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1.
Nat Commun ; 11(1): 4225, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839463

RESUMO

Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy. Here, we analyze exomes (n = 160), transcriptomes (n = 115), and low pass whole genomes (n = 146) from 167 gallbladder cancers (GBCs) from patients in Korea, India and Chile. In addition, we also sequence samples from 39 GBC high-risk patients and detect evidence of early cancer-related genomic lesions. Among the several significantly mutated genes not previously linked to GBC are ETS domain genes ELF3 and EHF, CTNNB1, APC, NSD1, KAT8, STK11 and NFE2L2. A majority of ELF3 alterations are frame-shift mutations that result in several cancer-specific neoantigens that activate T-cells indicating that they are cancer vaccine candidates. In addition, we identify recurrent alterations in KEAP1/NFE2L2 and WNT pathway in GBC. Taken together, these define multiple targetable therapeutic interventions opportunities for GBC treatment and management.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação da Fase de Leitura , Neoplasias da Vesícula Biliar/genética , Predisposição Genética para Doença/genética , Proteínas Proto-Oncogênicas c-ets/genética , Fatores de Transcrição/genética , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Chile , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Humanos , Índia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Proto-Oncogênicas c-ets/imunologia , Proteínas Proto-Oncogênicas c-ets/metabolismo , República da Coreia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt/genética , beta Catenina/genética , beta Catenina/metabolismo
2.
Chem Biol Interact ; 329: 109220, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32763245

RESUMO

The sepsis is considered as serious clinic-pathological condition related with high rate of morbidity and mortality in critical care settings. In the proposed study, the hydrazides derivatives N-(benzylidene)-2-((2-hydroxynaphthalen-1-yl)diazenyl)benzohydrazides (1-2) (NCHDH and NTHDH) were investigated against the LPS-induced sepsis in rodents. The NCHDH and NTHDH markedly improved the physiological sign and symptoms associated with the sepsis such as mortality, temperature, and clinical scoring compared to negative control group, which received only LPS (i.p.). The NCHDH and NTHDH also inhibited the production of the NO and MPO compared to the negative control. Furthermore, the treatment control improved the histological changes markedly of all the vital organs. Additionally, the Masson's trichrome and PAS (Periodic Acid Schiff) staining also showed improvement in the NCHDH and NTHDH treated group in contrast to LPS-induced group. The antioxidants were enhanced by the intervention of the NCHDH and NTHDH and the level of the MDA and POD were attenuated marginally compared to the LPS-induced group. The hematology study showed marked improvement and the reversal of the LPS-induced changes in blood composition compared to the negative control. The synthetic function of the liver and kidney were preserved in the NCHDH and NTHDH treated group compared to the LPS-induced group. The NCHDH and NTHDH markedly enhanced the Nrf2, HO-1 (Heme oxygenase-1), while attenuated the Keap1 and TRPV1 expression level as compared to LPS treated group. Furthermore, the NCHDH and NTHDH treatment showed marked increased in the mRNA expression level of the HSP70/90 proteins compared to the negative control.


Assuntos
Hidrazinas/farmacologia , Insuficiência de Múltiplos Órgãos/etiologia , Sepse/etiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Heme Oxigenase-1/metabolismo , Hidrazinas/química , Hidrazinas/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/mortalidade , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Sepse/tratamento farmacológico , Sepse/mortalidade , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
3.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(1): 67-72, 2020 Jan 28.
Artigo em Chinês | MEDLINE | ID: mdl-32476375

RESUMO

OBJECTIVE: Effects of Yiqi Huashi Tongluo Formula on oxidative stress and renal fibrosis of residual kidney were investigated in five/sixth nephrectomy rats. METHODS: The rat model of chronic renal failure after nephrectomy was established by Platt method. Two weeks after the operation, the rats were randomly divided into model group, Yiqi Huashi Tongluo Formula (YHT) group, benazepril online (BH) group and sham group, with 8 rats in each group. Treatment was initiated once a day for 12 weeks after successful modeling. Animals were treated once a day with intragastric administration for 12 weeks. (Aqueous solution of free decoction granules in YHT group was 0.276 g/100 g·d. BH group benazepril hydrochloride tablet aqueous solution 0.09 mg/100 g·d gavage; sham group and model group were gavage with 1 ml/100 g normal saline). Urine was collected with a metabolic cage at the end of the 12th week, and urine protein content was detected for 24 hours. The rats were then anesthetized to extract blood from the abdominal aorta and the kidneys. The pathological changes of left kidney were observed by HE staining and Masson staining. The activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA) in kidney homogenate were determined by colorimetry. Western blot assay was used to detect the expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2), kelch-like ech-associated protein-1 (Keap1), NADPH oxidase 4 (Nox4), transforming growth factor-binding 1(TGF-ß1), type I collagen (Collagen1) and Nrf2 in the nucleus in renal tissue. RESULTS: Compared with sham group, model group rats had severe glomerular injury and obvious fibrosis. Levels of Scr, BUN, MDA and 24-hour urine protein excretion, protein expressions of Keap1, Nox4, TGF-ß1 and Collagen1 were significantly increased (P<0.01), while SOD activity and Nrf2 expression were significantly decreased (P<0.01).Compared with the model group, the degree of glomerular lesion was reduced and fibrosis was less after YHT or BH intervention, and the levels of Scr, BUN, MDA, 24-hour urine protein excretion, protein expressions of Keap1, Nox4, TGF-ß1 and Collagen1 were significantly decreased (P<0.01), while SOD activity and Nrf2 expression were significantly increased (P<0.01). CONCLUSION: Through affecting the Nrf2/Keap1 signaling pathway and down-regulating the expression of TGF-ß1 protein, Yiqi Huashi Tongluo Formula improved the oxidative stress damage and fibrosis degree of residual kidney in the model rats with renal failure.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Nefropatias/tratamento farmacológico , Estresse Oxidativo , Animais , Fibrose , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Rim/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo
4.
Medicine (Baltimore) ; 99(26): e20433, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590729

