Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.352
Filtrar
1.
Zhongguo Zhong Yao Za Zhi ; 44(12): 2538-2543, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31359721

RESUMO

Bile acids( BAs),the major constituents of bile,are also known to be potential biomarkers of various diseases,especially liver disease. The systematic analysis of BAs is believed to be of great importance towards the clarification of the effective material basis for bile-type medicines,and the diagnosis and therapy of related diseases as well. As a part of systematic study on bile-type medicine ongoing in our group,this study lays emphasis on the isomer discrimination,and the improvement of analytical method of BAs. Further,this method was subsequently applied to elucidate in depth the chemical profile of BAs in yak bile. Regarding isomer discrimination for BAs,we constructed relative response-collision energy curves( RRCECs) by high performance liquid chromatographyion trap-time of flight-mass spectrometry( HPLC-IT-TOF-MS) in combination with high performance liquid chromatography-triple quadrupole-linear ion trap mass spectrometry( HPLC-Qtrap-MS). As a result,both the optimum collision energy( OCE) and CE_(50) exhibited great correlations with structural characteristics,thus enabling the isomer distinguishing,such as unconjugated BAs,glycine-conjugated BAs,and taurine-conjugated BAs. According to information provided by mass spectrometry,the comparison of OCE and CE_(50),retention time matching,combined with reference substances and database retrieval,a total of 30 bile acid derivatives were observed and identified in yak bile. The newly developed method could serve as a feasible tool for the in-depth characterization of BAs in bile and biological samples.


Assuntos
Ácidos e Sais Biliares/química , Bile/química , Animais , Bovinos , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , Taurina
2.
Food Chem ; 293: 127-133, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151592

RESUMO

Dried persimmon is thought to be a rich source of non-extractable polyphenols (NEPPs). Here, we analyzed the NEPP content of dried persimmon and its bile acid-binding activity in vitro. To determine total NEPP content and epicatechin equivalent (ECE) of intact NEPPs, acid hydrolysis and non-destructive methods with 70% (v/v) acetone-insoluble solids (AIS), respectively, were conducted using Folin-Ciocalteu reagent. The ECE of intact NEPPs exceeded 1000 mg/100 g in the non-destructive method, but total NEPP content was approximately 3900 mg/100 g with the acid hydrolysis method. Thiolysis showed that the non-extractable proanthocyanidins in dried persimmon mainly comprised epigallocatechin-gallate, epigallocatechin, epicatechin, and epicatechin-gallate. AIS from dried persimmon showed stronger bile acid-binding activity than AIS from apple, quince, and fresh astringent persimmon. These results suggest that the high content of NEPPs in dried persimmon may contribute to a strong bile acid-binding activity.


Assuntos
Ácidos e Sais Biliares/química , Diospyros/química , Polifenóis/química , Cromatografia Líquida de Alta Pressão , Diospyros/metabolismo , Frutas/química , Frutas/metabolismo , Hidrólise , Espectrometria de Massas , Molibdênio/química , Polifenóis/análise , Proantocianidinas/análise , Proantocianidinas/química , Compostos de Tungstênio/química
3.
Int J Nanomedicine ; 14: 3943-3953, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239664

RESUMO

Background: SKLB023, a novel 5-benzylidenethiazolidine-2,4-dione based-derivative, specifically inhibits inducible nitric oxide synthase and shows promise for treating non-alcoholic steatohepatitis (NASH). However, its poor water solubility and low bioavailability limits its clinical use. Here the drug was loaded into phosphatidylcholine-bile salt-mixed micelles (PBMM/SKLB023) to overcome these limitations. Methods: PBMM/SKLB023 was developed using a simple co-precipitation method, and formulation parameters were optimized. The pharmacokinetics of PBMM/SKLB023 were investigated in Wistar rats, and therapeutic efficacy was assessed in a mouse model of NASH induced by a diet deficient in methionine- and choline. Results: PBMM/SKLB023 particles were 11.36±2.08 nm based on dynamic light scattering, and loading the drug into micelles improved its water solubility 300-fold. PBMM/SKLB023 inhibited proliferation and activation of HSC-T6 cells more strongly than free SKLB023. PBMM/SKLB023 showed longer mean retention time and higher bioavailability than the free drug after intravenous injection in Wistar rats. In the mouse model of NASH, PBMM/SKLB023 alleviated hepatic lipid accumulation, inflammation, and fibrosis to a significantly greater extent than free SKLB023. Conclusion: PBMM/SKLB023 shows therapeutic potential for treating NASH and liver fibrosis.


