American Journal of Pathology最新文献

{"title":"This Month in AJP.","authors":"Chhavi Chauhan","doi":"10.1016/j.ajpath.2025.05.001","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.05.001","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085649","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}

{"title":"Cholestasis in alcohol-associated liver disease.","authors":"Shengmin Yan, Xiao-Ming Yin","doi":"10.1016/j.ajpath.2025.04.015","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.04.015","url":null,"abstract":"<p><p>Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality. ALD covers a spectrum of diseases ranging from mild and reversible hepatic steatosis to the development of fibrosis, cirrhosis, and alcohol-associated hepatitis (AH). AH is marked by a rapid onset of jaundice and elevated serum levels of aspartate aminotransferase in individuals with heavy alcohol use. It can progress to acute-on-chronic liver failure with a mortality rate of approximately 30% within the first month. Unfortunately, treatment options for AH are still limited. Cholestasis refers to an impairment in bile formation or flow, leading to clinical symptoms such as fatigue, pruritus, and jaundice. Cholestasis and biliary dysfunction are commonly seen in patients with AH and can significantly worsen the prognosis. However, the mechanisms and roles of cholestasis in ALD are not yet fully understood. In this review, we will summarize recent findings and explore the potential roles and mechanisms of cholestasis in the progression of ALD.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961029","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}

{"title":"Alcohol-Associated Hepatocarcinogenesis: Wnt/β-Catenin in Action.","authors":"Yuhua Xue, Tian Tian, Melak Ottallah, Mahfuza Mannan, Joshua Barkin, Brady Jin-Smith, Liya Pi","doi":"10.1016/j.ajpath.2025.04.016","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.04.016","url":null,"abstract":"<p><p>Chronic alcohol consumption is a leading global health concern, primarily due to its deleterious effects on liver function and its well-established association with hepatocellular carcinoma (HCC). Alcohol-related liver disease (ALD) encompasses a continuum-from reversible hepatic steatosis and steatohepatitis through progressive fibrosis and cirrhosis to overt HCC. Accumulating studies have revealed that the Wnt/β-catenin signaling pathway is an essential regulator in ALD pathogenesis, orchestrating diverse molecular, immunological, and epigenetic processes. Aberrant β-catenin activity disrupts redox homeostasis, promotes chronic inflammation, drives extracellular matrix (ECM) remodeling, and alters hepatocyte fate decisions, thereby creating a microenvironment that is highly conducive to carcinogenesis. Here, we provide a systemic review of the significant function of Wnt/β-catenin signaling in ALD, emphasizing its regulatory impact on liver fat accumulation, its inflammatory role in steatohepatitis, its involvement in fibrogenesis, and its tumor-promoting effects in alcohol-related HCC. In addition, we explore emerging therapeutic strategies-including direct Wnt modulators, combinatory therapeutics, and precision medicine approaches-that offer potential for early identification and tailored therapy of ALD.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957752","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}

{"title":"The PNPLA3 148M variant exacerbates alcohol-induced liver injury and tumorigenesis in mice.","authors":"Jung-Hyo Cho, Hyeong-Geug Kim, Menghao Huang, Shen Wang, Sheng Liu, Alex Lu, Kyle McCrocklin, Yang Zhang, Zhigang Fang, Juexin Wang, Wanqing Liu, Jun Wan, X Charlie Dong","doi":"10.1016/j.ajpath.2025.04.014","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.04.014","url":null,"abstract":"<p><p>Patatin-like phospholipase domain-containing 3 (PNPLA3) protein 148M variant is strongly associated with cirrhosis and hepatocellular carcinoma (HCC); however, the underlying mechanisms remain elusive. This study aimed to elucidate the role of the PNPLA3^148M variant in the alcohol-related HCC development. Control and humanized PNPLA3^148M transgenic mice were fed with an ethanol-containing diet for 12 weeks. The animals were examined for liver tumors. After the alcohol feeding, the PNPLA3^148M mice had 2-fold higher liver cancer incidence rates and larger tumor sizes than that in the control mice. Cancer stem cell markers in the PNPLA3^148M mouse livers were elevated relative to that in the control mouse livers. Alcohol detoxification was impaired in the PNPLA3^148M mouse livers. Hepatic oxidative stress and DNA damage were elevated in the PNPLA3^148M mice. Wnt/β-catenin and Yes-associated protein (YAP) and WW domain containing transcription regulator 1 (WWTR1/TAZ) were activated in the PNPLA3^148M mouse livers. Our data suggest that the PNPLA3^148M variant has a strong interaction with alcohol in the HCC development through attenuation of alcohol detoxification and promotion of oncogenic pathways. Targeting the PNPLA3^148M variant might be useful for the prevention or treatment of alcohol-associated HCC in patients carrying this variant.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959681","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}

