Vasoactive intestinal peptide induces neuroendocrine differentiation in the LNCaP prostate cancer cell line through PKA, ERK, and PI3K.

Background: Neuroendocrine (NE) differentiation in prostate cancer has been correlated with unfavorable clinical outcome. The mechanisms by which prostate cancer acquires NE properties are poorly understood, but several signaling pathways have been proposed. We have previously observed that vasoactive intestinal peptide (VIP) stimulates cAMP production mainly through VPAC(1) receptor, inducing NE differentiation in LNCaP cells.

Risk factors for low birth weight: a review.

Low birth weight (LBW) is one of the main predictors of infant mortality. The global incidence of LBW is around 17%, although estimates vary from 19% in the developing countries (countries where it is an important public health problem) to 5-7% in the developed countries. The incidence in Spain in the decade 1980-1989 was about 5.

Vasoactive intestinal peptide modulates proinflammatory mediator synthesis in osteoarthritic and rheumatoid synovial cells.

Objective: Vasoactive intestinal peptide (VIP) has demonstrated beneficial effects in several murine models of immune-mediated inflammation by inhibiting both the inflammatory and the autoimmune components of the disease. We investigate its potential to modulate the release of proinflammatory cytokines and chemokines by human synovial cells from patients with rheumatoid arthritis (RA).

Methods: Fresh suspensions of synovial tissue cells (STC) or cultured fibroblast-like synoviocytes (FLS) were obtained from patients with RA or osteoarthritis (OA).

VIP and PACAP are autocrine factors that protect the androgen-independent prostate cancer cell line PC-3 from apoptosis induced by serum withdrawal.

1. In the present study, we describe the expression of the neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as well as their receptors in PC-3 cells, a human prostate cancer cell line. In addition, we have investigated their role in apoptosis induced by serum starvation.

PACAP in immunity and inflammation.

The pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide belonging to the VIP/secretin/glucagon family of peptides, produced by the lymphoid cells, which exerts a wide spectrum of immunological functions controlling the homeostasis of immune system through different receptors expressed in various immunocompetent cells. In the last decade, PACAP has been clearly identified as a potent anti-inflammatory factor that exerts its function by regulating the production of both anti- and proinflammatory mediators. In this sense, PACAP prevents death by septic shock, an acute inflammatory disease with a high mortality.

Therapeutic effects of vasoactive intestinal peptide in the trinitrobenzene sulfonic acid mice model of Crohn's disease.

Background & Aims: Crohn's disease (CD) is a chronic debilitating disease of unknown etiology that is characterized by severe inflammation of the colon. Vasoactive intestinal peptide (VIP) has recently emerged as a promising candidate for treatment of inflammatory Th1-driven diseases. We studied the effect of VIP in trinitrobenzene sulfonic acid (TNBS)-induced colitis, which has clinical and molecular features in common with CD.

Pituitary adenylate-cyclase-activating polypeptide expression in the immune system.

Although pituitary adenylate-cyclase-activating polypeptide (PACAP) is a multifunctional and pleiotropic neuropeptide with many different immunomodulatory properties, investigations of its source in lymphoid organs are scarce. The present report contributes to the knowledge on the origin and synthesis of this peptide in immune cells of the lymphoid organs and peritoneum using immunohistochemistry, immunocytochemical staining, Western blot and RT-PCR methods. Our study reveals PACAP immunoreactivity in the thymus, spleen and lymph nodes.

Physical exercise, use of Plantago ovata and aspirin, and reduced risk of colon cancer.

To evaluate certain risk and protective factors for colon cancer in our population, we conducted a paired case-control study where cases were all people diagnosed with colon cancer who were registered at the Cancer Data Exchange Systems of the Community of Madrid between January 1995 and December 1996, and controls were randomly taken from electoral lists. The study population consisted of 424 persons. Using SPSS for Windows, variables were adjusted by multiple logistic regression.

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.

Anti-inflammatory role in septic shock of pituitary adenylate cyclase-activating polypeptide receptor.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two mediators synthesized by immune cells, specially under inflammatory and antigen stimulation conditions. Reports have shown that neuropeptides attenuate the deleterious consequences of septic shock both by down-regulating the production of proinflammatory mediators and by stimulating the production of anti-inflammatory cytokines by activated macrophages. In this study, we used a knockout for the PACAP receptor (PAC1(-/-)) to demonstrate an important protective role for PAC1 receptor in endotoxic shock.

