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1.
An Acad Bras Cienc ; 91(4): e20180930, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800697

RESUMO

We studied dynamic thiol/disulphide homeostasis, an indicator of oxidative stress, to investigate the effects of newly initiated exercise training on sedentary obese adults. Seventeen sedentary obese adults and 15 normal-weight controls were included in the sample for this study. The obese adults were given a physical exercise training program that lasted twelve weeks. Before and after the exercise training program, blood samples were collected, and serum thiol/disulphide parameters were measured by using a novel technique. Before the start of the exercise training, it was observed that thiol/disulphide homeostasis was impaired, and this impairment was positively correlated with body mass index in sedentary obese adults because of the higher reactive oxygen species production in adipose tissue. However, while the obese participants' body mass index significantly decreased, the thiol/disulphide homeostasis parameters in the obese adults did not change over time as calculated at the baseline and compared to the calculation after the twelve weeks of exercise training. Despite a decrease in body mass index that occurred after the twelve weeks of exercise training, there was a lack of improvement in the obesity-induced impairment of thiol/disulphide homeostasis, which suggests that a newly initiated exercise training program may lead to oxidative stress.


Assuntos
Dissulfetos/metabolismo , Exercício , Homeostase , Obesidade/reabilitação , Estresse Oxidativo , Compostos de Sulfidrila/metabolismo , Adulto , Índice de Massa Corporal , Peso Corporal , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Comportamento Sedentário
2.
BMC Plant Biol ; 19(1): 507, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752690

RESUMO

BACKGROUND: The ubiquitous signaling molecule melatonin (N-acetyl-5-methoxytryptamine) (MT) plays vital roles in plant development and stress tolerance. Selenium (Se) may be phytotoxic at high concentrations. Interactions between MT and Se (IV) stress in higher plants are poorly understood. The aim of this study was to evaluate the defensive roles of exogenous MT (0 µM, 50 µM, and 100 µM) against Se (IV) (0 µM, 50 µM, 100 µM, and 200 µM) stress based on the physiological and biochemical properties, thiol biosynthesis, and antioxidant system of Brassica napus plants subjected to these treatments. RESULTS: Se (IV) stress inhibited B. napus growth and biomass accumulation, reduced pigment content, and lowered net photosynthetic rate (Pn) and PSII photochemical efficiency (Fv/Fm) in a dose-dependent manner. All of the aforementioned responses were effectively alleviated by exogenous MT treatment. Exogenous MT mitigated oxidative damage and lipid peroxidation and protected the plasma membranes from Se toxicity by reducing Se-induced reactive oxygen species (ROS) accumulation. MT also alleviated osmotic stress by restoring foliar water and sugar levels. Relative to standalone Se treatment, the combination of MT and Se upregulated the ROS-detoxifying enzymes SOD, APX, GR, and CAT, increased proline, free amino acids, and the thiol components GSH, GSSG, GSH/GSSG, NPTs, PCs, and cys and upregulated the metabolic enzymes γ-ECS, GST, and PCS. Therefore, MT application attenuates Se-induce oxidative damage in plants. MT promotes the accumulation of chelating agents in the roots, detoxifies Se there, and impedes its further translocation to the leaves. CONCLUSIONS: Exogenous MT improves the physiological traits, antioxidant system, and thiol ligand biosynthesis in B. napus subjected to Se stress primarily by enhancing Se detoxification and sequestration especially at the root level. Our results reveal better understanding of Se-phytotoxicity and Se-stress alleviation by the adequate supply of MT. The mechanisms of MT-induced plant tolerance to Se stress have potential implications in developing novel strategies for safe crop production in Se-rich soils.


Assuntos
Antioxidantes/metabolismo , Brassica napus/fisiologia , Melatonina/metabolismo , Reguladores de Crescimento de Planta/metabolismo , Selênio/toxicidade , Compostos de Sulfidrila/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Oxirredução , Estresse Oxidativo , Folhas de Planta/fisiologia , Espécies Reativas de Oxigênio/metabolismo
3.
Int J Nanomedicine ; 14: 6073-6101, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686803