{"title":"Computationally Enabled Polychromatic Polarized Imaging Enables Mapping of Matrix Architectures that Promote Pancreatic Ductal Adenocarcinoma Dissemination.","authors":"Guhan Qian, Hongrong Zhang, Yuming Liu, Michael Shribak, Kevin W Eliceiri, Paolo P Provenzano","doi":"10.1016/j.ajpath.2025.04.017","DOIUrl":"10.1016/j.ajpath.2025.04.017","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDA) is an extremely metastatic and lethal disease. In PDA, extracellular matrix (ECM) architectures, known as tumor-associated collagen signatures (TACSs), regulate invasion and metastatic spread in both early dissemination and late-stage disease. As such, TACS has been suggested as a biomarker to aid in pathologic assessment. However, despite its significance, approaches to quantitatively capture these ECM patterns currently require advanced optical systems with signaling processing analysis. Here, we present an expansion of polychromatic polarized microscopy (PPM) with inherent angular information coupled to machine learning and computational pixel-wise analysis of TACS. Using this platform, we are able to accurately capture TACS architectures in hematoxylin and eosin-stained histology sections directly through PPM contrast. Moreover, PPM facilitated identification of transitions to dissemination architectures (ie, transitions from sequestration through expansion to dissemination from both PanINs and throughout PDA). Last, PPM evaluation of architectures in liver metastases, the most common metastatic site for PDA, demonstrates TACS-mediated focal and local invasion as well as identification of unique patterns anchoring aligned fibers into normal-adjacent tumor, suggesting that these patterns may be precursors to metastasis expansion and local spread from micrometastatic lesions. Combined, these findings demonstrate that PPM coupled to computational platforms is a powerful tool for analyzing ECM architecture that can be used to advance cancer microenvironment studies and provide clinically relevant diagnostic information.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966629","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}

{"title":"Deciphering the Dialogue between Brain Tumors, Neurons, and Astrocytes.","authors":"Leevi H Westerlund, Camilla K Bergström, Pirjo M Laakkonen, Vadim Le Joncour","doi":"10.1016/j.ajpath.2025.04.013","DOIUrl":"10.1016/j.ajpath.2025.04.013","url":null,"abstract":"<p><p>Glioblastoma (GB) and brain metastases (BM) from peripheral tumors account for most cases of tumors in the central nervous system (CNS) while also being the deadliest. From a structural point of view, malignant brain tumors are classically characterized by hypercellularity of glioma and vascular endothelial cells. Given these atypical histologic features, GB and BM have long been considered as \"foreign\" entities with few to no connections to the brain parenchyma. The identification of intricate connections established between GB cells and the brain parenchyma paired with the ability of peripheral metastatic cells to form functional synapses with neurons challenged the concept of brain tumors disconnected from the CNS. Tumor cell integration to the CNS alters brain functionality in patients and accelerates cancer progression. Next-generation precision medicine should therefore attempt to disconnect brain cancer cells from the brain. This review encompasses recent discoveries on the mechanisms underlying these relationships and discusses the impact of these connections on tumor progression. It also summarizes the therapeutic opportunities of interrupting the dialogue between healthy and neoplastic brains.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964178","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}

