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Sample records for acetaldehyde dehydrogenase aldh

  1. Pharmacological recruitment of aldehyde dehydrogenase 3A1 (ALDH3A1) to assist ALDH2 in acetaldehyde and ethanol metabolism in vivo

    PubMed Central

    Chen, Che-Hong; Cruz, Leslie A.; Mochly-Rosen, Daria

    2015-01-01

    Correcting a genetic mutation that leads to a loss of function has been a challenge. One such mutation is in aldehyde dehydrogenase 2 (ALDH2), denoted ALDH2*2. This mutation is present in ∼0.6 billion East Asians and results in accumulation of toxic acetaldehyde after consumption of ethanol. To temporarily increase metabolism of acetaldehyde in vivo, we describe an approach in which a pharmacologic agent recruited another ALDH to metabolize acetaldehyde. We focused on ALDH3A1, which is enriched in the upper aerodigestive track, and identified Alda-89 as a small molecule that enables ALDH3A1 to metabolize acetaldehyde. When given together with the ALDH2-specific activator, Alda-1, Alda-89 reduced acetaldehyde-induced behavioral impairment by causing a rapid reduction in blood ethanol and acetaldehyde levels after acute ethanol intoxication in both wild-type and ALDH2-deficient, ALDH2*1/*2, heterozygotic knock-in mice. The use of a pharmacologic agent to recruit an enzyme to metabolize a substrate that it usually does not metabolize may represent a novel means to temporarily increase elimination of toxic agents in vivo. PMID:25713355

  2. ALDH2 modulates autophagy flux to regulate acetaldehyde-mediated toxicity thresholds

    PubMed Central

    Tanaka, Koji; Whelan, Kelly A; Chandramouleeswaran, Prasanna M; Kagawa, Shingo; Rustgi, Sabrina L; Noguchi, Chiaki; Guha, Manti; Srinivasan, Satish; Amanuma, Yusuke; Ohashi, Shinya; Muto, Manabu; Klein-Szanto, Andres J; Noguchi, Eishi; Avadhani, Narayan G; Nakagawa, Hiroshi

    2016-01-01

    A polymorphic mutation in the acetaldehyde dehydrogenase 2 (ALDH2) gene has been epidemiologically linked to the high susceptibility to esophageal carcinogenesis for individuals with alcohol use disorders. Mice subjected to alcohol drinking show increased oxidative stress and DNA adduct formation in esophageal epithelia where Aldh2 loss augments alcohol-induced genotoxic effects; however, it remains elusive as to how esophageal epithelial cells with dysfunctional Aldh2 cope with oxidative stress related to alcohol metabolism. Here, we investigated the role of autophagy in murine esophageal epithelial cells (keratinocytes) exposed to ethanol and acetaldehyde. We find that ethanol and acetaldehyde trigger oxidative stress via mitochondrial superoxide in esophageal keratinocytes. Aldh2-deficient cells appeared to be highly susceptible to ethanol- or acetaldehyde-mediated toxicity. Alcohol dehydrogenase-mediated acetaldehyde production was implicated in ethanol-induced cell injury in Aldh2 deficient cells as ethanol-induced oxidative stress and cell death was partially inhibited by 4-methylpyrazole. Acetaldehyde activated autophagy flux in esophageal keratinocytes where Aldh2 deficiency increased dependence on autophagy to cope with ethanol-induced acetaldehyde-mediated oxidative stress. Pharmacological inhibition of autophagy flux by chloroquine stabilized p62/SQSTM1, and increased basal and acetaldehyde-mediate oxidative stress in Aldh2 deficient cells as documented in monolayer culture as well as single-cell derived three-dimensional esophageal organoids, recapitulating a physiological esophageal epithelial proliferation-differentiation gradient. Our innovative approach indicates, for the first time, that autophagy may provide cytoprotection to esophageal epithelial cells responding to oxidative stress that is induced by ethanol and its major metabolite acetaldehyde. Defining autophagymediated cytoprotection against alcohol-induced genotoxicity in the context of

  3. ALDH2 modulates autophagy flux to regulate acetaldehyde-mediated toxicity thresholds.

    PubMed

    Tanaka, Koji; Whelan, Kelly A; Chandramouleeswaran, Prasanna M; Kagawa, Shingo; Rustgi, Sabrina L; Noguchi, Chiaki; Guha, Manti; Srinivasan, Satish; Amanuma, Yusuke; Ohashi, Shinya; Muto, Manabu; Klein-Szanto, Andres J; Noguchi, Eishi; Avadhani, Narayan G; Nakagawa, Hiroshi

    2016-01-01

    A polymorphic mutation in the acetaldehyde dehydrogenase 2 (ALDH2) gene has been epidemiologically linked to the high susceptibility to esophageal carcinogenesis for individuals with alcohol use disorders. Mice subjected to alcohol drinking show increased oxidative stress and DNA adduct formation in esophageal epithelia where Aldh2 loss augments alcohol-induced genotoxic effects; however, it remains elusive as to how esophageal epithelial cells with dysfunctional Aldh2 cope with oxidative stress related to alcohol metabolism. Here, we investigated the role of autophagy in murine esophageal epithelial cells (keratinocytes) exposed to ethanol and acetaldehyde. We find that ethanol and acetaldehyde trigger oxidative stress via mitochondrial superoxide in esophageal keratinocytes. Aldh2-deficient cells appeared to be highly susceptible to ethanol- or acetaldehyde-mediated toxicity. Alcohol dehydrogenase-mediated acetaldehyde production was implicated in ethanol-induced cell injury in Aldh2 deficient cells as ethanol-induced oxidative stress and cell death was partially inhibited by 4-methylpyrazole. Acetaldehyde activated autophagy flux in esophageal keratinocytes where Aldh2 deficiency increased dependence on autophagy to cope with ethanol-induced acetaldehyde-mediated oxidative stress. Pharmacological inhibition of autophagy flux by chloroquine stabilized p62/SQSTM1, and increased basal and acetaldehyde-mediate oxidative stress in Aldh2 deficient cells as documented in monolayer culture as well as single-cell derived three-dimensional esophageal organoids, recapitulating a physiological esophageal epithelial proliferation-differentiation gradient. Our innovative approach indicates, for the first time, that autophagy may provide cytoprotection to esophageal epithelial cells responding to oxidative stress that is induced by ethanol and its major metabolite acetaldehyde. Defining autophagymediated cytoprotection against alcohol-induced genotoxicity in the context of

  4. Multiple alcohol dehydrogenases but no functional acetaldehyde dehydrogenase causing excessive acetaldehyde production from ethanol by oral streptococci

    PubMed Central

    Pavlova, Sylvia I.; Jin, Ling; Gasparovich, Stephen R.

    2013-01-01

    Ethanol consumption and poor oral hygiene are risk factors for oral and oesophageal cancers. Although oral streptococci have been found to produce excessive acetaldehyde from ethanol, little is known about the mechanism by which this carcinogen is produced. By screening 52 strains of diverse oral streptococcal species, we identified Streptococcus gordonii V2016 that produced the most acetaldehyde from ethanol. We then constructed gene deletion mutants in this strain and analysed them for alcohol and acetaldehyde dehydrogenases by zymograms. The results showed that S. gordonii V2016 expressed three primary alcohol dehydrogenases, AdhA, AdhB and AdhE, which all oxidize ethanol to acetaldehyde, but their preferred substrates were 1-propanol, 1-butanol and ethanol, respectively. Two additional dehydrogenases, S-AdhA and TdhA, were identified with specificities to the secondary alcohol 2-propanol and threonine, respectively, but not to ethanol. S. gordonii V2016 did not show a detectable acetaldehyde dehydrogenase even though its adhE gene encodes a putative bifunctional acetaldehyde/alcohol dehydrogenase. Mutants with adhE deletion showed greater tolerance to ethanol in comparison with the wild-type and mutant with adhA or adhB deletion, indicating that AdhE is the major alcohol dehydrogenase in S. gordonii. Analysis of 19 additional strains of S. gordonii, S. mitis, S. oralis, S. salivarius and S. sanguinis showed expressions of up to three alcohol dehydrogenases, but none showed detectable acetaldehyde dehydrogenase, except one strain that showed a novel ALDH. Therefore, expression of multiple alcohol dehydrogenases but no functional acetaldehyde dehydrogenase may contribute to excessive production of acetaldehyde from ethanol by certain oral streptococci. PMID:23637459

  5. Gene cloning, expression, and characterization of a novel acetaldehyde dehydrogenase from Issatchenkia terricola strain XJ-2.

    PubMed

    Yao, Zhengying; Zhang, Chong; Lu, Fengxia; Bie, Xiaomei; Lu, Zhaoxin

    2012-03-01

    Acetaldehyde is a known mutagen and carcinogen. Active aldehyde dehydrogenase (ALDH) represents an important mechanism for acetaldehyde detoxification. A yeast strain XJ-2 isolated from grape samples was found to produce acetaldehyde dehydrogenase with a high activity of 2.28 U/mg and identified as Issatchenkia terricola. The enzyme activity was validated by oxidizing acetaldehyde to acetate with NAD(+) as coenzyme based on the headspace gas chromatography analysis. A novel acetaldehyde dehydrogenase gene (ist-ALD) was cloned by combining SiteFinding-PCR and self-formed adaptor PCR. The ist-ALD gene comprised an open reading frame of 1,578 bp and encoded a protein of 525 amino acids. The predicted protein of ist-ALD showed the highest identity (73%) to ALDH from Pichia angusta. The ist-ALD gene was expressed in Escherichia coli, and the gene product (ist-ALDH) presented a productivity of 442.3 U/mL cells. The purified ist-ALDH was a homotetramer of 232 kDa consisting of 57 kDa-subunit according to the SDS-PAGE and native PAGE analysis. Ist-ALDH exhibited the optimal activity at pH 9.0 and 40°C, respectively. The activity of ist-ALDH was enhanced by K(+), NH4(+), dithiothreitol, and 2-mercaptoethanol but strongly inhibited by Ag(+), Hg(2+), Cu(2+), and phenylmethyl sulfonylfluoride. In the presence of NAD(+), ist-ALDH could oxidize many aliphatic, aromatic, and heterocyclic aldehydes, preferably acetaldehyde. Kinetic study revealed that ist-ALDH had a k (cat) value of 27.71/s and a k (cat)/K (m) value of 26.80 × 10(3)/(mol s) on acetaldehyde, demonstrating ist-ALDH, a catalytically active enzyme by comparing with other ALDHs. These studies indicated that ist-ALDH was a potential enzymatic product for acetaldehyde detoxification. PMID:21858493

  6. Aldehyde dehydrogenase (ALDH) in Alzheimer's and Parkinson's disease.

    PubMed

    Grünblatt, Edna; Riederer, Peter

    2016-02-01

    Evidence suggests that aldehyde dehydrogenase (ALDH; E.C. 1.2.1.3) gene, protein expression and activity are substantially decreased in the substantia nigra of patients with Parkinson's disease (PD). This holds especially true for cytosolic ALDH1A1, while mitochondrial ALDH2 is increased in the putamen of PD. Similarly, in Alzheimer's disease (AD) several studies in genetic, transcriptomic, protein and animal models suggest ALDH involvement in the neurodegeneration processes. Such data are in line with findings of increased toxic aldehydes, like for example malondialdehyde, nonenal, 3,4-dihydroxyphenylacetaldehyde and others. Genetic, transcriptomic and protein alterations may contribute to such data. Also in vitro and in vivo experimental work points to an important role of ALDH in the pathology of neurodegenerative disorders. Aims at investigating dysfunctions of aldehyde detoxification are suitable to define genetic/molecular targets for new therapeutic strategies balancing amine metabolism in devastating disorders like PD and probably also AD. PMID:25298080

  7. Ethanol and acetaldehyde differentially alter extracellular dopamine and serotonin in Aldh2-knockout mouse dorsal striatum: A reverse microdialysis study.

    PubMed

    Jamal, Mostofa; Ameno, Kiyoshi; Miki, Takanori; Tanaka, Naoko; Ito, Asuka; Ono, Junichiro; Takakura, Ayaka; Kumihashi, Mitsuru; Kinoshita, Hiroshi

    2016-01-01

    Dopamine (DA) and serotonin (5-HT) seem to be involved in several of the effects of ethanol (EtOH). Acetaldehyde (AcH), especially in the brain, induces effects that mimic those of EtOH. The purpose of this study was to investigate the effects of local perfusion of EtOH and AcH on extracellular DA and 5-HT in the dorsal striatum of Aldh2-knockout (Aldh2-KO) and wild-type (WT) mice. Aldh2-KO mice were used as a model of aldehyde dehydrogenase 2 deficiency in humans to examine the effects of AcH. Mice were perfused with Ringer's solution (control), EtOH (100, 200, or 500mM) and AcH (100, 200, or 500μM) into the dorsal striatum. Dialysate samples were collected every 5min, and then analyzed with HPLC coupled to an ECD. We found that local perfusion with 500mM EtOH increased extracellular levels of DA (p<0.05) in both Aldh2-KO and WT mice, while 5-HT levels remain unchanged. EtOH at a dose of 200mM also increased DA in WT mice, but this was limited to a 30-40-min time-point. In contrast, perfusion with 200 and 500μM AcH decreased both DA and 5-HT (p<0.05) in Aldh2-KO mice, but this decrease was not found in WT mice at any AcH dose, indicating an effect of AcH on DA and 5-HT levels. There were no genotype effects on the basal levels of DA and 5-HT. These results indicate that high EtOH can stimulate DA, whereas high AcH can depress both DA and 5-HT in the dorsal striatum of mice. PMID:26711020

  8. Low Km aldehyde dehydrogenase (ALDH2) polymorphism, alcohol-drinking behavior, and chromosome alterations in peripheral lymphocytes.

    PubMed Central

    Morimoto, K; Takeshita, T

    1996-01-01

    Excessive drinking of alcohol is now widely known to be one of the major lifestyle choices that ca effect health. Among the various effects of alcohol drinking, cytogenetic and other genotoxic effects are of major concern from the viewpoint of prevention of alcohol-related diseases. Alcohol is first metabolized to acetaldehyde, which directly causes various types of chromosomal DNA lesions and alcohol-related diseases, and is then further detoxified to the much less toxic metabolite acetate. About 50% of Oriental people are deficient in the aldehyde-dehydrogenase 2 isozyme (ALDH2) that can most efficiently detoxify acetaldehyde. We have performed a series of experiments to investigate how the genetic deficiency in ALDH2 affects the behavioral pattern for alcohol drinking and the sensitivity of peripheral lymphocytes to the induction of chromosome alterations by exposure to alcohol and alcohol-related chemicals. We found great effects of the ALDH2 genotypes on alcohol sensitivity and alcohol-drinking behavior. We also show that lymphocytes from habitual drinkers with the deficient ALDH2 enzyme had significantly higher frequencies of sister chromatid exchanges than those from ALDH2-proficient individuals. PMID:8781384

  9. Human aldehyde dehydrogenase 3A1 (ALDH3A1): biochemical characterization and immunohistochemical localization in the cornea.

    PubMed Central

    Pappa, Aglaia; Estey, Tia; Manzer, Rizwan; Brown, Donald; Vasiliou, Vasilis

    2003-01-01

    ALDH3A1 (aldehyde dehydrogenase 3A1) is expressed at high concentrations in the mammalian cornea and it is believed that it protects this vital tissue and the rest of the eye against UV-light-induced damage. The precise biological function(s) and cellular distribution of ALDH3A1 in the corneal tissue remain to be elucidated. Among the hypotheses proposed for ALDH3A1 function in cornea is detoxification of aldehydes formed during UV-induced lipid peroxidation. To investigate in detail the biochemical properties and distribution of this protein in the human cornea, we expressed human ALDH3A1 in Sf9 insect cells using a baculovirus vector and raised monoclonal antibodies against ALDH3A1. Recombinant ALDH3A1 protein was purified to homogeneity with a single-step affinity chromatography method using 5'-AMP-Sepharose 4B. Human ALDH3A1 demonstrated high substrate specificity for medium-chain (6 carbons and more) saturated and unsaturated aldehydes, including 4-hydroxy-2-nonenal, which are generated by the peroxidation of cellular lipids. Short-chain aliphatic aldehydes, such as acetaldehyde, propionaldehyde and malondialdehyde, were found to be very poor substrates for human ALDH3A1. In addition, ALDH3A1 metabolized glyceraldehyde poorly and did not metabolize glucose 6-phosphate, 6-phosphoglucono-delta-lactone and 6-phosphogluconate at all, suggesting that this enzyme is not involved in either glycolysis or the pentose phosphate pathway. Immunohistochemistry in human corneas, using the monoclonal antibodies described herein, revealed ALDH3A1 expression in epithelial cells and stromal keratocytes, but not in endothelial cells. Overall, these cumulative findings support the metabolic function of ALDH3A1 as a part of a corneal cellular defence mechanism against oxidative damage caused by aldehydic products of lipid peroxidation. Both recombinant human ALDH3A1 and the highly specific monoclonal antibodies described in the present paper may prove to be useful in probing

  10. Aldehyde Dehydrogenase-2 (ALDH2) Ameliorates Chronic Alcohol Ingestion-Induced Hepatic Steatosis and Inflammation: Role of Autophagy

    PubMed Central

    Guo, Rui; Xu, Xihui; Babcock, Sara A.; Zhang, Yingmei; Ren, Jun

    2014-01-01

    Background & Aims Mitochondrial aldehyde dehydrogenase (ALDH2) plays a critical role in the detoxification of the ethanol metabolite acetaldehyde. This study was designed to examine the impact of global ALDH2 overexpression on alcohol-induced hepatic steatosis. Methods Wild-type friendly virus B (FVB) and ALDH2 transgenic mice were placed on a 4% alcohol or control diet for 12 weeks. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin and cholesterol, hepatic triglyceride, steatosis, fat metabolism-related proteins, pro-inflammatory cytokines, glutathione (GSH), oxidized glutathione (GSSG), autophagy and autophagy signaling were examined. The role of autophagy was evaluated in ADH1-transfected human hepatocellular liver carcinoma cells (VA-13) treated with or without autophagy inducer rapamycin and lysosomal inhibitors. Results Chronic alcohol intake led to elevated AST, ALT, bilirubin, AST/ALT ratio, cholesterol, hepatic triglycerides, hepatic fat deposition as evidenced by H&E and oil Red O staining, associated with disturbed fat metabolism-related proteins (fatty acid synthase, SCD1), upregulated interleukin-6, TNF-α, cyclooxygenase, oxidative stress, and loss of autophagy, the effects of which were attenuated or ablated by ALDH2 transgene. Moreover, ethanol (100 mM) and acetaldehyde (100, 500 μM) increased levels of IL-6 and IFN-γ, and suppressed autophagy in VA-13 cells, the effects of which were markedly alleviated by rapamycin. In addition, lysosomal inhibitors mimicked ethanol-induced p62 accumulation with little additive effect with ethanol. Ethanol significantly suppressed LC3 conversion in the presence of lysosomal inhibitors. Conclusions In summary, our results revealed that ALDH2 plays a beneficial role in ameliorating chronic alcohol intake-induced hepatic steatosis and inflammation through regulation of autophagy. PMID:25457208

  11. Aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) polymorphisms exacerbate bladder cancer risk associated with alcohol drinking: gene-environment interaction.

    PubMed

    Masaoka, Hiroyuki; Ito, Hidemi; Soga, Norihito; Hosono, Satoyo; Oze, Isao; Watanabe, Miki; Tanaka, Hideo; Yokomizo, Akira; Hayashi, Norio; Eto, Masatoshi; Matsuo, Keitaro

    2016-06-01

    Although a range of chemical exposures (cigarette smoking and occupational exposure) are recognized risk factors for the development of bladder cancer (BCa), many epidemiological studies have demonstrated that alcohol drinking is not associated with BCa risk. Aldehyde dehydrogenase 2 (ALDH2; rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B; rs1229984, His47Arg) polymorphisms impact the accumulation of acetaldehyde, resulting in an increased risk of various cancers. To date, however, no studies evaluating the association between BCa risk and alcohol drinking have considered these polymorphisms. Here, we conducted a matched case-control study to investigate whether ALDH2 and ADH1B polymorphisms influence BCa risk associated with alcohol drinking. Cases were 74 BCa patients and controls were 740 first-visit outpatients without cancer at Aichi Cancer Center Hospital between January 2001 and December 2005. Odds ratio (OR), 95% confidence interval (CI) and gene-environment interaction were assessed by conditional logistic regression analysis with adjustment for potential confounders. Results showed that ALDH2 Glu/Lys was associated with a significantly increased risk of BCa compared with Glu/Glu (OR 2.03, 95% CI 1.14-3.62, P = 0.017). In contrast, ALDH2 Glu/Lys showed no increase in risk among the stratum of never drinkers compared with Glu/Glu, indicating a gene-environment interaction. ADH1B His/Arg had an OR of 1.98 (1.20-3.24, P = 0.007) compared with His/His. ADH1B Arg+ showed a similar OR and 95% CI. Individuals with ALDH2 Glu/Lys and ADH1B Arg+ had the highest risk of BCa compared with ALDH2 Glu/Glu and ADH1B His/His [OR 4.00 (1.81-8.87), P = 0.001]. PMID:26992901

  12. Biochemical characterization of a bifunctional acetaldehyde-alcohol dehydrogenase purified from a facultative anaerobic bacterium Citrobacter sp. S-77.

    PubMed

    Tsuji, Kohsei; Yoon, Ki-Seok; Ogo, Seiji

    2016-03-01

    Acetaldehyde-alcohol dehydrogenase (ADHE) is a bifunctional enzyme consisting of two domains of an N-terminal acetaldehyde dehydrogenase (ALDH) and a C-terminal alcohol dehydrogenase (ADH). The enzyme is known to be important in the cellular alcohol metabolism. However, the role of coenzyme A-acylating ADHE responsible for ethanol production from acetyl-CoA remains uncertain. Here, we present the purification and biochemical characterization of an ADHE from Citrobacter sp. S-77 (ADHES77). Interestingly, the ADHES77 was unable to be solubilized from membrane with detergents either 1% Triton X-100 or 1% Sulfobetaine 3-12. However, the enzyme was easily dissociated from membrane by high-salt buffers containing either 1.0 M NaCl or (NH4)2SO4 without detergents. The molecular weight of a native protein was estimated as approximately 400 kDa, consisting of four identical subunits of 96.3 kDa. Based on the specific activity and kinetic analysis, the ADHES77 tended to have catalytic reaction towards acetaldehyde elimination rather than acetaldehyde formation. Our experimental observation suggests that the ADHES77 may play a pivotal role in modulating intracellular acetaldehyde concentration. PMID:26216639

  13. Acetaldehyde and gastric cancer.

    PubMed

    Salaspuro, Mikko

    2011-04-01

    Aldehyde dehydrogenase (ALDH2) and alcohol dehydrogenase (ADH) gene polymorphisms associating with enhanced acetaldehyde exposure and markedly increased cancer risk in alcohol drinkers provide undisputable evidence for acetaldehyde being a local carcinogen not only in esophageal but also in gastric cancer. Accordingly, acetaldehyde associated with alcoholic beverages has recently been classified as a Group 1 carcinogen to humans. Microbes are responsible for the bulk of acetaldehyde production from ethanol both in saliva and Helicobacter pylori-infected and achlorhydric stomach. Acetaldehyde is the most abundant carcinogen in tobacco smoke and it readily dissolves into saliva during smoking. Many foodstuffs and 'non-alcoholic' beverages are important but unrecognized sources of local acetaldehyde exposure. The cumulative cancer risk associated with increasing acetaldehyde exposure suggests the need for worldwide screening of the acetaldehyde levels of alcoholic beverages and as well of the ethanol and acetaldehyde of food produced by fermentation. The generally regarded as safe status of acetaldehyde should be re-evaluated. The as low as reasonably achievable principle should be applied to the acetaldehyde of alcoholic and non-alcoholic beverages and food. Risk groups with ADH-and ALDH2 gene polymorphisms, H. pylori infection or achlorhydric atrophic gastritis, or both, should be screened and educated in this health issue. L-cysteine formulations binding carcinogenic acetaldehyde locally in the stomach provide new means for intervention studies. PMID:21401890

  14. Strong Protective Effect of The Aldehyde Dehydrogenase Gene (ALDH2) 504lys (*2) Allele Against Alcoholism And Alcohol-Induced Medical Diseases in Asians

    PubMed Central

    Li, Dawei; Zhao, Hongyu; Gelernter, Joel

    2013-01-01

    Alcohol is oxidized to acetaldehyde, which in turn is oxidized to acetate. The aldehyde dehydrogenase 2 gene (ALDH2) is the most important gene responsible for acetaldehyde metabolism. Individuals heterozygous or homozygous for the lys (A or *2) allele at the single nucleotide polymorphism (SNP) glu504lys (rs671) of ALDH2 have greatly reduced ability to metabolize acetaldehyde, which greatly decreases their risk for alcohol dependence (AD). Case-control studies have shown association between this SNP and alcohol dependence as well as alcohol-induced liver disease. However, some studies have produced insignificant results. Using cumulative data from the past 20 years predominately from Asian populations (from both English and Chinese publications), this meta-analysis sought to examine and update whether the aggregate data provide new evidence of statistical significance for the proposed association. Our results (9,678 cases and 7,331 controls from 53 studies) support a strong association of alcohol abuse and dependence, with allelic P value of 3×10−56 and OR of 0.23 (0.2, 0.28) under the random effects model. The dominant model (lys-lys + lys-glu vs. glu-glu) also showed strong association with P value of 1×10−44 and OR of 0.22 (0.18, 0.27). When stricter criteria and various sub-group analyses were applied, the association remained strong (for example, OR = 0.23 (0.18, 0.3) and P = 2×10−28 for the alcoholic patients with alcoholic liver disease, cirrhosis, or pancreatitis). These findings provide confirmation of the involvement of the human ALDH2 gene in the pathogenesis of AD as well as alcohol-induced medical illnesses in East-Asians. PMID:22102315

  15. ALDH1B1 links alcohol consumption and diabetes.

    PubMed

    Singh, Surendra; Chen, Ying; Matsumoto, Akiko; Orlicky, David J; Dong, Hongbin; Thompson, David C; Vasiliou, Vasilis

    2015-08-01

    Aldehyde dehydrogenase 1B1 (ALDH1B1) is a mitochondrial enzyme sharing 65% and 72% sequence identity with ALDH1A1 and ALDH2 proteins, respectively. Compared to the latter two ALDH isozymes, little is known about the physiological functions of ALDH1B1. Studies in humans indicate that ALDH1B1 may be associated with alcohol sensitivity and stem cells. Our recent in vitro studies using human ALDH1B1 showed that it metabolizes acetaldehyde and retinaldehyde. To investigate the in vivo role of ALDH1B1, we generated and characterized a global Aldh1b1 knockout mouse line. These knockout (KO) mice are fertile and show overtly good health. However, ethanol pharmacokinetic analysis revealed ∼40% increase in blood acetaldehyde levels in KO mice. Interestingly, the KO mice exhibited higher fasting blood glucose levels. Collectively, we show for the first time the functional in vivo role of ALDH1B1 in acetaldehyde metabolism and in maintaining glucose homeostasis. This mouse model is a valuable tool to investigate the mechanism by which alcohol may promote the development of diabetes. PMID:26086111

  16. Modeling-Dependent Protein Characterization of the Rice Aldehyde Dehydrogenase (ALDH) Superfamily Reveals Distinct Functional and Structural Features

    PubMed Central

    Kotchoni, Simeon O.; Jimenez-Lopez, Jose C.; Gao, Dongying; Edwards, Vincent; Gachomo, Emma W.; Margam, Venu M.; Seufferheld, Manfredo J.

    2010-01-01

    The completion of the rice genome sequence has made it possible to identify and characterize new genes and to perform comparative genomics studies across taxa. The aldehyde dehydrogenase (ALDH) gene superfamily encoding for NAD(P)+-dependent enzymes is found in all major plant and animal taxa. However, the characterization of plant ALDHs has lagged behind their animal- and prokaryotic-ALDH homologs. In plants, ALDHs are involved in abiotic stress tolerance, male sterility restoration, embryo development and seed viability and maturation. However, there is still no structural property-dependent functional characterization of ALDH protein superfamily in plants. In this paper, we identify members of the rice ALDH gene superfamily and use the evolutionary nesting events of retrotransposons and protein-modeling–based structural reconstitution to report the genetic and molecular and structural features of each member of the rice ALDH superfamily in abiotic/biotic stress responses and developmental processes. Our results indicate that rice-ALDHs are the most expanded plant ALDHs ever characterized. This work represents the first report of specific structural features mediating functionality of the whole families of ALDHs in an organism ever characterized. PMID:20634950

  17. Aldehyde dehydrogenase (ALDH) superfamily in plants: gene nomenclature and comparative genomics.

    PubMed

    Brocker, Chad; Vasiliou, Melpomene; Carpenter, Sarah; Carpenter, Christopher; Zhang, Yucheng; Wang, Xiping; Kotchoni, Simeon O; Wood, Andrew J; Kirch, Hans-Hubert; Kopečný, David; Nebert, Daniel W; Vasiliou, Vasilis

    2013-01-01

    In recent years, there has been a significant increase in the number of completely sequenced plant genomes. The comparison of fully sequenced genomes allows for identification of new gene family members, as well as comprehensive analysis of gene family evolution. The aldehyde dehydrogenase (ALDH) gene superfamily comprises a group of enzymes involved in the NAD(+)- or NADP(+)-dependent conversion of various aldehydes to their corresponding carboxylic acids. ALDH enzymes are involved in processing many aldehydes that serve as biogenic intermediates in a wide range of metabolic pathways. In addition, many of these enzymes function as 'aldehyde scavengers' by removing reactive aldehydes generated during the oxidative degradation of lipid membranes, also known as lipid peroxidation. Plants and animals share many ALDH families, and many genes are highly conserved between these two evolutionarily distinct groups. Conversely, both plants and animals also contain unique ALDH genes and families. Herein we carried out genome-wide identification of ALDH genes in a number of plant species-including Arabidopsis thaliana (thale crest), Chlamydomonas reinhardtii (unicellular algae), Oryza sativa (rice), Physcomitrella patens (moss), Vitis vinifera (grapevine) and Zea mays (maize). These data were then combined with previous analysis of Populus trichocarpa (poplar tree), Selaginella moellindorffii (gemmiferous spikemoss), Sorghum bicolor (sorghum) and Volvox carteri (colonial algae) for a comprehensive evolutionary comparison of the plant ALDH superfamily. As a result, newly identified genes can be more easily analyzed and gene names can be assigned according to current nomenclature guidelines; our goal is to clarify previously confusing and conflicting names and classifications that might confound results and prevent accurate comparisons between studies. PMID:23007552

  18. Impact of chronic low to moderate alcohol consumption on blood lipid and heart energy profile in acetaldehyde dehydrogenase 2-deficient mice

    PubMed Central

    Fan, Fan; Cao, Quan; Wang, Cong; Ma, Xin; Shen, Cheng; Liu, Xiang-wei; Bu, Li-ping; Zou, Yun-zeng; Hu, Kai; Sun, Ai-jun; Ge, Jun-bo

    2014-01-01

    Aim: To investigate the roles of acetaldehyde dehydrogenase 2 (ALDH2), the key enzyme of ethanol metabolism, in chronic low to moderate alcohol consumption-induced heart protective effects in mice. Methods: Twenty-one male wild-type (WT) or ALDH2-knockout (KO) mice were used in this study. In each genotype, 14 animals received alcohol (2.5%, 5% and 10% in week 1–3, respectively, and 18% in week 4–7), and 7 received water for 7 weeks. After the treatments, survival rate and general characteristics of the animals were evaluated. Serum ethanol and acetaldehyde levels and blood lipids were measured. Metabolomics was used to characterize the heart and serum metabolism profiles. Results: Chronic alcohol intake decreased the survival rate of KO mice by 50%, and significantly decreased their body weight, but did not affect those of WT mice. Chronic alcohol intake significantly increased the serum ethanol levels in both WT and KO mice, but KO mice had significantly higher serum acetaldehyde levels than WT mice. Chronic alcohol intake significantly increased the serum HDL cholesterol levels in WT mice, and did not change the serum HDL cholesterol levels in KO mice. After chronic alcohol intake, WT and KO mice showed differential heart and serum metabolism profiles, including the 3 main energy substrate types (lipids, glucose and amino acids) and three carboxylic acid cycles. Conclusion: Low to moderate alcohol consumption increases HDL cholesterol levels and improves heart energy metabolism profile in WT mice but not in ALDH2-KO mice. Thus, preserved ALDH2 function is essential for the protective effect of low to moderate alcohol on the cardiovascular system. PMID:24998256

  19. Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1).

    PubMed

    Yang, Shyh-Ming; Yasgar, Adam; Miller, Bettina; Lal-Nag, Madhu; Brimacombe, Kyle; Hu, Xin; Sun, Hongmao; Wang, Amy; Xu, Xin; Nguyen, Kimloan; Oppermann, Udo; Ferrer, Marc; Vasiliou, Vasilis; Simeonov, Anton; Jadhav, Ajit; Maloney, David J

    2015-08-13

    Aldehyde dehydrogenases (ALDHs) metabolize reactive aldehydes and possess important physiological and toxicological functions in areas such as CNS, metabolic disorders, and cancers. Increased ALDH (e.g., ALDH1A1) gene expression and catalytic activity are vital biomarkers in a number of malignancies and cancer stem cells, highlighting the need for the identification and development of small molecule ALDH inhibitors. A new series of theophylline-based analogs as potent ALDH1A1 inhibitors is described. The optimization of hits identified from a quantitative high throughput screening (qHTS) campaign led to analogs with improved potency and early ADME properties. This chemotype exhibits highly selective inhibition against ALDH1A1 over ALDH3A1, ALDH1B1, and ALDH2 isozymes as well as other dehydrogenases such as HPGD and HSD17β4. Moreover, the pharmacokinetic evaluation of selected analog 64 (NCT-501) is also highlighted. PMID:26207746

  20. Acetaldehyde

    Integrated Risk Information System (IRIS)

    Acetaldehyde ; CASRN 75 - 07 - 0 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic Effec

  1. Eukaryotic aldehyde dehydrogenase (ALDH) genes: human polymorphisms, and recommended nomenclature based on divergent evolution and chromosomal mapping.

    PubMed

    Vasiliou, V; Bairoch, A; Tipton, K F; Nebert, D W

    1999-08-01

    As currently being performed with an increasing number of superfamilies, a standardized gene nomenclature system is proposed here, based on divergent evolution, using multiple alignment analysis of all 86 eukaryotic aldehyde dehydrogenase (ALDH) amino-acid sequences known at this time. The ALDHs represent a superfamily of NAD(P)(+)-dependent enzymes having similar primary structures that oxidize a wide spectrum of endogenous and exogenous aliphatic and aromatic aldehydes. To date, a total of 54 animal, 15 plant, 14 yeast, and three fungal ALDH genes or cDNAs have been sequenced. These ALDHs can be divided into a total of 18 families (comprising 37 subfamilies), and all nonhuman ALDH genes are named here after the established human ALDH genes, when possible. An ALDH protein from one gene family is defined as having approximately < or = 40% amino-acid identity to that from another family. Two members of the same subfamily exhibit approximately > or = 60% amino-acid identity and are expected to be located at the same subchromosomal site. For naming each gene, it is proposed that the root symbol 'ALDH' denoting 'aldehyde dehydrogenase' be followed by an Arabic number representing the family and, when needed, a letter designating the subfamily and an Arabic number denoting the individual gene within the subfamily; all letters are capitalized in all mammals except mouse and fruit fly, e.g. 'human ALDH3A1 (mouse, Drosophila Aldh3a1).' It is suggested that the Human Gene Nomenclature Guidelines (http://++www.gene.ucl.ac.uk/nomenclature/guidelines.h tml) be used for all species other than mouse and Drosophila. Following these guidelines, the gene is italicized, whereas the corresponding cDNA, mRNA, protein or enzyme activity is written with upper-case letters and without italics, e.g. 'human, mouse or Drosophila ALDH3A1 cDNA, mRNA, or activity'. If an orthologous gene between species cannot be identified with certainty, sequential naming of these genes will be carried out

  2. Pepper aldehyde dehydrogenase CaALDH1 interacts with Xanthomonas effector AvrBsT and promotes effector-triggered cell death and defence responses.

    PubMed

    Kim, Nak Hyun; Hwang, Byung Kook

    2015-06-01

    Xanthomonas type III effector AvrBsT induces hypersensitive cell death and defence responses in pepper (Capsicum annuum) and Nicotiana benthamiana. Little is known about the host factors that interact with AvrBsT. Here, we identified pepper aldehyde dehydrogenase 1 (CaALDH1) as an AvrBsT-interacting protein. Bimolecular fluorescence complementation and co-immunoprecipitation assays confirmed the interaction between CaALDH1 and AvrBsT in planta. CaALDH1:smGFP fluorescence was detected in the cytoplasm. CaALDH1 expression in pepper was rapidly and strongly induced by avirulent Xanthomonas campestris pv. vesicatoria (Xcv) Ds1 (avrBsT) infection. Transient co-expression of CaALDH1 with avrBsT significantly enhanced avrBsT-triggered cell death in N. benthamiana leaves. Aldehyde dehydrogenase activity was higher in leaves transiently expressing CaALDH1, suggesting that CaALDH1 acts as a cell death enhancer, independently of AvrBsT. CaALDH1 silencing disrupted phenolic compound accumulation, H2O2 production, defence response gene expression, and cell death during avirulent Xcv Ds1 (avrBsT) infection. Transgenic Arabidopsis thaliana overexpressing CaALDH1 exhibited enhanced defence response to Pseudomonas syringae pv. tomato and Hyaloperonospora arabidopsidis infection. These results indicate that cytoplasmic CaALDH1 interacts with AvrBsT and promotes plant cell death and defence responses. PMID:25873668

  3. Discovery of a series of aromatic lactones as ALDH1/2-directed inhibitors

    PubMed Central

    Buchman, Cameron D.; Mahalingan, Krishna K.; Hurley, Thomas D.

    2015-01-01

    In humans, the aldehyde dehydrogenase superfamily consists of 19 isoenzymes which mostly catalyze the NAD(P)+-dependent oxidation of aldehydes. Many of these isoenzymes have overlapping substrate specificities and therefore their potential physiological functions may overlap. Thus the development of new isoenyzme-selective probes would be able to better delineate the function of a single isoenyzme and its individual contribution to the metabolism of a particular substrate. This specific study was designed to find a novel modulator of ALDH2, a mitochondrial ALDH isoenzyme most well-known for its role in acetaldehyde oxidation. 53 compounds were initially identified to modulate the activity of ALDH2 by a high-throughput esterase screen from a library of 63,000 compounds. Of these initial 53 compounds, 12 were found to also modulate the oxidation of propionaldehyde by ALDH2. Single concentration measurements at 10 μM compound were performed using ALDH1A1, ALDH1A2, ALDH1A3, ALDH2, ALDH1B1, ALDH3A1, ALDH4A1, and/or ALDH5A1 to determine the selectivity of these 12 compounds towards ALDH2. Four of the twelve compounds shared an aromatic lactone structure and were found to be potent inhibitors of the ALDH1/2 isoenzymes, but have no inhibitory effect on ALDH3A1, ALDH4A1 or ALDH5A1. Two of the aromatic lactones show selectivity within the ALDH1/2 class, and one appears to be selective for ALDH2 compared to all other isoenzymes tested. PMID:25641190

  4. Androgen regulation of aldehyde dehydrogenase 1A3 (ALDH1A3) in androgen responsive human prostate cancer cell LNCaP.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previous gene array data from our laboratory identified the retinoic acid (RA) biosynthesis enzyme aldehyde dehydrogenase 1A3 (ALDH1A3) as a putative androgen-responsive gene in prostate cancer epithelial cells (LNCaP). In the present study we attempted to identify if any of the three ALDH1A/RA synt...

  5. Development of Selective Inhibitors for Human Aldehyde Dehydrogenase 3A1 (ALDH3A1) for the Enhancement of Cyclophosphamide Cytotoxicity

    PubMed Central

    Parajuli, Bibek; Georgiadis, Taxiarchis M.; Fishel, Melissa L.; Hurley, Thomas D.

    2014-01-01

    Aldehyde dehydrogenase 3A1 (ALDH3A1) plays an important role in many cellular oxidative processes, including cancer chemo-resistance by metabolizing activated forms of oxazaphosphorine drugs such as cyclophosphamide (CP) and its analogues such as mafosfamide (MF), ifosfamide (IFM), 4-hydroperoxycyclophosphamide (4-HPCP). Compounds that can selectively target ALDH3A1 may permit delineation of its roles in these processes and could restore chemosensitivity in cancer cells that express this isoenzyme. Here we report the detailed kinetic and structural characterization of an ALDH3A1 selective inhibitor, CB29, previously identified in a high throughput screen. Kinetic and crystallographic studies demonstrate that CB29 binds within the aldehyde substrate-binding site of ALDH3A1. Cellular proliferation of ALDH3A1-expressing lung adenocarcinoma (A549) and glioblastoma (SF767) cell lines, as well as the ALDH3A1 non-expressing lung fibroblast cells, CCD-13Lu, is unaffected by treatment with CB29 and its analogues alone. However, the sensitivity toward the anti-proliferative effects of mafosfamide is enhanced by treatment with CB29 and its analogue in the tumour cells. In contrast, the sensitivity of CCD-13Lu cells toward mafosfamide was unaffected by the addition of these same compounds. CB29 is chemically distinct from the previously reported small molecule inhibitors of ALDH isoenzymes and does not inhibit ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1 or ALDH2 isoenzymes at concentrations up to 250 μM. Thus, CB29 is a novel small molecule inhibitor of ALDH3A1, which may be useful as a chemical tool to delineate the role of ALDH3A1 in numerous metabolic pathways, including sensitizing ALDH3A1-positive cancer cells to oxazaphosphorines. PMID:24677340

  6. Effects of acetaldehyde on brush border enzyme activities in human colon adenocarcinoma cell line Caco-2.

    PubMed

    Koivisto, T; Salaspuro, M

    1997-12-01

    The treatment of Caco-2 cells, a human colon adenocarcinoma cell line that closely resembles normal human small intestinal epithelial cells, with acetaldehyde resulted in significantly decreased activities of brush border enzymes sucrase, maltase, lactase, and gamma-glutamyltransferase; alkaline phosphatase activity was not affected. In the case of sucrase and maltase, the activities were also decreased by a combination of acetaldehyde and ethanol, although ethanol alone markedly increased them. The possibility that intraintestinal acetaldehyde, formed by intestinal microbes, might play a role in some small intestinal enzyme deficiencies observed earlier in alcoholics should therefore be considered. The mechanism by which acetaldehyde alters these enzyme activities remains unclear. The observation that acetaldehyde also disturbed cell polarization, an initial step in the process of differentiation in Caco-2 cells, indicates that acetaldehyde might decrease these enzyme activities by interfering with cell differentiation. Because ethanol and acetaldehyde metabolizing enzymes have not been previously studied from Caco-2 cells, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activities were also measured from these cells, and their ALDH isoenzyme pattern was characterized. Like many cancerous cell lines, Caco-2 cells were found to express no ADH. They, however, possessed ALDH activity that was comparable with normal colonic mucosal activity and also expressed the same ALDH classes (ALDHs 1 to 3) than normal human colonic mucosa. PMID:9438518

  7. Ectopic overexpression of the aldehyde dehydrogenase ALDH21 from Syntrichia caninervis in tobacco confers salt and drought stress tolerance.

    PubMed

    Yang, Honglan; Zhang, Daoyuan; Li, Haiyan; Dong, Lingfeng; Lan, Haiyan

    2015-10-01

    Aldehyde dehydrogenases are important enzymes that play vital roles in mitigating oxidative/electrophilic stress when plants are exposed to environmental stress. An aldehyde dehydrogenase gene from Syntrichia caninervis, ScALDH21, was introduced into tobacco using Agrobacterium-mediated transformation to generate ScALDH21-overexpressing tobacco plants to investigate its effect on drought and salt resistance. Detached leaves from ScALDH21-overexpressing tobacco plants showed less water loss than those from nontransgenic plants. When subjected to drought and salt stress, transgenic plants displayed higher germination ratios, higher root lengths, greater fresh weight, higher proline accumulation, lower malondialdehyde (MDA) contents and stronger photosynthetic capacities, as well as higher activities of antioxidant enzymes, i.e., superoxide dismutase, catalase and peroxidase, compared with control plants. Therefore, ScALDH21 overexpression in transgenic tobacco plants can enhance drought and salt tolerance and can be used as a candidate gene for the molecular breeding of salt- and drought-tolerant plants. PMID:26202169

  8. Tryptophan in Alcoholism Treatment II:  Inhibition of the Rat Liver Mitochondrial Low Km Aldehyde Dehydrogenase Activity, Elevation of Blood Acetaldehyde Concentration and Induction of Aversion to Alcohol by Combined Administration of Tryptophan and Benserazide

    PubMed Central

    Badawy, Abdulla A.-B.; Bano, Samina; Steptoe, Alex

    2011-01-01

    Aims: The aims were to provide proofs of mechanism and principle by establishing the ability of the amino acid L-tryptophan (Trp) combined with the kynureninase inhibitor benserazide (BSZ) to inhibit the liver mitochondrial low Km aldehyde dehydrogenase (ALDH) activity after administration and in vivo and to induce aversion to alcohol. Methods: Trp, BSZ or both were administered to male Wistar rats and ALDH activity was determined both in vitro in liver homogenates and in vivo (by measuring acetaldehyde accumulation in blood after ethanol administration). Alcohol consumption was studied in an aversion model in rats and in alcohol-preferring C57 mice. Results: Combined administration of Trp + BSZ, but neither compound alone, produced a strong inhibition of ALDH activity and an increase in blood acetaldehyde concentration after ethanol, and induced aversion to alcohol in rats and decreased preference in mice. Another kynureninase inhibitor, carbidopa, induced aversion to alcohol by itself, which was reversed by Trp co-administration. Conclusions: The present results establish a prior art for the use of a combination of Trp plus BSZ in the treatment of alcoholism by aversion, which merits rapid clinical development. PMID:21896551

  9. Aldehyde Dehydrogenase 2 (ALDH2) Polymorphism and the Risk of Alcoholic Liver Cirrhosis among East Asians: A Meta-Analysis

    PubMed Central

    He, Lei; Luo, Hesheng

    2016-01-01

    Purpose The aldehyde dehydrogenase 2 (ALDH2) gene has been implicated in the development of alcoholic liver cirrhosis (ALC) in East Asians. However, the results are inconsistent. In this study, a meta-analysis was performed to assess the associations between the ALDH2 polymorphism and the risk of ALC. Materials and Methods Relevant studies were retrieved by searching PubMed, Web of Science, CNKI, Wanfang and Veipu databases up to January 10, 2015. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using either the fixed- or random effects model. Results A total of twelve case-control studies included 1003 cases and 2011 controls were included. Overall, the ALDH2 polymorphism was associated with a decreased risk of ALC (*1/*2 vs. *1/*1: OR=0.78, 95% CI: 0.61–0.99). However, in stratification analysis by country, we failed to detect any association among Chinese, Korean or Japanese populations. Conclusion The pooled evidence suggests that ALDH2 polymorphism may be an important protective factor for ALC in East Asians. PMID:27189280

  10. Aberrant expression of aldehyde dehydrogenase 1A (ALDH1A) subfamily genes in acute lymphoblastic leukaemia is a common feature of T-lineage tumours.

    PubMed

    Longville, Brooke A C; Anderson, Denise; Welch, Mathew D; Kees, Ursula R; Greene, Wayne K

    2015-01-01

    The class 1A aldehyde dehydrogenase (ALDH1A) subfamily of genes encode enzymes that function at the apex of the retinoic acid (RA) signalling pathway. We detected aberrant expression of ALDH1A genes, particularly ALDH1A2, in a majority (72%) of primary paediatric T cell acute lymphoblastic leukaemia (T-ALL) specimens. ALDH1A expression was almost exclusive to T-lineage, but not B-lineage, ALL. To determine whether ALDH1A expression may have relevance to T-ALL cell growth and survival, the effect of inhibiting ALDH1A function was measured on a panel of human ALL cell lines. This revealed that T-ALL proliferation had a higher sensitivity to modulation of ALDH1A activity and RA signalling as compared to ALL cell lines of B-lineage. Consistent with these findings, the genes most highly correlated with ALDH1A2 expression were involved in cell proliferation and apoptosis. Evidence that such genes may be targets of regulation via RA signalling initiated by ALDH1A activity was provided by the TNFRSF10B gene, encoding the apoptotic death receptor TNFRSF10B (also termed TRAIL-R2), which negatively correlated with ALDH1A2 and showed elevated transcription following treatment of T-ALL cell lines with the ALDH1A inhibitor citral (3,7-dimethyl-2,6-octadienal). These data indicate that ALDH1A expression is a common event in T-ALL and supports a role for these enzymes in the pathobiology of this disease. PMID:25208926

  11. ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis.

    PubMed

    Jin, Shengfang; Chen, Jiang; Chen, Lizao; Histen, Gavin; Lin, Zhizhong; Gross, Stefan; Hixon, Jeffrey; Chen, Yue; Kung, Charles; Chen, Yiwei; Fu, Yufei; Lu, Yuxuan; Lin, Hui; Cai, Xiujun; Yang, Hua; Cairns, Rob A; Dorsch, Marion; Su, Shinsan M; Biller, Scott; Mak, Tak W; Cang, Yong

    2015-07-21

    Mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the liver removes toxic aldehydes including acetaldehyde, an intermediate of ethanol metabolism. Nearly 40% of East Asians inherit an inactive ALDH2*2 variant, which has a lysine-for-glutamate substitution at position 487 (E487K), and show a characteristic alcohol flush reaction after drinking and a higher risk for gastrointestinal cancers. Here we report the characterization of knockin mice in which the ALDH2(E487K) mutation is inserted into the endogenous murine Aldh2 locus. These mutants recapitulate essentially all human phenotypes including impaired clearance of acetaldehyde, increased sensitivity to acute or chronic alcohol-induced toxicity, and reduced ALDH2 expression due to a dominant-negative effect of the mutation. When treated with a chemical carcinogen, these mutants exhibit increased DNA damage response in hepatocytes, pronounced liver injury, and accelerated development of hepatocellular carcinoma (HCC). Importantly, ALDH2 protein levels are also significantly lower in patient HCC than in peritumor or normal liver tissues. Our results reveal that ALDH2 functions as a tumor suppressor by maintaining genomic stability in the liver, and the common human ALDH2 variant would present a significant risk factor for hepatocarcinogenesis. Our study suggests that the ALDH2*2 allele-alcohol interaction may be an even greater human public health hazard than previously appreciated. PMID:26150517

  12. Daidzin suppresses ethanol consumption by Syrian golden hamsters without blocking acetaldehyde metabolism.

    PubMed Central

    Keung, W M; Lazo, O; Kunze, L; Vallee, B L

    1995-01-01

    Daidzin is a potent, selective, and reversible inhibitor of human mitochondrial aldehyde dehydrogenase (ALDH) that suppresses free-choice ethanol intake by Syrian golden hamsters. Other ALDH inhibitors, such as disulfiram (Antabuse) and calcium citrate carbimide (Temposil), have also been shown to suppress ethanol intake of laboratory animals and are thought to act by inhibiting the metabolism of acetaldehyde produced from ingested ethanol. To determine whether or not daidzin inhibits acetaldehyde metabolism in vivo, plasma acetaldehyde in daidzin-treated hamsters was measured after the administration of a test dose of ethanol. Daidzin treatment (150 mg/kg per day i.p. for 6 days) significantly suppresses (> 70%) hamster ethanol intake but does not affect overall acetaldehyde metabolism. In contrast, after administration of the same ethanol dose, plasma acetaldehyde concentration in disulfiram-treated hamsters reaches 0.9 mM, 70 times higher than that of the control. In vitro, daidzin suppresses hamster liver mitochondria-catalyzed acetaldehyde oxidation very potently with an IC50 value of 0.4 microM, which is substantially lower than the daidzin concentration (70 microM) found in the liver mitochondria of daidzin-treated hamsters. These results indicate that (i) the action of daidzin differs from that proposed for the classic, broad-acting ALDH inhibitors (e.g., disulfiram), and (ii) the daidzin-sensitive mitochondrial ALDH is not the one and only enzyme that is essential for acetaldehyde metabolism in golden hamsters. PMID:7568058

  13. Essential role of aldehyde dehydrogenase 1A3 (ALDH1A3) for the maintenance of non-small cell lung cancer stem cells is associated with the STAT3 pathway

    PubMed Central

    Shao, Chunli; Sullivan, James P.; Girard, Luc; Augustyn, Alexander; Yenerall, Paul; Rodriguez, Jaime; Liu, Hui; Behrens, Carmen; Shay, Jerry W.; Wistuba, Ignacio I.; Minna, John D.

    2014-01-01

    Purpose Lung cancer stem cells (CSCs) with elevated aldehyde dehydrogenase (ALDH) activity are self-renewing, clonogenic and tumorigenic. The purpose of our study is to elucidate the mechanisms by which lung CSCs are regulated. Experimental Design A genome-wide gene expression analysis was performed to identify genes differentially expressed in the ALDH+ vs. ALDH− cells. RT-PCR, western blot and Aldefluor assay were used to validate identified genes. To explore the function in CSCs we manipulated their expression followed by colony and tumor formation assays. Results We identified a subset of genes that were differentially expressed in common in ALDH+ cells, among which ALDH1A3 was the most upregulated gene in ALDH+ vs. ALDH− cells. ShRNA-mediated knockdown of ALDH1A3 in NSCLCs resulted in a dramatic reduction in ALDH activity, clonogenicity and tumorigenicity, indicating that ALDH1A3 is required for tumorigenic properties. By contrast, overexpression of ALDH1A3 by itself it was not sufficient to increase tumorigenicity. The ALDH+ cells also expressed more activated Signal Transducers and Activators of Transcription 3 (STAT3) than ALDH− cells. Inhibition of STAT3 or its activator EZH2 genetically or pharmacologically diminished the level of ALDH+ cells and clonogenicity. Unexpectedly, ALDH1A3 was highly expressed in female, never smokers, well differentiated tumors, or adenocarcinoma. ALDH1A3 low expression was associated with poor overall survival. Conclusion Our data show that ALDH1A3 is the predominant ALDH isozyme responsible for ALDH activity and tumorigenicity in most NSCLCs, and that inhibiting either ALDH1A3 or the STAT3 pathway are potential therapeutic strategies to eliminate the ALDH+ subpopulation in NSCLCs. PMID:24907115

  14. Human ALDH1B1 polymorphisms may affect the metabolism of acetaldehyde and all-trans retinaldehyde – in vitro studies and computational modeling

    PubMed Central

    Jackson, Brian C.; Reigan, Philip; Miller, Bettina; Thompson, David C.; Vasiliou, Vasilis

    2014-01-01

    Purpose To elucidate additional substrate specificities of ALDH1B1 and determine the effect that human ALDH1B1 polymorphisms will have on substrate specificity. Methods Computational-based molecular modeling was used to predict the binding of the substrates propionaldehyde, 4-hydroxynonenal, nitroglycerin, and all-trans retinaldehyde to ALDH1B1. Based on positive in silico results, the capacity of purified human recombinant ALDH1B1 to metabolize nitroglycerin and all-trans retinaldehyde was explored. Additionally, metabolism of 4-HNE by ALDH1B1 was revisited. Databases queried to find human polymorphisms of ALDH1B1 identified three major variants: ALDH1B1*2 (A86V), ALDH1B1*3 (L107R), and ALDH1B1*5 (M253V). Computational modeling was used to predict the binding of substrates and of cofactor (NAD+) to the variants. These human polymorphisms were created and expressed in a bacterial system and specific activity was determined. Results ALDH1B1 metabolizes (and appears to be inhibited by) nitroglycerin and has favorable kinetics for the metabolism of all-trans retinaldehyde. ALDH1B1 metabolizes 4-HNE with higher apparent affinity than previously described, but with low throughput. Recombinant ALDH1B1*2 is catalytically inactive, whereas both ALDH1B1*3 and ALDH1B1*5 are catalytically active. Modeling indicated that the lack of activity in ALDH1B1*2 is likely due to poor NAD+ binding. Modeling also suggests that ALDH1B1*3 may be less able to metabolize all-trans retinaldehyde and that ALDH1B1*5 may bind NAD+ poorly. Conclusions ALDH1B1 metabolizes nitroglycerin and all-trans-retinaldehyde. One of the three human polymorphisms, ALDH1B1*2, is catalytically inactive, likely due to poor NAD+ binding. Expression of this variant may affect ALDH1B1-dependent metabolic functions in stem cells and ethanol metabolism. PMID:25413692

  15. Replacement of the initial steps of ethanol metabolism in Saccharomyces cerevisiae by ATP-independent acetylating acetaldehyde dehydrogenase.

    PubMed

    Kozak, Barbara U; van Rossum, Harmen M; Niemeijer, Matthijs S; van Dijk, Marlous; Benjamin, Kirsten; Wu, Liang; Daran, Jean-Marc G; Pronk, Jack T; van Maris, Antonius J A

    2016-03-01

    In Saccharomyces cerevisiae ethanol dissimilation is initiated by its oxidation and activation to cytosolic acetyl-CoA. The associated consumption of ATP strongly limits yields of biomass and acetyl-CoA-derived products. Here, we explore the implementation of an ATP-independent pathway for acetyl-CoA synthesis from ethanol that, in theory, enables biomass yield on ethanol that is up to 40% higher. To this end, all native yeast acetaldehyde dehydrogenases (ALDs) were replaced by heterologous acetylating acetaldehyde dehydrogenase (A-ALD). Engineered Ald(-) strains expressing different A-ALDs did not immediately grow on ethanol, but serial transfer in ethanol-grown batch cultures yielded growth rates of up to 70% of the wild-type value. Mutations in ACS1 were identified in all independently evolved strains and deletion of ACS1 enabled slow growth of non-evolved Ald(-) A-ALD strains on ethanol. Acquired mutations in A-ALD genes improved affinity-Vmax/Km for acetaldehyde. One of five evolved strains showed a significant 5% increase of its biomass yield in ethanol-limited chemostat cultures. Increased production of acetaldehyde and other by-products was identified as possible cause for lower than theoretically predicted biomass yields. This study proves that the native yeast pathway for conversion of ethanol to acetyl-CoA can be replaced by an engineered pathway with the potential to improve biomass and product yields. PMID:26818854

  16. The ALDH2 genotype, alcohol intake, and liver-function biomarkers among Japanese male workers.

    PubMed

    Takeshita, T; Yang, X; Morimoto, K

    2000-06-01

    A highly prevalent, atypical genotype in low Km aldehyde dehydrogenase (ALDH2) may influence alcohol-induced liver injury because of higher production of acetaldehyde in the liver. In the present study, we examined relationships between the ALDH2 genotype, alcohol intake, and liver-function biomarkers among Japanese male workers. Study subjects were 385 male workers in a metal plant in Japan, who were free from hepatic viruses and did not have higher aminotransferase activities (<100). The subjects completed a questionnaire on alcohol drinking habits and other lifestyles. The ALDH2 genotype was determined by the PCR method followed by restriction-enzyme digestion. In the moderately and heavily drinking groups, those with ALDH2*1/*2 exhibited significantly lower levels than those with ALDH2*1/*1 for all three parameters of liver function, whereas no such differences were observed in the least-drinking group. Multiple linear-regression analysis, adjusting for age, obesity, and smoking habits, revealed that aspartate aminotransferase activity was positively associated with alcohol intake only in those with ALDH2*1/*1. On the other hand, alanine transferase activity was negatively associated with alcohol intake only in those with ALDH2*1/*2. The present study indicates that effects of alcohol intake on liver-function biomarkers are likely to be modified by the ALDH2 genotype in adult males. PMID:10942105

  17. Succinic Semialdehyde Dehydrogenase Deficiency in a Chinese Boy: A Novel ALDH5A1 Mutation With Severe Phenotype.

    PubMed

    Tay, Chee Geap; Ariffin, Hany; Yap, Sufin; Rahmat, Kartini; Sthaneshwar, Pavai; Ong, Lai Choo

    2015-06-01

    Succinic semialdehyde dehydrogenase deficiency is a rare autosomal recessive disorder affecting catabolism of the neurotransmitter gamma-aminobutyric acid (GABA), with a wide range of clinical phenotype. We report a Malaysian Chinese boy with a severe early onset phenotype due to a previously unreported mutation. Urine organic acid chromatogram revealed elevated 4-hydroxybutyric acid. Magnetic resonance imaging (MRI) of the brain demonstrated cerebral atrophy with atypical putaminal involvement. Molecular genetic analysis showed a novel homozygous 3-bp deletion at the ALDH5A1 gene c.1501_1503del (p.Glu501del). Both parents were confirmed to be heterozygotes for the p.Glu501del mutation. The clinical course was complicated by the development of subdural hemorrhage probably as a result of rocking the child to sleep for erratic sleep-wake cycles. This case illustrates the need to recognize that trivial or unintentional shaking of such children, especially in the presence of cerebral atrophy, can lead to subdural hemorrhage. PMID:25122112

  18. PKC-ALDH2 Pathway Plays a Novel Role in Adipocyte Differentiation

    PubMed Central

    Yu, Yu-Hsiang; Liao, Pei-Ru; Guo, Chien-Jung; Chen, Che-Hong; Mochly-Rosen, Daria; Chuang, Lee-Ming

    2016-01-01

    The ALDH2 gene encodes the mitochondrial aldehyde dehydrogenase 2 (ALDH2), a critical enzyme involved in ethanol clearance through acetaldehyde metabolism. ALDH2 also catalyzes the metabolism of other bioreactive aldehydes, including propionaldehyde, butyraldehyde, and 4-hydroxykenals (4-HNE). Increased levels of 4-HNE in adipose tissue positively correlate with obesity and insulin resistance. However, it remains unclear whether ALDH2 is involved in regulation of adipocyte differentiation. Here, we found that ALDH2 protein levels were lower in white adipose tissue of high-fat diet-fed mice and ob/ob mice relative to lean mice. Knockdown of ALDH2 expression in 3T3-L1 preadipocytes caused an increase in intracellular 4-HNE, thereby attenuated adipocyte differentiation. By contrast, an ALDH2 activator, Alda-1, significantly accelerated adipogenesis, which was accompanied by an increase in adipogenic gene expression. Consistently, adipogenesis was reduced when protein kinase C ε (PKCε), an ALDH2 phosphorylating activator, was silenced in 3T3-L1 preadipocytes, whereas treatment with a PKCε agonist in 3T3-L1 preadipocytes enhanced adipogenesis. Whole-genome microarray profiling of Alda-1-treated cells demonstrated several upregulated transcripts encoding proteins involved in metabolism and the majority of these transcripts are for proteins involved in PPAR signaling pathways. Furthermore, PKCε-ALDH2 interaction alleviates 4-HNE induced aberrant PPARγ regulation on adipogenesis. Taken together, these results demonstrate that ALDH2 activation enhances adipogenesis and signaling pathways involving PPARγ. Thus, activation of PKCε-ALDH2 regulatory axis may be a therapeutic target for treating obesity and type 2 diabetes. PMID:27575855

  19. PKC-ALDH2 Pathway Plays a Novel Role in Adipocyte Differentiation.

    PubMed

    Yu, Yu-Hsiang; Liao, Pei-Ru; Guo, Chien-Jung; Chen, Che-Hong; Mochly-Rosen, Daria; Chuang, Lee-Ming

    2016-01-01

    The ALDH2 gene encodes the mitochondrial aldehyde dehydrogenase 2 (ALDH2), a critical enzyme involved in ethanol clearance through acetaldehyde metabolism. ALDH2 also catalyzes the metabolism of other bioreactive aldehydes, including propionaldehyde, butyraldehyde, and 4-hydroxykenals (4-HNE). Increased levels of 4-HNE in adipose tissue positively correlate with obesity and insulin resistance. However, it remains unclear whether ALDH2 is involved in regulation of adipocyte differentiation. Here, we found that ALDH2 protein levels were lower in white adipose tissue of high-fat diet-fed mice and ob/ob mice relative to lean mice. Knockdown of ALDH2 expression in 3T3-L1 preadipocytes caused an increase in intracellular 4-HNE, thereby attenuated adipocyte differentiation. By contrast, an ALDH2 activator, Alda-1, significantly accelerated adipogenesis, which was accompanied by an increase in adipogenic gene expression. Consistently, adipogenesis was reduced when protein kinase C ε (PKCε), an ALDH2 phosphorylating activator, was silenced in 3T3-L1 preadipocytes, whereas treatment with a PKCε agonist in 3T3-L1 preadipocytes enhanced adipogenesis. Whole-genome microarray profiling of Alda-1-treated cells demonstrated several upregulated transcripts encoding proteins involved in metabolism and the majority of these transcripts are for proteins involved in PPAR signaling pathways. Furthermore, PKCε-ALDH2 interaction alleviates 4-HNE induced aberrant PPARγ regulation on adipogenesis. Taken together, these results demonstrate that ALDH2 activation enhances adipogenesis and signaling pathways involving PPARγ. Thus, activation of PKCε-ALDH2 regulatory axis may be a therapeutic target for treating obesity and type 2 diabetes. PMID:27575855

  20. Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain

    PubMed Central

    Zambelli, Vanessa O.; Gross, Eric R.; Chen, Che-Hong; Gutierrez, Vanessa P.; Cury, Yara; Mochly-Rosen, Daria

    2014-01-01

    Exogenous aldehydes can cause pain in animal models, suggesting that aldehyde dehydrogenase 2 (ALDH2), which metabolizes many aldehydes, may regulate nociception. To test this hypothesis, we generated a knock-in mouse with an inactivating point mutation in ALDH2 (ALDH2*2), which is also present in human ALDH2 of ~540 million East Asians. The ALDH2*1/*2 heterozygotic mice exhibited a larger response to painful stimuli than their wild-type littermates, and this heightened nociception was inhibited by an ALDH2-selective activator (Alda-1). No effect on inflammation per se was observed. Using a rat model, we then showed that nociception tightly correlated with ALDH activity (R2=0.90) and that reduced nociception was associated with less early growth response protein 1 (EGR1) in the spinal cord and less reactive aldehyde accumulation at the insult site (including acetaldehyde and 4-hydroxynonenal). Further, acetaldehyde and formalin-induced nociceptive behavior was greater in the ALDH2*1/*2 mice than wild-type mice. Finally, Alda-1 treatment was also beneficial when given even after the inflammatory agent was administered. Our data in rodent models suggest that the mitochondrial enzyme ALDH2 regulates nociception and could serve as a molecular target for pain control, with ALDH2 activators, such as Alda-1, as potential non-narcotic cardiac-safe analgesics. Furthermore, our results suggest a possible genetic basis for East Asians’ apparent lower pain tolerance. PMID:25163478

  1. Structural shifts of aldehyde dehydrogenase enzymes were instrumental for the early evolution of retinoid-dependent axial patterning in metazoans.

    PubMed

    Sobreira, Tiago J P; Marlétaz, Ferdinand; Simões-Costa, Marcos; Schechtman, Deborah; Pereira, Alexandre C; Brunet, Frédéric; Sweeney, Sarah; Pani, Ariel; Aronowicz, Jochanan; Lowe, Christopher J; Davidson, Bradley; Laudet, Vincent; Bronner, Marianne; de Oliveira, Paulo S L; Schubert, Michael; Xavier-Neto, José

    2011-01-01

    Aldehyde dehydrogenases (ALDHs) catabolize toxic aldehydes and process the vitamin A-derived retinaldehyde into retinoic acid (RA), a small diffusible molecule and a pivotal chordate morphogen. In this study, we combine phylogenetic, structural, genomic, and developmental gene expression analyses to examine the evolutionary origins of ALDH substrate preference. Structural modeling reveals that processing of small aldehydes, such as acetaldehyde, by ALDH2, versus large aldehydes, including retinaldehyde, by ALDH1A is associated with small versus large substrate entry channels (SECs), respectively. Moreover, we show that metazoan ALDH1s and ALDH2s are members of a single ALDH1/2 clade and that during evolution, eukaryote ALDH1/2s often switched between large and small SECs after gene duplication, transforming constricted channels into wide opened ones and vice versa. Ancestral sequence reconstructions suggest that during the evolutionary emergence of RA signaling, the ancestral, narrow-channeled metazoan ALDH1/2 gave rise to large ALDH1 channels capable of accommodating bulky aldehydes, such as retinaldehyde, supporting the view that retinoid-dependent signaling arose from ancestral cellular detoxification mechanisms. Our analyses also indicate that, on a more restricted evolutionary scale, ALDH1 duplicates from invertebrate chordates (amphioxus and ascidian tunicates) underwent switches to smaller and narrower SECs. When combined with alterations in gene expression, these switches led to neofunctionalization from ALDH1-like roles in embryonic patterning to systemic, ALDH2-like roles, suggesting functional shifts from signaling to detoxification. PMID:21169504

  2. Structural shifts of aldehyde dehydrogenase enzymes were instrumental for the early evolution of retinoid-dependent axial patterning in metazoans

    PubMed Central

    Sobreira, Tiago J. P.; Marlétaz, Ferdinand; Simões-Costa, Marcos; Schechtman, Deborah; Pereira, Alexandre C.; Brunet, Frédéric; Sweeney, Sarah; Pani, Ariel; Aronowicz, Jochanan; Lowe, Christopher J.; Davidson, Bradley; Laudet, Vincent; Bronner, Marianne; de Oliveira, Paulo S. L.; Schubert, Michael; Xavier-Neto, José

    2011-01-01

    Aldehyde dehydrogenases (ALDHs) catabolize toxic aldehydes and process the vitamin A-derived retinaldehyde into retinoic acid (RA), a small diffusible molecule and a pivotal chordate morphogen. In this study, we combine phylogenetic, structural, genomic, and developmental gene expression analyses to examine the evolutionary origins of ALDH substrate preference. Structural modeling reveals that processing of small aldehydes, such as acetaldehyde, by ALDH2, versus large aldehydes, including retinaldehyde, by ALDH1A is associated with small versus large substrate entry channels (SECs), respectively. Moreover, we show that metazoan ALDH1s and ALDH2s are members of a single ALDH1/2 clade and that during evolution, eukaryote ALDH1/2s often switched between large and small SECs after gene duplication, transforming constricted channels into wide opened ones and vice versa. Ancestral sequence reconstructions suggest that during the evolutionary emergence of RA signaling, the ancestral, narrow-channeled metazoan ALDH1/2 gave rise to large ALDH1 channels capable of accommodating bulky aldehydes, such as retinaldehyde, supporting the view that retinoid-dependent signaling arose from ancestral cellular detoxification mechanisms. Our analyses also indicate that, on a more restricted evolutionary scale, ALDH1 duplicates from invertebrate chordates (amphioxus and ascidian tunicates) underwent switches to smaller and narrower SECs. When combined with alterations in gene expression, these switches led to neofunctionalization from ALDH1-like roles in embryonic patterning to systemic, ALDH2-like roles, suggesting functional shifts from signaling to detoxification. PMID:21169504

  3. Exploring the evolutionary route of the acquisition of betaine aldehyde dehydrogenase activity by plant ALDH10 enzymes: implications for the synthesis of the osmoprotectant glycine betaine

    PubMed Central

    2014-01-01

    Background Plant ALDH10 enzymes are aminoaldehyde dehydrogenases (AMADHs) that oxidize different ω-amino or trimethylammonium aldehydes, but only some of them have betaine aldehyde dehydrogenase (BADH) activity and produce the osmoprotectant glycine betaine (GB). The latter enzymes possess alanine or cysteine at position 441 (numbering of the spinach enzyme, SoBADH), while those ALDH10s that cannot oxidize betaine aldehyde (BAL) have isoleucine at this position. Only the plants that contain A441- or C441-type ALDH10 isoenzymes accumulate GB in response to osmotic stress. In this work we explored the evolutionary history of the acquisition of BAL specificity by plant ALDH10s. Results We performed extensive phylogenetic analyses and constructed and characterized, kinetically and structurally, four SoBADH variants that simulate the parsimonious intermediates in the evolutionary pathway from I441-type to A441- or C441-type enzymes. All mutants had a correct folding, average thermal stabilities and similar activity with aminopropionaldehyde, but whereas A441S and A441T exhibited significant activity with BAL, A441V and A441F did not. The kinetics of the mutants were consistent with their predicted structural features obtained by modeling, and confirmed the importance of position 441 for BAL specificity. The acquisition of BADH activity could have happened through any of these intermediates without detriment of the original function or protein stability. Phylogenetic studies showed that this event occurred independently several times during angiosperms evolution when an ALDH10 gene duplicate changed the critical Ile residue for Ala or Cys in two consecutive single mutations. ALDH10 isoenzymes frequently group in two clades within a plant family: one includes peroxisomal I441-type, the other peroxisomal and non-peroxisomal I441-, A441- or C441-type. Interestingly, high GB-accumulators plants have non-peroxisomal A441- or C441-type isoenzymes, while low-GB accumulators

  4. Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application

    PubMed Central

    Koppaka, Vindhya; Thompson, David C.; Chen, Ying; Ellermann, Manuel; Nicolaou, Kyriacos C.; Juvonen, Risto O.; Petersen, Dennis; Deitrich, Richard A.; Hurley, Thomas D.

    2012-01-01

    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. PMID:22544865

  5. Single-dose ethanol administration downregulates expression of cytochrome p450 2E1 mRNA in aldehyde dehydrogenase 2 knockout mice.

    PubMed

    Matsumoto, Akiko; Kawamoto, Toshihiro; Horita, Mikako; Takahashi, Tatsuya; Isse, Toyohi; Oyama, Tsunehiro; Ichiba, Masayoshi

    2007-12-01

    The polymorphism of aldehyde dehydrogenase 2 (ALDH2), denoted ALDH2*2, is very common in East Asian origin. Acetaldehyde, an intermediate metabolite of ethanol, is metabolized very slowly in people with ALDH2*2 because the mutant ALDH2 protein lacks the activity of acetaldehyde metabolism. On the other hand, it is well established that one of the cytochrome P450 enzymes, CYP2E1, is an activator of carcinogens (e.g., nitorosamines) and a generator of oxidative stress, and it is shown that CYP2E1 was induced by ethanol via gene transcriptional regulation. In the present study, to examine the consequences of ALDH2 polymorphism on transcriptional regulation of CYP2E1 in liver tissue, Aldh2+/+ and Aldh2-/- mice were orally administered 5 g/kg body weight of ethanol and the levels of CYP2E1 mRNA in liver tissue then analyzed. The level of CYP2E1 mRNA 12h after the ethanol administration tended to be higher than the 0-h group in Aldh2+/+ mice, however, it was significantly lower than the 0-h group in Aldh2-/- mice. These findings suggest that single-dose ethanol administration downregulates the expression of cytochrome p450 2E1 mRNA in the presence of inactive ALDH2. PMID:17980998

  6. The impact of mitochondrial aldehyde dehydrogenase (ALDH2) activation by Alda-1 on the behavioral and biochemical disturbances in animal model of depression.

    PubMed

    Stachowicz, Aneta; Głombik, Katarzyna; Olszanecki, Rafał; Basta-Kaim, Agnieszka; Suski, Maciej; Lasoń, Władysław; Korbut, Ryszard

    2016-01-01

    The etiology of depression remains still unclear. Recently, it has been proposed, that mitochondrial dysfunction may be associated with development of mood disorders, such as depression, bipolar disorder and anxiety disorders. Mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme responsible for the detoxification of reactive aldehydes, is considered to exert protective function in mitochondria. We investigated the influence of Alda-1, a small-molecule activator of ALDH2, on depressive- and anxiety-like behaviors in an animal model of depression - the prenatally stressed rats - using behavioral, molecular and proteomic methods. Prolonged Alda-1 administration significantly increased the climbing time, tended to reduce the immobility time and increased the swimming time of the prenatally stressed rats in the forced swim test. Moreover, treatment of prenatally stressed rats with Alda-1 significantly increased number of entries into the open arms of the maze and the time spent therein, as assessed by elevated plus-maze test. Such actions were associated with reduction of plasma 4-HNE-protein content, decrease of TNF-α mRNA and increase of PGC-1α (regulator of mitochondrial biogenesis) mRNA level in the frontal cortex and hippocampus of the prenatally stressed rats as well as with normalization of peripheral immune parameters and significant changes in expression of 6 and 4 proteins related to mitochondrial functions in the frontal cortex and hippocampus, respectively. Collectively, ALDH2 activation by Alda-1 led to a significant attenuation of depressive- and anxiety-like behaviors in the prenatally stressed rats. The pattern of changes suggested mitoprotective effect of Alda-1, however the exact functional consequences of the revealed alterations require further investigation. PMID:26254233

  7. A PBPK MODEL FOR EVALUATING THE IMPACT OF ALDEHYDE DEHYDROGENASE POLYMORPHISMS ON COMPARATIVE RAT AND HUMAN NASAL TISSUE ACETALDEHYDE DOSIMETRY

    EPA Science Inventory

    ABSTRACT: Acetaldehyde is an important intermediate in chemical synthesis and a byproduct of normal oxidative metabolism of several industrially important compounds including ethanol, ethyl acetate and vinyl acetate. Chronic inhalation of acetaldehyde leads to degeneratio...

  8. A PBPK model for evaluating the impact of aldehyde dehydrogenase polymorphisms on comparative rat and human nasal tissue acetaldehyde dosimetry*

    EPA Science Inventory

    Acetaldehyde is an important intermediate in the chemical synthesis and normal oxidative metabolism of several industrially important compounds, including ethanol, ethyl acetate, and vinyl acetate. Chronic inhalation of acetaldehyde leads to degeneration of the olfactory and resp...

  9. Inhibition of mitochondrial aldehyde dehydrogenase by nitric oxide-mediated S-nitrosylation

    PubMed Central

    Moon, Kwan-Hoon; Kim, Bong-Jo; Song, Byoung J.

    2005-01-01

    Mitochondrial aldehyde dehydrogenase (ALDH2) is responsible for the metabolism of acetaldehyde and other toxic lipid aldehydes. Despite many reports about the inhibition of ALDH2 by toxic chemicals, it is unknown whether nitric oxide (NO) can alter the ALDH2 activity in intact cells or in vivo animals. The aim of this study was to investigate the effects of NO on ALDH2 activity in H4IIE-C3 rat hepatoma cells. NO donors such as S-nitrosoglutathione (GSNO), S-nitroso-N-acetylpenicillamine, and 3-morpholinosydnonimine significantly increased the nitrite concentration while they inhibited the ALDH2 activity. Addition of GSH-ethylester (GSH-EE) completely blocked the GSNO-mediated ALDH2 inhibition and increased nitrite concentration. To directly demonstrate the NO-mediated S-nitrosylation and inactivation, ALDH2 was immunopurified from control or GSNO-treated cells and subjected to immunoblot analysis. The anti-nitrosocysteine antibody recognized the immunopurified ALDH2 only from the GSNO-treated samples. All these results indicate that S-nitrosylation of ALDH2 in intact cells leads to reversible inhibition of ALDH2 activity. PMID:16242127

  10. The thiocarbamate disulphide drug, disulfiram induces osteopenia in rats by inhibition of osteoblast function due to suppression of acetaldehyde dehydrogenase activity.

    PubMed

    Mittal, Monika; Khan, Kainat; Pal, Subhashis; Porwal, Konica; China, Shyamsundar Pal; Barbhuyan, Tarun K; Baghel, Khemraj S; Rawat, Tara; Sanyal, Sabyasachi; Bhadauria, Smrati; Sharma, Vishnu L; Chattopadhyay, Naibedya

    2014-05-01

    Dithiocarbamates (DTC), a sulfhydryl group containing compounds, are extensively used by humans that include metam and thiram due to their pesticide properties, and disulfiram (DSF) as an alcohol deterrent. We screened these DTC in an osteoblast viability assay. DSF exhibited the highest cytotoxicity (IC50 488nM). Loss in osteoblast viability and proliferation was due to induction of apoptosis via G1 arrest. DSF treatment to osteoblasts reduced glutathione (GSH) levels and exogenous addition of GSH prevented DSF-induced reactive oxygen species generation and osteoblast apoptosis. DSF also inhibited osteoblast differentiation in vitro and in vivo, and the effect was associated with inhibition of aldehyde dehydrogenase (ALDH) activity. Out of various ALDH isozymes, osteoblasts expressed only ALDH2 and DSF downregulated its transcript as well as activity. Alda-1, a specific activator of ALDH2, stimulated osteoblast differentiation. Subcutaneous injection of DSF over the calvarium of new born rats reduced the differentiation phenotype of calvarial osteoblasts but increased the mRNA levels of Runx-2 and osteocalcin. DSF treatment at a human-equivalent dose of 30 mg/kg p.o. to adult Sprague Dawley rats caused trabecular osteopenia and suppressed the formation of mineralized nodule by bone marrow stromal cells. Moreover, DSF diminished bone regeneration at the fracture site. In growing rats, DSF diminished growth plate height, primary and secondary spongiosa, mineralized osteoid and trabecular strength. Substantial decreased bone formation was also observed in the cortical site of these rats. We conclude that DSF has a strong osteopenia inducing effect by impairing osteoblast survival and differentiation due to the inhibition of ALDH2 function. PMID:24496638

  11. Refined Geographic Distribution of the Oriental ALDH2*504Lys (nee 487Lys) Variant

    PubMed Central

    Li, Hui; Borinskaya, Svetlana; Yoshimura, Kimio; Kal’ina, Nina; Marusin, Andrey; Stepanov, Vadim A.; Qin, Zhendong; Khaliq, Shagufta; Lee, Mi-Young; Yang, Yajun; Mohyuddin, Aisha; Gurwitz, David; Mehdi, Syed Qasim; Rogaev, Evgeny; Jin, Li; Yankovsky, Nikolay K.; Kidd, Judith R.; Kidd, Kenneth K.

    2010-01-01

    Summary Mitochondrial aldehyde dehydrogenase (ALDH2) is one of the most important enzymes in human alcohol metabolism. The oriental ALDH2*504Lys variant functions as a dominant negative greatly reducing activity in heterozygotes and abolishing activity in homozygotes. This allele is associated with serious disorders such as alcohol liver disease, late onset Alzheimer disease, colorectal cancer, and esophageal cancer, and is best known for protection against alcoholism. Many hundreds of papers in various languages have been published on this variant, providing allele frequency data for many different populations. To develop a highly refined global geographic distribution of ALDH2*504Lys, we have collected new data on 4,091 individuals from 86 population samples and assembled published data on a total of 80,691 individuals from 366 population samples. The allele is essentially absent in all parts of the world except East Asia. The ALDH2*504Lys allele has its highest frequency in Southeast China, and occurs in most areas of China, Japan, Korea, Mongolia, and Indochina with frequencies gradually declining radially from Southeast China. As the indigenous populations in South China have much lower frequencies than the southern Han migrants from Central China, we conclude that ALDH2*504Lys was carried by Han Chinese as they spread throughout East Asia. Esophageal cancer, with its highest incidence in East Asia, may be associated with ALDH2*504Lys because of a toxic effect of increased acetaldehyde in the tissue where ingested ethanol has its highest concentration. While the distributions of esophageal cancer and ALDH2*504Lys do not precisely correlate, that does not disprove the hypothesis. In general the study of fine scale geographic distributions of ALDH2*504Lys and diseases may help in understanding the multiple relationships among genes, diseases, environments, and cultures. PMID:19456322

  12. Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant

    SciTech Connect

    Perez-Miller, Samantha; Younus, Hina; Vanam, Ram; Chen, Che-Hong; Mochly-Rosen, Daria; Hurley, Thomas D.

    2010-04-19

    In approximately one billion people, a point mutation inactivates a key detoxifying enzyme, aldehyde dehydrogenase (ALDH2). This mitochondrial enzyme metabolizes toxic biogenic and environmental aldehydes, including the endogenously produced 4-hydroxynonenal (4HNE) and the environmental pollutant acrolein, and also bioactivates nitroglycerin. ALDH2 is best known, however, for its role in ethanol metabolism. The accumulation of acetaldehyde following the consumption of even a single alcoholic beverage leads to the Asian alcohol-induced flushing syndrome in ALDH2*2 homozygotes. The ALDH2*2 allele is semidominant, and heterozygotic individuals show a similar but less severe phenotype. We recently identified a small molecule, Alda-1, that activates wild-type ALDH2 and restores near-wild-type activity to ALDH2*2. The structures of Alda-1 bound to ALDH2 and ALDH2*2 reveal how Alda-1 activates the wild-type enzyme and how it restores the activity of ALDH2*2 by acting as a structural chaperone.

  13. Fructophilic characteristics of Fructobacillus spp. may be due to the absence of an alcohol/acetaldehyde dehydrogenase gene (adhE).

    PubMed

    Endo, Akihito; Tanaka, Naoto; Oikawa, Yo; Okada, Sanae; Dicks, Leon

    2014-04-01

    Fructophilic strains of Leuconostoc spp. have recently been reclassified to a new genus, i.e., Fructobacillus. Members of the genus are differentiated from Leuconostoc spp. by their preference for fructose on growth, requirement of an electron acceptor for glucose metabolism, and the inability to produce ethanol from the fermentation of glucose. In the present study, enzyme activities and genes involved in ethanol production were studied, since this is the key pathway for NAD(+)/NADH cycling in heterofermentative lactic acid bacteria. Fructobacillus spp. has a weak alcohol dehydrogenase activity and has no acetaldehyde dehydrogenase activity, whereas both enzymes are active in Leuconostoc mesenteroides. The bifunctional alcohol/acetaldehyde dehydrogenase gene, adhE, was described in Leuconostoc spp., but not in Fructobacillus spp. These results suggested that, due to the deficiency of the adhE gene, the normal pathway for ethanol production is absent in Fructobacillus spp. This leads to a shortage of NAD(+), and the requirement for an electron acceptor in glucose metabolism. Fructophilic characteristics, as observed for Fructobacillus spp., are thus due to the absence of the adhE gene, and a phenotype that most likely evolved as a result of regressive evolution. PMID:24352296

  14. ADH and ALDH polymorphisms and alcohol dependence in Mexican and Native Americans

    PubMed Central

    Ehlers, Cindy L.; Liang, Tiebing; Gizer, Ian R.

