45 results on '"Iaccarino N"'
Search Results
2. Eating disorders in obese outpatients attending difference clinics
- Author
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DE CAPRIO, C, Iaccarino, N, Crescenzo, A, Finelli, C, Cella, A, Bracale, Renata, Contaldo, F, and Pasanisi, F.
- Subjects
OBESE OUTPATIENTS ,EATING ATTITUDE TEST ,CLINICS - Published
- 1999
3. Monohydrazone Based G-Quadruplex Selective Ligands Induce DNA Damage and Genome Instability in Human Cancer Cells
- Author
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Jussara Amato, Giulia Miglietta, Nunzia Iaccarino, Antonio Randazzo, Giovanni Capranico, Bruno Pagano, Alessandra Locatelli, Ettore Novellino, Alberto Leoni, Rita Morigi, Amato J., Miglietta G., Morigi R., Iaccarino N., Locatelli A., Leoni A., Novellino E., Pagano B., Capranico G., Randazzo A., Amato, J., Miglietta, G., Morigi, R., Iaccarino, N., Locatelli, A., Leoni, A., Novellino, E., Pagano, B., Capranico, G., and Randazzo, A.
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Genome instability ,R-loop ,DNA damage ,Ligand ,Antineoplastic Agents ,G-quadruplex ,Ligands ,01 natural sciences ,Article ,Genomic Instability ,Antineoplastic Agent ,03 medical and health sciences ,Cell Line, Tumor ,Drug Discovery ,G-Quadruplexe ,Humans ,heterocyclic compounds ,030304 developmental biology ,0303 health sciences ,Genome ,Chemistry ,Hydrazones ,DNA ,Hydrazone ,In vitro ,0104 chemical sciences ,Cell biology ,G-Quadruplexes ,010404 medicinal & biomolecular chemistry ,Cell killing ,Cell culture ,Cancer cell ,Molecular Medicine ,G-quadruplex, R loop, ligand, non canonical DNA structures, biophysical studies, cancer cells ,Drug Screening Assays, Antitumor ,R-Loop Structures ,Human ,DNA Damage - Abstract
Targeting G-quadruplex structures is currently viewed as a promising anticancer strategy. Searching for potent and selective G-quadruplex binders, here we describe a small series of new monohydrazone derivatives designed as analogues of a lead which was proved to stabilize G-quadruplex structures and increase R loop levels in human cancer cells. To investigate the G-quadruplex binding properties of the new molecules, in vitro biophysical studies were performed employing both telomeric and oncogene promoter G-quadruplex-forming sequences. The obtained results allowed the identification of a highly selective G-quadruplex ligand that, when studied in human cancer cells, proved to be able to stabilize both G-quadruplexes and R loops and showed a potent cell killing activity associated with the formation of micronuclei, a clear sign of genome instability.
- Published
- 2020
4. On the thermodynamics of folding of an i-motif DNA in solution under favorable conditions
- Author
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Bruno Pagano, Federica D’Aria, Simona Marzano, Antonio Randazzo, Concetta Giancola, Jussara Amato, Nunzia Iaccarino, Amato, J., D'Aria, F., Marzano, S., Iaccarino, N., Randazzo, A., Giancola, C., and Pagano, B.
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Base pair ,General Physics and Astronomy ,Thermodynamics ,010402 general chemistry ,01 natural sciences ,DNA sequencing ,Cytosine ,Structure-Activity Relationship ,chemistry.chemical_compound ,Thermodynamic ,Principal Component Analysi ,Nucleotide Motifs ,Physical and Theoretical Chemistry ,Base Pairing ,Principal Component Analysis ,010405 organic chemistry ,Energetics ,DNA ,Hydrogen-Ion Concentration ,0104 chemical sciences ,Folding (chemistry) ,chemistry ,Motif (music) - Abstract
Under slightly acidic conditions, cytosine-rich DNA sequences can form non-canonical secondary structures called i-motifs, which occur as four stretches of cytosine repeats form hemi-protonated C·C+ base pairs. The growing interest in the i-motif structures as important components in functional DNA-based nanotechnology or as potential targets of anticancer drugs, increases the need for a deep understanding of the energetics of their structural transitions. Here, a combination of spectroscopic and calorimetric techniques is used to unravel the thermodynamics of folding of an i-motif DNA under favorable conditions. The results give new insights into the energetic aspects of i-motifs and show that thermodynamic and thermal stability are related but not identical properties of such DNA structures.
- Published
- 2021
5. Targeting of Telomeric Repeat-Containing RNA G-Quadruplexes: From Screening to Biophysical and Biological Characterization of a New Hit Compound
- Author
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Bruno Pagano, Erica Salvati, Simona Marzano, Stefano De Tito, Eleonora Vertecchi, Jussara Amato, Anna Di Porzio, Nunzia Iaccarino, Antonio Randazzo, Marzano, S., Pagano, B., Iaccarino, N., Di Porzio, A., De Tito, S., Vertecchi, E., Salvati, E., Randazzo, A., and Amato, J.
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TERRA G-quadruplex ,biophysical characterization ,conformation-selective ligand ,drug discovery ,in vitro biological assays ,Telomeric repeat-containing RNAs ,DNA damage ,QH301-705.5 ,Ligand ,Antineoplastic Agents ,G-quadruplex ,Ligands ,Catalysis ,Article ,Inorganic Chemistry ,Antineoplastic Agent ,chemistry.chemical_compound ,Structure-Activity Relationship ,In vitro biological assay ,Neoplasms ,G-Quadruplexe ,Humans ,Physical and Theoretical Chemistry ,Biology (General) ,Molecular Biology ,QD1-999 ,Spectroscopy ,Binding Sites ,Drug discovery ,Chemistry ,Organic Chemistry ,Binding Site ,RNA ,Promoter ,General Medicine ,DNA ,Telomere ,Computer Science Applications ,G-Quadruplexes ,Biochemistry ,Neoplasm ,Human ,DNA Damage - Abstract
DNA G-quadruplex (G4) structures, either within gene promoter sequences or at telomeres, have been extensively investigated as potential small-molecule therapeutic targets. However, although G4s forming at the telomeric DNA have been extensively investigated as anticancer targets, few studies focus on the telomeric repeat-containing RNA (TERRA), transcribed from telomeres, as potential pharmacological targets. Here, a virtual screening approach to identify a library of drug-like putative TERRA G4 binders, in tandem with circular dichroism melting assay to study their TERRA G4-stabilizing properties, led to the identification of a new hit compound. The affinity of this compound for TERRA RNA and some DNA G4s was analyzed through several biophysical techniques and its biological activity investigated in terms of antiproliferative effect, DNA damage response (DDR) activation, and TERRA RNA expression in high vs. low TERRA-expressing human cancer cells. The selected hit showed good affinity for TERRA G4 and no binding to double-stranded DNA. In addition, biological assays showed that this compound is endowed with a preferential cytotoxic effect on high TERRA-expressing cells, where it induces a DDR at telomeres, probably by displacing TERRA from telomeres. Our studies demonstrate that the identification of TERRA G4-targeting drugs with potential pharmacological effects is achievable, shedding light on new perspectives aimed at discovering new anticancer agents targeting these G4 structures.
- Published
- 2021
6. Assessing the influence of pH and cationic strength on i-motif DNA structure
- Author
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Jussara Amato, Riccardo Leardi, Nunzia Iaccarino, Bruno Pagano, Anna Di Porzio, Diego Brancaccio, Antonio Randazzo, Ettore Novellino, Iaccarino, N., Di Porzio, A., Amato, J., Pagano, B., Brancaccio, D., Novellino, E., Leardi, R., and Randazzo, A.
- Subjects
Circular dichroism ,Proton Magnetic Resonance Spectroscopy ,02 engineering and technology ,01 natural sciences ,Biochemistry ,Analytical Chemistry ,chemistry.chemical_compound ,Cations ,Multivariate data analysis ,Multivariate data analysi ,Design of experiment ,Chemistry ,Circular Dichroism ,010401 analytical chemistry ,Cationic polymerization ,DNA ,Hydrogen-Ion Concentration ,Nucleic acids (DNA/RNA) ,021001 nanoscience & nanotechnology ,NMR ,0104 chemical sciences ,Design of experiments ,i-Motif ,Nucleic Acid Conformation ,Biophysics ,0210 nano-technology - Abstract
The i-motif is a biologically relevant non-canonical DNA structure formed by cytosine-rich sequences. Despite the importance of the factors affecting the formation/stability of such a structure, like pH, cation type and concentration, no systematic study that simultaneously analysed their effect on the i-motif in vitro has been carried out so far. Therefore, here we report a systematic study that aims to evaluate the effect of these factors, and their possible interaction, on the formation of an i-motif structure. Our results confirm that pH plays the main role in i-motif formation. However, we demonstrate that the effect of the cation concentration on the i-motif is strictly dependent on the pH, while no significant differences are observed among the investigated cation types. Graphical abstract.
- Published
- 2019
7. Insights into telomeric G-quadruplex DNA recognition by HMGB1 protein
- Author
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Claudio Luchinat, Antonio Rosato, Jussara Amato, Ettore Novellino, Annamaria Biroccio, Linda Cerofolini, Stefano Giuntini, Bruno Pagano, Antonio Randazzo, Diego Brancaccio, Marco Fragai, Sara Iachettini, Pasquale Zizza, Nunzia Iaccarino, Amato, J., Cerofolini, L., Brancaccio, D., Giuntini, S., Iaccarino, N., Zizza, P., Iachettini, S., Biroccio, A., Novellino, E., Rosato, A., Fragai, M., Luchinat, C., Randazzo, A., and Pagano, B.
