American Journal of Pathology最新文献

{"title":"Sirtuin 7 Promotes Alcohol-Associated Liver Injury via Modulating Myeloid Cell Chemokine (C-C Motif) Ligand 2 Secretion through the NF-κB Signaling Pathway","authors":"Zhiqiang Wang ,&nbsp;Gaoshuang Liang ,&nbsp;Jinying Peng ,&nbsp;Yiying Gu ,&nbsp;Xiangwen Zhang ,&nbsp;Cong Ding ,&nbsp;Tingzi Yu ,&nbsp;Zhuan Li","doi":"10.1016/j.ajpath.2024.12.006","DOIUrl":"10.1016/j.ajpath.2024.12.006","url":null,"abstract":"<div><div>The pathogenesis of alcohol-associated liver disease (ALD) involves ethanol-induced enhancement of gut permeability, bacterial products released from intestine and intrahepatic inflammation, and liver damage. Hepatic macrophages play a crucial role in mediating inflammatory response by alcohol. Sirtuin 7 (SIRT7), a NAD⁺-dependent type III histone deacetylase, is being recognized as a therapeutic target in various human diseases. Emerging evidence shows that SIRT7 participates in immune regulation, but whether it is involved in ALD remains elusive. In the present study, myeloid cell–specific <em>Sirt7</em> knockout mice (<em>Lyz2-Sirt7</em>^−/−) were used to show that knockout <em>Sirt7</em> in myeloid cells significantly ameliorated alcohol-induced liver injury, inflammation, and cell infiltration, while only mildly affecting lipid metabolism pathways. Chemokine (C-C motif) ligand 2 (CCL2) was identified as the main target impaired by <em>Sirt7</em> knockout after alcohol. <em>In vitro</em> studies confirmed that <em>Sirt7</em> knockout impaired macrophages' ability of CCL2 secretion and monocyte recruiting, and exogenous CCL2 reversed this impairment. At the molecular level, knockout of <em>Sirt7</em> significantly impaired lipopolysaccharide-induced p65 phosphorylation and nuclear localization. More importantly, the SIRT7 inhibitor 40569 sufficiently decreased alcohol-induced liver injury and hepatic inflammation via preventing CCL2 <em>in vivo</em>. The current data thus uncovered a previously undescribed role of myeloid SIRT7 in mediating ALD via promoting CCL2 secretion through the NF-κB signaling pathway. Targeting SIRT7 might offer novel mechanism-based therapeutic options for ALD.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 575-588"},"PeriodicalIF":4.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine Learning–Based Pathomics Model Predicts Angiopoietin-2 Expression and Prognosis in Hepatocellular Carcinoma","authors":"Xinyi Huang ,&nbsp;Shuang Zheng ,&nbsp;Shuqi Li ,&nbsp;Yu Huang ,&nbsp;Wenhui Zhang ,&nbsp;Fang Liu ,&nbsp;Qinghua Cao","doi":"10.1016/j.ajpath.2024.12.005","DOIUrl":"10.1016/j.ajpath.2024.12.005","url":null,"abstract":"<div><div>Angiopoietin-2 (ANGPT2) shows promise as prognostic marker and therapeutic target in hepatocellular carcinoma (HCC). However, assessing ANGPT2 expression and prognostic potential using histopathology images viewed with naked eye is challenging. Herein, machine learning was employed to develop a pathomics model for analyzing histopathology images to predict ANGPT2 status. HCC cases obtained from The Cancer Genome Atlas (TCGA-HCC; <em>n</em> = 267) were randomly assigned to the training or testing set, and cases from a single center were employed as a validation set (<em>n</em> = 91). In the TCGA-HCC cohort, the group with high ANGPT2 expression had a significantly lower overall survival compared with the group with low ANGPT2. Histopathologic features in the training set were extracted, screened, and incorporated into a gradient-boosting machine model that generated a pathomics score, which successfully predicted ANGPT2 expression in the three data sets and showed remarkable risk stratification for overall survival in both the TCGA-HCC (<em>P</em> &lt; 0.0001) and single-center cohorts (<em>P</em> = 0.001). Multivariate analysis suggested that the pathomics score could serve as a predictor of prognosis (<em>P</em> &lt; 0.001). Bioinformatics analysis illustrated a distinction in tumor growth and development related gene–enriched pathways, vascular endothelial growth factor–related gene expression, and immune cell infiltration between high and low pathomics scores. This study indicates that the use of histopathology image features can enhance the prediction of molecular status and prognosis in HCC. The integration of image features with machine learning may improve prognosis prediction in HCC.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 561-574"},"PeriodicalIF":4.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferredoxin 2 Is Critical for Tumor Suppression and Lipid Homeostasis but Dispensable for Embryonic Development","authors":"Jin Zhang ,&nbsp;Yanhong Zhang ,&nbsp;Shakur Mohibi ,&nbsp;Vivian Perng ,&nbsp;Miranda Bustamante ,&nbsp;Yang Shi ,&nbsp;Kenichi Nakajima ,&nbsp;Mingyi Chen ,&nbsp;Xinbin Chen","doi":"10.1016/j.ajpath.2024.12.002","DOIUrl":"10.1016/j.ajpath.2024.12.002","url":null,"abstract":"<div><div>Ferredoxin 1 and 2 (FDX1/2) constitute an evolutionarily conserved FDX family of iron-sulfur cluster–containing proteins. FDX1/2 are cognate substrates of ferredoxin reductase and serve as conduits for electron transfer from NADPH to a set of proteins involved in biogenesis of corticosteroids, hemes, iron-sulfur cluster, and lipoylated proteins. Fdx1 is essential for embryonic development and lipid homeostasis. Herein, <em>Fdx2</em>-deficient mice were generated to explore the physiological role of FDX2. Interestingly, unlike <em>Fdx1</em>-null embryos, which were dead at embryonic day 10.5 to 13.5, <em>Fdx2</em>-null mice were viable. Both <em>Fdx2</em>-null and <em>Fdx2</em>-heterozygous mice had a short lifespan and were susceptible to spontaneous tumors and steatohepatitis. Moreover, FDX2 deficiency increased, whereas overexpression of FDX2 decreased cytoplasmic accumulation of lipid droplets. Consistently, FDX2 deficiency led to accumulation of cholesterol and triglycerides. Mechanistically, FDX2 deficiency suppressed expression of cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) and activated master lipid transcription regulators sterol regulatory element-binding proteins 1/2, thus leading to altered lipid metabolism. Untargeted lipidomic analysis showed that FDX2 deficiency led to altered biosynthesis of various lipid classes, including cardiolipins, cholesterol, ceramides, triglycerides, and fatty acids. In summary, these findings underline an indispensable role of FDX2 in tumor suppression and lipid homeostasis at both cellular and organismal levels without being a prerequisite for embryonic development.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 705-716"},"PeriodicalIF":4.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restorative Effects of Short-Chain Fatty Acids on Corneal Homeostasis Disrupted by Antibiotic-Induced Gut Dysbiosis","authors":"Sijing Liu ,&nbsp;Jiangman Liu ,&nbsp;Jiayan Xiang ,&nbsp;Ruyu Yan ,&nbsp;Senmao Li ,&nbsp;Qiwei Fan ,&nbsp;Liyuan Lu ,&nbsp;Jiaxin Wu ,&nbsp;Yunxia Xue ,&nbsp;Ting Fu ,&nbsp;Jun Liu ,&nbsp;Zhijie Li","doi":"10.1016/j.ajpath.2024.11.010","DOIUrl":"10.1016/j.ajpath.2024.11.010","url":null,"abstract":"<div><div>The gut microbiota plays a crucial regulatory role in various physiological processes, yet its impact on corneal homeostasis remains insufficiently understood. Here, the effects of antibiotic-induced gut dysbiosis (AIGD) and germ-free conditions were investigated on circadian gene expression, barrier integrity, nerve density, and immune cell activity in the corneas of mice. Both AIGD and germ-free