Base de dados : MEDLINE
Pesquisa : D04.210.500.221 [Categoria DeCS]
Referências encontradas : 146 [refinar]
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[PMID]:26860282
[Au] Autor:Ambrosio E; Barattin M; Bersani S; Shubber S; Uddin S; van der Walle CF; Caliceti P; Salmaso S
[Ad] Endereço:Department of Pharmaceutical and Pharmacological Sciences, Università degli Studi di Padova, via F. Marzolo 5, 35131 Padova, Italy.
[Ti] Título:A novel combined strategy for the physical PEGylation of polypeptides.
[So] Source:J Control Release;226:35-46, 2016 Mar 28.
[Is] ISSN:1873-4995
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Poly(ethylene glycol) (PEG) may be covalently conjugated to peptide drugs to overcome their rapid clearance but in doing so their potency can be lost. Here, a non-covalent approach was used to conjugate PEG bearing a terminal cholanic moiety (mPEG5kDa-cholane) to a 28 amino acid peptide, vasoactive intestinal peptide (VIP). Palmitoylation of the peptide was essential to facilitate physical interaction via a single binding site involving two mPEG5kDa-cholane molecules with an affinity constant of ~3·10(4)M(-1); these calorimetry data corroborating Scatchard analysis of dissolution data. The peptide/polymer complex (below 10-12nm diameter) provided for up to 5000-fold greater solubility of the peptide at pH7.4 (4µg/mL) and markedly increased peptide solution stability at 25°C over 30days. Mannitol enabled the complex to be lyophilized to yield a freeze-dried formulation which was efficiently reconstituted albeit with an ~10% decrease in solubility. The predominantly α-helical conformation of the peptide alone at pH5-6.5 was lost at pH7.4 but fully recovered with 2 molar equivalents of mPEG5kDa-cholane. After lyophilization and reconstitution an ~10% loss of α-helical conformation was observed, which may reflect the equivalent decrease in solubility. Pharmacokinetic studies following subcutaneous administration of the peptide (0.1mg/Kg) alone and with 2 molar equivalents of polymer showed that mPEG5kDa-cholane dramatically increased peptide concentration in the systemic circulation. This is the first demonstration of non-covalent PEGylation of acylated peptides, an important biologic class, which improves in vitro and in vivo properties, and thereby may prove an alternative to covalent PEGylation strategies.
[Mh] Termos MeSH primário: Colanos/química
Peptídeos/sangue
Peptídeos/química
Polietilenoglicóis/química
Peptídeo Intestinal Vasoativo/sangue
Peptídeo Intestinal Vasoativo/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Liofilização
Masculino
Ratos Sprague-Dawley
Solubilidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cholanes); 0 (Peptides); 30IQX730WE (Polyethylene Glycols); 37221-79-7 (Vasoactive Intestinal Peptide)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160211
[St] Status:MEDLINE


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[PMID]:26177448
[Au] Autor:Cipriani S; Renga B; D'Amore C; Simonetti M; De Tursi AA; Carino A; Monti MC; Sepe V; Zampella A; Fiorucci S
[Ad] Endereço:Department of Medicine University of Perugia, Perugia, Italy.
[Ti] Título:Impaired Itching Perception in Murine Models of Cholestasis Is Supported by Dysregulation of GPBAR1 Signaling.
[So] Source:PLoS One;10(7):e0129866, 2015.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: In cholestatic syndromes, body accumulation of bile acids is thought to cause itching. However, the mechanisms supporting this effect remain elusive. Recently, GPBAR1 (TGR5) a G-protein coupled receptor has been shown to mediate itching caused by intradermal administration of DCA and LCA. 6α-ethyl-3α, 7α-dihydroxy-24-nor-5ß-cholan-23-ol (BAR502) is a non-bile acid dual ligand for FXR and GPBAR1. METHODS: Cholestasis was induced in wild type and GPBAR1-/- mice by administration of α-naphthyl-isothiocyanate (ANIT) or 17α-ethynylestradiol. RESULTS: In naïve mice skin application of DCA, TLCA, 6-ECDCA, oleanolic and betulinic acid induces a GPBAR1 dependent pruritogenic response that could be desensitized by re-challenging the mice with the same GPBAR1 agonist. In wild type and GPBAR1-/- mice cholestasis induced by ANIT fails to induce spontaneous itching and abrogates scratching behavior caused by intradermal administration of DCA. In this model, co-treatment with BAR502 increases survival, attenuates serum alkaline phosphatase levels and robustly modulates the liver expression of canonical FXR target genes including OSTα, BSEP, SHP and MDR1, without inducing pruritus. Betulinic acid, a selective GPBAR1 ligand, failed to rescue wild type and GPBAR1-/- mice from ANIT cholestasis but did not induced itching. In the 17α-ethynylestradiol model BAR502 attenuates cholestasis and reshapes bile acid pool without inducing itching. CONCLUSIONS: The itching response to intradermal injection of GPBAR1 agonists desensitizes rapidly and is deactivated in models of cholestasis, explain the lack of correlation between bile acids levels and itching severity in cholestatic syndromes. In models of non-obstructive cholestasis, BAR502 attenuates liver injury without causing itching.
