Pub Date : 2025-07-24DOI: 10.1016/j.ajpath.2025.07.006
Rui Ran , Chao-Yang Gong , Zuo-Long Wu , Shun-Bai Zhang , Kai Zhang , Wen-Ming Zhou , Wei Song , Hao Dong , Yong-Qiang Shi , Kai-Sheng Zhou , Hai-Hong Zhang
Dysregulation of nucleus pulposus cells (NPCs) is a critical contributor to intervertebral disc degeneration (IDD). One characteristic of degenerated discs is the increased apoptosis of NPCs and the substantial degradation of the extracellular matrix (ECM). This study identified significantly reduced miR-204-5p levels in IDD tissues. Using lipopolysaccharide (LPS)-treated rat NPCs, miR-204-5p overexpression was found to suppress apoptosis, reduce ECM degradation, and enhance ECM synthesis. Mechanistically, SKI was identified as a direct target of miR-204-5p, with its expression markedly elevated in IDD tissues. Functional assays revealed that modulating SKI expression (overexpression or knockdown) influenced LPS-induced apoptosis, ECM synthesis, and degradation in NPCs. Notably, SKI overexpression exacerbated LPS-induced damage and counteracted the protective effects of miR-204-5p. Importantly, intradiscal delivery of agomiR-204-5p effectively alleviated IDD progression in vivo. Overall, these results emphasize the pivotal role of miR-204-5p in mitigating IDD by targeting SKI, thereby regulating NPC apoptosis and ECM homeostasis. The miR-204-5p/SKI axis thus presents a promising therapeutic avenue for treating IDD.
{"title":"miR-204-5p Mitigates Disc Degeneration via SKI-Mediated Modulation of Apoptotic Signaling and Matrix Remodeling in Nucleus Pulposus","authors":"Rui Ran , Chao-Yang Gong , Zuo-Long Wu , Shun-Bai Zhang , Kai Zhang , Wen-Ming Zhou , Wei Song , Hao Dong , Yong-Qiang Shi , Kai-Sheng Zhou , Hai-Hong Zhang","doi":"10.1016/j.ajpath.2025.07.006","DOIUrl":"10.1016/j.ajpath.2025.07.006","url":null,"abstract":"<div><div>Dysregulation of nucleus pulposus cells (NPCs) is a critical contributor to intervertebral disc degeneration (IDD). One characteristic of degenerated discs is the increased apoptosis of NPCs and the substantial degradation of the extracellular matrix (ECM). This study identified significantly reduced miR-204-5p levels in IDD tissues. Using lipopolysaccharide (LPS)-treated rat NPCs, miR-204-5p overexpression was found to suppress apoptosis, reduce ECM degradation, and enhance ECM synthesis. Mechanistically, <em>SKI</em> was identified as a direct target of miR-204-5p, with its expression markedly elevated in IDD tissues. Functional assays revealed that modulating <em>SKI</em> expression (overexpression or knockdown) influenced LPS-induced apoptosis, ECM synthesis, and degradation in NPCs. Notably, <em>SKI</em> overexpression exacerbated LPS-induced damage and counteracted the protective effects of miR-204-5p. Importantly, intradiscal delivery of agomiR-204-5p effectively alleviated IDD progression <em>in vivo</em>. Overall, these results emphasize the pivotal role of miR-204-5p in mitigating IDD by targeting <em>SKI</em>, thereby regulating NPC apoptosis and ECM homeostasis. The miR-204-5p/<em>SKI</em> axis thus presents a promising therapeutic avenue for treating IDD.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1905-1920"},"PeriodicalIF":3.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717307","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.2025.07.005
Meiricris Tomaz da Silva , Anirban Roy , Ashok Kumar
Loss of skeletal muscle mass and strength is a debilitating consequence of various chronic diseases, inflammatory myopathies, and neuromuscular disorders. Inflammation plays a major role in the perpetuation of myopathy in degenerative muscle diseases. Transforming growth factor-β–activated kinase 1 (TAK1) is a major signaling protein that mediates the activation of multiple intracellular signaling pathways in response to inflammatory cytokines and microbial products. Recent studies have demonstrated that TAK1 is essential for the growth and maintenance of skeletal muscle mass in adult mice. However, the effects of overstimulation of TAK1 activity in the regulation of skeletal muscle mass remain unknown. The present study investigated the effects of varying levels of TAK1 activation on skeletal muscle in adult mice. Results showed that although low levels of TAK1 activation improve skeletal muscle mass, sustained hyperactivation of TAK1 causes myopathy in adult mice. Excessive stimulation of TAK1 manifested pathologic features, such as myofiber degeneration and regeneration, cellular infiltration, increased expression of proinflammatory molecules, and interstitial fibrosis. Hyperactivation of TAK1 also up-regulated proteolytic systems and various catabolic signaling pathways in skeletal muscle of adult mice. Altogether, this study demonstrated that physiological levels of activation of TAK1 lead to myofiber hypertrophy, whereas its hyperactivation results in myofiber damage and other pathologic features resembling inflammatory myopathies.
