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1.
Nat Commun ; 10(1): 3761, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434880

RESUMO

The mechanisms underlying how cells subjected to genotoxic stress reestablish reduction-oxidation (redox) homeostasis to scavenge genotoxic stress-induced reactive oxygen species (ROS), which maintains the physiological function of cellular processes and cell survival, remain unclear. Herein, we report that, via a TCF-independent mechanism, genotoxic stress induces the enrichment of ß-catenin in chromatin, where it forms a complex with ATM phosphorylated-JDP2 and PRMT5. This elicits histone H3R2me1/H3R2me2s-induced transcriptional activation by the recruitment of the WDR5/MLL methyltransferase complexes and concomitant H3K4 methylation at the promoters of multiple genes in GSH-metabolic cascade. Treatment with OICR-9429, a small-molecule antagonist of the WDR5-MLL interaction, inhibits the ß-catenin/JDP2/PRMT5 complex-reestablished GSH metabolism, leading to a lethal increase in the already-elevated levels of ROS in the genotoxic-agent treated cancer cells. Therefore, our results unveil a plausible role for ß-catenin in reestablishing redox homeostasis upon genotoxic stress and shed light on the mechanisms of inducible chemotherapy resistance in cancer.


Assuntos
Dano ao DNA/fisiologia , Glutationa/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/metabolismo , beta Catenina/metabolismo , Células A549 , Animais , Compostos de Bifenilo/farmacologia , Linhagem Celular Tumoral , Cromatina , Di-Hidropiridinas/farmacologia , Feminino , Glutationa/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Homeostase , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteína de Leucina Linfoide-Mieloide/metabolismo , Neoplasias/metabolismo , Regiões Promotoras Genéticas , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Ativação Transcricional
2.
Chem Biol Interact ; 310: 108721, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31233715

RESUMO

OBJECTIVE: Increasing consumption of fructose is a major contributor to epidemic metabolic syndrome (MS), and the risk of renal disorders and/or injuries remains high among individuals with MS particularly during pregnancy. Glutamine (GLT) has been demonstrated to have a modulatory effect in MS and/or insulin resistance (IR). This study investigated the effect of GLT on renal lipid accumulation and glutathione depletion induced by high fructose-enriched drink (FED) in pregnant rats and also tested the hypothesis that the renoprotective role of GLT is by suppression of adenosine deaminase (ADA)/xanthine oxidase (XO)/uric acid (UA) pathway. METHODS: Pregnant Wistar rats weighing between 160 and 180 g were allotted into Control, GLT, FED and FED + GLT groups (6 rats/group). The groups received distilled water (vehicle, p. o.), 1 g/kg bw GLT (p.o.), 10% Fructose (w/v) and 10% Fructose (w/v) plus 1 g/kg bw GLT (p.o.) respectively, daily for 19 days. RESULTS: Data showed that FED caused IR, increased body weight gain, blood glucose, plasma insulin, creatinine, urea, lipid accumulation, lipid peroxidation, lactate production, aspartate transaminase and alanine aminotransferase, depressed Glucose-6-phosphate dehydrogenase, sodium-potassium-ATPase activities and glutathione. These alterations were accompanied by increased activity of ADA/XO/UA pathway. However, the FED-induced renal injury and its correlates were normalized by GLT supplementation. CONCLUSION: The present results demonstrate that renal lipid accumulation and glutathione depletion-driven renal injury in pregnant rats is accompanied by increased activity of ADA/XO/UA pathway. The findings also suggest that GLT would confer protection against renal injury by protecting against lipid accumulation and glutathionedepletion, at least in part, through suppression of ADA/XO/UA pathway.


Assuntos
Glutamina/farmacologia , Glutationa/análise , Resistência à Insulina , Lipídeos/análise , Neuroproteção/efeitos dos fármacos , Adenosina Desaminase/metabolismo , Animais , Feminino , Frutose/efeitos adversos , Glutationa/efeitos dos fármacos , Síndrome Metabólica , Gravidez , Ratos , Ratos Wistar , Ácido Úrico/metabolismo , Xantina Oxidase/metabolismo
3.
Inflammation ; 42(5): 1680-1691, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31115770

