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Pesquisa : D04.210.500.105.225.480 [Categoria DeCS]
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  1 / 923 MEDLINE  
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[PMID]:28610979
[Au] Autor:Arichi N; Fujiwara S; Ishizawa M; Makishima M; Hua DH; Yamada KI; Yamaoka Y; Takasu K
[Ad] Endereço:Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
[Ti] Título:Synthesis and biological evaluation of steroidal derivatives bearing a small ring as vitamin D receptor agonists.
[So] Source:Bioorg Med Chem Lett;27(15):3408-3411, 2017 08 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A novel series of 3-ketolithocholic acid derivatives as well as estrone derivatives bearing a small ring for the conformational fixation of the side chain were synthesized by using a catalytic [2+2] cycloaddition and a ring-contraction rearrangement. The steroidal derivatives were evaluated for transcriptional activation of vitamin D receptor by luciferase reporter assays. Among them, two estrone derivatives showed a higher efficacy of the transactivation of vitamin D receptor than 3-ketolithocholic acid, and the small ring moieties were found to be important for the efficacy.
[Mh] Termos MeSH primário: Estrona/farmacologia
Ácido Litocólico/análogos & derivados
Receptores de Calcitriol/agonistas
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Estrona/síntese química
Estrona/química
Seres Humanos
Ácido Litocólico/química
Ácido Litocólico/farmacologia
Conformação Molecular
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (3-ketolithocholic acid); 0 (Receptors, Calcitriol); 0 (VDR protein, human); 2DI9HA706A (Estrone); 5QU0I8393U (Lithocholic Acid)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE


  2 / 923 MEDLINE  
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[PMID]:28538412
[Au] Autor:Yu XH; Sun J; Wang Y; Zhou YB
[Ad] Endereço:Second Department of Cardiovascular, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China.
[Ti] Título:Biomarkers of unstable angina pectoris and yangxin decoction intervention: An exploratory metabonomics study of blood plasma.
[So] Source:Medicine (Baltimore);96(21):e6998, 2017 May.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: This study aimed to explore the related metabolic biomarkers and to observe the effects of Yangxin Decoction (YXD) on plasma metabolism of patients with unstable angina (UA). METHODS: In total, 10 patients with UA (intervention group) and 10 healthy participants (control group) were recruited for this study from January 2009 to December 2010. Plasma samples from both groups were analyzed using liquid chromatography mass spectrometry (LC-MS). Principle component analysis (PCA) and partial least squares (PLS) were used to explore the correlations between metabolic markers in patients with UA. RESULTS: The LC-MS results indicated that the serum levels of 5 potential metabolic markers, namely, ceramide, glycocholic acid, allocholic acid, lithocholic acid, and leukotriene (LT) B4, were significantly higher in the intervention group than those in the control group. CONCLUSION: The results of this study demonstrated potential metabolic markers that can be used to distinguish and diagnose patients with UA.
[Mh] Termos MeSH primário: Angina Instável/sangue
Angina Instável/tratamento farmacológico
Medicamentos de Ervas Chinesas/uso terapêutico
[Mh] Termos MeSH secundário: Administração Oral
Biomarcadores/sangue
Análise Química do Sangue
Ceramidas/sangue
Ácidos Cólicos/sangue
Cromatografia Líquida
Feminino
Ácido Glicocólico/sangue
Seres Humanos
Leucotrieno B4/sangue
Ácido Litocólico/sangue
Masculino
Espectrometria de Massas
Metabolômica
Meia-Idade
Análise de Componente Principal
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Ceramides); 0 (Cholic Acids); 0 (Drugs, Chinese Herbal); 0 (yangxin decoction); 1HGW4DR56D (Leukotriene B4); 2464-18-8 (allocholic acid); 5QU0I8393U (Lithocholic Acid); G59NX3I3RT (Glycocholic Acid)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170629
[Lr] Data última revisão:
170629
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170525
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000006998


  3 / 923 MEDLINE  
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[PMID]:28493883
[Au] Autor:Pols TWH; Puchner T; Korkmaz HI; Vos M; Soeters MR; de Vries CJM
[Ad] Endereço:Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
[Ti] Título:Lithocholic acid controls adaptive immune responses by inhibition of Th1 activation through the Vitamin D receptor.