{"title":"Hyperactivation of Transforming Growth Factor-β–Activated Kinase 1 Causes Skeletal Muscle Pathology Reminiscent of Inflammatory Myopathies","authors":"Meiricris Tomaz da Silva , Anirban Roy , Ashok Kumar","doi":"10.1016/j.ajpath.2025.07.005","DOIUrl":"10.1016/j.ajpath.2025.07.005","url":null,"abstract":"<div><div>Loss of skeletal muscle mass and strength is a debilitating consequence of various chronic diseases, inflammatory myopathies, and neuromuscular disorders. Inflammation plays a major role in the perpetuation of myopathy in degenerative muscle diseases. Transforming growth factor-β–activated kinase 1 (TAK1) is a major signaling protein that mediates the activation of multiple intracellular signaling pathways in response to inflammatory cytokines and microbial products. Recent studies have demonstrated that TAK1 is essential for the growth and maintenance of skeletal muscle mass in adult mice. However, the effects of overstimulation of TAK1 activity in the regulation of skeletal muscle mass remain unknown. The present study investigated the effects of varying levels of TAK1 activation on skeletal muscle in adult mice. Results showed that although low levels of TAK1 activation improve skeletal muscle mass, sustained hyperactivation of TAK1 causes myopathy in adult mice. Excessive stimulation of TAK1 manifested pathologic features, such as myofiber degeneration and regeneration, cellular infiltration, increased expression of proinflammatory molecules, and interstitial fibrosis. Hyperactivation of TAK1 also up-regulated proteolytic systems and various catabolic signaling pathways in skeletal muscle of adult mice. Altogether, this study demonstrated that physiological levels of activation of TAK1 lead to myofiber hypertrophy, whereas its hyperactivation results in myofiber damage and other pathologic features resembling inflammatory myopathies.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1885-1904"},"PeriodicalIF":3.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717295","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.2025.07.003
Wei Liu , Yan-Ting Lin , Dong-Ge Han , Ai-Chao Shi , Qiang Liu , Zhen-Tang Jing
Tumor necrosis factor-α (TNF-α) is a highly pleiotropic cytokine with a variety of biological functions, such as cell proliferation, metabolic activation, inflammatory response, and cell death. TNF-α can induce a variety of mechanisms to initiate hepatocyte apoptosis, resulting in subsequent liver damage. Hepatitis B virus surface antigen (HBsAg) is the most abundant hepatitis B virus protein in the hepatocyte during chronic virus infection. However, its role in TNF-α–mediated apoptosis of hepatocytes has not been revealed. We report here that HBsAg promotes TNF-α–mediated hepatocyte apoptosis through inhibiting TNF-α–mediated anti-apoptotic complex I–dependent NF-κB activation and enhancing TNF-α–mediated pro-apoptotic complex II assembly. Mechanistically, HBsAg-mediated inhibition of complex I assembly was associated with down-regulation of K63-linked receptor-interacting protein kinase 1 (RIPK1) ubiquitination through repression of cellular inhibitor of apoptosis protein-1 (cIAP1) expression. Secretion-deficient HBsAg variant S204R enhances their pro-apoptotic abilities via further inhibition of RIPK1 ubiquitination. Expression of HBsAg in mice injected with recombinant adenovirus-associated virus 8 promoted D-galactosamine/lipopolysaccharide–induced TNF-α–mediated liver injury and damage by a mouse model. In conclusion, HBsAg may predispose hepatocytes to TNF-α–mediated apoptosis and mice to acute liver injury by switching TNF-α–mediated anti-apoptotic complex I to pro-apoptotic complex II, showing novel insights into the underlying mechanisms of hepatitis B virus–associated liver injury.
