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1.
J Magn Reson Imaging ; 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34545977

RESUMO

BACKGROUND: Partial bile duct ligation (PBDL) model is a reliable cholestatic fibrosis experimental model that showed complex histopathological changes. Magnetic resonance imaging (MRI) features of PBDL have not been well characterized. PURPOSE: To investigate the potential of MRI parameters in assessing fibrosis in PBDL and explore the relationships between MRI and pathological features. ANIMAL MODEL: Established PBDL models. POPULATION: Fifty-four mice were randomly divided into four timepoints PBDL groups and one sham group. FIELD STRENGTH/SEQUENCE: 3.0 T; MRI sequences included T1-weighted fast spin-echo (FSE), T2-weighted single shot FSE, variable flip angle T1 mapping, multi-echo SE T2 mapping, multi-echo gradient-echo T2* mapping, and multi-b-value diffusion-weighted imaging. ASSESSMENT: MRI examination was performed at the corresponding timepoints after surgery. Native T1, ΔT1 (T1native-T1post), T2, T2*, apparent diffusion coefficient (ADC) values, histogram parameters (skewness and kurtosis), intravoxel incoherent motion parameters (f, D, and D* ) within the entire ligated (PBDL), non-ligated liver (PBDL), and whole liver (sham) were obtained. Fibrosis and inflammation were assessed in Masson and H&E staining slices using the Metavir and activity scoring system. STATISTICAL TESTS: One-way ANOVA, Spearman's rank correlation, and receiver operating characteristic curves were performed. P < 0.05 was considered statistically significant. RESULTS: Fibrosis and inflammation were finally staged as F3 and A3 in ligated livers but were not observed in non-ligated or sham livers. Ligated livers displayed significantly elevated native T1, ΔT1, T2, and reduced ADC and T2* than other livers. Spearman's correlation showed better correlation with inflammation (r = 0.809) than fibrosis (r = 0.635) in T2 and both ΔT1 and ADC showed stronger correlation with fibrosis (r = 0.704 and r = -0.718) than inflammation (r = 0.564 and r = -0.550). Area under the curve (AUC) for ΔT1 performed the highest (0.896). When combined with all relative parameters, AUC increased to 0.956. DATA CONCLUSION: Multiparametric MRI can evaluate and differentiate pathological changes in PBDL. ΔT1 and ADC better correlated with fibrosis while T2 stronger with inflammation. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

2.
Magn Reson Imaging ; 81: 75-81, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34147594

RESUMO

OBJECTIVE: To investigate the clinical feasibility of single-breath-hold (SBH) T2-weighted (T2WI) liver MRI with deep learning-based reconstruction in the evaluation of image quality and lesion delineation, compared with conventional multi-breath-hold (MBH) T2WI. METHODS: One hundred and fifty-two adult patients with suspected liver disease were prospectively enrolled. Two independent readers reviewed images acquired with conventional MBH-T2WI and SBH-T2WI at 3.0 T MR scanner. For image quality analyses, motion artifacts scores and boundary sharpness scores were compared using nonparametric Wilcoxon matched pairs tests between MBH-T2WI and SBH-T2WI. With the reference standard, 89 patients with 376 index lesions were included for lesion analyses. The lesion detection rates were compared by chi-square test, the lesion conspicuity scores and lesion-liver contrast ratio (CR) were compared using nonparametric Wilcoxon matched pairs tests between the two sequences. RESULTS: For both readers, motion artifacts scores of SBH-T2WI were significantly lower than MBH-T2WI (P < 0.001). Boundary sharpness scores of SBH-T2WI were significantly higher than MBH-T2WI (P < 0.001). The lesion detection rates for SBH-T2WI were significantly higher than MBH-T2WI (P < 0.001); the differences of lesion detection rates between the two sequences were statistically significant for small (≤ 10 mm) liver lesions (P < 0.001), while not significant for larger (> 10 mm) lesions (P > 0.05). Lesion conspicuity scores were significantly higher on SBH-T2WI than MBH-T2WI in the entire cohort as well as in both stratified subgroups of lesions ≤10 mm and > 10 mm (P < 0.001 for all). CRs for focal liver lesions were also significantly higher with SBH-T2WI (P < 0.001). CONCLUSION: The SBH-T2WI sequence with deep-learning based reconstruction showed promising performance as it provided significantly better image quality, lesion detectability, lesion conspicuity and contrast within a single breath-hold, compared with the conventional MBH-T2WI.


