Akira Sato, Hina Nemoto, Ayano Yabuki, Genta Sato, Yuta Ogawa, Makoto Ohira
{"title":"The role of ketone bodies in oxidized LDL-induced cell proliferation and lipid accumulation of macrophages","authors":"Akira Sato, Hina Nemoto, Ayano Yabuki, Genta Sato, Yuta Ogawa, Makoto Ohira","doi":"10.1111/iep.70002","DOIUrl":"https://doi.org/10.1111/iep.70002","url":null,"abstract":"<p>Ketone bodies (KBs), which include β-hydroxybutyric acid (β-HB) and acetoacetic acid (AcAc), play critical roles in organismal energy homeostasis; however, their effects on atherosclerosis remain unknown. In this study, we investigated the role of β-HB and AcAc on proliferation and lipid accumulation in macrophages by the uptake of oxidized LDL (Ox-LDL), causing the formation of atherosclerotic plaques, using mouse macrophage J774A.1 cells. Both β-HB and AcAc reduced cell proliferation, and AcAc increased lipid accumulation in Ox-LDL-treated J774A.1 cells. Western blotting showed that Ox-LDL decreased the protein expression of two KB-specific receptors, GPR41 and GPR43, both of which are known as potent modulators of inflammation, but had negligible effects on that of the β-HB-specific GPR109A in the cells. These results suggest that Ox-LDL may induce inflammatory responses by decreasing the protein expression of GPR41 and GPR43 in macrophages, and that AcAc, but not β-HB, may exacerbate Ox-LDL-caused atherosclerosis.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"106 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paula Andrea Saenz Suarez, Marcos Maciel Junior, Samara Camaçari de Carvalho, Humberto Santo Neto, Elaine Minatel, Maria Julia Marques
{"title":"Exercise combined with corticoid/omega-3 therapy positively affected skeletal and cardiac muscles in middle aged mdx mice","authors":"Paula Andrea Saenz Suarez, Marcos Maciel Junior, Samara Camaçari de Carvalho, Humberto Santo Neto, Elaine Minatel, Maria Julia Marques","doi":"10.1111/iep.70000","DOIUrl":"https://doi.org/10.1111/iep.70000","url":null,"abstract":"<p>Exercise has an important impact on skeletal muscle quality, emerging as an adjuvant therapy to ameliorate muscle inflammation and fibrosis in Duchenne muscular dystrophy (DMD). The aim of the present study was to investigate the benefit of exercise alone or in association with corticoid and omega-3 therapy in the middle aged mdx mouse model of DMD, Mdx mice (12 months of age) performed treadmill exercise (12.4 m/min, for 15 min, twice a week) for 4 weeks. Exercised mdx received deflazacort (1.2 mg/kg; gavage) alone or combined with omega-3 (300 mg/kg; gavage). Sedentary mdx, C57BL/10 and exercised mdx received mineral oil and served as control. At the endpoint (14 months of age), muscle function, respiratory function, electrocardiography (ECG), blood markers of myonecrosis (creatine kinase, CK; alanine aminotransferase, ALT; and aspartate aminotransferase, AST), muscle biomarkers of inflammation and fibrosis (western blot), area of fibrosis and histopathology of tibialis anterior, biceps brachii and diaphragm muscles were evaluated. Exercise and exercise-associated therapies improved behavioural activity (open field), muscle function (grip strength, four limb hanging test, hanging wire test and rotarod), VO<sub>2</sub> consumption, VCO<sub>2</sub> production and ECG. Functional benefits correlated with reduced myonecrosis (decreased CK, ALT, AST) and fibrosis. The muscles studied showed a reduction in inflammation biomarkers (NF-κB, IL-6 and TNF-α) and fibrosis (TGF-β and fibronectin) and an increase in calsequestrin (calcium buffering protein) and PGC1-α (muscle integrity marker). In conclusion, exercise alone or associated with corticosteroid/omega-3 therapy benefited limb, diaphragm and cardiac dystrophic muscles in middle-aged mdx mice.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"106 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143892968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ask Møbjerg, Sara Dietz Pedersen, Michael Kjaer, Ching-Yan Chloé Yeung