{"title":"Enhancement of Tumor Necrosis Factor-α–Mediated Hepatic Apoptosis and Liver Injury by Hepatitis B Virus Surface Antigen","authors":"Wei Liu , Yan-Ting Lin , Dong-Ge Han , Ai-Chao Shi , Qiang Liu , Zhen-Tang Jing","doi":"10.1016/j.ajpath.2025.07.003","DOIUrl":"10.1016/j.ajpath.2025.07.003","url":null,"abstract":"<div><div>Tumor necrosis factor-α (TNF-α) is a highly pleiotropic cytokine with a variety of biological functions, such as cell proliferation, metabolic activation, inflammatory response, and cell death. TNF-α can induce a variety of mechanisms to initiate hepatocyte apoptosis, resulting in subsequent liver damage. Hepatitis B virus surface antigen (HBsAg) is the most abundant hepatitis B virus protein in the hepatocyte during chronic virus infection. However, its role in TNF-α–mediated apoptosis of hepatocytes has not been revealed. We report here that HBsAg promotes TNF-α–mediated hepatocyte apoptosis through inhibiting TNF-α–mediated anti-apoptotic complex I–dependent NF-κB activation and enhancing TNF-α–mediated pro-apoptotic complex II assembly. Mechanistically, HBsAg-mediated inhibition of complex I assembly was associated with down-regulation of K63-linked receptor-interacting protein kinase 1 (RIPK1) ubiquitination through repression of cellular inhibitor of apoptosis protein-1 (cIAP1) expression. Secretion-deficient HBsAg variant S204R enhances their pro-apoptotic abilities via further inhibition of RIPK1 ubiquitination. Expression of HBsAg in mice injected with recombinant adenovirus-associated virus 8 promoted D-galactosamine/lipopolysaccharide–induced TNF-α–mediated liver injury and damage by a mouse model. In conclusion, HBsAg may predispose hepatocytes to TNF-α–mediated apoptosis and mice to acute liver injury by switching TNF-α–mediated anti-apoptotic complex I to pro-apoptotic complex II, showing novel insights into the underlying mechanisms of hepatitis B virus–associated liver injury.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1854-1868"},"PeriodicalIF":3.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717294","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.2025.07.004
Andrea Molina-Alvarez , Blanca Sanchez-Gonzalez , Luis Colomo , José Yélamos
B-cell lymphomas represent a heterogeneous group of malignancies characterized by complex genetic, epigenetic, and microenvironmental alterations. Defects in the DNA damage response (DDR) are critical drivers of lymphomagenesis, generating therapeutic vulnerabilities that can be exploited by targeting key DDR regulators, such as poly (ADP-ribose) polymerase-1 (PARP-1) and PARP-2. Preclinical studies demonstrate that DDR-defective B-cell lymphomas are highly sensitive to PARP-1/PARP-2 inhibition, and early-phase clinical trials using nonselective PARP inhibitors, either as monotherapy or in combination with chemotherapy, immunotherapy, or epigenetic agents, have yielded encouraging results. However, emerging evidence reveals that PARP-1 and PARP-2 play distinct roles in B-cell lymphoma pathogenesis: loss of PARP-1 accelerates lymphomagenesis, whereas loss of PARP-2 delays tumor progression. These findings challenge the current paradigm of pan-PARP inhibition and highlight the need for isoform-selective strategies. Although PARP-1–selective inhibitors have entered clinical trials for homologous recombination–deficient tumors, the development of PARP-2–selective inhibitors remains at an early stage. Future research should prioritize the design of PARP-2–targeted therapies, coupled with biomarker-driven patient selection and rational combination strategies that enhance DNA damage and modulate the tumor immune microenvironment. Selectively targeting PARP-2 offers a promising approach to improving outcomes for patients with aggressive, refractory, or relapsed B-cell lymphomas and represents a critical step forward in advancing precision oncology within hematologic malignancies.
