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1.
Anticancer Res ; 41(1): 327-334, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33419827

RESUMO

BACKGROUND/AIM: Pancreaticobiliary maljunction (PBM), a disease with reflux of pancreatic and bile juice in the pancreaticobiliary tract, is a high-risk factor for biliary tract cancer. The aim of this study was to investigate the mechanism of carcinogenesis in PBM using a metabolomics analysis of bile sampled during surgery. PATIENTS AND METHODS: Three patients with PBM without biliary tract cancer, four patients with extrahepatic bile duct cancer (EHBC), and three controls with benign disease were enrolled. Metabolomics analysis of bile samples was performed using capillary electrophoresis-mass spectrometry and liquid chromatography-mass spectrometry to discriminate the amino acid and lipidomic profiles. RESULTS: The principal component analysis in the capillary electrophoresis-mass spectrometry and liquid chromatography-mass spectrometry revealed similar metabolites in patients with PBM and those with EHBC; furthermore, there was a clear difference between patients with PBM or EHBC compared to controls. The amino acid profiles revealed the following 20 potential carcinogenic candidates for PBM: isoleucine, phenylalanine, tyrosine, leucine, tryptophan, arginine, lysine, valine, asparagine, methionine, aspartic acid, serine, threonine, histidine, glutamine, alanine, proline, glutamic acid, and pyruvic acid. The lipidomic profiles revealed the following 11 carcinogenic candidates: lysophosphatidylcholine, lysophosphatidylethanolamine, phosphatidyl glycerol, lysophosphatidyl glycerol, triacylglycerol, diacylglycerol, ceramide, sphyngomyeline, fatty acid, hyperforin, and vitamin D. Among these characteristic metabolites, the branched-chain amino acids, methionine and lysophosphatidylcholine are known to be related to carcinogenesis. CONCLUSION: The bile metabolites were extremely similar in patients with PBM and those with EHBC. Furthermore, amino acid and lipid metabolism was markedly different in patients with PBM or EHBC compared to healthy controls.


Assuntos
Neoplasias dos Ductos Biliares/etiologia , Bile/metabolismo , Transformação Celular Neoplásica/metabolismo , Suscetibilidade a Doenças , Má Junção Pancreaticobiliar/complicações , Má Junção Pancreaticobiliar/metabolismo , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/terapia , Cromatografia Líquida , Eletroforese Capilar , Feminino , Humanos , Masculino , Espectrometria de Massas , Metabolômica/métodos , Projetos Piloto , Medição de Risco , Fatores de Risco
2.
Aquat Toxicol ; 230: 105714, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33310674

RESUMO

Red Snapper (Lutjanus campechanus) were collected throughout the Gulf of Mexico (GoM) from 2011 to 2017 and analyzed for biliary (n = 496) fluorescent aromatic compounds (FACs), hepatic (n = 297) polycyclic aromatic hydrocarbons (PAHs) and microscopic hepatobiliary changes (MHC, n = 152). Gross and histological evaluations were conducted with liver tissues to identify and characterize pathological changes. This is the first report to interrelate hepatobiliary PAH concentrations and MHCs in Red Snapper. Hepatic PAHs measured in GoM Red Snapper ranged from 192 to 8530 ng g-1 w.w. and biliary FACs ranged from 480 to 1,100,000 ng FAC g-1 bile. Biliary FACs in Red Snapper collected along the west Florida Shelf and north central region declined after 2011 and were relatively stable until a sharp increase was noted in 2017. Increases in the PAH exposures are likely due to a number of sources including leaking infrastructure, annual spills, riverine input and the resuspension of contaminated sediments. In contrast, hepatic PAH concentrations were relatively stable indicating Red Snapper are able to maintain metabolic clearance however this energetic cost may be manifesting as microscopic hepatic changes (MHCs). Virtually all (99 %) of the evaluated Red Snapper had one to nine MHCs with an average of five coinciding changes in an individual fish. The observed changes were broadly classified as inflammatory responses, metabolic responses, degenerative lesions, nonneoplastic proliferation and neoplastic lesions. Biliary FACs were associated with parasitic infection and intracellular breakdown product accumulation such as intra-macrophage hemosiderin, lipofuscin and ceroid laden prevalence. Whereas, hepatic PAHs were associated with increased myxozoan plasmodia prevalence. This study evaluates relationships between hepatobiliary PAH concentrations and biometrics, somatic indices, condition factors and microscopic hepatic changes in Red Snapper located in the north central GoM. Together, these results may be signaling increased disease progression in Gulf of Mexico Red Snapper more than likely resulting from chronic environmental stressors including elevated PAH exposures and concentrations.


