American Journal of Pathology最新文献

Programmed Death Ligand-1 in Melanoma and Extracellular Vesicles Promotes Local and Regional Immune Suppression through M2-like Macrophage Polarization. 黑色素瘤和细胞外囊泡中的 PD-L1 通过 M2 样巨噬细胞极化促进局部和区域免疫抑制。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-01 Epub Date: 2024-10-29 DOI: 10.1016/j.ajpath.2024.09.011

Lili Huang, Jingbo Yang, Jinjin Zhu, Huaishan Wang, Liyun Dong, Yeye Guo, Yeqing Chen, Feng Zhang, David J Xu, Lingling Ou, Jaiden R Xu, Lei Guan, Quoc D Doan, Andrew Y Fan, Wenqun Zhong, Jina Ko, Chengyu Liang, Meenhard Herlyn, Wei Guo, Xiaowei Xu, Shujing Liu

{"title":"Programmed Death Ligand-1 in Melanoma and Extracellular Vesicles Promotes Local and Regional Immune Suppression through M2-like Macrophage Polarization.","authors":"Lili Huang, Jingbo Yang, Jinjin Zhu, Huaishan Wang, Liyun Dong, Yeye Guo, Yeqing Chen, Feng Zhang, David J Xu, Lingling Ou, Jaiden R Xu, Lei Guan, Quoc D Doan, Andrew Y Fan, Wenqun Zhong, Jina Ko, Chengyu Liang, Meenhard Herlyn, Wei Guo, Xiaowei Xu, Shujing Liu","doi":"10.1016/j.ajpath.2024.09.011","DOIUrl":"10.1016/j.ajpath.2024.09.011","url":null,"abstract":"Tumor-associated macrophages (TAMs) play dual roles (both pro- and antitumor) in tumor progression. TAMs induce programmed death ligand-1 (PD-L1) expression in cancer cells. However, the regulatory effects of PD-L1 in melanoma cells on TAM phenotypical switching remain underexplored. Herein, CD163 and MRC1 levels were significantly elevated in metastatic melanomas compared with those in primary melanomas, correlating with CD274 expression and predicted patient clinical outcomes. To study the mechanisms regulating M2-like polarization, PD-L1 was knocked out in both YUMM1.7 and B16-F10 melanoma cells. Knocking out PD-L1 (PD-L1KO) in melanoma resulted in a decelerated in vivo growth rate, accompanied by a significantly increased M1/M2 ratio, more dendritic cells, and enhanced activation of CD8+ T cells compared with wild-type (WT) melanoma cells. These alterations were associated with decreased expression of M2-associated chemokines (CCL2, CCL3, and CXCL2) and cytokines (IL6, IL10, and TGFB1). Mice harboring PD-L1KO melanomas exhibited elevated levels of CD8+ T cells in both the tumor-draining lymph nodes and the bloodstream compared with mice with PD-L1WT melanomas. Treatment with extracellular vesicles (EVs) derived from PD-L1KO melanoma resulted in a reduced tumor growth rate and fewer M2-like macrophages in the tumors compared with EVs from PD-L1WT melanomas. Therefore, these data suggest that PD-L1 in melanoma and melanoma-derived EVs induces M2-like polarization, contributing to local and regional immune suppression.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":"306-320"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556934","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

Sphingosine Kinase 2 Controls the Aggressive Phenotype of Oral Squamous Cell Carcinoma by Regulating miR-205 and miR-296 through p53. 鞘氨醇激酶 2 通过 p53 调节 miR-205 和 miR-296 来控制口腔鳞状细胞癌的侵袭性表型。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-01 Epub Date: 2024-10-28 DOI: 10.1016/j.ajpath.2024.09.009

Thaís Moré Milan, Gabriel Silva, Lucas Oliveira Sousa, Andréia Machado Leopoldino

