25 results on '"Santoriello M."'
Search Results
2. Counterregulation of cAMP-directed kinase activities controls ciliogenesis
- Author
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Porpora M, SAUCHELLA, SIMONA, Rinaldi L, Delle Donne R, Sepe M, Torres-Quesada O, Intartaglia D, Garbi C, Insabato L, Santoriello M, Bachmann VA, Synofzik M, Lindner HH, Conte I, Stefan E, Feliciello A., CONTE, IVAN, Porpora, M, Sauchella, Simona, Rinaldi, L, Delle Donne, R, Sepe, M, Torres-Quesada, O, Intartaglia, D, Garbi, C, Insabato, L, Santoriello, M, Bachmann, Va, Synofzik, M, Lindner, Hh, Conte, I, Stefan, E, Feliciello, A., and Conte, Ivan
- Subjects
PKA, cAMP, proteasome, primary cilium, NEK10, ubiquitin - Abstract
The primary cilium emanates from the cell surface of growth-arrested cells and plays a central role in vertebrate development and tissue homeostasis. The mechanisms that control ciliogenesis have been extensively explored. However, the intersection between GPCR signaling and the ubiquitin pathway in the control of cilium stability is unknown. Here, we observe that cAMP elevation promotes cilia resorption. At centriolar satellites, we identify a multimeric complex nucleated by PCM1 that includes two kinases, NEK10 and PKA, and the E3 ubiquitin ligase CHIP. We show that NEK10 is essential for ciliogenesis in mammals and for the development of medaka fish. PKA phosphorylation primes NEK10 for CHIP-mediated ubiquitination and proteolysis resulting in cilia resorption. Dearangement of this control mechanism occurs in proliferative and genetic disorders. These findings unveil a pericentriolar kinase signalosome that efficiently links the cAMP cascade with the ubiquitin-proteasome system, controlling essential aspects of ciliogenesis.
- Published
- 2018
3. Functional Characterization Of Carbonic Anhydrase Ix Interactome
- Author
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Sasso E., Vitale M., Boffo F.L., Monteleone F., Santoriello M., Garbi C., Sarnataro D., Scaloni A., De Simone G., Minopoli G., and Zambrano N.
- Published
- 2014
4. NEW INSIGHTS ON THE HIGHLY VERSATILE CARBONIC ANHYDRASE IX
- Author
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Vitale M., Monteleone F., Buanne P. Sasso E., Paolella L.A., Boffo F.L., Sabatella M., Crifò B., Santoriello M., Garbi C., Scaloni A., De Simone G., and Zambrano N.
- Published
- 2013
5. Differential p63 and p53 Expression in Human Keloid Fibroblasts and Hypertrophic Scar Fibroblasts
- Author
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De Felice, Bruna, primary, Ciarmiello, L.F., additional, Mondola, P., additional, Damiano, S., additional, Seru, R., additional, Argenziano, C., additional, Nacca, M., additional, Santoriello, M., additional, and Garbi, C., additional
- Published
- 2007
- Full Text
- View/download PDF
6. Compositions and sources of pollution in the Sarno river
- Author
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Santoriello, M., Proto, Antonio, Giordano, M., Francesco DE CARO, and Oriana Motta
7. 5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein
- Author
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Maria Rosaria Battista, Rajhans Sharma, Yves Mély, Marisabella Santoriello, Edith Monteagudo, Paola Fezzardi, Eleonore Real, Maurizio Zazzi, Vincenzo Summa, Mattia Mori, Maria Chiara Dasso Lang, Steven J. Harper, Savina Malancona, Antonella Cellucci, Manuel Pires, Martina Nibbio, Maurizio Botta, Roberto Speziale, Andreina Basta, Nadia Gennari, Francesco Saladini, Davide De Forni, Annalise Di Marco, Alessia Giannini, Lesia Kovalenko, Malancona, S., Mori, M., Fezzardi, P., Santoriello, M., Basta, A., Nibbio, M., Kovalenko, L., Speziale, R., Battista, M. R., Cellucci, A., Gennari, N., Monteagudo, E., Di Marco, A., Giannini, A., Sharma, R., Pires, M., Real, E., Zazzi, M., Dasso Lang, M. C., De Forni, D., Saladini, F., Mely, Y., Summa, V., Harper, S., and Botta, M.
- Subjects
Nucleocapsid protein ,Scaffold ,drug resistance ,010405 organic chemistry ,antiretroviral ,Organic Chemistry ,HIV ,RNA-binding protein ,Drug resistance ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,3. Good health ,Conserved sequence ,Nordihydroguaiaretic acid ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,NC inhibitor ,chemistry ,Viral replication ,Drug Discovery ,DNA ,dihydroxypyrimidine ,ADME - Abstract
[Image: see text] The HIV-1 nucleocapsid (NC) protein is a small basic DNA and RNA binding protein that is absolutely necessary for viral replication and thus represents a target of great interest to develop new anti-HIV agents. Moreover, the highly conserved sequence offers the opportunity to escape the drug resistance (DR) that emerged following the highly active antiretroviral therapy (HAART) treatment. On the basis of our previous research, nordihydroguaiaretic acid 1 acts as a NC inhibitor showing moderate antiviral activity and suboptimal drug-like properties due to the presence of the catechol moieties. A bioisosteric catechol replacement approach led us to identify the 5-dihydroxypyrimidine-6-carboxamide substructure as a privileged scaffold of a new class of HIV-1 NC inhibitors. Hit validation efforts led to the identification of optimized analogs, as represented by compound 28, showing improved NC inhibition and antiviral activity as well as good ADME and PK properties.