Assuntos
Bile/metabolismo , Monitoramento Ambiental/métodos , Fígado/efeitos dos fármacos , Fígado/patologia , Perciformes/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Florida , Golfo do México , Eliminação Hepatobiliar , Fígado/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/análise , Prevalência , Poluentes Químicos da Água/análise
3.
Phytomedicine ; 80: 153378, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33113499

RESUMO

BACKGROUND: In our previous study, we demonstrated the hepatoprotective effect of Herpetospermum pedunculosum in cholestatic rats. A bioassay-guided study also led to the identification and isolation of a lignan, dihydrodiconiferyl alcohol (DA) from the seeds of H. pedunculosum. PURPOSE: To investigate whether DA could alleviate cholestasis and determine the mechanisms underlying such action. METHODS: Male Sprague-Dawley (SD) rats were administered with DA (10, 20 or 40 mg/kg) intragastrically once daily for 7 days prior to treatment with α-naphthylisothiocyanate (ANIT) (60 mg/kg). We then evaluated the levels of a range of serum indicators, determined bile flow, and carried out histopathological analyses. Western blotting was then used to investigate the levels of inflammatory mediators and the Farnesoid X Receptor (FXR), proteins involved in the downstream biosynthesis of bile acids, and a range of transport proteins. Molecular docking was used to simulate the interaction between DA and FXR. Cell viability of human hepatocytes (L-02) cells was determined by MTT. Then, we treated guggulsterone-inhibited L-02 cells, Si-FXR L-02 cells, and FXR-overexpression cells with the FXR agonist GW4064 (6 µM) or DA (25, 50 and 100 µM) for 24 h before detecting gene and protein expression by RT-PCR and western blotting, respectively. RESULTS: DA significantly attenuated ANIT-induced cholestasis in SD rats by reducing liver function indicators in the serum, increasing bile flow, improving the recovery of histopathological injuries in the liver, and by alleviating pro-inflammatory cytokines in the liver. DA also increased the expression levels of FXR and altered the levels of downstream proteins in the liver tissues, thus indicating that DA might alleviate cholestasis by regulating the FXR. Molecular docking simulations predicted that DA was as an agonist of FXR. In vitro mechanical studies further showed that DA increased the mRNA and protein expression levels of FXR, Small Heterodimer Partner 1/2, Bile Salt Export Pump, Multidrug Resistance-associated Protein 2, and Na+/taurocholate Co-transporting Polypeptide, in both guggulsterone-inhibited and Si-FXR L-02 cells. Moreover, DA enhanced the mRNA and protein expression of FXR, and its downstream genes and proteins, in L-02 cells containing an FXR-overexpression plasmid. CONCLUSION: DA may represent an effective agonist for FXR has significant therapeutic potential for the treatment of cholestatic liver injury.


Assuntos
Colestase Intra-Hepática/tratamento farmacológico , Fenóis/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , 1-Naftilisotiocianato/toxicidade , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Bile/metabolismo , Ácidos e Sais Biliares/metabolismo , Colestase Intra-Hepática/induzido quimicamente , Colestase Intra-Hepática/metabolismo , Colestase Intra-Hepática/patologia , Cucurbitaceae/química , Hepatócitos/efeitos dos fármacos , Humanos , Isoxazóis/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Simulação de Acoplamento Molecular , Fenóis/química , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/genética
4.
Yakugaku Zasshi ; 140(11): 1329-1334, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33132268

RESUMO

Biliary lipids primarily consist of bile salts, phospholipids, and cholesterol. Bile salts have potent detergent properties and deleterious effects on the cell membrane and are cytotoxic to hepatocytes. We have previously reported that phosphatidylcholine (PC), the predominant bile phospholipid, protects hepatocytes from the cytotoxicity of bile salts, whereas cholesterol reverses the cytoprotective effects of PC against bile salts. ABCB4, a member of the ATP-binding cassette transporter family, secretes biliary phospholipids, especially PC, from the hepatocytes into the bile. Using Abcb4 knockout mice and HEK293 cells that stably expressed ABCB4, we examined the effects of taurine- or glycine-conjugated cholate, ursodeoxycholate, and hyodeoxycholate on the ABCB4-mediated efflux of PC. We observed that the biliary secretion of PC in wild-type mice significantly increased following infusion of all the tested bile salts, especially taurohyodeoxycholate. On the other hand, the biliary secretion of PC in Abcb4 knockout mice was not affected by the bile salt infusions. The results also demonstrated that the efflux of PC from ABCB4-expressing HEK293 cells was significantly stimulated by taurohyodeoxycholate, which has a strong potential to form mixed micelles with PC. Furthermore, the results of our study emphasized the possibility that the specific interactions of bile salts with ABCB4 are necessary for the release of PC molecules from the binding pocket of ABCB4 into the aqueous environment. Further understanding of this mechanism will aid in the development of novel therapeutic agents for cholestatic liver diseases.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/fisiologia , Ácidos e Sais Biliares/efeitos adversos , Bile/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/etiologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/genética , Desenvolvimento de Medicamentos , Fosfatidilcolinas/farmacologia , Fosfolipídeos/metabolismo , Ácido Taurodesoxicólico/análogos & derivados , Animais , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Colesterol/farmacologia , Células HEK293 , Hepatócitos/metabolismo , Humanos , Camundongos Knockout , Fosfatidilcolinas/metabolismo , Ácido Taurodesoxicólico/farmacologia
5.
Aquat Toxicol ; 227: 105590, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32891021

