RESUMO
Primary effusion lymphoma (PEL) is an aggressive neoplasm correlated with human herpesvirus 8 (HHV8). Metabolic reprogramming is a hallmark of cancers. The alterations in cellular metabolism are important to the survival of HHV8 latently infected cells. Pyruvate dehydrogenase (PDH) controls the flux of metabolites between glycolysis and the tricarboxylic acid cycle (TCA cycle) and is a key enzyme in cancer metabolic reprogramming. Glutaminolysis is required for the survival of PEL cells. Glutamate dehydrogenase 1 (GDH1) converts glutamate into α-ketoglutarate supplying the TCA cycle with intermediates to support anaplerosis. Previously we have observed that epigallocatechin-3-gallate (EGCG) can induce PEL cell death and N-acetyl cysteine (NAC) attenuates EGCG induced PEL cell death. In this study, results showed that EGCG upregulated the expression of glucose transporter GLUT3, and reduced the expression of pyruvate dehydrogenase E1-alpha (PDHA1), the major regulator of PDH, and GDH1. NAC could partially reverse the effects of EGCG in PEL cells. Overexpression of PDHA1 in PEL cells or supplement of α-ketoglutarate attenuated EGCG induced cell death. EGCG also reduced the levels of oncometabolite D-2-hydroxyglutarate (D2HG). These results suggest that EGCG may modulate the metabolism of PEL cells leading to cell death.
Assuntos
Catequina/análogos & derivados , Herpesvirus Humano 8 , Linfoma de Efusão Primária/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Piruvato Desidrogenase (Lipoamida)/genética , Catequina/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Glutaratos/metabolismo , Humanos , Linfoma de Efusão Primária/genética , Linfoma de Efusão Primária/virologiaRESUMO
BACKGROUND: Excessive alcohol intake can result in the oxidative stress in cells and the genetic variations of alcohol-metabolizing enzymes are responsible for the different degrees of toxicity of alcohol in several organs, such as the liver and immunological systems. We hypothesized that the alteration of oxidative stress due to some genetic variations of oxidative stress-related enzymes could result in changes of specific biomarkers, and heavy drinkers could be cautioned about the predictive likelihood to induce drinking-induced diseases. METHODS: A total of 108 heavy drinkers and 106 nonheavy drinkers were enrolled and the hematological, biochemical, and immunological tests were measured; the genotypes of oxidative stress-related enzymes, including manganese superoxide dismutase (MnSOD1183T>C), glutathione peroxidase 1 (GPX1Pro198Leu), catalase (CAT-262C>T), and myeloperoxidase (MPO-463G>A), were assayed by real-time polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). RESULTS: For the males, the levels of carbohydrate-deficient transferrin (CDT), malondialdehyde (MDA), CD4(+), immunoglobulin G (IgG), immunoglobulin M (IgM), and IL-6 were significantly different between the two groups. Furthermore, there were higher proportions of CD19(+) cells and lower TNF-α levels in heavy drinkers with the MnSOD C carriers, and there were higher percentages of CD19(+) cells and IL-6 levels in heavy drinkers with the combined genotypes of MnSOD C carriers and MPO A carriers. CONCLUSIONS: Our findings indicate that heavy drinkers may be cautioned predictive likelihood for them to induce drinking-induced diseases by analyzing their MnSOD genotypes and immunological biomarkers.
