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1.
Tumour Biol ; 42(7): 1010428320938494, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32628088

RESUMO

Radiotherapy and cisplatin lead to cell killing in head and neck squamous cell carcinoma patients, but adverse events and response to treatment are not the same in patients with similar clinicopathological aspects. The aim of this prospective study was to evaluate the roles of TP53 c.215G > C, FAS c.-671A > G, FAS c.-1378G > A, FASL c.-844 C > T, CASP3 c.-1191A > G, and CASP3 c.-182-247G > T single nucleotide variants in toxicity, response rate, and survival of cisplatin chemoradiation-treated head and neck squamous cell carcinoma patients. Genomic DNA was analyzed by polymerase chain reaction for genotyping. Differences between groups of patients were analyzed by chi-square test or Fisher's exact test, multiple logistic regression analysis, and Cox hazards model. One hundred nine patients with head and neck squamous cell carcinoma were enrolled in study. All patients were smokers and/or alcoholics. Patients with FAS c.-671GG genotype, FAS c.-671AG or GG genotype, and FASL c.-844CC genotype had 5.52 (95% confidence interval (CI): 1.42-21.43), 4.03 (95% CI: 1.51-10.79), and 5.77 (95% CI: 1.23-27.04) more chances of presenting chemoradiation-related anemia of grades 2-4, lymphopenia of grade 3 or 4, and ototoxicity of all grades, respectively, than those with the remaining genotypes. FAS c.-671GG genotype was also seen as an independent predictor of shorter event-free survival (hazard ratio (HR): 2.05; P = 0.007) and overall survival (HR: 1.83; P = 0.02) in our head and neck squamous cell carcinoma patients. These findings present, for the first time, preliminary evidence that inherited abnormalities in apoptosis pathway, related to FAS c.-671A > G and FASL c.-844 C > T single nucleotide variants, can alter toxicity and survival of tobacco- and alcohol-related head and neck squamous cell carcinoma patients homogeneously treated with cisplatin chemoradiation.


Assuntos
Proteína Ligante Fas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Receptor fas/genética , Adulto , Idoso , Álcoois/efeitos adversos , Quimiorradioterapia/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/induzido quimicamente , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Tabaco/efeitos adversos , Proteína Supressora de Tumor p53/genética
2.
Gene ; 741: 144516, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32119914

RESUMO

To study the influence of the PGC-1ß gene on chicken adipocyte proliferation and differentiation, we constructed RNA interference (RNAi) vectors that target the PGC-1ß gene and transfected these vectors into adipocytes. Oil Red O staining and a CCK-8 cell kit were used to determine cell triglyceride accumulation status and cell proliferation after transfection, respectively. The mRNA abundances of PGC-1ß and adipocyte-differentiation-related genes (PPARγ, C/EBPα, SREBP-1c, FAS, and A-FABP) were detected by real-time PCR. The results showed that the mRNA and protein abundances of PGC-1ß in PGC-1ß-shRNA transfected adipocytes were significantly lower than those in the control. Interference decreased cell differentiation, but did not depress the cell proliferation. PGC-1ß interference impeded the triglyceride accumulation, the mRNA expression levels of nuclear receptors PPARγ and SREBP-1c, and fatty acid synthetase (FAS), and both proteins PPARγ and SREBP-1c, and the fatty acids transporting protein A-FABP. Generally, PGC-1ß modulated the cell differentiation and triglyceride accumulation in chicken adipocytes.


Assuntos
Adipócitos/metabolismo , Adipogenia/genética , Diferenciação Celular/genética , Receptores Ativados por Proliferador de Peroxissomo/genética , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proliferação de Células/genética , Galinhas/genética , Galinhas/crescimento & desenvolvimento , Ácido Graxo Sintases/genética , Proteínas de Ligação a Ácido Graxo/genética , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , PPAR gama/genética , RNA Mensageiro , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Triglicerídeos/metabolismo , Receptor fas/genética
3.
Chem Biol Interact ; 320: 109005, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32109484

RESUMO

The mortality rates for acute myeloid leukemia are very high, necessitating the search for novel chemotherapeutic candidates. Herein, we investigated the anticancer potential of a new synthetic compound, 2-ethyl-3-methyliden-1-tosyl-2,3-dihydroquinolin-4-(1H)-one (AJ-374) against myeloid leukemia HL-60 cell line. This analog was selected from the small library of synthetic dihydroquinolinones on the basis of its strong antiproliferative activity against HL-60 cells and 30-fold lower cytotoxicity towards healthy HUVEC cells. AJ-374 promoted the arrest of the cells in the subG0/G1 phase of the cell cycle in the first 24 h. Treatment of HL-60 cells with AJ-374 caused an increase in annexin-V positive cells, activation of caspase-8, -9 and -3, dissipation of the mitochondrial membrane potential and enhancement of FAS protein level. Apoptosis induction triggered by this quinolinone was blocked by the pre-treatment of the cells with caspase-8, -9 and -3 inhibitors. The obtained results indicated that AJ-374-induced apoptosis was executed by both, the extrinsic and intrinsic pathways. The cytotoxic activity of AJ-374 was also associated with down-regulation of the mitogen-activated protein kinase (MAPK) pathway and was independent of reactive oxygen species generation. Taken together, these results suggest that AJ-374 exerts a potent anticancer effect on leukemia cells, with a wide safety margin, which makes this analog an attractive drug candidate for further testing.


