95 results on '"Dell'Aversana, C"'
Search Results
2. The impact of epigenetic landscape on ovarian cells in infertile older women undergoing IVF procedures
- Author
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Sgueglia, G, Longobardi, S, Valerio, D, Campitiello, Mr, Colacurci, N, Di Pietro, C, Battaglia, R, D'Hooghe, T, Altucci, L, Dell'Aversana, C, Sgueglia, Giulia, Longobardi, Salvatore, Valerio, Domenico, Campitiello, Maria Rosaria, Colacurci, Nicola, Di Pietro, Cinzia, Battaglia, Rosalia, D’Hooghe, Thoma, Altucci, Lucia, and Dell’Aversana, Carmela
- Subjects
Fertility ,IVF ,Reproduction ,Genetics ,Epigenetics, Fertility, IVF, Reproduction ,Epigenetics ,Molecular Biology ,Genetics (clinical) ,Developmental Biology - Abstract
The constant decline in fertility and older reproductive age is the major cause of low clinical pregnancy rates in industrialised countries. Epigenetic mechanisms impact on proper embryonic development in women undergoing in vitro fertilisation (IVF) protocols. Here, we describe the main epigenetic modifications that may influence female reproduction and could affect IVF success. Graphical Abstract
- Published
- 2023
3. Epigenetics in Acute Myeloid Leukemia
- Author
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Giorgio, C., primary, Dell'Aversana, C., additional, and Altucci, L., additional
- Published
- 2016
- Full Text
- View/download PDF
4. List of Contributors
- Author
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Abdelfatah, E., primary, Adamo, S., additional, Ahuja, N., additional, Al Eissa, M., additional, Alenghat, T., additional, Altorok, N., additional, Altucci, L., additional, Antonello, Z.A., additional, Arasaradnam, R.P., additional, Ben-Aderet, L., additional, Bhalla, S., additional, Bitzer, M., additional, Bloch, W., additional, Burrowes, S.G., additional, Butt, N.A., additional, Cacabelos, R., additional, Chen, H., additional, Chen, P., additional, Cheng, B., additional, Chun, P., additional, Cox, O.H., additional, Deblois, G., additional, Dekker, F.J., additional, Dell'Aversana, C., additional, Dvir-Ginzberg, M., additional, Eissenberg, J.C., additional, Elayan, J., additional, Fincher, A.S., additional, Fischer, A., additional, Giorgio, C., additional, Gomes, M.V., additional, Greenwood-Van Meerveld, B., additional, Hall, J.G., additional, Heil, C., additional, Jeffrey, K.L., additional, Jennings, M.P., additional, Jin, P., additional, Johnson, A.C., additional, Kahaleh, B., additional, Kelly, D.R., additional, Abi Khalil, C., additional, Koufaris, C., additional, Kriska, A., additional, Kristiansen, S., additional, Kumar, A., additional, Kundakovic, M., additional, Lee, R.S., additional, Levenson, A.S., additional, Li, G., additional, Ligon, C.O., additional, Lu, Q., additional, Luo, S., additional, Lupien, M., additional, Mahnke, A.H., additional, Malek, N.P., additional, Marroncelli, N., additional, Mehta, S., additional, Merbs, S.L., additional, Miller, R.L., additional, Miranda, R.C., additional, Moloney, R.D., additional, Moresi, V., additional, Moylan, C.A., additional, Murphy, S.K., additional, Nada, S., additional, Nagaraja, V., additional, Navada, S.C., additional, Nicolaidou, V., additional, Nucera, C., additional, Oliva, R., additional, Oliver, V.F., additional, Pagani, M., additional, Palacios, D., additional, Panzeri, I., additional, Patel, A., additional, Peng, H., additional, Pigna, E., additional, Prusator, D.K., additional, Raha, P., additional, Rossetti, G., additional, Salem, N.A., additional, Sananbenesi, F., additional, Schenk, A., additional, Seib, K.L., additional, Sharma, A., additional, Shu, L., additional, Singh, J., additional, Sölétormos, G., additional, Tajbakhsh, J., additional, Tollefsbol, T.O., additional, Torrellas, C., additional, Trojer, P., additional, Vaiserman, A., additional, van Bysterveldt, K.A., additional, Voyias, P.D., additional, Wang, H., additional, Wapenaar, H., additional, Xiao, J., additional, Zhang, Y., additional, Zhou, Z., additional, Zimmer, P., additional, and Zong, D., additional
- Published
- 2016
- Full Text
- View/download PDF
5. Erratum: miR-194-5p/BCLAF1 deregulation in AML tumorigenesis
- Author
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Dell'Aversana, C, Giorgio, C, D'Amato, L, Lania, G, Matarese, F, Saeed, S, Di Costanzo, A, Belsito Petrizzi, V, Ingenito, C, Martens, J H A, Pallavicini, I, Minucci, S, Carissimo, A, Stunnenberg, H G, and Altucci, L
- Published
- 2018
- Full Text
- View/download PDF
6. Age-related miRNome landscape of cumulus oophorus cells during controlled ovarian stimulation protocols in IVF cycles
- Author
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Dell’Aversana, C, primary, Cuomo, F, additional, Longobardi, S, additional, D’Hooghe, T, additional, Caprio, F, additional, Franci, G, additional, Santonastaso, M, additional, Colacurci, N, additional, Barone, S, additional, Pisaturo, V, additional, Valerio, D, additional, and Altucci, L, additional
- Published
- 2021
- Full Text
- View/download PDF
7. Age-related miRNome landscape of cumulus oophorus cells during controlled ovarian stimulation protocols in IVF cycles.
- Author
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Dell'Aversana, C, Cuomo, F, Longobardi, S, D'Hooghe, T, Caprio, F, Franci, G, Santonastaso, M, Colacurci, N, Barone, S, Pisaturo, V, Valerio, D, and Altucci, L
- Subjects
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CUMULUS cells (Embryology) , *EMBRYOS , *INDUCED ovulation , *OVARIAN function tests , *OVUM donation , *MITOGEN-activated protein kinases , *RNA polymerases , *REPRODUCTIVE technology , *RESEARCH , *OVUM , *MEDICAL cooperation , *EVALUATION research , *COMPARATIVE studies , *CELLS , *FERTILIZATION in vitro - Abstract
Study Question: Is the microRNA (miRNA) expression pattern of cumulus oophorus cells (COCs) in women undergoing medically assisted reproduction (MAR) procedures differentially modulated according to patient age and gonadotropin treatment strategy?Summary Answer: Maternal age is an independent factor impacting miRNA expression in COCs while gonadotropin treatment may affect follicular miRNA expression and IVF efficacy.What Is Known Already: Epigenetic mechanisms in female infertility are complex and poorly studied. DNA methylation, histone modifications, miRNAs and nucleosome positioning influence cellular machinery through positive and negative feedback mechanisms either alone or interactively. miRNAs are important regulators during oogenesis, spermatogenesis and early embryogenesis, and are reported to play a role in regulating crosstalk between the oocyte and COCs. Although miRNome analysis has been performed in female human reproductive tissues (endometrium, myometrium, cervix and ovaries), epigenetic modifications in women with infertility have not been explored in detail. In addition, the impact of gonadotropin treatments during MAR on miRNA expression in COCs has not been fully investigated.Study Design, Size, Duration: This study was carried out in 53 COC samples obtained from mature metaphase II (MII) oocytes in 53 women undergoing MAR treatment. A total of 38 samples for assay development were pooled by maternal age and gonadotropin treatment into four predetermined subgroups: ≥36 years and recombinant human FSH (r-hFSH), n = 10; ≥36 years and r-hFSH+ recombinant human-luteinizing hormone (r-hLH), n = 10; ≤35 years and r-hFSH, n = 9; ≤35 years and r-hFSH+r-hLH, n = 9. miRNome profiles were determined and compared between subgroups. Expression of defined miRNAs was validated in the remaining fifteen samples, representative of each subgroup, by quantitative polymerase chain reaction (PCR).Participants/materials, Setting, Methods: COCs were processed for miRNA-enriched total RNA extraction and pooled in homogeneous subgroups to obtain a sufficient amount and quality of starting material to perform the analysis. Each pooled sample underwent miRNA profiling using PCR assay system to examine expression of 752 human miRNAs without pre-amplification. Data were analyzed using the delta-delta Ct method for relative quantitation and prediction of target genes (with at least four algorithms predicting the same miRNA-gene interaction pair (HIT)>4). The miRSystem database provided functional annotation enrichment (raw P-value <0.05) of co-expressed miRNAs.Main Results and the Role Of Chance: We found distinctive miRNA expression profiles in each subgroup correlating with age and MAR stimulation. In addition, a number of selective and co-expressed miRNAs were revealed by comparative analysis. A cluster of 37 miRNAs were commonly but differentially expressed in all four pools. Significant differences were observed in expression regulation of 37 miRNAs between age groups (≤35 or ≥36) in women receiving r-hFSH+r-hLH compared to those receiving r-hFSH alone. Higher concentrations and increased numbers of miRNAs were recorded in younger than in older patients, regardless of treatment. Functional and expression studies performed to retrieve common miRNome profiles revealed an enrichment of biological functions in oocyte growth and maturation, embryo development, steroidogenesis, ovarian hyperstimulation, apoptosis and cell survival, glucagon and lipid metabolism, and cell trafficking. The highest scored pathways of target genes of the 37 common miRNAs were associated with mitogen-activated protein kinase (MAPK) signaling pathways, G alpha signaling, transcription regulation, tight junctions, RNA polymerase I and III, and mitochondrial transcription. We identified a potential age- and MAR stimulation-dependent signature in the miRNA landscape of COCs.Limitations, Reasons For Caution: We cannot rule out the possibility that other unknown individual genetic or clinical factors may have interfered with the reported results. Since miRNA profiling was conducted with a predefined array of target probes, other miRNA molecules, potentially modulated by age and hormonal stimulation, may have been missed in this study.Wider Implications Of the Findings: miRNA expression in COCs is modulated by gonadotropin treatment and correlates strongly with age. A better understanding of the expression patterns and functions of miRNAs may lead to the development of novel therapeutics to treat ovarian dysfunction and improve fertility in older women.Study Funding/competing Interest: This study was funded by Merck KGaA, Darmstadt, Germany. All authors declared no competing interest, except SL and TD who are fully employed by Merck KGaA.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
8. Erratum: miR-194-5p/BCLAF1 deregulation in AML tumorigenesis
- Author
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Dell'Aversana, C, primary, Giorgio, C, additional, D'Amato, L, additional, Lania, G, additional, Matarese, F, additional, Saeed, S, additional, Di Costanzo, A, additional, Belsito Petrizzi, V, additional, Ingenito, C, additional, Martens, J H A, additional, Pallavicini, I, additional, Minucci, S, additional, Carissimo, A, additional, Stunnenberg, H G, additional, and Altucci, L, additional
- Published
- 2017
- Full Text
- View/download PDF
9. miR-194-5p/BCLAF1 deregulation in AML tumorigenesis
- Author
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Dell'Aversana, C, primary, Giorgio, C, additional, D'Amato, L, additional, Lania, G, additional, Matarese, F, additional, Saeed, S, additional, Di Costanzo, A, additional, Belsito Petrizzi, V, additional, Ingenito, C, additional, Martens, J H A, additional, Pallavicini, I, additional, Minucci, S, additional, Carissimo, A, additional, Stunnenberg, H G, additional, and Altucci, L, additional
- Published
- 2017
- Full Text
- View/download PDF
10. Role of the silencing of genes that encode for HDAC1 and HDAC2 in the cell line of acute myeloid leukaemia U937
- Author
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CONTE M., DELL'AVERSANA C., FRANCI G., NEBBIOSO, Angela, ALTUCCI, Lucia, Conte, M., Dell'Aversana, C., Franci, G., Nebbioso, Angela, and Altucci, Lucia
- Published
- 2010
11. Impact of histone deacetylase inhibitors SAHA and MS-275 on DNA repair pathways in human mesenchymal stem cells' DNA repair
- Author
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DI BERNARDO, Giovanni, ALESSIO N, DELL'AVERSANA C, CASALE, Fiorina, CIPOLLARO, Marilena, ALTUCCI L. AND GALDERISI U., DI BERNARDO, Giovanni, Alessio, N, Dell'Aversana, C, Casale, Fiorina, Cipollaro, Marilena, and Altucci, L. AND GALDERISI U.
