Base de dados : MEDLINE
Pesquisa : D04.210.500.105.225.130 [Categoria DeCS]
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[PMID]:29254319
[Au] Autor:Musolino V; Gliozzi M; Carresi C; Maiuolo J; Mollace R; Bosco F; Scarano F; Scicchitano M; Maretta A; Palma E; Iannone M; Morittu VM; Gratteri S; Muscoli C; Fini M; Mollace V
[Ad] Endereço:Institute of Research for Food Safety and Health (IRC-FSH), Department of Health Science, Magna Græcia University of Catanzaro, Catanzaro, Italy.
[Ti] Título:Lipid-lowering effect of bergamot polyphenolic fraction: role of pancreatic cholesterol ester hydrolase.
[So] Source:J Biol Regul Homeost Agents;31(4):1087-1093, 2017 Oct-Dec.
[Is] ISSN:0393-974X
[Cp] País de publicação:Italy
[La] Idioma:eng
[Ab] Resumo:Bergamot polyphenolic fraction (BPF) has been shown to positively modulate several mechanisms involved in metabolic syndrome, suggesting its use in therapy. In particular, it is able to induce a significant amelioration of serum lipid profile in hyperlipemic patients at different levels. The purpose of our study was to investigate the effect of BPF on cholesterol absorption physiologically mediated by pancreatic cholesterol ester hydrolase (pCEH). An in vitro activity assay was performed to study the effect of BPF on pCEH, whereas the rate of cholesterol absorption was evaluated through in vivo studies. In particular, male, Sprague-Dawley rats (200–225 g) were fed either normal chow or chow supplemented with 0.5% cholic acid, 5.5% peanut oil, and varying amounts of cholesterol (0 to 1.5%). BPF (10 mg/Kg) was daily administrated by means of a gastric gavage to animals fed with lipid supplemented diet for 4 weeks and, at the end of the study, plasma lipids and liver cholesteryl esters were measured in all experimental groups. Our results show that BPF was able to inhibit pCEH activity and this effect was confirmed, in vivo, via detection of lymphatic cholesteryl ester in rats fed with a cholesterol-rich diet. This evidence clarifies a further mechanism responsible for the hypolipemic properties of BPF previously observed in humans, confirming its beneficial effect in the therapy of hypercholesterolemia and in the treatment of metabolic syndrome.
[Mh] Termos MeSH primário: Suplementos Nutricionais
Hiperlipidemias/tratamento farmacológico
Hipolipemiantes/farmacologia
Óleos Vegetais/farmacologia
Esterol Esterase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Colesterol/administração & dosagem
Colesterol/sangue
Ésteres do Colesterol/sangue
Ácido Cólico/administração & dosagem
Ácido Cólico/sangue
Absorção Gastrointestinal/fisiologia
Seres Humanos
Hiperlipidemias/metabolismo
Hiperlipidemias/patologia
Hipolipemiantes/metabolismo
Fígado/efeitos dos fármacos
Fígado/metabolismo
Masculino
Síndrome Metabólica/tratamento farmacológico
Síndrome Metabólica/metabolismo
Síndrome Metabólica/patologia
Óleos Vegetais/metabolismo
Ratos
Ratos Sprague-Dawley
Esterol Esterase/metabolismo
Triglicerídeos/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholesterol Esters); 0 (Hypolipidemic Agents); 0 (Plant Oils); 0 (Triglycerides); 39W1PKE3JI (bergamot oil); 97C5T2UQ7J (Cholesterol); EC 3.1.1.- (bile salt-stimulated lipase); EC 3.1.1.13 (Sterol Esterase); G1JO7801AE (Cholic Acid)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171220
[St] Status:MEDLINE


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[PMID]:28662517
[Au] Autor:Wang Z; Lv Q; Liu H; Wu Y; Bai Y; Cheng Y; Su Y; Cai Y; Yu J; Ma J; Bao J
[Ad] Endereço:Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China.
[Ti] Título:Caveolae Depletion Contributes to Vasorelaxant Effects of Chenodeoxycholic Acid.
