American Journal of Pathology最新文献_第5页

Gas1-Mediated Suppression of Hepatoblastoma Tumorigenesis.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-01-29 DOI: 10.1016/j.ajpath.2025.01.005

Keyao Chen, Huabo Wang, Bingwei Ma, Jessica Knapp, Colin Henchy, Jie Lu, Taylor Stevens, Sarangarajan Ranganathan, Edward V Prochownik

{"title":"Gas1-Mediated Suppression of Hepatoblastoma Tumorigenesis.","authors":"Keyao Chen, Huabo Wang, Bingwei Ma, Jessica Knapp, Colin Henchy, Jie Lu, Taylor Stevens, Sarangarajan Ranganathan, Edward V Prochownik","doi":"10.1016/j.ajpath.2025.01.005","DOIUrl":"10.1016/j.ajpath.2025.01.005","url":null,"abstract":"<p><p>Hepatoblastoma (HB), the most common pediatric liver cancer, is associated with dysregulated Wnt/β-catenin, Hippo, and/or nuclear factor erythroid 2 ligand 2/nuclear respiratory factor 2 (NFE2L2/NRF2) pathways. In mice, pairwise combinations of oncogenically active forms of the terminal transcription factors of these pathways, namely, β-catenin (B), Yes-associated protein (YAP; Y), and Nrf2 (N), generated HBs, with the triple combination (B + Y + N) being particularly potent. Each tumor group alters the expression of thousands of B-, Y-, and N-driven unique and common target genes. The identification of those most involved in transformation might reveal mechanisms and opportunities for therapy. Transcription profiling of >60 murine HBs revealed a common set of 22 BYN genes similarly deregulated in all cases. Most were associated with multiple cancer hallmarks, and their expression may correlate with survival in HBs, hepatocellular carcinomas, and other cancers. Among the most down-regulated of these genes was Gas1, which encodes a glycosylphosphatidylinositol-linked outer membrane protein. The restoration of Gas1 expression impaired B + Y + N-driven HB tumor growth in vivo and in HB-derived immortalized BY and BYN cell lines in vitro in a manner that requires membrane anchoring of the protein via its glycosylphosphatidylinositol moiety, implicating Gas1 as a proximal mediator of HB pathogenesis and validating the BYN gene set as deserving of additional scrutiny in future studies.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Development and Characterization of a Novel Rat Model for Emulating COPD-Associated Cor Pulmonale.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-01-29 DOI: 10.1016/j.ajpath.2025.01.003

Zhuoji Ma, Suiyang Tong, Yuhang Huang, Neng Wang, Guanjin Chen, Qianwen Bai, Jia Deng, Liang Zhou, Qiao Luo, Jian Wang, Wenju Lu, Lingdan Chen, Tao Wang

{"title":"Development and Characterization of a Novel Rat Model for Emulating COPD-Associated Cor Pulmonale.","authors":"Zhuoji Ma, Suiyang Tong, Yuhang Huang, Neng Wang, Guanjin Chen, Qianwen Bai, Jia Deng, Liang Zhou, Qiao Luo, Jian Wang, Wenju Lu, Lingdan Chen, Tao Wang","doi":"10.1016/j.ajpath.2025.01.003","DOIUrl":"10.1016/j.ajpath.2025.01.003","url":null,"abstract":"<p><p>Cor pulmonale, a condition marked by right ventricular dysfunction, is frequently associated with chronic obstructive pulmonary disease (COPD) and significantly worsens COPD prognosis. Despite the clinical relevance of cor pulmonale, development of effective treatments is hindered by the lack of animal models that accurately replicate the complex interplay between cor pulmonale and COPD. This study introduces a novel rat model combining cigarette smoke exposure with left pulmonary artery ligation to better mimic the pathophysiological features of COPD-related cor pulmonale. Pulmonary function tests revealed impaired lung function, and histologic assessments indicated emphysematous changes and inflammatory infiltration, consistent with COPD pathology. Furthermore, the model exhibited hallmarks of cor pulmonale, including right ventricular hypertrophy, fibrosis, and capillary rarefaction, alongside hemodynamic alterations indicative of pulmonary hypertension. This study's findings underscore the potential of the left pulmonary artery ligation + cigarette smoke rat model to advance understanding of COPD-related cor pulmonale pathophysiology and facilitate the development of targeted therapeutics.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Klotho Is Cardioprotective in the mdx Mouse Model of Duchenne Muscular Dystrophy.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-01-29 DOI: 10.1016/j.ajpath.2024.12.017

