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  1 / 19509 MEDLINE  
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[PMID]:29175453
[Au] Autor:Zhang Y; Lickteig AJ; Csanaky IL; Klaassen CD
[Ad] Endereço:School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China. Electronic address: youcai.zhang@tju.edu.cn.
[Ti] Título:Activation of PPARα decreases bile acids in livers of female mice while maintaining bile flow and biliary bile acid excretion.
[So] Source:Toxicol Appl Pharmacol;338:112-123, 2018 01 01.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fibrates are hypolipidemic drugs that act as activators of peroxisome proliferator-activated receptor α (PPARα). In both humans and rodents, females were reported to be less responsive to fibrates than males. Previous studies on fibrates and PPARα usually involved male mice, but little has been done in females. The present study aimed to provide the first comprehensive analysis of the effects of clofibrate (CLOF) and PPARα on bile acid (BA) homeostasis in female mice. Study in WT male mice showed that a 4-day CLOF treatment increased liver weight, bile flow, and biliary BA excretion, but decreased total BAs in both serum and liver. In contrast, WT female mice were less susceptible to these CLOF-mediated responses observed in males. In WT female mice, CLOF decreased total BAs in the liver, but had little effect on the mRNAs of hepatic BA-related genes. Next, a comparative analysis between WT and PPARα-null female mice showed that lack of PPARα in female mice decreased total BAs in serum, but had little effect on total BAs in liver or bile. However, lack of PPARα in female mice increased mRNAs of BA synthetic enzymes (Cyp7a1, Cyp8b1, Cyp27a1, and Cyp7b1) and transporters (Ntcp, Oatp1a1, Oatp1b2, and Mrp3). Furthermore, the increase of Cyp7a1 in PPARα-null female mice was associated with an increase in liver Fxr-Shp-Lrh-1 signaling. In conclusion, female mice are resistant to CLOF-mediated effects on BA metabolism observed in males, which could be attributed to PPARα-mediated suppression in females on genes involved in BA synthesis and transport.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Bile/metabolismo
Fígado/metabolismo
PPAR alfa/fisiologia
[Mh] Termos MeSH secundário: Animais
Colesterol/metabolismo
Colesterol 7-alfa-Hidroxilase/genética
Clofibrato/farmacologia
Feminino
Íleo/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (PPAR alpha); 97C5T2UQ7J (Cholesterol); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase); EC 1.14.14.23 (Cyp7a1 protein, mouse); HPN91K7FU3 (Clofibrate)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180311
[Lr] Data última revisão:
180311
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE


  2 / 19509 MEDLINE  
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[PMID]:29275233
[Au] Autor:Mostarda S; Passeri D; Carotti A; Cerra B; Colliva C; Benicchi T; Macchiarulo A; Pellicciari R; Gioiello A
[Ad] Endereço:Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1, 06123 Perugia, Italy.
[Ti] Título:Synthesis, physicochemical properties, and biological activity of bile acids 3-glucuronides: Novel insights into bile acid signalling and detoxification.
[So] Source:Eur J Med Chem;144:349-358, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Glucuronidation is considered an important detoxification pathway of bile acids especially in cholestatic conditions. Glucuronides are less toxic than the parent free forms and are more easily excreted in urine. However, the pathophysiological significance of bile acid glucuronidation is still controversial and debated among the scientific community. Progress in this field has been strongly limited by the lack of appropriate methods for the preparation of pure glucuronides in the amount needed for biological and pharmacological studies. In this work, we have developed a new synthesis of bile acid C3-glucuronides enabling the convenient preparation of gram-scale quantities. The synthesized compounds have been characterized in terms of physicochemical properties and abilities to modulate key nuclear receptors including the farnesoid X receptor (FXR). In particular, we found that C3-glucuronides of chenodeoxycholic acid and lithocholic acid, respectively the most abundant and potentially cytotoxic species formed in patients affected by cholestasis, behave as FXR agonists and positively regulate the gene expression of transporter proteins, the function of which is critical in human conditions related to imbalances of bile acid homeostasis.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/farmacologia
Glucuronídeos/farmacologia
Receptores Citoplasmáticos e Nucleares/agonistas
[Mh] Termos MeSH secundário: Ácidos e Sais Biliares/química
Química Física
Relação Dose-Resposta a Droga
Glucuronídeos/química
Células HEK293
Células Hep G2
Seres Humanos
Simulação de Dinâmica Molecular
Estrutura Molecular
Receptores Citoplasmáticos e Nucleares/genética
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Glucuronides); 0 (Receptors, Cytoplasmic and Nuclear); 0 (farnesoid X-activated receptor)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171225
[St] Status:MEDLINE


  3 / 19509 MEDLINE  
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[PMID]:29275230
[Au] Autor:Hermánková E; Zák A; Poláková L; Hobzová R; Hromádka R; Sirc J
[Ad] Endereço:Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovsky sq. 2, CZ-162 06 Prague, Czech Republic. Electronic address: hermankova@imc.cas.cz.