RESUMO

The aim of the present study was to investigate effects of defined mixtures of polycyclic aromatic hydrocarbons (PAHs) and perfluoroalkyl substances (PFASs), at low, environmentally relevant (1× = L), or high (20× = H) doses, on biological responses in Atlantic cod (Gadus morhua). To this end, farmed juvenile cod were exposed at day 0 and day 7 via intraperitoneal (i.p.) injections, in a two-week in vivo experiment. In total, there were 10 groups of fish (n = 21-22): two control groups, four separate exposure groups of PAH and PFAS mixtures (L, H), and four groups combining PAH and PFAS mixtures (L/L, H/L, L/H, H/H). Body burden analyses confirmed a dose-dependent accumulation of PFASs in cod liver and PAH metabolites in bile. The hepatosomatic index (HSI) was significantly reduced for three of the combined PAH/PFAS exposure groups (L-PAH/H-PFAS, H-PAH/L-PFAS, H-PAH/H-PFAS). Analysis of the hepatic proteome identified that pathways related to lipid degradation were significantly affected by PFAS exposure, including upregulation of enzymes in fatty acid degradation pathways, such as fatty acid ß-oxidation. The increased abundances of enzymes in lipid catabolic pathways paralleled with decreasing levels of triacylglycerols (TGs) in the H-PFAS exposure group, suggest that PFAS increase lipid catabolism in Atlantic cod. Markers of oxidative stress, including catalase and glutathione S-transferase activities were also induced by PFAS exposure. Only minor and non-significant differences between exposure groups and control were found for cyp1a and acox1 gene expressions, vitellogenin concentrations in plasma, Cyp1a protein synthesis and DNA fragmentation. In summary, our combined proteomics and lipidomics analyses indicate that PFAS may disrupt lipid homeostasis in Atlantic cod.


Assuntos
Fluorcarbonetos/toxicidade , Gadus morhua/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Bile/metabolismo , Biomarcadores/metabolismo , Fluorcarbonetos/análise , Lipidômica , Fígado/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/análise , Proteoma/metabolismo , Proteômica , Vitelogeninas/metabolismo , Poluentes Químicos da Água/análise
6.
Life Sci ; 259: 118352, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32860804

RESUMO

AIMS: Lipopolysaccharide (LPS) induces inflammatory cholestasis by impairing expression, localization, and function of carriers involved in bile formation, e.g. bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2). A specific therapy against this disease is still lacking. Therefore, we evaluated the anticholestatic effects of spironolactone (SL), a PXR ligand that regulates bile salt homeostasis, up-regulates Mrp2, and bears anti-inflammatory properties. MAIN METHODS: Male Wistar rats were divided into four groups: Control, SL (83.3 mg/kg/day of SL, i.p., for 3 days), LPS (2.5 mg/kg/day, i.p., at 8 am of the last 2 days, and 1.5 mg/kg/day at 8 pm of the last day), and SL + LPS. Biliary and plasma parameters and the expression, function, and localization of Mrp2 and Bsep were evaluated. KEY FINDINGS: SL partially prevented LPS-induced drop of basal bile flow by normalizing the bile salt-independent fraction of bile flow (BSIBF), via improvement of glutathione output. This was due to a recovery in Mrp2 transport function, the major canalicular glutathione transporter, estimated by monitoring the output of its exogenously administered substrate dibromosulfophthalein. SL counteracted the LPS-induced downregulation of Mrp2, but not that of Bsep, at both mRNA and protein levels. LPS induced endocytic internalization of both transporters, visualized by immunofluorescence followed by confocal microscopy, and SL partially prevented this relocalization. SL did not prevent the increase in IL-1ß, IL-6, and TNF-α plasma levels. SIGNIFICANCE: SL prevents the impairment in Mrp2 expression and localization, and the resulting recovery of Mrp2 function normalizes the BSIBF by improving glutathione excretion.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Colestase/tratamento farmacológico , Espironolactona/uso terapêutico , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Bile/metabolismo , Colestase/sangue , Colestase/metabolismo , Citocinas/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/efeitos adversos , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real
7.
PLoS One ; 15(7): e0235635, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614897

RESUMO

BACKGROUND: Normothermic ex vivo liver perfusion (NEVLP) is a promising strategy to increase the donor pool in liver transplantation. Small animal models are essential to further investigate questions regarding organ preservation and reconditioning by NEVLP. A dual vessel small animal NEVLP (dNEVLP) model was developed using metamizole as a vasodilator and compared to conventional portovenous single vessel NEVLP (sNEVLP). METHODS: Livers of male Wistar rats were perfused with erythrocyte-supplemented culture medium for six hours by either dNEVLP via hepatic artery and portal vein or portovenous sNEVLP. dNEVLP was performed either with or without metamizole treatment. Perfusion pressure and flow rates were constantly monitored. Transaminase levels were determined in the perfusate at the start and after three and six hours of perfusion. Bile secretion was monitored and bile LDH and GGT levels were measured hourly. Histopathological analysis was performed using liver and bile duct tissue samples after perfusion. RESULTS: Hepatic artery pressure was significantly lower in dNEVLP with metamizole administration. Compared to sNEVLP, dNEVLP with metamizole treatment showed higher bile production, lower levels of transaminases during and after perfusion as well as significantly lower necrosis in liver and bile duct tissue. Biochemical markers of bile duct injury showed the same trend. CONCLUSION: Our miniaturized dNEVLP system enables normothermic dual vessel rat liver perfusion. The administration of metamizole effectively ameliorates arterial vasospasm allowing for six hours of dNEVLP, with superior outcome compared to sNEVLP.