conditions significantly disrupted the overall transcriptomic profile and circadian transcriptomic oscillations in the cornea, as indicated by RNA sequencing. These molecular disturbances were accompanied by a reduction in corneal epithelial thickness, nerve density, corneal sensitivity, and compromised barrier function. Notably, supplementation with short-chain fatty acids (SCFAs) significantly restored corneal integrity in AIGD mice. Further single-cell sequencing revealed that SCFA receptors G-protein–coupled receptor 109A (<em>Hcar2</em>), olfactory receptor 78 (<em>Olfr78</em>), and G-protein–coupled receptor 43 (<em>Ffar2</em>) are expressed in corneal epithelial basal cells, embryonically derived macrophages, perivascular cells, and γδ T cells, respectively. In conclusion, this study demonstrated that the gut microbiota plays a critical role in corneal physiology by regulating circadian gene expression and maintaining barrier function. These findings enhance our understanding of the gut-eye axis, highlighting the cornea as a target for microbiota-derived metabolic signals and underlining the potential therapeutic value of SCFAs in treating corneal dysfunction.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 770-796"},"PeriodicalIF":4.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891619","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":"Computational Pathology Detection of Hypoxia-Induced Morphologic Changes in Breast Cancer","authors":"Petru Manescu ,&nbsp;Joseph Geradts ,&nbsp;Delmiro Fernandez-Reyes","doi":"10.1016/j.ajpath.2024.10.023","DOIUrl":"10.1016/j.ajpath.2024.10.023","url":null,"abstract":"<div><div>Understanding the tumor hypoxic microenvironment is crucial for grasping tumor biology, clinical progression, and treatment responses. This study presents a novel application of artificial intelligence in computational histopathology to evaluate hypoxia in breast cancer. Weakly supervised deep learning models can accurately detect morphologic changes associated with hypoxia in routine hematoxylin and eosin (H&amp;E)–stained whole slide images (WSIs). The HypOxNet model was trained on H&amp;E-stained WSIs from breast cancer primary sites (<em>n</em> = 1016) at ×40 magnification using data from The Cancer Genome Atlas. Hypoxia Buffa signature was used to measure hypoxia scores, which ranged from −43 to 47, and stratified the samples into hypoxic and normoxic based on these scores. This stratification represented the weak labels associated with each WSI. HypOxNet achieved an average area under the curve of 0.82 on test sets, identifying significant differences in cell morphology between hypoxic and normoxic tissue regions. Importantly, once trained, the HypOxNet model required only the readily available H&amp;E-stained slides, making it especially valuable in low-resource settings where additional gene expression assays are not available. These artificial intelligence–based hypoxia detection models can potentially be extended to other tumor types and seamlessly integrated into pathology workflows, offering a fast, cost-effective alternative to molecular testing.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 663-670"},"PeriodicalIF":4.