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Cell biology ,DNA repair ,DNA damage ,chemical and pharmacologic phenomena ,Biology ,G-quadruplex ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Structural Biology ,Transcription (biology) ,Escherichia coli ,Genetics ,Humans ,Gene silencing ,HMGB1 Protein ,Telomerase ,030304 developmental biology ,0303 health sciences ,DNA ,Telomere ,G-Quadruplexes ,chemistry ,Nucleic acid ,030220 oncology & carcinogenesis ,Magnetic Resonance Spectroscopy, Protein, K+ SOLUTION, BINDING, DOMAIN, CELLS, BOXES, D(TTAGGGT)(4), POLYMORPHISM, EXTENSION, COMPLEX ,Nucleic Acid Conformation - Abstract
HMGB1 is a ubiquitous non-histone protein, which biological effects depend on its expression and subcellular location. Inside the nucleus, HMGB1 is engaged in many DNA events such as DNA repair, transcription and telomere maintenance. HMGB1 has been reported to bind preferentially to bent DNA as well as to noncanonical DNA structures like 4-way junctions and, more recently, to G-quadruplexes. These are four-stranded conformations of nucleic acids involved in important cellular processes, including telomere maintenance. In this frame, G-quadruplex recognition by specific proteins represents a key event to modulate physiological or pathological pathways. Herein, to get insights into the telomeric G-quadruplex DNA recognition by HMGB1, we performed detailed biophysical studies complemented with biological analyses. The obtained results provided information about the molecular determinants for the interaction and showed that the structural variability of human telomeric G-quadruplex DNA may have significant implications in HMGB1 recognition. The biological data identified HMGB1 as a telomere-associated protein in both telomerase-positive and -negative tumor cells and showed that HMGB1 gene silencing in such cells induces telomere DNA damage foci. Altogether, these findings provide a deeper understanding of telomeric G-quadruplex recognition by HMGB1 and suggest that this protein could actually represent a new target for cancer therapy.
- Published
- 2019
8. Effects of sequence and base composition on the CD and TDS profiles of i-DNA
- Author
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Dehui Qiu, Jun Zhou, Nunzia Iaccarino, Jean-Louis Mergny, Bruno Pagano, Antonio Randazzo, Anna Di Porzio, Jussara Amato, Mingpan Cheng, Department of Pharmacy, University of Naples Federico II, Naples, Italy, Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), State Key Laboratory of Analytical Chemistry for Life Science [School of Chemistry and Chemical Engineering, Nanjing University], Nanjing University of Science and Technology (NJUST), Laboratoire d'Optique et Biosciences (LOB), École polytechnique (X)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Iaccarino, N., Cheng, M., Qiu, D., Pagano, B., Amato, J., Di Porzio, A., Zhou, J., Randazzo, A., Mergny, J. -L., University of Naples Federico II = Università degli studi di Napoli Federico II, and Mergny, Jean-Louis
- Subjects
multivariate data analysis ,Circular dichroism ,[CHIM.ANAL] Chemical Sciences/Analytical chemistry ,Base pair ,thermal difference spectroscopy ,[SDV]Life Sciences [q-bio] ,Sequence (biology) ,multivariate data analysi ,010402 general chemistry ,01 natural sciences ,Catalysis ,DNA sequencing ,Nucleic acid secondary structure ,Base (group theory) ,03 medical and health sciences ,chemistry.chemical_compound ,DNA Motifs ,[CHIM.ANAL]Chemical Sciences/Analytical chemistry ,[CHIM] Chemical Sciences ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[CHIM]Chemical Sciences ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,i-motif ,Research Articles ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,010405 organic chemistry ,Circular Dichroism ,General Medicine ,DNA ,General Chemistry ,Composition (combinatorics) ,0104 chemical sciences ,[SDV] Life Sciences [q-bio] ,Crystallography ,chemistry ,Nucleic Acid Conformation ,Spectrophotometry, Ultraviolet ,Research Article - Abstract
The i‐motif DNA, also known as i‐DNA, is a non‐canonical DNA secondary structure formed by cytosine‐rich sequences, consisting of two intercalated parallel‐stranded duplexes held together by hemi‐protonated cytosine–cytosine+ (C:C+) base pairs. The growing interest in the i‐DNA structure as a target in anticancer therapy increases the need for tools for a rapid and meaningful interpretation of the spectroscopic data of i‐DNA samples. Herein, we analyzed the circular dichroism (CD) and thermal difference UV‐absorbance spectra (TDS) of 255 DNA sequences by means of multivariate data analysis, aiming at unveiling peculiar spectral regions that could be used as diagnostic features during the analysis of i‐DNA‐forming sequences., i‐DNA is an emerging non‐canonical DNA secondary structure that represents a suitable target in anticancer therapy. A multivariate data analysis unveiled peculiar TDS and CD spectral regions that could be used for the structural determination of i‐DNA‐forming sequences.
- Published
- 2021
9. Structurally different mixed linkage β-glucan supplements differentially increase secondary bile acid excretion in hypercholesterolaemic rat faeces
- Author
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Morten Georg Jensen, Nunzia Iaccarino, Mette Skau Mikkelsen, Bekzod Khakimov, Tina Skau Nielsen, Søren Balling Engelsen, Antonio Randazzo, Iaccarino, N., Khakimov, B., Mikkelsen, M. S., Nielsen, T. S., Jensen, M. G., Randazzo, A., and Engelsen, So. B.
- Subjects
0301 basic medicine ,Male ,Lithocholic acid ,beta-Glucans ,medicine.drug_class ,Hypercholesterolemia ,BARLEY ,FIBER ,MASS ,Hyodeoxycholic acid ,01 natural sciences ,Excretion ,Bile Acids and Salts ,03 medical and health sciences ,chemistry.chemical_compound ,Feces ,medicine ,Animals ,Humans ,Food science ,Rats, Wistar ,Carcinogen ,Glucan ,Dietary Supplement ,chemistry.chemical_classification ,Bile acid ,Cholesterol ,Animal ,CHOLESTEROL ,010401 analytical chemistry ,Deoxycholic acid ,MEN ,Hordeum ,General Medicine ,QUANTIFICATION ,Bile Acids and Salt ,0104 chemical sciences ,Rats ,030104 developmental biology ,MOLECULAR-INTERACTIONS ,chemistry ,Dietary Supplements ,OAT BRAN ,Rat ,Fece ,LIQUID-CHROMATOGRAPHY ,LIPIDS ,Food Science ,Human - Abstract
Mixed linkage (1→3),(1→4)-β-d-glucan (BG) is a soluble fibre available from oat and barley grains that has been gaining interest due to its health-promoting role in cardiovascular diseases and its ability to modulate the glycaemic index which is beneficial for people with diabetes. This study investigates the effect of three purified barley BGs, with different molecular weight and block structure, on faecal bile acid excretion in hypercholesterolaemic rats. Wistar rats (48 male) were divided in four groups: Control group fed with the cellulose-rich diet (CON); Glucagel group fed with the commercial BG (GLU, 100 kDa), and rats fed with low molecular weight BG (LBG, 150 kDa) and medium molecular weight BG (MBG, 530 kDa). The bile acid profiles of rat faecal samples were measured using gas chromatography-mass spectrometry (GC-MS). A metabolite profiling approach led to the identification of 7 bile acids and 45 other compounds such as sterols, fatty acids and fatty alcohols. Subsequent application of ANOVA-simultaneous component analysis and Principal Component Analysis revealed that all three BG diets increased bile acid faecal excretion compared to the control group. The bile acid excretion was found to be different in all three BG diets and the MBG group showed a significantly higher level of faecal secondary bile acids, including deoxycholic acid, hyodeoxycholic acid, and lithocholic acid. We hypothesise that the hydrophobic surface of the secondary bile acids, which are known to cause colon cancer, has high affinity to the hydrophobic surfaces of cellulosic blocks of the BG. This in vivo study demonstrates that the molecular weight and/or block structures of BG modulate the excretion of secondary bile acids. This finding suggests that developing diets with designed BGs with an optimal molecular structure to trap carcinogenic bile acids can have a significant impact on counteracting cancer and other lifestyle associated diseases.
- Published
- 2019
10. Synthesis and Characterization of Bis-Triazolyl-Pyridine Derivatives as Noncanonical DNA-Interacting Compounds
- Author
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Sara Iachettini, Alfonso Carotenuto, Bruno Pagano, Pasquale Zizza, Stefano De Tito, Gian Cesare Tron, Jussara Amato, Simona Marzano, Nunzia Iaccarino, Federica Santoro, Diego Brancaccio, Anna Di Porzio, Annamaria Biroccio, Antonio Randazzo, Ubaldina Galli, Di Porzio, A., Galli, U., Amato, J., Zizza, P., Iachettini, S., Iaccarino, N., Marzano, S., Santoro, F., Brancaccio, D., Carotenuto, A., De Tito, S., Biroccio, A., Pagano, B., Tron, G. C., and Randazzo, A.
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Circular dichroism ,QH301-705.5 ,Pyridines ,Antineoplastic Agents ,Bone Neoplasms ,G-quadruplex ,Origin of replication ,Immunofluorescence microscopy ,Article ,Catalysis ,Inorganic Chemistry ,chemistry.chemical_compound ,Tumor Cells, Cultured ,Humans ,Biology (General) ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Spectroscopy ,Osteosarcoma ,Click chemistry ,Chemistry ,Organic Chemistry ,bis-triazolyl-pyridine derivatives ,Biophysical study ,Promoter ,DNA ,General Medicine ,In vitro ,Computer Science Applications ,G-Quadruplexes ,Folding (chemistry) ,Bis-triazolyl-pyridine derivative ,I-motif ,Biophysics ,Azo Compounds - Abstract
Besides the well-known double-helical conformation, DNA is capable of folding into various noncanonical arrangements, such as G-quadruplexes (G4s) and i-motifs (iMs), whose occurrence in gene promoters, replication origins, and telomeres highlights the breadth of biological processes that they might regulate. Particularly, previous studies have reported that G4 and iM structures may play different roles in controlling gene transcription. Anyway, molecular tools able to simultaneously stabilize/destabilize those structures are still needed to shed light on what happens at the biological level. Herein, a multicomponent reaction and a click chemistry functionalization were combined to generate a set of 31 bis-triazolyl-pyridine derivatives which were initially screened by circular dichroism for their ability to interact with different G4 and/or iM DNAs and to affect the thermal stability of these structures. All the compounds were then clustered through multivariate data analysis, based on such capability. The most promising compounds were subjected to a further biophysical and biological characterization, leading to the identification of two molecules simultaneously able to stabilize G4s and destabilize iMs, both in vitro and in living cells.