Assuntos
Acetanilidas/uso terapêutico , Micelas , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Tiazolidinedionas/uso terapêutico , Acetanilidas/sangue , Acetanilidas/química , Acetanilidas/farmacocinética , Animais , Ácidos e Sais Biliares/química , Modelos Animais de Doenças , Inflamação/patologia , Injeções Intravenosas , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , Fosfatidilcolinas/química , Ratos Wistar , Solubilidade , Tiazolidinedionas/sangue , Tiazolidinedionas/química , Tiazolidinedionas/farmacocinética
4.
Handb Exp Pharmacol ; 256: 137-165, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31201554

RESUMO

In the recent years, bile acid receptors FXR and GPBAR1 have attracted the interest of scientific community and companies, as they proved promising targets for the treatment of several diseases, ranging from liver cholestatic disorders to metabolic syndrome, inflammatory states, nonalcoholic steatohepatitis (NASH), and diabetes.Consequently, the development of dual FXR/GPBAR1 agonists, as well as selective targeting of one of these receptors, is considered a hopeful possibility in the treatment of these disorders. Because endogenous bile acids and steroidal ligands, which cover the same chemical space of bile acids, often target both receptor families, speculation on nonsteroidal ligands represents a promising and innovative strategy to selectively target GPBAR1 or FXR.In this review, we summarize the most recent acquisition on natural, semisynthetic, and synthetic steroidal and nonsteroidal ligands, able to interact with FXR and GPBAR1.


Assuntos
Ácidos e Sais Biliares/química , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Ácidos e Sais Biliares/farmacologia , Humanos , Ligantes
5.
J Dairy Sci ; 102(7): 5957-5961, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31128873

RESUMO

Some Lactobacillus strains may contribute to the health of the host when administered in adequate concentrations, demonstrating their probiotic potential. In contrast, Listeria monocytogenes is a foodborne pathogen that can cause enteropathy, meningoencephalitis, abortion, and septicemia. The aim of this survey was to evaluate the in vitro and in vivo probiotic potential of Lactobacillus plantarum B7 and Lactobacillus rhamnosus D1, isolated from Minas artisanal cheese of the Serra da Canastra (Minas Gerais, Brazil), against Lis. monocytogenes. We submitted B7 and D1 to in vitro testing (antibiogram, tolerance to bile salts and artificial gastric fluid, and spot-on-lawn) and in vivo testing (relative weight gain in mice). Both Lactobacillus strains demonstrated in vitro inhibitory activity against Lis. monocytogenes, as well as sensitivity to antimicrobials and resistance to gastric acids and bile salts. In the in vivo assays, mice treated with D1 gained more weight than mice in the other groups. These results indicate that D1 could have higher probiotic potential than B7 because improvements in feed conversion may help animals fight infection.


Assuntos
Queijo/microbiologia , Lactobacillus plantarum/química , Lactobacillus rhamnosus/química , Listeria monocytogenes/efeitos dos fármacos , Probióticos/farmacologia , Animais , Ácidos e Sais Biliares/química , Brasil , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana
6.
Anal Bioanal Chem ; 411(19): 4673-4682, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31098744

RESUMO

Bile acids (BAs) play an integral role in digestion through the absorption of nutrients, emulsification of fats and fat-soluble vitamins, and maintenance of cholesterol levels. Metabolic disruption, diabetes, colorectal cancer, and numerous other diseases have been linked with BA disruption, making improved BA analyses essential. To date, most BA measurements are performed using liquid chromatography separations in conjunction with mass spectrometry measurements (LC-MS). However, 10-40 min LC gradients are often used for BA analyses and these may not even be sufficient for distinguishing all the important isomers present in the human body. Ion mobility spectrometry (IMS) is a promising tool for BA evaluations due to its ability to quickly separate isomeric molecules with subtle structural differences. In this study, we utilized drift tube IMS (DTIMS) coupled with MS to characterize 56 different unlabeled BA standards and 16 deuterated versions. In the DTIMS-MS analyses of 12 isomer groups, BAs with smaller m/z values were easily separated in either their deprotonated or sodiated forms (or both). However, as the BAs grew in m/z value, they became more difficult to separate with two isomer groups being inseparable. Metal ions such as copper and zinc were then added to the overlapping BAs, and due to different binding sites, the resulting complexes were separable. Thus, the rapid structural measurements possible with DTIMS-MS show great potential for BAs measurements with and without prior LC separations.


