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1.
Anticancer Res ; 40(1): 401-404, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892593

RESUMO

BACKGROUND/AIM: Bile leakage after liver surgery is still a problem to be solved. Here, we introduce a simple new technique, the Clip on Staple method, a preventive measure for bile leakage after anatomical liver resection using a stapling device. PATIENTS AND METHODS: Before liver parenchymal transection, the roots of Glissonean pedicles for target segments were dissected and divided using the Endo-GIA™ Tri-Staple™ Curved Tip. After the parenchymal transection was completed, the full length of the stapled stump was reinforced by multiple clips. The DS Titanium Ligation Clip was used as the clipping device. RESULTS: Twenty patients underwent this technique during anatomical liver resections with stapling devices. No patient developed postoperative bile leakage of any grade. There was no reoperation or readmission within 90 days. CONCLUSION: The Clip on Staple method is simple and offers a preventive effect for postoperative bile leakage after anatomical liver resection using stapling devices.


Assuntos
Bile/metabolismo , Fígado/cirurgia , Instrumentos Cirúrgicos , Grampeamento Cirúrgico , Idoso , Idoso de 80 Anos ou mais , Hepatectomia , Humanos , Processamento de Imagem Assistida por Computador , Pessoa de Meia-Idade , Resultado do Tratamento
2.
Toxicol Lett ; 319: 225-236, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760063

RESUMO

N-Butylbenzenesulfonamide (NBBS) is a plasticizer detected in the environment suggesting potential human exposure. These studies investigated the in vitro hepatic clearance and disposition of [14C]NBBS in rodents following a single gavage (2, 20 or 200 mg/kg) or intravenous (IV) administration (20 mg/kg). NBBS was cleared slower in hepatocytes from humans compared to rodents. [14C]NBBS was well-absorbed in male rats following gavage administration and excreted extensively in urine (70-76 %) and feces (11-15 %) 72 h following administration. Following a 20 mg/kg gavage dose in male rats, 25 % of the dose was excreted in bile by 24 h suggesting that observed fecal excretion was due to biliary excretion. The radioactivity was distributed to tissues with 14 % and 8 % of the administered dose remaining in tissues at 24 and 72 h, respectively. There was no apparent dose-dependent effect in disposition in male rats. Disposition patterns were similar in female rats (urine, 83 %; feces, 14 %) and male (urine, 69 %; feces, 11 %) and female (urine, 72 %; feces, 9 %) mice following gavage administration of 20 mg/kg. The disposition following IV administration was similar to that of gavage. Urinary radiochemical profiles were similar between doses, routes, species, and sexes. Among numerous metabolites identified, oxidative metabolites of NBBS predominated.


Assuntos
Hepatócitos/metabolismo , Plastificantes/farmacocinética , Sulfonamidas/farmacocinética , Administração Intravenosa , Animais , Bile/metabolismo , Células Cultivadas , Fezes/química , Feminino , Humanos , Intubação Gastrointestinal , Masculino , Camundongos , Camundongos Endogâmicos , Plastificantes/metabolismo , Plastificantes/toxicidade , Ratos , Ratos Sprague-Dawley , Sulfonamidas/administração & dosagem , Sulfonamidas/metabolismo , Distribuição Tecidual
3.
Gut ; 69(1): 146-157, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30723104

