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1.
Gene ; 725: 144167, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31639434

RESUMO

Osteoporosis in advanced cholestatic and end-stage liver disease is related to low bone formation. Previous studies have demonstrated the deleterious consequences of lithocholic acid (LCA) and bilirubin on osteoblastic cells. These effects are partially or completely neutralized by ursodeoxycholic acid (UDCA). We have assessed the differential gene expression of osteoblastic cells under different culture conditions. The experiments were performed in human osteosarcoma cells (Saos-2) cultured with LCA (10 µM), bilirubin (50 µM) or UDCA (10 and 100 µM) at 2 and 24 h. Expression of 87 genes related to bone metabolism and other signalling pathways were assessed by TaqMan micro fluidic cards. Several genes were up-regulated by LCA, most of them pro-apoptotic (BAX, BCL10, BCL2L13, BCL2L14), but also MGP (matrix Gla protein), BGLAP (osteocalcin), SPP1 (osteopontin) and CYP24A1, and down-regulated bone morphogenic protein genes (BMP3 and BMP4) and DKK1 (Dickkopf-related protein 1). Parallel effects were observed with bilirubin, which up-regulated apoptotic genes and CSF2 (colony-stimulating factor 2) and down-regulated antiapoptotic genes (BCL2 and BCL2L1), BMP3, BMP4 and RUNX2. UDCA 100 µM had specific consequences since differential expression was observed, up-regulating BMP2, BMP4, BMP7, CALCR (calcitonin receptor), SPOCK3 (osteonectin), BGLAP (osteocalcin) and SPP1 (osteopontin), and down-regulating pro-apoptotic genes. Furthermore, most of the differential expression changes induced by both LCA and bilirubin were partially or completely neutralized by UDCA. Conclusion: Our observations reveal novel target genes, whose regulation by retained substances of cholestasis may provide additional insights into the pathogenesis of osteoporosis in cholestatic and end-stage liver diseases.


Assuntos
Bilirrubina/metabolismo , Osteoblastos/metabolismo , Osteoporose/genética , Apoptose/efeitos dos fármacos , Ácidos e Sais Biliares/metabolismo , Linhagem Celular Tumoral , Colestase/genética , Regulação para Baixo/efeitos dos fármacos , Perfil Genético , Humanos , Ácido Litocólico/farmacologia , Fígado/metabolismo , Fígado/fisiologia , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Osteoporose/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Regulação para Cima/efeitos dos fármacos , Ácido Ursodesoxicólico/farmacologia
2.
Medicine (Baltimore) ; 98(50): e18366, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852142

RESUMO

We aimed to compare the impact on survival among albumin-bilirubin (ALBI) grade, modified ALBI (mALBI) and our proposed combined ALBI grade and Mac-2 binding protein glycosylation isomer (M2BPGi) or FIB4 index grading system in chronic hepatitis C (CHC) related compensated liver cirrhosis (n = 165, 93 men and 72 women, median age = 67 years). Patients with ALBI grade 1, 2, and 3 were allocated a score of 1, 2, and 3 points, respectively. Patients with mALBI grade 1, 2A, and 2B were allocated a score of 1, 2, and 3 points, respectively. Patients with a high or low M2BPGi were allocated a score of 1 and 0 point. Patients with a high or low FIB4 index were allocated a score of 1 and 0 point. Sum of the point of ALBI (1, 2, or 3) and M2BPGi (0 or 1) or FIB4 index (0 or 1) was defined as ALBI-M2BPGi grade or ALBI-FIB4 grade. Prognostic accuracy was compared using the Akaike information criterion (AIC) value and time dependent receiver operating characteristics (ROC) curve analysis. The median follow-up duration was 5.422 years. AIC value for survival by ALBI-M2BPGi grade was the lowest among 4 prognostic models (AIC: 205.731 in ALBI grade, 200.913 in mALBI grade, 189.816 in ALBI-M2BPGi grade, and 204.671 in ALBI-FIB4 grade). All area under the ROC curves of ALBI-M2BPGi grade in each time point were higher than those of ALBI grade, mALBI grade, and ALBI-FIB4 grade. In conclusion, our proposed ALBI-M2BPGi grading system seems to be helpful for estimating prognosis in patients with CHC related compensated LC.


