87 results on '"Martelli, Fabio"'
Search Results
2. Regulatory miRNAs in Cardiovascular and Alzheimer's Disease: A Focus on Copper.
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Sacco, Anna, Martelli, Fabio, Pal, Amit, Saraceno, Claudia, Benussi, Luisa, Ghidoni, Roberta, Rongioletti, Mauro, and Squitti, Rosanna
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ALZHEIMER'S disease , *MICRORNA , *NON-coding RNA , *HYPOXIA-inducible factors , *ETIOLOGY of diseases - Abstract
Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), are key regulators of differentiation and development. In the cell, transcription factors regulate the production of miRNA in response to different external stimuli. Copper (Cu) is a heavy metal and an essential micronutrient with widespread industrial applications. It is involved in a number of vital biological processes encompassing respiration, blood cell line maturation, and immune responses. In recent years, the link between deregulation of miRNAs' functionality and the development of various pathologies as well as cardiovascular diseases (CVDs) has been extensively studied. Alzheimer's disease (AD) is the most common cause of dementia in the elderly with a complex disease etiology, and its link with Cu abnormalities is being increasingly studied. A direct interaction between COMMD1, a regulator of the Cu pathway, and hypoxia-inducible factor (HIF) HIF-1a does exist in ischemic injury, but little information has been collected on the role of Cu in hypoxia associated with AD thus far. The current review deals with this matter in an attempt to structurally discuss the link between miRNA expression and Cu dysregulation in AD and CVDs. [ABSTRACT FROM AUTHOR]
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- 2022
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3. p66ShcA and Oxidative Stress Modulate Myogenic Differentiation and Skeletal Muscle Regeneration after Hind Limb lschemia.
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Zaccagnini, Germana, Martelli, Fabio, Magenta, Alessandra, Cencioni, Chiara, Fasanaro, Pasquale, Nicoletti, Carmine, Biglioli, Paolo, Pelicci, Pier Giuseppe, and Capogrossi, Maurizio C.
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OXIDATIVE stress , *OXIDATION-reduction reaction , *MYOBLASTS , *CELL differentiation , *MUSCLE regeneration , *ISCHEMIA , *BIOCHEMISTRY - Abstract
Oxidative stress plays a pivotal role in ischemic injury, and p66ShcAko mice exhibit both lower oxidative stress and decreased tissue damage following hind limb ischemia. Thus, it was investigated whether tissue regeneration following acute hind limb ischemia was altered in p66ShcAko mice. Upon femoral artery dissection, muscle regeneration started earlier and was completed faster than in wild-type (WT) control. Moreover, faster regeneration was associated with decreased oxidative stress. Unlike ischemia, cardiotoxin injury induced similar skeletal muscle damage in both genotypes. However, p66ShcAko mice regenerated faster, in agreement with the regenerative advantage upon ischemia. Since no difference between p66ShcAwt and knock-out (ko) mice was found in blood perfusion recovery after ischemia, satellite cells (SCs), a resident population of myogenic progenitors, were examined. Similar SCs numbers were present in WT and ko mice. However, in vitro cultured p66ShcAko SCs displayed lower oxidative stress levels and higher proliferation rate and differentiated faster than WT, Furthermore, when exposed to sublethal H2O2 doses, p6ShcAko SCs were resistant to H2O2- induced inhibition of differentiation. Finally, myogenic conversion induced by MyoD overexpression was more efficient in p66ShcAko fibroblasts compared with WI. The present work demonstrates that oxidative stress and p66ShcA play a crucial role in the regenerative pathways activated by acute ischemia. [ABSTRACT FROM AUTHOR]
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- 2007
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4. P19ARF targets certain E2F species for degradation.
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Martelli, Fabio, Hamilton, Timothy, Silver, Daniel P., Sharpless, Norman E., Bardeesy, Nabeel, Rokas, Mikhail, DePinho, Ronald A., Livingston, David M., and Grossman, Steven R.
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TRANSCRIPTION factors , *PROTEINS , *CYTOLOGY - Abstract
Investigates the effects of alternative reading frame protein p19ARF on the abundance of E2F transcription factor family in cells. Destabiization of E2F1; Reduction in the endogenos stability E2F1 and E2F3; Association of p19ARF with E2F1, E2F2 and E2F3.
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- 2001
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5. MicroRNAs in Hypoxia Response.
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Greco, Simona and Martelli, Fabio
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MICRORNA , *HYPOXEMIA , *OXIDATIVE stress , *CARDIOVASCULAR diseases risk factors , *CANCER risk factors , *REGULATION of cell metabolism , *GENETICS - Abstract
Among the complex and articulated molecular mechanisms activated by hypoxia, microRNAs play a central role. Specifically, this Forum is dedicated to hypoxamiRs, defined as microRNAs that not only are directly regulated by hypoxia but also regulate cell responses to decreased oxygen tension. We assembled a collection of reviews and research communications by authoritative leaders in a variety of disciplines, describing hypoxamiRs from different angles. Fundamental technical issues as well as hypoxamiR impact on general events, such as metabolism and development, are critically reviewed. The regulation and the role of hypoxamiRs in cardiovascular diseases and in cancer are also addressed. An increased understanding of the function of hypoxamiR in gene regulatory networks of great physiopathological relevance may allow the development of innovative therapeutic approaches for all ischemic diseases. Antioxid. Redox Signal. 21, 1164-1166. [ABSTRACT FROM AUTHOR]
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- 2014
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6. Circular RNA regulatory role in pathological cardiac remodelling.
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Bibi, Alessia, Bartekova, Monika, Gandhi, Shrey, Greco, Simona, Madè, Alisia, Sarkar, Moumita, Stopa, Victoria, Tastsoglou, Spyros, Gonzalo‐Calvo, David, Devaux, Yvan, Emanueli, Costanza, Hatzigeorgiou, Artemis G., Nossent, A. Yaël, Zhou, Zhichao, and Martelli, Fabio
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Cardiac remodelling involves structural, cellular and molecular alterations in the heart after injury, resulting in progressive loss of heart function and ultimately leading to heart failure. Circular RNAs (circRNAs) are a recently rediscovered class of non‐coding RNAs that play regulatory roles in the pathogenesis of cardiovascular diseases, including heart failure. Thus, a more comprehensive understanding of the role of circRNAs in the processes governing cardiac remodelling may set the ground for the development of circRNA‐based diagnostic and therapeutic strategies. In this review, the current knowledge about circRNA origin, conservation, characteristics and function is summarized. Bioinformatics and wet‐lab methods used in circRNA research are discussed. The regulatory function of circRNAs in cardiac remodelling mechanisms such as cell death, cardiomyocyte hypertrophy, inflammation, fibrosis and metabolism is highlighted. Finally, key challenges and opportunities in circRNA research are discussed, and orientations for future work to address the pharmacological potential of circRNAs in heart failure are proposed. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Regulation of endogenous E2F1 stability by the retinoblastoma family proteins.
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Martelli, Fabio and Livingston, David M.
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RETINOBLASTOMA , *CELL cycle , *TRANSCRIPTION factors - Abstract
Presents information on a study which examined the participation of retinoblastoma family proteins in regulating cell-cycle progression by certain E2F transcription factor. Materials and methods; Results and discussion.
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- 1999
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8. Integration of epigenetic regulatory mechanisms in heart failure.
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Sopic, Miron, Robinson, Emma L., Emanueli, Costanza, Srivastava, Prashant, Angione, Claudio, Gaetano, Carlo, Condorelli, Gianluigi, Martelli, Fabio, Pedrazzini, Thierry, and Devaux, Yvan
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The number of “omics” approaches is continuously growing. Among others, epigenetics has appeared as an attractive area of investigation by the cardiovascular research community, notably considering its association with disease development. Complex diseases such as cardiovascular diseases have to be tackled using methods integrating different omics levels, so called “multi-omics” approaches. These approaches combine and co-analyze different levels of disease regulation. In this review, we present and discuss the role of epigenetic mechanisms in regulating gene expression and provide an integrated view of how these mechanisms are interlinked and regulate the development of cardiac disease, with a particular attention to heart failure. We focus on DNA, histone, and RNA modifications, and discuss the current methods and tools used for data integration and analysis. Enhancing the knowledge of these regulatory mechanisms may lead to novel therapeutic approaches and biomarkers for precision healthcare and improved clinical outcomes. [ABSTRACT FROM AUTHOR]
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- 2023
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9. circRNA-miRNA-mRNA Deregulated Network in Ischemic Heart Failure Patients.
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Madè, Alisia, Bibi, Alessia, Garcia-Manteiga, Jose Manuel, Tascini, Anna Sofia, Piella, Santiago Nicolas, Tikhomirov, Roman, Voellenkle, Christine, Gaetano, Carlo, Leszek, Przemyslaw, Castelvecchio, Serenella, Menicanti, Lorenzo, Martelli, Fabio, and Greco, Simona
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CIRCULAR RNA , *HEART failure patients , *NON-coding RNA , *ENDOTHELIAL cells , *CELL cycle , *MESSENGER RNA - Abstract
Noncoding RNAs (ncRNAs), which include circular RNAs (circRNAs) and microRNAs (miRNAs), regulate the development of cardiovascular diseases (CVD). Notably, circRNAs can interact with miRNAs, influencing their specific mRNA targets' levels and shaping a competing endogenous RNAs (ceRNA) network. However, these interactions and their respective functions remain largely unexplored in ischemic heart failure (IHF). This study is aimed at identifying circRNA-centered ceRNA networks in non-end-stage IHF. Approximately 662 circRNA-miRNA-mRNA interactions were identified in the heart by combining state-of-the-art bioinformatics tools with experimental data. Importantly, KEGG terms of the enriched mRNA indicated CVD-related signaling pathways. A specific network centered on circBPTF was validated experimentally. The levels of let-7a-5p, miR-18a-3p, miR-146b-5p, and miR-196b-5p were enriched in circBPTF pull-down experiments, and circBPTF silencing inhibited the expression of HDAC9 and LRRC17, which are targets of miR-196b-5p. Furthermore, as suggested by the enriched pathway terms of the circBPTF ceRNA network, circBPTF inhibition elicited endothelial cell cycle arrest. circBPTF expression increased in endothelial cells exposed to hypoxia, and its upregulation was confirmed in cardiac samples of 36 end-stage IHF patients compared to healthy controls. In conclusion, circRNAs act as miRNA sponges, regulating the functions of multiple mRNA targets, thus providing a novel vision of HF pathogenesis and laying the theoretical foundation for further experimental studies. [ABSTRACT FROM AUTHOR]
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- 2023
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10. HCG18, LEF1AS1 and lncCEACAM21 as biomarkers of disease severity in the peripheral blood mononuclear cells of COVID-19 patients.
