American Journal of Pathology最新文献_第3页

Updates on Tau-Related Drug Targets and Potential Disease-Modifying Therapies for Alzheimer's Disease. 阿尔茨海默病tau相关药物靶点和潜在疾病改善疗法的最新进展。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-19 DOI: 10.1016/j.ajpath.2025.05.020

Anabela Djurovic-Topalovic, Natalie G Horgan, Jessica S Fortin

引用次数: 0

Cross-Species Functional Genomic Screens Identify Novel Therapeutic Targets in Malignant Peripheral Nerve Sheath Tumors. 跨物种功能基因组筛选确定恶性周围神经鞘肿瘤的新治疗靶点。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-19 DOI: 10.1016/j.ajpath.2025.05.019

Brittany Turner-Ivey, Amanda M Prechtl, Stephen T Guest, Shannon W Doutt, Jody F Longo, Elizabeth Garrett-Mayer, Steven L Carroll

{"title":"Cross-Species Functional Genomic Screens Identify Novel Therapeutic Targets in Malignant Peripheral Nerve Sheath Tumors.","authors":"Brittany Turner-Ivey, Amanda M Prechtl, Stephen T Guest, Shannon W Doutt, Jody F Longo, Elizabeth Garrett-Mayer, Steven L Carroll","doi":"10.1016/j.ajpath.2025.05.019","DOIUrl":"10.1016/j.ajpath.2025.05.019","url":null,"abstract":"As oncogenic pathways are highly conserved in vertebrates, genetically engineered mouse models can potentially be used to identify therapeutic targets relevant to rare human cancers, such as malignant peripheral nerve sheath tumors (MPNSTs). To test this, genome-scale shRNA screens designed to identify genes driving proliferation and survival were performed in five MPNST cultures derived from P0-GGFβ3 mice and three human MPNST cell lines. Several hundred gene hits mediating proliferation and survival were identified in human and mouse MPNST cells, many of which have been implicated in proliferation and survival in other cancers and/or mediate the pathogenesis of other cancer types. These hits and their associated signaling pathways extensively overlapped in human and mouse MPNST cells. A drug discovery pathway based on the Drug-Gene Interaction Database was developed to identify hits encoding druggable targets. Five druggable targets were selected for validation, with four of the five agents tested proving effective against human MPNST cells (the DNA polymerase α1 inhibitor clofarabine, the DNA nucleotidylexotransferase inhibitor cordycepin, the BCL6 inhibitor 79-6, and the lysophosphatidic acid receptor 1/3 inhibitor Ki16425). Clofarabine was especially effective, potently reducing cell numbers at low nanomolar concentrations and inducing a senescent phenotype, possibly via the p53/p21 pathway. These results demonstrate the utility of cross-species functional oncogenomics for the discovery of novel therapeutic targets relevant to human MPNSTs and suggest that clofarabine warrants further evaluation for its therapeutic potential.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339818","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

Perilipin 2 Mediates Progression of Lung Adenocarcinoma by Modulating Lipid Metabolism. Perilipin 2通过调节脂质代谢介导肺腺癌的进展。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-18 DOI: 10.1016/j.ajpath.2025.05.016

Kana Miyata-Morita, Akira Kawashima, Mitsuo Kiriya, Hitoshi Dejima, Koji Saito, Yukinori Sakao, Koichi Suzuki, Yuko Sasajima, Shigeki Morita

{"title":"Perilipin 2 Mediates Progression of Lung Adenocarcinoma by Modulating Lipid Metabolism.","authors":"Kana Miyata-Morita, Akira Kawashima, Mitsuo Kiriya, Hitoshi Dejima, Koji Saito, Yukinori Sakao, Koichi Suzuki, Yuko Sasajima, Shigeki Morita","doi":"10.1016/j.ajpath.2025.05.016","DOIUrl":"10.1016/j.ajpath.2025.05.016","url":null,"abstract":"Perilipin 2 expression is related to poor prognosis of patients with various malignant tumors. It exists on the surface of lipid droplets (LDs), which store lipids that can be used as an energy source during cancer progression. However, the underlying mechanism of lipid metabolism involving LDs in the progression of lung adenocarcinoma is unclear. This study investigated the role of perilipin 2 in the regulation of lipid metabolism in lung adenocarcinoma, as well as patient prognosis. In clinicopathologic analyses, high perilipin 2 expression in adenocarcinomas was significantly associated with poor differentiation, blood vessel and pleural invasion, advanced cancer stage, and large tumor size relative to perilipin 2-negative cases. Furthermore, patients with high perilipin 2 expression had significantly shorter recurrence-free survival times. LD accumulation was significantly reduced in A549 and PC-9 lung adenocarcinoma cells with clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) genome editing-mediated knockout of PLIN2 expression. Treatment of these cells with extracellular oleic acid induced accumulation of LDs, but the total amount of accumulated LDs was low in PLIN2 knockout cells compared with control cells. Cell proliferation and migration ability was also significantly reduced in PLIN2 knockout cells. Together, these results suggest that perilipin 2 mediates aggressive cancer progression in lung adenocarcinoma by regulating LD accumulation, and thus may represent a potential target for suppressing lung adenocarcinoma.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336239","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

