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Sample records for aldehyde dehydrogenase-1 aldh1

  1. 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.

  2. 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...

  3. 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.

  4. Roles of histamine on the expression of aldehyde dehydrogenase 1 in endometrioid adenocarcinoma cell line.

    PubMed

    Wang, Yi; Jiang, Yang; Ikeda, Jun-Ichiro; Tian, Tian; Sato, Atsushi; Ohtsu, Hiroshi; Morii, Eiichi

    2014-10-01

    Cancer-initiating cells (CICs) are a limited number of cells that are essential for maintenance, recurrence, and metastasis of tumors. Aldehyde dehydrogenase 1 (ALDH1) has been recognized as a marker of CICs. We previously reported that ALDH1-high cases of uterine endometrioid adenocarcinoma showed poor prognosis, and that ALDH1 high population was more tumorigenic, invasive, and resistant to apoptosis than ALDH1 low population. Histamine plays a critical role in cancer cell proliferation, migration, and invasion. Here, we examined the effect of histamine on ALDH1 expression in endometrioid adenocarcinoma cell line. The addition of histamine increased ALDH1 high population, which was consistent with the result that histamine enhanced the invasive ability and the resistance to anticancer drug. Among 4 types of histamine receptors, histamine H1 and H2 receptor (H1R and H2R) were expressed in endometrioid adenocarcinoma cell line. The addition of H1R agonist but not H2R agonist increased ALDH1. The antagonist H1R but not H2R inhibited the effect of histamine on ALDH1 expression. These results indicated that histamine increased the expression of ALDH1 via H1R but not H2R. These findings may provide the evidence for exploring a new strategy to suppress CICs by inhibiting ALDH1 expression with histamine.

  5. 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

  6. Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity.

    PubMed

    Rasper, Michael; Schäfer, Andrea; Piontek, Guido; Teufel, Julian; Brockhoff, Gero; Ringel, Florian; Heindl, Stefan; Zimmer, Claus; Schlegel, Jürgen

    2010-10-01

    Glioblastoma (GBM) is the most aggressive primary brain tumor and is resistant to all therapeutic regimens. Relapse occurs regularly and might be caused by a poorly characterized tumor stem cell (TSC) subpopulation escaping therapy. We suggest aldehyde dehydrogenase 1 (ALDH1) as a novel stem cell marker in human GBM. Using the neurosphere formation assay as a functional method to identify brain TSCs, we show that high protein levels of ALDH1 facilitate neurosphere formation in established GBM cell lines. Even single ALDH1 positive cells give rise to colonies and neurospheres. Consequently, the inhibition of ALDH1 in vitro decreases both the number of neurospheres and their size. Cell lines without expression of ALDH1 do not form tumor spheroids under the same culturing conditions. High levels of ALDH1 seem to keep tumor cells in an undifferentiated, stem cell-like state indicated by the low expression of beta-III-tubulin. In contrast, ALDH1 inhibition induces premature cellular differentiation and reduces clonogenic capacity. Primary cell cultures obtained from fresh tumor samples approve the established GBM cell line results.

  7. Targeted therapy for a subset of acute myeloid leukemias that lack expression of aldehyde dehydrogenase 1A1.

    PubMed

    Gasparetto, Maura; Pei, Shanshan; Minhajuddin, Mohammad; Khan, Nabilah; Pollyea, Daniel A; Myers, Jason R; Ashton, John M; Becker, Michael W; Vasiliou, Vasilis; Humphries, Keith R; Jordan, Craig T; Smith, Clayton A

    2017-03-09

    Aldehyde dehydrogenase 1A1 (ALDH1A1) activity is high in hematopoietic stem cells and functions in part to protect stem cells from reactive aldehydes and other toxic compounds. In contrast, we found that ~25% of all acute myeloid leukemias expressed low or undetectable levels of ALDH1A1 and that this ALDH1A1- subset of leukemias correlates with good prognosis cytogenetics. ALDH1A1- cell lines as well as primary leukemia cells were found to be sensitive to treatment with compounds that directly and indirectly generate toxic ALDH substrates including 4-hydroxynonenal and the clinically relevant compounds arsenic trioxide and 4-hydroperoxycyclophosphamide. In contrast, normal hematopoietic stem cells were relatively resistant to these compounds. Using a murine xenotransplant model to emulate a clinical treatment strategy, established ALDH1A1- leukemias were also sensitive to in vivo treatment with cyclophosphamide combined with arsenic trioxide. These results demonstrate that targeting ALDH1A1- leukemic cells with toxic ALDH1A1 substrates such as arsenic and cyclophosphamide may be a novel targeted therapeutic strategy for this subset of acute myeloid leukemias.

  8. Comparison of quantum dot technology with conventional immunohistochemistry in examining aldehyde dehydrogenase 1A1 as a potential biomarker for lymph node metastasis of head and neck cancer.

    PubMed

    Xu, Jing; Müller, Susan; Nannapaneni, Sreenivas; Pan, Lin; Wang, Yuxiang; Peng, Xianghong; Wang, Dongsheng; Tighiouart, Mourad; Chen, Zhengjia; Saba, Nabil F; Beitler, Jonathan J; Shin, Dong M; Chen, Zhuo Georgia

    2012-07-01

    This study explored whether the expression of aldehyde dehydrogenase 1 (ALDH1A1) in the primary tumour correlated with lymph node metastasis (LNM) of squamous cell carcinoma of the head and neck (HNSCC). We used both quantum dot (QD)-based immunohistofluorescence (IHF) and conventional immunohistochemistry (IHC) to quantify ALDH1A1 expression in primary tumour samples taken from 96 HNSCC patients, 50 with disease in the lymph nodes and 46 without. The correlation between the quantified level of ALDH1A1 expression and LNM in HNSCC patients was evaluated with univariate and multivariate analysis. The prognostic value of ALDH1A1 was examined by Kaplan-Meier analysis and Wald test. ALDH1A1 was highly correlated with LNM in HNSCC patients (p<0.0001 by QD-based IHF and 0.039 by IHC). The two methods (QD-based IHF and conventional IHC) for quantification of ALDH1A1 were found to be comparable (R=0.75, p<0.0001), but QD-IHF was more sensitive and objective than IHC. The HNSCC patients with low ALDH1A1 expression had a higher 5-year survival rate than those with high ALDH1A1 level (p=0.025). Our study suggests that ALDH1A1 is a potential biomarker for predicting LNM in HNSCC patients, though it is not an independent prognostic factor for survival of HNSCC patients. Furthermore, QD-IHF has advantages over IHC in quantification of ALDH1A1 expression in HNSCC tissues.

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

    PubMed

    Gonnella, Thomas P; Keating, Jennifer M; Kjemhus, Jessica A; Picklo, Matthew J; Biggane, Joseph P

    2013-02-25

    Aldehyde dehydrogenase 1 (ALDH1A1) catalyzes the oxidation of toxic aldehydes to carboxylic acids. Physiologic levels of Mg(2+) ions decrease ALDH1 activity in part by increasing NADH binding affinity to the enzyme. By using time-resolved fluorescence spectroscopy, we have resolved the fluorescent lifetimes (τ) of free NADH in solution (τ=0.4 ns) and two enzyme-bound NADH states (τ=2.0 ns and τ=7.7 ns). We used this technique to investigate the effects of Mg(2+) ions on the ALDH1A1-NADH binding characteristics and enzyme catalysis. From the resolved free and bound NADH fluorescence signatures, the KD values for both NADH conformations in ALDH1A1 ranged from about 24 μM to 1 μM for Mg(2+) ion concentrations of 0-6000 μM, respectively. The rate constants for dissociation of the enzyme-NADH complex ranged from 0.03 s(-1) (6000 μM Mg(2+)) to 0.30s(-1) (0 μM Mg(2+)) as determined by addition of excess NAD(+) to prevent re-association of NADH and resolving the real-time NADH fluorescence signal. During the initial reaction of enzyme with NAD(+) and butyraldehyde, there was an immediate rise in the NADH fluorescence, due to the formation of bound NADH complexes, with a constant steady-state rate of production of free NADH. As the Mg(2+) ion concentration was increased, there was a consistent decrease of the enzyme catalytic turnover from 0.31 s(-1) (0 μM Mg(2+)) to 0.050 s(-1) (6000 μM Mg(2+)) and a distinct shift in steady-state conformational population from one that favors the ALDH1-NADH complex with the shorter fluorescence lifetime (33% excess) in the absence of magnesium ion to one that favors the ALDH1-NADH complex with the longer fluorescence lifetime (13% excess) at 6000 μM Mg(2+). This shift in conformational population at higher Mg(2+) ion concentrations and to lower enzyme activity may be due to longer residence time of the NADH in the ALDH1 pocket. The results from monitoring enzyme catalysis in the absence of magnesium suggests that the ALDH1

  10. Characterization of Two Distinct Structural Classes of Selective Aldehyde Dehydrogenase 1A1 Inhibitors

    PubMed Central

    Morgan, Cynthia A.; Hurley, Thomas D.

    2015-01-01

    Aldehyde dehydrogenases (ALDH) catalyze the irreversible oxidation of aldehydes to their corresponding carboxylic acid. Alterations in ALDH1A1 activity are associated with such diverse diseases as cancer, Parkinson’s disease, obesity, and cataracts. Inhibitors of ALDH1A1 could aid in illuminating the role of this enzyme in disease processes. However, there are no commercially available selective inhibitors for ALDH1A1. Here we characterize two distinct chemical classes of inhibitors that are selective for human ALDH1A1 compared to eight other ALDH isoenzymes. The prototypical members of each structural class, CM026 and CM037, exhibit sub-micromolar inhibition constants, but have different mechanisms of inhibition. The crystal structures of these compounds bound to ALDH1A1 demonstrate that they bind within the aldehyde binding pocket of ALDH1A1 and exploit the presence of a unique Glycine residue to achieve their selectivity. These two novel and selective ALDH1A1 inhibitors may serve as chemical tools to better understand the contributions of ALDH1A1 to normal biology and to disease states. PMID:25634381

  11. NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells.

    PubMed

    Zhao, Di; Mo, Yan; Li, Meng-Tian; Zou, Shao-Wu; Cheng, Zhou-Li; Sun, Yi-Ping; Xiong, Yue; Guan, Kun-Liang; Lei, Qun-Ying

    2014-12-01

    High aldehyde dehydrogenase (ALDH) activity is a marker commonly used to isolate stem cells, particularly breast cancer stem cells (CSCs). Here, we determined that ALDH1A1 activity is inhibited by acetylation of lysine 353 (K353) and that acetyltransferase P300/CBP-associated factor (PCAF) and deacetylase sirtuin 2 (SIRT2) are responsible for regulating the acetylation state of ALDH1A1 K353. Evaluation of breast carcinoma tissues from patients revealed that cells with high ALDH1 activity have low ALDH1A1 acetylation and are capable of self-renewal. Acetylation of ALDH1A1 inhibited both the stem cell population and self-renewal properties in breast cancer. Moreover, NOTCH signaling activated ALDH1A1 through the induction of SIRT2, leading to ALDH1A1 deacetylation and enzymatic activation to promote breast CSCs. In breast cancer xenograft models, replacement of endogenous ALDH1A1 with an acetylation mimetic mutant inhibited tumorigenesis and tumor growth. Together, the results from our study reveal a function and mechanism of ALDH1A1 acetylation in regulating breast CSCs.

  12. Effect of ALDH1 on prognosis and chemoresistance by breast cancer subtype.

    PubMed

    Kida, Kumiko; Ishikawa, Takashi; Yamada, Akimitsu; Shimada, Kazuhiro; Narui, Kazutaka; Sugae, Sadatoshi; Shimizu, Daisuke; Tanabe, Mikiko; Sasaki, Takeshi; Ichikawa, Yasushi; Endo, Itaru

    2016-04-01

    Aldehyde dehydrogenase 1 (ALDH1) has been identified as a breast cancer stem cell marker, but its value as a predictor of prognosis and chemoresistance is controversial. This study investigated the effect of ALDH1 on prognosis and chemoresponse by breast cancer subtype. We immunohistochemically analyzed 653 invasive breast cancer specimens and evaluated correlations among clinicopathological factors, survival status, response to neoadjuvant chemotherapy, and ALDH1 expression. Of 653 specimens, 139 (21.3 %) expressed ALDH1 in tumor cells. ALDH1 expression was correlated significantly with larger tumor size, node metastasis, higher nuclear grade, and with HER2(+) and progesterone/estrogen receptor (HR)(-) subtypes. ALDH1 expression was significantly observed in HER2 type and triple-negative breast cancer (TNBC). Patients with ALDH1(+) cancers had significantly shorter disease-free survival (P < 0001) and overall survival (P = 0.044). ALDH1 expression significantly affected prognosis of luminal types, but not TNBC and HER2-enriched types. For the 234 patients treated with neoadjuvant chemotherapy, pathological complete response (pCR) rate was significantly lower in ALDH1(+) cases (13.5 vs. 30.3 %, P = 0.003). pCR and ALDH1 expression were significantly correlated in TNBC patients (P = 0.003). ALDH1(+) breast cancers tended to be aggressive, with poor prognoses. Although ALDH1(+) TNBC showed higher chemoresistance, ALDH1 had significant impact on prognosis in the luminal type but not in TNBC.

  13. Inhibition of the Aldehyde Dehydrogenase 1/2 Family by Psoralen and Coumarin Derivatives.

    PubMed

    Buchman, Cameron D; Hurley, Thomas D

    2017-03-23

    Aldehyde dehydrogenase 2 (ALDH2), one of 19 ALDH superfamily members, catalyzes the NAD(+)-dependent oxidation of aldehydes to their respective carboxylic acids. In this study, we further characterized the inhibition of four psoralen and coumarin derivatives toward ALDH2 and compared them to the ALDH2 inhibitor daidzin for selectivity against five ALDH1/2 isoenzymes. Compound 2 (Ki = 19 nM) binds within the aldehyde-binding site of the free enzyme species of ALDH2. Thirty-three structural analogs were examined to develop a stronger SAR profile. Seven compounds maintained or improved upon the selectivity toward one of the five ALDH1/2 isoenzymes, including compound 36, a selective inhibitor for ALDH2 (Ki = 2.4 μM), and compound 32, which was 10-fold selective for ALDH1A1 (Ki = 1.2 μM) versus ALDH1A2. Further medicinal chemistry on the compounds' basic scaffold could enhance the potency and selectivity for ALDH1A1 or ALDH2 and generate chemical probes to examine the unique and overlapping functions of the ALDH1/2 isoenzymes.

  14. ALDH1 might influence the metastatic capability of HeLa cells.

    PubMed

    Yao, Tingting; Lu, Rongbiao; Li, Yiqing; Peng, Yongpai; Ding, Miao; Xie, Xiaofei; Lin, Zhongqiu

    2015-09-01

    Recent data suggest that tumor persistence and recurrence could be caused by the presence of cancer stem cells (CSCs). Aldehyde dehydrogenase 1 (ALDH1) has been implicated in cancer pathogenesis and used as a CSC marker. We previously reported that cervical carcinoma contains a small subpopulation of cells expressing ALDH1 [1]. In this study, we used small interfering RNA to suppress ALDH1 expression and introduced an ALDH1 reporting vector into HeLa cells followed by various in vitro assays. We showed that knockdown of ALDH1 expression reduced the cell migration ability of HeLa cells, whereas augmented expression of ALDH1 increased cell migration. However, there was no difference in the cellular proliferation, apoptosis, cell cycle, and invasion. These results indicate that ALDH1 is directly involved in HeLa migration.

  15. Crystal structure of human aldehyde dehydrogenase 1A3 complexed with NAD+ and retinoic acid

    PubMed Central

    Moretti, Andrea; Li, Jianfeng; Donini, Stefano; Sobol, Robert W.; Rizzi, Menico; Garavaglia, Silvia

    2016-01-01

    The aldehyde dehydrogenase family 1 member A3 (ALDH1A3) catalyzes the oxidation of retinal to the pleiotropic factor retinoic acid using NAD+. The level of ALDHs enzymatic activity has been used as a cancer stem cell marker and seems to correlate with tumour aggressiveness. Elevated ALDH1A3 expression in mesenchymal glioma stem cells highlights the potential of this isozyme as a prognosis marker and drug target. Here we report the first crystal structure of human ALDH1A3 complexed with NAD+ and the product all-trans retinoic acid (REA). The tetrameric ALDH1A3 folds into a three domain-based architecture highly conserved along the ALDHs family. The structural analysis revealed two different and coupled conformations for NAD+ and REA that we propose to represent two snapshots along the catalytic cycle. Indeed, the isoprenic moiety of REA points either toward the active site cysteine, or moves away adopting the product release conformation. Although ALDH1A3 shares high sequence identity with other members of the ALDH1A family, our structural analysis revealed few peculiar residues in the 1A3 isozyme active site. Our data provide information into the ALDH1As catalytic process and can be used for the structure-based design of selective inhibitors of potential medical interest. PMID:27759097

  16. Identification of aldehyde dehydrogenase 1A1 modulators using virtual screening.

    PubMed

    Kotraiah, Vinayaka; Pallares, Diego; Toema, Deanna; Kong, Dehe; Beausoleil, Eric

    2013-06-01

    The highly similar aldehyde dehydrogenase isozymes (ALDH1A1 and ALDH2) have been implicated in the metabolism of toxic biogenic aldehydes such as 3,4-dihydroxyphenylacetaldehyde (DOPAL) and 4-hydroxy-2E-nonenal. We report the down-regulation of ALDH1A1 mRNA found in substantia nigra tissue of human Parkinson's disease (PD) samples using the Genome-Wide SpliceArray(™) (GWSA(™)) technology. Since DOPAL can rapidly inactivate ALDH1A1 in vitro, we set up a DOPAL-induced ALDH1A1 inactivation assay and used this assay to demonstrate that Alda-1, a compound originally identified as an activator of ALDH2, can also activate ALDH1A1. We carried out a virtual screening of 19,943 compounds and the top 21 hits from this screen were tested in the DOPAL inactivation assay with ALDH1A1 which led to identification of an activator as well as two inhibitors among these hits. These findings represent an attractive starting point for developing higher potency activator compounds that may have utility in restoring the metabolism of DOPAL in PD.

  17. 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

  18. Aldehyde dehydrogenase 1A1 up-regulates stem cell markers in benzo[a]pyrene-induced malignant transformation of BEAS-2B cells.

    PubMed

    Liu, Yonghong; Lu, Ruitao; Gu, Junlian; Chen, Yanxuan; Zhang, Xueyan; Zhang, Lan; Wu, Hao; Hua, Wenfeng; Zeng, Jun

    2016-07-01

    Recently, Aldehyde dehydrogenase 1A1 (ALDH1A1) has been proposed to be a common marker of cancer stem cells and can be induced by benzo[a]pyrene (B[a]P) exposure. However, the underlying mechanism of how ALDH1A1 contributes to B[a]P-induced carcinogenesis in human bronchial epithelial cells remains unclear. Here, we found that B[a]P up-regulated expression levels of stem cell markers (ABCG2, SOX2, c-Myc and Klf4), epithelial-mesenchymal transition (EMT) associated genes (SNAIL1, ZEB1, TWIST and β-CATENIN) and cancer-related long non-coding RNAs (lncRNAs; HOTAIR and MALAT-1) in malignant B[a]P-transformed human bronchial epithelial cells (BEAS-2B-T cells), and these up-regulations were dependent on increased expression of ALDH1A1. The inhibition of endogenous ALDH1A1 expression down-regulated expression levels of stem cell markers and reversed the malignant phenotype as well as reduced the chemoresistance of BEAS-2B-T cells. In contrast, the overexpression of ALDH1A1 in BEAS-2B cells increased the expression of stem cell markers, facilitated cell transformation, promoted migratory ability and enhanced the drug resistance of BEAS-2B cells. Overall, our data indicates that ALDH1A1 promotes a stemness phenotype and plays a critical role in the BEAS-2B cell malignant transformation induced by B[a]P.

  19. Deficient Expression of Aldehyde Dehydrogenase 1A1 is Consistent With Increased Sensitivity of Gorlin Syndrome Patients to Radiation Carcinogenesis

    PubMed Central

    Wright, Aaron T.; Magnaldo, Thierry; Sontag, Ryan L.; Anderson, Lindsey N.; Sadler, Natalie C.; Piehowski, Paul D.; Gache, Yannick; Weber, Thomas J.

    2016-01-01

    Human phenotypes that are highly susceptible to radiation carcinogenesis have been identified. Sensitive phenotypes often display robust regulation of molecular features that modify biological response, which can facilitate identification of the pathways/networks that contribute to pathophysiological outcomes. Here we interrogate primary dermal fibroblasts isolated from Gorlin syndrome patients (GDFs), who display a pronounced inducible tumorigenic response to radiation, in comparison to normal human dermal fibroblasts (NHDFs). Our approach exploits newly developed thiol reactive probes to define changes in protein thiol profiles in live cell studies, which minimizes artifacts associated with cell lysis. Redox probes revealed deficient expression of an apparent 55 kDa protein thiol in GDFs from independent Gorlin syndrome patients, compared with NHDFs. Proteomics tentatively identified this protein as aldehyde dehydrogenase 1A1 (ALDH1A1), a key enzyme regulating retinoic acid synthesis, and ALDH1A1 protein deficiency in GDFs was confirmed by Western blot. A number of additional protein thiol differences in GDFs were identified, including radiation responsive annexin family members and lamin A/C. Collectively, candidates identified in our study have plausible implications for radiation health effects and cancer susceptibility. PMID:24285572

  20. Deficient expression of aldehyde dehydrogenase 1A1 is consistent with increased sensitivity of Gorlin syndrome patients to radiation carcinogenesis.

    PubMed

    Wright, Aaron T; Magnaldo, Thierry; Sontag, Ryan L; Anderson, Lindsey N; Sadler, Natalie C; Piehowski, Paul D; Gache, Yannick; Weber, Thomas J

    2015-06-01

    Human phenotypes that are highly susceptible to radiation carcinogenesis have been identified. Sensitive phenotypes often display robust regulation of molecular features that modify biological response, which can facilitate identification of the pathways/networks that contribute to pathophysiological outcomes. Here we interrogate primary dermal fibroblasts isolated from Gorlin syndrome patients (GDFs), who display a pronounced inducible tumorigenic response to radiation, in comparison to normal human dermal fibroblasts (NHDFs). Our approach exploits newly developed thiol reactive probes to define changes in protein thiol profiles in live cell studies, which minimizes artifacts associated with cell lysis. Redox probes revealed deficient expression of an apparent 55 kDa protein thiol in GDFs from independent Gorlin syndrome patients, compared with NHDFs. Proteomics tentatively identified this protein as aldehyde dehydrogenase 1A1 (ALDH1A1), a key enzyme regulating retinoic acid synthesis, and ALDH1A1 protein deficiency in GDFs was confirmed by Western blot. A number of additional protein thiol differences in GDFs were identified, including radiation responsive annexin family members and lamin A/C. Collectively, candidates identified in our study have plausible implications for radiation health effects and cancer susceptibility.

  1. The mechanism of discrimination between oxidized and reduced coenzyme in the aldehyde dehydrogenase domain of Aldh1l1.

    PubMed

    Tsybovsky, Yaroslav; Malakhau, Yuryi; Strickland, Kyle C; Krupenko, Sergey A

    2013-02-25

    Aldh1l1, also known as 10-formyltetrahydrofolate dehydrogenase (FDH), contains the carboxy-terminal domain (Ct-FDH), which is a structural and functional homolog of aldehyde dehydrogenases (ALDHs). This domain is capable of catalyzing the NADP(+)-dependent oxidation of short chain aldehydes to their corresponding acids, and similar to most ALDHs it has two conserved catalytic residues, Cys707 and Glu673. Previously, we demonstrated that in the Ct-FDH mechanism these residues define the conformation of the bound coenzyme and the affinity of its interaction with the protein. Specifically, the replacement of Cys707 with an alanine resulted in the enzyme lacking the ability to differentiate between the oxidized and reduced coenzyme. We suggested that this was due to the loss of a covalent bond between the cysteine and the C4N atom of nicotinamide ring of NADP(+) formed during Ct-FDH catalysis. To obtain further insight into the functional significance of the covalent bond between Cys707 and the coenzyme, and the overall role of the two catalytic residues in the coenzyme binding and positioning, we have now solved crystal structures of Ct-FDH in the complex with thio-NADP(+) and the complexes of the C707S mutant with NADP(+) and NADPH. This study has allowed us to trap the coenzyme in the contracted conformation, which provided a snapshot of the conformational processing of the coenzyme during the transition from oxidized to reduced form. Overall, the results of this study further support the previously proposed mechanism by which Cys707 helps to differentiate between the oxidized and reduced coenzyme during ALDH catalysis.

  2. Conserved catalytic residues of the ALDH1L1 aldehyde dehydrogenase domain control binding and discharging of the coenzyme.

    PubMed

    Tsybovsky, Yaroslav; Krupenko, Sergey A

    2011-07-01

    The C-terminal domain (C(t)-FDH) of 10-formyltetrahydrofolate dehydrogenase (FDH, ALDH1L1) is an NADP(+)-dependent oxidoreductase and a structural and functional homolog of aldehyde dehydrogenases. Here we report the crystal structures of several C(t)-FDH mutants in which two essential catalytic residues adjacent to the nicotinamide ring of bound NADP(+), Cys-707 and Glu-673, were replaced separately or simultaneously. The replacement of the glutamate with an alanine causes irreversible binding of the coenzyme without any noticeable conformational changes in the vicinity of the nicotinamide ring. Additional replacement of cysteine 707 with an alanine (E673A/C707A double mutant) did not affect this irreversible binding indicating that the lack of the glutamate is solely responsible for the enhanced interaction between the enzyme and the coenzyme. The substitution of the cysteine with an alanine did not affect binding of NADP(+) but resulted in the enzyme lacking the ability to differentiate between the oxidized and reduced coenzyme: unlike the wild-type C(t)-FDH/NADPH complex, in the C707A mutant the position of NADPH is identical to the position of NADP(+) with the nicotinamide ring well ordered within the catalytic center. Thus, whereas the glutamate restricts the affinity for the coenzyme, the cysteine is the sensor of the coenzyme redox state. These conclusions were confirmed by coenzyme binding experiments. Our study further suggests that the binding of the coenzyme is additionally controlled by a long-range communication between the catalytic center and the coenzyme-binding domain and points toward an α-helix involved in the adenine moiety binding as a participant of this communication.

  3. Deficient expression of aldehyde dehydrogenase 1A1 is consistent with increased sensitivity of Gorlin syndrome patients to radiation carcinogenesis

    DOE PAGES

    Wright, Aaron T.; Magnaldo, Thierry; Sontag, Ryan L.; ...

    2013-11-27

    Human phenotypes that are highly susceptible to radiation carcinogenesis have been identified. Sensitive phenotypes often display robust regulation of molecular features that modify biological response, which can facilitate identification of relevant pathways/networks. Here we interrogate primary dermal fibroblasts isolated from Gorlin syndrome patients (GDFs), who display a pronounced tumorigenic response to radiation, in comparison to normal human dermal fibroblasts (NHDFs). Our approach exploits newly developed thiol-reactive probes with a flexible click chemistry functional group to define changes in protein thiol profiles in live cell studies, which minimizes artifacts associated with cell lysis. We observe qualitative differences in protein thiol profilesmore » by SDS-PAGE analysis when detection by iodoacetamide vs maleimide probe chemistries are compared, and pretreatment of cells with hydrogen peroxide eliminates detection of the majority of SDS-PAGE bands. Redox probes revealed deficient expression of an apparent 55 kDa protein thiol in GDFs from independent donors, compared with NHDFs. Proteomics tentatively identified this protein as aldehyde dehydrogenase 1A1 (ALDH1A1), a key enzyme regulating retinoic acid synthesis, and this deficiency was confirmed by Western blot. Redox probes revealed additional protein thiol differences between GDFs and NHDFs, including radiation responsive annexin family members. Our results indicate a multifactorial basis for the unusual sensitivity of Gorlin syndrome to radiation carcinogenesis, and the pathways identified have plausible implications for radiation health effects.« less

  4. Deficient expression of aldehyde dehydrogenase 1A1 is consistent with increased sensitivity of Gorlin syndrome patients to radiation carcinogenesis

    SciTech Connect

    Wright, Aaron T.; Magnaldo, Thierry; Sontag, Ryan L.; Anderson, Lindsey N.; Sadler, Natalie C.; Piehowski, Paul D.; Gache, Yannick; Weber, Thomas J.

    2013-11-27

    Human phenotypes that are highly susceptible to radiation carcinogenesis have been identified. Sensitive phenotypes often display robust regulation of molecular features that modify biological response, which can facilitate identification of relevant pathways/networks. Here we interrogate primary dermal fibroblasts isolated from Gorlin syndrome patients (GDFs), who display a pronounced tumorigenic response to radiation, in comparison to normal human dermal fibroblasts (NHDFs). Our approach exploits newly developed thiol-reactive probes with a flexible click chemistry functional group to define changes in protein thiol profiles in live cell studies, which minimizes artifacts associated with cell lysis. We observe qualitative differences in protein thiol profiles by SDS-PAGE analysis when detection by iodoacetamide vs maleimide probe chemistries are compared, and pretreatment of cells with hydrogen peroxide eliminates detection of the majority of SDS-PAGE bands. Redox probes revealed deficient expression of an apparent 55 kDa protein thiol in GDFs from independent donors, compared with NHDFs. Proteomics tentatively identified this protein as aldehyde dehydrogenase 1A1 (ALDH1A1), a key enzyme regulating retinoic acid synthesis, and this deficiency was confirmed by Western blot. Redox probes revealed additional protein thiol differences between GDFs and NHDFs, including radiation responsive annexin family members. Our results indicate a multifactorial basis for the unusual sensitivity of Gorlin syndrome to radiation carcinogenesis, and the pathways identified have plausible implications for radiation health effects.

  5. Distinct prognostic values and potential drug targets of ALDH1 isoenzymes in non-small-cell lung cancer

    PubMed Central

    You, Qinghua; Guo, Huanchen; Xu, Dongxiang

    2015-01-01

    Increased aldehyde dehydrogenase 1 (ALDH1) activity has been found in the stem cell populations of leukemia and some solid tumors including non-small-cell lung cancer (NSCLC). However, which ALDH1’s isoenzymes are contributing to ALDH1 activity remains elusive. In addition, the prognostic value of individual ALDH1 isoenzyme is not clear. In the current study, we investigated the prognostic value of ALDH1 isoenzymes in NSCLC patients through the Kaplan–Meier plotter database, which contains updated gene expression data and survival information from a total of 1,926 NSCLC patients. High expression of ALDH1A1 mRNA was found to be correlated to a better overall survival (OS) in all NSCLC patients followed for 20 years (hazard ratio [HR] 0.88 [0.77–0.99], P=0.039). In addition, high expression of ALDH1A1 mRNA was also found to be correlated to better OS in adenocarcinoma (Ade) patients (HR 0.71 [0.57–0.9], P=0.0044) but not in squamous cell carcinoma (SCC) patients (HR 0.92 [0.72–1.16], P=0.48). High expression of ALDH1A2 and ALDH1B1 mRNA was found to be correlated to worser OS in all NSCLC patients, as well as in Ade, but not in SCC patients. High expression of both ALDH1A3 and ALDH1L1 mRNA was not found to be correlated to OS in all NSCLC patients. These results strongly support that ALDH1A1 mRNA in NSCLC is associated with better prognosis. In addition, our current study also supports that ALDH1A2 and ALDH1B1 might be major contributors to the ALDH1 activity in NSCLC, since high expression of ALDH1A2 and ALDH1B1 mRNA was found to be significantly correlated to worser OS in all NSCLC patients. Based on our study, ALDH1A2 and ALDH1B1 might be excellent potential drug targets for NSCLC patients. PMID:26366059

  6. ALDH1 and podoplanin expression patterns predict the risk of malignant transformation in oral leukoplakia

    PubMed Central

    Habiba, Umma; Hida, Kyoko; Kitamura, Tetsuya; Matsuda, Aya Yanagawa; Higashino, Fumihiro; Ito, Yoichi M.; Ohiro, Yoichi; Totsuka, Yasunori; Shindoh, Masanobu

    2017-01-01

    Oral leukoplakia (OL) is a clinically diagnosed preneoplastic lesion of the oral cavity with an increased oral cancer risk. However, the risk of malignant transformation is still difficult to assess. The objective of the present study was to examine the expression patterns of aldehyde dehydrogenase 1 (ALDH1) and podoplanin in OL, and to determine their roles in predicting oral cancer development. In the present study, the expression patterns of ALDH1 and podoplanin were determined in samples from 79 patients with OL. The association between protein expression and clinicopathological parameters, including oral cancer-free survival, was analyzed during a mean follow-up period of 3.4 years. Expression of ALDH1 and podoplanin was observed in 61 and 67% patients, respectively. Kaplan-Meier analysis demonstrated that the expression of the proteins was correlated with the risk of progression to oral cancer. Multivariate analysis revealed that expression of ALDH1 and podoplanin was associated with 3.02- and 2.62-fold increased risk of malignant transformation, respectively. The malignant transformation risk of OL was considerably higher in cases with expression of both proteins. Point-prevalence analysis revealed that 66% of patients with co-expression of ALDH1 and podoplanin developed oral cancer. Taken together, our data indicate that ALDH1 and podoplanin expression patterns in OL are associated with oral cancer development, suggesting that ALDH1 and podoplanin may be useful biomarkers to identify OL patients with a substantially high oral cancer risk. PMID:28123562

  7. ALDH1 and podoplanin expression patterns predict the risk of malignant transformation in oral leukoplakia.

    PubMed

    Habiba, Umma; Hida, Kyoko; Kitamura, Tetsuya; Matsuda, Aya Yanagawa; Higashino, Fumihiro; Ito, Yoichi M; Ohiro, Yoichi; Totsuka, Yasunori; Shindoh, Masanobu

    2017-01-01

    Oral leukoplakia (OL) is a clinically diagnosed preneoplastic lesion of the oral cavity with an increased oral cancer risk. However, the risk of malignant transformation is still difficult to assess. The objective of the present study was to examine the expression patterns of aldehyde dehydrogenase 1 (ALDH1) and podoplanin in OL, and to determine their roles in predicting oral cancer development. In the present study, the expression patterns of ALDH1 and podoplanin were determined in samples from 79 patients with OL. The association between protein expression and clinicopathological parameters, including oral cancer-free survival, was analyzed during a mean follow-up period of 3.4 years. Expression of ALDH1 and podoplanin was observed in 61 and 67% patients, respectively. Kaplan-Meier analysis demonstrated that the expression of the proteins was correlated with the risk of progression to oral cancer. Multivariate analysis revealed that expression of ALDH1 and podoplanin was associated with 3.02- and 2.62-fold increased risk of malignant transformation, respectively. The malignant transformation risk of OL was considerably higher in cases with expression of both proteins. Point-prevalence analysis revealed that 66% of patients with co-expression of ALDH1 and podoplanin developed oral cancer. Taken together, our data indicate that ALDH1 and podoplanin expression patterns in OL are associated with oral cancer development, suggesting that ALDH1 and podoplanin may be useful biomarkers to identify OL patients with a substantially high oral cancer risk.

  8. 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

  9. ALDH1A3 Mutations Cause Recessive Anophthalmia and Microphthalmia

    PubMed Central

    Fares-Taie, Lucas; Gerber, Sylvie; Chassaing, Nicolas; Clayton-Smith, Jill; Hanein, Sylvain; Silva, Eduardo; Serey, Margaux; Serre, Valérie; Gérard, Xavier; Baumann, Clarisse; Plessis, Ghislaine; Demeer, Bénédicte; Brétillon, Lionel; Bole, Christine; Nitschke, Patrick; Munnich, Arnold; Lyonnet, Stanislas; Calvas, Patrick; Kaplan, Josseline; Ragge, Nicola; Rozet, Jean-Michel

    2013-01-01

    Anophthalmia and microphthalmia (A/M) are early-eye-development anomalies resulting in absent or small ocular globes, respectively. A/M anomalies occur in syndromic or nonsyndromic forms. They are genetically heterogeneous, some mutations in some genes being responsible for both anophthalmia and microphthalmia. Using a combination of homozygosity mapping, exome sequencing, and Sanger sequencing, we identified homozygosity for one splice-site and two missense mutations in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) in three consanguineous families segregating A/M with occasional orbital cystic, neurological, and cardiac anomalies. ALDH1A3 is a key enzyme in the formation of a retinoic acid gradient along the dorso-ventral axis during early eye development. Transitory expression of mutant ALDH1A3 open reading frames showed that both missense mutations reduce the accumulation of the enzyme, potentially leading to altered retinoic acid synthesis. Although the role of retinoic acid signaling in eye development is well established, our findings provide genetic evidence of a direct link between retinoic-acid-synthesis dysfunction and early-eye-development anomalies in humans. PMID:23312594

  10. Blood ALDH1 and GST activity in diabetes type 2 and its correlation with glycated hemoglobin.

    PubMed

    Giebułtowicz, J; Sołobodowska, S; Bobilewicz, D; Wroczyński, P

    2014-01-01

    There is increasing evidence that oxidative stress (OS) plays a major role in the pathogenesis of diabetes mellitus (DM) and the development of its complications. As one of the consequences of OS is increased lipid peroxidation (LP), the aim of our studies was to check, how the activity of 2 enzymes involved in the detoxification of aldehydes formed during LP, glutathione S-transferase (GST) and aldehyde dehydrogenase 1 (ALDH 1) is changed in patients suffering from DM.GST and ALDH1A1 activities were determined in whole blood samples of DM type 2 patients (n=64) and healthy controls (n=60) using spectrophotometer (for GST activity) and fluorometer (for ALDH1 activity) and they were found to be significantly increased in diabetics when compared with healthy control (p<0.05). Intriguingly, grouping the DM patients on the basis of the glucose level and HbA1c revealed unusually low ALDH activity in the group of patients (n=16) with a relatively high level of these 2 parameters.The increase of ALDH1A1 and GST activity in DM seems to be associated with the severity of the disease and might be a compensatory effect against oxidative stress. Surprisingly low ALDH activity in DM patients with relatively high glucose and HbA1c levels can be a factor predisposing to the development of diabetic complications.

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

    PubMed Central

    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

  12. Evaluation of the Role of ALDH1 as Cancer Stem Cell Marker in Colorectal Carcinoma: An Immunohistochemical Study

    PubMed Central

    Aiad, Hayam Abd-El-Samie; Asaad, Nancy Yousif; Elkhouly, Enas Abobakr; Lasheen, Ayat Gamal

    2017-01-01

    Introduction Colorectal Carcinoma (CRC) is the third most commonly diagnosed cancer in males. Stem Cells (SC) may be involved in tumour growth, including colon cancer. Aldehyde Dehydrogenase 1 (ALDH1) is a detoxifying enzyme that might modulate SC proliferation. Aims To evaluate the immunohistochemical expression of ALDH1 as stem cell marker in the pathogenesis of colorectal carcinoma. Materials and Methods This retrospective study included 71 colorectal specimens (49 colorectal carcinoma, 13 adenoma and 9 normal cases) that were collected from Pathology Department, Faculty of Medicine, Menoufia University during the period from 2011 to 2015. All cases were stained by ALDH 1 antibody. Survival data were available for 31cases. Results There was a statistical significant association between epithelial positivity of ALDH1 and younger age (p=0.003), right sided tumour (p=0.038), presence of lymph node invasion (p= 0.04), ulcerating gross picture (p=0.01) and presence of vascular invasion (p=0.05). Moreover, there was statistical significant association between stromal positivity of ALDH1 and smaller tumour size (p=0.03) and inverse association between stromal expression of ALDH1 and grade of tumour (p=0.000) and perineural invasion (p= 0.05). Furthermore, there was an inverse significant relation between CD44 and ALDH1 expression (p=0.001). Univariate recurrence free survival analysis revealed the bad prognostic impact of high grade (p=0.03) and female sex (p=0.02) on patient outcome. Conclusion Epithelial expression of ALDH1 might be associated with poor prognosis while its stromal expression might be associated with good prognosis. PMID:28273973

  13. Effects of ellipticine on ALDH1A1-expressing breast cancer stem cells--an in vitro and in silico study.

    PubMed

    Pandrangi, Santhi Latha; Chikati, Rajasekhar; Chauhan, Pradeep Singh; Kumar, Chitta Suresh; Banarji, Anropa; Saxena, Sunita

    2014-01-01

    Targeting breast cancer stem cells (BCSCs) offers a promising strategy for breast cancer treatment. We examined the plant alkaloid ellipticine for its efficacy to inhibit the expression of aldehyde dehydrogenase 1 class A1 (ALDH1A1)-positive BCSCs by in vitro and in silico methods. At 3 mM concentration, ellipticine decreased the expression of ALDH1A1-positive BCSCs by 62% (p = 0.073) in the MCF7 cell line and by 53% (p = 0.024) in the SUM159 cell line compared to vehicle-treated cultures. Ellipticine significantly reduced the formation of mammospheres, whereas paclitaxel enhanced mammosphere formation in both the treated cell lines. Interestingly, when treated with a combination of ellipticine and paclitaxel, the percentage of ALDH1A1-positive BCSCs dropped by several fold in vitro. A homology model of Homo sapiens ALDH1A1 was built using the crystal structure of NAD-bound sheep liver class I aldehyde dehydrogenase [PDB ID: 1BXS] as a template. Molecular simulation and docking studies revealed that the amino acids Asn-117 and Asn-121, Glu-249, Cys-302, and Gln-350, present in the active site of human ALDH1A1, played a vital role in interacting with the drug. The present study suggests that ellipticine reduces the proliferation and self-renewal ability of ALDH1A1-positive BCSCs and can be used in combination with a cytotoxic drug like paclitaxel for potential targeting of BCSCs.

  14. Cancer stem cell marker ALDH1 expression is associated with lymph node metastasis and poor survival in esophageal squamous cell carcinoma: a study from high incidence area of northern China.

    PubMed

    Wang, Y; Zhe, H; Gao, P; Zhang, N; Li, G; Qin, J

    2012-08-01

    Tumor recurrence and metastasis is the leading cause of death in esophageal squamous cell carcinoma (ESCC). Cancer stem cell (CSC) may be responsible for tumor growth and maintenance of aggressive behavior. Aldehyde dehydrogenase 1 (ALDH1) has been proposed as one of the possible candidates for a CSC marker. The expression of ALDH1 may be correlated with the clinicopathologic factor and clinical outcome of patients with ESCC. The purpose of this study was to investigate the expression of ALDH1 protein in human ESCC tissues, and evaluated the clinical implication of ALDH1 expression for these patients. All 79 patients who underwent esophagectomy for ESCC between January 2005 and June 2006 were enrolled in this study. The expression of ALDH1 in ESCC and adjacent noncancerous tissues was analyzed by immunohistochemistry. ALDH1 was mainly expressed in ESCC cell nucleus. For the 79 ESCC patients, increased nuclear accumulation of ALDH1 was found in 12 (15.2%) specimens. ALDH1 expression was correlated with poor histological differentiation (P= 0.003), lymph node metastasis (P= 0.011), and late pathologic TNM classification (pTNM) staging (P= 0.003). Patients in ALDH1 positive group had a significantly poor 5-year overall survival than those in the negative group (8.3% vs. 52.2%, P= 0.025). We have demonstrated for the first time that the CSC marker, ALDH1, is expressed in human ESCC. The expression of ALDH1 protein in nucleus of the ESCC is significantly associated with lymph node metastasis and poor survival. Our results highly indicate the involvement of ALDH1 in the aggressive behavior of ESCC.

  15. 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...

  16. Synergistic upregulation of NONO and PSPC1 regulates Sertoli cell response to MEHP via modulation of ALDH1A1 signaling.

    PubMed

    Dong, Bing-Wei; Jin, Xiao-Hang; Yan, Chang-You; Yang, Tian; Cai, Guo-Qing; Lu, Jian

    2017-03-01

    Members of the Drosophila behavior/human splicing protein family, including splicing factor proline/glutamine rich (SFPQ), non-POU domain-containing octamer-binding protein (NONO), and paraspeckle protein component 1 (PSPC1), are abundantly expressed in testicular Sertoli cells (SCs), but their roles remain obscure. Here, we show that treatment with mono-(2-ethylhexyl) phthalate (MEHP), a well-known SC toxicant, selectively stimulates the expression levels of NONO and PSPC1. Simultaneous inhibition of NONO and PSPC1 expression in SCs enhances MEHP-induced oxidative stress and potentiates SC death. Mechanistically, NONO and PSPC1 transcriptionally activate aldehyde dehydrogenase 1 (Aldh1a1), by synergistically binding to the distinct CCGGAGTC sequence in the Aldh1a1 promoter. Together, the NONO/PSPC1-ALDH1A1 cascade may serve as an indispensable defense mechanism against MEHP insult in SCs.

  17. Prognostic Value of Cancer Stem Cell Marker ALDH1 Expression in Colorectal Cancer: A Systematic Review and Meta-Analysis

    PubMed Central

    Jiang, Bin; Chang, Weilong; Yuan, Wenzheng; Ma, Zhijun; Liu, Zhengyi; Shu, Xiaogang

    2015-01-01

    Objective Many studies have indicated the prognostic and clinicopathological value of aldehyde dehydrogenase 1 (ALDH1) in colorectal cancer (CRC) patients still remains controversial. Thus we performed this study to clarify the relationship between high ALDH1 expression in CRC and its impact on survival and clinicopathological features. Methods Publications for relevant studies in Pubmed, the Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI) through April 2015 were identified. Only articles describing ALDH1 antigen with immunohistochemistry in CRC were included. The software RevMan 5.1 was used to analyze the outcomes, including 5-year overall survival (OS), disease-free survival (DFS) and clinicopathological features. Results 9 studies with 1203 patients satisfying the criteria were included. The overall rate of high ALDH1 expression was 46.5% by immunohistochemical staining. High ALDH1 expression as an independent prognostic factor was significantly associated with the 5-year OS and DFS (OR = 0.42, 95%CI: 0.26–0.68, P = 0.0004; OR = 0.38, 95%CI: 0.24–0.59, P < 0.0001, respectively). High ALDH1 expression was highly correlated with the tumor (T) stage (T3 + T4 vs. T1 + T2; OR = 2.16, 95%CI: 1.09–4.28, P = 0.03), lymph node (N) stage (N1 + N2 vs. N0; OR = 1.8; 95%CI: 1.17–2.79, P = 0.008), and tumor differentiation (G3 vs. G1 + G2; OR = 1.88; 95%CI: 1.07–3.30, P = 0.03). However, high ALDH1 expression was not significantly correlated with the patient age (>60 years old vs. <60 years old; OR = 1.11, 95%CI: 0.63–1.94, P = 0.72). Conclusions High ALDH1 expression indicates a poor prognosis in CRC patients. Moreover, high ALDH1 expression correlates with the T stage, N stage, and tumor differentiation, but not with age. PMID:26682730

  18. In phyllodes tumour of the breast expression of c-kit but not of ALDH1A1 is associated with adverse clinico-pathological features.

    PubMed

    Chougule, Abhijit; Bal, Amanjit; Das, Ashim; Kohli, Pavneet Singh; Singh, Gurpreet

    2016-12-01

    Attempts at identification of an ideal prognostic/predictive biomarker in phyllodes tumour (PT) have not been fruitful so far. Studies evaluating c-kit expression in PT have shown contradictory results. Recently aldehyde dehydrogenase 1A1 (ALDH1A1) was proposed as a stem cell marker for malignant PT but its expression has not been studied in benign and borderline tumours. We aimed to evaluate expression and prognostic significance of c-kit and ALDH1A1 in different grades of PT. Epithelial and stromal c-kit and ALDH1A1 expression were studied in 104 PT cases (86 primary and 18 recurrent tumours) and compared with different clinico-pathological features and recurrence rates. Stromal c-kit expression at 1 % cutoff correlated with increasing tumour grade, larger tumour size, hypercellularity, nuclear atypia, stromal overgrowth, infiltrative margins and mitotic count. These associations, however, were lost with higher (5 or 10 %) cutoffs. Conversely, decreased c-kit expression in the epithelial component correlated with increasing tumour grade, regardless of the cutoffs used. Stromal ALDH1A1 expression did not have significant associations with tumour grade or other adverse clinico-pathological features, regardless of different cutoffs. None of the cases showed significant epithelial ALDH1A1 expression. Expression of c-kit was associated with poorer overall survival (p = 0.011), while ALDH1A1 expression was associated with shorter recurrence-free survival (p = 0.036). In conclusion, c-kit expression was associated with higher tumour grade and adverse clinico-pathological features. However, these associations are cutoff dependent, partly explaining the variability in previously reported studies. ALDH1A1 expression did not have significant correlations with tumour grade and adverse clinico-pathological variables.

  19. 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

  20. MiR-187 Targets the Androgen-Regulated Gene ALDH1A3 in Prostate Cancer.

    PubMed

    Casanova-Salas, Irene; Masiá, Esther; Armiñán, Ana; Calatrava, Ana; Mancarella, Caterina; Rubio-Briones, José; Scotlandi, Katia; Vicent, Maria Jesús; López-Guerrero, José Antonio

    2015-01-01

    miRNAs are predicted to control the activity of approximately 60% of all protein-coding genes participating in the regulation of several cellular processes and diseases, including cancer. Recently, we have demonstrated that miR-187 is significantly downregulated in prostate cancer (PCa) and here we propose a proteomic approach to identify its potential targets. For this purpose, PC-3 cells were transiently transfected with miR-187 precursor and miRNA mimic negative control. Proteins were analyzed by a two-dimensional difference gel electrophoresis (2D-DIGE) and defined as differentially regulated if the observed fold change was ±1.06. Then, MALDI-TOF MS analysis was performed after protein digestion and low abundance proteins were identified by LC-MS/MS. Peptides were identified by searching against the Expasy SWISS PROT database, and target validation was performed both in vitro by western blot and qRT-PCR and in clinical samples by qRT-PCR, immunohistochemistry and ELISA. DIGE analysis showed 9 differentially expressed spots (p<0.05) and 7 showed a down-regulated expression upon miR-187 re-introduction. Among these targets we identified aldehyde dehydrogenase 1A3 (ALDH1A3). ALDH1A3 expression was significantly downregulated in PC3, LNCaP and DU-145 cells after miR-187 re-introduction. Supporting these data, the expression of ALDH1A3 was found significantly (p<0.0001) up-regulated in PCa samples and inversely correlated (p<0.0001) with miR-187 expression, its expression being directly associated with Gleason score (p = 0.05). The expression of ALDH1A3 was measured in urine samples to evaluate the predictive capability of this biomarker for the presence of PCa and, at a signification level of 10%, PSA and also ALDH1A3 were significantly associated with a positive biopsy of PCa. In conclusion, our data illustrate for the first time the role of ALDH1A3 as a miR-187 target in PCa and provide insights in the utility of using this protein as a new biomarker for PCa.

  1. MiR-187 Targets the Androgen-Regulated Gene ALDH1A3 in Prostate Cancer

    PubMed Central

    Casanova-Salas, Irene; Masiá, Esther; Armiñán, Ana; Calatrava, Ana; Mancarella, Caterina; Rubio-Briones, José; Scotlandi, Katia; Vicent, Maria Jesús; López-Guerrero, José Antonio

    2015-01-01

    miRNAs are predicted to control the activity of approximately 60% of all protein-coding genes participating in the regulation of several cellular processes and diseases, including cancer. Recently, we have demonstrated that miR-187 is significantly downregulated in prostate cancer (PCa) and here we propose a proteomic approach to identify its potential targets. For this purpose, PC-3 cells were transiently transfected with miR-187 precursor and miRNA mimic negative control. Proteins were analyzed by a two-dimensional difference gel electrophoresis (2D-DIGE) and defined as differentially regulated if the observed fold change was ±1.06. Then, MALDI-TOF MS analysis was performed after protein digestion and low abundance proteins were identified by LC–MS/MS. Peptides were identified by searching against the Expasy SWISS PROT database, and target validation was performed both in vitro by western blot and qRT-PCR and in clinical samples by qRT-PCR, immunohistochemistry and ELISA. DIGE analysis showed 9 differentially expressed spots (p<0.05) and 7 showed a down-regulated expression upon miR-187 re-introduction. Among these targets we identified aldehyde dehydrogenase 1A3 (ALDH1A3). ALDH1A3 expression was significantly downregulated in PC3, LNCaP and DU-145 cells after miR-187 re-introduction. Supporting these data, the expression of ALDH1A3 was found significantly (p<0.0001) up-regulated in PCa samples and inversely correlated (p<0.0001) with miR-187 expression, its expression being directly associated with Gleason score (p = 0.05). The expression of ALDH1A3 was measured in urine samples to evaluate the predictive capability of this biomarker for the presence of PCa and, at a signification level of 10%, PSA and also ALDH1A3 were significantly associated with a positive biopsy of PCa. In conclusion, our data illustrate for the first time the role of ALDH1A3 as a miR-187 target in PCa and provide insights in the utility of using this protein as a new biomarker for PCa

  2. ALDH1A1 Deficiency in Gorlin Syndrome Suggests a Central Role for Retinoic Acid and ATM Deficits in Radiation Carcinogenesis.

    PubMed

    Weber, Thomas J; Magnaldo, Thierry; Xiong, Yijia

    2014-09-11

    We hypothesize that aldehyde dehydrogenase 1A1 (ALDH1A1) deficiency will result in impaired ataxia-telangiectasia mutated (ATM) activation in a retinoic acid-sensitive fashion. Data supporting this hypothesis include (1) reduced ATM activation in irradiated primary dermal fibroblasts from ALDH1A1-deficient Gorlin syndrome patients (GDFs), relative to ALDH1A1-positive normal human dermal fibroblasts (NHDFs) and (2) increased ATM activation by X-radiation in GDFs pretreated with retinoic acid, however, the impact of donor variability on ATM activation in fibroblasts was not assessed and is a prudent consideration in future studies. Clonogenic survival of irradiated cells showed differential responses to retinoic acid as a function of treatment time. Long-term (5 Day) retinoic acid treatment functioned as a radiosensitizer and was associated with downregulation of ATM protein levels. Short-term (7 h) retinoic acid treatment showed a trend toward increased survival of irradiated cells and did not downregulate ATM protein levels. Using a newly developed IncubATR technology, which defines changes in bulk chemical bond patterns in live cells, we can discriminate between the NHDF and GDF phenotypes, but treatment of GDFs with retinoic acid does not induce reversion of bulk chemical bond patterns associated with GDFs toward the NHDF phenotype. Collectively, our preliminary investigation of the Gorlin phenotype has identified deficient ALDH1A1 expression associated with deficient ATM activation as a possible susceptibility factor that is consistent with the high incidence of spontaneous and radiation-induced carcinogenesis in these patients. The IncubATR technology exhibits sufficient sensitivity to detect phenotypic differences in live cells that may be relevant to radiation health effects.

  3. ALDH1A1 Deficiency in Gorlin Syndrome Suggests a Central Role for Retinoic Acid and ATM Deficits in Radiation Carcinogenesis

    PubMed Central

    Weber, Thomas J.; Magnaldo, Thierry; Xiong, Yijia

    2014-01-01

    We hypothesize that aldehyde dehydrogenase 1A1 (ALDH1A1) deficiency will result in impaired ataxia-telangiectasia mutated (ATM) activation in a retinoic acid-sensitive fashion. Data supporting this hypothesis include (1) reduced ATM activation in irradiated primary dermal fibroblasts from ALDH1A1-deficient Gorlin syndrome patients (GDFs), relative to ALDH1A1-positive normal human dermal fibroblasts (NHDFs) and (2) increased ATM activation by X-radiation in GDFs pretreated with retinoic acid, however, the impact of donor variability on ATM activation in fibroblasts was not assessed and is a prudent consideration in future studies. Clonogenic survival of irradiated cells showed differential responses to retinoic acid as a function of treatment time. Long-term (5 Day) retinoic acid treatment functioned as a radiosensitizer and was associated with downregulation of ATM protein levels. Short-term (7 h) retinoic acid treatment showed a trend toward increased survival of irradiated cells and did not downregulate ATM protein levels. Using a newly developed IncubATR technology, which defines changes in bulk chemical bond patterns in live cells, we can discriminate between the NHDF and GDF phenotypes, but treatment of GDFs with retinoic acid does not induce reversion of bulk chemical bond patterns associated with GDFs toward the NHDF phenotype. Collectively, our preliminary investigation of the Gorlin phenotype has identified deficient ALDH1A1 expression associated with deficient ATM activation as a possible susceptibility factor that is consistent with the high incidence of spontaneous and radiation-induced carcinogenesis in these patients. The IncubATR technology exhibits sufficient sensitivity to detect phenotypic differences in live cells that may be relevant to radiation health effects. PMID:28250390

  4. Immunohistochemical Expression of CD56 and ALDH1 in Common Salivary Gland Tumors

    PubMed Central

    Seifi, Safoura; Seyedmajidi, Maryam; Salehinejad, Jahanshah; Gholinia, Hemmat; Aliakbarpour, Fatemeh

    2016-01-01

    Introduction: Natural killer (NK) cells, of which CD56 is a specific marker, play an important role in host defense against tumors. Cancer stem cells, of which aldehyde dehydrogenase isoform 1 (ALDH1) is an immunohistochemical marker, are a group of tumorigenic cells which are involved in migration and tumor recurrences. We aimed to evaluate the expression of ALDH1 and CD56 in common salivary gland tumors, as well as their relationship with each other and with a number of clinicopathologic factors. Materials and Methods: Forty-five paraffin blocks of salivary gland tumors (pleomorphic adenoma, mucoepidermoid carcinoma and adenoid cystic carcinoma, 15 samples each) were selected. Malignant tumors were classified into two groups: low-grade (including mucoepidermoid carcinoma grade I) and high-grade (including mucoepidermoid carcinoma grade III and adenoid cystic carcinoma). Immunohistochemical staining for ALDH1 and CD56 markers was performed. Data were analyzed using SPSS (20) and the Chi-square test. Results: CD56 expression was significantly higher in benign and high-grade malignant tumors (P=0.01). ALDH1 overexpressed in all three salivary tumors, but not to statistically significant degree (P=0.54). There was no statistically significant correlation between ALDH1 and CD56 expression with demographic factors (age, gender, or location of tumor; P>0.05). Conclusion: It appears that the number of NK cells and their function change in different types of salivary gland tumors (benign/malignant) and stroma. NK cells are important components of the anti-tumor system; therefore immune dysfunction is associated with tumor progression in tumors of the salivary gland. ALDH1 overexpression suggests its role in tumorogenesis, but ALDH1 is not involved in the morphogenesis of salivary gland tumors. PMID:28008389

  5. 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

  6. 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.

  7. Transcriptional activity of novel ALDH1L1 promoters in the rat brain following AAV vector-mediated gene transfer

    PubMed Central

    Mudannayake, Janitha M; Mouravlev, Alexandre; Fong, Dahna M; Young, Deborah

    2016-01-01

    Aldehyde dehydrogenase family 1, member L1 (ALDH1L1) is a recently characterized pan-astrocytic marker that is more homogenously expressed throughout the brain than the classic astrocytic marker, glial fibrillary acidic protein. We generated putative promoter sequence variants of the rat ALDH1L1 gene for use in adeno-associated viral vector-mediated gene transfer, with an aim to achieve selective regulation of transgene expression in astrocytes in the rat brain. Unexpectedly, ALDH1L1 promoter variants mediated transcriptional activity exclusively in neurons in the substantia nigra pars compacta as assessed by luciferase reporter expression at 3 weeks postvector infusion. This selectivity for neurons in the substantia nigra pars compacta also persisted in the context of adeno-associated viral serotype 5, 8 or 9 vector-mediated gene delivery. An in vivo promoter comparison showed the highest performing ALDH1L1 promoter variant mediated higher transgene expression than the neuronal-specific synapsin 1 and tyrosine hydroxylase promoters. The ALDH1L1 promoter was also transcriptionally active in dentate granule neurons following intrahippocampal adeno-associated viral vector infusion, whereas transgene expression was detected in both striatal neurons and astrocytes following vector infusion into the striatum. Our results demonstrate the potential suitability of the ALDH1L1 promoter as a new tool in the development of gene therapy and disease modelling applications. PMID:27990448

  8. 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.

  9. A High-Content Assay Enables the Automated Screening and Identification of Small Molecules with Specific ALDH1A1-Inhibitory Activity

    PubMed Central

    Yasgar, Adam; Titus, Steven A.; Wang, Yuhong; Danchik, Carina; Yang, Shyh-Ming; Vasiliou, Vasilis; Jadhav, Ajit; Maloney, David J.; Simeonov, Anton

    2017-01-01

    Aldehyde dehydrogenase enzymes (ALDHs) have a broad spectrum of biological activities through the oxidation of both endogenous and exogenous aldehydes. Increased expression of ALDH1A1 has been identified in a wide-range of human cancer stem cells and is associated with cancer relapse and poor prognosis, raising the potential of ALDH1A1 as a therapeutic target. To facilitate quantitative high-throughput screening (qHTS) campaigns for the discovery, characterization and structure-activity-relationship (SAR) studies of small molecule ALDH1A1 inhibitors with cellular activity, we show herein the miniaturization to 1536-well format and automation of a high-content cell-based ALDEFLUOR assay. We demonstrate the utility of this assay by generating dose-response curves on a comprehensive set of prior art inhibitors as well as hundreds of ALDH1A1 inhibitors synthesized in house. Finally, we established a screening paradigm using a pair of cell lines with low and high ALDH1A1 expression, respectively, to uncover novel cell-active ALDH1A1-specific inhibitors from a collection of over 1,000 small molecules. PMID:28129349

  10. ALDH1A Isozymes Are Markers of Human Melanoma Stem Cells and Potential Therapeutic Targets

    PubMed Central

    Luo, Yuchun; Dallaglio, Katiuscia; Chen, Ying; Robinson, William A; Robinson, Steven E; McCarter, Martin D; Wang, Jianbin; Gonzalez, Rene; Thompson, David C; Norris, David A; Roop, Dennis R; Vasiliou, Vasilis; Fujita, Mayumi

    2012-01-01

    Although the concept of cancer stem cells (CSCs) is well accepted for many tumors, the existence of such cells in human melanoma has been the subject of debate. In the present study, we demonstrate the existence of human melanoma cells that fulfill the criteria for CSCs (self-renewal and differentiation) by serially xenotransplanting cells into NOD/SCID mice. These cells possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes. ALDH-positive melanoma cells are more tumorigenic than ALDH-negative cells in both NOD/SCID mice and NSG mice. Biological analyses of the ALDH-positive melanoma cells reveal the ALDH isozymes to be key molecules regulating the function of these cells. Silencing ALDH1A by siRNA or shRNA leads to cell cycle arrest, apoptosis and decreased cell viability in vitro and reduced tumorigenesis in vivo. ALDH-positive melanoma cells are more resistant to chemotherapeutic agents and silencing ALDH1A by siRNA sensitizes melanoma cells to drug-induced cell death. Furthermore, we, for the first time, examined the molecular signatures of ALDH-positive CSCs from patient-derived tumor specimens. The signatures of melanoma CSCs include retinoic acid (RA)-driven target genes with RA response elements and genes associated with stem cell function. These findings implicate that ALDH isozymes are not only biomarkers of CSCs but also attractive therapeutic targets for human melanoma. Further investigation of these isozymes and genes will enhance our understanding of the molecular mechanisms governing CSCs and reveal new molecular targets for therapeutic intervention of cancer. PMID:22887839

  11. Integration of Inhibition Kinetics and Molecular Dynamics Simulations: A Urea-Mediated Folding Study on Acetaldehyde Dehydrogenase 1.

    PubMed

    Xu, Yingying; Lee, Jinhyuk; Lü, Zhi-Rong; Mu, Hang; Zhang, Qian; Park, Yong-Doo

    2016-07-01

    Understanding the mechanism of acetaldehyde dehydrogenase 1 (ALDH1) folding is important because this enzyme is directly involved in several types of cancers and other diseases. We investigated the urea-mediated unfolding of ALDH1 by integrating kinetic inhibition studies with computational molecular dynamics (MD) simulations. Conformational changes in the enzyme structure were also analyzed using intrinsic and 1-anilinonaphthalene-8-sulfonate (ANS)-binding fluorescence measurements. Kinetic studies revealed that the direct binding of urea to ALDH1 induces inactivation of ALDH1 in a manner of mixed-type inhibition. Tertiary structural changes associated with regional hydrophobic exposure of the active site were observed. The urea binding regions on ALDH1 were predicted by docking simulations and were partly shared with active site residues of ALDH1 and with interface residues of the oligomerization domain for tetramer formation. The docking results suggest that urea prevents formation of the ALDH1 normal shape for the tetramer state as well as entrance of the substrate into the active site. Our study provides insight into the structural changes that accompany urea-mediated unfolding of ALDH1 and the catalytic role associated with conformational changes.

  12. Loss of ALDH1A1 expression is an early event in the pathogenesis of ovarian high-grade serous carcinoma.

    PubMed

    Chui, M Herman; Wang, Yihong; Wu, Ren-Chin; Seidman, Jeffrey; Kurman, Robert J; Wang, Tian-Li; Shih, Ie-Ming

    2015-03-01

    Tumor-initiating cells are thought to share features with normal somatic stem cells. In mice, stem cells at the ovarian hilum have been shown to express the stem cell marker, aldehyde dehydrogenase isoform 1A1 (ALDH1A1), and are prone to malignant transformation. The potential relevance of this finding to humans has not been established. In this study, we used immunohistochemistry to assess the distribution of ALDH1A1 staining in the epithelium of human fallopian tubes, with particular reference to the transition of tubal epithelium to mesothelium (ie, tubal-mesothelial junction), ovarian surface epithelium, as well as putative precursors of ovarian high-grade serous carcinoma, namely, serous tubal intraepithelial carcinoma and 'p53 signatures,' and overt serous carcinoma. Expression of ALDH1A1 was detected in both secretory and ciliated tubal epithelial cells, tubal-mesothelial junctions and ovarian surface epithelium, but was absent in serous tubal intraepithelial carcinoma and p53 signatures. Positive staining in high-grade serous carcinoma, when present, was typically limited to rare tumor cells. In silico analyses of the mRNA expression data set from The Cancer Genome Atlas revealed downregulation of ALDH1A1 transcripts in high-grade serous carcinoma relative to normal tubal epithelium, and no association between ALDH1A1 expression levels and overall survival. Our results do not support ALDH1A1 as a specific marker of stem cells in human fallopian tube and demonstrate that its loss of expression is an early event in the development of high-grade serous carcinoma.

  13. 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

  14. Maternal and zygotic aldh1a2 activity is required for pancreas development in zebrafish.

    PubMed

    Alexa, Kristen; Choe, Seong-Kyu; Hirsch, Nicolas; Etheridge, Letitiah; Laver, Elizabeth; Sagerström, Charles G

    2009-12-11

    We have isolated and characterized a novel zebrafish pancreas mutant. Mutant embryos lack expression of isl1 and sst in the endocrine pancreas, but retain isl1 expression in the CNS. Non-endocrine endodermal gene expression is less affected in the mutant, with varying degrees of residual expression observed for pdx1, carbA, hhex, prox1, sid4, transferrin and ifabp. In addition, mutant embryos display a swollen pericardium and lack fin buds. Genetic mapping revealed a mutation resulting in a glycine to arginine change in the catalytic domain of the aldh1a2 gene, which is required for the production of retinoic acid from vitamin A. Comparison of our mutant (aldh1a2(um22)) to neckless (aldh1a2(i26)), a previously identified aldh1a2 mutant, revealed similarities in residual endodermal gene expression. In contrast, treatment with DEAB (diethylaminobenzaldehyde), a competitive reversible inhibitor of Aldh enzymes, produces a more severe phenotype with complete loss of endodermal gene expression, indicating that a source of Aldh activity persists in both mutants. We find that mRNA from the aldh1a2(um22) mutant allele is inactive, indicating that it represents a null allele. Instead, the residual Aldh activity is likely due to maternal aldh1a2, since we find that translation-blocking, but not splice-blocking, aldh1a2 morpholinos produce a phenotype similar to DEAB treatment. We conclude that Aldh1a2 is the primary Aldh acting during pancreas development and that maternal Aldh1a2 activity persists in aldh1a2(um22) and aldh1a2(i26) mutant embryos.

  15. RNAi-directed downregulation of betaine aldehyde dehydrogenase 1 (OsBADH1) results in decreased stress tolerance and increased oxidative markers without affecting glycine betaine biosynthesis in rice (Oryza sativa).

    PubMed

    Tang, Wei; Sun, Jiaqi; Liu, Jia; Liu, Fangfang; Yan, Jun; Gou, Xiaojun; Lu, Bao-Rong; Liu, Yongsheng

    2014-11-01

    As an important osmoprotectant, glycine betaine (GB) plays an essential role in resistance to abiotic stress in a variety of organisms, including rice (Oryza sativa L.). However, GB content is too low to be detectable in rice, although rice genome possesses several orthologs coding for betaine aldehyde dehydrogenase (BADH) involved in plant GB biosynthesis. Rice BADH1 (OsBADH1) has been shown to be targeted to peroxisome and its overexpression resulted in increased GB biosynthesis and tolerance to abiotic stress. In this study, we demonstrated a pivotal role of OsBADH1 in stress tolerance without altering GB biosynthesis capacity, using the RNA interference (RNAi) technique. OsBADH1 was ubiquitously expressed in different organs, including roots, stems, leaves and flowers. Transgenic rice lines downregulating OsBADH1 exhibited remarkably reduced tolerance to NaCl, drought and cold stresses. The decrease of stress tolerance occurring in the OsBADH1-RNAi repression lines was associated with an elevated level of malondialdehyde content and hydrogen peroxidation. No GB accumulation was detected in transgene-positive and transgene-negative lines derived from heterozygous transgenic T0 plants. Moreover, transgenic OsBADH1-RNAi repression lines showed significantly reduced seed set and yield. In conclusion, the downregulation of OsBADH1, even though not causing any change of GB content, was accounted for the reduction of ability to dehydrogenate the accumulating metabolism-derived aldehydes and subsequently resulted in decreased stress tolerance and crop productivity. These results suggest that OsBADH1 possesses an enzyme activity to catalyze other aldehydes in addition to betaine aldehyde (the precursor of GB) and thus alleviate their toxic effects under abiotic stresses.

