Activator protein-1 (AP-1): a bridge between life and death in lung epithelial (A549) cells under hypoxia

Fibrosis is the dramatic consequence of a dysregulated reparative process in which activated fibroblasts (myofibroblasts) and Transforming Growth Factor β1 (TGFβ1) play a central role. When exposed to TGFβ1, fibroblast and epithelial cells differentiate in myofibroblasts; in addition, endothelial cells may undergo endothelial-to-mesenchymal transition (EndoMT) and actively participate to the progression of fibrosis. Recently, the role of αv integrins, which recognize the Arg-Gly-Asp (RGD) tripeptide, in the release and signal transduction activation of TGFβ1 became evident. In this study, we present a class of triazole-derived RGD antagonists that interact with αvβ3 integrin. Above different compounds, the RGD-2 specifically interferes with integrin-dependent TGFβ1 EndoMT in Endothelial Colony-Forming Cells (ECPCs) derived from circulating Endothelial Precursor Cells (ECPCs). The RGD-2 decreases the amount of membrane-associated TGFβ1, and reduces both ALK5/TGFβ1 type I receptor expression and Smad2 phosphorylation in ECPCs. We found that RGD-2 antagonist reverts EndoMT, reducing α-smooth muscle actin (α-SMA) and vimentin expression in differentiated ECPCs. Our results outline the critical role of integrin in fibrosis progression and account for the opportunity of using integrins as target for anti-fibrotic therapeutic treatment.     

Synthesis, anti-tuberculosis activity, and 3D-QSAR study of ring-substituted-2/4-quinolinecarbaldehyde derivatives

We have previously identified ring-substituted quinolines as a new structural class of anti-tuberculosis agents. In our ongoing efforts at structural optimization of this class, four series of ring-substituted-2/4-quinolinecarbaldehyde derivatives were synthesized. All twenty-four compounds were synthesized using short and convenient one to two high yielding steps. The newly synthesized compounds were tested in vitro against drug-sensitive Mycobacterium tuberculosis H37Hv strain. Several derivatives were found to be promising inhibitors of M. tuberculosis. For example, derivatives 4a-c (Series 2), 7a-d (Series 3), and 8a-b (Series 4) displayed >90% inhibition at 6.25 microg/mL in the primary assay. The most active compounds, N-(2-fluorophenyl)-N'-quinolin-2-ylmethylene-hydrazine (4a), N-(2-adamantan-1-yl-quinolin-4-ylmethylene)-N'-(4-fluorophenyl)hydrazine (7c), and N-(2-cyclohexyl-quinolin-4-ylmethylene)-N'-(2-fluorophenyl)hydrazine (8a), exhibited 99% inhibition at the lowest tested concentration of 3.125 microg/mL against drug-sensitive M. tuberculosis H37Rv strain. The similarity index based on steric and electrostatic features of the molecules was used, in conjunction with principal component analysis and linear discriminant analysis, successively to classify the molecules based on their activity into two classes. This classification method gives us confidence in predicting the activity class of any new unsynthesized molecule belonging to these series.     

Polyamine synthesis and salvage pathways in the malaria parasite Plasmodium falciparum

We demonstrate, for the first time, a functional polyamine biosynthetic pathway in the malaria parasite Plasmodium falciparum that culminates in the synthesis of spermine. Additionally, we also report putrescine and spermidine salvage in the malaria parasite. Putrescine and spermidine transport in P. falciparum infected red blood cells is a highly specific, carrier mediated and active process, mediated by new transporters that differ from the transporters of uninfected red blood cells in their kinetic parameters, Vmax and km, as well as in their activation energy.     

