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  • 1
    Language: German
    In: Medicinal Chemistry, November 2010, Vol.6(6), pp.329-343
    Description: Microtubules are dynamic structures that play a crucial role in cellular division and are recognized as an important target for cancer therapy. In search of new compounds with strong antiproliferative activity and simple molecular structure, we have synthesized four different series of compounds in which different substituents were linked to the 4- or 5-position of the 2-amino-3-(3',4',5'-trimethoxybenzoyl) thiophene system. When these compounds were analyzed in vitro for their inhibition of cell proliferation, the 4-aryl substituted derivatives had little activity. In contrast, the presence of a methylene, oxymethyl, aminomethyl or methylenepiperazino moiety between the aryl and the 4-position of the thiophene ring resulted in statistically significant improvement in activity relative to the 4-aryl substituted derivatives. It is noteworthy that the antiproliferative effects of the synthesized compounds were more pronounced against human Molt/4 and CEM as compared with murine L1210 and FM3A cells. The effects of a selected series of compounds on cell cycle progression correlated well with their strong antiproliferative activity and inhibition of tubulin polymerization. We found that the antiproliferative effects of the most active compounds were associated with increase of the proportion of cells in the G2/M and sub-G1 phases of the cell cycle. The structure-activity relationships observed in the series of compounds described here should permit the design of more active molecules.
    Keywords: Thiophene ; Inhibition Of Tubulin Polymerization ; Inhibition Of Tumor Cell Growth ; Antiproliferative Agents ; Microtubules ; L1210 ; Fm3a ; Combretastatin A - 4 ; Ca - 4, 1 ; Combretaceae ; Phenstatin ; Colchicine ; Podophyllotoxin ; Piperazine ; N - Bromosuccinimide ; Toluene ; Nmr ; Knoevenagel' ; S Adduct ; Column Chromatography ; Tetrakis ; Flash Chromatography ; Gibco ; Zf - Coulter Counter ; Recording Spectrophotometer ; Facscan ; Anova ; Anova
    ISSN: 1573-4064
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  • 2
    Language: English
    In: Sensors & Actuators: B. Chemical, 01 March 2011, Vol.152(2), pp.206-213
    Description: Metal nanoislands (NIs) deposited on transparent surfaces can be a convenient plasmonic material for bio/organic sensors, under the condition that a stable morphology is reached. Plasmonic materials suitable for the fabrication of low cost biosensors based on localized surface plasmon resonance (LSPR) UV–Vis spectroscopy, are fabricated by a simple methodology based on thermal evaporation of Au on commercially available, transparent fluorine-doped tin oxide (FTO) surfaces. The LSPR UV–Vis spectroscopy performed in transmittance mode reveals: (i) a small energy shift, Δ , of the LSPR band under immersion both in organic solvent, and significantly in aqueous media, and (ii) a sensible and reproducible Δ under formation of organic SAMs on the NIs surface. These data indicate that the Au NIs when deposited on FTO substrate exhibit (i) strong adhesion and a high stability, and (ii) a good sensitivity to molecular interaction. The samples also show that the LSPR bands recover the original feature after being exposed to different type of SAMs. Significantly, the absorption maximum, of the Au-NIs LSPR spectra shows a red shift when SAMs incorporating single strands DNA are exposed to the complementary strands. The plasmonic system based on Au NI deposited on FTO surfaces because of (i) the inexpensive fabrication of stable NIs, (ii) the easy way to detect the molecular interaction occurring at their surface, and (iii) the sensitivity of their LSPR to molecular interaction represents a convenient platform for biosensors.
    Keywords: Localized Surface Plasmons ; Metal Nano Particles ; Bio-Sensors ; Fto ; Engineering
    ISSN: 0925-4005
    E-ISSN: 1873-3077
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  • 3
    Language: English
    In: International Journal of Oncology, Vol.41(6), pp.2119-2127
    Description: The activity of a peptide nucleic acid (PNA) targeting cancer-associated microRNA-221 is described. PNAs against miR-221 were designed in order to bind very efficiently to the target RNA strand and to undergo efficient uptake in the cells. A polyarginine-PNA conjugate targeted against miR-221 (Rpep-PNA-a221) showed both very high affinity for RNA and efficient cellular uptake without the addition of transfection reagents. Unmodified PNA with the same sequence displayed RNA binding, but cellular uptake was very poor. Consistently, only Rpep-PNA-a221 strongly inhibited miR-221. Targeting miR-221 by PNA resulted in i) lowering of the hybridization levels of miR-221 measured by RT-qPCR, ii) upregulation of p27 Kip1 gene expression, measured by RT-qPCR and western blot analysis. The major conclusion of this study is that efficient delivery of anti-miR PNA through a suitable peptide carrier (Rpep-PNA-a221) leads to inhibition of miR-221 activity, altering the expression of miR-221-regulated functions in breast cancer cells.
