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Biomedical subjects

M Delgado

Publications and source records attributed to M Delgado.

At least 37 records · Page 2Linked to original sources
PubMed2003

Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: players in innate and adaptive immunity.

Recent reports identified and described neural pathways, both hard-wiring and soluble mediators, that control and adjust the peripheral immune response. Immune organs are innervated by fibers rich in neurotransmitters and neuropeptides released in inflammatory conditions. Here we focus on the immunomodulatory role of two peptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP). VIP/PACAP are present and released from both innervation and immune cells, particularly Th2 cells, and immune cells express receptors for VIP/PACAP. VIP/PACAP have a general anti-inflammatory effect, both in innate and adaptive immunity. In innate immunity, VIP/PACAP inhibit the production of pro-inflammatory cytokines and chemokines from macrophages, microglia and dendritic cells. In addition, VIP/PACAP reduce the expression of costimulatory molecules (particularly CD80 and CD86) on the antigen-presenting cells, and therefore reduce stimulation of antigen-specific CD4+ T cells. In terms of adaptive immunity, VIP/PACAP promote Th2-type responses, and reduce the pro-inflammatory Th1-type responses. Several of the molecular mechanisms involved in the inhibition of cytokine and chemokine expression, and in the preferential development and/or survival of Th2 effects, are discussed.

Adenylyl Cyclases↗
PubMed2002

MRI shows abnormal white matter maturation in classical holoprosencephaly.

In an attempt to assess white matter maturation in holoprosencephaly (HPE), MRI scans of 47 patients with HPE were retrospectively reviewed. White matter maturation was delayed in 25/47 patients, including 24/29 patients with classic HPE who were </=12 months old at the time of imaging. Of interest, all six patients with the middle interhemispheric (MIH) variant of HPE had normal myelination, regardless of age. This study provides further evidence that the classic and MIH variants of HPE have different underlying causes.

Adolescent↗
PubMed2002

Smoking as a risk factor for preinvasive and invasive cervical lesions in female sex workers in Venezuela.

OBJECTIVES: To determine whether the number of cigarettes smoked per day and years of smoking were risk factors for preinvasive and invasive cervical lesions in Venezuelan female sex workers. METHODS: The clinical history of 438 female sex workers (FSWs) was taken and each received a gynecological examination, a Pap smear, and a colposcopic examination. A colposcopically-guided cervical biopsy was taken when the epithelium appeared abnormal. RESULTS: The FSWs' mean age was 32.16+/-8 years. Age at first sexual intercourse was 15.9+/-2 years, parity was 4.1+/-2.3, live births were 3+/-3, and age at first delivery was 16.6+/-4.7 years. Cervical biopsies were performed in 84 FSWs. Sixty-four of them (76.2%) had preinvasive or invasive lesions and 47 (73.4%) were current smokers (Relative Risk) (RR), 1.26; 95% confidence interval (CI), 1.02-1.55; P<0.03]. FSWs who smoked more than 20 cigarettes per day had an increased RR to get a premalignant or malignant cervical lesion (RR, 1.27; 95% CI, 1.02-1.52; P<0.03). There was no statistically significant difference between FSWs who smoked 20 cigarettes or more per day and FSWs who smoked less than 20 cigarettes per day (RR, 1.36; 95% CI, 0.81-2.29; P<0.25). FSWs who had been smoking for 5 years or more were at risk to develop preinvasive or invasive cervical lesions (RR, 1.37; 95% CI, 1.01-1.86; P<0.04). CONCLUSIONS: The risk for FSWs to develop preinvasive or invasive cervical lesions increased with the number of cigarettes they smoked per day and their years of smoking.

Adolescent↗
PubMed2001

Vasoactive intestinal peptide in the immune system: potential therapeutic role in inflammatory and autoimmune diseases.

Vasoactive intestinal peptide (VIP), a neuropeptide that is produced by lymphoid as well as neural cells, exerts a wide spectrum of immunological functions, controlling the homeostasis of the immune system through different receptors expressed in various immunocompetent cells. In the last decade, VIP has been clearly identified as a potent anti-inflammatory factor, which acts by regulating the production of both anti- and pro-inflammatory mediators. In this sense, VIP has been described to prevent death by septic shock, an acute inflammatory disease with a high mortality. In addition, VIP regulates the expression of co-stimulatory molecules, this being an action that may be related to modulating the shift toward Th1 and Th2 differentiation. We have recently reported that VIP prevents the deleterious effects of an experimental model of rheumatoid arthritis, by downregulating both inflammatory and autoimmune components of the disease. Therefore, VIP has been proposed as a promising candidate alternative treatment for acute and chronic inflammatory and autoimmune diseases such as septic shock, arthritis, multiple sclerosis, Crohn disease, or autoimmune diabetes.

