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1.
Nat Metab ; 3(3): 337-351, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33758417

RESUMO

Alcohol is among the most widely used psychoactive substances worldwide. Ethanol metabolites such as acetate, thought to be primarily the result of ethanol breakdown by hepatic aldehyde dehydrogenase 2 (ALDH2), contribute to alcohol's behavioural effects and alcoholism. Here, we show that ALDH2 is expressed in astrocytes in the mouse cerebellum and that ethanol metabolism by astrocytic ALDH2 mediates behavioural effects associated with ethanol intoxication. We show that ALDH2 is expressed in astrocytes in specific brain regions and that astrocytic, but not hepatocytic, ALDH2 is required to produce ethanol-derived acetate in the mouse cerebellum. Cerebellar astrocytic ALDH2 mediates low-dose ethanol-induced elevation of GABA levels, enhancement of tonic inhibition and impairment of balance and coordination skills. Thus, astrocytic ALDH2 controls the production, cellular and behavioural effects of alcohol metabolites in a brain-region-specific manner. Our data indicate that astrocytic ALDH2 is an important, but previously under-recognized, target in the brain to alter alcohol pharmacokinetics and potentially treat alcohol use disorder.


Assuntos
Aldeído-Desidrogenase Mitocondrial/metabolismo , Astrócitos/enzimologia , Comportamento/efeitos dos fármacos , Encéfalo/metabolismo , Etanol/toxicidade , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Encéfalo/citologia , Encéfalo/enzimologia , Feminino , Humanos , Masculino , Camundongos , Ácido gama-Aminobutírico/metabolismo
2.
Biochem Biophys Res Commun ; 533(4): 1427-1434, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33333711

RESUMO

Sympathetic stimulated-cardiac fibrosis imposes great significance on both disease progression and survival in the pathogenesis of many cardiovascular diseases. However, there are few effective therapies targeting it clinically. The cardioprotective effect of aldehyde dehydrogenase 2 (ALDH2) has been explored in many pathological conditions, whether it can exert benefit effects on chronic sympathetic stimulus-induced cardiac fibrosis remains unclear. In this study, we determined to explore the role of ALDH2 on isoproterenol (ISO)-induced cardiac fibroblasts (CF) proliferation and cardiac fibrosis. It was found that ALDH2 enzymatic activity was impaired in ISO-induced HCF proliferation and Aldh2 deficiency promoted mouse CF proliferation. Alda-1, an ALDH2 activator, exerted obvious suppressive effect on ISO-induced HCF proliferation, together with the induction of cell cycle arrest at G0/G1 phase and decreased expression of cyclin E1 and cyclin-dependent kinase 2 (CDK2). Mechanistically, the inhibitory role of Alda-1 on HCF proliferation was achieved by decreasing mitochondrial reactive oxygen species (ROS) production, which was partially reversed by rotenone, an inducer of ROS. In addition, wild-type mice treated with Alda-1 manifested with reduced fibrosis and better cardiac function after ISO pump. In summary, Alda-1 alleviates sympathetic excitation-induced cardiac fibrosis via decreasing mitochondrial ROS accumulation, highlighting ALDH2 activity as a promising drug target of cardiac fibrosis.


Assuntos
Aldeído-Desidrogenase Mitocondrial/metabolismo , Cardiomiopatias/patologia , Aldeído-Desidrogenase Mitocondrial/antagonistas & inibidores , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Benzamidas/farmacologia , Benzodioxóis/farmacologia , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/enzimologia , Cardiotônicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Eletrocardiografia , Fibroblastos/patologia , Fibrose , Ventrículos do Coração/patologia , Humanos , Isoproterenol/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo
3.
Chem Biol Interact ; 331: 109274, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33007288