Modulation of trophoblast stem cell and giant cell phenotypes: analyses using the Rcho-1 cell model

Trophoblast giant cells are located at the maternal-embryonic interface and have fundamental roles in the invasive and endocrine phenotypes of the rodent placenta. In this report, we describe the experimental modulation of trophoblast stem cell and trophoblast giant cell phenotypes using the Rcho-1 trophoblast cell model. Rcho-1 trophoblast cells can be manipulated to proliferate or differentiate into trophoblast giant cells. Differentiated Rcho-1 trophoblast cells are invasive and possess an endocrine phenotype, including the production of members of the prolactin (PRL) family. Dimethyl sulfoxide (DMSO), a known differentiation-inducing agent, was found to possess profound effects on the in vitro development of trophoblast cells. Exposure to DMSO, at non-toxic concentrations, inhibited trophoblast giant cell differentiation in a dose-dependent manner. These concentrations of DMSO did not significantly affect trophoblast cell proliferation or survival. Trophoblast cells exposed to DMSO exhibited an altered morphology; they were clustered in tightly packed colonies. Trophoblast giant cell formation was disrupted, as was the expression of members of the PRL gene family. The effects of DMSO were reversible. Removal of DMSO resulted in the formation of trophoblast giant cells and expression of the PRL gene family. The phenotype of the DMSO-treated cells was further determined by examining the expression of a battery of genes characteristic of trophoblast stem cells and differentiated trophoblast cell lineages. DMSO treatment had a striking stimulatory effect on eomesodermin expression and a reciprocal inhibitory effect on Hand1 expression. In summary, DMSO reversibly inhibits trophoblast differentiation and induces a quiescent state, which mimics some but not all aspects of the trophoblast stem cell phenotype.     

Genetic heterogeneitiy of Crigler-Najjar syndrome type I: A study of 14 cases

Crigler-Najjar syndrome type I (CN-I) is an autosomal recessive condition characterized by severe unconjugated hyperbilirubinemia caused by the lack of bilirubin-UDP-glucuronosyltransferase (B-UGT) activity in the liver. Two B-UGTs are coded for by a gene complex (UGT1) that maps to chromosome 2q37 and that also encodes two phenol-UDP-glucuronosyltransferases. Here, we report eleven mutations (including nine novel mutations) of the B-UGT1 gene in a large series of 14 unrelated CN-I children of various geographic origins: France (seven patients: A401P, Q357X, W335X, A368T, 1223insG, A291V, K426E, K437X); Portugal (two patients: G308E); Tunisia (two patients: Q357R); Turkey (one patient: S381R); Italy (two siblings: S381R). Interestingly, 6/14 mutant alleles carried by unrelated probands of French ancestry bore the A401P mutation, indicating a founder effect; this effect is probably also present in Portugal, Turkey, and Tunisia. Since mutations occurred in exons 2-5 shared by all mRNAs species of the gene, a combined deficiency of B-UGT and P-UGT was observed in the liver of five patients in whom these activities were measured. The present study confirms that CN-I is genetically heterogeneous and suggests that different founder effects are involved in Western Europe, the Middle East, and North Africa.These results were presented in part at the American Association for the Study of Liver Diseases, Chicago, November 4–7, 1993     

Karyotype studies in the genusNotopterus (Lacepede). the occurrence and fate of univalent chromosomes in spermatocytes ofN. Chitala

The present report is based on the karyotype studies of two species of fishes,Notopterus chitala andN. notopterus, collected from the river Jumna, Delhi, India. Both species possess a diploid number of 48 chromosomes, 12 of which are metacentric. The primary and secondary spermatocytes of one individual ofN. chitala have been found to possess varying numbers of univalent chromosomes. The possible origin and fate of the univalents are discussed.     

Antidepressants and brain respiration

Imipramine and clorgyline, at concentrations of 0.002 M, inhibit the respiration of brain tissue by 82 and 71 per cent respectively, while chloropromazine and tranylcypromine, at concentrations of 0.01 M, inhibit it about 25 per cent. Deprenyl and amphetamine at a concentration of 0.002 M inhibit brain tissue respiration by 12 and 18 per cent respectively. Respiration in brain is least affected by lithium chloride (only 5 per cent inhibition).     

Hidden Structural Modules in a Cooperative RNA Folding Transition

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