196,304 research outputs found

    Solubility improvement of an anthrax toxin peptide inhibitor by rational aminoacid randomization

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    We previously described a potent anthrax toxin inhibitor, based on a phage-library-selected peptide sequence, synthesized as a tetra-branched molecule on a lysine core and further modified for improvement of activity [Pini et al., Biochem. J., 2006, 395, 157]. This branched peptide had very low solubility because of several hydrophobic residues in the peptide sequence. This complicated molecule purification and manufacturing. Here we report a rational modification of the peptide sequence, obtained by construction and selection of several mini libraries of branched peptides, containing sequences randomized in non crucial positions of the original peptide. Mini libraries were screened for solubility and inhibitory activity. This procedure enabled us to obtain a new peptide with a better solubility and identical inhibitory activity

    Branched multimeric peptides for tumor diagnosis and therapy

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    The instant invention refers to in vivo stable branched peptides, in particular derived from the sequence of Neurotensin (NT) and Luteinizing hormone-releasing hormone (LHRH), conjugated to functional units for specific targeting of cancer cells, either for tumor diagnosis or therapy

    Interferons induce xanthine dehydrogenase gene expression in L929 cells

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    : Human interferon-alpha A/D (Bg/II) (IFN-alpha A/D) and mouse interferon-gamma (IFN-gamma) are shown to induce xanthine dehydrogenase (XD) mRNA in L929 fibroblastic cells. XD mRNA accumulation after IFN-alpha A/D treatment is relatively fast, being already evident after 4 h and reaching its maximum after 24 h. IFN-alpha A/D is active in inducing XD mRNA at 0.1 unit/ml and it is maximally active at 10(3) units/ml. The half-life of the XD message is unaffected by IFN-alpha A/D treatment, whereas the transcriptional activity of the XD gene and the concentrations of XD heterogeneous nuclear RNA are increased by 2- and 6-fold respectively. The effect of IFN-alpha A/D on XD mRNA is insensitive to cycloheximide, suggesting that protein synthesis de novo is not required. Experiments conducted with specific inhibitors suggest that protein kinase C, cyclic AMP and arachidonic acid metabolites derived from lipoxygenase or cyclooxygenase do not act as second-messenger molecules in the induction of XD mRNA by IFN-alpha A/D. XD mRNA is also induced in NIH3T3 fibroblastic cells, but not in F9 teratocarcinoma or B16 melanoma cells after treatment with IFN-alpha A/D. NIH3T3 are the only cells so far tested that have detectable XD and xanthine oxidase activities under basal conditions and after IFN-alpha A/D treatment, although their responsiveness to the cytokine is much less than that observed in L929 cells

    Venous Thromboembolism Prevention in Patients with Heart Failure: An Often Neglected Issue

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    Several epidemiological studies have shown a high prevalence of venous thromboembolism (VTE) complications in patients with acute heart failure; in addition, the level of risk associated with this disease is notable, ranging from 15 to 30%. Three large clinical trials have clearly demonstrated the efficacy and safety of pharmacological prophylaxis in internal medicine patients hospitalized for an acute medical disease; on the contrary, until now there are no studies which have evaluated antithrombotic prophylaxis in a selected population of patients with heart failure only. Moreover, discrepancies existing among recommendations reported in different guidelines may produce uncertainties in the management of VTE prevention in patients with heart failure and may contribute to an underuse of thromboprophylaxis in the daily clinical practice. The aim of this review is to analyze the existing evidence about VTE risk in patients with heart failure as well as the efficacy and safety of antithrombotic prevention, and to underline which are the most important unmet clinical issues for the optimal management of thromboprophylaxis in this particular clinical setting. Copyright (C) 2009 S. Karger AG, Base

    Endothelin-1 and bronchial hyperresponsiveness in the rabbit.

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    Endothelins (ETs) are a family of peptide mediators that have a number of biological properties, including the ability to act as potent bronchoconstrictors of isolated human airways. Moreover, elevated concentrations of ET-1 in the bronchoalveolar lavage fluid from patients with symptomatic asthma have also been detected. We investigated the possible contribution of ET-1 in the development of bronchial hyperresponsiveness and the role of inflammatory cell accumulation in rabbit lungs. Our data show that ET-1 challenge to rabbits does not modify basal lung function but results in an increased airway responsiveness to inhaled histamine. Endothelin-treated rabbits were 3-fold (P<0.01) more responsive to inhaled histamine when compared with vehicle-treated rabbits. This hyperresponsiveness was not associated with an alteration in either total or differential inflammatory cell numbers as assessed by bronchoalveolar lavage (BAL). Pre-treatment with capsaicin (80 mg/kg s.c.) did not alter basal lung function or basal responsiveness to inhaled histamine. While capsaicin had no significant effect on the acute bronchoconstriction induced by endothelin-1, this dose was sufficient to significantly inhibit the increase in airway responsiveness to inhaled histamine, achieved 24 h following endothelin-1 challenge. These results indicate that ET-1 may play a role in the development of bronchial hyperresponsiveness to inhaled histamine and that the maintenance of this state is unrelated to a detectable alteration in cellular infiltration within the airway lumen, but probably via the involvement of capsaicin-sensitive nerves
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