{"title":"Sphingosine Kinase 2 Controls the Aggressive Phenotype of Oral Squamous Cell Carcinoma by Regulating miR-205 and miR-296 through p53.","authors":"Thaís Moré Milan, Gabriel Silva, Lucas Oliveira Sousa, Andréia Machado Leopoldino","doi":"10.1016/j.ajpath.2024.09.009","DOIUrl":"10.1016/j.ajpath.2024.09.009","url":null,"abstract":"Alterations in miRNAs, p53, and sphingolipid metabolism are associated with head and neck squamous cell carcinoma (HNSCC). However, the role of sphingosine kinase (SK)-2, an enzyme crucial for sphingolipid metabolism, is poorly understood in HNSCC. The aim of this study was to investigate how SK2 and p53 interact to regulate miRNAs miR-205 and miR-296. Analysis of small-RNA sequencing data from nontumor oral keratinocytes with SK2 overexpression (NOK-SK2) compared to controls (NOK-Ø) revealed differential expression of >100 miRNAs being half-regulated by p53. The expression of miR-205 was down-regulated, and miR-296 was up-regulated, in NOK-SK2 cells; however, cells with SK2 knockdown and p53 overexpression showed an opposite profile. Proteins involved in miRNA biogenesis were increased in NOK-SK2 cells, while levels were decreased in NOK-SK2 cells with p53 overexpression. Transfection with miR-205 mimic and miR-296 inhibitor decreased the aggressiveness and the number of cancer stem-like cells in oral keratinocytes and oral carcinoma cells with SK2 regulation. Overexpression of miR-205 in HN12-SK2 cells decreased tumor-formation capacity, and NOK-SK2 cells abrogated tumor growth in mice. The results indicate crosstalk between SK2 and p53 in regulating miRNAs 205 and 296, which could be potential therapeutic targets in the treatment of HNSCC.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":"321-333"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543137","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

Ablation of CD44 Attenuates Adipogenesis in White Adipocytes via the Tryptophan 5-Hydroxylase 2/5-Hydroxytryptamine Axis to Protect Mice from High-Fat Diet-Induced Obesity. 通过 TPH2/5-HT 轴消减 CD44 可减轻白色脂肪细胞的脂肪生成，从而保护小鼠免受高脂饮食诱发的肥胖症。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-01 Epub Date: 2024-10-29 DOI: 10.1016/j.ajpath.2024.10.005

Yuting Wu, Jinyu Ma, Jing Chen, Xiaoyu Liu, Zhe Wang, Lan Luo, Cheng Sun

{"title":"Ablation of CD44 Attenuates Adipogenesis in White Adipocytes via the Tryptophan 5-Hydroxylase 2/5-Hydroxytryptamine Axis to Protect Mice from High-Fat Diet-Induced Obesity.","authors":"Yuting Wu, Jinyu Ma, Jing Chen, Xiaoyu Liu, Zhe Wang, Lan Luo, Cheng Sun","doi":"10.1016/j.ajpath.2024.10.005","DOIUrl":"10.1016/j.ajpath.2024.10.005","url":null,"abstract":"CD44 is a transmembrane protein that plays an essential role in transducing extracellular stimuli into intracellular signaling cascades, especially in cancer cells. Recent studies have shown that CD44 contributes to metabolic regulation. However, the effect of CD44 on adipogenesis in white adipose tissue (WAT) remains unclear. Herein, the expression of CD44 was largely increased in the inguinal and epididymal WAT of obese mice. Ablation or neutralization of CD44 inhibited adipogenesis in cultured adipocytes. CD44-deficient mice were resistant to high-fat diet-induced obesity and metabolic dysfunction. RNA-sequencing, together with functional studies, revealed that reduced expression of tryptophan 5-hydroxylase 2 (Tph2) in WAT was responsible for the repressed adipogenesis in the absence of CD44. The application of 5-hydroxytryptamine, a product of TPH2, rescued the repressed adipogenesis induced by CD44 neutralization. Moreover, the inhibition of TPH2 by p-chlorophenylalanine recapitulated the beneficial phenotypes observed in CD44-deficient mice. Taken together, these data indicate that CD44 plays a pivotal role in adipogenesis in WAT. In this regard, CD44 and its downstream target TPH2 may hold great therapeutic potential for treating excessive adiposity-related metabolic disorders, such as obesity, insulin resistance, and type 2 diabetes.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":"247-264"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543134","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

Multi-Class Segmentation Network Based on Tumor Tissue in Endometrial Cancer Pathology Images: ECMTrans-net. ECMTrans-net：基于子宫内膜癌病理图像中肿瘤组织的多类分割网络

