1,721,236 research outputs found
SISTEMI PEPTIDERGICI NELLA PROGRESSIONE DEL CARCINOMA PROSTATICO UMANO: NEUROPEPTIDE Y E SOMATOSTATINA
No full textAlcune molecole neuroendocrine, tra cui il neuropeptide Y (NPY) sembrano svolgere un ruolo importante nella progressione del carcinoma prostatico umano (CaP), essendo espressi nella prostata normale (fibre peptidergiche e cellule neuroendocrine) e patologica. In questo studio, la presenza e la funzione dei recettori per NPY (Y-Rs) sono state valutate in tre conosciuti modelli in vitro di CaP, le linee cellulari LNCaP (androgeno dipendente) e DU145 e PC3 (androgeno indipendenti). Tutte le linee cellulari hanno mostrato un’elevata espressione di proteina Y1-R (Western blot) ed una immunoreattività per Y1-R è stata riscontrata anche in preparati istologici di CaP. I geni codificanti per le isoforme recettoriali dell’NPY sono risultati differentemente espressi nelle cellule di CaP: Y1-R in tutti i cloni, Y2-R solamente in LNCaP, Y4-R solo in PC3 e Y5-R in nessuna linea cellulare (RT-PCR). Il trattamento con NPY ha indotto una riduzione della proliferazione delle cellule LNCaP e DU145 ed un aumento della stessa nelle PC3, con massima concentrazione efficace a 10-8 M. Questi effetti sono stati completamente aboliti in tutte le linee cellulari in presenza di BIBP3226, un antagonista specifico per il Y1-R. Il trattamento con NPY è risultato ridurre l’accumulo di cAMP indotto da forskolina solo nelle PC3, non ha modificato la concentrazione di Ca++ intracellulare in tutte le linee cellulari; e ha aumentato in modo rapido e transitorio i livelli di fosforilazione della proteina ERK1/2 nelle DU145 e PC3. In conclusione, recettori funzionali dell’NPY sono espressi nelle linee cellulari di CaP e l’isoforma Y1-R risulta associata in modo particolare alla modulazione della proliferazione cellulare. Questi dati suggeriscono che meccanismi correlati all’NPY possano essere rilevanti in certi stadi del carcinoma alla prostata, come la progressione della malattia durante la fase di androgeno-independenza
PCSK9 e aterosclerosi: solo LDL colesterolo? = PCSK9 and atherosclerosis: effects beyond LDL cholesterol
No full textL’identificazione della proteina PCSK9 (proproteina convertasi subtilisina/kexina di tipo 9), quale molecola in grado di regolare in maniera importante il colesterolo LDL (LDL-C), è di recente scoperta e numerosi studi stanno delineando la sua funzione fisiologica anche alla luce dell’approvazione per uso clinico di anticorpi monoclonali inibitori di tale proteina. Studi su modelli in vitro, pre-clinici e clinici indicano un possibile coinvolgimento di PCSK9 nella risposta infiammatoria, in particolare sul reclutamento di monociti proinfiammatori nella placca aterosclerotica e sull’espansione del suo core necrotico. PCSK9 sembra, inoltre, influenzare la risposta vascolare facilitando l’accumulo di cellule muscolari lisce vasali nella neointima e l’aggregazione piastrinica. Ad oggi, tuttavia, è ancora da definire l’entità dell’azione diretta di PCSK9 sull’aterosclerosi, indipendente dall’effetto sul metabolismo del LDL-C. Inoltre, l’inibizione di PCSK9 plasmatico, ad opera degli anticorpi monoclonali, potrebbe determinare non solo una riduzione significativa del LDL-C e del rischio cardiovascolare, ma anche un possibile effetto pleiotropico come, già, postulato per le statine. Nuove strategie terapeutiche, quali i siRNA e i vaccini, potenzialmente più efficaci degli anticorpi monoclonali nell’inibire la sintesi di PCSK9 a livello intracellulare, potrebbero aiutare a comprendere meglio i suoi eventuali effetti pleiotropi. La presente rassegna descrive le evidenze di un effetto diretto di PCSK9 sull’aterosclerosi e il suo possibile ruolo quale biomarcatore per la stratificazione del rischio cardiovascolare.The identi cation of PCSK9 (proprotein convertase subtilisin/kexin type 9), as a pivotal regulator of LDL cholesterol (LDL-C) is relatively recent, and a number of studies have described its physiological function. This is of particular interest since the approval of monoclonal antibodies anti PCSK9 for therapeutic use. Results from in vitro, clinical and pre-clinical studies, indicate a possible involvement of PCSK9 on in ammatory response, such as the recruitment of pro-in ammatory monocytes in the atherosclerotic plaque and the size of the necrotic core in human plaques. In addition, PCSK9 seems to in uence the vascular response facilitating the accumulation of smooth