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Greco, Simona, Made', Alisia, Mutoli, Martina, Zhang, Lu, Piella, Santiago Nicolas, Vausort, Mélanie, Lumley, Andrew I., Beltrami, Antonio Paolo, Srivastava, Prashant Kumar, Milani, Valentina, Boveri, Sara, Ranucci, Marco, Renna, Laura Valentina, Firat, Hüseyin, Bruno, Antonino, Spinetti, Gaia, Emanueli, Costanza, Devaux, Yvan, and Martelli, Fabio
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MONONUCLEAR leukocytes , *COVID-19 , *CYTOTOXIC T cells , *KILLER cells , *LINCRNA - Abstract
Background: Even after 3 years from SARS-CoV-2 identification, COVID-19 is still a persistent and dangerous global infectious disease. Significant improvements in our understanding of the disease pathophysiology have now been achieved. Nonetheless, reliable and accurate biomarkers for the early stratification of COVID-19 severity are still lacking. Long noncoding RNAs (LncRNAs) are ncRNAs longer than 200 nucleotides, regulating the transcription and translation of protein‐coding genes and they can be found in the peripheral blood, thus holding a promising biomarker potential. Specifically, peripheral blood mononuclear cells (PBMCs) have emerged as a source of indirect biomarkers mirroring the conditions of tissues: they include monocytes, B and T lymphocytes, and natural killer T cells (NKT), being highly informative for immune-related events. Methods: We profiled by RNA-Sequencing a panel of 2906 lncRNAs to investigate their modulation in PBMCs of a pilot group of COVID-19 patients, followed by qPCR validation in 111 hospitalized COVID-19 patients. Results: The levels of four lncRNAs were found to be decreased in association with COVID-19 mortality and disease severity: HLA Complex Group 18-242 and -244 (HCG18-242 and HCG18-244), Lymphoid Enhancer Binding Factor 1-antisense 1 (LEF1-AS1) and lncCEACAM21 (i.e. ENST00000601116.5, a lncRNA in the CEACAM21 locus). Interestingly, these deregulations were confirmed in an independent patient group of hospitalized patients and by the re-analysis of publicly available single-cell transcriptome datasets. The identified lncRNAs were expressed in all of the PBMC cell types and inversely correlated with the neutrophil/lymphocyte ratio (NLR), an inflammatory marker. In vitro, the expression of LEF1-AS1 and lncCEACAM21 was decreased upon THP-1 monocytes exposure to a relevant stimulus, hypoxia. Conclusion: The identified COVID-19-lncRNAs are proposed as potential innovative biomarkers of COVID-19 severity and mortality. [ABSTRACT FROM AUTHOR]
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- 2023
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11. Removing the brakes to cardiomyocyte cell cycle.
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Di Stefano, Valeria and Martelli, Fabio
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- 2011
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12. Cardiovascular complications of diabetes: role of non-coding RNAs in the crosstalk between immune and cardiovascular systems.
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Spinetti, Gaia, Mutoli, Martina, Greco, Simona, Riccio, Federica, Ben-Aicha, Soumaya, Kenneweg, Franziska, Jusic, Amela, de Gonzalo-Calvo, David, Nossent, Anne Yaël, Novella, Susana, Kararigas, Georgios, Thum, Thomas, Emanueli, Costanza, Devaux, Yvan, and Martelli, Fabio
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NON-coding RNA , *DIABETES complications , *CARDIOVASCULAR system , *CARDIOLOGICAL manifestations of general diseases , *HYPERGLYCEMIA , *METABOLIC disorders , *DISEASE risk factors - Abstract
Diabetes mellitus, a group of metabolic disorders characterized by high levels of blood glucose caused by insulin defect or impairment, is a major risk factor for cardiovascular diseases and related mortality. Patients with diabetes experience a state of chronic or intermittent hyperglycemia resulting in damage to the vasculature, leading to micro- and macro-vascular diseases. These conditions are associated with low-grade chronic inflammation and accelerated atherosclerosis. Several classes of leukocytes have been implicated in diabetic cardiovascular impairment. Although the molecular pathways through which diabetes elicits an inflammatory response have attracted significant attention, how they contribute to altering cardiovascular homeostasis is still incompletely understood. In this respect, non-coding RNAs (ncRNAs) are a still largely under-investigated class of transcripts that may play a fundamental role. This review article gathers the current knowledge on the function of ncRNAs in the crosstalk between immune and cardiovascular cells in the context of diabetic complications, highlighting the influence of biological sex in such mechanisms and exploring the potential role of ncRNAs as biomarkers and targets for treatments. The discussion closes by offering an overview of the ncRNAs involved in the increased cardiovascular risk suffered by patients with diabetes facing Sars-CoV-2 infection. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Peripheral blood RNA biomarkers for cardiovascular disease from bench to bedside: a position paper from the EU-CardioRNA COST action CA17129.
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Vanhaverbeke, Maarten, Attard, Ritienne, Bartekova, Monika, Ben-Aicha, Soumaya, Brandenburger, Timo, Gonzalo-Calvo, David de, Emanueli, Costanza, Farrugia, Rosienne, Grillari, Johannes, Hackl, Matthias, Kalocayova, Barbora, Martelli, Fabio, Scholz, Markus, Wettinger, Stephanie Bezzina, and Devaux, Yvan
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RNA , *NON-coding RNA , *CARDIOVASCULAR disease diagnosis , *HEART failure , *GENE expression , *CARDIOVASCULAR diseases , *BIOMARKERS - Abstract
Despite significant advances in the diagnosis and treatment of cardiovascular diseases, recent calls have emphasized the unmet need to improve precision-based approaches in cardiovascular disease. Although some studies provide preliminary evidence of the diagnostic and prognostic potential of circulating coding and non-coding RNAs, the complex RNA biology and lack of standardization have hampered the translation of these markers into clinical practice. In this position paper of the CardioRNA COST action CA17129, we provide recommendations to standardize the RNA development process in order to catalyse efforts to investigate novel RNAs for clinical use. We list the unmet clinical needs in cardiovascular disease, such as the identification of high-risk patients with ischaemic heart disease or heart failure who require more intensive therapies. The advantages and pitfalls of the different sample types, including RNAs from plasma, extracellular vesicles, and whole blood, are discussed in the sample matrix, together with their respective analytical methods. The effect of patient demographics and highly prevalent comorbidities, such as metabolic disorders, on the expression of the candidate RNA is presented and should be reported in biomarker studies. We discuss the statistical and regulatory aspects to translate a candidate RNA from a research use only assay to an in-vitro diagnostic test for clinical use. Optimal planning of this development track is required, with input from the researcher, statistician, industry, and regulatory partners. [ABSTRACT FROM AUTHOR]
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- 2022
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14. CircANKRD12 Is Induced in Endothelial Cell Response to Oxidative Stress.
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Voellenkle, Christine, Fuschi, Paola, Mutoli, Martina, Carrara, Matteo, Righini, Paolo, Nano, Giovanni, Gaetano, Carlo, and Martelli, Fabio
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CIRCULAR RNA , *ENDOTHELIAL cells , *OXIDATIVE stress , *CELLULAR signal transduction , *SKELETAL muscle , *TRANSCRIPTOMES , *CARDIOVASCULAR diseases - Abstract
Redox imbalance of the endothelial cells (ECs) plays a causative role in a variety of cardiovascular diseases. In order to better understand the molecular mechanisms of the endothelial response to oxidative stress, the involvement of circular RNAs (circRNAs) was investigated. CircRNAs are RNA species generated by a "back-splicing" event, which is the covalent linking of the 3′- and 5′-ends of exons. Bioinformatics analysis of the transcriptomic landscape of human ECs exposed to H2O2 allowed us to identify a subset of highly expressed circRNAs compared to their linear RNA counterparts, suggesting a potential biological relevance. Specifically, circular Ankyrin Repeat Domain 12 (circANKRD12), derived from the junction of exon 2 and exon 8 of the ANKRD12 gene (hsa_circ_0000826), was significantly induced in H2O2-treated ECs. Conversely, the linear RNA isoform of ANKRD12 was not modulated. An increased circular-to-linear ratio of ANKRD12 was also observed in cultured ECs exposed to hypoxia and in skeletal muscle biopsies of patients affected by critical limb ischemia (CLI), two conditions associated with redox imbalance and oxidative stress. The functional relevance of circANKRD12 was shown by the inhibition of EC formation of capillary-like structures upon silencing of the circular but not of the linear isoform of ANKRD12. Bioinformatics analysis of the circANKRD12–miRNA–mRNA regulatory network in H2O2-treated ECs identified the enrichment of the p53 and Foxo signaling pathways, both crucial in the cellular response to redox imbalance. In keeping with the antiproliferative action of the p53 pathway, circANKRD12 silencing inhibited EC proliferation. In conclusion, this study indicates circANKRD12 as an important player in ECs exposed to oxidative stress. [ABSTRACT FROM AUTHOR]
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- 2022
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15. Addressing the unsolved challenges in microRNA-based biomarker development: Suitable endogenous reference microRNAs for SARS-CoV-2 infection severity.