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-01 Epub Date: 2024-10-28 DOI: 10.1016/j.ajpath.2024.10.008

Tong Yang, Ping Li, Bo Liu, Yuchun Lv, Dage Fan, Yuling Fan, Peizhong Liu, Yaping Ni

{"title":"Multi-Class Segmentation Network Based on Tumor Tissue in Endometrial Cancer Pathology Images: ECMTrans-net.","authors":"Tong Yang, Ping Li, Bo Liu, Yuchun Lv, Dage Fan, Yuling Fan, Peizhong Liu, Yaping Ni","doi":"10.1016/j.ajpath.2024.10.008","DOIUrl":"10.1016/j.ajpath.2024.10.008","url":null,"abstract":"Endometrial cancer has the second highest incidence of malignant tumors in the female reproductive system. Accurate and efficient analysis of endometrial cancer pathology images is one of the important research components of computer-aided diagnosis. However, endometrial cancer pathology images have challenges such as smaller solid tumors, lesion areas varying in morphology, and difficulty distinguishing solid and nonsolid tumors, which would affect the accuracy of subsequent pathologic analyses. An Endometrial Cancer Multi-class Transformer Network (ECMTrans-net) is therefore proposed herein to improve the segmentation accuracy of endometrial cancer pathology images. An ECM-Attention module can sequentially infer attention maps along three separate dimensions (channel, local spatial, and global spatial) and multiply the attention maps and the input feature map for adaptive feature refinement. This approach may solve the problems of the small size of solid tumors and similar characteristics of solid tumors to nonsolid tumors and further improve the accuracy of segmentation of solid tumors. In addition, an ECM-Transformer module is proposed, which can fuse multi-class feature information and dynamically adjust the receptive field, solving the issue of complex tumor features. Experiments on the Solid Tumor Endometrial Cancer Pathological (ST-ECP) data set found that performance of the ECMTrans-net was superior to state-of-the-art image segmentation methods, and the average values of accuracy, Mean Intersection over Union, precision, and Dice coefficients were 0.952, 0.927, 0.931, and 0.901, respectively.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":"232-246"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543136","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

Segmental Regulation of Intestinal Motility by Colitis and the Adaptive Immune System in the Mouse Ileum and Colon. 小鼠回肠和结肠中结肠炎和适应性免疫系统对肠蠕动的节段性调控

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-01 Epub Date: 2024-11-17 DOI: 10.1016/j.ajpath.2024.10.020

Raquel Gomez-Bris, Pilar Rodríguez-Rodríguez, Marina Ortega-Zapero, Santiago Ruvira, Raquel Castillo-González, María-Jesús Fernández-Aceñero, Aránzazu Cruz-Adalia, Angela Saez, Silvia-Magdalena Arribas, Jose-Maria Gonzalez-Granado

{"title":"Segmental Regulation of Intestinal Motility by Colitis and the Adaptive Immune System in the Mouse Ileum and Colon.","authors":"Raquel Gomez-Bris, Pilar Rodríguez-Rodríguez, Marina Ortega-Zapero, Santiago Ruvira, Raquel Castillo-González, María-Jesús Fernández-Aceñero, Aránzazu Cruz-Adalia, Angela Saez, Silvia-Magdalena Arribas, Jose-Maria Gonzalez-Granado","doi":"10.1016/j.ajpath.2024.10.020","DOIUrl":"10.1016/j.ajpath.2024.10.020","url":null,"abstract":"Gastrointestinal motility disturbances are a hallmark of inflammatory bowel disease (IBD); however, their mechanisms remain unclear. This study used a dextran sulfate sodium-induced colitis mouse model, deficient in mature B and T lymphocytes, to assess intestinal motility and the role of the adaptive immune system in health and IBD. In healthy mice, the absence of adaptive lymphocytes reduced acetylcholine (ACh) sensitivity in the ileum. During colitis, it decreases motility by reducing the intensity and frequency of spontaneous contractions while increasing cholinergic responsiveness. In the proximal colon, adaptive immunity deficiency led to increased contractility and reduced ACh sensitivity in homeostasis, whereas colitis reduced contractile capacity. In the mid colon, immune-deficient mice had reduced ACh sensitivity in homeostasis and exacerbated contractile responses during colitis. In the distal colon, adaptive immunity loss reduced contractility in health and cholinergic responsiveness during colitis. These motility alterations were associated with altered acetylcholinesterase and M2/M3 muscarinic receptor expression. Notably, adaptive lymphocyte deficiency resulted in reduced tissue damage and lower tumor necrosis factor-α expression in the colon during colitis, paralleling intestinal motility changes. Overall, the adaptive immune system critically regulates motility and inflammation across different intestinal segments in IBD.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":"204-220"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674902","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