- Published
- 2021
11. Ancient Danish Apple Cultivars—A Comprehensive Metabolite and Sensory Profiling of Apple Juices
- Author
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Antonio Randazzo, Torben Bo Toldam-Andersen, Nanna Viereck, Nunzia Iaccarino, Mikael Agerlin Petersen, Birk Schütz, Søren Balling Engelsen, Camilla Varming, Iaccarino, N, Varming, C., Petersen, M. A., Viereck, N., Schütz, B., Toldam-Andersen, T. B., Randazzo, A., and Engelsen, S. B.
- Subjects
Apple juice ,Endocrinology, Diabetes and Metabolism ,Metabolite ,Ancient apple cultivars ,lcsh:QR1-502 ,01 natural sciences ,Biochemistry ,Sensory analysis ,Article ,lcsh:Microbiology ,sensory analysis ,chemistry.chemical_compound ,ancient apple cultivars ,0404 agricultural biotechnology ,Screening method ,Food science ,Cultivar ,apple juice ,Sugar ,Molecular Biology ,apple juice, ancient apple cultivars, Bruker-SGF Fruit Juice Screener, NMR, sensory analysis, HS-GC/MS ,Flavor ,Aroma ,biology ,010401 analytical chemistry ,food and beverages ,04 agricultural and veterinary sciences ,biology.organism_classification ,040401 food science ,NMR ,0104 chemical sciences ,chemistry ,Bruker-SGF Fruit Juice Screener ,Gas chromatography ,HS-GC/MS - Abstract
In recent decades, intensive selective breeding programs have allowed the development of disease-resistant and flavorsome apple cultivars while leading to a gradual decline of a large number of ancient varieties in many countries. However, the re-evaluation of such cultivars could lead to the production new apple-based products with health beneficial properties and/or unique flavor qualities. Herein, we report the comprehensive characterization of juices obtained from 86 old, mostly Danish, apple cultivars, by employing traditional analysis (ion chromatography,◦Brix, headspace gas chromatography/mass spectrometry (GC–MS), and panel test evaluation) as well as an innovative nuclear magnetic resonance (NMR)-based screening method developed by Bruker for fruit juices, known as Spin Generated Fingerprint (SGF) Profiling™. Principal component analysis showed large differences in aroma components and sensory characteristics, including odd peculiar odors and flavors such as apricot and peach, and very different levels of phenolic compounds, acids and sugars among the analyzed juices. Moreover, we observed a tendency for late-season juices to be characterized by higher◦Brix values, sugar content and they were perceived to be sweeter and more flavor intense than early-season juices. Our findings are useful for the production of specialty vintage-cultivar apple juices or mixed juices to obtain final products that are characterized both by healthy properties and peculiar sensory attributes.
- Published
- 2019
12. Impact of phytosterols on liver and distal colon metabolome in experimental murine colitis model: an explorative study
- Author
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Ettore Novellino, Antonio Randazzo, Roberta Budriesi, Jussara Amato, Anna Di Porzio, Bruno Pagano, Nunzia Iaccarino, Luca Bolelli, Matteo Micucci, Rita Aldini, Iaccarino N., Amato J., Pagano B., Di Porzio A., Micucci M., Bolelli L., Aldini R., Novellino E., Budriesi R., Randazzo A., Iaccarino, Nunzia, Amato, Jussara, Pagano, Bruno, DI PORZIO, Anna, Micucci, Matteo, Bolelli, Luca, Aldini, Rita, Novellino, Ettore, Budriesi, Roberta, and Randazzo, Antonio
- Subjects
Male ,multivariate data analysis ,Colon ,phytosterols ,Pharmaceutical Science ,Metabolomic ,Pharmacology ,multivariate data analysi ,01 natural sciences ,Gas Chromatography-Mass Spectrometry ,ulcerative coliti ,chemistry.chemical_compound ,Mice ,Metabolomics ,Drug Discovery ,Phytosterol ,medicine ,Metabolome ,Animals ,Colitis ,Inbred BALB C ,ulcerative colitis ,Mice, Inbred BALB C ,010405 organic chemistry ,Animal ,lcsh:RM1-950 ,Phytosterols ,General Medicine ,Metabolism ,medicine.disease ,Ulcerative colitis ,metabolomics ,0104 chemical sciences ,Citric acid cycle ,010404 medicinal & biomolecular chemistry ,GC-MS ,Liver ,Disease Models, Animal ,Dextran ,lcsh:Therapeutics. Pharmacology ,chemistry ,Disease Models ,Coliti ,Homeostasis ,Research Paper - Abstract
Phytosterols are known to reduce plasma cholesterol levels and thereby reduce cardiovascular risk. Studies conducted on human and animal models have demonstrated that these compounds have also anti-inflammatory effects. Recently, an experimental colitis model (dextran sulphate sodium-induced) has shown that pre-treatment with phytosterols decreases infiltration of inflammatory cells and accelerates mucosal healing. This study aims to understand the mechanism underlying the colitis by analysing the end-products of the metabolism in distal colon and liver excised from the same mice used in the previous work. In particular, an unsupervised gas chromatography-mass spectrometry (GC-MS) and NMR based metabolomics approach was employed to identify the metabolic pathways perturbed by the dextran sodium sulphate (DSS) insult (i.e. Krebs cycle, carbohydrate, amino acids, and nucleotide metabolism). Interestingly, phytosterols were able to restore the homeostatic equilibrium of the hepatic and colonic metabolome.
- Published
- 2019
13. Chemometrics-based analysis of the phytochemical profile and antioxidant activity of Salvia species from Iran.
- Author
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Moshari-Nasirkandi A, Iaccarino N, Romano F, Graziani G, Alirezalu A, Alipour H, and Amato J
- Subjects
- Iran, Chemometrics methods, Chromatography, High Pressure Liquid methods, Flavonoids analysis, Flavonoids chemistry, Polyphenols analysis, Polyphenols chemistry, Salvia chemistry, Antioxidants chemistry, Antioxidants analysis, Antioxidants pharmacology, Phytochemicals chemistry, Phytochemicals analysis, Phytochemicals pharmacology, Plant Extracts chemistry, Plant Extracts pharmacology
- Abstract
In recent years, the exploration of the therapeutic potential of Salvia has gained considerable attention, leading to a growing number of scientific studies emphasizing its pharmacological properties. Despite this, therapeutic applications of Salvia remain underexploited, requiring further investigation. Iran is a major center for sage diversity in Asia, boasting 60 Salvia species, 17 of which are unique to the area. This study aimed to comprehensively explore and compare the extracts of 102 Salvia samples belonging to 20 distinct Salvia species from Iran, providing a deeper understanding of their specific polyphenol content and, consequently, their antioxidant capabilities and potential therapeutic uses. All samples were analyzed to determine the contents of total phenolics, total flavonoids, total tannin, photosynthetic pigments, and ascorbic acid, along with their antioxidant activity. These data were then combined with the forty distinct chemical fingerprints identified by ultrafast high-pressure liquid chromatography coupled with high-resolution mass spectrometry. Multivariate data analysis was employed to find correlations and differences among the huge number of data obtained and to identify Salvia species with similar phytochemical and/or antioxidant properties. The results show that each Salvia species is characterized by a distinct class of polyphenols recognized for their antidiabetic, anti-inflammatory, cardioprotective and neuroprotective properties. Overall, our findings reveal the potential of some Salvia species for targeted therapeutic applications and provide a rational basis for the development of Salvia-derived nutraceuticals, ultimately improving the prospects for the use of Salvia in medicine., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
14. An Electrochemical Strip to Evaluate and to Discriminate Drug Encapsulation in Lipid Nanovectors.
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Romanò S, Angelillo A, Cimmino W, Iaccarino N, Nele V, Campani V, De Rosa G, and Cinti S
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- Methylene Blue chemistry, Nanoparticles chemistry, Lipids chemistry, Principal Component Analysis, Discriminant Analysis, Electrochemical Techniques, Liposomes chemistry
- Abstract
Lipid nanovectors (LNVs) represent potent and versatile tools in the field of drug delivery for a wide range of medical applications including cancer therapy and vaccines. With this Technical Note, we introduce a novel "portable", easy-to-use, and low-cost strategy for double use: (1) it allows one to both quantify the amount of cargo in LNV formulation and (2) classify the nature of formulation with the aim of chemometrics. In particular, an electrochemical strip, based on a screen-printed electrode, was exploited to detect methylene blue (MB) as the model cargo encapsulated in various liposomes (used as model LNV). The experimental setup, including release of the MB content and its electrochemical quantification were optimized through a multivariate design of experiment (DoE), obtaining a satisfactory 88-95% accuracy in comparison to standard methods. In addition, the use of principal component analysis-linear discriminant analysis (PCA-LDA) highlighted the satisfactory differentiation of liposomes. The combination of portable electroanalysis and multivariate analysis is a potent tool for enhancing quality control in the field of pharmaceutical technologies, and also in the field of diagnostics, this approach might be useful for application toward naturally occurring lipid nanoparticles, i.e., exosomes.
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- 2024
- Full Text
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15. Development of a multi-targeted chemotherapeutic approach based on G-quadruplex stabilisation and carbonic anhydrase inhibition.
