Cells最新文献

{"title":"Validation of Clinical-Grade Electroporation Systems for CRISPR-Cas9-Mediated Gene Therapy in Primary Hepatocytes for the Correction of Inherited Metabolic Liver Disease.","authors":"Justin Gibson, Abishek Dhungana, Menam Pokhrel, Benjamin Arthur, Pramita Suresh, Olumide Adebayo, Renee N Cottle","doi":"10.3390/cells14100711","DOIUrl":"10.3390/cells14100711","url":null,"abstract":"<p><p>Hepatocyte transplantation (HTx) combined with ex vivo gene therapy has garnered significant interest due to its potential for treating many inherited metabolic liver diseases. The biggest obstacle for HTx is achieving sufficient engraftment levels to rescue diseased phenotypes, which becomes more challenging when combined with ex vivo gene editing techniques. However, recent technological advancements have improved electroporation delivery efficiency, cell viability, and scalability for cell therapy. We recently demonstrated the impacts of electroporation for cell-based gene therapy in a mouse model of hereditary tyrosinemia type 1 (HT1). Here, we explore the use of the clinical-grade electroporator, the MaxCyte ExPERT GTx, utilized in the first FDA-approved CRISPR therapy, Casgevy, and evaluate its potential in primary hepatocytes in terms of delivery efficiency and cell viability. We assessed the gene editing efficiency and post-transplantation engraftment of hepatocytes from <i>mTmG</i> mice electroporated with CRISPR-Cas9-ribonucleoproteins (RNPs) targeting 4-hydroxyphenylpyruvate dioxygenase (<i>Hpd</i>) in a fumarylacetoacetate hydrolase (<i>Fah</i>)-deficient mouse model of HT1. After surgery, <i>Fah^-/-</i> graft recipients were cycled off and on nitisinone to achieve independence from drug-induced Hpd inhibition, an indicator of HT1 disease correction. Transplanted hepatocytes subjected to electroporation using the GTx system had a cell viability of 89.9% and 100% on-target gene editing efficiency. Recipients transplanted with GTx-electroporated cells showed a smaller weight reduction than controls transplanted with untransfected cells (7.9% and 13.8%, respectively). Further, there were no mortalities in the GTx-recipient mice, whereas there was 25% mortality in the control recipients. Mean donor cell engraftment was significantly higher in GTx-recipient mice compared to untransfected control recipients (97.9% and 81.6%, respectively). Our results indicate that the GTx system does not negatively impact hepatocyte functionality and engraftment potential, thereby demonstrating the promise of GTx electroporation in hepatocytes as a viable cell therapy for treating genetic diseases that affect the liver.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 10","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12109753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Risk and Protective Factors in Parkinson's Disease.","authors":"Iman Beheshti","doi":"10.3390/cells14100710","DOIUrl":"10.3390/cells14100710","url":null,"abstract":"<p><p>Understanding the risk and protective factors associated with Parkinson's disease (PD) is crucial for improving outcomes for patients, individuals at risk, healthcare providers, and healthcare systems. Studying these factors not only enhances our knowledge of the disease but also aids in developing effective prevention, management, and treatment strategies. This paper reviews the key risk and protective factors associated with PD, with a particular focus on the biological mechanisms underlying these factors. Risk factors include genetic mutations, racial predispositions, and environmental exposures, all of which contribute to an increased likelihood of developing PD or accelerating its progression. Conversely, protective factors, such as regular physical exercise, adherence to a Mediterranean diet, and higher urate levels, have the potential to reduce inflammation and support mitochondrial function, thereby mitigating the risk of disease. However, identifying and validating these factors presents significant challenges. These challenges include the absence of reliable biomarkers, intricate interactions between genetic and environmental components, and clinical heterogeneity observed in patients with PD. These barriers complicate the establishment of clear causal relationships and hinder the development of targeted preventive strategies. To overcome these challenges, we propose several solutions and recommendations. Understanding the mechanisms underlying risk factors may inform future research aimed at developing standardized and more accurate biomarkers for PD, facilitating earlier diagnosis and improved monitoring of disease progression. Additionally, we offer actionable recommendations for PD prevention and management tailored to healthy individuals, patients diagnosed with PD, and healthcare systems. These strategies aim to improve clinical outcomes, enhance the quality of life, and optimize healthcare delivery for PD.