RESUMO

In this study, the effects of tyrosol were investigated in DSS-induced experimental ulcerative colitis model. For this purpose, rats were divided into five groups of seven rats in each: control group, colitis group (DSS-4%), tyrosol group (tyrosol 20 mg/kg), sulfasalazine (sulfasalazine+DSS 100 mg/kg), and treatment group (tyrosol+DSS 20 mg/kg). In the study, the active substances were administered to all animals for a period of 21 days. At the end of the study, malondialdehyde (MDA) levels increased (p < 0.001); GSH level (p < 0.05) along with GSH.Px (p < 0.01) and CAT (p < 0.001) activities decreased in the DSS-induced colitis group. However, with the administration of tyrosol, MDA and GSH levels along with GSH.Px and CAT activities came to the same levels as the control group. In the colitis group, an increase occurred in IL-6, COX-2, and NF-κB parameters, which created a significant difference compared to the control group (p < 0.001). Similarly, TNF-α levels also significantly increased with the administration of DSS (p < 0.05) which created a significant difference compared to the control group, while there was no difference among the other groups. As for the Nrf-2 data, it decreased with the administration of DSS which created a significant difference compared to the control group (p < 0.05), while there was no difference in other groups. In the colitis-induced group, IL-6, COX-2, and NF-κB gene expression levels also similarly increased but returned to the normal levels with the administration of tyrosol. In the histopathological scoring, the negativity that increased with the administration of DSS returned to the normal levels with the administration of tyrosol+DSS. In conclusion, according to the data obtained, tyrosol fixed the destruction picture in the DSS-induced colitis model, giving rise to thought that it has a protective effect.


Assuntos
Antioxidantes/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Álcool Feniletílico/análogos & derivados , Substâncias Protetoras/uso terapêutico , Animais , Antioxidantes/farmacologia , Colite Ulcerativa/induzido quimicamente , Ciclo-Oxigenase 2/metabolismo , Sulfato de Dextrana , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Malondialdeído/metabolismo , NF-kappa B/metabolismo , Álcool Feniletílico/farmacologia , Álcool Feniletílico/uso terapêutico , Substâncias Protetoras/farmacologia , Ratos , Fator de Necrose Tumoral alfa/metabolismo
4.
Nutrients ; 11(4)2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30970573

RESUMO

Oxidative stress is believed to be associated with both postmenopausal disorders and cataract development. Previously, we have demonstrated that rosmarinic and sinapic acids, which are diet-derived antioxidative phenolic acids, counteracted some disorders induced by estrogen deficiency. Other studies have shown that some phenolic acids may reduce cataract development in various animal models. However, there is no data on the effect of phenolic acids on oxidative stress markers in the lenses of estrogen-deficient rats. The study aimed to investigate whether administration of rosmarinic acid and sinapic acid affects the antioxidative abilities and oxidative damage parameters in the lenses of estrogen-deficient rats. The study was conducted on three-month-old female Wistar rats. The ovariectomized rats were orally treated with rosmarinic acid at doses of 10 and 50 mg/kg or sinapic acid at doses of 5 and 25 mg/kg, for 4 weeks. The content of reduced glutathione (GSH), oxidized glutathione and amyloid ß1-42, as well as products of protein and lipid oxidation, were assessed. Moreover, the activities of superoxide dismutase, catalase, and some glutathione-related enzymes in the lenses were determined. Rosmarinic and sinapic acids in both doses resulted in an increase in the GSH content and glutathione reductase activity. They also improved parameters connected with protein oxidation. Since GSH plays an important role in maintaining the lens transparency, the increase in GSH content in lenses after the use of rosmarinic and sinapic acids seems to be beneficial. Therefore, both the investigated dietary compounds may be helpful in preventing cataract.


Assuntos
Antioxidantes/farmacologia , Cinamatos/farmacologia , Ácidos Cumáricos/farmacologia , Depsídeos/farmacologia , Glutationa/efeitos dos fármacos , Cristalino/efeitos dos fármacos , Animais , Catalase/metabolismo , Catarata/prevenção & controle , Estrogênios/deficiência , Feminino , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
5.
Am J Physiol Endocrinol Metab ; 316(5): E922-E930, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30888858

RESUMO

Doxorubicin (DOX) is an effective chemotherapeutic treatment with lasting side effects in heart and skeletal muscle. DOX is known to bind with iron, contributing to oxidative damage resulting in cardiac and skeletal muscle toxicity. However, major cellular changes to iron regulation in response to DOX are poorly understood in liver, heart, and skeletal muscle. Additionally, two cotreatments, exercise (EX) and metformin (MET), were studied for their effectiveness in reducing DOX toxicity by ameliorating iron dysregulation and preventing oxidative stress. The purposes of this study were to 1) characterize the DOX-induced changes of the major iron regulation pathway in liver, heart, and skeletal muscle and 2) to determine whether EX and MET exert their benefits by minimizing DOX-induced iron dysregulation. Mice were assigned to receive saline or DOX (15 mg/kg) treatments, paired with either EX (5 days) or MET (500 mg/kg), and were euthanized 3 days after DOX treatment. Results suggest that the cellular response to DOX is protective against oxidative stress by reducing iron availability. DOX increased iron storage capacity through elevated ferritin levels in liver, heart, and skeletal muscle. DOX reduced iron transport capacity through reduced transferrin receptor levels in heart and skeletal muscle. EX and MET cotreatments had protective effects in the liver through reduced transferrin receptor levels. At 3 days after DOX, oxidative stress was mild, as shown by normal glutathione and lipid peroxidation levels. Together these results suggest that the cellular response to reduce iron availability in response to DOX treatment is sufficient to match oxidative stress.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Hipoglicemiantes/farmacologia , Ferro/metabolismo , Metformina/farmacologia , Condicionamento Físico Animal , Animais , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Coração/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptores da Transferrina/efeitos dos fármacos , Receptores da Transferrina/metabolismo
6.
Phytomedicine ; 58: 152865, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30831465