RESUMO

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. Mutations in the adenomatous polyposis coli (APC) gene are pivotal in colorectal tumorigenesis. Recently, we demonstrated that aldehyde dehydrogenase 1B1 (ALDH1B1) knockdown dramatically reduced colon tumor growth in a mouse xenograft model. The purpose of the present preliminary study is to examine the effect of loss of ALDH1B1 in CRC development in an inducible colon-specific Apc mouse model. METHODS: ApcW/FCdx2ERT2-Cre mice develop uni-allelic inactivation of Apc specifically in colon epithelial cells following tamoxifen treatment. Aldh1b1-/- KO mice were crossed with ApcW/FCdx2ERT2-Cre mice. Six-month-old male ApcW/FCdx2ERT2-Cre/Aldh1b1-/-, and ApcW/FCdx2ERT2-Cre/Aldh1b1+/+ mice were treated with tamoxifen (50 mg/kg, i.p.) for three consecutive days. ApcW/F/Aldh1b1-/- and ApcW/F/Aldh1b1+/+ mice were treated with corn oil (i.e., tamoxifen vehicle control) for three consecutive days. Eighteen days later, mice were sacrificed and their colons examined microscopically, macroscopically and histologically for the presence of adenoma. RESULTS: All ApcW/FCdx2ERT2-Cre/Aldh1b1+/+ and ApcW/FCdx2ERT2-Cre/Aldh1b1-/- mice treated with tamoxifen developed colorectal adenoma. The ApcW/FCdx2ERT2-Cre/Aldh1b1-/- mice showed a significant decrease in the total volume of all ileal and colonic adenomas, and decreased incidence of large colonic adenoma compared to ApcW/FCdx2ERT2-Cre/Aldh1b1+/+ mice. Immunohistochemical analysis of p53 and ß-catenin showed a trend toward decreased expression score in colonic adenomas of ApcW/FCdx2ERT2-Cre/Aldh1b1-/- mice. CONCLUSION: The present preliminary study suggests that deletion of ALDH1B1 may protect against the full development of colorectal cancer. Further mechanistic studies are required to elucidate how ALDH1B1 contributes for colorectal cancer.


Assuntos
Polipose Adenomatosa do Colo/patologia , Aldeído-Desidrogenase Mitocondrial/metabolismo , Neoplasias Colorretais/patologia , Polipose Adenomatosa do Colo/metabolismo , /genética , Aldeído-Desidrogenase Mitocondrial/deficiência , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Genótipo , Intestino Grosso/metabolismo , Intestino Grosso/patologia , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Camundongos , Camundongos Knockout , Tamoxifeno , Proteína Supressora de Tumor p53/metabolismo , beta Catenina/metabolismo
4.
Nature ; 582(7811): 240-245, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32499647

RESUMO

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Aldeído-Desidrogenase Mitocondrial/genética , Alelos , Anquirinas/genética , Índice de Massa Corporal , Estudos de Casos e Controles , Europa (Continente)/etnologia , Proteínas do Olho/genética , Extremo Oriente/etnologia , Feminino , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/análise , Fatores de Transcrição/genética , Transcrição Genética
5.
BMC Med Genet ; 21(1): 118, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32487094

RESUMO

BACKGROUND: Fanconi anemia (FA) is the most common inherited bone marrow failure (BMF) syndrome with 22 related genes identified. The ALDH2 rs671variant has been proved related to accelerate the progression of BMF in FA patients. The phenotype and genetic basis of Chinese FA patients have not been investigated yet. METHODS: We analyzed the 22 FA-related genes of 63 BMF patients suspected to be FA. Clinical manifestations, morphological and cytogenetic feathers, ALDH2 genotypes, treatment, and outcomes of the definite cases were retrospectively studied. RESULTS: A total of 21 patients were confirmed the diagnosis of FA with the median age of BMF onset was 4-year-old. The number of patients manifested as congenital malformations and growth retardation were 20/21 and 14/21, respectively. BM dysplasia and cytogenetic abnormalities were found in 13/20 and 8/19 patients. All the patients with abnormal karyotypes also manifested as BM dysplasia or had evident blasts. Thirty-five different mutations were identified involving six genes and including twenty novel mutations. FANCA mutations contributed to 66.67% of cases. Eight patients harboring ALDH2-G/A genotype have a significantly younger age of BMF onset (p = 0.025). Within the 19 patients adhering to continuous follow-up, 15 patients underwent hematopoietic stem cell transplantations (HSCTs). During the 29 months of follow-up, 8/19 patients died, seven of which were HSCT-related, and one patient who did not receive HSCT died from severe infection. CONCLUSIONS: The phenotypic and genetic spectrum of Chinese FA patients is broad. Bone marrow dysplasia and cytogenetic abnormalities are prevalent and highly consistent. The overall outcome of HSCTs is disappointing. Nationwide multicenter studies are needed for the rarity and adverse outcome of this disease.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Estudos de Associação Genética , Genótipo , Mutação , Fenótipo , Adolescente , Medula Óssea/patologia , Criança , Pré-Escolar , Quebra Cromossômica , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Cariótipo , Masculino
6.
Medicine (Baltimore) ; 99(21): e20206, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481290