RESUMO

Bronchopulmonary dysplasia (BPD) is a chronic lung disease common in premature infants and is one of the leading causes of disability and death in newborns. The Keap-1/Nrf2 signaling pathway plays an important role in antioxidant and anti-inflammatory.Ten clean-grade, healthy pregnant Sprague-Dawley rats (purchased from Experimental Animal Center of Peking university, China) naturally gave birth to 55 neonatal rats from which 40 were selected and randomly divided into a hyperoxia group and a control group (N = 20, each). Thirty-two BPD patient samples are from Neonatal Department of the second Hospital of Jilin University from November 30, 2016 to May 1 2019.In present study, we observed that lung tissues of the control group did not undergo obvious pathological changes, whereas in the hyperoxia group, lung tissues had disordered structures. With increased time of hyperoxia exposure, the alveolar wall became attenuated. Under hypoxia conditions, the activity of oxidative stress-related enzymes (CAT, GSH-Px, SOD) in lung samples was significantly lower than that before treatment. The expression level of Keap1 mRNA and protein in the hyperoxia group was slightly lower than that of control group. The expression of Nrf2 and HO-1 mRNA and protein in the hyperoxia group was significantly higher than that of control group. For the infants with BPD, we found that the activity of SOD, GSH-Px, and CAT was significantly different from those of control group.We constructed a premature BPD animal model and found the abnormal of oxidative stress in different groups and the expression levels of Keap1/Nrf2 signaling pathway-related molecules, and we validated the results in premature infants with BPD.


Assuntos
Displasia Broncopulmonar/genética , Displasia Broncopulmonar/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Pulmão/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Animais , Animais Recém-Nascidos , Estudos de Casos e Controles , Catalase/metabolismo , Modelos Animais de Doenças , Feminino , Glutationa Peroxidase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Hiperóxia , Hipóxia , Recém-Nascido Prematuro , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Pulmão/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/genética , Gravidez , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Superóxido Dismutase/metabolismo
5.
Aquat Toxicol ; 224: 105516, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32485495

RESUMO

Summer outbreaks of the hepatobiliary syndrome in fish impose a heavy burden on aquaculture in China. Curcumin is a polyphenol with antioxidant activity that has been used to protect the health of fish livers, but the mechanism underlying its protective effect is unclear. In this study, an in vitro model of hepatocyte oxidative damage in Oreochromis niloticus was established using H2O2. Treatment with 5 mM H2O2 for 2.5 h markedly reduced cell viability and antioxidant activity and elevated lactate dehydrogenase (LDH) activity, indicating conditions that can be used to establish an oxidative stress model. Under H2O2 stress, curcumin pretreatment significantly maintained cell viability, reduced malondialdehyde (MDA) levels, and increased superoxide dismutase (SOD) activity. RNA-seq results showed that acute H2O2 treatment resulted in minor changes in gene expression, whereas curcumin changed the expression profile and affected cytochrome P450 (Cyp 450), glutathione (GSH) metabolism, and the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Several critical antioxidant defense signaling pathways were identified, and altered expression was confirmed by q-PCR. These results indicate that curcumin might upregulate PPAR expression by increasing Cyp2J2 expression. Further experiments showed that curcumin can upregulate the Nrf2-Keap1 signaling pathway at the transcriptional level, and this upregulation can induce downstream defense genes, including glutamate cysteine ligase catalytic subunit(GCLC) and glutamate cysteine ligase modifier subunit (GCLM), and thereby promote GSH synthesis and the expression of related antioxidases. This study might shed light on the effects of curcumin on the prevention and alleviation of liver diseases in fish.