Assuntos
Dipirona/farmacologia , Transplante de Fígado , Preservação de Órgãos/métodos , Vasodilatação/efeitos dos fármacos , Animais , Pressão Arterial/efeitos dos fármacos , Bile/metabolismo , Ductos Biliares/patologia , Artéria Hepática/patologia , Fígado/irrigação sanguínea , Fígado/patologia , Testes de Função Hepática , Masculino , Ratos , Ratos Wistar
8.
Medicine (Baltimore) ; 99(22): e20502, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481469

RESUMO

The aim of the study was to develop a new early noninvasive diagnostic model for primary biliary cholangitis (PBC).A total of 118 PBC patients who had undergone a liver biopsy were enrolled in the study, and were randomized into a model group (78 patients) and a validation group (40 patients). The patients' histological stages were based on the classifications of the Scheuer's stage. All common parameters and liver pathological results were analyzed. And total bile acid to platelet ratio, aspartate aminotransferase to platelet ratio index, fibrosis index based on 4 factors and red cell distribution width to platelet ratio were calculated.There were 106 (89.8%) women and 12 men in this study, and the number of patients in Scheuer stage I, II, III, and IV hepatic fibrosis was 52 (44.1%), 36 (30.5%), 26 (22.0%), and 4 (3.4%), respectively. The areas under the receiver operating characteristic curves of the total bile acid to platelet ratio (TPR), the aspartate aminotransferase to platelet ratio index, the fibrosis index based on 4 factors , and the red cell distribution width to platelet ratio for predicting advanced liver fibrosis were 0.771, 0.715, 0.618, and 0.517 respectively. The areas under the receiver operating characteristic curves of the TPR was higher than other non-invasive serological models.As a simple, inexpensive and easily accessible non-invasive liver fibrosis diagnostic model, the TPR may be a new noninvasive marker for predicting histologic severity of PBC.


Assuntos
Bile/metabolismo , Colangite/complicações , Cirrose Hepática Biliar/etiologia , Contagem de Plaquetas , Aspartato Aminotransferases/metabolismo , Biomarcadores/análise , Feminino , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes
9.
Toxicol Appl Pharmacol ; 398: 115032, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32387182

RESUMO

BACKGROUND AND PURPOSE: Irinotecan-induced diarrhea (IID) results from intestinal damages by its active metabolite SN-38. Alleviation of these damages has focused on lowering luminal SN-38 concentrations. However, it is unclear if the enteric bioavailability of SN-38 is mostly dependent on luminal SN-38 concentrations. EXPERIMENTAL APPROACH: Irinotecan (50 mg/kg, i.p. once daily for 6 days) was administered to female wildtype FVB, Mdr1a (-/-), Mrp2 (-/-) and Bcrp1 (-/-) mice for pharmacokinetic (PK), toxicokinetic (TK) and biodistribution studies. Plasma PK/TK profiles and tissues drug distribution were determined after first or sixth daily doses, along with activities of blood and gut esterases and intestinal Ugts. Caco-2 cells and bile-cannulate mice were used to further investigate intestinal and biliary disposition of irinotecan and its metabolites. KEY RESULTS: Significant differences in IID severity were observed with the susceptible rank of Bcrp1(-/-) > wildtype FVB > Mdr1a(-/-) > Mrp2(-/-). This rank order did not correlate with biliary excretion rates of SN-38/SN-38G. Rather, the severity was best correlated (R = 0.805) with the intestinal ratio of Css SN-38/SN-38G, a measure of gut Ugt activity. On the contrary, IID was poorly correlated with plasma AUC ratio of SN-38/SN-38G (R = 0.227). Increased intestinal esterase activities due to repeated dosing and gut efflux transporter functionality are the other key factors that determine SN-38 enteric exposures. CONCLUSION AND IMPLICATIONS: Intestinal SN-38 exposure is mainly affected by intestinal Ugt activities and blood esterase activities, and strongly correlated with severity of IID. Modulating intestinal SN-38 concentration and gut Ugt expression should be the focus of future studies to alleviate IID.