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Belmonte, Thalia, Perez-Pons, Manel, Benítez, Iván D., Molinero, Marta, García-Hidalgo, María C., Rodríguez-Muñoz, Carlos, Gort-Paniello, Clara, Moncusí-Moix, Anna, Madè, Alisia, Devaux, Yvan, Martelli, Fabio, Ortega, Alicia, González, Jessica, Torres, Gerard, Barbé, Ferran, and de Gonzalo-Calvo, David
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COVID-19 , *BIOMARKERS , *SARS-CoV-2 , *MICRORNA , *HOSPITAL admission & discharge - Abstract
Circulating cell-free microRNAs (miRNAs) are promising biomarkers for medical decision-making. Suitable endogenous controls are essential to ensure reproducibility. We aimed to identify and validate endogenous reference miRNAs for qPCR data normalization in samples from SARS-CoV-2-infected hospitalized patients. We used plasma samples (n = 170) from COVID-19 patients collected at hospital admission (COVID-Ponent project, www.clinicaltrials.gov/NCT04824677). First, 179 miRNAs were profiled using RT–qPCR. After stability assessment, candidates were validated using the same methodology. miRNA stability was analyzed using the geNorm, NormFinder and BestKeeper algorithms. Stability was further evaluated using an RNA-seq dataset derived from COVID-19 hospitalized patients, along with plasma samples from patients with critical COVID-19 profiled using RT-qPCR. In the screening phase, after strict control of expression levels, stability assessment selected eleven candidates (miR-17-5p, miR-20a-5p, miR-30e-5p, miR-106a-5p, miR-151a-5p, miR-185-5p, miR-191-5p, miR-423-3p, miR-425-5p, miR-484 and miR-625-5p). In the validation phase, all algorithms identified miR-106a-5p and miR-484 as top endogenous controls. No association was observed between these miRNAs and clinical or sociodemographic characteristics. Both miRNAs were stably detected and showed low variability in the additional analyses. In conclusion, a 2-miRNA panel composed of miR-106a-5p and miR-484 constitutes a first-line normalizer for miRNA-based biomarker development using qPCR in hospitalized patients infected with SARS-CoV-2. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Molecular Therapies for Myotonic Dystrophy Type 1: From Small Drugs to Gene Editing.
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Izzo, Mariapaola, Battistini, Jonathan, Provenzano, Claudia, Martelli, Fabio, Cardinali, Beatrice, and Falcone, Germana
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MYOTONIA atrophica , *GENOME editing , *FACIOSCAPULOHUMERAL muscular dystrophy , *MUSCULAR dystrophy , *CENTRAL nervous system , *MYOCARDIUM - Abstract
Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy affecting many different body tissues, predominantly skeletal and cardiac muscles and the central nervous system. The expansion of CTG repeats in the DM1 protein-kinase (DMPK) gene is the genetic cause of the disease. The pathogenetic mechanisms are mainly mediated by the production of a toxic expanded CUG transcript from the DMPK gene. With the availability of new knowledge, disease models, and technical tools, much progress has been made in the discovery of altered pathways and in the potential of therapeutic intervention, making the path to the clinic a closer reality. In this review, we describe and discuss the molecular therapeutic strategies for DM1, which are designed to directly target the CTG genomic tract, the expanded CUG transcript or downstream signaling molecules. [ABSTRACT FROM AUTHOR]
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- 2022
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17. Noncoding RNA in age-related cardiovascular diseases.
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Greco, Simona, Gorospe, Myriam, and Martelli, Fabio
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CARDIOVASCULAR diseases , *MEDICAL genetics , *NON-coding RNA , *MICRORNA , *GENE expression , *EUKARYOTIC genomes , *GENETIC transcription , *HOSTS (Biology) - Abstract
Eukaryotic gene expression is tightly regulated transcriptionally and post-transcriptionally by a host of noncoding (nc)RNAs. The best-studied class of short ncRNAs, microRNAs, mainly repress gene expression post-transcriptionally. Long noncoding (lnc)RNAs, which comprise RNAs differing widely in length and function, can regulate gene transcription as well as post-transcriptional mRNA fate. Collectively, ncRNAs affect a broad range of age-related physiologic deteriorations and pathologies, including reduced cardiovascular vigor and age-associated cardiovascular disease. This review presents an update of our understanding of regulatory ncRNAs contributing to cardiovascular health and disease as a function of advancing age. We will discuss (1) regulatory ncRNAs that control aging-associated cardiovascular homeostasis and disease, (2) the concepts, approaches, and methodologies needed to study regulatory ncRNAs in cardiovascular aging and (3) the challenges and opportunities that age-associated regulatory ncRNAs present in cardiovascular physiology and pathology. This article is part of a Special Issue entitled “CV Aging”. [ABSTRACT FROM AUTHOR]
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- 2015
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18. HypoxamiR Regulation and Function in Ischemic Cardiovascular Diseases.
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Greco, Simona, Gaetano, Carlo, and Martelli, Fabio
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CORONARY disease , *CORONARY heart disease risk factors , *MICRORNA , *HYPOXEMIA , *GENETIC regulation , *GENE expression , *GENETICS , *PHYSIOLOGY - Abstract
Significance: MicroRNAs (miRNAs) are deregulated and play a causal role in numerous cardiovascular diseases, including myocardial infarction, coronary artery disease, hypertension, heart failure, stroke, peripheral artery disease, kidney ischemia-reperfusion. Recent Advances: One crucial component of ischemic cardiovascular diseases is represented by hypoxia. Indeed, hypoxia is a powerful stimulus regulating the expression of a specific subset of miRNAs, named hypoxia-induced miRNAs (hypoxamiR). These miRNAs are fundamental regulators of the cell responses to decreased oxygen tension. Certain hypoxamiRs seem to have a particularly pervasive role, such as miR-210 that is virtually induced in all ischemic diseases tested so far. However, its specific function may change according to the physiopathological context. Critical Issues: The discovery of HypoxamiR dates back 6 years. Thus, despite a rapid growth in knowledge and attention, a deeper insight of the molecular mechanisms underpinning hypoxamiR regulation and function is needed. Future Directions: An extended understanding of the function of hypoxamiR in gene regulatory networks associated with cardiovascular diseases will allow the identification of novel molecular mechanisms of disease and indicate the development of innovative therapeutic approaches. Antioxid. Redox Signal. 21, 1202-1219. [ABSTRACT FROM AUTHOR]
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- 2014
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19. miR-210 hypoxamiR in Angiogenesis and Diabetes.
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Zaccagnini, Germana, Greco, Simona, Voellenkle, Christine, Gaetano, Carlo, and Martelli, Fabio
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NEOVASCULARIZATION , *CARDIOVASCULAR diseases , *DIABETES , *GENE ontology , *CELL proliferation , *CELL migration inhibition , *MICRORNA - Abstract
Significance: microRNA-210 (miR-210) is the master hypoxia-inducible miRNA (hypoxamiR) since it has been found to be significantly upregulated under hypoxia in a wide range of cell types. Recent advances: Gene ontology analysis of its targets indicates that miR-210 modulates several aspects of cellular response to hypoxia. Due to its high pleiotropy, miR-210 not only plays a protective role by fine-tuning mitochondrial metabolism and inhibiting red-ox imbalance and apoptosis, but it can also promote cell proliferation, differentiation, and migration, substantially contributing to angiogenesis. Critical issues: As most miRNAs, modulating different gene pathways, also miR-210 can potentially lead to different and even opposite effects, depending on the physio-pathological contexts in which it acts. Future direction: The use of miRNAs as therapeutics is a fast growing field. This review aimed at highlighting the role of miR-210 in angiogenesis in the context of ischemic cardiovascular diseases and diabetes in order to clarify the molecular mechanisms underpinning miR-210 action. Particular attention will be dedicated to experimentally validated miR-210 direct targets involved in cellular processes related to angiogenesis and diabetes mellitus, such as mitochondrial metabolism, redox balance, apoptosis, migration, and adhesion. Antioxid. Redox Signal. 36, 685–706. [ABSTRACT FROM AUTHOR]
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- 2022
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20. Oxidative Stress and Epigenetic Regulation in Ageing and Age-Related Diseases.
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Cencioni, Chiara, Spallotta, Francesco, Martelli, Fabio, Valente, Sergio, Mai, Antonello, Zeiher, Andreas M., and Gaetano, Carlo
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OXIDATIVE stress , *AGE factors in disease , *EPIGENETICS , *PHYSIOLOGICAL aspects of aging , *LIFESTYLES & health , *PATHOLOGICAL physiology - Abstract
Recent statistics indicate that the human population is ageing rapidly. Healthy, but also diseased, elderly people are increasing. This trend is particularly evident in Western countries, where healthier living conditions and better cures are available. To understand the process leading to age-associated alterations is, therefore, of the highest relevance for the development of new treatments for age-associated diseases, such as cancer, diabetes, Alzheimer and cardiovascular accidents. Mechanistically, it is well accepted that the accumulation of intracellular damage determined by reactive oxygen species (ROS) might orchestrate the progressive loss of control over biological homeostasis and the functional impairment typical of aged tissues. Here, we review how epigenetics takes part in the control of stress stimuli and the mechanisms of ageing physiology and physiopathology. Alteration of epigenetic enzyme activity, histone modifications and DNA-methylation is, in fact, typically associated with the ageing process. Specifically, ageing presents peculiar epigenetic markers that, taken altogether, form the still ill-defined "ageing epigenome". The comprehension of mechanisms and pathways leading to epigenetic modifications associated with ageing may help the development of anti-ageing therapies. [ABSTRACT FROM AUTHOR]
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- 2013
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21. miR-210: More than a silent player in hypoxia.
