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1.
Mol Pharmacol ; 98(2): 120-129, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32499331

RESUMO

Alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) are vital enzymes involved in the metabolism of a variety of alcohols. Differences in the expression and enzymatic activity of human ADHs and ALDHs correlate with individual variability in metabolizing alcohols and drugs and in the susceptibility to alcoholic liver disease. MicroRNAs (miRNAs) function as epigenetic modulators to regulate the expression of drug-metabolizing enzymes. To characterize miRNAs that target ADHs and ALDHs in human liver cells, we carried out a systematic bioinformatics analysis to analyze free energies of the interaction between miRNAs and their cognate sequences in ADH and ALDH transcripts and then calculated expression correlations between miRNAs and their targeting ADH and ALDH genes using a public data base. Candidate miRNAs were selected to evaluate bioinformatic predictions using a series of biochemical assays. Our results showed that 11 miRNAs have the potential to modulate the expression of two ADH and seven ALDH genes in the human liver. We found that hsa-miR-1301-3p suppressed the expression of ADH6, ALDH5A1, and ALDH8A1 in liver cells and blocked their induction by ethanol. In summary, our results revealed that hsa-miR-1301-3p plays an important role in ethanol metabolism by regulating ADH and ALDH gene expression. SIGNIFICANCE STATEMENT: Systematic bioinformatics analysis showed that 11 microRNAs might play regulatory roles in the expression of two alcohol dehydrogenase (ADH) and seven aldehyde dehydrogenase (ALDH) genes in the human liver. Experimental evidences proved that hsa-miR-1301-3p suppressed the expression of ADH6, ALDH5A1, and ALDH8A1 in liver cells and decreased their inducibility by ethanol.


Assuntos
Álcool Desidrogenase/genética , Aldeído Desidrogenase/genética , Fígado/metabolismo , MicroRNAs/genética , Succinato-Semialdeído Desidrogenase/genética , Acetaldeído/metabolismo , Acetatos/metabolismo , Linhagem Celular , Etanol/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Células Hep G2 , Humanos , Redes e Vias Metabólicas
2.
Proc Natl Acad Sci U S A ; 117(7): 3867-3873, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32024752

RESUMO

In plants, enhanced defense often compromises growth and development, which is regarded as trade-offs between growth and defense. Here we identified a gene, OsALDH2B1, that functions as a master regulator of the growth-defense trade-off in rice. OsALDH2B1 has its primary function as an aldehyde dehydrogenase and a moonlight function as a transcriptional regulator. Loss of function of OsALDH2B1 greatly enhanced resistance to broad-spectrum pathogens, including fungal blast, bacterial leaf blight, and leaf streak, but caused severe phenotypic changes such as male sterility and reduced plant size, grain size, and number. We showed that its primary function as a mitochondrial aldehyde dehydrogenase conditions male fertility. Its moonlight function of transcriptional regulation, featuring both repressing and activating activities, regulates a diverse range of biological processes involving brassinolide, G protein, jasmonic acid, and salicylic acid signaling pathways. Such regulations cause large impacts on the morphology and immunity of rice plants. The versatile functions of OsALDH2B1 provide an example of the genic basis of growth-defense trade-offs in plants.


Assuntos
Aldeído Desidrogenase/imunologia , Regulação da Expressão Gênica de Plantas , Oryza/crescimento & desenvolvimento , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Proteínas de Plantas/imunologia , Aldeído Desidrogenase/genética , Ciclopentanos/metabolismo , Resistência à Doença , Magnaporthe/fisiologia , Oryza/genética , Oryza/metabolismo , Oryza/microbiologia , Oxilipinas/metabolismo , Doenças das Plantas/genética , Proteínas de Plantas/genética , Ácido Salicílico/metabolismo
3.
Artigo em Inglês | MEDLINE | ID: mdl-32005394