Assuntos
Diarreia/induzido quimicamente , Glucuronosiltransferase/metabolismo , Intestinos/efeitos dos fármacos , Irinotecano/farmacologia , Animais , Antineoplásicos Fitogênicos , Área Sob a Curva , Bile/metabolismo , Sistema Biliar/efeitos dos fármacos , Sistema Biliar/metabolismo , Células CACO-2 , Linhagem Celular Tumoral , Diarreia/metabolismo , Esterases/metabolismo , Feminino , Humanos , Camundongos , Distribuição Tecidual/efeitos dos fármacos
10.
Chemosphere ; 256: 126928, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32442796

RESUMO

Phenols and trans-1,2-dihydro-1,2-diols are metabolites commonly formed in vivo in fish upon exposure to polycyclic aromatic hydrocarbons (PAHs). These metabolites are excreted via the bile and gas chromatography-mass spectrometry (GC-MS) analysis of bile is becoming more frequently used for evaluating PAH exposure levels in fish. Current protocols focus on the detection and quantification of phenols formed during in vivo oxidation of PAHs, leaving out analyses and quantification of other oxidation products such as trans-1,2-dihydro-1,2-diols, potentially underestimating exposure levels. Herein, four trans-1,2-dihydro-1,2-diols, namely trans-1,2-dihydronaphthalene-1,2-diol, trans-6-methyl-1,2-dihydronaphthalene-1,2-diol, trans-5,7-dimethyl-1,2-dihydronaphthalene-1,2-diol, and trans-4,6,7-trimethyl-1,2-dihydronaphthalene-1,2-diol, were successfully prepared and used as standards in the GC-MS analysis, aiming to further develop this qualitative and quantitative analytical method for the determination of PAH exposures. This study shows that the currently used GC-MS analysis, including sample workup, is not suitable for determining the quantity of the corresponding diols derived from naphthalene and methylated naphthalenes. Alternative approaches are needed to provide a correct estimate of PAH exposure levels.


Assuntos
Monitoramento Ambiental , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Bile/metabolismo , Peixes , Gadus morhua/metabolismo , Cromatografia Gasosa-Espectrometria de Massas/métodos , Naftalenos
11.
PLoS Negl Trop Dis ; 14(3): e0008220, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32226018

RESUMO

Human clonorchiasis, caused by Clonorchis sinensis, is endemic in East Asian countries. C. sinensis metacercariae excyst in the duodenum of mammalian hosts, migrate to the intrahepatic bile duct, and mature into adults in the milieu of bile. We have previously shown that newly excysted juvenile C. sinensis move chemotactically toward bile and bile acids. Here, the chemotactic behavior of adult C. sinensis (CsAd) toward bile and bile acids was investigated. CsAds moved toward 0.05-5% bile and were most attracted to 0.5% bile but moved away from 10% bile. Upon exposure to 1-10% bile, CsAds eventually stopped moving and then died quickly. Among bile acids, CsAds showed strong chemotaxis toward cholic acid (CA) and deoxycholic acid. On the contrary, CsAds repelled from lithocholic acid (LCA). Moreover, at higher than 10 mM LCA, CsAds became sluggish and eventually died. Dopamine D1 receptor antagonists (LE-300 and SKF-83566), D2/3 receptor antagonists (raclopride and its derivative CS-49612), and a dopamine re-uptake inhibitor inhibited CA-induced chemotaxis of CsAds almost completely. Clinically used antipsychotic drugs, namely chlorpromazine, haloperidol, and clozapine, are dopaminergic antagonists and are secreted into bile. They completely inhibited chemotaxis of CsAds toward CA. At the maximum doses used to treat patients, the three tested medicines only expelled 2-12% of CsAds from the experimentally infected rabbits, but reduced egg production by 64-79%. Thus, antipsychotic medicines with dopaminergic antagonism could be considered as new anthelmintic candidates for human C. sinensis infections.


Assuntos
Anti-Helmínticos/farmacologia , Antipsicóticos/farmacologia , Quimiotaxia/efeitos dos fármacos , Clonorchis sinensis/efeitos dos fármacos , Clonorchis sinensis/fisiologia , Antagonistas de Dopamina/farmacologia , Animais , Anti-Helmínticos/administração & dosagem , Antipsicóticos/administração & dosagem , Bile/metabolismo , Fatores Quimiotáticos/metabolismo , Ácido Cólico/metabolismo , Clonorquíase/tratamento farmacológico , Modelos Animais de Doenças , Antagonistas de Dopamina/administração & dosagem , Feminino , Fertilidade/efeitos dos fármacos , Humanos , Ácido Litocólico/metabolismo , Coelhos , Análise de Sobrevida , Resultado do Tratamento
12.
Zhongguo Zhong Yao Za Zhi ; 45(6): 1287-1296, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32281338

