Santiago, E. (Esteban)
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- Nitric oxide activates granule-associated DNase in human monocytes(Elsevier, 1998) Lopez-Moratalla, N. (Natalia); Pio, R. (Rubén); Rouzaut, A. (Ana); Santiago, E. (Esteban); Lopez-Zabalza, M.J. (María Jesús)Activated and differentiated human monocytes with a CD14+CD16+ phenotype were found to contain a DNase activity associated with secretion granules. Activated cells were obtained from patients with autoimmune diseases. Activation and differentiation of monocytes were also achieved after incubation of PBMC from healthy subjects with protein A (SpA) or immunopotentiating peptides. DNase activity corresponded to a 66-kDa protein, similar to that described in granules from T lymphocytes, active preferentially on double-strand DNA. DNA fragmentation activity increased when NO donors were present; the activity was higher in the presence of Ca2+, and at low pH values. The Ca2+-dependent activity was inhibited by Zn2+. NO-dependent activity was additive with that of Ca2+-dependent and it was not inhibited by Zn2+. Dithiothreitol did not modify the effect of NO on DNase activity. Incubation of PBMC in the presence of NMLA, an inhibitor of NO synthases, decreased this DNase activity. Data reported clearly suggest a regulatory role of NO in granule-associated DNase activity
- Inducible nitric oxide synthase in human lymphomononuclear cells activated by synthetic peptides derived from extracellular matrix proteins.(Elsevier, 1995) Lopez-Moratalla, N. (Natalia); Perez-Mediavilla, L.A. (Luis Alberto); Montuenga-Badia, L.M. (Luis M.); Calonge-Domínguez, M. (María); Santiago, E. (Esteban); Lopez-Zabalza, M.J. (María Jesús)Synthetic peptides with sequences present in extracellular matrix proteins are capable of causing the expression of the inducible form of nitric oxide synthase (iNOS), detected by immunocytochemistry, and the release of NO by human lymphomononuclear cells incubated in their presence. Active peptides are 15-mers containing a characteristic 2-6-11 motif in which the amino acid residue at position 2 is Leu, Ile, Val, Gly, Ala or Lys; the residue at position 6 is always Pro; and residue 11 is Glu or Asp. The induction of iNOS in human monocytes and macrophages could be involved in the cytotoxicity against tumor cell lines also elicited by these peptides.
- Activation of human T helper 1 and DNAase expression in CD4+ T cells induced by short immunomodulating peptides.(Elsevier, 1994) Lopez-Moratalla, N. (Natalia); Perez-Mediavilla, L.A. (Luis Alberto); Migliacio, M. (Marco); Santiago, E. (Esteban); Lopez-Zabalza, M.J. (María Jesús)Activation of human T helper 1 cells took place when lymphomononuclear cells from healthy donors were incubated in the presence of short synthetic peptides encompassing sequences present in extracellular matrix proteins. Active peptides conformed to a common structural pattern ("2-6-11 motif") [N.López-Moratalla et al., Biochem. Biophys. Acta (1994) 1221, 153-158] conferring immunomodulating properties. The release of IL-2 and IFN gamma, as well as LAK and NK-dependent cytotoxicity induced by these peptides, could be blocked by anti-HLA-DR antibody. Activated CD4+ cells isolated from the mixed incubated population contained secretion granules with DNAase activity. These results suggest that these immunomodulating peptides presented by HLA-II play a key role in the differentiation of CD4+ T cells towards a Th1 functional phenotype.
- Argentine plant extracts active against polymerase and ribonuclease H activities of HIV-1 reverse transcriptase(John Wiley and Sons, 1999) Ferraro, G. (Gabriela); Sanroman, M. (Marcos); Font, M. (María); Coussio, J. (Jorge); Monge, A. (Antonio); Hnatyszyn, O. (Oksana); Herrera, G. (Gilda); Martinez-Irujo, J.J. (Juan José); Martino, V.S. (Virginia S.); Santiago, E. (Esteban); Broussalis, A. (Adriana); Cuevas, M.T. (María T.); Muschietti, L. (Liliana); Lasarte, J.J. (Juan José)Lipophilic and hydrophilic extracts of four Argentine plants (Gamochaeta simplicaulis Cabr. 1, Achyrocline flaccida Wein. D. C. 2, Eupatorium buniifolium H. et A. 3, and Phyllanthus sellowianus Muell. Arg. 4) were examined in vitro for their ability to inhibit the polymerase and ribonuclease H (RNase H) activities of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) (wild and Y181C mutant types). The active extracts were also examined as inhibitors of viral replication in HLT4LacZ-1IIIB cell cultures, evaluating their cytotoxicity in parallel. Infusions 2I and 4I, among the crude extracts, showed the highest activity. These extracts were refractioned into four fractions; 2I4 and 4I4 were active as inhibitors of DNA-polymerase (wild and Y181C types) and RNase H activities. These fractions were potent as inhibitors of viral replication and were not cytotoxic. Refractionation of 2I4 yielded five new fractions, two of which, 2I4-4 and 2I4-5, showed notable activity. Refractionation of 4I4 yielded for new fractions; of these, 4I4-3 and 4I4-4 were active. The marked biological activity found in the infusion of A. flaccida and P. sellowianus makes them sufficiently attractive to be considered in the combined chemotherapy of the disease.