Assuntos
Ácidos e Sais Biliares/química , Espectrometria de Mobilidade Iônica/métodos , Ácidos e Sais Biliares/normas , Cobre/química , Humanos , Isomerismo , Estrutura Molecular , Padrões de Referência , Zinco/química
7.
Methods Mol Biol ; 1981: 133-147, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31016652

RESUMO

Cholestasis can be induced by obstruction of bile ducts or intrahepatic toxicity of drugs and chemicals. However, the mode of cell death during cholestasis, i.e., apoptosis or necrosis, has been controversial. There are fundamental reasons for the controversies, both of which are discussed here, namely the design of experiments and the use of parameters with limited specificity for a certain mode of cell death. Based on the assumption that cholestatic liver injury is caused by accumulation of bile acids, rodent (mainly rat) hepatocytes have been exposed to hydrophobic, glycine-conjugated bile acids, which resulted in apoptotic cell death. The problems with this experimental design are that in rodents bile acids are predominantly taurine conjugated and rodent hepatocytes are never exposed to these levels of glycine-conjugated bile acids. In contrast, taurine-conjugated bile acids trigger inflammatory gene activation in rodent hepatocytes and a necro-inflammatory injury in vivo. On the other hand, human hepatocytes are more resistant to glycine-conjugated bile acids and die by necrosis when exposed to high biliary levels of these bile acids. In this chapter, we describe multiple assays including the caspase activity assay, which is specific for apoptosis, and the general cell death assays alanine aminotransferase or lactate dehydrogenase activities in cell culture medium or plasma. An increase in these enzyme activities without caspase activity indicates necrotic cell death. Thus, both the experimental design and the selection of cell death parameters are critical for the relevance of the experiments for the human pathophysiology.


Assuntos
Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Alanina Transaminase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Ácidos e Sais Biliares/química , Ácidos e Sais Biliares/farmacologia , Caspases/metabolismo , Glicina/química , Humanos , L-Lactato Desidrogenase/metabolismo , Camundongos , Ratos , Taurina/química
8.
J Agric Food Chem ; 67(33): 9124-9138, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30969768

RESUMO

Bile acids are cholesterol-derived steroid molecules that serve various metabolic functions, particularly in the digestion of lipids. Gut microbes produce unconjugated and secondary bile acids through deconjugation and dehydroxylation reactions, respectively. Alterations in the gut microbiota have profound effects on bile acid metabolism, which can result in the development of gastrointestinal and metabolic diseases. Emerging research shows that diets rich in dietary fiber have substantial effects on the microbiota and human health. Plant-based foods are primary sources of bioactive compounds and dietary fiber, which are metabolized by microbes to produce different metabolites. However, the bioaccessibility of these compounds are not well-defined. In this review, we discuss the interaction of bile acids with dietary fiber, the gut microbiota, and their role in the bioaccessibility of bioactive compounds. To understand the possible mechanism by which bile acids bind fiber, molecular docking was performed between different dietary fiber and bile salts.


Assuntos
Bactérias/metabolismo , Ácidos e Sais Biliares/metabolismo , Fibras na Dieta/metabolismo , Microbioma Gastrointestinal , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Ácidos e Sais Biliares/química , Fibras na Dieta/análise , Trato Gastrointestinal/microbiologia , Humanos
9.
Chem Pharm Bull (Tokyo) ; 67(4): 333-340, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930437