RESUMO

Cholagogic traditional Chinese medicines refer to those that can promote bile secretion and excretion, strengthen gallbladder contraction and promote gallbladder emptying. They are mainly used to treat cholecystitis, gallstones, cholestasis, biliary tract infection, jaundice hepatitis and other diseases in clinical application. As a traditional medicine in our country, Chinese herbal medicines have many advantages, such as extensive resources, low cost, little or no toxic and side effects, and in addition, it is not easy for animals to produce drug resistance. With the progress of science and technology and the rapid development of traditional Chinese medicine, many achievements have been made in the research of cholagogic traditional Chinese medicines. Traditional Chinese medicine plays a cholagogic role mainly by promoting bile secretion, regulating SCP2 mRNA, FXR, BSEP and efflux transporter protein, dissolving cholesterol, promoting the relaxation of Oddi's sphincter and changing the composition of bile, etc. Traditional Chinese medicine decoction, traditional Chinese medicine preparation, Chinese medicine combined with acupuncture, ear acupoint pressing, soaking bath, western medicine and alike are often used to treat biliary system diseases in clinical practice. The effective rate of combination of traditional Chinese medicine and other methods was significantly higher than that of compound prescription, western medicine, acupuncture and soaking bath alone. General attack therapy and new therapies are also used in clinical treatment. The clinical effect of traditional Chinese medicine is remarkable. By means of literature review, the pharmacological effects, mechanism and clinical application of Chinese herbal medicines and compound prescriptions with gallbladder-promoting effect in the past 15 years were summarized in this paper. At the same time, some existing problems were found and prospects were expected.


Assuntos
Bile/metabolismo , Colagogos e Coleréticos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa , Animais , Prescrições
13.
J Pediatr ; 221: 251-254, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32303357

RESUMO

We identified biallelic pathogenic mutations in the Lipolysis-stimulated lipoprotein receptor (LSR) gene in a patient with infantile intrahepatic cholestasis. We established that mutations in the LSR gene, which encodes a protein which is critical for the formation of tricellular tight junctions in the liver, are a novel cause of pediatric cholestasis.


Assuntos
Colestase Intra-Hepática/genética , Mutação da Fase de Leitura , Receptores de Lipoproteínas/genética , Grupo com Ancestrais do Continente Asiático/genética , Bile/metabolismo , Biópsia , Pré-Escolar , Éxons , Feminino , Humanos , Japão , Fígado/patologia , Cirrose Hepática/patologia , Microscopia Eletrônica , Junções Íntimas/metabolismo
14.
Surg Today ; 50(10): 1232-1239, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32314016

RESUMO

PURPOSE: Confirmation of bile excretion into the gastrointestinal tract is important to exclude biliary atresia (BA). We compared the duodenal tube test (DTT) with hepatobiliary scintigraphy (HS) for their efficiency in detecting bile secretion. METHODS: The subjects of this retrospective study were 47 infants who underwent both DTT and HS to diagnose or exclude BA between January 2000 and March 2018. RESULTS: BA was diagnosed in 32 of the 47 patients, and 7 of the remaining 15 non-BA patients underwent intraoperative cholangiography. Among the various DTT parameters, the total bile acid in duodenal fluid (DF-TBA)/serum (S) gamma-glutamyl transferase (γGTP) ratio was found to be the most specific for BA, with sensitivity and specificity of 98.0-100%, respectively. One BA patient in whom cut off values were not met was a premature infant. The sensitivity and specificity of HS were 100-56.3%, respectively. The diagnostic accuracy of the DF-TBA/S-γGTP parameter was higher than that of HS (98.6% vs. 85.1%, respectively). CONCLUSIONS: The DTT could be more a specific method than HS to detect bile excretion. Thus, the DTT should be incorporated into the multidisciplinary diagnostic approach for the differential diagnosis of BA to prevent unnecessary intraoperative cholangiography in patients who do not have BA.


Assuntos
Ácidos e Sais Biliares/metabolismo , Bile/metabolismo , Atresia Biliar/diagnóstico , Biomarcadores/sangue , Biomarcadores/metabolismo , Cateteres , Colangiografia , Técnicas de Diagnóstico do Sistema Digestório , Duodeno/metabolismo , Cintilografia , gama-Glutamiltransferase/sangue , Atresia Biliar/diagnóstico por imagem , Diagnóstico Diferencial , Técnicas de Diagnóstico do Sistema Digestório/instrumentação , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade
15.
Chemosphere ; 253: 126678, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32278192

RESUMO

Hypoxia and petrogenic hydrocarbon contamination are two anthropogenic stressors that coexist in coastal environments. Although studies have estimated the impact of each stressor separately, few investigations have assessed the effects of these stressors in interaction. We therefore investigated the impact of these combined stressors on sea bass, (Dicentrarchus labrax) physiology. After experimental contamination with physically dispersed oil, fish were exposed to hypoxia or normoxia, and active/standard metabolic rates (AMR and SMR, respectively), and metabolic scope (MS) were estimated. At the protocol's end, the uptake of polycyclic aromatic hydrocarbons (PAHs) was estimated by evaluating relative concentrations of bile metabolites. In terms of bile metabolites, our results validated the uptake of PAHs by contaminated fish in our experimental settings, and further suggest that the hypoxic period after contamination does not reduce or increase compound metabolization processes. Our data showed significant effects of hypoxia on all metabolic rates: a significant drastic AMR reduction and significant SMR diminution led to decreased MS. We also found that oil contamination significantly impacted AMR and MS, but not SMR. These results suggested that when evaluated separately, hypoxia or oil affect the metabolic rate of sea bass. On the other hand, when evaluated in combination, no cumulative effects were observed, since fish exposed to both stressors did not show a stronger impact on metabolism than fish exposed to hypoxia alone. This suggests that oil impacts fish metabolism when fish occupy normoxic waters, and that oil does not magnify hypoxia-induced effects on fish metabolism.