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 10","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12110598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Targets of Oxidative Stress: Focus on Nuclear Factor Erythroid 2-Related Factor 2 Function in Leukemia and Other Cancers.","authors":"Syed K Hasan, Sundarraj Jayakumar, Eliezer Espina Barroso, Anup Jha, Gianfranco Catalano, Santosh K Sandur, Nelida I Noguera","doi":"10.3390/cells14100713","DOIUrl":"10.3390/cells14100713","url":null,"abstract":"<p><p>Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a central role in regulating cellular responses to oxidative stress. It governs the expression of a broad range of genes involved in antioxidant defense, detoxification, metabolism, and other cytoprotective pathways. In normal cells, the transient activation of Nrf2 serves as a protective mechanism to maintain redox homeostasis. However, the persistent or aberrant activation of Nrf2 in cancer cells has been implicated in tumor progression, metabolic reprogramming, and resistance to chemotherapy and radiotherapy. These dual roles underscore the complexity of Nrf2 signaling and its potential as a therapeutic target. A deeper understanding of Nrf2 regulation in both normal and malignant contexts is essential for the development of effective Nrf2-targeted therapies. This review provides a comprehensive overview of Nrf2 regulation and function, highlighting its unique features in cancer biology, particularly its role in metabolic adaptation and drug resistance. Special attention is given to the current knowledge of Nrf2's involvement in leukemia and emerging strategies for its therapeutic modulation.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 10","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12110329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FAM20B Gain-of-Function Blocks the Synthesis of Glycosaminoglycan Chains of Proteoglycans and Inhibits Proliferation and Migration of Glioblastoma Cells.","authors":"Lydia Barré, Irfan Shaukat, Mohamed Ouzzine","doi":"10.3390/cells14100712","DOIUrl":"10.3390/cells14100712","url":null,"abstract":"<p><p>Heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans (PGs) are essential regulators of many biological processes including cell differentiation, signalization, and proliferation. PGs interact mainly via their glycosaminoglycan (GAG) chains, with a large number of ligands including growth factors, enzymes, and extracellular matrix components, thereby modulating their biological activities. HSPGs and CSPGs share a common tetrasaccharide linker region, which undergoes modifications, particularly the phosphorylation of the xylose residue by the kinase FAM20B. Here, we demonstrated that <i>FAM20B</i> gain-of-function decreased, in a dose dependent manner, the synthesis of both CS- and HS-attached PGs. In addition, we showed that blockage of GAG chain synthesis by FAM20B was suppressed by the mutation of aspartic acid residues D289 and D309 of the catalytic domain. Interestingly, we bring evidence that, in contrast to FAM20B, expression of the 2-phosphoxylose phosphatase XYLP increases, in a dose dependent manner, GAG chain synthesis and rescues the blockage of GAG chains synthesis induced by FAM20B. In line with previous reports, we found that <i>FAM20B</i> loss-of-function reduced GAG chain synthesis. Finally, we found that FAM20B inhibited proliferation and migration of glioblastoma cells, thus revealing the critical role of GAG chains of PGs in glioblastoma cell tumorigenesis. This study revealed that both gain- and loss-of-function of <i>FAM20B</i> led to decreased GAG chain synthesis, therefore suggesting that a balance between phosphorylation and dephosphorylation of the xylose by FAM20B and XYLP, respectively, is probably an essential factor for the regulation of the rate of PG synthesis.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 10","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12110425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inverse Bicontinuous and Discontinuous Phases of Lipids, and Membrane Curvature.","authors":"John M Seddon","doi":"10.3390/cells14100716","DOIUrl":"10.3390/cells14100716","url":null,"abstract":"<p><p>In this review article I briefly describe lipid self-assembly, interfacial curvature, and lyotropic phase diagrams. I then go on to describe how the phase behaviour can be controlled, and the structure of lyotropic phases can be tuned, by various parameters such as temperature, hydrostatic pressure, or the addition of amphiphilic molecules such as fatty acids, diacylglycerols, and cholesterol. I then give a few illustrations of how such structures/phases may play roles in lipid-based biotechnologies, and in biomembrane systems.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 10","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12110378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current Challenges in Elucidating ALS Disease Mechanisms and Therapeutic Advances.","authors":"Smita Saxena, W David Arnold","doi":"10.3390/cells14100715","DOIUrl":"10.3390/cells14100715","url":null,"abstract":"<p><p>As a researcher and a physician working together to combat amyotrophic lateral sclerosis (ALS), we are acutely aware of both the urgent need for innovation and the persistent divide between laboratory discoveries and clinical care [...].</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 10","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12110534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harmonizing the Gut Microbiome and Cellular Immunotherapies: The Next Leap in Cancer Treatment.","authors":"Kendall Harrington, Khalid Shah","doi":"10.3390/cells14100708","DOIUrl":"10.3390/cells14100708","url":null,"abstract":"<p><p>The gut microbiome, a diverse community of microorganisms, plays a key role in shaping the host's immune system and modulating cancer therapies. Emerging evidence highlights its critical influence on the efficacy and toxicity of cell-based immunotherapies, including chimeric antigen receptor T cell, natural killer cell, and stem cell therapies. This review explores the interplay between gut microbiota and cellular immunotherapies, focusing on mechanisms by which microbial metabolites and microbial composition impact treatment outcomes. Furthermore, we discuss strategies to leverage the gut microbiome to optimize therapeutic efficacy and minimize adverse effects. A deeper understanding of the relationship between the gut microbiome and cellular immunotherapies can pave the way for more effective cell-based therapies for cancer.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 10","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12110395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Potential Role for c-MYC in the Regulation of Meibocyte Cell Stress.","authors":"Isabella Boyack, Autumn Berlied, Cornelia Peterson","doi":"10.3390/cells14100709","DOIUrl":"10.3390/cells14100709","url":null,"abstract":"<p><p>The integrated stress response (ISR) is a key regulator of cell survival, promoting apoptosis through the effector protein CHOP in instances of prolonged or severe stress. The ISR's role in the initiation and progression of epithelial malignancies has been investigated; however, the ISR has not been evaluated in ocular adnexal sebaceous carcinoma (SebCA). Though uncommon, mortality rates of up to 40% have been reported, and the mechanisms underlying SebCA tumorigenesis remain unresolved; however, <i>c-MYC</i> upregulation has been documented. Our objective was to determine the role of MYC in modulating the ISR in the Meibomian gland. Human Meibomian gland epithelial cells (HMGECs) were subject to both pharmacologic and genetic manipulations of MYC expression. Cytotoxicity, proliferation, and changes in protein and gene expression were assessed. Conditionally <i>MYC</i>-overexpressing mice were subject to topical 4-hydroxytamoxifen (4-OHT) induction of the eyelids prior to tissue harvest for histology, immunohistochemistry, immunoblotting, and qPCR. MYC-inhibited HMGECs exhibited dose-dependent decreased proliferation, increased CHOP expression, and increased apoptosis. Conversely, <i>MYC</i>-overexpressing HMGECs and Meibomian glands from 4-OHT-induced mice demonstrated suppressed CHOP expression, reduced apoptosis, and upregulated fatty acid synthase expression. These results suggest that MYC inhibition induces the ISR and promotes apoptosis, while MYC induction suppresses CHOP expression. High MYC expression may, therefore, serve as a mechanism for SebCA to elude cell death by promoting lipogenesis.