American Journal of Pathology最新文献

PD-L1 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 : 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":"PD-L1 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":"https://doi.org/10.1016/j.ajpath.2024.09.011","url":null,"abstract":"Tumor-associated macrophages (TAMs) exhibit dual roles in tumor progression. TAMs are known to induce PD-L1 expression in cancer cells. However, the regulatory effects of PD-L1 in melanoma cells on TAM phenotypical switching remain underexplored. Herein, our findings indicated that CD163 and MRC1 levels were significantly elevated in metastatic melanomas compared to 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. The data revealed that 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 to 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 TGFβ1). Mice harboring PD-L1KO melanomas exhibited elevated levels of CD8+ T cells in both the tumor-draining lymph nodes and the bloodstream, compared to 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 to EVs from PD-L1WT melanomas. Therefore, our 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":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-29","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 : 2024-10-28 DOI: 10.1016/j.ajpath.2024.09.009

Thaís Moré Milan, Gabriel da 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 da Silva, Lucas Oliveira Sousa, Andréia Machado Leopoldino","doi":"10.1016/j.ajpath.2024.09.009","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.09.009","url":null,"abstract":"Alterations in microRNAs, p53, and sphingolipid metabolism have been associated with head and neck squamous cell carcinoma (HNSCC). However, sphingosine kinase 2, a critical enzyme in sphingolipid metabolism, is poorly understood in HNSCC. Our aim was to investigate how SK2 and p53 interact to regulate miR-205 and miR-296. Analysis of small-RNA-seq data from non-tumor oral keratinocytes with SK2 overexpression (NOK-SK2) compared to NOK-control (NOK- Ø) revealed differential expression of more than 100 miRNAs being half regulated by p53. The expression of miR-205 was downregulated, and miR-296 was upregulated 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 their levels were decreased in NOK-SK2 cells with p53 overexpression. miR-205 mimic and miR-296 inhibitor decreased the aggressiveness and cancer stem-like cells in oral keratinocytes and oral carcinoma cells with SK2 deregulation. Overexpression of miR-205 in HN12-SK2 cells decreased tumor formation capacity and NOK-SK2 cells abrogated the tumor growth in mice. Our results indicate crosstalk between SK2 and p53 in regulating miR-205 and miR-296, which could be potential targets for HNSCC therapy.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-28","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 TPH2/5-HT 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 : 2024-10-28 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 TPH2/5-HT 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":"https://doi.org/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. Here, the results showed that the expression of CD44 was largely increased in the inguinal and epididymal WAT of obese mice. Ablation or neutralization of CD44 inhibits adipogenesis in cultured adipocytes. CD44 deficient mice are resistant to high-fat diet (HFD) induced obesity and metabolic dysfunction. RNA-seq, together with functional studies, revealed that reduced expression of tryptophan 5-hydroxylase 2 (Tph2) in WAT is responsible for the repressed adipogenesis in the absence of CD44. The application of 5-hydroxytryptamine (5-HT), a product of TPH2, rescues the repressed adipogenesis induced by CD44 neutralization. Moreover, the inhibition of TPH2 by p-chlorophenylalanine (pCPA) recapitulates 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":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-28","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

ECMTrans-net: Multi-class Segmentation Network Based on Tumor Tissue in Endometrial Cancer Pathology Images. 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 : 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":"ECMTrans-net: Multi-class Segmentation Network Based on Tumor Tissue in Endometrial Cancer Pathology Images.","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":"https://doi.org/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, and accurate and efficient endometrial cancer pathology image analysis is one of the important research components of computer-aided diagnosis. However, endometrial cancer pathologic images have the challenges of smaller solid tumors, lesion areas varying in morphology, and difficulty distinguishing solid and non-solid tumors, which would impact the accuracy of subsequent pathological analyses. Therefore, an Endometrial Cancer Multi-class Transformer Network (ECMTrans-net) is proposed to improve the segmentation accuracy of endometrial cancer pathology images. On the one hand, an ECM-Attention is proposed, which 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, solving the problems of the small size of solid tumors and similar characteristics of solid tumors to non-solid tumors and further improving the accuracy of segmentation of solid tumors. On the other hand, an ECM-Transformer 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) dataset show that the ECMTrans-net performs superior to state-of-the-art image segmentation methods, and the average values of Accuracy, MIoU, Precision, and Dice were 0.952, 0.927, 0.931 and 0.901, respectively.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-28","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

Chronic co-infection 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 : 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 co-infection 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":"https://doi.org/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 co-infections associated with severe disease. However, the dynamics of P. aeruginosa and S. aureus co-infection 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 co-infection with P. aeruginosa and S. aureus, using clinical and laboratory derived normal colony and SCV strains of S. aureus to evaluate the impact of phenotype on clinical outcomes. Rats co-infected with clinically derived S. aureus of both phenotypes experienced increased inflammation in the lung, but only the combination of P. aeruginosa and clinical normal colony S. aureus led to lung structural decline, including mucus obstruction and bronchiectasis. In regression analyses, damage was associated with a higher burden of P. aeruginosa, indicating that chronic co-infection with normal colony S. aureus and P. aeruginosa may support the progression CF lung decline driven by P. aeruginosa, which might be avoided when co-infecting S. aureus exhibits the SCV phenotype.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-28","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