- Published
- 2010
12. HDACs class II selective inhibition alters nuclear receptor dependent differentiation
- Author
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NEBBIOSO, Angela, DELL'AVERSANA C, BUGGE AK, SARNO R, VALENTE S, ROTILI D, MANZO F, TETI D, MANDRUP S, CIANA P, MAGGI AC, MAI A, GRONEMEYER H, ALTUCCI, Lucia, Nebbioso, Angela, Dell'Aversana, C, Bugge, Ak, Sarno, R, Valente, S, Rotili, D, Manzo, F, Teti, D, Mandrup, S, Ciana, P, Maggi, Ac, Mai, A, Gronemeyer, H, and Altucci, Lucia
- Subjects
Differentiation ,Epigenetic ,HDACs - Abstract
Epigenetic deregulation contributes to diseases including cancer, neurodegeneration, osteodystrophy, cardiovascular defects, and obesity. For this reason, several inhibitors for histone deacetylases (HDACs) are being validated as novel anti-cancer drugs in clinical studies and display important anti-proliferative activities. While most inhibitors act on both class I, II, and IV HDACs, evidence is accumulating that class I is directly involved in regulation of cell growth and death, whereas class II members regulate differentiation processes, such as muscle and neuronal differentiation. Here, we show that the novel class II-selective inhibitor MC1568 interferes with the RAR- and peroxisome proliferator-activated receptor γ (PPARγ)-mediated differentiation-inducing signaling pathways. In F9 cells, this inhibitor specifically blocks endodermal differentiation despite not affecting retinoic acid-induced maturation of promyelocytic NB4 cells. In 3T3-L1 cells, MC1568 attenuates PPARγ-induced adipogenesis, while the class I-selective MS275 blocked adipogenesis completely thus revealing a different mode of action and/or target profile of the two classes of HDACs. Using in vivo reporting PPRE-Luc mice, we find that MC1568 impairs PPARγ signaling mostly in the heart and adipose tissues. These results illustrate how HDAC functions can be dissected by selective inhibitors.
- Published
- 2010
13. Differential Expression Profiling of MicroRNAs in Human Cutaneous and Uveal Melanoma
- Author
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Venza, Mario, Visalli, Maria, Dell'Aversana, C, Altucci, L, Teti, Diana, and Venza, Isabella
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cutaneous melanoma ,microRNA ,uveal melanoma - Published
- 2012
14. Role of miRNAs in leukemogenesis and in epigenetic regulation
- Author
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Dell'Aversana, C, Sarno, R, Carissimo, A, Tambaro, Fp, Nebbioso, A, Teti, Diana, and Altucci, L.
- Subjects
miRNA ,leukemogenesis - Published
- 2010
15. Comment on: LncRNA SBF2-AS1 promotes hepatocellular carcinoma metastasis by regulating EMT and predicts unfavorable prognosis.
- Author
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Franci, G., Dell'Aversana, C., Stelitano, D., Rinaldi, M., and Altucci, L.
- Published
- 2019
- Full Text
- View/download PDF
16. Erratum: miR-194-5p/BCLAF1deregulation in AML tumorigenesis
- Author
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Dell'Aversana, C, Giorgio, C, D'Amato, L, Lania, G, Matarese, F, Saeed, S, Di Costanzo, A, Belsito Petrizzi, V, Ingenito, C, Martens, J H A, Pallavicini, I, Minucci, S, Carissimo, A, Stunnenberg, H G, and Altucci, L
- Abstract
Correction to: Leukemia (2017) 31, 2315–2325; doi:10.1038/leu.2017.64; published online 10 March 2017 Following the publication of this article, the authors noted a mistake in the author affiliations. 4. Centre for Research in Molecular Medicine, The University of Lahore, Lahore, Pakistan Should be replaced with:
- Published
- 2018
- Full Text
- View/download PDF
17. L'assistenza infermieristica al paziente pediatrico affetto da epidermolisi bollosa dopo TCSE allogenico.
- Author
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Francesia, B. M., Floriddia, A., and Dell'Aversana, C.
- Published
- 2013
18. HIF3A Inhibition Triggers Browning of White Adipocytes via Metabolic Rewiring
- Author
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Francesca Cuomo, Carmela Dell’Aversana, Teresa Chioccarelli, Veronica Porreca, Francesco Manfrevola, Chiara Papulino, Vincenzo Carafa, Rosaria Benedetti, Lucia Altucci, Gilda Cobellis, Cuomo, F., Dell'Aversana, C., Chioccarelli, T., Porreca, V., Manfrevola, F., Papulino, C., Carafa, V., Benedetti, R., Altucci, L., and Cobellis, G.
- Subjects
browning ,Cell and Developmental Biology ,QH301-705.5 ,Cell Biology ,thermogenesis ,Biology (General) ,sirts ,CB1 ,HIF3α ,Developmental Biology ,Original Research ,adipose tissue - Abstract
Maintenance of energy balance between intake and expenditure is a prerequisite of human health, disrupted in severe metabolic diseases, such as obesity and type 2 diabetes (T2D), mainly due to accumulation of white adipose tissue (WAT). WAT undergoes a morphological and energetic remodelling toward brown adipose tissue (BAT) and the BAT activation has anti-obesity potential. The mechanisms or the regulatory factors able to activate BAT thermogenesis have been only partially deciphered. Identifying novel regulators of BAT induction is a question of great importance for fighting obesity and T2D. Here, we evaluated the role of Hif3α in murine pre-adipocyte 3T3-L1 cell line, a versatile and well characterized biological model of adipogenesis, by gain- and loss-of function approaches and in thermogenesis-induced model in vivo. HIF3A is regulated by inflammation, it modulates lypolysis in adipose tissue of obese adults, but its role in energy metabolism has not previously been investigated. We characterized gene and protein expression patterns of adipogenesis and metabolic activity in vitro and mechanistically in vivo. Overexpression of Hif3α in differentiating adipocytes increases white fat cells, whereas silencing of Hif3α promotes “browning” of white cells, activating thermogenesis through upregulation of Ucp1, Elovl3, Prdm16, Dio2 and Ppargc1a genes. Investigating cell metabolism, Seahorse Real-Time Cell Metabolism Analysis showed that silencing of Hif3α resulted in a significant increase of mitochondrial uncoupling with a concomitant increase in acetyl-CoA metabolism and Sirt1 and Sirt3 expression. The causal Hif3α/Ucp1 inverse relation has been validated in Cannabinoid receptor 1 (CB1) knockout, a thermogenesis-induced model in vivo. Our data indicate that Hif3α inhibition triggers “browning” of white adipocytes activating the beneficial thermogenesis rewiring energy metabolism in vitro and in vivo. HIF3A is a novel player that controls the energy metabolism with potential applications in developing therapy to fight metabolic disorders, as obesity, T2D and ultimately cancer.
- Published
- 2022
19. Single-Cell Photothermal Analysis Induced by MoS2 Nanoparticles by Raman Spectroscopy
- Author
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Giulia Rusciano, Angela Capaccio, Antonio Sasso, Manjot Singh, Mohammadhassan Valadan, Carmela Dell’Aversana, Lucia Altucci, Carlo Altucci, Rusciano, G., Capaccio, A., Sasso, A., Singh, M., Valadan, M., Dell'Aversana, C., Altucci, L., Altucci, C., Rusciano, Giulia, Capaccio, Angela, Sasso, Antonio, Singh, Manjot, Valadan, Mohammadhassan, Dell'Aversana, Carmela, Altucci, Lucia, and Altucci, Carlo
- Subjects
temperature profiling in single cells ,single-cell Raman analysi ,Histology ,photothermal therapy ,Biomedical Engineering ,Bioengineering ,nanosheet ,MoS2 ,MoS ,Biotechnology - Abstract
Two-dimensional nanomaterials, such as MoS2 nanosheets, have been attracting increasing attention in cancer diagnosis and treatment, thanks to their peculiar physical and chemical properties. Although the mechanisms which regulate the interaction between these nanomaterials and cells are not yet completely understood, many studies have proved their efficient use in the photothermal treatment of cancer, and the response to MoS2 nanosheets at the single-cell level is less investigated. Clearly, this information can help in shedding light on the subtle cellular mechanisms ruling the interaction of this 2D material with cells and, eventually, to its cytotoxicity. In this study, we use confocal micro-Raman spectroscopy to reconstruct the thermal map of single cells targeted with MoS2 under continuous laser irradiation. The experiment is performed by analyzing the water O-H stretching band around 3,400 cm−1 whose tetrahedral structure is sensitive to the molecular environment and temperature. Compared to fluorescence-based approaches, this Raman-based strategy for temperature measurement does not suffer fluorophore instability, which can be significant under continuous laser irradiation. We demonstrate that irradiation of human breast cancer MCF7 cells targeted with MoS2 nanosheets causes a relevant photothermal effect, which is particularly high in the presence of MoS2 nanosheet aggregates. Laser-induced heating is strongly localized near such particles which, in turn, tend to accumulate near the cytoplasmic membrane. Globally, our experimental outcomes are expected to be important for tuning the nanosheet fabrication process.
- Published
- 2022
20. MicroRNA-Assisted Hormone Cell Signaling in Colorectal Cancer Resistance
- Author
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Lucia Altucci, Giulia Sgueglia, Elham Safadeh, Crescenzo Massaro, Carmela Dell'Aversana, Hendrik G. Stunnenberg, Massaro, C., Safadeh, E., Sgueglia, G., Stunnenberg, H. G., Altucci, L., and Dell'Aversana, C.
- Subjects
Cell signaling ,Colorectal cancer ,hormone signaling ,colorectal cancer ,Disease ,Drug resistance ,Review ,Gene expression ,microRNA ,Biomarkers, Tumor ,Medicine ,Animals ,Humans ,lcsh:QH301-705.5 ,drug resistance ,business.industry ,Cancer ,General Medicine ,medicine.disease ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,lcsh:Biology (General) ,Drug Resistance, Neoplasm ,Cancer research ,business ,Colorectal Neoplasms ,Hormone ,Signal Transduction - Abstract
Despite substantial progress in cancer therapy, colorectal cancer (CRC) is still the third leading cause of cancer death worldwide, mainly due to the acquisition of resistance and disease recurrence in patients. Growing evidence indicates that deregulation of hormone signaling pathways and their cross-talk with other signaling cascades inside CRC cells may have an impact on therapy resistance. MicroRNAs (miRNAs) are small conserved non-coding RNAs thatfunction as negative regulators in many gene expression processes. Key studies have identified miRNA alterations in cancer progression and drug resistance. In this review, we provide a comprehensive overview and assessment of miRNAs role in hormone signaling pathways in CRC drug resistance and their potential as future targets for overcoming resistance to treatment.