Assuntos
Aprendizado Profundo , Hepatopatias , Neoplasias Hepáticas , Adulto , Artefatos , Estudos de Viabilidade , Humanos , Aumento da Imagem , Fígado/diagnóstico por imagem , Hepatopatias/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Imageamento por Ressonância Magnética
3.
Math Biosci Eng ; 16(6): 7921-7933, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31698647

RESUMO

Background: An increasing number of patients with advanced non-small cell lung cancer (NSCLC) have a poor prognosis and develop progressive disease after receiving conventional treatments. In recent years, several novel therapies have been approved for later lines of therapy of previously treated NSCLC. Erlotinib, an EGFR tyrosine kinase inhibitor, was recommended as the second-line therapy for pre-treated patients. However, the use of erlotinib has been reported to represent different clinical effects and adverse effects. Objectives: The current study was aim to investigate the efficacy and safety of erlotinib versus chemotherapy in pre-treated patients with advanced NSCLC. Methods: Electronic databases were searched for eligible literatures updated on June 2018. Randomized-controlled trials assessing the efficacy and safety of erlotinib in pre-treated NSCLC were included, of which the main outcomes were ORR (objective response rate), PFS (progression-free survival), OS (overall survival) and AEs (adverse events). All the data were pooled with the corresponding 95% confidence interval using RevMan software. Sensitivity analyses and heterogeneity were quantitatively evaluated. Results: A total of 11 randomized controlled trials were included in this analysis. The group of erlotinib did not achieved benefit in progression-free survival (OR = 0.61, 95%CI = 0.33-1.12, P = 0.11), overall survival (OR = 0.98, 95%CI = 0.84-1.15, P = 0.81) as well with the objective response rate (OR = 0.77, 95%CI = 0.36-1.63, P = 0.49), respectively. In the results of subgroup analysis among the patients with EGFR wild-type, there is also no significant differences in overall survival with erlotinib (OR = 0.90, 95%CI = 0.78-1.04, P = 0.15) and progression-free survival (OR = 0.33, 95%CI = 0.09-1.18, P = 0.09). The most common treatment-related adverse events in the erlotinib group is rash (OR = 5.79, 95%CI = 2.12-15.77, P = 0.0006), and neutropenia (OR = 0.02, 95%CI = 0.01-0.10, P ≤ 0.00001) is more found in the control group. In addition, fatigue (P = 0.09) and diarrhea (P = 0.52), the difference between the two groups had no statistical significance. Conclusions: There was no significant difference noted with regard to efficacy and safety between erlotinib vs. chemotherapy as the later-line therapy for previously treated patients with NSCLC, even with subgroup patients who have wild-type EGFR tumors. While, erlotinib might increase the risk of rash, and decrease the risk of neutropenia, compared with the chemotherapy. Further research is needed to develop a database of all EGFR mutations and their individual impact on the differing treatments.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptores ErbB/genética , Cloridrato de Erlotinib/efeitos adversos , Exantema/induzido quimicamente , Humanos , Mutação , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Razão de Chances , Segurança do Paciente , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico
4.
Math Biosci Eng ; 16(4): 2942-2958, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-31137244

RESUMO

Colorectal cancer (CRC) is one of the most common malignancies, giving rise to serious financial burden globally. This study was designed to explore the potential mechanisms implicated with CRC and identify some key biomarkers. CRC-associated gene expression dataset (GSE32323) was downloaded from GEO database. The differentially expressed genes (DEGs) were selected out based on the GEO2R tool. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed to search the enriched pathways of these DEGs. Additionally, a protein-protein interaction (PPI) network was also constructed to visualize interactions between these DEGs. Quantitative Real-time PCR (qPCR) was further performed to valid the top5 up-regulated and top5 down-regulated genes in patients with CRC. Finally, the survival analysis of the top5 up-regulated and top5 down-regulated genes was conducted using GEPIA, aiming to clarify their potential effects on CRC. In this study, a total of 451 DEGs were captured (306 down-regulated genes and 145 up-regulated genes). Among these DEGs, the top5 up-regulated genes were DPEP1, KRT23, CLDN1, LGR5 and FOXQ1 while the top5 down-regulated genes were CLCA4, ZG16, SLC4A4, ADH1B and GCG. GO analysis revealed that these DEGs were mainly enriched in cell adhesion, cell proliferation, RNA polymerase II promoter and chemokine activity. KEGG analysis disclosed that the enriched pathway included mineral absorption, chemokine signaling pathway, transcriptional misregulation in cancer, pathways in cancer and PPAR signaling pathway. Survival analysis showed that the expression level of ZG16 may correlate with the prognosis of CRC patients. Furthermore, according to the connectivity degree of these DEGs, we selected out the top15 hub genes, namely MYC, CXCR1, TOP2A, CXCL12, SST, TIMP1, SPP1, PPBP, CDK1, THBS1, CXCL1, PYY, LPAR1, BMP2 and MMP3, which were expected to be promising therapeutic target in CRC. Collectively, our analysis unveiled potential biomarkers and candidate targets in CRC, which could be helpful to the diagnosis and treatment of CRC.