Assuntos
Bilirrubina/genética , Cirrose Hepática/genética , Albumina Sérica Humana/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/sangue , Antígenos de Neoplasias/genética , Bilirrubina/sangue , Bilirrubina/metabolismo , Feminino , Marcadores Genéticos , Humanos , Cirrose Hepática/mortalidade , Masculino , Glicoproteínas de Membrana/sangue , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Estudos Retrospectivos , Albumina Sérica Humana/metabolismo
3.
Pan Afr Med J ; 33: 262, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692740

RESUMO

Hyperbilirubinemia is one of the most widely seen cause of neonatal morbidity. Besides ABO and Rh isoimmunization, minor blood incompatibilities have been also been identified as the other causes of severe newborn jaundice. We report a newborn with indirect hyperbilirubinemia caused by minor blood group incompatibilities (P1, M, N, s and Duffy) whose hemolysis was successfully managed with intravenous immunoglobulin therapy. A thirty-two gestational weeks of preterm male baby became severely icteric on postnatal day 11, with a total bilirubin level of 14.66 mg/dl. Antibody screening tests revealed incompatibility on different minor groups (P1, M, N, s and Duffy (Fya ve Fyb)). On postnatal day thirteen, the level of bilirubin increased to 20.66 mg/dl although baby was under intensive phototherapy. After the administration of intravenous immunoglobulin and red blood cell transfusion, hemoglobin and total bilirubin levels became stabilised. Minor blood incompatibilities should be kept in mind during differential diagnosis of hemolytic anemia of the newborn. They share the same treatment algorithm with the other types hemolytic anemia. New studies revealed that intravenous immunoglobulin treatment in hemolytic anemia have some attractive and glamorous results. It should be seriously taken into consideration for treatment of minor blood incompatibilities.


Assuntos
Anemia Hemolítica/etiologia , Bilirrubina/metabolismo , Hiperbilirrubinemia/etiologia , Imunoglobulinas Intravenosas/administração & dosagem , Anemia Hemolítica/diagnóstico , Incompatibilidade de Grupos Sanguíneos/complicações , Diagnóstico Diferencial , Transfusão de Eritrócitos/métodos , Hemoglobinas/metabolismo , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Icterícia Neonatal/etiologia , Masculino
4.
J Surg Oncol ; 120(7): 1126-1136, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31578753

RESUMO

BACKGROUND AND OBJECTIVES: Albumin-bilirubin (ALBI) score was shown to correlate with liver function and tumor recurrence after hepatectomy for hepatocellular carcinoma (HCC). The aim of this study was to assess the prognostic value of ALBI grade in liver transplantation (LT) patients with HCC. METHODS: Pre-LT available independent predictors of recurrence-free survival (RFS) and microvascular tumor invasion (MVI) were determined in 123 patients with HCC. RESULTS: Posttransplant HCC recurrence rates were 10.5%, 15.9%, and 68.2% in ALBI grade 1, 2, and 3, respectively (P < .001). Along with serum α-fetoprotein (AFP) and C-reactive protein (CRP) levels, ALBI grades 1 or 2 was identified as an independent predictor of RFS (hazard ratio, 3.52; 95% confidence interval [CI], 1.577-7.842; P = .002). Furthermore, ALBI grade 3 proved to be the strongest indicator of MVI (odds ratio, 11.59; 95% CI, 3.412-39.381; P < .001). A novel oncological risk score-based on AFP, CRP, and ALBI grade provided the best discriminative capacity (c-statistic 0.806) in selecting liver recipients with low oncological risk profile. CONCLUSION: Preoperative ALBI grade seems to be valuable for refinement of oncological risk stratification at LT for HCC.


Assuntos
Bilirrubina/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Transplante de Fígado/mortalidade , Recidiva Local de Neoplasia/patologia , Medição de Risco/métodos , Albumina Sérica/metabolismo , Adulto , Idoso , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/cirurgia , Tomada de Decisão Clínica , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Cuidados Pré-Operatórios , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida
5.
Clin Nucl Med ; 44(11): 855-859, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31490312

RESUMO

PURPOSE OF THE REPORT: Oxidative stress is a leading factor in the pathogenesis of idiopathic Parkinson disease (IPD). Two intrinsic antioxidative molecules, bilirubin and uric acid, are known to protect dopaminergic neurons from oxidative stress in IPD. The objective of this study was to determine the relationship between basal serum levels of 2 molecules and dopaminergic deficit assessed by dopamine transporter imaging with F-fluorinated-N-3-fluoropropyl-2-ß-carboxymethoxy-3-ß-(4-iodophenyl)nortropane ([F]FP-CIT) PET/CT in patients with early-stage drug-naive IPD. METHODS: Cases of IPD patients who possess the levels of uric acid and bilirubin within a month from [F]FP-CIT PET/CT from January 2011 to December 2016 were retrospectively reviewed. As a control, the same criteria applied to patients with essential tremor (ET). PET images were analyzed using volume-of-interest templates for 12 striatal subregions and 1 occipital area, and the specific-to-nonspecific binding ratio (SNBR) was calculated. RESULTS: One hundred five patients with drug-naive, early-stage IPD and 62 patients with ET were finally included. Levels of bilirubin were significantly higher in the IPD group than in controls (P = 0.026), and bilirubin level was the factor showing the most correlations with SNBR in IPD (P < 0.001), whereas uric acid showed no such difference or relationship. Furthermore, levels of bilirubin showed a positive correlation with SNBR in more affected posterior putamen in the IPD group (Pearson correlation coefficient, ρ = 0.456; P < 0.001), but a negative one in the ET group (ρ = -0.440, P < 0.001). CONCLUSIONS: Bilirubin, not uric acid, was the most significant antioxidant marker for dopaminergic deficit in early-stage drug-naive IPD assessed by [F]FP-CIT PET/CT.


