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1.
Phytomedicine ; 68: 153153, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32018210

RESUMO

BACKGROUD: Cholestasis, accompanied by the accumulation of bile acids in body, may ultimately cause liver failure and cirrhosis. There have been limited therapies for cholesteric disorders. Therefore, development of appropriate therapeutic drugs for cholestasis is required. Picroside II is a bioactive component isolated from Picrorhiza scrophulariiflora Pennell, its mechanistic contributions to the anti-cholestasis effect have not been fully elucidated, especially the role of picroside II on bile acid homeostasis via nuclear receptors remains unclear. PURPOSE: This study was designed to investigate the hepatoprotective effect of picroside II against alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury and elucidate the mechanisms in vivo and in vitro. METHODS: The ANIT-induced cholestatic mouse model was used with or without picroside II treatment. Serum and bile biochemical indicators, as well as liver histopathological changes were examined. siRNA, Dual-luciferase reporter, quantitative real-time PCR and Western blot assay were used to demonstrate the farnesoid X receptor (FXR) pathway in the anti-cholestasis effects of picroside II in vivo and in vitro. RESULTS: Picroside II exerted hepatoprotective effect against ANIT-induced cholestasis by impaired hepatic function and tissue damage. Picroside II increased bile acid efflux transporter bile salt export pump (Bsep), uptake transporter sodium taurocholate cotransporting polypeptide (Ntcp), and bile acid metabolizing enzymes sulfate transferase 2a1 (Sult2a1) and UDP-glucuronosyltransferase 1a1 (Ugt1a1), whereas decreased the bile acid synthesis enzymes cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1). In addition, expression of FXR and the target gene Bsep was increased, whereas aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor alpha (PPARα) and their corresponding target genes were not significantly influenced by picroside II under cholestatic conditions. Furthermore, regulation of transporters and enzymes involved in bile acid homeostasis by picroside II were abrogated by FXR silencing in mouse primary cultured hepatocytes. Dual-luciferase reporter assay performed in HepG2 cells demonstrated FXR activation by picroside II. CONCLUSION: Our findings demonstrate that picroside II exerts protective effect on ANIT-induced cholestasis possibly through FXR activation that regulates the transporters and enzymes involved in bile acid homeostasis. Picroside II might be an effective approach for the prevention and treatment of cholestatic liver diseases.


Assuntos
Colestase/prevenção & controle , Cinamatos/farmacologia , Glucosídeos Iridoides/farmacologia , Hepatopatias/prevenção & controle , Receptores Citoplasmáticos e Nucleares/metabolismo , 1-Naftilisotiocianato/toxicidade , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Ácidos e Sais Biliares/genética , Ácidos e Sais Biliares/metabolismo , Colestase/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/efeitos dos fármacos , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia
2.
Eur J Pharmacol ; 857: 172461, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31220436

RESUMO

Estrogen-induced cholestasis is a common etiology of hepatic diseases in women with contraceptives administration, pregnancy or hormone replacement therapy. Farnesoid X receptor (FXR) is a member of nuclear receptor super family of ligand-activated transcription factors that is highly expressed in liver. FXR is acknowledged to contribute to the bile acid homeostasis, as well as the pathogenesis and progression of cholestasis. Specific targeting of FXR is an innovative approach for the treatment of cholestasis. The current study aimed to verify the anti-cholestasis effect of yangonin that is a natural product isolated from Kava via FXR signaling pathway in vivo and in vitro. The analyses of FXR gain- or loss-of-function were performed. Yangonin treatment ameliorates estrogen-induced cholestasis through increasing bile flow and biliary bile acid output. The mechanisms were an induction in the hepatic efflux transporters (Bsep and Mrp2) and an inhibition in hepatic uptake transporter (Ntcp) by yangonin. Likewise, yangonin through repressing Cyp7a1, Cyp8b1 and inducing Sult2a1 expression suppressed bile acid synthesis and promoted bile acid metabolism. Furthermore, yangonin improved estrogen-induced inflammatory cell infiltration and the inflammation gene expression. In vitro experiments further consolidated that yangonin alleviated estrogen-caused cholestasis via FXR activation. Noteworthily, the effects of yangonin were enhanced by FXR expression plasmids but abrogated by FXR siRNA. In conclusion, yangonin alleviates estrogen-induced cholestasis, due to FXR-mediated gene regulation.


Assuntos
Colestase/metabolismo , Colestase/prevenção & controle , Estrogênios/efeitos adversos , Pironas/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Sistema Biliar/efeitos dos fármacos , Sistema Biliar/metabolismo , Colestase/induzido quimicamente , Colestase/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
3.
Cochrane Database Syst Rev ; 6: CD013163, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31158919

