首页 > 最新文献

American Journal of Pathology最新文献

英文 中文
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 Q1 PATHOLOGY Pub 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

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. We used aristolochic acid nephropathy (AAN) and folic acid nephropathy models to establish the role of C5aR1 in kidney tubules during AKI in germline C5ar1-/- mice, myeloid cell-specific mice, 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 folic acid nephropathy. Our data indicate that C5aR1 signaling in kidney tubules exerts renoprotective effects against toxin-induced AKI by limiting overt glycolysis and maintaining mitochondrial function, revealing a novel link between the complement system and tubular cell metabolism.

急性肾损伤(AKI)仍然是住院治疗的一个主要原因,但治疗方案有限。虽然补体激活与 AKI 有关,但 C5a 受体 1(C5aR1)在肾小管细胞中的作用尚不清楚。我们利用马兜铃酸肾病(AAN)和叶酸肾病(FAN)模型,在种系C5ar1-/-小鼠、髓样细胞特异性和肾小管特异性C5ar1基因敲除小鼠中确定了AKI期间C5aR1在肾小管中的作用。注射马兜铃酸和叶酸后,C5ar1-/-小鼠的 AKI 严重程度增加,肾小管损伤程度加重。C5ar1-/-小鼠的巨噬细胞耗竭或骨髓细胞特异性C5ar1缺失不会影响AA诱导的AKI结果。RTECs的RNA测序数据显示,C5ar1缺失与线粒体代谢和ATP产生转录途径的下调有关。代谢研究证实,C5ar1-/- RTEC 的线粒体膜电位基线降低,损伤后线粒体氧化应激增加。此外,C5ar1-/- RTEC 在损伤后的糖酵解、葡萄糖摄取和乳酸生成均增强,AAN 小鼠肾脏的代谢组学分析也证实了这一点。肾小管特异性 C5ar1 基因敲除小鼠再现了在 C5ar1-/- AAN 和 FAN 小鼠中观察到的加重的 AKI。我们的数据表明,肾小管中的 C5aR1 信号通过限制明显的糖酵解和维持线粒体功能,对毒素诱导的 AKI 发挥肾保护作用,揭示了补体系统与肾小管细胞代谢之间的新联系。
{"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":"<p><p>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. We used aristolochic acid nephropathy (AAN) and folic acid nephropathy models to establish the role of C5aR1 in kidney tubules during AKI in germline C5ar1<sup>-/-</sup> mice, myeloid cell-specific mice, and kidney tubule-specific C5ar1 knockout mice. After aristolochic acid and folic acid injection, C5ar1<sup>-/-</sup> mice had increased AKI severity and a higher degree of tubular injury. Macrophage depletion in C5ar1<sup>-/-</sup> 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<sup>-/-</sup> RTECs. Moreover, C5ar1<sup>-/-</sup> 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<sup>-/-</sup> mice in AAN and folic acid nephropathy. Our data indicate that C5aR1 signaling in kidney tubules exerts renoprotective effects against toxin-induced AKI by limiting overt glycolysis and maintaining mitochondrial function, revealing a novel link between the complement system and tubular cell metabolism.</p>","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":"142455939","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 Q1 PATHOLOGY Pub Date : 2024-10-12 DOI: 10.1016/j.ajpath.2024.10.002
{"title":"This Month in AJP.","authors":"","doi":"10.1016/j.ajpath.2024.10.002","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.10.002","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455942","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 Impact of Generative Artificial Intelligence on Research Integrity in Scholarly Publishing. 生成式人工智能对学术出版中研究诚信的影响。
IF 4.7 2区 医学 Q1 PATHOLOGY Pub Date : 2024-10-11 DOI: 10.1016/j.ajpath.2024.10.001
Chhavi Chauhan, George Currie
{"title":"The Impact of Generative Artificial Intelligence on Research Integrity in Scholarly Publishing.","authors":"Chhavi Chauhan, George Currie","doi":"10.1016/j.ajpath.2024.10.001","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.10.001","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455941","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 Kidney Precision Medicine Project and Single-Cell Biology of the Injured Proximal Tubule. 肾脏精准医学项目和损伤近端小管的单细胞生物学。
IF 4.7 2区 医学 Q1 PATHOLOGY Pub Date : 2024-09-26 DOI: 10.1016/j.ajpath.2024.09.006
Danielle Janosevic, Thomas De Luca, Michael T Eadon