Assuntos
Bass/fisiologia , Poluição por Petróleo , Aerobiose/efeitos dos fármacos , Animais , Bass/metabolismo , Bile/metabolismo , Hidrocarbonetos/metabolismo , Hipóxia/metabolismo , Hipóxia/veterinária , Hidrocarbonetos Policíclicos Aromáticos/metabolismo
16.
Chem Biol Interact ; 324: 109062, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32198087

RESUMO

Ginsenoside Rg1 is an active ingredient extracted from the roots of ginsenoside, and an α-naphthylisothiocyanate (ANIT)-induced rat model of intrahepatic cholestasis was used to investigate the protective effect of Rg1 on cholestasis. 48 SD male rats were randomly divided into 6 groups: control group, model group, UDCA group (ursodeoxycholic acid), low-dose Rg1 group (10 mg/kg), medium-dose Rg1 group (20 mg/kg) and high-dose Rg1 group (40 mg/kg). The model group, the UDCA group and all the Rg1 group were then intragastrically administered with 80 mg/kg ANIT, and the control group were given equal volume of olive oil. Then the pathological changes in liver tissue were observed, the secretion of bile in the bile duct was measured, and the biochemical markers in serum were quantified, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), glutamyl transfer peptidase (GTP) and the content of total bilirubin (TBIL), direct bilirubin (DBIL), total bile acid (TBA). The contents of inflammatory mediators in serum were quantified, including tumor necrosis factor (TNF-α), γ-interferon (IFN-γ) and interleukin-1ß (IL-1ß). The contents of superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) in liver homogenate were quantified. Expression of farnesoid X receptor (FXR), transporters and metabolic enzymes in liver tissue was monitored. Rg1 treatment improved liver tissue pathological damage, promoted bile secretion and significantly reduced serum levels of the intrahepatic cholestasis markers ALT, AST, ALP, GTP, TBIL, DBIL and TBA. Rg1 increased the activity of SOD and GSH-Px in liver homogenate, while, reducing the serum levels of MDA and inflammatory mediators. Rg1 also regulated the expression of FXR, bile acid transporters and metabolic enzymes. Overall, Rg1 alleviated liver injury by improving secretion of bile and normalizing the activity of enzymes in the serum. The protective mechanism appeared to be related to the activation of FXR and regulation of liver transporters and metabolic enzymes.


Assuntos
Colestase Intra-Hepática/tratamento farmacológico , Ginsenosídeos/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Substâncias Protetoras/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , 1-Naftilisotiocianato , Animais , Bile/metabolismo , Biomarcadores/metabolismo , Colestase Intra-Hepática/induzido quimicamente , Colestase Intra-Hepática/patologia , Citocromo P-450 CYP3A/metabolismo , Citocinas/metabolismo , Glucuronosiltransferase/metabolismo , Glutationa Peroxidase/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Ratos Sprague-Dawley , Sulfotransferases/metabolismo , Superóxido Dismutase/metabolismo
17.
PLoS One ; 15(3): e0229745, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32163446

RESUMO

Ionic liquids are salts used in a variety of industrial processes, and being relatively non-volatile, are proposed as environmentally-friendly replacements for existing volatile liquids. Methylimidazolium ionic liquids resist complete degradation in the environment, likely because the imidazolium moiety does not exist naturally in biological systems. However, there is limited data available regarding their mammalian effects in vivo. This study aimed to examine the effects of exposing mice separately to 2 different methylimidazolium ionic liquids (BMI and M8OI) through their addition to drinking water. Potential effects on key target organs-the liver and kidney-were examined, as well as the gut microbiome. Adult male mice were exposed to drinking water containing ionic liquids at a concentration of 440 mg/L for 18 weeks prior to examination of tissues, serum, urine and the gut microbiome. Histopathology was performed on tissues and clinical chemistry on serum for biomarkers of hepatic and renal injury. Bacterial DNA was isolated from the gut contents and subjected to targeted 16S rRNA sequencing. Mild hepatic and renal effects were limited to glycogen depletion and mild degenerative changes respectively. No hepatic or renal adverse effects were observed. In contrast, ionic liquid exposure altered gut microbial composition but not overall alpha diversity. Proportional abundance of Lachnospiraceae, Clostridia and Coriobacteriaceae spp. were significantly greater in ionic liquid-exposed mice, as were predicted KEGG functional pathways associated with xenobiotic and amino acid metabolism. Exposure to ionic liquids via drinking water therefore resulted in marked changes in the gut microbiome in mice prior to any overt pathological effects in target organs. Ionic liquids may be an emerging risk to health through their potential effects on the gut microbiome, which is implicated in the causes and/or severity of an array of chronic disease in humans.


