Pub Date : 2025-08-26DOI: 10.1016/j.ajpath.2025.07.013
Doug Terry, Brian S. Robinson
Alcohol-associated diver disease is a major driver of end-stage liver diseases globally. Alcohol functions as a hepatotoxin by overwhelming cell stress response pathways and deregulating hepatocellular protein, amino acid, and lipid metabolism. In addition, alcohol alters innate and adaptive inflammatory immune responses and acts on extrahepatic organs to flood the liver with pro-inflammatory stimuli. Here we examine how galectins, a class of highly conserved carbohydrate-binding proteins, regulate liver homeostasis and pathology. Next, we define how galectins affect key pathways that drive alcohol-induced liver disease, including hepatocyte cell biology (eg, altered lipid metabolism, endoplasmic reticulum and lysosomal stress, mitochondrial dysfunction), innate and immune response, intestinal dysfunction, and liver fibrosis. We then document the roles of galectins in the setting of alcohol-associated liver disease. Finally, we discuss galectins as theragnostic markers and therapeutic targets for alcohol-associated liver disease and address key open questions in the field.
{"title":"The Sugar-Coated Truth of Alcohol-Associated Liver Disease","authors":"Doug Terry, Brian S. Robinson","doi":"10.1016/j.ajpath.2025.07.013","DOIUrl":"10.1016/j.ajpath.2025.07.013","url":null,"abstract":"<div><div>Alcohol-associated diver disease is a major driver of end-stage liver diseases globally. Alcohol functions as a hepatotoxin by overwhelming cell stress response pathways and deregulating hepatocellular protein, amino acid, and lipid metabolism. In addition, alcohol alters innate and adaptive inflammatory immune responses and acts on extrahepatic organs to flood the liver with pro-inflammatory stimuli. Here we examine how galectins, a class of highly conserved carbohydrate-binding proteins, regulate liver homeostasis and pathology. Next, we define how galectins affect key pathways that drive alcohol-induced liver disease, including hepatocyte cell biology (eg, altered lipid metabolism, endoplasmic reticulum and lysosomal stress, mitochondrial dysfunction), innate and immune response, intestinal dysfunction, and liver fibrosis. We then document the roles of galectins in the setting of alcohol-associated liver disease. Finally, we discuss galectins as theragnostic markers and therapeutic targets for alcohol-associated liver disease and address key open questions in the field.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 161-171"},"PeriodicalIF":3.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939071","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}
Pub Date : 2025-08-26DOI: 10.1016/j.ajpath.2025.07.012
Thales M.H. Dourado , Carlos R. Tirapelli
Adipose tissue plays a crucial role in energy storage, but it also acts as an endocrine organ by secreting hormones and proinflammatory molecules. It regulates various processes, including adipogenesis, metabolism, and inflammation. White and brown adipose tissue (WAT and BAT) consists of white and brown adipocytes, respectively, which differ in cellular structure and function. Adipocytes also make up a significant part of perivascular adipose tissue (PVAT), which forms a sheath-like structure around blood vessels. Current research indicates that WAT, BAT, and PVAT are negatively affected by ethanol (ethyl alcohol). The changes induced by ethanol in the storage, metabolic, and secretory functions of PVAT and WAT are linked to vascular and hepatic dysfunction. In this context, while adipose tissue is a target of the harmful effects of ethanol, it also contributes to its pathophysiological consequences. Although the function of BAT is impacted by ethanol, BAT exhibits a protective role against ethanol-induced liver disease. This review highlights both past and recent efforts to identify the mechanisms through which ethanol consumption alters adipocyte function, with a focus on findings from studies that explain the detrimental effects of ethanol on WAT and BAT, and discusses the interplay between adipose tissue and the liver, particularly its implications for alcoholic liver disease. Additionally, new data that elucidate the mechanisms underlying ethanol-induced dysfunction in PVAT are summarized.