Areli Jannes S Javier, Felicia M Kennedy, Xin Yi, Michelle Wehling-Henricks, James G Tidball, Kenneth E White, Carol A Witczak, Makoto Kuro-O, Steven S Welc

{"title":"Klotho Is Cardioprotective in the mdx Mouse Model of Duchenne Muscular Dystrophy.","authors":"Areli Jannes S Javier, Felicia M Kennedy, Xin Yi, Michelle Wehling-Henricks, James G Tidball, Kenneth E White, Carol A Witczak, Makoto Kuro-O, Steven S Welc","doi":"10.1016/j.ajpath.2024.12.017","DOIUrl":"10.1016/j.ajpath.2024.12.017","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is a lethal, progressive skeletal and cardiac myopathy. Cardiomyopathy is the leading cause of death in patients with DMD, but the molecular basis for heart failure is incompletely understood. As with humans, in the mdx mouse model of DMD, cardiac function is impaired after the onset of skeletal muscle pathology. Dysregulation of Klotho gene regulation in dystrophic skeletal muscles occurs at disease onset, affecting pathogenesis. Whether Klotho is protective against dystrophin-deficient cardiomyopathy is unknown. This study found that expression of a Klotho transgene prevented deficits in left ventricular ejection fraction and fractional shortening in mdx mice. Improvements in cardiac performance were associated with reductions in adverse cardiac remodeling, cardiac myocyte hypertrophy, and fibrosis. In addition, mdx mice expressed high concentrations of plasma fibroblast growth factor 23 (FGF23), and expression was increased locally in hearts. The cardioprotective effects of Klotho were not associated with differences in renal function or serum biochemistries, but transgene expression prevented increased expression of plasma FGF23 and cardiac Fgf23 mRNA expression. Cardiac reactive oxygen species, oxidative damage, mitochondrial damage, and apoptosis were reduced in transgenic hearts. Our findings also showed that FGF23 stimulates hypertrophic growth in dystrophic neonatal mouse ventricular myocytes in vitro, which was inhibited by co-stimulation with soluble Klotho. Taken together, these results show that Klotho prevented dystrophic cardiac remodeling and improved function.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

An Update on Animal Models of Alcohol-Associated Liver Disease.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-01-28 DOI: 10.1016/j.ajpath.2024.11.011

Peng Cao, Xiaojuan Chao, Hong-Min Ni, Wen-Xing Ding

{"title":"An Update on Animal Models of Alcohol-Associated Liver Disease.","authors":"Peng Cao, Xiaojuan Chao, Hong-Min Ni, Wen-Xing Ding","doi":"10.1016/j.ajpath.2024.11.011","DOIUrl":"10.1016/j.ajpath.2024.11.011","url":null,"abstract":"<p><p>Alcohol-associated liver disease (ALD) is a significant global health concern and a leading cause of liver disease-related deaths. However, the treatment options are limited due to the lack of animal models that accurately replicate ALD pathogenesis. An ideal ALD animal model should have pathological characteristics similar to those of human ALD, with a clear pathological process and ease of drug intervention. Over the years, researchers have focused on developing ideal ALD preclinical animal models by testing various methods, such as ad libitum drinking water with ethanol, acute, single large doses of ethanol gavage, multiple alcohol gavages in a short period, the Lieber-DeCarli liquid diet feeding model, the intragastric infusion model, and the Gao-binge model. With the increasing occurrence of obesity and metabolic dysfunction-associated steatotic liver disease, a new category of metabolic and alcohol-associated liver disease (MetALD) is also emerging. Studies have investigated the combined effects of a high-fat diet combined with binge alcohol or drinking water containing ethanol to mimic MetALD. In addition to mice, other species such as rats, guinea pigs, zebrafish, and non-human primates have also been tested to establish ALD preclinical models. This review aims to summarize current animal ALD models, particularly the emerging MetALD models, with the hope of providing a valuable reference for establishing more effective animal models in ALD studies in the future.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

P-Glycoprotein Drives Glioblastoma Survival and Chemotherapy Resistance: Potential as a Promising Liquid Biopsy Biomarker. p -糖蛋白驱动胶质母细胞瘤的生存和化疗耐药性：作为有前途的液体活检生物标志物的潜力。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-01-25 DOI: 10.1016/j.ajpath.2024.12.004

Carlos Pilotto Heming, Isabel de Souza Barbosa, Renan Lyra Miranda, Odile Nogueira Ugarte, Vitória Santório de São José, Vivaldo Moura Neto, Veronica Aran

