American Journal of Pathology最新文献_第3页

Nitric Oxide May Adversely Affect the Metabolism and Viability of Retinal Organoids Derived from Patients with Leber Hereditary Optic Neuropathy. 一氧化氮可能对Leber遗传性视神经病变患者视网膜类器官的代谢和活力产生不利影响。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-09 DOI: 10.1016/j.ajpath.2025.05.006

Fumio Takano, Megumi Kitamura, Kaori Ueda, Makoto Nakamura

{"title":"Nitric Oxide May Adversely Affect the Metabolism and Viability of Retinal Organoids Derived from Patients with Leber Hereditary Optic Neuropathy.","authors":"Fumio Takano, Megumi Kitamura, Kaori Ueda, Makoto Nakamura","doi":"10.1016/j.ajpath.2025.05.006","DOIUrl":"10.1016/j.ajpath.2025.05.006","url":null,"abstract":"Leber hereditary optic neuropathy (LHON) is a bilateral optic neuropathy associated with mitochondrial DNA (mtDNA) mutations characterized by parapapillary telangiectasia during the acute phase. However, its precise mechanism remains unclear. This study evaluated the effects of nitric oxide (NO) on retinal organoids (ROs) generated from induced pluripotent stem cells derived from patients with LHON. Established induced pluripotent stem cells from three patients with the m.11778G>A mutation (patient group) and three healthy individuals (control group) were differentiated into ROs. Changes in cell death ratios, mtDNA copy number, and metabolite profiles in the ROs following exposure to sodium nitroprusside (SNP), which was an NO donor, were compared between the two groups. At baseline, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cell ratios did not differ significantly, whereas the mtDNA copy number was significantly higher in the patient group. SNP exposure significantly increased the proportion of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells in the patient group but did not affect the mtDNA copy number. Relative concentrations of metabolites, including taurine and γ-aminobutyric acid, were initially reduced in the patient group, but increased following SNP exposure. These findings suggest that NO may promote retinal cell death and disrupt metabolite profiles in ROs derived from patients with LHON.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273989","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

Superresolution Microscopy Reveals Alterations in Clathrin Structure in Human Cancer Tissue. 超分辨率显微镜显示了人类癌症组织中网格蛋白结构的变化。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-09 DOI: 10.1016/j.ajpath.2025.05.008

Alan Greig, Rui Henrique, Boyu Xie, Christopher Thrasivoulou, Michael Millar, Aamir Ahmed

{"title":"Superresolution Microscopy Reveals Alterations in Clathrin Structure in Human Cancer Tissue.","authors":"Alan Greig, Rui Henrique, Boyu Xie, Christopher Thrasivoulou, Michael Millar, Aamir Ahmed","doi":"10.1016/j.ajpath.2025.05.008","DOIUrl":"10.1016/j.ajpath.2025.05.008","url":null,"abstract":"Superresolution microscopy holds great promise for detailed structural analysis of proteins, yet its application in the investigations of protein structures in situ remains sparse. Clathrin-coated pit-mediated endocytosis (CME) plays a key role in human cancer. This study aimed to discover whether there are structural changes in clathrin pits in cancer? This study used immunofluorescence combined with superresolution structured illumination microscopy (SR-SIM) on normal and cancerous prostate tissue to reveal novel details of clathrin structure and biology. We show clathrin (heavy-chain) plaques and pits, expression of adaptor protein 2 (a clathrin adaptor protein) and epidermal growth factor receptor (a receptor target for CME) at nanometer scale in human tissue, in situ, with immunofluorescence-SR-SIM. There is an increase in the size of the clathrin pits in high-grade cancer compared with low-grade or normal prostate tissue. These results demonstrate that SR-SIM can be used to identify protein structures at high resolution in clinical tissue sections and there is an increased cargo capacity due to the increase in the size of clathrin pits as a mechanism that facilitates aggressiveness of cancer. These results shed new light on the pathology of cancer and the role CME via clathrin may play in carcinogenesis.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273990","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

Correction. 修正。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-05 DOI: 10.1016/j.ajpath.2025.05.005

引用次数: 0

Pharmacologic Inhibition of Glutamate Dehydrogenase 1 Improves Functional Recovery of Neuromuscular Junctions and Muscle Function in Duchenne Muscular Dystrophy. 药物抑制谷氨酸脱氢酶1 （GLUD1）可改善杜氏肌营养不良患者神经肌肉连接功能恢复和肌肉功能。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-02 DOI: 10.1016/j.ajpath.2025.05.003

