Basma Baccouche, Maximilian McCann, Janani Rajasekar, Nguyễn Thị Thanh Nhàn, Kaori Yamada, Andrius Kazlauskas
{"title":"Activin A prevents hyper-responsiveness to VEGF in pathological blood vessels by perturbing the trafficking of activated VEGFR2.","authors":"Basma Baccouche, Maximilian McCann, Janani Rajasekar, Nguyễn Thị Thanh Nhàn, Kaori Yamada, Andrius Kazlauskas","doi":"10.1016/j.ajpath.2025.05.022","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.05.022","url":null,"abstract":"<p><p>While quality-of-life compromising afflictions such as diabetic retinopathy (DR) are driven by vascular endothelial growth factor (VEGF), there is a growing appreciation that the concentration of VEGF is not the only influencer of vascular dysfunction within the retina. Activin A (activin), a ligand of the transforming growth factor β superfamily (TGF-β), attenuated VEGF-induced VE-cadherin disorganization, pore formation, and permeability of primary human retinal endothelial cells (HRECs). Efforts to further investigate the mechanism of this phenomenon revealed that activin reduced the expression of Rab11, which was required for the activin effect. The activin effect was not observed in cells with suppressed expression of the endosomally-localized protein tyrosine phosphatase (PTP1b), whereas PTPs present on the plasma membrane were dispensable. Activin attenuated VEGF-mediated phosphorylation of VEGF receptor 2 (VEGFR2) at 30 min and longer post-stimulation time points. Together these data support the concept that activin suppressed VEGF-induced barrier relaxation by perturbing trafficking of activated VEGFR2. This activin-based suppression of responsiveness to VEGF was compromised in the endothelium of pathological blood vessels from patients who developed end-stage proliferative diabetic retinopathy (PDR). This defect rendered HRECs hyper-responsive to VEGF and was not observed in retinal vessels of diabetic mice, which do not develop the angiogenic forms of DR. These data provide novel insights regarding the pathogenesis of PDR in patients.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504503","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}
Lu Huang, Lydia Tai Wai, Kin-Sang Cho, Ajay Ashok, Maximilian Braun, Menglu Yang, Karen Chang, Anton Lennikov, Sarita Pooranawattanakul, Farris Elzaridi, Hio Tong Kam, Yizhen Tang, Qingfeng Li, Dong Feng Chen
{"title":"DNA Methylation Dynamics in a Mouse Model of Retinitis Pigmentosa.","authors":"Lu Huang, Lydia Tai Wai, Kin-Sang Cho, Ajay Ashok, Maximilian Braun, Menglu Yang, Karen Chang, Anton Lennikov, Sarita Pooranawattanakul, Farris Elzaridi, Hio Tong Kam, Yizhen Tang, Qingfeng Li, Dong Feng Chen","doi":"10.1016/j.ajpath.2025.05.021","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.05.021","url":null,"abstract":"<p><p>Retinitis pigmentosa (RP) is a group of sight-threatening genetic diseases characterized by progressive degeneration of photoreceptors, leading to severe vision loss from childhood to the adult. With limited treatment options, understanding the molecular mechanisms underlying RP is crucial. Evidence points to increased DNA methylation, especially in degenerating photoreceptors, as a contributing factor to retinal damage in RP. To exploit the molecular insights into methylation-driven pathways, this study investigates the DNA methylation patterns and their potential roles in photoreceptor degeneration in a mouse model of RP, specifically mice carrying a rhodopsin deficiency (Rho<sup>-/-</sup>). We observed elevated levels of DNA methyltransferases (DNMTs) and DNA methylation during photoreceptor degeneration. Importantly, weekly intravitreal injections of the pan DNMT inhibitor decitabine in Rho<sup>-/-</sup> mice significantly improved photoreceptor morphology and visual function, as evidenced by electroretinogram, spectral-domain optical coherence tomography, and optomotor response-based visual behavior assays. Further histological and immunohistochemical assessments revealed increased survival of cone photoreceptors and thicker outer nuclear layers in decitabine-treated mice compared to controls. Together, these findings reveal that the dynamics of DNA methylation correlate with photoreceptor degeneration. Inhibition of DNMTs mitigated the morphological and functional impairments associated with the genetic defects in photoreceptors, suggesting that targeting DNA methylation could be a viable therapeutic strategy for neuroprotection in RP.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504504","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}
