Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an infantile autosomal-recessive motor neuron disease caused by mutations in the immunoglobulin micro-binding protein 2. We investigated the potential of a spinal cord neural stem cell population isolated on the basis of aldehyde dehydrogenase (ALDH) activity to modify disease progression of nmd mice, an animal model of SMARD1. ALDH(hi)SSC(lo) stem cells are self-renewing and multipotent and when intrathecally transplanted in nmd mice generate motor neurons properly localized in the spinal cord ventral horns. Transplanted nmd animals presented delayed disease progression, sparing of motor neurons and ventral root axons and increased lifespan. To further investigate the molecular events responsible for these differences, microarray and real-time reverse transcription-polymerase chain reaction analyses of wild-type, mutated and transplanted nmd spinal cord were undertaken. We demonstrated a down-regulation of genes involved in excitatory amino acid toxicity and oxidative stress handling, as well as an up-regulation of genes related to the chromatin organization in nmd compared with wild-type mice, suggesting that they may play a role in SMARD1 pathogenesis. Spinal cord of nmd-transplanted mice expressed high transcript levels for genes related to neurogenesis such as doublecortin (DCX), LIS1 and drebrin. The presence of DCX-expressing cells in adult nmd spinal cord suggests that both exogenous and endogenous neurogeneses may contribute to the observed nmd phenotype amelioration.
Hum Mol Genet 2006 Jan 15
PMID:Transplanted ALDHhiSSClo neural stem cells generate motor neurons and delay disease progression of nmd mice, an animal model of SMARD1. 1633 14

Acetaldehyde, the major metabolite of ethanol, which is far more toxic and reactive than ethanol, may be responsible for alcohol-induced cardiac damage. This study was designed to examine the impact of facilitated acetaldehyde metabolism using transfection of human aldehyde dehydrogenase-2 (ALDH2) transgene on acetaldehyde- and ethanol-induced cell injury. Fetal human cardiac myocytes were transfected with ALDH2, the efficacy of which was verified by flow cytometry, Western blot and ALDH2 activity assays. Generation of reactive oxygen species (ROS) was detected using 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA). Apoptosis was evaluated by 4',6'-diamidino-2'-phenylindoladihydrochloride (DAPI) fluorescence microscopy, quantitative DNA fragmentation ELISA and caspase 3 activity. Acetaldehyde and ethanol elicited overt ROS generation and apoptosis in human cardiac myocytes following 24-48 h of incubation. Immunostaining revealed activation of the MAP kinase cascades ERK1/2, SAPK/JNK and p38 MAP kinase in acetaldehyde-treated myocytes. Interestingly, ALDH2 transgene significantly attenuated acetaldehyde-induced ROS generation, apoptosis and phosphorylation of ERK1/2 and SAPK/JNK. Time-dependent response (0-12 h) revealed ROS accumulation and activation of MAP kinases prior to acetaldehyde-induced apoptosis. In addition, acetaldehyde-induced ROS generation and apoptosis were antagonized by non-enzymatic antioxidants. Our results suggested that ALDH2 transgene overexpression may effectively alleviate acetaldehyde-elicited cell injury through an ERK1/2 and SPAK/JNK-dependent mechanism. Our data are consistent with the notion of acetaldehyde as a contributor to alcoholic cardiomyopathy and implicate the therapeutic potential of ALDH2 enzyme in alcoholic complications.
J Mol Cell Cardiol 2006 Feb
PMID:Attenuation of acetaldehyde-induced cell injury by overexpression of aldehyde dehydrogenase-2 (ALDH2) transgene in human cardiac myocytes: role of MAP kinase signaling. 1640 13