Assuntos
Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/imunologia , Antígenos CD/sangue , Citocinas/sangue , Estresse Oxidativo/genética , Oxirredutases/genética , Adulto , Idoso , Consumo de Bebidas Alcoólicas/epidemiologia , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Taiwan , Adulto JovemRESUMO
Alcohol metabolism involves several enzymes and the individual genetic variations in the alcohol metabolism are related to the absorption, distribution, and elimination of alcohol and metabolites such as acetaldehyde. Therefore, the genetic variations of alcohol-metabolizing enzymes are responsible for the different toxicity of alcohol in several organs like liver and immunological systems. The purpose of this study was to evaluate if the life styles such as drinking and smoking and the genetic variations of alcohol-metabolizing enzymes (ADH2, ALDH2, CYP2E1, and CAT) were associated with the immunological biomarkers. In this study, 105 high-risk drinkers and 102 low-risk drinkers who were excluded from the immune-related diseases and other critical diseases were enrolled to evaluate the immunological functions. Counts of white blood cells, mononuclear cells, and lymphocyte subpopulations, and liver and immunological function tests were measured. Genotypes of alcohol-metabolizing enzymes were assayed by a real-time PCR and PCR-restriction fragment length polymorphism. Generally, the activity of aspartate aminotransferase (AST) was higher than that of alanine aminotransferase (ALT) in alcoholics; however, the activities of AST and ALT were simultaneously elevated in general hepatitis except for alcohol-induced hepatitis. Thus, the higher ratio of AST/ALT was used to be a marker for the alcohol-induced abnormal liver function. Glutamyltransferase (GGT) is produced by the liver cell microsomes and is a useful laboratory marker as an indicator of early liver cell damage. An increase in GGT concentration has been regarded as a marker of alcohol consumption or liver disease. In addition, the synergistic effects of smoking and drinking on the count of white blood cell (WBC) and mononuclear cells were found to be significant. Furthermore, there were higher OR to become high-risk drinkers in subjects with the combination of ALDH2 (*1/*1) genotype and either genotype of ADH2 or CYP2E1 than the others with other combinations of genotypes. Additionally, there were more abnormal immunological tests in the subjects with higher activity of ADH2 and lower activity of ALDH2. Our results suggested that the habits of drinking, smoking, and betel chewing, and genetic variations of alcohol metabolism were associated with the immunological biomarkers.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Enzimas/metabolismo , Etanol/metabolismo , Polimorfismo Genético , Adulto , Idoso , Consumo de Bebidas Alcoólicas/imunologia , Enzimas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Excessive alcohol consumption can induce apoptosis in a variety of tissues and influence the antioxidant status in peripheral blood mononuclear cells (PBMC). This paper investigates the effects of whey protein concentrate (WPC) pretreated in PBMC on the apoptosis and antioxidant status after the treatment of alcohol. The results show that the percentages of apoptotic cells in the alcohol-treated group were higher than those in the group without alcohol treatment. Additionally, there was higher glutathione (GSH) peroxidase (GPx) activity when the PBMC were treated with 300 mg/dL of alcohol. With regard to the activity of GSH reductase (GRx), there was higher activity in the group pretreated with WPC than in the group with the treatment of alcohol only. On the contrary, the levels of GSH were reduced after the treatment of alcohol, but there was a higher level of GSH in the group pretreated with WPC. In this study, it was found that the increased level of GSH in PBMC might not be attributed to the effect of GRx because there was still a higher level of GSH in the group with the treatment of WPC and BCNU (a GRx inhibitor) in this study. The results indicated that PBMC pretreated with WPC might ameliorate alcohol-induced effects such as imbalance of the antioxidant status.
Assuntos
Etanol/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Proteínas do Leite/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Glutationa/sangue , Glutationa Peroxidase/sangue , Glutationa Redutase/sangue , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/enzimologia , Proteínas do Soro do LeiteRESUMO
BACKGROUND: Alcohol abuse has been implicated as an important factor for accidents. We evaluated the roles of different genetic combinations of the ADH2 and ALDH2 genotypes on biomarkers in trauma patients with excessive alcohol intake at our emergency department. METHODS: Blood samples were obtained from 80 patients and 88 age-matched controls. The biomarkers, including AST, ALT, GGT, and MDA, were assayed. The polymerase chain reaction-restriction fragment length polymorphism method was used to determine the genetic polymorphisms of ADH2 and ALDH2. RESULTS: There were significant differences in the levels of AST, ALT, GGT, MDA, and AST/ALT ratios between the 2 groups. In addition, MDA values and AST/ALT ratios were significantly higher in the patients with normal activity of ADH2 than the patients with low activity of ADH2. Meanwhile, regarding ALDH2 genotypes, there were significantly higher ratios of AST/ALT in the patients with low activity of ALDH2. The highest AST/ALT ratios and MDA values were in the patients with ADH2 (*2/*2) and ALDH2 (*1/*2 and *2/*2). CONCLUSIONS: In conclusion, our results indicated that alcohol-induced liver damage or oxidative stress might be influenced by the genetic variation of ADH2 or ALDH2. Therefore, the combinations of different ADH2 and ALDH2 genotypes may be influential markers for susceptibility to alcohol-induced liver damage.
Assuntos
Álcool Desidrogenase/genética , Intoxicação Alcoólica/enzimologia , Aldeído Desidrogenase/genética , Serviço Hospitalar de Emergência , Variação Genética , Ferimentos e Lesões/enzimologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
A case-control study was conducted to investigate the association between the consumption of local common foods that are rich in vitamin A and the risk of lung cancer in Taiwan. A total of 301 incident lung cancer cases, 602 hospital controls, and 602 neighborhood controls were recruited. The consumption of 13 food items and vitamin supplements was estimated by use of a food frequency questionnaire. The conditional logistic regression models were used to estimate the adjusted odds ratios (AOR) and 95% confidence intervals (CI) for lung cancer risk with each control group as reference by adjustment of covariates. A reduced risk for lung cancer was found to be associated with increased intakes of vitamin A, alpha-carotene, and beta-carotene from 13 food items. More servings of vegetables (AOR for the highest versus the lowest quartile = 0.67-0.70, 95% CI = 0.42-1.08, (plinear trend )= 0.04), garland chrysanthemum (AOR for the highest versus the lowest tertile = 0.58-0.74, 95% CI = 0.37-1.14, (plinear trend )<= 0.04) and sweet potato leaves (AOR for the highest versus the lowest tertile = 0.43-0.65, 95% CI = 0.28-0.96, (plinear trend )<= 0.03) were associated with the reduced risk for lung cancer. In conclusion, higher consumption of vitamin A-rich vegetables, especially garland chrysanthemum and sweet potato leaves might provide potential protection from lung cancer.
Assuntos
Chrysanthemum/química , Dieta , Ipomoea batatas/química , Neoplasias Pulmonares/epidemiologia , Avaliação Nutricional , Vitamina A/administração & dosagem , Idoso , Estudos de Casos e Controles , Intervalos de Confiança , Feminino , Análise de Alimentos , Humanos , Modelos Logísticos , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Folhas de Planta/química , Fatores de Risco , Fumar/efeitos adversos , Inquéritos e Questionários , Taiwan/epidemiologiaRESUMO
OBJECTIVES: The objective of this study was to investigate the distribution of genetic polymorphisms of alcohol-metabolizing enzymes in trauma patients with excessive alcohol consumption in the emergency department (ED). DESIGN AND METHODS: A total of 100 trauma patients and age-matched control subjects composed of 98 participants were enrolled in this study. The activities of liver enzymes and genotypes of alcohol-metabolizing enzymes, including ADH2, ALDH2, and CYP2E1, were analyzed with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: There was a significant difference in the allele frequencies of ALDH2 between the two groups. For the genotypes, there were significant differences in the genotype frequencies of ADH2 and ALDH2. There was also a significantly lower frequency in patients with the ALDH2*2 phenotype than those of the controls. For the activities of liver enzymes, there were significant differences between the two groups. For ADH2 and ALDH2, there were significantly higher ORs (odds ratios) in trauma patients with normal activity than those with weak or intermediate activity but there were no significant difference in CYP2E1 genotype between two groups. To investigate the interaction of alcohol-metabolizing enzyme genotypes, we have estimated the odds ratios in two alcohol-metabolizing pathways. The ORs of the combined genotypes of ADH2 (*1/*1+*1/*2) and ALDH2 (*1/*1) and the combined genotypes of either CYP2E1 (*c1/*c1) or CYP2E1 (*c1/*c2+*c2/*c2) and ALDH2 (*1/*1) were significantly higher than that of the reference group in the major and the minor pathway, respectively. CONCLUSIONS: Genetic variation of alcohol-metabolizing enzymes, especially ALDH2, may play an important role on the occasions of alcohol problems in the emergency department.