RESUMO

Background: Amphotericin B (AmB) as a liposomal formulation of AmBisome is the first line of treatment for the disease, visceral leishmaniasis, caused by the parasite Leishmania donovani. However, nephrotoxicity is very common due to poor water solubility and aggregation of AmB. This study aimed to develop a water-soluble covalent conjugate of gold nanoparticle (GNP) with AmB for improved antileishmanial efficacy and reduced cytotoxicity. Methods: Citrate-reduced GNPs (~39 nm) were functionalized with lipoic acid (LA), and the product GNP-LA (GL ~46 nm) was covalently conjugated with AmB using carboxyl-to-amine coupling chemistry to produce GNP-LA-AmB (GL-AmB ~48 nm). The nanoparticles were characterized by dynamic light scattering, transmission electron microscopy (TEM), and spectroscopic (ultraviolet-visible and infrared) methods. Experiments on AmB uptake of macrophages, ergosterol depletion of drug-treated parasites, cytokine ELISA, fluorescence anisotropy, flow cytometry, and gene expression studies established efficacy of GL-AmB over standard AmB. Results: Infrared spectroscopy confirmed the presence of a covalent amide bond in the conjugate. TEM images showed uniform size with smooth surfaces of GL-AmB nanoparticles. Efficiency of AmB conjugation was ~78%. Incubation in serum for 72 h showed <7% AmB release, indicating high stability of conjugate GL-AmB. GL-AmB with AmB equivalents showed ~5-fold enhanced antileishmanial activity compared with AmB against parasite-infected macrophages ex vivo. Macrophages treated with GL-AmB showed increased immunostimulatory Th1 (IL-12 and interferon-γ) response compared with standard AmB. In parallel, AmB uptake was ~5.5 and ~3.7-fold higher for GL-AmB-treated (P<0.001) macrophages within 1 and 2 h of treatment, respectively. The ergosterol content in GL-AmB-treated parasites was ~2-fold reduced compared with AmB-treated parasites. Moreover, GL-AmB was significantly less cytotoxic and hemolytic than AmB (P<0.01). Conclusion: GNP-based delivery of AmB can be a better, cheaper, and safer alternative than available AmB formulations.


Assuntos
Anfotericina B/síntese química , Antiprotozoários/farmacologia , Ouro/química , Nanopartículas Metálicas/química , Anfotericina B/química , Anfotericina B/farmacologia , Animais , Antiprotozoários/química , Candida albicans/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Difusão Dinâmica da Luz , Ergosterol/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/crescimento & desenvolvimento , Estágios do Ciclo de Vida/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Nanopartículas Metálicas/ultraestrutura , Camundongos , Carbonilação Proteica/efeitos dos fármacos , Compostos de Sulfidrila/metabolismo , Ácido Tióctico/química , Resultado do Tratamento
4.
AAPS PharmSciTech ; 20(8): 325, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659563

RESUMO

Localized intra-pocket, retentive, biodegradable, prolonged release thiolated membrane can provide an improved therapeutic efficacy of doxycycline at the site of action with evading off target side effects. To this end, thiolated chitosan-hyaluronic acid composite polymeric complex next-generation of the periodontal membrane was manufactured by solvent casting method. FTIR spectroscopic analysis displayed successful immobilization of thiol groups on the manufactured thiolated periodontal membrane. Moreover, XRD, DSC, AFM and TGA of the membrane confirmed the compatibility of ingredients and modifications in surface chemistry. The thiolated periodontal film was also investigated in terms of thickness, weight uniformity, water-uptake capacity, drug content, pH, entrapment efficiency, lysozymal degradation and release patterns. Also, mucoadhesion profile was explored on gingival mucosa. The immobilized thiol groups on thiolated chitosan and thiolated hyaluronate were found to be 168 ± 11 µM/g (mean ± SD, n = 3) and 189 ± 8 µM/g (mean ± SD, n = 3) respectively. Swelling capacity of the thiolated periodontal membrane was significantly ∼2-fold higher (p < 0.05) as compared to unmodified membrane. The obtained thiolated membrane depicted 3 -old higher mucoadhesive features as compared to the un-modified membrane. In vitro release kinetics indicated approximately more than 80% prolonged release within 7 days. Mechanical strength of the Thiolated bandage was also significantly ∼2-fold higher (p < 0.05) as compared to unmodified membrane. Ex-vivo retention study revealed enhanced retention of thiolated membrane as compared to unmodified membrane. In-vitro antimicrobial studies demonstrated that thiolated membrane could efficiently kill Porphyromonas gingivalis cells as compared to the native membrane. Moreover, ex-vivo biodegradation results indicated that 90% of the thiolated membrane was biodegradable in 28 days. Based on these findings, thiolated next-generation of the periodontal membrane seems to be promising for periodontitis therapy.


Assuntos
Antibacterianos/administração & dosagem , Doxiciclina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Bolsa Periodontal/tratamento farmacológico , Compostos de Sulfidrila/administração & dosagem , Adulto , Animais , Antibacterianos/metabolismo , Doxiciclina/química , Doxiciclina/metabolismo , Composição de Medicamentos , Avaliação Pré-Clínica de Medicamentos/métodos , Cabras , Humanos , Bolsa Periodontal/metabolismo , Compostos de Sulfidrila/química , Compostos de Sulfidrila/metabolismo , Adulto Jovem
5.
Infect Immun ; 88(1)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31611270

