American Journal of Pathology最新文献

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This Month in AJP 本月在AJP。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-10 DOI: 10.1016/j.ajpath.2025.09.011

引用次数: 0

Meeting Abstracts 会议摘要

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-01 DOI: 10.1016/j.ajpath.2025.10.001

引用次数: 0

Title Page 标题页

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-01 DOI: 10.1016/S0002-9440(25)00369-4

引用次数: 0

Periostin Deletion Reduces Corneal Opacity and the Infiltration of Immune Cells 骨膜蛋白缺失可减少角膜混浊和免疫细胞浸润。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-30 DOI: 10.1016/j.ajpath.2025.09.007

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

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.

角膜损伤引起的角膜混浊是导致失明的主要原因。细胞外基质（ECM）蛋白、细胞因子和免疫细胞的相互作用诱导角膜损伤后角膜混浊。骨膜蛋白分泌到ECM中，参与伤口愈合并与免疫细胞浸润有关。探讨了骨膜素在角膜创面愈合和角膜混浊形成中的作用。野生型（WT）和Postn敲除（KO）小鼠进行角膜中央切口。WT小鼠切口后骨膜蛋白表达水平显著升高，与纤维连接蛋白、α-SMA等创面愈合标志物水平升高、角膜混浊增加相关。然而，术后KO小鼠显示角膜混浊和免疫细胞浸润减少，尤其是骨髓系细胞。此外，促炎细胞因子（IL-1β、IL-6、C1q）水平在KO后小鼠中没有显著变化。结果表明，骨膜蛋白缺失通过调节细胞因子表达和免疫细胞募集，影响角膜创面愈合，减少角膜不透明。研究结果表明，骨膜蛋白可作为降低角膜混浊的潜在治疗靶点。

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引用次数: 0

Targeting RORγ to Boost Regulatory T cells and Ameliorate Diabetic Retinopathy in Mice 靶向RORγ促进调节性T细胞和改善小鼠糖尿病视网膜病变。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-30 DOI: 10.1016/j.ajpath.2025.09.006

Devy Deliyanti, Varaporn Suphapimol, Phoebe Ang, Abhirup Jayasimhan, Jennifer L. Wilkinson-Berka

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.

糖尿病视网膜病变是导致失明的主要原因之一，其特征是视网膜脉管系统受损，其中T细胞介导的炎症越来越被认为是一个重要的因素。视黄酸受体相关孤儿受体γ (RORγ)在调节表达转录因子Foxp3的抗炎调节性T细胞（Tregs）和促炎Th17细胞之间的平衡中起关键作用。我们假设SR2211抑制RORγ，同时靶向RORγ及其亚型RORγ γt，可以增加Tregs并减少Th17细胞，从而减少链佐菌素诱导的糖尿病视网膜病变模型中的炎症和血管病变。将表达Foxp3为红色荧光蛋白的小鼠用SR2211治疗糖尿病26周，并与糖尿病小鼠和非糖尿病对照组小鼠进行比较。在糖尿病小鼠的血液和淋巴组织中，用SR2211治疗可以恢复treg的数量，并将Th17细胞降低到糖尿病小鼠+对照体的水平。在糖尿病小鼠的视网膜中，与糖尿病小鼠+对照体相比，SR2211处理增加了Tregs，降低了小胶质细胞的活化，降低了促炎因子（包括白细胞介素- 17a、白细胞介素-6和肿瘤坏死因子）的表达，降低了血管渗漏、血管内皮生长因子和脱细胞毛细血管的表达。这些发现表明，RORγ/RORγ γt抑制能够调节特异性t细胞反应，抑制小胶质细胞激活，从而减少糖尿病视网膜病变的炎症和血管损伤。

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引用次数: 0

Hepatocyte-Specific MET Deletion Exacerbates Acetaminophen-Induced Hepatotoxicity in Mice 肝细胞特异性MET缺失加剧对乙酰氨基酚诱导的小鼠肝毒性。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-30 DOI: 10.1016/j.ajpath.2025.09.010

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

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.

尽管MET在部分肝切除术（PHx）后肝脏再生中的作用众所周知，但其在临床相关的对乙酰氨基酚（APAP）诱导的肝损伤（AILI）模型中的作用仍未被探索。aii明显不同于PHx，因为它与大量肝坏死有关。本研究旨在明确MET在AILI中的作用。给肝细胞特异性MET-KO小鼠注射毒性剂量的APAP，并评估肝损伤/再生参数。MET缺失显著加剧了最初的肝毒性，并因此损害了代偿性增殖反应，最终导致显著的死亡率。在机制上，MET缺失增强了jnk活化及其线粒体易位，导致线粒体过度氧化损伤，将细胞死亡诱导剂AIF释放到细胞质中。过量的JNK激活归因于AKT在缺乏met信号的情况下对JNK的抑制活性降低。AKT的药理激活降低了MET-KO小鼠的jnk激活和肝毒性。rna测序/免疫印迹不仅显示MET-KO小鼠的增殖/生存信号被抑制，而且细胞死亡/衰老途径被激活，同时未折叠蛋白反应受损。对已发表的单核rna测序数据的分析显示，apap诱导的ALF患者肝脏中的增殖与肝细胞中HGF/MET信号的强烈激活有关，空间转录组学显示坏死区周围HGF的显著诱导。有趣的是，在小鼠aili模型中，人类alf中35%的基因改变受到MET的调节。总之，本研究表明MET通过抑制线粒体细胞死亡信号通路，对抑制APAP过量后的肝毒性至关重要。

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引用次数: 0

The D2.B10-Dmdmdx/J Mouse Model of Duchenne Muscular Dystrophy Exhibits a Severe Mitochondrial Deficiency Not Observed in the C57BL/10ScSn-Dmdmdx/J Mouse D2。B10-Dmdmdx/J小鼠模型显示出C57BL/10ScSn-Dmdmdx/J小鼠未观察到的严重线粒体缺陷。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-30 DOI: 10.1016/j.ajpath.2025.09.005

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 A. Pacak , J. Patrick Gonzalez , Michael W. Lawlor

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.