RESUMO

In last decades, many scholars have studied the relationship between aldehyde dehydrogenase 2 (ALDH2) rs671 and ischemic stroke (IS), however, the results obtained from these studies were inconclusive. The purpose of this study was to investigate the association between rs671 and the risk of IS by systematically review.Two researchers independently screened relevant published literatures, derived data and estimated the risk of bias of the research in Pubmed, Embase, Ovid, China National Knowledge Infrastructure (CNKI), Cochrane Library and China Biomedical Literature Database throughout March 29, 2020. All statistical analyses were performed with the Stata 12.0 software. The data of the study was analyzed using fixed and random effects models. The results were expressed by odds ratio (OR) and 95% confidence interval (95%CI).A total of 10 articles were included this study. The total number of samples for all studies was 5265, including 2762 cases and 2503 controls. Statistical results indicated statistical differences between ALDH2 rs671 polymorphism and IS under dominant model (AA vs. AG + GG) and allelic model (A vs G), ORs (95% CI) were 1.66 (1.27-2.17) (P = .00) and 1.34 (1.05-1.71) (P = .02), respectively. But there was no statistical difference under recessive model (AA + AG vs GG), OR (95% CI) was 1.40 (0.99-1.97), P = .06.ALDH2 rs671 polymorphism was related to IS risk for Chinese population and the A allele of rs671 may be a risk factor of IS.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Isquemia Encefálica/diagnóstico , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/genética , Revisões Sistemáticas como Assunto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Fatores de Risco , Sensibilidade e Especificidade , Acidente Vascular Cerebral/patologia
7.
Int Heart J ; 61(3): 562-570, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32350201

RESUMO

Aldehyde dehydrogenase-2 (ALDH2) rs671 G>A polymorphism can influence the activity of ALDH2 and may be associated with the risk of essential hypertension (EH). Although many previous studies have explored such a relationship, the conclusion is still controversial.The PubMed, Embase, and China National Knowledge Infrastructure databases were searched on the ALDH2 gene and EH. We used the Newcastle-Ottawa Scale to evaluate the quality of the study. Then we calculated the strength of relationship between ALDH2 rs671 mutation and EH by utilizing odds ratios and 95% confidence intervals. Besides, subgroup analysis and sensitivity analysis were performed and the publication bias was assessed.There were 12 studies containing 8153 cases and 10,162 controls. Our meta-analysis showed significant association between ALDH2 rs671 polymorphism and EH in four genetic models (the allele model, the homozygote model, the heterozygote model, and the dominant model), whereas it did not indicate this connection in the recessive model. However, a trend of decreased risk still could be seen. Furthermore, we also found an obvious association between rs671 mutation and the risk of EH in the male group than in the female group in all five genetic models.We concluded that ALDH2 rs671 G>A polymorphism may decrease the risk of EH. Furthermore, susceptibility to EH reduced in males but not in females. As a variant in ALDH2, rs671 G>A could be an attractive candidate for genetic therapy of EH. In addition, more case-control studies should be conducted to strengthen our conclusion and evaluate the gene-gene and gene-environment interactions between the ALDH2 gene and EH.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Hipertensão Essencial/genética , Humanos , Polimorfismo de Nucleotídeo Único
8.
Sci Rep ; 10(1): 6564, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32300124

RESUMO

The associations between genetic polymorphisms in ADH1B (rs1229984) and ALDH2 (rs671), alcohol consumption, the effect of a combination of the two polymorphisms, and breast cancer risk were studied in a population of East-Asian women. In this study, 623 breast cancer cases and 1845 controls, aged 40 or above, were included. The association between ALDH2 polymorphism and breast cancer risk was validated in 2143 breast cancer cases and 3977 controls. Alcohol consumption increased the risk of breast cancer regardless of ADH1B and ALDH2 genotypes. The rs671 polymorphism of ALDH2 was independently associated with increased breast cancer risk (OR = 1.27, 95% CI = 1.02-1.58 per increment of A). The ADH1B rs1229984 polymorphism, and combined effects of the rs671 and rs1229984 polymorphisms, did not reveal any significant association with breast cancer. Stratification by menopausal status revealed that rs671 gene polymorphisms were significantly associated with breast cancer only in postmenopausal women (OR = 1.45, 95% CI = 1.03-2.05 per increment of A). This is the first study to demonstrate an independent association between ALDH2 gene variants and breast cancer in Asian women. Further studies are warranted to further elucidate the etiology of breast cancer as it relates to alcohol consumption in Asian women.