    2012-01-01

    Background Ethanol is primarily metabolized in the liver by 2 rate-limiting reactions: conversion of ethanol to acetaldehyde by alcohol dehydrogenase (ADH) and subsequent conversion of acetaldehyde to acetate by aldehyde dehydrogenase (ALDH). ADH and ALDH exist in multiple isozymes that differ in their kinetic properties. Notably, polymorphisms within the genes that encode for these isozymes vary in their allele frequencies between ethnic groups, and thus, they have been considered as candidate genes that may differentially influence risk for the development of alcohol dependence across ethnic groups. Objectives and Methods Associations between alcohol dependence and polymorphisms in ADH1B, ADH1C, and ALDH2, were compared in a community sample of Native Americans living on reservations (n=791) and Mexican Americans (n=391) living within the same county. Results Two Mexican Americans and no Native Americans possessed one ALDH2*2 allele. Presence of at least one ADH1B*2 allele was found in 7% of the Native Americans and 13% of the Mexican Americans, but was only associated with protection against alcohol dependence in the Mexican Americans. Presence of at least one ADH1B*3 allele was found in 4% if the Native Americans and 2% of the Mexican Americans, but was associated with protection against alcohol dependence only in the Native Americans. No associations between alcohol dependence and polymorphisms in ADH1C were found. Conclusions and Scientific Significance Polymorphisms in ADH1B are protective against alcoholism in these two populations; however, these findings do not explain the high prevalence of alcoholism in these populations. PMID:22931071

  15. Fatal acute alcohol intoxication in an ALDH2 heterozygote: a case report.

    PubMed

    Yamamoto, H; Tanegashima, A; Hosoe, H; Fukunaga, T

    2000-08-14

    On an evening in November, a 25-year-old man was found dead in his bedroom. There were many empty snap-out sheets for flunitrazepam tablets in the trash at his bedside. He had been beaten by a gang of young people earlier in the morning of the same day. At the medico-legal autopsy, although there were many bruises and/or abrasions on the whole body, only slight subdural hemorrhage was observed, and none of them was thought to be the cause of death. Flunitrazepam and its metabolites were not detected in his body fluid by gas chromatography-mass spectrometry (GC-MS). Marked lung edema and a severe congestion of organs were observed. His blood alcohol concentration from the femoral vein was 2.00 mg/ml. Fatal cases of acute alcohol intoxication usually have shown higher alcohol concentration (2.25-6.23 mg/ml). Although the genotype of aldehyde dehydrogenase 2 (ALDH2) has not previously been mentioned as a contributing factor in determining the cause of death, in this case the genotype of ALDH2 was ALDH2*1/2 and thus is important. Those who possess the ALDH2*2 gene show high concentrations of acetaldehyde (AcH) at even comparatively lower alcohol levels. Consequently, the cause of death was considered to be acute alcohol intoxication including AcH poisoning. PMID:10940605

  16. ALDH2 attenuates Dox-induced cardiotoxicity by inhibiting cardiac apoptosis and oxidative stress

    PubMed Central

    Gao, Yawen; Xu, Yan; Hua, Songwen; Zhou, Shenghua; Wang, Kangkai

    2015-01-01

    The anthracycline chemotherapy drug doxorubicin (DOX) is cardiotoxic. This study aimed to explore the effect of acetaldehyde dehydrogenase 2 (ALDH2), a detoxifying protein, on DOX-induced cardiotoxicity and unveil the underlying mechanisms. BALB/c mice were randomly divided in four groups: control group (no treatment), DOX group (DOX administration for myocardial damage induction), DOX + Daidzin group (DOX administration + Daidzin, an ALDH2 antagonist) and DOX + Alda-1 group (DOX administration + Alda-1, an ALDH2 agonist). Then, survival, haemodynamic parameters, expression of pro- and anti-apoptosis markers, reactive oxygen species (ROS) and 4-Hydroxynonenal (4-HNE) levels, expression and localization of NADPH oxidase 2 (NOX2) and its cytoplasmic subunit p47PHOX, and ALDH2 expression and activity were assessed. Mortality rates of 0, 35, 5, and 70% were obtained in the control, DOX, DOX + Alda-1, and DOX + Daidzin groups, respectively, at the ninth weekend. Compared with control animals, DOX treatment resulted in significantly reduced left ventricular systolic pressure (LVSP) and ± dp/dt, and overtly increased left ventricular end-diastolic pressure (LVEDP); increased Bax expression and caspase-3/7 activity, and reduced Bcl-2 expression in the myocardium; increased ROS (about 2 fold) and 4-HNE adduct (3 fold) levels in the myocardium; increased NOX2 protein expression and membrane translocation of P47PHOX. These effects were aggravated in the DOX + Daidzin group, DOX + Alda-1 treated animals showed partial or complete alleviation. Finally, Daidzin further reduced the DOX-repressed ALDH2 activity, which was partially rescued by Alda-1. These results indicated that ALDH2 attenuates DOX-induced cardiotoxicity by inhibiting oxidative stress, NOX2 expression and activity, and reducing myocardial apoptosis. PMID:26221217

  17. Impaired Regulation of ALDH2 Protein Expression Revealing a Yet Unknown Epigenetic Impact of rs886205 on Specific Methylation of a Negative Regulatory Promoter Region in Alcohol-Dependent Patients.

    PubMed

    Haschemi Nassab, Mani; Rhein, Mathias; Hagemeier, Lars; Kaeser, Marius; Muschler, Marc; Glahn, Alexander; Pich, Andreas; Heberlein, Annemarie; Kornhuber, Johannes; Bleich, Stefan; Frieling, Helge; Hillemacher, Thomas

    2016-01-01

    Acetaldehyde, the carcinogenic metabolite of ethanol known to provoke aversive symptoms of alcohol consumption, is predominantly eliminated by aldehyde dehydrogenase 2 (ALDH2). Reduced ALDH2 activity correlates with low alcohol tolerance and low risk for alcohol dependence. The ALDH2 promoter polymorphism rs886205 (A>G) is associated with decreased promoter activity, but a molecular mechanism and allele-dependent ALDH2 protein expression has not been described yet. On the basis of allele-dependent epigenetic effects, we analyzed the rs886205 genotype, methylation rates of cytosine-phosphatidyl-guanine (CpG)-sites within a regulatory promoter region and ALDH2 protein levels in 82 alcohol-dependent patients during a 2-week withdrawal and compared them to 34 matched controls. Patients without the G-allele of rs886205 showed higher methylation of the promoter region than controls and readily adapted epigenetically as well as on protein level during withdrawal, while patients with the G-allele displayed retarded methylation readjustment and no change in ALDH2 protein levels. Our data provide novel insights into an unknown genetic-epigenetic interaction, revealing impaired ALDH2 protein expression in patients with the G-allele of rs886205. Additionally, we checked for an association between rs886205 and protection against alcohol dependence and found a trend association between the G-allele and protection against alcohol dependence that needs replication in a larger Caucasian cohort. PMID:26339786

  18. Aldehyde dehydrogenase type 2 activation by adenosine and histamine inhibits ischemic norepinephrine release in cardiac sympathetic neurons: mediation by protein kinase Cε.

    PubMed

    Robador, Pablo A; Seyedi, Nahid; Chan, Noel Yan-Ki; Koda, Kenichiro; Levi, Roberto

    2012-10-01

    During myocardial ischemia/reperfusion, lipid peroxidation leads to the formation of toxic aldehydes that contribute to ischemic dysfunction. Mitochondrial aldehyde dehydrogenase type 2 (ALDH2) alleviates ischemic heart damage and reperfusion arrhythmias via aldehyde detoxification. Because excessive norepinephrine release in the heart is a pivotal arrhythmogenic mechanism, we hypothesized that neuronal ALDH2 activation might diminish ischemic norepinephrine release. Incubation of cardiac sympathetic nerve endings with acetaldehyde, at concentrations achieved in myocardial ischemia, caused a concentration-dependent increase in norepinephrine release. A major increase in norepinephrine release also occurred when sympathetic nerve endings were incubated in hypoxic conditions. ALDH2 activation substantially reduced acetaldehyde- and hypoxia-induced norepinephrine release, an action prevented by inhibition of ALDH2 or protein kinase Cε (PKCε). Selective activation of G(i/o)-coupled adenosine A(1), A(3), or histamine H(3) receptors markedly inhibited both acetaldehyde- and hypoxia-induced norepinephrine release. These effects were also abolished by PKCε and/or ALDH2 inhibition. Moreover, A(1)-, A(3)-, or H(3)-receptor activation increased ALDH2 activity in a sympathetic neuron model (differentiated PC12 cells stably transfected with H(3) receptors). This action was prevented by the inhibition of PKCε and ALDH2. Our findings suggest the existence in sympathetic neurons of a protective pathway initiated by A(1)-, A(3)-, and H(3)-receptor activation by adenosine and histamine released in close proximity of these terminals. This pathway comprises the sequential activation of PKCε and ALDH2, culminating in aldehyde detoxification and inhibition of hypoxic norepinephrine release. Thus, pharmacological activation of PKCε and ALDH2 in cardiac sympathetic nerves may have significant protective effects by alleviating norepinephrine-induced life-threatening arrhythmias that

  19. Expression and prognostic value of the aldehyde dehydrogenase 1 (ALDH1) and N-myc downstream regulated gene 2 (NDRG2) as potential markers in human astrocytomas.

    PubMed

    Goudarzi, Peyman Karimi; Mehrabi, Farzad; Khoshnood, Reza Jalili; Bagheri, Ali Baradaran; Ahmadi, Koorosh; Yahaghi, Emad; Abdolhoseinpour, Hesam

    2016-05-01

    In this study, immunohistochemical analysis was used to evaluate the expression of ALDH1 and NDRG2 in astrocytoma tissue samples and normal brain tissues. ALDH1 protein staining displayed that AlDH1 expression was not detectable in eight astrocytoma tissues (8/36) and in all of normal brain tissues. There was a significant difference between ALDH1 expression and WHO grades (P = 0.03). Furthermore, no correlation was determined between expression levels of ALDH1 and other clinicopathological characteristics including age, sex, and tumor size. Immunohistochemistry showed that a high level of NDRG2 protein expression was markedly detected in normal brain tissues and expression of NDRG2 protein was significantly decreased in astrocytoma tissues. There was a significant association between pathological grading and NDRG2 expression level (P < 0.001, Table 1), but no correlation was determined between expression levels of NDRG2 and other clinicopathological characteristics including age, sex, and tumor size. We also obtained detailed follow-up data and evaluated the association of ALDH1/NDRG2 expressions with overall survival. Kaplan-Meier survival and log-rank analysis indicated that the patients with high proportion of ALDH1-positive cells and low proportion of NDRG2-positive had shorter overall survival (P < 0.001; P = 0.001). Univariate analysis indicated that the high proportion of ALDH1-positive cells (P < 0.001), the low proportion of NDRG2-positive cells (P = 0.009), and the advanced grade (P < 0.005) were markedly linked to the prognosis in patients. Furthermore, in the multivariate analysis, ALDH1 cells' expression (P = 0.012), low proportion of NDRG2-positive cells (P = 0.025), and advanced grade (P < 0.03) were linked to poor overall survival. Our results suggest that NDRG2 expression is related to decreased survival rates and NDRG2 may be a potential marker in the astrocytoma prognosis. NDRG2 may be a potential marker

  20. Glu504Lys Single Nucleotide Polymorphism of Aldehyde Dehydrogenase 2 Gene and the Risk of Human Diseases

    PubMed Central

    Zhao, Yan; Wang, Chuancai

    2015-01-01

    Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial enzyme that is known for its important role in oxidation and detoxification of ethanol metabolite acetaldehyde. ALDH2 also metabolizes other reactive aldehydes such as 4-hydroxy-2-nonenal and acrolein. The Glu504Lys single nucleotide polymorphism (SNP) of ALDH2 gene, which is found in approximately 40% of the East Asian populations, causes defect in the enzyme activity of ALDH2, leading to alterations in acetaldehyde metabolism and alcohol-induced “flushing” syndrome. Evidence suggests that ALDH2 Glu504Lys SNP is a potential candidate genetic risk factor for a variety of chronic diseases such as cardiovascular disease, cancer, and late-onset Alzheimer's disease. In addition, the association between ALDH2 Glu504Lys SNP and the development of these chronic diseases appears to be affected by the interaction between the SNP and lifestyle factors such as alcohol consumption as well as by the presence of other genetic variations. PMID:26491656

  1. Inhibition of human alcohol and aldehyde dehydrogenases by aspirin and salicylate: assessment of the effects on first-pass metabolism of ethanol.

    PubMed

    Lee, Shou-Lun; Lee, Yung-Pin; Wu, Min-Li; Chi, Yu-Chou; Liu, Chiu-Ming; Lai, Ching-Long; Yin, Shih-Jiun

    2015-05-01

    Previous studies have reported that aspirin significantly reduced the first-pass metabolism (FPM) of ethanol in humans thereby increasing adverse effects of alcohol. The underlying causes, however, remain poorly understood. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), principal enzymes responsible for metabolism of ethanol, are complex enzyme families that exhibit functional polymorphisms among ethnic groups and distinct tissue distributions. We investigated the inhibition profiles by aspirin and its major metabolite salicylate of ethanol oxidation by recombinant human ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2, ADH2, and ADH4, and acetaldehyde oxidation by ALDH1A1 and ALDH2, at pH 7.5 and 0.5 mM NAD(+). Competitive inhibition pattern was found to be a predominant type among the ADHs and ALDHs studied, although noncompetitive and uncompetitive inhibitions were also detected in a few cases. The inhibition constants of salicylate for the ADHs and ALDHs were considerably lower than that of aspirin with the exception of ADH1A that can be ascribed to a substitution of Ala-93 at the bottom of substrate pocket as revealed by molecular docking experiments. Kinetic inhibition equation-based simulations show at higher therapeutic levels of blood plasma salicylate (1.5 mM) that the decrease of activities at 2-10 mM ethanol for ADH1A/ADH2 and ADH1B2/ADH1B3 are predicted to be 75-86% and 31-52%, respectively, and that the activity decline for ALDH1A1 and ALDH2 at 10-50 μM acetaldehyde to be 62-73%. Our findings suggest that salicylate may substantially inhibit hepatic FPM of alcohol at both the ADH and ALDH steps when concurrent intaking aspirin. PMID:25772736

  2. Gene Expression Profiling of NF1-Associated and Sporadic Pilocytic Astrocytoma Identifies Aldehyde Dehydrogenase 1 Family, Member L1 (ALDH1L1) as an Underexpressed Candidate Biomarker in Aggressive Subtypes

    PubMed Central

    Rodriguez, Fausto J.; Giannini, Caterina; Asmann, Yan W.; Sharma, Mukesh K.; Perry, Arie; Tibbetts, Kathleen M.; Jenkins, Robert B.; Scheithauer, Bernd W.; Anant, Shrikant; Jenkins, Sarah; Eberhart, Charles G.; Sarkaria, Jann N.; Gutmann, David H.

    2009-01-01

    Pilocytic astrocytomas (PAs) are WHO grade I gliomas; they most often affect children and young adults and occur in patients with neurofibromatosis type 1 (NF-1). To identify genes that are differentially expressed in sporadic (S-PA) versus NF-1-associated PAs (NF1-PAs) and those that might reflect differences in clinical behavior, we performed gene expression profiling using Affymetrix U133 Plus2.0 GeneChip arrays in 36 S-PAs and 11 NF1-PAs. Thirteen genes were over-expressed and another 13 genes were under-expressed in NF1-associated PAs relative to S-PAs. Immunohistochemical studies performed on 103 tumors, representing 2 independently generated tissue microarrays, confirmed the differential expression of CUGBP2 (p = 0.0014), RANBP9 (p = 0.0075), ITGAV1 (p = 0.0001), and INFGR1 (p = 0.024) proteins. One of the underexpressed genes, aldehyde dehydrogenase 1 family, member L1 (ALDH1L1), was also reduced in clinically aggressive compared to typical PAs (p = 0.01) and in PAs with increased cellularity and necrosis. Furthermore, in an additional independent set of tumors, weak to absent ALDH1L1 expression was found in 13/18 (72%) clinically aggressive PAs, in 8/9 (89%) PAs with pilomyxoid features, in 7/10 (70%) PAs with anaplastic transformation and in 16/21 (76%) diffusely infiltrating astrocytomas of various grades. In summary, we have identified a molecular signature that distinguishes NF1-PA from S-PA, and found that ALDH1L1 underexpression is associated with aggressive histology and/or biological behavior. PMID:19018242

  3. Rice Aldehyde Dehydrogenase7 Is Needed for Seed Maturation and Viability1[W][OA

    PubMed Central

    Shin, Jun-Hye; Kim, Sung-Ryul; An, Gynheung

    2009-01-01

    Aldehyde dehydrogenases (ALDHs) catalyze the irreversible oxidation of a wide range of reactive aldehydes to their corresponding carboxylic acids. Although the proteins have been studied from various organisms and at different growth stages, their roles in seed development have not been well elucidated. We obtained T-DNA insertional mutants in OsALDH7, which is remarkably inducible by oxidative and abiotic stresses. Interestingly, endosperms from the osaldh7 null mutants accumulated brown pigments during desiccation and storage. Extracts from the mutant seeds showed a maximum absorbance peak at 360 nm, the wavelength that melanoidin absorbs. Under UV light, those extracts also exhibited much stronger fluorescence than the wild type, suggesting that the pigments are melanoidin. These pigments started to accumulate in the late seed developmental stage, the time when OsALDH7 expression began to increase significantly. Purified OsALDH7 protein showed enzyme activities to malondialdehyde, acetaldehyde, and glyceraldehyde. These results suggest that OsALDH7 is involved in removing various aldehydes formed by oxidative stress during seed desiccation. The mutant seeds were more sensitive to our accelerated aging treatment and accumulated more malondialdehyde than the wild type. These data imply that OsALDH7 plays an important role in maintaining seed viability by detoxifying the aldehydes generated by lipid peroxidation. PMID:19052152

  4. Novel dehydrogenase catalyzes oxidative hydrolysis of carbon-nitrogen double bonds for hydrazone degradation.

    PubMed

    Itoh, Hideomi; Suzuta, Tetsuya; Hoshino, Takayuki; Takaya, Naoki

    2008-02-29

    Hydrazines and their derivatives are versatile artificial and natural compounds that are metabolized by elusive biological systems. Here we identified microorganisms that assimilate hydrazones and isolated the yeast, Candida palmioleophila MK883. When cultured with adipic acid bis(ethylidene hydrazide) as the sole source of carbon, C. palmioleophila MK883 degraded hydrazones and accumulated adipic acid dihydrazide. Cytosolic NAD+- or NADP+-dependent hydrazone dehydrogenase (Hdh) activity was detectable under these conditions. The production of Hdh was inducible by adipic acid bis(ethylidene hydrazide) and the hydrazone, varelic acid ethylidene hydrazide, under the control of carbon catabolite repression. Purified Hdh oxidized and hydrated the C=N double bond of acetaldehyde hydrazones by reducing NAD+ or NADP+ to produce relevant hydrazides and acetate, the latter of which the yeast assimilated. The deduced amino acid sequence revealed that Hdh belongs to the aldehyde dehydrogenase (Aldh) superfamily. Kinetic and mutagenesis studies showed that Hdh formed a ternary complex with the substrates and that conserved Cys is essential for the activity. The mechanism of Hdh is similar to that of Aldh, except that it catalyzed oxidative hydrolysis of hydrazones that requires adding a water molecule to the reaction catalyzed by conventional Aldh. Surprisingly, both Hdh and Aldh from baker's yeast (Ald4p) catalyzed the Hdh reaction as well as aldehyde oxidation. Our findings are unique in that we discovered a biological mechanism for hydrazone utilization and a novel function of proteins in the Aldh family that act on C=N compounds. PMID:18096698

  5. Polymorphisms in Alcohol Metabolism Genes ADH1B and ALDH2, Alcohol Consumption and Colorectal Cancer

    PubMed Central

    Crous-Bou, Marta; Rennert, Gad; Cuadras, Daniel; Salazar, Ramon; Cordero, David; Saltz Rennert, Hedy; Lejbkowicz, Flavio; Kopelovich, Levy; Monroe Lipkin, Steven; Bernard Gruber, Stephen; Moreno, Victor

    2013-01-01

    Background Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included alcohol intake, which is mainly metabolized to acetaldehyde by alcohol dehydrogenase and further oxidized to acetate by aldehyde dehydrogenase; consequently, the role of genes in the alcohol metabolism pathways is of particular interest. The aim of this study is to analyze the association between SNPs in ADH1B and ALDH2 genes and CRC risk, and also the main effect of alcohol consumption on CRC risk in the study population. Methodology/Principal Findings SNPs from ADH1B and ALDH2 genes, included in alcohol metabolism pathway, were genotyped in 1694 CRC cases and 1851 matched controls from the Molecular Epidemiology of Colorectal Cancer study. Information on clinicopathological characteristics, lifestyle and dietary habits were also obtained. Logistic regression and association analysis were conducted. A positive association between alcohol consumption and CRC risk was observed in male participants from the Molecular Epidemiology of Colorectal Cancer study (MECC) study (OR = 1.47; 95%CI = 1.18-1.81). Moreover, the SNPs rs1229984 in ADH1B gene was found to be associated with CRC risk: under the recessive model, the OR was 1.75 for A/A genotype (95%CI = 1.21-2.52; p-value = 0.0025). A path analysis based on structural equation modeling showed a direct effect of ADH1B gene polymorphisms on colorectal carcinogenesis and also an indirect effect mediated through alcohol consumption. Conclusions/Significance Genetic polymorphisms in the alcohol metabolism pathways have a potential role in colorectal carcinogenesis, probably due to the differences in the ethanol metabolism and acetaldehyde oxidation of these enzyme variants. PMID:24282520

  6. Isoflurane Preconditioning Confers Cardioprotection by Activation of ALDH2

    PubMed Central

    Lang, Xiao-E; Wang, Xiong; Zhang, Ke-Rang; Lv, Ji-Yuan; Jin, Jian-Hua; Li, Qing-Shan

    2013-01-01

    The volatile anesthetic, isoflurane, protects the heart from ischemia/reperfusion (I/R) injury. Aldehyde dehydrogenase 2 (ALDH2) is thought to be an endogenous mechanism against ischemia-reperfusion injury possibly through detoxification of toxic aldehydes. We investigated whether cardioprotection by isoflurane depends on activation of ALDH2.Anesthetized rats underwent 40 min of coronary artery occlusion followed by 120 min of reperfusion and were randomly assigned to the following groups: untreated controls, isoflurane preconditioning with and without an ALDH2 inhibitor, the direct activator of ALDH2 or a protein kinase C (PKCε) inhibitor. Pretreatment with isoflurane prior to ischemia reduced LDH and CK-MB levels and infarct size, while it increased phosphorylation of ALDH2, which could be blocked by the ALDH2 inhibitor, cyanamide. Isolated neonatal cardiomyocytes were treated with hypoxia followed by reoxygenation. Hypoxia/reoxygenation (H/R) increased cardiomyocyte apoptosis and injury which were attenuated by isoflurane and forced the activation of ALDH2. In contrast, the effect of isoflurane-induced protection was almost abolished by knockdown of ALDH2. Activation of ALDH2 and cardioprotection by isoflurane were substantially blocked by the PKCε inhibitor. Activation of ALDH2 by mitochondrial PKCε plays an important role in the cardioprotection of isoflurane in myocardium I/R injury. PMID:23468836

  7. Alcohol dehydrogenases in Acinetobacter sp. strain HO1-N: role in hexadecanse and hexadecanol metabolism

    SciTech Connect

    Singer, M.E.; Finnerty, W.R.

    1985-12-01

    Multiple alcohol dehydrogenases (ADH) were demonstrated in Acinetobacter sp. strain HO1-N. ADH-A and ADH-B were distinguished on the basis of electrophoretic mobility, pyridine nucleotide cofactor requirement, and substrate specificity. ADH-A is a soluble, NAD-linked, inducible ethanol dehydrogenase (EDH). An ethanol-negative mutant (Eth1) was isolated which contained 6.5% of wild-type EDH activity and was deficient in ADH-A. Eth1 exhibited normal growth on hexadecane and hexadecanol. A second ethanol-negative mutant (Eth3) was acetaldehyde dehydrogenase (ALDH) deficient, having 12.5% of wild-type ALDH activity. Eth3 had threefold-higher EDH activity than the wild-type strain. ALDH is a soluble, NAD-linked, ethanol-inducible enzyme. Eth3 exhibited normal growth on hexadecane, hexadecanol, and fatty aldehyde. ADH-B is soluble, constitutive, NADP-linked ADH which was active with medium-chain-length alcohols. Hexadecanol dehydrogenase (HDH), a soluble and membrane-bound, NAD-linked ADH, was induced 5- to 11-fold by growth on hexadecane or hexadecanol. HDH was distinct from ADH-A and ADH-B. NAD-linked HDH appears to possess a functional role in hexadecane and hexadecanol dissimilation.

  8. The prognostic roles of ALDH1 isoenzymes in gastric cancer

    PubMed Central

    Li, Kai; Guo, Xiaoguang; Wang, Ziwei; Li, Xiaofeng; Bu, Youquan; Bai, Xuefeng; Zheng, Liansheng; Huang, Ying

    2016-01-01

    Increased aldehyde dehydrogenase 1 (ALDH1) activity has been determined to be present in the stem cells of several kinds of cancers including gastric cancer (GC). Nevertheless, which ones of ALDH1’s isoenzymes are leading to ALDH1 activity remains elusive. In this study, we examined the prognostic value and hazard ratio (HR) of individual ALDH1 isoenzymes in patients with GC using “The Kaplan–Meier plotter” database. mRNA high expression level of ALDH1A1 was not found to be significantly correlated with the overall survival (OS) of all patients with GC followed for 20 years, HR =0.86 (95% confidence interval [CI]: 0.7–1.05), P=0.13. mRNA high expression level of ALDH1A2 was also not significantly correlated with OS for all patients with GC, HR =1.13 (95% CI: 0.91–1.41), P=0.25. mRNA high expression level of ALDH1A3 was found to be significantly correlated with worsened OS in either intestinal-type patients, HR =2.24 (95% CI: 1.44–3.49), P=0.00026, or diffuse-type patients, HR =1.91 (95% CI: 1.02–3.59), P=0.04. Interestingly, mRNA high expression level of ALDH1B1 was found to be significantly correlated with better OS for all patients with GC, HR =0.66 (95% CI: 0.53–0.81), P=7.8e–05, and mRNA high expression level of ALDH1L1 was found to be significantly correlated with worsened OS for all patients with GC, HR =1.23 (95% CI: 1–1.51), P=0.048. Furthermore, our results also indicate that ALDH1A3 and ALDH1L1 are potential major contributors to the ALDH1 activity in GC, since mRNA high expression levels of ALDH1A3 and ALDH1L1 were found to be significantly correlated with worsened OS for all patients with GC. Based on our study, ALDH1A3 and ALDH1L1 are potential prognostic markers and therapeutic targets for patients with GC. PMID:27354812

  9. Production of acetaldehyde by Zymomonas mobilis

    SciTech Connect

    Wecker, M.S.A.; Zall, R.R.

    1987-12-01

    Mutants of Zymomonas mobilis were selected for decreased alcohol dehydrogenase activity by using consecutively higher concentration of allyl alcohol. A mutant selected by using 100 mM allyl alcohol produced acetaldehyde at a level of 4.08 g/liter when the organism was grown in aerated batch cultures on a medium containing 4.0% (wt/wt) glucose. On the basis of the amount of glucose utilized, this level of acetaldehyde production represents nearly 40% of the maximum theoretical yield. Acetaldehyde produced during growth was continuously air stripped from the reactor. Acetaldehyde present in the exhaust stream was then trapped as the acetaldehyde-bisulfite addition product in an aqueous solution of sodium bisulfite and released by treatment with base. Acetaldehyde was found to inhibit growth of Z. mobilis at concentrations as low as 0.05% (wt/wt) acetaldehyde. An acetaldehyde-tolerant mutant of Z. mobilis was isolated after both mutagenesis with nitrosoguanidine and selection in the presence of vapor-phase acetaldehyde. The production of acetaldehyde has potential advantages over that of ethanol: lower energy requirements for production separation, efficient separation of product from dilute feed streams, continuous separation of product from the reactor, and a higher marketplace value.

  10. Production of Acetaldehyde by Zymomonas mobilis

    PubMed Central

    Wecker, Matt S. A.; Zall, Robert R.

    1987-01-01

    Mutants of Zymomonas mobilis were selected for decreased alcohol dehydrogenase activity by using consecutively higher concentrations of allyl alcohol. A mutant selected by using 100 mM allyl alcohol produced acetaldehyde at a level of 4.08 g/liter when the organism was grown in aerated batch cultures on a medium containing 4.0% (wt/wt) glucose. On the basis of the amount of glucose utilized, this level of acetaldehyde production represents nearly 40% of the maximum theoretical yield. Acetaldehyde produced during growth was continuously air stripped from the reactor. Acetaldehyde present in the exhaust stream was then trapped as the acetaldehyde-bisulfite addition product in an aqueous solution of sodium bisulfite and released by treatment with base. Acetaldehyde was found to inhibit growth of Z. mobilis at concentrations as low as 0.05% (wt/wt) acetaldehyde. An acetaldehyde-tolerant mutant of Z. mobilis was isolated after both mutagenesis with nitrosoguanidine and selection in the presence of vapor-phase acetaldehyde. The production of acetaldehyde has potential advantages over that of ethanol: lower energy requirements for product separation, efficient separation of product from dilute feed streams, continuous separation of product from the reactor, and a higher marketplace value. PMID:16347497

  11. Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism.

    PubMed

    Seitz, Helmut K; Stickel, Felix

    2010-06-01

    Chronic ethanol consumption is a strong risk factor for the development of certain types of cancer including those of the upper aerodigestive tract, the liver, the large intestine and the female breast. Multiple mechanisms are involved in alcohol-mediated carcinogenesis. Among those the action of acetaldehyde (AA), the first metabolite of ethanol oxidation is of particular interest. AA is toxic, mutagenic and carcinogenic in animal experiments. AA binds to DNA and forms carcinogenic adducts. Direct evidence of the role of AA in alcohol-associated carcinogenesis derived from genetic linkage studies in alcoholics. Polymorphisms or mutations of genes coding for AA generation or detoxifying enzymes resulting in elevated AA concentrations are associated with increased cancer risk. Approximately 40% of Japanese, Koreans or Chinese carry the AA dehydrogenase 2*2 (ALDH2*2) allele in its heterozygous form. This allele codes for an ALDH2 enzyme with little activity leading to high AA concentrations after the consumption of even small amounts of alcohol. When individuals with this allele consume ethanol chronically, a significant increased risk for upper alimentary tract and colorectal cancer is noted. In Caucasians, alcohol dehydrogenase 1C*1 (ADH1C*1) allele encodes for an ADH isoenzyme which produces 2.5 times more AA than the corresponding allele ADH1C*2. In studies with moderate to high alcohol intake, ADH1C*1 allele frequency and rate of homozygosity was found to be significantly associated with an increased risk for cancer of the upper aerodigestive tract, the liver, the colon and the female breast. These studies underline the important role of acetaldehyde in ethanol-mediated carcinogenesis. PMID:19847467

  12. Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations

    PubMed Central

    Arnold, Samuel L.; Kent, Travis; Hogarth, Cathryn A.; Schlatt, Stefan; Prasad, Bhagwat; Haenisch, Michael; Walsh, Thomas; Muller, Charles H.; Griswold, Michael D.; Amory, John K.; Isoherranen, Nina

    2015-01-01

    Retinoic acid (RA), the active metabolite of vitamin A, is required for spermatogenesis and many other biological processes. RA formation requires irreversible oxidation of retinal to RA by aldehyde dehydrogenase enzymes of the 1A family (ALDH1A). While ALDH1A1, ALDH1A2, and ALDH1A3 all form RA, the expression pattern and relative contribution of these enzymes to RA formation in the testis is unknown. In this study, novel methods to measure ALDH1A protein levels and intrinsic RA formation were used to accurately predict RA formation velocities in individual human testis samples and an association between RA formation and intratesticular RA concentrations was observed. The distinct localization of ALDH1A in the testis suggests a specific role for each enzyme in controlling RA formation. ALDH1A1 was found in Sertoli cells, while only ALDH1A2 was found in spermatogonia, spermatids, and spermatocytes. In the absence of cellular retinol binding protein (CRBP)1, ALDH1A1 was predicted to be the main contributor to intratesticular RA formation, but when CRBP1 was present, ALDH1A2 was predicted to be equally important in RA formation as ALDH1A1. This study provides a comprehensive novel methodology to evaluate RA homeostasis in human tissues and provides insight to how the individual ALDH1A enzymes mediate RA concentrations in specific cell types. PMID:25502770

  13. Malondialdehyde inhibits an AMPK-mediated nuclear translocation and repression activity of ALDH2 in transcription

    SciTech Connect

    Choi, Ji-Woong; Kim, Jae-Hwan; Cho, Sung-Chun; Ha, Moon-Kyung; Song, Kye-Yong; Youn, Hong-Duk; Park, Sang Chul

    2011-01-07

    Research highlights: {yields} ALDH2 is an MDA-modified protein in old rat kidney tissues. {yields} AMPK associates with ALDH2 and triggers the nuclear localization of ALDH2. {yields} ALDH2 serves as a general transcriptional repressor by associating with HDACs. {yields} MDA inhibits the AMPK-mediated translocation of ALDH2 and its repression activity. -- Abstract: Aging process results from deleterious damages by reactive oxygen species, in particular, various metabolic aldehydes. Aldehyde dehydrogenase 2 (ALDH2) is one of metabolic enzymes detoxifying various aldehydes under oxidative conditions. AMP-activated protein kinase (AMPK) plays a key role in controlling metabolic process. However, little was known about the relationship of ALDH2 with AMPK under oxidative conditions. Here, we, by using MDA-specific monoclonal antibody, screened the tissues of young and old rats for MDA-modified proteins and identified an ALDH2 as a prominent MDA-modified protein band in the old rat kidney tissue. ALDH2 associates with AMPK and is phosphorylated by AMPK. In addition, AICAR, an activator of AMP-activated protein kinase, induces the nuclear translocation of ALDH2. ALDH2 in nucleus is involved in general transcription repression by association with histone deacetylases. Furthermore, MDA modification inhibited the translocation of ALDH2 and the association with AMPK, and ultimately led to de-repression of transcription in the reporter system analysis. In this study, we have demonstrated that ALDH2 acts as a transcriptional repressor in response to AMPK activation, and MDA modifies ALDH2 and inhibits repressive activity of ALDH2 in general transcription. We thus suggest that increasing amount of MDA during aging process may interrupt the nuclear function of ALDH2, modulated by AMPK.

  14. Proliferating pancreatic beta-cells upregulate ALDH.

    PubMed

    Liu, Yinglan; Jiang, Xiaoxin; Zeng, Yong; Zhou, Hui; Yang, Jing; Cao, Renxian

    2014-12-01

    High levels of aldehyde dehydrogenase (ALDH) activity have been regarded as a specific feature of progenitor cells and stem cells. Hence, as an indicator of ALDH activity, aldefluor fluorescence has been widely used for the identification and isolation of stem and progenitor cells. ALDH activity was recently detected in embryonic mouse pancreas, and specifically and exclusively in adult centroacinar and terminal duct cells, suggesting that these duct cells may harbor cells of endocrine and exocrine differentiation potential in the adult pancreas. Here, we report the presence of aldefluor+ beta-cells in a beta-cell proliferation model, partial pancreatectomy. The aldefluor+ beta-cells are essentially all positive for Ki-67 and expressed high levels of cell-cycle activators such as CyclinD1, CyclinD2, and CDK4, suggesting that they are mitotic cells. Our data thus reveal a potential change in ALDH activity of proliferating beta-cells, which provides a novel method for the isolation and analysis of proliferating beta-cells. Moreover, our data also suggest that aldefluor lineage-tracing is not a proper method for analyzing progenitor or stem activity in the adult pancreas. PMID:25028343

  15. Impact of smoking on lung cancer risk is stronger in those with the homozygous aldehyde dehydrogenase 2 null allele in a Japanese population.

    PubMed

    Park, Ji Young; Matsuo, Keitaro; Suzuki, Takeshi; Ito, Hidemi; Hosono, Satoyo; Kawase, Takakazu; Watanabe, Miki; Oze, Isao; Hida, Toyoaki; Yatabe, Yasushi; Mitsudomi, Tetsuya; Takezaki, Toshiro; Tajima, Kazuo; Tanaka, Hideo

    2010-04-01

    The main lifestyle contributor to acetaldehyde exposure is the drinking of alcoholic beverages, but tobacco smoke also makes some contribution. Although acetaldehyde is associated with upper aerodigestive tract cancer risk, in accordance with genetically determined acetaldehyde metabolism, it is unclear whether lung cancer, a representative smoking-related cancer, is associated with acetaldehyde or genes impacting its metabolism. We conducted a case-control study to examine possible interaction between smoking and aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphism (rs671) on the risk of lung cancer in Japanese. Subjects were 718 lung cancer cases and 1416 non-cancer controls enrolled in the Hospital-based Epidemiologic Research Program at Aichi Cancer Center. Lifestyle factors, including smoking, were determined by self-administered questionnaire. We applied pack-years (PY; categorized into five levels: never, <15, <30, <45 and > or =45) as a marker of cumulative exposure to smoking. The impact of smoking, ALDH2 genotype, and their interaction on lung cancer risk were assessed by odds ratio (OR) and 95% confidence interval adjusted for potential confounders. Adjusted ORs for PY <15, <30, <45 and > or =45 relative to never smokers among those with Glu/Glu or Glu/Lys were 1.39, 1.80, 3.44 and 6.25, respectively (P-trend = 1.4 x 10(-30)). In contrast, ORs among Lys/Lys were 1.01, 10.2, 11.4 and 23.2, respectively (P-trend = 2.6 x 10(-7)). Interaction between ALDH2 genotype (Glu/Glu + Glu/Lys versus Lys/Lys) and cumulative smoking dose was statistically significant (P = 0.036) and was consistently observed in the analysis among never-drinkers (interaction P = 0.041). These results suggest that ALDH2 Lys/Lys, a null enzyme activity genotype, modifies the impact of smoking on the risk of lung cancer. PMID:20093384

  16. Biotransformation of ethanol to acetaldehyde by wild and mutant strains of methylotrophic yeast

    SciTech Connect

    Moroz, O.M.; Sibirnyi, A.A.; Ksheminskaya, G.P. |

    1995-05-01

    The conversion of ethanol to acetaldehyde by intact cells of wild and mutant strains of methylotrophic yeast Hansenula polymorpha was studied. It was established that mutations that lower the activity of aldehyde reductase and acetaldehyde dehydrogenase stimulate acetaldehyde accumulation. The highest accumulation of acetaldehyde was found in a mutant that possessed increased alcohol oxidase activity in growth on a medium with glucose. A decrease in formaldehyde dehydrogenase did not stimulate acetaldehyde accumulation. Bioconversion of ethanol to acetaldehyde was most effective at lowered temperatures due to marked suppression of catabolic alcohol oxidase inactivation, but not to the activity of this enzyme under indicated conditions. 27 refs., 4 figs., 3 tabs.

  17. Development of a high-throughput in vitro assay to identify selective inhibitors for human ALDH1A1

    PubMed Central

    Morgan, Cynthia A.; Hurley, Thomas D.

    2014-01-01

    The human aldehyde dehydrogenase (ALDH) superfamily consists of at least 19 enzymes that metabolize endogenous and exogenous aldehydes. Currently, there are no commercially available inhibitors that target ALDH1A1 but have little to no effect on the structurally and functionally similar ALDH2. Here we present the first human ALDH1A1 structure, as the apoenzyme and in complex with its cofactor NADH to a resolution of 1.75 Å and 2.1 Å, respectfully. Structural comparisons of the cofactor binding sites in ALDH1A1 with other closely related ALDH enzymes illustrate a high degree of similarity. In order to minimize discovery of compounds that inhibit both isoenzymes by interfering with their conserved cofactor binding sites, this study reports the use of an in vitro, NAD+-independent, esterase-based high-throughput screen (HTS) of 64,000 compounds to discover novel, selective inhibitors of ALDH1A1. We describe 256 hits that alter the esterase activity of ALDH1A1. The effects on aldehyde oxidation of 67 compounds were further analyzed, with 30 selectively inhibiting ALDH1A1 compared to ALDH2 and ALDH3A1. One compound inhibited ALDH1A1 and ALDH2, while another inhibited ALDH1A1, ALDH2, and the more distantly related ALDH3A1. The results presented here indicate that this in vitro enzyme activity screening protocol successfully identified ALDH1A1 inhibitors with a high degree of isoenzyme selectivity. The compounds identified via this screen plus the screening methodology itself represent a starting point for the development of highly potent and selective inhibitors of ALDH1A1 that may be utilized to better understand the role of this enzyme in both normal and disease states. PMID:25450233

  18. Recombinant human diamine oxidase activity is not inhibited by ethanol, acetaldehyde, disulfiram, diethyldithiocarbamate or cyanamide.

    PubMed

    Bartko, Johann; Gludovacz, Elisabeth; Petroczi, Karin; Borth, Nicole; Jilma, Bernd; Boehm, Thomas

    2016-08-01

    Human diamine oxidase (hDAO, EC 1.4.3.22) is the key enzyme in the degradation of extracellular histamine. Consumption of alcohol is a known trigger of mast cell degranulation in patients with mast cell activation syndrome. Ethanol may also interfere with enzymatic histamine degradation, but reports on the effects on DAO activity are controversial. There are also conflicting reports whether disulfiram, an FDA-approved agent in the treatment of alcohol dependence, inhibits DAO. We therefore investigated the inhibitory potential of ethanol and disulfiram and their metabolites on recombinant human DAO (rhDAO) in three different assay systems. Relevant concentrations of ethanol, acetaldehyde, and acetate did not inhibit rhDAO activity in an in vitro assay system using horseradish peroxidase (HRP) -mediated luminol oxidation. The aldehyde dehydrogenase (ALDH; EC 1.2.1.3) inhibitors cyanamide and its dimer dicyanamide also had no effect on DAO activity. In one assay system, the irreversible ALDH inhibitor disulfiram and its main metabolite diethyldithiocarbamate seemed to inhibit DAO activity. However, the decreased product formation was not due to a direct block of DAO activity but resulted from inhibition of peroxidase employed in the coupled system. Our in vitro data do not support a direct blocking effect of ethanol, disulfiram, and their metabolites on DAO activity in vivo. PMID:27401969

  19. SAXS fingerprints of aldehyde dehydrogenase oligomers.

    PubMed

    Tanner, John J

    2015-12-01

    Enzymes of the aldehyde dehydrogenase (ALDH) superfamily catalyze the nicotinamide adenine dinucleotide-dependent oxidation of aldehydes to carboxylic acids. ALDHs are important in detoxification of aldehydes, amino acid metabolism, embryogenesis and development, neurotransmission, oxidative stress, and cancer. Mutations in genes encoding ALDHs cause metabolic disorders, including alcohol flush reaction (ALDH2), Sjögren-Larsson syndrome (ALDH3A2), hyperprolinemia type II (ALDH4A1), γ-hydroxybutyric aciduria (ALDH5A1), methylmalonic aciduria (ALDH6A1), pyridoxine dependent epilepsy (ALDH7A1), and hyperammonemia (ALDH18A1). We previously reported crystal structures and small-angle X-ray scattering (SAXS) analyses of ALDHs exhibiting dimeric, tetrameric, and hexameric oligomeric states (Luo et al., Biochemistry 54 (2015) 5513-5522; Luo et al., J. Mol. Biol. 425 (2013) 3106-3120). Herein I provide the SAXS curves, radii of gyration, and distance distribution functions for the three types of ALDH oligomer. The SAXS curves and associated analysis provide diagnostic fingerprints that allow rapid identification of the type of ALDH oligomer that is present in solution. The data sets provided here serve as a benchmark for characterizing oligomerization of ALDHs. PMID:26693506

  20. Retinal Targets ALDH Positive Cancer Stem Cell and Alters the Phenotype of Highly Metastatic Osteosarcoma Cells

    PubMed Central

    Mu, Xiaodong; Patel, Stuti; Mektepbayeva, Damel; Mahjoub, Adel; Huard, Johnny; Weiss, Kurt

    2015-01-01

    Aldehyde dehydrogenase (ALDH) is a cancer stem cell marker. Retinoic acid has antitumor properties, including the induction of apoptosis and inhibition of proliferation. Retinal, the precursor of retinoic acid, can be oxidized to retinoic acid by dehydrogenases, including ALDH. We hypothesized that retinal could potentially be transformed to retinoic acid with higher efficiency by cancer stem cells, due to the higher ALDH activity. We previously observed that ALDH activity is greater in highly metastatic K7M2 osteosarcoma (OS) cells than in nonmetastatic K12 OS cells. We also demonstrated that ALDH activity correlates with clinical metastases in bone sarcoma patients, suggesting that ALDH may be a therapeutic target specific to cells with high metastatic potential. Our current results demonstrated that retinal preferentially affected the phenotypes of ALDH-high K7M2 cells in contrast to ALDH-low K12 cells, which could be mediated by the more efficient transformation of retinal to retinoic acid by ALDH in K7M2 cells. Retinal treatment of highly metastatic K7M2 cells decreased their proliferation, invasion capacity, and resistance to oxidative stress. Retinal altered the expression of metastasis-related genes. These observations indicate that retinal may be used to specifically target metastatic cancer stem cells in OS. PMID:26819566

  1. ALDH1A3, a metabolic target for cancer diagnosis and therapy.

    PubMed

    Duan, Jiang-Jie; Cai, Jiao; Guo, Yu-Feng; Bian, Xiu-Wu; Yu, Shi-Cang

    2016-09-01

    Metabolism reprogramming has been linked with the initiation, metastasis, and recurrence of cancer. The aldehyde dehydrogenase (ALDH) family is the most important enzyme system for aldehyde metabolism. The human ALDH family is composed of 19 members. ALDH1A3 participates in various physiological processes in human cells by oxidizing all-trans-retinal to retinoic acid. ALDH1A3 expression is regulated by many factors, and it is associated with the development, progression, and prognosis of cancers. In addition, ALDH1A3 influences a diverse range of biological characteristics within cancer stem cells and can act as a marker for these cells. Thus, growing evidence indicates that ALDH1A3 has the potential to be used as a target for cancer diagnosis and therapy. PMID:26991532

  2. NOX2 amplifies acetaldehyde-mediated cardiomyocyte mitochondrial dysfunction in alcoholic cardiomyopathy.

    PubMed

    Brandt, Moritz; Garlapati, Venkata; Oelze, Matthias; Sotiriou, Efthymios; Knorr, Maike; Kröller-Schön, Swenja; Kossmann, Sabine; Schönfelder, Tanja; Morawietz, Henning; Schulz, Eberhard; Schultheiss, Heinz-Peter; Daiber, Andreas; Münzel, Thomas; Wenzel, Philip

    2016-01-01

    Alcoholic cardiomyopathy (ACM) resulting from excess alcohol consumption is an important cause of heart failure (HF). Although it is assumed that the cardiotoxicity of the ethanol (EtOH)-metabolite acetaldehyde (ACA) is central for its development and progression, the exact mechanisms remain obscure. Murine cardiomyocytes (CMs) exposed to ACA or EtOH showed increased superoxide (O2(•-)) levels and decreased mitochondrial polarization, both being normalized by NADPH oxidase (NOX) inhibition. C57BL/6 mice and mice deficient for the ACA-degrading enzyme mitochondrial aldehyde dehydrogenase (ALDH-2(-/-)) were fed a 2% EtOH diet for 5 weeks creating an ACA-overload. 2% EtOH-fed ALDH-2(-/-) mice exhibited a decreased cardiac function, increased heart-to-body and lung-to-body weight ratios, increased cardiac levels of the lipid peroxidation product malondialdehyde (MDA) as well as increased NOX activity and NOX2/glycoprotein 91(phox) (NOX2/gp91(phox)) subunit expression compared to 2% EtOH-fed C57BL/6 mice. Echocardiography revealed that ALDH-2(-/-)/gp91(phox-/-) mice were protected from ACA-overload-induced HF after 5 weeks of 2% EtOH-diet, demonstrating that NOX2-derived O2(•-) contributes to the development of ACM. Translated to human pathophysiology, we found increased gp91(phox) expression in endomyocardial biopsies of ACM patients. In conclusion, ACM is promoted by ACA-driven mitochondrial dysfunction and can be improved by ablation of NOX2/gp91(phox). NOX2/gp91(phox) therefore might be a potential pharmacological target to treat ACM. PMID:27624556

  3. Impaired ALDH2 activity decreases the mitochondrial respiration in H9C2 cardiomyocytes.

    PubMed

    Mali, Vishal R; Deshpande, Mandar; Pan, Guodong; Thandavarayan, Rajarajan A; Palaniyandi, Suresh S

    2016-02-01

    Reactive oxygen species (ROS)-mediated reactive aldehydes induce cellular stress. In cardiovascular diseases such as ischemia-reperfusion injury, lipid-peroxidation derived reactive aldehydes such as 4-hydroxy-2-nonenal (4HNE) are known to contribute to the pathogenesis. 4HNE is involved in ROS formation, abnormal calcium handling and more importantly defective mitochondrial respiration. Aldehyde dehydrogenase (ALDH) superfamily contains NAD(P)(+)-dependent isozymes which can detoxify endogenous and exogenous aldehydes into non-toxic carboxylic acids. Therefore we hypothesize that 4HNE afflicts mitochondrial respiration and leads to cell death by impairing ALDH2 activity in cultured H9C2 cardiomyocyte cell lines. H9C2 cardiomyocytes were treated with 25, 50 and 75 μM 4HNE and its vehicle, ethanol as well as 25, 50 and 75 μM disulfiram (DSF), an inhibitor of ALDH2 and its vehicle (DMSO) for 4 h. 4HNE significantly decreased ALDH2 activity, ALDH2 protein levels, mitochondrial respiration and mitochondrial respiratory reserve capacity, and increased 4HNE adduct formation and cell death in cultured H9C2 cardiomyocytes. ALDH2 inhibition by DSF and ALDH2 siRNA attenuated ALDH2 activity besides reducing ALDH2 levels, mitochondrial respiration and mitochondrial respiratory reserve capacity and increased cell death. Our results indicate that ALDH2 impairment can lead to poor mitochondrial respiration and increased cell death in cultured H9C2 cardiomyocytes. PMID:26577527

  4. Biochemical basis of mitochondrial acetaldehyde dismutation in Saccharomyces cerevisiae.

    PubMed Central

    Thielen, J; Ciriacy, M

    1991-01-01

    As reported previously, Saccharomyces cerevisiae cells deficient in all four known genes coding for alcohol dehydrogenases (ADH1 through ADH4) produce considerable amounts of ethanol during aerobic growth on glucose. It has been suggested that ethanol production in such adh0 cells is a corollary of acetaldehyde dismutation in mitochondria. This could be substantiated further by showing that mitochondrial ethanol formation requires functional electron transport, while the proton gradient or oxidative phosphorylation does not interfere with reduction of acetaldehyde in isolated mitochondria. This acetaldehyde-reducing activity is different from classical alcohol dehydrogenases in that it is associated with the inner mitochondrial membrane and also is unable to carry out ethanol oxidation. The putative cofactor is NADH + H+ generated by a soluble, matrix-located aldehyde dehydrogenase upon acetaldehyde oxidation to acetate. This enzyme has been purified from mitochondria of glucose-grown cells. It is clearly different from the known mitochondrial aldehyde dehydrogenase, which is absent in glucose-grown cells. Both acetaldehyde-reducing and acetaldehyde-oxidizing activities are also present in the mitochondrial fraction of fermentation-proficient (ADH+) cells. Mitochondrial acetaldehyde dismutation may have some significance in the removal of surplus acetaldehyde and in the formation of acetate in mitochondria during aerobic glucose fermentation. Images FIG. 4 PMID:1938903

  5. ALDH1A3: A Marker of Mesenchymal Phenotype in Gliomas Associated with Cell Invasion

    PubMed Central

    Hu, Huimin; Huang, Hua; Bao, Zhaoshi; Yang, Pei; Wang, Yinyan; You, Gan; Yan, Wei; Jiang, Tao; Wang, Jiangfei; Zhang, Wei

    2015-01-01

    Aldehyde dehydrogenases (ALDH) is a family of enzymes including 19 members. For now, ALDH activity had been wildly used as a marker of cancer stem cells (CSCs). But biological functions of relevant isoforms and their clinical applications are still controversial. Here, we investigate the clinical significance and potential function of ALDH1A3 in gliomas. By whole-genome transcriptome microarray and mRNA sequencing analysis, we compared the expression of ALDH1A3 in high- and low- grade gliomas as well as different molecular subtypes. Microarray analysis was performed to identify the correlated genes of ALDH1A3. We further used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis to explore the biological function of ALDH1A3. Finally, by mRNA knockdown we revealed the relationship between ALDH1A3 and the ability of tumor invasion. ALDH1A3 overexpression was significantly associated with high grade as well as the higher mortality of gliomas in survival analysis. ALDH1A3 was characteristically highly expressed in Mesenchymal (Mes) subtype gliomas. Moreover, we found that ALDH1A3 was most relevant to extracellular matrix organization and cell adhesion biological process, and the ability of tumor invasion was suppressed after ALDH1A3 knockdown in vitro. In conclusion, ALDH1A3 can serve as a novel marker of Mes phenotype in gliomas with potential clinical prognostic value. The expression of ALDH1A3 is associated with tumor cell invasion. PMID:26575197

  6. NEK2 mediates ALDH1A1-dependent drug resistance in multiple myeloma

    PubMed Central

    Xia, Jiliang; Gu, Zhimin; Wendlandt, Erik; Zhan, Xin; Janz, Siegfried; Tricot, Guido; Zhan, Fenghuang

    2014-01-01

    We reported previously that increased expression of aldehyde dehydrogenase 1 (ALDH1) in multiple myeloma (MM) is a marker of tumor-initiating cells (TICs) that is further associated with chromosomal instability (CIN). Here we demonstrate that member A1 of the ALDH1 family of proteins, ALDH1A1, is most abundantly expressed in myeloma. Enforced expression of ALDH1A1 in myeloma cells led to increased clonogenicity, tumor formation in mice, and resistance to myeloma drugs in vitro and in vivo. The mechanism underlying these phenotypes included the ALDH1A1-dependent activation of drug-efflux pump, ABCB1, and survival proteins, AKT and BCL2. Over expression of ALDH1A1 in myeloma cells led to increased mRNA and protein levels of NIMA-related kinase 2 (NEK2), whereas shRNA-mediated knock down of NEK2 decreased drug efflux pump activity and drug resistance. The activation of NEK2 in myeloma cells relied on the ALDH1A1-dependent generation of the retinoid X receptor α (RXRα) ligand, 9-cis retinoic acid (9CRA) – not the retinoic acid receptor α (RARα) ligand, all-trans retinoic acid (ATRA). These findings implicate the ALDH1A1-RXRα-NEK2 pathway in drug resistance and disease relapse in myeloma and suggest that specific inhibitors of ALDH1A1 are worthy of consideration for clinical development of new approaches to overcome drug resistance in myeloma. PMID:25230277

  7. Aldehyde dehydrogenase 1A1 in stem cells and cancer

    PubMed Central

    Tomita, Hiroyuki; Tanaka, Kaori; Tanaka, Takuji; Hara, Akira

    2016-01-01

    The human genome contains 19 putatively functional aldehyde dehydrogenase (ALDH) genes, which encode enzymes critical for detoxification of endogenous and exogenous aldehyde substrates through NAD(P)+-dependent oxidation. ALDH1 has three main isotypes, ALDH1A1, ALDH1A2, and ALDH1A3, and is a marker of normal tissue stem cells (SC) and cancer stem cells (CSC), where it is involved in self-renewal, differentiation and self-protection. Experiments with murine and human cells indicate that ALDH1 activity, predominantly attributed to isotype ALDH1A1, is tissue- and cancer-specific. High ALDH1 activity and ALDH1A1 overexpression are associated with poor cancer prognosis, though high ALDH1 and ALDH1A1 levels do not always correlate with highly malignant phenotypes and poor clinical outcome. In cancer therapy, ALDH1A1 provides a useful therapeutic CSC target in tissue types that normally do not express high levels of ALDH1A1, including breast, lung, esophagus, colon and stomach. Here we review the functions and mechanisms of ALDH1A1, the key ALDH isozyme linked to SC populations and an important contributor to CSC function in cancers, and we outline its potential in future anticancer strategies. PMID:26783961

  8. ALDH3A1 Plays a Functional Role in Maintenance of Corneal Epithelial Homeostasis

    PubMed Central

    Mehta, Gaurav; Orlicky, David J.; Thompson, David C.; Jester, James V.; Vasiliou, Vasilis

    2016-01-01

    Aldehyde dehydrogenase 1A1 (ALDH1A1) and ALDH3A1 are corneal crystallins. They protect inner ocular tissues from ultraviolet radiation (UVR)-induced oxidative damage through catalytic and non-catalytic mechanisms. Additionally, ALDH3A1 has been postulated to play a regulatory role in the corneal epithelium based on several studies that report an inverse association between ALDH3A1 expression and corneal cell proliferation. The underlying molecular mechanisms and the physiological significance of such association remain poorly understood. In the current study, we established Tet-On human corneal epithelial cell (hTCEpi) lines, which express tetracycline-inducible wild-type (wt) or catalytically-inactive (mu) ALDH3A1. Utilizing this cellular model system, we confirmed that human ALDH3A1 decreases corneal cell proliferation; importantly, this effect appears to be partially mediated by its enzymatic activity. Mechanistically, wt-ALDH3A1, but not mu-ALDH3A1, promotes sequestering of tumor suppressor p53 in the nucleus. In the mouse cornea, however, augmented cell proliferation is noted only in Aldh1a1-/-/3a1-/- double knockout (DKO) mice, indicating in vivo the anti-proliferation effect of ALDH3A1 can be rescued by the presence of ALDH1A1. Interestingly, the hyper-proliferative epithelium of the DKO corneas display nearly complete loss of p53 expression, implying that p53 may be involved in ALDH3A1/1A1-mediated effect. In hTCEpi cells grown in high calcium concentration, mRNA levels of a panel of corneal differentiation markers were altered by ALDH3A1 expression and modulated by its enzyme activity. In conclusion, we show for the first time that: (i) ALDH3A1 decreases corneal epithelial proliferation through both non-enzymatic and enzymatic properties; (ii) ALDH1A1 contributes to the regulation of corneal cellular proliferation in vivo; and (iii) ALDH3A1 modulates corneal epithelial differentiation. Collectively, our studies indicate a functional role of ALDH3A1 in the

  9. Molecular and Catalytic Properties of the Aldehyde Dehydrogenase of Gluconacetobacter diazotrophicus, a Quinoheme Protein Containing Pyrroloquinoline Quinone, Cytochrome b, and Cytochrome c▿

    PubMed Central

    Gómez-Manzo, S.; Chavez-Pacheco, J. L.; Contreras-Zentella, M.; Sosa-Torres, M. E.; Arreguín-Espinosa, R.; Pérez de la Mora, M.; Membrillo-Hernández, J.; Escamilla, J. E.

    2010-01-01

    Several aldehyde dehydrogenase (ALDH) complexes have been purified from the membranes of acetic acid bacteria. The enzyme structures and the chemical nature of the prosthetic groups associated with these enzymes remain a matter of debate. We report here on the molecular and catalytic properties of the membrane-bound ALDH complex of the diazotrophic bacterium Gluconacetobacter diazotrophicus. The purified ALDH complex is a heterodimer comprising two subunits of 79.7 and 50 kDa, respectively. Reversed-phase high-pressure liquid chromatography (HPLC) and electron paramagnetic resonance spectroscopy led us to demonstrate, for the first time, the unequivocal presence of a pyrroloquinoline quinone prosthetic group associated with an ALDH complex from acetic acid bacteria. In addition, heme b was detected by UV-visible light (UV-Vis) spectroscopy and confirmed by reversed-phase HPLC. The smaller subunit bears three cytochromes c. Aliphatic aldehydes, but not formaldehyde, were suitable substrates. Using ferricyanide as an electron acceptor, the enzyme showed an optimum pH of 3.5 that shifted to pH 7.0 when phenazine methosulfate plus 2,6-dichlorophenolindophenol were the electron acceptors. Acetaldehyde did not reduce measurable levels of the cytochrome b and c centers; however, the dithionite-reduced hemes were conveniently oxidized by ubiquinone-1; this finding suggests that cytochrome b and the cytochromes c constitute an intramolecular redox sequence that delivers electrons to the membrane ubiquinone. PMID:20802042

  10. Bioactivation of Nitroglycerin by Purified Mitochondrial and Cytosolic Aldehyde Dehydrogenases*

    PubMed Central

    Beretta, Matteo; Gruber, Karl; Kollau, Alexander; Russwurm, Michael; Koesling, Doris; Goessler, Walter; Keung, Wing Ming; Schmidt, Kurt; Mayer, Bernd

    2008-01-01

    Metabolism of nitroglycerin (GTN) to 1,2-glycerol dinitrate (GDN) and nitrite by mitochondrial aldehyde dehydrogenase (ALDH2) is essentially involved in GTN bioactivation resulting in cyclic GMP-mediated vascular relaxation. The link between nitrite formation and activation of soluble guanylate cyclase (sGC) is still unclear. To test the hypothesis that the ALDH2 reaction is sufficient for GTN bioactivation, we measured GTN-induced formation of cGMP by purified sGC in the presence of purified ALDH2 and used a Clark-type electrode to probe for nitric oxide (NO) formation. In addition, we studied whether GTN bioactivation is a specific feature of ALDH2 or is also catalyzed by the cytosolic isoform (ALDH1). Purified ALDH1 and ALDH2 metabolized GTN to 1,2- and 1,3-GDN with predominant formation of the 1,2-isomer that was inhibited by chloral hydrate (ALDH1 and ALDH2) and daidzin (ALDH2). GTN had no effect on sGC activity in the presence of bovine serum albumin but caused pronounced cGMP accumulation in the presence of ALDH1 or ALDH2. The effects of the ALDH isoforms were dependent on the amount of added protein and, like 1,2-GDN formation, were sensitive to ALDH inhibitors. GTN caused biphasic sGC activation with apparent EC50 values of 42 ± 2.9 and 3.1 ± 0.4 μm in the presence of ALDH1 and ALDH2, respectively. Incubation of ALDH1 or ALDH2 with GTN resulted in sustained, chloral hydrate-sensitive formation of NO. These data may explain the coupling of ALDH2-catalyzed GTN metabolism to sGC activation in vascular smooth muscle. PMID:18450747

  11. Acetaldehyde production from ethanol by oral streptococci.

    PubMed

    Kurkivuori, Johanna; Salaspuro, Ville; Kaihovaara, Pertti; Kari, Kirsti; Rautemaa, Riina; Grönroos, Lisa; Meurman, Jukka H; Salaspuro, Mikko

    2007-02-01

    Alcohol is a well documented risk factor for upper digestive tract cancers. It has been shown that acetaldehyde, the first metabolite of ethanol is carcinogenic. The role of microbes in the production of acetaldehyde to the oral cavity has previously been described in several studies. In the present study, the aim was to investigate the capability of viridans group streptococci of normal oral flora to produce acetaldehyde in vitro during ethanol incubation. Furthermore, the aim was to measure the alcohol dehydrogenase (ADH) activity of the bacteria. Eight clinical strains and eight American Type Culture Collection (ATCC) strains of viridans group streptococci were selected for the study. Bacterial suspensions were incubated in two different ethanol concentrations, 11 mM and 1100 mM and the acetaldehyde was measured by gas chromatography. ADH-activity was measured by using a sensitive spectroscopy. The results show significant differences between the bacterial strains regarding acetaldehyde production capability and the detected ADH-activity. In particular, clinical strain of Streptococcus salivarius, both clinical and culture collection strains of Streptococcus intermedius and culture collection strain of Streptococcus mitis produced high amounts of acetaldehyde in 11 mM and 1100 mM ethanol incubation. All these four bacterial strains also showed significant ADH-enzyme activity. Twelve other strains were found to be low acetaldehyde producers. Consequently, our study shows that viridans group streptococci may play a role in metabolizing ethanol to carcinogenic acetaldehyde in the mouth. The observation supports the concept of a novel mechanism in the pathogenesis of oral cancer. PMID:16859955

  12. Alcohol oxidase is a novel pathogenicity factor for Cladosporium fulvum, but aldehyde dehydrogenase is dispensable.

    PubMed

    Segers, G; Bradshaw, N; Archer, D; Blissett, K; Oliver, R P

    2001-03-01

    Cladosporiumfulvum is a mitosporic ascomycete pathogen of tomato. A study of fungal genes expressed during carbon starvation in vitro identified several genes that were up regulated during growth in planta. These included genes predicted to encode acetaldehyde dehydrogenase (Aldh1) and alcohol oxidase (Aox1). An Aldh1 deletion mutant was constructed. This mutant lacked all detectable ALDH activity, had lost the ability to grow with ethanol as a carbon source, but was unaffected in pathogenicity. Aox1 expression was induced by carbon starvation and during the later stages of infection. The alcohol oxidase enzyme activity has broadly similar properties (Km values, substrate specificity, pH, and heat stability) to yeast enzymes. Antibodies raised to Hansenula polymorpha alcohol oxidase (AOX) detected antigens in Western blots of starved C. fulvum mycelium and infected plant material. Antigen reacting with the antibodies was localized to organelles resembling peroxisomes in starved mycelium and infected plants. Disruption mutants of Aox1 lacked detectable AOX activity and had markedly reduced pathogenicity as assayed by two different measures of fungal growth. These results identify alcohol oxidase as a novel pathogenicity factor and are discussed in relation to peroxisomal metabolism of fungal pathogens during growth in planta. PMID:11277434

  13. ALDH1B1 is a potential stem / progenitor marker for multiple pancreas progenitor pools

    PubMed Central

    Ioannou, Marilia; Serafimidis, Ioannis; Arnes, Luis; Sussel, Lori; Singh, Surendra; Vasiliou, Vasilis; Gavalas, Anthony

    2013-01-01

    Aldehyde Dehydrogenase (ALDH) genes are increasingly associated with stem / progenitor cell status but their role in the maintenance of pluripotency remains uncertain. In a screen conducted for downstream Ngn3 target genes using ES derived pancreas progenitors we identified Aldh1b1, encoding a mitochondrial enzyme, as one of the genes strongly up regulated in response to Ngn3 expression. We found both by in situ hybridization and immunofluorescence using a specific antibody that ALDH1B1 is exclusively expressed in the emerging pancreatic buds of the early embryo (9.5 dpc) in a Pdx1 dependent manner. Around the time of secondary transition, ALDH1B1 expression was restricted in the tip tripotent progenitors of the branching epithelium and in a subset of the trunk epithelium. Expression in the latter was Ngn3 dependent. Subsequently, ALDH1B1 expression persisted only in the tip cells that become restricted to the exocrine lineage and declined rapidly as these cells mature. In the adult pancreas we identified rare ALDH1B1+ cells that become abundant following pancreas injury in either the caerulein or streptozotocin paradigms. Blocking ALDH catalytic activity in pancreas embryonic explants resulted in reduced size of the explants and accelerated differentiation suggesting for the first time that ALDH activity may be necessary in the developing pancreas for the maintenance and expansion of progenitor pools. PMID:23142317

  14. Mechanisms involved in the protection of UV-induced protein inactivation by the corneal crystallin ALDH3A1.

    PubMed

    Estey, Tia; Cantore, Miriam; Weston, Philip A; Carpenter, John F; Petrash, J Mark; Vasiliou, Vasilis

    2007-02-16

    Various lines of evidence have shown that ALDH3A1 (aldehyde dehydrogenase 3A1) plays a critical and multifaceted role in protecting the cornea from UV-induced oxidative stress. ALDH3A1 is a corneal crystallin, which is defined as a protein recruited into the cornea for structural purposes without losing its primary function (i.e. metabolism). Although the primary role of ALDH3A1 in the metabolism of toxic aldehydes has been clearly demonstrated, including the detoxification of aldehydes produced during UV-induced lipid peroxidation, the structural role of ALDH3A1 in the cornea remains elusive. We therefore examined the potential contribution of ALDH3A1 in maintaining the optical integrity of the cornea by suppressing the aggregation and/or inactivation of other proteins through chaperone-like activity and other protective mechanisms. We found that ALDH3A1 underwent a structural transition near physiological temperatures to form a partially unfolded conformation that is suggestive of chaperone activity. Although this structural transition alone did not correlate with any protection, ALDH3A1 substantially reduced the inactivation of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal and malondialdehyde when co-incubated with NADP(+), reinforcing the importance of the metabolic function of this corneal enzyme in the detoxification of toxic aldehydes. A large excess of ALDH3A1 also protected glucose-6-phosphate dehydrogenase from inactivation because of direct exposure to UVB light, which suggests that ALDH3A1 may shield other proteins from damaging UV rays. Collectively, these data demonstrate that ALDH3A1 can reduce protein inactivation and/or aggregation not only by detoxification of reactive aldehydes but also by directly absorbing UV energy. This study provides for the first time mechanistic evidence supporting the structural role of the corneal crystallin ALDH3A1 as a UV-absorbing constituent of the cornea. PMID:17158879

  15. Targeting Aldehyde Dehydrogenase 2: New Therapeutic Opportunities

    PubMed Central

    Chen, Che-Hong; Ferreira, Julio Cesar Batista; Gross, Eric R.; Mochly-Rosen, Daria

    2014-01-01

    A family of detoxifying enzymes called aldehyde dehydrogenases (ALDHs) has been a subject of recent interest, as its role in detoxifying aldehydes that accumulate through metabolism and to which we are exposed from the environment has been elucidated. Although the human genome has 19 ALDH genes, one ALDH emerges as a particularly important enzyme in a variety of human pathologies. This ALDH, ALDH2, is located in the mitochondrial matrix with much known about its role in ethanol metabolism. Less known is a new body of research to be discussed in this review, suggesting that ALDH2 dysfunction may contribute to a variety of human diseases including cardiovascular diseases, diabetes, neurodegenerative diseases, stroke, and cancer. Recent studies suggest that ALDH2 dysfunction is also associated with Fanconi anemia, pain, osteoporosis, and the process of aging. Furthermore, an ALDH2 inactivating mutation (termed ALDH2*2) is the most common single point mutation in humans, and epidemiological studies suggest a correlation between this inactivating mutation and increased propensity for common human pathologies. These data together with studies in animal models and the use of new pharmacological tools that activate ALDH2 depict a new picture related to ALDH2 as a critical health-promoting enzyme. PMID:24382882

  16. NAD(P)-Dependent Aldehyde Dehydrogenases Induced during Growth of Ralstonia eutropha Strain Bo on Tetrahydrofurfuryl Alcohol

    PubMed Central

    Schräder, Thomas; Zarnt, Grit; Andreesen, Jan R.

    2001-01-01

    Different aldehyde dehydrogenases (AlDHs) were formed during growth of Ralstonia eutropha Bo on tetrahydrofurfuryl alcohol (THFA). One of these enzymes, AlDH 4, was purified and characterized as a homodimer containing no prosthetic groups, showing a strong substrate inhibition, and having an N-terminal sequence similar to those of various NAD(P)-dependent AlDHs. The conversion rate of THFA by the quinohemoprotein THFA dehydrogenase was increased by AlDH 4. PMID:11717302

  17. Aldehyde dehydrogenase 2 and head and neck cancer: a meta-analysis implementing a Mendelian randomization approach.

    PubMed

    Boccia, Stefania; Hashibe, Mia; Gallì, Paola; De Feo, Emma; Asakage, Takahiro; Hashimoto, Tomoko; Hiraki, Akio; Katoh, Takahiko; Nomura, Takeshi; Yokoyama, Akira; van Duijn, Cornelia M; Ricciardi, Gualtiero; Boffetta, Paolo

    2009-01-01

    Alcohol drinking at high doses is a risk factor for head and neck cancer, and exposure to acetaldehyde, the principle metabolite of alcohol, is supposed to account for the increased risk. Individuals homozygous for the 2 variant allele of aldehyde dehydrogenase 2 (ALDH2) are unable to metabolize acetaldehyde, which prevents them from alcohol drinking, whereas 1 2 have 6-fold higher blood acetaldehyde concentration postalcohol consumption with respect to 1 1. According to the concept of Mendelian randomization, because this polymorphism is distributed randomly during gamete formation, its association with head and neck cancer should be not confounded by smoking. We carried out a meta-analysis of ALDH2 and head and neck cancer searching for relevant studies on Medline and Embase up to January 31, 2008, and investigated the consistency between the expected odds ratio (OR) among drinkers from the largest pooled analysis among never smokers and the observed OR from this meta-analysis by an interaction test. Six studies were selected (945 cases, 2,917 controls). The OR of head and neck cancer among 2 2 was 0.53 [95% confidence interval (95% CI), 0.28-1.00] relative to 1 1 and 1.83 (95% CI, 1.21-2.77) among 1 2. The expected OR for head and neck cancer due to alcohol intake among 1 1 was 1.38 (95% CI, 0.88-2.17) and the observed OR among 1 1 compared with 2*2 from this meta-analysis was 1.88 (95% CI, 1.00-3.57; P for interaction = 0.43). Besides showing the effectiveness of the Mendelian randomization approach, these findings support the theory that alcohol increases head and neck cancer risk through the carcinogenic action of acetaldehyde. PMID:19124505

  18. Targeting Aldehyde Dehydrogenase Cancer Stem Cells in Ovarian Cancer

    PubMed Central

    Landen, Charles N.; Goodman, Blake; Katre, Ashwini A.; Steg, Adam D.; Nick, Alpa M.; Stone, Rebecca L.; Miller, Lance D.; Mejia, Pablo Vivas; Jennings, Nicolas B.; Gershenson, David M.; Bast, Robert C.; Coleman, Robert L.; Lopez-Berestein, Gabriel; Sood, Anil K.

    2010-01-01

    Aldehyde dehydrogenase-1A1 (ALDH1A1) expression characterizes a subpopulation of cells with tumor initiating or cancer stem cell properties in several malignancies. Our goal was to characterize the phenotype of ALDH1A1-positive ovarian cancer cells and examine the biological effects of ALDH1A1 gene silencing. In our analysis of multiple ovarian cancer cell lines, we found that ALDH1A1 expression and activity was significantly higher in taxane and platinum-resistant cell lines. In patient samples, 72.9% of ovarian cancers had ALDH1A1 expression, in whom the percent of ALDH1A1-positive cells correlated negatively with progression-free survival (6.05 v 13.81 months, p<0.035). Subpopulations of A2780cp20 cells with ALDH1A1 activity were isolated for orthotopic tumor initiating studies, where tumorigenicity was approximately 50-fold higher with ALDH1A1-positive cells. Interestingly, tumors derived from ALDH1A1-positive cells gave rise to both ALDH1A1-positive and ALDH1A1-negative populations, but ALDH1A1-negative cells could not generate ALDH1A1-positive cells. In an in vivo orthotopic mouse model of ovarian cancer, ALDH1A1 silencing using nanoliposomal siRNA sensitized both taxane- and platinum-resistant cell lines to chemotherapy, significantly reducing tumor growth in mice compared to chemotherapy alone (a 74–90% reduction, p<0.015). These data demonstrate that the ALDH1A1 subpopulation is associated with chemoresistance and outcome in ovarian cancer patients, and targeting ALDH1A1 sensitizes resistant cells to chemotherapy. ALDH1A1-positive cells have enhanced, but not absolute, tumorigenicity, but do have differentiation capacity lacking in ALDH1A1-negative cells. This enzyme may be important for identification and targeting of chemoresistant cell populations in ovarian cancer. PMID:20889728

  19. Development and validation of a 96-well cellular assay for the discovery of ALDH1A1 inhibitors.

    PubMed

    Ming, Wenyu; Ma, Wenzhen; Chen, Lisa H; Volk, Catherine; Michael, Mervyn Dodson; Xu, Yanping; Zhang, Fang; Wang, Xiaojun

    2013-07-01

    Retinoic acid, the active metabolite of vitamin A, plays important roles in various physiological and pathological processes. The two-step production of retinoic acid from vitamin A (retinol) is catalyzed by alcohol dehydrogenases and aldehyde dehydrogenases, which are potential therapeutic targets for numerous diseases, such as obesity, diabetes, and cancer. Currently, the lack of a suitable high-throughput cellular assay hinders efforts to identify therapeutic small molecular inhibitors of aldehyde dehydrogenase, such as ALDH1A1. In this report, we utilized high-content imaging technology and a commercially available cell permeable ALDH substrate to develop a 96-well cellular ALDH1A1 assay. This assay has a robust and sensitive readout and is amenable to automation. With this cellular assay, we identified potent selective ALDH1A1 inhibitors to explore the role of retinoic acid production in various preclinical disease models. PMID:23957476

  20. MUTAGENICITY ASSESSMENT OF ACETALDEHYDE

    EPA Science Inventory

    Acetaldehyde has been shown in studies by several different laboratories to be a clastogen and inducer of sister chromatid exchanges in cultured mammalian cells. Although there have been very few studies in intact mammals, the available evidence suggests that acetaldehyde produce...

  1. ALDH isozymes downregulation affects cell growth, cell motility and gene expression in lung cancer cells

    PubMed Central

    Moreb, Jan S; Baker, Henry V; Chang, Lung-Ji; Amaya, Maria; Lopez, M Cecilia; Ostmark, Blanca; Chou, Wayne

    2008-01-01

    Background Aldehyde dehydrogenase isozymes ALDH1A1 and ALDH3A1 are highly expressed in non small cell lung cancer. Neither the mechanisms nor the biologic significance for such over expression have been studied. Methods We have employed oligonucleotide microarrays to analyze changes in gene profiles in A549 lung cancer cell line in which ALDH activity was reduced by up to 95% using lentiviral mediated expression of siRNA against both isozymes (Lenti 1+3). Stringent analysis methods were used to identify gene expression patterns that are specific to the knock down of ALDH activity and significantly different in comparison to wild type A549 cells (WT) or cells similarly transduced with green fluorescent protein (GFP) siRNA. Results We confirmed significant and specific down regulation of ALDH1A1 and ALDH3A1 in Lenti 1+3 cells and in comparison to 12 other ALDH genes detected. The results of the microarray analysis were validated by real time RT-PCR on RNA obtained from Lenti 1+3 or WT cells treated with ALDH activity inhibitors. Detailed functional analysis was performed on 101 genes that were significantly different (P < 0.001) and their expression changed by ≥ 2 folds in the Lenti 1+3 group versus the control groups. There were 75 down regulated and 26 up regulated genes. Protein binding, organ development, signal transduction, transcription, lipid metabolism, and cell migration and adhesion were among the most affected pathways. Conclusion These molecular effects of the ALDH knock-down are associated with in vitro functional changes in the proliferation and motility of these cells and demonstrate the significance of ALDH enzymes in cell homeostasis with a potentially significant impact on the treatment of lung cancer. PMID:19025616

  2. Mitochondrial NAD Dependent Aldehyde Dehydrogenase either from Yeast or Human Replaces Yeast Cytoplasmic NADP Dependent Aldehyde Dehydrogenase for the Aerobic Growth of Yeast on Ethanol

    PubMed Central

    Mukhopadhyay, Abhijit; Wei, Baoxian; Weiner, Henry

    2013-01-01

    Background In a previous study, we deleted three aldehyde dehydrogenase (ALDH) genes, involved in ethanol metabolism, from yeast S. cerevisiae and found that the triple deleted yeast strain did not grow on ethanol as sole carbon source. The ALDHs were NADP dependent cytosolic ALDH1, NAD dependent mitochondrial ALDH2 and NAD/NADP dependent mitochondrial ALDH5. Double deleted strain ΔALDH2+ΔALDH5 or ΔALDH1+ΔALDH5 could grow on ethanol. However, the double deleted strain ΔALDH1+ΔALDH2 did not grow in ethanol. Methods Triple deleted yeast strain was used. Mitochondrial NAD dependent ALDH from yeast or human was placed in yeast cytosol. Results In the present study we found that a mutant form of cytoplasmic ALDH1 with very low activity barely supported the growth of the triple deleted strain (ΔALDH1+ΔALDH2+ΔALDH5) on ethanol. Finding the importance of NADP dependent ALDH1 on the growth of the strain on ethanol we examined if NAD dependent mitochondrial ALDH2 either from yeast or human would be able to support the growth of the triple deleted strain on ethanol if the mitochondrial form was placed in cytosol. We found that the NAD dependent mitochondrial ALDH2 from yeast or human was active in cytosol and supported the growth of the triple deleted strain on ethanol. Conclusion This study showed that coenzyme preference of ALDH is not critical in cytosol of yeast for the growth on ethanol. PMID:23454351

  3. Disruption of the Sjögren-Larsson Syndrome Gene Aldh3a2 in Mice Increases Keratinocyte Growth and Retards Skin Barrier Recovery.

    PubMed

    Naganuma, Tatsuro; Takagi, Shuyu; Kanetake, Tsukasa; Kitamura, Takuya; Hattori, Satoko; Miyakawa, Tsuyoshi; Sassa, Takayuki; Kihara, Akio

    2016-05-27

    The fatty aldehyde dehydrogenase (FALDH) ALDH3A2 is the causative gene of Sjögren Larsson syndrome (SLS). To date, the molecular mechanism underlying the symptoms characterizing SLS has been poorly understood. Using Aldh3a2(-/-) mice, we found here that Aldh3a2 was the major FALDH active in undifferentiated keratinocytes. Long-chain base metabolism was greatly impaired in Aldh3a2(-/-) keratinocytes. Phenotypically, the intercellular spaces were widened in the basal layer of the Aldh3a2(-/-) epidermis due to hyperproliferation of keratinocytes. Furthermore, oxidative stress-induced genes were up-regulated in Aldh3a2(-/-) keratinocytes. Upon keratinocyte differentiation, the activity of another FALDH, Aldh3b2, surpassed that of Aldh3a2 As a result, Aldh3a2(-/-) mice were indistinguishable from wild-type mice in terms of their whole epidermis FALDH activity, and their skin barrier function was uncompromised under normal conditions. However, perturbation of the stratum corneum caused increased transepidermal water loss and delayed barrier recovery in Aldh3a2(-/-) mice. In conclusion, Aldh3a2(-/-) mice replicated some aspects of SLS symptoms, especially at the basal layer of the epidermis. Our results suggest that hyperproliferation of keratinocytes via oxidative stress responses may partly contribute to the ichthyosis symptoms of SLS. PMID:27053112

  4. ALDH1A1-overexpressing cells are differentiated cells but not cancer stem or progenitor cells in human hepatocellular carcinoma

    PubMed Central

    Tanaka, Kaori; Tomita, Hiroyuki; Hisamatsu, Kenji; Nakashima, Takayuki; Hatano, Yuichiro; Sasaki, Yoshiyuki; Osada, Shinji; Tanaka, Takuji; Miyazaki, Tatsuhiko; Yoshida, Kazuhiro; Hara, Akira

    2015-01-01

    Aldehyde dehydrogenase 1A1 (ALDH1A1) is considered to be a cancer stem cell marker in several human malignancies. However, the role of ALDH1A1 in hepatocellular carcinoma (HCC) has not been well elucidated. In this study, we investigated the relationship between ALDH1A1 and clinicopathological findings and examined whether ALDH1A1 deserves to be a cancer stem cell marker in HCC. Sixty HCC samples obtained from surgical resection were collected for immunohistochemical (IHC) staining. Of these 60 samples, 47 samples of HCC tumorous and non-tumorous tissues were evaluated with qRT-PCR. There was no significant difference in the ALDH1A1-mRNA level between tumorous and non-tumorous tissues. Tumorous ALDH1A1-mRNA level had no relationship with the clinicopathological features. Immunoreactivity of ALDH1A1 was classified into two groups based on the percentage of ALDH1A1-overexpressing cells. The ALDH1A1-high group was significantly associated with low serum levels of α-fetoprotein, small tumor diameter, very little lymphovascular invasion, more differentiated pathology and good stage. The ALDH1A1-high group showed more favorable prognosis for recurrence-free survival. In double-staining IHC, ALDH1A1 was not co-expressed with BMI1, EpCAM, CD13, CD24, CD90 and CD133, which reported as cancer stem cell markers in HCC. In conclusion, ALDH1A1-overexpressing cells could appear to be differentiated cells rather than cancer stem cells in HCC. PMID:26160842

  5. NADH fluorescence lifetime analysis of the effect of magnesium ions on ALDH2

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aldehyde dehydrogenase 2 (ALDH2) catalyzes oxidation of toxic aldehydes to carboxylic acids. Physiologic levels of Mg2+ ions influence enzyme activity in part by increasing NADH binding affinity. Traditional fluorescence measurements monitor the blue shift of the NADH fluorescence spectrum to study ...

  6. Cloning and sequencing of the alcohol dehydrogenase II gene from Zymomonas mobilis

    DOEpatents

    Ingram, Lonnie O.; Conway, Tyrrell

    1992-01-01

    The alcohol dehydrogenase II gene from Zymomonas mobilis has been cloned and sequenced. This gene can be expressed at high levels in other organisms to produce acetaldehyde or to convert acetaldehyde to ethanol.

