American Journal of Pathology最新文献_第3页

Role of K_ir5.1 (Kcnj16) Channels in Regulating Renal Ammonia Metabolism during Metabolic Acidosis in Dahl Salt-Sensitive Rats. Kir5.1（Kcnj16）通道在调节达尔盐敏感大鼠代谢性酸中毒期间肾脏氨代谢中的作用

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-26 DOI: 10.1016/j.ajpath.2024.09.005

Biyang Xu, Vladislav Levchenko, Adrian Zietara, Sarah Fan, Christine A Klemens, Alexander Staruschenko

{"title":"Role of Kir5.1 (Kcnj16) Channels in Regulating Renal Ammonia Metabolism during Metabolic Acidosis in Dahl Salt-Sensitive Rats.","authors":"Biyang Xu, Vladislav Levchenko, Adrian Zietara, Sarah Fan, Christine A Klemens, Alexander Staruschenko","doi":"10.1016/j.ajpath.2024.09.005","DOIUrl":"10.1016/j.ajpath.2024.09.005","url":null,"abstract":"Maintaining acid-base homeostasis is critical for normal physiological function. The kidneys are essential for regulating acid-base homeostasis through maintaining systemic bicarbonate concentration. Chronic metabolic acidosis is an independent risk factor for chronic kidney diseases. Renal inwardly rectifying potassium channel Kir5.1 plays an essential role in maintaining resting membrane potential. Patients with loss-of-function mutations in the KCNJ16 gene, which encodes Kir5.1, reveal tubulopathy with hypokalemia, salt wasting, and hearing loss. Importantly, these mutations also disrupt acid-base balance, particularly causing metabolic acidosis. This study aimed to use Dahl salt-sensitive rats with a knockout of the Kcnj16 gene (SSKcnj16-/-) to investigate how the deletion of Kir5.1 affects the regulation of acid-base balance in salt-sensitive hypertension. Results indicated that SSKcnj16-/- rats displayed metabolic acidosis under a normal salt diet. Further analysis using RNA sequencing and Western blot analysis showed unchanged expression of proteins responsible for ammonia metabolism in the kidney of SSKcnj16-/- rats despite observed acidosis. However, there was a significant increase in the expression of bicarbonate transporter NBCe1, where there was a significant decrease in pendrin. In conclusion, the current study demonstrated that the loss of Kir5.1 impairs the sensitivity of ammonia metabolism in the kidney in response to metabolic acidosis, which provides mechanistic insights into developing potential therapeutics for conditions involving hypokalemia and acid-base abnormalities.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339401","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

Morphomolecular Pathology and Genomic Insights into the Cells of Origin of Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma. 胆管癌和肝细胞-胆管癌联合瘤起源细胞的形态分子病理学和基因组学见解。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-26 DOI: 10.1016/j.ajpath.2024.08.014

Rachel V Guest, Benjamin Goeppert, Jean-Charles Nault, Daniela Sia

{"title":"Morphomolecular Pathology and Genomic Insights into the Cells of Origin of Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma.","authors":"Rachel V Guest, Benjamin Goeppert, Jean-Charles Nault, Daniela Sia","doi":"10.1016/j.ajpath.2024.08.014","DOIUrl":"10.1016/j.ajpath.2024.08.014","url":null,"abstract":"Cholangiocarcinomas are a highly heterogeneous group of malignancies that, despite recent progress in the understanding of their molecular pathogenesis and clinical management, continue to pose a major challenge to public health. The traditional view posits that cholangiocarcinomas derive from the neoplastic transformation of cholangiocytes lining the biliary tree. However, increasing genetic and experimental evidence has recently pointed to a more complex, and nuanced, scenario for the potential cell of origin of cholangiocarcinomas. Hepatocytes as well as hepatic stem/progenitor cells are being considered as additional potential sources, depending on microenvironmental contexts, including liver injury. The hypothesis of potentially diverse cells of origin for cholangiocarcinoma, albeit controversial, is certainly not surprising given the plasticity of the cells populating the liver as well as the existence of liver cancer subtypes with mixed histologic and molecular features. This review carefully examines the current pathologic, genomic, and experimental evidence supporting the existence of multiple cells of origin of liver and biliary tract cancers, with particular focus on cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339400","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

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 : 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. miRNA and mRNA sequencing were performed on biobanked human kidney tissues obtained in the routine care of subjects with a diagnosis of AKI, minimal change disease, or without known kidney disease in nephrectomy tissue. mRNA analysis revealed that nephrectomy tissues exhibited an injury signature similar to that of AKI and 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":""},"PeriodicalIF":4.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Endothelial c-Src Mediates Neovascular Tuft Formation in Oxygen-Induced Retinopathy. 内皮细胞 c-Src 在氧诱导视网膜病变中介导新生血管丛的形成

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-25 DOI: 10.1016/j.ajpath.2024.09.003

Emmanuelle Frampton, Priyanka Som, Brittany Hill, Alexander Yu, Marina Naval-Sanchez, Chistian M Nefzger, Ivar Noordstra, Emma Gordon, Lilian Schimmel