{"title":"Role of the tendon circadian clock in tendinopathy and implications for therapeutics","authors":"Ask Møbjerg, Sara Dietz Pedersen, Michael Kjaer, Ching-Yan Chloé Yeung","doi":"10.1111/iep.70001","DOIUrl":"https://doi.org/10.1111/iep.70001","url":null,"abstract":"<p>Tendinopathy or tendon overuse injury is a major clinical problem for individuals and has a significant socio-economic cost. Its pathophysiology is not yet fully understood and involves multiple factors, including mechanical, cellular and molecular factors. The circadian rhythm has been shown to be a major regulator of extracellular matrix (ECM) homeostasis in several connective tissues, including tendon. Very recently, the human patellar tendon has been established as a peripheral clock tissue that exhibits dampening with chronic tendinopathy, and this has important translational and clinical relevance. This review summarises what is currently known about the role of the tendon circadian clock in collagen and tendon ECM homeostasis and proposes a role for circadian clock disruption in tendinopathy. A better understanding of the mechanisms that regulate tendon clock synchronisation could guide the development of new therapeutic strategies for managing tendon overuse injuries.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"106 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/iep.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143892969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Extracellular matrix: Dystroglycan interactions—Roles for the dystrophin-associated glycoprotein complex in skeletal tissue dynamics","authors":"Mark Hopkinson, Andrew A. Pitsillides","doi":"10.1111/iep.12525","DOIUrl":"https://doi.org/10.1111/iep.12525","url":null,"abstract":"<p>Contributions made by the dystrophin-associated glycoprotein complex (DGC) to cell–cell and cell-extracellular matrix (ECM) interactions are vital in development, homeostasis and pathobiology. This review explores how DGC functions may extend to skeletal pathophysiology by appraising the known roles of its major ECM ligands, and likely associated DGC signalling pathways, in regulating cartilage and bone cell behaviour and emergent skeletal phenotypes. These considerations will be contextualised by highlighting the potential of studies into the role of the DGC in isolated chondrocytes, osteoblasts and osteoclasts, and by fuller deliberation of skeletal phenotypes that may emerge in very young mice lacking vital, yet diverse core elements of the DGC. Our review points to roles for individual DGC components—including the glycosylation of dystroglycan itself—beyond the establishment of membrane stability which clearly accounts for severe muscle phenotypes in muscular dystrophy. It implies that the short stature, low bone mineral density, poor bone health and greater fracture risk in these patients, which has been attributed due to primary deficiencies in muscle-evoked skeletal loading, may instead arise due to primary roles for the DGC in controlling skeletal tissue (re)modelling.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"106 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/iep.12525","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"KLF9 aggravates the cardiomyocyte hypertrophy in hypertrophic obstructive cardiomyopathy through the lncRNA UCA1/p27 axis","authors":"Dayou Ding, Guangrong Zhao","doi":"10.1111/iep.12526","DOIUrl":"https://doi.org/10.1111/iep.12526","url":null,"abstract":"<p>Cardiac hypertrophy refers to an abnormal increase in the thickness of the heart muscle. Our study explores the role of Krüppel-like factor 9 (KLF9) in hypertrophic obstructive cardiomyopathy (HOCM)-induced cardiomyocyte hypertrophy, providing new targets for the treatment of HOCM. Cardiomyocytes were treated with isoproterenol (ISO). The levels of natriuretic peptide B (BNP)/natriuretic peptide A (ANP)/KLF9/long non-coding RNA urothelial carcinoma-associated 1 (lncRNA UCA1)/p27 were measured. Cell surface area and protein/DNA ratio were tested. The binding between KLF9 and the lncRNA UCA1 promoter and between zeste homologue 2 (EZH2) and lncRNA UCA1 was verified. The enrichment of histone H3 lysine 27 tri-methylation (H3K27me3) and EZH2 on the p27 promoter was analysed. ISO treatment increased KLF9 and lncRNA UCA1 expression and decreased p27 expression in cardiomyocytes. KLF9 knockdown inhibited ISO-induced cardiomyocyte hypertrophy, reduced ANP and BNP expression, and alleviated cardiomyocyte damage. KLF9 activated lncRNA UCA1 expression. LncRNA UCA1 recruited EZH2 to the p27 promoter region, increasing the enrichment of H3K27me3, thereby epigenetically suppressing p27 expression. LncRNA UCA1 overexpression or p27 downregulation reduced the protective effect of KLF9 downregulation on cardiomyocyte hypertrophy. In conclusion, KLF9 activates lncRNA UCA1 expression, and lncRNA UCA1 epigenetically suppresses p27 expression, thereby exacerbating cardiomyocyte hypertrophy in HOCM.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"106 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ling Zhang, Jingtao Song, Xin Xu, Donghong Sun, Huiting Huang, Yang Chen, Tao Zhang