Assuntos
Neoplasias Colorretais/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Neoplasias Colorretais/metabolismo , Biologia Computacional , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Conceitos Matemáticos , Prognóstico , Mapas de Interação de Proteínas/genética , Transdução de Sinais/genética
5.
J Dermatol ; 45(7): 867-870, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29740858

RESUMO

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease characterized by hamartomas in multiple organ systems. This study was performed in one familial and two sporadic cases with TSC. Two novel mutations (c.1884_1887delAAAG and c.5266A>G) and two previously reported mutations (c.4258_4261delTCAG and c.1960G>C) were identified by direct DNA sequencing. Of the four mutations, c.1884_1887delAAAG and c.1960G>C were found in a family and identified in the same allele by TA cloning sequencing. However, c.1960G>C was reported to be non-pathogenic. Furthermore, correlations between genotypes and phenotypes of Chinese Han patients since 2014 were performed by paired χ2 -tests in our published work review, which has not been reported. The results showed that patients with TSC2 mutations had a higher frequency of mental retardation and there were no significant differences of seizures and skin lesions with TSC1 mutations. Genetically, they had a higher frequency of familial inheritance.


Assuntos
Deficiência Intelectual/genética , Convulsões/genética , Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Encéfalo/diagnóstico por imagem , Criança , Análise Mutacional de DNA , Eletroencefalografia , Éxons/genética , Feminino , Genótipo , Humanos , Deficiência Intelectual/diagnóstico , Mutação , Fenótipo , Convulsões/diagnóstico , Pele/patologia , Tomografia Computadorizada por Raios X , Esclerose Tuberosa/diagnóstico por imagem , Esclerose Tuberosa/patologia , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa
7.
Acta Pharmacol Sin ; 37(4): 555-60, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26924289

RESUMO

AIM: To examine how the endogenous CYP3A4 phenotype and CYP3A5(*)3 genotype of Chinese renal transplant recipients influenced the dose-corrected trough concentration (C0/D) and weight-corrected daily dose (D/W) of tacrolimus. METHODS: A total of 101 medically stable kidney transplant recipients were enrolled, and their blood and urine samples were gathered. The endogenous CYP3A4 phenotype was assessed by the ratio of 6ß-hydroxycortisol and 6ß-hydroxycortisone to cortisol and cortisone in urine. CYP3A5(*)3 genotype was determined using PCR-RELP. RESULTS: In overall renal transplant recipients, a multiple regression analysis including the endogenous CYP3A4 phenotype, CYP3A5(*)3 genotype and post-operative period accounted for 60.1% of the variability in C0/D ratio; a regression equation consisting of the endogenous CYP3A4 phenotype, post-operative period, body mass index, CYP3A5(*)3 genotype, gender, total bilirubin and age explained 61.0% of the variability in D/W ratio. In CYP3A5(*)3/(*)3 subjects, a combination of the endogenous CYP3A4 phenotype, post-operative period and age was responsible for 65.3% of the variability in C0/D ratio; a predictive equation including the endogenous CYP3A4 phenotype, post-operative period, body mass index, gender and age explained 61.2% of the variability in the D/W ratio. Base on desired target range of tacrolimus trough concentrations, individual daily dosage regimen was calculated, and all the observed daily doses were within the predicted range. CONCLUSION: This study provides the equations to predict tacrolimus metabolism and dosage requirements based on the endogenous CYP3A4 phenotype, CYP3A5(*)3 genotype and other non-genetic variables.