Assuntos
Apoptose/efeitos dos fármacos , Quinolonas/farmacologia , Caspases/genética , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Proliferação de Células , Dano ao DNA/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Quinolonas/química , Espécies Reativas de Oxigênio , Reação em Cadeia da Polimerase em Tempo Real , Receptor fas/genética , Receptor fas/metabolismo
4.
J Card Surg ; 35(3): 564-570, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31945231

RESUMO

BACKGROUND AND AIM OF THE STUDY: Ischemic postconditioning (PostC) is considered to be one of the strongest mechanisms limiting the extent of myocardial infarction, and reducing ischemia-reperfusion (I/R) injury. I/R-induced myocardial injury results in apoptosis, autophagy, and necrosis. The aim of the present study was to investigate the roles of the necrotic gene cytochrome b-245 beta chain (Cybb); Cybb-related microRNA miR139-3p; the autophagy gene Beclin-1 (Becn1); proapoptotic genes Fas, Faslg and growth arrest and DNA-damage-inducible 45 alpha (Gadd45a); and apoptosis-related microRNA miR181a-1 levels on I/R injury, as well as, the potential protective effects of PostC through this gene and microRNAs. METHODS: The left main coronary artery was subjected to ischemia for 30 minutes, followed by reperfusion for 120 minutes. PostC involved three cycles of I/R, each lasting 10 seconds. Gene and microRNA levels were analyzed using a quantitative reverse transcription-polymerase chain reaction. RESULTS: Although an increase was observed in the expression levels of the Cybb, Fas, Faslg and Gadd45a genes, the miR139-3p, miR181a-1, and Becn1 expression levels were found to decrease with I/R injury. PostC was determined to restore the expression of all the genes to the normal levels. CONCLUSIONS: The abovementioned genes can be used as important prognostic markers in the diagnosis of reperfusion injury and in the evaluation of treatment efficacy. It was further noted that increased expression of CYBB, which is one of the target genes for miR139-3p, and a decreased expression of miR181a-1 may cause apoptosis by affecting Fas and Faslg signaling. PostC can inhibit apoptosis by increasing miR139-3p and miR181a-1 levels.


Assuntos
Apoptose/genética , Vasos Coronários , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Pós-Condicionamento Isquêmico , MicroRNAs/genética , MicroRNAs/metabolismo , Infarto do Miocárdio/genética , Traumatismo por Reperfusão Miocárdica/genética , NADPH Oxidase 2/genética , NADPH Oxidase 2/fisiologia , Proteínas/genética , Proteínas/metabolismo , Transdução de Sinais/fisiologia , Receptor fas/genética , Receptor fas/metabolismo , Vasos Coronários/metabolismo , Expressão Gênica , Humanos , Prognóstico , Transdução de Sinais/genética
5.
Biochem Biophys Res Commun ; 523(2): 473-480, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-31882118

RESUMO

The inducible activation system is valuable for investigating spatiotemporal roles of molecules. A chemically inducible activation system for Fas (CD95/APO-1), which works efficiently to induce apoptosis and leads non-apoptotic pathways, has not yet been developed. Here, we engineered a rapamycin-induced dimerization system of Fas consisting of FKBP and FRB proteins. Treatment of rapamycin specifically induces cellular apoptosis. In neurons and cells with high c-FLIP expression, rapamycin-induced Fas activation triggered the activation of the non-apoptotic pathway components instead of cell death. Intracranial delivery of the system could be utilized to induce apoptosis of tumor cells upon rapamycin treatment. Our results demonstrate a novel inducible Fas activation system which operates with high efficiency and temporal precision in vitro and in vivo promising a potential therapeutic strategy.