Animals↗
PubMed2001

Immunisation with phage-displayed variable region 2 from meningococcal PorA outer membrane protein induces bactericidal antibodies against Neisseria meningitidis.

The immunogenicity and functional activity of antibodies raised in mice against the cyclic disulphide peptide corresponding to the variable region 2 of PorA outer membrane protein from Neisseria meningitidis strain B385 (serosubtype P1.15), displayed on filamentous phage, were evaluated. The epitope, flanked either by cysteine or cysteine and three glycine residues, was expressed as a fusion to PVIII protein from M13. Immunisation of Balb/C mice with either phage generated antibody specific responses. Sera raised against the phage exposing the cyclic peptide through the three-glycine linker recognised the native protein better than those raised against the peptide with no linker. Only the phage displaying the cyclic peptide with linker was capable of inducing antibodies with bactericidal activity. These results indicate the possibility of using phage display for conformational peptide expression for immunisation to elicit functional antibody responses.

Adjuvants, Immunologic↗
PubMed2001

Pituitary adenylate cyclase-activating polypeptide inhibits collagen-induced arthritis: an experimental immunomodulatory therapy.

Rheumatoid arthritis is a chronic, systemic, autoimmune, and inflammatory disorder that affects the synovial lining of the joints. We describe the beneficial effects of the pituitary adenylate cyclase-activating polypeptide (PACAP) in the collagen-induced arthritis experimental murine model being proposed as a novel therapeutic approach in the treatment of rheumatoid arthritis. PACAP greatly decreases arthritis frequency and severity in the studied mice by improving clinical symptoms, ameliorating joint damage, and blocking both the inflammatory and autoimmune mediators which are the main keys of the pathogenesis of this disease. With this study, PACAP emerges as a promising candidate for the treatment of a pathology with a high world incidence but currently no effective treatment.

Adjuvants, Immunologic↗
PubMed2001

Antibacterial agents based on the cyclic D,L-alpha-peptide architecture.

The rapid emergence of bacterial infections that are resistant to many drugs underscores the need for new therapeutic agents. Here we report that six- and eight-residue cyclic d,l-alpha-peptides act preferentially on Gram-positive and/or Gram-negative bacterial membranes compared to mammalian cells, increase membrane permeability, collapse transmembrane ion potentials, and cause rapid cell death. The effectiveness of this class of materials as selective antibacterial agents is highlighted by the high efficacy observed against lethal methicillin-resistant Staphylococcus aureus infections in mice. Cyclic d,l-alpha-peptides are proteolytically stable, easy to synthesize, and can be derived from a potentially vast membrane-active sequence space. The unique abiotic structure of the cyclic peptides and their quick bactericidal action may also contribute to limit temporal acquirement of drug resistant bacteria. The low molecular weight d,l-alpha-peptides offer an attractive complement to the current arsenal of naturally derived antibiotics, and hold considerable potential in combating a variety of existing and emerging infectious diseases.

Animals↗
PubMed2001

Inhibition of endotoxin-induced macrophage chemokine production by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide in vitro and in vivo.

Inflammatory chemokines recruit various populations of immune cells that initiate and maintain the inflammatory response against foreign Ags. Although such a response is necessary for the elimination of the Ag, the inflammation has to be eventually resolved in a healthy organism. Neuropeptides such as vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP), released after antigenic stimulation, contribute to the termination of an inflammatory response primarily by inhibiting the production of proinflammatory cytokines. Here we investigated the effects of VIP and PACAP on chemokine production. We report that VIP and PACAP inhibit the expression of the macrophage-derived CXC chemokines macrophage inflammatory protein-2 and KC (IL-8), and of the CC chemokines MIP-1alpha, MIP-1beta, monocyte chemoattractant protein 1, and RANTES in vivo and in vitro. The inhibition of chemokine gene expression correlates with an inhibitory effect of VIP/PACAP on NF-kappaB binding and transactivating activity. The VIP/PACAP inhibition of both chemokine production and of NF-kappaB binding and transactivating activity is mediated through the specific VIP receptor VPAC1, and involves both cAMP-dependent and -independent intracellular pathways. In an in vivo model of acute peritonitis, the inhibition of chemokine production by VIP/PACAP leads to a significant reduction in the recruitment of polymorphonuclear cells, macrophages, and lymphocytes into the peritoneal cavity. These findings support the proposed role of VIP and PACAP as key endogenous anti-inflammatory agents and describe a novel mechanism, i.e., the inhibition of the production of macrophage-derived chemokines.

