Journal of Clinical Investigation最新文献_第3页

Lipid peroxidation and immune activation: TRAF3's double-edged strategy against glioblastoma. 脂质过氧化和免疫激活：TRAF3对胶质母细胞瘤的双刃剑策略。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI190471

Tzu-Yi Chia, Nishanth S Sadagopan, Jason Miska

引用次数: 0

Meal-feeding promotes skeletal growth by ghrelin-dependent enhancement of growth hormone rhythmicity. 膳食喂养通过生长素依赖性生长激素节律性增强促进骨骼生长。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI189202

Amanda Ke Hornsby, Richard C Brown, Thomas W Tilston, Harry A Smith, Alfonso Moreno-Cabañas, Bradley Arms-Williams, Anna L Hopkins, Katie D Taylor, Simran Kr Rogaly, Lois Hm Wells, Jamie J Walker, Jeffrey S Davies, Yuxiang Sun, Jeffrey M Zigman, James A Betts, Timothy Wells

{"title":"Meal-feeding promotes skeletal growth by ghrelin-dependent enhancement of growth hormone rhythmicity.","authors":"Amanda Ke Hornsby, Richard C Brown, Thomas W Tilston, Harry A Smith, Alfonso Moreno-Cabañas, Bradley Arms-Williams, Anna L Hopkins, Katie D Taylor, Simran Kr Rogaly, Lois Hm Wells, Jamie J Walker, Jeffrey S Davies, Yuxiang Sun, Jeffrey M Zigman, James A Betts, Timothy Wells","doi":"10.1172/JCI189202","DOIUrl":"https://doi.org/10.1172/JCI189202","url":null,"abstract":"The physiological impact of ultradian temporal feeding patterns remains a major unanswered question in nutritional science. We have employed automated and nasogastric feeding to address this question in male rodents and human volunteers. While grazing and meal-feeding reduced food intake in parallel (compared to ad libitum-fed rodents), body length and tibial epiphysial plate width were maintained in meal-fed rodents via the action of ghrelin and its receptor, GHS-R. Grazing and meal-feeding initially suppressed elevated pre-prandial ghrelin levels in rats, followed by either a sustained elevation in ghrelin in grazing rats or pre-prandial ghrelin surges in meal-fed rats. Episodic growth hormone (GH) secretion was largely unaffected in grazing rats, but meal-feeding tripled GH secretion, with burst height augmented and two additional bursts of GH per day. Continuous nasogastric infusion of enteral feed in humans failed to suppress circulating ghrelin, producing continuously elevated circulating GH with minimal rhythmicity. In contrast, bolus enteral infusion elicited post-prandial ghrelin troughs accompanied by reduced circulating GH, with enhanced ultradian rhythmicity. Taken together, our data imply that the contemporary shift from regular meals to snacking behaviour may be detrimental to optimal skeletal growth outcomes by sustaining circulating GH at levels associated with undernourishment and diminishing GH pulsatility.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764153","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

ACAT1 regulates tertiary lymphoid structures: A target for enhancing immunotherapy in non-small cell lung cancer. ACAT1调节三级淋巴样结构：增强非小细胞肺癌免疫治疗的靶点。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI191094

Sophie O'Keefe, Qiwei Wang

引用次数: 0

Metabolic dysfunction-associated steatotic liver disease and the gut microbiome: pathogenic insights and therapeutic innovations. 代谢功能障碍相关的脂肪变性肝病和肠道微生物组：致病的见解和治疗的创新。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI186423

Bernd Schnabl, Christopher J Damman, Rotonya M Carr

{"title":"Metabolic dysfunction-associated steatotic liver disease and the gut microbiome: pathogenic insights and therapeutic innovations.","authors":"Bernd Schnabl, Christopher J Damman, Rotonya M Carr","doi":"10.1172/JCI186423","DOIUrl":"10.1172/JCI186423","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of liver disease worldwide, and our understanding of its pathogenesis continues to evolve. MASLD progresses from steatosis to steatohepatitis, fibrosis, and cirrhosis, and this Review explores how the gut microbiome and their metabolites contribute to MASLD pathogenesis. We explore the complexity and importance of the intestinal barrier function and how disruptions of the intestinal barrier and dysbiosis work in concert to promote the onset and progression of MASLD. The Review focuses on specific bacterial, viral, and fungal communities that impact the trajectory of MASLD and how specific metabolites (including ethanol, bile acids, short chain fatty acids, and other metabolites) contribute to disease pathogenesis. Finally, we underscore how knowledge of the interaction between gut microbes and the intestinal barrier may be leveraged for MASLD microbial-based therapeutics. Here, we include a discussion of the therapeutic potential of prebiotics, probiotics, postbiotics, and microbial-derived metabolites.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 7","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752892","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

