Frontiers in molecular medicine最新文献

{"title":"Endothelial Function in Postmenopausal Women: The Possible Role of Heat Shock Protein 60 and Serum Androgens.","authors":"Eleni Armeni, Anastasia Soureti, Areti Augoulea, Asimina Chondrou, Nikolaos Drakoulis, George Kaparos, Dimitrios Delialis, Spyros Stefos, Lasthenis Angelidakis, Alexandros Sianis, Aggeliki-Maria Dimopoulou, Andreas Alexandrou, Stavroula Baka, Leon Aravantinos, Konstantinos Panoulis, Kimon Stamatelopoulos, Irene Lambrinoudaki","doi":"10.3389/fmmed.2022.933188","DOIUrl":"10.3389/fmmed.2022.933188","url":null,"abstract":"<p><p><b>Background:</b> Heat shock protein 60 (HSP60), a potentially homeostatic antigen, is involved in physiological and non-physiological conditions. Experimental data support the role of HSP60 in placental and mitochondrial steroidogenesis. Furthermore, HSP60 is translocated into the endothelial-cell plasma membrane and the extracellular space under stress conditions, promoting the atherosclerotic process. Therefore, we investigated the association between HSP60 and endothelial function in postmenopausal women, considering the possible atherogenic effect of androgenic hormones. <b>Methods:</b> This study included 123 healthy postmenopausal women. Exclusion criteria were treated hypertension or dyslipidaemia, menopause hormone therapy during the last 6 months, and previously diagnosed peripheral vascular disease or cardiovascular disease. Fasting venous blood samples were obtained for biochemical and hormonal assessment and evaluation of HSP60. Sonographic assessment of flow-mediated dilation (FMD) occurred immediately after that in one session. <b>Results:</b> Univariate analysis showed that women with FMD values below median 5.12% had lower logHSP60 values (low vs. high FMD, HSP60 values: 2.01 ± 1.16 ng/ml vs. 3.22 ± 1.17 ng/ml, <i>p</i>-value = 0.031). Multivariable analysis showed that logHSP60 was associated with FMD (b-coefficient = 0.171, <i>p</i>-value = 0.046), adjusting for traditional cardiovascular risk factors (TRFs) and insulin levels. Further adjustment for testosterone and DHEAS rendered the result non-significant. In the multivariable analysis, FMD was associated with insulin (b-coefficient = -0.166, <i>p</i>-value = 0.034), testosterone (b-coefficient = -0.165, <i>p</i>-value = 0.034), DHEAS (b-coefficient = -0.187, <i>p</i>-value = 0.017), adjusting for TRFs. <b>Discussion:</b> The results of this study indicate that the association between androgens and endothelial function is possibly mediated by HSP60 molecules, in women with low insulin resistance and androgenicity. Further prospective studies are needed to explore the significance of our findings.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"933188"},"PeriodicalIF":0.0,"publicationDate":"2022-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43099966","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 Review on Biomarkers for the Evaluation of Autoimmune Cholestatic Liver Diseases and Their Overlap Syndromes.","authors":"Henry H Nguyen, Marvin J Fritzler, Mark G Swain","doi":"10.3389/fmmed.2022.914505","DOIUrl":"10.3389/fmmed.2022.914505","url":null,"abstract":"<p><p>Autoimmune cholestatic liver disease includes both Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC). Both conditions result in impairment of hepatic bile flow ultimately leading to chronic liver injury, liver fibrosis and eventually end stage cirrhosis. Early and accurate diagnosis are important for the risk stratification, follow up and management of these patients. The underlying pathogenesis of these conditions have not been completely resolved and poses a barrier for the development of new diagnostic and prognostics tools. Current research work suggests that the pathogenesis of autoimmune cholestatic liver disease results from environmental, genetic, and a large component of underlying immune dysfunction. While the current available serum biomarkers and imaging modalities showcases progression in precision medicine for the management of autoimmune cholestatic liver disease, development of new biomarkers are still an area of need in this field. In this review, we will discuss the current and emerging biomarkers in patients with PBC, PSC, and a special population that exhibit overlap syndrome with autoimmune hepatitis (AIH). The use of these biomarkers for diagnosis and prognosis of these patients will be reviewed through the lens of the current understanding of the complex immune pathophysiology of these conditions.