American Journal of Pathology最新文献_第2页

miRNA and mRNA Signatures in Human Acute Kidney Injury Tissue. 人类急性肾损伤组织中的 miRNA 和 mRNA 信号。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-01-01 Epub Date: 2024-09-25 DOI: 10.1016/j.ajpath.2024.08.013

Danielle Janosevic, Thomas De Luca, Ricardo Melo Ferreira, Debora L Gisch, Ying-Hua Cheng, Takashi Hato, Jinghui Luo, Yingbao Yang, Jeffrey B Hodgin, Carrie L Phillips, Pierre C Dagher, Michael T Eadon

{"title":"miRNA and mRNA Signatures in Human Acute Kidney Injury Tissue.","authors":"Danielle Janosevic, Thomas De Luca, Ricardo Melo Ferreira, Debora L Gisch, Ying-Hua Cheng, Takashi Hato, Jinghui Luo, Yingbao Yang, Jeffrey B Hodgin, Carrie L Phillips, Pierre C Dagher, Michael T Eadon","doi":"10.1016/j.ajpath.2024.08.013","DOIUrl":"10.1016/j.ajpath.2024.08.013","url":null,"abstract":"Acute kidney injury (AKI) is an important contributor to the development of chronic kidney disease (CKD). There is a need to understand molecular mediators that drive recovery and progression to CKD. In particular, the regulatory role of miRNAs in AKI is poorly understood. Herein, miRNA and mRNA sequencing were performed on biobanked human kidney tissues obtained during the routine care of subjects with a diagnosis of AKI, minimal change disease, or on nephrectomy tissue with no known kidney disease. mRNA analysis revealed that nephrectomy tissues exhibited an injury signature similar to that of AKI which was not identified in minimal change disease samples. The transcriptomic signature of human AKI was enriched in pathways involved in cell adhesion, epithelial-to-mesenchymal transition, and cell cycle arrest (eg, CDH6, ITGB6, CDKN1A). In AKI, up-regulation of miR-146a, miR-155, miR-142, and miR-122 was associated with pathways involved in immune cell recruitment, inflammation, and epithelial-to-mesenchymal transition. miR-122 and miR-146 were associated with down-regulation of DDR2 and IGFBP6, which are genes involved in the recovery and progression of kidney disease. These data provide integrated miRNA signatures that complement mRNA and other epigenetic data available in kidney atlases.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":"102-114"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11686445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339399","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

A Newly Identified Protective Role of C5a Receptor 1 in Kidney Tubules against Toxin-Induced Acute Kidney Injury. 新发现的 C5aR1 在肾小管中对毒素引起的急性肾损伤的保护作用。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-01-01 Epub Date: 2024-10-18 DOI: 10.1016/j.ajpath.2024.10.003

Samuel Mon-Wei Yu, Emily King, Miguel Fribourg, Susan Hartzell, Liam Tsou, Logan Gee, Vivette D D'Agati, Joshua M Thurman, John Cijiang He, Paolo Cravedi

{"title":"A Newly Identified Protective Role of C5a Receptor 1 in Kidney Tubules against Toxin-Induced Acute Kidney Injury.","authors":"Samuel Mon-Wei Yu, Emily King, Miguel Fribourg, Susan Hartzell, Liam Tsou, Logan Gee, Vivette D D'Agati, Joshua M Thurman, John Cijiang He, Paolo Cravedi","doi":"10.1016/j.ajpath.2024.10.003","DOIUrl":"10.1016/j.ajpath.2024.10.003","url":null,"abstract":"Acute kidney injury (AKI) remains a major reason for hospitalization with limited therapeutic options. Although complement activation is implicated in AKI, the role of C5a receptor 1 (C5aR1) in kidney tubular cells is unclear. Herein, aristolochic acid nephropathy (AAN) and folic acid nephropathy (FAN) models were used to establish the role of C5aR1 in kidney tubules during AKI in germline C5ar1-/-, myeloid cell-specific, and kidney tubule-specific C5ar1 knockout mice. After aristolochic acid and folic acid injection, C5ar1-/- mice had increased AKI severity and a higher degree of tubular injury. Macrophage depletion in C5ar1-/- mice or myeloid cell-specific C5ar1 deletion did not affect the outcomes of aristolochic acid-induced AKI. RNA-sequencing data from renal tubular epithelial cells (RTECs) showed that C5ar1 deletion was associated with the down-regulation of mitochondrial metabolism and ATP production transcriptional pathways. Metabolic studies confirmed reduced mitochondrial membrane potential at baseline and increased mitochondrial oxidative stress after injury in C5ar1-/- RTECs. Moreover, C5ar1-/- RTECs had enhanced glycolysis, glucose uptake, and lactate production on injury, corroborated by metabolomics analysis of kidneys from AAN mice. Kidney tubule-specific C5ar1 knockout mice recapitulated exacerbated AKI observed in C5ar1-/- mice in AAN and FAN. These data indicate that C5aR1 signaling in kidney tubules exerts renoprotective effects against toxin-induced AKI by limiting overt glycolysis and maintaining mitochondrial function, thereby revealing a novel link between the complement system and tubular cell metabolism.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":"126-142"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11686444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455939","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

