American Journal of Pathology最新文献

{"title":"Involvement of Heat Shock Protein 47 in Osteophyte Formation of Knee Joint Osteoarthritis","authors":"Yuta Otsuka ,&nbsp;Arepati Adili ,&nbsp;Masahiro Momoeda ,&nbsp;Yoshifumi Negishi ,&nbsp;Haruka Kaneko ,&nbsp;Chiho Yoshinaga ,&nbsp;Yuka Kenzaki ,&nbsp;Takako Negishi-Koga ,&nbsp;Muneaki Ishijima ,&nbsp;Yasunori Okada","doi":"10.1016/j.ajpath.2025.03.003","DOIUrl":"10.1016/j.ajpath.2025.03.003","url":null,"abstract":"<div><div>Osteophytes contribute to the development and progression of knee osteoarthritis (OA). Although transforming growth factor-β (TGF-β) and bone morphogenic protein-2 (BMP2) are known to induce osteophytes, regulators of osteophyte formation remain elusive. This study aimed to search for molecules that modulate osteophytosis in a mouse knee OA model. Proteomic analysis, followed by immunohistochemistry of osteophyte and articular cartilage, identified heat shock protein 47 (HSP47), a molecular chaperone for procollagens, as a molecule selectively overexpressed by osteophyte fibrocartilaginous cells. The treatment of TGF-β3 and BMP2 to a three-dimensional pellet culture of mouse mesenchymal stem cells caused their differentiation into osteophyte-like cells accompanied with the up-regulation of HSP47. The pellet sizes of stimulated three-dimensional–cultured mesenchymal stem cells were significantly reduced by knockdown of HSP47 or treatment with AK778 (HSP47 inhibitor), because of increased apoptosis. Furthermore, intra-articular AK778 injections suppressed osteophyte formation in a mouse OA model. Importantly, the studies with human samples demonstrated HSP47 overexpression by osteophyte fibrocartilaginous cells in human OA knee joints. Similarly, the overexpression of HSP47 was observed in the TGF-β3– and BMP2-treated human osteophytic cell spheroids as well as the size reduction of spheroids by AK778 treatment. These findings highlight the promoting function of HSP47 in osteophyte formation in OA knee joints and suggest that therapeutic interventions targeting HSP47 may be of clinical value.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 7","pages":"Pages 1279-1293"},"PeriodicalIF":4.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961100","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}

{"title":"Leucine-Rich Repeat Kinase 2 Promotes Disintegration of Retinal Pigment Epithelial Cell","authors":"Yuka Suimon ,&nbsp;Moemi Nishimura ,&nbsp;Miyuki Murata ,&nbsp;Shiho Yoshida ,&nbsp;Koichi Yokoi ,&nbsp;Zhenyu Dong ,&nbsp;Noriyuki Kuno ,&nbsp;Shinobu Fujii ,&nbsp;Zen-Ichi Tanei ,&nbsp;Ichiro Yabe ,&nbsp;Kousuke Noda ,&nbsp;Susumu Ishida","doi":"10.1016/j.ajpath.2025.03.002","DOIUrl":"10.1016/j.ajpath.2025.03.002","url":null,"abstract":"<div><div>Recent epidemiologic studies have shown that patients with age-related macular degeneration (AMD) have a considerably higher risk of developing Parkinson disease (PD) later in life, suggesting a possible link between these diseases. However, the common mechanisms between these two diseases remain obscure, although the pathophysiology of each has been well investigated. This study was designed to explore the shared pathologic features of AMD and PD by focusing on leucine-rich repeat kinase 2 (LRRK2) and α-synuclein, both of which play crucial roles in PD pathogenesis. Immunohistochemistry for LRRK2 and α-synuclein was performed on human eye specimens. The effect of LRRK2 on retinal pigment epithelium (RPE) cell function was investigated using the RPE cell line hTERT-RPE1. Retinal morphology and function were examined in <em>LRRK2-G2019S</em> transgenic mice, representing mutants with increased kinase activity of LRRK2. Immunohistochemistry revealed that LRRK2 and α-synuclein were present in the RPE layer of the human eye. Overexpression of LRRK2 in RPE cells increased α-synuclein and induced cell death. LRRK2 inhibited α-synuclein degradation via phosphorylation of RAB, member RAS oncogene GTPases. <em>LRRK2-G2019S</em> transgenic mice exhibited apoptosis of RPE and photoreceptors, choroidal thinning, and reduced electroretinogram amplitude, on top of α-synuclein protein accumulation in the RPE cell layer. Taken together, the current study revealed that LRRK2 is one of the key molecules involved in the common pathologic mechanisms of AMD and PD.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 7","pages":"Pages 1294-1310"},"PeriodicalIF":4.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952632","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}