A Recognition System for Diagnosing Salivary Gland Neoplasms Based on Vision Transformer. 基于视觉变换器的唾液腺肿瘤诊断识别系统

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-01 Epub Date: 2024-10-26 DOI: 10.1016/j.ajpath.2024.09.010

Mao Li, Ze-Liang Shen, Hong-Chun Xian, Zhi-Jian Zheng, Zhen-Wei Yu, Xin-Hua Liang, Rui Gao, Ya-Ling Tang, Zhong Zhang

{"title":"A Recognition System for Diagnosing Salivary Gland Neoplasms Based on Vision Transformer.","authors":"Mao Li, Ze-Liang Shen, Hong-Chun Xian, Zhi-Jian Zheng, Zhen-Wei Yu, Xin-Hua Liang, Rui Gao, Ya-Ling Tang, Zhong Zhang","doi":"10.1016/j.ajpath.2024.09.010","DOIUrl":"10.1016/j.ajpath.2024.09.010","url":null,"abstract":"Salivary gland neoplasms (SGNs) represent a group of human neoplasms characterized by a remarkable cytomorphologic diversity, which frequently poses diagnostic challenges. Accurate histologic categorization of salivary gland tumors is crucial to make precise diagnoses and guide decisions regarding patient management. Within the scope of this study, a computer-aided diagnosis model using Vision Transformer (ViT), a cutting-edge deep learning model in computer vision, was developed to accurately classify the most prevalent subtypes of SGNs. These subtypes include pleomorphic adenoma, myoepithelioma, Warthin tumor, basal cell adenoma, oncocytic adenoma, cystadenoma, mucoepidermoid carcinoma, and salivary adenoid cystic carcinoma. The data set comprised 3046 whole slide images of histologically confirmed salivary gland tumors, encompassing nine distinct tissue categories. SGN-ViT exhibited impressive performance in classifying the eight salivary gland tumors, achieving an accuracy of 0.9966, an area under the receiver operating characteristic curve value of 0.9899, precision of 0.9848, recall of 0.9848, and an F1 score of 0.9848. Diagnostic performance of SGN-ViT surpassed that of benchmark models. In a subset of 100 whole slide images, SGN-ViT demonstrated comparable diagnostic performance to that of the chief pathologist while significantly reducing the diagnosis time. These observations indicate that SGN-ViT holds the potential to serve as a valuable computer-aided diagnostic tool for salivary gland tumors, enhancing the diagnostic accuracy of junior pathologists.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":"221-231"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567568","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

Evidence and Mechanism of Bile Acid-Mediated Gut-Brain Axis in Anxiety and Depression. 胆汁酸介导的肠脑轴在焦虑和抑郁中的作用证据和机制

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-01 Epub Date: 2024-11-19 DOI: 10.1016/j.ajpath.2024.10.019

Sydney O Idahosa, Rokia Diarra, Hernoor K Ranu, Raidah H Nasiri, Sei Higuchi

{"title":"Evidence and Mechanism of Bile Acid-Mediated Gut-Brain Axis in Anxiety and Depression.","authors":"Sydney O Idahosa, Rokia Diarra, Hernoor K Ranu, Raidah H Nasiri, Sei Higuchi","doi":"10.1016/j.ajpath.2024.10.019","DOIUrl":"10.1016/j.ajpath.2024.10.019","url":null,"abstract":"Bidirectional communication between the brain and gastrointestinal tract, called the gut-brain axis, is linked with our emotions. Intestinal lipids, hormones, and molecules, such as bile acids (BAs), impact our mood, motivation, and emotions via the gut-brain axis. BAs are synthesized from cholesterol in the liver and serve as a regulator of lipid metabolism and hormonal secretion in the intestine. Human studies have indicated that the alteration of plasma BA levels is associated with depression and anxiety. Several possible mechanisms, such as BA receptor-dependent and receptor-independent mechanisms, have been reported for emotional control. Animal studies have indicated that the deletion of BA receptors shows behavioral abnormalities. BAs regulate gut hormones, glucagon-like peptide-1 secretion, bioactive lipids, oleoylethanolamide, and the immune system function, which influences neural activities. Thus, BAs act as an emotional regulator. This review aims to summarize the following: clinical evidence of BA concentration linked to mental disorders, including depression and anxiety; and animal studies of BA-related signaling correlated with its neurobehavioral effect supporting its mechanism. We will also discuss future research required for further neurobehavioral treatment.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":"163-173"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680643","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