  7. The Oxidative Fermentation of Ethanol in Gluconacetobacter diazotrophicus Is a Two-Step Pathway Catalyzed by a Single Enzyme: Alcohol-Aldehyde Dehydrogenase (ADHa)

    PubMed Central

    Gómez-Manzo, Saúl; Escamilla, José E.; González-Valdez, Abigail; López-Velázquez, Gabriel; Vanoye-Carlo, América; Marcial-Quino, Jaime; de la Mora-de la Mora, Ignacio; Garcia-Torres, Itzhel; Enríquez-Flores, Sergio; Contreras-Zentella, Martha Lucinda; Arreguín-Espinosa, Roberto; Kroneck, Peter M. H.; Sosa-Torres, Martha Elena

    2015-01-01

    Gluconacetobacter diazotrophicus is a N2-fixing bacterium endophyte from sugar cane. The oxidation of ethanol to acetic acid of this organism takes place in the periplasmic space, and this reaction is catalyzed by two membrane-bound enzymes complexes: the alcohol dehydrogenase (ADH) and the aldehyde dehydrogenase (ALDH). We present strong evidence showing that the well-known membrane-bound Alcohol dehydrogenase (ADHa) of Ga. diazotrophicus is indeed a double function enzyme, which is able to use primary alcohols (C2–C6) and its respective aldehydes as alternate substrates. Moreover, the enzyme utilizes ethanol as a substrate in a reaction mechanism where this is subjected to a two-step oxidation process to produce acetic acid without releasing the acetaldehyde intermediary to the media. Moreover, we propose a mechanism that, under physiological conditions, might permit a massive conversion of ethanol to acetic acid, as usually occurs in the acetic acid bacteria, but without the transient accumulation of the highly toxic acetaldehyde. PMID:25574602

  8. The oxidative fermentation of ethanol in Gluconacetobacter diazotrophicus is a two-step pathway catalyzed by a single enzyme: alcohol-aldehyde Dehydrogenase (ADHa).

    PubMed

    Gómez-Manzo, Saúl; Escamilla, José E; González-Valdez, Abigail; López-Velázquez, Gabriel; Vanoye-Carlo, América; Marcial-Quino, Jaime; de la Mora-de la Mora, Ignacio; Garcia-Torres, Itzhel; Enríquez-Flores, Sergio; Contreras-Zentella, Martha Lucinda; Arreguín-Espinosa, Roberto; Kroneck, Peter M H; Sosa-Torres, Martha Elena

    2015-01-01

    Gluconacetobacter diazotrophicus is a N2-fixing bacterium endophyte from sugar cane. The oxidation of ethanol to acetic acid of this organism takes place in the periplasmic space, and this reaction is catalyzed by two membrane-bound enzymes complexes: the alcohol dehydrogenase (ADH) and the aldehyde dehydrogenase (ALDH). We present strong evidence showing that the well-known membrane-bound Alcohol dehydrogenase (ADHa) of Ga. diazotrophicus is indeed a double function enzyme, which is able to use primary alcohols (C2-C6) and its respective aldehydes as alternate substrates. Moreover, the enzyme utilizes ethanol as a substrate in a reaction mechanism where this is subjected to a two-step oxidation process to produce acetic acid without releasing the acetaldehyde intermediary to the media. Moreover, we propose a mechanism that, under physiological conditions, might permit a massive conversion of ethanol to acetic acid, as usually occurs in the acetic acid bacteria, but without the transient accumulation of the highly toxic acetaldehyde. PMID:25574602

  9. Aldehyde dehydrogenase activity promotes survival of human muscle precursor cells

    PubMed Central

    Jean, Elise; Laoudj-Chenivesse, Dalila; Notarnicola, Cécile; Rouger, Karl; Serratrice, Nicolas; Bonnieu, Anne; Gay, Stéphanie; Bacou, Francis; Duret, Cédric; Carnac, Gilles

    2011-01-01

    Abstract Aldehyde dehydrogenases (ALDH) are a family of enzymes that efficiently detoxify aldehydic products generated by reactive oxygen species and might therefore participate in cell survival. Because ALDH activity has been used to identify normal and malignant cells with stem cell properties, we asked whether human myogenic precursor cells (myoblasts) could be identified and isolated based on their levels of ALDH activity. Human muscle explant-derived cells were incubated with ALDEFLUOR, a fluorescent substrate for ALDH, and we determined by flow cytometry the level of enzyme activity. We found that ALDH activity positively correlated with the myoblast-CD56+ fraction in those cells, but, we also observed heterogeneity of ALDH activity levels within CD56-purified myoblasts. Using lentiviral mediated expression of shRNA we demonstrated that ALDH activity was associated with expression of Aldh1a1 protein. Surprisingly, ALDH activity and Aldh1a1 expression levels were very low in mouse, rat, rabbit and non-human primate myoblasts. Using different approaches, from pharmacological inhibition of ALDH activity by diethylaminobenzaldehyde, an inhibitor of class I ALDH, to cell fractionation by flow cytometry using the ALDEFLUOR assay, we characterized human myoblasts expressing low or high levels of ALDH. We correlated high ALDH activity ex vivo to resistance to hydrogen peroxide (H2O2)-induced cytotoxic effect and in vivo to improved cell viability when human myoblasts were transplanted into host muscle of immune deficient scid mice. Therefore detection of ALDH activity, as a purification strategy, could allow non-toxic and efficient isolation of a fraction of human myoblasts resistant to cytotoxic damage. PMID:19840193

  10. Aldehyde dehydrogenases: From eye crystallins to metabolic disease and cancer stem cells

    PubMed Central

    Vasiliou, Vasilis; Thompson, David C.; Smith, Clay; Fujita, Mayumi; Chen, Ying

    2014-01-01

    The aldehyde dehydrogenase (ALDH) superfamily is composed of nicotinamide adenine dinucleotide (phosphate) (NAD(P)+)-dependent enzymes that catalyze the oxidation of aldehydes to their corresponding carboxylic acids. To date, 24 ALDH gene families have been identified in the eukaryotic genome. In addition to aldehyde metabolizing capacity, ALDHs have additional catalytic (e.g. esterase and reductase) and non-catalytic activities. The latter include functioning as structural elements in the eye (crystallins) and as binding molecules to endobiotics and xenobiotics. Mutations in human ALDH genes and subsequent inborn errors in aldehyde metabolism are the molecular basis of several diseases. Most recently ALDH polymorphisms have been associated with gout and osteoporosis. Aldehyde dehydrogenase enzymes also play important roles in embryogenesis and development, neurotransmission, oxidative stress and cancer. This article serves as a comprehensive review of the current state of knowledge regarding the ALDH superfamily and the contribution of ALDHs to various physiological and pathophysiological processes. PMID:23159885

  11. Targeting ALDHbright human carcinoma initiating cells with ALDH1A1- specific CD8+ T cells

    PubMed Central

    Visus, Carmen; Wang, Yangyang; Lozano-Leon, Antonio; Ferris, Robert L.; Silver, Susan; Szczepanski, Miroslaw J.; Brand, Randall E.; Ferrone, Cristina R.; Whiteside, Theresa L.; Ferrone, Soldano; DeLeo, Albert B.; Wang, Xinhui

    2011-01-01

    Purpose Tumor cells expressing elevated aldehyde dehydrogenase (ALDH) activity attributed to ALDH1/3 isoforms have been identified as ALDHbright cells and have the properties attributed to cancer initiating cells (CIC). CIC represent the subpopulation of tumor cells that are resistant to conventional cancer treatments and highly tumorigenic in immunodeficient mice. They are considered to be responsible for tumor recurrence and metastasis. The ALDH1A1 isoform was previously identified as a tumor antigen recognized by CD8+ T cells. This study examines the ability of ALDH1A1-specific CD8+ T cells to eliminate ALDHbright cells and control tumor growth and metastases. Experimental Design ALDHbright cells were isolated by flow cytometry from HLA-A2+ human head and neck, breast and pancreas carcinoma cell lines using ALDEFLUOR® and tested for their tumorigenicity in immunodeficient mice. ALDH1A1-specific CD8+ T cells were generated in vitro and tested for their ability to eliminate CIC in vitro and in vivo by adoptive transfer to immunodeficient mice bearing human tumor xenografts. Results ALDHbright cells isolated by flow cytometry from HLA-A2+ breast, head and neck and pancreas carcinoma cell lines at low numbers (500 cells) were tumorigenic in immunodeficient mice. ALDHbright cells present in these cell lines, xenografts or surgically removed lesions were recognized by ALDH1A1-specific CD8+ T cells in vitro. Adoptive therapy with ALDH1A1-specific CD8+ T cells eliminated ALDHbright cells, inhibited tumor growth, metastases or prolonged survival of xenograft-bearing immunodeficient mice. Conclusions The results of this translational study strongly support the potential of ALDH1A1-based immunotherapy to selectively target CIC in human cancer. PMID:21856769

  12. ALDH Expression Characterizes G1-Phase Proliferating Beta Cells during Pregnancy

    PubMed Central

    Zhang, Lijuan; Wang, Lin; Liu, Xiaoliang; Zheng, Dongming; Liu, Sishi; Liu, Caixia

    2014-01-01

    High levels of aldehyde dehydrogenase (ALDH) activity have been detected in various progenitor and stem cells. Thus, Aldefluor fluorescence, which represents precisely the ALDH activity, has been widely used for the identification, evaluation, and isolation of stem and progenitor cells. Recently, ALDH activity was detected in embryonic and adult mouse pancreas, specifically in adult centroacinar and terminal duct cells supposed to harbor endocrine and exocrine progenitor cells in the adult pancreas. Nevertheless, ALDH activity and aldeflour fluorescence have not been examined in beta cells. Here, we report a dynamic increase in the number of aldeflour+ beta cells during pregnancy. Interestingly, nearly all these aldeflour+ beta cells are positive for Ki-67, suggesting that they are in an active cell cycle (G1, S and M phases). To determine precisely at which phase beta cells activate ALDH activity and thus become aldeflour+, we co-stained insulin with additional proliferation markers, phosphohistone3 (PHH3, a marker for M-phase proliferating cells) and Bromodeoxyuridine (BrdU, a marker for S-phase proliferating cells). Our data show little aldeflour+ beta cells that were positive for either PHH3, or BrdU, suggesting that beta cells activate ALDH and become Aldefluor+ when they enter G1-phase of active cell cycle, but may downregulate ALDH when they leave G1-phase and enter S phase. Our data thus reveal a potential change in ALDH activity of proliferating beta cells during pregnancy, which provides a novel method for isolation and analysis of proliferating beta cells. Moreover, our data also suggest that caution needs to be taken on interpretation of Aldefluor lineage-tracing data in pancreas. PMID:24787690

  13. ALDH1A1 induces resistance to CHOP in diffuse large B-cell lymphoma through activation of the JAK2/STAT3 pathway

    PubMed Central

    Jiang, Jinqiong; Liu, Yiping; Tang, Youhong; Li, Li; Zeng, Ruolan; Zeng, Shan; Zhong, Meizuo

    2016-01-01

    Increasing evidence has shown that aldehyde dehydrogenase 1A1 (ALDH1A1), a detoxifying enzyme, is responsible for chemoresistance in a variety of tumors. Although the majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), chemoresistance is a common cause of treatment failure. This study aims to investigate the significance of ALDH1A1 expression and the mechanism by which ALDH1A1 is involved in the chemoresistance of DLBCL cells. ALDH1A1 expression was assessed in 88 DLBCL tissues by immunohistochemistry. The association between ALDH1A1 expression and outcome was evaluated. We also investigated the effect of ALDH1A1 on CHOP resistance in DLBCL cells using functional analysis. ALDH1A1 expression levels were upregulated in patients with stable or progressive disease after CHOP and its expression positively correlated with expression of STAT3 and p-STAT3. In keeping with these observations, ALDH1A1 expression was significantly associated with short survival of DLBCL patients who received CHOP chemotherapy. In functional assays in Pfeiffer cells, overexpression of ALDH1A1 conferred resistance to CHOP, while silencing of ALDH1A1 using short hairpin RNA had the opposite effect. Furthermore, we also observed that ALDH1A1 could regulate the JAK2/STAT3 pathway, while inhibition of the JAK2/STAT3 pathway by WP1066 negated the effect of ALDH1A1 overexpression. These observations reveal that ALDH1A1 induces resistance to CHOP through activation of the JAK2/STAT3 pathway in DLBCL, and its targeting provides a potential strategic approach for reversing CHOP resistance. PMID:27621650

  14. ALDEHYDE DEHYDROGENASES EXPRESSION DURING POSTNATAL DEVELOPMENT: LIVER VS. LUNG

    EPA Science Inventory

    Aldehydes are highly reactive molecules present in the environment, and can be produced during biotransformation of xenobiotics. Although the lung can be a major target for aldehyde toxicity, development of aldehyde dehydrogenases (ALDHs), which detoxify aldehydes, in lung has be...

  15. Aldehyde dehydrogenase protein superfamily in maize.

    PubMed

    Zhou, Mei-Liang; Zhang, Qian; Zhou, Ming; Qi, Lei-Peng; Yang, Xiong-Bang; Zhang, Kai-Xuan; Pang, Jun-Feng; Zhu, Xue-Mei; Shao, Ji-Rong; Tang, Yi-Xiong; Wu, Yan-Min

    2012-11-01

    Maize (Zea mays ssp. mays L.) is an important model organism for fundamental research in the agro-biotechnology field. Aldehydes were generated in response to a suite of environmental stresses that perturb metabolism including salinity, dehydration, desiccation, and cold and heat shock. Many biologically important aldehydes are metabolized by the superfamily of NAD(P)(+)-dependent aldehyde dehydrogenases. Here, starting from the database of Z. mays, we identified 28 aldehyde dehydrogenase (ALDH) genes and 48 transcripts by the in silico cloning method using the ALDH-conserved domain amino acid sequence of Arabidopsis and rice as a probe. Phylogenetic analysis shows that all 28 members of the ALDH gene families were classified to ten distinct subfamilies. Microarray data and quantitative real-time PCR analysis reveal that ZmALDH9, ZmALDH13, and ZmALDH17 genes involve the function of drought stress, acid tolerance, and pathogens infection. These results suggested that these three ZmALDH genes might be potentially useful in maize genetic improvement. PMID:22983498

  16. [Biological actions of acetaldehyde].

    PubMed

    Ijiri, I

    1999-11-01

    Acetaldehyde (AcH), the first metabolite of ethanol (EtOH), is a chemically reactive and pharmacologically active compound. The author has been engaged in the study of AcH in cooperation with many researchers for three decades. We have found many biological actions of AcH which cause cardiovascular symptoms after drinking and also inhibited EtOH absorption via the canine and rat intestinal tract. This report covers the following five points. 1. The subjects were classified into a non-flushing group and a flushing group, according to the degree of facial flushing after drinking 200 ml of Sake (Japanese rice wire) at a rate of 100 ml per 5 min. Blood EtOH profile was much the same in both groups, yet peak blood AcH concentration in the flushing group was significantly higher than that in the non-flushing group. All subjects in the flushing group showed marked flushing and an increase in pulse rate after drinking, but these symptoms were not apparent in the non-flushing group. These results suggested that cardiovascular symptoms were caused by AcH itself. 2. Urinary excretions of both norepinephrine and epinephrine increased in the flushing cases after drinking Sake in comparison with those who drank the same volume of water. However, these catecholamines did not change in the non-flushing group. These results suggested that it is catecholamines released from the sympathetic nerve end or the adrenal medulla by AcH which caused an increase in pulse rate. 3. Bradykinin is released from high molecular kininogen by activated kallikrein and acts to dilate distal blood vessels and raise permeability in tissues. On the other hand, kallidin is released from low molecular kininogen by activated glandular kallikrein and its action is weaker than that of bradykinin. Blood low molecular kininogen levels in the flushing group decreased gradually after drinking and were mutually related to the blood AcH concentrations. But levels in the non-flushing group showed no difference

  17. Purity Determination of Acetaldehyde in an Acetaldehyde Certified Reference Material.

    PubMed

    Yamazaki, Taichi; Watanabe, Takuro; Nakamura, Satoe; Kato, Kenji

    2015-01-01

    Acetaldehyde is regulated as a toxic substance in various fields, and the method for monitoring or analysis of acetaldehyde is important. However, handling is difficult because of the high reactivity and low boiling point of acetaldehyde. Therefore, a reference material for high purity acetaldehyde with high accuracy was not available. Although the measuring method of acetaldehyde as a reagent is published in the Japanese Industrial Standard (JIS) where the specification of acetaldehyde purity is more than 80%, the analytical method described in JIS is not enough for an accuracy purity determination method. In this research, the high precision purity determination method for development of a certified reference material (CRM) of acetaldehyde was examined. By controlling the volatility and reactivity of acetaldehyde, we established the purity determination method of acetaldehyde with a relative standard uncertainty of less than 0.3%. Furthermore, this method was applied to develop a high purity acetaldehyde CRM with an expanded uncertainty of 0.005 kg kg(-1) (k = 2). PMID:26063006

  18. Role and structural characterization of plant aldehyde dehydrogenases from family 2 and family 7.

    PubMed

    Končitíková, Radka; Vigouroux, Armelle; Kopečná, Martina; Andree, Tomáš; Bartoš, Jan; Šebela, Marek; Moréra, Solange; Kopečný, David

    2015-05-15

    Aldehyde dehydrogenases (ALDHs) are responsible for oxidation of biogenic aldehyde intermediates as well as for cell detoxification of aldehydes generated during lipid peroxidation. So far, 13 ALDH families have been described in plants. In the present study, we provide a detailed biochemical characterization of plant ALDH2 and ALDH7 families by analysing maize and pea ALDH7 (ZmALDH7 and PsALDH7) and four maize cytosolic ALDH(cALDH)2 isoforms RF2C, RF2D, RF2E and RF2F [the first maize ALDH2 was discovered as a fertility restorer (RF2A)]. We report the crystal structures of ZmALDH7, RF2C and RF2F at high resolution. The ZmALDH7 structure shows that the three conserved residues Glu(120), Arg(300) and Thr(302) in the ALDH7 family are located in the substrate-binding site and are specific to this family. Our kinetic analysis demonstrates that α-aminoadipic semialdehyde, a lysine catabolism intermediate, is the preferred substrate for plant ALDH7. In contrast, aromatic aldehydes including benzaldehyde, anisaldehyde, cinnamaldehyde, coniferaldehyde and sinapaldehyde are the best substrates for cALDH2. In line with these results, the crystal structures of RF2C and RF2F reveal that their substrate-binding sites are similar and are formed by an aromatic cluster mainly composed of phenylalanine residues and several nonpolar residues. Gene expression studies indicate that the RF2C gene, which is strongly expressed in all organs, appears essential, suggesting that the crucial role of the enzyme would certainly be linked to the cell wall formation using aldehydes from phenylpropanoid pathway as substrates. Finally, plant ALDH7 may significantly contribute to osmoprotection because it oxidizes several aminoaldehydes leading to products known as osmolytes. PMID:25734422

  19. Prognostic values of aldehyde dehydrogenase 1 isoenzymes in ovarian cancer

    PubMed Central

    Ma, Yu-mei; Zhao, Shan

    2016-01-01

    Aldehyde dehydrogenase 1 (ALDH1) activity has been used as a functional stem cell marker to isolate cancer stem cells in different cancer types, including ovarian cancer. However, which ALDH1’s isoenzymes are contributing to ALDH1 activity in ovarian cancer remains elusive. In addition, the prognostic value of an individual ALDH1 isoenzyme in ovarian cancer is not clear. Thus, we accessed the prognostic value of ALDH1 isoenzymes in ovarian cancer patients through the “Kaplan–Meier plotter” online database, which can be used to determine the effect of the genes on ovarian cancer prognosis. We found that high mRNA expression of five ALDH1 isoenzymes, such as ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, and ALDH1L1, was not correlated with overall survival (OS) for all 1,306 ovarian cancer patients. In addition, all five of the ALDH1 isoenzymes’ high mRNA expression was found to be uncorrelated with OS in serous cancer or endometrioid cancer patients. However, ALDH1A3’s high mRNA expression is associated with worse OS in grade II ovarian cancer patients, hazard ratio (HR) 1.53 (1.14–2.07), P=0.005. ALDH1A2’s high mRNA expression is significantly associated with worse OS in TP53 wild-type ovarian cancer patients, HR 2.86 (1.56–5.08), P=0.00036. In addition, ALDH1A3’s high mRNA expression is significantly associated with better OS in TP53 wild-type ovarian cancer patients, HR 0.56 (0.32–1.00), P=0.04. Our results indicate that although ALDH1 isoenzyme mRNA might not be a prognostic marker for overall ovarian cancer patients, some isoenzymes, such as ALDH1A2 and ALDH1A3, might be a good prognostic marker for some types of ovarian cancer patients. PMID:27110126

  20. [Characterization of aldehyde dehydrogenase gene fragment from mung bean Vigna radiata using the polymerase chain reaction].

    PubMed

    Ponomarev, A G; Bubiakina, V V; Tatarinova, T D; Zelenin, S M

    1998-01-01

    Two degenerate oligonucleotide sequence primers and polymerase chain reactions on total DNA have been utilized to clone on 651--bp gene fragment coding the central part of amino acid sequence of an earlier unknown aldehyde dehydrogenase (ALDH) from mung bean. The deduced partial amino acid sequence for this aldehyde dehydrogenase shows about 65% sequence identity to ALDHs of Vibrio cholerae Rhodococcus sp., Alcaligenes eutrophus and about 45% sequence identity to mammalian ALDHs 1 and 2, ALDHs of Aspergillus niger and A, nidulans, the betain aldehyde dehydrogenase from spinach. Alignment of the mung bean aldehyde dehydrogenase partial amino acid sequence with the sequence of 16 NAD(P)(+)-dependent aldehyde dehydrogenases has demonstrated that all strictly conserved amino acid residues and all three conservative regions are identical. PMID:9778740

  1. Decarboxylation of Pyruvate to Acetaldehyde for Ethanol Production by Hyperthermophiles

    PubMed Central

    Eram, Mohammad S.; Ma, Kesen

    2013-01-01

    Pyruvate decarboxylase (PDC encoded by pdc) is a thiamine pyrophosphate (TPP)-containing enzyme responsible for the conversion of pyruvate to acetaldehyde in many mesophilic organisms. However, no pdc/PDC homolog has yet been found in fully sequenced genomes and proteomes of hyper/thermophiles. The only PDC activity reported in hyperthermophiles was a bifunctional, TPP- and CoA-dependent pyruvate ferredoxin oxidoreductase (POR)/PDC enzyme from the hyperthermophilic archaeon Pyrococcus furiosus. Another enzyme known to be involved in catalysis of acetaldehyde production from pyruvate is CoA-acetylating acetaldehyde dehydrogenase (AcDH encoded by mhpF and adhE). Pyruvate is oxidized into acetyl-CoA by either POR or pyruvate formate lyase (PFL), and AcDH catalyzes the reduction of acetyl-CoA to acetaldehyde in mesophilic organisms. AcDH is present in some mesophilic (such as clostridia) and thermophilic bacteria (e.g., Geobacillus and Thermoanaerobacter). However, no AcDH gene or protein homologs could be found in the released genomes and proteomes of hyperthermophiles. Moreover, no such activity was detectable from the cell-free extracts of different hyperthermophiles under different assay conditions. In conclusion, no commonly-known PDCs was found in hyperthermophiles. Instead of the commonly-known PDC, it appears that at least one multifunctional enzyme is responsible for catalyzing the non-oxidative decarboxylation of pyruvate to acetaldehyde in hyperthermophiles. PMID:24970182

  2. Acetaldehyde: A Chemical Whose Fortunes Have Changed.

    ERIC Educational Resources Information Center

    Wittcoff, Harold A.

    1983-01-01

    Describes industrial acetaldehyde synthesis/uses, explaining why acetaldehyde usage is declining in industry. Includes a discussion of the reaction chemistry, equations, and molecular structure diagrams. (JM)

  3. Coproduction of Acetaldehyde and Hydrogen during Glucose Fermentation by Escherichia coli ▿ †

    PubMed Central

    Zhu, Huilin; Gonzalez, Ramon; Bobik, Thomas A.

    2011-01-01

    Escherichia coli K-12 strain MG1655 was engineered to coproduce acetaldehyde and hydrogen during glucose fermentation by the use of exogenous acetyl-coenzyme A (acetyl-CoA) reductase (for the conversion of acetyl-CoA to acetaldehyde) and the native formate hydrogen lyase. A putative acetaldehyde dehydrogenase/acetyl-CoA reductase from Salmonella enterica (SeEutE) was cloned, produced at high levels, and purified by nickel affinity chromatography. In vitro assays showed that this enzyme had both acetaldehyde dehydrogenase activity (68.07 ± 1.63 μmol min−1 mg−1) and the desired acetyl-CoA reductase activity (49.23 ± 2.88 μmol min−1 mg−1). The eutE gene was engineered into an E. coli mutant lacking native glucose fermentation pathways (ΔadhE, ΔackA-pta, ΔldhA, and ΔfrdC). The engineered strain (ZH88) produced 4.91 ± 0.29 mM acetaldehyde while consuming 11.05 mM glucose but also produced 6.44 ± 0.26 mM ethanol. Studies showed that ethanol was produced by an unknown alcohol dehydrogenase(s) that converted the acetaldehyde produced by SeEutE to ethanol. Allyl alcohol was used to select for mutants with reduced alcohol dehydrogenase activity. Three allyl alcohol-resistant mutants were isolated; all produced more acetaldehyde and less ethanol than ZH88. It was also found that modifying the growth medium by adding 1 g of yeast extract/liter and lowering the pH to 6.0 further increased the coproduction of acetaldehyde and hydrogen. Under optimal conditions, strain ZH136 converted glucose to acetaldehyde and hydrogen in a 1:1 ratio with a specific acetaldehyde production rate of 0.68 ± 0.20 g h−1 g−1 dry cell weight and at 86% of the maximum theoretical yield. This specific production rate is the highest reported thus far and is promising for industrial application. The possibility of a more efficient “no-distill” ethanol fermentation procedure based on the coproduction of acetaldehyde and hydrogen is discussed. PMID:21803884

  4. Impacts of common variants in ALDH2 on coronary artery disease patients.

    PubMed

    Zhao, Jinzhao; You, Ling; Wang, Dao Wen; Cui, Wei

    2016-07-01

    Genome-wide association studies (GWAS) have identified Aldehyde dehydrogenase 2 (ALDH2) as a susceptibility locus for coronary artery disease (CAD) previously. However, the impacts of common variants in this gene on CAD and its outcomes have not been extensively studied. This study explored the association between the Tagging SNPs in ALDH2 and CAD as well as its main outcomes. Six common variants in ALDH2 were selected as tagging SNPs and two cohorts containing 7296 individuals were genotyped to investigate the impacts of ALDH2 on CAD and its main outcomes. The results show that the variant rs671 in ALDH2 is associated with an increased risk of CAD in southern Chinese (OR=1.26, 95%CI: 1.07-1.48, p=0.004), while not in northern Chinese (OR=1.00, 95%CI: 0.86-1.50, p=0.94). Meanwhile, we find that rs671 genotypes may not influence the outcomes of CAD (HR=1.11, 95%CI: 0.892-1.38, p=0.346). Additionally, we also tested the effect of rs671 genotype on CAD severity, while no significant association was found between them. In the subgroup analysis, the results revealed that rs671 were significantly associated with CAD (OR=1.24, 95%CI: 1.11-1.38, p<0.001) in non-alcoholic subjects. Overall, our findings indicate that the associations between rs671 in ALDH2 and CAD are regional disparity, and rs671 genotypes may not influence the main outcomes of CAD. PMID:26995653

  5. Aldehyde dehydrogenase activity selects for the holoclone phenotype in prostate cancer cells

    SciTech Connect

    Doherty, R.E.; Haywood-Small, S.L.; Sisley, K.; Cross, N.A.

    2011-11-04

    Highlights: Black-Right-Pointing-Pointer Isolated ALDH{sup Hi} PC3 cells preferentially form primitive holoclone-type colonies. Black-Right-Pointing-Pointer Primitive holoclone colonies are predominantly ALDH{sup Lo} but contain rare ALDH{sup Hi} cells. Black-Right-Pointing-Pointer Holoclone-forming cells are not restricted to the ALDH{sup Hi} population. Black-Right-Pointing-Pointer ALDH phenotypic plasticity occurs in PC3 cells (ALDH{sup Lo} to ALDH{sup Hi} and vice versa). Black-Right-Pointing-Pointer ALDH{sup Hi} cells are observed but very rare in PC3 spheroids grown in stem cell medium. -- Abstract: Aldehyde dehydrogenase 1 (ALDH) activity is considered to be a marker of cancer stem cells (CSCs) in many tumour models, since these cells are more proliferative and tumourigenic than ALDH{sup Lo} cells in experimental models. However it is unclear whether all CSC-like cells are within the ALDH{sup Hi} population, or whether all ALDH{sup Hi} cells are highly proliferative and tumourigenic. The ability to establish a stem cell hierarchy in vitro, whereby sub-populations of cells have differing proliferative and differentiation capacities, is an alternate indication of the presence of stem cell-like populations within cell lines. In this study, we have examined the interaction between ALDH status and the ability to establish a stem cell hierarchy in PC3 prostate cancer cells. We demonstrate that PC3 cells contain a stem cell hierarchy, and isolation of ALDH{sup Hi} cells enriches for the most primitive holoclone population, however holoclone formation is not restricted to ALDH{sup Hi} cells. In addition, we show that ALDH activity undergoes phenotypic plasticity, since the ALDH{sup Lo} population can develop ALDH{sup Hi} populations comparable to parental cells within 2 weeks in culture. Furthermore, we show that the majority of ALDH{sup Hi} cells are found within the least primitive paraclone population, which is circumvented by culturing PC3 cells as spheroids in

  6. Comparative study of the damage produced by acute ethanol and acetaldehyde treatment in a human fetal hepatic cell line.

    PubMed

    Olivares, I P; Bucio, L; Souza, V; Cárabez, A; Gutiérrez-Ruiz, M C

    1997-06-27

    The effects of acute ethanol and acetaldehyde treatment on cell proliferation, cell adhesion capacity, neutral red incorporation into lysosomes, glutathione content, protein sulfhydryl compounds, lipid peroxidation, inner mitochondrial membrane integrity (MTT test), lactate dehydrogenase activity (LDH) and ultrastructural alterations were investigated in a human fetal hepatic cell line (WRL-68 cells). WRL-68 cells were used, due to the fact that, although this cell line expresses some hepatic characteristics, it does not express alcohol dehydrogenase or cytochrome P450 activity, so it could be a good model to study the effect of the toxic agents per se. Cells were exposed during 120 min with 200 mM ethanol or 10 mM acetaldehyde. Under these conditions, cells presented 100% viability and no morphological alteration was observed by light microscopy. Acetaldehyde-treated cells reduced their proliferative capacity drastically while the ethanol-treated ones presented no difference with control cells. Cell adhesion to substrate, measured as time required to adhere to the substrate and time required to detach from the substrate, was diminished in acetaldehyde WRL-68-treated cells. Cytotoxicity measures as neutral red and MTT test showed that acetaldehyde-treated cells presented more damage than ethanol-treated ones. Cellular respiratory capacity was compromised by acetaldehyde treatment due to 40% less oxygen consumption than control cells. Lipid peroxidation values, measured as malondialdehyde production, were higher in ethanol-treated WRL-68 cells (127%) than in acetaldehyde-treated ones (60%) to control cell values. Lactate dehydrogenase activity (LDH) in extracellular media of ethanol-treated cells presented the highest values. GSH content was reduced 95% and thiol protein content was diminished severely in acetaldehyde-treated cells. Transmission electron microscopy showed more ultrastructural alterations in cells treated with acetaldehyde. The results indicate that

  7. ALDH1A1 Maintains Ovarian Cancer Stem Cell-Like Properties by Altered Regulation of Cell Cycle Checkpoint and DNA Repair Network Signaling

    PubMed Central

    Meng, Erhong; Mitra, Aparna; Tripathi, Kaushlendra; Finan, Michael A.; Scalici, Jennifer; McClellan, Steve; da Silva, Luciana Madeira; Reed, Eddie; Shevde, Lalita A.; Palle, Komaraiah; Rocconi, Rodney P.

    2014-01-01

    Objective Aldehyde dehydrogenase (ALDH) expressing cells have been characterized as possessing stem cell-like properties. We evaluated ALDH+ ovarian cancer stem cell-like properties and their role in platinum resistance. Methods Isogenic ovarian cancer cell lines for platinum sensitivity (A2780) and platinum resistant (A2780/CP70) as well as ascites from ovarian cancer patients were analyzed for ALDH+ by flow cytometry to determine its association to platinum resistance, recurrence and survival. A stable shRNA knockdown model for ALDH1A1 was utilized to determine its effect on cancer stem cell-like properties, cell cycle checkpoints, and DNA repair mediators. Results ALDH status directly correlated to platinum resistance in primary ovarian cancer samples obtained from ascites. Patients with ALDHHIGH displayed significantly lower progression free survival than the patients with ALDHLOW cells (9 vs. 3 months, respectively p<0.01). ALDH1A1-knockdown significantly attenuated clonogenic potential, PARP-1 protein levels, and reversed inherent platinum resistance. ALDH1A1-knockdown resulted in dramatic decrease of KLF4 and p21 protein levels thereby leading to S and G2 phase accumulation of cells. Increases in S and G2 cells demonstrated increased expression of replication stress associated Fanconi Anemia DNA repair proteins (FANCD2, FANCJ) and replication checkpoint (pS317 Chk1) were affected. ALDH1A1-knockdown induced DNA damage, evidenced by robust induction of γ-H2AX and BAX mediated apoptosis, with significant increases in BRCA1 expression, suggesting ALDH1A1-dependent regulation of cell cycle checkpoints and DNA repair networks in ovarian cancer stem-like cells. Conclusion This data suggests that ovarian cancer cells expressing ALDH1A1 may maintain platinum resistance by altered regulation of cell cycle checkpoint and DNA repair network signaling. PMID:25216266

  8. DEVELOPMENTAL EXPRESSION OF ALDEHYDE DEHYDROGENASE IN RAT: A COMPARISON OF LIVER AND LUNG DEVELOPMENT

    EPA Science Inventory

    Metabolism is one of the major determinants for age-related susceptibility changes to chemicals. Aldehydes are highly reactive molecules present in the environment and can be produced during biotransformation of xenobiotics. Aldehyde dehydrogenases (ALDH) are important in aldehyd...

  9. Sca-1+ cells from fetal heart with high aldehyde dehydrogenase activity exhibit enhanced gene expression for self-renewal, proliferation, and survival.

    PubMed

    Dey, Devaveena; Pan, Guodong; Varma, Nadimpalli Ravi S; Palaniyandi, Suresh Selvaraj

    2015-01-01

    Stem/progenitor cells from multiple tissues have been isolated based on enhanced activity of cytosolic aldehyde dehydrogenase (ALDH) enzyme. ALDH activity has emerged as a reliable marker for stem/progenitor cells, such that ALDH(bright/high) cells from multiple tissues have been shown to possess enhanced stemness properties (self-renewal and multipotency). So far though, not much is known about ALDH activity in specific fetal organs. In this study, we sought to analyze the presence and activity of the ALDH enzyme in the stem cell antigen-1-positive (Sca-1+) cells of fetal human heart. Biochemical assays showed that a subpopulation of Sca-1+ cells (15%) possess significantly high ALDH1 activity. This subpopulation showed increased expression of self-renewal markers compared to the ALDH(low) fraction. The ALDH(high) fraction also exhibited significant increase in proliferation and pro-survival gene expression. In addition, only the ALDH(high) and not the ALDH(low) fraction could give rise to all the cell types of the original population, demonstrating multipotency. ALDH(high) cells showed increased resistance against aldehyde challenge compared to ALDH(low) cells. These results indicate that ALDH(high) subpopulation of the cultured human fetal cells has enhanced self-renewal, multipotency, high proliferation, and survival, indicating that this might represent a primitive stem cell population within the fetal human heart. PMID:25861413

  10. Common ALDH2 genetic variants predict development of hypertension in the SAPPHIRe prospective cohort: Gene-environmental interaction with alcohol consumption

    PubMed Central

    2012-01-01

    Background Genetic variants near/within the ALDH2 gene encoding the mitochondrial aldehyde dehydrogenase 2 have been associated with blood pressure and hypertension in several case–control association studies in East Asian populations. Methods Three common tag single nucleotide polymorphisms (tagSNP) in the ALDH2 gene were genotyped in 1,134 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family cohort. We examined whether the ALDH2 SNP genotypes predicted the development of hypertension in the prospective SAPPHIRe cohort. Results Over an average follow-up period of 5.7 years, carriers homozygous for the rs2238152 T allele in the ALDH2 gene were more likely to progress to hypertension than were non-carriers (hazard ratio [HR], 2.88, 95% confidence interval [CI], 1.06-7.84, P = 0.03), corresponding to a population attributable risk of ~7.1%. The risk associated with the rs2238152 T allele were strongest in heavy/moderate alcohol drinkers and was reduced in non-drinkers, indicating an interaction between ALDH2 genetic variants and alcohol intake on the risk of hypertension (P for interaction = 0.04). The risk allele was associated with significantly lower ALDH2 gene expression levels in human adipose tissue. Conclusion ALDH2 genetic variants were associated with progression to hypertension in a prospective Chinese cohort. The association was modified by alcohol consumption. PMID:22839215

  11. Aldehyde Dehydrogenase 1A1: Friend or Foe to Female Metabolism?

    PubMed Central

    Petrosino, Jennifer M.; DiSilvestro, David; Ziouzenkova, Ouliana

    2014-01-01

    In this review, we summarize recent advances in understanding vitamin A-dependent regulation of sex-specific differences in metabolic diseases, inflammation, and certain cancers. We focus on the characterization of the aldehyde dehydrogenase-1 family of enzymes (ALDH1A1, ALDH1A2, ALDH1A3) that catalyze conversion of retinaldehyde to retinoic acid. Additionally, we propose a “horizontal transfer of signaling” from estrogen to retinoids through the action of ALDH1A1. Although estrogen does not directly influence expression of Aldh1a1, it has the ability to suppress Aldh1a2 and Aldh1a3, thereby establishing a female-specific mechanism for retinoic acid generation in target tissues. ALDH1A1 regulates adipogenesis, abdominal fat formation, glucose tolerance, and suppression of thermogenesis in adipocytes; in B cells, ALDH1A1 plays a protective role by inducing oncogene suppressors Rara and Pparg. Considering the conflicting responses of Aldh1a1 in a multitude of physiological processes, only tissue-specific regulation of Aldh1a1 can result in therapeutic effects. We have shown through successful implantation of tissue-specific Aldh1a1−/− preadipocytes that thermogenesis can be induced in wild-type adipose tissues to resolve diet-induced visceral obesity in females. We will briefly discuss the emerging role of ALDH1A1 in multiple myeloma, the regulation of reproduction, and immune responses, and conclude by discussing the role of ALDH1A1 in future therapeutic applications. PMID:24594504

  12. Ocular Aldehyde Dehydrogenases: Protection against Ultraviolet Damage and Maintenance of Transparency for Vision

    PubMed Central

    Chen, Ying; Thompson, David C.; Koppaka, Vindhya; Jester, James V.; Vasiliou, Vasilis

    2012-01-01

    Aldehyde dehydrogenase (ALDH) enzymes catalyze the NAD(P)+-dependent oxidation of a wide variety of endogenous and exogenous aldehydes to their corresponding acids. Some members of the ALDH superfamily of enzymes are abundantly expressed in the mammalian cornea and lens in a taxon-specific manner. Considered to be corneal and lens crystallins, they confer protective and transparent properties upon these ocular tissues. ALDH3A1 is highly expressed in the cornea of most mammals, with the exception of rabbit that expresses exclusively ALDH1A1 in the cornea. ALDH1A1 is present in both the cornea and lens of several animal species. As a result of their catalytic and non-catalytic functions, ALDH3A1 and ALDH1A1 proteins protect inner ocular tissues from ultraviolet radiation and reactive oxygen-induced damage. In addition, these corneal crystallins contribute to cellular transparency in corneal stromal keratocytes, supporting a structural role of these ALDH proteins. A putative regulatory function of ALDH3A1 on corneal cell proliferation has also been proposed. Finally, the three retinaldehye dehydrogenases cooperatively mediate retinoic acid signaling during the eye development. PMID:23098688

  13. Aldehyde Dehydrogenase 2 Has Cardioprotective Effects on Myocardial Ischaemia/Reperfusion Injury via Suppressing Mitophagy

    PubMed Central

    Ji, Wenqing; Wei, Shujian; Hao, Panpan; Xing, Junhui; Yuan, Qiuhuan; Wang, Jiali; Xu, Feng; Chen, Yuguo

    2016-01-01

    Mitophagy, a selective form of autophagy, is excessively activated in myocardial ischemia/reperfusion (I/R). The study investigated whether aldehyde dehydrogenase 2 (ALDH2) exerted its cardioprotective effect by regulating mitophagy. Myocardial infarct size and apoptosis after I/R in rats were ameliorated by Alda-1, an ALDH2 activator, and aggravated by ALDH2 inhibition. Both in I/R rats and hypoxia/reoxygenation H9C2 cells, ALDH2 activation suppressed phosphatase and tensin homolog-induced putative kinase 1 (PINK1)/Parkin expression, regulating mitophagy, by preventing 4-hydroxynonenal, reactive oxygen species and mitochondrial superoxide accumulation. Furthermore, the effect was enhanced by ALDH2 inhibition. Thus, ALDH2 may protect hearts against I/R injury by suppressing PINK1/Parkin–dependent mitophagy. PMID:27148058

  14. ALDH1-High Ovarian Cancer Stem-Like Cells Can Be Isolated from Serous and Clear Cell Adenocarcinoma Cells, and ALDH1 High Expression Is Associated with Poor Prognosis

    PubMed Central

    Kuroda, Takafumi; Hirohashi, Yoshihiko; Torigoe, Toshihiko; Yasuda, Kazuyo; Takahashi, Akari; Asanuma, Hiroko; Morita, Rena; Mariya, Tasuku; Asano, Takuya; Mizuuchi, Masahito; Saito, Tsuyoshi; Sato, Noriyuki

    2013-01-01

    Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as a small population of cancer cells that have high tumorigenicity. Furthermore, CSCs/CICs are resistant to several cancer therapies, and CSCs/CICs are therefore thought to be responsible for cancer recurrence after treatment and distant metastasis. In epithelial ovarian cancer (EOC) cases, disease recurrence after chemotherapy is frequently observed, suggesting ovarian CSCs/CICs are involved. There are four major histological subtypes in EOC, and serous adenocarcinoma and clear cell adenocarcinoma are high-grade malignancies. We therefore analyzed ovarian CSCs/CICs from ovarian carcinoma cell lines (serous adenocarcinoma and clear cell adenocarcinoma) and primary ovarian cancer cells in this study. We isolated ovarian CSCs/CICs as an aldehyde dehydrogenase 1 high (ALDH1high) population from 6 EOC cell lines (3 serous adenocarcinomas and 3 clear cell adenocarcinomas) by the ALDEFLUOR assay. ALDH1high cells showed greater sphere-forming ability, higher tumorigenicity and greater invasive capability, indicating that ovarian CSCs/CICs are enriched in ALDH1high cells. ALDH1high cells could also be isolated from 8 of 11 primary ovarian carcinoma samples. Immunohistochemical staining revealed that higher ALDH1 expression levels in ovary cancer cases are related to poorer prognosis in both serous adenocarcinoma cases and clear cell adenocarcinoma cases. Taken together, the results indicate that ALDH1 is a marker for ovarian CSCs/CICs and that the expression level of ALDH1 might be a novel biomarker for prediction of poor prognosis. PMID:23762304

  15. Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in Orientals.

    PubMed Central

    Yoshida, A; Huang, I Y; Ikawa, M

    1984-01-01

    Usual human livers contain two major aldehyde dehydrogenase [(ALDH) aldehyde:NAD+ oxidoreductase] isozymes--i.e., a cytosolic ALDH1 component and a mitochondrial ALDH2 component--whereas approximately equal to 50% of Orientals are "atypical" and have only the ALDH1 isozyme and are missing the ALDH2 isozyme. We previously demonstrated that atypical livers contain an enzymatically inactive but immunologically crossreactive material (CRM) corresponding to the ALDH2 component. The enzymatically active ALDH2 obtained from a usual liver and the CRM obtained from an atypical liver were reduced, S-carboxymethylated, and digested by trypsin. Separation of their digests by high-performance reverse-phase chromatography and by two-dimensional paper chromatography and electrophoresis revealed that ALDH2 contained a peptide sequence of -Glu-Leu-Gly-Glu-Ala-Gly-Leu-Gln-Ala-Asn-Val-Gln-Val-Lys- and that the glutamine adjacent to lysine was substituted by lysine in CRM. All other tryptic peptides, including eight peptides containing S-carboxymethylcysteine, were common in ALDH2 and CRM. It is concluded that a point mutation in the human ALDH2 locus produced the glutamine leads to lysine substitution and enzyme inactivation. Images PMID:6582480

  16. Association between ALDH1L1 gene polymorphism and neural tube defects in the Chinese Han population.

    PubMed

    Wu, Lihua; Lu, Xiaolin; Guo, Jin; Zhang, Ting; Wang, Fang; Bao, Yihua

    2016-07-01

    We investigated single-nucleotide polymorphisms (SNPs) in the aldehyde dehydrogenase family1 L1 gene (ALDH1L1) and their association with neural tube defects (NTDs) in the Chinese population. A total of 271 NTDs cases and 192 healthy controls were used in this study. A total of 112 selected SNPs in the ALDH1L1 gene were analyzed using the next-generation sequencing method. Statistical analysis was carried out to investigate the correlation between SNPs and patient susceptibility to NTDs. Statistical analysis revealed a significant correlation between the SNP sites rs4646733, rs2305225, and rs2276731 in the ALDH1L1 gene and NTDs. The TT genotype and T allele of rs4646733 in ALDH1L1 were associated with a significantly increased incidence of NTDs [odds ratio (OR) = 2.16, 95 % confidence interval (CI) 1.199-3.896 for genotype; and OR = 1.46, 95 % CI 1.092-1.971 for allele]. The AA genotype and A allele of rs2305225 in ALDH1L1 were associated with a significantly increased incidence of NTDs (OR = 2.03, 95 % CI 1.202-3.646 for genotype, and OR = 1.44, 95 % CI 1.096-1.905 for allele). The CT genotype and C allele of rs2276731 in ALDH1L1 significantly were associated with an increased incidence of NTDs (OR = 1.67, 95 % CI 1.129-2.491 with genotype, and OR = 1.32, 95 % CI 0.956-1.816 with allele).The polymorphic loci rs4646733, rs2305225, and rs2276731 in the ALDH1L1 gene maybe potential risk factors for NTDs in the Chinese population. PMID:26993122

  17. Association between ALDH1+/CD133+ stem-like cells and tumor angiogenesis in invasive ductal breast carcinoma

    PubMed Central

    LV, XINQUAN; WANG, YINGZI; SONG, YIMIN; PANG, XIA; LI, HUIXIANG

    2016-01-01

    The growth and metastasis of tumors is dependent on angiogenesis; however, the association between tumor stem cells (TSCs) and tumor angiogenesis remains to be elucidated. The present study aimed to investigate the expression of the TSC markers aldehyde dehydrogenase 1 (ALDH1) and cluster of differentiation 133 (CD133) in invasive ductal breast carcinoma, and identify their correlation with tumor angiogenesis. Stem-like cells from the breast tissue of 120 patients, who were diagnosed with invasive ductal breast carcinoma at The First Affiliated Hospital of Zhengzhou University (Zhengzhou, Henan, China) between January 2009 and December 2010, were collected by surgical resection and analyzed using immunohistochemical double staining. The expression of the vascular markers CD34, CD105 and vascular endothelial growth factor (VEGF) were determined using single staining. Overall, 25.83% (31/120) of the specimens contained a large number of ALDH1+/CD133+ stem-like cells (ALDH1+/CD133+ tumor). ALDH1+/CD133+ expression is associated with microvessel density, VEGF-positive rate and estrogen receptor expression (P<0.05); however, ALDH1+/CD133+ expression was not associated with age, tumor diameter, lymph node metastasis, histological classification, progesterone receptor expression or human epidermal growth factor receptor 2 expression (P>0.05). The ALDH1+/CD133+ tumor phenotype and expression of VEGF were identified to be correlated in the present study (P=0.020). The present study revealed a close association between breast cancer TSC markers, including ALDH1 and CD133, and tumor angiogenesis. The results of the present study may provide a novel target and treatment strategy for future studies investigating tumor growth and metastasis. PMID:26998072

  18. An Indian family with Sjögren-Larsson syndrome caused by a novel ALDH3A2 mutation.

    PubMed

    Sakai, Kaori; Akiyama, Masashi; Yanagi, Teruki; Nampoothiri, Sheela; Mampilly, Tony; Sunitha, V; Shimizu, Hiroshi

    2010-09-01

    Sjögren-Larsson syndrome is an autosomal-recessive hereditary disorder characterized by congenital ichthyosis, mental retardation and spastic diplegia or tetraplegia. It is known that mutations in the fatty aldehyde dehydrogenase (FALDH) gene (ALDH3A2) underlie SLS. We report two Indian sisters showing typical clinical features of SLS. Direct sequencing of the entire coding region of ALDH3A2 revealed a novel homozygous mutation, c.142G>T (p.Asp48Tyr) in exon 1, in both patients. Their parents harbored the mutation heterozygously. Mutant-allele-specific amplification analysis using PCR products as a template verified the mutation in the patients. The aspartic acid residue at the mutation site is located in the C-terminal portion of the second a-helix strand, a2, of N-terminal four helices of FALDH and the FALDH amino-acid sequence alignment shows that this aspartic acid residue is conserved among several diverse species. Until now, a number of mutations in ALDH3A2 have been shown to be responsible for SLS in Europe, the Middle East, Africa, and North and South America. However, in Asian populations, ALDH3A2 mutations have been identified only in Japanese SLS patients. Here we report an ALDH3A2 mutation for the first time in SLS patients in the Asian country other than Japan. The present results suggest that ALDH3A2 is a gene responsible for SLS in Asian populations. We hope ALDH3A2 mutation search will be globally available including many Asian countries in the future. PMID:20883264

  19. Neurodegeneration and motor dysfunction in mice lacking cytosolic and mitochondrial aldehyde dehydrogenases: implications for Parkinson's disease.

    PubMed

    Wey, Margaret Chia-Ying; Fernandez, Elizabeth; Martinez, Paul Anthony; Sullivan, Patricia; Goldstein, David S; Strong, Randy

    2012-01-01

    Previous studies have reported elevated levels of biogenic aldehydes in the brains of patients with Parkinson's disease (PD). In the brain, aldehydes are primarily detoxified by aldehyde dehydrogenases (ALDH). Reduced ALDH1 expression in surviving midbrain dopamine neurons has been reported in brains of patients who died with PD. In addition, impaired complex I activity, which is well documented in PD, reduces the availability of the NAD(+) co-factor required by multiple ALDH isoforms to catalyze the removal of biogenic aldehydes. We hypothesized that chronically decreased function of multiple aldehyde dehydrogenases consequent to exposure to environmental toxins and/or reduced ALDH expression, plays an important role in the pathophysiology of PD. To address this hypothesis, we generated mice null for Aldh1a1 and Aldh2, the two isoforms known to be expressed in substantia nigra dopamine neurons. Aldh1a1(-/-)×Aldh2(-/-) mice exhibited age-dependent deficits in motor performance assessed by gait analysis and by performance on an accelerating rotarod. Intraperitoneal administration of L-DOPA plus benserazide alleviated the deficits in motor performance. We observed a significant loss of neurons immunoreactive for tyrosine hydroxylase (TH) in the substantia nigra and a reduction of dopamine and metabolites in the striatum of Aldh1a1(-/-)×Aldh2(-/-) mice. We also observed significant increases in biogenic aldehydes reported to be neurotoxic, including 4-hydroxynonenal (4-HNE) and the aldehyde intermediate of dopamine metabolism, 3,4-dihydroxyphenylacetaldehyde (DOPAL). These results support the hypothesis that impaired detoxification of biogenic aldehydes may be important in the pathophysiology of PD and suggest that Aldh1a1(-/-)×Aldh2(-/-) mice may be a useful animal model of PD. PMID:22384032

  20. Fluorescence lifetime analysis and effect of magnesium ions on binding of NADH to human aldehyde dehydrogenase 1

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aldehyde dehydrogenase 1 (ALDH1) catalyzes oxidation of toxic aldehydes to carboxylic acids. Physiologic levels of Mg2+ ions influence ALDH1 activity in part by increasing NADH binding affinity to the enzyme thus reducing activity. By using time-resolved fluorescence spectroscopy, we have resolved t...

  1. Immunohistochemical analysis of aldehyde dehydrogenase isoforms and their association with estrogen-receptor status and disease progression in breast cancer

    PubMed Central

    Opdenaker, Lynn M; Arnold, Kimberly M; Pohlig, Ryan T; Padmanabhan, Jayasree S; Flynn, Daniel C; Sims-Mourtada, Jennifer

    2014-01-01

    In many types of tumors, especially breast tumors, aldehyde dehydrogenase (ALDH) activity has been used to identify cancer stem-like cells within the tumor. The presence and quantity of these cells are believed to predict the response of tumors to chemotherapy. Therefore, identification and eradication of these cells would be necessary to cure the patient. However, there are 19 different ALDH isoforms that could contribute to the enzyme activity. ALDH1A1 and ALDH1A3 are among the isoforms mostly responsible for the increased ALDH activity observed in these stem-like cells, although the main isoforms vary in different tissues and tumor types. In the study reported here, we attempted to determine if ALDH1A1 or ALDH1A3, specifically, correlate with tumor stage, grade, and hormone-receptor status in breast-cancer patients. While there was no significant correlation between ALDH1A1 and any of the parameters tested, we were able to identify a positive correlation between ALDH1A3 and tumor stage in triple-negative cancers. In addition, ALDH1A3 was negatively correlated with estrogen-receptor status. Our data suggest that ALDH1A3 could be utilized as a marker to identify stem-like cells within triple-negative tumors. PMID:25540596

  2. Targeting Aldehyde Dehydrogenase: a Potential Approach for Cell labeling

    PubMed Central

    Vaidyanathan, Ganesan; Song, Haijing; Affleck, Donna; McDougald, Darryl L.; Storms, Robert W.; Zalutksy, Michael R.; Chin, Bennett B.

    2009-01-01

    Introduction To advance the science and clinical application of stem cell therapy, the availability of a highly sensitive, quantitative, and translational method for tracking stem cells would be invaluable. Because hematopoetic stem cells express high levels of the cytosolic enzyme aldehyde dehydrogenase-1A1 (ALDH1), we sought to develop an agent that is specific to ALDH1 and thus to cells expressing the enzyme. Such an agent might be also helpful in identifying tumors that are resistant to cyclophosphomide chemotherapy because ALDH1 is known to be responsible for this resistance. Methods We developed schemes for the synthesis of two 3radioiodinated aldehdyes—N-formylmethyl-5-[*I]iodopyridine-3-carboxamide ([*I]FMIC) and 4-diethylamino-3-[*I]iodobenzaldehyde ([*I]DEIBA)—at no-carrier-added levels from their respective tin precursors. These agents were evaluated using pure ALDH1 and tumor cells that expressed the enzyme. Results The average radiochemical yields for the synthesis [125I]FMIC and [125I]DEIBA were 70 ± 5% and 47 ± 14%, respectively. ALDH1 converted both compounds to respective acids suggesting their suitability as ALDH1 imaging agents. Although ability of ALDH1 within the cells to oxidize one of these substrates was shown, specific uptake in ALDH-expressing tumor cells could not be demonstrated. Conclusion To pursue this approach for ALDH1 imaging, radiolabeled aldehydes need to be designed such that, in addition to being good substrates for ALDH1, the cognate products should be sufficiently polar so as to be retained within the cells. PMID:19875048

  3. 27 CFR 21.93 - Acetaldehyde.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Acetaldehyde. 21.93 Section 21.93 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT... Acetaldehyde. (a) Aldehyde content (as acetaldehyde). Not less than 95.0 percent by weight. (b)...

  4. 27 CFR 21.93 - Acetaldehyde.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2013-04-01 2013-04-01 false Acetaldehyde. 21.93 Section 21.93 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT... Acetaldehyde. (a) Aldehyde content (as acetaldehyde). Not less than 95.0 percent by weight. (b)...

  5. 27 CFR 21.93 - Acetaldehyde.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2011-04-01 2011-04-01 false Acetaldehyde. 21.93 Section 21.93 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT... Acetaldehyde. (a) Aldehyde content (as acetaldehyde). Not less than 95.0 percent by weight. (b)...

  6. Cloning and heterologous expression of two aryl-aldehyde dehydrogenases from the white-rot basidiomycete Phanerochaete chrysosporium

    SciTech Connect

    Nakamura, Tomofumi; Ichinose, Hirofumi; Wariishi, Hiroyuki

    2010-04-09

    We identified two aryl-aldehyde dehydrogenase proteins (PcALDH1 and PcALDH2) from the white-rot basidiomycete Phanerochaete chrysosporium. Both PcALDHs were translationally up-regulated in response to exogenous addition of vanillin, one of the key aromatic compounds in the pathway of lignin degradation by basidiomycetes. To clarify the catalytic functions of PcALDHs, we isolated full-length cDNAs encoding these proteins and heterologously expressed the recombinant enzymes using a pET/Escherichia coli system. The open reading frames of both PcALDH1 and PcALDH2 consisted of 1503 nucleotides. The deduced amino acid sequences of both proteins showed high homologies with aryl-aldehyde dehydrogenases from other organisms and contained ten conserved domains of ALDHs. Moreover, a novel glycine-rich motif 'GxGxxxG' was located at the NAD{sup +}-binding site. The recombinant PcALDHs catalyzed dehydrogenation reactions of several aryl-aldehyde compounds, including vanillin, to their corresponding aromatic acids. These results strongly suggested that PcALDHs metabolize aryl-aldehyde compounds generated during fungal degradation of lignin and various aromatic xenobiotics.

  7. An animal model of human aldehyde dehydrogenase deficiency

    SciTech Connect

    Chang, C.; Mann, J.; Yoshida, A.

    1994-09-01

    The genetic deficiency of ALDH2, a major mitochondrial aldehyde dehydrogenase, is intimately related to alcohol sensitivity and the degree of predisposition to alcoholic diseases in humans. The ultimate biological role of ALDH2 can be exposed by knocking out the ALDH2 gene in an animal model. As the first step for this line of studies, we cloned and characterized the ALDH2 gene from mouse C57/6J strain which is associated with a high alcohol preference. The gene spans 26 kbp and is composed of 13 exons. Embryonic stem cells were transfected with a replacement vector which contains a partially deleted exon3, a positive selection cassette (pPgk Neo), exon 4 with an artificial stop codon, exons 5, 6, 7, and a negative selection cassette (pMCI-Tk). Genomic DNAs prepared from drug resistant clones were analyzed by polymerase chain reaction and by Southern blot analysis to distinguish random integration from homologous recombination. Out of 132 clones examined, 8 had undergone homologous recombination at one of the ALDH2 alleles. The cloned transformed embryonic stem cells with a disrupted ALDH2 allele were injected into blastocysts. Transplantation of the blastocysts into surrogate mother mice yielded chimeric mice. The role of ALDH2 in alcohol preference, alcohol sensitivity and other biological and behavioral characteristics can be elucidated by examining the heterozygous and homozygous mutant strains produced by breeding of chimeric mice.

  8. Association and ancestry analysis of sequence variants in ADH and ALDH using alcohol-related phenotypes in a Native American community sample

    PubMed Central

    Peng, Qian; Gizer, Ian R.; Libiger, Ondrej; Bizon, Chris; Wilhelmsen, Kirk C.; Schork, Nicholas J.; Ehlers, Cindy L.

    2015-01-01

    Higher rates of alcohol use and other drug-dependence have been observed in some Native American populations relative to other ethnic groups in the U.S. Previous studies have shown that alcohol dehydrogenase (ADH) genes and aldehyde dehydrogenase (ALDH) genes may affect the risk of development of alcohol dependence, and that polymorphisms within these genes may differentially affect risk for the disorder depending on the ethnic group evaluated. We evaluated variations in the ADH and ALDH genes in a large study investigating risk factors for substance use in a Native American population. We assessed ancestry admixture and tested for associations between alcohol-related phenotypes in the genomic regions around the ADH1-7 and ALDH2 and ALDH1A1 genes. Seventy-two (72) ADH variants showed significant evidence of association with a severity level of alcohol drinking-related dependence symptoms phenotype. These significant variants spanned across the entire 7 ADH gene cluster regions. Two significant associations, one in ADH and one in ALDH2, were observed with alcohol dependence diagnosis. Seventeen (17) variants showed significant association with the largest number of alcohol drinks ingested during any 24-hour period. Variants in or near ADH7 were significantly negatively associated with alcohol-related phenotypes, suggesting a potential protective effect of this gene. In addition, our results suggested that a higher degree of Native American ancestry is associated with higher frequencies of potential risk variants and lower frequencies of potential protective variants for alcohol dependence phenotypes. PMID:25270064

  9. Number of nitrate groups determines reactivity and potency of organic nitrates: a proof of concept study in ALDH-2−/− mice

    PubMed Central

    Wenzel, P; Hink, U; Oelze, M; Seeling, A; Isse, T; Bruns, K; Steinhoff, L; Brandt, M; Kleschyov, A L; Schulz, E; Lange, K; Weiner, H; Lehmann, J; Lackner, K J; Kawamoto, T; Münzel, T; Daiber, A

    2007-01-01

    Background and purpose: Mitochondrial aldehyde dehydrogenase (ALDH-2) has been shown to provide a pathway for bioactivation of organic nitrates and to be prone to desensitization in response to highly potent, but not to less potent, nitrates. We therefore sought to support the hypothesis that bioactivation by ALDH-2 critically depends on the number of nitrate groups within the nitrovasodilator. Experimental approach: Nitrates with one (PEMN), two (PEDN; GDN), three (PETriN; glyceryl trinitrate, GTN) and four (pentaerithrityl tetranitrate, PETN) nitrate groups were investigated. Vasodilatory potency was measured in isometric tension studies using isolated aortic segments of wild type (WT) and ALDH-2−/− mice. Activity of the cGMP-dependent kinase-I (reflected by levels of phosphorylated VAsodilator Stimulated Phosphoprotein, P-VASP) was quantified by Western blot analysis, mitochondrial dehydrogenase activity by HPLC. Following incubation of isolated mitochondria with PETN, PETriN-chromophore and PEDN, metabolites were quantified using chemiluminescence nitrogen detection and mass spectrometry. Key results: Compared to WT, vasorelaxation in response to PETN, PETriN and GTN was attenuated about 10fold in ALDH-2−/− mice, identical to WT vessels preincubated with inhibitors of ALDH-2. Reduced vasodilator potency correlated with reduced P-VASP formation and diminished biotransformation of the tetranitrate- and trinitrate-compounds. None of these findings were observed for PEDN, GDN and PEMN. Conclusions and implications: Our results support the crucial role of ALDH-2 in bioactivating highly reactive nitrates like GTN, PETN and PETriN. ALDH-2-mediated relaxation by organic nitrates therefore depends mainly on the number of nitrate groups. Less potent nitrates like PEDN, GDN and PEMN are apparently biotransformed by other pathways. PMID:17220910

  10. Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease

    PubMed Central

    Fitzmaurice, Arthur G.; Rhodes, Shannon L.; Cockburn, Myles; Ritz, Beate

    2014-01-01

    Objective: The objective of this study was to determine whether environmental and genetic alterations of neuronal aldehyde dehydrogenase (ALDH) enzymes were associated with increased Parkinson disease (PD) risk in an epidemiologic study. Methods: A novel ex vivo assay was developed to identify pesticides that can inhibit neuronal ALDH activity. These were investigated for PD associations in a population-based case-control study, the Parkinson's Environment & Genes (PEG) Study. Common variants in the mitochondrial ALDH2 gene were genotyped to assess effect measure modification (statistical interaction) of the pesticide effects by genetic variation. Results: All of the metal-coordinating dithiocarbamates tested (e.g., maneb, ziram), 2 imidazoles (benomyl, triflumizole), 2 dicarboxymides (captan, folpet), and 1 organochlorine (dieldrin) inhibited ALDH activity, potentially via metabolic byproducts (e.g., carbon disulfide, thiophosgene). Fifteen screened pesticides did not inhibit ALDH. Exposures to ALDH-inhibiting pesticides were associated with 2- to 6-fold increases in PD risk; genetic variation in ALDH2 exacerbated PD risk in subjects exposed to ALDH-inhibiting pesticides. Conclusion: ALDH inhibition appears to be an important mechanism through which environmental toxicants contribute to PD pathogenesis, especially in genetically vulnerable individuals, suggesting several potential interventions to reduce PD occurrence or slow or reverse its progression. PMID:24491970

  11. Subchronic exposure to ethyl tertiary butyl ether resulting in genetic damage in Aldh2 knockout mice.

    PubMed

    Weng, Zuquan; Suda, Megumi; Ohtani, Katsumi; Mei, Nan; Kawamoto, Toshihiro; Nakajima, Tamie; Wang, Rui-Sheng

    2013-09-15

    Ethyl tertiary butyl ether (ETBE) is biofuel additive recently used in Japan and some other countries. Limited evidence shows that ETBE has low toxicity. Acetaldehyde (AA), however, as one primary metabolite of ETBE, is clearly genotoxic and has been considered to be a potential carcinogen. The aim of this study was to evaluate the effects of ALDH2 gene on ETBE-induced genotoxicity and metabolism of its metabolites after inhalation exposure to ETBE. A group of wild-type (WT) and Aldh2 knockout (KO) C57BL/6 mice were exposed to 500ppm ETBE for 1-6h, and the blood concentrations of ETBE metabolites, including AA, tert-butyl alcohol and 2-methyl-1,2-propanediol, were measured. Another group of mice of WT and KO were exposed to 0, 500, 1750, or 5000ppm ETBE for 6h/day with 5 days per weeks for 13 weeks. Genotoxic effects of ETBE in these mice were measured by the alkaline comet assay, 8-hydroxyguanine DNA-glycosylase modified comet assay and micronucleus test. With short-term exposure to ETBE, the blood concentrations of all the three metabolites in KO mice were significantly higher than the corresponding concentrations of those in WT mice of both sexes. After subchronic exposure to ETBE, there was significant increase in DNA damage in a dose-dependent manner in KO male mice, while only 5000ppm exposure significantly increased DNA damage in male WT mice. Overall, there was a significant sex difference in genetic damage in both genetic types of mice. These results showed that ALDH2 is involved in the detoxification of ETBE and lack of enzyme activity may greatly increase the sensitivity to the genotoxic effects of ETBE, and male mice were more sensitive than females. PMID:23810710

  12. mTOR-STAT3-notch signalling contributes to ALDH2-induced protection against cardiac contractile dysfunction and autophagy under alcoholism

    PubMed Central

    Ge, Wei; Ren, Jun

    2012-01-01

    Abstract Mitochondrial aldehyde dehydrogenase-2 (ALDH2) has been shown to benefit myopathic changes following alcohol intake, although the precise mechanism is still unclear. This study was designed to evaluate the role of ALDH2 on chronic alcohol intake-induced myocardial geometric and functional damage with a focus on autophagic signalling. Wild-type friendly virus B (FVB) and transgenic mice overexpressing ALDH2 driven by chicken β-actin promoter were fed a 4% alcohol liquid diet for 12 weeks. Cardiac geometry and function were assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate the essential autophagy markers, Akt and AMP-dependent protein kinase (AMPK) as well as their downstream signalling mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3). Alcohol intake altered cardiac geometry and function as demonstrated by lessened LV wall and septal thickness, enlarged end systolic and diastolic diameters, decreased fractional shortening and cell shortening, the effects of which were mitigated by ALDH2 transgene. Chronic alcohol intake triggered myocardial autophagy as shown by LC3B II isoform switch, as well as decreased phosphorylation of mTOR, the effects of which were ablated by ALDH2. Chronic alcohol intake suppressed phosphorylation of Akt and AMPK, which was reconciled by ALDH2. Levels of Notch1 and STAT3 phosphorylation were dampened by chronic alcohol intake in FVB but not ALDH2 myocardium. Moreover, the γ-secretase Notch inhibitor N-[N-(3,5-difluorophenacetyl)-1-alany1]-S-phenyglycine t-butyl ester exacerbated ethanol-induced cardiomyocyte contractile dysfunction, apoptosis and autophagy. In summary, these findings suggested that ALDH2 elicits cardioprotection against chronic alcohol intake-induced cardiac geometric and functional anomalies by inhibition of autophagy possibly via restoring the Akt-mTOR-STAT3-Notch signalling cascade. PMID:21609394

  13. Expression Levels of the Oxidative Stress Response Gene ALDH3A2 in Granulosa-Lutein Cells Are Related to Female Age and Infertility Diagnosis.

    PubMed

    González-Fernández, Rebeca; Hernández, Jairo; Martín-Vasallo, Pablo; Puopolo, Maria; Palumbo, Angela; Ávila, Julio

    2016-05-01

    Oxidative stress (OS) plays an important role in all physiological processes. The effect of OS on cellular processes is modulated by the ability of the cell to express genes implicated in the reversal of lipid, protein, and DNA injury. Aldehyde dehydrogenase 3, member A2 (ALDH3A2) is a ubiquitous enzyme involved in lipid detoxification. The objective of this study was to investigate the expression ofALDH3A2in human granulosa-lutein (GL) cells of women undergoing in vitro fertilization (IVF) and its relationship with age, infertility diagnosis, and IVF outcome variables. Relative expression levels ofALDH3A2were determined by quantitative reverse transcription-polymerase chain reaction. To investigate the effect of age onALDH3A2expression, 72 women between 18 and 44 years of age with no ovarian factor (NOF) were analyzed. To evaluate the effect of infertility diagnosis onALDH3A2expression, the following groups were analyzed: 22 oocyte donors (ODs), 24 women >40 years old (yo) with tubal or male factor and no ovarian pathology, 18 poor responders (PRs), 19 cases with endometriosis (EM), and 18 patients with polycystic ovarian syndrome (PCOS). In NOF,ALDH3A2expression correlated positively with age and with the doses of follicle-stimulating hormone and luteinizing hormone administered and negatively with the number of total and mature oocytes. When different groups were analyzed,ALDH3A2expression levels were higher in patients >40 yo and in PR compared to OD. On the contrary, EM and PCOS levels were lower than expected for age. These data suggest that GL cellALDH3A2expression levels correlate with age, cause of infertility, and ovarian response to stimulation. PMID:26449735

  14. Aldehyde Dehydrogenase Gene Superfamily in Populus: Organization and Expression Divergence between Paralogous Gene Pairs

    PubMed Central

    Tian, Feng-Xia; Zang, Jian-Lei; Wang, Tan; Xie, Yu-Li; Zhang, Jin; Hu, Jian-Jun

    2015-01-01

    Aldehyde dehydrogenases (ALDHs) constitute a superfamily of NAD(P)+-dependent enzymes that catalyze the irreversible oxidation of a wide range of reactive aldehydes to their corresponding nontoxic carboxylic acids. ALDHs have been studied in many organisms from bacteria to mammals; however, no systematic analyses incorporating genome organization, gene structure, expression profiles, and cis-acting elements have been conducted in the model tree species Populus trichocarpa thus far. In this study, a comprehensive analysis of the Populus ALDH gene superfamily was performed. A total of 26 Populus ALDH genes were found to be distributed across 12 chromosomes. Genomic organization analysis indicated that purifying selection may have played a pivotal role in the retention and maintenance of PtALDH gene families. The exon-intron organizations of PtALDHs were highly conserved within the same family, suggesting that the members of the same family also may have conserved functionalities. Microarray data and qRT-PCR analysis indicated that most PtALDHs had distinct tissue-specific expression patterns. The specificity of cis-acting elements in the promoter regions of the PtALDHs and the divergence of expression patterns between nine paralogous PtALDH gene pairs suggested that gene duplications may have freed the duplicate genes from the functional constraints. The expression levels of some ALDHs were up- or down-regulated by various abiotic stresses, implying that the products of these genes may be involved in the adaptation of Populus to abiotic stresses. Overall, the data obtained from our investigation contribute to a better understanding of the complexity of the Populus ALDH gene superfamily and provide insights into the function and evolution of ALDH gene families in vascular plants. PMID:25909656

  15. ALDH2 Activator Inhibits Increased Myocardial Infarction Injury by Nitroglycerin Tolerance

    PubMed Central

    Sun, Lihan; Ferreira, Julio Cesar Batista; Mochly-Rosen, Daria

    2012-01-01

    Nitroglycerin, which helps impaired cardiac function as it is converted to nitric oxide, is used worldwide to treat patients with various ischemic and congestive cardiac diseases, including angina pectoris. Nevertheless, after continuous treatment, the benefits of nitroglycerin are limited by the development of tolerance to the drug. Nitroglycerin tolerance is a result of inactivation of aldehyde dehydrogenase 2 (ALDH2), an enzyme essential for cardioprotection in animals subjected to myocardial infarction (MI). Here we tested the hypothesis that the tolerance that develops as a result of sustained nitroglycerin treatment increases cardiac injury by subsequent MI. In a rat model of MI, 16 hours of prior, sustained nitroglycerin treatment (7.2 mg/kg/day) resulted in infarcts that were twice as large as those in untreated control animals and in diminished cardiac function at 3 days and 2 weeks after the MI. We also sought to identify a potential treatment to protect against this increased cardiac damage. Nitroglycerin inhibited ALDH2 activity in vitro, an effect that was blocked by Alda-1, an activator of ALDH2. Co-administration of Alda-1 (16 mg/kg/day) with the nitroglycerin prevented the nitroglycerin-induced increase in cardiac dysfunction after MI in rats, at least in part by enhancing metabolism of reactive aldehyde adducts that impair normal protein functions. If our animal studies showing that nitroglycerin tolerance increases cardiac injury upon ischemic insult are corroborated in humans, activators of ALDH2 such as Alda-1 may help to protect MI patients from this nitroglycerin-induced increase in cardiac injury, while maintaining the cardiac benefits of the increased nitric oxide concentrations produced by nitroglycerin. PMID:22049071

  16. Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress.

    PubMed

    Singh, Surendra; Brocker, Chad; Koppaka, Vindhya; Chen, Ying; Jackson, Brian C; Matsumoto, Akiko; Thompson, David C; Vasiliou, Vasilis

    2013-03-01

    Reactive oxygen species (ROS) are continuously generated within living systems and the inability to manage ROS load leads to elevated oxidative stress and cell damage. Oxidative stress is coupled to the oxidative degradation of lipid membranes, also known as lipid peroxidation. This process generates over 200 types of aldehydes, many of which are highly reactive and toxic. Aldehyde dehydrogenases (ALDHs) metabolize endogenous and exogenous aldehydes and thereby mitigate oxidative/electrophilic stress in prokaryotic and eukaryotic organisms. ALDHs are found throughout the evolutionary gamut, from single-celled organisms to complex multicellular species. Not surprisingly, many ALDHs in evolutionarily distant, and seemingly unrelated, species perform similar functions, including protection against a variety of environmental stressors such as dehydration and ultraviolet radiation. The ability to act as an "aldehyde scavenger" during lipid peroxidation is another ostensibly universal ALDH function found across species. Upregulation of ALDHs is a stress response in bacteria (environmental and chemical stress), plants (dehydration, salinity, and oxidative stress), yeast (ethanol exposure and oxidative stress), Caenorhabditis elegans (lipid peroxidation), and mammals (oxidative stress and lipid peroxidation). Recent studies have also identified ALDH activity as an important feature of cancer stem cells. In these cells, ALDH expression helps abrogate oxidative stress and imparts resistance against chemotherapeutic agents such as oxazaphosphorine, taxane, and platinum drugs. The ALDH superfamily represents a fundamentally important class of enzymes that contributes significantly to the management of electrophilic/oxidative stress within living systems. Mutations in various ALDHs are associated with a variety of pathological conditions in humans, highlighting the fundamental importance of these enzymes in physiological and pathological processes. PMID:23195683

  17. Cucurbitacin I suppressed stem-like property and enhanced radiation-induced apoptosis in head and neck squamous carcinoma--derived CD44(+)ALDH1(+) cells.

    PubMed

    Chen, Yi-Wei; Chen, Kuan-Hsuan; Huang, Pin-I; Chen, Yu-Chih; Chiou, Guang-Yu; Lo, Wen-Liang; Tseng, Ling-Ming; Hsu, Han-Sui; Chang, Kuo-Wei; Chiou, Shih-Hwa

    2010-11-01

    Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer worldwide. Signal transducers and activators of transcription 3 (STAT3) signaling is reported to promote tumor malignancy and recurrence in HNSCC. Cucurbitacins, triterpenoid derivatives, are strong STAT3 inhibitors with anticancer properties. Recent studies have shown aldehyde dehydrogenase 1 (ALDH1) to be a marker of cancer stem cells (CSC) in HNSCC. The aim of this study was to investigate the therapeutic effect of cucurbitacin I in HNSCC-derived CSCs. Using immunohistochemical analysis, we firstly showed that CD44, ALDH1, and phosphorylated STAT3 (p-STAT3) were higher in high-grade HNSCCs, and that triple positivity for CD44/ALDH1/p-STAT3 indicated a worse prognosis for HNSCC patients. Secondly, CD44(+)ALDH1(+) cells isolated from seven HNSCC patients showed greater tumorigenicity, radioresistance, and high expression of stemness (Bmi-1/Oct-4/Nanog) and epithelial-mesenchymal-transitional (Snail/Twist) genes as p-STAT3 level increased. Furthermore, we found that cucurbitacin I (JSI-124) can effectively inhibit the expression of p-STAT3 and capacities for tumorigenicity, sphere formation, and radioresistance in HNSCC-CD44(+)ALDH1(+). Notably, 150 nmol/L cucurbitacin I effectively blocked STAT3 signaling and downstream survivin and Bcl-2 expression, and it induced apoptosis in HNSCC-CD44(+)ALDH1(+). Moreover, microarray data indicated that 100 nmol/L cucurbitacin I facilitated CD44(+)ALDH1(+) cells to differentiate into CD44⁻ALDH1⁻ and enhanced the radiosensitivity of HNSCC-CD44(+)ALDH1(+). Xenotransplant experiments revealed that cucurbitacin I combined with radiotherapy significantly suppressed tumorigenesis and lung metastasis and further improved the survival rate in HNSCC-CD44(+)ALDH1(+)-transplanted immunocompromised mice. Taken together, our data show that cucurbitacin I, STAT3 inhibitor, reduces radioresistant, distant-metastatic, and CSC-like properties of HNSCC-CD44(+)ALDH1(+) cells

  18. Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases

    SciTech Connect

    Khanna, Mary; Chen, Che-Hong; Kimble-Hill, Ann; Parajuli, Bibek; Perez-Miller, Samantha; Baskaran, Sulochanadevi; Kim, Jeewon; Dria, Karl; Vasiliou, Vasilis; Mochly-Rosen, Daria; Hurley, Thomas D.

    2012-10-23

    Human aldehyde dehydrogenases (ALDHs) comprise a family of 17 homologous enzymes that metabolize different biogenic and exogenic aldehydes. To date, there are relatively few general ALDH inhibitors that can be used to probe the contribution of this class of enzymes to particular metabolic pathways. Here, we report the discovery of a general class of ALDH inhibitors with a common mechanism of action. The combined data from kinetic studies, mass spectrometric measurements, and crystallographic analyses demonstrate that these inhibitors undergo an enzyme-mediated {beta}-elimination reaction generating a vinyl ketone intermediate that covalently modifies the active site cysteine residue present in these enzymes. The studies described here can provide the basis for rational approach to design ALDH isoenzyme-specific inhibitors as research tools and perhaps as drugs, to address diseases such as cancer where increased ALDH activity is associated with a cellular phenotype.

  19. A Personalized Medicine Approach for Asian Americans with the Aldehyde Dehydrogenase 2*2 Variant

    PubMed Central

    Gross, Eric R.; Zambelli, Vanessa O.; Small, Bryce A.; Ferreira, Julio C.B.; Chen, Che-Hong; Mochly-Rosen, Daria

    2015-01-01

    Asian Americans are one of the fastest-growing populations in the United States. A relatively large subset of this population carries a unique loss-of-function point mutation in aldehyde dehydrogenase 2 (ALDH2), ALDH2*2. Found in approximately 560 million people of East Asian descent, ALDH2*2 reduces enzymatic activity by approximately 60% to 80% in heterozygotes. Furthermore, this variant is associated with a higher risk for several diseases affecting many organ systems, including a particularly high incidence relative to the general population of esophageal cancer, myocardial infarction, and osteoporosis. In this review, we discuss the pathophysiology associated with the ALDH2*2 variant, describe why this variant needs to be considered when selecting drug treatments, and suggest a personalized medicine approach for Asian American carriers of this variant. We also discuss future clinical and translational perspectives regarding ALDH2*2 research. PMID:25292432

  20. IN VITRO ORGANIC NITRATE BIOACTIVATION TO NITRIC OXIDE BY RECOMBINANT ALDEHYDE DEHYDROGENASE 3A1

    PubMed Central

    Lin, Shunxin; Page, Nathaniel A.; Fung, Sun Mi; Fung, Ho-Leung

    2013-01-01

    Organic nitrates (ORNs) are commonly used anti-ischemic and anti-anginal agents, which serve as an exogenous source of the potent vasodilator nitric oxide (NO). Recently, both mitochondrial aldehyde dehydrogenase-2 (ALDH2) and cytosolic aldehyde dehydrogenase-1a1 (ALDH1A1) have been shown to exhibit the ability to selectively bioactivate various ORNs in vitro. The objective of the present research was to examine the potential role of ALDH3A1, another major cytosolic isoform of ALDH, in the in vitro bioactivation of various ORNs, and to estimate the enzyme kinetic parameters toward ORNs through mechanistic modeling. The extent of bioactivation was assayed by exposing recombinant ALDH3A1 to various concentrations of ORNs, and measuring the concentration-time profiles of released NO via a NO-specific electrode. Metabolite formation kinetics was monitored for nitroglycerin (NTG) using LC/MS/MS. Our results showed that ALDH3A1 mRNA and protein were highly expressed in C57BL/6 mouse aortic, cardiac, and hepatic tissues, and it was able to release NO from several ORNs, including NTG, isosorbide dinitrate (ISDN), isosorbide-2-mononitrate (IS-2-MN), and nicorandil with similar Vmax (0.175 – 0.503 nmol/min/mg of ALDH3A1), and Km values of 4.01, 46.5, 818 and 5.75 × 103 μM respectively. However, activation of isosorbide-5-mononitrate (IS-5-MN) by ALDH3A1 was undetectable in vitro. ALDH3A1 was also shown to denitrate NTG, producing primarily glyceryl 1, 2-dinitrate (1, 2-GDN) in preference to glyceryl 1, 3-dinitrate (1, 3-GDN). Therefore, ALDH3A1 may contribute to the bioactivation of ORNs in vivo. PMID:24126018

  1. Blood and liver acetaldehyde concentration in rats following acetaldehyde inhalation and intravenous and intragastric ethanol administration

    SciTech Connect

    Watanabe, A.; Hobara, N.; Nagashima, H.

    1986-10-01

    Ethanol is metabolized to acetaldehyde, a highly reactive product of ethanol oxidation. Ethanol might be blended with gasoline and used as a fuel in the future; biohazard of acetaldehyde inhalation must be discussed. Recent improvements in our ability to measure acetaldehyde levels in blood and various tissues have made the assessment of acetaldehyde's role in alcoholic organ intoxication possible. Blood and liver acetaldehyde concentrations in rats were reported as being linearly correlated following intragastric ethanol administration. Acetaldehyde was administered by inhalation to study its toxicity. However, liver concentrations following the inhalation was not investigated. The present communication describes the relationship between blood and liver acetaldehyde concentrations in rats following acetaldehyde inhalation and different routes of ethanol administration.

  2. Genetic polymorphisms of ADH1B, ADH1C and ALDH2 in Turkish alcoholics: lack of association with alcoholism and alcoholic cirrhosis

    PubMed Central

    Vatansever, Sezgin; Tekin, Fatih; Salman, Esin; Altintoprak, Ender; Coskunol, Hakan; Akarca, Ulus Salih

    2015-01-01

    No data exists regarding the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) gene polymorphisms in Turkish alcoholic cirrhotics. We studied the polymorphisms of ADH1B, ADH1C and ALDH2 genes in alcoholic cirrhotics and compared the results with non-cirrhotic alcoholics and healthy volunteers. Overall, 237 subjects were included for the study: 156 alcoholic patients (78 cirrhotics, 78 non-cirrhotic alcoholics) and 81 healthy volunteers. Three different single-nucleotide-polymorphism genotyping methods were used. ADH1C genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism method. The identified ADH1C genotypes were named according to the presence or absence of the enzyme restriction sites. ADH1B (Arg47Hys) genotyping was performed using the allele specific primer extension method, and ALDH2 (Glu487Lys) genotyping was performed by a multiplex polymerase chain reaction using two allele-specific primer pairs. For ADH1B, the frequency of allele *1 in the cirrhotics, non-cirrhotic alcoholics and healthy volunteers was 97.4%, 94.9% and 99.4%, respectively. For ADH1C, the frequency of allele *1 in the cirrhotics, non-cirrhotic alcoholics and healthy volunteers was 47%, 36.3% and 45%, respectively. There was no statistical difference between the groups for ADH1B and ADH1C (p>0.05). All alcoholic and non-alcoholic subjects (100%) had the allele *1 for ALDH2. The obtained results for ADH1B, ADH1C, and ALDH gene polymorphisms in the present study are similar to the results of Caucasian studies. ADH1B and ADH1C genetic variations are not related to the development of alcoholism or susceptibility to alcoholic cirrhosis. ALDH2 gene has no genetic variation in the Turkish population. PMID:26042511

  3. Proton transfer in acetaldehyde and acetaldehyde-water clusters: Vacuum ultraviolet photoionization experiment and theoretical calculations

    NASA Astrophysics Data System (ADS)

    Kostko, Oleg; Troy, Tyler P.; Bandyopadhyay, Biswajit; Ahmed, Musahid

    2015-03-01

    Acetaldehyde, a probable human carcinogen and of environmental importance, upon solvation provides a test bed for understanding proton transfer pathways and catalytic mechanisms. In this study, we report on single photon vacuum ultraviolet photoionization of small acetaldehyde and acetaldehyde-water clusters. Appearance energies of protonated clusters are extracted from the experimental photoionization efficiency curves and compared to electronic structure calculations. The comparison of experimental data to computational results provides mechanistic insight into the fragmentation mechanisms of the observed mass spectra. Using deuterated water for isotopic tagging, we observe that proton transfer is mediated via acetaldehyde and not water in protonated acetaldehyde-water clusters.