Assuntos
Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Imunossupressores/metabolismo , Transplante de Rim , Tacrolimo/metabolismo , Grupo com Ancestrais do Continente Asiático , Cortisona/análogos & derivados , Cortisona/sangue , Cortisona/urina , Humanos , Hidrocortisona/análogos & derivados , Hidrocortisona/sangue , Hidrocortisona/urina , Imunossupressores/administração & dosagem , Tacrolimo/administração & dosagem
8.
Exp Cell Res ; 332(1): 47-59, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25576381

RESUMO

Here we reported that co-administration of docetaxel and a cell-permeable short-chain ceramide (C6) resulted in a striking increase in growth inhibition and apoptosis in primary and transformed breast cells (MCF-7 and MDA-231), which were associated with mitochondrial permeability transition pore (mPTP) opening, a significant reactive oxygen species (ROS) production and the pro-apoptotic AMP-Protein Kinase (AMPK) as well as c-Jun N-terminal kinases (JNK) activations. Contrarily, the mPTP blocker sanglifehrin A (SfA) or the ROS scavenger N-acetyl-l-cysteine (NAC) largely inhibited co-administration-induced cytotoxicity. Further, cyclosporin A (CsA), the inhibitor of cyclophilin-D (Cyp-D, the key mPTP component), as well as Cyp-D RNA silencing also suppressed breast cancer cell death by the co-treatment, while cells overexpressing Cyp-D showed hypersensitivity to docetaxel. Meanwhile, JNK and AMPK inhibition alleviated cell death induced by the co-administration in cultured breast cancer cells. Significantly, C6 ceramide plus docetaxel caused dramatic human epidermal growth factor receptor (HER)-1/-2 degradation and downstream Akt/Erk inhibition in HER-2 expressing MDA-231 cells. These in vitro findings provide confidence in support of further development of C6 ceramide as an adjunct of docetaxel for the treatment of the metastatic breast cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose , Ceramidas/farmacologia , Taxoides/farmacologia , Adenilato Quinase/metabolismo , Neoplasias da Mama , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Docetaxel , Sinergismo Farmacológico , Receptores ErbB/metabolismo , Feminino , Células HEK293 , Humanos , Ácidos Hidroxâmicos/farmacologia , MAP Quinase Quinase 4/metabolismo , Células MCF-7 , Alvo Mecanístico do Complexo 1 de Rapamicina , Complexos Multiproteicos/metabolismo , Paclitaxel/farmacologia , Proteólise , Serina-Treonina Quinases TOR/metabolismo , Vorinostat
9.
Acta Pharmacol Sin ; 35(11): 1447-52, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25283504

RESUMO

AIM: Pharmacodynamic analysis of intravenous recombinant urate oxidase produced by Escherichia coli was performed in healthy subjects using a pharmacokinetic/pharmacodynamic (PK/PD) model. METHODS: A randomized, single-blind, placebo-controlled study was performed in 40 healthy Chinese subjects (4 groups of 10 subjects each, placebo 4:1 ratio) who received infusions of uricase (single doses of 0.1, 0.2, and 0.3 mg/kg; multiple doses of 0.2 mg·kg(-1)·d(-1) for 7 d). PK profiles were determined through plasma uricase activity, and PD profiles were established using uric acid levels in plasma and urine. The plasma PD parameter was estimated as changes in plasma uric acid levels as the effect in the indirect response model. Adverse events were also monitored. RESULTS: A two-compartment PK model with constant iv input and first-order output was used to describe the kinetic process of plasma uricase. The low value (2.8 U/L) of drug concentration that achieved 50% of maximum effect (EC50) indicated that low plasma uricase concentrations were sufficient to produce pharmacological effects. A strong relationship (r(2)=0.9991) between the mean uric acid concentration in blood and the mean uric acid excretion rate in urine in the range of 11 to 30 h after single dosing was found. Infusions of uricase were well tolerated in all subjects. CONCLUSION: The PK/PD model predicted the effective dose to be 0.1 mg/kg in healthy subjects. The excretion rate of uric acid in urine may be used as a new index for pharmacological effects in further clinical trials.