[So] Source:PLoS One;12(5):e0176715, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bile acids are established signaling molecules next to their role in the intestinal emulsification and uptake of lipids. We here aimed to identify a potential interaction between bile acids and CD4+ Th cells, which are central in adaptive immune responses. We screened distinct bile acid species for their potency to affect T cell function. Primary human and mouse CD4+ Th cells as well as Jurkat T cells were used to gain insight into the mechanism underlying these effects. We found that unconjugated lithocholic acid (LCA) impedes Th1 activation as measured by i) decreased production of the Th1 cytokines IFNγ and TNFαα, ii) decreased expression of the Th1 genes T-box protein expressed in T cells (T-bet), Stat-1 and Stat4, and iii) decreased STAT1α/ß phosphorylation. Importantly, we observed that LCA impairs Th1 activation at physiological relevant concentrations. Profiling of MAPK signaling pathways in Jurkat T cells uncovered an inhibition of ERK-1/2 phosphorylation upon LCA exposure, which could provide an explanation for the impaired Th1 activation. LCA induces these effects via Vitamin D receptor (VDR) signaling since VDR RNA silencing abrogated these effects. These data reveal for the first time that LCA controls adaptive immunity via inhibition of Th1 activation. Many factors influence LCA levels, including bile acid-based drugs and gut microbiota. Our data may suggest that these factors also impact on adaptive immunity via a yet unrecognized LCA-Th cell axis.
[Mh] Termos MeSH primário: Imunidade Adaptativa/efeitos dos fármacos
Ácido Litocólico/farmacologia
Ativação Linfocitária/efeitos dos fármacos
Receptores de Calcitriol/metabolismo
Células Th1/imunologia
[Mh] Termos MeSH secundário: Animais
Ácidos e Sais Biliares/metabolismo
Diferenciação Celular/efeitos dos fármacos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Interferon gama/genética
Interferon gama/metabolismo
Células Jurkat
Camundongos Endogâmicos C57BL
Fosforilação/efeitos dos fármacos
Células Th1/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Receptors, Calcitriol); 0 (VDR protein, human); 5QU0I8393U (Lithocholic Acid); 82115-62-6 (Interferon-gamma); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170512
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0176715


  4 / 923 MEDLINE  
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[PMID]:28360029
[Au] Autor:Ward JBJ; Lajczak NK; Kelly OB; O'Dwyer AM; Giddam AK; Ní Gabhann J; Franco P; Tambuwala MM; Jefferies CA; Keely S; Roda A; Keely SJ
[Ad] Endereço:Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
[Ti] Título:Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon.
[So] Source:Am J Physiol Gastrointest Liver Physiol;312(6):G550-G558, 2017 Jun 01.
[Is] ISSN:1522-1547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon. 312: G550-G558, 2017. First published March 30, 2017; doi:10.1152/ajpgi.00256.2016.-Inflammatory bowel diseases (IBD) comprise a group of common and debilitating chronic intestinal disorders for which currently available therapies are often unsatisfactory. The naturally occurring secondary bile acid, ursodeoxycholic acid (UDCA), has well-established anti-inflammatory and cytoprotective actions and may therefore be effective in treating IBD. We aimed to investigate regulation of colonic inflammatory responses by UDCA and to determine the potential impact of bacterial metabolism on its therapeutic actions. The anti-inflammatory efficacy of UDCA, a nonmetabolizable analog, 6α-methyl-UDCA (6-MUDCA), and its primary colonic metabolite lithocholic acid (LCA) was assessed in the murine dextran sodium sulfate (DSS) model of mucosal injury. The effects of bile acids on cytokine (TNF-α, IL-6, Il-1ß, and IFN-γ) release from cultured colonic epithelial cells and mouse colonic tissue in vivo were investigated. Luminal bile acids were measured by gas chromatography-mass spectrometry. UDCA attenuated release of proinflammatory cytokines from colonic epithelial cells in vitro and was protective against the development of colonic inflammation in vivo. In contrast, although 6-MUDCA mimicked the effects of UDCA on epithelial cytokine release in vitro, it was ineffective in preventing inflammation in the DSS model. In UDCA-treated mice, LCA became the most common colonic bile acid. Finally, LCA treatment more potently inhibited epithelial cytokine release and protected against DSS-induced mucosal inflammation than did UDCA. These studies identify a new role for the primary metabolite of UDCA, LCA, in preventing colonic inflammation and suggest that microbial metabolism of UDCA is necessary for the full expression of its protective actions. On the basis of its cytoprotective and anti-inflammatory actions, the secondary bile acid ursodeoxycholic acid (UDCA) has well-established uses in both traditional and Western medicine. We identify a new role for the primary metabolite of UDCA, lithocholic acid, as a potent inhibitor of intestinal inflammatory responses, and we present data to suggest that microbial metabolism of UDCA is necessary for the full expression of its protective effects against colonic inflammation.
