Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 59
Filtrar
Mais filtros










Filtros aplicados

Base de dados
Intervalo de ano de publicação
1.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188365, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32325165

RESUMO

Transcriptional factors (TFs) play a central role in governing gene expression under physiological conditions including the processes of embryonic development, metabolic homeostasis and response to extracellular stimuli. Conceivably, the aberrant dysregulations of TFs would dominantly result in various human disorders including tumorigenesis, diabetes and neurodegenerative diseases. Serving as the most evolutionarily reserved TFs, Fox family TFs have been explored to exert distinct biological functions in neoplastic development, by manipulating diverse gene expression. Recently, among the Fox family members, the pilot roles of FoxAs attract more attention due to their functions as both pioneer factor and transcriptional factor in human tumorigenesis, particularly in the sex-dimorphism tumors. Therefore, the pathological roles of FoxAs in tumorigenesis have been well-explored in modulating inflammation, immune response and metabolic homeostasis. In this review, we comprehensively summarize the impressive progression of FoxA functional annotation, clinical relevance, upstream regulators and downstream effectors, as well as valuable animal models, and highlight the potential strategies to target FoxAs for cancer therapies.


Assuntos
Antineoplásicos/farmacologia , Carcinogênese/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fatores Nucleares de Hepatócito/metabolismo , Neoplasias/genética , Animais , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Intervalo Livre de Doença , Fatores de Transcrição Forkhead/antagonistas & inibidores , Fatores Nucleares de Hepatócito/antagonistas & inibidores , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Neoplasias/patologia , Domínios Proteicos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
2.
Histol Histopathol ; 34(11): 1217-1227, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30848476

RESUMO

A normal counterpart and precancerous lesion that non-terminal respiratory unit (TRU) lung adenocarcinomas (LADCs) develop from have not been clarified. Non-TRU LADCs specifically express hepatocyte nuclear factor 4α (HNF4α). Thus, we have been interested in airway epithelial cells that express HNF4α as the potential precursor of non-TRU LADC. The purposes of the present study are to report the frequency and distribution of HNF4α-expressing cells at the different airway levels, and to investigate the potential significance of the expression of HNF4α in the histogenesis of non-TRU LADC with a special reference to the relationship to bronchiolar metaplasia in idiopathic interstitial pneumonia. We herein identified a minor subpopulation of epithelial cells that express HNF4α in a physiological state. This subpopulation was mainly located in the terminal bronchioles and had the appearance of ciliated cells, which were mutually exclusive from Clara cells and others that strongly expressed thyroid transcription factor 1. Furthermore, the expression of HNF4α was similar in bronchiolar metaplastic lesions and the terminal bronchioles, and some of the metaplastic lesions showed an unequivocally higher frequency and expression level of HNF4α, which was comparable to non-TRU LADC. In summary, this is the first study to describe a subpopulation of ciliated cells that express HNF4α as a potential normal counterpart for non-TRU LADCs and suggests that bronchiolar metaplastic lesions that strongly express HNF4α are a precancerous lesion for non-TRU LADCs.


Assuntos
Adenocarcinoma de Pulmão/etiologia , Células Epiteliais/metabolismo , Fatores Nucleares de Hepatócito , Neoplasias Pulmonares/etiologia , Lesões Pré-Cancerosas/metabolismo , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Bronquíolos/citologia , Bronquíolos/metabolismo , Bronquíolos/patologia , Células Epiteliais/citologia , Fatores Nucleares de Hepatócito/metabolismo , Humanos , Pneumonias Intersticiais Idiopáticas/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metaplasia/metabolismo , Metaplasia/patologia , Sistema Respiratório/citologia , Sistema Respiratório/metabolismo , Sistema Respiratório/patologia , Fator Nuclear 1 de Tireoide/metabolismo
3.
J Sex Med ; 15(11): 1527-1536, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30415809