Assuntos
Supressores da Gota/administração & dosagem , Supressores da Gota/farmacocinética , Modelos Biológicos , Urato Oxidase/administração & dosagem , Urato Oxidase/farmacocinética , China , Cálculos da Dosagem de Medicamento , Feminino , Supressores da Gota/sangue , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/sangue , Proteínas Recombinantes/farmacocinética , Eliminação Renal , Método Simples-Cego , Urato Oxidase/sangue , Ácido Úrico/sangue , Ácido Úrico/urina , Adulto Jovem
10.
BMC Cancer ; 14: 373, 2014 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-24886166

RESUMO

BACKGROUND: Pancreatic cancer is one of the most aggressive human malignancies with a extremely low 5-year survival rate. Hence, the search for more effective anti-pancreatic cancer agents is urgent. METHODS: PaTu8988 pancreatic cancer cells were treated with different concentrations of suberoylanilide hydroxamic acid (SAHA), cell survival, proliferation, migration and vasculogenic mimicry (VM) were analyzed. Associated signaling changes were also analyzed by RT-PCR and Western blots. RESULTS: Here, we reported that SAHA, a histone deacetylase inhibitor (HDACi), exerted significant inhibitory efficiency against pancreatic cancer cell survival, proliferation, migration and VM. SAHA dose-dependently inhibited PaTu8988 pancreatic cancer cell growth with the IC-50 of 3.4 ± 0. 7 µM. Meanwhile, SAHA suppressed PaTu8988 cell cycle progression through inducing G2/M arrest, which was associated with cyclin-dependent kinase 1 (CDK-1)/cyclin-B1 degradation and p21/p27 upregulation. Further, SAHA induced both apoptotic and non-apoptotic death of PaTu8988 cells. Significantly, SAHA suppressed PaTu8988 cell in vitro migration and cell-dominant tube formation or VM, which was accompanied by semaphorin-4D (Sema-4D) and integrin-ß5 down-regulation. Our evidences showed that Akt activation might be important for Sema-4D expression in PaTu8988 cells, and SAHA-induced Sema-4D down-regulation might be associated with Akt inhibition. CONCLUSIONS: This study is among the first to report the VM formation in cultured human pancreatic cancer cells. And we provided strong evidence to suggest that SAHA executes significant anti-VM efficiency in the progressive pancreatic cancer cells. Thus, SAHA could be further investigated as a promising anti-pancreatic cancer agent.


Assuntos
Inibidores de Histona Desacetilases/administração & dosagem , Histona Desacetilases/biossíntese , Ácidos Hidroxâmicos/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Proteína Quinase CDC2/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/genética , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Neoplasias Pancreáticas/patologia , Vorinostat
11.
Eur J Pharmacol ; 702(1-3): 258-63, 2013 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-23415746

RESUMO

α-DDB-DU, 2'-deoxy-3'-(4,4'-dimethoxy-2'-methoxycarbonyl-5,6,5',6'-bis(methylenedioxy)-1,1'-biphenyl-2-carboxyl)uridine, is a novel nucleoside analogue accomplished by linking α-DDB (α-dimenthoxy dicarboxylate biphenyl) and DU (2'-deoxyuridine) via an ester bond. In the current study, the anti-HBV activity and hepatoprotective effect of this compound were investigated both in vitro and in vivo. In the human HBV-transfected liver cell line HepG2.2.15, α-DDB-DU effectively suppressed the secretion of the HBV antigens in a dose-dependent manner, with inhibition rate of 42.31% for HBsAg and 31.52% for HBeAg at 5 µM on day 9. In addition, it could inhibit the viral DNA replication effectively at the concentration of 5 µM, with 81.18% intracellular inhibition and 88.55% extracellular inhibition, respectively, on day 9. In the duck hepatitis B virus (DHBV) infected model, DHBV DNA levels were markedly reduced after treatment with the α-DDB-DU at the dosages of 0.8 mg/kg day, 4 mg/kg day and 20 mg/kg day. The inhibition rate of α-DDB-DU at the dose of 20 mg/kg day reached 93.75% and 89.43%, in duck serum and liver, respectively, on day 10. Furthermore, the levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) in both serum and livers were notably reduced on day 10 and histopathological evaluation of the animals' livers indicated significant improvement. In conclusion, α-DDB-DU possesses significant inhibitory activity against HBV replication and ameliorates hepatic pathology significantly.