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Nocentini A, Di Porzio A, Bonardi A, Bazzicalupi C, Petreni A, Biver T, Bua S, Marzano S, Amato J, Pagano B, Iaccarino N, De Tito S, Amente S, Supuran CT, Randazzo A, and Gratteri P
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Cell Proliferation drug effects, Ligands, HeLa Cells, Antigens, Neoplasm metabolism, Models, Molecular, G-Quadruplexes drug effects, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrase Inhibitors chemistry, Carbonic Anhydrase Inhibitors chemical synthesis, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Carbonic Anhydrase IX antagonists & inhibitors, Carbonic Anhydrase IX metabolism, Carbonic Anhydrases metabolism, Drug Screening Assays, Antitumor, Dose-Response Relationship, Drug
- Abstract
A novel class of compounds designed to hit two anti-tumour targets, G-quadruplex structures and human carbonic anhydrases (hCAs) IX and XII is proposed. The induction/stabilisation of G-quadruplex structures by small molecules has emerged as an anticancer strategy, disrupting telomere maintenance and reducing oncogene expression. hCAs IX and XII are well-established anti-tumour targets, upregulated in many hypoxic tumours and contributing to metastasis. The ligands reported feature a berberine G-quadruplex stabiliser scaffold connected to a moiety inhibiting hCAs IX and XII. In vitro experiments showed that our compounds selectively stabilise G-quadruplex structures and inhibit hCAs IX and XII. The crystal structure of a telomeric G-quadruplex in complex with one of these ligands was obtained, shedding light on the ligand/target interaction mode. The most promising ligands showed significant cytotoxicity against CA IX-positive HeLa cancer cells in hypoxia, and the ability to stabilise G-quadruplexes within tumour cells.
- Published
- 2024
- Full Text
- View/download PDF
16. uL3 Regulates Redox Metabolism and Ferroptosis Sensitivity of p53-Deleted Colorectal Cancer Cells.
- Author
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Brignola C, Pecoraro A, Danisi C, Iaccarino N, Di Porzio A, Romano F, Carotenuto P, Russo G, and Russo A
- Abstract
Despite advancements in therapeutic strategies, the development of drug resistance and metastasis remains a serious concern for the efficacy of chemotherapy against colorectal cancer (CRC). We have previously demonstrated that low expression of ribosomal protein uL3 positively correlates with chemoresistance in CRC patients. Here, we demonstrated that the loss of uL3 increased the metastatic capacity of CRC cells in chick embryos. Metabolomic analysis revealed large perturbations in amino acid and glutathione metabolism in resistant uL3-silenced CRC cells, indicating that uL3 silencing dramatically triggered redox metabolic reprogramming. RNA-Seq data revealed a notable dysregulation of 108 genes related to ferroptosis in CRC patients. Solute Carrier Family 7 Member 11 (SLC7A11) is one of the most dysregulated genes; its mRNA stability is negatively regulated by uL3, and its expression is inversely correlated with uL3 levels. Inhibition of SLC7A11 with erastin impaired resistant uL3-silenced CRC cell survival by inducing ferroptosis. Of interest, the combined treatment erastin plus uL3 enhanced the chemotherapeutic sensitivity of uL3-silenced CRC cells to erastin. The antimetastatic potential of the combined strategy was evaluated in chick embryos. Overall, our study sheds light on uL3-mediated chemoresistance and provides evidence of a novel therapeutic approach, erastin plus uL3, to induce ferroptosis, establishing individualized therapy by examining p53, uL3 and SLC7A11 profiles in tumors.
- Published
- 2024
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17. A reverse translational approach reveals the protective roles of Mangifera indica in inflammatory bowel disease.
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Saviano A, Schettino A, Iaccarino N, Mansour AA, Begum J, Marigliano N, Raucci F, Romano F, Riccardi G, Mitidieri E, d'Emmanuele di Villa Bianca R, Bello I, Panza E, Smimmo M, Vellecco V, Rimmer P, Cheesbrough J, Zhi Z, Iqbal TH, Pieretti S, D'Amore VM, Marinelli L, La Pietra V, Sorrentino R, Costa L, Caso F, Scarpa R, Cirino G, Randazzo A, Bucci M, McGettrick HM, Iqbal AJ, and Maione F
- Subjects
- Adult, Humans, Animals, Tumor Necrosis Factor-alpha metabolism, Endothelial Cells metabolism, Intestinal Mucosa, Disease Models, Animal, Mangifera, Inflammatory Bowel Diseases, Colitis
- Abstract
Inflammatory bowel diseases (IBDs) are chronic intestinal disorders often characterized by a dysregulation of T cells, specifically T helper (Th) 1, 17 and T regulatory (Treg) repertoire. Increasing evidence demonstrates that dietary polyphenols from Mangifera indica L. extract (MIE, commonly known as mango) mitigate intestinal inflammation and splenic Th17/Treg ratio. In this study, we aimed to dissect the immunomodulatory and anti-inflammatory properties of MIE using a reverse translational approach, by initially using blood from an adult IBD inception cohort and then investigating the mechanism of action in a preclinical model of T cell-driven colitis. Of clinical relevance, MIE modulates TNF-α and IL-17 levels in LPS spiked sera from IBD patients as an ex vivo model of intestinal barrier breakdown. Preclinically, therapeutic administration of MIE significantly reduced colitis severity, pathogenic T-cell intestinal infiltrate and intestinal pro-inflammatory mediators (IL-6, IL-17A, TNF-α, IL-2, IL-22). Moreover, MIE reversed colitis-induced gut permeability and restored tight junction functionality and intestinal metabolites. Mechanistic insights revealed MIE had direct effects on blood vascular endothelial cells, blocking TNF-α/IFN-γ-induced up-regulation of COX-2 and the DP2 receptors. Collectively, we demonstrate the therapeutic potential of MIE to reverse the immunological perturbance during the onset of colitis and dampen the systemic inflammatory response, paving the way for its clinical use as nutraceutical and/or functional food., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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18. Effect of saline irrigation and plant-based biostimulant application on fiber hemp ( Cannabis sativa L.) growth and phytocannabinoid composition.
- Author
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Formisano C, Fiorentino N, Di Mola I, Iaccarino N, Gargiulo E, and Chianese G
- Abstract
Phytocannabinoids represent the hallmark of the secondary metabolism of Cannabis sativa . The content of major phytocannabinoids is closely related to genetic variation as well as abiotic elicitors such as temperature, drought, and saline stress. The present study aims to evaluate hemp response to saline irrigation supplied as NaCl solutions with an electrical conductivity (EC) of 2.0, 4.0, and 6.0 dS m
-1 (S1, S2, and S3, respectively) compared to a tap water control (S0). In addition, the potential beneficial effect of a plant-based biostimulant (a legume protein hydrolysate) in mitigating the detrimental effects of saline irrigation on crop growth and phytocannabinoid composition was investigated. Sodium chloride saline irrigation significantly reduced biomass production only with S2 and S3 treatments, in accordance with an induced nutrient imbalance, as evidenced by the mineral profile of leaves. Multivariate analysis revealed that the phytocannabinoid composition, both in inflorescences and leaves, was affected by the salinity level of the irrigation water. Interestingly, higher salinity levels (S2-S3) resulted in the predominance of cannabidiol (CBD), compared to lower salinity ones (S0-S1). Plant growth and nitrogen uptake were significantly increased by the biostimulant application, with significant mitigation of the detrimental effect of saline irrigations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SE declared a past collaboration/shared affiliation with the author(s) to the handling editor at the time of review., (Copyright © 2024 Formisano, Fiorentino, Di Mola, Iaccarino, Gargiulo and Chianese.)- Published
- 2024
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19. In vivo biological validation of in silico analysis: A novel approach for predicting the effects of TLR4 exon 3 polymorphisms on brucellosis.
- Author
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Gentile A, Fulgione A, Auzino B, Iovane V, Gallo D, Garramone R, Iaccarino N, Randazzo A, Iovane G, Cuomo P, Capparelli R, and Iannelli D
- Subjects
- Animals, Humans, Buffaloes microbiology, Brucella abortus, Biomarkers, Toll-Like Receptor 4 genetics, Toll-Like Receptor 4 metabolism, Brucellosis microbiology
- Abstract
The role of the Toll-like receptor 4 (TLR4) is of recognising intracellular and extracellular pathogens and of activating the immune response. This process can be compromised by single nucleotide polymorphisms (SNPs) which might affect the activity of several TLRs. The aim of this study is of ascertaining whether SNPs in the TLR4 of Bubalus bubalis infected by Brucella abortus, compromise the protein functionality. For this purpose, a computational analysis was performed. Next, computational predictions were confirmed by performing genotyping analysis. Finally, NMR-based metabolomics analysis was performed to identify potential biomarkers for brucellosis. The results indicate two SNPs (c. 672 A > C and c. 902 G > C) as risk factor for brucellosis in Bubalus bubalis, and three metabolites (lactate, 3-hydroxybutyrate and acetate) as biological markers for predicting the risk of developing the disease. These metabolites, together with TLR4 structural modifications in the MD2 interaction domain, are a clear signature of the immune system alteration during diverse Gram-negative bacterial infections. This suggests the possibility to extend this study to other pathogens, including Mycobacterium tuberculosis. In conclusion, this study combines multidisciplinary approaches to evaluate the biological and structural effects of SNPs on protein function., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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20. G-quadruplexes in cancer-related gene promoters: from identification to therapeutic targeting.
