Cells最新文献

{"title":"Loop Extrusion Machinery Impairments in Models and Disease.","authors":"Anastasiya Ryzhkova, Ekaterina Maltseva, Nariman Battulin, Evelyn Kabirova","doi":"10.3390/cells13221896","DOIUrl":"https://doi.org/10.3390/cells13221896","url":null,"abstract":"<p><p>Structural maintenance of chromosomes (SMC) complexes play a crucial role in organizing the three-dimensional structure of chromatin, facilitating key processes such as gene regulation, DNA repair, and chromosome segregation. This review explores the molecular mechanisms and biological significance of SMC-mediated loop extrusion complexes, including cohesin, condensins, and SMC5/6, focusing on their structure, their dynamic function during the cell cycle, and their impact on chromatin architecture. We discuss the implications of impairments in loop extrusion machinery as observed in experimental models and human diseases. Mutations affecting these complexes are linked to various developmental disorders and cancer, highlighting their importance in genome stability and transcriptional regulation. Advances in model systems and genomic techniques have provided deeper insights into the pathological roles of SMC complex dysfunction, offering potential therapeutic avenues for associated diseases.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multicellular Cancer-Stroma Spheres (CSS) for In Vitro Assessment of CAR-T Cell-Associated Toxicity.","authors":"Aigul R Rakhmatullina, Mariya A Zolotykh, Yuliya V Filina, Aigul Kh Valiullina, Ekaterina A Zmievskaya, Dina U Gafurbaeva, Aisylu R Sagdeeva, Emil R Bulatov, Albert A Rizvanov, Regina R Miftakhova","doi":"10.3390/cells13221892","DOIUrl":"https://doi.org/10.3390/cells13221892","url":null,"abstract":"<p><p>CAR-T therapy has revolutionized the field of oncology, offering a promising treatment option for cancer patients. However, the significant morbidity associated with therapy-related toxicity presents a major challenge to its widespread use. Despite extensive research into the underlying mechanisms of CAR-T therapy-related toxicity, there are still many unknowns. Furthermore, the lack of adequate in vitro models for assessing immunotoxicity and neurotoxicity further complicates the development of safer cellular therapies. Previously in our laboratory, we developed cancer-stroma spheres (CSS) composed of prostate adenocarcinoma PC3 cells and mesenchymal stem cells (MSC). Herein we present evidence that multicellular CSS could serve as a valuable in vitro model for toxicity studies related to CAR-T therapy. CSS containing CD19-overexpressing PC3M cells exhibited increased secretion of CAR-T cell toxicity-associated IL-8, MCP-1, and IP-10 in the presence of anti-CD19 CAR-T cells, compared to spheres derived from single cell types.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Animal Models of Febrile Seizures: Limitations and Recent Advances in the Field.","authors":"Alexandra V Griflyuk, Tatyana Y Postnikova, Aleksey V Zaitsev","doi":"10.3390/cells13221895","DOIUrl":"https://doi.org/10.3390/cells13221895","url":null,"abstract":"<p><p>Febrile seizures (FSs) are defined as seizures occurring in children aged 6 months to 5 years with a background of elevated body temperature. It is one of the most common neurological disorders of childhood, emphasizing the importance of understanding the causes of FSs and their impact on the developing nervous system. However, there are significant limitations to the technologies currently available for studying the etiology and pathophysiology of seizures in humans. It is currently not possible to adequately capture the subtle molecular and structural rearrangements of the nervous system that can occur after seizures in humans. The use of animal models can be invaluable for these purposes. The most commonly used models in modern research are hyperthermic models in rats and mice aged 10-12 days. While these models can reproduce many of the characteristics of FSs, they have certain limitations. This review outlines the key considerations when working with models of FSs, provides an overview of current approaches to producing seizures in different model subjects, and presents a summary of key findings regarding morphological and functional changes in the brain and behavioral alterations that have been identified in studies using animal models of FSs.