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1.
PLoS One ; 16(8): e0256942, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34464415

RESUMO

Under inadequate chilling conditions, hydrogen cyanamide (HC) is often used to promote budbreak and improve earliness of Southern highbush blueberry (Vaccinium corymbosum L. interspecific hybrids). However, HC is strictly regulated or even banned in some countries because of its high hazardous properties. Development of safer and effective alternatives to HC is critical to sustainable subtropical blueberry production. In this study, we examined the efficacy of HC and defoliants as bud dormancy-breaking agents for 'Emerald' blueberry. First, we compared water control, 1.0% HC (9.35 L ha-1), and three defoliants [potassium thiosulfate (KTS), urea, and zinc sulfate (ZS)] applied at 6.0% (28 kg ha-1). Model fitting analysis revealed that only HC and ZS advanced both defoliation and budbreak compared with the water control. HC-induced budbreak showed an exponential plateau function with a rapid phase occurring from 0 to 22 days after treatment (DAT), whereas ZS-induced budbreak showed a sigmoidal function with a rapid phase occurring from 15 to 44 DAT. The final budbreak percentage was similar in all treatments (71.7%-83.7%). Compared with the water control, HC and ZS increased yield by up to 171% and 41%, respectively, but the yield increase was statistically significant only for HC. Phytohormone profiling was performed for water-, HC- and ZS-treated flower buds. Both chemicals did not increase gibberellin 4 and indole-3-acetic acid production, but they caused a steady increase in jasmonic acid (JA) during budbreak. Compared with ZS, HC increased JA production to a greater extent and was the only chemical that reduced abscisic acid (ABA) concentrations during budbreak. A follow-up experiment tested ZS at six different rates (0-187 kg ha-1) but detected no significant dose-response on budbreak. These results collectively suggest that defoliants are not effective alternatives to HC, and that HC and ZS have different modes of action in budbreak induction. The high efficacy of HC as a dormancy-breaking agent could be due to its ability to reduce ABA concentrations in buds. Our results also suggest that JA accumulation is involved in budbreak induction in blueberry.


Assuntos
Mirtilos Azuis (Planta)/crescimento & desenvolvimento , Cianamida/farmacologia , Desfolhantes Químicos/farmacologia , Flores/crescimento & desenvolvimento , Reguladores de Crescimento de Plantas/fisiologia , Mirtilos Azuis (Planta)/efeitos dos fármacos , Mirtilos Azuis (Planta)/fisiologia , Flores/fisiologia , Frutas/crescimento & desenvolvimento , Dormência de Plantas/efeitos dos fármacos , Dormência de Plantas/fisiologia
2.
Ann Diagn Pathol ; 52: 151740, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33836412

RESUMO

Ground-glass (GG) hepatocytes are classically associated with chronic hepatitis B (HBV) infection, storage disorders, or cyanamide therapy. In a subset of cases, an exact etiology cannot be identified. In this study, we sought to characterize the clinical, histological, and ultrastructural findings associated with HBV-negative GG hepatocytes. Our institutional laboratory information system was searched from 2000 to 2019 for all cases of ground-glass hepatocytes. Ten liver biopsies with GG hepatocellular inclusions and negative HBV serology, no known history of storage disorders, or cyanamide therapy were reviewed. Half of the patients had history of organ transplantation and/or malignancy. These patients took on average 8.1 medications (range: 3-14) with the most common medications being immunosuppressive and health supplements. Histologically, GG hepatocytes show either peri-portal or centrizonal distribution. The inclusions are PAS-positive and diastase sensitive. Electron microscopy showed intracytoplasmic granular inclusions with low electron density, consistent with unstructured glycogen. In summary, GG hepatocytes are a rare finding in liver biopsies, but are more common in patients with hepatitis B. They can also be seen in HBV-negative patients who have polypharmacy. In these cases, they are the result of unstructured glycogen accumulation putatively due to altered cell metabolism.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatócitos/efeitos dos fármacos , Corpos de Inclusão/patologia , Neoplasias Hepáticas/patologia , Adulto , Idoso , Biópsia/métodos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Pré-Escolar , Cianamida/efeitos adversos , Cianamida/uso terapêutico , Citoplasma/metabolismo , Citoplasma/patologia , Citoplasma/ultraestrutura , Suplementos Nutricionais/efeitos adversos , Feminino , Glicogênio/metabolismo , Doença de Depósito de Glicogênio/complicações , Hepatite B Crônica/complicações , Hepatócitos/metabolismo , Hepatócitos/patologia , Hepatócitos/ultraestrutura , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Corpos de Inclusão/metabolismo , Corpos de Inclusão/ultraestrutura , Fígado/patologia , Masculino , Microscopia Eletrônica/métodos , Pessoa de Meia-Idade , Polimedicação
3.
Environ Sci Pollut Res Int ; 28(31): 42161-42176, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33797718