Assuntos
Antioxidantes/farmacologia , Curcumina/farmacologia , Hepatócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Tilápia/metabolismo , Transcriptoma/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Células Cultivadas , Curcumina/metabolismo , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Hepatócitos/metabolismo , Peróxido de Hidrogênio/toxicidade , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/genética , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tilápia/genética , Poluentes Químicos da Água/toxicidade
6.
Life Sci ; 256: 117958, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32553929

RESUMO

PROPOSE: Understanding the protective effect of exercise against ethanol-induced toxicity through the oxidative stress signaling pathway, apoptosis, and cholesterol metabolism is important to prevent development of cardiovascular diseases. METHODS: Thirty-two male Wistar rats were randomly divided into four equal groups as follow: control, exercise training (ET), ethanol (4 g/kg of body weight/day) and ET + ethanol. The ET and ET + Ethanol groups ran on the treadmill at 65% maximum running speed for 60 min for five sessions per week for eight weeks. The ethanol and ET + Ethanol groups received ethanol for eight weeks. At the end of the study, animals were anesthetized and blood and tissues were sampled to examine the biochemical and molecular evaluation. RESULTS: The results showed that the antioxidant enzymes activity decreased and MDA levels increased in the heart and liver of animals in ethanol group compared to control group. The levels of these oxidative biomarkers improved by ET in ET + Ethanol group compared to ethanol group. It showed that ET could protect the heart and liver against oxidative damage induced by ethanol through up-regulating the expression of the Nrf2/Keap-1/HO-1 pathway. ET could exert a cardioprotective effect on ethanol-induced apoptosis through down-regulating the Bax and the caspase-3 and via up-regulating the Bcl-2 expression in the heart. ET could also improve the impairment of cholesterol metabolism induced by ethanol. CONCLUSION: Exercise can protect against ethanol-induced toxicity through moderating the expression of genes which are involved in oxidative status, apoptosis and cholesterol metabolism.


Assuntos
Apoptose , Etanol/toxicidade , Heme Oxigenase-1/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fígado/patologia , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Condicionamento Físico Animal , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Biomarcadores/sangue , Caspase 3/genética , Caspase 3/metabolismo , Colesterol/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Lipídeos/sangue , Fígado/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
7.
Life Sci ; 256: 117923, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32522567

RESUMO

AIMS: Liver kinase B1 (LKB1) deficiency is associated with reduced expression of programmed death ligand 1 (PD-L1) and inferior clinical outcomes of PD-1/PD-L1 blockade in non-small cell lung cancer (NSCLC). This study aimed to investigate the mechanism by which LKB1 regulates PD-L1 expression and its role in programmed death 1 (PD-1) blockade therapy in NSCLC. MAIN METHODS: The impact of LKB1 on PD-L1 was assessed by western blot, qRT-PCR and immunohistochemistry in NSCLC. Activators/inhibitors of AMPK and NRF2 were applied to explore the mechanisms underlying the regulation of PD-L1 by LKB1. Efficiency of combined application of metformin and PD-1 blockade was evaluated in immunocompetent C57BL/6 mice. KEY FINDINGS: A remarkable positive correlation between LKB1 and PD-L1 expression was demonstrated in NSCLC tissues. Knockdown of LKB1 decreased PD-L1 in TC-1 cells, whereas overexpression of LKB1 increased PD-L1 in A549 cells. We further characterized that AMPK mediated the upregulation of PD-L1 by LKB1. Inhibition of AMPK or NRF2 markedly reduced PD-L1 in LKB1-intact NSCLC cells. In contrast, activation of AMPK or NRF2 reversed PD-L1 expression in LKB1-deficient NSCLC cells. Combined administration of metformin and anti-PD-1 antibody efficiently inhibited the growth of LKB1-intact tumors, whereas no obvious suppression was observed in LKB1-deficient tumors. SIGNIFICANCE: These findings demonstrated that LKB1 upregulates PD-L1 expression in NSCLC by activating the AMPK and KEAP1/NRF2 signaling. Activation of LKB1-AMPK with metformin improves the therapeutic effect of PD-1 blockade in NSCLC with wild-type LKB1.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Metformina/farmacologia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Células A549 , Animais , Anticorpos Monoclonais Humanizados/metabolismo , Antineoplásicos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Metformina/metabolismo , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Transdução de Sinais , Ativação Transcricional , Regulação para Cima
8.
Nat Commun ; 11(1): 2476, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32424161

RESUMO

Birds (Aves) display high metabolic rates and oxygen consumption relative to mammals, increasing reactive oxygen species (ROS) formation. Although excess ROS reduces lifespan by causing extensive cellular dysfunction and damage, birds are remarkably long-lived. We address this paradox by identifying the constitutive activation of the NRF2 master antioxidant response in Neoaves (~95% of bird species), providing an adaptive mechanism capable of counterbalancing high ROS levels. We demonstrate that a KEAP1 mutation in the Neoavian ancestor disrupted the repression of NRF2 by KEAP1, leading to constitutive NRF2 activity and decreased oxidative stress in wild Neoaves tissues and cells. Our evidence suggests this ancient mutation induced a compensatory program in NRF2-target genes with functions beyond redox regulation-including feather development-while enabling significant metabolic rate increases that avoid trade-offs with lifespan. The strategy of NRF2 activation sought by intense clinical investigation therefore appears to have also unlocked a massively successful evolutionary trajectory.


