Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Enzyme Inhib Med Chem ; 35(1): 96-108, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31690133

RESUMO

A series of analogues of Amb639752, a novel diacylglycerol kinase (DGK) inhibitor recently discovered by us via virtual screening, have been tested. The compounds were evaluated as DGK inhibitors on α, θ, and ζ isoforms, and as antagonists on serotonin receptors. From these assays emerged two novel compounds, namely 11 and 20, which with an IC50 respectively of 1.6 and 1.8 µM are the most potent inhibitors of DGKα discovered to date. Both compounds demonstrated the ability to restore apoptosis in a cellular model of X-linked lymphoproliferative disease as well as the capacity to reduce the migration of cancer cells, suggesting their potential utility in preventing metastasis. Finally, relying on experimental biological data, molecular modelling studies allow us to set a three-point pharmacophore model for DGK inhibitors.


Assuntos
Indóis/farmacologia , Lipase Lipoproteica/antagonistas & inibidores , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Indóis/síntese química , Indóis/química , Lipase Lipoproteica/metabolismo , Linfócitos/efeitos dos fármacos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Monócitos/efeitos dos fármacos , Piperazinas/síntese química , Piperazinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos
2.
Int J Mol Sci ; 20(3)2019 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-30682769

RESUMO

Unacylated ghrelin (UnGhr) exerts several beneficial actions on vascular function. The aim of this study was to assess the effects of UnGhr on high-fat induced endothelial dysfunction and its underlying mechanisms. Thoracic aortas from transgenic mice, which were overexpressing UnGhr and being control fed either a standard control diet (CD) or a high-fat diet (HFD) for 16 weeks, were harvested and used for the assessment of vascular reactivity, endothelial nitric oxide synthase (eNOS) expression and activity, thiobarbituric acid reactive substances (TBARS) and glutathione levels, and aortic lipid accumulation by Oil Red O staining. Relaxations due to acetylcholine and to DEA-NONOate were reduced (p < 0.05) in the HFD control aortas compared to vessels from the CD animals. Overexpression of UnGhr prevented HFD-induced vascular dysfunction, while eNOS expression and activity were similar in all vessels. HFD-induced vascular oxidative stress was demonstrated by increased (p < 0.05) aortic TBARS and glutathione in wild type (Wt) mice; however, this was not seen in UnGhr mice. Moreover, increased (p < 0.05) HFD-induced lipid accumulation in vessels from Wt mice was prevented by UnGhr overexpression. In conclusion, chronic UnGhr overexpression results in improved vascular function and reduced plaque formation through decreased vascular oxidative stress, without affecting the eNOS pathway. This research may provide new insight into the mechanisms underlying the beneficial effects of UnGhr on the vascular dysfunction associated with obesity and the metabolic syndrome.


Assuntos
Aterosclerose/metabolismo , Endotélio Vascular/metabolismo , Grelina/genética , Animais , Aorta/metabolismo , Aterosclerose/etiologia , Aterosclerose/genética , Dieta Hiperlipídica/efeitos adversos , Grelina/metabolismo , Metabolismo dos Lipídeos , Masculino , Camundongos , Óxido Nítrico Sintase Tipo III , Estresse Oxidativo , Regulação para Cima
3.
Eur J Med Chem ; 164: 378-390, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30611057

RESUMO

As part of an effort to identify druggable diacylglycerol kinase alpha (DGKα) inhibitors, we used an in-silico approach based on chemical homology with the two commercially available DGKα inhibitors R59022 and R59949. Ritanserin and compound AMB639752 emerged from the screening of 127 compounds, showing an inhibitory activity superior to the two commercial inhibitors, being furthermore specific for the alpha isoform of diacylglycerol kinase. Interestingly, AMB639752 was also devoid of serotoninergic activity. The ability of both ritanserin and AMB639752, by inhibiting DGKα in intact cells, to restore restimulation induced cell death (RICD) in SAP deficient lymphocytes was also tested. Both compounds restored RICD at concentrations lower than the two previously available inhibitors, indicating their potential use for the treatment of X-linked lymphoproliferative disease 1 (XLP-1), a rare genetic disorder in which DGKα activity is deregulated.