RESUMO

BACKGROUND: Conventionally used soybean oil-based lipid emulsion (S-LE) have high polyunsaturated fatty acid (PUFA) content and phytosterols that may contribute to adverse effects in preterm infants. The newer lipid emulsions (LE) from different lipid sources are currently available for use in preterm infants. OBJECTIVES: To compare the safety and efficacy of all LE for parenteral nutrition (PN) in preterm infants (less than 37 weeks' gestation) including preterm infants with surgical conditions or parenteral nutrition-associated liver disease (PNALD)/cholestasis using direct comparisons and pair-wise meta-analyses. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE (1946 to 18 June 2018), Embase (1974 to 18 July 2018), CINAHL (1982 to 18 June 2018), MIDRIS (1971 to 31 May 2018), conference proceedings, trial registries (ClinicalTrials.gov and WHO's Trials Registry and Platform), and reference lists of retrieved articles. SELECTION CRITERIA: Randomised or quasi-randomised controlled studies in preterm infants with or without surgical conditions or PNALD within the first six months of life. DATA COLLECTION AND ANALYSIS: Data collection and analysis conformed to the methods of Cochrane Neonatal. We used the GRADE approach to assess the quality of evidence for important outcomes in addition to reporting statistical significance of results. MAIN RESULTS: We included 29 studies (n = 2037) in this review. LE were classified in three broad groups: 1. all fish oil-containing LE including pure fish oil-LE (F-LE) and multisource LE (e.g. medium-chain triglycerides (MCT)-olive-fish-soybean oil-LE (MOFS-LE), MCT-fish-soybean oil-LE (MFS-LE) and olive-fish-soybean oil-LE (OFS-LE); 2. conventional S-LE; 3. alternative-LE (e.g. MCT-soybean oil-LE (MS-LE), olive-soybean oil-LE and borage oil-based LE).We considered the following broad comparisons: fish oil LE versus non-fish oil LE; fish oil LE versus another fish oil LE; alternative-LE versus S-LE; alternative-LE versus another alternative-LE in preterm infants less than 37 weeks' gestation, preterm infants with surgical conditions and preterm infants with PNALD/cholestasis. Separate subgroup comparisons of each LE preparation were included within these broader groups.Most studies in preterm infants used PN for mean duration of four weeks or less and for longer duration in infants with cholestasis or surgical conditions.We defined the primary outcome of PNALD/cholestasis as conjugated bilirubin (Cbil) 2 mg/dL or greater and resolution of PNALD/cholestasis as Cbil less than 2 mg/dL. There was heterogeneity in definitions used by the included studies with Cbil cut-offs ranging from 17.1 µmol/L (1 mg/dL) up to 50 µmol/L (about 3 mg/dL).In preterm infants, meta-analysis found no evidence of a difference in the incidence of PNALD/cholestasis (Cbil cut-off: 2 mg/dl) between fish oil-LEs and all non-fish oil LEs (typical risk ratio (RR) 0.61, 95% confidence interval (CI) 0.24 to 1.56; typical risk difference (RD) -0.03, 95% CI -0.08 to 0.02; 4 studies; n = 328; low-quality evidence).We also considered an outcome allowing for any definition of PNALD (different Cbil cutoffs). In the meta-analysis for PNALD/cholestasis, using any definition and restricted to low or unclear risk of bias studies, there was no evidence of a difference between fish oil LE and all non-fish oil LE for incidence of cholestasis (typical RR 0.80, 95% CI 0.53 to 1.21; typical RD -0.02, 95% CI -0.05 to 0.02; 10 studies; n = 1024; low-quality evidence). There was no evidence of difference in subgroup meta-analyses of individual LE types in any comparison.In preterm infants with surgical conditions or cholestasis, there was only one small study each reporting no evidence of a difference in incidence or resolution of cholestasis respectively with use of a pure F-LE versus S-LE (using a Cbil cut-off of 2 mg/dL).In preterm infants with PNALD/cholestasis (using any definition), the meta-analysis showed significantly less cholestasis with the use of fish oil-LE compared to S-LE (typical RR 0.54, 95% CI 0.32 to 0.91; typical RD -0.39, 95% CI -0.65 to -0.12; number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 2 to 9; 2 studies; n = 40; very low-quality evidence). However, this outcome had a very low number of participants from two small studies with methodological differences, one of which was terminated early, increasing the uncertainty about effect estimates.There were no differences between LE types in pair-wise meta-analyses for growth in preterm infants. There was paucity of studies in preterm infants with surgical conditions or cholestasis to perform meta-analyses for growth and most other outcomes.In the secondary outcomes for preterm infants, there was no difference between fish-oil LE and non-fish oil LE in meta-analysis for severe retinopathy of prematurity (ROP) (stage 3 or greater, or requiring surgery: typical RR 0.80, 95% CI 0.55 to 1.16; typical RD -0.03, 95% CI -0.07 to 0.02; 7 studies; n = 731; very low-quality evidence). There were no differences in the LE types in pair-wise meta-analyses for death, bronchopulmonary dysplasia (BPD), ventilation duration, patent ductus arteriosus, sepsis, necrotising enterocolitis, intraventricular haemorrhage, periventricular leukomalacia, jaundice, hyperglycaemia, hypertriglyceridaemia, intrahepatocellular lipid content and conjugated bilirubin levels in any comparison.In surgical infants, one study (n = 19) reported no differences in death, sepsis rates, Cbil and neurodevelopmental outcomes with pure F-LE versus S-LE.In infants with cholestasis, there were no evidence of differences in death or sepsis in meta-analyses between fish oil-LE and S-LE; (2 studies; n = 40; very low-quality evidence). AUTHORS' CONCLUSIONS: In the current review, we did not find any particular LE with or without fish oil to be better than another LE in preterm infants for prevention of PNALD/cholestasis, growth, mortality, ROP, BPD and other neonatal outcomes.In preterm infants with surgical conditions or cholestasis, there is currently insufficient evidence from randomised studies to determine with any certainty if fish oil LEs offer advantage in prevention or resolution of cholestasis or in any other clinical outcome.Further research, with larger well-designed trials, is warranted to evaluate the ideal composition of LE in preterm infants and the role of fish oil-containing and other LEs in the prevention and resolution of PNALD, ROP and other clinical outcomes.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Colestase/prevenção & controle , Óleos de Peixe/administração & dosagem , Recém-Nascido Prematuro , Nutrição Parenteral , Óleos Vegetais/administração & dosagem , Óleo de Soja/administração & dosagem , Ácido gama-Linolênico/administração & dosagem , Bilirrubina/sangue , Displasia Broncopulmonar/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Colestase/induzido quimicamente , Emulsões/administração & dosagem , Emulsões/química , Humanos , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Nutrição Parenteral/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Retinopatia da Prematuridade/prevenção & controle , Óleo de Soja/efeitos adversos , Procedimentos Cirúrgicos Operatórios
4.
Cochrane Database Syst Rev ; 6: CD013171, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31158920