Andreia Pereira-Nunes, Ummi Ammarah, Min Shang, Iris Charatsidou, Himal Sharma, Bruna Pereira Sorroche, Max Nobis, Thibaut Burg, Stijn Verschoren, Frédéric Relaix, Alessio Rotini, Ludo Van Den Bosch, Marcello Delfini, Emanuele Berardi, Massimiliano Mazzone

{"title":"Pharmacologic Inhibition of Glutamate Dehydrogenase 1 Improves Functional Recovery of Neuromuscular Junctions and Muscle Function in Duchenne Muscular Dystrophy.","authors":"Andreia Pereira-Nunes, Ummi Ammarah, Min Shang, Iris Charatsidou, Himal Sharma, Bruna Pereira Sorroche, Max Nobis, Thibaut Burg, Stijn Verschoren, Frédéric Relaix, Alessio Rotini, Ludo Van Den Bosch, Marcello Delfini, Emanuele Berardi, Massimiliano Mazzone","doi":"10.1016/j.ajpath.2025.05.003","DOIUrl":"10.1016/j.ajpath.2025.05.003","url":null,"abstract":"Presynaptic terminals of neuromuscular junctions (NMJs) are sensitive to glutamate, which contributes to NMJ plasticity and synaptic neurotransmission. However, the effect of glutamate on neurotransmission and its pharmacologic modulation in muscle pathologies are understudied. In this study, the efficacy of pharmacologic blockade of glutamate dehydrogenase (GLUD)-1 in mdx mice, a model of Duchenne muscular dystrophy, was investigated. The GLUD1 inhibitor R162 mitigated the malfunctioning of NMJs by enhancing glutamate release from muscle fibers and increasing its availability in the muscle interstitium. Glutamate binding to its N-methyl-d-aspartate receptor on the presynaptic bottom of NMJs resulted in the increased release of acetylcholine and functional recovery of the action potential and muscle contraction, ultimately improving muscle performance. Finally, the GLUD1 inhibitor did not affect the homeostatic control of NMJs and the behavior of either healthy or dystrophic mice. This study suggests a promising and feasible therapeutic approach, based on muscle glutamate exploitation, to treating Duchenne muscular dystrophy, an unmet need in the clinic so far.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224032","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 Angiofibrotic Switch in Retinal and Choroidal Vascular Diseases: Mechanistic Drivers of Angiogenesis and Endothelial-Mesenchymal Transition. 视网膜和脉络膜血管疾病中的血管纤维化转换：血管生成和内皮-间充质转化的机制驱动因素。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-02 DOI: 10.1016/j.ajpath.2025.05.004

Fergus C McLellan, Kelvin Huang, Elizabeth Wong, Daisy Y Shu

{"title":"The Angiofibrotic Switch in Retinal and Choroidal Vascular Diseases: Mechanistic Drivers of Angiogenesis and Endothelial-Mesenchymal Transition.","authors":"Fergus C McLellan, Kelvin Huang, Elizabeth Wong, Daisy Y Shu","doi":"10.1016/j.ajpath.2025.05.004","DOIUrl":"10.1016/j.ajpath.2025.05.004","url":null,"abstract":"The angiofibrotic switch refers to the pathologic transition from active angiogenesis to fibrosis, a process that contributes to disease progression in retinal and choroidal neovascular diseases, such as age-related macular degeneration and proliferative diabetic retinopathy. This switch marks the replacement of newly formed, fragile blood vessels with fibrotic tissue, ultimately leading to scarring and permanent vision loss. Understanding this process is crucial, as fibrosis results in severe visual impairment and, currently, no anti-fibrotic therapies exist. Central to the angiofibrotic switch is endothelial-mesenchymal transition, a process where endothelial cells lose their vascular endothelial identity and acquire mesenchymal properties, contributing to extracellular matrix deposition and fibrosis. This review explores the cellular and molecular mechanisms underlying the angiofibrotic switch, emphasizing the interplay between angiogenesis, endothelial-mesenchymal transition, and metabolic dysregulation in driving fibrosis. Key mediators, such as transforming growth factor-β and vascular endothelial growth factor, are discussed in the context of their dual roles in promoting angiogenesis and fibrosis. This review underlines the need for early detection methods and targeted therapies to mitigate the angiofibrotic switch and improve outcomes in patients with neovascular retinal and choroidal diseases. By unraveling the complexities of this transition, this review aims to provide a framework for developing innovative diagnostic and therapeutic strategies to prevent fibrosis and mitigate vision loss in retinal and choroidal neovascular diseases.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224033","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