Acute Disease↗
PubMed2001

Immunogenicity of recombinant class 1 protein from Neisseria meningitidis refolded into phospholipid vesicles and detergent.

The possibility of eliciting bactericidal antibodies against a recombinant class 1 protein (P1) from Neisseria meningitidis, joined to the first 45 amino acids of the neisserial LpdA protein (PM82), was examined. P1 was produced in Escherichia coli as intracellular inclusion bodies, from which it was purified and reconstituted by (a) inclusion into phospholipid vesicles and detergent and (b) refolding in 0.1% SDS. When Balb/c mice were immunised, high titres of subtype-specific bactericidal antibodies against P1 were obtained in both cases. These results suggest that in spite of being a denaturing agent, it is possible to use SDS to reconstitute the P1 protein in a conformation that exposes the immunodominat regions.

Animals↗
PubMed2001

Cutting edge: is vasoactive intestinal peptide a type 2 cytokine?

A component of the chemical language shared by the immune and nervous system is the expression of neuropeptides by immune cells. Vasoactive intestinal peptide (VIP) was shown to be produced by T lymphocytes. Here we investigate whether T cell subsets differentially express VIP. Our studies indicate that, upon specific Ag stimulation, Th2 and T2 cells, but not Th1 and T1 cells derived from TCR transgenic (Tg) mice, express VIP mRNA and protein, and secrete VIP. Following immunization with the specific Ag, significant levels of VIP are present in the serum of syngeneic, non-Tg hosts that receive Th2, but not Th1 Tg cells. Th2 Tg cells recovered from the non-Tg hosts immunized with the specific Ag, but not with an irrelevant Ag, express intracellular VIP. Because VIP is produced by Ag-stimulated type 2 T cells, and differentially affects Th1 and Th2 cells, could VIP be viewed as a type 2 cytokine?

Adoptive Transfer↗
PubMed2001

Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit expression of Fas ligand in activated T lymphocytes by regulating c-Myc, NF-kappa B, NF-AT, and early growth factors 2/3.

Activation-induced cell death in T cells, a major mechanism for limiting an ongoing immune response, is initiated by Ag reengagement and mediated through Fas/Fas ligand interactions. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP), two multifunctional neuropeptides, modulate innate and adaptive immunity. We reported previously that VIP/PACAP protect T cells from activation-induced cell death through down-regulation of Fas ligand (FasL). In this study, we investigate the molecular mechanisms involved in the protective effect of VIP and PACAP. VIP/PACAP reduce in a dose-dependent manner anti-CD3-induced apoptosis in 2B4.11 T cell hybridomas. The protective effect is mediated through the specific type 2 VIP receptor, and the cAMP/protein kinase A pathway. A functional study demonstrates that VIP/PACAP inhibit activation-induced FasL expression. VIP/PACAP inhibit the expression and/or DNA-binding activity of several transcriptional factors involved in FasL expression, i.e., c-myc, NF-kappaB, NF-ATp, and early growth factors (Egr) 2/3. The inhibition of NF-kappaB binding is due to the stabilization of I-kappaB (inhibitory protein that dissociates from NF-kappaB), through the inhibition of I-kappaB kinase alpha activity. Subsequently, p65 nuclear translocation is significantly reduced. The inhibition in NF-ATp binding results from a calcineurin-independent reduction in NF-ATp nuclear translocation. VIP/PACAP inhibit the expression of Egr2 and 3, but not of Egr1. The effects on the transcriptional factors are mediated through type 2 VIP receptor with cAMP as secondary messenger.