Cxcr3 promotes protection from colorectal cancer liver metastasis by driving NK cell infiltration and plasticity. Cxcr3通过驱动NK细胞浸润和可塑性，促进结直肠癌肝转移的保护作用。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI184036

Eleonora Russo, Chiara D'Aquino, Chiara Di Censo, Mattia Laffranchi, Luana Tomaipitinca, Valerio Licursi, Stefano Garofalo, Johann Promeuschel, Giovanna Peruzzi, Francesca Sozio, Anna Kaffke, Cecilia Garlanda, Ulf Panzer, Cristina Limatola, Christian A J Vosshenrich, Silvano Sozzani, Giuseppe Sciumè, Angela Santoni, Giovanni Bernardini

{"title":"Cxcr3 promotes protection from colorectal cancer liver metastasis by driving NK cell infiltration and plasticity.","authors":"Eleonora Russo, Chiara D'Aquino, Chiara Di Censo, Mattia Laffranchi, Luana Tomaipitinca, Valerio Licursi, Stefano Garofalo, Johann Promeuschel, Giovanna Peruzzi, Francesca Sozio, Anna Kaffke, Cecilia Garlanda, Ulf Panzer, Cristina Limatola, Christian A J Vosshenrich, Silvano Sozzani, Giuseppe Sciumè, Angela Santoni, Giovanni Bernardini","doi":"10.1172/JCI184036","DOIUrl":"https://doi.org/10.1172/JCI184036","url":null,"abstract":"The anti-metastatic activity of NK cells is well established in several cancer types, but the mechanisms underlying NK cell metastasis infiltration and acquisition of anti-tumor characteristics remain unclear. Herein, we investigated the cellular and molecular factors required to facilitate the generation of an ILC1-like CD49a+NK cell population within the liver metastasis (LM) environment of colorectal cancer (CRC). We show that CD49a+NK cells had the highest cytotoxic capacity among metastasis-infiltrating NK cells in the MC38 mouse model. Furthermore, the chemokine receptor CXCR3 promoted CD49a+NK cell accumulation and persistence in metastasis where NK cells co-localize with macrophages in CXCL9 and CXCL10 rich areas. By mining a published scRNA-seq dataset of a cohort of treatment-naïve CRC patients, we confirmed the accumulation of CXCR3+NK cells in metastatic samples. Conditional deletion of Cxcr3 in NKp46+ cells and antibody-mediated depletion of metastasis-associated macrophages impaired CD49a+NK cell development, indicating that CXCR3 and macrophages contribute to efficient NK cell localization and polarization in LM. Conversely, CXCR3neg NK cells maintained a CD49a- phenotype in metastasis with reduced parenchymal infiltration and tumor killing capacity. Furthermore, CD49a+NK cell accumulation was impaired in an independent SL4-induced CRC metastasis model, which fails to accumulate CXCL9+ macrophages. Together, our results highlight a role for CXCR3/ligand axis in promoting macrophage-dependent NK cell accumulation and functional sustenance in CRC LM.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764151","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 genetics of metabolic dysfunction-associated steatotic liver disease: from variants to cause to precision treatment. 代谢功能障碍相关脂肪变性肝病的人类遗传学：从变异到病因再到精确治疗

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI186424

Vincent L Chen, Annapurna Kuppa, Antonino Oliveri, Yanhua Chen, Prabhu Ponnandy, Puja B Patel, Nicholette D Palmer, Elizabeth K Speliotes