RESUMO

BACKGROUND: Hepatocyte nuclear factor-4α (HNF4A) can influence the risk of insulin resistance that is postulated to be an important link between metabolic syndrome (MetS) and testosterone deficiency (TD) in men. AIM: To investigate the relationship between single-nucleotide polymorphisms (SNPs) of HNF4A and the risk of developing MetS and TD in a population of aging Taiwanese men. METHODS: A free health screening of men over 40 years of age was conducted in a medical center in Kaohsiung City, Taiwan. All participants underwent a physical examination, answered a questionnaire on demographics and medical history, completed the Androgen Deficiency in The Aging Male questionnaire to assess clinical symptoms of TD, and provided 20-mL whole blood samples for biochemical, hormonal, and genetic evaluation. MAIN OUTCOME MEASURE: 3 common SNPs (rs11574736, rs1884613, and rs2144908) of HNF4A were selected and identified using a TaqMan 5' allelic discrimination assay. RESULTS: 559 men were enrolled for this study (mean age, 55.8± 4.9 years). Prevalence of TD was significantly higher (P = .031) in subjects with MetS (16.8%) than those without MetS (10.1%). In SNP rs1884613 of HNF4A, subjects with the C allele carried a 1.31- and 1.50-times higher risk of developing MetS and TD, respectively, compared to those with the G allele, after adjusting for potential covariates. In addition, subjects with the CC genotype were exposed to a 1.91- and 2.20-times higher risk of developing MetS and TD, respectively, compared to those with the GG genotype. CLINICAL IMPLICATIONS: Our findings may point to the importance of the role played by insulin resistance in the link between MetS and TD. STRENGTH & LIMITATIONS: Our current work is the first report with adequate sample size to evaluate the role of genetic variants of HNF4A on the risk of both MetS and TD in men. The limitations included subjects enrolled from a free health screening and single measurement of serum testosterone levels. CONCLUSION: The rs1884613 SNP marker of HNF4A is significantly associated with an increased risk for developing both MetS and TD in aging Taiwanese men. Further population-based studies utilizing larger samples of different ethnicities may be needed to confirm these preliminary results. Liu C-C, Lee Y-C, Hung S-P. Hepatocyte Nuclear Factor-4α P2 Promoter Variants Are Associated With the Risk of Metabolic Syndrome and Testosterone Deficiency in Aging Taiwanese Men. J Sex Med 2018;15:1527-1536.


Assuntos
Disfunção Erétil/genética , Fatores Nucleares de Hepatócito/genética , Síndrome Metabólica/genética , Regiões Promotoras Genéticas/genética , Testosterona/deficiência , Adulto , Idoso , Envelhecimento , Grupo com Ancestrais do Continente Asiático , Disfunção Erétil/sangue , Disfunção Erétil/epidemiologia , Genótipo , Humanos , Masculino , Saúde do Homem , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prevalência , Inquéritos e Questionários , Taiwan , Testosterona/sangue
4.
Nat Commun ; 9(1): 3284, 2018 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-30115930

RESUMO

Cytokines are involved in early host defense against pathogen infections. In particular, tumor necrosis factor (TNF) and interferon-gamma (IFN-γ) have critical functions in non-cytopathic elimination of hepatitis B virus (HBV) in hepatocytes. However, the molecular mechanisms and mediator molecules are largely unknown. Here we show that interleukin-32 (IL-32) is induced by TNF and IFN-γ in hepatocytes, and inhibits the replication of HBV by acting intracellularly to suppress HBV transcription and replication. The gamma isoform of IL-32 (IL-32γ) inhibits viral enhancer activities by downregulating liver-enriched transcription factors. Our data are validated in both an in vivo HBV mouse model and primary human hepatocytes. This study thus suggests that IL-32γ functions as intracellular effector in hepatocytes for suppressing HBV replication to implicate a possible mechanism of non-cytopathic viral clearance.


Assuntos
Antivirais/metabolismo , Citocinas/metabolismo , Vírus da Hepatite B/fisiologia , Interleucinas/metabolismo , Espaço Intracelular/metabolismo , Animais , Sequência de Bases , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação para Baixo , Elementos Facilitadores Genéticos/genética , Hepatite B Crônica/metabolismo , Hepatite B Crônica/patologia , Fatores Nucleares de Hepatócito/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Modelos Biológicos , Ligação Proteica , Transcrição Genética , Replicação Viral
5.
Pediatr Diabetes ; 19(7): 1164-1172, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29927023

