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1.
Therapie ; 70(1): 95-109, 2015.
Artigo em Inglês, Francês | MEDLINE | ID: mdl-25747841

RESUMO

The initiation of Horizon 2020--the European Union's 8th Framework Programme for Research and Innovation, allotted a budget of 79 billion euros--provides an opportunity to review France's participation in previous Framework Programmes. Indeed, French participation does not match either its scientific importance or its financial investment. While France contributed 16.5 to 17% of the EU's 7th Framework Programme research budget, its return through the funding of coordinated projects in which French teams are participating stands at around 12.5 to 13%, a shortfall of 600 million euros. Although the situation depends on the type of activity, French participation in clinical research appears to be smaller than that of its neighbours, with fewer responses to European calls for proposals. While France has many assets, which include the assured funding of clinical research, structured thematic networks and the initiation of major national programmes, it suffers from the dilution of resources due to France's regional development policy, the lack of multidisciplinarity and the ignorance of both the medical and scientific community and the institutions to which they belong as to how Horizon 2020 actually works. We propose three types of strategy to encourage proposals for coordinated clinical research projects or projects involving French teams, and to help in the drawing up of applications: Broaden the vision of our children, students and colleagues, helping them to adapt to the globalisation of knowledge throughout their educational and professional lives. Recognise the value of European actions to influence the European landscape and change mentalities. Help and support project initiators by pooling skills within a limited number of expert centres designed to assist them in their funding application. • Broaden the vision of our children, students and colleagues, helping them to adapt to the globalisation of knowledge throughout their educational and professional lives. • Recognise the value of European actions to influence the European landscape and change mentalities. • Help and support project initiators by pooling skills within a limited number of expert centres designed to assist them in their funding application.


Assuntos
Invenções , Pesquisa/organização & administração , Academias e Institutos/economia , Academias e Institutos/organização & administração , Pesquisa Biomédica/economia , Pesquisa Biomédica/estatística & dados numéricos , Pesquisa Biomédica/tendências , Orçamentos , União Europeia , Financiamento Governamental , França , Objetivos , Cooperação Internacional , Internacionalidade , Invenções/economia , Política Pública , Parcerias Público-Privadas , Pesquisa/economia , Pesquisa/legislação & jurisprudência , Pesquisa/tendências , Apoio à Pesquisa como Assunto , Alocação de Recursos
2.
Arterioscler Thromb Vasc Biol ; 30(4): 781-6, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20110577

RESUMO

OBJECTIVE: We previously reported that a systemic liver X receptor (LXR) agonist promoted macrophage reverse-cholesterol transport (mRCT) in vivo. Because LXR are expressed in multiple tissues involved in RCT (macrophages, liver, intestine), we analyzed the effect of tissue-specific LXR agonism on mRCT. METHODS AND RESULTS: In initial studies, the systemic LXR agonist GW3965 failed to promote mRCT in a setting in which LXR was expressed in macrophages but not in liver or intestine. To evaluate the effect of LXR activation specifically in small intestine on mRCT, wild-type mice were treated with either intestinal-specific LXR agonist (GW6340) or systemic LXR agonist (GW3965). Both GW3965 and GW6340 significantly promoted excretion of [(3)H]-sterol in feces by 162% and 52%, respectively. To evaluate the requirement for macrophage LXR activation, we assessed the ability of GW3965 to promote mRCT in wild-type mice using primary macrophages deficient in LXR alpha/beta vs wild-type macrophages. Whereas GW3965 treatment promoted fecal excretion compared with vehicle, its overall ability to promote mRCT was significantly attenuated using LXR alpha/beta knockout macrophages. CONCLUSIONS: We demonstrate that intestinal-specific LXR agonism promotes macrophage RCT in vivo and that macrophage LXR itself plays an important, but not predominant, role in promoting RCT in response to an LXR agonist.


