Journal of Clinical Investigation最新文献_第10页

Disruption of the KLHL37-N-Myc complex restores N-Myc degradation and arrests neuroblastoma growth in mouse models. 在小鼠模型中，破坏KLHL37-N-Myc复合体恢复N-Myc降解并阻止神经母细胞瘤生长。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-06-10 eCollection Date: 2025-07-15 DOI: 10.1172/JCI176655

Senfeng Xiang, Pengfei Chen, Xiaoxian Shi, Hanqi Cai, Zihan Shen, Luyang Liu, Aixiao Xu, Jianhua Zhang, Xingya Zhang, Shaowei Bing, Jinhu Wang, Xuejing Shao, Ji Cao, Bo Yang, Qiaojun He, Meidan Ying

{"title":"Disruption of the KLHL37-N-Myc complex restores N-Myc degradation and arrests neuroblastoma growth in mouse models.","authors":"Senfeng Xiang, Pengfei Chen, Xiaoxian Shi, Hanqi Cai, Zihan Shen, Luyang Liu, Aixiao Xu, Jianhua Zhang, Xingya Zhang, Shaowei Bing, Jinhu Wang, Xuejing Shao, Ji Cao, Bo Yang, Qiaojun He, Meidan Ying","doi":"10.1172/JCI176655","DOIUrl":"10.1172/JCI176655","url":null,"abstract":"The N-Myc gene MYCN amplification accounts for the most common genetic aberration in neuroblastoma and strongly predicts the aggressive progression and poor clinical prognosis. However, clinically effective therapies that directly target N-Myc activity are limited. N-Myc is a transcription factor, and its stability is tightly controlled by ubiquitination-dependent proteasomal degradation. Here, we discovered that Kelch-like protein 37 (KLHL37) played a crucial role in enhancing the protein stability of N-Myc in neuroblastoma. KLHL37 directly interacted with N-Myc to disrupt N-Myc-FBXW7 interaction, thereby stabilizing N-Myc and enabling tumor progression. Suppressing KLHL37 effectively induced the degradation of N-Myc and had a profound inhibitory effect on the growth of MYCN-amplified neuroblastoma. Notably, we identified RTA-408 as an inhibitor of KLHL37 to disrupt the KLHL37-N-Myc complex, promoting the degradation of N-Myc and suppressing neuroblastoma in vivo and in vitro. Moreover, we elucidated the therapeutic potential of RTA-408 for neuroblastoma using patient-derived neuroblastoma cell and patient-derived xenograft tumor models. RTA408's antitumor effects may not occur exclusively via KLHL37, and specific KLHL37 inhibitors are expected to be developed in the future. These findings not only uncover the biological function of KLHL37 in regulating N-Myc stability, but also indicate that KLHL37 inhibition is a promising therapeutic regimen for neuroblastoma, especially in patients with MYCN-amplified tumors.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266369","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

B cell deficiency induces cytotoxic memory CD8+ T cells during influenza-associated bacterial pneumonia. B细胞缺乏在流感相关性细菌性肺炎期间诱导细胞毒性记忆CD8+ T细胞。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-06-10 eCollection Date: 2025-08-15 DOI: 10.1172/JCI188342

Leigh M Miller, Alexis M Duray, Ellyse M Cipolla, Flavia Rago, Brooke P Dresden, Kristen L Parenteau, Abhigya Gupta, John F Alcorn

{"title":"B cell deficiency induces cytotoxic memory CD8+ T cells during influenza-associated bacterial pneumonia.","authors":"Leigh M Miller, Alexis M Duray, Ellyse M Cipolla, Flavia Rago, Brooke P Dresden, Kristen L Parenteau, Abhigya Gupta, John F Alcorn","doi":"10.1172/JCI188342","DOIUrl":"10.1172/JCI188342","url":null,"abstract":"Influenza-associated bacterial superinfections in the lung lead to increased morbidity and mortality. Nearly all people have preexisting memory to influenza virus, which can protect against subsequent infection in the lung. This study explored the role B cells play in protection against bacterial (Staphylococcus aureus or Klebsiella pneumoniae) superinfection with previous heterotypic influenza memory. B cell deficiency resulted in an increased inflammatory lung environment and lung tissue injury during superinfection. Loss of B cells increased populations of memory CD8+ T cells in the lung, and these CD8+ T cells were transcriptionally and functionally distinct from those of WT mice. Use of antibody-deficient mouse models showed that this phenotype was specifically due to loss of antibody production from B cells. Passive immunization with influenza antibody serum in B cell-deficient mice rescued the CD8+ T cell phenotype. CD8+ T cell depletion and lethal superinfection challenge experiments showed that the cytotoxic memory CD8+ T cells from B cell-deficient mice protect against superinfection bacterial burden and mortality. These findings provide insight into the importance of B cells for regulating immune responses against infection.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266368","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