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Devlin, Cecilia, Greco, Simona, Martelli, Fabio, and Ivan, Mircea
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RNA , *HYPOXEMIA , *CANCER prognosis , *NEOVASCULARIZATION , *DNA repair - Abstract
Multiple studies have consistently established that miR (microRNA)-210 induction is a feature of the hypoxic response in both normal and transformed cells. Here, we discuss the emerging biochemical functions of this miRNA and anticipate potential clinical applications. miR-210 is a robust target of hypoxia-inducible factor, and its overexpression has been detected in a variety of cardiovascular diseases and solid tumors. High levels of miR-210 have been linked to an in vivo hypoxic signature and associated with adverse prognosis in cancer patients. A wide spectrum of miR-210 targets have been identified, with roles in mitochondrial metabolism, angiogenesis, DNA repair, and cell survival. Such targets may broadly affect the evolution of tumors and other pathological settings, such as ischemic disorders. Harnessing the knowledge of miR-210's actions may lead to novel diagnostic and therapeutic approaches. © 2011 IUBMB IUBMB Life, 63(2): 94-100, 2011 [ABSTRACT FROM AUTHOR]
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- 2011
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22. Regulation of the endothelial cell cycle by the ubiquitin-proteasome system.
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Fasanaro, Pasquale, Capogrossi, Maurizio C., and Martelli, Fabio
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UBIQUITIN , *CELL cycle , *ENDOTHELIUM , *OXIDATIVE stress , *BIOLOGICAL rhythms - Abstract
Degradation of poly-ubiquitinated proteins by the 26S-proteasome complex represents a crucial quantitative control mechanism. The ubiquitin-proteasome system (UPS) plays a pivotal role in the complex molecular network regulating the progression both between and within each cell-cycle phase. Two major complexes are involved: the SKP1-CUL1-F-box-protein complex (SCF) and the anaphase-promoting complex/cyclosome (APC/C). Notwithstanding structural similarities, SCF and APC/C display different cellular functions and mechanisms of action. SCF modulates all cell-cycle stages and plays a prominent role at G1/S transition mainly through three regulatory subunits: Skp2, Fbw7, and β-TRCP. APC/C, regulated by Cdc20 or Cdh1 subunits, has a crucial role in mitosis. In this review, we will describe how the endothelial cell cycle is regulated by the UPS. We will illustrate the principal SCF- and APC/C-dependent molecular mechanisms that modulate cell growth, allowing a unidirectional cell-cycle progression. Then, we will focus our attention on UPS modulation by oxidative stress, a pathogenic stimulus that causes endothelial dysfunction and is involved in numerous cardiovascular diseases. [ABSTRACT FROM PUBLISHER]
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- 2010
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23. Hypoxia Inhibits Myogenic Differentiation through Accelerated MyoD Degradation.
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Di Carlo, Anna, De Mori, Roberta, Martelli, Fabio, Pompilio, Giulio, Capogrossi, Maurizio C., and Germani, Antonia
- Subjects
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TRANSCRIPTION factors , *HYPOXEMIA , *MYOBLASTS , *CELL differentiation , *CYTOLOGY , *CELL cycle - Abstract
Cells undergo a variety of biological responses when placed in hypoxic conditions, including alterations in metabolic state and growth rate. Here we investigated the effect of hypoxia on the ability of myogenic cells to differentiate in culture. Exposure of myoblasts to hypoxia strongly inhibited multinucleated myotube formation and the expression of differentiation markers. We showed that hypoxia reversibly inhibited MyoD, Myf5, and myogenin expression. One key step in skeletal muscle differentiation involves the up-regulation of the cell cycle-dependent kinase inhibitors p21 and p27 as well as the product of the retinoblastoma gene (pRb). Myoblasts cultured under hypoxic conditions in differentiation medium failed to up-regulate both p21 and pRb despite the G1 cell cycle arrest, as evidenced by p27 accumulation and pRb hypophosphorylation. Hypoxia-dependent inhibition of differentiation was associated with MyoD degradation by the ubiquitin-proteasome pathway. MyoD overexpression in C2C12 myoblasts overrode the differentiation block imposed by hypoxic conditions. Thus, hypoxia by inducing MyoD degradation blocked accumulation of early myogenic differentiation markers such as myogenin and p21 and pRb, preventing both permanent cell cycle withdraw and terminal differentiation. Our study revealed a novel anti-differentiation effect exerted by hypoxia in myogenic cells and identified MyoD degradation as a relevant target of hypoxia. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
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24. Active Localization of the Retinoblastoma Protein in Chromatin and Its Response to S Phase DNA Damage
- Author
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Avni, Dror, Yang, Hong, Martelli, Fabio, Hofmann, Francesco, ElShamy, Wael M., Ganesan, Shridar, Scully, Ralph, and Livingston, David M.
- Subjects
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PHOSPHATASES , *DNA , *RETINOBLASTOMA - Abstract
The Rb protein suppresses development of an abnormal state of endoreduplication arising after S phase DNA damage. In diploid, S phase cells, the activity of protein phosphatase 2A (PP2A) licenses the stable association of un(der)phosphorylated Rb with chromatin. After damage, chromatin–associated pRb is attracted to certain chromosomal replication initiation sites in the order in which they normally fire. Like S phase DNA damage in Rb−/− cells, specific interruption of PP2A function in irradiated, S phase wt cells also elicited a state of endoreduplication. Thus, PP2A normally licenses the recruitment of Rb to chromatin sites in S phase from which, after DNA damage, it relocalizes to selected replication control sites and suppresses abnormal, postdamage rereplicative activity. [Copyright &y& Elsevier]
- Published
- 2003
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25. Cardiovascular RNA markers and artificial intelligence may improve COVID-19 outcome: a position paper from the EU-CardioRNA COST Action CA17129.
- Author
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Badimon, Lina, Robinson, Emma L, Jusic, Amela, Carpusca, Irina, deWindt, Leon J, Emanueli, Costanza, Ferdinandy, Péter, Gu, Wei, Gyöngyösi, Mariann, Hackl, Matthias, Karaduzovic-Hadziabdic, Kanita, Lustrek, Mitja, Martelli, Fabio, Nham, Eric, Potočnjak, Ines, Satagopam, Venkata, Schneider, Reinhard, Thum, Thomas, and Devaux, Yvan
- Subjects
- *
ARTIFICIAL intelligence , *COVID-19 , *CARDIOVASCULAR diseases , *RNA , *HEART failure - Abstract
The coronavirus disease 2019 (COVID-19) pandemic has been as unprecedented as unexpected, affecting more than 105 million people worldwide as of 8 February 2020 and causing more than 2.3 million deaths according to the World Health Organization (WHO). Not only affecting the lungs but also provoking acute respiratory distress, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is able to infect multiple cell types including cardiac and vascular cells. Hence a significant proportion of infected patients develop cardiac events, such as arrhythmias and heart failure. Patients with cardiovascular comorbidities are at highest risk of cardiac death. To face the pandemic and limit its burden, health authorities have launched several fast-track calls for research projects aiming to develop rapid strategies to combat the disease, as well as longer-term projects to prepare for the future. Biomarkers have the possibility to aid in clinical decision-making and tailoring healthcare in order to improve patient quality of life. The biomarker potential of circulating RNAs has been recognized in several disease conditions, including cardiovascular disease. RNA biomarkers may be useful in the current COVID-19 situation. The discovery, validation, and marketing of novel biomarkers, including RNA biomarkers, require multi-centre studies by large and interdisciplinary collaborative networks, involving both the academia and the industry. Here, members of the EU-CardioRNA COST Action CA17129 summarize the current knowledge about the strain that COVID-19 places on the cardiovascular system and discuss how RNA biomarkers can aid to limit this burden. They present the benefits and challenges of the discovery of novel RNA biomarkers, the need for networking efforts, and the added value of artificial intelligence to achieve reliable advances. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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26. Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation.
- Author
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Virga, Federico, Cappellesso, Federica, Stijlemans, Benoit, Henze, Anne-Theres, Trotta, Rosa, Van Audenaerde, Jonas, Mirchandani, Ananda S., Sanchez-Garcia, Manuel A., Vandewalle, Jolien, Orso, Francesca, Riera-Domingo, Carla, Griffa, Alberto, Ivan, Cristina, Smits, Evelien, Laoui, Damya, Martelli, Fabio, Langouche, Lies, Van den Berghe, Greet, Feron, Olivier, and Ghesquière, Bart
- Subjects
- *
PERITONEAL macrophages , *BODY temperature , *GLYCOLYSIS , *B cells , *MACROPHAGES , *IMMUNOREGULATION , *COVID-19 , *BONE marrow cells - Published
- 2021
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27. RNAs in Brain and Heart Diseases †.
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Beis, Dimitris, Zerr, Inga, Martelli, Fabio, Doehner, Wolfram, and Devaux, Yvan
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BRAIN diseases , *HEART diseases , *NEUROLOGICAL disorders , *NON-coding RNA , *NEURAL codes , *COMORBIDITY , *CARDIOVASCULAR diseases - Abstract
In the era of single-cell analysis, one always has to keep in mind the systemic nature of various diseases and how these diseases could be optimally studied. Comorbidities of the heart in neurological diseases as well as of the brain in cardiovascular diseases are prevalent, but how interactions in the brain–heart axis affect disease development and progression has been poorly addressed. Several brain and heart diseases share common risk factors. A better understanding of the brain–heart interactions will provide better insights for future treatment and personalization of healthcare, for heart failure patients' benefit notably. We review here emerging evidence that studying noncoding RNAs in the brain–heart axis could be pivotal in understanding these interactions. We also introduce the Special Issue of the International Journal of Molecular Sciences RNAs in Brain and Heart Diseases—EU-CardioRNA COST Action. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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28. Dysregulation of microRNA expression in diabetic skin.