[Mh] Termos MeSH primário: Colestase/complicações
Prurido/metabolismo
Prurido/patologia
Receptores Acoplados a Proteínas-G/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Ácidos e Sais Biliares/efeitos adversos
Ácidos e Sais Biliares/sangue
Doença Hepática Induzida por Substâncias e Drogas/genética
Doença Hepática Induzida por Substâncias e Drogas/metabolismo
Colanos/metabolismo
Colanos/farmacologia
Colestase/induzido quimicamente
Colestase/fisiopatologia
Colestase/prevenção & controle
Modelos Animais de Doenças
Estrogênios/efeitos adversos
Deleção de Genes
Isotiocianatos/efeitos adversos
Ligantes
Masculino
Camundongos
Prurido/induzido quimicamente
Prurido/complicações
Receptores Citoplasmáticos e Nucleares/metabolismo
Receptores Acoplados a Proteínas-G/deficiência
Receptores Acoplados a Proteínas-G/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Cholanes); 0 (Estrogens); 0 (Gpbar1 protein, mouse); 0 (Isothiocyanates); 0 (Ligands); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Receptors, G-Protein-Coupled); 0 (farnesoid X-activated receptor); 3129-90-6 (isothiocyanic acid)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150716
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0129866


  3 / 146 MEDLINE  
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[PMID]:25247751
[Au] Autor:Festa C; Renga B; D'Amore C; Sepe V; Finamore C; De Marino S; Carino A; Cipriani S; Monti MC; Zampella A; Fiorucci S
[Ad] Endereço:Department of Pharmacy, University of Naples "Federico II" , Via D. Montesano 49, I-80131 Naples, Italy.
[Ti] Título:Exploitation of cholane scaffold for the discovery of potent and selective farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 1 (GP-BAR1) ligands.
[So] Source:J Med Chem;57(20):8477-95, 2014 Oct 23.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nuclear and G-protein coupled receptors are considered major targets for drug discovery. FXR and GP-BAR1, two bile acid-activated receptors, have gained increasing consideration as druggable receptors. Because endogenous bile acids often target both receptor families, the development of selective ligands has been proven difficult, exposing patients to side effects linked to an unwanted activation of one of the two receptors. In the present study, we describe a novel library of semisynthetic bile acid derivatives obtained by modifications on the cholane scaffold. The pharmacological characterization of this library led to the discovery of 7α-hydroxy-5ß-cholan-24-sulfate (7), 6ß-ethyl-3α,7ß-dihydroxy-5ß-cholan-24-ol (EUDCOH, 26), and 6α-ethyl-3α, 7α-dihydroxy-24-nor-5ß-cholan-23-ol (NorECDCOH, 30) as novel ligands for FXR and GP-BAR1 that might hold utility in the treatment of FXR and GP-BAR1 mediated disorders.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/química
Colanos/química
Receptores Citoplasmáticos e Nucleares/metabolismo
Receptores Acoplados a Proteínas-G/metabolismo
Bibliotecas de Moléculas Pequenas/farmacologia
[Mh] Termos MeSH secundário: Animais
Técnicas de Química Sintética
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Avaliação Pré-Clínica de Medicamentos/métodos
Células HEK293/efeitos dos fármacos
Células Hep G2/efeitos dos fármacos
Seres Humanos
Ligantes
Masculino
Camundongos Endogâmicos C57BL
Camundongos Mutantes
Terapia de Alvo Molecular
Prurido/tratamento farmacológico
Receptores Citoplasmáticos e Nucleares/genética
Receptores Acoplados a Proteínas-G/genética
Bibliotecas de Moléculas Pequenas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Cholanes); 0 (GPBAR1 protein, human); 0 (Gpbar1 protein, mouse); 0 (Ligands); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Receptors, G-Protein-Coupled); 0 (Small Molecule Libraries); 0 (farnesoid X-activated receptor)
[Em] Mês de entrada:1505
[Cu] Atualização por classe:141023
[Lr] Data última revisão:
141023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140924
[St] Status:MEDLINE
[do] DOI:10.1021/jm501273r


  4 / 146 MEDLINE  
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[PMID]:25192817
[Au] Autor:Salmaso S; Bersani S; Scomparin A; Balasso A; Brazzale C; Barattin M; Caliceti P
[Ad] Endereço:Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy.