RESUMO

BACKGROUND: Acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure in clinic. Fisetin (FST) is a phenolic compound that has been isolated from many natural products. PURPOSE: Our aim is to study the protection effect and mechanisms of FST on APAP-induced hepatotoxicity in endogenous metabolism and metabolomics in vitro and in vivo. METHODS: FST was i.g. administered to mice at 10, 20 and 40 mg/kg for 7 days and a single dose of APAP (400 mg/kg) was given on the last day. Serum and tissue were collected for biochemical analysis. L-02 cells were used to assess cell viability. LC-MS was used to study the metabolic fingerprinting in vivo and vitro. PCA and OPLS-DA were used to search the potential biomarkers (VIP > 1, p < 0.05). The pathway analysis was conducted on Metaboanalyst 4.0. Then liver oxidative stress indices and glutathione markers were examined using PCR and kits. RESULTS: ALT, AST, liver histological observation and cell viability results showed that FST could reverse APAP induced toxicology in mice and L-02 cells. In metabolomics study, 26 metabolites in vitro and 60 metabolites in vivo were identified by searching in the library and most of them decreased to normal level in FST treatment. It is observed in pathway analysis that the most significant pathway was glutathione metabolism. Furthermore, the results of mRNA and immunofluorescence showed that FST suppressed ROS formation in liver tissue and L-02 cells, as well as restored the expression of GPX1, GST and other antioxidative enzymes genes. CONCLUSION: Our results indicate that FST prevented APAP-induced hepatotoxicity by regulating glutathione metabolism and the expression of related antioxidative signals.


Assuntos
Acetaminofen/efeitos adversos , Antioxidantes/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Flavonoides/administração & dosagem , Glutationa/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Glutationa/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Espécies Reativas de Oxigênio/metabolismo
7.
Neurochem Res ; 44(5): 1167-1181, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30806880

RESUMO

Menadione (2-methyl-1,4-naphthoquinone) is a synthetic derivative of vitamin K that allows rapid redox cycling in cells and thereby generates reactive oxygen species (ROS). To test for the consequences of a treatment of brain astrocytes with menadione, we incubated primary astrocyte cultures with this compound. Incubation with menadione in concentrations of up to 30 µM did not affect cell viability. In contrast, exposure of astrocytes to 100 µM menadione caused a time-dependent impairment of cellular metabolism and cell functions as demonstrated by impaired glycolytic lactate production and strong increases in the activity of extracellular lactate dehydrogenase and in the number of propidium iodide-positive cells within 4 h of incubation. In addition, already 5 min after exposure of astrocytes to menadione a concentration-dependent increase in the number of ROS-positive cells as well as a concentration-dependent and transient accumulation of cellular glutathione disulfide (GSSG) were observed. The rapid intracellular GSSG accumulation was followed by an export of GSSG that was prevented in the presence of MK571, an inhibitor of the multidrug resistance protein 1 (Mrp1). Menadione-induced glutathione (GSH) oxidation and ROS formation were found accelerated after glucose-deprivation, while the presence of dicoumarol, an inhibitor of the menadione-reducing enzyme NQO1, did not affect the menadione-dependent GSSG accumulation. Our study demonstrates that menadione rapidly depletes cultured astrocytes of GSH via ROS-induced oxidation to GSSG that is subsequently exported via Mrp1.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Dissulfeto de Glutationa/efeitos dos fármacos , Vitamina K 3/farmacologia , Animais , Astrócitos/metabolismo , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Glicólise/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Oxirredução , Ratos Wistar
8.
Eur J Med Chem ; 167: 133-145, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30771601