- Published
- 2020
8. miR-34 modulates apoptotic gene expression in Ingenol mebutate treated keloid fibroblasts
- Author
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Margherita Santoriello, Corrado Garbi, Bruna De Felice, Massimo Nacca, Francesco Manfellotto, De Felice, B, Manfellotto, F, Garbi, C, Santoriello, M, and Nacca, M.
- Subjects
p53 ,0301 basic medicine ,Cancer Research ,Cell ,DNA Fragmentation ,Biology ,Biochemistry ,03 medical and health sciences ,Keloid ,microRNA-34a ,microRNA ,Gene expression ,Genetics ,medicine ,Humans ,skin and connective tissue diseases ,Fibroblast ,Molecular Biology ,Cells, Cultured ,keloids ,apoptosis ,Apoptosi ,Articles ,Fibroblasts ,Cell cycle ,medicine.disease ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Oncology ,MicroRNA 34a ,ingenol mebutate ,Cancer research ,Molecular Medicine ,Apoptotic signaling pathway ,Diterpenes - Abstract
Keloids are benign skin tumors that develop in individuals who have a positive family history of keloid disorders. Keloids are characterized by a deregulated wound-healing process, atypical fibroblasts with extreme deposition of extracellular matrix components, particularly collagen, increased cell proliferation and associated failure of apoptosis. Recently ingenol-mebutate has been used as a novel agent with anti-proliferative activity on human keloids as an alternative treatment option in patients, once conventional therapies have failed. We hypothesized that microRNAs (miR/miRNA) may be involved in the balance between lesion formation and repair. A comprehensive understanding of the molecular mechanism underlying the Ingenol-mebutate response in keloid fibroblast following Ingenol-mebutate exposure has been established previously. Therefore, the present study analyzed changes in miRNAs and apoptotic gene regulation in Ingenol-mebutate treated keloid fibroblast, by reverse transcription-quantitative polymerase chain reaction and a DNA fragmentation assay. The range of upregulated miRNAs and downregulated genes encoding cell death appeared to be associated with the degree of the morphological alterations in Ingenol-mebutate treated keloids. In particular, the upregulation of miR-34a was detected in keloid fibroblasts during and following Ingenol-mebutate exposure. Keloid fibroblasts that overexpressed miR-34a showed differential expression of genes involved in the apoptotic signaling pathway such as p53. In conclusion, the Ingenol-mebutate treatment used here was effective in reducing keloid fibroblast growth in cell culture experiments and the expression of particular miRNAs modulated the pro-apoptotic gene expression following Ingenol-mebutate treatment.
- Published
- 2018
9. Effect of selenocystine on gene expression profiles in human keloid fibroblasts
- Author
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Margherita Santoriello, Massimo Nacca, Bruna De Felice, Corrado Garbi, Robert R. Wilson, DE FELICE, Bruna, Garbi, C, Wilson, Rr, Santoriello, M, Nacca, M., De Felice, B., Garbi, Corrado, Wilson, R. R., and Santoriello, Margherita
- Subjects
Keloids, * Microarray, * Selenocystine, * Gene expression ,Programmed cell death ,Microarray ,Selenocystine ,Biology ,Extracellular matrix ,Keloid ,Gene expression ,medicine ,Genetics ,Humans ,Fibroblast ,Cell adhesion ,skin and connective tissue diseases ,Transcription factor ,Cells, Cultured ,Oligonucleotide Array Sequence Analysis ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Proteins ,Fibroblasts ,medicine.disease ,Selenocysteine ,medicine.anatomical_structure ,Gene Expression Regulation ,Immunology ,Keloids ,Cancer research - Abstract
In this study, selenocystine, a nutritionally available selenoamino acid, was identified for the first time as a novel agent with anti proliferative activity on human keloids. The 20 μM concentration after 48. h treatment used here was the most effective to reduce keloid fibroblast growth. We analyzed the gene expression profile of selenocystine treatment response in keloid fibroblasts by the microarray system to characterize the effects of selenocystine on human keloids. The major alterations in keloid fibroblasts following selenocystine exposure included up-regulation of the genes encoding cell death and transcription factors. Prominent down-regulation of genes involved in development, cell adhesion and cytoskeleton, as well as extra cellular matrix genes, usually strongly up-regulated in keloids, resulted following selenocystine exposure. The range of the down-regulated genes and the degree of the decreased expression appeared to be correlated with the degree of the morphological alterations in selenocystine treated keloids. © 2011 Elsevier Inc.
- Published
- 2011
- Full Text
- View/download PDF
10. Differential apoptosis markers in human keloids and hypertrophic scars fibroblasts
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Bruna De Felice, Alessandra Santillo, Robert R. Wilson, Corrado Garbi, Margherita Santoriello, De Felice, B., Garbi, Corrado, Santoriello, Margherita, Santillo, A., Wilson, R. R., DE FELICE, Bruna, Garbi, C. ., Santoriello, M. ., Santillo, Alessandra, and W. i. l. s. o. n., . R. R.