Assuntos
Adaptação Fisiológica , Antioxidantes/metabolismo , Aves/fisiologia , Plumas/crescimento & desenvolvimento , Longevidade/fisiologia , Animais , Metabolismo Basal , Evolução Biológica , Aves/genética , Núcleo Celular/metabolismo , Fibroblastos/metabolismo , Genômica , Glutationa Transferase/metabolismo , Células HEK293 , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Filogenia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Transporte Proteico , Ubiquitinação , Regulação para Cima/genética
9.
Food Chem ; 327: 127094, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32454270

RESUMO

In this study, a high-throughput strategy combined with MALDI TOF/TOF-MS and Discovery Studio 2017 was developed to screen peptides with certain functions from hydrolysate. Two dominant peptides, Ile-Cys-Arg-Asp (ICRD) and Leu-Cys-Gly-Glu-Cys (LCGEC), were predicted to have antioxidant activity by Discovery Studio 2017. Then the activity in vitro of peptides had been confirmed via DPPH assay. Both two peptides decreased apoptosis induced by UVB treatment in HaCaT cells and altered Keap1/Nrf2-ARE pathway transcription. Furthermore, the antioxidant activity of LCGEC was achieved after 6-week treatment in mice via regulating the Keap1/Nrf2-ARE pathway, inhibiting the release of proinflammatory cytokines, increasing the abundance of 3-indolepropionic acid and short-chain fatty acids production in feces and modulating gut microbiota composition. This study provided two tuna roe peptides with in vitro and in vivo antioxidant activity.


Assuntos
Antioxidantes/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Peptídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Atum , Animais , Linhagem Celular , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fator 2 Relacionado a NF-E2/metabolismo
10.
Phytomedicine ; 71: 153241, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32454347

RESUMO

BACKGROUND: Oxidative stress-triggered fatal hepatotoxicity is an essential pathogenic factor in acute liver failure (ALF). AIMS: To investigate the protective effect of daphnetin (Daph) on tert-butyl hydroperoxide (t-BHP) and acetaminophen (APAP)-induced hepatotoxicity through altering Nrf2/Trx-1 pathway activation. MATERIALS AND METHODS: In vivo, male C57BL/6 mice with Wild-type (WT) and Nrf2-/- were divided into five groups and acute liver injury model were established by APAP or LPS/GalN after injection with Daph (20, 40, or 80 mg/kg), seperately. Then, liver tissue and serum were collected for biochemical determination, TUNEL and H & E staining, and western blot analysis. In vitro, HepG2 cells were used to investigate the protective effect and mechanism of daphnetin against ROS and apoptosis induced by t-BHP via apoptosis detection, western blot, immunofluorescence analysis, and sgRNA transfection. RESULTS: Our results indicated that Daph efficiently inhibited t-BHP-stimulated hepatotoxicity, and modulated Trx-1 expression and Nrf2 activation which decreased Keap1-overexpression in HepG2 cells. Moreover, Daph inhibited t-BHP-excited hepatotoxicity and enhanced Trx-1 expression, which was reversed in Nrf2-/- HepG2 cells. In vivo, a survival rate analysis first suggested that Daph significantly reduced the lethality induced by APAP or GalN/LPS in a Nrf2-dependent or -independent manner by using Nrf2-/- mice, respectively. Next, further results implicated that Daph not only effectively alleviated APAP-induced an increase of ALT and AST levels, histopathological changes, ROS overproduction, malondialdehyde (MDA) formation and GSH/GSSG reduction, but it also relieved hepatic apoptosis by strengthening the suppression of cleaved-caspase-3 and expression of P53 protein. Additionally, Daph attenuated mitochondrial dysfunction by suppressing ASK1/JNK activation and decreasing apoptosis-inducing factor (AIF) and Cytochrome c release and Bax mitochondrial translocation. Daph inhibited inflammatory responses by inactivating the thioredoxin-interacting protein (Txnip)/NLRP3 inflammasome. Furthermore, Daph efficiently enhanced Nrf2 nuclear translocation and Trx-1 expression. However, these effects in WT mice were eliminated in Nrf2-/- mice. CONCLUSIONS: These investigations demonstrated that Daph treatment has protective potential against oxidative stress-driven hepatotoxicity by inhibition of ASK1/JNK and Txnip/NLRP3 activation, which may be strongly related to the Nrf2/Trx-1 upregulation.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Inflamassomos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Umbeliferonas/farmacologia , Acetaminofen/efeitos adversos , Animais , Proteínas de Transporte/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Células Hep G2 , Humanos , Inflamassomos/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , MAP Quinase Quinase 4/metabolismo , MAP Quinase Quinase Quinase 5/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/fisiologia , Substâncias Protetoras/farmacologia
11.
Life Sci ; 252: 117662, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32298739