RESUMO

Biliary lipids consist mainly of bile salts, phospholipids and cholesterol, which form mixed micelles and vesicles. Bile salts play various physiological roles but have damaging effects on cell membranes due to their detergent properties. The cytotoxicity of bile salts on hepatocytes leads to liver injuries and is largely determined by the bile salt species, the concentrations of bile salts, phospholipids and cholesterol, and the lipid composition of cell membranes. In bile, monomers and simple micelles of bile salts coexist with mixed micelles and vesicles in dynamic equilibrium, and contribute to the cytotoxicity on hepatocytes. The ATP-binding cassette (ABC) transporter family members, ABCB11, ABCB4 and ABCG5/ABCG8, mediate the biliary secretion of bile salts, phospholipids and cholesterol, respectively. Mutations in ABCB4 result in severe cholestatic diseases, and the biliary phospholipids are necessary for the attenuation of bile salt cytotoxicity. On the other hand, cholesterol reverses the cytoprotective effects of phospholipids against bile salts. In addition, phosphatidylethanolamine N-methyltransferase increases the cell resistance to bile salts by changing the phospholipid composition and structures of the apical membranes. In this review, we focus on the molecular mechanisms for the protection of hepatocytes against bile salt cytotoxicity. Further understanding of these mechanisms will help to develop new therapeutic strategies for cholestatic liver diseases.


Assuntos
Ácidos e Sais Biliares/toxicidade , Hepatócitos/efeitos dos fármacos , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Ácidos e Sais Biliares/química , Colesterol/química , Hepatócitos/citologia , Hepatócitos/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Micelas , Fosfolipídeos/química
10.
Int J Nanomedicine ; 14: 2267-2280, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31015758

RESUMO

Background: Gypenosides (GPS) have been used as traditional medicine for centuries with various pharmacological effects. However, its therapeutic effects were restricted owing to the poor lipid and water solubility and low absorption. This study aimed to develop nanostructured lipid carriers (NLCs) containing a bile salt formulation (sodium glycocholate, SGC) for GPS, and to evaluate the potential of the GPS-SGC-NLCs as an oral delivery system. Methods: The preparation of GPS-SGC-NLCs was investigated using a single-factor test and a central composite design of response surface methodology. In vitro release and pharmacokinetics studies were used to evaluate the dissolution and bioavailability of GPS. Furthermore, In vivo imaging and in situ intestinal perfusion studies were performed to investigate the absorption of the preparations in the gastrointestinal tract. Results: The optimised formulation yielded nanoparticles with an approximate diameter of 146.7 nm, polydispersity of 0.137, zeta potential of -56.0 mV, entrapment efficiency of 74.22% and drug loading of 4.89%. An in vitro dissolution analysis revealed the sustained release of contents from GPS-SGC-NLCs over 48 h with 56.4% of the drug released. A pharmacokinetic analysis revealed an 8.5-fold increase of bioavailability of the GPS-SGC-NLCs compared with GPS powder. In vivo imaging and in situ intestinal perfusion studies showed that SGC-NLCs could significantly increase the absorption of GPS in intestinal tract. In vitro cytotoxicity evaluated using Caco-2 cells demonstrated that GPS-SGC-NLCs decrease the cytotoxicity of the drug. Conclusion: The SGC-NLC formulation can significantly improve the absorption of GPS, which provides an effective approach for enhancing the oral absorption of drugs.


Assuntos
Ácidos e Sais Biliares/química , Portadores de Fármacos/química , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/métodos , Lipídeos/química , Nanoestruturas/química , Administração Oral , Animais , Células CACO-2 , Varredura Diferencial de Calorimetria , Morte Celular/efeitos dos fármacos , Gynostemma , Humanos , Intestinos/diagnóstico por imagem , Lipídeos/administração & dosagem , Masculino , Nanoestruturas/administração & dosagem , Nanoestruturas/ultraestrutura , Imagem Óptica , Tamanho da Partícula , Perfusão , Extratos Vegetais/administração & dosagem , Extratos Vegetais/sangue , Extratos Vegetais/farmacocinética , Ratos Sprague-Dawley , Ratos Wistar , Eletricidade Estática , Fatores de Tempo , Difração de Raios X
11.
Pak J Pharm Sci ; 32(1(Special)): 445-452, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30852483