Oxygen toxicity is one of the major risk factors in the development of the chronic lung disease or bronchopulmonary dysplasia in premature infants. Using proteomic analysis, we discovered that mitochondrial aldehyde dehydrogenase (mtALDH or ALDH2) was downregulated in neonatal rat lung after hyperoxic exposure. To study the role of mtALDH in hyperoxic lung injury, we overexpressed mtALDH in human lung epithelial cells (A549) and found that mtALDH significantly reduced hyperoxia-induced cell death. Compared with control cells (Neo-A549), the necrotic cell death in mtALDH-overexpressing cells (mtALDH-A549) decreased from 25.3 to 6.5%, 50.5 to 9.1%, and 52.4 to 15.1% after 24-, 48-, and 72-h hyperoxic exposure, respectively. The levels of intracellular and mitochondria-derived reactive oxygen species (ROS) in mtALDH-A549 cells after hyperoxic exposure were significantly lowered compared with Neo-A549 cells. mtALDH overexpression significantly stimulated extracellular signal-regulated kinase (ERK) phosphorylation under normoxic and hyperoxic conditions. Inhibition of ERK phosphorylation partially eliminated the protective effect of mtALDH in hyperoxia-induced cell death, suggesting ERK activation by mtALDH conferred cellular resistance to hyperoxia. mtALDH overexpression augmented Akt phosphorylation and maintained the total Akt level in mtALDH-A549 cells under normoxic and hyperoxic conditions. Inhibition of phosphatidylinositol 3-kinase (PI3K) activation by LY294002 in mtALDH-A549 cells significantly increased necrotic cell death after hyperoxic exposure, indicating that PI3K-Akt activation by mtALDH played an important role in cell survival after hyperoxia. Taken together, these data demonstrate that mtALDH overexpression attenuates hyperoxia-induced cell death in lung epithelial cells through reduction of ROS, activation of ERK/MAPK, and PI3K-Akt cell survival signaling pathways.
Am J Physiol Lung Cell Mol Physiol 2006 Nov
PMID:Mitochondrial aldehyde dehydrogenase attenuates hyperoxia-induced cell death through activation of ERK/MAPK and PI3K-Akt pathways in lung epithelial cells. 1678 56

Antiquitin (ALDH7) is a member of the aldehyde dehydrogenase superfamily. In plants, ALDH7 is inducible upon dehydration and is thus believed to possess an osmoregulatory role. On the other hand, however, its exact physiological function in animals remains elusive. We herein report the isolation of the black seabream (Acanthopagrus schlegeli) antiquitin gene (sbALDH7) and the functional characterization of its promoter region. The 1.6 kb 5'-flanking region of sbALDH7 exhibits an intense promoter activity (30-170 fold of the basal) in five mammalian and fish cell lines of different origins. Progressive 5'-deletion analysis suggests that the core promoter is located within the region -297/+41 whereas a cis-acting repressor of basal transcription is present in the region -878/-297. In silico analysis of this sbALDH7 promoter region does not reveal any osmotic response element. Instead, it contains potential binding sites for cell cycle related cis-elements such as CCAAT displacement protein and cell cycle-dependent element/cell cycle genes homology region.
Mol Cell Biochem 2007 Mar
PMID:Cloning of the black seabream (Acanthopagrus schlegeli) antiquitin gene and functional characterization of its promoter region. 1707 85

Antiquitin is a member of the aldehyde dehydrogenase superfamily. Sequence analyses indicate that the protein is highly conserved from plants to animals. The plant antiquitins are generally believed to play a role in osmoregulation and/or detoxification. The physiological functions of animal antiquitins remain largely elusive, their involvement in a number of human diseases has been implicated.
Cell Mol Life Sci 2006 Dec
PMID:Antiquitin, a relatively unexplored member in the superfamily of aldehyde dehydrogenases with diversified physiological functions. 1713 Oct 62

Aldehyde dehydrogenases catalyze the oxidation of aldehyde substrates to the corresponding carboxylic acids. Lactaldehyde dehydrogenase from Escherichia coli (aldA gene product, P25553) is an NAD(+)-dependent enzyme implicated in the metabolism of l-fucose and l-rhamnose. During the heterologous expression and purification of taxadiene synthase from the Pacific yew, lactaldehyde dehydrogenase from E. coli was identified as a minor (</=5%) side-product subsequent to its unexpected crystallization. Accordingly, we now report the serendipitous crystal structure determination of unliganded lactaldehyde dehydrogenase from E. coli determined by the technique of multiple isomorphous replacement using anomalous scattering at 2.2 A resolution. Additionally, we report the crystal structure of the ternary enzyme complex with products lactate and NADH at 2.1 A resolution, and the crystal structure of the enzyme complex with NADPH at 2.7 A resolution. The structure of the ternary complex reveals that the nicotinamide ring of the cofactor is disordered between two conformations: one with the ring positioned in the active site in the so-called hydrolysis conformation, and another with the ring extended out of the active site into the solvent region, designated the out conformation. This represents the first crystal structure of an aldehyde dehydrogenase-product complex. The active site pocket in which lactate binds is more constricted than that of medium-chain dehydrogenases such as the YdcW gene product of E. coli. The structure of the binary complex with NADPH reveals the first view of the structural basis of specificity for NADH: the negatively charged carboxylate group of E179 destabilizes the binding of the 2'-phosphate group of NADPH sterically and electrostatically, thereby accounting for the lack of enzyme activity with this cofactor.
J Mol Biol 2007 Feb 16
PMID:Crystal structure of lactaldehyde dehydrogenase from Escherichia coli and inferences regarding substrate and cofactor specificity. 1717 28

Many East Asian human populations harbor a high-frequency deficiency allele for the aldehyde dehydrogenase 2 (ALDH2) enzyme, a critical protein involved in the metabolism of ethanol. Here we use resequencing and long-range SNP haplotype data from a Japanese sample to test whether patterns of nucleotide diversity and linkage disequilibrium at this locus are compatible with a standard neutral model of evolution. Examination of the pattern of polymorphism at a locus such as this, where the frequency of a common allele is known a priori, introduces an ascertainment bias that must be corrected for in analyses of the frequency spectrum of polymorphisms. We apply a flexible and generally applicable simulation approach to correct for this bias in our ALDH2 data and, also, to explore the effect of bias on the commonly used summary statistics Tajima's D, Fu and Li's D, and Fay and Wu's H. Our study finds no evidence that the pattern of genetic variation at ALDH2 differs from that expected under a standard neutral model. However, our general examination of ascertainment bias indicates that a priori knowledge of segregating alleles greatly affects the expected distributions of summary statistics. Under many parameter combinations we find that ascertainment bias introduces an elevated rate of false positives when summary statistics are used to test for deviations from a standard neutral model. However, we also show that over a wide range of conditions the power of all summary statistics can be greatly increased by incorporating prior knowledge of segregating alleles.
J Mol Evol 2007 Mar
PMID:Ascertainment bias and the pattern of nucleotide diversity at the human ALDH2 locus in a Japanese population. 1722 65

The mechanisms of teratogenic effects of ethanol in Japanese medaka embryogenesis were investigated by testing the hypothesis that ethanol or its metabolite ameliorates the expression of ethanol metabolizing enzymes. We have previously demonstrated that ethanol is unable to alter the expression pattern of alcohol dehydrogenase (ADH) mRNA, the first enzyme of ethanol metabolism, in medaka embryos during development. We, therefore, extended our investigation to aldehyde dehydrogenase (ALDH) system, the next enzyme of alcohol metabolic pathway. As the first step towards studying the regulation of Aldh mRNA expression by ethanol, we have cloned a cDNA by reverse transcriptase polymerase chain reaction (RT-PCR) from adult Japanese medaka (Oryzias latipes) liver representing the medaka ALDH9 gene product, with a coding region of 1515 nucleotides. The deduced amino acid sequences share 81.2% identity with cod liver betaine aldehyde dehydrogenase (BADH, EC 1.2.1.8), and 71.1% identity with human ALDH9A1 sequences. RT-PCR analysis further showed that in adults Aldh9 mRNA is constitutively expressed in all organs tested (brain, eye, gill, GI, heart, liver, kidney, muscle, skin, testis and ovary). Using semi-quantitative (rRT-PCR) and quantitative real time RT-PCR (qRT-PCR), we detected Aldh9 mRNA at all time points of development and the expression was lowest between approximately 1 and 8 h post-fertilization (hpf). Treatment of the embryos with ethanol for 48 h post-fertilization (hpf) attenuates (delayed) the expression of Aldh9 mRNA. This delayed expression of Aldh9 mRNA by ethanol may enhance acetaldehyde concentration in the embryo and induce teratogenesis during development.
Comp Biochem Physiol B Biochem Mol Biol 2007 Mar
PMID:Ethanol attenuates Aldh9 mRNA expression in Japanese medaka (Oryzias latipes) embryogenesis. 1723 98