Assuntos
Engenharia de Proteínas/métodos , Sirolimo/farmacologia , Proteína 1A de Ligação a Tacrolimo/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Receptor fas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Células Cultivadas , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Humanos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Gravidez , Ratos Sprague-Dawley , Proteína 1A de Ligação a Tacrolimo/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Receptor fas/genética
6.
Brain Pathol ; 30(1): 106-119, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31228212

RESUMO

Over the last few decades, several common single nucleotide polymorphisms (SNPs) have been identified that correlate with clinical outcome in multiple sclerosis (MS), but the pathogenic mechanisms underlying the clinical effects of these SNPs are unknown. This is in part because of the difficulty in the functional translation of genotype into disease-relevant mechanisms. Building on our recent work showing the association of clinical disease course with post-mortem MS lesion characteristics, we hypothesized that SNPs that correlate with clinical disease course would also correlate with specific MS lesion characteristics in autopsy tissue. To test this hypothesis, 179 MS brain donors from the Netherlands Brain Bank MS autopsy cohort were genotyped for 102 SNPs, selected based on their reported associations with clinical outcome or their associations with genes that show differential gene expression in MS lesions. Three SNPs linked to MS clinical severity showed a significant association between the genotype and either the proportion of active lesions (rs2234978/FAS and rs11957313/KCNIP1) or the proportion of mixed active/inactive lesions (rs8056098/CLEC16A). Three SNPs linked to MS pathology-associated genes showed a significant association with either proportion of active lesions (rs3130253/MOG), incidence of cortical gray matter lesions (rs1064395/NCAN) or the proportion of remyelinated lesions (rs5742909/CTLA4). In addition, rs2234978/FAS T-allele carriers showed increased FAS gene expression levels in perivascular T cells and perilesional oligodendrocytes, cell types that have been implicated in MS lesion formation. Thus, by combining pathological characterization of MS brain autopsy tissue with genetics, we now start to translate genotypes linked to clinical outcomes in MS into mechanisms involved in MS lesion pathogenesis.


Assuntos
Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Autopsia/métodos , Encéfalo/patologia , Antígeno CTLA-4/genética , Estudos de Coortes , Progressão da Doença , Feminino , Predisposição Genética para Doença/genética , Genótipo , Substância Cinzenta/patologia , Humanos , Proteínas Interatuantes com Canais de Kv/genética , Lectinas Tipo C/genética , Masculino , Pessoa de Meia-Idade , Proteínas de Transporte de Monossacarídeos/genética , Oligodendroglia/patologia , Receptor fas/genética
7.
Oxid Med Cell Longev ; 2019: 1076512, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827667

RESUMO

Oxidative stress is a causal factor and key promoter of all kinds of reproductive disorders related to granulosa cell (GC) apoptosis that acts by dysregulating the expression of related genes. Various studies have suggested that grape seed procyanidin B2 (GSPB2) may protect GCs from oxidative injury, though the underlying mechanisms are not fully understood. Therefore, whether the beneficial effects of GSPB2 are associated with microRNAs, which have been suggested to play a critical role in GC apoptosis by regulating the expression of protein-coding genes, was investigated in this study. The results showed that GSPB2 treatment protected GCs from a H2O2-induced apoptosis, as detected by an MTT assay and TUNEL staining, and increased let-7a expression in GCs. Furthermore, let-7a overexpression markedly increased cell viability and inhibited H2O2-induced GC apoptosis. Furthermore, the overexpression of let-7a reduced the upregulation of Fas expression in H2O2-treated GCs at the mRNA and protein levels. Dual-luciferase reporter assay results indicated that let-7a directly targets the Fas 3'-UTR. Furthermore, the overexpression of let-7a enhanced the protective effects of GSPB2 against GC apoptosis induced by H2O2. These results indicate that GSPB2 inhibits H2O2-induced apoptosis of GCs, possibly through the upregulation of let-7a.


Assuntos
Biflavonoides/farmacologia , Catequina/farmacologia , MicroRNAs/metabolismo , Proantocianidinas/farmacologia , Regulação para Cima/efeitos dos fármacos , Vitis/química , Regiões 3' não Traduzidas , Animais , Apoptose/efeitos dos fármacos , Sequência de Bases , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células da Granulosa/citologia , Células da Granulosa/metabolismo , Extrato de Sementes de Uva/química , Peróxido de Hidrogênio/farmacologia , Ovário/citologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Alinhamento de Sequência , Suínos , Vitis/metabolismo , Receptor fas/química , Receptor fas/genética , Receptor fas/metabolismo
8.
Medicine (Baltimore) ; 98(49): e18240, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31804351