Assuntos
Diacilglicerol Quinase/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos/métodos , Transtornos Linfoproliferativos/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Morte Celular/efeitos dos fármacos , Simulação por Computador , Humanos , Piperidinas , Pirimidinonas , Quinazolinonas , Ritanserina , Tiazóis
4.
Endocrine ; 62(1): 129-135, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29846901

RESUMO

PURPOSE: Muscle regeneration depends on satellite cells (SCs), quiescent precursors that, in consequence of injury or pathological states such as muscular dystrophies, activate, proliferate, and differentiate to repair the damaged tissue. A subset of SCs undergoes self-renewal, thus preserving the SC pool and its regenerative potential. The peptides produced by the ghrelin gene, i.e., acylated ghrelin (AG), unacylated ghrelin (UnAG), and obestatin (Ob), affect skeletal muscle biology in several ways, not always with overlapping effects. In particular, UnAG and Ob promote SC self-renewal and myoblast differentiation, thus fostering muscle regeneration. METHODS: To delineate the endogenous contribution of preproghrelin in muscle regeneration, we evaluated the repair process in Ghrl-/- mice upon CTX-induced injury. RESULTS: Although muscles from Ghrl-/- mice do not visibly differ from WT muscles in term of weight, structure, and SCs content, muscle regeneration after CTX-induced injury is impaired in Ghrl-/- mice, indicating that ghrelin-derived peptides actively participate in muscle repair. Remarkably, the lack of ghrelin gene impacts SC self-renewal during regeneration. CONCLUSIONS: Although we cannot discern the specific Ghrl-derived peptide responsible for such activities, these data indicate that Ghrl contributes to a proper muscle regeneration.


Assuntos
Grelina/metabolismo , Músculo Esquelético/metabolismo , Regeneração/fisiologia , Células Satélites de Músculo Esquelético/metabolismo , Animais , Grelina/genética , Masculino , Camundongos , Camundongos Knockout
5.
Small GTPases ; 9(4): 310-315, 2018 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-27533792

RESUMO

Several families of small GTPases regulate a variety of fundamental cellular processes, encompassing growth factor signal transduction, vesicular trafficking and control of the cytoskeleton. Frequently, their action is hierarchical and complementary, but much of the detail of their functional interactions remains to be clarified. It is well established that Rab family members regulate a variety of intracellular vesicle trafficking pathways. Moreover, Rho family GTPases are pivotal for the control of the actin and microtubule cytoskeleton. However, the interplay between these 2 types of GTPases has been rarely reported. We discuss here our recent findings showing that Rab11, a key regulator of endosomal recycling, and Rac1, a central actin cytoskeleton regulator involved in lamellipodium formation and cell migration, interplay on endosomes through the Rab11 effector FIP3. In the context of the rapidly reactive T lymphocytes, Rab11-Rac1 endosomal functional interplay is important to control cell shape changes and cell symmetry during lymphocyte spreading and immunological synapse formation and ultimately modulate T cell activation.


Assuntos
Forma Celular , Endossomos/metabolismo , Quinase I-kappa B/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Humanos
7.
Stem Cells ; 35(7): 1733-1746, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28436144

RESUMO

Muscle regeneration depends on satellite cells (SCs), quiescent precursors that, in consequence of injury or in pathological states such as muscular dystrophies, activate, proliferate, and differentiate to repair the damaged tissue. A subset of SCs undergoes self-renewal, thus preserving the SC pool and its regenerative potential. Unacylated ghrelin (UnAG) is a circulating hormone that protects muscle from atrophy, promotes myoblast differentiation, and enhances ischemia-induced muscle regeneration. Here we show that UnAG increases SC activity and stimulates Par polarity complex/p38-mediated asymmetric division, fostering both SC self-renewal and myoblast differentiation. Because of those activities on different steps of muscle regeneration, we hypothesized a beneficial effect of UnAG in mdx dystrophic mice, in which the absence of dystrophin leads to chronic muscle degeneration, defective muscle regeneration, fibrosis, and, at later stages of the pathology, SC pool exhaustion. Upregulation of UnAG levels in mdx mice reduces muscle degeneration, improves muscle function, and increases dystrophin-null SC self-renewal, maintaining the SC pool. Our results suggest that UnAG has significant therapeutic potential for preserving the muscles in dystrophies. Stem Cells 2017;35:1733-1746.