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Baldini, Enke, Testa, Erika, Voellenkle, Christine, Domenico, Emanuela De, Cianfarani, Francesca, Martelli, Fabio, Ulisse, Salvatore, and Odorisio, Teresa
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MICRORNA , *SKIN , *PEOPLE with diabetes , *OXIDATIVE stress , *GENE expression - Abstract
• Molecular mechanisms underlying skin alterations in diabetes are largely unknown. • A general down-regulation of miRNA baseline expression was found in diabetic skin. • Down-regulated miRNAs control pathways involved in skin homeostasis. • Altered expression also involved pri-miRNAs and miRNA biogenesis genes. • These molecular defects likely contribute to diabetic skin manifestations. Clinical skin manifestations are common in diabetes; however, molecular mechanisms underlying such defects are largely unknown. Several findings indicate a role for microRNAs (miRNAs) in skin homeostasis. To investigate whether miRNA expression is altered in diabetic skin. Type 1 and 2 mouse models of diabetes were used. MiRNA profiling was performed on RNA extracted from the skin of type 1 diabetic mice and non-diabetic controls. Expression levels of pri-miRNAs and of miRNA-biogenesis genes were also analyzed. Biogenesis gene expression analysis was performed in human dermal fibroblasts cultured in hyperglycemic, hypoxic or oxidative stress conditions. Several miRNAs were differentially expressed in diabetic skin with a general down-modulation as compared to controls. Bioinformatics analysis of signature-miRNA target genes showed the enrichment in pathways involved in skin homeostasis, such as TGF-β and Wnt. MiRNA alteration in diabetic skin associated with reduced expression levels of DROSHA, DGCR8, XPO5, DICER1, AGO2, both as mRNA and protein. Reduced biogenesis gene expression did not correlate with accumulation of pri-miRNAs, which displayed differences in expression levels similar to those found for their mature miRNAs. Experiments with cultured fibroblasts showed that hypoxia and oxidative stress induced the down-regulation of miRNA-biogenesis genes in this skin cell type. A general down-regulation of differentially expressed miRNAs was found in diabetic skin. This alteration is part of and is dependent from a wider transcriptional defect also affecting the expression of pri-miRNAs and of genes responsible for miRNA biogenesis. Such an alteration is likely contributing to diabetic skin manifestations. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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29. Regulatory RNAs in Heart Failure.
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Gomes, Clarissa Pedrosa da Costa, Schroen, Blanche, Kuster, Gabriela M., Robinson, Emma L., Ford, Kerrie, Squire, Iain B., Heymans, Stephane, Martelli, Fabio, Emanueli, Costanza, Devaux, Yvan, Gomes, Clarissa Pedrosa Costa, and EU-CardioRNA COST Action (CA17129)
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HEART failure , *NON-coding RNA , *MESSENGER RNA , *CIRCULAR RNA , *RNA - Abstract
Cardiovascular disease is an enormous socioeconomic burden worldwide and remains a leading cause of mortality and disability despite significant efforts to improve treatments and personalize healthcare. Heart failure is the main manifestation of cardiovascular disease and has reached epidemic proportions. Heart failure follows a loss of cardiac homeostasis, which relies on a tight regulation of gene expression. This regulation is under the control of multiple types of RNA molecules, some encoding proteins (the so-called messenger RNAs) and others lacking protein-coding potential, named noncoding RNAs. In this review article, we aim to revisit the notion of regulatory RNA, which has been thus far mainly confined to noncoding RNA. Regulatory RNA, which we propose to abbreviate as regRNA, can include both protein-coding RNAs and noncoding RNAs, as long as they contribute, directly or indirectly, to the regulation of gene expression. We will address the regulation and functional role of messenger RNAs, microRNAs, long noncoding RNAs, and circular RNAs (ie, regRNAs) in heart failure. We will debate the utility of regRNAs to diagnose, prognosticate, and treat heart failure, and we will provide directions for future work. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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30. Epigenetic Signaling and RNA Regulation in Cardiovascular Diseases.
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Mongelli, Alessia, Atlante, Sandra, Bachetti, Tiziana, Martelli, Fabio, Farsetti, Antonella, and Gaetano, Carlo
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RNA , *CARDIOVASCULAR diseases , *RNA modification & restriction , *DNA structure , *SMALL molecules - Abstract
RNA epigenetics is perhaps the most recent field of interest for translational epigeneticists. RNA modifications create such an extensive network of epigenetically driven combinations whose role in physiology and pathophysiology is still far from being elucidated. Not surprisingly, some of the players determining changes in RNA structure are in common with those involved in DNA and chromatin structure regulation, while other molecules seem very specific to RNA. It is envisaged, then, that new small molecules, acting selectively on RNA epigenetic changes, will be reported soon, opening new therapeutic interventions based on the correction of the RNA epigenetic landscape. In this review, we shall summarize some aspects of RNA epigenetics limited to those in which the potential clinical translatability to cardiovascular disease is emerging [ABSTRACT FROM AUTHOR]
- Published
- 2020
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31. Long Noncoding Competing Endogenous RNA Networks in Age-Associated Cardiovascular Diseases.
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Greco, Simona, Gaetano, Carlo, and Martelli, Fabio
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LINCRNA , *NON-coding RNA , *RNA , *CARDIOVASCULAR diseases , *MICRORNA , *CELLULAR aging - Abstract
Cardiovascular diseases (CVDs) are the most serious health problem in the world, displaying high rates of morbidity and mortality. One of the main risk factors for CVDs is age. Indeed, several mechanisms are at play during aging, determining the functional decline of the cardiovascular system. Aging cells and tissues are characterized by diminished autophagy, causing the accumulation of damaged proteins and mitochondria, as well as by increased levels of oxidative stress, apoptosis, senescence and inflammation. These processes can induce a rapid deterioration of cellular quality-control systems. However, the molecular mechanisms of age-associated CVDs are only partially known, hampering the development of novel therapeutic strategies. Evidence has emerged indicating that noncoding RNAs (ncRNAs), such as long ncRNAs (lncRNAs) and micro RNAs (miRNAs), are implicated in most patho-physiological mechanisms. Specifically, lncRNAs can bind miRNAs and act as competing endogenous-RNAs (ceRNAs), therefore modulating the levels of the mRNAs targeted by the sponged miRNA. These complex lncRNA/miRNA/mRNA networks, by regulating autophagy, apoptosis, necrosis, senescence and inflammation, play a crucial role in the development of age-dependent CVDs. In this review, the emerging knowledge on lncRNA/miRNA/mRNA networks will be summarized and the way in which they influence age-related CVDs development will be discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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32. P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation.
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Savoia, Matteo, Cencioni, Chiara, Mori, Mattia, Atlante, Sandra, Zaccagnini, Germana, Devanna, Paolo, Di Marcotullio, Lucia, Botta, Bruno, Martelli, Fabio, Zeiher, Andreas M., Pontecorvi, Alfredo, Farsetti, Antonella, Spallotta, Francesco, and Gaetano, Carlo
- Abstract
The epigenetic enzyme p300/CBP-associated factor (PCAF) belongs to the GCN5-related N-acetyltransferase (GNAT) family together with GCN5. Although its transcriptional and post-translational function is well characterized, little is known about its properties as regulator of cell metabolism. Here, we report the mitochondrial localization of PCAF conferred by an 85 aa mitochondrial targeting sequence (MTS) at the N-terminal region of the protein. In mitochondria, one of the PCAF targets is the isocitrate dehydrogenase 2 (IDH2) acetylated at lysine 180. This PCAF-regulated post-translational modification might reduce IDH2 affinity for isocitrate as a result of a conformational shift involving predictively the tyrosine at position 179. Site-directed mutagenesis and functional studies indicate that PCAF regulates IDH2, acting at dual level during myoblast differentiation: at a transcriptional level together with MyoD, and at a post-translational level by direct modification of lysine acetylation in mitochondria. The latter event determines a decrease in IDH2 function with negative consequences on muscle fiber formation in C2C12 cells. Indeed, a MTS-deprived PCAF does not localize into mitochondria, remains enriched into the nucleus, and contributes to a significant increase of muscle-specific gene expression enhancing muscle differentiation. The role of PCAF in mitochondria is a novel finding shedding light on metabolic processes relevant to early muscle precursor differentiation. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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33. Noncoding RNAs in the Vascular System Response to Oxidative Stress.
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Fuschi, Paola, Maimone, Biagina, Gaetano, Carlo, and Martelli, Fabio
- Subjects
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NON-coding RNA , *OXIDATIVE stress , *VASCULAR diseases , *HYPOXEMIA , *HOMEOSTASIS - Abstract
Significance: Redox homeostasis plays a pivotal role in vascular cell function and its imbalance has a causal role in a variety of vascular diseases. Accordingly, the response of mammalian cells to redox cues requires precise transcriptional and post-transcriptional modulation of gene expression patterns. Recent Advances: Mounting evidence shows that nonprotein-coding RNAs (ncRNAs) are important for the functional regulation of most, if not all, cellular processes and tissues. Not surprisingly, a prominent role of ncRNAs has been identified also in the vascular system response to oxidative stress. Critical Issues: The highly heterogeneous family of ncRNAs has been divided into several groups. In this article we focus on two classes of regulatory ncRNAs: microRNAs and long ncRNAs (lncRNAs). Although knowledge in many circumstances, and especially for lncRNAs, is still fragmentary, ncRNAs are clinically interesting because of their diagnostic and therapeutic potential. We outline ncRNAs that are regulated by oxidative stress as well as ncRNAs that modulate reactive oxygen species production and scavenging. More importantly, we describe the role of these ncRNAs in vascular physiopathology and specifically in disease conditions wherein oxidative stress plays a crucial role, such as hypoxia and ischemia, ischemia reperfusion, inflammation, diabetes mellitus, and atherosclerosis. Future Directions: The therapeutic potential of ncRNAs in vascular diseases and in redox homeostasis is discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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34. Long Noncoding RNAs and Cardiac Disease.