RESUMO

Five Lactobacillus strains isolated from vegetable and dairy products showed 99% similarity with Lactobacillus plantarum 1(Lp-1) using API -CHL 50 kit. Most of them proved to be sensitive to bacterial cell-wall inhibitors i.e. penicillin, ampicillin, amoxicillin and methicillin as studied by disc-diffusion method. These strains manifested profound tolerance to acidic-stress where Lp86 and Lp36 exhibited a good survival pattern at pH-2 for 4 hr retaining a survival count of 85% and 50%, respectively. A high survival of 85.7% was witnessed in Lp86 in presence of protease while Lp36 maintained 94.55% and 92.65% of population under the influence of enzyme pancreatin and pepsin. All the strains displayed marked tolerance against trypsin as the count did not drop below 77%. Absorbance and growth in terms of cfu/ml for bile-tolerance was examined for concentrations reflecting those in the GIT of humans, all the Lp-1 strains when grown with 1% bile showed a drop in the viable count by 1 log cycle i.e. from 1010 to 109cfu/ml. Fulfilling the above mentioned criteria these probiotic candidates displayed their capacity to reach the colon as viable metabolically active cells after successfully surviving under conditions similar to the gastrointestinal tract of humans. Upon examining the viability and stability of these probiotic candidates in most common foods serving as vehicle for probiotic delivery to the intestine, it was noticed that all the isolates tested sustained a probiotic approved number of 107 cfu/ml for effective function as recommended by WHO, after a maximum storage for one month. Hence, it could be justified that the selected probiotic candidates possess prominent probiotic potential. Therefore, L. plantarum 1 strains could prove to be an efficient probiotic after further in vivo studies to explore its safety in human subjects.


Assuntos
Aderência Bacteriana , Lactobacillus plantarum/crescimento & desenvolvimento , Viabilidade Microbiana , Probióticos , Ácidos e Sais Biliares/química , Microbiologia de Alimentos , Suco Gástrico/química , Trato Gastrointestinal/microbiologia , Humanos , Técnicas In Vitro
12.
J Pharm Biomed Anal ; 170: 22-29, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30903926

RESUMO

We investigated the ultrastructural pattern of colloidal phases in human duodenal fluids. Aspirates were collected from three volunteers in both fasted and fed nutritional states. Analysis methods comprised the combination of asymmetric flow field-flow fractionation (AF4) and multi-angle laser light scattering (MALLS). Furthermore, dynamic light scattering (DLS) and diffusion-ordered NMR spectroscopy (DOSY-NMR) were employed as alternative analytical approaches for comparison. By AF4/MALLS, up to four, and in some cases up to five distinct co-existing fractions could be differentiated in the sub-micron size-range, which, in accordance with a previous study (Elvang et al., 2018), may be assigned to three main types, namely small bile salt micelles, intermediate size mixed bile salt/phospholipid micelles and large phospholipid aggregates / vesicles. Although more or less the same colloidal phases were found to co-exist in all aspirates, their prevalence was found to vary, both over time and between the three individual human volunteers. Any uniform changes of patterns of colloidal phases over time, however, could not be identified. On the other hand, prevalence of specific colloidal phases was identified for aspirates of individual volunteers, which correlated reasonably well with the prevalence of certain lipid species in their molecular composition. It remains to be investigated whether such prevalence of specific colloidal phases influences drug solubilizing capacity as well as drug absorption. If so, this may help to better understand the substantial inter-individual variability seen in many drug absorption profiles.


Assuntos
Líquidos Corporais/química , Coloides/química , Ácidos e Sais Biliares/química , Difusão , Difusão Dinâmica da Luz/métodos , Jejum , Fracionamento por Campo e Fluxo/métodos , Humanos , Micelas , Tamanho da Partícula , Fosfolipídeos/química , Solubilidade
13.
Curr Microbiol ; 76(5): 583-589, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30826907

RESUMO

Vibrio cholerae, the causative agent of severe watery diarrheal disease cholera, requires production of a number of virulence factors during infection which results from the activity of a cascading system of regulatory factors by sensing to different environmental signals. TcpP, a membrane-localized transcription activator in V. cholerae, activates virulence factors production by responding to human host signals. To better characterize the transmembrane helix in regard to its roles on TcpP positive effectors sensitivity, site-directed mutagenesis was performed to identify specific mutations in this region which could enhance TcpP transcription activity in the absence of stimuli, like bile salts. We found that TcpP L152A constitutively forms homodimer and activates toxT expression in the absence of bile salts. However, being active, TcpP L152A needs to form disulfide bonds between the cysteine residues in the periplasmic domain of TcpP. We also found that TcpP L152A showed a competitive advantage in the infant mouse colonization model by coadministrating the bile salt-sequestering resin cholestyramine. All these results demonstrate that the transmembrane helix of TcpP plays an important role in regulating TcpP transcription activity in response to its positive effectors.