RESUMO

BACKGROUND: Causative mutations cannot be identified in the majority of Asian patients with suspected maturity-onset diabetes of the young (MODY). OBJECTIVES: To elucidate the genetic basis of Japanese patients with MODY-like diabetes and gain insight into the etiology of patients without mutations in the major MODY genes. SUBJECTS: A total of 263 Japanese patients with early-onset, non-obese, MODY-like diabetes mellitus referred to Osaka City General Hospital for diagnosis. METHODS: Mutational analysis of the four major MODY genes (GCK, HNF1A, HNF4A, HNF1B) by Sanger sequencing. Mutation-positive and mutation-negative patients were further analyzed for clinical features. RESULTS: Mutations were identified in 103 (39.2%) patients; 57 mutations in GCK; 29, HNF1A; 7, HNF4A; and 10, HNF1B. Contrary to conventional diagnostic criteria, 18.4% of mutation-positive patients did not have affected parents and 8.2% were in the overweight range (body mass index [BMI] >85th percentile). HOMA-IR at diagnosis was elevated (>2) in 15 of 66 (22.7%) mutation-positive patients. Compared with mutation-positive patients, mutation-negative patients were significantly older (P = 0.003), and had higher BMI percentile at diagnosis (P = 0.0006). Interestingly, maternal inheritance of diabetes was significantly more common in mutation-negative patients (P = 0.0332) and these patients had significantly higher BMI percentile as compared with mutation-negative patients with paternal inheritance (P = 0.0106). CONCLUSIONS: Contrary to the conventional diagnostic criteria, de novo diabetes, overweight, and insulin-resistance are common in Japanese patients with mutation-positive MODY. A significant fraction of mutation-negative patients had features of early-onset type 2 diabetes common in Japanese, and non-Mendelian inheritance needs to be considered for these patients.


Assuntos
Diabetes Mellitus Tipo 2/genética , Fatores Nucleares de Hepatócito/genética , Herança Materna , Proteínas Serina-Treonina Quinases/genética , Adolescente , Adulto , Criança , Pré-Escolar , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Quinases do Centro Germinativo , Humanos , Japão/epidemiologia , Masculino , Adulto Jovem
6.
Curr Diab Rep ; 18(3): 12, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29450745

RESUMO

PURPOSE OF REVIEW: Monogenic diabetes accounts for 1-2% of all diabetes cases, but is frequently misdiagnosed as type 1, type 2, or gestational diabetes. Accurate genetic diagnosis directs management, such as no pharmacologic treatment for GCK-MODY, low-dose sulfonylureas for HNF1A-MODY and HNF4A-MODY, and high-dose sulfonylureas for KATP channel-related diabetes. While diabetes treatment is defined for the most common causes of monogenic diabetes, pregnancy poses a challenge to management. Here, we discuss the key issues in pregnancy affected by monogenic diabetes. RECENT FINDINGS: General recommendations for pregnancy affected by GCK-MODY determine need for maternal insulin treatment based on fetal mutation status. However, a recent study suggests macrosomia and miscarriage rates may be increased with this strategy. Recent demonstration of transplacental transfer of sulfonylureas also raises questions as to when insulin should be initiated in sulfonylurea-responsive forms of monogenic diabetes. Pregnancy represents a challenge in management of monogenic diabetes, where factors of maternal glycemic control, fetal mutation status, and transplacental transfer of medication must all be taken into consideration. Guidelines for pregnancy affected by monogenic diabetes will benefit from large, prospective studies to better define the need for and timing of initiation of insulin treatment.


Assuntos
Diabetes Mellitus Tipo 2/terapia , Gravidez em Diabéticas/terapia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Glucoquinase/genética , Fatores Nucleares de Hepatócito/genética , Humanos , Mutação , Canais de Potássio/genética , Gravidez , Gravidez em Diabéticas/diagnóstico , Gravidez em Diabéticas/genética , Gravidez em Diabéticas/fisiopatologia
7.
Gene Expr ; 18(1): 51-62, 2018 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-29212575

RESUMO

Hepatocyte to biliary transdifferentiation has been documented in various models of bile duct injury. In this process, mature hepatocytes transform into mature biliary epithelial cells by acquiring biliary phenotypic markers. Several signaling pathways including PI3 kinase, Notch, Hes1, Sox9, and Hippo are shown to be involved in the process. However, whether Oct4 is involved in hepatocyte to biliary transdifferentiation is unknown. We investigated the role of Oct4 in hepatocyte to biliary transdifferentiation utilizing an in vitro organoid culture system as a model of transdifferentiation. Oct4 was inhibited using adenovirus containing Oct4 shRNA. Hepatocyte-specific HNF-4α and biliary-specific HNF-1ß and CK19 expression were assessed to gauge the extent of transdifferentiation. Oct4 was induced during hepatocyte to biliary transdifferentiation. Oct4 inhibition significantly downregulated the appearance of biliary cells from hepatocytes. This was accompanied by a significant downregulation of signaling pathways including Notch, Sox9, and Hippo. Our findings suggest that Oct4 is crucial for hepatocyte to biliary transdifferentiation and maturation and that it acts upstream of Notch, Sox9, and Hippo signaling in this model. This finding identifies new signaling through Oct4 in plasticity between hepatocytes and biliary epithelial cells, which can be potentially utilized to identify new strategies in chronic biliary diseases.