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tissue Inhibitor of Metalloproteinase 2 Promotes Wound Healing by Suppressing Matrix Metalloproteinases and Inflammatory Cytokines in Corneal Epithelial Cells","authors":"Olufemi S. Folorunso,&nbsp;Nishant R. Sinha,&nbsp;Aastha Singh,&nbsp;Lei Xi,&nbsp;Vinay K. Pulimamidi,&nbsp;WonKyung J. Cho,&nbsp;Sharad K. Mittal,&nbsp;Sunil K. Chauhan","doi":"10.1016/j.ajpath.2024.11.007","DOIUrl":"10.1016/j.ajpath.2024.11.007","url":null,"abstract":"<div><div>Tissue inhibitors of metalloproteinases (TIMPs) modulate extracellular matrix remodeling for maintaining homeostasis and promoting cell migration and proliferation. Pathologic conditions can alter TIMP homeostasis and aggravate disease progression. The roles of TIMPs have been studied in tissue-related disorders; however, their contributions to tissue repair during corneal injury are undefined. Here, the TIMP expression in human corneal epithelial cells under homeostatic and inflammatory milieus was profiled to examine their contribution to the healing of injured corneal epithelia. Transcriptionally, <em>TIMP</em><em>2</em> was highly expressed in human corneal epithelial cells when stimulated with 100 ng/mL IL1B or scratch wounded. Unlike TIMP1, recombinant TIMP2 (rTIMP2) significantly promoted epithelial cell wound closure compared with untreated and TIMP2-neutralizing conditions. At 12 hours, the Ki-67⁺ cells significantly increased threefold in number compared with untreated cells, suggesting that rTIMP2 is associated with cell proliferation. Furthermore, rTIMP2 treatment significantly suppressed inflammatory cytokine expression (<em>IL</em><em>1</em><em>B</em>, <em>IL</em><em>6</em>, <em>IL</em><em>8</em>, and <em>TNF</em><em>A</em>) and injury-induced matrix metalloproteinases (<em>MMP</em><em>1</em>, <em>MMP</em><em>2</em>, <em>MMP</em><em>3</em>, <em>MMP</em><em>9</em>, <em>MMP</em><em>10</em>, and <em>MMP</em><em>13</em>). Topical treatment of injured mouse cornea with 0.1 mg/mL rTIMP2 significantly promoted corneal re-epithelialization and improved tissue integrity. The treatment suppressed the expression of inflammatory cytokines and MMPs, as well as the infiltration of neutrophils at the injury site. These findings indicate that TIMP2 promotes faster wound healing by suppressing injury-induced inflammation and MMP expression, suggesting a potential therapeutic target for corneal wound management.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 754-769"},"PeriodicalIF":4.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891639","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":"Characterization and Role of Glucagon-Like Peptide 1 Receptor in the Lacrimal Gland","authors":"Yan Sun,&nbsp;Yue Zhang,&nbsp;Fan Shi,&nbsp;Ye Li,&nbsp;Congyao Wang,&nbsp;Fenfen Yu,&nbsp;Tingting Chen,&nbsp;Xia Dong,&nbsp;Yuqi Xu,&nbsp;Yu Zhao,&nbsp;Pengxia Wan","doi":"10.1016/j.ajpath.2024.12.003","DOIUrl":"10.1016/j.ajpath.2024.12.003","url":null,"abstract":"<div><div>This study aimed to investigate the expression of glucagon-like peptide 1 receptor (GLP-1R) in the lacrimal gland and explore the effects of topical application of GLP-1R agonist on lacrimal gland function in a murine model of type 1 diabetes. Tear secretion was evaluated using phenol red threads, RNA sequencing was used to explore gene expression profiles associated with hyperglycemia-induced lacrimal gland injuries, and histologic analysis was conducted to evaluate the degree of damage. The expression of GLP-1R in the lacrimal gland was first identified, and a down-regulation trend associated with diabetes was observed. RNA-sequencing data from lacrimal gland tissues revealed that differentially expressed genes were enriched in inflammatory response pathways. Histologic analysis demonstrated persistent hyperglycemia-induced infiltration of inflammatory cells and progressive fibrosis in the lacrimal gland, resulting in atrophy and diminished tear secretion. Topical application of liraglutide effectively attenuated inflammation and alleviated fibrosis, thus promoting tear production in diabetic mice. Additionally, local intervention with liraglutide promoted autophagy degradation function in the lacrimal gland. This study represents the first validation of GLP-1R expression in the lacrimal gland and its down-regulation induced by diabetes. Additionally, these findings demonstrate that topical administration of liraglutide eye drops, a GLP-1R agonist, can effectively mitigate hyperglycemia-induced damage in the lacrimal gland while enhancing tear secretion.