RESUMO

BACKGROUND: FAS cell surface death receptor (FAS) gene has 2 common single nucleotide polymorphisms (SNPs) in its promoter, FAS-1377G > A (rs2234767) and FAS-670A > G (rs1800682). Several studies have investigated the role of these 2 polymorphisms in etiology of breast cancer in Asian population while the outcomes are inconsistent. To derive a more precise assessment of the association between breast cancer susceptibility with FAS gene promoter SNPs, a meta-analysis of published studies was performed. MATERIAL AND METHODS: We systematically searched PubMed, Embase, Web of Science, and the Chinese biomedical database (CBM) for papers published until November 1, 2018. Odds ratio (OR) with 95% confidential interval (95%CI) was conducted to evaluate the associations. Statistical analysis was conducted using Stata13.0 software. A total of 8 studies covering 2564 cases and 2633 controls were included. RESULTS: The integrated results suggest the following: For the FAS-1377G/A polymorphism, we only found significant associations for allele G vs allele A (OR = 1.100, 95%CI = 1.004-1.206, P = .040). After stratification by ethnicity, a significant association was observed only for the AA+GA vs GG genotype in East Asian populations (OR = 1.177, 95% CI = 1.010-1.371, P = .037). The association was not found in West Asian populations. For the FAS -670A/G polymorphism, no association with cancer risk was found in any comparison model. Sensitivity analysis suggests that the meta-analysis results obtained after excluding any single study were similar to the original ones, suggesting that the meta-analysis results were not significantly affected by any single study. CONCLUSION: These results indicated that FAS-1377G/A polymorphism may contribute to the increased breast cancer susceptibility and could be a promising target for cancer risk prediction. Further studies are needed to determine if the FAS gene confers a risk of breast cancer in other ethnic groups, such as Africans and Latin Americans.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/genética , Polimorfismo de Nucleotídeo Único , Receptor fas/genética , Ásia , Feminino , Predisposição Genética para Doença , Humanos
9.
Int J Mol Sci ; 20(23)2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31801245

RESUMO

BACKGROUND: Ovaries are sensitive to chemotherapy, which may lead to early depletion of primordial follicle reserve. One strategy for gonadal function preservation is temporary ovarian suppression with Gonadotropin Releasing Hormone agonists (GnRHa) during chemotherapy. To date, GnRHa protective mechanism of action remains not fully elucidated. METHODS: We collected 260 immature cumulus cell-oocyte complexes (COC) from 111 women < 38 years old, with a normal ovarian reserve. The COC were randomly assigned to the following groups: a) control; culture with the addition of b) GnRHa; c) cyclophosphamide; d) cyclophosphamide plus GnRHa. After in vitro treatments, RNA and proteins were extracted from oocytes and cumulus cells (CC), separately. Potential effects of drugs were evaluated on GnRH receptors, apoptosis pathways, ceramide pathway, and glutathione synthesis by quantitative PCR and, whenever possible, by Western blot. RESULTS: Cyclophosphamide triggered activation of the extrinsic pathway of apoptosis mediated by BAX in CC. The co-administration of GnRHa inhibited the apoptosis pathway in CC. According to our model, the GnRHa does not directly act on oocytes, which do not express GnRH receptors. Moreover, glutathione synthesis was decreased after GnRHa treatment both in CC and oocytes. CONCLUSION: Our data suggest that the protective mechanisms induced by GnRHa is mediated by an anti-apoptotic effect on CC.


Assuntos
Apoptose/efeitos dos fármacos , Células do Cúmulo/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/farmacologia , Receptores LHRH/genética , Proteína X Associada a bcl-2/genética , Adulto , Apoptose/genética , Caspase 3/genética , Caspase 3/metabolismo , Ceramidas/metabolismo , Células do Cúmulo/citologia , Células do Cúmulo/metabolismo , Ciclofosfamida/farmacologia , Feminino , Regulação da Expressão Gênica , Glutationa/metabolismo , Humanos , Oócitos/citologia , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Reserva Ovariana/genética , Receptores LHRH/metabolismo , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
10.
Clin Nucl Med ; 44(12): 949-955, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31689275

RESUMO

INTRODUCTION: Autoimmune lymphoproliferative syndrome (ALPS) is a rare immune dysregulatory condition, usually presenting in childhood with massive lymphadenopathy, splenomegaly, and an increased incidence of lymphoma. Methods to differentiate between benign ALPS adenopathy and lymphoma are needed. To this end, we evaluated the usefulness of FDG PET. METHODS: We prospectively evaluated 76 ALPS/ALPS-like patients including FS-7-associated surface antigen (FAS) germline mutation with (n = 4) and without lymphoma (n = 50), FAS-somatic (n = 6), ALPS-unknown (n = 6), and others (n = 10) who underwent FDG PET. Uptakes in 14 nodal sites, liver, and spleen were determined. RESULTS: In 76 ALPS patients, FDG PET showed uptake in multiple nodal sites in all but 1 patient. The highest SUVmax values in FAS mutation without lymphoma, FAS mutation with lymphoma, FAS somatic, ALPS-unknown, and other genetic mutations were a median (range) 9.2 (4.3-25), 16.2 (10.7-37.2), 7.6 (4.6-18.1), 11.5 (4.8-17.2), and 5.5 (0-15.3), respectively. Differences between uptake in the FAS group with and without lymphoma were statistically significant, but overlapped, making discrimination between individuals with/without lymphoma impossible. The spleen:liver uptake ratio was greater than 1 in 82% of patients. CONCLUSIONS: While statistically significant differences were observed in FAS mutation ALPS with and without lymphoma, the significant overlap in FDG uptake and visual appearance in many patients prevents discrimination between patients with and without lymphoma. Similar patterns of FDG biodistribution were noted between the various ALPS subgroups.