Assuntos
Transdiferenciação Celular , Hepatócitos/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Animais , Ductos Biliares/citologia , Células Cultivadas , Fatores Nucleares de Hepatócito/genética , Fatores Nucleares de Hepatócito/metabolismo , Hepatócitos/citologia , Masculino , Fator 3 de Transcrição de Octâmero/genética , Organoides/citologia , Organoides/metabolismo , Ratos , Ratos Endogâmicos F344 , Receptores Notch/genética , Receptores Notch/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais
8.
J Hepatol ; 68(5): 1033-1048, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29175243

RESUMO

The hepatocyte nuclear factors (HNFs) namely HNF1α/ß, FOXA1/2/3, HNF4α/γ and ONECUT1/2 are expressed in a variety of tissues and organs, including the liver, pancreas and kidney. The spatial and temporal manner of HNF expression regulates embryonic development and subsequently the development of multiple tissues during adulthood. Though the HNFs were initially identified individually based on their roles in the liver, numerous studies have now revealed that the HNFs cross-regulate one another and exhibit synergistic relationships in the regulation of tissue development and function. The complex HNF transcriptional regulatory networks have largely been elucidated in rodent models, but less so in human biological systems. Several heterozygous mutations in these HNFs were found to cause diseases in humans but not in rodents, suggesting clear species-specific differences in mutational mechanisms that remain to be uncovered. In this review, we compare and contrast the expression patterns of the HNFs, the HNF cross-regulatory networks and how these liver-enriched transcription factors serve multiple functions in the liver and beyond, extending our focus to the pancreas and kidney. We also summarise the insights gained from both human and rodent studies of mutations in several HNFs that are known to lead to different disease conditions.


Assuntos
Fatores Nucleares de Hepatócito/metabolismo , Fígado/metabolismo , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Fatores Nucleares de Hepatócito/química , Fatores Nucleares de Hepatócito/genética , Humanos , Rim/metabolismo , Fígado/crescimento & desenvolvimento , Redes e Vias Metabólicas , Mutação , Pâncreas/metabolismo , Distribuição Tecidual
9.
Biol Pharm Bull ; 40(11): 1846-1855, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29093331

RESUMO

This study aimed to examine the anti-diabetic effect of germinated waxy black rice (GWBR) using streptozotocin (STZ)-induced diabetic rats. In the diabetic rats, GWBR supplementation for 8 weeks reduced plasma blood glucose concentrations, improved glucose clearance and prevented diabetes-induced weight loss. Rats with STZ-induced diabetes who received GWBR supplementation exhibited decreased expression of sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter (GLUT) 2 genes and proteins in the small intestine via decreases in hepatocyte nuclear factor (HNF)-1α, HNF-1ß, and HNF-4α, transcriptional factors that are involved in the regulation of SGLT1 and GLUT2, compared with the rats with STZ-induced diabetes that did not receive GWBR supplements. GWBR supplementation also enhanced the expression of GLUT4 and the genes and proteins involved in GLUT4 translocation, such as insulin receptor (IR) and insulin receptor substrate 1 (IRS1), and increased the phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB, Akt) proteins in skeletal muscle. GWBR further increased glycogen synthase (GS) 1 by decreasing glycogen synthase kinase (GSK)-3ß in skeletal muscle. Interestingly, GWBR recovered STZ-impaired pancreatic ß-cells, resulting in increased insulin synthesis and secretion. In addition, GWBR reduced serum triglyceride, total cholesterol, low-density lipoprotein cholesterol, aspartate transferase and alanine transferase concentrations and increased high-density lipoprotein cholesterol concentrations. Taken together, these findings suggest that GWBR could be a candidate for improving the diabetic condition by regulating glucose uptake in the intestine and muscle and regulating the secretion of insulin from the pancreas.


Assuntos
Diabetes Mellitus Experimental/dietoterapia , Dislipidemias/dietoterapia , Glucose/metabolismo , Hiperglicemia/dietoterapia , Insulina/metabolismo , Oryza/química , Animais , Glicemia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Dislipidemias/sangue , Germinação , Transportador de Glucose Tipo 4/metabolismo , Fatores Nucleares de Hepatócito/metabolismo , Humanos , Hiperglicemia/sangue , Proteínas Substratos do Receptor de Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/enzimologia , Células Secretoras de Insulina/metabolismo , Intestino Delgado/enzimologia , Intestino Delgado/metabolismo , Lipídeos/sangue , Masculino , Músculo Esquelético/enzimologia , Músculo Esquelético/metabolismo , Oryza/crescimento & desenvolvimento , Ratos , Ratos Sprague-Dawley , Receptor de Insulina/metabolismo , Transportador 1 de Glucose-Sódio/metabolismo , Estreptozocina/toxicidade
10.
PLoS Pathog ; 13(2): e1006239, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28235042

