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1.
Hepatol Res ; 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32134538

RESUMO

AIMS: The artificial liver support system (ALSS) is recognized as a bridge to liver transplantation (LT) in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients. However, patient survival remains unknown. We aim to assess the effects of ALSS on survival in HBV-ACLF patients. METHODS: The clinical data of HBV-ACLF patients receiving standard medical treatment (SMT) plus ALSS (ALSS group, n=507) or only SMT (SMT group, n=417) were collected for survival assessment. The main endpoints were cumulative survival rates at days 21, 28 and 90. Four different rigorous analyses were performed to reduce bias and confounding. RESULTS: In the entire cohort, the cumulative survival rates at days 21, 28 and 90 were significantly higher in patients who underwent ALSS treatment (73.3% vs. 59.6%, 69.2% vs. 56.6%, 56.5% vs. 49.1%, respectively, P<0.01) than in those who underwent SMT only. In the 276-pair case-control matched cohort, a significantly higher survival rate was also observed in the ALSS group than in the SMT group on days 21, 28 and 90 (72.5% vs. 60.3%, 68.3% vs. 57.4%, 55.9% vs. 48.5%, respectively, P<0.05), especially in patients with ACLF-1 and -2. By a multivariable-adjusted analysis, ALSS treatment was associated with a significantly lower risk of mortality, especially for ACLF-2 at days 21, 28 and 90. These findings were also confirmed through propensity score matching and inverse probability treatment weighting analysis. CONCLUSIONS: ALSS treatment can improve the short-term survival and associated with a significantly lower risk of short-term mortality in patients with HBV-ACLF, especially ACLF-2.

2.
Amino Acids ; 52(3): 453-463, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32108265

RESUMO

The calpain-1-activated apoptotic pathway plays a key role in right ventricular hypertrophy (RVH). Taurine has been shown to attenuate apoptosis by inhibiting calpain activity. This experiment aimed to determine whether taurine could prevent RVH by inhibiting the calpain-1/cytochrome c apoptotic pathway. The broilers were given 1% taurine dissolved in drinking water and were raised at 10 °C ~ 12 °C from day 21 to day 42. At 21 d, 28 d, 35 d and 42 d, the right ventricular (RV) tissues were collected. Increased RVH index, angiotensin II, norepinephrine and atrial natriuretic peptide mRNA expression were reduced by taurine in the broiler RVs. Taurine obviously inhibited cardiomyocyte apoptosis via maintaining the mitochondrial membrane potential and decreased the activation of caspase-9 and caspase-3 in the broiler RVs. The antioxidant assay demonstrated that taurine enhanced the activities of superoxide dismutase, total antioxidant capacity and glutathione peroxidase and the glutathione/glutathione disulfide ratio. Western blot results revealed that taurine also downregulated the expression of calpain-1 and cytosolic cytochrome c while upregulating the expression of Bcl-2/Bax and mitochondrial cytochrome c in broiler cardiomyocytes during RVH. In summary, we found that taurine could enhance cardiomyocyte antioxidant ability and further prevented cardiomyocyte apoptosis by inhibiting the calpain-1/cytochrome c pathway during RVH in broilers.

3.
Clin Gastroenterol Hepatol ; 18(2): 457-467.e21, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31306800

RESUMO

BACKGROUND & AIMS: Treatment of chronic hepatitis B virus (HBV) infection with entecavir suppresses virus replication and reduces disease progression, but could require life-long therapy. To investigate clinical outcome events and safety associated with long-term treatment with entecavir, we followed up patients treated with entecavir or another standard-of-care HBV nucleos(t)ide analogue for up to 10 years. We assessed long-term outcomes and relationships with virologic response. METHODS: Patients with chronic HBV infection at 299 centers in Asia, Europe, and North and South America were assigned randomly to groups that received entecavir (n = 6216) or an investigator-selected nonentecavir HBV nucleos(t)ide analogue (n = 6162). Study participants were followed up for up to 10 years in hospital-based or community clinics. Key end points were time to adjudicated clinical outcome events and serious adverse events. In a substudy, we examined relationships between these events and virologic response. RESULTS: There were no significant differences between groups in time to event assessments for primary end points including malignant neoplasms, liver-related HBV disease progression, and death. There were no differences between groups in the secondary end points of nonhepatocellular carcinoma malignant neoplasms and hepatocellular carcinoma. In a substudy of 5305 patients in China, virologic response, regardless of treatment group, was associated with a reduced risk of liver-related HBV disease progression (hazard ratio, 0.09; 95% CI, 0.038-0.221) and hepatocellular carcinoma (hazard ratio, 0.03; 95% CI, 0.009-0.113). Twelve patients given entecavir (0.2%) and 50 patients given nonentecavir drugs (0.8%) reported treatment-related serious adverse events. CONCLUSIONS: In a randomized controlled trial of patients with chronic HBV infection, we associated entecavir therapy with a low rate of adverse events over 10 years of follow-up evaluation. Patients receiving entecavir vs another nucleos(t)ide analogue had comparable rates of liver- and non-liver-related clinical outcome events. Participants in a China cohort who maintained a virologic response, regardless of treatment group, had a reduced risk of HBV-related outcome events including hepatocellular carcinoma. ClinicalTrials.gov identifier no: NCT00388674.