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Dysfunction-Associated Steatotic Liver Disease and Alcohol-Associated Liver Disease: Liver DNA Methylation Analysis-A Systematic Review.","authors":"Daniela Stols-Gonçalves, Abraham S Meijnikman, Luca Schiliró Tristão, Clara Lucato Dos Santos, Nerissa P Denswil, Joanne Verheij, Wanderley M Bernardo, Max Nieuwdorp","doi":"10.3390/cells13221893","DOIUrl":"https://doi.org/10.3390/cells13221893","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated liver disease (MASLD) and alcohol-associated liver disease (ALD) are among the leading causes of liver disease worldwide. The exact roles of epigenetic factors in both diseases remains largely unknown. In this context, liver DNA methylation remains a field that requires further exploration and understanding.</p><p><strong>Methods: </strong>We performed a systematic review of liver DNA methylation in humans with MASLD or ALD using Ovid MEDLINE, Ovid Embase, and Cochrane Library. We included human studies where liver DNA methylation was assessed in patients with MASLD and/or ALD. The Rayyan platform was used to select studies. Risk of bias was assessed with the \"risk of bias in non-randomized studies of interventions\" tool, ROBINS-I. We performed pathway analysis using the most important differentially methylated genes selected in each article.</p><p><strong>Results: </strong>Fifteen articles were included in this systematic review. The risk of bias was moderate to serious in all articles and bias due to confounding and patient selection was high. Sixteen common pathways, containing differentially methylated genes, including cancer pathways, were identified in both diseases.</p><p><strong>Conclusions: </strong>There are common pathways, containing differentially methylated genes, in ALD and MASLD, such as pathways in cancer and peroxisome proliferator-activated receptor (PPAR) signaling pathways. In MASLD, the insulin signaling pathway is one of the most important, and in ALD, the MAPK signaling pathway is the most important. Our study adds one more piece to the puzzle of the mechanisms involved in steatotic liver disease.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Two Sides of Indoleamine 2,3-Dioxygenase 2 (IDO2).","authors":"Chiara Suvieri, Maria Laura Belladonna, Claudia Volpi","doi":"10.3390/cells13221894","DOIUrl":"https://doi.org/10.3390/cells13221894","url":null,"abstract":"<p><p>Indoleamine 2,3-dioxygenase 1 (<i>IDO1</i>) and <i>IDO2</i> originated from gene duplication before vertebrate divergence. While IDO1 has a well-defined role in immune regulation, the biological role of IDO2 remains unclear. Discovered in 2007, <i>IDO2</i> is located near the <i>IDO1</i> gene. Because of their high sequence similarity, IDO2 was initially thought to be a tryptophan (Trp)-degrading enzyme like IDO1. Differently from what expected, IDO2 displays extremely low catalytic activity toward Trp. Nevertheless, many studies, often contradictory, have tried to demonstrate that IDO2 modulates immune responses by catabolizing Trp into kynurenine, an unconvincing hypothesis linked to an incomplete understanding of IDO2's activity. In this study, we review IDO2's functional role beyond Trp metabolism. IDO2's evolutionary persistence across species, despite being almost inactive as an enzyme, suggests it has some relevant biological importance. <i>IDO2</i> expression in human normal cells is poor, but significant in various cancers, with two prevalent SNPs. Overall, the comparison of IDO2 to IDO1 as a Trp-degrading enzyme may have led to misunderstandings about IDO2's true physiological and pathological roles. New insights suggest that IDO2 might function more as a signaling molecule, particularly in cancer contexts, and further studies could reveal its potential as a target for cancer therapy.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Possible Role of Endothelial-Derived Cellular and Exosomal-miRNAs in Lipid-Mediated Diabetic Retinopathy: Microarray Studies.","authors":"Khaled Elmasry, Samar Habib, Inas Helwa, Mariam Lotfy Khaled, Ahmed S Ibrahim, Amany Tawfik, Mohamed Al-Shabrawey","doi":"10.3390/cells13221886","DOIUrl":"https://doi.org/10.3390/cells13221886","url":null,"abstract":"<p><p>Diabetic retinopathy (DR) is a salient cause of blindness worldwide. There is still an immense need to understand the pathophysiology of DR to discover better diagnostic and therapeutic modalities. Human retinal endothelial cells (HRECs) were treated with 15-HETE or D-glucose, then miRNAs were isolated, and a microarray was performed. MirWALK 2 and Ingenuity Pathway Analysis (IPA) were used to analyze the microarray results. Exosomal miRNAs from 15-HETE-treated HRECs were isolated, microarrayed, and then imported into IPA for further analysis. The microarray results showed that 