RESUMO

Antibiotic-resistant Klebsiella pneumoniae isolates constitute a great clinical challenge. One important resistance mechanism in K. pneumoniae is the metallo-ß-lactamases (MBLs), which require zinc for their function. Thus, zinc chelation could be a strategy to resensitize K. pneumoniae to ß-lactams. However, the potential role for endogenous zinc chelators for this purpose remains to be explored. The aim was to search for endogenous factors that could resensitize MBL-expressing K. pneumoniae to cefotaxime (CTX). Clinical K. pneumoniae isolates expressing different MBLs were screened for sensitivity to CTX in supernatants from human HT-29 colonic epithelial cells. Factors influencing CTX susceptibility were isolated and identified with chromatographic and biochemical methods. Free zinc was measured with a Zinquin assay, the thiol content was assessed with a fluorometric thiol assay, and the reducing ability of the supernatant was measured with a fluorescent l-cystine probe. Urine samples from healthy volunteers were used to validate findings ex vivo VIM-1-expressing K. pneumoniae regained susceptibility to CTX when grown in supernatants from HT-29 cells. This effect was mediated via free thiols in the supernatant, including l-cysteine, and could be prevented by inhibiting thioredoxin reductase activity in the supernatant. Free thiols in urine samples appeared to have a similar function in restoring CTX activity against VIM-1-expressing K. pneumoniae in a zinc-dependent manner. We have identified l-cysteine as an endogenous zinc chelator resulting in the resensitization of VIM-1-expressing K. pneumoniae to CTX. These results suggest that natural zinc chelators in combination with conventional antibiotics could be used to treat infections caused by VIM-1-expressing pathogens.


Assuntos
Antibacterianos/farmacologia , Cefotaxima/farmacologia , Quelantes/metabolismo , Klebsiella pneumoniae/enzimologia , Compostos de Sulfidrila/metabolismo , Zinco/metabolismo , beta-Lactamases/metabolismo , Células HT29 , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Resistência beta-Lactâmica
6.
Nat Commun ; 10(1): 4073, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501427

RESUMO

Several antitumor therapies work by increasing reactive oxygen species (ROS) within the tumor micromilieu. Here, we reveal that L-plastin (LPL), an established tumor marker, is reversibly regulated by ROS-induced thiol oxidation on Cys101, which forms a disulfide bridge with Cys42. LPL reduction is mediated by the Thioredoxin1 (TRX1) system, as shown by TRX1 trapping, TRX1 knockdown and blockade of Thioredoxin1 reductase (TRXR1) with auranofin. LPL oxidation diminishes its actin-bundling capacity. Ratiometric imaging using an LPL-roGFP-Orp1 fusion protein and a dimedone-based proximity ligation assay (PLA) reveal that LPL oxidation occurs primarily in actin-based cellular extrusions and strongly inhibits cell spreading and filopodial extension formation in tumor cells. This effect is accompanied by decreased tumor cell migration, invasion and extracellular matrix (ECM) degradation. Since LPL oxidation occurs following treatment of tumors with auranofin or γ-irradiation, it may be a molecular mechanism contributing to the effectiveness of tumor treatment with redox-altering therapies.


Assuntos
Actinas/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/metabolismo , Neoplasias/metabolismo , Alquilação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Extensões da Superfície Celular/metabolismo , Cisteína/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Humanos , Peróxido de Hidrogênio/toxicidade , Modelos Biológicos , Mutação/genética , Oxirredução , Compostos de Sulfidrila/metabolismo , Tiorredoxina Redutase 1/metabolismo
7.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370193

RESUMO

Prior experiments illustrated reactive oxygen species (ROS) overproduction in maize plants infested with bird-cherry-oat (Rhopalosiphum padi L.) aphids. However, there is no available data unveiling the impact of aphids feeding on oxidative damages of crucial macromolecules in maize tissues. Therefore, the purpose of the current study was to evaluate the scale of oxidative damages of genomic DNA, total RNA and mRNA, proteins, and lipids in seedling leaves of two maize genotypes (Zlota Karlowa and Waza cvs-susceptible and relatively resistant to the aphids, respectively). The content of oxidized guanosine residues (8-hydroxy-2'-deoxyguanosine; 8-OHdG) in genomic DNA, 8-hydroxyguanosine (8-OHG) in RNA molecules, protein carbonyl groups, total thiols (T-SH), protein-bound thiols (PB-SH), non-protein thiols (NP-SH), malondialdehyde (MDA) and electrolyte leakage (EL) levels in maze plants were determined. In addition, the electrical penetration graphs (EPG) technique was used to monitor and the aphid stylet positioning and feeding modes in the hosts. Maize seedlings were infested with 0 (control), 30 or 60 R. padi adult apterae per plant. Substantial increases in the levels of RNA, protein and lipid oxidation markers in response to aphid herbivory, but no significant oxidative damages of genomic DNA, were found. Alterations in the studied parameters were dependent on maize genotype, insect abundance and infestation time.