[So] Source:Cell Physiol Biochem;42(3):1013-1024, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: High concentration of bile acids (BAs) induces hydrophobicity-dependent vasorelaxtant effects with hydrophobic BAs showing greater responses than hydrophilic BAs, of which the underlying mechanisms are still unclear. Caveolae are invaginations on membranes of endothelial cells (ECs) entraping endothelial nitric oxide synthase (eNOS) to prevent its activation, which plays a critical role in regulation of vascular function. The purpose of the present study was to investigate the role of caveolae in vasorelaxant effects of BAs. METHODS: Chenodeoxycholic acid (CDCA) and cholic acid (CA) were used to represent hydrophobic and hydrophilic BA, respectively. Vascular responses of abdominal aorta were measured by isometric force recording. Morphology of caveolae was examined by transmission electron microscopy. Protein expression of total eNOS (t-eNOS) or phosphorylated eNOS (p-eNOS) was determined by Western blot. Nitric oxide (NO) content was observed by fluorometric assay. RESULTS: We demonstrated that CDCA as well as Methyl-ß-cyclodextrin (MCD), a commonly used reagent for cholesterol depletion, reduced potassium chloride (KCl)- or phenylephrine (PE)-elicited vasoconstriction (P < 0.05), and enhanced acetylcholine (Ach)-elicited vasodilatation (P < 0.05) in endothelium-intact abdominal aorta but not in endothelium-denuded or CA-treated vessels. CDCA and MCD, but not CA significantly disrupted caveolae structure on ECs of abdominal aorta which was recovered by cholesterol incubation (P < 0.05). Protein expression of t-eNOS was significantly decreased (P < 0.05), and that of p-eNOS together with NO content was significantly increased in CDCA- and MCD- but not CA-treated vessels (P < 0.05) as compared with vehicle. The effect was reversed by either endothelium-denudation or cholesterol replenishment. Moreover, with cholesterol incubation, no significant differences were found in vascular responses among CDCA-, CA- or vehicle-treated vessels. CONCLUSION: These results indicate that CDCA diminishes caveolae on ECs of abdominal aorta promoting eNOS phosphorylation and NO production which contributes to its vasorelaxtant effect.
[Mh] Termos MeSH primário: Aorta/efeitos dos fármacos
Cavéolas/efeitos dos fármacos
Ácido Quenodesoxicólico/farmacologia
Endotélio Vascular/efeitos dos fármacos
Vasodilatação/efeitos dos fármacos
Vasodilatadores/farmacologia
[Mh] Termos MeSH secundário: Animais
Aorta/fisiologia
Cavéolas/metabolismo
Cavéolas/ultraestrutura
Ácido Cólico/farmacologia
Endotélio Vascular/metabolismo
Endotélio Vascular/ultraestrutura
Masculino
Óxido Nítrico/análise
Óxido Nítrico/metabolismo
Óxido Nítrico Sintase Tipo III/análise
Óxido Nítrico Sintase Tipo III/metabolismo
Ratos Sprague-Dawley
Vasoconstrição/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Vasodilator Agents); 0GEI24LG0J (Chenodeoxycholic Acid); 31C4KY9ESH (Nitric Oxide); EC 1.14.13.39 (Nitric Oxide Synthase Type III); G1JO7801AE (Cholic Acid)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170630
[St] Status:MEDLINE
[do] DOI:10.1159/000478683


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[PMID]:28330474
[Au] Autor:Giricz Z; Koncsos G; Rajtík T; Varga ZV; Baranyai T; Csonka C; Szobi A; Adameová A; Gottlieb RA; Ferdinandy P
[Ad] Endereço:Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1089, Budapest, Hungary. giricz.zoltan@med.semmelweis-univ.hu.
[Ti] Título:Hypercholesterolemia downregulates autophagy in the rat heart.
[So] Source:Lipids Health Dis;16(1):60, 2017 Mar 23.
