线粒体醛脱氢酶对心脏保护作用的研究进展

线粒体醛脱氢酶(ALDH2)是醛脱氢酶的亚型之一,具有脱氢酶和酯酶等多种酶功能。体内乙醇、氨基酸、生物胺、维生素、类固醇及脂质的代谢过程中会产生众多醛类物质。ALDH2在辅助因子NAD(P)+的参与下将醛类物质脱氢成为相应的羧酸,对减轻醛类物质对机体的毒性作用具有重要意义。ALDH2发挥酯酶功能则不需要辅助因子,可将羧酸酯或者其他酸转化为相应的羧酸和醇。近年的研究表明,ALDH2酶活性的下降将加重酒精、缺血等多种因素引起的心肌损伤和促进硝酸甘油耐受的发生,因此针对ALDH2开发和研制特异性激动剂,将为心脏疾病的药物防治提供新思路。     

乙醛脱氢酶2基因多态性与肝脏相关疾病的研究进展

乙醛脱氢酶（ALDH）是一种二磷吡啶核苷酸连接酶,可以使乙醛分解代谢为水和二氧化碳。ALDH2是ALDH的19种同工酶之一,有着三种不同酶活性,究其原因主要由其12号染色体上编码的rs671核苷酸多态性位点上碱基A突变被碱基G取代,从而使其编码的多肽链上第504位氨基酸由谷氨酸变为赖氨酸,从而导致其酶活性的变化;ALDH2的酶活性越高,代谢乙醛能力越强。ALDH2基因多态性在不同人群不用地域中有不同的特点。同时ALDH2还参与多种不同信号通路的调节,从而使其在多种疾病,如冠心病、肥胖症、肝癌的等的疾病中存在潜在治疗靶点。本文主要对ALDH2基因多态性在酒精性肝病、非酒精性脂肪性肝病、肝癌等肝脏相关疾病中的发生机制进行阐述总结。     

人类乙醛脱氢酶II及其激动剂的研究进展

人类乙醛脱氢酶Ⅱ(aldehyde dehydrogenasesII,ALDH2)具有脱氢酶和酯酶等多种酶的功能,ALDH2活性的增强将减轻因酒精、缺血等多种因素引起的肝脏、心肌损伤及某些癌症的发生。本文通过对国内外文献的分析、整理和归纳,较为全面的介绍了ALDH2及其激动剂的研究现状。     

选择性β3肾上腺素受体激动剂研究进展

人体B3上腺素受体（β3AR）激动剂对肥胖症、2型糖尿病、肠蠕动功能障碍、前列腺疾病，异常脂蛋白血症、尿频、尿失禁等疾病的动物模型均有治疗作用。现根据其化学结构分类讨论β3AR激动剂的研究进展，以便明确其构效关系，为设计活性更高、选择性更好的β3AR激动剂提供参考。     

云南彝族酒精依赖综合征与ALDH2基因多态性的关联研究

目的獉獉:研究乙醛脱氢酶2(ALDH2)基因多态性与云南彝族酒精依赖综合征的相关性。方法獉獉:采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)分析法,检测云南彝族酒精依赖病例组和健康对照组ALDH2的等位基因和基因型。结果獉獉:在云南彝族酒精依赖患者组和健康对照组中只检测到ALDH2*1一种等位基因,其基因型均为纯合子ALDH2*1/*1。通过与本课题前期研究的云南汉族比较,发现云南彝族人群的ALDH2*1/*1基因型频率和ALDH2*1等位基因频率均高于云南汉族,差异有统计学意义(P<0.001)。结论獉獉:云南彝族人群携带有高酶活性的ALDH2*1等位基因。云南彝族酒精依赖综合征的发病与ALDH2基因有关。     

已上市胰高血糖素样肽-1受体激动剂的研究进展

胰高血糖素样肽-1受体激动剂（GLP-1RAs）治疗2型糖尿病受到广泛关注,其不仅具有优异的降糖优势,还有控制体质量,调节血脂,改善胰岛β细胞功能等特点,同时低血糖或体质量增加的不良反应发生率较低。自2005年至今,已经有7个GLP-1RAs经美国食品药品监督管理局批准上市,即艾塞那肽、利拉鲁肽、艾塞那肽长效制剂、阿必鲁肽、度拉糖肽、利西拉来和索马鲁肽;在中国上市的有贝那鲁肽和洛塞那肽。对已经上市的9个GLP-1Ras治疗2型糖尿病的临床研究进展进行综述。     

乙醛脱氢酶2基因多态性与癌症的关系及药物治疗的研究进展

乙醛脱氢酶2(ALDH2)是人类肝脏中氧化乙醛的关键酶,能将乙醛转化为乙酸,在酒精的代谢过程中,ALDH2发挥着重要的解毒作用.当ALDH2的酶活性受其编码基因ALDH2多态性的影响而致酶活性下降时会导致乙醛在体内蓄积,增加癌症风险.越来越多的研究表明ALDH2的基因多态性与肿瘤的发生、发展密切相关.就ALDH2的基因...     