- Subjects
Adult ,Male ,p53 ,Pathology ,medicine.medical_specialty ,Cicatrix, Hypertrophic ,DNA damage ,Clinical Biochemistry ,Scars ,Apoptosis ,Biology ,Hypertrophic scar ,chemistry.chemical_compound ,Keloid ,medicine ,Humans ,Propidium iodide ,skin and connective tissue diseases ,Molecular Biology ,Cells, Cultured ,Wound Healing ,Apoptosi ,ROS ,Cell Biology ,General Medicine ,Fibroblasts ,medicine.disease ,chemistry ,ΔNp63 ,DNA fragmentation ,Female ,Tumor Suppressor Protein p53 ,medicine.symptom ,Reactive Oxygen Species ,Wound healing ,Biomarkers - Abstract
Keloids are benign skin tumors and are the effect of a dysregulated wound-healing process in genetically predisposed patients. They are characterized by formation of excess scar tissue beyond the boundaries of the wound. Keloids are often confused with hypertrophic scars because of an apparent lack of morphologic differences. The molecular distinction between scars and keloid is still controversial and, until today, there is no appropriate treatment yet for keloid disease. In this study, we have found, for the first time, p53 mutations in both hypertrophic scar and keloids fibroblasts from cultured cells to various extents. Since p53 plays a central role in the DNA damage response by inducing cell cycle arrest and/or apoptotic cell death, we also set up time course experiments making cell cultures at different times to investigate the phenomenon of apoptosis and its involvement in the process of pathological scarring in both hypertrophic scars and keloids. The extent of apoptosis in this study was investigated by DNA fragmentation and MTT assays, propidium iodide staining, p53 expression, and subcellular distribution. Moreover, the correlation of apoptosis and ROS levels in keloid and hypertrophic scars fibroblasts was assessed. Understanding the molecular mechanisms that determine the regulation of apoptosis during wound healing might allow us to therapeutically modulate these pathways so that apoptotic cell death is reactivated in dysregulated and hypertrophic cells. © Springer Science+Business Media, LLC. 2009.
- Published
- 2009
11. PTPD1 supports receptor stability and mitogenic signaling in bladder cancer cells
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Monia Porpora, Mario Galgani, Massimo Mascolo, Maria Quarto, Domenico di Lorenzo, Margherita Santoriello, Corrado Garbi, Luigi Insabato, Annalisa Carlucci, Max E. Gottesman, Vincenzo Altieri, Antonio Feliciello, Luigi Terracciano, Carlucci, A., Porpora, M., Garbi, Corrado, Galgani, M., Santoriello, M., Mascolo, Massimo, di Lorenzo, D., Altieri, V., Quarto, Maria, Terracciano, L., Gottesman, M. E., Insabato, Luigi, and Feliciello, Antonio
- Subjects
Receptor recycling ,Endosome ,Kinesins ,Biology ,Biochemistry ,Receptor tyrosine kinase ,Cell Movement ,Cell Line, Tumor ,Biomarkers, Tumor ,Humans ,Neoplasm Invasiveness ,Gene Silencing ,Receptor ,Molecular Biology ,Cytoskeleton ,Cell Biology ,Protein Tyrosine Phosphatases, Non-Receptor ,Actin cytoskeleton ,Actins ,Cell biology ,ErbB Receptors ,Gene Expression Regulation, Neoplastic ,HEK293 Cells ,Endocytic vesicle ,Urinary Bladder Neoplasms ,Cancer cell ,biology.protein ,Signal transduction ,Signal Transduction - Abstract
PTPD1, a cytosolic non-receptor protein-tyrosine phosphatase, stimulates the Src-EGF transduction pathway. Localization of PTPD1 at actin cytoskeleton and adhesion sites is required for cell scattering and migration. Here, we show that during EGF stimulation, PTPD1 is rapidly recruited to endocytic vesicles containing the EGF receptor. Endosomal localization of PTPD1 is mediated by interaction with KIF16B, an endosomal kinesin that modulates receptor recycling at the plasma membrane. Silencing of PTPD1 promotes degradation of EGF receptor and inhibits downstream ERK signaling. We also found that PTPD1 is markedly increased in bladder cancer tissue samples. PTPD1 levels positively correlated with the grading and invasiveness potential of these tumors. Transgenic expression of an inactive PTPD1 mutant or genetic knockdown of the endogenous PTPD1 severely inhibited both growth and motility of human bladder cancer cells. These findings identify PTPD1 as a novel component of the endocytic machinery that impacts on EGF receptor stability and on growth and motility of bladder cancer cells.