{"title":"P-Glycoprotein Drives Glioblastoma Survival and Chemotherapy Resistance: Potential as a Promising Liquid Biopsy Biomarker.","authors":"Carlos Pilotto Heming, Isabel de Souza Barbosa, Renan Lyra Miranda, Odile Nogueira Ugarte, Vitória Santório de São José, Vivaldo Moura Neto, Veronica Aran","doi":"10.1016/j.ajpath.2024.12.004","DOIUrl":"10.1016/j.ajpath.2024.12.004","url":null,"abstract":"<p><p>Drug resistance is a major challenge in cancer therapy, and the expression of efflux pumps such as P-glycoprotein (P-gp, ABCB1) often correlates with poor prognosis in various tumors, including glioblastoma (GB). Considering that different roles for these proteins have been established in the biology of various tumors, this study aimed to investigate the functions of P-gp in GB-derived cells by evaluating its survival, migratory, and apoptosis-regulating capabilities, as well as its potential as a liquid biopsy biomarker. P-gp expression was diminished via siRNA to determine its exact role in GB biology. The P-gp mRNA levels were evaluated by using quantitative real-time RT-PCR. With respect to liquid biopsy, circulating cell-free RNA was extracted from plasma belonging to patients diagnosed with GB, and P-gp levels were compared with matching tumor tissues using digital PCR. P-gp silencing significantly decreased viability, increased apoptosis, and enhanced chemotherapy sensitivity in GB cells, although it did not affect migratory patterns. Finally, P-gp expression levels in circulating cell-free RNA from patients with GB matched tumor tissue, whereas healthy volunteers appeared to bear no circulating P-gp. Taken together, the results indicate that P-gp affects GB tumor biology beyond its known role in drug resistance and could integrate a broader molecular signature for future diagnosis via liquid biopsy.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

E3 Ubiquitin Ligase TRIM7 Alleviates Lipopolysaccharide-Induced Acute Lung Injury via Inhibiting NLRP3 Inflammasome Activation

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-01-24 DOI: 10.1016/j.ajpath.2024.12.016

Youna Wang , Xiaohong Xu , Peng Zhang , Sha Hu , Li Zhang , Hongbin Chen

{"title":"E3 Ubiquitin Ligase TRIM7 Alleviates Lipopolysaccharide-Induced Acute Lung Injury via Inhibiting NLRP3 Inflammasome Activation","authors":"Youna Wang , Xiaohong Xu , Peng Zhang , Sha Hu , Li Zhang , Hongbin Chen","doi":"10.1016/j.ajpath.2024.12.016","DOIUrl":"10.1016/j.ajpath.2024.12.016","url":null,"abstract":"<div><div>Acute lung injury (ALI) is a common clinical disease with high mortality, characterized by tissue damage caused by excessive activation of inflammation. TRIM7 is an E3 ligase that plays an important role in regulating viral infection, tumor progression, and innate immune response. However, its function in ALI is unclear. In this study, lipopolysaccharide (LPS) was used to stimulate C57BL/6j mice and HULEC-5a cells to establish ALI models <em>in vivo</em> and <em>in vitro</em>. TRIM7 expression was down-regulated during ALI. Furthermore, overexpressing TRIM7 in HULEC-5a cells relieved cell damage and inflammatory activation induced by LPS stimulation. TRIM7 knockdown had the opposite effect. Trim7-overexpressing mice were established by endotracheal injection of adeno-associated virus 6-<em>Trim7</em> virus <em>in vivo</em>; the ALI model was then induced by LPS stimulation. Overexpression of TRIM7 could alleviate lung tissue injury, pulmonary interstitial hemorrhage, increased alveolar and vascular permeability, inflammatory cell infiltration, and secretion of inflammatory factors induced by LPS stimulation. Mechanistically, TRIM7 inhibited the expression of NOD-, LRR- and pyrin domain-containing 3 (NLRP3) and the activation of the NLRP3 inflammasome. The regulatory effect of TRIM7 on ALI depended on the NLRP3 inflammasome. This investigation, for the first time, showed the inhibitory effect of TRIM7 on ALI and activation of the NLRP3 inflammasome, providing new targets and ideas for the research on the mechanism and treatment of ALI.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 639-651"},"PeriodicalIF":4.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 Biological Intersection Between Chemotherapy-Related Cognitive Impairment and Alzheimer Disease. 化疗相关认知障碍与阿尔茨海默病之间的生物学交叉。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-01-23 DOI: 10.1016/j.ajpath.2024.12.013