Autocrine Transforming Growth Factor-β Signaling Promotes Cell Motility and Chemokine Secretion in an Angiomyolipoma-Derived Cell Model of Lymphangioleiomyomatosis. 在淋巴管平滑肌脂肪瘤细胞模型中，自分泌TGF-β信号促进细胞运动和趋化因子分泌。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-05-30 DOI: 10.1016/j.ajpath.2025.04.019

Anna Moskal, Rafał Myrczek, Mateusz Wawro, Lara Ruiz Auladell, Alexandra Baiges, Irene Garcia, Francesca Mateo Gonzalez, Miquel Angel Pujana, Jakub Kochan, Alicja Hinz, Elżbieta Radzikowska, Sophie Lucas, Joanna Bereta, Renata Mezyk-Kopec

{"title":"Autocrine Transforming Growth Factor-β Signaling Promotes Cell Motility and Chemokine Secretion in an Angiomyolipoma-Derived Cell Model of Lymphangioleiomyomatosis.","authors":"Anna Moskal, Rafał Myrczek, Mateusz Wawro, Lara Ruiz Auladell, Alexandra Baiges, Irene Garcia, Francesca Mateo Gonzalez, Miquel Angel Pujana, Jakub Kochan, Alicja Hinz, Elżbieta Radzikowska, Sophie Lucas, Joanna Bereta, Renata Mezyk-Kopec","doi":"10.1016/j.ajpath.2025.04.019","DOIUrl":"10.1016/j.ajpath.2025.04.019","url":null,"abstract":"Lymphangioleiomyomatosis (LAM) is a rare systemic disease that affects young women and is classified as a low-grade metastasizing neoplasm. It is characterized by uncontrolled proliferation of LAM cells within the lung parenchyma, which results from loss-of-function mutations in tuberous sclerosis complex 2 (TSC2) or 1 (TSC1) and activation of the mechanistic target of rapamycin complex 1. Abnormal cell growth leads to cyst formation and lung damage. Rapamycin-based therapy is the only approved treatment. Although it stabilizes the lung function in most patients, it has several limitations. Therefore, new therapeutic strategies are needed. This study examined the role of transforming growth factor-β (TGF-β), a pleiotropic cytokine with well-established protumorigenic activity, in LAM cell biology. Using a TSC2-deficient angiomyolipoma-derived cell line, it was found that TSC2-/- cells exhibited a higher expression of TGFβ1 and TGFβ3 than cells with restored TSC2 expression. Additionally, TSC2-/- cells expressed glycoprotein-A repetitions predominant and integrin β8, which promote TGF-β activation. Inhibition of TGF-β signaling in TSC2-/- cells reduced their migration in a wound healing assay, impaired transmigration through a three-dimensional matrix, and decreased the expression of monocyte chemoattractant protein-1. These findings provide new insights into the regulation of processes contributing to LAM progression and point to TGF-β as one of the potential targets for LAM treatment.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198062","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

Mitochondrial Protease AFG3L2 Inhibits Ferroptosis of Intestinal Epithelial Cells through PPARA/GPX4 Signaling Pathway to Improve Experimental Enteritis. 线粒体蛋白酶AFG3L2通过PPARA/GPX4信号通路抑制肠上皮细胞铁下垂，改善实验性肠炎。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-05-30 DOI: 10.1016/j.ajpath.2025.05.002

Wei Chen, Zeyan Xu, Jingjing Jiang, Wen Feng, Baiwen Li

{"title":"Mitochondrial Protease AFG3L2 Inhibits Ferroptosis of Intestinal Epithelial Cells through PPARA/GPX4 Signaling Pathway to Improve Experimental Enteritis.","authors":"Wei Chen, Zeyan Xu, Jingjing Jiang, Wen Feng, Baiwen Li","doi":"10.1016/j.ajpath.2025.05.002","DOIUrl":"10.1016/j.ajpath.2025.05.002","url":null,"abstract":"The pathogenesis of Crohn's disease (CD) remains unclear, with mitochondrial dysfunction and ferroptosis emerging as important contributors. However, the specific mechanisms linking mitochondria, ferroptosis, and CD are not well understood. Through bioinformatics analysis using the Gene Expression Omnibus database, AFG3L2 was identified as a key mitochondrial gene and subjected to functional enrichment and immune infiltration analyses. Lipopolysaccharide-induced NCM460 cells were used in vitro. Overexpression of AFG3L2 inhibited the release of inflammatory factors, enhanced antioxidant capacity, and reduced reactive oxygen species production. In addition, AFG3L2 overexpression activated the peroxisome proliferator-activated receptor-A (PPARA) signaling pathway and promoted the nuclear translocation of PPARA. As a downstream target of PPARA, glutathione peroxidase 4 (GPX4) transcriptional activity was regulated by PPARA. AFG3L2 facilitated the binding of PPARA to the GPX4 promoter region, thereby enhancing GPX4 transcription. Importantly, the regulation of GPX4 by AFG3L2 was dependent on the activation of PPARA. 2,4,6-Trinitrobenzenesulfonic acid-induced colitis in mice was used as an in vivo model. Overexpression of AFG3L2 preserved mitochondrial ultrastructure, suppressed intestinal inflammation, and promoted the expression of PPARA and GPX4. In summary, the results of this study reveal the protective role of the AFG3L2/PPARA/GPX4 axis in maintaining intestinal mucosal integrity and suggest it as a potential therapeutic target for CD.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198064","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

Exploratory Study of Prognostic Plasma Biomarkers in Patients with Pulmonary Arterial Hypertension. 肺动脉高压患者预后血浆生物标志物的探索性研究。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-05-30 DOI: 10.1016/j.ajpath.2025.04.018

Yukimitsu Kuwabara, Tetsuro Yokokawa, Sarah-Eve Lemay, Mélanie Sauvaget, Sandra Martineau, Sandra Breuils-Bonnet, François Potus, Sébastien Bonnet, Steeve Provencher, Olivier Boucherat

{"title":"Exploratory Study of Prognostic Plasma Biomarkers in Patients with Pulmonary Arterial Hypertension.","authors":"Yukimitsu Kuwabara, Tetsuro Yokokawa, Sarah-Eve Lemay, Mélanie Sauvaget, Sandra Martineau, Sandra Breuils-Bonnet, François Potus, Sébastien Bonnet, Steeve Provencher, Olivier Boucherat","doi":"10.1016/j.ajpath.2025.04.018","DOIUrl":"10.1016/j.ajpath.2025.04.018","url":null,"abstract":"Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular lumen occlusion, ultimately leading to right ventricular failure and death. Risk stratification is essential for the management of patients with PAH. So far, B-type natriuretic peptide and its N-terminal pro-form are the only circulating biomarkers used as part of composite PAH risk assessment tools. Identification of other biomarkers of vascular or systemic origin may also be valuable to provide additional information on disease severity and prognosis. Using proximity extension assay, >700 proteins related to oncology and neurology were measured in the plasma of 60 patients with PAH and 28 age- and sex-matched controls. Among the 114 proteins found to be significantly up-regulated in patients with PAH, 14 were independently associated with death/lung transplantation after adjustment for the 2015 European Society of Cardiology/European Respiratory Society, the REVEAL 2.0 risk scores, and the refined four-stratum risk assessment model. Among them, EDA2R, WFDC2, and TNFRSF10B displayed incremental prognostic value on top of these predictive models. Combining previously published proteomic data sets generated from different panels with the same cohort, a set of 23 proteins was identified, many of which are strongly associated with chronological age, that predict outcome of patients with PAH after adjusting for risk assessment tools. In conclusion, we identified proteins likely involved in the pathophysiology of the disease and potential candidates to prognostic enrichment.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198063","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 American Journal of Pathology’s Contribution to Advancing the Understanding of the Pathogenesis of Atherosclerosis 《美国病理学杂志》对推进对动脉粥样硬化发病机制理解的贡献

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-05-23 DOI: 10.1016/j.ajpath.2024.11.012

Avrum I. Gotlieb

引用次数: 0

Crosstalk between Hepatic Stellate Cells and Hepatic Macrophages in Metabolic Dysfunction–Associated Steatohepatitis 代谢功能障碍相关脂肪性肝炎中肝星状细胞和肝巨噬细胞间的串扰

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-05-23 DOI: 10.1016/j.ajpath.2025.02.003

Haoran Zhong , Chen Liu , Zhiwei Huang , Peng Tan , Hao Chen , Wenguang Fu

引用次数: 0