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  • 1
    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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  • 2
    In: PLoS ONE, 2015, Vol.10(4)
    Description: Expression and regulation of microRNAs is an emerging issue in erythroid differentiation and globin gene expression in hemoglobin disorders. In the first part of this study microarray analysis was performed both in mithramycin-induced K562 cells and erythroid precursors from healthy subjects or β-thalassemia patients producing low or high levels of fetal hemoglobin. We demonstrated that: (a) microRNA-210 expression is higher in erythroid precursors from β-thalassemia patients with high production of fetal hemoglobin; (b) microRNA-210 increases as a consequence of mithramycin treatment of K562 cells and human erythroid progenitors both from healthy and β-thalassemia subjects; (c) this increase is associated with erythroid induction and elevated expression of γ-globin genes; (d) an anti-microRNA against microRNA-210 interferes with the mithramycin-induced changes of gene expression. In the second part of the study we have obtained convergent evidences suggesting raptor mRNA as a putative target of microRNA-210. Indeed, microRNA-210 binding sites of its 3’-UTR region were involved in expression and are targets of microRNA-210-mediated modulation in a luciferase reporter assays. Furthermore, (i) raptor mRNA and protein are down-regulated upon mithramycin-induction both in K562 cells and erythroid progenitors from healthy and β-thalassemia subjects. In addition, (ii) administration of anti-microRNA-210 to K562 cells decreased endogenous microRNA-210 and increased raptor mRNA and protein expression. Finally, (iii) treatment of K562 cells with premicroRNA-210 led to a decrease of raptor mRNA and protein. In conclusion, microRNA-210 and raptor are involved in mithramycin-mediated erythroid differentiation of K562 cells and participate to the fine-tuning and control of γ-globin gene expression in erythroid precursor cells.
    Keywords: Research Article
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Bioorganic & Medicinal Chemistry, 01 January 2015, Vol.23(1), pp.264-271
    Description: Recent interest in flavonoids has increased greatly due to their biological and pharmacological activities. Flavonoids, consist of a large group of low molecular weight polyphenolic substances, naturally occurring in fruits, vegetables, tea, and wine, and are an integral part of the human diet. Rutin is a common dietary flavonoid that is widely consumed worldwide from plant-derived beverages and foods as traditional and folk medicine remedy as well. Rutin exhibit important pharmacological activities, including anti-oxidation, anti-inflammation, anti-diabetic, anti-adipogenic, neuroprotective and hormone therapy. Here, we present the synthesis, antimicrobial, antiproliferative and pro-apoptotic effect on human leukemic K562 cells of compound , a new semi-synthetic derivative of Rutin as compared to Rutin itself. The new derivative was also included in finished topical formulations to evaluate a potential application to the dermatology field in view of the antioxidant/antimicrobial/antiinflammatory properties. Stability studies were performed by HPLC; PCL assay and ORAC tests were used to determine the antioxidant activity. presented an antioxidant activity very close to that of the parent Rutin while bearing much better lipophilic character. Regarding antiproliferative effects on the human K562 cell line, was found to be more effective than parent Rutin. Preliminary experiments demonstrated that inhibits NF-kB activity and promotes cellular apoptosis.