Gaurav Sarode, Ming-Fo Hsu, Fawaz G Haj, Sergio Barace, Josepmaria Argemi, Mengfei Liu, Prisha Pandita, Sheng Cao, Vijay H Shah, Dorina Gui, Ramon Bataller, Vikrant Rachakonda
{"title":"Interleukin-6 Trans Signaling Regulates Neutrophilic Inflammation in Alcohol-Associated Hepatitis.","authors":"Gaurav Sarode, Ming-Fo Hsu, Fawaz G Haj, Sergio Barace, Josepmaria Argemi, Mengfei Liu, Prisha Pandita, Sheng Cao, Vijay H Shah, Dorina Gui, Ramon Bataller, Vikrant Rachakonda","doi":"10.1016/j.ajpath.2025.05.023","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.05.023","url":null,"abstract":"<p><p>Alcohol-associated hepatitis (AH) is a form of acute on chronic liver failure characterized by intrahepatic neutrophilic inflammation. In hepatocytes, IL-6 can signal through membrane-bound (classical signaling) or soluble (trans signaling) IL-6 receptors to regulate liver injury responses. The goal of this study was to determine the role of IL-6 trans signaling in the pathophysiology of AH. Liver RNA-Seq from alcohol-related liver disease patients demonstrated declining IL-6 receptor (IL-6R) expression with increasing AH severity, and TGF-β1 was the strongest negative regulator of IL-6R expression; however, STAT3-dependent gene expression increased in severe AH. In vitro, HepG2 cells were exposed to TGF-β1 to inhibit IL-6R expression, followed by STAT3 activation with 1) IL-6 to stimulate classical signaling or 2) hyper-IL-6, a recombinant IL-6/IL-6Rα peptide, to activate trans signaling. Only hyper-IL-6, but not IL-6, restored STAT3 activation in the face of suppressed IL-6R. RNA-Seq was performed on hyper-IL-6-stimulated cells, yielding a gene signature identifying a subset of AH patients with 1) enhanced IL-6TS activity 2) increased intrahepatic neutrophilic infiltration and 3) transcriptional enrichment of leukocyte migration pathways. Female mice treated with a 10-day chronic-plus binge ethanol model exhibited enhanced STAT3 activation despite reduced hepatic IL-6R expression, leading to increased expression of neutrophilic activators with colocalization of Ly6G+ leukocytes and STAT3-positive hepatocytes. IL-6 trans signaling preserves hepatocyte STAT3-dependent gene expression and neutrophilic inflammation in AH.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493448","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}
Ning Lu , Mei Zhang , Lu Lu , Yan-zhao Liu , Xiao-dong Liu , Hai-hong Zhang
{"title":"Retraction Notice to “Insulin-Induced Gene 2 Expression Is Associated with Breast Cancer Metastasis” [Am J Pathol 191 (2021) 385–395]","authors":"Ning Lu , Mei Zhang , Lu Lu , Yan-zhao Liu , Xiao-dong Liu , Hai-hong Zhang","doi":"10.1016/j.ajpath.2025.04.012","DOIUrl":"10.1016/j.ajpath.2025.04.012","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 7","pages":"Page 1358"},"PeriodicalIF":4.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144472428","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}
Houman Homayoun, Michael R DeChellis-Marks, Julia Kofler, Gabriella Fricklas, Amanda M Gleixner, Fang-Cheng Yeh, David Lacomis, Charleen T Chu, Christopher J Donnelly