[Ti] Título:A novel soluble supramolecular system for sustained rh-GH delivery.
[So] Source:J Control Release;194:168-77, 2014 Nov 28.
[Is] ISSN:1873-4995
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Methoxy-poly(ethylene glycol)s bearing a terminal cholanic moiety (mPEG(5kDa)-cholane, mPEG(10kDa)-cholane and mPEG(20kDa)-cholane) were physically combined with recombinant human growth hormone (rh-GH) to obtain supramolecular assemblies for sustained hormone delivery. The association constants (Ka) calculated by Scatchard analysis of size exclusion chromatography (SEC) data were in the order of 10(5)M(-1). The complete rh-GH association with mPEG(5kDa)-cholane, mPEG(10kDa)-cholane and mPEG(20kDa)-cholane was achieved with 7.5 ± 1.1, 3.9 ± 0.4 and 2.6 ± 0.4 w/w% rh-GH/mPEG-cholane, respectively. Isothermal titration calorimetry (ITC) yielded association constants similar to that calculated by SEC and showed that rh-GH has 21-25 binding sites for mPEG-cholane, regardless the polymer molecular weight. Dialysis studies showed that the mPEG-cholane association strongly delays the protein release; 80-90% of the associated rh-GH was released in 200 h. However, during the first 8h the protein formulations obtained with mPEG(10kDa)-cholane and mPEG(20kDa)-cholane showed a burst release of 8 and 28%, respectively. Circular dichroism (CD) analyses showed that the mPEG(5kDa)-cholane association does not alter the secondary structure of the protein. Furthermore, mPEG(5kDa)-cholane was found to enhance both the enzymatic and physical stability of rh-GH. In vivo pharmacokinetic and pharmacodynamic studies were performed by subcutaneous administration of rh-GH and rh-GH/mPEG(5kDa)-cholane to normal and hypophysectomised rats. The study showed that mPEG(5kDa)-cholane decreases the maximal concentration in the blood but prolongs the body exposure of the protein, which resulted in 55% bioavailability increase. Finally, rh-GH formulated with mPEG(5kDa)-cholane yielded prolonged weight increase of hypophysectomised rats as compared to rh-GH in buffer or formulated with mPEG(5kDa)-OH. After the second administration the weight of the animals treated with rh-GH formulated with mPEG(5kDa)-cholane was about 2 times higher than that obtained with equal dose of non-formulated rh-GH.
[Mh] Termos MeSH primário: Hormônio do Crescimento/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Área Sob a Curva
Disponibilidade Biológica
Colanos/química
Preparações de Ação Retardada
Sistemas de Liberação de Medicamentos
Estabilidade de Medicamentos
Feminino
Hormônio do Crescimento/farmacocinética
Seres Humanos
Hipofisectomia
Masculino
Modelos Moleculares
Polietilenoglicóis/química
Ratos
Ratos Sprague-Dawley
Proteínas Recombinantes/administração & dosagem
Reologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cholanes); 0 (Delayed-Action Preparations); 0 (Recombinant Proteins); 30IQX730WE (Polyethylene Glycols); 9002-72-6 (Growth Hormone)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140907
[St] Status:MEDLINE


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[PMID]:24828006
[Au] Autor:Hodnik Z; Peterlin Masic L; Tomasic T; Smodis D; D'Amore C; Fiorucci S; Kikelj D
[Ad] Endereço:Faculty of Pharmacy, University of Ljubljana , Askerceva 7, 1000 Ljubljana, Slovenia.
[Ti] Título:Bazedoxifene-scaffold-based mimetics of solomonsterols A and B as novel pregnane X receptor antagonists.