Assuntos
Bilirrubina/metabolismo , Neostriado/metabolismo , Doença de Parkinson/metabolismo , Tropanos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neostriado/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Adulto Jovem
6.
Biomed Res Int ; 2019: 6272174, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467903

RESUMO

Objective: The spectrum of UDP-glucuronyl transferase A1 (UGT1A1) variants in hereditary unconjugated hyperbilirubinemia varies markedly between different ethnic populations. This study evaluated the UGT1A1 genotypes in hyperbilirubinemia patients from southeastern China. Methods: We enrolled 60 patients from southeastern China (44 men and 16 women; age range: 3-76 years) with unconjugated hyperbilirubinemia and performed genetic analysis of the UGT1A1 gene by direct sequencing. Results: For patients with Gilbert syndrome, 85% (47/55) harbored pathogenic variants of UGT1A1⁎60. Both UGT1A1⁎28 and UGT1A1⁎81 were detected in the promoter region of UGT1A1. Additionally, 83% (20/24) of patients with Gilbert syndrome heterozygous for UGT1A1⁎60 had an association with heterozygous variation of UGT1A1⁎28 or UGT1A1⁎81, while 91% (21/23) of Gilbert syndrome patients homozygous for UGT1A1⁎60 had biallelic variations of UGT1A1⁎28 and UGT1A1⁎81. We detected 213 UGT1A1 allelic variants, including six novel variations, with the most frequent allele being the UGT1A1⁎60, followed by UGT1A1⁎28 and UGT1A1⁎6. All of the patients showed multiple sites of variants in UGT1A1; however, variation number was not associated with bilirubin levels (P>0.05). Conclusions: The spectrum of UGT1A1 variants in southeastern Chinese patients was distinct from other ethnic populations. Our findings broaden the knowledge concerning traits associated with UGT1A1 variants and help profile genotype-phenotype correlations in hyperbilirubinemia patients.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Glucuronosiltransferase/genética , Hiperbilirrubinemia/genética , Adolescente , Adulto , Idoso , Alelos , Bilirrubina/genética , Bilirrubina/metabolismo , Criança , Pré-Escolar , China , Feminino , Frequência do Gene , Genética Populacional , Genótipo , Humanos , Hiperbilirrubinemia/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
7.
Forensic Sci Int ; 302: 109831, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31255841

RESUMO

The dating of bruises can be of crucial interest in clinical forensic medicine, but the macroscopic or photographic evaluation of a bruise has not been regarded as reliable. Several methods have thus been regularly evaluated for this purpose, with reflectance spectrometry yielding promising results. The objective of this study is to evaluate the value of a bilirubinometer as a tool for dating bruises on living victims. A clinical follow-up was carried out on patients presenting a bruise with a known onset. Using a bilirubinometer, we obtained daily measurements of the bruise (bili-bruise) and of healthy skin (bili-skin). Potential confounding factors were collected: age, sex, body mass index, trauma mechanism and Fitzpatrick skin phototype. We followed 20 patients for a total of 88 measurements of bruises. Bili-skin values showed significant differences according to skin phototype. Differences between the bili-bruise and bili-skin values (Δ-bili) followed an increase phase, peaking between 3 and 5 days, and then there was a decrease phase. No significant Δ-bili value differences were observed based on the suspected confounding factors. Our results are in favour of a peak Δ-bili value generally at day 4 or 5 post-trauma. Notably, decreasing values were not observed before day 3. Decreasing Δ-bili values would then indicate a bruise resulting from an injury formed at least 3 days before the first measurement. Complementary work confirming such data would enable improvement of the performance of bruise dating in forensic medicine.


Assuntos
Bilirrubina/metabolismo , Contusões/patologia , Patologia Legal/métodos , Pele/metabolismo , Espectrofotometria , Contusões/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pigmentação da Pele , Fatores de Tempo
8.
BMC Gastroenterol ; 19(1): 66, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31046687