[Is] ISSN:1476-511X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: We have previously shown that efficiency of ischemic conditioning is diminished in hypercholesterolemia and that autophagy is necessary for cardioprotection. However, it is unknown whether isolated hypercholesterolemia disturbs autophagy or the mammalian target of rapamycin (mTOR) pathways. Therefore, we investigated whether isolated hypercholesterolemia modulates cardiac autophagy-related pathways or programmed cell death mechanisms such as apoptosis and necroptosis in rat heart. METHODS: Male Wistar rats were fed either normal chow (NORM; n = 9) or with 2% cholesterol and 0.25% cholic acid-enriched diet (CHOL; n = 9) for 12 weeks. CHOL rats exhibited a 41% increase in plasma total cholesterol level over that of NORM rats (4.09 mmol/L vs. 2.89 mmol/L) at the end of diet period. Animals were sacrificed, hearts were excised and briefly washed out. Left ventricles were snap-frozen for determination of markers of autophagy, mTOR pathway, apoptosis, and necroptosis by Western blot. RESULTS: Isolated hypercholesterolemia was associated with a significant reduction in expression of cardiac autophagy markers such as LC3-II, Beclin-1, Rubicon and RAB7 as compared to controls. Phosphorylation of ribosomal S6, a surrogate marker for mTOR activity, was increased in CHOL samples. Cleaved caspase-3, a marker of apoptosis, increased in CHOL hearts, while no difference in the expression of necroptotic marker RIP1, RIP3 and MLKL was detected between treatments. CONCLUSIONS: This is the first comprehensive analysis of autophagy and programmed cell death pathways of apoptosis and necroptosis in hearts of hypercholesterolemic rats. Our data show that isolated hypercholesterolemia suppresses basal cardiac autophagy and that the decrease in autophagy may be a result of an activated mTOR pathway. Reduced autophagy was accompanied by increased apoptosis, while cardiac necroptosis was not modulated by isolated hypercholesterolemia. Decreased basal autophagy and elevated apoptosis may be responsible for the loss of cardioprotection reported in hypercholesterolemic animals.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Autofagia/efeitos dos fármacos
Colesterol/efeitos adversos
Ácido Cólico/efeitos adversos
Hipercolesterolemia/metabolismo
[Mh] Termos MeSH secundário: Animais
Beclina-1/genética
Beclina-1/metabolismo
Biomarcadores/metabolismo
Caspase 3/genética
Caspase 3/metabolismo
Colesterol/administração & dosagem
Ácido Cólico/administração & dosagem
Dieta Hiperlipídica/efeitos adversos
Regulação da Expressão Gênica/efeitos dos fármacos
Coração/efeitos dos fármacos
Hipercolesterolemia/etiologia
Hipercolesterolemia/genética
Hipercolesterolemia/patologia
Masculino
Proteínas Associadas aos Microtúbulos/genética
Proteínas Associadas aos Microtúbulos/metabolismo
Necrose/etiologia
Necrose/genética
Necrose/metabolismo
Necrose/patologia
Proteínas Quinases/genética
Proteínas Quinases/metabolismo
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/metabolismo
Ratos
Ratos Wistar
Proteína Serina-Treonina Quinases de Interação com Receptores/genética
Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
Proteínas Quinases S6 Ribossômicas/genética
Proteínas Quinases S6 Ribossômicas/metabolismo
Transdução de Sinais
Serina-Treonina Quinases TOR/genética
Serina-Treonina Quinases TOR/metabolismo
Proteínas rab de Ligação ao GTP/genética
Proteínas rab de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Beclin-1); 0 (Becn1 protein, rat); 0 (Biomarkers); 0 (LC3 protein, rat); 0 (Microtubule-Associated Proteins); 152989-05-4 (rab7 protein); 97C5T2UQ7J (Cholesterol); EC 2.7.- (MLKL protein, rat); EC 2.7.- (Protein Kinases); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (mTOR protein, rat); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (RIP1 protein, rat); EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases); EC 2.7.11.1 (Ribosomal Protein S6 Kinases); EC 2.7.11.1 (receptor-interacting protein 3, rat); EC 3.4.22.- (Casp3 protein, rat); EC 3.4.22.- (Caspase 3); EC 3.6.5.2 (rab GTP-Binding Proteins); G1JO7801AE (Cholic Acid)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1186/s12944-017-0455-0


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[PMID]:28280334
[Au] Autor:Li Y; Zhu C
[Ad] Endereço:Department of Drug Delivery Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China.
[Ti] Título:Mechanism of hepatic targeting via oral administration of DSPE-PEG-cholic acid-modified nanoliposomes.
[So] Source:Int J Nanomedicine;12:1673-1684, 2017.
[Is] ISSN:1178-2013
[Cp] País de publicação:New Zealand
[La] Idioma:eng
[Ab] Resumo:In oral administration, gastrointestinal physiological environment, gastrointestinal epithelial cell membranes, and blood circulation are typical biological barriers to hepatic delivery of ligand-modified nanoparticle drug delivery systems. To elucidate the mechanism of oral hepatic targeting of cholic acid receptor-mediated nanoliposomes (LPs) (distearoyl phosphatidylethanolamine-polyethylene glycol-cholic acid-modified LPs, CA-LPs), evaluations were performed on colon cancer Caco-2 cell monolayers, liver cancer HepG2 cells, and a rat intestinal perfusion model. CA-LPs, ~100 nm in diameter, exhibited sustained-release behavior and had the greatest stability in rat gastrointestinal fluid and serum for both size and entrapment efficiency. CA-LPs demonstrated highest transport across Caco-2 cells and highest cellular uptake by HepG2 cells. The enhanced endocytosis of CA-LPs was found to be mediated by Na /taurocholate cotransporting polypeptide and involved the caveolin-mediated endocytosis pathway. Further, we used fluorescence resonance energy transfer (FRET) technology to show that the CA-LPs maintained their structural integrity in part during the transport across the Caco-2 cell monolayer and uptake by HepG2 cells.
[Mh] Termos MeSH primário: Ácido Cólico/química
Sistemas de Liberação de Medicamentos
Fígado/metabolismo
Nanopartículas/química
Fosfatidiletanolaminas/química
Polietilenoglicóis/química
[Mh] Termos MeSH secundário: Administração Oral
Animais
Transporte Biológico/efeitos dos fármacos
Células CACO-2
Doxorrubicina/farmacologia
Estabilidade de Medicamentos
Endocitose/efeitos dos fármacos
Transferência Ressonante de Energia de Fluorescência
Células Hep G2
Seres Humanos
Intestinos/efeitos dos fármacos
Intestinos/metabolismo
Lipossomos
Fígado/efeitos dos fármacos
Camundongos
Modelos Animais
Perfusão
Ratos Sprague-Dawley
Temperatura Ambiente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Liposomes); 0 (Phosphatidylethanolamines); 0 (polyethylene glycol-distearoylphosphatidylethanolamine); 30IQX730WE (Polyethylene Glycols); 80168379AG (Doxorubicin); G1JO7801AE (Cholic Acid)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170508
[Lr] Data última revisão:
170508
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170311
[St] Status:MEDLINE
[do] DOI:10.2147/IJN.S125047


  5 / 1325 MEDLINE  
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[PMID]:28125709
[Au] Autor:Valanejad L; Nadolny C; Shiffka S; Chen Y; You S; Deng R
[Ad] Endereço:Department of Biomedical and Pharmaceutical Sciences, Center for Pharmacogenomics and Molecular Therapy, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, United States of America.
[Ti] Título:Differential Feedback Regulation of Δ4-3-Oxosteroid 5ß-Reductase Expression by Bile Acids.
[So] Source:PLoS One;12(1):e0170960, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Δ4-3-oxosteroid 5ß-reductase is member D1 of the aldo-keto reductase family 1 (AKR1D1), which catalyzes 5ß-reduction of molecules with a 3-oxo-4-ene structure. Bile acid intermediates and most of the steroid hormones carry the 3-oxo-4-ene structure. Therefore, AKR1D1 plays critical roles in both bile acid synthesis and steroid hormone metabolism. Currently our understanding on transcriptional regulation of AKR1D1 under physiological and pathological conditions is very limited. In this study, we investigated the regulatory effects of primary bile acids, chenodeoxycholic acid (CDCA) and cholic acid (CA), on AKR1D1 expression. The expression levels of AKR1D1 mRNA and protein in vitro and in vivo following bile acid treatments were determined by real-time PCR and Western blotting. We found that CDCA markedly repressed AKR1D1 expression in vitro in human hepatoma HepG2 cells and in vivo in mice. On the contrary, CA significantly upregulated AKR1D1 expression in HepG2 cells and in mice. Further mechanistic investigations revealed that the farnesoid x receptor (FXR) signaling pathway was not involved in regulating AKR1D1 by bile acids. Instead, CDCA and CA regulated AKR1D1 through the mitogen-activated protein kinases/c-Jun N-terminal kinases (MAPK/JNK) signaling pathway. Inhibition of the MAPK/JNK pathway effectively abolished CDCA and CA-mediated regulation of AKR1D1. It was thus determined that AKR1D1 expression was regulated by CDCA and CA through modulating the MAPK/JNK signaling pathway. In conclusion, AKR1D1 expression was differentially regulated by primary bile acids through negative and positive feedback mechanisms. The findings indicated that both bile acid concentrations and compositions play important roles in regulating AKR1D1 expression, and consequently bile acid synthesis and steroid hormone metabolism.