{"title":"Poly (ADP-Ribose) Polymerase 1 and 2 in B-Cell Lymphoma","authors":"Andrea Molina-Alvarez , Blanca Sanchez-Gonzalez , Luis Colomo , José Yélamos","doi":"10.1016/j.ajpath.2025.07.004","DOIUrl":"10.1016/j.ajpath.2025.07.004","url":null,"abstract":"<div><div>B-cell lymphomas represent a heterogeneous group of malignancies characterized by complex genetic, epigenetic, and microenvironmental alterations. Defects in the DNA damage response (DDR) are critical drivers of lymphomagenesis, generating therapeutic vulnerabilities that can be exploited by targeting key DDR regulators, such as poly (ADP-ribose) polymerase-1 (PARP-1) and PARP-2. Preclinical studies demonstrate that DDR-defective B-cell lymphomas are highly sensitive to PARP-1/PARP-2 inhibition, and early-phase clinical trials using nonselective PARP inhibitors, either as monotherapy or in combination with chemotherapy, immunotherapy, or epigenetic agents, have yielded encouraging results. However, emerging evidence reveals that PARP-1 and PARP-2 play distinct roles in B-cell lymphoma pathogenesis: loss of PARP-1 accelerates lymphomagenesis, whereas loss of PARP-2 delays tumor progression. These findings challenge the current paradigm of pan-PARP inhibition and highlight the need for isoform-selective strategies. Although PARP-1–selective inhibitors have entered clinical trials for homologous recombination–deficient tumors, the development of PARP-2–selective inhibitors remains at an early stage. Future research should prioritize the design of PARP-2–targeted therapies, coupled with biomarker-driven patient selection and rational combination strategies that enhance DNA damage and modulate the tumor immune microenvironment. Selectively targeting PARP-2 offers a promising approach to improving outcomes for patients with aggressive, refractory, or relapsed B-cell lymphomas and represents a critical step forward in advancing precision oncology within hematologic malignancies.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1776-1787"},"PeriodicalIF":3.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717309","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 : 2025-07-23DOI: 10.1016/j.ajpath.2025.07.002
Fred Sanfilippo
Receiving guidance and help from mentors is an essential component of career development and planning, especially in academic medicine and biomedical research, where the availability of resources and job opportunities are becoming more challenging. Mentors share their wisdom, experience, content expertise, and networks with mentees to provide ideas and feedback, identify and open opportunities, deal with problems and avoid mistakes, and especially to assist in evaluating the many personal and professional factors involved in decision making about career paths and job options. Identifying, engaging, and utilizing mentors appropriately is a key part of career development, and effective mentorship can come from several sources, including personal interactions, passive role models, and artificial intelligence. Providing mentorship is an important responsibility that includes various risks and benefits that should be clearly understood before the role of mentor is undertaken. Moreover, mentors should carefully assess whom to accept as a mentee by considering the time, skills, and interest needed to meet their own expectations along with those of their prospective mentees. With increasing awareness of the value of mentorship, more academic health centers, medical schools, and departments provide programs to help their students, trainees, faculty, and staff better access, understand, and take advantage of mentorship opportunities, as well as offer programs to enhance the skills and abilities of those interested in being effective mentors.
{"title":"The Importance of Mentorship in Career Development","authors":"Fred Sanfilippo","doi":"10.1016/j.ajpath.2025.07.002","DOIUrl":"10.1016/j.ajpath.2025.07.002","url":null,"abstract":"<div><div>Receiving guidance and help from mentors is an essential component of career development and planning, especially in academic medicine and biomedical research, where the availability of resources and job opportunities are becoming more challenging. Mentors share their wisdom, experience, content expertise, and networks with mentees to provide ideas and feedback, identify and open opportunities, deal with problems and avoid mistakes, and especially to assist in evaluating the many personal and professional factors involved in decision making about career paths and job options. Identifying, engaging, and utilizing mentors appropriately is a key part of career development, and effective mentorship can come from several sources, including personal interactions, passive role models, and artificial intelligence. Providing mentorship is an important responsibility that includes various risks and benefits that should be clearly understood before the role of mentor is undertaken. Moreover, mentors should carefully assess whom to accept as a mentee by considering the time, skills, and interest needed to meet their own expectations along with those of their prospective mentees. With increasing awareness of the value of mentorship, more academic health centers, medical schools, and departments provide programs to help their students, trainees, faculty, and staff better access, understand, and take advantage of mentorship opportunities, as well as offer programs to enhance the skills and abilities of those interested in being effective mentors.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1758-1765"},"PeriodicalIF":3.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717311","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 : 2025-07-23DOI: 10.1016/j.ajpath.2025.06.012
Na Li , Shuai Wu , Xiaodan Li , Meng Yan , Yifu Ding , Lingjuan Zhang , David A. Brenner , Xiao Liu , Tatiana Kisseleva
Metabolic dysfunction–associated steatohepatitis (MASH), an advanced stage of metabolic dysfunction–associated steatotic liver disease, is characterized by significant hepatic fibrosis and inflammation. The pan-peroxisome proliferator–activated receptor (pan-PPAR) agonist IVA337 (lanifibranor) has shown potential as an anti-MASH therapeutic, although its mechanisms of action remain incompletely understood. This study explores the effects and mechanisms of IVA337 using two distinct MASH models: two-dimensional (2D) primary human hepatic stellate cells (HSCs) stimulated with transforming growth factor β1 (TGF-β1), and three-dimensional (3D) liver spheroids comprising primary hepatocytes, HSCs, and non-parenchymal cells. In TGF-β1–stimulated HSCs, IVA337 effectively suppressed the expression of fibrosis-related genes, including PAI1, COL1A1, and ACAT2, as well as the inflammatory gene IL6. 3D mouse and human liver spheroid models of MASH, characterized by elevated fibrotic gene expression, were established. IVA337 treatment not only attenuated fibrotic gene expression but also restored lipid content in the MASH spheroids, as evidenced by BODIPY staining. Immunostaining further confirmed a reduction in α-smooth muscle actin and collagen 1 levels after IVA337 treatment. Bulk RNA sequencing and Gene Ontology analysis revealed several lipid metabolism–related genes as key effectors downstream of IVA337. In addition, IVA337 modulated multiple signaling pathways, including IL-17, tumor necrosis factor, NF-κB, phosphatidylinositol 3 kinase/protein kinase B, and mitogen-activated protein kinase. Collectively, these findings show that IVA337 effectively mitigates fibrosis development in both 2D and 3D MASH models by restoring lipid homeostasis and regulating crucial fibrotic and inflammatory pathways.