{"title":"Endothelial c-Src Mediates Neovascular Tuft Formation in Oxygen-Induced Retinopathy.","authors":"Emmanuelle Frampton, Priyanka Som, Brittany Hill, Alexander Yu, Marina Naval-Sanchez, Chistian M Nefzger, Ivar Noordstra, Emma Gordon, Lilian Schimmel","doi":"10.1016/j.ajpath.2024.09.003","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.09.003","url":null,"abstract":"Vascular retinopathy, characterized by abnormal blood vessel growth in the retina, frequently results in vision impairment or loss. Neovascular tufts, a distinctive pathologic feature of this condition, are highly leaky blood vessel structures, exacerbating secondary complications. Despite their clinical significance, the mechanisms underlying tuft development are not fully elucidated, posing challenges for effective management and treatment of vascular retinopathy. This study investigates the role of c-Src in neovascular tuft formation. Although c-Src has been acknowledged as a pivotal regulator in developmental angiogenesis within the retinal vasculature, its specific role in governing pathologic retinal angiogenesis remains to be fully understood. The oxygen-induced retinopathy model was used for neovascular tuft formation in both Cre-mediated vascular-specific c-Src knockout mice and wild-type littermates. High-resolution imaging and analysis of isolated retinas were conducted. c-Src depletion demonstrated a significant reduction in neovascular tufts within the oxygen-induced retinopathy model. This decrease in tuft formation was observed independently of any alterations in cell death, cell proliferation, or cell adhesion, and the absence of c-Src did not impact tuft pericyte coverage and junctional morphology. These findings underline the critical role of c-Src in the pathogenesis of neovascular tufts in vascular retinopathy. Understanding the molecular mechanisms involving c-Src may offer valuable insights for the development of targeted therapies aimed at mitigating vision-threatening complications associated with retinopathy.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339397","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

Hepatic Nuclear Receptors in Cholestasis-to-Cholangiocarcinoma Pathology. 胆汁淤积到胆管癌病理学中的肝核受体

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-24 DOI: 10.1016/j.ajpath.2024.07.023

Inyoung Cheon, Minwook Kim, Kang Ho Kim, Sungjin Ko

引用次数: 0

Calpain-1 Up-Regulation Promotes Bleomycin-Induced Pulmonary Fibrosis by Activating Ferroptosis. 钙蛋白酶-1的上调通过激活铁蛋白沉积促进博莱霉素诱导的肺纤维化。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-24 DOI: 10.1016/j.ajpath.2024.09.004

Silin Wei, Yu Liu, Chenyang Ran, Yunhan Li, Bailin Tang, Meili Lu, Hongxin Wang

{"title":"Calpain-1 Up-Regulation Promotes Bleomycin-Induced Pulmonary Fibrosis by Activating Ferroptosis.","authors":"Silin Wei, Yu Liu, Chenyang Ran, Yunhan Li, Bailin Tang, Meili Lu, Hongxin Wang","doi":"10.1016/j.ajpath.2024.09.004","DOIUrl":"10.1016/j.ajpath.2024.09.004","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal disease. Calpain-1 was shown to be an effective therapeutic target for vascular endothelial dysfunction and pulmonary hypertension. However, the role of calpain-1 in bleomycin (BLM)-induced IPF has not been defined. The aim of this study was to assess the targeting of calpain-1 by activating ferroptosis in BLM-treated knockout mice and murine lung epithelial-12 cells. In this study, the role of calpain-1 in the regulation of IPF was investigated using a BLM-induced IPF mouse model. The results of our study showed that increased expression of calpain-1 was accompanied by increased fibrosis, lipid peroxidation, iron ion accumulation, and YAP levels and decreased levels of p-AMPK in BLM-induced IPF. MDL-28170 (calpain-1 inhibition) treatment and calpain-1 knockdown alleviated ferroptosis and IPF induced by BLM. Overexpression of calpain-1 in murine lung epithelial-12 cells further exacerbated iron accumulation and IPF. Mechanistically, lentivirus-mediated up-regulation of calpain-1 inhibited AMPK activity and promoted the nuclear translocation of YAP, leading to high levels of acyl-CoA synthetase long-chain family 4 -and transferrin receptor protein 1 and triggering a ferroptosis response that ultimately exacerbated BLM-induced lung fibrosis. Calpain-1 inhibition reversed these results and ameliorated BLM-induced IPF. In conclusion, these findings suggest that the calpain-1-acyl-CoA synthetase long-chain family 4-transferrin receptor protein 1-ferroptosis-positive regulatory axis contributes to BLM-induced IPF, which indicates that calpain-1 has potential therapeutic value for the treatment of IPF.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339395","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

Retraction notice to “Bone Marrow Ablation Demonstrates That Excess Endogenous Parathyroid Hormone Plays Distinct Roles in Trabecular and Cortical Bone” [Am J Pathol 181 (2012) 234–244] 骨髓消融显示过量内源性甲状旁腺激素在骨小梁和骨皮质中发挥着不同作用》的撤稿通知 [Am J Pathol 181 (2012) 234-244]

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-23 DOI: 10.1016/j.ajpath.2024.08.004