The mRNA Stability of PIEZO1, Regulated by Methyltransferase-Like 3 via N6-Methylation of Adenosine Modification in a YTH 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 : 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 YTH 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. The results showed that 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 improves the abnormal retinal function of diabetic mice and impedes 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). These studies revealed that 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 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 the degradation of PIEZO1 mRNA is accelerated by METTL3/YTHDF2-mediated m6A modification.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-28","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

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 : 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":"https://doi.org/10.1016/j.ajpath.2024.09.010","url":null,"abstract":"Salivary gland neoplasms (SGNs) represent a group of human neoplasms characterized by a remarkable cyto-morphological diversity, which frequently poses diagnostic challenges. Accurate histological categorization of salivary tumors is crucial to make precise diagnoses and guide decisions regarding patient management. Within the scope of this study, a computer-aided diagnosis model utilizing Vision Transformer, a cutting-edge deep-learning model in computer vision, has been developed to accurately classify the most prevalent subtypes of SGNs. These subtypes include pleomorphic adenoma, myoepithelioma, Warthin's tumor, basal cell adenoma, oncocytic adenoma, cystadenoma, mucoepidermoid carcinoma and salivary adenoid cystic carcinoma. The dataset comprised 3046 whole slide images (WSIs) 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 AUC value of 0.9899, precision of 0.9848, recall of 0.9848, and an F1-score of 0.9848. When compared to benchmark models, SGN-ViT surpassed them in terms of diagnostic performance. In a subset of 100 WSIs, SGN-ViT demonstrated comparable diagnostic performance to that of the chief pathologist while significantly reducing the diagnosis time, indicating that SGN-ViT held the potential to serve as a valuable computer-aided diagnostic tool for salivary tumors, enhancing the diagnostic accuracy of junior pathologists.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-26","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

Chronic PPARα/γ and CB₂R agonist treatments attenuated visceral adipose tissue (VAT)-derived extracellular vesicle-related VAT and intestinal abnormalities in NASH mice. 慢性 PPARα/γ 和 CB2R 激动剂治疗可减轻 NASH 小鼠内脏脂肪组织（VAT）衍生的细胞外囊泡相关的 VAT 和肠道异常。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-10-26 DOI: 10.1016/j.ajpath.2024.10.006

Chia-Chang Huang, Ching-Hsiang Wang, Hsiao-Yun Yeh, Hung-Cheng Tsai, Ching-Wen Yang, Tzu-Hao Li, Chien-Wei Su, Ying-Ying Yang, Han-Chieh Lin, Ming-Chih Hou

{"title":"Chronic PPARα/γ and CB2R agonist treatments attenuated visceral adipose tissue (VAT)-derived extracellular vesicle-related VAT and intestinal abnormalities in NASH mice.","authors":"Chia-Chang Huang, Ching-Hsiang Wang, Hsiao-Yun Yeh, Hung-Cheng Tsai, Ching-Wen Yang, Tzu-Hao Li, Chien-Wei Su, Ying-Ying Yang, Han-Chieh Lin, Ming-Chih Hou","doi":"10.1016/j.ajpath.2024.10.006","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.10.006","url":null,"abstract":"This study explores the mechanisms and combined effects of chronic peroxisome proliferator-activated receptor (PPAR)α/γ and cannabinoid receptor 2 (CB2R) agonists on visceral adipose tissue (VAT)-derived extracellular vesicle (EVs) release and associated systemic/VAT inflammation, decreased VAT capillary density/fibrosis, and intestinal inflammation/hyperpermeability in nonalcoholic steatohepatitis (NASH) mice. NASH mice receiving 1 month of PPARα/γ agonist aleglitazar (10 mg/kg/day), CB2R agonist JWH015 (3 mg/kg/day) alone or combined. High EV release from VAT of NASH mice was associated with severe systemic/VAT/intestinal inflammation, reduced capillary network of VAT, and intestinal hyperpermeability. Combined JWH015 with aleglitazar treatment significantly suppressed HFD-induced obesity/adiposity, inhibited VAT expansion, reduced VAT inflammation/fibrosis, normalized VAT capillary network, and attenuated intestinal mucosal injury, inflammation, and hyperpermeability in NASH+aleg+JWH015 mice. The inhibition of AT-derived EV release and hypoxia inducible factor (HIF)1α levels in AT-derived EV, normalization of CB2R, PPARα, PPARγ, PPARγ1, PPARγ2, tight junction proteins, VEGF/CD31 expression, and downregulations of HIF1α, MCP-1 and TGFβ1 were observed in the VAT and intestine of the NASH+aleg+jwh015 group. In vitro experiments revealed that PPARα/γ and CB2R activation attenuated NASH AT-derived EV (EVnash)-induced pathogenic changes in the J774/SVEC4-10/Caco2 /3T3-L1 cell system. This study suggested that VAT-derived EVs contribute to the pathogenesis of NAFLD and that combined PPARα/γ and CB2R agonist treatment reduces VAT-released EV release and HIF1/MCP-1 signals to ameliorate hepatic steatosis and VAT/intestine abnormalities of NASH mice.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567571","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 miR-665/SOST Axis Regulates the Phenotypes of Bone Marrow Mesenchymal Stem Cells and Osteoporotic Symptoms in Female Mice miR-665/SOST 轴调控雌性小鼠骨髓间充质干细胞的表型和骨质疏松症状