Assuntos
Síndrome Linfoproliferativa Autoimune/diagnóstico por imagem , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons , Adolescente , Adulto , Síndrome Linfoproliferativa Autoimune/complicações , Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/metabolismo , Criança , Pré-Escolar , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Linfoma/complicações , Masculino , Mutação , Esplenomegalia/complicações , Distribuição Tecidual , Adulto Jovem , Receptor fas/genética
11.
Infect Genet Evol ; 76: 104003, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31425784

RESUMO

Apoptosis is a universal cellular defense mechanism against senescent, damaged, genetically mutated, or virally-infected cells. It also is critical for the maintenance of liver health. Fas and FasL system act as a major death pathway that triggers apoptosis cascade in the liver. In this systematic review and meta-analysis, we aimed to investigate the relationship between four major polymorphisms of Fas and FasL genes with susceptibility to or clearance of HBV infection. All the eligible studies were extracted from PubMed and Scopus with no date and language restriction. ORs with 95% CIs were used to evaluate the strength of the association based on the following genetic models: (1) the allelic, (2) the homozygote, (3) the dominant, and (4) the recessive models. Totally 7 related articles were included in this meta-analysis; 5 studies of 7 related articles investigated FasL -844C/T (rs763110) polymorphism, 4 studies investigated FasL IVS2nt-124, 6 studies investigated Fas -670 A/G (rs1800682), and 4 studies investigated Fas -1377 A/G (rs2234767) polymorphism. This meta-analysis showed that there is no statistically significant association between the risk or clearance of HBV infection and four studied Fas and FasL polymorphisms in their allelic comparison or genetic models. Fas -670, Fas -1377, FasL -124, and FasL -844 polymorphisms did not show any significant association with the clearance or risk of HBV infection. Therefore, it seems that susceptibility to HBV infection or clearance of it is not affected by Fas and FasL genetic polymorphisms. But, to reach a definitive conclusion, further studies with a larger sample size of different ethnicity are still needed.


Assuntos
Proteína Ligante Fas/genética , Hepatite B/genética , Polimorfismo de Nucleotídeo Único , Receptor fas/genética , Predisposição Genética para Doença , Hepatite B/virologia , Vírus da Hepatite B/isolamento & purificação , Homozigoto , Humanos , Razão de Chances , Regiões Promotoras Genéticas
12.
Toxicol Appl Pharmacol ; 381: 114730, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31445928

RESUMO

Vinyl chloride (VC) is a common industrial organochlorine, shown to cause hepatic angiosarcoma and hepatic steatosis. However, the role of endoplasmic reticulum stress (ERS) and oxidative stress (OS) in hepatic steatosis after subchronic exposure to VC in mice, is unclear. Based on body weight, forty healthy SPF male C57BL/6 J mice were randomly divided into a control group and three VC exposure groups (57.3, 286.7, and 1433.6 ppm) (n = 10 each). VC was administered by static inhalation in a 50 L sealed plexiglass inhalation chamber for 2 h per day, five days per week for 16 weeks. Serum and liver tissues were analyzed for liver enzymes and lipids. Hepatic cytochrome P450 2E1 (CYP2E1) and OS related indicators malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were measured. The mRNA expressions of ERS downstream genes, including glycoregulatory protein-78 (GRP-78), sterol regulatory element binding protein-1 (SREBP-1), Acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) were detected by real-time PCR (RT-PCR) and their protein levels examined by western blotting. The CYP2E1 levels increased after VC administration in a dose-dependent manner. MDA levels increased (P < .05) and SOD and GSH levels decreased (P < .05) in the liver of each group with the increase in the dose of VC. ERS and expressions of downstream genes (GRP-78, SREBP-1, ACC, and FAS) were enhanced after VC administration. These results suggested that OS and ERS could be induced by VC, which may lead to an increase in fatty acid synthesis in the liver, further aggravating hepatic steatosis.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado Gorduroso/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Cloreto de Vinil/toxicidade , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Administração por Inalação , Animais , Citocromo P-450 CYP2E1/metabolismo , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
13.
Nat Commun ; 10(1): 2924, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266950