- Published
- 2010
12. Janus effect of glucocorticoids on differentiation of muscle fibro/adipogenic progenitors.
- Author
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Cerquone Perpetuini A, Giuliani G, Reggio A, Cerretani M, Santoriello M, Stefanelli R, Palma A, Vumbaca S, Harper S, Castagnoli L, Bresciani A, and Cesareni G
- Subjects
- Adipogenesis drug effects, Animals, Budesonide administration & dosage, Budesonide pharmacology, Cell Differentiation physiology, Cells, Cultured, Cyclic AMP metabolism, Mice, Inbred C57BL, Mice, Inbred mdx, Microscopy, Fluorescence, Muscle Development physiology, Muscle, Skeletal drug effects, Muscle, Skeletal pathology, Muscular Dystrophy, Duchenne drug therapy, Muscular Dystrophy, Duchenne pathology, PPAR gamma metabolism, Receptors, Glucocorticoid metabolism, Satellite Cells, Skeletal Muscle cytology, Satellite Cells, Skeletal Muscle drug effects, Satellite Cells, Skeletal Muscle pathology, Stem Cells cytology, Stem Cells drug effects, Stem Cells pathology, Transcription Factors metabolism, Cell Differentiation drug effects, Drug Evaluation, Preclinical methods, Glucocorticoids pharmacology, Muscle Development drug effects, Muscle, Skeletal cytology
- Abstract
Muscle resident fibro-adipogenic progenitors (FAPs), support muscle regeneration by releasing cytokines that stimulate the differentiation of myogenic stem cells. However, in non-physiological contexts (myopathies, atrophy, aging) FAPs cause fibrotic and fat infiltrations that impair muscle function. We set out to perform a fluorescence microscopy-based screening to identify compounds that perturb the differentiation trajectories of these multipotent stem cells. From a primary screen of 1,120 FDA/EMA approved drugs, we identified 34 compounds as potential inhibitors of adipogenic differentiation of FAPs isolated from the murine model (mdx) of Duchenne muscular dystrophy (DMD). The hit list from this screen was surprisingly enriched with compounds from the glucocorticoid (GCs) chemical class, drugs that are known to promote adipogenesis in vitro and in vivo. To shed light on these data, three GCs identified in our screening efforts were characterized by different approaches. We found that like dexamethasone, budesonide inhibits adipogenesis induced by insulin in sub-confluent FAPs. However, both drugs have a pro-adipogenic impact when the adipogenic mix contains factors that increase the concentration of cAMP. Gene expression analysis demonstrated that treatment with glucocorticoids induces the transcription of Gilz/Tsc22d3, an inhibitor of the adipogenic master regulator PPARγ, only in anti-adipogenic conditions. Additionally, alongside their anti-adipogenic effect, GCs are shown to promote terminal differentiation of satellite cells. Both the anti-adipogenic and pro-myogenic effects are mediated by the glucocorticoid receptor and are not observed in the presence of receptor inhibitors. Steroid administration currently represents the standard treatment for DMD patients, the rationale being based on their anti-inflammatory effects. The findings presented here offer new insights on additional glucocorticoid effects on muscle stem cells that may affect muscle homeostasis and physiology.
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- 2020
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13. 5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein.
- Author
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Malancona S, Mori M, Fezzardi P, Santoriello M, Basta A, Nibbio M, Kovalenko L, Speziale R, Battista MR, Cellucci A, Gennari N, Monteagudo E, Di Marco A, Giannini A, Sharma R, Pires M, Real E, Zazzi M, Dasso Lang MC, De Forni D, Saladini F, Mely Y, Summa V, Harper S, and Botta M
- Abstract
The HIV-1 nucleocapsid (NC) protein is a small basic DNA and RNA binding protein that is absolutely necessary for viral replication and thus represents a target of great interest to develop new anti-HIV agents. Moreover, the highly conserved sequence offers the opportunity to escape the drug resistance (DR) that emerged following the highly active antiretroviral therapy (HAART) treatment. On the basis of our previous research, nordihydroguaiaretic acid 1 acts as a NC inhibitor showing moderate antiviral activity and suboptimal drug-like properties due to the presence of the catechol moieties. A bioisosteric catechol replacement approach led us to identify the 5-dihydroxypyrimidine-6-carboxamide substructure as a privileged scaffold of a new class of HIV-1 NC inhibitors. Hit validation efforts led to the identification of optimized analogs, as represented by compound 28 , showing improved NC inhibition and antiviral activity as well as good ADME and PK properties., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)
- Published
- 2020
- Full Text
- View/download PDF
14. Modeling and Surveillance of Reporting Delays of Mosquitoes and Humans Infected With West Nile Virus and Associations With Accuracy of West Nile Virus Forecasts.
- Author
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DeFelice NB, Birger R, DeFelice N, Gagner A, Campbell SR, Romano C, Santoriello M, Henke J, Wittie J, Cole B, Kaiser C, and Shaman J
- Subjects
- Animals, Culicidae virology, Disease Outbreaks statistics & numerical data, Humans, Public Health methods, Retrospective Studies, Seasons, Time Factors, United States epidemiology, Data Accuracy, Disease Notification statistics & numerical data, Forecasting methods, Public Health statistics & numerical data, West Nile Fever epidemiology, West Nile virus
- Abstract
Importance: West Nile virus (WNV) is the leading cause of domestically acquired arboviral disease., Objective: To develop real-time WNV forecasts of infected mosquitoes and human cases., Design, Setting, and Participants: Real-time forecasts of WNV in 4 geographically dispersed locations in the United States were generated using a WNV model-inference forecasting system previously validated with retrospective data. Analysis was performed to evaluate how observational reporting delays of mosquito WNV assay results and human medical records were associated with real-time forecast accuracy., Exposures: Mosquitoes positive for WNV and human cases., Main Outcomes and Measures: Delays in reporting mosquito WNV assay results and human medical records and the association of these delays with real-time WNV forecast accuracy., Results: Substantial delays in data reporting exist for both infected mosquitoes and human WNV cases. For human cases, confirmed data (n = 37) lagged behind the onset of illness by a mean (SD) of 5.5 (2.3) weeks (range, 2-14 weeks). These human case reporting lags reduced mean forecast accuracy for the total number of human cases over the season in 110 simulated outbreaks for 2 forecasting systems by 26% and 14%, from 2 weeks before to 3 weeks after the predicted peak of infected mosquitoes. This period is the time span during which 47% of human cases are reported. Of 7064 mosquito pools, 500 (7%) tested positive; the reporting lag for these data associated with viral testing at a state laboratory was a mean (SD) of 6.6 (2.6) days (range, 4-11 days). This reporting lag was associated with decreased mean forecast accuracy for the 3 mosquito infection indicators, timing, magnitude, and season, by approximately 5% for both forecasting systems., Conclusions and Relevance: Delays in reporting human WNV disease and infected mosquito information are associated with difficulties in outbreak surveillance and decreased real-time forecast accuracy. Infected mosquito lags were short enough that skillful forecasts could still be generated for mosquito infection indicators, but the human WNV case lags were too great to support accurate forecasting in real time. Forecasting WNV is potentially an important evidence-based decision support tool for public health officials and mosquito abatement districts; however, to operationalize real-time forecasting, more resources are needed to reduce human case reporting lags between illness onset and case confirmation.