[Mh] Termos MeSH primário: Ácido Quenodesoxicólico/farmacologia
Ácido Cólico/farmacologia
Regulação da Expressão Gênica/efeitos dos fármacos
Oxirredutases/metabolismo
[Mh] Termos MeSH secundário: Animais
Células Hep G2
Seres Humanos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Camundongos
Oxirredutases/genética
Receptores Citoplasmáticos e Nucleares/genética
Receptores Citoplasmáticos e Nucleares/metabolismo
Transdução de Sinais/efeitos dos fármacos
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Cytoplasmic and Nuclear); 0 (farnesoid X-activated receptor); 0GEI24LG0J (Chenodeoxycholic Acid); EC 1.- (Oxidoreductases); EC 1.3.99.6 (3-oxo-5 beta-steroid delta 4-dehydrogenase); G1JO7801AE (Cholic Acid)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170127
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0170960


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[PMID]:28094989
[Au] Autor:Zhang K; Jia YG; Tsai IH; Strandman S; Ren L; Hong L; Zhang G; Guan Y; Zhang Y; Zhu XX
[Ad] Endereço:Département de Chimie, Université de Montréal , C.P. 6128, Succ. Centre-ville, Montreal, QC H3C 3J7, Canada.
[Ti] Título:"Bitter-Sweet" Polymeric Micelles Formed by Block Copolymers from Glucosamine and Cholic Acid.
[So] Source:Biomacromolecules;18(3):778-786, 2017 Mar 13.
[Is] ISSN:1526-4602
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Natural compounds glucosamine and cholic acid have been used to make acrylic monomers which are subsequently used to prepare amphiphilic block copolymers by reversible addition-fragmentation chain transfer (RAFT) polymerization. Despite the striking difference in polarity and solubility, three diblock copolymers consisting of glucosamine and cholic acid pendants with different hydrophilic and hydrophobic chain lengths have been synthesized without the use of protecting groups. They are shown to self-assemble into polymeric micelles with a "bitter" bile acid core and "sweet" sugar shell in aqueous solutions, as evidenced by dynamic light scattering and transmission electron microscopy. The critical micelle concentration varies with the hydrophobic/hydrophilic ratio, ranging from 0.62 to 1.31 mg/L. Longer chains of polymers induced the formation of larger micelles in range of 50-70 nm. These micelles can solubilize hydrophobic compounds such as Nile Red in aqueous solutions. Their loading capacity mainly depends upon the hydrophobic/hydrophilic ratio of the polymers, and may be also related to the length of the hydrophilic block. These polymeric micelles allowed for a 10-fold increase in the aqueous solubility of paclitaxel and showed no cytotoxicity below the concentration of 500 mg/L. Such properties make these polymeric micelles interesting reservoirs for hydrophobic molecules and drugs for biomedical applications.
[Mh] Termos MeSH primário: Ácido Cólico/química
Glucosamina/química
Micelas
Polímeros/química
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Portadores de Fármacos/química
Interações Hidrofóbicas e Hidrofílicas
Espectroscopia de Ressonância Magnética
Camundongos
Oxazinas/química
Paclitaxel/química
Polietilenoglicóis/química
Polimerização
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drug Carriers); 0 (Micelles); 0 (Oxazines); 0 (Polymers); 30IQX730WE (Polyethylene Glycols); G1JO7801AE (Cholic Acid); N08U5BOQ1K (Glucosamine); P476F1L81G (nile red); P88XT4IS4D (Paclitaxel)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170118
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biomac.6b01640


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[PMID]:27871908
[Au] Autor:Carazo A; Hyrsova L; Dusek J; Chodounska H; Horvatova A; Berka K; Bazgier V; Gan-Schreier H; Chamulitrat W; Kudova E; Pavek P
[Ad] Endereço:Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, Hradec Kralove CZ500 05, Czechia.
[Ti] Título:Acetylated deoxycholic (DCA) and cholic (CA) acids are potent ligands of pregnane X (PXR) receptor.
[So] Source:Toxicol Lett;265:86-96, 2017 Jan 04.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The Pregnane X (PXR), Vitamin D (VDR) and Farnesoid X (FXR) nuclear receptors have been shown to be receptors of bile acids controlling their detoxification or synthesis. Chenodeoxycholic (CDCA) and lithocholic (LCA) acids are ligands of FXR and VDR, respectively, whereas 3-keto and acetylated derivates of LCA have been described as ligands for all three receptors. In this study, we hypothesized that oxidation or acetylation at position 3, 7 and 12 of bile acids DCA (deoxycholic acid), LCA, CA (cholic acid), and CDCA by detoxification enzymes or microbiome may have an effect on the interactions with bile acid nuclear receptors. We employed reporter gene assays in HepG2 cells, the TR-FRET assay with recombinant PXR and RT-PCR to study the effects of acetylated and keto bile acids on the nuclear receptors activation and their target gene expression in differentiated hepatic HepaRG cells. We demonstrate that the DCA 3,12-diacetate and CA 3,7,12-triacetate derivatives are ligands of PXR and DCA 3,12-diacetate induces PXR target genes such as CYP3A4, CYP2B6 and ABCB1/MDR1. In conclusion, we found that acetylated DCA and CA are potent ligands of PXR. Whether the acetylated bile acid derivatives are novel endogenous ligands of PXR with detoxification or physiological functions should be further studied in ongoing experiments.
[Mh] Termos MeSH primário: Ácido Cólico/química
Ácido Desoxicólico/química
Receptores de Esteroides/química
[Mh] Termos MeSH secundário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética
Acetilação
Animais
Técnicas de Cultura de Células
Ácido Cólico/metabolismo
Ácido Cólico/farmacologia
Citocromo P-450 CYP2B6/genética
Citocromo P-450 CYP3A/genética
Ácido Desoxicólico/metabolismo
Ácido Desoxicólico/farmacologia
Relação Dose-Resposta a Droga
Genes Reporter
Células Hep G2
Hepatócitos/efeitos dos fármacos
Hepatócitos/enzimologia
Hepatócitos/metabolismo
Seres Humanos
Ligantes
Camundongos
Simulação de Acoplamento Molecular
Oxirredução
Plasmídeos
Ligação Proteica
Receptores de Calcitriol/química
Receptores de Calcitriol/genética
Receptores de Calcitriol/metabolismo
Receptores Citoplasmáticos e Nucleares/química
Receptores Citoplasmáticos e Nucleares/genética
Receptores Citoplasmáticos e Nucleares/metabolismo
Receptores de Esteroides/genética
Receptores de Esteroides/metabolismo
Transfecção
Técnicas do Sistema de Duplo-Híbrido
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Ligands); 0 (Receptors, Calcitriol); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Receptors, Steroid); 0 (farnesoid X-activated receptor); 0 (pregnane X receptor); 005990WHZZ (Deoxycholic Acid); EC 1.14.14.1 (Cytochrome P-450 CYP2B6); EC 1.14.14.1 (Cytochrome P-450 CYP3A); G1JO7801AE (Cholic Acid)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161123
[St] Status:MEDLINE


  8 / 1325 MEDLINE  
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[PMID]:27822917
[Au] Autor:Chen Y; Wu S; Tian Y; Kong J
[Ad] Endereço:Department of General Surgery, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Heping District, Shenyang, Liaoning Province, 110004, China.
[Ti] Título:Phosphorylation and subcellular localization of Na /H exchanger isoform 3 (NHE ) are associated with altered gallbladder absorptive function after formation of cholesterol gallstones.
[So] Source:J Physiol Biochem;73(1):133-139, 2017 Feb.
[Is] ISSN:1877-8755
[Cp] País de publicação:Spain
[La] Idioma:eng
[Ab] Resumo:Na /H exchanger isoform 3 (NHE ) dysfunction is thought to contribute to the altered gallbladder absorption that occurs in cholesterol gallstone disease, but the mechanism is unknown. The current study was undertaken to examine the expression, phosphorylation, and subcellular localization of NHE in gallbladder epithelium cells (GBECs) of male C57BL/6 mice on a control or lithogenic diet. Thirty-six 8-week-old male C57BL/6 mice were randomly assigned to receive a high cholesterol diet or a regular diet for 8 weeks. Gallstone formation was recorded. Gallbladder bile cholesterol, phospholipid, and total bile acids were examined. RT-PCR was used to measure NHE mRNA expression. NHE protein expression and subcellular localization were examined by Western blotting and immunofluorescence microscopy, respectively. Gallstones were formed in all mice fed the lithogenic diet. Despite higher NHE mRNA expression in gallbladders of the mice on the lithogenic diet than in those on the control diet, there was no significant difference in expression of total NHE protein. However, a higher level of NHE phosphorylated at serine-552 (P-NHE ) was seen on the lithogenic diet. In immunofluorescence studies, NHE protein was expressed both on the apical membrane and in the cytoplasm of mouse GBEC. This pattern of subcellular distribution of NHE strongly corroborates an exchanger trafficking mechanism in NHE activity regulation in mouse GBEC. We conclude that increased phosphorylation of NHE following gallstone formation leads to turnover of the exchanger, resulting in decreased gallbladder concentrating function.
[Mh] Termos MeSH primário: Absorção Fisiológica
Epitélio/metabolismo
Vesícula Biliar/metabolismo
Cálculos Biliares/metabolismo
Regulação da Expressão Gênica
Processamento de Proteína Pós-Traducional
Trocadores de Sódio-Hidrogênio/metabolismo
[Mh] Termos MeSH secundário: Animais
Colesterol na Dieta/efeitos adversos
Ácido Cólico/efeitos adversos
Dieta Hiperlipídica/efeitos adversos
Epitélio/patologia
Epitélio/fisiopatologia
Vesícula Biliar/patologia
Vesícula Biliar/fisiopatologia
Cálculos Biliares/etiologia
Cálculos Biliares/patologia
Cálculos Biliares/fisiopatologia
Masculino
Camundongos Endogâmicos C57BL
Fosforilação
Estabilidade Proteica
Transporte Proteico
RNA Mensageiro/metabolismo
Distribuição Aleatória
Serina/metabolismo
Trocador 3 de Sódio-Hidrogênio
Trocadores de Sódio-Hidrogênio/química
Trocadores de Sódio-Hidrogênio/genética
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholesterol, Dietary); 0 (RNA, Messenger); 0 (Slc9a3 protein, mouse); 0 (Sodium-Hydrogen Exchanger 3); 0 (Sodium-Hydrogen Exchangers); 452VLY9402 (Serine); G1JO7801AE (Cholic Acid)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161109
[St] Status:MEDLINE
[do] DOI:10.1007/s13105-016-0533-1


  9 / 1325 MEDLINE  
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[PMID]:27801580
[Au] Autor:Yu Y; Sabulski MJ; Schell WA; Pires MM; Perfect JR; Regen SL
[Ad] Endereço:Department of Chemistry, Lehigh University , Bethlehem, Pennsylvania 18015, United States.
[Ti] Título:Simple Strategy for Taming Membrane-Disrupting Antibiotics.
[So] Source:Bioconjug Chem;27(12):2850-2853, 2016 Dec 21.
[Is] ISSN:1520-4812
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A strategy has been devised for increasing the cellular selectivity of membrane-disrupting antibiotics based on the attachment of a facially amphiphilic sterol. Using Amphotericin B (AmB) as a prototype, covalent attachment of cholic acid bound to a series of α,ω-diamines has led to a dramatic reduction in hemolytic activity, a significant reduction in toxicity toward HEK293T cells, and significant retention of antifungal activity.
[Mh] Termos MeSH primário: Antibacterianos/química
Antibacterianos/farmacologia
Membrana Celular/efeitos dos fármacos
[Mh] Termos MeSH secundário: Anfotericina B/química
Anfotericina B/farmacologia
Antibacterianos/efeitos adversos
Antifúngicos/química
Antifúngicos/farmacologia
Candida/efeitos dos fármacos
Ácido Cólico/química
Células HEK293/efeitos dos fármacos
Seres Humanos
Testes de Sensibilidade Microbiana
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Antifungal Agents); 7XU7A7DROE (Amphotericin B); G1JO7801AE (Cholic Acid)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170605
[Lr] Data última revisão:
170605
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161102
[St] Status:MEDLINE
[do] DOI:10.1021/acs.bioconjchem.6b00629


  10 / 1325 MEDLINE  
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[PMID]:27639250
[Au] Autor:Kulkarni SR; Soroka CJ; Hagey LR; Boyer JL
[Ad] Endereço:Department of Internal Medicine and Yale Liver Center, Yale University School of Medicine, New Haven, CT.
[Ti] Título:Sirtuin 1 activation alleviates cholestatic liver injury in a cholic acid-fed mouse model of cholestasis.
[So] Source:Hepatology;64(6):2151-2164, 2016 Dec.
[Is] ISSN:1527-3350
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sirtuin1 (Sirt1; mammalian homolog of Saccharomyces cerevisiae enzyme Sir2) is a transcriptional and transactivational regulator of murine farnesoid X receptor (Fxr), which is the primary bile acid (BA) sensor, and critical regulator of BA metabolism in physiological and pathophysiological conditions. Previous studies have suggested compromised Sirt1 expression in rodent models of cholestatic liver injury. We hypothesized that Sirt1 could be potentially targeted to alleviate cholestatic liver injury. In cultured primary human hepatocytes, SIRT1 messenger RNA was down-regulated after GCA treatment, potentially through induction of microRNA (miR)-34a, whereas tauroursodeoxycholic acid induced SIRT1 expression without affecting miR-34a expression. Sirt1 expression was also significantly down-regulated in three mouse models of liver injury (bile duct ligation, 1% cholic acid [CA] fed, and the Mdr2 mouse). Mice fed CA diet also demonstrated hepatic FXR hyperacetylation and induction of the Janus kinase/p53 pathway. Mice fed a CA diet and concurrently administered the Sirt1 activator, SRT1720 (50 mg/kg/day, orally), demonstrated 40% and 45% decrease in plasma alanine aminotransferase and BA levels, respectively. SRT1720 increased hepatic BA hydrophilicity by increasing tri- and tetrahydroxylated and decreasing the dihydroxylated BA fraction. SRT1720 administration also inhibited hepatic BA synthesis, potentially through ileal fibroblast growth factor 15- and Fxr-mediated inhibition of cytochrome p450 (Cyp) 7a1 and Cyp27a1, along with increased hepatic BA hydroxylation in association with Cyp2b10 induction. SRT1720 administration significantly induced renal multidrug resistance-associated protein 2 and 4, peroxisome proliferator-activated receptor gamma coactivator 1-α, and constitutive androstance receptor expression along with ∼2-fold increase in urinary BA concentrations. CONCLUSION: SRT1720 administration alleviates cholestatic liver injury in mice by increasing hydrophilicity of hepatic BA composition and decreasing plasma BA concentration through increased BA excretion into urine. Thus, use of small-molecule activators of Sirt1 presents a novel therapeutic target for cholestatic liver injury. (Hepatology 2016;64:2151-2164).
[Mh] Termos MeSH primário: Colestase/tratamento farmacológico
Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico
Hepatopatias/tratamento farmacológico
Sirtuína 1/efeitos dos fármacos
Sirtuína 1/fisiologia
[Mh] Termos MeSH secundário: Animais
Colestase/complicações
Ácido Cólico/administração & dosagem
Modelos Animais de Doenças
Hepatopatias/etiologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heterocyclic Compounds, 4 or More Rings); 0 (SRT1720); EC 3.5.1.- (Sirtuin 1); G1JO7801AE (Cholic Acid)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170731
[Lr] Data última revisão:
170731
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160918
[St] Status:MEDLINE
[do] DOI:10.1002/hep.28826



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