RESUMO

BACKGROUND: Quality of life (QOL) assessments with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-HCC18, C30 and HCC18 index scores have been shown to be prognostic factors for overall survival (OS) in patients with hepatocellular carcinoma (HCC), independent of disease stage and liver function. Liver function parameters (including bilirubin, albumin, international normalized ratio [INR], Child-Pugh class, ALBI grade, MELD, alkaline phosphatase [ALP]-to-platelet ratio, albumin-to-ALP ratio) have also been found to be independent prognostic factors for OS in HCC patients. There has been scanty data on whether QOL and baseline liver function per se are correlated in HCC patients. This study investigates the correlations between baseline QOL data and liver function variables in HCC patients. METHODS: From 2007 to 2011, 517 patients were enrolled. Baseline QOL was assessed at diagnosis using the EORTC QLQ-C30 and QLQ-HCC18; thereafter C30 and HCC18 index scores were derived. Clinical and laboratory data were collected. For liver function assessment, Child-Pugh class, ALBI grade, MELD, ALP-to-platelet ratio and albumin-to-ALP ratio were derived. Correlation analyses were performed between QOL and liver function data. RESULTS: Complete QOL data were available in 472 HCC patients. After adjusting for clinical variables, significant correlations were found between QOL (QLQ-C30 and QLQ-HCC18) and dichotomized liver function variables (including Child-Pugh class, ALBI grade and the presence of ascites). It was demonstrated that QOL had significant and potentially clinically important correlations with continuous liver function variables (albumin, bilirubin, ALP and albumin-to-ALP ratio), with the highest Spearman's rank correlation coefficient (rho) exceeding 0.4. HCC18 and C30 index scores were also significantly correlated with these liver function variables. HCC18 index score, which had rho up to 0.37, generally performed better than C30 index score, which had rho up to 0.33. CONCLUSIONS: In HCC patients, baseline QOL assessment (using EORTC QLQ-C30, QLQ-HCC18, C30 index-score or HCC18 index-score) is significantly correlated with liver function. Based on the findings of this study, future trials are warranted to assess whether treatment to enhance liver function could improve HCC patients' QOL.


Assuntos
Carcinoma Hepatocelular/fisiopatologia , Neoplasias Hepáticas/fisiopatologia , Fígado/fisiopatologia , Qualidade de Vida , Idoso , Albuminas/metabolismo , Fosfatase Alcalina/metabolismo , Ascite/etiologia , Bilirrubina/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Coeficiente Internacional Normatizado , Fígado/metabolismo , Testes de Função Hepática , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Contagem de Plaquetas , Inquéritos e Questionários , Análise de Sobrevida
9.
Eur Radiol ; 29(11): 5813-5822, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31020338

RESUMO

PURPOSE: To identify independent confounding variables of gadoxetate-enhanced hepatobiliary-phase liver MRI using multiple regression analysis. MATERIALS AND METHODS: The institutional review board generally approved retrospective analyses and all patients provided written informed consent. One hundred ten patients who underwent a standardized 3.0-T gadoxetate-enhanced liver MRI between November 2008 and June 2013 were retrospectively reviewed. The gadoxetate liver enhancement normalized to enhancement in the erector spinae muscle (relative signal enhancement, SE) was related to biochemical laboratory parameters and descriptive patient characteristics (patient age, body mass index) using non-parametric univariate correlation analysis followed by a multiple linear regression model. RESULTS: Using univariate statistics, relative SE was inversely correlated with patient age, ALP, AST, total bilirubin, gamma-glutamyltransferase, INR, model of end-stage liver disease score, and proportionally with albumin and hemoglobin (all p < 0.01). In a multiple regression analysis, total bilirubin (p = 0.001), serum albumin (p = 0.016), and patient age (p = 0.018) were independently correlated with relative liver SE (n = 110). CONCLUSION: A multiple regression analysis showed that high total bilirubin, low serum albumin, or advanced age was associated with low hepatobiliary-phase gadoxetate parenchymal liver enhancement. In these patients, the lower contrast-to-noise ratio might impair diagnostic evaluation of non-enhancing liver lesions (e.g., HCC, liver metastasis). KEY POINTS: • A multiple regression analysis identified independent confounding variables of hepatobiliary-phase gadoxetate liver enhancement. • High bilirubin, low albumin, or advanced age was associated with low enhancement. • Diagnostic evaluation might be hampered in these patients.


Assuntos
Bilirrubina/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Albumina Sérica/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Meios de Contraste , Feminino , Gadolínio DTPA , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , gama-Glutamiltransferase/metabolismo
10.
Oxid Med Cell Longev ; 2019: 6026902, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30891115