RESUMO

Nitric oxide (NO) is an intracellular messenger that mediates stress responses. Several plant aldehyde dehydrogenase (ALDH) genes are expressed during abiotic stress conditions to reduce the level of cytotoxic aldehydes. We investigated a possible interference between NO and ALDHs, using the isoform ALDH3H1 of Arabidopsis thaliana as model. The physiological NO donor; S-nitrosoglutathione (GSNO), inhibits ALDH3H1 in a time- and concentration-dependent manner. Mutagenesis and ESI-MS/MS analyses show that all Cys residues of ALDH3H1 are targets of GSNO-mediated S-nitrosation. Chemical labelling indicates that the deactivation is due to the conversion of the catalytic thiol into a catalytically non-active nitrosothiol. GSNO has the same effect on the chloroplastic ALDH3I1, suggesting that susceptibility of the catalytic Cys to NO is a common feature of ALDHs. S-Nitrosation and enzymatic inhibition of ALDH were reverted by reducing agents. Our study proves that the function of ALDHs does not exclusively depend on transcriptional regulation, with stress-induced expression, but may be also susceptible to posttranslational regulation through S-nitrosation. We discuss the potential involvement of S-nitrosoglutathione reductase (GSNOR), binding specific cofactors and reducing partners in a protective system of ALDHs in vivo, which will be experimentally corroborated in our forthcoming study.


Assuntos
Aldeído Desidrogenase/genética , Proteínas de Arabidopsis/genética , Arabidopsis/genética , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico/metabolismo , S-Nitrosoglutationa/farmacologia , Aldeído Desidrogenase/metabolismo , Arabidopsis/química , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Nitrosação , Estresse Fisiológico
4.
Sci Rep ; 10(1): 2716, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066820

RESUMO

A growing proportion of head and neck cancers (HNC) result from HPV infection. Between HNC aetiological groups (HPV positive and HPV negative) clinical evidence demonstrates significantly better treatment response among HPV positive cancers. Cancer stem cells (CSCs) are identified in HNC tumour populations as agents of treatment resistance and a target for tumour control. This study examines dynamic responses in populations of a CSC phenotype in HNC cell lines following X-irradiation at therapeutic levels, and comparing between HPV statuses. Variations in CSC density between HPV groups showed no correlation with better clinical outcomes seen in the HPV positive status. CSC populations in HPV positive cell lines ranged from 1.9 to 4.8%, and 2.6 to 9.9% for HPV negative. Following 4 Gy X- irradiation however, HPV negative cell lines demonstrated more frequent and significantly greater escalation in CSC proportions, being 3-fold that of the HPV positive group at 72 hours post irradiation. CSC proportions of tumour populations are not fixed but subject to change in response to radiation at therapeutic dose levels. These findings imply a potential effect of aetiology on radio-responsiveness in CSCs, illustrating that clonogen treatment response may be more informative of therapy outcomes than inherent population density alone.


Assuntos
Aldeído Desidrogenase/genética , Receptores de Hialuronatos/genética , Células-Tronco Neoplásicas/efeitos da radiação , Papillomaviridae/patogenicidade , Tolerância a Radiação/genética , Idoso , Aldeído Desidrogenase/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Contagem de Células , Linhagem Celular Tumoral , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Receptores de Hialuronatos/imunologia , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Papillomaviridae/crescimento & desenvolvimento , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/radioterapia , Tolerância a Radiação/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Raios X
5.
Sci Rep ; 10(1): 1097, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974410

RESUMO

p53 and aldehyde dehydrogenase (ALDH) have been implicated in key tumorigenesis processes including cancer initiating cell (CIC) maintenance; however, the relationship between these two mediators remains poorly defined. In this study, ALDH isoform expression diversity was revealed in CICs with disparate p53 functional states: gain of function, high risk p53 mutation (p53HRmut) and wildtype p53 (p53WT) inactivated by the human papillomavirus 16 (HPV16) E6 oncogene. Interrogation of head and neck squamous cell carcinoma (HNSCC) cell lines and patient tumors showed that HPV16+/p53WT cases have higher ALDH variance score (AVS), a measure of tumor ALDH isoform expression diversity, compared to HPV-/p53HRmut cases (p = 0.03). AVS and several individual ALDH isoforms were associated with prognosis in HPV16+/p53WT HNSCC but not in HPV-/p53HRmut HNSCC. Knockdown of the dominant ALDH isoform in high AVS HNSCC depleted the CIC pool in vitro and in vivo. Our results demonstrate that p53 functional states are associated with distinct ALDH isoform transcriptomic signatures. Moreover, tumor ALDH profiling may provide insight on which ALDH isoform to target in high AVS HNSCC tumors to deplete the CIC population.


Assuntos
Aldeído Desidrogenase/genética , Infecções por Papillomavirus/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Aldeído Desidrogenase/metabolismo , Animais , Feminino , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/fisiologia , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Camundongos , Células-Tronco Neoplásicas/metabolismo , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/enzimologia , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transcriptoma , Proteína Supressora de Tumor p53/genética
6.
Food Chem Toxicol ; 135: 110890, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31628963

RESUMO

Alcoholic liver disease is a major cause of morbidity and mortality worldwide. In this work, a food-grade recombinant Bacillus subtilis co-expressing both alcohol dehydrogenase from Saccharomyces cerevisiae (scADH) and aldehyde dehydrogenase from Issatchenkia terricola (istALDH) were successfully constructed via double-crossover homologous recombination. When cultured at 37 °C for 48 h, the activities of scADH and istALDH were 57.56 ±â€¯7.44 and 81.41 ±â€¯8.26 U/mL, respectively. In pH 4.0, the alcohol degradation rate of recombinant B. subtilis fmb8 was 33% and the ΔLog10 was 0.1, indicating that fmb8 could be used as whole-cell biocatalysts for biodegradation of alcohols under low pH conditions. Mice experiments indicated that recombinant B. subtilis significantly alleviate recombinant alcohol-induced increases of mouse liver index, blood alcohol content, and serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase activities. Furthermore, recombinant B. subtilis significantly reduced liver malondialdehyde levels and increased total antioxidant capacity and superoxide dismutase levels in mouse liver. Overall, our findings suggested that food-grade B. subtilis fmb8 co-expressing scADH and istALDH could be used as a potential probiotic for alcohol detoxification and alleviation of alcoholic liver injury.


Assuntos
Álcool Desidrogenase/genética , Aldeído Desidrogenase/genética , Bacillus subtilis/genética , Etanol/toxicidade , Inativação Metabólica , Álcool Desidrogenase/metabolismo , Aldeído Desidrogenase/metabolismo , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Etanol/sangue , Recombinação Homóloga , Camundongos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
7.
Dev Med Child Neurol ; 62(3): 315-321, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31737911

RESUMO

AIM: To characterize the clinical and genetic characteristics of a large cohort of patients with pyridoxine-dependent epilepsy (PDE). METHOD: We retrospectively collected clinical and genetic information of 33 (15 males, 18 females; mean [SD] age 4y 11mo [2y 5mo]; 1y 3mo-10y 4mo) patients with PDE from 31 unrelated families at a single centre. RESULTS: There were many types of seizures, with focal seizures in 32 cases. Dravet syndrome was suspected clinically in two patients. Electroencephalogram (EEG) was normal in seven patients at the initial stage and then in 17 patients during pyridoxine maintenance therapy. Genetic studies revealed 26 kinds of variants in ALDH7A1 and four in PLPBP with 18 variants unreported previously, and 48 ALDH7A1 variants were located in exon 11, 12, 14, and 17 or intron 9 and 11. In addition, three patients carried different exons deletion. Among these, seizures could be controlled for several years in one patient by levetiracetam monotherapy. Another patient remained seizure free for up to 7 months without therapy. All patients received oral pyridoxine treatment, with only one case (with exon 8-13 deletion) showing poor control. INTERPRETATION: This study illustrates the range of clinical presentations and genetic causes in PDE, as well as responsiveness to antiepileptic drugs. A relationship between EEG and pyridoxine therapy could be seen in many cases. Seizure control was seen in all with pyridoxine monotherapy except for one patient. WHAT THIS PAPER ADDS: There is a parallel relationship between electroencephalogram and pyridoxine therapy in many patients. Patients with pyridoxine-dependent epilepsy may respond well to low-dose pyridoxine.


Assuntos
Aldeído Desidrogenase/genética , Epilepsia/diagnóstico , Proteínas/genética , Encéfalo/fisiopatologia , Criança , Pré-Escolar , China , Análise Mutacional de DNA , Eletroencefalografia , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Masculino , Mutação , Estudos Retrospectivos
8.
Epilepsia ; 61(1): e1-e6, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31849043

RESUMO

Pyridoxine-dependent epilepsy (PDE) is a genetic metabolic disease caused by inborn errors affecting vitamin B6 metabolism, which typically presents with neonatal seizures resistant to antiepileptic drugs (AEDs). Treatment with pyridoxine terminates seizures and prevents neurological decline. We describe a case in which the diagnosis was established at the age of 22 years. Birth and development were normal, but there was a history of three isolated tonic-clonic seizures during childhood and adolescence. At the age of 18 years, she developed frequent focal motor seizures, many evolving into tonic-clonic seizures. Electroencephalography identified a focus in the posterior right hemisphere, but magnetic resonance imaging of the brain was normal. Over the next 3 years, she was hospitalized with uncontrolled seizures on six occasions and spent a total of 121 days in intensive care. The seizures proved resistant to 12 different AEDs. Exome sequencing revealed two pathogenic mutations in ALDH7A1. Since starting on pyridoxine 50 mg once daily, she has been seizure-free, all AEDs have been withdrawn, and cognition has improved to premorbid levels. This case illustrates the importance of considering PDE in drug-resistant epilepsy in adults.


Assuntos
Epilepsia/diagnóstico , Estado Epiléptico/genética , Adolescente , Idade de Início , Aldeído Desidrogenase/genética , Epilepsia/complicações , Epilepsia/genética , Feminino , Humanos , Mutação , Piridoxina/deficiência , Piridoxina/uso terapêutico , Estado Epiléptico/diagnóstico , Estado Epiléptico/tratamento farmacológico , Adulto Jovem
9.
J Biotechnol ; 307: 125-130, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31726082

RESUMO

Catalytic transformation of biomass-derived furans into value-added chemicals and biofuels has received considerable interest recently. In this work, aldehyde dehydrogenases (ALDHs) were identified from Comamonas testosteroni SC1588 for the oxidation of bio-based furans into furan carboxylic acids. Of the whole-cell biocatalysts constructed, Escherichia coli expressing a vanillin dehydrogenase (E. coli_CtVDH1) proved to be the best for the oxidation of 5-hydroxymethylfurfural (HMF). 5-Hydroxymethyl-2-furancarboxylic acid (HMFCA) was obtained in the yield of approximately 92 % within 12 h using this recombinant strain when the HMF concentration was up to 200 mM. In a fed-batch process, 292 mM of HMFCA was produced within 20.5 h, thereby providing a productivity as high as 2.0 g/L h. Other furan carboxylic acids were synthesized in the yields of 83-95%. Besides, the partially purified HMF was smoothly converted into HMFCA by this recombinant strain, with a 90% yield.


Assuntos
Aldeído Desidrogenase/metabolismo , Aldeído Oxirredutases/metabolismo , Escherichia coli/enzimologia , Furaldeído/análogos & derivados , Furanos/metabolismo , Aldeído Desidrogenase/genética , Aldeído Oxirredutases/genética , Biocatálise , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Furaldeído/química , Furaldeído/metabolismo , Furanos/química , Oxirredução , Proteínas Recombinantes
10.
Food Chem Toxicol ; 136: 111070, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31870920

RESUMO

While liver injury is commonly associated with excessive alcohol consumption, how liver injury affects alcohol metabolism and drinking preference remains unclear. To answer these questions, we measured the expression and activity of alcohol dehydrogenase 1 (ADH1) and acetaldehyde dehydrogenase 2 (ALDH2) enzymes, ethanol and acetaldehyde levels in vivo, and binge-like and preferential drinking behaviors with drinking in the dark and two-bottle choice in animal models with liver injury. Acute and chronic carbon tetrachloride (CCl4), and acute LPS-induced liver injury repressed hepatic ALDH2 activity and expression and consequently, blood and liver acetaldehyde concentrations were increased in these models. In addition, chronic CCl4 and acute LPS treatment inhibited hepatic ADH1 expression and activity, leading to increases in blood and liver ethanol concentrations. Consistent with the increase in acetaldehyde levels, alcohol drinking behaviors were reduced in mice with acute or chronic liver injury. Furthermore, oxidative stress induced by hydrogen peroxide attenuated ADH1 and ALDH2 activity post-transcriptionally, while proinflammatory cytokines led to transcriptional repression of ADH1 and ALDH2 in cultured hepatocytes, which correlated with the repression of transcription factor HNF4α. Collectively, our data suggest that alcohol metabolism is suppressed by inflammation and oxidative stress, which is correlated with decreased drinking behavior.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Etanol/efeitos adversos , Hepatopatias/imunologia , Fígado/lesões , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/imunologia , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/imunologia , Animais , Etanol/metabolismo , Fator 6 Nuclear de Hepatócito/genética , Fator 6 Nuclear de Hepatócito/imunologia , Humanos , Fígado/imunologia , Hepatopatias/etiologia , Hepatopatias/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL
11.
Chemosphere ; 239: 124747, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31514003

RESUMO

BACKGROUNDS: Polychlorinated biphenyls are persistent environmental pollutants associated with the onset of non-alcoholic fatty liver disease in humans, but there is limited information on the underlying mechanism. In the present study, we investigated the alterations in gene expression profiles in normal human liver cells L-02 following exposure to 2, 3, 3', 4, 4', 5 - hexachlorobiphenyl (PCB 156), a potent compound that may induce non-alcoholic fatty liver disease. METHODS: The L-02 cells were exposed to PCB 156 for 72 h and the contents of intracellular triacylglyceride and total cholesterol were subsequently measured. Microarray analysis of mRNAs and long non-coding RNAs (lncRNAs) in the cells was also performed after 3.4 µM PCB 156 treatment. RESULTS: Exposure to PCB 156 (3.4 µM, 72 h) resulted in significant increases of triacylglyceride and total cholesterol concentrations in L-02 cells. Microarray analysis identified 222 differentially expressed mRNAs and 628 differentially expressed lncRNAs. Gene Ontology and pathway analyses associated the differentially expressed mRNAs with metabolic and inflammatory processes. Moreover, lncRNA-mRNA co-expression network revealed 36 network pairs comprising 10 differentially expressed mRNAs and 34 dysregulated lncRNAs. The results of bioinformatics analysis further indicated that dysregulated lncRNA NONHSAT174696, lncRNA NONHSAT179219, and lncRNA NONHSAT161887, as the regulators of EDAR, CYP1B1, and ALDH3A1 respectively, played an important role in the PCB 156-induced lipid metabolism disorder. CONCLUSION: Our findings provide an overview of differentially expressed mRNAs and lncRNAs in L-02 cells exposed to PCB 156, and contribute to the field of polychlorinated biphenyl-induced non-alcoholic fatty liver disease.


Assuntos
Fígado/efeitos dos fármacos , Bifenilos Policlorados/toxicidade , Transcriptoma/efeitos dos fármacos , Aldeído Desidrogenase/genética , Linhagem Celular , Colesterol/metabolismo , Citocromo P-450 CYP1B1/genética , Receptor Edar/genética , Perfilação da Expressão Gênica , Humanos , Fígado/citologia , Fígado/fisiologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/patologia , Análise de Sequência com Séries de Oligonucleotídeos , RNA Longo não Codificante , RNA Mensageiro/metabolismo , Testes de Toxicidade , Triglicerídeos/metabolismo
12.
Fa Yi Xue Za Zhi ; 35(5): 576-580, 2019 Oct.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-31833292

RESUMO

Abstract: Objective To explore the change rules of blood ethanol and blood acetaldehyde concentration, the impairment of psychomotor functions of different acetaldehyde dehydrogenase (ALDH) 2 genotype individuals after alcohol consumption and the relationship among them. Methods The ALDH2 genotypes in seventy-nine healthy volunteers were obtained by SNaPshotTM method, then divided into ALDH2*1/*1 (wild type) and ALDH2*1/*2 (mutant type) group. After volunteers consumed 1.0 g/kg of alcohol, blood ethanol concentration and blood acetaldehyde concentration at a series of time points before and after alcohol consumption and psychomotor functions, such as, visual selective response time, auditory simple response time and tracking experiment were detected. Biphasic alcohol response questionnaires were collected. Results After alcohol consumption, ALDH2*1/*2 group's blood ethanol and blood acetaldehyde concentration reached the peak earlier than ALDH2*1/*1 group. Its blood acetaldehyde concentration was higher than that of ALDH2*1/*1 group, 1-6 h after alcohol consumption. The psychomotor functions, such as visual selective response time and auditory simple response time in ALDH2*1/*2 group were more significantly impaired than those in ALDH2*1/*1 group after alcohol consumption. There was no statistical significance between the two groups in excitement or sedation reactions (P>0.05). Pearson correlation coefficient test showed that blood acetaldehyde concentration was related with psychomotor function. Conclusion There are significant differences between the psychomotor function of ALDH2 wild type and mutant type individuals after alcohol consumption estimated to be related to the difference in blood acetaldehyde concentration after alcohol consumption.


Assuntos
Acetaldeído/sangue , Consumo de Bebidas Alcoólicas , Aldeído Desidrogenase/genética , Etanol/metabolismo , Polimorfismo Genético/genética , Desempenho Psicomotor/efeitos dos fármacos , Acetaldeído/metabolismo , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/sangue , Aldeído-Desidrogenase Mitocondrial , Aldeído Oxirredutases , Etanol/administração & dosagem , Etanol/sangue , Genótipo , Humanos , Desempenho Psicomotor/fisiologia
13.
Chem Biol Interact ; 314: 108822, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31580832

RESUMO

Aldehyde dehydrogenase (ALDH) activity is not only a valuable marker for cancer cells with stem-like features, but also plays a vital role in drug resistance and disease progression in many tumors including melanoma. However, the precise role of ALDH activity in patient prognosis remains unclear. In this study, using the Cancer Genome Atlas (TCGA) RNA-sequencing expression data, we analyzed gene expression of ALDH isozymes in melanoma tumors to define the expression patterns and the prognostic and predictive values of these enzymes. We found that ALDH1A1 and ALDH1A3 had both higher and broader expression ranges in melanoma patients, and that ALDH1A3 expression correlated with better overall survival in metastatic melanoma. Further, stratification of the TCGA cohorts by the mutational subtypes of melanoma specifically revealed that expression of ALDH1A3 correlated with better prognosis in metastatic BRAF-mutant melanoma while expression of ALDH1A1 correlated with better prognosis in BRAF wild-type melanoma. Gene set enrichment analysis (GSEA) of these cohorts identified upregulation in oxidative phosphorylation, adipogenesis, and fatty acid metabolism signaling in ALDH1Alo patients, suggesting BRAF/MEK inhibitor resistance in that subset of patients. On the other hand, GSEA of ALDH1A3hi cohorts revealed upregulation in glycolysis, hypoxia and angiogenesis, suggesting BRAF/MEK inhibitor sensitivity in that subset of patients. Gene expression analysis using pre-treatment tumor samples supports high ALDH1A3 expression before BRAF/MEK inhibitor treatment as predictive of better treatment response in BRAF-mutant melanoma patients. Our study provides evidence that high ALDH1A3 mRNA expression is not only a prognostic marker but also a predictive marker for BRAF/MEK inhibitor treatment response in BRAF-mutant metastatic melanoma patients.


Assuntos
Aldeído Desidrogenase/genética , Aldeído Oxirredutases/genética , Melanoma/patologia , RNA Mensageiro/metabolismo , Idoso , Aldeído Desidrogenase/metabolismo , Aldeído Desidrogenase 1 , Aldeído Oxirredutases/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/metabolismo , Melanoma/mortalidade , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Retinal Desidrogenase
14.
Nat Commun ; 10(1): 4068, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492851

RESUMO

The aldehyde dehydrogenase (ALDH) family of metabolic enzymes converts aldehydes to carboxylates. Here, we find that the reductive consequence of ALDH7A1 activity, which generates NADH (nicotinamide adenine dinucleotide, reduced form) from NAD, underlies how ALDH7A1 coordinates a broad inhibition of the intracellular transport pathways. Studying vesicle formation by the Coat Protein I (COPI) complex, we elucidate that NADH generated by ALDH7A1 targets Brefeldin-A ADP-Ribosylated Substrate (BARS) to inhibit COPI vesicle fission. Moreover, defining a physiologic role for the broad transport inhibition exerted by ALDH7A1, we find that it acts to reduce energy consumption during hypoxia and starvation to promote cellular energy homeostasis. These findings advance the understanding of intracellular transport by revealing how the coordination of multiple pathways can be achieved, and also defining circumstances when such coordination is needed, as well as uncovering an unexpected way that NADH acts in cellular energetics.


Assuntos
Oxirredutases do Álcool/metabolismo , Aldeído Desidrogenase/metabolismo , Proteínas de Ligação a DNA/metabolismo , Metabolismo Energético , Homeostase , Espaço Intracelular/metabolismo , Oxirredutases do Álcool/genética , Aldeído Desidrogenase/genética , Transporte Biológico , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/metabolismo , Hipóxia Celular , Proteínas de Ligação a DNA/genética , Células HEK293 , Células HeLa , Humanos , NAD/metabolismo , Transdução de Sinais , Inanição
15.
Sex Dev ; 13(3): 125-136, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31416086

RESUMO

Subsequent to somatic gonadal sexual differentiation, germ cells enter meiosis or mitotic arrest in the ovary or testis, respectively. Among mice, these processes occur almost synchronically in fetal gonads and depend, among other factors, on the levels of retinoic acid (RA). In contrast to those in mice, rabbit germ cells enter meiosis or mitotic arrest after birth and coexist with proliferating germ cells. Here, we studied the somatic cell context in which germ cells enter meiosis or mitotic arrest in the rabbit. Using confocal immunofluorescence and real-time PCR, we studied the expression profiles of ALDH1A1 and ALDH1A2 and, comprising 2 genes required for RA synthesis, 2 meiosis markers STRA8 and SYCP3 as well as 2 genes involved in meiosis inhibition, CYP26B1 and NANOS2. We found that although both meiosis and mitotic arrest initiate after birth, these 2 processes are regulated in a way similar to the human fetal gonad. Current results reinforce the value of the neonatal rabbit gonad as an alternative experimental model for analyzing the direct effect of environmental factors during critical stages of germ cell establishment.


Assuntos
Regulação da Expressão Gênica , Gônadas/citologia , Meiose , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Animais , Biomarcadores/metabolismo , Proliferação de Células , Feminino , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Ovário/citologia , Ovário/ultraestrutura , Coelhos , Ácido Retinoico 4 Hidroxilase/genética , Ácido Retinoico 4 Hidroxilase/metabolismo , Testículo/citologia , Testículo/ultraestrutura
16.
Adv Exp Med Biol ; 1193: 89-106, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368099

RESUMO

Heart failure (HF) is a structural or functional cardiac abnormal syndrome characterized with series of symptoms and signs such as breathlessness, fatigue, pulmonary crackles, and peripheral edema. Being a terminal phase of most myocardial lesions, HF has become a leading cause of mobility and mortality worldwide, associated with heavy clinical burden and economic costs affecting over 23 million people [14]. There is an increase to 5.5% with systolic dysfunction and an increase to 36.0% with diastolic dysfunction in people 60 years or older [85]. The costs accompanied with heart failure stand 2-3% of the total healthcare system expenditure in high-income countries and are expected to increase >2-fold in the next 2 decades [34].


Assuntos
Aldeído Desidrogenase/genética , Insuficiência Cardíaca/genética , Custos de Cuidados de Saúde , Insuficiência Cardíaca/economia , Humanos
17.
BMC Vet Res ; 15(1): 224, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266490

RESUMO

BACKGROUND: As a kind of opportunist pathogen, Staphylococcus xylosus (S. xylosus) can cause mastitis. Antibiotics are widely used for treating infected animals and tylosin is a member of such group. Thus, the continuous use of antibiotics in dairy livestock enterprise will go a long way in increasing tylosin resistance. However, the mechanism of tylosin-resistant S. xylosus is not clear. Here, isobaric tag for relative and absolute quantitation (iTRAQ)-based quantitative proteomics methods was used to find resistance-related proteins. RESULTS: We compared the differential expression of S. xylosus in response to tylosin stress by iTRAQ. A total of 155 proteins (59 up-regulated, 96 down-regulated) with the fold-change of >1.2 or <0.8 (p value ≤0.05) were observed between the S. xylosus treated with 1/2 MIC (0.25 µg/mL) tylosin and the untreated S. xylosus. Bioinformatic analysis revealed that these proteins play important roles in stress-response and transcription. Then, in order to verify the relationship between the above changed proteins and mechanism of tylosin-resistant S. xylosus, we induced the tylosin-resistant S. xylosus, and performed quantitative PCR analysis to verify the changes in the transcription proteins and the stress-response proteins in tylosin-resistant S. xylosus at the mRNA level. The data displayed that ribosomal protein L23 (rplw), thioredoxin(trxA) and Aldehyde dehydrogenase A(aldA-1) are up-regulated in the tylosin-resistant S. xylosus, compared with the tylosin-sensitive strains. CONCLUSION: Our findings demonstrate the important of stress-response and transcription in the tylosin resistance of S. xylosus and provide an insight into the prevention of this resistance, which would aid in finding new medicines .


Assuntos
Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Proteoma/análise , Staphylococcus/efeitos dos fármacos , Tilosina/farmacologia , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Antibacterianos/farmacologia , Proteínas de Bactérias/isolamento & purificação , Farmacorresistência Bacteriana/genética , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Proteômica/métodos , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Staphylococcus/genética , Staphylococcus/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
18.
J Biotechnol ; 303: 1-7, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31310781

RESUMO

Phenolic aldehydes from lignocellulose pretreatment harshly inhibit the viability and metabolism of ethanol fermenting strains. Direct conversion of phenolic aldehydes is usually incomplete due to their low water solubility and recalcitrance to bioconversion. Here we consolidated phenolic aldehydes bioconversion and ethanol fermentation in a typical ethanologenic bacterium Zymomonas mobilis by constructing an intracellular oxidative pathway. The gene PP_2680 encoding NAD+-dependent aldehyde dehydrogenase from Pseudomonas putida KT2440 was expressed in Z. mobilis ZM4. The expression significantly improved both aldehyde inhibitor conversion and ethanol fermentability in corn stover hydrolysate. The purified PP_2680 aldehyde dehydrogenase showed strong in vitro oxidative capacity on phenolic aldehydes and its in vivo expression significantly up-regulated the key genes in the ED pathway and the oxidative phosphorylation. This study provided an important concept of simultaneous biodetoxification and fermentation in ethanologenic strains for the improvement of ethanol fermentability.


Assuntos
Aldeído Desidrogenase/metabolismo , Etanol/metabolismo , Zymomonas/crescimento & desenvolvimento , Aldeído Desidrogenase/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Celulose , Fermentação , Regulação Bacteriana da Expressão Gênica , Fosforilação Oxidativa , Pseudomonas putida/enzimologia , Zea mays/química , Zymomonas/enzimologia , Zymomonas/genética
19.
Appl Microbiol Biotechnol ; 103(14): 5917-5923, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31111182

RESUMO

Aliphatic medium-chain alkanes, a major component of gasoline, diesel, and jet fuels, are drop-in compatible fuels. Microorganisms with the capacity to produce medium-chain alkanes are promising for the bio-production of drop-in fuel. We found that Klebsiella sp. NBRC100048 has the ability to produce medium-chain alkanes from medium-chain aldehydes. We cloned a gene involved in conversion of aldehydes to alkanes by using a genomic fosmid library derived from Klebsiella sp. NBRC100048. The gene termed orf2991 encodes 506 amino acids and shows 62% sequence homology to the aldehyde dehydrogenase of Escherichia coli, aldB. The finding of orf2991 as a novel alkane-synthesizing enzyme gene similar to E. coli aldehyde dehydrogenase family, which is generally known to catalyze a reaction oxidizing aldehydes to fatty acids, indicated a novel function of aldehyde dehydrogenase. This finding is not only significant academically but allows developing the novel manufacturing methods of alkanes fermentation.


Assuntos
Alcanos/metabolismo , Proteínas de Bactérias/genética , Klebsiella/genética , Aldeído Desidrogenase/genética , Aldeídos/metabolismo , Proteínas de Bactérias/metabolismo , Biocombustíveis , Clonagem Molecular , Escherichia coli/genética , Biblioteca Genômica , Klebsiella/metabolismo , Engenharia Metabólica , Homologia de Sequência
20.
Chem Biol Interact ; 305: 86-97, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-30928398

RESUMO

Substrate inhibition by the aldehyde has been observed for decades in NAD(P)+-dependent aldehyde dehydrogenase (ALDH) enzymes, which follow a Bi Bi ordered steady-state kinetic mechanism. In this work, by using theoretical simulations of different possible substrate inhibition mechanisms in monosubstrate and Bi Bi ordered steady-state reactions, we explored the kind and extent of errors arising when estimating the kinetic parameters and determining the kinetic mechanisms if substrate inhibition is intentionally or unintentionally ignored. We found that, in every mechanism, fitting the initial velocity data of apparently non-inhibitory substrate concentrations to a rectangular hyperbola produces important errors, not only in the estimation of Vmax values, which were underestimated as expected, but, surprisingly, even more in the estimation of Km values, which led to overestimation of the Vmax/Km values. We show that the greater errors in Km arises from fitting data that do experience substrate inhibition, although it may not be evident, to a Michaelis-Menten equation, which causes overestimation of the data at low substrate concentrations. Similarly, we show that if substrate inhibition is not fully assessed when inhibitors are evaluated, the estimated inhibition constants will have significant errors, and the type of inhibition could be grossly mistaken. We exemplify these errors with experimental results obtained with the betaine aldehyde dehydrogenase from spinach showing the errors predicted by the theoretical simulations and that these errors are increased in the presence of NADH, which in this enzyme favors aldehyde substrate inhibition. Therefore, we strongly recommend assessing substrate inhibition by the aldehyde in every ALDH kinetic study, particularly when inhibitors are evaluated. The common practices of using an apparently non-inhibitory concentration range of the aldehyde or a single high concentration of the aldehyde or the coenzyme when varying the other to determine true kinetic parameters should be abandoned.


Assuntos
Aldeído Desidrogenase/metabolismo , Aldeídos/metabolismo , Proteínas de Plantas/metabolismo , Proteínas Recombinantes/metabolismo , Aldeído Desidrogenase/antagonistas & inibidores , Aldeído Desidrogenase/genética , Aldeídos/química , Cinética , NAD/metabolismo , Proteínas de Plantas/antagonistas & inibidores , Proteínas de Plantas/genética , Proteínas Recombinantes/genética , Spinacia oleracea/enzimologia , Especificidade por Substrato
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