{"title":"The Role of Perivascular Adipose Tissue, White Adipose Tissue, and Brown Adipose Tissue in the Pathophysiological Effects of Ethanol","authors":"Thales M.H. Dourado , Carlos R. Tirapelli","doi":"10.1016/j.ajpath.2025.07.012","DOIUrl":"10.1016/j.ajpath.2025.07.012","url":null,"abstract":"<div><div>Adipose tissue plays a crucial role in energy storage, but it also acts as an endocrine organ by secreting hormones and proinflammatory molecules. It regulates various processes, including adipogenesis, metabolism, and inflammation. White and brown adipose tissue (WAT and BAT) consists of white and brown adipocytes, respectively, which differ in cellular structure and function. Adipocytes also make up a significant part of perivascular adipose tissue (PVAT), which forms a sheath-like structure around blood vessels. Current research indicates that WAT, BAT, and PVAT are negatively affected by ethanol (ethyl alcohol). The changes induced by ethanol in the storage, metabolic, and secretory functions of PVAT and WAT are linked to vascular and hepatic dysfunction. In this context, while adipose tissue is a target of the harmful effects of ethanol, it also contributes to its pathophysiological consequences. Although the function of BAT is impacted by ethanol, BAT exhibits a protective role against ethanol-induced liver disease. This review highlights both past and recent efforts to identify the mechanisms through which ethanol consumption alters adipocyte function, with a focus on findings from studies that explain the detrimental effects of ethanol on WAT and BAT, and discusses the interplay between adipose tissue and the liver, particularly its implications for alcoholic liver disease. Additionally, new data that elucidate the mechanisms underlying ethanol-induced dysfunction in PVAT are summarized.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 172-181"},"PeriodicalIF":3.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939057","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}
Pub Date : 2025-08-26DOI: 10.1016/j.ajpath.2025.07.011
Dariusz Pytel, Jody Fromm Longo
Proteinopathies are neurodegenerative disorders that are characterized by accumulation of misfolded toxic protein aggregates that lead to synaptic and neuronal dysfunction. Although genetically, clinically, and pathologically distinct, a common feature of these diseases is disruption of protein homeostasis (proteostasis), which causes accumulation of misfolded proteins. The machinery mediating proteostasis exquisitely balances and interlaces protein synthesis, protein folding and trafficking, and protein degradation processes within the proteostasis network to maintain homeostasis. The proteostasis network governs a functional and dynamic proteome by modulating the timing, location, and stoichiometry of protein expression, surveillance, and maintenance of protein folding and removal of misfolded or excess proteins. Although a functional proteome is essential for the health of all cell types, this is especially true for neurons, which are prone to enhanced cellular stress. Aging is the most important risk factor for proteostasis decline and the development of proteinopathies. However, germline and somatic mutations can also functionally impair components of the proteostasis network. Post-mitotic cells, particularly neurons, are rendered further susceptible to proteostasis dysfunction because of their extended lifespan. This review discusses the interconnections between the functional components mediating proteostasis in neuronal cells and how aberrations in proteostasis contribute to neuronal dysfunction and disease.
{"title":"The Proteostasis Network in Proteinopathies","authors":"Dariusz Pytel, Jody Fromm Longo","doi":"10.1016/j.ajpath.2025.07.011","DOIUrl":"10.1016/j.ajpath.2025.07.011","url":null,"abstract":"<div><div>Proteinopathies are neurodegenerative disorders that are characterized by accumulation of misfolded toxic protein aggregates that lead to synaptic and neuronal dysfunction. Although genetically, clinically, and pathologically distinct, a common feature of these diseases is disruption of protein homeostasis (proteostasis), which causes accumulation of misfolded proteins. The machinery mediating proteostasis exquisitely balances and interlaces protein synthesis, protein folding and trafficking, and protein degradation processes within the proteostasis network to maintain homeostasis. The proteostasis network governs a functional and dynamic proteome by modulating the timing, location, and stoichiometry of protein expression, surveillance, and maintenance of protein folding and removal of misfolded or excess proteins. Although a functional proteome is essential for the health of all cell types, this is especially true for neurons, which are prone to enhanced cellular stress. Aging is the most important risk factor for proteostasis decline and the development of proteinopathies. However, germline and somatic mutations can also functionally impair components of the proteostasis network. Post-mitotic cells, particularly neurons, are rendered further susceptible to proteostasis dysfunction because of their extended lifespan. This review discusses the interconnections between the functional components mediating proteostasis in neuronal cells and how aberrations in proteostasis contribute to neuronal dysfunction and disease.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 11","pages":"Pages 1998-2014"},"PeriodicalIF":3.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938985","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}
Pub Date : 2025-08-26DOI: 10.1016/j.ajpath.2025.07.010
Delia Y. Omar , Mathilda M. Willoughby , Nourhan Mostafa , Kelly Otakhor , Saumya Bhatt , Mohammad A. Abbas Zaidi , Micah B. Schott
Alcohol-associated liver disease poses a significant global health burden, with alcoholic steatohepatitis (ASH) representing a severe subtype driven by chronic alcohol consumption, hepatic inflammation, and limited treatment options. Central to ASH pathogenesis is the dysregulation of lipid droplet (LD) dynamics in hepatocytes. This review explores the critical role of LDs, focusing on alcohol-induced disruptions in LD biogenesis and catabolism. Chronic ethanol exposure enhances LD biogenesis from lipid import and de novo lipogenesis, while impairing LD catabolism by inhibiting lipolysis and lipophagy. Also, the review article examines alcohol's effect on remodeling the LD proteome and lipidome, including post-translational modifications. Additionally, LDs emerge as morphologic markers in hepatic stellate cells, where their loss drives fibrosis. Recent advances highlight potential therapeutic targets, such as restoring lipophagy or modulating LD biogenesis, offering hope for effective ASH treatments. This review underlines LDs as pivotal organelles in ASH progression and therapeutic innovation.
