Biomedical subjects

Marta Carretero

Publications and source records attributed to Marta Carretero.

7 recordsLinked to original sources

PubMed2004

Hepatitis C virus core protein regulates p300/CBP co-activation function. Possible role in the regulation of NF-AT1 transcriptional activity.

Hepatitis C virus (HCV) core is a viral structural protein; it also participates in some cellular processes, including transcriptional regulation. However, the mechanisms of core-mediated transcriptional regulation remain poorly understood. Oncogenic virus proteins often target p300/CBP, a known co-activator of a wide variety of transcription factors, to regulate the expression of cellular and viral genes. Here we demonstrate, for the first time, that HCV core protein interacts with p300/CBP and enhances both its acetyl-transferase and transcriptional activities. In addition, we demonstrate that nuclear core protein activates the NH2-terminal transcription activation domain (TAD) of NF-AT1 in a p300/CBP-dependent manner. We propose a model in which core protein regulates the co-activation function of p300/CBP and activates NF-AT1, and probably other p300/CBP-regulated transcription factors, by a novel mechanism involving the regulation of the acetylation state of histones and/or components of the transcriptional machinery.

Acetylation↗

PubMed2004

A cutaneous gene therapy approach to treat infection through keratinocyte-targeted overexpression of antimicrobial peptides.

Infection represents a major associated problem in severely burned patients, as it causes skin graft failure and increases the risk of mortality. Topical and systemic antibiotic treatment is limited by the appearance of resistant bacterial strains. Antimicrobial peptides (AMPs) are gene-encoded "natural antibiotics" that form part of the innate mechanism of defense and may be active against such antibiotic-resistant microorganisms. Several microbicidal peptides are expressed in human skin under inflammatory conditions, and their function is not only limited to microbial killing but also influences tissue repair and adaptive immunity. Protein delivery through cutaneous gene therapy is a promising therapeutic tool for both skin and nonskin diseases. Here we present a gene transfer approach aimed at delivering antimicrobial peptides from keratinocytes. Adenoviral vectors encoding antimicrobial peptide genes were used to infect human keratinocytes growing either on plastic or as part of cultured skin equivalents. Inhibition of bacterial growth occurred both in conditioned media and in direct contact with AMPs gene-transduced keratinocytes. In addition, we showed cooperative effects after transfer of combinations of genes encoding for AMPs with structural differences. Combined cutaneous tissue engineering in conjunction with (microbicidal) gene therapy emerges as a tailored therapeutic approach that is useful for wound coverage and, in this case, concomitantly combating infection.

Adenoviridae↗

PubMed2004

Inhibition of xenografted human melanoma growth and prevention of metastasis development by dual antiangiogenic/antitumor activities of pigment epithelium-derived factor.

Human melanoma mortality is associated with the growth of metastasis in selected organs including the lungs, liver, and brain. In this study, we examined the consequences of overexpression of pigment epithelium-derived factor (PEDF), a neurotrophic factor and potent angiogenesis inhibitor, on both melanoma primary tumor growth and metastasis development. PEDF overexpression by melanoma cells greatly inhibited subcutaneous tumor formation and completely prevented lung and liver metastasis in immunocompromised mice after tail vein injection of metastatic human melanoma cell lines. Whereas the effects of PEDF on primary tumor xenografts appear mostly associated with inhibition of the angiogenic tumor response, abrogation of melanoma metastasis appears to depend on direct PEDF effects on both migration and survival of melanoma cells. PEDF-mediated inhibition of melanoma metastases could thus have a major impact on existing therapies for melanoma.

Animals↗

PubMed2004

Decrease of the platelet 5-HT2A receptor function by long-term imipramine treatment in endogenous depression.

BACKGROUND: Animal studies have found that many antidepressants induce decreases in both the density and the functional activity of the serotonin 2A (5-HT2A) receptor subtype. However, the extrapolation of findings to humans has been inconclusive. A physiological platelet response mediated by this receptor, the serotonin-amplified platelet aggregation, was measured to study whether long-term antidepressant treatment induces changes in 5-HT2A receptor functioning in endogenous depressed patients. METHOD: The percentage of serotonin-amplified platelet aggregation to adenosine diphosphate (ADP) was studied in 15 untreated patients with major depressive disorder (DSM-IV) with endogenous features (Newcastle scale). This index was used as an indirect measurement of the functional status of platelet 5-HT2A receptors. Aggregation studies were repeated once remission of the symptoms was achieved during treatment with imipramine (150-300 mg/day). A group of 15 concurrent normal subjects was used as a control. RESULTS: A statistically significant decrease (p = 0.038) in the percentage of serotonin-amplified platelet aggregation to ADP was observed when remission was achieved (after 145 +/- 27 days). CONCLUSIONS: The results showed a decrease in a platelet functional response mediated by 5-HT2A receptors following effective imipramine treatment, suggesting that desensitization or down-regulation of the 5-HT2A receptor function could be linked to the therapeutic effect of some antidepressants. The data also support the use of platelet aggregometry as a surrogate measurement of antidepressant action, particularly in intra-subject designs.