杜氏肌营养不良症（DMD）是由DMD基因突变导致骨骼肌/心肌肌营养不良蛋白缺乏和功能进行性丧失引起的。虽然DMD的遗传原因已被彻底研究，但其能量后果尚未在动物模型中得到很好的检验。此前，该实验室检查了不同疾病严重程度的线虫性肌病小鼠模型的线粒体功能；在这里，通过比较较轻的C57BL/10ScSn-Dmdmdx/J （B10-mdx）和较严重的D2来评估DMD的线粒体表型。B10-Dmdmdx/J小鼠（D2-mdx）模型。D2-mdx表现出线粒体呼吸明显减少，ATP浓度检测不到，线粒体膜电位增加，电子传递链酶活性改变。相比之下，B10-mdx仅表现出轻微的线粒体表型，包括ATP含量降低。D2-mdx小鼠具有基因修饰因子，包括LTBP4和ANXA6，这些基因修饰因子已被证明可以改变人类DMD的严重程度。然而，这些修饰因子并不能解释mdx小鼠的线粒体差异。两种模型均接受微肌营养不良蛋白AAV基因治疗，以评估肌营养不良蛋白恢复是否挽救了线粒体表型。基因治疗减轻了B10-mdx小鼠的ATP缺乏症，但仅改善了D2-mdx小鼠的线粒体膜电位。D2-mdx线粒体表型的确切原因尚不清楚，但在选择用于DMD研究的动物模型时，应考虑影响线粒体表型的继发性疾病过程。

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引用次数: 0

The Gut Microbiome as a Possible Mediator in Autoimmunity and Cardiovascular Disease 肠道微生物群作为自身免疫和心血管疾病的可能中介：共享途径和治疗意义。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-26 DOI: 10.1016/j.ajpath.2025.08.015

Marina M. Bellet , Francesco Curcio , Luigi Frati , Marilena Pariano , Luigina Romani , Massimiliano M. Corsi-Romanelli

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.

这篇综述探讨了肠道微生物组在桥接自身免疫和心血管疾病（cvd）中的新作用。生态失调，肠道微生物组成失衡，破坏免疫调节、代谢途径和血管健康，可能导致自身免疫性疾病和心血管疾病。微生物代谢物如短链脂肪酸、三甲胺n -氧化物、色氨酸衍生物和胆汁酸在调节炎症、脂质代谢和内皮功能中起着关键作用。特定的细菌种类，包括prausnitzii Faecalibacterium， Akkermansia muciniphila和双歧杆菌，对自身免疫和心血管疾病表现出双重保护作用。通过阐明这些相互关联的机制，这项工作强调了微生物组靶向治疗的潜力，如益生菌、益生元和饮食干预，同时解决自身免疫性疾病和降低心血管风险。了解肠道微生物群、免疫系统和心血管健康之间复杂的相互作用，为开发旨在恢复微生物平衡和改善患者预后的创新治疗策略开辟了新的途径。

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引用次数: 0

Decreased Glycolysis Due to Lactate Dehydrogenase A N6-Methyladenosine Methylation in Endometrium of Endometriosis Impairs Its Decidualization and Contributes to Related Infertility 子宫内膜异位症患者因LDHA m6A甲基化导致糖酵解减少，损害其去个体化并导致相关不孕。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-26 DOI: 10.1016/j.ajpath.2025.08.016

Ruiweng Weng, Yi Liu, Wenqian Xiong

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.

子宫内膜异位症相关的不孕症是一个普遍的生殖健康问题的全球意义。子宫内膜功能异常越来越被认为是影响个体不孕的关键因素。在本研究中，从子宫内膜异位症患者获得的分泌期子宫内膜组织中观察到糖酵解活性显著降低，这种代谢缺陷归因于乳酸脱氢酶a （LDHA）表达下调。在小鼠模型中发现，糖酵解受损可诱导子宫内膜脱个体化缺陷，并导致子宫内膜异位症相关不孕。从机制上说，抑制LDHA促进了活性氧（ROS）的产生和子宫内膜基质细胞的凋亡，最终导致基质细胞脱胞化受损。此外，在子宫内膜异位症患者的异位子宫内膜中证实LDHA表达降低，这与n6 -甲基腺苷（m6A）去甲基化活性降低有关。这种m6A去甲基化的衰减反过来归因于alkB同源物5 （ALKBH5）的表达下调，ALKBH5是负责m6A去甲基化修饰的关键酶。总之，我们的研究结果表明，子宫内膜异位症患者异位子宫内膜中m6A甲基化水平升高会损害子宫内膜糖酵解代谢和子宫内膜间质细胞的脱个体化，从而导致子宫内膜异位症相关不孕。这种病理级联是由LDHA表达下调介导的。

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引用次数: 0

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] “超激活Akt和mTORC1信号驱动的异常CD8+ t细胞反应和记忆分化对ataxi -毛细血管扩张小鼠模型的影响”[J] .中华病理学杂志，2011(11):2740-2751。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-23 DOI: 10.1016/j.ajpath.2025.08.002

Anthony D. D’Souza , Ian A. Parish , Sharen E. McKay , Susan M. Kaech , Gerald S. Shadel

引用次数: 0

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