Assuntos
Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas/genética , Aldeído-Desidrogenase Mitocondrial/genética , Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Predisposição Genética para Doença , Adulto , Feminino , Genótipo , Humanos , Menopausa/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
9.
Ann Rheum Dis ; 79(5): 657-665, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32238385

RESUMO

OBJECTIVES: Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000-3000 years. METHODS: Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. RESULTS: In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10-8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients' gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. CONCLUSIONS: Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Aldeído-Desidrogenase Mitocondrial/genética , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Gota/genética , Proteínas de Neoplasias/genética , Estudos de Casos e Controles , Loci Gênicos , Genótipo , Gota/epidemiologia , Humanos , Incidência , Japão , Masculino , Fenótipo , Prognóstico , Valores de Referência , Medição de Risco , Índice de Gravidade de Doença
10.
BMC Cardiovasc Disord ; 20(1): 127, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32160861

RESUMO

BACKGROUND: Acute coronary syndrome (ACS) is the most serious type of coronary heart disease and is a global medical burden. The pathogenesis of ACS is very complex and still poorly understood. Epidemiologic studies have revealed that the manifestation of ACS are the results of the interactions between multiple environmental and genetic factors. The present study aimed to investigate the role of polymorphisms of MTHFR C677T and ALDH2 Glu504Lys as risk factors for ACS in a Hakka population in southern China. METHODS: Between September 1, 2015 and October 31, 2017, a total of 1957 individuals, including 860 ACS patients and 1097 controls were recruited. Blood samples were collected and genotypes were determined by DNA microarray chip method and direct sequencing method. RESULTS: For the MTHFR C677T polymorphism, frequencies of CC, CT, and TT genotypes were 53.60% versus 55.33, 39.53% versus 38.65 and 6.86% versus 6.02% in patients with ACS versus controls, respectively(p > 0.05). The differences in genotype frequencies between the ACS patients and controls in the three genetic model were not statistically significant. For the ALDH2 Glu504Lys polymorphism, the frequencies of ALDH2*1*1, ALDH2*1*2, and ALDH2*2*2 genotypes were 48.72, 42.67 and 8.6% in the ACS patients, respectively, while these were 53.33, 39.11 and 7.57% in the controls, respectively, showing no significant difference in the distribution of the ALDH2 genotype between the groups. Using the wild genotype ALDH2*1*1 as reference, relative risk analysis revealed a slightly increased risk for ACS in individuals with the ALDH2*1*2 plus ALDH2*2*2 genotypes (odds ratio (OR) = 1.203, 95% confidence interval (CI) = 1.006-1.438, p = 0.043). In a multivariate logistic regression model, even after adjusting for potential covariates, the association between ALDH2 *2 allele and ACS remained significant (OR = 1.242, 95% CI = 1.045-1.561, p = 0.038). CONCLUSIONS: We present findings regarding the possible clinical impact of the ALDH2*2 variant on ACS patients in a Hakka population in southern China and our findings might help to stratify the high-risk ACS patients and implement appropriate strategies for this genetic subpopulation to ultimately guide the precision preventive procedures in the future.


Assuntos
Síndrome Coronariana Aguda/genética , Aldeído-Desidrogenase Mitocondrial/genética , Grupo com Ancestrais do Continente Asiático/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Síndrome Coronariana Aguda/diagnóstico por imagem , Síndrome Coronariana Aguda/etnologia , Idoso , China/epidemiologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Fatores de Risco
11.
Arch Biochem Biophys ; 686: 108329, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32151565

RESUMO

In the body, alcohol dehydrogenase rapidly converts ethanol to its toxic metabolite, acetaldehyde, which is further metabolized to non-toxic acetic acid by aldehyde dehydrogenase (ALDH). 6-(methylsulfinyl)hexyl isothiocyanate (6-MSITC), a major bioactive compound in Wasabi (Wasabia japonica) has various physiological effects such as anti-oxidative, anti-inflammatory and anti-cancer effects. However, the effect of 6-MSITC on alcohol metabolism has not been studied. In this study, we investigated the effects of 6-MSITC on hepatic ALDH activity and protein expression both in vitro and in vivo. 6-MSITC inhibited ethanol- and acetaldehyde-induced cytotoxicity. Treatment with 6-MSITC to HepG2 cells enhanced ALDH activity through the induction of mitochondrial ALDH2 expression, but not cytosolic ALDH1A1. Knockdown of Nrf2 canceled the 6-MSITC-induced ALDH2 expression, indicating that Nrf2 regulated ALDH2 expression. Moreover, 6-MSITC increased the nuclear translocation of Nrf2 and the expression levels of HO-1 and SOD2, Nrf2-regulated phase II drug-metabolizing enzymes. Oral administration of 6-MSITC increased the mitochondrial ALDH2 activity and its expression in the liver of C57BL/6J mice. These results suggested that 6-MSITC is possible to protect acetaldehyde toxicity in hepatocytes by induction of mitochondrial ALDH2 expression through Nrf2/ARE pathway.