[Mh] Termos MeSH primário: Anti-Inflamatórios/farmacologia
Colite/prevenção & controle
Colo/efeitos dos fármacos
Mucosa Intestinal/efeitos dos fármacos
Ácido Litocólico/farmacologia
Ácido Ursodesoxicólico/farmacologia
[Mh] Termos MeSH secundário: Animais
Bactérias/metabolismo
Biotransformação
Colite/induzido quimicamente
Colite/metabolismo
Colite/microbiologia
Colo/metabolismo
Colo/microbiologia
Colo/patologia
Citocinas/metabolismo
Sulfato de Dextrana
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Microbioma Gastrointestinal
Células HT29
Seres Humanos
Mediadores da Inflamação/metabolismo
Mucosa Intestinal/metabolismo
Mucosa Intestinal/microbiologia
Mucosa Intestinal/patologia
Masculino
Camundongos Endogâmicos C57BL
Fatores de Tempo
Ácido Ursodesoxicólico/análogos & derivados
Ácido Ursodesoxicólico/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (6-methylursodeoxycholic acid); 0 (Anti-Inflammatory Agents); 0 (Cytokines); 0 (Inflammation Mediators); 5QU0I8393U (Lithocholic Acid); 724L30Y2QR (Ursodeoxycholic Acid); 9042-14-2 (Dextran Sulfate)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170401
[St] Status:MEDLINE
[do] DOI:10.1152/ajpgi.00256.2016


  5 / 923 MEDLINE  
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[PMID]:28318299
[Au] Autor:Marchionatti AM; Pérez A; Rivoira MA; Rodríguez VA; Tolosa de Talamoni NG
[Ad] Endereço:Laboratorio "Dr. Fernando Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Pabellón Argentina, 2do. Piso, Ciudad Universitaria, 5000 Córdoba, Argentina.
[Ti] Título:Lithocholic acid: a new emergent protector of intestinal calcium absorption under oxidant conditions.
[So] Source:Biochem Cell Biol;95(2):273-279, 2017 Apr.
[Is] ISSN:1208-6002
[Cp] País de publicação:Canada
[La] Idioma:eng
[Ab] Resumo:LCA and 1,25(OH) D are vitamin D receptor ligands with different binding affinity. The secosteroid stimulates intestinal Ca absorption. Whether LCA alters this process remains unknown. The aim of our work was to determine the effect of LCA on intestinal Ca absorption in the absence or presence of NaDOC, bile acid that inhibits the cation transport. The data show that LCA by itself did not alter intestinal Ca absorption, but prevented the inhibitory effect of NaDOC. The concomitant administration of LCA avoided the reduction of intestinal alkaline phosphatase activity caused by NaDOC. In addition, LCA blocked a decrease caused by NaDOC on gene and protein expression of molecules involved in the transcellular pathway of intestinal Ca absorption. The oxidative stress and apoptosis triggered by NaDOC were abrogated by LCA co-treatment. In conclusion, LCA placed in the intestinal lumen protects intestinal Ca absorption against the inhibitory effects caused by NaDOC. LCA avoids the reduction of the transcellular Ca movement, apparently by blocking the oxidative stress and apoptosis triggered by NaDOC, normalizing the gene and protein expression of molecules involved in Ca movement. Therefore, LCA might become a possible treatment to improve intestinal calcium absorption under oxidant conditions.