    Keywords: Rutin Hexapropionate ; Antioxidant ; Antifungal ; Antiproliferative ; Apoptosis ; Dermo-Cosmetic ; Venous Circulation ; Eye Bags ; Coupe Rose ; Cellulite ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0968-0896
    E-ISSN: 1464-3391
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  • 4
    Language: English
    In: Bioorganic & Medicinal Chemistry, 2006, Vol.14(15), pp.5204-5210
    Description: Several bile acid derivatives and their platinum(II) bonded forms were tested as potential inducers of erythroid differentiation of human leukemic K562 cells. -[(3-Dehydrocholanoyliden- -tartrate)-diammineplatinum(II)] stimulates erythroid differentiation of K562 cells and an increase of fetal hemoglobin (HbF) production in erythroid precursor cells from peripheral blood. In this study, we compared some bile acid derivatives and their platinum(II) complexes with respect to their ability to induce erythroid differentiation of human leukemic K562 cells. The complexes analyzed were -[(3-dehydrocholanoyliden- -tartrate)-diammineplatinum(II)] (compound ) and -[di(dehydrocholanoate)-bis(triphenylphosphine)-platinum(II)] (compound ), together with their free ligands, respectively, 3-dehydrocholanoyliden- -tartaric acid (compound ) and dehydrocholanoic acid ( ), and their parent compounds, respectively, cisplatin and -[dichloride-bis(triphenylphosphine)-platinum(II)] ( ). We found that compound stimulates erythroid differentiation of K562 cells and an increase of fetal hemoglobin (HbF) production in erythroid precursor cells isolated from peripheral blood of human subjects. This increase is similar to that obtained by hydroxyurea, a potent inducer of HbF production both in vitro and in vivo. Another important conclusion of this study is related to the evaluation of the effects of compound on production of γ-globin mRNA in human erythroid precursors grown in the two-stage liquid culture system. We demonstrated that compound induces preferential accumulation of γ-globin mRNA. The results presented in this manuscript could have practical impact, since it is well known that an increase in HbF production could ameliorate the clinical status of patients with β-thalassemia and sickle cell anemia.
    Keywords: Bile Acid Derivatives ; Platinum Complexes ; Erythroid Differentiation ; Γ-Globin ; Fetal Hemoglobin ; Β-Thalassemia ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0968-0896
    E-ISSN: 1464-3391
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  • 5
    Language: English
    In: Epigenomics, February 2012, Vol.4(1), pp.51-65
    Description: miRNAs are a family of small ncRNAs that regulate gene expression by targeting mRNAs in a sequence-specific manner, inducing translational repression or mRNA degradation. In this review, we present and discuss the available literature on the expression of miRNAs in erythroid cells. There are several experimental systems that can be employed for studies focusing on the relationship between miRNAs and erythroid differentiation, including human embryonic stem cells forced to erythroid differentiation, K562 and UT-7 cells induced to hemoglobin production by chemical compounds, erythropoietin-treated erythroid precursor cells from normal subjects or patients affected by hematological disease and in vivo systems, such as zebrafish embryos. Several miRNAs were identified as deeply involved in the erythroid phenotype, including miR-15a, miR-16-1, miR-126, miR-144, miR-451 and miR-210. Several functions related with erythroid cells were demonstrated to be regulated by these miRNAs, including maturation and proliferation of early erythroid cells, expression of fetal γ-globin genes and enucleation. These identified erythroid specific miRNAs represent the starting point to develop new protocols for miRNA therapeutics, based on both anti-miR molecules or miRNA replacement.
    Keywords: Cell Differentiation ; Erythroid Cells -- Cytology ; Micrornas -- Metabolism
    ISSN: 17501911
    E-ISSN: 1750-192X
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  • 6
    Language: English
    In: BMC Biochemistry, April 15, 2011, Vol.12, p.15
    Description: Background Cystic fibrosis (CF) airway pathology is a fatal, autosomal, recessive genetic disease characterized by extensive lung inflammation. After induction by TNF-[alpha], elevated concentrations of several pro-inflammatory cytokines (i.e. IL-6, IL-1[beta]) and chemokines (i.e. IL-8) are released from airway epithelial cells. In order to reduce the excessive inflammatory response in the airways of CF patients, new therapies have been developed and in this respect, medicinal plant extracts have been studied. In this article we have investigated the possible use of bergamot extracts (Citrus bergamia Risso) and their identified components to alter the expression of IL-8 associated with the cystic fibrosis airway pathology. Methods The extracts were chemically characterized by .sup.1.sup.H-NMR (nuclear magnetic resonance), GC-FID (gas chromatography-flame ionization detector), GC-MS (gas chromatography-mass spectrometry) and HPLC (high pressure liquid chromatography). Both bergamot extracts and main detected chemical constituents were assayed for their biological activity measuring (a) cytokines and chemokines in culture supernatants released from cystic fibrosis IB3-1 cells treated with TNF-[alpha] by Bio-Plex cytokine assay; (b) accumulation of IL-8 mRNA by real-time PCR. Results The extracts obtained from bergamot (Citrus bergamia Risso) epicarps contain components displaying an inhibitory activity on IL-8. Particularly, the most active molecules were bergapten and citropten. These effects have been confirmed by analyzing mRNA levels and protein release in the CF cellular models IB3-1 and CuFi-1 induced with TNF-[alpha] or exposed to heat-inactivated Pseudomonas aeruginosa. Conclusions These obtained results clearly indicate that bergapten and citropten are strong inhibitors of IL-8 expression and could be proposed for further studies to verify possible anti-inflammatory properties to reduce lung inflammation in CF patients.