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 797-810"},"PeriodicalIF":4.7,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891600","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":"Tmco1-Deficient Mice Exhibit a High Incidence of Otitis Media Associated with Impaired Bone Homeostasis in the Middle Ear","authors":"Yaning Dong ,&nbsp;Peng Ma ,&nbsp;Shuli Wang ,&nbsp;Lan Wang ,&nbsp;Yingying Chen ,&nbsp;Fangfang Zhao ,&nbsp;Keyan Yang ,&nbsp;Xiaolin Zhang ,&nbsp;Hongchun Zhao ,&nbsp;Bo Li ,&nbsp;Ruishuang Geng ,&nbsp;Tie-shan Tang ,&nbsp;Qingyin Zheng ,&nbsp;Tihua Zheng","doi":"10.1016/j.ajpath.2024.11.008","DOIUrl":"10.1016/j.ajpath.2024.11.008","url":null,"abstract":"<div><div>Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome (CFSMR1; Online Inheritance in Man number <span><span>213980</span><svg><path></path></svg></span>) is characterized by craniofacial dysmorphism, skeletal anomalies, and mental retardation. However, reports of hearing issues have been limited. To investigate hearing-related aspects of CFSMR1, <em>Tmco1</em> knockout mice (<em>Tmco1</em>^{<em>−/−</em>}) exhibiting similar symptoms to human patients were used in this study. Otitis media (OM) was discovered in approximately 80% of <em>Tmco1</em>^{<em>−/−</em>} mice, which led to moderate conductive hearing loss at 3 months old and further progressed to deafness 2 months later. Pathology studies of <em>Tmco1</em>^{<em>−/−</em>} mice revealed a thickened middle ear (ME) epithelium and pronounced inflammatory infiltrates in the ME cavity and Eustachian tube of <em>Tmco1</em>^{<em>−/−</em>} OM mice. Micro–computed tomography scan of 5-month–old <em>Tmco1</em>^{<em>−/−</em>} OM mice showed significantly reduced ME volume and ME malformation. Tartrate-resistant acid phosphatase and Runt-related transcription factor 2, receptor activator of NF-κB ligand expression in ME revealed increased osteoclast activity and significantly decreased bone formation, suggesting potential causes of ME malformation. This study represents the first report of the audiological characteristics and the elucidation of potential mechanisms in <em>Tmco1</em>^{<em>−/−</em>} mice. It enriches our understanding of the phenotypes associated with CFSMR1 in the field of otology and provides a promising model for chronic OM with conductive hearing loss.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 690-704"},"PeriodicalIF":4.7,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891640","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":"IL-35 May Prevent the Exacerbation of Aspiration Pneumonia Involving Porphyromonas gingivalis by Suppressing IL-17 Production","authors":"Shotaro Kawamura ,&nbsp;Hisashi Goto ,&nbsp;Takeshi Kikuchi ,&nbsp;Teppei Okabe ,&nbsp;Yoshiaki Hasegawa ,&nbsp;Yoshihiko Sugita ,&nbsp;Hirotaka Fujitsuka ,&nbsp;Ryosuke Kataoka ,&nbsp;Koudai Katsumata ,&nbsp;Ryoma Goto ,&nbsp;Yuiko Suzuki ,&nbsp;Jun-ichiro Hayashi ,&nbsp;Masayuki Umemura ,&nbsp;Akio Mitani","doi":"10.1016/j.ajpath.2024.11.009","DOIUrl":"10.1016/j.ajpath.2024.11.009","url":null,"abstract":"<div><div>Periodontitis is associated with aspiration pneumonia. However, the relationship between periodontitis and aspiration pneumonia remains unclear. This study investigated the virulence factor of <em>Porphyromonas gingivalis</em>, which exacerbates aspiration pneumonia, and the role of IL-35, an inhibitory heterodimeric cytokine of Epstein-Barr virus-induced gene 3 (EBI3) and p35, in aspiration pneumonia