{"title":"Novel Kinesin Family 1A Variants Linked to Atypical Parkinsonism Elicit Altered Neuronal TDP-43 Interactions and Dendritic Atrophy.","authors":"Houman Homayoun, Michael R DeChellis-Marks, Julia Kofler, Gabriella Fricklas, Amanda M Gleixner, Fang-Cheng Yeh, David Lacomis, Charleen T Chu, Christopher J Donnelly","doi":"10.1016/j.ajpath.2025.05.018","DOIUrl":"10.1016/j.ajpath.2025.05.018","url":null,"abstract":"<p><p>Analysis of iPSC-derived neurons from the son of a father-son pair with novel familial Variants of Uncertain Significance in KIF1A [c.408C>G (p.Asp136Glu); c.3914G>A (p.Arg1305His)] reveal pathological features of altered TDP-43 localization, interactions and stunted dendritic arbors. Both patients developed spasticity and parkinsonism in their mid-60s, with the father dying at age 71. There was impaired putamenal dopamine uptake with preserved uptake in the caudate nuclei, and decreased anisotropy by tractography in multiple motor pathways. Given shared transcriptional mechanisms of hindbrain and spinal cord developmental patterning among neurons of the motor circuitry, iPSC-derived motor neurons from fibroblasts donated by the son were created to investigate the impact of KIF1A mutations on TDP-43 subcellular localization, biochemical interactions of endogenous wildtype- and mutant-KIF1A and endogenous TDP-43, and the pathological impact of these KIF1A variants on dendritic arborization using Sholl analysis. Neuropathological assessment of the father, who shared the same KIF1A variants, revealed tauopathy and TDP-43 proteinopathy throughout the brainstem. Quantitative imaging of patient iPSC neurons identified TDP-43 mislocalization to the soma and dendritic atrophy. The KIF1A variant also elicited decreased biochemical interactions of both itself and TDP-43 with a spectrum of known TDP-43-associated proteins. These data suggest that this novel KIF1A mutant mediates altered TDP-43 interactions, stunting of the synaptic architecture, and clinical phenotypes coincident with neurodegenerative movement disorders.</p>","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":"144339819","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}
Anabela Djurovic-Topalovic, Natalie G Horgan, Jessica S Fortin
{"title":"Updates on tau-related drug targets and potential disease-modifying therapies for Alzheimer's disease.","authors":"Anabela Djurovic-Topalovic, Natalie G Horgan, Jessica S Fortin","doi":"10.1016/j.ajpath.2025.05.020","DOIUrl":"10.1016/j.ajpath.2025.05.020","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a chronic multifactorial neurodegenerative disease affecting a large proportion of the elderly population with detrimental psychological and socioeconomic impacts. This review starts with a brief overview of the molecular aspects of AD. It aims to provide recent updates on several potential protein targets studied as valid therapeutic approaches such as Bassoon protein, triggering receptor expressed on myeloid cells 2 (TREM2), phosphorylated tau (chimeric molecules DEPTAC and PhosTAC), O-GlcNAcase (OGA), and misfolded protein seeds. This review emphasizes the importance of pursuing a multifaceted approach to diversify and synergize the current AD pharmacotherapy.</p>","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":"144339820","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}
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":"<p><p>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 P<sub>0</sub>-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 POLA1 inhibitor clofarabine, DNTT inhibitor cordycepin, BCL6 inhibitor 79-6 and LPAR1/3 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.</p>","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}
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":"<p><p>Perilipin 2 expression is related to poor prognosis of patients with various malignant tumors. Perilipin 2 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. Herein, 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. In A549 and PC-9 lung adenocarcinoma cells with CRISPR/Cas9 genome editing-mediated knockout of perilipin2 expression, LD accumulation was significantly reduced. Treatment of these cells with extracellular oleic acid induced accumulation of LDs, but the total amount of accumulated LDs was low in perilipin 2 knockout cells compared with control cells. Cell proliferation and migration ability was also significantly reduced in perilipin 2 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.</p>","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}
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":"<p><p>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.</p>","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}