    Keywords: Plant Extracts -- Health Aspects ; Plant Extracts -- Research ; Gene Expression -- Research ; Epithelial Cells -- Physiological Aspects ; Epithelial Cells -- Research ; Interleukin-8 -- Genetic Aspects ; Interleukin-8 -- Research ; Interleukin-8 -- Physiological Aspects ; Cystic Fibrosis -- Research ; Cystic Fibrosis -- Genetic Aspects
    ISSN: 1471-2091
    Source: Cengage Learning, Inc.
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  • 7
    Language: English
    In: BMC Biochemistry, April 15, 2011, Vol.12, p.15
    Description: Background Cystic fibrosis (CF) airway pathology is a fatal, autosomal, recessive genetic disease characterized by extensive lung inflammation. After induction by TNF-[alpha], elevated concentrations of several pro-inflammatory cytokines (i.e. IL-6, IL-1[beta]) and chemokines (i.e. IL-8) are released from airway epithelial cells. In order to reduce the excessive inflammatory response in the airways of CF patients, new therapies have been developed and in this respect, medicinal plant extracts have been studied. In this article we have investigated the possible use of bergamot extracts (Citrus bergamia Risso) and their identified components to alter the expression of IL-8 associated with the cystic fibrosis airway pathology. Methods The extracts were chemically characterized by .sup.1.sup.H-NMR (nuclear magnetic resonance), GC-FID (gas chromatography-flame ionization detector), GC-MS (gas chromatography-mass spectrometry) and HPLC (high pressure liquid chromatography). Both bergamot extracts and main detected chemical constituents were assayed for their biological activity measuring (a) cytokines and chemokines in culture supernatants released from cystic fibrosis IB3-1 cells treated with TNF-[alpha] by Bio-Plex cytokine assay; (b) accumulation of IL-8 mRNA by real-time PCR. Results The extracts obtained from bergamot (Citrus bergamia Risso) epicarps contain components displaying an inhibitory activity on IL-8. Particularly, the most active molecules were bergapten and citropten. These effects have been confirmed by analyzing mRNA levels and protein release in the CF cellular models IB3-1 and CuFi-1 induced with TNF-[alpha] or exposed to heat-inactivated Pseudomonas aeruginosa. Conclusions These obtained results clearly indicate that bergapten and citropten are strong inhibitors of IL-8 expression and could be proposed for further studies to verify possible anti-inflammatory properties to reduce lung inflammation in CF patients.
    Keywords: Plant Extracts -- Health Aspects ; Plant Extracts -- Research ; Gene Expression -- Research ; Epithelial Cells -- Physiological Aspects ; Epithelial Cells -- Research ; Interleukin-8 -- Genetic Aspects ; Interleukin-8 -- Research ; Interleukin-8 -- Physiological Aspects ; Cystic Fibrosis -- Research ; Cystic Fibrosis -- Genetic Aspects
    ISSN: 1471-2091
    Source: Cengage Learning, Inc.