[Mh] Termos MeSH primário: Cálcio/metabolismo
Ácido Desoxicólico/antagonistas & inibidores
Duodeno/efeitos dos fármacos
Enterócitos/efeitos dos fármacos
Absorção Intestinal/efeitos dos fármacos
Ácido Litocólico/farmacologia
[Mh] Termos MeSH secundário: Fosfatase Alcalina/genética
Fosfatase Alcalina/metabolismo
Animais
Animais Recém-Nascidos
Apoptose/efeitos dos fármacos
Calcitriol/metabolismo
Galinhas
Ácido Desoxicólico/farmacologia
Duodeno/metabolismo
Enterócitos/citologia
Enterócitos/metabolismo
Regulação da Expressão Gênica/efeitos dos fármacos
Absorção Intestinal/fisiologia
Transporte de Íons/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Estresse Oxidativo
ATPases Transportadoras de Cálcio da Membrana Plasmática/genética
ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo
Carbonilação Proteica/efeitos dos fármacos
Receptores de Calcitriol/genética
Receptores de Calcitriol/metabolismo
Trocador de Sódio e Cálcio/genética
Trocador de Sódio e Cálcio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Calcitriol); 0 (Sodium-Calcium Exchanger); 0 (sodium-calcium exchanger 1); 005990WHZZ (Deoxycholic Acid); 5QU0I8393U (Lithocholic Acid); EC 3.1.3.1 (Alkaline Phosphatase); EC 3.6.3.8 (Plasma Membrane Calcium-Transporting ATPases); FXC9231JVH (Calcitriol); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170525
[Lr] Data última revisão:
170525
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170321
[St] Status:MEDLINE
[do] DOI:10.1139/bcb-2016-0164


  6 / 923 MEDLINE  
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[PMID]:28128437
[Au] Autor:Zeng H; Jiang Y; Chen P; Fan X; Li D; Liu A; Ma X; Xie W; Liu P; Gonzalez FJ; Huang M; Bi H
[Ad] Endereço:School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
[Ti] Título:Schisandrol B protects against cholestatic liver injury through pregnane X receptors.
[So] Source:Br J Pharmacol;174(8):672-688, 2017 Apr.
[Is] ISSN:1476-5381
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND PURPOSE: Currently, ursodeoxycholic acid and obeticholic acid are the only two FDA-approved drugs for cholestatic liver diseases. Thus, new therapeutic approaches need to be developed. Here we have evaluated the anti-cholestasis effects of Schisandrol B (SolB), a bioactive compound isolated from Schisandra sphenanthera. EXPERIMENTAL APPROACH: Hepatoprotective effect of SolB against intrahepatic cholestasis, induced by lithocholic acid (LCA), was evaluated in mice. Metabolomic analysis and gene analysis were used to assess involvement of pregnane X receptor (PXR). Molecular docking, cell-based reporter gene analysis and knockout mice were used to demonstrate the critical role of the PXR pathway in the anti-cholestasis effects of SolB. KEY RESULTS: SolB protected against LCA-induced intrahepatic cholestasis. Furthermore, therapeutic treatment with SolB decreased mortality in cholestatic mice. Metabolomics and gene analysis showed that SolB accelerated metabolism of bile acids, promoted bile acid efflux into the intestine, and induced hepatic expression of the PXR-target genes Cyp3a11, Ugt1a1, and Oatp2, which are involved in bile acid homeostasis. Mechanistic studies showed that SolB activated human PXR and up-regulated PXR target genes in human cell lines. Additionally, SolB did not protect Pxr-null mice from liver injury induced by intrahepatic cholestasis, thus providing genetic evidence that the effect of SolB was PXR-dependent. CONCLUSION AND IMPLICATIONS: These findings provide direct evidence for the hepatoprotective effects of SolB against cholestasis by activating PXR. Therefore, SolB may provide a new and effective approach to the prevention and treatment of cholestatic liver diseases.
