Biomedicines最新文献

{"title":"Metabolic, Microvascular, and Structural Predictors of Long-Term Functional Changes Evaluated by Multifocal Electroretinogram in Type 1 Diabetes.","authors":"Mariacristina Parravano, Serena Fragiotta, Eliana Costanzo, Fabiana Picconi, Paola Giorno, Daniele De Geronimo, Daniela Giannini, Monica Varano, Vincenzo Parisi, Lucia Ziccardi","doi":"10.3390/biomedicines12112614","DOIUrl":"10.3390/biomedicines12112614","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to analyze the potential pathogenic connection between metabolic factors, photoreceptor cell rearrangements, retinal microvascular perfusion, and functional parameters through multifocal electroretinography (mfERG) in type 1 diabetes mellitus (DM1).</p><p><strong>Methods: </strong>This prospective observational cohort study enrolled DM1 patients (40.5 ± 9.1 years) with mild nonproliferative diabetic retinopathy followed for 4 years. Patients were subjected to multimodal imaging, which included color fundus photography, optical coherence tomography (OCT), OCT angiography, adaptive optics (AO), and mfERG. OCTA slabs were analyzed using ImageJ software (software version 2.3.0/1.53f) to calculate perfusion density (PD) at both superficial (SCP) and deep (DCP) capillary plexuses, as well as flow deficit percentage (FD%) at the choriocapillaris (CC). To calculate cone metrics on AO at the parafovea, including cone density (CD), linear dispersion index (LDi), and heterogeneity packing index (Hpi%) in the parafovea, the images were post-processed using a MATLAB algorithm. The mfERG P1 implicit time (IT) and N1-P1 response amplitude density (RAD) from R1 (foveal area), R2 (parafoveal area), and the unified rings R1 + R2 were evaluated.</p><p><strong>Results: </strong>A total of 22 patients (22 eyes) were enrolled. No significant differences were noted in central mfERG amplitude and implicit time-averaged values (<i>p</i> > 0.05, all). The main factor influencing R1 IT was HbA1c, while R1 RAD was affected by Hpi and CC FD%. R1 + R2 IT was influenced by Hpi, LDi (<i>p</i> > 0.001, all), and modifications in the perfusion density in the SCP (<i>p</i> < 0.001) and DCP (<i>p</i> = 0.03) at the parafovea. In contrast, R1 + R2 RAD were associated with HbA1c (<i>p</i> = 0.02) and Hpi (<i>p</i> < 0.001).</p><p><strong>Conclusions: </strong>Microvascular changes and glucometabolic factors are key elements influencing the long-term morphofunctional alterations at the photoreceptor level in DM1.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"12 11","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11592090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipocyte-Mediated Electrophysiological Remodeling of PKP-2 Mutant Human Pluripotent Stem Cell-Derived Cardiomyocytes.","authors":"Justin Morrissette-McAlmon, Christianne J Chua, Alexander Arking, Stanley Chun Ming Wu, Roald Teuben, Elaine Zhelan Chen, Leslie Tung, Kenneth R Boheler","doi":"10.3390/biomedicines12112601","DOIUrl":"10.3390/biomedicines12112601","url":null,"abstract":"<p><strong>Background: </strong>Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder responsible for nearly a quarter of sports-related sudden cardiac deaths. ACM cases caused by mutations in desmosome proteins lead to right ventricular enlargement, the loss of cardiomyocytes, and fibrofatty tissue replacement, disrupting electrical and mechanical stability. It is currently unknown how paracrine factors secreted by infiltrating fatty tissues affect ACM cardiomyocyte electrophysiology.</p><p><strong>Methods: </strong>A normal and a PKP2 mutant (c.971_972InsT) ACM hiPSC line were cultivated and differentiated into cardiomyocytes (CMs). Adipocytes were differentiated from human adipose stem cells, and adipocyte conditioned medium (AdCM) was collected. Optical mapping and phenotypic analyses were conducted on human iPSC-cardiomyocytes (hiPSC-CMs) cultured in cardiac maintenance medium (CMM) and either with AdCM or specific cytokines.</p><p><strong>Results: </strong>Significant differences were observed in voltage parameters such as the action potential duration (APD₈₀, APD₃₀), conduction velocity (CV), and CV heterogeneity. When cultured in AdCM relative to CMM, the APD₈₀ increased and the CV decreased significantly in both groups; however, the magnitudes of changes often differed significantly between 1 and 7 days of cultivation. Cytokine exposure (IL-6, IL-8, MCP-1, CFD) affected the APD and CV in both the normal and PKP2 mutant hiPSC-CMs, with opposite effects. NF-kB signaling was also found to differ between the normal and PKP2 mutant hiPSC-CMs in response to AdCM and IL-6.