RESUMO

AIMS: Bronchopulmonary dysplasia (BPD) is a severe respiratory complication in preterm infants. This study reveals the molecular mechanism of autophagic agonists regulating the Nrf2-ARE pathway via p62 to improve alveolar development in BPD rats. MAIN METHODS: Newborn Sprague-Dawley rats were randomly exposed to a hyperoxic environment (FiO2 = 0.85) for 14 days and rapamycin (RAPA) was intraperitoneally injected on alternate days into hyperoxia-exposed mice. Alveolar development was assessed using HE and RAC values. Markers associated with the p62-Keap1-Nrf2-ARE pathway were detected by western blot, immunohistochemistry, and RT-PCR. Co-localization of proteins was determined using double immunofluorescence staining. KEY FINDINGS: At the levels of lung tissue and primary type II alveolar epithelial cells, the enhanced binding between phosphorylated p62 and Keap1 disrupted the nuclear transport of Nrf2. The activated Nrf2 was insufficient to reverse alveolar simplification. The autophagy agonist was able to inhibit p62 phosphorylation, promote Keap1 degradation, increase Nrf2 nuclear transport, augment downstream antioxidant enzyme expression, and enhance antioxidant capacity, thereby improving the simplification of alveolar structure in BPD rats. SIGNIFICANCE: The use of autophagy agonists to enhance the Nrf2-ARE pathway activity and promote alveolar development could be a novel target in antioxidant therapy for BPD.


Assuntos
Autofagia/efeitos dos fármacos , Displasia Broncopulmonar/fisiopatologia , Alvéolos Pulmonares/metabolismo , Sirolimo/farmacologia , Animais , Animais Recém-Nascidos , Elementos de Resposta Antioxidante , Antioxidantes/metabolismo , Modelos Animais de Doenças , Humanos , Hiperóxia/complicações , Recém-Nascido , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Sprague-Dawley
12.
Chem Biol Interact ; 324: 109086, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32275923

RESUMO

Oxidative stress-induced apoptosis of retinal ganglion cells (RGCs) contributes to the development and progression of glaucoma. Sestrin2 (Sesn2), a stress-inducible protein, has a potent antioxidant capacity that can provide cytoprotection against various noxious stimuli. However, whether Sesn2 is involved in protecting RGCs from oxidative stress remains unexplored. The purpose of this study was to evaluate the role of Sesn2 in regulating hydrogen peroxide (H2O2)-induced oxidative stress of RGCs. Here, we showed that Sesn2 expression was induced in RGCs following H2O2 exposure. Sesn2 depletion markedly exacerbated H2O2-induced apoptosis and reactive oxygen species (ROS) generation in RGCs. Notably, upregulation of Sesn2 significantly decreased H2O2-induced apoptosis and ROS generation. Moreover, Sesn2 overexpression increased the nuclear translocation of nuclear factor erythroid-derived 2-like 2 (Nrf2), elevated Nrf2/antioxidant response element (ARE)-mediated transcriptional activity and upregulated the expression of Nrf2 target genes in H2O2-stimulated RGCs. Interestingly, we found that Sesn2 promoted Nrf2/ARE activation through downregulation of kelch-like ECH-associated protein 1 (Keap1). Restoration of Keap1 or inhibition of Nrf2 significantly reversed the Sesn2-mediated protective effect in H2O2-stimulated RGCs. In conclusion, these results elucidated that Sesn2 confers a protective effect in RGCs against H2O2-induced oxidative stress by reinforcing Nrf2/ARE activation via downregulation of Keap1. Our study suggests that the Sesn2/Keap1/Nrf2 axis may play an important role in retinal degeneration in glaucoma.


Assuntos
Apoptose/fisiologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Nucleares/metabolismo , Estresse Oxidativo/fisiologia , Células Ganglionares da Retina/metabolismo , Animais , Elementos de Resposta Antioxidante/fisiologia , Apoptose/efeitos dos fármacos , Regulação para Baixo , Peróxido de Hidrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Células Ganglionares da Retina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima
13.
Mol Cell Biol ; 40(13)2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32284348

RESUMO

The KEAP1-NRF2 pathway is the principal protective response to oxidative and electrophilic stresses. Under homeostatic conditions, KEAP1 forms part of an E3 ubiquitin ligase, which tightly regulates the activity of the transcription factor NRF2 by targeting it for ubiquitination and proteasome-dependent degradation. In response to stress, an intricate molecular mechanism facilitated by sensor cysteines within KEAP1 allows NRF2 to escape ubiquitination, accumulate within the cell, and translocate to the nucleus, where it can promote its antioxidant transcription program. Recent advances have revealed that KEAP1 contains multiple stress sensors and inactivation modalities, which together allow diverse cellular inputs, from oxidative stress and cellular metabolites to dysregulated autophagy, to regulate NRF2 activity. This integration of the KEAP1-NRF2 system into multiple cellular signaling and metabolic pathways places NRF2 activation as a critical regulatory node in many disease phenotypes and suggests that the pharmaceutical modulation of NRF2's cytoprotective activity will be beneficial for human health in a broad range of noncommunicable diseases.