Assuntos
Distrofina/genética , Grelina/genética , Músculo Esquelético/metabolismo , Distrofia Muscular Animal/metabolismo , Regeneração/genética , Células Satélites de Músculo Esquelético/metabolismo , Acilação , Animais , Contagem de Células , Diferenciação Celular , Distrofina/metabolismo , Fibrose , Regulação da Expressão Gênica , Grelina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Músculo Esquelético/patologia , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/patologia , Fenótipo , Células Satélites de Músculo Esquelético/patologia , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
J Cell Physiol ; 232(9): 2550-2557, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27731506

RESUMO

Phosphatidylinositol (PI) signaling is an essential regulator of cell motility and proliferation. A portion of PI metabolism and signaling takes place in the nuclear compartment of eukaryotic cells, where an array of kinases and phosphatases localize and modulate PI. Among these, Diacylglycerol Kinases (DGKs) are a class of phosphotransferases that phosphorylate diacylglycerol and induce the synthesis of phosphatidic acid. Nuclear DGKalpha modulates cell cycle progression, and its activity or expression can lead to changes in the phosphorylated status of the Retinoblastoma protein, thus, impairing G1/S transition and, subsequently, inducing cell cycle arrest, which is often uncoupled with apoptosis or autophagy induction. Here we report for the first time not only that the DGKalpha isoform is highly expressed in the nuclei of human erythroleukemia cell line K562, but also that its nuclear activity drives K562 cells through the G1/S transition during cell cycle progression. J. Cell. Physiol. 232: 2550-2557, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Núcleo Celular/enzimologia , Proliferação de Células , Diacilglicerol Quinase/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Leucemia Eritroblástica Aguda/enzimologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/patologia , Proliferação de Células/efeitos dos fármacos , Diacilglicerol Quinase/antagonistas & inibidores , Diacilglicerol Quinase/genética , Relação Dose-Resposta a Droga , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Isoenzimas , Células K562 , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/patologia , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Fatores de Tempo , Transfecção
9.
Front Cell Dev Biol ; 4: 140, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27965956

RESUMO

Diacylglycerol kinases (DGKs) terminate diacylglycerol (DAG) signaling and promote phosphatidic acid (PA) production. Isoform specific regulation of DGKs activity and localization allows DGKs to shape the DAG and PA gradients. The capacity of DGKs to constrain the areas of DAG signaling is exemplified by their role in defining the contact interface between T cells and antigen presenting cells: the immune synapse. Upon T cell receptor engagement, both DGK α and ζ metabolize DAG at the immune synapse thus constraining DAG signaling. Interestingly, their activity and localization are not fully redundant because DGKζ activity metabolizes the bulk of DAG in the cell, whereas DGKα limits the DAG signaling area localizing specifically at the periphery of the immune synapse. When DGKs terminate DAG signaling, the local PA production defines a new signaling domain, where PA recruits and activates a second wave of effector proteins. The best-characterized example is the role of DGKs in protrusion elongation and cell migration. Indeed, upon growth factor stimulation, several DGK isoforms, such as α, ζ, and γ, are recruited and activated at the plasma membrane. Here, local PA production controls cell migration by finely modulating cytoskeletal remodeling and integrin recycling. Interestingly, DGK-produced PA also controls the localization and activity of key players in cell polarity such as aPKC, Par3, and integrin ß1. Thus, T cell polarization and directional migration may be just two instances of the general contribution of DGKs to the definition of cell polarity by local specification of membrane identity signaling.