RESUMO

BACKGROUND: Lipid emulsions (LE) form a vital component of infant nutrition for critically ill, late preterm or term infants, particularly for those with gastrointestinal failure. Conventionally used soybean oil-based LE (S-LE) have high polyunsaturated fatty acid (PUFA) content and phytosterols, which may contribute to adverse effects including parenteral nutrition-associated liver disease (PNALD). OBJECTIVES: To compare the safety and efficacy of all LE for parenteral nutrition (PN) in term and late preterm infants (between 34 weeks' gestation and 36 weeks' and six days' gestation) with or without surgical conditions or PNALD within first six months of life, using all possible direct comparisons. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE (1946 to 18 June 2018), Embase (1974 to 18 June 2018), CINAHL (1982 to 18 June 2018), MIDRIS (1971 to 31 May 2018), conference proceedings, trial registries (ClinicalTrials.gov and the WHO's Trials Registry), and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled studies in term and late preterm infants, with or without surgical conditions or PNALD. DATA COLLECTION AND ANALYSIS: Data collection and analysis conformed to the methods of Cochrane Neonatal. We used the GRADE approach to assess the quality of evidence for important outcomes in addition to reporting the conventional statistical significance of results. MAIN RESULTS: The review included nine randomised studies (n = 273). LE were classified in three broad groups: 1. all fish oil-containing LE including pure fish oil (F-LE) and multisource LE (e.g. medium-chain triglycerides (MCT)-olive-fish-soybean oil-LE (MOFS-LE), MCT-fish-soy oil-LE (MFS-LE) and olive-fish-soy-LE (OFS-LE)); 2. conventional pure S-LE; 3. alternative-LE (e.g. MCT-soy-LE (MS-LE), olive-soy-LE (OS-LE) and borage oil-based LE).We considered four broad comparisons: 1. all fish oil LE versus non-fish oil LE (6 studies; n = 182); 2. fish oil LE versus another fish oil LE (0 studies); 3. alternative-LE versus S-LE (3 studies; n = 91); 4. alternative-LE versus another alternative-LE (0 studies) in term and late preterm infants (0 studies), term and late preterm infants with surgical conditions (7 studies; n = 233) and term and late preterm infants with PNALD/cholestasis (2 studies; n = 40).PNALD/cholestasis was defined as conjugated bilirubin (Cbil) 2 mg/dL or greater and resolution of PNALD/cholestasis as Cbil less than 2 mg/dL. We put no restriction on timing of PNALD detection. There was heterogeneity in definitions and time points for detecting PNALD in the included studies.We found one study each in surgical infants and in infants with cholestasis, showing no evidence of difference in incidence or resolution of PNALD/cholestasis (Cbil cut-off: 2 mg/dL) with use of fish oil-containing LE compared to S-LE.We considered an outcome allowing for any definition of PNALD (different Cbil cut-off levels). In infants with surgical conditions and no pre-existing PNALD, meta-analysis showed no difference in the incidence of PNALD/cholestasis (any definition) with use of fish oil-containing LE compared to S-LE (typical risk ratio (RR) 1.20, 95% confidence interval (CI) 0.38 to 3.76; typical risk difference (RD) 0.03, 95% CI -0.14 to 0.20; 2 studies; n = 68; low-quality evidence). In infants with PNALD/cholestasis (any definition), use of fish oil-LEs was associated with significantly less cholestasis compared to the S-LE group (typical risk ratio (RR) 0.54, 95% confidence interval (CI) 0.32 to 0.91; typical risk difference (RD) -0.39, 95% CI -0.65 to -0.12; number needed to treat for additional beneficial outcome (NNTB) 3, 95% CI 2 to 9; 2 studies; n = 40; very low-quality evidence). This outcome had very low number of participants from two small studies with differences in study methodology and early termination in one study, which increased uncertainty about the effect estimates.One study in infants with cholestasis reported significantly better weight gain with a pure fish oil LE compared to a 10% S-LE (45 g/week, 95% CI 15.0 to 75.0; n = 16; very low-quality evidence). There were no significant differences in growth parameters in studies with surgical populations.For the secondary outcomes, in infants with cholestasis, one study (n = 24) reported significantly lower conjugated bilirubin levels but higher gamma glutamyl transferase levels with MOFS-LE (SMOFlipid) versus S-LE (Intralipid) and another study (n = 16), which was terminated early, reported significantly higher rates of rise in alanine aminotransferase (ALT) and conjugated bilirubin levels in the S-LE group compared to pure F-LE (Omegaven).In surgical infants, two studies each reported on hypertriglyceridaemia and Cbil levels with one study in each outcome showing significant benefit with use of a F-LE and the other study showing no difference between the groups. Meta-analysis was not performed for either of these outcomes as there were only two studies showing conflicting results with high heterogeneity between the studies.There was no evidence of differences in death, sepsis, alkaline phosphatase and ALT levels in infants with surgical conditions or cholestasis (very low-quality evidence).One study reported neurodevelopmental outcomes at six and 24 months in infants with surgical conditions (n = 11) with no evidence of difference with use of pure F-LE versus S-LE. Another study in infants with cholestasis (n = 16) reported no difference in head growth velocity between pure F-LE versus S-LE.GRADE quality of evidence ranged from low to very low as the included studies were small single-centre studies. Three of the six studies that contributed data to the review were terminated early for various reasons. AUTHORS' CONCLUSIONS: Based on the current review, there is insufficient data from randomised studies to determine with any certainty, the potential benefit of any LE including fish oil-containing LEs over another LE, for prevention or resolution of PNALD/cholestasis or any other outcomes in term and late preterm infants with underlying surgical conditions or cholestasis. There were no studies in infants without surgical conditions or cholestasis.Further research is required to establish role of fish oil or lipids from other sources in LEs to improve PNALD/cholestasis, and other clinical outcomes in parenterally fed term and late preterm infants.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Colestase/prevenção & controle , Óleos de Peixe/administração & dosagem , Recém-Nascido Prematuro , Nutrição Parenteral , Óleo de Soja/efeitos adversos , Bilirrubina/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Colestase/induzido quimicamente , Colestase/diagnóstico , Emulsões/efeitos adversos , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Azeite de Oliva/administração & dosagem , Nutrição Parenteral/efeitos adversos , Fosfolipídeos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Óleo de Soja/administração & dosagem , Óleo de Soja/química , Procedimentos Cirúrgicos Operatórios , Nascimento a Termo
5.
Food Funct ; 10(7): 3839-3850, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31210195