[So] Source:J Med Chem;57(11):4819-33, 2014 Jun 12.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pregnane X receptor (PXR), a member of the NR1I nuclear receptor family, acts as a xenobiotic sensor and a paramount transcriptional regulator of drug-metabolizing enzymes and transporters. The overexpression of PXR in various cancer cells indicates the importance of PXR as a drug target for countering multidrug resistance in anticancer treatments. We describe the discovery of novel bazedoxifene-scaffold-based PXR antagonists inspired by the marine sulfated steroids solomonsterol A and B as natural leads. A luciferase reporter assay on a PXR-transfected HepG2 cell line identified compounds 19-24 as promising PXR antagonists. Further structure-activity relationship studies of the most active PXR antagonist from the series (compound 20, IC50 = 11 µM) revealed the importance of hydroxyl groups as hydrogen-bond donors for PXR antagonistic activity. PXR antagonists 20 and 24 (IC50 = 14 µM), in addition to the downregulation of PXR expression, exhibited inhibition of PXR-induced CYP3A4 expression, which illustrates their potential to suppress PXR-regulated phase-I drug metabolism.
[Mh] Termos MeSH primário: Catecóis/síntese química
Colanos/química
Hidroquinonas/síntese química
Indóis/síntese química
Receptores de Esteroides/antagonistas & inibidores
Ésteres do Ácido Sulfúrico/química
[Mh] Termos MeSH secundário: Catecóis/química
Catecóis/farmacologia
Citocromo P-450 CYP3A
Inibidores do Citocromo P-450 CYP3A
Regulação para Baixo
Genes Reporter
Células Hep G2
Seres Humanos
Ligações de Hidrogênio
Hidroquinonas/química
Hidroquinonas/farmacologia
Indóis/química
Indóis/farmacologia
Luciferases/genética
Modelos Moleculares
Mimetismo Molecular
Receptores de Esteroides/agonistas
Receptores de Esteroides/metabolismo
Relação Estrutura-Atividade
Ativação Transcricional
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (24-norcholan-2,3,24-tryl-2,3,23-sulfuric acid); 0 (4-(5-(3-hydroxypropoxy)-3-methyl-1H-indol-2-yl)benzene-1,2-diol); 0 (4-(5-hydroxy-3-methyl-1H-indol-2-yl)benzene-1,2-diol); 0 (Catechols); 0 (Cholanes); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Hydroquinones); 0 (Indoles); 0 (Receptors, Steroid); 0 (Sulfuric Acid Esters); 0 (cholan-2,3,24-tryl-2,3,24-trisulfate); 0 (pregnane X receptor); EC 1.13.12.- (Luciferases); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); Q16TT9C5BK (bazedoxifene)
[Em] Mês de entrada:1408
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140516
[St] Status:MEDLINE
[do] DOI:10.1021/jm500351m


  6 / 146 MEDLINE  
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[PMID]:24387325
[Au] Autor:D'Amore C; Di Leva FS; Sepe V; Renga B; Del Gaudio C; D'Auria MV; Zampella A; Fiorucci S; Limongelli V
[Ad] Endereço:Drug Discovery and Development, Istituto Italiano di Tecnologia , Via Morego, 30, 16163 Genoa, Italy.
[Ti] Título:Design, synthesis, and biological evaluation of potent dual agonists of nuclear and membrane bile acid receptors.
[So] Source:J Med Chem;57(3):937-54, 2014 Feb 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bile acids exert genomic and nongenomic effects by interacting with membrane G-protein-coupled receptors, including the bile acid receptor GP-BAR1, and nuclear receptors, such as the farnesoid X receptor (FXR). These receptors regulate overlapping metabolic functions; thus, GP-BAR1/FXR dual agonists, by enhancing the biological response, represent an innovative strategy for the treatment of enteroendocrine disorders. Here, we report the design, total synthesis, and in vitro/in vivo pharmacological evaluation of a new generation of dual bile acid receptor agonists, with the most potent compound, 19, showing promising pharmacological profiles. We show that compound 19 activates GP-BAR1, FXR, and FXR regulated genes in the liver, increases the intracellular concentration of cAMP, and stimulates the release of the potent insulinotropic hormone GLP-1, resulting in a promising drug candidate for the treatment of metabolic disorders. We also elucidate the binding mode of the most potent dual agonists in the two receptors through a series of computations providing the molecular basis for dual GP-BAR1/FXR agonism.