10.
Diabetes ; 65(4): 874-86, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26822085

RESUMO

Excess reactive oxygen species (ROS) generation and inflammation may contribute to obesity-associated skeletal muscle insulin resistance. Ghrelin is a gastric hormone whose unacylated form (UnAG) is associated with whole-body insulin sensitivity in humans and may reduce oxidative stress in nonmuscle cells in vitro. We hypothesized that UnAG 1) lowers muscle ROS production and inflammation and enhances tissue insulin action in lean rats and 2) prevents muscle metabolic alterations and normalizes insulin resistance and hyperglycemia in high-fat diet (HFD)-induced obesity. In 12-week-old lean rats, UnAG (4-day, twice-daily subcutaneous 200-µg injections) reduced gastrocnemius mitochondrial ROS generation and inflammatory cytokines while enhancing AKT-dependent signaling and insulin-stimulated glucose uptake. In HFD-treated mice, chronic UnAG overexpression prevented obesity-associated hyperglycemia and whole-body insulin resistance (insulin tolerance test) as well as muscle oxidative stress, inflammation, and altered insulin signaling. In myotubes, UnAG consistently lowered mitochondrial ROS production and enhanced insulin signaling, whereas UnAG effects were prevented by small interfering RNA-mediated silencing of the autophagy mediator ATG5. Thus, UnAG lowers mitochondrial ROS production and inflammation while enhancing insulin action in rodent skeletal muscle. In HFD-induced obesity, these effects prevent hyperglycemia and insulin resistance. Stimulated muscle autophagy could contribute to UnAG activities. These findings support UnAG as a therapeutic strategy for obesity-associated metabolic alterations.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Grelina/farmacologia , Hiperglicemia/etiologia , Hiperglicemia/prevenção & controle , Inflamação/prevenção & controle , Músculo Esquelético/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Resistência à Insulina , Masculino , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
11.
Sci Transl Med ; 8(321): 321ra7, 2016 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-26764158

RESUMO

X-linked lymphoproliferative disease (XLP-1) is an often-fatal primary immunodeficiency associated with the exuberant expansion of activated CD8(+) T cells after Epstein-Barr virus (EBV) infection. XLP-1 is caused by defects in signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), an adaptor protein that modulates T cell receptor (TCR)-induced signaling. SAP-deficient T cells exhibit impaired TCR restimulation-induced cell death (RICD) and diminished TCR-induced inhibition of diacylglycerol kinase α (DGKα), leading to increased diacylglycerol metabolism and decreased signaling through Ras and PKCθ (protein kinase Cθ). We show that down-regulation of DGKα activity in SAP-deficient T cells restores diacylglycerol signaling at the immune synapse and rescues RICD via induction of the proapoptotic proteins NUR77 and NOR1. Pharmacological inhibition of DGKα prevents the excessive CD8(+) T cell expansion and interferon-γ production that occur in SAP-deficient mice after lymphocytic choriomeningitis virus infection without impairing lytic activity. Collectively, these data highlight DGKα as a viable therapeutic target to reverse the life-threatening EBV-associated immunopathology that occurs in XLP-1 patients.


Assuntos
Diacilglicerol Quinase/antagonistas & inibidores , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Morte Celular/efeitos dos fármacos , Citocinas/biossíntese , Diacilglicerol Quinase/metabolismo , Inativação Gênica/efeitos dos fármacos , Humanos , Sinapses Imunológicas/efeitos dos fármacos , Sinapses Imunológicas/metabolismo , Ativação Linfocitária , Contagem de Linfócitos , Transtornos Linfoproliferativos/tratamento farmacológico , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/deficiência , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/metabolismo , Tiazóis/farmacologia , Proteínas ras/metabolismo
12.
Nat Commun ; 6: 7388, 2015 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-26066847

RESUMO

Functional screening of expression libraries in vivo would offer the possibility of identifying novel biotherapeutics without a priori knowledge of their biochemical function. Here we describe a procedure for the functional selection of tissue-protective factors based on the in vivo delivery of arrayed cDNA libraries from the mouse secretome using adeno-associated virus (AAV) vectors. Application of this technique, which we call FunSel, in the context of acute ischaemia, revealed that the peptide ghrelin protects skeletal muscle and heart from ischaemic damage. When delivered to the heart using an AAV9 vector, ghrelin markedly reduces infarct size and preserves cardiac function over time. This protective activity associates with the capacity of ghrelin to sustain autophagy and remove dysfunctional mitochondria after myocardial infarction. Our findings describe an innovative tool to identify biological therapeutics and reveal a novel role of ghrelin as an inducer of myoprotective autophagy.


