Frontiers in molecular medicine最新文献

{"title":"Combined analysis of host IFN-γ, IL-2 and IP-10 as potential LTBI biomarkers in ESAT-6/CFP-10 stimulated blood","authors":"Antony Rapulana, Thabo Mpotje, O. Baiyegunhi, Hlumani Ndlovu, Theresa K. Smit, Timothy D. McHugh, Mohlopheni J Marakalala","doi":"10.3389/fmmed.2024.1345510","DOIUrl":"https://doi.org/10.3389/fmmed.2024.1345510","url":null,"abstract":"Background: Accurate diagnosis of latent tuberculosis infected (LTBI) individuals is important in identifying individuals at risk of developing active tuberculosis. Current diagnosis of LTBI routinely relies on the detection and measurement of immune responses using the Tuberculin Skin Test (TST) and interferon gamma release assays (IGRAs). However, IGRA, which detects Mycobacterium tuberculosis specific IFN-γ, is associated with frequent indeterminate results, particularly in immunosuppressed patients. There is a need to identify more sensitive LTBI point of care diagnostic biomarkers. The aim of this study was to assess the validity of early secreted antigen target 6 kDa (ESAT-6) and culture filtrate protein 10 (CFP-10) stimulated plasma to identify additional cytokines and chemokines as potential biomarkers of LTBI.Method: The levels of 27 cytokines and chemokines were measured by Bio-Plex Pro cytokine, chemokine and growth factor assay in ESAT-6 and CFP-10 co-stimulated plasma from 20 LTBI participants with positive IGRA (Quantiferon TB Gold plus) and 20 healthy controls with negative IGRA. Traditional ELISA was used to validate the abundance of the best performing markers in 70 LTBI and 72 healthy participants. All participants were HIV negative.Results: We found that Interleukin 1 receptor antagonist (IL1ra) (p = 0.0056), Interleukin 2 (IL-2) (p < 0.0001), Interleukin 13 (IL-13) (p < 0.0001), Interferon gamma-induced protein 10 (IP-10) (p < 0.0001), and Macrophage inflammatory protein-1 beta (MIP1b) (p = 0.0010) were significantly higher in stimulated plasma of LTBI compared to healthy individuals. Stimulated plasma IL-2 (cutoff 100 pg/mL), IP-10 (cutoff 300 pg/mL) and IL-13 (5 pg/mL) showed potential in diagnosing LTBI with PPV = 100%, 0.89.4%, and 80.9% and NPV = 86.9%, 0.85.7%, and 84.2%, respectively.Conclusion: Our data shows that co-stimulating whole blood with ESAT-6 and CFP-10 may help distinguish LTBI from healthy individuals. We also identified IL-2 and IP-10 as potential biomarkers that could be added to the currently used IFN-γ release assays in detection of LTBI.","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"41 51","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139594884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in metabolic dysfunction associated Steatotic liver disease (MASLD)","authors":"Claudia Theys, Tineke Vanderhaeghen, E. Van Dijck, Cedric Peleman, Anne Scheepers, Joe Ibrahim, Ligia Mateiu, S. Timmermans, Tom Vanden Berghe, Sven M. Francque, Wim Van Hul, Claude Libert, Wim Vanden Berghe","doi":"10.3389/fmmed.2023.1283170","DOIUrl":"https://doi.org/10.3389/fmmed.2023.1283170","url":null,"abstract":"Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is a growing epidemic with an estimated prevalence of 20%–30% in Europe and the most common cause of chronic liver disease worldwide. The onset and progression of MASLD are orchestrated by an interplay of the metabolic environment with genetic and epigenetic factors. Emerging evidence suggests altered DNA methylation pattern as a major determinant of MASLD pathogenesis coinciding with progressive DNA hypermethylation and gene silencing of the liver-specific nuclear receptor PPARα, a key regulator of lipid metabolism. To investigate how PPARα loss of function contributes to epigenetic dysregulation in MASLD pathology, we studied DNA methylation changes in liver biopsies of WT and hepatocyte-specific PPARα KO mice, following a 6-week CDAHFD (choline-deficient, L-amino acid-defined, high-fat diet) or chow diet. Interestingly, genetic loss of PPARα function in hepatocyte-specific KO mice could be phenocopied by a 6-week CDAHFD diet in WT mice which promotes epigenetic silencing of PPARα function via DNA hypermethylation, similar to MASLD pathology. Remarkably, genetic and lipid diet-induced loss of PPARα function triggers compensatory activation of multiple lipid sensing transcription factors and epigenetic writer-eraser-reader proteins, which promotes the epigenetic transition from lipid metabolic stress towards ferroptosis and pyroptosis lipid hepatoxicity pathways associated with advanced MASLD. In conclusion, we show that PPARα function is essential to support lipid homeostasis and to suppress the epigenetic progression of ferroptosis-pyroptosis lipid damage associated pathways towards MASLD fibrosis.","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"31 20","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139444909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: The role of glial cells in neurodegeneration","authors":"Piera Pasinelli, Kathrin Meyer, L. Ferraiuolo, Robert A. Culibrk, Rita Sattler","doi":"10.3389/fmmed.2023.1337286","DOIUrl":"https://doi.org/10.3389/fmmed.2023.1337286","url":null,"abstract":"","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"52 20","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139385739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial adjustment of bioenergetics, a possible determinant of contractile adaptation and development of contractile failure","authors":"Marten Szibor, Marie Mühlon, Torsten Doenst, Jaakko L. O. Pohjoismäki","doi":"10.3389/fmmed.2023.1305960","DOIUrl":"https://doi.org/10.3389/fmmed.2023.1305960","url":null,"abstract":"Cardiomyocytes