RESUMO

The FoxA family of pioneer transcription factors regulates hepatitis B virus (HBV) transcription, and hence viral replication. Hepatocyte-specific FoxA-deficiency in the HBV transgenic mouse model of chronic infection prevents the transcription of the viral DNA genome as a result of the failure of the developmentally controlled conversion of 5-methylcytosine residues to cytosine during postnatal hepatic maturation. These observations suggest that pioneer transcription factors such as FoxA, which mark genes for expression at subsequent developmental steps in the cellular differentiation program, mediate their effects by reversing the DNA methylation status of their target genes to permit their ensuing expression when the appropriate tissue-specific transcription factor combinations arise during development. Furthermore, as the FoxA-deficient HBV transgenic mice are viable, the specific developmental timing, abundance and isoform type of pioneer factor expression must permit all essential liver gene expression to occur at a level sufficient to support adequate liver function. This implies that pioneer transcription factors can recognize and mark their target genes in distinct developmental manners dependent upon, at least in part, the concentration and affinity of FoxA for its binding sites within enhancer and promoter regulatory sequence elements. This selective marking of cellular genes for expression by the FoxA pioneer factor compared to HBV may offer the opportunity for the specific silencing of HBV gene expression and hence the resolution of chronic HBV infections which are responsible for approximately one million deaths worldwide annually due to liver cirrhosis and hepatocellular carcinoma.


Assuntos
DNA Viral/metabolismo , Regulação Viral da Expressão Gênica/fisiologia , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/virologia , Fatores Nucleares de Hepatócito/deficiência , Animais , Metilação de DNA/fisiologia , Modelos Animais de Doenças , Hepatite B Crônica/genética , Fígado/metabolismo , Fígado/virologia , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase , Fatores de Transcrição/metabolismo , Replicação Viral/fisiologia
11.
Zhonghua Yi Xue Za Zhi ; 96(34): 2739-2743, 2016 Sep 13.
Artigo em Chinês | MEDLINE | ID: mdl-27667109

RESUMO

Objective: To profile the gene expression changes associated with endoplasmic reticulum stress in INS-1-3 cells induced by thapsigargin (TG) and tunicamycin (TM). Methods: Normal cultured INS-1-3 cells were used as a control. TG and TM were used to induce endoplasmic reticulum stress in INS-1-3 cells. Digital gene expression profiling technique was used to detect differentially expressed gene. The changes of gene expression were detected by expression pattern clustering analysis, gene ontology (GO) function and pathway enrichment analysis. Real time polymerase chain reaction (RT-PCR) was used to verify the key changes of gene expression. Results: Compared with the control group, there were 57 (45 up-regulated, 12 down-regulated) and 135 (99 up-regulated, 36 down-regulated) differentially expressed genes in TG and TM group, respectively. GO function enrichment analyses indicated that the main enrichment was in the endoplasmic reticulum. In signaling pathway analysis, the identified pathways were related with endoplasmic reticulum stress, antigen processing and presentation, protein export, and most of all, the maturity onset diabetes of the young (MODY) pathway. Conclusion: Under the condition of endoplasmic reticulum stress, the related expression changes of transcriptional factors in MODY signaling pathway may be related with the impaired function in islet beta cells.


Assuntos
Estresse do Retículo Endoplasmático , Fatores Nucleares de Hepatócito/genética , Animais , Linhagem Celular , Retículo Endoplasmático , Transdução de Sinais , Tapsigargina , Tunicamicina , Regulação para Cima
12.
World J Gastroenterol ; 22(31): 7017-29, 2016 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-27610013

RESUMO

Approximately 350 million people are estimated to be persistently infected with hepatitis B virus (HBV) worldwide. HBV maintains persistent infection by employing covalently closed circular DNA (cccDNA), a template for all HBV RNAs. Chronic hepatitis B (CHB) patients are currently treated with nucleos(t)ide analogs such as lamivudine, adefovir, entecavir, and tenofovir. However, these treatments rarely cure CHB because they are unable to inhibit cccDNA transcription and inhibit only a late stage in the HBV life cycle (the reverse transcription step in the nucleocapsid). Therefore, an understanding of the factors regulating cccDNA transcription is required to stop this process. Among numerous factors, hepatocyte nuclear factors (HNFs) play the most important roles in cccDNA transcription, especially in the generation of viral genomic RNA, a template for HBV replication. Therefore, proper control of HNF function could lead to the inhibition of HBV replication. In this review, we summarize and discuss the current understanding of the roles of HNFs in the HBV life cycle and the upstream factors that regulate HNFs. This knowledge will enable the identification of new therapeutic targets to cure CHB.