  4. The effects of a ketogenic diet on ATP concentrations and the number of hippocampal mitochondria in Aldh5a1−/− mice

    PubMed Central

    Nylen, Kirk; Velazquez, Jose Luis Perez; Sayed, Venus; Gibson, K. Michael; Burnham, W.M.; Snead, O. Carter

    2009-01-01

    Summary BACKGROUND Succinic semialdehyde dehydrogenase (SSADH) deficiency is an inborn error of GABA metabolism characterized clinically by ataxia, psychomotor retardation and seizures. A mouse model of SSADH deficiency, the Aldh5a1−/− mouse, has been used to study the pathophysiology and treatment of this disorder. Recent work from our group has shown that the ketogenic diet (KD) is effective in normalizing the Aldh5a1−/− phenotype, although the mechanism of the effect remains unclear. METHODS Here, we examine the effects of a KD on the number of hippocampal mitochondria as well as on ATP levels in hippocampus. Electron microscopy was performed to determine the number of mitochondria in the hippocampus of Aldh5a1−/− mice. Adenosine triphosphate (ATP) levels were measured in hippocampal extracts. RESULTS Our results show that the KD increases the number of mitochondria in Aldh5a1−/− mice. We also show that Aldh5a1−/− mice have significant reductions in hippocampal ATP levels as compared to controls, and that the KD restores ATP in mutant mice to normal levels. CONCLUSIONS & GENERAL SIGNIFICANCE Taken together, our data suggest that the KD’s actions on brain mitochondria may play a role in the diet’s ability to treat murine SSADH deficiency. PMID:19168117

  5. A novel dithiocarbamate analogue with potentially decreased ALDH inhibition has copper-dependent proteasome-inhibitory and apoptosis-inducing activity in human breast cancer cells

    PubMed Central

    Wang, Fei; Zhai, Shumei; Liu, Xiaojun; Li, Liwen; Wu, Shirley; Dou, Q. Ping; Yan, Bing

    2013-01-01

    Dithiocarbamates are a class of sulfur-based metal-chelating compounds with various applications in medicine. We reported previously that certain members of dithiocarbamates, such as diethyldithiocarbamate, disulfiram (DSF) and pyrrolidine dithiocarbamate (PDTC), were able to bind with tumor cellular copper to inhibit tumor growth through the inhibition of proteasome activity and induction of cancer cell apoptosis. Since the DSF is an irreversible inhibitor of aldehyde dehydrogenase (ALDH), its ALDH-inhibitory activity might potentially affect its usefulness as an anti-cancer drug. For the purpose of selecting potent anti-cancer compounds that are not ALDH inhibitors and mapping out preliminary structure–activity relationship trends for these novel compounds, we synthesized a series of PDTC analogues and chose three novel compounds to study their ALDH-inhibitory activity, proteasome-inhibitory activity as well as the cancer cell apoptosis-inducing activity. The results showed that compared to DSF, compound 9 has less ALDH inhibition activity, and the in vitro results also proved the positive effects of 9-Cu in proteasome inhibition and apoptosis induction in breast cancer cells, suggesting that 9 as a lead compound could be developed into a novel proteasome inhibitor anti-cancer drug. PMID:21035945

  6. 27 CFR 21.93 - Acetaldehyde.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2012-04-01 2012-04-01 false Acetaldehyde. 21.93 Section 21.93 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS FORMULAS FOR DENATURED ALCOHOL AND RUM Specifications for Denaturants § 21.93 Acetaldehyde. (a) Aldehyde content...

  7. 27 CFR 21.93 - Acetaldehyde.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2014-04-01 2014-04-01 false Acetaldehyde. 21.93 Section 21.93 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY ALCOHOL FORMULAS FOR DENATURED ALCOHOL AND RUM Specifications for Denaturants § 21.93 Acetaldehyde. (a) Aldehyde content...

  8. Extended flow cytometry characterization of normal bone marrow progenitor cells by simultaneous detection of aldehyde dehydrogenase and early hematopoietic antigens: implication for erythroid differentiation studies

    PubMed Central

    Mirabelli, Peppino; Di Noto, Rosa; Lo Pardo, Catia; Morabito, Paolo; Abate, Giovanna; Gorrese, Marisa; Raia, Maddalena; Pascariello, Caterina; Scalia, Giulia; Gemei, Marica; Mariotti, Elisabetta; Del Vecchio, Luigi

    2008-01-01

    Background Aldehyde dehydrogenase (ALDH) is a cytosolic enzyme highly expressed in hematopoietic precursors from cord blood and granulocyte-colony stimulating factor mobilized peripheral blood, as well as in bone marrow from patients with acute myeloblastic leukemia. As regards human normal bone marrow, detailed characterization of ALDH+ cells has been addressed by one single study (Gentry et al, 2007). The goal of our work was to provide new information about the dissection of normal bone marrow progenitor cells based upon the simultaneous detection by flow cytometry of ALDH and early hematopoietic antigens, with particular attention to the expression of ALDH on erythroid precursors. To this aim, we used three kinds of approach: i) multidimensional analytical flow cytometry, detecting ALDH and early hematopoietic antigens in normal bone marrow; ii) fluorescence activated cell sorting of distinct subpopulations of progenitor cells, followed by in vitro induction of erythroid differentiation; iii) detection of ALDH+ cellular subsets in bone marrow from pure red cell aplasia patients. Results In normal bone marrow, we identified three populations of cells, namely ALDH+CD34+, ALDH-CD34+ and ALDH+CD34- (median percentages were 0.52, 0.53 and 0.57, respectively). As compared to ALDH-CD34+ cells, ALDH+CD34+ cells expressed the phenotypic profile of primitive hematopoietic progenitor cells, with brighter expression of CD117 and CD133, accompanied by lower display of CD38 and CD45RA. Of interest, ALDH+CD34- population disclosed a straightforward erythroid commitment, on the basis of three orders of evidences. First of all, ALDH+CD34- cells showed a CD71bright, CD105+, CD45- phenotype. Secondly, induction of differentiation experiments evidenced a clear-cut expression of glycophorin A (CD235a). Finally, ALDH+CD34- precursors were not detectable in patients with pure red cell aplasia (PRCA). Conclusion Our study, comparing surface antigen expression of ALDH+/CD34+, ALDH

  9. Rationale and design for PACE: patients with intermittent claudication injected with ALDH bright cells.

    PubMed

    Perin, Emerson C; Murphy, Michael; Cooke, John P; Moyé, Lem; Henry, Timothy D; Bettencourt, Judy; Gahremanpour, Amir; Leeper, Nicholas; Anderson, R David; Hiatt, William R; Lima, Joao A; Venkatesh, Bharath; Sayre, Shelly L; Vojvodic, Rachel W; Taylor, Doris A; Ebert, Ray F; Hirsch, Alan T

    2014-11-01

    Peripheral artery disease (PAD) is recognized as a public health issue because of its prevalence, functional limitations, and increased risk of systemic ischemic events. Current treatments for claudication, the primary symptom in patients with PAD, have limitations. Cells identified using cytosolic enzyme aldehyde dehydrogenase (ALDH) may benefit patients with severe PAD but has not been studied in patients with claudication. PACE is a randomized, double-blind, placebo-controlled clinical trial conducted by the Cardiovascular Cell Therapy Research Network to assess the safety and efficacy of autologous bone marrow-derived ALDH(br) cells delivered by direct intramuscular injections in 80 patients with symptom-limiting intermittent claudication. Eligible patients will have a significant stenosis or occlusion of infrainguinal arteries and a resting ankle-brachial index less than 0.90 and will be randomized 1:1 to cell or placebo treatment with a 1-year follow-up. The primary end points are the change in peak walking time and leg collateral arterial anatomy, calf muscle blood flow, and tissue perfusion as determined by magnetic resonance imaging at 6 months compared with baseline. The latter 3 measurements are new physiologic lower extremity tissue perfusion and PAD imaging-based end points that may help to quantify the biologic and mechanistic effects of cell therapy. This trial will collect important mechanistic and clinical information on the safety and efficacy of ALDH(br) cells in patients with claudication and provide valuable insight into the utility of advanced magnetic resonance imaging end points. PMID:25440794

  10. Aldehyde dehydrogenase 1A1 circumscribes high invasive glioma cells and predicts poor prognosis.

    PubMed

    Xu, Sen-Lin; Liu, Sha; Cui, Wei; Shi, Yu; Liu, Qin; Duan, Jiang-Jie; Yu, Shi-Cang; Zhang, Xia; Cui, You-Hong; Kung, Hsiang-Fu; Bian, Xiu-Wu

    2015-01-01

    Glioma is the most aggressive brain tumor with high invasiveness and poor prognosis. More reliable, sensitive and practical biomarkers to reveal glioma high invasiveness remain to be explored for the guidance of therapy. We herein evaluated the diagnostic and prognostic value of aldehyde dehydrogenase 1A1 (ALDH1A1) in the glioma specimens from 237 patients, and found that ADLH1A1 was frequently overexpressed in the high-grade glioma (WHO grade III-IV) as compared to the low-grade glioma (WHO grade I-II) patients. The tumor cells with ALDH1A1 expression were more abundant in the region between tumor and the borderline of adjacent tissue as compared to the central part of the tumor. ALDH1A1 overexpression was associated with poor differentiation and dismal prognosis. Notably, the overall and disease-free survivals of the patients who had ALDH1A1(+) tumor cells sparsely located in the adjacent tissue were much worse. Furthermore, ALDH1A1 expression was correlated with the "classical-like" (CL) subtype as we examined GBM specimens from 72 patients. Multivariate Cox regression analysis revealed that ALDH1A1 was an independent marker for glioma patients' outcome. Mechanistically, both in vitro and in vivo studies revealed that ALDH1A1(+) cells isolated from either a glioblastoma cell line U251 or primary glioblastoma cells displayed significant invasiveness, clonogenicity, and proliferation as compared to ALDH1A1(-) cells, due to increased levels of mRNA and protein for matrix metalloproteinase 2, 7 and 9 (MMP2, MMP7 and MMP9). These results indicate that ALDH1A1(+) cells contribute to the progression of glioma including invasion, proliferation and poor prognosis, and suggest that targeting ALDH1A1 may have important implications for the treatment of highly invasive glioma. PMID:26101711

  11. [Determination methods for human blood acetaldehyde].

    PubMed

    Fukunaga, T; Yamamoto, H; Tanegashima, A

    1998-06-01

    Although a number of reports on human blood acetaldehyde have been published, most of them during alcohol intoxication are still various in each researcher. The difficult problems are summarized as follows; 1) low boiling point of acetaldehyde, 2) low level in blood, 3) rapid disappearance in blood, and 4) artefactual formation during the procedures. The most crucial problem is the artefactual formation from ethanol or other sources during the procedures. Hemolysation, heating and/or other analytical procedures cause the artefacts. In this report, several methods for the determination and the evaluation of the acetaldehyde levels are reviewed. PMID:9701996

  12. c-Fos immunoreactivity in prefrontal, basal ganglia and limbic areas of the rat brain after central and peripheral administration of ethanol and its metabolite acetaldehyde

    PubMed Central

    Segovia, Kristen N.; Vontell, Regina; López-Cruz, Laura; Salamone, John D.; Correa, Mercè

    2013-01-01

    Considerable evidence indicates that the metabolite of ethanol (EtOH), acetaldehyde, is biologically active. Acetaldehyde can be formed from EtOH peripherally mainly by alcohol dehydrogenase (ADH), and also centrally by catalase. EtOH and acetaldehyde show differences in their behavioral effects depending upon the route of administration. In terms of their effects on motor activity and motivated behaviors, when administered peripherally acetaldehyde tends to be more potent than EtOH but shows very similar potency administered centrally. Since dopamine (DA) rich areas have an important role in regulating both motor activity and motivation, the present studies were undertaken to compare the effects of central (intraventricular, ICV) and peripheral (intraperitoneal, IP) administration of EtOH and acetaldehyde on a cellular marker of brain activity, c-Fos immunoreactivity, in DA innervated areas. Male Sprague-Dawley rats received an IP injection of vehicle, EtOH (0.5 or 2.5 g/kg) or acetaldehyde (0.1 or 0.5 g/kg) or an ICV injection of vehicle, EtOH or acetaldehyde (2.8 or 14.0 μmoles). IP administration of EtOH minimally induced c-Fos in some regions of the prefrontal cortex and basal ganglia, mainly at the low dose (0.5 g/kg), while IP acetaldehyde induced c-Fos in virtually all the structures studied at both doses. Acetaldehyde administered centrally increased c-Fos in all areas studied, a pattern that was very similar to EtOH. Thus, IP administered acetaldehyde was more efficacious than EtOH at inducing c-Fos expression. However, the general pattern of c-Fos induction promoted by ICV EtOH and acetaldehyde was similar. These results are consistent with the pattern observed in behavioral studies in which both substances produced the same magnitude of effect when injected centrally, and produced differences in potency after peripheral administration. PMID:23745109

  13. Induction of ALDH activity in intestinal dendritic cells by Lactobacillus plantarum NRIC0380.

    PubMed

    Yoshida, Tadashi; Enomoto, Mai; Nakayama, Sayuri; Adachi, Yu; Fujiwara, Wataru; Sugiyama, Hisashi; Shimojoh, Manabu; Okada, Sanae; Hattori, Makoto

    2013-01-01

    Lactic acid bacteria have been reported to have various immune-regulating activities. We also found in the previous study that the oral administration of heat-killed Lactobacillus plantarum NRIC0380 induced CD4(+)CD25(+)Foxp3(+) cells (Treg cells). We examine in this present study the influence of NRIC0380 on the function of intestinal dendritic cells (DCs) in vitro and in vivo. The aldehyde dehydrogenase (ALDH) activity was significantly induced in DCs obtained from the mesenteric lymph node (MLN) by culturing with NRIC0380. The oral administration of NRIC0380 also significantly increased ALDH-positive DCs in MLN. NRIC0380 significantly enhanced the production of TGF-β from MLN cells in vitro. These effects were not apparent in cells from the Peyer's patch (PP) and spleen (SPL). NRIC0380 also significantly enhanced the expression of B7-H1 on DCs of all organs in vitro. The effects of NRIC0380 on DCs, especially those located in MLN, might be involved in its function to induce Treg cells. PMID:24018660

  14. Structure of betaine aldehyde dehydrogenase at 2.1 A resolution.

    PubMed Central

    Johansson, K.; El-Ahmad, M.; Ramaswamy, S.; Hjelmqvist, L.; Jörnvall, H.; Eklund, H.

    1998-01-01

    The three-dimensional structure of betaine aldehyde dehydrogenase, the most abundant aldehyde dehydrogenase (ALDH) of cod liver, has been determined at 2.1 A resolution by the X-ray crystallographic method of molecular replacement. This enzyme represents a novel structure of the highly multiple ALDH, with at least 12 distinct classes in humans. This betaine ALDH of class 9 is different from the two recently determined ALDH structures (classes 2 and 3). Like these, the betaine ALDH structure has three domains, one coenzyme binding domain, one catalytic domain, and one oligomerization domain. Crystals grown in the presence or absence of NAD+ have very similar structures and no significant conformational change occurs upon coenzyme binding. This is probably due to the tight interactions between domains within the subunit and between subunits in the tetramer. The oligomerization domains link the catalytic domains together into two 20-stranded pleated sheet structures. The overall structure is similar to that of the tetrameric bovine class 2 and dimeric rat class 3 ALDH, but the coenzyme binding with the nicotinamide in anti conformation, resembles that of class 2 rather than of class 3. PMID:9792097

  15. Comparative and evolutionary studies of vertebrate ALDH1A-like genes and proteins.

    PubMed

    Holmes, Roger S

    2015-06-01

    Vertebrate ALDH1A-like genes encode cytosolic enzymes capable of metabolizing all-trans-retinaldehyde to retinoic acid which is a molecular 'signal' guiding vertebrate development and adipogenesis. Bioinformatic analyses of vertebrate and invertebrate genomes were undertaken using known ALDH1A1, ALDH1A2 and ALDH1A3 amino acid sequences. Comparative analyses of the corresponding human genes provided evidence for distinct modes of gene regulation and expression with putative transcription factor binding sites (TFBS), CpG islands and micro-RNA binding sites identified for the human genes. ALDH1A-like sequences were identified for all mammalian, bird, lizard and frog genomes examined, whereas fish genomes displayed a more restricted distribution pattern for ALDH1A1 and ALDH1A3 genes. The ALDH1A1 gene was absent in many bony fish genomes examined, with the ALDH1A3 gene also absent in the medaka and tilapia genomes. Multiple ALDH1A1-like genes were identified in mouse, rat and marsupial genomes. Vertebrate ALDH1A1, ALDH1A2 and ALDH1A3 subunit sequences were highly conserved throughout vertebrate evolution. Comparative amino acid substitution rates showed that mammalian ALDH1A2 sequences were more highly conserved than for the ALDH1A1 and ALDH1A3 sequences. Phylogenetic studies supported an hypothesis for ALDH1A2 as a likely primordial gene originating in invertebrate genomes and undergoing sequential gene duplication to generate two additional genes, ALDH1A1 and ALDH1A3, in most vertebrate genomes. PMID:25446856

  16. Psychotropics regulate Skp1a, Aldh1a1, and Hspa8 transcription--potential to delay Parkinson's disease.

    PubMed

    Lauterbach, Edward C

    2013-01-10

    Recently, the genes p19 S-phase kinase-associated protein 1A (SKP1), huntingtin interacting protein-2 (UBE2K), aldehyde dehydrogenase family 1 subfamily A1 (ALDH1A1), 19 S proteasomal protein PSMC4, and heat shock 70-kDa protein 8 (HSPA8) have been found to predict the onset and progression of Parkinson's disease (PD). These findings prompted a review of the effects of commonly prescribed psychiatric medicines, drugs that are used in treating PD, on the expression of these genes. Findings in the published medical literature were reviewed and gene expression data in the Gene Expression Omnibus Profiles database were analyzed. The results indicate that fluoxetine upregulated the risk-attenuating genes Skp1a and Aldh1a1 and olanzapine downregulated risk-enhancing Hspa8 while also downregulating Aldh1a1. Less conclusive evidence suggested that fluoxetine might also downregulate Hspa8 and clozapine might downregulate risk-enhancing Ube2k, but that olanzapine might upregulate Ube2k. Together, the present findings suggest that these psychotropics may delay PD onset (fluoxetine, olanzapine, and perhaps clozapine) and progression (fluoxetine, clozapine, and perhaps olanzapine). These gene expression findings should be replicated by RT-PCR studies in humans and, if confirmed, these drugs should then be studied in animal models and PD patients. PMID:23046827

  17. Biological evaluation and 3D-QSAR studies of curcumin analogues as aldehyde dehydrogenase 1 inhibitors.

    PubMed

    Wang, Hui; Du, Zhiyun; Zhang, Changyuan; Tang, Zhikai; He, Yan; Zhang, Qiuyan; Zhao, Jun; Zheng, Xi

    2014-01-01

    Aldehyde dehydrogenase 1 (ALDH1) is reported as a biomarker for identifying some cancer stem cells, and down-regulation or inhibition of the enzyme can be effective in anti-drug resistance and a potent therapeutic for some tumours. In this paper, the inhibitory activity, mechanism mode, molecular docking and 3D-QSAR (three-dimensional quantitative structure activity relationship) of curcumin analogues (CAs) against ALDH1 were studied. Results demonstrated that curcumin and CAs possessed potent inhibitory activity against ALDH1, and the CAs compound with ortho di-hydroxyl groups showed the most potent inhibitory activity. This study indicates that CAs may represent a new class of ALDH1 inhibitor. PMID:24840575

  18. Molecular mechanism of null expression of aldehyde dehydrogenase-1 in rat liver

    SciTech Connect

    Chen, J.; Yoshida, Akira; Yanagawa, Yuchio

    1996-04-01

    In isozyme systems in general, the pattern of tissue-dependent expression of a given type of isozyme is uniform in various mammalian species. In contrast, a major cytosolic aldehyde dehydrogenase isozyme, termed ALDH1, which is strongly expressed in the livers of humans and other mammals, is hardly detectable in rat liver. Thirteen nucleotides existing in the 5{prime}-promoter region of human, marmoset, and mouse ALDH1 genes are absent in the four rat strains examined. When the 13 nucleotides were deleted from a chloramphenicol acetyltransferase expression construct, which contained the 5{prime} promoter region of the human ALDH1 gene and a low-background promoterless chloramphenicol acetyltransferase expression vector, the expression activity was severely diminished in human hepatic cells. Thus, deletion of the 13 nucleotides in the promoter region of the gene can account for the lack of ALDH1 expression in rat liver. 16 refs., 3 figs.

  19. Development of industrial brewing yeast with low acetaldehyde production and improved flavor stability.

    PubMed

    Wang, Jinjing; Shen, Nan; Yin, Hua; Liu, Chunfeng; Li, Yongxian; Li, Qi

    2013-02-01

    Higher acetaldehyde concentration in beer is one of the main concerns of current beer industry in China. Acetaldehyde is always synthesized during beer brewing by the metabolism of yeast. Here, using ethanol as the sole carbon source and 4-methylpyrazole as the selection marker, we constructed a new mutant strain with lower acetaldehyde production and improved ethanol tolerance via traditional mutagenesis strategy. European Brewery Convention tube fermentation tests comparing the fermentation broths of mutant strain and industrial brewing strain showed that the acetaldehyde concentration of mutant strain was 81.67 % lower, whereas its resistant staling value was 1.0-fold higher. Owing to the mutation, the alcohol dehydrogenase activity of the mutant strain decreased to about 30 % of the wild-type strain. In the meantime, the fermentation performance of the newly screened strain has little difference compared with the wild-type strain, and there are no safety problems regarding the industrial usage of the mutant strain. Therefore, we suggest that the newly screened strain could be directly applied to brewing industry. PMID:23296804

  20. Elimination of ALDH+ breast tumor initiating cells by docosahexanoic acid and/or gamma tocotrienol through SHP-1 inhibition of Stat3 signaling.

    PubMed

    Xiong, Ailian; Yu, Weiping; Liu, Yaobin; Sanders, Bob G; Kline, Kimberly

    2016-05-01

    Study investigated the ability of docosahexaenoic acid (DHA) alone and in combination with gamma-tocotrienol (γT3) to eliminate aldehyde dehydrogenase positive (ALDH+) cells and to inhibit mammosphere formation, biomarker and functional assay for tumor initiating cells (TICs), respectively, in human triple negative breast cancer cells (TNBCs), and investigated possible mechanisms of action. DHA upregulated Src homology region 2 domain-containing protein tyrosine phosphatase-1 (SHP-1) protein levels and suppressed levels of phosphorylated signal transducer and activator of transcription-3 (pStat3) and its downstream mediators c-Myc, and cyclin D1. siRNA to SHP-1 enhanced the percentage of ALDH+ cells and Stat-3 signaling, as well as inhibited, in part, the ability of DHA to reduce the percentage of ALDH+ cells and Stat-3 signaling. γT3 alone and in combination with DHA reduced ALDH+ TNBCs, up-regulated SHP-1 protein levels, and suppressed Stat-3 signaling. Taken together, data demonstrate the anti-TIC potential of achievable concentrations of DHA alone as well as in combination with γT3. PMID:25648304

  1. Aldehyde dehydrogenase-independent bioactivation of nitroglycerin in porcine and bovine blood vessels.

    PubMed

    Neubauer, Regina; Wölkart, Gerald; Opelt, Marissa; Schwarzenegger, Christine; Hofinger, Marielies; Neubauer, Andrea; Kollau, Alexander; Schmidt, Kurt; Schrammel, Astrid; Mayer, Bernd

    2015-02-15

    The vascular bioactivation of the antianginal drug nitroglycerin (GTN), yielding 1,2-glycerol dinitrate and nitric oxide or a related activator of soluble guanylate cyclase, is catalyzed by aldehyde dehydrogenase-2 (ALDH2) in rodent and human blood vessels. The essential role of ALDH2 has been confirmed in many studies and is considered as general principle of GTN-induced vasodilation in mammals. However, this view is challenged by an early report showing that diphenyleneiodonium, which we recently characterized as potent ALDH2 inhibitor, has no effect on GTN-induced relaxation of bovine coronary arteries (De La Lande et al., 1996). We investigated this issue and found that inhibition of ALDH2 attenuates GTN-induced coronary vasodilation in isolated perfused rat hearts but has no effect on relaxation to GTN of bovine and porcine coronary arteries. This observation is explained by low levels of ALDH2 protein expression in bovine coronary arteries and several types of porcine blood vessels. ALDH2 mRNA expression and the rates of GTN denitration were similarly low, excluding a significant contribution of ALDH2 to the bioactivation of GTN in these vessels. Attempts to identify the responsible pathway with enzyme inhibitors did not provide conclusive evidence for the involvement of ALDH3A1, cytochrome P450, or GSH-S-transferase. Thus, the present manuscript describes a hitherto unrecognized pathway of GTN bioactivation in bovine and porcine blood vessels. If present in the human vasculature, this pathway might contribute to the therapeutic effects of organic nitrates that are not metabolized by ALDH2. PMID:25576686

  2. Aldehyde dehydrogenase 2 activation in heart failure restores mitochondrial function and improves ventricular function and remodelling

    PubMed Central

    Gomes, Katia M.S.; Campos, Juliane C.; Bechara, Luiz R.G.; Queliconi, Bruno; Lima, Vanessa M.; Disatnik, Marie-Helene; Magno, Paulo; Chen, Che-Hong; Brum, Patricia C.; Kowaltowski, Alicia J.; Mochly-Rosen, Daria; Ferreira, Julio C.B.

    2014-01-01

    Aims We previously demonstrated that pharmacological activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) protects the heart against acute ischaemia/reperfusion injury. Here, we determined the benefits of chronic activation of ALDH2 on the progression of heart failure (HF) using a post-myocardial infarction model. Methods and results We showed that a 6-week treatment of myocardial infarction-induced HF rats with a selective ALDH2 activator (Alda-1), starting 4 weeks after myocardial infarction at a time when ventricular remodelling and cardiac dysfunction were present, improved cardiomyocyte shortening, cardiac function, left ventricular compliance and diastolic function under basal conditions, and after isoproterenol stimulation. Importantly, sustained Alda-1 treatment showed no toxicity and promoted a cardiac anti-remodelling effect by suppressing myocardial hypertrophy and fibrosis. Moreover, accumulation of 4-hydroxynonenal (4-HNE)-protein adducts and protein carbonyls seen in HF was not observed in Alda-1-treated rats, suggesting that increasing the activity of ALDH2 contributes to the reduction of aldehydic load in failing hearts. ALDH2 activation was associated with improved mitochondrial function, including elevated mitochondrial respiratory control ratios and reduced H2O2 release. Importantly, selective ALDH2 activation decreased mitochondrial Ca2+-induced permeability transition and cytochrome c release in failing hearts. Further supporting a mitochondrial mechanism for ALDH2, Alda-1 treatment preserved mitochondrial function upon in vitro aldehydic load. Conclusions Selective activation of mitochondrial ALDH2 is sufficient to improve the HF outcome by reducing the toxic effects of aldehydic overload on mitochondrial bioenergetics and reactive oxygen species generation, suggesting that ALDH2 activators, such as Alda-1, have a potential therapeutic value for treating HF patients. PMID:24817685

  3. Aldehyde dehydrogenase-independent bioactivation of nitroglycerin in porcine and bovine blood vessels

    PubMed Central

    Neubauer, Regina; Wölkart, Gerald; Opelt, Marissa; Schwarzenegger, Christine; Hofinger, Marielies; Neubauer, Andrea; Kollau, Alexander; Schmidt, Kurt; Schrammel, Astrid; Mayer, Bernd

    2015-01-01

    The vascular bioactivation of the antianginal drug nitroglycerin (GTN), yielding 1,2-glycerol dinitrate and nitric oxide or a related activator of soluble guanylate cyclase, is catalyzed by aldehyde dehydrogenase-2 (ALDH2) in rodent and human blood vessels. The essential role of ALDH2 has been confirmed in many studies and is considered as general principle of GTN-induced vasodilation in mammals. However, this view is challenged by an early report showing that diphenyleneiodonium, which we recently characterized as potent ALDH2 inhibitor, has no effect on GTN-induced relaxation of bovine coronary arteries (De La Lande et al., 1996). We investigated this issue and found that inhibition of ALDH2 attenuates GTN-induced coronary vasodilation in isolated perfused rat hearts but has no effect on relaxation to GTN of bovine and porcine coronary arteries. This observation is explained by low levels of ALDH2 protein expression in bovine coronary arteries and several types of porcine blood vessels. ALDH2 mRNA expression and the rates of GTN denitration were similarly low, excluding a significant contribution of ALDH2 to the bioactivation of GTN in these vessels. Attempts to identify the responsible pathway with enzyme inhibitors did not provide conclusive evidence for the involvement of ALDH3A1, cytochrome P450, or GSH-S-transferase. Thus, the present manuscript describes a hitherto unrecognized pathway of GTN bioactivation in bovine and porcine blood vessels. If present in the human vasculature, this pathway might contribute to the therapeutic effects of organic nitrates that are not metabolized by ALDH2. PMID:25576686

  4. Human Aldehyde Dehydrogenase Genes: Alternatively-Spliced Transcriptional Variants and Their Suggested Nomenclature

    PubMed Central

    Black, William J.; Stagos, Dimitrios; Marchitti, Satori A.; Nebert, Daniel W.; Tipton, Keith F.; Bairoch, Amos; Vasiliou, Vasilis

    2011-01-01

    OBJECTIVE The human aldehyde dehydrogenase (ALDH) gene superfamily consists of 19 genes encoding enzymes critical for NAD(P)+-dependent oxidation of endogenous and exogenous aldehydes, including drugs and environmental toxicants. Mutations in ALDH genes are the molecular basis of several disease states (e.g. Sjögren-Larsson syndrome, pyridoxine-dependent seizures, and type II hyperprolinemia) and may contribute to the etiology of complex diseases such as cancer and Alzheimer’s disease. The aim of this nomenclature update was to identify splice transcriptional variants principally for the human ALDH genes. METHODS Data-mining methods were used to retrieve all human ALDH sequences. Alternatively-spliced transcriptional variants were determined based upon: a) criteria for sequence integrity and genomic alignment; b) evidence of multiple independent cDNA sequences corresponding to a variant sequence; and c) if available, empirical evidence of variants from the literature. RESULTS AND CONCLUSION Alternatively-spliced transcriptional variants and their encoded proteins exist for most of the human ALDH genes; however, their function and significance remain to be established. When compared with the human genome, rat and mouse include an additional gene, Aldh1a7, in the ALDH1A subfamily. In order to avoid confusion when identifying splice variants in various genomes, nomenclature guidelines for the naming of such alternative transcriptional variants and proteins are recommended herein. In addition, a web database (www.aldh.org) has been developed to provide up-to-date information and nomenclature guidelines for the ALDH superfamily. PMID:19823103

  5. Structural Basis of Substrate Recognition by Aldehyde Dehydrogenase 7A1.

    PubMed

    Luo, Min; Tanner, John J

    2015-09-01

    Aldehyde dehydrogenase 7A1 (ALDH7A1) is part of lysine catabolism and catalyzes the NAD(+)-dependent oxidation of α-aminoadipate semialdehyde to α-aminoadipate. Herein, we describe a structural study of human ALDH7A1 focused on substrate recognition. Five crystal structures and small-angle X-ray scattering data are reported, including the first crystal structure of any ALDH7 family member complexed with α-aminoadipate. The product binds with the ε-carboxylate in the oxyanion hole, the aliphatic chain packed into an aromatic box, and the distal end of the product anchored by electrostatic interactions with five conserved residues. This binding mode resembles that of glutamate bound to the proline catabolic enzyme ALDH4A1. Analysis of ALDH7A1 and ALDH4A1 structures suggests key interactions that underlie substrate discrimination. Structures of apo ALDH7A1 reveal dramatic conformational differences from the product complex. Product binding is associated with a 16 Å movement of the C-terminus into the active site, which stabilizes the active conformation of the aldehyde substrate anchor loop. The fact that the C-terminus is part of the active site was hitherto unknown. Interestingly, the C-terminus and aldehyde anchor loop are disordered in a new tetragonal crystal form of the apoenzyme, implying that these parts of the enzyme are highly flexible. Our results suggest that the active site of ALDH7A1 is disassembled when the aldehyde site is vacant, and the C-terminus is a mobile element that forms quaternary structural interactions that aid aldehyde binding. These results are relevant to the c.1512delG genetic deletion associated with pyridoxine-dependent epilepsy, which alters the C-terminus of ALDH7A1. PMID:26260980

  6. Mesenchymal Stem/Stromal Cells Derived From a Reproductive Tissue Niche Under Oxidative Stress Have High Aldehyde Dehydrogenase Activity.

    PubMed

    Kusuma, Gina D; Abumaree, Mohamed H; Pertile, Mark D; Perkins, Anthony V; Brennecke, Shaun P; Kalionis, Bill

    2016-06-01

    The use of mesenchymal stem/stromal cells (MSC) in regenerative medicine often requires MSC to function in environments of high oxidative stress. Human pregnancy is a condition where the mother's tissues, and in particular her circulatory system, are exposed to increased levels of oxidative stress. MSC in the maternal decidua basalis (DMSC) are in a vascular niche, and thus would be exposed to oxidative stress products in the maternal circulation. Aldehyde dehydrogenases (ALDH) are a large family of enzymes which detoxify aldehydes and thereby protect stem cells against oxidative damage. A subpopulation of MSC express high levels of ALDH (ALDH(br)) and these are more potent in repairing and regenerating tissues. DMSC was compared with chorionic villous MSC (CMSC) derived from the human placenta. CMSC reside in vascular niche and are exposed to the fetal circulation, which is in lower oxidative state. We screened an ALDH isozyme cDNA array and determined that relative to CMSC, DMSC expressed high levels of ALDH1 family members, predominantly ALDH1A1. Immunocytochemistry gave qualitative confirmation at the protein level. Immunofluorescence detected ALDH1 immunoreactivity in the DMSC and CMSC vascular niche. The percentage of ALDH(br) cells was calculated by Aldefluor assay and DMSC showed a significantly higher percentage of ALDH(br) cells than CMSC. Finally, flow sorted ALDH(br) cells were functionally potent in colony forming unit assays. DMSC, which are derived from pregnancy tissues that are naturally exposed to high levels of oxidative stress, may be better candidates for regenerative therapies where MSC must function in high oxidative stress environments. PMID:26880140

  7. Aldehyde dehydrogenase 2 activation in aged heart improves the autophagy by reducing the carbonyl modification on SIRT1.

    PubMed

    Wu, Bing; Yu, Lu; Wang, Yishi; Wang, Hongtao; Li, Chen; Yin, Yue; Yang, Jingrun; Wang, Zhifa; Zheng, Qiangsun; Ma, Heng

    2016-01-19

    Cardiac aging is characterized by accumulation of damaged proteins and decline of autophagic efficiency. Here, by forestalling SIRT1 carbonylated inactivation in aged heart, we determined the benefits of activation of aldehyde dehydrogenase 2 (ALDH2) on the autophagy. In this study, the ALDH2 KO mice progressively developed age-related heart dysfunction and showed reduction in the life span, which strongly suggests that ALDH2 ablation leads to cardiac aging. What's more, aged hearts displayed a significant decrease ALDH2 activity, resulting in accumulation of 4-HNE-protein adducts and protein carbonyls, impairment in the autophagy flux, and, consequently, deteriorated cardiac function after starvation. Sustained Alda-1 (selective ALDH2 activator) treatment increased cardiac ALDH2 activity and abrogated these effects. Using SIRT1 deficient heterozygous (Sirt1+/-) mice, we found that SIRT1 was necessary for ALDH2 activation-induced autophagy. We further demonstrated that ALDH2 activation attenuated SIRT1 carbonylation and improved SIRT1 activity, thereby increasing the deacetylation of nuclear LC3 and FoxO1. Sequentially, ALDH2 enhanced SIRT1 regulates LC3-Atg7 interaction and FoxO1 increased Rab7 expression, which were both necessary and sufficient for restoring autophagy flux. These results highlight that both accumulation of proteotoxic carbonyl stress linkage with autophagy decline contribute to heart senescence. ALDH2 activation is adequate to improve the autophagy flux by reducing the carbonyl modification on SIRT1, which in turn plays an important role in maintaining cardiac health during aging. PMID:26741505

  8. Heterogeneous Interactions of Acetaldehyde and Sulfuric Acid

    NASA Technical Reports Server (NTRS)

    Michelsen, R. R.; Ashbourn, S. F. M.; Iraci, L. T.

    2004-01-01

    The uptake of acetaldehyde [CH3CHO] by aqueous sulfuric acid has been studied via Knudsen cell experiments over ranges of temperature (210-250 K) and acid concentration (40-80 wt. %) representative of the upper troposphere. The Henry's law constants for acetaldehyde calculated from these data range from 6 x 10(exp 2) M/atm for 40 wt. % H2SO4 at 228 K to 2 x 10(exp 5) M/atm for 80 wt. % H2SO4 at 212 K. In some instances, acetaldehyde uptake exhibits apparent steady-state loss. The possible sources of this behavior, including polymerization, will be explored. Furthermore, the implications for heterogeneous reactions of aldehydes in sulfate aerosols in the upper troposphere will be discussed.

  9. Decomposition of acetaldehyde : experiment and detailed theory.

    SciTech Connect

    Gupte, K. S.; Kiefer, J. H.; Tranter, R. S.; Klippenstein, S. J.; Harding, L. B.; Chemistry; Univ. of Illinois at Chicago

    2007-01-01

    The classic pyrolytic decomposition of acetaldehyde has been examined to the higher temperatures used in combustion and also lower pressures with 85 laser-schlieren, shock-tube measurements of density gradient covering 40-500 torr and 1550-2400 K. This work is supplemented and modeled with a CASPT2 based variable reaction coordinate RRKM prediction of the dissociation kinetics. These RRKM predictions are then incorporated in good two-dimensional master equation fits of the strong falloff seen in the laser-schlieren experiments, and also that shown in some previous shock-tube results using UV absorption of the acetaldehyde as diagnostic. The laser-schlieren data provide not only unambiguous dissociation rates but also solid indications of the secondary chemistry. Modeling of the full density gradient profiles offers good estimates of rates for H-atom abstraction from both the acetaldehyde and the HCO radical, again at high temperatures.

  10. Ethylene oxide and acetaldehyde in hot cores

    NASA Astrophysics Data System (ADS)

    Occhiogrosso, A.; Vasyunin, A.; Herbst, E.; Viti, S.; Ward, M. D.; Price, S. D.; Brown, W. A.

    2014-04-01

    Context. Ethylene oxide (c-C2H4O), and its isomer acetaldehyde (CH3CHO), are important complex organic molecules because of their potential role in the formation of amino acids. The discovery of ethylene oxide in hot cores suggests the presence of ring-shaped molecules with more than 3 carbon atoms such as furan (c-C4H4O), to which ribose, the sugar found in DNA, is closely related. Aims: Despite the fact that acetaldehyde is ubiquitous in the interstellar medium, ethylene oxide has not yet been detected in cold sources. We aim to understand the chemistry of the formation and loss of ethylene oxide in hot and cold interstellar objects (i) by including in a revised gas-grain network some recent experimental results on grain surfaces and (ii) by comparison with the chemical behaviour of its isomer, acetaldehyde. Methods: We introduce a complete chemical network for ethylene oxide using a revised gas-grain chemical model. We test the code for the case of a hot core. The model allows us to predict the gaseous and solid ethylene oxide abundances during a cooling-down phase prior to star formation and during the subsequent warm-up phase. We can therefore predict at what temperatures ethylene oxide forms on grain surfaces and at what temperature it starts to desorb into the gas phase. Results: The model reproduces the observed gaseous abundances of ethylene oxide and acetaldehyde towards high-mass star-forming regions. In addition, our results show that ethylene oxide may be present in outer and cooler regions of hot cores where its isomer has already been detected. Our new results are compared with previous results, which focused on the formation of ethylene oxide only. Conclusions: Despite their different chemical structures, the chemistry of ethylene oxide is coupled to that of acetaldehyde, suggesting that acetaldehyde may be used as a tracer for ethylene oxide towards cold cores.

  11. Effect of acetaldehyde generated from ethanol by ADH-transfected CHO cells on their membrane fatty acid profiles.

    PubMed

    Meskar, A; Holownia, A; Bardou, L G; Menez, J F

    1996-01-01

    Ethanol has been previously shown to reduce the unsaturated fatty acid content of cell membranes. It is not known, however, if the observed deleterious effects are due to ethanol itself or its metabolite, acetaldehyde. The present study was undertaken to assess the effect of acetaldehyde produced from ethanol by alcohol-deyhdrogenase-transfected Chinese hamster ovary Cells on the membrane lipids and the lipid peroxidation measured by free and bound malondialdehyde (MDA). The effects of ethanol alone was assessed in the presence of 4-methylpyrazole (4-MP), an inhibitor of alcohol dehydrogenase. After 8 days of incubation, total cellular lipids were extracted, subjected to TLC, and analyzed by gas chromatography. MDA concentration were determined by thiobarbituric acid reaction followed by HPLC detection. The level of acetaldehyde in the culture medium increased with concentration of ethanol from 5 to 20 mM as did the lipid peroxidation. Total cholesterol, phospholipids, and triglycerids all increased with increasing concentration of acetaldehyde. These effects were due to acetaldehyde as they were blocked by 4-MP. Some changes in fatty acid profiles were observed by effect of ethanol itself. PMID:8949957

  12. Autocrine function of aldehyde dehydrogenase 1 as a determinant of diet- and sex-specific differences in visceral adiposity.

    PubMed

    Yasmeen, Rumana; Reichert, Barbara; Deiuliis, Jeffrey; Yang, Fangping; Lynch, Alisha; Meyers, Joseph; Sharlach, Molly; Shin, Sangsu; Volz, Katharina S; Green, Kari B; Lee, Kichoon; Alder, Hansjuerg; Duester, Gregg; Zechner, Rudolf; Rajagopalan, Sanjay; Ziouzenkova, Ouliana

    2013-01-01

    Mechanisms for sex- and depot-specific fat formation are unclear. We investigated the role of retinoic acid (RA) production by aldehyde dehydrogenase 1 (Aldh1a1, -a2, and -a3), the major RA-producing enzymes, on sex-specific fat depot formation. Female Aldh1a1(-/-) mice, but not males, were resistant to high-fat (HF) diet-induced visceral adipose formation, whereas subcutaneous fat was reduced similarly in both groups. Sexual dimorphism in visceral fat (VF) was attributable to elevated adipose triglyceride lipase (Atgl) protein expression localized in clusters of multilocular uncoupling protein 1 (Ucp1)-positive cells in female Aldh1a1(-/-) mice compared with males. Estrogen decreased Aldh1a3 expression, limiting conversion of retinaldehyde (Rald) to RA. Rald effectively induced Atgl levels via nongenomic mechanisms, demonstrating indirect regulation by estrogen. Experiments in transgenic mice expressing an RA receptor response element (RARE-lacZ) revealed HF diet-induced RARE activation in VF of females but not males. In humans, stromal cells isolated from VF of obese subjects also expressed higher levels of Aldh1 enzymes compared with lean subjects. Our data suggest that an HF diet mediates VF formation through a sex-specific autocrine Aldh1 switch, in which Rald-mediated lipolysis in Ucp1-positive visceral adipocytes is replaced by RA-mediated lipid accumulation. Our data suggest that Aldh1 is a potential target for sex-specific antiobesity therapy. PMID:22933113

  13. MUC1-C Oncoprotein Activates ERK→C/EBPβ Signaling and Induction of Aldehyde Dehydrogenase 1A1 in Breast Cancer Cells*

    PubMed Central

    Alam, Maroof; Ahmad, Rehan; Rajabi, Hasan; Kharbanda, Akriti; Kufe, Donald

    2013-01-01

    Aldehyde dehydrogenase 1A1 (ALDH1A1) activity is used as a marker of breast cancer stem cells; however, little is known about the regulation of ALDH1A1 expression. Mucin 1 (MUC1) is a heterodimeric protein that is aberrantly overexpressed in most human breast cancers. In studies of breast cancer cells stably silenced for MUC1 or overexpressing the oncogenic MUC1-C subunit, we demonstrate that MUC1-C is sufficient for induction of MEK→ERK signaling and that treatment with a MUC1-C inhibitor suppresses ERK activation. In turn, MUC1-C induces ERK-mediated phosphorylation and activation of the CCAAT/enhancer-binding protein β (C/EBPβ) transcription factor. The results further show that MUC1-C and C/EBPβ form a complex on the ALDH1A1 gene promoter and activate ALDH1A1 gene transcription. MUC1-C-induced up-regulation of ALDH1A1 expression is associated with increases in ALDH activity and is detectable in stem-like cells when expanded as mammospheres. These findings demonstrate that MUC1-C (i) activates a previously unrecognized ERK→C/EBPβ→ALDH1A1 pathway, and (ii) promotes the induction of ALDH activity in breast cancer cells. PMID:24043631

  14. Pharmacological treatments and strategies for reducing oral and intestinal acetaldehyde.

    PubMed

    Salaspuro, Ville

    2007-01-01

    Strong epidemiological, genetic and biochemical evidence indicates that local acetaldehyde exposure is a major factor behind gastrointestinal cancers especially associated with alcohol drinking and smoking. Thus, reducing the exposure to carcinogenic acetaldehyde either by decreasing the production or by eliminating acetaldehyde locally might offer a preventive strategy against acetaldehyde-induced gastrointestinal cancers. Thiol products, such as the amino acid cysteine, are known to be able to protect against acetaldehyde toxicity. Cysteine is able to bind acetaldehyde efficiently by forming a stable thiazolidine-carboxylic acid compound. Special cysteine preparations (such as lozenge and chewing gum) have already been developed to bind smoking and alcohol drinking derived acetaldehyde from the oral cavity. Most importantly, these type of drug formulations offer a novel method for intervention studies aimed to resolve the eventual role of acetaldehyde in the pathogenesis of upper digestive tract cancers. Acetaldehyde exposure could also be influenced by modifying the acetaldehyde producing microbiota. With regard to the upper digestive tract, acetaldehyde production from ingested ethanol could be significantly reduced by using an antiseptic mouthwash, chlorhexidine. In the large intestine acetaldehyde production could be markedly decreased either by reducing the Gram-negative microbes by ciprofloxacin antibiotic or by lowering the intraluminal pH by lactulose. PMID:17590993

  15. Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily

    PubMed Central

    Marchitti, Satori A; Brocker, Chad; Stagos, Dimitrios; Vasiliou, Vasilis

    2009-01-01

    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 Sjögren-Larsson syndrome, type II hyperprolinemia, γ-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. PMID:18611112

  16. Aldehyde dehydrogenase 2 is associated with cognitive functions in patients with Parkinson’s disease

    PubMed Central

    Yu, Rwei-Ling; Tan, Chun-Hsiang; Lu, Ying-Che; Wu, Ruey-Meei

    2016-01-01

    Neurotransmitter degradation has been proposed to cause the accumulation of neurotoxic metabolites. The metabolism of these metabolites involves aldehyde dehydrogenase 2 (ALDH2). The Asian-specific single nucleotide polymorphism rs671 causes reduced enzyme activity. This study aims to explore whether Parkinson’s disease (PD) patients with reduced ALDH2 activity owing to the rs671 polymorphism are at risk for neuropsychological impairments. A total of 139 PD patients were recruited. Each participant was assessed for medical characteristics and their ALDH2 genotype. The Mini-Mental State Examination (MMSE), the Clinical Dementia Rating Scale and the Frontal Behavioral Inventory were used to measure neuropsychological functions. We found that the MMSE scores were significantly lower in patients with inactive ALDH2 (U = 1873.5, p = 0.02). The presence of cognitive impairments was significantly more frequent in the inactive ALDH2 group (46.0%) than in the active ALDH2 group (26.3%) (χ2 = 5.886, p = 0.01). The inactive group showed significant deterioration in hobbies and exhibited more severe “disorganization” and “hyper-sexuality” behaviours. The additive effects of the allele on the development of cognitive impairments in PD patients may be an important finding that provides further insight into the pathogenic mechanism of cognitive dysfunction in PD. PMID:27453488

  17. Role of disulfiram in the in vitro inhibition of rat liver mitochondrial aldehyde dehydrogenase.

    PubMed

    Shen, M L; Lipsky, J J; Naylor, S

    2000-10-01

    The alcohol aversion therapy drug disulfiram has been shown to inhibit hepatic aldehyde dehydrogenase (ALDH), one of the key enzymes involved in ethanol metabolism. It is believed by some that disulfiram could be one of the active inhibitors in vivo. However, the actual interaction between disulfiram and ALDH remains ambiguous. We report here that when disulfiram inhibited recombinant rat liver mitochondrial ALDH (rlmALDH) in vitro, no significant molecular mass increase was detected during the first 30 min as determined by on-line HPLC-electrospray ionization mass spectrometry (LC-MS). This indicated that the inhibition in vitro was not caused directly by covalent adduct formation on the enzyme. We subsequently subjected both control and disulfiram-inhibited rlmALDH to Glu-C proteolytic digestion. LC-MS analysis of the Glu-C digestion of disulfiram-inhibited enzyme revealed that one peptide of M(r) = 4821, which contained the putative active site of the enzyme, exhibited a mass decrease of 2 amu as compared with the same peptide found in the Glu-C digestion of the control (M(r) = 4823). We believe that the loss of 2 amu indicated that inhibition of rlmALDH in vitro was due to formation of an intramolecular disulfide bond between two of the three adjacent cysteines in the active site, possibly via a very rapid and unstable mixed disulfide interchange reaction. Further confirmation of the intramolecular disulfide bond formation came from the fact that by adding dithiothreitol (DTT) we were able to recover partial enzyme activity. In addition, the peptide of M(r) = 4821 observed in the Glu-C digestion of the disulfiram-treated ALDH reverted to M(r) = 4823 after treatment with DTT, which indicated that the disulfide bond was reduced. We, thereby, conclude that disulfiram inhibited rlmALDH by forming an intramolecular disulfide, possibly via a fast intermolecular disulfiram interchange reaction. PMID:10974203

  18. Transport and intracellular accumulation of acetaldehyde in Saccharomyces cerevisiae

    SciTech Connect

    Stanley, G.A.; Pamment, N.B. )

    1993-06-05

    The rate of acetaldehyde efflux from yeast cells and its intracellular concentration were studied in the light of recent suggestions that acetaldehyde inhibition may be an important factor in yeast ethanol fermentations. When the medium surrounding cells containing ethanol and acetaldehyde was suddenly diluted, the rate of efflux of acetaldehyde was slow relative to the rate of ethanol efflux, suggesting that acetaldehyde, unlike ethanol, may accumulate intracellularly. Intracellular acetaldehyde concentrations were measured during high cell density fermentations, using direct injection gas chromatography to avoid the need to concentrate or disrupt the cells. Intracellular acetaldehyde concentrations substantially exceeded the extracellular concentrations throughout fermentation and were generally much higher than the acetaldehyde concentrations normally recorded in the culture broth in ethanol fermentations. The technique used was sensitive to the time taken to cool and freeze the samples. Measured intracellular acetaldehyde concentrations fell rapidly as the time taken to freeze the suspensions was extended beyond 2 s. The results add weight to recent claims that acetaldehyde toxicity is responsible for some of the effects previously ascribed to ethanol in alcohol fermentations, especially Zymomonas fermentations. Further work is required to confirm the importance of acetaldehyde toxicity under other culture conditions.

  19. Malignant phyllodes tumors display mesenchymal stem cell features and aldehyde dehydrogenase/disialoganglioside identify their tumor stem cells

    PubMed Central

    2014-01-01

    Introduction Although breast phyllodes tumors are rare, there is no effective therapy other than surgery. Little is known about their tumor biology. A malignant phyllodes tumor contains heterologous stromal elements, and can transform into rhabdomyosarcoma, liposarcoma and osteosarcoma. These versatile properties prompted us to explore their possible relationship to mesenchymal stem cells (MSCs) and to search for the presence of cancer stem cells (CSCs) in phyllodes tumors. Methods Paraffin sections of malignant phyllodes tumors were examined for various markers by immunohistochemical staining. Xenografts of human primary phyllodes tumors were established by injecting freshly isolated tumor cells into the mammary fat pad of non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. To search for CSCs, xenografted tumor cells were sorted into various subpopulations by flow cytometry and examined for their in vitro mammosphere forming capacity, in vivo tumorigenicity in NOD-SCID mice and their ability to undergo differentiation. Results Immunohistochemical analysis revealed the expression of the following 10 markers: CD44, CD29, CD106, CD166, CD105, CD90, disialoganglioside (GD2), CD117, Aldehyde dehydrogenase 1 (ALDH), and Oct-4, and 7 clinically relevant markers (CD10, CD34, p53, p63, Ki-67, Bcl-2, vimentin, and Globo H) in all 51 malignant phyllodes tumors examined, albeit to different extents. Four xenografts were successfully established from human primary phyllodes tumors. In vitro, ALDH+ cells sorted from xenografts displayed approximately 10-fold greater mammosphere-forming capacity than ALDH- cells. GD2+ cells showed a 3.9-fold greater capacity than GD2- cells. ALDH+/GD2+cells displayed 12.8-fold greater mammosphere forming ability than ALDH-/GD2- cells. In vivo, the tumor-initiating frequency of ALDH+/GD2+ cells were up to 33-fold higher than that of ALDH+ cells, with as few as 50 ALDH+/GD2+ cells being sufficient for engraftment. Moreover, we

  20. Aldehyde dehydrogenase 3A1 is robustly upregulated in gastric cancer stem-like cells and associated with tumorigenesis.

    PubMed

    Wu, Di; Mou, Yi-Ping; Chen, Ke; Cai, Jia-Qin; Zhou, Yu-Cheng; Pan, Yu; Xu, Xiao-Wu; Zhou, Wei; Gao, Jia-Qi; Chen, Ding-Wei; Zhang, Ren-Chao

    2016-08-01

    Enhanced aldehyde dehydrogenase (ALDH) activity has been shown to serve as a hallmark for cancer stem cells (CSCs). Recent evidence suggests that its role as a stem cell-related marker has come down to the specific isoform. However, little is known about the specific ALDH isoform contributing to aldefluor activity in gastric cancer. In this study, we isolated ALDHbright cells from 2 human gastric cancer cell lines MKN-45 and SGC‑7901 by using an Aldefluor assay and found elevated self-renewal, differentiation and tumorigenicity, as demonstration of stemness characteristics. We also found that ALDHbright cells expressed decreased levels of E-cadherin but increased levels of Snail and Vimentin, indication of an epithelial-mesenchymal transition (EMT) phenotype which may be responsible for the enhanced metastatic potential. Since further research and prognostic application based on ALDH prevalence require the quantification of the specific ALDH isoform, we characterized the expression of all 19 ALDH isoforms in the sorted gastric cancer cell lines by quantitative real-time polymerase chain reaction (qRT-PCR). Compared with the non-stem counterparts, robust upregulation of ALDH-3A1 was observed in these gastric cancer stem-like cells. Furthermore, we performed immunohistological analysis on 93 fixed patient gastric tumor samples and found that ALDH-3A1 expression correlated well with gastric cancer dysplasia and grades, differentiation, lymph node metastasis and cancer stage. Our data, therefore, provide strong evidence that ALDH-3A1 is a novel gastric cancer stem cell related marker with potential prognostic values and demonstrate a clear association between ALDH-3A1 prevalence and gastric cancer progression. PMID:27279633

  1. Mitochondrial aldehyde dehydrogenase protects against doxorubicin cardiotoxicity through a transient receptor potential channel vanilloid 1-mediated mechanism.

    PubMed

    Ge, Wei; Yuan, Ming; Ceylan, Asli F; Wang, Xiaoming; Ren, Jun

    2016-04-01

    Cardiotoxicity is one of the major life-threatening effects encountered in cancer chemotherapy with doxorubicin and other anthracyclines. Mitochondrial aldehyde dehydrogenase (ALDH2) may alleviate doxorubicin toxicity although the mechanism remains elusive. This study was designed to evaluate the impact of ALDH2 overexpression on doxorubicin-induced myocardial damage with a focus on mitochondrial injury. Wild-type (WT) and transgenic mice overexpressing ALDH2 driven by chicken β-actin promoter were challenged with doxorubicin (15mg/kg, single i.p. injection, for 6days) and cardiac mechanical function was assessed using the echocardiographic and IonOptix systems. Western blot analysis was used to evaluate intracellular Ca(2+) regulatory and mitochondrial proteins, PKA and its downstream signal eNOS. Doxorubicin challenge altered cardiac geometry and function evidenced by enlarged left ventricular end systolic and diastolic diameters, decreased factional shortening, cell shortening and intracellular Ca(2+) rise, prolonged relengthening and intracellular Ca(2+) decay, the effects of which were attenuated by ALDH2. Doxorubicin challenge compromised mitochondrial integrity and upregulated 4-HNE and UCP-2 levels while downregulating levels of TRPV1, SERCA2a and PGC-1α, the effects of which were alleviated by ALDH2. Doxorubicin-induced cardiac functional defect and apoptosis were reversed by the TRPV1 agonist SA13353 and the ALDH-2 agonist Alda-1 whereas the TRPV1 antagonist capsazepine nullified ALDH2/Alda-1-induced protection. Doxorubicin suppressed phosphorylation of PKA and eNOS, the effect of which was reversed by ALDH2. Moreover, 4-HNE mimicked doxorubicin-induced cardiomyocyte anomalies, the effect of which was ablated by SA13353. Taken together, our results suggested that ALDH2 may rescue against doxorubicin cardiac toxicity possibly through a TRPV1-mediated protection of mitochondrial integrity. PMID:26692169

  2. Purification, characterization, and cDNA cloning of opine dehydrogenases from the polychaete rockworm Marphysa sanguinea.

    PubMed

    Endo, Noriyuki; Kan-no, Nobuhiro; Nagahisa, Eizoh

    2007-06-01

    Alanopine dehydrogenase (AlDH) and three isoforms of strombine/alanopine dehydrogenase (St/AlDH) were purified from muscle tissue of the polychaete rockworm Marphysa sanguinea. The four enzymes, which can be distinguished by the isoelectric point, are monomeric 42 kDa proteins, possess similar pH-activity profiles, and display specificity for pyruvate and NAD(H). The three isoforms of St/AlDH show equivalent Km and Vmax for glycine and L-alanine and for D-strombine and meso-alanopine. Free amino acid levels in the muscle and D-strombine accumulation in vivo during muscle activity suggest that St/AlDHs function physiologically as StDH. AlDH shows specificity for L-alanine and meso-alanopine, but not for glycine or D-strombine. The amino acid sequences of AlDH and one of the St/AlDH isoforms were determined by a combination of amino acid sequence analysis and cDNA cloning. St/AlDH cDNA consisted of 1586 bp nucleotides that encode a 399-residue protein (43,346.70 Da), and AlDH cDNA consisted of 1587 bp nucleotides that encode a 399-residue protein (43,886.68 Da). The two amino acid sequences deduced from the cDNA displayed 67% amino acid identity, with greatest similarity to that of tauropine dehydrogenase from the polychaete Arabella iricolor. PMID:17350870

  3. Isolated tumoral pyruvate dehydrogenase can synthesize acetoin which inhibits pyruvate oxidation as well as other aldehydes.

    PubMed

    Baggetto, L G; Lehninger, A L

    1987-05-29

    Oxidation of 1 mM pyruvate by Ehrlich and AS30-D tumor mitochondria is inhibited by acetoin, an unusual and important metabolite of pyruvate utilization by cancer cells, by acetaldehyde, methylglyoxal and excess pyruvate. The respiratory inhibition is reversed by other substrates added to pyruvate and also by 0.5 mM ATP. Kinetic properties of pyruvate dehydrogenase complex isolated from these tumor mitochondria have been studied. This complex appears to be able to synthesize acetoin from acetaldehyde plus pyruvate and is competitively inhibited by acetoin. The role of a new regulatory pattern for tumoral pyruvate dehydrogenase is presented. PMID:3593337

  4. Incomplete penetrance of biallelic ALDH1A3 mutations.

    PubMed

    Plaisancié, Julie; Brémond-Gignac, Dominique; Demeer, Bénédicte; Gaston, Véronique; Verloes, Alain; Fares-Taie, Lucas; Gerber, Sylvie; Rozet, Jean-Michel; Calvas, Patrick; Chassaing, Nicolas

    2016-04-01

    The formation of a properly shaped eye is a complex developmental event that requires the coordination of many induction processes and differentiation pathways. Microphthalmia and anophthalmia (MA) represent the most severe defects that can affect the ocular globe during embryonic development. When genetic, these ocular disorders exhibit large genetic heterogeneity and extreme variable expressivity. Around 20 monogenic diseases are known to be associated with MA as main phenotype and the penetrance of mutations is usually full in the patients. Some of these genes encode proteins involved in the vitamin A pathway, tightly regulated during eye development. One of those retinoic acid synthesis genes is ALDH1A3 and biallelic mutations in that gene have been recently found to lead to MA phenotype in patients. Interestingly, we report here the lack of ocular defect in a girl carrying the same homozygous mutation in the ALDH1A3 gene than the affected members of her family. Thus, this report brings new information for the phenotype-genotype correlation of ALDH1A3 mutations and raises important questions, especially in terms of genetic counselling given to the patients and their families. Furthermore, these data contribute to the more general understanding that we have for the complex genetic inheritance of these MA phenotypes. PMID:26873617

  5. Macrophage and dendritic cell subsets in IBD: ALDH+ cells are reduced in colon tissue of patients with ulcerative colitis regardless of inflammation

    PubMed Central

    Magnusson, Maria K; Brynjólfsson, Siggeir F; Dige, Anders; Uronen-Hansson, Heli; Börjesson, Lars G.; Bengtsson, Jonas L.; Gudjonsson, Sigurdur; Öhman, Lena; Agnholt, Jørgen; Sjövall, Henrik; Agace, William W; Wick, Mary Jo

    2015-01-01

    Disruption of the homeostatic balance of intestinal dendritic cells (DCs) and macrophages (MQs) may contribute to inflammatory bowel disease. We characterized DC and MQ populations, including their ability to produce retinoic acid, in clinical material encompassing Crohn’s ileitis, Crohn’s colitis and ulcerative colitis (UC) as well as mesenteric lymph nodes (MLNs) draining these sites. Increased CD14+DRint MQs characterized inflamed intestinal mucosa while total CD141+ or CD1c+ DCs numbers were unchanged. However, CD103+ DCs, including CD141+CD103+ and CD1c+CD103+ DCs, were reduced in inflamed intestine. In MLNs, two CD14− DC populations were identified: CD11cintHLADRhi and CD11chiHLADRint cells. A marked increase of CD11chiHLADRint DC, particularly DRintCD1c+ DCs, characterized MLNs draining inflamed intestine. The fraction of DC and MQ populations expressing aldehyde dehydrogenase (ALDH) activity, reflecting retinoic acid synthesis, in UC colon, both in active disease and remission, were reduced compared to controls and inflamed Crohn’s colon. In contrast, no difference in the frequency of ALDH+ cells among blood precursors was detected between UC patients in remission and non-inflamed controls. This suggests that ALDH activity in myeloid cells in the colon of UC patients, regardless of whether the disease is active or in remission, is influenced by the intestinal environment. PMID:26080709

  6. JNK1/2 regulate Bid by direct phosphorylation at Thr59 in response to ALDH1L1

    PubMed Central

    Prakasam, A; Ghose, S; Oleinik, N V; Bethard, J R; Peterson, Y K; Krupenko, N I; Krupenko, S A

    2014-01-01

    BH3 interacting-domain death agonist (Bid) is a BH3-only pro-apoptotic member of the Bcl-2 family of proteins. Its function in apoptosis is associated with the proteolytic cleavage to the truncated form tBid, mainly by caspase-8. tBid translocates to mitochondria and assists Bax and Bak in induction of apoptosis. c-Jun N-terminal kinase (JNK)-dependent alternative processing of Bid to jBid was also reported. We have previously shown that the folate stress enzyme 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) activates JNK1 and JNK2 in cancer cells as a pro-apoptotic response. Here we report that in PC-3 prostate cancer cells, JNK1/2 phosphorylate Bid at Thr59 within the caspase cleavage site in response to ALDH1L1. In vitro, all three JNK isoforms, JNK 1–3, phosphorylated Thr59 of Bid with JNK1 being the least active. Thr59 phosphorylation protected Bid from cleavage by caspase-8, resulting in strong accumulation of the full-length protein and its translocation to mitochondria. Interestingly, although we did not observe jBid in response to ALDH1L1 in PC-3 cells, transient expression of Bid mutants lacking the caspase-8 cleavage site resulted in strong accumulation of jBid. Of note, a T59D mutant mimicking constitutive phosphorylation revealed more profound cleavage of Bid to jBid. JNK-driven Bid accumulation had a pro-apoptotic effect in our study: small interfering RNA silencing of either JNK1/2 or Bid prevented Bid phosphorylation and accumulation, and rescued ALDH1L1-expressing cells. As full-length Bid is a weaker apoptogen than tBid, we propose that the phosphorylation of Bid by JNKs, followed by the accumulation of the full-length protein, delays attainment of apoptosis, and allows the cell to evaluate the stress and make a decision regarding the response strategy. This mechanism perhaps can be modified by the alternative cleavage of phospho-T59 Bid to jBid at some conditions. PMID:25077544

  7. Interaction of DRD2TaqI, COMT, and ALDH2 genes associated with bipolar II disorder comorbid with anxiety disorders in Han Chinese in Taiwan.

    PubMed

    Hu, Ming-Chuan; Lee, Sheng-Yu; Wang, Tzu-Yun; Chang, Yun-Hsuan; Chen, Shiou-Lan; Chen, Shih-Heng; Chu, Chun-Hsien; Wang, Chen-Lin; Lee, I Hui; Chen, Po See; Yang, Yen Kuang; Lu, Ru-Band

    2015-06-01

    It is hypothesized that dopaminergic genes-dopamine type-2 receptor (DRD2), aldehyde dehydrogenase 2 (ALDH2), and catechol-O-methyltransferase (COMT)-are associated with bipolar disorder (BP) and anxiety disorder (AD). Bipolar II (BP-II) is reported to be highly comorbid with AD. We examined whether interactions among these three genes are susceptibility factors in BP-II with AD (BP-II(+AD)) and without AD (BP-II(-AD)). In this study, we hypothesize that the interaction of the dopaminergic genes between BP-II(+AD) and BP-II(-AD) is significant different. We recruited 1260 participants: 495 with BP-II(-AD), 170 with BP-II(+AD), and 595 healthy controls without BP-II or AD. Genotyping was done using polymerase chain reactions plus restriction fragment length polymorphism analysis. Genotypic frequencies of the DRD2TaqIA, COMT, and ALDH2 polymorphisms between the two BP-II groups were nonsignificant. In logistic regression, the ALDH2 and DRD2TaqIA genes showed a main effect that was protective against BP-II(-AD) (odds ratio [OR] = 0.497, p = 0.010, and OR = 0.415, p = 0.017, respectively). The interaction of DRD2TaqIA A1/A1 and ALDH2*1/*1 had a significant risk effect on the BP-II(-AD) group (OR = 7.177, p < 0.001). However, the interaction of DRD2TaqIA A1/A1, ALDH2*1/*1, and COMTMet/Met&Val/Met become a weak protective factor against BP-II(-AD) (OR = 0.205, p = 0.047). All of the significant results described above are found only in BP-II(-AD). This study supports the hypothesis the interaction of the dopaminergic genes between BP-II(+AD) and BP-II(-AD) is significant different,, and provides additional evidence that the DRD2TaqIA A1/A1, ALDH2*1/*1 and COMT genes interact in BP-II(-AD) but not in BP-II(+AD). PMID:25430946

  8. Reliability of a flushing questionnaire and the ethanol patch test in screening for inactive aldehyde dehydrogenase-2 and alcohol-related cancer risk.

    PubMed

    Yokoyama, A; Muramatsu, T; Ohmori, T; Kumagai, Y; Higuchi, S; Ishii, H

    1997-12-01

    Molecular epidemiology of esophageal and upper aerodigestive tract cancers revealed that alcohol is more carcinogenic in persons with inactive aldehyde dehydrogenase-2 (ALDH2) than in those with active ALDH2. A simple questionnaire has been developed to screen for the facial flushing that occurs in persons with inactive ALDH2 when they drink even a single glass of beer. In this study, 266 of 284 consecutive male Japanese clinic patients (age > or = 50 years) completed the flushing questionnaire, and 239 underwent the ethanol patch test (a cutaneous model for the flushing response). Blinded genotyping showed inactive ALDH2 for 94.4% (102 of 108) of subjects who reported always flushing (early in their drinking history or currently) and for 47.7% (21 of 44) of those who reported sometimes flushing, whereas 95.6% (109 of 114) of subjects reporting that they never exhibited facial flushing had active ALDH2. When all three categories of flushing (current always, former always, and sometimes) were collapsed into one, the questionnaire's sensitivity and specificity for identifying inactive ALDH2 were 96.1 and 79.0%, respectively, compared with 72.4 and 71.4% for the ethanol patch test. The results suggest the utility of this simple flushing questionnaire in daily practice, as well as large-scale studies to assess cancer risks associated with drinking and ALDH2 and for activities aimed at preventing alcohol-related cancer. PMID:9419411

  9. Folate, alcohol, and aldehyde dehydrogenase 2 polymorphism and the risk of oral and pharyngeal cancer in Japanese.

    PubMed

    Matsuo, Keitaro; Rossi, Marta; Negri, Eva; Oze, Isao; Hosono, Satoyo; Ito, Hidemi; Watanabe, Miki; Yatabe, Yasushi; Hasegawa, Yasuhisa; Tanaka, Hideo; Tajima, Kazuo; La Vecchia, Carlo

    2012-03-01

    Folate consumption is inversely associated with the risk of oral and pharyngeal cancer (OPC) and potentially interacts with alcohol drinking in the risk of OPC. Aldehyde dehydrogenase 2 (ALDH2) gene polymorphism is known to interact with alcohol consumption. The aim of this study was to investigate potential interaction between folate, alcohol drinking, and ALDH2 polymorphism in the risk of OPC in a Japanese population. The study group comprised 409 head and neck cancer cases and 1227 age-matched and sex-matched noncancer controls; of these, 251 cases and 759 controls were evaluated for ALDH rs671 polymorphism. Associations were assessed by odds ratios and 95% confidence intervals in multiple logistic regression models. We observed an inverse association between folate consumption and OPC risk. The odds ratio for high folate intake was 0.53 (95% confidence interval: 0.36-0.77) relative to low intake (P trend=0.003). This association was consistent across strata of sex, age, smoking, and ALDH2 genotypes. Interaction between folate consumption, drinking, and ALDH2 genotype was remarkable (three-way interaction, P<0.001). We observed significant interaction among folate, drinking, and ALDH2 genotype in the Japanese population. PMID:21946912

  10. Acetaldehyde inhibition of protein synthesis in isolated rat pancreatic acini

    SciTech Connect

    Majumdar, A.P.; Haiman, M.J.; Zylbert, B.A.; Billy, H.T.; Vesenka, G.D.; Geokas, M.C.

    1986-03-30

    Exposure of isolated dispersed pancreatic acini to increasing concentrations of ethanol (5 to 500 mM) or acetaldehyde (0.5 to 100 mM) produced a progressive inhibition of (3H)leucine incorporation into both cellular (those remaining in the cell) and secretory (those released into the medium) proteins. Whereas 500 mM ethanol caused 90-95% inhibition in the synthesis of cellular and secretory proteins, the concentration of acetaldehyde needed to produce a similar inhibition was found to be 50 mM. All subsequent experiments were performed with 12.5 mM acetaldehyde, a concentration that consistently inhibited acinar protein synthesis by about 50%. The acetaldehyde-mediated inhibition of acinar protein synthesis was partially normalized when this metabolite was removed after 30 min during a 90-min incubation period. In the presence of acetaldehyde, the secretion of 3H-pulse-labeled proteins, but not amylase, trypsinogen, or chymotrypsinogen, was greatly depressed. Acetaldehyde also caused a marked reduction in (3H)uridine incorporation into acinar RNA. The entry of (3H)uridine, (3H)leucine, and (3H)aminoisobutyric acid into isolated acini was found to be slightly (15-25%) decreased by acetaldehyde. It is concluded that acetaldehyde exerts a direct toxic effect on isolated dispersed pancreatic acini as evidenced by diminution of both protein and RNA synthesis and decreased secretion of the newly synthesized proteins. This inhibitory effect of acetaldehyde could be partially reversed.

  11. Prebiotic synthesis of imidazole-4-acetaldehyde and histidine

    NASA Technical Reports Server (NTRS)

    Shen, Chun; Oro, J.; Yang, Lily; Miller, Stanley L.

    1987-01-01

    The prebiotic synthesis of imidazole-4-acetaldehyde and imidazole-4-glycol from erythrose and formamidine has been demonstrated as well as the prebiotic synthesis of imidazole-4-ethanol and imidazole-4-glycol from erythrose, formaldehyde, and ammonia. The maximum yields of imidazole-4-acetaldehyde, imidazole-4-ethanol, and imidazole-4-glycol obtained in these reactions are 1.6, 5.4, and 6.8 percent respectively, based on the erythrose. Imidazole-4-acetaldehyde would have been converted to histidine on the primitive earth by a Strecker synthesis, and several prebiotic reactions would convert imidazole-4-glycol and imidazole-4-ethanol to imidazole-4-acetaldehyde.

  12. Rationale and Design for PACE: Patients with Intermittent Claudication Injected with ALDH Bright Cells

    PubMed Central

    Perin, Emerson C.; Murphy, Michael; Cooke, John P.; Moyé, Lem; Henry, Timothy D.; Bettencourt, Judy; Gahremanpour, Amir; Leeper, Nicholas; Anderson, R. David; Hiatt, William R.; Lima, Joao A.; Venkatesh, Bharath; Sayre, Shelly L.; Vojvodic, Rachel W.; Taylor, Doris A.; Ebert, Ray F.; Hirsch, Alan T.

    2014-01-01

    Peripheral artery disease (PAD) is recognized as a public health issue because of its prevalence, functional limitations, and increased risk of systemic ischemic events. Current treatments for claudication, the primary symptom in PAD patients, have limitations. Cells identified usingcytosolic enzyme aldehyde dehydrogenase (ALDH) may benefit patients with severe PAD but has not been studied in patients with claudication. PACE is a randomized, double-blind, placebo-controlled clinical trial conducted by the Cardiovascular Cell Therapy Research Network (CCTRN) to assess the safety and efficacy of autologous bone marrow–derived ALDHbr cells delivered by direct intramuscular injections in 80 patients with symptom-limiting intermittent claudication. Eligible patients will have a significant stenosis or occlusion of infrainguinal arteries and a resting ankle-brachial index <0.90 and will be randomized 1:1 to cell or placebo treatment with a 1-year follow-up. The primary endpoints are the change in peak walking time and leg collateral arterial anatomy, calf muscle blood flow, and tissue perfusion as determined by magnetic resonance (MR) imaging at 6 months compared to baseline. The latter 3 measurements are new physiologic lower extremity tissue perfusion and PAD imaging-based endpoints that may help to quantify the biologic and mechanistic effects of cell therapy. This trial will collect important mechanistic and clinical information on the safety and efficacy of ALDHbr cells in patients with claudication and provide valuable insight into the utility of advanced MR imaging endpoints. PMID:25440794

  13. Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans

    PubMed Central

    Arif, Sayqa; Borgognone, Alessandra; Lin, Erica Lai-Sze; O'Sullivan, Aine G; Sharma, Vishal; Drury, Nigel E; Menon, Ashvini; Nightingale, Peter; Mascaro, Jorge; Bonser, Robert S; Horowitz, John D; Feelisch, Martin; Frenneaux, Michael P; Madhani, Melanie

    2015-01-01

    Background and Purpose Hypoxic conditions favour the reduction of nitrite to nitric oxide (NO) to elicit vasodilatation, but the mechanism(s) responsible for bioconversion remains ill defined. In the present study, we assess the role of aldehyde dehydrogenase 2 (ALDH2) in nitrite bioactivation under normoxia and hypoxia in the rat and human vasculature. Experimental Approach The role of ALDH2 in vascular responses to nitrite was studied using rat thoracic aorta and gluteal subcutaneous fat resistance vessels from patients with heart failure (HF; 16 patients) in vitro and by measurement of changes in forearm blood flow (FBF) during intra-arterial nitrite infusion (21 patients) in vivo. Specifically, we investigated the effects of (i) ALDH2 inhibition by cyanamide or propionaldehyde and the (ii) tolerance-independent inactivation of ALDH2 by glyceryl trinitrate (GTN) on the vasodilator activity of nitrite. In each setting, nitrite effects were measured via evaluation of the concentration–response relationship under normoxic and hypoxic conditions in the absence or presence of ALDH2 inhibitors. Key Results Both in rat aorta and human resistance vessels, dilatation to nitrite was diminished following ALDH2 inhibition, in particular under hypoxia. In humans there was a non-significant trend towards attenuation of nitrite-mediated increases in FBF. Conclusions and Implications In human and rat vascular tissue in vitro, hypoxic nitrite-mediated vasodilatation involves ALDH2. In patients with HF in vivo, the role of this enzyme in nitrite bioactivation is at the most, modest, suggesting the involvement of other more important mechanisms. PMID:25754766

  14. Rotenone Decreases Intracellular Aldehyde Dehydrogenase Activity: Implications for the Pathogenesis of Parkinson Disease

    PubMed Central

    Goldstein, David S.; Sullivan, Patti; Cooney, Adele; Jinsmaa, Yunden; Kopin, Irwin J.; Sharabi, Yehonatan

    2015-01-01

    Repeated systemic administration of the mitochondrial complex I inhibitor rotenone produces a rodent model of Parkinson disease (PD). Mechanisms of relatively selective rotenone-induced damage to nigrostriatal dopaminergic neurons remain incompletely understood. According to the “catecholaldehyde hypothesis,” buildup of the autotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) contributes to PD pathogenesis. Vesicular uptake blockade increases DOPAL levels, and DOPAL is detoxified mainly by aldehyde dehydrogenase (ALDH). We tested whether rotenone interferes with vesicular uptake and intracellular ALDH activity. Endogenous and F-labeled catechols were measured in PC12 cells incubated with rotenone (0-1000 nM, 180 minutes), without or with F-dopamine (2 μM) to track vesicular uptake and catecholamine metabolism. Rotenone dose-dependently increased DOPAL, F-DOPAL, and 3,4-dihydroxyphenylethanol (DOPET) levels while decreasing dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels and the ratio of dopamine to the sum of its deaminated metabolites. In test tubes, rotenone did not affect conversion of DOPAL to DOPAC by ALDH when NAD+ was supplied, whereas the direct-acting ALDH inhibitor benomyl markedly increased DOPAL and decreased DOPAC concentrations in the reaction mixtures. We propose that rotenone builds up intracellular DOPAL by decreasing ALDH activity and attenuating vesicular sequestration of cytoplasmic catecholamines. The results provide a novel mechanism for selective rotenone-induced toxicity in dopaminergic neurons. PMID:25645689

  15. Effect of various chemicals on the aldehyde dehydrogenase activity of the rat liver cytosol.

    PubMed

    Marselos, M; Vasiliou, V

    1991-01-01

    The cytosolic activity of aldehyde dehydrogenase (ALDH) was studied in the rat liver, after acute administration of various carcinogenic and chemically related compounds. Male Wistar rats were treated with 27 different chemicals, including polycyclic aromatic hydrocarbons, aromatic amines, nitrosamines, azo dyes, as well as with some known direct-acting carcinogens. The cytosolic ALDH activity of the liver was determined either with propionaldehyde and NAD (P/NAD), or with benzaldehyde and NADP (B/NADP). The activity of ALDH remained unaffected after treatment with 1-naphthylamine, nitrosamines and also with the direct-acting chemical carcinogens tested. On the contrary, polycyclic aromatic hydrocarbons, polychlorinated biphenyls (Arochlor 1254) and 2-naphthylamine produced a remarkable increase of ALDH. In general, the response to the effectors was disproportionate between the two types of enzyme activity, being much in favour for the B/NADP activity. This fact resulted to an inversion of the ratio B/NADP vs. P/NAD, which under constitutive conditions is lower than 1. In this respect, the most potent compounds were found to be polychlorinated biphenyls, 3-methylcholanthrene, benzo(a)pyrene and 1,2,5,6-dibenzoanthracene. Our results suggest that the B/NADP activity of the soluble ALDH is greatly induced after treatment with compounds possessing aromatic ring(s) in their molecule. It is not known, if this response of the hepatocytes is related with the process of chemical carcinogenesis. PMID:2060039

  16. Aldehyde Dehydrogenase Activity Identifies a Population of Human Skeletal Muscle Cells With High Myogenic Capacities

    PubMed Central

    Vauchez, Karine; Marolleau, Jean-Pierre; Schmid, Michel; Khattar, Patricia; Chapel, Alain; Catelain, Cyril; Lecourt, Séverine; Larghéro, Jérôme; Fiszman, Marc; Vilquin, Jean-Thomas

    2009-01-01

    Aldehyde dehydrogenase 1A1 (ALDH) activity is one hallmark of human bone marrow (BM), umbilical cord blood (UCB), and peripheral blood (PB) primitive progenitors presenting high reconstitution capacities in vivo. In this study, we have identified ALDH+ cells within human skeletal muscles, and have analyzed their phenotypical and functional characteristics. Immunohistofluorescence analysis of human muscle tissue sections revealed rare endomysial cells. Flow cytometry analysis using the fluorescent substrate of ALDH, Aldefluor, identified brightly stained (ALDHbr) cells with low side scatter (SSClo), in enzymatically dissociated muscle biopsies, thereafter abbreviated as SMALD+ (for skeletal muscle ALDH+) cells. Phenotypical analysis discriminated two sub-populations according to CD34 expression: SMALD+/CD34− and SMALD+/CD34+ cells. These sub-populations did not initially express endothelial (CD31), hematopoietic (CD45), and myogenic (CD56) markers. Upon sorting, however, whereas SMALD+/CD34+ cells developed in vitro as a heterogeneous population of CD56− cells able to differentiate in adipoblasts, the SMALD+/CD34− fraction developed in vitro as a highly enriched population of CD56+ myoblasts able to form myotubes. Moreover, only the SMALD+/CD34− population maintained a strong myogenic potential in vivo upon intramuscular transplantation. Our results suggest that ALDH activity is a novel marker for a population of new human skeletal muscle progenitors presenting a potential for cell biology and cell therapy. PMID:19738599

  17. Acetaldehyde and hexanaldehyde from cultured white cells

    PubMed Central

    Shin, Hye-Won; Umber, Brandon J; Meinardi, Simone; Leu, Szu-Yun; Zaldivar, Frank; Blake, Donald R; Cooper, Dan M

    2009-01-01

    Background Noninvasive detection of innate immune function such as the accumulation of neutrophils remains a challenge in many areas of clinical medicine. We hypothesized that granulocytes could generate volatile organic compounds. Methods To begin to test this, we developed a bioreactor and analytical GC-MS system to accurately identify and quantify gases in trace concentrations (parts per billion) emitted solely from cell/media culture. A human promyelocytic leukemia cell line, HL60, frequently used to assess neutrophil function, was grown in serum-free medium. Results HL60 cells released acetaldehyde and hexanaldehyde in a time-dependent manner. The mean ± SD concentration of acetaldehyde in the headspace above the cultured cells following 4-, 24- and 48-h incubation was 157 ± 13 ppbv, 490 ± 99 ppbv, 698 ± 87 ppbv. For hexanaldehyde these values were 1 ± 0.3 ppbv, 8 ± 2 ppbv, and 11 ± 2 ppbv. In addition, our experimental system permitted us to identify confounding trace gas contaminants such as styrene. Conclusion This study demonstrates that human immune cells known to mimic the function of innate immune cells, like neutrophils, produce volatile gases that can be measured in vitro in trace amounts. PMID:19402909

  18. Structural and Functional Consequences of Coenzyme Binding to the Inactive Asian Variant of Mitochondrial Aldehyde Dehydrogenase: Roles of Residues 475 and 487

    SciTech Connect

    Larson,H.; Zhou, J.; Chen, Z.; Stamler, J.; Weiner, H.; Hurley, T.

    2007-01-01

    The common mitochondrial aldehyde dehydrogenase (ALDH2) ALDH2*2 polymorphism is associated with impaired ethanol metabolism and decreased efficacy of nitroglycerin treatment. These physiological effects are due to the substitution of Lys for Glu-487 that reduces the k{sub cat} for these processes and increases the K{sub m} for NAD{sup +}, as compared with ALDH2. In this study, we sought to understand the nature of the interactions that give rise to the loss of structural integrity and low activity in ALDH2*2 even when complexed with coenzyme. Consequently, we have solved the crystal structure of ALDH2*2 complexed with coenzyme to 2.5 {angstrom}. We have also solved the structures of a mutated form of ALDH2 where Arg-475 is replaced by Gln (R475Q). The structural and functional properties of the R475Q enzyme are intermediate between those of wild-type and the ALDH2*2 enzymes. In both cases, the binding of coenzyme restores most of the structural deficits observed in the apoenzyme structures. The binding of coenzyme to the R475Q enzyme restores its structure and catalytic properties to near wild-type levels. In contrast, the disordered helix within the coenzyme binding pocket of ALDH2*2 is reordered, but the active site is only partially reordered. Consistent with the structural data, ALDH2*2 showed a concentration-dependent increase in esterase activity and nitroglycerin reductase activity upon addition of coenzyme, but the levels of activity do not approach those of the wild-type enzyme or that of the R475Q enzyme. The data presented shows that Glu-487 maintains a critical function in linking the structure of the coenzyme binding site to that of the active site through its interactions with Arg-264 and Arg-475, and in doing so, creates the stable structural scaffold conducive to catalysis.