  16. Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue

    PubMed Central

    Kiefer, Florian W; Vernochet, Cecile; O’Brien, Patrick; Spoerl, Steffen; Brown, Jonathan D; Nallamshetty, Shriram; Zeyda, Maximilian; Stulnig, Thomas M; Cohen, David E; Kahn, C Ronald; Plutzky, Jorge

    2013-01-01

    Promoting brown adipose tissue (BAT) formation and function may reduce obesity. Recent data link retinoids to energy balance, but a specific role for retinoid metabolism in white versus brown fat is unknown. Retinaldehyde dehydrogenases (Aldhs), also known as aldehyde dehydrogenases, are rate-limiting enzymes that convert retinaldehyde (Rald) to retinoic acid. Here we show that Aldh1a1 is expressed predominately in white adipose tissue (WAT), including visceral depots in mice and humans. Deficiency of the Aldh1a1 gene induced a BAT-like transcriptional program in WAT that drove uncoupled respiration and adaptive thermogenesis. WAT-selective Aldh1a1 knockdown conferred this BAT program in obese mice, limiting weight gain and improving glucose homeostasis. Rald induced uncoupling protein-1 (Ucp1) mRNA and protein levels in white adipocytes by selectively activating the retinoic acid receptor (RAR), recruiting the coactivator PGC-1α and inducing Ucp1 promoter activity. These data establish Aldh1a1 and its substrate Rald as previously unrecognized determinants of adipocyte plasticity and adaptive thermogenesis, which may have potential therapeutic implications. PMID:22561685

  17. ALDH1A2 — EDRN Public Portal

    Cancer.gov

    From NCBI Gene: This protein belongs to the aldehyde dehydrogenase family of proteins. The product of this gene is an enzyme that catalyzes the synthesis of retinoic acid (RA) from retinaldehyde. Retinoic acid, the active derivative of vitamin A (retinol), is a hormonal signaling molecule that functions in developing and adult tissues. The studies of a similar mouse gene suggest that this enzyme and the cytochrome CYP26A1, concurrently establish local embryonic retinoic acid levels which facilitate posterior organ development and prevent spina bifida. Four transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, May 2011

  18. ALDH1A2 (RALDH2) genetic variation in human congenital heart disease

    PubMed Central

    2009-01-01

    Background Signaling by the vitamin A-derived morphogen retinoic acid (RA) is required at multiple steps of cardiac development. Since conversion of retinaldehyde to RA by retinaldehyde dehydrogenase type II (ALDH1A2, a.k.a RALDH2) is critical for cardiac development, we screened patients with congenital heart disease (CHDs) for genetic variation at the ALDH1A2 locus. Methods One-hundred and thirty-three CHD patients were screened for genetic variation at the ALDH1A2 locus through bi-directional sequencing. In addition, six SNPs (rs2704188, rs1441815, rs3784259, rs1530293, rs1899430) at the same locus were studied using a TDT-based association approach in 101 CHD trios. Observed mutations were modeled through molecular mechanics (MM) simulations using the AMBER 9 package, Sander and Pmemd programs. Sequence conservation of observed mutations was evaluated through phylogenetic tree construction from ungapped alignments containing ALDH8 s, ALDH1Ls, ALDH1 s and ALDH2 s. Trees were generated by the Neighbor Joining method. Variations potentially affecting splicing mechanisms were cloned and functional assays were designed to test splicing alterations using the pSPL3 splicing assay. Results We describe in Tetralogy of Fallot (TOF) the mutations Ala151Ser and Ile157Thr that change non-polar to polar residues at exon 4. Exon 4 encodes part of the highly-conserved tetramerization domain, a structural motif required for ALDH oligomerization. Molecular mechanics simulation studies of the two mutations indicate that they hinder tetramerization. We determined that the SNP rs16939660, previously associated with spina bifida and observed in patients with TOF, does not affect splicing. Moreover, association studies performed with classical models and with the transmission disequilibrium test (TDT) design using single marker genotype, or haplotype information do not show differences between cases and controls. Conclusion In summary, our screen indicates that ALDH1A2 genetic

  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.

  20. 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

  1. Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue

    PubMed Central

    Landrier, Jean-Francois; Kasiri, Elnaz; Karkeni, Esma; Mihály, Johanna; Béke, Gabriella; Weiss, Kathrin; Lucas, Renata; Aydemir, Gamze; Salles, Jérome; Walrand, Stéphane; de Lera, Angel R.; Rühl, Ralph

    2017-01-01

    Adiponectin is an adipocyte-derived adipokine with potent antidiabetic, anti-inflammatory, and antiatherogenic activity. Long-term, high-fat diet results in gain of body weight, adiposity, further inflammatory-based cardiovascular diseases, and reduced adiponectin secretion. Vitamin A derivatives/retinoids are involved in several of these processes, which mainly take place in white adipose tissue (WAT). In this study, we examined adiponectin expression as a function of dietary high-fat and high–vitamin A conditions in mice. A decrease of adiponectin expression in addition to an up-regulation of aldehyde dehydrogenase A1 (ALDH1A1), retinoid signaling, and retinoic acid response element signaling was selectively observed in WAT of mice fed a normal–vitamin A, high-fat diet. Reduced adiponectin expression in WAT was also observed in mice fed a high–vitamin A diet. Adipocyte cell culture revealed that endogenous and synthetic retinoic acid receptor (RAR)α- and RARγ-selective agonists, as well as a synthetic retinoid X receptor agonist, efficiently reduced adiponectin expression, whereas ALDH1A1 expression only increased with RAR agonists. We conclude that reduced adiponectin expression under high-fat dietary conditions is dependent on 1) increased ALDH1A1 expression in adipocytes, which does not increase all-trans-retinoic acid levels; 2) further RAR ligand–induced, WAT-selective, increased retinoic acid response element–mediated signaling; and 3) RAR ligand–dependent reduction of adiponectin expression.—Landrier, J.-F., Kasiri, E., Karkeni, E., Mihály, J., Béke, G., Weiss, K., Lucas, R., Aydemir, G., Salles, J., Walrand, S., de Lera, A. R., Rühl, R. Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue. PMID:27729412

  2. Inducible targeting of CNS astrocytes in Aldh1l1-CreERT2 BAC transgenic mice

    PubMed Central

    Winchenbach, Jan; Düking, Tim; Berghoff, Stefan A.; Stumpf, Sina K.; Hülsmann, Swen; Nave, Klaus-Armin; Saher, Gesine

    2016-01-01

    Background: Studying astrocytes in higher brain functions has been hampered by the lack of genetic tools for the efficient expression of inducible Cre recombinase throughout the CNS, including the neocortex. Methods: Therefore, we generated BAC transgenic mice, in which CreERT2 is expressed under control of the Aldh1l1 regulatory region. Results: When crossbred to Cre reporter mice, adult Aldh1l1-CreERT2 mice show efficient gene targeting in astrocytes. No such Cre-mediated recombination was detectable in CNS neurons, oligodendrocytes, and microglia. As expected, Aldh1l1-CreERT2 expression was evident in several peripheral organs, including liver and kidney. Conclusions: Taken together, Aldh1l1-CreERT2 mice are a useful tool for studying astrocytes in neurovascular coupling, brain metabolism, synaptic plasticity and other aspects of neuron-glia interactions. PMID:28149504

  3. 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.

  4. Expression of aldehyde dehydrogenase family 1 member A1 and high mobility group box 1 in oropharyngeal squamous cell carcinoma in association with survival time

    PubMed Central

    Qian, Xu; Coordes, Annekatrin; Kaufmann, Andreas M.; Albers, Andreas E.

    2016-01-01

    Despite the development of novel multimodal treatment combinations in advanced oropharyngeal squamous cell carcinoma (OSCC), outcomes remain poor. The identification of specifically validated biomarkers is required to understand the underlying molecular mechanisms, to evaluate treatment efficiency and to develop novel therapeutic targets. The present study, therefore, examined the presence of aldehyde dehydrogenase family 1 member A1 (ALDH1A1) and high mobility group box 1 (HMGB1) expression in primary OSCC and analyzed the impact on survival time. In 59 patients with OSCC, the expression of ALDH1A1, p16 and HMGB1, and their clinicopathological data were analyzed. HMGB1 positivity was significantly increased in patients with T1-2 stage disease compared with T3-4 stage disease (P<0.001), whereas ALDH1A1 positivity was not. ALDH1A1+ tumors showed significantly lower differentiation than ALDH1A1− tumors (P=0.018). Multivariate analysis showed that ALDH1A1 positivity (P=0.041) and nodal status (N2-3) (P=0.036) predicted a poor prognosis. In this patient cohort, ALDH1A1 and nodal status were identified as independent predictors of a shorter overall survival time. The study results, therefore, provide evidence of the prognostic value of ALDH1A1 as a marker for cancer stem cells and nodal status in OSCC patients. PMID:27900016

  5. Expression of aldehyde dehydrogenase family 1 member A1 and high mobility group box 1 in oropharyngeal squamous cell carcinoma in association with survival time.

    PubMed

    Qian, Xu; Coordes, Annekatrin; Kaufmann, Andreas M; Albers, Andreas E

    2016-11-01

    Despite the development of novel multimodal treatment combinations in advanced oropharyngeal squamous cell carcinoma (OSCC), outcomes remain poor. The identification of specifically validated biomarkers is required to understand the underlying molecular mechanisms, to evaluate treatment efficiency and to develop novel therapeutic targets. The present study, therefore, examined the presence of aldehyde dehydrogenase family 1 member A1 (ALDH1A1) and high mobility group box 1 (HMGB1) expression in primary OSCC and analyzed the impact on survival time. In 59 patients with OSCC, the expression of ALDH1A1, p16 and HMGB1, and their clinicopathological data were analyzed. HMGB1 positivity was significantly increased in patients with T1-2 stage disease compared with T3-4 stage disease (P<0.001), whereas ALDH1A1 positivity was not. ALDH1A1(+) tumors showed significantly lower differentiation than ALDH1A1(-) tumors (P=0.018). Multivariate analysis showed that ALDH1A1 positivity (P=0.041) and nodal status (N2-3) (P=0.036) predicted a poor prognosis. In this patient cohort, ALDH1A1 and nodal status were identified as independent predictors of a shorter overall survival time. The study results, therefore, provide evidence of the prognostic value of ALDH1A1 as a marker for cancer stem cells and nodal status in OSCC patients.

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

    PubMed

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

    2016-02-19

    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.

  7. ALDH1A1 mRNA expression in association with prognosis of triple-negative breast cancer.

    PubMed

    Liu, Yan; Baglia, Michelle; Zheng, Ying; Blot, William; Bao, Ping-Ping; Cai, Hui; Nechuta, Sarah; Zheng, Wei; Cai, Qiuyin; Shu, Xiao Ou

    2015-12-01

    ALDH1 is a crucial element in the retinoic acid signaling pathway regulating the self-renewal and differentiation of normal stem cells, and may play an important role in cancer progression. However, research on ALDH1 gene expression and breast cancer prognosis has yielded conflicting results. We evaluated the association between tumor tissue ALDH1A1/ALDH1A3 mRNA expression and triple-negative breast cancer (TNBC) prognosis in the Shanghai Breast Cancer Survival Study (SBCSS, N=463), Nashville Breast Health Study (NBHS, N=86), and Southern Community Cohort Study (SCCS, N=47). Gene expression was measured in RNA isolated from breast cancer tissues. In the SBCSS, higher ALDH1A1 mRNA level was associated with improved disease-free (HR=0.87, 95% CI: 0.80-0.95, per log unit change) and overall survival (HR=0.85, 95% CI: 0.78-0.93 per log unit change) independent of age at diagnosis, TNM stage and treatment. We replicated the findings for overall survival in the NBHS and SCCS (HR = 0.27, 95% CI: 0.10-0.73) and for disease-free survival by a meta-analysis of four publicly-available gene expression datasets (HR = 0.86, 95% CI: 0.76-0.97). No significant association was found for ALDH1A3.Our study suggests high expression of ALDH1A1 mRNA in tumor tissues may be an independent predictor of a favorable TNBC outcome.

  8. ALDH1A1 mRNA expression in association with prognosis of triple-negative breast cancer

    PubMed Central

    Liu, Yan; Baglia, Michelle; Zheng, Ying; Blot, William; Bao, Ping-Ping; Cai, Hui; Nechuta, Sarah; Zheng, Wei; Cai, Qiuyin; Shu, Xiao Ou

    2015-01-01

    ALDH1 is a crucial element in the retinoic acid signaling pathway regulating the self-renewal and differentiation of normal stem cells, and may play an important role in cancer progression. However, research on ALDH1 gene expressionand breast cancer prognosis has yielded conflicting results. We evaluated the association between tumor tissue ALDH1A1/ALDH1A3 mRNA expression and triple-negative breast cancer (TNBC) prognosis in the Shanghai Breast Cancer Survival Study (SBCSS, N=463), Nashville Breast Health Study (NBHS, N=86), and Southern Community Cohort Study (SCCS, N=47). Gene expression was measured in RNA isolated from breast cancer tissues. In the SBCSS, higher ALDH1A1 mRNA level was associated with improved disease-free (HR=0.87, 95% CI: 0.80-0.95, per log unit change) and overall survival (HR=0.85, 95% CI: 0.78-0.93 per log unit change) independent of age at diagnosis, TNM stage and treatment. We replicated the findings for overall survival in the NBHS and SCCS (HR = 0.27, 95% CI: 0.10-0.73) and for disease-free survival by a meta-analysis of four publicly-available gene expression datasets (HR = 0.86, 95% CI: 0.76-0.97). No significant association was found for ALDH1A3. Our study suggests high expression of ALDH1A1 mRNA in tumor tissues may be an independent predictor of a favorable TNBC outcome. PMID:26462023

  9. Consequences of Lineage-Specific Gene Loss on Functional Evolution of Surviving Paralogs: ALDH1A and Retinoic Acid Signaling in Vertebrate Genomes

    PubMed Central

    Cañestro, Cristian; Catchen, Julian M.; Rodríguez-Marí, Adriana; Yokoi, Hayato; Postlethwait, John H.

    2009-01-01

    Genome duplications increase genetic diversity and may facilitate the evolution of gene subfunctions. Little attention, however, has focused on the evolutionary impact of lineage-specific gene loss. Here, we show that identifying lineage-specific gene loss after genome duplication is important for understanding the evolution of gene subfunctions in surviving paralogs and for improving functional connectivity among human and model organism genomes. We examine the general principles of gene loss following duplication, coupled with expression analysis of the retinaldehyde dehydrogenase Aldh1a gene family during retinoic acid signaling in eye development as a case study. Humans have three ALDH1A genes, but teleosts have just one or two. We used comparative genomics and conserved syntenies to identify loss of ohnologs (paralogs derived from genome duplication) and to clarify uncertain phylogenies. Analysis showed that Aldh1a1 and Aldh1a2 form a clade that is sister to Aldh1a3-related genes. Genome comparisons showed secondarily loss of aldh1a1 in teleosts, revealing that Aldh1a1 is not a tetrapod innovation and that aldh1a3 was recently lost in medaka, making it the first known vertebrate with a single aldh1a gene. Interestingly, results revealed asymmetric distribution of surviving ohnologs between co-orthologous teleost chromosome segments, suggesting that local genome architecture can influence ohnolog survival. We propose a model that reconstructs the chromosomal history of the Aldh1a family in the ancestral vertebrate genome, coupled with the evolution of gene functions in surviving Aldh1a ohnologs after R1, R2, and R3 genome duplications. Results provide evidence for early subfunctionalization and late subfunction-partitioning and suggest a mechanistic model based on altered regulation leading to heterochronic gene expression to explain the acquisition or modification of subfunctions by surviving ohnologs that preserve unaltered ancestral developmental programs in

  10. Aldehyde dehydrogenase inhibition combined with phenformin treatment reversed NSCLC through ATP depletion

    PubMed Central

    Lee, Jae-Seon; Nam, Boas; Seong, Tae Wha; Son, Jaekyoung; Jang, Hyonchol; Hong, Kyeong Man; Lee, Cheolju; Kim, Soo-Youl

    2016-01-01

    Among ALDH isoforms, ALDH1L1 in the folate pathway showed highly increased expression in non-small-cell lung cancer cells (NSCLC). Based on the basic mechanism of ALDH converting aldehyde to carboxylic acid with by-product NADH, we suggested that ALDH1L1 may contribute to ATP production using NADH through oxidative phosphorylation. ALDH1L1 knockdown reduced ATP production by up to 60% concomitantly with decrease of NADH in NSCLC. ALDH inhibitor, gossypol, also reduced ATP production in a dose dependent manner together with decrease of NADH level in NSCLC. A combination treatment of gossypol with phenformin, mitochondrial complex I inhibitor, synergized ATP depletion, which efficiently induced cell death. Pre-clinical xenograft model using human NSCLC demonstrated a remarkable therapeutic response to the combined treatment of gossypol and phenformin. PMID:27384481

  11. Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring

    PubMed Central

    Ahadome, Sarah D.; Abraham, David J.; Rayapureddi, Suryanarayana; Saw, Valerie P.; Saban, Daniel R.; Calder, Virginia L.; Norman, Jill T.; Ponticos, Markella; Daniels, Julie T.; Dart, John K.

    2016-01-01

    Mucous membrane pemphigoid (MMP) is a systemic mucosal scarring disease, commonly causing blindness, for which there is no antifibrotic therapy. Aldehyde dehydrogenase family 1 (ALDH1) is upregulated in both ocular MMP (OMMP) conjunctiva and cultured fibroblasts. Application of the ALDH metabolite, retinoic acid (RA), to normal human conjunctival fibroblasts in vitro induced a diseased phenotype. Conversely, application of ALDH inhibitors, including disulfiram, to OMMP fibroblasts in vitro restored their functionality to that of normal controls. ALDH1 is also upregulated in the mucosa of the mouse model of scarring allergic eye disease (AED), used here as a surrogate for OMMP, in which topical application of disulfiram decreased fibrosis in vivo. These data suggest that progressive scarring in OMMP results from ALDH/RA fibroblast autoregulation, that the ALDH1 subfamily has a central role in immune-mediated ocular mucosal scarring, and that ALDH inhibition with disulfiram is a potential and readily translatable antifibrotic therapy. PMID:27699226

  12. DOXIL when combined with Withaferin A (WFA) targets ALDH1 positive cancer stem cells in ovarian cancer.

    PubMed

    Kakar, Sham S; Worth, Christopher A; Wang, Zhenglong; Carter, Kelsey; Ratajczak, Mariusz; Gunjal, Pranesh

    Ovarian cancer is a highly aggressive and deadly disease. Currently, the treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, mainly cisplatin or carboplatin combined with paclitaxel. Although this regimen is initially effective in a high percentage of cases, unfortunately, after few months of initial treatment, tumor relapse occurs due to platinum-resistance. DOXIL (liposomal preparation of doxorubicin) is a choice of drug for recurrent ovarian cancer. However, its response rate is very low and is accompanied by myocardial toxicity. Resistance to chemotherapy and recurrence of cancer is primarily attributed to the presence of cancer stem cells (CSCs), a small population of cells present in cancer. Effect of DOXIL and withaferin A (WFA), both alone and in combination, was investigated on cell proliferation of ovarian cancer cell line A2780 and tumor growth in SCID mice bearing i.p. ovarian tumors. ALDH1 cells were isolated from A2780 using cell sorter, and effect of DOXIL and WFA both alone and in combination on tumorigenic function of ALDH1 was studied using spheroids formation assays in vitro. Western blots were performed to examine the expression of ALDH1 and Notch 1 genes. In our studies, we showed, for the first time, that DOXIL when combined with withaferin A (WFA) elicits synergistic effect on inhibition of cell proliferation of ovarian cancer cells and inhibits the expression of ALDH1 protein, a marker for ALDH1 positive cancer stem cells (CSCs), and Notch1, a signaling pathway gene required for self-renewal of CSCs. Inhibition of expression of both ALDH1 and Notch1 genes by WFA was found to be dose dependent, whereas DOXIL (200 nM) was found to be ineffective. SCID mice, bearing i.p. ovarian tumors, were treated with a small dose of DOXIL (2 mg/kg) in combination with a sub-optimal dose of WFA (2 mg/kg) which resulted in a highly significant (60% to 70%) reduction in tumor growth, and complete inhibition of metastasis

  13. Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1

    PubMed Central

    Coyle, Krysta M.; Murphy, J. Patrick; Vidovic, Dejan; Vaghar-Kashani, Ahmad; Dean, Cheryl A.; Sultan, Mohammad; Clements, Derek; Wallace, Melissa; Thomas, Margaret L.; Hundert, Amos; Giacomantonio, Carman A.; Helyer, Lucy; Gujar, Shashi A.; Lee, Patrick W.K.; Weaver, Ian C.G.; Marcato, Paola

    2016-01-01

    Breast cancer subtyping, based on the expression of hormone receptors and other genes, can determine patient prognosis and potential options for targeted therapy. Among breast cancer subtypes, tumors of basal-like and claudin-low subtypes are typically associated with worse patient outcomes, are primarily classified as triple-negative breast cancers (TNBC), and cannot be treated with existing hormone-receptor-targeted therapies. Understanding the molecular basis of these subtypes will lead to the development of more effective treatment options for TNBC. In this study, we focus on retinoic acid receptor responder 1 (RARRES1) as a paradigm to determine if breast cancer subtype dictates protein function and gene expression regulation. Patient tumor dataset analysis and gene expression studies of a 26 cell-line panel, representing the five breast cancer subtypes, demonstrate that RARRES1 expression is greatest in basal-like TNBCs. Cell proliferation and tumor growth assays reveal that RARRES1 is a tumor suppressor in TNBC. Furthermore, gene expression studies, Illumina HumanMethylation450 arrays, and chromatin immunoprecipitation demonstrate that expression of RARRES1 is retained in basal-like breast cancers due to hypomethylation of the promoter. Additionally, expression of the cancer stem cell marker, aldehyde dehydrogenase 1A3, which provides the required ligand (retinoic acid) for RARRES1 transcription, is also specific to the basal-like subtype. We functionally demonstrate that the combination of promoter methylation and retinoic acid signaling dictates expression of tumor suppressor RARRES1 in a subtype-specific manner. These findings provide a precedent for a therapeutically-inducible tumor suppressor and suggest novel avenues of therapeutic intervention for patients with basal-like breast cancer. PMID:27286452

  14. 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

  15. 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.

  16. 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

  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. Induced Expression of Cancer Stem Cell Markers ALDH1A3 and Sox-2 in Hierarchical Reconstitution of Apoptosis-resistant Human Breast Cancer Cells

    PubMed Central

    Kashii-Magaribuchi, Karin; Takeuchi, Rie; Haisa, Yuko; Sakamoto, Akemi; Itoh, Aimi; Izawa, Yuki; Isa, Miyuki; Fukuzawa, Mayu; Murakami, Motonobu; Takahashi, Rei

    2016-01-01

    We established an experimental system that can induce p53-dependent apoptosis by doxycycline treatment to analyze characteristics of the apoptosis-resistant cancer cell subpopulation in the human breast cancer cell line HCC1937. Expression patterns of the stem cell markers, ALDH1A3 and Sox-2, the luminal differentiation marker, GATA3 and the proliferation index marker, Ki-67 were analyzed using immunostaining and fluorescence-activated cell sorting (FACS). After doxycycline treatment, the number of viable cells was gradually decreased over seven days in a time-dependent manner due to p53-induced apoptosis; however, the number of smaller-sized ALDH1A3+ cells assessed by immunostaining increased sharply after 1 day of doxycycline treatment, suggesting their apoptosis-resistant nature. The expression of ALDH1A3 was also detected in 78% of small-sized Ki-67+ proliferating progenitor cells, followed by the transient expression of GATA3, which presumably indicated the ability to differentiate into luminal progenitor cells. Although 42.2–58.5% of residual cells were positive for both ALDH1A3 and GATA3, their expression patterns exhibited an inverse correlation. The expression pattern of another stem cell marker, Sox-2, was similar, but more drastically altered after p53 induction compared with ALDH1A3. These findings may aid in understanding the hierarchical responses of cancer stem cells to therapeutic stresses. PMID:27917009

  19. Retinoic acid homeostasis through aldh1a2 and cyp26a1 mediates meiotic entry in Nile tilapia (Oreochromis niloticus).

    PubMed

    Feng, Ruijuan; Fang, Lingling; Cheng, Yunying; He, Xue; Jiang, Wentao; Dong, Ranran; Shi, Hongjuan; Jiang, Dongneng; Sun, Lina; Wang, Deshou

    2015-05-15

    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.

  20. 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.

  1. Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling.

    PubMed

    Sullivan, James P; Spinola, Monica; Dodge, Michael; Raso, Maria G; Behrens, Carmen; Gao, Boning; Schuster, Katja; Shao, Chunli; Larsen, Jill E; Sullivan, Laura A; Honorio, Sofia; Xie, Yang; Scaglioni, Pier P; DiMaio, J Michael; Gazdar, Adi F; Shay, Jerry W; Wistuba, Ignacio I; Minna, John D

    2010-12-01

    Aldehyde dehydrogenase (ALDH) is a candidate marker for lung cancer cells with stem cell-like properties. Immunohistochemical staining of a large panel of primary non-small cell lung cancer (NSCLC) samples for ALDH1A1, ALDH3A1, and CD133 revealed a significant correlation between ALDH1A1 (but not ALDH3A1 or CD133) expression and poor prognosis in patients including those with stage I and N0 disease. Flow cytometric analysis of a panel of lung cancer cell lines and patient tumors revealed that most NSCLCs contain a subpopulation of cells with elevated ALDH activity, and that this activity is associated with ALDH1A1 expression. Isolated ALDH(+) lung cancer cells were observed to be highly tumorigenic and clonogenic as well as capable of self-renewal compared with their ALDH(-) counterparts. Expression analysis of sorted cells revealed elevated Notch pathway transcript expression in ALDH(+) cells. Suppression of the Notch pathway by treatment with either a γ-secretase inhibitor or stable expression of shRNA against NOTCH3 resulted in a significant decrease in ALDH(+) lung cancer cells, commensurate with a reduction in tumor cell proliferation and clonogenicity. Taken together, these findings indicate that ALDH selects for a subpopulation of self-renewing NSCLC stem-like cells with increased tumorigenic potential, that NSCLCs harboring tumor cells with ALDH1A1 expression have inferior prognosis, and that ALDH1A1 and CD133 identify different tumor subpopulations. Therapeutic targeting of the Notch pathway reduces this ALDH(+) component, implicating Notch signaling in lung cancer stem cell maintenance.

  2. Characterization of Cardiac-Resident Progenitor Cells Expressing High Aldehyde Dehydrogenase Activity

    PubMed Central

    Roehrich, Marc-Estienne; Spicher, Albert; Milano, Giuseppina; Vassalli, Giuseppe

    2013-01-01

    High aldehyde dehydrogenase (ALDH) activity has been associated with stem and progenitor cells in various tissues. Human cord blood and bone marrow ALDH-bright (ALDHbr) cells have displayed angiogenic activity in preclinical studies and have been shown to be safe in clinical trials in patients with ischemic cardiovascular disease. The presence of ALDHbr cells in the heart has not been evaluated so far. We have characterized ALDHbr cells isolated from mouse hearts. One percent of nonmyocytic cells from neonatal and adult hearts were ALDHbr. ALDHvery-br cells were more frequent in neonatal hearts than adult. ALDHbr cells were more frequent in atria than ventricles. Expression of ALDH1A1 isozyme transcripts was highest in ALDHvery-br cells, intermediate in ALDHbr cells, and lowest in ALDHdim cells. ALDH1A2 expression was highest in ALDHvery-br cells, intermediate in ALDHdim cells, and lowest in ALDHbr cells. ALDH1A3 and ALDH2 expression was detectable in ALDHvery-br and ALDHbr cells, unlike ALDHdim cells, albeit at lower levels compared with ALDH1A1 and ALDH1A2. Freshly isolated ALDHbr cells were enriched for cells expressing stem cell antigen-1, CD34, CD90, CD44, and CD106. ALDHbr cells, unlike ALDHdim cells, could be grown in culture for more than 40 passages. They expressed sarcomeric α-actinin and could be differentiated along multiple mesenchymal lineages. However, the proportion of ALDHbr cells declined with cell passage. In conclusion, the cardiac-derived ALDHbr population is enriched for progenitor cells that exhibit mesenchymal progenitor-like characteristics and can be expanded in culture. The regenerative potential of cardiac-derived ALDHbr cells remains to be evaluated. PMID:23484127

  3. Zebrafish foxc1a plays a crucial role in early somitogenesis by restricting the expression of aldh1a2 directly.

    PubMed

    Li, Jingyun; Yue, Yunyun; Dong, Xiaohua; Jia, Wenshuang; Li, Kui; Liang, Dong; Dong, Zhangji; Wang, Xiaoxiao; Nan, Xiaoxi; Zhang, Qinxin; Zhao, Qingshun

    2015-04-17

    Foxc1a is a member of the forkhead transcription factors. It plays an essential role in zebrafish somitogenesis. However, little is known about the molecular mechanisms underlying its controlling somitogenesis. To uncover how foxc1a regulates zebrafish somitogenesis, we generated foxc1a knock-out zebrafish using TALEN (transcription activator-like effector nuclease) technology. The foxc1a null embryos exhibited defective somites at early development. Analyses on the expressions of the key genes that control processes of somitogenesis revealed that foxc1a controlled early somitogenesis by regulating the expression of myod1. In the somites of foxc1a knock-out embryos, expressions of fgf8a and deltaC were abolished, whereas the expression of aldh1a2 (responsible for providing retinoic acid signaling) was significantly increased. Once the increased retinoic acid level in the foxc1a null embryos was reduced by knocking down aldh1a2, the reduced expression of myod1 was partially rescued by resuming expressions of fgf8a and deltaC in the somites of the mutant embryos. Moreover, a chromatin immunoprecipitation assay on zebrafish embryos revealed that Foxc1a bound aldh1a2 promoter directly. On the other hand, neither knocking down fgf8a nor inhibiting Notch signaling affected the expression of aldh1a2, although knocking down fgf8a reduced expression of deltaC in the somites of zebrafish embryos at early somitogenesis and vice versa. Taken together, our results demonstrate that foxc1a plays an essential role in early somitogenesis by controlling Fgf and Notch signaling through restricting the expression of aldh1a2 in paraxial mesoderm directly.

  4. Beta 1-integrin ligation and TLR ligation enhance GM-CSF–induced ALDH1A2 expression in dendritic cells, but differentially regulate their anti-inflammatory properties

    PubMed Central

    Yokota-Nakatsuma, Aya; Ohoka, Yoshiharu; Takeuchi, Hajime; Song, Si-Young; Iwata, Makoto

    2016-01-01

    Retinoic acid (RA)–producing CD103+ mature dendritic cells (DCs) in mesenteric lymph nodes (MLNs) play crucial roles in gut immunity. GM-CSF and RA contribute to the expression of the RA-producing enzyme ALDH1A2. However, additional signals appeared to be required for inducing ALDH1A2high mature DCs from immature DCs. We found here that TLR ligands (Ls) and immobilized E-cadherin could provide such signals in FLT3-L–generated bone marrow (BM)–derived DCs after treatment with GM-CSF and the RA receptor agonist Am80. The TLR-L-treated DCs produced proinflammatory cytokines unlike normal ALDH1A2high MLN-DCs, whereas the E-cadherin-treated DCs did not. Immobilized VCAM-1 and semaphorin 7 A exerted effects similar to those of E-cadherin. Soluble anti-integrin β1 antibodies or inhibitors of integrin signaling molecules suppressed the effects of these immobilized proteins, whereas immobilized anti-integrin β1 antibodies enhanced the GM-CSF/Am80-induced ALDH1A2 expression without inducing proinflammatory cytokines. Sequential stimulation of splenic pre-DCs with GM-CSF/Am80 and immobilized E-cadherin or anti-integrin β1 antibody also induced differentiation to mature DCs with high ALDH activity. The E-cadherin-treated BM-DCs induced gut-tropic Foxp3+ T cells and alleviated DSS–induced colitis, whereas the TLR-L-treated DCs aggravated DSS–induced colitis. The results suggest that integrin β1-mediated signals contribute to the differentiation and maturation of RA-producing anti-inflammatory DCs. PMID:27897208

  5. Sam68 promotes self-renewal and glycolytic metabolism in mouse neural progenitor cells by modulating Aldh1a3 pre-mRNA 3'-end processing

    PubMed Central

    La Rosa, Piergiorgio; Bielli, Pamela; Compagnucci, Claudia; Cesari, Eleonora; Volpe, Elisabetta; Farioli Vecchioli, Stefano; Sette, Claudio

    2016-01-01

    The balance between self-renewal and differentiation of neural progenitor cells (NPCs) dictates neurogenesis and proper brain development. We found that the RNA- binding protein Sam68 (Khdrbs1) is strongly expressed in neurogenic areas of the neocortex and supports the self-renewing potential of mouse NPCs. Knockout of Khdrbs1 constricted the pool of proliferating NPCs by accelerating their cell cycle exit and differentiation into post-mitotic neurons. Sam68 function was linked to regulation of Aldh1a3 pre-mRNA 3'-end processing. Binding of Sam68 to an intronic polyadenylation site prevents its recognition and premature transcript termination, favoring expression of a functional enzyme. The lower ALDH1A3 expression and activity in Khdrbs1-/- NPCs results in reduced glycolysis and clonogenicity, thus depleting the embryonic NPC pool and limiting cortical expansion. Our study identifies Sam68 as a key regulator of NPC self-renewal and establishes a novel link between modulation of ALDH1A3 expression and maintenance of high glycolytic metabolism in the developing cortex. DOI: http://dx.doi.org/10.7554/eLife.20750.001 PMID:27845622

  6. Benomyl, aldehyde dehydrogenase, DOPAL, and the catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease.

    PubMed

    Casida, John E; Ford, Breanna; Jinsmaa, Yunden; Sullivan, Patti; Cooney, Adele; Goldstein, David S

    2014-08-18

    The dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is detoxified mainly by aldehyde dehydrogenase (ALDH). We find that the fungicide benomyl potently and rapidly inhibits ALDH and builds up DOPAL in vivo in mouse striatum and in vitro in PC12 cells and human cultured fibroblasts and glial cells. The in vivo results resemble those noted previously with knockouts of the genes encoding ALDH1A1 and 2, a mouse model of aging-related Parkinson's disease (PD). Exposure to pesticides that inhibit ALDH may therefore increase PD risk via DOPAL buildup. This study lends support to the "catecholaldehyde hypothesis" that the autotoxic dopamine metabolite DOPAL plays a pathogenic role in PD.

  7. 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.

  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.

  9. 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

  10. Same difference: A pilot study of cyclin D1, bcl-2, AMACR, and ALDH-1 identifies significant differences in expression between primary colon adenocarcinoma and its metastases.

    PubMed

    Oakley, Gerard J; Denning, Krista L; Graffeo, Vincent; Griswold, Doreen C; Davis, Adam R; Brown, Linda G

    2016-11-01

    Tumor heterogeneity implies the possibility of significantly different expression of key pathways between primary and metastatic clones. Colon adenocarcinoma is one of the few tumors where current practice includes resection of primary and isolated organ metastases simultaneously without neoadjuvant therapy. We performed a pilot study on 28 cases of colon adenocarcinoma resected simultaneously with metastases in patients with no history of neoadjuvant therapy. We assayed matched primary and metastatic tumors from each patient with common diagnostic antibodies to Bcl-2, Cyclin D1, AMACR, and ALDH-1 by immunohistochemistry with semi-quantitative interpretation on archived formalin fixed, paraffin embedded samples. We were powered for large, consistent differences between primary and metastatic expression, and found 21 of 28 had a significant difference in expression of at least one of the four proteins, accounting for multiplicity of testing. Cyclin D1 had significantly more cases with differential metastatic:primary expression than would be expected by chance alone (p-value 0.0043), favoring higher expression in the metastatic sample. Bcl-2 and ALDH-1 had trends in this direction (p-value 0.078 each). Proportionately more cases with significant differences were identified when a liver metastasis was tested. We conclude differences in expression between metastatic and primary colon adenocarcinoma within the same patient exist, and may have therapeutic and biomarker testing consequences.

  11. ALDH1-positive cancer stem cells predict engraftment of primary breast tumors and are governed by a common stem cell program.

    PubMed

    Charafe-Jauffret, Emmanuelle; Ginestier, Christophe; Bertucci, François; Cabaud, Olivier; Wicinski, Julien; Finetti, Pascal; Josselin, Emmanuelle; Adelaide, José; Nguyen, Tien-Tuan; Monville, Florence; Jacquemier, Jocelyne; Thomassin-Piana, Jeanne; Pinna, Guillaume; Jalaguier, Aurélie; Lambaudie, Eric; Houvenaeghel, Gilles; Xerri, Luc; Harel-Bellan, Annick; Chaffanet, Max; Viens, Patrice; Birnbaum, Daniel

    2013-12-15

    Cancer stem-like cells (CSC) have been widely studied, but their clinical relevance has yet to be established in breast cancer. Here, we report the establishment of primary breast tumor-derived xenografts (PDX) that encompass the main diversity of human breast cancer and retain the major clinicopathologic features of primary tumors. Successful engraftment was correlated with the presence of ALDH1-positive CSCs, which predicted prognosis in patients. The xenografts we developed showed a hierarchical cell organization of breast cancer with the ALDH1-positive CSCs constituting the tumorigenic cell population. Analysis of gene expression from functionally validated CSCs yielded a breast CSC signature and identified a core transcriptional program of 19 genes shared with murine embryonic, hematopoietic, and neural stem cells. This generalized stem cell program allowed the identification of potential CSC regulators, which were related mainly to metabolic processes. Using an siRNA genetic screen designed to target the 19 genes, we validated the functional role of this stem cell program in the regulation of breast CSC biology. Our work offers a proof of the functional importance of CSCs in breast cancer, and it establishes the reliability of PDXs for use in developing personalized CSC therapies for patients with breast cancer.

  12. Glutamate dehydrogenase 1 and SIRT4 regulate glial development.

    PubMed

    Komlos, Daniel; Mann, Kara D; Zhuo, Yue; Ricupero, Christopher L; Hart, Ronald P; Liu, Alice Y-C; Firestein, Bonnie L

    2013-03-01

    Congenital hyperinsulinism/hyperammonemia (HI/HA) syndrome is caused by an activation mutation of glutamate dehydrogenase 1 (GDH1), a mitochondrial enzyme responsible for the reversible interconversion between glutamate and α-ketoglutarate. The syndrome presents clinically with hyperammonemia, significant episodic hypoglycemia, seizures, and frequent incidences of developmental and learning defects. Clinical research has implicated that although some of the developmental and neurological defects may be attributed to hypoglycemia, some characteristics cannot be ascribed to low glucose and as hyperammonemia is generally mild and asymptomatic, there exists the possibility that altered GDH1 activity within the brain leads to some clinical changes. GDH1 is allosterically regulated by many factors, and has been shown to be inhibited by the ADP-ribosyltransferase sirtuin 4 (SIRT4), a mitochondrially localized sirtuin. Here we show that SIRT4 is localized to mitochondria within the brain. SIRT4 is highly expressed in glial cells, specifically astrocytes, in the postnatal brain and in radial glia during embryogenesis. Furthermore, SIRT4 protein decreases in expression during development. We show that factors known to allosterically regulate GDH1 alter gliogenesis in CTX8 cells, a novel radial glial cell line. We find that SIRT4 and GDH1 overexpression play antagonistic roles in regulating gliogenesis and that a mutant variant of GDH1 found in HI/HA patients accelerates the development of glia from cultured radial glia cells.

  13. Daidzin inhibits mitochondrial aldehyde dehydrogenase and suppresses ethanol intake of Syrian golden hamsters.

    PubMed

    Keung, W M; Klyosov, A A; Vallee, B L

    1997-03-04

    Daidzin is the major active principle in extracts of radix puerariae, a traditional Chinese medication that suppresses the ethanol intake of Syrian golden hamsters. It is the first isoflavone recognized to have this effect. Daidzin is also a potent and selective inhibitor of human mitochondrial aldehyde dehydrogenase (ALDH-2). To establish a link between these two activities, we have tested a series of synthetic structural analogs of daidzin. The results demonstrate a direct correlation between ALDH-2 inhibition and ethanol intake suppression and raise the possibility that daidzin may, in fact, suppress ethanol intake of golden hamsters by inhibiting ALDH-2. Hamster liver contains not only mitochondrial ALDH-2 but also high concentrations of a cytosolic form, ALDH-1, which is a very efficient catalyst of acetaldehyde oxidation. Further, the cytosolic isozyme is completely resistant to daidzin inhibition. This unusual property of the hamster ALDH-1 isozyme accounts for the fact we previously observed that daidzin can suppress ethanol intake of this species without blocking acetaldehyde metabolism. Thus, the mechanism by which daidzin suppresses ethanol intake in golden hamsters clearly differs from that proposed for the classic ALDH inhibitor disulfiram. We postulate that a physiological pathway catalyzed by ALDH-2, so far undefined, controls ethanol intake of golden hamsters and mediates the antidipsotropic effect of daidzin.

  14. Microbial Engineering for Aldehyde Synthesis

    PubMed Central

    Kunjapur, Aditya M.

    2015-01-01

    Aldehydes are a class of chemicals with many industrial uses. Several aldehydes are responsible for flavors and fragrances present in plants, but aldehydes are not known to accumulate in most natural microorganisms. In many cases, microbial production of aldehydes presents an attractive alternative to extraction from plants or chemical synthesis. During the past 2 decades, a variety of aldehyde biosynthetic enzymes have undergone detailed characterization. Although metabolic pathways that result in alcohol synthesis via aldehyde intermediates were long known, only recent investigations in model microbes such as Escherichia coli have succeeded in minimizing the rapid endogenous conversion of aldehydes into their corresponding alcohols. Such efforts have provided a foundation for microbial aldehyde synthesis and broader utilization of aldehydes as intermediates for other synthetically challenging biochemical classes. However, aldehyde toxicity imposes a practical limit on achievable aldehyde titers and remains an issue of academic and commercial interest. In this minireview, we summarize published efforts of microbial engineering for aldehyde synthesis, with an emphasis on de novo synthesis, engineered aldehyde accumulation in E. coli, and the challenge of aldehyde toxicity. PMID:25576610

  15. Aldehyde dehydrogenase 3A1 associates with prostate tumorigenesis

    PubMed Central

    Yan, J; De Melo, J; Cutz, J-C; Aziz, T; Tang, D

    2014-01-01

    Background: Accumulating evidence demonstrates high levels of aldehyde dehydrogense (ALDH) activity in human cancer types, in part, because of its association with cancer stem cells. Whereas ALDH1A1 and ALDH7A1 isoforms were reported to associate with prostate tumorigenesis, whether other ALDH isoforms are associated with prostate cancer (PC) remains unclear. Methods: ALDH3A1 expression was analysed in various PC cell lines. Xenograft tumours and 54 primary and metastatic PC tumours were stained using immunohistochemistry for ALDH3A1 expression. Results: In comparison with the non-stem counterparts, a robust upregulation of ALDH3A1 was observed in DU145-derived PC stem cells (PCSCs). As DU145 PCSCs produced xenograft tumours with more advanced features compared with those derived from DU145 cells, higher levels of ALDH3A1 were detected in the former; a dramatic elevation of ALDH3A1 occurred in DU145 cell-derived lung metastasis compared with local xenograft tumours. Furthermore, while ALDH3A1 was not observed in prostate glands, ALDH3A1 was clearly present in PIN, and further increased in carcinomas. In comparison with the paired local carcinomas, ALDH3A1 was upregulated in lymph node metastatic tumours; the presence of ALDH3A1 in bone metastatic PC was also demonstrated. Conclusions: We report here the association of ALDH3A1 with PC progression. PMID:24762960

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

    PubMed Central

    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

  17. Inhibition of human alcohol and aldehyde dehydrogenases by cimetidine and assessment of its effects on ethanol metabolism.

    PubMed

    Lai, Ching-Long; Li, Yeung-Pin; Liu, Chiu-Ming; Hsieh, Hsiu-Shan; Yin, Shih-Jiun

    2013-02-25

    Previous studies have reported that cimetidine, an H2-receptor antagonist used to treat gastric and duodenal ulcers, can inhibit alcohol dehydrogenases (ADHs) and ethanol metabolism. Human alcohol dehydrogenases and aldehyde dehydrogenases (ALDHs), the 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 by cimetidine of alcohol oxidation by recombinant human ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2, ADH2, and ADH4, and aldehyde oxidation by ALDH1A1 and ALDH2 at pH 7.5 and a cytosolic NAD(+) concentration. Cimetidine acted as competitive or noncompetitive inhibitors for the ADH and ALDH isozymes/allozymes with near mM inhibition constants. The metabolic interactions between cimetidine and ethanol/acetaldehyde were assessed by computer simulation using the inhibition equations and the determined kinetic constants. At therapeutic drug levels (0.015 mM) and physiologically relevant concentrations of ethanol (10 mM) and acetaldehyde (10 μM) in target tissues, cimetidine could weakly inhibit (<5%) the activities of ADH1B2 and ADH1B3 in liver, ADH2 in liver and small intestine, ADH4 in stomach, and ALDH1A1 in the three tissues, but not significantly affect ADH1A, ADH1B1, ADH1C1/2, or ALDH2. At higher drug levels, which may accumulate in cells (0.2 mM), the activities of the weakly-inhibited enzymes may be decreased more significantly. The quantitative effects of cimetidine on metabolism of ethanol and other physiological substrates of ADHs need further investigation.

  18. Development of Selective Inhibitors for Aldehyde Dehydrogenases Based on Substituted Indole-2,3-diones

    PubMed Central

    2015-01-01

    Aldehyde dehydrogenases (ALDH) participate in multiple metabolic pathways and have been indicated to play a role in several cancerous disease states. Our laboratory is interested in developing novel and selective ALDH inhibitors. We looked to further work recently published by developing a class of isoenzyme-selective inhibitors using similar indole-2,3-diones that exhibit differential inhibition of ALDH1A1, ALDH2, and ALDH3A1. Kinetic and X-ray crystallography data suggest that these inhibitors are competitive against aldehyde binding, forming direct interactions with active-site cysteine residues. The selectivity is precise in that these compounds appear to interact directly with the catalytic nucleophile, Cys243, in ALDH3A1 but not in ALDH2. In ALDH2, the 3-keto group is surrounded by the adjacent Cys301/303. Surprisingly, the orientation of the interaction changes depending on the nature of the substitutions on the basic indole ring structure and correlates well with the observed structure–activity relationships for each ALDH isoenzyme. PMID:24444054

  19. Aldehyde-stabilized cryopreservation.

    PubMed

    McIntyre, Robert L; Fahy, Gregory M

    2015-12-01

    We describe here a new cryobiological and neurobiological technique, aldehyde-stabilized cryopreservation (ASC), which demonstrates the relevance and utility of advanced cryopreservation science for the neurobiological research community. ASC is a new brain-banking technique designed to facilitate neuroanatomic research such as connectomics research, and has the unique ability to combine stable long term ice-free sample storage with excellent anatomical resolution. To demonstrate the feasibility of ASC, we perfuse-fixed rabbit and pig brains with a glutaraldehyde-based fixative, then slowly perfused increasing concentrations of ethylene glycol over several hours in a manner similar to techniques used for whole organ cryopreservation. Once 65% w/v ethylene glycol was reached, we vitrified brains at -135 °C for indefinite long-term storage. Vitrified brains were rewarmed and the cryoprotectant removed either by perfusion or gradual diffusion from brain slices. We evaluated ASC-processed brains by electron microscopy of multiple regions across the whole brain and by Focused Ion Beam Milling and Scanning Electron Microscopy (FIB-SEM) imaging of selected brain volumes. Preservation was uniformly excellent: processes were easily traceable and synapses were crisp in both species. Aldehyde-stabilized cryopreservation has many advantages over other brain-banking techniques: chemicals are delivered via perfusion, which enables easy scaling to brains of any size; vitrification ensures that the ultrastructure of the brain will not degrade even over very long storage times; and the cryoprotectant can be removed, yielding a perfusable aldehyde-preserved brain which is suitable for a wide variety of brain assays.

  20. Germline genetic variants in ABCB1, ABCC1, and ALDH1A1 and risk of hematological and gastrointestinal toxicities in a SWOG Phase III trial S0221 for breast cancer

    PubMed Central

    Yao, Song; Sucheston, Lara E.; Zhao, Hua; Barlow, William E.; Zirpoli, Gary; Liu, Song; Moore, Halle C.F.; Budd, G. Thomas; Hershman, Dawn L.; Davis, Warren; Ciupak, Gregory L.; Stewart, James A.; Isaacs, Claudine; Hobday, Timothy J.; Salim, Muhammad; Hortobagyi, Gabriel N.; Gralow, Julie R.; Livingston, Robert B.; Albain, Kathy S.; Hayes, Daniel F.; Ambrosone, Christine B.

    2013-01-01

    Hematological and gastrointestinal toxicities are common among patients treated with cyclophosphamide and doxorubicin for breast cancer. To examine whether single nucleotide polymorphisms (SNPs) in key pharmacokinetic genes were associated with risk of hematological or gastrointestinal toxicity, we analyzed 78 SNPs in ABCB1, ABCC1 and ALDH1A1 in 882 breast cancer patients enrolled in the SWOG trial S0221 and treated with cyclophosphamide and doxorubicin. A two-SNP haplotype in ALDH1A1 was associated with an increased risk of grade 3 and 4 hematological toxicity (odds ratio [OR]=1.44, 95% confidence interval [CI]=1.16-1.78), which remained significant after correction for multiple comparisons. In addition, 4 SNPs in ABCC1 were associated with gastrointestinal toxicity. Our findings provide evidence that SNPs in pharmacokinetic genes may have an impact on the development of chemotherapy-related toxicities. This is a necessary first step towards building a clinical tool that will help assess risk of adverse outcomes prior to administration of chemotherapy. PMID:23999597

  1. Alcohol, Aldehydes, Adducts and Airways

    PubMed Central

    Sapkota, Muna; Wyatt, Todd A.

    2015-01-01

    Drinking alcohol and smoking cigarettes results in the formation of reactive aldehydes in the lung, which are capable of forming adducts with several proteins and DNA. Acetaldehyde and malondialdehyde are the major aldehydes generated in high levels in the lung of subjects with alcohol use disorder who smoke cigarettes. In addition to the above aldehydes, several other aldehydes like 4-hydroxynonenal, formaldehyde and acrolein are also detected in the lung due to exposure to toxic gases, vapors and chemicals. These aldehydes react with nucleophilic targets in cells such as DNA, lipids and proteins to form both stable and unstable adducts. This adduction may disturb cellular functions as well as damage proteins, nucleic acids and lipids. Among several adducts formed in the lung, malondialdehyde DNA (MDA-DNA) adduct and hybrid malondialdehyde-acetaldehyde (MAA) protein adducts have been shown to initiate several pathological conditions in the lung. MDA-DNA adducts are pre-mutagenic in mammalian cells and induce frame shift and base-pair substitution mutations, whereas MAA protein adducts have been shown to induce inflammation and inhibit wound healing. This review provides an insight into different reactive aldehyde adducts and their role in the pathogenesis of lung disease. PMID:26556381

  2. Inhibition of human alcohol and aldehyde dehydrogenases by acetaminophen: Assessment of the effects on first-pass metabolism of ethanol.

    PubMed

    Lee, Yung-Pin; Liao, Jian-Tong; Cheng, Ya-Wen; Wu, Ting-Lun; Lee, Shou-Lun; Liu, Jong-Kang; Yin, Shih-Jiun

    2013-11-01

    Acetaminophen is one of the most widely used over-the-counter analgesic, antipyretic medications. Use of acetaminophen and alcohol are commonly associated. Previous studies showed that acetaminophen might affect bioavailability of ethanol by inhibiting gastric alcohol dehydrogenase (ADH). However, potential inhibitions by acetaminophen of first-pass metabolism (FPM) of ethanol, catalyzed by the human ADH family and by relevant aldehyde dehydrogenase (ALDH) isozymes, remain undefined. ADH and ALDH both exhibit racially distinct allozymes and tissue-specific distribution of isozymes, and are principal enzymes responsible for ethanol metabolism in humans. In this study, we investigated acetaminophen inhibition of ethanol oxidation with recombinant human ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2, ADH2, and ADH4, and inhibition of acetaldehyde oxidation with recombinant human ALDH1A1 and ALDH2. The investigations were done at near physiological pH 7.5 and with a cytoplasmic coenzyme concentration of 0.5 mM NAD(+). Acetaminophen acted as a noncompetitive inhibitor for ADH enzymes, with the slope inhibition constants (Kis) ranging from 0.90 mM (ADH2) to 20 mM (ADH1A), and the intercept inhibition constants (Kii) ranging from 1.4 mM (ADH1C allozymes) to 19 mM (ADH1A). Acetaminophen exhibited noncompetitive inhibition for ALDH2 (Kis = 3.0 mM and Kii = 2.2 mM), but competitive inhibition for ALDH1A1 (Kis = 0.96 mM). The metabolic interactions between acetaminophen and ethanol/acetaldehyde were assessed by computer simulation using inhibition equations and the determined kinetic constants. At therapeutic to subtoxic plasma levels of acetaminophen (i.e., 0.2-0.5 mM) and physiologically relevant concentrations of ethanol (10 mM) and acetaldehyde (10 μm) in target tissues, acetaminophen could inhibit ADH1C allozymes (12-26%) and ADH2 (14-28%) in the liver and small intestine, ADH4 (15-31%) in the stomach, and ALDH1A1 (16-33%) and ALDH2 (8.3-19%) in all 3 tissues. The

  3. New insights into glioma classification based on isocitrate dehydrogenase 1 and 2 gene status.

    PubMed

    Shibahara, Ichiyo; Sonoda, Yukihiko; Kanamori, Masayuki; Saito, Ryuta; Kumabe, Toshihiro; Tominaga, Teiji

    2011-07-01

    In glioma, mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) genes have been receiving attention. IDH1/2 mutations are frequently found in grade II and III gliomas. These genetic alterations occur very early in gliomagenesis and strongly predict favorable outcome in patients with high-grade gliomas. Despite the evolution of studies on this topic, the underlying mechanism of the IDH1/2 mutations remains unknown. Here, we briefly review the current knowledge of IDH1/2 and discuss molecular diagnostics based on IDH1/2 gene status.

  4. Identification of disulfide bond formation between MitoNEET and glutamate dehydrogenase 1.

    PubMed

    Roberts, Morgan E; Crail, Jacquelyn P; Laffoon, Megan M; Fernandez, William G; Menze, Michael A; Konkle, Mary E

    2013-12-17

    MitoNEET is a protein that was identified as a drug target for diabetes, but its cellular function as well as its role in diabetes remains elusive. Protein pull-down experiments identified glutamate dehydrogenase 1 (GDH1) as a potential binding partner. GDH1 is a key metabolic enzyme with emerging roles in insulin regulation. MitoNEET forms a covalent complex with GDH1 through disulfide bond formation and acts as an activator. Proteomic analysis identified the specific cysteine residues that participate in the disulfide bond. This is the first report that effectively links mitoNEET to activation of the insulin regulator GDH1.

  5. Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth.

    PubMed

    Jin, Lingtao; Li, Dan; Alesi, Gina N; Fan, Jun; Kang, Hee-Bum; Lu, Zhou; Boggon, Titus J; Jin, Peng; Yi, Hong; Wright, Elizabeth R; Duong, Duc; Seyfried, Nicholas T; Egnatchik, Robert; DeBerardinis, Ralph J; Magliocca, Kelly R; He, Chuan; Arellano, Martha L; Khoury, Hanna J; Shin, Dong M; Khuri, Fadlo R; Kang, Sumin

    2015-02-09

    How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) is commonly upregulated in human cancers. GDH1 is important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a reactive oxygen species scavenging enzyme glutathione peroxidase 1. Targeting GDH1 by shRNA or a small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth.

  6. Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth

    PubMed Central

    Jin, Lingtao; Li, Dan; Alesi, Gina N.; Fan, Jun; Kang, Hee-Bum; Lu, Zhou; Boggon, Titus J.; Jin, Peng; Yi, Hong; Wright, Elizabeth R.; Duong, Duc; Seyfried, Nicholas T.; Egnatchik, Robert; DeBerardinis, Ralph J.; Magliocca, Kelly R.; He, Chuan; Arellano, Martha L.; Khoury, Hanna J.; Shin, Dong M.; Khuri, Fadlo R.; Kang, Sumin

    2015-01-01

    SUMMARY How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) is commonly upregulated in human cancers. GDH1 is important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate (α-KG) and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a ROS scavenging enzyme glutathione peroxidase 1 (GPx1). Targeting GDH1 by shRNA or a small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth. PMID:25670081

  7. Genome-Wide Meta-Analysis of Homocysteine and Methionine Metabolism Identifies Five One Carbon Metabolism Loci and a Novel Association of ALDH1L1 with Ischemic Stroke

    PubMed Central

    Chen, Fang; Liu, Xuan; Keene, Keith L.; Jacques, Paul; Chen, Wei-Min; Weinstein, Galit; Hsu, Fang-Chi; Beiser, Alexa; Wang, Liewei; Bookman, Ebony; Doheny, Kimberly F.; Wolf, Philip A.; Zilka, Michelle; Selhub, Jacob; Nelson, Sarah; Gogarten, Stephanie M.; Worrall, Bradford B.; Seshadri, Sudha; Sale, Michèle M.

    2014-01-01

    Circulating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia), dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS) and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p = 1.60×10−63], CBS [p = 3.15×10−26], CPS1 [p = 9.10×10−13], ALDH1L1 [p = 7.3×10−13] and PSPH [p = 1.17×10−16]) were strongly associated with the difference between pre- and post-methionine load test tHcy levels (ΔPOST). Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of ΔPOST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with ΔPOST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets

  8. Genome-wide meta-analysis of homocysteine and methionine metabolism identifies five one carbon metabolism loci and a novel association of ALDH1L1 with ischemic stroke.

    PubMed

    Williams, Stephen R; Yang, Qiong; Chen, Fang; Liu, Xuan; Keene, Keith L; Jacques, Paul; Chen, Wei-Min; Weinstein, Galit; Hsu, Fang-Chi; Beiser, Alexa; Wang, Liewei; Bookman, Ebony; Doheny, Kimberly F; Wolf, Philip A; Zilka, Michelle; Selhub, Jacob; Nelson, Sarah; Gogarten, Stephanie M; Worrall, Bradford B; Seshadri, Sudha; Sale, Michèle M

    2014-03-01

    Circulating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia), dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS) and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p = 1.60 × 10(-63)], CBS [p = 3.15 × 10(-26)], CPS1 [p = 9.10 × 10(-13)], ALDH1L1 [p = 7.3 × 10(-13)] and PSPH [p = 1.17 × 10(-16)]) were strongly associated with the difference between pre- and post-methionine load test tHcy levels (ΔPOST). Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of ΔPOST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with ΔPOST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets.

  9. Aldehyde dehydrogenase (ALDH) 3A1 expression by the human keratocyte and its repair phenotypes.

    PubMed

    Pei, Ying; Reins, Rose Y; McDermott, Alison M

    2006-11-01

    Transparency is essential for normal corneal function. Recent studies suggest that corneal cells express high levels of so-called corneal crystallins, such as aldehyde dehydrogenase (ALDH) and transketolase (TKT) that contribute to maintaining cellular transparency. Stromal injury leads to the appearance of repair phenotype keratocytes, the corneal fibroblast and myofibroblast. Previous studies on keratocytes from species such as bovine and rabbit indicate that the transformation from the normal to repair phenotype is accompanied by a loss of corneal crystallin expression, which may be associated with loss of cellular transparency. Here we investigated if a similar loss occurs with human keratocyte repair phenotypes. Human corneal epithelial cells were collected by scraping and keratocytes were isolated by collagenase digestion from cadaveric corneas. The cells were either processed immediately (freshly isolated keratocytes) or were cultured in the presence of 10% fetal bovine serum or transforming growth factor-beta to induce transformation to the corneal fibroblast and myofibroblast phenotypes, respectively. RT-PCR, western blotting and immunolabeling were used to detect mRNA and protein expression of ALDH isozymes and TKT. ALDH enzyme activity was also quantitated and immunolabeling was performed to determine the expression of ALDH3A1 in human corneal tissue sections from normal and diseased corneas. Human corneal keratocytes isolated from three donors expressed ALDH1A1 and ALDH3A1 mRNA, and one donor also expressed ALDH2 and TKT. Corneal epithelial cells expressed ALDH1A1, ALDH2, ALDH3A1 and TKT. Compared to normal keratocytes, corneal fibroblast expression of ALDH3A1 mRNA was reduced by 27% (n=5). ALDH3A1 protein expression as detected by western blotting was markedly reduced in passage zero fibroblasts and undetectable in higher passages (n=3). TKT protein expression was reduced in fibroblasts compared to keratocytes (n=2). ALDH3A1 enzyme activity was not

  10. Improved resistance to transition metals of a cobalt-substituted alcohol dehydrogenase 1 from Saccharomyces cerevisiae.

    PubMed

    Cavaletto, M; Pessione, E; Vanni, A; Giunta, C

    2001-11-17

    Cobalt-substituted alcohol dehydrogenase 1 was purified from a yeast culture of Saccharomyces cerevisiae. Its reactivity towards different transition metals was tested and compared with the native zinc enzyme. The cobalt enzyme displayed a catalytic efficiency 100-fold higher than that of the zinc enzyme. Copper, nickel and cadmium exerted a mixed-type inhibition, with a scale of inhibition efficiency: Cu(2+)>Ni(2+)>Cd(2+). In general, a higher resistance of the modified protein to the inhibitory action of transition metals was observed, with two orders of magnitude for copper I(50). The presence of nickel in the complexes enzyme-coenzyme-inhibitor-substrate resulted in a decrease of the ampholytic nature of the catalytic site. On the contrary, cadmium and copper exerted an enhancement of this parameter. Electrostatic or other types of interactions may be involved in conferring a good resistance in the basic pH range, making cobalt enzyme very suitable for biotechnological processes.

  11. 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...

  12. Alcohol dehydrogenase 1B genotype and fetal alcohol syndrome: a HuGE minireview.

    PubMed

    Green, Ridgely Fisk; Stoler, Joan Marilyn

    2007-07-01

    Fetal alcohol syndrome (FAS), 1 of the most common developmental disabilities in the United States, occurs at a rate of 0.5-2.0:1000 live births. Animal model, family, and twin studies suggest a genetic component to FAS susceptibility. Alcohol dehydrogenases (ADHs) catalyze the rate-limiting step in alcohol metabolism. Studies of genetic associations with FAS have focused on the alcohol dehydrogenase 1B (ADH1B) gene, comparing mothers and children with the alleles ADH1B*2 or ADH1B*3, associated with faster ethanol metabolism, with those homozygous for ADH1B*1. While most studies have found a protective effect for genotypes containing ADH1B*2 or ADH1B*3, results have been conflicting, and further investigation into the association between the ADH1B genotype and FAS is needed. Whether increased alcohol intake accounts for the elevated risk reported for the ADH1B*1/ADH1B*1 genotype should be addressed, and future studies would benefit from consistent case definitions, enhanced exposure measurements, larger sample sizes, and careful study design.

  13. Prognostic and diagnostic potential of isocitrate dehydrogenase 1 in esophageal squamous cell carcinoma

    PubMed Central

    Chen, Xuan; Li, Qingbao; Wang, Cong; Xu, Wenzhe; Han, Lihui; Liu, Yuan; Liu, Bowen; Guan, Shanghui; Tan, Bingxu; Wang, Jianbo; Wang, Nana; Song, Qingxu; Jia, Yibin; Wang, Jianzhen; Zhao, Linli; Cheng, Yufeng

    2016-01-01

    We aimed to investigate the pattern of expression and clinical significance of isocitrate dehydrogenase 1(IDH1) in esophageal squamous cell carcinoma (ESCC). The IDH1 expression was determined by quantitative real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis using 38 pairs of frozen tissues. Enzyme-linked immunosorbent assay was employed to measure 67 pairs of serum samples from patients and their controls to evaluate its diagnostic value. Immunohistochemistry analysis of 111 formalin-fixed paraffin embedded tissue samples was conducted for explaining its prognostic value. After shRNA transfection, CCK8 and clonal efficiency assays were carried on for verifying the function of IDH1 in vitro. Increased expression at mRNA (P < 0.001) and protein levels (immunohistochemistry: P < 0.001, Western blot analysis: P < 0.001) were observed. Similarly, the IDH1 expression in serum from patients with ESCC was significantly upregulated relative to that from healthy controls (P < 0.001). Kaplan–Meier curve indicated that IDH1 upregulation predicted worse overall survival (OS) and progression-free survival (PFS). Univariate and multivariate analyses identified IDH1 expression as an independent prognostic factor for OS and PFS. Furthermore, OD450 values and colony numbers were decreased in sh-IDH1 groups (all P < 0.05). In conclusion, IDH1 is upregulated in patients with ESCC and can be used as a good potential biomarker for diagnosis and prognosis. PMID:27863386

  14. Regulation of human cerebrospinal fluid malate dehydrogenase 1 in sporadic Creutzfeldt-Jakob disease patients

    PubMed Central

    Schmitz, Matthias; Llorens, Franc; Pracht, Alexander; Thom, Tobias; Correia, Ângela; Zafar, Saima; Ferrer, Isidre; Zerr, Inga

    2016-01-01

    The identification of reliable diagnostic biomarkers in differential diagnosis of neurodegenerative diseases is an ongoing topic. A previous two-dimensional proteomic study on cerebrospinal fluid (CSF) revealed an elevated level of an enzyme, mitochondrial malate dehydrogenase 1 (MDH1), in sporadic Creutzfeldt-Jakob disease (sCJD) patients. Here, we could demonstrate the expression of MDH1 in neurons as well as in the neuropil. Its levels are lower in sCJD brains than in control brains. An examination of CSF-MDH1 in sCJD patients by ELISA revealed a significant elevation of CSF-MDH1 levels in sCJD patients (independently from the PRNP codon 129 MV genotype or the prion protein scrapie (PrPSc) type) in comparison to controls. In combination with total tau (tau), CSF-MDH1 detection exhibited a high diagnostic accuracy for sCJD diagnosis with a sensitivity of 97.5% and a specificity of 95.6%. A correlation study of MDH1 level in CSF with other neurodegenerative marker proteins revealed a significant positive correlation between MDH1 concentration with tau, 14-3-3 and neuron specific enolase level. In conclusion, our study indicated the potential of MDH1 in combination with tau as an additional biomarker in sCJD improving diagnostic accuracy of tau markedly. PMID:27852982

  15. Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1.

    PubMed

    Law, Jason M; Stark, Sebastian C; Liu, Ke; Liang, Norah E; Hussain, Mahmud M; Leiendecker, Matthias; Ito, Daisuke; Verho, Oscar; Stern, Andrew M; Johnston, Stephen E; Zhang, Yan-Ling; Dunn, Gavin P; Shamji, Alykhan F; Schreiber, Stuart L

    2016-10-13

    Evidence suggests that specific mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) are critical for the initiation and maintenance of certain tumor types and that inhibiting these mutant enzymes with small molecules may be therapeutically beneficial. In order to discover mutant allele-selective IDH1 inhibitors with chemical features distinct from existing probes, we screened a collection of small molecules derived from diversity-oriented synthesis. The assay identified compounds that inhibit the IDH1-R132H mutant allele commonly found in glioma. Here, we report the discovery of a potent (IC50 = 50 nM) series of IDH1-R132H inhibitors having 8-membered ring sulfonamides as exemplified by the compound BRD2879. The inhibitors suppress (R)-2-hydroxyglutarate production in cells without apparent toxicity. Although the solubility and pharmacokinetic properties of the specific inhibitor BRD2879 prevent its use in vivo, the scaffold presents a validated starting point for the synthesis of future IDH1-R132H inhibitors having improved pharmacological properties.

  16. Gossypol enantiomers potently inhibit human placental 3β-hydroxysteroid dehydrogenase 1 and aromatase activities.

    PubMed

    Dong, Yaoyao; Mao, Baiping; Li, Linxi; Guan, Hongguo; Su, Ying; Li, Xiaoheng; Lian, Qingquan; Huang, Ping; Ge, Ren-Shan

    2016-03-01

    Gossypol is a chemical isolated from cotton seeds. It exists as (+) or (-) enantiomer and has been tested for anticancer, abortion-inducing, and male contraception. Progesterone formed from pregnenolone by 3β-hydroxysteroid dehydrogenase 1 (HSD3B1) and estradiol from androgen by aromatase (CYP19A1) are critical for the maintenance of pregnancy or associated with some cancers. In this study we compared the potencies of (+)- and (-)-gossypol enantiomers in the inhibition of HSD3B1 and aromatase activities as well as progesterone and estradiol production in human placental JEG-3 cells. (+) Gossypol showed potent inhibition on human placental HSD3B1 with IC50 value of 2.3 μM, while (-) gossypol weakly inhibited it with IC50 over 100 μM. In contrast, (-) gossypol moderately inhibited CYP19A1 activity with IC50 of 23 μM, while (+) gossypol had no inhibition when the highest concentration (100 μM) was tested. (+) Gossypol enantiomer competitively inhibited HSD3B1 against substrate pregnenolone and showed mixed mode against NAD(+). (-) Gossypol competitively inhibited CYP19A1 against substrate testosterone. Gossypol enantiomers showed different potency related to their inhibition on human HSD3B1 and CYP19A1. Whether gossypol enantiomer is used alone or in combination relies on its application and beneficial effects.

  17. 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.

  18. Cyanobacterial aldehyde deformylase oxygenation of aldehydes yields n-1 aldehydes and alcohols in addition to alkanes.

    PubMed

    Aukema, Kelly G; Makris, Thomas M; Stoian, Sebastian A; Richman, Jack E; Münck, Eckard; Lipscomb, John D; Wackett, Lawrence P

    2013-10-04

    Aldehyde-deformylating oxygenase (ADO) catalyzes O2-dependent release of the terminal carbon of a biological substrate, octadecanal, to yield formate and heptadecane in a reaction that requires external reducing equivalents. We show here that ADO also catalyzes incorporation of an oxygen atom from O2 into the alkane product to yield alcohol and aldehyde products. Oxygenation of the alkane product is much more pronounced with C9-10 aldehyde substrates, so that use of nonanal as the substrate yields similar amounts of octane, octanal, and octanol products. When using doubly-labeled [1,2-(13)C]-octanal as the substrate, the heptane, heptanal and heptanol products each contained a single (13)C-label in the C-1 carbons atoms. The only one-carbon product identified was formate. [(18)O]-O2 incorporation studies demonstrated formation of [(18)O]-alcohol product, but rapid solvent exchange prevented similar determination for the aldehyde product. Addition of [1-(13)C]-nonanol with decanal as the substrate at the outset of the reaction resulted in formation of [1-(13)C]-nonanal. No (13)C-product was formed in the absence of decanal. ADO contains an oxygen-bridged dinuclear iron cluster. The observation of alcohol and aldehyde products derived from the initially formed alkane product suggests a reactive species similar to that formed by methane monooxygenase (MMO) and other members of the bacterial multicomponent monooxygenase family. Accordingly, characterization by EPR and Mössbauer spectroscopies shows that the electronic structure of the ADO cluster is similar, but not identical, to that of MMO hydroxylase component. In particular, the two irons of ADO reside in nearly identical environments in both the oxidized and fully reduced states, whereas those of MMOH show distinct differences. These favorable characteristics of the iron sites allow a comprehensive determination of the spin Hamiltonian parameters describing the electronic state of the diferrous cluster for the

  19. Process for producing furan from furfural aldehyde

    DOEpatents

    Diebold, J.P.; Evans, R.J.

    1987-04-06

    A process of producing furan and derivatives thereof as disclosed. The process includes generating furfural aldehyde vapors and then passing those vapors over a zeolite catalyst at a temperature and for a residence time effective to decarbonylate the furfural aldehydes to form furans and derivatives thereof. The resultant furan vapors and derivatives are then separated. In a preferred form, the furfural aldehyde vapors are generated during the process of converting biomass materials to liquid and gaseous fuels.

  20. Microsphere coated substrate containing reactive aldehyde groups

    NASA Technical Reports Server (NTRS)

    Rembaum, Alan (Inventor); Yen, Richard C. K. (Inventor)

    1984-01-01

    A synthetic organic resin is coated with a continuous layer of contiguous, tangential, individual microspheres having a uniform diameter preferably between 100 Angstroms and 2000 Angstroms. The microspheres are an addition polymerized polymer of an unsaturated aldehyde containing 4 to 20 carbon atoms and are covalently bonded to the substrate by means of high energy radiation grafting. The microspheres contain reactive aldehyde groups and can form conjugates with proteins such as enzymes or other aldehyde reactive materials.

  1. Process for producing furan from furfural aldehyde

    DOEpatents

    Diebold, James P.; Evans, Robert J.