Assuntos
Hepatite B Crônica/etiologia , Fatores Nucleares de Hepatócito/fisiologia , Proteínas Estimuladoras de Ligação a CCAAT/fisiologia , DNA Circular/fisiologia , Elementos Facilitadores Genéticos , Regulação Viral da Expressão Gênica , Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , Humanos , MicroRNAs/fisiologia , Fatores de Transcrição/fisiologia
13.
Pharmacogenomics ; 17(14): 1547-71, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27561454

RESUMO

Great research effort has been focused on elucidating the contribution of host genetic variability on pharmacological outcomes in cancer. Nuclear receptors have emerged as mediators between environmental stimuli and drug pharmacokinetics and pharmacodynamics. The pregnane X receptor, constitutive androstane receptor and hepatocyte nuclear factors have been reported to regulate transcription of genes that encode drug metabolizing enzymes and transporters. Altered nuclear receptor expression has been shown to affect the metabolism and pharmacological profile of traditional chemotherapeutics and targeted agents. Accordingly, polymorphic variants in these genes have been studied as pharmacogenetic markers of outcome variability. This review summarizes the state of knowledge about the roles played by pregnane X receptor, constitutive androstane receptor and hepatocyte nuclear factor expression and genetics as predictive markers of anticancer drug toxicity and efficacy, which can improve cancer precision medicine.


Assuntos
Fatores Nucleares de Hepatócito/fisiologia , Neoplasias/tratamento farmacológico , Medicina de Precisão , Receptores Citoplasmáticos e Nucleares/fisiologia , Receptores de Esteroides/fisiologia , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Fatores Nucleares de Hepatócito/genética , Humanos , Neoplasias/genética , Receptor de Pregnano X , Receptores Citoplasmáticos e Nucleares/genética , Receptores de Esteroides/genética
14.
Cancer Biol Ther ; 17(5): 558-65, 2016 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-27124543

RESUMO

Mesenchymal stem cells (MSCs) hold promise as cellular vehicles for the delivery of therapeutic gene products because they can be isolated, expanded, and genetically modified in vitro and possess tumor-oriented homing capacity in vivo. (1) Hepatocyte nuclear factor 4α (HNF4α) is a dominant transcriptional regulator of hepatocyte differentiation and hepatocellular carcinogenesis (HCC). (2,3) We have previously demonstrated that overexpression of HNF4α activates various hepatic-specific genes and enhances MSC differentiation. (4) However, the extent that overexpression of HNF4α in MSCs influences HCC progression has yet to be examined. Here we sought to investigate what effect MSCs overexpressing HNF4α (MSC-HNF4α) have on human hepatoma cells in vitro and in vivo. Conditioned medium collected from in vitro MSC-HNF4α cultures significantly inhibited hepatoma cell growth and metastasis compared with controls. Additionally, nude mice administered MSC-HNF4α exhibited significantly smaller tumors compared with controls in vivo. Immunoblot analysis of HCC cells treated with MSC-HNF4α displayed downregulated ß-catenin, cyclinD1, c-Myc, MMP2 and MMP9. Taken together, our results demonstrate that MSC-HNF4α inhibits HCC progression by reducing hepatoma cell growth and metastasis through downregulation of the Wnt/ß-catenin signaling pathway.


Assuntos
Carcinoma Hepatocelular/genética , Fatores Nucleares de Hepatócito/metabolismo , Neoplasias Hepáticas/genética , Células-Tronco Mesenquimais/metabolismo , Via de Sinalização Wnt/genética , Animais , Carcinoma Hepatocelular/patologia , Proliferação de Células , Regulação para Baixo , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , Transfecção
15.
Can J Diabetes ; 40(5): 455-461, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27103109

