102,042 research outputs found
Multi-task evaluation of TMA analogues as anti-inflammatory treatments for CF lung disease
No full textPrincipal objective of the project (FFC #22/2019, PI: Prof. Ilaria Lampronti) was the implementation of the knowledge on new-generation TMA analogues, in order to develop new drugs for the CF pulmonary disease, through the evaluation of simultaneous dualistic activity (anti-inflammatory and modulating activities). Since the transcription factor NF-kB plays a critical role in IL-8 expression, the use of agents able to interfere with the NF-kB pathway represents an interesting therapeutic strategy (Cabrini G, 2020).
All our research was aimed at designing and developing molecules capable of acting both as anti-inflammatories, inhibiting the NF-kB pathway, and as CFTR correctors, in order to obtain a single drug with double activity in the future. The experimental plan was focalized on in vitro and in vivo models to deeply and fully study the new psoralen derivatives. Of course, another key objective was to check that both the in vitro and in vivo side effects were absent, or at least very attenuated. In addition to the planned experiments, we also tested our analogues using numerous in vitro and in vivo assays (described in the “Results” chapter) to obtain reliable results.
The study of the possible synergism between selected TMA derivatives and other known anti-inflammatory (Ibuprofen) or anti-microbial (Tobramycin, Colistin, Ciprofloxacin and Azithromycin) agents currently used in CF patients was performed. Finally, our goal was to start the process leading to possible patent protection and exploitation or to the orphan drug designation (ODD) of one TMA derivative in order to finalize our research by the develop of a product with relevant biological activity for the CF treatment and attractive for industrial partners
Effects of analogues of 4,6,4???-trymethylangelicin on erythroid differentiation and NF-kB activity
No full textRecently we demonstrated that 4,6,4’-trimethylangelicin (TMA) is a
strong inhibitor of NF-kB and IL-8 gene expression in cystic fibrosis
cells (Tamanini et al., 2011) and it is able to induce erythroid
differentiation and increase of gamma-globin gene expression
(Lampronti et al., 2009). To verify whether these effects can be
differentially retained in TMA derivatives, we have characterized 26
synthetic analogues. The effects on erythroid differentiation was
analyzed on human leukemic K562 cells following detection of the
proportion of benzidine positive (hemoglobin containing cells). The
effects on NF-kB-mediated induction of pro-inflammatory genes was
first verified by eletrophoretic mobility shift assay (EMSA). The most
active NF-kB inhibitors were then tested for the ability to inhibit NF-
kB-directed upregulation of IL-8 gene expression in cystic fibrosis IB3-
1 cells treated with TNF-α. The obtained results demonstrate that some
compounds (e.g. 4-hydroxymethyl-6,4’-dimethyl angelicin) inhibit NF-
kB/DNA interactions (IC50 = 40μM) and strongly induce erythroid
differentiation (50% benzidine-positive cells); on the contrary, other
compounds (e.g. 4,6,4’,5’-tetramethyl angelicin, 4-methoxymethyl-
6,4’-dimethyl angelicin and 6-chloro-4,4’-dimethyl angelicin) inhibit
NF-kB/DNA interactions (IC50 = 12μM), with low or no effects on
erythoid differentiation; on the other hands 4-methyl-5-methoxy
angelicin was found to be capable to induce erythroid differentiation
(30% benzidine-positive cells) without inhibitory effects on NF-
kB/DNA interactions. Therefore, the effects on inhibition of NF-kB
and induction of erythroid differentiation can be separately operating in
TMA analogues, allowing the identification of functional groups
possibly involved in these biological effects. Interestingly, 4,6,4’,5’-
tetramethyl angelicin was able to inhibit the NF-kB-directed upregulation of IL-8 in TNF-α treated IB3-1 cells
Supramolecular metathesis: co-former exchange in co-crystals of pyrazine with (R, R)-,(S, S)-,(R, S)-and (S, S/R, R)-tartaric acid
No full textCo-crystals of dextro-(R,R), levo-(S,S), meso-(R,S) and racemic (R,R–S,S)-tartaric acid with pyrazine were obtained by manual kneading and slurry experiments; subsequent reactions in the solid state between these co-crystals and the various forms of tartaric acid in the solid state and via slurry show that co-former exchange takes place according to the sequence of stability [(R,S)-ta]2·py > (S,S/R,R)-ta·py > (R,R)-ta·py or (S,S)-ta·py
1,2,4-triazoles. Improved synthesis of 5-substituited 4-amino-3mercato-(4H)-1,2,4 triazoles and a facile route to 3,6-disubstituited 1,24-triazolo[3,4b][1,3,4]thiadiazoles
No full textThe reaction of thiocarbohydrazide with carboxylic acids at the melting temperature allows an improved preparation of the 5-substituted 4-amino-3-mercapto-1,2,4-triazole heterocycles. The crude 4-amino-5-mercapto-1,2,4-triazoles react easily with carboxylic acids or carboxylic acid chlorides to afford the 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole ring system
Novel biological activity of psoralens. Induction of accumulation of g-globin mRNA in human erythroid cells
No full textAlteration of lead-glazed ware and amphorae from shipwreacks in the Black Sea (Ukraine).
No full textComparative Antiproliferative activities of wood and seeds essential oils of Juniperus Oxycedrus L. against K562 human chronic myelogenous leukemia cells
No full textThe species Juniperus oxycedrus L. is a member of Cupressaceae family. The chemical composition and antiproliferative activity of wood and seeds essential oils of J. oxycedrus, grown wild in Lebanon, were evaluated in order to investigate whether these products could be used as sources of functional compounds. The most abundant components of the seeds essential oils were pinene, β-myrcene, limonene and δ-cadinene, while wood oil components included δ-cadinene, cis-thujopsene, τ-muurolol, widdrol, epi-cubenol, β-caryophyllene and calacorene. Both wood and seeds essential oils inhibited the proliferation of K562 cell line with ic50 values of 39.8±2.7 and 147.7±3.6 g-mL, respectively. The J. oxycedrus wood oil showed erythroid differentiation of 16.0±2.0percent at a concentration of 5 g-mL, while the seeds essential oil showed erythroid differentiation of 25.0±2.8percent at a concentration of 50 g-mL. © 2013 © 2013 Taylor and Francis.Adams R. P., 2007, IDENTIFICATION ESSEN; Barrero Alejandro F., 1993, Flavour and Fragrance Journal, V8, P185, DOI 10.1002-ffj.2730080404; Bianchi N, 2000, BIOCHEM PHARMACOL, V60, P31, DOI 10.1016-S0006-2952(00)00297-5; Bianchi N, 2001, BRIT J HAEMATOL, V113, P951, DOI 10.1046-j.1365-2141.2001.02843.x; Bouhlal K., 1988, PARFUMS COSMETIQUES, V83, P73; Catelani G, 2002, BIOORGAN MED CHEM, V10, P347, DOI 10.1016-S0968-0896(01)00285-1; Cavaleiro C, 2006, J APPL MICROBIOL, V100, P1333, DOI 10.1111-j.1365-2672.2006.02862.x; Chiarabelli C, 2003, HAEMATOLOGICA, V88, P826; Cortesi R, 1998, EUR J HAEMATOL, V61, P295; Sanchez De Medina F., 1994, Planta Medica, V60, P197, DOI 10.1055-s-2006-959457; Fibach E, 2003, BLOOD, V102, P1276, DOI 10.1182-blood-2002-10-3095; Franco J.A., 1964, FLORA EUROPAEA, V1; Gambari R, 2007, CURR MED CHEM, V14, P199, DOI 10.2174-092986707779313318; Guerrini A, 2009, J AGR FOOD CHEM, V57, P4103, DOI 10.1021-jf803489p; Hanene M, 2012, NAT PROD RES, V26, P810, DOI 10.1080-14786419.2011.558014; Iyama E.W., 2003, J EXP HAEMATOL, V31, P592; Lampronti D., 2003, PHYTOMEDICINE, V10, P300; Lampronti I, 2006, INT J ONCOL, V29, P989; Loizzo MR, 2007, FOOD CHEM, V105, P572, DOI 10.1016-j.foodchem.2007.04.015; Loizzo M.R., 2008, CHEM BIODIVERS, V5, P481; Moreno L, 1998, PHARMACOL TOXICOL, V82, P108; Perrine SP, 2011, J CLIN PHARMACOL, V51, P1186, DOI 10.1177-0091270010379810; Puissant A, 2008, FASEB J, V22, P1894, DOI 10.1096-fj.07-101394; Rathore Ritesh, 2003, Med Health R I, V86, P240; Saab A.M., 2012, PLANTA MED, V78, P1; Salido S, 2002, J ETHNOPHARMACOL, V81, P129, DOI 10.1016-S0378-8741(02)00045-4; Tohme G., 2000, 1001 FLOWERS LEBANON, P3090
The ethanol fraction from the stem of Berberis libanotica inhibits the viability of adult T cell leukemia
No full textAim. In the Mediterranean countries, several described medicinal plants are derived from Lebanon. According to Tohme et al. there are 2597 species in Lebanon. More than fifty two percent are endemic to Lebanon. In this paper we show that the ethanol fraction of the stem of Berberis libanotica is able to inhibit the viability of HTLV-1 positive (HuT-102) and HTLV-1 negative (CEM) cell lines of malignant T-cell leukemia. Methods. After traditional maceration to extract the ethanol fraction from Berberis libanotica stem, the in vitro viability was assayed. Results. The results suggest that Berberis libanotica (a Lebanese medicinal plant) contains a substantial amount of secondary metabolites such as alkaloids powerful in inhibiting the viability of HuT-102 and CEM cell lines. Conclusion. The obtained results demonstrate a novel anticancer property of Berberis libanotica stem extracts, in addition to the previously reported anti-inflammatory activity.Abi Saab S, 2008, LEBAN SCI J, V9, P99; Barbour EK, 2004, J ETHNOPHARMACOL, V93, P1, DOI 10.1016-j.jep.2004.02.027; Bazarbachi A, 2001, VIRUS RES, V78, P79, DOI 10.1016-S0168-1702(01)00286-6; Bazarbachi A, 2011, BLOOD, V118, P1736, DOI 10.1182-blood-2011-03-345702; Darwiche N, 2007, EXPERT OPIN DRUG DIS, V2, P361, DOI 10.1517-17460441.2.3.361; FOLEY GE, 1965, CANCER, V18, P522, DOI 10.1002-1097-0142(196504)18:4522::AID-CNCR28201804183.0.CO;2-J; Gritsanapan W, 2009, J HLTH RES, V23, P59; Hande KR, 1998, EUR J CANCER, V34, P1514, DOI 10.1016-S0959-8049(98)00228-7; Harakeh S, 2004, CHEM-BIOL INTERACT, V148, P101, DOI 10.1016-j.cbi.2004.05.002; Ishitsuka K, 2008, EUR J HAEMATOL, V80, P185, DOI 10.1111-j.1600-0609.2007.01016.x; Khan M, 2010, MUTAT RES-FUND MOL M, V683, P123, DOI 10.1016-j.mrfmmm.2009.11.001; Lampronti I, 2008, EVID-BASED COMPL ALT, V5, P303, DOI 10.1093-ecam-nem042; Lampronti I, 2006, INT J ONCOL, V29, P989; Lampronti I, 2005, MINERVA BIOTECH, V17, P153; Matsuoka M, 2005, RETROVIROLOGY, V2, DOI 10.1186-1742-4690-2-27; Taylor JM, 2008, APOPTOSIS, V13, P733, DOI 10.1007-s10495-008-0208-7; Tohme G, 2007, ILLUSTRATED FLORA LE, P610; Yoshida M, 2010, P JPN ACAD B-PHYS, V86, P117, DOI 10.2183-pjab.86.11712
Surface plasmon resonance based analysis of the binding of LYAR protein to the rs368698783 (G>A) polymorphic Aγ-globin gene sequences mutated in β-thalassemia
No full textRecent studies have identified and characterized a novel putative transcriptional repressor site in a 5′ untranslated region of the Aγ-globin gene that interacts with the Ly-1 antibody reactive clone (LYAR) protein. LYAR binds the 5’-GGTTAT-3’ site of the Aγ-globin gene, and this molecular interaction causes repression of gene transcription. In β-thalassemia patients, a polymorphism has been demonstrated (the rs368698783 G>A polymorphism) within the 5′- GGTTAT-3′ LYAR-binding site of the Aγ-globin gene. The major results gathered from surface plasmon resonance based biospecific interaction analysis (SPR-BIA) studies (using crude nuclear extracts, LYAR-enriched lysates, and recombinant LYAR) support the concept that the rs368698783 G>A polymorphism of the Aγ-globin gene attenuates the efficiency of LYAR binding to the LYAR-binding site. This conclusion was fully confirmed by a molecular docking analysis. This might lead to a very important difference in erythroid cells from β-thalassemia patients in respect to basal and induced levels of production of fetal hemoglobin. The novelty of the reported SPR-BIA method is that it allows the characterization and validation of the altered binding of a key nuclear factor (LYAR) to mutated LYAR-binding sites. These results, in addition to theoretical implications, should be considered of interest in applied pharmacology studies as a basis for the screening of drugs able to inhibit LYAR–DNA interactions. This might lead to the identification of molecules facilitating induced increase of γ-globin gene expression and fetal hemoglobin production in erythroid cells, which is associated with possible reduction of the clinical severity of the β-thalassemia phenotype
Surface plasmon resonance based analysis of the binding of LYAR protein to the rs368698783 (G\>A) polymorphic A?-globin gene sequences mutated in ?-thalassemia
No full textRecent studies have identified and characterized a novel putative transcriptional repressor site in a 5′ untranslated region of the Aγ-globin gene that interacts with the Ly-1 antibody reactive clone (LYAR) protein. LYAR binds the 5’-GGTTAT-3’ site of the Aγ-globin gene, and this molecular interaction causes repression of gene transcription. In β-thalassemia patients, a polymorphism has been demonstrated (the rs368698783 G>A polymorphism) within the 5′-GGTTAT-3′ LYAR-binding site of the Aγ-globin gene. The major results gathered from surface plasmon resonance based biospecific interaction analysis (SPR-BIA) studies (using crude nuclear extracts, LYAR-enriched lysates, and recombinant LYAR) support the concept that the rs368698783 G>A polymorphism of the Aγ-globin gene attenuates the efficiency of LYAR binding to the LYAR-binding site. This conclusion was fully confirmed by a molecular docking analysis. This might lead to a very important difference in erythroid cells from β-thalassemia patients in respect to basal and induced levels of production of fetal hemoglobin. The novelty of the reported SPR-BIA method is that it allows the characterization and validation of the altered binding of a key nuclear factor (LYAR) to mutated LYAR-binding sites. These results, in addition to theoretical implications, should be considered of interest in applied pharmacology studies as a basis for the screening of drugs able to inhibit LYAR–DNA interactions. This might lead to the identification of molecules facilitating induced increase of γ-globin gene expression and fetal hemoglobin production in erythroid cells, which is associated with possible reduction of the clinical severity of the β-thalassemia phenotype
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