Assuntos
Acetaldeído/metabolismo , Aldeído-Desidrogenase Mitocondrial/metabolismo , Antineoplásicos/farmacologia , Hepatócitos/metabolismo , Isotiocianatos/farmacologia , Acetaldeído/toxicidade , Alanina Transaminase/metabolismo , Álcool Desidrogenase/metabolismo , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Aspartato Aminotransferases/metabolismo , Etanol/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Heme Oxigenase-1/metabolismo , Células Hep G2 , Humanos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Fosforilação , Superóxido Dismutase/metabolismo
13.
Neurotox Res ; 37(3): 702-713, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32062779

RESUMO

We aimed to investigate whether ethanol (EtOH) and acetaldehyde (AcH) can affect glutamate and its receptors GluN1 and GluA1 in the hippocampus of Aldh2-knockout (Aldh2-KO) and C57BL/6N (wild-type (WT)) mice. To do this, we first examined the effect of local administration of EtOH (100 mM, 200 mM, and 500 mM) and AcH (100 µM, 200 µM, and 500 µM) on extracellular glutamate levels in freely moving mice. Retrodialysis of 200 mM and 500 mM EtOH into the hippocampus of WT and Aldh2-KO mice produced significant decreases in extracellular glutamate levels (p < 0.05). A dose of 500 mM EtOH induced a greater decrease in Aldh2-KO mice (p < 0.05) than in WT mice, indicating the action of AcH. Similarly, perfusion of 200 µM and 500 µM AcH decreased glutamate in Aldh2-KO mice (p < 0.05), but this decrease was not seen in WT mice at any AcH dose. Second, we tested whether the EtOH- and AcH-induced decrease in glutamate was associated with decreases in GluN1 and GluA1 expression, as measured by real-time PCR and Western blot. We found a significant decrease in GluN1 (p < 0.05) and GluA1 (p < 0.05) subunits after a high dose of EtOH (4.0 g/kg) and AcH (200 mg/kg) in WT mice. However, a 2.0 g/kg dose of EtOH did not produce a consistent decrease in GluN1 or GluA1 between messenger RNA and protein. In Aldh2-KO mice, all three doses of EtOH (1.0 g/kg, 2.0 g/kg, and 4.0 g/kg) and AcH (50 mg/kg, 100 mg/kg, and 200 mg/kg) decreased GluN1 expression (p < 0.05), while moderate-to-high doses of EtOH (2.0 g/kg and 4.0 g/kg) and AcH (100 mg/kg and 200 mg/kg) decreased GluA1 expression (p < 0.05). Together, these in vivo and ex vivo data suggest that EtOH and AcH decrease extracellular glutamate in the hippocampus of mice with a concomitant decrease in GluN1 and GluA1 subunits, but these effects require relatively high concentrations and may, therefore, explain the consequences of EtOH intoxication.


Assuntos
Acetaldeído/toxicidade , Aldeído-Desidrogenase Mitocondrial/metabolismo , Etanol/toxicidade , Ácido Glutâmico/metabolismo , Hipocampo/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Feminino , Hipocampo/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
14.
Pharmacogenet Genomics ; 30(3): 54-60, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32084087