RESUMO

OBJECTIVE: We explored the hypothesis that TGR5, the bile acid (BA) G-protein-coupled receptor highly expressed in biliary epithelial cells, protects the liver against BA overload through the regulation of biliary epithelium permeability. DESIGN: Experiments were performed under basal and TGR5 agonist treatment. In vitro transepithelial electric resistance (TER) and FITC-dextran diffusion were measured in different cell lines. In vivo FITC-dextran was injected in the gallbladder (GB) lumen and traced in plasma. Tight junction proteins and TGR5-induced signalling were investigated in vitro and in vivo (wild-type [WT] and TGR5-KO livers and GB). WT and TGR5-KO mice were submitted to bile duct ligation or alpha-naphtylisothiocyanate intoxication under vehicle or TGR5 agonist treatment, and liver injury was studied. RESULTS: In vitro TGR5 stimulation increased TER and reduced paracellular permeability for dextran. In vivo dextran diffusion after GB injection was increased in TGR5-knock-out (KO) as compared with WT mice and decreased on TGR5 stimulation. In TGR5-KO bile ducts and GB, junctional adhesion molecule A (JAM-A) was hypophosphorylated and selectively downregulated among TJP analysed. TGR5 stimulation induced JAM-A phosphorylation and stabilisation both in vitro and in vivo, associated with protein kinase C-ζ activation. TGR5 agonist-induced TER increase as well as JAM-A protein stabilisation was dependent on JAM-A Ser285 phosphorylation. TGR5 agonist-treated mice were protected from cholestasis-induced liver injury, and this protection was significantly impaired in JAM-A-KO mice. CONCLUSION: The BA receptor TGR5 regulates biliary epithelial barrier function in vitro and in vivo through an impact on JAM-A expression and phosphorylation, thereby protecting liver parenchyma against bile leakage.


Assuntos
Sistema Biliar/fisiopatologia , Colestase Intra-Hepática/prevenção & controle , Receptores Acoplados a Proteínas-G/fisiologia , Animais , Bile/metabolismo , Ácidos e Sais Biliares/metabolismo , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Colestase Intra-Hepática/metabolismo , Impedância Elétrica , Epitélio/fisiopatologia , Ácidos Isonipecóticos/farmacologia , Ácidos Isonipecóticos/uso terapêutico , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oximas/farmacologia , Oximas/uso terapêutico , Permeabilidade , Fosforilação/fisiologia , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas-G/agonistas , Transdução de Sinais/fisiologia , Proteínas de Junções Íntimas/metabolismo
4.
Anticancer Res ; 39(10): 5449-5459, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570439

RESUMO

BACKGROUND/AIM: Epigenetic abnormalities in microRNAs (miRNAs) have not been analyzed in samples other than pancreaticobiliary tissues in patients with pancreaticobiliary cancer (PBC). To identify miRNAs specific for PBC, the present study analyzed the methylation of tumor-suppressive miRNAs in bile from patients with pancreaticobiliary diseases. MATERIALS AND METHODS: Bile was collected endoscopically or percutaneously from 52 patients with pancreatic cancer, 26 with biliary tract cancer, and 20 with benign pancreaticobiliary diseases. Sequences encoding 16 tumor-suppressive miRNAs were amplified by polymerase chain reaction and sequenced, and their methylation rates were determined. RESULTS: The methylation rates of miR-1247 and miR-200a were significantly higher in patients with pancreatic cancer, and biliary tract cancer than in those with benign diseases, and the methylation rate of miR-200b was significantly higher in patients with pancreatic cancer than in those with benign diseases. CONCLUSION: Methylation of miR-1247, miR-200a, and miR-200b in bile may be useful for distinguishing PBC from benign diseases.


Assuntos
Neoplasias do Sistema Biliar/genética , Metilação de DNA/genética , MicroRNAs/genética , Neoplasias Pancreáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Bile/metabolismo , Epigenômica/métodos , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade
5.
Mol Med Rep ; 20(2): 1103-1112, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173186

RESUMO

DL0410, a dual­action cholinesterase inhibitor and histamine­3 receptor antagonist with a novel structural scaffold, may be a potential candidate for the treatment of Alzheimer's disease (AD). To the best of the authors' knowledge, this is the first study to demonstrate a reliable method for the measurement of DL0410 in rat plasma, brain, bile, urine and feces samples, and identification of its primary metabolites. The pharmacokinetic properties of DL0410 were analyzed by liquid chromatography­mass spectrometry at oral doses of 25, 50 and 100 mg/kg and intravenous dose of 5 mg/kg. The investigation of the excretion and metabolism of DL0410 was determined following liquid­liquid extraction for biliary, urinary and fecal samples. Finally, the cytochrome (CY)P450 isoforms involved in the production of DL0410 metabolites with recombinant human cytochrome P450 enzymes were characterized. The results suggested that DL0410 was not well absorbed; however, was distributed to the entorhinal cortex and hippocampus of the brain. A total of two common metabolites of the reduction of DL0140 in the bile, urine and feces were identified and CYP2D6 was involved in this reaction. The pharmacokinetic results of DL0410 provided information for the illustration of its pharmacodynamic properties, mechanism of action and promoted its continued evaluation as a therapeutic agent for AD treatment.