Assuntos
Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica , Vibrio cholerae/genética , Fatores de Virulência/genética , Animais , Ácidos e Sais Biliares/química , Resina de Colestiramina/química , Escherichia coli/genética , Expressão Gênica , Camundongos , Camundongos Endogâmicos ICR , Mutagênese Sítio-Dirigida , Fatores de Transcrição/genética , Ativação Transcricional , Vibrio cholerae/metabolismo , Virulência/genética , Fatores de Virulência/metabolismo
14.
Drug Dev Ind Pharm ; 45(6): 995-998, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30892088

RESUMO

Novel fatty acid-bile acid conjugates (1a-1k) were designed and synthesized by coupling of the fatty acids to the 3-OH of bile acids using lysine for linkage. In the conjugates, the 24-COOH of the bile acids was kept intact to preserve liver-specific recognition. The ability of the newly synthesized conjugates (at 100 mg/kg dosage) to reduce total cholesterol (TC) and triglyceride (TG) levels in mice fed with high-fat diet (HFD) was evaluated. Conjugates of stearic acid with cholic acid and palmitic acid with ursodeoxycholic acid (at dosages of 50, 100, and 200 mg/kg) were further evaluated to determine their ability to reduce aspartate aminotransferase (AST), alanine aminotransferase (ALT), TC, and TG levels in mice fed with HFD. All conjugates showed potent hypolipidemic activity. Further investigation revealed that compounds 1c and 1 g not only dose-dependently reduced serum levels of TC and TG, but also inhibited the elevation of serum AST and ALT levels in mice fed with HFD. Thus, compounds 1c and 1 g are promising hypolipidemic agents with hepatocyte protective effects against HFD-induced liver damage.


Assuntos
Ácidos e Sais Biliares/administração & dosagem , Ácidos Graxos/administração & dosagem , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Fígado/efeitos dos fármacos , Animais , Ácidos e Sais Biliares/química , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ácidos Graxos/química , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/etiologia , Hiperlipidemias/patologia , Hipolipemiantes/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Lisina/química , Camundongos , Triglicerídeos/sangue
15.
Biophys Chem ; 248: 16-27, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30850307

RESUMO

The bile salts and phospholipids are secreted by the gallbladder to form dietary mixed micelles in which the solvation of poorly absorbed lipophilic drugs and nutraceuticals take place. A comprehensive understanding of the micellization and structure of the mixed micelles are crucial to design effective delivery systems for such substances. In this study, the evolution of the dietary mixed micelle formation under physiologically relevant concentrations and the dependence of structural properties on micelle size were investigated through coarse-grained molecular dynamics simulations. The MARTINI force field was used to model cholate and POPC as the representative bile salt and phospholipid, respectively. The micellization behavior was similar under both fasted and fed state concentrations. Total lipids concentration and the micelle size did not affect the internal structure of the micelles. All the micelles were slightly ellipsoidal in shape independent of their size. The extent of deviation from spherical geometry was found to depend on the micellar POPC/cholate ratio. We also found that the surface and core packing density of the micelles increased with micelle size. The former resulted in more perpendicular alignments of cholates with respect to the surface, while the latter resulted in an improved alignment of POPC tails with the radial direction and more uniform core density.


Assuntos
Dieta , Micelas , Simulação de Dinâmica Molecular , Ácidos e Sais Biliares/química , Fosfatidilcolinas/química
16.
Dig Liver Dis ; 51(4): 570-576, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30803859

