American Journal of Pathology最新文献

{"title":"Meeting Abstracts","authors":"","doi":"10.1016/j.ajpath.2025.10.001","DOIUrl":"10.1016/j.ajpath.2025.10.001","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages S1-S17"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145335025","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":"Title Page","authors":"","doi":"10.1016/S0002-9440(25)00369-4","DOIUrl":"10.1016/S0002-9440(25)00369-4","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Page OFC"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145335027","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":"Periostin Deletion Reduces Corneal Opacity and the Infiltration of Immune Cells.","authors":"Hyemin Seong, Chieun Song, Mingyo Kim, Woong-Sun Yoo, Mee-Young Choi, Réka Dorottya Varga, Yong-Ho Choe, Bina Lee, Seung Pil Yun, Young-Sik Yoo, Youngsub Eom, Choun-Ki Joo, Jinsung Yang, Seong-Jae Kim","doi":"10.1016/j.ajpath.2025.09.007","DOIUrl":"10.1016/j.ajpath.2025.09.007","url":null,"abstract":"<p><p>Corneal opacity resulting from corneal injury is a leading cause of blindness. The interaction of extracellular matrix (ECM) proteins, cytokines, and immune cells induces corneal opacity after corneal injury. Periostin, which is secreted into the ECM, is involved in wound healing and is associated with immune cell infiltration. The function of periostin in corneal wound healing and in the development of corneal opacity was investigated. Wild-type (WT) and Postn knockout (KO) mice underwent central corneal incision. Periostin expression level was significantly increased after the incision in WT mice, correlating with higher levels of wound healing markers, such as fibronectin and α-smooth muscle actin, and increased corneal opacity. However, Postn KO mice showed reduced corneal opacity and immune cell infiltration, particularly from myeloid lineage cells after incision. In addition, pro-inflammatory cytokine levels (IL-1β, IL-6, and C1q) were not significantly changed in Postn KO mice. The results suggest that periostin deletion impairs corneal wound healing and reduces opacity by regulating cytokine expression and immune cell recruitment. The findings indicate that periostin can be a potential therapeutic target for reducing corneal opacity.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211317","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":"Targeting RORγ to Boost Regulatory T cells and Ameliorate Diabetic Retinopathy in Mice.","authors":"Devy Deliyanti, Varaporn Suphapimol, Phoebe Ang, Abhirup Jayasimhan, Jennifer L Wilkinson-Berka","doi":"10.1016/j.ajpath.2025.09.006","DOIUrl":"10.1016/j.ajpath.2025.09.006","url":null,"abstract":"<p><p>Diabetic retinopathy, a leading cause of blindness, features damage to the retinal vasculature, where T-cell-mediated inflammation is increasingly recognized as an important contributor. Retinoic acid receptor-related orphan receptor gamma (RORγ) plays a key role in regulating the balance between anti-inflammatory regulatory T cells (Tregs) expressing the transcription factor Foxp3 and proinflammatory Th17 cells. It was hypothesized that inhibiting RORγ with SR2211, targeting both RORγ and its isoform RORγt, increases Tregs and reduces Th17 cells, resulting in reduced inflammation and vasculopathy in a streptozotocin-induced model of diabetic retinopathy. Mice expressing Foxp3 as a red fluorescent protein were treated with SR2211 for 26 weeks of diabetes, and comparisons made to diabetic mice administered vehicle and non-diabetic control mice. In blood and lymphoid tissues of diabetic mice, treatment with SR2211 restored the number of Tregs and reduced Th17 cells to the levels of diabetic mice + vehicle. In the retina of diabetic mice, treatment with SR2211 increased Tregs and reduced the activation of microglia cells, the expression of proinflammatory factors including IL-17A, IL-6 and tumor necrosis factor, vascular leakage, vascular endothelial growth factor, and acellular capillaries, compared with diabetic mice + vehicle. These findings indicate the ability of RORγ/RORγt inhibition to modulate specific T-cell responses and suppress microglia activation to reduce inflammation and vascular damage in diabetic retinopathy.