Assuntos
Compostos de Bifenilo/farmacocinética , Inibidores da Colinesterase/farmacocinética , Citocromo P-450 CYP2D6/metabolismo , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Piperidinas/farmacocinética , Doença de Alzheimer/tratamento farmacológico , Animais , Bile/metabolismo , Compostos de Bifenilo/análise , Compostos de Bifenilo/uso terapêutico , Líquidos Corporais/metabolismo , Encéfalo/metabolismo , Inibidores da Colinesterase/análise , Inibidores da Colinesterase/uso terapêutico , Fezes/química , Feminino , Antagonistas dos Receptores Histamínicos H3/análise , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Humanos , Masculino , Piperidinas/análise , Piperidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley
7.
J Agric Food Chem ; 67(19): 5530-5543, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31025561

RESUMO

Acacetin, a dietary component, is abundant in acacia honey and has superior anticancer activities. To date, no research on the metabolism of acacetin has been reported. In the current research, an online detection strategy of ultra-high-performance liquid chromatography connected to a quadrupole time-of-flight mass spectrometer (UHPLC-Q-TOF-MS/MS) was utilized for metabolite identification in vivo (rat plasma, bile, urine, and feces) and in vitro (rat liver microsomes). A total of 31 metabolites were structurally characterized in rats, and 25 metabolites were detected in rat liver microsomes, among which, 4 metabolites were compared with standards. Oxidation, the loss of CH2, reduction, hydrolysis, glucuronide conjugation, sulfate conjugation, methylation, and N-acetylation were the main metabolic pathways of acacetin. This study is the first to characterize acacetin metabolites in vivo and in vitro, and the results of this study offer novel and valuable evidence for a comprehensive understanding of the safety and efficacy of acacetin.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Flavonas/química , Flavonas/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Bile/química , Bile/metabolismo , Fezes/química , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Plasma/química , Ratos , Ratos Wistar
8.
Methods Mol Biol ; 1981: 363-372, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31016667

RESUMO

Cholangiopathies, including primary sclerosing cholangitis, are a group of heterogeneous diseases characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile duct epithelium. Studies, especially of primary sclerosing cholangitis, have been hampered by the difficulty in accessing the cholangiocyte, instability of in vitro culture systems, and reliance on (limited) samples from end-stage disease. Here we describe a novel method of culturing biliary cells from bile of primary sclerosing cholangitis patients undergoing endoscopic retrograde cholangiopancreatography for clinical indications. These 3D organoid cultures demonstrate a biliary phenotype, can be maintained in vitro, and biobanked for future analyses. Given the need for diagnostic and therapeutic endoscopic retrograde cholangiopancreatography throughout the disease in many primary sclerosing cholangitis patients, this method can provide longitudinal studies in individual patients, allowing for a correlation of gene expression with disease status. These organoids can react to inflammatory stimuli, resulting in the secretion of chemo/cytokines indicative of the reactive immune phenotype characteristic of primary sclerosing cholangitis. Therefore, bile-derived organoids provide a model to study the pathogenesis and pharmacotherapeutic treatment of cholangiopathies.


Assuntos
Colangite Esclerosante/metabolismo , Colangite Esclerosante/patologia , Bile/metabolismo , Ductos Biliares/metabolismo , Ductos Biliares/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Organoides/metabolismo , Organoides/patologia , Células-Tronco/metabolismo , Células-Tronco/patologia
9.
Food Chem ; 291: 157-166, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31006454

