Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 227
Filtrar
1.
J Oral Pathol Med ; 49(1): 82-90, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31402483

RESUMO

BACKGROUND: Progressive telomere shortening with age or chronic inflammation may lead to genomic instability that characterizes the early stage of carcinogenesis. Certain risk factors, such as drinking alcoholic beverages or smoking, predispose the oral mucosa to squamous cell carcinoma. The ADH1B and ALDH2 genotypes can influence the risk of cancer due to alcohol drinking. In the present study, we analyzed chromosomal instability due to telomere shortening in the oral mucosa in relation to cancer risk factors. DESIGN: Using our quantitative fluorescence in situ hybridization (Q-FISH) technique, we estimated telomere lengths (TL) in the background mucosa from 23 cases of mucosal carcinoma, 12 cases of oral epithelial dysplasia, and 21 non-neoplasia cases. ALDH2 and ADH1B genotypes were determined using DNA extracted from paraffin sections. We analyzed TL in relation to alcohol drinking, smoking, and cancer multiplicity. RESULTS: Telomeres in the backgrounds of dysplasia and mucosal carcinoma were significantly shorter than in controls. In comparison with adult controls, telomeres were significantly (P = .038) shorter in the ADH1B less-active type (ADH1B*1/*1), but not (P = .841) in the ALDH2 inactive type (ALDH2*1/*2 or *2/*2). Cancer multiplicity and smoking had no significant relationship with TL. CONCLUSION: Telomeres in the oral epithelium are shorter in cases of oral dysplasia or mucosal carcinoma than in non-neoplasia. Unlike the esophageal epithelium of alcoholics, they are also shorter in individuals with the less-active rather than the active ADH1B gene. Telomeres in the oral epithelium may be directly affected by alcohol drinking.


Assuntos
Álcool Desidrogenase/genética , Aldeído-Desidrogenase Mitocondrial/genética , Encurtamento do Telômero , Adulto , Consumo de Bebidas Alcoólicas , Genótipo , Humanos , Hibridização in Situ Fluorescente , Polimorfismo Genético
2.
Acta Biochim Pol ; 66(4): 627-632, 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31883320

RESUMO

The aim of the study presented here was an attempt to answer the question posed in the title: Is the mechanism of nitroglycerin tolerance associated with aldehyde dehydrogenase (ALDH) activity? Here, we investigated the effect of administration (separately or jointly) of lipoic acid (LA), nitroglycerin (GTN), and disulfiram (DSF; an irreversible in vivo inhibitor of all ALDH isozymes (including ALDH2)), on the development of tolerance to GTN. We also assessed the total activity of ALDH in the rat liver homogenates. Our data revealed that not only DSF and GTN inhibited the total ALDH activity in the rat liver, but LA also proved to be an inhibitor of this enzyme. At the same time, the obtained results demonstrated that the GTN tolerance did not develop in GTN, DSF and LA jointly treated rats, but did develop in GTN and DSF jointly treated rats. This means that the ability of LA to prevent GTN tolerance is not associated with the total ALDH activity in the rat liver. In this context, the fact that animals jointly receiving GTN and DSF developed tolerance to GTN, and in animals that in addition to GTN and DSF also received LA such tolerance did not develop, is - in our opinion - a sufficient premise to conclude that the nitrate tolerance certainly is not caused by a decrease in the activity of any of the ALDH isoenzymes present in the rat liver, including ALDH2. However, many questions still await an answer, including the basic one: What is the mechanism of tolerance to nitroglycerin?


Assuntos
Aldeído-Desidrogenase Mitocondrial/antagonistas & inibidores , Dissulfiram/farmacologia , Tolerância a Medicamentos/genética , Nitroglicerina/farmacologia , Aldeído Desidrogenase 1/antagonistas & inibidores , Aldeído Desidrogenase 1/genética , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Humanos , Oxirredução/efeitos dos fármacos , Ratos , Ácido Tióctico/farmacologia
3.
BMC Genomics ; 20(1): 983, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842750