muscle cells in the neointima and to facilitate the platelet aggregation. However, to what extent PCSK9 acts directly on the vascular wall still needs to be determined. Nevertheless, the effect of monoclonal antibodies anti PCSK9 could determine not only a strong reduction of LDL-C, but also a potential pleiotropic effect, as previously suggested with statins. New therapeutic strategies such as siRNA and vaccine, potentially more ef- fective than monoclonal antibodies to inhibit the intracellular PCSK9, may help to better understand the potential pleiotropic effects of PCSK9. In the present review, it will be described the direct role of PCSK9 on atherosclerosis and its potential use as circulating biomarker for a better strati cation of the cardiovascular risk
Somatostatin, Somatostatin Analogs and Somatostatin Receptor Dynamics in The Biology of Cancer Progression
No full textThe pharmacological effects (i.e., inhibition of endocrine secretion and cell proliferation) mediated by the hormone somatostatin (SRIF) are derived from its universal high-affinity binding to five different G proteincoupled receptors (GPCRs), named sst1-5. However, SRIF has a half-life of less than 3 min, whereas the available mono- and bi-specific SRIF preferential analogs show prolonged half-life and increased potency. These compounds may control tumor development, cell proliferation and metastatization by direct actions, including cell division arrest in G0/G1 phase (i.e., induction of cyclin-dependent kinase inhibitor p27(kip1) or p21(Cip1)), induction of apoptosis (i.e., induction of p53 and Bax) and suppression of cell invasion. Along with these direct actions on the biology of cancer progression, in vivo SRIF analogs may also regulate tumor growth through indirect actions, by suppressing the secretion of growth-promoting hormones and growth factors and angiogenesis. Interestingly, when ssts are co-expressed, they may interact forming homo- or heterodimers, also with other GPCRs such as type 2 dopamine receptor and the μ-opioid receptor 1, altering their original pharmacological and functional properties. Dimers can be not only constitutive, but perhaps also ligandpromoted: hence, compounds with high affinity for different ssts isoforms may be used to achieve effects elicited by specific dimers. Future developments in the knowledge of ssts dynamics upon SRIF and SRIF analogs binding in neoplastic tissues may allow the full elucidation of the pathophysiological role of this system and the exploitation of the therapeutic potential of its modulation
Neuropeptide Y-Y1 receptors mediate the effects of Neuropeptide Y on prostate cancer cell growth
No full textNeuroendocrine molecules play a significant role in the progression of human prostate cancer (PCa) and its neuroendocrine differentiation has been associated to a worse prognosis. Among these molecules, the pleiotropic peptide neuropeptide Y (NPY) was found to be expressed in the human prostate and may show some relevance in PCa progression. In this study, we evaluated the direct effect of NPY on the growth of the human PCa cell lines LNCaP (androgen dependent) and DU145 and PC3 (androgen independent). The Y1-R subtype was found to be expressed in all PCa cell lines at the gene and protein level. Moreover, Y2-R and Y4-R genes were found to be expressed in PC3 cells and in LNCaP/DU145 cells, respectively. Treatment with 10−8 M NPY reduced the proliferation of LNCaP and DU145 cells and increased that of PC3 cells. The specific Y1-R antagonist BIBP3226 (10−6 M) abolished such effects, suggesting a mandatory role of Y1-R in this process. LNCaP cells showed elevated constitutive levels of phosphorylated extracellular kinase RK (ERK)1/2, which were not affected by NPY. In DU145 cells, treatment with 10−8 M NPY stimulated a long-lasting (>6 h) ERK1/2 phosphorylation, whereas, in PC3 cells, this effect was rapid, transient and mediated by protein kinase C, since it was abolished by pretreatment with the specific PKC inhibitor GF109203X (10−7 M). In DU145 and PC3 cells, NPY-induced ERK1/2 phosphorylation was prevented by a pretreatment with BIBP3226, further suggesting the involvement of Y1-R. Treatment with 10−8 M NPY reduced forskolin-stimulated cAMP accumulation only in PC3 cells, and did not change intracellular calcium concentration in any PCa cell line. Our data suggest that Y1-R activation by NPY represents an important regulator of the proliferation different PCa cell lines, with stimulatory or inhibitory effects depending on the peculiar intracellular signalling pattern activated in each clone