RESUMO

Recent studies have investigated the roles of FXR deficiency in the pathogenesis of alcoholic liver disease (ALD). However, the underlying molecular mechanisms remain unclear. In this study, FXR knockout (FXR-/-) and wild-type (WT) mice were subjected to chronic-plus-binge alcohol feeding to study the effect of FXR deficiency on ALD development. The degree of liver injury was greater in FXR-/- mice compared to WT mice. Ethanol feeding enhanced hepatic steatosis in FXR-/- mice, accompanied by decreased mRNA levels of Pparα and Srebp-1c. The expression of Lcn2 was increased by ethanol treatment, despite unchanged expression of pro-inflammatory cytokines Tnfα, Il6 and Il-1ß. Furthermore, ethanol treatment altered bile acid (BA) homeostasis to a greater extent in FXR-/- mice, as well as serum and hepatic BA pool composition. The mRNA levels of hepatic Cyp7a1 and Shp, as well as intestinal Fgf15, were decreased in WT mice with ethanol feeding, which were further reduced in FXR-/- mice. Levels of both primary and secondary BAs were markedly elevated in FXR-/- mice, which were further increased after ethanol treatment. Moreover, hepatic MAPK signaling pathways were disturbed presumably by increased hepatic BA levels. In summary, FXR deficiency increased hepatic steatosis and altered BA pool composition, contributing to worsened liver toxicity.


Assuntos
Ácidos e Sais Biliares/química , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/fisiopatologia , Fígado/patologia , Proteínas de Ligação a RNA/genética , Animais , Etanol/toxicidade , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout
17.
Thromb Haemost ; 119(4): 567-575, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30769363

RESUMO

Endocannabinoids are a group of arachidonic acid-derived lipid mediators binding to cannabinoid receptors CB1 and CB2. An overactivity of the endocannabinoid system plays a pathophysiological role in the development of visceral obesity and insulin resistance. Moreover, elevated circulating endocannabinoid levels are also prevalent in atherosclerosis. The pathophysiological increase of endocannabinoid levels is due to an altered expression of endocannabinoid synthesizing and degrading enzymes induced by inflammatory mediators such as cytokines or lipids. Emerging experimental evidence suggests that enhanced endocannabinoid signalling affects atherosclerosis via multiple effects, including a modulation of vascular inflammation, leukocyte recruitment, macrophage cholesterol metabolism and consequently atherosclerotic plaque stability. In addition, recent findings in various metabolic disease models highlight the relevance of peripheral CB1 cannabinoid receptors in adipose tissue, liver and pancreas, which crucially regulate lipid and glucose metabolism as well as macrophage properties in these organs. This suggests that targeting the endocannabinoid system in the vasculature and peripheral organs might have a therapeutic potential for atherosclerosis by inhibiting vascular inflammation and improving metabolic risk factors. This review will provide a brief update on the effects of endocannabinoid signalling in atherosclerosis and related metabolic complications.


Assuntos
Aterosclerose/metabolismo , Endocanabinoides/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais , Tecido Adiposo/metabolismo , Animais , Ácido Araquidônico/química , Ácidos e Sais Biliares/química , Glicemia/metabolismo , Sistema Cardiovascular/metabolismo , Citocinas/metabolismo , Humanos , Inflamação , Resistência à Insulina , Ligantes , Metabolismo dos Lipídeos , Lipídeos/química , Fígado/metabolismo , Camundongos , Camundongos Knockout , Obesidade Abdominal/metabolismo , Pâncreas/metabolismo , Receptores de Canabinoides/metabolismo , Fatores de Risco
18.
Food Funct ; 10(3): 1455-1464, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30768114

RESUMO

The management of lead (Pb) exposure and toxicity remains a major public health priority worldwide. In our previous study, the probiotic strain Lactobacillus plantarum CCFM8661 prevented Pb absorption in mice via intestinal sequestration. This follow-up study aimed to evaluate the additional protective mechanism of L. plantarum CCFM8661 with a focus on its regulation of enterohepatic circulation. We first confirmed the relationship between the enterohepatic circulations of Pb and bile acid (BA) by administering a BA sequestrant, cholestyramine, to mice with a high Pb burden. Our data further showed that L. plantarum CCFM8661 significantly induced hepatic BA synthesis, enhanced bile flow and biliary glutathione output, and increased fecal BA excretion in the mice, which in turn increased biliary Pb output and enhanced fecal Pb excretion. This regulation was associated with the alterations in the expression of target genes in the enterohepatic farnesoid X receptor-fibroblast growth factor (FXR-FGF15) axis and could be reversed using an FXR agonist, GW4064. Pre-treatment with antibiotics also abolished the L. plantarum CCFM8661-induced effects on BA and Pb enterohepatic circulation. These results suggest that L. plantarum CCFM8661 induces fecal Pb excretion by regulating BA enterohepatic circulation. This regulation is associated with the down-regulation of the FXR-FGF15 axis and is partly dependent on the gut microbiota of mice.