Macrophage-Kruppel-Like Factor 6 Signaling Promotes Experimental Atherogenesis. 巨噬细胞-克虏伯样因子6信号传导促进实验性动脉粥样硬化。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-18 DOI: 10.1016/j.ajpath.2025.05.014

Hang Pong Ng, Atif Zafar, Rachel Diamond-Zaluski, Gun-Dong Kim, Kartik Bhat, Owen Meadows, Yashwant Pantra, E Ricky Chan, Jonathan D Smith, Ganapati H Mahabeleshwar

{"title":"Macrophage-Kruppel-Like Factor 6 Signaling Promotes Experimental Atherogenesis.","authors":"Hang Pong Ng, Atif Zafar, Rachel Diamond-Zaluski, Gun-Dong Kim, Kartik Bhat, Owen Meadows, Yashwant Pantra, E Ricky Chan, Jonathan D Smith, Ganapati H Mahabeleshwar","doi":"10.1016/j.ajpath.2025.05.014","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.05.014","url":null,"abstract":"A hallmark event in the development of atherosclerotic plaque is the accumulation of lipid-laden macrophages in the subendothelial layers of affected blood vessels. Macrophages are key players in all stages of atherogenesis, including plaque initiation, growth, and rupture, as well as healing of ruptured plaques. In this context, macrophages are the principal innate immune cells that modulate atherogenesis by engaging in various processes, such as inflammation, extracellular matrix degradation, phagocytosis, and efferocytosis. Here, this report shows that Kruppel-like factor 6 (KLF6) deficiency attenuates proinflammatory gene expression in macrophages and experimentally induced atherosclerotic plaque development. In vivo studies show that myeloid-KLF6 deficiency on Apoe-null background significantly curtails high-fat/high-cholesterol diet-induced atherosclerotic lesion formation and macrophage abundance in atherosclerotic plaques. Integrated transcriptomics and Gene Set Enrichment Analysis show that KLF6 deficiency significantly curtails a large number of tumor necrosis factor (TNF)-induced gene targets, TNF-induced interferon-γ response, interferon-α response, and inflammatory response signaling in macrophages. At the molecular level, KLF6 promotes IRF1 signaling to enhance TNF-induced proinflammatory gene expression in macrophages. Collectively, study results show that KLF6 promotes proinflammatory gene expression in macrophages and boosts experimentally induced atherosclerotic plaque formation in vivo.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482844","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

Hypoxia-Inducible Factor-1α-Induced Astrocytic D-Dopachrome Tautomerase Activates Microglial Inflammatory Response following Spinal Cord Injury. hif -1α诱导的星形细胞d -多巴胺自变性酶激活脊髓损伤后的小胶质细胞炎症反应。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-18 DOI: 10.1016/j.ajpath.2025.05.015

Aicheng Li, Mengdi Li, Si Xu, Li Niu, Shaolan Li, Yue Zhou, Zhilong Cao, Rixin Cai, Bingqiang He, Aisong Guo, Aihong Li, Honghua Song, Yongjun Wang, Yingjie Wang