{"title":"Silencing long non-coding RNA linc00689 suppresses the growth and invasion of osteosarcoma cells by targeting miR-129-5p/NUSAP1","authors":"Ling Zhang, Jingtao Song, Xin Xu, Donghong Sun, Huiting Huang, Yang Chen, Tao Zhang","doi":"10.1111/iep.12524","DOIUrl":"10.1111/iep.12524","url":null,"abstract":"<p>Long non-coding RNAs (lncRNAs) have been reported to play a critical role in the progression and metastasis of osteosarcoma. Recently, long intergenic non-protein coding RNA 689 (linc00689) has been shown to be involved in glioma. However, the precise role of linc00689 in osteosarcoma is unknown. In this study, our data demonstrated that silencing linc00689 by siRNA markedly suppressed the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of MG63 and SAOS-2 cells. Bioinformatics analysis and dual-luciferase reporter assay revealed that linc00689 could bind to miR-129-5p. Moreover, NUSAP1 was a target of miR-129-5p and positively regulated by linc00689. Further, NUSAP1 overexpression enhanced MG63 cell behaviour and abolished the inhibitory effects of linc00689 knockdown on the proliferation, migration, invasion and EMT of MG63 cells. In conclusion, linc00689 exerts an oncogenic role in the progression of osteosarcoma, which works via the miR-129-5p/NUSAP1 axis.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"106 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Review of methodology and re-analysis of lipidomic data focusing on specialised pro-resolution lipid mediators (SPMs) in a human model of resolving inflammation","authors":"Natalie Z. M. Homer, Ruth Andrew, Derek W. Gilroy","doi":"10.1111/iep.12523","DOIUrl":"10.1111/iep.12523","url":null,"abstract":"<p>Using a model of UV-killed <i>E. coli</i> driven dermal inflammation in healthy human volunteers, we originally reported that following inflammatory resolution there was infiltration of macrophages, which, through prostanoids including prostaglandin (PG) E<sub>2</sub>, imprints long-term tissue immunity. In addition to the prostanoids, data on levels of Specialised Pro-Resolution Lipid Mediators (SPMs) throughout inflammatory onset, resolution and post-resolution phases of this model were presented, but as illustrations rather than as primary data. Therefore, in response to a request for increased transparency, a subset of the original data from our human UV-killed <i>E. coli</i> model was re-analysed by two experts from an independent laboratory alongside a review of the methodology used. The prostanoids were detected robustly following re-analysis but the areas of the chromatographic peaks of the SPM lipid mediators were too small to yield amounts that could be reliably detected and/or quantified using community standards. Importantly, with prostanoids including PGE<sub>2</sub> being robustly detected, this re-analysis does not alter the original report that post-resolution PGs imprint tissue immunity. Here we show the outcome of this re-analysis and review the biology surrounding SPMs as a result.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"106 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Junxiao Ren, Rui Li, Chen Meng, Yongqing Xu, Chuan Li
{"title":"Identification of BCL3 as a biomarker for chondrocyte programmed cell death in osteoarthritis","authors":"Junxiao Ren, Rui Li, Chen Meng, Yongqing Xu, Chuan Li","doi":"10.1111/iep.12522","DOIUrl":"10.1111/iep.12522","url":null,"abstract":"<p>Osteoarthritis (OA) is a condition that is widely prevalent and causes joint pain and disability, with programmed cell death (PCD) playing a role in its pathogenesis. This study aimed to identify biomarkers associated with PCD in OA and explore their potential roles. Three RNA-sequencing datasets (GSE114007, GSE51588 and GSE220243) related to OA were analysed. Differential expression and weighted gene co-expression network identified key differentially expressed PCD-related genes (DE-PRMGs). Potential biomarkers were identified and validated through receiver operating characteristic (ROC) curves, correlation analyses, gene set enrichment analysis, single-cell expression and RT-qPCR. A total of 45 DE-PRMGs were identified, affecting pathways like TNF signalling and RNA degradation. BCL3, TREM2 and NRP2 were prioritized as potential OA biomarkers, which are associated with ribosome function and immune cell infiltration and potentially linked to PCD. The functional role of one of the molecules identified, BCL3, was explored further using a cell model of inflammation induced chondrocytes. BCL3 was significantly down regulated in OA samples from the public dataset and clinical samples analysed by RT-qPCR. BCL3 overexpression reduced apoptosis in chondrocytes stimulated with inflammatory cytokines. Thus the functional studies highlighted the anti-apoptotic role of BCL3 in chondrocytes and provide new insights into OA pathogenesis with potential for future therapeutic development.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"106 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marcela Arteaga-Silva, Rosa María Vigueras-Villaseñor, Gustavo Guillen-Herrera, Daniel Adrian Landero-Huerta, Itzel Jatziri Contreras-García, Sergio Montes, Camilo Ríos, Ofelia Limón-Morales, Julio César Rojas-Castañeda