Assuntos
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Animais , Autofagia , Humanos , Redes e Vias Metabólicas , Estresse Oxidativo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
14.
Life Sci ; 253: 117584, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32220623

RESUMO

Accumulating recent studies have demonstrated the preventive and therapeutic effects of polyphonic compounds such as quercetin in colorectal cancer. Therefore, we aimed to evaluate the underlying mechanisms for positive effects of quercetin in rats with 1,2-dimethylhydrazine (DMH)- induced colorectal cancer. For this purpose, male Wistar rats were classified as 6 groups, including group 1 without any intervention, group 2 as quercetin received rats (50 mg/kg), groups 3 as DMH received rats (20 mg/kg) group 4-6 DMH and quercetin received rats. DNA damage, DNA repair, the expression levels and activities of enzymic antioxidants, non-enzymic antioxidants, and NRF2/Keap1 signaling were evaluated in colon tissues of all groups. Our results showed significant suppression of DNA damage and induction of DNA repair in DMH + Quercetin groups, particularly in entire-period in comparison to other groups (p < .05). The expression levels and activities of enzymic and non-enzymic antioxidants were increased in DMH + Quercetin groups (p < .05). Lipid and protein peroxidation were significantly suppressed in DMH + Quercetin groups (p < .05). In addition, quercetin also modulated NRF2/Keap1 signaling and its targets, detoxifying enzymes in DMH + Quercetin groups. Our finding demonstrated that quercetin supplementation effectively reversed DMH-mediated oxidative stress and DNA damage through targeting NRF2/Keap1 signaling pathway.


Assuntos
1,2-Dimetilidrazina/metabolismo , Carcinógenos/metabolismo , Neoplasias do Colo/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Quercetina/química , 1,2-Dimetilidrazina/toxicidade , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Carcinógenos/química , Carcinógenos/toxicidade , Catalase/metabolismo , Dano ao DNA/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/química , Masculino , Neoplasias Experimentais , Estresse Oxidativo/efeitos dos fármacos , Quercetina/metabolismo , Quercetina/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio , Transdução de Sinais
15.
Life Sci ; 253: 117581, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32209424

RESUMO

AIMS: Cisplatin (CDDP) is an effective antineoplastic agent, however, its serious nephrotoxicity limits therapeutic use. Human growth hormone (hGH) has proved antioxidant and anti-inflammatory activities. The present study aimed to investigate the nephroprotective effects of hGH against CDDP-induced nephrotoxicity and the mechanisms underlying this nephroprotection. MAIN METHODS: Male albino rats injected with CDDP (7 mg/kg) and nephrotoxicity indices, oxidative stress and inflammatory biomarkers (high mobility group box protein-1 (HMGB-1), soluble epoxide hydrolase (sEH), and nuclear factor-kappa B (NF-κB)) were assessed. Also, insulin-like growth factor-1 (IGF-1) and Nuclear factor-erythroid-2 (Nrf2)/heme oxygenase-1 (HO-1) pathway were assessed. KEY FINDINGS: hGH (1 mg/kg) improved kidney function and antioxidant systems and showed intact renal tubular epithelium. Cisplatin upregulated the HMGB-1/NF-κB and downregulated Nrf2/HO-1 pathways which were reversed by hGH and aligned with increased renal IGF-1 expression. Also, IGF-1/sEH crosstalk might be involved in hGH nephroprotection. Moreover, hGH downregulated HSP70 and caspase-3 expressions. SIGNIFICANCE: these results concluded that hGH can attenuate the inflammation and oxidative stress attained by CDDP probably through inhibition of Nrf2/HO-1 pathway. We also suggested that Keap1/Nrf2-mediated upregulation of the antioxidant HO-1 might inhibit HMGB-1/NF-κB signaling and thus provide the principal protection mechanism offered by hGH against CDDP-induced kidney injury.


Assuntos
Lesão Renal Aguda/prevenção & controle , Cisplatino/efeitos adversos , Hormônio do Crescimento/metabolismo , Heme Oxigenase-1/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Animais , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/metabolismo , Antineoplásicos/efeitos adversos , Antineoplásicos/metabolismo , Antioxidantes/efeitos adversos , Antioxidantes/farmacologia , Caspase 3/metabolismo , Cisplatino/metabolismo , Modelos Animais de Doenças , Epóxido Hidrolases/metabolismo , Hormônio do Crescimento/farmacologia , Proteínas HMGB/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Hormônio do Crescimento Humano , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais
16.
Biochem Pharmacol ; 175: 113900, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32156661