{"title":"Lipid Droplet Dynamics in Alcoholic Steatohepatitis","authors":"Delia Y. Omar , Mathilda M. Willoughby , Nourhan Mostafa , Kelly Otakhor , Saumya Bhatt , Mohammad A. Abbas Zaidi , Micah B. Schott","doi":"10.1016/j.ajpath.2025.07.010","DOIUrl":"10.1016/j.ajpath.2025.07.010","url":null,"abstract":"<div><div>Alcohol-associated liver disease poses a significant global health burden, with alcoholic steatohepatitis (ASH) representing a severe subtype driven by chronic alcohol consumption, hepatic inflammation, and limited treatment options. Central to ASH pathogenesis is the dysregulation of lipid droplet (LD) dynamics in hepatocytes. This review explores the critical role of LDs, focusing on alcohol-induced disruptions in LD biogenesis and catabolism. Chronic ethanol exposure enhances LD biogenesis from lipid import and <em>de novo</em> lipogenesis, while impairing LD catabolism by inhibiting lipolysis and lipophagy. Also, the review article examines alcohol's effect on remodeling the LD proteome and lipidome, including post-translational modifications. Additionally, LDs emerge as morphologic markers in hepatic stellate cells, where their loss drives fibrosis. Recent advances highlight potential therapeutic targets, such as restoring lipophagy or modulating LD biogenesis, offering hope for effective ASH treatments. This review underlines LDs as pivotal organelles in ASH progression and therapeutic innovation.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 20-34"},"PeriodicalIF":3.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939040","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}
Pub Date : 2025-08-22DOI: 10.1016/j.ajpath.2025.02.010
Yomna Badawi , Christi L. Kolarcik
{"title":"Navigating the Road to Progress in Neurodegeneration","authors":"Yomna Badawi , Christi L. Kolarcik","doi":"10.1016/j.ajpath.2025.02.010","DOIUrl":"10.1016/j.ajpath.2025.02.010","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 9","pages":"Pages 1572-1574"},"PeriodicalIF":3.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889132","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}
Pub Date : 2025-08-08DOI: 10.1016/j.ajpath.2025.08.001
{"title":"This Month in AJP","authors":"","doi":"10.1016/j.ajpath.2025.08.001","DOIUrl":"10.1016/j.ajpath.2025.08.001","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Page 1755"},"PeriodicalIF":3.6,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815578","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}
Pub Date : 2025-08-08DOI: 10.1016/j.ajpath.2025.07.007
Elaine L. Bearer
Cognitive impairment due to vascular pathology was recognized by Otto Binswanger in 1894, before Alois Alzheimer presented his findings in 1907. Vascular causes of cognitive impairment are likely due to a range of pathologies that are still, a hundred years later, unknown. Recent epidemiologic evidence from post-mortem human brains reports cases may be afflicted by Alzheimer's disease, vascular disease, or both. Although it is well known that hypertension and diabetes affect vasculature throughout the body as well as brain, other types of underlying causes that primarily affect cerebral vessels are understudied. Consensus guidelines exist for histopathologic diagnosis of Alzheimer's disease, but are limited for cerebrovascular diseases. Here, first, the anatomy of brain vasculature is reviewed. Next, a schema for categorization of vascular pathologies is proposed, followed by examples that illustrate these pathologies together with stains useful for their detection. Scoring pathologies across many cases according to this schema will subdivide vascular dementias into their underlying, potentially treatable, categories. The recent discovery of micro/nanoplastics in the brain and their association with vasculature will have a profound influence on how vascular-pathology–associated cognitive impairment is understood and diagnosed. Going forward, anatomic pathologists will need to apply this categorization to triage types of cerebrovascular pathology and begin to dissect its underlying causes, consequences, and potential treatments.