RESUMO

BACKGROUND: Phenomics provides new technologies and platforms as a systematic phenome-genome approach. However, few studies have reported on the systematic mining of shared genetics among clinical biochemical indices based on phenomics methods, especially in China. This study aimed to apply phenomics to systematically explore shared genetics among 29 biochemical indices based on the Fangchenggang Area Male Health and Examination Survey cohort. RESULT: A total of 1999 subjects with 29 biochemical indices and 709,211 single nucleotide polymorphisms (SNPs) were subjected to phenomics analysis. Three bioinformatics methods, namely, Pearson's test, Jaccard's index, and linkage disequilibrium score regression, were used. The results showed that 29 biochemical indices were from a network. IgA, IgG, IgE, IgM, HCY, AFP and B12 were in the central community of 29 biochemical indices. Key genes and loci associated with metabolism traits were further identified, and shared genetics analysis showed that 29 SNPs (P < 10- 4) were associated with three or more traits. After integrating the SNPs related to two or more traits with the GWAS catalogue, 31 SNPs were found to be associated with several diseases (P < 10- 8). Using ALDH2 as an example to preliminarily explore its biological function, we also confirmed that the rs671 (ALDH2) polymorphism affected multiple traits of osteogenesis and adipogenesis differentiation in 3 T3-L1 preadipocytes. CONCLUSION: All these findings indicated a network of shared genetics and 29 biochemical indices, which will help fully understand the genetics participating in biochemical metabolism.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Fenômica/métodos , Locos de Características Quantitativas , Células 3T3-L1 , Adulto , Idoso , Animais , Diferenciação Celular , China , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
4.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(5): 737-742, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31762247

RESUMO

OBJECTIVE: To establish SNaPShot-fluorescence capillary analysis (SNaPShot-FCA) assay for rapid detection of the genotype of aldehyde dehydrogenase 2 gene (ALDH2) rs671 locus. METHODS: The genomic DNA was extracted from peripheral blood cells. Using R6G-ddATP and cy5-ddGTP as fluorescent substrates, the ALDH2 gene was amplified by SNaPShot to generate DNA products with different fluorescent dyes at the 3' end. FCA was used to detect the products separated by agarose gel electrophoresis and recovered by gel recovery kit, and the genetype of ALDH2 polymorphism was analyzed by fluorescence spectrum. The samples were tested three times repeatedly and compared with the results of DNA sequencing. RESULTS: The optimal concentrations of R6G-ddATP and cy5-ddGTP were 1.4 µmol/L and 8.0 µmol/L, respectively. 106 samples were tested for ALDH2 genotype by SNaPShot-FCA under optimal conditions, including 67 of wild type (GG), 38 of hybrid type (AG), and 1 of mutant type (AA), which were consistent with the sequencing results. CONCLUSION: This study successfully established the SNaPShot-FCA for the micro-detection of ALDH2 genotype for the rapid screening and identification of ALDH2 gene.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Genótipo , Análise de Sequência de DNA/métodos , Fluorescência , Humanos
5.
Life Sci ; 239: 117015, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678551

RESUMO

Obstructive renal injury and drug-induced nephrotoxicity are the two most common causes of renal fibrosis diseases. However, whether these two different pathogeny induced same pathological outcomes contain common genetic targets or signaling pathway, the current research has not paid great attention. GSE121190 and GSE35257 were downloaded from the Gene Expression Omnibus (GEO) database. While GSE121190 represents a differential expression profile in kidney of mice with unilateral ureteral obstruction (UUO) model, GSE35257 represents cisplatin nephrotoxicity model. By using GEO2R, 965 differential expression genes (DEGs) in GSE121190 and 930 DEGs in GSE35257 were identified. 43 co-DEGs were shared and were extracted for protein-protein interaction (PPI) analysis. Subsequently, three shared pathways including glycolysis/gluconeogenesis, fatty acid degradation and pathways in cancer were involved in two models with Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. We reconfirmed that these three pathways have relatively high scores by using Gene Set Enrichment Analysis (GSEA) software. Additionally, further bioinformatic analysis showed that Aldehyde dehydrogenase-2 (Aldh2) involved in the progression of renal fibrosis by mediating glycolysis pathway. Then real-time PCR and western blotting were performed to validate the expression of Aldh2 in kidney tissue after three different etiologies that caused renal fibrosis. Basically consistent with our bioinformatics results, our experiment showed that the expression of Aldh2 is the most significantly decreased in the UUO model, followed by ischemia-reperfusion injury (IRI) model and finally the cisplatin-induced model. Thus, Aldh2 can act as a common potential genetic target for different renal fibrosis diseases.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Nefropatias/tratamento farmacológico , Nefropatias/enzimologia , Aldeído-Desidrogenase Mitocondrial/efeitos dos fármacos , Animais , Cisplatino/toxicidade , Biologia Computacional , Bases de Dados Genéticas , Fibrose , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Nefropatias/induzido quimicamente , Nefropatias/genética , Camundongos , Camundongos Endogâmicos BALB C , Mapas de Interação de Proteínas , Obstrução Ureteral/complicações , Obstrução Ureteral/genética , Obstrução Ureteral/patologia
6.
Yakugaku Zasshi ; 139(8): 1111-1119, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31366848