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Romano F, Di Porzio A, Iaccarino N, Riccardi G, Di Lorenzo R, Laneri S, Pagano B, Amato J, and Randazzo A
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- Humans, DNA chemistry, DNA genetics, DNA metabolism, Patents as Topic, Promoter Regions, Genetic, Ligands, G-Quadruplexes, Antineoplastic Agents pharmacology, Neoplasms drug therapy, Neoplasms genetics
- Abstract
Introduction: Guanine-rich DNA sequences can fold into four-stranded noncanonical secondary structures called G-quadruplexes (G4s) which are widely distributed in functional regions of the human genome, such as telomeres and gene promoter regions. Compelling evidence suggests their involvement in key genome functions such as gene expression and genome stability. Notably, the abundance of G4-forming sequences near transcription start sites suggests their potential involvement in regulating oncogenes., Areas Covered: This review provides an overview of current knowledge on G4s in human oncogene promoters. The most representative G4-binding ligands have also been documented. The objective of this work is to present a comprehensive overview of the most promising targets for the development of novel and highly specific anticancer drugs capable of selectively impacting the expression of individual or a limited number of genes., Expert Opinion: Modulation of G4 formation by specific ligands has been proposed as a powerful new tool to treat cancer through the control of oncogene expression. Actually, most of G4-binding small molecules seem to simultaneously target a range of gene promoter G4s, potentially influencing several critical driver genes in cancer, thus producing significant therapeutic benefits.
- Published
- 2023
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21. Comparison of the biological effects of gadodiamide (Omniscan) and gadoteridol (ProHance) by means of multi-organ and plasma metabolomics.
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Romano F, Di Gregorio E, Riccardi G, Furlan C, Cavallini N, Savorani F, Di Porzio A, De Tito S, Randazzo A, Gianolio E, and Iaccarino N
- Subjects
- Mice, Animals, Gadolinium DTPA metabolism, Contrast Media toxicity, Contrast Media metabolism, Brain metabolism, Magnetic Resonance Imaging, Gadolinium toxicity, Gadolinium metabolism, Organometallic Compounds toxicity
- Abstract
Gadolinium-based contrast agents (GBCAs) are massively employed in radiology to increase the diagnostic power of MRI. However, investigations aiming at detecting possible metabolic perturbations or adverse health effects due to gadolinium deposition are still lacking. In this work, aqueous organs extract and plasma samples were analyzed by GC-MS and
1 H-NMR, respectively, to investigate the effects of multiple administrations of one linear (Omniscan) and one macrocyclic (ProHance) GBCA, on the main metabolic pathways in healthy mice. Multivariate analysis revealed that plasma metabolome was not differently perturbed by the two GBCAs, while, the multiorgan analysis displayed a clear separation of the Omniscan-treated from the control and the ProHance-treated groups. Interestingly, the most affected organs were the brain, cerebellum and liver. Thus, this work paves the way to both the safest use of the commercially available GBCAs and the development of new GBCAs characterized by lower general toxicity.- Published
- 2023
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22. Over-Expressed GATA-1 S , the Short Isoform of the Hematopoietic Transcriptional Factor GATA-1, Inhibits Ferroptosis in K562 Myeloid Leukemia Cells by Preventing Lipid Peroxidation.
- Author
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Trombetti S, Iaccarino N, Riccio P, Sessa R, Catapano R, Salvatore M, Luka S, de Nicola S, Izzo P, Roperto S, Maddalena P, Randazzo A, and Grosso M
- Abstract
Ferroptosis is a recently recognized form of regulated cell death involving lipid peroxidation. Glutathione peroxidase 4 (GPX4) plays a central role in the regulation of ferroptosis through the suppression of lipid peroxidation generation. Connections have been reported between ferroptosis, lipid metabolism, cancer onset, and drug resistance. Recently, interest has grown in ferroptosis induction as a potential strategy to overcome drug resistance in hematological malignancies. GATA-1 is a key transcriptional factor controlling hematopoiesis-related gene expression. Two GATA-1 isoforms, the full-length protein (GATA-1
FL ) and a shorter isoform (GATA-1S ), are described. A balanced GATA-1FL /GATA-1S ratio helps to control hematopoiesis, with GATA-1S overexpression being associated with hematological malignancies by promoting proliferation and survival pathways in hematopoietic precursors. Recently, optical techniques allowed us to highlight different lipid profiles associated with the expression of GATA-1 isoforms, thus raising the hypothesis that ferroptosis-regulated processes could be involved. Lipidomic and functional analysis were conducted to elucidate these mechanisms. Studies on lipid peroxidation production, cell viability, cell death, and gene expression were used to evaluate the impact of GPX4 inhibition. Here, we provide the first evidence that over-expressed GATA-1S prevents K562 myeloid leukemia cells from lipid peroxidation-induced ferroptosis. Targeting ferroptosis is a promising strategy to overcome chemoresistance. Therefore, our results could provide novel potential therapeutic approaches and targets to overcome drug resistance in hematological malignancies.- Published
- 2023
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23. Histone lysine demethylase inhibition reprograms prostate cancer metabolism and mechanics.
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Chianese U, Papulino C, Passaro E, Evers TM, Babaei M, Toraldo A, De Marchi T, Niméus E, Carafa V, Nicoletti MM, Del Gaudio N, Iaccarino N, Randazzo A, Rotili D, Mai A, Cappabianca S, Mashaghi A, Ciardiello F, Altucci L, and Benedetti R
- Subjects
- Androgen Antagonists therapeutic use, Androgens metabolism, Gene Expression Regulation, Neoplastic, Humans, Lipids, Male, Proteomics, Histone Demethylases genetics, Histone Demethylases metabolism, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
Objective: Aberrant activity of androgen receptor (AR) is the primary cause underlying development and progression of prostate cancer (PCa) and castration-resistant PCa (CRPC). Androgen signaling regulates gene transcription and lipid metabolism, facilitating tumor growth and therapy resistance in early and advanced PCa. Although direct AR signaling inhibitors exist, AR expression and function can also be epigenetically regulated. Specifically, lysine (K)-specific demethylases (KDMs), which are often overexpressed in PCa and CRPC phenotypes, regulate the AR transcriptional program., Methods: We investigated LSD1/UTX inhibition, two KDMs, in PCa and CRPC using a multi-omics approach. We first performed a mitochondrial stress test to evaluate respiratory capacity after treatment with MC3324, a dual KDM-inhibitor, and then carried out lipidomic, proteomic, and metabolic analyses. We also investigated mechanical cellular properties with acoustic force spectroscopy., Results: MC3324 induced a global increase in H3K4me2 and H3K27me3 accompanied by significant growth arrest and apoptosis in androgen-responsive and -unresponsive PCa systems. LSD1/UTX inhibition downregulated AR at both transcriptional and non-transcriptional level, showing cancer selectivity, indicating its potential use in resistance to androgen deprivation therapy. Since MC3324 impaired metabolic activity, by modifying the protein and lipid content in PCa and CRPC cell lines. Epigenetic inhibition of LSD1/UTX disrupted mitochondrial ATP production and mediated lipid plasticity, which affected the phosphocholine class, an important structural element for the cell membrane in PCa and CRPC associated with changes in physical and mechanical properties of cancer cells., Conclusions: Our data suggest a network in which epigenetics, hormone signaling, metabolite availability, lipid content, and mechano-metabolic process are closely related. This network may be able to identify additional hotspots for pharmacological intervention and underscores the key role of KDM-mediated epigenetic modulation in PCa and CRPC., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2022
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24. Conformational plasticity of DNA secondary structures: probing the conversion between i-motif and hairpin species by circular dichroism and ultraviolet resonance Raman spectroscopies.
- Author
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Amato J, Iaccarino N, D'Aria F, D'Amico F, Randazzo A, Giancola C, Cesàro A, Di Fonzo S, and Pagano B
- Subjects
- Circular Dichroism, DNA chemistry, Nucleic Acid Conformation, Spectrum Analysis, Raman, G-Quadruplexes
- Abstract
The promoter regions of important oncogenes such as BCL2 and KRAS contain GC-rich sequences that can form distinctive noncanonical DNA structures involved in the regulation of transcription: G-quadruplexes on the G-rich strand and i-motifs on the C-rich strand. Interestingly, BCL2 and KRAS promoter i-motifs are highly dynamic in nature and exist in a pH-dependent equilibrium with hairpin and even with hybrid i-motif/hairpin species. Herein, the effects of pH and presence of cell-mimicking molecular crowding conditions on conformational equilibria of the BCL2 and KRAS i-motif-forming sequences were investigated by ultraviolet resonance Raman (UVRR) and circular dichroism (CD) spectroscopies. Multivariate analysis of CD data was essential to model the presence and identity of the species involved. Analysis of UVRR spectra measured as a function of pH, performed also by the two-dimensional correlation spectroscopy (2D-COS) technique, showed the role of several functional groups in the DNA conformational transitions, and provided structural and dynamic information. Thus, the UVRR investigation of intramolecular interactions and of local and environmental dynamics in promoting the different species induced by the solution conditions provided valuable insights into i-motif conformational transitions. The combined use of the two spectroscopic tools is emphasized by the relevant possibility of working in the same DNA concentration range and by the heterospectral UVRR/CD 2D-COS analysis. The results of this study shed light on the factors that can influence at the molecular level the equilibrium between the different conformational species putatively involved in the oncogene expression.
- Published
- 2022
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25. Synthesis and Characterization of Bis-Triazolyl-Pyridine Derivatives as Noncanonical DNA-Interacting Compounds.
- Author
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Di Porzio A, Galli U, Amato J, Zizza P, Iachettini S, Iaccarino N, Marzano S, Santoro F, Brancaccio D, Carotenuto A, De Tito S, Biroccio A, Pagano B, Tron GC, and Randazzo A
- Subjects
- Bone Neoplasms drug therapy, Bone Neoplasms pathology, DNA chemistry, Humans, Osteosarcoma pathology, Tumor Cells, Cultured, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Azo Compounds chemistry, DNA metabolism, G-Quadruplexes, Osteosarcoma drug therapy, Pyridines chemistry
- Abstract
Besides the well-known double-helical conformation, DNA is capable of folding into various noncanonical arrangements, such as G-quadruplexes (G4s) and i-motifs (iMs), whose occurrence in gene promoters, replication origins, and telomeres highlights the breadth of biological processes that they might regulate. Particularly, previous studies have reported that G4 and iM structures may play different roles in controlling gene transcription. Anyway, molecular tools able to simultaneously stabilize/destabilize those structures are still needed to shed light on what happens at the biological level. Herein, a multicomponent reaction and a click chemistry functionalization were combined to generate a set of 31 bis-triazolyl-pyridine derivatives which were initially screened by circular dichroism for their ability to interact with different G4 and/or iM DNAs and to affect the thermal stability of these structures. All the compounds were then clustered through multivariate data analysis, based on such capability. The most promising compounds were subjected to a further biophysical and biological characterization, leading to the identification of two molecules simultaneously able to stabilize G4s and destabilize iMs, both in vitro and in living cells.