Expression of full-length dystrophin reverses muscular dystrophy defects in young and old mdx4cv mice. 全长肌营养不良蛋白的表达逆转了年轻和年老mdx4cv小鼠的肌营养不良缺陷。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-06-10 eCollection Date: 2025-08-01 DOI: 10.1172/JCI189075

Hichem Tasfaout, Timothy S McMillen, Theodore R Reyes, Christine L Halbert, Rong Tian, Michael Regnier, Jeffrey S Chamberlain

{"title":"Expression of full-length dystrophin reverses muscular dystrophy defects in young and old mdx4cv mice.","authors":"Hichem Tasfaout, Timothy S McMillen, Theodore R Reyes, Christine L Halbert, Rong Tian, Michael Regnier, Jeffrey S Chamberlain","doi":"10.1172/JCI189075","DOIUrl":"10.1172/JCI189075","url":null,"abstract":"Gene replacement therapies mediated by adeno-associated viral (AAV) vectors represent a promising approach for treating genetic diseases. However, their modest packaging capacity (~4.7 kb) remains an important constraint and significantly limits their application for genetic disorders involving large genes. A prominent example is Duchenne muscular dystrophy (DMD), whose protein product dystrophin is generated from a 11.2 kb segment of the DMD mRNA. Here, we explored methods that enable efficient expression of full-length dystrophin via triple AAV codelivery. This method exploits the protein trans-splicing mechanism mediated by split inteins. We identified a combination of efficient and specific split intein pairs that enabled the reconstitution of full-length dystrophin from 3 dystrophin fragments. We show that systemic delivery of low doses of the myotropic AAVMYO1 in mdx4cv mice led to efficient expression of full-length dystrophin in the hind limb, diaphragm, and heart muscles. Notably, muscle morphology and physiology were significantly improved in triple-AAV-treated mdx4cv mice versus saline-treated controls. This method shows the feasibility of expressing large proteins from several fragments that were delivered using low doses of myotropic AAV vectors. It can be adapted to other large genes involved in disorders for which gene replacement remains challenged by the modest AAV cargo capacity.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12321383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266370","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

Impact of SGLT2 inhibitors on cerebrospinal fluid dynamics and implications for hydrocephalus management. SGLT2抑制剂对脑脊液动力学的影响及其对脑积水治疗的影响

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-06-10 eCollection Date: 2025-08-01 DOI: 10.1172/JCI188584

Nishanth S Sadagopan, Rushmin Khazanchi, Rishi Jain, Amy B Heimberger, Stephen T Magill

引用次数: 0

The macrophage-intrinsic MDA5/IRF5 axis drives HIV-1 intron-containing RNA-induced inflammatory responses. 巨噬细胞内生性MDA5-IRF5轴驱动HIV-1内含子rna诱导的炎症反应。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-06-10 eCollection Date: 2025-08-15 DOI: 10.1172/JCI187663

Sita Ramaswamy, Hisashi Akiyama, Jacob Berrigan, Andrés A Quiñones-Molina, Alex J Olson, Yunhan Chen, YanMei Liang, Andrew J Henderson, Archana Asundi, Manish Sagar, Suryaram Gummuluru