RESUMO

Cholestatic liver injury induced by estrogen is a common clinical syndrome in women undergoing oral administration of contraceptives, pregnancy or hormone replacement therapy. Estrogen-induced cholestasis is associated with the accumulation of endogenous bile acids, which play critical roles in the disease progression and symptoms. In the present study, we described the protective effect of auraptene, a simple coumarin present in the peels of citrus fruits, such as grapefruit, against 17α-ethinylestradiol (EE)-induced cholestasis, and further elucidated the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect. Auraptene treatment alleviated EE-induced cholestasis through increasing the bile flow and biliary bile acid output. The mechanism underlying the alleviated cholestasis by auraptene was associated with the increased efflux and inhibited hepatic uptake of bile acids via an induction of efflux transporters (Bsep and Mrp2) and downregulation of Ntcp. Furthermore, auraptene reduced the bile acid synthesis through repressing Cyp7a1 and Cyp8b1, and increased the bile acid metabolism through an induction in the gene expression of Sult2a1. The mentioned genes involved in the bile acid homeostasis were modulated by FXR. We further demonstrated that the changes in transporters and enzymes, as well as ameliorated liver histology by auraptene, were abrogated by the FXR antagonist guggulsterone. In conclusion, auraptene alleviated EE-induced cholestasis due to FXR-mediated gene regulation.


Assuntos
Colestase/tratamento farmacológico , Colestase/prevenção & controle , Citrus/química , Cumarínicos/farmacologia , Extratos Vegetais/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Doença Hepática Induzida por Substâncias e Drogas , Colestase/induzido quimicamente , Colesterol 7-alfa-Hidroxilase , Fígado/lesões , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Esteroide 12-alfa-Hidroxilase/metabolismo , Sulfotransferases/metabolismo , Simportadores/metabolismo
6.
BMC Gastroenterol ; 19(1): 40, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30866837

RESUMO

BACKGROUND: The major concern in liver transplantation of grafts from donation after circulatory death (DCD) donors remains the high incidence of non-anastomotic biliary strictures (NAS). Machine perfusion has been proposed as an alternative strategy for organ preservation which reduces ischemia-reperfusion injury (IRI). Experimental studies have shown that dual hypothermic oxygenated machine perfusion (DHOPE) is associated with less IRI, improved hepatocellular function, and better preserved mitochondrial and endothelial function compared to conventional static cold storage (SCS). Moreover, DHOPE was safely applied with promising results in a recently performed phase-1 study. The aim of the current study is to determine the efficacy of DHOPE in reducing the incidence of NAS after DCD liver transplantation. METHODS: This is an international multicenter randomized controlled trial. Adult patients (≥18 yrs. old) undergoing transplantation of a DCD donor liver (Maastricht category III) will be randomized between the intervention and control group. In the intervention group, livers will be subjected to two hours of end-ischemic DHOPE after SCS and before implantation. In the control group, livers will be subjected to care as usual with conventional SCS only. Primary outcome is the incidence of symptomatic NAS diagnosed by a blinded adjudication committee. In all patients, magnetic resonance cholangiography will be obtained at six months after transplantation. DISCUSSION: DHOPE is associated with reduced IRI of the bile ducts. Whether reduced IRI of the bile ducts leads to lower incidence of NAS after DCD liver transplantation can only be examined in a randomized controlled trial. TRIAL REGISTRATION: The trial was registered in Clinicaltrials.gov in September 2015 with the identifier NCT02584283 .


Assuntos
Colestase/prevenção & controle , Hipotermia Induzida/métodos , Transplante de Fígado/efeitos adversos , Preservação de Órgãos/métodos , Perfusão/métodos , Traumatismo por Reperfusão/prevenção & controle , Adulto , Método Duplo-Cego , Humanos , Complicações Pós-Operatórias , Doadores de Tecidos , Obtenção de Tecidos e Órgãos/métodos
7.
Neonatal Netw ; 38(1): 39-45, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30679255

RESUMO

Parenteral nutrition (PN) is frequently required by extremely preterm infants due to gastrointestinal immaturity and complications of prematurity. Parenteral nutrition-associated cholestasis (PNAC) and intestinal failure-associated liver disease (IFALD) are common complications of prolonged PN. Plant-based intravenous lipid emulsions, containing proinflammatory omega-6 fatty acids and phytosterols, may contribute to these conditions as well as other comorbidities such as bronchopulmonary dysplasia and retinopathy of prematurity. Intravenous lipid emulsions containing animal-based fats, such as fish oil, contain fewer proinflammatory omega-6 fatty acids and more anti-inflammatory omega-3 fatty acids and antioxidants. SMOFlipid, recently Food and Drug Administration (FDA)-approved for adult use, is a blend of plant- and animal-based lipid emulsions with a favorable omega-6:omega-3 ratio that may prevent the development and progression of PNAC/IFALD in infants. Careful review of data supporting this alternative intravenous lipid emulsion is required prior to widespread use in neonatal intensive care.


Assuntos
Colestase , Emulsões Gordurosas Intravenosas , Doenças do Prematuro/terapia , Nutrição Parenteral , Colestase/diagnóstico , Colestase/etiologia , Colestase/prevenção & controle , Emulsões Gordurosas Intravenosas/administração & dosagem , Emulsões Gordurosas Intravenosas/efeitos adversos , Emulsões Gordurosas Intravenosas/farmacologia , Humanos , Lactente , Lactente Extremamente Prematuro , Recém-Nascido de Baixo Peso/crescimento & desenvolvimento , Recém-Nascido de Baixo Peso/fisiologia , Recém-Nascido , Enfermagem Neonatal/educação , Nutrição Parenteral/efeitos adversos , Nutrição Parenteral/métodos , Planejamento de Assistência ao Paciente/normas
8.
Clin Sci (Lond) ; 133(1): 117-134, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30538149