Assuntos
Microbioma Gastrointestinal , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Líquidos Iônicos/administração & dosagem , Líquidos Iônicos/farmacologia , Administração Oral , Animais , Bactérias/classificação , Bile/metabolismo , Biodiversidade , Microbioma Gastrointestinal/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Metaboloma , Camundongos Endogâmicos C57BL
18.
J Appl Microbiol ; 129(2): 367-377, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32027767

RESUMO

AIMS: Exposure of Listeria monocytogenes to osmotic stress can induce increased resistance to subsequent lethal exposure to cell envelope stressors, such as nisin and bile salts. We wanted to determine if similar cross-protection phenotypes could occur when L. monocytogenes strains were treated with osmotic stress and exposed to sublethal levels of the cell envelope stressor, bile. METHOD AND RESULTS: Growth phenotypes were measured for six L. monocytogenes strains exposed to 6% NaCl, 0·3 and 1% bile in BHI. To evaluate cross-protection, cells were pre-exposed to 6% NaCl, followed by exposure to BHI+1% bile for 26 h and vice versa. Significant increases in λ (lag phase) and doubling time were observed under salt and bile stresses compared with BHI alone. Average λ and Nmax (maximum cell density) in 0·3 and 1% bile for all strains were significantly lower than that in 6% NaCl. Pre-exposure to 6% NaCl followed by exposure to 1% bile significantly increased λ (P < 0·05), whereas pre-exposure to 1% bile followed by exposure to 6% NaCl led to formation of filamentous cells, with no changes in cell density over 26 h. CONCLUSIONS: Variation in growth characteristics was observed among strains exposed to bile. Exposure to osmotic stress did not lead to increased resistance to bile. Exposure to bile significantly impacted the ability of L. monocytogenes to adapt to grow under osmotic stress, where cells did not multiply but formed filamentous cells. SIGNIFICANCE AND IMPACT OF THE STUDY: Pre-exposure to a cell envelope stress and subsequent exposure to an osmotic stress appears to pose a significant stress to L. monocytogenes cells.


Assuntos
Bile/metabolismo , Listeria monocytogenes/fisiologia , Cloreto de Sódio/metabolismo , Microbiologia de Alimentos , Cinética , Listeria monocytogenes/citologia , Listeria monocytogenes/crescimento & desenvolvimento , Listeria monocytogenes/metabolismo , Estresse Fisiológico
19.
Xenobiotica ; 50(8): 967-979, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32003293

RESUMO

1. Darolutamide is a novel selective androgen receptor antagonist consisting of two pharmacologically equipotent diastereoisomers. The absorption, distribution, metabolism and excretion properties of darolutamide in rats are reported.2. Non- or [14C]-labelled darolutamide, its diastereoisomers and major metabolite were studied in intact and bile duct-cannulated rats (oral and intravenous administration), and rat hepatocytes.3. Darolutamide was quickly (1 h to reach maximum plasma concentration) and completely absorbed after oral administration. Absolute bioavailability was high. Keto-darolutamide was the most abundant metabolite in rat hepatocytes and the only major one in plasma. Interconversion between diastereoisomers was observed.4. After oral administration, radioactivity distributed widely and homogeneously. Penetration into brain was low (brain/blood ratio = 0.079). Elimination was rapid from most tissues. Excretion occurred rapidly, and routes were similar irrespective of administration routes. Complete mass balance was reached by 168 h post-dose. Most radioactivity (61-64%) was excreted in faeces, while relevant amounts (30-33%) were also excreted into urine. The main clearance routes were metabolism via oxidative reactions and glucuronidation. After intravenous administration, a relevant extent of the dose (20%) underwent extrabiliary excretion as darolutamide.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacocinética , Pirazóis/farmacocinética , Administração Oral , Animais , Bile/metabolismo , Disponibilidade Biológica , Líquidos Corporais , Fezes , Absorção Intestinal , Ratos , Distribuição Tecidual
20.
AANA J ; 88(1): 71-76, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32008621

RESUMO

Enterohepatic recirculation (EHRC) is a multistaged process with the following sequence: liver metabolism, bile secretion, gut metabolism, and reabsorption from the gut back to the systemic circulation. Enterohepatic recirculation prolongs drug half-lives and may be associated with the generation of 1 or more secondary plasma peaks. For EHRC to occur, there is substantial dependence on the flora residing in the gastrointestinal (GI) tract. The role of gut microflora is so essential to our overall homeostasis that it is referred to by some authorities as an endocrine organ or "a second brain." Hepatic metabolism plays the dominant role in the fate of drugs and other xenobiotics that we encounter. The liver is rich in a host of chemical manipulators that can hydrolyze, reduce, oxidize, and conjugate xenobiotics. Many drugs, morphine being a good example, are inactivated by glucuronide or sulfate conjugation, with subsequent movement into the bile and eventual emptying into the GI tract. Once in the GI tract, enzymes produced by gut flora can hydrolyze conjugated drugs in the small and large intestine, resulting in the active form reemerging, with reabsorption likely. The clinical relevance of EHRC is discussed with its major implications for efficacy and safety.


Assuntos
Anestesia Geral , Anestésicos/farmacocinética , Bile/metabolismo , Fígado/metabolismo , Circulação Êntero-Hepática , Humanos , Enfermeiras Anestesistas , Período Perioperatório
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