Chronic Coinfection with Pseudomonas aeruginosa and Normal Colony Staphylococcus aureus Causes Lung Structural Damage in the Cystic Fibrosis Rat. 铜绿假单胞菌和正常菌落金黄色葡萄球菌的慢性联合感染会导致囊性纤维化大鼠肺部结构损伤。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-01 Epub Date: 2024-10-28 DOI: 10.1016/j.ajpath.2024.09.008

Gretchen E Bollar, Johnathan D Keith, Denise D Stanford, Ashley M Oden, S Vamsee Raju, T Spencer Poore, Susan E Birket

{"title":"Chronic Coinfection with Pseudomonas aeruginosa and Normal Colony Staphylococcus aureus Causes Lung Structural Damage in the Cystic Fibrosis Rat.","authors":"Gretchen E Bollar, Johnathan D Keith, Denise D Stanford, Ashley M Oden, S Vamsee Raju, T Spencer Poore, Susan E Birket","doi":"10.1016/j.ajpath.2024.09.008","DOIUrl":"10.1016/j.ajpath.2024.09.008","url":null,"abstract":"Cystic fibrosis (CF) respiratory outcomes are heavily influenced by complications of infection. Pseudomonas aeruginosa and Staphylococcus aureus are the most common colonizers of the cystic fibrosis lung, and frequently overlap to cause chronic and persistent coinfections associated with severe disease. However, the dynamics of P. aeruginosa and S. aureus coinfection and its impacts on the development of CF lung structural damage are poorly understood. Additionally, small colony variants (SCVs) of S. aureus have been associated with P. aeruginosa infections in people with CF, but their role in disease progression is largely unknown. In this work, the CF rat was used to model chronic lung coinfection with P. aeruginosa and S. aureus, using clinically and laboratory-derived normal colony and SCV strains of S. aureus to evaluate the impact of phenotype on clinical outcomes. Rats coinfected with clinically derived S. aureus of both phenotypes experienced increased inflammation in the lung. However, only the combination of P. aeruginosa and clinically normal colony S. aureus led to lung structural decline, including mucus obstruction and bronchiectasis. Regression analyses showed that the damage was associated with a higher burden of P. aeruginosa. These data indicate that chronic coinfection with normal colony S. aureus and P. aeruginosa may support the progression CF lung decline driven by P. aeruginosa, which might be avoided when coinfecting S. aureus exhibits the SCV phenotype.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":"174-187"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543135","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

CDR1as Deficiency Prevents Photoreceptor Degeneration by Regulating miR-7a-5p/α-syn/Parthanatos Pathway in Retinal Detachment. CDR1as 缺陷通过调节视网膜脱离中的 miR-7a-5p/α-syn/Parthanatos 通路防止感光细胞退化

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-01 Epub Date: 2024-11-19 DOI: 10.1016/j.ajpath.2024.10.015