depend on mitochondrial oxidative phosphorylation (OXPHOS) for energy metabolism, which is facilitated by the mitochondrial electron transfer system (ETS). In a series of thermogenic redox reactions, electrons are shuttled through the ETS to oxygen as the final electron acceptor. This electron transfer is coupled to proton translocation across the inner mitochondrial membrane, which itself is the main driving force for ATP production. Oxygen availability is thus a prerequisite for ATP production and consequently contractility. Notably, cardiomyocytes are exceptionally large cells and densely packed with contractile structures, which constrains intracellular oxygen distribution. Moreover, oxygen must pass through layers of actively respiring mitochondria to reach the ones located in the innermost contractile compartment. Indeed, uneven oxygen distribution was observed in cardiomyocytes, suggesting that local ATP supply may also vary according to oxygen availability. Here, we discuss how spatial adjustment of bioenergetics to intracellular oxygen fluctuations may underlie cardiac contractile adaptation and how this adaptation may pose a risk for the development of contractile failure.","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"9 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138596873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Myocardium regeneration and cardioprotection","authors":"Martina Iengo, Ester Topa, A. Cuomo, Maria Cristina Luise, Francesco Fiore, Marika Rizza, Mattia Miccio, Elena Di Sarro, Giuseppe Ciaccio, Chiara Di Lorenzo, Valentina Mercurio, Sang-Bing Ong, S. Zacchigna, C. Tocchetti","doi":"10.3389/fmmed.2023.1293183","DOIUrl":"https://doi.org/10.3389/fmmed.2023.1293183","url":null,"abstract":"","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139321409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elaborating the potential of Artficial Intelligence in automated CAR-T cell manufacturing","authors":"Niklas Bäckel, Simon Hort, Tamás Kis, David F. Nettleton, Joseph R. Egan, John J. L. Jacobs, Dennis Grunert, Robert H. Schmitt","doi":"10.3389/fmmed.2023.1250508","DOIUrl":"https://doi.org/10.3389/fmmed.2023.1250508","url":null,"abstract":"This paper discusses the challenges of producing CAR-T cells for cancer treatment and the potential for Artificial Intelligence (AI) for its improvement. CAR-T cell therapy was approved in 2018 as the first Advanced Therapy Medicinal Product (ATMP) for treating acute leukemia and lymphoma. ATMPs are cell- and gene-based therapies that show great promise for treating various cancers and hereditary diseases. While some new ATMPs have been approved, ongoing clinical trials are expected to lead to the approval of many more. However, the production of CAR-T cells presents a significant challenge due to the high costs associated with the manufacturing process, making the therapy very expensive (approx. $400,000). Furthermore, autologous CAR-T therapy is limited to a make-to-order approach, which makes scaling economical production difficult. First attempts are being made to automate this multi-step manufacturing process, which will not only directly reduce the high manufacturing costs but will also enable comprehensive data collection. AI technologies have the ability to analyze this data and convert it into knowledge and insights. In order to exploit these opportunities, this paper analyses the data potential in the automated CAR-T production process and creates a mapping to the capabilities of AI applications. The paper explores the possible use of AI in analyzing the data generated during the automated process and its capabilities to further improve the efficiency and cost-effectiveness of CAR-T cell production.","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"144 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136238351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytes in stroke-induced neurodegeneration: a timeline.","authors":"Eileen Collyer, Elena Blanco-Suarez","doi":"10.3389/fmmed.2023.1240862","DOIUrl":"10.3389/fmmed.2023.1240862","url":null,"abstract":"<p><p>Stroke is a condition characterized by sudden deprivation of blood flow to a brain region and defined by different post-injury phases, which involve various molecular and cellular cascades. At an early stage during the acute phase, fast initial cell death occurs, followed by inflammation and scarring. This is followed by a sub-acute or recovery phase when endogenous plasticity mechanisms may promote spontaneous recovery, depending on various factors that are yet to be completely understood. At later time points, stroke leads to greater neurodegeneration compared to healthy controls in both clinical and preclinical studies, this is evident during the chronic phase when recovery slows down and neurodegenerative signatures appear. Astrocytes have been studied in the context of ischemic stroke due to their role in glutamate re-uptake, as components of the neurovascular unit, as building blocks of the glial scar, and synaptic plasticity regulators. All these roles render astrocytes interesting, yet understudied players in the context of stroke-induced neurodegeneration. With this review, we provide a summary of previous research, highlight astrocytes as potential therapeutic targets, and formulate questions about the role of astrocytes in the mechanisms during the acute, sub-acute, and chronic post-stroke phases that may lead to neurorestoration or neurodegeneration.