Assuntos
Afídeos/fisiologia , Regulação da Expressão Gênica de Plantas , Interações Hospedeiro-Parasita/genética , Folhas de Planta/genética , Proteínas de Plantas/genética , Zea mays/genética , /metabolismo , Animais , Afídeos/patogenicidade , DNA de Plantas/genética , DNA de Plantas/metabolismo , Genótipo , Guanosina/análogos & derivados , Guanosina/metabolismo , Lipídeos/química , Malondialdeído/metabolismo , Oxirredução , Estresse Oxidativo , Doenças das Plantas/genética , Doenças das Plantas/parasitologia , Folhas de Planta/parasitologia , Proteínas de Plantas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA de Plantas/genética , RNA de Plantas/metabolismo , Plântula/genética , Plântula/parasitologia , Compostos de Sulfidrila/metabolismo , Zea mays/parasitologia
8.
Neurochem Res ; 44(9): 2202-2214, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31422521

RESUMO

Methylmalonic acidemia is a genetic disease characterized by accumulation of organic acids, such as methylmalonic (MMA) and malonic (MA) acids. Considering that the accumulation of MMA and MA causes several damages due to oxidative stress, antioxidants are thought to play a pivotal role in preventing deleterious effects associated with exposure to such compounds. Ilex paraguariensis (IP) was used here to test the hypothesis that supplementation with the aqueous extract of this plant could exert protective effect against MMA or MA induced mortality, behavioral and/or biochemical changes in Drosophila melanogaster (DM). Initially, a curve time- and dose-response to MMA (1-10 mM), MA (1-10 mM) and IP (63-500 µM) was performed. Thereafter, flies were concomitantly exposed to MA (5 mM), MMA (5 mM) and/or IP (250 µg/mL) during 15 days for survival assay, and for 48 hs to MA (1 or 5 mM), MMA (1 or 5 mM) and/or IP (250 µg/mL) for subsequent investigations. Both MMA and MA exposure resulted in higher incidence of mortality, a worse performance in the negative geotaxis assay and increased locomotion in open-field test as compared with control group. Furthermore, a marked increase in non-protein thiol (NPSH) and in thiobarbituric acid reactive substances (TBARS) levels, decrease in superoxide dismutase (SOD), catalase and acetylcholinesterase (AChE) activities, and decrease in MTT and resazurin reduction were noted in MMA or MA treated groups. IP treatment offered significant protection against all alterations associated to MMA or MA exposure. This study confirm the hypothesis that supplementation with IP offers protection against changes associated to MMA or MA exposure in DM, due, at least in part, to its antioxidant effect.


Assuntos
Antioxidantes/farmacologia , Drosophila melanogaster/efeitos dos fármacos , Ilex paraguariensis/química , Malonatos/toxicidade , Extratos Vegetais/farmacologia , Animais , Feminino , Locomoção/efeitos dos fármacos , Masculino , Compostos de Sulfidrila/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
9.
Chem Biol Interact ; 311: 108787, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31400341

RESUMO

Antipsychotic drugs interfere with the antioxidant defense system provoking complex and often toxicological effects. Here we examined differences in plasma albumin reduced free thiol (SH) group content and its reactivity as a consequence of clozapine (CLZ) and ziprasidone (ZIP) binding. Chronic administration of CLZ reduced, whereas treatment with ZIP increased albumin-SH content in rats. Regardless of the ratio of stearic acid (SA) bound to protein, in vitro binding of ZIP to human serum albumin (HSA) increased both the SH group level and reactivity. In contrast, the effect of CLZ on HSA-SH reactivity was dependent on HSA to SA molar ratio. CLZ binding was accompanied by an increase in HSA-SH reactivity in samples with normal, but a reduction of its reactivity level with higher SA/HSA ratio, compared to drug-free samples. We demonstrate by steady-state fluorescence quenching studies that an increase in SA binding to HSA is associated with a significant reduction of binding constant for both antipsychotics. In addition, this is the first report of quantitative characterization of ZIP binding to HSA. Our findings suggest that albumin-SH content and reactivity is modulated by ZIP towards an increased antioxidant defense capacity in circulation, as opposed to CLZ, which can contribute to the safer, more effective treatment of schizophrenia.