    Keywords: Micrornas ; Peptide Nucleic Acids ; Delivery ; Mir-221 ; P27
    ISSN: 1019-6439
    E-ISSN: 1791-2423
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  • 4
    Language: English
    In: International Journal of Molecular Medicine, June 2012, Vol.29(6), pp.974-982
    Description: Thalassemia and sickle-cell anemia (SCA) present a major public health problem in countries where the number of carriers and affected individuals is high. As a result of the abnormalities in hemoglobin production, cells of thalassemia and SCA patients exhibit oxidative stress, which ultimately is responsible for the chronic anemia observed. Therefore, identification of compounds exhibiting both antioxidant and hemoglobin-inducing activities is highly needed. Our results demonstrate resveratrol to be such a compound. This was shown both in the human K562 cell line, as well as in erythroid precursors derived from normal donors and β-thalassemia patients. Resveratrol was shown to exhibit antioxidant activity and to stimulate the expression of the γ-globin genes and the accumulation of fetal hemoglobin (HbF). To the best of our knowledge, this is the first report pointing to such a double effect of resveratrol. Since this natural product is already marketed as an antioxidant, future investigations should concentrate on demonstrating its potential to augment HbF production in experimental animal models (e.g., thalassemia and SCA mice) as well as in patients. We believe that the potential of clinical use of resveratrol as an antioxidant and HbF stimulator may offer a simple and inexpensive treatment to patients.
    Keywords: Medicine;
    ISSN: 1107-3756
    E-ISSN: 1791244X
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  • 5
    In: Evidence-Based Complementary and Alternative Medicine, 2011, Vol.2011, 4 pages
    Description: Year by year, the characterization of the biological activity of natural products is becoming more competitive and complex, with the involvement in this research area of experts belonging to different scientific fields, including chemistry, biochemistry, molecular biology, immunology and bioinformatics. These fields are becoming of great interest for several high-impact scientific journals, including . The available literature in general, and a survey of reviews and original articles recently published, establishes that natural products, including extracts from medicinal plants and essential oils, retain interesting therapeutic activities, including antitumor, antiviral, anti-inflammatory, pro-apoptotic and differentiating properties. In this commentary, we focus attention on interest in networks based on complementary activation and comparative evaluation of different experimental strategies applied to the discovery and characterization of bioactive natural products. A representative flow chart is shown in the paper.
    Keywords: Commentary;
    ISSN: 1741-427X
    E-ISSN: 1741-4288
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  • 6
    Language: English
    In: Thalassemia Reports, 01 December 2014, Vol.4(3)
    Description: The β-thalassaemias are a group of severe and rare anaemias with monogenic inheritance, a complex systemic phenotype and several treatment-related complications, caused by more than 300 mutations of the β-globin gene. Novel therapeutic protocols, most of which are based on still experimental treatments, show great promise but significant variability of success between patients. These strategies include chemical/ molecular induction of the endogenous β-like g-globin gene or the restoration of clinically relevant β-globin levels by gene therapy. A small number of modifiers with significant impact on disease penetrance, severity and efficacy of treatments are known, but most remain elusive. Improvements of existing treatment regimens and optimization and application of novel treatments will critically depend on the characterization of additional disease modifiers and the stratification of patients for customized treatment regimens. This requires extensive analyses based on “OMICS”, an English-language neologism which refer to different but connected fields in molecular biology and biochemistry, such as genomics, transcriptomics, exomics, proteomics, metabolomics. The major objective of OMICS is a collective characterization of pools of biological molecules (gene sequences, transcripts, proteins and protein domains) controlling biological structures, functions and dynamics, including several involved in pathological conditions. One of the most interesting observations of genomics in β-thalassaemias is the association between genomic