RESUMO

Carotenoids are lipophilic phytochemicals; their intake has been associated with reduced chronic diseases. However, their absorption depends on emulsification during digestion and incorporation into mixed micelles, requiring digestive enzymes, gastric peristalsis, bile, and dietary lipids. In this study, we investigated whether whey-protein-isolate (WPI), a commonly consumed protein source, can modulate ß-carotene bioaccessibility in vitro, especially under incomplete digestive conditions, i.e. under low digestive enzyme concentrations. Thus, amounts of pepsin, pancreatin, bile, co-digested lipids and kinetic energy and gastric digestion time were modified, and WPI at concentrations equivalent to 0/25/50% of the protein recommended dietary allowance (approx. 60 g/d) were added to ß-carotene dissolved in oil. WPI enhanced bioaccessibility by up to 20% (p < 0.001), especially under higher simulated peristalsis or reduced amount of dietary lipids. Conversely, they impaired bioaccessibility to one third (p < 0.001) under incomplete digestive conditions. WPI modulated ß-carotene bioaccessibility depending on digestive conditions.


Assuntos
Disponibilidade Biológica , Proteínas do Soro do Leite/metabolismo , beta Caroteno/metabolismo , Bile/metabolismo , Carotenoides/metabolismo , Digestão , Humanos , Técnicas In Vitro , Micelas , Pancreatina/metabolismo , Pepsina A/metabolismo , Espectrofotometria
10.
Appl Microbiol Biotechnol ; 103(9): 3819-3827, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30887172

RESUMO

Bioengineering of probiotics allows the improvement of their beneficial characteristics. In this work, we develop a molecular tool that would allow the activation of desirable traits in probiotics once they reach the intestine. The activity of upstream regions of bile-inducible genes of Lactobacillus casei BL23 and Lactobacillus plantarum WCFS1 was analyzed using plasmids encoding an anaerobic fluorescent protein as reporter. The promoter P16090 from Lb. casei BL23 was selected and its bile induction confirmed in Lb. casei BL23, Lb. plantarum WCFS1, and in Lactobacillus rhamnosus and Lactobacillus reuteri strains. However, the induction did not occur in Lactococcus lactis MG1363 or Bifidobacterium strains. Studies with different bile compounds revealed the importance of cholic acid in the bile induction process. Induction of fluorescence was also confirmed for transformed Lb. casei BL23 under simulated colonic conditions and in the presence of intestinal microbiota. The developed vector, pNZ:16090-aFP, constitutes a promising tool suitable for the expression of genes of interest under intestinal conditions in probiotic strains of the species Lb. casei, Lb. plantarum, Lb. rhamnosus, and Lb. reuteri.


Assuntos
Bile/metabolismo , Regulação Bacteriana da Expressão Gênica , Lactobacillus casei/genética , Lactobacillus plantarum/genética , Lactobacillus rhamnosus/genética , Humanos , Intestinos/microbiologia , Lactobacillus casei/metabolismo , Lactobacillus plantarum/metabolismo , Lactobacillus rhamnosus/metabolismo , Probióticos/análise , Probióticos/metabolismo , Regiões Promotoras Genéticas
11.
Surg Clin North Am ; 99(2): 215-229, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30846031

RESUMO

Bile is composed of multiple macromolecules, including bile acids, free cholesterol, phospholipids, bilirubin, and inorganic ions that aid in digestion, nutrient absorption, and disposal of the insoluble products of heme catabolism. The synthesis and release of bile acids is tightly controlled and dependent on feedback mechanisms that regulate enterohepatic circulation. Alterations in bile composition, impaired gallbladder relaxation, and accelerated nucleation are the principal mechanisms leading to biliary stone formation. Various physiologic conditions and disease states alter bile composition and metabolism, thus increasing the risk of developing gallstones.


Assuntos
Bile/metabolismo , Colelitíase/etiologia , Ácidos e Sais Biliares/metabolismo , Humanos
12.
Biomed Pharmacother ; 112: 108701, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30818137