Assuntos
Benzoatos/farmacologia , Benzilaminas/farmacologia , Colesterol/metabolismo , Intestino Delgado/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Receptores Nucleares Órfãos/agonistas , Animais , Transporte Biológico , Linhagem Celular , Fezes/química , Intestino Delgado/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Fatores de Tempo
4.
J Lipid Res ; 50(10): 2046-54, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19439761

RESUMO

Peroxisome proliferator-activated receptor delta (PPARdelta) is involved in regulation of energy homeostasis. Activation of PPARdelta markedly increases fecal neutral sterol secretion, the last step in reverse cholesterol transport. This phenomenon can neither be explained by increased hepatobiliary cholesterol secretion, nor by reduced cholesterol absorption. To test the hypothesis that PPARdelta activation leads to stimulation of transintestinal cholesterol efflux (TICE), we quantified it by intestine perfusions in FVB mice treated with PPARdelta agonist GW610742. To exclude the effects on cholesterol absorption, mice were also treated with cholesterol absorption inhibitor ezetimibe or ezetimibe/GW610742. GW601742 treatment had little effect on plasma lipid levels but stimulated both fecal neutral sterol excretion ( approximately 200%) and TICE ( approximately 100%). GW610742 decreased intestinal Npc1l1 expression but had no effect on Abcg5/Abcg8. Interestingly, expression of Rab9 and LIMPII, encoding proteins involved in intracellular cholesterol trafficking, was increased upon PPARdelta activation. Although treatment with ezetimibe alone had no effect on TICE, it reduced the effect of GW610742 on TICE. These data show that activation of PPARdelta stimulates fecal cholesterol excretion in mice, primarily by the two-fold increase in TICE, indicating that this pathway provides an interesting target for the development of drugs aiming at the prevention of atherosclerosis.


Assuntos
Transporte Biológico/efeitos dos fármacos , Colesterol/metabolismo , Mucosa Intestinal/metabolismo , PPAR delta/metabolismo , Animais , Ingestão de Alimentos/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Lipoproteínas/metabolismo , Fígado/metabolismo , Masculino , Camundongos , PPAR delta/genética , RNA Mensageiro , Tiazóis/farmacologia
5.
Endocrinology ; 149(10): 5128-35, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18566121

RESUMO

Liver X receptor-alpha (LXRalpha) and LXRbeta are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They have been identified as key players in cholesterol homeostasis and lipid and glucose metabolism as well as immune and inflammatory responses. In the small intestine, LXRs have been shown not only to regulate cholesterol absorption and excretion but also to promote high-density lipoprotein biogenesis via the ATP-binding cassette A1 signaling pathway. Here, using gene expression assays, we identified PPARalpha as an intestine-specific LXR target gene. Chronic administration of LXR synthetic agonists led to a significant increase of PPARalpha mRNA levels in the small intestine but not in the liver. In addition, this specific PPARalpha gene up-regulation occurred in the duodenum, jejunum, and ileum in a dose-dependent manner and translated at the protein level as demonstrated by Western blot analysis. Furthermore, PPARalpha gene induction was completely abolished in LXR-deficient mice. Finally, the physiological relevance of LXR-mediated PPARalpha up-regulation in the small intestine was assessed in PPARalpha-deficient mice. Administration of a synthetic LXR agonist to wild-type mice led to the induction of several PPARalpha target genes including PDK4 and CPT1. Those effects were completely abolished in PPARalpha-deficient mice, demonstrating the biological relevance of this LXR-PPARalpha transcriptional cascade. Taken together, these results demonstrate that PPARalpha is an intestine-specific LXR target gene and suggest the existence of a transcriptional cross talk between those members of the nuclear receptor superfamily.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Intestinos/fisiologia , PPAR alfa/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Benzoatos/farmacologia , Benzilaminas/farmacologia , Proteínas de Ligação a DNA/agonistas , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica/fisiologia , Homeostase/fisiologia , Hidrocarbonetos Fluorados , Metabolismo dos Lipídeos/fisiologia , Fígado/fisiologia , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Especificidade de Órgãos , Receptores Nucleares Órfãos , PPAR alfa/metabolismo , RNA Mensageiro/metabolismo , Receptor Cross-Talk/fisiologia , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/genética , Sulfonamidas/farmacologia , Transcrição Gênica/fisiologia , Ativação Transcricional
7.
J Med Chem ; 49(7): 2210-21, 2006 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-16570917

RESUMO

Inhibitors of transforming growth factor beta (TGF-beta) type I receptor (ALK5) offer a novel approach for the treatment of fibrotic diseases such as renal, hepatic, and pulmonary fibrosis. The optimization of a novel phenylpyridine pyrazole series (1a) led to the identification of potent, selective, and orally active ALK5 inhibitors. The cellular potency and pharmacokinetics profiles of these derivatives were improved and several compounds presented antifibrotic activity when orally administered to rats in an acute liver model of dimethylnitrosamine- (DMN-) induced expression of collagen IA1 mRNA, a major gene contributing to excessive extra cellular matrix deposit. One of the most potent ALK5 inhibitors identified in this chemical series, compound 13d (GW788388), reduced the expression of collagen IA1 by 80% at a dose of 1 mg/kg twice a day (b.i.d.). This compound significantly reduced the expression of collagen IA1 mRNA when administered orally at 10 mg/kg once a day (u.i.d.) in a model of puromycin aminonucleoside-induced renal fibrosis.


Assuntos
Receptores de Ativinas Tipo I/antagonistas & inibidores , Benzamidas/síntese química , Pirazóis/síntese química , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Doença Aguda , Administração Oral , Animais , Benzamidas/farmacocinética , Benzamidas/farmacologia , Colágeno Tipo I/antagonistas & inibidores , Colágeno Tipo I/biossíntese , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Dimetilnitrosamina , Fibrose , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Masculino , Modelos Moleculares , Proteínas Serina-Treonina Quinases , Puromicina Aminonucleosídeo , Pirazóis/farmacocinética , Pirazóis/farmacologia , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Receptor do Fator de Crescimento Transformador beta Tipo I , Relação Estrutura-Atividade
8.
Drug News Perspect ; 19(2): 85-90, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16628263

RESUMO

Liver fibrosis is the result of an unbalanced wound healing response to a chronic hepatic injury. Transforming growth factor-beta (TGF-beta) plays a major role in this process via the activation of hepatic stellate cells. Various approaches have been tested in animal models of fibrosis to block the effects of TGF-beta, including antibodies and soluble receptors. Here, we discuss the potential use of TGF-beta signaling inhibitors, acting at the TGF-beta type I receptor kinase (ALK5) level, as a possible therapy for liver fibrosis. Thus far, there is only one ALK5 inhibitor (GW6604) for which activity in models of liver fibrosis has been described, showing clear antifibrotic effects resulting in liver function improvement. However, due to the pleiotropic effects of TGF-beta, the beneficial antifibrotic effects of ALK5 inhibition should be carefully balanced against the potential risk of unwanted effects stemming from chronic treatment.


Assuntos
Receptores de Ativinas Tipo I/antagonistas & inibidores , Cirrose Hepática/tratamento farmacológico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Humanos , Cirrose Hepática/patologia , Proteínas Serina-Treonina Quinases , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Piridinas/efeitos adversos , Piridinas/farmacologia , Receptor do Fator de Crescimento Transformador beta Tipo I , Fator de Crescimento Transformador beta/fisiologia
9.
Br J Pharmacol ; 145(2): 166-77, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15723089

RESUMO

1 Chronic liver disease is characterized by an exacerbated accumulation of matrix, causing progressive fibrosis, which may lead to cirrhosis. Transforming growth factor beta (TGF-beta), a well-known profibrotic cytokine, transduces its signal through the ALK5 ser/thr kinase receptor, and increases transcription of different genes including PAI-1 and collagens. The identification of GW6604 (2-phenyl-4-(3-pyridin-2-yl-1H-pyrazol-4-yl)pyridine), an ALK5 inhibitor, allowed us to evaluate the therapeutic potential of inhibiting TGF-beta pathway in different models of liver disease. 2 A cellular assay was used to identify GW6604 as a TGF-beta signaling pathway inhibitor. This ALK5 inhibitor was then tested in a model of liver hepatectomy in TGF-beta-overexpressing transgenic mice, in an acute model of liver disease and in a chronic model of dimethylnitrosamine (DMN)-induced liver fibrosis. 3 In vitro, GW6604 inhibited autophosphorylation of ALK5 with an IC(50) of 140 nM and in a cellular assay inhibited TGF-beta-induced transcription of PAI-1 (IC(50): 500 nM). In vivo, GW6604 (40 mg kg(-1) p.o.) increased liver regeneration in TGF-beta-overexpressing mice, which had undergone partial hepatectomy. In an acute model of liver disease, GW6604 reduced by 80% the expression of collagen IA1. In a chronic model of DMN-induced fibrosis where DMN was administered for 6 weeks and GW6604 dosed for the last 3 weeks (80 mg kg(-1) p.o., b.i.d.), mortality was prevented and DMN-induced elevations of mRNA encoding for collagen IA1, IA2, III, TIMP-1 and TGF-beta were reduced by 50-75%. Inhibition of matrix genes overexpression was accompanied by reduced matrix deposition and reduction in liver function deterioration, as assessed by bilirubin and liver enzyme levels. 4 Our results suggest that inhibition of ALK5 could be an attractive new approach to treatment of liver fibrotic diseases by both preventing matrix deposition and promoting hepatocyte regeneration.


Assuntos
Receptores de Ativinas Tipo I/antagonistas & inibidores , Dimetilnitrosamina , Cirrose Hepática/prevenção & controle , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/antagonistas & inibidores , Receptores de Ativinas Tipo I/metabolismo , Doença Aguda , Animais , Linhagem Celular Tumoral , Doença Crônica , Hepatectomia , Humanos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Regeneração Hepática/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Fosforilação , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Inibidor 1 de Ativador de Plasminogênio/genética , Proteínas Serina-Treonina Quinases , Ratos , Ratos Sprague-Dawley , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Transcrição Gênica , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/fisiologia
10.
J Med Chem ; 47(18): 4494-506, 2004 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-15317461

RESUMO

Optimization of the screening hit 1 led to the identification of novel 1,5-naphthyridine aminothiazole and pyrazole derivatives, which are potent and selective inhibitors of the transforming growth factor-beta type I receptor, ALK5. Compounds 15 and 19, which inhibited ALK5 autophosphorylation with IC50 = 6 and 4 nM, respectively, showed potent activities in both binding and cellular assays and exhibited selectivity over p38 mitogen-activated protein kinase. The X-ray crystal structure of 19 in complex with human ALK5 is described, confirming the binding mode proposed from docking studies.


Assuntos
Receptores de Ativinas Tipo I/antagonistas & inibidores , Naftiridinas/síntese química , Naftiridinas/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Sítios de Ligação , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Fosforilação/efeitos dos fármacos , Ligação Proteica , Proteínas Serina-Treonina Quinases , Pirazóis/síntese química , Pirazóis/farmacologia , Receptor do Fator de Crescimento Transformador beta Tipo I , Relação Estrutura-Atividade
11.
Toxicol Pathol ; 35(2): 284-95, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17366323

RESUMO

TGF-beta, and its type 1 (ALK5) receptor, are critical to the pathogenesis of fibrosis. In toxicologic studies of 4 or more days in 10-week-old Sprague-Dawley rats, using an ALK5 inhibitor (GW788388), expansion of hypertrophic and proliferation zones of femoral physes were noted. Subphyseal hyperostosis, chondrocyte hypertrophy/hyperplasia, and increased matrix were present. Physeal zones were laser microdissected from ALK5 inhibitor-treated and control rats sacrificed after 3 days of treatment. Transcripts for TGF-beta1, TGF-beta2, ALK5, IHH, VEGF, BMP-7, IGF-1, bFGF, and PTHrP were amplified by real-time PCR. IGF and IHH increased in all physis zones with treatment, but were most prominent in prehypertrophic zones. TGF-beta2, bFGF and BMP7 expression increased in proliferative, pre-and hypertrophic zones. PTHrP expression was elevated in proliferative zones but decreased in hypertrophic zones. VEGF expression was increased after treatment in pre- and hypertrophic zones. ALK5 expression was elevated in prehypertrophic zones. Zymography demonstrated gelatinolytic activity was reduced after treatment. Apoptotic markers (TUNEL and caspase-3) were decreased in hypertrophic zones. Proliferation assessed by Topoisomerase II and Ki67 was increased in multiple zones. Movat stains demonstrated that proteoglycan deposition was altered. Physeal changes occurred at doses well above those resulting in fibrosis. Interactions of factors is important in producing the physeal dysplasia phenotype.


Assuntos
Receptores de Ativinas Tipo I/metabolismo , Doenças do Desenvolvimento Ósseo/induzido quimicamente , Lâmina de Crescimento/patologia , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/fisiologia , Receptores de Ativinas Tipo I/antagonistas & inibidores , Receptores de Ativinas Tipo I/genética , Animais , Benzamidas/efeitos adversos , Doenças do Desenvolvimento Ósseo/patologia , Proliferação de Células , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Lâmina de Crescimento/efeitos dos fármacos , Proteínas Serina-Treonina Quinases , Pirazóis/efeitos adversos , Ratos , Ratos Sprague-Dawley , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/fisiologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/fisiologia
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