- Published
- 2019
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15. miR-34 modulates apoptotic gene expression in Ingenol mebutate treated keloid fibroblasts.
- Author
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De Felice B, Manfellotto F, Garbi C, Santoriello M, and Nacca M
- Subjects
- Cells, Cultured, DNA Fragmentation drug effects, Fibroblasts metabolism, Fibroblasts pathology, Humans, Keloid genetics, Keloid pathology, Apoptosis drug effects, Diterpenes pharmacology, Fibroblasts drug effects, Gene Expression Regulation drug effects, Keloid drug therapy, MicroRNAs genetics
- Abstract
Keloids are benign skin tumors that develop in individuals who have a positive family history of keloid disorders. Keloids are characterized by a deregulated wound‑healing process, atypical fibroblasts with extreme deposition of extracellular matrix components, particularly collagen, increased cell proliferation and associated failure of apoptosis. Recently ingenol‑mebutate has been used as a novel agent with anti‑proliferative activity on human keloids as an alternative treatment option in patients, once conventional therapies have failed. We hypothesized that microRNAs (miR/miRNA) may be involved in the balance between lesion formation and repair. A comprehensive understanding of the molecular mechanism underlying the Ingenol‑mebutate response in keloid fibroblast following Ingenol‑mebutate exposure has been established previously. Therefore, the present study analyzed changes in miRNAs and apoptotic gene regulation in Ingenol‑mebutate treated keloid fibroblast, by reverse transcription‑quantitative polymerase chain reaction and a DNA fragmentation assay. The range of upregulated miRNAs and downregulated genes encoding cell death appeared to be associated with the degree of the morphological alterations in Ingenol‑mebutate treated keloids. In particular, the upregulation of miR‑34a was detected in keloid fibroblasts during and following Ingenol‑mebutate exposure. Keloid fibroblasts that overexpressed miR‑34a showed differential expression of genes involved in the apoptotic signaling pathway such as p53. In conclusion, the Ingenol‑mebutate treatment used here was effective in reducing keloid fibroblast growth in cell culture experiments and the expression of particular miRNAs modulated the pro‑apoptotic gene expression following Ingenol-mebutate treatment.
- Published
- 2018
- Full Text
- View/download PDF
16. Binding of carbonic anhydrase IX to 45S rDNA genes is prevented by exportin-1 in hypoxic cells.
- Author
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Sasso E, Vitale M, Monteleone F, Boffo FL, Santoriello M, Sarnataro D, Garbi C, Sabatella M, Crifò B, Paolella LA, Minopoli G, Winum JY, and Zambrano N
- Subjects
- Acidosis genetics, Acidosis metabolism, Antigens, Neoplasm genetics, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Carbonic Anhydrase IX, Carbonic Anhydrases genetics, Cell Hypoxia genetics, Cell Line, Tumor, Cell Nucleus genetics, Cell Nucleus metabolism, Chromatin genetics, Chromatin metabolism, DNA, Ribosomal genetics, HEK293 Cells, Humans, Karyopherins genetics, Promoter Regions, Genetic drug effects, Receptors, Cytoplasmic and Nuclear genetics, Transcription, Genetic genetics, Exportin 1 Protein, Antigens, Neoplasm metabolism, Carbonic Anhydrases metabolism, Cell Hypoxia physiology, DNA, Ribosomal metabolism, Karyopherins metabolism, Receptors, Cytoplasmic and Nuclear metabolism
- Abstract
Carbonic anhydrase IX (CA IX) is a surrogate marker of hypoxia, involved in survival and pH regulation in hypoxic cells. We have recently characterized its interactome, describing a set of proteins interacting with CA IX, mainly in hypoxic cells, including several members of the nucleocytoplasmic shuttling apparatuses. Accordingly, we described complex subcellular localization for this enzyme in human cells, as well as the redistribution of a carbonic anhydrase IX pool to nucleoli during hypoxia. Starting from this evidence, we analyzed the possible contribution of carbonic anhydrase IX to transcription of the 45 S rDNA genes, a process occurring in nucleoli. We highlighted the binding of carbonic anhydrase IX to nucleolar chromatin, which is regulated by oxygen levels. In fact, CA IX was found on 45 S rDNA gene promoters in normoxic cells and less represented on these sites, in hypoxic cells and in cells subjected to acetazolamide-induced acidosis. Both conditions were associated with increased representation of carbonic anhydrase IX/exportin-1 complexes in nucleoli. 45 S rRNA transcript levels were accordingly downrepresented. Inhibition of nuclear export by leptomycin B suggests a model in which exportin-1 acts as a decoy, in hypoxic cells, preventing carbonic anhydrase IX association with 45 S rDNA gene promoters.
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- 2015
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17. Antifungal activity of azole compounds CPA18 and CPA109 against azole-susceptible and -resistant strains of Candida albicans.