RESUMO

We previously demonstrated in in vitro and ex vivo models that physiological concentrations of unconjugated bilirubin (BR) prevent oxidative stress (OS)-induced hepatocanalicular dysfunction and cholestasis. Here, we aimed to ascertain, in the whole rat, whether a similar cholestatic OS injury can be counteracted by heme oxygenase-1 (HO-1) induction that consequently elevates endogenous BR levels. This was achieved through the administration of hemin, an inducer of HO-1, the rate-limiting step in BR generation. We found that BR peaked between 6 and 8 h after hemin administration. During this time period, HO-1 induction fully prevented the pro-oxidant tert-butylhydroperoxide (tBuOOH)-induced drop in bile flow, and in the biliary excretion of bile salts and glutathione, the two main driving forces of bile flow; this was associated with preservation of the membrane localization of their respective canalicular transporters, bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2), which are otherwise endocytosed by OS. HO-1 induction counteracted the oxidation of intracellular proteins and membrane lipids induced by tBuOOH, and fully prevented the increase in the oxidized-to-total glutathione (GSHt) ratio, a sensitive parameter of hepatocellular OS. Compensatory elevations of the activity of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) were also prevented. We conclude that in vivo HO-1 induction protects the liver from acute oxidative injury, thus preventing consequent cholestasis. This reveals an important role for the induction of HO-1 and the consequently elevated levels of BR in preserving biliary secretory function under OS conditions, thus representing a novel therapeutic tool to limit the cholestatic injury that bears an oxidative background.


Assuntos
Antioxidantes/farmacologia , Colestase/prevenção & controle , Heme Oxigenase (Desciclizante)/biossíntese , Hemina/farmacologia , Fígado/efeitos dos fármacos , Estresse Oxidativo , Animais , Bile/metabolismo , Bilirrubina/metabolismo , Catalase/metabolismo , Colestase/induzido quimicamente , Colestase/enzimologia , Colestase/patologia , Modelos Animais de Doenças , Indução Enzimática , Glutationa/metabolismo , Fígado/enzimologia , Fígado/patologia , Masculino , Ratos Wistar , Superóxido Dismutase/metabolismo , terc-Butil Hidroperóxido
10.
Molecules ; 23(9)2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30205454

RESUMO

The objective of this study was to evaluate the hepatoprotective and metabolic effects of rosmarinic acid (RA) in rats. RA [100 mg/kg body weight (BW)] was intragastrically (i.g.) administered to Sprague-Dawley (SD) rats once a day for seven consecutive days. The rats were then i.g. administered α-naphthylisothiocyanate (ANIT) (80 mg/kg once on the 5th day) to induce acute intrahepatic cholestasis after the last administration of RA. Blood samples were collected at different time points (0.083 h, 0.17 h, 0.33 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 20 h) after administration, and the levels of RA were estimated by HPLC. Plasma and bile biochemical analysis, bile flow rate, and liver histopathology were measured to evaluate the hepatoprotective effect of RA. The PK-PD curves showed obviously clockwise (AST and ALT) or anticlockwise (TBA, TBIL). Pretreatment with RA at different doses significantly restrained ANIT-induced pathological changes in bile rate, TBA, TBIL, ALT, AST (p < 0.05 or p < 0.01). The relationship between RA concentration and its hepatoprotective effects on acute cholestasis responses was assessed by PK-PD modeling.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Colestase/prevenção & controle , Cinamatos/farmacologia , Cinamatos/farmacocinética , Depsídeos/farmacologia , Depsídeos/farmacocinética , 1-Naftilisotiocianato/toxicidade , Doença Aguda , Animais , Bile/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colestase/sangue , Colestase/metabolismo , Colestase/patologia , Cromatografia Líquida de Alta Pressão , Cinamatos/sangue , Depsídeos/sangue , Limite de Detecção , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Modelos Biológicos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrofotometria Ultravioleta
11.
J Hepatol ; 69(6): 1326-1334, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30144553

RESUMO

BACKGROUND & AIMS: Caspase 8 (CASP8) is the apical initiator caspase in death receptor-mediated apoptosis. Strong evidence for a link between death receptor signaling pathways and cholestasis has recently emerged. Herein, we investigated the role of CASP8-dependent and independent pathways during experimental cholestasis. METHODS: Liver injury was characterized in a cohort of human sera (n = 28) and biopsies from patients with stage IV primary biliary cholangitis. In parallel, mice with either specific deletion of Casp8 in liver parenchymal cells (Casp8Δhepa) or hepatocytes (Casp8Δhep), and mice with constitutive Ripk3 (Ripk3-/-) deletion, were subjected to surgical ligation of the common bile duct (BDL) from 2 to 28 days. Floxed (Casp8fl/fl) and Ripk3+/+ mice were used as controls. Moreover, the pan-caspase inhibitor IDN-7314 was used, and cell death mechanisms were studied in primary isolated hepatocytes. RESULTS: Overexpression of activated caspase 3, CASP8 and RIPK3 was characteristic of liver explants from patients with primary biliary cholangitis. Twenty-eight days after BDL, Casp8Δhepamice showed decreased necrotic foci, serum aminotransferase levels and apoptosis along with diminished compensatory proliferation and ductular reaction. These results correlated with a decreased inflammatory profile and ameliorated liver fibrogenesis. A similar phenotype was observed in Ripk3-/- mice. IDN-7314 treatment decreased CASP8 levels but failed to prevent BDL-induced cholestasis, independently of CASP8 in hepatocytes. CONCLUSION: These findings show that intervention against CASP8 in liver parenchymal cells - specifically in cholangiocytes - might be a beneficial option for treating obstructive cholestasis, while broad pan-caspase inhibition might trigger undesirable side effects. LAY SUMMARY: Loss of caspase 8 - a protein involved in programmed cell death - in liver parenchymal cells protects against experimental cholestasis. Therefore, specific pharmacological intervention against caspase 8 might be a valid alternative for the treatment of obstructive cholestasis in the clinic, whereas broad pan-caspase inhibiting drugs might trigger undesirable side effects.