{"title":"Exploring Vascular Contributions to Cognitive Impairment with Focus on Small-Vessel Disease of White Matter and Micro/nanoplastics","authors":"Elaine L. Bearer","doi":"10.1016/j.ajpath.2025.07.007","DOIUrl":"10.1016/j.ajpath.2025.07.007","url":null,"abstract":"<div><div>Cognitive impairment due to vascular pathology was recognized by Otto Binswanger in 1894, before Alois Alzheimer presented his findings in 1907. Vascular causes of cognitive impairment are likely due to a range of pathologies that are still, a hundred years later, unknown. Recent epidemiologic evidence from post-mortem human brains reports cases may be afflicted by Alzheimer's disease, vascular disease, or both. Although it is well known that hypertension and diabetes affect vasculature throughout the body as well as brain, other types of underlying causes that primarily affect cerebral vessels are understudied. Consensus guidelines exist for histopathologic diagnosis of Alzheimer's disease, but are limited for cerebrovascular diseases. Here, first, the anatomy of brain vasculature is reviewed. Next, a schema for categorization of vascular pathologies is proposed, followed by examples that illustrate these pathologies together with stains useful for their detection. Scoring pathologies across many cases according to this schema will subdivide vascular dementias into their underlying, potentially treatable, categories. The recent discovery of micro/nanoplastics in the brain and their association with vasculature will have a profound influence on how vascular-pathology–associated cognitive impairment is understood and diagnosed. Going forward, anatomic pathologists will need to apply this categorization to triage types of cerebrovascular pathology and begin to dissect its underlying causes, consequences, and potential treatments.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 11","pages":"Pages 2059-2074"},"PeriodicalIF":3.6,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815576","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}
Pub Date : 2025-08-08DOI: 10.1016/j.ajpath.2025.07.008
Katharine J. Babcock , Bobak Abdolmohammadi , Ann C. McKee
Exposure to repeated head impacts (RHIs), such as those experienced in contact sports or military service, can lead to the development of chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy. CTE cannot be diagnosed during life, only by post-mortem neuropathologic examination. The pathognomonic lesion of CTE consists of a perivascular accumulation of hyperphosphorylated tau as neurofibrillary tangles and dotlike neurites, preferentially at the depths of cortical sulci. The biomechanics of RHI involve acceleration, deceleration, and rotational forces that distort brain tissue and strain fragile structures, such as blood vessels and axons, especially in the crevices of the brain, where these forces are localized. CTE is unique from other tauopathies in its molecular structure, pattern, and regional distribution of tau. Studies in American football, rugby, and ice hockey players demonstrate a dose-response relationship between years of exposure to sport and increased CTE risk and severity. The clinical symptoms associated with CTE are classified as traumatic encephalopathy syndrome. Exposure to RHI also increases the deposition of other pathologic proteins, including β-amyloid, α-synuclein, and transactive response DNA-binding protein (TDP-43), raising the risk for other neurodegenerations, such as Alzheimer disease, Lewy body disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis.