Assuntos
Antivirais/farmacologia , Benzodioxóis/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Uridina/análogos & derivados , Animais , Benzodioxóis/uso terapêutico , DNA Viral/análise , Patos , Feminino , Células Hep G2 , Hepatite B/tratamento farmacológico , Hepatite B/patologia , Hepatite B/virologia , Antígenos de Superfície da Hepatite B/imunologia , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/virologia , Masculino , Uridina/farmacologia , Uridina/uso terapêutico
12.
Eur J Pharmacol ; 683(1-3): 10-5, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22387093

RESUMO

Hepatitis B virus (HBV) infection causes major public health problems worldwide. The clinical limitation of current antiviral drugs for HBV, such as lamivudine, is the emergence of drug-resistant viral strains during prolonged antiviral therapy. Cepharanthine hydrochloride (CH), a natural alkaloid-derived compound, has been reported to possess potent activity against various viruses. The present study was performed to evaluate the in vitro activity of CH against clinical wild-type and lamivudine-resistant HBV isolates in transiently transfected cells. HBV DNA was extracted from serum samples collected both before lamivudine therapy and at the time of viral breakthrough and was amplified by polymerase chain reaction (PCR). The amplicons were cloned into a novel expression vector, pHY106, which can initiate the intracellular HBV replication cycle after cell transfection. Following transfection of the cloned amplicon into HepG2 cells, a drug susceptibility assay was performed. The level of viral antigen, HBeAg, was determined by enzyme-linked immunosorbent assay (ELISA). Quantitative real-time PCR (Q-PCR) was used for determining the amount of intracellular HBV DNA. Heat stress cognate 70 (Hsc70), a host protein required for HBV replication, was also analyzed by reverse transcription PCR (RT-PCR) to explore the possible antiviral mechanism of CH. The results showed that CH inhibited replication and HBeAg production by either wild-type or lamivudine-resistant HBV clinical isolates in a dose-dependent manner. The Hsc70 mRNA was also downregulated significantly. In conclusion, CH is active against both wild-type and lamivudine-resistant HBV clinical isolates, and its activity may be associated with its inhibition of host Hsc70.


Assuntos
Antivirais/farmacologia , Benzilisoquinolinas/farmacologia , Farmacorresistência Viral , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Lamivudina/uso terapêutico , Replicação Viral/efeitos dos fármacos , Adulto , Antivirais/efeitos adversos , Benzilisoquinolinas/efeitos adversos , Sobrevivência Celular/efeitos dos fármacos , China , DNA Viral/sangue , DNA Viral/isolamento & purificação , DNA Viral/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSC70/genética , Proteínas de Choque Térmico HSC70/metabolismo , Células Hep G2 , Hepatite B/sangue , Hepatite B/virologia , Antígenos E da Hepatite B/genética , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Vírus da Hepatite B/fisiologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Concentração Inibidora 50 , Masculino , RNA Mensageiro/metabolismo , Proteínas Recombinantes/metabolismo
13.
Zhonghua Yi Xue Za Zhi ; 91(20): 1393-6, 2011 May 31.
Artigo em Chinês | MEDLINE | ID: mdl-21756810

RESUMO

OBJECTIVE: To explore the mRNA and protein expressions of Runx3 gene in papillary thyroid carcinoma (PTC). METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to detect the Runx3 mRNA and protein levels in 67 human PTC specimens and their matched adjacent non-cancerous epithelium (NCE). RESULTS: The relative expression value of Runx3 mRNA was 0.31 ± 0.07 in PTC versus 0.92 ± 0.08 in NCE (t = 38.251, P < 0.05). In PTC, it was correlated with the tumor pathological grade and lymph node metastasis (χ(2) = 5.511, 6.492, P < 0.05). The integral optical density value of Runx3 protein confirmed was 1012 ± 221 in PTC versus 1993 ± 199 in NCE (t = 18.413, P < 0.05). In PTC, it was correlated with the tumor TNM stage, pathological grade and lymph node metastasis (χ(2) = 5.550, 9.678, 5.070, P < 0.05). Furthermore there was a distinct correlation between the mRNA and protein expressions of Runx3 gene (χ(2) = 42.699, P < 0.05). CONCLUSION: The mRNA and protein expressions of Runx3 gene in PTC were lower than those in NCE. A lower expression of Runx3 gene may play an important role in the carcinogenesis and progression of PTC.