Adult↗

PubMed2002

The hepatitis B virus X protein binds to and activates the NH(2)-terminal trans-activation domain of nuclear factor of activated T cells-1.

We have previously reported that the hepatitis B virus X protein (HBx) activates nuclear factor of activated T cells (NF-AT), a key regulator of the immune system, by a calcium/calcineurin-dependent pathway, involving dephosphorylation and nuclear translocation of this transcription factor. In addition, we showed that HBx synergizes with potent calcium-mobilizing stimuli to activate NF-AT-dependent transcription, suggesting that additional mechanisms might also be operative in the activation of NF-AT by HBx. Here we demonstrate that HBx activates the NH(2)-terminal transcription activation domain (TAD) of NF-AT1 by a mechanism involving protein-protein interaction. Targeting of HBx to the nucleus did not affect its ability to induce the transcriptional activity of NF-AT1. In contrast, mutations of HBx affecting its functional interaction with general transcription factors abrogated the HBx-induced activity of NF-AT1. Together these results indicate that HBx may exert its function by acting as a nuclear coactivator of NF-AT1.

Binding Sites↗

PubMed2002

Platelet 5-HT2A-receptor-mediated induction of aggregation is not altered in major depression.

BACKGROUND: Studies of the 5-HT(2A) receptor subtype in major depression have focused on the density of these receptors in neuronal cells and platelets, showing an up-regulation secondary to a deficit in serotonergic activity in major depression. However, their functional state has often been disregarded. The aim of the study was to investigate whether depressed patients show abnormalities in the function of the 5-HT(2A) receptor pathway in platelets. METHOD: The percentage of serotonin-amplified platelet aggregation to adenosine diphosphate (ADP) was assessed in 30 untreated patients with major depressive disorder and in 15 controls. Since 5-HT(2A) platelet receptors mediate the serotonin-induced platelet aggregation response, this index was used as a measure of the functional status of the platelet 5-HT(2A) receptor pathway. RESULTS: There was no significant difference in the percentage of serotonin-amplified platelet aggregation to ADP between depressed patients and controls. No correlation with the severity of depression, as assessed by the Hamilton scale, was found. CONCLUSION: The results showed no consistent changes in the platelet aggregating responses to serotonin in the depressed patients. Therefore this study does not support the hypothesis of an alteration of the functional status of platelet 5-HT(2A) receptors in major depression.

Adenosine Diphosphate↗

PubMed2002

Platelet adhesion onto a polystyrene surface under static conditions: role of specific platelet receptors and effect of divalent cations.

An experimental model was used to elucidate the basic mechanisms involved in the interaction of platelets with an artificial surface. The role of divalent cations and the involvement of specific platelet membrane receptors were evaluated. Isolated platelets were allowed to interact with a polystyrene surface for 20 min in the presence of divalent cations (Ca2+, Mg2+ or Zn2+), a chelating agent (ethylenediaminetetraacetic, EDTA), and specific antibodies to the main platelet receptors, glycoproteins (GP) Ib and IIb-IIIa. The degree of platelet interaction was evaluated using light and electron microscopy. Morphometric analysis was performed to follow up the progression of platelet shape changes after surface activation. Neither Ca2+ nor Mg2+ influenced the number of adherent platelets or the degree of spreading on the polymer. Only Zn2+ induced a statistically significant increase in the rate of platelet adhesion (P<0.01) with higher proportion of fully spread platelets (P<0.01). Chelation of internal pools of divalent cations did not modify the rates of platelet adhesion but prevented platelet spreading. Presence of monoclonal antibodies to GPIb and GP IIb-IIIa did not result in significant differences in the studied parameters. These results suggest that platelet adhesion onto artificial surfaces, in the absence of flow and plasma proteins, is more dependent on cellular motility, where Zn2+ could play an important role, and less dependent on major receptorial mechanisms.

Antibodies, Monoclonal↗