激动线粒体乙醛脱氢酶2对高糖诱导的大鼠心肌细胞MMP-14及TIMP-4的影响北大核心CSCD

目的探讨基质金属蛋白酶14(MMP-14)、基质金属蛋白酶组织抑制因子4(TIMP-4)是否参与线粒体乙醛脱氢酶2(ALDH2)抗高糖诱导的原代大鼠心肌细胞损伤。方法不同浓度葡萄糖干预原代大鼠心肌细胞,MTT法检测不同时间点细胞活力,确定高糖诱导的心肌细胞损伤模型。实验分为正常对照组(NG,5.5 mmol·L^(-1))、NG+ALDH2激动剂Alda-1组、高糖组(HG,30 mmol·L^(-1)),HG+Alda-1组。MTT法和DHE染色分别检测细胞活力及氧化应激水平,Western blot检测ALDH2、MMP-14、TIMP-4蛋白表达。结果根据细胞活力检测确定30 mmol·L^(-1)葡萄糖干预48 h为损伤模型。与NG组比较,HG组细胞活力、ALDH2、MMP-14蛋白表达、MMP-14/TIMP-4比值均降低,氧化应激、TIMP-4蛋白水平升高;与HG组比较,Alda-1干预后细胞活力、ALDH2及MMP-14蛋白表达、MMP-14/TIMP-4比值升高,氧化应激及TIMP-4蛋白表达降低。结论激动ALDH2可改善高糖引起的心肌细胞损伤,可能与抑制氧化应激、促进MMP-14蛋白表达、抑制TIMP-4蛋白表达有关。     

ALDH1和CD133表达预测胃腺癌化疗疗效的价值

目的 通过检测乙醛脱氢酶1（acetaldehyde dehydrogenase，ALDH1）和分化簇133（cluster of differentiation 133，CD133）在胃腺癌内的表达情况，探讨其预测胃腺癌化疗疗效的价值。方法 采用免疫组化方法检测2018年3月-2019年5月衡水市人民医院收治的以奥沙利铂为基础行化疗的81例患者胃腺癌组织ALDH1和CD133蛋白表达情况，CT评估化疗疗效，分析ALDH1和CD133蛋白表达与化疗疗效的关系。结果 81例胃腺癌患者疾病进展（progressive disease，PD）28例，疾病稳定（stable disease，SD）38例，部分缓解（partial response，PR）13例，完全缓解（complete response，CR）2例，化疗有效率（SD+PR+CR）65.4%。单因素分析结果显示ALDH1蛋白表达阳性、CD133蛋白表达阳性及分化程度好的患者化疗疗效较ALDH1蛋白阴性、CD133蛋白阴性、分化程度差患者化疗有效率明显较低，差异具有统计学意义（P<0.05），而性别、年龄、病变部位、临床分期及淋巴结转移与胃腺癌化疗疗效无明显相关。多因素分析结果显示ALDH1蛋白和CD133蛋白阳性表达是评估进展期胃腺癌患者化疗疗效的独立预测因素。结论 胃腺癌组织ALDH1和CD133表达可能成为预测胃腺癌化疗疗效的重要分子生物学指标，可为胃腺癌个体化治疗提供参考依据。     

子宫内膜异位症患者中LXA4、MMP-9和ALDH1的表达意义

目的 探究脂氧素A4(LXA4)、基质金属蛋白酶-9(MMP-9)和乙醛脱氢酶1(ALDH1)在子宫内膜异位症患者中的表达意义.方法 选取2011年1月至2015年10月子宫内膜异位症患者128例作为试验组,患者均经病理检测以及腹腔镜检测确诊,同时选取同期健康体检女性50例作为对照组,通过酶联免疫吸附法对2组受检者实施LXA4、MMP-9和ALDH1水平检测,对比其检测结果的差异性,同时对试验组LXA4、MMP-9和ALDH1水平与其痛经评分和疾病分期的相关性进行分析.结果 试验组子宫内膜异位症患者的血清LXA4(298.07±21.13)ng/L、MMP-9(161.01±10.41)ug/L、ALDH1(3.23±0.12)ng/L水平与对照组健康体检者的血清LXA4(564.24±40.13)ng/L、MMP-9(42.01±9.30)ug/L、ALDH1(0.99±0.24)ng/L水平相比,差异有统计学意义(P<0.05).随着子宫内膜异位症患者的r-AFS分期升高、痛经程度加重,其LXA4水平逐渐降低,MMP-9、ALDH1水平逐渐升高,差异有统计学意义(P<0.05).结论 LXA4、MMP-9和ALDH1异常表达与患者子宫内膜异位症的发生与发展有着密切的关系,联合对LXA4、MMP-9和ALDH1进行检测,利于子宫内膜异位症患者疾病的早期诊断.     

Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application

Aldehyde dehydrogenases (ALDHs) belong to a superfamily of enzymes that play a key role in the metabolism of aldehydes of both endogenous and exogenous derivation. The human ALDH superfamily comprises 19 isozymes that possess important physiological and toxicological functions. The ALDH1A subfamily plays a pivotal role in embryogenesis and development by mediating retinoic acid signaling. ALDH2, as a key enzyme that oxidizes acetaldehyde, is crucial for alcohol metabolism. ALDH1A1 and ALDH3A1 are lens and corneal crystallins, which are essential elements of the cellular defense mechanism against ultraviolet radiation-induced damage in ocular tissues. Many ALDH isozymes are important in oxidizing reactive aldehydes derived from lipid peroxidation and thereby help maintain cellular homeostasis. Increased expression and activity of ALDH isozymes have been reported in various human cancers and are associated with cancer relapse. As a direct consequence of their significant physiological and toxicological roles, inhibitors of the ALDH enzymes have been developed to treat human diseases. This review summarizes known ALDH inhibitors, their mechanisms of action, isozyme selectivity, potency, and clinical uses. The purpose of this review is to 1) establish the current status of pharmacological inhibition of the ALDHs, 2) provide a rationale for the continued development of ALDH isozyme-selective inhibitors, and 3) identify the challenges and potential therapeutic rewards associated with the creation of such agents.     

Polymorphisms of human aldehyde dehydrogenases. Consequences for drug metabolism and disease

Aldehyde dehydrogenases (ALDHs), a superfamily of NAD(P)(+)-dependent enzymes with similar primary structures, catalyze the oxidation of a wide spectrum of endogenous and exogenous aliphatic and aromatic aldehydes. Thus far, 16 ALDH genes with distinct chromosomal locations have been identified in the human genome. Polymorphism in ALDH2 is associated with altered acetaldehyde metabolism, decreased risk of alcoholism and increased risk of ethanol-induced cancers. Polymorphisms in ALDH3A2, ALDH4A1, ALDH5A1 and ALDH6A1 are associated with metabolic diseases generally characterized by neurologic complications. Mutations in ALDH3A2 cause loss of enzymatic activity and are the molecular basis of Sj?gren-Larsson syndrome. Mutations in ALDH4A1 are associated with type II hyperprolinemia. Deficiency in ALDH5A1 causes 4-hydroxybutyric aciduria. Lack of ALDH6A1 appears to be associated with developmental delay. Allelic variants of the ALDH1A1, ALDH1B1, ALDH3A1 and ALDH9A1 genes have also been observed but not yet characterized. This review describes consequences of ALDH polymorphisms with respect to drug metabolism and disease.     

Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily

BACKGROUND: Aldehydes are highly reactive molecules. While several non-P450 enzyme systems participate in their metabolism, one of the most important is the aldehyde dehydrogenase (ALDH) superfamily, composed of NAD(P)+-dependent enzymes that catalyze aldehyde oxidation. OBJECTIVE: This article presents a review of what is currently known about each member of the human ALDH superfamily including the pathophysiological significance of these enzymes. METHODS: Relevant literature involving all members of the human ALDH family was extensively reviewed, with the primary focus on recent and novel findings. CONCLUSION: To date, 19 ALDH genes have been identified in the human genome and mutations in these genes and subsequent inborn errors in aldehyde metabolism are the molecular basis of several diseases, including Sj?gren-Larsson syndrome, type II hyperprolinemia, gamma-hydroxybutyric aciduria and pyridoxine-dependent seizures. ALDH enzymes also play important roles in embryogenesis and development, neurotransmission, oxidative stress and cancer. Finally, ALDH enzymes display multiple catalytic and non-catalytic functions including ester hydrolysis, antioxidant properties, xenobiotic bioactivation and UV light absorption.     