- Published
- 2021
21. Outer Membrane Vesicles Derived from Klebsiella pneumoniae Are a Driving Force for Horizontal Gene Transfer
- Author
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Massimiliano Galdiero, Marilena Galdiero, Gianluigi Franci, Federica Dell'Annunziata, Giuliana Donadio, Fabrizio Dal Piaz, Carmela Dell'Aversana, Viviana Izzo, Giovanni Boccia, Anna De Filippis, Veronica Folliero, Nunzianna Doti, Lucia Altucci, Dell'Annunziata, F., Dell'Aversana, C., Doti, N., Donadio, G., Dal Piaz, F., Izzo, V., De Filippis, A., Galdiero, M., Altucci, L., Boccia, G., Folliero, V., Franci, G., Dell'Annunziata, Federica, Dell’Aversana, Carmela, Doti, Nunzianna, Donadio, Giuliana, Dal Piaz, Fabrizio, Izzo, Viviana, DE FILIPPIS, Anna, Galdiero, Marilena, Altucci, Lucia, Boccia, Giovanni, Galdiero, Massimiliano, Folliero, Veronica, and Franci, Gianluigi
- Subjects
Klebsiella pneumoniae ,Gene Dosage ,medicine.disease_cause ,Plasmid ,Cytoplasmic Vesicle ,Biology (General) ,Spectroscopy ,Phylogeny ,DNA ,Gram-negative bacteria ,Horizontal gene transfer ,Outer membrane vesicles ,General Medicine ,Computer Science Applications ,Anti-Bacterial Agents ,Chemistry ,horizontal gene transfer ,Bacterial outer membrane ,Plasmids ,Gene Transfer, Horizontal ,QH301-705.5 ,Bacterial Protein ,Biology ,Catalysis ,Article ,Microbiology ,Inorganic Chemistry ,Antibiotic resistance ,Bacterial Proteins ,Anti-Bacterial Agent ,Drug Resistance, Bacterial ,medicine ,Physical and Theoretical Chemistry ,Molecular Biology ,Gene ,Escherichia coli ,QD1-999 ,Pseudomonas aeruginosa ,Outer membrane vesicle ,Organic Chemistry ,Cytoplasmic Vesicles ,Outer Membrane Vesicles ,biology.organism_classification ,Low copy number ,Bacteria ,Transformation efficiency - Abstract
Gram-negative bacteria release Outer Membrane Vesicles (OMVs) into the extracellular environment. Recent studies recognized these vesicles as vectors to horizontal gene transfer, however, the parameters that mediate OMVs transfer within bacterial communities remain unclear. The present study highlights for the first time the transfer of plasmids containing resistance genes via OMVs derived from Klebsiella pneumoniae (K. pneumoniae). This mechanism confers DNA protection, it is plasmid copy number dependent with a ratio of 3.6 times among high copy number plasmid (pGR) versus low copy number plasmid (PRM), and the transformation efficiency was 3.6 times greater. Therefore, the DNA amount in the vesicular lumen and the efficacy of horizontal gene transfer was strictly dependent on the identity of the plasmid. Moreover, the role of K. pneumoniae-OMVs in interspecies transfer was described. The transfer ability was not related to the phylogenetic characteristics between the donor and the recipient species. K. pneumoniae-OMVs transferred plasmid to Escherichia coli, Salmonella enterica, Pseudomonas aeruginosa and Burkholderia cepacia. These findings address the pivotal role of K. pneumoniae-OMVs as vectors for antimicrobial resistance genes spread, contributing to the development of antibiotic resistance in the microbial communities.
- Published
- 2021
22. Age-related miRNome landscape of cumulus oophorus cells during controlled ovarian stimulation protocols in IVF cycles
- Author
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Gianluigi Franci, V Pisaturo, Nicola Colacurci, Lucia Altucci, Carmela Dell'Aversana, Salvatore Longobardi, Francesca Caprio, Thomas D'Hooghe, F Cuomo, Marianna Santonastaso, S Barone, D Valerio, Dell'Aversana, C, Cuomo, F, Longobardi, S, D'Hooghe, T, Caprio, F, Franci, G, Santonastaso, M, Colacurci, N, Barone, S, Pisaturo, V, Valerio, D, and Altucci, L
- Subjects
Infertility ,medically assisted reproduction ,medicine.drug_class ,gonadotropin stimulation ,Fertilization in Vitro ,Biology ,Oogenesis ,Andrology ,03 medical and health sciences ,0302 clinical medicine ,Ovulation Induction ,Germany ,microRNA ,medicine ,Humans ,Epigenetics ,cumulus oophorus cells ,cumulus oophorus cell ,030304 developmental biology ,miRNA ,Aged ,0303 health sciences ,030219 obstetrics & reproductive medicine ,Cumulus Cells ,aging ,epigenetics ,Female ,Oocytes ,Rehabilitation ,Obstetrics and Gynecology ,Original Articles ,medicine.disease ,AcademicSubjects/MED00905 ,Cumulus oophorus ,Real-time polymerase chain reaction ,Reproductive Medicine ,DNA methylation ,Gonadotropin ,epigenetic - Abstract
STUDY QUESTION Is the microRNA (miRNA) expression pattern of cumulus oophorus cells (COCs) in women undergoing medically assisted reproduction (MAR) procedures differentially modulated according to patient age and gonadotropin treatment strategy? SUMMARY ANSWER Maternal age is an independent factor impacting miRNA expression in COCs while gonadotropin treatment may affect follicular miRNA expression and IVF efficacy. WHAT IS KNOWN ALREADY Epigenetic mechanisms in female infertility are complex and poorly studied. DNA methylation, histone modifications, miRNAs and nucleosome positioning influence cellular machinery through positive and negative feedback mechanisms either alone or interactively. miRNAs are important regulators during oogenesis, spermatogenesis and early embryogenesis, and are reported to play a role in regulating crosstalk between the oocyte and COCs. Although miRNome analysis has been performed in female human reproductive tissues (endometrium, myometrium, cervix and ovaries), epigenetic modifications in women with infertility have not been explored in detail. In addition, the impact of gonadotropin treatments during MAR on miRNA expression in COCs has not been fully investigated. STUDY DESIGN, SIZE, DURATION This study was carried out in 53 COC samples obtained from mature metaphase II (MII) oocytes in 53 women undergoing MAR treatment. A total of 38 samples for assay development were pooled by maternal age and gonadotropin treatment into four predetermined subgroups: ≥36 years and recombinant human FSH (r-hFSH), n = 10; ≥36 years and r-hFSH+ recombinant human-luteinizing hormone (r-hLH), n = 10; ≤35 years and r-hFSH, n = 9; ≤35 years and r-hFSH+r-hLH, n = 9. miRNome profiles were determined and compared between subgroups. Expression of defined miRNAs was validated in the remaining fifteen samples, representative of each subgroup, by quantitative polymerase chain reaction (PCR). PARTICIPANTS/MATERIALS, SETTING, METHODS COCs were processed for miRNA-enriched total RNA extraction and pooled in homogeneous subgroups to obtain a sufficient amount and quality of starting material to perform the analysis. Each pooled sample underwent miRNA profiling using PCR assay system to examine expression of 752 human miRNAs without pre-amplification. Data were analyzed using the delta-delta Ct method for relative quantitation and prediction of target genes (with at least four algorithms predicting the same miRNA-gene interaction pair (HIT)>4). The miRSystem database provided functional annotation enrichment (raw P-value MAIN RESULTS AND THE ROLE OF CHANCE We found distinctive miRNA expression profiles in each subgroup correlating with age and MAR stimulation. In addition, a number of selective and co-expressed miRNAs were revealed by comparative analysis. A cluster of 37 miRNAs were commonly but differentially expressed in all four pools. Significant differences were observed in expression regulation of 37 miRNAs between age groups (≤35 or ≥36) in women receiving r-hFSH+r-hLH compared to those receiving r-hFSH alone. Higher concentrations and increased numbers of miRNAs were recorded in younger than in older patients, regardless of treatment. Functional and expression studies performed to retrieve common miRNome profiles revealed an enrichment of biological functions in oocyte growth and maturation, embryo development, steroidogenesis, ovarian hyperstimulation, apoptosis and cell survival, glucagon and lipid metabolism, and cell trafficking. The highest scored pathways of target genes of the 37 common miRNAs were associated with mitogen-activated protein kinase (MAPK) signaling pathways, G alpha signaling, transcription regulation, tight junctions, RNA polymerase I and III, and mitochondrial transcription. We identified a potential age- and MAR stimulation-dependent signature in the miRNA landscape of COCs. LIMITATIONS, REASONS FOR CAUTION We cannot rule out the possibility that other unknown individual genetic or clinical factors may have interfered with the reported results. Since miRNA profiling was conducted with a predefined array of target probes, other miRNA molecules, potentially modulated by age and hormonal stimulation, may have been missed in this study. WIDER IMPLICATIONS OF THE FINDINGS miRNA expression in COCs is modulated by gonadotropin treatment and correlates strongly with age. A better understanding of the expression patterns and functions of miRNAs may lead to the development of novel therapeutics to treat ovarian dysfunction and improve fertility in older women. STUDY FUNDING/COMPETING INTEREST This study was funded by Merck KGaA, Darmstadt, Germany. All authors declared no competing interest, except SL and TD who are fully employed by Merck KGaA. TRIAL REGISTRATION NUMBER N/A
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- 2021
23. Extracellular vesicle-based nucleic acid delivery:Current advances and future perspectives in cancer therapeutic strategies
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Crescenzo Massaro, Carmela Dell'Aversana, Giulia Sgueglia, Lucia Altucci, Victoria Frattolillo, S Rubina Baglio, Massaro, C., Sgueglia, G., Frattolillo, V., Baglio, S. R., Altucci, L., and Dell'Aversana, C.
- Subjects
0303 health sciences ,Chemistry ,Immunogenicity ,Genetic enhancement ,lcsh:RS1-441 ,Pharmaceutical Science ,Cancer ,Computational biology ,Extracellular vesicle ,medicine.disease ,Extracellular vesicles ,lcsh:Pharmacy and materia medica ,03 medical and health sciences ,0302 clinical medicine ,Gene therapy ,Selective transfer ,030220 oncology & carcinogenesis ,Nucleic acid delivery ,Nucleic acid ,medicine ,extracellular vesicles ,030304 developmental biology - Abstract
Extracellular vesicles (EVs) are sophisticated and sensitive messengers released by cells to communicate with and influence distant and neighboring cells via selective transfer of bioactive content, including protein lipids and nucleic acids. EVs have therefore attracted broad interest as new and refined potential therapeutic systems in many diseases, including cancer, due to their low immunogenicity, non-toxicity, and elevated bioavailability. They might serve as safe and effective vehicles for the transport of therapeutic molecules to specific tissues and cells. In this review, we focus on EVs as a vehicle for gene therapy in cancer. We describe recent developments in EV engineering to achieve efficient intracellular delivery of cancer therapeutics and avoid off-target effects, to provide an overview of the potential applications of EV-mediated gene therapy and the most promising biomedical advances.
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- 2020
24. Outer membrane vesicles derived from klebsiella pneumoniae influence the mirna expression profile in human bronchial epithelial beas-2b cells
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Fabrizio Dal Piaz, Concetta Paola Ilisso, Giuliana Donadio, Federica Dell'Annunziata, Carmela Dell'Aversana, Massimiliano Galdiero, Lucia Altucci, Giuseppe Greco, Veronica Folliero, Alessandra Coppola, Marilena Galdiero, Marina Porcelli, Francesca Martora, Gianluigi Franci, Annarita Falanga, Dell'Annunziata, F., Ilisso, C. P., Dell'Aversana, C., Greco, G., Coppola, A., Martora, F., Piaz, F. D., Donadio, G., Falanga, A., Galdiero, M., Altucci, L., Porcelli, M., Folliero, V., Franci, G., Dell'Annunziata, Federica, Ilisso, Concetta Paola, Dell'Aversana, Carmela, Greco, Giuseppe, Coppola, Alessandra, Martora, Francesca, Dal Piaz, Fabrizio, Donadio, Giuliana, Falanga, Annarita, Galdiero, Marilena, Altucci, Lucia, Galdiero, Massimiliano, Porcelli, Marina, Folliero, Veronica, and Franci, Gianluigi
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0301 basic medicine ,Microbiology (medical) ,Klebsiella pneumoniae ,medicine.medical_treatment ,030106 microbiology ,Virulence ,Microbiology ,Article ,03 medical and health sciences ,Immune system ,Virology ,microRNA ,Gene expression ,medicine ,Immune response ,lcsh:QH301-705.5 ,biology ,Microarray analysis techniques ,Outer membrane vesicle ,MiRNA ,Outer membrane vesicles ,Target genes ,biology.organism_classification ,030104 developmental biology ,Cytokine ,lcsh:Biology (General) ,Bacterial outer membrane ,outer membrane vesicles - Abstract
Klebsiella pneumoniae is an opportunistic pathogen that causes nosocomial and community-acquired infections. The spread of resistant strains of K. pneumoniae represents a growing threat to human health, due to the exhaustion of effective treatments. K. pneumoniae releases outer membrane vesicles (OMVs). OMVs are a vehicle for the transport of virulence factors to host cells, causing cell injury. Previous studies have shown changes of gene expression in human bronchial epithelial cells after treatment with K. pneumoniae OMVs. These variations in gene expression could be regulated through microRNAs (miRNAs), which participate in several biological mechanisms. Thereafter, miRNA expression profiles in human bronchial epithelial cells were evaluated during infection with standard and clinical K. pneumoniae strains. Microarray analysis and RT-qPCR identified the dysregulation of miR-223, hsa-miR-21, hsa-miR-25 and hsa-let-7g miRNA sequences. Target gene prediction revealed the essential role of these miRNAs in the regulation of host immune responses involving NF-ĸB (miR-223), TLR4 (hsa-miR-21), cytokine (hsa-miR-25) and IL-6 (hsa-let-7g miRNA) signalling pathways. The current study provides the first large scale expression profile of miRNAs from lung cells and predicted gene targets, following exposure to K. pneumoniae OMVs. Our results suggest the importance of OMVs in the inflammatory response.