{"title":"Title Page","authors":"","doi":"10.1016/S0002-9440(25)00107-5","DOIUrl":"10.1016/S0002-9440(25)00107-5","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Page OFC"},"PeriodicalIF":4.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859879","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}

{"title":"Meeting Abstracts","authors":"","doi":"10.1016/S0002-9440(25)00109-9","DOIUrl":"10.1016/S0002-9440(25)00109-9","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages S1-S35"},"PeriodicalIF":4.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859881","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}

{"title":"Insights from the Seminal Findings from Puhr et al on the Mechanisms of Docetaxel Resistance in Prostate Cancer","authors":"Zoran Culig","doi":"10.1016/j.ajpath.2024.08.015","DOIUrl":"10.1016/j.ajpath.2024.08.015","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 612-614"},"PeriodicalIF":4.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143684821","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}

{"title":"Zinc Finger Protein Znf296 Is a Cardiac-Specific Splicing Regulator Required for Cardiomyocyte Formation","authors":"Xianpeng Li ,&nbsp;Shuaiqi Yang ,&nbsp;Lu Wang ,&nbsp;Xiangmin Zhang ,&nbsp;Ailong Zhang ,&nbsp;Yunchao Wang ,&nbsp;De-Li Shi ,&nbsp;Hongyan Li","doi":"10.1016/j.ajpath.2025.02.006","DOIUrl":"10.1016/j.ajpath.2025.02.006","url":null,"abstract":"<div><div>Heart formation and function are tightly regulated at transcriptional and post-transcriptional levels. The dysfunction of cardiac cell–specific regulatory genes leads to various heart diseases. Heart failure is one of the most severe and complex cardiovascular diseases, which could be fatal if not treated promptly. However, the exact causes of heart failure are still unclear, especially at the level of single-gene causation. Here, an essential role was uncovered for the zinc finger protein Znf296 in heart development and cardiac contractile function. Specifically, <em>znf296</em>-deficient zebrafish embryos displayed heart defects characterized by decreased systolic and diastolic capacities of the ventricle and atrium. This was associated with reduced numbers and disrupted structural integrity of cardiomyocytes, including disorganized cytoskeleton and absence of sarcomeres. Mechanistically, the loss of Znf296 altered the alternative splicing of a subset of genes important for heart development and disease, such as <em>mef2ca</em>, <em>sparc</em>, <em>tpm2</em>, <em>camk2g1</em>, <em>tnnt3b</em>, and <em>pdlim5b</em>. Furthermore, Znf296 biochemically and functionally interacted with myelin transcription factor 1-like, a (Myt1la) in regulating cardiac-specific splicing and heart development. Importantly, ZNF296 also regulated alternative splicing in human cardiomyocytes to maintain structural integrity. These results suggest that Znf296 plays a conserved role for the differentiation of cardiomyocytes and the proper function of the cardiovascular system.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 6","pages":"Pages 1057-1073"},"PeriodicalIF":4.7,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690879","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}