[Ti] Título:Polymeric bile acid sequestrants: Review of design, in vitro binding activities, and hypocholesterolemic effects.
[So] Source:Eur J Med Chem;144:300-317, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Polymeric bile acid sequestrants (BAS) have recently attracted much attention as lipid-lowering agents. These non-absorbable materials specifically bind bile acids (BAs) in the intestine, preventing bile acid (BA) reabsorption into the blood through enterohepatic circulation. Therefore, it is important to understand the structure-property relationships between the polymer sequestrant and its ability to bind specific BAs molecules. In this review, we describe pleiotropic effects of bile acids, and we focus on BAS with various molecular architectures that result in different mechanisms of BA sequestration. Here, we present 1) amphiphilic polymers based on poly(meth)acrylates, poly(meth)acrylamides, polyalkylamines and polyallylamines containing quaternary ammonium groups, 2) cyclodextrins, and 3) BAS prepared via molecular imprinting methods. The synthetic approaches leading to individual BAS preparation, as well as results of their in vitro BA binding activities and in vivo lipid-lowering activities, are discussed.
[Mh] Termos MeSH primário: Anticolesterolemiantes/farmacologia
Ácidos e Sais Biliares/farmacologia
Desenho de Drogas
Hipercolesterolemia/tratamento farmacológico
Polímeros/farmacologia
[Mh] Termos MeSH secundário: Animais
Anticolesterolemiantes/síntese química
Anticolesterolemiantes/química
Ácidos e Sais Biliares/síntese química
Ácidos e Sais Biliares/química
Sítios de Ligação/efeitos dos fármacos
Seres Humanos
Estrutura Molecular
Polímeros/síntese química
Polímeros/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anticholesteremic Agents); 0 (Bile Acids and Salts); 0 (Polymers)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171225
[St] Status:MEDLINE


  4 / 19509 MEDLINE  
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[PMID]:27774647
[Au] Autor:Desai MS; Mathur B; Eblimit Z; Vasquez H; Taegtmeyer H; Karpen SJ; Penny DJ; Moore DD; Anakk S
[Ad] Endereço:Section of Pediatric Critical Care, Baylor College of Medicine, Houston, TX.
[Ti] Título:Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart.
[So] Source:Hepatology;65(1):189-201, 2017 01.
[Is] ISSN:1527-3350
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cardiac dysfunction in patients with liver cirrhosis is strongly associated with increased serum bile acid concentrations. Here we show that excess bile acids decrease fatty acid oxidation in cardiomyocytes and can cause heart dysfunction, a cardiac syndrome that we term cholecardia. Farnesoid X receptor; Small Heterodimer Partner double knockout mice, a model for bile acid overload, display cardiac hypertrophy, bradycardia, and exercise intolerance. In addition, double knockout mice exhibit an impaired cardiac response to catecholamine challenge. Consistent with this decreased cardiac function, we show that elevated serum bile acids reduce cardiac fatty acid oxidation both in vivo and ex vivo. We find that increased bile acid levels suppress expression of proliferator-activated receptor-γ coactivator 1α, a key regulator of fatty acid metabolism, and that proliferator-activated receptor-γ coactivator 1α overexpression in cardiac cells was able to rescue the bile acid-mediated reduction in fatty acid oxidation genes. Importantly, intestinal bile acid sequestration with cholestyramine was sufficient to reverse the observed heart dysfunction in the double knockout mice. CONCLUSIONS: Decreased proliferator-activated receptor-γ coactivator 1α expression contributes to the metabolic dysfunction in cholecardia so that reducing serum bile acid concentrations may be beneficial against the metabolic and pathological changes in the heart. (Hepatology 2017;65:189-201).