4.
Antiviral Res ; 170: 104579, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31398372

RESUMO

This study aimed to investigate clinical occurrence and significance of the rtS78T/sC69* mutation of hepatitis B virus (HBV). A total of 22,009 consecutive chronic HBV-infected patients who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital (Original name Beijing 302 Hospital) from 2007 to 2016 were enrolled. Serum samples were collected for sequence analysis of HBV reverse-transcriptase (RT) and S regions. Phenotypic analysis was performed to evaluate the viral replication capacity and drug susceptibility. The rtS78T mutation was detected in 0.83% (182/22,009) of the patients' samples. All mutations simultaneously created a stop codon at sC69 (sC69*). The prevalence of rtS78T/sC69* did not differ significantly between the patients with and without entecavir/tenofovir treatment. Of the 182 mutation-positive samples, 41 (22.5%) were detected with signature drug-resistance mutations to adefovir (n = 26), lamivudine (n = 11), entecavir (n = 3), and lamivudine plus adefovir (n = 1). The HBV DNA and RNA levels of the rtS78T/sC69* mutant were significantly increased compared to the wild-type; while the mutant had undetectable secreted and intracellular HBsAg, and its half maximal effective concentration to lamivudine, adefovir, entecavir, and tenofovir were 3.73-, 1.61-, 4.76-, and 3.71-fold of the wild-type, respectively. Artificial elimination of the rtS78T mutation had a limited effect on the drug susceptibilities. The data obtained in the present study suggested that the emergence of the rtS78T/sC69* mutation was not closely related to entecavir/tenofovir treatment and itself appeared insufficient to confer drug resistance unless it coexisted with signature drug-resistance mutations.

5.
Adv Exp Med Biol ; 1155: 119-131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468391

RESUMO

Excessive consumption causes alcoholic liver disease (ALD), which injures hepatocytes and induces imbalance of lipid metabolism. Taurine is known to protect the liver from various liver injuries, and relieve lipid profile. Our previous studies also found that taurine can prevent or cure ALD, reduce fat deposition, but the mechanism remains unclear. In the present study, ALD rat model was established by administration of alcohol, pyrazole and high fat diet. Two percent taurine was administered at the same time or after ALD model establishment. Serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), serum and hepatic TC, TG, HDL-C and LDL-C were analyzed. Real-Time RT-PCR was conducted to detect the mRNA expressions of fatty acid synthetase (FAS), acetyl-CoA catboxylase (ACC), carnitine palmitoyl transferase 1 (CPT-1), 3-Hydroxy-3-methyl glutaric acid acyl Coenzyme A reductase (HMGCR), peroxisome proliferators activated receptor α (PPARα) and sterol regulatory element-binding protein 1c (SREBP-1c). The results showed that serum ALT, AST, serum and hepatic TC, TG and LDL-C were higher, while HDL-C in ALD model rats was lower than normal rats, the changes of which can be significantly relieved by taurine administration. mRNA expressions of ACC, FAS, CPT-1, HMGCR, PPARα and SREBP-1c which were significantly changed by ethanol can also be regulated by taurine. The results indicated that taurine can prevent and repair hepatic injury of ALD rats and balance lipid metabolism indexes in the liver, the mechanisms may involves in the regulation of related enzymes and transcriptional regulators participated in lipid metabolism.


Assuntos
Metabolismo dos Lipídeos , Hepatopatias Alcoólicas/tratamento farmacológico , Taurina/farmacologia , Animais , Fígado/metabolismo , Fígado/fisiopatologia , Ratos
6.
Adv Exp Med Biol ; 1155: 133-146, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468392

RESUMO

Metabolic syndrome is a lifestyle-related disease caused by high nutrient condition and lack of exercise. The insulin resistance due to obesity has attracted attention as an underlying mechanism of metabolic syndrome. Insulin resistance refers to reduced insulin sensitivity in insulin target tissues. In this case, in order to maintain normal blood glucose levels, a compensatory large amount of insulin is released, leading to the occurrence of hyperinsulinemia. Taurine is widely distributed in animal tissues. Although it is not involved in protein synthesis, taurine plays an important role in maintaining the body's physiological function. In this experiment, insulin resistance model was induced by high fat and high sugar diet. Two percent taurine was added in drinking water to explore the mechanism of taurine in insulin resistance and to provide theoretical basis for using taurine to improve insulin resistance. The result showed that high-fat and high-sugar diet could decrease insulin sensitivity, and taurine could improve it by oral glucose tolerance test. Moreover, serum TG, TC were higher, while HDL-C in rats fed with high sugar and high fat diet was lower than normal rats, the changes of which can be significantly relieved by 2% taurine administration. mRNA and protein expressions of IRS1, and GLUT4 which were significantly changed by high sugar and high fat diet can also be regulated by 2% taurine. The results indicated that taurine can improve insulin sensitivity through remediating lipid metabolism disorder and regulating the expressions of IRS and GLUT4.