Single-cell RNA sequencing (scRNA-seq) has led to major advances in our understanding of proximal tubule subtypes in health and disease. The proximal tubule serves essential functions in overall homeostasis, but pathologic or physiological perturbations can affect its transcriptomic signature and corresponding tasks. These alterations in proximal tubular cells are often described within a scRNA-seq atlas as cell states, which are pathophysiological subclassifications based on molecular and morphologic changes in a cell's response to that injury compared with its native state. This review describes the major cell states defined in the Kidney Precision Medicine Project's scRNA-seq atlas. The review then identifies the overlap between the Kidney Precision Medicine Project and other seminal works that may use different nomenclature or cluster proximal tubule cells at different resolutions to define cell state subtypes. The goal is for the reader to understand the key transcriptomic markers of important cellular injury and regeneration processes across this highly dynamic and evolving field.

单细胞 RNA 测序(scRNA-seq)使我们对健康和疾病中近端小管亚型的了解取得了重大进展。近端小管在整体平衡中发挥着重要功能,但病理或生理干扰会影响其转录组特征和相应的任务。近端肾小管细胞的这些变化通常在 scRNA-seq 图谱中被描述为细胞状态,这是一种病理生理学亚分类,基于细胞对损伤的反应与其原生状态相比在分子和形态上发生的变化。本综述介绍了肾脏精准医学项目(KPMP)scRNA-seq图谱中定义的主要细胞状态。然后,综述将指出 KPMP 与其他开创性工作之间的重叠之处,这些工作可能使用不同的术语或以不同的分辨率对近端小管细胞进行分组,以定义细胞状态亚型。目的是让读者了解这一高度动态和不断发展的领域中重要细胞损伤和再生过程的关键转录组标记。
{"title":"The Kidney Precision Medicine Project and Single-Cell Biology of the Injured Proximal Tubule.","authors":"Danielle Janosevic, Thomas De Luca, Michael T Eadon","doi":"10.1016/j.ajpath.2024.09.006","DOIUrl":"10.1016/j.ajpath.2024.09.006","url":null,"abstract":"<p><p>Single-cell RNA sequencing (scRNA-seq) has led to major advances in our understanding of proximal tubule subtypes in health and disease. The proximal tubule serves essential functions in overall homeostasis, but pathologic or physiological perturbations can affect its transcriptomic signature and corresponding tasks. These alterations in proximal tubular cells are often described within a scRNA-seq atlas as cell states, which are pathophysiological subclassifications based on molecular and morphologic changes in a cell's response to that injury compared with its native state. This review describes the major cell states defined in the Kidney Precision Medicine Project's scRNA-seq atlas. The review then identifies the overlap between the Kidney Precision Medicine Project and other seminal works that may use different nomenclature or cluster proximal tubule cells at different resolutions to define cell state subtypes. The goal is for the reader to understand the key transcriptomic markers of important cellular injury and regeneration processes across this highly dynamic and evolving field.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339402","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
Endoplasmic Reticulum Stress Delays Choroid Development in the HCAR1 Knockout Mouse. 内质网应激导致 HCAR1 基因敲除小鼠脉络膜发育延迟
IF 4.7 2区 医学 Q1 PATHOLOGY Pub Date : 2024-09-26 DOI: 10.1016/j.ajpath.2024.09.002
Monir Modaresinejad, Xiaojuan Yang, Mohammad Ali Mohammad Nezhady, Tang Zhu, Emmanuel Bajon, Xin Hou, Houda Tahiri, Pierre Hardy, José Carlos Rivera, Pierre Lachapelle, Sylvain Chemtob