RESUMO

Dormex is widely used as a plant growth regulator in developing countries such as Egypt as well as worldwide. Despite the widespread use of Dormex, little is known about the exact mechanism of action and toxic profile. The current study aims to outline the factors that predict in-hospital outcome and the need for intensive care unit (ICU) admission among the patients who presented with acute hydrogen cyanamide exposure as well as to evaluate the roles of the Multiple Organ Dysfunction Score (MODS) and the Sequential Organ Failure Assessment (SOFA) score as unfavorable outcome predictors. This is a retrospective cross-sectional study including all cases diagnosed with acute hydrogen cyanamide exposure who presented to the Tanta Poison Control Center during the past 6 years (January 1, 2015-January 1, 2020). Patient data were collected in a case report form, including the history of exposure, clinical data, laboratory investigations, and radiologic studies. Four scoring systems were carried out upon presentation: the Glasgow Coma Scale, poison severity score, MODS, and SOFA score. Thirty-five patients were enrolled in the current study. Most of the presented cases were males exposed unintentionally in an occupational setting. The mean participant age was 34.1 ± 15.51 years. The most common presenting complaints were throat irritation in all cases, vomiting and hallucinations presented equally in 68.6%, and headache occurred in 51.4%, whereas skin and mucous membrane burn was present in 40% of cases. Patients showing one or more of the following criteria were expected to have an urgent need for ICU admission: MODS >3.5, SOFA >4.5, length of hospital stay >30 hours, prothrombin time >14.75 seconds, serum glutamic pyruvic transaminase >67.5 U/L, and serum glutamic oxaloacetic transaminase >58.5 U/L. When the length of hospital stay was combined with the four scoring systems, only MODS yielded a significant prediction. Study results indicate that MODS and SOFA scores are considered excellent outcome predictors; MODS is more accurate, specific, and treatment independent, whereas the use of the SOFA score is more feasible with simple cardiovascular function assessment.


Assuntos
Cianamida , Escores de Disfunção Orgânica , Adolescente , Adulto , Estudos Transversais , Hospitais , Humanos , Hidrogênio , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos , Estudos Retrospectivos , Adulto Jovem
4.
J Org Chem ; 86(4): 3546-3554, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33538590

RESUMO

The convenient preparation of N2-unprotected five-membered cyclic guanidines was achieved through a cascade [3 + 2] cycloaddition between organo-cyanamides and α-haloamides under mild conditions in good to excellent yields (up to 99%). The corresponding cyclic guanidines could be easily transformed into hydantoins via hydrolysis.


Assuntos
Cianamida , Guanidinas , Reação de Cicloadição , Guanidina , Hidrólise
5.
Plant J ; 104(5): 1251-1268, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32989852

RESUMO

Ethylene signaling appears critical for grape bud dormancy release. We therefore focused on identification and characterization of potential downstream targets and events, assuming that they participate in the regulation of dormancy release. Because ethylene responding factors (ERF) are natural candidates for targets of ethylene signaling, we initially characterized the behavior of two VvERF-VIIs, which we identified within a gene set induced by dormancy release stimuli. As expected, these VvERF-VIIs are localized within the nucleus, and are stabilized upon decreases in oxygen availability within the dormant buds. Less expected, the proteins are also stabilized upon hydrogen cyanamide (HC) application under normoxic conditions, and their levels peak at deepest dormancy under vineyard conditions. We proceeded to catalog the response of all bud-expressed ERFs, and identified additional ERFs that respond similarly to ethylene, HC, azide and hypoxia. We also identified a core set of genes that are similarly affected by treatment with ethylene and with various dormancy release stimuli. Interestingly, the functional annotations of this core set center around response to energy crisis and renewal of energy resources via autophagy-mediated catabolism. Because ERF-VIIs are stabilized under energy shortage and reshape cell metabolism to allow energy regeneration, we propose that: (i) the availability of VvERF-VIIs is a consequence of an energy crisis within the bud; (ii) VvERF-VIIs function as part of an energy-regenerating mechanism, which activates anaerobic metabolism and autophagy-mediated macromolecule catabolism; and (iii) activation of catabolism serves as the mandatory switch and the driving force for activation of the growth-inhibited meristem during bud-break.


Assuntos
Etilenos/metabolismo , Dormência de Plantas/fisiologia , Proteínas de Plantas/genética , Vitis/fisiologia , Cianamida/farmacologia , Etilenos/farmacologia , Regulação da Expressão Gênica de Plantas , Hipóxia/metabolismo , Dormência de Plantas/efeitos dos fármacos , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Estabilidade Proteica , Estações do Ano , Transdução de Sinais , Azida Sódica/farmacologia , Tabaco/genética , Vitis/efeitos dos fármacos
6.
J Enzyme Inhib Med Chem ; 35(1): 1736-1742, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32928007

RESUMO

Gut microbial ß-glucuronidases have the ability to deconjugate glucuronides of some drugs, thus have been considered as an important drug target to alleviate the drug metabolites-induced gastrointestinal toxicity. In this study, thiazolidin-2-cyanamide derivatives containing 5-phenyl-2-furan moiety (1-13) were evaluated for inhibitory activity against Escherichia coli ß-glucuronidase (EcGUS). All of them showed more potent inhibition than a commonly used positive control, d-saccharic acid 1,4-lactone, with the IC50 values ranging from 1.2 µM to 23.1 µM. Inhibition kinetics studies indicated that compound 1-3 were competitive type inhibitors for EcGUS. Molecular docking studies were performed and predicted the potential molecular determinants for their potent inhibitory effects towards EcGUS. Structure-inhibitory activity relationship study revealed that chloro substitution on the phenyl moiety was essential for EcGUS inhibition, which would help researchers to design and develop more effective thiazolidin-2-cyanamide type inhibitors against EcGUS.


Assuntos
Cianamida/farmacologia , Escherichia coli/enzimologia , Glucuronidase/antagonistas & inibidores , Glicoproteínas/farmacologia , Tiazolidinas/farmacologia , Cianamida/química , Relação Dose-Resposta a Droga , Glucuronidase/metabolismo , Glicoproteínas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiazolidinas/química
7.
Proc Natl Acad Sci U S A ; 117(24): 13267-13274, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32487725

RESUMO

Continuous reaction networks, which do not rely on purification or timely additions of reagents, serve as models for chemical evolution and have been demonstrated for compounds thought to have played important roles for the origins of life such as amino acids, hydroxy acids, and sugars. Step-by-step chemical protocols for ribonucleotide synthesis are known, but demonstrating their synthesis in the context of continuous reaction networks remains a major challenge. Herein, compounds proposed to be important for prebiotic RNA synthesis, including glycolaldehyde, cyanamide, 2-aminooxazole, and 2-aminoimidazole, are generated from a continuous reaction network, starting from an aqueous mixture of NaCl, NH4Cl, phosphate, and HCN as the only carbon source. No well-timed addition of any other reagents is required. The reaction network is driven by a combination of γ radiolysis and dry-down. γ Radiolysis results in a complex mixture of organics, including the glycolaldehyde-derived glyceronitrile and cyanamide. This mixture is then dried down, generating free glycolaldehyde that then reacts with cyanamide/NH3 to furnish a combination of 2-aminooxazole and 2-aminoimidazole. This continuous reaction network models how precursors for generating RNA and other classes of compounds may arise spontaneously from a complex mixture that originates from simple reagents.


Assuntos
Evolução Química , Modelos Químicos , RNA/química , RNA/síntese química , Acetaldeído/análogos & derivados , Acetaldeído/síntese química , Acetaldeído/química , Cianamida/síntese química , Cianamida/química , Raios gama , Imidazóis/síntese química , Imidazóis/química , Origem da Vida , Oxazóis/síntese química , Oxazóis/química , Fotoquímica , Água/química
8.
J Chem Phys ; 152(7): 074201, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32087671

RESUMO

Cyanamides (NCN) have been shown to have a larger transition dipole strength than cyano-probes. In addition, they have similar structural characteristics and vibrational lifetimes to the azido-group, suggesting their utility as infrared (IR) spectroscopic reporters for structural dynamics in biomolecules. To access the efficacy of NCN as an IR probe to capture the changes in the local environment, several model systems were evaluated via 2D IR spectroscopy. Previous work by Cho [G. Lee, D. Kossowska, J. Lim, S. Kim, H. Han, K. Kwak, and M. Cho, J. Phys. Chem. B 122(14), 4035-4044 (2018)] showed that phenylalanine analogues containing NCN show strong anharmonic coupling that can complicate the interpretation of structural dynamics. However, when NCN is embedded in 5-membered ring scaffolds, as in N-cyanomaleimide and N-cyanosuccinimide, a unique band structure is observed in the 2D IR spectrum that is not predicted by simple anharmonic frequency calculations. Further investigation indicated that electron delocalization plays a role in the origins of the band structure. In particular, the origin of the lower frequency transitions is likely a result of direct interaction with the solvent.


Assuntos
Cianamida/química , Simulação de Dinâmica Molecular , Teoria da Densidade Funcional , Estrutura Molecular , Espectrofotometria Infravermelho
10.
Alcohol Clin Exp Res ; 44(1): 45-55, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31693194

RESUMO

BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2) protects against alcohol-evoked cardiac dysfunction in male rodents, but its role in the estrogen (E2 )-dependent hypersensitivity of female rats to alcohol-evoked myocardial oxidative stress and dysfunction is not known. METHODS: We addressed this question by studying the effect of cyanamide (ALDH2 inhibitor) on cardiac function, blood pressure, alcohol-metabolizing enzyme (alcohol dehydrogenase, cytochrome P450 2E1, catalase, and ALDH2) activities, and cardiac redox status (reactive oxygen species, ROS; malondialdehyde, MDA) in the absence or presence of ethanol (EtOH) in female sham-operated (SO) and ovariectomized (OVX) rats. RESULTS: Cyanamide attenuated the EtOH-evoked myocardial dysfunction (reduced dP/dtmax and LVDP) in SO rats. EtOH, cyanamide, or their combination did not alter dP/dtmax or LVDP in OVX rats. Cyanamide induced cardiac oxidative stress and abrogated the subsequent alcohol-evoked increases in ROS and MDA levels in SO rats. Neither EtOH nor cyanamide influenced ROS or MDA levels in OVX rats. Importantly, cyanamide exaggerated EtOH-evoked hypotension in SO and uncovered this hypotensive response in OVX rats, which implicates ALDH2 in the vasodilating effect of EtOH. CONCLUSIONS: Contrary to our hypothesis, cyanamide attenuated the E2 -dependent cardiac dysfunction caused by alcohol, likely by preconditioning the heart to oxidative stress, while exacerbating the vasodilating effect of alcohol. The latter might predispose to syncope when cyanamide and alcohol are combined in females.


Assuntos
Aldeído-Desidrogenase Mitocondrial/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Etanol/toxicidade , Cardiopatias/induzido quimicamente , Cardiopatias/tratamento farmacológico , Hipotensão/induzido quimicamente , Aldeído-Desidrogenase Mitocondrial/metabolismo , Animais , Cianamida/farmacologia , Cianamida/uso terapêutico , Inibidores Enzimáticos/farmacologia , Etanol/administração & dosagem , Feminino , Cardiopatias/enzimologia , Hipotensão/metabolismo , Ovariectomia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
11.
Carcinogenesis ; 41(2): 194-202, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-31074772

RESUMO

Alcohol consumption is the key risk factor for the development of esophageal squamous cell carcinoma (ESCC), and acetaldehyde, a metabolite of alcohol, is an alcohol-derived major carcinogen that causes DNA damage. Aldehyde dehydrogenase2 (ALDH2) is an enzyme that detoxifies acetaldehyde, and its activity is reduced by ALDH2 gene polymorphism. Reduction in ALDH2 activity increases blood, salivary and breath acetaldehyde levels after alcohol intake, and it is deeply associated with the development of ESCC. Heavy alcohol consumption in individuals with ALDH2 gene polymorphism significantly elevates the risk of ESCC; however, effective prevention has not been established yet. In this study, we investigated the protective effects of Alda-1, a small molecule ALDH2 activator, on alcohol-mediated esophageal DNA damage. Here, we generated novel genetically engineered knock-in mice that express the human ALDH2*1 (wild-type allele) or ALDH2*2 gene (mutant allele). Those mice were crossed, and human ALDH2*1/*1, ALDH2*1/*2 and ALDH2*2/*2 knock-in mice were established. They were given 10% ethanol for 7 days in the presence or absence of Alda-1, and we measured the levels of esophageal DNA damage, represented by DNA adduct (N2-ethylidene-2'-deoxyguanosine). Alda-1 significantly increased hepatic ALDH2 activity both in human ALDH2*1/*2 and/or ALDH2*2/*2 knock-in mice and reduced esophageal DNA damage levels after alcohol drinking. Conversely, cyanamide, an ALDH2-inhibitor, significantly exacerbated esophageal DNA adduct level in C57BL/6N mice induced by alcohol drinking. These results indicate the protective effects of ALDH2 activation by Alda-1 on esophageal DNA damage levels in individuals with ALDH2 gene polymorphism, providing a new insight into acetaldehyde-mediated esophageal carcinogenesis and prevention.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Aldeído-Desidrogenase Mitocondrial/metabolismo , Benzamidas/administração & dosagem , Benzodioxóis/administração & dosagem , Carcinogênese/efeitos dos fármacos , Neoplasias Esofágicas/prevenção & controle , Carcinoma de Células Escamosas do Esôfago/prevenção & controle , Acetaldeído/metabolismo , Acetaldeído/toxicidade , Aldeído-Desidrogenase Mitocondrial/antagonistas & inibidores , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Carcinogênese/induzido quimicamente , Carcinogênese/genética , Cianamida/administração & dosagem , Adutos de DNA/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Mucosa Esofágica/efeitos dos fármacos , Mucosa Esofágica/patologia , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/etiologia , Carcinoma de Células Escamosas do Esôfago/patologia , Etanol/metabolismo , Etanol/toxicidade , Técnicas de Introdução de Genes , Humanos , Masculino , Camundongos Transgênicos , Mutação , Neoplasias Experimentais/etiologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/prevenção & controle , Polimorfismo Genético , Fatores de Risco
13.
Bioorg Med Chem ; 28(1): 115195, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31761726

RESUMO

N-acylethanolamine acid amidase (NAAA) inhibition represents an exciting novel approach to treat inflammation and pain. NAAA is a cysteine amidase which preferentially hydrolyzes the endogenous biolipids palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). PEA is an endogenous agonist of the nuclear peroxisome proliferator-activated receptor-α (PPAR-α), which is a key regulator of inflammation and pain. Thus, blocking the degradation of PEA with NAAA inhibitors results in augmentation of the PEA/PPAR-α signaling pathway and regulation of inflammatory and pain processes. We have prepared a new series of NAAA inhibitors exploring the azetidine-nitrile (cyanamide) pharmacophore that led to the discovery of highly potent and selective compounds. Key analogs demonstrated single-digit nanomolar potency for hNAAA and showed >100-fold selectivity against serine hydrolases FAAH, MGL and ABHD6, and cysteine protease cathepsin K. Additionally, we have identified potent and selective dual NAAA-FAAH inhibitors to investigate a potential synergism between two distinct anti-inflammatory molecular pathways, the PEA/PPAR-α anti-inflammatory signaling pathway,1-4 and the cannabinoid receptors CB1 and CB2 pathways which are known for their antiinflammatory and antinociceptive properties.5-8 Our ligand design strategy followed a traditional structure-activity relationship (SAR) approach and was supported by molecular modeling studies of reported X-ray structures of hNAAA. Several inhibitors were evaluated in stability assays and demonstrated very good plasma stability (t1/2 > 2 h; human and rodents). The disclosed cyanamides represent promising new pharmacological tools to investigate the potential role of NAAA inhibitors and dual NAAA-FAAH inhibitors as therapeutic agents for the treatment of inflammation and pain.


Assuntos
Amidoidrolases/antagonistas & inibidores , Cianamida/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Amidoidrolases/metabolismo , Animais , Cianamida/síntese química , Cianamida/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
14.
Neurotoxicology ; 75: 174-185, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31550440

RESUMO

Developmentally-lead (Pb)-exposed rats showed an enhanced vulnerability to the stimulating and motivational effects of ethanol (EtOH). This is accompanied by differential activity of the brain EtOH-metabolizing enzymes catalase (CAT) and mitochondrial aldehyde dehydrogenase (ALDH2). Based on the theory that brain acetaldehyde accumulation is associated with the reinforcing properties of EtOH, this study sought to determine brain CAT and ALDH2 expression in limbic areas of control and Pb-exposed animals after voluntary EtOH intake. Thirty-five-day-old rats perinatally exposed to 220 ppm Pb were offered with water or increasing EtOH solutions (2-10% v/v) during 28 days until postnatal day (PND) 63. Once intake was stable, the animals were administered: 1) saline (SAL; test days 21-24 or 21-28, as corresponds), or 2) a CAT inhibitor: 3-amine 1, 2, 4-triazole (AT; 250 mg/kg intraperitoneally [i.p.], 5 h before the last eight EtOH intake sessions -test days 21-24 and 25-28), or 3) a CAT booster: 3-nitropropionic acid (3NPA; 20 mg/kg subcutaneously [s.c.], 45 min before the last four EtOH intake sessions -test days 25-28). Two additional groups were centrally-administered cyanamide (CY, an ALDH2 inhibitor, 0.3 mg i.c.v. immediately before the last four EtOH sessions, test days 25-28) or its corresponding vehicle (VEH). Lead exposure increased EtOH intake, an effect potentiated in both groups by 3NPA or CY pretreatments and reduced by AT, albeit selectivity in the Pb group. Catalase abundance in limbic areas parallels these observations in the Pb group, showing higher CAT expression in all areas after EtOH consumption respect to the controls, an effect prevented by AT administration. In contrast, ALDH2 expression was reduced in the Pb animals after EtOH intake, with CY potentiating this effect in all brain areas under study. Based on these results and on previous evidences, we suggest that Pb exposure promotes acetaldehyde accumulation in limbic regions, providing some insights into the mechanism of action that underlies the vulnerability to the excessive EtOH consumption reported in these animals.


Assuntos
Encéfalo/efeitos dos fármacos , Etanol/farmacologia , Intoxicação do Sistema Nervoso por Chumbo/metabolismo , Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Aldeído-Desidrogenase Mitocondrial/antagonistas & inibidores , Aldeído-Desidrogenase Mitocondrial/metabolismo , Animais , Encéfalo/enzimologia , Encéfalo/metabolismo , Catalase/metabolismo , Cianamida/farmacologia , Feminino , Masculino , Nitrocompostos/farmacologia , Propionatos/farmacologia , Ratos , Ratos Wistar
15.
Angew Chem Int Ed Engl ; 58(37): 13087-13092, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31276284

RESUMO

Organisms use enzymes to ensure a flow of substrates through biosynthetic pathways. How the earliest form of life established biosynthetic networks and prevented hydrolysis of intermediates without enzymes is unclear. Organocatalysts may have played the role of enzymes. Quantitative analysis of reactions of adenosine 5'-monophosphate and glycine that produce peptides, pyrophosphates, and RNA chains reveals that organocapture by heterocycles gives hydrolytically stabilized intermediates with balanced reactivity. We determined rate constants for 20 reactions in aqueous solutions containing a carbodiimide and measured product formation with cyanamide as a condensing agent. Organocapture favors reactions that are kinetically slow but productive, and networks, over single transformations. Heterocycles can increase the metabolic efficiency more than two-fold, with up to 0.6 useful bonds per fuel molecule spent, boosting the efficiency of life-like reaction systems in the absence of enzymes.


Assuntos
Aminoácidos/química , Carbodi-Imidas/química , Compostos Heterocíclicos/química , Nucleotídeos/química , Água/química , Monofosfato de Adenosina/química , Trifosfato de Adenosina/química , Catálise , Cianamida/química , Cinética
16.
Chem Commun (Camb) ; 55(54): 7796-7799, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31214673

RESUMO

Disclosed herein is a novel, metal-free synthesis of γ-lactams through the radical-mediated nitration-aminocarbonylation of unactivated olefins. The reaction is initiated by a nitro radical generated from the homolysis of tert-butyl nitrite. The intramolecular cyanamide serves as the aminocarbonylating reagent. This protocol offers an environment-benign method to produce the synthetically valuable nitromethyl substituted γ-lactams.


Assuntos
Alcenos/química , Lactamas/síntese química , Cianamida/química , Ciclização , Radicais Livres/química , Química Verde/métodos , Modelos Químicos , Nitritos/química , Estereoisomerismo
17.
J Biol Chem ; 294(27): 10674-10685, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31152065

RESUMO

Cyanamide (H2N-CN) is used to break bud dormancy in woody plants and to deter alcohol use in humans. The biological effects of cyanamide in both these cases require the enzyme catalase. We previously demonstrated that Saccharomyces cerevisiae exposed to cyanamide resulted in strong induction of DDI2 gene expression. Ddi2 enzymatically hydrates cyanamide to urea and belongs to the family of HD-domain metalloenzymes (named after conserved active-site metal-binding His and Asp residues). Here, we report the X-ray structure of yeast Ddi2 to 2.6 Å resolution, revealing that Ddi2 is a dimeric zinc metalloenzyme. We also confirm that Ddi2 shares structural similarity with other known HD-domain proteins. HD residues His-55, His-88, and Asp-89 coordinate the active-site zinc, and the fourth zinc ligand is a water/hydroxide molecule. Other HD domain enzymes have a second aspartate metal ligand, but in Ddi2 this residue (Thr-157) does not interact with the zinc ion. Several Ddi2 active-site point mutations exhibited reduced catalytic activity. We kinetically and structurally characterized H137N and T157V mutants of Ddi2. A cyanamide soak of the Ddi2-T157V enzyme revealed cyanamide bound directly to the Zn2+ ion, having displaced the zinc-bound water molecule. The mode of cyanamide binding to Ddi2 resembles cyanamide binding to the active-site zinc of carbonic anhydrase, a known cyanamide hydratase. Finally, we observed that the sensitivity of ddi2Δ ddi3Δ to cyanamide was not rescued by plasmids harboring ddi2-H137N or ddi2-TI57V variants, demonstrating that yeast cells require a functioning cyanamide hydratase to overcome cyanamide-induced growth defects.


Assuntos
Hidroliases/química , Proteínas de Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Domínio Catalítico , Cianamida/química , Cianamida/metabolismo , Dimerização , Hidroliases/genética , Hidroliases/metabolismo , Inativação Metabólica , Cinética , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Alinhamento de Sequência , Especificidade por Substrato , Zinco/química , Zinco/metabolismo
18.
Sci Rep ; 9(1): 9281, 2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31243303

RESUMO

The ability to store information is believed to have been crucial for the origin and evolution of life; however, little is known about the genetic polymers relevant to abiogenesis. Nitrogen heterocycles (N-heterocycles) are plausible components of such polymers as they may have been readily available on early Earth and are the means by which the extant genetic macromolecules RNA and DNA store information. Here, we report the reactivity of numerous N-heterocycles in highly complex mixtures, which were generated using a Miller-Urey spark discharge apparatus with either a reducing or neutral atmosphere, to investigate how N-heterocycles are modified under plausible prebiotic conditions. High throughput mass spectrometry was used to identify N-heterocycle adducts. Additionally, tandem mass spectrometry and nuclear magnetic resonance spectroscopy were used to elucidate reaction pathways for select reactions. Remarkably, we found that the majority of N-heterocycles, including the canonical nucleobases, gain short carbonyl side chains in our complex mixtures via a Strecker-like synthesis or Michael addition. These types of N-heterocycle adducts are subunits of the proposed RNA precursor, peptide nucleic acids (PNAs). The ease with which these carbonylated heterocycles form under both reducing and neutral atmospheres is suggestive that PNAs could be prebiotically feasible on early Earth.


Assuntos
Compostos Heterocíclicos/química , Nitrogênio/química , Precursores de Ácido Nucleico/química , Ácidos Nucleicos Peptídicos/química , Acetonitrilas/química , Catálise , Cianamida/química , DNA/química , Planeta Terra , Evolução Química , Substâncias Macromoleculares/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Origem da Vida , Polímeros/química , RNA/química
19.
BMC Genomics ; 20(1): 1034, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31888462

RESUMO

BACKGROUND: Grape buds exhibit non-uniform, or delayed, break in early spring in subtropical regions because the accumulation of chilling is insufficient. Hydrogen cyanamide (H2CN2, HC) can partially replace chilling to effectively promote bud sprouting and is used widely in warm winter areas. However, the exact underlying mechanism of grape bud release from endodormancy induced by HC remains elusive. RESULTS: In this study, the transcriptome of grape winter buds under in vitro conditions following HC and water treatment (control) was analyzed using RNA-seq technology. A total of 6772 differentially expressed genes (DEGs) were identified. Furthermore, the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that starch and sucrose metabolism and plant hormone signaling transduction were most enriched out of the 50 total pathways. HC treatment induced the upregulated expression of sucrose synthase (SUS), sucrose phosphate synthase (SPS), α-amylase (AM), and ß-amylase (BM) and downregulated expression of sucrose invertase (INV), hexokinase (HK), fructokinase (FK), soluble starch synthase (SS), and granule-bound starch synthase (GBSS). Hence, the starch concentration in the HC-treated group was significantly lower than that in control, whereas soluble sugar content in the HC-treated group increased quickly and was higher than that in control between 0 and 8 d. The concentration of indoleacetic acid (IAA) and zeatin (ZT) increased, whereas that of abscisic acid (ABA) and gibberellin (GA) decreased in HC treated group, which coincided with the expression level of genes involved in above hormone signals. The content of hydrogen peroxide (H2O2) and enzyme activity of superoxide dismutase (SOD) and peroxidase (POD) were increased in grape buds with HC treatment, whereas catalase (CAT) activity was decreased. HC treatment increased the expression of POD, SOD, primary amine oxidase (PAO), polyamine oxidase (PAOX), and glutathione peroxidase (GSH-Px). CONCLUSION: Based on these results, it is possible to propose a mechanistic model that underlies the regulation of endodormancy release in grapevine buds by exogenous HC application.


Assuntos
Metabolismo dos Carboidratos , Cianamida/metabolismo , Hidrogênio/metabolismo , Dormência de Plantas , Reguladores de Crescimento de Plantas/metabolismo , Vitis/fisiologia , Ácido Abscísico/metabolismo , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Ontologia Genética , Redes e Vias Metabólicas , Proteínas de Plantas/metabolismo , Transdução de Sinais , Amido/metabolismo , Açúcares/metabolismo , Transcriptoma
20.
Nat Commun ; 9(1): 5173, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30538230

RESUMO

The plausibility of any model in science comes from the extent of its interconnections to other models that are grounded in different premises and reasoning. Focusing research on paradoxes in those models, logic whereby they appear to generate unacceptable conclusions from seemingly indisputable premises, helps find those interconnections.


Assuntos
Planeta Terra , Evolução Química , Modelos Químicos , Origem da Vida , Acetileno/análogos & derivados , Acetileno/química , Amônia/química , Cianamida/química , Cianeto de Hidrogênio/química , Metano/química , Nitrilas/química , RNA/síntese química , RNA/química , Água/química
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