- Published
- 2021
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26. Targeting of Telomeric Repeat-Containing RNA G-Quadruplexes: From Screening to Biophysical and Biological Characterization of a New Hit Compound.
- Author
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Marzano S, Pagano B, Iaccarino N, Di Porzio A, De Tito S, Vertecchi E, Salvati E, Randazzo A, and Amato J
- Subjects
- Antineoplastic Agents pharmacology, Binding Sites drug effects, Binding Sites genetics, DNA genetics, DNA Damage drug effects, DNA Damage genetics, G-Quadruplexes drug effects, Humans, Ligands, Neoplasms drug therapy, Neoplasms genetics, Structure-Activity Relationship, Telomere drug effects, RNA genetics, Telomere genetics
- Abstract
DNA G-quadruplex (G4) structures, either within gene promoter sequences or at telomeres, have been extensively investigated as potential small-molecule therapeutic targets. However, although G4s forming at the telomeric DNA have been extensively investigated as anticancer targets, few studies focus on the telomeric repeat-containing RNA (TERRA), transcribed from telomeres, as potential pharmacological targets. Here, a virtual screening approach to identify a library of drug-like putative TERRA G4 binders, in tandem with circular dichroism melting assay to study their TERRA G4-stabilizing properties, led to the identification of a new hit compound. The affinity of this compound for TERRA RNA and some DNA G4s was analyzed through several biophysical techniques and its biological activity investigated in terms of antiproliferative effect, DNA damage response (DDR) activation, and TERRA RNA expression in high vs. low TERRA-expressing human cancer cells. The selected hit showed good affinity for TERRA G4 and no binding to double-stranded DNA. In addition, biological assays showed that this compound is endowed with a preferential cytotoxic effect on high TERRA-expressing cells, where it induces a DDR at telomeres, probably by displacing TERRA from telomeres. Our studies demonstrate that the identification of TERRA G4-targeting drugs with potential pharmacological effects is achievable, shedding light on new perspectives aimed at discovering new anticancer agents targeting these G4 structures.
- Published
- 2021
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27. On the thermodynamics of folding of an i-motif DNA in solution under favorable conditions.
- Author
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Amato J, D'Aria F, Marzano S, Iaccarino N, Randazzo A, Giancola C, and Pagano B
- Subjects
- Base Pairing, Cytosine chemistry, Hydrogen-Ion Concentration, Principal Component Analysis, Structure-Activity Relationship, Thermodynamics, DNA chemistry, Nucleotide Motifs
- Abstract
Under slightly acidic conditions, cytosine-rich DNA sequences can form non-canonical secondary structures called i-motifs, which occur as four stretches of cytosine repeats form hemi-protonated C·C+ base pairs. The growing interest in the i-motif structures as important components in functional DNA-based nanotechnology or as potential targets of anticancer drugs, increases the need for a deep understanding of the energetics of their structural transitions. Here, a combination of spectroscopic and calorimetric techniques is used to unravel the thermodynamics of folding of an i-motif DNA under favorable conditions. The results give new insights into the energetic aspects of i-motifs and show that thermodynamic and thermal stability are related but not identical properties of such DNA structures.
- Published
- 2021
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28. Effects of Sequence and Base Composition on the CD and TDS Profiles of i-DNA.
- Author
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Iaccarino N, Cheng M, Qiu D, Pagano B, Amato J, Di Porzio A, Zhou J, Randazzo A, and Mergny JL
- Subjects
- Circular Dichroism, Nucleic Acid Conformation, Spectrophotometry, Ultraviolet, DNA chemistry
- Abstract
The i-motif DNA, also known as i-DNA, is a non-canonical DNA secondary structure formed by cytosine-rich sequences, consisting of two intercalated parallel-stranded duplexes held together by hemi-protonated cytosine-cytosine
+ (C:C+ ) base pairs. The growing interest in the i-DNA structure as a target in anticancer therapy increases the need for tools for a rapid and meaningful interpretation of the spectroscopic data of i-DNA samples. Herein, we analyzed the circular dichroism (CD) and thermal difference UV-absorbance spectra (TDS) of 255 DNA sequences by means of multivariate data analysis, aiming at unveiling peculiar spectral regions that could be used as diagnostic features during the analysis of i-DNA-forming sequences., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)- Published
- 2021
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29. Toward G-Quadruplex-Based Anticancer Agents: Biophysical and Biological Studies of Novel AS1411 Derivatives.
- Author
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Ogloblina AM, Iaccarino N, Capasso D, Di Gaetano S, Garzarella EU, Dolinnaya NG, Yakubovskaya MG, Pagano B, Amato J, and Randazzo A
- Subjects
- Antineoplastic Agents pharmacokinetics, Apoptosis drug effects, Aptamers, Nucleotide pharmacology, Circular Dichroism, DNA Topoisomerases, Type I metabolism, Deoxyribonucleases metabolism, Drug Screening Assays, Antitumor methods, Drug Stability, Female, Fluorescence Resonance Energy Transfer, Humans, MCF-7 Cells, Magnetic Resonance Spectroscopy, Oligodeoxyribonucleotides pharmacology, Phosphoproteins metabolism, RNA-Binding Proteins metabolism, Surface Plasmon Resonance, Thymine chemistry, Topoisomerase I Inhibitors chemistry, Topoisomerase I Inhibitors pharmacology, Nucleolin, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Aptamers, Nucleotide chemistry, Nucleic Acid Heteroduplexes chemistry, Oligodeoxyribonucleotides chemistry
- Abstract
Certain G-quadruplex forming guanine-rich oligonucleotides (GROs), including AS1411, are endowed with cancer-selective antiproliferative activity. They are known to bind to nucleolin protein, resulting in the inhibition of nucleolin-mediated phenomena. However, multiple nucleolin-independent biological effects of GROs have also been reported, allowing them to be considered promising candidates for multi-targeted cancer therapy. Herein, with the aim of optimizing AS1411 structural features to find GROs with improved anticancer properties, we have studied a small library of AS1411 derivatives differing in the sequence length and base composition. The AS1411 derivatives were characterized by using circular dichroism and nuclear magnetic resonance spectroscopies and then investigated for their enzymatic resistance in serum and nuclear extract, as well as for their ability to bind nucleolin, inhibit topoisomerase I, and affect the viability of MCF-7 human breast adenocarcinoma cells. All derivatives showed higher thermal stability and inhibitory effect against topoisomerase I than AS1411. In addition, most of them showed an improved antiproliferative activity on MCF-7 cells compared to AS1411 despite a weaker binding to nucleolin. Our results support the hypothesis that the antiproliferative properties of GROs are due to multi-targeted effects.
- Published
- 2020
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30. Monohydrazone Based G-Quadruplex Selective Ligands Induce DNA Damage and Genome Instability in Human Cancer Cells.
- Author
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Amato J, Miglietta G, Morigi R, Iaccarino N, Locatelli A, Leoni A, Novellino E, Pagano B, Capranico G, and Randazzo A
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents metabolism, Cell Line, Tumor, DNA genetics, DNA metabolism, Drug Screening Assays, Antitumor, Genome drug effects, Humans, Hydrazones chemical synthesis, Hydrazones metabolism, Ligands, R-Loop Structures drug effects, Antineoplastic Agents pharmacology, DNA drug effects, DNA Damage drug effects, G-Quadruplexes drug effects, Genomic Instability drug effects, Hydrazones pharmacology
- Abstract
Targeting G-quadruplex structures is currently viewed as a promising anticancer strategy. Searching for potent and selective G-quadruplex binders, here we describe a small series of new monohydrazone derivatives designed as analogues of a lead which was proved to stabilize G-quadruplex structures and increase R loop levels in human cancer cells. To investigate the G-quadruplex binding properties of the new molecules, in vitro biophysical studies were performed employing both telomeric and oncogene promoter G-quadruplex-forming sequences. The obtained results allowed the identification of a highly selective G-quadruplex ligand that, when studied in human cancer cells, proved to be able to stabilize both G-quadruplexes and R loops and showed a potent cell killing activity associated with the formation of micronuclei, a clear sign of genome instability.
- Published
- 2020
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31. Structurally different mixed linkage β-glucan supplements differentially increase secondary bile acid excretion in hypercholesterolaemic rat faeces.