{"title":"Hypoxia-Inducible Factor-1α-Induced Astrocytic D-Dopachrome Tautomerase Activates Microglial Inflammatory Response following Spinal Cord Injury.","authors":"Aicheng Li, Mengdi Li, Si Xu, Li Niu, Shaolan Li, Yue Zhou, Zhilong Cao, Rixin Cai, Bingqiang He, Aisong Guo, Aihong Li, Honghua Song, Yongjun Wang, Yingjie Wang","doi":"10.1016/j.ajpath.2025.05.015","DOIUrl":"10.1016/j.ajpath.2025.05.015","url":null,"abstract":"Spinal cord injury (SCI) often results in severe hypoxia and excessive activation of neuroinflammation, which aggravates neuropathology and neurologic dysfunction. D-dopachrome tautomerase (D-DT), the homolog of macrophage migration inhibitory factor, is a key proinflammatory mediator implicated in inflammatory diseases of multiple tissues. However, its relation with hypoxia and the potential impact on neuroinflammation following SCI remain elusive. Herein, the dynamic expression of D-DT, p65NF-κB, and the downstream proinflammatory cytokines tumor necrosis factor-α, IL-1β, and IL-6 at the lesion site was determined following SCI. D-DT inhibitor 4-(3-carboxyphenyl)-2,5pyridinedicarboxylic acid was applied to evaluate its effects on the inflammatory responses of the injured tissues. By using an in vitro cell model, the D-DT-mediated activation of microglia and the underlying regulatory mechanism were also investigated, showing that CD74/mitogen-activated protein kinase signaling was driven by D-DT to activate microglial inflammation. Analysis of rat D-DT promoter identified the binding element of hypoxia-inducible factor-1α. Hypoxia or dimethyloxallyl glycine stimulation of astrocytes was shown efficient in promoting the expression of hypoxia-inducible factor-1α and D-DT, whereas incubation of the microglia with the astrocytes' conditional medium was able to increase the production of tumor necrosis factor-α, IL-1β, and IL-6. Pharmacologic treatment of the subjects with 4-(3-carboxyphenyl)-2,5pyridinedicarboxylic acid or LW6 following SCI remarkably promoted the recovery of rat locomotor function. The results have presented a novel neuropathologic function of D-DT, which might be beneficial for development of potential drug targeting neuroinflammation.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336238","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

Distinct Role of Dural and Leptomeningeal Macrophages in Maintaining Cerebrospinal Fluid Drainage to Meningeal Lymphatic Vessels. 硬脑膜和小脑膜巨噬细胞在维持脑脊液向脑膜淋巴管引流中的独特作用。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-18 DOI: 10.1016/j.ajpath.2025.05.017

Vikrim Lohat, Raffay Ilyas, Qing Wei, Darellynn Oo, Jingna Xue, Isabelle Horsman, Keith Keane, Matthew Stephens, Pierre-Yves von der Weid, Shan Liao

{"title":"Distinct Role of Dural and Leptomeningeal Macrophages in Maintaining Cerebrospinal Fluid Drainage to Meningeal Lymphatic Vessels.","authors":"Vikrim Lohat, Raffay Ilyas, Qing Wei, Darellynn Oo, Jingna Xue, Isabelle Horsman, Keith Keane, Matthew Stephens, Pierre-Yves von der Weid, Shan Liao","doi":"10.1016/j.ajpath.2025.05.017","DOIUrl":"10.1016/j.ajpath.2025.05.017","url":null,"abstract":"Cerebrospinal fluid (CSF) drains along the perivascular space, known as the glymphatic system, to the meninges, where meningeal lymphatic vessels (MLVs) remove toxic products with excess CSF from the brain. Macrophages are widely present in the leptomeninges and dura mater of meninges. However, whether leptomeningeal and dural macrophages play the same or distinct roles in maintaining optimal CSF drainage remains unclear. By intracisterna magna injection of clodronate liposomes, we observed a comprehensive depletion of leptomeningeal macrophages, a selective reduction in dural sinus-associated macrophages, a decreased density of MLVs, and disrupted CSF drainage. Further studies showed that macrophage depletion was associated with the infiltration of monocytes and the recovery of monocyte-derived macrophages. By day 14 after clodronate liposome, although both dural macrophages and MLVs had recovered, leptomeningeal macrophages and CSF drainage had not been restored. Furthermore, the study showed that i.p. injection of anti-colony-stimulating factor 1 receptor antibody selectively depleted macrophages in the dura mater but not in the leptomeninges, without affecting MLVs or CSF drainage. The study suggests that leptomeningeal macrophages, distinct from the dural macrophages, are essential for CSF drainage to the MLVs.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336237","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 本月在AJP。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-13 DOI: 10.1016/j.ajpath.2025.06.001

引用次数: 0

Identification of Preclinical Biomarkers of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) versus MASLD and Increased Alcohol Intake and the Impact of Diet. MASLD与MetALD临床前生物标志物的鉴定及饮食的影响。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-12 DOI: 10.1016/j.ajpath.2025.05.013

Tyler C Gripshover, Rui S Treves, Josiah E Hardesty

{"title":"Identification of Preclinical Biomarkers of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) versus MASLD and Increased Alcohol Intake and the Impact of Diet.","authors":"Tyler C Gripshover, Rui S Treves, Josiah E Hardesty","doi":"10.1016/j.ajpath.2025.05.013","DOIUrl":"10.1016/j.ajpath.2025.05.013","url":null,"abstract":"Recent diagnostic advancements have characterized metabolic dysfunction-associated steatotic liver disease (MASLD) and increased alcohol intake (MetALD) if alcohol consumption is ≥ 20 or 30 g/d, females and males, respectively. Available treatments may affect dietary behavior or treat organ pathology but have limited effectiveness. There is a preclinical need for an animal model of MetALD that can assess concurrent diet and alcohol consumption on organ pathology to establish treatment strategies. Male, C57BL/6J mice were randomly assigned to six dietary groups for 13 weeks containing the following: ±chow diet (CD), ±high-fat diet (HFD), and water or 10% (v/v) ethanol. Glucose tolerance testing was performed at week 10. Physiological measures were assessed, and cecal 16S rRNA and liver mRNA sequencing were performed. HFD + ethanol (MetALD) mice had exacerbated dyslipidemia and gut dysbiosis relative to HFD + water (MASLD) mice. CD + HFD + ethanol mice had reduced glucagon-like peptide-1 relative to HFD + ethanol mice. MASLD and MetALD mice had altered transcription factor regulatory networks, which were altered with CD access. Kupffer cell markers are lower in HFD + ethanol mice relative to other groups. Diet and ethanol have distinct physiological effects in this MetALD model. Mice provided CD + HFD had worsened metabolic syndrome, but improved liver injury and microbiome diversity compared with HFD mice. Hepatic gene markers and microbiome changes of MASLD were identified. This preclinical model helps identify novel therapeutics to treat MASLD and MetALD.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293206","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 Link between Alcohol Consumption and Kidney Injury. 饮酒与肾损伤之间的联系

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-11 DOI: 10.1016/j.ajpath.2025.05.011

Burhan Yokus, Luca Maccioni, Lihong Fu, György Haskó, Laura E Nagy, Bin Gao, Pal Pacher

{"title":"The Link between Alcohol Consumption and Kidney Injury.","authors":"Burhan Yokus, Luca Maccioni, Lihong Fu, György Haskó, Laura E Nagy, Bin Gao, Pal Pacher","doi":"10.1016/j.ajpath.2025.05.011","DOIUrl":"10.1016/j.ajpath.2025.05.011","url":null,"abstract":"Alcohol consumption contributes to systemic organ dysfunction, but its direct effect on kidney health is unclear. Epidemiologic studies have shown inconsistent findings due to a reliance on conventional markers, such as serum creatinine and blood urea nitrogen, which are insensitive to early chronic kidney disease and influenced by factors such as muscle mass, diet, and hydration status. Experimental studies have indicated that alcohol may directly exacerbate renal damage through mitochondrial dysfunction, oxidative stress, and inflammation. Furthermore, indirect effects from alcohol-induced altered intestinal permeability and microbiome, liver injury, microcirculatory/cardiac dysfunction and muscle damage may also facilitate kidney damage. Notably, alcohol-related liver disease can lead to hepatorenal syndrome, a severe type of kidney dysfunction driven by circulatory disturbances and systemic inflammation. This overview explores the adverse effects of alcohol misuse on kidney health and disease, emphasizing the need for comprehensive epidemiologic studies with more sensitive kidney injury biomarkers. It also highlights the importance of using clinically relevant preclinical models to clarify the underlying mechanisms of alcohol-related kidney injury and to enhance the understanding of its long-term clinical consequences.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293208","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

Microbiota in Alcohol-Associated Organ Damage. 酒精相关器官损伤中的微生物群

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-11 DOI: 10.1016/j.ajpath.2025.05.012

Aenne Harberts, Bernd Schnabl

{"title":"Microbiota in Alcohol-Associated Organ Damage.","authors":"Aenne Harberts, Bernd Schnabl","doi":"10.1016/j.ajpath.2025.05.012","DOIUrl":"10.1016/j.ajpath.2025.05.012","url":null,"abstract":"Alcohol-associated organ damage is a major cause of morbidity and mortality worldwide, with the liver being the primarily affected organ. Emerging evidence highlights the gut microbiota as a key driver in alcohol-associated liver disease. Changes in the microbiota composition, microbial translocation, and a dysregulated immune response culminate in inflammation and tissue injury. Persistent liver injury eventually promotes disease progression from steatohepatitis to fibrosis and cirrhosis. In this review, an overview of microbiota alterations observed in patients with chronic alcohol consumption is provided and the mechanisms by which microbiota contributes to alcohol-associated damage across various organ systems are explored. Emphasis is placed on changes in the gut microbiota and its role in alcohol-associated liver disease, the disease condition with the most robust evidence linking microbiota-related changes to organ injury. Additionally, key areas where further research is needed to address unresolved questions are highlighted. Finally, emerging therapeutic strategies targeting the microbiota to treat alcohol use disorders and prevent alcohol-associated liver diseases are discussed.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293207","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