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/fisiologia
Cardiomiopatias/etiologia
Cardiomiopatias/metabolismo
[Mh] Termos MeSH secundário: Animais
Ácidos e Sais Biliares/sangue
Cardiomiopatias/sangue
Cardiomiopatias/fisiopatologia
Ácidos Graxos/metabolismo
Masculino
Camundongos
Camundongos Knockout
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Fatty Acids)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:180121
[Lr] Data última revisão:
180121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE
[do] DOI:10.1002/hep.28890


  5 / 19509 MEDLINE  
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[PMID]:29262351
[Au] Autor:Cao W; Kayama H; Chen ML; Delmas A; Sun A; Kim SY; Rangarajan ES; McKevitt K; Beck AP; Jackson CB; Crynen G; Oikonomopoulos A; Lacey PN; Martinez GJ; Izard T; Lorenz RG; Rodriguez-Palacios A; Cominelli F; Abreu MT; Hommes DW; Koralov SB; Takeda K; Sundrud MS
[Ad] Endereço:Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL 33458, USA.
[Ti] Título:The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids.
[So] Source:Immunity;47(6):1182-1196.e10, 2017 Dec 19.
[Is] ISSN:1097-4180
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CD4 T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4 T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn's disease-like ileitis following transfer into Rag1 hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1 mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn's disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis.
[Mh] Termos MeSH primário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/imunologia
Ácidos e Sais Biliares/imunologia
Linfócitos T CD4-Positivos/imunologia
Doença de Crohn/imunologia
Ileíte/imunologia
Mucosa Intestinal/imunologia
[Mh] Termos MeSH secundário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/deficiência
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética
Acridinas/farmacologia
Adulto
Animais
Ácidos e Sais Biliares/metabolismo
Ácidos e Sais Biliares/farmacologia
Transporte Biológico
Linfócitos T CD4-Positivos/efeitos dos fármacos
Linfócitos T CD4-Positivos/patologia
Doença de Crohn/genética
Doença de Crohn/patologia
Modelos Animais de Doenças
Feminino
Regulação da Expressão Gênica
Proteínas de Homeodomínio/genética
Proteínas de Homeodomínio/imunologia
Homeostase/imunologia
Seres Humanos
Ileíte/genética
Ileíte/patologia
Íleo/imunologia
Íleo/patologia
Imunidade nas Mucosas
Mucosa Intestinal/patologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Meia-Idade
Estresse Oxidativo
Transdução de Sinais
Tetra-Hidroisoquinolinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Acridines); 0 (Bile Acids and Salts); 0 (Homeodomain Proteins); 0 (Tetrahydroisoquinolines); 128559-51-3 (RAG-1 protein); N488540F94 (Elacridar)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180109
[Lr] Data última revisão:
180109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE


  6 / 19509 MEDLINE  
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[PMID]:29198707
[Au] Autor:Wang F; Lu Z; Wang X; Zhang Y
[Ad] Endereço:School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
[Ti] Título:Impaired vagus function in rats suppresses bile acid synthesis in the liver by disrupting tight junctions and activating Fxr-Fgf15 signaling in the intestine.
[So] Source:Biochem Biophys Res Commun;495(1):1490-1496, 2018 01 01.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bile acids (BAs) circulate between the liver and intestine, and regulate the homeostasis of glucose, lipid, and energy. Recent studies demonstrated an essential role of BAs in neurological diseases, suggesting an interaction between BAs and the nervous system. In the present study, we showed that impaired vagus function in rats induced by vagotomy resulted in an increase in bile flow without causing liver injury. The concentrations of unconjugated and glycine-conjugated BAs were increased in both serum and bile of rats after vagotomy, which was due to impaired tight junctions and thus increased passive absorption of BAs in the intestine. Vagotomy markedly suppressed the expression of the rate-limiting BA synthetic enzyme Cyp7a1, which was not due to activation of Fxr-Shp signaling in the liver, but due to activation of Fxr-Fgf15 signaling in the intestine. Furthermore, vagotomy produced a BA profile in the bile favorable for Fxr activation by decreasing tauro-ß-muricholic acid, a natural Fxr antagonist, and increasing glyco-chenodeoxycholic acid, a natural Fxr agonist. In summary, the present study provides the first comprehensive analysis of the critical role of the vagus nerve in regulating BA metabolism and signaling pathway.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/secreção
Fatores de Crescimento de Fibroblastos/metabolismo
Íleo/metabolismo
Fígado/secreção
Receptores Citoplasmáticos e Nucleares/metabolismo
Junções Íntimas/metabolismo
Doenças do Nervo Vago/fisiopatologia
[Mh] Termos MeSH secundário: Animais
Fígado/patologia
Masculino
Ratos
Ratos Wistar
Transdução de Sinais
Junções Íntimas/patologia
Doenças do Nervo Vago/complicações
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (FGF19 protein, rat); 0 (Receptors, Cytoplasmic and Nuclear); 0 (farnesoid X-activated receptor); 62031-54-3 (Fibroblast Growth Factors)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE


  7 / 19509 MEDLINE  
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[PMID]:29198703
[Au] Autor:Kim S; Han SY; Yu KS; Han D; Ahn HJ; Jo JE; Kim JH; Shin J; Park HW
[Ad] Endereço:Department of Cell Biology, Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon 35365, South Korea.
[Ti] Título:Impaired autophagy promotes bile acid-induced hepatic injury and accumulation of ubiquitinated proteins.
[So] Source:Biochem Biophys Res Commun;495(1):1541-1547, 2018 01 01.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chronic exposure to hydrophobic bile acids such as chenodeoxycholic acid (CDCA) and cholic acid (CA) in the liver during cholestasis causes hepatotoxicity and inflammatory response. However, the detailed mechanisms regarding the role of autophagy in cholestatic hepatotoxicity remain largely unknown. Here we determined autophagic clearance in livers of bile duct-ligated mice, in which bile acids accumulate, and in human hepatoma HepG2 cells treated with CDCA and CA. The accumulation of bile acids caused defective autophagic clearance, shown by the accumulation of insoluble p62 and ubiquitinated proteins and cell death accompanied by caspase-3 processing. Hepatocytes exposed to bile acids also showed the accumulation of autophagosomes via suppressed autophagy flux. Treatment of CDCA markedly suppressed Beclin-1 expression, which exhibits a higher cytotoxicity than CA. Moreover, pharmacological or genetic inhibition of autophagy enhanced bile acid-induced cell death. Finally, in vivo, bile duct ligation led to aberrant accumulation of p62 and ubiquitinated proteins in the liver. Our data demonstrate that inhibited autophagy is an essential component of liver injury during cholestasis.
[Mh] Termos MeSH primário: Autofagia
Ácidos e Sais Biliares/secreção
Hepatopatias/metabolismo
Hepatopatias/patologia
Fígado/metabolismo
Proteínas Ubiquitinadas/biossíntese
[Mh] Termos MeSH secundário: Animais
Células Hep G2
Seres Humanos
Fígado/patologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Ubiquitinação
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Ubiquitinated Proteins)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE


  8 / 19509 MEDLINE  
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[PMID]:28455390
[Au] Autor:Christian WV; Hinkle PM
[Ad] Endereço:Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, U.S.A.
[Ti] Título:Global functions of extracellular, transmembrane and cytoplasmic domains of organic solute transporter ß-subunit.
[So] Source:Biochem J;474(12):1981-1992, 2017 05 25.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Transport of bile acids across the basolateral membrane of the intestinal enterocyte is carried out by the organic solute transporter (Ost) composed of a seven-transmembrane domain (TMD) subunit (Ostα) and an ancillary single TMD subunit (Ostß). Although previous investigations have demonstrated the importance of the TMD of Ostß for its activity, further studies were conducted to assess the contributions of other regions of the Ostß subunit. Transport activity was retained when Ostß was truncated to contain only the TMD with 15 additional residues on each side and co-expressed with Ostα, whereas shorter fragments were inactive. To probe the broader functions of Ostß segments, chimeric proteins were constructed in which N-terminal, TMD or C-terminal regions of Ostß were fused to corresponding regions of receptor activity-modifying protein (RAMP1), a single TMD protein required by several seven-TMD G-protein-coupled receptors including the calcitonin receptor-like receptor (CLR). Ostß/RAMP1 chimeras were expressed with Ostα and CLR. As expected, replacing the Ostß TMD abolished transport activity; however, replacing either the entire N-terminal or entire C-terminal domain of Ostß with RAMP1 sequences did not prevent plasma membrane localization or the ability to support [ H]taurocholate uptake. Co-immunoprecipitation experiments revealed that the C-terminus of Ostß is a previously unrecognized site of interaction with Ostα. All chimeras containing N-terminal RAMP1 segments allowed co-expressed CLR to respond to agonists with strong increases in cyclic AMP. These results provide new insights into the structure and function of the heteromeric Ost transporter complex.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Proteínas de Membrana Transportadoras/metabolismo
[Mh] Termos MeSH secundário: Absorção Fisiológica/efeitos dos fármacos
Animais
Transporte Biológico/efeitos dos fármacos
Peptídeo Relacionado com Gene de Calcitonina/genética
Peptídeo Relacionado com Gene de Calcitonina/metabolismo
Proteína Semelhante a Receptor de Calcitonina/agonistas
Proteína Semelhante a Receptor de Calcitonina/genética
Proteína Semelhante a Receptor de Calcitonina/metabolismo
AMP Cíclico/metabolismo
Células HEK293
Seres Humanos
Imunoprecipitação
Proteínas de Membrana Transportadoras/química
Proteínas de Membrana Transportadoras/genética
Camundongos
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Domínios e Motivos de Interação entre Proteínas
Transporte Proteico
Proteína 1 Modificadora da Atividade de Receptores/química
Proteína 1 Modificadora da Atividade de Receptores/genética
Proteína 1 Modificadora da Atividade de Receptores/metabolismo
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Sistemas do Segundo Mensageiro/efeitos dos fármacos
Homologia Estrutural de Proteína
Ácido Taurocólico/metabolismo
Trítio
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (CALCA protein, human); 0 (CALCRL protein, human); 0 (Calcitonin Receptor-Like Protein); 0 (Membrane Transport Proteins); 0 (Peptide Fragments); 0 (Ramp1 protein, mouse); 0 (Receptor Activity-Modifying Protein 1); 0 (Recombinant Fusion Proteins); 0 (organic solute transporter alpha, mouse); 0 (organic solute transporter beta, mouse); 10028-17-8 (Tritium); 5E090O0G3Z (Taurocholic Acid); 83652-28-2 (Calcitonin Gene-Related Peptide); E0399OZS9N (Cyclic AMP)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171217
[Lr] Data última revisão:
171217
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20161093


  9 / 19509 MEDLINE  
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[PMID]:27776768
[Au] Autor:Waters LJ; Shokry DS; Parkes GMB; Mitchell JC
[Ad] Endereço:School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, UK. Electronic address: l.waters@hud.ac.uk.
[Ti] Título:The Use of Bile Salt Micelles for the Prediction of Human Intestinal Absorption.
[So] Source:J Pharm Sci;105(12):3611-3614, 2016 Dec.
[Is] ISSN:1520-6017
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human intestinal absorption (HIA) will dictate biopharmaceutical performance through its influence on absorption, distribution, metabolism, and elimination and can vary significantly depending upon the nature of the compound under consideration. In this study, an in vitro assay method is proposed for the prediction of HIA through the measurement of drug solubility in an aqueous phase containing micellar bile salt, namely sodium deoxycholate. A series of twenty compounds, displaying a range of physicochemical properties and known HIA values, were analyzed using UV spectroscopy to determine a solubilization ratio for each compound. A micelle/water partition coefficient (K ) was calculated and then used to develop an equation through simple linear regression; logit HIA = -0.919 + 0.4618 logK (R = 0.85). From this equation, a value for % HIA was determined which compared well with literature. Furthermore, 4 additional drugs were then analyzed using the developed equation and found to match well with literature, confirming the suitability of the method. Using a simple, economic, and robust UV bile salt assay allows prediction of HIA and avoids many of the disadvantages of other techniques, such as animal-based methods.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Absorção Intestinal/fisiologia
Micelas
[Mh] Termos MeSH secundário: Ácidos e Sais Biliares/administração & dosagem
Interações Medicamentosas/fisiologia
Previsões
Seres Humanos
Absorção Intestinal/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Micelles)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171201
[Lr] Data última revisão:
171201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE


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[PMID]:28464377
[Au] Autor:Midgett CR; Almagro-Moreno S; Pellegrini M; Taylor RK; Skorupski K; Kull FJ
[Ad] Endereço:Department of Chemistry, Dartmouth College, Hanover, NH, 03755, USA.
[Ti] Título:Bile salts and alkaline pH reciprocally modulate the interaction between the periplasmic domains of Vibrio cholerae ToxR and ToxS.
[So] Source:Mol Microbiol;105(2):258-272, 2017 Jul.
[Is] ISSN:1365-2958
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:ToxR is a transmembrane transcription factor that is essential for virulence gene expression and human colonization by Vibrio cholerae. ToxR requires its operon partner ToxS, a periplasmic integral membrane protein, for full activity. These two proteins are thought to interact through their respective periplasmic domains, ToxRp and ToxSp. In addition, ToxR is thought to be responsive to various environmental cues, such as bile salts and alkaline pH, but how these factors influence ToxR is not yet understood. Using NMR and reciprocal pull down assays, we present the first direct evidence that ToxR and ToxS physically interact. Furthermore, using NMR and DSF, it was shown that the bile salts cholate and chenodeoxycholate interact with purified ToxRp and destabilize it. Surprisingly, bile salt destabilization of ToxRp enhanced the interaction between ToxRp and ToxSp. In contrast, alkaline pH, which is one of the factors that leads to ToxR proteolysis, decreased the interaction between ToxRp and ToxSp. Taken together, these data suggest a model whereby bile salts or other detergents destabilize ToxR, increasing its interaction with ToxS to promote full ToxR activity. Subsequently, as V. cholerae alkalinizes its environment in late stationary phase, the interaction between the two proteins decreases, allowing ToxR proteolysis to proceed.
[Mh] Termos MeSH primário: Proteínas de Bactérias/genética
Proteínas de Ligação a DNA/genética
Proteínas de Membrana/genética
Fatores de Transcrição/genética
[Mh] Termos MeSH secundário: Proteínas de Bactérias/metabolismo
Ácidos e Sais Biliares/metabolismo
Proteínas de Ligação a DNA/metabolismo
Regulação Bacteriana da Expressão Gênica/genética
Concentração de Íons de Hidrogênio
Proteínas de Membrana/metabolismo
Óperon/genética
Periplasma/metabolismo
Domínios Proteicos/genética
Proteólise
Fatores de Transcrição/metabolismo
Vibrio cholerae/genética
Virulência/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Bile Acids and Salts); 0 (DNA-Binding Proteins); 0 (Membrane Proteins); 0 (Transcription Factors); 0 (toxR protein, Vibrio cholerae); 135315-97-8 (ToxS protein, Vibrio cholerae)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1111/mmi.13699



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