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Greco, Simona, Salgado Somoza, Antonio, Devaux, Yvan, and Martelli, Fabio
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HEART disease diagnosis , *NON-coding RNA , *BIOMARKERS , *EPIGENETICS , *GENE expression - Abstract
Significance: To maintain homeostasis, gene expression has to be tightly regulated by complex and multiple mechanisms occurring at the epigenetic, transcriptional, and post-transcriptional levels. One crucial regulatory component is represented by long noncoding RNAs (lncRNAs), nonprotein-coding RNA species implicated in all of these levels. Thus, lncRNAs have been associated with any given process or pathway of interest in a variety of systems, including the heart. Recent Advances: Mounting evidence implicates lncRNAs in cardiovascular diseases (CVD) and progression and their presence in the blood of heart disease patients indicates that they are attractive potential biomarkers. Critical Issues: Our understanding of the regulation and molecular mechanisms of action of most lncRNAs remains rudimentary. A challenge is represented by their often low evolutionary sequence conservation that limits the use of animal models for preclinical studies. Nevertheless, a growing number of lncRNAs with an impact on heart function is rapidly accumulating. In this study, we will discuss (i) lncRNAs that control heart homeostasis and disease; (ii) concepts, approaches, and methodologies necessary to study lncRNAs in the heart; and (iii) challenges posed and opportunities presented by lncRNAs as potential therapeutic targets and biomarkers. Future Directions: A deeper knowledge of the molecular mechanisms underpinning CVDs is necessary to develop more effective treatments. Further studies are needed to clarify the regulation and function of lncRNAs in the heart before they can be considered as therapeutic targets and disease biomarkers. Antioxid. Redox Signal. 29, 880–901. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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35. Oxidative Stress-Induced miR-200c Disrupts the Regulatory Loop Among SIRT1, FOXO1, and eNOS.
- Author
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Carlomosti, Fabrizio, D'Agostino, Marco, Beji, Sara, Torcinaro, Alessio, Rizzi, Roberto, Zaccagnini, Germana, Maimone, Biagina, Di Stefano, Valeria, De Santa, Francesca, Cordisco, Sonia, Antonini, Annalisa, Ciarapica, Roberta, Dellambra, Elena, Martelli, Fabio, Avitabile, Daniele, Capogrossi, Maurizio Colognesi, and Magenta, Alessandra
- Subjects
- *
OXIDATIVE stress , *REACTIVE oxygen species , *ENDOTHELIAL cells , *ISCHEMIA , *FREE radicals , *AGING , *MICRORNA , *NITRIC oxide - Abstract
Aims: Reactive oxygen species (ROS) play a pivotal role in different pathologic conditions, including ischemia, diabetes, and aging.We previously showed that ROS enhance miR-200c expression, causing endothelial cell (EC) apoptosis and senescence. Herein, we dissect the interaction among miR-200c and three strictly related proteins that modulate EC function and ROS production: sirtuin 1 (SIRT1), endothelial nitric oxide synthase (eNOS), and forkhead box O1 (FOXO1). Moreover, the role of miR-200c on ROS modulation was also investigated. Results: Wedemonstrated that miR-200c directly targets SIRT1, eNOS, and FOXO1; via this mechanism, miR-200c decreased NO and increased the acetylation of SIRT1 targets, that is, FOXO1 and p53. FOXO1 acetylation inhibited its transcriptional activity on target genes, that is, SIRT1 and the ROS scavengers, catalase and manganese superoxide dismutase. In keeping, miR-200c increased ROS production and induced p66Shc protein phosphorylation in Ser-36; this mechanism upregulated ROS and inhibited FOXO1 transcription, reinforcing this molecular circuitry. These in vitro results were validated in three in vivo models of oxidative stress, that is, human skin fibroblasts from old donors, femoral arteries from old mice, and a murine model of hindlimb ischemia. In all cases, miR- 200c was higher versus control and its targets, that is, SIRT1, eNOS, and FOXO1, were downmodulated. In the mouse hindlimb ischemia model, anti-miR-200c treatment rescued these targets and improved limb perfusion. Innovation and Conclusion: miR-200c disrupts SIRT1/FOXO1/eNOS regulatory loop. This event promotes ROS production and decreases NO, contributing to endothelial dysfunction under conditions of increased oxidative stress such as aging and ischemia. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
36. Increased BACE1-AS long noncoding RNA and β-amyloid levels in heart failure.
- Author
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Greco, Simona, Zaccagnini, Germana, Fuschi, Paola, Voellenkle, Christine, Carrara, Matteo, Sadeghi, Iman, Bearzi, Claudia, Maimone, Biagina, Castelvecchio, Serenella, Stellos, Konstantinos, Gaetano, Carlo, Menicanti, Lorenzo, and Martelli, Fabio
- Subjects
- *
NON-coding RNA , *ALZHEIMER'S disease , *HEART failure , *GENE expression , *HEART cells - Abstract
Aims Antisense long noncoding RNAs (ncRNAs) are transcripts emerging from the opposite strand of a coding-RNA region and their role in heart failure (HF) is largely unl
- Published
- 2017
- Full Text
- View/download PDF
37. The double life of cardiac mesenchymal cells: Epimetabolic sensors and therapeutic assets for heart regeneration.
- Author
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Cencioni, Chiara, Atlante, Sandra, Savoia, Matteo, Martelli, Fabio, Farsetti, Antonella, Capogrossi, Maurizio C., Zeiher, Andreas M., Gaetano, Carlo, and Spallotta, Francesco
- Subjects
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CARDIAC regeneration , *MESENCHYMAL stem cells , *DIABETES risk factors , *AGE factors in disease , *BIOSENSORS , *HEART fibrosis - Abstract
Organ-specific mesenchymal cells naturally reside in the stroma, where they are exposed to some environmental variables affecting their biology and functions. Risk factors such as diabetes or aging influence their adaptive response. In these cases, permanent epigenetic modifications may be introduced in the cells with important consequences on their local homeostatic activity and therapeutic potential. Numerous results suggest that mesenchymal cells, virtually present in every organ, may contribute to tissue regeneration mostly by paracrine mechanisms. Intriguingly, the heart is emerging as a source of different cells, including pericytes, cardiac progenitors, and cardiac fibroblasts. According to phenotypic, functional, and molecular criteria, these should be classified as mesenchymal cells. Not surprisingly, in recent years, the attention on these cells as therapeutic tools has grown exponentially, although only very preliminary data have been obtained in clinical trials to date. In this review, we summarized the state of the art about the phenotypic features, functions, regenerative properties, and clinical applicability of mesenchymal cells, with a particular focus on those of cardiac origin. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
38. Long noncoding RNA dysregulation in ischemic heart failure.
- Author
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Greco, Simona, Zaccagnini, Germana, Perfetti, Alessandra, Fuschi, Paola, Valaperta, Rea, Voellenkle, Christine, Castelvecchio, Serenella, Gaetano, Carlo, Finato, Nicoletta, Beltrami, Antonio Paolo, Menicanti, Lorenzo, and Martelli, Fabio
- Subjects
- *
HEART failure , *NON-coding RNA , *RNA physiology , *LEFT heart ventricle diseases , *HEART failure patients , *GENE ontology , *GENETICS , *CORONARY heart disease complications , *RNA metabolism , *ANIMAL experimentation , *BIOLOGICAL models , *CHRONIC diseases , *CORONARY disease , *GENES , *CARDIAC hypertrophy , *MICE , *RESEARCH funding , *RNA , *GENE expression profiling , *DISEASE complications ,RESEARCH evaluation - Abstract
Background: Long noncoding RNAs (lncRNAs) are non-protein coding transcripts regulating a variety of physiological and pathological functions. However, their implication in heart failure is still largely unknown. The aim of this study is to identify and characterize lncRNAs deregulated in patients affected by ischemic heart failure.Methods: LncRNAs were profiled and validated in left ventricle biopsies of 18 patients affected by non end-stage dilated ischemic cardiomyopathy and 17 matched controls. Further validations were performed in left ventricle samples derived from explanted hearts of end-stage heart failure patients and in a mouse model of cardiac hypertrophy, obtained by transverse aortic constriction. Peripheral blood mononuclear cells of heart failure patients were also analyzed. LncRNA distribution in the heart was assessed by in situ hybridization. Function of the deregulated lncRNA was explored analyzing the expression of the neighbor mRNAs and by gene ontology analysis of the correlating coding transcripts.Results: Fourteen lncRNAs were significantly modulated in non end-stage heart failure patients, identifying a heart failure lncRNA signature. Nine of these lncRNAs (CDKN2B-AS1/ANRIL, EGOT, H19, HOTAIR, LOC285194/TUSC7, RMRP, RNY5, SOX2-OT and SRA1) were also confirmed in end-stage failing hearts. Intriguingly, among the conserved lncRNAs, h19, rmrp and hotair were also induced in a mouse model of heart hypertrophy. CDKN2B-AS1/ANRIL, HOTAIR and LOC285194/TUSC7 showed similar modulation in peripheral blood mononuclear cells and heart tissue, suggesting a potential role as disease biomarkers. Interestingly, RMRP displayed a ubiquitous nuclear distribution, while H19 RNA was more abundant in blood vessels and was both cytoplasmic and nuclear. Gene ontology analysis of the mRNAs displaying a significant correlation in expression with heart failure lncRNAs identified numerous pathways and functions involved in heart failure progression.Conclusions: These data strongly suggest lncRNA implication in the molecular mechanisms underpinning HF. [ABSTRACT FROM AUTHOR]- Published
- 2016
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- View/download PDF
39. Magnetic Resonance Imaging Allows the Evaluation of Tissue Damage and Regeneration in a Mouse Model of Critical Limb Ischemia.
- Author
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Zaccagnini, Germana, Palmisano, Anna, Canu, Tamara, Maimone, Biagina, Lo Russo, Francesco M., Ambrogi, Federico, Gaetano, Carlo, De Cobelli, Francesco, Del Maschio, Alessandro, Esposito, Antonio, and Martelli, Fabio
- Subjects
- *
MAGNETIC resonance imaging , *DISEASES of the anatomical extremities , *SKELETAL muscle injuries , *MORPHOMETRICS , *LABORATORY mice - Abstract
Magnetic resonance imaging (MRI) provides non-invasive, repetitive measures in the same individual, allowing the study of a physio-pathological event over time. In this study, we tested the performance of 7 Tesla multi-parametric MRI to monitor the dynamic changes of mouse skeletal muscle injury and regeneration upon acute ischemia induced by femoral artery dissection. T2-mapping (T2 relaxation time), diffusion-tensor imaging (Fractional Anisotropy) and perfusion by Dynamic Contrast-Enhanced MRI (K-trans) were measured and imaging results were correlated with histological morphometric analysis in both Gastrocnemius and Tibialis anterior muscles. We found that tissue damage positively correlated with T2-relaxation time, while myofiber regeneration and capillary density positively correlated with Fractional Anisotropy. Interestingly, K-trans positively correlated with capillary density. Accordingly, repeated MRI measurements between day 1 and day 28 after surgery in ischemic muscles showed that: 1) T2-relaxation time rapidly increased upon ischemia and then gradually declined, returning almost to basal level in the last phases of the regeneration process; 2) Fractional Anisotropy dropped upon ischemic damage induction and then recovered along with muscle regeneration and neoangiogenesis; 3) K-trans reached a minimum upon ischemia, then progressively recovered. Overall, Gastrocnemius and Tibialis anterior muscles displayed similar patterns of MRI parameters dynamic, with more marked responses and less variability in Tibialis anterior. We conclude that MRI provides quantitative information about both tissue damage after ischemia and the subsequent vascular and muscle regeneration, accounting for the differences between subjects and, within the same individual, between different muscles. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
40. Tumor-Promoting Effects of Myeloid-Derived Suppressor Cells Are Potentiated by Hypoxia-Induced Expression of miR-210.