The subretina, composed of the choroid and the retinal pigment epithelium (RPE), bears a critical role in proper vision. In addition to phagocytosis of photoreceptor debris, the RPE shuttles oxygen and nutrients to the neuroretina. For their own energy production, RPE cells mainly rely on lactate, a major by-product of glycolysis. Lactate, in turn, is believed to convey most of its biological effects via the hydroxycarboxylic acid receptor 1 (HCAR1). Here, the lactate-specific receptor, HCAR1, is found to be exclusively expressed in the RPE cells within the subretina, and Hcar1-/- mice exhibit a substantially thinner choroidal vasculature during development. Notably, the angiogenic properties of lactate on the choroid are impacted by the absence of Hcar1. HCAR1-deficient mice exhibit elevated endoplasmic reticulum stress along with eukaryotic initiation factor 2α phosphorylation, a significant decrease in the global protein translation rate, and a lower proliferation rate of choroidal vasculature. Strikingly, inhibition of the integrated stress response using an inhibitor that reverses the effect of eukaryotic initiation factor 2α phosphorylation restores protein translation and rescues choroidal thinning. These results provide evidence that lactate signalling via HCAR1 is important for choroidal development/angiogenesis and highlight the importance of this receptor in establishing mature vision.

视网膜下由脉络膜和视网膜色素上皮(RPE)组成,对正常视觉起着至关重要的作用。除了吞噬光感受器碎片外,RPE 还将氧气和营养物质输送到神经视网膜。RPE 细胞自身产生能量主要依靠乳酸,这是糖酵解的一种主要副产品。而乳酸被认为是通过羟基羧酸受体 1(HCAR1)传递其大部分生物效应的。研究发现,乳酸特异性受体 HCAR1 只在视网膜下的 RPE 细胞中表达,而 Hcar1-/- 小鼠在发育过程中脉络膜血管明显变细。值得注意的是,乳酸对脉络膜的血管生成特性会因 Hcar1 的缺失而受到影响。缺乏 HCAR1 的小鼠表现出内质网应激升高,真核起始因子 2α 磷酸化,整体蛋白质翻译率显著下降,脉络膜血管增殖率降低。令人震惊的是,使用能逆转真核细胞启动因子 2α 磷酸化效应的抑制剂抑制综合应激反应,可恢复蛋白质翻译并挽救脉络膜变薄。这些结果提供了证据,证明通过 HCAR1 发出的乳酸信号对脉络膜的发育/血管生成很重要,并强调了该受体在建立成熟视觉中的重要性。
{"title":"Endoplasmic Reticulum Stress Delays Choroid Development in the HCAR1 Knockout Mouse.","authors":"Monir Modaresinejad, Xiaojuan Yang, Mohammad Ali Mohammad Nezhady, Tang Zhu, Emmanuel Bajon, Xin Hou, Houda Tahiri, Pierre Hardy, José Carlos Rivera, Pierre Lachapelle, Sylvain Chemtob","doi":"10.1016/j.ajpath.2024.09.002","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.09.002","url":null,"abstract":"<p><p>The subretina, composed of the choroid and the retinal pigment epithelium (RPE), bears a critical role in proper vision. In addition to phagocytosis of photoreceptor debris, the RPE shuttles oxygen and nutrients to the neuroretina. For their own energy production, RPE cells mainly rely on lactate, a major by-product of glycolysis. Lactate, in turn, is believed to convey most of its biological effects via the hydroxycarboxylic acid receptor 1 (HCAR1). Here, the lactate-specific receptor, HCAR1, is found to be exclusively expressed in the RPE cells within the subretina, and Hcar1<sup>-/-</sup> mice exhibit a substantially thinner choroidal vasculature during development. Notably, the angiogenic properties of lactate on the choroid are impacted by the absence of Hcar1. HCAR1-deficient mice exhibit elevated endoplasmic reticulum stress along with eukaryotic initiation factor 2α phosphorylation, a significant decrease in the global protein translation rate, and a lower proliferation rate of choroidal vasculature. Strikingly, inhibition of the integrated stress response using an inhibitor that reverses the effect of eukaryotic initiation factor 2α phosphorylation restores protein translation and rescues choroidal thinning. These results provide evidence that lactate signalling via HCAR1 is important for choroidal development/angiogenesis and highlight the importance of this receptor in establishing mature vision.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339396","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
Role of Kir5.1 (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 Q1 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

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.