RESUMO

Fas induces apoptosis in activated T cell to maintain immune homeostasis, but the effects of non-apoptotic Fas signaling on T cells remain unclear. Here we show that Fas promotes TH9 cell differentiation by activating NF-κB via Ca2+-dependent PKC-ß activation. In addition, PKC-ß also phosphorylates p38 to inactivate NFAT1 and reduce NFAT1-NF-κB synergy to promote the Fas-induced TH9 transcription program. Fas ligation exacerbates inflammatory bowel disease by increasing TH9 cell differentiation, and promotes antitumor activity in p38 inhibitor-treated TH9 cells. Furthermore, low-dose p38 inhibitor suppresses tumor growth without inducing systemic adverse effects. In patients with tumor, relatively high TH9 cell numbers are associated with good prognosis. Our study thus implicates Fas in CD4+ T cells as a target for inflammatory bowel disease therapy. Furthermore, simultaneous Fas ligation and low-dose p38 inhibition may be an effective approach for TH9 cell induction and cancer therapy.


Assuntos
Diferenciação Celular , Doenças Inflamatórias Intestinais/imunologia , Transdução de Sinais , Linfócitos T Reguladores/citologia , Receptor fas/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , NF-kappa B/genética , NF-kappa B/imunologia , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/imunologia , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/terapia , Proteína Quinase C beta/genética , Proteína Quinase C beta/imunologia , Linfócitos T Reguladores/imunologia , Receptor fas/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
14.
J Agric Food Chem ; 67(27): 7660-7673, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31250646

RESUMO

Mushrooms are customary influential sources of pharmaceutically active metabolites. Usually lanostane-type triterpenoids from mushrooms had prospective for cancer disease treatments. Recently, a triterpenoid, astrakurkurol obtained from the fresh basidiocarps of the edible mushroom Astraeus hygrometricus, drew attention as a new cytotoxic therapeutic. The structural stability of this triterpenoid had been established with the amalgamation of density functional theory (DFT) calculations and study of single-crystal X-ray diffraction. To successfully manifest astrakurkurol as a potent cytotoxic therapeutics, a wide apprehension on the molecular and cellular mechanisms underlying their action is prerequisite. On this account, our study was directed to scrutinize the influence of this triterpenoid on human hepatocellular cancer cell model Hep3B. Encapsulating all experimental facts revealed that astrakurkurol had significantly decreased cell viability in a concentration-dependent manner. This effect was unveiled to be apoptosis, documented by DNA fragmentation, chromatin condensation, nuclear shrinkage, membrane blebing, and imbalance of cell cycle distribution. Astrakurkurol persuaded the expression of death receptor associated proteins (Fas), which triggered caspase-8 activation following tBid cleavage. Moreover, tBid mediated ROS generation, which triggered mitochondrial dysfunction and activated the mitochondrial apoptotic events. Astrakurkurol cytotoxicity was based on caspase-8-mediated intrinsic apoptotic pathway and was associated with inhibition at Akt and NF-κB pathway. Astrakurkurol had also inhibited the migration of Hep3B cells, indicating its antimigratory potential. These findings led us to introduce astrakurkurol as a feasible and natural source for a safer cytotoxic drug against hepatocellular carcinoma.


Assuntos
Antineoplásicos/farmacologia , Basidiomycota/química , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 8/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Modelos Moleculares , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Difração de Raios X , Receptor fas/genética
15.
Am J Chin Med ; 47(4): 879-893, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31179723

RESUMO

Yang-Yin-Qing-Fei-Tang (YYQFT) is a well-known traditional Chinese medicine used in the treatment of chronic obstructive pulmonary emphysema, bronchitis, cytomegaloviral pneumonia, but the mechanisms of the medicine are not clear. This study aimed to identify the active components of YYQFT and elucidate the underlying mechanism on non-small cell lung cancer. First, YYQFT was extracted with different solvents, and then the most effective extract was determined by assessing their effects on non-small cell lung cancer cell growth. Second, several active compounds from YYQFT were identified, and quercetin was the one of the important active ingredients. Subsequently, the in vivo antitumor activity of quercetin was confirmed in a lung cancer xenograft model in mice. 200 µ g/mL quercetin significantly reduced tumor volume without affecting body weight of the mice. Furthermore, induction of apoptosis by quercetin was detected in tumor tissues treated with quercetin. Multiple apoptosis related genes including p53, Bax and Fas were upregulated by quercetin in tumor tissue and the ratio of Bax/Bcl-2 was increased accordingly. Our results demonstrated that quercetin, as the main effective component of the YYQFT, has potent inhibitory activity on non-small cell lung cancer by regulating the ratio of Bax/Bcl-2.