- Author
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Noman, Muhammad Zaeem, Janji, Bassam, Shijun Hu, Wu, Joseph C., Martelli, Fabio, Bronte, Vincenzo, and Chouaib, Salem
- Subjects
- *
TUMORS , *HYPOXEMIA , *GENE expression , *CANCER genetics , *CANCER cells - Abstract
Myeloid-derived suppressor cells (MDSC) contribute significantly to the malignant characters conferred by hypoxic tumor microenvironments. However, selective biomarkers of MDSC function in this critical setting have not been defined. Here, we report that miR-210 expression is elevated by hypoxia-inducible factor-1a (HIF1a) in MDSC localized to tumors, compared with splenic MDSC from tumor-bearing mice. In tumor MDSC, we determined that HIF1α was bound directly to a transcriptionally active hypoxia-response element in the miR-210 proximal promoter. miR-210 overexpression was sufficient to enhance MDSC-mediated T-cell suppression under normoxic conditions, while targeting hypoxia-induced miR-210 was sufficient to decrease MDSC function against T cells. Mechanistic investigations revealed that miR-210 modulated MDSC function by increasing arginase activity and nitric oxide production, without affecting reactive oxygen species, IL6, or IL10 production or expression of PD-L1. In splenic MDSC, miR-210 regulated Arg1, Cxcl12, and IL16 at the levels of both mRNA and protein, the reversal of which under normoxic conditions decreased T-cell--suppressive effects and IFNg production. Interestingly, miR-210 overexpression or targeting IL16 or CXCL12 enhanced the immunosuppressive activity of MDSC in vivo, resulting in increased tumor growth. Taken together, these results provide a preclinical rationale to explore miR-210 inhibitory oligonucleotides as adjuvants to boost immunotherapeutic responses in cancer patients. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
41. Sirtuin function in aging heart and vessels.
- Author
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Cencioni, Chiara, Spallotta, Francesco, Mai, Antonello, Martelli, Fabio, Farsetti, Antonella, Zeiher, Andreas M., and Gaetano, Carlo
- Subjects
- *
SIRTUINS , *CARDIOVASCULAR diseases , *METABOLIC disorders , *HISTONE deacetylase , *LONGEVITY , *NAD (Coenzyme) , *BLOOD sugar ,HEART aging - Abstract
Age is the most important risk factor for metabolic alterations and cardiovascular accidents. Although class III histone deacetylases, alias Sirtuins, have been appealed as “the fountain of youth” their role in longevity control and prevention of aging-associated disease is still under debate. Indeed, several lines of evidence indicate that sirtuin activity is strictly linked to metabolism and dependent on NAD + synthesis both often altered as aging progresses. During aging the cardiovascular system is attacked by a variety of environmental stresses, including those determined by high blood glucose and lipid levels, or by the presence of oxidized lipoproteins which, among others, determine important oxidative stress signals. In such a milieu, heart and vessels develop a functional impairment leading to atherosclerosis, ischemia, heart insufficiency and failure. Sirtuins, which are believed to have a positive impact on cardiovascular physiology and physiopathology, are distributed in different subcellular compartments including the nucleus, the cytoplasm and the mitochondria, where they regulate expression and function of a large variety of target genes and proteins. Remarkably, experimental animal models indicate resveratrol, the first natural compound described to positively regulate the activity of sirtuins, as able to protect the endothelium and the heart exposed to a variety of stress agents. This review will focus on the regulation and function of mammalian sirtuins with special attention paid to their role as cardiovascular “defenders” giving indication of their targets of potential relevance for the development of future therapeutics. This article is part of a Special Issue entitled CV Aging. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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42. Proliferation of Multiple Cell Types in the Skeletal Muscle Tissue Elicited by Acute p21 Suppression.
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Biferi, Maria Grazia, Nicoletti, Carmine, Falcone, Germana, Puggioni, Eleonora M R, Passaro, Nunzia, Mazzola, Alessia, Pajalunga, Deborah, Zaccagnini, Germana, Rizzuto, Emanuele, Auricchio, Alberto, Zentilin, Lorena, De Luca, Gabriele, Giacca, Mauro, Martelli, Fabio, Musio, Antonio, Musarò, Antonio, and Crescenzi, Marco
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STRIATED muscle , *SKELETAL muscle , *MEDICINE , *DNA , *ADENO-associated virus - Abstract
Although in the last decades the molecular underpinnings of the cell cycle have been unraveled, the acquired knowledge has been rarely translated into practical applications. Here, we investigate the feasibility and safety of triggering proliferation in vivo by temporary suppression of the cyclin-dependent kinase inhibitor, p21. Adeno-associated virus (AAV)-mediated, acute knockdown of p21 in intact skeletal muscles elicited proliferation of multiple, otherwise quiescent cell types, notably including satellite cells. Compared with controls, p21-suppressed muscles exhibited a striking two- to threefold expansion in cellularity and increased fiber numbers by 10 days post-transduction, with no detectable inflammation. These changes partially persisted for at least 60 days, indicating that the muscles had undergone lasting modifications. Furthermore, morphological hyperplasia was accompanied by 20% increases in maximum strength and resistance to fatigue. To assess the safety of transiently suppressing p21, cells subjected to p21 knockdown in vitro were analyzed for γ-H2AX accumulation, DNA fragmentation, cytogenetic abnormalities, ploidy, and mutations. Moreover, the differentiation competence of p21-suppressed myoblasts was investigated. These assays confirmed that transient suppression of p21 causes no genetic damage and does not impair differentiation. Our results establish the basis for further exploring the manipulation of the cell cycle as a strategy in regenerative medicine. [ABSTRACT FROM AUTHOR]
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- 2015
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43. Hypoxia-Induced miR-210 Modulates Tissue Response to Acute Peripheral Ischemia.
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Zaccagnini, Germana, Maimone, Biagina, Di Stefano, Valeria, Fasanaro, Pasquale, Greco, Simona, Perfetti, Alessandra, Capogrossi, Maurizio C., Gaetano, Carlo, and Martelli, Fabio
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HYPOXEMIA , *ISCHEMIA , *MICRORNA genetics , *OXIDATIVE stress , *GENE expression profiling , *ANIMAL disease models - Abstract
Aims: Peripheral artery disease is caused by the restriction or occlusion of arteries supplying the leg. Better understanding of the molecular mechanisms underpinning tissue response to ischemia is urgently needed to improve therapeutic options. The aim of this study is to investigate hypoxia-induced miR-210 regulation and its role in a mouse model of hindlimb ischemia. Results: miR-210 expression was induced by femoral artery dissection. To study the role of miR-210, its function was inhibited by the systemic administration of a miR-210 complementary locked nucleic acid (LNA)-oligonucleotide (anti-miR-210). In the ischemic skeletal muscle, anti-miR-210 caused a marked decrease of miR-210 compared with LNA-scramble control, while miR-210 target expression increased accordingly. Histological evaluation of acute tissue damage showed that miR-210 inhibition increased both apoptosis at 1 day and necrosis at 3 days. Capillary density decrease caused by ischemia was significantly more pronounced in anti-miR-210-treated mice; residual limb perfusion decreased accordingly. To investigate the molecular mechanisms underpinning the increased damage triggered by miR-210 blockade, we tested the impact of anti-miR-210 treatment on the transcriptome. Gene expression analysis highlighted the deregulation of mitochondrial function and redox balance. Accordingly, oxidative damage was more severe in the ischemic limb of anti-miR-210-treated mice and miR-210 inhibition increased oxidative metabolism. Further, oxidative-stress resistant p66Shc-null mice displayed decreased tissue damage following ischemia. Innovation: This study identifies miR-210 as a crucial element in the adaptive mechanisms to acute peripheral ischemia. Conclusions: The physiopathological significance of miR-210 is context dependent. In the ischemic skeletal muscle it seems to be cytoprotective, regulating oxidative metabolism and oxidative stress. Antioxid. Redox Signal. 21, 1177-1188. [ABSTRACT FROM AUTHOR]
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- 2014
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44. Epigenetic mechanisms of hyperglycemic memory.
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Cencioni, Chiara, Spallotta, Francesco, Greco, Simona, Martelli, Fabio, Zeiher, Andreas M., and Gaetano, Carlo
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EPIGENETICS , *HYPERGLYCEMIA , *DIABETES complications , *BLOOD sugar , *MOLECULAR structure of chromatin , *GENE expression - Abstract
Highlights: [•] Diabetic complications progress even after blood glucose control is therapeutically achieved. [•] The epigenetic machinery regulates chromatin structure, synchronizing metabolic information with gene expression. [•] Persisting epigenetic marks keep memory of previous transient hyperglycemic events. [•] Epidrugs may represent a potential novel therapeutic option for diabetic patients. [ABSTRACT FROM AUTHOR]
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- 2014
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45. Plasma microRNAs as biomarkers for myotonic dystrophy type 1.