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211330","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":"Hepatocyte-Specific MET Deletion Exacerbates Acetaminophen-Induced Hepatotoxicity in Mice.","authors":"Siddhi Jain, Ranjan Mukherjee, Gillian Williams, Jia-Jun Liu, Lanuza A P Faccioli, Zhiping Hu, Rodrigo M Florentino, George K Michalopoulos, Alejandro Soto-Gutierrez, Silvia Liu, Joseph Locker, Bharat Bhushan","doi":"10.1016/j.ajpath.2025.09.010","DOIUrl":"10.1016/j.ajpath.2025.09.010","url":null,"abstract":"<p><p>Despite the well-known role of MET in liver regeneration after partial hepatectomy, its role in the clinically relevant acetaminophen (APAP)-induced liver injury (AILI) model remains unexplored. AILI markedly differs from partial hepatectomy because it is associated with massive liver necrosis. This study aims to delineate the role of MET specifically in AILI. Hepatocyte-specific MET knockout (MET KO) mice were administered a toxic dose of APAP and assessed for liver injury/regeneration parameters. MET deletion strikingly exacerbated the initial hepatotoxicity and consequentially impaired the compensatory proliferative response, culminating in significant mortality. Mechanistically, MET deletion enhanced c-Jun N-terminal kinase (JNK) activation and its mitochondrial translocation, resulting in excessive mitochondrial oxidative damage, releasing apoptosis-inducing factor into cytosol. Excess JNK activation was attributed to reduced inhibitory activity of AKT on JNK in the absence of MET signaling. Pharmacologic activation of AKT reduced JNK activation and hepatotoxicity in MET KO mice. RNA-sequencing/immunoblotting not only showed repression of proliferative/survival signaling but also activation of cell death/senescence pathways along with an impaired unfolded protein response in MET KO mice. Analysis of published single-nucleus RNA-sequencing data showed that proliferation in livers from patients with APAP-induced acute liver failure was associated with strong activation of hepatocyte growth factor/MET signaling in hepatocytes, with spatial transcriptomics showing striking induction of hepatocyte growth factor surrounding the necrotic zones. Interestingly, 35% of the genes altered in human acute liver failure were regulated by MET in the mouse AILI model. The current study shows that MET is crucial for restraining hepatotoxicity after APAP overdose via inhibition of the mitochondrial cell death signaling pathway.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211340","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 D2.B10-Dmd^mdx/J Mouse Model of Duchenne Muscular Dystrophy Exhibits a Severe Mitochondrial Deficiency Not Observed in the C57BL/10ScSn-Dmd^mdx/J Mouse.","authors":"Jennifer A Tinklenberg, Jessica Sutton, Rebecca A Slick, Hui Meng, Margaret Haberman, Mariah J Prom, Margaret J Beatka, Tatyana A Vetter, Audrey L Daugherty, Christina Pacak, J Patrick Gonzalez, Michael W Lawlor","doi":"10.1016/j.ajpath.2025.09.005","DOIUrl":"10.1016/j.ajpath.2025.09.005","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, resulting in dystrophin deficiency in skeletal/cardiac muscle and progressive loss of function. Although the genetic causes of DMD have been thoroughly investigated, the energetic consequences have not been well examined across animal models. Previously, the laboratory examined mitochondrial function across nemaline myopathy mouse models of varying disease severity; here, mitochondrial phenotypes in DMD are assessed through the comparison of the milder C57BL/10ScSn-Dmd^mdx/J (B10-mdx) and the more severe D2.B10-Dmd^mdx/J mouse (D2-mdx) mouse models. D2-mdx exhibit a significant decrease in mitochondrial respiration, undetectable ATP concentrations, increased mitochondrial membrane potential, and alterations in electron transport chain enzyme activities. In contrast, B10-mdx show only mild mitochondrial phenotypes, including decreased ATP content. The D2-mdx mouse has genetic modifiers, including latent transforming growth factor-β-binding protein 4 (LTBP4) and annexin A6, that have been shown to alter DMD severity in humans. However, these modifiers did not account for mitochondrial differences seen in mdx mice. Both models were treated with a microdystrophin adeno-associated virus gene therapy to assess whether dystrophin restoration rescued mitochondrial phenotypes. Gene therapy attenuated the ATP deficiency in the B10-mdx mice, but only improved mitochondrial membrane potentials in D2-mdx mice. The exact cause of the D2-mdx mitochondrial phenotypes remains unknown, but secondary disease processes that affect mitochondrial phenotypes should be taken into consideration when choosing an animal model for DMD studies.