RESUMO

OBJECTIVE: This study sought to evaluate the impacts of interactions between the alcohol dehydrogenase-1B (rs1229984) genotype and the aldehyde dehydrogenase-2 (rs671) genotype on alcohol flushing, alcohol reeking on the day after drinking, and the age distribution in alcohol-dependent patients. METHODS: The study subjects were 4107 Japanese alcohol-dependent men who underwent alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 genotyping: 4051 patients were asked about their current or former tendency to experience facial flushing after drinking a glass of beer, and 969 patients were asked about whether they had ever been told that they reeked of alcohol more than 12 hours after they had stopped drinking. RESULTS: Current, former, and never flushing were reported in 3.5, 14.9, and 81.5%, respectively, of the subject, and alcohol reeking after more than 12 hours in 36.1% of the subjects. The fast-metabolizing ADH1B*2(+) genotype (*1/*2 or *2/*2) and the inactive ALDH2*2(+) genotype (*1/*2 or *2/*2) affected the multivariate odds ratios for current or former flushing [odds ratio, 95% confidence interval = 2.27 (1.79-2.86) and 23.0 (18.6-28.5), respectively, vs. *2(-) genotype] and for alcohol reeking [0.39 (0.29-0.52) and 1.56 (1.09-2.25), respectively, vs. *2(-) genotype]. An age-dependent decrease in the ADH1B*2(-) and ALDH2*2(-) combination from 32.3% in the 30-39-year age group to 12.5% in the 70-79-year age group and an age-dependent increase in the ADH1B*2(+) and ALDH2*2(-) combination from 52.5% in the 30-39-year age group to 70.5% in the 70-79-year age group were observed (P < 0.0001 for trend). The frequencies of the ADH1B*2(-) and ALDH2*2(+) combination (4.7-6.2%) and the ADH1B*2(+) and ALDH2*2(+) combination (8.9-12.0%) did not change markedly with increasing age. CONCLUSION: Interactions between the alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 genotypes modified alcohol flushing, alcohol reeking on the day after drinking, and the age distribution. These findings support the protective roles of the ADH1B*2(+) and ALDH2*2(+) genotypes against the development of alcohol dependence.


Assuntos
Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Aldeído-Desidrogenase Mitocondrial/genética , Rubor/genética , Adulto , Distribuição por Idade , Idoso , Álcool Desidrogenase/sangue , Aldeído-Desidrogenase Mitocondrial/sangue , Estudos de Associação Genética , Genótipo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo Genético , Análise de Regressão , Inquéritos e Questionários
15.
Am J Physiol Regul Integr Comp Physiol ; 318(4): R677-R690, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32048867

RESUMO

Acetaldehyde dehydrogenase 2 (ALDH2) is an enzyme involved in redox homeostasis as well as the detoxification process in alcohol metabolism. Nearly 8% of the world's population have an inactivating mutation in the ALDH2 gene. However, the expression patterns and specific functions of ALDH2 in skeletal muscles are still unclear. Herein, we report that ALDH2 is expressed in skeletal muscle and is localized to the mitochondrial fraction. Oxidative muscles had a higher amount of ALDH2 protein than glycolytic muscles. We next comprehensively investigated whether ALDH2 knockout in mice induces mitochondrial adaptations in gastrocnemius muscle (for example, content, enzymatic activity, respiratory function, supercomplex formation, and functional networking). We found that ALDH2 deficiency resulted in partial mitochondrial dysfunction in gastrocnemius muscle because it increased mitochondrial reactive oxygen species (ROS) emission (2',7'-dichlorofluorescein and MitoSOX oxidation rate during respiration) and the frequency of regional mitochondrial depolarization. Moreover, we determined whether ALDH2 deficiency and the related mitochondrial dysfunction trigger mitochondrial stress and quality control responses in gastrocnemius muscle (for example, mitophagy markers, dynamics, and the unfolded protein response). We found that ALDH2 deficiency upregulated the mitochondrial serine protease Omi/HtrA2 (a marker of the activation of a branch of the mitochondrial unfolded protein response). In summary, ALDH2 deficiency leads to greater mitochondrial ROS production, but homeostasis can be maintained via an appropriate stress response.


Assuntos
Aldeído-Desidrogenase Mitocondrial/metabolismo , Genótipo , Serina Peptidase 2 de Requerimento de Alta Temperatura A/metabolismo , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Regulação da Expressão Gênica , Serina Peptidase 2 de Requerimento de Alta Temperatura A/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Consumo de Oxigênio
16.
Cancer Res ; 80(7): 1601-1610, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32005715