{"title":"The macrophage-intrinsic MDA5/IRF5 axis drives HIV-1 intron-containing RNA-induced inflammatory responses.","authors":"Sita Ramaswamy, Hisashi Akiyama, Jacob Berrigan, Andrés A Quiñones-Molina, Alex J Olson, Yunhan Chen, YanMei Liang, Andrew J Henderson, Archana Asundi, Manish Sagar, Suryaram Gummuluru","doi":"10.1172/JCI187663","DOIUrl":"10.1172/JCI187663","url":null,"abstract":"Despite effective antiretroviral therapy, transcriptionally competent HIV-1 reservoirs remain and contribute to persistent immune activation in people living with HIV (PWH). HIV-1-infected macrophages are important mediators of chronic innate immune activation, though the mechanisms remain unclear. We previously reported that nuclear export and cytoplasmic expression of HIV-1 intron-containing RNA (icRNA) activates mitochondrial antiviral signaling (MAVS) protein-mediated type I IFN responses in macrophages. In this study, we demonstrate an essential role of melanoma differentiation-associated protein 5 (MDA5) in sensing HIV-1 icRNA and promoting MAVS-dependent interferon regulatory factor 5 (IRF5) activation in macrophages. Suppression of MDA5 but not retinoic acid-inducible gene I expression nor disruption of the endosomal TLR pathway abrogated HIV-1 icRNA-induced type I IFN responses and IP-10 expression in macrophages. Furthermore, induction of IP-10 in macrophages upon HIV-1 icRNA sensing by MDA5 was dependent on IRF5. Additionally, monocytes and monocyte-derived macrophages (MDMs) from older (>50 years) individuals exhibited constitutively higher levels of IRF5 expression compared with younger (<35 years) individuals, and HIV-1 icRNA-induced IP-10 expression was significantly enhanced in older macrophages, which was attenuated upon ablation of IRF5 expression, suggesting that IRF5 functions as a major mediator of proinflammatory response downstream of MDA5-dependent HIV-1 icRNA sensing, dysregulation of which might contribute to chronic inflammation in older PWH.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266374","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

CAR-T cells targeting CD155 reduce tumor burden in preclinical models of leukemia and solid tumors. 靶向CD155的CAR-T细胞在白血病和实体瘤的临床前模型中减轻肿瘤负担。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-06-06 eCollection Date: 2025-08-01 DOI: 10.1172/JCI189920

Tianchen Xiong, Ge Wang, Peng Yu, Zhenlong Li, Debao Li, Jianying Zhang, Song Lu, Ruiqi Yang, Xiaolong Lian, Jianhong Mi, Rui Ma, Zhiyao Li, Guido Marcucci, Tingting Zhao, Michael A Caligiuri, Jianhua Yu

{"title":"CAR-T cells targeting CD155 reduce tumor burden in preclinical models of leukemia and solid tumors.","authors":"Tianchen Xiong, Ge Wang, Peng Yu, Zhenlong Li, Debao Li, Jianying Zhang, Song Lu, Ruiqi Yang, Xiaolong Lian, Jianhong Mi, Rui Ma, Zhiyao Li, Guido Marcucci, Tingting Zhao, Michael A Caligiuri, Jianhua Yu","doi":"10.1172/JCI189920","DOIUrl":"10.1172/JCI189920","url":null,"abstract":"CAR-T cells are a powerful yet expensive tool in cancer immunotherapy. Although their use in targeting hematological malignancies is well established, using a single CAR-T cell therapy to treat both hematological and solid tumors, which can reduce cost, remains largely unexplored. In this study, we identified CD155, an adhesion molecule that is upregulated during tumor progression, as a target for CAR-T cell therapy in both leukemia and solid tumors. We engineered CAR-T cells using human and mouse anti-CD155 antibodies generated from a Berkeley Lights' Beacon platform. These CAR-T cells demonstrated potent antitumor activity, significantly reducing tumor burden in preclinical models of acute myeloid leukemia, non-small cell lung cancer, and pancreatic cancer. To reduce potential allogeneic rejection, we generated CAR-T cells using humanized anti-CD155 antibody sequences that retained efficacy. Additionally, murine CAR-T cells targeting mouse CD155 exhibited limited toxic side effects in immunocompetent mice, highlighting the favorable safety profile of this therapy. These findings suggest that CD155 can be targeted by CD155 CAR-T cells safely and effectively, representing an innovative cellular therapeutic strategy that has the potential to expand its scope across both AML and multiple solid tumors, thereby lowering the cost of cellular immunotherapy, especially as allogenic, universal, and off-the-shelf CAR-T cell therapies advance to the clinic.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12321399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248158","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

CXCL10 secreted by SPRY1-deficient epidermal keratinocytes fuels joint inflammation in psoriatic arthritis via CD14 signaling. 由spry1缺失的表皮角质形成细胞分泌的CXCL10通过CD14信号通路促进银屑病关节炎的关节炎症。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-06-05 eCollection Date: 2025-08-01 DOI: 10.1172/JCI186135

Fan Xu, Ying-Zhe Cui, Xing-Yu Yang, Yu-Xin Zheng, Xi-Bei Chen, Hao Zhou, Zhao-Yuan Wang, Yuan Zhou, Yi Lu, Ying-Ying Li, Li-Ran Ye, Ni-Chang Fu, Si-Qi Chen, Xue-Yan Chen, Min Zheng, Yong Yang, Xiao-Yong Man