Histopathologic Analysis of Human Kidney Spatial Transcriptomics Data: Toward Precision Pathology. 基于组织病理学的人类肾脏空间转录组学数据分析：迈向精准病理学。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-01-01 Epub Date: 2024-08-02 DOI: 10.1016/j.ajpath.2024.06.011

Pierre Isnard, Dian Li, Qiao Xuanyuan, Haojia Wu, Benjamin D Humphreys

{"title":"Histopathologic Analysis of Human Kidney Spatial Transcriptomics Data: Toward Precision Pathology.","authors":"Pierre Isnard, Dian Li, Qiao Xuanyuan, Haojia Wu, Benjamin D Humphreys","doi":"10.1016/j.ajpath.2024.06.011","DOIUrl":"10.1016/j.ajpath.2024.06.011","url":null,"abstract":"The application of spatial transcriptomics (ST) technologies is booming and has already yielded important insights across many different tissues and disease models. In nephrology, ST technologies have helped to decipher the cellular and molecular mechanisms in kidney diseases and have allowed the recent creation of spatially anchored human kidney atlases of healthy and diseased kidney tissues. During ST data analysis, the computationally annotated clusters are often superimposed on a histologic image without their initial identification being based on the morphologic and/or spatial analyses of the tissues and lesions. Herein, histopathologic ST data from a human kidney sample were modeled to correspond as closely as possible to the kidney biopsy sample in a health care or research context. This study shows the feasibility of a morphology-based approach to interpreting ST data, helping to improve our understanding of the lesion phenomena at work in chronic kidney disease at both the cellular and the molecular level. Finally, the newly identified pathology-based clusters could be accurately projected onto other slides from nephrectomy or needle biopsy samples. Thus, they serve as a reference for analyzing other kidney tissues, paving the way for the future of molecular microscopy and precision pathology.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":"69-88"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11686452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888197","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

Advances in Single-Cell Sequencing and Spatial Profiling of Kidney Disease.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-01-01 DOI: 10.1016/j.ajpath.2024.10.010

Amit Verma, Parker C Wilson

引用次数: 0

CORRECTION. 更正。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-01-01 Epub Date: 2024-11-07 DOI: 10.1016/j.ajpath.2024.10.009

引用次数: 0

SIRT7 Promotes Alcohol Associated Liver Injury via Modulating Myeloid Cell CCL2 Secretion through NF-κB Signaling Pathway.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-31 DOI: 10.1016/j.ajpath.2024.12.006

Zhiqiang Wang, Gaoshuang Liang, Jinying Peng, Yiying Gu, Xiangwen Zhang, Cong Ding, Tingzi Yu, Zhuan Li

{"title":"SIRT7 Promotes Alcohol Associated Liver Injury via Modulating Myeloid Cell CCL2 Secretion through NF-κB Signaling Pathway.","authors":"Zhiqiang Wang, Gaoshuang Liang, Jinying Peng, Yiying Gu, Xiangwen Zhang, Cong Ding, Tingzi Yu, Zhuan Li","doi":"10.1016/j.ajpath.2024.12.006","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.12.006","url":null,"abstract":"The pathogenesis of Alcohol-associated liver disease (ALD) is complex, involving ethanol-induced enhancement of gut permeability results in the release of bacterial products from the intestine. This triggers intrahepatic inflammation and liver damage, with hepatic macrophages playing key roles in the inflammatory response to alcohol. SIRT7 a NAD+-dependent type III histone deacetylase, is being recognized as a potential therapeutic target in various human diseases including cancer. Emerging evidence show that SIRT7 participates in immune regulation whether is involve in ALD remain elusive. In present study using myeloid cell-specific Sirt7 knockout mice (Lyz2-Sirt7-/-), we observed that knockout Sirt7 in myeloid cells significantly ameliorated alcohol-induced liver injury, inflammation, and cell infiltration, while only mildly affecting lipid metabolism pathways. We further identified CCL2 as the main target impaired by Sirt7 knockout after alcohol. In vitro studies confirmed that Sirt7 knockout impaired macrophages' ability of CCL2 secretion and monocyte recruiting, and exogenous CCL2 reversed this impairment. At molecular level, we found that knockout of Sirt7 significantly impaired LPS induced p65 phosphorylation and nuclear localization. More importantly, the SIRT7 inhibitor 40569 sufficiently decreased alcohol induced liver injury and hepatic inflammation via preventing CCL2 in vivo. Our data thus uncover previously undescribed role of myeloid SIRT7 in mediating ALD via promoting CCL2 secretion through NF-κB signaling pathway. Targeting SIRT7 might offer novel mechanism based therapeutic options of ALD.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920521","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