RESUMO

Bilirubin is considered to be one of the most potent endogenous antioxidants in humans. Its serum concentrations are predominantly affected by the activity of hepatic bilirubin UDP-glucuronosyl transferase (UGT1A1). Our objective was to analyze the potential bilirubin-modulating effects of natural polyphenols from milk thistle (Silybum marianum), a hepatoprotective herb. Human hepatoblastoma HepG2 cells were exposed to major polyphenolic compounds isolated from milk thistle. Based on in vitro studies, 2,3-dehydrosilybins A and B were selected as the most efficient compounds and applied either intraperitoneally or orally for seven days to C57BL/6 mice. After, UGT1A1 mRNA expression, serum, intrahepatic bilirubin concentrations, and lipoperoxidation in the liver tissue were analyzed. All natural polyphenols used increased intracellular concentration of bilirubin in HepG2 cells to a similar extent as atazanavir, a known bilirubinemia-enhancing agent. Intraperitoneal application of 2,3-dehydrosilybins A and B (the most efficient flavonoids from in vitro studies) to mice (50 mg/kg) led to a significant downregulation of UGT1A1 mRNA expression (46 ± 3% of controls, p < 0.005) in the liver and also to a significant increase of the intracellular bilirubin concentration (0.98 ± 0.03vs.1.21 ± 0.02 nmol/mg, p < 0.05). Simultaneously, a significant decrease of lipoperoxidation (61 ± 2% of controls, p < 0.005) was detected in the liver tissue of treated animals, and similar results were also observed after oral treatment. Importantly, both application routes also led to a significant elevation of serum bilirubin concentrations (125 ± 3% and 160 ± 22% of the controls after intraperitoneal and oral administration, respectively, p < 0.005 in both cases). In conclusion, polyphenolic compounds contained in silymarin, in particular 2,3-dehydrosilybins A and B, affect hepatic and serum bilirubin concentrations, as well as lipoperoxidation in the liver. This phenomenon might contribute to the hepatoprotective effects of silymarin.


Assuntos
Bilirrubina/metabolismo , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Silimarina/isolamento & purificação , Silimarina/farmacologia , Animais , Flavonoides/química , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Hep G2 , Humanos , Espaço Intracelular/metabolismo , Fígado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Silibina/administração & dosagem , Silibina/farmacologia
11.
Biosci Trends ; 13(1): 23-31, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30814402

RESUMO

Cholestasis is a pathological process in which bile drainage is poor for a variety of reasons. Many studies have shown that cholestatic liver injury is a neutrophil-mediated inflammatory response, and oxidative stress induced by neutrophils is the main mechanism of liver cell death. The literature summarizes the bile acid signaling pathway, the neutrophil chemotaxis recruitment process during cholestasis, and the oxidative stress damage produced by neutrophil activation, summarizes the latest research progress. Sphingosine-1-phosphate receptor (S1PR) is a potential therapeutic target for cholestasis that reduces neutrophil aggregation without inhibiting systemic immune status. Early growth response factor 1 (Egr-1) may play a central role in the inflammation induced by cholestasis, and it is also a potential therapeutic target to inhibit the inflammation induced by cholestasis. Strengthening the antioxidant system of hepatocytes to cope with oxidative stress of neutrophils is a feasible treatment for cholestatic liver injury.


Assuntos
Colestase Intra-Hepática/imunologia , Animais , Ácidos e Sais Biliares/metabolismo , Bilirrubina/metabolismo , Colestase Intra-Hepática/metabolismo , Humanos , Imunidade Inata , Terapia de Alvo Molecular , Neutrófilos/fisiologia , Transdução de Sinais
12.
Nat Rev Gastroenterol Hepatol ; 16(6): 346-360, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30903105

RESUMO

Neonatal cholestasis is a group of rare disorders of impaired bile flow characterized by conjugated hyperbilirubinaemia in the newborn and young infant. Neonatal cholestasis is never physiological but rather is a sign of hepatobiliary and/or metabolic disorders, some of which might be fatal if not identified and treated rapidly. A step-wise timely evaluation is essential to quickly identify those causes amenable to treatment and to offer accurate prognosis. The aetiology of neonatal cholestasis now includes an expanding group of molecularly defined entities with overlapping clinical presentations. In the past two decades, our understanding of the molecular basis of many of these cholestatic diseases has improved markedly. Simultaneous next-generation sequencing for multiple genes and whole-exome or whole-genome sequencing now enable rapid and affordable molecular diagnosis for many of these disorders that cannot be directly diagnosed from standard blood tests or liver biopsy. Unfortunately, despite these advances, the aetiology and optimal therapeutic approach of the most common of these disorders, biliary atresia, remain unclear. The goals of this Review are to discuss the aetiologies, algorithms for evaluation and current and emerging therapeutic options for neonatal cholestasis.


Assuntos
Bilirrubina/metabolismo , Colagogos e Coleréticos/uso terapêutico , Colestase , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Técnicas de Diagnóstico Molecular/métodos , Triagem Neonatal/métodos , Apoio Nutricional/métodos , Colestase/diagnóstico , Colestase/metabolismo , Colestase/terapia , Diagnóstico Precoce , Humanos , Recém-Nascido
13.
J Clin Pharm Ther ; 44(4): 572-578, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30851209