Assuntos
Clozapina/química , Ácidos Graxos/química , Piperazinas/química , Albumina Sérica/química , Compostos de Sulfidrila/química , Tiazóis/química , Animais , Clozapina/metabolismo , Ácidos Graxos/metabolismo , Humanos , Masculino , Piperazinas/metabolismo , Ligação Proteica , Ratos , Ratos Wistar , Albumina Sérica/metabolismo , Espectrometria de Fluorescência , Espectrofotometria , Compostos de Sulfidrila/análise , Compostos de Sulfidrila/metabolismo , Tiazóis/metabolismo
10.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1126-1127: 121738, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31377566

RESUMO

Myocardial Infarction (MI) is one of the most common causes of deaths worldwide. Thiols have been reported to play a key role in physiological and pathological processes of MI. Comprehensive analysis of thiols would be conducive to fully elucidate the relation between thiols and MI. In the current study, we analyze the metabolomic differences of thiols in serum between MI patients (n = 30) and healthy controls (HCs, n = 30) by stable isotope labeling-dispersive solid phase extraction-liquid chromatography-full scan-Orbitrap-mass spectrometry analysis (IL-DSPE-LC-full scan-Orbitrap MS) method. We detected 300 potential thiols in serum of MI patients and HCs, among which, 67 thiols were positively or putatively identified. Furthermore, we found that the levels of 71 thiols in serum exhibited significant difference between MI patients and HCs. In the transsulfuration pathway, we observed that Cys and Hcys were upregulated, while GSH were downregulated. Our results provide a comprehensive understanding of thiols metabolome in human serum between MI patients and HCs.


Assuntos
Metabolômica/métodos , Infarto do Miocárdio/metabolismo , Compostos de Sulfidrila/sangue , Compostos de Sulfidrila/metabolismo , Cromatografia Líquida/métodos , Análise por Conglomerados , Humanos , Marcação por Isótopo/métodos , Espectrometria de Massas , Metaboloma/fisiologia , Infarto do Miocárdio/sangue
11.
BMC Biotechnol ; 19(1): 49, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31319821

RESUMO

BACKGROUND: S-Phenyl-L-cysteine is regarded as having potential applicability as an antiretroviral/protease inhibitor for human immunodeficiency virus (HIV). In the present study, optically active S-phenyl-L-cysteine was prepared in a highly efficient manner from inexpensive bromobenzene using tryptophan synthase through a chemoenzymatic method. RESULTS: The chemoenzymatic method used a four-step reaction sequence. The process started with the reaction of magnesium and bromobenzene, followed by a Grignard reaction, and then hydrolysis and enzymatic synthesis using tryptophan synthase. Through this approach, S-phenyl-L-cysteine was chemoenzymatically synthesized using tryptophan synthase from thiophenol and L-serine as the starting material. CONCLUSIONS: High-purity, optically active S-phenyl-L-cysteine was efficiently and inexpensively obtained in a total yield of 81.3% (> 99.9% purity).


Assuntos
Química Orgânica/métodos , Cisteína/análogos & derivados , Compostos Organometálicos/metabolismo , Triptofano Sintase/metabolismo , Bromobenzenos/química , Bromobenzenos/metabolismo , Cisteína/química , Cisteína/metabolismo , Magnésio/química , Magnésio/metabolismo , Modelos Químicos , Estrutura Molecular , Compostos Organometálicos/química , Fenóis/química , Fenóis/metabolismo , Serina/química , Serina/metabolismo , Compostos de Sulfidrila/química , Compostos de Sulfidrila/metabolismo , Triptofano Sintase/química
12.
Chem Biol Interact ; 310: 108733, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276663

RESUMO

Plumbagin (PLB) is an active secondary metabolite extracted from the roots of Plumbago rosea. In this study, we report that plumbagin effectively induces paraptosis by triggering extensive cytoplasmic vacuolation followed by cell death in triple negative breast cancer cells (MDA-MB-231), cervical cancer cells (HeLa) and non-small lung cancer cells (A549) but not in normal lung fibroblast cells (WI-38). The vacuoles originated from the dilation of the endoplasmic reticulum (ER) and were found to be empty. The cell death induced by plumbagin was neither apoptotic nor autophagic. Plumbagin induced ER stress mainly by inhibiting the chymotrypsin-like activity of 26S proteasome as also evident from the accumulation of polyubiquitinated proteins. The vacuolation and cell death were found to be independent of reactive oxygen species generation but was effectively inhibited by thiol antioxidant suggesting that plumbagin could modify the sulfur homeostasis in the cellular milieu. Plumbagin also resulted in a decrease in mitochondrial membrane potential eventually decreasing the ATP production. This is the first study to show that Plumbagin induces paraptosis through proteasome inhibition and disruption of sulfhydryl homeostasis and thus further opens up the lead molecule to potential therapeutic strategies for apoptosis-resistant cancers.