{"title":"Perinatal exposure to lead alters male reproductive behaviour and immunoreactivity of androgen and oestrogen receptors in the brain","authors":"Marcela Arteaga-Silva, Rosa María Vigueras-Villaseñor, Gustavo Guillen-Herrera, Daniel Adrian Landero-Huerta, Itzel Jatziri Contreras-García, Sergio Montes, Camilo Ríos, Ofelia Limón-Morales, Julio César Rojas-Castañeda","doi":"10.1111/iep.12521","DOIUrl":"10.1111/iep.12521","url":null,"abstract":"<p>Lead (Pb) exposure during perinatal development alters testosterone (T) concentrations and delays puberty in children and laboratory rodents. In addition, exposure to the metal during adult life decreases T and libido in men and affects male reproductive behaviour (MRB) in rats. MRB is regulated by various brain nuclei including the medial preoptic area (MPOa) and the medial amygdala (MeA), in which T and oestradiol (E<sub>2</sub>) act through their respective androgen (AR) and oestrogen (ER) receptors. However, the mechanism by which MRB is affected by Pb exposure is not known. The objectives of the present study were to evaluate whether perinatal Pb exposure affects MRB and the number of cells immunoreactive to AR and ERα in the MPOa and the MeA. Male Wistar rats exposed to Pb (320 ppm) in drinking water from the beginning of pregnancy until weaning were used. The experimental group experienced significant alterations in MRB, an important decrease in T and E<sub>2</sub> concentrations, and a significant increase in Pb concentrations in the blood, MPOa (hypothalamus) and MeA. In addition, in the studied areas the number of cells immunoreactive to AR and ERα, or detected using the Nissl technique, decreased significantly. These results show that perinatal exposure to Pb alters MRB. This event may be related to a decrease in both the concentrations of sex hormones and the number of cells that express their receptors as well as in the neuronal Nissl staining population. This ultimately affects the quality of life of the individual.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"106 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Janiele Staianov, Jeiciele Mayara Rodrigues Struz, Rafaela Viana Vieira, Rafael Messias Luiz, Ana Carla Zarpelon-Schutz, Kádima Nayara Teixeira, Juliana Bernardi-Wenzel
{"title":"Histomorphometric analysis of excisional cutaneous wounds with different diameters in an animal model","authors":"Janiele Staianov, Jeiciele Mayara Rodrigues Struz, Rafaela Viana Vieira, Rafael Messias Luiz, Ana Carla Zarpelon-Schutz, Kádima Nayara Teixeira, Juliana Bernardi-Wenzel","doi":"10.1111/iep.12520","DOIUrl":"10.1111/iep.12520","url":null,"abstract":"<p>The skin wound model in rats is a fundamental stage in preclinical trials, but there is a lack of standardization in these trials regarding the initial wound area, making analysis and comparison between studies difficult. Therefore, this study evaluates the healing progression of excisional skin lesions of varying diameters in Wistar rats, aiming to identify the optimal wound size for monitoring treatment effects on wound healing. Excisions of 0.8, 1.5, 2.0 and 3.0 cm in diameter were made on the back of the animals. Thirty animals were used per treatment and evaluated on days 3, 7, 10, 14 and 21 after surgery. The lesions were cleaned daily with saline solution until they were completely closed. The 0.8 cm group showed complete repair on D14, while in the other groups, the wounds persisted until day 21, with a reddened surface and no complete epidermal coverage, but with greater keratinization and presence of appendages in the 1.5 cm lesions. Therefore, as a standardization model for creating skin wounds, we suggest using 1.5 or 2.0 cm excisions, considering that 0.8 cm wounds close very early and 3.0 cm wounds, although behaving similarly to 2.0 cm wounds, are more invasive for the animals. The 1.5 cm model proved to be suitable for closure within 21 days. When evaluating a product intended to accelerate wound healing, 2.0 cm lesions are recommended to assess the effectiveness of the treatment.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"105 6","pages":"235-245"},"PeriodicalIF":1.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}