</p><p><strong>Conclusions: </strong>Our study shows that hiPSC-CMs from normal and mPKP2 ACM lines exhibit distinct molecular and functional responses to paracrine factors, with differences in RNA expression and electrophysiology. These different responses to paracrine factors may contribute to arrhythmogenic propensity.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"12 11","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11592320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alterations in the Levels of Urinary Exosomal MicroRNA-183-5p and MicroRNA-125a-5p in Individuals with Type 2 Diabetes Mellitus.","authors":"Yixuan Fang, Shiyi Sun, Jing Wu, Guanjian Liu, Qinqin Wu, Xingwu Ran","doi":"10.3390/biomedicines12112608","DOIUrl":"10.3390/biomedicines12112608","url":null,"abstract":"<p><p><b>Background:</b> Type 2 diabetes mellitus (T2DM) is a metabolic disorder, and urinary exosomal microRNAs (miRNAs) were utilized as potential disease prediction or diagnostic biomarkers in numerous studies. This study investigated the differential expression of urinary exosomal miRNAs between non-diabetes mellitus (NDM) individuals and those with T2DM. <b>Aim:</b> To elucidate the association between urinary exosomal miRNAs and T2DM. <b>Methods</b>: We recruited patients diagnosed with T2DM and NDM individuals in West China Hospital, Sichuan University, from November 2023 to February 2024. Subsequently, we performed sequencing of urinary exosomal microRNAs in both groups. The obtained sequencing results were further validated using RT-qPCR in both the training set and the validation set. Additionally, we conducted logistic regression analysis and Spearman correlation analysis on miRNAs with significant differential expression, as well as analysis of their biological functions. <b>Results</b>: A total of 118 urine samples were collected, 59 from individuals diagnosed with T2DM and 59 from NDM. There were differentially expressed miR-183-5p (<i>p</i> = 0.034) and miR-125a-5p (<i>p</i> = 0.008) between the two groups. Furthermore, multivariate regression analysis demonstrated that higher miR-125a-5p levels were negatively associated with the risk of T2DM (<i>p</i> = 0.044; OR: 0.046; 95% CI: 0.002, 0.922). Bioinformatics analysis indicated that the target genes of miR-183-5p were predominantly involved in insulin signaling and glucose transport processes, while those target genes of miR-125a-5p primarily mediated autophagy. <b>Conclusions</b>: miR-183-5p and miR-125a-5p might be involved in the pathogenesis of T2DM, while higher urinary exosomal miR-125a-5p was negatively associated with the risk of T2DM.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"12 11","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>C11orf58</i> (Hero20) Gene Polymorphism: Contribution to Ischemic Stroke Risk and Interactions with Other Heat-Resistant Obscure Chaperones.","authors":"Irina Shilenok, Ksenia Kobzeva, Vladislav Soldatov, Alexey Deykin, Olga Bushueva","doi":"10.3390/biomedicines12112603","DOIUrl":"10.3390/biomedicines12112603","url":null,"abstract":"<p><p><b>Background</b>: Recently identified Hero proteins, which possess chaperone-like functions, are promising candidates for research into atherosclerosis-related diseases, including ischemic stroke (IS). <b>Methods</b>: 2204 Russian subjects (917 IS patients and 1287 controls) were genotyped for fifteen common SNPs in Hero20 gene <i>C11orf58</i> using probe-based PCR and the MassArray-4 system. <b>Results</b>: Six <i>C11orf58</i> SNPs were significantly associated with an increased risk of IS in the overall group (OG) and significantly modified by smoking (SMK) and low fruit/vegetable intake (LFVI): rs10766342 (effect allele (EA) A; P(_OG = 0.02; _SMK = 0.009; _LFVI = 0.04)), rs11024032 (EA T; P(_OG = 0.01; _SMK = 0.01; _LFVI = 0.036)), rs11826990 (EA G; P(_OG = 0.007; _SMK = 0.004; _LFVI = 0.03)), rs3203295 (EA C; P(_OG = 0.016; _SMK = 0.01; _LFVI = 0.04)), rs10832676 (EA G; P(_OG = 0.006; _SMK = 0.002; _LFVI = 0.01)), rs4757429 (EA T; P(_OG = 0.02; _SMK = 0.04; _LFVI = 0.04)). The top ten intergenic interactions of Hero genes (two-, three-, and four-locus models) involved exclusively polymorphic loci of <i>C11orf58</i> and <i>C19orf53</i> and were characterized by synergic and additive (independent) effects between SNPs. <b>Conclusions</b>: Thus, <i>C11orf58</i> gene polymorphism represents a major risk factor for IS. Bioinformatic analysis showed the involvement of <i>C11orf58</i> SNPs in molecular mechanisms of IS mediated by their role in the regulation of redox homeostasis, inflammation, vascular remodeling, apoptosis, vasculogenesis, neurogenesis, lipid metabolism, proteostasis, hypoxia, cell signaling, and stress response. In terms of intergenic interactions, <i>C11orf58</i> interacts most closely with <i>C19orf53</i>.