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  • 8
    Language: English
    In: European Journal of Pharmacology, 2011, Vol.672(1), pp.30-37
    Description: The K562 cell line has been proposed as a useful experimental system to identify anti-tumor compounds acting by inducing terminal erythroid differentiation. K562 cells exhibit a low proportion of hemoglobin-synthesizing cells under standard cell growth conditions, but are able to undergo terminal erythroid differentiation when treated with a variety of anti-tumor compounds. In this paper we report a screening study on a set of different modified C(5) uracil derivatives for the evaluation of their antiproliferative effect in connection with erythroid differentiation pathways, and for defining a new class of drug candidates for the treatment of chronic myelogenous leukemia. Activity of the derivatives tested can be classified in two effect: an antiproliferative effect linked to a high level of erythroid differentiation activity and an antiproliferative effect without activation of gamma globin genes The highest antiproliferative effect and erythroid induction was shown by compound , a thymine derivative bearing a -octyl chain on nitrogen N(1), whereas thymine did not show any effect, suggesting the importance of the linear alkyl chain in position N(1). To our knowledge this compound should be considered among the most efficient inducers of erythroid differentiation of K562 cells. This work is the starting point for the quest of more effective and specific drugs for the induction of terminal erythroid differentiation, for leading new insights in the treatment of neoplastic diseases with molecules acting by inducing differentiation rather than by simply exerting cytotoxic effects.
    Keywords: Erythroid Differentiation ; Tumor Growth ; Isoorotic Acid Derivative ; Chronic Myelogenous Leukemia ; Beta-Thalassemia ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0014-2999
    E-ISSN: 1879-0712
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  • 9
    Language: English
    In: European Journal of Pharmacology, 05 April 2015, Vol.752, pp.84-91
    Description: Several investigations have demonstrated a mild clinical status in patients with β-globin disorders and congenital high persistence of foetal haemoglobin. This can be mimicked by a pharmacological increase of foetal γ-globin genes expression and foetal haemoglobin production. Our goal was to apply a multistep assay including few screening methods (benzidine staining, RT-PCR and HPLC analyses) and erythroid cellular model systems (the K562 cell line and erythroid precursors collected from peripheral blood) to select erythroid differentiation agents with foetal haemoglobin inducing potential. With this methodology, we have identified a butyric acid derivative, namely the 4174 cyclopropanecarboxylic acid compound, able to induce erythroid differentiation without antiproliferative effect in K562 cells and increase of γ-globin gene expression in erythroid precursor cells. The results are relevant for pharmacological treatments of haemoglobinopathies, including β-thalassaemia and sickle cell anaemia.
    Keywords: Butyrate Analogues ; Erythroid Differentiation ; Foetal Haemoglobin Production ; Γ-Globin Mrna Induction ; Real-Time Pcr ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0014-2999
    E-ISSN: 1879-0712
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  • 10
    Language: English
    In: Bioorganic & Medicinal Chemistry, 01 December 2010, Vol.18(23), pp.8341-8349
    Description: Four commercial available furocoumarin derivatives were selected from VS studies of a focus library against NF-κB for further biological evaluation. Three of the identified molecules ( , and ) significantly inhibited NF-κB dependent biological functions and might be of interest for experimental therapy of cystic fibrosis. In the present study, a structured-based virtual screening (VS) of differently substituted furocoumarins and analogues has been carried out against nuclear factor kappa B (NF-κB), with the objective of selecting molecules able to inhibit the binding of this transcription factor to the DNA. The focus library was developed starting from chemical structures obtained from the literature, as well as retrieving compounds from available commercial databases. A two dimensional substructure searching method based on four different chemical scaffolds was used for this purpose. Among the 10 highest-scored ligands selected from the docking studies, five commercially available molecules were investigated in biological assays. Four furocoumarin derivatives showed IC values in the range of 40–100 μM in inhibiting NF-κB/DNA interactions studied by electrophoretic mobility shift assay (EMSA). Three compounds significantly inhibited NF-κB dependent biological functions (expression of IL-8) in cellular analysis based on infection of cystic fibrosis IB3-1 cells. These findings validated the virtual screening approach here presented and reinforce the successful results of our previously computational studies aimed at the identification of molecules targeting NF-κB. The discovered novel compounds could be of relevance to identify more potent inhibitors of NF-κB dependent biological functions beneficial to control lung inflammation occurring in patients affected by cystic fibrosis.
    Keywords: Nf-Κb ; Virtual Screening ; Inhibitors ; Furocoumarin ; Cystic Fibrosis ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0968-0896
    E-ISSN: 1464-3391
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