    1988-01-01

    A process of producing furan and derivatives thereof is disclosed. The process includes generating furfural aldehyde vapors and then passing those vapors over a zeolite catalyst at a temperature and for a residence time effective to decarbonylate the furfural aldehydes to form furans and derivatives thereof. The resultant furan vapors and derivatives are then separated. In a preferred form, the furfural aldehyde vapors are generated during the process of converting biomass materials to liquid and gaseous fuels.

  2. Microfluidics for rapid detection of isocitrate dehydrogenase 1 mutation for intraoperative application.

    PubMed

    Aibaidula, Abudumijiti; Zhao, Wang; Wu, Jin-Song; Chen, Hong; Shi, Zhi-Feng; Zheng, Lu-Lu; Mao, Ying; Zhou, Liang-Fu; Sui, Guo-Dong

    2016-06-01

    OBJECT Conventional methods for isocitrate dehydrogenase 1 (IDH1) detection, such as DNA sequencing and immunohistochemistry, are time- and labor-consuming and cannot be applied for intraoperative analysis. To develop a new approach for rapid analysis of IDH1 mutation from tiny tumor samples, this study used microfluidics as a method for IDH1 mutation detection. METHODS Forty-seven glioma tumor samples were used; IDH1 mutation status was investigated by immunohistochemistry and DNA sequencing. The microfluidic device was fabricated from polydimethylsiloxane following standard soft lithography. The immunoanalysis was conducted in the microfluidic chip. Fluorescence images of the on-chip microcolumn taken by the charge-coupled device camera were collected as the analytical results readout. Fluorescence signals were analyzed by NIS-Elements software to gather detailed information about the IDH1 concentration in the tissue samples. RESULTS DNA sequencing identified IDH1 R132H mutation in 33 of 47 tumor samples. The fluorescence signal for IDH1-mutant samples was 5.49 ± 1.87 compared with 3.90 ± 1.33 for wild type (p = 0.005). Thus, microfluidics was capable of distinguishing IDH1-mutant tumor samples from wild-type samples. When the cutoff value was 4.11, the sensitivity of microfluidics was 87.9% and the specificity was 64.3%. CONCLUSIONS This new approach was capable of analyzing IDH1 mutation status of tiny tissue samples within 30 minutes using intraoperative microsampling. This approach might also be applied for rapid pathological diagnosis of diffuse gliomas, thus guiding personalized resection.

  3. Xanthine dehydrogenase-1 silencing in Aedes aegypti mosquitoes promotes a blood feeding-induced adulticidal activity.

    PubMed

    Isoe, Jun; Petchampai, Natthida; Isoe, Yurika E; Co, Katrina; Mazzalupo, Stacy; Scaraffia, Patricia Y

    2017-02-08

    Aedesaegypti has 2 genes encoding xanthine dehydrogenase (XDH). We analyzed XDH1 and XDH2 gene expression by real-time quantitative PCR in tissues from sugar- and blood-fed females. Differential XDH1 and XDH2 gene expression was observed in tissues dissected throughout a time course. We next exposed females to blood meals supplemented with allopurinol, a well-characterized XDH inhibitor. We also tested the effects of injecting double-stranded RNA (dsRNA) against XDH1, XDH2, or both. Disruption of XDH by allopurinol or XDH1 by RNA interference significantly affected mosquito survival, causing a disruption in blood digestion, excretion, oviposition, and reproduction. XDH1-deficient mosquitoes showed a persistence of serine proteases in the midgut at 48 h after blood feeding and a reduction in the uptake of vitellogenin by the ovaries. Surprisingly, analysis of the fat body from dsRNA-XDH1-injected mosquitoes fell into 2 groups: one group was characterized by a reduction of the XDH1 transcript, whereas the other group was characterized by an up-regulation of several transcripts including XDH1, glutamine synthetase, alanine aminotransferase, catalase, superoxide dismutase, ornithine decarboxylase, glutamate receptor, and ammonia transporter. Our data demonstrate that XDH1 plays an essential role and that XDH1 has the potential to be used as a metabolic target for Ae.aegypti vector control.-Isoe, J., Petchampai, N., Isoe, Y. E., Co, K., Mazzalupo, S., Scaraffia, P. Y. Xanthine dehydrogenase-1 silencing in Aedes aegypti mosquitoes promotes a blood feeding-induced adulticidal activity.

  4. Predicting the likelihood of an isocitrate dehydrogenase 1 or 2 mutation in diagnoses of infiltrative glioma

    PubMed Central

    Chen, Li; Voronovich, Zoya; Clark, Kenneth; Hands, Isaac; Mannas, Jonathan; Walsh, Meggen; Nikiforova, Marina N.; Durbin, Eric B.; Weiss, Heidi; Horbinski, Craig

    2014-01-01

    Background Several variables are associated with the likelihood of isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation in gliomas, though no guidelines yet exist for when testing is warranted, especially when an R132H IDH1 immunostain is negative. Methods A cohort of 89 patients was used to build IDH1/2 mutation prediction models in World Health Organization grades II–IV gliomas, and an external cohort of 100 patients was used for validation. Logistic regression and backward model selection with the Akaike information criterion were used to develop prediction models. Results A multivariable model, incorporating patient age, glioblastoma multiforme diagnosis, and prior history of grade II or III glioma, was developed to predict IDH1/2 mutation probability. This model generated an area under the curve (AUC) of 0.934 (95% CI: 0.878, 0.978) in the external validation cohort and 0.941 (95% CI: 0.918, 0.962) in the cohort of The Cancer Genome Atlas. When R132H IDH1 immunostain information was added, AUC increased to 0.986 (95% CI: 0.967, 0.998). This model had an AUC of 0.947 (95% CI: 0.891, 0.995) in predicting whether an R132H IDH1 immunonegative case harbored a less common IDH1 or IDH2 mutation. The models were also 94% accurate in predicting IDH1/2 mutation status in gliomas from The Cancer Genome Atlas. An interactive web-based application for calculating the probability of an IDH1/2 mutation is now available using these models. Conclusions We have integrated multiple variables to generate a probability of an IDH1/2 mutation. The associated web-based application can help triage diffuse gliomas that would benefit from mutation testing in both clinical and research settings. PMID:24860178

  5. Assessment of the Association between Isocitrate Dehydrogenase 1 Mutation and Mortality Risk of Glioblastoma Patients.

    PubMed

    Dai, Yuting; Ning, Xianbin; Han, Guoqian; Li, Wei

    2016-04-01

    Previous studies showed that isocitrate dehydrogenase 1 (IDH1) mutation might be a prognostic biomarker of prognosis in glioblastoma (GBM) patients, but the outcomes were various. A meta-analysis of published studies was carried out to reach a reliable assessment of the association between IDH1 mutation and mortality of GBM patients. Relative risks (RRs) with 95% confidence intervals (95%CIs) were pooled using meta-analysis to assess risk of mortality in patients with IDH1 mutation. A total of 20 studies (3 prospective cohort and 17 retrospective cohort studies) were finally included into the meta-analysis. Meta-analysis of total included studies suggested that GBM patients with IDH1 mutation had decreased risk of mortality compared those patients without IDH1 mutation (RR = 0.43, 95%CI 0.35-0.54, P < 0.001). GBM patients with IDH1 mutation from European countries had also decreased mortality risk compared with those patients without IDH1 mutation (RR = 0.35, 95%CI 0.25-0.49, P < 0.001), but GBM patients with IDH1 mutation from Asians only dad 32% decrease of mortality risk compared with those patients without IDH1 mutation (RR = 0.68, 95%CI 0.49-0.94, P = 0.018). The findings from the meta-analysis provide strong evidence for the association between IDH1 mutation and decreased mortality risk of GBM patients. In addition, there is an obvious difference in the mortality risk of GBM patients with IDH1 mutation between western and eastern countries.

  6. DIFFERENTIATING THE TOXICITY OF CARCINOGENIC ALDEHYDES FROM NONCARCINOGENIC ALDEHYDES IN THE RAT NOSE USING CDNA ARRAYS

    EPA Science Inventory

    Differentiating the Toxicity of Carcinogenic Aldehydes from Noncarcinogenic Aldehydes in the Rat Nose Using cDNA Arrays.

    Formaldehyde is a widely used aldehyde in many industrial settings, the tanning process, household products, and is a contaminant in cigarette smoke. H...

  7. On the role of microsomal aldehyde dehydrogenase in metabolism of aldehydic products of lipid peroxidation.

    PubMed

    Antonenkov, V D; Pirozhkov, S V; Panchenko, L F

    1987-11-30

    To elucidate a possible role of membrane-bound aldehyde dehydrogenase in the detoxication of aldehydic products of lipid peroxidation, the substrate specificity of the highly purified microsomal enzyme was investigated. The aldehyde dehydrogenase was active with different aliphatic aldehydes including 4-hydroxyalkenals, but did not react with malonic dialdehyde. When Fe/ADP-ascorbate-induced lipid peroxidation of arachidonic acid was carried out in an in vitro system, the formation of products which react with microsomal aldehyde dehydrogenase was observed parallel with malonic dialdehyde accumulation.

  8. Aldehyde-containing urea-absorbing polysaccharides

    NASA Technical Reports Server (NTRS)

    Mueller, W. A.; Hsu, G. C.; Marsh, H. E., Jr. (Inventor)

    1977-01-01

    A novel aldehyde containing polymer (ACP) is prepared by reaction of a polysaccharide with periodate to introduce aldehyde groups onto the C2 - C3 carbon atoms. By introduction of ether and ester groups onto the pendant primary hydroxyl solubility characteristics are modified. The ACP is utilized to absorb nitrogen bases such as urea in vitro or in vivo.

  9. Aldehyde Detection in Electronic Cigarette Aerosols

    PubMed Central

    2017-01-01

    Acetaldehyde, acrolein, and formaldehyde are the principal toxic aldehydes present in cigarette smoke and contribute to the risk of cardiovascular disease and noncancerous pulmonary disease. The rapid growth of the use of electronic cigarettes (e-cigarettes) has raised concerns over emissions of these harmful aldehydes. This work determines emissions of these aldehydes in both free and bound (aldehyde–hemiacetal) forms and other carbonyls from the use of e-cigarettes. A novel silicon microreactor with a coating phase of 4-(2-aminooxyethyl)-morpholin-4-ium chloride (AMAH) was used to trap carbonyl compounds in the aerosols of e-cigarettes via oximation reactions. AMAH–aldehyde adducts were measured using gas chromatography–mass spectrometry. 1H nuclear magnetic resonance spectroscopy was used to analyze hemiacetals in the aerosols. These aldehydes were detected in the aerosols of all e-cigarettes. Newer-generation e-cigarette devices generated more aldehydes than the first-generation e-cigarettes because of higher battery power output. Formaldehyde–hemiacetal was detected in the aerosols generated from some e-liquids using the newer e-cigarette devices at a battery power output of 11.7 W and above. The emission of these aldehydes from all e-cigarettes, especially higher levels of aldehydes from the newer-generation e-cigarette devices, indicates the risk of using e-cigarettes. PMID:28393137

  10. 11β-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes

    SciTech Connect

    Itoi, Saori; Terao, Mika Murota, Hiroyuki; Katayama, Ichiro

    2013-10-18

    Highlights: •We investigate the role of 11β-HSD1 in skin inflammation. •Various stimuli increase expression of 11β-HSD1 in keratinocytes. •11β-HSD1 knockdown by siRNA decreases cortisol levels in media. •11β-HSD1 knockdown abrogates the response to pro-inflammatory cytokines. •Low-dose versus high-dose cortisol has opposing effects on keratinocyte inflammation. -- Abstract: The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactive cortisone into active cortisol is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11β-HSD1 in skin inflammation. Expression of 11β-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1β and TNFα. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11β-HSD1 in response to pro-inflammatory cytokines, we knocked down 11β-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1β or TNFα stimulation was attenuated in NHEKs transfected with si11β-HSD1 compared with control cells. In addition, IL-1β-induced IL-6 production was enhanced in cultures containing 1 × 10{sup −13} M cortisol, whereas 1 × 10{sup −5} M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11β-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol

  11. Isocitrate dehydrogenase 1 R132H mutation is not detected in angiocentric glioma.

    PubMed

    Raghunathan, Aditya; Olar, Adriana; Vogel, Hannes; Parker, John R; Coventry, Susan C; Debski, Robert; Albarracin, Constance T; Aldape, Kenneth D; Cahill, Daniel P; Powell, Suzanne Z; Fuller, Gregory N

    2012-08-01

    Mutations of isocitrate dehydrogenase-1 gene (IDH1), most commonly resulting in replacement of arginine at position 132 by histidine (R132H), have been described in World Health Organization grade II and III diffuse gliomas and secondary glioblastoma. Immunohistochemistry using a mouse monoclonal antibody has a high specificity and sensitivity for detecting IDH1 R132H mutant protein in sections from formalin-fixed, paraffin-embedded tissue. Angiocentric glioma (AG), a unique neoplasm with mixed phenotypic features of diffuse glioma and ependymoma, has recently been codified as a grade I neoplasm in the 2007 World Health Organization classification of central nervous system tumors. The present study was designed to evaluate IDH1 R132H protein in AG. Three cases of AG were collected, and the diagnoses were confirmed. Expression of mutant IDH1 R132H protein was determined by immunohistochemistry on representative formalin-fixed, paraffin-embedded sections using the antihuman mouse monoclonal antibody IDH1 R132H (Dianova, Hamburg, Germany). Known IDH1 mutation-positive and IDH1 wild-type cases of grade II to IV glioma served as positive and negative controls. All 3 patients were male, aged 3, 5, and 15 years, with intra-axial tumors in the right posterior parietal-occipital lobe, right frontal lobe, and left frontal lobe, respectively. All 3 cases showed characteristic morphologic features of AG, including a monomorphous population of slender bipolar cells that diffusely infiltrated cortical parenchyma and ensheathed cortical blood vessels radially and longitudinally. All 3 cases were negative for the presence of IDH1 R132H mutant protein (0/3). All control cases showed appropriate reactivity. IDH1 R132H mutation has been described as a common molecular signature of grade II and III diffuse gliomas and secondary glioblastoma; however, AG, which exhibits some features of diffuse glioma, has not been evaluated. The absence of mutant IDH1 R132H protein expression in AG

  12. Toward aldehyde and alkane production by removing aldehyde reductase activity in Escherichia coli.

    PubMed

    Rodriguez, Gabriel M; Atsumi, Shota

    2014-09-01

    Advances in synthetic biology and metabolic engineering have enabled the construction of novel biological routes to valuable chemicals using suitable microbial hosts. Aldehydes serve as chemical feedstocks in the synthesis of rubbers, plastics, and other larger molecules. Microbial production of alkanes is dependent on the formation of a fatty aldehyde intermediate which is converted to an alkane by an aldehyde deformylating oxygenase (ADO). However, microbial hosts such as Escherichia coli are plagued by many highly active endogenous aldehyde reductases (ALRs) that convert aldehydes to alcohols, which greatly complicates strain engineering for aldehyde and alkane production. It has been shown that the endogenous ALR activity outcompetes the ADO enzyme for fatty aldehyde substrate. The large degree of ALR redundancy coupled with an incomplete database of ALRs represents a significant obstacle in engineering E. coli for either aldehyde or alkane production. In this study, we identified 44 ALR candidates encoded in the E. coli genome using bioinformatics tools, and undertook a comprehensive screening by measuring the ability of these enzymes to produce isobutanol. From the pool of 44 candidates, we found five new ALRs using this screening method (YahK, DkgA, GldA, YbbO, and YghA). Combined deletions of all 13 known ALRs resulted in a 90-99% reduction in endogenous ALR activity for a wide range of aldehyde substrates (C2-C12). Elucidation of the ALRs found in E. coli could guide one in reducing competing alcohol formation during alkane or aldehyde production.

  13. The oxidation of yeast alcohol dehydrogenase-1 by hydrogen peroxide in vitro.

    PubMed

    Men, Lijie; Wang, Yinsheng

    2007-01-01

    Yeast alcohol dehydrogenase (YADH) plays an important role in the conversion of alcohols to aldehydes or ketones. YADH-1 is a zinc-containing protein, and it accounts for the major part of ADH activity in growing baker's yeast. To gain insight into how oxidative modification of the enzyme affects its function, we exposed YADH-1 to hydrogen peroxide in vitro and assessed the oxidized protein by LC-MS/MS analysis of proteolytic cleavage products of the protein and by measurements of enzymatic activity, zinc release, and thiol/thiolate loss. The results illustrated that Cys43 and Cys153, which reside at the active site of the protein, could be selectively oxidized to cysteine sulfinic acid (Cys-SO2H) and cysteine sulfonic acid (Cys-SO3H). In addition, H2O2 induced the formation of three disulfide bonds: Cys43-Cys153 in the catalytic domain, Cys103-Cys111 in the noncatalytic zinc center, and Cys276-Cys277. Therefore, our results support the notion that the oxidation of cysteine residues in the zinc-binding domain of proteins can go beyond the formation of disulfide bond(s); the formation of Cys-SO2H and Cys-SO3H is also possible. Furthermore, most methionines could be oxidized to methionine sulfoxides. Quantitative measurement results revealed that, among all the cysteine residues, Cys43 was the most susceptible to H2O2 oxidation, and the major oxidation products of this cysteine were Cys-SO2H and Cys-SO3H. The oxidation of Cys43 might be responsible for the inactivation of the enzyme upon H2O2 treatment.

  14. 3D-QSAR and docking studies on 1-hydroxypyridin-2-one compounds as mutant isocitrate dehydrogenase 1 inhibitors

    NASA Astrophysics Data System (ADS)

    Wang, Zhenya; Chang, Yiqun; Han, Yushui; Liu, Kangjia; Hou, Jinsong; Dai, Chengli; Zhai, Yuanhao; Guo, Jialiang; Sun, Pinghua; Lin, Jing; Chen, Weimin

    2016-11-01

    Mutation of isocitrate dehydrogenase 1 (IDH1) which is frequently found in certain cancers such as glioma, sarcoma and acute myeloid leukemia, has been proven to be a potent drug target for cancer therapy. In silico methodologies such as 3D-QSAR and molecular docking were performed to explore compounds with better mutant isocitrate dehydrogenase 1 (MIDH1) inhibitory activity using a series of 40 newly reported 1-hydroxypyridin-2-one compounds as MIDH1 inhibitors. The satisfactory CoMFA and CoMSIA models obtained after internal and external cross-validation gave q2 values of 0.691 and 0.535, r2 values of 0.984 and 0.936, respectively. 3D contour maps generated from CoMFA and CoMSIA along with the docking results provided information about the structural requirements for better MIDH1 inhibitory activity. Based on the structure-activity relationship, 17 new potent molecules with better predicted activity than the most active compound in the literature have been designed.

  15. Breast cancer stem cells and intrinsic subtypes: controversies rage on.

    PubMed

    Nakshatri, Harikrishna; Srour, Edward F; Badve, Sunil

    2009-01-01

    Heterogeneity is a well-documented phenomenon in breast cancer; one of the explanations for this phenomenon is the presence of cancer stem cells (CSCs) with the capacity to differentiate along divergent pathways. These CSCs undergo asymmetric and symmetric division resulting in both expansion of the stem cell pool and the production of morphologically and functionally distinct differentiated daughter cells. Breast cancer cells that express the cell surface molecule CD44 but lack the expression of CD24 have been described as CSCs. Breast cancer cells expressing elevated levels of Aldehyde Dehydrogenase 1 (ALDH1) are also described as CSCs with ALDH1+/CD44+/CD24- subpopulation displaying highest tumorigenic potential in NOD/SCID models. The CSC hypothesis for tumor heterogeneity raises three important questions. First, in unrelated gene expression studies, breast cancers have been classified to five intrinsic subtypes; luminal type A, luminal type B, basal type, ErbB2/HER2-positive and normal-like. Therefore, do these intrinsic subtypes of breast cancer have distinct CSCs of their own or are ALDH1+ or CD44+/CD24- cells common CSCs for all intrinsic subtypes? Secondly, do ALDH1+ or CD44+/CD24- CSCs originate from normal cells of same phenotype or can differentiated cancer cells acquire ALDH1 or CD44+/CD24- status due to mutagenic events? Third, do ALDH1+, ALDH1-, CD44+/CD24- and non-CD44+/CD24- cancer cells differ in their ability to metastasize and respond to chemotherapy? In this review, we present our views on these questions based on studies conducted by several laboratories including ours and present evidence for a strong association of CD44+/CD24- phenotype with basal-like or mesenchymal-like cancer cells.

  16. Two-carbon homologation of aldehydes and ketones to a,ß-unsaturated aldehydes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phosphonate reagents were developed for the two-carbon homologation of aldehydes or ketones to unbranched- or methyl-branched a,ß-unsaturated aldehydes. The phosphonate reagents, diethyl methylformyl-2-phosphonate dimethylhydrazone and diethyl ethylformyl-2-phosphonate dimethylhydrazone, contained a...

  17. Neurochemical and motor changes in mice with combined mutations linked to Parkinson’s disease

    PubMed Central

    Bai, Xiang; Wey, Margaret Chia-Ying; Martinez, Paul Anthony; Shi, Chao; Fernandez, Elizabeth; Strong, Randy

    2017-01-01

    ABSTRACT Considerable evidence suggests that oxidative stress plays a role in the pathogenesis of Parkinson’s disease (PD), the most prevalent neurodegenerative movement disorder. Reduced expression of aldehyde dehydrogenase-1 (ALDH1) and glutathione peroxidase-1 (GPX1), enzymes that function to detoxify aldehydes and hydroxyl radicals, respectively, has been reported in the substantia nigra of patients who died with PD. To determine whether deficiency in these two genes contributes to the pathogenesis of PD, mice were generated with homozygous null mutations of both Aldh1a1 (the murine homolog of ALDH1) and Gpx1 genes [knockout (KO) mice]. At 6 and 18 months of age, KO mice showed a significantly decreased latency to fall in the automated accelerating rotarod test and increased time to complete the pole test opamine levels were not altered; however, the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and the DOPAC/dopamine ratio were significantly reduced at 18 months of age. Proteins adducted with 4-hydroxynonenal, the end-product of lipid peroxidation, were increased in the. midbrain and striatum of KO mice at 6 and 18 months. In conclusion, dual mutations in Gpx1 and Aldh1a1 genes are associated with motor deficits and increased lipid peroxidation in adult mice. PMID:28326165

  18. Intercalation of Aldehydes into Vanadyl Phosphate

    NASA Astrophysics Data System (ADS)

    Melánová, Klára; Beneš, Ludvík.; Zima, Vítězslav; Votinský, Jiří

    2001-02-01

    Intercalates of VOPO4 with several aliphatic aldehydes, benzaldehyde, and 4-methylbenzaldehyde were prepared and characterized by thermogravimetric analysis, X-ray diffractometry, and IR and UV-vis spectroscopies. Aliphatic aldehyde intercalates are unstable and the guests undergo aldol condensation and oxidation. The arrangement of the guest molecules in the interlayer space of the host is discussed. A part of aliphatic aldehydes is anchored to the host layers by coordination of their carbonyl oxygen to the vanadium atom; the rest is probably bonded by weak van der Waals forces. In the benzaldehyde and 4-methylbenzaldehyde intercalates, all guest molecules are coordinated to the vanadium atoms with their benzene rings perpendicular to the sheets of the host.

  19. Betaine aldehyde dehydrogenase isozymes of spinach

    SciTech Connect

    Hanson, A.D.; Weretilnyk, E.A.; Weigel, P.

    1986-04-01

    Betaine is synthesized in spinach chloroplasts via the pathway Choline ..-->.. Betaine Aldehyde ..-->.. Betaine; the second step is catalyzed by betaine aldehyde dehydrogenase (BADH). The subcellular distribution of BADH was determined in leaf protoplast lysates; BADH isozymes were separated by 6-9% native PAGE. The chloroplast stromal fraction contains a single BADH isozyme (number1) that accounts for > 80% of the total protoplast activity; the extrachloroplastic fraction has a minor isozyme (number2) which migrates more slowly than number1. Both isozymes appear specific for betaine aldehyde, are more active with NAD than NADP, and show a ca. 3-fold activity increase in salinized leaves. The phenotype of a natural variant of isozyme number1 suggests that the enzyme is a dimer.

  20. Oxidation of Aromatic Aldehydes Using Oxone

    ERIC Educational Resources Information Center

    Gandhari, Rajani; Maddukuri, Padma P.; Thottumkara, Vinod K.

    2007-01-01

    The experiment demonstrating the feasibility of using water as a solvent for organic reactions which highlights the cost and environmental benefits of its use is presented. The experiment encourages students to think in terms of the reaction mechanism of the oxidation of aldehydes knowing that potassium persulfate is the active oxidant in Oxone…

  1. The First Mammalian Aldehyde Oxidase Crystal Structure

    PubMed Central

    Coelho, Catarina; Mahro, Martin; Trincão, José; Carvalho, Alexandra T. P.; Ramos, Maria João; Terao, Mineko; Garattini, Enrico; Leimkühler, Silke; Romão, Maria João

    2012-01-01

    Aldehyde oxidases (AOXs) are homodimeric proteins belonging to the xanthine oxidase family of molybdenum-containing enzymes. Each 150-kDa monomer contains a FAD redox cofactor, two spectroscopically distinct [2Fe-2S] clusters, and a molybdenum cofactor located within the protein active site. AOXs are characterized by broad range substrate specificity, oxidizing different aldehydes and aromatic N-heterocycles. Despite increasing recognition of its role in the metabolism of drugs and xenobiotics, the physiological function of the protein is still largely unknown. We have crystallized and solved the crystal structure of mouse liver aldehyde oxidase 3 to 2.9 Å. This is the first mammalian AOX whose structure has been solved. The structure provides important insights into the protein active center and further evidence on the catalytic differences characterizing AOX and xanthine oxidoreductase. The mouse liver aldehyde oxidase 3 three-dimensional structure combined with kinetic, mutagenesis data, molecular docking, and molecular dynamics studies make a decisive contribution to understand the molecular basis of its rather broad substrate specificity. PMID:23019336

  2. Biomimetic flavin-catalyzed aldehyde oxidation.

    PubMed

    Murray, Alexander T; Matton, Pascal; Fairhurst, Nathan W G; John, Matthew P; Carbery, David R

    2012-07-20

    The oxidation of alkyl and aryl aldehydes to their corresponding carboxylic acids has been achieved through the action of a biomimetic bridged flavin catalyst. The reaction uses readily available 35% aqueous hydrogen peroxide and is operationally simple. The oxidation is a green and sustainable reaction, obviating chlorinated solvents with minimal byproducts.

  3. Biomarkers of exposure to endogenous oxidative and aldehyde stress.

    PubMed

    Bruce, W Robert; Lee, Owen; Liu, Zhen; Marcon, Norman; Minkin, Salomon; O'Brien, Peter J

    2011-08-01

    We observed an unexpectedly strong association of three different endogenous aldehydes and noted that the association could be explained by multiple reactions in which oxidative stress increased the formation of endogenous aldehydes and endogenous aldehydes increased oxidative stress. These interactions make it reasonable to assess multiple exposures to endogenous oxidative and aldehyde stress with less specific measures such as advanced glycation end-products or protein carbonyls.

  4. 40 CFR 721.639 - Amine aldehyde condensate.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Amine aldehyde condensate. 721.639... Substances § 721.639 Amine aldehyde condensate. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as an amine aldehyde condensate (PMN...

  5. 40 CFR 721.639 - Amine aldehyde condensate.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Amine aldehyde condensate. 721.639... Substances § 721.639 Amine aldehyde condensate. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as an amine aldehyde condensate (PMN...

  6. 40 CFR 721.639 - Amine aldehyde condensate.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Amine aldehyde condensate. 721.639... Substances § 721.639 Amine aldehyde condensate. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as an amine aldehyde condensate (PMN...

  7. 40 CFR 721.639 - Amine aldehyde condensate.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Amine aldehyde condensate. 721.639... Substances § 721.639 Amine aldehyde condensate. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as an amine aldehyde condensate (PMN...

  8. 40 CFR 721.639 - Amine aldehyde condensate.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Amine aldehyde condensate. 721.639... Substances § 721.639 Amine aldehyde condensate. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as an amine aldehyde condensate (PMN...

  9. Pistacia lentiscus Oleoresin: Virtual Screening and Identification of Masticadienonic and Isomasticadienonic Acids as Inhibitors of 11β-Hydroxysteroid Dehydrogenase 1.

    PubMed

    Vuorinen, Anna; Seibert, Julia; Papageorgiou, Vassilios P; Rollinger, Judith M; Odermatt, Alex; Schuster, Daniela; Assimopoulou, Andreana N

    2015-04-01

    In traditional medicine, the oleoresinous gum of Pistacia lentiscus var. chia, so-called mastic gum, has been used to treat multiple conditions such as coughs, sore throats, eczema, dyslipidemia, and diabetes. Mastic gum is rich in triterpenes, which have been postulated to exert antidiabetic effects and improve lipid metabolism. In fact, there is evidence of oleanonic acid, a constituent of mastic gum, acting as a peroxisome proliferator-activated receptor γ agonist, and mastic gum being antidiabetic in mice in vivo. Despite these findings, the exact antidiabetic mechanism of mastic gum remains unknown. Glucocorticoids play a key role in regulating glucose and fatty acid metabolism, and inhibition of 11β-hydroxysteroid dehydrogenase 1 that converts inactive cortisone to active cortisol has been proposed as a promising approach to combat metabolic disturbances including diabetes. In this study, a pharmacophore-based virtual screening was applied to filter a natural product database for possible 11β-hydroxysteroid dehydrogenase 1 inhibitors. The hit list analysis was especially focused on the triterpenoids present in Pistacia species. Multiple triterpenoids, such as masticadienonic acid and isomasticadienonic acid, main constituents of mastic gum, were identified. Indeed, masticadienonic acid and isomasticadienonic acid selectively inhibited 11β-hydroxysteroid dehydrogenase 1 over 11β-hydroxysteroid dehydrogenase 2 at low micromolar concentrations. These findings suggest that inhibition of 11β-hydroxysteroid dehydrogenase 1 contributes to the antidiabetic activity of mastic gum.

  10. Aldehyde-induced xanthine oxidase activity in raw milk.

    PubMed

    Steffensen, Charlotte L; Andersen, Henrik J; Nielsen, Jacob H

    2002-12-04

    In the present study, the aldehyde-induced pro-oxidative activity of xanthine oxidase was followed in an accelerated raw milk system using spin-trap electron spin resonance (ESR) spectroscopy. The aldehydes acetaldehyde, propanal, hexanal, trans-2-hexenal, trans-2-heptenal, trans-2-nonenal, and 3-methyl-2-butenal were all found to initiate radical reactions when added to milk. Formation of superoxide through aldehyde-induced xanthine oxidase activity is suggested as the initial reaction, as all tested aldehydes were shown to trigger superoxide formation in an ultrahigh temperature (UHT) milk model system with added xanthine oxidase. It was found that addition of aldehydes to milk initially increased the ascorbyl radical concentration with a subsequent decay due to ascorbate depletion, which renders the formation of superoxide in milk with added aldehyde. The present study shows for the first time potential acceleration of oxidative events in milk through aldehyde-induced xanthine oxidase activity.

  11. Anatomical location differences between mutated and wild-type isocitrate dehydrogenase 1 in low-grade gliomas.

    PubMed

    Yu, Jinhua; Shi, Zhifeng; Ji, Chunhong; Lian, Yuxi; Wang, Yuanyuan; Chen, Liang; Mao, Ying

    2017-01-06

    Anatomical location of gliomas has been considered as a factor implicating the contributions of a specific precursor cells during the tumor growth. Isocitrate dehydrogenase 1 (IDH1) is a pathognomonic biomarker with a significant impact on the development of gliomas and remarkable prognostic effect. The correlation between anatomical location of tumor and IDH1 states for low-grade gliomas was analyzed quantitatively in this study. Ninety-two patients diagnosed of low-grade glioma pathologically were recruited in this study, including 65 patients with IDH1-mutated glioma and 27 patients with wide-type IDH1. A convolutional neural network was designed to segment the tumor from three-dimensional magnetic resonance imaging images. Voxel-based lesion symptom mapping was then employed to study the tumor location distribution differences between gliomas with mutated and wild-type IDH1. In order to characterize the location differences quantitatively, the Automated Anatomical Labeling Atlas was used to partition the standard brain atlas into 116 anatomical volumes of interests (AVOIs). The percentages of tumors with different IDH1 states in 116 AVOIs were calculated and compared. Support vector machine and AdaBoost algorithms were used to estimate the IDH1 status based on the 116 location features of each patient. Experimental results proved that the quantitative tumor location measurement could be a very important group of imaging features in biomarker estimation based on radiomics analysis of glioma.

  12. Identification of a novel inactivating mutation in Isocitrate Dehydrogenase 1 (IDH1-R314C) in a high grade astrocytoma

    PubMed Central

    van Lith, Sanne A. M.; Navis, Anna C.; Lenting, Krissie; Verrijp, Kiek; Schepens, Jan T. G.; Hendriks, Wiljan J. A. J.; Schubert, Nil A.; Venselaar, Hanka; Wevers, Ron A.; van Rooij, Arno; Wesseling, Pieter; Molenaar, Remco J.; van Noorden, Cornelis J. F.; Pusch, Stefan; Tops, Bastiaan; Leenders, William P. J.

    2016-01-01

    The majority of low-grade and secondary high-grade gliomas carry heterozygous hotspot mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) or the mitochondrial variant IDH2. These mutations mostly involve Arg132 in IDH1, and Arg172 or Arg140 in IDH2. Whereas IDHs convert isocitrate to alpha-ketoglutarate (α-KG) with simultaneous reduction of NADP+ to NADPH, these IDH mutants reduce α-KG to D-2-hydroxyglutarate (D-2-HG) while oxidizing NADPH. D-2-HG is a proposed oncometabolite, acting via competitive inhibition of α-KG-dependent enzymes that are involved in metabolism and epigenetic regulation. However, much less is known about the implications of the metabolic stress, imposed by decreased α-KG and NADPH production, for tumor biology. We here present a novel heterozygous IDH1 mutation, IDH1R314C, which was identified by targeted next generation sequencing of a high grade glioma from which a mouse xenograft model and a cell line were generated. IDH1R314C lacks isocitrate-to-α-KG conversion activity due to reduced affinity for NADP+, and differs from the IDH1R132 mutants in that it does not produce D-2-HG. Because IDH1R314C is defective in producing α-KG and NADPH, without concomitant production of the D-2-HG, it represents a valuable tool to study the effects of IDH1-dysfunction on cellular metabolism in the absence of this oncometabolite. PMID:27460417

  13. Individual variation in hepatic aldehyde oxidase activity.

    PubMed

    Al-Salmy, H S

    2001-04-01

    Aldehyde oxidase (AO) is a molybdo-flavo enzyme expressed predominantly in the liver, lung, and kidney. AO plays a major role in oxidation of aldehydes, as well as oxidation of various N-heterocyclic compounds of pharmacological and toxicological importance including antiviral (famciclovir), antimalarial (quinine), antitumour (methotrexate), and nicotine. The aim of this study was to investigate cytosolic aldehyde oxidase activity in human liver. Cytosolic AO was characterised using both the metabolism of N-[(2-dimethylamino)ethyl] acridine-4-carboxamide (DACA) and benzaldehyde to form DACA-9(10H)-acridone (quantified by HPLC with fluorescence detection) and benzoic acid (quantified spectrophotometrically). Thirteen livers (10 female, 3 male) were examined. The intrinsic clearance (Vmax/Km) of DACA varied 18-fold (0.03-0.50 m/min/mg). Vmax ranged from 0.20-3.10 nmol/ min/mg, and Km ranged from 3.5-14.2 microM. In the same specimens, the intrinsic clearance for benzaldehyde varied 5-fold (0.40-1.8 ml/min/mg). Vmax ranged from 3.60-12.6 nmol/min/mg and Km ranged from 3.6-14.6 microM. Furthermore, there were no differences in AO activity between male and female human livers, nor was there any relationship to age of donor (range 29-73 years), smoking status, or disease status. In conclusion, our results showed that there are variations in AO activity in human liver. These variations in aldehyde oxidase activity might reflect individual variations or they might be due to AO stability during processing and storage.

  14. Retinol status and expression of retinol-related proteins in methionine-choline deficient rats.

    PubMed

    Miyazaki, Hiroshi; Takitani, Kimitaka; Koh, Maki; Inoue, Akiko; Kishi, Kanta; Tamai, Hiroshi

    2014-01-01

    Retinol and its derivative, retinoic acid, have pleiotropic functions including vision, immunity, hematopoiesis, reproduction, cell differentiation/growth, and development. Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases in developed countries and encompasses a broad spectrum of forms, ranging from steatosis to steatohepatitis, which develops further to cirrhosis. Retinol status has an important role in liver homeostasis. The purpose of this study was to evaluate the retinol status and expression of retinol-related proteins, including enzymes and binding proteins, in methionine-choline deficient (MCD) rats as a model of NAFLD. We examined retinol levels in the plasma and liver and gene expression for β-carotene 15,15'-monooxygenase (BCMO), lecithIn: retinol acyltransferase (LRAT), aldehyde dehydrogenase 1A1 (ALDH1A1), ALDH1A2, and cellular retinol binding protein (CRBP)-I in MCD rats. The plasma retinol levels in MCD rats were lower than those in the controls, whereas hepatic retinol levels in MCD rats were higher. BCMO expression in the intestine and liver in MCD rats was lower, whereas that in the testes and the kidneys was higher than in control rats. Expression of LRAT, CRBP-I, ALDH1A1, and ALDH1A2 in the liver of MCD rats was also higher. Altered expression of retinol-related proteins may affect retinol status in NAFLD.

  15. The role of glycerol-3-phosphate dehydrogenase 1 in the progression of fatty liver after acute ethanol administration in mice.

    PubMed

    Sato, Tomoki; Morita, Akihito; Mori, Nobuko; Miura, Shinji

    2014-02-21

    Acute ethanol consumption leads to the accumulation of triglycerides (TGs) in hepatocytes. The increase in lipogenesis and reduction of fatty acid oxidation are implicated as the mechanisms underlying ethanol-induced hepatic TG accumulation. Although glycerol-3-phosphate (Gro3P), formed by glycerol kinase (GYK) or glycerol-3-phosphate dehydrogenase 1 (GPD1), is also required for TG synthesis, the roles of GYK and GPD1 have been the subject of some debate. In this study, we examine (1) the expression of genes involved in Gro3P production in the liver of C57BL/6J mice in the context of hepatic TG accumulation after acute ethanol intake, and (2) the role of GPD1 in the progression of ethanol-induced fatty liver using GPD1 null mice. As a result, in C57BL/6J mice, ethanol-induced hepatic TG accumulation began within 2h and was 1.7-fold greater than that observed in the control group after 6h. The up-regulation of GPD1 began 2h after administering ethanol, and significantly increased 6h later with the concomitant escalation in the glycolytic gene expression. The incorporation of (14)C-labelled glucose into TG glycerol moieties increased during the same period. On the other hand, in GPD1 null mice carrying normal GYK activity, no significant increase in hepatic TG level was observed after acute ethanol intake. In conclusion, GPD1 and glycolytic gene expression is up-regulated by ethanol, and GPD1-mediated incorporation of glucose into TG glycerol moieties together with increased lipogenesis, is suggested to play an important role in ethanol-induced hepatic TG accumulation.

  16. Leflunomide induces NAD(P)H quinone dehydrogenase 1 enzyme via the aryl hydrocarbon receptor in neonatal mice.

    PubMed

    Shrestha, Amrit Kumar; Patel, Ananddeep; Menon, Renuka T; Jiang, Weiwu; Wang, Lihua; Moorthy, Bhagavatula; Shivanna, Binoy

    2017-03-25

    Aryl hydrocarbon receptor (AhR) has been increasingly recognized to play a crucial role in normal physiological homeostasis. Additionally, disrupted AhR signaling leads to several pathological states in the lung and liver. AhR activation transcriptionally induces detoxifying enzymes such as cytochrome P450 (CYP) 1A and NAD(P)H quinone dehydrogenase 1 (NQO1). The toxicity profiles of the classical AhR ligands such as 3-methylcholanthrene and dioxins limit their use as a therapeutic agent in humans. Hence, there is a need to identify nontoxic AhR ligands to develop AhR as a clinically relevant druggable target. Recently, we demonstrated that leflunomide, a FDA approved drug, used to treat rheumatoid arthritis in humans, induces CYP1A enzymes in adult mice via the AhR. However, the mechanisms by which this drug induces NQO1 in vivo are unknown. Therefore, we tested the hypothesis that leflunomide will induce pulmonary and hepatic NQO1 enzyme in neonatal mice via AhR-dependent mechanism(s). Leflunomide elicited significant induction of pulmonary CYP1A1 and NQO1 expression in neonatal mice. Interestingly, the dose at which leflunomide increased NQO1 was significantly higher than that required to induce CYP1A1 enzyme. Likewise, it also enhanced hepatic CYP1A1, 1A2 and NQO1 expression in WT mice. In contrast, leflunomide failed to induce these enzymes in AhR-null mice. Our results indicate that leflunomide induces pulmonary and hepatic CYP1A and NQO1 enzymes via the AhR in neonatal mice. These findings have important implications to prevent and/or treat disorders such as bronchopulmonary dysplasia in human infants where AhR may play a crucial role in the disease pathogenesis.

  17. Aldehyde Oxidase 4 Plays a Critical Role in Delaying Silique Senescence by Catalyzing Aldehyde Detoxification1[OPEN

    PubMed Central

    Yarmolinsky, Dmitry; Soltabayeva, Aigerim; Samani, Talya

    2017-01-01

    The Arabidopsis (Arabidopsis thaliana) aldehyde oxidases are a multigene family of four oxidases (AAO1–AAO4) that oxidize a variety of aldehydes, among them abscisic aldehyde, which is oxidized to the phytohormone abscisic acid. Toxic aldehydes are generated in plants both under normal conditions and in response to stress. The detoxification of such aldehydes by oxidation is attributed to aldehyde dehydrogenases but never to aldehyde oxidases. The feasibility of the detoxification of aldehydes in siliques via oxidation by AAO4 was demonstrated, first, by its ability to efficiently oxidize an array of aromatic and aliphatic aldehydes, including the reactive carbonyl species (RCS) acrolein, hydroxyl-2-nonenal, and malondialdehyde. Next, exogenous application of several aldehydes to siliques in AAO4 knockout (KO) Arabidopsis plants induced severe tissue damage and enhanced malondialdehyde levels and senescence symptoms, but not in wild-type siliques. Furthermore, abiotic stresses such as dark and ultraviolet C irradiation caused an increase in endogenous RCS and higher expression levels of senescence marker genes, leading to premature senescence of KO siliques, whereas RCS and senescence marker levels in wild-type siliques were hardly affected. Finally, in naturally senesced KO siliques, higher endogenous RCS levels were associated with enhanced senescence molecular markers, chlorophyll degradation, and earlier seed shattering compared with the wild type. The aldehyde-dependent differential generation of superoxide and hydrogen peroxide by AAO4 and the induction of AAO4 expression by hydrogen peroxide shown here suggest a self-amplification mechanism for detoxifying additional reactive aldehydes produced during stress. Taken together, our results indicate that AAO4 plays a critical role in delaying senescence in siliques by catalyzing aldehyde detoxification. PMID:28188272

  18. 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.

  19. The role of glycerol-3-phosphate dehydrogenase 1 in the progression of fatty liver after acute ethanol administration in mice

    SciTech Connect

    Sato, Tomoki; Morita, Akihito; Mori, Nobuko; Miura, Shinji

    2014-02-21

    Highlights: • Ethanol administration increased GPD1 mRNA expression. • Ethanol administration increased glucose incorporation into TG glycerol moieties. • No increase in hepatic TG levels was observed in ethanol-injected GPD1 null mice. • We propose that GPD1 is required for ethanol-induced TG accumulation in the liver. - Abstract: Acute ethanol consumption leads to the accumulation of triglycerides (TGs) in hepatocytes. The increase in lipogenesis and reduction of fatty acid oxidation are implicated as the mechanisms underlying ethanol-induced hepatic TG accumulation. Although glycerol-3-phosphate (Gro3P), formed by glycerol kinase (GYK) or glycerol-3-phosphate dehydrogenase 1 (GPD1), is also required for TG synthesis, the roles of GYK and GPD1 have been the subject of some debate. In this study, we examine (1) the expression of genes involved in Gro3P production in the liver of C57BL/6J mice in the context of hepatic TG accumulation after acute ethanol intake, and (2) the role of GPD1 in the progression of ethanol-induced fatty liver using GPD1 null mice. As a result, in C57BL/6J mice, ethanol-induced hepatic TG accumulation began within 2 h and was 1.7-fold greater than that observed in the control group after 6 h. The up-regulation of GPD1 began 2 h after administering ethanol, and significantly increased 6 h later with the concomitant escalation in the glycolytic gene expression. The incorporation of {sup 14}C-labelled glucose into TG glycerol moieties increased during the same period. On the other hand, in GPD1 null mice carrying normal GYK activity, no significant increase in hepatic TG level was observed after acute ethanol intake. In conclusion, GPD1 and glycolytic gene expression is up-regulated by ethanol, and GPD1-mediated incorporation of glucose into TG glycerol moieties together with increased lipogenesis, is suggested to play an important role in ethanol-induced hepatic TG accumulation.

  20. 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

  1. Relationships within the aldehyde dehydrogenase extended family.

    PubMed Central

    Perozich, J.; Nicholas, H.; Wang, B. C.; Lindahl, R.; Hempel, J.

    1999-01-01

    One hundred-forty-five full-length aldehyde dehydrogenase-related sequences were aligned to determine relationships within the aldehyde dehydrogenase (ALDH) extended family. The alignment reveals only four invariant residues: two glycines, a phenylalanine involved in NAD binding, and a glutamic acid that coordinates the nicotinamide ribose in certain E-NAD binary complex crystal structures, but which may also serve as a general base for the catalytic reaction. The cysteine that provides the catalytic thiol and its closest neighbor in space, an asparagine residue, are conserved in all ALDHs with demonstrated dehydrogenase activity. Sixteen residues are conserved in at least 95% of the sequences; 12 of these cluster into seven sequence motifs conserved in almost all ALDHs. These motifs cluster around the active site of the enzyme. Phylogenetic analysis of these ALDHs indicates at least 13 ALDH families, most of which have previously been identified but not grouped separately by alignment. ALDHs cluster into two main trunks of the phylogenetic tree. The largest, the "Class 3" trunk, contains mostly substrate-specific ALDH families, as well as the class 3 ALDH family itself. The other trunk, the "Class 1/2" trunk, contains mostly variable substrate ALDH families, including the class 1 and 2 ALDH families. Divergence of the substrate-specific ALDHs occurred earlier than the division between ALDHs with broad substrate specificities. A site on the World Wide Web has also been devoted to this alignment project. PMID:10210192

  2. OLFACTORY RESPONSES OF BLOWFLIES TO ALIPHATIC ALDEHYDES

    PubMed Central

    Dethier, V. G.

    1954-01-01

    The response of the blowfly Phormia regina to stimulation by aldehydes in the vapor phase has been studied by means of a specially designed olfactometer. The median rejection threshold and the maximum acceptance threshold were selected as criteria of response. For both acceptance and rejection the distribution of thresholds in the population is normal with respect to the logarithm of concentration. When thresholds are expressed as molar concentrations, the values decrease progressively as chain length is increased. There is no attraction beyond decanal and no rejection beyond dodecanal. When thresholds are expressed as activities, most members of the aldehyde series are approximately equally stimulating at rejection and equally stimulating at acceptance. The relationship is most exact over the middle range of chain lengths. There is a tendency for the terminal members to stimulate at higher activities. These relationships are in close agreement with those which were found earlier to apply to the normal aliphatic alcohols. The similarity between the relative actions of the members of the two series suggests that the relation of equal olfactory stimulation at equal thermodynamic activities by homologous aliphatic compounds at least for homologues of intermediate chain length may be of rather general application in olfaction. PMID:13174780

  3. Molecular Mechanisms of Aldehyde Toxicity: A Chemical Perspective

    PubMed Central

    2015-01-01

    Aldehydes are electrophilic compounds to which humans are pervasively exposed. Despite a significant health risk due to exposure, the mechanisms of aldehyde toxicity are poorly understood. This ambiguity is likely due to the structural diversity of aldehyde derivatives and corresponding differences in chemical reactions and biological targets. To gain mechanistic insight, we have used parameters based on the hard and soft, acids and bases (HSAB) theory to profile the different aldehyde subclasses with respect to electronic character (softness, hardness), electrophilic reactivity (electrophilic index), and biological nucleophilic targets. Our analyses indicate that short chain aldehydes and longer chain saturated alkanals are hard electrophiles that cause toxicity by forming adducts with hard biological nucleophiles, e.g., primary nitrogen groups on lysine residues. In contrast, α,β-unsaturated carbonyl derivatives, alkenals, and the α-oxoaldehydes are soft electrophiles that preferentially react with soft nucleophilic thiolate groups on cysteine residues. The aldehydes can therefore be grouped into subclasses according to common electronic characteristics (softness/hardness) and molecular mechanisms of toxicity. As we will discuss, the toxic potencies of these subgroups are generally related to corresponding electrophilicities. For some aldehydes, however, predictions of toxicity based on electrophilicity are less accurate due to inherent physicochemical variables that limit target accessibility, e.g., steric hindrance and solubility. The unsaturated aldehydes are also members of the conjugated type-2 alkene chemical class that includes α,β-unsaturated amide, ketone, and ester derivatives. Type-2 alkenes are electrophiles of varying softness and electrophilicity that share a common mechanism of toxicity. Therefore, exposure to an environmental mixture of unsaturated carbonyl derivatives could cause “type-2 alkene toxicity” through additive interactions

  4. Aldose Reductase-catalyzed Reduction of Aldehyde Phospholipids

    PubMed Central

    Srivastava, Sanjay; Spite, Matthew; Trent, John O.; West, Matthew B.; Ahmed, Yonis; Bhatnagar, Aruni

    2012-01-01

    SUMMARY Oxidation of unsaturated phospholipids results in the generation of aldehyde side chains that remain esterified to the phospholipid backbone. Such “core” aldehydes elicit immune responses and promote inflammation. However, the biochemical mechanisms by which phospholipid aldehydes are metabolized or detoxified are not well understood. In the studies reported here, we examined whether aldose reductase (AR), which reduces hydrophobic aldehydes, metabolizes phospholipid aldehydes. Incubation with AR led to the reduction of 5-oxovaleroyl, 7-oxo-5-heptenoyl, 5-hydroxy-6-oxo-caproyl, and 5-hydroxy-8-oxo-6-octenoyl phospholipids generated upon oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC). The enzyme also catalyzed the reduction of phospholipid aldehydes generated from the oxidation of 1-alkyl, and 1-alkenyl analogs of PAPC, and 1-palmitoyl-2-arachidonoyl phosphatidic acid or phosphoglycerol. Aldose reductase catalyzed the reduction of chemically synthesized 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphatidylcholine (POVPC) with a Km of 10 μM. Addition of POVPC to the culture medium led to incorporation and reduction of the aldehyde in COS-7 and THP-1 cells. Reduction of POVPC in these cells was prevented by the AR inhibitors sorbinil and tolrestat and was increased in COS-7 cells overexpressing AR. Together, these observations suggest that AR may be a significant participant in the metabolism of several structurally diverse phospholipid aldehydes. This metabolism may be a critical regulator of the pro-inflammatory and immunogenic effects of oxidized phospholipids. PMID:15465833

  5. The epimerization of peptide aldehydes--a systematic study.

    PubMed

    Ganneau, Cécile; Moulin, Aline; Demange, Luc; Martinez, Jean; Fehrentz, Jean-Alain

    2006-07-01

    Peptide aldehydes are interesting targets as enzyme inhibitors, and can be used for pseudopeptide chemistry or ligation. However, they are known to be subjected to epimerization during synthesis or purification. By (1)H NMR, a model dipeptide aldehyde can be used to check the possible epimerization occurring during synthesis. Various purification methods were investigated, but none was free from epimerization.

  6. 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...

  7. 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.

  8. Characterization of five fatty aldehyde dehydrogenase enzymes from Marinobacter and Acinetobacter: structural insights into the aldehyde binding pocket.

    PubMed

    Bertram, Jonathan H; Mulliner, Kalene M; Shi, Ke; Plunkett, Mary H; Nixon, Peter; Serratore, Nicholas A; Douglas, Christopher J; Aihara, Hideki; Barney, Brett M

    2017-04-07

    Enzymes involved in lipid biosynthesis and metabolism play an important role in energy conversion and storage, and in the function of structural components such as cell membranes. The fatty aldehyde dehydrogenase (FAldDH) plays a central function in the metabolism of lipid intermediates, oxidizing fatty aldehydes to the corresponding fatty acid, and competing with pathways that would further reduce the fatty aldehydes to fatty alcohols or require the fatty aldehydes to produce alkanes. In this report, the genes for four putative FAldDH enzymes from Marinobacter aquaeolei VT8 and an additional enzyme from Acinetobacter baylyi were heterologously expressed in Escherichia coli and shown to display FAldDH activity. Five enzymes (Maqu_0438, Maqu_3316, Maqu_3410, Maqu_3572 and WP_004927398) were found to act on aldehydes ranging from acetaldehyde to hexadecanal, and also acted on the unsaturated long-chain palmitoleyl and oleyl aldehydes. A comparison of the specificity of these enzymes with various aldehydes is presented. Crystallization trials yielded diffraction quality crystals of one particular FAldDH (Maqu_3316) from M. aquaeolei VT8. Crystals were independently treated with both the NAD(+) cofactor and the aldehyde substrate decanal, revealing specific details of the likely substrate binding pocket for this class of enzymes. A likely model for how the catalysis by the enzyme is accomplished is also provided.Importance: This study provides a comparison of multiple enzymes with the ability to oxidize fatty aldehydes to fatty acids, and provides a likely picture of how the fatty aldehyde and NAD(+) is bound to the enzyme to facilitate catalysis. Based on the information obtained from this structural analysis and the comparisons of specificity for the five enzymes that were characterized, correlations may be drawn to the potential roles played by specific residues within the structure.

  9. Stem cell marker-positive stellate cells and mast cells are reduced in benign-appearing bladder tissue in patients with urothelial carcinoma.

    PubMed

    Isfoss, Björn L; Busch, Christer; Hermelin, Helena; Vermedal, Anette T; Kile, Marianne; Braathen, Geir J; Majak, Bernard; Berner, Aasmund

    2014-04-01

    Survival after invasive bladder cancer has improved less than that of other common non-skin cancers. In many types of malignancy, treatment failure has been attributed to therapy-resistant stem-like cancer cells. Our aim was therefore to determine identities of stem cell marker-positive cells in bladder cancer tissue and to investigate possible associations between these cells and different forms of bladder neoplasia. We investigated tissue from 52 patients with bladder neoplasia and 18 patients with benign bladder conditions, from a cohort that had been previously described with regard to diagnosis and outcome. The samples were analysed immunohistologically for the stem cell markers aldehyde dehydrogenase 1 A1 (ALDH1) and CD44, and markers of cell differentiation. The majority of stem cell marker-positive cells were located in connective tissue, and a smaller fraction in epithelial tissue. Stem cell marker-positive cells exhibiting possible stem cell characteristics included cells in deeper locations of benign and malignant epithelium, and sub-endothelial cells in patients with or without neoplasia. Stem cell marker-positive cells with non-stem cell character included stellate cells, mast cells, endothelial cells, foamy histiocytes, and neurons. Significantly, ALDH1+ stellate cells and ALDH1+ mast cells were reduced in number in stroma of benign-appearing mucosa of bladder cancer patients. The stem cell markers ALDH1 and CD44 label several types of differentiated cells in bladder tissue. ALDH1+ stellate cells and mast cells appear to be reduced in stroma of normal-appearing mucosa of bladder cancer patients, and may be part of a "field effect" in cancer-near areas.

  10. Human liver aldehyde dehydrogenase: coenzyme binding

    SciTech Connect

    Kosley, L.L.; Pietruszko, R.

    1987-05-01

    The binding of (U-/sup 14/C) NAD to mitochondrial (E2) and cytoplasmin(E1) aldehyde dehydrogenase was measured by gel filtration and sedimentation techniques. The binding data for NAD and (E1) yielded linear Scatchard plots giving a dissociation constant of 25 (+/- 8) uM and the stoichiometry of 2 mol of NAD bound per mol of E1. The binding data for NAD and (E2) gave nonlinear Scatchard plots. The binding of NADH to E2 was measured via fluorescence enhancement; this could not be done with E1 because there was no signal. The dissociation constant for E2 by this technique was 0.7 (+/- 0.4) uM and stoichiometry of 1.0 was obtained. The binding of (U-/sup 14/C) NADH to (E1) and (E2) was also measured by the sedimentation technique. The binding data for (E1) and NADH gave linear Scatchard plots giving a dissociation constant of 13 (+/- 6) uM and the stoichiometry of 2.0. The binding data for NADH to (E2) gave nonlinear Scatchard plots. With (E1), the dissociation constants for both NAD and NADH are similar to those determined kinetically, but the stoichiometry is only half of that found by stopped flow technique. With (E2) the dissociation constant by fluorometric procedure was 2 orders of magnitude less than that from catalytic reaction.

  11. Molecular Structure and Reactivity in the Pyrolysis of Aldehydes

    NASA Astrophysics Data System (ADS)

    Sias, Eric; Cole, Sarah; Sowards, John; Warner, Brian; Wright, Emily; McCunn, Laura R.

    2016-06-01

    The effect of alkyl chain structure on pyrolysis mechanisms has been investigated in a series of aldehydes. Isovaleraldehyde, CH_3CH(CH_3)CH_2CHO, and pivaldehyde, (CH_3)_3CCHO, were subject to thermal decomposition in a resistively heated SiC tubular reactor at 800-1200 °C. Matrix-isolation FTIR spectroscopy was used to identify pyrolysis products. Carbon monoxide and isobutene were major products from each of the aldehydes, which is consistent with what is known from previous studies of unbranched alkyl-chain aldehydes. Other products observed include vinyl alcohol, propene, acetylene, and ethylene, revealing complexities to be considered in the pyrolysis of large, branched-chain aldehydes.

  12. A kinetic estimate of the free aldehyde content of aldoses

    NASA Technical Reports Server (NTRS)

    Dworkin, J. P.; Miller, S. L.; Bada, J. L. (Principal Investigator)

    2000-01-01

    The relative free aldehyde content of eight hexoses and four pentoses has been estimated within about 10% from the rate constants for their reaction with urazole (1,2,4-triazole-3,5-dione). These values of the percent free aldehyde are in agreement with those estimated from CD measurements, but are more accurate. The relative free aldehyde contents for the aldoses were then correlated to various literature NMR measurements to obtain the absolute values. This procedure was also done for three deoxyaldoses, which react much more rapidly than can be accounted for by the free aldehyde content. This difference in reactivity between aldoses and deoxyaldoses is due to the inductive effect of the H versus the OH on C-2'. This may help explain why deoxyribonucleosides hydrolyze much more rapidly than ribonucleosides.

  13. Silver-catalyzed synthesis of amides from amines and aldehydes

    DOEpatents

    Madix, Robert J; Zhou, Ling; Xu, Bingjun; Friend, Cynthia M; Freyschlag, Cassandra G

    2014-11-18

    The invention provides a method for producing amides via the reaction of aldehydes and amines with oxygen adsorbed on a metallic silver or silver alloy catalyst. An exemplary reaction is shown in Scheme 1: (I), (II), (III). ##STR00001##

  14. Novel Aldehyde-Terminated Dendrimers; Synthesis and Cytotoxicity Assay

    PubMed Central

    Hamidi, Aliasghar; Sharifi, Simin; Davaran, Soodabeh; Ghasemi, Saeed; Omidi, Yadollah; Rashidi, Mohammad-Reza

    2012-01-01

    Introduction Polyamidoamine (PAMAM) dendrimers are a unique family of dendritic polymers with numerous pharmaceutical and biomedical applications. One major problem with these polymers is their cytotoxicity. The purpose of this study was to synthesize novel dendrimers with aldehyde terminal groups and compare their cytotoxicity with that of dendri¬mers containing amine-terminated groups. Methods G1(first generation) and G2 (second generation) dendrimers with amine-terminated groups were synthesized by divergent method and then the amine-terminated groups were converted to the aldehyde groups using surface modification of the functional group inversion (FGI) method. The cytotoxicity of the novel G1 and G2 polyamidoaldehyde (PAMAL) dendrimers together with that of G1 and G2 PAMAM-NH2 dendrimers was investigated by MTT assay using MCF-7 cell line. Results The results showed that cytotoxicity of dendrimers with aldehyde-terminated groups is much lower than that of G1 and G2 PAMAM-NH2 dendri¬mers. Conclusion Dendrimers with aldehyde-terminated groups could be used as novel and convenient carriers for drug delivery with low cytotoxic effect compared with the amine-terminated dendrimers. The results revealed that the same generations of the dendri¬mers with aldehyde-terminated groups are far less toxic than the corresponding amine-terminated dendrimers. PMID:23678447

  15. Polyvinyl alcohol cross-linked with two aldehydes

    NASA Technical Reports Server (NTRS)

    Sheibley, D. W.; Rieker, L. L.; Hsu, L. C.; Manzo, M. A. (Inventor)

    1982-01-01

    A film forming polyvinyl alcohol resin is admixed, in aqueous solution, with a dialdehyde crosslinking agent which is capable of crosslinking the polyvinyl alcohol resin and a water soluble acid aldehyde containing a reactive aldehyde group capable of reacting with hydroxyl groups in the polyvinyl alcohol resin and an ionizable acid hydrogen atom. The dialdehyde is present in an amount sufficient to react with from 1 to 20% by weight of the theoretical amount required to react with all of the hydroxyl groups of the polyvinyl alcohol. The amount of acid aldehyde is from 1 to 50% by weight, same basis, and is sufficient to reduce the pH of the aqueous admixture to 5 or less. The admixture is then formed into a desired physical shape, such as by casting a sheet or film, and the shaped material is then heated to simultaneously dry and crosslink the article.

  16. Preparation of 1-C-glycosyl aldehydes by reductive hydrolysis.

    PubMed

    Sipos, Szabolcs; Jablonkai, István

    2011-09-06

    Reductive hydrolysis of various protected glycosyl cyanides was carried out using DIBAL-H to form aldimine alane intermediates which were then hydrolyzed under mildly acidic condition to provide the corresponding aldehyde derivatives. While 1-C-formyl glycal and 2-deoxy glycosyl derivatives were stable during isolation and storage 1-C-glycosyl formaldehydes in the gluco, galacto and manno series were sensitive and decomposition occurred by 2-alkyloxy elimination. A one-pot method using N,N'-diphenylethylenediamine to trap these aldehydes in stable form was developed. Reductive hydrolysis of glycosyl cyanides offers valuable aldehyde building blocks in a convenient way which can be applied in the synthesis of complex C-glycosides.

  17. Synthesis of biotinylated aldehyde polymers for biomolecule conjugation.

    PubMed

    Alconcel, Steevens N S; Kim, Sung Hye; Tao, Lei; Maynard, Heather D

    2013-06-25

    Biotinylated polymers with side-chain aldehydes were prepared for use as multifunctional scaffolds. Two different biotin-containing chain transfer agents (CTAs) and an aldehyde-containing monomer, 6-oxohexyl acrylate (6OHA), are synthesized. Poly(ethylene glycol) methyl ether acrylate (PEGA) and 6OHA are copolymerized by reversible addition-fragmentation chain transfer (RAFT) polymerization in the presence of the biotinylated CTAs. The resulting polymers are analyzed by GPC and(1) H NMR spectroscopy. The polymer end groups contained a disulfide bond, which could be readily reduced in solution to remove the biotin. Reactivity of the aldehyde side chains is demonstrated by oxime and hydrazone formation at the polymer side chains, and conjugate formation of fluorescently labeled polymers with streptavidin is investigated by gel electrophoresis.

  18. Direct β-Alkylation of Aldehydes via Photoredox Organocatalysis

    PubMed Central

    2015-01-01

    Direct β-alkylation of saturated aldehydes has been accomplished by synergistically combining photoredox catalysis and organocatalysis. Photon-induced enamine oxidation provides an activated β-enaminyl radical intermediate, which readily combines with a wide range of Michael acceptors to produce β-alkyl aldehydes in a highly efficient manner. Furthermore, this redox-neutral, atom-economical C–H functionalization protocol can be achieved both inter- and intramolecularly. Mechanistic studies by various spectroscopic methods suggest that a reductive quenching pathway is operable. PMID:24754456

  19. 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

  20. 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

  1. Triggering the approach of an arene or heteroarene towards an aldehyde via Lewis acid-aldehyde communication.

    PubMed

    Pratihar, Sanjay

    2016-03-14

    The present work reports a combined experimental/computational study of the Lewis acid promoted hydroxyalkylation reaction involving aldehyde and arene/heteroarene and reveals a mechanism in which the rate determining aldehyde to alcohol formation via a four-member cyclic transition state (TS) involves a transfer of hydrogen from arene/heteroarene C-H to aldehyde oxygen with the breaking of the C-H bond and formation of C-C and O-H bonds. The effect of different Sn(iv) derivatives on the hydroxyalkylation reaction from different in situ NMR and computational studies reveals that although the exergonic formation of the intermediate and its gained electrophilicity at the carbonyl carbon drive the reaction in SnCl4 compared to other Sn(iv) derivatives, the overall reaction is low yielding because of its stable intermediate. With respect to different aldehydes, LA promoted hydroxylation was found to be more feasible for an electron withdrawing aldehyde compared to electron rich aldehyde because of lower stability, enhanced electrophilicity gained at the aldehyde center, and a lower activation barrier between its intermediate and TS in the former as compared to the latter. The relative stability of the LA-aldehyde adduct decreases in the order SnCl4 > AlCl3 > InCl3 > BF3 > ZnCl2 > TiCl4 > SiCl4, while the activation barrier (ΔG(#)) between intermediate and transition states increases in the order AlCl3 < SnCl4 < InCl3 < BF3 < TiCl4 < ZnCl2 < SiCl4. On the other hand, the activation barriers in the case of different arenes/heteroarenes are in the order of indole < furan < anisole < thiophene < toluene < benzene < chlorobenzene < cyanobenzene, which suggests a facile reaction in the case of indole and the most difficult reaction in the case of cyanobenzene. The ease of formation of the corresponding diaryl methyl carbocation from the alcohol-LA intermediate is responsible for the determination of the undesired product and is found to be more viable in the case of strong

  2. Effects of aldehydes on the growth and lipid accumulation of oleaginous yeast Trichosporon fermentans.

    PubMed

    Huang, Chao; Wu, Hong; Liu, Qiu-ping; Li, Yuan-yuan; Zong, Min-hua

    2011-05-11

    The effects of five representative aldehydes in lignocellulosic hydrolysates on the growth and the lipid accumulation of oleaginous yeast Trichosporon fermentans were investigated for the first time. There was no relationship between the hydrophobicity and the toxicity of aldehyde, and 5-hydroxymethylfurfural was less toxic than aromatic aldehydes and furfural. Binary combination of aromatic aldehydes caused a synergistic inhibitory effect, but combination of furan and aromatic aldehydes reduced the inhibition instead. A longer lag phase was found due to the presence of aldehydes and the decrease of sugar consumption rate, but more xylose was utilized by T. fermentans in the presence of aldehydes, especially at their low concentrations. The variation of malic enzyme activity was not related to the delay of lipid accumulation. Furthermore, the inhibition of aldehydes on cell growth was more dependent on inoculum size, temperature, and initial pH than that on lipid content.

  3. A versatile and green mechanochemical route for aldehyde-oxime conversions.

    PubMed

    Aakeröy, Christer B; Sinha, Abhijeet S; Epa, Kanishka N; Spartz, Christine L; Desper, John

    2012-11-28

    A robust, facile and solvent-free mechanochemical path for aldehyde-oxime transformations using hydroxylamine and NaOH is explored; the method is suitable for aromatic and aliphatic aldehydes decorated with a range of substituents.

  4. Applicability of the theory of thermodynamic similarity to predict the enthalpies of vaporization of aliphatic aldehydes

    NASA Astrophysics Data System (ADS)

    Esina, Z. N.; Korchuganova, M. R.

    2015-06-01

    The theory of thermodynamic similarity is used to predict the enthalpies of vaporization of aliphatic aldehydes. The predicted data allow us to calculate the phase diagrams of liquid-vapor equilibrium in a binary water-aliphatic aldehyde system.

  5. 27 CFR 24.183 - Use of distillates containing aldehydes.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... the fermentation of wine and then returned to the distilled spirits plant from which distillates were... fermentation of wine made from a different kind of fruit. Distillates containing aldehydes which are received... AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS WINE Production of Wine § 24.183 Use...

  6. 27 CFR 24.183 - Use of distillates containing aldehydes.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... the fermentation of wine and then returned to the distilled spirits plant from which distillates were... fermentation of wine made from a different kind of fruit. Distillates containing aldehydes which are received... AND TRADE BUREAU, DEPARTMENT OF THE TREASURY ALCOHOL WINE Production of Wine § 24.183 Use...

  7. 27 CFR 24.183 - Use of distillates containing aldehydes.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... the fermentation of wine and then returned to the distilled spirits plant from which distillates were... fermentation of wine made from a different kind of fruit. Distillates containing aldehydes which are received... AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS WINE Production of Wine § 24.183 Use...

  8. 27 CFR 24.183 - Use of distillates containing aldehydes.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... the fermentation of wine and then returned to the distilled spirits plant from which distillates were... fermentation of wine made from a different kind of fruit. Distillates containing aldehydes which are received... AND TRADE BUREAU, DEPARTMENT OF THE TREASURY ALCOHOL WINE Production of Wine § 24.183 Use...

  9. 27 CFR 24.183 - Use of distillates containing aldehydes.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... the fermentation of wine and then returned to the distilled spirits plant from which distillates were... fermentation of wine made from a different kind of fruit. Distillates containing aldehydes which are received... AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS WINE Production of Wine § 24.183 Use...

  10. Interaction of aldehydes derived from lipid peroxidation and membrane proteins

    PubMed Central

    Pizzimenti, Stefania; Ciamporcero, Eric; Daga, Martina; Pettazzoni, Piergiorgio; Arcaro, Alessia; Cetrangolo, Gianpaolo; Minelli, Rosalba; Dianzani, Chiara; Lepore, Alessio; Gentile, Fabrizio; Barrera, Giuseppina

    2013-01-01

    A great variety of compounds are formed during lipid peroxidation of polyunsaturated fatty acids of membrane phospholipids. Among them, bioactive aldehydes, such as 4-hydroxyalkenals, malondialdehyde (MDA) and acrolein, have received particular attention since they have been considered as toxic messengers that can propagate and amplify oxidative injury. In the 4-hydroxyalkenal class, 4-hydroxy-2-nonenal (HNE) is the most intensively studied aldehyde, in relation not only to its toxic function, but also to its physiological role. Indeed, HNE can be found at low concentrations in human tissues and plasma and participates in the control of biological processes, such as signal transduction, cell proliferation, and differentiation. Moreover, at low doses, HNE exerts an anti-cancer effect, by inhibiting cell proliferation, angiogenesis, cell adhesion and by inducing differentiation and/or apoptosis in various tumor cell lines. It is very likely that a substantial fraction of the effects observed in cellular responses, induced by HNE and related aldehydes, be mediated by their interaction with proteins, resulting in the formation of covalent adducts or in the modulation of their expression and/or activity. In this review we focus on membrane proteins affected by lipid peroxidation-derived aldehydes, under physiological and pathological conditions. PMID:24027536

  11. Reaction of benzoxasilocines with aromatic aldehydes: Synthesis of homopterocarpans

    PubMed Central

    Álvarez-Corral, Míriam; López-Sánchez, Cristóbal; Jiménez-González, Leticia; Rosales, Antonio; Muñoz-Dorado, Manuel; Rodríguez-García, Ignacio

    2007-01-01

    Condensation of 2H-benzo[g][1,2]oxasilocines with aromatic aldehydes in the presence of boron trifluoride affords mixtures of cis/trans 2-phenyl-3-vinylchromans with moderate yields. These can be transformed into homopterocarpans, a synthetic group of substances homologous to the natural isoflavonoid pterocarpans. PMID:17288601

  12. Aldehyde dehydrogenase activity in Lactococcus chungangensis: Application in cream cheese to reduce aldehyde in alcohol metabolism.