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"12 11","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11592265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"mTOR Inhibitors Modulate the Biological Nature of TGF-β2-Treated or -Untreated Human Trabecular Meshwork Cells in Different Manners.","authors":"Megumi Watanabe, Tatsuya Sato, Toshiyuki Yano, Megumi Higashide, Toshifumi Ogawa, Nami Nishikiori, Masato Furuhashi, Hiroshi Ohguro","doi":"10.3390/biomedicines12112604","DOIUrl":"10.3390/biomedicines12112604","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Mammalian target of rapamycin (mTOR) inhibition may have been suggested to have a beneficial effect on the glaucomatous human trabecular meshwork (HTM). To study the effects of the mTOR inhibitors rapamycin (Rapa) and Torin1 on the glaucomatous HTM, transforming growth factor-β2 (TGF-β2)-treated two-dimensionally (2D) and three-dimensionally (3D) cultured HTM cells were used. <b>Methods:</b> We evaluated (1) the levels of autophagy via Western blot analysis using a specific antibody against microtubule-associated protein 1 light chain 3 (LC3), (2) barrier capacity based on transepithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC) permeability (2D), (3) cellular metabolic functions (2D), (4) the size and stiffness of spheroids, and (5) the mRNA expression of ECM proteins. <b>Results:</b> TGF-β2-induced inhibition of autophagy was significantly inhibited by Rapa and Torin1. Rapa and Torin1 substantially decreased barrier capacity in both TGF-β2-untreated and TGF-β2-treated HTM cells. Cellular metabolic analysis indicated that Rapa, but not Torin1, substantially enhanced both mitochondrial and glycolytic functions of TGF-β2-untreated HTM cells. In the physical properties of spheroids, TGF-β2 resulted in the formation of down-sized and stiffened spheroids. mTOR inhibitors decreased the size but not the stiffness of TGF-β2-untreated spheroids and significantly reduced the TGF-β2-related increase in the stiffness but not the size of spheroids. The diverse effects of mTOR inhibitors on TGF-β2-untreated and TGF-β2-treated spheroids were also observed in the mRNA expression of extracellular matrix proteins. <b>Conclusions:</b> The results taken together suggest that mTOR inhibitors significantly influence the biological aspects of both a single layer and multiple layers of the TGF-β2-treated HTM and untreated HTM.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"12 11","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Osteopontin and Clinical Outcomes in Hemodialysis Patients.","authors":"Claudia Torino, Federico Carbone, Patrizia Pizzini, Sabrina Mezzatesta, Graziella D'Arrigo, Mercedes Gori, Luca Liberale, Margherita Moriero, Cristina Michelauz, Federica Frè, Simone Isoppo, Aurora Gavoci, Federica La Rosa, Alessandro Scuricini, Amedeo Tirandi, Davide Ramoni, Francesca Mallamaci, Giovanni Tripepi, Fabrizio Montecucco, Carmine Zoccali","doi":"10.3390/biomedicines12112605","DOIUrl":"10.3390/biomedicines12112605","url":null,"abstract":"<p><strong>Background/objectives: </strong>Chronic kidney disease (CKD) and end-stage kidney disease (ESKD) are significant public health issues, with cardiovascular morbidity and mortality being the leading causes of death in hemodialysis patients. Osteopontin (OPN), a multifunctional glycoprotein, has emerged as a potential biomarker for vascular disease in CKD due to its role in inflammation, tissue remodeling, and calcification.</p><p><strong>Methods: </strong>This cohort study included 1124 hemodialysis patients from the PROGREDIRE study, a registry involving 35 dialysis units in Southern Italy. Serum osteopontin levels were measured using enzyme-linked immunosorbent assay (ELISA). The primary endpoints were all-cause and cardiovascular mortality. Multivariate Cox regression analyses were performed to assess the association between osteopontin levels and mortality, adjusting for traditional risk factors, biomarkers of inflammation, nutritional status, and ESKD-related factors.</p><p><strong>Results: </strong>During a mean follow-up of 2.8 years, 478 patients died, 271 from cardiovascular causes. Independent correlates of osteopontin included alkaline phosphatase and parathyroid hormone. Elevated osteopontin levels were significantly associated with increased all-cause mortality (HR 1.19, 95% CI 1.09-1.31, <i>p</i> < 0.001) and cardiovascular mortality (HR 1.22, 95% CI 1.08-1.38, <i>p</i> = 0.001) after adjusting for confounders.