Assuntos
Ácidos e Sais Biliares/fisiologia , Lactobacillus plantarum/classificação , Chumbo/farmacocinética , Fígado/efeitos dos fármacos , Fígado/fisiologia , Animais , Ácidos e Sais Biliares/química , Fezes/química , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/química , Chumbo/sangue , Chumbo/química , Chumbo/metabolismo , Fígado/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Probióticos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Distribuição Aleatória
19.
Molecules ; 24(3)2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30736477

RESUMO

Enzyme-assisted derivatization for sterol analysis (EADSA) is a technology designed to enhance sensitivity and specificity for sterol analysis using electrospray ionization⁻mass spectrometry. To date it has only been exploited on sterols with a 3ß-hydroxy-5-ene or 3ß-hydroxy-5α-hydrogen structure, using bacterial cholesterol oxidase enzyme to convert the 3ß-hydroxy group to a 3-oxo group for subsequent derivatization with the positively charged Girard hydrazine reagents, or on substrates with a native oxo group. Here we describe an extension of the technology by substituting 3α-hydroxysteroid dehydrogenase (3α-HSD) for cholesterol oxidase, making the method applicable to sterols with a 3α-hydroxy-5ß-hydrogen structure. The 3α-HSD enzyme works efficiently on bile alcohols and bile acids with this stereochemistry. However, as found by others, derivatization of the resultant 3-oxo group with a hydrazine reagent does not go to completion in the absence of a conjugating double bond in the sterol structure. Nevertheless, Girard P derivatives of bile alcohols and C27 acids give an intense molecular ion ([M]⁺) upon electrospray ionization and informative fragmentation spectra. The method shows promise for analysis of bile alcohols and 3α-hydroxy-5ß-C27-acids, enhancing the range of sterols that can be analyzed at high sensitivity in sterolomic studies.


Assuntos
Ácidos e Sais Biliares/análise , Colestanóis/análise , Espectrometria de Massas por Ionização por Electrospray/métodos , Betaína/análogos & derivados , Ácidos e Sais Biliares/química , Colestanóis/química , Cromatografia Líquida , Hidroxiesteroide Desidrogenases/química , Espectrometria de Massas , Oxirredução , Esteróis/análise , Esteróis/química , Especificidade por Substrato
20.
J Biol Chem ; 294(10): 3359-3366, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30647128

RESUMO

Bile acids are critical metabolites in the gastrointestinal tract and contribute to maintaining intestinal immune homeostasis through cross-talk with the gut microbiota. The conversion of bile acids by the gut microbiome is now recognized as a factor affecting both host metabolism and immune responses, but its physiological roles remain unclear. We conducted a screen for microbiome metabolites that would function as inflammasome activators and herein report the identification of 12-oxo-lithocholic acid (BAA485), a potential microbiome-derived bile acid metabolite. We demonstrate that the more potent analogue 11-oxo-12S-hydroxylithocholic acid methyl ester (BAA473) can induce secretion of interleukin-18 (IL-18) through activation of the inflammasome in both myeloid and intestinal epithelial cells. Using a genome-wide CRISPR screen with compound induced pyroptosis in THP-1 cells, we identified that inflammasome activation by BAA473 is pyrin-dependent (MEFV). To our knowledge, the bile acid analogues BAA485 and BAA473 are the first small molecule activators of the pyrin inflammasome. We surmise that pyrin inflammasome activation through microbiota-modified bile acid metabolites such as BAA473 and BAA485 plays a role in gut microbiota regulated intestinal immune response. The discovery of these two bioactive compounds may help to further unveil the importance of pyrin in gut homeostasis and autoimmune diseases.


Assuntos
Ácidos e Sais Biliares/imunologia , Células Epiteliais/imunologia , Microbioma Gastrointestinal/imunologia , Imunidade nas Mucosas , Inflamassomos/imunologia , Mucosa Intestinal/imunologia , Pirina/imunologia , Ácidos e Sais Biliares/química , Humanos , Células Mieloides/imunologia , Células THP-1
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA