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1.
Life Sci ; 242: 117240, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31891722

RESUMO

Lycium barbarum polysaccharides (LBP) are derived from Wolfberry and have antioxidant activities. This study aimed to evaluate the efficacy of LBP for kidney injury in a rat model of sepsis. Male rats were divided randomly to control group (Con), LPS group (LPS), ulinastatin group (ULI), low dose LBP group (LBP-1), middle dose LBP group (LBP-2) and high dose LBP group (LBP-3). After intraperitoneal injection of LPS (5 mg/kg) to make sepsis model (LPS group), 10,000 U/kg ulinastatin were given in ULI group, and 200, 400 and 800 mg/kg LBP was given in LBP-1, -2, -3 group, respectively. Serum IL-1ß, IL-6, IL-8, TNF-α and NF-κB levels were measured by ELISA. Nrf2, Keap1, NF-κB, HO-1 and NQO1 expression levels were detected by PCR and Western blot analysis. We found that LBP decreased the levels of NF-κB and pro-inflammatory cytokines while attenuated kidney injury. In addition, LBP regulated Keap1-Nrf2/ARE signaling pathway in the kidney. In conclusion, LBP attenuates inflammation injury in the kidney via possible regulation of Keap1-Nrf2/ARE signaling.


Assuntos
Lesão Renal Aguda/prevenção & controle , Elementos de Resposta Antioxidante/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Sepse/complicações , Transdução de Sinais/efeitos dos fármacos , Animais , Western Blotting , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real
2.
IET Syst Biol ; 13(5): 243-250, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31538958

RESUMO

In humans, oxidative stress is involved in the development of diabetes, cancer, hypertension, Alzheimers' disease, and heart failure. One of the mechanisms in the cellular defence against oxidative stress is the activation of the Nrf2-antioxidant response element (ARE) signalling pathway. Computation of activity, efficacy, and potency score of ARE signalling pathway and to propose a multi-level prediction scheme for the same is the main aim of the study as it contributes in a big amount to the improvement of oxidative stress in humans. Applying the process of knowledge discovery from data, required knowledge is gathered and then machine learning techniques are applied to propose a multi-level scheme. The validation of the proposed scheme is done using the K-fold cross-validation method and an accuracy of 90% is achieved for prediction of activity score for ARE molecules which determine their power to refine oxidative stress.


Assuntos
Biologia Computacional/métodos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Elementos de Resposta Antioxidante/efeitos dos fármacos , Modelos Estatísticos , Curva ROC
3.
J Agric Food Chem ; 67(29): 8227-8234, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31299148

RESUMO

The mechanisms underlying neurodegenerative diseases are not fully understood yet. However, an increasing amount of evidence has suggested that these disorders are related to oxidative stress. We reported herein that lipoamide (LM), a neutral amide derivative of lipoic acid (LA), could resist oxidative stress-mediated neuronal cell damage. LM is more potent than LA in alleviating hydrogen peroxide- or 6-hydroxydopamine-induced PC12 cell injury. Our results reveal that LM promotes the nuclear accumulation of NFE2-related factor 2 (Nrf2), following with the activation of expression of Nrf2-governed antioxidant and detoxifying enzymes. Notably, silencing Nrf2 gene annuls the protection of LM, which demonstrates that Nrf2 is engaged in this cytoprotection. Our findings suggest that LM might be used as a potential therapeutic candidate for oxidative stress-related neurological disorders.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ácido Tióctico/análogos & derivados , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Células PC12 , Ratos , Transdução de Sinais/efeitos dos fármacos , Ácido Tióctico/farmacologia
4.
Food Funct ; 10(8): 4593-4607, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31289794

RESUMO

Drug-induced nephrotoxicity contributes to acute kidney injury (AKI) and represents a major problem in the clinical setting. We investigated the possible involvement of NLRP3 inflammasome activation in methotrexate (MTX)-induced nephrotoxicity and the protective potential of ferulic acid (FA), pointing out the role of PPARγ and Nrf2/HO-1 signaling. Rats that received MTX showed a significant increase in circulating creatinine and urea, and kidney Kim-1 levels along with multiple histological alterations. Reactive oxygen species (ROS), malondialdehyde and nitric oxide levels showed a significant increase in the kidney of rats that received MTX, while antioxidant defenses were diminished. FA ameliorated kidney function markers, prevented histological alterations, suppressed ROS production and enhanced antioxidant defenses. FA inhibited MTX-induced inflammasome activation as showed by the decreased phosphorylation of NF-κB, and expression of NLRP3, caspase-1 and IL-1ß. MTX caused apoptosis marked by increased expression of BAX, cytochrome c and caspase-3, and suppressed Bcl-2, effects that were significantly reversed in FA-treated groups. In addition, FA up-regulated Nrf2/ARE/HO-1 signaling and PPARγ expression in the kidney of MTX-induced rats. In conclusion, activation of NLRP3 inflammasome may represent a new mechanism for MTX nephrotoxicity. FA up-regulated PPARγ and Nrf2 signaling, prevented overproduction of ROS, and suppressed NF-κB/NLRP3 inflammasome axis and apoptosis in the kidney of MTX-induced rats.


Assuntos
Lesão Renal Aguda/prevenção & controle , Ácidos Cumáricos/administração & dosagem , Heme Oxigenase (Desciclizante)/metabolismo , Inflamassomos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , PPAR gama/metabolismo , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/genética , Lesão Renal Aguda/metabolismo , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/genética , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/genética , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Metotrexato/efeitos adversos , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , PPAR gama/genética , Substâncias Protetoras/administração & dosagem , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
Oxid Med Cell Longev ; 2019: 7283683, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308876

RESUMO

Antioxidative stress provides a cardioprotective effect during myocardial ischemia/reperfusion (I/R). Previous research has demonstrated that the blockade of transient receptor potential vanilloid 4 (TRPV4) attenuates myocardial I/R injury. However, the underlying mechanism remains unclear. The current study is aimed at investigating the antioxidative activity of TRPV4 inhibition and elucidating the underlying mechanisms in vitro and ex vivo. We found that the inhibiting TRPV4 by the selective TRPV4 blocker HC-067047 or specific TRPV4-siRNA significantly reduces reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) levels in H9C2 cells exposed to hypoxia/reoxygenation (H/R). Meanwhile, the activity of antioxidative enzymes, particularly superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), is enhanced. Furthermore, after H/R, HC-067047 treatment increases the expression of P-Akt and the translocation of nuclear factor E2-related factor 2 (Nrf2) and related antioxidant response element (ARE) mainly including SOD, GSH-Px, and catalase (CAT). LY294002, an Akt inhibitor, suppresses HC-067047 and specific TRPV4-siRNA-induced Nrf2 expression and its nuclear accumulation. Nrf2 siRNA attenuates HC-067047 and specific TRPV4-siRNA-induced ARE expression. In addition, treatment with LY294002 or Nrf2 siRNA significantly attenuates the antioxidant and anti-injury effects of HC-067047 in vitro. Finally, in experiments on isolated rat hearts, we confirmed the antioxidative stress roles of TRPV4 inhibition during myocardial I/R and the application of exogenous H2O2. In conclusion, the inhibition of TRPV4 exerts cardioprotective effects through enhancing antioxidative enzyme activity and expressions via the Akt/Nrf2/ARE pathway.


Assuntos
Antioxidantes/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Elementos de Resposta Antioxidante/genética , Catalase/metabolismo , Cromonas/farmacologia , Peróxido de Hidrogênio/metabolismo , Masculino , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Fator 2 Relacionado a NF-E2 , Proteína Oncogênica v-akt/antagonistas & inibidores , Proteína Oncogênica v-akt/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pirróis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
6.
Eur J Pharmacol ; 859: 172516, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31265839

RESUMO

Angiotensin II (Ang II) is a vasoactive peptide that elevates arterial blood pressure and leads to hypertension. Ang II has been reported to induce endothelial dysfunction by induction of apoptosis and oxidative stress in vascular endothelial cells. Sirtuin6 (SIRT6) has emerged as a critical regulator for modulating Ang II-induced injury of the cardiovascular system. However, little is known about the role of SIRT6 in regulating Ang II-induced injury in vascular endothelial cells. Here, our results showed that SIRT6 expression was decreased in vascular endothelial cells exposed to Ang II. This was accompanied by decreased cell viabilities as well as increased apoptosis and the production of reactive oxygen species. Functional experiments showed that the overexpression of SIRT6 significantly prohibited Ang II-induced apoptosis and reactive oxygen species generation, while silencing SIRT6 resulted in the opposite effect. Notably, our results showed that overexpression of SIRT6 resulted in a significant increase in the nuclear expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated the expression of the Nrf2 target gene in vascular endothelial cells exposed to Ang II. Moreover, knockdown of Nrf2 significantly blocked the SIRT6-mediated protection effect against Ang II-induced apoptosis and reactive oxygen species generation. Taken together, these results demonstrate that SIRT6 overexpression alleviates Ang II-induced apoptosis and oxidative stress in vascular endothelial cells by promoting Nrf2 antioxidant signaling. Our study suggests that SIRT6 may serve as a potential therapeutic target for treating hypertension associated with endothelial dysfunction.


Assuntos
Angiotensina II/farmacologia , Elementos de Resposta Antioxidante/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Células Endoteliais/citologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sirtuínas/metabolismo , Linhagem Celular , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuínas/genética
7.
BMC Complement Altern Med ; 19(1): 139, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221142

RESUMO

BACKGROUND: Several studies have found that caffeic acid (CA), a well-known phytochemical, displays important antioxidant and anti-cancer activities. However, no evidence exists on the protective effect and its mechanisms that CA treatment alone has against oxidative stress induced by tert-butyl hydroperoxide (t-BHP) in HepG2 cells. METHODS: Hepatoprotective activities such as cell viability, mRNA expression, and report gene assay were measured using HepG2 cell. Three types of genes and proteins related with detoxification in liver were used for measuring the hepatoprotective effects. Statistical analysis was performed using one-way ANOVA test and differences among groups were evaluated by Tukey's studentized range tests. RESULTS: The present study indicate that treatment with CA up-regulates heme oxygenase-1 (HO-1) and glutamate-cysteine ligase (GCL) mRNA and protein expressions in a CA-dose-dependent manner. In addition, translocation of nuclear factor-E2 p45-related factor (Nrf2) from the cytoplasm to the nucleus and phosphorylation of extracellular signal-regulated kinase, ERK and c-Jun N-terminal kinase, JNK which have been shown to be involved in mitogen-activated protein kinases, MAPKs are significantly enhanced by CA treatment. Furthermore, in cell nuclei, CA enhances the 5'-flanking regulatory region of human antioxidant response element (ARE) and activates the ARE binding site. CONCLUSION: Therefore, CA proved to be a stimulant of the expression of detoxification enzymes such as HO-1, GCLC, and GCLM through the ERK/Nrf2 pathway, and it may be an effective chemoprotective agent for protecting liver damage against oxidative damage.


Assuntos
Ácidos Cafeicos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Hepáticas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , terc-Butil Hidroperóxido/toxicidade , Elementos de Resposta Antioxidante/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/genética , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Hep G2 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Neoplasias Hepáticas/genética , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo
8.
Biofactors ; 45(4): 563-574, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31131946

RESUMO

Isoflavones are one group of the major flavonoids and possess multiple biological activities due to their antioxidant properties. However, a clear antioxidant mechanism of dietary isoflavones is still remained to be answered. In this study, the effects of isoflavones on the nuclear factor E2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway and the underlying molecular mechanisms were investigated. Results showed that isoflavones are potential Nrf2-ARE activators while their activities were structure dependent. Biochanin A (BCA), an O-methylated isoflavone with low direct antioxidant activity, can effectively protect HepG2 cells against tert-butyl hydroperoxide (t-BHP)-induced oxidative damage via activation of the Nrf2 signaling, and thereby the induction of downstream cytoprotective enzymes including NAD(P)H quinone oxidoreductase-1, heme oxygenasae-1, and glutamate-cysteine ligase catalytic subunit. A molecular docking study revealed that BCA could directly bind into the pocket of Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1), a cytoplasmic suppressor of Nrf2, to facilitate Nrf2 activation. The upstream mitogen-activated protein kinase (MAPK) pathways were also involved in the activation of Nrf2 signaling. These findings indicate that the protective actions of dietary isoflavones against oxidative damage may be at least partly due to their ability to enhance the intracellular antioxidant response system by modulating the Nrf2-ARE signaling pathway.


Assuntos
Elementos de Resposta Antioxidante/efeitos dos fármacos , Antioxidantes/farmacologia , Genisteína/farmacologia , Proteínas Quinases Ativadas por Mitógeno/genética , Fator 2 Relacionado a NF-E2/genética , Espécies Reativas de Oxigênio/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Hep G2 , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NADH NADPH Oxirredutases/genética , NADH NADPH Oxirredutases/metabolismo , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Oxidantes/antagonistas & inibidores , Oxidantes/farmacologia , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , terc-Butil Hidroperóxido/antagonistas & inibidores , terc-Butil Hidroperóxido/farmacologia
9.
Nutrients ; 11(4)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30987009

RESUMO

Certain antioxidative flavonoids are known to activate nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates cellular antioxidants and detoxifying response and is reportedly highly activated in many types of cancers. Few studies on the potential undesired effects of flavonoid intake during chemotherapy have been conducted, yet Nrf2 activators could favor cancer cell survival by attenuating chemotherapeutic efficiency. This study aimed to examine if luteolin, an Nrf2 activator, hinders chemotherapeutic activity of oxaliplatin, a potent anticancer agent for colorectal cancer, in HCT116 cells. Luteolin treatment strongly increased the transcriptional activity of the antioxidant response element in HCT116 cells and induced the protein expression of heme oxygenase-1, which were indicative of its Nrf2-inducing potential. Intriguingly, 25 µM luteolin reduced cell viability through apoptotic induction, which was intensified in p53-expressing cells while 1 µM oxaliplatin caused cell cycle arrest at G0/G1-phase via the p53/p21-dependent mechanism. Moreover, luteolin treatment was found to reduce oxaliplatin-treated p53-null cell viability and colony counts further, thereby demonstrating an additional effect of luteolin in the killing of human colorectal tumor HCT116 cells not expressing functional p53 protein. The findings suggest that luteolin can induce p53-mediated apoptosis regardless of oxaliplatin treatment and may eliminate oxaliplatin-resistant p53-null colorectal cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Luteolina/farmacologia , Oxaliplatina/farmacologia , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Elementos de Resposta Antioxidante/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células HCT116 , Heme Oxigenase-1/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
10.
Biofactors ; 45(4): 616-626, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30951611

RESUMO

Chlorogenic acid (CA), the ester of caffeic acid and quinic acid, is one of the most abundant polyphenols in coffee, and has multiple pharmacological functions. The present study is designed to explore the protection provided by CA against hydrogen peroxide (H2 O2 )-induced oxidative damages in the rat pheochromocytoma cells, and the underlying mechanisms engaged in this process. CA displays robust free radical-scavenging activity in vitro. More importantly, CA strikingly rescues the cells from the H2 O2 -mediated oxidative insults. Mechanistic studies revealed that CA upregulates a panel of phase II cytoprotective species, such as heme oxygenase-1, NAD(P)H: quinone oxidoreductase 1, glutathione, thioredoxin reductase 1, and thioredoxin 1. This neuroprotection is dependent on the activation of the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), as knockdown of Nrf2 abolishes such effect. Our results demonstrate that CA provides dual neuroprotection via directly neutralizing free radicals and indirectly inducing expression of Nrf2-driven cytoprotective enzymes, and suggest a potential therapeutic usage of CA as a neuroprotective agent. Coffee is one of the most popular drinks in the world, and our discovery may also contribute to understanding the beneficial effects of regular coffee consumption. © 2019 BioFactors, 45 (4):616-626, 2019.


Assuntos
Elementos de Resposta Antioxidante/efeitos dos fármacos , Antioxidantes/farmacologia , Ácido Clorogênico/farmacologia , Fator 2 Relacionado a NF-E2/genética , Fármacos Neuroprotetores/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Animais , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Glutationa/agonistas , Glutationa/metabolismo , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Picratos/antagonistas & inibidores , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Ácidos Sulfônicos/antagonistas & inibidores , Tiorredoxina Redutase 1/genética , Tiorredoxina Redutase 1/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
11.
Int J Mol Sci ; 20(4)2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30823534

RESUMO

Paracetamol is responsible for acute liver failure in humans and experimental animals when taken at high doses and transformed into a reactive metabolite by the liver cytochrome P450. On the other hand, nutmeg is rich with many phytochemical ingredients that are known for their ability to inhibit cytochrome P450. Hence, the present experiment was aimed at studying the hepatoprotective effect of Myristica fragrans (nutmeg), kernel extract (MFKE) in respect to paracetamol (acetaminophen; N-acetyl-p-amino-phenol (APAP))-induced hepatotoxicity in rats, focusing on its antioxidant, anti-inflammatory, and anti-apoptotic activities. Liver toxicity was induced in rats by a single oral administration of APAP (2 g/kg). To evaluate the hepatoprotective effect of MFKE against this APAP-induced hepatotoxicity, rats were pre-treated with either oral administration of MFKE at 300 mg/kg daily for seven days or silymarin at 50 mg/kg as a standard hepatoprotective agent. APAP intoxication caused a drastic elevation in liver function markers (transaminases, alkaline phosphatase, and total bilirubin), oxidative stress indicators (lipid peroxidation and nitric oxide), inflammatory biomarkers (tumour necrosis factor-α, interleukin-1ß, inducible nitric oxide synthase, and nuclear factor ĸB) and the pro-apoptotic BCL2 Associated X (Bax) and caspases-3 genes. Furthermore, analyses of rat liver tissue revealed that APAP significantly depleted glutathione and inhibited the activities of antioxidant enzymes in addition to downregulating two key anti-apoptotic genes: Cellular FLICE (FADD-like IL-1ß-converting enzyme)-inhibitory protein (c-FLIP) and B-cell lymphoma 2 (Bcl-2). Pre-treatment with MFKE, however, attenuated APAP-induced liver toxicity by reversing all of these toxicity biomarkers. This hepatoprotective effect of MFKE was further confirmed by improvement in histopathological findings. Interestingly, the hepatoprotective effect of MFKE was comparable to that offered by the reference hepatoprotector, silymarin. In conclusion, our results revealed that MFKE had antioxidant, anti-inflammatory, and anti-apoptotic properties, and it is suggested that this hepatoprotective effect could be linked to its ability to promote the nuclear factor erythroid 2⁻related factor 2 (Nrf2)/antioxidant responsive element (ARE) pathway.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Myristica/química , Extratos Vegetais/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Heme Oxigenase (Desciclizante)/genética , Masculino , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar , Silimarina/farmacologia , Silimarina/uso terapêutico
12.
Toxicol Lett ; 308: 24-33, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30910607

RESUMO

Dibutyl phthalate (DBP)-induced germ cell apoptosis contributes to male reproductive toxicity, however, the primary target organelle of DBP or the molecular events triggered by DBP to initiate germ cell apoptosis remain unclear. Our previous studies demonstrated DBP could stimulate the production of intracellular reactive oxygen species (ROS), which served as an upstream mediator of activation of endoplasmic reticulum (ER) stress in mouse spermatocyte-derived GC-2 cells. In the present study, the impacts of DBP-induced ROS generation on the mitochondria-related damage and the associations between ER stress and mitochondrial-related damage were investigated in GC-2 cells. We observed significant decreases of mitochondrial mass, mtDNA copy number, COX IV protein level, and ATP level in DBP-treated GC-2 cells in a dose-dependent manner. And DBP activated mitochondrial-related apoptosis, indicated by the elevation of cytoplasmic cytochrome C (Cyt C) and the activation of caspase-9/3 cascade. Pretreatment with antioxidant melatonin obviously attenuated DBP-induced mitochondrial damage and mitochondrial-dependent apoptosis in GC-2 cells, indicating the role of ROS in DBP-caused testicular toxicity. In response to oxidative stress, the Nrf2/ARE axis was activated in DBP-treated GC-2 cells to counteract ROS overproduction and subsequent mitochondrial damage. Further experiments showed DBP treatment increased the phosphorylated expression of ER stress-related protein PERK. GSK2606414, a specific inhibitor of PERK, partly attenuated the expression of Nrf2. And both DBP-induced mitochondrial damage in GC-2 cells and mitochondrial-dependent apoptosis of the germ cells in rat testes were further aggravated by PERK inhibition. Taken together, our data suggest that PERK regulates the Nrf2/ARE antioxidant pathway functioning as a self-defense mechanism against ROS-related mitochondrial damage induced by DBP in male germ cells.


Assuntos
Elementos de Resposta Antioxidante/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Dibutilftalato/toxicidade , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Espermatócitos/efeitos dos fármacos , eIF-2 Quinase/metabolismo , Animais , Linhagem Celular , Masculino , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Espermatócitos/metabolismo , Espermatócitos/patologia , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia
13.
Molecules ; 24(4)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30781396

RESUMO

Fisetin, a dietary flavonoid, is reported to have cellular antioxidant activity with an unclear mechanism. In this study, we investigated the effect of fisetin on the nuclear factor, erythroid 2-like 2 (Nrf2) signaling pathway in HepG2 cells to explore the cellular antioxidant mechanism. Fisetin upregulated the mRNA expression of heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase modifier subunit (GCLM), and NAD(P)H quinone oxidoreductase-1 (NQO1), and induced the protein of HO-1 but had no significant effect on the protein of GCLC, GCLM and NQO1. Moreover, nuclear accumulation of Nrf2 was clearly observed by immunofluorescence analysis and western blotting after fisetin treatment, and an enhanced luciferase activity of antioxidant response element (ARE)-regulated transactivation was obtained by dual-luciferase reporter gene assays. In addition, fisetin upregulated the protein level of Nrf2 and downregulated the protein level of Kelch-like ECH-associated protein 1 (Keap1). However, fisetin had no significant effect on Nrf2 mRNA expression. When protein synthesis was inhibited with cycloheximide (CHX), fisetin prolonged the half-life of Nrf2 from 15 min to 45 min. When blocking Nrf2 degradation with proteasome inhibitor MG132, ubiquitinated proteins were enhanced, and fisetin reduced ubiquitination of Nrf2. Taken together, fisetin translocated Nrf2 into the nucleus and upregulated the expression of downstream HO-1 gene by inhibiting the degradation of Nrf2 at the post-transcriptional level. These data provide the molecular mechanism to understand the cellular antioxidant activity of fisetin.


Assuntos
Antioxidantes/farmacologia , Flavonoides/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Elementos de Resposta Antioxidante/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamato-Cisteína Ligase/metabolismo , Heme Oxigenase-1/metabolismo , Células Hep G2 , Humanos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos
14.
Int J Mol Sci ; 20(3)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717178

RESUMO

Cadmium (Cd) is harmful for humans and animals, especially for the reproductive system. However, the mechanism of its toxicity has not been elucidated, and how to alleviate its toxicity is very important. This study aimed to explore the role and mechanism of action of sulforaphane (SFN) in protecting mouse Leydigs (TM3) cells from cadmium (Cd)-induced damage. The half-maximal inhibitory concentration (IC50) of Cd and the safe doses of SFN were determined using a methyl thiazolyl tetrazolium (MTT) assay. The testosterone secretion from TM3 cells was measured using the enzyme-linked immunosorbent assay. The intracellular oxidative stress was evaluated using corresponding kits. The cell apoptosis was detected using flow cytometry. The mRNA expression of genes associated with NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling was detected using reverse transcription⁻polymerase chain reaction, including Nrf2, heme oxygenase I (HO-1), glutathione peroxidase (GSH-Px), NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), and γ-glutamylcysteine synthetase (γ-GCS). The protein expression of Nrf2, GSH-Px, HO-1, γ-GCS, and NQO1 was detected using Western blot analysis. The results showed that the IC50 of Cd to TM3 cells was 51.4 µmol/L. SFN reduced the release of lactate dehydrogenase from Cd-exposed cells. Cd + SFN 2.5 treatment significantly elevated testosterone concentration compared with the Cd group (p < 0.05). SFN significantly increased total superoxide dismutase (T-SOD) and GSH-Px activity and GSH content in Cd-treated cells (p < 0.05; p < 0.01), inhibited the production of malondialdehyde or reactive oxygen species caused by Cd (p < 0.05; p < 0.01), and reduced the apoptotic rate of Cd-induced TM3 cells (p < 0.01). SFN upregulated the mRNA expression of Nrf2, GSH-Px, HO-1, NQO1, and γ-GCS in Cd-treated cells, indicating the protective effect of SFN against Cd-induced oxidative stress or cell apoptosis by activating the Nrf2/ARE signaling pathway.


Assuntos
Antioxidantes/farmacologia , Cloreto de Cádmio/antagonistas & inibidores , Isotiocianatos/farmacologia , Células Intersticiais do Testículo/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Transdução de Sinais/efeitos dos fármacos , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Cloreto de Cádmio/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Intersticiais do Testículo/citologia , Células Intersticiais do Testículo/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Testosterona/biossíntese
15.
Life Sci ; 221: 259-266, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30769116

RESUMO

AIMS: Edaravone potentially alleviates cognitive deficits in a mouse model of Alzheimer's disease (AD). However, the mechanism of edaravone in suppressing AD progression remains unclear. We aim to investigate the mechanism of edaravone in suppressing oxidative stress-mediated AD progression in vitro. MAIN METHODS: Human neuroblastoma SH-SY5Y cells were pretreated with different concentrations of edaravone prior to the induction by Aß25-35. Cell viability, apoptosis, reactive oxygen species, and expression of antioxidative response elements (ARE) including Nrf2, SOD, and HO-1 were assessed. KEY FINDINGS: The results showed that apoptosis and reactive oxygen species levels significantly increased in Aß25-35-treated cells, whereas the mRNA and protein levels of Nrf2, SOD and HO-1 decreased. The opposite changes were observed in cells that were pre-treated with edaravone, particularly at a concentration of 40 µM. Aß25-35-treatment suppressed Nrf2 expression and nuclear translocation were rescued by Edaravone. Genetic inhibition of Nrf2 greatly decreased the protective effect of edaravone against cell apoptosis and cytotoxicity induced by Aß25-35, accompanied by decreases in SOD and HO-1 expression. SIGNIFICANCE: Activation of the Nrf2/ARE signaling pathway may underlie the protective effects of edaravone against the oxidative damage associated with Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides/efeitos dos fármacos , Edaravone/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/efeitos adversos , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Humanos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Neuroblastoma , Fármacos Neuroprotetores , Oxirredução , Fragmentos de Peptídeos/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Superóxido Dismutase-1/efeitos dos fármacos
16.
Pharmacology ; 103(5-6): 236-245, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30699431

RESUMO

BACKGROUND: Systemic oxidative stress has been reported to play a central role in the pathogenesis of kidney function decline. The nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is one of the important endogenous antioxidant stress pathways in cells. This study aims to investigate whether shenduning granule can ameliorate oxidative stress in kidney tissues by activating the Nrf2/ARE pathway, and explores the detailed underlying mechanism. METHODS: A total of 120 male Sprague-Dawley rats were randomly assigned to the sham-operated and operation groups. Rats in the operation group underwent 5/6 nephrectomy. Two weeks later, rats in the operation group were further randomly divided into 5 groups: model group, low-dose, medium-dose and high-dose shenduning granule groups, and losartan group. Rats in each group were given the same volume of corresponding liquid orally. Serum creatinine (SCr), blood urea nitrogen (BUN), 24-h urinary protein, malondialdehyde (MDA) and superoxide dismutase (SOD), Nrf2, heme oxygenase-1 (HO-1), and γ-glutamyl-cysteine synthetase (γ-GCS) were determined. RESULTS: Shenduning granule could markedly elevate HO-1, NRF2, γ-GCS and SOD (p < 0.05), and significantly decreased MDA, 24-h urinary protein, SCr and BUN in rats (p < 0.05). CONCLUSION: Shenduning granule can improve renal antioxidative stress activity in rats, exhibiting a renoprotective effect. The potential mechanism is likely exerted by the activation of the Nrf2/ARE pathway.


Assuntos
Nefropatias/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Nefropatias/etiologia , Nefropatias/fisiopatologia , Masculino , Malondialdeído/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Plantas Medicinais/química , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo
17.
Biomed Pharmacother ; 111: 676-685, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30611992

RESUMO

Olive leaf extract (OLE) has potential health benefits and protects against cytotoxicity in different organs. However, nothing has yet been reported on its potential to prevent cyclophosphamide (CP)-induced nephrotoxicity. This study investigated the possible protective effect of OLE on CP-induced kidney injury in rats, focusing on oxidative stress, inflammation, apoptosis and Nrf2/ARE/HO-1 signaling. Rats received 100 or 200 mg/kg body weight OLE for 15 days and a single injection of 150 mg/kg CP at day 16. CP induced kidney injury evidenced by the significantly increased serum creatinine and urea, and histopathological alterations, including glomerular atrophy, interstitial hemorrhage, dilated urinary space and necrosis. CP-induced rats exhibited increased kidney lipid peroxidation, protein carbonyl, nitric oxide (NO) and pro-inflammatory cytokines, and up-regulated NF-κB, Bax, cytochrome c and caspase-3. OLE ameliorated kidney function markers and prevented CP-induced tissue damage. In addition, OLE significantly prevented oxidative stress, inflammation and apoptosis by enhancing the antioxidant defenses and Bcl-2 expression, and suppressing the pro-inflammatory and pro-apoptotic markers NF-κB, Bax, cytochrome c and caspase-3. OLE up-regulated Nrf2, HO-1 and NQO-1 expression in the kidney of CP-induced rats. In conclusion, OLE has a substantial protective role against CP-induced nephrotoxicity in rats by up-regulating the Nrf2/ARE/HO-1 signaling, enhancing the antioxidant activity and attenuating inflammation and apoptosis.


Assuntos
Elementos de Resposta Antioxidante/efeitos dos fármacos , Ciclofosfamida/toxicidade , Heme Oxigenase (Desciclizante)/biossíntese , Rim/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/biossíntese , Olea , Estresse Oxidativo/efeitos dos fármacos , Animais , Elementos de Resposta Antioxidante/fisiologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Relação Dose-Resposta a Droga , Depuradores de Radicais Livres/isolamento & purificação , Depuradores de Radicais Livres/farmacologia , Depuradores de Radicais Livres/uso terapêutico , Imunossupressores/toxicidade , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/prevenção & controle , Rim/metabolismo , Rim/patologia , Masculino , Estresse Oxidativo/fisiologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Folhas de Planta , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
18.
Biol Trace Elem Res ; 188(1): 2-10, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30196486

RESUMO

Boron is abundant in vegetables, nuts, legumes, and fruit and intake is associated with reduced risk of cancer and DNA damage and increased antioxidant status. Blood boric acid (BA) levels are approximately 10 µM BA in men at the mean US boron intake. Treatment of DU-145 human prostate cancer cells with 10 µM BA stimulates phosphorylation of elongation initiation factor 2α (eIF2α) at Ser51 leading to activation of the eIF2α/ATF4 pathway which activates the DNA damage-inducible protein GADD34. In the present study, we used MEF WT and MEF PERK (±) cells to test the hypothesis that BA-activated eIF2α phosphorylation requires protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activates Nrf2 and the antioxidant response element (ARE). BA (10 µM) increased phosphorylation of eIF2α Ser51 in MEF WT cells at 1 h, but not in MEF Perk -/- cells exposed for as long as 6 h. GCN2 kinase-dependent phosphorylation of eIF2α Ser51 was activated in MEF PERK -/- cells by amino acid starvation. Nrf2 phosphorylation is PERK dependent and when activated is translocated from the cytoplasm to the nucleus where it acts as a transcription factor for ARE. DU-145 cells were treated with 10 µM BA and Nrf2 measured by immunofluorescence. Cytoplasmic Nrf2 was translocated to the nucleus at 1.5-2 h in DU-145 and MEF WT cells, but not MEF PERK -/- cells. Real-time PCR was used to measure mRNA levels of three ARE genes (HMOX-1, NQO1, and GCLC). Treatment with 10 µM BA increased the mRNA levels of all three genes at 1-4 h in DU-145 cells and HMOX1 and GCLC in MEF WT cells. These results extend the known boric acid signaling pathway to ARE-regulated genes. The BA signaling pathway can be expressed using the schematic [BA + cADPR → cADPR-BA → [[ER]i Ca2+↓] → 3 pathways: PERK/eIF2αP → pathways ATF4 and Nrf2; and [[ER]i Ca2+↓] → ER stress → ATF6 pathway. This signaling pathway provides a framework that links many of the molecular changes that underpin the biological effects of boron intake.


Assuntos
Antioxidantes/farmacologia , Ácidos Bóricos/farmacologia , Boro/farmacologia , Dano ao DNA/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Oligoelementos/farmacologia , eIF-2 Quinase/efeitos dos fármacos , Aminoácidos/deficiência , Elementos de Resposta Antioxidante/efeitos dos fármacos , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Citoplasma/efeitos dos fármacos , Fator de Iniciação 1 em Eucariotos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Translocação Genética/efeitos dos fármacos
19.
Ecotoxicol Environ Saf ; 170: 172-179, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30529616

RESUMO

Epidemiological studies have demonstrated an association between ambient particulate pollution and adverse health effects in humans. The antioxidant-responsive element (ARE) cytoprotective system mediated by the transcription factor NF-E2 p45-related factor 2 (Nrf2) serves as a primary defense against the oxidative stress triggered by particulate matter. In this study, using a cell-based ARE-reporter assay, the fine fractions of the fly ash collected from the municipal solid waste incinerators at four cities in China were examined for their ability to activate Nrf2/ARE signaling. We found that, at a non-lethal dose, all the fly ash samples were able to activate the ARE-reporter gene in a dose- and redox-dependent manner, and this was correlated with their cytotoxicity and their ability to induce DNA damage. Study of the kinetics revealed that fly ash particles elicited a prolonged activation of the ARE-reporter activity. Upon exposure to the particles, the ARE-luciferase activity significantly increased in 2 h, reached a peak at 24 h, and remained high level at 72 h. This was in contrast to the transient activation of the ARE-reporter gene triggered by the Nrf2 activators tert-butylhydroquinone and sulforaphane, while ARE-luciferase activity dropped to the basal level at 72 h from the peak at 24 h. These results demonstrate the robustness of using cell-based ARE-reporter assays to evaluate the oxidative potential of fly ash. Our novel findings suggest that the sustained activation of the Nrf2/ARE signaling pathway induced by fly ash particles perturbs cellular redox homeostasis, which in turn contributes to toxicity.


Assuntos
Elementos de Resposta Antioxidante/efeitos dos fármacos , Cinza de Carvão/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Sobrevivência Celular/efeitos dos fármacos , China , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Hidroquinonas , Incineração , Isotiocianatos , Células MCF-7 , Fator 2 Relacionado a NF-E2/genética , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/toxicidade
20.
Neurochem Int ; 122: 208-215, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30508559

RESUMO

The sustenance of redox homeostasis in brain is the crucial factor to treat Parkinson's disease (PD). Nuclear factor (erythroid-derived 2)-like 2 factor (Nrf2)-mediated antioxidant response is well known for the main cellular endogenous defense mechanisms against oxidative stress. This study investigated for the first time the effects and possible mechanisms of action of Ukgansan on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in both in vitro and in vivo models of PD. We investigated the protective effect of Ukgansan against 6-OHDA with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. In addition, we demonstrated that Ukgansan significantly increased the expression of antioxidant response elements (ARE) and pro-survival protein as Bcl2 and suppressed the expression of pro-apoptotic factors, such as Bax, cytochrome c, and caspase-3 using immunoblotting. For the in vivo study, we used a mouse model of PD involving stereotaxic injection of 6-OHDA into the striatum (ST). Ukgansan alleviated motor dysfunctions induced by 6-OHDA followed by pole, open-field, and rotation tests. Dopaminergic neuronal loss and Nrf2 activation were evaluated by immunohistochemistry in the mouse ST and substantia nigra pars compacta (SNpc) regions. Ukgansan significantly protected dopaminergic neurons from 6-OHDA toxicity in mouse ST and SNpc by activating Nrf2. These results indicate that Ukgansan inhibited 6-OHDA-induced dopaminergic neuronal cell damage via activation of Nrf2 and its related factors in 6-OHDA-induced dopaminergic loss in vitro and in vivo. Thus, Ukgansan might delay the progression of PD via maintenance of redox homeostasis.


Assuntos
Antioxidantes/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/efeitos adversos , Oxidopamina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos , Fármacos Neuroprotetores/farmacologia
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