Assuntos
Morte Celular/efeitos dos fármacos , Naftoquinonas/farmacologia , Neoplasias/patologia , Linhagem Celular , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Homeostase , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Naftoquinonas/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteassoma/farmacologia , Compostos de Sulfidrila/metabolismo , Vacúolos/metabolismo
13.
Eklem Hastalik Cerrahisi ; 30(2): 117-23, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31291859

RESUMO

OBJECTIVES: This study aims to detect the levels of some biochemical markers in A1 pulley tissue of type 2 diabetic trigger finger patients to enlighten the mechanisms leading to cellular complications. PATIENTS AND METHODS: The study included 35 trigger finger patients (5 males, 30 females; mean age 53.9±9.15 years; range, 37 to 71 years). We measured total thiol (total-SH) levels to determine the status of the non-enzymatic antioxidant defense system and advanced oxidation protein product (AOPP) levels to determine levels of oxidative protein modification in pulley tissues of trigger finger patients with or without diabetes. Extracellular matrix degradation was assessed by measuring levels of sialic acid (SA) in the pulley tissue. RESULTS: Total-SH values for the groups with and without diabetes were 22.7±1.6 vs. 38.9±5.2 nmol/mg protein, respectively, while AOPP values were 472.5±131.6 vs.175.6±9.9 mmol/g protein, respectively. The SA levels of diabetic and nondiabetic patients were 0.4±0.0 vs. 0.63±0.1 nmol/mg protein, respectively. CONCLUSION: Our results revealed that tissue SA levels and tissue SH levels decreased and AOPP levels increased disproportionally in the A1 pulley tissue of diabetic patients, which may indicate the role of oxidative protein damage and extracellular matrix changes in diabetic trigger finger etiology.


Assuntos
Produtos da Oxidação Avançada de Proteínas/metabolismo , Tecido Conjuntivo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Compostos de Sulfidrila/metabolismo , Dedo em Gatilho/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dedo em Gatilho/complicações
14.
Nutrients ; 11(6)2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31181621

RESUMO

Glutathione (GSH) has poor pharmacokinetic properties; thus, several derivatives and biosynthetic precursors have been proposed as GSH-boosting drugs. I-152 is a conjugate of N-acetyl-cysteine (NAC) and S-acetyl-ß-mercaptoethylamine (SMEA) designed to release the parent drugs (i.e., NAC and ß-mercaptoethylamine or cysteamine, MEA). NAC is a precursor of L-cysteine, while MEA is an aminothiol able to increase GSH content; thus, I-152 represents the very first attempt to combine two pro-GSH molecules. In this review, the in-vitro and in-vivo metabolism, pro-GSH activity and antiviral and immunomodulatory properties of I-152 are discussed. Under physiological GSH conditions, low I-152 doses increase cellular GSH content; by contrast, high doses cause GSH depletion but yield a high content of NAC, MEA and I-152, which can be used to resynthesize GSH. Preliminary in-vivo studies suggest that the molecule reaches mouse organs, including the brain, where its metabolites, NAC and MEA, are detected. In cell cultures, I-152 replenishes experimentally depleted GSH levels. Moreover, administration of I-152 to C57BL/6 mice infected with the retroviral complex LP-BM5 is effective in contrasting virus-induced GSH depletion, exerting at the same time antiviral and immunomodulatory functions. I-152 acts as a pro-GSH agent; however, GSH derivatives and NAC cannot completely replicate its effects. The co-delivery of different thiol species may lead to unpredictable outcomes, which warrant further investigation.


Assuntos
Acetilcisteína/metabolismo , Cisteamina/metabolismo , Glutationa/metabolismo , Pró-Fármacos/farmacologia , Animais , Antivirais/metabolismo , Antivirais/farmacologia , Glutationa/deficiência , Humanos , Fatores Imunológicos/metabolismo , Fatores Imunológicos/farmacologia , Pró-Fármacos/metabolismo , Retroviridae/efeitos dos fármacos , Compostos de Sulfidrila/metabolismo , Viroses/metabolismo
15.
Tuberculosis (Edinb) ; 116: 44-55, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31153518

RESUMO

Low molecular weight (LMW) thiols are molecules with a functional sulfhydryl group that enable them to detoxify reactive oxygen species, reactive nitrogen species and other free radicals. Their roles range from their ability to modulate the immune system to their ability to prevent damage of biological molecules such as DNA and proteins by protecting against oxidative, nitrosative and acidic stress. LMW thiols are synthesized and found in both eukaryotes and prokaryotes. Due to their beneficial role to both eukaryotes and prokaryotes, their specific functions need to be elucidated, most especially in pathogenic prokaryotes such as Mycobacterium tuberculosis (M.tb), in order to provide a rationale for targeting their biosynthesis for drug development. Ergothioneine (ERG), mycothiol (MSH) and gamma-glutamylcysteine (GGC) are LMW thiols that have been shown to interplay to protect M.tb against cellular stress. Though ERG, MSH and GGC seem to have overlapping functions, studies are gradually revealing their unique physiological roles. Understanding their unique physiological role during the course of tuberculosis (TB) infection, would pave the way for the development of drugs that target their biosynthetic pathway. This review identifies the knowledge gap in the unique physiological roles of LMW thiols and proposes their mechanistic roles based on previous studies. In addition, it gives an update on identified inhibitors of their biosynthetic enzymes.