Assuntos
Resistência à Insulina , Metabolismo dos Lipídeos , Músculo Esquelético/efeitos dos fármacos , Taurina/farmacologia , Animais , Dieta Hiperlipídica/efeitos adversos , Açúcares da Dieta/efeitos adversos , Músculo Esquelético/fisiologia , Ratos
7.
Adv Exp Med Biol ; 1155: 147-154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468393

RESUMO

It has been confirmed by our laboratory that taurine could decrease uric acid levels in hyperuricemic rats and regulate the expressions of some urate transporters. The present study aims to investigate the effects of taurine on uric acid uptake in human renal proximal tubular epithelial cells (HK-2). The cell growth inhibition rate was measured by MTS assay, which was up to 50% after treatment with 1.5 mmol/L uric acid. After administration of 15 mmol/L taurine, the inhibition rate and uric acid uptake were both significantly decreased. Then the HK-2 cells were grouped as follows: control group (C); model group (M), in which 1.5 mmol/L uric acid was added to the medium; taurine group (MT), in which 1.5 mmol/L uric acid and 15 mmol/L taurine were added to the medium; and taurine control group (T), in which 15 mmol/L taurine was added to the medium. The mRNA and protein expression levels of URAT1 and GLUT9 were measured by real-time PCR and western-blot. The results showed that URAT1 and GLUT9 mRNA/protein expression levels in group M were significantly increased compared with group C, and they were both down-regulated in MT group. In addition, the expression levels of these two transporters in group T were significantly lower than group C. The results indicated that taurine could inhibit uric acid uptake and down-regulate the expressions of URAT1 and GLUT9 in HK-2 cells.


Assuntos
Células Epiteliais/efeitos dos fármacos , Taurina/farmacologia , Ácido Úrico/metabolismo , Linhagem Celular , Células Epiteliais/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Humanos , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo
8.
Adv Exp Med Biol ; 1155: 155-162, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468394

RESUMO

Fragile X syndrome is an X-linked dominant disorder and the most common cause of inherited mental retardation. It is caused by trinucleotide repeat expansion in the fragile X mental retardation 1 gene (FMR1) at the Xq27.3. The expansion blocks expression of the gene product, Fragile X Mental Retardation Protein (FMRP). The syndrome includes mild to moderate mental retardation and behavioral manifestations such as tactile defensiveness, gaze avoidance, repetitive motor mannerisms, perseverative (repetitive) speech, hyperarousal and it frequently includes seizures. This behavioral phenotype overlaps significantly with autism spectrum disorder. The knockout mice lack normal Fmr1 protein and show macro-orchidism, learning deficits, and hyperactivity. Consequently, this knockout mouse may serve as a valuable tool in the elucidation of the physiological role of FMR1 and the mechanisms involved in macroorchidism, abnormal behavior, abnormalities comparable to those of human fragile X patients. In this study we evaluated the effects of taurine on the testicular physiology to better understand the cellular mechanisms underlying macro-orchidism. We found that there was a significant decrease in the number of Leydig cells in the testis of fragile X mouse. Furthermore, the expression of somatostatin was drastically decreased and differential expression pattern of CDK5 in fragile X mouse testis. In the control testis, CDK is expressed in primary and secondary spermatids whereas in the Fmr1 ko mice CDK 5 is expressed mainly in spermatogonia. Taurine supplementation led to an increase in CDK5 expression in both controls and Ko mice. CDKs (Cyclin-dependent kinases) are a group of serine/threonine protein kinases activated by binding to a regulatory subunit cyclin. Over 20 functionally diverse proteins involved in cytoskeleton dynamics, cell adhesion, transport, and membrane trafficking act as CDK5 substrates elucidating the molecular mechanisms of CDK5 function. CDK5 phosphorylates a diverse list of substrates, implicating it in the regulation of a range of cellular processes. CDK5 is expressed in Leydig cells, Sertoli cells, spermatogonia and peritubular cells indicating a role in spermatogenesis. In this study we examined the expression levels of CDK5 and how it is affected by taurine supplementation in the testes and found that taurine plays an important role in testicular physiology and corrected some of the pathophysiology observed in the fragile x mouse testis.


Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Taurina/farmacologia , Testículo/fisiopatologia , Animais , Suplementos Nutricionais , Modelos Animais de Doenças , Síndrome do Cromossomo X Frágil/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Expansão das Repetições de Trinucleotídeos
9.
Adv Exp Med Biol ; 1155: 451-462, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468422

RESUMO

Objective To determine whether taurine has protective effects on chicken myocardial apoptosis induced by hypoxic condition through inhibiting calpain-1 derived mitochondrial apoptotic pathway. Methods Chicken primary embryonic myocardial cells were isolated and cultured at 37 °C under a 5% CO2 atmosphere. Firstly the optimum concentration of taurine or PD150606 was chosen by detecting the cell viability. Chicken cardiomyocytes were cultured in 95% N2-5% CO2 atmosphere for 12 h to produce hypoxic conditions. Before hypoxic treatment, 10 mM taurine and 10 uM PD150606 (a specific calpains inhibitor) were added separately or together. The cell apoptosis was detected by acridine orange/ethidium bromide (AO/EB) double staining. Western blotting was used to determine the protein expressions of calpain-1, cytochrome c, Bcl-2, procaspase-9 and procaspase-3 in the cardiomyocytes. Results Taurine administration effectively attenuated the myocardial apoptosis under hypoxic condition, reduced the calpain-1 protein level. In addition, pre-treated taurine could up-regulate the protein expressions of Bcl-2 and procaspase-3 in hypoxic myocardial cells, down-regulate protein expression levels of cytochrome c and procaspase-9. Moreover, taurine exhibited same inhibition effect as PD150606 on the cell apoptosis and proteins express under hypoxic condition. Conclusions Taurine could attenuate the chicken cardiomyocyte apoptosis impaired by hypoxia through inhibiting calpian-1-derived mitochondrial apoptotic pathway in vitro.


Assuntos
Apoptose , Calpaína/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Taurina/farmacologia , Acrilatos/farmacologia , Animais , Hipóxia Celular , Células Cultivadas , Galinhas , Mitocôndrias
10.
Adv Exp Med Biol ; 1155: 675-689, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468439

RESUMO

In order to provide a theoretical basis for the amelioration of heat stress-related diseases in broilers by taurine supplementation, the effect of taurine on the viability and antioxidant ability of aortic endothelial cells in broilers under heat stress was investigated in the present study. In this experiment, 10d healthy broilers were sacrificed, then aortic tissue was used for aortic endothelial cells isolation and cultivation. Tissue patching was used to cultivate primary broiler aortic endothelial cells. The 3rd to 5th generations of cells were used and randomly divided into five groups, including the control group (C), the heat-stressed group (HS), the Tau(HS + LTau) group, the Tau(HS + MTau) group and the Tau(HS + HTau) group. Cells were cultivated for 24 h in a cell incubator (37 °C, 5%CO2). Then heat-stressed cells were placed in a 43 °C thermostatic water bath for 6 h, followed by incubation in the cell incubator under 37°Cfor 1 h. The results were as follows (1) Based on MTT colorimetry and AO/EB staining, the activity of aortic endothelial cells was decreased, but the rate of apoptosis was increased in the HS group. Compared with the HS group, the taurine groups showed significantly higher level in relative survival rates (P < 0.05), and significantly lower apoptosis rates (P < 0.05); (2) compared to control group, LDH activity and MDA content of endothelial cells in the HS group were significantly increased (P < 0.01), while the levels of T-SOD, GSH-Px and T-AOC were significantly decreased (P < 0.01). The LDH activity and MDA content of endothelial cells were significantly lower in Tau group than those of HS group (P < 0.05), while the T-SOD activity, GSH-Px activity and T-AOC of endothelial cells were significantly increased (P < 0.05) in the taurine group. The results show that HS decreases antioxidant capacity, which causes severe oxidative damage to the endothelial cells; while taurine administration prevents the decline in LDH activity and MDA content, and increases the activity of several antioxidant enzymes, including SOD, GSH-Px and T-AOC, which implies that taurine can improve the broiler aortic endothelial cells activity and antioxidant ability under heat stress.