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1240862"},"PeriodicalIF":0.0,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42901964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How can we use stem cell-derived cardiomyocytes to understand the involvement of energetic metabolism in alterations of cardiac function?","authors":"Sabine Rebs, Katrin Streckfuss-Bömeke","doi":"10.3389/fmmed.2023.1222986","DOIUrl":"10.3389/fmmed.2023.1222986","url":null,"abstract":"<p><p>Mutations in the mitochondrial-DNA or mitochondria related nuclear-encoded-DNA lead to various multisystemic disorders collectively termed mitochondrial diseases. One in three cases of mitochondrial disease affects the heart muscle, which is called mitochondrial cardiomyopathy (MCM) and is associated with hypertrophic, dilated, and noncompact cardiomyopathy. The heart is an organ with high energy demand, and mitochondria occupy 30%-40% of its cardiomyocyte-cell volume. Mitochondrial dysfunction leads to energy depletion and has detrimental effects on cardiac performance. However, disease development and progression in the context of mitochondrial and nuclear DNA mutations, remains incompletely understood. The system of induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM) is an excellent platform to study MCM since the unique genetic identity to their donors enables a robust recapitulation of the predicted phenotypes in a dish on a patient-specific level. Here, we focus on recent insights into MCM studied by patient-specific iPSC-CM and further discuss research gaps and advances in metabolic maturation of iPSC-CM, which is crucial for the study of mitochondrial dysfunction and to develop novel therapeutic strategies.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1222986"},"PeriodicalIF":0.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285589/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42102278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A method for temporal-spatial multivariate genomic analysis of acute wound healing via tissue stratification: a porcine negative pressure therapy pilot study.","authors":"Jacob G Hodge, Sumedha Gunewardena, Richard A Korentager, David S Zamierowski, Jennifer L Robinson, Adam J Mellott","doi":"10.3389/fmmed.2023.1195822","DOIUrl":"10.3389/fmmed.2023.1195822","url":null,"abstract":"<p><p><b>Introduction:</b> Wound therapies are capable of modulating the complex molecular signaling profile of tissue regeneration. However traditional, bulk tissue analysis results in nonspecific expressional profiles and diluted signaling that lacks temporal-spatial information. <b>Methods:</b> An acute incisional porcine wound model was developed in the context of negative pressure wound therapy (NPWT). Dressing materials were inserted into wounds with or without NPWT exposure and evaluated over 8-hours. Upon wound explantation, tissue was stratified and dissected into the epidermis, dermis, or subcutaneous layer, or left undissected as a bulk sample and all groups processed for RNAseq. RNAseq of stratified layers provided spatial localization of expressional changes within defined tissue regions, including angiogenesis, inflammation, and matrix remodeling. <b>Results:</b> Different expressional profiles were observed between individual tissue layers relative to each other within a single wound group and between each individual layer relative to bulk analysis. Tissue stratification identified unique differentially expressed genes within specific layers of tissue that were hidden during bulk analysis, as well as amplification of weak signals and/or inversion of signaling between two layers of the same wound, suggesting that two layers of skin can cancel out signaling within bulk analytical approaches. <b>Discussion:</b> The unique wound stratification and spatial RNAseq approach in this study provides a new methodology to observe expressional patterns more precisely within tissue that may have otherwise not been detectable. Together these experimental data offer novel insight into early expressional patterns and genomic profiles, within and between tissue layers, in wound healing pathways that could potentially help guide clinical decisions and improve wound outcomes.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1195822"},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47534691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial calcium signaling and redox homeostasis in cardiac health and disease.","authors":"Tudor-Alexandru Popoiu, Christoph Maack, Edoardo Bertero","doi":"10.3389/fmmed.2023.1235188","DOIUrl":"10.3389/fmmed.2023.1235188","url":null,"abstract":"<p><p>The energy demand of cardiomyocytes changes continuously in response to variations in cardiac workload. Cardiac excitation-contraction coupling is fueled primarily by adenosine triphosphate (ATP) production by oxidative phosphorylation in mitochondria. The rate of mitochondrial oxidative metabolism is matched to the rate of ATP consumption in the cytosol by the parallel activation of oxidative phosphorylation by calcium (Ca²⁺) and adenosine diphosphate (ADP). During cardiac workload transitions, Ca²⁺ accumulates in the mitochondrial matrix, where it stimulates the activity of the tricarboxylic acid cycle. In this review, we describe how mitochondria internalize and extrude Ca²⁺, the relevance of this process for ATP production and redox homeostasis in the healthy heart, and how derangements in ion handling cause mitochondrial and cardiomyocyte dysfunction in heart failure.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"1 1","pages":"1235188"},"PeriodicalIF":0.0,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42058449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}