15-HETE downregulated 343 miRNAs and upregulated 297 miRNAs in HRECs. High glucose treatment induced a differential expression of HREC-miRNAs where 185 miRNAs were downregulated and 244 were upregulated. Comparing the impact of 15-HETE versus DG or diabetic mouse retina elaborated commonly changing miRNAs. Pathway and target analysis for miRNAs changed in 15-HETE-treated HRECs revealed multiple targets and pathways that may be involved in 15-HETE-induced retinal endothelial dysfunction. The HREC-exosomal miRNAs were differentially expressed after 15-HETE treatment, with 34 miRNAs downregulated and 45 miRNAs upregulated, impacting different cellular pathways. Here, we show that 15-HETE induces various changes in the cellular and exosomal miRNA profile of HRECs, highlighting the importance of targeting the 12/15 lipoxygenase pathway in DR.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytogenomic Characterization of Murine Neuroblastoma Cell Line Neuro-2a and Its Two Derivatives Neuro-2a TR-Alpha and Neuro-2a TR-Beta.","authors":"Lioba Hergenhahn, Niklas Padutsch, Shaymaa Azawi, Ralf Weiskirchen, Thomas Liehr, Martina Rinčic","doi":"10.3390/cells13221889","DOIUrl":"https://doi.org/10.3390/cells13221889","url":null,"abstract":"<p><strong>Background: </strong>The Neuro-2a cell line, derived from a murine neuroblastoma (NB), was established as early as 1969 and originates from a transplantable tumor that arose spontaneously in an A/Jax male mouse in 1940. Since then, it has been applied in over 10,000 studies and is used by the World Organization for Animal Health for the routine diagnosis of rabies. Surprisingly, however, Neuro-2a has never been genetically characterized in detail; this study fills that gap.</p><p><strong>Methods: </strong>The Neuro-2a cell line and two of its derivatives, Neuro-2a TR-alpha and Neuro-2a TR-beta, were analyzed for their chromosomal constitution using molecular cytogenetic approaches. Array comparative genomic hybridization was performed to characterize copy number alterations.</p><p><strong>Results: </strong>Neuro-2A has a hyper-tetraploid karyotype with 70 to 97 chromosomes per cell, and the karyotypes of its two examined derivatives were quite similar. Neither of them had a Y-chromosome. The complex karyotype of Neuro-2a includes mitotically stable dicentres, neocentrics, and complex rearrangements resembling chromothripsis events. Although no amplification of euchromatin or oncogenes was detected, there are five derivative chromosomes with the amplification of centromere-near heterochromatic material and 1-5 additional derivatives consisting only of such material.</p><p><strong>Conclusions: </strong>Since satellite DNA amplification has recently been found in advanced human tumors, this finding may be the corresponding equivalent in mice. An in silico translation of the obtained results into the human genome indicated that Neuro-2A is suitable as a model for advanced human NB.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HC-HA/PTX3 from Human Amniotic Membrane Induced Differential Gene Expressions in DRG Neurons: Insights into the Modulation of Pain.","authors":"Shao-Qiu He, Chi Zhang, Xue-Wei Wang, Qian Huang, Jing Liu, Qing Lin, Hua He, Da-Zhi Yang, Scheffer C Tseng, Yun Guan","doi":"10.3390/cells13221887","DOIUrl":"https://doi.org/10.3390/cells13221887","url":null,"abstract":"<p><p><b>Background:</b> The biologics derived from human amniotic membranes (AMs) demonstrate potential pain-inhibitory effects in clinical settings. However, the molecular basis underlying this therapeutic effect remains elusive. HC-HA/PTX3 is a unique water-soluble regenerative matrix that is purified from human AMs. We examined whether HC-HA/PTX3 can modulate the gene networks and transcriptional signatures in the dorsal root ganglia (DRG) neurons transmitting peripheral sensory inputs to the spinal cord. <b>Methods:</b> We conducted bulk RNA-sequencing (RNA-seq) of mouse DRG neurons after treating them with HC-HA/PTX3 (15 µg/mL) for 10 min and 24 h in culture. Differential gene expression analysis was performed using the limma package, and Gene Ontology (GO) and protein-protein interaction (PPI) analyses were conducted to identify the networks of pain-related genes. Western blotting and in vitro calcium imaging were used to examine the protein levels and signaling of pro-opiomelanocortin (POMC) in DRG neurons. <b>Results:</b> Compared to the vehicle-treated group, 24 h treatment with HC-HA/PTX3 induced 2047 differentially expressed genes (DEGs), which were centered on the ATPase activity, receptor-ligand activity, and extracellular matrix pathways. Importantly, PPI analysis revealed that over 50 of these DEGs are closely related to pain and analgesia. Notably, HC-HA/PTX3 increased the expression and signaling pathway of POMC, which may affect opioid analgesia. <b>Conclusions:</b> HC-HA/PTX3 induced profound changes in the gene expression in DRG neurons, centered around various neurochemical mechanisms associated with pain modulation. Our findings suggest that HC-HA/PTX3 may be an important biological active component in human AMs that partly underlies its pain inhibitory effect, presenting a new strategy for pain treatment.