Oxysterol nuclear receptors liver X receptor (LXR)alpha and LXRbeta are known to regulate lipid homeostasis in cells exposed to high amounts of cholesterol and/or fatty acids. In order to elucidate the specific and redundant roles of the LXRs in the testis, we explored the reproductive phenotypes of mice deficient of LXRalpha, LXRbeta, and both, of which only the lxralpha;beta-/- mice are infertile by 5 months of age. We demonstrate that LXRalpha-deficient mice had lower levels of testicular testosterone that correlated with a higher apoptotic rate of the germ cells. LXRbeta-deficient mice showed increased lipid accumulation in the Sertoli cells and a lower proliferation rate of the germ cells. In lxralpha;beta-/- mice, fatty acid metabolism was affected through a decrease of srebp1c and increase in scd1 mRNA expression. The retinoid acid signaling pathway was also altered in lxralpha;beta-/- mice, with a higher accumulation of all-trans retinoid receptor alpha, all-trans retinoid receptor beta, and retinoic aldehyde dehydrogenase-2 mRNA. Combination of these alterations might explain the deleterious phenotype of infertility observed only in lxralpha;beta-/- mice, even though lipid homeostasis seemed to be first altered. Wild-type mice treated with a specific LXR agonist showed an increase of testosterone production involving both LXR isoforms. Altogether, these data identify new roles of each LXR, collaborating to maintain both integrity and functions of the testis.
Mol Endocrinol 2007 May
PMID:Multiple roles of the nuclear receptors for oxysterols liver X receptor to maintain male fertility. 1734 95

Chronic administration of nitroglycerin (NTG) induces nitrate tolerance. Among possible underlying mechanisms, increased vascular production of reactive oxygen species (ROS) has emerged as a principal mechanism. Using cell culture and animal models of nitrate tolerance, we aimed to assess the impact of nitrates on NAD(P)H oxidases and aldehyde dehydrogenase 2 (ALDH2) expression. Rats and vascular smooth muscle cells were treated with NTG. Vascular reactivity was assessed by isometric tension studies. Superoxide was detected by dihydroethidium staining. Gene expression was measured by real-time polymerase chain reaction. NAD(P)H oxidase activity was measured using lucigenin-enhanced chemiluminescence. ALDH activity was measured biochemically, and NO consumption electrochemically. Nitrate tolerance was induced in rats by treatment with NTG for 3 days, and detected as impaired endothelium-dependent and -independent relaxation of aortic segments. Although superoxide production was increased in all aortic layers, expression of nox1, nox2 and nox4 was significantly decreased. Similarly, in vascular smooth muscle cells exposed to NTG for 6-24 h, NAD(P)H oxidase activity was increased, in spite of nox1 downregulation. In addition, expression and activity of ALDH-2 was decreased in nitrate-tolerant rings. Furthermore, exogenous addition of ALDH decreased superoxide generation in vitro and attenuated NO consumption in vascular smooth muscle cell homogenates. Our data suggest that in nitrate tolerance, activation of nox enzymes more than compensates for their downregulation, resulting in a net increase in superoxide and NO consumption. Furthermore, reduced ALDH-2 activity and expression leads to decreased NTG bioconversion. Therefore, both mechanisms reduce NO availability and impair vasorelaxation.
J Mol Cell Cardiol 2007 Jun
PMID:Increased superoxide production in nitrate tolerance is associated with NAD(P)H oxidase and aldehyde dehydrogenase 2 downregulation. 1749 33


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