{"title":"Peroxisome Proliferator–Activated Receptor Agonist IVA337 Alleviates Inflammation and Fibrosis in MASH by Restoring Lipid Homeostasis","authors":"Na Li , Shuai Wu , Xiaodan Li , Meng Yan , Yifu Ding , Lingjuan Zhang , David A. Brenner , Xiao Liu , Tatiana Kisseleva","doi":"10.1016/j.ajpath.2025.06.012","DOIUrl":"10.1016/j.ajpath.2025.06.012","url":null,"abstract":"<div><div>Metabolic dysfunction–associated steatohepatitis (MASH), an advanced stage of metabolic dysfunction–associated steatotic liver disease, is characterized by significant hepatic fibrosis and inflammation. The pan-peroxisome proliferator–activated receptor (pan-PPAR) agonist IVA337 (lanifibranor) has shown potential as an anti-MASH therapeutic, although its mechanisms of action remain incompletely understood. This study explores the effects and mechanisms of IVA337 using two distinct MASH models: two-dimensional (2D) primary human hepatic stellate cells (HSCs) stimulated with transforming growth factor β1 (TGF-β1), and three-dimensional (3D) liver spheroids comprising primary hepatocytes, HSCs, and non-parenchymal cells. In TGF-β1–stimulated HSCs, IVA337 effectively suppressed the expression of fibrosis-related genes, including <em>PAI1, COL1A1,</em> and <em>ACAT2</em>, as well as the inflammatory gene <em>IL</em><em>6</em>. 3D mouse and human liver spheroid models of MASH, characterized by elevated fibrotic gene expression, were established. IVA337 treatment not only attenuated fibrotic gene expression but also restored lipid content in the MASH spheroids, as evidenced by BODIPY staining. Immunostaining further confirmed a reduction in α-smooth muscle actin and collagen 1 levels after IVA337 treatment. Bulk RNA sequencing and Gene Ontology analysis revealed several lipid metabolism–related genes as key effectors downstream of IVA337. In addition, IVA337 modulated multiple signaling pathways, including IL-17, tumor necrosis factor, NF-κB, phosphatidylinositol 3 kinase/protein kinase B, and mitogen-activated protein kinase. Collectively, these findings show that IVA337 effectively mitigates fibrosis development in both 2D and 3D MASH models by restoring lipid homeostasis and regulating crucial fibrotic and inflammatory pathways.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1822-1838"},"PeriodicalIF":3.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717310","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 : 2025-07-18DOI: 10.1016/j.ajpath.2025.06.007
Liang Shao , Ji Zhang , Fan Hu , Wen Chai , Yuxuan Zhou , Pengtao Zou , Ping Zhang
Parkinson disease (PD) is a commonly diagnosed neurodegenerative disease with rising prevalence globally. However, the pathology of PD remains largely undefined. The aim of this study was to gain a better understanding of microglial mitophagy in PD. A 1-methyl-1,2,3,6-tetrahydropyidine (MPTP)-induced PD mouse model was established and validated by behavior tests. Western blot and immunofluorescence (IF) analyses showed that autophagy was enhanced in MPTP-induced PD mice. IF, quantitative real-time PCR, Western blot, and co-immunoprecipitation analyses also revealed that silencing of heat shock protein 90α (Hsp90α) protected against mitophagy in PD mice. In the microglia/dopaminergic neuron co-culture system, enzyme-linked immunosorbent assay, transmission electron microscopy, JC-1 staining, measurement of ATP content, Annexin V/propidium iodide and fluorescein isothiocyanate staining showed that lack of Hsp90α in MPTP-treated microglia attenuated dopaminergic neuronal death via suppressing mitophagy. IF staining and co-immunoprecipitation confirmed that Hsp90α formed a complex with activator of Hsp90 ATPase activity 1 (AHSA1), and this complex targeted the mitochondrial molecular switch TOMM70 in microglia. The Hsp90α inhibitor geldanamycin and AHSA1 knockdown further revealed that the AHSA1/Hsp90α complex regulated microglial mitophagy by targeting TOMM70 in MPTP-treated microglia and PD mice. In conclusion, the AHSA1/Hsp90α complex facilitated microglial mitophagy by targeting TOMM70 in PD.