Molecular genetics of human aldehyde dehydrogenase.

Four non-allelic genes, which encode four different aldehyde dehydrogenase (ALDH) isozymes, have been cloned and characterized at the present time. The coding nucleotide sequences, and organization of introns and exons of these genes have been elucidated. The ALDH1 gene encodes the major cytosolic ALDH1 existing in the liver and other tissues. The genetic deficiency of this isozyme was found at a low frequency (< 10%) in both Caucasians and Orientals. The deficiency and alcohol sensitivity character are inherited together in one large Caucasian family examined. The ALDH1 gene contains two hormone response elements in its upstream 5' region. The ALDH2 gene encodes the major liver mitochondrial ALDH2 which has a very low Km for acetaldehyde. The atypical ALDH2(2) allele is common (about 30%) in Orientals; and subjects with ALDH2(2) allele, both homozygous and heterozygous status, lack ALDH activity. These individuals are alcohol sensitive and have a markedly reduced risk in developing alcoholism and alcoholic liver diseases. The ALDH3 gene produces a cytosolic ALDH3 isozyme existing in the stomach and liver carcinoma but hardly in normal liver. The ALDH3 locus is polymorphic in Orientals and presumably other populations. The ALDH5 gene, which is expressed in testes and liver, is highly polymorphic in both Caucasians and Orientals. The variation of these two loci may affect the development of alcohol-related problems.     

增殖的胰腺β细胞可上调肿瘤干细胞标志物ALDH

目的：探讨肿瘤干细胞标志物乙醛脱氢酶（ALDH）在小鼠胰腺β细胞增殖模型中的表达情况。方法通过胰腺部分切除术构建小鼠胰腺β细胞增殖的模型，采用流式细胞术和免疫荧光检测其胰腺β细胞中ALDH的表达，采用Western blot检测细胞周期相关蛋白CyclinD1、CDK2及CDK4的表达。结果胰腺部分切除术后2周的胰岛细胞中aldefluor＋细胞明显增多，Ki-67＋β细胞比例明显升高，且aldefluor＋细胞CyclinD1、CyclinD2和CDK4蛋白表达水平均明显高于aldefluor－细胞。胰腺部分切除术后小鼠胰腺中的ALDH＋细胞绝大部分均为β细胞。结论胰腺部分切除术诱导的增殖胰岛β细胞具有较高的ALDH活性，aldefluor荧光标记可能作为筛选增殖β细胞的标记物。     

淫羊藿苷促进关节软骨损伤修复作用机制研究进展

淫羊藿苷是补肾类中药淫羊藿的主要活性成分,属异戊烯基黄酮醇类化合物,具有免疫调节、抗炎、抗氧化应激、抗肿瘤、抗衰老和抗骨质疏松等多种药理活性,对神经、免疫、肿瘤、内分泌、心脑血管和肌肉骨骼系统等疾病均具有良好的功效,尤其对骨骼系统疾病具有多通道、多靶点的活性作用,在关节软骨损伤性疾病中具有潜在应用优势。淫羊藿苷可通过促进软骨细胞增殖分化及抑制过度凋亡、减少炎症因子释放、抑制软骨下骨结构重塑、促进关节软骨细胞外基质合成、促进骨髓间充质干细胞迁移和成软骨分化等多种作用机制来促进关节软骨损伤修复。对淫羊藿苷在治疗关节软骨损伤疾病中发挥不同修复作用及其机制进行综述,以期为深入研究和相关药物研发提供参考依据。     

Integrating biological and behavioral factors in alcohol use risk: the role of ALDH2 status and alcohol expectancies in a sample of Asian Americans

Prior studies have shown that the ALDH2*2 genetic variant, most common in individuals of Asian descent, is related to heightened sensitivity to alcohol and can serve as a protective factor against alcohol problems. This study explored the effect of this factor on alcohol expectancies. It was hypothesized that (a) individuals with ALDH2*2 alleles would have lower positive expectancies and higher negative expectancies, (b) expectancies would mediate the ALDH2-drinking relation, and (c) ALDH2 status would moderate the expectancy-drinking relation. Data were collected from 171 Asian American university students. Positive expectancy and ALDH2 status were correlated with alcohol use. Mediation and moderation hypotheses were supported only in the female sample. Results were not significant for negative expectancies. These results indicate that ALDH2 status may protect against drinking by lowering positive expectancies and reducing the expectancy-drinking relationship.     

Genetics of Alcohol and Aldehyde Dehydrogenases

Abstract: This paper reviews the genetic status of the two key enzymes of alcohol metabolism in humans, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Human ADH is encoded by at least five genes, giving rise to three classes of enzyme. The Class I genes are located on chromosome 4 and encode three homologous polypeptides α, β and γ-ADH, generating six isozymes in homozygous individuals. The ADH2 (β subunit) gene coding sequence is interrupted by eight introns and spans approximately 15 kilobases. Polymorphisms at the ADH2 and ADH3 (γ subunit) loci generate allelic isozymes in human populations of which two have widely divergent kinetic properties. Class II (π-ADH) and Class III (khgr;-ADH) ADH genes encode subunits that are more divergent in sequence, reflecting earlier evolutionary origins, as compared with the three human Class I genes. The Class III gene (ADH5) is localized on human chromosome 4, near the Class I genes. Human ALDHs are encoded by at least three genes giving rise to two major liver isozymes, ALDH1 and ALDH2, differentially localized in cytosol and mitochondria respectively, and ALDH3, exhibiting high activity in human stomach. cDNA nucleotide and subunit amino acid sequences for the ALDH1 and ALDH2 isozymes reflect 68% structural identity. A high frequency polymorphism exists for ALDH2 in Mongoloid populations, which has been associated with alcohol sensitivity. Human ALDH genes have been mapped to three separate chromosomes: ALDH₁ (chromosome 9); ALDH₂ (chromosome 12); and ALDH₃ (chromosome 17).     

Classification of alcohol metabolizing enzymes and polymorphisms--specificity in Japanese]

Multiple forms and gene loci of human alcohol dehydrogenase (ADH EC: 1.2.1.3) and aldehyde dehydrogenase (ALDH, EC: 1.2.1.3) in the major pathway of alcohol metabolism have been found and characterized in the last two decades. With the coenzyme NAD, these enzymes catalyze the reversible conversion of organic alcohols to ketones or aldehydes, and aldehyde to acetic acid. The ADH genes are mapped to chromosome 4p21-25, but the ALDH genes are localized at different chromosomes. The cytochrome P450 2E1 (CYP2E1) gene, which is mapped to chromosome 10q24.3-qter contributes also the conversion of ethanol to acetaldehyde. Genetic polymorphisms have been reported in these alcohol metabolizing enzymes. The metabolisms of alcohol and acetaldehyde in liver and blood after drinking alcohol are thought to be influenced by the interactive action of these enzymes. Amongst the five major classes of the ADH subunits (alpha, beta, gamma, pi, chi, sigma), beta and gamma subunits show genetic polymorphisms. Recently a new nomenclature for ALDH genes has been recommend based on divergent evolution and chromosomal mapping. Two major isoforms designated as cytosolic ALDH1 and mitochondrial ALDH2 can be distinguished by their electrophoretic and kinetic properties as well as by their subcellular localization. Mitochondrial ALDH2 is a major enzyme in the oxidation of acetaldehyde derived from ethanol metabolism. The catalytic deficiency of ALDH2 isozyme is responsible for flushing and other vasomotor symptoms caused by higher acetaldehyde levels after alcohol intake. So far, frequencies of the two alleles of ALDH2 in Mongoloid have been reported in the different population groups. The catalytic deficiency of ALDH2 is caused by a structural point mutation at amino acid position 487, where a substitution of Glu to Lys resulting from a transition of G (C) to A (T) at 1510 nucleotide from the initiation codon has occurred. Individuals deficient in ALDH2 activity refrain from excessive drinking of alcohol due to the aversive reactions, leading to protection against alcoholism. Prevalence of the ALDH2*1 allele is associated with alcoholism, and subsequent studies have confirmed the allelic association with alcoholism in different ethnic groups. The effects of polymorphisms of ADH2 and CYP2E1 remained controversial, even in the same ethnic group. Investigation of mutations for the transacting cis-element in promoter region of the ALDH2 gene will provide important information with respect to regulation of this gene. Transfection assays using the first 600 bp of the upstream nucleotide sequences indicated that a region from -75 to -120 was necessary for the ALDH2 gene expression, and especially NF-Y/CP1 binding site from -92 to -96 (CCAAT box) is important in the expression of the gene. A novel polymorphism due to the nucleotide replacement at -357 G to A was found in all the population groups. Alcoholism is thought to be a multifactorial disease with complex mode of inheritance in addition to psychological and social factors, and many studies of family, adoption and twins concerning alcoholism have revealed that hereditary factor is an important determinant for developing alcoholism. Genetic association studies have contributed to the identification of a number of genetic risk factors for the chronic diseases influenced by genetic disorders and environmental factors.