{"title":"Uncovering the Unique Roles of Cathepsins B and L in Purkinje Cells Using Nervous System-Specific CTSB and CTSL Double-Deficient Mice.","authors":"Takahito Sanada, Chigure Suzuki, Junji Yamaguchi, Takashi Ueno, Juan Alejandro Oliva Trejo, Soichiro Kakuta, Norihiro Tada, Masaki Ohmuraya, Isei Tanida, Yasuo Uchiyama","doi":"10.1016/j.ajpath.2025.04.011","DOIUrl":"10.1016/j.ajpath.2025.04.011","url":null,"abstract":"<p><p>Defects in the autophagy-lysosomal degradation pathway contribute to neurodegenerative diseases. Cathepsins B (CtsB) and L (CtsL) are major lysosomal cysteine proteases. Mice deficient in both CtsB and CtsL exhibit abnormalities not only in neural tissue but in other organs, such as heart and liver, with most dying at approximately 16 days of age. To investigate the roles of CtsB and CtsL in the nervous system, nervous system-specific CTSB and CTSL double-knockout mice (CtsB/L-NES) were generated. These mice displayed tail elevation, motor dysfunction, and hyperactivity. In adulthood, they developed cerebellar atrophy, with Purkinje cells in the cerebellar cortex showing selective loss of phospholipase C β4-positive and Zebrin II-negative Purkinje cells in a striped pattern. Ubiquitin-positive structures accumulated in the perikarya and axons of Purkinje cells, reflecting impaired autophagy-lysosomal degradation. Activation of astrocytes and microglia was observed in Purkinje cell loss regions. Electron microscopy revealed granular osmiophilic deposit-like structures in perikarya, autophagosome-like accumulations in axons, and a reduction in synaptic vesicles at active regions of swollen axon terminals in Purkinje cells. Additionally, neuronal loss was observed specifically in the ventral posterior lateral and ventral posterior medial nuclei of the thalamus. These findings demonstrate CtsB and CtsL are essential for survival of Purkinje cells in the cerebellum and neurons in the ventral posterior lateral and ventral posterior medial nuclei of the thalamus.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961951","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}

{"title":"FKBP10 Silencing Alleviates Gluteal Muscle Contracture by Inhibiting Fibrosis and Restoring Autophagy via HSP47/SMAD3 Pathway Inactivation.","authors":"Haixia Xu, Jingjiang Yao, Qiao Jin, Ji Yao, Lu Ren, Jiaoyan Zhu, Wei Luo, Peng Zheng, Liangjun Li, Junjie Zhou","doi":"10.1016/j.ajpath.2025.04.005","DOIUrl":"10.1016/j.ajpath.2025.04.005","url":null,"abstract":"<p><p>Fibrosis drives gluteal muscle contracture (GMC) progression, with FKBP prolyl isomerase 10 (FKBP10) playing a key role. The aim of this study was to explore the molecular mechanism by which FKBP10 regulates GMC. Expression levels of FKBP10, heat shock protein 47 (HSP47), SMAD3, autophagy, and fibrosis-related indicators were analyzed for correlations. Histologic staining was used to assess tissue damage and fibrosis. The GMC rat model was constructed by injecting methanol penicillin. The interaction between FKBP10 and HSP47 was also detected. Results showed that FKBP10 expression was up-regulated in the gluteal muscle of patients with GMC and rats, accompanied by obvious damage and fibrosis. Elevated levels of transforming growth factor beta 1 (TGF-β1), α-smooth muscle actin (α-SMA), collagen I, collagen III, vimentin, fibronectin, p62, and LC3, along with decreased levels of matrix metalloproteinase-9 and LC3II/I, Beclin 1, p62, and ATG7, indicated weakened autophagy. FKBP10 expression correlated negatively with autophagy indicators and positively with HSP47 and fibrosis indicators. FKBP10 was found to interact with HSP47. Knockdown of FKBP10 down-regulated the levels of HSP47 and phosphorylated SMAD3/SMAD3. Furthermore, knockdown of FKBP10, HSP47, and rapamycin partially reversed the TGF-β1-induced effect. Conversely, 3-methyl adenine and HSP47 overexpression enhanced TGF-β1-induced effects. In GMC rats, FKBP10 knockdown reduced tissue damage and fibrosis, reversed HSP47, phosphorylated SMAD3/SMAD3, fibrosis, and autophagy indicator levels, and reduced autophagy and LC3 levels. In summary, silencing FKBP10 inactivated the HSP47/SMAD3 signaling pathway, inhibited fibrosis, and ameliorated autophagy defects, thereby alleviating GMC.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962063","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}