{"title":"AHSA1/Hsp90α Complex Facilitates Microglial Mitophagy by Targeting TOMM70 in Parkinson Disease","authors":"Liang Shao , Ji Zhang , Fan Hu , Wen Chai , Yuxuan Zhou , Pengtao Zou , Ping Zhang","doi":"10.1016/j.ajpath.2025.06.007","DOIUrl":"10.1016/j.ajpath.2025.06.007","url":null,"abstract":"<div><div>Parkinson disease (PD) is a commonly diagnosed neurodegenerative disease with rising prevalence globally. However, the pathology of PD remains largely undefined. The aim of this study was to gain a better understanding of microglial mitophagy in PD. A 1-methyl-1,2,3,6-tetrahydropyidine (MPTP)-induced PD mouse model was established and validated by behavior tests. Western blot and immunofluorescence (IF) analyses showed that autophagy was enhanced in MPTP-induced PD mice. IF, quantitative real-time PCR, Western blot, and co-immunoprecipitation analyses also revealed that silencing of heat shock protein 90α (Hsp90α) protected against mitophagy in PD mice. In the microglia/dopaminergic neuron co-culture system, enzyme-linked immunosorbent assay, transmission electron microscopy, JC-1 staining, measurement of ATP content, Annexin V/propidium iodide and fluorescein isothiocyanate staining showed that lack of Hsp90α in MPTP-treated microglia attenuated dopaminergic neuronal death via suppressing mitophagy. IF staining and co-immunoprecipitation confirmed that Hsp90α formed a complex with activator of Hsp90 ATPase activity 1 (AHSA1), and this complex targeted the mitochondrial molecular switch TOMM70 in microglia. The Hsp90α inhibitor geldanamycin and AHSA1 knockdown further revealed that the AHSA1/Hsp90α complex regulated microglial mitophagy by targeting TOMM70 in MPTP-treated microglia and PD mice. In conclusion, the AHSA1/Hsp90α complex facilitated microglial mitophagy by targeting TOMM70 in PD.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 11","pages":"Pages 2197-2212"},"PeriodicalIF":3.6,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673712","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 : 2025-07-17DOI: 10.1016/j.ajpath.2025.06.008
Joseph M. Schrader , Feng Xu , Xiaoyue Zhu , Mark Majchrzak , Judianne Davis , William E. Van Nostrand
Cerebral amyloid angiopathy (CAA) is a common age-related disorder, a prominent comorbidity of Alzheimer disease (AD), and causes vascular cognitive impairment and dementia. A previously developed novel transgenic rat model (rTg-D) expresses the human familial CAA Dutch E22Q mutant amyloid β-protein in brain with hemizygous (HEM) animals developing arteriolar CAA type-2 pathology. In this study, homozygous (HOM) rTg-D rats developed more extensive CAA type-2, characterized by abundant fibrillar amyloid accumulation, including parenchymal congophilic plaques and dyshoric vascular amyloid. Similar to the vascular amyloid, fibrillar amyloid plaques in rTg-D HOM rats were predominantly composed of amyloid β40. The rTg-D HOM rats exhibited pronounced astrocytic and microglial responses as well as phosphorylated tau accumulating in surrounding dystrophic neurites and early tangle-like structures. Cerebral proteomic analyses revealed that while rTg-D HEM rats and rTg-D HOM rats shared some common differentially expressed proteins compared with wild-type rats, rTg-D HOM rats exhibited many more elevated proteins. Because the parenchymal fibrillar plaques of rTg-D HOM rats resemble those seen in AD, the cerebral proteomes were compared between rTg-D HOM rats and a transgenic rat model of AD. This analysis showed that they shared many differentially expressed proteins and activated pathways, including activation of transforming growth factor-β1 signaling and swarming of neutrophils. In conclusion, the present findings show that rTg-D HOM rats develop more severe CAA type-2 pathology than rTg-D HEM rats coupled with AD-like pathologic features, making them a valuable model for studying the intersection of vascular amyloidosis and neurodegeneration.