</p><p><strong>Conclusions: </strong>Elevated osteopontin levels are associated with increased all-cause and cardiovascular mortality in hemodialysis patients. These findings implicate osteopontin in the high risk for death and cardiovascular disease in the hemodialysis population. Intervention studies are needed to definitively test this hypothesis.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"12 11","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11592156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uricase-Expressing Engineered Macrophages Alleviate Murine Hyperuricemia.","authors":"Yu-Zhong Feng, Hao Cheng, Guo-Qing Xiong, Jia-Zhen Cui, Zhi-Li Chen, Yuan-Yuan Lu, Zhi-Xin Meng, Chen Zhu, Hao-Long Dong, Xiang-Hua Xiong, Gang Liu, Qing-Yang Wang, Hui-Peng Chen","doi":"10.3390/biomedicines12112602","DOIUrl":"10.3390/biomedicines12112602","url":null,"abstract":"<p><p><b>Background</b>: Uricase, or urate oxidase (Uox) is a key enzyme in uric acid (UA) metabolism and has been applied in clinical treatment of human hyperuricemia (HUA). However, the current clinically applied uricases, despite their potent urate-lowering capacity, tend to form anti-drug antibodies because of their immunogenicity, leading to increased risk of anaphylaxis, faster drug clearance and reduced or even complete loss of therapeutic effect, limiting their clinical application. In this study, we constructed engineered macrophages that stably expressed uricase, which might serve as a promising alternative to the direct injection of uricases. <b>Materials and Methods</b>: Engineered macrophages RAW264.7 cells were injected intravenously to treat hyperuricemic KM mice. Serum uric acid and bio-indicators for renal and hepatic functions were detected by an automatic biochemical analyzer; inflammatory cytokines were determined by ELISA; the livers and kidneys of the mice were sectioned for histological examination. <b>Results</b>: The uricase-expressing macrophages reduced UA levels from 300 ± 1.5 μmol/L to 101 ± 8.3 μmol/L in vitro. And in an HUA mouse model established by gavage with yeast extract, intravenous injection of the engineered macrophages could reduce the serum uric acid (sUA) of mice to normal level on the 14th day of modeling, with a decrease of 48.6%, and the urate-lowering effect was comparable to that of the first-line clinical drug allopurinol. In terms of safety, engineered macrophages did not cause liver or kidney dysfunction in mice, nor did they induce systemic immune response. <b>Conclusions</b>: Using macrophages as a chassis to deliver uricase might be a new, safe and effective strategy for the treatment and control of hyperuricemia.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"12 11","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11592275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rhabdomyolysis After Prolonged Tourniquet Application Is Associated with Reversible Acute Kidney Injury (AKI) in Rats.","authors":"Thomas J Walters, Luciana N Torres, Kathy L Ryan, Robert V Hainline, Stephanie M Lipiec, Ijeoma E Obi, Jennifer Ybarra, Casey E Niland, Lusha Xiang","doi":"10.3390/biomedicines12112607","DOIUrl":"10.3390/biomedicines12112607","url":null,"abstract":"<p><p>Extremity trauma, including ischemia (e.g., prolonged tourniquet application or crush), is common among battlefield injuries. Injured muscle releases toxins leading to rhabdomyolysis and, potentially, acute kidney injury (AKI). The goal of this study was to characterize sequelae of ischemic extremity injury over 72 h, focusing on time courses of rhabdomyolysis and AKI. Male Sprague Dawley rats were placed into two groups. Ischemic injury was produced in anesthetized rats using bilateral tourniquets (TK; n = 10) for 5 h; control (CON; n = 9) rats were treated identically without TK application. Indicators of rhabdomyolysis and renal function were measured in conscious rats 1 day preinjury (baseline, BL) and then at 1.5, 24, 48, and 72 h post-TK release. Prolonged TK application produced necrosis in both muscle and bone marrow but not in kidney. The wet/dry weights indicated edema in injured limbs at 72 h (4.1 (0.5) (TK) vs. 2.9 (0.1) (CON); <i>p</i> < 0.001). TK rats exhibited a 100-fold increase in creatine kinase activity compared to CON at 1.5 h (20,040 (7265) U/L vs. 195 (86) U/L (mean (SD); <i>p</i> < 0.0001). TK decreased the mean glomerular filtration rate (GFR; <i>p</i> < 0.001) at 1.5 h, but these values recovered by 24 h in concert with elevated urinary flow and alkalinization. Prolonged ischemic extremity injury therefore produced severe rhabdomyolysis without irreversible renal damage.