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Perfetti, Alessandra, Greco, Simona, Bugiardini, Enrico, Cardani, Rosanna, Gaia, Paola, Gaetano, Carlo, Meola, Giovanni, and Martelli, Fabio
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BLOOD plasma , *MICRORNA , *BIOMARKERS , *GENE expression , *MYOTONIA atrophica , *PROGNOSIS , *DIAGNOSIS , *PATIENTS - Abstract
Abstract: Myotonic dystrophy type 1 (DM1) lacks non-invasive and easy to measure biomarkers, still largely relying on semi-quantitative tests for diagnostic and prognostic purposes. Muscle biopsies provide valuable data, but their use is limited by their invasiveness. microRNA (miRNAs) are small non-coding RNAs regulating gene expression that are also present in biological fluids and may serve as diseases biomarkers. Thus, we tested plasma miRNAs in the blood of 36 DM1 patients and 36 controls. First, a wide miRNA panel was profiled in a patient subset, followed by validation using all recruited subjects. We identified a signature of nine deregulated miRNAs in DM1 patients: eight miRNAs were increased (miR-133a, miR-193b, miR-191, miR-140-3p, miR-454, miR-574, miR-885-5p, miR-886-3p) and one (miR-27b) was decreased. Next, the levels of these miRNAs were used to calculate a “DM1-miRNAs score”. We found that both miR-133a levels and DM1-miRNAs score discriminated DM1 from controls significantly and Receiver–Operator Characteristic curves displayed an area under the curve of 0.94 and 0.97, respectively. Interestingly, both miR-133a levels and DM1-miRNAs score displayed an inverse correlation with skeletal muscle strength and displayed higher values in more compromised patients. In conclusion, we identified a characteristic plasma miRNA signature of DM1. Although preliminary, this study indicates miRNAs as potential DM1 humoral biomarkers. [Copyright &y& Elsevier]
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- 2014
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46. The Histone Acetylase Activator Pentadecylidenemalonate 1b Rescues Proliferation and Differentiation in the Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients.
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Vecellio, Matteo, Spallotta, Francesco, Nanni, Simona, Colussi, Claudia, Cencioni, Chiara, Derlet, Anja, Bassetti, Beatrice, Tilenni, Manuela, Carena, Maria Cristina, Farsetti, Antonella, Sbardella, Gianluca, Castellano, Sabrina, Mai, Antonello, Martelli, Fabio, Pompilio, Giulio, Capogrossi, Maurizio C., Rossini, Alessandra, Dimmeler, Stefanie, Zeiher, Andreas, and Gaetano, Carlo
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DIABETES , *MESENCHYMAL stem cells , *TYPE 2 diabetes , *PEOPLE with diabetes , *HISTONE acetylation - Abstract
This study investigates the diabetes-associated alterations present in cardiac mesenchymal cells (CMSC) obtained from normoglycemic (ND-CMSC) and type 2 diabetic patients (D-CMSC), identifying the histone acetylase (HAT) activator pentadecylidenemalonate 1b (SPV106) as a potential pharmacological intervention to restore cellular function. D-CMSC were characterized by a reduced proliferation rate, diminished phosphorylation at histone H3 serine 10 (H3S10P), decreased differentiation potential, and premature cellular senescence. A global histone code profiling of D-CMSC revealed that acetylation on histone H3 lysine 9 (H3K9Ac) and lysine 14 (H3K14Ac) was decreased, whereas the trimethylation of H3K9Ac and lysine 27 significantly increased. These observations were paralleled by a down-regulation of the GCN5-related N-acetyltransferases (GNAT) p300/CBP-associated factor and its isoform 5-α general control of amino acid synthesis (GCN5a), determining a relative decrease in total HAT activity. DNA CpG island hypermethylation was detected at promoters of genes involved in cell growth control and genomic stability. Remarkably, treatment with the GNAT proactivator SPV106 restored normal levels of H3K9Ac and H3K14Ac, reduced DNA CpG hypermethylation, and recovered D-CMSC proliferation and differentiation. These results suggest that epigenetic interventions may reverse alterations in human CMSC obtained from diabetic patients. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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47. Genome Wide Identification of Aberrant Alternative Splicing Events in Myotonic Dystrophy Type 2.
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Perfetti, Alessandra, Greco, Simona, Fasanaro, Pasquale, Bugiardini, Enrico, Cardani, Rosanna, Manteiga, Jose M. Garcia., Riba, Michela, Cittaro, Davide, Stupka, Elia, Meola, Giovanni, and Martelli, Fabio
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MYOTONIA atrophica , *ALTERNATIVE RNA splicing , *INTRONS , *PATHOLOGICAL physiology , *MOLECULAR genetics , *CELLULAR signal transduction - Abstract
Myotonic dystrophy type 2 (DM2) is a genetic, autosomal dominant disease due to expansion of tetraplet (CCTG) repetitions in the first intron of the ZNF9/CNBP gene. DM2 is a multisystemic disorder affecting the skeletal muscle, the heart, the eye and the endocrine system. According to the proposed pathological mechanism, the expanded tetraplets have an RNA toxic effect, disrupting the splicing of many mRNAs. Thus, the identification of aberrantly spliced transcripts is instrumental for our understanding of the molecular mechanisms underpinning the disease. The aim of this study was the identification of new aberrant alternative splicing events in DM2 patients. By genome wide analysis of 10 DM2 patients and 10 controls (CTR), we identified 273 alternative spliced exons in 218 genes. While many aberrant splicing events were already identified in the past, most were new. A subset of these events was validated by qPCR assays in 19 DM2 and 15 CTR subjects. To gain insight into the molecular pathways involving the identified aberrantly spliced genes, we performed a bioinformatics analysis with Ingenuity system. This analysis indicated a deregulation of development, cell survival, metabolism, calcium signaling and contractility. In conclusion, our genome wide analysis provided a database of aberrant splicing events in the skeletal muscle of DM2 patients. The affected genes are involved in numerous pathways and networks important for muscle physio-pathology, suggesting that the identified variants may contribute to DM2 pathogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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48. Noncoding RNAs: Emerging Players in Muscular Dystrophies.
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Falcone, Germana, Perfetti, Alessandra, Cardinali, Beatrice, and Martelli, Fabio
- Abstract
The fascinating world of noncoding RNAs has recently come to light, thanks to the development of powerful sequencing technologies, revealing a variety of RNA molecules playing important regulatory functions in most, if not all, cellular processes. Many noncoding RNAs have been implicated in regulatory networks that are determinant for skeletal muscle differentiation and disease. In this review, we outline the noncoding RNAs involved in physiological mechanisms of myogenesis and those that appear dysregulated in muscle dystrophies, also discussing their potential use as disease biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]
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- 2014
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49. Transcriptional Profiling of Hmgb1-Induced Myocardial Repair Identifies a Key Role for Notch Signaling.
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Limana, Federica, Esposito, Grazia, Fasanaro, Pasquale, Foglio, Eleonora, Arcelli, Diego, Voellenkle, Christine, Di Carlo, Anna, Avitabile, Daniele, Martelli, Fabio, Antonio Russo, Matteo, Pompilio, Giulio, Germani, Antonia, and C Capogrossi, Maurizio
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MYOCARDIAL infarction , *ANIMAL models in research , *GENE expression , *GENETIC regulation , *REGENERATION (Biology) - Abstract
Exogenous high-mobility group box 1 protein (HMGB1) administration to the mouse heart, during acute myocardial infarction (MI), results in cardiac regeneration via resident c-kit+ cell (CPC) activation. Aim of the present study was to identify the molecular pathways involved in HMGB1-induced heart repair. Gene expression profiling was performed to identify differentially expressed genes in the infarcted and bordering regions of untreated and HMGB1-treated mouse hearts, 3 days after MI. Functional categorization of the transcripts, accomplished using Ingenuity Pathway Analysis software (IPA), revealed that genes involved in tissue regeneration, that is, cardiogenesis, vasculogenesis and angiogenesis, were present both in the infarcted area and in the peri-infarct zone; HMGB1 treatment further increased the expression of these genes. IPA revealed the involvement of Notch signaling pathways in HMGB1-treated hearts. Importantly, HMGB1 determined a 35 and 58% increase in cardiomyocytes and CPCs expressing Notch intracellular cytoplasmic domain, respectively. Further, Notch inhibition by systemic treatment with the γ-secretase inhibitor DAPT, which blocked the proteolytic activation of Notch receptors, reduced the number of CPCs, their proliferative fraction, and cardiomyogenic differentiation in HMGB1-treated infarcted hearts. The present study gives insight into the molecular processes involved in HMGB1-mediated cardiac regeneration and indicates Notch signaling as a key player.Molecular Therapy (2013); 21 10, 1841-1851. doi:10.1038/mt.2013.137 [ABSTRACT FROM AUTHOR]
- Published
- 2013
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50. Oxidative Stress and MicroRNAs in Vascular Diseases.
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Magenta, Alessandra, Greco, Simona, Gaetano, Carlo, and Martelli, Fabio
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MICRORNA , *OXIDATIVE stress , *VASCULAR diseases , *REACTIVE oxygen species , *VASCULAR smooth muscle - Abstract
Oxidative stress has been demonstrated to play a causal role in different vascular diseases, such as hypertension, diabetic vasculopathy, hypercholesterolemia and atherosclerosis. Indeed, increased reactive oxygen species (ROS) production is known to impair endothelial and vascular smooth muscle cell functions, contributing to the development of cardiovascular diseases. MicroRNAs (miRNAs) are non-coding RNA molecules that modulate the stability and/or the translational efficiency of target messenger RNAs. They have been shown to be modulated in most biological processes, including in cellular responses to redox imbalance. In particular, miR-200 family members play a crucial role in oxidative-stress dependent endothelial dysfunction, as well as in cardiovascular complications of diabetes and obesity. In addition, different miRNAs, such as miR-210, have been demonstrated to play a key role in mitochondrial metabolism, therefore modulating ROS production and sensitivity. In this review, we will discuss miRNAs modulated by ROS or involved in ROS production, and implicated in vascular diseases in which redox imbalance has a pathogenetic role. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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