[Mh] Termos MeSH primário: Colestase/prevenção & controle
Ciclo-Octanos/farmacologia
Dioxóis/farmacologia
Lignanas/farmacologia
Fígado/efeitos dos fármacos
Fígado/lesões
Receptores de Esteroides/metabolismo
[Mh] Termos MeSH secundário: Animais
Colestase/induzido quimicamente
Ácido Litocólico
Fígado/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclooctanes); 0 (Dioxoles); 0 (Lignans); 0 (Receptors, Steroid); 0 (pregnane X receptor); 58546-54-6 (schizandrol B); 5QU0I8393U (Lithocholic Acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170128
[St] Status:MEDLINE
[do] DOI:10.1111/bph.13729


  7 / 923 MEDLINE  
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[PMID]:28116898
[Au] Autor:Zheng MM; Chen KC; Wang RF; Li H; Li CX; Xu JH
[Ad] Endereço:State Key Laboratory of Bioreactor Engineering and ‡Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology , Shanghai 200237, P. R. China.
[Ti] Título:Engineering 7ß-Hydroxysteroid Dehydrogenase for Enhanced Ursodeoxycholic Acid Production by Multiobjective Directed Evolution.
[So] Source:J Agric Food Chem;65(6):1178-1185, 2017 Feb 15.
[Is] ISSN:1520-5118
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ursodeoxycholic acid (UDCA) is the main active ingredient of natural bear bile powder with multiple pharmacological functions. 7ß-Hydroxysteroid dehydrogenase (HSDH) is a key biocatalyst for the synthesis of UDCA. However, all the 7ß-HSDHs reported commonly suffer from poor activity and thermostability, resulting in limited productivity of UDCA. In this study, a multiobjective directed evolution (MODE) strategy was proposed and applied to improve the activity, thermostability, and pH optimum of a 7ß-HSDH. The best variant (V ) showed a specific activity 5.5-fold higher than and a half-life 3-fold longer than those of the wild type. In addition, the pH optimum of the variant was shifted to a weakly alkaline value. In the cascade reaction, the productivity of UDCA with V increased to 942 g L day , in contrast to 141 g L day with the wild type. Therefore, this study provides a useful strategy for improving the catalytic efficiency of a key enzyme that significantly facilitated the bioproduction of UDCA.
[Mh] Termos MeSH primário: Hidroxiesteroide Desidrogenases/genética
Hidroxiesteroide Desidrogenases/metabolismo
Engenharia de Proteínas/métodos
Ácido Ursodesoxicólico/metabolismo
[Mh] Termos MeSH secundário: Evolução Molecular Direcionada/métodos
Concentração de Íons de Hidrogênio
Hidroxiesteroide Desidrogenases/química
Ácido Litocólico/análogos & derivados
Ácido Litocólico/metabolismo
Mutagênese Sítio-Dirigida
Reação em Cadeia da Polimerase/métodos
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Ácido Ursodesoxicólico/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Recombinant Proteins); 4651-67-6 (7-ketolithocholic acid); 5QU0I8393U (Lithocholic Acid); 724L30Y2QR (Ursodeoxycholic Acid); EC 1.1.- (Hydroxysteroid Dehydrogenases); EC 1.1.1.- (7 beta-hydroxysteroid dehydrogenase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170602
[Lr] Data última revisão:
170602
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170125
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jafc.6b05428


  8 / 923 MEDLINE  
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[PMID]:28115221
[Au] Autor:Ikarashi N; Ogawa S; Hirobe R; Kon R; Kusunoki Y; Yamashita M; Mizukami N; Kaneko M; Wakui N; Machida Y; Sugiyama K
[Ad] Endereço:Department of Clinical Pharmacokinetics, Hoshi University, Japan.
[Ti] Título:Epigallocatechin gallate induces a hepatospecific decrease in the CYP3A expression level by altering intestinal flora.
[So] Source:Eur J Pharm Sci;100:211-218, 2017 Mar 30.