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211343","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 Gut Microbiome as a Possible Mediator in Autoimmunity and Cardiovascular Disease: Shared Pathways and Therapeutic Implications.","authors":"Marina M Bellet, Francesco Curcio, Luigi Frati, Marilena Pariano, Luigina Romani, Massimiliano M Corsi-Romanelli","doi":"10.1016/j.ajpath.2025.08.015","DOIUrl":"10.1016/j.ajpath.2025.08.015","url":null,"abstract":"<p><p>This review explores the emerging role of the gut microbiome in bridging autoimmunity and cardiovascular diseases. Dysbiosis, an imbalance in gut microbial composition, disrupts immune regulation, metabolic pathways, and vascular health, likely contributing to both autoimmune disorders and cardiovascular diseases. Microbial metabolites, such as short-chain fatty acids, trimethylamine N-oxide, tryptophan derivatives, and bile acids, play critical roles in modulating inflammation, lipid metabolism, and endothelial function. Specific bacterial species, including Faecalibacterium prausnitzii, Akkermansia muciniphila, and Bifidobacterium species., exhibit dual protective effects against autoimmune and cardiovascular pathologies. By elucidating these interconnected mechanisms, this work highlights the potential of microbiome-targeted therapies, such as probiotics, prebiotics, and dietary interventions, to concurrently address autoimmune diseases and reduce cardiovascular risk. Understanding the complex interactions between the gut microbiota, immune system, and cardiovascular health opens new avenues for developing innovative therapeutic strategies aimed at restoring microbial balance and improving patient outcomes.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184590","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":"Decreased Glycolysis Due to Lactate Dehydrogenase A N6-Methyladenosine Methylation in Endometrium of Endometriosis Impairs Its Decidualization and Contributes to Related Infertility.","authors":"Ruiweng Weng, Yi Liu, Wenqian Xiong","doi":"10.1016/j.ajpath.2025.08.016","DOIUrl":"10.1016/j.ajpath.2025.08.016","url":null,"abstract":"<p><p>Endometriosis-related infertility is a prevalent reproductive health concern of global significance. Functional abnormalities of the endometrium are increasingly recognized as a pivotal contributor to infertility in affected individuals. In the present study, a significant reduction in glycolytic activity was observed in secretory-phase endometrial tissues obtained from patients with endometriosis, and this metabolic defect was attributed to down-regulated expression of lactate dehydrogenase A (LDHA). This impaired glycolysis was found to induce defective endometrial decidualization and contribute to endometriosis-related infertility in a mouse model. Mechanistically, inhibition of LDHA promoted the production of reactive oxygen species and apoptosis of endometrial stromal cells, ultimately resulting in compromised stromal cell decidualization. Furthermore, reduced LDHA expression was confirmed in the eutopic endometrium of patients with endometriosis, which was associated with decreased N6-methyladenosine (m⁶A) demethylation activity. This attenuation of m⁶A demethylation was, in turn, attributed to the down-regulated expression of alkB homolog 5-a key enzyme responsible for m⁶A demethylation modification. Collectively, the findings demonstrate that elevated m⁶A methylation levels in the eutopic endometrium of patients with endometriosis impair endometrial glycolytic metabolism and decidualization of endometrial stromal cells, thereby contributing to endometriosis-related infertility. This pathologic cascade is mediated by the down-regulation of LDHA expression.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184551","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":"Retraction Notice to “Aberrant CD8+ T-Cell Responses and Memory Differentiation upon Viral Infection of an Ataxia-Telangiectasia Mouse Model Driven by Hyper-Activated Akt and mTORC1 Signaling” [Am J Pathol 178 (2011) 2740–2751]","authors":"Anthony D. D’Souza ,&nbsp;Ian A. Parish ,&nbsp;Sharen E. McKay ,&nbsp;Susan M. Kaech ,&nbsp;Gerald S. Shadel","doi":"10.1016/j.ajpath.2025.08.002","DOIUrl":"10.1016/j.ajpath.2025.08.002","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Page 1961"},"PeriodicalIF":3.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145120553","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":"From The American Journal of Pathology's Archives","authors":"Chris Albanese,&nbsp;Olga C. Rodriguez","doi":"10.1016/j.ajpath.2025.02.011","DOIUrl":"10.1016/j.ajpath.2025.02.011","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1756-1757"},"PeriodicalIF":3.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145120555","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}