RESUMO

Natural bear bile has been used for liver disease in East Asia for thousands of years. However, its use has restrictions. In the current study, the therapeutic effects and potential mechanisms of cultured bear bile powder (CBBP) against hepatic fibrosis were evaluated in a dimethylnitrosamine (DMN)-induced rat model. CBBP treatment significantly improved DMN-induced hepatic necrosis and inflammatory infiltration. Additionally, CBBP remarkably alleviated the increased hepatic collagen content and expression of alpha-smooth muscle actin. Serum metabolomics revealed that 14 serum metabolites, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were decreased in DMN-treated rats, which was reversed by CBBP. Pathway analyses revealed that the main metabolic pathways affected by CBBP were related to fatty acid biosynthesis and metabolism, and biosynthesis of unsaturated fatty acids. EPA and DHA are ligands of peroxisome proliferator activated receptors (PPARs). CBBP treatment significantly stimulated liver mRNA and protein expression of PPARα and PPARγ. CBBP also markedly increased liver expression of PPARα target genes, which are involved in fatty acid ß-oxidation, and down-regulated IL-6, a downstream inflammatory gene of PPARγ. In conclusion, CBBP has the potential to attenuate liver fibrosis and its mechanism involves the promotion of the liver expression of PPARα and PPARγ. Our results may help in the development of a novel substitute for bear bile and therapeutic strategies for fibrotic liver diseases.


Assuntos
Bile/metabolismo , Citoproteção/efeitos dos fármacos , Dimetilnitrosamina/toxicidade , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Animais , Bile/química , Citoproteção/fisiologia , Relação Dose-Resposta a Droga , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Cirrose Hepática Experimental/prevenção & controle , Distribuição Aleatória , Ratos , Ratos Wistar , Ursidae
13.
Surg Oncol ; 28: 195-200, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30851900

RESUMO

AIMS: Increasing evidence has demonstrated that serum soluble B7H3(sB7-H3) is a useful tumor marker for cancer diagnosis and prognostic evaluations. Whether sB7-H3 expressed in the bile is related to the progression of malignant biliary strictures must be clarified. METHODS: Bile sB7-H3 was obtained via endoscopic retrograde cholangiopancreatography (ERCP) from 323 patients suspected to have malignant biliary strictures and was detected using a B7H3 ELISA kit. Diagnostic value was compared among bile sB7-H3, CA19-9, CA12-5, and CEA and ERCP-based cytological/tissue examination. Additionally, the correlations between the bile sB7-H3 concentration and the clinical characteristics of malignant biliary strictures were studied. RESULTS: The bile sB7-H3 levels of patients with malignant biliary strictures were significantly higher than those in patients with benign biliary strictures (P < 0.001). The AUC values of the receiver operating characteristic(ROC) curves for CA19-9, CA12-5 and CEA were 0.764, 0.475 and 0.399, respectively, which were significantly lower than that of sB7-H3 (0.878); the sensitivities of ERCP-based cytological and tissue examinations were 55.7% and 66.4%, respectively, which were far lower than that of bile sB7-H3(81.2%). A high level of sB7-H3 in patients with malignant biliary strictures was found to be correlated with vascular invasion(P < 0.001), lymph node metastasis(P < 0.001), distant metastasis (P < 0.001) and tumor-node-metastasis (TNM) stage(P = 0.01). The overall survival rate of the patients in the high sB7-H3 group was significantly lower than that of the patients in the low sB7-H3 group(P = 0.014). CONCLUSIONS: Bile sB7-H3 could serve as a valuable biomarker for patients with malignant biliary strictures and high levels of bile sB7-H3 were associated with poor clinical outcomes.


Assuntos
Antígenos B7/metabolismo , Neoplasias dos Ductos Biliares/diagnóstico , Bile/metabolismo , Biomarcadores Tumorais/metabolismo , Constrição Patológica/diagnóstico , Neoplasias dos Ductos Biliares/metabolismo , Colangiopancreatografia Retrógrada Endoscópica , Constrição Patológica/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida
14.
Nutrients ; 11(2)2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30791497

RESUMO

A dysregulation of nutrient exchange between tissues (gut, liver, muscles, adipose) occurs during overnutrition and could induce obesity and metabolic diseases. We aimed to evaluate how, in overfed mini pigs, nutrients use and partition were regulated in the gut and liver. Net nutrients fluxes were assessed in the fed (PP) and post absorptive (PA) states at 1, 14 and 60 days of adaptation to overfeeding in five adult Yucatan female multicatheterized minipigs. Pigs PA glycaemia and PP-induced hyperglycemia remained unchanged over the experimental period, suggesting that the management of the excess of energy intake allowed the maintenance of glucose levels. This was associated with (1) an increased PA plasma insulin, (2) an increased gut lactate production (increased lactate net release +89%, 1 h PP, D1 vs. D60) probably from an increased glucose oxidation, (3) a shift in utilization of gluconeogenic precursor (lactate, propionate) in the liver, and (4) a reduced gut utilization of nitrogen moieties for energy purposes (glutamine), a nitrogen sparing effect at the whole body level (decreased plasma urea in PA (-24% D1 vs. D60) and PP states) and a specific increased level of AA involved in lipids handling and bile recycling in the gut lumen (taurine and glycine).