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- 2020
25. The Pan-Sirtuin Inhibitor MC2494 Regulates Mitochondrial Function in a Leukemia Cell Line
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Gilda Cobellis, Marzia Di Donato, Giulia Sgueglia, Dante Rotili, Antonello Mai, Laura Della Torre, Vincenzo Carafa, Angela Nebbioso, Angela Chambery, Carmela Dell'Aversana, Rosita Russo, Federica Sarno, Francesca Cuomo, Lucia Altucci, Carafa, V, Russo, R, Della Torre, L, Cuomo, F, Dell'Aversana, C, Sarno, F, Sgueglia, G, Di Donato, M, Rotili, D, Mai, A, Nebbioso, A, Cobellis, G, Chambery, A, Altucci, L, Carafa, Vincenzo, Russo, Rosita, Della Torre, Laura, Cuomo, Francesca, Dell'Aversana, Carmela, Sarno, Federica, Sgueglia, Giulia, Di Donato, Marzia, Rotili, Dante, Mai, Antonello, Nebbioso, Angela, Cobellis, Gilda, Chambery, Angela, and Altucci, Lucia
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0301 basic medicine ,Cancer Research ,Mitochondrion ,lcsh:RC254-282 ,energy production ,03 medical and health sciences ,0302 clinical medicine ,sirtuins ,Organelle ,medicine ,cancer ,epigenetic ,leukemia ,mitochondria ,proteomic analysis ,Epigenetics ,cancer, leukemia ,Original Research ,ATP synthase ,biology ,proteomic analysi ,Cancer ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell biology ,030104 developmental biology ,Oncology ,Mitochondrial biogenesis ,030220 oncology & carcinogenesis ,Sirtuin ,biology.protein ,Function (biology) - Abstract
The involvement of sirtuins (SIRTs) in modulating metabolic and stress response pathways is attracting growing scientific interest. Some SIRT family members are located in mitochondria, dynamic organelles that perform several crucial functions essential for eukaryotic life. Mitochondrial dysfunction has emerged as having a key role in a number of human diseases, including cancer. Here, we investigated mitochondrial damage resulting from treatment with a recently characterized pan-SIRT inhibitor, MC2494. MC2494 was able to block mitochondrial biogenesis and function in terms of ATP synthesis and energy metabolism, suggesting that it might orchestrate cell response to metabolic stress and thereby interfere with cancer promotion and progression. Targeting mitochondrial function could thus be considered a potential anticancer strategy for use in clinical therapy.
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- 2020
26. Amelioration of diastolic dysfunction by dapagliflozin in a non-diabetic model involves coronary endothelium
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Francesco Rossi, Donato Cappetta, Agostino Miccichè, Silvio Naviglio, Annalisa Capuano, Loreta Pia Ciuffreda, Raffaele Coppini, Lucia Altucci, Cristina Scavone, Chiara Palandri, Liberato Berrino, Anna Cozzolino, Filippo Crea, Eleonora Cianflone, Domenico D'Amario, Marcello Rota, Konrad Urbanek, Antonella De Angelis, Carmela Dell'Aversana, Lorenzo Santini, Cappetta, D., De Angelis, A., Ciuffreda, L. P., Coppini, R., Cozzolino, A., Micciche, A., Dell'Aversana, C., D'Amario, D., Cianflone, E., Scavone, C., Santini, L., Palandri, C., Naviglio, S., Crea, F., Rota, M., Altucci, L., Rossi, F., Capuano, A., Urbanek, K., and Berrino, L.
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0301 basic medicine ,Male ,Heart disease ,H ,Pharmacology ,Coronary endothelium ,Dapagliflozin ,Diastolic dysfunction ,Na(+)/H(+)exchanger 1 ,Ventricular Function, Left ,chemistry.chemical_compound ,Ventricular Dysfunction, Left ,0302 clinical medicine ,Glucosides ,Diastole ,Myocytes, Cardiac ,Endothelial dysfunction ,Cardioprotection ,Sodium-Hydrogen Exchanger 1 ,Coronary Vessels ,030220 oncology & carcinogenesis ,Nitric Oxide Synthase Type III ,+ ,exchanger 1 ,Endothelial activation ,03 medical and health sciences ,Sodium-Glucose Transporter 1 ,Sodium-Glucose Transporter 2 ,medicine ,Animals ,Na ,Calcium Signaling ,Benzhydryl Compounds ,Sodium-Glucose Transporter 2 Inhibitors ,Heart Failure ,Rats, Inbred Dahl ,business.industry ,Sodium ,Endothelial Cells ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Blood pressure ,chemistry ,Heart catheterization ,Settore MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE ,Endothelium, Vascular ,Heart failure with preserved ejection fraction ,business - Abstract
The results of trials with sodium-glucose cotransporter 2 (SGLT2) inhibitors raised the possibility that this class of drugs provides cardiovascular benefits independently from their anti-diabetic effects, although the mechanisms are unknown. Therefore, we tested the effects of SGLT2 inhibitor dapagliflozin on the progression of experimental heart disease in a non-diabetic model of heart failure with preserved ejection fraction. Dahl salt-sensitive rats were fed a high-salt diet to induce hypertension and diastolic dysfunction and were then treated with dapagliflozin for six weeks. Dapagliflozin ameliorated diastolic function as documented by echo-Doppler and heart catheterization, while blood pressure remained markedly elevated. Chronic in vivo treatment with dapagliflozin reduced diastolic Ca2+ and Na+ overload and increased Ca2+ transient amplitude in ventricular cardiomyocytes, although no direct action of dapagliflozin on isolated cardiomyocytes was observed. Dapagliflozin reversed endothelial activation and endothelial nitric oxide synthase deficit, with reduced cardiac inflammation and consequent attenuation of pro-fibrotic signaling. The potential involvement of coronary endothelium was supported by the endothelial upregulation of Na+/H+ exchanger 1in vivo and direct effects on dapagliflozin on the activity of this exchanger in endothelial cells in vitro. In conclusions, several mechanisms may cumulatively play a significant role in the dapagliflozin-associated cardioprotection. Dapagliflozin ameliorates diastolic function and exerts a positive effect on the myocardium, possibly targeting coronary endothelium. The lower degree of endothelial dysfunction, inflammation and fibrosis translate into improved myocardial performance.
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- 2020
27. Advanced Assays in Epigenetics
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Federica Sarno, Mariarosaria Conte, Carmela Dell'Aversana, Cristina Giorgio, Lucia Altucci, Mai, Antonello, Dell’Aversana, C, Sarno, F, Conte, M, Giorgio, C, and Altucci, L
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Computer science ,Cellular functions ,Identification (biology) ,Computational biology ,Epigenome ,Epigenetics ,Epigenetica - Abstract
Nowadays, science is proving that our body possesses incredible self-healing and self-repairing ability. These mechanisms are markedly influenced by our lifestyle, environmental factors and also our beliefs, thoughts, emotions and intentions. A change in the aforementioned factors can affect or even alter completely the tendency for expression. During this process, our enormous code base, the DNA, will be read and the manifestation which will be expressed is heavily influenced by epigenetic marks. These marks are either written, read or modified. So we are based not only on plain code, but we are the modifiers of the code through readers, writers and erasers. So we have a profound vibrational effect on our continually evolving genetic code. We are the programmers of the code. DNA activation is our “software upgrade”. The specific scientific term “epigenetics” for these code reading, writing and erasing has been first defined in 1942 by C.H. Waddington. This term has been used in various contexts. Etymologically speaking, epigenetics deals with a precise branch of genetics as the Greek prefix epi means “after”, “post” or “additionally”. Today, in the molecular realm, all three meanings of epi are somewhat proven in the rapidly growing body of literature especially in the last decade dealing with fundamental processes in a living cell which are outside of the classical genetic processes and sources of genetic information like the DNA base pair sequence. Today researches try to link an observed phenomenon or a disease down to the molecular level. Besides the longer known epigenetic targets such as histone deacetylases or DNA methyltransferases, a whole bunch of new enzymes and enzyme complexes have been discovered in the last 15 years. This book mainly discusses the recent advances in the drug development of epigenetic modulators from a medicinal chemist’s viewpoint. Modern techniques in biology, biochemistry and chemical biology allow researchers faster than ever to describe and discover new epigenetic players as well as novel functions of old and known ones. Medicinal chemistry plays a fundamental role in the discovery process as it provides not only tools to better understand the function of an epigenetic player but also novel therapy options where aberrant epigenetic mechanisms are involved. The book comprises 16 chapters. Each chapter includes a short introduction for a single epigenetic target or a target family ranging from structural biology aspects to cell biology and biochemistry. Most of the space is devoted to target modulation, either inhibition or activation. The authors give an insight into the discovery and development of mainly small organic molecules and also peptides influencing epigenetic pathways. Modern aspects of drug design such as new methodologies, ranging from computational approaches, crystallography to structural biology are presented with hands-on examples.
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- 2019
28. LncRNA SBF2-AS1 promotes hepatocellular carcinoma metastasis by regulating EMT and predicts unfavorable prognosis
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Y-T, Zhang, B-P, Li, B, Zhang, P, Ma, Q-L, Wu, L, Ming, L-M, Xie, Franci, G, Dell'Aversana, C, Stelitano, D, Rinaldi, M, and Altucci, L
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Male ,Carcinoma, Hepatocellular ,Epithelial-Mesenchymal Transition ,Prognosi ,Liver Neoplasms ,Hep G2 Cells ,Middle Aged ,Prognosis ,Gene Expression Regulation, Neoplastic ,Liver Neoplasm ,Cell Movement ,Humans ,Female ,Neoplasm Invasiveness ,RNA, Long Noncoding ,Human ,Cell Proliferation ,Retrospective Studies ,Signal Transduction - Abstract
Recent studies have furthered our understanding of the function of long noncoding RNAs (lncRNAs) in numerous biological processes, including cancer. The present study aimed to investigate the expression of lncRNA SBF2-AS1 (SBF2-AS1) in patients with hepatocellular carcinoma (HCC) and to investigate its effect on HCC cells.Using quantitative reverse transcription-polymerase chain reaction, we detected SBF2-AS1 expression in HCC cell lines and primary tumor tissues. The associations between SBF2-AS1 expression and the clinicopathological factors and outcome of HCC patients were statistically analyzed. MTT assay and transwell assay were performed to determine the proliferation, migration and invasion, respectively. In addition, we evaluated the activation of Mesenchymal-epithelial transition (EMT) pathway by Western blot.We found that SBF2-AS1 expression levels were significantly up-regulated in HCC tissues and cell lines compared with the corresponding noncancerous liver tissues and normal hepatic cell line. In addition, high SBF2-AS1 expression levels were correlated with vein invasion (p = 0.008) and TNM stage (p = 0.013). Furthermore, Kaplan-Meier survival analysis indicated that high expressions of SBF2-AS1 were correlated with shorter overall survival of HCC patients. Univariate and multivariate analysis identified high SBF2-AS1 expression as an unfavorable prognostic factor for overall survival. Further functional analysis demonstrated that knockdown of SBF2-AS1 significantly inhibited HCC cells proliferation, migration and invasion. Mechanistically, we found that SBF2-AS1 could promote the activation of EMT pathway, which was demonstrated by measuring the expression levels of EMT-related markers.SBF2-AS1 might be considered as a novel molecule involved in HCC development, which provides a potential therapeutic target for HCC.