RESUMO

A new single nucleotide polymorphisms (SNP) genotyping method has been developed and validated using biological specimens directly as templates for TaqMan PCR without general DNA extraction and purification procedure from dried saliva samples attached on water-soluble papers. This new method can set up at ease and complete PCR analysis including data interpretation in under two hours with additional advantages of application for large-scale clinical research, diagnostics, and epidemiological studies at low cost. Specifically, SNP genotyping of alcohol metabolism-related genes ADH1B (rs1229984) and ALDH2 (rs671) were demonstrated by TaqMan PCR assay using dried saliva samples in the present investigation. In this protocol, by simplifying experimental operations and improving efficiency, omitting and simplifying the time and laborious DNA purification process, it is possible to shorten the experiment time and reduce the risk of human error such as contamination. Furthermore it became possible with great cost reduction. We succeeded in dramatically improving the judgment rate and accuracy of SNP genotyping by the master mix reagent for commercial available real-time TaqMan PCR. Moreover, it becomes possible to stably introduce template DNA into the reaction system, and it will be possible to apply it to copy number variation (CNV) by TaqMan probe method. The SNP analysis process using this optimized water-soluble paper will be applied to gene polymorphism analysis of drug metabolizing enzyme gene CYP, etc., to help efforts to realize personalized medicine.


Assuntos
Álcool Desidrogenase/genética , Álcoois/metabolismo , Aldeído-Desidrogenase Mitocondrial/genética , Genótipo , Técnicas de Genotipagem/métodos , Polimorfismo de Nucleotídeo Único/genética , Variações do Número de Cópias de DNA , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Saliva
7.
Adv Exp Med Biol ; 1193: 35-52, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368096

RESUMO

Aldehydes, which are present within the air as well as food and beverage sources, are highly reactive molecules that can be cytotoxic, mutagenic, and carcinogenic. To prevent harm from reactive aldehyde exposure, the enzyme aldehyde dehydrogenase 2 (ALDH2) metabolizes reactive aldehydes to a less toxic form. However, the genetic variant of ALDH2, ALDH2*2, significantly reduces the ability to metabolize reactive aldehydes in humans. Therefore, frequent environmental aldehyde exposure, coupled with inefficient aldehyde metabolism, could potentially lead to an increased health risk for diseases such as cancer or cardiovascular disease.Here, we discuss the environmental sources of reactive aldehydes and the potential health implications particularly for those with an ALDH2*2 genetic variant. We also suggest when considering the ALDH2*2 genetic variant the safety limits of reactive aldehyde exposure may have to be reevaluated. Moreover, the ALDH2*2 genetic variant can also be used as an example for how to implement precision medicine in the field of environmental health sciences.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Aldeídos/efeitos adversos , Exposição Ambiental/efeitos adversos , Humanos
8.
Adv Exp Med Biol ; 1193: 53-67, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368097

RESUMO

Aldehyde dehydrogenase 2 (ALDH2) is a non-cytochrome P450 mitochondrial aldehyde oxidizing enzyme. It is best known for its role in the metabolism of acetaldehyde, a common metabolite from alcohol drinking. More evidences have been accumulated in recent years to indicate a greater role of ALDH2 in the metabolism of other endogenous and exogenous aldehydes, especially lipid peroxidation-derived reactive aldehyde under oxidative stress. Many cardiovascular diseases are associated with oxidative stress and mitochondria dysfunction. Considering that an estimated 560 million East Asians carry a common ALDH2 deficient variant which causes the well-known alcohol flushing syndrome due to acetaldehyde accumulation, the importance of understanding the role of ALDH2 in these diseases should be highlighted. There are several unfavorable cardiovascular conditions that are associated with ALDH2 deficiency. This chapter reviews the function of ALDH2 in various pathological conditions of the heart in relation to aldehyde toxicity. It also highlights the importance and clinical implications of interaction between ALDH2 deficiency and alcohol drinking on cardiovascular disease among the East Asians.