Active Transport, Cell Nucleus↗
PubMed2001

Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit nuclear factor-kappa B-dependent gene activation at multiple levels in the human monocytic cell line THP-1.

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) suppress monocyte/macrophage production of proinflammatory agents. The transcription factor NF-kappa B regulates the transcription of most agents. VIP/PACAP inhibit NF-kappa B transactivation in the lipopolysaccharide-stimulated human monocytic cell line THP-1 at multiple levels. First, VIP/PACAP inhibit p65 nuclear translocation and NF-kappa B DNA binding by stabilizing the inhibitor I kappa B alpha. Second, VIP/PACAP induce phosphorylation of the CRE-binding protein (CREB) and its binding to the CREB-binding protein (CBP). This results in a decrease in p65.CBP complexes, which further reduces NF-kappa B transactivation. Third, VIP and PACAP reduce the phosphorylation of the TATA box-binding protein (TBP), resulting in a reduction in TBP binding to both p65 and the TATA box. All these effects are mediated through the specific receptor VPAC1. The cAMP/cAMP-dependent protein kinase pathway mediates the effects on CBP and TBP, whereas a cAMP-independent pathway is the major transducer for the effects on p65 nuclear translocation. Since NF-kappaB represents a focal point for various stimuli and induces the expression of many proinflammatory genes, its targeting by VIP and PACAP positions them as important anti-inflammatory agents. The VIP/PACAP inhibition of NF-kappa B at various levels and through different transduction pathways could offer a significant advantage over other anti-inflammatory agents.

CREB-Binding Protein↗
PubMed2001

VIP and PACAP inhibit Fas ligand-mediated bystander lysis by CD4(+) T cells.

FasL/Fas-mediated lysis represents the major cytotoxic mechanism for CD4(+) effectors, with important consequences for immune cell homeostasis. Upon stimulation by specific antigen-presenting cells (APCs), CD4(+) effectors can lyse the cognate APCs (direct targets) and neighboring innocent bystanders. Previously we showed that the neuropeptides VIP and PACAP prevent FasL expression and activation-induced cell death in T cells. In this study we investigated the effects of VIP and PACAP on FasL expression and subsequent direct and bystander lysis by CD4(+) effectors generated in vivo. VIP/PACAP inhibit FasL expression in allogeneic effectors, and reduce Fas-mediated cytotoxicity against specific allotargets and syngeneic bystanders. VIP/PACAP also inhibit FasL expression in antigen-specific CD4(+) effectors, and reduce their cytotoxic activity against both the stimulatory APC, and syngeneic or allogeneic bystanders. Since bystander lysis is involved in the pathogenesis of several autoimmune and inflammatory diseases, the identification of regulatory factors that limit this process is highly significant.

Animals↗
PubMed2001

Bacterial colonization of endotracheal tubes in intubated neonates.

OBJECTIVE: To obtain in vivo bacterial colonization profiles on endotracheal tubes at different sites in the neonatal airway in an attempt to better characterize one potential element of chondritis. DESIGN: A case series in which cultures were obtained from calculated segments of 33 endotracheal tubes immediately following extubation. This allowed for sampling at specific levels of the airway corresponding to the trachea, the subglottis, and the oropharynx. Data collected included gender, race, duration of intubation, use of antibiotic therapy, comorbidities, gestational age at birth and extubation, crown-rump length, weight, radiographic distance from tube tip to carina, and culture results. SETTING: Newborn intensive care unit at a tertiary care medical center. PATIENTS: Twenty-nine neonates intubated for longer than 24 hours (range, 24 hours to 15 days). MAIN OUTCOME MEASURES: Bacterial and fungal cultures obtained from 3 endotracheal tube segments for each extubation. RESULTS: A statistically significant difference (P < .05) was found in colonization rates between patients intubated for less than 4 days and those intubated for longer periods. No significant difference was noted in bacterial profile between the 3 sites. CONCLUSIONS: Data demonstrate that bacterial colonization of an indwelling object in the neonatal airway increases with the duration of intubation. Furthermore, 4 days seems to represent a critical period in the formation of such colonization (possibly in the form of a biofilm). These bacteria may contribute to the chondritis known to precede the development of subglottic stenosis. Further studies are indicated to suggest ways to interrupt this process and reduce the incidence of airway injury.

Bacteria↗