{"title":"Notch Signaling Aggravates Helicobacter pylori-Induced Inflammation by Promoting Macrophage Activation and Proinflammatory Th1/Th17 Responses.","authors":"Yunxuan He, Danli Xiao, Hongfei Zhu, Chuxi Chen, Qiaoyuan Liu, Jinling Xie, Lvying Wei, Yueqi Dai, Yunshan Ning, Yan Li","doi":"10.1016/j.ajpath.2025.04.007","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.04.007","url":null,"abstract":"<p><p>The role of Notch signaling in regulating the immune response in infectious and inflammatory diseases has been extensively reported. However, its specific involvement in Helicobacter pylori infection is yet to be fully understood. In this study, in vitro analysis utilizing real-time quantitative PCR and Western blot revealed that H. pylori triggers the activation of Notch signaling in murine bone marrow-derived macrophages (BMDMs) and co-cultured CD4⁺ T cells, a process mediated by the Notch ligand protein jagged-1 (Jag1). There was a reciprocal enhancement between Jag1-Notch signaling and NF-κB pathway in H. pylori-infected macrophages. Pretreatment with a Notch signaling inhibitor, DAPT, reduced the expression of inflammatory mediators in macrophages, modulated their phenotype, and inhibited Th1 differentiation. In vivo, after treatment with DAPT in H. pylori-infected mice, the differentiation of Th1 and Th17 was decreased on flow cytometry analysis. Hematoxylin and eosin staining revealed reduced gastric mucosa inflammation, and enzyme-linked immunosorbent assay results demonstrated decreased levels of serum inflammatory cytokines. Furthermore, the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) results showed that DAPT treatment improved the apoptosis of gastric mucosal cells. Collectively, the findings indicate that Notch signaling is implicated in exacerbating H. pylori-induced inflammation by promoting macrophage activation and Th1/Th17 responses, highlighting its potential as a therapeutic target for alleviating the progression of H. pylori-related diseases.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970246","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}

{"title":"Insulin-Like Growth Factor 2 mRNA-Binding Protein 2 Drives Subchondral Bone Damage in Temporomandibular Joint Osteoarthritis through Peroxisome Proliferator-Activated Receptor γ/C-FOS-Regulated Dual Pathways: Nuclear Factor of Activated T Cells 1 Signaling and Autophagy-Related 16-Like 2-Mediated Autophagy.","authors":"Ziyan Jiang, Jie Zhao, Youde Liang, Zhao Gao, Yanan Sun, Yaying Hu, Junchen Pan, Xing Long, Jiali Zhang","doi":"10.1016/j.ajpath.2025.04.008","DOIUrl":"10.1016/j.ajpath.2025.04.008","url":null,"abstract":"<p><p>Overactivated osteoclastogenesis leading to abnormal subchondral bone loss is the main feature of temporomandibular joint osteoarthritis (TMJOA) deterioration. The role of N6-methyladenosine in osteoclast-mediated subchondral bone loss in TMJOA remains unknown. Here, we found that an N6-methyladenosine reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) was essential for mature osteoclast induction. In TMJ tissues of patients with TMJOA, the expression of IGF2BP2 was increased. Moreover, IGF2BP2 was augmented in subchondral bone of monosodium iodoacetate (MIA)-induced TMJOA mice. Igf2bp2 deficiency attenuated MIA-induced subchondral bone loss and suppressed osteoclast function. Mechanistically, IGF2BP2 directly stabilized Pparg and Fos mRNA to enhance the nuclear factor of activated T cells 1 (NFATC1) signaling, thereby inducing osteoclast maturation. Furthermore, the stabilized peroxisome proliferator-activated receptor γ (PPARγ) promoted the transcription of Fos, resulting in a further amplified signaling of NFATC1. In Igf2bp2-deficient cells, overexpression of PPARγ and C-FOS rescued the function of osteoclasts through restoring reduced levels of NFATC1. On the other hand, the IGF2BP2/PPARγ/C-FOS axis facilitated the formation of osteoclasts by restoring the inhibited autophagy levels through the down-regulation of autophagy-related 16-like 2. Using an IGF2BP2 inhibitor, CWI1-2, hindered osteoclast formation and mitigated synovial inflammation, cartilage degeneration, and bone destruction in MIA-induced TMJOA mice. In summary, IGF2BP2 may be a novel regulator of osteoclastogenesis of TMJOA pathogenesis, and aggravates TMJOA pathology via stabilizing Pparg and Fos mRNA, which promotes NFATC1-mediated osteoclast signaling and autophagy-related 16-like 2-mediated autophagy.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957567","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}