Jun Yan , Weiwei Sun , Jing Zhang , David Goltzman , Dengshun Miao

引用次数: 0

Glucocorticoid Receptor Signaling Is Critical for Mouse Corneal Development, Inhibition of Inflammatory Response, and Neovascularization of the Cornea 糖皮质激素受体信号对小鼠角膜发育、炎症反应抑制和角膜新生血管至关重要

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-23 DOI: 10.1016/j.ajpath.2024.06.005

Mahita Kadmiel , David Diaz-Jimenez , Robert H. Oakley , Maria G. Petrillo , Bo He , Xiaojiang Xu , John A. Cidlowski

{"title":"Glucocorticoid Receptor Signaling Is Critical for Mouse Corneal Development, Inhibition of Inflammatory Response, and Neovascularization of the Cornea","authors":"Mahita Kadmiel , David Diaz-Jimenez , Robert H. Oakley , Maria G. Petrillo , Bo He , Xiaojiang Xu , John A. Cidlowski","doi":"10.1016/j.ajpath.2024.06.005","DOIUrl":"10.1016/j.ajpath.2024.06.005","url":null,"abstract":"<div><div>The cornea protects the interior of the eye from external agents such as bacteria, viruses, and debris. Synthetic glucocorticoids are widely prescribed in the treatment of ocular infections and disorders. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR); however, the molecular and physiological functions of GR signaling in the cornea are poorly understood. This study found that treatment of mice with glucocorticoid eye drops led to a profound regulation of the corneal transcriptome. These glucocorticoid-regulated genes were associated with multiple biological functions, including the immune response. To understand the direct role of GR signaling in the cornea, mice with conditional knockout of GRs in the corneal epithelium were generated. Mice lacking corneal GRs exhibited microphthalmia, loss of pupils, a deformed and opaque lens, and mislocalization of key structural proteins within the corneal epithelial layers. Global transcriptomic approaches revealed that loss of GR signaling in the cornea also resulted in the dysregulation of a large cohort of genes strongly associated with an enhanced inflammatory response. Finally, corneal GR signaling was required for preventing neovascularization of blood and lymphatic vessels and thereby immune cell infiltration of the cornea. These results reveal that corneal GR signaling plays a critical role in ocular development and in maintaining the homeostasis of the eye.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 10","pages":"Pages 1938-1950"},"PeriodicalIF":4.7,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142311819","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

Testosterone-Induced H3K27 Deacetylation Participates in Granulosa Cell Proliferation Suppression and Pathogenesis of Polycystic Ovary Syndrome. 睾酮诱导的 H3K27 去乙酰化参与了颗粒细胞增殖抑制和多囊卵巢综合征的发病机制。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-05 DOI: 10.1016/j.ajpath.2024.08.012

Xiaomei Tong, Zhanhong Hu, Hanjing Zhou, Yingyi Zhang, Yin-Li Zhang, Songying Zhang, Jiamin Jin

{"title":"Testosterone-Induced H3K27 Deacetylation Participates in Granulosa Cell Proliferation Suppression and Pathogenesis of Polycystic Ovary Syndrome.","authors":"Xiaomei Tong, Zhanhong Hu, Hanjing Zhou, Yingyi Zhang, Yin-Li Zhang, Songying Zhang, Jiamin Jin","doi":"10.1016/j.ajpath.2024.08.012","DOIUrl":"10.1016/j.ajpath.2024.08.012","url":null,"abstract":"Polycystic ovary syndrome (PCOS) is the leading cause of infertility in reproductive-age women. Hyperandrogenism, polycystic ovaries, and chronic anovulation are its typical clinical features. However, the correlation between hyperandrogenism and ovarian follicle growth aberrations remains undisclosed. To advance our understanding of the molecular alterations in ovarian granulosa cells (GCs) with excessive androgen, epigenetic changes and affected gene expression in human granulosa-lutein cells and immortalized human GCs were evaluated. A PCOS mouse model induced by dihydrotestosterone was also established. This study found excessive testosterone significantly decreased the acetylation of lysine 27 on histone H3 (H3K27ac). H3K27ac chromatin immunoprecipitation- sequencing data showed down-regulated expression of cell cycle-related genes (CCND1/CCND3/PCNA), which was confirmed by real-time quantitative PCR and Western blot analysis. Testosterone application impeding cell proliferation was also proved by Ki-67 immunofluorescence and flow-cytometric analysis. Moreover, testosterone influenced CK2α nuclear translocation, which increased the phosphorylation level of histone deacetylase 2 (HDAC2). Inhibition of CK2α nuclear translocation or silenced HDAC2 expression efficiently retarded H3K27 acetylation. Meanwhile, PCOS mouse model experiments also demonstrated decreased H3K27ac and enhanced HDAC2 phosphorylation in GCs. Cell proliferation-related genes were also down-regulated in PCOS mouse GCs. In conclusion, hyperandrogenism in human and mouse GCs caused H3K27Ac aberrations, which are associated with CK2α nuclear translocation and HDAC2 phosphorylation, participating in abnormal follicle development in patients with PCOS.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144954","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

This Month in AJP 本月 AJP。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-05 DOI: 10.1016/j.ajpath.2024.09.001

引用次数: 0