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Several authors have demonstrated the relationship between voriconazole concentrations and the risk of therapeutic failure and adverse events However, the information about voriconazole concentrations in the critically ill patient is scarce. The aim of this study was to analyse the plasma concentrations and pharmacokinetic behaviour of voriconazole in critically ill patients and their association with the treatment response and development of toxicity. METHODS: A prospective, observational study was conducted. Patients admitted to an intensive care unit and on treatment with intravenous voriconazole were included. Plasma concentrations were measured between days 4 and 7 from the start of the treatment. The pharmacokinetic analysis was performed using the NONMEM® software. A regression model was used to evaluate the variables associated with the values outside the therapeutic range, as well as the relationship between the plasma concentrations and the treatment response and the development of hepatotoxicity. RESULTS AND DISCUSSION: A total of 33 patients were included. Plasma concentrations outside the therapeutic range (1-5.5 mg/L) were observed in 15 patients, being above the established range in 9 (27.3%) cases, and below it in 6 (18.2%) cases. The presence of a bilirubin value of >1.5 mg/dL and a C-reactive protein >100 mg/dL was associated with supra-therapeutic concentrations. Voriconazole concentrations greater than 5.5 mg/dL were associated with the development of hepatotoxicity. WHAT IS NEW AND CONCLUSIONS: There is a wide variation in voriconazole concentrations in critically ill patients, being associated with a high frequency of adverse events. Close monitoring of these values is required in order to decrease the risk of therapeutic failure and toxicity.


Assuntos
Antifúngicos/sangue , Antifúngicos/farmacocinética , Voriconazol/sangue , Voriconazol/farmacocinética , Bilirrubina/metabolismo , Estado Terminal , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Plasma/metabolismo , Estudos Prospectivos
14.
Pak J Pharm Sci ; 32(1(Supplementary)): 301-308, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30829207

RESUMO

Carbon tetrachloride (CCl4) is one of the chemicals used in industry reported to accelerate the risk of liver diseases in workers especially in developing countries, if it is not handled carefully. Therefore, the present study conducted to evaluate the liver protective and oxidative stress reducing activities of methanolic (MFEt) and aqueous methanolic fruits (AqMFEt) extracts of Withania coagulans against CCl4-induced liver damage in rats. These fruits extracts in oral doses of 800 mg/kg were found effective in their respective test groups in decreasing weight loss, maintaining hepatic membrane integrity, biosynthetic and conjugative abilities by improving liver and bile duct specific enzymes (alanine and aspartate transferases, alkaline phosphatase, γ-glutamyltranstransferase), total protein and bilirubin profiles, uric acid levels plus uplifting the efficacy of hepatic antioxidant enzymes and protein by minimizing lipid peroxidation. All these beneficial effects confirmed by observing normal anatomical features of liver tissues in test groups. Total phenolic compounds were found high in AqMFEt. Interestingly, for the first time, gallic acid and rutin are identified and quantified in these extracts and thought to improve hepatoprotective potential of W. coagulans.


Assuntos
Ácido Gálico/farmacologia , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rutina/farmacologia , Withania/química , Animais , Bilirrubina/metabolismo , Peso Corporal/efeitos dos fármacos , Tetracloreto de Carbono/toxicidade , Enzimas/metabolismo , Feminino , Fígado/enzimologia , Fígado/patologia , Metanol/química , Fenóis/análise , Extratos Vegetais/química , Plantas Medicinais/química , Substâncias Protetoras/farmacologia , Ratos Wistar
15.
J Complement Integr Med ; 16(3)2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30735482

RESUMO

Background The cytotoxic properties of nanoparticles have attracted a great deal of attention in the field of nanoscience and nanotechnology due to their small size and ability to penetrate cellular membranes. Methods The silver nanoparticles were synthesized using Elaeodendron croceum stem bark and characterized. The oral acute toxicity studies were carried out by administration of 500, 1000, 2000 mg/kg body weight to Wister rats in respective groups. An in vitro cytotoxicity assay was evaluated in MDA-MB-231 breast cancer cells using the WST-1 Cell Proliferation assay. The percentage of cell viability after treatment with aqueous extracts of Elaeodendron croceum (ECE) and Elaeodendron croceum silver nanoparticles (ECAgNPs) was compared with that of paclitaxel. Results The in vivo studies revealed that the LD50 was higher than 2000 mg/kg and there was no significant difference (p>0.05) between the treatment groups compared with the control group for mean organ-to-body weight ratio except in the liver and in all hematological parameters except WBC and hematocrit. Similarly, there was no significant difference (p>0.05) for serum electrolytes (Na+, Mg2+ K+, Cl-, and Ca2+), total protein, urea, É£-glutamyl transferase (GGT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), albumin, total and conjugated bilirubin between the treatment and the control group. However, there were changes in creatinine, urea, and cholesterol. In the in vitro assays, ECE and ECAgNPs showed IC50 values of 70.87±2.99 and 138.8±3.98 µg/mL respectively against MDA-MB-231 cells compared to paclitaxel, which showed an IC50 value of 80 ng/mL. Conclusion The results showed that the LD50 of the ECE and ECAgNPs in Wister rats was determined to be greater than 2000 mg/kg body weight. The aqueous extract also showed more cytotoxic than the ECAgNPs suggesting that the toxic compounds in aqueous extract were involved in the capping of the AgNPs.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Celastraceae/química , Nanopartículas Metálicas/toxicidade , Prata/toxicidade , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Aspartato Aminotransferases/metabolismo , Bilirrubina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Nanopartículas Metálicas/química , Casca de Planta/química , Caules de Planta/química , Ratos , Ratos Wistar , Prata/química
16.
Diabetes Res Clin Pract ; 149: 1-8, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30711436