sequences and high fetal haemoglobin (HbF) levels, in consideration of the fact that high HbF levels are usually associated with milder forms of β-thalassaemia. Related to this issue, is the possibility to predict response to different therapeutic protocols on the basis of genomic analyses. For instance, three major loci (Xmn1-HBG2 single nucleotide polymorphism, HBS1L-MYB intergenic region on chromosome 6q, and BCL11A) contribute to high HbF production. Pharmacogenomic analysis of the effects of hydroxyurea (HU) on HbF production in a collection of β-thalassemia and sickle cell disease (SCD) patients allowed the identification of genomic signatures associated with high HbF. Therefore, it can hypothesized that genomic studies might predict the response of patients to treatments based on hydroxyurea, which is at present the most used HbF inducer in pharmacological therapy of β-thalassaemia. Transcriptomic/proteomic studies allowed to identify the zinc finger transcription factor B-cell lymphoma/leukemia 11A (BCL11A) as the major repressor of HbF expression. The field of research on g-globin gene repressors (including BCL11A) is of top interest, since several approaches can lead to pharmacologically-mediated inhibition of the expression of g-globin gene repressors, leading to gglobin gene activation. Among these strategies, we underline direct targeting of the transcription factors by aptamers or decoy molecules, as well as inhibition of the mRNA coding g-globin gene repressors with shRNAs, antisense molecules, peptide nucleic acids (PNAs) and microRNAs. In this respect, the THALAMOSS FP7 Project (THALAssaemia MOdular Stratification System for personalized therapy of β-thalassemia, www.thalamoss.eu) aims develop a universal sets of markers and techniques for stratification of β-thalassaemia patients into treatment subgroups for (a) onset and frequency of blood transfusions, (b) choice of iron chelation, (c) induction of fetal hemoglobin, (d) prospective efficacy of gene-therapy. The impact of THALAMOSS is the provision of novel biomarkers for distinct treatment subgroups in β-thalassaemia (500–1000 samples from participating medical centres), identified by combined genomics, proteomics, transcriptomics and tissue culture assays, the development of new or improved products for the cell isolation, characterization and treatment of β-thalassaemia patients and the establishment of routine techniques for detection of these markers and stratification of patients into treatment groups. Translation of these activities into the product portfolio and R&D methodology of participating SMEs will be a major boost for them as well as for the field. THALAMOSS tools and technologies will (a) facilitate identification of novel diagnostic tests, drugs and treatments specific to patient subgroups and (b) guide conventional and novel therapeutic approaches for β-thalassaemia, including personalized medical treatments.
    Keywords: Β-Thalassaemias ; Genomics ; Transcriptomics ; Proteomics ; Hbf Induction ; Gene Therapy ; Medicine
    ISSN: 2039-4357
    E-ISSN: 2039-4365
    Source: Directory of Open Access Journals (DOAJ)
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  • 7
    Language: English
    In: The Journal of biological chemistry, 02 December 2016, Vol.291(49), pp.25742-25748
    Description: The synthetic antimicrobial peptide SET-M33 has strong activity against bacterial infections caused by Gram-negative bacteria. It is currently in preclinical development as a new drug to treat lung infections caused by Gram-negative bacteria. Here we report its strong anti-inflammatory activity in terms of reduced expression of a number of cytokines, enzymes, and signal transduction factors involved in inflammation triggered by LPS from Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli Sixteen cytokines and other major agents involved in inflammation were analyzed in macrophages and bronchial cells after stimulation with LPS and incubation with SET-M33. The bronchial cells were obtained from a cystic fibrosis patient. A number of these proteins showed up to 100% reduction in expression as measured by RT-PCR, Western blotting, or Luminex technology. LPS neutralization was also demonstrated in vivo by challenging bronchoalveolar lavage of SET-M33-treated mice with LPS, which led to a sharp reduction in TNF-α with respect to non-SET-M33-treated animals. We also describe a strong activity of SET-M33 in stimulating cell migration of keratinocytes in wound healing experiments in vitro, demonstrating a powerful immunomodulatory action generally characteristic of molecules taking part in innate immunity.