- Author
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Calabrese EC, Castellano S, Santoriello M, Sgherri C, Quartacci MF, Calucci L, Warrilow AG, Lamb DC, Kelly SL, Milite C, Granata I, Sbardella G, Stefancich G, Maresca B, and Porta A
- Subjects
- Animals, Antifungal Agents toxicity, Azoles toxicity, Candida albicans growth & development, Candida albicans physiology, Cell Membrane drug effects, Cell Membrane physiology, Cell Survival drug effects, Drug Synergism, Filipin metabolism, Hyphae drug effects, Hyphae growth & development, Hyphae physiology, Macrophages drug effects, Mice, Microbial Sensitivity Tests, Microbial Viability drug effects, Propidium metabolism, Staining and Labeling, Antifungal Agents pharmacology, Azoles pharmacology, Candida albicans drug effects
- Abstract
Objectives: In this study we investigated the in vitro fungistatic and fungicidal activities of CPA18 and CPA109, two azole compounds with original structural features, alone and in combination with fluconazole against fluconazole-susceptible and -resistant Candida albicans strains., Methods: Antifungal activities were measured by MIC evaluation and time-kill studies. Azole binding analysis was performed by UV-Vis spectroscopy. Hyphal growth inhibition and filipin and propidium iodide staining assays were used for morphological analysis. An analysis of membrane lipids was also performed to gauge alterations in membrane composition and integrity. Synergism was calculated using fractional inhibitory concentration indices (FICIs). Evaluation of cytotoxicity towards murine macrophages was performed to verify selective antifungal activity., Results: Even though their binding affinity to C. albicans Erg11p is comparable to that of fluconazole, CPA compounds are active against resistant strains of C. albicans with a mutation in ERG11 sequences and/or overexpressing the ABC transporter genes CDR1 and CDR2, which encode ATP-dependent efflux pumps. Moreover, CPA18 is fungistatic, even against the two resistant strains, and was found to be synergistic with fluconazole. Differently from fluconazole and other related azoles, CPA compounds induced marked changes in membrane permeability and dramatic alterations in membrane lipid composition., Conclusions: Our outcomes suggest that CPA compounds are able to overcome major mechanisms of resistance in C. albicans. Also, they are promising candidates for combination treatment that could reduce the toxicity caused by high fluconazole doses, particularly in immunocompromised patients.
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- 2013
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18. MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells.
- Author
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Rocco A, Compare D, Liguori E, Cianflone A, Pirozzi G, Tirino V, Bertoni A, Santoriello M, Garbi C, D'Armiento M, Staibano S, and Nardone G
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, ATP Binding Cassette Transporter, Subfamily B, Member 1 immunology, Aborted Fetus, Adult, Aged, Antigens, Neoplasm immunology, Antigens, Neoplasm metabolism, Apoptosis, Biomarkers, Tumor immunology, Cell Line, Tumor, DNA Methylation, Female, Gastric Mucosa metabolism, Gastric Mucosa pathology, Gastritis metabolism, Gastritis pathology, Gastritis therapy, Gene Silencing drug effects, Helicobacter Infections complications, Helicobacter Infections metabolism, Helicobacter pylori, Humans, Immunohistochemistry methods, Immunoprecipitation methods, Male, Metaplasia metabolism, Metaplasia pathology, Microscopy, Confocal methods, Middle Aged, Promoter Regions, Genetic, RNA, Small Interfering pharmacology, Stomach cytology, Stomach Neoplasms immunology, Stomach Neoplasms microbiology, Stomach Neoplasms therapy, bcl-X Protein immunology, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Biomarkers, Tumor metabolism, Cell Survival, Stomach Neoplasms metabolism, bcl-X Protein metabolism
- Abstract
P-glycoprotein (P-gp), traditionally linked to cancer poor prognosis and multidrug resistance, is undetectable in normal gastric mucosa and overexpressed in gastric cancer (GC). We propose that P-gp may be involved in Helicobacter pylori (Hp)-related gastric carcinogenesis by inhibiting apoptosis. Aim of the study was to evaluate the expression of P-gp in fetal stomach and in Hp-related gastric carcinogenesis, the epigenetic control of the multi-drug resistance-1 (MDR1) gene, the localization and interaction between P-gp and Bcl-x(L) and the effect of the selective silencing of P-gp on cell survival. P-gp and Bcl-xl expression was evaluated by immunohistochemistry on 28 spontaneously abortive human fetuses, 66 Hp-negative subjects, 138 Hp-positive chronic gastritis (CG) of whom 28 with intestinal metaplasia (IM) and 45 intestinal type GCs. P-gp/Bcl-x(L) colocalization was investigated by confocal immunofluorescence microscopy and protein-protein interaction by co-immunoprecipitation, in basal conditions and after stress-induced apoptosis, in GC cell lines AGS and MKN-28 and hepatocellular carcinoma cell line Hep-G2. The role of P-gp in controlling apoptosis was evaluated by knocking down its expression with a specific small interfering RNAs in stressed AGS and MKN-28 cell lines. P-gp is expressed in the gastric mucosa of all human fetuses while, it is undetectable in adult normal mucosa and re-expressed in 30/110 Hp-positive non-IM-CG, 28/28 IM-CG and 40/45 GCs. P-gp expression directly correlates with that of Bcl-x(L) and with the promoter hypomethylation of the MDR1 gene. In GC cell lines, P-gp is localized on the plasma membrane and mitochondria where it colocalizes with Bcl-x(L). Co-immunoprecipitation confirms the physical interaction between P-gp and Bcl-x(L) in AGS, MKN-28 and Hep-G2, at both basal level and after stress-induced apoptosis. The selective silencing of P-gp sensitizes GC cells to stress-induced apoptosis. P-gp behaves as an oncofetal protein that, by cross-talking with Bcl-x(L), acts as an anti-apoptotic agent in Hp-related gastric carcinogenesis.
- Published
- 2012
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19. Modulation of cell differentiation, proliferation, and tumor growth by dihydrobenzyloxopyrimidine non-nucleoside reverse transcriptase inhibitors.
- Author
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Sbardella G, Mai A, Bartolini S, Castellano S, Cirilli R, Rotili D, Milite C, Santoriello M, Orlando S, Sciamanna I, Serafino A, Lavia P, and Spadafora C
- Subjects
- Animals, Apoptosis drug effects, Cell Line, Tumor, Dose-Response Relationship, Drug, Fluorescent Antibody Technique, Indirect, Humans, Melanoma pathology, Melanoma prevention & control, Mice, Mice, Nude, Microscopy, Confocal, Molecular Structure, Pyrimidinones chemistry, Pyrimidinones pharmacology, Reverse Transcriptase Inhibitors chemistry, Xenograft Model Antitumor Assays, Cell Differentiation drug effects, Cell Proliferation drug effects, Reverse Transcriptase Inhibitors pharmacology, Tumor Burden drug effects
- Abstract
A series of 5-alkyl-2-(alkylthio)-6-(1-(2,6-difluorophenyl)propyl)-3,4-dihydropyrimidin-4(3H)-one derivatives (3a-h) belonging to the F(2)-DABOs class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) are endowed with a strong antiproliferative effect and induce cytodifferentiation in A375 melanoma cells. Among tested compounds, the most potent is 3g (SPV122), which also induces apoptosis in a cell-density-dependent manner and antagonizes tumor growth in animal models. All these effects are similar or even more pronounced than those previously reported for other nucleoside or non-nucleoside inhibitors of reverse transcriptase or by functional knockout of the reverse-transcriptase-encoding long interspersed element 1 by RNA interference (RNAi). Taken together with our previously reported results, these data further confirm our idea that cellular alterations induced by NNRTIs are a consequence of the inhibition of the endogenous reverse transcriptase in A375 cells and support the potential of NNRTIs as valuable agents in cancer therapy., (© 2011 American Chemical Society)
- Published
- 2011
- Full Text
- View/download PDF
20. Effect of selenocystine on gene expression profiles in human keloid fibroblasts.
- Author
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De Felice B, Garbi C, Wilson RR, Santoriello M, and Nacca M
- Subjects
- Cells, Cultured, Humans, Keloid pathology, Oligonucleotide Array Sequence Analysis, Proteins genetics, Proteins metabolism, Reverse Transcriptase Polymerase Chain Reaction, Fibroblasts drug effects, Fibroblasts metabolism, Gene Expression Profiling, Gene Expression Regulation drug effects, Keloid metabolism, Selenocysteine pharmacology
- Abstract
In this study, selenocystine, a nutritionally available selenoamino acid, was identified for the first time as a novel agent with anti proliferative activity on human keloids. The 20 μM concentration after 48 h treatment used here was the most effective to reduce keloid fibroblast growth. We analyzed the gene expression profile of selenocystine treatment response in keloid fibroblasts by the microarray system to characterize the effects of selenocystine on human keloids. The major alterations in keloid fibroblasts following selenocystine exposure included up-regulation of the genes encoding cell death and transcription factors. Prominent down-regulation of genes involved in development, cell adhesion and cytoskeleton, as well as extra cellular matrix genes, usually strongly up-regulated in keloids, resulted following selenocystine exposure. The range of the down-regulated genes and the degree of the decreased expression appeared to be correlated with the degree of the morphological alterations in selenocystine treated keloids., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
21. PTPD1 supports receptor stability and mitogenic signaling in bladder cancer cells.
- Author
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Carlucci A, Porpora M, Garbi C, Galgani M, Santoriello M, Mascolo M, di Lorenzo D, Altieri V, Quarto M, Terracciano L, Gottesman ME, Insabato L, and Feliciello A
- Subjects
- Actins chemistry, Biomarkers, Tumor, Cell Line, Tumor, Cell Movement, Cytoskeleton metabolism, Gene Silencing, HEK293 Cells, Humans, Kinesins chemistry, Neoplasm Invasiveness, Signal Transduction, ErbB Receptors metabolism, Gene Expression Regulation, Neoplastic, Protein Tyrosine Phosphatases, Non-Receptor metabolism, Urinary Bladder Neoplasms metabolism
- Abstract
PTPD1, a cytosolic non-receptor protein-tyrosine phosphatase, stimulates the Src-EGF transduction pathway. Localization of PTPD1 at actin cytoskeleton and adhesion sites is required for cell scattering and migration. Here, we show that during EGF stimulation, PTPD1 is rapidly recruited to endocytic vesicles containing the EGF receptor. Endosomal localization of PTPD1 is mediated by interaction with KIF16B, an endosomal kinesin that modulates receptor recycling at the plasma membrane. Silencing of PTPD1 promotes degradation of EGF receptor and inhibits downstream ERK signaling. We also found that PTPD1 is markedly increased in bladder cancer tissue samples. PTPD1 levels positively correlated with the grading and invasiveness potential of these tumors. Transgenic expression of an inactive PTPD1 mutant or genetic knockdown of the endogenous PTPD1 severely inhibited both growth and motility of human bladder cancer cells. These findings identify PTPD1 as a novel component of the endocytic machinery that impacts on EGF receptor stability and on growth and motility of bladder cancer cells.