{"title":"Parenchymal and Dyshoric Fibrillar Amyloid Pathology in the rTg-D Rat Model of Cerebral Amyloid Angiopathy Type-2","authors":"Joseph M. Schrader , Feng Xu , Xiaoyue Zhu , Mark Majchrzak , Judianne Davis , William E. Van Nostrand","doi":"10.1016/j.ajpath.2025.06.008","DOIUrl":"10.1016/j.ajpath.2025.06.008","url":null,"abstract":"<div><div>Cerebral amyloid angiopathy (CAA) is a common age-related disorder, a prominent comorbidity of Alzheimer disease (AD), and causes vascular cognitive impairment and dementia. A previously developed novel transgenic rat model (rTg-D) expresses the human familial CAA Dutch E22Q mutant amyloid β-protein in brain with hemizygous (HEM) animals developing arteriolar CAA type-2 pathology. In this study, homozygous (HOM) rTg-D rats developed more extensive CAA type-2, characterized by abundant fibrillar amyloid accumulation, including parenchymal congophilic plaques and dyshoric vascular amyloid. Similar to the vascular amyloid, fibrillar amyloid plaques in rTg-D HOM rats were predominantly composed of amyloid β40. The rTg-D HOM rats exhibited pronounced astrocytic and microglial responses as well as phosphorylated tau accumulating in surrounding dystrophic neurites and early tangle-like structures. Cerebral proteomic analyses revealed that while rTg-D HEM rats and rTg-D HOM rats shared some common differentially expressed proteins compared with wild-type rats, rTg-D HOM rats exhibited many more elevated proteins. Because the parenchymal fibrillar plaques of rTg-D HOM rats resemble those seen in AD, the cerebral proteomes were compared between rTg-D HOM rats and a transgenic rat model of AD. This analysis showed that they shared many differentially expressed proteins and activated pathways, including activation of transforming growth factor-β1 signaling and swarming of neutrophils. In conclusion, the present findings show that rTg-D HOM rats develop more severe CAA type-2 pathology than rTg-D HEM rats coupled with AD-like pathologic features, making them a valuable model for studying the intersection of vascular amyloidosis and neurodegeneration.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 11","pages":"Pages 2213-2232"},"PeriodicalIF":3.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666866","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 : 2025-07-17DOI: 10.1016/j.ajpath.2025.06.009
Mengmeng Zhang , Jingjing Ji , Jiayi Song , Chenchen An , Wangxiang Pei , Qianwen Fan , Li Zuo , Hua Wang
Alcohol-associated liver disease (ALD) is a progressive liver disorder induced by chronic excessive alcohol consumption, affecting approximately 3.5% of the global population. The clinical spectrum of ALD encompasses simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and the potential development of hepatocellular carcinoma. The pathogenesis of ALD involves a complex interplay of factors, including direct cell damage caused by alcohol and its metabolites, hepatic inflammation, immune dysregulation, and oxidative stress. Additionally, alcohol-induced dysbiosis and the subsequent imbalance of gut homeostasis further exacerbate the progression of ALD. While nutritional support and abstinence from alcohol remain the cornerstones of ALD management, growing evidence supports the therapeutic potential of targeting key pathologic processes such as inflammation, cellular oxidative stress, lipid metabolism, and strategies that promote liver regeneration and inhibit fibrosis. Emerging treatment approaches aimed at modulating the gut–liver–brain axis and targeting innate immune cells offer promising new avenues for ALD therapy. For patients with end-stage ALD, liver transplantation remains the only viable treatment option. This review summarizes the current epidemiology, pathogenesis, pathophysiology, natural history, and recent advancements in the therapeutic management of ALD, with the goal of providing further insight into the treatment of ALD and improve patient outcomes.