Matthew Torre, Camila A Zanella, Mel B Feany

引用次数: 0

Brain Connectivity, Neural Networks, and Resilience in Aging and Neurodegeneration.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-01-23 DOI: 10.1016/j.ajpath.2024.12.014

Diego Szczupak, Lovisa LjungQvist Brinson, Christi L Kolarcik

{"title":"Brain Connectivity, Neural Networks, and Resilience in Aging and Neurodegeneration.","authors":"Diego Szczupak, Lovisa LjungQvist Brinson, Christi L Kolarcik","doi":"10.1016/j.ajpath.2024.12.014","DOIUrl":"10.1016/j.ajpath.2024.12.014","url":null,"abstract":"<p><p>The importance of complex systems has become increasingly evident in recent years. The nervous system is one such example, with neural networks sitting at the intersection of complex networks and biology. A particularly exciting feature is the resilience of complex systems. For example, the ability of the nervous system to perform even in the face of challenges that include neuronal loss, neuroinflammation, protein accumulation, axonal disruptions, and metabolic stress is an intriguing and exciting line of investigation. In neurodegenerative diseases, neural network resilience is responsible for the time between the earliest disease-linked changes and clinical symptom onset and disease diagnosis. In this way, connectivity resilience of neurons within the complex network of cells that make up the nervous system has significant implications. This review provides an overview of relevant concepts related to complex systems with a focus on the connectivity of the nervous system. It discusses the development of the neural network and how a delicate balance determines how this complex system responds to injury, with examples illustrating maladaptive plasticity. The review then addresses the implications of these concepts, methods to understand brain connectivity and neural networks, and recent research efforts aimed at understanding neurodegeneration from this perspective. This study aims to provide foundational knowledge and an overview of current research directions in this evolving and exciting area of neuroscience.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Piezo2 Is a Key Mechanoreceptor in Lung Fibrosis that Drives Myofibroblast Differentiation Piezo2 是肺纤维化过程中的一个关键机械感受器，可驱动肌成纤维细胞分化。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-01-22 DOI: 10.1016/j.ajpath.2024.12.015

Margaret A.T. Freeberg , Sarah V. Camus , Valentina Robila , Apostolos Perelas , Thomas H. Thatcher , Patricia J. Sime

{"title":"Piezo2 Is a Key Mechanoreceptor in Lung Fibrosis that Drives Myofibroblast Differentiation","authors":"Margaret A.T. Freeberg , Sarah V. Camus , Valentina Robila , Apostolos Perelas , Thomas H. Thatcher , Patricia J. Sime","doi":"10.1016/j.ajpath.2024.12.015","DOIUrl":"10.1016/j.ajpath.2024.12.015","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases have limited treatment options. Fibroblasts are key effector cells that sense matrix stiffness through conformation changes in mechanically sensitive receptors, leading to activation of downstream profibrotic pathways. Here, the role of Piezo2, a mechanosensitive ion channel, in human and mouse lung fibrosis, and its function in myofibroblast differentiation in primary human lung fibroblasts (HLFs) was investigated. Human samples from patients with IPF and mouse tissue from bleomycin-induced pulmonary fibrosis were assessed. Primary HLFs from nonfibrotic donors were grown on substrates of different stiffness to induce myofibroblast differentiation and treated with a Piezo2 inhibitor. Piezo2 expression was up-regulated in tissue from patients with IPF and in fibrotic mouse lung tissue. Additionally, analysis of published single-cell RNA-sequencing data showed that Piezo2 was expressed in the profibrotic collagen triple helix repeat containing 1 (Cthrc1)<sup>+</sup> fibroblast subpopulation. Myofibroblast differentiation was increased in HLFs grown on substrates with fibrotic levels of stiffness compared with that seen in softer substrates. Piezo2 inhibition reduced stiffness-induced expression α-smooth muscle actin and fibronectin in HLFs. Piezo2 expression was elevated in fibrotic lung disease in both patients and rodents, and its presence was key in the differentiation of fibroblasts to the profibrotic myofibroblasts. Blocking Piezo2 may play a key role in fibrosis and, thus, be a novel therapeutic approach to treat pulmonary fibrosis.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 626-638"},"PeriodicalIF":4.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

This Month in AJP 本月在AJP。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-01-14 DOI: 10.1016/j.ajpath.2025.01.001

引用次数: 0