22 research outputs found
Regulation of Transforming Growth Factor-ÎČ1âdriven Lung Fibrosis by Galectin-3
Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic dysregulated response to alveolar epithelial injury with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers. Galectin-3 is a beta-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies. Objectives: To examine the role of galectin-3 in pulmonary fibrosis. Methods: We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung fibrosis. Further mechanistic studies were performed in vitro and on samples from patients with IPF. Measurements and Main Results: Transforming growth factor (TGF)-beta and bleomycin-induced lung fibrosis was dramatically reduced in mice deficient in galectin-3, manifest by reduced TGF-beta 1 induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of beta-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of galectin -3, TD139, blocked TGF-beta-induced beta-catenin activation in vitro and in vivo and attenuated the late-stage progression of lung fibrosis after bleomycin. There was increased expression of galectin-3 in the bronchoalveolar lavage fluid and serum from patients with stable IPF compared with nonspecific interstitial pneumonitis and controls, which rose sharply during an acute exacerbation suggesting that. galectin-3 may be a marker of active fibrosis in IPF and that strategies that block galectin-3 may be effective in treating acute fibrotic exacerbations of IPF. Conclusions: This study identifies galectin-3 as an important regulator of lung fibrosis and provides a proof of principle for galectin-3 inhibition as a potential novel therapeutic strategy for IPF
Conception, synthÚse, étude de l'équilibre tautomérique et évaluation biologique de nouveaux analogues de l'adduit Isiniazide-NAD(H) comme inhibiteur d'InhA de Mycobacterium tuberculosis
TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF
Ring-Chain Tautomerism of Simplified analogues of Isoniazid - NAD (P) Adducts : an Experimental and Theoretical Study
International audienc
Synthesis and antitumor evaluation of analogues of the marine pyrroloiminoquinone tsitsikammamines.
Two series of analogues of the marine pyrroloiminoquinone alkaloids tsitsikammamine have been synthesized on the basis of a Michael addition between 2'-amino-1-(4-methoxyphenyl)-ethanol and two indolediones. All the compounds were evaluated in vitro for antiproliferative activity against distinct cancer cell lines.Journal Articleinfo:eu-repo/semantics/publishe
Synthesis of 3-azido-3-deoxy-beta-d-galactopyranosides.
Three efficient routes to 3-azido-3-deoxy-beta-d-galactopyranosides were developed relying on a double inversion protocol at C3. Two of the routes were demonstrated to work with both O- and S-glycosides. In all three routes, the 2-O-acetyl-3-azido-4,6-O-benzylidene-3-deoxy-beta-d-galactopyranosides were obtained by an azide inversion of the key intermediates 2-O-acetyl-4,6-O-benzylidene-3-O-trifluoromethanesulfonyl-beta-d-gulopyranosides. The intermediate gulopyranosides were in turn obtained from 2-O-acetyl-4,6-O-benzylidene-3-O-trifluoromethanesulfonyl-beta-d-galactopyranosides, installed in one pot from the 4,6-O-benzylidene-beta-d-galactopyranosides, by inversion with nitrite or acetate. For O-glycosides, the gulopyranoside configuration could alternatively be obtained from the 4,6-O-benzylidene-beta-d-galactopyranoside by elimination to give the 2,3-dianhydro derivative followed by a highly stereoselective cis-dihydroxylation
Preliminary Investigations of the Effect of Lipophilic Analogues of the Active Metabolite of Isoniazid Toward Bacterial and Plasmodial Strains
International audienceFive lipophilic analogues 1 â5 of the active metabolite of the antitubercular drug isoniazid (INH), selected as inhibitors of Mycobacterium smegmatis and Mycobacterium tuberculosis growth, were evaluated for their activity against Corynebacterium glutamicum (lacking in InhA activity), Escherichia coli (to test mycobacteria selectivity), and Plasmodium falciparum (as possible parasite target). Compound 3 was the only one that did not inhibit C. glutamicum growth. The poor InhA inhibitors 1 and 2 were able to inhibit C. glutamicum and their anti(myco)bacterial mechanisms of action involve targets other than InhA. For the effective InhA inhibitors 4 and 5 , also active against C. glutamicum and M. tuberculosis strains, more than one pathway should be envisaged to explain their actions. Pyridineâbase ring analogues (1 , 2, and 3 ) have no ability to inhibit the growth of E. coli even at a high concentration. Compound 3 thus exhibited a selective inhibitory action toward M. tuberculosis, while it was inactive on C. glutamicum and on E. coli growth. It presented an activity profile similar to that of INH suggesting InhA inhibition as one of the possible mechanisms of action. Finally, although a homologue of the reductase InhA exists in the FASâII system of P. falciparum , 3 was unable to display antiplasmodial activity
Skin Sensitization of Epoxyaldehydes: Importance of Conjugation
Structureâactivity
relationship (SAR) models are important
tools for predicting the skin sensitization potential of new compounds
without animal testing. In compounds possessing a structural alert
(aldehyde) and an activation alert (double bond), it is important
to consider bioactivation/autoxidation (e.g., epoxidation). In the
present study, we have explored a series of aldehydes with regard
to contact allergy. The chemical reactivity of these 6 aldehydes toward
a model hexapeptide was investigated, and their skin sensitization
potencies were evaluated using the local lymph node assay (LLNA).
Overall, we observed a similar trend for the <i>in vitro</i> reactivity and the <i>in vivo</i> sensitization potency
for the structural analogues in this study. The highly reactive conjugated
aldehydes (α,ÎČ-unsaturated aldehydes and 2,3-epoxyaldehydes)
are sensitizing moieties, while nonconjugated aldehydes and nonterminal
aliphatic epoxides show low reactivity and low sensitization potency.
Our data show the importance of not only double bond conjugation to
aldehyde but also epoxideâaldehyde conjugation. The observations
indicate that the formation of nonconjugated epoxides by bioactivation
or autoxidation is not sufficient to significantly increase the sensitization
potency of weakly sensitizing parent compounds
Analogues of the Epoxy Resin Monomer Diglycidyl Ether of Bisphenol F: Effects on Contact Allergenic Potency and Cytotoxicity
Diglycidyl ethers of bisphenol A (DGEBA) and bisphenol
F (DGEBF)
are widely used as components in epoxy resin thermosetting products.
They are known to cause occupational and nonoccupational allergic
contact dermatitis. The aim of this study is to investigate analogues
of DGEBF with regard to contact allergy and cytotoxicity. A comprehensive
knowledge of the structural features that contribute to the allergenic
and cytotoxic effects of DGEBF will guide the development of future
novel epoxy resin systems with reduced health hazards for those coming
into contact with them. It was found that the allergenic effects of
DGEBF were dependent on its terminal epoxide groups. In contrast,
it was found that the cytotoxicity in monolayer cell culture was dependent
not only on the presence of epoxide groups but also on other structural
features