Cholinergic regulation of neuropeptide Y synthesis and release in human neuroblastorna cells
No full textThe biosynthesis and release of neuropeptide Y (NPY) is regulated by several factors. Here, the effect of the muscarinic agonist carbachol on NPY biosynthesis and release was analyzed utilizing the SH-SY5Y human neuroblastoma cell line. We observed that: (a) carbachol moderately increased the post-translational cleavage of proNPY to NPY; (b) carbachol treatment stimulated NPY accumulation into the medium in a time- and dose-related manner; (c) protein kinase C activation is involved in carbachol-mediated NPY synthesis/release (>6h). In conclusion, the present observations support the hypothesis that muscarinic receptor activation regulates the biosynthesis and secretion of NPY
Proprotein convertase subtilisin/kexin type 9 (PCSK9) and metabolic syndrome : insights on insulin resistance, inflammation, and atherogenic dyslipidemia
No full textLow-density lipoprotein (LDL) cholesterol plays a pivotal role in the pathogenesis of atherosclerotic cardiovascular disease (CVD). The discovery that proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a key regulator pathway for hepatic LDL receptor (LDLR) degradation sheds light on new uncovered issues regarding LDL-C homeostasis. Indeed, as confirmed by phase II and III clinical trials with monoclonal antibodies, targeting PCSK9 represents the newest and most promising pharmacological tool for the treatment of hypercholesterolemia and related CVD. However, clinical, genetic, and experimental evidence indicates that PCSK9 may be either a cause or an effect in the context of metabolic syndrome (MetS), a condition comprising a cluster of risk factors including insulin resistance, obesity, hypertension, and atherogenic dyslipidemia. The latter is characterized by a triad of hypertriglyceridemia, low plasma concentrations of high-density lipoproteins, and qualitative changes in LDLs. PCSK9 levels seem to correlate with many of these lipid parameters as well as with the insulin sensitivity indices, although the molecular mechanisms behind this association are still unknown or not completely elucidated. Nevertheless, this area of research represents an important starting point for a better understanding of the physiological role of PCSK9, also considering the recent approval of new therapies involving anti-PCSK9. Thus, in the present review, we will discuss the current knowledge on the role of PCSK9 in the context of MetS, alteration of lipids, glucose homeostasis, and inflammation
Molecular aspects of adipokine-bone interactions
No full textAdipose tissue is an endocrine organ able to produce a wide series of pleiotropic molecules, defined "adipokines". In addition to the regulation of food intake and energy metabolism, adipokines are also implicated in the complex control of bone biology and specifically of bone remodeling. Leptin, the most studied adipokine, promotes satiety and energy expenditure and its circulating levels are proportional to fat mass. Some paradoxical findings originally suggested the involvement of leptin in controlling bone mass. For example, obese postmenopausal women, with elevated circulating leptin and leptin resistance, appear protected against the development of osteoporosis. Moreover, genetically leptin-deficient mice, which are hypogonadal and obese, display a decreased trabecular volume in long bones, but an increased vertebral bone mass, which is reduced by leptin administration. The complex mechanisms of leptin regulation of bone mass appear to involve selected hypothalamic neuronal populations and the sympathetic outflow, with an important role of osteoblastic β2-adrenergic receptors. Adiponectin is another adipokine, which promotes insulin sensitivity and is reduced in obese and diabetic subjects. Adiponectin appears to exert a negative effect on bone mass and seems to be an independent predictor of lower bone mass. Although the adipokines resistin and visfatin do not seem to significantly affect bone metabolism, the potential impact of them and other adipokines is still to be determined. Moreover, the molecular adipokine-bone interactions should also be considered in the context of the adipokine changes observed in diseases such as obesity and the metabolic syndrome
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