Machine learning-based pathomics model predicts ANGPT2 expression and prognosis in hepatocellular carcinoma.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-31 DOI: 10.1016/j.ajpath.2024.12.005

Xinyi Huang, Shuang Zheng, Shuqi Li, Yu Huang, Wenhui Zhang, Fang Liu, Qinghua Cao

{"title":"Machine learning-based pathomics model predicts ANGPT2 expression and prognosis in hepatocellular carcinoma.","authors":"Xinyi Huang, Shuang Zheng, Shuqi Li, Yu Huang, Wenhui Zhang, Fang Liu, Qinghua Cao","doi":"10.1016/j.ajpath.2024.12.005","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.12.005","url":null,"abstract":"Angiopoietin 2 (ANGPT2) is a promising prognostic marker and therapeutic target in hepatocellular carcinoma (HCC). However, assessing ANGPT2 expression and prognosis from histopathological images with naked eye is challenging. In this study, machine learning was employed to develop a pathomics model that analyzed histopathological images to predict ANGPT2 status. 267 cases, obtained from TCGA-HCC were divided into training and testing set. 91 cases from a single center were employed as a validation set. ANGPT2 was demonstrated up-regulated in HCC and patients with high ANGPT2 expression had a significant overall survival (OS) decline in TCGA-HCC cohort. Histopathological features in the training set were extracted, screened, and incorporated into a gradient boosting machine (GBM) model that generated pathomics score (PS), which successfully identified ANGPT2 expression level in three sets and showed remarkable risk stratification for OS in TCGA-HCC cohort (P < 0.0001) and the single center cohort (P = 0.001). Multivariate analysis suggested that PS could serve as a predictor for prognosis (P < 0.001). Bioinformatics analysis illustrated distinction of tumor growth and development related gene enriched pathways, VEGF-related genes expression and immune cell infiltration in different PS value. Our research indicates that histopathological image features can enhance prediction of molecular status and prognosis in HCC. The integration of image features with machine learning has potential for improving prognosis prediction in HCC.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920517","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

Ferredoxin 2 is critical for tumor suppression and lipid homeostasis but dispensable for embryonic development.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-26 DOI: 10.1016/j.ajpath.2024.12.002

Jin Zhang, Yanhong Zhang, Shakur Mohibi, Vivian Perng, Miranda Bustamante, Yang Shi, Kenichi Nakajima, Mingyi Chen, Xinbin Chen

{"title":"Ferredoxin 2 is critical for tumor suppression and lipid homeostasis but dispensable for embryonic development.","authors":"Jin Zhang, Yanhong Zhang, Shakur Mohibi, Vivian Perng, Miranda Bustamante, Yang Shi, Kenichi Nakajima, Mingyi Chen, Xinbin Chen","doi":"10.1016/j.ajpath.2024.12.002","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.12.002","url":null,"abstract":"Ferredoxin 1 and 2 (FDX1/2) constitute an evolutionarily conserved FDX family of iron-sulfur cluster (ISC) containing proteins. FDX1/2 are cognate substrates of ferredoxin reductase (FDXR) and serve as conduits for electron transfer from NADPH to a set of proteins involved in biogenesis of steroids, hemes, ISC and lipoylated proteins. Recently, we showed that Fdx1 is essential for embryonic development and lipid homeostasis. To explore the physiological role of FDX2, we generated Fdx2-deficient mice. Interestingly, we found that unlike Fdx1-null embryos, which were dead at embryonic day 10.5 to 13.5, Fdx2-null mice were viable. We also found that both Fdx2-null and Fdx2-heterozygous mice had a short lifespan and were susceptible to spontaneous tumors and steatohepatitis. Moreover, we found that FDX2-deficiency increased whereas overexpression of FDX2 decreased cytoplasmic accumulation of lipid droplets. Consistently, we found that FDX2 deficiency led to accumulation of cholesterol and triglycerides. Mechanistically, we found that FDX2 deficiency suppressed expression of cholesterol transporter ABCA1 and activated master lipid transcription regulators SREBP1/2, thus leading to altered lipid metabolism. Untargeted lipidomic analysis showed that FDX2 deficiency led to altered biosynthesis of various lipid classes, including cardiolipins, cholesterol, ceramides, triglycerides, and fatty acids. In summary, our findings underscore an indispensable role of FDX2 in tumor suppression and lipid homeostasis at both cellular and organismal levels without being a prerequisite for embryonic development.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891609","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