    Keywords: Lps ; Anti-Inflammatory Agents ; Antimicrobial Peptide (Amp) ; Drug Discovery ; Infectious Disease ; Inflammation ; Anti-Inflammatory Agents -- Pharmacology ; Bronchi -- Metabolism ; Cystic Fibrosis -- Metabolism ; Immunologic Factors -- Pharmacology ; Lipopolysaccharides -- Toxicity
    E-ISSN: 1083-351X
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  • 8
    Language: English
    In: Journal of medicinal chemistry, 14 March 2013, Vol.56(5), pp.1830-42
    Description: Some new psoralen derivatives were synthesized and evaluated as inhibitors of NF-κB/DNA interaction, with the aim to investigate the structural determinants required to inhibit this interaction. Starting from molecular docking studies, several possible protein binding sites were proposed and several three-dimensional quantitative structure-activity relationship (3D-QSAR) models were built using the docked poses of 29 (the most active psoralen in the series) as templates for alignment of the inhibitors. The selected best model was validated through the prediction of the activity of 17 novel compounds. All the experimental data agreed with the computational experiments, supporting the reliability of the computational approach. The hypothesis about the interaction with NF-κB was also supported by surface plasmon resonance based assays using compound 29. All the collected data allowed the identification of compound 29 as a potential candidate for the development of pharmaceutical strategies against the inflammatory phenotype of cystic fibrosis.
    Keywords: Furocoumarins -- Pharmacology
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 9
    Language: English
    In: Analytical chemistry, 03 September 2013, Vol.85(17), pp.8219-24
    Description: Manipulating single biological objects is a major unmet challenge of biomedicine. Herein, we describe a lab-on-a-chip platform based on dielectrophoresis (DEP). The DEParray is a prototypal version consisting of 320 × 320 arrayed electrodes generating 〉10,000 spherical DEP cages. It allows the capture and software-guided movement to predetermined spatial coordinates of single biological objects. With the DEParray we demonstrate (a) forced interaction between a single, preselected target cell and a programmable number of either microspheres or natural killer (NK) cells, (b) on-chip immunophenotypic discrimination of individual cells based on differential rosetting with microspheres functionalized with monoclonal antibodies to an inhibitory NK cell ligand (HLA-G), (c) on-chip, real-time (few minutes) assessment of immune lysis by either visual inspection or semiautomated, time-lapse reading of a fluorescent dye released from NK cell-sensitive targets, and (d) manipulation and immunophenotyping with limiting amounts (about 500) cells. To our knowledge, this is the first report describing a DEP-based lab-on-a-chip platform for the quick, arrayed, software-guided binding of individually moved biological objects, the targeting of single cells with microspheres, and the real-time characterization of immunophenotypes. The DEParray candidates as a discovery tool for novel cell:cell interactions with no prior (immuno)phenotypic knowledge.
    Keywords: Microspheres ; Electrophoresis, Microchip -- Methods ; Killer Cells, Natural -- Metabolism
    ISSN: 00032700
    E-ISSN: 1520-6882
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  • 10
    Language: English
    In: PLoS ONE, 01 January 2017, Vol.12(2), p.e0172756
    Description: The β-thalassemias are genetic disorder caused by more than 200 mutations in the β-globin gene, resulting in a total (β0) or partial (β+) deficit of the globin chain synthesis. The most frequent Mediterranean mutations for β-thalassemia are: β039, β+IVSI-110, β+IVSI-6 and β0IVSI-1. Several molecular techniques for the detection of point mutations have been developed based on the amplification of the DNA target by polymerase chain reaction (PCR), but they could be labor-intensive and technically demanding. On the contrary, TaqMan® genotyping assays are a simple, sensitive and versatile method suitable for the single nucleotide polymorphism (SNP) genotyping affecting the human β-globin gene. Four TaqMan® genotyping assays for the most common β-thalassemia mutations present in the Mediterranean area were designed and validated for the genotype characterization of genomic DNA extracted from 94 subjects comprising 25 healthy donors, 33 healthy carriers and 36 β-thalassemia patients. In addition, 15 specimens at late gestation (21-39 gestational weeks) and 11 at early gestation (5-18 gestational weeks) were collected from pregnant women, and circulating cell-free fetal DNAs were extracted and analyzed with these four genotyping assays. We developed four simple, inexpensive and versatile genotyping assays for the postnatal and prenatal identification of the thalassemia mutations β039, β+IVSI-110, β+IVSI-6, β0IVSI-1. These genotyping assays are able to detect paternally inherited point mutations in the fetus and could be efficiently employed for non-invasive prenatal diagnosis of β-globin gene mutations, starting from the 9th gestational week.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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