Assuntos
Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Adolescente , Adulto , Idoso , Carcinoma , Carcinoma Papilar , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/genética , Adulto Jovem
14.
Artigo em Chinês | MEDLINE | ID: mdl-21781566

RESUMO

OBJECTIVE: To study the relationship between status of methylation of human runt-related transcription factor 3 (RUNX3) gene promoter in papillary thyroid carcinoma (PTC). METHODS: Methylation-specific PCR and immunohistochemical SP technique were used to detect the methylation of RUNX3 gene promoter and expression of its protein in 56 cases of PTC and their matched adjacent non-carcinous epithelium (NCE). RESULTS: In NCE, there was no methylation of RUNX3 gene promoter, while in PTC the methylation rate was 35.7%(20/56), which was related to the tumor TNM stage, pathological grade and lymph node metastasis (P < 0.05). The positive rates of RUNX3 protein expression in NCE and PTC were 100.0% and 60.7%, respectively, with a significant difference (χ(2) = 27.378, P < 0.05). In PTC, the positive rates of RUNX3 protein expression in gradeI and grade II were 70.0% and 37.5%, respectively (P < 0.05); the rates were 46.7% and 76.9% in lymph node metastasis group and no metastasis group, respectively (P < 0.05). Moreover, there was a distinct correlation between methylation of RUNX3 gene promoter and expression of its protein (χ(2) = 21.62, P < 0.01). CONCLUSIONS: Methylation of promoter might be one of the important factors of inactivation of RUNX3 gene, and might play an important role in carcinogenesis and progression of PTC.


Assuntos
Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Metilação de DNA , Regiões Promotoras Genéticas , Neoplasias da Glândula Tireoide/metabolismo , Adolescente , Adulto , Idoso , Carcinoma , Carcinoma Papilar , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/patologia , Adulto Jovem
15.
Artigo em Chinês | MEDLINE | ID: mdl-21575418

RESUMO

OBJECTIVE: To study the expressions of Piwil2 protein and mRNA in papillary thyroid carcinoma (PTC) and the relationship between Piwil2 and the invasion and metastasis of PTC. METHODS: Immunohistochemistry and in situ hybridization were used to detect the expression of Piwil2 protein and mRNA in 60 cases of PTC with the matched adjacent non-cancerous epithelium (NCE). RESULTS: The positive rates of Piwil2 protein expression in PTC and NCE were 88.3% (53/60) and 10.0% (6/60) respectively, with significant difference (χ² = 73.654, P < 0.01). The positive rates of Piwil2 mRNA expression in PTC and NCE were 85.0% (51/60) and 6.7% (4/60) respectively, also with significant difference (χ(2) = 74.148, P < 0.01). Up-regulated expressions of Piwil2 protein and mRNA were related to the invasion and metastasis of PTC (P < 0.05). CONCLUSIONS: Piwil2 may play a role in the invasion and metastasis of PTC.


Assuntos
Proteínas/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Adolescente , Adulto , Idoso , Proteínas Argonauta , Carcinoma , Carcinoma Papilar , Criança , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Proteínas/genética , RNA Mensageiro/genética , Câncer Papilífero da Tireoide , Adulto Jovem
17.
Antiviral Res ; 84(2): 150-8, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19699238

RESUMO

Coxsackie virus B3 (CVB3) is believed to be a major contributor to viral myocarditis since virus-associated apoptosis plays a role in the pathogenesis of experimental myocarditis. In this study, we investigated the in vitro and in vivo antiviral activities of Phyllaemblicin B, the main ellagitannin compound isolated from Phyllanthus emblica, a Chinese herb medicine, against CVB3. Herein we report that Phyllaemblicin B inhibited CVB3-mediated cytopathic effects on HeLa cells with an IC(50) value of 7.75+/-0.15microg/mL. In an in vivo assay, treatment with 12mgkg(-1)d(-1) Phyllaemblicin B reduced cardiac CVB3 titers, decreased the activities of LDH and CK in murine serum, and alleviated pathological damages of cardiac muscle in myocarditic mice. Moreover, Phyllaemblicin B clearly inhibited CVB3-associated apoptosis effects both in vitro and in vivo. These results show that Phyllaemblicin B exerts significant antiviral activities against CVB3. Therefore, Phyllaemblicin B may represent a potential therapeutic agent for viral myocarditis.


Assuntos
Apoptose/efeitos dos fármacos , Infecções por Coxsackievirus/tratamento farmacológico , Enterovirus Humano B/efeitos dos fármacos , Glicosídeos , Coração/virologia , Miocardite/tratamento farmacológico , Animais , Antivirais/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Infecções por Coxsackievirus/virologia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Enterovirus Humano B/genética , Enterovirus Humano B/isolamento & purificação , Enterovirus Humano B/patogenicidade , Glicosídeos/química , Glicosídeos/farmacologia , Glicosídeos/uso terapêutico , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/virologia , Miocárdio
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