RESUMO

A genetic variant on aldehyde dehydrogenase 2 (ALDH2 rs671, Glu504Lys) contributes to carcinogenesis after alcohol consumption. Somewhat conversely, the ALDH2 Lys allele also confers a protective effect against alcohol-induced carcinogenesis by decreasing alcohol consumption due to acetaldehyde-related adverse effects. Here, we applied a mediation analysis to five case-control studies for head and neck, esophageal, stomach, small intestine, and colorectal cancers, with 4,099 cases and 6,065 controls, and explored the potentially heterogeneous impact of alcohol drinking on digestive tract carcinogenesis by decomposing the total effect of the ALDH2 Lys allele on digestive tract cancer risk into the two opposing effects of the carcinogenic effect (direct effect) and the protective effect (indirect effect mediated by drinking behavior). Alcohol was associated with an increased risk of most digestive tract cancers, but significant direct effects were observed only for upper gastrointestinal tract cancer risk, and varied substantially by site, with ORs (95% confidence interval) of 1.83 (1.43-2.36) for head and neck cancer, 21.15 (9.11-49.12) for esophageal cancer, and 1.65 (1.38-1.96) for stomach cancer. In contrast, a significant protective indirect effect was observed on risk for all cancers, except small intestine cancer. These findings suggest that alcohol is a major risk factor for digestive tract cancers, but its impact as a surrogate for acetaldehyde exposure appears heterogeneous by site. Meanwhile, the behavior-related effect of the ALDH2 Lys allele results in a decreased risk of most digestive tract cancers. SIGNIFICANCE: These findings support that genetic alcohol avoidance is a factor against alcohol-induced cancers.


Assuntos
Carcinogênese/efeitos dos fármacos , Etanol/efeitos adversos , Neoplasias Gastrointestinais/epidemiologia , Trato Gastrointestinal/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/epidemiologia , Acetaldeído/metabolismo , Acetaldeído/toxicidade , Adulto , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Carcinogênese/genética , Estudos de Casos e Controles , Etanol/metabolismo , Feminino , Neoplasias Gastrointestinais/induzido quimicamente , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Trato Gastrointestinal/patologia , Neoplasias de Cabeça e Pescoço/induzido quimicamente , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
17.
Biochem Genet ; 58(2): 322-334, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32006143

RESUMO

Genetic factors play an important role in determining the susceptibility to ischemic stroke. Herein, we examined the association of an aldehyde dehydrogenase 2 (ALDH2) gene polymorphism with cerebral infarction. Patients with cerebral infarction (n = 963) and healthy controls (n = 921) were included. Genotyping was performed using gene chip platform analysis, and Sanger sequencing was used to confirm ALDH2 genotypes. The risk prediction of ALDH2 polymorphisms for cerebral infarction was examined under three genetic modes of inheritance. For males, ALDH2*2/*2 genotype was a significant risk factor for cerebral infarction in the co-dominant model (age-, smoking-, and drinking-adjusted OR 1.514, 95% CI 1.005-2.282, p = 0.047) and the recessive model (age-, smoking-, and drinking-adjusted OR 1.601, 95% CI 1.078-2.379, p = 0.020). However, for females, ALDH2*2/*2 genotype was a protective factor for cerebral infarction in the co-dominant model (age-, smoking-, and drinking-adjusted OR 0.450 95% CI 0.215-0.941, p = 0.034) and the recessive model (age-, smoking-, and drinking-adjusted OR 0.440, 95% CI 0.214-0.903, p = 0.025). Further, logistic regression analysis revealed that age, smoking, hypertension, hyperlipidemia, and hypercholesterolemia were significant risks for the presence of cerebral infarction. In conclusion, these findings support an association of ALDH2 gene polymorphisms with ischemic stroke in a Chinese Hakka population. In particular, homozygote ALDH2*2/*2 may be a risk factor for cerebral infarction in males, but contribute to reduced risk for cerebral infarction in females.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Infarto Cerebral/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Infarto Cerebral/epidemiologia , China , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Estudos Retrospectivos
18.
Circ J ; 84(3): 479-486, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32009064

RESUMO

BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2) plays a central role in the biotransformation of glyceryl trinitrate (GTN) or nitroglycerin, which is widely used for the treatment of coronary artery disease (CAD). The deficient variant ALDH2 genotype (ALDH2*2) is prevalent among East Asians. This study examined whether there are differences in nitroglycerine-mediated dilation (NMD) and flow-mediated dilation (FMD) response between wildALDH2*1/*1and variantALDH2*2patients with CAD.Methods and Results:The study subjects comprised 55 coronary spastic angina (CSA) patients, confirmed by coronary angiography and intracoronary injection of acetylcholine (42 men and 13 women, mean age 68.0±9.0 years). They underwent NMD and FMD tests in the morning before and after continuous transdermal GTN administration for 48 h. NMD was lower at baseline inALDH2*2than in theALDH2*1/*1group (P=0.0499) and decreased significantly in both groups (P<0.0001 and P<0.0001, respectively) after GTN, with significantly lower levels in theALDH2*2group (P=0.0002). FMD decreased significantly in bothALDH2*1/*1andALDH2*2groups (P<0.0001and P=0.0002, respectively) after continuous GTN administration, with no significant differences between the 2 groups both before and after GTN. CONCLUSIONS: Continuous administration of GTN produced endothelial dysfunction as well as nitrate tolerance in bothALDH2*1/1andALDH2*2patients with CSA.ALDH2*2attenuated GTN response and exacerbated GTN tolerance, but not endothelial dysfunction, as compared toALDH2*1/*1in patients with CSA.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Angina Pectoris/tratamento farmacológico , Angina Pectoris/genética , Grupo com Ancestrais do Continente Asiático/genética , Vasoespasmo Coronário/tratamento farmacológico , Vasoespasmo Coronário/genética , Resistência a Medicamentos/genética , Nitroglicerina/administração & dosagem , Polimorfismo Genético , Vasoconstrição/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Idoso , Angina Pectoris/etnologia , Angina Pectoris/fisiopatologia , Vasoespasmo Coronário/etnologia , Vasoespasmo Coronário/fisiopatologia , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Nitroglicerina/efeitos adversos , Vasoconstrição/genética , Vasodilatadores/efeitos adversos
19.
Sci Rep ; 10(1): 3641, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32107439

RESUMO

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) encode essential alcohol-metabolizing enzymes. While alcohol use is associated with spontaneously deep intracerebral haemorrhage (SDICH), particularly in males, the activities and genetic variants of ADH and ALDH may affect SDICH development. This case-control study was conducted to identify the interaction of alcohol use and SDICH with five single-nucleotide polymorphisms (SNPs): ADH1B rs1229984, ADH1C rs2241894, ALDH2 rs671, ALDH2 rs886205, and ALDH2 rs4648328. We enrolled 208 patients with SDICH and 244 healthy controls in a Taiwanese population. ALDH2 rs671 was significantly associated with SDICH in the dominant (P < 0.001) and additive models (P = 0.007). ALDH2 rs4648328 was borderline significantly associated with SDICH in the recessive (P = 0.024) or additive models (P = 0.030). In alcohol-using patients, the ALDH2 rs671 GG genotype was associated with SDICH risk compared to the GA+AA genotype (P = 0.010). ADH1B rs1229984, ADH1C rs2241894, and ALDH2 rs886205 did not demonstrate association with SDICH. Thus, the ALDH2 rs671 GG genotype is a risk factor for SDICH. Because the genetic distributions of ALDH2 rs671 exhibited strong ethnic heterogeneity, further studies in different populations are needed to validate these findings.


Assuntos
Álcool Desidrogenase/genética , Aldeído-Desidrogenase Mitocondrial/genética , Hemorragia Cerebral/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Idoso , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologia
20.
World J Surg Oncol ; 18(1): 21, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31987047

RESUMO

BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2) and cytochrome p450 2E1 (CYP2E1) are important alcohol-metabolizing enzymes. The aim of this meta-analysis was to evaluate the association of ALDH2 rs671 and CYP2E1 rs2031920 polymorphisms with hepatocellular carcinoma (HCC) susceptibility in East Asians. METHODS: A systematic search strategy was implemented in MEDLINE, PubMed, Scopus, Embase, and China Academic Journals databases. Nineteen case-control studies were selected for inclusion. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated through random-effects or fixed-effects models. Subgroup analysis, meta-regression, sensitivity analysis, cumulative meta-analysis, and evaluation of publication bias were performed. RESULTS: The overall meta-analysis did not find a significant association of ALDH2 rs671 and CYP2E1 rs2031920 genotypes with HCC susceptibility in East Asians. In addition, stratified analysis by country, Hardy-Weinberg equilibrium status, and source of controls also did not identify any association. CONCLUSION: The ALDH2 rs671 and CYP2E1 rs2031920 polymorphisms are not associated with HCC susceptibility in East Asians.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Carcinoma Hepatocelular/genética , Citocromo P-450 CYP2E1/genética , Neoplasias Hepáticas/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Associação Genética , Genótipo , Humanos , Polimorfismo Genético , Prognóstico
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