{"title":"Recent Advances in Chronic Traumatic Encephalopathy","authors":"Katharine J. Babcock , Bobak Abdolmohammadi , Ann C. McKee","doi":"10.1016/j.ajpath.2025.07.008","DOIUrl":"10.1016/j.ajpath.2025.07.008","url":null,"abstract":"<div><div>Exposure to repeated head impacts (RHIs), such as those experienced in contact sports or military service, can lead to the development of chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy. CTE cannot be diagnosed during life, only by post-mortem neuropathologic examination. The pathognomonic lesion of CTE consists of a perivascular accumulation of hyperphosphorylated tau as neurofibrillary tangles and dotlike neurites, preferentially at the depths of cortical sulci. The biomechanics of RHI involve acceleration, deceleration, and rotational forces that distort brain tissue and strain fragile structures, such as blood vessels and axons, especially in the crevices of the brain, where these forces are localized. CTE is unique from other tauopathies in its molecular structure, pattern, and regional distribution of tau. Studies in American football, rugby, and ice hockey players demonstrate a dose-response relationship between years of exposure to sport and increased CTE risk and severity. The clinical symptoms associated with CTE are classified as traumatic encephalopathy syndrome. Exposure to RHI also increases the deposition of other pathologic proteins, including β-amyloid, α-synuclein, and transactive response DNA-binding protein (TDP-43), raising the risk for other neurodegenerations, such as Alzheimer disease, Lewy body disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 11","pages":"Pages 2048-2058"},"PeriodicalIF":3.6,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815577","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}
Osteonecrosis of the femoral head (ONFH) is an orthopaedic disease with multifaceted pathogenesis. The role of long noncoding RNA (lncRNA) taurine-up-regulated gene 1 (TUG1) in ONFH remains unexplored. Thus, lncRNA expression profiles in subchondral bone from patients with ONFH and healthy controls were analyzed using microarray analysis, RT-qPCR, and bioinformatics. To evaluate the effect of TUG1 on osteogenic differentiation, TUG1 was overexpressed or knocked down in human bone marrow mesenchymal stem cells (hBMSCs), assessed via quantitative RT-PCR, Western blot analysis, and staining assays. In vivo, TUG1 was knocked down using adeno-associated viruses in a rat ONFH model. Micro–computed tomography, histology, enzyme-linked immunosorbent assay, quantitative RT-PCR, and immunohistochemistry were used to assess bone mass and osteogenic markers. TUG1 was significantly down-regulated in ONFH subchondral bone. Overexpression of TUG1 in hBMSCs up-regulated osteogenesis-related genes and proteins (runt-related transcription factor 2, osteopontin, osteocalcin, collagen type I alpha 1 chain, bone morphogenetic protein 2, and β-catenin), enhanced alkaline phosphatase activity, and increased mineralization. Conversely, TUG1 knockdown reduced these markers. In vivo, TUG1 knockdown disrupted bone microstructure and decreased osteogenic marker expression in the femoral head. This study revealed that TUG1 is down-regulated in ONFH subchondral bone, leading to osteogenic dysfunction through the Wnt/β-catenin pathway. It provided a better understanding of lncRNA's regulatory role in local osteonecrosis and offered new insights into ONFH pathogenesis. This study provides a reference for future research and treatment strategies.
{"title":"The Long Noncoding RNA TUG1 Is Down-Regulated in Osteonecrosis of the Femoral Head and Enhances the Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells by Stimulating the Wnt/β-Catenin Pathway","authors":"Xudong Duan, Jiewen Zhang, Yiwei Zhao, Guanzhi Liu, Zixuan Wu, Zidong Wu, Yutian Lei, Fangze Xing, Ruomu Cao, Heng Li, Ning Kong, Chengyan Liu, Yiyang Li, Run Tian, Kunzheng Wang, Pei Yang","doi":"10.1016/j.ajpath.2025.04.020","DOIUrl":"10.1016/j.ajpath.2025.04.020","url":null,"abstract":"<div><div>Osteonecrosis of the femoral head (ONFH) is an orthopaedic disease with multifaceted pathogenesis. The role of long noncoding RNA (lncRNA) taurine-up-regulated gene 1 (<em>TUG1</em>) in ONFH remains unexplored. Thus, lncRNA expression profiles in subchondral bone from patients with ONFH and healthy controls were analyzed using microarray analysis, RT-qPCR, and bioinformatics. To evaluate the effect of <em>TUG1</em> on osteogenic differentiation, <em>TUG1</em> was overexpressed or knocked down in human bone marrow mesenchymal stem cells (hBMSCs), assessed via quantitative RT-PCR, Western blot analysis, and staining assays. <em>In vivo</em>, <em>TUG1</em> was knocked down using adeno-associated viruses in a rat ONFH model. Micro–computed tomography, histology, enzyme-linked immunosorbent assay, quantitative RT-PCR, and immunohistochemistry were used to assess bone mass and osteogenic markers. <em>TUG1</em> was significantly down-regulated in ONFH subchondral