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 10","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12109776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>miR-370-3p</i> Inhibited the Proliferation of Sheep Dermal Papilla Cells by Inhibiting the Expression of <i>SMAD4</i>.","authors":"Jiaqi Fu, Dan Wang, Wenqing Liu, Yu Qi, Caihong Zhang, Huansong Li, Jinshun Cai, Shuang Ji, Lichun Zhang, Fuliang Sun","doi":"10.3390/cells14100714","DOIUrl":"10.3390/cells14100714","url":null,"abstract":"<p><p>The proliferation and maturation of hair follicles in follicular papilla cells are predominantly governed by miRNAs, which significantly influence the cell cycle, apoptosis, and proliferation. <i>miR-370-3p</i> has been associated with several biological processes and targets <i>SMAD4</i>, a crucial component in hair follicle development. Tissue expression profiling revealed significant differences in <i>miR-370-3p</i> levels between skin tissues of the two sheep breeds in January and October, as well as between tissues of the Xinji fine-wool sheep and Small-tail Han sheep. <i>SMAD4</i> exhibited significant differences in tissue-specific expression in the heart, spleen, skin, lungs, and muscles from Xinji fine-wool sheep and Small-tail Han sheep. Bioinformatics analysis and dual-luciferase reporter assays validated the regulatory interaction between <i>miR-370-3p</i> and <i>SMAD4</i>. CCK-8 experiments demonstrated that <i>miR-370-3p</i>'s targeting of <i>SMAD4</i> suppressed cell growth. Cell cycle analysis demonstrated that <i>miR-370-3p</i>'s targeting of <i>SMAD4</i> influenced the cell cycle. Annexin V-FITC/PI dual labeling demonstrated that <i>miR-370-3p</i>'s targeting of <i>SMAD4</i> promoted cell apoptosis. RT-qPCR data demonstrated that <i>miR-370-3p</i>'s targeting of <i>SMAD4</i> elevated the expression of <i>JUN</i>, <i>c-MYC</i>, and <i>TCF7L2</i> while suppressing β-catenin expression. Western blot (WB) analysis demonstrated that <i>miR-370-3p</i> targeting of <i>SMAD4</i> significantly promoted c-MYC expression while inhibiting CCND1, CCND2, and β-catenin expression. <i>miR-370-3p</i> and <i>SMAD4</i> exhibit spatiotemporal expression differences in sheep skin tissues, with widespread expression across various tissues. Furthermore, it confirmed that <i>miR-370-3p</i> targets <i>SMAD4</i> to inhibit follicular papilla cell proliferation, promote apoptosis, and influence the cell cycle.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 10","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12110447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathological Mechanisms Involved in HIV-Associated Lymphomagenesis: Novel Targeted Therapeutic Approaches.","authors":"Mihaela Straista, Francesca Caccuri, Nicoleta Arnaut, Arnaldo Caruso, Mark Slevin","doi":"10.3390/cells14100705","DOIUrl":"10.3390/cells14100705","url":null,"abstract":"<p><p>The intricate interplay of direct and indirect mechanisms relating to immune dysfunction, chronic inflammation, and viral proteins represents a key factor of lymphomagenesis in HIV-infected patients. Indirect mechanisms based on cytokine dysregulation, HIV-induced immune dysfunction, and co-infections with oncogenic viruses induce chronic B-cell activation and generation of a prone environment for malignant transformation and tumor growth. Direct mechanisms arise from oncogenic influences of p17, Tat, and Nef HIV proteins, which generate genomic instability, alteration of cellular signaling, and activation of oncogenic pathways. Vp17's implication in lymphomagenesis and angiogenesis, ensured by activation of PAR1/EGFR/PI3K/Akt and MEK/ERK1/2 pathways, emphasizes the critical need for developing therapeutic strategies that target their signaling mechanisms. This review shows an insight into the pathological mechanisms involved in lymphomagenesis in HIV-infected individuals, focusing on finding novel therapeutic approaches directed at immune rehabilitation and oncogenic signaling pathways.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 10","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12109901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}