{"title":"CXCL10 secreted by SPRY1-deficient epidermal keratinocytes fuels joint inflammation in psoriatic arthritis via CD14 signaling.","authors":"Fan Xu, Ying-Zhe Cui, Xing-Yu Yang, Yu-Xin Zheng, Xi-Bei Chen, Hao Zhou, Zhao-Yuan Wang, Yuan Zhou, Yi Lu, Ying-Ying Li, Li-Ran Ye, Ni-Chang Fu, Si-Qi Chen, Xue-Yan Chen, Min Zheng, Yong Yang, Xiao-Yong Man","doi":"10.1172/JCI186135","DOIUrl":"10.1172/JCI186135","url":null,"abstract":"Psoriatic arthritis (PsA) is a multifaceted, chronic inflammatory disease affecting the skin, joints, and entheses, and it is a major comorbidity of psoriasis. Most patients with PsA present with psoriasis before articular involvement; however, the molecular and cellular mechanisms underlying the link between cutaneous psoriasis and PsA are poorly understood. Here, we found that epidermis-specific SPRY1-deficient mice spontaneously developed PsA-like inflammation involving both the skin and joints. Excessive CXCL10 was secreted by SPRY1-deficient epidermal keratinocytes through enhanced activation of JAK1/2/STAT1 signaling, and CXCL10 blockade attenuated PsA-like inflammation. Of note, CXCL10 was found to bind to CD14, but not CXCR3, to promote the TNF-α production of periarticular CD14hi macrophages via PI3K/AKT and NF-κB signaling pathways. Collectively, this study reveals that SPRY1 deficiency in the epidermis is sufficient to drive both skin and joint inflammation, and it identifies keratinocyte-derived CXCL10 and periarticular CD14hi macrophages as critical links in the skin-joint crosstalk leading to PsA. This keratinocyte SPRY1/CXCL10/periarticular CD14hi macrophage/TNF-α axis provides valuable insights into the mechanisms underlying the transition from psoriasis to PsA and suggests potential therapeutic targets for preventing this progression.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12321389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234221","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

Diet-induced obesity promotes endothelial cell desensitization to VEGF-A and permanent islet vessel dysfunction in mice. 饮食诱导的肥胖促进小鼠内皮细胞对VEGF-A的脱敏和永久性胰岛血管功能障碍。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-06-05 eCollection Date: 2025-08-01 DOI: 10.1172/JCI177601

Yan Xiong, Andrea Dicker, Montse Visa, Erwin Ilegems, Per-Olof Berggren

{"title":"Diet-induced obesity promotes endothelial cell desensitization to VEGF-A and permanent islet vessel dysfunction in mice.","authors":"Yan Xiong, Andrea Dicker, Montse Visa, Erwin Ilegems, Per-Olof Berggren","doi":"10.1172/JCI177601","DOIUrl":"10.1172/JCI177601","url":null,"abstract":"Pancreatic islet microvasculature is essential for optimal islet function and glucose homeostasis. However, islet vessel pathogenesis in obesity and its role in the manifestation of metabolic disorders remain understudied. Here, we depict the time-resolved decline of intra-islet endothelial cell responsiveness to VEGF-A and islet vessel function in a mouse model of diet-induced obesity. Longitudinal imaging of sentinel islets transplanted into mouse eyes revealed substantial vascular remodeling and diminished VEGF-A response in islet endothelial cells after 12 weeks of Western diet (WD) feeding. This led to islet vessel barrier dysfunction and hemodynamic dysregulation, delaying transportation of secreted insulin into the blood. Notably, islet vessels exhibited a metabolic memory of previous WD feeding. Neither VEGF-A sensitivity nor the other vascular alterations was fully restored by control diet refeeding, resulting in modest yet significant impairment in glucose clearance despite normalized insulin sensitivity. Mechanistic analysis implicated hyperactivation of atypical PKC under both WD and recovery conditions, which inhibited VEGFR2 internalization and blunted VEGF-A-triggered signal transduction in endothelial cells. In summary, prolonged WD feeding causes irreversible islet endothelial cell desensitization to VEGF-A and islet vessel dysfunction, directly undermining glucose homeostasis.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12321391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248159","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 microRNA miR-30a blocks adipose tissue fibrosis accumulation in obesity. microRNA miR-30a阻断肥胖中脂肪组织纤维化的积累。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-06-05 eCollection Date: 2025-08-01 DOI: 10.1172/JCI175566