bone. Overexpression of <em>TUG1</em> in hBMSCs up-regulated osteogenesis-related genes and proteins (runt-related transcription factor 2, osteopontin, osteocalcin, collagen type I alpha 1 chain, bone morphogenetic protein 2, and β-catenin), enhanced alkaline phosphatase activity, and increased mineralization. Conversely, <em>TUG1</em> knockdown reduced these markers. <em>In vivo</em>, <em>TUG1</em> knockdown disrupted bone microstructure and decreased osteogenic marker expression in the femoral head. This study revealed that <em>TUG1</em> is down-regulated in ONFH subchondral bone, leading to osteogenic dysfunction through the Wnt/β-catenin pathway. It provided a better understanding of lncRNA's regulatory role in local osteonecrosis and offered new insights into ONFH pathogenesis. This study provides a reference for future research and treatment strategies.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 8","pages":"Pages 1523-1536"},"PeriodicalIF":4.7,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144696732","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}
Pub Date : 2025-07-24DOI: 10.1016/j.ajpath.2025.06.013
Yuanyuan Xu , Chao Qin , Mengrou Zhang , Qi Wu , Zhun Li , Hui Mo , Chaochao Chen , Aijun Zhou , Jianming Li , Wen Ni
Despite advancements in diagnosis and therapy, chemotherapy resistance and metastasis remain significant challenges for colorectal cancer (CRC) patients. Addressing resistance to cell death is crucial for improving cancer treatment outcomes. NOP2/Sun RNA methyltransferase 5 (NSUN5) has been implicated in cancers, but its role in chemotherapy resistance in CRC remains unclear. This study revealed that NSUN5 was highly expressed in CRC through bioinformatics analysis and validation with local cohort. High expression of NSUN5 predicted poorer disease-free survival in CRC patients. Nsun5−/− mice exhibited reduced tumor incidence and malignancy in the AOM/DSS-induced CRC model. Knockdown or knockout of NSUN5 resulted in diminished proliferation and migration in CRC cell lines, effects that were reversed by NSUN5 overexpression or reintroduction. Intriguingly, overexpression of NSUN5 conferred resistance to doxorubicin, an effective chemotherapeutic agent that leads to DNA damage, whereas NSUN5 deficiency increased CRC cells' sensitivity to doxorubicin, both in vitro and in vivo. Mechanistically, NSUN5 up-regulated the expression of BRCA2 and the BRCA1-interacting helicase 1 (BRIP1), and interacted with these proteins to prevent cell death in response to DNA damage. Analysis of the local cohort and public data sets showed positive correlations between NSUN5, BRCA2, and BRIP1 in CRC. These findings demonstrate the role of NSUN5 in CRC from the perspective of chemotherapy resistance, potentially offering innovative insights into clinical therapy and prognosis of CRC.
{"title":"NSUN5 Mediates Resistance to Doxorubicin via Up-regulation of DNA Damage Repair Proteins BRCA2 and BRIP1 in Colorectal Cancer","authors":"Yuanyuan Xu , Chao Qin , Mengrou Zhang , Qi Wu , Zhun Li , Hui Mo , Chaochao Chen , Aijun Zhou , Jianming Li , Wen Ni","doi":"10.1016/j.ajpath.2025.06.013","DOIUrl":"10.1016/j.ajpath.2025.06.013","url":null,"abstract":"<div><div>Despite advancements in diagnosis and therapy, chemotherapy resistance and metastasis remain significant challenges for colorectal cancer (CRC) patients. Addressing resistance to cell death is crucial for improving cancer treatment outcomes. NOP2/Sun RNA methyltransferase 5 (NSUN5) has been implicated in cancers, but its role in chemotherapy resistance in CRC remains unclear. This study revealed that NSUN5 was highly expressed in CRC through bioinformatics analysis and validation with local cohort. High expression of NSUN5 predicted poorer disease-free survival in CRC patients. <em>Nsun5</em><sup>−/−</sup> mice exhibited reduced tumor incidence and malignancy in the AOM/DSS-induced CRC model. Knockdown or knockout of NSUN5 resulted in diminished proliferation and migration in CRC cell lines, effects that were reversed by NSUN5 overexpression or reintroduction. Intriguingly, overexpression of NSUN5 conferred resistance to doxorubicin, an effective chemotherapeutic agent that leads to DNA damage, whereas NSUN5 deficiency increased CRC cells' sensitivity to doxorubicin, both <em>in vitro</em> and <em>in vivo</em>. Mechanistically, NSUN5 up-regulated the expression of BRCA2 and the BRCA1-interacting helicase 1 (BRIP1), and interacted with these proteins to prevent cell death in response to DNA damage. Analysis of the local cohort and public data sets showed positive correlations between NSUN5, BRCA2, and BRIP1 in CRC. These findings demonstrate the role of NSUN5 in CRC from the perspective of chemotherapy resistance, potentially offering innovative insights into clinical therapy and prognosis of CRC.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1921-1935"},"PeriodicalIF":3.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717308","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号