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- 2018
29. HDAC2 deregulation in tumorigenesis is causally connected to repression of immune modulation and defense escape
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Ciro Abbondanza, Mariarosaria Conte, Rosaria Benedetti, Angela Nebbioso, Annamaria Carissimo, Valeria Belsito Petrizzi, Lucia Altucci, Francesca Petraglia, Carmela Dell'Aversana, Alfonso Maria D’Arco, Conte, M, Dell'Aversana, C, Benedetti, R, Petraglia, F, Carissimo, A, Petrizzi, Vb, D'Arco, Am, Abbondanza, Ciro, Nebbioso, Angela, and Altucci, Lucia
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Male ,Time Factors ,Pyridines ,Blotting, Western ,Histone Deacetylase 2 ,Biology ,Hydroxamic Acids ,Transcriptome ,HDAC inhibitors ,HLA Antigens ,Cell Line, Tumor ,medicine ,Transcriptional regulation ,Humans ,Gene silencing ,Epigenetics ,Promoter Regions, Genetic ,Vorinostat ,Aged ,Cell Proliferation ,Cancer ,Regulation of gene expression ,Leukemia ,Reverse Transcriptase Polymerase Chain Reaction ,Histone deacetylase 2 ,U937 Cells ,Middle Aged ,HDAC2 ,3. Good health ,Gene Expression Regulation, Neoplastic ,Histone Deacetylase Inhibitors ,HLA ,Gene expression profiling ,Oncology ,Leukemia, Myeloid ,Gene Knockdown Techniques ,Acute Disease ,Benzamides ,MHC class II ,Cancer research ,Female ,Protein Binding ,Research Paper ,medicine.drug - Abstract
Histone deacetylase 2 (HDAC2) is overexpressed or mutated in several disorders such as hematological cancers, and plays a critical role in transcriptional regulation, cell cycle progression and developmental processes. Here, we performed comparative transcriptome analyses in acute myeloid leukemia to investigate the biological implications of HDAC2 silencing versus its enzymatic inhibition using epigenetic-based drug(s). By gene expression analysis of HDAC2-silenced vs wild-type cells, we found that HDAC2 has a specific role in leukemogenesis. Gene expression profiling of U937 cell line with or without treatment of the well-known HDAC inhibitor vorinostat (SAHA) identifies and characterizes several gene clusters where inhibition of HDAC2 ‘mimics’ its silencing, as well as those where HDAC2 is selectively and exclusively regulated by HDAC2 protein expression levels. These findings may represent an important tool for better understanding the mechanisms underpinning immune regulation, particularly in the study of major histocompatibility complex class II genes.
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- 2014
30. Mir-194-5p/BCLAF1 deregulation in AML tumorigenesis
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Lucia Altucci, S. Minucci, Concetta Ingenito, Isabella Pallavicini, Loredana D’Amato, V Belsito Petrizzi, A. Di Costanzo, Carmela Dell'Aversana, Sadia Saeed, Filomena Matarese, Annamaria Carissimo, G Lania, Hendrik G. Stunnenberg, Joost H.A. Martens, Cristina Giorgio, Dell'Aversana, C., Giorgio, C, D'Amato, L., Lania, G., Matarese, F., Saeed, S., Di Costanzo, A., Belsito Petrizzi, V., Ingenito, C., Martens, J. H. A., Pallavicini, I., Minucci, S., Carissimo, A., Stunnenberg, H. G., and Altucci, Lucia
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0301 basic medicine ,Cancer Research ,Myeloid ,medicine.drug_class ,Cellular differentiation ,Down-Regulation ,Apoptosis ,Biology ,medicine.disease_cause ,Acute myeloid leukaemia ,03 medical and health sciences ,Cancer epigenetics ,Cell Line, Tumor ,miR-194-5p/BCLAF1 ,microRNA ,medicine ,Humans ,Molecular Biology ,Oncogenesis ,Regulation of gene expression ,Tumor Suppressor Proteins ,Cell Cycle ,Histone deacetylase inhibitor ,Myeloid leukemia ,Cell Differentiation ,Hematology ,3. Good health ,Repressor Proteins ,Leukemia, Myeloid, Acute ,MicroRNAs ,Haematopoiesis ,Anesthesiology and Pain Medicine ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Oncology ,miRNAs ,Immunology ,Cancer research ,Original Article ,Erratum ,Carcinogenesis - Abstract
Contains fulltext : 168891.pdf (Publisher’s version ) (Open Access) Deregulation of epigenetic mechanisms, including microRNA, contributes to leukemogenesis and drug resistance by interfering with cancer-specific molecular pathways. Here, we show that the balance between miR-194-5p and its newly discovered target BCL2-associated transcription factor 1 (BCLAF1) regulates differentiation and survival of normal hematopoietic progenitors. In acute myeloid leukemias this balance is perturbed, locking cells into an immature, potentially /`immortal/' state. Enhanced expression of miR-194-5p by treatment with the histone deacetylase inhibitor SAHA or by exogenous miR-194-5p expression re-sensitizes cells to differentiation and apoptosis by inducing BCLAF1 to shuttle between nucleus and cytosol. miR-194-5p/BCLAF1 balance was found commonly deregulated in 60 primary acute myeloid leukemia patients and was largely restored by ex vivo SAHA treatment. Our findings link treatment responsiveness to re-instatement of miR-194-5p/BCLAF1 balance. 11 p.
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- 2017
31. MicroRNA-34a regulates doxorubicin-induced cardiotoxicity in rat
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Francesco Rossi, Rosa Russo, Elena Piegari, Grazia Esposito, Lucia Altucci, Carmela Dell'Aversana, Konrad Urbanek, Liberato Berrino, Donato Cappetta, Antonella De Angelis, Piegari, Elena, Russo, Rosa, Cappetta, Donato, Esposito, Grazia, Urbanek, Konrad, Dell'Aversana, Carmela, Altucci, Lucia, Berrino, Liberato, Rossi, Francesco, DE ANGELIS, Antonella, Piegari, E, Russo, R, Cappetta, D, Esposito, G, Urbanek, K, Dell'Aversana, C, Altucci, L, Berrino, L, Rossi, F, and De Angelis, A
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0301 basic medicine ,Senescence ,Apoptosis ,Pharmacology ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,Paracrine signalling ,SIRT1 ,Sirtuin 1 ,Animals ,Gene silencing ,Medicine ,cellular senescence ,Doxorubicin ,Cells, Cultured ,Cyclin-Dependent Kinase Inhibitor p16 ,Cell Proliferation ,Cardioprotection ,Cardiotoxicity ,Antibiotics, Antineoplastic ,business.industry ,doxorubicin-induced cardiotoxicity ,Endothelial Cells ,Acetylation ,Heart ,Rats, Inbred F344 ,Rats ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,MicroRNA 34a ,Female ,rat cardiac progenitor cells ,Tumor Suppressor Protein p53 ,Cardiomyopathies ,business ,Biomarkers ,Myoblasts, Cardiac ,miR-34a ,Research Paper ,medicine.drug - Abstract
// Elena Piegari 1, * , Rosa Russo 1, * , Donato Cappetta 1 , Grazia Esposito 1 , Konrad Urbanek 1 , Carmela Dell’Aversana 2 , Lucia Altucci 2, 3 , Liberato Berrino 1 , Francesco Rossi 1 , Antonella De Angelis 1 1 Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy 2 Institute of Genetics and Biophysics, IGB ‘Adriano Buzzati-Traverso’, Naples, Italy 3 Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy * These authors have contributed equally to this work Correspondence to: Elena Piegari, email: elena.piegari@unina2.it Keywords: miR-34a, doxorubicin-induced cardiotoxicity, rat cardiac progenitor cells, SIRT1, cellular senescence Received: February 03, 2016 Accepted: July 26, 2016 Published: August 22, 2016 ABSTRACT New strategies to prevent and early detect the cardiotoxic effects of the anticancer drug doxorubicin (DOXO) are required. MicroRNAs emerged as potential diagnostic, therapeutic and prognostic approaches in cardiovascular diseases. MiR-34a has a role in cardiac dysfunction and ageing and is involved in several cellular processes associated with DOXO cardiotoxicity. Our in vitro and in vivo results indicated that after DOXO exposure the levels of miR-34a are enhanced in cardiac cells, including Cardiac Progenitor Cells (CPCs). Since one of the determining event responsible for the initiation and evolution of the DOXO toxicity arises at the level of the CPC compartment, we evaluated if miR-34a pharmacological inhibition in these cells ameliorates the detrimental aftermath of the drug. AntimiR-34a has beneficial consequences on vitality, proliferation, apoptosis and senescence of DOXO-treated rat CPC. These effects are mediated by an increase of prosurvival miR-34a targets Bcl-2 and SIRT1, accompanied by a decrease of acetylated-p53 and p16 INK4a . Importantly, miR-34a silencing also reduces the release of this miRNA from DOXO-exposed rCPCs, decreasing its negative paracrine effects on other rat cardiac cells. In conclusion, the silencing of miR-34a could represent a future therapeutic option for cardioprotection in DOXO toxicity and at the same time, it could be considered as a circulating biomarker for anthracycline-induced cardiac damage.
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- 2016
32. Impact of histone deacetylase inhibitors SAHA and MS-275 on DNA repair pathways in human mesenchymal stem cells
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Fiorina Casale, Nicola Alessio, Diana Teti, Giovanni Di Bernardo, Lucia Altucci, Marilena Cipollaro, Carmela Dell'Aversana, Umberto Galderisi, DI BERNARDO, Giovanni, Alessio, N, Dell'Aversana, C, Casale, Fiorina, Teti, D, Cipollaro, Marilena, Altucci, Lucia, and Galderisi, Umberto
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DNA Repair ,Pyridines ,Physiology ,DNA damage ,DNA repair ,Clinical Biochemistry ,Antineoplastic Agents ,Biology ,Hydroxamic Acids ,03 medical and health sciences ,0302 clinical medicine ,STROMAL CELLS ,HDAC INHIBITORS ,PHASE-I ,APOPTOSIS ,CANCER ,DIFFERENTIATION ,medicine ,Humans ,Vorinostat ,030304 developmental biology ,0303 health sciences ,Gene Expression Profiling ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Molecular biology ,3. Good health ,Histone Deacetylase Inhibitors ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Benzamides ,Cancer cell ,Cancer research ,DNA mismatch repair ,Histone deacetylase ,DNA Damage ,Nucleotide excision repair ,medicine.drug - Abstract
Histone deacetylase inhibitors (HDACis) have received considerable attention for their anti-tumoral properties. We report here the effects of two HDACis, SAHA and MS-275, on the biology of mesenchymal stem cells (MSCs). It is well known that HDACis trigger both DNA damage responses and actual DNA damage in cancer cells. On this premise, we evaluated HDACis influence on DNA damage pathways in MSCs. We analyzed a panel of genes involved in the regulation of base and nucleotide excision repair, mismatch repair, and double strand break repair. That a majority of the analyzed genes displayed significant expression changes upon incubation with SAHA or MS-275 suggested that regulation of their expression is greatly affected by HDACis. The complex expression pattern, with some genes up-regulated and other under-expressed, did not allow to foresee whether these changes allow cells cope with stressful DNA damaging stimuli. Furthermore, we evaluated the biological outcome following treatment of MSCs with DNA damaging agents (H(2)O(2) and UV) in presence of HDACis. In these settings, MSCs treated with H(2)O(2) or UV radiation underwent apoptosis and/or senescence, and pre-incubation with HDACi exacerbated cell death phenomena. Accordingly, the number of cells harboring 8-oxo-7,8-dihydroguanine (8oxodG), a hallmark of DNA oxidative damage, was significantly higher in samples incubated with HDACis compared to controls. In summary, our findings suggest that SAHA and MS-275, even at low effective doses, can alter the biology of MSCs, diminishing their ability to survive the effects of DNA-damaging agents.
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- 2010
33. Histone Deacetylase Inhibitors Promote Apoptosis and Senescence in Human Mesenchymal Stem Cells
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Tiziana Squillaro, Lucia Altucci, Marco Miceli, Marilena Cipollaro, Umberto Galderisi, Carmela Dell'Aversana, Giovanni Di Bernardo, Antonino Cascino, Di Bernardo, Giovanni, Squillaro, Tiziana, Dell???aversana, Carmela, Miceli, Marco, Cipollaro, Marilena, Cascino, Antonino, Altucci, Lucia, Galderisi, Umberto, DI BERNARDO, Giovanni, Squillaro, T, Dell'Aversana, C, Miceli, M, and Cascino, A
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Pyridines ,Apoptosis ,Biology ,Senescence ,Hydroxamic Acids ,Flow cytometry ,Annexin ,Neoplasms ,Histone Deacetylase Inhibitor ,medicine ,Humans ,Enzyme Inhibitors ,Cellular Senescence ,Vorinostat ,medicine.diagnostic_test ,Cell Cycle ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Hematology ,Cell cycle ,apoptosi ,Molecular biology ,Histone Deacetylase Inhibitors ,Human Mesenchymal Stem Cell ,medicine.anatomical_structure ,Benzamides ,Cancer research ,Bone marrow ,Histone deacetylase ,Stem cell ,Developmental Biology - Abstract
Histone deacetylase inhibitors (HDACi) have received a great amount of attention for their antitumoral properties. Suberoyl anilide hydroxamic acid (SAHA) and MS-275 are among the more promising HDACi for cancer treatments. Although these HDACi compounds exert low toxicity on normal cells, the therapies based on these molecules can cause side effects that can greatly impair the functions of the bone marrow microenvironment. This is a complex system that contains several types of stem cells, such as mesenchymal stem cells (MSCs). We conducted comparative studies on the effects of SAHA and MS-275 on human MSCs in order to ascertain if these compounds can impair the physiology of MSCs. Both SAHA and MS-275 induced an arrest in the cell cycle along with the induction of apoptotic pathways as evidenced by fl ow cytometry, annexin assay, detection of activated caspase 9, and molecular analysis of Bax/Bcl-2 expression. The MS-275 treatment induced an increase of senescent cells, whereas in cells treated with SAHA, we detected a reduction of senescent cells compared to the control. We hypothesize that SAHA preferentially transactivates apoptotic genes, thereby inducing a great majority of the damaged cells to die by programmed cell death rather than senescence. Following the HDACi treatment, we observed a decrease in the expression of some genes that are involved in the regulation of stem cell properties. This suggests that SAHA and MS-275 could also be involved in the impairment of the stemness characteristics of MSCs. The phenomena that were induced by HDACi treatment were associated with an upregulation of several cyclin kinase inhibitors. By contrast, the p53-p21 pathway is apparently not involved in these processes.
- Published
- 2009
34. ARHGEF3 controls HDACi-induced differentiation via RhoA-dependent pathways in acute myeloid leukemias
- Author
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Lucia Altucci, Lucia Scisciola, Angela Nebbioso, Annamaria Carissimo, Mariarosaria Conte, Alfonso Ciotta, Carmela Dell'Aversana, Loredana D’Amato, D'Amato, L, Dell'Aversana, C, Conte, M, Ciotta, A, Scisciola, Lucia, Carissimo, A, Nebbioso, Angela, and Altucci, Lucia
- Subjects
Cancer Research ,RHOA ,Cellular differentiation ,Monocyte-Macrophage Precursor Cells ,Histone Deacetylases ,chemistry.chemical_compound ,HDAC inhibitors ,ELK1 ,HDAC inhibitor ,ARHGEF3 ,Cell Line, Tumor ,cancer ,Humans ,Molecular Biology ,Protein Kinase Inhibitors ,Myelopoiesis ,rho-Associated Kinases ,Acute myeloid leukemia ,biology ,U937 cell ,Kinase ,Entinostat ,Myeloid leukemia ,Cell biology ,Histone Deacetylase Inhibitors ,Leukemia, Myeloid, Acute ,Protein Transport ,chemistry ,Differentiation ,biology.protein ,Cancer research ,Signal transduction ,rhoA GTP-Binding Protein ,Rho Guanine Nucleotide Exchange Factors ,Signal Transduction ,Research Paper - Abstract
Altered expression and activity of histone deacetylases (HDACs) have been correlated with tumorigenesis. Inhibitors of HDACs (HDACi) induce acetylation of histone and non-histone proteins affecting gene expression, cell cycle progression, cell migration, terminal differentiation and cell death. Here, we analyzed the regulation of ARHGEF3, a RhoA-specific guanine nucleotide exchange factor, by the HDACi MS275 (entinostat). MS275 is a well-known benzamide-based HDACi, which induces differentiation of the monoblastic-like human histiocytic lymphoma cell line U937 to monocytes/macrophages. Incubation of U937 cells with MS275 resulted in an up regulation of ARHGEF3, followed by a significant enhancement of the marker of macrophage differentiation CD68. ARHGEF3 protein is primarily nuclear, but MS275 treatment rapidly induced its translocation into the cytoplasm. ARHGEF3 cytoplasmic localization is associated with activation of the RhoA/Rho-associated Kinase (ROCK) pathway. In addition to cytoskeletal rearrangements orchestrated by RhoA, we showed that ARHGEF3/RhoA-dependent signals involve activation of SAPK/JNK and then Elk1 transcription factor. Importantly, MS275-induced CD68 expression was blocked by exposure of U937 cells to exoenzyme C3 transferase and Y27632, inhibitors of Rho and ROCK respectively. Moreover, ARHGEF3 silencing prevented RhoA activation leading to a reduction in SAPK/JNK phosphorylation, Elk1 activation and CD68 expression, suggesting a crucial role for ARHGEF3 in myeloid differentiation. Taken together, our results demonstrate that ARHGEF3 modulates acute myeloid leukemia differentiation through activation of RhoA and pathways directly controlled by small GTPase family proteins. The finding that GEF protein modulation by HDAC inhibition impacts on cell differentiation may be important for understanding the antitumor mechanism(s) by which HDACi treatment stimulates differentiation in cancer.
- Published
- 2014
35. Identification of NuRSERY, a New Functional HDAC Complex Composed by HDAC5, GATA1, EKLF and pERK Present in Human Erythroid Cells
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Lucia Altucci, James J. Bieker, Angela Nebbioso, Lilian Varricchio, Giuliano Grazzini, Antonello Mai, Anna Rita Migliaccio, Giovanni Migliaccio, Carmela Dell'Aversana, Varricchio, L, Dell'Aversana, C, Nebbioso, Angela, Migliaccio, G, Altucci, Lucia, Mai, A, Grazzini, G, Bieker, Jj, Migliaccio, A. R., Nebbioso, A, Altucci, L, and FRANCO MIGLIACCIO, ANNA RITA
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Cytoplasm ,Erythroblasts ,Cellular differentiation ,EKLF ,Erythropoiesis ,GATA1 ,Histone deacetylase inhibitors ,Histone deacetylases ,Cell Differentiation ,Cell Nucleus ,Cells, Cultured ,Erythroid Cells ,GATA1 Transcription Factor ,Hematopoietic Stem Cells ,Histone Deacetylases ,Humans ,K562 Cells ,Kruppel-Like Transcription Factors ,Megakaryocytes ,Phosphorylation ,eIF-2 Kinase ,Biochemistry ,Cell Biology ,Biology ,Article ,HDAC ,Globin ,Histone deacetylase 5 ,HDAC HDAC5, GATA1, EKLF and pERK erythroid ,HDAC3 ,Molecular biology ,Mi-2/NuRD complex ,hematopiesis ,epigenetic ,K562 cells - Abstract
To clarify the role of HDACs in erythropoiesis, expression, activity and function of class I (HDAC1, HDAC2, HDAC3) and class Ha (HDAC4, HDAC5) HDACs during in vitro maturation of human erythroblasts were compared. During erythroid maturation, expression of HDAC1, HDAC2 and HDAC3 remained constant and activity and GATA1 association (its partner of the NuRD complex), of HDAC1 increased. By contrast, HDAC4 content drastically decreased and HDAC5 remained constant in content but decreased in activity. In erythroid cells, pull down experiments identified the presence of a novel complex formed by HDAC5, GATA1, EKLF and pERK which was instead undetectable in cells of the megakaryocytic lineage. With erythroid maturation, association among HDAC5, GATA1 and EKLF persisted but levels of pERK sharply decreased. Treatment of erythroleukemic cells with inhibitors of ERK phosphorylation reduced by >90% the total and nuclear content of HDAC5, GATA1 and EKLF, suggesting that ERK phosphorylation is required for the formation of this complex. Based on the function of class Ha HDACs as chaperones of other proteins to the nucleus and the erythroid-specificity of HDAC5 localization, this novel HDAC complex was named nuclear remodeling shuttle elythroid (NuRSERY). Exposure of erythroid cells to the class II-selective HDAC inhibitor (HDACi) APHA9 increased gamma/(gamma+beta) globin expression ratios (Mai et al., 2007), suggesting that NuRSERY may regulate globin gene expression. In agreement with this hypothesis, exposure of erythroid cells to APHA9 greatly reduced the association among HDAC5, GATA1 and EKLF. Since exposure to APHA9 did not affect survival rates or p21 activation, NuRSERY may represent a novel, possibly less toxic, target for epigenetic therapies of hemoglobinopaties and other disorders. (C) 2014 Elsevier Ltd. All rights reserved.
- Published
- 2014
36. Synthetic approaches to DNMT inhibitor SGI-1027 and effects on the U937 leukemia cell line
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Patricia García-Domínguez, Angel R. de Lera, Rosana Alvarez, Carmela Dell'Aversana, Lucia Altucci, García Domínguez, P, Dell'Aversana, C, Alvarez, R, Altucci, Lucia, and de Lera, A. R.
- Subjects
Clinical Biochemistry ,DNMT ,Pharmaceutical Science ,Biochemistry ,Catalysis ,Leukemia cell line ,Drug Discovery ,Humans ,DNA (Cytosine-5-)-Methyltransferases ,Epigenetics ,Enzyme Inhibitors ,Molecular Biology ,Cancer ,Leukemia ,U937 cell ,Chemistry ,Organic Chemistry ,DNMT Inhibitor ,Cell Cycle Checkpoints ,U937 Cells ,Cell cycle ,Bond formation ,Molecular biology ,Pyrimidines ,Cell culture ,DNA methylation ,Aminoquinolines ,Molecular Medicine ,Palladium - Abstract
The known DNMT inhibitor SGI-1027 4 has been synthesized using as key steps Pd-catalyzed Ar-N bond formation reactions performed in a sequential or convergent manner. In the former approach, a by-product, which corresponds to the incorporation of two units of 4-chloroquinoline, was also isolated. The biological effects of compound 4 in the U937 human leukemia cell line are also described.
- Published
- 2013
37. HDAC inhibitors repress BARD1 isoform expression in acute myeloid leukemia cells via activation of miR-19a and/or b
- Author
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Lucia Altucci, Angela Nebbioso, Tiziana Izzo, Felicetto Ferrara, Mariarosaria Conte, Ilaria Lepore, Guillermo Garcia-Manero, Francesco Paolo Tambaro, Maxim Pilyugin, Irmgard Irminger-Finger, Floriana De Bellis, Carmela Dell'Aversana, Lepore, I, Dell'Aversana, C, Pilyugin, M, Conte, Mariarosaria, Nebbioso, Angela, De Bellis, F, Tambaro, Fp, Izzo, T, Garcia Manero, G, Ferrara, F, Irminger Finger, I, and Altucci, Lucia
- Subjects
Tumor suppressor gene ,medicine.drug_class ,Ubiquitin-Protein Ligases ,lcsh:Medicine ,HL-60 Cells ,Biology ,Hydroxamic Acids ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,HDAC inhibitors ,BARD1 ,microRNA ,medicine ,Humans ,Protein Isoforms ,RNA, Neoplasm ,lcsh:Science ,skin and connective tissue diseases ,Vorinostat ,miRNA ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Leukemia ,Multidisciplinary ,Gene Expression Regulation, Leukemic ,Tumor Suppressor Proteins ,lcsh:R ,Histone deacetylase inhibitor ,Myeloid leukemia ,U937 Cells ,medicine.disease ,3. Good health ,Histone Deacetylase Inhibitors ,Leukemia, Myeloid, Acute ,MicroRNAs ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,lcsh:Q ,K562 Cells ,Research Article ,medicine.drug - Abstract
Over the past years BARD1 (BRCA1-associated RING domain 1) has been considered as both a BRCA1 (BReast Cancer susceptibility gene 1, early onset) interactor and tumor suppressor gene mutated in breast and ovarian cancers. Despite its role as a stable heterodimer with BRCA1, increasing evidence indicates that BARD1 also has BRCA1-independent oncogenic functions. Here, we investigate BARD1 expression and function in human acute myeloid leukemias and its modulation by epigenetic mechanism(s) and microRNAs. We show that the HDACi (histone deacetylase inhibitor) Vorinostat reduces BARD1 mRNA levels by increasing miR-19a and miR-19b expression levels. Moreover, we identify a specific BARD1 isoform, which might act as tumor diagnostic and prognostic markers.
- Published
- 2013
38. MePR: A Novel Human Mesenchymal Progenitor Model with Characteristics of Pluripotency
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Lucia Perone, Gianluigi Franci, Annamaria Carissimo, Francesca Petraglia, Francesca Ricciardiello, Massimo Cancemi, Marco Miceli, Giuseppe Maria Maruotti, Marco Savarese, Lucia Altucci, Carmela Dell'Aversana, Pasquale Martinelli, Miceli, M, Franci, G, Dell Aversana, C, Ricciardiello, F, Petraglia, F, Carissimo, A, Perone, L, Maruotti, Gm, Savarese, M, Martinelli, P, Cancemi, M, Altucci, Lucia, Dell'Aversana, C, Martinelli, Pasquale, and Altucci, L.
- Subjects
Adult ,Pluripotent Stem Cells ,Pluripotency ,medicine.medical_treatment ,Cellular differentiation ,Cell Culture Techniques ,Cell- and Tissue-Based Therapy ,Biology ,Stem cell marker ,Young Adult ,Chondrocytes ,Original Research Reports ,Pregnancy ,Stem Cell ,medicine ,Humans ,Progenitor cell ,Induced pluripotent stem cell ,Molecular Biology ,Cells, Cultured ,Homeodomain Proteins ,Osteoblasts ,Mesenchymal stem cell ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,Hematology ,Stem-cell therapy ,Nanog Homeobox Protein ,Amniotic Fluid ,Cell biology ,Adult Stem Cells ,Differentiation ,Immunology ,Female ,Stem cell ,Octamer Transcription Factor-3 ,Developmental Biology ,Adult stem cell - Abstract
Human embryo stem cells or adult tissues are excellent models for discovery and characterization of differentiation processes. The aims of regenerative medicine are to define the molecular and physiological mechanisms that govern stem cells and differentiation. Human mesenchymal stem cells (hMSCs) are multipotent adult stem cells that are able to differentiate into a variety of cell types under controlled conditions both in vivo and in vitro, and they have the remarkable ability of self-renewal. hMSCs derived from amniotic fluid and characterized by the expression of Oct-4 and Nanog, typical markers of pluripotent cells, represent an excellent model for studies on stemness. Unfortunately, the limited amount of cells available from each donation and, above all, the limited number of replications do not allow for detailed studies. Here, we report on the immortalization and characterization of novel mesenchymal progenitor (MePR) cell lines from amniotic fluid-derived hMSCs, whose biological properties are similar to primary amniocytes. Our data indicate that MePR cells display the multipotency potential and differentiation rates of hMSCs, thus representing a useful model to study both mechanisms of differentiation and pharmacological approaches to induce selective differentiation. In particular, MePR-2B cells, which carry a bona fide normal karyotype, might be used in basic stem cell research, leading to the development of new approaches for stem cell therapy and tissue engineering.
- Published
- 2013
39. Identification of PR-SET7 and EZH2 selective inhibitors inducing cell death in human leukemia U937 cells
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Antonello Mai, Lucia Altucci, Maria Tardugno, Gianluca Sbardella, Ilaria Lepore, Salvatore Di Maro, Sergio Valente, Ettore Novellino, Stefano Tomassi, Roberta Costi, Sabrina Castellano, Roberto Di Santo, Carmela Dell'Aversana, Department of Medicinal Chemistry and Technologies, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Dipartimento di Patologia Generale, Seconda Università degli studi di Napoli, Dipartimento di Scienze Farmaceutiche e Biomediche, Università degli Studi di Salerno (UNISA), Department of Pharmacy Naples, Université de Naples, Valente, S, Lepore, I, Dell'Aversana, C, Tardugno, M, Castellano, S, Sbardella, G, Tomassi, S, DI MARO, Salvatore, Novellino, E, Di Santo, R, Costi, R, Altucci, Lucia, Mai, A., S., Valente, I., Lepore, C., Dell'Aversana, M., Tardugno, S., Castellano, G., Sbardella, Tomassi, Stefano, Novellino, Ettore, R., Di Santo, R., Costi, L., Altucci, and A., Mai
- Subjects
MESH: Cell Death ,Cellular differentiation ,MESH: Cell Cycle ,Biochemistry ,Histone methylation ,Substrate Specificity ,Histones ,0302 clinical medicine ,Histocompatibility Antigens ,Enzyme Inhibitors ,chemistry.chemical_classification ,MESH: Histones ,0303 health sciences ,Leukemia ,Cell Death ,U937 cell ,medicine.diagnostic_test ,Cell Cycle ,MESH: Drug Screening Assays, Antitumor ,Polycomb Repressive Complex 2 ,Epigenetic ,Cell Differentiation ,General Medicine ,Cell cycle ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,3. Good health ,MESH: Enzyme Inhibitors ,030220 oncology & carcinogenesis ,MESH: Granulocytes ,Histone Methyltransferases ,MESH: Polycomb Repressive Complex 2 ,MESH: Cell Differentiation ,Programmed cell death ,MESH: Cell Line, Tumor ,macromolecular substances ,Biology ,Methylation ,MESH: Methylation ,03 medical and health sciences ,Western blot ,Cell Line, Tumor ,MESH: Leukemia ,medicine ,Humans ,Enhancer of Zeste Homolog 2 Protein ,030304 developmental biology ,MESH: Humans ,MESH: Histocompatibility Antigens ,MESH: Histone-Lysine N-Methyltransferase ,Histone-Lysine N-Methyltransferase ,Epi-drug ,medicine.disease ,Molecular biology ,Enzyme ,chemistry ,Cell culture ,Bis(bromo- and dibromo-phenol) compound ,MESH: Substrate Specificity ,Drug Screening Assays, Antitumor ,Granulocytes - Abstract
Chemical manipulations undertaken on some bis(bromo- and dibromo-phenol) compounds previously reported by us as wide-spectrum epigenetic inhibitors let us to identify bis (bromo- and dibromo-methoxyphenyl) derivatives highly selective for PR-SET7 and EZH2 (compounds 4, 5, 9, and 10). Western blot analyses were carried out in U937 cells to determine the effects of such compounds on the methyl marks related to the tested enzymes (H3K4me1, H3K9me2, H4H20me1, and H3K27me3). The 1,5-bis(3-bromo-4-methoxyphenyl)penta-1,4-dien-3- one 4 (EC50 vs EZH2 = 74.9 μM), tested in U937 cells at 50 μM, induced massive cell death and 28% of granulocytic differentiation, highlighting the potential use of EZH2 inhibitors in cancer. © 2012 Elsevier Masson SAS. All rights reserved.
- Published
- 2012
40. New synthetic approach to paullones and characterization of their SIRT1 inhibitory activity
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Lucia Altucci, Esther Vaz, Rosana Alvarez, Carmela Dell'Aversana, Sara Soto, Angel R. de Lera, Soto, S, Vaz, E, Dell'Aversana, C, Alvarez, R, Altucci, Lucia, and de Lera, A. R.
- Subjects
Stereochemistry ,Biochemistry ,law.invention ,chemistry.chemical_compound ,SIRT1 ,Sirtuin 1 ,law ,Cell Line, Tumor ,Amide ,Humans ,cancer ,Inducer ,Enzyme Inhibitors ,Physical and Theoretical Chemistry ,chemistry.chemical_classification ,Cell Cycle ,Organic Chemistry ,Benzazepines ,Cell cycle ,Recombinant Proteins ,In vitro ,Enzyme ,chemistry ,Cell culture ,Intramolecular force ,Recombinant DNA ,epigenetic - Abstract
A series of 7,12-dihydroindolo[3,2-d][1]benzazepine-6(5H)-ones (paullones) substituted at C9/C10 (Br) and C2 (Me, CF(3), CO(2)Me) have been synthesized by a one-pot Suzuki-Miyaura cross-coupling of an o-aminoarylboronic acid and methyl 2-iodoindoleacetate followed by intramolecular amide formation. Other approaches to the paullone scaffold based on Pd-catalyzed C-H activation were unsuccessful. In vitro enzymatic assay with recombinant human SIRT-1 indicated a strong inhibitory profile for the series, in particular the analogue with a methoxycarbonyl group at C2 and a bromine at C9. These compounds are, in general, inducers of granulocyte differentiation of the U937 acute leukemia cell line and cause a marked increase in pre-G1 of the cell cycle.
- Published
- 2012
41. miRNA-mediated deregulation in leukemia
- Author
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Carmela eDell'Aversana, Lucia eAltucci, Dell'Aversana, C., and Altucci, Lucia
- Subjects
Programmed cell death ,lcsh:QH426-470 ,Biology ,Mini Review Article ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,microRNA ,Genetics ,medicine ,Epigenetics ,Gene ,Genetics (clinical) ,Cancer ,miRNA ,030304 developmental biology ,0303 health sciences ,Leukemia ,epigenetics ,Epigenetic ,medicine.disease ,Hematopoiesis ,lcsh:Genetics ,Haematopoiesis ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine - Abstract
MicroRNAs (miRNAs) are small non-coding RNAs 18-25 nucleotides (nt) long able to fine-tune post-transcriptional gene expression. Extensive investigation into biogenesis, mechanism of action and functions of miRNAs has clearly revealed their prompt control in developmental timing, differentiation, proliferation, cell death, and metabolism. Deregulation of miRNA-mediated pathways may contribute to pathological conditions such as tumors, including hematological cancers, thus suggesting that miRNAs act both as tumor-suppressor genes (TSG) and oncogenes (OG). Here, we provide an overview of the current understanding of the aberration of miRNA biogenesis, activity, and post-transcriptional control in leukemogenesis.
- Published
- 2012
42. HDAC modulation and cell death in the clinic
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Ilaria Lepore, Carmela Dell'Aversana, Lucia Altucci, Dell’Aversana, C., Lepore, I., and Altucci, Lucia
- Subjects
Histone Acetyltransferases ,Histone deacetylase 5 ,Cell Death ,Histone deacetylase 2 ,HDAC11 ,Antineoplastic Agents ,Cell Biology ,Pharmacology ,Biology ,epigenetic treatment ,apoptosi ,Chromatin remodeling ,Histone Deacetylases ,Epigenesis, Genetic ,Gene Expression Regulation, Neoplastic ,Histone Deacetylase Inhibitors ,Clinical trials ,Histone ,HDAC ,Cancer research ,biology.protein ,Humans ,Epigenetics ,Cancer epigenetics ,Cancer - Abstract
Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are two opposing classes of enzymes, which finely regulate the balance of histone acetylation affecting chromatin packaging and gene expression. Imbalanced acetylation has been associated with carcinogenesis and cancer progression. In contrast to genetic mutations, epigenetic changes are potentially reversible. This implies that epigenetic alterations are amenable to pharmacological interventions. Accordingly, some epigenetic-based drugs (epidrugs) have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for cancer treatment. Here, we focus on the biological features of HDAC inhibitors (HDACis), analyzing the mechanism(s) of action and their current use in clinical practice. (C) 2012 Elsevier Inc. All rights reserved.
- Published
- 2011
43. HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment
- Author
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Barbara Illi, Carmela Dell'Aversana, Stefania Straino, Annalisa Antonini, Chiara Mozzetta, Gianluca Ragone, Giulia Piaggio, Paola Gallinari, Claudia Colussi, Lucia Altucci, Maurizio C. Capogrossi, Emilio Clementi, Mario Pescatori, Pier Lorenzo Puri, Germana Zaccagnini, Carlo Gaetano, Christian Steinkühler, Jessica Rosati, Antonello Mai, Aymone Gurtner, Fabio Martelli, Giulia Minetti, Colussi, C, Mozzetta, C, Gurtner, A, Illi, B, Rosati, J, Straino, S, Ragone, G, Pescatori, M, Zaccagnini, G, Antonini, A, Minetti, G, Martelli, F, Piaggio, G, Gallinari, P, Steinkulher, C, Clementi, E, Dell'Aversana, C, Altucci, Lucia, Mai, A, Capogrossi, Mc, Puri, Pl, and Gaetano, C.
- Subjects
musculoskeletal diseases ,Satellite Cells, Skeletal Muscle ,Nitrogen ,Pyridines ,Duchenne muscular dystrophy ,Histone Deacetylase 2 ,Nitric Oxide ,Endothelial NOS ,Histone Deacetylases ,Epigenesis, Genetic ,Myoblasts ,Mice ,HDAC ,In vivo ,medicine ,Animals ,Enzyme Inhibitors ,RNA, Small Interfering ,Muscular dystrophy ,skeletal muscle ,Muscle, Skeletal ,Cells, Cultured ,Distrophy ,Multidisciplinary ,biology ,Histone deacetylase 2 ,epigenetic ,Biological Sciences ,Muscular Dystrophy, Animal ,medicine.disease ,Molecular biology ,Histone Deacetylase Inhibitors ,Mice, Inbred C57BL ,Muscular Dystrophy, Duchenne ,Repressor Proteins ,Benzamides ,Mice, Inbred mdx ,Cancer research ,biology.protein ,Histone deacetylase ,Dystrophin ,Deacetylase activity - Abstract
The overlapping histological and biochemical features underlying the beneficial effect of deacetylase inhibitors and NO donors in dystrophic muscles suggest an unanticipated molecular link among dystrophin, NO signaling, and the histone deacetylases (HDACs). Higher global deacetylase activity and selective increased expression of the class I histone deacetylase HDAC2 were detected in muscles of dystrophin-deficient MDX mice. In vitro and in vivo siRNA-mediated down-regulation of HDAC2 in dystrophic muscles was sufficient to replicate the morphological and functional benefits observed with deacetylase inhibitors and NO donors. We found that restoration of NO signaling in vivo, by adenoviral-mediated expression of a constitutively active endothelial NOS mutant in MDX muscles, and in vitro, by exposing MDX-derived satellite cells to NO donors, resulted in HDAC2 blockade by cysteine S-nitrosylation. These data reveal a special contribution of HDAC2 in the pathogenesis of Duchenne muscular dystrophy and indicate that HDAC2 inhibition by NO-dependent S-nitrosylation is important for the therapeutic response to NO donors in MDX mice. They also define a common target for independent pharmacological interventions in the treatment of Duchenne muscular dystrophy.
- Published
- 2008
44. Tumor-secreted extracellular vesicles counteract therapy response by triggering inflammatory mesenchymal stem cell development.
- Author
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Massaro C, Sensoy HN, Mulders M, De Schrijver C, Gomez-Martin C, Simon-Nieto J, Lagerweij T, Atmopawiro A, Perez-Boza J, Bebelman M, Bosch L, Foderaro S, Neves Ferreira M, van Eijndhoven MAJ, van Weering JRT, Dell'Aversana C, Altucci L, Savci-Heijink CD, van de Donk NWCJ, Giorgio C, Brandolini L, Allegretti M, Pegtel DM, and Baglio SR
- Abstract
Purpose: Therapy resistance is a major clinical hurdle in bone cancer treatment and seems to be largely driven by poorly understood microenvironmental factors. Recent evidence suggests a critical role for a unique subpopulation of mesenchymal stem cells with inflammatory features (iMSCs), though their origin and function remained unexplored. We demonstrate that cancer-secreted extracellular vesicles (EVs) trigger the development of iMSCs, which hinder therapy response in vivo, and set out to identify strategies to counteract their function., Experimental Design: The role of iMSCs in therapy resistance was evaluated in an orthotopic xenograft mouse model of osteosarcoma. EV-induced alterations of the MSC transcriptome were analyzed and compared with scRNA-seq data of osteosarcoma and multiple myeloma patient biopsies. Functional assays identified EV components driving iMSC development. We assessed the efficacy of clinical drugs in blocking iMSC-induced resistance in vivo., Results: We found that iMSCs are induced by interaction with cancer EVs and completely abrogate the antimetastatic effect of TGFb signaling inhibition. Importantly, EV-induced iMSCs faithfully recapitulate the inflammatory single-cell RNA signature of stromal cells enriched in multiple myeloma and osteosarcoma patient biopsies. Mechanistically, cancer EVs act through two distinct mechanisms. EV-associated TGFb induces IL6 production, while the EV-RNA cargo enhances TLR3-mediated chemokine production. We reveal that simultaneous blockade of downstream EV-activated pathways with ladarixin and tocilizumab disrupts metastasis formation and overcomes iMSC-induced resistance., Conclusions: Our observations establish iMSCs as major contributors to drug resistance, reveal EVs as physiological triggers of iMSC development and highlight a promising combination strategy to improve therapy response in bone cancer patients.
- Published
- 2024
- Full Text
- View/download PDF
45. Cancer Therapy Resistance: Choosing Kinase Inhibitors.
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Dell'Aversana C, Sarno F, Benedetti R, Megchelenbrink WL, and Cappetta D
- Abstract
Recent advances in comprehending the essential molecular mechanisms that govern cancer signaling have revealed the pivotal involvement of kinases in the development and progression of various cancer types [...].
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- 2024
- Full Text
- View/download PDF
46. Initial Phase of Anthracycline Cardiotoxicity Involves Cardiac Fibroblasts Activation and Metabolic Switch.
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Telesca M, Donniacuo M, Bellocchio G, Riemma MA, Mele E, Dell'Aversana C, Sgueglia G, Cianflone E, Cappetta D, Torella D, Altucci L, Castaldo G, Rossi F, Berrino L, Urbanek K, and De Angelis A
- Abstract
The application of doxorubicin (DOX) is hampered by cardiotoxicity, with diastolic dysfunction as the earliest manifestation. Fibrosis leads to impaired relaxation, but the mechanisms that operate shortly after DOX exposure are not clear. We asked whether the activation of cardiac fibroblasts (CFs) anticipates myocardial dysfunction and evaluated the effects of DOX on CF metabolism. CFs were isolated from the hearts of rats after the first injection of DOX. In another experiment, CFs were exposed to DOX in vitro. Cell phenotype and metabolism were determined. Early effects of DOX consisted of diastolic dysfunction and unchanged ejection fraction. Markers of pro-fibrotic remodeling and evidence of CF transformation were present immediately after treatment completion. Oxygen consumption rate and extracellular acidification revealed an increased metabolic activity of CFs and a switch to glycolytic energy production. These effects were consistent in CFs isolated from the hearts of DOX-treated animals and in naïve CFs exposed to DOX in vitro. The metabolic switch was paralleled with the phenotype change of CFs that upregulated markers of myofibroblast differentiation and the activation of pro-fibrotic signaling. In conclusion, the metabolic switch and activation of CFs anticipate DOX-induced damage and represent a novel target in the early phase of anthracycline cardiomyopathy.
- Published
- 2023
- Full Text
- View/download PDF
47. Exploring hematic crasis variations in cancer patients following SARS-CoV-2 vaccination: a real-practice study.
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Montella L, Dell'Aversana C, Pacella D, Troise S, Russo P, Cacciapuoti V, Ottaiano A, Di Marino L, Coppola P, Liguori C, Berretta M, Maddaluno S, Altucci L, and Facchini G
- Abstract
SARS-CoV-2 vaccination is strongly recommended, particularly for fragile patients such as those undergoing active oncological treatments. It is crucial to conduct post-marketing surveillance in this patient population. In our study, we conducted a retrospective analysis of real-world data, including 136 patients who received SARS-CoV-2 vaccines and were undergoing anticancer treatments between March 1st and June 30th, 2021. All patients received mRNA vaccines, namely Pfizer-BioNTech's COMIRNATY (BNT162b2 mRNA) and Moderna's mRNA-1273 COVID-19 vaccines. We collected blood samples from the patients one week to 10 days before and after vaccine administration to assess full blood count with white cell differentials. Additionally, we monitored serology titers to detect any previous SARS-CoV-2 infection before hospital admission and tracked changes over time. Our findings revealed a significant occurrence of leukopenia following both the first and second vaccine doses among patients receiving chemotherapy and chemo-immunotherapy. Importantly, this effect was independent of demographic factors such as sex, age, and Body Mass Index. In the chemo-immunotherapy treated group, we observed that concomitant immune-mediated diseases were significantly associated with leukopenia following the second vaccine dose. Notably, in healthy subjects, transient neutropenia was recognized as an adverse event following vaccination. The observed lymphocytopenia during SARS-CoV-2 infection, combined with the impact on leukocyte counts observed in our study, underscores the need for larger post-marketing surveillance studies. Despite a treatment delay occurring in 6.6% of patients, the administration of mRNA vaccines did not have a significant impact on the treatment schedule in our series. These findings from a real-world setting provide valuable insights and suggest avenues for further prospective studies to explore potential complex interactions specific to this patient population., (© 2023. BioMed Central Ltd., part of Springer Nature.)
- Published
- 2023
- Full Text
- View/download PDF
48. The impact of epigenetic landscape on ovarian cells in infertile older women undergoing IVF procedures.
- Author
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Sgueglia G, Longobardi S, Valerio D, Campitiello MR, Colacurci N, Di Pietro C, Battaglia R, D'Hooghe T, Altucci L, and Dell'Aversana C
- Subjects
- Pregnancy, Female, Humans, Aged, Pregnancy Rate, Fertilization in Vitro adverse effects, Fertility, DNA Methylation, Infertility, Female genetics, Infertility, Female therapy
- Abstract
The constant decline in fertility and older reproductive age is the major cause of low clinical pregnancy rates in industrialised countries. Epigenetic mechanisms impact on proper embryonic development in women undergoing in vitro fertilisation (IVF) protocols. Here, we describe the main epigenetic modifications that may influence female reproduction and could affect IVF success., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
49. MicroRNA Expression Profiling Using Agilent One-Color Microarray.
- Author
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Dell'Aversana C, Sgueglia G, Del Gaudio N, and Altucci L
- Subjects
- Humans, Microarray Analysis, Genomics, Technology, Autoimmune Diseases, MicroRNAs genetics
- Abstract
MicroRNA (miRNA) expression profiling is an important tool to identify miRNA regulation in physiological or pathological states. This technique has a large number of molecular diagnostic applications, including cancer, cardiovascular and autoimmune diseases, and forensics. To date, a multitude of high-throughput genomic approaches have been developed. Here, we focus on miRNA expression profiling by microarray using SurePrint technology, providing a description of both the workflow and methods for expression profiling by Agilent One-Color Microarray., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
- Full Text
- View/download PDF
50. Correction to: Exosomal MicroRNAs: Comprehensive Methods from Exosome Isolation to miRNA Extraction and Purity Analysis.
- Author
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D'Agostino E, Muro A, Sgueglia G, Massaro C, Dell'Aversana C, and Altucci L
- Published
- 2023
- Full Text
- View/download PDF
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