Biomedical subjects

Maria Vittoria Verga Falzacappa

Publications and source records attributed to Maria Vittoria Verga Falzacappa.

6 recordsLinked to original sources

PubMed2006

STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation.

Hepcidin is a key iron-regulatory hormone produced by the liver. Inappropriately low hepcidin levels cause iron overload, while increased hepcidin expression plays an important role in the anemia of inflammation (AI) by restricting intestinal iron absorption and macrophage iron release. Its expression is modulated in response to body iron stores, hypoxia, and inflammatory and infectious stimuli involving at least in part cytokines secreted by macrophages. In this study we established and characterized IL6-mediated hepcidin activation in the human liver cell line Huh7. We show that the proximal 165 bp of the hepcidin promoter is critical for hepcidin activation in response to exogenously administered IL6 or to conditioned medium from the monocyte/macrophage cell line THP-1. Importantly, we show that hepcidin activation by these stimuli requires a STAT3 binding motif located at position -64/-72 of the promoter. The same STAT binding site is also required for high basal-level hepcidin mRNA expression under control culture conditions, and siRNA-mediated RNA knockdown of STAT3 strongly reduces hepcidin mRNA expression. These results identify a missing link in the acute-phase activation of hepcidin and establish STAT3 as a key effector of baseline hepcidin expression and during inflammatory conditions.

Acute-Phase Reaction↗

PubMed2006

Solid-phase synthesis, characterization, and antibacterial activities of metallocene-peptide bioconjugates.

This work shows how the introduction of an organometallic group enhances and modifies the specificity of biologically active peptides. Ferrocene was chosen as an organometallic group because it has been shown to alter the pharmacodynamic profile of bioactive compounds. A comparison with the isosteric cobaltocenium group allows one to explore the influence of charge and redox potential on the biological activity of the conjugates. Arginine and tryptophan containing peptides H-WRWRWR-NH(2) and H-RWRWRW-NH(2) and the metallocene peptide bioconjugates [M]-C(O)-RWRWR-NH(2) and [M]-C(O)-WRWRW-NH(2), where [M]=[Co(Cp)(C(5)H(4))](+), [Fe(Cp)(C(5)H(4))] were prepared by solid-phase peptide synthesis (SPPS). They were purified by HPLC, characterized by ESIMS and NMR spectroscopy, and tested for antibacterial properties against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus using the minimum inhibitory concentration (MIC) test. In most cases, no metal-specific activity could be observed. However, the conjugate [Fe(Cp)(C(5)H(4))-C(O)-WRWRW-NH(2)] 6 was found to be particularly effective against the Gram-positive S. aureus. The activity of this metallocene-pentapeptide conjugate (7.1 microM) was even better than the 20 amino acid naturally occurring pilosulin 2, which was used as a positive control. Unlike all other compounds tested, which were most active against the Gram-negative E. coli strain, the ferrocene conjugate 6 was the only compound in this series that was most active against Gram-positive bacteria. Given the health concerns resulting from multidrug resistant S. aureus strains, the incorporation of metallocenes may provide a novel line of attack.

Amino Acid Sequence↗

PubMed2005

Hepcidin: iron-hormone and anti-microbial peptide.

Hepcidin is a beta-defensin-like peptide and a principle regulator of systemic iron homeostasis. In concordance with this dual function its expression is modulated by systemic iron requirements and in response to infectious and inflammatory stimuli. Studies of hepcidin provide novel insight into the molecular mechanisms involved in maintaining iron homeostasis in the healthy state and iron redistribution in response to chronic infections and inflammation. Furthermore, a deregulation of hepcidin may cause elevated intestinal iron absorption that hallmarks a group of frequent iron overload disorders, the Hereditary Hemochromatosis. The aim of this review is to discuss hepcidin function in iron-homeostasis under normal physiological and pathophysiological conditions.

Amino Acid Sequence↗

PubMed2005

Primate beta-defensins--structure, function and evolution.

Host defense peptides (HDPs) are endogenous antibiotics that play a multifunctional role in the innate immunity of mammals. Among these, beta-defensins contribute to mucosal and epithelial defense, also acting as signal molecules for cellular components of innate and adaptive immunity. Numerous members of this family have been identified in mammalian and avian species, and genomic studies in human and mouse indicate a considerable complexity in their gene organization. Recent reports on the evolution of primate and rodent members of this family indicate quite a complex pattern of variation. In this review we briefly discuss the evolution of mammalian beta-defensins in relation to other types of defensins, and then concentrate on the evolution of beta-defensins 1 to 4 in primates. In particular, the surprisingly varied patterns of evolution, which range from neutral or weakly purifying, to positive selection to a high level of conservation are analyzed in terms of possible genetics, structural or functional implications, as well as to observed variations on the antimicrobial activity in vitro. The role of polymorphisms in the genes encoding for these host defense peptides in determining susceptibility to human diseases are also briefly considered.

Amino Acid Sequence↗

PubMed2004

Effects of positively selected sequence variations in human and Macaca fascicularis beta-defensins 2 on antimicrobial activity.

The evolution of orthologous genes coding for beta-defensin 2 (BD2) in primates has been subject to positive selection during the divergence of the platyrrhines from the catarrhines and of the Cercopithecidae from the Hylobatidae, great apes, and humans. Three peptides have been selected for a functional analysis of the effects of sequence variations on the direct antimicrobial activity: human BD2 (hBD2), Macaca fascicularis BD2 (mfaBD2), and a variant of the human peptide lacking Asp(4), (-D)hBD2, which is characteristic only of the human/great ape peptides. hBD2 and mfaBD2 showed a significant difference in specificity, the former being more active towards Escherichia coli and the later towards Staphylococcus aureus and Candida albicans. Asp(4) in the human peptide appears to be important, as (-D)hBD2 was less structured and had a markedly lower antimicrobial activity. The evolution of beta-defensin 2 in primates may thus have been driven, at least in part, by different environmental pressures so as to modulate antimicrobial activity.

Amino Acid Sequence↗

PubMed2003

A study of host defence peptide beta-defensin 3 in primates.

We have investigated the molecular evolution of the gene coding for beta-defensin 3 (DEFB103) in 17 primate species including humans. Unlike the DEFB4 genes (coding for beta-defensin 2) [Boniotto, Tossi, Del Pero, Sgubin, Antcheva, Santon and Masters (2003) Genes Immun. 4, 251-257], DEFB103 shows a marked degree of conservation in humans, Great Apes and New and Old World monkeys. Only the Hylobates concolor defensin hcBD3 showed an amino acid variation Arg17-->Trp17 that could have a functional implication, as it disrupts an intramolecular salt bridge with Glu27, which locally decreases the charge and may favour dimerization in the human congener hBD3. This is thought to involve the formation of an intermolecular salt bridge between Glu28 and Lys32 on another monomer [Schibli, Hunter, Aseyev, Starner, Wiencek, McCray, Tack and Vogel (2002) J. Biol. Chem. 277, 8279-8289]. To test the role of dimerization in mediating biological activity, we synthesized hBD3, hcBD3 and an artificial peptide in which the Lys26-Glu27-Glu28 stretch was replaced by the equivalent Phe-Thr-Lys stretch from human beta-defensin 1 and we characterized their structure and anti-microbial activity. Although the structuring and dimerization of these peptides were found to differ significantly, this did not appear to affect markedly the anti-microbial potency, the broad spectrum of activity or the insensitivity of the anti-microbial action to the salinity of the medium.

Amino Acid Sequence↗