  19. 40 CFR 721.10036 - Acetaldehyde based polymer (generic).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Acetaldehyde based polymer (generic... Specific Chemical Substances § 721.10036 Acetaldehyde based polymer (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as...

  20. 40 CFR 721.10036 - Acetaldehyde based polymer (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Acetaldehyde based polymer (generic... Specific Chemical Substances § 721.10036 Acetaldehyde based polymer (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as...

  1. 40 CFR 721.10036 - Acetaldehyde based polymer (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Acetaldehyde based polymer (generic... Specific Chemical Substances § 721.10036 Acetaldehyde based polymer (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as...

  2. Catalytic oxidation of ethanol and acetaldehyde in supercritical carbon dioxide

    SciTech Connect

    Zhou, L.; Akgerman, A.

    1995-05-01

    Supercritical fluid (SCF) extraction has been receiving increasing attention for the remediation of environmental matrices contaminated with organic compounds. Catalytic oxidation of ethanol and acetaldehyde over a 4.45% Pt/TiO{sub 2} catalyst in supercritical carbon dioxide was studied in a 1/2 in. fixed bed reactor. Experiments for ethanol oxidation were performed at temperatures from 423 to 573 K and at a pressure of 8.96 MPa with a 5:1 molar ratio of oxygen to ethanol in the feed. Acetaldehyde oxidation was performed at temperatures from 423 to 548 K and at 8.96 MPa with an approximate 4.7:1 molar ratio of oxygen to acetaldehyde in the feed. In addition to CO{sub 2}, the complete oxidation product, acetaldehyde and trace amounts of CO were generated during ethanol oxidation, while a trace amount of CO was the only partial oxidation product during acetaldehyde oxidation. A parallel and consecutive reaction mechanism was postulated for ethanol oxidation, whereas dissociative adsorption of acetaldehyde on the catalyst surface and surface reaction rate control were postulated for acetaldehyde oxidation. The kinetic parameters in the rate expressions based on the mechanisms were obtained by fitting the experimental data with the results of the model calculation. The models were used to predict the conversion and yield for ethanol oxidation and acetaldehyde oxidation.

  3. 40 CFR 721.10036 - Acetaldehyde based polymer (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Acetaldehyde based polymer (generic... Specific Chemical Substances § 721.10036 Acetaldehyde based polymer (generic). (a) Chemical substance and... based polymer (PMN P-02-406) is subject to reporting under this section for the significant new...

  4. 40 CFR 721.10036 - Acetaldehyde based polymer (generic).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Acetaldehyde based polymer (generic... Specific Chemical Substances § 721.10036 Acetaldehyde based polymer (generic). (a) Chemical substance and... based polymer (PMN P-02-406) is subject to reporting under this section for the significant new...

  5. Enhanced aldehyde dehydrogenase activity by regenerating NAD+ in Klebsiella pneumoniae and implications for the glycerol dissimilation pathways.

    PubMed

    Li, Ying; Su, Mingyue; Ge, Xizhen; Tian, Pingfang

    2013-10-01

    In Klebsiella pneumoniae, 3-hydroxypropaldehyde is converted to 3-hydroxypropionic acid (3-HP) by aldehyde dehydrogenase (ALDH) with NAD(+) as a cofactor. Although ALDH overexpression stimulates the formation of 3-HP, it ceases to accumulate when NAD(+) is exhausted. Here we show that NAD(+) regeneration, together with ALDH overexpression, facilitates 3-HP production and benefits cell growth. Three distinct NAD(+)-regenerating enzymes: NADH oxidase and NADH dehydrogenase from K. pneumoniae, and glycerol-3-phosphate dehydrogenase (GPD1) from Saccharomyces cerevisiae, were individually expressed in K. pneumoniae. In vitro assay showed their higher activities than that of the control, indicating their capacities to regenerate NAD(+). When they were respectively co-expressed with ALD4, an ALDH from S. cerevisiae, the activities of ALD4 were significantly elevated compared with that expressing ALD4 alone, suggesting that the regenerated NAD(+) enhanced the activity of ALD4. More interestingly, the growth rates of all NAD(+)-regenerating strains were prolonged in comparison with the control, indicating that NAD(+) regeneration stimulated cell proliferation. This study not only reveals the reliance of ALD4 activity on NAD(+) availability but also provides a method for regulating the dha regulon. PMID:23794046

  6. Acetaldehyde photochemistry on TiO2(110)

    SciTech Connect

    Zehr, Robert T.; Henderson, Michael A.

    2008-07-01

    The ultraviolet (UV) photon induced decomposition of acetaldehyde absorbed on the oxidized retile TIO2(110) surface was studied with photon stimulated desorption (PSD) and theral programmed desorption (TPD). Acetaldehyde desorbs molecularly from TiO2(110) with minor decomposition channels yielding butene on the reduced TiO2 surface and acetate on the oxidized TiO2 surface. Acetaldehyde absorbed on oxidized TiO2(110) undergoes a facile thermal reaction to form a photoactive acetaldehyde-oxygen complex. UV irradiation of the acetaldehyde-oxygen complex resulting in the ejection of methyl radical into gas phase and conversion of the surface bound fragment to formate.

  7. Acetaldehyde Photochemistry on TiO2(110)

    SciTech Connect

    Zehr, Robert T.; Henderson, Michael A.

    2008-07-01

    The ultraviolet (UV) photon induced decomposition of acetaldehyde adsorbed on the oxidized rutile TiO2(110) surface was studied with photon stimulated desorption (PSD) and thermal programmed desorption (TPD). Acetaldehyde desorbs molecularly from TiO2(110) with minor decomposition channels yielding butene on the reduced TiO2 surface and acetate on the oxidized TiO2 surface. Acetaldehyde adsorbed on oxidized TiO2(110) undergoes a facile thermal reaction to form a photoactive acetaldehyde-oxygen complex. UV irradiation of the acetaldehyde-oxygen complex initiated photofragmentation of the complex resulting in the ejection of methyl radical into gas phase and conversion of the surface bound fragment to formate.

  8. Mechanism of acetaldehyde-induced deactivation of microbial lipases

    PubMed Central

    2011-01-01

    Background Microbial lipases represent the most important class of biocatalysts used for a wealth of applications in organic synthesis. An often applied reaction is the lipase-catalyzed transesterification of vinyl esters and alcohols resulting in the formation of acetaldehyde which is known to deactivate microbial lipases, presumably by structural changes caused by initial Schiff-base formation at solvent accessible lysine residues. Previous studies showed that several lipases were sensitive toward acetaldehyde deactivation whereas others were insensitive; however, a general explanation of the acetaldehyde-induced inactivation mechanism is missing. Results Based on five microbial lipases from Candida rugosa, Rhizopus oryzae, Pseudomonas fluorescens and Bacillus subtilis we demonstrate that the protonation state of lysine ε-amino groups is decisive for their sensitivity toward acetaldehyde. Analysis of the diverse modification products of Bacillus subtilis lipases in the presence of acetaldehyde revealed several stable products such as α,β-unsaturated polyenals, which result from base and/or amino acid catalyzed aldol condensation of acetaldehyde. Our studies indicate that these products induce the formation of stable Michael-adducts at solvent-accessible amino acids and thus lead to enzyme deactivation. Further, our results indicate Schiff-base formation with acetaldehyde to be involved in crosslinking of lipase molecules. Conclusions Differences in stability observed with various commercially available microbial lipases most probably result from different purification procedures carried out by the respective manufacturers. We observed that the pH of the buffer used prior to lyophilization of the enzyme sample is of utmost importance. The mechanism of acetaldehyde-induced deactivation of microbial lipases involves the generation of α,β-unsaturated polyenals from acetaldehyde which subsequently form stable Michael-adducts with the enzymes. Lyophilization of

  9. Musashi-1 Expression is a Prognostic Factor in Ovarian Adenocarcinoma and Correlates with ALDH-1 Expression.

    PubMed

    Chen, Pu-xiang; Li, Qiao-yan; Yang, Zhulin

    2015-09-01

    The presence of cancer stem-like cells (CSCs) has been demonstrated to be associated with tumor metastasis, chemoresistance, and rapid recurrence of various tumors. The impact of CSC-related markers in the metastasis and prognosis of ovarian cancer has not been well established. In this study, the protein expression of musashi-1 and ALDH1 was measured using immunohistochemistry. Results demonstrated that the percentage of positive musashi-1 and ALDH1 expression were significantly higher in ovarian serous adenocarcinomas, mucinous adenocarcinomas and clear cell adenocarcinomas than in cystadenomas and normal tissues. The percentage of positive musashi-1 and ALDH1 expression were significantly lower in patients identified with clinical stage I or II ovarian adenocarcinomas without lymph node metastasis compared to patients with clinical stage III or IV tumors and lymph node metastasis. The expression of musashi-1 and ALDH1 was found to be highly consistent in ovarian adenocarcinomas. Univariate Kaplan-Meier analysis showed a negative correlation between musashi-1 or ALDH1 expression and overall survival. Multivariate Cox regression analysis showed that positive expression of musashi-1 or ALDH1 in ovarian adenocarcinoma was an independent predictor of poor prognosis. Our study suggested that musashi-1 and ALDH1 expression are closely related to metastasis of ovarian adenocarcinoma. The positive expression of musashi-1 and ALDH1 might be a poor-prognostic factor of ovarian adenocarcinoma. PMID:25971681

  10. Alcohol Dehydrogenase-1B (rs1229984) and Aldehyde Dehydrogenase-2 (rs671) Genotypes Are Strong Determinants of the Serum Triglyceride and Cholesterol Levels of Japanese Alcoholic Men

    PubMed Central

    Yokoyama, Akira; Yokoyama, Tetsuji; Matsui, Toshifumi; Mizukami, Takeshi; Kimura, Mitsuru; Matsushita, Sachio; Higuchi, Susumu; Maruyama, Katsuya

    2015-01-01

    Background Elevated serum triglyceride (TG) and high-density-lipoprotein cholesterol (HDL-C) levels are common in drinkers. The fast-metabolizing alcohol dehydrogenase-1B encoded by the ADH1B*2 allele (vs. ADH1B*1/*1 genotype) and inactive aldehyde dehydrogenase-2 encoded by the ALDH2*2 allele (vs. ALDH2*1/*1 genotype) modify ethanol metabolism and are prevalent (≈90% and ≈40%, respectively) in East Asians. We attempted to evaluate the associations between the ADH1B and ALDH2 genotypes and lipid levels in alcoholics. Methods The population consisted of 1806 Japanese alcoholic men (≥40 years) who had undergone ADH1B and ALDH2 genotyping and whose serum TG, total cholesterol, and HDL-C levels in the fasting state had been measured within 3 days after admission. Results High serum levels of TG (≥150 mg/dl), HDL-C (>80 mg/dl), and low-density-lipoprotein cholesterol (LDL-C calculated by the Friedewald formula ≥140 mg/dl) were observed in 24.3%, 16.8%, and 15.6%, respectively, of the subjects. Diabetes, cirrhosis, smoking, and body mass index (BMI) affected the serum lipid levels. Multivariate analysis revealed that the presence of the ADH1B*2 allele and the active ALDH2*1/*1 genotype increased the odds ratio (OR; 95% confidence interval) for a high TG level (2.22 [1.67–2.94] and 1.39 [0.99–1.96], respectively), and decreased the OR for a high HDL-C level (0.37 [0.28–0.49] and 0.51 [0.37–0.69], respectively). The presence of the ADH1B*2 allele decreased the OR for a high LDL-C level (0.60 [0.45–0.80]). The ADH1B*2 plus ALDH2*1/*1 combination yielded the highest ORs for high TG levels and lowest OR for a high HDL-C level. The genotype effects were more prominent in relation to the higher levels of TG (≥220 mg/dl) and HDL-C (≥100 mg/dl). Conclusions The fast-metabolizing ADH1B and active ALDH2, and especially a combination of the two were strongly associated with higher serum TG levels and lower serum HDL-C levels of alcoholics. The fast

  11. Proteomic analysis in pterygium; upregulated protein expression of ALDH3A1, PDIA3, and PRDX2

    PubMed Central

    Kim, Sun Woong; Lee, Jonghoon; Lee, Boram

    2014-01-01

    Purpose To identify differentially expressed proteins in the pterygium compared to healthy conjunctiva using a proteomic analysis. Methods Pterygial and healthy conjunctival tissues were obtained from 24 patients undergoing pterygium excision. Total proteins of the pterygia and healthy conjunctiva were analyzed with one-dimensional electrophoresis, and protein bands of interest were excised and subjected to liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-MS/MS) using Thermo’s Finnigan ProteomeX workstation LTQ linear ion trap MS/MS. Using bioinformatics, differentially expressed proteins were classified, and three proteins closely involved in the response to oxidative stress were selected for further validation. Differential expression of these proteins was confirmed with western blot and immunohistochemistry. Results A web-based gene ontology program, DAVID, was used to classify 230 proteins that were differentially expressed in pterygial tissues. Among these genes, we chose three proteins, aldehyde dehydrogenase, dimeric NADP-preferring (ALDH3A1), protein disulfide-isomerase A3 (PDIA3), and peroxiredoxin-2 (PRDX2), that were significantly upregulated in pterygium and further increased in recurrent pterygium. Immunohistochemistry and western blot analysis confirmed that these three proteins were mainly detected in the basal epithelial layer, and their expression was significantly increased in the pterygium compared to normal conjunctiva. Conclusions This study reported increased expression of ALDH3A1, PDIA3, and PRDX2 in pterygia using a proteomic approach. These proteins are presumed to have a protective role against oxidative stress-induced apoptosis. This result is consistent with the hypothesis that oxidative stress is a significant factor in the pathogenesis of pterygia. PMID:25221425

  12. 40 CFR 80.56 - Measurement methods for formaldehyde and acetaldehyde.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... and acetaldehyde. 80.56 Section 80.56 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Measurement methods for formaldehyde and acetaldehyde. (a) Formaldehyde and acetaldehyde will be measured by... acetaldehyde are used to determine the response, repeatability, and limit of quantitation of the HPLC...

  13. Lack of evidence for sustained blood acetaldehyde concentrations during alcohol detoxification.

    PubMed

    Nijm, W P; Borge, G F; Origitano, T; Teas, G; Goldfarb, C; Collins, M A

    1978-04-01

    Contrary to a published report, blood acetaldehyde concentrations become undetectable in patients 1--2 days following admission for alcohol detoxification. The persistently elevated blood acetaldehydes reported by others probably were due to artifactual formation during analysis. Nevertheless, our admission blood acetaldehyde concentrations are significant enough to support the contention that acetaldehyde has a cytotoxic role in alcoholic disease. PMID:663401

  14. Prognostic value of ALDH1 expression in lung cancer: a meta-analysis

    PubMed Central

    Huo, Wei; Du, Min; Pan, Xinyan; Zhu, Xiaomin; Li, Zhimin

    2015-01-01

    Objective: ALDH1 has recently been reported as a marker of cancer stem-like cells in lung cancer. However, the predictive value of ALDH1 in lung cancer remains controversial. In this study, we aimed to evaluate the association of ALDH1 expression with the clinicopathological features and outcomes of lung cancer patients through a meta-analysis. Methods: Publications that assessed the clinical or prognostic significance of ALDH1 in lung cancer up to October 2014 were identified. A meta-analysis was performed to clarify the association between ALDH1 expression and clinical outcomes. Results: Ten eligible publications with 1836 patients were included. The analysis of these data showed that ALDH1 expression was highly correlated with lymph node metastasis (pooled OR = 1.45, 95% CI: 1.04-2.02, P = 0.027), decreased overall survival (pooled RR: 2.25, 95% CI: 1.15-4.41, P = 0.019), and decreased disease-free survival (pooled RR: 1.63, 95% CI: 1.01-2.64, P = 0.047). Conclusion: Patients with ALDH1-positive lung cancer had poor prognosis, which was associated with common clinicopathological poor prognostic factors. PMID:25932135

  15. ALDH2 polymorphism is associated with fasting blood glucose through alcohol consumption in Japanese men

    PubMed Central

    Yin, Guang; Naito, Mariko; Wakai, Kenji; Morita, Emi; Kawai, Sayo; Hamajima, Nobuyuki; Suzuki, Sadao; Kita, Yoshikuni; Takezaki, Toshiro; Tanaka, Keitaro; Morita, Makiko; Uemura, Hirokazu; Ozaki, Etsuko; Hosono, Satoyo; Mikami, Haruo; Kubo, Michiaki; Tanaka, Hideo

    2016-01-01

    ABSTRACT Associations between alcohol consumption and type 2 diabetes risk are inconsistent in epidemiologic studies. This study investigated the associations of ADH1B and ALDH2 polymorphisms with fasting blood glucose levels, and the impact of the associations of alcohol consumption with fasting blood glucose levels in Japanese individuals. This cross-sectional study included 907 men and 912 women, aged 35–69 years. The subjects were selected from among the Japan Multi-institutional Collaborative Cohort study across six areas of Japan. The ADH1B and ALDH2 polymorphisms were genotyped by Invader Assays. The ALDH2 Glu504Lys genotypes were associated with different levels of fasting blood glucose in men (P = 0.04). Mean fasting glucose level was positively associated with alcohol consumption in men with the ALDH2 504 Lys allele (Ptrend = 0.02), but not in men with the ALDH2 504Glu/Glu genotype (Ptrend = 0.45), resulting in no statistically significant interaction (P = 0.38). Alcohol consumption was associated with elevated fasting blood glucose levels compared with non-consumers in men (Ptrend = 0.002). The ADH1B Arg48His polymorphism was not associated with FBG levels overall or after stratification for alcohol consumption. These findings suggest that the ALDH2 polymorphism is associated with different levels of fasting blood glucose through alcohol consumption in Japanese men. The interaction of ALDH2 polymorphisms in the association between alcohol consumption and fasting blood glucose warrants further investigation. PMID:27303105

  16. Aldehydic load and aldehyde dehydrogenase 2 profile during the progression of post-myocardial infarction cardiomyopathy: benefits of Alda-1

    PubMed Central

    Gomes, Katia M.S.; Bechara, Luiz R.G.; Lima, Vanessa M.; Ribeiro, Márcio A.C.; Campos, Juliane C.; Dourado, Paulo M.; Kowaltowski, Alicia J.; Mochly-Rosen, Daria; Ferreira, Julio C.B.

    2015-01-01

    Background/Objectives We previously demonstrated that reducing cardiac aldehydic load by aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme responsible for metabolizing the major lipid peroxidation product, protects against acute ischemia/reperfusion injury and chronic heart failure. However, time-dependent changes in ALDH2 profile, aldehydic load and mitochondrial bioenergetics during progression of post-myocardial infarction (post-MI) cardiomyopathy is unknown and should be established to determine the optimal time window for drug treatment. Methods Here we characterized cardiac ALDH2 activity and expression, lipid peroxidation, 4-hydroxy-2-nonenal (4-HNE) adduct formation, glutathione pool and mitochondrial energy metabolism and H2O2 release during the 4 weeks after permanent left anterior descending (LAD) coronary artery occlusion in rats. Results We observed a sustained disruption of cardiac mitochondrial function during the progression of post-MI cardiomyopathy, characterized by >50% reduced mitochondrial respiratory control ratios and up to 2 fold increase in H2O2 release. Mitochondrial dysfunction was accompanied by accumulation of cardiac and circulating lipid peroxides and 4-HNE protein adducts and down-regulation of electron transport chain complexes I and V. Moreover, increased aldehydic load was associated with a 90% reduction in cardiac ALDH2 activity and increased glutathione pool. Further supporting an ALDH2 mechanism, sustained Alda-1 treatment (starting 24hrs after permanent LAD occlusion surgery) prevented aldehydic overload, mitochondrial dysfunction and improved ventricular function in post-MI cardiomyopathy rats. Conclusion Taken together, our findings demonstrate a disrupted mitochondrial metabolism along with an insufficient cardiac ALDH2-mediated aldehyde clearance during the progression of ventricular dysfunction, suggesting a potential therapeutic value of ALDH2 activators during the progression of post-myocardial infarction

  17. Acetaldehyde-induced cytotoxicity involves induction of spermine oxidase at the transcriptional level.

    PubMed

    Uemura, Takeshi; Tanaka, Yuka; Higashi, Kyohei; Miyamori, Daisuke; Takasaka, Tomokazu; Nagano, Tatsuo; Toida, Toshihiko; Yoshimoto, Kanji; Igarashi, Kazuei; Ikegaya, Hiroshi

    2013-08-01

    Ethanol consumption causes serious liver injury including cirrhosis and hepatocellular carcinoma. Ethanol is metabolized mainly in the liver to acetic acid through acetaldehyde. We investigated the effect of ethanol and acetaldehyde on polyamine metabolism since polyamines are essential factors for normal cellular functions. We found that acetaldehyde induced spermine oxidase (SMO) at the transcriptional level in HepG2 cells. The levels and activities of ornithine decarboxylase (ODC) and spermidine/spermine acetyltransferase (SSAT) were not affected by acetaldehyde. Spermidine content was increased and spermine content was decreased by acetaldehyde treatment. Knockdown of SMO expression using siRNA reduced acetaldehyde toxicity. Acetaldehyde exposure increased free acrolein levels. An increase of acrolein by acetaldehyde was SMO dependent. Our results indicate that cytotoxicity of acetaldehyde involves, at least in part, oxidation of spermine to spermidine by SMO, which is induced by acetaldehyde. PMID:23707493

  18. Vascular Bioactivation of Nitroglycerin by Aldehyde Dehydrogenase-2

    PubMed Central

    Lang, Barbara S.; Gorren, Antonius C. F.; Oberdorfer, Gustav; Wenzl, M. Verena; Furdui, Cristina M.; Poole, Leslie B.; Mayer, Bernd; Gruber, Karl

    2012-01-01

    Aldehyde dehydrogenase-2 (ALDH2) catalyzes the bioactivation of nitroglycerin (glyceryl trinitrate, GTN) in blood vessels, resulting in vasodilation by nitric oxide (NO) or a related species. Because the mechanism of this reaction is still unclear we determined the three-dimensional structures of wild-type (WT) ALDH2 and of a triple mutant of the protein that exhibits low denitration activity (E268Q/C301S/C303S) in complex with GTN. The structure of the triple mutant showed that GTN binds to the active site via polar contacts to the oxyanion hole and to residues 268 and 301 as well as by van der Waals interactions to hydrophobic residues of the catalytic pocket. The structure of the GTN-soaked wild-type protein revealed a thionitrate adduct to Cys-302 as the first reaction intermediate, which was also found by mass spectrometry (MS) experiments. In addition, the MS data identified sulfinic acid as the irreversibly inactivated enzyme species. Assuming that the structures of the triple mutant and wild-type ALDH2 reflect binding of GTN to the catalytic site and the first reaction step, respectively, superposition of the two structures indicates that denitration of GTN is initiated by nucleophilic attack of Cys-302 at one of the terminal nitrate groups, resulting in formation of the observed thionitrate intermediate and release of 1,2-glyceryl dinitrate. Our results shed light on the molecular mechanism of the GTN denitration reaction and provide useful information on the structural requirements for high affinity binding of organic nitrates to the catalytic site of ALDH2. PMID:22988236

  19. Intracellular localization of aldehyde dehydrogenase in rat liver

    PubMed Central

    Marjanen, Leo

    1972-01-01

    1. Distribution of aldehyde dehydrogenase activity in rat liver was studied by measuring the rate of disappearance of acetaldehyde in the presence of each of the subcellular fractions. These were obtained by rough separation of particulate fractions from the soluble portion of the cell, by differential centrifugation, and by isopycnic gradient centrifugation. 2. The maximal rate of acetaldehyde oxidation was 3.7 μmol/min per g, with an apparent Km value below 10−5m. The highest rate of activity was observed in phosphate buffers of high Pi concentration (above 60mm). 3. The activity measured was completely dependent on NAD+. 4. The microsomal fraction and the nuclei were inactive in the assay. Of the total activity 80% was found in the mitochondrial fraction and the remaining 20% in the cytoplasm. 5. The distribution pattern is important from the point of view of acetaldehyde oxidation during ethanol metabolism. The apparent discrepancy of the results obtained by different workers and the localization of acetaldehyde oxidation in vivo is discussed. PMID:4346744

  20. A specific affinity reagent to distinguish aldehyde dehydrogenases and oxidases. Enzymes catalyzing aldehyde oxidation in an adult moth

    SciTech Connect

    Tasayco, M.L.; Prestwich, G.D. )

    1990-02-25

    Aldehyde dehydrogenase (ALDH) and oxidase (AO) enzymes from the tissue extracts of male and female tobacco budworm moth (Heliothis virescens) were identified after electrophoretic protein separation. AO activity was visualized using formazan- or horseradish peroxidase-mediated staining coupled to the AO-catalyzed oxidation of benzaldehyde. A set of six soluble AO enzymes with isoelectric points from pI 4.6 to 5.3 were detected primarily in the antennal extracts. Partially purified antennal AO enzymes also oxidized both (Z)-9-tetradecenal and (Z)-11-hexadecenal, the two major pheromone components of this moth. ALDH activity was detected using a tritium-labeled affinity reagent based on a known irreversible inhibitor of this enzyme. This labeled vinyl ketone, (3H)(Z)-1,11-hexadecadien-3-one, was synthesized and used to covalently modify the soluble ALDH enzymes from tissue extracts. Molecular subunits of potential ALDH enzymes were visualized in the fluorescence autoradiograms of sodium dodecyl sulfate-polyacrylamide gel electrophoresis-separated proteins of the antenna, head, and leg tissues. Covalent modification of these protein subunits decreased specifically in the presence of excess pheromone aldehyde or benzaldehyde. Labeled vinyl ketones are thus novel tools for the identification of molecular subunits of ALDH enzymes.

  1. Implication of an Aldehyde Dehydrogenase Gene and a Phosphinothricin N-Acetyltransferase Gene in the Diversity of Pseudomonas cichorii Virulence

    PubMed Central

    Tanaka, Masayuki; Wali, Ullah Md; Nakayashiki, Hitoshi; Fukuda, Tatsuya; Mizumoto, Hiroyuki; Ohnishi, Kouhei; Kiba, Akinori; Hikichi, Yasufumi

    2011-01-01

    Pseudomonas cichorii harbors the hrp genes. hrp-mutants lose their virulence on eggplant but not on lettuce. A phosphinothricin N-acetyltransferase gene (pat) is located between hrpL and an aldehyde dehydrogenase gene (aldH) in the genome of P. cichorii. Comparison of nucleotide sequences and composition of the genes among pseudomonads suggests a common ancestor of hrp and pat between P. cichorii strains and P. viridiflava strains harboring the single hrp pathogenicity island. In contrast, phylogenetic diversification of aldH corresponded to species diversification amongst pseudomonads. In this study, the involvement of aldH and pat in P. cichorii virulence was analyzed. An aldH-deleted mutant (ΔaldH) and a pat-deleted mutant (Δpat) lost their virulence on eggplant but not on lettuce. P. cichorii expressed both genes in eggplant leaves, independent of HrpL, the transcriptional activator for the hrp. Inoculation into Asteraceae species susceptible to P. cichorii showed that the involvement of hrp, pat and aldH in P. cichorii virulence is independent of each other and has no relationship with the phylogeny of Asteraceae species based on the nucleotide sequences of ndhF and rbcL. It is thus thought that not only the hrp genes but also pat and aldH are implicated in the diversity of P. cichorii virulence on susceptible host plant species. PMID:24704843

  2. Association between Carotid Intima-media Thickness and Aldehyde Dehydrogenase 2 Glu504Lys Polymorphism in Chinese Han with Essential Hypertension

    PubMed Central

    Ma, Xiao-Xiang; Zheng, Shu-Zhan; Shu, Yan; Wang, Yong; Chen, Xiao-Ping

    2016-01-01

    Background: Aldehyde dehydrogenase 2 (ALDH2) is involved in the pathophysiological processes of cardiovascular diseases. Recent studies showed that mutant ALDH2 could increase oxidative stress and is a susceptible factor for hypertension. In addition, wild-type ALDH2 could improve the endothelial functions, therefore reducing the risk of developing atherosclerosis. The aim of the present study was to explore the frequency of the Glu504Lys polymorphism of the ALDH2 gene and its relation to carotid intima-media thickness (CIMT) in a group of patients with essential hypertension (EH) and to investigate the association between the Glu504Lys polymorphism and CIMT in Chinese Han patients with EH. Methods: In this study, 410 Chinese Han patients with EH who received physical examinations at the People's Hospital of Sichuan Province (China) were selected. DNA microarray chip was used for the genotyping of the Glu504Lys polymorphism of the ALDH2 gene. The differences in CIMT among patients with different Glu504Lys ALDH2 genotypes were analyzed. Results: The mean CIMT of the patients carrying AA/AG and GG genotypes was 1.02 ± 0.31 mm and 0.78 ± 0.28 mm, respectively. One-way ANOVA showed that the CIMT of the patients carrying the AA/AG genotype was significantly higher than in the ones carrying the GG genotype (P < 0.001). Multivariate logistic regression showed that the Glu504Lys AA/AG genotype of the ALDH2 gene was one of the major factors influencing the CIMT in patients with EH (odds ratio = 3.731, 95% confidence interval = 1.589–8.124, P = 0.001). Conclusions: The Glu504Lys polymorphism of the ALDH2 gene is associated with the CIMT of Chinese Han patients with EH in Sichuan, China. PMID:27270535

  3. The Involvement of Acetaldehyde in Ethanol-Induced Cell Cycle Impairment

    PubMed Central

    Scheer, Marc A.; Schneider, Katrina J.; Finnigan, Rochelle L.; Maloney, Eamon P.; Wells, Mark A.; Clemens, Dahn L.

    2016-01-01

    Background: Hepatocytes metabolize the vast majority of ingested ethanol. This metabolic activity results in hepatic toxicity and impairs the ability of hepatocytes to replicate. Previous work by our group has shown that ethanol metabolism results in a G2/M cell cycle arrest. The intent of these studies was to discern the roles of acetaldehyde and reactive oxygen, two of the major by-products of ethanol metabolism, in the G2/M cell cycle arrest. Methods: To investigate the role of ethanol metabolites in the cell cycle arrest, VA-13 and VL-17A cells were used. These are recombinant Hep G2 cells that express alcohol dehydrogenase or alcohol dehydrogenase and cytochrome P450 2E1, respectively. Cells were cultured with or without ethanol, lacking or containing the antioxidants N-acetylcysteine (NAC) or trolox, for three days. Cellular accumulation was monitored by the DNA content of the cultures. The accumulation of the cyclin-dependent kinase, Cdc2 in the inactive phosphorylated form (p-Cdc2) and the cyclin-dependent kinase inhibitor p21 were determined by immunoblot analysis. Results: Cultures maintained in the presence of ethanol demonstrated a G2/M cell cycle arrest that was associated with a reduction in DNA content and increased levels of p-Cdc2 and p21, compared with cells cultured in its absence. Inclusion of antioxidants in the ethanol containing media was unable to rescue the cells from the cell cycle arrest or these ethanol metabolism-mediated effects. Additionally, culturing the cells in the presence of acetaldehyde alone resulted in increased levels of p-Cdc2 and p21. Conclusions: Acetaldehyde produced during ethanol oxidation has a major role in the ethanol metabolism-mediated G2/M cell cycle arrest, and the concurrent accumulation of p21 and p-Cdc2. Although reactive oxygen species are thought to have a significant role in ethanol-induced hepatocellular damage, they may have a less important role in the inability of hepatocytes to replace dead or damaged

  4. Atmospheric Vinyl Alcohol to Acetaldehyde Tautomerization Revisited.

    PubMed

    Peeters, Jozef; Nguyen, Vinh Son; Müller, Jean-François

    2015-10-15

    The atmospheric oxidation of vinyl alcohol (VA) produced by photoisomerization of acetaldehyde (AA) is thought to be a source of formic acid (FA). Nevertheless, a recent theoretical study predicted a high rate coefficient k1(298 K) of ≈10(-14) cm(3) molecule(-1) s(-1) for the FA-catalyzed tautomerization reaction 1 of VA back into AA, which suggests that FA buffers its own production from VA. However, the unusually high frequency factor implied by that study prompted us to reinvestigate reaction 1 . On the basis of a high-level ab initio potential energy profile, we first established that transition state theory is applicable, and derived a k1(298 K) of only ≈2 × 10(-20) cm(3) molecule(-1) s(-1), concluding that the reaction is negligible. Instead, we propose and rationalize another important VA sink: its uptake by aqueous aerosol and cloud droplets followed by fast liquid-phase tautomerization to AA; global modeling puts the average lifetime by this sink at a few hours, similar to oxidation by OH. PMID:26722769

  5. ALDH2 is associated to alcohol dependence and is the major genetic determinant of "daily maximum drinks" in a GWAS study of an isolated rural Chinese sample.

    PubMed

    Quillen, Ellen E; Chen, Xiang-Ding; Almasy, Laura; Yang, Fang; He, Hao; Li, Xi; Wang, Xu-Yi; Liu, Tie-Qiao; Hao, Wei; Deng, Hong-Wen; Kranzler, Henry R; Gelernter, Joel

    2014-03-01

    Alcohol dependence (AD) is a moderately heritable phenotype with a small number of known risk genes mapped via linkage or candidate gene studies. We considered 313 males from among 595 members of documented, extended pedigrees in which AD segregates collected in Northern Hunan Province, China. A joint analysis of both males and females could not be performed as the difference in alcohol consumption variance was too large. Genome-wide association analyses were performed for approximately 300,000 single nucleotide polymorphisms (SNPs). Significant associations found in the ALDH2 region for AD (minimum P = 4.73 × 10(-8)) and two AD-related phenotypes: flushing response (minimum P = 4.75 × 10(-26)) and maximum drinks in a 24-hr period (minimum P = 1.54 × 10(-16)). Association of previous candidate SNP, rs10774610 in CCDC63, was confirmed but resulted from linkage disequilibrium with ALDH2. ALDH2 is strongly associated with flushing response, AD, and maximum drinks in males, with nonsynonymous SNP rs671 explaining 29.2%, 7.9%, and 22.9% of phenotypic variation, respectively, in this sample. When rs671 was considered as a candidate SNP in females, it explained 23.6% of the variation in flushing response, but alcohol consumption rates were too low among females-despite familial enrichment for AD-for an adequate test of association for either AD or maximum drinks. These results support a mediating effect of aldehyde dehydrogenase deficiency on alcohol consumption in males and a secondary, culturally mediated limitation on alcohol consumption by females that should be appropriately modeled in future studies of alcohol consumption in populations where this may be a factor. PMID:24277619

  6. CARDIAC OVEREXPRESSION OF ALCOHOL DEHYDROGENASE EXACERBATES CARDIAC CONTRACTILE DYSFUNCTION, LIPID PEROXIDATION, AND PROTEIN DAMAGE AFTER CHRONIC ETHANOL INGESTION

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Alcoholic cardiomyopathy is manifested as ventricular dysfunction although its specific toxic mechanism(s) remains obscure. This study was designed to examine the impact of enhanced acetaldehyde (ACA) exposure on cardiac function via cardiac-specific over-expression of alcohol dehydrogenase (ADH) fo...

  7. Alcohol and aldehyde dehydrogenase polymorphisms in Chinese and Indian populations.

    PubMed

    Tan, Ene-Choo; Lim, Leslie; Leong, Jern-Yi; Lim, Jing-Yan; Lee, Arthur; Yang, Jun; Tan, Chay-Hoon; Winslow, Munidasa

    2010-01-01

    The association between two functional polymorphisms in alcohol dehydrogenase (ADH2/ADH1B) and aldehyde dehydrogenase (ALDH2) genes and alcohol dependence was examined in 182 Chinese and Indian patients undergoing treatment for alcohol dependence and 184 screened control subjects from Singapore. All subjects were screened by the Alcohol Use Disorders Identification Test (AUDIT). Patients were also administered the Severity of Alcohol Dependence Questionnaire (SADQ). Polymorphisms were genotyped by allele-specific polymerase chain reaction and selected genotypes confirmed by DNA sequencing or restriction fragment length polymorphism. Our results showed that frequencies of ADH1B*2 and ALDH2*2 were higher in controls compared to alcohol-dependent subjects for both Chinese and Indians. Frequencies of these two alleles were also higher in the 104 Chinese controls compared to the 80 Indian controls. None of the eight Chinese who were homozygous for both protective alleles was alcohol dependent. The higher frequencies of the protective alleles could explain the lower rate of alcohol dependence in Chinese. PMID:20025435

  8. Protein expression of CYP1A1, CYP1B1, ALDH1A1, and ALDH2 in young patients with oral squamous cell carcinoma.

    PubMed

    Kaminagakura, E; Caris, A; Coutinho-Camillo, C; Soares, F A; Takahama-Júnior, A; Kowalski, L P

    2016-06-01

    The purpose of this study was to evaluate the expression of the enzymes involved in the biotransformation of tobacco and alcohol. A study group of 41 young patients (≤40 years old) with oral squamous cell carcinoma (OSCC) was compared to 59 control subjects (≥50 years old) with tumours of similar clinical stages and topographies. The immunohistochemical expression of CYP1A1, CYP1B1, ALDH1A1, and ALDH2 was evaluated using the tissue microarray technique. There was a predominance of males, smokers, and alcohol drinkers in both groups. Most tumours were located in the tongue (43.9% vs. 50.8%), were well-differentiated (63.4% vs. 56.6%), and were in clinical stages III or IV (80.5% vs. 78.0%). No difference was observed in the expression of CYP1A1, ALDH1A1, or ALDH2 between the two groups. CYP1A1 and ALDH2 protein expression had no influence on the prognosis. The immunoexpression of CYP1B1 was significantly higher in the control group than in the young group (P<0.001). The 5-year relapse-free survival was better in patients with CYP1B1 overexpression vs. protein underexpression (64% vs. 25%; P<0.05), regardless of age. ALDH1A1 expression improved relapse-free survival in young patients. These results suggest a lower risk of recurrence with increased metabolism of carcinogens by CYP1B1. Further studies involving other genes and proteins are necessary to complement the results of this research. PMID:26944893

  9. Aldh2 knockout mice were more sensitive to DNA damage in leukocytes due to ethyl tertiary butyl ether exposure.

    PubMed

    Weng, Zuquan; Suda, Megumi; Ohtani, Katsumi; Mei, Nan; Kawamoto, Toshihiro; Nakajima, Tamie; Wang, Rui-Sheng

    2011-01-01

    To clarify the genotoxicity of ethyl tertiary butyl ether (ETBE), a gasoline additive, male and female C57BL/6 mice of Aldh2+/+ and Aldh2-/- genotypes, aged 8 wk, were exposed to 0, 500, 1,750, or 5,000 ppm ETBE for 6 h/day, 5 d per week for 13 wk. DNA damage in leukocytes was measured by the alkaline comet assay and expressed quantitatively as Tail Intensity (TI). For male mice, TI was significantly higher in all three groups exposed to ETBE than in those without exposure within Aldh2-/- mice, whereas within Aldh2+/+ mice, TI increased only in those exposed to 5,000 ppm of ETBE as compared with mice without exposure. For female mice, a significant increase in TI values was observed in the group exposed to 5,000 ppm of ETBE as compared with those without exposure within Aldh2-/- mice; TI in Aldh2-/- mice exposed to 1,750 and 5,000 ppm was significantly higher than in Aldh2+/+ mice without exposure. TI did not significantly increase in any of the groups exposed to ETBE within female Aldh2+/+ mice. Based on the results we suggest that Aldh2-/- mice are more sensitive to DNA damage caused by ETBE than Aldh2+/+ mice and that males seem more susceptible to this effect than females. PMID:21372431

  10. Evaluation of alcohol dehydrogenase and aldehyde dehydrogenase enzymes as bi-enzymatic anodes in a membraneless ethanol microfluidic fuel cell

    NASA Astrophysics Data System (ADS)

    Galindo-de-la-Rosa, J.; Arjona, N.; Arriaga, L. G.; Ledesma-García, J.; Guerra-Balcázar, M.

    2015-12-01

    Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (AldH) enzymes were immobilized by covalent binding and used as the anode in a bi-enzymatic membraneless ethanol hybrid microfluidic fuel cell. The purpose of using both enzymes was to optimize the ethanol electro-oxidation reaction (EOR) by using ADH toward its direct oxidation and AldH for the oxidation of aldehydes as by-products of the EOR. For this reason, three enzymatic bioanode configurations were evaluated according with the location of enzymes: combined, vertical and horizontally separated. In the combined configuration, a current density of 16.3 mA cm-2, a voltage of 1.14 V and a power density of 7.02 mW cm-2 were obtained. When enzymes were separately placed in a horizontal and vertical position the ocp drops to 0.94 V and to 0.68 V, respectively. The current density also falls to values of 13.63 and 5.05 mA cm-2. The decrease of cell performance of bioanodes with separated enzymes compared with the combined bioanode was of 31.7% and 86.87% for the horizontal and the vertical array.

  11. ALDH18A1-related cutis laxa syndrome with cyclic vomiting.

    PubMed

    Nozaki, Fumihito; Kusunoki, Takashi; Okamoto, Nobuhiko; Yamamoto, Yuto; Miya, Fuyuki; Tsunoda, Tatsuhiko; Kosaki, Kenjiro; Kumada, Tomohiro; Shibata, Minoru; Fujii, Tatsuya

    2016-08-01

    Cutis laxa (CL) syndromes are connective tissue disorders characterized by redundant, sagging, inelastic and wrinkled skin, with organ involvement. Here, we describe a patient with ALDH18A1-related CL who developed cyclic vomiting. The patient was a 12-year-old boy who presented with poor postnatal growth, hypotonia, short stature, joint hyperlaxity, microcephaly, strabismus, bilateral cataracts, facial dysmorphism and severe mental retardation. Bone radiographs showed osteopenia and osteoporosis, and magnetic resonance angiography showed marked kinking and tortuosity of the brain vessels. These findings were clinically compatible with ALDH18A1-related CL. Molecular analysis revealed a de novo heterozygous mutation (p.R138Q) in ALDH18A1. No mutations were found in PYCR1 gene. The patient developed cyclic vomiting with decreased blood levels of ornithine, citrulline, arginine and proline without hyperammonemia and other hypoaminoacidemias were also found. ALDH18A1 encodes Δ(1)-pyrroline-5-carboxylate synthase, which is related to the biosynthesis of ornithine, citrulline, arginine, and proline. Cyclic vomiting has never been reported in other ALDH18A1-related CL patients. This is the first case report of ALDH18A1-related CL with cyclic vomiting associated with amino acid abnormalities. PMID:26829900

  12. Photocatalyzed oxidation of ethanol and acetaldehyde in humidified air

    SciTech Connect

    Sauer, M.L.; Ollis, D.F.

    1996-02-01

    Photocatalysis is considered as a potential air treatment and purification technology. Photocatalyzed oxidation of ethanol and acetaldehyde in humidified air was carried out to establish a first complete kinetic model for a photocatalyzed multispecies network. Two photocatalysts were examined in a batch, recirculation reactor, near-UV illuminated TiO{sub 2} (anatase) coated (i) on the surface of a nonporous quartz glass plate and (ii) on a porous ceramic honeycomb monolith. The former contained only illuminated (active) surfaces, the latter consisted of substantial {open_quotes}dark{close_quotes} surfaces coated with a thin layer of illuminated (active) catalyst. Ethanol was photooxidized to acetaldehyde and formaldehyde intermediates, and eventually to carbon dioxide and water products. The catalyst and monolith surfaces adsorbed appreciable fractions of the trace ethanol, acetaldehyde, formaldehyde, carbon dioxide and water present. Ethanol, acetaldehyde, and carbon dioxide adsorption isotherms were measured on both catalysts; the formaldehyde adsorption isotherms were assumed identical to those of acetaldehyde. On the fully illuminated glass plate reactor, all four species were accounted for, and closure of a transient carbon mass balance was demonstrated. Completion of a transient carbon mass balance on the monolith reactor required inclusion of additional reaction intermediates (acetic and formic acids), which appear to reversibly accumulate on only the dark surfaces. The ethanol and acetaldehyde photocatalyzed oxidation kinetic networks were modeled using Langmuir-Hinshelwood rate forms combined with adsorption isotherms for reactant, intermediates, and product CO{sub 2}. For both the quartz plate and monolith catalysts, satisfactory kinetic models were developed to predict the entire time course of ethanol and acetaldehyde multicomponent batch conversions. 43 refs., 16 figs.

  13. Variability of ethanol and acetaldehyde concentrations in rainwater

    NASA Astrophysics Data System (ADS)

    Kieber, R. J.; Tatum, S.; Willey, J. D.; Avery, G. B.; Mead, R. N.

    2014-02-01

    Ethanol and acetaldehyde concentrations were measured in 52 rain events collected between January 25, 2011 and March 4, 2012 in Wilmington, North Carolina, USA. Ethanol concentrations ranged from 23 nM to 908 nM with a volume weighted average concentration of 192 ± 20 nM while acetaldehyde ranged from 23 nM to 909 nM with a volume weighted average concentration of 193 ± 25 nM. There was a great deal of variability in the abundance of ethanol and acetaldehyde between rain events driven primarily by temporal and air mass back trajectory influences. The ratio of ethanol to acetaldehyde was at a minimum during periods of peak solar intensity underscoring the importance of alcohol oxidation by a photochemically generated oxidant such as hydroxyl radical in the gas and/or aqueous phase. Ethanol and acetaldehyde concentrations were not strongly correlated with rain amount suggesting that gas-phase concentrations were not significantly depleted during the storm or that they were resupplied during the course of the rain event. The concentration of ethanol and acetaldehyde were correlated with nitrate and non-sea salt sulfate suggesting the importance of terrestrial and anthropogenic inputs at this location. Comparison of future ethanol and acetaldehyde concentrations in rainwater to the data presented in this study will help delineate potential consequences of these labile oxygenated volatile organic compounds (OVOCs) on the chemistry of the troposphere as the United States transitions to more ethanol blended fuels. Aqueous phase impacts of increasing ethanol concentrations will be particularly significant to the oxidizing capacity of atmospheric waters because of its reactivity with OH and HO2 radicals in solution. Increased rainwater concentrations could also have significant ramifications on receiving watersheds because of the biogeochemical lability of the alcohol.

  14. An enzyme-amplified microtiter plate assay for ethanol: Its application to the detection of peanut ethanol and alcohol dehydrogenase

    SciTech Connect

    Chung, S.Y.; Vercellotti, J.R.; Sanders, T.H.

    1995-12-01

    A calorimetric microliter plate assay for ethanol amplified by aldehyde dehydrogenase (ALDH) was developed. In the assay ethanol from a sample took part in a chain-reaction catalyzed by alcohol dehydrogenase (ADH) and amplified by ALDH in the presence of NAD{sup +}, diaphorase, and p-ibdonitrotetrazolium-violet (INT-violet)(a precursor of red product). The resultant reaction gave a red color, the intensity of which was proportional to the amount of ethanol present. Using the technique, the content of activity from peanuts of differing maturity and curing stages were determined respectively. Data showed that immature peanuts had a higher level of ethanol and a lower ADH activity than mature peanuts, and that the level of ethanol and ADH activity decreased with the curing time. This indicates that peanut maturity and curing have an effect on ethanol. Also, this implies that other peanut volatiles could be affected in the same way as ethanol, a major volatile in peanuts.

  15. β-Escin inhibits NNK-induced lung adenocarcinoma and ALDH1A1 and RhoA/Rock expression in A/J mice and growth of H460 human lung cancer cells.

    PubMed

    Patlolla, Jagan M R; Qian, Li; Biddick, Laura; Zhang, Yuting; Desai, Dhimant; Amin, Shantu; Lightfoot, Stan; Rao, Chinthalapally V

    2013-10-01

    Lung cancer is the leading cause of cancer-related deaths. β-Escin, a triterpene saponin isolated from horse chestnut seeds, was tested for inhibition of lung adenoma and adenocarcinoma induced by the tobacco carcinogen 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice; and its possible mode of action was evaluated using the H460 human lung cancer cell line. At 6 weeks of age, 35 mice were fed AIN-76A-modified diet, and one week later, lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 μmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed either control or experimental diets containing 500 ppm for 20 weeks (10 control, 5 β-escin) or 36 weeks (15 control, 5 β-escin) and evaluated for lung tumor via histopathologic methods. Administration of 500 ppm β-escin significantly suppressed lung tumor (adenoma + adenocarcinoma) formation by more than 40% (P < 0.0015) at 20 weeks and by 53.3% (P < 0.0001) at 37 weeks. β-Escin inhibited NNK-induced lung adenocarcinoma formation by 65% (P < 0.001) at 20 weeks and by 53% (P < 0.0001) at 37 weeks. Immunohistochemical analysis revealed that lung tumors from mice exposed to β-escin showed significantly reduced aldehyde dehydrogenase (ALDH)1A1 and phospho-Akt (p-Akt) expression when compared with those in mice fed control diet. Aldefluor assay for ALDH revealed that among H460 lung cancer cells treated with different concentrations of β-escin (0-40 μmol/L), the subpopulation of cells with elevated ALDH activity was inhibited significantly. Our findings suggest that β-escin inhibits tobacco carcinogen-induced lung tumor formation by modulating ALDH1A1-positive cells and RhoA/Rock signaling. PMID:23963803

  16. Inorganic acid-catalyzed tautomerization of vinyl alcohol to acetaldehyde

    NASA Astrophysics Data System (ADS)

    Karton, Amir

    2014-01-01

    The vinyl alcohol-acetaldehyde tautomerization reaction has recently received considerable attention as a potential route for the formation of organic acids in the troposphere (Andrews et al., 2012 [7]). We examine the catalytic effect of inorganic acids in the troposphere (e.g. HNO3, H2SO4 and HClO4) on the vinyl alcohol-acetaldehyde tautomerization reaction, by means high-level thermochemical procedures. We show that H2SO4 and HClO4 catalysts lead to near-zero reaction barrier heights for the vinyl alcohol → acetaldehyde reaction, and to low reaction barrier heights in the reverse direction (ΔH298‡=40.6 and 39.5 kJ mol, respectively).

  17. ALDH2 polymorphism is associated with fasting blood glucose through alcohol consumption in Japanese men.

    PubMed

    Yin, Guang; Naito, Mariko; Wakai, Kenji; Morita, Emi; Kawai, Sayo; Hamajima, Nobuyuki; Suzuki, Sadao; Kita, Yoshikuni; Takezaki, Toshiro; Tanaka, Keitaro; Morita, Makiko; Uemura, Hirokazu; Ozaki, Etsuko; Hosono, Satoyo; Mikami, Haruo; Kubo, Michiaki; Tanaka, Hideo

    2016-05-01

    Associations between alcohol consumption and type 2 diabetes risk are inconsistent in epidemiologic studies. This study investigated the associations of ADH1B and ALDH2 polymorphisms with fasting blood glucose levels, and the impact of the associations of alcohol consumption with fasting blood glucose levels in Japanese individuals. This cross-sectional study included 907 men and 912 women, aged 35-69 years. The subjects were selected from among the Japan Multi-institutional Collaborative Cohort study across six areas of Japan. The ADH1B and ALDH2 polymorphisms were genotyped by Invader Assays. The ALDH2 Glu504Lys genotypes were associated with different levels of fasting blood glucose in men (P = 0.04). Mean fasting glucose level was positively associated with alcohol consumption in men with the ALDH2 504 Lys allele (P trend = 0.02), but not in men with the ALDH2 504Glu/Glu genotype (P trend = 0.45), resulting in no statistically significant interaction (P = 0.38). Alcohol consumption was associated with elevated fasting blood glucose levels compared with non-consumers in men (P trend = 0.002). The ADH1B Arg48His polymorphism was not associated with FBG levels overall or after stratification for alcohol consumption. These findings suggest that the ALDH2 polymorphism is associated with different levels of fasting blood glucose through alcohol consumption in Japanese men. The interaction of ALDH2 polymorphisms in the association between alcohol consumption and fasting blood glucose warrants further investigation. PMID:27303105

  18. Aldehyde Dehydrogenase 1a1 Mediates a GABA Synthesis Pathway in Midbrain Dopaminergic Neurons

    PubMed Central

    Kim, Jae-Ick; Ganesan, Subhashree; Luo, Sarah X.; Wu, Yu-Wei; Park, Esther; Huang, Eric J.; Chen, Lu; Ding, Jun B.

    2016-01-01

    Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here we show that GABA corelease in dopamine neurons does not utilize the conventional GABA synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol at binge drinking blood alcohol concentrations and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction. PMID:26430123

  19. Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors.

    PubMed

    Venton, G; Pérez-Alea, M; Baier, C; Fournet, G; Quash, G; Labiad, Y; Martin, G; Sanderson, F; Poullin, P; Suchon, P; Farnault, L; Nguyen, C; Brunet, C; Ceylan, I; Costello, R T

    2016-01-01

    The vast majority of patients with acute myeloid leukemia (AML) achieve complete remission (CR) after standard induction chemotherapy. However, the majority subsequently relapse and die of the disease. A leukemia stem cell (LSC) paradigm has been invoked to explain this failure of CR to reliably translate into cure. Indeed, LSCs are highly enriched in CD34+CD38- leukemic cells that exhibit positive aldehyde dehydrogenase activity (ALDH+) on flow cytometry, these LSCs are resistant to currently existing treatments in AML such as cytarabine and anthracycline that, at the cost of great toxicity on normal cells, are highly active against the leukemic bulk, but spare the LSCs responsible for relapse. To try to combat the LSC population selectively, a well-characterized ALDH inhibitor by the trivial name of dimethyl ampal thiolester (DIMATE) was assessed on sorted CD34+CD38- subpopulations from AML patients and healthy patients. ALDH activity and cell viability were monitored by flow cytometry. From enzyme kinetic studies DIMATE is an active enzyme-dependent, competitive, irreversible inhibitor of ALDH1. On cells in culture, DIMATE is a powerful inhibitor of ALDHs 1 and 3, has a major cytotoxic activity on human AML cell lines. Moreover, DIMATE is highly active against leukemic populations enriched in LSCs, but, unlike conventional chemotherapy, DIMATE is not toxic for healthy hematopoietic stem cells which retained, after treatment, their self-renewing and multi-lineage differentiation capacity in immunodeficient mice, xenografted with human leukemic cells. DIMATE eradicates specifically human AML cells and spares healthy mouse hematologic cells. PMID:27611922

  20. Effects on sister chromatid exchange frequency of aldehyde dehydrogenase 2 genotype and smoking in vinyl chloride workers.

    PubMed

    Wong, R H; Wang, J D; Hsieh, L L; Du, C L; Cheng, T J

    1998-12-01

    Vinyl chloride monomer (VCM) is a human carcinogen. However, the exact mechanism of carcinogenesis remains unclear. VCM may be metabolized by cytochrome P450 2E1 (CYP2E1), aldehyde dehydrogenase 2 (ALDH2) and glutathione S-transferases (GSTs). Thus workers with inherited variant metabolic enzyme activities may have an altered risk of genotoxicity. This study was designed to investigate which risk factors might affect sister chromatid exchange (SCE) frequency in polyvinyl chloride (PVC) workers. Study subjects were 44 male workers from three PVC factories. Questionnaires were administered to obtain detailed histories of cigarette smoking, alcohol consumption, occupations, and medications. SCE frequency in peripheral lymphocytes was determined using a standardized method, and CYP2E1, GSTM1, GSTT1 and ALDH2 genotypes were identified by the polymerase chain reaction (PCR). Analysis revealed that smoking status and exposure to VCM were significantly associated with increased SCE frequency. The presence of ALDH2 1-2/2-2 genotypes was also significantly associated with an elevation of SCE frequency (9. 5 vs. 8.1, p<0.01). However, CYP2E1, GSTM1 or GSTT1 genotypes were not significantly associated with SCE frequency. When various genotypes were considered together, combination of CYP2E1 c1c2/c2c2 with ALDH2 1-2/2-2 showed an additive effect on SCE frequency. Similar results were also found for the combination of smoking with CYP2E1, or smoking with ALDH2. These results suggest that VCM workers with ALDH2 1-2/2-2 genotypes, who also smoke, may have increased risk of DNA damage. PMID:9838066

  1. Gas phase acetaldehyde production in a continuous bioreactor

    SciTech Connect

    Hwang, Soon Ook . Dept. of Chemical Engineering); Trantolo, D.J. . Center for Biotechnology Engineering); Wise, D.L. . Dept. of Chemical Engineering Northeastern Univ., Boston, MA . Center for Biotechnology Engineering)

    1993-08-20

    The gas phase continuous production of acetaldehyde was studied with particular emphasis on the development of biocatalyst (alcohol oxidase on solid phase support materials) for a fixed bed reactor. Based on the experimental results in a batch bioreactor, the biocatalysts were prepared by immobilization of alcohol oxidase on Amberlite IRA-400, packed into a column, and the continuous acetaldehyde production in the gas phase by alcohol oxidase was performed. The effects of the reaction temperature, flow rates of gaseous stream, and ethanol vapor concentration on the performance of the continuous bioreactor were investigated.

  2. Glucose-6-phosphate dehydrogenase

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/003671.htm Glucose-6-phosphate dehydrogenase test To use the sharing features on this page, please enable JavaScript. Glucose-6-phosphate dehydrogenase (G6PD) is a type of ...

  3. [A gas chromatographic method for determining acetaldehyde in cadaver blood].

    PubMed

    Savich, V I; Valladares, Kh A; Gusakov, Iu A; Skachko, Z M

    1990-01-01

    Gas-chromatographic method of acetaldehyde detection in blood of subjects who died of alcoholic intoxication is suggested. Method is simple, does not require additional expenses, can be readily used in medicolegal practice and in difficult cases it may help the expert to make an objective conclusion on the cause of death. PMID:2087747

  4. BIOGENIC SOURCES FOR FORMALDEHYDE AND ACETALDEHYDE DURING SUMMER MONTHS

    EPA Science Inventory

    Photochemical modeling estimated contributions to ambient concentrations of formaldehyde and acetaldehyde from biogenic emissions over the continental United States during January 2001 (Eos Trans. AGU, 83(47), Fall Meet. Suppl., Abstract A52B-0117). Results showed that maximum co...

  5. The longitudinal effect of the aldehyde dehydrogenase 2*2 allele on the risk for nonalcoholic fatty liver disease.

    PubMed

    Oniki, K; Morita, K; Watanabe, T; Kajiwara, A; Otake, K; Nakagawa, K; Sasaki, Y; Ogata, Y; Saruwatari, J

    2016-01-01

    Aldehyde dehydrogenase 2 (ALDH2) detoxifies toxic aldehydes and has a key role in protecting the liver. An elevated gamma-glutamyl transferase (GGT) level is related to oxidative stress and nonalcoholic fatty liver disease (NAFLD). We herein investigated the association between inactive ALDH2*2 allele (rs671) and the risk of NAFLD, including the relationship to the GGT level. A retrospective follow-up study (mean 5.4±1.1 years) was conducted among 341 Japanese health screening program participants. The receiver operating characteristic curve indicated that the GGT level predicted the development of NAFLD (area under the curve: 0.65, P<0.05) with a cutoff value of 25.5 IUl(-1). The longitudinal risk of NAFLD was higher in the ALDH2*2 allele carriers than in the noncarriers (odds ratio (OR): 2.30, 95% confidence interval (CI): 1.21-4.40), and the risk was further increased among the *2 allele carriers with GGT values ⩾25.5 IUl(-1) (OR: 4.28, 95% CI: 1.80-10.19). On the other hand, there were no significant changes in the subjects' body weight and body mass index during observation period. The ALDH2*2 allele, in relation to the GGT level, may potentially be a novel risk factor for NAFLD. PMID:27214654

  6. The longitudinal effect of the aldehyde dehydrogenase 2*2 allele on the risk for nonalcoholic fatty liver disease

    PubMed Central

    Oniki, K; Morita, K; Watanabe, T; Kajiwara, A; Otake, K; Nakagawa, K; Sasaki, Y; Ogata, Y; Saruwatari, J

    2016-01-01

    Aldehyde dehydrogenase 2 (ALDH2) detoxifies toxic aldehydes and has a key role in protecting the liver. An elevated gamma-glutamyl transferase (GGT) level is related to oxidative stress and nonalcoholic fatty liver disease (NAFLD). We herein investigated the association between inactive ALDH2*2 allele (rs671) and the risk of NAFLD, including the relationship to the GGT level. A retrospective follow-up study (mean 5.4±1.1 years) was conducted among 341 Japanese health screening program participants. The receiver operating characteristic curve indicated that the GGT level predicted the development of NAFLD (area under the curve: 0.65, P<0.05) with a cutoff value of 25.5 IUl−1. The longitudinal risk of NAFLD was higher in the ALDH2*2 allele carriers than in the noncarriers (odds ratio (OR): 2.30, 95% confidence interval (CI): 1.21–4.40), and the risk was further increased among the *2 allele carriers with GGT values ⩾25.5 IUl−1 (OR: 4.28, 95% CI: 1.80–10.19). On the other hand, there were no significant changes in the subjects' body weight and body mass index during observation period. The ALDH2*2 allele, in relation to the GGT level, may potentially be a novel risk factor for NAFLD. PMID:27214654

  7. Aldehyde dehydrogenase 3A1 promotes multi-modality resistance and alters gene expression profile in human breast adenocarcinoma MCF-7 cells.

    PubMed

    Voulgaridou, Georgia-Persephoni; Kiziridou, Magdalini; Mantso, Theodora; Chlichlia, Katerina; Galanis, Alex; Koukourakis, Michael I; Franco, Rodrigo; Panayiotidis, Mihalis I; Pappa, Aglaia

    2016-08-01

    Aldehyde dehydrogenases participate in a variety of cellular homeostatic mechanisms like metabolism, proliferation, differentiation, apoptosis, whereas recently, they have been implicated in normal and cancer cell stemness. We explored roles for ALDH3A1 in conferring resistance to chemotherapeutics/radiation/oxidative stress and whether ectopic overexpression of ALDH3A1 could lead to alterations of gene expression profile associated with cancer stem cell-like phenotype. MCF-7 cells were stably transfected either with an empty vector (mock) or human aldehyde dehydrogenase 3A1 cDNA. The expression of aldehyde dehydrogenase 3A1 in MCF-7 cells was associated with altered cell proliferation rate and enhanced cell resistance against various chemotherapeutic drugs (4-hydroxyperoxycyclophosphamide, doxorubicin, etoposide, and 5-fluorouracil). Aldehyde dehydrogenase 3A1 expression also led to increased tolerance of MCF-7 cells to gamma radiation and hydrogen peroxide-induced stress. Furthermore, aldehyde dehydrogenase 3A1-expressing MCF-7 cells exhibited gene up-regulation of cyclins A, B1, B2, and down-regulation of cyclin D1 as well as transcription factors p21, CXR4, Notch1, SOX2, SOX4, OCT4, and JAG1. When compared to mock cells, no changes were observed in mRNA levels of ABCA2 and ABCB1 protein pumps with only a minor decrease of the ABCG2 pump in the aldehyde dehydrogenase 3A1-expressing cells. Also, the adhesion molecules EpCAM and CD49F were also found to be up-regulated in aldehyde dehydrogenase 3A1expressing cells. Taken together, ALDH3A1 confers a multi-modality resistance phenotype in MCF-7 cells associated with slower growth rate, increased clonogenic capacity, and altered gene expression profile, underlining its significance in cell homeostasis. PMID:27276244

  8. Aromatic Amines Exert Contrasting Effects on the Anticoagulant Effect of Acetaldehyde upon APTT

    PubMed Central

    Hall, La'Teese; Murrey, Sarah J.; Brecher, Arthur S.

    2014-01-01

    The pharmacological effects of amphetamine, procaine, procainamide, DOPA, isoproterenol, and atenolol upon activated partial thromboplastin time in the absence and presence of acetaldehyde have been investigated. In the absence of acetaldehyde, amphetamine and isoproterenol exhibit a procoagulant effect upon activated partial thromboplastin time, whereas atenolol and procaine display anticoagulant effects upon activated partial thromboplastin time. DOPA and procainamide do not alter activated partial thromboplastin time. Premixtures of procaine with acetaldehyde produce an additive anticoagulant effect on activated partial thromboplastin time, suggesting independent action of these compounds upon clotting factors. Premixtures of amphetamine with acetaldehyde, as well as atenolol with acetaldehyde, generate a detoxication of the anticoagulant effect of acetaldehyde upon activated partial thromboplastin time. A similar statistically significant decrease in activated partial thromboplastin time is seen when procainamide is premixed with acetaldehyde for 20 minutes at room temperature. Premixtures of DOPA and isoproterenol with acetaldehyde do not affect an alteration in activated partial thromboplastin time relative to acetaldehyde alone. Hence, a selective interaction of atenolol, procaine, and amphetamine with acetaldehyde to produce detoxication of the acetaldehyde is suggested, undoubtedly due to the presence of amino, hydroxyl, or amide groups in these drugs. PMID:25548568

  9. Dehydrogenase genes in the ectomycorrhizal fungus Tricholoma vaccinum: A role for Ald1 in mycorrhizal symbiosis.

    PubMed

    Henke, Catarina; Jung, Elke-Martina; Voit, Annekatrin; Kothe, Erika; Krause, Katrin

    2016-02-01

    Ectomycorrhizal symbiosis is important for forest ecosystem functioning with tree-fungal cooperation increasing performance and countering stress conditions. Aldehyde dehydrogenases (ALDHs) are key enzymes for detoxification and thus may play a role in stress response of the symbiotic association. With this focus, eight dehydrogenases, Ald1 through Ald7 and TyrA, of the ectomycorrhizal basidiomycete Tricholoma vaccinum were characterized and phylogenetically investigated. Functional analysis was performed through differential expression analysis by feeding different, environmentally important substances. A strong effect of indole-3-acetic acid (IAA) was identified, linking mycorrhiza formation and auxin signaling between the symbiosis partners. We investigated ald1 overexpressing strains for performance in mycorrhiza with the host tree spruce (Picea abies) and observed an increased width of the apoplast, accommodating the Hartig' net hyphae of the T. vaccinum over-expressing transformants. The results support a role for Ald1 in ectomycorrhiza formation and underline functional differentiation within fungal aldehyde dehydrogenases in the family 1 of ALDHs. PMID:26344933

  10. ALDH16A1 is a novel non-catalytic enzyme that may be involved in the etiology of gout via protein–protein interactions with HPRT1

    PubMed Central

    Vasiliou, Vasilis; Sandoval, Monica; Backos, Donald S.; Jackson, Brian C.; Chen, Ying; Reigan, Philip; Lanaspa, Miguel A.; Johnson, Richard J.; Koppaka, Vindhya; Thompson, David C.

    2013-01-01

    Gout, a common form of inflammatory arthritis, is strongly associated with elevated uric acid concentrations in the blood (hyperuricemia). A recent study in Icelanders identified a rare missense single nucleotide polymorphism (SNP) in the ALDH16A1 gene, ALDH16A1*2, to be associated with gout and serum uric acid levels. ALDH16A1 is a novel and rather unique member of the ALDH superfamily in relation to its gene and protein structures. ALDH16 genes are present in fish, amphibians, protista, bacteria but absent from archaea, fungi and plants. In most mammalian species, two ALDH16A1 spliced variants (ALDH16A1, long form and ALDH16A1_v2, short form) have been identified and both are expressed in HepG-2, HK-2 and HK-293 human cell lines. The ALDH16 proteins contain two ALDH domains (as opposed to one in the other members of the superfamily), four transmembrane and one coiled-coil domains. The active site of ALDH16 proteins from bacterial, frog and lower animals contain the catalytically important cysteine residue (Cys-302); this residue is absent from the mammalian and fish orthologs. Molecular modeling predicts that both the short and long forms of human ALDH16A1 protein would lack catalytic activity but may interact with the hypoxanthine-guanine phosphoribosyltransferase (HPRT1) protein, a key enzyme involved in uric acid metabolism and gout. Interestingly, such protein-protein interactions with HPRT1 are predicted to be impaired for the long or short forms of ALDH16A1*2. These results lead to the intriguing possibility that association between ALDH16A1 and HPRT1 may be required for optimal HPRT activity with disruption of this interaction possibly contributing to the hyperuricemia seen in ALDH16A1*2 carriers. PMID:23348497

  11. Association of Genetically Determined Aldehyde Dehydrogenase 2 Activity with Diabetic Complications in Relation to Alcohol Consumption in Japanese Patients with Type 2 Diabetes Mellitus: The Fukuoka Diabetes Registry.

    PubMed

    Idewaki, Yasuhiro; Iwase, Masanori; Fujii, Hiroki; Ohkuma, Toshiaki; Ide, Hitoshi; Kaizu, Shinako; Jodai, Tamaki; Kikuchi, Yohei; Hirano, Atsushi; Nakamura, Udai; Kubo, Michiaki; Kitazono, Takanari

    2015-01-01

    Aldehyde dehydrogenase 2 (ALDH2) detoxifies aldehyde produced during ethanol metabolism and oxidative stress. A genetic defect in this enzyme is common in East Asians and determines alcohol consumption behaviors. We investigated the impact of genetically determined ALDH2 activity on diabetic microvascular and macrovascular complications in relation to drinking habits in Japanese patients with type 2 diabetes mellitus. An ALDH2 single-nucleotide polymorphism (rs671) was genotyped in 4,400 patients. Additionally, the relationship of clinical characteristics with ALDH2 activity (ALDH2 *1/*1 active enzyme activity vs. *1/*2 or *2/*2 inactive enzyme activity) and drinking habits (lifetime abstainers vs. former or current drinkers) was investigated cross-sectionally (n = 691 in *1/*1 abstainers, n = 1,315 in abstainers with *2, n = 1,711 in *1/*1 drinkers, n = 683 in drinkers with *2). The multiple logistic regression analysis for diabetic complications was adjusted for age, sex, current smoking habits, leisure-time physical activity, depressive symptoms, diabetes duration, body mass index, hemoglobin A1c, insulin use, high-density lipoprotein cholesterol, systolic blood pressure and renin-angiotensin system inhibitors use. Albuminuria prevalence was significantly lower in the drinkers with *2 than that of other groups (odds ratio [95% confidence interval (CI)]: *1/*1 abstainers as the referent, 0.94 [0.76-1.16] in abstainers with *2, 1.00 [0.80-1.26] in *1/*1 drinkers, 0.71 [0.54-0.93] in drinkers with *2). Retinal photocoagulation prevalence was also lower in drinkers with ALDH2 *2 than that of other groups. In contrast, myocardial infarction was significantly increased in ALDH2 *2 carriers compared with that in ALDH2 *1/*1 abstainers (odds ratio [95% CI]: *1/*1 abstainers as the referent, 2.63 [1.28-6.13] in abstainers with *2, 1.89 [0.89-4.51] in *1/*1 drinkers, 2.35 [1.06-5.79] in drinkers with *2). In summary, patients with type 2 diabetes and ALDH2 *2 displayed a

  12. Association of Genetically Determined Aldehyde Dehydrogenase 2 Activity with Diabetic Complications in Relation to Alcohol Consumption in Japanese Patients with Type 2 Diabetes Mellitus: The Fukuoka Diabetes Registry

    PubMed Central

    Idewaki, Yasuhiro; Iwase, Masanori; Fujii, Hiroki; Ohkuma, Toshiaki; Ide, Hitoshi; Kaizu, Shinako; Jodai, Tamaki; Kikuchi, Yohei; Hirano, Atsushi; Nakamura, Udai; Kubo, Michiaki; Kitazono, Takanari

    2015-01-01

    Aldehyde dehydrogenase 2 (ALDH2) detoxifies aldehyde produced during ethanol metabolism and oxidative stress. A genetic defect in this enzyme is common in East Asians and determines alcohol consumption behaviors. We investigated the impact of genetically determined ALDH2 activity on diabetic microvascular and macrovascular complications in relation to drinking habits in Japanese patients with type 2 diabetes mellitus. An ALDH2 single-nucleotide polymorphism (rs671) was genotyped in 4,400 patients. Additionally, the relationship of clinical characteristics with ALDH2 activity (ALDH2 *1/*1 active enzyme activity vs. *1/*2 or *2/*2 inactive enzyme activity) and drinking habits (lifetime abstainers vs. former or current drinkers) was investigated cross-sectionally (n = 691 in *1/*1 abstainers, n = 1,315 in abstainers with *2, n = 1,711 in *1/*1 drinkers, n = 683 in drinkers with *2). The multiple logistic regression analysis for diabetic complications was adjusted for age, sex, current smoking habits, leisure-time physical activity, depressive symptoms, diabetes duration, body mass index, hemoglobin A1c, insulin use, high-density lipoprotein cholesterol, systolic blood pressure and renin-angiotensin system inhibitors use. Albuminuria prevalence was significantly lower in the drinkers with *2 than that of other groups (odds ratio [95% confidence interval (CI)]: *1/*1 abstainers as the referent, 0.94 [0.76–1.16] in abstainers with *2, 1.00 [0.80–1.26] in *1/*1 drinkers, 0.71 [0.54–0.93] in drinkers with *2). Retinal photocoagulation prevalence was also lower in drinkers with ALDH2 *2 than that of other groups. In contrast, myocardial infarction was significantly increased in ALDH2 *2 carriers compared with that in ALDH2 *1/*1 abstainers (odds ratio [95% CI]: *1/*1 abstainers as the referent, 2.63 [1.28–6.13] in abstainers with *2, 1.89 [0.89–4.51] in *1/*1 drinkers, 2.35 [1.06–5.79] in drinkers with *2). In summary, patients with type 2 diabetes and ALDH2 *2

  13. Meta-Analyses of ALDH2 and ADH1B with Alcohol Dependence in Asians

    ERIC Educational Resources Information Center

    Luczak, Susan E.; Glatt, Stephen J.; Wall, Tamara J.

    2006-01-01

    Meta-analyses were conducted to determine the magnitude of relationships between polymorphisms in 2 genes, ALDH2 and ADH1B, with alcohol dependence in Asians. For each gene, possession of 1 variant [asterisk]2 allele was protective against alcohol dependence, and possession of a 2nd [asterisk]2 allele did not offer significant additional…

  14. NADH fluorescence lifetime analysis of the effect of magnesium ions on ALDH2

    Technology Transfer Automated Retrieval System (TEKTRAN)

    ALDH2 catalyzes oxidation of toxic aldehydes to their corresponding carboxylic acids. Magnesium ions influence enzyme activity in part by increasing NADH binding affinity. Traditional fluorescence measurements have monitored the blue shift of the NADH fluorescence spectrum to elucidate the extent of...

  15. Behavioral and biochemical evidence of the role of acetaldehyde in the motivational effects of ethanol

    PubMed Central

    Peana, Alessandra T.; Acquas, Elio

    2013-01-01

    Since Chevens' report, in the early 50's that his patients under treatment with the aldehyde dehydrogenase inhibitor, antabuse, could experience beneficial effects when drinking small volumes of alcoholic beverages, the role of acetaldehyde (ACD) in the effects of ethanol has been thoroughly investigated on pre-clinical grounds. Thus, after more than 25 years of intense research, a large number of studies have been published on the motivational properties of ACD itself as well as on the role that ethanol-derived ACD plays in the effects of ethanol. Accordingly, in particular with respect to the motivational properties of ethanol, these studies were developed following two main strategies: on one hand, were aimed to challenge the suggestion that also ACD may exert motivational properties on its own, while, on the other, with the aid of enzymatic manipulations or ACD inactivation, were aimed to test the hypothesis that ethanol-derived ACD might have a role in ethanol motivational effects. Furthermore, recent evidence significantly contributed to highlight, as possible mechanisms of action of ACD, its ability to commit either dopaminergic and opioidergic transmission as well as to activate the Extracellular signal Regulated Kinase cascade transduction pathway in reward-related brain structures. In conclusion, and despite the observation that ACD seems also to have inherited the elusive nature of its parent compound, the behavioral and biochemical evidence reviewed points to ACD as a neuroactive molecule able, on its own and as ethanol metabolite, to exert motivational effects. PMID:23874276

  16. [Abilities of acetaldehyde removal in different water-treating techniques].

    PubMed

    Zhang, Chun-Lei; Wang, Dan; Wang, Dong-Sheng; Chen, Chao; Fan, Kang-Ping

    2011-03-01

    The effect of acetaldehyde removal by several kinds of water-treating technologies is experienced in laboratory and the results reveal that traditional water-treating processes have hardly any useful results and the absorption of GAC does no better either for its efficiency depending on the GAC service time greatly and with a very short leakage time. However, the micro-biological degradation process in the BAC filter can consume more than 95% acetaldehyde in 13 minutes when the biomass has been fully acclimatized. The acclimation process usually lasts 4-30 h under field conditions depending on the stabilization and maturity of the original biomass on the carbon, but can be shortened remarkably by means of inhibiting the activity of existing biomass or artificially inoculating acclimatized microbe. PMID:21634164

  17. Fibulin-3-mediated inhibition of epithelial-to-mesenchymal transition and self-renewal of ALDH+ lung cancer stem cells through IGF1R signaling.

    PubMed

    Kim, I G; Kim, S Y; Choi, S I; Lee, J H; Kim, K C; Cho, E W

    2014-07-24

    Fibulins (FBLNs), a family of extracellular matrix proteins, have recently been shown to act as tumor suppressors or activators in different cancers, and the underlying molecular mechanisms of their action in cancer remain unclear. We have previously shown that the expression of FBLN3 is suppressed by promoter hypermethylation and is associated with invasiveness in aggressive non-small cell lung cancer. In this study, we evaluated the roles and signaling mechanism of FBLN3 in lung cancer stem cells (CSCs). Forced expression of FBLN3 suppressed invasion and migration of lung adenocarcinoma cells and decreased the expression of epithelial-to-mesenchymal transition (EMT) activators, including N-cadherin and Snail. Stemness activities of lung adenocarcinoma cells were also suppressed by FBLN3 as indicated by a decrease in spheroid formation and the levels of stemness markers such as Sox2 and β-catenin. These effects of FBLN3 were mediated by the glycogen synthase kinase-3β, GSK3β/β-catenin pathway, and the upstream regulators of GSK3β, including phosphoinositide 3-kinase (PI3K)/AKT and insulin-like growth factor-1 receptor (IGF1R), were inactivated by FBLN3. Moreover, IGF1R was shown to be a direct target of FBLN3, which competitively inhibited insulin-like growth factor (IGF) action. To confirm the effect of FBLN3 on lung CSCs, aldehyde dehydrogenase-positive (ALDH+) A549 lung CSCs were sorted and treated with recombinant FBLN3 protein. FBLN3 clearly suppressed EMT, stemness activity and the over-activated IGF1R/PI3K/AKT/GSK3β pathway of the ALDH+ CSC subpopulation. In addition, injection of recombinant FBLN3 protein around subcutaneous xenografts established with ALDH+ CSCs in athymic nude mice significantly suppressed tumor growth and progression. Overall, our results show that FBLN3 suppresses both EMT and self-renewal of the lung CSCs by modulating the IGF1R/PI3K/AKT/GSK3β pathway and that FBLN3 would be useful as an alternative CSC therapy. PMID:24013232

  18. Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats

    PubMed Central

    Peer, Cody J.; Strope, Jonathan D.; Beedie, Shaunna; Ley, Ariel M.; Holly, Alesia; Calis, Karim; Farkas, Ronald; Parepally, Jagan; Men, Angela; Fadiran, Emmanuel O.; Scott, Pamela; Jenkins, Marjorie; Theodore, William H.; Sissung, Tristan M.

    2016-01-01

    Objectives: The recommended zolpidem starting dose was lowered in females (5 mg vs. 10 mg) since side effects were more frequent and severe than those of males; the mechanism underlying sex differences in pharmacokinetics (PK) is unknown. We hypothesized that such differences were caused by known sex-related variability in alcohol dehydrogenase (ADH) expression. Methods: Male, female, and castrated male rats were administered 2.6 mg/kg zolpidem, ± disulfiram (ADH/ALDH pathway inhibitor) to compare PK changes induced by sex and gonadal hormones. PK analyses were conducted in rat plasma and rat brain. Key findings: Sex differences in PK were evident: females had a higher CMAX (112.4 vs. 68.1 ug/L) and AUC (537.8 vs. 231.8 h∗ug/L) than uncastrated males. Castration induced an earlier TMAX (0.25 vs. 1 h), greater CMAX (109.1 vs. 68.1 ug/L), and a corresponding AUC increase (339.7 vs. 231.8 h∗ug/L). Administration of disulfiram caused more drastic CMAX and TMAX changes in male vs. female rats that mirrored the effects of castration on first-pass metabolism, suggesting that the observed PK differences may be caused by ADH/ALDH expression. Brain concentrations paralleled plasma concentrations. Conclusion: These findings indicate that sex differences in zolpidem PK are influenced by variation in the expression of ADH/ALDH due to gonadal androgens. PMID:27574509

  19. Aldehyde Dehydrogenase Expression Drives Human Regulatory T Cell Resistance to Posttransplantation Cyclophosphamide

    PubMed Central

    Kanakry, Christopher G.; Ganguly, Sudipto; Zahurak, Marianna; Bolaños-Meade, Javier; Thoburn, Christopher; Perkins, Brandy; Fuchs, Ephraim J.; Jones, Richard J.; Hess, Allan D.; Luznik, Leo

    2014-01-01

    High-dose, posttransplantation cyclophosphamide (PTCy) is an effective strategy for preventing graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT). However, the mechanisms by which PTCy modulates alloimmune responses are not well understood. We studied early T cell reconstitution in patients undergoing alloBMT with PTCy and the effects of mafosfamide, a cyclophosphamide (Cy) analog, on CD4+ T cells in allogeneic mixed lymphocyte reactions (MLRs) in vitro. Patients exhibited reductions in naïve, potentially alloreactive conventional CD4+ T cells with relative preservation of memory CD4+Foxp3+ T cells. In particular, CD4+CD45RA−Foxp3+hi effector regulatory T cells (Tregs) recovered rapidly after alloBMT and, unexpectedly, were present at higher levels in patients with GVHD. CD4+Foxp3+ T cells from patients and from allogeneic MLRs expressed relatively high levels of aldehyde dehydrogenase (ALDH), the major in vivo mechanism of Cy resistance. Treatment of MLR cultures with the ALDH inhibitor diethylaminobenzaldehyde reduced the activation and proliferation of CD4+ T cells and sensitized Tregs to mafosfamide. Finally, removing Tregs from peripheral blood lymphocyte grafts obviated PTCy's GVHD-protective effect in a xenogeneic transplant model. Together, these findings suggest that Treg resistance to Cy through expression of ALDH may contribute to the clinical activity of PTCy in preventing GVHD. PMID:24225944

  20. Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice.

    PubMed

    Kim-Muller, Ja Young; Fan, Jason; Kim, Young Jung R; Lee, Seung-Ah; Ishida, Emi; Blaner, William S; Accili, Domenico

    2016-01-01

    Insulin-producing β cells become dedifferentiated during diabetes progression. An impaired ability to select substrates for oxidative phosphorylation, or metabolic inflexibility, initiates progression from β-cell dysfunction to β-cell dedifferentiation. The identification of pathways involved in dedifferentiation may provide clues to its reversal. Here we isolate and functionally characterize failing β cells from various experimental models of diabetes and report a striking enrichment in the expression of aldehyde dehydrogenase 1 isoform A3 (ALDH(+)) as β cells become dedifferentiated. Flow-sorted ALDH(+) islet cells demonstrate impaired glucose-induced insulin secretion, are depleted of Foxo1 and MafA, and include a Neurogenin3-positive subset. RNA sequencing analysis demonstrates that ALDH(+) cells are characterized by: (i) impaired oxidative phosphorylation and mitochondrial complex I, IV and V; (ii) activated RICTOR; and (iii) progenitor cell markers. We propose that impaired mitochondrial function marks the progression from metabolic inflexibility to dedifferentiation in the natural history of β-cell failure. PMID:27572106

  1. Formaldehyde and acetaldehyde emissions from residential wood combustion in Portugal

    NASA Astrophysics Data System (ADS)

    Cerqueira, Mário; Gomes, Luís; Tarelho, Luís; Pio, Casimiro

    2013-06-01

    A series of experiments were conducted to characterize formaldehyde and acetaldehyde emissions from residential combustion of common wood species growing in Portugal. Five types of wood were investigated: maritime pine (Pinus pinaster), eucalyptus (Eucalyptus globulus), cork oak (Quercus suber), holm oak (Quercus rotundifolia) and pyrenean oak (Quercus pyrenaica). Laboratory experiments were performed with a typical wood stove used for domestic heating in Portugal and operating under realistic home conditions. Aldehydes were sampled from diluted combustion flue gas using silica cartridges coated with 2,4-dinitrophenylhydrazine and analyzed by high performance liquid chromatography with diode array detection. The average formaldehyde to acetaldehyde concentration ratio (molar basis) in the stove flue gas was in the range of 2.1-2.9. Among the tested wood types, pyrenean oak produced the highest emissions for both formaldehyde and acetaldehyde: 1772 ± 649 and 1110 ± 454 mg kg-1 biomass burned (dry basis), respectively. By contrast, maritime pine produced the lowest emissions: 653 ± 151 and 371 ± 162 mg kg-1 biomass (dry basis) burned, respectively. Aldehydes were sampled separately during distinct periods of the holm oak wood combustion cycles. Significant variations in the flue gas concentrations were found, with higher values measured during the devolatilization stage than in the flaming and smoldering stages.

  2. The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1

    PubMed Central

    Scharer, Gunter; Brocker, Chad; Vasiliou, Vasilis; Creadon-Swindell, Geralyn; Gallagher, Renata C.; Spector, Elaine

    2011-01-01

    Pyridoxine-dependent epilepsy is a disorder associated with severe seizures that may be caused by deficient activity of α-aminoadipic semialdehyde dehydrogenase, encoded by the ALDH7A1 gene, with accumulation of α-aminoadipic semialdehyde and piperideine-6-carboxylic acid. The latter reacts with pyridoxal-phosphate, explaining the effective treatment with pyridoxine. We report the clinical phenotype of three patients, their mutations and those of 12 additional patients identified in our clinical molecular laboratory. There were six missense, one nonsense, and five splice-site mutations, and two small deletions. Mutations c.1217_1218delAT, I431F, IVS-1(+2)T>G, IVS-2(+1)G>A, and IVS-12(+1)G>A are novel. Some disease alleles were recurring: E399Q (eight times), G477R (six times), R82X (two times), and c.1217_1218delAT (two times). A systematic review of mutations from the literature indicates that missense mutations cluster around exons 14, 15, and 16. Nine mutations represent 61% of alleles. Molecular modeling of missense mutations allows classification into three groups: those that affect NAD+binding or catalysis, those that affect the substrate binding site, and those that affect multimerization. There are three clinical phenotypes: patients with complete seizure control with pyridoxine and normal developmental outcome (group 1) including our first patient; patients with complete seizure control with pyridoxine but with developmental delay (group 2), including our other two patients; and patients with persistent seizures despite pyridoxine treatment and with developmental delay (group 3). There is preliminary evidence for a genotype-phenotype correlation with patients from group 1 having mutations with residual activity. There is evidence from patients with similar genotypes for nongenetic factors contributing to the phenotypic spectrum. PMID:20814824

  3. On the Reaction Mechanism of Acetaldehyde Decomposition on Mo(110)

    SciTech Connect

    Mei, Donghai; Karim, Ayman M.; Wang, Yong

    2012-02-16

    The strong Mo-O bond strength provides promising reactivity of Mo-based catalysts for the deoxygenation of biomass-derived oxygenates. Combining the novel dimer saddle point searching method with periodic spin-polarized density functional theory calculations, we investigated the reaction pathways of a acetaldehyde decomposition on the clean Mo(110) surface. Two reaction pathways were identified, a selective deoxygenation and a nonselective fragmentation pathways. We found that acetaldehyde preferentially adsorbs at the pseudo 3-fold hollow site in the η2(C,O) configuration on Mo(110). Among four possible bond (β-C-H, γ-C-H, C-O and C-C) cleavages, the initial decomposition of the adsorbed acetaldehyde produces either ethylidene via the C-O bond scission or acetyl via the β-C-H bond scission while the C-C and the γ-C-H bond cleavages of acetaldehyde leading to the formation of methyl (and formyl) and formylmethyl are unlikely. Further dehydrogenations of ethylidene into either ethylidyne or vinyl are competing and very facile with low activation barriers of 0.24 and 0.31 eV, respectively. Concurrently, the formed acetyl would deoxygenate into ethylidyne via the C-O cleavage rather than breaking the C-C or the C-H bonds. The selective deoxygenation of acetaldehyde forming ethylene is inhibited by relatively weaker hydrogenation capability of the Mo(110) surface. Instead, the nonselective pathway via vinyl and vinylidene dehydrogenations to ethynyl as the final hydrocarbon fragment is kinetically favorable. On the other hand, the strong interaction between ethylene and the Mo(110) surface also leads to ethylene decomposition instead of desorption into the gas phase. This work was financially supported by the National Advanced Biofuels Consortium (NABC). Computing time was granted by a user project (emsl42292) at the Molecular Science Computing Facility in the William R. Wiley Environmental Molecular Sciences Laboratory (EMSL). This work was financially supported

  4. Purification and properties of the inducible coenzyme A-linked butyraldehyde dehydrogenase from Clostridium acetobutylicum.

    PubMed Central

    Palosaari, N R; Rogers, P

    1988-01-01

    The coenzyme A (CoA)-linked butyraldehyde dehydrogenase (BAD) from Clostridium acetobutylicum was characterized and purified to homogeneity. The enzyme was induced over 200-fold, coincident with a shift from an acidogenic to a solventogenic fermentation, during batch culture growth. The increase in enzyme activity was found to require new protein synthesis since induction was blocked by the addition of rifampin and antibody against the purified enzyme showed the appearance of enzyme antigen beginning at the shift of the fermentation and increasing coordinately with the increase in enzyme specific activity. The CoA-linked acetaldehyde dehydrogenase was copurified with BAD during an 89-fold purification, indicating that one enzyme accounts for the synthesis of the two aldehyde intermediates for both butanol and ethanol production. Butanol dehydrogenase activity was clearly separate from the BAD enzyme activity on TEAE cellulose. A molecular weight of 115,000 was determined for the native enzyme, and the enzyme subunit had a molecular weight of 56,000 indicating that the active form is a homodimer. Kinetic constants were determined in both the forward and reverse directions. In the reverse direction both the Vmax and the apparent affinity for butyraldehyde and caproaldehyde were significantly greater than they were for acetaldehyde, while in the forward direction, the Vmax for butyryl-CoA was fivefold that for acetyl-CoA. These and other properties of BAD indicate that this enzyme is distinctly different from other reported CoA-dependent aldehyde dehydrogenases. Images PMID:3384801

  5. Acetone and Acetaldehyde Exchange Above a Managed Temperate Mountain Grassland

    NASA Astrophysics Data System (ADS)

    Hörtnagl, L. J.; Bamberger, I.; Graus, M.; Ruuskanen, T.; Schnitzhofer, R.; Hansel, A.; Wohlfahrt, G.

    2011-12-01

    The exchange of acetone and acetaldehyde was measured above an intensively managed hay meadow in the Stubai Valley (Tyrol, Austria) during the growing seasons in 2008 and 2009. Half-hourly fluxes of both compounds were calculated by means of the virtual disjunct eddy covariance (vDEC) method by combining the 3-dimensional wind data from a sonic anemometer with the compound specific volume mixing ratios quantified with a proton-transfer-reaction mass spectrometer (PTR-MS). The cutting of the meadow resulted in the largest perturbation of the VOC exchange rates. Peak emissions for both VOC species were observed during and right after the cutting of the meadow, with rates of up to 12.1 and 10.1 nmol m-2 s-1 for acetaldehyde and acetone, respectively, reflecting the drying of the wounded plant material. During certain time periods, undisturbed by management events, both compounds exhibited a clear diurnal cycle. Emission rates of up to 3.7 nmol m-2 s-1 for acetaldehyde and 3.2 nmol m-2 s-1 for acetone were measured in October 2008, while a uptake of both compounds with rates of up to 1.8 and 2.1 nmol m-2 s-1, respectively, could be observed in May 2009, when also clear compensation points of 0.3 ppb for acetaldehyde and 1.0 ppb for acetone were observed. In an effort to explore the controls on observed exchange patterns, a simple and multiple linear regression analysis was conducted. A clear interconnection between VOC concentrations and VOC exchange could be seen only in May 2009, when concentration values alone explained 30.6% and 11.7% of the acetaldehyde and acetone flux variance, respectively. However, when trying to predict the observed exchange patterns of both VOC species in a multiple linear regression based on supporting environmental measurements - including air and soil temperature, soil water content and PAR among others - the analysis yielded unsatisfactory results, accounting for 10% and 4% of the observed acetaldehyde and acetone flux variance over both

  6. A coniferyl aldehyde dehydrogenase gene from Pseudomonas sp. strain HR199 enhances the conversion of coniferyl aldehyde by Saccharomyces cerevisiae.

    PubMed

    Adeboye, Peter Temitope; Olsson, Lisbeth; Bettiga, Maurizio

    2016-07-01

    The conversion of coniferyl aldehyde to cinnamic acids by Saccharomyces cerevisiae under aerobic growth conditions was previously observed. Bacteria such as Pseudomonas have been shown to harbor specialized enzymes for converting coniferyl aldehyde but no comparable enzymes have been identified in S. cerevisiae. CALDH from Pseudomonas was expressed in S. cerevisiae. An acetaldehyde dehydrogenase (Ald5) was also hypothesized to be actively involved in the conversion of coniferyl aldehyde under aerobic growth conditions in S. cerevisiae. In a second S. cerevisiae strain, the acetaldehyde dehydrogenase (ALD5) was deleted. A prototrophic control strain was also engineered. The engineered S. cerevisiae strains were cultivated in the presence of 1.1mM coniferyl aldehyde under aerobic condition in bioreactors. The results confirmed that expression of CALDH increased endogenous conversion of coniferyl aldehyde in S. cerevisiae and ALD5 is actively involved with the conversion of coniferyl aldehyde in S. cerevisiae. PMID:27070284

  7. Effect of acetaldehyde on Saccharomyces cerevisiae and Zymomonas mobilis subjected to environmental shocks

    SciTech Connect

    Stanley, G.A.; Hobley, T.J.; Pamment, N.B.

    1997-01-05

    The lag phase of Saccharomyces cerevisiae subjected to a step increase in temperature or ethanol concentration was reduced by as much as 60% when acetaldehyde was added to the medium at concentrations less than 0.1 g/L. Maximum specific growth rates were also substantially increased. Even greater proportional reductions in lag time due to acetaldehyde addition were observed for ethanol-shocked cultures of Zymomonas mobilis. Acetaldehyde had no effect on S. cerevisiae cultures started from stationary phase inocula in the absence of environmental shock and its lag-reducing effects were greater in complex medium than in a defined synthetic medium. Acetaldehyde reacted strongly with the ingredients of complex culture media. It is proposed that the effect of added acetaldehyde may be to compensate for the inability of cells to maintain transmembrane acetaldehyde gradients following an environmental shock.

  8. Adsorption and Reaction of Acetaldehyde over CeO(X)(111) Thin Films

    SciTech Connect

    Chen, Tsung-Liang; Mahurin, Shannon Mark

    2011-01-01

    This study reports the interaction of acetaldehyde with well-ordered CeO{sub X}(111) thin film surfaces. The fully oxidized CeO{sub 2}(111) surface shows a weak interaction with acetaldehyde with the sole desorption product (TPD) being the parent molecule at 210 K. The chemisorbed molecule binds to the surface as the {eta}{sub 1}-acetaldehyde species rather than through a bridge-bonded dioxy configuration. Acetaldehyde chemisorbs strongly on reduced CeO{sub 2-X}(111) with nonrecombinative and recombinative acetaldehyde desorbing at 405 and 550-600 K, respectively. Deoxygenation and dehydration also occur, producing ethylene and acetylene at 580 and 620 K, respectively. Acetaldehyde initially adsorbs in the {eta}{sub 1} configuration and then converts to a carbanion species with both C=C and C=O bond character above 300 K.

  9. Adsorption and Reaction of Acetaldehyde over CeOx(111) Thin Films

    SciTech Connect

    T Chen; D Mullins

    2011-12-31

    This study reports the interaction of acetaldehyde with well-ordered CeO{sub X}(111) thin film surfaces. The fully oxidized CeO{sub 2}(111) surface shows a weak interaction with acetaldehyde with the sole desorption product (TPD) being the parent molecule at 210 K. The chemisorbed molecule binds to the surface as the {eta}{sub 1}-acetaldehyde species rather than through a bridge-bonded dioxy configuration. Acetaldehyde chemisorbs strongly on reduced CeO{sub 2-X}(111) with nonrecombinative and recombinative acetaldehyde desorbing at 405 and 550-600 K, respectively. Deoxygenation and dehydration also occur, producing ethylene and acetylene at 580 and 620 K, respectively. Acetaldehyde initially adsorbs in the {eta}{sub 1} configuration and then converts to a carbanion species with both C {double_bond} C and C {double_bond} O bond character above 300 K.

  10. The role of acetaldehyde in the pathogenesis of acute alcoholic pancreatitis.

    PubMed Central

    Nordback, I H; MacGowan, S; Potter, J J; Cameron, J L

    1991-01-01

    Acetaldehyde (AA), the first product of ethanol metabolism, has been suggested as an important mediator in alcoholic pancreatitis, but experimental evidence has not been convincing. Prior work using the isolated perfused canine pancreas preparation has suggested that toxic oxygen metabolites generated by xanthine oxidase (XO) may mediate the early injury in pancreatitis. Xanthine oxidase is capable of oxidizing AA, and during this oxidation free radicals are released. The hypothesis that acute alcoholic pancreatitis may be initiated by AA in the presence of active XO (converted from xanthine dehydrogenase [XD]) was tested in the authors' experimental preparation by converting XD to XO by a period of ischemia, and infusing AA. Control preparations remained normal throughout the 4-hour perfusion (weight gain, 7 +/- 4 g; amylase activity, 1162 +/- 202 U/dL). One hour of ischemia or infusion of AA at 25 mg/hr or at 50 mg/hr without ischemia did not induce changes in the preparation. Acetaldehyde at 250 mg/hr induced minimal edema and weight gain (16 +/- 4 g; p less than 0.05), but not significant hyperamylasemia. Changes also were not observed when 1-hour ischemia was followed by a bolus of ethanol (1.5 g) or sodium acetate (3.0 g), or by infusion of 25 mg/hr of AA. One hour of ischemia followed by infusion of AA at 50 mg/hr or at 250 mg/hr induced edema, hemorrhage, weight gain (22 +/- 7 g [p less than 0.05] and 26 +/- 17 g [p less than 0.05]) and hyperamylasemia (2249 +/- 1034 U/dL [p less than 0.05] and 2602 +/- 1412 U/dL [p less than 0.05]). Moreover infusion of AA at 250 mg/hr after 2 hours of ischemia potentiated the weight gain (62 +/- 20 g versus 30 +/- 14 g [p less than 0.05]), but not the hyperamylasemia (3404 +/- 589 U/dL versus 2862 +/- 1525 U/dL) as compared with 2 hours of ischemia alone. Pancreatitis induced by 1 hour of ischemia followed by AA at 50 mg/hr could be inhibited by pretreatment with the free radical scavengers superoxide dismutase and

  11. Divergent pathways of acetaldehyde and ethanol decarbonylation on the Rh(111) surface

    SciTech Connect

    Houtman, C.J.; Barteau, M.A. )

    1991-08-01

    The decomposition reactions of acetaldehyde and ethanol on the Rh(111) surface were compared in temperature-programmed desorption (TPD) and high-resolution electron energy loss spectroscopy (HREELS) experiments. The decarbonylation of acetaldehyde produced methane at 267 K in TPD. For acetaldehyde coverages less than 0.05 monolayer, no methane was desorbed, but for a coverage that saturated the first layer, methane was produced with 50% selectivity. Coadsorbing deuterium with a low coverage of acetaldehyde resulted in the enhancement of methane production. This result indicates that the selectivity to methane was partially controlled by the availability of hydrogen atoms on the surface required to hydrogenate the hydrocarbon species produced by acetaldehyde decarbonylation. Monodeuterated methane was the primary methane product observed after these coadsorption experiments. Thus it was concluded that acetaldehyde decarbonylates via a methyl migration mechanism on the Rh(111) surface. Decarbonylation of ethanol did not produce methane. The absence of methane production indicated that the decomposition of ethanol on the Rh(111) surface did not proceed via dehydrogenation to adsorbed acetaldehyde, but instead, ethanol appeared to dehydrogenate by methyl hydrogen abstraction resulting in the formation of an oxametallacycle. Since this proposed intermediate rapidly dehydrogenated to carbon monoxide and surface carbon, it was difficult to characterize spectroscopically. The existence of an ethanol decomposition pathway that does not include acetaldehyde intermediates indicates that ethanol formation on supported Rh catalysts may not be the result of acetaldehyde hydrogenation.

  12. Accumulation of ALDH1-positive cells after neoadjuvant chemotherapy predicts treatment resistance and prognosticates poor outcome in ovarian cancer

    PubMed Central

    Debald, Manuel; Rostamzadeh, Babak; Thiesler, Thore; Schröder, Lars; Barchet, Winfried; Abramian, Alina; Kaiser, Christina; Kristiansen, Glen; Kuhn, Walther; Kübler, Kirsten

    2015-01-01

    Although ovarian cancer is a highly chemosensitive disease, it is only infrequently cured. One of the major reasons lies in the presence of drug-resistant cancer stem-like cells, sufficient to fuel recurrence. We phenotyped cancer stem-like cells by flow cytometry and immunohistochemistry in 55 matched samples before and after taxane/platinum-based neoadjuvant chemotherapy. All used markers of stemness (ALDH1, CD24, CD117, CD133) isolated low frequencies of malignant cells. ALDH1 was the most valuable marker for tracking stemness in vivo. The enrichment of ALDH1 expression after treatment was associated with a poor response to chemotherapy, with platinum resistance and independently prognosticated unfavorable outcome. Our results suggest that increased ALDH1 expression after treatment identifies patients with aggressive tumor phenotypes. PMID:25999351

  13. Accumulation of ALDH1-positive cells after neoadjuvant chemotherapy predicts treatment resistance and prognosticates poor outcome in ovarian cancer.

    PubMed

    Ayub, Tiyasha H; Keyver-Paik, Mignon-Denise; Debald, Manuel; Rostamzadeh, Babak; Thiesler, Thore; Schröder, Lars; Barchet, Winfried; Abramian, Alina; Kaiser, Christina; Kristiansen, Glen; Kuhn, Walther; Kübler, Kirsten

    2015-06-30

    Although ovarian cancer is a highly chemosensitive disease, it is only infrequently cured. One of the major reasons lies in the presence of drug-resistant cancer stem-like cells, sufficient to fuel recurrence. We phenotyped cancer stem-like cells by flow cytometry and immunohistochemistry in 55 matched samples before and after taxane/platinum-based neoadjuvant chemotherapy. All used markers of stemness (ALDH1, CD24, CD117, CD133) isolated low frequencies of malignant cells. ALDH1 was the most valuable marker for tracking stemness in vivo. The enrichment of ALDH1 expression after treatment was associated with a poor response to chemotherapy, with platinum resistance and independently prognosticated unfavorable outcome. Our results suggest that increased ALDH1 expression after treatment identifies patients with aggressive tumor phenotypes. PMID:25999351

  14. Tea triterpenoidal saponins from the roots of Camellia sinensis have inhibitory effects against alcohol dehydrogenase.

    PubMed

    Varughese, Titto; Manir, Md Maniruzzaman; Rahaman, Mozahidur; Kim, Jeong Kee; Lee, Byeong-Gon; Moon, Surk-Sik

    2011-12-01

    Ten new polyhydroxyolean-12-ene pentacyclic triterpenoidal saponins, named rogchaponins 1-10, were isolated from the methanolic extract of the roots of Camellia sinensis by a series of chromatographic methods (silica gel flash column and C18 MPLC followed by C18 HPLC). Their structures were established by 1D and 2D-NMR techniques along with IR and HR-TOF-MS. Rogchaponins R4 ( 4) and R5 (5) showed inhibitory activities against yeast alcohol dehydrogenase (ADH) with IC (50) values of 16.1 ± 3.2 and 15.4 ± 3.3 µM, respectively. A 4-methylpyrazole positive control exhibited an IC (50) of 2750 ± 50 µM. However, the saponins showed no inhibitory activity against yeast aldehyde dehydrogenase (ALDH). PMID:21786220

  15. Terahertz Spectroscopy of Deuterated Acetaldehyde: CH_2DCHO

    NASA Astrophysics Data System (ADS)

    Margulès, L.; Motiyenko, R. A.; Coudert, L. H.; Guillemin, J.-C.

    2014-06-01

    This study follows our recent investigations about deuterated methyl-top species of complex organic molecules: methanol, methyl formate, In particular these works led the first ISM detection of HCOOCH_2D and CH_2DOCH_3. Acetaldehyde is not very abundant in the ISM, but this is a very interesting case from the spectroscopic point of view as it is an intermediate case between methyl formate and methanol. In the normal species of acetaldehyde, the barrier to internal rotation which is close to the value in methyl formate: 373 cm-1. However, the value of the Coriolis coupling constant ρ is 0.33 in acetaldehyde which is a much larger value than in methyl formate, 0.08, meaning that the coupling between the torsion and the overall rotation is more important. The sample was not a commercial one and half of its amount is the normal species which leads to a more difficult line assignment. The spectra were recorded in Lille between 75 and 950 GHz with a solid-state submillimeter-wave spectrometer. The starting point of the analysis was the centimeter-wave measurements carried out for the sym and asym- conformers. A comparison between the approach developed for deuterated methyl formate (HCOOCH_2D), based on the water dimer formalism, and that designed recently for deuterated methanola (CH_2DOH) will be presented. This work is supported by the CNES and the Action sur Projets de l'INSU, PCMI. Coudert, L. H.; et al. J. Chem. Phys., 140, (2014) 64307 Coudert, L. H.; et al. ApJ, 779, (2013) 119 Richard, C.; et al. A&A, 552, (2013) A117 Smirnov, I. A.; et al. J. Mol. Spectrosc., 295 (2014) 44 Ilyushin, V.; et al. J. Mol. Spectrosc., 255 (2009) 32 Turner, P. H.; and Cox, A. P. Chem. Phys. Lett., 42, (1976) 84 Turner, P. H.; Cox, A. P.; and Hardy, J. A. J.C.S. Farady Trans., 2, (1981) 1217

  16. Structural Determinants of Oligomerization of !1-Pyrroline-5-Carboxylate Dehydrogenase: Identification of a Hexamerization Hot Spot

    PubMed Central

    Luo, Min; Singh, Ranjan K.; Tanner, John J.

    2013-01-01

    The aldehyde dehydrogenase (ALDH) superfamily member !1-pyrroline-5-carboxylate dehydrogenase (P5CDH) catalyzes the NAD+-dependent oxidation of glutamate semialdehyde to glutamate, which is the final step of proline catabolism. Defects in P5CDH activity lead to the metabolic disorder type II hyperprolinemia, P5CDH is essential for virulence of the fungal pathogen Cryptococcus neoformans, and bacterial P5CDHs have been targeted for vaccine development. Although the enzyme oligomeric state is known to be important for ALDH function, the oligomerization of P5CDH has remained relatively unstudied. Here we determine the oligomeric states and quaternary structures of four bacterial P5CDHs using a combination of small-angle X-ray scattering, X-ray crystallography, and dynamic light scattering. The P5CDHs from Thermus thermophilus and Deinococcus radiodurans form trimer-of-dimers hexamers in solution, which is the first observation of a hexameric ALDH in solution. In contrast, two Bacillus P5CDHs form dimers in solution but do not assemble into a higher order oligomer. Site-directed mutagenesis was used to identify a hexamerization hot spot that is centered on an arginine residue in the NAD+-binding domain. Mutation of this critical Arg residue to Ala in either of the hexameric enzymes prevents hexamer formation in solution. Paradoxically, the dimeric Arg-to-Ala T. thermophilus mutant enzyme packs as a hexamer in the crystal state, which illustrates the challenges associated with predicting the biological assembly in solution from crystal structures. The observation of different oligomeric states among P5CDHs suggests potential differences in cooperativity and protein-protein interactions. PMID:23747974

  17. ALDH1A1 provides a source of meiosis-inducing retinoic acid in mouse fetal ovaries

    PubMed Central

    Bowles, Josephine; Feng, Chun-Wei; Miles, Kim; Ineson, Jessica; Spiller, Cassy; Koopman, Peter

    2016-01-01

    Substantial evidence exists that during fetal ovarian development in mammals, retinoic acid (RA) induces germ cells to express the pre-meiotic marker Stra8 and enter meiosis, and that these effects are prevented in the fetal testis by the RA-degrading P450 enzyme CYP26B1. Nonetheless, the role of RA has been disputed principally because germ cells in embryos lacking two major RA-synthesizing enzymes, ALDH1A2 and ALDH1A3, remain able to enter meiosis. Here we show that a third RA-synthesizing enzyme, ALDH1A1, is expressed in fetal ovaries, providing a likely source of RA in the absence of ALDH1A2 and ALDH1A3. In ovaries lacking ALDH1A1, the onset of germ cell meiosis is delayed. Our data resolve the conundrum posed by conflicting published data sets and reconfirm the model that meiosis is triggered by endogenous RA in the developing ovary. PMID:26892828

  18. The absence of aldehyde dehydrogenase 1 A1-positive cells in benign mammary stroma is associated with risk factors for breast cancer

    PubMed Central

    Isfoss, Björn Logi; Holmqvist, Bo; Jernström, Helena; Alm, Per; Olsson, Håkan

    2016-01-01

    In this study, aldehyde dehydrogenase 1 (ALDH1)-expressing cells in stroma of histologically normal breast tissue from premenopausal women were investigated in situ regarding cellular morphology, cell distribution, and relation to the additional stem cell markers, CD44 (+) and CD24 (−). These results were correlated with hormonal and genetic risk factors for breast cancer. Triple immunofluorescence labeling was performed on tissues from premenopausal women with a family history of breast cancer, and breast reduction specimens from premenopausal women with no family history of breast cancer were used as a control group. The majority of ALDH1-immunoreactive cells in stroma were spindle-shaped or polygonal, and such cells that were CD44− and CD24− were absent in the breast stroma of a significantly larger number of nulliparous than parous women. A less common morphological type of ALDH1-positive cells in stroma was round or oval in shape, and such cells that were CD44+ and CD24− were absent in a significant number of women with a family history of breast cancer. The CD44+/CD24− immunophenotype is consistent with stem cells, and the round/oval morphology suggests mesenchymal cells. This study demonstrates that there are two morphologically distinct types of ALDH1-positive cells in histologically benign mammary stroma, and the absence of these cells is correlated with clinical risk factors for breast cancer in premenopausal women. PMID:27313475

  19. The absence of aldehyde dehydrogenase 1 A1-positive cells in benign mammary stroma is associated with risk factors for breast cancer.

    PubMed

    Isfoss, Björn Logi; Holmqvist, Bo; Jernström, Helena; Alm, Per; Olsson, Håkan

    2016-01-01

    In this study, aldehyde dehydrogenase 1 (ALDH1)-expressing cells in stroma of histologically normal breast tissue from premenopausal women were investigated in situ regarding cellular morphology, cell distribution, and relation to the additional stem cell markers, CD44 (+) and CD24 (-). These results were correlated with hormonal and genetic risk factors for breast cancer. Triple immunofluorescence labeling was performed on tissues from premenopausal women with a family history of breast cancer, and breast reduction specimens from premenopausal women with no family history of breast cancer were used as a control group. The majority of ALDH1-immunoreactive cells in stroma were spindle-shaped or polygonal, and such cells that were CD44(-) and CD24(-) were absent in the breast stroma of a significantly larger number of nulliparous than parous women. A less common morphological type of ALDH1-positive cells in stroma was round or oval in shape, and such cells that were CD44(+) and CD24(-) were absent in a significant number of women with a family history of breast cancer. The CD44(+)/CD24(-) immunophenotype is consistent with stem cells, and the round/oval morphology suggests mesenchymal cells. This study demonstrates that there are two morphologically distinct types of ALDH1-positive cells in histologically benign mammary stroma, and the absence of these cells is correlated with clinical risk factors for breast cancer in premenopausal women. PMID:27313475

  20. Genomic organization and expression of the human fatty aldehyde dehydrogenase gene (FALDH)

    SciTech Connect

    Rogers, G.R.; Markova, N.G.; Compton, J.G.

    1997-01-15

    Mutations in the fatty aldehyde dehydrogenase (FALDH) gene cause Sjoegren-Larsson syndrome (SLS) - a disease characterized by mental retardation, spasticity, and congenital ichthyosis. To facilitate mutation analysis in SLS and to study the pathogenesis of FALDH deficiency, we have determined the structural organization and characterized expression of the FALDH (proposed designation ALDH10) gene. The gene consists of 10 exons spanning about 30.5 kb. A TATA-less promoter is associated with the major transcription initiation site found to be 258 hp upstream of the ATG codon. The G4C-rich sequences surrounding the transcription initiation site encompassed regulatory elements that interacted with proteins in HeLa nuclear extracts and were able to promote transcription in vitro. FALDH is widely expressed as three transcripts of 2, 3.8, and 4.0 kb, which originate from multiple polyadenylation signals in the 3{prime} UTR. An alternatively spliced mRNA was detected that contains an extra exon and encodes an enzyme that is likely to have altered membrane-binding properties. The FALDH gene lies only 50-85 kb from ALDH3, an aldehyde dehydrogenase gene that has homologous sequence and intron/exon structure. 25 refs., 4 figs., 1 tab.

  1. Acetaldehyde stimulates monocyte adhesion in a P-selectin- and TNFα-dependent manner

    PubMed Central

    Redmond, Eileen M.; Morrow, David; Kundimi, Sreenath; Miller-Graziano, Carol L.; Cullen, John P.

    2016-01-01

    Objective The aim of this study was to determine the effects of acetaldehyde on various steps of the monocyte recruitment cascade. Methods Human umbilical venous endothelial cells (HUVEC), primary blood monocytes (PBM) and THP-1 monocytes, were treated with acetaldehyde (0.1–0 μM) for 6 h. Monocyte adherence experiments were performed using 2′,7′-bis(2-carboxyethyl)-5,6-carboxyfluorescein-acetoxymethylester labeled PBM or 3H-thymidine labeled THP-1 cells. HUVEC TNFα mRNA and protein levels were determined by quantitative real-time PCR and immunoassay, respectively, and HUVEC P-selectin and monocyte CCR2 expression were determined by FACS analysis. Results Acetaldehyde dose-dependently increased the number of CCR2 positive THP-1 monocytes, with a maximal increase of ~50% observed in the presence of 10 μM acetaldehyde. There was a significant increase in both the number of P-selectin positive cells and P-selectin receptor density when HUVEC were incubated with acetaldehyde. HUVEC TNFα mRNA expression and secretion were enhanced by acetaldehyde. Moreover, acetaldehyde increased THP-1 and PBM adhesion to HUVEC. Inhibition of P-selectin or TNFα, using antibodies or siRNA-directed gene knockdown, attenuated acetaldehyde-induced monocyte adhesion. In conclusion, acetaldehyde increased the number of CCR2 positive monocytes and stimulated endothelial cell P-selectin and TNFα expression. Moreover, acetaldehyde increased monocyte adhesion to endothelial cells, an effect that was both P-selectin- and TNFα-dependent. Conclusion These effects of acetaldehyde may contribute, in part, to the increase in coronary heart disease that is associated with binge patterns of alcohol consumption. PMID:19036374

  2. Increasing Anaerobic Acetate Consumption and Ethanol Yields in Saccharomyces cerevisiae with NADPH-Specific Alcohol Dehydrogenase

    PubMed Central

    Henningsen, Brooks M.; Hon, Shuen; Covalla, Sean F.; Sonu, Carolina; Argyros, D. Aaron; Barrett, Trisha F.; Wiswall, Erin; Froehlich, Allan C.

    2015-01-01

    Saccharomyces cerevisiae has recently been engineered to use acetate, a primary inhibitor in lignocellulosic hydrolysates, as a cosubstrate during anaerobic ethanolic fermentation. However, the original metabolic pathway devised to convert acetate to ethanol uses NADH-specific acetylating acetaldehyde dehydrogenase and alcohol dehydrogenase and quickly becomes constrained by limited NADH availability, even when glycerol formation is abolished. We present alcohol dehydrogenase as a novel target for anaerobic redox engineering of S. cerevisiae. Introduction of an NADPH-specific alcohol dehydrogenase (NADPH-ADH) not only reduces the NADH demand of the acetate-to-ethanol pathway but also allows the cell to effectively exchange NADPH for NADH during sugar fermentation. Unlike NADH, NADPH can be freely generated under anoxic conditions, via the oxidative pentose phosphate pathway. We show that an industrial bioethanol strain engineered with the original pathway (expressing acetylating acetaldehyde dehydrogenase from Bifidobacterium adolescentis and with deletions of glycerol-3-phosphate dehydrogenase genes GPD1 and GPD2) consumed 1.9 g liter−1 acetate during fermentation of 114 g liter−1 glucose. Combined with a decrease in glycerol production from 4.0 to 0.1 g liter−1, this increased the ethanol yield by 4% over that for the wild type. We provide evidence that acetate consumption in this strain is indeed limited by NADH availability. By introducing an NADPH-ADH from Entamoeba histolytica and with overexpression of ACS2 and ZWF1, we increased acetate consumption to 5.3 g liter−1 and raised the ethanol yield to 7% above the wild-type level. PMID:26386051

  3. Increasing anaerobic acetate consumption and ethanol yields in Saccharomyces cerevisiae with NADPH-specific alcohol dehydrogenase.

    PubMed

    Henningsen, Brooks M; Hon, Shuen; Covalla, Sean F; Sonu, Carolina; Argyros, D Aaron; Barrett, Trisha F; Wiswall, Erin; Froehlich, Allan C; Zelle, Rintze M

    2015-12-01

    Saccharomyces cerevisiae has recently been engineered to use acetate, a primary inhibitor in lignocellulosic hydrolysates, as a cosubstrate during anaerobic ethanolic fermentation. However, the original metabolic pathway devised to convert acetate to ethanol uses NADH-specific acetylating acetaldehyde dehydrogenase and alcohol dehydrogenase and quickly becomes constrained by limited NADH availability, even when glycerol formation is abolished. We present alcohol dehydrogenase as a novel target for anaerobic redox engineering of S. cerevisiae. Introduction of an NADPH-specific alcohol dehydrogenase (NADPH-ADH) not only reduces the NADH demand of the acetate-to-ethanol pathway but also allows the cell to effectively exchange NADPH for NADH during sugar fermentation. Unlike NADH, NADPH can be freely generated under anoxic conditions, via the oxidative pentose phosphate pathway. We show that an industrial bioethanol strain engineered with the original pathway (expressing acetylating acetaldehyde dehydrogenase from Bifidobacterium adolescentis and with deletions of glycerol-3-phosphate dehydrogenase genes GPD1 and GPD2) consumed 1.9 g liter(-1) acetate during fermentation of 114 g liter(-1) glucose. Combined with a decrease in glycerol production from 4.0 to 0.1 g liter(-1), this increased the ethanol yield by 4% over that for the wild type. We provide evidence that acetate consumption in this strain is indeed limited by NADH availability. By introducing an NADPH-ADH from Entamoeba histolytica and with overexpression of ACS2 and ZWF1, we increased acetate consumption to 5.3 g liter(-1) and raised the ethanol yield to 7% above the wild-type level. PMID:26386051

  4. Plant Formate Dehydrogenase

    SciTech Connect

    John Markwell

    2005-01-10

    The research in this study identified formate dehydrogenase, an enzyme that plays a metabolic role on the periphery of one-carbon metabolism, has an unusual localization in Arabidopsis thaliana and that the enzyme has an unusual kinetic plasticity. These properties make it possible that this enzyme could be engineered to attempt to engineer plants with an improved photosynthetic efficiency. We have produced transgenic Arabidopsis and tobacco plants with increased expression of the formate dehydrogenase enzyme to initiate further studies.

  5. Aldh1 Expression and Activity Increase During Tumor Evolution in Sarcoma Cancer Stem Cell Populations

    PubMed Central

    Martinez-Cruzado, Lucia; Tornin, Juan; Santos, Laura; Rodriguez, Aida; García-Castro, Javier; Morís, Francisco; Rodriguez, Rene

    2016-01-01

    Tumors evolve from initial tumorigenic events into increasingly aggressive behaviors in a process usually driven by subpopulations of cancer stem cells (CSCs). Mesenchymal stromal/stem cells (MSCs) may act as the cell-of-origin for sarcomas, and CSCs that present MSC features have been identified in sarcomas due to their ability to grow as self-renewed floating spheres (tumorspheres). Accordingly, we previously developed sarcoma models using human MSCs transformed with relevant oncogenic events. To study the evolution/emergence of CSC subpopulations during tumor progression, we compared the tumorigenic properties of bulk adherent cultures and tumorsphere-forming subpopulations both in the sarcoma cell-of-origin models (transformed MSCs) and in their corresponding tumor xenograft-derived cells. Tumor formation assays showed that the tumorsphere cultures from xenograft-derived cells, but not from the cell-of-origin models, were enriched in CSCs, providing evidence of the emergence of bona fide CSCs subpopulations during tumor progression. Relevant CSC-related factors, such as ALDH1 and SOX2, were increasingly upregulated in CSCs during tumor progression, and importantly, the increased levels and activity of ALDH1 in these subpopulations were associated with enhanced tumorigenicity. In addition to being a CSC marker, our findings indicate that ALDH1 could also be useful for tracking the malignant potential of CSC subpopulations during sarcoma evolution. PMID:27292183

  6. Aldh1 Expression and Activity Increase During Tumor Evolution in Sarcoma Cancer Stem Cell Populations.

    PubMed

    Martinez-Cruzado, Lucia; Tornin, Juan; Santos, Laura; Rodriguez, Aida; García-Castro, Javier; Morís, Francisco; Rodriguez, Rene

    2016-01-01

    Tumors evolve from initial tumorigenic events into increasingly aggressive behaviors in a process usually driven by subpopulations of cancer stem cells (CSCs). Mesenchymal stromal/stem cells (MSCs) may act as the cell-of-origin for sarcomas, and CSCs that present MSC features have been identified in sarcomas due to their ability to grow as self-renewed floating spheres (tumorspheres). Accordingly, we previously developed sarcoma models using human MSCs transformed with relevant oncogenic events. To study the evolution/emergence of CSC subpopulations during tumor progression, we compared the tumorigenic properties of bulk adherent cultures and tumorsphere-forming subpopulations both in the sarcoma cell-of-origin models (transformed MSCs) and in their corresponding tumor xenograft-derived cells. Tumor formation assays showed that the tumorsphere cultures from xenograft-derived cells, but not from the cell-of-origin models, were enriched in CSCs, providing evidence of the emergence of bona fide CSCs subpopulations during tumor progression. Relevant CSC-related factors, such as ALDH1 and SOX2, were increasingly upregulated in CSCs during tumor progression, and importantly, the increased levels and activity of ALDH1 in these subpopulations were associated with enhanced tumorigenicity. In addition to being a CSC marker, our findings indicate that ALDH1 could also be useful for tracking the malignant potential of CSC subpopulations during sarcoma evolution. PMID:27292183

  7. The detection of acetaldehyde in cold dust clouds

    NASA Technical Reports Server (NTRS)

    Matthews, H. E.; Friber, P.; Irvine, W. M.

    1985-01-01

    Observations of the 1(01)-0(00) rotational transitions of A and E state acetaldehyde are reported. The transitions were detected, for the first time in interstellar space, in the cold dust clouds TMC-1 and L134N, and in Sgr B2. This is also the first time acetaldehyde has been found in a dust cloud and is the most complex oxygen-bearing molecule yet known in this environment. A column density of 6 x 10 to the 12th/sq cm in TMC-1, comparable to many other species detected there, and an approximately equal column density in L134N are formed. In the direction of Sgr B2, the CH3CHO profile appears to consist of broad emission features from the hot molecular cloud core, together with absorption features resulting from intervening colder material. The possible detection of HC9N toward IRC + 10 deg 216 through its J = 33-32 transition is also reported. Implications for cold dust cloud chemistry and excitation are discussed.

  8. Roaming radical kinetics in the decomposition of acetaldehyde.

    SciTech Connect

    Harding, L. B.; Georgievskii, Y.; Klippenstein, S. J.; Chemical Sciences and Engineering Division

    2010-01-01

    A novel theoretical framework for predicting the branching between roaming and bond fission channels in molecular dissociations is described and applied to the decomposition of acetaldehyde. This reduced dimensional trajectory (RDT) approach, which is motivated by the long-range nature of the roaming, bond fission, and abstraction dynamical bottlenecks, involves the propagation of rigid-body trajectories on an analytic potential energy surface. The analytic potential is obtained from fits to large-scale multireference ab initio electronic structure calculations. The final potential includes one-dimensional corrections from higher-level electronic structure calculations and for the effect of conserved mode variations along both the addition and abstraction paths. The corrections along the abstraction path play a significant role in the predicted branching. Master equation simulations are used to transform the microcanonical branching ratios obtained from the RDT simulations to the temperature- and pressure-dependent branching ratios observed in thermal decomposition experiments. For completeness, a transition-state theory treatment of the contributions of the tight transition states for the molecular channels is included in the theoretical analyses. The theoretically predicted branching between molecules and radicals in the thermal decomposition of acetaldehyde is in reasonable agreement with the corresponding shock tube measurement described in the companion paper. The prediction for the ratio of the tight to roaming contributions to the molecular channel also agrees well with results extracted from recent experimental and experimental/theoretical photodissociation studies.

  9. Studies on the mechanism of acetaldehyde-mediated inhibition of rat liver transaminases.

    PubMed

    Solomon, L R

    1987-09-30

    Incubation of mitochondria-depleted rat liver homogenates with 5 mmol/l acetaldehyde at 37 degrees C for 1 h inhibited both aspartate and alanine aminotransferases by 30%. Inhibition was prevented by decreasing temperature to 4 degrees C or by preincubating homogenates with cyanate but was unaffected by cyanamide and methylpyrazole which block acetaldehyde oxidation and reduction respectively. Cyanate-sensitive acetaldehyde-mediated inhibition of purified porcine heart transaminases was also demonstrated in the presence of rat liver homogenate but not in Tris/sucrose medium. Moreover, porcine transaminases were inhibited by trichloroacetic acid extracts of rat liver homogenates previously incubated with acetaldehyde but not by extracts of homogenates incubated with both acetaldehyde and cyanate. These findings suggest that acetaldehyde-mediated transaminase inhibition requires further non-oxidative metabolism of acetaldehyde. Since transaminase activities were not restored by addition of pyridoxal 5'-phosphate to the assay systems, acetaldehyde-induced transaminase inhibition does not appear to be mediated by displacement or depletion of this B6 coenzyme. PMID:3677417

  10. Acetaldehyde alters MAP kinase signalling and epigenetic histone modifications in hepatocytes.

    PubMed

    Shukla, Shivendra D; Lee, Youn Ju; Park, Pil-hoon; Aroor, Annayya R

    2007-01-01

    Although both oxidative and non-oxidative metabolites of ethanol are involved in generating ethanol matabolic stress (Emess), the oxidative metabolite acetaldehyde plays a critical role in the cellular actions of ethanol. We have investigated the effects of acetaldehyde on p42/44 MAP kinase, p46/p54 c-jun N-terminal kinase (JNK1/JNK2) and p38 MAP kinase in hepatocytes. Acetaldehyde caused temporal activation of p42/44 MAPK followed by JNK, but the activation of the p42/44 MAPK was not a prerequisite for the JNK activation. Activation ofJNK1 by acetaldehyde was greater than JNK2. Ethanol and acetaldehyde activatedJNK have opposing roles; ethanol-induced JNK activation increased apoptosis whereas that by acetaldehyde decreased apoptosis. Acetaldehyde also caused histone H3 acetylation at Lys9 and phosphorylation of histone H3 at Serl0 and 28, the latter being dependent on p38 MAP kinase. Phosphorylation at Ser28 was higher than at Serl0. Thus acetaldehyde distinctively alters MAP kinase signalling and histone modifications, processes involved in transcriptional activation. PMID:17590997

  11. The hydrogen-storing microporous silica 'Microcluster' reduces acetaldehyde contained in a distilled spirit.

    PubMed

    Kato, Shinya; Miwa, Nobuhiko

    2016-12-01

    Acetaldehyde is a detrimental substance produced in alcoholic liquor aging. We assessed an ability of hydrogen-storing microporous silica 'Microcluster' (MC+) to reduce acetaldehyde, as compared with autoclave-dehydrogenated MC+ (MC-). Acetaldehyde was quantified spectrophotometrically by an enzymatic method. Authentic acetaldehyde was treated by MC+ for 20min, and decreased from 43.4ppm to 10.9ppm, but maintained at 49.3ppm by MC-. On the other hand, acetaldehyde contained in a distilled spirit was decreased from 29.5ppm to 3.1ppm at 20min by MC+, but not decreased by MC-. Addition of MC+ or MC- to distilled water without acetaldehyde showed no seeming effect on the quantification used. Accordingly acetaldehyde in a distilled spirit is reduced to ethanol by hydrogen contained in MC+, but not by the silica moiety of MC+. Hydrogen gas of 1.2mL was released for 20min from MC+ of 0.59g in water, resulting in dissolved hydrogen of 1.09ppm and an oxidation- reduction potential of -687.0mV indicative of a marked reducing ability. Thus, MC+ has an ability to reduce acetaldehyde in a distilled spirit due to dissolved hydrogen released from MC+. PMID:27612695

  12. Oxygen vacancy-assisted coupling and enolization of acetaldehyde on CeO2(111).

    PubMed

    Calaza, Florencia C; Xu, Ye; Mullins, David R; Overbury, Steven H

    2012-10-31

    The temperature-dependent adsorption and reaction of acetaldehyde (CH(3)CHO) on a fully oxidized and a highly reduced thin-film CeO(2)(111) surface have been investigated using a combination of reflection-absorption infrared spectroscopy (RAIRS) and periodic density functional theory (DFT+U) calculations. On the fully oxidized surface, acetaldehyde adsorbs weakly through its carbonyl O interacting with a lattice Ce(4+) cation in the η(1)-O configuration. This state desorbs at 210 K without reaction. On the highly reduced surface, new vibrational signatures appear below 220 K. They are identified by RAIRS and DFT as a dimer state formed from the coupling of the carbonyl O and the acyl C of two acetaldehyde molecules. This dimer state remains up to 400 K before decomposing to produce another distinct set of vibrational signatures, which are identified as the enolate form of acetaldehyde (CH(2)CHO¯). Furthermore, the calculated activation barriers for the coupling of acetaldehyde, the decomposition of the dimer state, and the recombinative desorption of enolate and H as acetaldehyde are in good agreement with previously reported TPD results for acetaldehyde adsorbed on reduced CeO(2)(111) [Chen et al. J. Phys. Chem. C 2011, 115, 3385]. The present findings demonstrate that surface oxygen vacancies alter the reactivity of the CeO(2)(111) surface and play a crucial role in stabilizing and activating acetaldehyde for coupling reactions. PMID:23020248

  13. Removal of acetaldehyde and skatole in gas by a corona-discharge reactor

    SciTech Connect

    Sano, Noriaki; Nagamoto, Toshiki; Hamon, Hajime; Suzuki, Tetsuo; Okazaki, Morio

    1997-09-01

    Recently, ultrahigh gas purification has been important in many cases, such as, for example, (1) removal of dioxin from incineration plants, (2) complete removal of radioactive iodine compounds from nuclear fuel recycling, (3) simultaneous removal of NO{sub x} and SO{sub x} in exhaust gases from cogeneration plants, (4) removal or decomposition of chlorofluorocarbons, and (5) supply of purified gas for semiconductor industries. A corona-discharge reactor, called a deposition-type reactor, was applied to remove acetaldehyde and skatole from nitrogen and an oxygen-nitrogen mixture. In the removal from nitrogen, acetaldehyde and skatole are negatively ionized and removed by depositing at the anode surface. In simultaneous removals of acetaldehyde and skatole, it is found that skatole has a higher reactivity of electron attachment than acetaldehyde. In the removal of acetaldehyde from an oxygen-nitrogen mixture, 40 molecules of acetaldehyde were removed by one electron. The reason for the extremely high removal efficiency is considered to be based on the ozone reaction and the formation of negative-ion clusters. Stabilization energies of the negative-ion clusters were estimated by ab initio molecular orbital calculation. Skatole was removed from a nitrogen-oxygen mixture perfectly with extremely low discharge current by the ozone reaction. Simultaneous removals of acetaldehyde and skatole from a nitrogen-oxygen mixture suggest that coexisting skatole inhibits the removal of acetaldehyde.

  14. Dissociative electron attachments to ethanol and acetaldehyde: A combined experimental and simulation study

    NASA Astrophysics Data System (ADS)

    Wang, Xu-Dong; Xuan, Chuan-Jin; Feng, Wen-Ling; Tian, Shan Xi

    2015-02-01

    Dissociation dynamics of the temporary negative ions of ethanol and acetaldehyde formed by the low-energy electron attachments is investigated by using the anion velocity map imaging technique and ab initio molecular dynamics simulations. The momentum images of the dominant fragments O-/OH- and CH3- are recorded, indicating the low kinetic energies of O-/OH- for ethanol while the low and high kinetic energy distributions of O- ions for acetaldehyde. The CH3- image for acetaldehyde also shows the low kinetic energy. With help of the dynamics simulations, the fragmentation processes are qualitatively clarified. A new cascade dissociation pathway to produce the slow O- ion via the dehydrogenated intermediate, CH3CHO- (acetaldehyde anion), is proposed for the dissociative electron attachment to ethanol. After the electron attachment to acetaldehyde molecule, the slow CH3- is produced quickly in the two-body dissociation with the internal energy redistributions in different aspects before bond cleavages.

  15. Impairment of histone H1 DNA binding by adduct formation with acetaldehyde

    SciTech Connect

    Niemela, O.; Mannermaa, R.; Oikarinen, J. )

    1990-01-01

    Incubation of histone H1 with pharmacologically relevant concentrations of acetaldehyde resulted in the formation of spontaneously stable acetaldehyde-protein linkages. The reaction of acetaldehyde and H1 purified from rat liver either by a DNA recognition site affinity chromatography or by perchloric acid extraction occurred primarily at the lysine residues in the carboxyterminal tail of H1, which is crucial for its function as a eukaryotic repressor. It was further shown using an H1-lacZ fusion protein produced in E. coli and the protein isolated from rat liver that the formation of acetaldehyde adducts with H1 impair its DNA binding properties. They propose that such a reaction may occur in vivo and lead to an inability to repress genes in the liver upon excessive alcohol consumption. This mechanism may play a role in acetaldehyde-induced collagen synthesis in alcoholics.

  16. The Crystal Structure of a Ternary Complex of Betaine Aldehyde Dehydrogenase from Pseudomonas aeruginosa Provides New Insight Into the Reaction Mechansim and Shows A Novel Binding Mode of the 2'-Phosphate of NADP+ and A Novel Cation Binding Site

    SciTech Connect

    Gonzalez-Segura, L.; Rudino-Pinera, E; Munoz-Clares, R; Horjales, E

    2009-01-01

    In the human pathogen Pseudomonas aeruginosa, the NAD(P)+-dependent betaine aldehyde dehydrogenase (PaBADH) may play the dual role of assimilating carbon and nitrogen from choline or choline precursors-abundant at infection sites-and producing glycine betaine and NADPH, potentially protective against the high-osmolarity and oxidative stresses prevalent in the infected tissues. Disruption of the PaBADH gene negatively affects the growth of bacteria, suggesting that this enzyme could be a target for antibiotic design. PaBADH is one of the few ALDHs that efficiently use NADP+ and one of the even fewer that require K+ ions for stability. Crystals of PaBADH were obtained under aerobic conditions in the presence of 2-mercaptoethanol, glycerol, NADP+ and K+ ions. The three-dimensional structure was determined at 2.1-A resolution. The catalytic cysteine (C286, corresponding to C302 of ALDH2) is oxidized to sulfenic acid or forms a mixed disulfide with 2-mercaptoethanol. The glutamyl residue involved in the deacylation step (E252, corresponding to E268 of ALDH2) is in two conformations, suggesting a proton relay system formed by two well-conserved residues (E464 and K162, corresponding to E476 and K178, respectively, of ALDH2) that connects E252 with the bulk water. In some active sites, a bound glycerol molecule mimics the thiohemiacetal intermediate; its hydroxyl oxygen is hydrogen bonded to the nitrogen of the amide groups of the side chain of the conserved N153 (N169 of ALDH2) and those of the main chain of C286, which form the 'oxyanion hole.' The nicotinamide moiety of the nucleotide is not observed in the crystal, and the adenine moiety binds in the usual way. A salt bridge between E179 (E195 of ALDH2) and R40 (E53 of ALDH2) moves the carboxylate group of the former away from the 2?-phosphate of the NADP+, thus avoiding steric clashes and/or electrostatic repulsion between the two groups. Finally, the crystal shows two K+ binding sites per subunit. One is in an

  17. Activity and electrophoretic profiles of liver aldehyde dehydrogenases from mice of inbred strains with different alcohol preference.

    PubMed

    Yamazaki, H; Nishiguchi, K; Miyamoto, R; Ogita, Z I; Nakanishi, S

    1983-01-01

    1. The activity of low Km-aldehyde dehydrogenase (ALDH) in the liver mitochondrial fraction (MT-fraction) from male C57BL/6J strain mice (alcohol preferring) was significantly higher than that from DBA/2 mice (alcohol avoiding). The F1 hybrids (C57BL/6J X DBA/2) did not exhibit the intermediate activity to these two strains. 2. Strain differences in liver mitochondrial ALDH isozymes were observed by isoelectric focusing. C57BL/6J strain had two isozymes at pH 7.1 while DBA/2 had no band at this pH. F1 hybrid mice had similar two bands with lower density to those of C57BL/6J at pH 7.1. There was no difference in zymograms of the soluble fraction between C57BL/6J and DBA/2 strains. 3. The present results suggest that the difference in alcohol preference of mice may depend on some restricted ALDH isozymes with different pl or electric mobility rather than the enzymatic activity in the liver MT-fraction. PMID:6822317

  18. Mitochondrial aldehyde dehydrogenase mediates vasodilator responses of glyceryl trinitrate and sodium nitrite in the pulmonary vascular bed of the rat.

    PubMed

    Badejo, Adeleke M; Hodnette, Chris; Dhaliwal, Jasdeep S; Casey, David B; Pankey, Edward; Murthy, Subramanyam N; Nossaman, Bobby D; Hyman, Albert L; Kadowitz, Philip J

    2010-09-01

    It has been reported that mitochondrial aldehyde dehydrogenase (ALDH2) catalyzes the formation of glyceryl dinitrate and inorganic nitrite from glyceryl trinitrate (GTN), leading to an increase in cGMP and vasodilation in the coronary and systemic vascular beds. However, the role of nitric oxide (NO) formed from nitrite in mediating the response to GTN in the pulmonary vascular bed is uncertain. The purpose of the present study was to determine if nitrite plays a role in mediating vasodilator responses to GTN. In this study, intravenous injections of GTN and sodium nitrite decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressure under baseline and elevated tone conditions and decreases in systemic arterial pressure in response to GTN and sodium nitrite were attenuated by cyanamide, an ALDH2 inhibitor, whereas responses to the NO donor, sodium nitroprusside (SNP), were not altered. The decreases in pulmonary and systemic arterial pressure in response to GTN and SNP were not altered by allopurinol, an inhibitor of xanthine oxidoreductase, whereas responses to sodium nitrite were attenuated. GTN was approximately 1,000-fold more potent than sodium nitrite in decreasing pulmonary and systemic arterial pressures. These results suggest that ALDH2 plays an important role in the bioactivation of GTN and nitrite in the pulmonary and systemic vascular beds and that the reduction of nitrite to vasoactive NO does not play an important role in mediating vasodilator responses to GTN in the intact chest rat. PMID:20543077

  19. Mitochondrial aldehyde dehydrogenase mediates vasodilator responses of glyceryl trinitrate and sodium nitrite in the pulmonary vascular bed of the rat

    PubMed Central

    Badejo, Adeleke M.; Hodnette, Chris; Dhaliwal, Jasdeep S.; Casey, David B.; Pankey, Edward; Murthy, Subramanyam N.; Nossaman, Bobby D.; Hyman, Albert L.

    2010-01-01

    It has been reported that mitochondrial aldehyde dehydrogenase (ALDH2) catalyzes the formation of glyceryl dinitrate and inorganic nitrite from glyceryl trinitrate (GTN), leading to an increase in cGMP and vasodilation in the coronary and systemic vascular beds. However, the role of nitric oxide (NO) formed from nitrite in mediating the response to GTN in the pulmonary vascular bed is uncertain. The purpose of the present study was to determine if nitrite plays a role in mediating vasodilator responses to GTN. In this study, intravenous injections of GTN and sodium nitrite decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressure under baseline and elevated tone conditions and decreases in systemic arterial pressure in response to GTN and sodium nitrite were attenuated by cyanamide, an ALDH2 inhibitor, whereas responses to the NO donor, sodium nitroprusside (SNP), were not altered. The decreases in pulmonary and systemic arterial pressure in response to GTN and SNP were not altered by allopurinol, an inhibitor of xanthine oxidoreductase, whereas responses to sodium nitrite were attenuated. GTN was ∼1,000-fold more potent than sodium nitrite in decreasing pulmonary and systemic arterial pressures. These results suggest that ALDH2 plays an important role in the bioactivation of GTN and nitrite in the pulmonary and systemic vascular beds and that the reduction of nitrite to vasoactive NO does not play an important role in mediating vasodilator responses to GTN in the intact chest rat. PMID:20543077

  20. Resolving Some Paradoxes in the Thermal Decomposition Mechanism of Acetaldehyde.

    PubMed

    Sivaramakrishnan, Raghu; Michael, Joe V; Harding, Lawrence B; Klippenstein, Stephen J

    2015-07-16

    The mechanism for the thermal decomposition of acetaldehyde has been revisited with an analysis of literature kinetics experiments using theoretical kinetics. The present modeling study was motivated by recent observations, with very sensitive diagnostics, of some unexpected products in high temperature microtubular reactor experiments on the thermal decomposition of CH3CHO and its deuterated analogs, CH3CDO, CD3CHO, and CD3CDO. The observations of these products prompted the authors of these studies to suggest that the enol tautomer, CH2CHOH (vinyl alcohol), is a primary intermediate in the thermal decomposition of acetaldehyde. The present modeling efforts on acetaldehyde decomposition incorporate a master equation reanalysis of the CH3CHO potential energy surface (PES). The lowest-energy process on this PES is an isomerization of CH3CHO to CH2CHOH. However, the subsequent product channels for CH2CHOH are substantially higher in energy, and the only unimolecular process that can be thermally accessed is a reisomerization to CH3CHO. The incorporation of these new theoretical kinetics predictions into models for selected literature experiments on CH3CHO thermal decomposition confirms our earlier experiment and theory-based conclusions that the dominant decomposition process in CH3CHO at high temperatures is C-C bond fission with a minor contribution (∼10-20%) from the roaming mechanism to form CH4 and CO. The present modeling efforts also incorporate a master-equation analysis of the H + CH2CHOH potential energy surface. This bimolecular reaction is the primary mechanism for removal of CH2CHOH, which can accumulate to minor amounts at high temperatures, T > 1000 K, in most lab-scale experiments that use large initial concentrations of CH3CHO. Our modeling efforts indicate that the observation of ketene, water, and acetylene in the recent microtubular experiments are primarily due to bimolecular reactions of CH3CHO and CH2CHOH with H-atoms and have no bearing on

  1. Computer modeling of cool flames and ignition of acetaldehyde

    SciTech Connect

    Cavanagh, J.; Cox, R.A. ); Olson, G. )

    1990-10-01

    A detailed mechanism for the oxidation of acetaldehyde at temperatures between 500-1000 K has been assembled using 77 elementary reactions involving 32 reactant, product, and intermediate species. Rate coefficients were taken from recent critical evaluations of experimental data. Where experimental measurements were not available, the rate parameters were estimated from the body of currently available kinetics information. The mechanism was shown to predict correctly the rates and products observed in CH{sub 3}CHO oxidation studies in a low-pressure in a stirred flow reactor and at high pressure in a rapid compression machine. The oscillatory phenomena in the flow system and the two-stage ignition observed at high pressure were satisfactorily described by the mechanism. It is shown that cool flames are caused by degenerate branching mainly by peracetic acid and that hydrogen peroxide promotes hot ignition.

  2. Pyrolysis of Acetaldehyde: a Fleeting Glimpse of Vinylidene

    NASA Astrophysics Data System (ADS)

    Vasilou, A. J.; Piech, K. M.; Ellison, G. B.; Golan, A.; Kostko, O.; Ahmed, M.; Osborn, D. L.; Daily, J. W.; Nimlos, M. R.; Stanton, J. F.

    2011-06-01

    The thermal decomposition of acetaldehyde has been studied in a heated silicon carbide ``microtubular reactor", with products monitored by both photoionization mass spectrometry and matrix-isolation Fourier transform infrared spectroscopy. A well-known, and observed, route of decomposition occurs when the weakest C-C bond is broken; this process leads to methyl and formyl radicals. In addition to this, we find evidence for two additional channels: CH_3CHO + Δ → H_2CCO (ketene) and CH_3CHO + Δ → C_2H_2 (acetylene), reactions that also generate molecular hydrogen and water, respectively. This talk focuses on the last pathway, which proceeds via vinyl alcohol. Evidence is presented that the high temperature unimolecular dehydration of vinyl alcohol proceeds by two mechanisms; one of these is a (1,2) elimination that directly yields acetylene, and the other is a (1,1) elimination that necessarily accesses the vinylidene isomer of C_2H_2 as an intermediate.

  3. Velocity-map imaging study of the photodissociation of acetaldehyde

    SciTech Connect

    Cruse, H.A.; Softley, T.P.

    2005-03-22

    Velocity-map imaging studies are reported for the photodissociation of acetaldehyde over a range of photolysis wavelengths (317.5-282.5 nm). Images are obtained for both the HCO and CH{sub 3} fragments. The mean rotational energy of both fragments increases with photodissociation energy, with a lesser degree of excitation in the CH{sub 3} fragment. The CH{sub 3} images demonstrate that the CH{sub 3} fragments are rotationally aligned with respect to the recoil direction and this is interpreted, and well modeled, on the basis of a propensity for forming CH{sub 3} fragments with M{approx}K, where M is the projection of the rotational angular momentum along the recoil direction. The origin of the CH{sub 3} rotation is conserved motion from the torsional and methyl-rocking modes of the parent molecule. Nonstatistical vibrational distributions for the CH{sub 3} fragment are obtained at higher energies.

  4. Prognostic Value of Drinking Status and Aldehyde Dehydrogenase 2 Polymorphism in Patients With Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Kawakita, Daisuke; Oze, Isao; Hosono, Satoyo; Ito, Hidemi; Watanabe, Miki; Yatabe, Yasushi; Hasegawa, Yasuhisa; Murakami, Shingo; Tanaka, Hideo; Matsuo, Keitaro

    2016-01-01

    Background The association between alcohol drinking, aldehyde dehydrogenase 2 (ALDH2) polymorphism, and survival in patients with head and neck squamous cell carcinoma (HNSCC) remains unclear. Methods We performed a retrospective cohort study of 267 HNSCC patients at Aichi Cancer Center. Of these, 65 patients (24%) were non-drinkers, 104 (39%) were light drinkers (ethanol <46 g or <5 days/week), 46 (17%) were moderate drinkers (ethanol intake 46–68 g/day and ≥5 days/week), and 52 (20%) were heavy drinkers (ethanol intake ≥69 g and ≥5 days/week). The prognostic value of pre-treatment drinking status and ALDH2 polymorphism was investigated using multivariate proportional hazard models. Results Drinking status was associated with disease-free survival (DFS) in HNSCC patients, with marginal statistical significance (5-year DFS: 67.9% [95% confidence interval {CI}, 53.8–78.4%] for non-drinkers, 57.6% [95% CI, 47.4–66.6%] for light drinkers, 46.1% [95% CI, 30.8–60.1%] for moderate drinkers, and 43.5% [95% CI, 29.3–56.9%] for heavy drinkers; P = 0.088). However, this association lost significance when multivariate analyses were adjusted for established prognostic factors. ALDH2 genotype was not significantly associated with DFS in HNSCC patients (5-year DFS: 85.7% [95% CI, 53.9–96.2%] for Lys/Lys, 56.2% [95% CI, 47.4–64.1%] for Glu/Lys, and 50.5% [95% CI, 40.3–59.7%] for Glu/Glu; P = 0.154). After stratification by ALDH2 genotype, we observed a significant positive dose-response relationship between drinking status and DFS in HNSCC patients with ALDH2 Glu/Glu (P trend = 0.029). Conclusions In this study, we identified a significant positive dose-response relationship between pre-treatment drinking status and DFS in HNSCC patients with ALDH2 Glu/Glu. To confirm this association, further study is warranted. PMID:26804037

  5. Aldehyde dehydrogenase inhibitors: alpha,beta-acetylenic N-substituted aminothiolesters are reversible growth inhibitors of normal epithelial but irreversible apoptogens for cancer epithelial cells from human prostate in culture.

    PubMed

    Quash, Gerard; Fournet, Guy; Courvoisier, Charlotte; Martinez, Rosa M; Chantepie, Jacqueline; Paret, Marie Julie; Pharaboz, Julie; Joly-Pharaboz, Marie Odile; Goré, Jacques; André, Jean; Reichert, Uwe

    2008-05-01

    The pharmacomodulation of the N atom of alpha,beta-acetylenic aminothiolesters or the replacement of the thiolester moiety by more electrophilic groups did not permit any clear rationale to be established for improving the selective growth-inhibitory activity of this family of compounds over that of the previously synthesized alpha,beta-acetylenic aminothiolesters DIMATE and MATE [G. Quash, G. Fournet, J. Chantepie, J. Goré, C. Ardiet, D. Ardail, Y. Michal, U. Reichert, Biochem Pharmacol 64 (2002) 1279-92]. Hence DIMATE and MATE were investigated more thoroughly for selectivity and growth-inhibitory activity using human prostate epithelial normal cells (HPENC) on the one hand and human prostate epithelial cancer cells (DU145) on the other. Unequivocal evidence was obtained showing that both compounds were reversible growth inhibitors of HPENC but irreversible growth inhibitors of DU145. Growth-inhibition of DU145 was due to the induction of early apoptosis as revealed by the flow cytometric analytical profile of inhibitor-treated cells, of the decrease in the redox potential and increase in superoxide anion content of their mitochondria. Of the two intracellular enzymes: aldehyde dehydrogenases 1 and 3 (ALDH1 and ALDH3) targeted by DIMATE and MATE, ALDH3 was inhibited to the same extent by both compounds whereas ALDH1 was less susceptible to inhibition by MATE. As the induction of ALDH3 by xenobiotics is hormone-dependent, MATE, the more selective of the two inhibitors, is a useful tool not only for examining the role of the ALDH3 isoform in hormone-sensitive and resistant prostate cancer cells in culture but also for investigating if it can inhibit the growth of xenografts of prostate cancer in immunodeficient mice. PMID:17692435

  6. Role of apoptotic hepatocytes in HCV dissemination: regulation by acetaldehyde.

    PubMed

    Ganesan, Murali; Natarajan, Sathish Kumar; Zhang, Jinjin; Mott, Justin L; Poluektova, Larisa I; McVicker, Benita L; Kharbanda, Kusum K; Tuma, Dean J; Osna, Natalia A

    2016-06-01

    Alcohol consumption exacerbates hepatitis C virus (HCV) pathogenesis and promotes disease progression, although the mechanisms are not quite clear. We have previously observed that acetaldehyde (Ach) continuously produced by the acetaldehyde-generating system (AGS), temporarily enhanced HCV RNA levels, followed by a decrease to normal or lower levels, which corresponded to apoptosis induction. Here, we studied whether Ach-induced apoptosis caused depletion of HCV-infected cells and what role apoptotic bodies (AB) play in HCV-alcohol crosstalk. In liver cells exposed to AGS, we observed the induction of miR-122 and miR-34a. As miR-34a has been associated with apoptotic signaling and miR-122 with HCV replication, these findings may suggest that cells with intensive viral replication undergo apoptosis. Furthermore, when AGS-induced apoptosis was blocked by a pan-caspase inhibitor, the expression of HCV RNA was not changed. AB from HCV-infected cells contained HCV core protein and the assembled HCV particle that infect intact hepatocytes, thereby promoting the spread of infection. In addition, AB are captured by macrophages to switch their cytokine profile to the proinflammatory one. Macrophages exposed to HCV(+) AB expressed more IL-1β, IL-18, IL-6, and IL-10 mRNAs compared with those exposed to HCV(-) AB. The generation of AB from AGS-treated HCV-infected cells even enhanced the induction of aforementioned cytokines. We conclude that HCV and alcohol metabolites trigger the formation of AB containing HCV particles. The consequent spread of HCV to neighboring hepatocytes via infected AB, as well as the induction of liver inflammation by AB-mediated macrophage activation potentially exacerbate the HCV infection course by alcohol and worsen disease progression. PMID:27056722

  7. Effect of indole-3-carbinol on ethanol-induced liver injury and acetaldehyde-stimulated hepatic stellate cells activation using precision-cut rat liver slices.

    PubMed

    Guo, Yu; Wu, Xiao-Qian; Zhang, Chun; Liao, Zhang-Xiu; Wu, Yong; Xia, Zheng-Yuan; Wang, Hui

    2010-12-01

    1. Indole-3-carbinol (I3C), a major indole compound found in high levels in cruciferous vegetables, shows a broad spectrum of biological activities. However, few studies have reported the effect of I3C on alcoholic liver injury. In the present study, we investigated the protective effect of I3C on acute ethanol-induced hepatotoxicity and acetaldehyde-stimulated hepatic stellate cells (HSC) activation using precision-cut liver slices (PCLS). 2. Rat PCLS were incubated with 50 mmol/L ethanol or 350 μmol/L acetaldehyde, and different concentrations (100-400 μmol/L) of I3C were added into the culture system of these two liver injury models, respectively. Hepatotoxicity was assessed by measuring enzyme leakage and malondialdehyde (MDA) content in tissue. Activities of alcoholic enzymes were also determined. α-Smooth muscle actin (α-SMA), transforming growth factor (TGF-β(1) ) and hydroxyproline (HYP) were used as indices to evaluate the activation of HSC. In addition, matrix metalloproteinase-1 (MMP-1) and the tissue inhibitor of metalloproteinase (TIMP-1) were observed to estimate collagen degradation. 3. I3C significantly reduced the enzyme leakage in ethanol-treated slices. In I3C groups, cytochrome P450 (CYP) 2E1 activities were inhibited by 40.9-51.8%, whereas alcohol dehydrogenase (ADH) activity was enhanced 1.6-fold compared with the ethanol-treated group. I3C also showed an inhibitory effect against HSC activation and collagen production stimulated by acetaldehyde. After being incubated with I3C (400 μmol/L), the expression of MMP-1 was markedly enhanced, whereas TIMP-1 was decreased. 4. These results showed that I3C protected PCLS against alcoholic liver injury, which might be associated with the regulation of ethanol metabolic enzymes, attenuation of oxidative injury and acceleration of collagen degradation. PMID:20880187

  8. ALDH/CD44 identifies uniquely tumorigenic cancer stem cells in salivary gland mucoepidermoid carcinomas.

    PubMed

    Adams, April; Warner, Kristy; Pearson, Alexander T; Zhang, Zhaocheng; Kim, Hong Sun; Mochizuki, Daiki; Basura, Gregory; Helman, Joseph; Mantesso, Andrea; Castilho, Rogério M; Wicha, Max S; Nör, Jacques E

    2015-09-29

    A small sub-population of cells characterized by increased tumorigenic potential, ability to self-renew and to differentiate into cells that make up the tumor bulk, has been characterized in some (but not all) tumor types. These unique cells, namedcancer stem cells, are considered drivers of tumor progression in these tumors. The purpose of this work is to understand if cancer stem cells play a functional role in the tumorigenesis of salivary gland mucoepidermoid carcinomas. Here, we investigated the expression of putative cancer stem cell markers (ALDH, CD10, CD24, CD44) in primary human mucoepidermoid carcinomas by immunofluorescence, in vitro salisphere assays, and in vivo tumorigenicity assays in immunodeficient mice. Human mucoepidermoid carcinoma cells (UM-HMC-1, UM-HMC-3A, UM-HMC-3B) sorted for high levels of ALDH activity and CD44 expression (ALDHhighCD44high) consistently formed primary and secondary salispheres in vitro, and showed enhanced tumorigenic potential in vivo (defined as time to tumor palpability, tumor growth after palpability), when compared to ALDHlowCD44low cells. Cells sorted for CD10/CD24, and CD10/CD44 showed varying trends of salisphere formation, but consistently low in vivo tumorigenic potential. And finally, cells sorted for CD44/CD24 showed inconsistent results in salisphere formation and tumorigenic potential assays when different cell lines were evaluated. Collectively, these data demonstrate that salivary gland mucoepidermoid carcinomas contain a small population of cancer stem cells with enhanced tumorigenic potential and that are characterized by high ALDH activity and CD44 expression. These results suggest that patients with mucoepidermoid carcinoma might benefit from therapies that ablate these highly tumorigenic cells. PMID:26449187

  9. STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH{sup +}/CD133{sup +} stem cell-like human colon cancer cells

    SciTech Connect

    Lin, Li; Fuchs, James; Li, Chenglong; Olson, Veronica; Bekaii-Saab, Tanios; Lin, Jiayuh

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells. Black-Right-Pointing-Pointer STAT3 inhibitor, FLLL32 inhibits P-STAT3 and STAT3 target genes in colon cancer stem-like cells. Black-Right-Pointing-Pointer Inhibition of STAT3 resulted in decreased cell viability and reduced numbers of tumorspheres. Black-Right-Pointing-Pointer STAT3 is required for survival and tumorsphere forming capacity in colon cancer stem-like cells. Black-Right-Pointing-Pointer Targeting STAT3 in cancer stem-like cells may offer a novel treatment approach for colon cancer. -- Abstract: Persistent activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in colon cancer. Increasing evidence suggests the existence of a small population of colon cancer stem or cancer-initiating cells may be responsible for tumor initiation, metastasis, and resistance to chemotherapy and radiation. Whether STAT3 plays a role in colon cancer-initiating cells and the effect of STAT3 inhibition is still unknown. Flow cytometry was used to isolate colon cancer stem-like cells from three independent human colon cancer cell lines characterized by both aldehyde dehydrogenase (ALDH)-positive and CD133-positive subpopulation (ALDH{sup +}/CD133{sup +}). The effects of STAT3 inhibition in colon cancer stem-like cells were examined. The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells and was reduced by a STAT3-selective small molecular inhibitor, FLLL32. FLLL32 also inhibited the expression of potential STAT3 downstream target genes in colon cancer stem-like cells including survivin, Bcl-XL, as well as Notch-1, -3, and -4, which may be involved in stem cell function. Furthermore, FLLL32 inhibited cell viability and tumorsphere formation as well as induced cleaved caspase-3 in colon cancer stem-like cells. FLLL32 is more potent than curcumin as evidenced with lower

  10. Murine and Human Myogenic Cells Identified by Elevated Aldehyde Dehydrogenase Activity: Implications for Muscle Regeneration and Repair

    PubMed Central

    Vella, Joseph B.; Thompson, Seth D.; Bucsek, Mark J.; Song, Minjung; Huard, Johnny

    2011-01-01

    Background Despite the initial promise of myoblast transfer therapy to restore dystrophin in Duchenne muscular dystrophy patients, clinical efficacy has been limited, primarily by poor cell survival post-transplantation. Murine muscle derived stem cells (MDSCs) isolated from slowly adhering cells (SACs) via the preplate technique, induce greater muscle regeneration than murine myoblasts, primarily due to improved post-transplantation survival, which is conferred by their increased stress resistance capacity. Aldehyde dehydrogenase (ALDH) represents a family of enzymes with important morphogenic as well as oxidative damage mitigating roles and has been found to be a marker of stem cells in both normal and malignant tissue. In this study, we hypothesized that elevated ALDH levels could identify murine and human muscle derived cell (hMDC) progenitors, endowed with enhanced stress resistance and muscle regeneration capacity. Methodology/Principal Findings Skeletal muscle progenitors were isolated from murine and human skeletal muscle by a modified preplate technique and unfractionated enzymatic digestion, respectively. ALDHhi subpopulations isolated by fluorescence activate cell sorting demonstrated increased proliferation and myogenic differentiation capacities compared to their ALDHlo counterparts when cultivated in oxidative and inflammatory stress media conditions. This behavior correlated with increased intracellular levels of reduced glutathione and superoxide dismutase. ALDHhi murine myoblasts were observed to exhibit an increased muscle regenerative potential compared to ALDHlo myoblasts, undergo multipotent differentiation (osteogenic and chondrogenic), and were found predominately in the SAC fraction, characteristics that are also observed in murine MDSCs. Likewise, human ALDHhi hMDCs demonstrated superior muscle regenerative capacity compared to ALDHlo hMDCs. Conclusions The methodology of isolating myogenic cells on the basis of elevated ALDH activity

  11. A single sip of a strong alcoholic beverage causes exposure to carcinogenic concentrations of acetaldehyde in the oral cavity.

    PubMed

    Linderborg, Klas; Salaspuro, Mikko; Väkeväinen, Satu

    2011-09-01

    The aim of this study was to explore oral exposure to carcinogenic (group 1) acetaldehyde after single sips of strong alcoholic beverages containing no or high concentrations of acetaldehyde. Eight volunteers tasted 5 ml of ethanol diluted to 40 vol.% with no acetaldehyde and 40 vol.% calvados containing 2400 μM acetaldehyde. Salivary acetaldehyde and ethanol concentrations were measured by gas chromatography. The protocol was repeated after ingestion of ethanol (0.5 g/kg body weight). Salivary acetaldehyde concentration was significantly higher after sipping calvados than after sipping ethanol at 30s both with (215 vs. 128 μmol/l, p<0.05) and without (258 vs. 89 μmol/l, p<0.05) alcohol ingestion. From 2 min onwards there were no significant differences in the decreasing salivary acetaldehyde concentration, which remained above the level of carcinogenicity still at 10 min. The systemic alcohol distribution from blood to saliva had no additional effect on salivary acetaldehyde after sipping of the alcoholic beverages. Carcinogenic concentrations of acetaldehyde are produced from ethanol in the oral cavity instantly after a small sip of strong alcoholic beverage, and the exposure continues for at least 10 min. Acetaldehyde present in the beverage has a short-term effect on total acetaldehyde exposure. PMID:21641957

  12. Separation of dehydrogenases on polyaminomethylstyrene.

    PubMed

    Schöpp, W; Meinert, S; Thyfronitou, J; Aurich, H

    1975-01-29

    The binding of dehydrogenases, especially alcohol dehydrogenase, and other proteins to several ion exchangers and hydrophobic polymers was investigated. Quantitative parameters for the stability of the polymer-protein complexes (obtained form double reciprocal plots) indicate a high but different affinity of many proteins for polyaminomethylstyrene. The chromatography of a mixture of five dehydrogenases and human serum albumin on polyaminomethylstyrene is described. PMID:237012

  13. First cases of pyridoxine-dependent epilepsy in Bulgaria: novel mutation in the ALDH7A1 gene.

    PubMed

    Tincheva, Savina; Todorov, Tihomir; Todorova, Albena; Georgieva, Ralica; Stamatov, Dimitar; Yordanova, Iglika; Kadiyska, Tanya; Georgieva, Bilyana; Bojidarova, Maria; Tacheva, Genoveva; Litvinenko, Ivan; Mitev, Vanyo

    2015-12-01

    Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder characterized by intractable seizures in neonates and infants. The seizures cannot be controlled with antiepileptic medications but respond both clinically and electrographically to large daily supplements of pyridoxine (vitamin B6). PDE is caused by mutations in the ALDH7A1 gene. Molecular genetic analysis of the ALDH7A1 gene was performed in seven patients, referred with clinical diagnosis of PDE. Mutations were detected in a dizygotic twin pair and a non-related boy with classical form of PDE. Direct sequencing of the ALDH7A1 gene revealed one novel (c.297delG, p.Trp99*) and two already reported (c.328C>T, p.Arg110*; c.584A>G, p.Asn195Ser) mutations. Here, we report the first genetically proven cases of PDE in Bulgaria. PMID:26232297

  14. Isolation and characterization of an inducible NAD-dependent butyraldehyde dehydrogenase from clostridium acetobutylicum

    SciTech Connect

    Schreiber, W.; Duerre, P.

    1996-12-31

    A NAD-dependent butyraldehyde dehydrogenase (BAD) has been purified from C. acetobutylicum DSM 792 and DSM 173 1. This key enzyme of butanol production, catalyzing the conversion of butyryl-CoA to butyraldehyde, was induced shortly before the onset of butanol production and proved to be oxygen-sensitive. A one step purification procedure on reactive green 19 allowed to purify the enzyme to homogeneity. The purified protein was found to be extremely unstable and could only partially be stabilized by addition of mercaptoethanol and storage below -20{degrees}C. The enzyme subunit had a molecular mass of 39.5 kDa. In the reverse reaction (butyryl-CoA-forming) the apparent pH optimum was 9.75 and Vmax was significantly higher with butyraldehyde and propionaldehyde than with acetaldehyde. BAD could also use NADP+, but NAD+ was the preferred coenzyme for the reverse reaction. The N-terminal amino acid sequence of the C. acetobutylicurn DSM 792 protein showed high homology to glyceraldehyde-3-phosphate dehydrogenases (GAP), especially to the protein of C. pasteurianum. Genomic libraries of C. acetobutylicum DSM 792 were screened by hybridization using PCR-generated heterologous probes encoding the gap gene of C. pasteurianum. Sequence analysis of the positive clones revealed high homology, but no identity to the N-terminal amino acid sequence of the butyraldehyde dehydrogenase. Thus, BAD from C. acetobutylicum is distinctly different from other reported aldehyde dehydrogenases with butyraldehyde dehydrogenase activity.

  15. Hairpin Ribozyme Genes Curtail Alcohol Drinking: from Rational Design to in vivo Effects in the Rat.

    PubMed

    Sapag, Amalia; Irrazábal, Thergiory; Lobos-González, Lorena; Muñoz-Brauning, Carlos R; Quintanilla, María Elena; Tampier, Lutske

    2016-01-01

    Ribozyme genes were designed to reduce voluntary alcohol drinking in a rat model of alcohol dependence. Acetaldehyde generated from alcohol in the liver is metabolized by the mitochondrial aldehyde dehydrogenase (ALDH2) such that diminishing ALDH2 activity leads to the aversive effects of blood acetaldehyde upon alcohol intake. A stepwise approach was followed to design genes encoding ribozymes targeted to the rat ALDH2 mRNA. In vitro studies of accessibility to oligonucleotides identified suitable target sites in the mRNA, one of which fulfilled hammerhead and hairpin ribozyme requirements (CGGUC). Ribozyme genes delivered in plasmid constructs were tested in rat cells in culture. While the hairpin ribozyme reduced ALDH2 activity 56% by cleavage and blockade (P < 0.0001), the hammerhead ribozyme elicited minor effects by blockade. The hairpin ribozyme was tested in vivo by adenoviral gene delivery to UChB alcohol drinker rats. Ethanol intake was curtailed 47% for 34 days (P < 0.0001), while blood acetaldehyde more than doubled upon ethanol administration and ALDH2 activity dropped 25% in liver homogenates, not affecting other ALDH isoforms. Thus, hairpin ribozymes targeted to 16 nt in the ALDH2 mRNA provide durable and specific effects in vivo, representing an improvement on previous work and encouraging development of gene therapy for alcoholism. PMID:27404720

  16. Identification of rs671, a common variant of ALDH2, as a gout susceptibility locus.

    PubMed

    Sakiyama, Masayuki; Matsuo, Hirotaka; Nakaoka, Hirofumi; Yamamoto, Ken; Nakayama, Akiyoshi; Nakamura, Takahiro; Kawai, Sayo; Okada, Rieko; Ooyama, Hiroshi; Shimizu, Toru; Shinomiya, Nariyoshi

    2016-01-01

    Gout is a common disease resulting from hyperuricemia. Recently, a genome-wide association study identified an association between gout and a single nucleotide polymorphism (SNP) rs2188380, located on an intergenic region between MYL2 and CUX2 on chromosome 12. However, other genes around rs2188380 could possibly be gout susceptibility genes. Therefore, we performed a fine-mapping study of the MYL2-CUX2 region. From 8,595 SNPs in the MYL2-CUX2 region, 9 tag SNPs were selected, and genotyping of 1,048 male gout patients and 1,334 male controls was performed by TaqMan method. Eight SNPs showed significant associations with gout after Bonferroni correction. rs671 (Glu504Lys) of ALDH2 had the most significant association with gout (P = 1.7 × 10(-18), odds ratio = 0.53). After adjustment for rs671, the other 8 SNPs no longer showed a significant association with gout, while the significant association of rs671 remained. rs671 has been reportedly associated with alcohol drinking behavior, and it is well-known that alcohol drinking elevates serum uric acid levels. These data suggest that rs671, a common functional SNP of ALDH2, is a genuine gout-associated SNP in the MYL2-CUX2 locus and that "A" allele (Lys) of rs671 plays a protective role in the development of gout. PMID:27181629

  17. Identification of rs671, a common variant of ALDH2, as a gout susceptibility locus

    PubMed Central

    Sakiyama, Masayuki; Matsuo, Hirotaka; Nakaoka, Hirofumi; Yamamoto, Ken; Nakayama, Akiyoshi; Nakamura, Takahiro; Kawai, Sayo; Okada, Rieko; Ooyama, Hiroshi; Shimizu, Toru; Shinomiya, Nariyoshi

    2016-01-01

    Gout is a common disease resulting from hyperuricemia. Recently, a genome-wide association study identified an association between gout and a single nucleotide polymorphism (SNP) rs2188380, located on an intergenic region between MYL2 and CUX2 on chromosome 12. However, other genes around rs2188380 could possibly be gout susceptibility genes. Therefore, we performed a fine-mapping study of the MYL2-CUX2 region. From 8,595 SNPs in the MYL2-CUX2 region, 9 tag SNPs were selected, and genotyping of 1,048 male gout patients and 1,334 male controls was performed by TaqMan method. Eight SNPs showed significant associations with gout after Bonferroni correction. rs671 (Glu504Lys) of ALDH2 had the most significant association with gout (P = 1.7 × 10−18, odds ratio = 0.53). After adjustment for rs671, the other 8 SNPs no longer showed a significant association with gout, while the significant association of rs671 remained. rs671 has been reportedly associated with alcohol drinking behavior, and it is well-known that alcohol drinking elevates serum uric acid levels. These data suggest that rs671, a common functional SNP of ALDH2, is a genuine gout-associated SNP in the MYL2-CUX2 locus and that “A” allele (Lys) of rs671 plays a protective role in the development of gout. PMID:27181629

  18. Rosiglitazone protects human neuroblastoma SH-SY5Y cells against acetaldehyde-induced cytotoxicity

    SciTech Connect

    Jung, Tae Woo; Lee, Ji Young; Shim, Wan Sub; Kang, Eun Seok; Kim, Soo Kyung; Ahn, Chul Woo; Lee, Hyun Chul; Cha, Bong Soo . E-mail: bscha@yumc.yonsei.ac.kr

    2006-02-03

    Acetaldehyde, an inhibitor of mitochondrial function, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with elevation of the intracellular reactive oxygen species level and apoptosis. Rosiglitazone, a peroxisome proliferator-activated receptor-{gamma} agonist, has been known to show various non-hypoglycemic effects, including anti-inflammatory, anti-atherogenic, and anti-apoptotic. In this study, we investigated the protective effects of rosiglitazone on acetaldehyde-induced apoptosis in human neuroblastoma SH-SY5Y cells and attempted to examine its mechanism. Acetaldehyde-induced apoptosis was moderately reversed by rosiglitazone treatment. Our results suggest that the protective effects of rosiglitazone on acetaldehyde-induced apoptosis may be ascribed to ability to induce the expression of anti-oxidant enzymes and to regulate Bcl-2 and Bax expression. These data indicate that rosiglitazone may provide a useful therapeutic strategy for the prevention of progressive neurodegenerative disease such as Parkinson's disease.

  19. Acetaldehyde Adsorption and Reaction onCeO2(100) Thin Films

    SciTech Connect

    Mullins, David R; Albrecht, Peter M

    2013-01-01

    This study reports and compares the adsorption and dissociation of acetaldehyde on oxidized and reduced CeOX(100) thin films. Acetaldehyde reacts and decomposes on fully oxidized CeO2(100) whereas it desorbs molecularly at low temperature on CeO2(111). The primary products are CO, CO2 and water along with trace amounts of crotonaldehyde and acetylene. The acetaldehyde adsorbs as the 2-acetaldehyde species, dioxyethylene. Decomposition proceeds by dehydrogenation through acetate and enolate intermediates. The reaction pathway is similar on the reduced CeO2-X(100) surface however the inability to react with surface O on the reduced surface results in H2 rather than H2O desorption and C is left on the surface rather than producing CO and CO2. C-O bond cleavage in the enolate intermediate followed by reaction with surface H results in ethylene desorption.

  20. Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency

    PubMed Central

    2009-01-01

    Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5A1 [ALDH5A1]; locus 6p22) occupies a central position in central nervous system (CNS) neurotransmitter metabolism as one of two enzymes necessary for γ-aminobutyric acid (GABA) recycling from the synaptic cleft. Its importance is highlighted by the neurometabolic disease associated with its inherited deficiency in humans, as well as the severe epileptic phenotype observed in Aldh5a1-/- knockout mice. Expanding evidence now suggests, however, that even subtle decreases in human SSADH activity, associated with rare and common single nucleotide polymorphisms, may produce subclinical pathological effects. SSADH, in conjunction with aldo-keto reductase 7A2 (AKR7A2), represent two neural enzymes responsible for further catabolism of succinic semialdehyde, producing either succinate (SSADH) or γ-hydroxybutyrate (GHB; AKR7A2). A GABA analogue, GHB is a short-chain fatty alcohol with unusual properties in the CNS and a long pharmacological history. Moreover, SSADH occupies a further role in the CNS as the enzyme responsible for further metabolism of the lipid peroxidation aldehyde 4-hydroxy-2-nonenal (4-HNE), an intermediate known to induce oxidant stress. Accordingly, subtle decreases in SSADH activity may have the capacity to lead to regional accumulation of neurotoxic intermediates (GHB, 4-HNE). Polymorphisms in SSADH gene structure may also associate with quantitative traits, including intelligence quotient and life expectancy. Further population-based studies of human SSADH activity promise to reveal additional properties of its function and additional roles in CNS tissue. PMID:19164088

  1. Biological production of acetaldehyde from ethanol using non-growing Pichia pastoris whole cells

    SciTech Connect

    Chiang, Heien-Kun; Foutch, G.L.; Fish, W.W.

    1991-12-31

    Acetaldehyde has been produced biologically using whole-cell Pichia Pass in a semibatch fermentor. Ethanol and air were fed continuously, and the product, acetaldehyde, was removed by the air stream. Operation of the reactor exceeded 100 h, maintaining high alcohol oxidase activity. Low cell-mass concentration (9.9 g/L) minimized product inhibition. Ethanol concentration in the broth, oxygen concentration in the air, and pH were evaluated for their effects on the fermentation process.

  2. Effects of acetaldehyde on hepatocyte glycerol uptake and cell size: implication of Aquaporin 9

    PubMed Central

    Potter, James J.; Koteish, Ayman; Hamilton, James; Liu, Xiaopu; Liu, Kun; Agre, Peter; Mezey, Esteban

    2010-01-01

    Background The effects of ethanol and acetaldehyde on uptake of glycerol and on cell size of hepatocytes and a role Aquaporin 9 (AQP9), a glycerol transport channel, were evaluated. Methods The studies were done in primary rat and mouse hepatocytes. The uptake of [14C] glycerol was determined with hepatocytes in suspension. For determination of cell size, rat hepatocytes on coated dishes were incubated with a lipophilic fluorochrome that is incorporated into the cell membrane and examined by confocal microscopy. A three dimensional z scan of the cell was performed, and the middle slice of the z scan was used for area measurements. Results Acute exposure to acetaldehyde, but not to ethanol, causes a rapid increase in the uptake of glycerol and an increase in hepatocyte size, which was inhibited by HgCl2, an inhibitor of aquaporins. This was not observed in hepatocytes from AQP9 knockout mice, nor observed by direct application of acetaldehyde to AQP9 expressed in Xenopus Laevis oocytes. Prolonged 24 hours exposure to either acetaldehyde or ethanol did not result in an increase in glycerol uptake by rat hepatocytes. Acetaldehyde decreased AQP9 mRNA and AQP9 protein, while ethanol decreased AQP9 mRNA but not AQP9 protein. Ethanol, but not acetaldehyde, increased the activities of glycerol kinase and phosphoenolpyruvate carboxykinase. Conclusions The acute effects of acetaldehyde, while mediated by AQP9, are probably influenced by binding of acetaldehyde to hepatocyte membranes and changes in cell permeability. The effects of ethanol in enhancing glucose kinase, and phosphoenolpyruvate carboxykinase leading to increased formation of glycerol-3-phosphate most likely contribute to alcoholic fatty liver. PMID:21294757

  3. Expression, Purification, Crystallization And Preliminary X-Ray Studies of Histamine Dehydrogenase From Nocardioides Simplex

    SciTech Connect

    Reed, T.M.; Hirakawa, H.; Mure, M.; Scott, E.E.; Limburg, J.

    2009-05-21

    Histamine dehydrogenase (HADH) from Nocardioides simplex catalyzes the oxidative deamination of histamine to produce imidazole acetaldehyde and an ammonium ion. HADH is functionally related to trimethylamine dehydrogenase (TMADH), but HADH has strict substrate specificity towards histamine. HADH is a homodimer, with each 76 kDa subunit containing two redox cofactors: a [4Fe-4S] cluster and an unusual covalently bound flavin mononucleotide, 6-S-cysteinyl-FMN. In order to understand the substrate specificity of HADH, it was sought to determine its structure by X-ray crystallography. This enzyme has been expressed recombinantly in Escherichia coli and successfully crystallized in two forms. Diffraction data were collected to 2.7 {angstrom} resolution at the SSRL synchrotron with 99.7% completeness. The crystals belonged to the orthorhombic space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 101.14, b = 107.03, c = 153.35 {angstrom}.

  4. Mitigation of Radiation-Induced Dermatitis by Activation of Aldehyde Dehydrogenase 2 Using Topical Alda-1 in Mice1

    PubMed Central

    Ning, Shoucheng; Budas, Grant R.; Churchill, Eric N.; Chen, Che-Hong; Knox, Susan J.; Mochly-Rosen, Daria

    2012-01-01

    Ning, S., Budas, G. R., Churchill, E. N., Chen, C., Knox, S. J. and Mochly-Rosen, D. Mitigation of Radiation-Induced Dermatitis by Activation of Aldehyde Dehydrogenase 2 Using Topical Alda-1 in Mice. Radiation-induced dermatitis is a debilitating clinical problem in cancer patients undergoing cancer radiation therapy. It is also a possible outcome of exposure to high levels of radiation due to accident or hostile activity. We report that activation of aldehyde dehydrogenase 2 (ALDH2) enzymatic activity using the allosteric agonist, Alda-1, significantly reduced 4-hydroxynonenal adducts accumulation, delayed the onset of radiation dermatitis and substantially reduced symptoms in a clinically-relevant model of radiation-induced dermatitis. Importantly, Alda-1 did not radioprotect tumors in mice. Rather, it increased the sensitivity of the tumors to radiation therapy. This is the first report of reactive aldehydes playing a role in the intrinsic radiosensitivity of normal and tumor tissues. Our findings suggest that ALDH2 represents a novel target for the treatment of radiation dermatitis without reducing the benefit of radiotherapy. PMID:22404739

  5. The alcohol dehydrogenase isoenzyme alcohol dehydrogenase IV as a candidate marker of Helicobacter pylori infection

    PubMed Central

    Laniewska-Dunaj, Magdalena; Strumnik, Anna; Szmitkowski, Maciej

    2014-01-01

    Introduction Helicobacter pylori infection is associated with decreased alcohol dehydrogenase (ADH) activity in the gastric mucosa. The decrease in gastric ADH activity depends on the severity of inflammation and mucosal injury. This damage can be a reason of the release of enzyme from gastric mucosa and leads to the increase of the ADH activity in the sera of patients with H. pylori infection. Material and methods Serum samples were taken from 140 patients with H. pylori infection. Total ADH activity was measured by photometric method with p-nitrosodimethylaniline as a substrate and ALDH activity by the fluorometric method with 6-methoxy-2-naphtaldehyde. For the measurement of the activity of class I and II isoenzymes we employed the fluorometric methods, with class-specific fluorogenic substrates. The activity of class III ADH was measured by the photometric method with n-octanol and class IV with m-nitrobenzaldehyde as a substrate. Results The activity of ADH IV in the serum of patients with H. pylori infection increased about 42% (7.86 mU/l) in the comparison to the control level (4.52 mU/l). Total activity of ADH was 1105 mU/l in patients group and 682 mU/l in control. The diagnostic sensitivity for ADH IV was 88%, specificity 90%, positive and negative predictive values were 91% and 84% respectively. Area under ROC curve for ADH IV was 0.84. Conclusions Helicobacter pylori infection of gastric mucosa is reflected in the serum by significant increase of class IV and total ADH activity. The results suggest a potential role for ADH IV as a marker of H. pylori infection. PMID:25395946

  6. The total margin of exposure of ethanol and acetaldehyde for heavy drinkers consuming cider or vodka.

    PubMed

    Lachenmeier, Dirk W; Gill, Jan S; Chick, Jonathan; Rehm, Jürgen

    2015-09-01

    Heavy drinkers in Scotland may consume 1600 g ethanol per week. Due to its low price, cider may be preferred over other beverages. Anecdotal evidence has linked cider to specific health hazards beyond other alcoholic beverages. To examine this hypothesis, nine apple and pear cider samples were chemically analysed for constituents and contaminants. None of the products exceeded regulatory or toxicological thresholds, but the regular occurrence of acetaldehyde in cider was detected. To provide a quantitative risk assessment, two collectives of exclusive drinkers of cider and vodka were compared and the intake of acetaldehyde was estimated using probabilistic Monte-Carlo type analysis. The cider consumers were found to ingest more than 200-times the amount of acetaldehyde consumed by vodka consumers. The margins of exposure (MOE) of acetaldehyde were 224 for the cider and over 220,000 for vodka consumers. However, if the effects of ethanol were considered in a cumulative assessment of the combined MOE, the effect of acetaldehyde was minor and the combined MOE for both groups was 0.3. We suggest that alcohol policy priority should be given on reducing ethanol intake by measures such as minimum pricing, rather than to focus on acetaldehyde. PMID:26116882

  7. Effect of rinsing with ethanol-containing mouthrinses on the production of salivary acetaldehyde.

    PubMed

    Moazzez, Rebecca; Thompson, Hayley; Palmer, Richard M; Wilson, Ron F; Proctor, Gordon B; Wade, William G

    2011-12-01

    It has been suggested that the use of alcohol-containing mouthrinses could lead to the presence of acetaldehyde in saliva. In this cross-over study, salivary acetaldehyde levels and microbial profiles were determined before and after rinsing with ethanol-containing mouthrinses with essential oils (EO) and cetyl pyridinium chloride (CPC) as the active ingredients, and with 21.6% ethanol and water controls. After rinsing with all ethanol-containing rinses, acetaldehyde was detected in saliva after 30 s but declined to low levels after 5 min. The highest peak levels were seen with the ethanol control (median = 82.9 μM at 2 min) and were significantly higher than those seen at the same time after rinsing with the EO rinse (43.1 μM). There was no correlation between microbial counts or plaque scores and acetaldehyde levels, although dividing the subjects on the basis of a peak acetaldehyde salivary concentration of > 90.8 μM after the ethanol rinse revealed that the high responders were highly significantly more likely to harbour salivary yeasts than were the low responders. Rinsing with ethanol-containing mouthrinses causes a rapid, but transient, increase in salivary acetaldehyde levels. PMID:22112029

  8. Atmospheric chemistry of toxic contaminants 2. Saturated aliphatics: Acetaldehyde, dioxane, ethylene glycol ethers, propylene oxide

    SciTech Connect

    Grosjean, D. )

    1990-11-01

    Detailed mechanisms are outlined for the chemical reactions that contribute to in-situ formation and atmospheric removal of the saturated aliphatic contaminants acetaldehyde, dioxane, ethylene glycol ethers (methyl, ethyl, n-butyl) and propylene oxide. In-situ formation is of major importance for acetaldehyde. In-situ removal involves reaction with OH (all compounds) and, for acetaldehyde, photolysis and reaction with NO{sub 3}. Acetaldehyde, dioxane, and the ethers are rapidly removed (half-lives of less than one day), leading to PAN (acetaldehyde) and to 2-oxodioxane and formaldehyde (dioxane). Reaction products of the glycol ethers include a large number of hydroxyesters, hydroxyacids, and hydroxycarbonyls. Propylene oxide reacts only slowly with OH, with an atmospheric half-life of 3 - 10 days, to yeild formaldehyde, acetaldehyde, and PAN. Uncertainties in the reaction mechanisms for dioxane, the glycol ethers, and propylene oxide are discussed and include C-C vs C-O bond scission in alkoxy radicals as well as alkoxy radical unimolecular decomposition vs reaction with oxygen.

  9. Theoretical survey of the reaction between osmium and acetaldehyde

    NASA Astrophysics Data System (ADS)

    Dai, Guo-Liang; Wang, Chuan-Feng

    2012-05-01

    The mechanism of the reaction of osmium atom with acetaldehyde has been investigated with a DFT approach. All the stationary points are determined at the UB3LYP/ sdd/6-311++G** level of the theory. Both ground and excited state potential energy surfaces are investigated in detail. The present results show that the title reaction start with the formation of a CH3CHO-metal complex followed by C-C, aldehyde C-H, C-O, and methyl C-H activation. These reactions can lead to four different products (HOsCH3 + CO, OsCO + CH4, OsCOCH3 + H, and OsO + C2H4). The minimum energy reaction path is found to involve the spin inversion in the initial reaction step. This potential energy curve-crossing dramatically affects reaction exothermic. The present results may be helpful in understanding the mechanism of the title reaction and further experimental investigation of the reaction.

  10. Acetaldehyde involvement in ethanol's postabsortive effects during early ontogeny.

    PubMed

    March, Samanta M; Abate, P; Molina, Juan C

    2013-01-01

    Clinical and biomedical studies sustains the notion that early ontogeny is a vulnerable window to the impact of alcohol. Experiences with the drug during these stages increase latter disposition to prefer, use or abuse ethanol. This period of enhanced sensitivity to ethanol is accompanied by a high rate of activity in the central catalase system, which metabolizes ethanol in the brain. Acetaldehyde (ACD), the first oxidation product of ethanol, has been found to share many neurobehavioral effects with the drug. Cumulative evidence supports this notion in models employing adults. Nevertheless very few studies have been conducted to analyze the role of ACD in ethanol postabsorptive effects, in newborns or infant rats. In this work we review recent experimental literature that syndicates ACD as a mediator agent of reinforcing aspects of ethanol, during early ontogenetic stages. We also show a meta-analytical correlational approach that proposes how differences in the activity of brain catalase across ontogeny, could be modulating patterns of ethanol consumption. PMID:23801947

  11. Acetaldehyde involvement in ethanol's postabsortive effects during early ontogeny

    PubMed Central

    March, Samanta M.; Abate, P.; Molina, Juan C.

    2013-01-01

    Clinical and biomedical studies sustains the notion that early ontogeny is a vulnerable window to the impact of alcohol. Experiences with the drug during these stages increase latter disposition to prefer, use or abuse ethanol. This period of enhanced sensitivity to ethanol is accompanied by a high rate of activity in the central catalase system, which metabolizes ethanol in the brain. Acetaldehyde (ACD), the first oxidation product of ethanol, has been found to share many neurobehavioral effects with the drug. Cumulative evidence supports this notion in models employing adults. Nevertheless very few studies have been conducted to analyze the role of ACD in ethanol postabsorptive effects, in newborns or infant rats. In this work we review recent experimental literature that syndicates ACD as a mediator agent of reinforcing aspects of ethanol, during early ontogenetic stages. We also show a meta-analytical correlational approach that proposes how differences in the activity of brain catalase across ontogeny, could be modulating patterns of ethanol consumption. PMID:23801947

  12. Transcriptional regulation of the human ALDH1A1 promoter by the oncogenic homeoprotein TLX1/HOX11

    PubMed Central

    Rice, Kim L.; Heidari, Mansour; Taplin, Ross H.; Kees, Ursula R.; Greene, Wayne K.

    2009-01-01

    The homeoprotein TLX1, which is essential to spleen organogenesis and oncogenic when aberrantly expressed in immature T cells, functions as a bifunctional transcriptional regulator, being capable of activation or repression depending on cell type and/or promoter context. However, the detailed mechanisms by which it regulates the transcription of target genes such as ALDH1A1 remains to be elucidated. We therefore functionally assessed the ability of TLX1 to regulate ALDH1A1 expression in two hematopoietic cell lines, PER-117 T-leukemic cells and human erythroleukemic (HEL) cells, by use of luciferase reporter and mobility shift assays. We showed that TLX1 physically interacts with the general transcription factor TFIIB via its homeodomain, and identified two activities in respect to TLX1-mediated regulation of the CCAAT box-containing ALDH1A1 promoter. The first involved CCAAT-dependent transcriptional repression via perturbation of GATA factor-containing protein complexes assembled at a non-canonical TATA (GATA) box. A structurally intact homeodomain was essential for repression by TLX1 although direct DNA binding was not required. The second activity, which involved CCAAT-independent transcriptional activation did not require an intact homeodomain, indicating that the activation and repression functions of TLX1 are distinct. These findings confirm ALDH1A1 gene regulation by TLX1 and support an indirect model for TLX1 function, in which protein-protein interactions, rather than DNA binding at specific sites, are crucial for its transcriptional activity.

  13. Cyanobacterial NADPH dehydrogenase complexes

    SciTech Connect

    Ogawa, Teruo; Mi, Hualing

    2007-07-01

    Cyanobacteria possess functionally distinct multiple NADPH dehydrogenase (NDH-1) complexes that are essential to CO2 uptake, photosystem-1 cyclic electron transport and respiration. The unique nature of cyanobacterial NDH-1 complexes is the presence of subunits involved in CO2 uptake. Other than CO2 uptake, chloroplastic NDH-1 complex has similar role as cyanobacterial NDH-1 complexes in photosystem-1 cyclic electron transport and respiration (chlororespiration). In this mini-review we focus on the structure and function of cyanobacterial NDH-1 complexes and their phylogeny. The function of chloroplastic NDH-1 complex and characteristics of plants defective in NDH-1 are also described forcomparison.

  14. Effect of (L)-cysteine on acetaldehyde self-administration.

    PubMed

    Peana, Alessandra T; Muggironi, Giulia; Fois, Giulia R; Zinellu, Manuel; Sirca, Donatella; Diana, Marco

    2012-08-01

    Acetaldehyde (ACD), the first metabolite of ethanol, has been implicated in several behavioural actions of alcohol, including its reinforcing effects. Recently, we reported that l-cysteine, a sequestrating agent of ACD, reduced oral ethanol self-administration and that ACD was orally self-administered. This study examined the effects of l-cysteine pre-treatment during the acquisition and maintenance phases of ACD (0.2%) self-administration as well as on the deprivation effect after ACD extinction and on a progressive ratio (PR) schedule of reinforcement. In a separate PR schedule of reinforcement, the effect of l-cysteine was assessed on the break-point produced by ethanol (10%). Furthermore, we tested the effect of l-cysteine on saccharin (0.2%) reinforcement. Wistar rats were trained to self-administer ACD by nose poking on a fixed ratio (FR1) schedule in 30-min daily sessions. Responses on an active nose-poke caused delivery of ACD solution, whereas responses on an inactive nose-poke had no consequences. l-cysteine reduced the acquisition (40 mg/kg), the maintenance and the deprivation effect (100 mg/kg) of ACD self-administration. Furthermore, at the same dose, l-cysteine (120 mg/kg) decreased both ACD and ethanol break point. In addition, l-cysteine was unable to suppress the different responses for saccharin, suggesting that its effect did not relate to an unspecific decrease in a general motivational state. Compared to saline, l-cysteine did not modify responses on inactive nose-pokes, suggesting an absence of a non-specific behavioural activation. Taken together, these results could support the hypotheses that ACD possesses reinforcing properties and l-cysteine reduces motivation to self-administer ACD. PMID:22440691

  15. Increased Expression of Aldehyde Dehydrogenase 2 Reduces Renal Cell Apoptosis During Ischemia/Reperfusion Injury After Hypothermic Machine Perfusion.

    PubMed

    Zhong, Zibiao; Hu, Qianchao; Fu, Zhen; Wang, Ren; Xiong, Yan; Zhang, Yang; Liu, Zhongzhong; Wang, Yanfeng; Ye, Qifa

    2016-06-01

    Hypothermic machine perfusion (MP) can reduce graft's injury after kidney transplantation; however, the mechanism has not been elucidated. In the past decade, many studies showed that aldehyde dehydrogenase 2 (ALDH2) is a protease which can inhibit cell apoptosis. Therefore, this study aims to explore whether ALDH2 takes part in reducing organ damage after MP. Eighteen healthy male New Zealand rabbits (12 weeks old, weight 3.0 ± 0.3 kg) were randomly divided into three groups: normal group, MP group, and cold storage (CS) group (n = 6). The left kidney of rabbits underwent warm ischemia for 35 min through clamping the left renal pedicle and then reperfusion for 1 h. Left kidneys were preserved by MP or CS (4°C for 4 h) in vivo followed by the right nephrectomy and 24-h reperfusion, and then the specimens and blood were collected. Finally, concentration of urine creatinine (Cr), blood urea nitrogen (BUN), and 4-HNE were tested. Renal apoptosis was detected by TUNEL staining, and the expression of ALDH2, cleaved-caspase 3, bcl-2/ bax, MAPK in renal tissue was detected by immunohistochemistry or Western blot; 24 h after surgery, the concentration of Cr in MP group was 355 ± 71μmol/L, in CS group was 511 ± 44 μmol/L (P < 0.05), while the BUN was 15.02 ± 2.34 mmol/L in MP group, 22.64 ± 3.58 mmol/L in CS group (P < 0.05). The rate of apoptosis and expression of cleaved caspase-3, p-P38, p-ERK, and p-JNK in MP group was significantly lower than that in CS group (P < 0.05), while expression of ALDH2 and bcl-2/bax in MP group was significantly higher than that in CS group (P < 0.05); expression of cleaved caspase-3 in both MP and CS group significantly increased as compared with that in normal group (P < 0.05). In conclusion, increased expression of ALDH2 can reduce the renal cell apoptosis through inhibiting MAPK pathway during ischemia/reperfusion injury (IRI) after hypothermic MP. PMID:26582147

  16. 9-O-acetylated sialic acids differentiating normal haematopoietic precursors from leukemic stem cells with high aldehyde dehydrogenase activity in children with acute lymphoblastic leukaemia.

    PubMed

    Chowdhury, Suchandra; Chandra, Sarmila; Mandal, Chitra

    2014-10-01

    Childhood acute lymphoblastic leukaemia (ALL) originates from mutations in haematopoietic progenitor cells (HPCs). For high-risk patients, treated with intensified post-remission chemotherapy, haematopoietic stem cell (HSC) transplantation is considered. Autologous HSC transplantation needs improvisation till date. Previous studies established enhanced disease-associated expression of 9-O-acetylated sialoglycoproteins (Neu5,9Ac2-GPs) on lymphoblasts of these patients at diagnosis, followed by its decrease with clinical remission and reappearance with relapse. Based on this differential expression of Neu5,9Ac2-GPs, identification of a normal HPC population was targeted from patients at diagnosis. This study identifies two distinct haematopoietic progenitor populations from bone marrow of diagnostic ALL patients, exploring the differential expression of Neu5,9Ac2-GPs with stem cell (CD34, CD90, CD117, CD133), haematopoietic (CD45), lineage-commitment (CD38) antigens and cytosolic aldehyde dehydrogenase (ALDH). Normal haematopoietic progenitor cells (ALDH(+)SSC(lo)CD45(hi)Neu5,9Ac2 -GPs(lo)CD34(+)CD38(-)CD90(+)CD117(+)CD133(+)) differentiated into morphologically different, lineage-specific colonies, being crucial for autologous HSC transplantation while leukemic stem cells (ALDH(+)SSC(lo)CD45(lo)Neu5,9Ac2 -GPs(hi)CD34(+)CD38(+)CD90(-)CD117(-)CD133(-)) lacking this ability can be potential targets for minimal residual disease detection and drug-targeted immunotherapy. PMID:25283637

  17. A comparison of glucose oxidase and aldose dehydrogenase as mediated anodes in printed glucose/oxygen enzymatic fuel cells using ABTS/laccase cathodes.

    PubMed

    Jenkins, Peter; Tuurala, Saara; Vaari, Anu; Valkiainen, Matti; Smolander, Maria; Leech, Dónal

    2012-10-01

    Current generation by mediated enzyme electron transfer at electrode surfaces can be harnessed to provide biosensors and redox reactions in enzymatic fuel cells. A glucose/oxygen enzymatic fuel cell can provide power for portable and implantable electronic devices. High volume production of enzymatic fuel cell prototypes will likely require printing of electrode and catalytic materials. Here we report on preparation and performance of, completely enzymatic, printed glucose/oxygen biofuel cells. The cells are based on filter paper coated with conducting carbon inks, enzyme and mediator. A comparison of cell performance using a range of mediators for either glucose oxidase (GOx) or aldose dehydrogenase (ALDH) oxidation of glucose at the anode and ABTS and a fungal laccase, for reduction of oxygen at the cathode, is reported. Highest power output, although of limited stability, is observed for ALDH anodes mediated by an osmium complex, providing a maximum power density of 3.5 μW cm(-2) at 0.34 V, when coupled to a laccase/ABTS cathode. The stability of cell voltage in a biobattery format, above a threshold of 200 mV under a moderate 75 kΩ load, is used to benchmark printed fuel cell performance. Highest stability is obtained for printed fuel cells using ALDH, providing cell voltages over the threshold for up to 74 h, compared to only 2 h for cells with anodes using GOx. These results provide promising directions for further development of mass-producible, completely enzymatic, printed biofuel cells. PMID:22200380

  18. Reversible, partial inactivation of plant betaine aldehyde dehydrogenase by betaine aldehyde: mechanism and possible physiological implications.

    PubMed

    Zárate-Romero, Andrés; Murillo-Melo, Darío S; Mújica-Jiménez, Carlos; Montiel, Carmina; Muñoz-Clares, Rosario A

    2016-04-01

    In plants, the last step in the biosynthesis of the osmoprotectant glycine betaine (GB) is the NAD(+)-dependent oxidation of betaine aldehyde (BAL) catalysed by some aldehyde dehydrogenase (ALDH) 10 enzymes that exhibit betaine aldehyde dehydrogenase (BADH) activity. Given the irreversibility of the reaction, the short-term regulation of these enzymes is of great physiological relevance to avoid adverse decreases in the NAD(+):NADH ratio. In the present study, we report that the Spinacia oleracea BADH (SoBADH) is reversibly and partially inactivated by BAL in the absence of NAD(+)in a time- and concentration-dependent mode. Crystallographic evidence indicates that the non-essential Cys(450)(SoBADH numbering) forms a thiohemiacetal with BAL, totally blocking the productive binding of the aldehyde. It is of interest that, in contrast to Cys(450), the catalytic cysteine (Cys(291)) did not react with BAL in the absence of NAD(+) The trimethylammonium group of BAL binds in the same position in the inactivating or productive modes. Accordingly, BAL does not inactivate the C(450)SSoBADH mutant and the degree of inactivation of the A(441)I and A(441)C mutants corresponds to their very different abilities to bind the trimethylammonium group. Cys(450)and the neighbouring residues that participate in stabilizing the thiohemiacetal are strictly conserved in plant ALDH10 enzymes with proven or predicted BADH activity, suggesting that inactivation by BAL is their common feature. Under osmotic stress conditions, this novel partial and reversible covalent regulatory mechanism may contribute to preventing NAD(+)exhaustion, while still permitting the synthesis of high amounts of GB and avoiding the accumulation of the toxic BAL. PMID:26792760

  19. Mechanistic understanding of hydrogenation of acetaldehyde on Au(111): A DFT investigation

    NASA Astrophysics Data System (ADS)

    Meng, Qingsen; Shen, Yongli; Xu, Jing; Ma, Xinbin; Gong, Jinlong

    2012-11-01

    This paper describes the reaction pathways for hydrogenation of acetaldehyde on atomic hydrogen pre-adsorbed Au(111) employing density functional theory (DFT) calculations. All the surface species involved in the reaction scheme have low diffusion barriers, suggesting that the rearrangement and movement of these species on the surface are facile under reaction condition. The hydroxyethyl is proposed to be the intermediate for the hydrogenation of acetaldehyde, and the activation energy for its formation is 0.37 eV. Additionally, the coupling reaction of hydroxyethyl and acetaldehyde - resulting in the formation of the ethylidene ethylene glycol (CH3C*HOCH(CH3)OH) species - also readily occurs at the reaction condition. Two-dimensional (2-D) polyacetaldehyde ((CH3CHO)2) can be easily hydrogenated to ethylidene ethylene glycol or ethoxy hemiacetal (CH3CH2OCH(CH3)O*); the latter can be converted to ethanol and acetaldehyde via further hydrogenation. As the hydrogenation products of ethylidene ethylene glycol and ethoxy hemiacetal, ethoxyethanol (CH3CH2OCH(CH3)OH) can be deeply hydrogenated to hydroxyethyl and ethanol. Our calculations also suggest that the formation of an ethoxyl intermediate is not likely, which agrees with the experimental observation that no deuterated acetaldehydes have been detected in isotopic measurements.

  20. Adsorption and Reaction of Acetaldehyde on Stoichiometric and Defective SrTiO₃(100) Surfaces

    SciTech Connect

    Wang, Li Q.; Ferris, Kim F.; Azad, Samina; Engelhard, Mark H.; Peden, Charles HF.

    2004-02-05

    The adsorption and reaction of acetaldehyde (CH{sub 3}CHO), on stoichiometric (TiO{sub 2}-terminated) and reduced SrTiO{sub 3}(100) surfaces, have been investigated using temperature-programmed desorption (TPD) and X-ray photoelectron spectroscopy (XPS). Acetaldehyde adsorbs molecularly on the stoichiometric SrTiO{sub 3}(100) surface that contains predominantly Ti{sup 4+} cations. The Ti{sup 4+} sites on the stoichiometric SrTiO{sub 3}(100) surface are not sufficiently active for surface reactions such as aldol condensation, as opposed to the Ti{sup 4+} ions on the TiO{sub 2}(001) surface. However, decomposition and redox reactions of acetaldehyde occur in the presence of surface defects created by Ar{sup +} sputtering. The decomposition products following reactions of acetaldehyde on the defective surface include H{sub 2}, C{sub 2}H{sub 4}, CO, C{sub 4}H{sub 6}, and C{sub 4}H{sub 8}. Reductive coupling, to produce C{sub 2}H{sub 4} and C{sub 4}H{sub 8} is the main reaction pathway for decomposition of acetaldehyde on the sputter reduced SrTiO{sub 3}(100) surface.

  1. Dissociative electron attachments to ethanol and acetaldehyde: A combined experimental and simulation study

    SciTech Connect

    Wang, Xu-Dong; Xuan, Chuan-Jin; Feng, Wen-Ling; Tian, Shan Xi

    2015-02-14

    Dissociation dynamics of the temporary negative ions of ethanol and acetaldehyde formed by the low-energy electron attachments is investigated by using the anion velocity map imaging technique and ab initio molecular dynamics simulations. The momentum images of the dominant fragments O{sup −}/OH{sup −} and CH{sub 3}{sup −} are recorded, indicating the low kinetic energies of O{sup −}/OH{sup −} for ethanol while the low and high kinetic energy distributions of O{sup −} ions for acetaldehyde. The CH{sub 3}{sup −} image for acetaldehyde also shows the low kinetic energy. With help of the dynamics simulations, the fragmentation processes are qualitatively clarified. A new cascade dissociation pathway to produce the slow O{sup −} ion via the dehydrogenated intermediate, CH{sub 3}CHO{sup −} (acetaldehyde anion), is proposed for the dissociative electron attachment to ethanol. After the electron attachment to acetaldehyde molecule, the slow CH{sub 3}{sup −} is produced quickly in the two-body dissociation with the internal energy redistributions in different aspects before bond cleavages.

  2. Correlations between serum proteins modified by acetaldehyde and biochemical variables in heavy drinkers.

    PubMed Central

    Wickramasinghe, S N; Marjot, D H; Rosalki, S B; Fink, R S

    1989-01-01

    A strong and highly significant correlation was observed between serum aspartate transaminase (AST) activity and an index of the cytotoxic activity associated with serum proteins modified by acetaldehyde in a group of 24 heavy drinkers. A weaker but significant correlation (R = 0.564, p = 0.008) was found between total serum creatine kinase activity and this index of serum cytotoxicity. As it is likely that the concentration of circulating modified protein was largely determined by the quantity of free acetaldehyde generated in the liver and that the AST activity was mainly derived from damaged hepatocytes, the data indicate a correlation between hepatic acetaldehyde generation and hepatocyte damage. This correlation may indicate either that increased quantities of acetaldehyde are released by damaged hepatocytes or that acetaldehyde is hepatotoxic in vivo. As only the creatine kinase isoenzyme present in skeletal muscle (CK-MM) was demonstrable in the serum in all but one of our patients, the data also suggest that circulating modified serum proteins may be toxic towards skeletal muscle cells. PMID:2703546

  3. Genetics Home Reference: pyruvate dehydrogenase deficiency

    MedlinePlus

    ... control the activity of the complex: pyruvate dehydrogenase phosphatase turns on (activates) the complex, while pyruvate dehydrogenase ... binding protein (the PDHX gene), and pyruvate dehydrogenase phosphatase (the PDP1 gene) have been identified in people ...

  4. Cofactor Specificity of the Bifunctional Alcohol and Aldehyde Dehydrogenase (AdhE) in Wild-Type and Mutant Clostridium thermocellum and Thermoanaerobacterium saccharolyticum

    PubMed Central

    Zheng, Tianyong; Olson, Daniel G.; Tian, Liang; Bomble, Yannick J.; Himmel, Michael E.; Lo, Jonathan; Hon, Shuen; Shaw, A. Joe; van Dijken, Johannes P.

    2015-01-01

    ABSTRACT Clostridium thermocellum and Thermoanaerobacterium saccharolyticum are thermophilic bacteria that have been engineered to produce ethanol from the cellulose and hemicellulose fractions of biomass, respectively. Although engineered strains of T. saccharolyticum produce ethanol with a yield of 90% of the theoretical maximum, engineered strains of C. thermocellum produce ethanol at lower yields (∼50% of the theoretical maximum). In the course of engineering these strains, a number of mutations have been discovered in their adhE genes, which encode both alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) enzymes. To understand the effects of these mutations, the adhE genes from six strains of C. thermocellum and T. saccharolyticum were cloned and expressed in Escherichia coli, the enzymes produced were purified by affinity chromatography, and enzyme activity was measured. In wild-type strains of both organisms, NADH was the preferred cofactor for both ALDH and ADH activities. In high-ethanol-producing (ethanologen) strains of T. saccharolyticum, both ALDH and ADH activities showed increased NADPH-linked activity. Interestingly, the AdhE protein of the ethanologenic strain of C. thermocellum has acquired high NADPH-linked ADH activity while maintaining NADH-linked ALDH and ADH activities at wild-type levels. When single amino acid mutations in AdhE that caused increased NADPH-linked ADH activity were introduced into C. thermocellum and T. saccharolyticum, ethanol production increased in both organisms. Structural analysis of the wild-type and mutant AdhE proteins was performed to provide explanations for the cofactor specificity change on a molecular level. IMPORTANCE This work describes the characterization of the AdhE enzyme from different strains of C. thermocellum and T. saccharolyticum. C. thermocellum and T. saccharolyticum are thermophilic anaerobes that have been engineered to make high yields of ethanol and can solubilize components of

  5. Acetaldehyde and parkinsonism: role of CYP450 2E1

    PubMed Central

    Vaglini, Francesca; Viaggi, Cristina; Piro, Valentina; Pardini, Carla; Gerace, Claudio; Scarselli, Marco; Corsini, Giovanni Umberto

    2013-01-01

    The present review update the relationship between acetaldehyde (ACE) and parkinsonism with a specific focus on the role of P450 system and CYP 2E1 isozyme particularly. We have indicated that ACE is able to enhance the parkinsonism induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin able to damage the nigrostriatal dopaminergic pathway. Similarly diethyldithiocarbamate, the main metabolite of disulfiram, a drug widely used to control alcoholism, diallylsulfide (DAS) and phenylisothiocyanate also markedly enhance the toxin-related parkinsonism. All these compounds are substrate/inhibitors of CYP450 2E1 isozyme. The presence of CYP 2E1 has been detected in the dopamine (DA) neurons of rodent Substantia Nigra (SN), but a precise function of the enzyme has not been elucidated yet. By treating CYP 2E1 knockout (KO) mice with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, the SN induced lesion was significantly reduced when compared with the lesion observed in wild-type animals. Several in vivo and in vitro studies led to the conclusion that CYP 2E1 may enhance the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice by increasing free radical production inside the dopaminergic neurons. ACE is a good substrate for CYP 2E1 enzyme as the other substrate-inhibitors and by this way may facilitate the susceptibility of dopaminergic neurons to toxic events. The literature suggests that ethanol and/or disulfiram may be responsible for toxic parkinsonism in human and it indicates that basal ganglia are the major targets of disulfiram toxicity. A very recent study reports that there are a decreased methylation of the CYP 2E1 gene and increased expression of CYP 2E1 mRNA in Parkinson's disease (PD) patient brains. This study suggests that epigenetic variants of this cytochrome contribute to the susceptibility, thus confirming multiples lines of evidence which indicate a link between environmental toxins and PD. PMID:23801948

  6. Impact of bioethanol fuel implementation in transport based on modelled acetaldehyde concentration in the urban environment.

    PubMed

    Sundvor, Ingrid; López-Aparicio, Susana

    2014-10-15

    This study shows the results obtained from emission and air dispersion modelling of acetaldehyde in the city of Oslo and associated with the circulation of bioethanol vehicles. Two scenarios of bioethanol implementation, both realistic and hypothetical, have been considered under winter conditions; 1) realistic baseline scenario, which corresponds to the current situation in Oslo where one bus line is running with bioethanol (E95; 95% ethanol-5% petrol) among petrol and diesel vehicles; and 2) a hypothetical scenario characterized by a full implementation of high-blend bioethanol (i.e. E85) as fuel for transportation, and thus an entire bioethanol fleet. The results indicate that a full implementation of bioethanol will have a certain impact on urban air quality due to direct emissions of acetaldehyde. Acetaldehyde emissions are estimated to increase by 233% and concentration levels increase up to 650% with regard to the baseline. PMID:25064718

  7. Redirection of the Reaction Specificity of a Thermophilic Acetolactate Synthase toward Acetaldehyde Formation

    PubMed Central

    Cheng, Maria; Yoshiyasu, Hayato; Okano, Kenji; Ohtake, Hisao; Honda, Kohsuke

    2016-01-01

    Acetolactate synthase and pyruvate decarboxylase are thiamine pyrophosphate-dependent enzymes that convert pyruvate into acetolactate and acetaldehyde, respectively. Although the former are encoded in the genomes of many thermophiles and hyperthermophiles, the latter has been found only in mesophilic organisms. In this study, the reaction specificity of acetolactate synthase from Thermus thermophilus was redirected to catalyze acetaldehyde formation to develop a thermophilic pyruvate decarboxylase. Error-prone PCR and mutant library screening led to the identification of a quadruple mutant with 3.1-fold higher acetaldehyde-forming activity than the wild-type. Site-directed mutagenesis experiments revealed that the increased activity of the mutant was due to H474R amino acid substitution, which likely generated two new hydrogen bonds near the thiamine pyrophosphate-binding site. These hydrogen bonds might result in the better accessibility of H+ to the substrate-cofactor-enzyme intermediate and a shift in the reaction specificity of the enzyme. PMID:26731734

  8. Feasibility studies of a fuel cell for cogeneration of homogeneously catalyzed acetaldehyde and electricity from ethanol

    SciTech Connect

    Malhotra, S.; Datta, R.

    1996-10-01

    The development and feasibility of a novel fuel cell for simultaneously generating electricity and homogeneously catalyzed acetaldehyde from ethanol are reported. The fuel cell is based on the supported molten-salt electrocatalysis technique that allows use of homogeneous (liquid-phase) catalysts in fuel cells for the first time. The electrocatalytic reaction combines the chemistry of the Wacker process conventionally used for acetaldehyde production from the partial oxidation of ethylene and that of the Veba-Chemie method. Nafion membranes impregnated with different electrolytic materials were used in the fuel cell as electrolytes to allow operation at reaction temperatures up to 165 C. Results obtained are comparable to those reported in the literature on partial oxidation of ethylene to acetaldehyde in a fuel cell based on conventional heterogeneous electrocatalysts.

  9. Artisanal alcohol production in Mayan Guatemala: chemical safety evaluation with special regard to acetaldehyde contamination.

    PubMed

    Kanteres, Fotis; Rehm, Jürgen; Lachenmeier, Dirk W

    2009-11-01

    There is a lack of knowledge regarding the composition, production, distribution, and consumption of artisanal alcohol, particularly in the developing world. In Nahualá, an indigenous Mayan municipality located in highland Guatemala, heavy alcohol consumption appears to have had a significant negative impact on health, a major role in cases of violence and domestic abuse, and a link to street habitation. Cuxa, an artisanally, as well as commercially produced sugarcane alcohol, is widely consumed by heavy drinkers in this community. Cuxa samples from all distribution points in the community were obtained and chemically analyzed for health-relevant constituents and contaminants including methanol, acetaldehyde, higher alcohols, and metals. From those, only acetaldehyde was confirmed to be present in unusually high levels (up to 126 g/hl of pure alcohol), particularly in samples that were produced clandestinely. Acetaldehyde has been evaluated as "possibly carcinogenic" and has also been identified as having significant human exposure in a recent risk assessment. This study explores the reasons for the elevated levels of acetaldehyde, through both sampling and analyses of raw and intermediary products of cuxa production, as well as interviews from producers of the clandestine alcohol. For further insight, we experimentally produced this alcohol in our laboratory, based on the directions provided by the producers, as well as materials from the town itself. Based on these data, the origin of the acetaldehyde contamination appears to be due to chemical changes induced during processing, with the major causative factors consisting of poor hygiene, aerobic working conditions, and inadequate yeast strains, compounded by flawed distillation methodology that neglects separation of the first fractions of the distillate. These results indicate a preventable public health concern for consumers, which can be overcome through education about good manufacturing practices, as well

  10. EPAC activation inhibits acetaldehyde-induced activation and proliferation of hepatic stellate cell via Rap1.

    PubMed

    Yang, Yan; Yang, Feng; Wu, Xiaojuan; Lv, Xiongwen; Li, Jun

    2016-05-01

    Hepatic stellate cells (HSCs) activation represents an essential event during alcoholic liver fibrosis (ALF). Previous studies have demonstrated that the rat HSCs could be significantly activated after exposure to 200 μmol/L acetaldehyde for 48 h, and the cAMP/PKA signaling pathways were also dramatically upregulated in activated HSCs isolated from alcoholic fibrotic rat liver. Exchange protein activated by cAMP (EPAC) is a family of guanine nucleotide exchange factors (GEFs) for the small Ras-like GTPases Rap, and is being considered as a vital mediator of cAMP signaling in parallel with the principal cAMP target protein kinase A (PKA). Our data showed that both cAMP/PKA and cAMP/EPAC signaling pathways were involved in acetaldehyde-induced HSCs. Acetaldehyde could reduce the expression of EPAC1 while enhancing the expression of EPAC2. The cAMP analog Me-cAMP, which stimulates the EPAC/Rap1 pathway, could significantly decrease the proliferation and collagen synthesis of acetaldehyde-induced HSCs. Furthermore, depletion of EPAC2, but not EPAC1, prevented the activation of HSC measured as the production of α-SMA and collagen type I and III, indicating that EPAC1 appears to have protective effects on acetaldehyde-induced HSCs. Curiously, activation of PKA or EPAC perhaps has opposite effects on the synthesis of collagen and α-SMA: EPAC activation by Me-cAMP increased the levels of GTP-bound (activated) Rap1 while PKA activation by Phe-cAMP had no significant effects on such binding. These results suggested that EPAC activation could inhibit the activation and proliferation of acetaldehyde-induced HSCs via Rap1. PMID:26854595

  11. Quantification of DNA adducts in lungs, liver and brain of rats exposed to acetaldehyde.

    PubMed

    Garcia, Camila C M; Batista, Guilherme L; Freitas, Florêncio P; Lopes, Fernando S; Sanchez, Angélica B; Gutz, Ivano G R; Di Mascio, Paolo; Medeiros, Marisa H G

    2014-10-01

    Air pollution is a major risk for human health. Acetaldehyde is an environmental pollutant present in tobacco smoke, vehicle exhaust and several food products. Formation of DNA adducts has been regarded as a critical factor in the mechanisms of acetaldehyde mutagenicity and carcinogenesis. Acetaldehyde reacts with 2'-deoxyguanosine in DNA to primarily form N(2)-ethylidene-2'-deoxyguanosine (N(2)-ethylidene-dGuo). The subsequent reaction of N(2)-ethylidene-dGuo with another molecule of acetaldehyde gives rise to 1,N(2)-propano-2´-deoxyguanosine (1,N(2)-propanodGuo). In this study, on-line reverse-phase high-performance liquid chromatography (HPLC) separation with tandem mass spectrometry detection was utilized for the accurate quantification of 1,N(2)-propanodGuo and 1,N(2)-etheno-2'-deoxyguanosine (1,N(2)-edGuo) in tissues of rats exposed to 12 ppb, 33 ppb and 96 ppb acetaldehyde in atmospheric air for 50 days. A significant increase in the levels of 1,N(2)-propanodGuo was observed in lung tissues of rats exposed to 12 ppb (7.8/10(8) dGuo); 33 ppb (8.9/10(8) dGuo) and 96 ppb (11.6/10(8) dGuo) compared to controls (4.2/10(8) dGuo). For comparative purposes, the levels of 1,N(2)-etheno-2'-deoxyguanosine (1,N(2)-edGuo), which is produced from a,b-unsaturated aldehydes formed during the lipid peroxidation process were also measured. Elevated levels of 1,N(2)-edGuo were observed only in lung tissues of animals exposed to 96 ppb acetaldehyde. 1,N(2)-propanodGuo also differed quantitatively in liver but not in brain. The monitoring of 1,N(2)-propanodGuo levels in tissues provides important information on acetaldehyde genotoxicity and may contribute to the elucidation of the mechanisms associated with acetaldehyde exposure and cancer risk. Supported byFAPESP:2011/10048-5, CAPES, INCT Redoxoma:573530/2008-4,NAP Redoxoma: 2011.1.9352.1.8, CEPID Redoxoma:2013/07937-8. PMID:26461370

  12. Acetaldehyde Induces Cytotoxicity of SH-SY5Y Cells via Inhibition of Akt Activation and Induction of Oxidative Stress

    PubMed Central

    Yan, Tingting; Zhao, Yan; Zhang, Xia

    2016-01-01

    Excessive alcohol consumption can lead to brain tissue damage and cognitive dysfunction. It has been shown that heavy drinking is associated with an earlier onset of neurodegenerative diseases such as Alzheimer's disease. Acetaldehyde, the most toxic metabolite of ethanol, is speculated to mediate the brain tissue damage and cognitive dysfunction induced by the chronic excessive consumption of alcohol. However, the exact mechanisms by which acetaldehyde induces neurotoxicity are not totally understood. In this study, we investigated the cytotoxic effects of acetaldehyde in SH-SY5Y cells and found that acetaldehyde induced apoptosis of SH-SY5Y cells by downregulating the expression of antiapoptotic Bcl-2 and Bcl-xL and upregulating the expression of proapoptotic Bax. Acetaldehyde treatment led to a significant decrease in the levels of activated Akt and cyclic AMP-responsive element binding protein (CREB). In addition, acetaldehyde induced the activation of p38 mitogen-activated protein kinase (MAPK) while inhibiting the activation of extracellular signal-regulated kinases (ERKs, p44/p42MAPK). Meanwhile, acetaldehyde treatment caused an increase in the production of reactive oxygen species and elevated the oxidative stress in SH-SY5Y cells. Therefore, acetaldehyde induces cytotoxicity of SH-SY5Y cells via promotion of apoptotic signaling, inhibition of cell survival pathway, and induction of oxidative stress. PMID:26649137

  13. Whole-Exome Sequencing in a South American Cohort Links ALDH1A3, FOXN1 and Retinoic Acid Regulation Pathways to Autism Spectrum Disorders

    PubMed Central

    Moreno-Ramos, Oscar A.; Olivares, Ana María; Haider, Neena B.; de Autismo, Liga Colombiana; Lattig, María Claudia

    2015-01-01

    Autism spectrum disorders (ASDs) are a range of complex neurodevelopmental conditions principally characterized by dysfunctions linked to mental development. Previous studies have shown that there are more than 1000 genes likely involved in ASD, expressed mainly in brain and highly interconnected among them. We applied whole exome sequencing in Colombian—South American trios. Two missense novel SNVs were found in the same child: ALDH1A3 (RefSeq NM_000693: c.1514T>C (p.I505T)) and FOXN1 (RefSeq NM_003593: c.146C>T (p.S49L)). Gene expression studies reveal that Aldh1a3 and Foxn1 are expressed in ~E13.5 mouse embryonic brain, as well as in adult piriform cortex (PC; ~P30). Conserved Retinoic Acid Response Elements (RAREs) upstream of human ALDH1A3 and FOXN1 and in mouse Aldh1a3 and Foxn1 genes were revealed using bioinformatic approximation. Chromatin immunoprecipitation (ChIP) assay using Retinoid Acid Receptor B (Rarb) as the immunoprecipitation target suggests RA regulation of Aldh1a3 and Foxn1 in mice. Our results frame a possible link of RA regulation in brain to ASD etiology, and a feasible non-additive effect of two apparently unrelated variants in ALDH1A3 and FOXN1 recognizing that every result given by next generation sequencing should be cautiously analyzed, as it might be an incidental finding. PMID:26352270

  14. Whole-Exome Sequencing in a South American Cohort Links ALDH1A3, FOXN1 and Retinoic Acid Regulation Pathways to Autism Spectrum Disorders.

    PubMed

    Moreno-Ramos, Oscar A; Olivares, Ana María; Haider, Neena B; de Autismo, Liga Colombiana; Lattig, María Claudia

    2015-01-01

    Autism spectrum disorders (ASDs) are a range of complex neurodevelopmental conditions principally characterized by dysfunctions linked to mental development. Previous studies have shown that there are more than 1000 genes likely involved in ASD, expressed mainly in brain and highly interconnected among them. We applied whole exome sequencing in Colombian-South American trios. Two missense novel SNVs were found in the same child: ALDH1A3 (RefSeq NM_000693: c.1514T>C (p.I505T)) and FOXN1 (RefSeq NM_003593: c.146C>T (p.S49L)). Gene expression studies reveal that Aldh1a3 and Foxn1 are expressed in ~E13.5 mouse embryonic brain, as well as in adult piriform cortex (PC; ~P30). Conserved Retinoic Acid Response Elements (RAREs) upstream of human ALDH1A3 and FOXN1 and in mouse Aldh1a3 and Foxn1 genes were revealed using bioinformatic approximation. Chromatin immunoprecipitation (ChIP) assay using Retinoid Acid Receptor B (Rarb) as the immunoprecipitation target suggests RA regulation of Aldh1a3 and Foxn1 in mice. Our results frame a possible link of RA regulation in brain to ASD etiology, and a feasible non-additive effect of two apparently unrelated variants in ALDH1A3 and FOXN1 recognizing that every result given by next generation sequencing should be cautiously analyzed, as it might be an incidental finding. PMID:26352270

  15. Inhibition of telomerase activity preferentially targets aldehyde dehydrogenase-positive cancer stem-like cells in lung cancer

    PubMed Central

    2011-01-01

    Background Mortality rates for advanced lung cancer have not declined for decades, even with the implementation of novel chemotherapeutic regimens or the use of tyrosine kinase inhibitors. Cancer Stem Cells (CSCs) are thought to be responsible for resistance to chemo/radiotherapy. Therefore, targeting CSCs with novel compounds may be an effective approach to reduce lung tumor growth and metastasis. We have isolated and characterized CSCs from non-small cell lung cancer (NSCLC) cell lines and measured their telomerase activity, telomere length, and sensitivity to the novel telomerase inhibitor MST312. Results The aldehyde dehydrogenase (ALDH) positive lung cancer cell fraction is enriched in markers of stemness and endowed with stem cell properties. ALDH+ CSCs display longer telomeres than the non-CSC population. Interestingly, MST312 has a strong antiproliferative effect on lung CSCs and induces p21, p27 and apoptosis in the whole tumor population. MST312 acts through activation of the ATM/pH2AX DNA damage pathway (short-term effect) and through decrease in telomere length (long-term effect). Administration of this telomerase inhibitor (40 mg/kg) in the H460 xenograft model results in significant tumor shrinkage (70% reduction, compared to controls). Combination therapy consisting of irradiation (10Gy) plus administration of MST312 did not improve the therapeutic efficacy of the telomerase inhibitor alone. Treatment with MST312 reduces significantly the number of ALDH+ CSCs and their telomeric length in vivo. Conclusions We conclude that antitelomeric therapy using MST312 mainly targets lung CSCs and may represent a novel approach for effective treatment of lung cancer. PMID:21827695

  16. Lactate dehydrogenase-elevating virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This book chapter describes the taxonomic classification of Lactate dehydrogenase-elevating virus (LDV). Included are: host, genome, classification, morphology, physicochemical and physical properties, nucleic acid, proteins, lipids, carbohydrates, geographic range, phylogenetic properties, biologic...

  17. Substrate specificity, substrate channeling, and allostery in BphJ: an acylating aldehyde dehydrogenase associated with the pyruvate aldolase BphI.

    PubMed

    Baker, Perrin; Carere, Jason; Seah, Stephen Y K

    2012-06-01

    BphJ, a nonphosphorylating acylating aldehyde dehydrogenase, catalyzes the conversion of aldehydes to form acyl-coenzyme A in the presence of NAD(+) and coenzyme A (CoA). The enzyme is structurally related to the nonacylating aldehyde dehydrogenases, aspartate-β-semialdehyde dehydrogenase and phosphorylating glyceraldehyde-3-phosphate dehydrogenase. Cys-131 was identified as the catalytic thiol in BphJ, and pH profiles together with site-specific mutagenesis data demonstrated that the catalytic thiol is not activated by an aspartate residue, as previously proposed. In contrast to the wild-type enzyme that had similar specificities for two- or three-carbon aldehydes, an I195A variant was observed to have a 20-fold higher catalytic efficiency for butyraldehyde and pentaldehyde compared to the catalytic efficiency of the wild type toward its natural substrate, acetaldehyde. BphJ forms a heterotetrameric complex with the class II aldolase BphI that channels aldehydes produced in the aldol cleavage reaction to the dehydrogenase via a molecular tunnel. Replacement of Ile-171 and Ile-195 with bulkier amino acid residues resulted in no more than a 35% reduction in acetaldehyde channeling efficiency, showing that these residues are not critical in gating the exit of the channel. Likewise, the replacement of Asn-170 in BphJ with alanine and aspartate did not substantially alter aldehyde channeling efficiencies. Levels of activation of BphI by BphJ N170A, N170D, and I171A were reduced by ≥3-fold in the presence of NADH and ≥4.5-fold when BphJ was undergoing turnover, indicating that allosteric activation of the aldolase has been compromised in these variants. The results demonstrate that the dehydrogenase coordinates the catalytic activity of BphI through allostery rather than through aldehyde channeling. PMID:22574886

  18. 40 CFR 80.56 - Measurement methods for formaldehyde and acetaldehyde.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 16 2010-07-01 2010-07-01 false Measurement methods for formaldehyde and acetaldehyde. 80.56 Section 80.56 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) REGULATION OF FUELS AND FUEL ADDITIVES Reformulated Gasoline § 80.56 Measurement methods for formaldehyde...

  19. PRIMARY PROCESSES IN THE PHOTOLYSIS OF ACETALDEHYDE AT 3000 A AND 25 DEGREES C

    EPA Science Inventory

    The quantum yields of the gaseous products CH4, CO, and H2 have been determined in 3000-A photolyses of acetaldehyde and its mixtures with CO2, i-C4H8, and O2. The results help define the nature and the quantum yields of the primary processes.

  20. BIOGENIC SOURCES OF FORMALDEHYDE AND ACETALDEHYDE DURING SUMMER AND WINTER CONDITIONS

    EPA Science Inventory

    Photochemical modeling estimated contributions to ambient concentrations of formaldehyde and acetaldehyde from biogenic emissions over the continental United States during January 2001 (Eos Trans. AGU, 83(47), Fall Meet. Suppl., Abstract A52B-0117). Results showed that maximum co...

  1. Formaldehyde and acetaldehyde in a high traffic street of Rio de Janeiro, Brazil

    NASA Astrophysics Data System (ADS)

    Corrêa, Sérgio M.; Martins, Eduardo M.; Arbilla, Graciela

    The data for formaldehyde and acetaldehyde levels in ambient air of the city of Rio de Janeiro, obtained in the period from 4 December 1998 to 17 January 2001 is presented. A total of 28 samples were collected at a downtown area, where emissions may be mainly attributed to the vehicular fleet. Values between 1.52 and 54.31 ppb for formaldehyde and between 2.36 and 45.60 ppb for acetaldehyde were obtained. The high acetaldehyde/formaldehyde ratios (0.76 to 1.61) are a consequence of the use of oxygenated fuels. Brazilian cities are unique in that the vehicles use hydrated ethanol (over 4 million of light duty vehicles), gasohol (a mixture with gasoline and 24% v/v of ethanol) and diesel fuels. The analysis of vehicle exhaust and model simulations of the air quality in August and December 1999, confirmed that the high levels of acetaldehyde could be attributed to direct emissions of the vehicular fleet and to the photochemical initiated oxidation of organic compounds.

  2. Involvement of the endogenous opioid system in the psychopharmacological actions of ethanol: the role of acetaldehyde

    PubMed Central

    Font, Laura; Luján, Miguel Á.; Pastor, Raúl

    2013-01-01

    Significant evidence implicates the endogenous opioid system (EOS) (opioid peptides and receptors) in the mechanisms underlying the psychopharmacological effects of ethanol. Ethanol modulates opioidergic signaling and function at different levels, including biosynthesis, release, and degradation of opioid peptides, as well as binding of endogenous ligands to opioid receptors. The role of β-endorphin and µ-opioid receptors (OR) have been suggested to be of particular importance in mediating some of the behavioral effects of ethanol, including psychomotor stimulation and sensitization, consumption and conditioned place preference (CPP). Ethanol increases the release of β-endorphin from the hypothalamic arcuate nucleus (NArc), which can modulate activity of other neurotransmitter systems such as mesolimbic dopamine (DA). The precise mechanism by which ethanol induces a release of β-endorphin, thereby inducing behavioral responses, remains to be elucidated. The present review summarizes accumulative data suggesting that the first metabolite of ethanol, the psychoactive compound acetaldehyde, could participate in such mechanism. Two lines of research involving acetaldehyde are reviewed: (1) implications of the formation of acetaldehyde in brain areas such as the NArc, with high expression of ethanol metabolizing enzymes and presence of cell bodies of endorphinic neurons and (2) the formation of condensation products between DA and acetaldehyde such as salsolinol, which exerts its actions via OR. PMID:23914161

  3. 40 CFR 721.10662 - Acetaldehyde, substituted-, reaction products with 2-butyne-1, 4-diol (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...-, reaction products with 2-butyne-1, 4-diol (generic). (a) Chemical substance and significant new uses... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Acetaldehyde, substituted-, reaction... ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT SIGNIFICANT NEW USES OF...

  4. 40 CFR 721.10662 - Acetaldehyde, substituted-, reaction products with 2-butyne-1, 4-diol (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...-, reaction products with 2-butyne-1, 4-diol (generic). (a) Chemical substance and significant new uses... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Acetaldehyde, substituted-, reaction... ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT SIGNIFICANT NEW USES OF...

  5. Modeling the IR Spectra of Acetaldehyde from a New Vibrational Configuration Interaction Method

    SciTech Connect

    Begue, Didier; Pouchan, Claude

    2007-12-26

    In this paper we present a new vibrational configuration interaction method known as a parallel vibrational multiple window configuration interaction P lowbar VMWCI which generates several VCI matrices and enables the variational treatment of medium size molecular systems. Application to acetaldehyde gives a new interpretation of the MIR experimental data.

  6. Regional Sources of Atmospheric Formaldehyde and Acetaldehyde, and Implications for Atmospheric Modeling

    EPA Science Inventory

    Formaldehyde and acetaldehyde concentrations over the Eastern half of the United States are simulated with a 3-D air quality model to identify the most important chemical precursors under January and July conditions. We find that both aldehydes primarily result from photochemical...

  7. Alcohol Dehydrogenase from Methylobacterium organophilum

    PubMed Central

    Wolf, H. J.; Hanson, R. S.

    1978-01-01

    The alcohol dehydrogenase from Methylobacterium organophilum, a facultative methane-oxidizing bacterium, has been purified to homogeneity as indicated by sodium dodecyl sulfate-gel electrophoresis. It has several properties in common with the alcohol dehydrogenases from other methylotrophic bacteria. The active enzyme is a dimeric protein, both subunits having molecular weights of about 62,000. The enzyme exhibits broad substrate specificity for primary alcohols and catalyzes the two-step oxidation of methanol to formate. The apparent Michaelis constants of the enzyme are 2.9 × 10−5 M for methanol and 8.2 × 10−5 M for formaldehyde. Activity of the purified enzyme is dependent on phenazine methosulfate. Certain characteristics of this enzyme distinguish it from the other alcohol dehydrogenases of other methylotrophic bacteria. Ammonia is not required for, but stimulates the activity of newly purified enzyme. An absolute dependence on ammonia develops after storage of the purified enzyme. Activity is not inhibited by phosphate. The fluorescence spectrum of the enzyme indicates that it and the cofactor associated with it may be chemically different from the alcohol dehydrogenases from other methylotrophic bacteria. The alcohol dehydrogenases of Hyphomicrobium WC-65, Pseudomonas methanica, Methylosinus trichosporium, and several facultative methylotrophs are serologically related to the enzyme purified in this study. The enzymes of Rhodopseudomonas acidophila and of organisms of the Methylococcus group did not cross-react with the antiserum prepared against the alcohol dehydrogenase of M. organophilum. Images PMID:80974

  8. Acetaldehyde stimulation of net gluconeogenic carbon movement from applied malic Acid in tomato fruit pericarp tissue.

    PubMed

    Halinska, A; Frenkel, C

    1991-03-01

    Applied acetaldehyde is known to lead to sugar accumulation in fruit including tomatoes (Lycopersicon esculentum) (O Paz, HW Janes, BA Prevost, C Frenkel [1982] J Food Sci 47: 270-274) presumably due to stimulation of gluconeogenesis. This conjecture was examined using tomato fruit pericarp discs as a test system and applied i-[U-(14)C]malic acid as the source for gluconeogenic carbon mobilization. The label from malate was recovered in respiratory CO(2), in other organic acids, in ethanol insoluble material, and an appreciable amount in the ethanol soluble sugar fraction. In Rutgers tomatoes, the label recovery in the sugar fraction and an attendant label reduction in the organic acids fraction intensified with fruit ripening. In both Rutgers and in the nonripening tomato rin, these processes were markedly stimulated by 4000 ppm acetaldehyde. The onset of label apportioning from malic acids to sugars coincided with decreased levels of fructose-2,6-biphosphate, the gluconeogenesis inhibitor. In acetaldehyde-treated tissues, with enhanced label mobilization, this decline reached one-half to one third of the initial fructose-2,6-biphosphate levels. Application of 30 micromolar fructose-2,6-biphosphate or 2,5-anhydro-d-mannitol in turn led to a precipitous reduction in the label flow to sugars presumably due to inhibition of fructose-1,6-biphosphatase by the compounds. We conclude that malic and perhaps other organic acids are carbon sources for gluconeogenesis occurring normally in ripening tomatoes. The process is stimulated by acetaldehyde apparently by attenuating the fructose-2,6-biphosphate levels. The mode of the acetaldehyde regulation of fructose-2,6-biphosphate metabolism awaits clarification. PMID:16668078

  9. Abundances of ethylene oxide and acetaldehyde in hot molecular cloud cores

    NASA Technical Reports Server (NTRS)

    Nummelin, A.; Dickens, J. E.; Bergman, P.; Hjalmarson, A.; Irvine, W. M.; Ikeda, M.; Ohishi, M.

    1998-01-01

    We have searched for millimetre-wave line emission from ethylene oxide (c-C2H4O) and its structural isomer acetaldehyde (CH3CHO) in 11 molecular clouds using SEST. Ethylene oxide and acetaldehyde were detected through multiple lines in the hot cores NGC 6334F, G327.3-0.6, G31.41+0.31, and G34.3+0.2. Acetaldehyde was also detected towards G10.47+0.03, G322.2+0.6, and Orion 3'N, and one ethylene oxide line was tentatively detected in G10.47+0.03. Column densities and rotational excitation temperatures were derived using a procedure which fits the observed line intensifies by finding the minimum chi 2-value. The resulting rotational excitation temperatures of ethylene oxide and acetaldehyde are in the range 16-38 K, indicating that these species are excited in the outer, cooler parts of the hot cores or that the excitation is significantly subthermal. For an assumed source size of 20", the deduced column densities are (0.6-1)x10(14) cm-2 for ethylene oxide and (2-5)x10(14) cm-2 for acetaldehyde. The fractional abundances with respect to H2 are X[c-C2H4O]=(2-6)xl0(-10), and X[CH3CHO]=(0.8-3)x10(-9). The ratio X[CH3CHO]/X[c-C2H4O] varies between 2.6 (NGC 6334F) and 8.5 (G327.3-0.6). We also detected and analysed multiple transitions of CH3OH, CH3OCH3, C2H5OH, and HCOOH. The chemical, and possibly evolutionary, states of NGC 6334F, G327.3-0.6, G31.41+0.31, and G34.3+0.2 seem to be very similar.

  10. The utility of STAT6 and ALDH1 expression in the differential diagnosis of solitary fibrous tumor versus prostate-specific stromal neoplasms.

    PubMed

    Guner, Gunes; Bishop, Justin A; Bezerra, Stephania M; Taheri, Diana; Zahavi, David J; Mendoza Rodriguez, Maria Angelica; Sharma, Rajni; Epstein, Jonathan I; Netto, George J

    2016-08-01

    Solitary fibrous tumor (SFT) diagnosis in prostate can be challenging on small biopsies. Prostatic stromal tumors of unknown malignant potential (STUMP) and SFT have overlapping features. NAB2-STAT6 gene fusions that were recently identified in various SFTs lead to nuclear translocalization of STAT6. Nuclear STAT6 immunostaining is now considered an adjunct for SFT diagnosis. We evaluated STAT6 and an emerging stemness marker, ALDH1, in the differential diagnosis of SFT versus prostatic stromal lesions. Sixteen STUMPs, 12 SFTs, and 4 prostatic stromal sarcomas (12 needle biopsies, 13 radical prostatectomies, 7 transurethral resections) were retrieved (1995-2015). Sections were stained with polyclonal STAT6 antibody (Santa Cruz Biotechnology, Santa Cruz, CA; S20, 1:100) and monoclonal ALDH1 antibody (BD Biosciences, San Jose, CA; clone 44, 1:250). In STAT6 cases, only unequivocal nuclear staining (with/without cytoplasmic staining) was considered positive. Cytoplasmic ALDH1 staining was counted positive. Ten of 11 evaluable SFTs demonstrated strong and diffuse nuclear STAT6 positivity; 4 of 16 STUMPs had nuclear staining that was weak (1/4) or focal (1/4). ALDH1 positivity was seen in 10 of 12 evaluable SFTs and 3 of 15 STUMPs. Prostatic stromal sarcomas were STAT6 negative (4/4); 2 of 4 were ALDH1 positive. The sensitivity and specificity for STAT6 for the diagnosis of SFT were 91% and 75%, respectively. Coexpression of STAT6 and ALDH1 yielded the same sensitivity but improved the specificity (100%) for the diagnosis of SFT. STAT6 is a useful marker in the differential diagnosis of SFT versus STUMP. Using STAT6 and ALDH1 together increases specificity. STUMPs can show STAT6 positivity, and when they do, it is likely to be weak or focal. PMID:27068523

  11. Modeling of experimental treatment of acetaldehyde-laden air and phenol-containing water using corona discharge technique.

    PubMed

    Faungnawakij, Kajornsak; Sano, Noriaki; Charinpanitkul, Tawatchai; Tanthapanichakoon, Wiwut

    2006-03-01

    Acetaldehyde-laden air and phenol-contaminated water were experimentally treated using corona discharge reactions and gas absorption in a single water-film column. Mathematical modeling of the combined treatment was developed in this work. Efficient removal of the gaseous acetaldehyde was achieved while the corona discharge reactions produced short-lived species such as O and O- as well as ozone. Direct contact of the radicals and ions with water was known to produce aqueous OH radical, which contributes to the decomposition of organic contaminants: phenol, absorbed acetaldehyde, and intermediate byproducts in the water. The influence of initial phenol concentration ranging from 15 to 50 mg L(-1) and that of influent acetaldehyde ranging from 0 to 200 ppm were experimentally investigated and used to build the math model. The maximum energetic efficiency of TOC, phenol, and acetaldehyde were obtained at 25.6 x 10(-9) mol carbon J(-1), 25.0 x 10(-9) mol phenol J(-1), and 2.0 x 10(-9) mol acetaldehyde J(-1), respectively. The predictions for the decomposition of acetaldehyde, phenol, and their intermediates were found to be in good agreement with the experimental results. PMID:16568779

  12. Formation of 2-propanol in condensed molecular films of acetaldehyde following electron impact ionisation-induced proton transfer*

    NASA Astrophysics Data System (ADS)

    Borrmann, Tobias; Swiderek, Petra

    2016-06-01

    Experimental studies on thin condensed layers of acetaldehyde have previously revealed that electron exposure at an energy above the ionisation threshold leads to formation of 2-propanol. However, the mechanism of this reaction remained unclear. Therefore, a computational approach is used to explore the electron-induced reactions of acetaldehyde yielding 2-propanol. Starting from hydrogen-bonded dimers of acetaldehyde we show that the initial ionisation event triggers proton transfer between the two acetaldehyde moieties resulting in a hydrogen-bonded complex of a [OCCH3] radical and a protonated acetaldehyde cation. Given an excess energy of up to 0.75 eV and a favourable arrangement, a methyl radical released upon dissociation of the CC bond within the [OCCH3] radical can migrate to the carbonyl carbon of the protonated acetaldehyde cation. This produces a 2-propanol radical cation and CO. Neutral 2-propanol is then obtained by recombination with a second electron. A mechanism involving ionisation-driven proton transfer is thus proposed as pathway to the formation of 2-propanol during electron exposure of condensed layers of acetaldehyde.

  13. Catalytic and Molecular Properties of the Quinohemoprotein Tetrahydrofurfuryl Alcohol Dehydrogenase from Ralstonia eutropha Strain Bo

    PubMed Central

    Zarnt, Grit; Schräder, Thomas; Andreesen, Jan R.

    2001-01-01

    The quinohemoprotein tetrahydrofurfuryl alcohol dehydrogenase (THFA-DH) from Ralstonia eutropha strain Bo was investigated for its catalytic properties. The apparent kcat/Km and Ki values for several substrates were determined using ferricyanide as an artificial electron acceptor. The highest catalytic efficiency was obtained with n-pentanol exhibiting a kcat/Km value of 788 × 104 M−1 s−1. The enzyme showed substrate inhibition kinetics for most of the alcohols and aldehydes investigated. A stereoselective oxidation of chiral alcohols with a varying enantiomeric preference was observed. Initial rate studies using ethanol and acetaldehyde as substrates revealed that a ping-pong mechanism can be assumed for in vitro catalysis of THFA-DH. The gene encoding THFA-DH from R. eutropha strain Bo (tfaA) has been cloned and sequenced. The derived amino acid sequence showed an identity of up to 67% to the sequence of various quinoprotein and quinohemoprotein dehydrogenases. A comparison of the deduced sequence with the N-terminal amino acid sequence previously determined by Edman degradation analysis suggested the presence of a signal sequence of 27 residues. The primary structure of TfaA indicated that the protein has a tertiary structure quite similar to those of other quinoprotein dehydrogenases. PMID:11222593

  14. Structural and kinetic characterization of recombinant 2-hydroxymuconate semialdehyde dehydrogenase from Pseudomonas putida G7.

    PubMed

    Araújo, Simara Semíramis de; Neves, Cíntia Mara Leal; Guimarães, Samuel Leite; Whitman, Christian P; Johnson, William H; Aparicio, Ricardo; Nagem, Ronaldo Alves Pinto

    2015-08-01

    The first enzyme in the oxalocrotonate branch of the naphthalene-degradation lower pathway in Pseudomonas putida G7 is NahI, a 2-hydroxymuconate semialdehyde dehydrogenase which converts 2-hydroxymuconate semialdehyde to 2-hydroxymuconate in the presence of NAD(+). NahI is in family 8 (ALDH8) of the NAD(P)(+)-dependent aldehyde dehydrogenase superfamily. In this work, we report the cloning, expression, purification and preliminary structural and kinetic characterization of the recombinant NahI. The nahI gene was subcloned into a T7 expression vector and the enzyme was overexpressed in Escherichia coli ArcticExpress as a hexa-histidine-tagged fusion protein. After purification by affinity and size-exclusion chromatography, dynamic light scattering and small-angle X-ray scattering experiments were conducted to analyze the oligomeric state and the overall shape of the enzyme in solution. The protein is a tetramer in solution and has nearly perfect 222 point group symmetry. Protein stability and secondary structure content were evaluated by a circular dichroism spectroscopy assay under different thermal conditions. Furthermore, kinetic assays were conducted and, for the first time, KM (1.3±0.3μM) and kcat (0.9s(-1)) values were determined at presumed NAD(+) saturation. NahI is highly specific for its biological substrate and has no activity with salicylaldehyde, another intermediate in the naphthalene-degradation pathway. PMID:26032336

  15. Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

    PubMed Central

    Kim, Kyung-Jin; Pearl, Phillip L.; Jensen, Kimmo; Snead, O. Carter; Malaspina, Patrizia; Jakobs, Cornelis

    2011-01-01

    Abstract Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1, ALDH5A1; E.C. 1.2.1.24; OMIM 610045, 271980) deficiency is a rare heritable disorder that disrupts the metabolism of the inhibitory neurotransmitter 4-aminobutyric acid (GABA). Identified in conjunction with increased urinary excretion of the GABA analog gamma-hydroxybutyric acid (GHB), numerous patients have been identified worldwide and the autosomal-recessive disorder has been modeled in mice. The phenotype is one of nonprogressive neurological dysfunction in which seizures may be prominently displayed. The murine model is a reasonable phenocopy of the human disorder, yet the severity of the seizure disorder in the mouse exceeds that observed in SSADH-deficient patients. Abnormalities in GABAergic and GHBergic neurotransmission, documented in patients and mice, form a component of disease pathophysiology, although numerous other disturbances (metabolite accumulations, myelin abnormalities, oxidant stress, neurosteroid depletion, altered bioenergetics, etc.) are also likely to be involved in developing the disease phenotype. Most recently, the demonstration of a redox control system in the SSADH protein active site has provided new insights into the regulation of SSADH by the cellular oxidation/reduction potential. The current review summarizes some 30 years of research on this protein and disease, addressing pathological mechanisms in human and mouse at the protein, metabolic, molecular, and whole-animal level. Antioxid. Redox Signal. 15, 691–718. PMID:20973619

  16. Ethanol Disrupts Chondrification of the Neurocranial Cartilages in Medaka Embryos without Affecting Aldehyde Dehydrogenase 1A2 (Aldh1A2) Promoter Methylation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Medaka (Oryzias latipes) embryos at different developmental stages were exposed to ethanol for 48 h, then allowed to hatch. Teratogenic effects were evaluated in hatchlings after examining chondrocranial cartilage deformities. Ethanol disrupted cartilage development in medaka in a dose and developme...

  17. Retinoic acid homeostasis through aldh1a2 and cyp26a1 mediates meiotic entry in Nile tilapia (Oreochromis niloticus)

    PubMed Central

    Feng, Ruijuan; Fang, Lingling; Cheng, Yunying; He, Xue; Jiang, Wentao; Dong, Ranran; Shi, Hongjuan; Jiang, Dongneng; Sun, Lina; Wang, Deshou

    2015-01-01

    Meiosis is a process unique to the differentiation of germ cells. Retinoic acid (RA) is the key factor controlling the sex-specific timing of meiotic initiation in tetrapods; however, the role of RA in meiotic initiation in teleosts has remained unclear. In this study, the genes encoding RA synthase aldh1a2, and catabolic enzyme cyp26a1 were isolated from Nile tilapia (Oreochromis niloticus), a species without stra8. The expression of aldh1a2 was up-regulated and expression of cyp26a1 was down-regulated before the meiotic initiation in ovaries and in testes. Treatment with RA synthase inhibitor or disruption of Aldh1a2 by CRISPR/Cas9 resulted in delayed meiotic initiation, with simultaneous down-regulation of cyp26a1 and up-regulation of sycp3. By contrast, treatment with an inhibitor of RA catabolic enzyme and disruption of cyp26a1 resulted in earlier meiotic initiation, with increased expression of aldh1a2 and sycp3. Additionally, treatment of XY fish with estrogen (E2) and XX fish with fadrozole led to sex reversal and reversion of meiotic initiation. These results indicate that RA is indispensable for meiotic initiation in teleosts via a stra8 independent signaling pathway where both aldh1a2 and cyp26a1 are critical. In contrast to mammals, E2 is a major regulator of sex determination and meiotic initiation in teleosts. PMID:25976364

  18. Michael hydratase alcohol dehydrogenase or just alcohol dehydrogenase?

    PubMed Central

    2014-01-01

    The Michael hydratase – alcohol dehydrogenase (MhyADH) from Alicycliphilus denitrificans was previously identified as a bi-functional enzyme performing a hydration of α,β-unsaturated ketones and subsequent oxidation of the formed alcohols. The investigations of the bi-functionality were based on a spectrophotometric assay and an activity staining in a native gel of the dehydrogenase. New insights in the recently discovered organocatalytic Michael addition of water led to the conclusion that the previously performed experiments to identify MhyADH as a bi-functional enzyme and their results need to be reconsidered and the reliability of the methodology used needs to be critically evaluated. PMID:24949265

  19. Structure and function of phosphonoacetaldehyde dehydrogenase: the missing link in phosphonoacetate formation

    PubMed Central

    Agarwal, Vinayak; Peck, Spencer C.; Chen, Jui-Hui; Borisova, Svetlana A.; Chekan, Jonathan R.; van der Donk, Wilfred A.; Nair, Satish K.

    2015-01-01

    Summary Phosphonates (C-PO32−) have application as antibiotics, herbicides and detergents. In some environments, these molecules represent the predominant source for phosphorus, and several microbes have evolved dedicated enzymatic machineries for phosphonate degradation. For example, most common naturally occurring phosphonates can be catabolized to either phosphonoacetaldehyde or phosphonoacetate, which can then be hydrolyzed to generate inorganic phosphate and acetaldehyde or acetate, respectively. The phosphonoacetaldehyde oxidase gene (phnY) links these two hydrolytic processes and provides a previously unknown catabolic mechanism for phosphonoacetate production in the microbial metabolome. Here, we present biochemical characterization of PhnY and high-resolution crystal structures of the apo state, as well as complexes with substrate, cofactor and product. Kinetic analysis of active site mutants demonstrates how a highly conserved aldehyde dehydrogenase active site has been modified in nature to generate activity with a phosphonate substrate. PMID:24361046

  20. Mutant alcohol dehydrogenase leads to improved ethanol tolerance in Clostridium thermocellum

    SciTech Connect

    Brown, Steven D; Guss, Adam M; Karpinets, Tatiana V; Parks, Jerry M; Smolin, Nikolai; Yang, Shihui; Land, Miriam L; Klingeman, Dawn Marie; Bhandiwad, Ashwini; Rodriguez, Jr., Miguel; Raman, Babu; Shao, Xiongjun; Mielenz, Jonathan R; Smith, Jeremy C; Keller, Martin; Lynd, Lee R

    2011-01-01

    Clostridium thermocellum is a thermophilic, obligately anaerobic, Gram-positive bacterium that is a candidate microorganism for converting cellulosic biomass into ethanol through consolidated bioprocessing. Ethanol intolerance is an important metric in terms of process economics, and tolerance has often been described as a complex and likely multigenic trait for which complex gene interactions come into play. Here, we resequence the genome of an ethanol-tolerant mutant, show that the tolerant phenotype is primarily due to a mutated bifunctional acetaldehyde-CoA/alcohol dehydrogenase gene (adhE), hypothesize based on structural analysis that cofactor specificity may be affected, and confirm this hypothesis using enzyme assays. Biochemical assays confirm a complete loss of NADH-dependent activity with concomitant acquisition of NADPH-dependent activity, which likely affects electron flow in the mutant. The simplicity of the genetic basis for the ethanol-tolerant phenotype observed here informs rational engineering of mutant microbial strains for cellulosic ethanol production.

  1. Complex Behavior of ALDH1A1 and IGFBP1 in Liver Metastasis from a Colorectal Cancer.

    PubMed

    Kim, Jin Cheon; Ha, Ye Jin; Tak, Ka Hee; Roh, Seon Ae; Kim, Chan Wook; Kim, Tae Won; Kim, Seon-Kyu; Kim, Seon-Young; Cho, Dong-Hyung; Kim, Yong Sung

    2016-01-01

    Using our data set (GSE50760) previously established by RNA sequencing, the present study aimed to identify upregulated genes associated with colorectal cancer (CRC) liver metastasis (CLM) and verify their biological behavior. The potential roles of candidate genes in tumors were assessed using cell proliferation and invasion assays. Tissue samples were collected from 18 CRC patients with synchronous CLM and two CRC cell lines (SW480 and SW620) were used for transfection and cloning. The roles of the genes identified in CLM were verified using immunohistochemistry in 48 nude mice after intrasplenic transplantation of CRC cells. mRNA and protein expression was determined by quantitative real-time reverse transcription polymerase chain reaction and western blot, respectively. Nine genes were initially selected according to the relevance of their molecular function and biological process and, finally, ALDH1A1 and IGFBP1 were chosen based on differential mRNA expression and a positive correlation with protein expression. The overexpression of ALDH1A1 and IGFBP1 significantly and time-dependently decreased cell proliferation (p ≤ 0.001-0.003) and suppressed invasiveness by ≥3-fold over control cells (p < 0.001) in the SW480 cell line, whereas they had a slight effect on reducing SW620 cell proliferation. The protein expression levels of E-cadherin, N-cadherin, claudin-1, and vimentin were significantly higher in CLM than in primary tumor tissues (p < 0.05). However, the cadherin switch, namely, N-cadherin overexpression with reduced E-cadherin expression, was not observed in CLM tissues and transfected CRC cells. Irrespective of reduced proliferation and invasion found on in vitro cell assays, persistent overexpression of β-catenin, vimentin, and ZO-1 in IGFBP1-overexpressing SW480 cells possibly contributed to CLM development in mice implanted with IGFBP1-overexpressing SW480 cells (CLM occurrences: SW480/IGFBP1-transfected mice vs. SW480/vector- and SW480/ALDH1A1

  2. Complex Behavior of ALDH1A1 and IGFBP1 in Liver Metastasis from a Colorectal Cancer

    PubMed Central

    Kim, Jin Cheon; Ha, Ye Jin; Tak, Ka Hee; Roh, Seon Ae; Kim, Chan Wook; Kim, Tae Won; Kim, Seon-Kyu; Kim, Seon-Young; Cho, Dong-Hyung; Kim, Yong Sung

    2016-01-01

    Using our data set (GSE50760) previously established by RNA sequencing, the present study aimed to identify upregulated genes associated with colorectal cancer (CRC) liver metastasis (CLM) and verify their biological behavior. The potential roles of candidate genes in tumors were assessed using cell proliferation and invasion assays. Tissue samples were collected from 18 CRC patients with synchronous CLM and two CRC cell lines (SW480 and SW620) were used for transfection and cloning. The roles of the genes identified in CLM were verified using immunohistochemistry in 48 nude mice after intrasplenic transplantation of CRC cells. mRNA and protein expression was determined by quantitative real-time reverse transcription polymerase chain reaction and western blot, respectively. Nine genes were initially selected according to the relevance of their molecular function and biological process and, finally, ALDH1A1 and IGFBP1 were chosen based on differential mRNA expression and a positive correlation with protein expression. The overexpression of ALDH1A1 and IGFBP1 significantly and time-dependently decreased cell proliferation (p ≤ 0.001–0.003) and suppressed invasiveness by ≥3-fold over control cells (p < 0.001) in the SW480 cell line, whereas they had a slight effect on reducing SW620 cell proliferation. The protein expression levels of E-cadherin, N-cadherin, claudin-1, and vimentin were significantly higher in CLM than in primary tumor tissues (p < 0.05). However, the cadherin switch, namely, N-cadherin overexpression with reduced E-cadherin expression, was not observed in CLM tissues and transfected CRC cells. Irrespective of reduced proliferation and invasion found on in vitro cell assays, persistent overexpression of β-catenin, vimentin, and ZO-1 in IGFBP1-overexpressing SW480 cells possibly contributed to CLM development in mice implanted with IGFBP1-overexpressing SW480 cells (CLM occurrences: SW480/IGFBP1-transfected mice vs. SW480/vector- and SW480/ALDH1

  3. Acetaldehyde as an Intermediate in the Electroreduction of Carbon Monoxide to Ethanol on Oxide‐Derived Copper

    PubMed Central

    Bertheussen, Erlend; Verdaguer‐Casadevall, Arnau; Ravasio, Davide; Montoya, Joseph H.; Trimarco, Daniel B.; Roy, Claudie; Meier, Sebastian; Wendland, Jürgen; Nørskov, Jens K.