维持酸碱平衡对正常生理功能至关重要。肾脏是通过维持全身碳酸氢盐浓度来调节酸碱平衡的重要器官。慢性代谢性酸中毒是慢性肾脏疾病的一个独立风险因素。肾脏内向整流钾通道 Kir5.1 在维持静息膜电位方面发挥着重要作用。编码 Kir5.1 的 KCNJ16 基因发生功能缺失突变的患者会出现低钾血症、盐耗竭和听力损失等肾小管病变。重要的是,这些基因突变还会破坏酸碱平衡,尤其是导致代谢性酸中毒。本研究旨在利用敲除 Kcnj16 基因(SSKcnj16-/-)的 Dahl 盐敏感大鼠,研究 Kir5.1 基因缺失如何影响盐敏感高血压患者的酸碱平衡调节。结果表明,SSKcnj16-/-大鼠在正常盐(NS)饮食下表现出代谢性酸中毒。使用 RNA-Sequncing 和 Western 印迹技术进行的进一步分析表明,尽管观察到了酸中毒,但 SSKcnj16-/- 大鼠肾脏中负责氨代谢的蛋白质表达没有变化。然而,碳酸氢盐转运体 NBCe1 的表达明显增加,而 pendrin 的表达则明显减少。总之,目前的研究表明,Kir5.1的缺失会损害肾脏中氨代谢对代谢性酸中毒的敏感性,这为开发涉及低钾血症和酸碱异常的潜在疗法提供了机理上的启示。
{"title":"Role of K<sub>ir</sub>5.1 (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":"<p><p>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 K<sub>ir</sub>5.1 plays an essential role in maintaining resting membrane potential. Patients with loss-of-function mutations in the KCNJ16 gene, which encodes K<sub>ir</sub>5.1, 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 (SS<sup>Kcnj16-/-</sup>) to investigate how the deletion of K<sub>ir</sub>5.1 affects the regulation of acid-base balance in salt-sensitive hypertension. Results indicated that SS<sup>Kcnj16-/-</sup> 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 SS<sup>Kcnj16-/-</sup> 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 K<sub>ir</sub>5.1 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.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"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 Q1 PATHOLOGY Pub Date : 2024-09-26 DOI: 10.1016/j.ajpath.2024.08.014
Rachel V Guest, Benjamin Goeppert, Jean-Charles Nault, Daniela Sia

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.

胆管癌是一类高度异质性的恶性肿瘤,尽管近年来对其分子发病机制和临床治疗的认识取得了进展,但它仍对公共卫生构成重大挑战。传统观点认为,胆管癌源于胆管内胆管细胞的肿瘤性转化。然而,最近越来越多的遗传和实验证据表明,胆管癌的潜在起源细胞有可能更加复杂和微妙,肝细胞和肝干细胞/祖细胞被认为是额外的潜在来源,这取决于包括肝损伤在内的微环境背景。鉴于肝脏中细胞的可塑性以及具有混合组织学和分子特征的肝癌亚型的存在,CCA潜在来源细胞多样化的假说尽管存在争议,但肯定不足为奇。本综述仔细研究了目前支持肝癌和胆道癌存在多种起源细胞的病理学、基因组学和实验证据,尤其关注胆管癌和肝细胞-胆管癌合并症。
{"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":"<p><p>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.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"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 Q1 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

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.

急性肾损伤(AKI)是导致慢性肾脏病(CKD)发展的重要因素。我们需要了解推动恢复和发展为慢性肾脏病的分子介质。mRNA分析表明,Ref组织表现出与AKI相似的损伤特征,但在MCD样本中没有发现。人类 AKI 的转录组特征富含参与细胞粘附、上皮细胞向间质转化和细胞周期停滞的通路(如 CDH6、ITGB6、CDKN1A)。在 AKI 中,miR-146a、miR-155、miR-142、miR-122 的上调与免疫细胞招募、炎症和上皮细胞向间质转化的通路相关。这些数据提供了综合的 miRNA 特征,补充了肾脏图谱中的 mRNA 和其他表观遗传学数据。
{"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":"<p><p>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.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"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 Q1 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

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.