Restorative Effects of Short-Chain Fatty Acids on Corneal Homeostasis Disrupted by Antibiotic-Induced Gut Dysbiosis.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-26 DOI: 10.1016/j.ajpath.2024.11.010

Sijing Liu, Jiangman Liu, Jiayan Xiang, Ruyu Yan, Senmao Li, Qiwei Fan, Liyuan Lu, Jiaxin Wu, Yunxia Xue, Ting Fu, Jun Liu, Zhijie Li

{"title":"Restorative Effects of Short-Chain Fatty Acids on Corneal Homeostasis Disrupted by Antibiotic-Induced Gut Dysbiosis.","authors":"Sijing Liu, Jiangman Liu, Jiayan Xiang, Ruyu Yan, Senmao Li, Qiwei Fan, Liyuan Lu, Jiaxin Wu, Yunxia Xue, Ting Fu, Jun Liu, Zhijie Li","doi":"10.1016/j.ajpath.2024.11.010","DOIUrl":"10.1016/j.ajpath.2024.11.010","url":null,"abstract":"The gut microbiota plays a crucial regulatory role in various physiological processes, yet its impact on corneal homeostasis remains insufficiently understood. Here, we investigate the effects of antibiotic-induced gut dysbiosis (AIGD) and germ-free conditions on circadian gene expression, barrier integrity, nerve density, and immune cell activity in the corneas of mice. Through RNA sequencing, we found that both AIGD and germ-free conditions significantly disrupted the overall transcriptomic profile and circadian transcriptomic oscillations in the cornea. These molecular disturbances were accompanied by a reduction in corneal epithelial thickness, nerve density, corneal sensitivity, and compromised barrier function. Notably, supplementation with short-chain fatty acids (SCFAs) significantly restored corneal integrity in AIGD mice. Further single-cell sequencing revealed that SCFA receptors G-protein-coupled receptor 109A (Hcar2), olfactory receptor 78 (Olfr78), and G-protein-coupled receptor 43 (Ffar2) are expressed in corneal epithelial basal cells, embryonically derived macrophages, perivascular cells, and γδ T cells, respectively. In conclusion, this study demonstrates that the gut microbiota plays a critical role in corneal physiology by regulating circadian gene expression and maintaining barrier function. These findings enhance our understanding of the gut-eye axis, highlighting the cornea as a target for microbiota-derived metabolic signals and underlining the potential therapeutic value of SCFAs in treating corneal dysfunction.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891619","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

Computational Pathology Detection of Hypoxia-Induced Morphologic Changes in Breast Cancer.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-26 DOI: 10.1016/j.ajpath.2024.10.023

Petru Manescu, Joseph Geradts, Delmiro Fernandez-Reyes

{"title":"Computational Pathology Detection of Hypoxia-Induced Morphologic Changes in Breast Cancer.","authors":"Petru Manescu, Joseph Geradts, Delmiro Fernandez-Reyes","doi":"10.1016/j.ajpath.2024.10.023","DOIUrl":"10.1016/j.ajpath.2024.10.023","url":null,"abstract":"Understanding the tumor hypoxic microenvironment is crucial for grasping tumor biology, clinical progression, and treatment responses. This study presents a novel application of artificial intelligence in computational histopathology to evaluate hypoxia in breast cancer. Weakly supervised deep learning models can accurately detect morphologic changes associated with hypoxia in routine hematoxylin and eosin (H&E)-stained whole slide images (WSIs). Our model, HypOxNet, was trained on H&E-stained WSIs from breast cancer primary sites (n = 1016) at ×40 magnification using data from The Cancer Genome Atlas. We used the Hypoxia Buffa signature to measure hypoxia scores, which ranged from -43 to 47, and stratified the samples into hypoxic and normoxic based on these scores. This stratification represented the weak labels associated with each WSI. HypOxNet achieved an average area under the curve of 0.82 on test sets, identifying significant differences in cell morphology between hypoxic and normoxic tissue regions. Importantly, once trained, the HypOxNet model requires only the readily available H&E-stained slides, making it especially valuable in low-resource settings where additional gene expression assays are not available. These artificial intelligence-based hypoxia detection models can potentially be extended to other tumor types and seamlessly integrated into pathology workflows, offering a fast, cost-effective alternative to molecular testing.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891606","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