[Is] ISSN:1879-0720
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:In previous studies, we showed that a high-dose intake of green tea polyphenol (GP) induced a hepatospecific decrease in the expression and activity of the drug-metabolizing enzyme cytochrome P450 3A (CYP3A). In this study, we examined whether this decrease in CYP3A expression is induced by epigallocatechin gallate (EGCG), which is the main component of GP. After a diet containing 1.5% EGCG was given to mice, the hepatic CYP3A expression was measured. The level of intestinal bacteria of Clostridium spp., the concentration of lithocholic acid (LCA) in the feces, and the level of the translocation of pregnane X receptor (PXR) to the nucleus in the liver were examined. A decrease in the CYP3A expression level was observed beginning on the second day of the treatment with EGCG. The level of translocation of PXR to the nucleus was significantly lower in the EGCG group. The fecal level of LCA was clearly decreased by the EGCG treatment. The level of intestinal bacteria of Clostridium spp. was also decreased by the EGCG treatment. It is clear that the hepatospecific decrease in the CYP3A expression level observed after a high-dose intake of GP was caused by EGCG. Because EGCG, which is not absorbed from the intestine, causes a decrease in the level of LCA-producing bacteria in the colon, the level of LCA in the liver decreases, resulting in a decrease in the nuclear translocation of PXR, which in turn leads to the observed decrease in the expression level of CYP3A.
[Mh] Termos MeSH primário: Catequina/análogos & derivados
Citocromo P-450 CYP3A/genética
Microbioma Gastrointestinal/efeitos dos fármacos
Intestinos/efeitos dos fármacos
Fígado/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Catequina/sangue
Catequina/farmacocinética
Catequina/farmacologia
Linhagem Celular Tumoral
Clostridium/efeitos dos fármacos
Clostridium/genética
Fezes/química
Seres Humanos
Intestinos/microbiologia
Ácido Litocólico/metabolismo
Fígado/metabolismo
Masculino
Camundongos Endogâmicos ICR
RNA Ribossômico 16S/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Ribosomal, 16S); 5QU0I8393U (Lithocholic Acid); 8R1V1STN48 (Catechin); BQM438CTEL (epigallocatechin gallate); EC 1.14.14.1 (Cytochrome P-450 CYP3A)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170703
[Lr] Data última revisão:
170703
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170125
[St] Status:MEDLINE


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[PMID]:28005388
[Au] Autor:Incerti M; Russo S; Callegari D; Pala D; Giorgio C; Zanotti I; Barocelli E; Vicini P; Vacondio F; Rivara S; Castelli R; Tognolini M; Lodola A
[Ad] Endereço:Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
[Ti] Título:Metadynamics for Perspective Drug Design: Computationally Driven Synthesis of New Protein-Protein Interaction Inhibitors Targeting the EphA2 Receptor.
[So] Source:J Med Chem;60(2):787-796, 2017 Jan 26.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metadynamics (META-D) is emerging as a powerful method for the computation of the multidimensional free-energy surface (FES) describing the protein-ligand binding process. Herein, the FES of unbinding of the antagonist N-(3α-hydroxy-5ß-cholan-24-oyl)-l-ß-homotryptophan (UniPR129) from its EphA2 receptor was reconstructed by META-D simulations. The characterization of the free-energy minima identified on this FES proposes a binding mode fully consistent with previously reported and new structure-activity relationship data. To validate this binding mode, new N-(3α-hydroxy-5ß-cholan-24-oyl)-l-ß-homotryptophan derivatives were designed, synthesized, and tested for their ability to displace ephrin-A1 from the EphA2 receptor. Among them, two antagonists, namely compounds 21 and 22, displayed high affinity versus the EphA2 receptor and resulted endowed with better physicochemical and pharmacokinetic properties than the parent compound. These findings highlight the importance of free-energy calculations in drug design, confirming that META-D simulations can be used to successfully design novel bioactive compounds.
[Mh] Termos MeSH primário: Simulação por Computador
Desenho de Drogas
Ácido Litocólico/análogos & derivados
Receptor EphA2/antagonistas & inibidores
Triptofano/análogos & derivados
[Mh] Termos MeSH secundário: Animais
Estabilidade de Medicamentos
Ligantes
Ácido Litocólico/administração & dosagem
Ácido Litocólico/síntese química
Ácido Litocólico/química
Ácido Litocólico/farmacocinética
Masculino
Camundongos
Microssomos Hepáticos/metabolismo
Modelos Químicos
Simulação de Acoplamento Molecular
Ligação Proteica
Receptor EphA2/química
Relação Estrutura-Atividade
Triptofano/administração & dosagem
Triptofano/síntese química
Triptofano/química
Triptofano/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (UniPR129); 5QU0I8393U (Lithocholic Acid); 8DUH1N11BX (Tryptophan); EC 2.7.10.1 (Receptor, EphA2)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170704
[Lr] Data última revisão:
170704
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161223
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b01642


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[PMID]:27932556
[Au] Autor:Sun R; Yang N; Kong B; Cao B; Feng D; Yu X; Ge C; Huang J; Shen J; Wang P; Feng S; Fei F; Guo J; He J; Aa N; Chen Q; Pan Y; Schumacher JD; Yang CS; Guo GL; Aa J; Wang G
[Ad] Endereço:State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.