RESUMO

During hemolysis, free heme released from damaged RBCs impairs adjacent cells. As a response, heme induces its metabolic degradation via heme oxygenase-1 (HO-1), activated by NF-E2-related factor 2 (NRF2), the master stress response transcription factor. Heme is well considered a signaling molecule, but how heme does activate NRF2 is not well understood. K562, human pro-erythroid cells responding to hemin (ferric chloride heme), were employed to uncover the major role of Kelch-like ECH-associated protein 1 (KEAP1)/NRF2 stress response signaling, embedded in hemin-induced cytotoxicity (HIC), at ≥50 µM. The intracellular pools of hemin were found to determine the progression from the reversible cell growth inhibition to non-apoptotic cell death. Hemin-induced accumulation of both reactive oxygen species (ROS) and ubiquitinated proteins provoked disturbed cellular proteostasis. Immediate accumulation and nuclear translocation of NRF2 were recorded as defensive adaptation. The NRF2-driven genes encoding glutamate-cysteine ligase (GCLC) and cystine/glutamate antiporter (xCT) were substantially activated. Hemin orchestrated a defensive pathway involving the management of cellular non-protein thiols, via an increase in GSH levels and secretion of cysteine. Mechanistically, hemin stabilized NRF2 protein levels selectively by inhibiting the KEAP1-driven ubiquitination of NRF2, while allowing KEAP1 ubiquitination. High-molecular-weight ubiquitinated KEAP1 variants formed in hemin-treated cells degraded in proteasomes, while a portion of them translocated into the nucleus. The KEAP1/NRF2 system can be revealed as a basic homeostatic mechanism, activated in cells encountering free heme, both in healthy and diseased state. Its activation provides a multi-target cytoprotective platform to develop agents preventing heme toxicity.


Assuntos
Citotoxinas/toxicidade , Células Eritroides/metabolismo , Hemina/toxicidade , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/fisiologia , Relação Dose-Resposta a Droga , Células Eritroides/efeitos dos fármacos , Humanos , Células K562 , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
17.
Biochim Biophys Acta Proteins Proteom ; 1868(7): 140405, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32120017

RESUMO

The proteins Keap1 and Nrf2 together act as a cytoprotective mechanism that enables cells to overcome electrophilic and oxidative stress. Research has shown that manipulating this system by modulating the Keap1-Nrf2 interaction either through inhibition at the binding interface or via the covalent modification of Keap1 could provide a powerful therapeutic strategy for a range of diseases. However, despite intensive investigation of the system and significant progress in the development of inhibitory small molecules, there is still much to learn about the pathways associated with the Keap1-Nrf2 system and the structural details underpinning its mechanism of action. In this review, we discuss how a deeper understanding could prove revolutionary in the development of new inhibitors and activators as well as guiding how to best harness Keap1 for targeted protein degradation.


Assuntos
Descoberta de Drogas , Proteína 1 Associada a ECH Semelhante a Kelch/química , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/química , Fator 2 Relacionado a NF-E2/metabolismo , Sítios de Ligação , Proteínas Culina/metabolismo , Humanos , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Ubiquitina-Proteína Ligases/metabolismo
18.
J Anim Sci ; 98(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32161959

RESUMO

Accumulating evidences indicate that plant extracts and probiotics are effective antioxidant substitutes which play important roles in animal production. However, the comparative study of the mechanism underlying the antioxidant property of Illicium verum extracts (IVE) and probiotics with added glucose oxidase (PGO) on piglets remains to be explored. This study evaluated the difference and the interaction effect of IVE and PGO on serum, liver, and jejunum antioxidant capacity of weaned piglets. A total of 32 weaned piglets (Duroc × Landrace × Yorkshire) at the age of 28 d with an average body weight of 14.96 ± 0.32 kg were randomly divided into four treatments with eight replicates per treatment in a 2 × 2 factorial arrangement. Treatments included basal diet (IVE-PGO-), basal diet + 1,000 mg/kg PGO (IVE-PGO+), basal diet + 500 mg/kg IVE (IVE+PGO-), and basal diet + 500 mg/kg IVE + 1,000 mg/kg PGO (IVE+PGO+). All the piglets were housed individually for the 42-d trial period after 7-d adaptation. The piglets were euthanized at the end of the experiment and the liver and jejunum samples were taken and subjected to immunohistochemistry, Western blotting, as well as antioxidant and qRT-PCR analysis. Significant interactions were observed between IVE and PGO for total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px) in serum (42 d), liver, and jejunum; malondialdehyde (MDA) in serum (21 d); and mRNA and protein expression of kelch sample related protein-1 (Keap1) and nuclear factor erythroid-2 related factor (Nrf2)/Keap1 in the liver and jejunum (P < 0.05). Both IVE and PGO improved (P < 0.05) T-SOD and GSH-Px in the serum (42 d), liver, and jejunum, and the mRNA and protein expression of Nrf2 and Nrf2/Keap1 in the liver and jejunum, but decreased (P < 0.05) MDA in the serum (21 d) and the mRNA and protein expression of Keap1 in the liver and jejunum. Immunohistochemical results confirmed that IVE and PGO enhanced the positive reactions of Nrf2 but weakened Keap1 in both the liver and jejunum. In conclusion, the results confirmed that IVE (500 mg/kg) and PGO (1,000 mg/kg) can improve the antioxidant capacity of weaned piglets and that the interaction effect between IVE and PGO is significant. At the same time, the fact that IVE and PGO activate the Nrf2/Keap1 in the liver and jejunum signaling pathway suggests that they play an important role in the ameliorative antioxidant capacity of weaned piglets. Therefore, the combination of IVE and PGO could be recommended as a new potential alternative to antibiotics in piglets' diets.