Assuntos
Antioxidantes/metabolismo , Células Endoteliais/efeitos dos fármacos , Resposta ao Choque Térmico , Taurina/farmacologia , Animais , Células Cultivadas , Galinhas , Células Endoteliais/metabolismo , Malondialdeído
11.
J Med Virol ; 91(10): 1811-1817, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31209906

RESUMO

BACKGROUND: The safety and necessity of hepatitis B immunoglobulin (HBIG) in preventing the mother-to-child transmission of hepatitis B virus (HBV) are still controversial because of its unclear mechanism of action and the inconsistent injection programs used during gestation. OBJECTIVES: This study aimed to show the dynamic transportation and distribution of HBIG in the maternal body and to provide evidence for its clinical efficacy in preventing mother-to-child HBV transmission. STUDY DESIGN: Pregnant mice were injected with Cy7-labeled mouse anti-human monoclonal hepatitis B surface antibodies through the tail vein. In vivo imaging technology was used to observe the dynamic transportation and distribution of HBIG in the pregnant mice. RESULTS: HBIG fluorescence signals were higher in the uterus than in the liver, spleen, and kidneys. Fluorescence signals in the uterine region were obviously higher at the third trimester than at early and mid pregnancy. CONCLUSIONS: HBIG is gradually deposited in the mouse placenta during pregnancy, with the phenomenon being more significant in the third trimester.

12.
Mol Med Rep ; 19(4): 2716-2728, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30720140

RESUMO

Due to the rising abuse of ketamine usage in recent years, ketamine­induced urinary tract syndrome has received increasing attention. The present study aimed to investigate the molecular mechanism underlying ketamine­associated cystitis in a mouse model. Female C57BL/6 mice were randomly divided into two groups: One group was treated with ketamine (100 mg/kg/day of ketamine for 20 weeks), whereas, the control group was treated with saline solution. In each group, micturition frequency and urine volume were examined to assess urinary voiding functions. Mouse bladders were extracted and samples were examined for pathological and morphological alterations using hematoxylin and eosin staining, Masson's trichrome staining and scanning electron microscopy. A cDNA microarray was conducted to investigate the differentially expressed genes following treatment with ketamine. The results suggested that bladder hyperactivity increased in the mice treated with ketamine. Furthermore, treatment with ketamine resulted in a smooth apical epithelial surface, subepithelial vascular congestion and lymphoplasmacytic aggregation. Microarray analysis identified a number of genes involved in extracellular matrix accumulation, which is associated with connective tissue fibrosis progression, and in calcium signaling regulation, that was associated with urinary bladder smooth muscle contraction. Collectively, the present results suggested that these differentially expressed genes may serve critical roles in ketamine­induced alterations of micturition patterns and urothelial pathogenesis. Furthermore, the present findings may provide a theoretical basis for the development of effective therapies to treat ketamine­induced urinary tract syndrome.


Assuntos
Sinalização do Cálcio , Matriz Extracelular/metabolismo , Ketamina/efeitos adversos , Doenças da Bexiga Urinária/etiologia , Doenças da Bexiga Urinária/metabolismo , Animais , Biomarcadores , Peso Corporal , Modelos Animais de Doenças , Feminino , Camundongos , Modelos Biológicos , Membrana Mucosa/metabolismo , Membrana Mucosa/patologia , Doenças da Bexiga Urinária/patologia , Doenças da Bexiga Urinária/fisiopatologia
13.
Ultraschall Med ; 40(2): 237-246, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30630194

RESUMO

PURPOSE: To prospectively assess liver fibrosis with two-dimensional shear wave elastography (2D-SWE) in patients with chronic hepatitis B (CHB) and to compare the performance of this modality with that of serum indices using Scheuer scoring from liver biopsies as the reference standard. MATERIALS AND METHODS: 123 patients with CHB underwent 2D-SWE measurements and serological tests between April 2016 and February 2018. The 2D-SWE and serum indices in the diagnosis of liver fibrosis were assessed using receiver operating characteristic (ROC) analyses. RESULTS: The areas under ROC (AUCs) for 2D-SWE, aspartate transaminase-to-platelet ratio index, fibrosis index based on the four factors, Forns score, King's score, FibroIndex, red cell distribution width-to-platelet ratio, Hepascore, type IV collagen, and hyaluronic acid were 0.851, 0.738, 0.701, 0.739, 0.734, 0.711, 0.692, 0.601, 0.640, and 0.522, respectively, in the diagnosis of substantial fibrosis, 0.975, 0.819, 0.792, 0.829, 0.818, 0.807, 0.732, 0.572, 0.676, and 0.544, respectively, in the diagnosis of severe fibrosis, and 0.972, 0.883, 0.862, 0.908, 0.889, 0.918, 0.808, 0.601, 0.807, and 0.775, respectively, in the diagnosis of cirrhosis. The AUCs of 2D-SWE in the diagnosis of substantial fibrosis, severe fibrosis, and cirrhosis were significantly higher than those of the serum indices (p < 0.05). CONCLUSION: 2D-SWE is a reliable noninvasive method for the assessment of liver fibrosis in patients with CHB with better diagnostic performance than that of nine serum fibrosis indices.


Assuntos
Técnicas de Imagem por Elasticidade , Hepatite B Crônica , Cirrose Hepática , Biópsia , Hepatite B Crônica/complicações , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico por imagem , Estudos Prospectivos , Curva ROC
14.
J Pharm Pharmacol ; 70(9): 1253-1261, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29943490

RESUMO

OBJECTIVES: Hypercholesterolaemia is a major risk factor for developing atherosclerosis. Increased consumption of fruits and vegetables is recommended to hypercholesterolaemic patients. In this study, the hypocholesterolaemic effect of apigenin and luteolin was evaluated in a hamster model. METHODS: Hamsters were put on a high-cholesterol diet for 9 weeks, and apigenin or luteolin was administered in the diet at 60 and 300 ppm. KEY FINDINGS: Both apigenin and luteolin supplementations could attenuate the aorta plaque formation by 30% and 20%, respectively. Apigenin-fed hamsters at both dosages displayed a 1.5-fold increase in hepatic Ldlr expression and a 40% reduction in non-HDL cholesterol level as compared with those in the control fed a high-cholesterol (HC) diet. Besides, faecal elimination of cholesterol was facilitated by 20% in the hamsters with high apigenin consumption. Suppressing the expression of the cholesterol transporter ncp1l1 in the intestinal mucosa could block the cholesterol absorption and promote its elimination. The differential regulations of ncp1l1 and Ldlr appeared to be the underlying hypocholesterolaemic mechanism of apigenin in this model system. Luteolin supplementation, on the other hand, had no effect on the blood cholesterol. CONCLUSIONS: This study illustrated that dietary administration of apigenin attenuated HC feeding-induced hypercholesterolemia in hamsters.


Assuntos
Apigenina/administração & dosagem , Colesterol na Dieta/efeitos adversos , Hipercolesterolemia/etiologia , Hipercolesterolemia/prevenção & controle , Animais , Cricetinae , Hipercolesterolemia/sangue , Masculino , Mesocricetus
15.
Artigo em Inglês | MEDLINE | ID: mdl-29763690

RESUMO

The environmental polycyclic aromatic hydrocarbons (PAH) and dioxins are carcinogens and their adverse effects have been largely attributed to the activation of AhR. Hesperetin is a flavonone found abundantly in citrus fruits and has been shown to be a biologically active agent. In the present study, the effect of hesperetin on the nuclear translocation of AhR and the downstream gene expression was investigated in MCF-7 cells. Confocal microscopy indicated that 7, 12-dimethylbenz[α]anthracene (DMBA) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) -induced nuclear translocation of AhR was deterred by hesperetin treatment. The reduced nuclear translocation could also be observed in Western analysis. Reporter-gene assay further illustrated that the induced XRE transactivation was weakened by the treatment of hesperetin. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay demonstrated that the gene expressions of CYP1A1, 1A2, and 1B1 followed the same pattern of AhR translocation. These results suggested that hesperetin counteracted AhR transactivation and suppressed the downstream gene expression.


Assuntos
Antineoplásicos Fitogênicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Neoplasias da Mama/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Hesperidina/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , 9,10-Dimetil-1,2-benzantraceno/antagonistas & inibidores , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/patologia , Neoplasias da Mama/prevenção & controle , Carcinógenos Ambientais/química , Carcinógenos Ambientais/toxicidade , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP1A1/química , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/química , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP1B1/antagonistas & inibidores , Citocromo P-450 CYP1B1/química , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Suplementos Nutricionais , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Reporter/efeitos dos fármacos , Humanos , Células MCF-7 , Microscopia Confocal , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Dibenzodioxinas Policloradas/antagonistas & inibidores , Dibenzodioxinas Policloradas/química , Receptores de Hidrocarboneto Arílico/metabolismo
16.
Amino Acids ; 50(7): 863-875, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29626300

RESUMO

One pathogenic mechanism of ethanol-induced liver injury is the excessive production of reactive oxygen species (ROS), which may result in alcoholic liver disease (ALD) characterized by cell death due to necrosis and apoptosis. Taurine was proved to protect against liver damage. However, whether taurine attenuates ethanol-induced hepatic apoptosis remains unknown. The present study aims to elucidate this effect and its underlying mechanism. Taurine was administered to ALD rats and an in vitro experiment in which taurine was added to primary rat hepatocytes cultured with ethanol was conducted. Mitochondrial function and anti-oxidative capacity of the liver were tested. TUNEL and AO-EB double staining were conducted to detect apoptosis of liver cells. Expressions of factors and proteins involved in mitochondrial and death receptor pathways were detected by RT-PCR and Western-blot. The results showed that taurine inhibited the decline of cell functions and apoptosis in hepatocytes cultured with ethanol. Furthermore, increased malondialdehyde (MDA) and reduced superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), cytochrome c oxidase (COX) and NADH dehydrogenase (ND) in ALD rats were mediated by taurine. RT-PCR and western-blot results revealed that taurine down-regulated expression of Bax, Fas, Fas ligand (FasL), caspase 3 and caspase 9 while up-regulating the expression of Bcl-2 in ethanol-cultured hepatocytes. In summary, taurine inhibit ethanol-induced hepatic apoptosis by regulating mitochondrial or death receptor pathways.


Assuntos
Apoptose/efeitos dos fármacos , Etanol/efeitos adversos , Hepatócitos/metabolismo , Mitocôndrias Hepáticas/metabolismo , Receptores de Morte Celular/metabolismo , Taurina/farmacologia , Animais , Etanol/farmacologia , Hepatócitos/patologia , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Masculino , Mitocôndrias Hepáticas/patologia , Ratos , Ratos Wistar
17.
Ultrasound Med Biol ; 44(6): 1177-1186, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29609809

RESUMO

This study was conducted to evaluate the value of acoustic structure quantification (ASQ) technology versus that of point shear wave speed measurement (PSWSM) imaging technology for the assessment of liver fibrosis stage. A total of 104 patients with chronic hepatitis B (CHB) and 30 healthy control patients underwent ASQ and PSWSM examinations. Seven quantitative parameters were obtained from ASQ, and a principal component analysis was used to establish the integrative indicators. A quantitative parameter, known as the shear wave speed (SWS, m/s), was obtained from the PSWSM. The METAVIR scores for the assessment of pathologic liver fibrosis were used as a benchmark. Liver fibrosis stages exhibited a good correlation with the integrative indicators and SWS (r = 0.682, p <0.001; r = 0.651, p <0.001). The areas under the receiver operating characteristic curves for ASQ and PSWSM were 0.705 and 0.854 for mild liver fibrosis (F ≥ 1, p = 0.045), 0.813 and 0.743 for significant liver fibrosis (F ≥ 2, p = 0.115), 0.839 and 0.857 for severe liver fibrosis (F ≥ 3, p = 0.417) and 0.874 and 0.971 for liver cirrhosis (F = 4, p = 0.016), respectively. In conclusion, both ASQ and PSWSM were promising ultrasonic methods for assessing liver fibrosis in patients with CHB; however, PSWSM was more valuable for identifying mild liver fibrosis (F ≥ 1) and cirrhosis (F = 4) than ASQ, and the combination of PSWSM and ASQ improved the accuracy of diagnosing severe liver fibrosis (F ≥ 3).


Assuntos
Técnicas de Imagem por Elasticidade/métodos , Hepatite B Crônica/complicações , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/etiologia , Adolescente , Adulto , Feminino , Humanos , Fígado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
18.
Exp Ther Med ; 15(4): 3231-3238, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29545840

RESUMO

The present study aimed to evaluate whether thymosin α1 (Tα1) increases survival rates through the improvement of immunofunction and inhibition of hepatocyte apoptosis in rats with acute liver failure (ALF). A total of 25 rats were randomly divided into the control group (CG), the model group (MG) and the treatment group (TG). The CG received an intraperitoneal injection of saline (2 ml). The ALF rat model was established by the intraperitoneal injection of D-galactosamine (700 mg/kg) and lipopolysaccharide (10 µg/kg). The TG received an intraperitoneal injection of Tα1 (0.03 mg/kg) 1 h prior to and 30 min after modeling. The survival rates of the rats were recorded. An additional 63 rats were randomly divided into a CG (n=3), MG (n=30) and TG (n=30). Three rats were sacrificed at 3, 6, 9 and 12 h after establishment of the rat model to detect plasma alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), tumor necrosis factor (TNF)-α and interleukin-10 (IL-10). Liver samples were stained with hematoxylin and eosin and TUNEL, and reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to detect B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) in liver tissue. The results indicated that the survival rate of the TG was significantly higher compared with that of the MG at 24 h (P<0.05). Plasma ALT, AST and TBIL in the MG and TG increased over time (3-12 h), with ALT, AST and TBIL observed to be significantly lower in the TG compared with the MG at each time-point (P<0.05). Hepatocellular necrosis, hemorrhage and inflammatory cell infiltration of ALF were aggravated over time (3-12 h) in the MG and TG. Notably, in the Tα1-treated rats, the hepatocytes appeared healthier with fewer apoptotic cells compared with those from the MG at the same time-points. Hepatocyte apoptotic index increased in the TG and MG, but was significantly lower in the TG compared with the MG at each time-point (P<0.05) in TUNEL assays. Plasma TNF-α and IL-10 in the MG and TG increased over time (3-12 h), with TNF-α observed to be significantly lower in the TG compared with the MG at each time-point (P<0.05), however, IL-10 was observed to be significantly higher in the TG compared with the MG at each time-point (P<0.05). Bax mRNA expression was significantly lower in the TG compared with the MG at each time-point (P<0.05), whereas Bcl-2 was significantly higher (P<0.05). In conclusion, Tα1 improved survival rates in an ALF rat model by downregulating TNF-α and upregulating IL-10, leading to the attenuation of hepatic inflammation and hepatocyte apoptosis.

19.
Gut ; 67(12): 2181-2191, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-28928275

RESUMO

OBJECTIVE: The definition of acute-on-chronic liver failure (ACLF) based on cirrhosis, irrespective of aetiology, remains controversial. This study aimed to clarify the clinicopathological characteristics of patients with hepatitis B virus-related ACLF (HBV-ACLF) in a prospective study and develop new diagnostic criteria and a prognostic score for such patients. DESIGN: The clinical data from 1322 hospitalised patients with acute decompensation of cirrhosis or severe liver injury due to chronic hepatitis B (CHB) at 13 liver centres in China were used to develop new diagnostic and prognostic criteria. RESULTS: Of the patients assessed using the Chronic Liver Failure Consortium criteria with the exception of cirrhosis, 391 patients with ACLF were identified: 92 with non-cirrhotic HBV-ACLF, 271 with cirrhotic HBV-ACLF and 28 with ACLF with cirrhosis caused by non-HBV aetiologies (non-HBV-ACLF). The short-term (28/90 days) mortality of the patients with HBV-ACLF were significantly higher than those of the patients with non-HBV-ACLF. Total bilirubin (TB) ≥12 mg/dL and an international normalised ratio (INR) ≥1.5 was proposed as an additional diagnostic indicator of HBV-ACLF, and 19.3% of patients with an HBV aetiology were additionally diagnosed with ACLF. The new prognostic score (0.741×INR+0.523×HBV-SOFA+0.026×age+0.003×TB) for short-term mortality was superior to five other scores based on both discovery and external validation studies. CONCLUSIONS: Regardless of the presence of cirrhosis, patients with CHB, TB ≥12 mg/dL and INR ≥1.5 should be diagnosed with ACLF. The new criteria diagnosed nearly 20% more patients with an HBV aetiology with ACLF, thus increasing their opportunity to receive timely intensive management.


Assuntos
Insuficiência Hepática Crônica Agudizada/diagnóstico , Hepatite B Crônica/diagnóstico , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/microbiologia , Insuficiência Hepática Crônica Agudizada/mortalidade , Adulto , Bilirrubina/sangue , Biomarcadores/sangue , China/epidemiologia , Feminino , Hepatite B Crônica/mortalidade , Humanos , Coeficiente Internacional Normatizado , Cirrose Hepática/complicações , Cirrose Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença
20.
J Med Virol ; 90(2): 263-270, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28876463

RESUMO

Mutations in hepatitis B virus (HBV) S gene are one of factors contributing to occult HBV infection (OBI). The study aimed to uncover the impact of OBI-related S-gene mutations on the detectability of hepatitis B surface antigen (HBsAg). Nine representative mutations within the major hydrophilic region of the S region were investigated. These included six (M1-M6) from an OBI patient with HBV-related hepatocellular carcinoma, and three (M7-M9) from three OBI blood donors. Recombinant plasmids on the basis of pTriEx-mod-1.1 HBV and pcDNA3.1(-)/myc-His A vectors were constructed for each and transfected into HepG2 or Huh7 cells, respectively. Electrochemical luminescence, ELISA, Western blotting, and confocal immunofluorescence were used to examine HBsAg expression and antigenicity. In comparison to wild-type strain, supernatant and intracellular HBsAg levels of the nine mutants were reduced by 56.39-99.09% and 42.76-99.77% upon Roche quantitative Elecsys assay, respectively. Confocal immunofluorescence showed that relative intensity ratios of HBsAg-myc-His fusion protein detected by anti-HBs and anti-His-tag were lower by 11.87-76.27% for the nine mutants compared to the wild-type strain. Specifically, M1-M5 mutants that we firstly found recently were 33.14%, 76.27%, 57.93%, 53.37%, and 40.88% lower, respectively. Consistent results were obtained using double-antibody sandwich ELISA assays (anti-myc + anti-HBs vs anti-myc + anti-His). Antigenicity reduction played a major role for the poor detectability of HBsAg caused by the OBI-related mutations, although decreased HBsAg expression of some mutants and anti-HBs in samples might play coordinated roles. Taken together, antigenicity reduction contributes mostly to poor detectability of HBsAg caused by these OBI-related mutations.


Assuntos
Testes Diagnósticos de Rotina/métodos , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/diagnóstico , Imunoensaio/métodos , Proteínas Mutantes/sangue , Antígenos de Superfície da Hepatite B/genética , Humanos , Proteínas Mutantes/genética , Sensibilidade e Especificidade
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