RESUMO

A novel series of tetrahydroisoquinoline-benzimidazole hybrids have been designed and synthesized as multifunctional agents against Alzheimer's disease (AD). These compounds were evaluated for their inhibition of neuroinflammation and human ß-secretase (hBACE1), and neuroprotective activity. Among them, compound BD3 possessed significant anti-neuroinflammatory activity (IC50 = 5.07 µM against nitric oxide production) through inhibiting the expression and secretion of proinflammatory cytokines in BV2 cells. Compound BD3 also exhibited moderate hBACE1 inhibitory activity (65.7% inhibition at 20 µM) and potent neuroprotective effect by increasing GSH level and reducing ROS production (91.8% cell viability at 5 µM). Parallel artificial membrane permeation assay demonstrated that BD3 could cross the blood-brain barrier (BBB). Thus, this study demonstrates that the compounds with tetrahydroisoquinoline-benzimidazole scaffold are potential anti-AD agents, and they are worth for the further development.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzimidazóis/uso terapêutico , Desenho de Drogas , Tetra-Hidroisoquinolinas/uso terapêutico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Benzimidazóis/química , Benzimidazóis/farmacologia , Linhagem Celular , Permeabilidade da Membrana Celular , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Inflamação/tratamento farmacológico , Camundongos , Fármacos Neuroprotetores/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia
9.
Psychiatry Res ; 270: 430-437, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30316170

RESUMO

Post-traumatic stress disorder (PTSD) may occur after exposure to stressful, fearful or troubling events. Until now, there is no curable medication for this disorder. Cerebrolysin is a neuropeptide, which has an important role in the treatment of vascular dementia. In this study, the probable protective effect of cerebrolysin on PTSD-induced memory impairment was investigated. To induce PTSD, the single prolonged stress (SPS) model was used. Rats were allocated into four groups: control (vehicle-treated), CBL (administrated cerebrolysin 2.5 ml/kg by intraperitoneal route for 4 weeks), SPS (as a model of PTSD and administered vehicle), and CBL-SPS (exposed to SPS and administered cerebrolysin for 4 weeks). Learning and memory were assessed using the radial arm water maze (RAWM). Results showed that SPS impaired both short- and long- term memories; and chronic cerebrolysin administration prevented such effect. Cerebrolysin also prevented decreases in hippocampal GSH levels and GSH/GSSG ratios, and increased GSSG and TBARs, levels induced by PTSD. In conclusion, a protective effect of cerebrolysin administration against SPS model of PTSD induced short- and long- term memory impairment was characterized. This protection could be accomplished, at least partly, by prevention of PTSD induced increase in oxidative stress in the hippocampus via the use of cerebrolysin.


Assuntos
Aminoácidos/farmacologia , Hipocampo/efeitos dos fármacos , Transtornos da Memória/prevenção & controle , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/psicologia , Animais , Modelos Animais de Doenças , Medo , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Dissulfeto de Glutationa/efeitos dos fármacos , Dissulfeto de Glutationa/metabolismo , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Restrição Física , Natação , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
10.
Acta Cir Bras ; 33(7): 609-618, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30110062

RESUMO

PURPOSE: To investigate the gastroprotective effect of methanol extract of E. spectabilis and its major component isoorientin. METHODS: Effects of isoorientin and methanol extract of E. spectabilis were investigated in indomethacin-induced gastric damage model on rats. Famotidine was used as the standard antiulcer drug. Numerical density of ulcer areas and oxidative status were determined on stomach tissues of rats. RESULTS: All doses of isoorientin and methanol extract decreased MDA level and increased SOD activity and GSH levels in the stomach tissue of rats. When numerical density of ulcer areas were analized, the 500 mg/kg dose of methanol extract (84%) exhibited a similar effect to 20 mg/kg dose of standart drug famotidine (87%). CONCLUSIONS: The gastroprotective effects of E. spectabilis and its major constituent isoorientin in rats for the first time. Detailed analyses suggested that potential antioxidant activity of both plant extract and isoorientin mediates the gastroprotective effect.


Assuntos
Antiulcerosos/farmacologia , Antioxidantes/farmacologia , Luteolina/farmacologia , Metanol/farmacologia , Extratos Vegetais/farmacologia , Úlcera Gástrica/tratamento farmacológico , Xanthorrhoeaceae/química , Animais , Relação Dose-Resposta a Droga , Glutationa/análise , Glutationa/efeitos dos fármacos , Indometacina , Masculino , Malondialdeído/análise , Ratos Wistar , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Úlcera Gástrica/patologia , Superóxido Dismutase/análise , Superóxido Dismutase/efeitos dos fármacos , Resultado do Tratamento
11.
Niger J Physiol Sci ; 33(1): 83-88, 2018 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-30091737

RESUMO

Poisoning from Organophosphates (OPs), especially Dichlorvos (DDVP) has become endemic due to theincreasing use in house hold and agricultural pests control, with most marked effects in the nervous system. However, it isevidenced that natural antioxidants are efficacious against OPs toxicity. Thus, this study investigated the possible antidotalefficacy of Nigella sativa oil (NSO) in Dichlovos (DDVP) induced oxidative and neuronal damages in Wistar rats. DDVPwas administered at sub-chronic daily dosage of 8.8 mg/kg.bw for 7 days and a post-administration of NSO at 1 ml/kg.bwfor the subsequent 7 days. The rats were euthanized on the 15thday, blood sample collected via cardiac puncture, centrifugedand the plasma used for biochemical analysis of total antioxidant capacity (TAC), reduced glutathione (GSH) and totalreactive oxygen species (ROS), while the frontal, occipital and cerebellar cortices and the medulla were removed for histomorphological examinations. The results showed significant (P≤0.05) decrease in plasma TAC and GSH, while a significant(P≤0.05) increase in ROS was recorded, and some vacuolation around the neurons especially in the frontal and cerebellarcortices following DDVP exposure. However, post treatment with NSO was observed to be efficacious in the recovery ofthe oxidative activities and the neuro-architectural integrities. Thus, it can be concluded that the antioxidant capacity of NSOcould be efficacious against OPs induced oxidative damages, especially in dichlorvos accidents.


Assuntos
Antioxidantes/farmacologia , Diclorvós/farmacologia , Neurônios/efeitos dos fármacos , Nigella sativa/efeitos dos fármacos , Animais , Glutationa/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar
12.
Free Radic Biol Med ; 124: 431-446, 2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-29981371

RESUMO

In photodynamic therapy (PDT), the elevated glutathione (GSH) of cancer cells have two sides for treatment efficacy, activation pre-drug by removing activity suppressor part (advantages) and consumption reactive oxygen species (ROS) to confer PDT resistance (disadvantages). Preparation all-in-one system by simple method to make best use of the advantages and bypass the disadvantages still were remains a technical challenge. Herein, we report a robust PDT nanoparticle with above function based on a self-assembled pyridine modified Zinc phthalocyanine (ZnPc-DTP). The activity suppressor and active part of ZnPc-DTP were linked by disulfide bond. After targeting cancer cells, GSH can react with ZnPc-DTP nanoparticles by cutting disulfide bond to release its active part (ZnPc-SH) and oxidize GSH. In vitro and in vivo results indicated that ZnPc-SH can effective suppress tumor growth under the low antioxidant tumor microenvironment (TME).


Assuntos
Antioxidantes/farmacologia , Glutationa/efeitos dos fármacos , Indóis/farmacologia , Nanopartículas/química , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desenho de Drogas , Humanos , Fotoquimioterapia/métodos
13.
World Neurosurg ; 120: e33-e41, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30031958

RESUMO

OBJECTIVE: Spinal cord ischemia is a serious and catastrophic clinicopathologic condition. Despite studies reported over the last 20 years, alternative and efficient treatment options remain unclear. We examined the neuroprotective effects of vigabatrin on a spinal ischemia-reperfusion model. METHODS: We divided 24 New Zealand rabbits into 4 groups (control, ischemia reperfusion, and low-dose and high-dose vigabatrin). The control group underwent only abdominal surgery, whereas an abdominal aortic cross-clamp model of spinal ischemia was performed in the other groups. Clips were removed after 30 minutes and 50 and 150 mg/kg vigabatrin was administered intraperitoneally to the low-dose and high-dose groups, respectively. Neurologic examination was performed for 48 hours, after which the rabbits were sacrificed and a blood sample obtained. Biochemical examination of malondialdehyde, advanced oxidation protein products, total nitric oxide, and glutathione levels and superoxide dismutase activities in plasma and tissue sample, and histopathologic examination of the spinal cord were performed and statistical results compared between the groups. RESULTS: Low-dose vigabatrin had statistically significant effects of neuroprotection on spinal ischemia. Although high-dose vigabatrin had similar effects, the results were not statistically significant for all parameters of biochemical analysis. In addition, histopathologic examination showed some toxic effects of high-dose vigabatrin. CONCLUSIONS: Neuroprotective effects of vigabatrin are shown. For clinical use, further studies are needed.


Assuntos
GABAérgicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/metabolismo , Isquemia do Cordão Espinal/metabolismo , Medula Espinal/efeitos dos fármacos , Vigabatrina/farmacologia , Produtos da Oxidação Avançada de Proteínas/efeitos dos fármacos , Produtos da Oxidação Avançada de Proteínas/metabolismo , Animais , Constrição , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Masculino , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Coelhos , Medula Espinal/metabolismo , Medula Espinal/patologia
14.
Biomed Res Int ; 2018: 5672637, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30050937

RESUMO

Glutathione (GSH) plays crucial roles in regulating the hepatotoxicity of Microcystin-LR (MCLR) by inhibiting oxidative stress or by toxin conjugation. Based on MCLR conjugation product preparation and purification, the direct and indirect regulation pathways for GSH were fully evaluated. Protein phosphatase inhibition analysis verified that GSH conjugation was an effective pathway to regulate the inhibition effect of MCLR, while GSH had slight influence on the toxicity of MCLR. Research on oxidative stress showed that both regulation pathways could reduce the formation of reactive oxygen species (stimulated by MCLR and regulated by NADH oxidase) and regulate the adverse effects on antioxidant enzymes. By evaluating the contributions for both pathways, it could be found that the indirect pathway had significant contribution to eliminating cellular reactive oxygen species and regulating protein phosphatases inhibition, while the direct regulation pathway had moderate influence. As glutathione transferases facilitated the transformation of MCLR, the hepatotoxicity of MCLR could be effectively regulated by GSH conjugation pathway, especially with abundant exogenous GSH.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Glutationa/efeitos dos fármacos , Microcistinas/toxicidade , Animais , Glutationa/metabolismo , Humanos , Estresse Oxidativo , Coelhos
15.
ACS Chem Neurosci ; 9(12): 3108-3116, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29989791

RESUMO

Honokiol (Hon), a polyphenol and main active ingredient from the bark of Magnolia officinalis, has been documented as having multiple pharmacological functions, including neuroprotection. However, the mechanisms underlying its neuroprotective effects are not well-defined. In this study, we reported that Hon attenuates the H2O2- or 6-hydroxydopamine (6-OHDA)-induced apoptosis of PC12 cells by increasing the glutathione level and upregulating a multitude of cytoprotective proteins, including heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, thioredoxin 1, and thioredoxin reductase 1. Further studies reveal that Hon promotes transcription factor Nrf2 nuclear translocation and activation. Moreover, the cytoprotection of Hon was antagonized by silence of Nrf2 expression, highlighting the fact that Nrf2 is critically engaged in the cellular functions of Hon. Taken together, our study identified that Hon is an effective agonist of Nrf2 in the neuronal system and displays potent neuroprotection against oxidative stress-mediated PC12 cell damage. These findings indicate that Hon is promising for further development as a therapeutic drug against oxidative stress-related neurodegenerative disorders.


Assuntos
Compostos de Bifenilo/farmacologia , Lignanas/farmacologia , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Adrenérgicos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Heme Oxigenase (Desciclizante)/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Peróxido de Hidrogênio/farmacologia , NAD(P)H Desidrogenase (Quinona)/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/metabolismo , Oxidantes/farmacologia , Oxidopamina/farmacologia , Células PC12 , Ratos , Tiorredoxina Redutase 1/efeitos dos fármacos , Tiorredoxina Redutase 1/metabolismo , Tiorredoxinas/efeitos dos fármacos , Tiorredoxinas/metabolismo
16.
Acta Biol Hung ; 69(2): 115-124, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29888671

RESUMO

In the present study the effect of capsaicin was studied on PD model flies expressing human alpha synuclein. First the potential of scavenging superoxide anion and free radicals by capsaicin at doses of 20, 40, 80 and 100 µM was estimated. The PD flies were allowed to feed separately on the diet containg 20, 40, 80 and 100 µM of capsaicin, respectively, for 24 days. After 24 days of exposure, fly head homogenate was prepared from each group and was used to estimate glutathione (GSH), protein carbonyl (PC), dopamine content, lipid peroxidation (LPO), glutathione-S-transferase (GST) and monoamine oxidase (MAO) activity. A dose dependent significant increase in the potential of scavenging superoxide anions and free radicals by capsaicin was observed for the doses of 20, 40, 80 and 100 µM. The exposure of capsaicin not only significantly increased the GSH (max. by 1.37-fold), and dopamine (max. by 1.56-fold) content but also reduced LPO (max. by 1.8-fold), GST (max. by 1.26-fold), MAO activities (max. by 1.60-fold) and PC content (max. by 1.95-fold), compared to unexposed PD flies (p < 0.05). The results suggest the protective role of capsaicin against the PD symptoms.


Assuntos
Capsaicina/farmacologia , Dopamina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/metabolismo , Fármacos do Sistema Sensorial/farmacologia , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Drosophila , Radicais Livres/metabolismo , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Transferase/efeitos dos fármacos , Glutationa Transferase/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Monoaminoxidase/efeitos dos fármacos , Monoaminoxidase/metabolismo , Doença de Parkinson/genética , Carbonilação Proteica/efeitos dos fármacos , Superóxidos/metabolismo , alfa-Sinucleína/genética
17.
Biol Res ; 51(1): 17, 2018 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-29891016

RESUMO

BACKGROUND: Improper control on reactive oxygen species (ROS) elimination process and formation of free radicals causes tissue dysfunction. Pineal hormone melatonin is considered a potent regulator of such oxidative damage in different vertebrates. Aim of the current communication is to evaluate the levels of oxidative stress and ROS induced damage, and amelioration of oxidative status through melatonin induced activation of signaling pathways. Hepatocytes were isolated from adult Labeo rohita and exposed to H2O2 at three different doses (12.5, 25 and 50 µM) to observe peroxide induced damage in fish hepatocytes. Melatonin (25, 50 and 100 µg/ml) was administered against the highest dose of H2O2. Enzymatic and non-enzymatic antioxidants such as malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) was measured spectrophotometrically. Expression level of heat shock proteins (HSP70 and HSP90), HSPs-associated signaling molecules (Akt, ERK, cytosolic and nuclear NFkB), and melatonin receptor was also measured by western blotting analysis. RESULTS: H2O2 induced oxidative stress significantly altered (P < 0.05) MDA and GSH level, SOD and CAT activity, and up regulated HSP70 and HSP90 expression in carp hepatocytes. Signaling proteins exhibited differential modulation as revealed from their expression patterns in H2O2-exposed fish hepatocytes, in comparison with control hepatocytes. Melatonin treatment of H2O2-stressed fish hepatocytes restored basal cellular oxidative status in a dose dependent manner. Melatonin was observed to be inducer of signaling process by modulation of signaling molecules and melatonin receptor. CONCLUSIONS: The results suggest that exogenous melatonin at the concentration of 100 µg/ml is required to improve oxidative status of the H2O2-stressed fish hepatocytes. In H2O2 exposed hepatocytes, melatonin modulates expression of HSP70 and HSP90 that enable the hepatocytes to become stress tolerant and survive by altering the actions of ERK, Akt, cytosolic and nuclear NFkB in the signal transduction pathways. Study also confirms that melatonin could act through melatonin receptor coupled to ERK/Akt signaling pathways. This understanding of the mechanism by which melatonin regulates oxidative status in the stressed hepatocytes may initiate the development of novel strategies for hepatic disease therapy in future.


Assuntos
Hepatócitos/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Melatonina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Western Blotting , Catalase/efeitos dos fármacos , Catalase/metabolismo , Peixes , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Hepatócitos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Malondialdeído/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Espectrofotometria , Superóxido Dismutase/efeitos dos fármacos
18.
Metab Brain Dis ; 33(5): 1573-1584, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29934859

RESUMO

The physiopathology of anxiety or depression related to diabetes is still poorly understood. The treatment with antidepressant drugs is a huge challenge due to theirs adherence low rate and many adverse effects. Thus, the seeking for a better treatment for these associated diseases is of utmost importance. Given that the oxidative stress in different tissues occurs in diabetes and anxiety or depression as well, the antioxidant gallic acid becomes an interesting compound to be investigated. Thus, the effects of long-term treatment with gallic acid (0, 10, 20 and 40 mg/kg; gavage) were evaluated in diabetic (DBT) animals submitted to the elevated plus-maze (EPM), the light-dark transition (LDT) tests and modified forced swim test (mFST). Also, indirect parameters of oxidative stress, lipid peroxidation (LPO) and reduced glutathione (GSH) levels were evaluated in the hippocampus (HIP) and prefrontal cortex (PFC). The results showed that DBT animals presented a decrease in the spent time in the open arms, in the end arm exploration and head dips when evaluated in the EPM test; moreover, a decrease in the spent time in the lit compartment of LDT test was observed, suggesting an anxiogenic-like behavior. During the mFST, an increase in the mean counts of immobility and a decrease in the mean counts of swimming and climbing were observed, indicating a depressive-like behavior. These aversive behaviors were more pronounced when compared to normoglycemic (NGL) animals and streptozotocin-treated animals that not become DBT. In addition, DBT rats showed an increase in the oxidative stress parameters in the HIP and PFC that was reversed by the gallic acid treatment (lowest dose - 10 mg/kg), i.e., the treatment decreased the elevated LPO levels and increased the reduced GSH in the HIP and PFC. Also, gallic acid treatment was able to produce an anxiolytic-like effect in the EPM and LDT tests, but not antidepressant-like effect in the FST. Taken together, the results suggest that the antioxidant/neuroprotective effect of gallic acid treatment in HIP and PFC of DBT animals may be essential to the anxiolytic-like effect.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Antioxidantes/farmacologia , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Diabetes Mellitus Experimental/psicologia , Ácido Gálico/farmacologia , Animais , Ansiolíticos/administração & dosagem , Antidepressivos/administração & dosagem , Antioxidantes/administração & dosagem , Ansiedade/etiologia , Ansiedade/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Depressão/etiologia , Depressão/fisiopatologia , Diabetes Mellitus Experimental/induzido quimicamente , Modelos Animais de Doenças , Fluoxetina/administração & dosagem , Fluoxetina/farmacologia , Ácido Gálico/administração & dosagem , Glutationa/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hiperglicemia/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , Estreptozocina
19.
Free Radic Biol Med ; 124: 342-352, 2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-29935260

RESUMO

Altered redox homeostasis including higher levels of copper, reduced glutathione (GSH) and reactive oxygen species (ROS) in cancer cells than in normal cells illustrates their redox vulnerability, and has opened a window for developing prooxidative anticancer agents (PAAs) to hit this status. However, how to design PAAs with high selectivity in killing cancer cells over normal cells remains a challenge. Herein we designed a 3-hydroxyflavone-inspired copper pro-ionophore (PHF) as a potent PAA based on the GSH-mediated conversion of 2,4-dinitrobenzenesulfonates to enols. Mechanistic investigation reveals that it is capable of exploiting increased levels of GSH in cancer cells to in situ release an active ionophore, 3-hydroxyflavone, inducing redox imbalance (copper accumulation, GSH depletion and ROS generation) and achieving highly selective killing of cancer cells upon specific transport of small amounts of Cu(II). To the best of our knowledge, it is the first example of Cu(II) pro-ionophore type of PAA which hits (changes) the three birds (abnormal copper, GSH and ROS levels in cancer cells) with one stone (PHF) in terms of its ability to induce preferentially redox imbalance of cancer cells by copper accumulation, GSH depletion and ROS generation.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Glutationa/metabolismo , Ionóforos/farmacologia , Oxirredução/efeitos dos fármacos , Linhagem Celular Tumoral , Cobre , Desenho de Drogas , Glutationa/efeitos dos fármacos , Humanos , Espécies Reativas de Oxigênio/metabolismo
20.
Chemosphere ; 208: 749-756, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29902759

RESUMO

Metals and pesticides are common pollutants and the modulation of biomarkers can indicate sub-lethal influences on the physiology of organisms inhabiting impacted aquatic systems. We examined the effects of mercury and the organophosphate pesticide dimethoate on EROD, MROD, glutathione S-transferase (GST), acetylcholine esterase (AChE), metallothionein (MT) and glutathione (GSH) in the signal crayfish (Pacifastacus leniusculus). Crayfish were injected with mercury chloride or dimethoate (0.3, 0.6, 0.9 µg kg-1) and dissected after 72 h. EROD activity in the hepatopancreas did not change in response to mercury chloride treatment but exhibited a dose dependent decrease at all concentrations of dimethoate tested. MROD (hepatopancreas) exhibited a significant decrease at the 0.9 µg kg-1 treatment for both chemicals. GST (hepatopancreas) demonstrated a significant dose dependent decrease at all concentrations of both mercury chloride and dimethoate. AChE (tail muscle) decreased at the 0.6 and 0.9 µg kg-1 concentrations of dimethoate and 0.9 µg kg-1 mercury chloride. In gill tissue, MT increased in response to 0.3 and 0.6 µg kg-1 of mercury chloride but no effect was observed at the 0.9 µg kg-1 concentration of mercury chloride or any concentrations of dimethoate tested. MT did not change in response to mercury or dimethoate in tail tissue. Furthermore, neither chemical modulated GSH concentrations. Our results indicate that, apart from GSH, these markers are sensitive to the pollutants tested and that animals exposed in the wild are potentially compromised in their ability to detoxify environmental contaminants and carry out normal cellular processes.


Assuntos
Astacoidea/enzimologia , Dimetoato/toxicidade , Mercúrio/toxicidade , Acetilcolinesterase/efeitos dos fármacos , Animais , Astacoidea/efeitos dos fármacos , Brânquias , Glutationa/efeitos dos fármacos , Glutationa Transferase/efeitos dos fármacos , Hepatopâncreas/efeitos dos fármacos , Inseticidas/farmacologia , Mercúrio/farmacologia , Metalotioneína/efeitos dos fármacos , Distribuição Tecidual
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