Assuntos
Illicium , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/farmacologia , Probióticos/administração & dosagem , Suínos/fisiologia , Animais , Antioxidantes/metabolismo , Dieta , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucose Oxidase/administração & dosagem , Glutationa Peroxidase/metabolismo , Jejuno/metabolismo , Fígado/metabolismo , Malondialdeído/metabolismo , Extratos Vegetais/administração & dosagem , Superóxido Dismutase/metabolismo , Desmame
19.
Poult Sci ; 99(3): 1454-1461, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32115031

RESUMO

The aim of the present study was to evaluate the effect of glutamine (Gln) on modulating heat stress-induced oxidative damage in the broiler thigh muscle through nuclear factor erythroid 2-related 2/Kelch-like ECH-associated protein 1 (Nrf2-Keap1) pathway. Three-hundred 22-day-old Arbor Acres broilers were reallocated into 5 groups: a control group (24 °C) fed with basal diet and 4 heat stress (HS) groups (34 °C for 8 h/D) fed with basal diet containing 0, 0.5, 1.0, and 1.5% Gln. This experiment lasted 21 D. Heat stress decreased (P < 0.05) pH, redness, and Gln levels, and increased (P < 0.05) luminance, water loss rate, and cooking loss (CL) values of the thigh meat. Compared with the HS group, supplementation with 1.5% Gln increased (P < 0.05) pH, redness, and Gln levels, but decreased (P < 0.05) luminance and CL values in the thigh meat. There were significant decreases (P < 0.05) in glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), and Nrf2 levels, but significant increases (P < 0.05) in the malondialdehyde (MDA) and Keap1 levels of the thigh muscle after HS treatment. Compared with the HS group, supplementation with 1.0, and 1.5% Gln decreased (P < 0.05) MDA and Keap1 levels; supplementation with 1.5% Gln increased (P < 0.05) GSH, GSH-Px, T-AOC, CAT, SOD, and Nrf2 levels in the thigh muscle of heat-stressed broilers. Furthermore, HS decreased (P < 0.05) Nrf2, SOD, CAT, and GSH-Px mRNA expression levels, but increased (P < 0.05) Keap1 mRNA level in the thigh muscle of broiler. Dietary supplementation with 1.5% Gln increased (P < 0.05) Nrf2, GSH-Px, CAT, and SOD mRNA expression levels, but decreased (P < 0.05) Keap1 mRNA level in the thigh muscle of heat-stressed broilers. In conclusion, dietary Gln improved the resistance of heat-stressed broiler muscles to oxidative damage possibly through reversing the muscle Gln level and inducing the expression of the Nrf2-Keap1 pathway.


Assuntos
Galinhas/fisiologia , Glutamina/metabolismo , Transtornos de Estresse por Calor/veterinária , Músculo Esquelético/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Ração Animal/análise , Animais , Proteínas Aviárias/metabolismo , Dieta/veterinária , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Feminino , Glutamina/administração & dosagem , Transtornos de Estresse por Calor/tratamento farmacológico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Carne/análise , Músculo Esquelético/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Distribuição Aleatória , Coxa da Perna
20.
Mycotoxin Res ; 36(3): 287-299, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32076947

RESUMO

Deoxynivalenol (DON) is a type B trichothecenes that is widely contaminating human and animal foods, leading to several toxicological implications if ingested. Induction of oxidative stress and production of lipid peroxides were suggested to be the reasons for DON-induced cytotoxicity. However, detailed and comprehensive profiling of DON-related lipid hydroperoxides was not identified. Furthermore, the mechanisms behind DON-induced cytotoxicity and oxidative stress have received less attention. Zinc (Zn) is an essential element that has antioxidant activities; however, the protective effects of Zn against DON-induced adverse effects were not examined. Therefore, this study was undertaken to investigate DON-induced cytotoxicity and oxidative damage to human HepG2 cell lines. Furthermore, a quantitative estimation for the formed lipid hydroperoxides was conducted using LC-MS/MS. In addition, DON-induced transcriptomic changes on the inflammatory markers and antioxidant enzymes were quantitatively examined using qPCR. The protective effects of Zn against DON-induced cytotoxicity and oxidative stress, the formation of lipid hydroperoxides (LPOOH), and antioxidant status in HepG2 cells were investigated. Finally, the effects of DON and Zn on the Nrf2-Keap1 pathway were further explored. The achieved results indicated that DON caused significant cytotoxicity in HepG2 cells accompanied by significant oxidative damage and induction of the inflammatory markers. Identification of DON-related LPOOH revealed the formation of 22 LPOOH species including 14 phosphatidylcholine hydroperoxides, 5 triacylglycerol hydroperoxides, and 3 cholesteryl ester hydroperoxides. DON caused significant downregulation of Nrf2-regulated antioxidant enzymes. Zn administration led to significant protection of HepG2 cells against DON-induced adverse effects, probably via activation of the Nrf2-Keap1 pathway.


Assuntos
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Peróxidos Lipídicos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Tricotecenos/toxicidade , Zinco/farmacologia , Células Hep G2 , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Peróxidos Lipídicos/química , Fator 2 Relacionado a NF-E2/genética , Oxirredução/efeitos dos fármacos
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