RESUMO

AIMS: It was recently reported that lactate acts as a metabolic mediator and rises in the diabetic state, but the physiological effects are as yet poorly understood. The objective of the current study was to evaluate the significance of serum lactate elevation in type 2 diabetes mellitus (T2DM) patients. METHODS: Fasting serum lactate levels, hematological and inflammatory serum markers and anthropometric parameters, obtained employing bioelectric impedance analysis, were measured in 103 patients with T2DM. RESULTS: Statistically significant correlations of serum lactate levels with C-reactive peptide, insulin, aspartate aminotransferase, alanine aminotransferase (ALT), serum lipids, total bilirubin, adiponectin, homeostasis model assessment-insulin resistance, body weight, body mass index and body fat (weight or percentage of subcutaneous fat, visceral fat or total body fat), but neither fasting plasma glucose nor HbA1c, were detected. Stepwise regression analysis showed ALT to be independently positively associated with total bilirubin, while being negatively associated with serum lactate levels. Furthermore, serum lactate levels were significantly higher in patients with ALT-predominant liver dysfunction. CONCLUSION: We found fasting serum lactate elevation in T2DM patients to be associated with the serum levels of ALT and total bilirubin independently of blood glucose control. TRIAL REGISTRATION: UMIN clinical trials registry (UMIN000029178).


Assuntos
Alanina Transaminase/metabolismo , Bilirrubina/metabolismo , Diabetes Mellitus Tipo 2/sangue , Lactatos/metabolismo , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Phys Chem Chem Phys ; 21(5): 2365-2371, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30666332

RESUMO

Fluorescent proteins (FPs) have become fundamental tools for live cell imaging. Most FPs currently used are members of the green fluorescent protein super-family, but new fluorophores such as bilin-FPs are being developed and optimized. In particular, the UnaG FP incorporates bilirubin (BR) as a chromophore, enhancing its fluorescence quantum yield by three orders of magnitude relative to that in solution. To investigate the mechanism of this dramatic enhancement and provide a basis for further engineering of UnaG and other tetrapyrrole-based fluorophores, we performed picosecond fluorescence and femtosecond transient absorption measurements of BR bound to UnaG and its N57A site-directed mutant. The dynamics of wt-UnaG, which has a fluorescence QY of 0.51, are largely homogeneous, showing an excited state relaxation of ∼200 ps, and a 2.2 ns excited-state lifetime decay with a kinetic isotope effect (KIE) of 1.1 for D2O vs. H2O buffer. In contrast, for UnaG N57A (fluorescence QY 0.01) the results show a large spectral inhomogeneity with excited state decay timescales of 47 and 200 ps and a KIE of 1.4. The non-radiative deactivation of the excited state is limited by proton transfer. The loss of direct hydrogen bonds to the endo-vinyl dipyrrinone moiety of BR leads to high flexibility and structural heterogeneity of UnaG N57A, as seen in the X-ray crystal structure.


Assuntos
Bilirrubina/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Bilirrubina/química , Bilirrubina/efeitos da radiação , Sítios de Ligação , Fluorescência , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/efeitos da radiação , Ligações de Hidrogênio , Luz , Mutação , Ligação Proteica
18.
Int J Biol Macromol ; 128: 74-79, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30684573

RESUMO

Fibrinogen, a protein involved in blood coagulation, is very susceptible to oxidation. Oxidation alters its function and usually makes it more thrombogenic. Bilirubin, an end-product of the haem degradation in vertebrates, is known for its antioxidant properties. The present paper describes interaction between fibrinogen and bilirubin, and the influence of bilirubin on the formation of fibrin and protection against oxidation. The binding constant of 4.5 × 104 M-1 was determined for the fibrinogen/bilirubin complex at 37 °C. There is no change in secondary and tertiary structure of fibrinogen or its thermal stability upon bilirubin binding. The binding site of fibrinogen is not stereospecific for bilirubin and is able to accommodate both bilirubin conformers. A change in absorption maximum of bilirubin occurs upon its interaction with fibrinogen, suggesting an alteration in the conformation of bilirubin to the more cyclic one. Bilirubin exerts antioxidant effect on fibrinogen, preventing its carbonylation and aggregation. The presence of bilirubin induces the formation of fibrin with thicker fibres, as assessed by the coagulation assay. Fibrinogen and bilirubin interact at physiological concentrations, bilirubin may act as an antioxidant for fibrinogen and may modulate an important event in haemostasis, which altogether suggests possible physiological relevance of this interaction.


Assuntos
Bilirrubina/química , Bilirrubina/metabolismo , Fibrinogênio/química , Fibrinogênio/metabolismo , Coagulação Sanguínea , Testes de Coagulação Sanguínea , Dicroísmo Circular , Fluorometria , Humanos , Oxirredução , Ligação Proteica , Termodinâmica
19.
Int J Hyperthermia ; 36(1): 328-336, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30689465

RESUMO

PURPOSE: To assess the efficacy of the albumin-bilirubin (ALBI) grade on assessing long-term outcomes of computed tomography (CT)-guided percutaneous microwave ablation (CT-PMWA) in the treatment of patients with intrahepatic cholangiocarcinoma (ICC). METHODS: Between April 2011 and March 2018, 78 patients who underwent CT-PMWA were enrolled in this study. Overall survival (OS) and recurrence-free survival (RFS) were compared in the groups stratified by the ALBI grade and Child-Pugh score. Cox proportional hazard regression analyses were performed to determine independent predictors of OS and RFS. RESULTS: After a median follow-up of 22.7 months (range 1-86.7 months), 67 patients had died. The cumulative 1-, 3-, and 5-year OS rates were 89.5%, 52.2%, and 35.0%, respectively. Stratified by the ALBI grade, the cumulative 1-, 3-, and 5-year OS rates were 100%, 69.2%, and 25.6% for patients with the grade 1, respectively. For patients with the ALBI grade 2, the cumulative 1-, 3-, and 5-year OS rates were 41.0%, 10.3%, and 10.3%, respectively. Patients with a hepatic function of the ALBI grade 1 had significantly higher OS rates than patients with the ALBI grade 2 (p < .001). The multivariate analysis showed tumor size (Hazard Ratio[HR] 95% Confidence Interval[CI]:9.03[1.01-80.52], p = .049) and the ALBI grade (HR[95%CI]:9.56[1.58-58.00], p = .014) were associated with OS, and tumor size (HR: 2.03[0.69-8.04], p = .049) was associated with RFS. CONCLUSIONS: The preliminary data of this study showed the ALBI grade was effective to predict long-term outcomes of CT-PMWA in ICCs. Further study is necessary to validate our results by a large, multi-center patient cohort.


Assuntos
Neoplasias dos Ductos Biliares/sangue , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Bilirrubina/metabolismo , Ablação por Cateter/métodos , Colangiocarcinoma/sangue , Colangiocarcinoma/diagnóstico por imagem , Albumina Sérica/metabolismo , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Feminino , Humanos , Masculino , Valor Preditivo dos Testes
20.
Mol Med Rep ; 19(2): 1185-1193, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30569102

RESUMO

Cholestasis is a devastating liver condition which is increasing in prevalence worldwide; however, its underlying pathogenic mechanisms remain to be fully elucidated. It was hypothesised that melatonin may alleviate the hepatic injury associated with cholestasis due to its established antioxidant effects. Therefore, the effect and potential anticholestatic properties of melatonin were investigated in rats with α­naphthylisothiocyanate (ANIT)­induced liver injury, a common animal model that mimics the cholestasis­associated liver injury in humans. The rats received intraperitoneal injection of ANIT with or without subsequent treatment with melatonin, and were sacrificed 24 h later. The serum biochemistry parameters of the liver were measured using conventional laboratory assays, and the liver tissue was subjected to conventional histological examination, reverse transcription­quantitative polymerase chain reaction analysis and western blotting. The levels of alanine transaminase, aspartate transaminase, total bilirubin, direct bilirubin, total bile acids, alkaline phosphatase, γ­glutamyl transferase and glutathione were restored in rats treated with melatonin. Histological examination provided further evidence supporting the protective effect of melatonin against ANIT­induced cholestasis. In addition, the mRNA and protein expression levels of glutamate cysteine ligase, phosphorylated Akt and nuclear factor­erythroid 2­related factor­2 were restored in rats treated with melatonin. These findings indicate that melatonin is a natural agent that appears to be promising for the treatment of cholestasis, and that the anticholestatic effects of melatonin involve the alleviation of oxidative stress.


Assuntos
1-Naftilisotiocianato/farmacologia , Colestase/induzido quimicamente , Colestase/tratamento farmacológico , Melatonina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Alanina Transaminase/metabolismo , Animais , Antioxidantes/farmacologia , Aspartato Aminotransferases/metabolismo , Ácidos e Sais Biliares/metabolismo , Bilirrubina/metabolismo , Colestase/metabolismo , Glutamato-Cisteína Ligase/metabolismo , Glutationa/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
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