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"914505"},"PeriodicalIF":0.0,"publicationDate":"2022-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43625765","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":"Gestational Dating by Urine Metabolic Profile at High Resolution Weekly Sampling Timepoints: Discovery and Validation.","authors":"Karl G Sylvester, Shiying Hao, Zhen Li, Zhi Han, Lu Tian, Subhashini Ladella, Ronald J Wong, Gary M Shaw, David K Stevenson, Harvey J Cohen, John C Whitin, Doff B McElhinney, Xuefeng B Ling","doi":"10.3389/fmmed.2022.844280","DOIUrl":"10.3389/fmmed.2022.844280","url":null,"abstract":"<p><p><b>Background:</b> Pregnancy triggers longitudinal metabolic alterations in women to allow precisely-programmed fetal growth. Comprehensive characterization of such a \"metabolic clock\" of pregnancy may provide a molecular reference in relation to studies of adverse pregnancy outcomes. However, a high-resolution temporal profile of metabolites along a healthy pregnancy remains to be defined. <b>Methods:</b> Two independent, normal pregnancy cohorts with high-density weekly urine sampling (discovery: 478 samples from 19 subjects at California; validation: 171 samples from 10 subjects at Alabama) were studied. Urine samples were profiled by liquid chromatography-mass spectrometry (LC-MS) for untargeted metabolomics, which was applied for gestational age dating and prediction of time to delivery. <b>Results:</b> 5,473 urinary metabolic features were identified. Partial least-squares discriminant analysis on features with robust signals (<i>n</i> = 1,716) revealed that the samples were distributed on the basis of the first two principal components according to their gestational age. Pathways of bile secretion, steroid hormone biosynthesis, pantohenate, and CoA biosynthesis, benzoate degradation, and phenylpropanoid biosynthesis were significantly regulated, which was collectively applied to discover and validate a predictive model that accurately captures the chronology of pregnancy. With six urine metabolites (acetylcholine, estriol-3-glucuronide, dehydroepiandrosterone sulfate, α-lactose, hydroxyexanoy-carnitine, and l-carnitine), models were constructed based on gradient-boosting decision trees to date gestational age in high accordance with ultrasound results, and to accurately predict time to delivery. <b>Conclusion:</b> Our study characterizes the weekly baseline profile of the human pregnancy metabolome, which provides a high-resolution molecular reference for future studies of adverse pregnancy outcomes.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"844280"},"PeriodicalIF":0.0,"publicationDate":"2022-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42151944","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":"Decoding Genetic Markers of Multiple Phenotypic Layers Through Biologically Constrained Genome-To-Phenome Bayesian Sparse Regression.","authors":"Marie Deprez, Julien Moreira, Maxime Sermesant, Marco Lorenzi","doi":"10.3389/fmmed.2022.830956","DOIUrl":"10.3389/fmmed.2022.830956","url":null,"abstract":"<p><p>The applicability of multivariate approaches for the joint analysis of genomics and phenomics information is currently limited by the lack of scalability, and by the difficulty of interpreting the related findings from a biological perspective. To tackle these limitations, we present Bayesian Genome-to-Phenome Sparse Regression (G2PSR), a novel multivariate regression method based on sparse SNP-gene constraints. The statistical framework of G2PSR is based on a Bayesian neural network, were constraints on SNPs-genes associations are integrated by incorporating <i>a priori</i> knowledge linking variants to their respective genes, to then reconstruct the phenotypic data in the output layer. Interpretability is promoted by inducing sparsity on the genes through variational dropout, allowing to estimate the uncertainty associated with each gene, and related SNPs, in the reconstruction task. Ultimately, G2PSR is conceived to prevent multiple testing correction and to assess the combined effect of SNPs, thus increasing the statistical power in detecting genome-to-phenome associations. The effectiveness of G2PSR was demonstrated on synthetic and real data, with respect to state-of-the-art methods based on group-wise sparsity constraints. The application on real data consisted in an imaging-genetics analysis on the Alzheimer's Disease Neuroimaging Initiative data, relating SNPs from more than 3,500 genes to clinical and multi-variate brain volumetric information. The experimental results show that our method can provide accurate selection of relevant genes in dataset with large SNPs-to-samples ratio, thus overcoming the main limitations of current genome-to-phenome association methods.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"830956"},"PeriodicalIF":0.0,"publicationDate":"2022-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41890824","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":"Long Non-Coding RNAs in Cardiac Hypertrophy.","authors":"Nicolò Mangraviti, Leon J De Windt","doi":"10.3389/fmmed.2022.836418","DOIUrl":"10.3389/fmmed.2022.836418","url":null,"abstract":"<p><p>Heart disease represents one of the main challenges in modern medicine with insufficient treatment options. Whole genome sequencing allowed for the discovery of several classes of non-coding RNA (ncRNA) and widened our understanding of disease regulatory circuits. The intrinsic ability of long ncRNAs (lncRNAs) and circular RNAs (circRNAs) to regulate gene expression by a plethora of mechanisms make them candidates for conceptually new treatment options. However, important questions remain to be addressed before we can fully exploit the therapeutic potential of these molecules. Increasing our knowledge of their mechanisms of action and refining the approaches for modulating lncRNAs expression are just a few of the challenges we face. The accurate identification of novel lncRNAs is hampered by their relatively poor cross-species sequence conservation and their low and context-dependent expression pattern. Nevertheless, progress has been made in their annotation in recent years, while a few experimental studies have confirmed the value of lncRNAs as new mechanisms in the development of cardiac hypertrophy and other cardiovascular diseases. Here, we explore cardiac lncRNA biology and the evidence that this class of molecules has therapeutic benefit to treat cardiac hypertrophy.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"836418"},"PeriodicalIF":0.0,"publicationDate":"2022-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41486308","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":"Computational Approaches Integrated in a Digital Ecosystem Platform for a Rare Disease.","authors":"Anna Visibelli, Vittoria Cicaloni, Ottavia Spiga, Annalisa Santucci","doi":"10.3389/fmmed.2022.827340","DOIUrl":"10.3389/fmmed.2022.827340","url":null,"abstract":"<p><p>Alkaptonuria (AKU) is an ultra-rare autosomal recessive disease caused by a mutation in the homogentisate 1,2-dioxygenase gene. One of the main obstacles in studying AKU and other ultra-rare diseases, is the lack of a standardized methodology to assess disease severity or response to treatment. Based on that, a multi-purpose digital platform, called ApreciseKUre, was implemented to facilitate data collection, integration and analysis for patients affected by AKU. It includes genetic, biochemical, histopathological, clinical, therapeutic resources and Quality of Life (QoL) scores that can be shared among registered researchers and clinicians to create a Precision Medicine Ecosystem. The combination of machine learning applications to analyse and re-interpret data available in the ApreciseKUre clearly indicated the potential direct benefits to achieve patients' stratification and the consequent tailoring of care and treatments to a specific subgroup of patients. In order to generate a comprehensive patient profile, computational modeling and database construction support the identification of potential new biomarkers, paving the way for more personalized therapy to maximize the benefit-risk ratio. In this work, different Machine Learning implemented approaches were described.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"827340"},"PeriodicalIF":0.0,"publicationDate":"2022-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46888665","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":"Perspectives on Bulk-Tissue RNA Sequencing and Single-Cell RNA Sequencing for Cardiac Transcriptomics.","authors":"Jana-Charlotte Hegenbarth, Giuliana Lezzoche, Leon J De Windt, Monika Stoll","doi":"10.3389/fmmed.2022.839338","DOIUrl":"10.3389/fmmed.2022.839338","url":null,"abstract":"<p><p>The heart has been the center of numerous transcriptomic studies in the past decade. Even though our knowledge of the key organ in our cardiovascular system has significantly increased over the last years, it is still not fully understood yet. In recent years, extensive efforts were made to understand the genetic and transcriptomic contribution to cardiac function and failure in more detail. The advent of Next Generation Sequencing (NGS) technologies has brought many discoveries but it is unable to comprehend the finely orchestrated interactions between and within the various cell types of the heart. With the emergence of single-cell sequencing more than 10 years ago, researchers gained a valuable new tool to enable the exploration of new subpopulations of cells, cell-cell interactions, and integration of multi-omic approaches at a single-cell resolution. Despite this innovation, it is essential to make an informed choice regarding the appropriate technique for transcriptomic studies, especially when working with myocardial tissue. Here, we provide a primer for researchers interested in transcriptomics using NGS technologies.