Feiyu Jin, Yuanye Yan, Ziyang Ye, Lisong Wang, Can Deng, Jiazhen Jiang, Kai Dong

{"title":"CDR1as Deficiency Prevents Photoreceptor Degeneration by Regulating miR-7a-5p/α-syn/Parthanatos Pathway in Retinal Detachment.","authors":"Feiyu Jin, Yuanye Yan, Ziyang Ye, Lisong Wang, Can Deng, Jiazhen Jiang, Kai Dong","doi":"10.1016/j.ajpath.2024.10.015","DOIUrl":"10.1016/j.ajpath.2024.10.015","url":null,"abstract":"Retinal detachment (RD) is the separation of the neural retina from the retinal pigment epithelium, with photoreceptor degeneration being a major cause of irreversible vision loss. Herein, ischemia and hypoxia after RD decreased the level of miR-7a-5p (miR-7) and promoted the expression of its main target, α-synuclein (α-syn), which activated the parthanatos pathway and led to photoreceptor damage. Circular RNA CDR1as is an antisense transcript of cerebellar degeneration-associated protein 1, which functions as a \"sponge\" for miR-7, thereby regulating the abundance and activity of miR-7. In this study, CDR1as expression was elevated after RD. Adeno-associated virus serotype 9 vector containing the shRNA-CDR1as sequence was used to inhibit CDR1as expression via subretinal injection. Hematoxylin and eosin staining and transmission electron microscopy revealed that the morphology and outer nuclear layer thickness of the retina were preserved and photoreceptor cell death was decreased after experimental RD in mice. Mechanistically, CDR1as deficiency significantly increased the expression of miR-7, then decreased the expression of α-syn, poly (ADP-ribose) polymerase 1, apoptosis-inducing factor, and migration inhibitory factor. Furthermore, visual function was improved as shown by Morris water maze experiments in the mouse model of RD. These findings suggest a surprisingly neuroprotective role for CDR1as deficiency, which is probably mediated by enhancing miR-7 activity and inhibiting α-syn/poly (ADP-ribose) polymerase 1/apoptosis-inducing factor pathway, thereby preventing photoreceptor degeneration.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":"293-305"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680641","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 mRNA Stability of PIEZO1, Regulated by Methyltransferase-Like 3 via N⁶-Methylation of Adenosine Modification in a YT521-B Homology Domain Family 2-Dependent Manner, Facilitates the Progression of Diabetic Retinopathy. PIEZO1 的 mRNA 稳定性由 METTL3 通过 m6A 修饰以 YTHDF2 依赖性方式调控，促进了糖尿病视网膜病变的进展。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-01 Epub Date: 2024-10-28 DOI: 10.1016/j.ajpath.2024.10.007

Ning Han, Na Yu, Li Yu

{"title":"The mRNA Stability of PIEZO1, Regulated by Methyltransferase-Like 3 via N6-Methylation of Adenosine Modification in a YT521-B Homology Domain Family 2-Dependent Manner, Facilitates the Progression of Diabetic Retinopathy.","authors":"Ning Han, Na Yu, Li Yu","doi":"10.1016/j.ajpath.2024.10.007","DOIUrl":"10.1016/j.ajpath.2024.10.007","url":null,"abstract":"Diabetic retinopathy (DR) is the major ocular complication of diabetes caused by chronic hyperglycemia, which leads to incurable blindness. Currently, the effectiveness of therapeutic interventions is limited. This study aimed to investigate the function of piezo-type mechanosensitive ion channel component 1 (PIEZO1) and its potential regulatory mechanism in DR progression. PIEZO1 expression was up-regulated in the retinal tissues of streptozotocin-induced diabetic mice and high-glucose (HG)-triggered Müller cells. Functionally, the knockdown of PIEZO1 improved the abnormal retinal function of diabetic mice and impeded inflammatory cytokine secretion and gliosis of Müller cells under HG conditions. Mechanistic investigations using RNA immunoprecipitation-real-time quantitative PCR, methylation RNA immunoprecipitation-real-time quantitative PCR, and luciferase reporter assays demonstrated that PIEZO1 was a downstream target of methyltransferase-like 3 (METTL3). METTL3-mediated N6-methyladenosine (m6A) modification within the coding sequence of PIEZO1 mRNA significantly shortened its half-life. In HG-stimulated cells, there was a negative regulatory relationship between PIEZO1 and YTH (YT521-B homology) domain family 2 (YTHDF2), a recognized m6A reader. The loss of YTHDF2 resulted in an extended half-life of PIEZO1 in cells with overexpression of METTL3, indicating that the effect of METTL3 on the mRNA stability of PIEZO1 was dependent on YTHDF2. Taken together, this study demonstrated the protective role of the PIEZO1 silencing in DR development, and that the degradation of PIEZO1 mRNA is accelerated by METTL3/YTHDF2-mediated m6A modification.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":"265-280"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543048","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