- Published
- 2010
- Full Text
- View/download PDF
22. PED interacts with Rac1 and regulates cell migration/invasion processes in human non-small cell lung cancer cells.
- Author
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Zanca C, Cozzolino F, Quintavalle C, Di Costanzo S, Ricci-Vitiani L, Santoriello M, Monti M, Pucci P, and Condorelli G
- Subjects
- Apoptosis Regulatory Proteins, Cell Line, Enzyme Activation, Enzyme Inhibitors metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, Humans, Intracellular Signaling Peptides and Proteins genetics, MAP Kinase Signaling System physiology, Neoplasm Invasiveness, Phosphoproteins genetics, rac1 GTP-Binding Protein genetics, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Cell Movement physiology, Intracellular Signaling Peptides and Proteins metabolism, Phosphoproteins metabolism, rac1 GTP-Binding Protein metabolism
- Abstract
PED (phosphoprotein enriched in diabetes) is a 15 kDa protein involved in many cellular pathways and human diseases including type II diabetes and cancer. We recently reported that PED is overexpressed in human cancers and mediates resistance to induced apoptosis. To better understand its role in cancer, we investigated on PED interactome in non-small cell lung cancer (NSCLC). By the Tandem Affinity Purification (TAP), we identified and characterized among others, Rac1, a member of mammalian Rho GTPase protein family, as PED-interacting protein. In this study we show that PED coadiuvates Rac1 activation by regulating AKT mediated Rac1-Ser(71) phosphorylation. Furthermore, we show that the expression of a constitutively active Rac, affected PED-Ser(104) phosphorylation, which is important for PED-regulated ERK 1/2 nuclear localization. Through specific Rac1-siRNA or its pharmacological inhibition, we demonstrate that PED augments migration and invasion in a Rac1-dependent manner in NSCLC. In conclusion, we show for the first time that PED and Rac1 interact and that this interaction modulates cell migration/invasion processes in cancer cells through ERK1/2 pathway., ((c) 2010 Wiley-Liss, Inc.)
- Published
- 2010
- Full Text
- View/download PDF
23. Unprecedented synthesis of a novel amino quinone ring system via oxidative decarboxylation of quinone-based alpha,alpha-amino esters.
- Author
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Campiglia P, Aquino C, Bertamino A, De Simone N, Sala M, Castellano S, Santoriello M, Grieco P, Novellino E, and Gomez-Monterrey IM
- Subjects
- Amines chemistry, Hydrolysis, Oxidation-Reduction, Benzoquinones chemical synthesis, Benzoquinones chemistry, Carboxylic Acids chemistry, Esters chemistry
- Abstract
An unusual and efficient method for the synthesis of new quinone-based amine and its derivatives from the corresponding alpha,alpha-amino ester is described. The procedure involves the quinone-based system's oxidative decarboxylation via hydride transfer throughout basic hydrolysis. This synthetic method provides, with good yields, rapid access to new potentially cytotoxic quinones.
- Published
- 2010
- Full Text
- View/download PDF
24. Differential apoptosis markers in human keloids and hypertrophic scars fibroblasts.
- Author
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De Felice B, Garbi C, Santoriello M, Santillo A, and Wilson RR
- Subjects
- Adult, Biomarkers metabolism, Cells, Cultured, Female, Humans, Male, Reactive Oxygen Species metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Wound Healing, Apoptosis, Cicatrix, Hypertrophic metabolism, Fibroblasts metabolism, Keloid metabolism
- Abstract
Keloids are benign skin tumors and are the effect of a dysregulated wound-healing process in genetically predisposed patients. They are characterized by formation of excess scar tissue beyond the boundaries of the wound. Keloids are often confused with hypertrophic scars because of an apparent lack of morphologic differences. The molecular distinction between scars and keloid is still controversial and, until today, there is no appropriate treatment yet for keloid disease. In this study, we have found, for the first time, p53 mutations in both hypertrophic scar and keloids fibroblasts from cultured cells to various extents. Since p53 plays a central role in the DNA damage response by inducing cell cycle arrest and/or apoptotic cell death, we also set up time course experiments making cell cultures at different times to investigate the phenomenon of apoptosis and its involvement in the process of pathological scarring in both hypertrophic scars and keloids. The extent of apoptosis in this study was investigated by DNA fragmentation and MTT assays, propidium iodide staining, p53 expression, and subcellular distribution. Moreover, the correlation of apoptosis and ROS levels in keloid and hypertrophic scars fibroblasts was assessed. Understanding the molecular mechanisms that determine the regulation of apoptosis during wound healing might allow us to therapeutically modulate these pathways so that apoptotic cell death is reactivated in dysregulated and hypertrophic cells.
- Published
- 2009
- Full Text
- View/download PDF
25. CYP19 (aromatase): exploring the scaffold flexibility for novel selective inhibitors.
- Author
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Castellano S, Stefancich G, Ragno R, Schewe K, Santoriello M, Caroli A, Hartmann RW, and Sbardella G
- Subjects
- Antifungal Agents chemical synthesis, Aromatase Inhibitors chemical synthesis, Ligands, Quantitative Structure-Activity Relationship, Antifungal Agents pharmacology, Aromatase Inhibitors pharmacology, Drug Design, Steroid 17-alpha-Hydroxylase antagonists & inhibitors
- Abstract
Several derivatives out of a series of antifungal agents exhibited a good inhibitory potency against aromatase as well as a fairly good selectivity toward CYP17, even if lacking H-bond accepting substituents. Their common structural feature is a flexible backbone that did not fit into previously reported CYP19 models. Thus, a ligand-based approach was exploited to develop a novel statistically robust, self-consistent and predictive 3D-QSAR model herein proposed as a helpful tool to design new aromatase inhibitors.
- Published
- 2008
- Full Text
- View/download PDF
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