Pradip K Saha, Robert Sharp, Aaron R Cox, Rabie Habib, Michael J Bolt, Jessica B Felix, Claudia E Ramirez Bustamante, Xin Li, Sung Yun Jung, Kang Ho Kim, Kai Sun, Huaizhu Wu, Samuel Klein, Sean M Hartig

{"title":"The microRNA miR-30a blocks adipose tissue fibrosis accumulation in obesity.","authors":"Pradip K Saha, Robert Sharp, Aaron R Cox, Rabie Habib, Michael J Bolt, Jessica B Felix, Claudia E Ramirez Bustamante, Xin Li, Sung Yun Jung, Kang Ho Kim, Kai Sun, Huaizhu Wu, Samuel Klein, Sean M Hartig","doi":"10.1172/JCI175566","DOIUrl":"10.1172/JCI175566","url":null,"abstract":"White adipose tissue (WAT) fibrosis occurring in obesity contributes to the inflammatory and metabolic comorbidities of insulin resistance and type 2 diabetes, yet the mechanisms involved remain poorly understood. Here, we report a role for the broadly conserved miRNA miR-30a as a regulator of WAT fibrosis and systemic glucose metabolism. Mice modified to express miR-30a at elevated levels in adipose tissues maintain insulin sensitivity coupled with reduced fatty liver disease when fed a high-fat diet. These effects were attributable to cell-autonomous functions of miR-30a that potently increase expression of adipocyte-specific genes. Proteomic screening revealed miR-30a limits profibrotic programs in subcutaneous WAT, at least in part, by repressing PAI-1, a dominant regulator of fibrinolysis and biomarker of insulin resistance. Conversely, mouse adipocytes lacking miR-30a exhibited greater expression of fibrosis markers with disrupted cellular metabolism. Lastly, miR-30a expression negatively correlates with PAI-1 levels in subcutaneous WAT from people with obesity, further supporting an antifibrotic role for miR-30a. Together, these findings uncover miR-30a as a critical regulator of adipose tissue fibrosis that predicts metabolically healthy obesity in people and mice.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12321386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234222","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

Panose prevents acute-on-chronic liver failure by reducing bacterial infection in mice. Panose通过减少小鼠的细菌感染来预防急性慢性肝衰竭。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-06-03 eCollection Date: 2025-07-15 DOI: 10.1172/JCI184653

Jiaxin Li, Shihao Xie, Meiling Chen, Changze Hong, Yuqi Chen, Fengyuan Lyu, Niexin Tang, Tianqi Chen, Lingyan Zhao, Weihao Zou, Hongjuan Peng, Jingna Bao, Peng Gu, Bernd Schnabl, Jinjun Chen, Peng Chen

{"title":"Panose prevents acute-on-chronic liver failure by reducing bacterial infection in mice.","authors":"Jiaxin Li, Shihao Xie, Meiling Chen, Changze Hong, Yuqi Chen, Fengyuan Lyu, Niexin Tang, Tianqi Chen, Lingyan Zhao, Weihao Zou, Hongjuan Peng, Jingna Bao, Peng Gu, Bernd Schnabl, Jinjun Chen, Peng Chen","doi":"10.1172/JCI184653","DOIUrl":"10.1172/JCI184653","url":null,"abstract":"Acute-on-chronic liver failure (ACLF) is a leading cause of global liver-related mortality. Bacterial infection, especially in patients with decompensated cirrhosis, commonly triggers ACLF and is difficult to treat with antibiotics. Therefore, finding alternative strategies for preventing and managing bacterial infection is an urgent priority. Here, we observed that patients with bacterial infection and decompensated cirrhosis, as well as ACLF mice, exhibited lower fecal panose levels than uninfected controls. Megamonas funiformis, with 4α-glucanosyltransferase (4αGT) as a key enzyme for panose production, was identified as a potential panose producer. Animal experiments demonstrated that panose efficiently reduced liver injury and extended survival in ACLF mice by mitigating bacterial infection. Further results revealed that panose enhanced resistance to bacterial infection by inhibiting oxidative stress-induced gut barrier disruption, thereby limiting bacterial dissemination. Mechanistically, panose interacted with the solute carrier family 7 member 11 (SLC7A11, also known as xCT) protein to boost antioxidant glutathione levels in intestinal epithelial cells. These findings highlight panose's potential in preventing bacterial infection, offering a valuable insight into mitigating ACLF progression.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248160","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