Assuntos
Apoptose/genética , Autofagia/genética , Grelina/genética , Mitocôndrias Cardíacas/metabolismo , Infarto do Miocárdio/genética , Animais , Animais Recém-Nascidos , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Dependovirus , Doxorrubicina/farmacologia , Perfilação da Expressão Gênica , Biblioteca Gênica , Técnicas de Transferência de Genes , Vetores Genéticos , Membro Posterior/irrigação sanguínea , Técnicas Imunoenzimáticas , Marcação In Situ das Extremidades Cortadas , Isquemia/genética , Isquemia/metabolismo , Camundongos , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Mitocôndrias Cardíacas/ultraestrutura , Músculo Esquelético/irrigação sanguínea , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Ultrassonografia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia
13.
Int J Endocrinol ; 2015: 385682, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25960743

RESUMO

Fibrosis can affect almost all tissues and organs, it often represents the terminal stage of chronic diseases, and it is regarded as a major health issue for which efficient therapies are needed. Tissue injury, by inducing necrosis/apoptosis, triggers inflammatory response that, in turn, promotes fibroblast activation and pathological deposition of extracellular matrix. Acylated and unacylated ghrelin are the main products of the ghrelin gene. The acylated form, through its receptor GHSR-1a, stimulates appetite and growth hormone (GH) release. Although unacylated ghrelin does not bind or activate GHSR-1a, it shares with the acylated form several biological activities. Ghrelin peptides exhibit anti-inflammatory, antioxidative, and antiapoptotic activities, suggesting that they might represent an efficient approach to prevent or reduce fibrosis. The aim of this review is to summarize the available evidence regarding the effects of acylated and unacylated ghrelin on different pathologies and experimental models in which fibrosis is a predominant characteristic.

14.
J Interferon Cytokine Res ; 35(6): 441-53, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25715050

RESUMO

The nuclear interferon-inducible-16 (IFI16) protein acts as DNA sensor in inflammasome signaling and as viral restriction factor. Following Herpesvirus infection or UV-B treatment, IFI16 delocalizes from the nucleus to the cytoplasm and is eventually released into the extracellular milieu. Recently, our group has demonstrated the occurrence of IFI16 in sera of systemic-autoimmune patients that hampers biological activity of endothelia through high-affinity membrane binding. As a continuation, we studied the activity of endotoxin-free recombinant IFI16 (rIFI16) protein on primary endothelial cells. rIFI16 caused dose/time-dependent upregulation of IL-6, IL-8, CCL2, CCL5, CCL20, ICAM1, VCAM1, and TLR4, while secretion of IL-6 and IL-8 was amplified with lipopolysaccharide synergy. Overall, cytokine secretion was completely inhibited in MyD88-silenced cells and partially by TLR4-neutralizing antibodies. By screening downstream signaling pathways, we found that IFI16 activates p38, p44/42 MAP kinases, and NF-kB. In particular, activation of p38 is an early event required for subsequent p44/42 MAP kinases activity and cytokine induction indicating a key role of this kinase in IFI16 signaling. Altogether, our data conclude that extracellular IFI16 protein alone or by synergy with lipopolysaccharide acts like Damage-associated molecular patterns propagating "Danger Signal" through MyD88-dependent TLR-pathway.


Assuntos
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Inflamassomos/efeitos dos fármacos , Proteínas Nucleares/farmacologia , Fosfoproteínas/farmacologia , Fator de Transcrição RelA/agonistas , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Anticorpos Neutralizantes/farmacologia , Citocinas/biossíntese , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamassomos/metabolismo , Lipopolissacarídeos/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Fosfoproteínas/biossíntese , Fosfoproteínas/genética , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Transdução de Sinais , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
PLoS One ; 9(6): e97144, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24887021