Neuroendocrine differentiation of the LNCaP prostate cancer cell line maintains the expression and function of VIP and PACAP receptors.

The molecular mechanisms involved in differentiation of prostate cancer cells to a neuroendocrine (NE) cell phenotype are not well understood. Here we used the androgen-dependent human prostate cancer cell line LNCaP to perform a systematic and broad analysis of the expression, pharmacology, and functionality of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) receptors. Reverse transcription polymerase chain reaction experiments, together with pharmacological approaches with a set of specific agonists and antagonists, demonstrated the presence of the three VIP/PACAP receptor subtypes (PAC1, VPAC1, and VPAC2 with a major role for VPAC1, acting through adenylate cyclase (AC) stimulation.

Proline residue 280 in the second extracellular loop (EC2) of the VPAC2 receptor is essential for the receptor structure.

Inspection of the amino acid sequence of the human VPAC1 and the VPAC2 receptors after alignment of the conserved residues indicates that the second extracellular loop (EC2) is one amino acid shorter in the VPAC1 receptor due to the lack of a proline residue in position 294. We hypothesized that this could be of importance for receptor structure and/or for ligand recognition. Insertion by directed mutagenesis of a proline in that position (294 VPAC1) had little consequence on the binding of several agonists but reduced the affinity for the VPAC1 antagonist.

Vasoactive intestinal peptide (VIP) stimulates rat prostatic epithelial cell proliferation.

Background: Androgens play a major role in supporting normal growth and functional maintenance in the prostate. However, this gland contains an array of neuroendocrine peptides that can play a regulatory role in its physiopathology. Among these peptides, one of the best studied is vasoactive intestinal peptide (VIP), which is abundant in autonomic nerves surrounding both human and rat prostatic acini.

Expression of vasoactive intestinal peptide (VIP) receptors in human uterus.

We show the existence of functional vasoactive intestinal peptide (VIP) receptors in normal human female genital tract (endometrium, myometrium, ovary and Fallopian tube) as well as in leiomyoma (a frequent uterine pathology). The correlation between VIP binding and stimulation of adenylyl cyclase activity for all studied tissues was linear (r = 0.86) suggesting the expression of VIP receptors throughout the human female genital tract.

Two basic residues of the h-VPAC1 receptor second transmembrane helix are essential for ligand binding and signal transduction.

We mutated the vasoactive intestinal peptide (VIP) Asp(3) residue and two VPAC(1) receptor second transmembrane helix basic residues (Arg(188) and Lys(195)). VIP had a lower affinity for R188Q, R188L, K195Q, and K195I VPAC(1) receptors than for VPAC(1) receptors. [Asn(3)] VIP and [Gln(3)] VIP had lower affinities than VIP for VPAC(1) receptors but higher affinities for the mutant receptors; the two basic amino acids facilitated the introduction of the negatively charged aspartate inside the transmembrane domain.

Characterization of a novel VPAC(1) selective agonist and identification of the receptor domains implicated in the carboxyl-terminal peptide recognition.

Vasoactive Intestinal Polypeptide (VIP) interacts with a high affinity to two subclasses of G protein coupled receptors named VPAC(1) and VPAC(2), and has a 3 - 10 fold preference for VPAC(1) over VPAC(2) receptors. Selective ligands for each receptor subclass were recently described. [R(16)]-PACAP (1 - 23) and [L(22)]-VIP are two selective VPAC(1) agonists.

Different vasoactive intestinal polypeptide receptor domains are involved in the selective recognition of two VPAC(2)-selective ligands.

A vasoactive intestinal polypeptide (VIP) analog, acylated on the amino-terminal histidine by hexanoic acid (C(6)-VIP), behaved as a VPAC(2) preferring agonist in binding and functional studies on human VIP receptors, and radioiodinated C(6)-VIP was a suitable ligand for binding studies on wild-type and chimeric receptors. We evaluated the properties of C(6)-VIP, its analog AcHis(1)-VIP, and the VPAC(2)-selective agonist Ro 25-1553 on the wild-type VPAC(1) and VPAC(2) receptors and on the chimeric receptors exchanging the different domains between both receptors. VIP had a normal affinity and efficacy on the chimeras starting with the amino-terminal VPAC(2) receptor sequence.

Evidence for multiple rat VPAC1 receptor states with different affinities for agonists.

We compare the binding properties of [125I-VIP] and [125I]-Ro 25 1553 to VPAC1 receptors, expressed in stably transfected CHO cells. [125I]-VIP labelled two VPAC1 receptor states, while [125I]-Ro 25 1553 labelled selectively a limited number of high-affinity receptors. This high-affinity state probably corresponds to an agonist-receptor-Gs ternary complex as its properties (guanyl nucleotides, EC50 values and maximal effect) were affected by cholera toxin pre-treatment.

Vasoactive intestinal polypeptide VPAC1 and VPAC2 receptor chimeras identify domains responsible for the specificity of ligand binding and activation.

In order to identify the receptor domains responsible for the VPAC1 selectivity of the VIP1 agonist, [Lys15, Arg16, Leu27] VIP (1-7)/GRF (8-27) and VIP1 antagonist, Ac His1 [D-Phe2, Lys15, Arg16, Leu27] VIP (3-7)/GRF (8-27), we evaluated their binding and functional properties on chimeric VPAC1/VPAC2 receptors. Our results suggest that the N-terminal extracellular domain is responsible for the selectivity of the VIP1 antagonist. Selective recognition of the VIP1 agonist was supported by a larger receptor area: in addition to the N-terminal domain, the first extracellular loop, as well as additional determinants in the distal part of the VPAC1 receptor were involved.

Vasoactive intestinal polypeptide receptor VPAC(1) subtype is predominant in rat prostate membranes.

Background: The 28-amino-acid neuropeptide vasoactive intestinal peptide (VIP) might play an important role in the physiology of the prostate, since it stimulates glandular secretion, inhibits muscle contraction, stimulates proliferation of epithelial cells, and increases the secretion of prostate-specific antigen (PSA). This neuropeptide may act through interaction with two types of high-affinity receptors, named VPAC(1) and VPAC(2) receptors. Recently, selective agonists and antagonists for each receptor subtype were synthesized.

Effects of chronic ethanol ingestion on the vasoactive intestinal peptide receptor-effector system from rat seminal vesicle membranes.

We studied the modifications of the vasoactive intestinal peptide (VIP) receptor/effector system from the rat seminal vesicle after chronic ethanol ingestion. Ethanol treatment resulted in a decreased height of the secretory epithelium of seminal vesicle as well as in a weight loss of this gland. These morphological changes were accompanied by an increase of immunoreactive vasoactive intestinal peptide (VIP) levels and a decrease of the stimulatory effect of VIP adenylate cyclase activity in the seminal vesicle.

G-protein regulation of adenylate cyclase activity in rat prostatic membranes after chronic ethanol ingestion.

Background: The possibility that long-term ethanol ingestion might alter either vasoactive intestinal peptide (VIP) content, VIP binding to membrane receptors, G-protein levels or adenylate cyclase activity in rat prostate was tested, as ethanol produces serious alterations in the hypothalamic-pituitary-gonadal axis and several modifications on different elements on signal transduction pathways in other systems.

Methods: Prostatic membranes from control and ethanol-treated (for 4 weeks) rats were used to study adenylate cyclase stimulation as well as for the immunodetection of stimulatory (alpha(s)) and inhibitory (alpha(i)1-2) G-protein subunits. Studies on VIP binding and cross-linking to receptors were performed using [125I]VIP.

Ontogenic development of the adenylyl cyclase enzyme and the alpha s, alpha i1 and alpha i2 G-protein regulatory subunits from rat prostate.

The expression of alpha s, alpha i1 and alpha i2 G-protein subunits measured by immunoblot increased in the rat prostate during sexual maturation, supporting their involvement in proliferation/differentiation. Northern blotting gave transcripts of 1.8 and 4 kb for alpha s, 1.

Dopamine enhances somatostatin receptor-mediated inhibition of adenylate cyclase in rat striatum and hippocampus.

Although there is evidence that suggests that dopamine (DA) has stimulatory effects on somatostatinergic transmission, it is unknown to date if DA increases the activity of the somatostatin (SS) receptor-effector system in the rat brain. In this study, we evaluated the effects of the administration of DA and the DA D1-like (D1, D5) receptor antagonist SCH 23390 and the D2-like (D2, D3, D4) receptor antagonist spiperone on the SS receptor-adenylate cyclase (AC) system in the Sprague-Dawley rat striatum and hippocampus. An intracerebroventricular injection of DA (0.