RESUMO

Maturity-onset diabetes of the young (MODY) is a group of monogenic diseases that results in primary defects in insulin secretion and dominantly inherited forms of nonautoimmune diabetes. Although many genes may be associated with monogenic diabetes, heterozygous mutations in 6 of them are responsible for the majority of cases of MODY. Glucokinase (GCK)-MODY is due to mutations in the glucokinase gene, 3 MODY subtypes are associated with mutations in the hepatocyte nuclear factor (HNF) transcription factors, and 2 others with mutations in ABCC8 and KCNJ11, which encode the subunits of the ATP-dependent potassium channel in pancreatic beta cells. GCK-MODY and HNF1A-MODY are the most common subtypes. The clinical presentation of MODY subtypes has been reported to differ according to the gene involved, and the diagnosis of MODY may be considered in various clinical circumstances. However, except in patients with GCK-MODY whose phenotype is very homogeneous, in most cases the penetrance and expressivity of a given molecular abnormality vary greatly among patients and, conversely, alterations in various genes may lead to similar phenotypes. Moreover, differential diagnosis among more common forms of diabetes may be difficult, particularly with type 2 diabetes. Thus, careful assessment of the personal and family histories of patients with diabetes is mandatory to select those in whom genetic screening is worthwhile. The diagnosis of monogenic diabetes has many consequences in terms of prognosis, therapeutics and family screening.


Assuntos
Diabetes Mellitus/diagnóstico , Doenças Raras/diagnóstico , Adolescente , Criança , Diabetes Mellitus/genética , Diabetes Mellitus/terapia , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Regulação da Expressão Gênica , Testes Genéticos , Glucoquinase/genética , Fatores Nucleares de Hepatócito/genética , Humanos , Masculino , Canais de Potássio Corretores do Fluxo de Internalização/genética , Guias de Prática Clínica como Assunto , Doenças Raras/genética , Doenças Raras/terapia , Receptores Sulfonilureia/genética
16.
Mol Gen Mikrobiol Virusol ; 34(3): 98-103, 2016.
Artigo em Russo | MEDLINE | ID: mdl-30383931

RESUMO

The embryonic development and carcinogenesis are controlled by many transcription factors. The regulatory systems involved in embryogenesis of an organ are also involved in the tumor development in the same organ. FOX family proteins are transcription factors, which play a key role in these processes. The pioneering factors of the FOXA subfamily act at the very early stages of the embryonic development by interacting with condensed chromatin and thereby enabling the expression of the formerly silent important transcription factors. The role of these factors in tumor development is currently not fully elucidated, although recent studies indicate the important contribution of the FOXA subfamily proteins at the early stages of carcinogenesis. This review is restricted to the role of the FOXA factors in embryogenesis of the pancreas and their significance in the development of the pancreatic ductal adenocarcinoma.


Assuntos
Transformação Celular Neoplásica , Embrião de Mamíferos , Desenvolvimento Embrionário , Fatores Nucleares de Hepatócito , Proteínas de Neoplasias , Neoplasias Pancreáticas , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Fatores Nucleares de Hepatócito/genética , Fatores Nucleares de Hepatócito/metabolismo , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia
17.
J Hepatol ; 64(2): 268-277, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26409214

RESUMO

BACKGROUND & AIMS: Cytokines are key molecules implicated in the defense against virus infection. Tumor necrosis factor-alpha (TNF-α) is well known to block the replication of hepatitis B virus (HBV). However, the molecular mechanism and the downstream effector molecules remain largely unknown. METHODS: In this study, we investigated the antiviral effect and mechanism of p22-FLIP (FLICE-inhibitory protein) by ectopic expression in vitro and in vivo. In addition, to provide the biological relevance of our study, we examined that the p22-FLIP is involved in TNF-α-mediated suppression of HBV in primary human hepatocytes. RESULTS: We found that p22-FLIP, a newly discovered c-FLIP cleavage product, inhibited HBV replication at the transcriptional level in both hepatoma cells and primary human hepatocytes, and that c-FLIP conversion to p22-FLIP was stimulated by the TNF-α/NF-κB pathway. p22-FLIP inhibited HBV replication through the upregulation of HNF3ß but downregulation of HNF4α, thus inhibiting both HBV enhancer elements. Finally, p22-FLIP potently inhibited HBV DNA replication in a mouse model of HBV replication. CONCLUSIONS: Taken together, these findings suggest that the anti-apoptotic p22-FLIP serves a novel function of inhibiting HBV transcription, and mediates the antiviral effect of TNF-α against HBV replication.