{"title":"Current Therapeutic Targets for Alcohol-Associated Liver Disease","authors":"Mengmeng Zhang , Jingjing Ji , Jiayi Song , Chenchen An , Wangxiang Pei , Qianwen Fan , Li Zuo , Hua Wang","doi":"10.1016/j.ajpath.2025.06.009","DOIUrl":"10.1016/j.ajpath.2025.06.009","url":null,"abstract":"<div><div>Alcohol-associated liver disease (ALD) is a progressive liver disorder induced by chronic excessive alcohol consumption, affecting approximately 3.5% of the global population. The clinical spectrum of ALD encompasses simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and the potential development of hepatocellular carcinoma. The pathogenesis of ALD involves a complex interplay of factors, including direct cell damage caused by alcohol and its metabolites, hepatic inflammation, immune dysregulation, and oxidative stress. Additionally, alcohol-induced dysbiosis and the subsequent imbalance of gut homeostasis further exacerbate the progression of ALD. While nutritional support and abstinence from alcohol remain the cornerstones of ALD management, growing evidence supports the therapeutic potential of targeting key pathologic processes such as inflammation, cellular oxidative stress, lipid metabolism, and strategies that promote liver regeneration and inhibit fibrosis. Emerging treatment approaches aimed at modulating the gut–liver–brain axis and targeting innate immune cells offer promising new avenues for ALD therapy. For patients with end-stage ALD, liver transplantation remains the only viable treatment option. This review summarizes the current epidemiology, pathogenesis, pathophysiology, natural history, and recent advancements in the therapeutic management of ALD, with the goal of providing further insight into the treatment of ALD and improve patient outcomes.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 121-135"},"PeriodicalIF":3.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666865","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 : 2025-07-17DOI: 10.1016/j.ajpath.2025.05.025
Keishla M. Rodríguez-Graciani, Paticia E. Molina, Liz Simon
At-risk alcohol use has significant adverse effects on multiple tissue and organ systems, including the skeletal muscle. The pathophysiological mechanisms underlying alcohol-induced dysfunctional skeletal muscle (SKM) mass are multifactorial, involving decreased protein synthesis, increased protein degradation, impaired glucose homeostasis, bioenergetic dysregulation, aberrant extracellular matrix remodeling, impaired satellite cell function, circadian rhythm disruption, and epigenomic adaptations. This review provides a brief overview of these major alcohol-induced mechanisms of SKM dysfunction. Additionally, the review examines the current literature on alcohol-mediated SKM maladaptations in the context of comorbidities such as aging, alcohol-related liver disease, systemic and diet-induced metabolic dysregulation, cancer cachexia, and musculoskeletal pain. Although alcohol-induced skeletal muscle alterations may function as both the cause and consequence of these comorbid conditions, critical research gaps remain, particularly in the need for systematic clinical studies complemented by preclinical mechanistic research. Notably, 40% to 60% of people with at-risk alcohol use exhibit skeletal muscle maladaptations, yet data on associated healthcare or productivity loss costs are lacking. A comprehensive understanding of alcohol-induced SKM dysfunction is warranted for developing targeted interventions to reduce healthcare costs and improve quality of life in this population.
{"title":"Alcohol-Mediated Skeletal Muscle Adaptations and Their Impact on Comorbidities","authors":"Keishla M. Rodríguez-Graciani, Paticia E. Molina, Liz Simon","doi":"10.1016/j.ajpath.2025.05.025","DOIUrl":"10.1016/j.ajpath.2025.05.025","url":null,"abstract":"<div><div>At-risk alcohol use has significant adverse effects on multiple tissue and organ systems, including the skeletal muscle. The pathophysiological mechanisms underlying alcohol-induced dysfunctional skeletal muscle (SKM) mass are multifactorial, involving decreased protein synthesis, increased protein degradation, impaired glucose homeostasis, bioenergetic dysregulation, aberrant extracellular matrix remodeling, impaired satellite cell function, circadian rhythm disruption, and epigenomic adaptations. This review provides a brief overview of these major alcohol-induced mechanisms of SKM dysfunction. Additionally, the review examines the current literature on alcohol-mediated SKM maladaptations in the context of comorbidities such as aging, alcohol-related liver disease, systemic and diet-induced metabolic dysregulation, cancer cachexia, and musculoskeletal pain. Although alcohol-induced skeletal muscle alterations may function as both the cause and consequence of these comorbid conditions, critical research gaps remain, particularly in the need for systematic clinical studies complemented by preclinical mechanistic research. Notably, 40% to 60% of people with at-risk alcohol use exhibit skeletal muscle maladaptations, yet data on associated healthcare or productivity loss costs are lacking. A comprehensive understanding of alcohol-induced SKM dysfunction is warranted for developing targeted interventions to reduce healthcare costs and improve quality of life in this population.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 92-103"},"PeriodicalIF":3.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666863","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}
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