RESUMO

Diacylglycerol kinase α (DGKα), by phosphorylating diacylglycerol into phosphatidic acid, provides a key signal driving cell migration and matrix invasion. We previously demonstrated that in epithelial cells activation of DGKα activity promotes cytoskeletal remodeling and matrix invasion by recruiting atypical PKC at ruffling sites and by promoting RCP-mediated recycling of α5ß1 integrin to the tip of pseudopods. In here we investigate the signaling pathway by which DGKα mediates SDF-1α-induced matrix invasion of MDA-MB-231 invasive breast carcinoma cells. Indeed we showed that, following SDF-1α stimulation, DGKα is activated and localized at cell protrusion, thus promoting their elongation and mediating SDF-1α induced MMP-9 metalloproteinase secretion and matrix invasion. Phosphatidic acid generated by DGKα promotes localization at cell protrusions of atypical PKCs which play an essential role downstream of DGKα by promoting Rac-mediated protrusion elongation and localized recruitment of ß1 integrin and MMP-9. We finally demonstrate that activation of DGKα, atypical PKCs signaling and ß1 integrin are all essential for MDA-MB-231 invasiveness. These data indicates the existence of a SDF-1α induced DGKα - atypical PKC - ß1 integrin signaling pathway, which is essential for matrix invasion of carcinoma cells.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quimiocina CXCL12/farmacologia , Diacilglicerol Quinase/metabolismo , Integrina beta1/metabolismo , Proteína Quinase C/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica , Transporte Proteico/efeitos dos fármacos , Pseudópodes/efeitos dos fármacos , Pseudópodes/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo
16.
Curr Opin Clin Nutr Metab Care ; 17(3): 236-40, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24572833

RESUMO

PURPOSE OF REVIEW: Muscle wasting is a comorbidity often associated with a wide range of disorders that severely affects patient prognosis and quality of life. Ghrelin, through its receptor GHSR-1a, stimulates appetite and growth hormone (GH) release. Several studies indicate that ghrelin administration is a valid treatment for cachexia because it improves muscle mass and function, likely by restoring a positive energy balance. RECENT FINDINGS: In addition to its GHSR-1a-mediated effects on muscle mass, ghrelin acts directly on skeletal muscle, wherein it exerts a protective activity against muscle wasting. This direct activity is independent of GHSR-1a and is shared by the unacylated form of ghrelin, which does not bind GHSR-1a and is devoid of the effects on appetite and GH release. SUMMARY: Both the acylated and unacylated forms of ghrelin might have therapeutic potential for the treatment of skeletal muscle wasting.


Assuntos
Grelina/química , Grelina/uso terapêutico , Atrofia Muscular/tratamento farmacológico , Síndrome de Emaciação/tratamento farmacológico , Acilação , Caquexia/tratamento farmacológico , Humanos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Atrofia Muscular/fisiopatologia , Receptores de Grelina/fisiologia
17.
Biomedicines ; 3(1): 1-31, 2014 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-28536396

RESUMO

The "hepatocyte growth factor" also known as "scatter factor", is a multifunctional cytokine with the peculiar ability of simultaneously triggering epithelial cell proliferation, movement and survival. The combination of those proprieties results in the induction of an epithelial to mesenchymal transition in target cells, fundamental for embryogenesis but also exploited by tumor cells during metastatization. The hepatocyte growth factor receptor, MET, is a proto-oncogene and a prototypical transmembrane tyrosine kinase receptor. Inhere we discuss the MET molecular structure and the hepatocyte growth factor driven physiological signaling which coordinates epithelial proliferation, motility and morphogenesis.

18.
Int Rev Neurobiol ; 108: 207-21, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24083436

RESUMO

Promoting neuromuscular recovery after neural injury is a major clinical issue. While techniques for nerve reconstruction are continuously improving and most peripheral nerve lesions can be repaired today, recovery of the lost function is usually unsatisfactory. This evidence claims for innovative nonsurgical therapeutic strategies that can implement the outcome after neural repair. Although no pharmacological approach for improving posttraumatic neuromuscular recovery has still entered clinical practice, various molecules are explored in experimental models of neural repair. One of such molecules is the circulating peptide hormone ghrelin. This hormone has proved to have a positive effect on neural repair after central nervous system lesion, and very recently its effectiveness has also been demonstrated in preventing posttraumatic skeletal muscle atrophy. By contrast, no information is still available about its effectiveness on peripheral nerve regeneration although preliminary data from our laboratory suggest that this molecule can have an effect also in promoting axonal regeneration after nerve injury and repair. Should this be confirmed, ghrelin might represent an ideal candidate as a therapeutic agent for improving posttraumatic neuromuscular recovery because of its putative effects at all the various structural levels involved in this regeneration process, namely, the central nervous system, the peripheral nerve, and the target skeletal muscle.