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"839338"},"PeriodicalIF":0.0,"publicationDate":"2022-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49259346","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":"Current Understanding of piRNA in Cardiovascular Diseases.","authors":"Iokfai Cheang, Qingqing Zhu, Shengen Liao, Xinli Li","doi":"10.3389/fmmed.2021.791931","DOIUrl":"10.3389/fmmed.2021.791931","url":null,"abstract":"<p><p>The relationship regarding non-coding genomes and cardiovascular disease (CVD) has been explored in the past decade. As one of the leading causes of death, there remains a lack of sensitive and specific genomic biomarkers in the diagnosis and prognosis of CVD. Piwi-interacting RNA (piRNA) is a group of small non-coding RNA (ncRNA) which associated with Piwi proteins. There is an emerging strong body of evidence in support of a role for ncRNAs, including piRNAs, in pathogenesis and prognosis of CVD. This article reviews the current evidence for piRNA-regulated mechanisms in CVD, which could lead to the development of new therapeutic strategies for prevention and treatment.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"1 1","pages":"791931"},"PeriodicalIF":0.0,"publicationDate":"2022-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42487574","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":"Nicotinamide Riboside Improves Cardiac Function and Prolongs Survival After Disruption of the Cardiomyocyte Clock.","authors":"Pieterjan Dierickx,&nbsp;Bryce J Carpenter,&nbsp;Isaac Celwyn,&nbsp;Daniel P Kelly,&nbsp;Joseph A Baur,&nbsp;Mitchell A Lazar","doi":"10.3389/fmmed.2022.887733","DOIUrl":"https://doi.org/10.3389/fmmed.2022.887733","url":null,"abstract":"<p><p>The REV-ERB nuclear receptors are key components of the circadian clock. Loss of REV-ERBs in the mouse heart causes dilated cardiomyopathy and premature lethality. This is associated with a marked reduction in NAD⁺ production, but whether this plays a role in the pathophysiology of this heart failure model is not known. Here, we show that supplementation with the NAD⁺ precursor NR as a dietary supplement improves heart function and extends the lifespan of female mice lacking cardiac REV-ERBs. Thus, boosting NAD⁺ levels can improve cardiac function in a setting of heart failure caused by disruption of circadian clock factors, providing new insights into the links between the circadian clock, energy metabolism, and cardiac function.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10310318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9770881","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":"Selective Inhibition of Bromodomain-Containing Protein 4 Reduces Myofibroblast Transdifferentiation and Pulmonary Fibrosis.","authors":"Ksenija Bernau,&nbsp;Melissa Skibba,&nbsp;Jonathan P Leet,&nbsp;Sierra Furey,&nbsp;Carson Gehl,&nbsp;Yi Li,&nbsp;Jia Zhou,&nbsp;Nathan Sandbo,&nbsp;Allan R Brasier","doi":"10.3389/fmmed.2022.842558","DOIUrl":"https://doi.org/10.3389/fmmed.2022.842558","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis is a lethal disease driven by myofibroblast expansion. Currently no therapies exist that target the epigenetic mechanisms controlling myofibroblast transdifferentiation, which is responsible for unregulated extracellular matrix (ECM) production. We have recently shown that bromodomain-containing protein 4 (BRD4), an epigenetic regulator that forms a scaffold for nuclear activators and transcription factors, is essential for TGFβ-induced myofibroblast transdifferentiation. However, its role in the development and progression of pulmonary fibrosis <i>in vivo</i> has not been established. Here, we evaluate the hypothesis that BRD4 bromodomain interactions mediate myofibroblast expansion and fibrosing disease <i>in vivo</i>. C57BL/6J mice challenged with intratracheal bleomycin were systemically treated with a selective allosteric inhibitor of the BRD4 bromodomain 1 (BD1), ZL0591 (10 mg/kg), during the established fibrotic phase (14 days post-bleomycin) in a rigorous therapeutic paradigm. Eleven days after initiation of ZL0591 treatment (25 days post-bleomycin), we detected a significant improvement in blood O₂ saturation compared to bleomycin/vehicle control. Twenty-eight days post-bleomycin, we observed a reduction in the volumetric Hounsfield Unit (HU) density by micro computed tomography (μCT) in the ZL0591-treated group, as well as a reduction in collagen deposition (hydroxyproline content) and severity of injury (Ashcroft scoring). Myofibroblast transdifferentiation was measured by smooth muscle α-actin (αSMA) staining, indicating a loss of this cell population in the ZL0591-treated group, and corresponded to reduced transcript levels of myofibroblast-associated extracellular matrix genes, tenascin-C and collagen 1α1. We conclude that BRD4 BD1 interactions are critical for myofibroblast transdifferentiation and fibrotic progression in a mouse model of pulmonary fibrosis.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9245900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40556920","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}