血管性视网膜病变的特点是视网膜血管异常增生,经常导致视力受损或丧失。新生血管丛是这种疾病的一个显著病理特征,是一种高度渗漏的血管结构,会加剧继发性并发症。尽管血管丛具有重要的临床意义,但其发生机制尚未完全阐明,这给有效管理和治疗血管性视网膜病变带来了挑战。本研究探讨了 c-Src 在新生血管丛形成中的作用。虽然 c-Src 被认为是视网膜血管发育过程中血管生成的关键调节因子,但它在病理性视网膜血管生成中的具体作用仍有待全面了解。我们利用氧诱导视网膜病变模型,在 Cre 介导的血管特异性 c-Src 基因敲除小鼠和野生型小鼠体内检测新生血管丛的形成。在氧诱导视网膜病变模型中,c-Src 基因剔除小鼠的新生血管丛明显减少。这种血管丛形成的减少与细胞死亡、细胞增殖或细胞粘附的任何改变无关,而且 c-Src 的缺失不会影响血管丛周细胞的覆盖率和连接形态。这些发现强调了 c-Src 在血管性视网膜病变新生血管丛发病机制中的关键作用。了解涉及c-Src的分子机制可为开发旨在减轻视网膜病变相关并发症威胁视力的靶向疗法提供宝贵的见解。
{"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":"<p><p>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.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"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 Q1 PATHOLOGY Pub Date : 2024-09-24 DOI: 10.1016/j.ajpath.2024.07.023
Inyoung Cheon, Minwook Kim, Kang Ho Kim, Sungjin Ko

Cholestasis, characterized by impaired bile flow, is associated with an increased risk of cholangiocarcinoma (CCA), a malignancy originating from the biliary epithelium and hepatocytes. Hepatic nuclear receptors (NRs) are pivotal in regulating bile acid and metabolic homeostasis, and their dysregulation is implicated in cholestatic liver diseases and the progression of liver cancer. This review elucidates the role of various hepatic NRs in the pathogenesis of cholestasis-to-CCA progression. We explore their impact on bile acid metabolism as well as their interactions with other signaling pathways implicated in CCA development. Additionally, we introduce available murine models of cholestasis/primary sclerosing cholangitis leading to CCA and discuss the clinical potential of targeting hepatic NRs as a promising approach for the prevention and treatment of cholestatic liver diseases and CCA. Understanding the complex interplay between hepatic NRs and cholestasis-to-CCA pathology holds promise for the development of novel preventive and therapeutic strategies for this devastating disease.

胆汁淤积症的特点是胆汁流动受阻,它与胆管癌(CCA)风险增加有关,胆管癌是一种源自胆道上皮和肝细胞的恶性肿瘤。肝脏核受体(NRs)在调节胆汁酸和代谢平衡中起着关键作用,它们的失调与胆汁淤积性肝病和肝癌的进展有关。本综述阐明了各种肝脏 NRs 在胆汁淤积性肝癌进展的发病机制中的作用。我们探讨了它们对胆汁酸代谢的影响,以及它们与其他涉及 CCA 发展的信号通路之间的相互作用。此外,我们还介绍了现有的胆汁淤积症/原发性硬化性胆管炎(PSC)导致 CCA 的小鼠模型,并讨论了靶向肝 NRs 作为预防和治疗胆汁淤积性肝病和 CCA 的一种有前景的方法的临床潜力。了解肝NRs与胆汁淤积性肝病到CCA病理之间复杂的相互作用,有望为这一毁灭性疾病开发出新的预防和治疗策略。
{"title":"Hepatic Nuclear Receptors in Cholestasis-to-Cholangiocarcinoma Pathology.","authors":"Inyoung Cheon, Minwook Kim, Kang Ho Kim, Sungjin Ko","doi":"10.1016/j.ajpath.2024.07.023","DOIUrl":"10.1016/j.ajpath.2024.07.023","url":null,"abstract":"<p><p>Cholestasis, characterized by impaired bile flow, is associated with an increased risk of cholangiocarcinoma (CCA), a malignancy originating from the biliary epithelium and hepatocytes. Hepatic nuclear receptors (NRs) are pivotal in regulating bile acid and metabolic homeostasis, and their dysregulation is implicated in cholestatic liver diseases and the progression of liver cancer. This review elucidates the role of various hepatic NRs in the pathogenesis of cholestasis-to-CCA progression. We explore their impact on bile acid metabolism as well as their interactions with other signaling pathways implicated in CCA development. Additionally, we introduce available murine models of cholestasis/primary sclerosing cholangitis leading to CCA and discuss the clinical potential of targeting hepatic NRs as a promising approach for the prevention and treatment of cholestatic liver diseases and CCA. Understanding the complex interplay between hepatic NRs and cholestasis-to-CCA pathology holds promise for the development of novel preventive and therapeutic strategies for this devastating disease.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339398","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
期刊
American Journal of Pathology
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1