Assuntos
Mycobacterium tuberculosis/metabolismo , Compostos de Sulfidrila/metabolismo , Tuberculose/microbiologia , Animais , Antituberculosos/uso terapêutico , Cisteína/metabolismo , Dipeptídeos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Enzimas/metabolismo , Ergotioneína/metabolismo , Glicopeptídeos/metabolismo , Humanos , Inositol/metabolismo , Terapia de Alvo Molecular , Peso Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade , Tuberculose/tratamento farmacológico
16.
Food Chem ; 293: 529-536, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151644

RESUMO

The effect of glucose oxidase (GOx) catalytic oxidation on the efficacy of gallic acid (GA) to modify the chemical structure and gelling behavior of myofibrillar protein (MP) was investigated. In contrast to non-oxidized MP samples where GA induced very little changes, GA (0, 6, 30, and 60 µmol/g MP) under GOx treatment promoted sulfhydryl and amine loss (up to 58% and 49%, respectively). The attenuation of intrinsic tryptophan fluorescence in the GA/GOx-treated MP corroborated the finding. The gelling capacity of MP, corresponding to disulfide and non-disulfide bond formation in protein aggregates, was markedly enhanced by 60 µmol GA under GOx, up to 86% in gel storage modulus G' and 53% in gel strength. The GOx-aided GA modification of MP could be a potential ingredient strategy in meat processing to promote textural attributes of cooked products.


Assuntos
Ácido Gálico/química , Géis/química , Glucose Oxidase/metabolismo , Proteínas Musculares/química , Aminas/química , Aminas/metabolismo , Animais , Ácido Gálico/metabolismo , Carne/análise , Microscopia Eletrônica de Varredura , Proteínas Musculares/metabolismo , Oxirredução , Reologia , Compostos de Sulfidrila/química , Compostos de Sulfidrila/metabolismo
17.
J Plant Physiol ; 239: 61-70, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31200171

RESUMO

Seeds are the basis of propagation for the common beech (Fagus sylvatica L.), but the seed set of the beech is unsteady, with 5-10 years between abundant crops. Beech seeds are very difficult to store and lose their viability quickly even in optimum storage conditions. To date, it has not been possible to determine factors indicative of the aging process and the loss of viability of beech seeds during storage. To address this important economic challenge and interesting scientific problem, we analyzed the adjustment of the redox state during the development and storage of seeds. Many metabolic processes are based on reduction and oxidation reactions. Thiol proteins control and react to the redox state in the cells. The level of thiol proteins increased during seed maturation and decreased during storage. Gel-based redox proteomics identified 17 proteins in beech seeds during development. The proteins could be assigned to processes like metabolism and antioxidant functions. During storage, the number of proteins decreased to only six, i.e., oxidoreductases, peptidases, hydrolases and isomerases. The occurrence of peroxiredoxins (PRX) as thiol peroxidases and redox regulators indicates an important role of cytosolic 1CysPRX and PRXIIC, mitochondrial PRXIIF, and plastidic PRXIIE, 2CysPRX, and PRXQ in beech seeds during development and storage. Particularly, 2CysPRX was present in beech seeds during development and storage and may perform an important function in regulation of the redox state during both seed development and storage. The role of thiol proteins in the regulation of the redox state during the development and storage of beech seeds is discussed.


Assuntos
Fagus/metabolismo , Sementes/metabolismo , Compostos de Sulfidrila/metabolismo , Fagus/crescimento & desenvolvimento , Germinação , Oxirredução , Peroxirredoxinas/metabolismo , Proteínas de Plantas/metabolismo , Sementes/crescimento & desenvolvimento
18.
Environ Sci Pollut Res Int ; 26(24): 24372-24379, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31230238

RESUMO

The Eucalyptus cultivation acreage was large in Guangxi provinces. Guanglin 9 (Eucalyptus grandis × Eucalyptus urophylla) is a widely cultivated Eucalyptus species and has been found to grow normally in soils contaminated by heavy metals such as arsenic (As), but the detoxification mechanisms are not clear yet. Through hydroponic experiment, the adsorption and detoxification of As in Eucalyptus were studied from three aspects, namely subcellular distribution of As, chemical forms of As, and the response of sulfhydryl substances. The subcellular distribution data showed that in the Eucalyptus roots, As was mainly present in the soluble fraction (66.3-79.9%), in leaves in the soluble fraction (50.6-53.8%), and the cell wall fraction (35.6-40.0%) under As stress. The chemical form data showed that in roots, As was mainly present in ethanol extraction state (29.5-40.0%), deionized water extraction state (28.3-31.7%), and sodium chloride extraction state (24.1-33.8%). As stress can induce the formation of non-protein thiols (NPT), glutathione (GSH), and phytochelatins (PCs). With the increasing As concentration, the NPT (maximum increase 55.9%) and GSH (maximum increase 79.9%) contents in roots significantly increased, while the PC content significantly increased and then significantly decreased. It is concluded that the As detoxification mechanisms of Eucalyptus are mainly vacuolar compartmentalization and the chelation of sulfhydryl substances, while cell wall adsorption and As chemical forms have limited effects on As detoxification.