{"title":"Human genetics of metabolic dysfunction-associated steatotic liver disease: from variants to cause to precision treatment.","authors":"Vincent L Chen, Annapurna Kuppa, Antonino Oliveri, Yanhua Chen, Prabhu Ponnandy, Puja B Patel, Nicholette D Palmer, Elizabeth K Speliotes","doi":"10.1172/JCI186424","DOIUrl":"10.1172/JCI186424","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by increased hepatic steatosis with cardiometabolic disease and is a leading cause of advanced liver disease. We review here the genetic basis of MASLD. The genetic variants most consistently associated with hepatic steatosis implicate genes involved in lipoprotein input or output, glucose metabolism, adiposity/fat distribution, insulin resistance, or mitochondrial/ER biology. The distinct mechanisms by which these variants promote hepatic steatosis result in distinct effects on cardiometabolic disease that may be best suited to precision medicine. Recent work on gene-environment interactions has shown that genetic risk is not fixed and may be exacerbated or attenuated by modifiable (diet, exercise, alcohol intake) and nonmodifiable environmental risk factors. Some steatosis-associated variants, notably those in patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), are associated with risk of developing adverse liver-related outcomes and provide information beyond clinical risk stratification tools, especially in individuals at intermediate to high risk for disease. Future work to better characterize disease heterogeneity by combining genetics with clinical risk factors to holistically predict risk and develop therapies based on genetic risk is required.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 7","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752882","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

HoxBlinc: a key driver of chromatin dynamics in NUP98 fusion-driven leukemia. HoxBlinc: NUP98融合驱动白血病中染色质动力学的关键驱动因素。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI191355

Jian Xu, Wei Du

引用次数: 0

Insights into protection against Mycobacterium tuberculosis infection: time to officially confirm another phenotype? 预防结核分枝杆菌感染的见解：是时候正式确认另一种表型了？

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI191423

Todia P Setiabudiawan, Philip C Hill, Andrew R DiNardo, Reinout van Crevel

引用次数: 0

Spermidine restricts neonatal inflammation via metabolic shaping of polymorphonuclear myeloid-derived suppressor cells. 亚精胺通过多形核髓源性抑制细胞的代谢塑造限制新生儿炎症。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI183559

Jiale Chen, Lin Zhu, Zhaohai Cui, Yuxin Zhang, Ran Jia, Dongmei Zhou, Bo Hu, Wei Zhong, Jin Xu, Lijuan Zhang, Pan Zhou, Wenyi Mi, Haitao Wang, Zhi Yao, Ying Yu, Qiang Liu, Jie Zhou

{"title":"Spermidine restricts neonatal inflammation via metabolic shaping of polymorphonuclear myeloid-derived suppressor cells.","authors":"Jiale Chen, Lin Zhu, Zhaohai Cui, Yuxin Zhang, Ran Jia, Dongmei Zhou, Bo Hu, Wei Zhong, Jin Xu, Lijuan Zhang, Pan Zhou, Wenyi Mi, Haitao Wang, Zhi Yao, Ying Yu, Qiang Liu, Jie Zhou","doi":"10.1172/JCI183559","DOIUrl":"10.1172/JCI183559","url":null,"abstract":"Newborns exhibit a heightened vulnerability to inflammatory disorders due to their underdeveloped immune system, yet the underlying mechanisms remain poorly understood. Here we report that plasma spermidine is correlated with the maturity of human newborns and reduced risk of inflammation. Administration of spermidine led to the remission of neonatal inflammation in mice. Mechanistic studies revealed that spermidine enhanced the generation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) via downstream eIF5A hypusination. Genetic deficiency or pharmacological inhibition of deoxyhypusine synthase (DHPS), a key enzyme of hypusinated eIF5A (eIF5AHyp), diminished the immunosuppressive activity of PMN-MDSCs, leading to aggravated neonatal inflammation. The eIF5AHyp pathway was found to enhance the immunosuppressive function via histone acetylation-mediated epigenetic transcription of immunosuppressive signatures in PMN-MDSCs. These findings demonstrate the spermidine-eIF5AHyp metabolic axis as a master switch to restrict neonatal inflammation.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 7","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752917","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

Unveiling the cholesterol-hemangioma axis: a path to new treatments. 揭示胆固醇-血管瘤轴：一条新疗法之路。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI193039

M Luisa Iruela-Arispe

引用次数: 0