1,721,013 research outputs found
Pharmacology and physiopathology of the brain endothelin system: an overview
No full textAbstract
The endothelin system, consisting of three peptides, two peptidases and two G-protein coupled receptors, is widely expressed in the brain cell types and brain-derived tumor cell lines. The stimulation of endothelin receptors elicits a variety of short- and long-term changes at cellular level but the effects of the pharmacological modulation of the endothelin system in brain physiology and pathophysiology are, at the present time, poorly understood. Altered expression of endothelins (ETs) in reactive astrocytes has been observed in many pathological conditions of the human brain, such as infarcts, lacunae, traumatic conditions, Alzheimer's disease and inflammatory diseases of the brain. In addition, recent studies have shown that endothelin antagonists might inhibit growth and induce cell death in human melanoma cells in vitro and in vivo, and have emphasized a possible role of endothelin peptides as autocrine or paracrine factor in the proliferation and dissemination of tumor cell lines. Given the fact that brain cell and a variety of brain tumor cell lines express functional endothelin receptors, further studies are warranted to demonstrate a possible therapeutic role of endothelin agonists and antagonist in the pharmacological treatment of brain-related diseases and brain tumors
Therapeutic targeting of g-protein coupled receptor-mediated epidermal growth factor recptor transactivation in human glioma brain tumors.
No full textThe epidermal growth factor receptor (EGFR) is the main tyrosine kinase receptor dysregulated or overexpressed in brain cancer types and its expression is directly correlated with tumor malignancy and unfavorable prognosis. Recently, the availability of endogenous EGFR ligands has been reported to be also regulated indirectly by the activation of several G-protein-coupled receptors (GPCRs) in many cancer cell types. This EGFR transactivation mechanism requires the initial activation of a GPCR that in turn induces the cleavage of membrane-bound EGFR ligands precursors via the involvement of the family of disintegrin and metalloproteases (ADAMs). The discovery of ADAMs in this transactivation mechanism led to the development of small molecule inhibitors. In this minireview we describe the expression of GPCR, ADAMs and EGFR ligands in human glioma brain tumors and the characteristics of small molecule ADAMs inhibitors. The addition of ADAM inhibitors to our pharmacological arsenal could enhance the outcome of combination therapies when using EGFR inhibitors against human brain tumors
Brain infiltration by cancer cells: different roads to the same target?
No full textBrain infiltration by cancer cells is a complex process in which metastatic cells detached from the primary tumor must firstly survive in the blood flow, cross the blood brain barrier (BBB) and finally colonize a foreign microenvironment. The cells that successfully bypass the cellular barriers surrounding capillaries, proliferate to form micrometastasis and trigger the angiogenetic process. Different molecular mechanisms have been proposed to explain the metastatic behaviour of solid tumors that infiltrate brain tissue; in this review the most recent findings concerning mechanisms and genes potentially involved in brain metastasis, that differ according to primary tumor types, will be discussed. The three tumors that more frequently develop brain metastasis, lung cancer, breast cancer and melanoma, will be considered and, in addition, the role of BBB and the process of endothelial to mesenchymal transition in cancer metastasis will be briefly described
Endothelin-1 regulates astrocyte proliferation and reactive gliosis via a JNK/c-Jun signaling pathway.
No full textAbstract
Reactive gliosis is characterized by enhanced glial fibrillary acidic protein (GFAP) expression, cellular hypertrophy, and astrocyte proliferation. The cellular and molecular mechanisms underlying this process are still largely undefined. We investigated the role of endothelin-1 (ET-1) in reactive gliosis in corpus callosum after lysolecithin (LPC)-induced focal demyelination and in cultured astrocytes. We show that ET-1 levels are upregulated in demyelinated lesions within 5 d after LPC injection, together with enhanced astrocyte proliferation, GFAP expression, and JNK phosphorylation. Infusion of the pan-ET-receptor (ET-R) antagonist Bosentan or the selective ET(B)-R antagonist BQ788 into the corpus callosum prevented postlesion astrocyte proliferation and JNK phosphorylation. In cultured astrocytes, ET-1-induced activation of ET(B)-Rs promotes a reactive phenotype by enhancing both GFAP expression and astrocyte proliferation. In the same cells, ET-1 activates both JNK and p38MAPK pathways, and induces c-Jun expression at the mRNA and protein levels. By using selective pharmacological inhibitors, we also provide evidence that ET-1 induces astrocyte proliferation and GFAP expression through activation of ERK- and JNK-dependent pathways, consistent with the previous observation of ET-1-induced activation of ERK (Schinelli et al., 2001). Finally, we show by gain and loss of function that increased c-Jun expression enhances the proliferative response of astrocytes to ET-1, whereas c-jun siRNA prevents ET-1-induced cell proliferation. Our results indicate that the effects of ET-1 on astrocyte proliferation depend on c-Jun induction and activation through ERK- and JNK-dependent pathways, and suggest that ET-R-associated pathways might represent important targets to control reactive gliosis
Opposing actions of D1- and D2-dopamine receptors on arachidonic acid release and cyclic AMP production in striatal neurons
No full textModulation of dopamine-induced cAMP production in rat striatal cultures by the calcium ionophore A23187 and by phorbol-12-myristate-13-acetate
No full text
Integrins and exosomes, a dangerous liaison in cancer progression
Full text linkIntegrin activity and function is classically related to the bi-directional regulation of cell-extracellular matrix (ECM) contacts that regulate a number of cell pathways linked to cell adhesion, cell detachment from ECM, cell migration, and anoikis. Interestingly, emerging data continue to uncover new roles for integrins in cancer-relevant pathways, particularly concerning the regulation of immune cell activity in the tumor niche, like myeloid cell differentiation and function and, very recently, the regulation of metastatic processes by exosomes. Exosomes are deeply involved in cell-cell communication processes and several studies have shown that integrins found in tumor-associated exosomes can promote cancer progression by two novel cooperative mechanisms: horizontal transfer of integrin transcripts as vescicle cargo, and selection of target tissues to form new tumor niches during metastatic spread by integrins carried on the exosome’s surface. In this review we will discuss mounting evidence that contribute to the development of a new picture for integrins in cancer, highlighting the role of integrins in the processes that leads to tumor niche formation. In particular, the role of the periostin pathway in the recruitment of tumor-associated macrophages, and the proposed contribution of exosome-derived integrins in the metastatic spread will be discussed. Finally, in light of the above considerations, an evaluation of integrins as possible therapeutic targets will be conducted.</jats:p
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