- Synthesis and evaluation of new Reissert analogs as HIV-1 RT inhibitors. 2. Benzo[f]quinoline and pyridine derivatives(Informa Healthcare, 1997) Borras-Cuesta, F. (Francisco); Alvarez, E. (E.); Sanmartin-Grijalba, C. (Carmen); Nadal, E. (Ernest); Font, M. (María); Prieto, I. (Inés); Monge, A. (Antonio); Martinez-Irujo, J.J. (Juan José); Sarobe, P. (Pablo); Santiago, E. (Esteban); Ruiz, I. (I); Lasarte, J.J. (Juan José)The synthesis and preliminary evaluation of new benzo[f]quinoline and pyridine derivatives, obtained by application of the Reissert method and its modifications, as HIV-1 RT inhibitors and anti-infectives are presented. The most active products against HIV-1 RT wild type are the ethyl 2-cyano-1,2-dihydrobenzo[f]quinoline-1-carboxylate 2b, propyl 2-cyano-1,2-dihydrobenzo[f]quinoline-1-carboxylate 2c, and 2-cyano-1-(2'-furoyl)-1,2-dihydrobenzo[f]quinoline 2n, which maintain their activity against the mutant type P236L, resulting inactive against the Y181C type. Using the data previously obtained by our research team for analogous series derived from quinoline as reference, the compounds which have now been obtained present an increase in the cytotoxic character attributable to the introduction of a benzene ring fused with the quinoline base nucleus, as well as a decrease of the activity as HIV-1 RT inhibitors when the quinoline benzenic ring is eliminated.
- Co-expression of inducible nitric oxide synthase and arginases in different human monocyte subsets. Apoptosis regulated by endogenous NO(Elsevier, 1999) Lopez-Moratalla, N. (Natalia); Subira, M.L. (María L.); Domingo-de-Miguel, E. (Eduardo); Rouzaut, A. (Ana); Miguel-Vázquez, C. (Carlos) de; Gonzalez-Hernandez, A. (Alvaro); Santiago, E. (Esteban)Human monocyte subsets, isolated from cultures of mononuclear cells, or freshly obtained from patients with multiple sclerosis, Graves' disease or pemphigus vulgaris, differed in phenotype, apoptotic features, mRNA levels of arginase II (A-II) and the inducible form of nitric oxide synthase (iNOS). Liver-type arginase I mRNA was present in all subsets. Apoptosis was followed by the expression of T cell intracellular antigen (TIA) and the simultaneous detection of DNA stainability by propidium iodine and annexin V binding. Apoptosis was practically absent both in activated CD14(++)CD33(++)DR(++)CD25(++)CD69(++)CD71(++/+) CD16(-) cells, expressing A-II mRNA and having arginase activity, but not iNOS mRNA, and in not fully mature large CD14(++)CD16(+)CD23(+)DR(++) monocytes, expressing simultaneously both mRNAs and having both enzyme activities. However, differentiated small CD14(+/++)CD16(+)CD69(+)CD25(+/-)CD71(++)CD23(+) DR(++) monocytes, expressing high levels of iNOS mRNA, exhibited apoptotic signs. Amounts of NO synthesised by monocytes co-expressing iNOS and arginase changed with the addition of arginine or an iNOS inhibitor; in that case a correlation of NO production and apoptotic features was observed. Data suggest a regulatory role for endogenous NO in apoptosis of stimulated and differentiated monocytes, and also that iNOS and A-II, when simultaneously present, could control the production of NO as a consequence of their competition for arginine.
- Immunomodulation induced by synthetic peptides derived from Staphylococcus aureus protein A(Elsevier, 1994) Lopez-Moratalla, N. (Natalia); Subira, M.L. (María L.); Perez-Mediavilla, L.A. (Luis Alberto); Borras-Cuesta, F. (Francisco); Santiago, E. (Esteban); Lopez-Zabalza, M.J. (María Jesús)Peptides from 10 to 22 amino acids containing sequences encompassed by Staphylococcus aureus protein A were synthesized. Some of these peptides, when present in cultures of lymphomononuclear cells from healthy donors or from cancer patients (melanoma, breast carcinoma, non-Hodgkin lymphoma and renal cell carcinoma) promoted: (i) changes in the phenotype of the lymphomononuclear population, (ii) stimulation of monocytes (release of IL-1 and TNF-alpha), and (iii) an increase in cytotoxicity against K562, Daudi and HT-29 cells. Isolated monocytes responded also to those peptides with a release of IL-1 and TNF alpha and an increase of cytotoxicity against HT-29 cells. It was found that the active peptides had the following structural pattern: a length of at least 15 amino-acid residues with a proline at position 6, valine, leucine, isoleucine, glycine, alanine or lysine at position 2, and glutamic or aspartic acid at position 11. Replacement of Pro at position 6 with any other residue turned the peptide inactive. Replacement of residues at positions 2 and 11 with amino-acid residues other than those required for activity resulted in compounds with a marked decrease in the immunomodulating properties described, or lacking these properties altogether.