[Mh] Termos MeSH primário: Colanos/síntese química
Hipoglicemiantes/síntese química
Receptores Citoplasmáticos e Nucleares/agonistas
Receptores Acoplados a Proteínas-G/agonistas
[Mh] Termos MeSH secundário: Colanos/química
Colanos/farmacologia
Desenho de Drogas
Células HEK293
Seres Humanos
Hipoglicemiantes/química
Hipoglicemiantes/farmacologia
Simulação de Acoplamento Molecular
Ligação Proteica
Receptores Citoplasmáticos e Nucleares/química
Receptores Acoplados a Proteínas-G/química
Estereoisomerismo
Relação Estrutura-Atividade
Ativação Transcricional
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cholanes); 0 (GPBAR1 protein, human); 0 (Hypoglycemic Agents); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Receptors, G-Protein-Coupled); 0 (farnesoid X-activated receptor)
[Em] Mês de entrada:1404
[Cu] Atualização por classe:140213
[Lr] Data última revisão:
140213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140107
[St] Status:MEDLINE
[do] DOI:10.1021/jm401873d


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[PMID]:24368568
[Au] Autor:Mencarelli A; D'Amore C; Renga B; Cipriani S; Carino A; Sepe V; Perissutti E; D'Auria MV; Zampella A; Distrutti E; Fiorucci S
[Ti] Título:Solomonsterol A, a marine pregnane-X-receptor agonist, attenuates inflammation and immune dysfunction in a mouse model of arthritis.
[So] Source:Mar Drugs;12(1):36-53, 2013 Dec 24.
[Is] ISSN:1660-3397
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:In the present study we provide evidence that solomonsterol A, a selective pregnane X receptor (PXR) agonist isolated from the marine sponge Theonella swinhoei, exerts anti-inflammatory activity and attenuates systemic inflammation and immune dysfunction in a mouse model of rheumatoid arthritis. Solomonsterol A was effective in protecting against the development of arthritis induced by injecting transgenic mice harboring a humanized PXR, with anti-collagen antibodies (CAIA) with beneficial effects on joint histopathology and local inflammatory response reducing the expression of inflammatory markers (TNFα, IFNγ and IL-17 and chemokines MIP1α and RANTES) in draining lymph nodes. Solomonsterol A rescued mice from systemic inflammation were assessed by measuring arthritis score, CRP and cytokines in the blood. In summary, the present study provides a molecular basis for the regulation of systemic local and systemic immunity by PXR agonists.
[Mh] Termos MeSH primário: Anti-Inflamatórios
Artrite Reumatoide/tratamento farmacológico
Colanos/farmacologia
Síndromes de Imunodeficiência/tratamento farmacológico
Poríferos/química
Receptores de Esteroides/agonistas
Ésteres do Ácido Sulfúrico/farmacologia
[Mh] Termos MeSH secundário: Animais
Artrite Reumatoide/induzido quimicamente
Artrite Reumatoide/patologia
Proteína C-Reativa/metabolismo
Cartilagem/patologia
Quimiocina CCL3/metabolismo
Quimiocina CCL5/metabolismo
Colágeno Tipo II
Citocinas/sangue
Hepatócitos/efeitos dos fármacos
Seres Humanos
Interferon gama/metabolismo
Interleucina-17/metabolismo
Fígado/efeitos dos fármacos
Fígado/metabolismo
Linfonodos/efeitos dos fármacos
Linfonodos/metabolismo
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Modelos Moleculares
Conformação Molecular
Receptores de Esteroides/biossíntese
Receptores de Esteroides/genética
Ativação Transcricional
Fator de Necrose Tumoral alfa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Chemokine CCL3); 0 (Chemokine CCL5); 0 (Cholanes); 0 (Collagen Type II); 0 (Cytokines); 0 (Interleukin-17); 0 (Receptors, Steroid); 0 (Sulfuric Acid Esters); 0 (Tumor Necrosis Factor-alpha); 0 (cholan-2,3,24-tryl-2,3,24-trisulfate); 0 (pregnane X receptor); 82115-62-6 (Interferon-gamma); 9007-41-4 (C-Reactive Protein)
[Em] Mês de entrada:1409
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131226
[St] Status:MEDLINE
[do] DOI:10.3390/md12010036


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[PMID]:23455312
[Au] Autor:Bukiya AN; McMillan JE; Fedinec AL; Patil SA; Miller DD; Leffler CW; Parrill AL; Dopico AM
[Ad] Endereço:Departments of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
[Ti] Título:Cerebrovascular dilation via selective targeting of the cholane steroid-recognition site in the BK channel ß1-subunit by a novel nonsteroidal agent.
[So] Source:Mol Pharmacol;83(5):1030-44, 2013 May.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Ca(2+)/voltage-gated K(+) large conductance (BK) channel ß1 subunit is particularly abundant in vascular smooth muscle. By determining their phenotype, BK ß1 allows the BK channels to reduce myogenic tone, facilitating vasodilation. The endogenous steroid lithocholic acid (LCA) dilates cerebral arteries via BK channel activation, which requires recognition by a BK ß1 site that includes Thr169. Whether exogenous nonsteroidal agents can access this site to selectively activate ß1-containing BK channels and evoke vasodilation remain unknown. We performed a chemical structure database similarity search using LCA as a template, along with a two-step reaction to generate sodium 3-hydroxyolean-12-en-30-oate (HENA). HENA activated the BK (cbv1 + ß1) channels cloned from rat cerebral artery myocytes with a potency (EC50 = 53 µM) similar to and an efficacy (×2.5 potentiation) significantly greater than that of LCA. This HENA action was replicated on native channels in rat cerebral artery myocytes. HENA failed to activate the channels made of cbv1 + ß2, ß3, ß4, or ß1T169A, indicating that this drug selectively targets ß1-containing BK channels via the BK ß1 steroid-sensing site. HENA (3-45 µM) dilated the rat and C57BL/6 mouse pressurized cerebral arteries. Consistent with the electrophysiologic results, this effect was larger than that of LCA. HENA failed to dilate the arteries from the KCNMB1 knockout mouse, underscoring BK ß1's role in HENA action. Finally, carotid artery-infusion of HENA (45 µM) dilated the pial cerebral arterioles via selective BK-channel targeting. In conclusion, we have identified for the first time a nonsteroidal agent that selectively activates ß1-containing BK channels by targeting the steroid-sensing site in BK ß1, rendering vasodilation.
[Mh] Termos MeSH primário: Artérias Cerebrais/efeitos dos fármacos
Colanos/farmacologia
Subunidades beta do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo
Esteroides/farmacologia
Vasodilatação/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Artérias Cerebrais/metabolismo
Colanos/química
Feminino
Subunidades beta do Canal de Potássio Ativado por Cálcio de Condutância Alta/química
Ácido Litocólico/farmacologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Monócitos/efeitos dos fármacos
Monócitos/metabolismo
Ratos
Ratos Sprague-Dawley
Esteroides/química
Xenopus laevis
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Cholanes); 0 (KCNMB1 protein, rat); 0 (Kcnmb1 protein, mouse); 0 (Large-Conductance Calcium-Activated Potassium Channel beta Subunits); 0 (Steroids); 5QU0I8393U (Lithocholic Acid)
[Em] Mês de entrada:1309
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130305
[St] Status:MEDLINE
[do] DOI:10.1124/mol.112.083519


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[PMID]:23000093
[Au] Autor:Fiorucci S; Distrutti E; Bifulco G; D'Auria MV; Zampella A
[Ad] Endereço:Dipartimento di Medicina Clinica e Sperimentale, Nuova Facoltà di Medicina e Chirurgia, 06132 Perugia, Italy. fiorucci@unipg.it
[Ti] Título:Marine sponge steroids as nuclear receptor ligands.
[So] Source:Trends Pharmacol Sci;33(11):591-601, 2012 Nov.
[Is] ISSN:1873-3735
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nuclear receptors (NRs) are a large family of evolutionarily conserved and ligand-regulated transcription factors. The farnesoid X receptor (FXR) and the pregnane X receptor (PXR) are two bile-acid-activated receptors highly expressed in enterohepatic tissues essential for bile acids and xenobiotic metabolism. More than 1600 new steroidal structures have been isolated from marine organisms. Chemical, structural, and pharmacological characterization of sponge steroid libraries has allowed the identification of steroids that regulate FXR and PXR: selective FXR antagonists, FXR modulators, FXR antagonists endowed with PXR agonism, and selective PXR agonists. Selective FXR antagonists (theonellasterol) have proven effective in protecting against liver injury in models of cholestasis. Selective PXR agonists (natural and synthetic solomonsterols) have been effective in reducing nuclear factor (NF)-κB activity and intestinal inflammation. Identification of marine steroids endowed with dual FXR and PXR agonism-antagonism probably reflects the common identity of the unique ancestral precursor of these NRs. These findings pave the way to the development of novel FXR and PXR agonists and antagonists to target human diseases.
[Mh] Termos MeSH primário: Colanos/farmacologia
Poríferos/química
Receptores Citoplasmáticos e Nucleares/metabolismo
Receptores de Esteroides/metabolismo
Esteróis/farmacologia
Ésteres do Ácido Sulfúrico/farmacologia
[Mh] Termos MeSH secundário: Animais
Ácidos e Sais Biliares/metabolismo
Evolução Molecular
Seres Humanos
Ligantes
NF-kappa B/metabolismo
Receptores Citoplasmáticos e Nucleares/agonistas
Receptores Citoplasmáticos e Nucleares/química
Receptores Citoplasmáticos e Nucleares/genética
Receptores de Esteroides/antagonistas & inibidores
Receptores de Esteroides/química
Receptores de Esteroides/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (7-hydroxytheonellasterol); 0 (Bile Acids and Salts); 0 (Cholanes); 0 (Ligands); 0 (NF-kappa B); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Receptors, Steroid); 0 (Sterols); 0 (Sulfuric Acid Esters); 0 (cholan-2,3,24-tryl-2,3,24-trisulfate); 0 (farnesoid X-activated receptor); 0 (pregnane X receptor)
[Em] Mês de entrada:1302
[Cu] Atualização por classe:121026
[Lr] Data última revisão:
121026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120925
[St] Status:MEDLINE


  10 / 146 MEDLINE  
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[PMID]:22733410
[Au] Autor:Sepe V; Ummarino R; D'Auria MV; Lauro G; Bifulco G; D'Amore C; Renga B; Fiorucci S; Zampella A
[Ad] Endereço:Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli Federico II, via D. Montesano 49, 80131 Napoli, Italy.
[Ti] Título:Modification in the side chain of solomonsterol A: discovery of cholestan disulfate as a potent pregnane-X-receptor agonist.
[So] Source:Org Biomol Chem;10(31):6350-62, 2012 Aug 21.
[Is] ISSN:1477-0539
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Seven synthetic analogues of the PXR (pregnane-X-receptor) potent natural agonist solomonsterol A were prepared by total synthesis. Their activity toward PXR was assessed by transactivation and RT-PCR assays. The study discloses cholestan disulfate (8) as a new, simplified agonist of PXR. By in vitro studies on hepatic cells we have demonstrated that this compound is a potent PXR agonist and functional characterization in human macrophages and hepatic stellate cells provided evidence that cholestan disulfate (8) has the ability to modulate the immune response triggered by bacterial endotoxin as well as to counter-activate hepatic stellate cell activation induced by thrombin. Because inhibition of immune-driven circuits might have relevance in the treatment of inflammation and liver fibrosis, the present data support the development of cholestan disulfate (8) in preclinical models of inflammatory diseases.
[Mh] Termos MeSH primário: Colanos/química
Colanos/farmacologia
Colestanóis/química
Colestanóis/farmacologia
Receptores de Esteroides/agonistas
Ésteres do Ácido Sulfúrico/química
Ésteres do Ácido Sulfúrico/farmacologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Colanos/síntese química
Colestanóis/síntese química
Citocinas/imunologia
Células Hep G2
Hepatócitos/efeitos dos fármacos
Hepatócitos/imunologia
Seres Humanos
Lipopolissacarídeos/imunologia
Macrófagos/efeitos dos fármacos
Macrófagos/imunologia
Modelos Moleculares
Poríferos/química
Poríferos/classificação
Ratos
Receptores de Esteroides/imunologia
Ésteres do Ácido Sulfúrico/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cholanes); 0 (Cholestanols); 0 (Cytokines); 0 (Lipopolysaccharides); 0 (Receptors, Steroid); 0 (Sulfuric Acid Esters); 0 (cholan-2,3,24-tryl-2,3,24-trisulfate); 0 (pregnane X receptor)
[Em] Mês de entrada:1211
[Cu] Atualização por classe:120718
[Lr] Data última revisão:
120718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120627
[St] Status:MEDLINE
[do] DOI:10.1039/c2ob25800e



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