    PubMed

    Konkit, Maytiya; Choi, Woo Jin; Kim, Wonyong

    2016-03-01

    Previous studies have shown that the metabolic capability of colonic microflora may be at least as high as that of the liver or higher than that of the whole human body. Aldehyde dehydrogenase (ALDH) is an enzyme produced by these bacteria that can metabolize acetaldehyde, produce from ethanol to acetate. Lactococcus species, which is commonly used as a starter in dairy products, was recently found to possess the ALDH gene, and the activity of this enzyme was determined. In this study, the ALDH activity of Lactococcus chungangensis CAU 28(T) and 11 other type strains in the genus Lactococcus was studied. Only 5 species, 3 of dairy origin (Lactococcus lactis ssp. lactis KCTC 3769(T), Lactococcus lactis ssp. cremoris KCCM 40699(T), and Lactococcus raffinolactis DSM 20443(T)) and 2 of nondairy origin (Lactococcus fujiensis NJ317(T) and L. chungangensis CAU 28(T)), showed ALDH activity and possessed a gene encoding ALDH. All of these strains were capable of making cream cheese. Among the strains, L. chungangensis produced cream cheese that contained the highest level of ALDH and was found to reduce the level of acetaldehyde in the serum of mice. These results predict a promising role for L. chungangensis CAU28(T) to be used in cheese that can be developed as functional food.

  13. Antibiotics from basidiomycetes. 26. Phlebiakauranol aldehyde an antifungal and cytotoxic metabolite from Punctularia atropurpurascens.

    PubMed

    Anke, H; Casser, I; Steglich, W; Pommer, E H

    1987-04-01

    Phlebiakauranol aldehyde and the corresponding alcohol were isolated from cultures of Punctularia atropurpurascens. The aldehyde but not the alcohol exhibited strong antifungal activity against several phytopathogens as well as antibacterial and cytotoxic activities. Two acetylated derivatives prepared from the aldehyde showed only very weak antifungal and antibacterial and moderate cytotoxic activities. We therefore assume, that the aldehyde group together with the high number of hydroxyl groups are responsible for the biological activity of the compound.

  14. Oxidative metabolic pathway of lenvatinib mediated by aldehyde oxidase.

    PubMed

    Inoue, Kazuko; Mizuo, Hitoshi; Kawaguchi, Shinki; Fukuda, Katsuyuki; Kusano, Kazutomi; Yoshimura, Tsutomu

    2014-08-01

    Lenvatinib is a multityrosine kinase inhibitor that inhibits vascular endothelial growth factor receptors, and is being developed as an anticancer drug. P450s are involved in one of the elimination pathways of lenvatinib, and mono-oxidized metabolites, such as N-oxide (M3) and desmethylated metabolite (M2), form in rats, dogs, monkeys, and humans. Meanwhile, two other oxidative metabolites are produced only in monkey and human liver S9 fractions, and their structures have been identified using high-resolution mass spectrometry as a quinolinone form of lenvatinib (M3') and a quinolinone form of desmethylated lenvatinib (M2'). The formation of M3' from lenvatinib occurred independently of NADPH and was effectively inhibited by typical inhibitors of aldehyde oxidase, indicating the involvement of aldehyde oxidase, but not P450s, in this pathway. M2' was a dioxidized metabolite arising from a combination of mono-oxidation and desmethylation and could only be produced from M2 in a NADPH-independent manner; M2' could not be generated from M3 or M3'. These results suggested that M2' is formed from lenvatinib by a unique two-step pathway through M2. Although both lenvatinib and M2 were substrates for aldehyde oxidase, an enzyme kinetic study indicated that M2 was a much more favorable substrate than lenvatinib. No inhibitory activities of lenvatinib, M2', or M3' and no significant inhibitory activities of M2 or M3 on aldehyde oxidase were observed, suggesting a low possibility of drug-drug interactions in combination therapy with substrates of aldehyde oxidase.

  15. Selective Inhibition of Mutant Isocitrate Dehydrogenase 1 (IDH1) via Disruption of a Metal Binding Network by an Allosteric Small Molecule

    PubMed Central

    Deng, Gejing; Shen, Junqing; Yin, Ming; McManus, Jessica; Mathieu, Magali; Gee, Patricia; He, Timothy; Shi, Chaomei; Bedel, Olivier; McLean, Larry R.; Le-Strat, Frank; Zhang, Ying; Marquette, Jean-Pierre; Gao, Qiang; Zhang, Bailin; Rak, Alexey; Hoffmann, Dietmar; Rooney, Eamonn; Vassort, Aurelie; Englaro, Walter; Li, Yi; Patel, Vinod; Adrian, Francisco; Gross, Stefan; Wiederschain, Dmitri; Cheng, Hong; Licht, Stuart

    2015-01-01

    Cancer-associated point mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) confer a neomorphic enzymatic activity: the reduction of α-ketoglutarate to d-2-hydroxyglutaric acid, which is proposed to act as an oncogenic metabolite by inducing hypermethylation of histones and DNA. Although selective inhibitors of mutant IDH1 and IDH2 have been identified and are currently under investigation as potential cancer therapeutics, the mechanistic basis for their selectivity is not yet well understood. A high throughput screen for selective inhibitors of IDH1 bearing the oncogenic mutation R132H identified compound 1, a bis-imidazole phenol that inhibits d-2-hydroxyglutaric acid production in cells. We investigated the mode of inhibition of compound 1 and a previously published IDH1 mutant inhibitor with a different chemical scaffold. Steady-state kinetics and biophysical studies show that both of these compounds selectively inhibit mutant IDH1 by binding to an allosteric site and that inhibition is competitive with respect to Mg2+. A crystal structure of compound 1 complexed with R132H IDH1 indicates that the inhibitor binds at the dimer interface and makes direct contact with a residue involved in binding of the catalytically essential divalent cation. These results show that targeting a divalent cation binding residue can enable selective inhibition of mutant IDH1 and suggest that differences in magnesium binding between wild-type and mutant enzymes may contribute to the inhibitors' selectivity for the mutant enzyme. PMID:25391653

  16. 11β-Hydroxysteroid dehydrogenase-1 is involved in bile acid homeostasis by modulating fatty acid transport protein-5 in the liver of micea

    PubMed Central

    Penno, Carlos A.; Morgan, Stuart A.; Rose, Adam J.; Herzig, Stephan; Lavery, Gareth G.; Odermatt, Alex

    2014-01-01

    11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) plays a key role in glucocorticoid receptor (GR) activation. Besides, it metabolizes some oxysterols and bile acids (BAs). The GR regulates BA homeostasis; however, the impact of impaired 11β-HSD1 activity remained unknown. We profiled plasma and liver BAs in liver-specific and global 11β-HSD1-deficient mice. 11β-HSD1-deficiency resulted in elevated circulating unconjugated BAs, an effect more pronounced in global than liver-specific knockout mice. Gene expression analyses revealed decreased expression of the BA-CoA ligase Fatp5, suggesting impaired BA amidation. Reduced organic anion-transporting polypeptide-1A1 (Oatp1a1) and enhanced organic solute-transporter-β (Ostb) mRNA expression were observed in livers from global 11β-HSD1-deficient mice. The impact of 11β-HSD1-deficiency on BA homeostasis seems to be GR-independent because intrahepatic corticosterone and GR target gene expression were not substantially decreased in livers from global knockout mice. Moreover, Fatp5 expression in livers from hepatocyte-specific GR knockout mice was unchanged. The results revealed a role for 11β-HSD1 in BA homeostasis. PMID:25061560

  17. Sustained translational repression of lactate dehydrogenase 1 in Toxoplasma gondii bradyzoites is conferred by a small regulatory RNA hairpin.

    PubMed

    Holmes, Michael; Itaas, Vaunell; Ananvoranich, Sirinart

    2014-11-01

    In response to environmental stresses, Toxoplasma gondii induces a global translational repression which allows for the remodeling of its transcriptome. While some transcripts are preferentially translated, another subset is translationally repressed and maintained in bradyzoites. Although little is known of how transcripts are targeted for sustained translational repression, the targeting probably operates through an RNA-centric mechanism relying on the recognition of cis-acting elements. In this study, we sought to determine if the targeting of transcripts through recognizable cis-acting elements could be responsible for the transcript-specific sustained translational repression displayed by Toxoplasma bradyzoites. We examined the UTRs of a translationally repressed gene, lactate dehydrogenase 1, and found a 40 nucleotide regulatory element in its 5'UTR. This element specifically induces translational repression in otherwise constitutively expressed transcripts. Mutational studies revealed that the formation of a small 16 nucleotide regulatory RNA hairpin is essential for this activity. We suggest that this hairpin may act as the nucleation site for the binding of an as yet to be identified trans-acting factor that allows for the transcript to be targeted for translational repression removal from the active translational pool. To our knowledge, this is the first report characterizing a specific cis-acting element contributing to post-transcriptional gene regulation in Toxoplasma and suggests the presence of a pathway by which the parasites can recognize, identify and specifically target transcripts for sustained translational repression under stressful conditions.

  18. New preparation of diethyl methylformylphosphonate dimethylhydrazone: A reagent for aldehyde homologation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The phosphonate reagent, diethyl methylformyl-2-phosphonate dimethylhydrazone contains a protected aldehyde group instead of the usual ester group. It can be used for the two-carbon homologation of aldehydes to a, ß-unsaturated aldehydes. The reagent can be prepared in good overall yield (82%) and...

  19. GRE2 from Scheffersomyces stipitis as an aldehyde reductase contributes tolerance to aldehyde inhibitors derived from lignocellulosic biomass

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Scheffersomyces (Pichia) stipitis is one of the most promising yeasts for industrial bioethanol production from lignocellulosic biomass. S. stipitis is able to in situ detoxify aldehyde inhibitors [such as furfural and 5-hydroxymethylfurfural (HMF)] to less toxic corresponding alcohols. However, the...

  20. Targeting breast cancer stem cells in triple-negative breast cancer using a combination of LBH589 and salinomycin.

    PubMed

    Kai, Masaya; Kanaya, Noriko; Wu, Shang V; Mendez, Carlos; Nguyen, Duc; Luu, Thehang; Chen, Shiuan

    2015-06-01

    The aim of this study is to investigate the efficacy of combining a histone deacetylase inhibitor (LBH589) and a breast cancer stem cells (BCSC)-targeting agent (salinomycin) as a novel combination therapy for triple-negative breast cancer (TNBC). We performed in vitro studies using the TNBC cell lines to examine the combined effect. We used the mammosphere and ALDEFLUOR assays to estimate BCSC self-renewal capacity and distribution of BCSCs, respectively. Synergistic analysis was performed using CalcuSyn software. For in vivo studies, aldehyde dehydrogenase 1 ALDH1-positive cells were injected into non-obese diabetic/severe combined immunodeficiency gamma (NSG) mice. After tumor formation, mice were treated with LBH589, salinomycin, or in combination. In a second mouse model, HCC1937 cells were first treated with each treatment and then injected into NSG mice. For mechanistic analysis, immunohistochemistry and Western blot analysis were performed using cell and tumor samples. HCC1937 cells displayed BCSC properties including self-renewal capacity, an ALDH1-positive cell population, and the ability to form tumors. Treatment of HCC1937 cells with LBH589 and salinomycin had a potent synergistic effect inhibiting TNBC cell proliferation, ALDH1-positive cells, and mammosphere growth. In xenograft mouse models treated with LBH589 and salinomycin, the drug combination effectively and synergistically inhibited tumor growth of ALDH1-positive cells. The drug combination exerted its effects by inducing apoptosis, arresting the cell cycle, and regulating epithelial-mesenchymal transition (EMT). Combination of LBH589 and salinomycin has a synergistic inhibitory effect on TNBC BCSCs by inducing apoptosis, arresting the cell cycle, and regulating EMT; with no apparent associated severe toxicity. This drug combination could therefore offer a new targeted therapeutic strategy for TNBC and warrants further clinical study in patients with TNBC.

  1. Three-Dimensional Cell Culture Environment Promotes Partial Recovery of the Native Corneal Keratocyte Phenotype from a Subcultured Population

    PubMed Central

    Thompson, Russell E.; Boraas, Liana C.; Sowder, Miranda; Bechtel, Marta K.

    2013-01-01

    Corneal disease is the fourth leading cause of blindness. According to the World Health Organization, roughly 1.6 million people globally are blind as a result of this disease. The only current treatment for corneal opacity is a corneal tissue transplant. Unfortunately, the demand for tissue exceeds supply, making a tissue-engineered in vitro cornea highly desirable. For an in vitro cornea to be useful, it must be transparent, which requires downregulation of the light-scattering intracellular protein alpha-smooth muscle actin (αSMA) and upregulation of the native corneal marker, aldehyde dehydrogenase 1A1 (ALDH1A1). This study focuses on the effects of a three-dimensional (3D) matrix on the expression levels of αSMA and ALDH1A1 by a subcultured population of rabbit corneal keratocytes and the comparison of the 3D matrix effects to other culture conditions. We show that, through western blot and quantitative real-time PCR, the presence of collagen strongly downregulates αSMA. Further, 3D cultures maintain low actin expression even in the presence of a proinflammatory cytokine, transforming growth factor-beta (TGF-β). Finally, 3D culture conditions show a partial recovery of ALDH1A1 expression, which has never been previously observed in a serum-exposed subcultured cell population. Overall, this study suggests that 3D culture is not only a relatively stronger signal than both collagen and TGF-β, it is also sufficient to induce some recovery of ALDH1A1 and the native corneal phenotype despite the presence of serum. PMID:23410050

  2. Morphological and Immunohistochemical Study of Ovarian and Tubal Dysplasia Associated with Tamoxifen

    PubMed Central

    Chene, G.; Radosevic-Robin, N.; Tardieu, A.S.; Cayre, A.; Raoelfils, I.; Dechelotte, P.; Dauplat, J.; Penault-Llorca, F.

    2014-01-01

    Ovarian epithelial dysplasia was initially described in material from prophylactic oophorectomies for BReast CAncer gene (BRCA) mutation. Similar histopathological abnormalities have been revealed after ovulation stimulation. Given that tamoxifen (TAM) has a clomid-like effect and is sometimes used to induce ovulation, we studied the morphological features and immunohistochemical expression patterns of neoplasia-associated markers in adnexectomies previously exposed to TAM for breast cancer. We blindly reviewed 173 histopathological slides of adnexectomies according to three groups – oophorectomies associated with TAM exposure (n=42), oophorectomies associated with clomiphene exposure (n=15) and a spontaneously fertile non cancerous control group (n=116). Morphological features (with an ovarian and tubal dysplasia scoring system) and immunohistochemical expression patterns of Ki-67, p53 and Aldehyde dehydrogenase 1 (ALDH1 is an enzyme significantly associated with earlystage ovarian cancer) were evaluated and correlated. Mean tubal dysplasia score was significantly higher in the TAM group and clomiphen group than in controls (respectively 7.8 vs 3.5, P<0.007 and 6.8 vs 3.5, P=0.008). There is no statistical difference for the ovarian score in TAM group in comparison with the control group whereas we found a significant score for clomiphen group (6.5, P=0.009). Increased ALDH1 expression was observed in the two exposed group whereas expression patterns of Ki67 and p53 were moderate. Interestingly, ALDH1 expression was low in non-dysplastic epithelium, high in dysplasia, and constantly low in the two carcinoma. Furthemore, we confirm our previous results showing that ALDH1 may be a useful tissue biomarker in the subtle histopathological diagnosis of tubo-ovarian dysplasia. PMID:24998918

  3. Effects of Methoxychlor and Its Metabolite Hydroxychlor on Human Placental 3β-Hydroxysteroid Dehydrogenase 1 and Aromatase in JEG-3 Cells.

    PubMed

    Liu, Shiwen; Mao, Baiping; Bai, Yanfang; Liu, Jianpeng; Li, Huitao; Li, Xiaoheng; Lian, Qingquan; Ge, Ren-Shan

    2016-01-01

    Progesterone and estradiol produced by the human placenta are critical for maintenance of pregnancy and fetal development. In the human placenta, 3β-hydroxysteroid dehydrogenase 1 (HSD3B1) is responsible for the formation of progesterone from pregnenolone and aromatase (CYP19A1) for the production of estradiol from androgen. Insecticide methoxychlor (MXC) and its metabolite hydroxychlor (HPTE) may disrupt the activities of these 2 enzymes. In this study, we investigated the effects of MXC and HPTE on steroid production in human placental JEG-3 cells and on HSD3B1 and CYP19A1 activities. MXC and HPTE inhibited progesterone and estradiol production in JEG-3 cells. MXC and HPTE were potent HSD3B1 inhibitors with the half maximal inhibitory concentration (IC50) values of 2.339 ± 0.096 and 1.918 ± 0.078 μmol/l, respectively. MXC had no inhibition on CYP19A1 at 100 μmol/l, while HPTE was a weak inhibitor with IC50 of 97.16 ± 0.10 μmol/l. When pregnenolone was used to determine the inhibitory mode, MXC and HPTE were found to be competitive inhibitors of HSD3B1. When cofactor NAD+ was used, MXC and HPTE were the noncompetitive inhibitors of HSD3B1. When testosterone was used, HPTE was a mixed inhibitor of CYP19A1. In conclusion, MXC and HPTE are potent inhibitors of human HSD3B1, and HPTE is a weak CYP19A1 inhibitor.

  4. Somatic mutations of isocitrate dehydrogenases 1 and 2 are prognostic and follow-up markers in patients with acute myeloid leukaemia with normal karyotype

    PubMed Central

    Karan-Djurasevic, Teodora; Marjanovic, Irena; Tosic, Natasa; Mitrovic, Mirjana; Djunic, Irena; Colovic, Natasa; Vidovic, Ana; Suvajdzic-Vukovic, Nada; Tomin, Dragica; Pavlovic, Sonja

    2016-01-01

    Abstract Background Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes are frequent molecular lesions in acute myeloid leukaemia with normal karyotype (AML-NK). The effects of IDH mutations on clinical features and treatment outcome in AML-NK have been widely investigated, but only a few studies monitored these mutations during follow-up. Patients and methods In our study samples from 110 adult de novo AML-NK were studied for the presence of IDH1 and IDH2 mutations, their associations with other prognostic markers and disease outcome. We also analyzed the stability of these mutations during the course of the disease in complete remission (CR) and relapse. Results IDH mutations were found in 25 (23%) patients. IDH+ patients tend to have lower CR rate compared to IDH-patients (44% vs 62.2%, p = 0.152), and had slightly lower disease free survival (12 months vs 17 months; p = 0.091). On the other hand, the presence of IDH mutations had significant impact on overall survival (2 vs 7 months; p = 0.039). The stability of IDH mutations were studied sequentially in 19 IDH+ patients. All of them lost the mutation in CR, and the same IDH mutations were detected in relapsed samples. Conclusions Our study shows that the presence of IDH mutations confer an adverse effect in AML-NK patients, which in combination with other molecular markers can lead to an improved risk stratification and better treatment. Also, IDH mutations are very stable during the course of the disease and can be potentially used as markers for minimal residual disease detection. PMID:27904446

  5. Decreased 11β-Hydroxysteroid Dehydrogenase 1 Level and Activity in Murine Pancreatic Islets Caused by Insulin-Like Growth Factor I Overexpression

    PubMed Central

    Chowdhury, Subrata; Grimm, Larson; Gong, Ying Jia Kate; Wang, Beixi; Li, Bing; Srikant, Coimbatore B.; Gao, Zu-hua; Liu, Jun-Li

    2015-01-01

    We have reported a high expression of IGF-I in pancreatic islet β-cells of transgenic mice under the metallothionein promoter. cDNA microarray analysis of the islets revealed that the expression of 82 genes was significantly altered compared to wild-type mice. Of these, 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), which is responsible for the conversion of inert cortisone (11-dehydrocorticosterone, DHC in rodents) to active cortisol (corticosterone) in the liver and adipose tissues, has not been identified previously as an IGF-I target in pancreatic islets. We characterized the changes in its protein level, enzyme activity and glucose-stimulated insulin secretion. In freshly isolated islets, the level of 11β-HSD1 protein was significantly lower in MT-IGF mice. Using dual-labeled immunofluorescence, 11β-HSD1 was observed exclusively in glucagon-producing, islet α-cells but at a lower level in transgenic vs. wild-type animals. MT-IGF islets also exhibited reduced enzymatic activities. Dexamethasone (DEX) and DHC inhibited glucose-stimulated insulin secretion from freshly isolated islets of wild-type mice. In the islets of MT-IGF mice, 48-h pre-incubation of DEX caused a significant decrease in insulin release, while the effect of DHC was largely blunted consistent with diminished 11β-HSD1 activity. In order to establish the function of intracrine glucocorticoids, we overexpressed 11β-HSD1 cDNA in MIN6 insulinoma cells, which together with DHC caused apoptosis and a significant decrease in proliferation. Both effects were abolished with the treatment of an 11β-HSD1 inhibitor. Our results demonstrate an inhibitory effect of IGF-I on 11β-HSD1 expression and activity within the pancreatic islets, which may mediate part of the IGF-I effects on cell proliferation, survival and insulin secretion. PMID:26305481

  6. Curcumin as a Potent and Selective Inhibitor of 11β-Hydroxysteroid Dehydrogenase 1: Improving Lipid Profiles in High-Fat-Diet-Treated Rats

    PubMed Central

    Lian, Qing-Quan; Zhou, Shu-Hua; Guo, Jingjing; Zhou, Hong-Yu; Chu, Yanhui; Ge, Ren-Shan

    2013-01-01

    Background 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activates glucocorticoid locally in liver and fat tissues to aggravate metabolic syndrome. 11β-HSD1 selective inhibitor can be used to treat metabolic syndrome. Curcumin and its derivatives as selective inhibitors of 11β-HSD1 have not been reported. Methodology Curcumin and its 12 derivatives were tested for their potencies of inhibitory effects on human and rat 11β-HSD1 with selectivity against 11β-HSD2. 200 mg/kg curcumin was gavaged to adult male Sprague-Dawley rats with high-fat-diet-induced metabolic syndrome for 2 months. Results and Conclusions Curcumin exhibited inhibitory potency against human and rat 11β-HSD1 in intact cells with IC50 values of 2.29 and 5.79 µM, respectively, with selectivity against 11β-HSD2 (IC50, 14.56 and 11.92 µM). Curcumin was a competitive inhibitor of human and rat 11β-HSD1. Curcumin reduced serum glucose, cholesterol, triglyceride, low density lipoprotein levels in high-fat-diet-induced obese rats. Four curcumin derivatives had much higher potencies for Inhibition of 11β-HSD1. One of them is (1E,4E)-1,5-bis(thiophen-2-yl) penta-1,4-dien-3-one (compound 6), which had IC50 values of 93 and 184 nM for human and rat 11β-HSD1, respectively. Compound 6 did not inhibit human and rat kidney 11β-HSD2 at 100 µM. In conclusion, curcumin is effective for the treatment of metabolic syndrome and four novel curcumin derivatives had high potencies for inhibition of human 11β-HSD1 with selectivity against 11β-HSD2. PMID:23533564

  7. Rice alcohol dehydrogenase 1 promotes survival and has a major impact on carbohydrate metabolism in the embryo and endosperm when seeds are germinated in partially oxygenated water

    PubMed Central

    Takahashi, Hirokazu; Greenway, Hank; Matsumura, Hideo; Tsutsumi, Nobuhiro; Nakazono, Mikio

    2014-01-01

    Background and Aims Rice (Oryza sativa) has the rare ability to germinate and elongate a coleoptile under oxygen-deficient conditions, which include both hypoxia and anoxia. It has previously been shown that ALCOHOL DEHYDROGENASE 1 (ADH1) is required for cell division and cell elongation in the coleoptile of submerged rice seedlings by means of studies using a rice ADH1-deficient mutant, reduced adh activity (rad). The aim of this study was to understand how low ADH1 in rice affects carbohydrate metabolism in the embryo and endosperm, and lactate and alanine synthesis in the embryo during germination and subsequent coleoptile growth in submerged seedlings. Methods Wild-type and rad mutant rice seeds were germinated and grown under complete submergence. At 1, 3, 5 and 7 d after imbibition, the embryo and endosperm were separated and several of their metabolites were measured and compared. Key results In the rad embryo, the rate of ethanol fermentation was halved, while lactate and alanine concentrations were 2·4- and 5·7- fold higher in the mutant than in the wild type. Glucose and fructose concentrations in the embryos increased with time in the wild type, but not in the rad mutant. The rad mutant endosperm had lower amounts of the α-amylases RAMY1A and RAMY3D, resulting in less starch degradation and lower glucose concentrations. Conclusions These results suggest that ADH1 is essential for sugar metabolism via glycolysis to ethanol fermentation in both the embryo and endosperm. In the endosperm, energy is presumably needed for synthesis of the amylases and for sucrose synthesis in the endosperm, as well as for sugar transport to the embryo. PMID:24431339

  8. Aldehyde dehydrogenase is used by cancer cells for energy metabolism

    PubMed Central

    Kang, Joon Hee; Lee, Seon-Hyeong; Hong, Dongwan; Lee, Jae-Seon; Ahn, Hee-Sung; Ahn, Ju-Hyun; Seong, Tae Wha; Lee, Chang-Hun; Jang, Hyonchol; Hong, Kyeong Man; Lee, Cheolju; Lee, Jae-Ho; Kim, Soo-Youl

    2016-01-01

    We found that non-small-cell lung cancer (NSCLC) cells express high levels of multiple aldehyde dehydrogenase (ALDH) isoforms via an informatics analysis of metabolic enzymes in NSCLC and immunohistochemical staining of NSCLC clinical tumor samples. Using a multiple reaction-monitoring mass spectrometry analysis, we found that multiple ALDH isozymes were generally abundant in NSCLC cells compared with their levels in normal IMR-90 human lung cells. As a result of the catalytic reaction mediated by ALDH, NADH is produced as a by-product from the conversion of aldehyde to carboxylic acid. We hypothesized that the NADH produced by ALDH may be a reliable energy source for ATP production in NSCLC. This study revealed that NADH production by ALDH contributes significantly to ATP production in NSCLC. Furthermore, gossypol, a pan-ALDH inhibitor, markedly reduced the level of ATP. Gossypol combined with phenformin synergistically reduced the ATP levels, which efficiently induced cell death following cell cycle arrest. PMID:27885254

  9. An Overview of the Chemistry and Biology of Reactive Aldehydes

    PubMed Central

    Fritz, Kristofer S.; Petersen, Dennis R.

    2012-01-01

    The non-enzymatic free radical generation of reactive aldehydes is known to contribute to diseases of sustained oxidative stress including rheumatoid arthritis, atherosclerosis, neurodegenerative and a number of liver diseases. At the same time, the accumulation of lipid electrophiles has been demonstrated to play a role in cell signaling events through modification of proteins critical for cellular homeostasis. Given the broad scope of reactivity profiles and the ability to modify numerous proteomic and genomic processes, new emphasis is being placed on a systems-based analysis of the consequences of electrophilic adduction. This review focuses on the generation and chemical reactivity of lipid-derived aldehydes with a special focus on the homeostatic responses to electrophilic stress. PMID:22750507

  10. Aldehyde Dehydrogenases in Cellular Responses to Oxidative/electrophilic Stress

    PubMed Central

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

    2013-01-01

    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 like dehydration and ultraviolet radiation. The ability to act as an ‘aldehyde scavenger’ during lipid peroxidation is another ostensibly universal ALDH function found across species. Up-regulation 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 significantly contributes to the management of electrophilic/oxidative stress within living systems. Mutations in various ALDHs are associated with a variety of pathological conditions in humans, underscoring the fundamental importance of these enzymes in physiological and pathological processes. PMID:23195683

  11. Nickel-Catalyzed Coupling of Alkenes, Aldehydes, and Silyl Triflates

    PubMed Central

    Ng, Sze-sze; Ho, Chun-Yu; Jamison, Timothy F.

    2011-01-01

    A full account of two recently developed nickel-catalyzed coupling reactions of alkenes, aldehydes and silyl triflates is presented. These reactions provide either allylic alcohol or homoallylic alcohol derivatives selectively, depending on the ligand employed. These processes are believed to be mechanistically distinct from Lewis acid-catalyzed carbonyl-ene reactions, and several lines of evidence supporting this hypothesis are discussed. PMID:16939275

  12. Henry's law constants of some environmentally important aldehydes

    SciTech Connect

    Betterton, E.A.; Hoffmann, M.R.

    1988-12-01

    The Henry's law constants of seven aldehydes have been determined as a function of temperature by bubble-column and by head-space techniques. The compounds were chosen for their potential importance in the polluted troposphere and to allow structure-reactivity patterns to be investigated. The results (at 25/degree/C) are as follows (in units of M atm/sup /minus/1/): chloral, 3.44 /times/ 10/sup 5/; glyoxal, greater than or equal to3 /times/ 10/sup 5/; methylglyoxal, 3.71 /times/ 10/sup 3/; formaldehyde, 2.97 /times/ 10/sup 3/; benzaldehyde, 3.74 /times/ 10/sup 1/; hydroxyacetaldehyde, 4.14 /times/ 10/sup 4/; acetaldehyde, 1.14 /times/ 10/sup 1/. A plot of Taft's parameter, ..sigma..sigma*, vs log H* (the apparent Henry's law constant) gives a straight line with a slope of 1.72. H* for formaldehyde is anomalously high, as expected, but the extremely high value for hydroxyacetaldehyde was unexpected and may indicate that ..cap alpha..-hydroxy-substituted aldehydes could have an usually high affinity for the aqueous phase. The intrinsic Henry's law constants, H, corrected for hydration, do not show a clear structure-reactivity pattern for this series of aldehydes.

  13. Peptide aldehyde inhibitors of hepatitis A virus 3C proteinase.

    PubMed

    Malcolm, B A; Lowe, C; Shechosky, S; McKay, R T; Yang, C C; Shah, V J; Simon, R J; Vederas, J C; Santi, D V

    1995-06-27

    Picornaviral 3C proteinases are a group of closely related thiol proteinases responsible for processing of the viral polyprotein into its component proteins. These proteinases adopt a chymotrypsin-like fold [Allaire et al. (1994) Nature 369, 72-77; Matthews et al. (1994) Cell 77, 761-771] and a display an active-site configuration like those of the serine proteinases. Peptide-aldehydes based on the preferred peptide substrates for hepatitis A virus (HAV) 3C proteinase were synthesized by reduction of a thioester precursor. Acetyl-Leu-Ala-Ala-(N,N'-dimethylglutaminal) was found to be a reversible, slow-binding inhibitor for HAV 3C with a Ki* of (4.2 +/- 0.8) x 10(-8) M. This inhibitor showed 50-fold less activity against the highly homologous human rhinovirus (strain 14) 3C proteinase, whose peptide substrate specificity is slightly different, suggesting a high degree of selectivity. NMR spectrometry of the adduct of the 13C-labeled inhibitor with the HAV-3C proteinase indicate that a thiohemiacetal is formed between the enzyme and the aldehyde carbon as previously noted for peptide-aldehyde inhibitors of papain [Lewis & Wolfenden (1977) Biochemistry 16,4890-4894; Gamcsik et al. (1983) J. Am. Chem. Soc. 105, 6324-6325]. The adduct can also be observed by electrospray mass spectrometry.

  14. The serotonin aldehyde, 5-HIAL, oligomerizes alpha-synuclein.

    PubMed

    Jinsmaa, Yunden; Cooney, Adele; Sullivan, Patricia; Sharabi, Yehonatan; Goldstein, David S

    2015-03-17

    In Parkinson's disease (PD) alpha-synuclein oligomers are thought to be pathogenic, and 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate aldehyde intermediate in neuronal dopamine metabolism, potently oligomerizes alpha-synuclein. PD involves alpha-synuclein deposition in brainstem raphe nuclei; however, whether 5-hydroxyindoleacetaldehyde (5-HIAL), the aldehyde of serotonin, oligomerizes alpha-synuclein has been unknown. In this study we tested whether 5-HIAL oligomerizes alpha-synuclein in vitro and in PC12 cells conditionally over-expressing alpha-synuclein. Alpha-synuclein oligomers were quantified by western blotting after incubation of alpha-synuclein with serotonin and monoamine oxidase-A (MAO-A) to generate 5-HIAL or dopamine to generate DOPAL. Oligomerization of alpha-synuclein in PC12 cells over-expressing the protein was compared between vehicle-treated cells and cells incubated with levodopa to generate DOPAL or 5-hydroxytryptophan to generate 5-HIAL. Monoamine aldehyde mediation of the oligomerization was assessed using the MAO inhibitor, pargyline. Dopamine and serotonin incubated with MAO-A both strongly oligomerized alpha-synuclein (more than 10 times control); pargyline blocked the oligomerization. In synuclein overexpressing PC12 cells, levodopa and 5-hydroxytryptophan elicited pargyline-sensitive alpha-synuclein oligomerization. 5-HIAL oligomerizes alpha-synuclein both in vitro and in synuclein-overexpressing PC12 cells, in a manner similar to DOPAL. The findings may help explain loss of serotonergic neurons in PD.

  15. Oxidative damage in keratinocytes exposed to cigarette smoke and aldehydes.

    PubMed

    Avezov, Katia; Reznick, Abraham Z; Aizenbud, Dror

    2014-06-01

    Cigarette smoke (CS) is a significant environmental source of human exposure to chemically active saturated (acetaldehyde) and α,β-unsaturated aldehydes (acrolein) inducing protein carbonylation and dysfunction. The exposure of oral tissues to environmental hazards is immense, especially in smokers. The objectives of the current study were to examine the effect of aldehydes originating from CS on intracellular proteins of oral keratinocytes and to observe the antioxidant response in these cells. Intracellular protein carbonyl modification under CS, acrolein and acetaldehyde exposure in the HaCaT keratinocyte cell line, representing oral keratinocytes was examined by Western blot. Possible intracellular enzymatic dysfunction under the above conditions was examined by lactate dehydrogenase (LDH) activity assay. Oxidative stress response was investigated, by DCF (2,7-dichlorodihydrofluorescein) assay and GSH (glutathione) oxidation. Intracellular protein carbonyls increased 5.2 times after CS exposure and 2.7 times after exposure to 1 μmol of acrolein. DCF assay revealed an increase of fluorescence intensity 3.2 and 3.1 times after CS and acrolein exposure, respectively. CS caused a 72.5% decrease in intracellular GSH levels compared to controls. Activity of intracellular LDH was preserved. α,β-Unsaturated aldehydes from CS are capable of intracellular protein carbonylation and have a role in intracellular oxidative stress elevation in keratinocytes, probably due to the reduction in GSH levels.

  16. Coexpression of EpCAM, CD44 Variant Isoforms and Claudin-7 in Anaplastic Thyroid Carcinoma

    PubMed Central

    Okada, Toshihiro; Nakamura, Teruo; Watanabe, Takayuki; Onoda, Naoyoshi; Ashida, Atsuko; Okuyama, Ryuhei; Ito, Ken-ichi

    2014-01-01

    Background Anaplastic thyroid cancer is considered to be one of the most aggressive human malignancies, and the mean survival time after diagnosis is approximately six months, regardless of treatments. This study aimed to examine how EpCAM and its related molecules are involved in the characteristics of anaplastic thyroid carcinoma. Methodology/Principal Findings Two differentiated thyroid cancer cell lines (TPC-1 and FTC-133), and two anaplastic thyroid cancer cell lines (FRO, ACT-1) were analyzed for expression of CD44 standard isoform (CD44s), CD44 variant isoforms, and EpCAM, and human aldehyde dehydrogenase-1 (ALDH1) enzymatic activity using flow cytometry. CD44s expression was higher in TPC-1 and FTC-133 than in the FRO and ACT-1, whereas ALDH1 activities were higher in FRO and ACT-1 than in TPC-1 and FTC-133. An inverse correlation between CD44s expression and ALDH1 activity was observed in all thyroid cancer cell lines. As for the expressions of CD44 variant isoforms, ACT-1 showed higher and FRO showed moderate CD44v6 expressions, whereas either TPC-1 or FTC-133 showed negative CD44v6 expression. EpCAM expressions in FRO and ACT-1 were higher than those in TPC-1 and FTC-133, and EpCAM expressions inversely correlated with those of CD44s. A positive correlation was observed between EpCAM expression and ALDH1 activity in thyroid cancer cell lines. In the RT-PCR analysis, the expression levels of EpCAM, caludin-7 and ALDH1 in FRO and ATC-1 cells were significantly higher than those in TPC-1 and FTC-133 cells. In clinical specimens of thyroid cancers, nuclear expression of EpCAM and high expression of CD44v6 were detected significantly more frequently in anaplastic carcinomas. Conclusions/Significance Our study suggests the possibility that EpCAM, together with CD44v6 and claudin-7 as well as ALDH1, may be involved in the development of the aggressive phenotype of anaplastic thyroid carcinoma. Our findings may suggest a novel therapeutic strategy for treatment

  17. Metabolic engineering of glycine betaine synthesis: plant betaine aldehyde dehydrogenases lacking typical transit peptides are targeted to tobacco chloroplasts where they confer betaine aldehyde resistance.

    PubMed

    Rathinasabapathi, B; McCue, K F; Gage, D A; Hanson, A D

    1994-01-01

    Certain higher plants synthesize and accumulate glycine betaine, a compound with osmoprotectant properties. Biosynthesis of glycine betaine proceeds via the pathway choline-->betaine aldehyde-->glycine betaine. Plants such as tobacco (Nicotiana tabacum L.) which do not accumulate glycine betaine lack the enzymes catalyzing both reactions. As a step towards engineering glycine betaine accumulation into a non-accumulator, spinach and sugar beet complementary-DNA sequences encoding the second enzyme of glycine-betaine synthesis (betaine aldehyde dehydrogenase, BADH, EC 1.2.1.8) were expressed in tobacco. Despite the absence of a typical transit peptide, BADH was targeted to the chloroplast in leaves of transgenic plants. Levels of extractable BADH were comparable to those in spinach and sugar beet, and the molecular weight, isoenzyme profile and Km for betaine aldehyde of the BADH enzymes from transgenic plants were the same as for native spinach or sugar beet BADH. Transgenic plants converted supplied betaine aldehyde to glycine betaine at high rates, demonstrating that they were able to transport betaine aldehyde across both the plasma membrane and the chloroplast envelope. The glycine betaine produced in this way was not further metabolized and reached concentrations similar to those in plants which accumulate glycine betaine naturally. Betaine aldehyde was toxic to non-transformed tobacco tissues whereas transgenic tissues were resistant due to detoxification of betaine aldehyde to glycine betaine. Betaine aldehyded ehydrogenase is therefore of interest as a potential selectable marker, as well as in the metabolic engineering of osmoprotectant biosynthesis.

  18. Salivary aldehyde dehydrogenase - temporal and population variability, correlations with drinking and smoking habits and activity towards aldehydes contained in food.

    PubMed

    Giebułtowicz, Joanna; Dziadek, Marta; Wroczyński, Piotr; Woźnicka, Katarzyna; Wojno, Barbara; Pietrzak, Monika; Wierzchowski, Jacek

    2010-01-01

    Fluorimetric method based on oxidation of the fluorogenic 6-methoxy-2-naphthaldehyde was applied to evaluate temporal and population variability of the specific activity of salivary aldehyde dehydrogenase (ALDH) and the degree of its inactivation in healthy human population. Analyzed was also its dependence on drinking and smoking habits, coffee consumption, and its sensitivity to N-acetylcysteine. Both the specific activity of salivary ALDH and the degree of its inactivation were highly variable during the day, with the highest activities recorded in the morning hours. The activities were also highly variable both intra- and interpersonally, and negatively correlated with age, and this correlation was stronger for the subgroup of volunteers declaring abstinence from alcohol and tobacco. Moderately positive correlations of salivary ALDH specific activity with alcohol consumption and tobacco smoking were also recorded (r(s) ~0.27; p=0.004 and r(s) =0.30; p=0.001, respectively). Moderate coffee consumption correlated positively with the inactivation of salivary ALDH, particularly in the subgroup of non-drinking and non-smoking volunteers. It was found that mechanical stimulation of the saliva flow increases the specific activity of salivary ALDH. The specific activity of the salivary ALDH was strongly and positively correlated with that of superoxide dismutase, and somewhat less with salivary peroxidase. The antioxidant-containing drug N-acetylcysteine increased activity of salivary ALDH presumably by preventing its inactivation in the oral cavity. Some food-related aldehydes, mainly cinnamic aldehyde and anisaldehyde, were excellent substrates of the salivary ALDH3A1 enzyme, while alkenals, particularly those with short chain, were characterized by lower affinity towards this enzyme but high catalytic constants. The protective role of salivary ALDH against aldehydes in food and those found in the cigarette smoke is discussed, as well as its participation in

  19. GRE2 from Scheffersomyces stipitis as an aldehyde reductase contributes tolerance to aldehyde inhibitors derived from lignocellulosic biomass.

    PubMed

    Wang, Xu; Ma, Menggen; Liu, Z Lewis; Xiang, Quanju; Li, Xi; Liu, Na; Zhang, Xiaoping

    2016-08-01

    Scheffersomyces (Pichia) stipitis is one of the most promising yeasts for industrial bioethanol production from lignocellulosic biomass. S. stipitis is able to in situ detoxify aldehyde inhibitors (such as furfural and 5-hydroxymethylfurfural (HMF)) to less toxic corresponding alcohols. However, the reduction enzymes involved in this reaction remain largely unknown. In this study, we reported that an uncharacterized open reading frame PICST_72153 (putative GRE2) from S. stipitis was highly induced in response to furfural and HMF stresses. Overexpression of this gene in Saccharomyces cerevisiae improved yeast tolerance to furfural and HMF. GRE2 was identified as an aldehyde reductase which can reduce furfural to FM with either NADH or NADPH as the co-factor and reduce HMF to FDM with NADPH as the co-factor. This enzyme can also reduce multiple aldehydes to their corresponding alcohols. Amino acid sequence analysis indicated that it is a member of the subclass "intermediate" of the short-chain dehydrogenase/reductase (SDR) superfamily. Although GRE2 from S. stipitis is similar to GRE2 from S. cerevisiae in a three-dimensional structure, some differences were predicted. GRE2 from S. stipitis forms loops at D133-E137 and T143-N145 locations with two α-helices at E154-K157 and E252-A254 locations, different GRE2 from S. cerevisiae with an α-helix at D133-E137 and a β-sheet at T143-N145 locations, and two loops at E154-K157 and E252-A254 locations. This research provided guidelines for the study of other SDR enzymes from S. stipitis and other yeasts on tolerant mechanisms to aldehyde inhibitors derived from lignocellulosic biomass.

  20. Dominant factors controlling concentrations of aldehydes in rain, fog, dew water, and in the gas phase

    NASA Astrophysics Data System (ADS)

    Matsumoto, Kiyoshi; Kawai, Shunji; Igawa, Manabu

    Low-molecular weight aldehyde compounds in rain, fog, dew water, and in the gas phase were measured at urban and suburban mountain sites, to characterize the chemical composition of aldehydes in liquid droplets and in the gas phase in the ambient atmosphere, and discuss the factors controlling wet removal processes of aldehydes. Higher concentrations of total aldehydes were found in dew water than in rain and fog water due to the small amount of water volume. Both formaldehyde and acetaldehyde were detected as dominant aldehydes in the gas phase. Secondary formation processes are dominant sources for both aldehydes in the suburban site, whereas primary sources are relatively important for the urban atmosphere. In rainwater, by contrast, formaldehyde was the most abundant aldehyde, followed by glyoxal. Glyoxal was detected as the most dominant aldehyde in fog and dew water. Acetaldehyde was not detected as a main component in liquid droplets in spite of its abundance in the gas phase. Water solubility of each aldehyde compound and dilution effect by water are critical factors that control the compositions and concentrations of these aldehydes in ambient liquid droplets.

  1. Interstellar Aldehydes and their corresponding Reduced Alcohols: Interstellar Propanol?

    NASA Astrophysics Data System (ADS)

    Etim, Emmanuel; Chakrabarti, Sandip Kumar; Das, Ankan; Gorai, Prasanta; Arunan, Elangannan

    2016-07-01

    There is a well-defined trend of aldehydes and their corresponding reduced alcohols among the known interstellar molecules; methanal (CH_2O) and methanol (CH_3OH); ethenone (C_2H_2O) and vinyl alcohol (CH_2CHOH); ethanal (C_2H_4O) and ethanol(C_2H_5OH); glycolaldehyde (C_2H_4O_2) and ethylene glycol(C_2H_6O_2). The reduced alcohol of propanal (CH_3CH_2CHO) which is propanol (CH_3CH_2CH_2OH) has not yet been observed but its isomer; ethyl methyl ether (CH_3CH_2OCH_3) is a known interstellar molecule. In this article, different studies are carried out in investigating the trend between aldehydes and their corresponding reduced alcohols and the deviation from the trend. Kinetically and with respect to the formation route, alcohols could have been produced from their corresponding reduced aldehydes via two successive hydrogen additions. This is plausible because of (a) the unquestionable high abundance of hydrogen, (b) presence of energy sources within some of the molecular clouds and (c) the ease at which successive hydrogen addition reaction occurs. In terms of stability, the observed alcohols are thermodynamically favorable as compared to their isomers. Regarding the formation process, the hydrogen addition reactions are believed to proceed on the surface of the interstellar grains which leads to the effect of interstellar hydrogen bonding. From the studies, propanol and propan-2-ol are found to be more strongly attached to the surface of the interstellar dust grains which affects its overall gas phase abundance as compared to its isomer ethyl methyl ether which has been observed.

  2. N-Heterocyclic carbene-mediated oxidative esterification of aldehydes: ester formation and mechanistic studies.

    PubMed

    Maji, Biswajit; Vedachalan, Seenuvasan; Ge, Xin; Cai, Shuting; Liu, Xue-Wei

    2011-05-06

    An unexpected N-heterocyclic carbene-catalyzed esterification of α,β-unsaturated aldehydes including aromatic aldehydes with reactive cinnamyl bromides in the presence of air oxygen or MnO(2) as an oxidant is described. In the presence of oxygen, halogenated and electron-deficient aldehydes react smoothly to furnish esters in good yields. Great efforts have been made on mechanistic studies to deduce a plausible mechanism, based on the experimental results and isotopic labeling experiment.

  3. Solution-phase automated synthesis of an α-amino aldehyde as a versatile intermediate

    PubMed Central

    Masui, Hisashi; Yosugi, Sae; Fuse, Shinichiro

    2017-01-01

    A solution-phase automated synthesis of the versatile synthetic intermediate, Garner’s aldehyde, was demonstrated. tert-Butoxycarbonyl (Boc) protection, acetal formation, and reduction of the ester to the corresponding aldehyde were performed utilizing our originally developed automated synthesizer, ChemKonzert. The developed procedure was also useful for the synthesis of Garner’s aldehyde analogues possessing fluorenylmethyloxycarbonyl (Fmoc) or benzyloxycarbonyl (Cbz) protection. PMID:28228851

  4. Electron transmission through a class of anthracene aldehyde molecules

    NASA Astrophysics Data System (ADS)

    Petreska, Irina; Ohanesjan, Vladimir; Pejov, Ljupco; Kocarev, Ljupco

    2016-03-01

    Transmission of electrons via metal-molecule-metal junctions, involving rotor-stator anthracene aldehyde molecules is investigated. Two model barriers having input parameters evaluated from accurate ab initio calculations are proposed and the transmission coefficients are obtained by using the quasiclassical approximation. Transmission coefficients further enter in the integral for the net current, utilizing Simmons' method. Conformational dependence of the tunneling processes is evident and the presence of the side groups enhances the functionality of the future single-molecule based electronic devices.

  5. A Simple Litmus Test for Aldehyde Oxidase Metabolism of Heteroarenes

    PubMed Central

    2015-01-01

    The bioavailability of aromatic azaheterocyclic drugs can be affected by the activity of aldehyde oxidase (AO). Susceptibility to AO metabolism is difficult to predict computationally and can be complicated in vivo by differences between species. Here we report the use of bis(((difluoromethyl)sulfinyl)oxy)zinc (DFMS) as a source of CF2H radical for a rapid and inexpensive chemical “litmus test” for the early identification of heteroaromatic drug candidates that have a high probability of metabolism by AO. PMID:24472070

  6. Nuclear alkylated pyridine aldehyde polymers and conductive compositions thereof

    NASA Technical Reports Server (NTRS)

    Rembaum, A.; Singer, S. (Inventor)

    1970-01-01

    A thermally stable, relatively conductive polymer was disclosed. The polymer was synthesized by condensing in the presence of catalyst a 2, 4, or 6 nuclear alklylated 2, 3, or 4 pyridine aldehyde or quaternary derivatives thereof to form a polymer. The pyridine groups were liked by olefinic groups between 2-4, 2-6, 2-3, 3-4, 3-6 or 4-6 positions. Conductive compositions were prepared by dissolving the quaternary polymer and an organic charge transfer complexing agent such as TCNQ in a mutual solvent such as methanol.

  7. Polyetherurethane oligomers with aldehyde groups as additives for lubricating oils

    SciTech Connect

    Nikolaev, V.N.; Abramov, E.G.; Tenyushev, A.I.

    1995-01-01

    Polyetherurethane oligomers with aldehyde groups, which we synthesized from polyoxypropylene diols (molecular weight 500, 1000, 1500, 2000, or 3000) with toluene diisocyanate and salicylaldehyde, are of interest as additives for lubricating oils. The effects of these oligomers on the service properties and physicochemical characteristics of lubricating oils were investigated by methods prreviously described. As the lube base stocks we used castor oil, a polyoxypropylene diol and a polyethoxysiloxane. The oligomers are readily soluble in organic solvents and in the lube base stocks, and their solutions are stable during storage and use. We found that the optimal concentration of oligomers is 5%, providing the best lubricating properties, in particular the best antiwear properties.

  8. [Pollution Characteristics of Aldehydes and Ketones Compounds in the Exhaust of Beijing Typical Restaurants].

    PubMed

    Cheng, Jing-chen; Cui, Tong; He, Wan-qing; Nie, Lei; Wang, Jun-ling; Pan, Tao

    2015-08-01

    Aldehydes and ketones compounds, as one of the components in the exhaust of restaurants, are a class of volatile organic compounds (VOCs) with strong chemical reactivity. However, there is no systematic study on aldehydes and ketones compounds in the exhaust of restaurants. To further clarify the food source emission levels of aldehydes and ketones compounds and controlling measures, to access city group catering VOCs emissions control decision-making basis, this study selected 8 Beijing restaurants with different types. The aldehydes and ketones compounds were sampled using DNPH-silica tube, and then ultra performance liquid chromatography was used for quantitative measurement. The aldehydes and ketones concentrations of reference volume condition from 8 restaurants in descending order were Roasted Duck restaurant, Chinese Style Barbecue, Home Dishes, Western Fast-food, School Canteen, Chinese Style Fast-food, Sichuan Cuisine, Huaiyang Cuisine. The results showed that the range of aldehydes and ketones compounds (C1-C9) concentrations of reference volume condition in the exhaust of restaurants was 115.47-1035.99 microg x m(-3). The composition of aldehydes and ketones compounds in the exhaust of sampled restaurants was obviously different. The percentages of C1-C3 were above 40% in the exhaust from Chinese style restaurants. Fast food might emit more C4-C9 aldehydes and ketones compounds. From the current situation of existing aldehydes and ketones compounds control, the removal efficiency of high voltage electrostatic purifiers widely used in Beijing is limited.

  9. The Complete Molecular Geometry of Salicyl Aldehyde from Rotational Spectroscopy

    NASA Astrophysics Data System (ADS)

    Dorosh, O.; Bialkowska-Jaworska, E.; Kisiel, Z.; Pszczolkowski, L.; Kanska, M.; Krygowski, T. M.; Maeder, H.

    2013-06-01

    Salicyl aldehyde is a well known planar molecule containing an internal hydrogen bond. In preparing the publication of our previous report of the study of its rotational spectrum we have taken the opportunity to update the structure determination of this molecule to the complete r_e^{SE} geometry. The molecule contains 15 atoms and we have used supersonic expansion FTMW spectroscopy to obtain rotational constants for a total 26 different isotopic species, including all singly substitued species relative to the parent molecule. The ^{13}C and ^{18}O substitutions were measured in natural abundance, while deuterium substitutions were carried out synthetically. The r_e^{SE} determination requires the calculation of vibration-rotation changes in rotational constants from an ab initio anharmonic force field, which necessitates some compromises in the level of calculation for a molecule of the size of salicyl aldehyde. For this reason we studied the five lowest vibrationally excited states, by using the combination of room-temperature mm-wave spectroscopy and waveguide Fourier transform cm-wave spectroscopy. The experimental excited state rotational constants were then used to calibrate the anharmonic force field calculation. The resulting r_e^{SE} geometry is compared with other types of geometry determination possible from this data, with emphasis on the effect of the near zero principal coordinate of the important C_2 atom. Z.Kisiel et al., 61^{st} OSU Symposium on Molecular Spectroscopy, The Ohio State University, Ohio 2006, RI-12.

  10. Toxic Diatom Aldehydes Affect Defence Gene Networks in Sea Urchins

    PubMed Central

    Varrella, Stefano; Ruocco, Nadia; Ianora, Adrianna; Bentley, Matt G.; Costantini, Maria

    2016-01-01

    Marine organisms possess a series of cellular strategies to counteract the negative effects of toxic compounds, including the massive reorganization of gene expression networks. Here we report the modulated dose-dependent response of activated genes by diatom polyunsaturated aldehydes (PUAs) in the sea urchin Paracentrotus lividus. PUAs are secondary metabolites deriving from the oxidation of fatty acids, inducing deleterious effects on the reproduction and development of planktonic and benthic organisms that feed on these unicellular algae and with anti-cancer activity. Our previous results showed that PUAs target several genes, implicated in different functional processes in this sea urchin. Using interactomic Ingenuity Pathway Analysis we now show that the genes targeted by PUAs are correlated with four HUB genes, NF-κB, p53, δ-2-catenin and HIF1A, which have not been previously reported for P. lividus. We propose a working model describing hypothetical pathways potentially involved in toxic aldehyde stress response in sea urchins. This represents the first report on gene networks affected by PUAs, opening new perspectives in understanding the cellular mechanisms underlying the response of benthic organisms to diatom exposure. PMID:26914213

  11. Daidzin: a potent, selective inhibitor of human mitochondrial aldehyde dehydrogenase.

    PubMed

    Keung, W M; Vallee, B L

    1993-02-15

    Human mitochondrial aldehyde dehydrogenase (ALDH-I) is potently, reversibly, and selectively inhibited by an isoflavone isolated from Radix puerariae and identified as daidzin, the 7-glucoside of 4',7-dihydroxyisoflavone. Kinetic analysis with formaldehyde as substrate reveals that daidzin inhibits ALDH-I competitively with respect to formaldehyde with a Ki of 40 nM, and uncompetitively with respect to the coenzyme NAD+. The human cytosolic aldehyde dehydrogenase isozyme (ALDH-II) is nearly 3 orders of magnitude less sensitive to daidzin inhibition. Daidzin does not inhibit human class I, II, or III alcohol dehydrogenases, nor does it have any significant effect on biological systems that are known to be affected by other isoflavones. Among more than 40 structurally related compounds surveyed, 12 inhibit ALDH-I, but only prunetin and 5-hydroxydaidzin (genistin) combine high selectivity and potency, although they are 7- to 15-fold less potent than daidzin. Structure-function relationships have established a basis for the design and synthesis of additional ALDH inhibitors that could both be yet more potent and specific.

  12. Fluorescein Tri-Aldehyde Promotes the Selective Detection of Homocysteine.

    PubMed

    Barve, Aabha; Lowry, Mark; Escobedo, Jorge O; Thainashmuthu, Josephrajan; Strongin, Robert M

    2016-03-01

    Elevated homocysteine levels are a well-known independent risk factor for cardiovascular disease. To date, relatively few selective fluorescent probes for homocysteine detection have been reported. The lack of sensing reagents and remaining challenges largely derive from issues of sensitivity and/or selectivity. For example, homocysteine is a structural homologue of the more abundant (ca, 20-25 fold) aminothiol cysteine, differing only by an additional methylene group side chain. Fluorescein tri-aldehyde, described herein, has been designed and synthesized as a sensitive and selective fluorophore for the detection of homocysteine in human plasma samples. It responds to analytes selectively via a photoinduced electron transfer (PET) inhibition process that is modulated by predictable analyte-dye product hybridization and ionization states. Mulliken population analysis of fluorescein tri-aldehyde and its reaction products reveals that the characteristic formation of multiple cationic of homocysteine-derived heterocycles leads to enhanced relative negative charge build up on the proximal phenolate oxygen of the fluorophore as a contributing factor to selective emission enhancement.

  13. Modulation of therapy-induced senescence by reactive lipid aldehydes

    PubMed Central

    Flor, A C; Doshi, A P; Kron, S J

    2016-01-01

    Current understanding points to unrepairable chromosomal damage as the critical determinant of accelerated senescence in cancer cells treated with radiation or chemotherapy. Nonetheless, the potent senescence inducer etoposide not only targets topoisomerase II to induce DNA damage but also produces abundant free radicals, increasing cellular reactive oxygen species (ROS). Toward examining roles for DNA damage and oxidative stress in therapy-induced senescence, we developed a quantitative flow cytometric senescence assay and screened 36 redox-active agents as enhancers of an otherwise ineffective dose of radiation. While senescence failed to correlate with total ROS, the radiation enhancers, etoposide and the other effective topoisomerase inhibitors each produced high levels of lipid peroxidation. The reactive aldehyde 4-hydroxy-2-nonenal, a lipid peroxidation end product, was sufficient to induce senescence in irradiated cells. In turn, sequestering aldehydes with hydralazine blocked effects of etoposide and other senescence inducers. These results suggest that lipid peroxidation potentiates DNA damage from radiation and chemotherapy to drive therapy-induced senescence. PMID:27453792

  14. Aldehyde dehydrogenase 2 in cardiac protection: a new therapeutic target?

    PubMed Central

    Budas, Grant R; Disatnik, Marie- Hélène; Mochly-Rosen, Daria

    2010-01-01

    Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is emerging as a key enzyme involved in cytoprotection in the heart. ALDH2 mediates both the detoxification of reactive aldehydes such as acetaldehyde and 4-hydroxy-2-nonenal (4-HNE) and the bioactivation of nitroglycerin (GTN) to nitric oxide (NO). In addition, chronic nitrate treatment results in ALDH2 inhibition and contributes to nitrate tolerance. Our lab recently identified ALDH2 to be a key mediator of endogenous cytoprotection. We reported that ALDH2 is phosphorylated and activated by the survival kinase protein kinase C epsilon (PKCε) and found a strong inverse correlation between ALDH2 activity and infarct size. We also identified a small molecule ALDH2 activator (Alda-1) which reduces myocardial infarct size induced by ischemia/reperfusion in vivo. In this review, we discuss evidence that ALDH2 is a key mediator of endogenous survival signaling in the heart, suggest possible cardioprotective mechanisms mediated by ALDH2, and discuss potential clinical implications of these findings. PMID:20005475

  15. Single amino acid polymorphism in aldehyde dehydrogenase gene superfamily.

    PubMed

    Priyadharshini Christy, J; George Priya Doss, C

    2015-01-01

    The aldehyde dehydrogenase gene superfamily comprises of 19 genes and 3 pseudogenes. These superfamily genes play a vital role in the formation of molecules that are involved in life processes, and detoxification of endogenous and exogenous aldehydes. ALDH superfamily genes associated mutations are implicated in various diseases, such as pyridoxine-dependent seizures, gamma-hydroxybutyric aciduria, type II Hyperprolinemia, Sjogren-Larsson syndrome including cancer and Alzheimer's disease. Accumulation of large DNA variations data especially Single Amino acid Polymorphisms (SAPs) in public databases related to ALDH superfamily genes insisted us to conduct a survey on the disease associated mutations and predict their function impact on protein structure and function. Overall this study provides an update and highlights the importance of pathogenic mutations in associated diseases. Using KD4v and Project HOPE a computational based platform, we summarized all the deleterious properties of SAPs in ALDH superfamily genes by the providing valuable insight into structural alteration rendered due to mutation. We hope this review might provide a way to define the deleteriousness of a SAP and helps to understand the molecular basis of the associated disease and also permits precise diagnosis and treatment in the near future.

  16. Mechanism of aldehyde oxidation catalyzed by horse liver alcohol dehydrogenase.

    PubMed

    Olson, L P; Luo, J; Almarsson, O; Bruice, T C

    1996-07-30

    The mechanism of oxidation of benzaldehyde to benzoic acid catalyzed by horse liver alcohol dehydrogenase (HLADH) has been investigated using the HLADH structure at 2.1 A resolution with NAD+ and pentafluorobenzyl alcohol in the active site [Ramaswamy et al. (1994) Biochemistry 33,5230-5237]. Constructs for molecular dynamics (MD) investigations with HLADH were obtained by a best-fit superimposition of benzaldehyde or its hydrate on the pentafluorobenzyl alcohol bound to the active site Zn(II)ion. Equilibrium bond lengths, angles, and dihedral parameters for Zn(II) bonding residues His67, Cys46, and Cys174 were obtained from small-molecule X-ray crystal structures and an ab initio-derived parameterization of zinc in HLADH [Ryde, U. (1995) Proteins: Struct., Funct., Genet. 21,40-56]. Dynamic simulations in CHARMM were carried out on the following three constructs to 100 ps: (MD1) enzyme with NAD+, benzaldehyde, and zinc-ligated HO-in the active site; (MD2) enzyme with NAD+ and hydrated benzaldehyde monoanion bound to zinc via the pro-R oxygen, with a proton residing on the pro-S oxygen; and (MD3) enzyme with NAD+ and hydrated benzaldehyde monoanion bound to zinc via the pro-S oxygen, with a proton residing on the pro-R oxygen. Analyses were done of 800 sample conformations taken in the last 40 ps of dynamics. Structures from MD1 and MD3 were used to define the initial spatial arrangements of reactive functionalities for semiempirical PM3 calculations. Using PM3, model systems were calculated of ground states and some transition states for aldehyde hydration, hydride transfer, and subsequent proton shuttling. With benzaldehyde and zinc-bound hydroxide ion in the active site, the oxygen of Zn(II)-OH resided at a distance of 2.8-5.5 A from the aldehyde carbonyl carbon during the dynamics simulation. This may be compared to the PM3 transition state for attack of the Zn(II)-OH oxygen on the benzaldehyde carbonyl carbon, which has an O...C distance of 1.877 A. HLADH

  17. A Novel NADPH-Dependent Aldehyde Reductase Gene from Saccharomyces cerevisiae NRRL Y-12632 Involved in the Detoxification of Aldehyde Inhibitors Derived from Lignocellulosic Biomass Conversion

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aldehyde inhibitors such as furfural, 5-hydroxymethylfurfural (HMF), anisaldehyde, benzaldehyde, cinnamaldehyde, and phenylaldehyde are commonly generated during lignocellulosic biomass conversion process for low-cost cellulosic ethanol production that interferes with subsequent microbial growth and...

  18. Biogenic aldehyde(s) derived from the action of monoamine oxidase may mediate the antidipsotropic effect of daidzin.

    PubMed

    Keung, W M

    2001-01-30

    Daidzin, a major active principle of an ancient herbal treatment for 'alcohol addiction', was first shown to suppress ethanol intake in Syrian golden hamsters. Since then this activity has been confirmed in Wistar rats, Fawn hooded rats, genetically bred alcohol preferring P rats and African green moneys under various experimental conditions, including two-level operant, two-bottle free-choice, limited access, and alcohol-deprivation paradigms. In vitro, daidzin is a potent and selective inhibitor of mitochondrial aldehyde dehydrogenase (ALDH-2). However, in vivo, it does not affect overall acetaldehyde metabolism in golden hamsters. Using isolated hamster liver mitochondria and 5-hydroxytryptamine (5-HT) and dopamine (DA) as the substrates, we demonstrated that daidzin inhibits the second but not the first step of the MAO/ALDH-2 pathway, the major pathway that catalyzes monoamine metabolism in mitochondria. Correlation studies using structural analogs of daidzin led to the hypothesis that the mitochondrial MAO/ALDH-2 pathway may be the site of action of daidzin and that one or more biogenic aldehydes such as 5-hydroxyindole-3-acetaldehyde (5-HIAL) and/or DOPAL derived from the action of monoamine oxidase (MAO) may be mediators of its antidipsotropic action.

  19. 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.

  20. Effects of cooking method, cooking oil, and food type on aldehyde emissions in cooking oil fumes.

    PubMed

    Peng, Chiung-Yu; Lan, Cheng-Hang; Lin, Pei-Chen; Kuo, Yi-Chun

    2017-02-15

    Cooking oil fumes (COFs) contain a mixture of chemicals. Of all chemicals, aldehydes draw a great attention since several of them are considered carcinogenic and formation of long-chain aldehydes is related to fatty acids in cooking oils. The objectives of this research were to compare aldehyde compositions and concentrations in COFs produced by different cooking oils, cooking methods, and food types and to suggest better cooking practices. This study compared aldehydes in COFs produced using four cooking oils (palm oil, rapeseed oil, sunflower oil, and soybean oil), three cooking methods (stir frying, pan frying, and deep frying), and two foods (potato and pork loin) in a typical kitchen. Results showed the highest total aldehyde emissions in cooking methods were produced by deep frying, followed by pan frying then by stir frying. Sunflower oil had the highest emissions of total aldehydes, regardless of cooking method and food type whereas rapeseed oil and palm oil had relatively lower emissions. This study suggests that using gentle cooking methods (e.g., stir frying) and using oils low in unsaturated fatty acids (e.g., palm oil or rapeseed oil) can reduce the production of aldehydes in COFs, especially long-chain aldehydes such as hexanal and t,t-2,4-DDE.

  1. Peptide-catalyzed 1,4-addition reactions of aldehydes to nitroolefins.

    PubMed

    Kastl, Robert; Arakawa, Yukihiro; Duschmalé, Jörg; Wiesner, Markus; Wennemers, Helma

    2013-01-01

    Conjugate addition reactions of aldehydes to nitroolefins provide synthetically useful gamma-nitroaldehydes. Here we summarize our research on peptide-catalyzed conjugate addition reactions of aldehydes to differently substituted nitroolefins. We show that peptides of the general type Pro-Pro-Xaa (Xaa = acidic amino acid) are not only highly active, robust and stereoselective catalysts but have also remarkable chemoselectivities.

  2. The rhodium catalyzed three-component reaction of diazoacetates, titanium(IV) alkoxides and aldehydes.

    PubMed

    Lu, Chong-Dao; Liu, Hui; Chen, Zhi-Yong; Hu, Wen-Hao; Mi, Ai-Qiao

    2005-05-28

    The rhodium(II)-catalyzed three-component reaction of diazoacetates, titanium alkoxides and aldehydes is shown to give alpha-alkoxyl-beta-hydroxyl acid derivatives; the novel C-C bond formation reaction is proposed to occur through oxonium ylides derived from diazo compounds and titanium alkoxides, and followed by intermolecular trapping by aldehydes.

  3. Acyclovir-induced nephrotoxicity: the role of the acyclovir aldehyde metabolite.

    PubMed

    Gunness, Patrina; Aleksa, Katarina; Bend, John; Koren, Gideon

    2011-11-01

    For decades, acyclovir-induced nephrotoxicity was believed to be secondary to crystalluria. Clinical evidence of nephrotoxicity in the absence of crystalluria suggests that acyclovir induces direct insult to renal tubular cells. We postulated that acyclovir is metabolized by the alcohol dehydrogenase (ADH) enzyme to acyclovir aldehyde, which is metabolized by the aldehyde dehydrognase 2 (ALDH2) enzyme to 9-carboxymethoxymethylguanine (CMMG). We hypothesized that acyclovir aldehyde plays a role in acyclovir-induced nephrotoxicity. Human renal proximal tubular (HK-2) cells were used as our in vitro model. Western blot and enzymes activities assays were performed to determine whether the HK-2 cells express ADH and ALDH2 isozymes, respectively. Cytotoxicity (measured as a function of cell viability) assays were conducted to determine (1) whether the acyclovir aldehyde plays a role in acyclovir-induced nephrotoxicity and (2) whether CMMG induces cell death. A colorimetric assay was performed to determine whether acyclovir was metabolized to an aldehyde in vitro. Our results illustrated that (1) HK-2 cells express ADH and ALDH2 isozymes, (2) 4-methylpyrazole rendered significant protection against cell death, (3) CMMG does not induce cell death, and (4) acyclovir was metabolized to an aldehyde in tubular cells. These data indicate that acyclovir aldehyde is produced in HK-2 cells and that inhibition of its production by 4-methylpyrazole offers significant protection from cell death in vitro, suggesting that acyclovir aldehyde may cause the direct renal tubular insult associated with acyclovir.

  4. Carbinol derivatives via rhodium-catalyzed addition of potassium trifluoro(organo)borates to aldehydes.

    PubMed

    Pucheault, Mathieu; Darses, Sylvain; Genet, Jean-Pierre

    2005-10-07

    Reaction of potassium aryltrifluoroborates with aldehydes, in the presence of a rhodium catalyst, afforded carbinol derivatives in high yields under mild aqueous conditions; this efficient reaction proved to be general, allowing the production of highly hindered diarylmethanols and aliphatic aldehydes were also reactive under these conditions.

  5. Draft Genome Sequence of Aldehyde-Degrading Strain Halomonas axialensis ACH-L-8

    PubMed Central

    Ye, Jun; Ren, Chong; Shan, Xiexie

    2016-01-01

    Halomonas axialensis ACH-L-8, a deep-sea strain isolated from the South China Sea, has the ability to degrade aldehydes. Here, we present an annotated draft genome sequence of this species, which could provide fundamental molecular information on the aldehydes-degrading mechanism. PMID:27081145

  6. Expression pattern, ethanol-metabolizing activities, and cellular localization of alcohol and aldehyde dehydrogenases in human large bowel: association of the functional polymorphisms of ADH and ALDH genes with hemorrhoids and colorectal cancer.