- Author
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Iaccarino N, Khakimov B, Mikkelsen MS, Nielsen TS, Jensen MG, Randazzo A, and Engelsen SB
- Subjects
- Animals, Bile Acids and Salts chemistry, Dietary Supplements analysis, Hordeum chemistry, Humans, Hypercholesterolemia metabolism, Male, Rats, Rats, Wistar, Bile Acids and Salts metabolism, Feces chemistry, Hypercholesterolemia drug therapy, beta-Glucans administration & dosage, beta-Glucans chemistry
- Abstract
Mixed linkage (1→3),(1→4)-β-d-glucan (BG) is a soluble fibre available from oat and barley grains that has been gaining interest due to its health-promoting role in cardiovascular diseases and its ability to modulate the glycaemic index which is beneficial for people with diabetes. This study investigates the effect of three purified barley BGs, with different molecular weight and block structure, on faecal bile acid excretion in hypercholesterolaemic rats. Wistar rats (48 male) were divided in four groups: Control group fed with the cellulose-rich diet (CON); Glucagel group fed with the commercial BG (GLU, 100 kDa), and rats fed with low molecular weight BG (LBG, 150 kDa) and medium molecular weight BG (MBG, 530 kDa). The bile acid profiles of rat faecal samples were measured using gas chromatography-mass spectrometry (GC-MS). A metabolite profiling approach led to the identification of 7 bile acids and 45 other compounds such as sterols, fatty acids and fatty alcohols. Subsequent application of ANOVA-simultaneous component analysis and Principal Component Analysis revealed that all three BG diets increased bile acid faecal excretion compared to the control group. The bile acid excretion was found to be different in all three BG diets and the MBG group showed a significantly higher level of faecal secondary bile acids, including deoxycholic acid, hyodeoxycholic acid, and lithocholic acid. We hypothesise that the hydrophobic surface of the secondary bile acids, which are known to cause colon cancer, has high affinity to the hydrophobic surfaces of cellulosic blocks of the BG. This in vivo study demonstrates that the molecular weight and/or block structures of BG modulate the excretion of secondary bile acids. This finding suggests that developing diets with designed BGs with an optimal molecular structure to trap carcinogenic bile acids can have a significant impact on counteracting cancer and other lifestyle associated diseases.
- Published
- 2020
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32. Impact of phytosterols on liver and distal colon metabolome in experimental murine colitis model: an explorative study.
- Author
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Iaccarino N, Amato J, Pagano B, Di Porzio A, Micucci M, Bolelli L, Aldini R, Novellino E, Budriesi R, and Randazzo A
- Subjects
- Animals, Colitis metabolism, Colitis pathology, Colon metabolism, Gas Chromatography-Mass Spectrometry, Liver metabolism, Male, Metabolomics, Mice, Mice, Inbred BALB C, Colitis drug therapy, Colon drug effects, Disease Models, Animal, Liver drug effects, Phytosterols pharmacology
- Abstract
Phytosterols are known to reduce plasma cholesterol levels and thereby reduce cardiovascular risk. Studies conducted on human and animal models have demonstrated that these compounds have also anti-inflammatory effects. Recently, an experimental colitis model (dextran sulphate sodium-induced) has shown that pre-treatment with phytosterols decreases infiltration of inflammatory cells and accelerates mucosal healing. This study aims to understand the mechanism underlying the colitis by analysing the end-products of the metabolism in distal colon and liver excised from the same mice used in the previous work. In particular, an unsupervised gas chromatography-mass spectrometry (GC-MS) and NMR based metabolomics approach was employed to identify the metabolic pathways perturbed by the dextran sodium sulphate (DSS) insult (i.e. Krebs cycle, carbohydrate, amino acids, and nucleotide metabolism). Interestingly, phytosterols were able to restore the homeostatic equilibrium of the hepatic and colonic metabolome.
- Published
- 2019
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33. G-Quadruplex Binders Induce Immunogenic Cell Death Markers in Aggressive Breast Cancer Cells.
- Author
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Di Somma S, Amato J, Iaccarino N, Pagano B, Randazzo A, Portella G, and Malfitano AM
- Abstract
Background: DNA G-quadruplex (G4) structures represent potential anti-cancer targets. In this study, we compared the effect of two G4-targeting compounds, C066-3108 and the gold standard BRACO-19., Methods: In breast and prostate cancer cells, cytotoxicity induced by both molecules was measured by a sulforhodamine B assay. In breast cancer cells, cycle, apoptosis, the formation of G4 structures, calreticulin and high mobility group box 1 (HMGB1), as well as T cell activation, were analyzed by flow cytometry and adenosine triphosphate (ATP) by luminescence., Results: Both ligands inhibited cell survival and induced DNA damage. In MCF-7 cells, G4 ligands increased the subG0/G1 phase of the cell cycle inducing apoptosis and reduced intracellular ATP. In untreated MCF-7 cells, we observed a slight presence of G4 structures associated with the G2/M phase. In MDA-MB231 cells, G4 ligands decreased the G1 and enhanced the G2/M phase. We observed a decrease of intracellular ATP, calreticulin cell surface exposure and an increase of HMGB1, accompanied by T cell activation. Both compounds induced G4 structure formation in the subG0/G1 phase., Conclusions: Our data report similar effects for both compounds and the first evidence that G4 ligands induce the release of danger signals associated with immunogenic cell death and induction of T cell activation.
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- 2019
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34. Screening of DNA G-quadruplex stabilizing ligands by nano differential scanning fluorimetry.
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Pagano B, Iaccarino N, Di Porzio A, Randazzo A, and Amato J
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- Acridines chemistry, Acridines metabolism, Aminoquinolines chemistry, Aminoquinolines metabolism, Circular Dichroism, DNA genetics, DNA metabolism, Humans, Ligands, Picolinic Acids chemistry, Picolinic Acids metabolism, Proof of Concept Study, Transition Temperature, DNA analysis, Fluorometry methods, G-Quadruplexes
- Abstract
G-quadruplex (G4) nucleic acid structures are involved in a number of different diseases and their drug-induced stabilization is deemed to be a promising therapeutic approach. Herein is reported a proof of principle study on the use of nano differential scanning fluorimetry for a rapid and accurate analysis of G4-stabilizing ligands, exploiting the fluorescence properties of a 2-aminopurine modified G4-forming oligonucleotide.
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- 2019
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35. Assessing the influence of pH and cationic strength on i-motif DNA structure.
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Iaccarino N, Di Porzio A, Amato J, Pagano B, Brancaccio D, Novellino E, Leardi R, and Randazzo A
- Subjects
- Circular Dichroism, Proton Magnetic Resonance Spectroscopy, Cations, DNA chemistry, Hydrogen-Ion Concentration, Nucleic Acid Conformation
- Abstract
The i-motif is a biologically relevant non-canonical DNA structure formed by cytosine-rich sequences. Despite the importance of the factors affecting the formation/stability of such a structure, like pH, cation type and concentration, no systematic study that simultaneously analysed their effect on the i-motif in vitro has been carried out so far. Therefore, here we report a systematic study that aims to evaluate the effect of these factors, and their possible interaction, on the formation of an i-motif structure. Our results confirm that pH plays the main role in i-motif formation. However, we demonstrate that the effect of the cation concentration on the i-motif is strictly dependent on the pH, while no significant differences are observed among the investigated cation types. Graphical abstract.
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- 2019
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36. Insights into telomeric G-quadruplex DNA recognition by HMGB1 protein.
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Amato J, Cerofolini L, Brancaccio D, Giuntini S, Iaccarino N, Zizza P, Iachettini S, Biroccio A, Novellino E, Rosato A, Fragai M, Luchinat C, Randazzo A, and Pagano B
- Subjects
- DNA chemistry, DNA genetics, Escherichia coli genetics, HMGB1 Protein chemistry, Humans, Telomerase chemistry, Telomerase genetics, Telomere chemistry, G-Quadruplexes, HMGB1 Protein genetics, Nucleic Acid Conformation, Telomere genetics
- Abstract
HMGB1 is a ubiquitous non-histone protein, which biological effects depend on its expression and subcellular location. Inside the nucleus, HMGB1 is engaged in many DNA events such as DNA repair, transcription and telomere maintenance. HMGB1 has been reported to bind preferentially to bent DNA as well as to noncanonical DNA structures like 4-way junctions and, more recently, to G-quadruplexes. These are four-stranded conformations of nucleic acids involved in important cellular processes, including telomere maintenance. In this frame, G-quadruplex recognition by specific proteins represents a key event to modulate physiological or pathological pathways. Herein, to get insights into the telomeric G-quadruplex DNA recognition by HMGB1, we performed detailed biophysical studies complemented with biological analyses. The obtained results provided information about the molecular determinants for the interaction and showed that the structural variability of human telomeric G-quadruplex DNA may have significant implications in HMGB1 recognition. The biological data identified HMGB1 as a telomere-associated protein in both telomerase-positive and -negative tumor cells and showed that HMGB1 gene silencing in such cells induces telomere DNA damage foci. Altogether, these findings provide a deeper understanding of telomeric G-quadruplex recognition by HMGB1 and suggest that this protein could actually represent a new target for cancer therapy., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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- 2019
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37. Ancient Danish Apple Cultivars-A Comprehensive Metabolite and Sensory Profiling of Apple Juices.
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Iaccarino N, Varming C, Agerlin Petersen M, Viereck N, Schütz B, Toldam-Andersen TB, Randazzo A, and Balling Engelsen S
- Abstract
In recent decades, intensive selective breeding programs have allowed the development of disease-resistant and flavorsome apple cultivars while leading to a gradual decline of a large number of ancient varieties in many countries. However, the re-evaluation of such cultivars could lead to the production new apple-based products with health beneficial properties and/or unique flavor qualities. Herein, we report the comprehensive characterization of juices obtained from 86 old, mostly Danish, apple cultivars, by employing traditional analysis (ion chromatography, °Brix, headspace gas chromatography/mass spectrometry (GC-MS), and panel test evaluation) as well as an innovative nuclear magnetic resonance (NMR)-based screening method developed by Bruker for fruit juices, known as Spin Generated Fingerprint (SGF) Profiling™. Principal component analysis showed large differences in aroma components and sensory characteristics, including odd peculiar odors and flavors such as apricot and peach, and very different levels of phenolic compounds, acids and sugars among the analyzed juices. Moreover, we observed a tendency for late-season juices to be characterized by higher °Brix values, sugar content and they were perceived to be sweeter and more flavor intense than early-season juices. Our findings are useful for the production of specialty vintage-cultivar apple juices or mixed juices to obtain final products that are characterized both by healthy properties and peculiar sensory attributes.
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- 2019
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38. HMGB1 binds to the KRAS promoter G-quadruplex: a new player in oncogene transcriptional regulation?