Assuntos
Caspase 8/metabolismo , Colestase/patologia , Hepatócitos/metabolismo , Cirrose Hepática Biliar/patologia , Fígado/patologia , Adulto , Animais , Apoptose/efeitos dos fármacos , Biópsia , Caspase 3/metabolismo , Caspase 8/genética , Inibidores de Caspase/farmacologia , Colestase/prevenção & controle , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Fibrose/prevenção & controle , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Necrose , Tecido Parenquimatoso/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
12.
Acta Pharmacol Sin ; 39(12): 1865-1873, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30061734

RESUMO

Cholestasis is a common feature of liver injury, which manifests as bile acid excretion and/or enterohepatic circulation disorders. However, very few effective therapies exist for cholestasis. Recently, 18ß-Glycyrrhetinic acid (18b-GA), a major metabolic component of glycyrrhizin, which is the main ingredient of licorice, was reported to protect against alpha-naphthylisothiocyanate (ANIT)-induced cholestasis. However, its protective mechanism remains unclear. We hypothesized that 18b-GA may stimulate the signaling pathway of bile acid (BA) transportation in hepatocytes, resulting its hepatoprotective effect. According to the results, 18b-GA markedly attenuated ANIT-induced liver injury as indicated the hepatic plasma chemistry index and histopathology examination. In addition, the expression levels of nuclear factors, including Sirt1, FXR and Nrf2, and their target efflux transporters in the liver, which mainly mediate bile acid homeostasis in hepatocytes, significantly increased. Furthermore, we first revealed that 18b-GA treatment significantly activated FXR, and which can be significantly reduced by EX-527 (a potent and selective Sirt1 inhibitor), indicating that 18b-GA activates FXR through Sirt1. Taken together, 18b-GA confers hepatoprotection against ANIT-induced cholestasis by activating FXR through Sirt1, which promotes gene expression of the efflux transporter, and consequently attenuates dysregulation of bile acid homeostasis in hepatocyte compartments.


Assuntos
Colestase/prevenção & controle , Ácido Glicirretínico/análogos & derivados , Substâncias Protetoras/uso terapêutico , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , 1-Naftilisotiocianato , Animais , Colestase/induzido quimicamente , Ácido Glicirretínico/uso terapêutico , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Ratos Sprague-Dawley
14.
Liver Transpl ; 24(6): 820-830, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29637720

RESUMO

In adults, cirrhotic cardiomyopathy (CCM) has a significant incidence and impact on liver transplantation. For pediatric liver transplantation (pLT), data on liver-induced cardiac changes are scarce, and in particular, the comparison between cirrhotic and noncirrhotic liver disease has not been investigated. We retrospectively evaluated cardiac changes associated with CCM by echocardiography and 12-lead electrocardiogram in 198 pLT-candidates (median age 4.1 years) 4.2 before and 12 months after pLT. Results were correlated with the stage of liver fibrosis and cholestasis before transplantation. The left ventricular end-diastolic diameter (LVIDd) z score, left ventricular mass z score, and left ventricular mass index were significantly higher in cirrhotic patients (-0.10 versus 0.98, P < 0.001; -1.55 versus -0.42, P = 0.001; 78.99 versus 125.64 g/m2 , P = 0.001, respectively) compared with children with noncirrhotic liver disease. Pathological z scores (>2SDS) for the LVIDd occurred more frequently in cirrhotic patients compared with patients with noncirrhotic liver disease (31/169 versus 1/29; P = 0.03) and were significantly associated with cholestasis. All observed cardiac changes were reversible 1 year after pLT. Pathological LVIDd z scores correlated highly with intensive care unit (ICU) stay (9.6 days versus 17.1 days, respectively, P = 0.002) but not with patient survival pre-LT or post-LT. In contrast to other studies, prolonged QTc time was not associated with liver cirrhosis in our patients. In conclusion, CCM-associated cardiac changes in pLT candidates with cirrhotic liver disease are frequent, mild, and associated with cholestasis and reversible after pLT. They may impact peritransplant care and posttransplant hospitalization time. Further prospective evaluation is warranted. In particular, for QTc time prolongation etiological factors, possible protective effects of ursodeoxycholic acid treatment and the use as a screening parameter for CCM should be verified. Liver Transplantation 24 820-830 2018 AASLD.


Assuntos
Cardiomiopatias/epidemiologia , Colestase/complicações , Doença Hepática Terminal/cirurgia , Cirrose Hepática/cirurgia , Transplante de Fígado , Adolescente , Cardiomiopatias/diagnóstico , Cardiomiopatias/etiologia , Criança , Pré-Escolar , Colagogos e Coleréticos/uso terapêutico , Colestase/epidemiologia , Colestase/prevenção & controle , Ecocardiografia , Eletrocardiografia , Doença Hepática Terminal/complicações , Doença Hepática Terminal/mortalidade , Feminino , Humanos , Incidência , Lactente , Tempo de Internação/estatística & dados numéricos , Cirrose Hepática/complicações , Cirrose Hepática/mortalidade , Masculino , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Ácido Ursodesoxicólico/uso terapêutico
15.
Int J Mol Sci ; 19(4)2018 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-29642532

RESUMO

The in vivo relevance of ursodeoxycholate (UDCA) treatment (100 mg/kg/day, per oral tid for 5 days before cholestasis induction followed by the same dosing for 5 days) on hepatic function was investigated in rats with 17α-ethinylestradiol (EE, 10 mg/kg, subcutaneous for 5 days)-induced experimental cholestasis. The bile flow rate and the expression level of hepatic multidrug resistance-associated protein 2 (Mrp 2) that were decreased in cholestasis were restored after UDCA treatment. Consistent with this, the biliary excretion clearance (CLexc,bile) of a representative Mrp2 substrate-methotrexate (MTX)-was decreased in cholestatic rats but was restored after UDCA treatment. Consequently, the plasma concentrations of MTX, which were increased by cholestasis, were decreased to control levels by UDCA treatment. Thus, the restoration of CLexc,bile appears to be associated with the increase in Mrp2 expression on the canalicular membrane by UDCA treatment followed by Mrp2-mediated biliary excretion of MTX. On the other hand, the hepatic uptake clearance (CLup,liver) of MTX was unchanged by cholestasis or UDCA treatment, suggestive of the absence of any association between the uptake process and the overall biliary excretion of MTX. Since UDCA has been known to induce the expression of canalicular MRP2 in humans, UDCA treatment might be effective in humans to maintain or accelerate the hepatobiliary elimination of xenobiotics or metabolic conjugates that are MRP2 substrates.