{"title":"The Microbial Metabolite δ-Valerobetaine Strengthens the Gut Epithelial Barrier","authors":"Lauren C. Askew ,&nbsp;C. Anthony Gacasan ,&nbsp;Maria E. Barbian ,&nbsp;Jaclyn Weinberg ,&nbsp;Liping Luo ,&nbsp;Brian S. Robinson ,&nbsp;Dean P. Jones ,&nbsp;Christopher D. Scharer ,&nbsp;Rheinallt M. Jones","doi":"10.1016/j.ajpath.2025.02.007","DOIUrl":"10.1016/j.ajpath.2025.02.007","url":null,"abstract":"<div><div>Metabolic processes within gut microbes generate bioactive metabolites that impact intestinal epithelial barrier function. Herein, gnotobiotic mice and mass spectrometry–based metabolomics were used to identify novel metabolites in host tissues of microbial origin. Of those detected, the gut microbe–generated metabolite δ-valerobetaine (δ-VB) is a potent inhibitor of <span>l</span>-carnitine biosynthesis and a modulator of fatty acid oxidation by mitochondria in liver cells. The bioactivity of δ-VB toward gut epithelial barrier function was assessed. Germ-free mice are devoid of δ-VB, and administration of δ-VB to germ-free mice induced the enrichment of transcript sets associated with gut mitochondrial respiration and fatty acid oxidation in colonic tissue. Furthermore, δ-VB induced the differential expression of genes that function in barrier function in germ-free and conventionally raised mice. Functionally, δ-VB decreased gut barrier permeability and augmented wound healing in cultured gut epithelial cells and elicited cytoprotective and prorestitutive effects in a mouse model of colonic injury. These data indicate that the microbial-derived metabolite δ-VB is a modulator of gut epithelium function, and thus is a molecular target to potentially manage microbiome-host dysbiosis in intestinal health and disease.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 6","pages":"Pages 1109-1123"},"PeriodicalIF":4.7,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690875","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}

{"title":"Glycosylation Triggers Cathepsin D Maturation and Secretion to Promote Gastric Cancer Development","authors":"Liling Niu ,&nbsp;Xunzhu Zhou ,&nbsp;Deman Li ,&nbsp;Yongye Zheng ,&nbsp;Hui Li","doi":"10.1016/j.ajpath.2025.02.009","DOIUrl":"10.1016/j.ajpath.2025.02.009","url":null,"abstract":"<div><div>Cathepsin D (CTSD) is a lysosomal aspartic protease with high expression in cancers. CTSD localized in different subcellular regions performs distinct roles. However, the precise regulation of its intracellular trafficking and extracellular secretion remains incompletely understood. This study showed that glycosylation modifications of CTSD determined its maturation and secretion in gastric cancer (GC) cells. Specifically, glycosylation at asparagine 134 (N134) dictated the intracellular trafficking and maturation of CTSD within lysosomes, through facilitating its sorting into COPII vesicles. Glycosylation at asparagine 263 (N263) was essential for the secretion of the proenzyme form of CTSD (pro-CTSD) via a novel pathway dependent on the small GTPase Rab3D. Notably, the extracellular release of pro-CTSD occurred more rapidly than its intracellular trafficking from the endoplasmic reticulum to lysosomes. This enhanced secretion speed may rapidly elevate the levels of pro-CTSD in the tumor microenvironment in response to extracellular stimuli. Ultimately, glycosylation at N134 and N263 regulated the autophagy and cell proliferation, respectively. These findings show the role of glycosylation in triggering the maturation and secretion of CTSD in GC cells. Through modulating its cellular trafficking, differential glycosylation modifications of CTSD defined the malignant behavior of GC cells.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 6","pages":"Pages 1172-1187"},"PeriodicalIF":4.7,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690858","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}

{"title":"Human Mucin-2–Producing Colonic Goblet-Like Cells Secrete the Chemokine CXCL8 by Activating Multiple Proinflammatory Pathways in Response to Entamoeba histolytica","authors":"Ariel Kim ,&nbsp;Hayley Gorman ,&nbsp;France Moreau ,&nbsp;Mackenzie McManus ,&nbsp;Antoine Dufour ,&nbsp;Kris Chadee","doi":"10.1016/j.ajpath.2025.02.008","DOIUrl":"10.1016/j.ajpath.2025.02.008","url":null,"abstract":"<div><div>The mucus layer produced by highly stressed goblet cells forms a protective shield in the gut to protect the underlying mucosal epithelial cells from external threats. Hypersecretion and depletion of mucin-2 (MUC2) mucin from goblet cells is characteristic of symptomatic <em>Entamoeba histolytica</em> infections. It was hypothesized that MUC2 depleted goblet cells could mount a second line of innate host defense by producing proinflammatory cytokines. To investigate this, whether <em>E. histolytica</em> could stimulate proinflammatory responses in wild-type (WT) high MUC2 mucin-producing goblet-like cells and in clustered regularly interspaced palindromic repeats and CRISPR-associated protein 9 (CRISPR-Cas9) gene-edited <em>MUC2KO</em> cells was investigated. In response to live <em>E. histolytica</em> and soluble <em>E. histolytica</em> proteins, WT, and to a lesser extent, <em>MUC2KO</em> cells produced high levels of CXCL8. <em>Entamoeba histolytica</em> temporally induced greater levels of CXCL8 mRNA expression and protein secretion in WT versus <em>MUC2KO</em> cells, which was abrogated with alleviation of endoplasmic reticulum stress with the NADPH-oxidase inhibitor diphenyleneiodonium chloride. WT cells produced elevated reactive oxygen species that induced longer half-lives of CXCL8 transcripts, which was abrogated with diphenyleneiodonium chloride. Western blot and proteomic analyses revealed that WT cells, but not <em>MUC2KO</em> cells, were basally primed to respond to external stressors and responded to <em>E. histolytica</em> through rapid activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase, mitogen-activated protein kinase/p38, and phosphatidylinositol 3-kinase/Akt pathways, to induce CXCL8. These results suggest that colonic goblet-like cells defend against <em>E. histolytica</em> infections by hypersecreting mucus and produce the chemokine, CXCL8, to recruit neutrophils.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 6","pages":"Pages 1085-1108"},"PeriodicalIF":4.7,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690862","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}

{"title":"Machine Learning and Mendelian Randomization Reveal a Tumor Immune Cell Profile for Predicting Bladder Cancer Risk and Immunotherapy Outcomes","authors":"Fei Teng ,&nbsp;Renjie Zhang ,&nbsp;Yunyi Wang ,&nbsp;Qian Li ,&nbsp;Bei Wang ,&nbsp;Huijing Chen ,&nbsp;Tongtong Liu ,&nbsp;Zehua Liu ,&nbsp;Jia Meng ,&nbsp;Ce Wang ,&nbsp;Shilei Dong ,&nbsp;Yanhong Li","doi":"10.1016/j.ajpath.2025.01.016","DOIUrl":"10.1016/j.ajpath.2025.01.016","url":null,"abstract":"<div><div>This study’s objective was to develop predictive models for bladder cancer (BLCA) using tumor infiltrated immune cell (TIIC)-related genes. Multiple RNA expression data and scRNA-seq were downloaded from the TCGA and GEO databases. A tissue specificity index was calculated and a computational framework developed to identify TIIC signature scores based on three algorithms. Univariate Cox analysis was performed, and the TIIC-related model was generated by 20 machine learning algorithms. A significant correlation between TIIC signature score and survival status, tumor stage, and TNM staging system was found. Patients in the high-score BLCA group had more favorable survival outcomes and enhanced response to PD-L1 immunotherapy as compared to those in the low-score group. This TIIC model showed better performance in prognosing BLCA. Diverse frequencies of mutations were observed in human chromosomes across groups categorized by TIIC score. No statistically significant correlation was observed between noncancerous bladder conditions and BLCA when examining the single nucleotide polymorphisms (SNPs) associated with the genes in the prognostic model. However, a statistically significant association was found at the SNP sites of <em>rs3763840</em>. There was no significant association between bladder stones and BLCA, but there was a significant association on the SNP sites of <em>rs3763840</em>. A novel TIIC signature score was constructed for the prognosis and immunotherapy for BLCA, which offers direction for predicting overall survival of patients with BLCA.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 6","pages":"Pages 1141-1157"},"PeriodicalIF":4.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690869","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}