Assuntos
Acetaldeído/efeitos adversos , Consumo de Bebidas Alcoólicas , Aldeído-Desidrogenase Mitocondrial/genética , Doenças Cardiovasculares/genética , Grupo com Ancestrais do Continente Asiático , Humanos
9.
Adv Exp Med Biol ; 1193: 69-87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368098

RESUMO

Despite the role of aldehyde dehydrogenase 2 (ALDH2) in the detoxification of endogenous aldehydes, the defective polymorphism (rs671), which is highly prevalent among East Asians, does not show a serious phenotype, such as congenital abnormality. However, unfavorable and favorable impacts of the variant allele, ALDH2*2, on various disease risks have been reported. The underlying mechanisms are often complicated due to the compensatory aldehyde detoxification systems. As the phenotypes emerge due to overlapping environmental factors (e.g., alcohol intake and tobacco smoke) or individual vulnerabilities (e.g., aging and apolipoprotein E ε4 allele), polymorphism is therefore considered to be important in the field of preventative medicine. For example, it is important to recognize that ALDH2*2 carriers are at a high risk of alcohol drinking-related cancers; however, their drinking habit has less adverse effects on physiological indices, such as blood pressure, body mass index, levels of lipids, and hepatic deviation enzymes in the blood, than in non-ALDH2*2 carriers. Therefore, opportunities to reconsider their excessive drinking habit before adverse events occur can be missed. To perform effective disease prevention, the effects of ALDH2*2 on various diseases and the biological mechanisms should be clarified.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Aldeído-Desidrogenase Mitocondrial/genética , Polimorfismo Genético , Alelos , Grupo com Ancestrais do Continente Asiático , Humanos
10.
Adv Exp Med Biol ; 1193: 107-120, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368100

RESUMO

Myocardial ischemia-reperfusion (IR) injury during acute myocardial infarction or open-heart surgery would promote oxidative stress, leading to the accumulation of reactive aldehydes that cause cardiac damage. It has been well demonstrated that aldehyde dehydrogenase (ALDH)-2 is an important cardioprotective enzyme for its central role in the detoxification of reactive aldehydes. ALDH2 activation by small molecule activators is a promising approach for cardioprotection for myocardial IR injury.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Traumatismo por Reperfusão Miocárdica/genética , Miocárdio/enzimologia , Humanos , Mitocôndrias Cardíacas , Estresse Oxidativo
11.
Adv Exp Med Biol ; 1193: 121-134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368101

RESUMO

Coronary spasm plays an important role in the pathogenesis of ischemic heart disease, including angina pectoris, acute myocardial infarction (AMI), silent myocardial ischemia, and sudden death. The prevalence of coronary spasm is higher among East Asians probably due to genetic as well as environmental factors. ALDH2 eliminates toxic aldehydes including 4-hydroxy-2-nonenal (4-HNE) derived from lipid peroxidation and acrolein in tobacco smoking as well as ethanol-derived acetaldehyde and thereby protects tissues and cells from oxidative damage. Deficient variant ALDH2*2 genotype is prevalent among East Asians and is a significant risk factor for both coronary spasm and AMI through accumulation of toxic aldehydes, thereby contributing to oxidative stress, endothelial damage, vasoconstriction, and thrombosis. Toxic aldehydes are thus identified as risk factors to be targeted for the treatment of coronary spasm and AMI.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Vasoespasmo Coronário/genética , Infarto do Miocárdio/genética , Grupo com Ancestrais do Continente Asiático , Genótipo , Humanos
12.
Adv Exp Med Biol ; 1193: 135-154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368102

RESUMO

Obesity is multifactorial and complex. Remarkable progress has been made recently in search for polygenic obesity through genome-wide association study (GWAS), but biology of polygenic effects on obesity is largely poor. This review summarizes the available evidence and provides an overview of the links between ALDH2 variants and adiposity, which were firstly and mainly derived from studies of polygenic obesity and also indirectly investigated by using cell lines and mice. The genetic association studies have observed consistent associations of ALDH2 variants with obesity-related traits including BMI, waist circumference (WC), waist-to-hip ratio (WHR), and visceral fat accumulation. In consideration of ALDH2 variants with enzyme activity and alcohol consumption behavior in physiological mechanism studies, we proposed a model by which the physiological and behavioral consequences of alcohol consumption serve as an intermediary process between polymorphisms in ALDH2 and obesity.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Obesidade/genética , Adiposidade/genética , Animais , Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Polimorfismo de Nucleotídeo Único , Circunferência da Cintura , Relação Cintura-Quadril
13.
Adv Exp Med Biol ; 1193: 155-174, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368103

RESUMO

A major pathophysiological mechanism behind the development of diabetic heart diseases is oxidative stress mediated by toxic reactive aldehydes such as 4-hydroxynonenal (4HNE). Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial enzyme that has been found to detoxify these deleterious aldehydes and thereby mitigate cardiac damage. Furthermore, its protective role in cellular signaling reverses aberrations caused by hyperglycemia, thereby protecting cardiac function. This chapter assesses the role of ALDH2 in diabetic heart diseases by examining preclinical studies where ALDH2 activity is perturbed in both decreased and increased directions. In doing so, issues in improving ALDH2 activity in select human populations are elucidated, and further research directions are discussed.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Diabetes Mellitus/genética , Cardiopatias/genética , Aldeídos/efeitos adversos , Cardiopatias/complicações , Humanos , Estresse Oxidativo
14.
Adv Exp Med Biol ; 1193: 175-194, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368104

RESUMO

Sepsis, defined as life-threatening tissue damage and organ dysfunction caused by a dysregulated host response to infection, is a critical disease which imposes global health burden. Sepsis-induced organ dysfunction, including circulatory and cardiac dysfunction, hepatic dysfunction, renal dysfunction, etc., contributes to high mortality and long-term disability of sepsis patients. Altered inflammatory response, ROS and reactive aldehyde stress, mitochondrial dysfunction, and programmed cell death pathways (necrosis, apoptosis, and autophagy) have been demonstrated to play crucial roles in septic organ dysfunction. Unfortunately, except for infection control and supportive therapies, no specific therapy exists for sepsis. New specific therapeutic targets are highly warranted. Emerging studies suggested a role of potential therapeutic target of ALDH2, a tetrameric enzyme located in mitochondria to detoxify aldehydes, in septic organ dysfunction. In this article, we will review the presentations and pathophysiology of septic organ dysfunction, as well as summarize and discuss the recent insights regarding ALDH2 in sepsis.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Sepse/genética , Apoptose , Autofagia , Humanos , Mitocôndrias/enzimologia
15.
Adv Exp Med Biol ; 1193: 195-210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368105

RESUMO

Cerebral stroke is one of the leading causes of mortality and disability worldwide. The prevalence of cerebral stroke is the result of the synergistic effect of genetic susceptibility and numerous vascular risk factors, including hypertension, diabetes, excessive alcohol intake, obesity, and dyslipidemia. Mitochondrial aldehyde dehydrogenase (ALDH2) is a vital enzyme metabolizing various acetaldehyde and toxic aldehydes. The ALDH2 enzymatic activity is severely decreased in the individuals with ALDH2*2 gene mutation, especially in East Asians. Increasing epidemiological surveys have revealed that ALDH2 genetic polymorphism is closely associated with the increasing incidence of cardiovascular risk factors and cerebral stroke. Evidence from experimental studies has also suggested that ALDH2 facilitates the clearance of reactive aldehydes and reduces the size of cerebral infarct. Therefore, targeting ALDH2 may represent a promising avenue for protection against stroke injury. This review will mainly focus on clinical and epidemiological evidence and the underlying molecular mechanisms involved in the protective effect of ALDH2 in stroke-related injury.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Acidente Vascular Cerebral/genética , Predisposição Genética para Doença , Humanos , Polimorfismo Genético
16.
Adv Exp Med Biol ; 1193: 211-220, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368106

RESUMO

Aldehyde dehydrogenase 2 (ALDH2) is an important member of the functional aldehyde dehydrogenases (ALDHs) family in human beings, playing a fundamental role in the detoxification of acetaldehyde and other aldehydes. In recent years, a number of researches have given attention to the association between ALDH2 and atherosclerosis, which provided insights on targeting ALDH2 for therapeutic intervention of atherosclerosis. In this review, these inspiring studies will be discussed, and the clinical implications and concerns will be expounded.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Aterosclerose/genética , Acetaldeído , Aldeídos , Humanos
17.
Adv Exp Med Biol ; 1193: 221-228, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368107

RESUMO

Aldehyde dehydrogenase 2 (ALDH2) is a member of ALDH family. ALDH1 has been widely recognized for its roles in carcinogenesis and cancer therapy; however, investigation for ALDH2 in cancer is seldom mentioned. The ALDH2 point mutation ALDH2*2 is the most frequent human gene variant, and it is present in approximately 560 million East Asians. ALDH2*2 demonstrates its effect on alcohol consumption limiting and alcoholism developing protection, and this variant is recently found to have an important impact on human health. This chapter focuses on its potential effect on cancer therapy, especially for chemotherapeutics with anthracyclines.


Assuntos
Consumo de Bebidas Alcoólicas , Aldeído-Desidrogenase Mitocondrial/genética , Antraciclinas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Alcoolismo/genética , Humanos
18.
Adv Exp Med Biol ; 1193: 229-236, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368108

RESUMO

Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in the detoxification of toxic aldehydes, especially acetaldehyde, which is commonly considered as a carcinogen. ALDH2 mutation and impaired enzymatic activity will cause acetaldehyde accumulation and thus participate in the development of cancers. It deserves more attention since around 40% of East Asian population carry the inactive ALDH2 allele. Moreover, the risk for cancers will be even higher when ALDH2 mutation combined with heavy alcohol consumption, suggesting a genetic-environmental interaction in carcinogenesis. This may provide us with a potential target for cancer prevention and treatment.


Assuntos
Consumo de Bebidas Alcoólicas , Aldeído-Desidrogenase Mitocondrial/genética , Interação Gene-Ambiente , Acetaldeído , Carcinogênese , Humanos
19.
Adv Exp Med Biol ; 1193: 237-253, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368109

RESUMO

Aging is a complex irreversible biological process associated with increased prevalence of chronic disease and high healthcare burden. Several theories have been proposed for the biology of aging including free radical accumulation, DNA damage, apoptosis, telomere shortening, autophagy failure, and disturbed autonomic response. Aging is also closely associated with progressive deterioration of cardiovascular and neurological functions. Linkage, genome-wide association (GWAS), and next-generation sequencing analysis have confirmed a number of susceptibility loci for aging, in particular, Alzheimer's disease. Recent evidence from our group and others also revealed a tie between genetic mutation of mitochondrial aldehyde dehydrogenase (ALDH2) and life span as well as cardiovascular aging. ALDH2 represents the single most gene with the greatest number of human genetic polymorphism and is deemed an important enzyme for detoxification of reactive aldehydes. Here, we will briefly review the tie between ALDH2 and cardiovascular aging process. While recent work on ALDH2 research has broadened the pathogenic mechanisms of ALDH2 mutation or deficiency, therapeutic potential targeting ALDH2 in the elderly still remains debatable.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Sistema Cardiovascular , Longevidade/genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo Genético
20.
Biomed Res Int ; 2019: 2476252, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467875

RESUMO

Severe hemorrhagic shock and resuscitation (HS/R) can lead to lung injury, resulting in respiratory insufficiency. We investigated whether treatment with Alda-1, an ALDH2 activator, decreased lung injury induced by severe HS/R in a rat model. Male Sprague-Dawley rats were randomized into three groups, hemorrhagic shock + placebo, hemorrhagic shock + Alda-1, and sham. All animals were heparinized, and then 50% of the total calculated blood volume was collected over 60 minutes. After 40 minutes of hemorrhagic shock, animals were reinfused with the shed blood over 40 minutes and then observed for an additional 2 hours. Concentrations of 4-HNE, TNF-α, IL-6, and ALDH2 activity were detected; lung injury and lung wet-to-dry weight ratios were assessed. Expression of occludin and ZO-1 proteins in lung tissues was also determined. At 2 hours after resuscitation, lung injury was significantly reduced and the wet-to-dry weight ratio was notably decreased in the Alda-1 group compared with placebo (P<0.05). Alda-1 treatment also significantly increased the activity of ALDH2 and decreased the levels of toxic 4-HNE (P<0.05). In the Alda-1 group, IL-6 and TNF-α were dramatically decreased compared with placebo-treated animals (P<0.05). Expression of occludin and ZO-1 proteins was significantly decreased in the placebo group compared with the Alda-1 group (P<0.05). Thus, in a rat model of severe HS/R, treatment with Alda-1 increased the activity of ALDH2, significantly accelerated the clearance of reactive aldehydes, and concomitantly alleviated lung injury through improvement of pulmonary epithelial barrier integrity resulting in decreased alveolar epithelial tissue permeability, lung edema, and diffuse infiltration of inflammatory cells.


Assuntos
Aldeídos/metabolismo , Benzamidas/farmacologia , Benzodioxóis/farmacologia , Lesão Pulmonar/tratamento farmacológico , Pulmão/efeitos dos fármacos , Choque Hemorrágico/tratamento farmacológico , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Modelos Animais de Doenças , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Epitélio/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Ocludina/genética , Ratos , Choque Hemorrágico/genética , Choque Hemorrágico/patologia , Fator de Necrose Tumoral alfa/genética , Proteína da Zônula de Oclusão-1/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA