Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.382
Filtrar
1.
Medicine (Baltimore) ; 100(34): e27019, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449475

RESUMO

ABSTRACT: Early and accurate identification of various conditions that can cause parkinsonian symptoms is important for determining treatment policies. Currently dopamine transporter (DAT) imaging using FP-CIT, glucose metabolism imaging using fluorodeoxyglucose, cerebral blood flow image using ethyl cysteinate dimer (ECD), and others are used for differentiation. However, the use of multiple modalities is inconvenient and costly. In the present retrospective study, we evaluated the correlation between regional brain uptake ratios (URs) in perfusion FP-CIT PET and ECD SPECT images.Twenty patients with Parkinson's symptoms underwent perfusion DAT positron emission tomography (18F-FP-CIT PET/CT) and cerebral blood flow tomography (99mTc-ECD SPECT) within a 2-week period. Perfusion 18F-FP-CIT PET/CT and 99mTc-ECD SPECT URs of 19 brain regions (bilateral frontal, temporal, parietal and occipital lobes, bilateral caudate nucleus, bilateral putamen, bilateral insula, bilateral cingulate gyrus, bilateral thalamus, and brainstem) were directly compared and correlations were analyzed.Average 18F-FP-CIT PET/CT regional perfusion URs were higher than 99mTc-ECD SPECT URs. Uptake ratios were well correlated in all 19 regions (except right putamen), and especially in dopamine poor regions (cerebral cortex). In left putamen, URs were significantly correlated, but the correlation coefficient was lower than those of other regions.A single tracer dual phase N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane test seems to be helpful for differential diagnosis of parkinsonian disorders. Large-scale, longitudinal studies on complementary diseases with parkinsonian patterns are required to investigate differences in correlations between perfusion 18F-FP-CIT PET/CT and 99mTc-ECD SPECT over time.


Assuntos
Encéfalo/diagnóstico por imagem , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Idoso , Encéfalo/patologia , Cisteína/análogos & derivados , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Radioisótopos de Flúor , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Organotecnécio , Transtornos Parkinsonianos/diagnóstico , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Tropanos
2.
ACS Appl Mater Interfaces ; 13(24): 28424-28432, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34121386

RESUMO

Circumventing the impact of agrochemicals on aquatic environments has become a necessity for health and ecological reasons. Herein, we report the use of a family of five eco-friendly water-stable isoreticular metal-organic frameworks (MOFs), prepared from amino acids, as adsorbents for the removal of neonicotinoid insecticides (thiamethoxam, clothianidin, imidacloprid, acetamiprid, and thiacloprid) from water. Among them, the three MOFs containing thioether-based residues show remarkable removal efficiency. In particular, the novel multivariate MOF {SrIICuII6[(S,S)-methox]1.5[(S,S)-Mecysmox]1.50(OH)2(H2O)}·36H2O (5), featuring narrow functional channels decorated with both -CH2SCH3 and -CH2CH2SCH3 thioalkyl chains-from l-methionine and l-methylcysteine amino acid-derived ligands, respectively-stands out and exhibits the higher removal efficiency, being capable to capture 100% of acetamiprid and thiacloprid in a single capture step under dynamic solid-phase extraction conditions-less than 30 s. Such unusual combination of outstanding efficiency, high stability in environmental conditions, and low-cost straightforward synthesis in 5 places this material among the most attractive adsorbents reported for the removal of this type of contaminants.


Assuntos
Inseticidas/isolamento & purificação , Estruturas Metalorgânicas/química , Neonicotinoides/isolamento & purificação , Sulfetos/química , Poluentes Químicos da Água/isolamento & purificação , Adsorção , Cisteína/análogos & derivados , Cisteína/química , Inseticidas/química , Metionina/química , Neonicotinoides/química , Extração em Fase Sólida/métodos , Poluentes Químicos da Água/química , Purificação da Água/métodos
3.
Inorg Chem ; 60(13): 9880-9898, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34130457

RESUMO

In the search for potential new metal-based antitumor agents, two series of nonclassical palladium(II) pincer complexes based on functionalized amides with S-modified cysteine and homocysteine residues have been prepared and fully characterized by 1D and 2D NMR (1H, 13C, COSY, HMQC or HSQC, 1H-13C, and 1H-15N HMBC) and IR spectroscopy and, in some cases, X-ray diffraction. Most of the resulting complexes exhibit a high level of cytotoxic activity against several human cancer cell lines, including colon (HCT116), breast (MCF7), and prostate (PC3) cancers. Some of the compounds under consideration are also efficient in both native and doxorubicin-resistant transformed breast cells HBL100, suggesting the prospects for the creation of therapeutic agents based on the related compounds that would be able to overcome drug resistance. An analysis of different aspects of their biological effects on living cells has revealed a remarkable ability of the S-modified derivatives to induce cell apoptosis and efficient cellular uptake of their fluorescein-conjugated counterpart, confirming the high anticancer potential of Pd(II) pincer complexes derived from functionalized amides with S-donor amino acid pendant arms.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Cisteína/farmacologia , Paládio/farmacologia , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cisteína/análogos & derivados , Cisteína/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Paládio/química
4.
Phys Chem Chem Phys ; 23(24): 13512-13525, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34124727

RESUMO

Cysteine and N-acetylated cysteine derivatives are ubiquitous in biological systems; they have thiol groups that bind NO to form S-nitrosothiols (RSNOs) such as S-nitrosocysteine (CySNO), S-nitroso-N-acetylcysteine (NacSNO), and S-nitroso-N-acetylpenicillamine (NapSNO). Although they have been utilised as thermally or catalytically decomposing NO donors, their photochemical applications are yet to be fully explored owing to the lack of photodissociation dynamics. To this end, the photoexcitation dynamics of these RSNOs in water at 330 nm were investigated using femtosecond time-resolved infrared (TRIR) spectroscopy over a broad time range encompassing the entire reaction, which includes the primary reaction, secondary reactions of the reaction intermediates, and product formation. We discovered that the acetate and amide groups in these RSNOs have strong vibrational bands sensitive to the bondage of NO and the electronic state of the compound, which facilitates the identification of reaction intermediates involved in photoexcitation. The simplest thiol available with the acetate group-thioglycolic acid-was nitrosylated; it produced S-nitrosothioglycolic acid (TgSNO) and was comparatively investigated. Transient absorption bands in the TRIR spectra of the RSNOs were assigned using quantum chemical calculations. Photoexcited cysteine-related RSNOs either decompose into RS and NO within 0.3 ps after excitation at 330 nm with a primary quantum yield (Φ1) of 0.46-1 or relax into an electronically excited intermediate state lying at 42 ± 3 kcal mol-1 above the ground state, which relaxes into the ground state with a time constant of 460-520 ps. A majority (62-80%) of the RS radical geminately rebinds with NO at a time constant of 3-7 ps. The remaining RS reacts with the neighbouring RSNO, which produces additional NO and RSSR with a (nearly) diffusion-limited rate constant that doubles the amount of NO produced; further, it remarkably extends the time window for the dissociated NO to react with the target compound. The final fraction of NO produced from these RSNOs at 330 nm was 0.32-0.58, and it depends on the geminate rebinding yield and Φ1. The detailed dynamics of the photoexcited RSNO can be utilised in the quantitative application of these RSNOs in practical use and in the synthesis of more efficient photoactivated NO precursors.


Assuntos
Cisteína/química , Teoria da Densidade Funcional , Óxido Nítrico/química , Água/química , Cisteína/análogos & derivados , Estrutura Molecular
5.
Molecules ; 26(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34071846

RESUMO

This study was conducted to determine the potential interaction of aged garlic extract (AGE) with carvedilol (CAR), as well as to investigate the role of S-allyl-l-cysteine (SAC), an active constituent of AGE, in rats with isoproterenol (ISO)-induced myocardial dysfunction. At the end of three weeks of treatment with AGE (2 and 5 mL/kg) or SAC (13.1 and 32.76 mg/kg), either alone or along with CAR (10 mg/kg) in the respective groups of animals, ISO was administered subcutaneously to induce myocardial damage. Myocardial infarction (MI) diagnostic predictor enzymes, lactate dehydrogenase (LDH) and creatinine kinase (CK-MB), were measured in both serum and heart tissue homogenates (HTH). Superoxide dismutase (SOD), catalase, and thiobarbituric acid reactive species (TBARS) were estimated in HTH. When compared with other groups, the combined therapy of high doses of AGE and SAC given alone or together with CAR caused a significant decrease in serum LDH and CK-MB activities. Further, significant rise in the LDH and CK-MB activities in HTH was noticed in the combined groups of AGE and SAC with CAR. It was also observed that both doses of AGE and SAC significantly increased endogenous antioxidants in HTH. Furthermore, histopathological observations corroborated the biochemical findings. The cytoprotective potential of SAC and AGE were dose-dependent, and SAC was more potent than AGE. The protection offered by aged garlic may be attributed to SAC. Overall, the results indicated that a high dose of AGE and its constituent SAC, when combined with carvedilol, has a synergistic effect in preventing morphological and physiological changes in the myocardium during ISO-induced myocardial damage.


Assuntos
Carvedilol/administração & dosagem , Cisteína/análogos & derivados , Alho/metabolismo , Coração/efeitos dos fármacos , Miocárdio/patologia , Extratos Vegetais/farmacologia , Animais , Antioxidantes/química , Catalase/metabolismo , Creatina Quinase Forma MB/metabolismo , Cisteína/administração & dosagem , Feminino , Hemodinâmica , Isoproterenol/química , L-Lactato Desidrogenase/metabolismo , Necrose , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico
6.
J Chem Theory Comput ; 17(6): 3554-3570, 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34009984

RESUMO

Nonstandard amino acids are both abundant in nature, where they play a key role in various cellular processes, and can be synthesized in laboratories, for example, for the manufacture of a range of pharmaceutical agents. In this work, we have extended the additive all-atom CHARMM36 and CHARMM General force field (CGenFF) to a large set of 333 nonstandard amino acids. These include both amino acids with nonstandard side chains, such as post-translationally modified and artificial amino acids, as well as amino acids with modified backbone groups, such as chromophores composed of several amino acids. Model compounds representative of the nonstandard amino acids were parametrized for protonation states that are likely at the physiological pH of 7 and, for some more common residues, in both d- and l-stereoisomers. Considering all protonation, tautomeric, and stereoisomeric forms, a total of 406 nonstandard amino acids were parametrized. Emphasis was placed on the quality of both intra- and intermolecular parameters. Partial charges were derived using quantum mechanical (QM) data on model compound dipole moments, electrostatic potentials, and interactions with water. Optimization of all intramolecular parameters, including torsion angle parameters, was performed against information from QM adiabatic potential energy surface (PES) scans. Special emphasis was put on the quality of terms corresponding to PES around rotatable dihedral angles. Validation of the force field was based on molecular dynamics simulations of 20 protein complexes containing different nonstandard amino acids. Overall, the presented parameters will allow for computational studies of a wide range of proteins containing nonstandard amino acids, including natural and artificial residues.


Assuntos
Aminoácidos/química , Cisteína/análogos & derivados , Cisteína/química , Concentração de Íons de Hidrogênio , Simulação de Dinâmica Molecular , Proteínas/química , Teoria Quântica , Eletricidade Estática , Estereoisomerismo , Triptofano/análogos & derivados , Triptofano/química , Água/química
7.
ACS Infect Dis ; 7(6): 1666-1679, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-33939919

RESUMO

Coenzyme A (CoA) is a ubiquitous cofactor present in all living cells and estimated to be required for up to 9% of intracellular enzymatic reactions. Mycobacterium tuberculosis (Mtb) relies on its own ability to biosynthesize CoA to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the pathway to CoA biosynthesis is recognized as a potential source of novel tuberculosis drug targets. In prior work, we genetically validated CoaBC as a bactericidal drug target in Mtb in vitro and in vivo. Here, we describe the identification of compound 1f, a small molecule inhibitor of the 4'-phosphopantothenoyl-l-cysteine synthetase (PPCS; CoaB) domain of the bifunctional Mtb CoaBC, and show that this compound displays on-target activity in Mtb. Compound 1f was found to inhibit CoaBC uncompetitively with respect to 4'-phosphopantothenate, the substrate for the CoaB-catalyzed reaction. Furthermore, metabolomic profiling of wild-type Mtb H37Rv following exposure to compound 1f produced a signature consistent with perturbations in pantothenate and CoA biosynthesis. As the first report of a direct small molecule inhibitor of Mtb CoaBC displaying target-selective whole-cell activity, this study confirms the druggability of CoaBC and chemically validates this target.


Assuntos
Mycobacterium tuberculosis , Peptídeo Sintases/antagonistas & inibidores , Coenzima A , Cisteína/análogos & derivados , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/genética , Ácido Pantotênico/análogos & derivados , Peptídeo Sintases/genética
8.
Food Res Int ; 143: 110295, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33992394

RESUMO

The molecular formation mechanism of 2-furfurylthiol in the glucose-cysteine reaction is not reported. Knowledge of the molecular interaction of glucose and ribose on the generation of 2-furfurylthiol is still unclear. The carbon module labeling (CAMOLA) technical approach was applied to elucidate the formation mechanism of 2-furfurylthiol in the glucose-cysteine reaction. The effect of ribose on the glucose-cysteine reaction was also evaluated. The results showed that 2-furfural and 2-furanmethanol were important intermediates for the formation of 2-furfurylthiol. Irrespective of the heating time, 2-furfurylthiol was mainly generated from an intact C5 glucose skeleton (88-89%), whereas the recombination of glucose fragments had minimal contribution. 2-Furfural could be generated from the Maillard reaction between glucose and cysteine or glucose alone, which further formed 2-furanmethanol. Immediately, 2-furfurylthiol could arise from the reaction of 2-furanmethanol and H2S from cysteine. Moreover, the reaction of glucose, ribose, and cysteine could generate 2-furfural, 2-furanmethanol, and 2-furfurylthiol by an addition effect confirmed by the model reaction and food system.


Assuntos
Cisteína , Ribose , Cisteína/análogos & derivados , Furanos , Glucose/análogos & derivados , Compostos de Sulfidrila
9.
Mol Cell ; 81(12): 2669-2681.e9, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-33894155

RESUMO

Posttranslational modification (PTM), through the recruitment of effector proteins (i.e., "readers") that signal downstream events, plays key roles in regulating a variety of cellular processes. To understand how a PTM is recognized, it is necessary to find its readers and, importantly, the location of the binding pockets responsible for PTM recognition. Although various methods have been developed to identify PTM readers, it remains a challenge to directly map the PTM-binding regions, especially for intrinsically disordered domains. Here, we demonstrate a photo-crosslinkable, clickable, and cleavable tri-functional amino acid, ADdis-Cys, that when coupled with mass spectrometry (ADdis-Cys-MS) can not only identify PTM readers from complex proteomes but also simultaneously map their PTM-recognition modules. Using ADdis-Cys-MS, we successfully identify the binding sites of several reader-PTM interactions, among which we discover human C1QBP as a histone chaperone. This robust method should find wide applications in examining other histone or non-histone PTM-mediated protein-protein interactions.


Assuntos
Aminoácidos/química , Aminoácidos/metabolismo , Mapeamento de Interação de Proteínas/métodos , Aminoácidos/genética , Sítios de Ligação , Química Click/métodos , Reagentes para Ligações Cruzadas , Cisteína/análogos & derivados , Cisteína/síntese química , Cisteína/química , Histonas/metabolismo , Humanos , Espectrometria de Massas/métodos , Mapas de Interação de Proteínas/genética , Mapas de Interação de Proteínas/fisiologia , Processamento de Proteína Pós-Traducional/genética , Processamento de Proteína Pós-Traducional/fisiologia , Proteoma/metabolismo , Proteômica/métodos
10.
Medicine (Baltimore) ; 100(15): e25557, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33847685

RESUMO

ABSTRACT: The heterogeneity of brain perfusion is related to the risk factors of thromboembolic events such as antiphospholipid syndrome. However, the effectiveness of brain perfusion heterogeneity as a marker to predict thromboembolic events has not been confirmed. Our objective was to evaluate the effectiveness of brain perfusion heterogeneity as a marker to predict the development of cerebrovascular accidents. In this retrospective cohort study, patients who underwent Tc-99m ECD brain SPECT from January 1, 2006 through December 31, 2008 were included. Each study was reoriented with the Talairach space provided by the NeuroGam Software package. Heterogeneity of brain perfusion was measured as the coefficient of variation. The study outcome was the risk of cerebral vascular accidents in patients with increased heterogeneity of brain perfusion between January 1, 2006 and December 31, 2015. A multiple Cox proportional hazards model was applied to evaluate the risk of cerebrovascular accidents. A total of 70 patients were included in this study. The median age was 39 years (range, 28 - 59 years). There were 55 (78.6%) women. For increased heterogeneity of brain perfusion, the hazard ratio of cerebrovascular accidents was 2.68 (95% CI, 1.41 - 5.09; P = .003) after adjusting for age, sex, hypertension, diabetes mellitus, and dyslipidemia. Our study suggests that increased heterogeneity of brain perfusion is associated with an increased risk of cerebrovascular accidents.


Assuntos
Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular , Medição de Risco/métodos , Acidente Vascular Cerebral/etiologia , Tomografia Computadorizada de Emissão de Fóton Único/estatística & dados numéricos , Adulto , Biomarcadores/análise , Encéfalo/fisiopatologia , Cisteína/análogos & derivados , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Organotecnécio , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Tomografia Computadorizada de Emissão de Fóton Único/métodos
11.
BMC Plant Biol ; 21(1): 174, 2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33838642

RESUMO

BACKGROUND: Allium sativum (garlic) is an economically important food source and medicinal plant rich in sulfides and other protective substances such as alliin, the precursor of allicin biosynthesis. Cysteine, serine and sulfur is the precursor of alliin biosynthesis. However, little is known about the alliin content under abiotic stress or the mechanism by which it is synthesized. RESULTS: The findings revealed that the content of alliin was lowest in the garlic roots, and highest in the buds. Furthermore, alliin levels decreased in mature leaves following wounding. Transcriptome data generated over time after wounding further revealed significant up-regulation of genes integral to the biosynthetic pathways of cysteine and serine in mature garlic leaves. CONCLUSIONS: The findings suggest that differential expression of cysteine, serine and sulfide-related genes underlies the accumulation of alliin and its precursors in garlic, providing a basis for further analyses of alliin biosynthesis.


Assuntos
Cisteína/análogos & derivados , Alho/genética , Expressão Gênica , Folhas de Planta/fisiologia , Cisteína/biossíntese , Sulfóxidos
12.
Molecules ; 26(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803601

RESUMO

Hypogonadism, associated with low levels of testosterone synthesis, has been implicated in several diseases. Recently, the quest for natural alternatives to prevent and treat hypogonadism has gained increasing research interest. To this end, the present study explored the effect of S-allyl cysteine (SAC), a characteristic organosulfur compound in aged-garlic extract, on testosterone production. SAC was administered at 50 mg/kg body weight intraperitoneally into 7-week-old BALB/c male mice in a single-dose experiment. Plasma levels of testosterone and luteinizing hormone (LH) and testis levels of proteins involved in steroidogenesis were measured by enzymatic immunoassay and Western blot, respectively. In addition, mouse testis-derived I-10 cells were also used to investigate the effect of SAC on steroidogenesis. In the animal experiment, SAC significantly elevated testosterone levels in both the plasma and the testis without changing the LH level in plasma and increased phosphorylated protein kinase A (p-PKA) levels. Similar results were also observed in I-10 cells. The findings demonstrating the increasing effect of SAC on p-PKA and mRNA levels of Cyp11a suggest that SAC increases the testosterone level by activating the PKA pathway and could be a potential target for hypogonadism therapeutics.


Assuntos
Cisteína/análogos & derivados , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testosterona/biossíntese , Animais , Linhagem Celular , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Cisteína/farmacologia , Ativação Enzimática/efeitos dos fármacos , Alho/química , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Hormônio Luteinizante/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação , Testículo/citologia , Testosterona/sangue
13.
J Alzheimers Dis ; 80(1): 331-335, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33523013

RESUMO

BACKGROUND: Cerebral microbleeds (CMBs) in patients with Parkinson's disease (PD) or dementia with Lewy bodies (DLB) have not been adequately studied. OBJECTIVE: This study aims to find a difference in the total number, prevalence, and common locations of CMBs between PD and DLB and evaluate 99 mTc-ECD SPECT subtraction images of these two diseases. METHODS: We examined 112 patients with PD (53 males and 59 females; age: 77.4±3.6 years) and 28 age-matched patients with DLB (15 males and 13 females; age: 77.1±6.7 years) using brain magnetic resonance imaging (MRI) and 99 mTc-ECD SPECT subtraction imaging. RESULTS: The total number of CMBs was higher in patients with DLB (41.2%) than in those with PD (11.5%), and the prevalence was significantly higher in the former (0.7±1.1) than the latter (0.2±0.5, p < 0.05). The odds ratio was 5.4 (95% confidence interval [CI]: 1.7-17.4). Furthermore, CMBs were commonly located in the basal ganglia of patients with PD (6 out of 87 patients) but in the occipital lobe of patients with DLB (8 out of 17 patients). 99 mTc-ECD SPECT subtraction imaging indicated lower cerebral blood flow in the posterior cingulate gyrus among the patients with CMB-positive DLB than among those with CMB-positive PD; additionally, the cerebral blood flow was lower in the bilateral basal ganglia and midbrain among patients with CMB-positive DLB compared to those with CMB-negative DLB. CONCLUSION: A reduction in occipital glucose metabolism may be related to CMBs in the occipital lobe of patients with DLB.


Assuntos
Hemorragias Intracranianas/diagnóstico por imagem , Doença por Corpos de Lewy/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Angiografia Digital , Gânglios da Base/diagnóstico por imagem , Circulação Cerebrovascular , Cisteína/análogos & derivados , Feminino , Glucose/metabolismo , Giro do Cíngulo/diagnóstico por imagem , Humanos , Hemorragias Intracranianas/complicações , Hemorragias Intracranianas/psicologia , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/psicologia , Angiografia por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Mesencéfalo/diagnóstico por imagem , Testes Neuropsicológicos , Lobo Occipital/diagnóstico por imagem , Compostos de Organotecnécio , Doença de Parkinson/complicações , Doença de Parkinson/psicologia , Prevalência , Tomografia Computadorizada de Emissão de Fóton Único
14.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33573055

RESUMO

Two types of melanin pigments, brown to black eumelanin and yellow to reddish brown pheomelanin, are biosynthesized through a branched reaction, which is associated with the key intermediate dopaquinone (DQ). In the presence of l-cysteine, DQ immediately binds to the -SH group, resulting in the formation of cysteinyldopa necessary for the pheomelanin production. l-Cysteine prefers to bond with aromatic carbons adjacent to the carbonyl groups, namely C5 and C2. Surprisingly, this Michael addition takes place at 1,6-position of the C5 (and to some extent at C2) rather than usually expected 1,4-position. Such an anomaly on the reactivity necessitates an atomic-scale understanding of the binding mechanism. Using density functional theory-based calculations, we investigated the binding of l-cysteine thiolate (Cys-S-) to DQ. Interestingly, the C2-S bonded intermediate was less energetically stable than the C6-S bonded case. Furthermore, the most preferred Cys-S--attacked intermediate is at the carbon-carbon bridge between the two carbonyls (C3-C4 bridge site) but not on the C5 site. This structure allows the Cys-S- to migrate onto the adjacent C5 or C2 with small activation energies. Further simulation demonstrated a possible conversion pathway of the C5-S (and C2-S) intermediate into 5-S-cysteinyldopa (and 2-S-cysteinyldopa), which is the experimentally identified major (and minor) product. Based on the results, we propose that the binding of Cys-S- to DQ proceeds via the following path: (i) coordination of Cys-S- to C3-C4 bridge, (ii) migration of Cys-S- to C5 (C2), (iii) proton rearrangement from cysteinyl -NH3+ to O4 (O3), and (iv) proton rearrangement from C5 (C2) to O3 (O4).


Assuntos
Benzoquinonas/química , Cisteína/análogos & derivados , Cisteinildopa/química , Di-Hidroxifenilalanina/análogos & derivados , Sítios de Ligação , Cisteína/química , Teoria da Densidade Funcional , Di-Hidroxifenilalanina/química , Melaninas/química , Modelos Moleculares , Prótons
15.
Inorg Chem ; 60(7): 4646-4656, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33587617

RESUMO

Methylmercury (CH3Hg+) binding to catalytically fundamental cysteine and selenocysteine of peroxide-reducing enzymes has long been postulated as the origin of its toxicological activity. Only very recently, CH3Hg+ binding to the selenocysteine of thioredoxin reductase has been directly observed [Pickering, I. J. Inorg. Chem., 2020, 59, 2711-2718], but the precise influence of the toxicant on the peroxide-reducing potential of such a residue has never been investigated. In this work, we employ state-of-the-art density functional theory calculations to study the reactivity of molecular models of the free and toxified enzymes. Trends in activation energies are discussed with attention to the biological consequences and are rationalized within the chemically intuitive framework provided by the activation strain model. With respect to the free, protonated amino acids, CH3Hg+ binding promotes oxidation of the S or Se nucleus, suggesting that chalcogenoxide formation might occur in the toxified enzyme, even if the actual rate of peroxide reduction is almost certainly lowered as suggested by comparison with fully deprotonated amino acids models.


Assuntos
Cisteína/química , Compostos de Metilmercúrio/química , Peróxidos/química , Sítios de Ligação , Cisteína/análogos & derivados , Teoria da Densidade Funcional , Estrutura Molecular , Oxirredução
16.
Oxid Med Cell Longev ; 2021: 6621232, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33574976

RESUMO

Pulmonary hypertension (PH) is a progressive and life-threatening chronic disease in which increased pulmonary artery pressure (PAP) and pulmonary vasculature remodeling are prevalent. Inhaled nitric oxide (NO) has been used in newborns to decrease PAP in the clinic; however, the effects of NO endogenous derivatives, S-nitrosothiols (SNO), on PH are still unknown. We have reported that S-nitroso-L-cysteine (CSNO), one of the endogenous derivatives of NO, inhibited RhoA activity through oxidative nitrosation of its C16/20 residues, which may be beneficial for both vasodilation and remodeling. In this study, we presented data to show that inhaled CSNO attenuated PAP in the monocrotaline- (MCT-) induced PH rats and, moreover, improved right ventricular (RV) hypertrophy and fibrosis induced by RV overloaded pressure. In addition, aerosolized CSNO significantly inhibited the hyperactivation of signal transducers and activators of transduction 3 (STAT3) and extracellular regulated protein kinases (ERK) pathways in the lung of MCT-induced rats. CSNO also regulated the expression of smooth muscle contractile protein and improved aberrant endoplasmic reticulum (ER) stress and mitophagy in lung tissues following MCT induction. On the other hand, CSNO inhibited reactive oxygen species (ROS) production in vitro, which is induced by angiotensin II (AngII) as well as interleukin 6 (IL-6). In addition, CSNO inhibited excessive ER stress and mitophagy induced by AngII and IL-6 in vitro; finally, STAT3 and ERK phosphorylation was inhibited by CSNO in a concentration-dependent manner. Taken together, CSNO led to pulmonary artery relaxation and regulated pulmonary circulation remodeling through anti-ROS and anti-inflammatory pathways and may be used as a therapeutic option for PH treatment.


Assuntos
Anti-Inflamatórios/uso terapêutico , Cisteína/análogos & derivados , Hipertensão Pulmonar/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , S-Nitrosotióis/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Colágeno/metabolismo , Cisteína/farmacologia , Cisteína/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/complicações , Hipertrofia Ventricular Direita/tratamento farmacológico , Hipertrofia Ventricular Direita/fisiopatologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Metaloproteinases da Matriz/metabolismo , Mitofagia/efeitos dos fármacos , Monocrotalina , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , S-Nitrosotióis/farmacologia , Fator de Transcrição STAT3/metabolismo , Remodelação Vascular/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
17.
Anal Chem ; 93(5): 2907-2915, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33522244

RESUMO

Cysteine (Cys) is prone to diverse post-translational modifications in proteins, including oxidation into sulfenic acid (Cys-SOH) by reactive oxygen species generated under oxidative stress. Detection of low-concentration and metastable Cys-SOH within complex biological matrices is challenging due to the dynamic concentration range of proteins in the samples. Herein, visible laser-induced dissociation (LID) implemented in a mass spectrometer was used for streamlining the detection of Cys oxidized proteins owing to proper derivatization of Cys-SOH with a chromophore tag functionalized with a cyclohexanedione group. Once grafted, peptides undergo a high fragmentation yield under LID, leading concomitantly to informative backbone ions and to a chromophore reporter ion. Seventy-nine percent of the Cys-containing tryptic peptides derived from human serum albumin and serotransferrin tracked by parallel reaction monitoring (PRM) were detected as targets subjected to oxidation. These candidates as well as Cys-containing peptides predicted by in silico trypsin digestion of five other human plasma proteins were then tracked in real plasma samples to pinpoint the endogenous Cys-SOH subpopulation. Most of the targeted peptides were detected in all plasma samples by LID-PRM, with significant differences in their relative amounts. By eliminating the signal of interfering co-eluted compounds, LID-PRM surpasses conventional HCD (higher-energy collisional dissociation)-PRM in detecting grafted Cys-SOH-containing peptides and allows now to foresee clinical applications in large human cohorts.


Assuntos
Cisteína , Ácidos Sulfênicos , Proteínas Sanguíneas , Cisteína/análogos & derivados , Cisteína/metabolismo , Humanos , Espectrometria de Massas , Oxirredução , Estresse Oxidativo
18.
Toxicol Appl Pharmacol ; 416: 115469, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33640343

RESUMO

Heat stress-induced oxidative stress in bovine mammary epithelial cells (BMECs) threatens the normal growth and development of bovine mammary tissue, resulting in lower milk production of dairy cows. The aim of the present study is to investigate the protective effects of S-allyl cysteine (SAC), an organosulfur component extracted from aged garlic, on heat stress-induced oxidative stress and apoptosis in BMECs and to explore its underlying mechanisms. Our results showed that heat stress treatment considerably decreased cell viability, whereas SAC treatment dose-dependently restored cell viability of BMECs under heat-stress conditions. In addition, SAC protected BMECs from heat stress-induced oxidative damage by inhibiting the excessive accumulation of reactive oxygen species (ROS) and increasing the activity of antioxidant enzymes. It also inhibited heat stress-induced apoptosis by reducing the ratio of Bax/Bcl-2 and blocking proteolytic the cleavage of caspase-3 in BMECs. Interestingly, we found that the protective effect of SAC on heat stress-induced oxidative stress and apoptosis was dependent on the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. SAC promoted the Nrf2 nuclear translocation in heat stress-induced BMECs. The results were also validated by Nrf2 and Keap1 knockdown experiments further demonstrating that Nrf-2 was indeed involved in the protective effect of SAC on heat stress-induced oxidative damage and apoptosis. In summary, our results showed that SAC could protect BMECs from heat stress-induced injury by mediating the Nrf2/HO-1 signaling pathway, suggesting that SAC could be considered as a therapeutic drug for attenuating heat stress-induced mammary gland diseases.


Assuntos
Antioxidantes/farmacologia , Cisteína/análogos & derivados , Células Epiteliais/efeitos dos fármacos , Resposta ao Choque Térmico/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Glândulas Mamárias Animais/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Bovinos , Células Cultivadas , Cisteína/farmacologia , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Feminino , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Glândulas Mamárias Animais/enzimologia , Glândulas Mamárias Animais/patologia , Transdução de Sinais
19.
ACS Biomater Sci Eng ; 7(3): 1242-1251, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33586954

RESUMO

Multiple sclerosis (MS) is a demyelinating chronic autoimmune inflammatory disease of the central nervous system (CNS). A large amount of proinflammatory cytokines is released in the CNS from the self-reactive T cells infiltrate, leading to the destruction of the myelin sheath and contributing to the development of MS. Several drugs have emerged in recent years to treat MS, and studies have shown that gold nanoparticles (GNPs) have anti-inflammatory properties in autoimmune diseases. Thus, the effects of GNP conjugation to ethylene dicysteine diethyl ester (ECD) were evaluated in C57BL/6 female mice exposed to experimental MS. Animals were exposed to experimental autoimmune encephalitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG35-55) in complete Freund's adjuvant supplemented with Mycobacterium tuberculosis. The clinical and cerebral effects of the different doses of ECD-GNPs (0.3, 0.6, and 1.0 mg/kg) were first studied, and the results showed that the group treated with 0.6 mg/kg ECD-GNPs improved clinical symptoms, inflammatory infiltrate, and myelin integrity. In the following step, GNPs and ECD-GNPs (0.6 mg/kg) showed improvements in the clinical signs of the disease. Moreover, there was a reduction in the levels of proinflammatory cytokines in both groups compared to EAE, and only the isolated use of GNPs increased IL-4 expression. Both NF-κB and TGFß immunoexpression were significantly reduced following EAE + GNPs and EAE + ECD-GNPs treatment. In conclusion, GNPs and ECD-GNPs at 0.6 mg/kg attenuate the neurological signs of EAE likely due to inhibition of neuroinflammation induced by EAE.


Assuntos
Encefalomielite Autoimune Experimental , Nanopartículas Metálicas , Animais , Cisteína/análogos & derivados , Encefalomielite Autoimune Experimental/induzido quimicamente , Ésteres , Feminino , Ouro , Nanopartículas Metálicas/toxicidade , Camundongos , Camundongos Endogâmicos C57BL
20.
Int J Mol Sci ; 22(2)2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33435325

RESUMO

Oxidative stress plays a key role in the pathophysiology of retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, which are the major causes of irreversible blindness in developed countries. An excess of reactive oxygen species (ROS) can directly cause functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells, and retinal ganglion cells. Antioxidants may represent a preventive/therapeutic strategy and reduce the risk of progression of AMD. Among antioxidants, N-acetyl-L-cysteine (NAC) is widely studied and has been proposed to have therapeutic benefit in treating AMD by mitigating oxidative damage in RPE. Here, we demonstrate that N-acetyl-L-cysteine ethyl ester (NACET), a lipophilic cell-permeable cysteine derivative, increases the viability in oxidative stressed RPE cells more efficiently than NAC by reacting directly and more rapidly with oxidizing agents, and that NACET, but not NAC, pretreatment predisposes RPE cells to oxidative stress resistance and increases the intracellular reduced glutathione (GSH) pool available to act as natural antioxidant defense. Moreover, we demonstrate the ability of NACET to increase GSH levels in rats' eyes after oral administration. In conclusion, even if experiments in AMD animal models are still needed, our data suggest that NACET may play an important role in preventing and treating retinal diseases associated with oxidative stress, and may represent a valid and more efficient alternative to NAC in therapeutic protocols in which NAC has already shown promising results.


Assuntos
Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Cisteína/análogos & derivados , Estresse Oxidativo/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Acetilcisteína/análogos & derivados , Animais , Antioxidantes/química , Linhagem Celular , Cisteína/química , Cisteína/farmacologia , Humanos , Masculino , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...