Assuntos
Ácidos e Sais Biliares/química , Colestase/prevenção & controle , Etinilestradiol/efeitos adversos , Metotrexato/sangue , Ácido Ursodesoxicólico/administração & dosagem , Transportadores de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Animais , Colestase/sangue , Colestase/induzido quimicamente , Colestase/metabolismo , Regulação para Baixo , Esquema de Medicação , Masculino , Ratos , Resultado do Tratamento , Ácido Ursodesoxicólico/farmacologia
16.
Toxicol Appl Pharmacol ; 348: 105-116, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29660435

RESUMO

Cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Recently obeticholic acid (OCA) which is a farnesoid X receptor (FXR) agonist was approved by FDA to treat cholestatic liver diseases, which provided us a newly therapeutic strategy against cholestasis. The purpose of the current study is to screen novel FXR agonists and verify the anti-cholestasis effect of yangonin in vivo and in vitro. The computational strategy of two-dimensional virtual screening was used to search for new FXR agonists, and dual-luciferase reporter gene assay was used to further demonstrate FXR activation by yangonin. Then, the hepatoprotective effect of yangonin via FXR activation against cholestasis and hepatotoxity was evaluated in mice and was investigated using FXR silence in cells. Yangonin was found to activate FXR to exert hepatoprotective effect against cholestatic liver injury. Dynamic change analysis of bile acids and gene analysis revealed that yangonin promoted bile acid efflux into bile and reduced hepatic uptake via the regulation of FXR-target genes Bsep, Mrp2 and Ntcp expression. Furthermore, yangonin modulated enzymes involved in bile acid synthesis and metabolism including Cyp7a1 Cyp8b1 and Sult2a1. In addition, yangonin promoted liver repair and suppressed liver inflammation. However, the changes in these genes and protein, as well as ameliorative liver histology induced by yangonin were abrogated by FXR antagonist guggulsterone in vivo and FXR siRNA in vitro. Yangonin produces protective effect against cholestasis via FXR activation. Yangonin may be an effective approach for the prevention and treatment for cholestatic liver diseases.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Colestase/prevenção & controle , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Pironas/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Ácidos e Sais Biliares/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colestase/genética , Colestase/metabolismo , Colestase/patologia , Citoproteção/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Ligantes , Fígado/metabolismo , Fígado/patologia , Regeneração Hepática/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Substâncias Protetoras/química , Pironas/química , Interferência de RNA , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
17.
Eur J Pharmacol ; 824: 64-71, 2018 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-29427579

RESUMO

Accumulation of toxic bile acids in liver could cause cholestasis and liver injury. The purpose of the current study is to evaluate the hepatoprotective effect of yangonin, a product isolated from an edible botanical Kava against lithocholic acid (LCA)-induced cholestasis, and further to elucidate the involvement of farnesoid X receptor (FXR) in the anticholestatic effect using in vivo and in vitro experiments. The cholestatic liver injury model was established by intraperitoneal injections of LCA in C57BL/6 mice. Serum biomarkers and H&E staining were used to identify the amelioration of cholestasis after yangonin treatment. Mice hepatocytes culture, gene silencing experiment, real-time PCR and Western blot assay were used to elucidate the mechanisms underlying yangonin hepatoprotection. The results indicated that yangonin promoted bile acid efflux and reduced hepatic uptake via an induction in FXR-target genes Bsep, Mrp2 expression and an inhibition in Ntcp, all of which are responsible for bile acid transport. Furthermore, yangonin reduced bile acid synthesis through repressing FXR-target genes Cyp7a1 and Cyp8b1, and increased bile acid metabolism through an induction in gene expression of Sult2a1, which are involved in bile acid synthesis and metabolism. In addition, yangonin suppressed liver inflammation through repressing inflammation-related gene NF-κB, TNF-α and IL-1ß. In vitro evidences showed that the changes in transporters and enzymes induced by yangonin were abrogated when FXR was silenced. In conclusions, yangonin produces protective effect against LCA-induced hepatotoxity and cholestasis due to FXR-mediated regulation. Yangonin may be an effective approach for the prevention against cholestatic liver diseases.


Assuntos
Colestase/induzido quimicamente , Colestase/prevenção & controle , Kava/química , Ácido Litocólico/toxicidade , Fígado/efeitos dos fármacos , Fígado/patologia , Pironas/farmacologia , Animais , Linhagem Celular , Colestase/metabolismo , Colestase/patologia , Citoproteção/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Homeostase/efeitos dos fármacos , Ácido Litocólico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pironas/isolamento & purificação , Receptores Citoplasmáticos e Nucleares/metabolismo
18.
J Hepatobiliary Pancreat Sci ; 25(3): 195-205, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29360226

RESUMO

BACKGROUND: The purpose of the present study was to investigate the effect and potential mechanism of chlorogenic acid (CA) on liver injury induced by cholestasis in a rat model of bile duct ligation (BDL). METHODS: Rats received vehicle or CA (20, 50, or 100 mg/kg per day) orally for 3 days. On the 4th day, the rats underwent sham or BDL surgery, and were orally administrated vehicle or CA for 3 or 7 days. mRNA and protein expression levels were evaluated by qRT-PCR and western blot. RESULTS: After BDL, plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and total bile acids (TBA) were increased and typical pathological changes were observed in liver morphology. Hepatic uptake transporters (Ntcp, Oatp 1a4, and Oatp 1b2) were downregulated, while efflux transporters (Bsep and Mrp 2/3/4) were upregulated. BDL inhibited the expressions of Cyp7a1, Cyp8b1, and Cyp27a1 and induced Ugt1a1. CA treatment decreased ALT, AST, TBIL, and TBA (P < 0.05) and alleviated the liver pathological changes. The degree of expression changes in the transporters and enzymes was extended by CA (P < 0.05). SIRT1 protein was induced after CA treatment in BDL rats. CONCLUSIONS: Chlorogenic acid attenuated hepatotoxicity and cholestasis by decreasing the uptake and synthesis of bilirubin and bile acids and accelerating the metabolism and efflux of bilirubin and bile acids.


Assuntos
Ácidos e Sais Biliares/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ácido Clorogênico/farmacologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Sirtuína 1/metabolismo , Acetilação , Animais , Ductos Biliares/cirurgia , Biomarcadores/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colestase/prevenção & controle , Modelos Animais de Doenças , Humanos , Ligadura , Fígado/efeitos dos fármacos , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Sensibilidade e Especificidade
19.
Br J Pharmacol ; 175(5): 810-829, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29235094

RESUMO

BACKGROUND AND PURPOSE: The aim of this study was to investigate the ameliorative effects of corilagin on intrahepatic cholestasis induced by regulating liver farnesoid X receptor (FXR)-associated pathways in vitro and in vivo. EXPERIMENTAL APPROACH: Cellular and animal models were treated with different concentrations of corilagin. In the cellular experiments, FXR expression was up-regulated by either lentiviral transduction or GW4064 treatment and down-regulated by either siRNA technology or treatment with guggulsterones. Real-time PCR and Western blotting were employed to detect the mRNA and protein levels of FXR, SHP1, SHP2, UGT2B4, BSEP, CYP7A1, CYP7B1, NTCP, MRP2 and SULT2A1. Immunohistochemistry was used to examine the expression of BSEP in liver tissues. Rat liver function and pathological changes in hepatic tissue were assessed using biochemical tests and haematoxylin and eosin staining. RESULTS: Corilagin increased the mRNA and protein levels of FXR, SHP1, SHP2, UGT2B4, BSEP, MRP2 and SULT2A1, and decreased those of CYP7A1, CYP7B1 and NTCP. After either up- or down-regulating FXR using different methods, corilagin could still increase the mRNA and protein levels of FXR, SHP1, SHP2, UGT2B4, BSEP, MRP2 and SULT2A1 and decrease the protein levels of CYP7A1, CYP7B1 and NTCP, especially when administered at a high concentration. Corilagin also exerted a notable effect on the pathological manifestations of intrahepatic cholestasis, BSEP staining in liver tissues and liver function. CONCLUSIONS AND IMPLICATIONS: Corilagin exerts a protective effect in hepatocytes and can prevent the deleterious activities of intrahepatic cholestasis by stimulating FXR-associated pathways.


Assuntos
Colestase/prevenção & controle , Glucosídeos/farmacologia , Taninos Hidrolisáveis/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Colesterol 7-alfa-Hidroxilase/metabolismo , Família 7 do Citocromo P450/metabolismo , Dexametasona/farmacologia , Regulação para Baixo/efeitos dos fármacos , Glucosídeos/efeitos adversos , Glucuronosiltransferase/metabolismo , Humanos , Taninos Hidrolisáveis/efeitos adversos , Isoxazóis/farmacologia , Fígado/metabolismo , Masculino , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Pregnenodionas/farmacologia , Cultura Primária de Células , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , RNA Interferente Pequeno/farmacologia , Ratos , Receptores Citoplasmáticos e Nucleares/agonistas , Esteroide Hidroxilases/metabolismo , Sulfotransferases/metabolismo , Simportadores/metabolismo , Regulação para Cima/efeitos dos fármacos , Ácido Ursodesoxicólico/farmacologia
20.
J Pediatr ; 194: 87-93.e1, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29269199

RESUMO

OBJECTIVES: To examine whether a mixed lipid emulsion reduces the incidence of parenteral nutrition associated cholestasis (PNAC) in extremely low birth weight (ELBW, <1000 g) infants. STUDY DESIGN: This double-blind randomized trial of 230 ELBW infants (June 2012-October 2015) was performed at a single level IV neonatal intensive care unit. Patients received either a mixed lipid emulsion composed of soybean oil, medium chain triglycerides, olive oil, and fish oil-(intervention) or a soybean oil-based lipid emulsion (control) for parenteral nutrition. The primary outcome measure was PNAC (conjugated bilirubin >1.5 mg/dL [25 µmol/L] at 2 consecutive measurements). The study was powered to detect a reduction of PNAC from 25% to 10%. RESULTS: Reasons for noneligibility of 274 infants screened were refusal to participate (n = 16), death (n = 10), withdrawal of treatment (n = 5), higher order multiples (n = 9), and parents not available for consent (n = 4). Intention to treat analysis was carried out in 223 infants (7 infants excluded after randomization). Parenteral nutrition associated cholestasis was 11 of 110 (10.1%) in the intervention and 18 of 113 (15.9%) in the control group (P = .20). Multivariable analyses showed no statistically significant difference in the intention to treat (aOR 0.428, 95% CI 0.155-1.187; P = .10) or per protocol population (aOR 0.457, 95% CI 0.155-1.347; P = .16). There was no statistically significant effect on any other neonatal morbidity. CONCLUSIONS: The incidence of parenteral nutrition associated cholestasis was not significantly reduced using a mixed lipid emulsion in ELBW infants. TRIAL REGISTRATION: ClinicalTrials.govNCT01585935.


Assuntos
Colestase/prevenção & controle , Óleos de Peixe/uso terapêutico , Azeite de Oliva/uso terapêutico , Nutrição Parenteral/efeitos adversos , Óleo de Soja/uso terapêutico , Triglicerídeos/uso terapêutico , Colestase/etiologia , Método Duplo-Cego , Emulsões , Feminino , Humanos , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino
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