Assuntos
Antineoplásicos Fitogênicos , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Medicamentos de Ervas Chinesas/química , Neoplasias Pulmonares/patologia , Quercetina/farmacologia , Animais , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Transplante de Neoplasias , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quercetina/isolamento & purificação , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
16.
Gen Physiol Biophys ; 38(3): 215-225, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31184308

RESUMO

The purpose of the study is to examine the protective effect of resveratrol on the fatty acid synthase gene expression against the side-effects of risperidone in an experimental model in rat liver. In this study, thirty-five female Spraque-Dawley rats were divided into five groups (n = 7): Control, RIS (2 mg/kg risperidone daily), RSV1 (2 mg/kg risperidone + 20 mg/kg resveratrol), RSV2 (2 mg/kg risperidone + 40 mg/kg resveratrol), and RSV3 group (2 mg/kg risperidone + 80 mg/kg resveratrol). On treatment day 15, liver tissue was taken for analysis. The resveratrol treatment significantly reduced weight gain as opposed to the risperidone administration. Moreover, the fatty acid synthase gene expression level increased significantly in RSV1 group (p = 0.011). In addition, resveratrol enhanced the total antioxidant status, high-density lipoprotein cholesterol levels and decreased alanine aminotransferase, aspartate aminotransferase, total cholesterol, gamma glutamyl transpeptidase, low density lipoprotein cholesterol, oxidative stress index, triglycerides, and total oxidant status levels significantly (p < 0.05). In conclusion, this study revealed that treatment with resveratrol might protect liver tissue against the side--effects of risperidone over fatty acid synthase gene expression. Resveratrol could be an effective course of therapy for enhancing therapeutic efficacy.


Assuntos
Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Substâncias Protetoras/farmacologia , Resveratrol/farmacologia , Risperidona , Receptor fas/genética , Animais , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Feminino , Fígado/efeitos dos fármacos , Fígado/patologia , Ratos , Ratos Sprague-Dawley
17.
Int J Mol Sci ; 20(11)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31142011

RESUMO

Nonalcoholic fatty liver disease is a frequent liver malady, which can progress to cirrhosis, the end-stage liver disease if proper treatment is not applied. Omega-3 fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid, have been clinically proven to lower serum triglyceride levels. Various physiological activities of omega-3 fatty acids are due to their agonistic actions on G-protein-coupled receptor 40 (GPR40) and GPR120. Lipid droplets (LD) accumulation in hepatocytes confirmed that DHA treatment reduced the number of larger ( >10 µm2) LDs, as well as the total area of LDs. Moreover, DHA lowered protein and mRNA expression levels of lipogenic enzymes such as fatty acid synthase (FAS), acetyl-CoA carboxylase and stearoyl-CoA desaturase-1 (SCD-1) in primary hepatocytes incubated with liver X receptor (LXR) agonist T0901317 or high glucose and insulin. DHA also decreased protein expression of nuclear and precursor sterol response-element binding protein (SREBP)-1, a key lipogenesis transcription factor. We further found that exposure of murine primary hepatocytes to DHA for 12 h increased GPR40 and GPR120 mRNA levels. Specific agonists (Compound A for GPR120 and AMG-1638 for GPR40), hepatocytes from GPR120 knock-out mice and GPR40 selective antagonist (GW1100) were used to assess whether DHA's antilipogenic effects are mediated through GPR120 or GPR40. Compound A did not decrease SREBP-1 and FAS protein expression in hepatocytes exposed to T0901317 or high glucose with insulin. Moreover, DHA downregulated lipogenesis enzyme expression in GPR120-null hepatocytes. In contrast, AMG-1638 lowered SREBP-1 and SCD-1 protein levels. Additionally, GW1100, a GPR40 antagonist, reversed the antilipogenic effects of DHA. Collectively, our data demonstrate that DHA downregulates the expression SREBP-1-mediated lipogenic enzymes via GPR40 in primary hepatocytes.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Hepatócitos/metabolismo , Lipogênese , Receptores Acoplados a Proteínas-G/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Células Cultivadas , Ácidos Graxos Ômega-3/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
18.
J Assist Reprod Genet ; 36(5): 995-1002, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30937706

RESUMO

PURPOSE: Idiopathic recurrent pregnancy loss (RPL) is a multifactorial reproductive disorder where an impaired control of apoptosis is likely involved. Triggering the cell death mechanism occurs in a spatiotemporal manner and is strongly related to a healthy pregnancy. Single nucleotide polymorphisms (SNPs) at the regulatory regions of genes are known to influence the expression patterns of apoptosis-related molecules. METHODS: A total of 296 unrelated female Brazilian patients were evaluated for clinical-demographic variables and genetic factors: 140 women who had experienced an unexplained RPL (with at least two consecutive abortions) and 156 healthy multiparous women. In all patients, six SNPs were evaluated in genes of apoptosis-related pathways: FAS (rs2234767, rs1800682), FAS-L (rs763110, rs5030772), BAX (rs4645878), and BCL-2 (rs2279115) by PCR followed by a restriction fragment length polymorphism (RFLP)-based analysis. RESULTS: The BAX-248GA genotype is independently associated with idiopathic RPL [adjusted OR = 0.30, 95% CI 0.13-0.70, P = 0.005] susceptibility. In the same multivariate model, the variables ethnicity, smoking, and alcohol consumption were statistically associated with RPL susceptibility (P < 0.05). No association with RPL susceptibility was reported for the remaining SNPs. CONCLUSION: Our study is the first to evaluate the role of the main SNPs from both the extrinsic and intrinsic apoptosis pathways in RPL susceptibility. The association of BAX-248G/A with RPL susceptibility suggests that maternal predisposition for RPL has an essential contribution from genes involved in the delicate balance of endometrium cell turnover (cell death/proliferation). Therefore, apoptotic genes may represent promising targets for future studies on healthy pregnancies and the spectrum of pregnancy disorders.


Assuntos
Aborto Habitual/genética , Proteína Ligante Fas/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína X Associada a bcl-2/genética , Receptor fas/genética , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Gravidez , Prognóstico , Adulto Jovem
19.
Free Radic Res ; 53(5): 486-496, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31010354

RESUMO

Aim: Stimulation of Fas death receptor is introduced as a major cause of non-alcoholic steatohepatitis (NASH) progression through suppression of cell viability. Therefore, the blocking of death pathways is hypothesised to be express new approaches to NASH therapy. For this purpose, current experiment applied synthetic small interference RNA (SiRNA) to trigger Fas death receptor and to show its potential therapeutic role in designed NASH model. Methods: Male mice were placed on a western diet (WD) for 8 weeks and exposed to cigarette smoke during the last 4 weeks of feeding to induce NASH model. In the next step, Fas SiRNA was injected to mice aiming to examine specific Fas gene silencing, after 8 weeks. As a control, mice received scrambled SiRNA. Reversible possibility of disease was examined by 3 weeks of recovery. Results: Analysis of data is accompanied with the significant histopathological changes (steatosis, ballooning and inflammation), increased lipid profile and hepatic enzyme activities (AST, ALT, ALP) plus TBARS as well as decreased antioxidants levels in NASH model. Upon Fas-SiRNA injection, almost all measured parameters of NASH such as overexpression of Fas receptor, caspase3, NF-kB genes and marked increase of hepatic TNF-α were significantly restored and were remained nearly unchanged following recovery liking as scrambled groups. Conclusions: The suppression of Fas receptor signalling subsequent RNAi therapy may represent an applicable strategy to decline hepatocyte damages and so NASH progression in mice.


Assuntos
Fumar Cigarros/efeitos adversos , Dieta Ocidental/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/terapia , RNA Interferente Pequeno/genética , Receptor fas/genética , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos , NF-kappa B/genética , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Receptor fas/antagonistas & inibidores , Receptor fas/metabolismo
20.
Food Funct ; 10(5): 2417-2425, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-30964474

RESUMO

d-Psicose is a new-generation sugar substitute with a low calorie count and can still offer the desirable sweetness. The objective of this study was to investigate the antiobesity potential of d-psicose and the possible mechanism using Wistar rats as the animal model. The animals were divided into five groups and supplemented with diets containing 5% of different carbohydrates, such as glucose, fructose, cellulose, d-psicose, and a control diet, for 4 weeks. After sacrifice, blood lipid profile, tissue morphology, and related genes participating in lipid metabolism were analyzed. The results indicated that the supplementation by d-psicose leads to minimum fat accumulation in rats when compared with the other carbohydrates. The blood lipid profile and antioxidative activity of the rat were also improved. d-Psicose can regulate lipid metabolism by increasing the lipid-metabolism-related enzymes such as SDH in serum and liver and HL in the liver. d-Psicose can prevent fat accumulation by suppressing the expression of lipogenesis-related gene ACCα and hepatic fatty acid uptake gene (FAS and SREBP-1c), while stimulating the expression for fatty-acid-oxidation-related gene including AMPK2α, HSL, and PPARα. In conclusion, d-psicose can be considered to be a healthy alternative to traditional sweeteners.


Assuntos
Fármacos Antiobesidade/metabolismo , Frutose/metabolismo , Metabolismo dos Lipídeos , Obesidade/dietoterapia , Animais , Glucose/metabolismo , Humanos , Insulina/metabolismo , Lipídeos/sangue , Masculino , Obesidade/genética , Obesidade/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Ratos , Ratos Wistar , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
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