[Ti] Título:Orally Administered Berberine Modulates Hepatic Lipid Metabolism by Altering Microbial Bile Acid Metabolism and the Intestinal FXR Signaling Pathway.
[So] Source:Mol Pharmacol;91(2):110-122, 2017 Feb.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previous studies suggest that the lipid-lowering effect of berberine (BBR) involves actions on the low-density lipoprotein receptor and the AMP-activated protein kinase signaling pathways. However, the implication of these mechanisms is unclear because of the low bioavailability of BBR. Because the main action site of BBR is the gut and intestinal farnesoid X receptor (FXR) plays a pivotal role in the regulation of lipid metabolism, we hypothesized that the effects of BBR on intestinal FXR signaling pathway might account for its pharmacological effectiveness. Using wild type (WT) and intestine-specific FXR knockout (FXR ) mice, we found that BBR prevented the development of high-fat-diet-induced obesity and ameliorated triglyceride accumulation in livers of WT, but not FXR mice. BBR increased conjugated bile acids in serum and their excretion in feces. Furthermore, BBR inhibited bile salt hydrolase (BSH) activity in gut microbiota, and significantly increased the levels of tauro-conjugated bile acids, especially tauro-cholic acid(TCA), in the intestine. Both BBR and TCA treatment activated the intestinal FXR pathway and reduced the expression of fatty-acid translocase Cd36 in the liver. These results indicate that BBR may exert its lipid-lowering effect primarily in the gut by modulating the turnover of bile acids and subsequently the ileal FXR signaling pathway. In summary, we provide the first evidence to suggest a new mechanism of BBR action in the intestine that involves, sequentially, inhibiting BSH, elevating TCA, and activating FXR, which lead to the suppression of hepatic expression of Cd36 that results in reduced uptake of long-chain fatty acids in the liver.
[Mh] Termos MeSH primário: Bactérias/metabolismo
Berberina/administração & dosagem
Berberina/farmacologia
Ácidos e Sais Biliares/metabolismo
Intestinos/metabolismo
Metabolismo dos Lipídeos/efeitos dos fármacos
Fígado/metabolismo
Receptores Citoplasmáticos e Nucleares/metabolismo
[Mh] Termos MeSH secundário: Animais
Bactérias/efeitos dos fármacos
Berberina/uso terapêutico
Ácidos e Sais Biliares/sangue
Peso Corporal/efeitos dos fármacos
Antígenos CD36/genética
Antígenos CD36/metabolismo
Dieta Hiperlipídica
Fezes/química
Microbioma Gastrointestinal/efeitos dos fármacos
Regulação da Expressão Gênica/efeitos dos fármacos
Hipolipemiantes/farmacologia
Hipolipemiantes/uso terapêutico
Metabolismo dos Lipídeos/genética
Ácido Litocólico/farmacologia
Fígado/efeitos dos fármacos
Masculino
Camundongos Endogâmicos C57BL
Obesidade/sangue
Obesidade/tratamento farmacológico
Obesidade/genética
Obesidade/prevenção & controle
Transdução de Sinais/efeitos dos fármacos
Ácido Taurocólico/farmacologia
Triglicerídeos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (CD36 Antigens); 0 (Hypolipidemic Agents); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Triglycerides); 0 (farnesoid X-activated receptor); 0I8Y3P32UF (Berberine); 5E090O0G3Z (Taurocholic Acid); 5QU0I8393U (Lithocholic Acid)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161210
[St] Status:MEDLINE
[do] DOI:10.1124/mol.116.106617



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