Assuntos
Glicemia/metabolismo , Metabolismo dos Carboidratos , Metabolismo Energético , Trato Gastrointestinal/metabolismo , Hiperfagia/metabolismo , Fígado/metabolismo , Nitrogênio/metabolismo , Adaptação Fisiológica , Aminoácidos/sangue , Animais , Bile/metabolismo , Ingestão de Energia , Ácidos Graxos Voláteis/metabolismo , Feminino , Gluconeogênese , Hiperglicemia/metabolismo , Insulina/sangue , Ácido Láctico/metabolismo , Estado Nutricional , Obesidade/etiologia , Obesidade/metabolismo , Período Pós-Prandial , Suínos , Porco Miniatura , Ureia/sangue
15.
Curr Mol Pharmacol ; 12(2): 139-146, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30747091

RESUMO

BACKGROUND: Balanced coagonists of glucagon-like peptide-1 (GLP-1) and glucagon receptors are emerging therapies for the treatment of obesity and diabetes. Such coagonists also regulate lipid metabolism, independent of their body weight lowering effects. Many actions of the coagonists are partly mediated by fibroblast growth factor 21 (FGF21) signaling, with the major exception of bile homeostasis. Since thyroid hormone is an important regulator of bile homeostasis, we studied the involvement of thyroid hormone in coagonist-induced changes in lipid and bile metabolism. METHODS: We evaluated the effect of a single dose of coagonist Aib2 C24 chimera2 at 150 to 10000 µg/kg on tetraiodothyronine (T4) and triiodothyronine (T3) in high-fat diet-induced obese (DIO) mice and chow-fed mice. Repeated dose treatment of coagonist (150 µg/kg, subcutaneously) was assessed in four mice models namely, on lipid and bile homeostasis in DIO mice, propylthiouracil (PTU)-treated DIO mice, methimazole (MTM)-treated DIO mice and choline-deficient, L-amino acid-defined, highfat diet (CDAHFD)-induced nonalcoholic steatohepatitis (NASH). RESULTS: Single dose treatment of coagonist did not alter serum T3 and T4 in chow-fed mice and DIO mice. Coagonist treatment improved lipid metabolism and biliary cholesterol excretion. Chronic treatment of GLP-1 and glucagon coagonist did not alter serum T3 in hypothyroid DIO mice and CDAHFDinduced NASH. Coagonist increased serum T4 in DIO mice after 4 and 40 weeks of treatment, though no change in T4 levels was observed in hypothyroid mice or mice with NASH. CONCLUSION: Our data demonstrate that coagonist of GLP-1 and glucagon receptors does not modulate bile homeostasis via thyroid signaling.


Assuntos
Bile/metabolismo , Peptídeo 1 Semelhante ao Glucagon/agonistas , Receptores de Glucagon/agonistas , Tiroxina/sangue , Tri-Iodotironina/sangue , Animais , Dieta Hiperlipídica , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Metimazol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/etiologia , Obesidade/metabolismo , Propiltiouracila/farmacologia , Receptores de Glucagon/metabolismo , Triglicerídeos/análise
16.
BMC Microbiol ; 19(1): 33, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736731