    PubMed

    Chiang, Chien-Ping; Jao, Shu-Wen; Lee, Shiao-Pieng; Chen, Pei-Chi; Chung, Chia-Chi; Lee, Shou-Lun; Nieh, Shin; Yin, Shih-Jiun

    2012-02-01

    Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for metabolism of ethanol. Functional polymorphisms of ADH1B, ADH1C, and ALDH2 genes occur among racial populations. The goal of this study was to systematically determine the functional expressions and cellular localization of ADHs and ALDHs in human rectal mucosa, the lesions of adenocarcinoma and hemorrhoid, and the genetic association of allelic variations of ADH and ALDH with large bowel disorders. Twenty-one surgical specimens of rectal adenocarcinoma and the adjacent normal mucosa, including 16 paired tissues of rectal tumor, normal mucosae of rectum and sigmoid colon from the same individuals, and 18 surgical mixed hemorrhoid specimens and leukocyte DNA samples from 103 colorectal cancer patients, 67 hemorrhoid patients, and 545 control subjects recruited in previous study, were investigated. The isozyme/allozyme expression patterns of ADH and ALDH were identified by isoelectric focusing and the activities were assayed spectrophotometrically. The protein contents of ADH/ALDH isozymes were determined by immunoblotting using the corresponding purified class-specific antibodies; the cellular activity and protein localizations were detected by immunohistochemistry and histochemistry, respectively. Genotypes of ADH1B, ADH1C, and ALDH2 were determined by polymerase chain reaction-restriction fragment length polymorphisms. At 33mM ethanol, pH 7.5, the activity of ADH1C*1/1 phenotypes exhibited 87% higher than that of the ADH1C*1/*2 phenotypes in normal rectal mucosa. The activity of ALDH2-active phenotypes of rectal mucosa was 33% greater than ALDH2-inactive phenotypes at 200μM acetaldehyde. The protein contents in normal rectal mucosa were in the following order: ADH1>ALDH2>ADH3≈ALDH1A1, whereas those of ADH2, ADH4, and ALDH3A1 were fairly low. Both activity and content of ADH1 were significantly decreased in rectal tumors, whereas the ALDH activity remained

  7. Spacecraft Maximum Allowable Concentrations (SMACs) for C3 to C8 Aliphatic Saturated Aldehydes

    NASA Technical Reports Server (NTRS)

    Langford, Shannon D.

    2007-01-01

    Spacecraft maximum allowable concentrations (SMACs) for C3 to C8, straight-chain, aliphatic aldehydes have been previously assessed and have been documented in volume 4 of Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants (James, 2000). These aldehydes as well as associated physical properties are shown in Table 1. The C3 to C8 aliphatic aldehydes can enter the habitable compartments and contaminate breathing air of spacecraft by several routes including incomplete oxidation of alcohols in the Environmental Control and Life Support System (ECLSS) air revitalization subsystem, as a byproduct of human metabolism, through materials off-gassing, or during food preparation. These aldehydes have been detected in the atmosphere of manned space vehicles in the past. Analysis performed by NASA of crew cabin air samples from the Russian Mir Space Station revealed the presence of C3 to C8 aldehydes at concentrations peaking at approximately 0.1 mg/cu m.

  8. Synthesis of bio-based aldehyde from seaweed polysaccharide and its interaction with bovine serum albumin.

    PubMed

    Kholiya, Faisal; Chaudhary, Jai Prakash; Vadodariya, Nilesh; Meena, Ramavatar

    2016-10-05

    Here, we demonstrate a successful synthesis of bio-based aldehyde namely dialdehyde-carboxymethylagarose (DCMA) using carboxymethyagarose (CMA). Further reaction parameters (i.e. reaction temperature, pH and periodate concentration) were optimized to achieve maximum aldehyde content and product yield. The synthesis of DCMA was confirmed by employing FTIR, (1)H NMR, XRD, SEM, AFM, TGA, DSC, EA and GPC techniques. To investigate the aldehyde functionality, DCMA was allowed to interact with BSA and obtained results were found to be comparable with that of synthetic aldehyde (Formaldehyde). Further interaction of DCMA with BSA was confirmed by using UV-vis, FTIR, fluorescent spectroscopy, CD and DLS analysis. Results of this study revealed that bio-based aldehyde behaves like formaldehyde. This study adds value to abundant marine biopolymers and opens the new research area for polymer researchers.

  9. Chromatographic approaches for determination of low-molecular mass aldehydes in bio-oil.

    PubMed

    Tessini, Catherine; Müller, Niels; Mardones, Claudia; Meier, Dietrich; Berg, Alex; von Baer, Dietrich

    2012-01-06

    HPLC-UV and GC/MS determination of aldehydes in bio-oil were evaluated. HPLC-UV preceded by derivatization with 2,4-dinitrophenylhydrazine allows separation and detection of bio-oil aldehydes, but the derivatization affected the bio-oil stability reducing their quantitative applicability. GC/MS determination of aldehydes was reached by derivatization with o-(2,3,4,5,6-pentafluorobenzyl) hydroxylamine hydrochloride. Two approaches for this reaction were evaluated. The first: "in solution derivatization and head space extraction" and the second: "on fiber derivatization SPME", the latter through an automatic procedure. Both sample treatments allows the quantification of most important aliphatic aldehydes in bio-oil, being the SPME approach more efficient. The aldehyde concentrations in bio-oil were ~2% formaldehyde, ~!0.1% acetaldehyde and ~0.05% propionaldehyde.

  10. Colorimetric monitoring of solid-phase aldehydes using 2,4-dinitrophenylhydrazine.

    PubMed

    Shannon, Simon K; Barany, George

    2004-01-01

    A simple and rapid method to achieve colorimetric monitoring of resin-bound aldehydes, based on ambient temperature reaction with 2,4-dinitrophenylhydrazine (DNPH) in the presence of dilute acid, has been developed as an adjunct to solid-phase organic synthesis and combinatorial chemistry. By this test, the presence of aldehydes is indicated by a red to dark-orange appearance, within a minute. Alternatively, resins that are free of aldehydes or in which aldehyde functions have reacted completely retain their original color. The DNPH test was demonstrated for poly(ethylene glycol)-polystyrene (PEG-PS), aminomethyl polystyrene (AMP), cross-linked ethoxylate acrylate resin (CLEAR), and acryloylated O,O'-bis(2-aminopropyl)poly(ethylene glycol) (PEGA) supports and gave results visible to the naked eye at levels as low as 18 micromol of aldehyde per gram of resin.

  11. The first zinc-promoted, environmentally friendly, and highly efficient acetoxyallylation of aldehydes in aqueous ammonium chloride.

    PubMed

    Lombardo, M; Girotti, R; Morganti, S; Trombini, C

    2001-11-21

    An exceptionally mild acetoxyallylation of aldehydes in water promoted by zinc is reported, using 3-bromo-1-acetoxyprop-1-ene as starting material; simple diastereoselectivity mainly depends on the nature of the aldehyde.

  12. Studies on organic indole-3-aldehyde single crystals

    NASA Astrophysics Data System (ADS)

    Haja Hameed, A. S.; Ravi, G.; Dhanasekaran, R.; Ramasamy, P.

    Indole-3-aldehyde (IA) is a new organic nonlinear material for which its solubility in methanol and acetone was found out using the apparatus fabricated by the authors. In order to get the good-quality crystals, methods of evaporation of solvent at room temperature and slow cooling of saturated solution at boiling temperature were adopted. Simulated lattice parameter values were found out using experimentally known " d" values. The etching and mechanical strength studies on different planes of the crystal were carried out. Decomposition temperature, weight loss and different functional bond frequencies associated with the crystal were also found out from differential thermal analysis (DTA), thermo-gravimetric analysis (TGA) and Fourier transform infra-red (FTIR) spectroscopic analysis, respectively.

  13. Does acute exposure to aldehydes impair pulmonary function and structure?

    PubMed

    Abreu, Mariana de; Neto, Alcendino Cândido; Carvalho, Giovanna; Casquillo, Natalia Vasconcelos; Carvalho, Niedja; Okuro, Renata; Ribeiro, Gabriel C Motta; Machado, Mariana; Cardozo, Aléxia; Silva, Aline Santos E; Barboza, Thiago; Vasconcellos, Luiz Ricardo; Rodrigues, Danielle Araujo; Camilo, Luciana; Carneiro, Leticia de A M; Jandre, Frederico; Pino, Alexandre V; Giannella-Neto, Antonio; Zin, Walter A; Corrêa, Leonardo Holanda Travassos; Souza, Marcio Nogueira de; Carvalho, Alysson R

    2016-07-15

    Mixtures of anhydrous ethyl alcohol and gasoline substituted for pure gasoline as a fuel in many Brazilian vehicles. Consequently, the concentrations of volatile organic compounds (VOCs) such as ketones, other organic compounds, and particularly aldehydes increased in many Brazilian cities. The current study aims to investigate whether formaldehyde, acetaldehyde, or mixtures of both impair lung function, morphology, inflammatory and redox responses at environmentally relevant concentrations. For such purpose, C57BL/6 mice were exposed to either medical compressed air or to 4 different mixtures of formaldehyde and acetaldehyde. Eight hours later animals were anesthetized, paralyzed and lung mechanics and morphology, inflammatory cells and IL-1β, KC, TNF-α, IL-6, CCL2, MCP-1 contents, superoxide dismutase and catalalase activities were determined. The extra pulmonary respiratory tract was also analyzed. No differences could be detected between any exposed and control groups. In conclusion, no morpho-functional alterations were detected in exposed mice in relation to the control group.

  14. Electron impact ionization of cycloalkanes, aldehydes, and ketones

    SciTech Connect

    Gupta, Dhanoj; Antony, Bobby

    2014-08-07

    The theoretical calculations of electron impact total ionization cross section for cycloalkane, aldehyde, and ketone group molecules are undertaken from ionization threshold to 2 keV. The present calculations are based on the spherical complex optical potential formalism and complex scattering potential ionization contribution method. The results of most of the targets studied compare fairly well with the recent measurements, wherever available and the cross sections for many targets are predicted for the first time. The correlation between the peak of ionization cross sections with number of target electrons and target parameters is also reported. It was found that the cross sections at their maximum depend linearly with the number of target electrons and with other target parameters, confirming the consistency of the values reported here.

  15. Enzymatic oxidation of phthalazine with guinea pig liver aldehyde oxidase and liver slices: inhibition by isovanillin.

    PubMed

    Panoutsopoulos, Georgios I; Beedham, Christine

    2004-01-01

    The enzymes aldehyde oxidase and xanthine oxidase catalyze the oxidation of a wide range of N-heterocycles and aldehydes. These enzymes are widely known for their role in the metabolism of N-heterocyclic xenobiotics where they provide a protective barrier by aiding in the detoxification of ingested nitrogen-containing heterocycles. Isovanillin has been shown to inhibit the metabolism of aromatic aldehydes by aldehyde oxidase, but its inhibition towards the heterocyclic compounds has not been studied. The present investigation examines the oxidation of phthalazine in the absence and in the presence of the inhibitor isovanillin by partially purified aldehyde oxidase from guinea pig liver. In addition, the interaction of phthalazine with freshly prepared guinea pig liver slices, both in the absence and presence of specific inhibitors of several liver oxidizing enzymes, was investigated. ldehyde oxidase rapidly converted phthalazine into 1-phthalazinone, which was completely inhibited in the presence of isovanillin (a specific inhibitor of aldehyde oxidase). In freshly prepared liver slices, phthalazine was also rapidly converted to 1-phthalazinone. The formation of 1-phthalazinone was completely inhibited by isovanillin, whereas disulfiram (a specific inhibitor of aldehyde dehydrogenase) only inhibited 1-phthalazinone formation by 24% and allopurinol (a specific inhibitor of xanthine oxidase) had little effect. Therefore, isovanillin has been proved as an inhibitor of the metabolism of heterocyclic substrates, such as phthalazine, by guinea pig liver aldehyde oxidase, since it had not been tested before. Thus it would appear from the inhibitor results that aldehyde oxidase is the predominant enzyme in the oxidation of phthalazine to 1-phthalazinone in freshly prepared guinea pig liver slices, whereas xanthine oxidase only contributes to a small extent and aldehyde dehydrogenase does not take any part.

  16. Pharmacological activities of cilantro's aliphatic aldehydes against Leishmania donovani.

    PubMed

    Donega, Mateus A; Mello, Simone C; Moraes, Rita M; Jain, Surendra K; Tekwani, Babu L; Cantrell, Charles L

    2014-12-01

    Leishmaniasis is a chronic infectious disease caused by different Leishmania species. Global occurrences of this disease are primarily limited to tropical and subtropical regions. Treatments are available; however, patients complain of side effects. Different species of plants have been screened as a potential source of new drugs against leishmaniasis. In this study, we investigated the antileishmanial activity of cilantro (Coriandrum sativum) essential oil and its main components: (E)-2-undecenal, (E)-2-decenal, (E)-2-dodecenal, decanal, dodecanal, and tetradecanal. The essential oil of C. sativum leaves inhibits growth of Leishmani donovani promastigotes in culture with an IC50 of 26.58 ± 6.11 µg/mL. The aliphatic aldehydes (E)-2-decenal (7.85 ± 0.28 µg/mL), (E)-2-undecenal (2.81 ± 0.21 µg/mL), and (E)-2-dodecenal (4.35 ± 0.15 µg/mL), all isolated from C. sativum essential oil, are effective inhibitors of in vitro cultures of L. donovani promastigotes. Aldehydes (E)-2-decenal, (E)-2-undecenal, and (E)-2-dodecenal were also evaluated against axenic amastigotes and IC50 values were determined to be 2.47 ± 0.25 µg/mL, 1.25 ± 0.11 µg/mL, and 4.78 ± 1.12 µg/mL, respectively. (E)-2-Undecenal and (E)-2-dodecenal demonstrated IC50 values of 5.65 ± 0.19 µg/mL and 9.60 ± 0.89 µg/mL, respectively, against macrophage amastigotes. These cilantro compounds showed no cytotoxicity against THP-1 macrophages.

  17. [Effects of panthenol and carnitine on aldehyde metabolic enzymes in rats with tetrachloromethane-induced liver injury].

    PubMed

    Satanovskaia, V I; Pron'ko, P S; Gaĭshmanova, A V; Miskevich, D A

    2009-01-01

    Tetrachloromethane (2 g/kg, intragastric) produced a decrease in the activity of NAD- and NADH- dependent aldehyde dehydrogenases with high Km for aldehydes in rat liver. Panthenol and L-carnitine administered separately normalized the activity of aldehyde dehydrogenases, while a combination of the drugs did not produce any significant effect.

  18. Alcohol and aldehyde dehydrogenase polymorphisms and a new strategy for prevention and screening for cancer in the upper aerodigestive tract in East Asians.

    PubMed

    Yokoyama, Akira; Omori, Tai; Yokoyama, Tetsuji

    2010-01-01

    The ethanol in alcoholic beverages and the acetaldehyde associated with alcohol consumption are Group 1 human carcinogens (WHO, International Agency for Research on Cancer). The combination of alcohol consumption, tobacco smoking, the inactive heterozygous aldehyde dehydrogenase-2 genotype (ALDH2*1/*2) and the less-active homozygous alcohol dehydrogenase-1B genotype (ADH1B*1/*1) increases the risk of squamous cell carcinoma (SCC) in the upper aerodigestive tract (UADT) in a multiplicative fashion in East Asians. In addition to being exposed to locally high levels of ethanol, the UADT is exposed to a very high concentration of acetaldehyde from a variety of sources, including that as an ingredient of alcoholic beverages per se and that found in tobacco smoke; acetaldehyde is also produced by salivary microorganisms and mucosal enzymes and is present as blood acetaldehyde. The inefficient degradation of acetaldehyde by weakly expressed ALDH2 in the UADT may be cri! tical to the local accumulation of acetaldehyde, especially in ALDH2*1/*2 carriers. ADH1B*1/*1 carriers tend to experience less intense alcohol flushing and are highly susceptible to heavy drinking and alcoholism. Heavy drinking by persons with the less-active ADH1B*1/*1 leads to longer exposure of the UADT to salivary ethanol and acetaldehyde. The ALDH2*1/*2 genotype is a very strong predictor of synchronous and metachronous multiple SCCs in the UADT. High red cell mean corpuscular volume (MCV), esophageal dysplasia, and melanosis in the UADT, all of which are frequently found in ALDH2*1/*2 drinkers, are useful for identifying high-risk individuals. We invented a simple flushing questionnaire that enables prediction of the ALDH2 phenotype. New health appraisal models that include ALDH2 genotype, the simple flushing questionnaire, or MCV are powerful tools for devising a new strategy for prevention and screening for UADT cancer in East Asians.

  19. Genetic polymorphisms of alcohol dehydrogense-1B and aldehyde dehydrogenase-2, alcohol flushing, mean corpuscular volume, and aerodigestive tract neoplasia in Japanese drinkers.

    PubMed

    Yokoyama, Akira; Mizukami, Takeshi; Yokoyama, Tetsuji

    2015-01-01

    Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) modulate exposure levels to ethanol/acetaldehyde. Endoscopic screening of 6,014 Japanese alcoholics yielded high detection rates of esophageal squamous cell carcinoma (SCC; 4.1%) and head and neck SCC (1.0%). The risks of upper aerodigestive tract SCC/dysplasia, especially of multiple SCC/dysplasia, were increased in a multiplicative fashion by the presence of a combination of slow-metabolizing ADH1B*1/*1 and inactive heterozygous ALDH2*1/*2 because of prolonged exposure to higher concentrations of ethanol/acetaldehyde. A questionnaire asking about current and past facial flushing after drinking a glass (≈180 mL) of beer is a reliable tool for detecting the presence of inactive ALDH2. We invented a health-risk appraisal (HRA) model including the flushing questionnaire and drinking, smoking, and dietary habits. Esophageal SCC was detected at a high rate by endoscopic mass-screening in high HRA score persons. A total of 5.0% of 4,879 alcoholics had a history of (4.0%) or newly diagnosed (1.0%) gastric cancer. Their high frequency of a history of gastric cancer is partly explained by gastrectomy being a risk factor for alcoholism because of altered ethanol metabolism, e.g., by blood ethanol level overshooting. The combination of H. pylori-associated atrophic gastritis and ALDH2*1/*2 showed the greatest risk of gastric cancer in alcoholics. High detection rates of advanced colorectal adenoma/carcinoma were found in alcoholics, 15.7% of 744 immunochemical fecal occult blood test (IFOBT)-negative alcoholics and 31.5% of the 393 IFOBT-positive alcoholics. Macrocytosis with an MCV≥106 fl increased the risk of neoplasia in the entire aerodigestive tract of alcoholics, suggesting that poor nutrition as well as ethanol/acetaldehyde exposure plays an important role in neoplasia.

  20. Fatty aldehyde and fatty alcohol metabolism: review and importance for epidermal structure and function.

    PubMed

    Rizzo, William B

    2014-03-01

    Normal fatty aldehyde and alcohol metabolism is essential for epidermal differentiation and function. Long-chain aldehydes are produced by catabolism of several lipids including fatty alcohols, sphingolipids, ether glycerolipids, isoprenoid alcohols and certain aliphatic lipids that undergo α- or ω-oxidation. The fatty aldehyde generated by these pathways is chiefly metabolized to fatty acid by fatty aldehyde dehydrogenase (FALDH, alternately known as ALDH3A2), which also functions to oxidize fatty alcohols as a component of the fatty alcohol:NAD oxidoreductase (FAO) enzyme complex. Genetic deficiency of FALDH/FAO in patients with Sjögren-Larsson syndrome (SLS) results in accumulation of fatty aldehydes, fatty alcohols and related lipids (ether glycerolipids, wax esters) in cultured keratinocytes. These biochemical changes are associated with abnormalities in formation of lamellar bodies in the stratum granulosum and impaired delivery of their precursor membranes to the stratum corneum (SC). The defective extracellular SC membranes are responsible for a leaky epidermal water barrier and ichthyosis. Although lamellar bodies appear to be the pathogenic target for abnormal fatty aldehyde/alcohol metabolism in SLS, the precise biochemical mechanisms are yet to be elucidated. Nevertheless, studies in SLS highlight the critical importance of FALDH and normal fatty aldehyde/alcohol metabolism for epidermal function. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.

  1. Control of aldehyde emissions in the diesel engines with alcoholic fuels.

    PubMed

    Krishna, M V S Murali; Varaprasad, C M; Reddy, C Venkata Ramana

    2006-01-01

    The major pollutants emitted from compression ignition (CI) engine with diesel as fuel are smoke and nitrogen oxides (NOx). When the diesel engine is run with alternate fuels, there is need to check alcohols (methanol or ethanol) and aldehydes also. Alcohols cannot be used directly in diesel engine and hence engine modification is essential as alcohols have low cetane number and high latent hear of vaporization. Hence, for use of alcohol in diesel engine, it needs hot combustion chamber, which is provided by low heat rejection (LHR) diesel engine with an air gap insulated piston with superni crown and air gap insulated liner with superni insert. In the present study, the pollution levels of aldehydes are reported with the use of methanol and ethanol as alternate fuels in LHR diesel engine with varying injection pressure, injection timings with different percentage of alcohol induction. The aldehydes (formaldehyde and acetaldehyde) in the exhaust were estimated by wet chemical technique with high performance liquid chromatograph (HPLC). Aldehyde emissions increased with an increase in alcohol induction. The LHR engine showed a decrease in aldehyde emissions when compared to conventional engine. However, the variation of injection pressure showed a marginal effect in reducing aldehydes, while advancing the injection timing reduced aldehyde emissions.

  2. Properties of aldehyde dehydrogenas from chemically-induced rat hepatomas and normal rat liver.

    PubMed

    Lindahl, R

    1980-01-01

    The subcellular distribution and properties of four aldehyde dehydrogenase isozymes (I-IV) identified in 2-acetylaminofluorene-induced rat hepatomas and three aldehyde dehydrogenase (I-III) identified in normal rat liver are compared. In normal liver, mitochondria (50%) and microsomes (27%) possess the majority of the aldehyde dehydrogenase (AlDH), with cytosol possessing little activity. Isozymes I-III can be identified in both fractions and can be differentiated on the basis of substrate and coenzyme specificity, substrate Km, inhibition by disulfiram and anti-hepatoma aldehyde dehydrogenase sera, and/or isoelectric point. Hepatomas possess considerable cytosolic AlDH (20%), in addition to mitochondrial (23%) and microsomal (35%) activity. Although isozymes I-III are present in tumor mitochondria and microsomes, little isozyme I or II is found in cytosol. Hepatoma cytosolic AlDH is composed (50%) of a hepatoma-specific isozyme (IV), differing in several properties from isozymes I-III; the remainder of the tumor cytosolic activity is due to isozyme III (48%). The data indicate that expression of the tumor-specific aldehyde dehydrogenase phenotype requires both qualitative and quantitative changes involving cytosolic and microsomal aldehyde dehydrogenase. The qualitative change requires the derepression of a gene for an aldehyde dehydrogenase expressed in normal liver only following exposure to potentially harmful xenobiotics. The quantitative change involves both an increase in activity and change in subcellular location of a basal, normal liver AlDH isozyme.

  3. Fatty Aldehyde and Fatty Alcohol Metabolism: Review and Importance for Epidermal Structure and Function

    PubMed Central

    Rizzo, William B.

    2014-01-01

    Normal fatty aldehyde and alcohol metabolism is essential for epidermal differentiation and function. Long-chain aldehydes are produced by catabolism of several lipids including fatty alcohols, sphingolipids, ether glycerolipids, isoprenoid alcohols and certain aliphatic lipids that undergo α- or ω-oxidation. The fatty aldehyde generated by these pathways is chiefly metabolized to fatty acid by fatty aldehyde dehydrogenase (FALDH, alternately known as ALDH3A2), which also functions to oxidize fatty alcohols as a component of the fatty alcohol:NAD oxidoreductase (FAO) enzyme complex. Genetic deficiency of FALDH/FAO in patients with Sjögren-Larsson syndrome (SLS) results in accumulation of fatty aldehydes, fatty alcohols and related lipids (ether glycerolipids, wax esters) in cultured keratinocytes. These biochemical changes are associated with abnormalities in formation of lamellar bodies in the stratum granulosum and impaired delivery of their precursor membranes to the stratum corneum (SC). The defective extracellular SC membranes are responsible for a leaky epidermal water barrier and ichthyosis. Although lamellar bodies appear to be the pathogenic target for abnormal fatty aldehyde/alcohol metabolism in SLS, the precise biochemical mechanisms are yet to be elucidated. Nevertheless, studies in SLS highlight the critical importance of FALDH and normal fatty aldehyde/alcohol metabolism for epidermal function. PMID:24036493

  4. Prognostic significance of stem cell-related marker expression and its correlation with histologic subtypes in lung adenocarcinoma

    PubMed Central

    Park, Eunhyang; Park, Soo Young; Sun, Ping-Li; Jin, Yan; Kim, Ji Eun; Jheon, Sanghoon; Kim, Kwhanmien; Lee, Choon Taek

    2016-01-01

    Cancer stem cells (CSCs) are a small subset of tumor cells that exhibit stem cell-like properties and contribute in treatment failure. To clarify the expression and prognostic significance of several CSC markers in non-small cell lung cancer, we retrospectively analyzed 368 patients with adenocarcinoma (n = 226) or squamous cell carcinoma (n = 142). We correlated the expression of six CSC markers – CD133, CD44, aldehyde dehydrogenase 1 (ALDH1), sex determining region Y-box 2 (SOX2), octamer binding transcription factor 4 (OCT4), and Nanog – with clinicopathologic and molecular variables and survival outcomes. In adenocarcinoma, CD133, ALDH1 and CD44 expression was associated with low pathologic stage and absence of lymphovascular invasion, while Nanog expression correlated with high histologic grade, lymphatic invasion and increased expression of Snail-1, a transcription factor associated with epithelial-mesenchymal transition. CSC marker expression was also associated with histologic subtypes in adenocarcinoma. Multivariate analysis showed that high Nanog expression was an independent factor associated with a poor prognosis in adenocarcinoma. CSC markers had no prognostic value in squamous cell carcinoma. These results suggest that Nanog is an independent negative prognostic factor that may be associated with epithelial-mesenchymal transition in lung adenocarcinoma. PMID:27285762

  5. Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer.

    PubMed

    Aguilera, Óscar; González-Sancho, José Manuel; Zazo, Sandra; Rincón, Raúl; Fernández, Agustín F; Tapia, Olga; Canals, Francesc; Morte, Beatriz; Calvanese, Vincenzo; Orgaz, José L; Niell, Núria; Aguilar, Susana; Freije, José M; Graña, Osvaldo; Pisano, David G; Borrero, Aurea; Martínez-Useros, Javier; Jiménez, Benilde; Fraga, Mario F; García-Foncillas, Jesús; López-Otín, Carlos; Lafarga, Miguel; Rojo, Federico; Muñoz, Alberto

    2015-03-20

    Sporadic colorectal cancer (CRC) insurgence and progression depend on the activation of Wnt/β-catenin signaling. Dickkopf (DKK)-1 is an extracellular inhibitor of Wnt/β-catenin signaling that also has undefined β-catenin-independent actions. Here we report for the first time that a proportion of DKK-1 locates within the nucleus of healthy small intestine and colon mucosa, and of CRC cells at specific chromatin sites of active transcription. Moreover, we show that DKK-1 regulates several cancer-related genes including the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) and Ral-binding protein 1-associated Eps domain-containing 2 (REPS2), which are involved in detoxification of chemotherapeutic agents. Nuclear DKK-1 expression is lost along CRC progression; however, it remains high in a subset (15%) of CRC patients (n = 699) and associates with decreased progression-free survival (PFS) after chemotherapy administration and overall survival (OS) [adjusted HR, 1.65; 95% confidence interval (CI), 1.23-2.21; P = 0.002)]. Overexpression of ALDH1A1 and REPS2 associates with nuclear DKK-1 expression in tumors and correlates with decreased OS (P = 0.001 and 0.014) and PFS. In summary, our findings demonstrate a novel location of DKK-1 within the cell nucleus and support a role of nuclear DKK-1 as a predictive biomarker of chemoresistance in colorectal cancer.

  6. Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer

    PubMed Central

    Zazo, Sandra; Rincón, Raúl; Fernández, Agustín F.; Tapia, Olga; Canals, Francesc; Morte, Beatriz; Calvanese, Vincenzo; Orgaz, José L.; Niell, Núria; Aguilar, Susana; Freije, José M.; Graña, Osvaldo; Pisano, David G.; Borrero, Aurea; Martínez-Useros, Javier; Jiménez, Benilde; Fraga, Mario F.; García-Foncillas, Jesús; López-Otín, Carlos; Lafarga, Miguel; Rojo, Federico; Muñoz, Alberto

    2015-01-01

    Sporadic colorectal cancer (CRC) insurgence and progression depend on the activation of Wnt/β-catenin signaling. Dickkopf (DKK)-1 is an extracellular inhibitor of Wnt/β-catenin signaling that also has undefined β-catenin-independent actions. Here we report for the first time that a proportion of DKK-1 locates within the nucleus of healthy small intestine and colon mucosa, and of CRC cells at specific chromatin sites of active transcription. Moreover, we show that DKK-1 regulates several cancer-related genes including the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) and Ral-binding protein 1-associated Eps domain-containing 2 (REPS2), which are involved in detoxification of chemotherapeutic agents. Nuclear DKK-1 expression is lost along CRC progression; however, it remains high in a subset (15%) of CRC patients (n = 699) and associates with decreased progression-free survival (PFS) after chemotherapy administration and overall survival (OS) [adjusted HR, 1.65; 95% confidence interval (CI), 1.23-2.21; P = 0.002)]. Overexpression of ALDH1A1 and REPS2 associates with nuclear DKK-1 expression in tumors and correlates with decreased OS (P = 0.001 and 0.014) and PFS. In summary, our findings demonstrate a novel location of DKK-1 within the cell nucleus and support a role of nuclear DKK-1 as a predictive biomarker of chemoresistance in colorectal cancer. PMID:25788273

  7. Direct Access to β-Fluorinated Aldehydes by Nitrite-Modified Wacker Oxidation.

    PubMed

    Chu, Crystal K; Ziegler, Daniel T; Carr, Brian; Wickens, Zachary K; Grubbs, Robert H

    2016-07-11

    An aldehyde-selective Wacker-type oxidation of allylic fluorides proceeds with a nitrite catalyst. The method represents a direct route to prepare β-fluorinated aldehydes. Allylic fluorides bearing a variety of functional groups are transformed in high yield and very high regioselectivity. Additionally, the unpurified aldehyde products serve as versatile intermediates, thus enabling access to a diverse array of fluorinated building blocks. Preliminary mechanistic investigations suggest that inductive effects have a strong influence on the rate and regioselectivity of the oxidation.

  8. Formal [4 + 2] cycloaddition of donor-acceptor cyclobutanes and aldehydes: stereoselective access to substituted tetrahydropyrans.

    PubMed

    Parsons, Andrew T; Johnson, Jeffrey S

    2009-10-14

    A highly diastereoselective synthesis of 2,6-cis-disubstituted tetrahydropyrans (THPs) via Lewis acid-catalyzed formal [4 + 2] cycloaddition of donor-acceptor cyclobutanes and aldehydes has been developed. THP products are formed in up to 96% yield and 99:1 diastereoselectivity. Aromatic, cinnamyl, and aliphatic aldehydes are competent dipolarophiles in this system. This methodology was extended to a [[2 + 2] + 2] cycloaddition of 4-methoxystyrene, dimethyl methylidene malonate, and an aldehyde to furnish THPs directly without prior isolation of the cyclobutane.

  9. [The role of hepatic and erythrocyte aldehyde dehydrogenase in the development of burn toxemia in rats].

    PubMed

    Solov'eva, A G

    2009-01-01

    The study was designed to examine catalytic properties of non-specific aldehyde dehydrogenase from rat liver and erythrocyte as the main markers of endogenous intoxication after burn. Enzymatic activity was assayed from changes in the rate of NADH synthesis during acetaldehyde oxidation. Burn was shown to decrease it both in the liver and in erythrocytes which resulted in the accumulation of toxic aldehydes and the development of intoxication. Simultaneous fall in alcohol dehydrogenase and lactate dehydrogenase activities is supposed to contribute to the decrease of aldehyde dehydrogenase activity as a result of thermal injury.

  10. Transformations of several monoterpenoids in the presence of aldehydes in supercritical solvents

    NASA Astrophysics Data System (ADS)

    Anikeev, V. I.; Sivcev, V. P.; Il'ina, I. V.; Korchagina, D. V.; Statsenko, O. B.; Volcho, K. P.; Salakhutdinov, N. F.

    2013-03-01

    The reactivity of verbenol epoxide and isopulegol in supercritical solvents in the presence of aromatic aldehydes was studied using a flow type reactor and a heterogeneous catalyst (Al2O3) or no catalyst. The intramolecular transformations or interactions of reagents with the solvent prevailed in all cases; the yield of the products of intermolecular reactions of terpenoids with aldehydes was up to 1%. The aldehydes did not interact with verbenol epoxide but produced a considerable effect on the distribution of its isomerization products.

  11. An Efficient Synthesis of 2-Substituted Benzimidazoles via Photocatalytic Condensation of o-Phenylenediamines and Aldehydes.

    PubMed

    Kovvuri, Jeshma; Nagaraju, Burri; Kamal, Ahmed; Srivastava, Ajay K

    2016-10-10

    A photocatalytic method has been developed for the efficient synthesis of functionalized benzimidazoles. This protocol involves photocatalytic condensation of o-phenylenediamines with various aldehydes using the Rose Bengal as photocatalyst. The method was found to be general and was successfully employed for accessing pharmaceutically important benzimidazoles by the condensation of aromatic, heteroaromatic and aliphatic aldehydes with o-phenylenediamines, in good-to-excellent yields. Notably, the method was found to be effective for the condensation of less reactive heterocyclic aldehydes with o-phenylenediamines.

  12. A SeCSe-Pd(II) pincer complex as a highly efficient catalyst for allylation of aldehydes with allyltributyltin.

    PubMed

    Yao, Qingwei; Sheets, Matthew

    2006-07-07

    An air- and moisture-stable SeCSe-Pd(II) pincer complex was synthesized and found to catalyze the nucleophilic allylation of aldehydes with allyltributyltin. The allylation of a variety of aromatic and aliphatic aldehydes to give the corresponding homoallyl alcohols was performed at room temperature to 60 degrees C in yields ranging from 50% (for typical aliphatic aldehydes) to up to 97% (for aromatic aldehydes) using 5 x 10(-3) to 1 mol % of the Pd catalyst. NMR spectroscopic study indicated that a sigma-allylpalladium intermediate was formed and possibly functions as the nucleophilic species that undergoes addition to the aldehydes.

  13. Reactive ring-opened aldehyde metabolites in benzene hematotoxicity.

    PubMed Central

    Witz, G; Zhang, Z; Goldstein, B D

    1996-01-01

    The hematotoxicity of benzene is mediated by reactive benzene metabolites and possibly by other intermediates including reactive oxygen species. We previously hypothesized that ring-opened metabolites may significantly contribute to benzene hematotoxicity. Consistent with this hypothesis, our studies initially demonstrated that benzene is metabolized in vitro to trans-trans-muconaldehyde (MUC), a reactive six-carbon diene dialdehyde, and that MUC is toxic to the bone marrow in a manner similar to benzene. Benzene toxicity most likely involves interactions among several metabolites that operate by different mechanisms to produce more than one biological effect. Our studies indicate that MUC coadministered with hydroquinone is a particularly potent metabolite combination that causes bone marrow damage, suggesting that the involvement of ring-opened metabolites in benzene toxicity may be related to their biological effects in combination with other benzene metabolites. Studies in our laboratory and by others indicate that MUC is metabolized to a variety of compounds by oxidation or reduction of the aldehyde groups. The aldehydic MUC metabolite 6-hydroxy-trans-trans-2,4-hexadienal (CHO-M-OH), similar to MUC but to a lesser extent, is reactive toward glutathione, mutagenic in V79 cells, and hematotoxic in mice. It is formed by monoreduction of MUC, a process that is reversible and could be of biological significance in benzene bone marrow toxicity. The MUC metabolite 6-hydroxy-trans-trans-2,4-hexadienoic (COOH-M-OH) is an end product of MUC metabolism in vitro. Our studies indicate that COOH-M-OH is a urinary metabolite of benzene in mice, a finding that provides further indirect evidence for the in vivo formation of MUC from benzene. Mechanistic studies showed the formation of cis-trans-muconaldehyde in addition to MUC from benzene incubated in a hydroxyl radical-generating Fenton system. These results suggest that the benzene ring is initially opened to cis

  14. Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease.

    PubMed

    Fitzmaurice, Arthur G; Rhodes, Shannon L; Lulla, Aaron; Murphy, Niall P; Lam, Hoa A; O'Donnell, Kelley C; Barnhill, Lisa; Casida, John E; Cockburn, Myles; Sagasti, Alvaro; Stahl, Mark C; Maidment, Nigel T; Ritz, Beate; Bronstein, Jeff M

    2013-01-08

    Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the substantia nigra. Pesticide exposure has been associated with PD occurrence, and we previously reported that the fungicide benomyl interferes with several cellular processes potentially relevant to PD pathogenesis. Here we propose that benomyl, via its bioactivated thiocarbamate sulfoxide metabolite, inhibits aldehyde dehydrogenase (ALDH), leading to accumulation of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), preferential degeneration of dopaminergic neurons, and development of PD. This hypothesis is supported by multiple lines of evidence. (i) We previously showed in mice the metabolism of benomyl to S-methyl N-butylthiocarbamate sulfoxide, which inhibits ALDH at nanomolar levels. We report here that benomyl exposure in primary mesencephalic neurons (ii) inhibits ALDH and (iii) alters dopamine homeostasis. It induces selective dopaminergic neuronal damage (iv) in vitro in primary mesencephalic cultures and (v) in vivo in a zebrafish system. (vi) In vitro cell loss was attenuated by reducing DOPAL formation. (vii) In our epidemiology study, higher exposure to benomyl was associated with increased PD risk. This ALDH model for PD etiology may help explain the selective vulnerability of dopaminergic neurons in PD and provide a potential mechanism through which environmental toxicants contribute to PD pathogenesis.

  15. Sodium borohydride removes aldehyde inhibitors for enhancing biohydrogen fermentation.

    PubMed

    Lin, Richen; Cheng, Jun; Ding, Lingkan; Song, Wenlu; Zhou, Junhu; Cen, Kefa

    2015-12-01

    To enhance biohydrogen production from glucose and xylose in the presence of aldehyde inhibitors, reducing agent (i.e., sodium borohydride) was in situ added for effective detoxification. The detoxification efficiencies of furfural (96.7%) and 5-hydroxymethylfurfural (5-HMF, 91.7%) with 30mM NaBH4 were much higher than those of vanillin (77.3%) and syringaldehyde (69.3%). Biohydrogen fermentation was completely inhibited without detoxification, probably because of the consumption of nicotinamide adenine dinucleotide (NADH) by inhibitors reduction (R-CHO+2NADH→R-CH2OH+2NAD(+)). Addition of 30mM NaBH4 provided the reducing power necessary for inhibitors reduction (4R-CHO+NaBH4+2H2O→4R-CH2OH+NaBO2). The recovered reducing power in fermentation resulted in 99.3% recovery of the hydrogen yield and 64.6% recovery of peak production rate. Metabolite production and carbon conversion after detoxification significantly increased to 63.7mM and 81.9%, respectively.

  16. Measurements Alcohols, Ketones, and Aldehydes During Trace-P

    NASA Astrophysics Data System (ADS)

    Apel, E. C.; Riemer, D. D.; Hills, A.; Lueb, R.; Fried, A.; Sachse, G.; Crawford, J.; Singh, H.; Blake, D.

    2002-12-01

    A sensitive and selective instrument (fast gas chromatographic mass spectrometer - FGCMS) was developed for the continuous measurement of oxygenated volatile organic compounds (OVOCs: alcohols, ketones and aldehydes (except for formaldehyde)) containing fewer than 6 carbon atoms and subsequently deployed during the NASA's TRACE-P (Transport and Chemical Evolution over the Pacific) experiment. This paper will briefly describe the instrument and present results obtained from 15 mission flights. Dramatic differences were observed in the mixing ratios and vertical profiles of the longer-lived species, acetone and methanol, compared to the shorter-lived species. For example, between 6 and 7 km, the median mixing ratios for the two longest lived species measured, acetone and methanol, are 765 pptv and 1061 pptv, respectively whereas the combined mixing ratio for all other species measured was less than 500 pptv. A large variety of air masses were encountered during this experiment and this is reflected in the behavior of the measured OVOCs. Relationships between the OVOCs and other trace species will be explored. Implications of these measurements for our current understanding of global tropospheric chemistry will be discussed.

  17. Aldehyde dehydrogenase 2 inhibits inflammatory response and regulates atherosclerotic plaque

    PubMed Central

    Wei, Shu-jian; Zhang, Ming-xiang; Wang, Xu-ping; Yuan, Qiu-huan; Xue, Li; Wang, Jia-li; Cui, Zhao-qiang; Zhang, Yun; Xu, Feng; Chen, Yu-guo

    2016-01-01

    Previous studies demonstrated that aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which eliminates ALDH2 activity down to 1%-6%, is a susceptibility gene for coronary disease. Here we investigated the underlying mechanisms based on our prior clinical and experimental studies. Male apoE−/− mice were transfected with GFP, ALDH2-overexpression and ALDH2-RNAi lentivirus respectively (n=20 each) after constrictive collars were placed around the right common carotid arteries. Consequently, ALDH2 gene silencing led to an increased en face plaque area, more unstable plaque with heavier accumulation of lipids, more macrophages, less smooth muscle cells and collagen, which were associated with aggravated inflammation. However, ALDH2 overexpression displayed opposing effects. We also found that ALDH2 activity decreased in atherosclerotic plaques of human and aged apoE−/− mice. Moreover, in vitro experiments with human umbilical vein endothelial cells further illustrated that, inhibition of ALDH2 activity resulted in elevating inflammatory molecules, an increase of nuclear translocation of NF-κB, and enhanced phosphorylation of NF-κB p65, AP-1 c-Jun, Jun-N terminal kinase and p38 MAPK, while ALDH2 activation could trigger contrary effects. These findings suggested that ALDH2 can influence plaque development and vulnerability, and inflammation via MAPK, NF-κB and AP-1 signaling pathways. PMID:27191745

  18. Biosynthesis of C9-aldehydes in the moss Physcomitrella patens.

    PubMed

    Stumpe, Michael; Bode, Julia; Göbel, Cornelia; Wichard, Thomas; Schaaf, Andreas; Frank, Wolfgang; Frank, Markus; Reski, Ralf; Pohnert, Georg; Feussner, Ivo

    2006-03-01

    After wounding, the moss Physcomitrella patens emits fatty acid derived volatiles like octenal, octenols and (2E)-nonenal. Flowering plants produce nonenal from C18-fatty acids via lipoxygenase and hydroperoxide lyase reactions, but the moss exploits the C20 precursor arachidonic acid for the formation of these oxylipins. We describe the isolation of the first cDNA (PpHPL) encoding a hydroperoxide lyase from a lower eukaryotic organism. The physiological pathway allocation and characterization of a downstream enal-isomerase gives a new picture for the formation of fatty acid derived volatiles from lower plants. Expression of a fusion protein with a yellow fluorescent protein in moss protoplasts showed that PpHPL was found in clusters in membranes of plastids. PpHPL can be classified as an unspecific hydroperoxide lyase having a substrate preference for 9-hydroperoxides of C18-fatty acids but also the predominant substrate 12-hydroperoxy arachidonic acid is accepted. Feeding experiments using arachidonic acid show an increase in the 12-hydroperoxide being metabolized to C8-aldehydes/alcohols and (3Z)-nonenal, which is rapidly isomerized to (2E)-nonenal. PpHPL knock out lines failed to emit (2E)-nonenal while formation of C8-volatiles was not affected indicating that in contrast to flowering plants, PpHPL is only involved in formation of a specific subset of volatiles.

  19. Aldehyde dehydrogenases in cancer stem cells: potential as therapeutic targets

    PubMed Central

    Clark, David W.

    2016-01-01

    Resistance to current chemotherapeutic or radiation-based cancer treatment strategies is a serious concern. Cancer stem cells (CSCs) are typically able to evade treatment and establish a recurrent tumor or metastasis, and it is these that lead to the majority of cancer deaths. Therefore, a major current goal is to develop treatment strategies that eliminate the resistant CSCs as well as the bulk tumor cells in order to achieve complete disease clearance. Aldehyde dehydrogenases (ALDHs) are important for maintenance and differentiation of stem cells as well as normal development. There is expanding evidence that ALDH expression increases in response to therapy and promotes chemoresistance and survival mechanisms in CSCs. This perspective will discuss a paper by Cojoc and colleagues recently published in Cancer Research, that indicates ALDHs play a key role in resistance to radiation therapy and tumor recurrence in prostate cancer. The authors suggest that ALDHs are a potential therapeutic target for treatment prostate cancer patients to limit radiation resistance and disease recurrence. The findings are consistent with work from other cancers showing ALDHs are major contributors of CSC signaling and resistance to anti-cancer treatments. This perspective will address representative work concerning the validity of ALDH and the associated retinoic acid signaling pathway as chemotherapeutic targets for prostate as well as other cancers. PMID:28149880

  20. Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease

    PubMed Central

    Fitzmaurice, Arthur G.; Rhodes, Shannon L.; Lulla, Aaron; Murphy, Niall P.; Lam, Hoa A.; O’Donnell, Kelley C.; Barnhill, Lisa; Casida, John E.; Cockburn, Myles; Sagasti, Alvaro; Stahl, Mark C.; Maidment, Nigel T.; Ritz, Beate; Bronstein, Jeff M.

    2013-01-01

    Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the substantia nigra. Pesticide exposure has been associated with PD occurrence, and we previously reported that the fungicide benomyl interferes with several cellular processes potentially relevant to PD pathogenesis. Here we propose that benomyl, via its bioactivated thiocarbamate sulfoxide metabolite, inhibits aldehyde dehydrogenase (ALDH), leading to accumulation of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), preferential degeneration of dopaminergic neurons, and development of PD. This hypothesis is supported by multiple lines of evidence. (i) We previously showed in mice the metabolism of benomyl to S-methyl N-butylthiocarbamate sulfoxide, which inhibits ALDH at nanomolar levels. We report here that benomyl exposure in primary mesencephalic neurons (ii) inhibits ALDH and (iii) alters dopamine homeostasis. It induces selective dopaminergic neuronal damage (iv) in vitro in primary mesencephalic cultures and (v) in vivo in a zebrafish system. (vi) In vitro cell loss was attenuated by reducing DOPAL formation. (vii) In our epidemiology study, higher exposure to benomyl was associated with increased PD risk. This ALDH model for PD etiology may help explain the selective vulnerability of dopaminergic neurons in PD and provide a potential mechanism through which environmental toxicants contribute to PD pathogenesis. PMID:23267077

  1. 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.

  2. Nasal pungency and odor of homologous aldehydes and carboxylic acids.

    PubMed

    Cometto-Muñiz, J E; Cain, W S; Abraham, M H

    1998-01-01

    Airborne substances can stimulate both the olfactory and the trigeminal nerve in the nose, giving rise to odor and pungent (irritant) sensations, respectively. Nose, eye, and throat irritation constitute common adverse effects in indoor environments. We measured odor and nasal pungency thresholds for homologous aliphatic aldehydes (butanal through octanal) and carboxylic acids (formic, acetic, butanoic, hexanoic, and octanoic). Nasal pungency was measured in subjects lacking olfaction (i.e., anosmics) to avoid odor biases. Similar to other homologous series, odor and pungency thresholds declined (i.e., sensory potency increased) with increasing carbon chain length. A previously derived quantitative structure-activity relationship (QSAR) based on solvation energies predicted all nasal pungency thresholds, except for acetic acid, implying that a key step in the mechanism for threshold pungency involves transfer of the inhaled substance from the vapor phase to the receptive biological phase. In contrast, acetic acid - with a pungency threshold lower than predicted - is likely to produce threshold pungency through direct chemical reaction with the mucosa. Both in the series studied here and in those studied previously, we reach a member at longer chain-lengths beyond which pungency fades. The evidence suggests a biological cut-off, presumably based upon molecular size, across the various series.

  3. Aldehydes and hydrogen peroxide as mediators of ozone toxicity

    SciTech Connect

    Pryor, W.A.; Church, D.F.; Das, B. )

    1991-03-15

    The unsaturated fatty acids (UFA) in lung lining fluids and cell membranes are a primary target for the reaction of ozone in the lung. The authors propose that ozone reacts with UFA in loci that are sufficiently aquated so the carbonyl oxide is captured by water. The data show that the stoichiometry and products from the reaction of ozone with either emulsions of UFA from oleic through arachidonate or with liposomes made from dioleoyl phosphadidyl choline (PC) are accurately described by eq 1. Soy PC also gives 1 mole of H{sub 2}O{sub 2} per mol of ozone used. Rat lung lavage and rat rbc ghosts give ca. 50% yields of H{sub 2}O{sub 2} based on ozone reacted, presumably due to the reaction of thiol-containing proteins with ozone to give H{sub 2}O{sub 2}. Thus, aldehydes and H{sub 2}O{sub 2} can be used as markers of ozone damage and probably are responsible for much of the pathology caused by ozone, particularly at sites other than immediate air/tissue boundary.

  4. Pd(0)-Catalyzed PMHS reductions of aromatic acid chlorides to aldehydes.

    PubMed

    Lee, Kyoungsoo; Maleczka, Robert E

    2006-04-27

    [reaction: see text] Contrary to previous reports, polymethylhydrosiloxane (PMHS) under Pd(0) catalysis can efficiently reduce aryl acid chlorides to their corresponding aldehydes without requiring an additional reductant, provided the reactions are run in the presence of fluoride.

  5. An efficient enantioselective method for asymmetric Michael addition of nitroalkanes to alpha,beta-unsaturated aldehydes.

    PubMed

    Wang, Yongcan; Li, Pengfei; Liang, Xinmiao; Zhang, Tony Y; Ye, Jinxing

    2008-03-14

    The addition of nitroalkanes to alpha,beta-unsaturated aldehydes under the catalysis of (S)-2-(diphenyl(trimethylsilyloxy)methyl)pyrrolidine and lithium acetate as additive afforded gamma-nitroaldehydes in good yield and up to 97% ee.

  6. Lubricant and fuel compositions containing reaction products of polyalkenyl succinimides, aldehydes, and triazoles

    SciTech Connect

    Blain, D.A.; Cardis, A.B.; McGonigle, S.S.

    1990-10-16

    This patent describes an additive for liquid hydrocarbon fuel composition, particularly diesel fuels. The additive composition is the reaction product of polyalkenyl-substituted succinimides, aldehydes, and triazoles. It also finds use in lubricant compositions.

  7. Unsymmetrical E-Alkenes from the Stereoselective Reductive Coupling of Two Aldehydes.

    PubMed

    Esfandiarfard, Keyhan; Mai, Juri; Ott, Sascha

    2017-03-01

    The unprecedented formation of unsymmetrical alkenes from the intermolecular reductive coupling of two different aldehydes is described. In contrast to the McMurry reaction which affords statistical product mixtures, selectivity in the reported procedure is achieved by a sequential ionic mechanism in which a first aldehyde is reacted with a phosphanylphosphonate to afford a phosphaalkene intermediate which, upon activation by hydroxide, reacts with a second aldehyde to the unsymmetrical E-alkenes. The described reaction is free of transition metals and proceeds under ambient temperature within minutes in good to excellent overall yields. It is a new methodology to use feedstock aldehydes for the direct production of C═C double bond-containing products and may impact how chemists think of multistep synthetic sequences in the future.

  8. A new resistance source of aldehyde reductase functions from Scheffersomyces stipitis against biomass fermentation inhibitor furfural

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aldehyde inhibitory compounds derived from lignocellulosic biomass pretreatment are a major class of toxic chemicals that interfere with microbial growth and subsequent fermentation for advanced biofuels production. This study identified five uncharacterized putative genes of Scheffersomyces stipiti...

  9. Reaction of aminals of conjugated omega-dimethylamino aldehydes with indandione

    SciTech Connect

    Krasnaya, Zh.A.; Stytsenko, T.S.; Gusev, D.G.; Prokof'ev, E.P.

    1987-01-20

    Conjugated omega-dimethylamino ..beta..-diketones with two to five double bonds and trimethylidyne- and pentamethylidyneoxanine salts are formed in the condensation of animals of conjugated ..beta..-dimethylamino aldehydes with indandione.

  10. Fatty aldehyde dehydrogenases in Acinetobacter sp. strain HO1-N: role in hexadecanol metabolism.

    PubMed Central

    Singer, M E; Finnerty, W R

    1985-01-01

    The role of fatty aldehyde dehydrogenases (FALDHs) in hexadecane and hexadecanol metabolism was studied in Acinetobacter sp. strain HO1-N. Two distinct FALDHs were demonstrated in Acinetobacter sp. strain HO1-N: a membrane-bound, NADP-dependent FALDH activity induced 5-, 15-, and 9-fold by growth on hexadecanol, dodecyl aldehyde, and hexadecane, respectively, and a constitutive, NAD-dependent, membrane-localized FALDH. The NADP-dependent FALDH exhibited apparent Km and Vmax values for decyl aldehyde of 5.0, 13.0, 18.0, and 18.3 microM and 537.0, 500.0, 25.0, and 38.0 nmol/min in hexadecane-, hexadecanol-, ethanol-, palmitate-grown cells, respectively. FALDH isozymes ald-a, ald-b, and ald-c were demonstrated by gel electrophoresis in extracts of hexadecane- and hexadecanol-grown cells. ald-a, ald-b, and ald-d were present in dodecyl aldehyde-grown cells, while palmitate-grown control cells contained ald-b and ald-d. Dodecyl aldehyde-negative mutants were isolated and grouped into two phenotypic classes based on growth: class 1 mutants were hexadecane and hexadecanol negative and class 2 mutants were hexadecane and hexadecanol positive. Specific activity of NADP-dependent FALDH in Ald21 (class 1 mutant) was 85% lower than that of wild-type FALDH, while the specific activity of Ald24 (class 2 mutant) was 55% greater than that of wild-type FALDH. Ald21R, a dodecyl aldehyde-positive revertant able to grow on hexadecane, hexadecanol, and dodecyl aldehyde, exhibited a 100% increase in the specific activity of the NADP-dependent FALDH. The oxidation of [3H]hexadecane byAld21 yielded the accumulation of 61% more fatty aldehyde than the wild type, while Ald24 accumulated 27% more fatty aldehyde, 95% more fatty alcohol, and 65% more wax ester than the wild type. This study provides genetic and physiological evidence for the role of fatty aldehyde as an essential metabolic intermediate and NADP-dependent FALDH as a key enzyme in the dissimilation of hexadecane, hexadecanol

  11. Rh(I)-Catalyzed Intermolecular Hydroacylation: Enantioselective Cross-Coupling of Aldehydes and Ketoamides

    PubMed Central

    2015-01-01

    Under Rh(I) catalysis, α-ketoamides undergo intermolecular hydroacylation with aliphatic aldehydes. A newly designed Josiphos ligand enables access to α-acyloxyamides with high atom-economy and enantioselectivity. On the basis of mechanistic and kinetic studies, we propose a pathway in which rhodium plays a dual role in activating the aldehyde for cross-coupling. A stereochemical model is provided to rationalize the sense of enantioinduction observed. PMID:24937681

  12. Substrate-Directed Hydroacylation: Rh-Catalyzed Coupling of Vinyl Phenols and Non-Chelating Aldehydes

    PubMed Central

    Murphy, Stephen K.; Bruch, Achim

    2014-01-01

    We report a protocol for branched-selective hydroacylation of vinylphenols with aryl, alkenyl and alkyl aldehydes. This cross-coupling yields α-aryl ketones that can be cyclized to benzofurans, and it enables access to eupomatenoid natural products in four steps or less from eugenol. Excellent reactivity and high levels of branched regioselectivity are obtained. We propose that aldehyde decarbonylation is overcome by using an anionic directing group on the olefin and a small bite-angle diphosphine ligand. PMID:24478146

  13. Unexpected ring-opening reactions of aziridines with aldehydes catalyzed by nucleophilic carbenes under aerobic conditions.

    PubMed

    Liu, Yan-Kai; Li, Rui; Yue, Lei; Li, Bang-Jing; Chen, Ying-Chun; Wu, Yong; Ding, Li-Sheng

    2006-04-13

    [reaction: see text] The chemoselective ring opening of N-tosyl aziridines with aldehydes catalyzed by an N-heterocyclic carbene was investigated under aerobic conditions. Unexpected carboxylates of 1,2-amino alcohols from the corresponding aldehydes, rather than the acyl anion ring-opened beta-amino ketones, were exclusively obtained. A plausible mechanism for this unprecedented carbene-mediated reaction was also proposed.

  14. Photoredox Activation for the Direct β-Arylation of Ketones and Aldehydes

    PubMed Central

    Pirnot, Michael T.; Rankic, Danica A.; Martin, David B. C.; MacMillan, David W. C.

    2013-01-01

    The direct β-activation of saturated aldehydes and ketones has long been an elusive transformation. We found that photoredox catalysis in combination with organocatalysis can lead to the transient generation of 5π-electron β-enaminyl radicals from ketones and aldehydes that rapidly couple with cyano-substituted aryl rings at the carbonyl β-position. This mode of activation is suitable for a broad range of carbonyl β-functionalization reactions and is amenable to enantioselective catalysis. PMID:23539600

  15. Copper(II)/amine synergistically catalyzed enantioselective alkylation of cyclic N-acyl hemiaminals with aldehydes.

    PubMed

    Sun, Shutao; Mao, Ying; Lou, Hongxiang; Liu, Lei

    2015-07-07

    The first catalytic asymmetric alkylation of N-acyl quinoliniums with aldehydes has been described. A copper/amine synergistic catalytic system has been developed, allowing the addition of functionalized aldehydes to a wide range of electronically varied N-acyl quinoliniums in good yields with excellent enantiocontrol. The synergistic catalytic system was also effective for N-acyl dihydroisoquinoliniums and β-caboliniums, demonstrating the general applicability of the protocol in the enantioselective alkylation of diverse cyclic N-acyl hemiaminals.

  16. Functionalization vs. fragmentation: n-aldehyde oxidation mechanisms and secondary organic aerosol formation.

    PubMed

    Chacon-Madrid, Heber J; Presto, Albert A; Donahue, Neil M

    2010-11-14

    Because of their relatively well-understood chemistry and atmospheric relevance, aldehydes represent a good model system for carbon-carbon fragmentation reactions in organic-aerosol aging mechanisms. Small aldehydes such as ethanal and propanal react with OH radicals under high NO(x) conditions to form formaldehyde and ethanal, respectively, with nearly unit yield. CO(2) is formed as a coproduct. This path implies the formation of the C(n-1) aldehyde, or an aldehyde with one fewer methylene group than the parent. However, as the carbon number of the n-aldehyde increases, reaction with the carbon backbone becomes more likely and the C(n-1) formation path becomes less important. In this work we oxidized n-pentanal, n-octanal, n-undecanal and n-tridecanal with OH radicals at high NO(x). The C(n-1) aldehyde molar yields after the peroxyl radical + NO reaction were 69 ± 15, 36 ± 10, 16 ± 5 and 4 ± 1%, respectively. Complementary structure-activity relationship calculations of important rate constants enable estimates of branching ratios between several intermediates of the C(n)n-aldehyde reaction with OH: C(n) peroxyacyl nitrate versus C(n) alkoxyacyl radical formation, C(n-1) alkyl nitrate versus C(n-1) alkoxy radical, and C(n-1) aldehyde formation versus isomerization products. We also measured SOA mass yields, which we compare with analogous n-alkanes to understand the effect of fragmentation on organic-aerosol formation.

  17. Sources and concentrations of aldehydes and ketones in indoor environments in the UK

    SciTech Connect

    Crump, D.R.; Gardiner, D. )

    1989-01-01

    Individual aldehydes and ketones can be separated, identified and quantitatively estimated by trapping the 2,4-dinitrophenylhydrazine (DNPH) derivatives and analysis by HPLC. Appropriate methods and detection limits are reported. Many sources of formaldehyde have been identified by this means and some are found to emit other aldehydes and ketones. The application of this method to determine the concentration of these compounds in the atmospheres of buildings is described and the results compared with those obtained using chromotropic acid or MBTH.

  18. Detoxification of aldehydes by histidine-containing dipeptides: from chemistry to clinical implications

    PubMed Central

    Xie, Zhengzhi; Baba, Shahid P.; Sweeney, Brooke R.; Barski, Oleg A.

    2015-01-01

    Aldehydes are generated by oxidized lipids and carbohydrates at increased levels under conditions of metabolic imbalance and oxidative stress during atherosclerosis, myocardial and cerebral ischemia, diabetes, neurodegenerative diseases and trauma. In most tissues, aldehydes are detoxified by oxidoreductases that catalyze the oxidation or the reduction of aldehydes or enzymatic and nonenzymatic conjugation with low molecular weight thiols and amines, such as glutathione and histidine dipeptides. Histidine dipeptides are present in micromolar to millimolar range in the tissues of vertebrates, where they are involved in a variety of physiological functions such as pH buffering, metal chelation, oxidant and aldehyde scavenging. Histidine dipeptides such as carnosine form Michael adducts with lipid-derived unsaturated aldehydes, and react with carbohydrate-derived oxo- and hydroxy- aldehydes forming products of unknown structure. Although these peptides react with electrophilic molecules at lower rate than glutathione, they can protect glutathione from modification by oxidant and they may be important for aldehyde quenching in glutathione-depleted cells or extracellular space where glutathione is scarce. Consistent with in vitro findings, treatment with carnosine has been shown to diminish ischemic injury, improve glucose control, ameliorate the development of complications in animal models of diabetes and obesity, promote wound healing and decrease atherosclerosis. The protective effects of carnosine have been linked to its anti-oxidant properties, it ability to promote glycolysis, detoxify reactive aldehydes and enhance histamine levels. Thus, treatment with carnosine and related histidine dipeptides may be a promising strategy for the prevention and treatment of diseases associated with high carbonyl load. PMID:23313711

  19. Mass spectral determination of aldehydes, ketones, and carboxylic acids using 1,1-dimethylhydrazine.

    PubMed

    McDaniel, C A; Howard, R W

    1985-03-01

    Analyses of nanogram to milligram quantities of aliphatic aldehydes, fatty acids, and unhindered aliphatic ketones such as those typically found in pheromonal blends have been effected by treating these mixtures with 1,1-dimethylhydrazine. The aldehydes and ketones formN,N-dimethylhydrazones, while the fatty acids form methyl esters. Structural elucidation of the reaction products was achieved using EI and CI gas chromatography-mass spectrometry.

  20. Aldose and aldehyde reductases : structure-function studies on the coenzyme and inhibitor-binding sites.

    SciTech Connect

    El-Kabbani, O.; Old, S. E.; Ginell, S. L.; Carper, D. A.; Biosciences Division; Monash Univ.; NIH

    1999-09-03

    PURPOSE: To identify the structural features responsible for the differences in coenzyme and inhibitor specificities of aldose and aldehyde reductases. METHODS: The crystal structure of porcine aldehyde reductase in complex with NADPH and the aldose reductase inhibitor sorbinil was determined. The contribution of each amino acid lining the coenzyme-binding site to the binding of NADPH was calculated using the Discover package. In human aldose reductase, the role of the non-conserved Pro 216 (Ser in aldehyde reductase) in the binding of coenzyme was examined by site-directed mutagenesis. RESULTS: Sorbinil binds to the active site of aldehyde reductase and is hydrogen-bonded to Trp 22, Tyr 50, His 113, and the non-conserved Arg 312. Unlike tolrestat, the binding of sorbinil does not induce a change in the side chain conformation of Arg 312. Mutation of Pro 216 to Ser in aldose reductase makes the binding of coenzyme more similar to that of aldehyde reductase. CONCLUSIONS: The participation of non-conserved active site residues in the binding of inhibitors and the differences in the structural changes required for the binding to occur are responsible for the differences in the potency of inhibition of aldose and aldehyde reductases. We report that the non-conserved Pro 216 in aldose reductase contributes to the tight binding of NADPH.

  1. Gibberellin Metabolism in Maize (The Stepwise Conversion of Gibberellin A12-Aldehyde to Gibberellin A20.

    PubMed

    Kobayashi, M.; Spray, C. R.; Phinney, B. O.; Gaskin, P.; MacMillan, J.

    1996-02-01

    The stepwise metabolism of gibberellin A12-aldehyde (GA12-aldehyde) to GA20 is demonstrated from seedling shoots of maize (Zea mays L.). The labeled substrates [13C,3H]GA12-aldehyde, [13C,3H]GA12, [14C4]GA53, [14C4/2H2]GA44, and [14C4/2H2]GA19 were fed individually to dwarf-5 vegetative shoots. Both [13C,3H]GA12-aldehyde and [13C,3H]GA12 were also added individually to normal shoots. The labeled metabolites were identified by full-scan gas chromatography-mass spectrometry and Kovats retention indices. GA12-aldehyde was metabolized to GA53-aldehyde, GA12, GA53, GA44, and GA19; GA12 was metabolized to 2[beta]-hydroxy-GA12, GA53, 2[beta]-hydroxyGA53, GA44, 2[beta]-hydroxyGA44, and GA19; GA53 was metabolized to GA44, GA19, GA20, and GA1; GA44 was metabolized to GA19; and GA19 was metabolized to GA20. These results, together with previously published data from this laboratory, document the most completely defined gibberellin pathway for the vegetative tissues of higher plants.

  2. Accurate determination of aldehydes in amine catalysts or amines by 2,4-dinitrophenylhydrazine derivatization.

    PubMed

    Barman, Bhajendra N

    2014-01-31

    Carbonyl compounds, specifically aldehydes, present in amine catalysts or amines are determined by reversed-phase liquid chromatography using ultraviolet detection of their corresponding 2,4-dinitrophenylhydrazones. The primary focus has been to establish optimum conditions for determining aldehydes accurately because these add exposure concerns when the amine catalysts are used to manufacture polyurethane products. Concentrations of aldehydes determined by this method are found to vary with the pH of the aqueous amine solution and the derivatization time, the latter being problematic when the derivatization reaction proceeds slowly and not to completion in neutral and basic media. Accurate determination of aldehydes in amines through derivatization can be carried out at an effective solution pH of about 2 and with derivatization time of 20min. Hydrochloric acid has been used for neutralization of an amine. For complete derivatization, it is essential to protonate all nitrogen atoms in the amine. An approach for the determination of an adequate amount of acid needed for complete derivatization has been described. Several 0.2M buffer solutions varying in pH from 4 to 8 have also been used to make amine solutions for carrying out derivatization of aldehydes. These solutions have effective pHs of 10 or higher and provide much lower aldehyde concentrations compared to their true values. Mechanisms for the formation of 2,4-dinitrophenylhydrazones in both acidic and basic media are discussed.

  3. Brain, liver and plasma unsaturated aldehydes in nutritional encephalomalacia of chicks.

    PubMed

    Fuhrmann, H; Sallmann, H P

    2000-04-01

    Vitamin E deficiency and linoleic acid-feeding lead to nutritional encephalomalacia (NE) in chicks, affecting the cerebellum exclusively. The relevance of lipid peroxidation (LPO) products to the pathogenesis of the disease was studied. Laying hens received a diet low in vitamin E. Resulting chicks were assigned to four groups fed either with linoleic (C18: 2n-6) or linolenic (C18: 3n-3) acid together with 1 or 50 p.p.m. vitamin E. Nine days post-hatching NE occurred in the vitamin E-deficient group fed linoleic acid. With each chick showing NE, a healthy one from all four groups was killed. Unsaturated aldehydes were determined in plasma, liver, cerebrum and cerebellum. Results underlined that the type of dietary fat is decisive for the aldehyde pattern. In the liver of linoleic acid-fed animals total aldehydes were increased. Diseased animals had increased aldehydes stemming from n-3 fatty acids. In plasma, vitamin E deficiency led to higher malondialdehyde and OH-nonenal concentrations. In brain, neither vitamin E deficiency nor NE were accompanied by increased aldehyde concentrations. In consequence a direct role of unsaturated aldehydes for the development of NE in the cerebellum is not probable.

  4. Effect of selected aldehydes on the growth and fermentation of ethanologenic Escherichia coli

    SciTech Connect

    Zaldivar, J.; Ingram, L.O.; Martinez, A. |

    1999-10-05

    Bioethanol production from lignocellulosic raw-materials requires the hydrolysis of carbohydrate polymers into a fermentable syrup. During the hydrolysis of hemicellulose with dilute acid, a variety of toxic compounds are produced such as soluble aromatic aldehydes from lignin and furfural from pentose destruction. In this study, the authors have investigated the toxicity of representative aldehydes (furfural, 5-hydroxymethlyfurfural, 4-hydroxybenzaldehyde, syringaldehyde, and vanillin) as inhibitors of growth and ethanol production by ethanologenic derivatives of Escherichia coli B (strains K011 and LY01). Aromatic aldyhydes were at least twice as toxic as furfural of 5-hydroxymethylfurfural on a weight basis. The toxicities of all aldehydes (and ethanol) except furfural were additive when tested in binary combinations. In all cases, combinations with furfural were unexpectedly toxic. Although the potency of these aldehydes was directly related to hydrophobicity indicating a hydrophobic site of action, none caused sufficient membrane damage to allow the leakage of intracellular magnesium even when present at sixfold the concentrations required for growth inhibition. Of the aldehydes tested, only furfural strongly inhibited ethanol production in vitro. A comparison with published results for other microorganisms indicates that LY01 is equivalent or more resistant than other biocatalysts to the aldehydes examined in this study.

  5. Introduction of aldehyde vs. carboxylic groups to cellulose nanofibers using laccase/TEMPO mediated oxidation.

    PubMed

    Jaušovec, Darja; Vogrinčič, Robert; Kokol, Vanja

    2015-02-13

    The chemo-enzymatic modification of cellulose nanofibers (CNFs) using laccase as biocatalysts and TEMPO or 4-Amino-TEMPO as mediators under mild aqueous conditions (pH 5, 30 °C) has been investigated to introduce surface active aldehyde groups. 4-Amino TEMPO turned out to be kinetically 0.5-times (50%) more active mediator, resulting to oxoammonium cation intermediacy generated and its in situ regeneration during the modification of CNFs. Accordingly, beside of around 750 mmol/kg terminally-located aldehydes, originated during CNFs isolation, the reaction resulted to about 140% increase of C6-located aldehydes at optimal conditions, without reducing CNFs crystallinity. While only the C6-aldehydes were wholly transformed into the carboxyls after additional post-treatment using NaOH according to the Cannizzaro reaction, the post-oxidation with air-oxygen in EtOH/water medium or NaClO2 resulted to no- or very small amounts of carboxyls created, respectively, at a simultaneous loss of all C6- and some terminal-aldehydes in the latter due to the formation of highly-resistant hemiacetal covalent linkages with available cellulose hydroxyls. The results indicated a new way of preparing and stabilizing highly reactive C6-aldehydes on cellulose, and their exploitation in the development of new nanocellulose-based materials.