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"12 11","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11592118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Contactin-1 as a Potential Biomarker and Therapeutic Target in Neuroblastoma.","authors":"Christa N Grant, Carson A Wills, Xiaoming Liu, Longgui Chen, Zhenqiu Liu, Hong-Gang Wang","doi":"10.3390/biomedicines12112606","DOIUrl":"10.3390/biomedicines12112606","url":null,"abstract":"<p><strong>Background: </strong>Neuroblastoma is a common pediatric solid tumor with poor outcomes in high-risk patients. The identification of new therapeutic biomarkers is critical for the treatment of disease.</p><p><strong>Methods: </strong>An analysis of large publicly available datasets of tumor gene expression was performed. In vivo studies were performed to elucidate the role of contactin-1 (CNTN1) in tumor progression.</p><p><strong>Results: </strong>Expression of the glycoprotein CNTN1 is elevated in neuroblastoma compared to other tumor types. CNTN1 expression is higher in stage 1 and non-MYCN-amplified tumors, compared to more aggressive stage 4 and MYCN-amplified tumors. Moreover, high CNTN1 expression is associated with increased overall survival in neuroblastoma patients. In vivo studies demonstrate reduced metastasis in mice xenografted with CNTN1 knockout tumors compared to wildtype.</p><p><strong>Conclusions: </strong>The results of this study suggest that CNTN1 is a potential biomarker and therapeutic target in neuroblastoma. Further investigation of CNTN1 could have significant clinical implications for improving neuroblastoma treatment.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"12 11","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of the <i>Egr2</i> Promoter Antisense RNA in Modulating the Schwann Cell Chromatin Landscape.","authors":"Margot Martinez Moreno, David Karambizi, Hyeyeon Hwang, Kristen Fregoso, Madison J Michles, Eduardo Fajardo, Andras Fiser, Nikos Tapinos","doi":"10.3390/biomedicines12112594","DOIUrl":"10.3390/biomedicines12112594","url":null,"abstract":"<p><p><b>Background</b>: Schwann cells (SCs) and their plasticity contribute to the peripheral nervous system's capacity for nerve regeneration after injury. The <i>Egr2/Krox20</i> promoter antisense RNA (Egr2-AS) recruits chromatin remodeling complexes to inhibit <i>Egr2</i> transcription following peripheral nerve injury. <b>Methods</b>: RNA-seq and ATAC-seq were performed on control cells, Lenti-GFP-transduced cells, and cells overexpressing Egr2-AS (Lenti-AS). Egr2 AS-RNA was cloned into the pLVX-DsRed-Express2-N1 lentiviral expression vector (Clontech, Mountain View, CA, USA), and the levels of AS-RNA expression were determined. Ezh2 and Wdr5 were immunoprecipitated from rat SCs and RT-qPCR was performed against AS-Egr2 RNA. ChIP followed by DNA purification columns was used to perform qPCR for relevant promoters. Hi-C, HiC-DC+, R, Bioconductor, and TOBIAS were used for significant and differential loop analysis, identifications of COREs and CORE-promotor loops, comparisons of TF activity at promoter sites, and identification of site-specific TF footprints. OnTAD was used to detect TADs, and Juicer was used to identify A/B compartments. <b>Results</b>: Here we show that a Neuregulin-ErbB2/3 signaling axis mediates binding of the Egr2-AS to YY1^Ser184 and regulates its expression. Egr2-AS modulates the chromatin accessibility of Schwann cells and interacts with two distinct histone modification complexes. It binds to EZH2 and WDR5 and enables targeting of H3K27me3 and H3K4me3 to promoters of <i>Egr2</i> and <i>C-JUN,</i> respectively. Expression of the Egr2-AS results in reorganization of the global chromatin landscape and quantitative changes in the loop formation and contact frequency at domain boundaries exhibiting enrichment for AP-1 genes. In addition, the Egr2-AS induces changes in the hierarchical TADs and increases transcription factor binding scores on an inter-TAD loop between a super-enhancer regulatory hub and the promoter of <i>mTOR</i>. <b>Conclusions</b>: Our results show that Neuregulin-ErbB2/3-YY1 regulates the expression of Egr2-AS, which mediates remodeling of the chromatin landscape in Schwann cells.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"12 11","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11592338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}