    2015-01-01

    Abstract Oxide‐derived copper (OD‐Cu) electrodes exhibit unprecedented CO reduction performance towards liquid fuels, producing ethanol and acetate with >50 % Faradaic efficiency at −0.3 V (vs. RHE). By using static headspace‐gas chromatography for liquid phase analysis, we identify acetaldehyde as a minor product and key intermediate in the electroreduction of CO to ethanol on OD‐Cu electrodes. Acetaldehyde is produced with a Faradaic efficiency of ≈5 % at −0.33 V (vs. RHE). We show that acetaldehyde forms at low steady‐state concentrations, and that free acetaldehyde is difficult to detect in alkaline solutions using NMR spectroscopy, requiring alternative methods for detection and quantification. Our results represent an important step towards understanding the CO reduction mechanism on OD‐Cu electrodes. PMID:26692282

  4. Acetaldehyde as an intermediate in the electroreduction of carbon monoxide to ethanol on oxide-derived copper

    DOE PAGESBeta

    Bertheussen, Erlend; Verdaguer-Casadevall, Arnau; Ravasio, Davide; Montoya, Joseph H.; Trimarco, Daniel B.; Roy, Claudie; Meier, Sebastian; Wendland, Jürgen; Nørskov, Jens K.; Stephens, Ifan E. L.; et al

    2015-12-21

    Oxide-derived copper (OD-Cu) electrodes exhibit unprecedented CO reduction performance towards liquid fuels, producing ethanol and acetate with >50 % Faradaic efficiency at -0.3 V (vs. RHE). By using static headspace-gas chromatography for liquid phase analysis, we identify acetaldehyde as a minor product and key intermediate in the electroreduction of CO to ethanol on OD-Cu electrodes. Acetaldehyde is produced with a Faradaic efficiency of ≈5 % at -0.33 V (vs. RHE). We show that acetaldehyde forms at low steady-state concentrations, and that free acetaldehyde is difficult to detect in alkaline solutions using NMR spectroscopy, requiring alternative methods for detection and quantification.more » Our results indicate an important step towards understanding the CO reduction mechanism on OD-Cu electrodes.« less

  5. Acetaldehyde as an intermediate in the electroreduction of carbon monoxide to ethanol on oxide-derived copper

    SciTech Connect

    Bertheussen, Erlend; Verdaguer-Casadevall, Arnau; Ravasio, Davide; Montoya, Joseph H.; Trimarco, Daniel B.; Roy, Claudie; Meier, Sebastian; Wendland, Jürgen; Nørskov, Jens K.; Stephens, Ifan E. L.; Chorkendorff, Ib

    2015-12-21

    Oxide-derived copper (OD-Cu) electrodes exhibit unprecedented CO reduction performance towards liquid fuels, producing ethanol and acetate with >50 % Faradaic efficiency at -0.3 V (vs. RHE). By using static headspace-gas chromatography for liquid phase analysis, we identify acetaldehyde as a minor product and key intermediate in the electroreduction of CO to ethanol on OD-Cu electrodes. Acetaldehyde is produced with a Faradaic efficiency of ≈5 % at -0.33 V (vs. RHE). We show that acetaldehyde forms at low steady-state concentrations, and that free acetaldehyde is difficult to detect in alkaline solutions using NMR spectroscopy, requiring alternative methods for detection and quantification. Our results indicate an important step towards understanding the CO reduction mechanism on OD-Cu electrodes.

  6. Ambient temperature operated acetaldehyde vapour detection of spray deposited cobalt doped zinc oxide thin film.

    PubMed

    Shalini, S; Balamurugan, D

    2016-03-15

    Undoped and Co-doped ZnO thin films were prepared by a home built spray pyrolysis method. X-ray diffraction results indicate that both undoped and Co-doped ZnO have a polycrystalline nature and a preferential orientation peak in the (002) plane. From a field-emission scanning electron micrographs of annealed films, a uniform distribution of nanoparticles along with nanorods was observed. UV-Visible measurement indicated that all the films are transparent in the visible region. The electrical resistance was also reported. The acetaldehyde sensing behaviour of the prepared undoped and Co-doped ZnO thin films was studied using the chemi-resistive method at ambient temperature (∼30 °C). In the presence of 10 ppm of acetaldehyde vapour, the Co-doped ZnO thin films showed good sensing response of 74% with fast response and recovery time of 3 s and 110 s respectively. PMID:26748067

  7. [Medichronal lowers blood ethanol and acetaldehyde and restores the concentration of catecholamines in rat tissues].

    PubMed

    Bozhko HKZh; Boĭko, T P; Kostiukovs'ka, L S

    1995-01-01

    Variation of ethanol and acetaldehyde concentrations in blood, catecholamines in hypothalamus, brain stem and hemispheres, heart and adrenal glands, serotonin in the same structures of the brain, thin intestine and blood in rats was studied. Isolated action of medichronal during 10 days against the background of prolonged administration of moderate doses of ethanol significantly lowered ethanol and acetaldehyde concentration in the animal blood. Medichronal increased the level of noradrenaline, lowered under the conditions of ethanol intoxication in the hypothalamus, and increased adrenalina level in the heart; noradrenaline level in adrenal glands is restored. The amount of serotonin in the blood and tissues increased under the conditions of ethanol intoxication did not vary under the action of medichronal. The obtained results indicate to pronounced detoxication influence of medichronal. One of the mechanisms of its action is normalizing the catecholamine changes caused by the ethanol intoxication in tissues. PMID:8592777

  8. Photocatalytic and thermal catalytic oxidation of acetaldehyde on Pt/TiO{sub 2}

    SciTech Connect

    Falconer, J.L.; Magrini-Bair, K.A.

    1998-10-01

    Low concentrations of acetaldehyde in air (60 ppm) were oxidized over TiO{sub 2} (Degussa P25) and 0.5% Pt/TiO{sub 2} catalysts from 24 to 200 C by photocatalytic and thermal catalytic reactions. On Pt/TiO{sub 2}, the contribution by photocatalytic oxidation (PCO) is a maximum at 140 C, where conversion is 2.8 times that at 24 C. Titania without Pt deactivates rapidly during PCO at elevated temperature due to a thermal catalytic reaction that takes place in parallel with PCO, but the addition of Pt dramatically slows deactivation. Apparently, Pt supplies spillover oxygen onto the TiO{sub 2}, and the oxygen oxidizes the acetaldehyde decomposition products in a dark reaction. Deactivated TiO{sub 2} without Pt was regenerated by PCO at room temperature. Seven distinct reactions (photocatalytic and thermal catalytic) are identified on Pt/TiO{sub 2}.

  9. Proton transfer reactions between nitric acid and acetone, hydroxyacetone, acetaldehyde and benzaldehyde in the solid phase.

    PubMed

    Lasne, Jérôme; Laffon, Carine; Parent, Philippe

    2012-12-01

    The heterogeneous and homogeneous reactions of acetone, hydroxyacetone, acetaldehyde and benzaldehyde with solid nitric acid (HNO(3)) films have been studied with Reflection-Absorption Infrared Spectroscopy (RAIRS) under Ultra-High Vacuum (UHV) conditions in the 90-170 K temperature range. In the bulk or at the surface of the films, nitric acid transfers its proton to the carbonyl function of the organic molecules, producing protonated acetone-H(+), hydroxyacetone-H(+), acetaldehyde-H(+) and benzaldehyde-H(+), and nitrate anions NO(3)(-), a reaction not observed when nitric acid is previously hydrated [J. Lasne, C. Laffon and Ph. Parent, Phys. Chem. Chem. Phys., 2012, 14, 697]. This provides a molecular-scale description of the carbonyl protonation reaction in an acid medium, the first step of the acid-catalyzed condensation of carbonyl compounds, fuelling the growth of secondary organic aerosols (SOA) in the atmosphere. PMID:23090634

  10. Spectrophotometric study and potentiometric titration between sulfite and nitrite ions using acetaldehyde complex of nitroprusside as a carrier

    SciTech Connect

    Ahmed, Y.Z.; Abd-Elmottalb, M.

    1985-11-01

    A complex between sodium nitroprusside (NP) and acetaldehyde of 1:1 in aqueous solution of pH 10 has been prepared and used as an analytical reagent for the spectrophotometric determination of sulfite and nitrite ions. Nitrite ion can be titrated against sulfite ion and vise versa in equivalent amounts with high accuracy in the presence of the acetaldehyde complex of nitroprusside as a carrier using a potentiometric titration technique. 9 references, 3 figures, 2 tables.

  11. Genetics Home Reference: lactate dehydrogenase deficiency

    MedlinePlus

    ... dehydrogenase-B pieces (subunits) of the lactate dehydrogenase enzyme. This enzyme is found throughout the body and is important ... cells. There are five different forms of this enzyme, each made up of four protein subunits. Various ...

  12. (3s←n) REMPI of jet-cooled acetaldehyde using two laser beams

    NASA Astrophysics Data System (ADS)

    Philis, J. G.; Kosmidis, C.

    2001-05-01

    The 3s←n Rydberg transition of acetaldehyde has been studied by a two-color experiment (545 and 272.5 nm light) by means of a TOF mass spectrometer. The recorded spectra are in close resemblance to the known one-color (2R+1) MPI spectra (364 nm). Nevertheless, the observed mass spectra are different. These differences are discussed in detail. Moreover, two-photon resonances of atomic carbon have been detected, indicating complete dissociation of some neutral fragments.

  13. Enzymic conversion of ethanol to acetaldehyde as a model recovery system

    SciTech Connect

    Kierstan, M.

    1982-10-01

    Ethanol is readily produced by use of traditional fermentation processes using yeasts, and more recently by use of immobilized cell systems. However, the product concentrations obtained in these systems are limited by the inhibitory effects on the microorganisms of the product, ethanol. Furthermore, the dilute product concentrations thus obtained combined with the relatively high boiling point of ethanol result in systems which require a high degree of energy input for product recovery. Recent advances in genetic engineering techniques offer opportunities for improving the characteristics of the yeasts used in ethanol production. These techniques also provide the potential for improving the production yields of microbial enzymes for specific applications. With this consideration in mind work was undertaken on an enzymic system for removal from a fermentation media of an ethanol product which also results in upgrading of the product. Conversion of ethanol to acetaldehyde can be achieved without the involvement of nicotinamide cofactors by use of the enzyme alcohol oxidase obtainable from Candida boidinii. The product acetaldehyde has a relatively low boiling point (21 degrees C) and, therefore, readily evaporates from systems operating above this temperature. This is compatible with normal operating temperatures for ethanol production. The acetaldehyde so produced can then be readily condensed and be utilized or chemically converted to other products. The production of acetaldehyde is accompanied by production of hydrogen peroxide. The effect of the removal of this product, by the use of catalase, on the primary process was also investigated. The system outlined has potential for development into an immobilized enzyme or cell system which may be made compatible with an immobilized Saccharomyces cerevisiae system for improved efficiency of glucose utilization.

  14. Fibulin-3 negatively regulates ALDH1 via c-MET suppression and increases γ-radiation-induced sensitivity in some pancreatic cancer cell lines

    SciTech Connect

    Kim, In-Gyu; Lee, Jae-Ha; Kim, Seo-Yoen; Kim, Jeong-Yul; Cho, Eun-Wie

    2014-11-21

    Highlights: • FBLN-3 gene was poorly expressed in some pancreatic cancer lines. • FBLN-3 promoter region was highly methylated in some pancreatic cancer cell lines. • FBLN-3 inhibited c-MET activation and expression and reduced cellular level of ALDH1. • FBLN-3/c-Met/ALDH1 axis modulates stemness and EMT in pancreatic cancer cells. - Abstract: Fibulin-3 (FBLN-3) has been postulated to be either a tumor suppressor or promoter depending on the cell type, and hypermethylation of the FBLN-3 promoter is often associated with human disease, especially cancer. We report that the promoter region of the FBLN-3 was significantly methylated (>95%) in some pancreatic cancer cell lines and thus FBLN-3 was poorly expressed in pancreatic cancer cell lines such as AsPC-1 and MiaPaCa-2. FBLN-3 overexpression significantly down-regulated the cellular level of c-MET and inhibited hepatocyte growth factor-induced c-MET activation, which were closely associated with γ-radiation resistance of cancer cells. Moreover, we also showed that c-MET suppression or inactivation decreased the cellular level of ALDH1 isozymes (ALDH1A1 or ALDH1A3), which serve as cancer stem cell markers, and subsequently induced inhibition of cell growth in pancreatic cancer cells. Therefore, forced overexpression of FBLN-3 sensitized cells to cytotoxic agents such as γ-radiation and strongly inhibited the stemness and epithelial to mesenchymal transition (EMT) property of pancreatic cancer cells. On the other hand, if FBLN3 was suppressed in FBLN-3-expressing BxPC3 cells, the results were opposite. This study provides the first demonstration that the FBLN-3/c-MET/ALDH1 axis in pancreatic cancer cells partially modulates stemness and EMT as well as sensitization of cells to the detrimental effects of γ-radiation.

  15. Acetaldehyde Oxime, A Product Formed during the In Vivo Nitrate Reductase Assay of Soybean Leaves 1

    PubMed Central

    Mulvaney, Charlene S.; Hageman, Richard H.

    1984-01-01

    Evolution of nitrogen oxides (NO(x), primarily as nitric oxide) from soybean (Glycine max [L.] Merr.) leaves during purged in vivo nitrate reductase assays had been reported; however, these reports were based on a method that had been used for determination of NO(x) in air. This method also detects other N compounds. Preliminary work led us to doubt that the evolved N was nitric oxide. Studies were undertaken to identify the N compound evolved from the in vivo assay that had been reported as NO(x). Material for identification was obtained by cryogenic trapping and fractional distillation, and by chemical trapping procedures. Mass spectrometry, ultraviolet spectroscopy, and 15N-labeled nitrate were used to identify the compounds evolved and to determine whether these compounds were derived from nitrate. Acetaldehyde oxime was identified as the predominant N compound evolved and this compound is readily detected by the method for NO(x) determination. Substantial quantities of acetaldehyde oxime (16.2 micromoles per gram fresh weight per hour) were evolved during the in vivo assay. Small amounts of nitrous oxide (0.63 micrograms N per gram fresh weight per hour) were evolved, but this compound is not detected as NO(x). Acetaldehyde oxime and nitrous oxide were both produced as a result of nitrate (15NO3−) reduction during the assay. PMID:16663781

  16. Acetaldehyde Oxime, A Product Formed during the In Vivo Nitrate Reductase Assay of Soybean Leaves.

    PubMed

    Mulvaney, C S; Hageman, R H

    1984-09-01

    Evolution of nitrogen oxides (NO((x)), primarily as nitric oxide) from soybean (Glycine max [L.] Merr.) leaves during purged in vivo nitrate reductase assays had been reported; however, these reports were based on a method that had been used for determination of NO((x)) in air. This method also detects other N compounds. Preliminary work led us to doubt that the evolved N was nitric oxide. Studies were undertaken to identify the N compound evolved from the in vivo assay that had been reported as NO((x)). Material for identification was obtained by cryogenic trapping and fractional distillation, and by chemical trapping procedures. Mass spectrometry, ultraviolet spectroscopy, and (15)N-labeled nitrate were used to identify the compounds evolved and to determine whether these compounds were derived from nitrate. Acetaldehyde oxime was identified as the predominant N compound evolved and this compound is readily detected by the method for NO((x)) determination. Substantial quantities of acetaldehyde oxime (16.2 micromoles per gram fresh weight per hour) were evolved during the in vivo assay. Small amounts of nitrous oxide (0.63 micrograms N per gram fresh weight per hour) were evolved, but this compound is not detected as NO((x)). Acetaldehyde oxime and nitrous oxide were both produced as a result of nitrate ((15)NO(3) (-)) reduction during the assay. PMID:16663781

  17. Cholesterol Enhances the Toxic Effect of Ethanol and Acetaldehyde in Primary Mouse Hepatocytes

    PubMed Central

    López-Islas, Anayelly; Chagoya-Hazas, Victoria; Pérez-Aguilar, Benjamin; Palestino-Domínguez, Mayrel; Souza, Verónica; Miranda, Roxana U.; Bucio, Leticia; Gómez-Quiroz, Luis Enrique; Gutiérrez-Ruiz, María-Concepción

    2016-01-01

    Obesity and alcohol consumption are risk factors for hepatic steatosis, and both commonly coexist. Our objective was to evaluate the effect of ethanol and acetaldehyde on primary hepatocytes obtained from mice fed for two days with a high cholesterol (HC) diet. HC hepatocytes increased lipid and cholesterol content. HC diet sensitized hepatocytes to the toxic effect of ethanol and acetaldehyde. Cyp2E1 content increased with HC diet, as well as in those treated with ethanol or acetaldehyde, while the activity of this enzyme determined in microsomes increased in the HC and in all ethanol treated hepatocytes, HC and CW. Oxidized proteins were increased in the HC cultures treated or not with the toxins. Transmission electron microscopy showed endoplasmic reticulum (ER) stress and megamitochondria in hepatocytes treated with ethanol as in HC and the ethanol HC treated hepatocytes. ER stress determined by PERK content was increased in ethanol treated hepatocytes from HC mice and CW. Nuclear translocation of ATF6 was observed in HC hepatocytes treated with ethanol, results that indicate that lipids overload and ethanol treatment favor ER stress. Oxidative stress, ER stress, and mitochondrial damage underlie potential mechanisms for increased damage in steatotic hepatocyte treated with ethanol. PMID:26788255

  18. Risk assessment for the Italian population of acetaldehyde in alcoholic and non-alcoholic beverages.

    PubMed

    Paiano, Viviana; Bianchi, Giancarlo; Davoli, Enrico; Negri, Eva; Fanelli, Roberto; Fattore, Elena

    2014-07-01

    Acetaldehyde is a naturally-occurring carcinogenic compound, present in different food items, especially in alcoholic beverages. The aims of this study were to measure acetaldehyde concentration in different beverages consumed in Italy and to estimate the potential cancer risk. The analytical procedure was based on headspace solid-phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS), using the isotopic dilution method. The margin of exposure (MOE) approach of the European Food Safety Authority (EFSA) was used for risk characterisation. The highest concentrations (median, min-max) were detected in grappa samples (499, 23.4-1850mg/l), followed by fruit-based liqueurs and spirits (62.0, 5.23-483mg/l) and wine (68.0, 18.1-477mg/l); the lowest were detected in gin (0.91, 0.78-1.90mg/l). The lowest MOE was estimated for high wine consumers (69). These results suggest that regulatory measures and consumer guidance may be necessary for acetaldehyde in beverages. PMID:24518311

  19. Effects of acetaldehyde and acrolein on blood pressure in guanethidine-pretreated hypertensive rats

    SciTech Connect

    Green, M.A.; Egle, J.L. Jr.

    1983-06-15

    These experiments were undertaken to study the effect of the interaction of the antihypertensive agent guanethidine and two aldehydes possessing sympathomimetic activity on the blood pressure of spontaneously hypertensive rats (SHR). Acetaldehyde, when administered iv to acutely guanethidine-pretreated (15 mg/kg) SHRs under urethane anesthesia, caused a potentiated pressor response in the dose range of 3 to 40 mg/kg. When administered iv to chronically guanethidine-pretreated SHRs, a pressor response was noted at low doses and a depressor response at high doses. Acrolein (0.05 to 0.5 mg/kg) produced a pressor response at low doses and a depressor response at high doses in both acutely and chronically guanethidine-pretreated SHRs. Pressor responses, particularly to acetaldehyde, may be due to an enlarged tyramine-releasable pool, hyperreactivity of alpha adrenergic receptors of SHRs, or guanethidine inhibition of norepinephrine reuptake. Depressor responses to high doses of aldehydes may be attributed to vagal stimulation or direct vasodilation. It is concluded that there is a significant interaction between the aldehydes and guanethidine which may have implications for someone undergoing treatment with guanethidine for hypertension while being exposed to acetaldehyde and related compounds from ethanol and tobacco smoke.

  20. Astrochemistry at work in the L1157-B1 shock: acetaldehyde formation

    NASA Astrophysics Data System (ADS)

    Codella, C.; Fontani, F.; Ceccarelli, C.; Podio, L.; Viti, S.; Bachiller, R.; Benedettini, M.; Lefloch, B.

    2015-04-01

    The formation of complex organic molecules (COMs) in protostellar environments is a hotly debated topic. In particular, the relative importance of the gas phase processes as compared to a direct formation of COMs on the dust grain surfaces is so far unknown. We report here the first high-resolution images of acetaldehyde (CH3CHO) emission towards the chemically rich protostellar shock L1157-B1, obtained at 2 mm with the IRAM Plateau de Bure interferometer. Six blueshifted CH3CHO lines with Eu = 26-35 K have been detected. The acetaldehyde spatial distribution follows the young (˜ 2000 yr) outflow cavity produced by the impact of the jet with the ambient medium, indicating that this COM is closely associated with the region enriched by iced species evaporated from dust mantles and released into the gas phase. A high CH3CHO relative abundance, 2-3 × 10-8, is inferred, similarly to what found in hot corinos. Astrochemical modelling indicates that gas phase reactions can produce the observed quantity of acetaldehyde only if a large fraction of carbon, of the order of 0.1 per cent, is locked into iced hydrocarbons.

  1. Effects and action mechanisms of Korean pear (Pyrus pyrifolia cv. Shingo) on alcohol detoxification.

    PubMed

    Lee, Ho-Sun; Isse, Toyoshi; Kawamoto, Toshihiro; Woo, Hyun-Su; Kim, An Keun; Park, Jong Y; Yang, Mihi

    2012-11-01

    Korean pear (Pyrus pyrifolia cv. Shingo) has been used as a traditional medicine for alleviating alcohol hangover. However, scientific evidence for its effectiveness or mechanism is not clearly established. To investigate its mechanism of alcohol detoxification, both in vitro and in vivo studies were performed with an aldehyde dehydrogenase 2 (ALDH2) alternated animal model. The pear extract (10 mL/kg bw) was administered to Aldh2 normal (C57BL/6) and deficient (Aldh2 -/-) male mice. After 30 min, ethanol (1 g or 2 g/kg bw) was administered to the mice via gavage. Levels of alcohol and acetaldehyde in blood were quantified by GC/MS. First, it was observed that the pears stimulated both alcohol dehydrogenase (ADH) and ALDH activities by 2∼3-  and 1.3-fold in in vitro studies, respectively. Second, mouse PK data (AUC(∞) and C(max) ) showed that the pear extract decreased the alcohol level in blood regardless of ALDH2 genotype. Third, the pear increased the acetaldehyde level in blood in Aldh2 deficient mice but not in Aldh2 normal mice. Therefore, the consistent in vitro and in vivo data suggest that Korean pears stimulate the two key alcohol-metabolizing enzymes. These stimulations could be the main mechanism of the Korean pear for alcohol detoxification. Finally, the results suggest that polymorphisms of human ALDH2 could bring out individual variations in the effects of Korean pear on alcohol detoxification. PMID:22451246

  2. Conversion of Suspected Food Carcinogen 5-Hydroxymethylfurfural by Sulfotransferases and Aldehyde Dehydrogenases in Postmitochondrial Tissue Preparations of Humans, Mice, and Rats.

    PubMed

    Sachse, Benjamin; Meinl, Walter; Glatt, Hansruedi; Monien, Bernhard H

    2016-01-01

    The food contaminant 5-hydroxymethylfurfural (HMF) is formed by heat- and acid-catalyzed reactions from carbohydrates. More than 80% of HMF is metabolized by oxidation of the aldehyde group in mice and rats. Sulfo conjugation yields mutagenic 5-sulfoxymethylfurfural, the probable cause for the neoplastic effects observed in HMF-treated rodents. Considerable metabolic differences between species hinder assessing the tumorigenic risk associated with human dietary HMF uptake. Here, we assayed HMF turnover catalyzed by sulfotransferases or by aldehyde dehydrogenases (ALDHs) in postmitochondrial preparations from liver, kidney, colon, and lung of humans, mice, and rats. The tissues-specific clearance capacities of HMF sulfo conjugation (CL(SC)) and ALDH-catalyzed oxidation (CL(OX)) were concentrated to the liver. The hepatic clearance CL(SC) in mice (males: 487 µl/min/kg bw, females: 2520 µl/min/kg bw) and rats (males: 430 µl/min/kg bw, females: 198 µl/min/kg bw) were considerably higher than those in humans (males: 21.2 µl/min/kg bw, females: 32.2 µl/min/kg bw). The ALDH-related clearance rates CLOX in mice (males: 3400 ml/min/kg bw, females: 1410 ml/min/kg bw) were higher than those of humans (males: 436 ml/min/kg bw, females: 646 ml/min/kg bw) and rats (males: 627 ml/min/kg bw, females: 679 ml/min/kg bw). The ratio of CL(OX) to CL(SC) was lowest in female mice. This finding indicated that HMF sulfo conjugation was most substantial in the liver of female mice, a target tissue for HMF-induced neoplastic effects, and that humans may be less sensitive regarding HMF sulfo conjugation compared with the rodent models. PMID:26454887

  3. Histamine H4-receptors inhibit mast cell renin release in ischemia/reperfusion via protein kinase C ε-dependent aldehyde dehydrogenase type-2 activation.

    PubMed

    Aldi, Silvia; Takano, Ken-ichi; Tomita, Kengo; Koda, Kenichiro; Chan, Noel Y-K; Marino, Alice; Salazar-Rodriguez, Mariselis; Thurmond, Robin L; Levi, Roberto

    2014-06-01

    Renin released by ischemia/reperfusion (I/R) from cardiac mast cells (MCs) activates a local renin-angiotensin system (RAS) causing arrhythmic dysfunction. Ischemic preconditioning (IPC) inhibits MC renin release and consequent activation of this local RAS. We postulated that MC histamine H4-receptors (H4Rs), being Gαi/o-coupled, might activate a protein kinase C isotype-ε (PKCε)-aldehyde dehydrogenase type-2 (ALDH2) cascade, ultimately eliminating MC-degranulating and renin-releasing effects of aldehydes formed in I/R and associated arrhythmias. We tested this hypothesis in ex vivo hearts, human mastocytoma cells, and bone marrow-derived MCs from wild-type and H4R knockout mice. We found that activation of MC H4Rs mimics the cardioprotective anti-RAS effects of IPC and that protection depends on the sequential activation of PKCε and ALDH2 in MCs, reducing aldehyde-induced MC degranulation and renin release and alleviating reperfusion arrhythmias. These cardioprotective effects are mimicked by selective H4R agonists and disappear when H4Rs are pharmacologically blocked or genetically deleted. Our results uncover a novel cardioprotective pathway in I/R, whereby activation of H4Rs on the MC membrane, possibly by MC-derived histamine, leads sequentially to PKCε and ALDH2 activation, reduction of toxic aldehyde-induced MC renin release, prevention of RAS activation, reduction of norepinephrine release, and ultimately to alleviation of reperfusion arrhythmias. This newly discovered protective pathway suggests that MC H4Rs may represent a new pharmacologic and therapeutic target for the direct alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure. PMID:24696042

  4. Case of Sjögren-Larsson syndrome with a large deletion in the ALDH3A2 gene confirmed by single nucleotide polymorphism array analysis.

    PubMed

    Gaboon, Nagwa E A; Jelani, Musharraf; Almramhi, Mona M; Mohamoud, Hussein S A; Al-Aama, Jumana Y

    2015-07-01

    Sjögren-Larsson syndrome (SLS) is a neurocutaneous disorder inherited in an autosomal recessive fashion. SLS patients are characterized by lipid metabolism error, primarily leading to cardinal signs of ichthyosis, spasticity and mental retardation. Additional signs include short stature, epilepsy, retinal abnormalities and photophobia. More than 90 mutations of the ALDH3A2 gene have been reported for SLS, and such variants can be successfully detected at a rate of 94% by direct DNA sequencing. We performed direct sequencing of ALDH3A2 gene from the index patient, however, no mutation could be detected. HumanCytoSNPs12 array analysis and subsequent targeted single nucleotide polymorphism analysis revealed a novel deletion mutation at chromosome 17p11.2. This 67-Kb region includes the first five coding exons of ALDH3A2, and is flanked by rs2245639 and rs962801. To the best of our knowledge, this mutation is novel and our findings broaden the mutation spectrum of ALDH3A2 causing SLS phenotype. PMID:25855245

  5. Clinical diagnosis, treatment, and ALDH7A1 mutations in pyridoxine-dependent epilepsy in three Chinese infants.

    PubMed

    Yang, Zhixian; Yang, Xiaoling; Wu, Ye; Wang, Jingmin; Zhang, Yuehua; Xiong, Hui; Jiang, Yuwu; Qin, Jiong

    2014-01-01

    Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder that causes seizures in neonates and infants. Mutations of the ALDH7A1 gene are now recognized as the molecular basis PDE and help to define this disease. Three Chinese children with PDE were clinically analyzed, followed by treatment and examination of the ALDH7A1 mutations. The seizures of the 3 patients were all resistant to multiple anticonvulsants (2 to 7 types). For case 1, onset of seizures was at the age of 2 months. His seizures were well controlled by intravenous pyridoxine for several days at the age of 3 months 20 days and recurred at intervals of 13, 14 and 38 days after pyridoxine withdrawn for 3 times. At the age of 7 months, symptoms of PDE appeared and uninterrupted oral pyridoxine started. For case 2, her seizures occurred at 8 days after birth. After administration of multiple antiepileptic drugs observed ineffective, high-dose pyridoxine continuous therapy was taken at the age of 10 months and the significant treatment effect induced a diagnostic PDE. Seizure onset in case 3 was at the first day of birth. He experienced inadvertently pyridoxine therapy several times (first time at 2 days after birth) and achieved good therapeutic effect, which was confirmed by physicians until 4 months 10 days. The treatment process in our 3 patients suggested that pyridoxine should be early and purposefully used in patients with early onset seizures. ALDH7A1 gene mutation analysis revealed compound heterozygous mutations in each case: heterozygous c.410G>A (p.G137E) and IVS11+1G>A in case 1, heterozygous c.952G>C (p.A318P) and heterozygous c.965C>T (p.A322V) in case 2, and heterozygous c.902A>T (p.N301I) and IVS11+1G>A in case 3. Only p.N301I was reported previously, all other mutations were novel. This is the first time to report cases of Chinese patients diagnosed with PDE by molecular genetic analysis. PMID:24664145

  6. Clinical Diagnosis, Treatment, and ALDH7A1 Mutations in Pyridoxine-Dependent Epilepsy in Three Chinese Infants

    PubMed Central

    Yang, Zhixian; Yang, Xiaoling; Wu, Ye; Wang, Jingmin; Zhang, Yuehua; Xiong, Hui; Jiang, Yuwu; Qin, Jiong

    2014-01-01

    Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder that causes seizures in neonates and infants. Mutations of the ALDH7A1 gene are now recognized as the molecular basis PDE and help to define this disease. Three Chinese children with PDE were clinically analyzed, followed by treatment and examination of the ALDH7A1 mutations. The seizures of the 3 patients were all resistant to multiple anticonvulsants (2 to 7 types). For case 1, onset of seizures was at the age of 2 months. His seizures were well controlled by intravenous pyridoxine for several days at the age of 3 months 20 days and recurred at intervals of 13, 14 and 38 days after pyridoxine withdrawn for 3 times. At the age of 7 months, symptoms of PDE appeared and uninterrupted oral pyridoxine started. For case 2, her seizures occurred at 8 days after birth. After administration of multiple antiepileptic drugs observed ineffective, high-dose pyridoxine continuous therapy was taken at the age of 10 months and the significant treatment effect induced a diagnostic PDE. Seizure onset in case 3 was at the first day of birth. He experienced inadvertently pyridoxine therapy several times (first time at 2 days after birth) and achieved good therapeutic effect, which was confirmed by physicians until 4 months 10 days. The treatment process in our 3 patients suggested that pyridoxine should be early and purposefully used in patients with early onset seizures. ALDH7A1 gene mutation analysis revealed compound heterozygous mutations in each case: heterozygous c.410G>A (p.G137E) and IVS11+1G>A in case 1, heterozygous c.952G>C (p.A318P) and heterozygous c.965C>T (p.A322V) in case 2, and heterozygous c.902A>T (p.N301I) and IVS11+1G>A in case 3. Only p.N301I was reported previously, all other mutations were novel. This is the first time to report cases of Chinese patients diagnosed with PDE by molecular genetic analysis. PMID:24664145

  7. Cupriavidus necator JMP134 rapidly reduces furfural with a Zn-dependent alcohol dehydrogenase.

    PubMed

    Li, Qunrui; Metthew Lam, L K; Xun, Luying

    2011-11-01

    Ethanol is a renewable biofuel, and it can be produced from lignocellulosic biomass. The biomass is usually converted to hydrolysates that consist of sugar and sugar derivatives, such as furfural. Yeast ferments sugar to ethanol, but furfural higher than 3 mM is inhibitory. It can take several days for yeast cells to reduce furfural to non-inhibitory furfuryl alcohol before producing ethanol. Bioreduction of furfural to furfuryl alcohol before fermentation may relieve yeast from furfural toxicity. We observed that Cupriavidus necator JMP134, a strict aerobe, rapidly reduced 17 mM furfural to less than 3 mM within 14 min with cell turbidity of 1.0 at 600 nm at 50°C. The rapid reduction consumed ethanol. The "furfural reductase" (FurX) was purified, and it oxidized ethanol to acetaldehyde and reduced furfural to furfuryl alcohol with NAD(+) as the cofactor. The protein was identified with mass spectrometry fingerprinting to be a hypothetical protein belonging to Zn-dependent alcohol dehydrogenase family. The furX-inactivation mutant of C. necator JMP134 lost the ability to rapidly reduce furfural, and Escherichia coli producing recombinant FurX gained the ability. Thus, an alcohol dehydrogenase enabled bacteria to rapidly reduce furfural with ethanol as the reducing power. PMID:21526390

  8. Kinetics of cytochrome P450 2E1-catalyzed oxidation of ethanol to acetic acid via acetaldehyde.

    PubMed

    Bell-Parikh, L C; Guengerich, F P

    1999-08-20

    The P450 2E1-catalyzed oxidation of ethanol to acetaldehyde is characterized by a kinetic deuterium isotope effect that increases K(m) with no effect on k(cat), and rate-limiting product release has been proposed to account for the lack of an isotope effect on k(cat) (Bell, L. C., and Guengerich, F. P. (1997) J. Biol. Chem. 272, 29643-29651). Acetaldehyde is also a substrate for P450 2E1 oxidation to acetic acid, and k(cat)/K(m) for this reaction is at least 1 order of magnitude greater than that for ethanol oxidation to acetaldehyde. Acetic acid accounts for 90% of the products generated from ethanol in a 10-min reaction, and the contribution of this second oxidation has been overlooked in many previous studies. The noncompetitive intermolecular kinetic hydrogen isotope effects on acetaldehyde oxidation to acetic acid ((H)(k(cat)/K(m))/(D)(k(cat)/K(m)) = 4.5, and (D)k(cat) = 1.5) are comparable with the isotope effects typically observed for ethanol oxidation to acetaldehyde, and k(cat) is similar for both reactions, suggesting a possible common catalytic mechanism. Rapid quench kinetic experiments indicate that acetic acid is formed rapidly from added acetaldehyde (approximately 450 min(-1)) with burst kinetics. Pulse-chase experiments reveal that, at a subsaturating concentration of ethanol, approximately 90% of the acetaldehyde intermediate is directly converted to acetic acid without dissociation from the enzyme active site. Competition experiments suggest that P450 2E1 binds acetic acid and acetaldehyde with relatively high K(d) values, which preclude simple tight binding as an explanation for rate-limiting product release. The existence of a rate-determining step between product formation and release is postulated. Also proposed is a conformational change in P450 2E1 occurring during the course of oxidation and the discrimination of P450 2E1 between acetaldehyde and its hydrated form, the gem-diol. This multistep P450 reaction is characterized by kinetic

  9. Acetaldehyde removal using an atmospheric non-thermal plasma combined with a packed bed: role of the adsorption process.

    PubMed

    Klett, C; Duten, X; Tieng, S; Touchard, S; Jestin, P; Hassouni, K; Vega-González, A

    2014-08-30

    This work is an attempt in order to help towards understanding the influence of the adsorption process on the removal of a VOC (acetaldehyde, CH3CHO) using cyclic non thermal plasma (NTP) combined with a packed-bed of a catalyst support, α-Al2O3. In the first part, the results obtained by placing the saturated alumina pellets inside the plasma discharge zone are discussed, in terms of acetaldehyde removal, CO and CO2 production. In the second part, adsorption of CH3CHO, CO, CO2 and O3 was carried out, from single and multicomponent mixtures of the different compounds. The results showed that (i) the adsorption capacities followed the order CH3CHO≫  CO2>CO; (ii) O3 was decomposed on the alumina surface; (iii) CO oxidation occurred on the surface when O3 was present. In the third part, diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) was used to follow the alumina surface during acetaldehyde adsorption. DRIFTS measurements demonstrated that besides the bands of molecularly adsorbed acetaldehyde, several absorptions appeared on the spectra showing the intermediate surface transformation of acetaldehyde already at 300K. Finally, the relationship between the adsorption results and the NTP combined with a packed-bed process is discussed. PMID:25072139

  10. Adsorption and Reaction of Acetaldehyde on Shape-Controlled CeO2 Nanocrystals: Elucidation of Structure-function Relationships

    SciTech Connect

    Mann, Amanda K; Wu, Zili; Calaza, Florencia; Overbury, Steven {Steve} H

    2014-01-01

    CeO2 cubes with {100} facets, octahedra with {111} facets, and wires with highly defective structures were utilized to probe the structure-dependent reactivity of acetaldehyde. Using temperature-programmed desorption (TPD), temperature-programmed surface reactions (TPSR), and in situ infrared spectroscopy it was found that acetaldehyde desorbs unreacted or undergoes reduction, coupling, or C-C bond scission reactions depending on the surface structure of CeO2. Room temperature FTIR indicates that acetaldehyde binds primarily as 1-acetaldehyde on the octahedra, in a variety of conformations on the cubes, including coupling products and acetate and enolate species, and primarily as coupling products on the wires. The percent consumption of acetaldehyde follows the order of wires > cubes > octahedra. All the nanoshapes produce the coupling product crotonaldehyde; however, the selectivity to produce ethanol follows the order wires cubes >> octahedra. The selectivity and other differences can be attributed to the variation in the basicity of the surfaces, defects densities, coordination numbers of surface atoms, and the reducibility of the nanoshapes.

  11. Adsorption and Reaction of Acetaldehyde on Stoichiometric and Defective SrTiO{sub 3}(100) Surfaces

    SciTech Connect

    Wang, Li Q.; Ferris, Kim F.; Azad, Samina; Engelhard, Mark H.; Peden, Charles HF.

    2004-02-05

    The adsorption and reaction of acetaldehyde (CH{sub 3}CHO), on stoichiometric (TiO{sub 2}-terminated) and reduced SrTiO{sub 3}(100) surfaces, have been investigated using temperature-programmed desorption (TPD) and X-ray photoelectron spectroscopy (XPS). Acetaldehyde adsorbs molecularly on the stoichiometric SrTiO{sub 3}(100) surface that contains predominantly Ti{sup 4+} cations. The Ti{sup 4+} sites on the stoichiometric SrTiO{sub 3}(100) surface are not sufficiently active for surface reactions such as aldol condensation, as opposed to the Ti{sup 4+} ions on the TiO{sub 2}(001) surface. However, decomposition and redox reactions of acetaldehyde occur in the presence of surface defects created by Ar{sup +} sputtering. The decomposition products following reactions of acetaldehyde on the defective surface include H{sub 2}, C{sub 2}H{sub 4}, CO, C{sub 4}H{sub 6} and C{sub 4}H{sub 8}. Reductive coupling, to produce C{sub 2}H{sub 4} and C{sub 4}H{sub 8}, is the main reaction pathway for decomposition of acetaldehyde on the sputter reduced SrTiO{sub 3}(100) surface.

  12. What’s in that Drink: The Biological Actions of Ethanol, Acetaldehyde, and Salsolinol

    PubMed Central

    Deehan, Gerald A.; Brodie, Mark S.; Rodd, Zachary A.

    2016-01-01

    Alcohol abuse and alcoholism represent substantial problems that affect a large portion of individuals throughout the world. Extensive research continues to be conducted in an effort to identify the biological basis of the reinforcing properties of alcohol in order to develop effective pharmacotherapeutic and behavioral interventions. One theory that has developed within the alcohol field over the past 4 decades postulates that the reinforcing properties of alcohol are due to the action of the metabolites/products of alcohol within the central nervous system (CNS). The most extreme version of this theory suggests that the biologically active metabolites/products of alcohol, created from the breakdown from alcohol, are the ultimate source of the reinforcing properties of alcohol. The contrary theory proposes that the reinforcing properties of alcohol are mediated completely through the interaction of the ethanol molecule with several neurochemical systems within the CNS. While there are scientific findings that offer support for both of these stances, the reinforcing properties of alcohol are most likely generated through a complex series of peripheral and central effects of both alcohol and its metabolites. Nonetheless, the development of a greater understanding for how the metabolites/products of alcohol contribute to the reinforcing properties of alcohol is an important factor in the development of efficacious pharmacotherapies for alcohol abuse and alcoholism. This chapter is intended to provide a historical perspective of the role of acetaldehyde (the first metabolite of alcohol) in alcohol reinforcement as well as review the basic research literature on the effects of acetaldehyde (and acetaldehyde metabolites/products) within the CNS and how these function with regard to alcohol reward. PMID:22351424

  13. Millimeter and submillimeter wave spectra of mono-13C-acetaldehydes

    NASA Astrophysics Data System (ADS)

    Margulès, L.; Motiyenko, R. A.; Ilyushin, V. V.; Guillemin, J. C.

    2015-07-01

    Context. The acetaldehyde molecule is ubiquitous in the interstellar medium of our galaxy, and due to its dense and complex spectrum, large dipole moment, and several low-lying torsional states, acetaldehyde is considered to be a "weed" molecule for radio astronomy observations. Mono-13C acetaldehydes 13CH3CHO and CH313CHO are likely to be identified in astronomical surveys, such as those available with the very sensitive ALMA telescope. Laboratory measurements and analysis of the millimeter and submillimeter-wave spectra are the prerequisites for the successful radioastronomical search for the new interstellar molecular species, as well as for new isotopologs of already detected interstellar molecules. Aims: In this context, to provide reliable predictions of 13CH3CHO and CH313CHO spectra in millimeter and submillimeter wave ranges, we study rotational spectra of these species in the frequency range from 50 to 945 GHz. Methods: The spectra of mono-13C acetaldehydes were recorded using the spectrometer based on Schottky-diode frequencymultiplication chains in the Lille laboratory. The rotational spectra of 13CH3CHO and CH313CHO molecules were analyzed using the Rho axis method. Results: In the recorded spectra we have assigned 6884 for the 13CH3CHO species and 6458 for CH313CHO species new rotational transitions belonging to the ground, first, and second excited torsional states. These measurements were fitted together with previously published data to the Hamiltonian models that use 91 and 87 parameters to achieve overall weighted rms deviations 0.88 for the 13CH3CHO species and 0.95 for CH313CHO. On the basis of the new spectroscopic results, predictions of transition frequencies in the frequency range up to 1 THz with J ≤ 60 and Ka ≤ 20 are presented for both isotopologs. Full Tables 3-6 are only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/579/A46

  14. Sensitive gas chromatographic detection of acetaldehyde and acetone using a reduction gas detector

    NASA Technical Reports Server (NTRS)

    O'Hara, Dean; Singh, Hanwant B.

    1988-01-01

    The response of a newly available mercuric oxide Reduction Gas Detector (RGD-2) to subpicomole and larger quantities of acetaldehyde and acetone is tested. The RGD-2 is found to be capable of subpicomole detection for these carbonyls and is more sensitive than an FID (Flame Ionization Detector) by an order of magnitude. Operating parameters can be further optimized to make the RGD-2 some 20-40 times more sensitive than an FID. The detector is linear over a wide range and is easily adapted to a conventional gas chromatograph (GC). Such a GC-RGD-2 system should be suitable for atmospheric carbonyl measurements in clean as well as polluted environments.

  15. Murine hepatic aldehyde dehydrogenase 1a1 is a major contributor to oxidation of aldehydes formed by lipid peroxidation

    PubMed Central

    Makia, Ngome L.; Bojang, Pasano; Falkner, K. Cameron; Conklin, Daniel J.; Prough, Russell A.

    2015-01-01

    Reactive lipid aldehydes are implicated in the pathogenesis of various oxidative stress-mediated diseases, including non-alcoholic steatohepatitis, atherosclerosis, Alzheimer’s and cataract. In the present study, we sought to define which hepatic Aldh isoform plays a major role in detoxification of lipid-derived aldehydes, such as acrolein and HNE by enzyme kinetic and gene expression studies. The catalytic efficiencies for metabolism of acrolein by Aldh1a1 was comparable to that of Aldh3a1 (Vmax/Km = 23). However, Aldh1a1 exhibits far higher affinity for acrolein (Km = 23.2 μM) compared to Aldh3a1 (Km = 464 μM). Aldh1a1 displays a 3-fold higher catalytic efficiency for HNE than Aldh3a1 (218 vs 69 ml/min/mg). The endogenous Aldh1a1 gene was highly expressed in mouse liver and a liver-derived cell line (Hepa-1c1c7) compared to Aldh2, Aldh1b1 and Aldh3a1. Aldh1a1 mRNA levels was 34-fold and 73-fold higher than Aldh2 in mouse liver and Hepa-1c1c7 cells respectively. Aldh3a1 gene was absent in mouse liver, but moderately expressed in Hepa-1c1c7 cells compared to Aldh1a1. We demonstrated that knockdown of Aldh1a1 expression by siRNA caused Hepa-1c1c7 cells to be more sensitive to acrolein-induced cell death and resulted in increased accumulation of acrolein-protein adducts and caspase 3 activation. These results indicate that Aldh1a1 plays a major role in cellular defense against oxidative damage induced by reactive lipid aldehydes in mouse liver. We also noted that hepatic Aldh1a1 mRNA levels were significantly increased (≈ 3 fold) in acrolein-fed mice compared to control. In addition, hepatic cytosolic ALDH activity was induced by acrolein when 1 mM NAD+ was used as cofactor, suggesting an Aldh1a1-protective mechanism against acrolein toxicity in mice liver. Thus, mechanisms to induce Aldh1a1 gene expression may provide a useful rationale for therapeutic protection against oxidative stress-induced pathologies. PMID:21256123

  16. Formaldehyde dehydrogenase preparations from Methylococcus capsulatus (Bath) comprise methanol dehydrogenase and methylene tetrahydromethanopterin dehydrogenase.

    PubMed

    Adeosun, Ekundayo K; Smith, Thomas J; Hoberg, Anne-Mette; Velarde, Giles; Ford, Robert; Dalton, Howard

    2004-03-01

    In methylotrophic bacteria, formaldehyde is an important but potentially toxic metabolic intermediate that can be assimilated into biomass or oxidized to yield energy. Previously reported was the purification of an NAD(P)(+)-dependent formaldehyde dehydrogenase (FDH) from the obligate methane-oxidizing methylotroph Methylococcus capsulatus (Bath), presumably important in formaldehyde oxidation, which required a heat-stable factor (known as the modifin) for FDH activity. Here, the major protein component of this FDH preparation was shown by biophysical techniques to comprise subunits of 64 and 8 kDa in an alpha(2)beta(2) arrangement. N-terminal sequencing of the subunits of FDH, together with enzymological characterization, showed that the alpha(2)beta(2) tetramer was a quinoprotein methanol dehydrogenase of the type found in other methylotrophs. The FDH preparations were shown to contain a highly active NAD(P)(+)-dependent methylene tetrahydromethanopterin dehydrogenase that was the probable source of the NAD(P)(+)-dependent formaldehyde oxidation activity. These results support previous findings that methylotrophs possess multiple pathways for formaldehyde dissimilation. PMID:14993320

  17. Hypothesis of demodicidosis rosacea flushing etiopathogenesis.

    PubMed

    Robledo, Mary Ann; Orduz, Mariana

    2015-04-01

    Most of the patients with erythematotelangiectatic rosacea are characterized by flushing, oedema and telangiectasia. The etiopathogenesis of the flushing in rosacea patients is unknown. Clinically the flushing in rosacea is similar to the "Asian flushing syndrome". Most Asians have an overactive alcohol dehydrogenase (ADH) that tends to break down alcohol into acetaldehyde faster. People with "Asians flushing syndrome" have a genetic disorder with the Aldehyde Dehydrogenase 2(∗)2 (ALDH2(∗)2) allele. This is the reason why they do not metabolize very well the acetaldehyde that comes from the alcohol, which means that acetaldehyde takes much longer to clear from their blood. ALDH2 enzyme is primarily responsible for oxidation of acetaldehyde derived from ethanol metabolism, as well as oxidation of various other endogenous and exogenous aldehydes. Acetaldehyde produces the vasodilatation in the "Asian flushing syndrome". The antibodies against the GroEl chaperonin protein, a 62-kDa heat shock protein were found in the Bacillus oleronius isolated from Demodex mites, in rosacea patients. The GroEl chaperonin protein is a protein that plays a key role in normal folding of ALDH2. If the GroEl chaperonin antibodies found in patients with rosacea, cross react with the human GroEl chaperonin protein, they will not fold normally the ALDH2, and then the enzyme will not metabolize the acetaldehyde. Many of the patients with rosacea have a concomitant infection with Helicobacter pylori in their stomach. The H.pylori produces high amounts of acetaldehyde, which comes from their metabolism of ethanol or carbohydrates. As a result, high amounts of acetaldehyde will circulate for longer time in the blood, until the liver CYP2E1(p450) enzyme system finally metabilizes the acetaldehyde, during that period of time the patients will experience a flushing as well as the people with the "Asian flushing syndrome" suffer when they drink ethanol. To prove the hypothesis it is necessary

  18. Mineralization of gaseous acetaldehyde by electrochemically generated Co(III) in H2SO4 with wet scrubber combinatorial system.

    PubMed

    Govindan, Muthuraman; Chung, Sang-Joon; Moon, Il-Shik

    2012-06-11

    Electrochemically generated Co(III) mediated catalytic room temperature incineration of acetaldehyde, which is one of volatile organic compounds (VOCs), combined with wet scrubbing system was developed and investigated. Depending on the electrolyte's type, absorption come removal efficiency is varied. In presence of electrogenerated Co(III) in sulfuric acid, acetaldehyde was mineralized to CO2 and not like only absorption in pure sulfuric acid. The Co(III) mediated catalytic incineration led to oxidative absorption and elimination to CO2, which was evidenced with titration, CO2, and cyclic voltammetric analyses. Experimental conditions, such as current density, concentration of mediator, and gas molar flow rate were optimized. By the optimization of the experimental conditions, the complete mineralization of acetaldehyde was realized at a room temperature using electrochemically generated Co(III) with wet scrubber combinatorial system. PMID:22551057

  19. Multi-Walled Carbon Nanotubes as a Catalyst for Gas-Phase Oxidation of Ethanol to Acetaldehyde.

    PubMed

    Wang, Jia; Huang, Rui; Feng, Zhenbao; Liu, Hongyang; Su, Dangsheng

    2016-07-21

    Multi-walled carbon nanotubes (CNTs) were directly used as a sustainable and green catalyst to convert ethanol into acetaldehyde in the presence of molecular oxygen. The C=O groups generated on the nanocarbon surface were demonstrated as active sites for the selective oxidation of ethanol to acetaldehyde. The transformation of disordered carbon debris on the CNT surface to ordered graphitic structures induced by thermal-treatment significantly enhanced the stability of the active C=O groups, and thus the catalytic performance. A high reactivity with approximately 60 % ethanol conversion and 93 % acetaldehyde selectivity was obtained over the optimized CNT catalyst at 270 °C. More importantly, the catalytic performance was quite stable even after 500 h, which is comparable with a supported gold catalyst. The robust catalytic performance displayed the potential application of CNTs in the industrial catalysis field. PMID:27282126

  20. The effects of acetaldehyde, glyoxal and acetic acid on the heterogeneous reaction of nitrogen dioxide on gamma-alumina.

    PubMed

    Sun, Zhenyu; Kong, Lingdong; Ding, Xiaoxiao; Du, Chengtian; Zhao, Xi; Chen, Jianmin; Fu, Hongbo; Yang, Xin; Cheng, Tiantao

    2016-04-14

    Heterogeneous reactions of nitrogen oxides on the surface of aluminium oxide result in the formation of adsorbed nitrite and nitrate. However, little is known about the effects of other species on these heterogeneous reactions and their products. In this study, diffuse reflectance infrared spectroscopy (DRIFTS) was used to analyze the process of the heterogeneous reaction of NO2 on the surface of aluminium oxide particles in the presence of pre-adsorbed organic species (acetaldehyde, glyoxal and acetic acid) at 298 K and reveal the influence of these organic species on the formation of adsorbed nitrite and nitrate. It was found that the pre-adsorption of organic species (acetaldehyde, glyoxal and acetic acid) on γ-Al2O3 could suppress the formation of nitrate to different extents. Under the same experimental conditions, the suppression of the formation of nitrate by the pre-adsorption of acetic acid is much stronger than that by pre-adsorption of acetaldehyde and glyoxal, indicating that the influence of acetic acid on the heterogeneous reaction of NO2 is different from that of acetaldehyde and glyoxal. Surface nitrite is formed and identified to be an intermediate product. For the heterogeneous reaction of NO2 on the surface of γ-Al2O3 with and without the pre-adsorption of acetaldehyde and glyoxal, it is firstly formed and then gradually disappears as the reaction proceeds, but for the reaction with the pre-adsorption of acetic acid, it is the final main product besides nitrate. This indicates that the pre-adsorption of acetic acid would promote the formation of nitrite, while the others would not change the trend of the formation of nitrite. The possible influence mechanisms of the pre-adsorption of acetaldehyde, glyoxal and acetic acid on the heterogeneous conversion of NO2 on γ-Al2O3 are proposed and atmospheric implications based on these results are discussed. PMID:26745767

  1. Structural and kinetic characterization of recombinant 2-hydroxymuconate semialdehyde dehydrogenase from Pseudomonas putida G7

    PubMed Central

    de Araújo, Simara Semíramis; Neves, Cíntia Mara Leal; Guimarães, Samuel Leite; Whitman, Christian P.; Johnson, William H.; Aparicio, Ricardo; Nagem, Ronaldo Alves Pinto

    2016-01-01

    The first enzyme in the oxalocrotonate branch of the naphthalene-degradation lower pathway in Pseudomonas putida G7 is NahI, a 2-hydroxymuconate semialdehyde dehydrogenase required for conversion of 2-hydroxymuconate semialdehyde to 2-hydroxymuconate in the presence of NAD+. NahI is in one family of the NAD(P)+-dependent aldehyde dehydrogenase superfamily (ALDH8). In this work, we report the cloning, expression, purification and preliminary structural and kinetic characterization of the recombinant NahI. The nahI gene was subcloned into a T7 expression vector and the enzyme was overexpressed in Escherichia coli ArcticExpress at 12 ºC as an N-terminal hexa-histidine-tagged fusion protein (6xHis-NahI). After the soluble protein was purified by affinity and size-exclusion chromatography, dynamic light scattering and small-angle X-ray scattering experiments were conducted to analyze the oligomeric state and the overall shape of the enzyme in solution. The protein is a tetramer in solution and has nearly perfect 222 point group symmetry. Protein stability and secondary structure content were also evaluated by a circular dichroism spectroscopy assay under different thermal conditions. Furthermore, kinetic assays were conducted for the recombinant enzyme and, for the first time, KM (1.3 ± 0.3 μM) and kcat (0.9 s−1) values were determined for this enzyme (at presumed NAD+ saturation). NahI is highly specific for its biological substrate (2-hydroxymuconate semialdehyde) and has no activity with salicylaldehyde, another intermediate in the naphthalene-degradation pathway. PMID:26032336

  2. Cellobiose dehydrogenase in cellulose degradation

    SciTech Connect

    Eriksson, L.; Igarashi, Kiyohiko; Samejima, Masahiro

    1996-10-01

    Cellobiose dehydrogenase is produced by a variety of fungi. Although it was already discovered during the 70`s, it`s role in cellulose and lignin degradation is yet ambiguous. The enzyme contains both heme and FAD as prosthetic groups, and seems to have a domain specifically designed to bind the enzyme to cellulose. It`s affinity to amorphous cellulose is higher than to crystalline cellulose. We will report on the binding behavior of the enzyme, its usefulness in elucidation of cellulose structures and also, possibilities for applications such as its use in measuring individual and synergistic mechanisms for cellulose degradation by endo- and exo-glucanases.

  3. The (impossible?) formation of acetaldehyde on the grain surfaces: insights from quantum chemical calculations

    NASA Astrophysics Data System (ADS)

    Enrique-Romero, J.; Rimola, A.; Ceccarelli, C.; Balucani, N.

    2016-06-01

    Complex Organic Molecules (COMs) have been detected in the interstellar medium (ISM). However, it is not clear whether their synthesis occurs on the icy surfaces of interstellar grains or via a series of gas-phase reactions. As a test case of the COMs synthesis in the ISM, we present new quantum chemical calculations on the formation of acetaldehyde (CH3CHO) from the coupling of the HCO and CH3 radicals, both in gas phase and on water ice surfaces. The binding energies of HCO and CH3 on the amorphous water ice were also computed (2333 and 734 K, respectively). Results indicate that, in gas phase, the products could be either CH3CHO, CH4 + CO, or CH3OCH, depending on the relative orientation of the two radicals. However, on the amorphous water ice, only the CH4 + CO product is possible due to the geometrical constraints imposed by the water ice surface. Therefore, acetaldehyde cannot be synthesized by the CH3 + HCO coupling on the icy grains. We discuss the implications of these results and other cases, such as ethylene glycol and dimethyl ether, in which similar situations can occur, suggesting that formation of these molecules on the grain surfaces might be unlikely.

  4. Oxidation of Ethanol to Acetaldehyde over Na-promoted vanadium oxide catalysts

    SciTech Connect

    Chimentao, Ricardo J.; Herrera, Jose L.; Kwak, Ja Hun; Medina, Francesc; Wang, Yong; Peden, Charles HF

    2007-11-20

    Sodium-promoted vanadium oxide catalysts supported on MCM-41 and TiO2 (anatase) were investigated for the partial oxidation of ethanol to acetaldehyde. The catalysts were prepared by incipient wetness impregnation with a vanadium oxide content of 6 wt. %. The experimental characterization was performed by X-ray diffraction (XRD), N2 adsorption, temperature programmed reduction (TPR), and diffuse reflectance UV-Vis. Temperature programmed oxidation (TPO) was also used to identify carbon deposits on the spent catalysts. The presence of sodium plays a strong role in the dispersion and reducibility of the vanadium species as detected by TPR analysis and optical absorption spectroscopy. While sodium addition increases the dispersion of the VOx species, its presence also decreases their reducibility. Additionally, TPO of the spent catalysts revealed that an increase in the Na loading decreases the carbon deposition during reaction. In the case of the catalysts supported on MCM-41, these modifications were mirrored by a change in the activity and selectivity to acetaldehyde. Additionally, on the VOx/TiO2 catalysts the catalytic activity decreased with increasing sodium content in the catalyst. A model in which sodium affects dispersion, reducibility and also acidity of the supported-vanadia species is proposed to explain all these observations.

  5. Regional sources of atmospheric formaldehyde and acetaldehyde, and implications for atmospheric modeling

    NASA Astrophysics Data System (ADS)

    Luecken, D. J.; Hutzell, W. T.; Strum, M. L.; Pouliot, G. A.

    2012-02-01

    Formaldehyde and acetaldehyde concentrations over the Eastern half of the United States are simulated with a 3-D air quality model to identify the most important chemical precursors under January and July conditions. We find that both aldehydes primarily result from photochemical production, although 25% or more result from direct emissions in urban areas during winter. Isoprene is the major precursor of formaldehyde in most areas during summer, contributing 20-60% of total production, with the magnitude being spatially variable. Other alkenes from anthropogenic and/or biogenic emissions dominate formaldehyde production in winter, contributing 60-85% of total formation, and are prominent contributors in summer. Alkenes, including biogenic alkenes, dominate acetaldehyde production during both seasons. These conclusions are based on the degradation of emitted VOCs described by the SAPRC07TB chemical mechanism, but even this detailed model has difficulty reproducing observed values better than a factor of 2. The substantial role of isoprene and other alkenes in aldehyde formation emphasizes that we examine and improve emission estimates of these compounds. Until we can estimate the emissions and understand the chemistry of VOC precursors to aldehyde formation with greater certainty, it will be difficult to accurately predict atmospheric concentrations of aldehydes and develop strategies to reduce their concentrations.

  6. Aldehyde dehydrogenase and ATP binding cassette transporter G2 (ABCG2) functional assays isolate different populations of prostate stem cells where ABCG2 function selects for cells with increased stem cell activity

    PubMed Central

    2013-01-01

    Introduction High expression of aldehyde dehydrogenase1A1 (ALDH1A1) is observed in many organs and tumors and may identify benign and cancer stem cell populations. Methods In the current study, the stem cell characteristics were determined in cells isolated from human prostate cell lines and clinical prostate specimens based upon the ALDEFLUOR™ assay. Cells isolated based on the ALDEFLUOR™ assay were compared to cells isolated based on ATP binding cassette transporter G2 (ABCG2) activity using the side population assay. To test for stem cell characteristics of self-renewal and multipotency, cells with high and low ALDH1A1 activity, based on the ALDEFLUOR™ assay (ALDHHi and ALDHLow), were isolated from prostate clinical specimens and were recombined with rat urogenital sinus mesenchyme to induce prostate gland formation. Results The percentage of ALDHHi cells in prostate cell lines (RWPE-1, RWPE-2, CWR-R1, and DU-145) was 0.5 to 6%, similarly in non-tumor and tumor clinical specimens the percentage of ALDHHi cells was 0.6 to 4%. Recombinants using ALDHHi cells serially generated prostate tissue up to three generations with as few as 250 starting cells. Immunohistochemical analysis of the recombinants using ALDHHi cells contained prostatic glands frequently expressing androgen receptor (AR), p63, chromogranin A, ALDH1A1, ABCG2, and prostate specific antigen (PSA), compared to their ALDHLow counterparts. Inhibition of ALDH resulted in the reduction of sphere formation capabilities in the CWR-R1, but not in the RWPE-2 and DU-145, prostate cell lines. ABCG2 inhibition resulted in a more robust decrease of sphere formation in androgen sensitive cell lines, CWR-R1 and RWPE-2, but not androgen insensitive DU-145. ALDH1A1 expression was enriched in ALDHHi cells and non-side population cells. ABCG2 expression was only enriched in side population cells. Conclusions The percentage of ALDHHi cells in prostate cell lines and prostate tissue was consistently higher compared

  7. Mitochondrial Aldehyde Dehydrogenase Activation by Alda‐1 Inhibits Atherosclerosis and Attenuates Hepatic Steatosis in Apolipoprotein E‐Knockout Mice

    PubMed Central

    Stachowicz, Aneta; Olszanecki, Rafał; Suski, Maciej; Wiśniewska, Anna; Totoń‐Żurańska, Justyna; Madej, Józef; Jawień, Jacek; Białas, Magdalena; Okoń, Krzysztof; Gajda, Mariusz; Głombik, Katarzyna; Basta‐Kaim, Agnieszka; Korbut, Ryszard

    2014-01-01

    Background Mitochondrial dysfunction has been shown to play an important role in the development of atherosclerosis and nonalcoholic fatty liver disease (NAFLD). Mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme responsible for the detoxification of reactive aldehydes, is considered to exert protective function in mitochondria. We investigated the influence of Alda‐1, an activator of ALDH2, on atherogenesis and on the liver steatosis in apolipoprotein E knockout (apoE−/−) mice. Methods and Results Alda‐1 caused decrease of atherosclerotic lesions approximately 25% as estimated by “en face” and “cross‐section” methods without influence on plasma lipid profile, atherosclerosis‐related markers of inflammation, and macrophage and smooth muscle content in the plaques. Plaque nitrotyrosine was not changed upon Alda‐1 treatment, and there were no changes in aortic mRNA levels of factors involved in antioxidative defense, regulation of apoptosis, mitogenesis, and autophagy. Hematoxylin/eosin staining showed decrease of steatotic changes in liver of Alda‐1‐treated apoE−/− mice. Alda‐1 attenuated formation of 4‐hydroxy‐2‐nonenal (4‐HNE) protein adducts and decreased triglyceride content in liver tissue. Two‐dimensional electrophoresis coupled with mass spectrometry identified 20 differentially expressed mitochondrial proteins upon Alda‐1 treatment in liver of apoE−/− mice, mostly proteins related to metabolism and oxidative stress. The most up‐regulated were the proteins that participated in beta oxidation of fatty acids. Conclusions Collectively, Alda‐1 inhibited atherosclerosis and attenuated NAFLD in apoE−/− mice. The pattern of changes suggests a beneficial effect of Alda‐1 in NAFLD; however, the exact liver functional consequences of the revealed alterations as well as the mechanism(s) of antiatherosclerotic Alda‐1 action require further investigation. PMID:25392542

  8. Betaine aldehyde dehydrogenase in sorghum.

    PubMed Central

    Wood, A J; Saneoka, H; Rhodes, D; Joly, R J; Goldsbrough, P B

    1996-01-01

    The ability to synthesize and accumulate glycine betaine is wide-spread among angiosperms and is thought to contribute to salt and drought tolerance. In plants glycine betaine is synthesized by the two-step oxidation of choline via the intermediate betaine aldehyde, catalyzed by choline monooxygenase and betaine aldehyde dehydrogenase (BADH). Two sorghum (Sorghum bicolor) cDNA clones, BADH1 and BADH15, putatively encoding betaine aldehyde dehydrogenase were isolated and characterized. BADH1 is a truncated cDNA of 1391 bp. BADH15 is a full-length cDNA clone, 1812 bp in length, predicted to encode a protein of 53.6 kD. The predicted amino acid sequences of BADH1 and BADH15 share significant homology with other plant BADHs. The effects of water deficit on BADH mRNA expression, leaf water relations, and glycine betaine accumulation were investigated in leaves of preflowering sorghum plants. BADH1 and BADH15 mRNA were both induced by water deficit and their expression coincided with the observed glycine betaine accumulation. During the course of 17 d, the leaf water potential in stressed sorghum plants reached -2.3 MPa. In response to water deficit, glycine betaine levels increased 26-fold and proline levels increased 108-fold. In severely stressed plants, proline accounted for > 60% of the total free amino acid pool. Accumulation of these compatible solutes significantly contributed to osmotic potential and allowed a maximal osmotic adjustment of 0.405 MPa. PMID:8934627

  9. Astaxanthin Inhibits Acetaldehyde-Induced Cytotoxicity in SH-SY5Y Cells by Modulating Akt/CREB and p38MAPK/ERK Signaling Pathways

    PubMed Central

    Yan, Tingting; Zhao, Yan; Zhang, Xia; Lin, Xiaotong

    2016-01-01

    Excessive alcohol consumption can lead to brain tissue damage and cognitive dysfunction. Acetaldehyde, the most toxic metabolite of ethanol, mediates the brain tissue damage and cognitive dysfunction induced by chronic excessive alcohol consumption. In this study, the effect of astaxanthin, a marine bioactive compound, on acetaldehyde-induced cytotoxicity was investigated in SH-SY5Y cells. It was found that astaxanthin protected cells from apoptosis by ameliorating the effect of acetaldehyde on the expression of Bcl-2 family proteins, preventing the reduction of anti-apoptotic protein Bcl-2 and the increase of pro-apoptotic protein Bak induced by acetaldehyde. Further analyses showed that astaxanthin treatment inhibited acetaldehyde-induced reduction of the levels of activated Akt and cyclic AMP-responsive element binding protein (CREB). Astaxanthin treatment also prevented acetaldehyde-induced increase of the level of activated p38 mitogen-activated protein kinase (MAPK) and decrease of the level of activated extracellular signal-regulated kinases (ERKs). Activation of Akt/CREB pathway promotes cell survival and is involved in the upregulation of Bcl-2 gene. P38MAPK plays a critical role in apoptotic events while ERKs mediates the inhibition of apoptosis. Thus, astaxanthin may inhibit acetaldehyde-induced apoptosis through promoting the activation of Akt/CREB and ERKs and blocking the activation of p38MAPK. In addition, astaxanthin treatment suppressed the oxidative stress induced by acetaldehyde and restored the antioxidative capacity of SH-SY5Y cells. Therefore, astaxanthin may protect cells against acetaldehyde-induced cytotoxicity through maintaining redox balance and modulating apoptotic and survival signals. The results suggest that astaxanthin treatment may be beneficial for preventing neurotoxicity associated with acetaldehyde and excessive alcohol consumption. PMID:26978376

  10. Astaxanthin Inhibits Acetaldehyde-Induced Cytotoxicity in SH-SY5Y Cells by Modulating Akt/CREB and p38MAPK/ERK Signaling Pathways.

    PubMed

    Yan, Tingting; Zhao, Yan; Zhang, Xia; Lin, Xiaotong

    2016-03-01

    Excessive alcohol consumption can lead to brain tissue damage and cognitive dysfunction. Acetaldehyde, the most toxic metabolite of ethanol, mediates the brain tissue damage and cognitive dysfunction induced by chronic excessive alcohol consumption. In this study, the effect of astaxanthin, a marine bioactive compound, on acetaldehyde-induced cytotoxicity was investigated in SH-SY5Y cells. It was found that astaxanthin protected cells from apoptosis by ameliorating the effect of acetaldehyde on the expression of Bcl-2 family proteins, preventing the reduction of anti-apoptotic protein Bcl-2 and the increase of pro-apoptotic protein Bak induced by acetaldehyde. Further analyses showed that astaxanthin treatment inhibited acetaldehyde-induced reduction of the levels of activated Akt and cyclic AMP-responsive element binding protein (CREB). Astaxanthin treatment also prevented acetaldehyde-induced increase of the level of activated p38 mitogen-activated protein kinase (MAPK) and decrease of the level of activated extracellular signal-regulated kinases (ERKs). Activation of Akt/CREB pathway promotes cell survival and is involved in the upregulation of Bcl-2 gene. P38MAPK plays a critical role in apoptotic events while ERKs mediates the inhibition of apoptosis. Thus, astaxanthin may inhibit acetaldehyde-induced apoptosis through promoting the activation of Akt/CREB and ERKs and blocking the activation of p38MAPK. In addition, astaxanthin treatment suppressed the oxidative stress induced by acetaldehyde and restored the antioxidative capacity of SH-SY5Y cells. Therefore, astaxanthin may protect cells against acetaldehyde-induced cytotoxicity through maintaining redox balance and modulating apoptotic and survival signals. The results suggest that astaxanthin treatment may be beneficial for preventing neurotoxicity associated with acetaldehyde and excessive alcohol consumption. PMID:26978376

  11. Thz Spectroscopy of 13C Isotopic Species of a "weed": Acetaldehyde

    NASA Astrophysics Data System (ADS)

    Margulès, L.; Motiyenko, R. A.; Guillemin, J.-C.

    2011-06-01

    Our studies of the isotopic species of 13C and D isotopologues of methyl formate (HCOOCH_3), have allowed the detection of more than 600 lines in Orion. This confirms that many observed U-lines are coming from isotopic species of one of the most abundant molecules in space. Since its first detection in 1976 in SgrB2 and in Orion A, acetaldehyde (CH_3CHO) was detected in many other numerous objects. If its deuterated species (CD_3CHO and CH_3CDO) have been previously studied in the millimeterwave range, the data concerning the 13C species are limited to few lines measured in 1957 up to 40 GHz. In this context we decided to study the 13C species of acetaldehyde. Acetaldehyde molecule displays a large amplitude motion: the hindered rotation of the methyl group with respect to the rest of the molecule. The analysis is performed with the Rho Axis Method. Recent versions of the codes include high orders term in order to reproduce the observed frequencies for large quantum numbers values as J-values as high as 70a,b,. Measurements and analysis of the rotational spectra of 13C isotopic species are in progress in Lille with a solid-state submillimetre-wave spectrometer (50-950 GHz), the first results will be presented. This work is supported by the contract ANR-08-BLAN-0054 and by the Programme National de Physico-Chimie du Milieu Interstellaire (PCMI-CNRS). Carvajal, M.; Margulès, L.; Tercero, B.; et al.A&A 500, (2009) 1109 Margulès, L.; Huet, T. R.; Demaison J.; et al.,ApJ 714, (2010) 1120. Ikeda, M.; Ohishi, M.; Nummelin, A.; et al., ApJ, 560, (2001) 792 Kleiner, I.; Lopez, J.-C.; Blanco, S.; et al.J. Mol. Spectrosc. 197, (1999) 275 Elkeurti M.; Coudert, L. H.; Medvedev, I. R.; et al.J. Mol. Spectrosc. 263, (2010) 145 Kilb, R.W.; Lin, C.C.; and Wilson, E.B.J. Chem. Phys. 26, (1957) 1695 Kleiner, I. J. Mol. Spectrosc. 260, (2010) 1 Ilyushin, V.V.; Kryvda, A; and Alekseev, E;J. Mol. Spectrosc. 255, (2009) 32

  12. Experimental and modeling study of the oxidation of acetaldehyde in an atmospheric-pressure pulsed corona discharge

    NASA Astrophysics Data System (ADS)

    Klett, C.; Touchard, S.; Vega-Gonzalez, A.; Redolfi, M.; Bonnin, X.; Hassouni, K.; Duten, X.

    2012-08-01

    This paper reports the results obtained for the degradation of acetaldehyde by an atmospheric plasma corona discharge working in a pulsed regime. It was shown that a few hundred ppm of acetaldehyde diluted in a pure N2 gas flow can be removed up to 80% by a discharge fed with an electric power lower than 1 W. Under the same conditions, adding up to 5% of O2 allowed the removal of up to 95% of the initial acetaldehyde. The main identified end products were CO2, CO and methanol. A quasi-homogeneous zero-dimensional chemical model was developed to investigate the respective efficiency of the discharge and post-discharge periods in the global removal of the pollutant. The identified main pathways of acetaldehyde degradation were quenching of N2 metastable states during plasma pulses and oxidation by O and OH radicals during the post-discharge. This latter contribution increased with input power because of ozone accumulation in the gas mixture acting as an additional oxygen reservoir.

  13. Biomarkers of Exposure and Effect in Human Lymphoblastoid TK6 Cells Following [13C2]-Acetaldehyde Exposure

    PubMed Central

    Swenberg, James A.

    2013-01-01

    The dose-response relationship for biomarkers of exposure (N2-ethylidene-dG adducts) and effect (cell survival and micronucleus formation) was determined across 4.5 orders of magnitude (50nM–2mM) using [13C2]-acetaldehyde exposures to human lymphoblastoid TK6 cells for 12h. There was a clear increase in exogenous N 2-ethylidene-dG formation at exposure concentrations ≥ 1µM, whereas the endogenous adducts remained nearly constant across all exposure concentrations, with an average of 3.0 adducts/107 dG. Exogenous adducts were lower than endogenous adducts at concentrations ≤ 10µM and were greater than endogenous adducts at concentrations ≥ 250µM. When the endogenous and exogenous adducts were summed together, statistically significant increases in total adduct formation over the endogenous background occurred at 50µM. Cell survival and micronucleus formation were monitored across the exposure range and statistically significant decreases in cell survival and increases in micronucleus formation occurred at ≥ 1000µM. This research supports the hypothesis that endogenously produced reactive species, including acetaldehyde, are always present and constitute the majority of the observed biological effects following very low exposures to exogenous acetaldehyde. These data can replace default assumptions of linear extrapolation to very low doses of exogenous acetaldehyde for risk prediction. PMID:23425604

  14. Quantitative Determination of Acetaldehyde in Foods Using Automated Digestion with Simulated Gastric Fluid Followed by Headspace Gas Chromatography

    PubMed Central

    Uebelacker, Michael; Lachenmeier, Dirk W.

    2011-01-01

    Acetaldehyde (ethanal) is a genotoxic carcinogen, which may occur naturally or as an added flavour in foods. We have developed an efficient method to analyze the compound in a wide variety of food matrices. The analysis is conducted using headspace (HS) gas chromatography (GC) with flame ionization detector. Using a robot autosampler, the samples are digested in full automation with simulated gastric fluid (1 h at 37°C) under shaking, which frees acetaldehyde loosely bound to matrix compounds. Afterwards, an aliquot of the HS is injected into the GC system. Standard addition was applied for quantification to compensate for matrix effects. The precision of the method was sufficient (<3% coefficient of variation). The limit of detection was 0.01 mg/L and the limit of quantification was 0.04 mg/L. 140 authentic samples were analyzed. The acetaldehyde content in apples was 0.97 ± 0.80 mg/kg, orange juice contained 3.86 ± 2.88 mg/kg. The highest concentration was determined in a yoghurt (17 mg/kg). A first-exposure estimation resulted in a daily acetaldehyde intake of less than 0.1 mg/kg bodyweight from food, which is considerably lower than the exposures from alcohol consumption or tobacco smoking. PMID:21747735

  15. Effect of oxygen on the conversion of acetaldehyde in homogeneous plasmas of N2/O2/CH3CHO mixtures

    NASA Astrophysics Data System (ADS)

    Faider, W.; Pasquiers, S.; Blin-Simiand, N.; Magne, L.

    2013-12-01

    A photo-triggered discharge producing a homogeneous plasma was used to investigate, experimentally and with the help of a self-consistent 0D model, the decomposition processes of acetaldehyde (concentration up to 0.5%) in N2/O2/CH3CHO mixtures containing up to 20% oxygen, at a total pressure of 460 mbar. This work follows a previous one about N2/CH3CHO, having provided the necessary data about the quenching of the N2 metastable states by the acetaldehyde molecule. For the condition of the experiment, it was shown that oxygen has a weak influence on the acetaldehyde removal. Nevertheless, the kinetic reactions involved drastically change when the oxygen percentage is increased. Quenching reactions gradually give way to oxidation reactions by O(3P) and OH. Oxidation by OH dominates for a high acetaldehyde concentration or a high oxygen percentage. Moreover, CH3 is an important primary compound for the formation of CH4 and C2H6. Ethane is less populated than methane in the whole range of oxygen percentage values studied, and there are still hydrocarbon molecules in the gas mixture at 20% oxygen. This is well explained by the adopted kinetic scheme.

  16. Long-term treatment outcome of two patients with pyridoxine-dependent epilepsy caused by ALDH7A1 mutations: normal neurocognitive outcome.

    PubMed

    Nasr, Enas; Mamak, Eva; Feigenbaum, Anette; Donner, Elizabeth J; Mercimek-Mahmutoglu, Saadet

    2015-04-01

    Pyridoxine-dependent epilepsy is an autosomal recessively inherited disorder of lysine catabolism caused by mutations in the ALDH7A1 gene. We report 2 patients with normal neurocognitive outcome (full-scale IQ of 108 and 74) and their more than 10 years' treatment outcome on pyridoxine monotherapy. Both patients had specific borderline impairments in visual processing speed. More long-term treatment outcome reports will increase our knowledge about the natural history of the disease. PMID:24789515

  17. Characterization of polymorphisms of genes ADH2, ADH3, ALDH2 and CYP2E1 and relationship to the alcoholism in a Colombian population

    PubMed Central

    Méndez, Claudia

    2015-01-01

    Objective: Identify and characterize polymorphisms of genes ADH2, ADH3, ALDH2 and CYP2E1 in a Colombian population residing in the city of Bogotá and determine its possible relationship to the alcoholism. Methods: ADH2, ADH3, ALDH2, and CYP2E1 genotypes a population of 148 individuals with non-problematic alcohol and 65 individuals with alcoholism were determined with TaqMan probes and PCR-RFLP. DNA was obtained from peripheral blood white cells. Results: Significant difference was found in family history of alcoholism and use of other psychoactive substances to compare alcoholics with controls. When allelic frequencies for each category (gender) were considered, frequency of A2 allele carriers in ADH2 was found higher in male patients than controls. In women, the relative frequency for c1 allele in CYP2E1 was lower in controls than alcoholics. The ALDH2 locus is monomorphic. No significant differences in allele distributions of the loci examined to compare two populations were observed, however when stratifying the same trend was found that these differences tended to be significant. Conclusions: This study allows us to conclude the positive association between family history of alcoholism and alcoholism suggesting that there is a favourable hereditary predisposition. Since substance dependence requires interaction of multiple genes, the combination of genotypes ADH2 * 2, CYP2E1 * 1 combined with genotype homozygous ALDH2 * 1 found in this study could be leading to the population to a potential risk to alcoholism. PMID:26848198

  18. Co-transforming bar and CsALDH Genes Enhanced Resistance to Herbicide and Drought and Salt Stress in Transgenic Alfalfa (Medicago sativa L.)

    PubMed Central

    Duan, Zhen; Zhang, Daiyu; Zhang, Jianquan; Di, Hongyan; Wu, Fan; Hu, Xiaowen; Meng, Xuanchen; Luo, Kai; Zhang, Jiyu; Wang, Yanrong

    2015-01-01

    Drought and high salinity are two major abiotic factors that restrict the productivity of alfalfa. By application of the Agrobacterium-mediated transformation method, an oxidative responsive gene, CsALDH12A1, from the desert grass Cleistogenes songorica together with the bar gene associated with herbicide resistance, were co-transformed into alfalfa (Medicago sativa L.). From the all 90 transformants, 16 were positive as screened by spraying 1 mL L-1 10% Basta solution and molecularly diagnosis using PCR. Real-time PCR analysis indicated that drought and salt stress induced high CsALDH expression in the leaves of the transgenic plants. The CsALDH expression levels under drought (15 d) and salt stress (200 mM NaCl) were 6.11 and 6.87 times higher than in the control plants, respectively. In comparison to the WT plants, no abnormal phenotypes were observed among the transgenic plants, which showed significant enhancement of tolerance to 15 d of drought and 10 d of salinity treatment. Evaluation of the physiological and biochemical indices during drought and salt stress of the transgenic plants revealed relatively lower Na+ content and higher K+ content in the leaves relative to the WT plants, a reduction of toxic on effects and maintenance of osmotic adjustment. In addition, the transgenic plants could maintain a higher relative water content level, higher shoot biomass, fewer changes in the photosystem, decreased membrane injury, and a lower level of osmotic stress. These results indicate that the co-expression of the introduced bar and CsALDH genes enhanced the herbicide, drought and salt tolerance of alfalfa and therefore can potentially be used as a novel genetic resource for the future breeding programs to develop new cultivars. PMID:26734025

  19. Modulation of ALDH5A1 and SLC22A7 by microRNA hsa-miR-29a-3p in human liver cells.

    PubMed

    Yu, Dianke; Tolleson, William H; Knox, Bridgett; Jin, Yaqiong; Guo, Lei; Guo, Yongli; Kadlubar, Susan A; Ning, Baitang

    2015-12-15

    Observed variations in drug responses among patients may result from differences in heritable genetic traits or from alterations in the epigenetic regulation of drug metabolizing enzymes and transporters (DMETs). MicroRNAs (miRNAs), a group of small non-coding RNAs, provide an epigenetic mechanism for fine-tuning the expression of targeted DMET genes by regulating the efficiency of protein translation and by decreasing mRNA stability via enhanced degradation. In the current study we systematically screened 374 important genes encoding DMETs for potential response elements to hsa-miR-29a-3p, a highly abundant miRNA in human liver. RNA electrophoresis mobility shift assays displayed direct interactions between hsa-miR-29a-3p and its cognate targets within the mRNA transcripts for the ABCC6, SLC22A7 and ALDH5A1 genes. The expression of luciferase reporter genes containing the 3'-UTRs of SLC22A7 or ALDH5A1 and the expression of endogenous SLC22A7 and ALDH5A1 were each suppressed by transfection with hsa-miR-29a-3p mimics. Importantly, chemically-induced up-regulation of hsa-miR-29a-3p correlated inversely with the expression of SLC22A7 and ALDH5A1. However, our studies failed to detect suppressive effects of hsa-miR-29a-3p on ABCC6 expression, which might be explained by the notion that the interaction of hsa-miR-29a-3p and ABCC6 mRNA was unable to recruit ribonucleoproteins to form a RNA-induced silencing complex. PMID:26428001

  20. Single motoneuron succinate dehydrogenase activity.

    PubMed

    Chalmers, G R; Edgerton, V R

    1989-07-01

    We have developed a quantitative histochemical assay for measurement of succinate dehydrogenase (SDH) activity in single motoneurons. A computer image processing system was used to quantify the histochemical enzyme reaction product and to follow the time course of the reaction. The optimal concentration for each of the ingredients of the incubation medium for the SDH reaction was determined and the importance of using histochemical "blanks" in the determination of enzymatic activity was demonstrated. The enzymatic activity was linear with respect to reaction time and tissue thickness. The procedure described meets the criteria generally considered essential for establishment of a quantitative histochemical assay. The assay was then used to examine the SDH activity of cat and rat motoneurons. It was found that motoneurons with a small soma size had a wide range of SDH activity, whereas those with a large soma size were restricted to low SDH activity. PMID:2732457