Assuntos
Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Vírus da Hepatite B , Fator de Necrose Tumoral alfa , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/farmacologia , Linhagem Celular , DNA Viral/metabolismo , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/fisiologia , Fatores Nucleares de Hepatócito/metabolismo , Hepatócitos/metabolismo , Humanos , Camundongos , Modelos Animais , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
18.
Curr Mol Med ; 15(5): 412-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26166417

RESUMO

Apoptosis is a prominent characteristic in the pathogenesis of liver disease. The molecular mechanism of hepatic apoptosis is not well understood. Liver injury induces a downregulation of hepatocyte nuclear factor 6 (HNF6) that is negatively correlated with the degree of apoptosis. However, an enhancement of HNF6 can relieve hepatic apoptosis and impede the progression of liver disease. HNF6 has distinct mechanisms to modulate hepatic apoptosis. Pathophysiological role of HNF6 may be apoptosis-resistant and liver-protective during different types of liver injury. The enhancing modality of HNF6 is a novel therapeutic intervention for liver disease.


Assuntos
Apoptose , Fator 6 Nuclear de Hepatócito/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Animais , Apoptose/genética , Expressão Gênica , Regulação da Expressão Gênica , Fator 6 Nuclear de Hepatócito/genética , Fatores Nucleares de Hepatócito/metabolismo , Hepatócitos/patologia , Humanos , Fígado/patologia , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/patologia , Ligação Proteica , Transdução de Sinais
19.
Stem Cell Reports ; 3(2): 339-52, 2014 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-25254346

RESUMO

Planarians can regenerate any missing body part in a process requiring dividing cells called neoblasts. Historically, neoblasts have largely been considered a homogeneous stem cell population. Most studies, however, analyzed neoblasts at the population rather than the single-cell level, leaving the degree of heterogeneity in this population unresolved. We combined RNA sequencing of neoblasts from wounded planarians with expression screening and identified 33 transcription factors transcribed in specific differentiated cells and in small fractions of neoblasts during regeneration. Many neoblast subsets expressing distinct tissue-associated transcription factors were present, suggesting candidate specification into many lineages. Consistent with this possibility, klf, pax3/7, and FoxA were required for the differentiation of cintillo-expressing sensory neurons, dopamine-ß-hydroxylase-expressing neurons, and the pharynx, respectively. Together, these results suggest that specification of cell fate for most-to-all regenerative lineages occurs within neoblasts, with regenerative cells of blastemas being generated from a highly heterogeneous collection of lineage-specified neoblasts.


Assuntos
Células-Tronco/citologia , Animais , Sequência de Bases , Diferenciação Celular , Fatores Nucleares de Hepatócito/genética , Fatores Nucleares de Hepatócito/metabolismo , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Dados de Sequência Molecular , Fatores de Transcrição Box Pareados/antagonistas & inibidores , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Planárias , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Regeneração , Células Receptoras Sensoriais/citologia , Células Receptoras Sensoriais/metabolismo , Análise de Sequência de RNA , Células-Tronco/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
20.
PLoS One ; 9(9): e107246, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25198130

RESUMO

The human forkhead box A1 (FOXA1) and A2 (FOXA2) transcription factors have been found to control estrogen and androgen signaling through co-regulating target genes with sex hormone receptors. Here we used an integrative strategy to examine the hypothesis that genetic variants at FOXA1/2 binding elements may be associated with sexual dimorphism of hepatocellular carcinoma (HCC) risk. Firstly we extracted chromatin immunoprecipitation-sequencing (ChIP-seq) data of FOXA1, FOXA2 and estrogen receptor 1(ERα) from ENCODE database to obtain dual target regions of FOXA/ERα, and further intersected these regions with genes' promoters. Then we used MATCH program to predict FOXA binding elements, in which genetic variants were retrieved by dbSNP database (NCBI, build 134). A total of 15 candidate variants were identified in this stage. Secondly we performed a case-control study with 1,081 HCC patients and 2,008 matched controls and found a significant association of SERPINA6-rs1998056 with female HCC risk under common genetic models (e.g. GG versus CC: OR = 2.03, 95% CI = 1.26-3.27, P = 0.004). Moreover, results from our real-time quantitative polymerase chain reaction (qPCR) using 72 normal liver tissues adjacent to the tumors showed that SERPINA6 expression was significantly different among different genotypes of this variant (GG versus CC: P = 0.032; Group test: P = 0.060). In summary, our study suggested that SERPINA6-rs1998056 regulated by FOXA/ERα might be associated with female HCC risk.


Assuntos
Carcinoma Hepatocelular/genética , Receptor alfa de Estrogênio/metabolismo , Genômica , Fatores Nucleares de Hepatócito/metabolismo , Neoplasias Hepáticas/genética , Polimorfismo de Nucleotídeo Único , Transcortina/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Células Hep G2 , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Fator 3-beta Nuclear de Hepatócito/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/patologia , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA