1,721,385 research outputs found
Hormonal control of the neuropeptide Y system
No full textNeuropeptide Y (NPY) and the related receptors represent a widely diffused system that is involved in the regulation of multiple biological functions. NPY, a 36-aminoacid peptide expressed in several areas of the nervous system, is a pleiotropic factor participating to the control of some physiological processes, such as cognitive functions, eating behavior, circadian rhythms. neuroendocrine mechanisms, reproductive and cardiovascular functions. NPY acts through a series of G-protein-associated membrane receptors (NPY-Rs), characterized by different tissue distribution and affinity for the ligand. The expression and secretion of NPY and the expression of NPY-R isoforms are controlled by a very wide range of agents, acting in an endocrine and/or paracrine fashion. NPY and NPY-Rs appear to be strongly involved in the control of eating behavior; their expression is modulated by changes of food intake and energy balance and is disrupted in several animal models of obesity and diabetes. Moreover, the hypothalamic NPY system appears to integrate signals of energy balance in the modulation of the reproductive axis. Agents that stimulate their expression include activators of intracellular signalling pathways (protein kinase A and C), classical neurotransmitters, steroid and peptide hormones and growth factors, while other agents (leptin, insulin and retinoic acid) have been shown to be inhibitory. Interestingly, some agents, like retinoic acid, have been shown to modulate the expression of both NPY and NPY-Rs in the same direction, thus providing a fine mechanism for the tuning of the system. The regulation of NPY/NPY-R expression and function appears to be part of a complex system controlling multiple physiological functions, and its disruption might be relevant in the pathophysiology of disease states such as obesity
Aldosterone receptor antagonists: biology and novel therapeutic applications
No full textA dysregulation of the aldosterone system has been involved in the pathophysiology of cardiovascular diseases, including myocardial failure and, partially, essential hypertension. In humans and in rat models, aldosterone action induces heart remodeling and interstitial and perivascular myocardial fibrosis. Therefore, a rationale for using aldosterone antagonists (ARAs) of the spironolactone, family, which have been available for decades for the treatment of aldosterone excess syndromes, has now emerged. The development of compounds such as eplerenone, with a greater selectivity for mineralocorticoid receptors, is promising also in terms of reduction of endocrine side effects. The use of ARAs for the treatment of myocardial failure and selected cases of hypertension, in combination with the current therapy, has been strongly supported by trials such as the Randomized Aldactone Evaluation Study (RALES) and the Eplerenone Neurohormonal Efficacy and Survival Study (EPHESUS). Thus, the addition of ARAs to the conventional therapy appears beneficial, leading to an improved survival rate and a reduced incidence of cardiac complications
Expression of neuropeptide Y receptors in human prostate cancer cells
No full textBackground: Neuroendocrine molecules are now believed to play a significant role in the progression of human prostate cancer (CaP), especially in the androgen-independent stage. Materials and methods: In the present study, we evaluated the presence and the function of the receptors for neuropeptide Y (NPY) in human CaP cell lines (the androgen-dependent LNCaP, and the androgen-independent DU 145 and PC-3). Results: The presence of high-affinity binding sites for NPY was shown on PC-3 cells (radioreceptor assay). Reverse transcription-polymerase chain reaction analysis indicated that these sites correspond to the Y1 and Y2 receptor isoforms. A Y1 receptor protein (70 kDa) was also detected in PC-3 cell extracts by Western blot analysis. The activation of these receptors by NPY resulted in a reduction of forskolin-induced cAMP accumulation and an increase of [Ca2+]i. Moreover, a prolonged treatment with NPY induced a dose-related proliferation of PC-3 cells. Conclusions: By showing that NPY receptors are expressed in the androgen-independent cell line PC-3 and that their activation results in cell proliferation, the present date suggest that NPY-related mechanisms might be relevant in certain stages of CaP, such as the progression of the disease during the androgen-independent stage
A potential mechanism for copper amplification of prostaglandin E2 action: attenuation of prostaglandin E2-induced efflux of cyclic AMP from median eminence explants
No full textIt is known that prostaglandin E2 (PGE2) stimulation of LHRH release from the median eminence-arcuate nucleus (MEA) is mediated by the cAMP pathway, and a short pretreatment with copper markedly amplifies this release process. Because stimulation of cAMP accumulation is accompanied by cAMP efflux in many tissues, we considered the possibility that attenuation of cAMP efflux is one mechanism by which copper can enhance PGE2 action. When rat MEA explants were incubated in vitro, PGE2 induced a rapid (<2.5 min) and sustained (15 min) increase in cAMP efflux, the degree of which was a function of [PGE2]: by 5 min exposure to 10 μM PGE2, efflux was 8-fold greater than the control (no PGE2) and it accounted for 12.4% of the total (tissue + medium) cAMP. Unlike the dramatic increase in cAMP efflux, PGE2 induced a moderate increase in cAMP content (49%) and in the incorporation of [3H] adenine into [3H] cAMP (78%); this increase was transient: it was evident after a 2.5 but not after a 5 min period of PGE2 exposure. Copper pretreatment did not alter this PGE2-induced increase in tissue cAMP content. In contrast, copper markedly inhibited (by 49%-66%) PGE2-induced cAMP efflux and this inhibition was noted regardless of the length of PGE2 exposure and PGE2 concentration. There was no evidence for hydrolysis of [3H]3′, 5′-cAMP included in the medium during the incubation with PGE2 with and without copper pretreatment. In summary, copper attenuated PGE2-induced cAMP efflux from MEA explants and this attenuation is not a consequence of a reduction in the availability of intracellular cAMP nor of hydrolysis of cAMP extracellularly,
Aldosterone receptor antagonists: biology and novel therapeutical applications
No full textRecent studies suggest that a dysregulation of the aldosterone system is involved in the pathophysiology of different cardiovascular diseases, including myocardial failure and several cases of essential hypertension. In both rat models and in humans, aldosterone action has been shown to induce heart remodeling and interstitial and perivascular fibrosis of the myocardium. For these reasons, a rationale for the use of aldosterone antagonists (ARAs) of the spirolactone family, which have been available for decades in the treatment of aldosterone excess syndromes, has now emerged. Moreover, the recent validation of their use, in combination with the current therapy, for the treatment of these cardiovascular diseases by trials like the RALES Study has further strenghtened this approach. The development of compounds, like eplerenone, with a greater selectivity for mineralocorticoid receptors, seems promising also in terms of reduction of endocrine side effects. The addition of aldosterone antagonists to the conventional therapy of myocardial failure and of selected cases of hypertension thus appears beneficial, resulting in an improved survival rate and a reduced incidence of cardiac complications. This review article, after a brief recall of the physiology of the aldosterone system, addresses the emerging role of aldosterone in cardiovascular diseases, considers the pharmacology of ARAs and the novel therapeutical applications of these compounds in hypertension and heart failure
An early and transient period of protein synthesis is required for induction of neuropeptide Y-mRNA by phorbol ester and forskolin in aggregate cultures of fetal brain cells
No full textWe have previously shown that both forskolin (F) and phorbol ester (P) induce neuropeptide Y (NPY) production by aggregate cultures formed from dissociated fetal rat brains. In this study, we addressed the question: Do F/P induce NPY-mRNA in aggregate cultures and if so, does induction require active protein kinases and on-going protein synthesis? On Northern blots, the NPY cDNA hybridized to a single species of about 0.8 kb. F and P each induced a time-dependent increase in NPY-mRNA relative abundance, and this was inhibited by staurosporin, an inhibitor of both protein kinase A and C. Cycloheximide (CHX) inhibited F/P induction of mRNA in a time-dependent manner. When aggregates were incubated with F + P for a total 12 h period, CHX added along with F + P (0 h) completely inhibited, CHX added 1.5 h after F + P partially inhibited, and CHX added 6 h after F + P did not inhibit the increase in NPY-mRNA. To rule out the possibility that this inhibitory profile reflects toxicity of CHX, blots were re-hybridized with a SRIF cRNA probe and, as expected for SRIF gene, a 12 h exposure to CHX did not inhibit F + P induction of SRIF-mRNA. Close inspection of the blots (derived from 1.5% agarose gels) suggested the presence in F/P-treated aggregates of 2 species NPY-mRNA [ ≈ 0.75 and ≈ 0.85 kb, most likely differing in the length of poly(A) tail (Jamal et al., 1991)]; size-fractionation on a higher resolution gel (3% agarose) resolved the F/P induced mRNA into 2 distinct bands, while mRNA from untreated cultures migrated as a single band - the 0.75 kb. Thus, F and P each induces NPY-mRNA abundance in a process requiring protein synthesis and the activity of protein kinases. The fact that the requirement for protein synthesis is restricted to the early ( < 6 h) period of induction of mRNA is consistent with the involvement of immediate-early response genes and with the classification of NPY gene as a slow responding gene. The increase in NPY-mRNA abundance and the preferential induction of a larger molecular size NPY-mRNA suggests regulation of NPY expression at a transcriptional and a post-transcriptional level
Il controllo dell’appetito e della sazietà nell’uomo : basi biologiche e applicazioni cliniche
No full textForskolin and phorbol ester stimulation of neuropeptide Y (NPY) production and secretion by aggregating fetal brain cells in culture: evidence for regulation of NPY biosynthesis at a transcriptional and post-transcriptional level
No full textUsing fetal brain cells in culture, we have previously shown that activation of the cAMP pathway by forskolin induces the production and secretion of neuropeptide Y (NPY). In this study we wished to ascertain 1) if activation of the protein kinase C pathway induces NPY production and/or secretion and if there is synergism between the pathways, and 2) the role of protein/RNA synthesis and influx of extracellular calcium. Aggregates, formed from dissociated cells obtained from the hypothalamus-olfactory tubercle area of 17-day-old rat fetuses, were cultured in serum-free medium for 12 days. The NPY content of aggregates incubated for 24 h with solvent (control) was 4.4 ng/flask, and the medium content was 7.6 ng. Forskolin (10 μM) or phorbol 12-myristate 13-acetate (PMA; 20 nM) marginally affected aggregate content, but each increased medium content 2- to 3-fold; forskolin and PMA were additive. When cycloheximide (75 μM) was included along with forskolin, PMA, or forskolin plus PMA for a period of 10 h, the increase in NPY medium content was abolished. Actinomycin D (Act-D; 5 μg/ ml) inhibited the response to each secretagogue in a time-dependent manner. When Act-D was included along with forskolin, PMA, or forskolin plus PMA for a total period of 12 or 24 h, the 12 h increase in content was not affected, whereas the 24 h increase was abolished. When the presence of Act-D was limited to 0-24, 6-24, or 12-24 h, and forskolin plus PMA were included for the entire 24-h period, the increase in NPY content was inhibited by 94%, 57%, and 12%, respectively. Verapamil (100 μM) totally inhibited the 24 h response to forskolin and partially (40-50%) inhibited the response to PMA or forskolin plus PMA. In none of these conditions was the inhibition of the increase in medium NPY content accompanied by an increase in aggregate content, nor was the NPY content of aggregate/ medium of control cultures affected. In summary, 1) forskolin and PMA induce an increase in NPY content and secretion by a process requiring both RNA and protein synthesis; 2) there is no evidence for synergism between the two agents; 3) the mRNA species essential for the induced increase in NPY content and secretion (including NPY mRNA itself) exhibit an apparent overall half-life greater than 12 h; and 4) a major fraction of the culture content of NPY is secreted, and this occurs independently of influx of extracellular calcium via a verapamil-sensitive process; the latter, however, is required for forskolin and a partial one for PMA induction of the increase in NPY content. These results are consistent with the cAMP and protein kinase C pathways regulating three major events in the cultured NPY neuron: transcription, translation, and secretion
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