RESUMO

BACKGROUND: Lactobacillus mucosae DPC 6426 has previously demonstrated potentially cardio-protective properties, in the form of dyslipidaemia and hypercholesterolemia correction in an apolipoprotein-E deficient mouse model. This study aims to characterise the manner in which this microbe may modulate host bile pool composition and immune response, in the context of cardiovascular disease. Lactobacillus mucosae DPC 6426 was assessed for bile salt hydrolase activity and specificity. The microbe was compared against several other enteric strains of the same species, as well as a confirmed bile salt hydrolase-active strain, Lactobacillus reuteri APC 2587. RESULTS: Quantitative bile salt hydrolase assays revealed that enzymatic extracts from Lactobacillus reuteri APC 2587 and Lactobacillus mucosae DPC 6426 demonstrate the greatest activity in vitro. Bile acid profiling of porcine and murine bile following incubation with Lactobacillus mucosae DPC 6426 confirmed a preference for hydrolysis of glyco-conjugated bile acids. In addition, the purified exopolysaccharide and secretome of Lactobacillus mucosae DPC 6426 were investigated for immunomodulatory capabilities using RAW264.7 macrophages. Gene expression data revealed that both fractions stimulated increases in interleukin-6 and interleukin-10 gene transcription in the murine macrophages, while the entire secretome was necessary to increase CD206 transcription. Moreover, the exopolysaccharide elicited a dose-dependent increase in nitric oxide and interleukin-10 production from RAW264.7 macrophages, concurrent with increased tumour necrosis factor-α secretion at all doses. CONCLUSIONS: This study indicates that Lactobacillus mucosae DPC 6426 modulates both bile pool composition and immune system tone in a manner which may contribute significantly to the previously identified cardio-protective phenotype.


Assuntos
Amidoidrolases/biossíntese , Bile/metabolismo , Imunomodulação , Lactobacillus/enzimologia , Lactobacillus/imunologia , Macrófagos/imunologia , Animais , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/microbiologia , Glicosiltransferases/metabolismo , Hidrólise , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Lactobacillus reuteri/enzimologia , Lectinas Tipo C/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Lectinas de Ligação a Manose/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Polissacarídeos Bacterianos/farmacologia , Células RAW 264.7 , Receptores de Superfície Celular/metabolismo , Suínos , Fator de Necrose Tumoral alfa/metabolismo
17.
Drug Metab Dispos ; 47(5): 525-534, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30765394

RESUMO

Fasiglifam, a potent and highly selective agonist of G protein-coupled receptor 40, was developed for the treatment of type 2 diabetes mellitus. However, phase III clinical programs were terminated owing to liver safety concerns. Fasiglifam-related liver toxicity was also observed in repeat-dose dog toxicology studies, characterized by granulomatous inflammation with crystal formation in the liver and/or bile ducts. These histopathological changes were not observed in rat toxicology studies. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis of dog liver sections obtained from a repeat-dose toxicology study indicated that the crystalline material in the affected dog liver contained fasiglifam and fasiglifam glucuronide (fasiglifam-G). Nonclinical mechanistic studies indicated that after 14 days of repeated oral dosing with [14C]fasiglifam at 200 mg/kg per day to dogs, the concentrations of fasiglifam and fasiglifam-G in the bile exceeded the solubility limit of these compounds in the bile (approximately 3000 µg/ml). After single oral 2- and 200-mg/kg doses administered to rats and dogs, fasiglifam and fasiglifam-G concentrations in dog bile were 5- to 10-fold higher than those in rat bile for the same dose of fasiglifam, while the bile flow rate adjusted by body weight was 4- to 8-fold lower in dogs than in rats. High fasiglifam and fasiglifam-G concentrations in dog bile together with lower bile flow rate could cause crystal formation in dog bile, resulting in secondary granulomatous inflammation in the dog liver.


Assuntos
Benzofuranos/efeitos adversos , Benzofuranos/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Fígado/efeitos dos fármacos , Sulfonas/efeitos adversos , Sulfonas/metabolismo , Animais , Bile/metabolismo , Cães , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
18.
Expert Rev Gastroenterol Hepatol ; 13(2): 157-171, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30791781

RESUMO

INTRODUCTION: Cholesterol gallstone disease have relationships with various conditions linked with insulin resistance, but also with heart disease, atherosclerosis, and cancer. These associations derive from mechanisms active at a local (i.e. gallbladder, bile) and a systemic level and are involved in inflammation, hormones, nuclear receptors, signaling molecules, epigenetic modulation of gene expression, and gut microbiota. Despite advanced knowledge of these pathways, the available therapeutic options for symptomatic gallstone patients remain limited. Therapy includes oral litholysis by the bile acid ursodeoxycholic acid (UDCA) in a small subgroup of patients at high risk of postdissolution recurrence, or laparoscopic cholecystectomy, which is the therapeutic radical gold standard treatment. Cholecystectomy, however, may not be a neutral event, and potentially generates health problems, including the metabolic syndrome. Areas covered: Several studies on risk factors and pathogenesis of cholesterol gallstone disease, acting at a systemic level have been reviewed through a PubMed search. Authors have focused on primary prevention and novel potential therapeutic strategies. Expert commentary: The ultimate goal appears to target the manageable systemic mechanisms responsible for gallstone occurrence, pointing to primary prevention measures. Changes must target lifestyles, as well as experimenting innovative pharmacological tools in subgroups of patients at high risk of developing gallstones.


Assuntos
Bile/metabolismo , Colelitíase/prevenção & controle , Colesterol/metabolismo , Fármacos Gastrointestinais/uso terapêutico , Prevenção Primária/métodos , Comportamento de Redução do Risco , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Animais , Colelitíase/diagnóstico , Colelitíase/epidemiologia , Colelitíase/metabolismo , Exercício , Fármacos Gastrointestinais/efeitos adversos , Humanos , Fatores de Proteção , Fatores de Risco , Resultado do Tratamento
19.
J Appl Microbiol ; 126(5): 1551-1557, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30790408

RESUMO

AIMS: To identify the mechanism in which way maltodextrin enhance bile tolerance in Lactobacillus plantarum Lp-115. METHODS AND RESULTS: Based on determining the OD600 value and counting the numbers of viable cells by the pour plate method, the results showed that maltodextrin could not promote the strain growth directly, but could enhance the tolerance of bile in Lp-115. The OD600 value of L. plantarum Lp-115 cultured in MRSB broth with maltodextrin was three times higher than the control value. After supplementing the medium with 4·0% maltodextrin, the highest survival rate was observed when the bile concentration is 0.3%. CONCLUSIONS: In summary, maltodextrin exhibited a significant improvement of bile tolerance and it could enhance cell hydrophobicity, shift the fatty acid composition of the membrane and induce the expression of a bile salt hydrolase gene (pva3) significantly. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report concerning the mechanism of maltodextrin enhancing the bile tolerance. This study promotes the application of maltodextrin as a choice to protect probiotic L. plantarum strains against the bile salt stress.


Assuntos
Ácidos e Sais Biliares/farmacologia , Bile , Lactobacillus plantarum , Polissacarídeos/farmacologia , Técnicas Bacteriológicas , Bile/metabolismo , Bile/fisiologia , Meios de Cultura , Lactobacillus plantarum/efeitos dos fármacos , Lactobacillus plantarum/metabolismo , Viabilidade Microbiana/efeitos dos fármacos
20.
J Pharm Biomed Anal ; 168: 155-162, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30807920

RESUMO

Icariin, the major flavonoid constituent of the traditional Chinese medicine Epimedii Folium, is extensively researched owing to its comprehensive beneficial effects. This study aimed at identifying the in vivo metabolites and the metabolic profiling in rats after oral administration at a dose of icariin (100 mg/kg) with the aid of an ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF-MS/MS) and metabolynx™ software. A total of 25 metabolites were detected and 4 of them were compared with standard substances. Among them, 10 metabolites were reported for the first time. The results indicated that the principal metabolism pathways of icariin in rat were hydroxylation and the conjugation with glucuronide. It also confirmed that M2, M14, M18 and M23 were the major circulating forms of icariin in rats following oral administration. Demethylation, dehydrogenation, epoxidation, reduction, oxidation were also observed and the epoxidation and reduction on the isopentenyl were regarded as new metabolic patterns of icariin. Moreover, this study could enrich the understanding of the metabolism of icariin and help to elucidate the metabolic profiling of other prenylflavonoids.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Flavonoides/análise , Metabolômica/métodos , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Bile/metabolismo , Flavonoides/administração & dosagem , Flavonoides/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
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