Assuntos
Arsênico/toxicidade , Eucalyptus/fisiologia , Poluentes do Solo/toxicidade , Arsênico/análise , Parede Celular/metabolismo , Quelantes/farmacologia , China , Eucalyptus/efeitos dos fármacos , Glutationa/metabolismo , Hidroponia , Inativação Metabólica/fisiologia , Metais Pesados/análise , Fitoquelatinas/metabolismo , Folhas de Planta/metabolismo , Raízes de Plantas/metabolismo , Solo/química , Poluentes do Solo/análise , Compostos de Sulfidrila/metabolismo
19.
Ecotoxicol Environ Saf ; 179: 222-231, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31048218

RESUMO

Hydrogen sulfide (H2S), a multifunctional gasotransmitter, participates in a wide range of cellular signal transduction and pathophysiological processes. Cystathionine gamma-lyase (CSE) acts as a major H2S-generating enzyme in peripheral organs and tissues. As a cysteine-rich and heavy metal-binding protein, metallothionein-1 (MT-1) is known to protect cells from various environmental stresses. Here we demonstrated that exposure of cadmium (Cd) induced oxidative stress, depleted intracellular thiols, and stimulated apoptotic cell death in mouse myoblast cells. CSE expression and H2S production were significantly enhanced by Cd treatment. NaHS, a well-known H2S donor, at physiologically relevant concentration significantly alleviated Cd-induced damage in both myoblasts and mouse skeletal muscles. In contrast, down-regulation of CSE/H2S system deteriorated Cd-stimulated oxidative stress and cell death. Exposure of the cells to Cd lead to increased expressions of metal regulatory transcription factor 1 and MT-1, while siRNA-mediated MT-1 knockdown alleviated Cd-induced CSE expression and caused more oxidative stress and cell death. In addition, H2S post-translationally modified MT-1 by S-sulfhydration and stabilized zinc-protein complex. Taken together, these data suggest that CSE/H2S system would protect myoblasts and skeletal muscles from Cd-induced damage by S-sufhydrating MT-1.


Assuntos
Cádmio/toxicidade , Cistationina gama-Liase/genética , Poluentes Ambientais/toxicidade , Sulfeto de Hidrogênio/metabolismo , Metalotioneína/metabolismo , Mioblastos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Mioblastos/metabolismo , Mioblastos/patologia , Estresse Oxidativo/efeitos dos fármacos , Compostos de Sulfidrila/metabolismo , Sulfetos/farmacologia
20.
PLoS One ; 14(5): e0216606, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31067274

RESUMO

Thiol moieties are major targets for cold plasma-derived nitrogen and oxygen species, making CAPs convenient tools to modulate redox-signaling pathways in cells and tissues. The underlying biochemical pathways are currently under investigation but especially the role of CAP derived RNS is barely understood. Their potential role in protein thiol nitrosylation would be relevant in inflammatory processes such as wound healing and improving their specific production by CAP would allow for enhanced treatment options beyond the current application. The impact of a modified kINPen 09 argon plasma jet with nitrogen shielding on cysteine as a thiol-carrying model substance was investigated by FTIR spectroscopy and high-resolution mass spectrometry. The deposition of short-lived radical species was measured by electron paramagnetic resonance spectroscopy, long-lived species were quantified by ion chromatography (NO2-, NO3-) and xylenol orange assay (H2O2). Product profiles were compared to samples treated with the so-called COST jet, being introduced by a European COST initiative as a reference device, using both reference conditions as well as conditions adjusted to kINPen gas mixtures. While thiol oxidation was dominant under all tested conditions, an Ar + N2/O2 gas compositions combined with a nitrogen curtain fostered nitric oxide deposition and the desired generation of S-nitrosocysteine. Interestingly, the COST-jet revealed significant differences in its chemical properties in comparison to the kINPen by showing a more stable production of RNS with different gas admixtures, indicating a different •NO production pathway. Taken together, results indicate various chemical properties of kINPen and COST-jet as well as highlight the potential of plasma tuning not only by gas admixtures alone but by adjusting the surrounding atmosphere as well.


Assuntos
Nitrogênio/química , Nitrogênio/metabolismo , Oxigênio/química , Oxigênio/metabolismo , Gases em Plasma/química , Gases em Plasma/metabolismo , Compostos de Sulfidrila/metabolismo , Pressão Atmosférica , Gases/química , Gases/metabolismo , Peróxido de Hidrogênio/metabolismo , Oxirredução , Transdução de Sinais , Compostos de Sulfidrila/química
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