  6. Reduced aldehyde dehydrogenase expression in preeclamptic decidual mesenchymal stem/stromal cells is restored by aldehyde dehydrogenase agonists

    PubMed Central

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

    2017-01-01

    High resistance to oxidative stress is a common feature of mesenchymal stem/stromal cells (MSC) and is associated with higher cell survival and ability to respond to oxidative damage. Aldehyde dehydrogenase (ALDH) activity is a candidate “universal” marker for stem cells. ALDH expression was significantly lower in decidual MSC (DMSC) isolated from preeclamptic (PE) patients. ALDH gene knockdown by siRNA transfection was performed to create a cell culture model of the reduced ALDH expression detected in PE-DMSC. We showed that ALDH activity in DMSC is associated with resistance to hydrogen peroxide (H2O2)-induced toxicity. Our data provide evidence that ALDH expression in DMSC is required for cellular resistance to oxidative stress. Furthermore, candidate ALDH activators were screened and two of the compounds were effective in upregulating ALDH expression. This study provides a proof-of-principle that the restoration of ALDH activity in diseased MSC is a rational basis for a therapeutic strategy to improve MSC resistance to cytotoxic damage. PMID:28205523

  7. Residues that influence coenzyme preference in the aldehyde dehydrogenases.

    PubMed

    González-Segura, Lilian; Riveros-Rosas, Héctor; Julián-Sánchez, Adriana; Muñoz-Clares, Rosario A

    2015-06-05

    To find out the residues that influence the coenzyme preference of aldehyde dehydrogenases (ALDHs), we reviewed, analyzed and correlated data from their known crystal structures and amino-acid sequences with their published kinetic parameters for NAD(P)(+). We found that the conformation of the Rossmann-fold loops participating in binding the adenosine ribose is very conserved among ALDHs, so that coenzyme specificity is mainly determined by the nature of the residue at position 195 (human ALDH2 numbering). Enzymes with glutamate or proline at 195 prefer NAD(+) because the side-chains of these residues electrostatically and/or sterically repel the 2'-phosphate group of NADP(+). But contrary to the conformational rigidity of proline, the conformational flexibility of glutamate may allow NADP(+)-binding in some enzymes by moving the carboxyl group away from the 2'-phosphate group, which is possible if a small neutral residue is located at position 224, and favored if the residue at position 53 interacts with Glu195 in a NADP(+)-compatible conformation. Of the residues found at position 195, only glutamate interacts with the NAD(+)-adenosine ribose; glutamine and histidine cannot since their side-chain points are opposite to the ribose, probably because the absence of the electrostatic attraction by the conserved nearby Lys192, or its electrostatic repulsion, respectively. The shorter side-chains of other residues-aspartate, serine, threonine, alanine, valine, leucine, or isoleucine-are distant from the ribose but leave room for binding the 2'-phosphate group. Generally, enzymes having a residue different from Glu bind NAD(+) with less affinity, but they can also bind NADP(+) even sometimes with higher affinity than NAD(+), as do enzymes containing Thr/Ser/Gln195. Coenzyme preference is a variable feature within many ALDH families, consistent with being mainly dependent on a single residue that apparently has no other structural or functional roles, and therefore can

  8. Aldehyde measurements in indoor environments in Strasbourg (France)

    NASA Astrophysics Data System (ADS)

    Marchand, C.; Bulliot, B.; Le Calvé, S.; Mirabel, Ph.

    Formaldehyde and acetaldehyde concentrations have been measured in indoor environments of various public spaces (railway station, airport, shopping center, libraries, underground parking garage, etc.) of Strasbourg area (east of France). In addition, formaldehyde, acetaldehyde propionaldehyde and hexanal concentrations have been measured in 22 private homes in the same area. In most of the sampling sites, indoor and outdoor formaldehyde and acetaldehyde concentrations were measured simultaneously. Gaseous aldehydes levels were quantified by a conventional DNHP-derivatization method followed by liquid chromatography coupled to UV detection. Outdoor formaldehyde and acetaldehyde concentrations were both in the range 1-10 μg m -3, the highest values being measured at the airport and railway station. Indoor concentrations were strongly dependant upon the sampling sites. In homes, the average concentrations were 37 μg m -3 (living rooms) and 46 μg m -3 (bedrooms) for formaldehyde, 15 μg m -3 (living rooms) and 18 μg m -3 (bedrooms) for acetaldehyde, 1.2 μg m -3 (living rooms) and 1.6 μg m -3 (bedrooms) for propionaldehyde, 9 μg m -3 (living rooms) and 10 μg m -3 (bedrooms) for hexanal. However, concentrations as high as 123, 80 and 47 μg m -3 have been found for formaldehyde, acetaldehyde and hexanal respectively. In public spaces, the highest formaldehyde concentration (62 μg m -3) was found in a library and the highest concentration of acetaldehyde (26 μg m -3) in the hall of a shopping center. Additional measurements of formaldehyde and acetaldehyde were made inside a car both at rest or in a fluid or heavy traffic as well as in a room where cigarettes were smoked. Our data have been discussed and compared with those of previous studies.

  9. Characterization of aldehyde oxidase enzyme activity in cryopreserved human hepatocytes.

    PubMed

    Hutzler, J Matthew; Yang, Young-Sun; Albaugh, Daniel; Fullenwider, Cody L; Schmenk, Jennifer; Fisher, Michael B

    2012-02-01

    Substrates of aldehyde oxidase (AO), for which human clinical pharmacokinetics are reported, were selected and evaluated in pooled mixed-gender cryopreserved human hepatocytes in an effort to quantitatively characterize AO activity. Estimated hepatic clearance (Cl(h)) for BIBX1382, carbazeran, O⁶-benzylguanine, zaleplon, and XK-469 using cryopreserved hepatocytes was 18, 17, 12, <4.3, and <4.3 ml · min⁻¹ · kg⁻¹, respectively. The observed metabolic clearance in cryopreserved hepatocytes was confirmed to be a result of AO-mediated metabolism via two approaches. Metabolite identification after incubations in the presence of H₂¹⁸O confirmed that the predominant oxidative metabolite was generated by AO, as expected isotope patterns in mass spectra were observed after analysis by high-resolution mass spectrometry. Second, clearance values were efficiently attenuated upon coincubation with hydralazine, an inhibitor of AO. The low exposure after oral doses of BIBX1382 and carbazeran (∼5% F) would have been fairly well predicted using simple hepatic extraction (f(h)) values derived from cryopreserved hepatocytes. In addition, the estimated hepatic clearance value for O⁶-benzylguanine was within ∼80% of the observed total clearance in humans after intravenous administration (15 ml · min⁻¹ · kg⁻¹), indicating a reasonable level of quantitative activity from this in vitro system. However, a 3.5-fold underprediction of total clearance was observed for zaleplon, despite the 5-oxo metabolite being clearly observed. These data taken together suggest that the use of cryopreserved hepatocytes may be a practical approach for assessing AO-mediated metabolism in discovery and potentially useful for predicting hepatic clearance of AO substrates.

  10. Identification and Characterization of an Antennae-Specific Aldehyde Oxidase from the Navel Orangeworm

    PubMed Central

    Choo, Young-Moo; Pelletier, Julien; Atungulu, Elizabeth; Leal, Walter S.

    2013-01-01

    Antennae-specific odorant-degrading enzymes (ODEs) are postulated to inactivate odorant molecules after they convey their signal. Different classes of insect ODEs are specific to esters, alcohols, and aldehydes – the major functional groups of female-produced, hydrophobic sex pheromones from moth species. Esterases that rapidly inactive acetate and other esters have been well-studied, but less is known about aldehyde oxidases (AOXs). Here we report cloning of an aldehyde oxidase, AtraAOX2, from the antennae of the navel orangeworm (NOW), Amyelois transitella, and the first activity characterization of a recombinant insect AOX. AtraAOX2 gene spans 3,813 bp and encodes a protein with 1,270 amino acid residues. AtraAOX2 cDNA was expressed in baculovirus-infected insect Sf21 cells as a ≈280 kDa homodimer with 140 kDa subunits. Recombinant AtraAOX2 degraded Z11Z13–16Ald and plant volatile aldehydes as substrates. However, as expected for aldehyde oxidases, recombinant AtraAOX2 did not show specificity for Z11Z13–16Ald, the main constituent of the sex pheromone, but showed high activity for plant volatile aldehydes. Our data suggest AtraAOX2 might be involved in degradation of a diversity of aldehydes including sex pheromones, plant-derived semiochemicals, and chemical cues for oviposition sites. Additionally, AtraAOX2 could protect the insect's olfactory system from xenobiotics, including pesticides that might reach the sensillar lymph surrounding the olfactory receptor neurons. PMID:23826341

  11. Non-specific recognition in phagocytosis: ingestion of aldehyde-treated erythrocytes by rat peritoneal macrophages.

    PubMed Central

    Capo, C; Bongrand, P; Benoliel, A M; Depieds, R

    1979-01-01

    Particles were chemically modified with aldehydes and incubated with rat peritoneal cells for phagocytosis. All dialdehydes and lower monaldehydes tested (methanal, ethanal and propanal) made sheep erythrocytes phagocytosable. Failure of higher monaldehydes to induce phagocytosis of treated erythrocytes was not due to lack of reactivity with red cell membranes. All erythrocytes tested (bird and mammal red cells were used) and rat thymocytes were phagocytosed by rat macrophages after incubation with aldehyde. Treatment of Candida albicans did not induce phagocytosis: this failure was not due to lack of aldehyde binding (as demonstrated with [14C]-methanal) nor to anti-phagocytic properties of the parasite membrane. Sheep erythrocytes were submitted to enzymatic treatment (pronase, trypsin, neuraminidase) or incubated with succinic anhydride (to block free NH2 groups) or iodacetamide (to block free SH groups) before aldehyde treatment: phagocytosis was not decreased, which suggested that aldehydes did not act by altering some definite surface structure of the treated particles. Treatment of erythrocytes with cross-linking compounds such as tetraazotized o-dianisidine (coupling occurs mainly on tyrosine and histidine residues) or l-ethyl(3-dimethyl aminopropyl) carbodiimide (a bivalent reagent binding free COOH groups) did not induce any substantial phagocytosis of erythrocytes. Phagocytosis of aldehyde treated erythrocytes was partly correlated with hydrophobicity of these cells, as measured with a two-phase partition system. It is concluded that aldehyde-mediated phagocytosis of erythrocytes is mainly due to cross-linking of red cell membrane structures, probably involving free OH groups, which must increase local rigidity and thereby modify hydrophobicity of the red cell surface. Images Figure 1 PMID:437841

  12. Non-specific recognition in phagocytosis: ingestion of aldehyde-treated erythrocytes by rat peritoneal macrophages.

    PubMed

    Capo, C; Bongrand, P; Benoliel, A M; Depieds, R

    1979-03-01

    Particles were chemically modified with aldehydes and incubated with rat peritoneal cells for phagocytosis. All dialdehydes and lower monaldehydes tested (methanal, ethanal and propanal) made sheep erythrocytes phagocytosable. Failure of higher monaldehydes to induce phagocytosis of treated erythrocytes was not due to lack of reactivity with red cell membranes. All erythrocytes tested (bird and mammal red cells were used) and rat thymocytes were phagocytosed by rat macrophages after incubation with aldehyde. Treatment of Candida albicans did not induce phagocytosis: this failure was not due to lack of aldehyde binding (as demonstrated with [14C]-methanal) nor to anti-phagocytic properties of the parasite membrane. Sheep erythrocytes were submitted to enzymatic treatment (pronase, trypsin, neuraminidase) or incubated with succinic anhydride (to block free NH2 groups) or iodacetamide (to block free SH groups) before aldehyde treatment: phagocytosis was not decreased, which suggested that aldehydes did not act by altering some definite surface structure of the treated particles. Treatment of erythrocytes with cross-linking compounds such as tetraazotized o-dianisidine (coupling occurs mainly on tyrosine and histidine residues) or l-ethyl(3-dimethyl aminopropyl) carbodiimide (a bivalent reagent binding free COOH groups) did not induce any substantial phagocytosis of erythrocytes. Phagocytosis of aldehyde treated erythrocytes was partly correlated with hydrophobicity of these cells, as measured with a two-phase partition system. It is concluded that aldehyde-mediated phagocytosis of erythrocytes is mainly due to cross-linking of red cell membrane structures, probably involving free OH groups, which must increase local rigidity and thereby modify hydrophobicity of the red cell surface.

  13. The Pivotal Role of Aldehyde Toxicity in Autism Spectrum Disorder: The Therapeutic Potential of Micronutrient Supplementation

    PubMed Central

    Jurnak, Frances

    2015-01-01

    Autism spectrum disorder (ASD) is characterized by social and communication impairments as well as by restricted, repetitive patterns of behavior and interests. Genomic studies have not revealed dominant genetic errors common to all forms of ASD. So ASD is assumed to be a complex disorder due to mutations in hundreds of common variants. Other theories argue that spontaneous DNA mutations and/or environmental factors contribute to as much as 50% of ASD. In reviewing potential genetic linkages between autism and alcoholism, it became apparent that all theories of ASD are consistent with aldehyde toxicity, in which endogenous and exogenous aldehydes accumulate as a consequence of mutations in key enzymes. Aldehyde toxicity is characterized by cell-localized, micronutrient deficiencies in sulfur-containing antioxidants, thiamine (B1), pyridoxine (B6), folate, Zn2+, possibly Mg2+, and retinoic acid, causing oxidative stress and a cascade of metabolic disturbances. Aldehydes also react with selective cytosolic and membrane proteins in the cell of origin; then some types migrate to damage neighboring cells. Reactive aldehydes also form adducts with DNA, selectively mutating bases and inducing strand breakage. This article reviews the relevant genomic, biochemical, and nutritional literature, which supports the central hypothesis that most ASD symptoms are consistent with symptoms of aldehyde toxicity. The hypothesis represents a paradigm shift in thinking and has profound implications for clinical detection, treatment, and even prevention of ASD. Insight is offered as to which neurologically afflicted children might successfully be treated with micronutrients and which children are unlikely to be helped. The aldehyde toxicity hypothesis likely applies to other neurological disorders. PMID:27330305

  14. Chemo- and Diastereoselective N-Heterocyclic Carbene-Catalyzed Cross-Benzoin Reactions Using N-Boc-α-amino Aldehydes.

    PubMed

    Haghshenas, Pouyan; Gravel, Michel

    2016-09-16

    N-Boc-α-amino aldehydes are shown to be excellent partners in cross-benzoin reactions with aliphatic or heteroaromatic aldehydes. The chemoselectivity of the reaction and the facial selectivity on the amino aldehyde allow cross-benzoin products to be obtained in good yields and good diastereomeric ratios. The developed method is utilized as the key step in a concise total synthesis of d-arabino-phytosphingosine.

  15. Sampling intercomparisons for aldehydes in simulated workplace air.

    PubMed

    Goelen, E; Lambrechts, M; Geyskens, F

    1997-05-01

    Thirty one laboratories of various EU Member States have participated in two interlaboratory comparisons in order to assess errors of personal sampling methods associated with both the sampling and the analytical steps. In contrast to conventional quality control schemes, this project particularly focuses attention on the sampling and identification step; it is executed by means of sampling exercises and has included discussions on potential sources of error. In a sampling exercise, participants come to a central facility and perform measurements on synthetic workplace air in a laboratory installation. Concentration levels of formaldehyde, acrolein, glutaraldehyde and acetaldehyde between 0.1 and 2 times the limit value for workplace air were prepared at various humidity levels and with acetone, occasionally, as interferent. Sampling times varied from 1-4 h. The related analytical work is performed at the analyst's own laboratory. The intention is for each participant to determine the observed value of the delivered standard atmosphere using the sampling method of his own choice. Trueness (bias), precision and relative overall uncertainty of each method-laboratory combination is calculated and verified towards compliance with EN 482, which outlines minimum performance criteria. The first challenge involved the precise gas phase generation of the selected analytes in high air flows (up to 300 1 min-1) and calculating the true value only by direct reference to primary standards. This was accomplished by modifying the capillary dosage injection technique so that reactive compounds, like low molecular mass aldehydes, could be dosed with the same accuracy and precision as unreactive solvents. A permeation tube with high emission rate was developed for formaldehyde. Up to ten different sampling techniques were evaluated. The measurement methods used by the majority of the participants were based on pumped sampling on silica cartridges (or tubes) and glass fiber filters

  16. Acaricidal effects of natural six-carbon and nine-carbon aldehydes on stored-product mites.

    PubMed

    Hubert, Jan; Münzbergová, Zuzana; Nesvorná, Marta; Poltronieri, Palmiro; Santino, Angelo

    2008-04-01

    The toxicities of three plant volatiles, (2E)-hexenal, (2E, 6Z)-nonadienal and (2E)-nonenal, intermediate products of the oxylipin biosynthesis pathway, were tested on three mites of importance for medical purposes and as pests. The aldehydes were diluted in hexane separately and incorporated into diets in ranges of 4-143 mg g(-1). The final density of mites in control and aldehyde-enriched diets was compared after 21 days. The aldehydes were toxic to the mites, whose final density showed an inverse correlation with aldehyde concentration. In addition to the effects of aldehyde concentration, the final density of mites was also influenced by the different aldehydes tested and the interaction among aldehyde concentration and chemical structure. In a functional combination of aldehydes and species, the doses calculated for growth inhibition and eradication of mites ranged from 4 to 35 mg g(-1) and from 36 to 314 mg g(-1), respectively. Due to the protective role displayed by natural six-carbon and nine-carbon aldehydes, these compounds are potential candidates for controlling stored-product mites in stored food and feed products.

  17. Aldehydes in Artic Snow at Barrow (AK) during the Barrow 2009 Field Campaign

    NASA Astrophysics Data System (ADS)

    Barret, Manuel; Houdier, Stephan; Gallet, Jean-Charles; Domine, Florent; Beine, Harry; Jacobi, Hans-Werner; Weibring, Petter; Walega, James; Fried, Alan; Richter, Dirk

    2010-05-01

    Aldehydes (RCHO) are key reactive intermediates in hydrocarbon oxidation and in OH cycling. They are also emitted and taken up by the snowpack and a combination of both physical and photochemical processes are likely involved. Since the photolysis of aldehydes is a source of HOx radicals, these exchanges can modify the oxidative capacity of the overlying air. Formaldehyde (HCHO), acetaldehyde (MeCHO), glyoxal (CHOCHO) and methylglyoxal (MeCOCHO) concentrations were measured in over 250 snow samples collected during the Barrow 2009 campaign between late February and mid April 2009. Both continental and marine snowpacks were studied as well as frost flowers on sea ice. We found that HCHO was the most abundant aldehyde (1 to 9 µg/L), but significant concentrations of dicarbonyls glyoxal and methylglyoxal were also measured for the first time in Arctic snow. Similar concentrations were measured for the continental and marine snowpacks but some frost flowers exhibited HCHO concentrations as high as 150 µg/L. Daily cycles in the surface snow were observed for HCHO and CH3CHO but also for the dicarbonyls and we concluded to a photochemical production of these species from organic precursors. Additional data such as gas phase concentrations for the measured aldehydes and snow physical properties (specific surface area, density …) will be used to discuss on the location of aldehydes in the snow. This is essential to identify and quantify the physical processes that occur during the exchange of trace gases between the snow and the atmosphere.

  18. Toxicity of polyunsaturated aldehydes of diatoms to Indo-Pacific bioindicator organism Echinometra mathaei.

    PubMed

    Sartori, Davide; Gaion, Andrea

    2016-01-01

    Although it is well known suitability of early developmental stages of sea urchin as recommended model for pollutant toxicity testing, little is known about the sensitivity of Indo-Pacific species Echinometra mathaei to polyunsaturated aldehydes. In this study, the effect of three short chain aldehydes, 2,4-decadienal (DD), 2,4-octadienal (OD) and 2,4-heptadienal (HD), normally found in many diatoms, such as Skeletonema costatum, Skeletonema marinoi and Thalassiosira rotula, was evaluated on larval development of E. mathaei embryos. Aldehydes affected larval development in a dose-dependent manner, in particular HD>OD>DD; the results of this study highlighted the higher sensitivity of this species toward aldehydes compared with data registered for other sea urchin species. In comparison with studies reported in the literature, contrasting results were observed during our tests; therefore, an increasing toxic effect was registered with decreasing the chain length of aldehydes. This work could provide new insights in the development of new toxicological assays toward most sensitive species.

  19. Monounsaturated Fatty Acids Are Substrates for Aldehyde Generation in Tellurite-Exposed Escherichia coli

    PubMed Central

    Pradenas, Gonzalo A.; Díaz-Vásquez, Waldo A.; Pérez-Donoso, José M.; Vásquez, Claudio C.

    2013-01-01

    Reactive oxygen species (ROS) damage macromolecules and cellular components in nearly all kinds of cells and often generate toxic intracellular byproducts. In this work, aldehyde generation derived from the Escherichia coli membrane oxidation as well as membrane fatty acid profiles, protein oxidation, and bacterial resistance to oxidative stress elicitors was evaluated. Studies included wild-type cells as well as cells exhibiting a modulated monounsaturated fatty acid (MUFA) ratio. The hydroxyaldehyde 4-hydroxy 2-nonenal was found to be most likely produced by E. coli, whose levels are dependent upon exposure to oxidative stress elicitors. Aldehyde amounts and markers of oxidative damage decreased upon exposure to E. coli containing low MUFA ratios, which was paralleled by a concomitant increase in resistance to ROS-generating compounds. MUFAs ratio, lipid peroxidation, and aldehyde generation were found to be directly related; that is, the lower the MUFAs ratio, the lower the peroxide and aldehyde generation levels. These results provide additional evidence about MUFAs being targets for membrane lipid oxidation and their relevance in aldehyde generation. PMID:23991420

  20. Aldehyde Dehydrogenases in Arabidopsis thaliana: Biochemical Requirements, Metabolic Pathways, and Functional Analysis.

    PubMed

    Stiti, Naim; Missihoun, Tagnon D; Kotchoni, Simeon O; Kirch, Hans-Hubert; Bartels, Dorothea

    2011-01-01

    Aldehyde dehydrogenases (ALDHs) are a family of enzymes which catalyze the oxidation of reactive aldehydes to their corresponding carboxylic acids. Here we summarize molecular genetic and biochemical analyses of selected ArabidopsisALDH genes. Aldehyde molecules are very reactive and are involved in many metabolic processes but when they accumulate in excess they become toxic. Thus activity of aldehyde dehydrogenases is important in regulating the homeostasis of aldehydes. Overexpression of some ALDH genes demonstrated an improved abiotic stress tolerance. Despite the fact that several reports are available describing a role for specific ALDHs, their precise physiological roles are often still unclear. Therefore a number of genetic and biochemical tools have been generated to address the function with an emphasis on stress-related ALDHs. ALDHs exert their functions in different cellular compartments and often in a developmental and tissue specific manner. To investigate substrate specificity, catalytic efficiencies have been determined using a range of substrates varying in carbon chain length and degree of carbon oxidation. Mutational approaches identified amino acid residues critical for coenzyme usage and enzyme activities.

  1. Evaluation of the toxicity of stress-related aldehydes to photosynthesis in chloroplasts.

    PubMed

    Mano, Jun'ichi; Miyatake, Fumitaka; Hiraoka, Eiji; Tamoi, Masahiro

    2009-09-01

    Aldehydes produced under various environmental stresses can cause cellular injury in plants, but their toxicology in photosynthesis has been scarcely investigated. We here evaluated their effects on photosynthetic reactions in chloroplasts isolated from Spinacia oleracea L. leaves. Aldehydes that are known to stem from lipid peroxides inactivated the CO(2) photoreduction to various extents, while their corresponding alcohols and carboxylic acids did not affect photosynthesis. alpha,beta-Unsaturated aldehydes (2-alkenals) showed greater inactivation than the saturated aliphatic aldehydes. The oxygenated short aldehydes malondialdehyde, methylglyoxal, glycolaldehyde and glyceraldehyde showed only weak toxicity to photosynthesis. Among tested 2-alkenals, 2-propenal (acrolein) was the most toxic, and then followed 4-hydroxy-(E)-2-nonenal and (E)-2-hexenal. While the CO(2)-photoreduction was inactivated, envelope intactness and photosynthetic electron transport activity (H(2)O --> ferredoxin) were only slightly affected. In the acrolein-treated chloroplasts, the Calvin cycle enzymes phosphoribulokinase, glyceraldehyde-3-phosphate dehydrogenase, fructose-1,6-bisphophatase, sedoheptulose-1,7-bisphosphatase, aldolase, and Rubisco were irreversibly inactivated. Acrolein treatment caused a rapid drop of the glutathione pool, prior to the inactivation of photosynthesis. GSH exogenously added to chloroplasts suppressed the acrolein-induced inactivation of photosynthesis, but ascorbic acid did not show such a protective effect. Thus, lipid peroxide-derived 2-alkenals can inhibit photosynthesis by depleting GSH in chloroplasts and then inactivating multiple enzymes in the Calvin cycle.

  2. Nitrite promotes protein carbonylation and Strecker aldehyde formation in experimental fermented sausages: are both events connected?

    PubMed

    Villaverde, A; Ventanas, J; Estévez, M

    2014-12-01

    The role played by curing agents (nitrite, ascorbate) on protein oxidation and Strecker aldehyde formation is studied. To fulfill this objective, increasing concentrations of nitrite (0, 75 and 150ppm) and ascorbate (0, 250 and 500ppm) were added to sausages subjected to a 54day drying process. The concurrence of intense proteolysis, protein carbonylation and formation of Strecker aldehydes during processing of sausages suggests that α-aminoadipic semialdehyde (AAS) and γ-glutamic semialdehyde (GGS) may be implicated in the formation of Strecker aldehydes. The fact that nitrite (150ppm, ingoing amount) significantly promoted the formation of protein carbonyls at early stages of processing and the subsequent formation of Strecker aldehydes provides strength to this hypothesis. Ascorbate (125 and 250ppm) controlled the overall extent of protein carbonylation in sausages without declining the formation of Strecker aldehydes. These results may contribute to understanding the chemistry fundamentals of the positive influence of nitrite on the flavor and overall acceptability of cured muscle foods.

  3. Simulation chamber studies on the NO3 chemistry of atmospheric aldehydes

    NASA Astrophysics Data System (ADS)

    Bossmeyer, J.; Brauers, T.; Richter, C.; Rohrer, F.; Wegener, R.; Wahner, A.

    2006-09-01

    Absolute reaction rate studies of NO3 radicals with 4 aldehydes were performed in the atmosphere simulation chamber SAPHIR at the Research Center Jülich. Rate coefficients (ethanal: 2.6 +/- 0.5, propanal: 5.8 +/- 1.0, butanal: 11.9 +/- 1.4, benzaldehyde: 2.2 +/- 0.6; in 10-15 cm3 s-1 at 300 K) were determined from measured concentration-time profiles of aldehydes and NO3 at near ambient conditions. The values for the aliphatic aldehydes are in good agreement with the most recent recommendations (IUPAC Subcommittee on Gas Kinetic Data Evaluation for Atmospheric Chemistry: Evaluated kinetic and photochemical data for atmospheric chemistry, 2005, available at http://www.iupac-kinetic.ch.cam.ac.uk). The measured concentration-time profiles of precursor aldehydes, NO3, NO2, and of product aldehydes were compared to model calculations based on the MCM v3 (Jenkin et al., 2003; Saunders et al., 2003). Differences between measurements and model are attributed to a major interference of the GC system to peroxyacyl nitrates. In addition modifications to the rate constants in the MCM are suggested.

  4. Concentration of simple aldehydes by sulfite-containing double-layer hydroxide minerals: implications for biopoesis

    NASA Technical Reports Server (NTRS)

    Pitsch, S.; Krishnamurthy, R.; Arrhenius, G.; Bada, J. L. (Principal Investigator)

    2000-01-01

    Environmental conditions play an important role in conceptual studies of prebiotically relevant chemical reactions that could have led to functional biomolecules. The necessary source compounds are likely to have been present in dilute solution, raising the question of how to achieve selective concentration and to reach activation. With the assumption of an initial 'RNA World', the questions of production, concentration, and interaction of aldehydes and aldehyde phosphates, potential precursors of sugar phosphates, come into the foreground. As a possible concentration process for simple, uncharged aldehydes, we investigated their adduct formation with sulfite ion bound in the interlayer of positively charged expanding-sheet-structure double-layer hydroxide minerals. Minerals of this type, initially with chloride as interlayer counter anion, have previously been shown to induce concentration and subsequent aldolization of aldehyde phosphates to form tetrose, pentose, and hexose phosphates. The reversible uptake of the simple aldehydes formaldehyde, glycolaldehyde, and glyceraldehyde by adduct formation with the immobilized sulfite ions is characterized by equilibrium constants of K=1.5, 9, and 11, respectively. This translates into an observable uptake at concentrations exceeding 50 mM.

  5. The role of aldehyde oxidase in ethanol-induced hepatic lipid peroxidation in the rat.

    PubMed Central

    Shaw, S; Jayatilleke, E

    1990-01-01

    Hepatic lipid peroxidation has been implicated in the pathogenesis of alcohol-induced liver injury, but the mechanism(s) by which ethanol metabolism or resultant free radicals initiate lipid peroxidation is not fully defined. The role of the molybdenum-containing enzymes aldehyde oxidase and xanthine oxidase in the generation of such free radicals was investigated by measuring alkane production (lipoperoxidation products) in isolated rat hepatocytes during ethanol metabolism. Inhibition of aldehyde oxidase and xanthine oxidase (by feeding tungstate at 100 mg/day per kg) decreased alkane production (80-95%), whereas allopurinol (20 mg/kg by mouth), a marked inhibitor of xanthine oxidase, inhibited alkane production by only 35-50%. Addition of acetaldehyde (0-100 microM) (in the presence of 50 microM-4-methylpyrazole) increased alkane production in a dose-dependent manner (Km of aldehyde oxidase for acetaldehyde 1 mM); menadione, an inhibitor of aldehyde oxidase, virtually inhibited alkane production. Desferrioxamine (5-10 microM) completely abolished alkane production induced by both ethanol and acetaldehyde, indicating the importance of catalytic iron. Thus free radicals generated during the metabolism of acetaldehyde by aldehyde oxidase may be a fundamental mechanism in the initiation of alcohol-induced liver injury. PMID:2363695

  6. Quantification of aldehydes emissions from alternative and renewable aviation fuels using a gas turbine engine

    NASA Astrophysics Data System (ADS)

    Li, Hu; Altaher, Mohamed A.; Wilson, Chris W.; Blakey, Simon; Chung, Winson; Rye, Lucas

    2014-02-01

    In this research three renewable aviation fuel blends including two HEFA (Hydrotreated Ester and Fatty Acid) blends and one FAE (Fatty Acids Ethyl Ester) blend with conventional Jet A-1 along with a GTL (Gas To Liquid) fuel have been tested for their aldehydes emissions on a small gas turbine engine. Three strong ozone formation precursors: formaldehyde, acetaldehyde and acrolein were measured in the exhaust at different operational modes and compared to neat Jet A-1. The aim is to assess the impact of renewable and alternative aviation fuels on aldehydes emissions from aircraft gas turbine engines so as to provide informed knowledge for the future deployment of new fuels in aviation. The results show that formaldehyde was a major aldehyde species emitted with a fraction of around 60% of total measured aldehydes emissions for all fuels. Acrolein was the second major emitted aldehyde species with a fraction of ˜30%. Acetaldehyde emissions were very low for all the fuels and below the detention limit of the instrument. The formaldehyde emissions at cold idle were up to two to threefold higher than that at full power. The fractions of formaldehyde were 6-10% and 20% of total hydrocarbon emissions in ppm at idle and full power respectively and doubled on a g kg-1-fuel basis.

  7. Flavoring Compounds Dominate Toxic Aldehyde Production during E-Cigarette Vaping.

    PubMed

    Khlystov, Andrey; Samburova, Vera

    2016-12-06

    The growing popularity of electronic cigarettes (e-cigarettes) raises concerns about the possibility of adverse health effects to primary users and people exposed to e-cigarette vapors. E-Cigarettes offer a very wide variety of flavors, which is one of the main factors that attract new, especially young, users. How flavoring compounds in e-cigarette liquids affect the chemical composition and toxicity of e-cigarette vapors is practically unknown. Although e-cigarettes are marketed as safer alternatives to traditional cigarettes, several studies have demonstrated formation of toxic aldehydes in e-cigarette vapors during vaping. So far, aldehyde formation has been attributed to thermal decomposition of the main components of e-cigarette e-liquids (propylene glycol and glycerol), while the role of flavoring compounds has been ignored. In this study, we have measured several toxic aldehydes produced by three popular brands of e-cigarettes with flavored and unflavored e-liquids. We show that, within the tested e-cigarette brands, thermal decomposition of flavoring compounds dominates formation of aldehydes during vaping, producing levels that exceed occupational safety standards. Production of aldehydes was found to be exponentially dependent on concentration of flavoring compounds. These findings stress the need for a further, thorough investigation of the effect of flavoring compounds on the toxicity of e-cigarettes.

  8. Regulation of NF-κB-Induced Inflammatory Signaling by Lipid Peroxidation-Derived Aldehydes

    PubMed Central

    Yadav, Umesh C. S.; Ramana, Kota V.

    2013-01-01

    Oxidative stress plays a critical role in the pathophysiology of a wide range of diseases including cancer. This view has broadened significantly with the recent discoveries that reactive oxygen species initiated lipid peroxidation leads to the formation of potentially toxic lipid aldehyde species such as 4-hydroxy-trans-2-nonenal (HNE), acrolein, and malondialdehyde which activate various signaling intermediates that regulate cellular activity and dysfunction via a process called redox signaling. The lipid aldehyde species formed during synchronized enzymatic pathways result in the posttranslational modification of proteins and DNA leading to cytotoxicity and genotoxicty. Among the lipid aldehyde species, HNE has been widely accepted as a most toxic and abundant lipid aldehyde generated during lipid peroxidation. HNE and its glutathione conjugates have been shown to regulate redox-sensitive transcription factors such as NF-κB and AP-1 via signaling through various protein kinase cascades. Activation of redox-sensitive transcription factors and their nuclear localization leads to transcriptional induction of several genes responsible for cell survival, differentiation, and death. In this review, we describe the mechanisms by which the lipid aldehydes transduce activation of NF-κB signaling pathways that may help to develop therapeutic strategies for the prevention of a number of inflammatory diseases. PMID:23710287

  9. Concentrations and determinants of gaseous aldehydes in 162 homes in Strasbourg (France)

    NASA Astrophysics Data System (ADS)

    Marchand, C.; Le Calvé, S.; Mirabel, Ph.; Glasser, N.; Casset, A.; Schneider, N.; de Blay, F.

    Aldehydes concentrations were measured in 162 homes in the Strasbourg area (East of France) in the context of a case/control study pairing asthmatic and non-asthmatic people. The surveyed people have completed a questionnaire aiming to characterize the indoor homes and the people life practices. Gaseous aldehyde levels were quantified by a conventional DNHP-derivatization method followed by HPLC/UV. Formaldehyde, acetaldehyde and hexanal were the main encountered aldehydes with mean concentrations of 32.2±14.6, 14.3±9.7 and 8.6±8.1 μg m -3, respectively, while propionaldehyde and benzaldehyde concentrations were usually <3 μg m -3. The aldehydes concentrations simultaneously measured in both bedroom and living room were not significantly different except for formaldehyde and were correlated between them meaning that indoor air was quite homogenous in homes. Combination of information collected in our questionnaires and statistical analysis was used to investigate indoor aldehydes determinants. Even if formaldehyde sources are theoretically well identified, they are multiple so that it was difficult to determine the main parameters influencing its concentrations in domestic environment. Higher hexanal concentrations were related to new coatings such as painting, wallpapers and laminate floorings. Hexanal concentration decreased with both coating and furniture ages so that this compound may be considered as a tracer of these emissions.

  10. A molecularly defined iron-catalyst for the selective hydrogenation of α,β-unsaturated aldehydes.

    PubMed

    Wienhöfer, Gerrit; Westerhaus, Felix A; Junge, Kathrin; Ludwig, Ralf; Beller, Matthias

    2013-06-10

    A selective iron-based catalyst system for the hydrogenation of α,β-unsaturated aldehydes to allylic alcohols is presented. Applying the defined iron-tetraphos complex [FeF(L)][BF4] (L = P(PhPPh2)3) in the presence of trifluoroacetic acid a broad range of aldehydes are reduced in high yields using low catalyst loadings (0.05-1 mol %). Excellent chemoselectivity for the reduction of aldehydes in the presence of other reducible moieties, for example, ketones, olefins, esters, etc. is achieved. Based on the in situ detected hydride species [FeH(H2)(L)](+) a catalytic cycle is proposed that is supported by computational calculations.

  11. Pulsed corona discharge oxidation of aqueous lignin: decomposition and aldehydes formation.

    PubMed

    Panorel, Iris; Kaijanen, Laura; Kornev, Iakov; Preis, Sergei; Louhi-Kultanen, Marjatta; Sirén, Heli

    2014-01-01

    Lignin is the mass waste product of pulp and paper industry mostly incinerated for energy recovery. Lignin is, however, a substantial source of raw material for derivatives currently produced in costly wet oxidation processes. The pulsed corona discharge (PCD) for the first time was applied to lignin oxidation aiming a cost-effective environmentally friendly lignin removal and transformation to aldehydes. The experimental research into treatment of coniferous kraft lignin aqueous solutions was undertaken to establish the dependence of lignin oxidation and aldehyde formation on the discharge parameters, initial concentration of lignin and gas phase composition. The rate and the energy efficiency of lignin oxidation increased with increasing oxygen concentration reaching up to 82 g kW-1 h-1 in 89% vol. oxygen. Oxidation energy efficiency in PCD treatment exceeds the one for conventional ozonation by the factor of two under the experimental conditions. Oxidation at low oxygen concentrations showed a tendency of the increasing aldehydes and glyoxylic acid formation yield.

  12. Effects of light and copper ions on volatile aldehydes of milk and milk fractions

    SciTech Connect

    Jeno, W.; Bassette, R.; Crang, R.E.

    1988-09-01

    Raw, laboratory-pasteurized and plant-pasteurized homogenized milks were exposed to copper ions (5 ppm), to sunlight or fluorescent light and the effects determined on the composition of volatile aldehydes. The greatest change due to copper treatment was an increase in n-hexanal; acetaldehyde showed the least response in each of the sources of milk. The responses were similar from all three sources of milk with laboratory-pasteurized milk samples showing the greatest responses for each aldehyde analyzed. Similar milk samples exposed to sunlight also showed an increase in volatile aldehydes from all milk sources but with the greatest response being acetaldehyde and n-pentanal components. The milk fraction most susceptible to changes in the presence of light was neutralized whey, whereas resuspended cream was most susceptible to copper exposure. Overall, dialyzed whey appeared to be influenced more than other milk fractions by both light and copper ions.

  13. Catalytic production of methyl acrylates by gold-mediated cross coupling of unsaturated aldehydes with methanol

    NASA Astrophysics Data System (ADS)

    Karakalos, Stavros; Zugic, Branko; Stowers, Kara J.; Biener, Monika M.; Biener, Juergen; Friend, Cynthia M.; Madix, Robert J.

    2016-10-01

    Modern methods of esterification, one of the most important reactions in organic synthesis, are reaching their limits, as far as waste and expense are concerned. Novel chemical approaches to ester formation are therefore of importance. Here we report a simple procedure free of caustic reagents or byproducts for the facile direct oxidative methyl esterification of aldehydes over nanoporous Au catalysts. Complementary model studies on single crystal gold surfaces establish the fundamental reactions involved. We find that methanol more readily reacts with adsorbed active oxygen than do the aldehydes, but that once the aldehydes do react, they form strongly-bound acrylates that block reactive sites and decrease the yields of acrylic esters under steady flow conditions at 420 K. Significant improvements in yield can be achieved by operating at higher temperatures, which render the site-blocking acrylates unstable.

  14. Simulation of Aldehyde Emissions from an Ethanol Fueled Spark Ignition Engine and Comparison with FTIR Measurements

    NASA Astrophysics Data System (ADS)

    Barros Zaránte, Paola Helena; Sodre, Jose Ricardo

    2016-09-01

    This paper presents a mathematical model that calculates aldehyde emissions in the exhaust of a spark ignition engine fueled with ethanol. The numerical model for aldehyde emissions was developed using FORTRAN software, with the input data obtained from a dedicated engine cycle simulation software, AVL BOOST. The model calculates formaldehyde and acetaldehyde emissions, formed from the partial oxidation of methane, ethane and unburned ethanol. The calculated values were compared with experimental data obtained by Fourier Transform Infrared Spectroscopy (FTIR). The experiments were performed with a mid-size sedan powered by a 1.4-liter spark ignition engine on a chassis dynamometer. In general, the results demonstrate that the concentrations of aldehydes and the source elements increased with engine speed and exhaust gas temperature. A reasonable agreement between simulated and measured values was achieved.

  15. Target-Specific Capture of Environmentally Relevant Gaseous Aldehydes and Carboxylic Acids with Functional Nanoparticles.

    PubMed

    Campbell, McKenzie L; Guerra, Fernanda D; Dhulekar, Jhilmil; Alexis, Frank; Whitehead, Daniel C

    2015-10-12

    Aldehyde and carboxylic acid volatile organic compounds (VOCs) present significant environmental concern due to their prevalence in the atmosphere. We developed biodegradable functional nanoparticles comprised of poly(d,l-lactic acid)-poly(ethylene glycol)-poly(ethyleneimine) (PDLLA-PEG-PEI) block co-polymers that capture these VOCs by chemical reaction. Polymeric nanoparticles (NPs) preparation involved nanoprecipitation and surface functionalization with branched PEI. The PDLLA-PEG-PEI NPs were characterized by using TGA, IR, (1) H NMR, elemental analysis, and TEM. The materials feature 1°, 2°, and 3° amines on their surface, capable of capturing aldehydes and carboxylic acids from gaseous mixtures. Aldehydes were captured by a condensation reaction forming imines, whereas carboxylic acids were captured by acid/base reaction. These materials reacted selectively with target contaminants obviating off-target binding when challenged by other VOCs with orthogonal reactivity. The NPs outperformed conventional activated carbon sorbents.

  16. Synthesis of (α,α-difluoropropargyl)phosphonates via aldehyde-to-alkyne homologation.

    PubMed

    Pajkert, Romana; Röschenthaler, Gerd-Volker

    2013-04-19

    An efficient synthetic methodology to a series of novel alkynes bearing a difluoromethylenephosphonate function via a Corey-Fuchs-type sequence starting from (diethoxyphosphoryl)difluoroacetic aldehyde is described. Dehydrobromination of the intermediate (3,3-dibromodifluoroallyl)phosphonate with potassium tert-butoxide gave rise to the corresponding bromoalkyne, whereas upon treatment with lithium base, the generation of ((diethoxyphosphoryl)difluoropropynyl)lithium has been achieved for the first time. The synthetic potential of this lithium reagent was further demonstrated by its reactions with selected electrophiles such as aldehydes, ketones, triflates, chlorophosphines, and chlorosilanes, leading to the corresponding propargyl phosphonates in good to excellent yields. However, in the case, of sterically hindered aldehydes, (α-fluoroallenyl)phosphonates were the solely isolated products.

  17. Palladium and platinum catalyzed addition of allylstannanes to aldehydes and imines

    SciTech Connect

    Nakamura, Hiroyuki; Yamamoto, Yoshinori

    1995-12-31

    The reaction of allylstannanes with aldehydes in THF was catalyzed by Pd(II) or Pt(II) complexes (10 mole %) either at room temperature or at reflux, giving the corresponding homoallyl alcohols in high to good yields. Among the catalysts examined, PtCl{sub 2}(PPh{sub 3}){sub 2} gave the best result. Aromatic, aliphatic, and {alpha},{beta}-unsaturated aldehydes can be utilized and even cyclohexanone undergoes the allylation reaction. Allyl and methallyltributylstannane reacted very smoothly. Crotyltributylstannane also reacted with aldehydes to give the branched homoallyl alcohols in good yields, but the reaction speed was slower than that of allylstannane. Detailed mechanistic studies of the Pd(II) catalyzed allylation, using NMR spectra, revealed that bis-{pi}-allyl palladium 5 is a key intermediate for the catalytic cycle and it exhibits nucleophilic reactivity.

  18. Structurally simple pyridine N-oxides as efficient organocatalysts for the enantioselective allylation of aromatic aldehydes.

    PubMed

    Pignataro, Luca; Benaglia, Maurizio; Annunziata, Rita; Cinquini, Mauro; Cozzi, Franco

    2006-02-17

    A series of structurally simple pyridine N-oxides have readily been assembled from inexpensive amino acids and tested as organocatalysts in the allylation of aldehydes with allyl(trichloro)silane to afford homoallylic alcohols. (S)-proline-based catalysts afforded the products derived from aromatic aldehydes in fair to good yields and in up to 84% enantiomeric excess (ee). The allylation of heteroaromatic, unsaturated, and aliphatic aldehydes was less satisfactory. By running the reaction in the presence of achiral and chiral additives and structurally different catalysts, we collected some insights into the relationship between the stereochemical outcome and the catalyst's structural features. Even if the ee's obtained are inferior to the best values observed with other catalysts, this work concurs to show that structurally simple pyridine N-oxides can also promote the allylation reaction with satisfactory stereocontrol.

  19. Vapour-phase gold-surface-mediated coupling of aldehydes with methanol.

    PubMed

    Xu, Bingjun; Liu, Xiaoying; Haubrich, Jan; Friend, Cynthia M

    2010-01-01

    Selective coupling of oxygenates is critical to many synthetic processes, including those necessary for the development of alternative fuels. We report a general process for selective coupling of aldehydes and methanol as a route to ester synthesis. All steps are mediated by oxygen-covered metallic gold nanoparticles on Au(111). Remarkably, cross-coupling of methanol with formaldehyde, acetaldehyde, benzaldehyde and benzeneacetaldehyde to methyl esters is promoted by oxygen-covered Au(111) below room temperature with high selectivity. The high selectivity is attributed to the ease of nucleophilic attack of the aldehydes by the methoxy intermediate-formed from methanol on the surface-which yields the methyl esters. The competing combustion occurs via attack of both methanol and the aldehydes by oxygen. The mechanistic model constructed in this study provides insight into factors that control selectivity and clearly elucidates the crucial role of Au nanoparticles as active species in the catalytic oxidation of alcohols, even in solution.

  20. A catalytic reactor for the organocatalyzed enantioselective continuous flow alkylation of aldehydes.

    PubMed

    Porta, Riccardo; Benaglia, Maurizio; Puglisi, Alessandra; Mandoli, Alessandro; Gualandi, Andrea; Cozzi, Pier Giorgio

    2014-12-01

    The use of immobilized metal-free catalysts offers the unique possibility to develop sustainable processes in flow mode. The challenging intermolecular organocatalyzed enantioselective alkylation of aldehydes was performed for the first time under continuous flow conditions. By using a packed-bed reactor filled with readily available supported enantiopure imidazolidinone, different aldehydes were treated with three distinct cationic electrophiles. In the organocatalyzed α-alkylation of aldehydes with 1,3-benzodithiolylium tetrafluoroborate, excellent enantioselectivities, in some cases even better than those obtained in the flask process (up to 95% ee at 25 °C), and high productivity (more than 3800 h(-1) ) were obtained, which thus shows that a catalytic reactor may continuously produce enantiomerically enriched compounds. Treatment of the alkylated products with Raney-nickel furnished enantiomerically enriched α-methyl derivatives, key intermediates for active pharmaceutical ingredients and natural products.

  1. Transition-metal-free coupling reaction of vinylcyclopropanes with aldehydes catalyzed by tin hydride.

    PubMed

    Ieki, Ryosuke; Kani, Yuria; Tsunoi, Shinji; Shibata, Ikuya

    2015-04-13

    Donor-acceptor cyclopropanes are useful building blocks for catalytic cycloaddition reactions with a range of electrophiles to give various cyclic products. In contrast, relatively few methods are available for the synthesis of homoallylic alcohols through coupling of vinylcyclopropanes (VCPs) with aldehydes, even with transition-metal catalysts. Here, we report that the hydrostannation of vinylcyclopropanes (VCPs) was effectively promoted by dibutyliodotin hydride (Bu2 SnIH). The resultant allylic tin compounds reacted easily with aldehydes. Furthermore, the use of Bu2 SnIH was effectively catalytic in the presence of hydrosilane as a hydride source, which established a coupling reaction of VCPs with aldehydes for the synthesis of homoallylic alcohols without the use of transition-metal catalysts. In contrast to conventional catalytic reactions of VCPs, the presented method allowed the use of several VCPs in addition to conventional donor-acceptor cyclopropanes.

  2. Ubiquitin-aldehyde: a general inhibitor of ubiquitin-recycling processes.

    PubMed Central

    Hershko, A; Rose, I A

    1987-01-01

    The generation and characterization of ubiquitin (Ub)-aldehyde, a potent inhibitor of Ub-C-terminal hydrolase, has previously been reported. We now examine the action of this compound on the Ub-mediated proteolytic pathway using the system derived from rabbit reticulocytes. Addition of Ub-aldehyde was found to strongly inhibit breakdown of added 125I-labeled lysozyme, but inhibition was overcome by increasing concentrations of Ub. The following evidence shows the effect of Ub-aldehyde on protein breakdown to be indirectly caused by its interference with the recycling of Ub, leading to exhaustion of the supply of free Ub: Ub-aldehyde markedly increased the accumulation of Ub-protein conjugates coincident with a much decreased rate of conjugate breakdown. release of Ub from isolated Ub-protein conjugates in the absence of ATP (and therefore not coupled to protein degradation) is markedly inhibited by Ub-aldehyde. On the other hand, the ATP-dependent degradation of the protein moiety of Ub conjugates, which is an integral part of the proteolytic process, is not inhibited by this agent. Direct measurement of levels of free Ub showed a rapid disappearance caused by the inhibitor. The Ub is found to be distributed in derivatives of a wide range of molecular weight classes. It thus seems that Ub-aldehyde, previously demonstrated to inhibit the hydrolysis of Ub conjugates of small molecules, also inhibits the activity of a series of enzymes that regenerate free Ub from adducts with proteins and intermediates in protein breakdown. Images PMID:3031653

  3. Ubiquitin-aldehyde: a general inhibitor of ubiquitin-recycling processes

    SciTech Connect

    Hershko, A.; Rose, I.A.

    1987-04-01

    The generation and characterization of ubiquitin (Ub)-aldehyde, a potent inhibitor of Ub-C-terminal hydrolase, has previously been reported. The authors examine the action of this compound on the Ub-mediated proteolytic pathway using the system derived from rabbit reticulocytes. Addition of Ub-aldehyde was found to strongly inhibit breakdown of added /sup 125/I-labeled lysozyme, but inhibition was overcome by increasing concentrations of Ub. The following evidence shows the effect of Ub-aldehyde on protein breakdown to be indirectly caused by its interference with the recycling of Ub, leading to exhaustion of the supply of free Ub: (i) Ub-aldehyde markedly increased the accumulation of Ub-protein conjugates coincident with a much decreased rate of conjugate breakdown; (ii) release of Ub from isolated Ub-protein conjugates in the absence of ATP (and therefore not coupled to protein degradation) is markedly inhibited by Ub-aldehyde. On the other hand, the ATP-dependent degradation of the protein moiety of Ub conjugates, which is an integral part of the proteolytic process, is not inhibited by this agent; (iii) direct measurement of levels of free Ub showed a rapid disappearance caused by the inhibitor. The Ub is found to be distributed in derivatives of a wide range of molecular weight classes. It thus seems that Ub-aldehyde, previously demonstrated to inhibit the hydrolysis of Ub conjugates of small molecules, also inhibits the activity of a series of enzymes that regenerate free Ub from adducts with proteins and intermediates in protein breakdown.

  4. Occupational Exposure to Volatile Organic Compounds and Aldehydes in the U.S. Trucking Industry

    PubMed Central

    DAVIS, M. E.; BLICHARZ, A. P.; HART, J. E.; LADEN, F.; GARSHICK, E.; SMITH, T. J.

    2008-01-01

    Diesel exhaust is a complex chemical mixture that has been linked to lung cancer mortality in a number of epidemiologic studies. However, the dose–response relationship remains largely undefined, and the specific components responsible for carcinogenicity have not been identified. Although previous focus has been on the particulate phase, diesel exhaust includes a vapor phase of numerous volatile organic compounds (VOCs) and aldehydes that are either known or suspected carcinogens, such as 1,3-butadiene, benzene, and formaldehyde. However, there are relatively few studies that quantify exposure to VOCs and aldehydes in diesel-heavy and other exhaust-related microenvironments. As part of a nationwide assessment of exposure to diesel exhaust in the trucking industry, we collected measurements of VOCs and aldehydes at 15 different U.S. trucking terminals and in city truck drivers (with 6 repeat site visits), observing average shift concentrations in truck cabs and at multiple background and work area locations within each terminal. In this paper, we characterize occupational exposure to 18 different VOCs and aldehydes, as well as relationships with particulate mass (elemental carbon in PM < 1 μ m and PM2.5) across locations to determine source characteristics. Our results show that occupational exposure to VOCs and aldehydes varies significantly across the different sampling locations within each terminal, with significantly higher exposures noted in the work environments over background levels (p < 0.01). A structural equation model performed well in predicting terminal exposures to VOCs and aldehydes as a function of job, background levels, weather conditions, proximity to a major road, and geographic location (R2 = 0.2–0.4 work area; R2 = 0.5–0.9 background). PMID:17993162

  5. Enantioselective Multicomponent Condensation Reactions of Phenols, Aldehydes, and Boronates Catalyzed by Chiral Biphenols.

    PubMed

    Barbato, Keith S; Luan, Yi; Ramella, Daniele; Panek, James S; Schaus, Scott E

    2015-12-04

    Chiral diols and biphenols catalyze the multicomponent condensation reaction of phenols, aldehydes, and alkenyl or aryl boronates. The condensation products are formed in good yields and enantioselectivities. The reaction proceeds via an initial Friedel-Crafts alkylation of the aldehyde and phenol to yield an ortho-quinone methide that undergoes an enantioselective boronate addition. A cyclization pathway was discovered while exploring the scope of the reaction that provides access to chiral 2,4-diaryl chroman products, the core of which is a structural motif found in natural products.

  6. Paternò-Büchi reaction between furan and heterocyclic aldehydes: oxetane formation vs. metathesis.

    PubMed

    D'Auria, Maurizio; Racioppi, Rocco; Viggiani, Licia

    2010-08-01

    The photochemical reaction of 2-substituted heterocyclic aldehydes with furan gave the corresponding exo oxetane derivatives through the excited triplet state. However, in situ the oxetane derivatives were converted through a metathesis reaction into the corresponding Z,E-butadienyl formate derivatives. On the contrary, 3-substituted heterocyclic aldehydes gave the corresponding exo oxetane derivatives. The effect of 2-substituted heterocyclic ring in order to facilitate the metathesis reaction is explained considering the possible participation of the pi aromatic orbitals in the oxetane C-O bond cleavage.

  7. Allylation of aldehydes and imines: promoted by reuseable polymer-supported sulfonamide of N-glycine.

    PubMed

    Li, Gui-long; Zhao, Gang

    2006-02-16

    [reaction: see text] A allylation of aldehydes and imines (generated in situ from aldehydes and amines) with allyltributyltin promoted by recoverable and reusable the polymer-supported sulfonamide of N-glycine has been developed. Good to high yields were obtained in various cases. Most of the SnBu(3) residue can be recovered as Bu(3)SnCl. Highly stereoselective synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine 7 was achieved by using the P4a-mediated allylation of Boc-l-phenylglycinal as a key step.

  8. Semi-catalytic reduction of secondary amides to imines and aldehydes.

    PubMed

    Lee, Sun-Hwa; Nikonov, Georgii I

    2014-06-21

    Secondary amides can be reduced by silane HSiMe2Ph into imines and aldehydes by a two-stage process involving prior conversion of amides into iminoyl chlorides followed by catalytic reduction mediated by the ruthenium complex [Cp(i-Pr3P)Ru(NCCH3)2]PF6 (1). Alkyl and aryl amides bearing halogen, ketone, and ester groups were converted with moderate to good yields under mild reaction conditions to the corresponding imines and aldehydes. This procedure does not work for substrates bearing the nitro-group and fails for heteroaromatic amides. In the case of cyano substituted amides, the cyano group is reduced to imine.

  9. Synthesis of chiral alpha-amino aldehydes linked by their amine function to solid support.

    PubMed

    Cantel, Sonia; Heitz, Annie; Martinez, Jean; Fehrentz, Jean-Alain

    2004-09-01

    The anchoring of an alpha-amino-acid derivative by its amine function on to a solid support allows some chemical reactions starting from the carboxylic acid function. This paper describes the preparation of alpha-amino aldehydes linked to the support by their amine function. This was performed by reduction with LiAlH4 of the corresponding Weinreb amide linked to the resin. The aldehydes obtained were then involved in Wittig or reductive amination reactions. In addition, the linked Weinreb amide was reacted with methylmagnesium bromide to yield the corresponding ketone. After cleavage from the support, the compounds were obtained in good to excellent yields and characterized.

  10. Transition metal free catalytic hydroboration of aldehydes and aldimines by amidinato silane.

    PubMed

    Bisai, Milan Kumar; Pahar, Sanjukta; Das, Tamal; Vanka, Kumar; Sen, Sakya S

    2017-02-21

    The transition metal free catalytic hydroboration of aldehydes and ketones is very limited and has not been reported with a well-defined silicon(iv) compound. Therefore, we chose to evaluate the previously reported silicon(iv) hydride [PhC(NtBu)2SiHCl2], (1) as a single component catalyst and found that it catalyzes the reductive hydroboration of a range of aldehydes with pinacolborane (HBpin) under ambient conditions. In addition, compound 1 can catalyze imine hydroboration. DFT calculation was carried out to understand the mechanism.

  11. Evolution of Research on the DNA Adduct Chemistry of N-Nitrosopyrrolidine and Related Aldehydes

    PubMed Central

    Hecht, Stephen S.; Upadhyaya, Pramod; Wang, Mingyao

    2011-01-01

    This perspective reviews our work on the identification of DNA adducts of N-nitrosopyrrolidine and some related aldehydes. The research began as a focused project to investigate mechanisms of cyclic nitrosamine carcinogenesis but expanded into other areas as aldehyde metabolites of NPYR were shown to have their own diverse DNA adduct chemistry. A total of 69 structurally distinct DNA adducts were identified and some of these, found in human tissues, have provided intriguing leads for investigating carcinogenesis mechanisms in humans due to exposure to both endogenous and exogenous agents. PMID:21480629

  12. Inhibitory effects of terpene alcohols and aldehydes on growth of green alga Chlorella pyrenoidosa

    SciTech Connect

    Ikawa, Miyoshi; Mosley, S.P.; Barbero, L.J. )

    1992-10-01

    The growth of the green alga Chlorella pyrenoidosa was inhibited by terpene alcohols and the terpene aldehyde citral. The strongest activity was shown by citral. Nerol, geraniol, and citronellol also showed pronounced activity. Strong inhibition was linked to acyclic terpenes containing a primary alcohol or aldehyde function. Inhibition appeared to be taking place through the vapor phase rather than by diffusion through the agar medium from the terpene-treated paper disks used in the system. Inhibition through agar diffusion was shown by certain aged samples of terpene hydrocarbons but not by recently purchased samples.

  13. Enantioselective Ethylation of Various Aldehydes Catalyzed by Readily Accessible Chiral Diols.

    PubMed

    Gök, Yaşar; Kiliçarslan, Seda; Gök, Halil Zeki; Karayiğit, İlker Ümit

    2016-08-01

    Four chiral C2 -symmetric diols were synthesized in a straightforward three-step reaction and demonstrated excellent enantioselectivities and good overall yields. Their catalytic activities were examined via the addition of diethylzinc to various aldehydes. The enantioselective addition of diethylzinc to 2-methoxybenzaldehyde gave the corresponding chiral secondary alcohol with high yields (up to 95%) and moderate to good enantiomeric excess (up to 88%). All synthesized ligands were evaluated in the addition of diethylzinc to various aldehydes in the presence of an additional metal such as Ti(IV) complexes. Chirality 28:593-598, 2016. © 2016 Wiley Periodicals, Inc.

  14. Peptide-Catalyzed Stereoselective Conjugate Addition Reactions of Aldehydes to Maleimide.

    PubMed

    Grünenfelder, Claudio E; Kisunzu, Jessica K; Wennemers, Helma

    2016-07-18

    The tripeptide H-dPro-Pro-Asn-NH2 is presented as a catalyst for asymmetric conjugate addition reactions of aldehydes to maleimide. The peptidic catalyst promotes the reaction between various aldehydes and unprotected maleimide with high stereoselectivities and yields. The obtained products were readily derivatized to the corresponding pyrrolidines, lactams, lactones, and peptide-like compounds. (1) H NMR spectroscopic, crystallographic, and computational investigations provided insight into the conformational properties of H-dPro-Pro-Asn-NH2 and revealed the importance of hydrogen bonding between the peptide and maleimide for catalyzing the stereoselective C-C bond formation.

  15. Enantioselective Multicomponent Condensation Reactions of Phenols, Aldehydes, and Boronates Catalyzed by Chiral Biphenols

    PubMed Central

    Barbato, Keith S.; Luan, Yi; Ramella, Daniele; Panek, James S.; Schaus, Scott E.

    2015-01-01

    Chiral diols and biphenols catalyze the multicomponent condensation reaction of phenols, aldehydes, and alkenyl or aryl boronates. The condensation products are formed in good yields and enantioselectivities. The reaction proceeds via an initial Friedel Crafts alkylation of the aldehyde and phenol to yield an ortho-quinone methide that undergoes an enantioselective boronate addition. A cyclization pathway was discovered while exploring the scope of the reaction that provides access to chiral 2,4-diaryl chroman products, the core of which is a structural motif found in natural products. PMID:26576776

  16. Effects of the biodiesel blend fuel on aldehyde emissions from diesel engine exhaust

    NASA Astrophysics Data System (ADS)

    Peng, Chiung-Yu; Yang, Hsi-Hsien; Lan, Cheng-Hang; Chien, Shu-Mei

    Interest in use of biodiesel fuels derived from vegetable oils or animal fats as alternative fuels for petroleum-based diesels has increased due to biodiesels having similar properties of those of diesels, and characteristics of renewability, biodegradability and potential beneficial effects on exhaust emissions. Generally, exhaust emissions of regulated pollutants are widely studied and the results favor biodiesels on CO, HC and particulate emissions; however, limited and inconsistent data are showed for unregulated pollutants, such as carbonyl compounds, which are also important indicators for evaluating available vehicle fuels. For better understanding biodiesel, this study examines the effects of the biodiesel blend fuel on aldehyde chemical emissions from diesel engine exhausts in comparison with those from the diesel fuel. Test engines (Mitsubishi 4M40-2AT1) with four cylinders, a total displacement of 2.84 L, maximum horsepower of 80.9 kW at 3700 rpm, and maximum torque of 217.6 N m at 2000 rpm, were mounted and operated on a Schenck DyNAS 335 dynamometer. Exhaust emission tests were performed several times for each fuel under the US transient cycle protocol from mileages of 0-80,000 km with an interval of 20,000 km, and two additional measurements were carried out at 40,000 and 80,000 km after maintenance, respectively. Aldehyde samples were collected from diluted exhaust by using a constant volume sampling system. Samples were extracted and analyzed by the HPLC/UV system. Dominant aldehydes of both fuels' exhausts are formaldehyde and acetaldehyde. These compounds together account for over 75% of total aldehyde emissions. Total aldehyde emissions for B20 (20% waste cooking oil biodiesel and 80% diesel) and diesel fuels are in the ranges of 15.4-26.9 mg bhp-h -1 and 21.3-28.6 mg bhp-h -1, respectively. The effects of increasing mileages and maintenance practice on aldehyde emissions are insignificant for both fuels. B20 generates slightly less emission than

  17. Novel 11β-hydroxysteroid dehydrogenase 1 inhibitors reduce cortisol levels in keratinocytes and improve dermal collagen content in human ex vivo skin after exposure to cortisone and UV

    PubMed Central

    Geotti-Bianchini, Piero; Wandeler, Eliane; Kratschmar, Denise V.; Heidl, Marc; Campiche, Remo; Jackson, Eileen

    2017-01-01

    Activity and selectivity assessment of new bi-aryl amide 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors, prepared in a modular manner via Suzuki cross-coupling, are described. Several compounds inhibiting 11β-HSD1 at nanomolar concentrations were identified. Compounds 2b, 3e, 7b and 12e were shown to selectively inhibit 11β-HSD1 over 11β-HSD2, 17β-HSD1 and 17β-HSD2. These inhibitors also potently inhibited 11β-HSD1 activity in intact HEK-293 cells expressing the recombinant enzyme and in intact primary human keratinocytes expressing endogenous 11β-HSD1. Moreover, compounds 2b, 3e and 12e were tested for their activity in human skin biopsies. They were able to prevent, at least in part, both the cortisone- and the UV-mediated decreases in collagen content. Thus, inhibition of 11β-HSD1 by these compounds can be further investigated to delay or prevent UV-mediated skin damage and skin aging. PMID:28152550

  18. Substrate specificity of guinea pig liver aldehyde oxidase and bovine milk xanthine oxidase for methyl- and nitrobenzaldehydes.

    PubMed

    Veskoukis, Aristidis S; Kouretas, Demetrios; Panoutsopoulos, Georgios I

    2006-01-01

    Both aldehyde oxidase and xanthine oxidase catalyze the oxidation of a wide range of N-heterocycles and aldehydes. These enzymes are important in the oxidation of N-heterocyclic xenobiotics, whereas their role in the oxidation of xenobiotic aldehydes is usually ignored. The present investigation describes the interaction of methyl- and nitrosubstituted benzaldehydes, in the ortho-, meta- and parapositions, with guinea pig liver aldehyde oxidase and bovine milk xanthine oxidase. The kinetic constants showed that most substituted benzaldehydes are excellent substrates of aldehyde oxidase with lower affinities for xanthine oxidase. Low Km values for aldehyde oxidase were observed with most benzaldehydes tested, with 3-nitrobenzaldehyde having the lowest Km value and 3-methylbenzaldehyde being the best substrate in terms of substrate efficiency (Ks). Additionally, low Km values for xanthine oxidase were found with most benzaldehydes tested. However, all benzaldehydes also had low Vmax values, which made them poor substrates of xanthine oxidase. It is therefore possible that aldehyde oxidase may be critical in the oxidation of xenobiotic and endobiotic derived aldehydes and its role in such reactions should not be ignored.

  19. Kinetics of forming aldehydes in frying oils and their distribution in French fries revealed by LC-MS-based chemometrics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aldehydes are major secondary lipid oxidation products (LOPs) from heating vegetable oils and deep frying. The routes and reactions that generate aldehydes have been extensively investigated, but the sequences and kinetics of their formation in oils are poorly defined. In this study, a platform comb...

  20. Direct access to ketones from aldehydes via rhodium-catalyzed cross-coupling reaction with potassium trifluoro(organo)borates.

    PubMed

    Pucheault, Mathieu; Darses, Sylvain; Genet, Jean-Pierre

    2004-12-01

    A direct cross-coupling reaction of aromatic aldehydes with potassium trifluoro(organo)borates afforded ketones in high yields and under mild conditions in the presence of a rhodium catalyst and acetone. This new reaction, involving a formal aldehyde C-H bond activation, is believed to proceed via a Heck-type mechanism followed by hydride transfer to acetone.

  1. Quantification of aldehyde terminated heparin by SEC-MALLS-UV for the surface functionalization of polycaprolactone biomaterials.

    PubMed

    Irvine, Scott A; Steele, Terry W J; Bhuthalingam, Ramya; Li, Min; Boujday, Souhir; Prawirasatya, Melissa; Neoh, Koon Gee; Boey, Freddy Yin Chiang; Venkatraman, Subbu S

    2015-08-01

    A straight forward strategy of heparin surface grafting employs a terminal reactive-aldehyde group introduced through nitrous acid depolymerization. An advanced method that allows simultaneously monitoring of both heparin molar mass and monomer/aldehyde ratio by size exclusion chromatography, multi-angle laser light scattering and UV-absorbance (SEC-MALLS-UV) has been developed to improve upon heparin surface grafting. Advancements over older methods allow quantitative characterization by direct (aldehyde absorbance) and indirect (Schiff-based absorbance) evaluation of terminal functional aldehydes. The indirect quantitation of functional aldehydes through labeling with aniline (and the formation of a Schiff-base) allows independent quantitation of both polymer mass and terminal functional groups with the applicable UV mass extinction coefficients determined. The protocol was subsequently used to synthesize an optimized heparin-aldehyde that had minimal polydispersity (PDI<2) and high reaction yields (yield >60% by mass). The 8 kDa weight averaged molar mass heparin-aldehyde was then grafted on polycaprolactone (PCL), a common implant material. This optimized heparin-aldehyde retained its antithrombin activity, assessed in freshly drawn blood or surface immobilized on PCL films. Anticoagulant activity was equal to or better than the 24 kDa unmodified heparin it was fragmented from.

  2. Stereodivergent Coupling of Aldehydes and Alkynes via Synergistic Catalysis Using Rh and Jacobsen's Amine.

    PubMed

    Cruz, Faben A; Dong, Vy M

    2017-01-25

    We report an enantioselective coupling between α-branched aldehydes and alkynes to generate vicinal quaternary and tertiary carbon stereocenters. The choice of Rh and organocatalyst combination allows for access to all possible stereoisomers with high enantio-, diastereo-, and regioselectivity. Our study highlights the power of catalysis to activate two common functional groups and provide access to divergent stereoisomers and constitutional structures.

  3. One-pot reductive mono-N-alkylation of aniline and nitroarene derivatives using aldehydes.

    PubMed

    Byun, Eunyoung; Hong, Bomi; De Castro, Kathlia A; Lim, Minkyung; Rhee, Hakjune

    2007-12-07

    One-pot reductive mono-N-alkylation of aniline and nitroarene derivatives using various aldehydes by Pd/C catalyst in aqueous 2-propanol solvent with ammonium formate as in situ hydrogen donor is illustrated. The reaction proceeded smoothly and selectively with excellent yield at room temperature. Our protocol presents a facile, economical, and environmentally benign alternative for reductive amination.

  4. 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

  5. Dirhodium carboxylates catalyzed enantioselective coupling reactions of α-diazophosphonates, anilines, and electron-deficient aldehydes.

    PubMed

    Zhou, Cong-Ying; Wang, Jing-Cui; Wei, Jinhu; Xu, Zhen-Jiang; Guo, Zhen; Low, Kam-Hung; Che, Chi-Ming

    2012-11-05

    Chiral dirhodium carboxylate complexes ([Rh(2)(S-PTAD)(4)] or [Rh(2)(S-PTTL)(4)]) efficiently catalyze asymmetric three-component coupling reactions of α-diazophosphonates, anilines, and electron-deficient aldehydes to give α-amino-β-hydroxyphosphonates. The high level of enantiocontrol provides evidence for the intermediacy of metal-bound ammonium ylide in the product-forming step.

  6. Modulation of ethanol stress tolerance by aldehyde dehydrogenase in the mycorrhizal fungus Tricholoma vaccinum.

    PubMed

    Asiimwe, Theodore; Krause, Katrin; Schlunk, Ines; Kothe, Erika

    2012-08-01

    We report the first mycorrhizal fungal aldehyde dehydrogenase gene, ald1, which was isolated from the basidiomycete Tricholoma vaccinum. The gene, encoding a protein Ald1 of 502 amino acids, is up-regulated in ectomycorrhiza. Phylogenetic analyses using 53 specific fungal aldehyde dehydrogenases from all major phyla in the kingdom of fungi including Ald1 and two partial sequences of T. vaccinum were performed to get an insight in the evolution of the aldehyde dehydrogenase family. By using competitive and real-time RT-PCR, ald1 is up-regulated in response to alcohol and aldehyde-related stress. Furthermore, heterologous expression of ald1 in Escherichia coli and subsequent in vitro enzyme activity assay demonstrated the oxidation of propionaldehyde and butyraldehyde with different kinetics using either NAD(+) or NADP(+) as cofactors. In addition, overexpression of ald1 in T. vaccinum after Agrobacterium tumefaciens-mediated transformation increased ethanol stress tolerance. These results demonstrate the ability of Ald1 to circumvent ethanol stress, a critical function in mycorrhizal habitats.

  7. APPLICATION OF MULTISPECTRAL TECHNIQUES TO THE PRECISE IDENTIFICATION OF ALDEHYDES IN THE ENVIRONMENT

    EPA Science Inventory

    By using gas chromatography coupled with low- and high-resolution electron impact mass spectrometry, low- and high-resolution chemical ionization mass spectrometry, and Fourier transform infrared spectroscopy, eight straight-chain aldehydes were identified in a water sample taken...

  8. A Theoretical Study of the Methyl and Aldehyde Torsion FIR Spectra in Symmetric Propanal Isotopomers

    NASA Astrophysics Data System (ADS)

    Smeyers, Y. G.; Villa, M.; Uc, V. H.; Vivier-Bunge, A.

    2000-05-01

    This paper is an extension of the techniques developed by us [A. Vivier-Bunge, V. H. Uc, and Y. G. Smeyers, J. Chem. Phys. 109, 2279 (1998)] for standard propanal. In that paper the potential energy surface for the simultaneous methyl and asymmetric aldehydic torsions was calculated at RHF/MP2 level using the 6-311(3df,p) basis set for propanal. The fit of the energy values to symmetry-adapted functional forms was carried out by using the 28 energy values which retain the C3 dynamical symmetry of the methyl group in the optimization procedure. With this potential, as well as with the kinetic parameters and the electric dipole moment variations, the FIR frequencies and intensities for the methyl and aldehyde torsions of seven symmetric isotopomers of propanal were determined theoretically using two-dimensional calculations. The calculated spectra of propanal and three of its isotopomers were compared with the available experimental data. It is found that the calculations for the cis conformer satisfactorily reproduce the aldehyde and methyl torsion spectra and furnish also methyl torsionally excited progressions for the aldehyde torsion modes. The methyl torsion frequencies agree especially well whenever the methyl group is nondeuterated. The small deviations encountered for the deuterated compound are probably due to some mass effect, such as the zero-point vibrational energy correction, which is not taken into account in the present calculations. Finally, the influence of the deuteration on the intensities is discussed.

  9. Directing-group-assisted copper-catalyzed oxidative esterification of phenols with aldehydes.

    PubMed

    Zheng, Yong; Song, Wei-Bin; Xuan, Li-Jiang

    2015-11-28

    A directing-group-assisted copper-catalyzed oxidative esterification of phenols with aldehydes using TBHP as an oxidant was described. This methodology which showed the advantages of base, ligand free, short routes and functional group tolerance could be used as an alternative protocol for the classical esterification reactions.

  10. A Cascade Resulting in the Reductive Ethynylation of Aldehydes: Dissection of its Components

    PubMed Central

    Lee, Dongjoo; Danishefsky, Samuel J.

    2010-01-01

    A mild and efficient two-carbon homologation of aldehydes exploiting multiple modes of KOt-Bu was developed. This process involves a sequential Peterson allenylation/allene-alkyne isomerization/protodesilylation in a single-flask operation. The differential roles played by the various elements of the process were demonstrated through dissection experiments. PMID:20201522

  11. Metathesis reactions of tris(adamantylimido)methylrhenium and aldehydes and imines

    SciTech Connect

    Wang, W.D.; Espenson, J.H.

    1999-11-22

    The tris(imido)methylrhenium compound CH{sub 3}Re(NAd){sub 3} (Ad = 1-adamantyl) was prepared and characterized. It reacts with aromatic aldehydes ArCHO forming the imines ArCH{double{underscore}bond} NAd. The reaction occurs in three stages, during which CH{sub 3}Re(NAd){sub 2}O and CH{sub 3}Re(NAd)O{sub 2} could be detected. In the third and slowest stage CH{sub 3}ReO{sub 3} (MTO) was formed, eventually in quantitative yield. The second-order rate constant for PhCHO in C{sub 6}D{sub 6} at 298 K is 1.4 x 10{sup {minus}4} L/mol s. Electron-donating substituents at the para-position of ArCHO cause a significant diminution in rate. Treated by the Hammett equation, the reaction constant is {rho} = +0.90. The reactions between CH{sub 3}Re(NAd){sub 3} and linear aliphatic aldehydes occur much faster than do reactions of nonlinear aliphatic or aromatic aldehydes, indicating an important steric effect. Ketones do not react. The imidorhenium complex evidently undergoes a metathesis reaction with the aldehyde. Analogously, CH{sub 3}Re(NAd){sub 3} reacts with imines. Imine-imine metathesis is catalyzed by MTO homogeneously and by MTO supported on Nb{sub 2}O{sub 5}.

  12. Nepetanal and nepetanoate: a new diterpene aldehyde and a benzene derivative ester from Nepeta juncea.

    PubMed

    Hussain, Javid; Jamila, Nargis; Khan, Farman Ullah; Devkota, Krishna Prasad; Shah, M Raza; Anwar, Saeed

    2009-07-01

    One new tricyclic clerodane type diterpene aldehyde nepetanal (1) and one new benzene derivative nepetanoate (2) have been isolated from a plant Nepeta juncea together with two known compounds oleanolic acid (3) and ursolic acid (4). The structures of the isolated compounds were elucidated by means of modern spectroscopic techniques and comparison with literature data.

  13. On the history of basic fuchsin and aldehyde-Schiff reactions from 1862 to 1935.

    PubMed

    Puchtler, H; Meloan, S N; Brewton, B R

    1975-01-01

    The nature of products formed by aldehydes and Schiff's reagent, whether they are sulfonic or sulfinic acid compounds, has been the subject of much discussion. It seems therefore timely to review early studies of aldehyde-Schiff reactions, including the history of pararosanilin and related dyes. Dyes of the basic fuchsin group have been studied extensively since 1862, and their triphenylmethane structure was established in 1878. The currently used structural formulas were introduced around the turn of the century. Reactions of basic fuchsin with aldehydes, with and without addition of SO2, were investigated by Schiff in the 1860's i.e. before the structure of these dyes was known. In 1900 Prud'homme showed that the reaction products of basic fuschsin, sodium bisulfite and formaldehyde are alkylated and sulfonated derivatives of the parent compound; further chemical studies indicated attachment of the sulfonic acid group to the carbon atom of the aldehyde. Prud'homme's findings were repeatedly confirmed during the following decades. Wieland and Scheuing were apparently unaware of these studies and introduced the sulfinic acid theory in 1921; furthermore, they considered substitution at two amino group of Schiff's reagent essential for formation of the colored compound. However, later chemical and spectroscopic studies showed no evidence of-N-sulfinic acids but supported the sulfonic acid theory of Prud'homme.

  14. Dual Lewis Acid/Lewis Base Catalyzed Acylcyanation of Aldehydes: A Mechanistic Study.

    PubMed

    Laurell Nash, Anna; Hertzberg, Robin; Wen, Ye-Qian; Dahlgren, Björn; Brinck, Tore; Moberg, Christina

    2016-03-07

    A mechanistic investigation, which included a Hammett correlation analysis, evaluation of the effect of variation of catalyst composition, and low-temperature NMR spectroscopy studies, of the Lewis acid-Lewis base catalyzed addition of acetyl cyanide to prochiral aldehydes provides support for a reaction route that involves Lewis base activation of the acyl cyanide with formation of a potent acylating agent and cyanide ion. The cyanide ion adds to the carbonyl group of the Lewis acid activated aldehyde. O-Acylation by the acylated Lewis base to form the final cyanohydrin ester occurs prior to decomplexation from titanium. For less reactive aldehydes, the addition of cyanide is the rate-determining step, whereas, for more reactive, electron-deficient aldehydes, cyanide addition is rapid and reversible and is followed by rate-limiting acylation. The resting state of the catalyst lies outside the catalytic cycle and is believed to be a monomeric titanium complex with two alcoholate ligands, which only slowly converts into the product.

  15. Electrophilic activation of aldehydes "on water": a facile route to dipyrromethanes.

    PubMed

    Zoli, Luca; Cozzi, Pier Giorgio

    2009-01-01

    Shaken .. and stirred: Dipyrromethane, an important building block in porphyrin chemistry, can be easily accessed by a reaction performed on water in the absence of Lewis acids. Thus, a variety of substituted dipyrromethanes were prepared in moderate to good yields using a range of aldehydes.

  16. A HIGHLY STEREOSELECTIVE, NOVEL COUPLING REACTION BETWEEN ALKYNES WITH ALDEHYDES. (R828129)

    EPA Science Inventory

    In the presence of indium triflate or gallium chloride, a novel coupling between internal alkynes and aldehydes occurred to give unsaturated ketones and [4+1] annulation products.


    Graphical Abstrac...

  17. Structural and functional analysis of betaine aldehyde dehydrogenase from Staphylococcus aureus

    PubMed Central

    Halavaty, Andrei S.; Rich, Rebecca L.; Chen, Chao; Joo, Jeong Chan; Minasov, George; Dubrovska, Ievgeniia; Winsor, James R.; Myszka, David G.; Duban, Mark; Shuvalova, Ludmilla; Yakunin, Alexander F.; Anderson, Wayne F.

    2015-01-01

    When exposed to high osmolarity, methicillin-resistant Staphylococcus aureus (MRSA) restores its growth and establishes a new steady state by accumulating the osmoprotectant metabolite betaine. Effective osmoregulation has also been implicated in the acquirement of a profound antibiotic resistance by MRSA. Betaine can be obtained from the bacterial habitat or produced intracellularly from choline via the toxic betaine aldehyde (BA) employing the choline dehydrogenase and betaine aldehyde dehydrogenase (BADH) enzymes. Here, it is shown that the putative betaine aldehyde dehydrogenase SACOL2628 from the early MRSA isolate COL (SaBADH) utilizes betaine aldehyde as the primary substrate and nicotinamide adenine dinucleotide (NAD+) as the cofactor. Surface plasmon resonance experiments revealed that the affinity of NAD+, NADH and BA for SaBADH is affected by temperature, pH and buffer composition. Five crystal structures of the wild type and three structures of the Gly234Ser mutant of SaBADH in the apo and holo forms provide details of the molecular mechanisms of activity and substrate specificity/inhibition of this enzyme. PMID:25945581

  18. Asymmetric intramolecular α-cyclopropanation of aldehydes using a donor/acceptor carbene mimetic

    PubMed Central

    Luo, Chaosheng; Wang, Zhen; Huang, Yong

    2015-01-01

    Enantioselective α-alkylation of carbonyl is considered as one of the most important processes for asymmetric synthesis. Common alkylation agents, that is, alkyl halides, are notorious substrates for both Lewis acids and organocatalysts. Recently, olefins emerged as a benign alkylating species via photo/radical mechanisms. However, examples of enantioselective alkylation of aldehydes/ketones are scarce and direct asymmetric dialkylation remains elusive. Here we report an intramolecular α-cyclopropanation reaction of olefinic aldehydes to form chiral cyclopropane aldehydes. We demonstrate that an α-iodo aldehyde can function as a donor/acceptor carbene equivalent, which engages in a formal [2+1] annulation with a tethered double bond. Privileged bicyclo[3.1.0]hexane-type scaffolds are prepared in good optical purity using a chiral amine. The synthetic utility of the products is demonstrated by versatile transformations of the bridgehead formyl functionality. We expect the concept of using α-iodo iminium as a donor/acceptor carbene surrogate will find wide applications in chemical reaction development. PMID:26644194

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

    PubMed

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

    2014-08-27

    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 (R(2) = 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 in the wild-type mice. Finally, Alda-1 treatment was even beneficial when given 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.

  20. An improved protocol for the Pd-catalyzed alpha-arylation of aldehydes with aryl halides.

    PubMed

    Martín, Rubén; Buchwald, Stephen L

    2008-10-16

    An improved protocol for the Pd-catalyzed alpha-arylation of aldehydes with aryl halides has been developed. The new catalytic system allows for the coupling of an array of substrates including challenging electron-rich aryl bromides and less reactive aryl chlorides. The utility of this method has been demonstrated in a new total synthesis of (+/-)-sporochnol.

  1. Aldehyde Recognition and Discrimination by Mammalian Odorant Receptors via Functional Group-Specific Hydration Chemistry

    PubMed Central

    2015-01-01

    The mammalian odorant receptors (ORs) form a chemical-detecting interface between the atmosphere and the nervous system. This large gene family is composed of hundreds of membrane proteins predicted to form as many unique small molecule binding niches within their G-protein coupled receptor (GPCR) framework, but very little is known about the molecular recognition strategies they use to bind and discriminate between small molecule odorants. Using rationally designed synthetic analogs of a typical aliphatic aldehyde, we report evidence that among the ORs showing specificity for the aldehyde functional group, a significant percentage detect the aldehyde through its ability to react with water to form a 1,1-geminal (gem)-diol. Evidence is presented indicating that the rat OR-I7, an often-studied and modeled OR known to require the aldehyde function of octanal for activation, is likely one of the gem-diol activated receptors. A homology model based on an activated GPCR X-ray structure provides a structural hypothesis for activation of OR-I7 by the gem-diol of octanal. PMID:25181321

  2. New HPLC methods to quantitate terpenoid aldehydes in foliage of cotton (Gossypium)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The cotton plant (Gossypium) produces protective terpenoid aldehydes in lysigenous pigment glands. These terpenoids include hemigossypolone, hemigossypolone-6-methyl ether, gossypol, gossypol-6-methyl ether, gossypol-6,6'-dimethyl ether, heliocides H1, H2, H3 and H4, and heliocides B1, B2, B3 and B4...

  3. Mn(0)-mediated chemoselective reduction of aldehydes. Application to the synthesis of α-deuterioalcohols.

    PubMed

    Jiménez, Tania; Barea, Elisa; Oltra, J Enrique; Cuerva, Juan M; Justicia, José

    2010-10-15

    A mild, simple, safe, chemoselective reduction of different kinds of aldehydes to the corresponding alcohols mediated by the Mn dust/water system is described. In addition to this, the use of D(2)O leads to the synthesis of α-deuterated alcohols and constitutes an efficient, inexpensive alternative for the preparation of these compounds.

  4. Catalytic asymmetric synthesis of O-acetyl cyanohydrins from KCN, Ac2O and aldehydes.

    PubMed

    Belokon, Yuri N; Gutnov, Andrey V; Moskalenko, Margarita A; Yashkina, Lidia V; Lesovoy, Denis E; Ikonnikov, Nicolai S; Larichev, Vladimir S; North, Michael

    2002-02-07

    A (salen)titanium catalyst has been found to induce the asymmetric addition of potassium cyanide and acetic anhydride to aldehydes, giving enantiomerically enriched cyanohydrin esters with up to 92% enantiomeric excess using just 1 mol% of the catalyst. This is the first report of the asymmetric synthesis of cyanohydrin derivatives using a cyanide source which is non-volatile and inexpensive.

  5. Structural and functional analysis of betaine aldehyde dehydrogenase from Staphylococcus aureus.

    PubMed

    Halavaty, Andrei S; Rich, Rebecca L; Chen, Chao; Joo, Jeong Chan; Minasov, George; Dubrovska, Ievgeniia; Winsor, James R; Myszka, David G; Duban, Mark; Shuvalova, Ludmilla; Yakunin, Alexander F; Anderson, Wayne F

    2015-05-01

    When exposed to high osmolarity, methicillin-resistant Staphylococcus aureus (MRSA) restores its growth and establishes a new steady state by accumulating the osmoprotectant metabolite betaine. Effective osmoregulation has also been implicated in the acquirement of a profound antibiotic resistance by MRSA. Betaine can be obtained from the bacterial habitat or produced intracellularly from choline via the toxic betaine aldehyde (BA) employing the choline dehydrogenase and betaine aldehyde dehydrogenase (BADH) enzymes. Here, it is shown that the putative betaine aldehyde dehydrogenase SACOL2628 from the early MRSA isolate COL (SaBADH) utilizes betaine aldehyde as the primary substrate and nicotinamide adenine dinucleotide (NAD(+)) as the cofactor. Surface plasmon resonance experiments revealed that the affinity of NAD(+), NADH and BA for SaBADH is affected by temperature, pH and buffer composition. Five crystal structures of the wild type and three structures of the Gly234Ser mutant of SaBADH in the apo and holo forms provide details of the molecular mechanisms of activity and substrate specificity/inhibition of this enzyme.

  6. Two-Carbon Homologation of Ketones to 3-Methyl Unsaturated Aldehydes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The usual scheme of two-carbon homologation of ketones to 3-methyl unsaturated aldehydes by Horner-Wadsworth-Emmons condensations with phosphonate esters, such as triethyl-2-phosphonoacetate, involves three steps. The phosphonate condensation step results in extension of the carbon chain by two carb...

  7. SmI(2)-promoted oxidation of aldehydes in the presence of electron-rich heteroatoms.

    PubMed

    Smith, Amos B; Lee, Dongjoo; Adams, Christopher M; Kozlowski, Marisa C

    2002-12-12

    [reaction: see text] The Evans-Tishchenko reaction provides an efficient and practical solution for the oxidation of aldehydes possessing sensitive electron-rich heteroatoms to the corresponding esters. Careful selection of the sacrificial beta-hydroxy ketone provides considerable subsequent flexibility to access the desired carboxylic acid.

  8. Rice aldehyde dehydrogenase7 is needed for seed maturation and viability.

    PubMed

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

    2009-02-01

    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.

  9. A novel protein modification generating an aldehyde group in sulfatases: its role in catalysis and disease.

    PubMed

    von Figura, K; Schmidt, B; Selmer, T; Dierks, T

    1998-06-01

    In multiple sulfatase deficiency, a rare human lysosomal storage disorder, all known sulfatases are synthesized as catalytically poorly active polypeptides. Analysis of the latter has shown that they lack a protein modification that was detected in all members of the sulfatase family. This novel protein modification generates a 2-amino-3-oxopropanoic acid (C alpha-formylglycine) residue by oxidation of the thiol group of a cysteine that is conserved among all eukaryotic sulfatases. The oxidation occurs in the endoplasmic reticulum at a stage when the nascent polypeptide is not yet folded. The aldehyde is part of the catalytic site and is likely to act as an aldehyde hydrate. One of the geminal hydroxyl groups accepts the sulfate during sulfate ester cleavage leading to the formation of a covalently sulfated enzyme intermediate. The other hydroxyl is required for the subsequent elimination of the sulfate and regeneration of the aldehyde group. In some prokaryotic members of the sulfatase gene family, the DNA sequence predicts a serine residue, and not a cysteine. Analysis of one of these prokaryotic sulfatases, however, revealed the presence of the C alpha-formylglycine indicating that the aldehyde group is essential for all members of the sulfatase family and that it can be generated from either cysteine or serine.

  10. Substrate-Controlled Diastereoselectivity Reversal in NHC-Catalyzed Cross-Benzoin Reactions Using N-Boc-N-Bn-Protected α-Amino Aldehydes.

    PubMed

    Haghshenas, Pouyan; Quail, J Wilson; Gravel, Michel

    2016-12-16

    The effectiveness of utilizing N-Bn-N-Boc-α-amino aldehydes in cross-benzoin reactions with heteroaromatic aldehydes is demonstrated. The reaction is both chemoselective and syn-selective, making it complementary to the anti-selective cross-benzoin reaction of NHBoc-α-amino aldehydes. Good diastereoselectivity is obtained for a variety of amino aldehydes, including nonhindered ones. A Felkin-Anh model can be used to rationalize the observed diastereoselectivity.

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

    PubMed Central

    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.

    2012-01-01

    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 outgenome-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

  12. Cytochrome P450BM-3 reduces aldehydes to alcohols through a direct hydride transfer

    SciTech Connect

    Kaspera, Ruediger; Sahele, Tariku; Lakatos, Kyle; Totah, Rheem A.

    2012-02-17

    Highlights: Black-Right-Pointing-Pointer Cytochrome P450BM-3 reduced aldehydes to alcohols efficiently (k{sub cat} {approx} 25 min{sup -1}). Black-Right-Pointing-Pointer Reduction is a direct hydride transfer from R-NADP{sup 2}H to the carbonyl moiety. Black-Right-Pointing-Pointer P450 domain variants enhance reduction through potential allosteric/redox interactions. Black-Right-Pointing-Pointer Novel reaction will have implications for metabolism of xenobiotics. -- Abstract: Cytochrome P450BM-3 catalyzed the reduction of lipophilic aldehydes to alcohols efficiently. A k{sub cat} of {approx}25 min{sup -1} was obtained for the reduction of methoxy benzaldehyde with wild type P450BM-3 protein which was higher than in the isolated reductase domain (BMR) alone and increased in specific P450-domain variants. The reduction was caused by a direct hydride transfer from preferentially R-NADP{sup 2}H to the carbonyl moiety of the substrate. Weak substrate-P450-binding of the aldehyde, turnover with the reductase domain alone, a deuterium incorporation in the product from NADP{sup 2}H but not D{sub 2}O, and no inhibition by imidazole suggests the reductase domain of P450BM-3 as the potential catalytic site. However, increased aldehyde reduction by P450 domain variants (P450BM-3 F87A T268A) may involve allosteric or redox mechanistic interactions between heme and reductase domains. This is a novel reduction of aldehydes by P450BM-3 involving a direct hydride transfer and could have implications for the metabolism of endogenous substrates or xenobiotics.

  13. Role of aldehyde chemistry and NOx concentrations in secondary organic aerosol formation

    NASA Astrophysics Data System (ADS)

    Chan, A. W. H.; Chan, M. N.; Surratt, J. D.; Chhabra, P. S.; Loza, C. L.; Crounse, J. D.; Yee, L. D.; Flagan, R. C.; Wennberg, P. O.; Seinfeld, J. H.

    2010-08-01

    Aldehydes are an important class of products from atmospheric oxidation of hydrocarbons. Isoprene (2-methyl-1,3-butadiene), the most abundantly emitted atmospheric non-methane hydrocarbon, produces a significant amount of secondary organic aerosol (SOA) via methacrolein (a C4-unsaturated aldehyde) under urban high-NOx conditions. Previously, we have identified peroxy methacryloyl nitrate (MPAN) as the important intermediate to isoprene and methacrolein SOA in this NOx regime. Here we show that as a result of this chemistry, NO2 enhances SOA formation from methacrolein and two other α, β-unsaturated aldehydes, specifically acrolein and crotonaldehyde, a NOx effect on SOA formation previously unrecognized. Oligoesters of dihydroxycarboxylic acids and hydroxynitrooxycarboxylic acids are observed to increase with increasing NO2/NO ratio, and previous characterizations are confirmed by both online and offline high-resolution mass spectrometry techniques. Molecular structure also determines the amount of SOA formation, as the SOA mass yields are the highest for aldehydes that are α, β-unsaturated and contain an additional methyl group on the α-carbon. Aerosol formation from 2-methyl-3-buten-2-ol (MBO232) is insignificant, even under high-NO2 conditions, as PAN (peroxy acyl nitrate, RC(O)OONO2) formation is structurally unfavorable. At atmospherically relevant NO2/NO ratios (3-8), the SOA yields from isoprene high-NOx photooxidation are 3 times greater than previously measured at lower NO2/NO ratios. At sufficiently high NO2 concentrations, in systems of α, β-unsaturated aldehydes, SOA formation from subsequent oxidation of products from acyl peroxyl radicals+NO2 can exceed that from RO2+HO2 reactions under the same inorganic seed conditions, making RO2+NO2 an important channel for SOA formation.

  14. Role of aldehyde chemistry and NOx concentrations in secondary organic aerosol formation

    NASA Astrophysics Data System (ADS)

    Chan, A. W. H.; Chan, M. N.; Surratt, J. D.; Chhabra, P. S.; Loza, C. L.; Crounse, J. D.; Yee, L. D.; Flagan, R. C.; Wennberg, P. O.; Seinfeld, J. H.

    2010-04-01

    Aldehydes are an important class of products from atmospheric oxidation of hydrocarbons. Isoprene (2-methyl-1,3-butadiene), the most abundantly emitted atmospheric non-methane hydrocarbon, produces a significant amount of secondary organic aerosol (SOA) via methacrolein (a C4-unsaturated aldehyde) under urban high-NOx conditions. Previously, we have identified peroxy methacryloyl nitrate (MPAN) as the important intermediate to isoprene and methacrolein SOA in this NOx regime. Here we show that as a result of this chemistry, NO2 enhances SOA formation from methacrolein and two other α, β-unsaturated aldehydes, specifically acrolein and crotonaldehyde, a NOx effect on SOA formation previously unrecognized. Oligoesters of dihydroxycarboxylic acids and hydroxynitrooxycarboxylic acids are observed to increase with increasing NO2/NO ratio, and previous characterizations are confirmed by both online and offline high-resolution mass spectrometry techniques. Molecular structure also determines the amount of SOA formation, as the SOA mass yields are the highest for aldehydes that are α, β-unsaturated and contain an additional methyl group on the α-carbon. Aerosol formation from 2-methyl-3-buten-2-ol (MBO232) is insignificant, even under high-NO2 conditions, as PAN (peroxy acyl nitrate, RC(O)OONO2) formation is structurally unfavorable. At atmospherically relevant NO2/NO ratios, the SOA yields from isoprene high-NOxphotooxidation are 3 times greater than previously measured at lower NO2/NO ratios. At sufficiently high NO2 concentrations, in systems of α, β-unsaturated aldehydes, SOA formation from subsequent oxidation of products from acyl peroxyl radicals+NO2 can exceed that from RO2+HO2 reactions under the same inorganic seed conditions, making RO2+NO2 an important channel for SOA formation.

  15. Aldehyde modification and alum coadjuvancy enhance anti-TNF-α autovaccination and mitigate arthritis in rat.

    PubMed

    Bavoso, Alfonso; Ostuni, Angela; De Vendel, Jolanda; Bracalello, Angelo; Shcheglova, Tatiana; Makker, Sudesh; Tramontano, Alfonso

    2015-05-01

    Experimental vaccination to induce antibodies (Abs) capable of cytokine antagonism shows promise as a novel immunotherapy for chronic inflammatory disease. We prepared a hybrid antigen consisting of residues 141-235 of rat TNF-α fused to the C-terminus of glutathione-S-transferase (GST), chemically modified to incorporate aldehyde residues, for development of an auto-vaccine eliciting anti-rTNF-α Abs. In rat immunization the soluble aldehyde-modified fusion protein did not generate observable Ab responses. By contrast, vaccination with the aldehyde-modified fusion protein adsorbed on alum induced anti-TNF-α autoAbs with high titer and neutralizing activity. Induction of adjuvant arthritis in rats pre-immunized with unmodified fusion protein or a control protein in alum resulted in severe inflammation and joint damage, whereas the disease induced in rats immunized with the aldehyde-bearing fusion protein in alum was markedly attenuated. Similar results were obtained in a collagen-induced rat arthritis model. Anti-collagen II IgG Ab titers did not deviate significantly in groups pre-immunized with modified fusion protein and control protein, suggesting that anti-TNF vaccination did not skew the immune response related to disease induction. This study demonstrates synergy between particulate alum and protein bound carbonyl residues for enhancement of protein immunogenicity. The antigen-specific co-adjuvant system could prove advantageous for breaking tolerance in emerging auto-vaccination therapies targeting inflammatory cytokines as well as for enhancing a broader category of subunit vaccines. Aldehyde adduction introduces a minimal modification which, together with the established use of alum as a safe adjuvant for human use, could be favorable for further vaccine development.

  16. Role of aldehydes in the toxic and mutagenic effects of nitrosamines.

    PubMed

    Peterson, Lisa A; Urban, Anna M; Vu, Choua C; Cummings, Meredith E; Brown, Lee C; Warmka, Janel K; Li, Li; Wattenberg, Elizabeth V; Patel, Yesha; Stram, Daniel O; Pegg, Anthony E

    2013-10-21

    α-Hydroxynitrosamine metabolites of nitrosamines decompose to a reactive diazohydroxide and an aldehyde. To test the hypothesis that the aldehydes contribute to the harmful effects of nitrosamines, the toxic and mutagenic activities of three model methylating agents were compared in Chinese hamster ovary cells expressing or not expressing human O⁶-alkylguanine DNA alkyltransferase (AGT). N-Nitrosomethylurethane (NMUr), acetoxymethylmethylnitrosamine (AMMN), and 4-(methylnitrosamino)-4-acetoxy-1-(3-pyridyl)-1-butanone (NNK-4-OAc) are all activated by ester hydrolysis to methanediazohydroxide. NMUr does not form an aldehyde, whereas AMMN generates formaldehyde, and NNK-4-OAc produces 4-oxo-1-(3-pyridyl)-1-butanone (OPB). Since these compounds were likely to alkylate DNA to different extents, the toxic and mutagenic activities of these compounds were normalized to the levels of the most cytotoxic and mutagenic DNA adduct, O⁶-mG, to assess if the aldehydes contributed to the toxicological properties of these methylating agents. Levels of 7-mG indicated that the differences in cytotoxic and mutagenic effects of these compounds resulted from differences in their ability to methylate DNA. When normalized against the levels of O⁶-mG, there was no difference between these three compounds in cells that lacked AGT. However, AMMN and NNK-4-OAc were more toxic than NMUr in cells expressing AGT when normalized against O⁶-mG levels. In addition, AMMN was more mutagenic than NNK-4-OAc and MNUr in these cells. These findings demonstrate that the aldehyde decomposition products of nitrosamines can contribute to the cytotoxic and/or mutagenic activity of methylating nitrosamines.

  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.

  18. A validated enantioselective LC-MS/MS assay for quantification of a major chiral metabolite of an achiral 11-β-hydroxysteroid-dehydrogenase 1 inhibitor in human plasma: Application to a clinical pharmacokinetic study.

    PubMed

    Furlong, Michael T; Ji, Qin C; Iacono, Lisa; Dang, Oanh; Noren, Marzena; Bruce, John; Aubry, Anne-Françoise; Arnold, Mark E

    2016-06-01

    BMS-823778 is a potent 11-β-hydroxysteroid-dehydrogenase 1 (11βHSD-1) inhibitor and a potential therapeutic agent for type 2 diabetes mellitus (T2DM). A high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated to enable reliable separation and quantification of both enantiomers of a chiral hydroxy metabolite (BMT-094817) in human plasma. Following liquid-liquid extraction in a 96-well plate format, chromatographic separation of the metabolite enantiomers was achieved by isocratic elution on a Chiralpak IA-3 column. Chromatographic conditions were optimized to ensure separation of both metabolite enantiomers. Metabolite enantiomers and stable isotope-labeled (SIL) internal standards were detected by positive ion electrospray tandem mass spectrometry. The LC-MS/MS assay was validated over a concentration range of 0.200-200ng/mL. Intra- and inter-assay precision values for replicate quality control samples were less than 9.9% for both enantiomers during the assay validation. Mean quality control accuracy values were within ±7.3%. Assay recoveries were high (>75%) and consistent across the assay range. The metabolite enantiomers were stable in human blood for 2h on ice. The analytes were also stable in human plasma for 25h at room temperature, 34days at -20°C and -70°C, and following five freeze-thaw cycles. No interconversion of the metabolite enantiomers was detected under any bioanalytical stress conditions, from blood collection/processing through extracted sample storage. The validated assay was successfully applied to the quantification of both metabolite enantiomers in human plasma in support of a human pharmacokinetic study.

  19. Aldehyde oxidase-catalysed oxidation of methotrexate in the liver of guinea-pig, rabbit and man.

    PubMed

    Jordan, C G; Rashidi, M R; Laljee, H; Clarke, S E; Brown, J E; Beedham, C

    1999-04-01

    Although 7-hydroxymethotrexate is a major metabolite of methotrexate during high-dose therapy, negligible methotrexate-oxidizing activity has been found in-vitro in the liver in man. The goals of this study were to determine the role of aldehyde oxidase in the metabolism of methotrexate to 7-hydroxymethotrexate in the liver and to study the effects of inhibitors and other substrates on the metabolism of methotrexate. Methotrexate, (+/-)-methotrexate and (-)-methotrexate were incubated with partially purified aldehyde oxidase from the liver of rabbit, guinea-pig and man and the products analysed by HPLC. Rabbit liver aldehyde oxidase was used for purposes of comparison. In-vitro aldehyde oxidase from the liver of man catalyses the oxidation of methotrexate to 7-hydroxymethotrexate, but the turnover is low. However, formation of 7-hydroxy-methotrexate from all forms of methotrexate by the liver in guinea-pig and man was significantly inhibited in the presence of 100 microM menadione and chlorpromazine, potent inhibitors of aldehyde oxidase. Allopurinol (100 microM) had a negligible inhibitory effect on liver aldehyde oxidase from guinea-pig and man. Allopurinol is a xanthine oxidase inhibitor. The production of 7-hydroxymethotrexate was enhanced in the presence of allopurinol. Although aldehyde oxidase is also responsible for some of this conversion, it is also possible that the closely related xanthine oxidase is responsible for the formation of 7-hydroxymethotrexate. By employing potent selective inhibitors of aldehyde oxidase, menadione and chlorpromazine, we have demonstrated for the first time that liver aldehyde oxidase from man is minimally involved in methotrexate oxidation.

  20. Crystal structure of eta-crystallin: adaptation of a class 1 aldehyde dehydrogenase for a new role in the eye lens.

    PubMed

    Bateman, O A; Purkiss, A G; van Montfort, R; Slingsby, C; Graham, C; Wistow, G

    2003-04-22

    Eta-crystallin is a retinal dehydrogenase that has acquired a role as a structural protein in the eye lens of elephant shrews, members of an ancient order of mammals. While it retains some activity toward retinal, which is oxidized to retinoic acid, the protein has acquired a number of specific sequence changes that have presumably been selected to enhance the lens role. The crystal structure of eta-crystallin, in common with class 1 and 2 ALDHs, is a dimer of dimers. It has a better-defined NAD binding site than those of related mammalian ALDH1 enzymes with the cofactor bound in the "hydride transfer" position in all four monomers with small differences about the dimer dyads. Although the active site is well conserved, the substrate-binding site is larger in eta-crystallin, and there are some mutations to the substrate access tunnel that might affect binding or release of substrate and product. It is possible that eta-crystallin has lost flexibility to improve its role in the lens. Enhanced binding of cofactor could enable it to act as a UV/blue light filter in the lens, improving visual acuity. The structure not only gives a view of a "natural mutant" of ALDH1 illustrating the adaptive conflict that can arise in multifunctional proteins, but also provides a well-ordered NAD binding site structure for this class of enzymes with important roles in development and health.

  1. Enantioselective Direct α-Amination of Aldehydes via a Photoredox Mechanism: A Strategy for Asymmetric Amine Fragment Coupling

    PubMed Central

    Cecere, Giuseppe; Koenig, Christian M.; Alleva, Jennifer L.

    2013-01-01

    The direct, asymmetric α-amination of aldehydes has been accomplished via a combination of photoredox and organocatalysis. Photon-generated, nitrogen-centered radicals undergo enantioselective α-addition to catalytically formed chiral enamines to directly produce stable α-amino aldehyde adducts bearing synthetically useful amine substitution patterns. Incorporation of a photolabile group on the amine precursor obviates the need to employ a photoredox catalyst in this transformation. Importantly, this photoinduced transformation allows direct and enantioselective access to α-amino aldehyde products that do not require post-reaction manipulation. PMID:23869694

  2. Selective Radical Amination of Aldehydic C(sp2)–H Bonds with Fluoroaryl Azides via Co(II)-Based Metalloradical Catalysis: Synthesis of N-Fluoroaryl Amides from Aldehydes under Neutral and Nonoxidative Conditions

    PubMed Central

    Jin, Li-Mei; Lu, Hongjian; Cui, Yuan; Lizardi, Christopher L.; Arzua, Thiago N.; Wojtas, Lukasz; Cui, Xin

    2014-01-01

    The Co(II) complex of the D2h-symmetric amidoporphyrin 3,5-DitBu-IbuPhyrin, [Co(P1)], has proven to be an effective metalloradical catalyst for intermolecular amination of C(sp2)–H bonds of aldehydes with fluoroaryl azides. The [Co(P1)]-catalyzed process can employ aldehydes as the limiting reagents and operate under neutral and non-oxidative conditions, generating nitrogen gas as the only byproduct. The metalloradical aldehydic C–H amination is suitable for different combinations of aldehydes and fluoroaryl azides, producing the corresponding N-fluoroaryl amides in good to excellent yields. A series of mechanistic studies support a stepwise radical mechanism for the Co(II)-catalyzed intermolecular C–H amination. PMID:25071929

  3. Reconstitution of Formylglycine-generating Enzyme with Copper(II) for Aldehyde Tag Conversion

    PubMed Central

    Holder, Patrick G.; Jones, Lesley C.; Drake, Penelope M.; Barfield, Robyn M.; Bañas, Stefanie; de Hart, Gregory W.; Baker, Jeanne; Rabuka, David

    2015-01-01

    To further our aim of synthesizing aldehyde-tagged proteins for research and biotechnology applications, we developed methods for recombinant production of aerobic formylglycine-generating enzyme (FGE) in good yield. We then optimized the FGE biocatalytic reaction conditions for conversion of cysteine to formylglycine in aldehyde tags on intact monoclonal antibodies. During the development of these conditions, we discovered that pretreating FGE with copper(II) is required for high turnover rates and yields. After further investigation, we confirmed that both aerobic prokaryotic (Streptomyces coelicolor) and eukaryotic (Homo sapiens) FGEs contain a copper cofactor. The complete kinetic parameters for both forms of FGE are described, along with a proposed mechanism for FGE catalysis that accounts for the copper-dependent activity. PMID:25931126

  4. Biomass Vanillin-Derived Polymeric Microspheres Containing Functional Aldehyde Groups: Preparation, Characterization, and Application as Adsorbent.

    PubMed

    Zhang, Huanyu; Yong, Xueyong; Zhou, Jinyong; Deng, Jianping; Wu, Youping

    2016-02-03

    The contribution reports the first polymeric microspheres derived from a biomass, vanillin. It reacted with methacryloyl chloride, providing monomer vanillin methacrylate (VMA), which underwent suspension polymerization in aqueous media and yielded microspheres in high yield (>90 wt %). By controlling the N2 bubbling mode and by optimizing the cosolvent for dissolving the solid monomer, the microspheres were endowed with surface pores, demonstrated by SEM images and mercury intrusion porosimetry measurement. Taking advantage of the reactive aldehyde groups, the microspheres further reacted with glycine, thereby leading to a novel type of Schiff-base chelating material. The functionalized microspheres demonstrated remarkable adsorption toward Cu(2+) (maximum, 135 mg/g) which was taken as representative for metal ions. The present study provides an unprecedented class of biobased polymeric microspheres showing large potentials as adsorbents in wastewater treatment. Also importantly, the reactive aldehyde groups may enable the microspheres to be used as novel materials for immobilizing biomacromolecules, e.g. enzymes.

  5. Metal-Free Trifluoromethylation of Aromatic and Heteroaromatic Aldehydes and Ketones

    PubMed Central

    2015-01-01

    The ability to convert simple and common substrates into fluoroalkyl derivatives under mild conditions remains an important goal for medicinal and agricultural chemists. One representative example of a desirable transformation involves the conversion of aromatic and heteroaromatic ketones and aldehydes into aryl and heteroaryl β,β,β-trifluoroethylarenes and -heteroarenes. The traditional approach for this net transformation involves stoichiometric metals and/or multistep reaction sequences that consume excessive time, material, and labor resources while providing low yields of products. To complement these traditional strategies, we report a one-pot metal-free decarboxylative procedure for accessing β,β,β-trifluoroethylarenes and -heteroarenes from readily available ketones and aldehydes. This method features several benefits, including ease of operation, readily available reagents, mild reaction conditions, high functional-group compatibility, and scalability. PMID:25001876

  6. Selective deoxygenation of aldehydes and alcohols on molybdenum carbide (Mo2C) surfaces

    NASA Astrophysics Data System (ADS)

    Xiong, Ke; Yu, Weiting; Chen, Jingguang G.

    2014-12-01

    The selective deoxygenation of aldehydes and alcohols without cleaving the Csbnd C bond is crucial for upgrading bio-oil and other biomass-derived molecules to useful fuels and chemicals. In this work, propanal, 1-propanol, furfural and furfuryl alcohol were selected as probe molecules to study the deoxygenation of aldehydes and alcohols on molybdenum carbide (Mo2C) prepared over a Mo(1 1 0) surface. The reaction pathways were investigated using temperature programmed desorption (TPD) and high resolution electron energy loss spectroscopy (HREELS). The deoxygenation of propanal and 1-propanol went through a similar intermediate (propoxide or η2(C,O)-propanal) to produce propene. The deoxygenation of furfural and furfuryl alcohol produced a surface intermediate similar to adsorbed 2-methylfuran. The comparison of these results revealed the promising deoxygenation performance of Mo2C, as well as the effect of the furan ring on the selective deoxygenation of the Cdbnd O and Csbnd OH bonds.

  7. 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.

  8. Effects of aliphatic aldehydes on the growth and patulin production of Penicillium expansum in apple juice.

    PubMed

    Taguchi, Tomoyasu; Kozutsumi, Daisuke; Nakamura, Ruka; Sato, Yoshio; Ishihara, Atsushi; Nakajima, Hiromitsu

    2013-01-01

    The effects of 16 aliphatic aldehydes with 3-10 carbons on the growth and patulin production of Penicillium expansum were examined. When P. expansum spores were inoculated into apple juice broth, some alkenals, including 2-propenal, (E)-2-butenal, (E)-2-pentenal, and (E)-2-hexenal, inhibited fungal growth and patulin production. Their minimal inhibitory concentrations were 5, 50, 80, and 80 µg/mL respectively. Vital staining indicated that these alkenals killed mycelia within 4 h. Treatment of the spores with these aldehydes also resulted in rapid loss of germination ability, within 0.5-2 d. On the other hand, aliphatic aldehydes with 8-10 carbons significantly enhanced patulin production without affecting fungal growth: 300 µg/mL of octanal and 100 µg/mL of (E)-2-octenal increased the patulin concentrations in the culture broth by as much as 8.6- and 7.8-fold as compared to that of the control culture respectively. The expression of the genes involved in patulin biosynthesis in P. expansum was investigated in mycelia cultured in apple juice broth containing 300 µg/mL of octanal for 3.5, 5, and 7 d. Transcription of the msas gene, encoding 6-methylsalicylic acid synthase, which catalyzed the first step in the patulin biosynthetic pathway was remarkably high in the 3.5-d and 5-d-old cultures as compared with the control. However, octanal did not any increase the transcription of the msas in the 7-d-old culture or that of the other two genes, IDH and the peab1, in culture. Thus the enhanced patulin accumulation with supplementation with these aldehydes is attributable to the increased amount of the msas transcript.

  9. 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

  10. Aldehydes in Relation to Air Pollution Sources: A Case Study around the Beijing Olympics

    PubMed Central

    Altemose, Brent; Gong, Jicheng; Zhu, Tong; Hu, Min; Zhang, Liwen; Cheng, Hong; Zhang, Lin; Tong, Jian; Kipen, Howard M.; Strickland, Pamela Ohman; Meng, Qingyu; Robson, Mark G.; Zhang, Junfeng

    2015-01-01

    This study was carried out to characterize three aldehydes of health concern (formaldehyde, acetaldehyde, and acrolein) at a central Beijing site in the summer and early fall of 2008 (from June to October). Aldehydes in polluted atmospheres come from both primary and secondary sources, which limits the control strategies for these reactive compounds. Measurements were made before, during, and after the Beijing Olympics to examine whether the dramatic air pollution control measures implemented during the Olympics had an impact on concentrations of the three aldehydes and their underlying primary and secondary sources. Average concentrations of formaldehyde, acetaldehyde and acrolein were 29.3±15.1 μg/m3, 27.1±15.7 μg/m3 and 2.3±1.0 μg/m3, respectively, for the entire period of measurements, all being at the high end of concentration ranges measured in cities around the world in photochemical smog seasons. Formaldehyde and acrolein increased during the pollution control period compared to the pre-Olympic Games, followed the changing pattern of temperature, and were significantly correlated with ozone and with a secondary formation factor identified by principal component analysis (PCA). In contrast, acetaldehyde had a reduction in mean concentration during the Olympic air pollution control period compared to the pre-Olympic period and was significantly correlated with several pollutants emitted from local emission sources (e.g., NO2, CO, and PM2.5). Acetaldehyde was also more strongly associated with primary emission sources including vegetative burning and oil combustion factors identified through the PCA. All three aldehydes were lower during the post-Olympic sampling period compared to the before and during Olympic periods, likely due to seasonal and regional effects. Our findings point to the complexity of source control strategies for secondary pollutants. PMID:25883528

  11. Enantioselective intramolecular aldehyde α-alkylation with simple olefins: direct access to homo-ene products.

    PubMed

    Comito, Robert J; Finelli, Fernanda G; MacMillan, David W C

    2013-06-26

    A highly selective method for the synthesis of asymmetrically substituted carbocycles and heterocycles from unactivated aldehyde-olefin precursors has been achieved via enantioselective SOMO-catalysis. Addition of a catalytically generated enamine radical cation across a pendent olefin serves to establish a general asymmetric strategy toward the production of a wide range of formyl-substituted rings with alkene transposition. Conceptually, this novel mechanism allows direct access to "homo-ene"-type products.

  12. Fatty aldehyde dehydrogenase multigene family involved in the assimilation of n-alkanes in Yarrowia lipolytica.

    PubMed

    Iwama, Ryo; Kobayashi, Satoshi; Ohta, Akinori; Horiuchi, Hiroyuki; Fukuda, Ryouichi

    2014-11-28

    In the n-alkane assimilating yeast Yarrowia lipolytica, n-alkanes are oxidized to fatty acids via fatty alcohols and fatty aldehydes, after which they are utilized as carbon sources. Here, we show that four genes (HFD1-HFD4) encoding fatty aldehyde dehydrogenases (FALDHs) are involved in the metabolism of n-alkanes in Y. lipolytica. A mutant, in which all of four HFD genes are deleted (Δhfd1-4 strain), could not grow on n-alkanes of 12-18 carbons; however, the expression of one of those HFD genes restored its growth on n-alkanes. Production of Hfd2Ap or Hfd2Bp, translation products of transcript variants generated from HFD2 by the absence or presence of splicing, also supported the growth of the Δhfd1-4 strain on n-alkanes. The FALDH activity in the extract of the wild-type strain was increased when cells were incubated in the presence of n-decane, whereas this elevation in FALDH activity by n-decane was not observed in Δhfd1-4 strain extract. Substantial FALDH activities were detected in the extracts of Escherichia coli cells expressing the HFD genes. Fluorescent microscopic observation suggests that Hfd3p and Hfd2Bp are localized predominantly in the peroxisome, whereas Hfd1p and Hfd2Ap are localized in both the endoplasmic reticulum and the peroxisome. These results suggest that the HFD multigene family is responsible for the oxidation of fatty aldehydes to fatty acids in the metabolism of n-alkanes, and raise the possibility that Hfd proteins have diversified by gene multiplication and RNA splicing to efficiently assimilate or detoxify fatty aldehydes in Y. lipolytica.

  13. Aldehydes in relation to air pollution sources: A case study around the Beijing Olympics

    NASA Astrophysics Data System (ADS)

    Altemose, Brent; Gong, Jicheng; Zhu, Tong; Hu, Min; Zhang, Liwen; Cheng, Hong; Zhang, Lin; Tong, Jian; Kipen, Howard M.; Ohman-Strickland, Pamela; Meng, Qingyu; Robson, Mark G.; Zhang, Junfeng

    2015-05-01

    This study was carried out to characterize three aldehydes of health concern (formaldehyde, acetaldehyde, and acrolein) at a central Beijing site in the summer and early fall of 2008 (from June to October). Aldehydes in polluted atmospheres come from both primary and secondary sources, which limits the control strategies for these reactive compounds. Measurements were made before, during, and after the Beijing Olympics to examine whether the dramatic air pollution control measures implemented during the Olympics had an impact on concentrations of the three aldehydes and their underlying primary and secondary sources. Average concentrations of formaldehyde, acetaldehyde and acrolein were 29.3 ± 15.1 μg/m3, 27.1 ± 15.7 μg/m3 and 2.3 ± 1.0 μg/m3, respectively, for the entire period of measurements, all being at the high end of concentration ranges measured in cities around the world in photochemical smog seasons. Formaldehyde and acrolein increased during the pollution control period compared to the pre-Olympic Games, followed the changing pattern of temperature, and were significantly correlated with ozone and with a secondary formation factor identified by principal component analysis (PCA). In contrast, acetaldehyde had a reduction in mean concentration during the Olympic air pollution control period compared to the pre-Olympic period and was significantly correlated with several pollutants emitted from local emission sources (e.g., NO2, CO, and PM2.5). Acetaldehyde was also more strongly associated with primary emission sources including vegetative burning and oil combustion factors identified through the PCA. All three aldehydes were lower during the post-Olympic sampling period compared to the before and during Olympic periods, likely due to seasonal and regional effects. Our findings point to the complexity of source control strategies for secondary pollutants.

  14. Stereoselective Arylation of Amino Aldehydes: Overriding Natural Substrate Control through Chelation.

    PubMed

    Martins, Bruna S; Moro, Angélica V; Lüdtke, Diogo S

    2017-03-03

    The chelation-controlled arylation reaction of chiral, enantiopure acyclic α-amino aldehydes enabled by a B/Zn exchange reaction between arylboronic acids and Et2Zn is reported. The presence of dibenzyl substituents at the nitrogen plays a key role in the stereochemical outcome of the reaction, and chelation is favored over the natural tendency of this type of substrate to undergo Felkin-Anh controlled additions with organomagnesium and organolithium reagents.

  15. STIMULATION OF TARSAL RECEPTORS OF THE BLOWFLY BY ALIPHATIC ALDEHYDES AND KETONES

    PubMed Central

    Chadwick, L. E.; Dethier, V. G.

    1949-01-01

    Rejection of eight aldehydes, eight ketones, five secondary alcohols, and 3-pentanol has been studied in the blowfly Phormia regina Meigen. The data agree with results previously reported for normal alcohols and several series of glycols in showing a logarithmic increase in stimulating effect with increasing chain length. The order of increasing effectiveness among the different species of compounds thus far investigated is the following: polyglycols, diols, secondary alcohols, iso-alcohols, normal alcohols, ketones, iso-aldehydes, normal aldehydes. Curves relating the logarithms of threshold concentration to the logarithms of chain length for diols, alcohols, aldehydes, and ketones show inflections in the 3 to 6 carbon range. Above and below the region of inflection the curves are nearly rectilinear. The slopes for the upper limbs (smaller molecules) are of the order of –2; for the lower limbs, about –10. Comparisons of the threshold data with numerical values for molecular weights, molecular areas and volumes, oil-water distribution coefficients, activity coefficients, standard free energies, vapor pressures, boiling points, melting points, dipole moments, dielectric constants, and degree of association are discussed briefly, and it is concluded that none of the comparisons serves to bring the data from the several series and from the two portions of each series into a single homogeneous system. A qualitative comparison with water solubilities shows fewer discrepancies. It is suggested that the existence of a combination of aqueous and lipoid phases at the receptor surface would fit best with what is presently known about the relationship between chemical structure and stimulating effect in contact chemoreception. In this hypothesis the smaller and more highly water-soluble compounds are envisaged as gaining access to the receptors partly through the aqueous phase, the larger molecules predominantly through the lipoid phase. PMID:18114559

  16. Nitrous oxide activation by a cobalt(ii) complex for aldehyde oxidation under mild conditions.

    PubMed

    Corona, Teresa; Company, Anna

    2016-10-07

    Nitrous oxide (N2O) is a waste gas produced in many industrial processes with an important environmental impact. Thus, its application as an oxidant is highly desirable because it produces innocuous N2 as a by-product. In this work we report a new cobalt(ii) complex that reacts with N2O under mild conditions and the catalytic application of this system to carry out the oxidation of aldehydes.

  17. Aldehydes in Relation to Air Pollution Sources: A Case Study around the Beijing Olympics.

    PubMed

    Altemose, Brent; Gong, Jicheng; Zhu, Tong; Hu, Min; Zhang, Liwen; Cheng, Hong; Zhang, Lin; Tong, Jian; Kipen, Howard M; Strickland, Pamela Ohman; Meng, Qingyu; Robson, Mark G; Zhang, Junfeng

    2015-05-01

    This study was carried out to characterize three aldehydes of health concern (formaldehyde, acetaldehyde, and acrolein) at a central Beijing site in the summer and early fall of 2008 (from June to October). Aldehydes in polluted atmospheres come from both primary and secondary sources, which limits the control strategies for these reactive compounds. Measurements were made before, during, and after the Beijing Olympics to examine whether the dramatic air pollution control measures implemented during the Olympics had an impact on concentrations of the three aldehydes and their underlying primary and secondary sources. Average concentrations of formaldehyde, acetaldehyde and acrolein were 29.3±15.1 μg/m(3), 27.1±15.7 μg/m(3) and 2.3±1.0 μg/m(3), respectively, for the entire period of measurements, all being at the high end of concentration ranges measured in cities around the world in photochemical smog seasons. Formaldehyde and acrolein increased during the pollution control period compared to the pre-Olympic Games, followed the changing pattern of temperature, and were significantly correlated with ozone and with a secondary formation factor identified by principal component analysis (PCA). In contrast, acetaldehyde had a reduction in mean concentration during the Olympic air pollution control period compared to the pre-Olympic period and was significantly correlated with several pollutants emitted from local emission sources (e.g., NO2, CO, and PM2.5). Acetaldehyde was also more strongly associated with primary emission sources including vegetative burning and oil combustion factors identified through the PCA. All three aldehydes were lower during the post-Olympic sampling period compared to the before and during Olympic periods, likely due to seasonal and regional effects. Our findings point to the complexity of source control strategies for secondary pollutants.

  18. Indoor aldehydes concentration and emission rate of formaldehyde in libraries and private reading rooms

    NASA Astrophysics Data System (ADS)

    Kim, Jeonghoon; Kim, Seojin; Lee, Kiyoung; Yoon, Dongwon; Lee, Jiryang; Ju, DaeYoung

    2013-06-01

    Aldehydes are of particularly interest due to their potential adverse impact on human health. Formaldehyde is one of the most abundant indoor pollutants. To improve indoor air quality, identifying and removing the major emission sources of formaldehyde would be desirable. The purposes of this study were to determine aldehyde concentrations in libraries and reading rooms and to identify emission sources of formaldehyde in private reading rooms. Indoor aldehyde concentrations were quantified at 66 facilities, including public libraries, children's libraries, public reading rooms, and private reading rooms, in the Seoul metropolitan area. Emission fluxes of formaldehyde from the surfaces of desks, chairs, floors, walls, and ceilings in 19 private reading rooms were measured using a passive emission colorimetric sensor. Indoor aldehyde (formaldehyde, acetaldehyde, propioaldehyde, benzaldehyde, and hexaldehyde) levels were significantly higher than outdoor levels. Indoor formaldehyde geometric mean concentrations in private reading rooms (119.3 μg m-3) were significantly higher than in public libraries (29.2 μg m-3), children's libraries (29.3 μg m-3), and public reading rooms (40.8 μg m-3). Indoor formaldehyde levels were associated with relative humidity. In private reading rooms, the emission rates from desks (255.5 ± 214.8 μg h-1) and walls (231.7 ± 192.3 μg h-1) were significantly higher than that from chairs (79.6 ± 88.5 μg h-1). Desks (31%) and walls (29%) were the major emission sources of formaldehyde in 14 facilities in which measurements exceeded the indoor standard of 100 μg m-3. The age of interior materials was a significant factor for indoor formaldehyde emission flux. Controlling the emission rates of desks and walls is recommended to improve formaldehyde concentrations in private reading rooms.

  19. Metabolism of zaleplon by human liver: evidence for involvement of aldehyde oxidase.

    PubMed

    Lake, B G; Ball, S E; Kao, J; Renwick, A B; Price, R J; Scatina, J A

    2002-10-01

    1. The metabolism of Zaleplon (CL-284,846; ZAL) has been studied in precision-cut human liver slices and liver cytosol preparations. 2. Human liver slices metabolized ZAL to a number of products including 5-oxo-ZAL (M2), N-desethyl-5-oxo-ZAL (M1) and N-desethyl-ZAL (DZAL), the latter metabolite being known to be formed by CYP3A forms. 3. Human liver cytosol preparations catalysed the metabolism of ZAL to M2. Kinetic analysis of three cytosol preparations revealed mean (+/- SEM) K(m) and V(max) of 93 +/- 18 mm and 317 +/- 241 pmol/min/mg protein, respectively. 4. Using 16 individual human liver cytosol preparations a 33-fold variability in the metabolism of 80 micro M ZAL to M2 was observed. Correlations were observed between M2 formation and the metabolism of the aldehyde oxidase substrates phenanthridine (r(2) = 0.774) and phthalazine (r(2) = 0.460). 5. The metabolism of 80 micro M ZAL to M2 in liver cytosol preparations was markedly inhibited by the aldehyde oxidase inhibitors chlorpromazine, promethazine, hydralazine and menadione. Additional kinetic analysis suggested that chlorpromazine and promethazine were non-competitive inhibitors of M2 formation with K(i) of 2.3 and 1.9 micro M, respectively. ZAL metabolism to M2 was also inhibited by cimetidine. 6. Incubations conducted with human liver cytosol and H(2)(18)O demonstrated that the oxygen atom incorporated into ZAL and DZAL to form M2 and M1, respectively, was derived from water and not from molecular oxygen. 7. In summary, by correlation analysis, chemical inhibition and H(2)(18)O incorporation studies, ZAL metabolism to M2 in human liver appears to be catalysed by aldehyde oxidase. With human liver slices, ZAL was metabolized to products dependent on both aldehyde oxidase and CYP3A forms.

  20. Electrophoretic characterization of aldehyde-fixed red blood cells, kidney cells, lynphocytes and chamber coatings

    NASA Technical Reports Server (NTRS)

    1976-01-01

    Ground-based electrokinetic data on the electrophoresis flight experiment to be flown on the Apollo-Soyuz Test Project experiment MA-011 are stipulated. Aldehyde-fixed red blood cells, embryonic kidney cells and lymphocytes were evaluated by analytical particle electrophoresis. The results which aided in the interpretation of the final analysis of the MA-011 experiment are documented. The electrophoresis chamber surface modifications, the buffer, and the material used in the column system are also discussed.

  1. Attenuation of p38α MAPK stress response signaling delays the in vivo aging of skeletal muscle myofibers and progenitor cells

    PubMed Central

    Papaconstantinou, John; Wang, Chen Z.; Zhang, Min; Yang, San; Deford, James; Bulavin, Dmitry V.; Ansari, Naseem H.

    2015-01-01

    Functional competence and self-renewal of mammalian skeletal muscle myofibers and progenitor cells declines with age. Progression of the muscle aging phenotype involves the decline of juvenile protective factors i.e., proteins whose beneficial functions translate directly to the quality of life, and self-renewal of progenitor cells. These characteristics occur simultaneously with the age-associated increase of p38α stress response signaling. This suggests that the maintenance of low levels of p38α activity of juvenile tissues may delay or attenuate aging. We used the dominant negative haploinsufficient p38α mouse (DN-p38αAF/+) to demonstrate that in vivo attenuation of p38α activity in the gastrocnemius of the aged mutant delays age-associated processes that include: a) the decline of the juvenile protective factors, BubR1, aldehyde dehydrogenase 1A (ALDH1A1), and aldehyde dehydrogenase 2 (ALDH2); b) attenuated expression of p16Ink4a and p19Arf tumor suppressor genes of the Cdkn2a locus; c) decreased levels of hydroxynonenal protein adducts, expression of COX2 and iNOS; d) decline of the senescent progenitor cell pool level and d) the loss of gastrocnemius muscle mass. We propose that elevated P-p38α activity promotes skeletal muscle aging and that the homeostasis of p38α impacts the maintenance of a beneficial healthspan. PMID:26423835

  2. Attenuation of p38α MAPK stress response signaling delays the in vivo aging of skeletal muscle myofibers and progenitor cells.

    PubMed

    Papaconstantinou, John; Wang, Chen Z; Zhang, Min; Yang, San; Deford, James; Bulavin, Dmitry V; Ansari, Naseem H

    2015-09-01

    Functional competence and self-renewal of mammalian skeletal muscle myofibers and progenitor cells declines with age. Progression of the muscle aging phenotype involves the decline of juvenile protective factorsi.e., proteins whose beneficial functions translate directly to the quality of life, and self-renewal of progenitor cells. These characteristics occur simultaneously with the age-associated increase of p38α stress response signaling. This suggests that the maintenance of low levels of p38α activity of juvenile tissues may delay or attenuate aging. We used the dominant negative haploinsufficient p38α mouse (DN-p38α(AF/+)) to demonstrate that in vivo attenuation of p38α activity in the gastrocnemius of the aged mutant delays age-associated processes that include: a) the decline of the juvenile protective factors, BubR1, aldehyde dehydrogenase 1A (ALDH1A1), and aldehyde dehydrogenase 2 (ALDH2); b) attenuated expression of p16(Ink4a) and p19(Arf) tumor suppressor genes of the Cdkn2a locus; c) decreased levels of hydroxynonenal protein adducts, expression of COX2 and iNOS; d) decline of the senescent progenitor cell pool level and d) the loss of gastrocnemius muscle mass. We propose that elevated P-p38α activity promotes skeletal muscle aging and that the homeostasis of p38α impacts the maintenance of a beneficial healthspan.

  3. Nickel-catalyzed enantioselective alkylative coupling of alkynes and aldehydes: synthesis of chiral allylic alcohols with tetrasubstituted olefins.

    PubMed

    Yang, Yun; Zhu, Shou-Fei; Zhou, Chang-Yue; Zhou, Qi-Lin

    2008-10-29

    A highly efficient nickel-catalyzed asymmetric alkylative coupling of alkynes, aldehydes, and dimethylzinc has been realized by using bulky spirobiindane phosphoramidite ligands, affording allylic alcohols with a tetrasubstituted olefin functionality in high yields, high regioselectivities, and excellent enantioselectivities.

  4. Ultra-high olfactory sensitivity for the human sperm-attractant aromatic aldehyde bourgeonal in CD-1 mice.

    PubMed

    Larsson, Linda; Laska, Matthias

    2011-12-01

    Recent studies have shown that certain aromatic aldehydes are ligands for olfactory receptors expressed in mammalian sperm cells and induce sperm chemotaxis. Using a conditioning paradigm, the olfactory sensitivity of five CD-1 mice for seven aromatic aldehydes was investigated. With all seven stimuli, the mice discriminated concentrations as low as 0.01 ppm (parts per million) from the solvent, and with bourgeonal the animals even detected concentrations as low as 0.1 ppq (parts per quadrillion) which constitutes the lowest olfactory detection threshold value reported in this species so far. The presence of a tertiary butyl group in para-position (relative to the functional aldehyde group) combined with a lack of an additional alkyl group next to the functional aldehyde group may be responsible for the extraordinary sensitivity of the mice for bourgeonal.

  5. An insight into the mechanism of the aerobic oxidation of aldehydes catalyzed by N-heterocyclic carbenes.

    PubMed

    Bortolini, O; Chiappe, C; Fogagnolo, M; Giovannini, P P; Massi, A; Pomelli, C S; Ragno, D

    2014-02-25

    N-Heterocyclic carbene catalysis for the aerobic oxidation and esterification of aromatic aldehydes was monitored by ESI-MS (MS/MS) and the key intermediates were intercepted and characterized using the charge-tag strategy.

  6. Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed by Chiral O,N,O-tridentate Phenol Ligands Derived From Camphor.

    PubMed

    Lee, Dong-Sheng; Chang, Shu-Ming; Ho, Chun-Ying; Lu, Ta-Jung

    2016-01-01

    Chiral O,N,O-tridentate phenol ligands bearing a camphor backbone were found to be effective chiral catalysts for the enantioselective addition of diethylzinc to aromatic aldehydes, resulting in high enantioselectivities (80-95% ee) at room temperature.

  7. Transcriptome analysis of Zymomonas mobilis ZM4 reveals mechanisms of tolerance and detoxification of phenolic aldehyde inhibitors from lignocellulose pretreatment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Phenolic aldehydes generated from lignocellulose pretreatment exhibited severe toxic inhibitions on microbial growth and fermentation. Numerous tolerance studies against furfural, 5-hydroxymethyl-2-furaldehyde (HMF), acetate, and ethanol were reported, but studies on inhibition of phenol...

  8. Identification and characterization of aldehyde dehydrogenase 9 from Lampetra japonica and its protective role against cytotoxicity.

    PubMed

    Zhao, Chunhui; Wang, Dan; Feng, Bin; Gou, Meng; Liu, Xin; Li, Qingwei

    2015-09-01

    Aldehyde dehydrogenases (ALDHs), which oxidize aldehyde to corresponding acids, play a major role in the detoxification of various endogenous and exogenous aldehydes. In this study, we cloned and characterized ALDH9 (designated LjALDH9) from Arctic lamprey Lampetra japonica. The open reading frame of LjALDH9 was 1566 bp, encoding 521 amino acids with a predicted molecular mass of 55.68 kDa. LjALDH9 protein had a signal peptide and Aldedh domain with the active site Cys315. In addition, LjALDH9 shares high sequence homology with ALDH9 of jawed vertebrates. Real-time quantitative PCR revealed that LjALDH9 was highly expressed in the buccal gland. A reactive LjALDH9 protein was obtained by prokaryotic expression, two-step-denaturing and refolding and affinity purification. During enzyme activity analysis of recombinant LjALDH9, we found that the most suitable reaction conditions were pH7.0, 16-23 °C and Mn(2+) as the activator. Our study provides theoretical proof that LjALDH9 plays an important role in the parasitic life phase of lamprey.

  9. Nitric Oxide Mediates the Stress Response Induced by Diatom Aldehydes in the Sea Urchin Paracentrotus lividus

    PubMed Central

    Romano, Giovanna; Costantini, Maria; Buttino, Isabella; Ianora, Adrianna; Palumbo, Anna

    2011-01-01

    Diatoms are ubiquitous and abundant primary producers that have been traditionally considered as a beneficial food source for grazers and for the transfer of carbon through marine food webs. However, many diatom species produce polyunsaturated aldehydes that disrupt development in the offspring of grazers that feed on these unicellular algae. Here we provide evidence that production of the physiological messenger nitric oxide increases after treatment with the polyunsaturated aldehyde decadienal in embryos of the sea urchin Paracentrotus lividus. At high decadienal concentrations, nitric oxide mediates initial apoptotic events leading to loss of mitochondrial functionality through the generation of peroxynitrite. At low decadienal concentrations, nitric oxide contributes to the activation of hsp70 gene expression thereby protecting embryos against the toxic effects of this aldehyde. When nitric oxide levels were lowered by inhibiting nitric oxide synthase activity, the expression of hsp70 in swimming blastula decreased and the proportion of abnormal plutei increased. However, in later pluteus stages nitric oxide was no longer able to exert this protective function: hsp70 and nitric oxide synthase expression decreased with a consequent increase in the expression of caspase-8. Our findings that nitric oxide production increases rapidly in response to a toxic exogenous stimulus opens new perspectives on the possible role of this gas as an important messenger to environmental stress in sea urchins and for understanding the cellular mechanisms underlying toxicity during diatom blooms. PMID:22022485

  10. Nitric oxide mediates the stress response induced by diatom aldehydes in the sea urchin Paracentrotus lividus.

    PubMed

    Romano, Giovanna; Costantini, Maria; Buttino, Isabella; Ianora, Adrianna; Palumbo, Anna

    2011-01-01

    Diatoms are ubiquitous and abundant primary producers that have been traditionally considered as a beneficial food source for grazers and for the transfer of carbon through marine food webs. However, many diatom species produce polyunsaturated aldehydes that disrupt development in the offspring of grazers that feed on these unicellular algae. Here we provide evidence that production of the physiological messenger nitric oxide increases after treatment with the polyunsaturated aldehyde decadienal in embryos of the sea urchin Paracentrotus lividus. At high decadienal concentrations, nitric oxide mediates initial apoptotic events leading to loss of mitochondrial functionality through the generation of peroxynitrite. At low decadienal concentrations, nitric oxide contributes to the activation of hsp70 gene expression thereby protecting embryos against the toxic effects of this aldehyde. When nitric oxide levels were lowered by inhibiting nitric oxide synthase activity, the expression of hsp70 in swimming blastula decreased and the proportion of abnormal plutei increased. However, in later pluteus stages nitric oxide was no longer able to exert this protective function: hsp70 and nitric oxide synthase expression decreased with a consequent increase in the expression of caspase-8. Our findings that nitric oxide production increases rapidly in response to a toxic exogenous stimulus opens new perspectives on the possible role of this gas as an important messenger to environmental stress in sea urchins and for understanding the cellular mechanisms underlying toxicity during diatom blooms.

  11. Aldehydes and sugars from evolved precometary ice analogs: importance of ices in astrochemical and prebiotic evolution.

    PubMed

    de Marcellus, Pierre; Meinert, Cornelia; Myrgorodska, Iuliia; Nahon, Laurent; Buhse, Thomas; d'Hendecourt, Louis Le Sergeant; Meierhenrich, Uwe J

    2015-01-27

    Evolved interstellar ices observed in dense protostellar molecular clouds may arguably be considered as part of precometary materials that will later fall on primitive telluric planets, bringing a wealth of complex organic compounds. In our laboratory, experiments reproducing the photo/thermochemical evolution of these ices are routinely performed. Following previous amino acid identifications in the resulting room temperature organic residues, we have searched for a different family of molecules of potential prebiotic interest. Using multidimensional gas chromatography coupled to time-of-flight mass spectrometry, we have detected 10 aldehydes, including the sugar-related glycolaldehyde and glyceraldehyde--two species considered as key prebiotic intermediates in the first steps toward the synthesis of ribonucleotides in a planetary environment. The presence of ammonia in water and methanol ice mixtures appears essential for the recovery of these aldehydes in the refractory organic residue at room temperature, although these products are free of nitrogen. We finally point out the importance of detecting aldehydes and sugars in extraterrestrial environments, in the gas phase of hot molecular clouds, and, more importantly, in comets and in primitive meteorites that have most probably seeded the Earth with organic material as early as 4.2 billion years ago.

  12. Reductive detoxification of acrolein as a potential role for aldehyde reductase (AKR1A) in mammals.

    PubMed

    Kurahashi, Toshihiro; Kwon, Myoungsu; Homma, Takujiro; Saito, Yuka; Lee, Jaeyong; Takahashi, Motoko; Yamada, Ken-Ichi; Miyata, Satoshi; Fujii, Junichi

    2014-09-12

    Aldehyde reductase (AKR1A), a member of the aldo-keto reductase superfamily, suppresses diabetic complications via a reduction in metabolic intermediates; it also plays a role in ascorbic acid biosynthesis in mice. Because primates cannot synthesize ascorbic acid, a principle role of AKR1A appears to be the reductive detoxification of aldehydes. In this study, we isolated and immortalized mouse embryonic fibroblasts (MEFs) from wild-type (WT) and human Akr1a-transgenic (Tg) mice and used them to investigate the potential roles of AKR1A under culture conditions. Tg MEFs showed higher methylglyoxal- and acrolein-reducing activities than WT MEFs and also were more resistant to cytotoxicity. Enzymatic analyses of purified rat AKR1A showed that the efficiency of the acrolein reduction was about 20% that of glyceraldehyde. Ascorbic acid levels were quite low in the MEFs, and while the administration of ascorbic acid to the cells increased the intracellular levels of ascorbic acid, it had no affect on the resistance to acrolein. Endoplasmic reticulum stress and protein carbonylation induced by acrolein treatment were less evident in Tg MEFs than in WT MEFs. These data collectively indicate that one of the principle roles of AKR1A in primates is the reductive detoxification of aldehydes, notably acrolein, and protection from its detrimental effects.

  13. Aldehydes and sugars from evolved precometary ice analogs: Importance of ices in astrochemical and prebiotic evolution

    PubMed Central

    de Marcellus, Pierre; Meinert, Cornelia; Myrgorodska, Iuliia; Nahon, Laurent; Buhse, Thomas; d’Hendecourt, Louis Le Sergeant; Meierhenrich, Uwe J.

    2015-01-01

    Evolved interstellar ices observed in dense protostellar molecular clouds may arguably be considered as part of precometary materials that will later fall on primitive telluric planets, bringing a wealth of complex organic compounds. In our laboratory, experiments reproducing the photo/thermochemical evolution of these ices are routinely performed. Following previous amino acid identifications in the resulting room temperature organic residues, we have searched for a different family of molecules of potential prebiotic interest. Using multidimensional gas chromatography coupled to time-of-flight mass spectrometry, we have detected 10 aldehydes, including the sugar-related glycolaldehyde and glyceraldehyde—two species considered as key prebiotic intermediates in the first steps toward the synthesis of ribonucleotides in a planetary environment. The presence of ammonia in water and methanol ice mixtures appears essential for the recovery of these aldehydes in the refractory organic residue at room temperature, although these products are free of nitrogen. We finally point out the importance of detecting aldehydes and sugars in extraterrestrial environments, in the gas phase of hot molecular clouds, and, more importantly, in comets and in primitive meteorites that have most probably seeded the Earth with organic material as early as 4.2 billion years ago. PMID:25583475

  14. Lung morphometry changes in prevention of airway remodeling by protocatechuic aldehyde in asthmatic mice

    PubMed Central

    Zhang, Jiankai; Ma, Mulan; Qin, Dongyun; Huang, Jianping; Cui, Xiaojun; Wu, Yongfu; Yang, Huiling; Fu, Hui; Liao, Cui

    2015-01-01

    Airway remodeling can lead to irreversible airflow obstruction and persistent airway hyper-responsiveness, which is the pathological basis of refractory asthma. To investigate the preventive effect of protocatechuic aldehyde on airway remodeling in asthmatic mice by lung morphometry methods. BALB/c mice were used to establish model of airway remodeling by ovalbumin (OVA) inhalation. Bronchoalveolar lavage fluid (BALF) were collected for eosinophils (EOS) count and detection of interleukin 4 (IL-4), interleukin-13 (IL-13) and interferon (IFN-γ) content. The left lung pathological sections were performed HE, AB-PAS and Masson staining. The epithelial lamina thickness of the left main bronchus (Re), the smooth muscle layer thickness (Rm), the number of goblet cells and goblet cell area percentage (%Ac) and gas side of the road and vascular collagen deposition (%Aco, %Avc) situation were measured. Protocatechuic aldehyde gavage made the reduction of BALF EOS count. IL-4 and IL-13 levels also decreased, while the IFN-γ level increased. The left main bronchus Re, Rm, goblet cell count, Ac% and Aco% and Avc% reduced. Protocatechuic aldehyde can significantly control airway inflammation and prevent airway remodeling. PMID:26221226

  15. Enhancement of the Stability of a Prolipase from Rhizopus oryzae toward Aldehydes by Saturation Mutagenesis▿

    PubMed Central

    Di Lorenzo, Mirella; Hidalgo, Aurelio; Molina, Rafael; Hermoso, Juan A.; Pirozzi, Domenico; Bornscheuer, Uwe T.

    2007-01-01

    A prolipase from Rhizopus oryzae (proROL) was engineered in order to increase its stability toward lipid oxidation products such as aldehydes with the aim of improving its performance in oleochemical industries. Out of 22 amino acid residues (15 Lys and 7 His) prone to react with aldehydes, 6 Lys and all His residues (except for the catalytic histidine) were chosen and subjected to saturation mutagenesis. In order to quickly and reliably identify stability mutants within the resulting libraries, active variants were prescreened by an activity staining method on agar plates. Active mutants were expressed in Escherichia coli Origami in a 96-well microtiterplate format, and a stability test using octanal as a model deactivating agent was performed. The most stable histidine mutant (H201S) conferred a stability increase of 60%, which was further enhanced to 100% by combination with a lysine mutant (H201S/K168I). This increase in stability was also confirmed for other aldehydes. Interestingly, the mutations did not affect specific activity, as this was still similar to the wild-type enzyme. PMID:17890336

  16. Hydrazide and hydrazine reagents as reactive matrices for MALDI-MS to detect gaseous aldehydes.

    PubMed

    Shigeri, Yasushi; Ikeda, Shinya; Yasuda, Akikazu; Ando, Masanori; Sato, Hiroaki; Kinumi, Tomoya

    2014-08-01

    The reagents 19 hydrazide and 14 hydrazine were examined to function as reactive matrices for matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to detect gaseous aldehydes. Among them, two hydrazide (2-hydroxybenzohydrazide and 3-hydroxy-2-naphthoic acid hydrazide) and two hydrazine reagents [2-hydrazinoquinoline and 2,4-dinitrophenylhydrazine (DNPH)] were found to react efficiently with carbonyl groups of gaseous aldehydes (formaldehyde, acetaldehyde and propionaldehyde); these are the main factors for sick building syndrome and operate as reactive matrices for MALDI-MS. Results from accurate mass measurements by JMS-S3000 Spiral-TOF suggested that protonated ion peaks corresponding to [M + H](+) from the resulting derivatives were observed in all cases with the gaseous aldehydes in an incubation, time-dependent manner. The two hydrazide and two hydrazine reagents all possessed absorbances at 337 nm (wavelength of MALDI nitrogen laser), with, significant electrical conductivity of the matrix crystal and functional groups, such as hydroxy group and amino group, being important for desorption/ionization efficiency in MALDI-MS. To our knowledge, this is the first report that gaseous molecules could be derivatized and detected directly in a single step by MALDI-MS using novel reactive matrices that were derivatizing agents with the ability to enhance desorption/ionization efficiency.

  17. Drude polarizable force field for aliphatic ketones and aldehydes, and their associated acyclic carbohydrates

    NASA Astrophysics Data System (ADS)

    Small, Meagan C.; Aytenfisu, Asaminew H.; Lin, Fang-Yu; He, Xibing; MacKerell, Alexander D.

    2017-02-01

    The majority of computer simulations exploring biomolecular function employ Class I additive force fields (FF), which do not treat polarization explicitly. Accordingly, much effort has been made into developing models that go beyond the additive approximation. Development and optimization of the Drude polarizable FF has yielded parameters for selected lipids, proteins, DNA and a limited number of carbohydrates. The work presented here details parametrization of aliphatic aldehydes and ketones (viz. acetaldehyde, propionaldehyde, butaryaldehyde, isobutaryaldehyde, acetone, and butanone) as well as their associated acyclic sugars (uc(d)-allose and uc(d)-psicose). LJ parameters are optimized targeting experimental heats of vaporization and molecular volumes, while the electrostatic parameters are optimized targeting QM water interactions, dipole moments, and molecular polarizabilities. Bonded parameters are targeted to both QM and crystal survey values, with the models for ketones and aldehydes shown to be in good agreement with QM and experimental target data. The reported heats of vaporization and molecular volumes represent a compromise between the studied model compounds. Simulations of the model compounds show an increase in the magnitude and the fluctuations of the dipole moments in moving from gas phase to condensed phases, which is a phenomenon that the additive FF is intrinsically unable to reproduce. The result is a polarizable model for aliphatic ketones and aldehydes including the acyclic sugars uc(d)-allose and uc(d)-psicose, thereby extending the available biomolecules in the Drude polarizable FF.

  18. Aldehydes, hydrogen peroxide, and organic radicals as mediators of ozone toxicity

    SciTech Connect

    Pryor, W.A.; Church, D.F. )

    1991-01-01

    It is generally agreed that unsaturated fatty acids (UFA) are an important class of target molecule for reaction with ozone when polluted air is inhaled. Most discussions have implicated the UFA in cell membranes, but lung lining fluids also contain fatty acids that are from 20 to 40% unsaturated. Since UFA in lung lining fluids exist in a highly aquated environment, ozonation would be expected to produce aldehydes and hydrogen peroxide, rather than the Criegee ozonide. In agreement with this expectation, the authors find that ozonations of emulsions of fatty acids containing from one to four double bonds give one mole of H2O2 for each mole of ozone reacted. Ozonation of oleic acid emulsions and dioleoyl phosphatidyl choline gives similar results, with two moles of aldehydes and one mole of H2O2 formed per mole of ozone reacted. The net reaction that occurs when ozone reacts with pulmonary lipids is suggested to be given by equation 1. (formula: see text). From 5 to 10% yields of Criegee ozonides also appear to be formed. In addition, a direct reaction of unknown mechanism occurs between ozone and UFA in homogeneous organic solution, in homogeneous solutions in water, in aqueous emulsions, and in lipid bilayers to give organic radicals that can be spin trapped. These radicals are suggested to be responsible for initiating lipid peroxidation of polyunsaturated fatty acids. Thus, aldehydes, hydrogen peroxide, and directly produced organic radicals are suggested to be mediators of ozone-induced pathology.39 references.

  19. Efficient conversion of primary azides to aldehydes catalyzed by active site variants of myoglobin

    PubMed Central

    Giovani, Simone; Singh, Ritesh; Fasan, Rudi

    2015-01-01

    The oxidation of primary azides to aldehydes constitutes a convenient but underdeveloped transformation for which no efficient methods are available. Here, we demonstrate that engineered variants of the hemoprotein myoglobin can catalyze this transformation with high efficiency (up to 8,500 turnovers) and selectivity across a range of structurally diverse aryl-substituted primary azides. Mutagenesis of the 'distal' histidine residue was particularly effective in enhancing the azide oxidation reactivity of myoglobin, enabling these reactions to proceed in good to excellent yields (37-89%) and to be carried out at a synthetically useful scale. Kinetic isotope effect, isotope labeling, and substrate binding experiments support a mechanism involving heme-catalyzed decomposition of the organic azide followed by alpha hydrogen deprotonation to generate an aldimine which, upon hydrolysis, releases the aldehyde product. This work provides the first example of a biocatalytic azide-to-aldehyde conversion and expands the range of non-native chemical transformations accessible through hemoprotein-mediated catalysis. PMID:26900445

  20. ‘Dopamine-first’ mechanism enables the rational engineering of the norcoclaurine synthase aldehyde activity profile

    PubMed Central

    Lichman, Benjamin R; Gershater, Markus C; Lamming, Eleanor D; Pesnot, Thomas; Sula, Altin; Keep, Nicholas H; Hailes, Helen C; Ward, John M

    2015-01-01

    Norcoclaurine synthase (NCS) (EC 4.2.1.78) catalyzes the Pictet–Spengler condensation of dopamine and an aldehyde, forming a substituted (S)-tetrahydroisoquinoline, a pharmaceutically important moiety. This unique activity has led to NCS being used for both in vitro biocatalysis and in vivo recombinant metabolism. Future engineering of NCS activity to enable the synthesis of diverse tetrahydroisoquinolines is dependent on an understanding of the NCS mechanism and kinetics. We assess two proposed mechanisms for NCS activity: (a) one based on the holo X-ray crystal structure and (b) the ‘dopamine-first’ mechanism based on computational docking. Thalictrum flavum NCS variant activities support the dopamine-first mechanism. Suppression of the non-enzymatic background reaction reveals novel kinetic parameters for NCS, showing it to act with low catalytic efficiency. This kinetic behaviour can account for the ineffectiveness of recombinant NCS in in vivo systems, and also suggests NCS may have an in planta role as a metabolic gatekeeper. The amino acid substitution L76A, situated in the proposed aldehyde binding site, results in the alteration of the enzyme's aldehyde activity profile. This both verifies the dopamine-first mechanism and demonstrates the potential for the rational engineering of NCS activity. PMID:25620686

  1. Evidence that Additions of Grignard Reagents to Aliphatic Aldehydes Do Not Involve Single-Electron-Transfer Processes.

    PubMed

    Otte, Douglas A L; Woerpel, K A

    2015-08-07

    Addition of allylmagnesium reagents to an aliphatic aldehyde bearing a radical clock gave only addition products and no evidence of ring-opened products that would suggest single-electron-transfer reactions. The analogous Barbier reaction also did not provide evidence for a single-electron-transfer mechanism in the addition step. Other Grignard reagents (methyl-, vinyl-, t-Bu-, and triphenylmethylmagnesium halides) also do not appear to add to an alkyl aldehyde by a single-electron-transfer mechanism.

  2. The Intramolecular Asymmetric Allylation of Aldehydes via Organo-SOMO Catalysis: A Novel Approach to Ring Construction.

    PubMed

    Pham, Phong V; Ashton, Kate; Macmillan, David W C

    2011-08-01

    The intramolecular asymmetric cyclization of aldehydes has been accomplished using singly occupied molecular orbital (SOMO) catalysis. Selective oxidation of chiral enamines (formed by the condensation of an aldehyde and a secondary amine catalyst) leads to the formation of a 3π-electron radical species. These chiral SOMO-activated radical cations undergo enantioselective cyclization with an array of pendent allylsilanes thus efficiently providing a new approach to the construction of five-, six- and seven-membered carbocycles and heterocycles.

  3. Kinetics of Forming Aldehydes in Frying Oils and Their Distribution in French Fries Revealed by LC-MS-Based Chemometrics.

    PubMed

    Wang, Lei; Csallany, A Saari; Kerr, Brian J; Shurson, Gerald C; Chen, Chi

    2016-05-18

    In this study, the kinetics of aldehyde formation in heated frying oils was characterized by 2-hydrazinoquinoline derivatization, liquid chromatography-mass spectrometry (LC-MS) analysis, principal component analysis (PCA), and hierarchical cluster analysis (HCA). The aldehydes contributing to time-dependent separation of heated soybean oil (HSO) in a PCA model were grouped by the HCA into three clusters (A1, A2, and B) on the basis of their kinetics and fatty acid precursors. The increases of 4-hydroxynonenal (4-HNE) and the A2-to-B ratio in HSO were well-correlated with the duration of thermal stress. Chemometric and quantitative analysis of three frying oils (soybean, corn, and canola oils) and French fry extracts further supported the associations between aldehyde profiles and fatty acid precursors and also revealed that the concentrations of pentanal, hexanal, acrolein, and the A2-to-B ratio in French fry extracts were more comparable to their values in the frying oils than other unsaturated aldehydes. All of these results suggest the roles of specific aldehydes or aldehyde clusters as novel markers of the lipid oxidation status for frying oils or fried foods.

  4. DNA-support coupling for transcription factor purification. Comparison of aldehyde, cyanogen bromide and N-hydroxysuccinimide chemistries.

    PubMed

    Chockalingam, Priya Sethu; Gadgil, Himanshu; Jarrett, Harry W

    2002-01-04

    Purification of transcription factor IIIA on internal control region DNA coupled to aldehyde-silica is described and compared with purification on cyanogen bromide-activated Sepharose and Bio-Rad Affi-Gel-10. The Affi-Gel support results in mixed-mode chromatography; both ion-exchange and affinity modes contribute. Coupling DNA to aldehyde-silica is advantageous in that it has no ion-exchange properties and performs as well as DNA coupled to CNBr-activated Sepharose. Purification of lac repressor on aldehyde-silica, and CAAT enhancer binding protein on Affi-Gel also shows the advantages of a neutral support and the disadvantages of mixed-mode chromatography for transcription factor purification. Aldehyde-silica couples to alkylamines and to the amines of adenine, guanine, and cytosine nucleoside bases. Reaction occurs with either single- or double-stranded DNA, although it is less efficient with the latter. Overall, the results demonstrate that predominantly neutral coupling chemistries, such as aldehyde or CNBr-mediated coupling, have distinct advantages for transcription factor purification. Since the CNBr chemistry has not yet been applied to silica supports, aldehyde-silica coupling is currently the most attractive method for DNA affinity HPLC.

  5. Rate constants for aqueous-phase reactions of hydroxyl radical ({center_dot}OH) with aldehydes and ketones

    SciTech Connect

    Allen, J.M.; Allen, S.K.

    1995-12-31

    A wide variety of aldehydes and ketones are formed in the troposphere by the gas-phase oxidation of hydrocarbons. These compounds are expected to readily partition into cloud, fog, and aquated aerosol drops where they can participate in a variety of aqueous-phase reactions. It has been previously demonstrated by other researchers that aqueous-phase photochemical reactions involving aromatic aldehydes and ketones may lead to the formation of hydrogen peroxide. Hydrogen peroxide is an important oxidant for S(IV) and is also an {center_dot}OH precursor. Aldehydes and ketones may also participate in other aqueous-phase reactions within atmospheric water drops including reactions with {center_dot}OH. Rate constants for reactions involving {center_dot}OH in aqueous solutions have been reported for only a limited number of tropospheric aldehydes and ketones. The authors have measured the rate constants for aqueous-phase reactions of {center_dot}OH with several tropospheric aldehydes and ketones by the technique of competition kinetics. Hydroxyl radicals were generated by continuous illumination at 313 nm of an aqueous acidified solution containing Fe(ClO{sub 4}){sub 3}, an {center_dot}OH scavenger, the aldehyde or ketone whose rate constant was to be measured, and a standard for which the rate constant for reaction with {center_dot}OH is well known. Nitrobenzene was used as the standard in all experiments. Loss of the aldehyde or ketone and the standard were monitored by HPLC. Losses attributable to direct photolysis and dark reactions were minimal.

  6. Identification of long chain specific aldehyde reductase and its use in enhanced fatty alcohol production in E. coli.

    PubMed

    Fatma, Zia; Jawed, Kamran; Mattam, Anu Jose; Yazdani, Syed Shams

    2016-09-01

    Long chain fatty alcohols have wide application in chemical industries and transportation sector. There is no direct natural reservoir for long chain fatty alcohol production, thus many groups explored metabolic engineering approaches for its microbial production. Escherichia coli has been the major microbial platform for this effort, however, terminal endogenous enzyme responsible for converting fatty aldehydes of chain length C14-C18 to corresponding fatty alcohols is still been elusive. Through our in silico analysis we selected 35 endogenous enzymes of E. coli having potential of converting long chain fatty aldehydes to fatty alcohols and studied their role under in vivo condition. We found that deletion of ybbO gene, which encodes NADP(+) dependent aldehyde reductase, led to >90% reduction in long chain fatty alcohol production. This feature was found to be strain transcending and reinstalling ybbO gene via plasmid retained the ability of mutant to produce long chain fatty alcohols. Enzyme kinetic study revealed that YbbO has wide substrate specificity ranging from C6 to C18 aldehyde, with maximum affinity and efficiency for C18 and C16 chain length aldehyde, respectively. Along with endogenous production of fatty aldehyde via optimized heterologous expression of cyanobaterial acyl-ACP reductase (AAR), YbbO overexpression resulted in 169mg/L of long chain fatty alcohols. Further engineering involving modulation of fatty acid as well as of phospholipid biosynthesis pathway improved fatty alcohol production by 60%. Finally, the engineered strain produced 1989mg/L of long chain fatty alcohol in bioreactor under fed-batch cultivation condition. Our study shows for the first time a predominant role of a single enzyme in production of long chain fatty alcohols from fatty aldehydes as well as of modulation of phospholipid pathway in increasing the fatty alcohol production.

  7. Direct enzyme assay evidence confirms aldehyde reductase function of Ydr541cp and Ygl039wp from Saccharomyces cerevisiae.

    PubMed

    Moon, Jaewoong; Liu, Z Lewis

    2015-04-01

    The aldehyde reductase gene ARI1 is a recently characterized member of an intermediate subfamily within the short-chain dehydrogenase/reductase (SDR) superfamily that clarified mechanisms of in situ detoxification of 2-furaldehyde and 5-hydroxymethyl-2-furaldehyde by Saccharomyces cerevisiae. Uncharacterized open reading frames (ORFs) are common among tolerant candidate genes identified for lignocellulose-to-advanced biofuels conversion. This study presents partially purified proteins of two ORFs, YDR541C and YGL039W, and direct enzyme assay evidence against aldehyde-inhibitory compounds commonly encountered during lignocellulosic biomass fermentation processes. Each of the partially purified proteins encoded by these ORFs showed a molecular mass of approximately 38 kDa, similar to Ari1p, a protein encoded by aldehyde reductase gene. Both proteins demonstrated strong aldehyde reduction activities toward 14 aldehyde substrates, with high levels of reduction activity for Ydr541cp toward both aromatic and aliphatic aldehydes. While Ydr541cp was observed to have a significantly higher specific enzyme activity at 20 U/mg using co-factor NADPH, Ygl039wp displayed a NADH preference at 25 U/mg in reduction of butylaldehyde. Amino acid sequence analysis identified a characteristic catalytic triad, Ser, Tyr and Lys; a conserved catalytic motif of Tyr-X-X-X-Lys; and a cofactor-binding sequence motif, Gly-X-X-Gly-X-X-Ala, near the N-terminus that are shared by Ydr541cp, Ygl039wp, Yol151wp/GRE2 and Ari1p. Findings of aldehyde reductase genes contribute to the yeast gene annotation and aids development of the next-generation biocatalyst for advanced biofuels production.

  8. Structure-based mutational studies of substrate inhibition of betaine aldehyde dehydrogenase BetB from Staphylococcus aureus.

    PubMed

    Chen, Chao; Joo, Jeong Chan; Brown, Greg; Stolnikova, Ekaterina; Halavaty, Andrei S; Savchenko, Alexei; Anderson, Wayne F; Yakunin, Alexander F

    2014-07-01

    Inhibition of enzyme activity by high concentrations of substrate and/or cofactor is a general phenomenon demonstrated in many enzymes, including aldehyde dehydrogenases. Here we show that the uncharacterized protein BetB (SA2613) from Staphylococcus aureus is a highly specific betaine aldehyde dehydrogenase, which exhibits substrate inhibition at concentrations of betaine aldehyde as low as 0.15 mM. In contrast, the aldehyde dehydrogenase YdcW from Escherichia coli, which is also active against betaine aldehyde, shows no inhibition by this substrate. Using the crystal structures of BetB and YdcW, we performed a structure-based mutational analysis of BetB and introduced the YdcW residues into the BetB active site. From a total of 32 mutations, those in five residues located in the substrate binding pocket (Val288, Ser290, His448, Tyr450, and Trp456) greatly reduced the substrate inhibition of BetB, whereas the double mutant protein H448F/Y450L demonstrated a complete loss of substrate inhibition. Substrate inhibition was also reduced by mutations of the semiconserved Gly234 (to Ser, Thr, or Ala) located in the BetB NAD(+) binding site, suggesting some cooperativity between the cofactor and substrate binding sites. Substrate docking analysis of the BetB and YdcW active sites revealed that the wild-type BetB can bind betaine aldehyde in both productive and nonproductive conformations, whereas only the productive binding mode can be modeled in the active sites of YdcW and the BetB mutant proteins with reduced substrate inhibition. Thus, our results suggest that the molecular mechanism of substrate inhibition of BetB is associated with the nonproductive binding of betaine aldehyde.

  9. Human papillomavirus 16 (HPV16) enhances tumor growth and cancer stemness of HPV-negative oral/oropharyngeal squamous cell carcinoma cells via miR-181 regulation.

    PubMed

    Lee, Sung Hee; Lee, Chang-Ryul; Rigas, Nicole Kristina; Kim, Reuben H; Kang, Mo K; Park, No-Hee; Shin, Ki-Hyuk

    2015-12-01

    High-risk human papillomaviruses (e.g., HPV16, HPV18) are closely associated with the development of head and neck cancers including oral/oropharyngeal squamous cell carcinoma (OSCC). We previously demonstrated immortalization of normal human oral keratinocytes by introducing high-risk HPV whole genome, suggesting that HPV infection plays an important role in the early stage of oral carcinogenesis. Although HPV infection may occur in different stages of cancer development, roles of HPV in exacerbating malignant phenotypes in already-transformed cells in the context of cancer stemness are not clearly defined. In this study, we investigated the role of HPV16 in promoting the virulence of HPV-negative OSCC. Introducing HPV16 whole genome in HPV-negative OSCC increased malignant growth and self-renewal capacity, a key characteristic of cancer stem cells (CSCs). HPV16 also enhanced other CSC properties, including aldehyde dehydrogenase 1 (ALDH1) activity, migration/invasion, and CSC-related factor expression. Mechanistically, we found that HPV16 inhibited the expression of miR-181a and miR-181d (miR-181a/d) at the transcriptional level. Ectopic expression of miR-181a/d decreased anchorage independent growth and CSC phenotype of HPV16-transfected OSCC. Furthermore, silencing of miR-181a/d target genes, i.e., K-ras and ALDH1, abrogated the effects of HPV16 in HPV16-transfected OSCC, supporting the functional importance of HPV16/miR-181a/d axis in HPV-mediated oral carcinogenesis. Our study suggests that high-risk HPV infection further promotes malignancy in HPV-negative OSCC by enhancing cancer stemness via miR-181a/d regulation. Consequently, miR-181a/d may represent a novel therapeutic agent for the treatment of HPV-positive OSCC.

  10. Identification of genes involved in Epstein-Barr virus-associated nasopharyngeal carcinoma

    PubMed Central

    Wang, Junguo; Mei, Fang; Gao, Xia; Wang, Shoulin

    2016-01-01

    Nasopharyngeal carcinoma (NPC) is the most common cancer originating from the nasopharynx, and can be induced by infection with Epstein-Barr virus (EBV). To study the mechanisms of EBV-associated NPC, a microarray of the GSE12452 dataset was analyzed. GSE12452 was downloaded from Gene Expression Omnibus and consisted of 31 NPC samples and 10 normal healthy nasopharyngeal tissue samples. The differentially-expressed genes (DEGs) were screened using the linear models for microarray data package in R. Using Database for Annotation, Visualization and Integrated Discovery software, potential functions of the DEGs were predicted by Gene Ontology and pathway enrichment analyses. With the information from the Search Tool for the Retrieval of Interacting Genes/Proteins database, the protein-protein interaction (PPI) network was visualized by Cytoscape. Furthermore, modules of the PPI network were searched using ClusterONE in Cytoscape. A total of 951 DEGs were screened in the NPC samples compared with the normal healthy nasopharyngeal tissue samples. Function enrichment indicated that the upregulated genes were associated with the cell cycle, cytoskeleton organization and DNA metabolism. Meanwhile, the downregulated genes were mainly associated with cell differentiation, hormone metabolism, inflammatory response and immune response. PPI networks for the DEGs suggested that upregulated mitotic arrest deficient 2-like 1 (MAD2L1; degree=133), proliferating cell nuclear antigen (PCNA; degree=125) and cyclin B1 (CCNB1; degree=115), and downregulated member A1 of aldehyde dehydrogenase 1 (ALDH1A1; degree=15) may be of great importance as they exhibited higher degrees on interaction. Mucin 1 (MUC1) was a key node of module 4. Overall, the study indicated that MAD2L1, CCNB1, PCNA, ALDH1A1 and MUC1 may have a correlation with EBV-associated NPC. PMID:27698802

  11. Regulation of nonsmall-cell lung cancer stem cell like cells by neurotransmitters and opioid peptides.

    PubMed

    Banerjee, Jheelam; Papu John, Arokya M S; Schuller, Hildegard M

    2015-12-15

    Nonsmall-cell lung cancer (NSCLC) is the leading type of lung cancer and has a poor prognosis. We have shown that chronic stress promoted NSCLC xenografts in mice via stress neurotransmitter-activated cAMP signaling downstream of beta-adrenergic receptors and incidental beta-blocker therapy was reported to improve clinical outcomes in NSCLC patients. These findings suggest that psychological stress promotes NSCLC whereas pharmacologically or psychologically induced decreases in cAMP may inhibit NSCLC. Cancer stem cells are thought to drive the development, progression and resistance to therapy of NSCLC. However, their potential regulation by stress neurotransmitters has not been investigated. In the current study, epinephrine increased the number of cancer stem cell like cells (CSCs) from three NSCLC cell lines in spheroid formation assays while enhancing intracellular cAMP and the stem cell markers sonic hedgehog (SHH), aldehyde dehydrogenase-1 (ALDH-1) and Gli1, effects reversed by GABA or dynorphin B via Gαi -mediated inhibition of cAMP formation. The growth of NSCLC xenografts in a mouse model of stress reduction was significantly reduced as compared with mice maintained under standard conditions. Stress reduction reduced serum levels of corticosterone, norepinephrine and epinephrine while the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and opioid peptides increased. Stress reduction significantly reduced cAMP, VEGF, p-ERK, p-AKT, p-CREB, p-SRc, SHH, ALDH-1 and Gli1 in xenograft tissues whereas cleaved caspase-3 and p53 were induced. We conclude that stress neurotransmitters activate CSCs in NSCLC via multiple cAMP-mediated pathways and that pharmacologically or psychologically induced decreases in cAMP signaling may improve clinical outcomes in NSCLC patients.

  12. Slc5a8, a Na+-coupled high-affinity transporter for short-chain fatty acids, is a conditional tumour suppressor in colon that protects against colitis and colon cancer under low-fibre dietary conditions.

    PubMed

    Gurav, Ashish; Sivaprakasam, Sathish; Bhutia, Yangzom D; Boettger, Thomas; Singh, Nagendra; Ganapathy, Vadivel

    2015-07-15

    Mammalian colon harbours trillions of bacteria under physiological conditions; this symbiosis is made possible because of a tolerized response from the mucosal immune system. The mechanisms underlying this tolerogenic phenomenon remain poorly understood. In the present study we show that Slc5a8 (solute carrier gene family 5a, member 8), a Na(+)-coupled high-affinity transporter in colon for the bacterial fermentation product butyrate, plays a critical role in this process. Among various immune cells in colon, dendritic cells (DCs) are unique not only in their accessibility to luminal contents but also in their ability to induce tolerogenic phenotype in T-cells. We found that DCs exposed to butyrate express the immunosuppressive enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and aldehyde dehydrogenase 1A2 (Aldh1A2), promote conversion of naive T-cells into immunosuppressive forkhead box P3(+) (FoxP3(+)) Tregs (regulatory T-cells) and suppress conversion of naive T-cells into pro-inflammatory interferon (IFN)-γ-producing cells. Slc5a8-null DCs do not induce IDO1 and Aldh1A2 and do not generate Tregs or suppress IFN-γ-producing T-cells in response to butyrate. We also provide in vivo evidence for an obligatory role for Slc5a8 in suppression of IFN-γ-producing T-cells. Furthermore, Slc5a8 protects against colitis and colon cancer under conditions of low-fibre intake but not when dietary fibre intake is optimal. This agrees with the high-affinity nature of the transporter to mediate butyrate entry into cells. We conclude that Slc5a8 is an obligatory link between dietary fibre and mucosal immune system via the bacterial metabolite butyrate and that this transporter is a conditional tumour suppressor in colon linked to dietary fibre content.

  13. Gene Expression in Single Cells Isolated from the CWR-R1 Prostate Cancer Cell Line and Human Prostate Tissue Based on the Side Population Phenotype

    PubMed Central

    Gangavarapu, Kalyan J; Miller, Austin; Huss, Wendy J

    2016-01-01

    Defining biological signals at the single cell level can identify cancer initiating driver mutations. Techniques to isolate single cells such as microfluidics sorting and magnetic capturing systems have limitations such as: high cost, labor intense, and the requirement of a large number of cells. Therefore, the goal of our current study is to identify a cost and labor effective, reliable, and reproducible technique that allows single cell isolation for analysis to promote regular laboratory use, including standard reverse transcription PCR (RT-PCR). In the current study, we utilized single prostate cells isolated from the CWR-R1 prostate cancer cell line and human prostate clinical specimens, based on the ATP binding cassette (ABC) transporter efflux of dye cycle violet (DCV), side population assay. Expression of four genes: ABCG2; Aldehyde dehydrogenase1A1 (ALDH1A1); androgen receptor (AR); and embryonic stem cell marker, Oct-4, were determined. Results from the current study in the CWR-R1 cell line showed ABCG2 and ALDH1A1 gene expression in 67% of single side population cells and in 17% or 100% of non-side population cells respectively. Studies using single cells isolated from clinical specimens showed that the Oct-4 gene is detected in only 22% of single side population cells and in 78% of single non-side population cells. Whereas, AR gene expression is in 100% single side population and non-side population cells isolated from the same human prostate clinical specimen. These studies show that performing RT-PCR on single cells isolated by FACS can be successfully conducted to determine gene expression in single cells from cell lines and enzymatically digested tissue. While these studies provide a simple yes/no expression readout, the more sensitive quantitative RT-PCR would be able to provide even more information if necessary. PMID:27785389

  14. Slc5a8, a Na+-coupled high-affinity transporter for short-chain fatty acids, is a conditional tumor suppressor in colon that protects against colitis and colon cancer under low-fiber dietary conditions

    PubMed Central

    Gurav, Ashish; Sivaprakasam, Sathish; Bhutia, Yangzom D.; Boettger, Thomas; Singh, Nagendra; Ganapathy, Vadivel

    2016-01-01

    Summary Mammalian colon harbors trillions of bacteria under physiologic conditions; this symbiosis is made possible because of a tolerized response from the mucosal immune system. The mechanisms underlying this tolerogenic phenomenon remain poorly understood. Here we show that Slc5a8, a Na+-coupled high-affinity transporter in colon for the bacterial fermentation product butyrate, plays a critical role in this process. Among various immune cells in colon, dendritic cells (DCs) are unique not only in their accessibility to luminal contents but also in their ability to induce tolerogenic phenotype in T cells. We found that DCs exposed to butyrate express the immunosuppressive enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and aldehyde dehydrogenase 1A2 (Aldh1A2), promote conversion of naïve T cells into immunosuppressive FoxP3+ Tregs, and suppress conversion of naïve T cells into pro-inflammatory IFN-γ-producing cells. Slc5a8-null DCs do not induce IDO1 and Aldh1A2 and do not generate Tregs or suppress IFN-γ-producing T cells in response to butyrate. We also provide in vivo evidence for an obligatory role for Slc5a8 in suppression of IFN-γ-producing T cells. Furthermore, Slc5a8 protects against colitis and colon cancer under conditions of low-fiber intake but not when dietary fiber intake is optimal. This agrees with the high-affinity nature of the transporter to mediate butyrate entry into cells. We conclude that Slc5a8 is an obligatory link between dietary fiber and mucosal immune system via the bacterial metabolite butyrate, and that this transporter is a conditional tumor suppressor in colon linked to dietary fiber content. PMID:25984582

  15. DNA-Templated Polymerization of Side-Chain-Functionalized Peptide Nucleic Acid Aldehydes

    PubMed Central

    Kleiner, Ralph E.; Brudno, Yevgeny; Birnbaum, Michael E.; Liu, David R.

    2009-01-01

    The DNA-templated polymerization of synthetic building blocks provides a potential route to the laboratory evolution of sequence-defined polymers with structures and properties not necessarily limited to those of natural biopolymers. We previously reported the efficient and sequence-specific DNA-templated polymerization of peptide nucleic acid (PNA) aldehydes. Here, we report the enzyme-free, DNA-templated polymerization of side-chain-functionalized PNA tetramer and pentamer aldehydes. We observed that the polymerization of tetramer and pentamer PNA building blocks with a single lysine-based side chain at various positions in the building block could proceed efficiently and sequence-specifically. In addition, DNA-templated polymerization also proceeded efficiently and in a sequence-specific manner with pentamer PNA aldehydes containing two or three lysine side chains in a single building block to generate more densely functionalized polymers. To further our understanding of side-chain compatibility and expand the capabilities of this system, we also examined the polymerization efficiencies of 20 pentamer building blocks each containing one of five different side-chain groups and four different side-chain regio- and stereochemistries. Polymerization reactions were efficient for all five different side-chain groups and for three of the four combinations of side-chain regio- and stereochemistries. Differences in the efficiency and initial rate of polymerization correlate with the apparent melting temperature of each building block, which is dependent on side-chain regio- and stereochemistry, but relatively insensitive to side-chain structure among the substrates tested. Our findings represent a significant step towards the evolution of sequence-defined synthetic polymers and also demonstrate that enzyme-free nucleic acid-templated polymerization can occur efficiently using substrates with a wide range of side-chain structures, functionalization positions within each

  16. The Impact of Single Nucleotide Polymorphisms on Human Aldehyde OxidaseS

    PubMed Central

    Hartmann, Tobias; Terao, Mineko; Garattini, Enrico; Teutloff, Christian; Alfaro, Joshua F.; Jones, Jeffrey P.; Leimkühler, Silke

    2012-01-01

    Aldehyde oxidase (AO) is a complex molybdo-flavoprotein that belongs to the xanthine oxidase family. AO is active as a homodimer, and each 150-kDa monomer binds two distinct [2Fe2S] clusters, FAD, and the molybdenum cofactor. AO has an important role in the metabolism of drugs based on its broad substrate specificity oxidizing aromatic aza-heterocycles, for example, N1-methylnicotinamide and N-methylphthalazinium, or aldehydes, such as benzaldehyde, retinal, and vanillin. Sequencing the 35 coding exons of the human AOX1 gene in a sample of 180 Italian individuals led to the identification of relatively frequent, synonymous, missense and nonsense single-nucleotide polymorphisms (SNPs). Human aldehyde oxidase (hAOX1) was purified after heterologous expression in Escherichia coli. The recombinant protein was obtained with a purity of 95% and a yield of 50 μg/l E. coli culture. Site-directed mutagenesis of the hAOX1 cDNA allowed the purification of protein variants bearing the amino acid changes R802C, R921H, N1135S, and H1297R, which correspond to some of the identified SNPs. The hAOX1 variants were purified and compared with the wild-type protein relative to activity, oligomerization state, and metal content. Our data show that the mutation of each amino acid residue has a variable impact on the ability of hAOX1 to metabolize selected substrates. Thus, the human population is characterized by the presence of functionally inactive hAOX1 allelic variants as well as variants encoding enzymes with different catalytic activities. Our results indicate that the presence of these allelic variants should be considered for the design of future drugs. PMID:22279051

  17. Evidence for two-step binding of reduced nicotinamide-adenine dinucleotide to aldehyde dehydrogenase.

    PubMed Central

    MacGibbon, A K; Buckley, P D; Blackwell, L F

    1977-01-01

    The displacement of NADH from cytoplasmic aldehyde dehydrogenase (EC 1.2.1.3) from sheep liver was studied by using NAD+, 1,10-phenanthroline, ADP-ribose, deamino-NAD+ and pyridine-3-aldehyde-adenine dinucleotide as displacing agents, by following the decrease in fluorescence as a function of time. The data obtained could be fitted by assuming two first-order processes were occurring, a faster process with an apparent rate constant of 0.85 +/- 0.20 s-1 and a relative amplitude of 60 +/- 10% and a slower process with an apparent rate constant of 0.20 +/- 0.05 s-1 and a relative amplitude of 40 +/- 10% (except for pyridine-3-aldehyde-adenine dinucleotide, where the apparent rate constant for the slow process was 0.05 s-1). The displacement rates did not change significantly when the pH was varied from 6.0 to 9.0. Kinetic data are also reported for the dependence of the rate of binding of NADH to the enzyme on the total concentration of NADH. Detailed arguments are presented based on the isolation and purification procedures, the equilibrium coenzyme-binding studies and the kinetic data, which lead to the following model for the release of NADH from the enzyme: (formula: see article). The parameters that best fit the data are: k + 1 = 0.2 s-1; k - 1 = 0.05 s-1; k + 2 = 0.8 s-1 and k - 2 = 5 X 10(5)litre-mol-1-s-1. The slow phase of the NADH release is similar to the steady-state turnover number for substrates such as acetaldehyde and propionaldehyde and appears to contribute significantly to the limitation of the steady-state rate. Images Fig. 1. Fig. 2. Fig. 3. Fig. 5. PMID:21657

  18. Fluorescence method for enzyme analysis which couples aromatic amines with aromatic aldehydes

    DOEpatents

    Smith, Robert E.; Dolbeare, Frank A.

    1979-01-01

    Analysis of proteinases is accomplished using conventional amino acid containing aromatic amine substrates. Aromatic amines such as 4-methoxy-2-naphthylamine (4M2NA), 2-naphthylamine, aminoisophthalic acid dimethyl ester, p-nitroaniline, 5-methoxy-1-aminofluorene and coumarin derivatives resulting from enzymatic hydrolysis of the substrate couples with aromatic aldehydes such as 5-nitrosalicylaldehyde (5-NSA), benzaldehyde and p-nitrobenzaldehyde to produce Schiff-base complexes which are water insoluble. Certain Schiff-base complexes produce a shift from blue to orange-red (visible) fluorescence. Such complexes are useful in the assay of enzymes.

  19. Fluorescence method for enzyme analysis which couples aromatic amines with aromatic aldehydes

    DOEpatents

    Smith, R.E.; Dolbeare, F.A.

    1980-10-21

    Analysis of proteinases is accomplished using conventional amino acid containing aromatic amine substrates. Aromatic amines such as 4-methoxy-2-naphthylamine (4M2NA), 2-naphthylamine, aminoisophthalic acid dimethyl ester, p-nitroaniline, 4-methoxy-1-aminofluorene and coumarin derivatives resulting from enzymatic hydrolysis of the substrate couples with aromatic aldehydes such as 5-nitrosalicylaldehyde (5-NSA), benzaldehyde and p-nitrobenzaldehyde to produce Schiff-base complexes which are water insoluble. Certain Schiff-base complexes produce a shift from blue to orange-red (visible) fluorescence. Such complexes are useful in the assay of enzymes. No Drawings

  20. Gyrinidal: A Sesquiterpenoid Aldehyde from the Defensive Glands of Gyrinid Beetles*

    PubMed Central

    Meinwald, J.; Opheim, K.; Eisner, T.

    1972-01-01

    Three species of gyrinid beetles (Gyrinus ventralis, Dineutes hornii, and D. serrulatus) have been found to produce the nor-sesquiterpenoid aldehyde gyrinidal in the secretion of their pygidial defensive glands. This highly functionalized terpene is shown to be (E,E,E)-3,7-dimethyl-8,11-dioxo-2,6,9-dodecatrienal on the basis of spectral evidence and chemical degradation. While a very wide range of sesquiterpenoid structures occur in nature, gyrinidal appears to be the most highly oxidized acyclic sesquiterpene known. Images PMID:4504334

  1. Fluorescence method for enzyme analysis which couples aromatic amines with aromatic aldehydes

    DOEpatents

    Smith, Robert E. [557 Escondido Cir., Livermore, CA 94550; Dolbeare, Frank A. [5178 Diane La., Livermore, CA 94550

    1980-10-21

    Analysis of proteinases is accomplished using conventional amino acid containing aromatic amine substrates. Aromatic amines such as 4-methoxy-2-naphthylamine (4M2NA), 2-naphthylamine, aminoisophthalic acid dimethyl ester, p-nitroaniline, 4-methoxy-1-aminofluorene and coumarin derivatives resulting from enzymatic hydrolysis of the substrate couples with aromatic aldehydes such as 5-nitrosalicylaldehyde (5-NSA), benzaldehyde and p-nitrobenzaldehyde to produce Schiff-base complexes which are water insoluble. Certain Schiff-base complexes produce a shift from blue to orange-red (visible) fluorescence. Such complexes are useful in the assay of enzymes.

  2. A C-terminal Aldehyde Analog of the Insect Kinins Inhibits Diuresis in the Housefly

    DTIC Science & Technology

    2006-09-21

    p e p t i d e s 2 8 ( 2 0 0 7 ) 1 4 6 – 1 5 2A C-terminal aldehyde analog of the insect kinins inhibits diuresis in the housefly Ronald J. Nachman a...secretion in crickets, but shows inhibition of both in vitro and in vivo diuresis in the housefly. R-LK-CHO reduced the total amount of urine voided over 3 h...to stimulate Malpighian tubule fluid secretion [2,25]. In the housefly, muscakinin has been implicated in the control of diuresis in response to

  3. Catalyzed asymmetric aryl transfer reactions to aldehydes with boronic acids as aryl source.

    PubMed

    Bolm, Carsten; Rudolph, Jens

    2002-12-18

    Chiral diaryl methanols are important intermediates for the synthesis of biologically active compounds. Here, we describe a flexible method for their catalyzed asymmetric synthesis from readily available starting materials. Noteworthy is the fact that with a single catalyst both enantiomers of the product are accessible simply by choosing the appropriate combination of aryl boronic acid or aldehyde as aryl donor and acceptor, respectively. The catalysis with a planar-chiral ferrocene is easy to perform and yields a broad range of products with excellent enantioselectivities (up to 98% ee).

  4. Aminosilica materials as adsorbents for the selective removal of aldehydes and ketones from simulated bio-oil.

    PubMed

    Drese, Jeffrey H; Talley, Anne D; Jones, Christopher W

    2011-03-21

    The fast pyrolysis of biomass is a potential route to the production of liquid biorenewable fuel sources. However, degradation of the bio-oil mixtures due to reaction of oxygenates, such as aldehydes and ketones, reduces the stability of the liquids and can impact long-term storage and shipping. Herein, solid aminosilica adsorbents are described for the selective adsorptive removal of reactive aldehyde and ketone species. Three aminosilica adsorbents are prepared through the reaction of amine-containing silanes with pore-expanded mesoporous silica. A fourth aminosilica adsorbent is prepared through the ring-opening polymerization of aziridine from pore-expanded mesoporous silica. Adsorption experiments with a representative mixture of bio-oil model compounds are presented using each adsorbent at room temperature and 45 °C. The adsorbent comprising only primary amines adsorbs the largest amount of aldehydes and ketones. The overall reactivity of this adsorbent increases with increasing temperature. Additional aldehyde screening experiments show that the reactivity of aldehydes with aminosilicas varies depending on their chemical functionality. Initial attempts to regenerate an aminosilica adsorbent by acid hydrolysis show that they can be at least partially regenerated for further use.

  5. Molecular characterization of an aldehyde/alcohol dehydrogenase gene from Clostridium acetobutylicum ATCC 824.

    PubMed Central

    Nair, R V; Bennett, G N; Papoutsakis, E T

    1994-01-01

    A gene (aad) coding for an aldehyde/alcohol dehydrogenase (AAD) was identified immediately upstream of the previously cloned ctfA (J. W. Cary, D. J. Petersen, E. T. Papoutsakis, and G. N. Bennett, Appl. Environ. Microbiol. 56:1576-1583, 1990) of Clostridium acetobutylicum ATCC 824 and sequenced. The 2,619-bp aad codes for a 96,517-Da protein. Primer extension analysis identified two transcriptional start sites 83 and 243 bp upstream of the aad start codon. The N-terminal section of AAD shows homology to aldehyde dehydrogenases of bacterial, fungal, mammalian, and plant origin, while the C-terminal section shows homology to alcohol dehydrogenases of bacterial (which includes three clostridial alcohol dehydrogenases) and yeast origin. AAD exhibits considerable amino acid homology (56% identity) over its entire sequence to the trifunctional protein encoded by adhE from Escherichia coli. Expression of aad from a plasmid in C. acetobutylicum showed that AAD, which appears as a approximately 96-kDa band in denaturing protein gels, provides elevated activities of NADH-dependent butanol dehydrogenase, NAD-dependent acetaldehyde dehydrogenase and butyraldehyde dehydrogenase, and a small increase in NADH-dependent ethanol dehydrogenase. A 957-bp open reading frame that could potentially encode a 36,704-Da protein was identified upstream of aad. Images PMID:8300540

  6. Monte Carlo simulations of mixtures involving ketones and aldehydes by a direct bubble pressure calculation.

    PubMed

    Ferrando, Nicolas; Lachet, Véronique; Boutin, Anne

    2010-07-08

    Ketone and aldehyde molecules are involved in a large variety of industrial applications. Because they are mainly present mixed with other compounds, the prediction of phase equilibrium of mixtures involving these classes of molecules is of first interest particularly to design and optimize separation processes. The main goal of this work is to propose a transferable force field for ketones and aldehydes that allows accurate molecular simulations of not only pure compounds but also complex mixtures. The proposed force field is based on the anisotropic united-atoms AUA4 potential developed for hydrocarbons, and it introduces only one new atom, the carbonyl oxygen. The Lennard-Jones parameters of this oxygen atom have been adjusted on saturated thermodynamic properties of both acetone and acetaldehyde. To simulate mixtures, Monte Carlo simulations are carried out in a specific pseudoensemble which allows a direct calculation of the bubble pressure. For polar mixtures involved in this study, we show that this approach is an interesting alternative to classical calculations in the isothermal-isobaric Gibbs ensemble. The pressure-composition diagrams of polar + polar and polar + nonpolar binary mixtures are well reproduced. Mutual solubilities as well as azeotrope location, if present, are accurately predicted without any empirical binary interaction parameters or readjustment. Such result highlights the transferability of the proposed force field, which is an essential feature toward the simulation of complex oxygenated mixtures of industrial interest.

  7. Heredity mode of genetic polymorphism in aldehyde oxidase activity in Donryu strain rats.

    PubMed

    Adachi, M; Itoh, K; Abe, H; Tanaka, Y

    2008-01-01

    Donryu strain rats show genetic polymorphisms in the aldehyde oxidase gene, resulting in the phenotypic expression of ultrarapid metabolizers with homozygous nucleotide sequences (337G, 2604C), extensive metabolizers with heterozygous nucleotide sequences (377G/A, 2604C/T), and poor metabolizers with homozygous nucleotide sequences (377A, 2604T). In the mating experiments the ratio of the number of ultrarapid metabolizers, extensive metabolizers, and poor metabolizers rats in the F1 generation from the heterozygous F0 extensive metabolizers male and female rats was roughly 0.6 : 1.5 : 1, and the ratio converged to approximately 1 : 2 : 1 in the F2 generation from the heterozygous F1 extensive metabolizers male and female rats. On the contrary, all the F2 generation from homozygous F1 ultrarapid metabolizers male and female rats or from homozygous F1 poor metabolizers male and female rats had the ultrarapid metabolizers or the poor metabolizers genotypes and phenotypes. The genotypes completely agreed with the phenotypes in all individuals of F0, F1, and F2 generations. The results indicate that the genetic polymorphism of aldehyde oxidase in Donryu strain rats obeys Mendelian heredity. The reason for a low ratio of the ultrarapid metabolizers rats in the commercially available Donryu strain rats - not more than several per cent - compared with the ratio expected from the Mendelian rule is unknown.

  8. The theoretical and experimental study on dicalcium phosphate dehydrate loading with protocatechuic aldehyde.

    PubMed

    Guo, Yuehua; Qu, Shuxin; Lu, Xiong; Xie, Haodong; Zhang, Hongping; Weng, Jie

    2010-07-01

    The aim of this study is to investigate the interaction between dicalcium phosphate dihydrate (CaHPO(4) x 2H(2)O, DCPD) and Protocatechuic aldehyde (C(7)H(6)O(3), Pca), which is the water-soluble constituents of Chinese Medicine, Salvia Miltiorrhiza Bunge (SMB), by calculating the absorption energy through molecular dynamics simulation. Furthermore, the effects of functional groups of Pca and temperature on Pca adsorbed by DCPD are calculated respectively. DCPD/Pca and DCPD were analyzed by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TG). The simulation results showed that Pca mostly absorbed on the (0 2 0) surface of DCPD. The aldehyde group of Pca played a moren important role on the adsorption of Pca on DCPD than hydroxyl did, while temperature had no distinct effects on the adsorption. XRD results indicated that Pca induced the preferential growth of (0 2 0) crystal surface in DCPC/Pca whereas it had no influence on the crystal structure, the crystallinity and grain size of DCPD. FTIR and TG results showed that the characteristic peak of Pca was at 1295 cm(-1) and the content of Pca in DCPD was 16%, respectively. The present results show that molecular dynamics simulation is a very effective and complementary method to study the interaction between materials and medicine.

  9. Defensome against Toxic Diatom Aldehydes in the Sea Urchin Paracentrotus lividus

    PubMed Central

    Marrone, Vincenzo; Ianora, Adrianna; Palumbo, Anna; Costantini, Maria

    2012-01-01

    Many diatom species produce polyunsaturated aldehydes, such as decadienal, which compromise embryonic and larval development in benthic organisms. Here newly fertilized Paracentrotus lividus sea urchins were exposed to low concentration of decadienal and the expression levels of sixteen genes, implicated in a broad range of functional responses, were followed by Real Time qPCR in order to identify potential decadienal targets. We show that at low decadienal concentrations the sea urchin Paracentrotus lividus places in motion different classes of genes to defend itself against this toxic aldehyde, activating hsp60 and two proteases, hat and BP10, at the blastula stage and hsp56 and several other genes (14-3-3ε, p38 MAPK, MTase, and GS) at the prism stage. At this latter stage all genes involved in skeletogenesis (Nec, uni, SM50 and SM30) were also down-expressed, following developmental abnormalities that mainly affected skeleton morphogenesis. Moreover, sea urchin embryos treated with increasing concentrations of decadienal revealed a dose-dependent response of activated target genes. Finally, we suggest that this orchestrated defense system against decadienal represents part of the chemical defensome of P. lividus affording protection from environmental toxicants. PMID:22363721

  10. Mitochondrial aldehyde dehydrogenase prevents ROS-induced vascular contraction in angiotensin-II hypertensive mice.

    PubMed

    Choi, Hyehun; Tostes, Rita C; Webb, R Clinton

    2011-01-01

    Mitochondrial aldehyde dehydrogenase (ALDH2) is an enzyme that detoxifies aldehydes to carboxylic acids. ALDH2 deficiency is known to increase oxidative stress, which is the imbalance between reactive oxygen species (ROS) generation and antioxidant defense activity. Increased ROS contribute to vascular dysfunction and structural remodeling in hypertension. We hypothesized that ALDH2 plays a protective role to reduce vascular contraction in angiotensin-II (AngII) hypertensive mice. Endothelium-denuded aortic rings from C57BL6 mice, treated with AngII (3.6 μg/kg/min, 14 days), were used to measure isometric force development. Rings treated with daidzin (10 μmol/L), an ALDH2 inhibitor, potentiated contractile responses to phenylephrine (PE) in AngII mice. Tempol (1 mmol/L) and catalase (600 U/mL) attenuated the augmented contractile effect of daidzin. In normotensive mice, contraction to PE in the presence of the daidzin was not different from control, untreated values. AngII aortic rings transfected with ALDH2 recombinant protein decreased contractile responses to PE compared with control. These data suggest that ALDH2 reduces vascular contraction in AngII hypertensive mice. Because tempol and catalase blocked the contractile response of the ALDH2 inhibitor, ROS generation by AngII may be decreased by ALDH2, thereby preventing ROS-induced contraction.

  11. Oligonucleotide Immobilization and Hybridization on Aldehyde-Functionalized Poly(2-hydroxyethyl methacrylate) Brushes.

    PubMed

    Bilgic, Tugba; Klok, Harm-Anton

    2015-11-09

    DNA biosensing requires high oligonucleotide binding capacity interface chemistries that can be tuned to maximize probe presentation as well as hybridization efficiency. This contribution investigates the feasibility of aldehyde-functionalized poly(2-hydroxyethyl methacrylate) (PHEMA) brush-based interfaces for oligonucleotide binding and hybridization. These polymer brushes, which allow covalent immobilization of oligonucleotides, are prepared by surface-initiated atom transfer radical polymerization (SI-ATRP) of HEMA followed by a postpolymerization oxidation step to generate side chain aldehyde groups. A series of polymer brushes covering a range of film thicknesses and grafting densities was investigated with regard to their oligonucleotide binding capacity as well as their ability to support oligonucleotide hybridization. Densely grafted brushes were found to have probe oligonucleotide binding capacities of up to ∼30 pmol/cm(2). Increasing the thickness of these densely grafted brush films, however, resulted in a decrease in the oligonucleotide binding capacity. Less densely grafted brushes possess binding capacities of ∼10 pmol/cm(2), which did not significantly depend on film thickness. The oligonucleotide hybridization efficiencies, however, were highest (93%) on those brushes that present the lowest surface concentration of the probe oligonucleotide. These results highlight the importance of optimizing the probe oligonucleotide surface concentration and binding interface chemistry. The versatility and tunability of the PHEMA-based brushes presented herein makes these films a very attractive platform for the immobilization and hybridization of oligonucleotides.

  12. Defensome against toxic diatom aldehydes in the sea urchin Paracentrotus lividus.

    PubMed

    Marrone, Vincenzo; Piscopo, Marina; Romano, Giovanna; Ianora, Adrianna; Palumbo, Anna; Costantini, Maria

    2012-01-01

    Many diatom species produce polyunsaturated aldehydes, such as decadienal, which compromise embryonic and larval development in benthic organisms. Here newly fertilized Paracentrotus lividus sea urchins were exposed to low concentration of decadienal and the expression levels of sixteen genes, implicated in a broad range of functional responses, were followed by Real Time qPCR in order to identify potential decadienal targets. We show that at low decadienal concentrations the sea urchin Paracentrotus lividus places in motion different classes of genes to defend itself against this toxic aldehyde, activating hsp60 and two proteases, hat and BP10, at the blastula stage and hsp56 and several other genes (14-3-3ε, p38 MAPK, MTase, and GS) at the prism stage. At this latter stage all genes involved in skeletogenesis (Nec, uni, SM50 and SM30) were also down-expressed, following developmental abnormalities that mainly affected skeleton morphogenesis. Moreover, sea urchin embryos treated with increasing concentrations of decadienal revealed a dose-dependent response of activated target genes. Finally, we suggest that this orchestrated defense system against decadienal represents part of the chemical defensome of P. lividus affording protection from environmental toxicants.

  13. NADP-Dependent Aldehyde Dehydrogenase from Archaeon Pyrobaculum sp.1860: Structural and Functional Features

    PubMed Central

    Petrova, Tatiana E.; Artemova, Natalia V.; Boyko, Konstantin M.; Shabalin, Ivan G.; Rakitina, Tatiana V.; Polyakov, Konstantin M.; Popov, Vladimir O.

    2016-01-01

    We present the functional and structural characterization of the first archaeal thermostable NADP-dependent aldehyde dehydrogenase AlDHPyr1147. In vitro, AlDHPyr1147 catalyzes the irreversible oxidation of short aliphatic aldehydes at 60–85°С, and the affinity of AlDHPyr1147 to the NADP+ at 60°С is comparable to that for mesophilic analogues at 25°С. We determined the structures of the apo form of AlDHPyr1147 (3.04 Å resolution), three binary complexes with the coenzyme (1.90, 2.06, and 2.19 Å), and the ternary complex with the coenzyme and isobutyraldehyde as a substrate (2.66 Å). The nicotinamide moiety of the coenzyme is disordered in two binary complexes, while it is ordered in the ternary complex, as well as in the binary complex obtained after additional soaking with the substrate. AlDHPyr1147 structures demonstrate the strengthening of the dimeric contact (as compared with the analogues) and the concerted conformational flexibility of catalytic Cys287 and Glu253, as well as Leu254 and the nicotinamide moiety of the coenzyme. A comparison of the active sites of AlDHPyr1147 and dehydrogenases characterized earlier suggests that proton relay systems, which were previously proposed for dehydrogenases of this family, are blocked in AlDHPyr1147, and the proton release in the latter can occur through the substrate channel. PMID:27956891

  14. Cross-linking connectivity in bone collagen fibrils: the COOH-terminal locus of free aldehyde

    NASA Technical Reports Server (NTRS)

    Otsubo, K.; Katz, E. P.; Mechanic, G. L.; Yamauchi, M.

    1992-01-01

    Quantitative analyses of the chemical state of the 16c residue of the alpha 1 chain of bone collagen were performed on samples from fetal (4-6-month embryo) and mature (2-3 year old) bovine animals. All of this residue could be accounted for in terms of three chemical states, in relative amounts which depended upon the age of the animal. Most of the residue was incorporated into either bifunctional or trifunctional cross-links. Some of it, however, was present as free aldehyde, and the content increased with maturation. This was established by isolating and characterizing the aldehyde-containing peptides generated by tryptic digestion of NaB3H4-reduced mature bone collagen. We have concluded that the connectivity of COOH-terminal cross-linking in bone collagen fibrils changes with maturation in the following way: at first, each 16c residue in each of the two alpha 1 chains of the collagen molecule is incorporated into a sheet-like pattern of intermolecular iminium cross-links, which stabilizes the young, nonmineralized fibril as a whole. In time, some of these labile cross-links maturate into pyridinoline while others dissociate back to their precursor form. The latter is likely due to changes in the molecular packing brought about by the mineralization of the collagen fibrils. The resultant reduction in cross-linking connectivity may provide a mechanism for enhancing certain mechanical characteristics of the skeleton of a mature animal.

  15. Potential polyunsaturated aldehydes in the Strait of Gibraltar under two tidal regimes.

    PubMed

    Morillo-García, Soledad; Valcárcel-Pérez, Nerea; Cózar, Andrés; Ortega, María J; Macías, Diego; Ramírez-Romero, Eduardo; García, Carlos M; Echevarría, Fidel; Bartual, Ana

    2014-03-13

    Diatoms, a major component of the large-sized phytoplankton, are able to produce and release polyunsaturated aldehydes after cell disruption (potential PUAs or pPUA). These organisms are dominant in the large phytoplankton fraction (>10 µm) in the Strait of Gibraltar, the only connection between the Mediterranean Sea and the Atlantic Ocean. In this area, the hydrodynamics exerts a strong control on the composition and physiological state of the phytoplankton. This environment offers a great opportunity to analyze and compare the little known distribution of larger sized PUA producers in nature and, moreover, to study how environmental variables could affect the ranges and potential distribution of these compounds. Our results showed that, at both tidal regimes studied (Spring and Neap tides), diatoms in the Strait of Gibraltar are able to produce three aldehydes: Heptadienal, Octadienal and Decadienal, with a significant dominance of Decadienal production. The PUA released by mechanical cell disruption of large-sized collected cells (pPUA) ranged from 0.01 to 12.3 pmol from cells in 1 L, and from 0.1 to 9.8 fmol cell⁻¹. Tidal regime affected the abundance, distribution and the level of physiological stress of diatoms in the Strait. During Spring tides, diatoms were more abundant, usually grouped nearer the coastal basin and showed less physiological stress than during Neap tides. Our results suggest a significant general increase in the pPUA productivity with increasing physiological stress for the cell also significantly associated to low nitrate availability.

  16. Absorption Reveals and Hydrogen Addition Explains New Interstellar Aldehydes: Propenal and Propanal

    NASA Technical Reports Server (NTRS)

    Hollis, J. M.; Jewell, P. R.; Lovas, F. J.; Remijan, A.; Mollendal, H.

    2004-01-01

    New interstellar molecules propenal (CH2CHCHO) and propanal (CH3CH2CHO) have been detected largely in absorption toward the star-forming region Sagittarius B2(N) by means of rotational transitions observed with the 100-m Green Bank Telescope (GBT) operating in the range of 18 GHz (lambda approximately 1.7 cm) to 26 GHz (lambda approximately 1.2 cm). The GBT was also used to observe the previously reported interstellar aldehyde propynal (HC2CHO) in Sagittarius B2(N) which is known for large molecules believed to form on interstellar grains. The presence of these three interstellar aldehydes toward Sagittarius B2(N) strongly suggests that simple hydrogen addition on interstellar grains accounts for successively larger molecular species: from propynal to propenal and from propenal to propanal. Energy sources within Sagittarius B2(N) likely permit the hydrogen addition reactions on grain surfaces to proceed. This work demonstrates that successive hydrogen addition is probably an important chemistry route in the formation of a number of complex interstellar molecules. We also searched for but did not detect the three-carbon sugar glyceraldehyde (CH2OHCHOHCHO).

  17. The four aldehyde oxidases of Drosophila melanogaster have different gene expression patterns and enzyme substrate specificities.

    PubMed

    Marelja, Zvonimir; Dambowsky, Miriam; Bolis, Marco; Georgiou, Marina L; Garattini, Enrico; Missirlis, Fanis; Leimkühler, Silke

    2014-06-15

    In the genome of Drosophila melanogaster, four genes coding for aldehyde oxidases (AOX1-4) were identified on chromosome 3. Phylogenetic analysis showed that the AOX gene cluster evolved via independent duplication events in the vertebrate and invertebrate lineages. The functional role and the substrate specificity of the distinct Drosophila AOX enzymes is unknown. Two loss-of-function mutant alleles in this gene region, low pyridoxal oxidase (Po(lpo)) and aldehyde oxidase-1 (Aldox-1(n1)) are associated with a phenotype characterized by undetectable AOX enzymatic activity. However, the genes involved and the corresponding mutations have not yet been identified. In this study we characterized the activities, substrate specificities and expression profiles of the four AOX enzymes in D. melanogaster. We show that the Po(lpo)-associated phenotype is the consequence of a structural alteration of the AOX1 gene. We identified an 11-bp deletion in the Po(lpo) allele, resulting in a frame-shift event, which removes the molybdenum cofactor domain of the encoded enzyme. Furthermore, we show that AOX2 activity is detectable only during metamorphosis and characterize a Minos-AOX2 insertion in this developmental gene that disrupts its activity. We demonstrate that the Aldox-1(n1) phenotype maps to the AOX3 gene and AOX4 activity is not detectable in our assays.

  18. Aldehyde-modified proteins as mediators of early inflammation in atherosclerotic disease.

    PubMed

    Antoniak, Derrick T; Duryee, Michael J; Mikuls, Ted R; Thiele, Geoffrey M; Anderson, Daniel R

    2015-12-01

    Inflammation is widely accepted to play a major role in atherosclerosis and other cardiovascular diseases. However, the exact mechanism(s) by which inflammation exerts its pathogenic effect remains poorly understood. A number of oxidatively modified proteins have been associated with cardiovascular disease. Recently, attention has been given to the oxidative compound of malondialdehyde and acetaldehyde, two reactive aldehydes known to covalently bind and adduct macromolecules. These products have been shown to form stable malondialdehyde-acetaldehyde (MAA) adducts that are reactive and induce immune responses. These adducts have been found in inflamed and diseased cardiovascular tissue of patients. Antibodies to these adducted proteins are measurable in the serum of diseased patients. The isotypes involved in the immune response to MAA (i.e., IgM, IgG, and IgA) are predictive of atherosclerotic disease progression and cardiovascular events such as an acute myocardial infarction or coronary artery bypass grafting. Therefore, it is the purpose of this article to review the past and current knowledge of aldehyde-modified proteins and their role in cardiovascular disease.

  19. Structure and mechanism of action of the hydroxy aryl aldehyde class of IRE1 endoribonuclease inhibitors

    PubMed Central

    Sanches, Mario; Duffy, Nicole M.; Talukdar, Manisha; Thevakumaran, Nero; Chiovitti, David; Canny, Marella D.; Lee, Kenneth; Kurinov, Igor; Uehling, David; Al-awar, Rima; Poda, Gennadiy; Prakesch, Michael; Wilson, Brian; Tam, Victor; Schweitzer, Colleen; Toro, Andras; Lucas, Julie L.; Vuga, Danka; Lehmann, Lynn; Durocher, Daniel; Zeng, Qingping; Patterson, John B.; Sicheri, Frank

    2014-01-01

    Endoplasmic reticulum (ER) stress activates the unfolded protein response and its dysfunction is linked to multiple diseases. The stress transducer IRE1α is a transmembrane kinase endoribonuclease (RNase) that cleaves mRNA substrates to re-establish ER homeostasis. Aromatic ring systems containing hydroxy-aldehyde moieties, termed hydroxy aryl aldehydes (HAA), selectively inhibit IRE1α RNase and thus represent a novel chemical series for therapeutic development. We solved crystal structures of murine IRE1α in complex with three HAA inhibitors. HAA inhibitors engage a shallow pocket at the RNase active site through pi-stacking interactions with His910 and Phe889, an essential Schiff base with Lys907 and a H-bond with Tyr892. Structure activity studies and mutational analysis of contact residues define the optimal chemical space of inhibitors and validate the inhibitor binding site. These studies lay the foundation for understanding both the biochemical and cellular functions of IRE1α using small molecule inhibitors and suggest new avenues for inhibitor design. PMID:25164867

  20. Sensitive Determination of Volatile Organic Compounds and Aldehydes in Tattoo Inks.

    PubMed

    Lim, Hyun-Hee; Shin, Ho-Sang

    2017-02-01

    As the popularity of body art including tattoo ink has increased, the safety associated with it has become an important interest. In this study, twenty volatile organic compounds (VOCs) and two aldehydes in tattoo inks were identified and quantified. Headspace and gas chromatography-mass spectrometry (HS GC-MS) for the VOCs and HS GC-MS based on derivatization with 2,2,2-trifluoroethylhydrazine (TFEH) for aldehydes was developed. Benzene, chloroform, toluene, ethylbenzene, m-xylene, p-xylene, o-xylene, propylbenzene, chlorobenzene, tert-butylbenzene, 1,3,5-trimethylbenzene, styrene, 1,2,4-trimethylbenzene, 2-chlorotoluene, 4-chlorotoluene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, 1,2-dichlorobenzene, 1,2,4-trichlorobenzene and isopropyl alcohol were detected with the concentration range of 0.02-207,000 mg/kg in 16 different tattoo inks. Formaldehyde and acetaldehyde were detected with the concentration range of 0.4-308 mg/kg in the same samples. Our analytical results represent solvents used intentionally or non-intentionally in tattoo inks, and thus they may provide important information for national regulation.

  1. The effect of disulfiram on the aldehyde dehydrogenases of sheep liver.

    PubMed Central

    Kitson, T M

    1975-01-01

    1. The effect of disulfiram on the activity of the cytoplasmic and mitochondrial aldehyde dehydrogenases of sheep liver was studied. 2. Disulfiram causes an immediate inhibition of the enzyme reaction. The effect on the cytoplasmic enzyme is much greater than on the mitochondrial enzyme. 3. In both cases, the initial partial inhibition is followed by a gradual irreversible loss of activity. 4. The pH-rate profile of the inactivation of the mitochondrial enzyme by disulfiram and the pH-dependence of the maximum velocity of the enzyme-catalysed reaction are both consistent with the involvement of a thiol group. 5. Excess of 2-mercaptoethanol or GSH abolishes the effect of disulfiram. However, equimolar amounts of either of these reagents and disulfiram cause an effect greater than does disulfiram alone. It was shown that the mixed disulphide, Et2N-CS-SS-CH2-CH2OH, strongly inhibits aldehyde dehydrogenase. 6. The inhibitory effect of diethyldithiocarbamate in vitro is due mainly to contamination by disulfiram. PMID:3167

  2. The role lipid aldehydes and ALEs in the pathogenesis of diabetic retinopathy.

    PubMed

    Curtis, Tim

    2014-10-01

    Diabetic retinopathy is one of the most common causes of blindness in people of working age in developed countries. The retinal vasculature is central to the development of diabetic retinopathy, but there is accumulating evidence that neuroretinal dysfunction and degeneration also contributes to the aetiology and progression of this disease. The precise mechanisms through which diabetes causes neuroretinal dysfunction and degeneration remain to be fully established, but recent evidence from our own group has suggested that lipid aldehyde generation and the formation of advanced lipoxidation end-products (ALEs) plays a key contributory role. In the present talk, I will outline our recent data suggesting that the progressive and selective accumulation of the acrolein-derived ALE, FDP-lysine, in retinal Müller glial cells during diabetes is involved in the pathogenesis of neuroretinal dysfunction during diabetic retinopathy. More recent unpublished data will also be presented suggesting that FDP-lysine accumulation in the diabetic retina may occur primarily through a mechanism involving the downregulation of aldehyde detoxification enzymes. Current studies examining potential therapeutic strategies for preventing ALE accumulation in the diabetic retina will also be briefly discussed.

  3. Evaluation of rhesus monkey and guinea pig hepatic cytosol fractions as models for human aldehyde oxidase.

    PubMed

    Choughule, Kanika V; Barr, John T; Jones, Jeffrey P

    2013-10-01

    Aldehyde oxidase (AOX) is a cytosolic enzyme expressed across a wide range of species, including guinea pig and rhesus monkey. These species are believed to be the best preclin