- Synthesis and anti-HIV-1 activities of new pyrimido[5,4-b]indoles(Elsevier, 1999) Merino, I. (Isidro); Alberdi, E. (Elena); Borras-Cuesta, F. (Francisco); Font, M. (María); Monge, A. (Antonio); Prieto, I. (Isidro); Sarobe, P. (Pablo); Santiago, E. (Esteban); Martinez-de-Irujo, J.J. (Juan José); Lasarte, J.J. (Juan José)A set of new pyrimido[5,4-b]indole derivatives that are structurally related to some non-nucleside HIV-1 reverse transcriptase inhibitors were synthesized and biologically evaluated for their activity as inhibitors of wild and mutant HIV-1 RT types in an 'in vitro' recombinant HIV-1 RT screening assay, as well as anti-infectives in HLT4lacZ-1IIIB cells. Preliminary structure-activity relationships suggest that activity is promoted by simultaneous substitution in positions 2 and 4, especially when chains of alkyldiamine type are present, and by electron-releasing substituents (methoxy) in positions 7 and 8. The inactivity or the very low activity of title derivatives does not suggest interest in AIDS therapy.
- Inducible nitric oxide synthase in monocytes from patients with Graves' disease(Elsevier, 1996) Lopez-Moratalla, N. (Natalia); Perez-Mediavilla, L.A. (Luis Alberto); Aymerich-Soler, M.S. (María Soledad); Gonzalez-Hernandez, A. (Alvaro); Burrell, M.A. (María Ángela); Santiago, E. (Esteban); Calleja, A. (Amparo)The presence of inducible nitric oxide synthase (iNOS) in fresh monocytes from patients with Graves' disease was demonstrated for the first time. Immunophenotypic analysis showed a profile reflecting a state of activation and differentiation of monocytes. Incubation of lymphomononuclear cells from healthy volunteers in the presence of synthetic peptides with sequences related to thyroid autoantigens (TSH receptor, thyroid peroxidase, or thyroglobulin) led to a stimulation of monocytes manifested by a change in phenotype and expression of iNOS. This expression did not take place on isolated monocytes, unless products associated with Th1 activity were present in the medium. Active peptides contained a characteristic "2-6-11" motif already described [López-Moratalla et al. (1995) Biochim. Biophys. Acta 1265, 181-188]. These results are suggestive of a new role for autoantigens in the pathogenesis of Graves' disease: that of inducing the expression of iNOS and activating the monocyte possibly underlying the autoimmune response.
- Synthesis and evaluation of new Reissert analogs as HIV-1 reverse transcriptase inhibitors. 1. Quinoline and quinoxaline derivatives(Gordon and Breach, 1997) Merino, I. (Isidro); Cuartero, A. (A); Alberdi, E. (Elena); Borras-Cuesta, F. (Francisco); Fidalgo, M.J. (M. J.); Alvarez, E. (E.); Sanmartin-Grijalba, C. (Carmen); Nadal, E. (Ernest); Font, M. (María); Prieto, I. (Inés); Losa, M.J. (M.J.); Monge, A. (Antonio); Martinez-Irujo, J.J. (Juan José); Sarobe, P. (Pablo); Santiago, E. (Esteban); Ruiz, I. (I); Lasarte, J.J. (Juan José)The synthesis and preliminary evaluation of new quinoline and quinoxaline derivatives (obtained by applying the original Reissert method, conveniently modified) as HIV-1 Reverse Transcriptase (RT) inhibitors are presented in this paper; likewise, the first structure-activity relationships are also proposed. Propyl 2-cyano-1(2H)-quinolin-carboxylate 2e, isopropyl 2-cyano-1 (2H)-quinolincarboxylate 2f, butyl 2-cyano-1 (2H)-quinolincarboxylate 2g and isobutyl 2-cyano-1 (2H)-quinolincarboxylate 2h have been selected as lead compounds. These compounds are active against the HIV-1 RT mutant type P236L (2f, IC50 = 1.2 microM) and present activity as anti-infective agents in HLT41acZ-1IIIB cells, showing no cytotoxicity at the active concentrations.