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Amato J, Madanayake TW, Iaccarino N, Novellino E, Randazzo A, Hurley LH, and Pagano B
- Subjects
- Cell Line, Tumor, Fluorescein chemistry, Fluorescent Dyes chemistry, Gene Expression Regulation, HMGB1 Protein genetics, Humans, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins p21(ras) genetics, RNA, Small Interfering genetics, G-Quadruplexes, HMGB1 Protein metabolism, Proto-Oncogene Proteins p21(ras) metabolism
- Abstract
This communication reports on a possible distinct role of HMGB1 protein. Biophysical studies revealed that HMGB1 binds and stabilizes the G-quadruplex of the KRAS promoter element that is responsible for most of the transcriptional activity. Biological data showed that inhibition of HMGB1 increases KRAS expression. These results suggest that HMGB1 could play a role in the gene transcriptional regulation via the functional recognition of the G-quadruplex.
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- 2018
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39. Common G-Quadruplex Binding Agents Found to Interact With i-Motif-Forming DNA: Unexpected Multi-Target-Directed Compounds.
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Pagano A, Iaccarino N, Abdelhamid MAS, Brancaccio D, Garzarella EU, Di Porzio A, Novellino E, Waller ZAE, Pagano B, Amato J, and Randazzo A
- Abstract
G-quadruplex (G4) and i-motif (iM) are four-stranded non-canonical nucleic acid structural arrangements. Recent evidences suggest that these DNA structures exist in living cells and could be involved in several cancer-related processes, thus representing an attractive target for anticancer drug discovery. Efforts toward the development of G4 targeting compounds have led to a number of effective bioactive ligands. Herein, employing several biophysical methodologies, we studied the ability of some well-known G4 ligands to interact with iM-forming DNA. The data showed that the investigated compounds are actually able to interact with both DNA in vitro , thus acting de facto as multi-target-directed agents. Interestingly, while all the compounds stabilize the G4, some of them significantly reduce the stability of the iM. The present study highlights the importance, when studying G4-targeting compounds, of evaluating also their behavior toward the i-motif counterpart.
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- 2018
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40. Discovery of the first dual G-triplex/G-quadruplex stabilizing compound: a new opportunity in the targeting of G-rich DNA structures?
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Amato J, Pagano A, Cosconati S, Amendola G, Fotticchia I, Iaccarino N, Marinello J, De Magis A, Capranico G, Novellino E, Pagano B, and Randazzo A
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents metabolism, Binding Sites, Calorimetry, Differential Scanning, Cell Line, Tumor, Cell Proliferation drug effects, Circular Dichroism, DNA, Neoplasm chemistry, DNA, Neoplasm metabolism, Dose-Response Relationship, Drug, Guanosine metabolism, Humans, Inhibitory Concentration 50, Ligands, Magnetic Resonance Spectroscopy, Molecular Docking Simulation, Native Polyacrylamide Gel Electrophoresis, Osteosarcoma genetics, Osteosarcoma pathology, Structure-Activity Relationship, Time Factors, Antineoplastic Agents pharmacology, DNA, Neoplasm drug effects, Drug Design, G-Quadruplexes drug effects, Guanosine chemistry, Osteosarcoma drug therapy
- Abstract
Background: Guanine-rich DNA motifs can form non-canonical structures known as G-quadruplexes, whose role in tumorigenic processes makes them attractive drug-target candidates for cancer therapy. Recent studies revealed that the folding and unfolding pathways of G-quadruplexes proceed through a quite stable intermediate named G-triplex., Methods: Virtual screening was employed to identify a small set of putative G-triplex ligands. The G-triplex stabilizing properties of these compounds were analyzed by CD melting assay. DSC, non-denaturing gel electrophoresis, NMR and molecular modeling studies were performed to investigate the interaction between the selected compound 1 and G-rich DNA structures. Cytotoxic activity of 1 was evaluated by MTT cell proliferation assay., Results: The experiments led to the identification of a promising hit that was shown to bind preferentially to G-triplex and parallel-stranded G-quadruplexes over duplex and antiparallel G-quadruplexes. Molecular modeling results suggested a partial end-stacking of 1 to the external G-triad/G-tetrads as a binding mode. Biological assays showed that 1 is endowed with cytotoxic effect on human osteosarcoma cells., Conclusions: A tandem application of virtual screening along with the experimental investigation was employed to discover a G-triplex-targeting ligand. Experiments revealed that the selected compound actually acts as a dual G-triplex/G-quadruplex stabilizer, thus stimulating further studies aimed at its optimization., General Significance: The discovery of molecules able to bind and stabilize G-triplex structures is highly appealing, but their transient state makes challenging their recognition. These findings suggest that the identification of ligands with dual G-triplex/G-quadruplex stabilizing properties may represent a new route for the design of anticancer agents targeting the G-rich DNA structures. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio., (Copyright © 2016 Elsevier B.V. All rights reserved.)
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- 2017
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41. Development of an Optimized Protocol for NMR Metabolomics Studies of Human Colon Cancer Cell Lines and First Insight from Testing of the Protocol Using DNA G-Quadruplex Ligands as Novel Anti-Cancer Drugs.
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Lauri I, Savorani F, Iaccarino N, Zizza P, Pavone LM, Novellino E, Engelsen SB, and Randazzo A
- Abstract
The study of cell lines by nuclear magnetic resonance (NMR) spectroscopy metabolomics represents a powerful tool to understand how the local metabolism and biochemical pathways are influenced by external or internal stimuli. In particular, the use of adherent mammalian cells is emerging in the metabolomics field in order to understand the molecular mechanism of disease progression or, for example, the cellular response to drug treatments. Hereto metabolomics investigations for this kind of cells have generally been limited to mass spectrometry studies. This study proposes an optimized protocol for the analysis of the endo-metabolome of human colon cancer cells (HCT116) by NMR. The protocol includes experimental conditions such as washing, quenching and extraction. In order to test the proposed protocol, it was applied to an exploratory study of cancer cells with and without treatment by anti-cancer drugs, such as DNA G-quadruplex binders and Adriamycin (a traditional anti-cancer drug). The exploratory NMR metabolomics analysis resulted in NMR assignment of all endo-metabolites that could be detected and provided preliminary insights about the biological behavior of the drugs tested.
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- 2016
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42. Looking for efficient G-quadruplex ligands: evidence for selective stabilizing properties and telomere damage by drug-like molecules.
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Pagano B, Amato J, Iaccarino N, Cingolani C, Zizza P, Biroccio A, Novellino E, and Randazzo A
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Base Sequence, Cell Line, DNA chemistry, Humans, Ligands, Molecular Docking Simulation, Nucleic Acid Denaturation drug effects, Telomere chemistry, Drug Design, G-Quadruplexes drug effects, Telomere drug effects
- Abstract
There is currently significant interest in the development of G-quadruplex-interactive compounds, given the relationship between the ability to stabilize these non-canonical DNA structures and anticancer activity. In this study, a set of biophysical assays was applied to evaluate the binding of six drug-like ligands to DNA G-quadruplexes with different folding topologies. Interestingly, two of the investigated ligands showed selective G-quadruplex-stabilizing properties and biological activity. These compounds may represent useful leads for the development of more potent and selective ligands., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
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- 2015
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43. Identification of novel interactors of human telomeric G-quadruplex DNA.
- Author
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Pagano B, Margarucci L, Zizza P, Amato J, Iaccarino N, Cassiano C, Salvati E, Novellino E, Biroccio A, Casapullo A, and Randazzo A
- Subjects
- Base Sequence, DNA genetics, HCT116 Cells, Humans, DNA chemistry, DNA metabolism, DNA-Binding Proteins metabolism, G-Quadruplexes, Proteomics, Telomere genetics
- Abstract
A chemoproteomic-driven approach was used to investigate the interaction network between human telomeric G-quadruplex DNA and nuclear proteins. We identified novel G-quadruplex binding partners, able to recognize these DNA structures at chromosome ends, suggesting a possible, and so far unknown, role of these proteins in telomere functions.
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- 2015
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44. Noncanonical DNA secondary structures as drug targets: the prospect of the i-motif.
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Amato J, Iaccarino N, Randazzo A, Novellino E, and Pagano B
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Drug Design, Gene Expression Regulation, Neoplastic drug effects, Humans, Nucleic Acid Conformation, Nucleotide Motifs, DNA chemistry, DNA drug effects
- Abstract
Under certain conditions, specific DNA sequences have the potential to adopt noncanonical secondary structures, such as i-motifs. Interestingly, these DNA stretches are not randomly located throughout the genome but rather frequently clustered in regulatory regions of oncogenes and in telomeres, the terminal regions of chromosomes. Recent evidences suggest that i-motif DNA structures exist in living cells and could be involved in a variety of biological processes, such as replication, regulation of oncogene expression, and telomere functions. Therefore, the targeting of i-motif DNA is an emerging research area in medicinal chemistry. Bringing these noncanonical structures into focus as targets for anticancer drug design and gene regulation processes could be crucial for a better understanding of their biological functions and to open the way to new, effective strategies for cancer treatment., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2014
- Full Text
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45. Bis-indole derivatives with antitumor activity turn out to be specific ligands of human telomeric G-quadruplex.
- Author
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Amato J, Iaccarino N, Pagano B, Morigi R, Locatelli A, Leoni A, Rambaldi M, Zizza P, Biroccio A, Novellino E, and Randazzo A
- Abstract
Bis-indolinone derivatives having either 2,6-disubstituted pyridine core (1a and 1b) or 1,10-disubstituted phenanthroline core (2a and 2b), already known to have antitumor activity, have been tested as potential G-quadruplex binders. Compounds 2a and 2b are able to selectively stabilize G-quadruplex over duplex DNA, and also to discriminate among different G-quadruplex structures, having a particular affinity for the parallel form of the human telomeric G-quadruplex. Both compounds are also able to induce telomeric DNA damage that may explain the activity of these compounds.
- Published
- 2014
- Full Text
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