Assuntos
Grelina/sangue , Fármacos Neuromusculares/sangue , Traumatismos dos Nervos Periféricos/sangue , Recuperação de Função Fisiológica/fisiologia , Animais , Axônios/metabolismo , Grelina/uso terapêutico , Humanos , Regeneração Nervosa/fisiologia , Fármacos Neuromusculares/uso terapêutico , Traumatismos dos Nervos Periféricos/tratamento farmacológico
19.
J Clin Invest ; 123(2): 611-22, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23281394

RESUMO

Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghrelin is a peptide hormone that stimulates growth hormone (GH) release and positive energy balance through binding to the receptor GHSR-1a. Only acylated ghrelin (AG), but not the unacylated form (UnAG), can bind GHSR-1a; however, UnAG and AG share several GHSR-1a-independent biological activities. Here we investigated whether UnAG and AG could protect against skeletal muscle atrophy in a GHSR-1a-independent manner. We found that both AG and UnAG inhibited dexamethasone-induced skeletal muscle atrophy and atrogene expression through PI3Kß-, mTORC2-, and p38-mediated pathways in myotubes. Upregulation of circulating UnAG in mice impaired skeletal muscle atrophy induced by either fasting or denervation without stimulating muscle hypertrophy and GHSR-1a-mediated activation of the GH/IGF-1 axis. In Ghsr-deficient mice, both AG and UnAG induced phosphorylation of Akt in skeletal muscle and impaired fasting-induced atrophy. These results demonstrate that AG and UnAG act on a common, unidentified receptor to block skeletal muscle atrophy in a GH-independent manner.


Assuntos
Grelina/química , Grelina/farmacologia , Atrofia Muscular/prevenção & controle , Acilação , Animais , Caquexia/metabolismo , Caquexia/prevenção & controle , Linhagem Celular , Grelina/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Complexos Multiproteicos/metabolismo , Denervação Muscular , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Grelina/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
20.
Hematol Oncol ; 31(1): 22-8, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22488585

RESUMO

We investigated immunodeficiency-related non-Hodgkin lymphoma for the presence of molecular alterations affecting negative regulators of the Janus family protein tyrosine kinase/signal transducer and activator of transcription pathway. Protein tyrosine phosphatase, non-receptor type 6/Src homology 2-containing tyrosine phosphatase-1 epigenetic silencing was recurrent in primary effusion lymphoma (100%), and diffuse large B-cell lymphoma (63%), with a higher prevalence in the non-germinal centre subtype, and was associated with the activation of the Janus family protein tyrosine kinase/signal transducer and activator of transcription 3 pathway. Suppressor of cytokine signalling (SOCS)1 and SOCS3 epigenetic silencing were occasionally detected, whereas SOCS1 was frequently mutated in diffuse large B-cell lymphoma and polymorphic post-transplant lymphoproliferative disorders, possibly as a cause of aberrant somatic hypermutation. However, the mutation profile of the coding region of the gene was different from that expected from the aberrant somatic hypermutation process, suggesting that, at least in some cases, SOCS1 mutations may have been selected for their functional activity.


Assuntos
Citocinas/fisiologia , Metilação de DNA , Linfoma Relacionado a AIDS/genética , Transtornos Linfoproliferativos/genética , Proteínas de Neoplasias/genética , Complicações Pós-Operatórias/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Linhagem Celular Tumoral , Evolução Clonal , Análise Mutacional de DNA , DNA de Neoplasias/genética , Humanos , Hospedeiro Imunocomprometido , Janus Quinases/fisiologia , Linfoma Relacionado a AIDS/fisiopatologia , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/fisiopatologia , Mutação , Proteínas de Neoplasias/fisiologia , Transplante de Órgãos , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/fisiopatologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/fisiologia , Estudos Retrospectivos , Fatores de Transcrição STAT/fisiologia , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA