The EVI1/KDM6B/H3K27me3/LAPTM4B signaling pathway was also identified in EVI1hi human leukemia cell lines. We found that hyperactivation of the LAPTM4B-driven mTOR pathway was crucial for the growth of EVI1hi leukemia cells. Knockdown of Laptm4b partially rescued Evi1-induced abnormal hematopoiesis in vivo. Thus, our study establishes a mouse model to investigate EVI1hi myeloid malignancies, demonstrating the significance of the EVI1-mediated KDM6B/H3K27me3/LAPTM4B signaling axis in their maintenance.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 24","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836534","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
Immune-molecular interactions in high-grade serous ovarian cancer distinguish long-term survivors.
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-12-16 DOI: 10.1172/JCI184790
Jeanette E Boudreau
{"title":"Immune-molecular interactions in high-grade serous ovarian cancer distinguish long-term survivors.","authors":"Jeanette E Boudreau","doi":"10.1172/JCI184790","DOIUrl":"10.1172/JCI184790","url":null,"abstract":"<p><p>The approach and efficacy of treatments for high-grade serous carcinoma (HGSC) of the ovary have changed little in decades. Although numerous studies demonstrated immune infiltration as frequent and prognostically beneficial, clinical trials of immunotherapies have generated benefit in fewer than 15% of patients. In this issue of the JCI, Nelson and colleagues compiled 1,233 HGSC samples from patients across four continents and compared the molecular and immunologic features that associate with long-term survival (greater than 10 years). Diversity among HGSC tumors is well defined, but this study explored the combined influence of immunologic and molecular features. Long-term survivors harbored tumors with high epithelial content and overrepresentation of the C4/differentiated molecular signature, with cytotoxic T and B cells infiltrating to the tumor epithelium and stroma, respectively. These findings highlight features that might underly poor responsiveness to existing immunotherapies of most HGSC tumors and considerations for the design of future, more precise treatments for HGSC.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 24","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836548","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
Balancing immune response: SHP1 controls neutrophil activation in inflamed lungs. 平衡免疫反应：SHP1 控制着发炎肺部的中性粒细胞活化。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-12-16 DOI: 10.1172/JCI187056
Laxman Ghimire, Hongbo R Luo
{"title":"Balancing immune response: SHP1 controls neutrophil activation in inflamed lungs.","authors":"Laxman Ghimire, Hongbo R Luo","doi":"10.1172/JCI187056","DOIUrl":"10.1172/JCI187056","url":null,"abstract":"<p><p>Following respiratory infection or injury, neutrophil hyperactivation can damage surrounding lung tissue by releasing harmful compounds. In this issue of the JCI, Moussavi-Harami and colleagues identified tyrosine phosphatase SHP1 as a key negative regulator of neutrophil activation in acute respiratory distress syndrome (ARDS). Neutrophil-specific Shp1 disruption leads to hyperinflammation, pulmonary hemorrhage, and increased mortality in both sterile and pathogen-induced acute lung injury (ALI). Large intravascular neutrophil clusters and excessive PAD4-independent neutrophil extracellular traps (NETs) were identified as key features of lung injury. Mechanistically, Shp1 deficiency resulted in uncontrolled SYK kinase activation, driving chaotic neutrophil hyperactivation and inflammation.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 24","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836496","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
Crizanlizumab for retinal vasculopathy with cerebral leukoencephalopathy in a phase II clinical study. Crizanlizumab治疗视网膜血管病变合并脑白质脑病的II期临床研究。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-12-16 DOI: 10.1172/JCI189023
Wilson X Wang, Dan Spiegelman, P Kumar Rao, Rennie L Rhee, Andria L Ford, Jonathan J Miner, Rajendra S Apte
{"title":"Crizanlizumab for retinal vasculopathy with cerebral leukoencephalopathy in a phase II clinical study.","authors":"Wilson X Wang, Dan Spiegelman, P Kumar Rao, Rennie L Rhee, Andria L Ford, Jonathan J Miner, Rajendra S Apte","doi":"10.1172/JCI189023","DOIUrl":"10.1172/JCI189023","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 24","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836524","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
SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts. SGLT2 抑制会改变健康和衰竭大鼠心脏的底物利用和线粒体氧化还原。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-12-16 DOI: 10.1172/JCI176708
Leigh Goedeke, Yina Ma, Rafael C Gaspar, Ali Nasiri, Jieun Lee, Dongyan Zhang, Katrine Douglas Galsgaard, Xiaoyue Hu, Jiasheng Zhang, Nicole Guerrera, Xiruo Li, Traci LaMoia, Brandon T Hubbard, Sofie Haedersdal, Xiaohong Wu, John Stack, Sylvie Dufour, Gina Marie Butrico, Mario Kahn, Rachel J Perry, Gary W Cline, Lawrence H Young, Gerald I Shulman
{"title":"SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts.","authors":"Leigh Goedeke, Yina Ma, Rafael C Gaspar, Ali Nasiri, Jieun Lee, Dongyan Zhang, Katrine Douglas Galsgaard, Xiaoyue Hu, Jiasheng Zhang, Nicole Guerrera, Xiruo Li, Traci LaMoia, Brandon T Hubbard, Sofie Haedersdal, Xiaohong Wu, John Stack, Sylvie Dufour, Gina Marie Butrico, Mario Kahn, Rachel J Perry, Gary W Cline, Lawrence H Young, Gerald I Shulman","doi":"10.1172/JCI176708","DOIUrl":"10.1172/JCI176708","url":null,"abstract":"<p><p>Previous studies highlight the potential for sodium-glucose cotransporter type 2 (SGLT2) inhibitors (SGLT2i) to exert cardioprotective effects in heart failure by increasing plasma ketones and shifting myocardial fuel utilization toward ketone oxidation. However, SGLT2i have multiple in vivo effects and the differential impact of SGLT2i treatment and ketone supplementation on cardiac metabolism remains unclear. Here, using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology combined with infusions of [13C6]glucose or [13C4]βOHB, we demonstrate that acute SGLT2 inhibition with dapagliflozin shifts relative rates of myocardial mitochondrial metabolism toward ketone oxidation, decreasing pyruvate oxidation with little effect on fatty acid oxidation in awake rats. Shifts in myocardial ketone oxidation persisted when plasma glucose levels were maintained. In contrast, acute βOHB infusion similarly augmented ketone oxidation, but markedly reduced fatty acid oxidation and did not alter glucose uptake or pyruvate oxidation. After inducing heart failure, dapagliflozin increased relative rates of ketone and fatty acid oxidation, but decreased pyruvate oxidation. Dapagliflozin increased mitochondrial redox and reduced myocardial oxidative stress in heart failure, which was associated with improvements in left ventricular ejection fraction after 3 weeks of treatment. Thus, SGLT2i have pleiotropic effects on systemic and heart metabolism, which are distinct from ketone supplementation and may contribute to the long-term cardioprotective benefits of SGLT2i.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 24","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836556","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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