using <em>Ebi3</em> knockout (KO) mice. Aspiration pneumonia was induced by the intratracheal injection of <em>Streptococcus pneumoniae</em> and <em>P. gingivalis</em> culture supernatant (mixed infection). Leupeptin was used to inhibit gingipain, a virulence factor of <em>P. gingivalis</em>. Four days after infection, lung tissues were collected for analyses. The percentage of interstitium in the group with mixed infection and leupeptin treatment was significantly reduced compared with the nonleupeptin administration group. Additionally, the percentage of interstitium in the field of <em>Ebi3</em> KO mice was significantly increased compared with wild-type (WT) mice in mixed infection. IL-35 production in WT mice with mixed infection was significantly increased compared with the control group. IL-17 production in <em>Ebi3</em> KO mice was significantly increased compared with WT mice with mixed infection. These findings suggest that gingipain exacerbates aspiration pneumonia and that IL-35 may contribute to suppressing the exacerbation of aspiration pneumonia.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 652-662"},"PeriodicalIF":4.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P46Shc Inhibits Mitochondrial ACAA2 Thiolase, Exacerbating Mitochondrial Injury and Inflammation in Aging Livers","authors":"Yuan Li ,&nbsp;Weiguo Fan ,&nbsp;Tzu-Han Lo ,&nbsp;Joy X. Jiang ,&nbsp;Sarah R. Fish ,&nbsp;Alexey Tomilov ,&nbsp;Antonios Chronopoulos ,&nbsp;Vidushi Bansal ,&nbsp;Gergely Mozes ,&nbsp;Lorand Vancza ,&nbsp;Koshi Kunimoto ,&nbsp;Jiayu Ye ,&nbsp;Laren Becker ,&nbsp;Suvarthi Das ,&nbsp;Hyesuk Park ,&nbsp;Yi Wei ,&nbsp;Sara Ranjbarvaziri ,&nbsp;Daniel Bernstein ,&nbsp;Jon Ramsey ,&nbsp;Gino Cortopassi ,&nbsp;Natalie J. Török","doi":"10.1016/j.ajpath.2024.10.022","DOIUrl":"10.1016/j.ajpath.2024.10.022","url":null,"abstract":"<div><div>Mitochondrial maladaptation and dysfunction contribute to the progression of metabolic dysfunction-associated steatohepatitis (MASH). Induction of Shc is implicated in progressive MASH during aging and the cytoplasmic p52Shc isoform in the activation of redox enzyme NOX2. The mitochondrial Shc isoform p46Shc represses acetyl-coenzyme A acyltransferase 2 (ACAA2) <em>in vitro</em>. ACAA2 is a key enzyme for lipid β-oxidation; however, the metabolic consequences of <em>in vivo</em> p46Shc induction are unknown. In the current study, p46Shc-inducible mice were generated; these and littermate controls were aged and fed chow or fast-food (high-fat and high-fructose) diet. p46Shc induction increased liver injury, inflammation, and lipid peroxidation. p46Shc overexpression did not significantly change liver triglycerides. On electron microscopy studies, mitochondria were swollen with aberrant cristae. p46Shc induction reduced mitochondrial oxygen consumption as measured by Oroboros, as well as suppressed the production of β-hydroxybutyrate, the central metabolite of therapeutic ketosis. Mitochondria exhibited increased production of reactive oxidative species. By contrast, the expression of dominant negative p46Shc reduced ACAA2 thiolase activity, improved β-oxidation, and reduced lipid peroxidation and production of reactive oxidative species. In summary, these studies support the concept that p46Shc induction in aging represses ACAA2, resulting in decreased mitochondrial β-oxidation and increased lipid peroxidation. Maintaining β-oxidation and ketogenesis could prevent liver injury, and targeting Shc-related maladaptive responses could be a successful therapeutic strategy in aging/MASH.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 528-541"},"PeriodicalIF":4.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902597","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}