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of a Spectral Flow Cytometry Single-Tube Panel for the Clinical Diagnosis and Follow-Up of Children and Adolescents with B-Cell Acute Lymphoblastic Leukemia.","authors":"Gonzalo García-Aguilera, Ana Castillo-Robleda, Alejandro Sanz, Manuel Ramírez","doi":"10.3390/cells13221891","DOIUrl":"https://doi.org/10.3390/cells13221891","url":null,"abstract":"<p><p>The ability of flow cytometry to identify and quantify the presence of cell populations defined by their expression profile of specific markers has made this technique a powerful and routinary tool in clinical diagnostic practice. Specifically in the field of hematological malignancies, flow cytometry allows the identification of the correct type and lineage of each patient's disease and also sensitively quantifies the presence of the disease at precise moments during treatment, that is, levels of measurable residual disease (MRD). The quantification of MRD by flow cytometry has allowed the adaptation of tailored therapies to patients, contributing to the improvement of the results of the different protocols in recent decades. In this context, our objective in the present work was to evaluate the potential impact that spectral flow cytometry can provide compared to conventional cytometry, which is the one usually used in clinics. We present here a comparative study of both technologies, spectral versus conventional flow cytometry, in primary samples corresponding to the diagnosis and follow-up of children and adolescents with acute lymphoblastic leukemia. Our initial experience demonstrates the feasibility of incorporating spectral flow cytometry into the routine workflow of a reference laboratory.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impairment of Glucose Uptake Induced by Elevated Intracellular Ca²⁺ in Hippocampal Neurons of Malignant Hyperthermia-Susceptible Mice.","authors":"Arkady Uryash, Alfredo Mijares, Jose A Adams, Jose R Lopez","doi":"10.3390/cells13221888","DOIUrl":"https://doi.org/10.3390/cells13221888","url":null,"abstract":"<p><p>Malignant hyperthermia (MH) is a genetic disorder triggered by depolarizing muscle relaxants or halogenated inhalational anesthetics in genetically predisposed individuals who have a chronic elevated intracellular Ca²⁺ concentration ([Ca²⁺]_i) in their muscle cells. We have reported that the muscle dysregulation of [Ca²⁺]_i impairs glucose uptake, leading to the development of insulin resistance in two rodent experimental models. In this study, we simultaneously measured the [Ca²⁺]_i and glucose uptake in single enzymatically isolated hippocampal pyramidal neurons from wild-type (WT) and MH-R163C mice. The [Ca²⁺]_i was recorded using a Ca²⁺-selective microelectrode, and the glucose uptake was assessed utilizing the fluorescent glucose analog 2-NBDG. The MH-R163C hippocampal neurons exhibited elevated [Ca²⁺]_i and impaired insulin-dependent glucose uptake compared with the WT neurons. Additionally, exposure to isoflurane exacerbated these deficiencies in the MH-R163C neurons, while the WT neurons remained unaffected. Lowering [Ca²⁺]_i using a Ca²⁺-free solution, SAR7334, or dantrolene increased the glucose uptake in the MH-R163C neurons without significantly affecting the WT neurons. However, further reduction of the [Ca²⁺]_i below the physiological level using BAPTA decreased the insulin-dependent glucose uptake in both genotypes. Furthermore, the homogenates of the MH-R163C hippocampal neurons showed an altered protein expression of the PI3K/Akt signaling pathway and GLUT4 compared with the WT mice. Our study demonstrated that the chronic elevation of [Ca²⁺]_i was sufficient to compromise the insulin-dependent glucose uptake in the MH-R163C hippocampal neurons. Moreover, reducing the [Ca²⁺]_i within a specific range (100-130 nM) could reverse insulin resistance, a hallmark of type 2 diabetes mellitus (T2D).</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}