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-10-24 DOI: 10.1016/j.ajpath.2024.07.022

{"title":"The miR-665/SOST Axis Regulates the Phenotypes of Bone Marrow Mesenchymal Stem Cells and Osteoporotic Symptoms in Female Mice","authors":"","doi":"10.1016/j.ajpath.2024.07.022","DOIUrl":"10.1016/j.ajpath.2024.07.022","url":null,"abstract":"<div><div>Osteoporosis is a common degenerative skeletal disease among older people, especially postmenopausal women. Bone marrow mesenchymal stem cells (BMSCs), the progenitors of osteoblasts, are essential to the pathophysiology of osteoporosis. Herein, targeting miRNAs with differential expression in dysfunctional BMSCs was accomplished by bioinformatics analysis based on public databases. Target mRNAs were predicted and applied for signaling pathway and function enrichment annotations. In vitro and in vivo effects of selected miRNA on BMSC proliferation and osteogenesis were investigated, the putative binding between selected miRNA and predicted target mRNA was verified, and the co-effects of the miRNA/mRNA axis on BMSCs were determined. miRNA 665 (miR-665) was down-regulated in osteoporotic BMSCs compared with normal BMSCs and elevated in BMSCs experiencing osteogenic differentiation. In BMSCs, miR-665 overexpression promoted cell proliferation and osteogenic differentiation. miR-665 targeted the Wnt signaling inhibitor sclerostin (SOST) and inhibited SOST mRNA and protein expression. SOST overexpression inhibited BMSC cell proliferation and osteogenic differentiation. When co-transduced to BMSCs, SOST knockdown significantly reversed the effects of miR-665 on BMSCs. In ovariectomy (OVX)-induced osteoporosis model mice, OVX remarkably decreased bone mass, whereas miR-665 overexpression partially improved OVX-induced bone mass loss. miR-665 was down-regulated in osteoporotic BMSCs and up-regulated in osteogenically differentiated BMSCs. In conclusion, the miR-665/SOST axis modulates BMSC proliferation, osteogenic differentiation, and OVX-induced osteoporosis in mice, possibly through Wnt signaling.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492994","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 Novel Deep Learning Approach for Analyzing Glomerular Basement Membrane Lesions in a Mouse Model of X-Linked Alport Syndrome. 分析 X 连锁阿尔波特综合征小鼠模型肾小球基底膜病变的新型深度学习方法。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-10-18 DOI: 10.1016/j.ajpath.2024.10.004

Kunio Kawanishi, Masaki Baba, Ryosuke Kobayashi, Ryotaro Hori, Kentaro Hashikami, Kenta Danbayashi, Takako Iwachido, Mitsuyasu Kat

{"title":"A Novel Deep Learning Approach for Analyzing Glomerular Basement Membrane Lesions in a Mouse Model of X-Linked Alport Syndrome.","authors":"Kunio Kawanishi, Masaki Baba, Ryosuke Kobayashi, Ryotaro Hori, Kentaro Hashikami, Kenta Danbayashi, Takako Iwachido, Mitsuyasu Kat","doi":"10.1016/j.ajpath.2024.10.004","DOIUrl":"10.1016/j.ajpath.2024.10.004","url":null,"abstract":"Alport syndrome is a rare kidney disease typically more severe in males due to its X-linked inheritance. However, female patients with heterozygous X-linked Alport syndrome (XLAS) can develop renal failure over time, necessitating accurate pathologic assessment for effective therapy. A key pathologic finding in female patients with XLAS is the mosaic pattern of partial loss of α5 chains of type IV collagen. This study, using a mouse model of XLAS with a nonsense mutation (R471∗) in the Col4a5 gene, analogous to human XLAS, aimed to examine the consistency of this pattern with the glomerular basement membrane (GBM) structure. A modified periodic acid-methenamine silver staining method was developed for clearer GBM visualization. The integrated images from COL4α5-stained fluorescence, periodic acid-methenamine silver, and low-vacuum scanning electron microscopy into a single-slide section and applied supervised deep learning to predict GBM lesions. Results showed significant individual variability in urinary protein levels and histologic lesions. Pathologic parameters, including crescent formation, focal segmental glomerulosclerosis, and the COL4α5/α2 ratio, correlated with clinical parameters like urinary protein and plasma creatinine levels. Integrated low-vacuum scanning electron microscopy analysis revealed dense GBM regions corresponded to areas where COL4α5 was preserved, whereas coarse GBM (basket-weave lesions) occurred in COL4α5-deficient regions. These advanced techniques can enhance biopsy-based diagnosis of Alport syndrome and aid in developing artificial intelligence diagnostic tools for diseases involving basement membrane lesions.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455940","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}

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