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1.
J Agric Food Chem ; 67(46): 12844-12853, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31668063

RESUMO

Flazin is a ß-carboline-derived alkaloid found in Japanese fermented foods. Here, the potential of flazin as an antioxidant food was studied with particular reference to its effect on the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) system in human hepatocytes (C3A). Flazin and flazin analogues including the decarboxylated derivative perlolyrine were chemically synthesized and compared with each other and with chlorogenic acid and curcumin. Among these compounds, flazin showed the lowest cytotoxicity (IC50 < 500 µM) and the highest capacity to activate the Keap1-Nrf2 system. It provided the largest (>3-fold of the control) cytoprotection ability against a pro-oxidant, although its radical absorbance capacity was relatively low. Flazin increased the expressions of Nrf2-dependent phase II enzyme genes and their products (NQO1, GSTP, and GSH proteins). The strong cytoprotection ability of flazin associated with low log P (0-3) is shared by sulforaphane and 3,5-dihydroxy-4-methoxybenzyl alcohol, suggesting the potential value of flazin and flazin-rich foods for the prevention of oxidation-related health disorders.


Assuntos
Carbolinas/farmacologia , Furanos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , 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 , Transdução de Sinais/efeitos dos fármacos
2.
Nat Commun ; 10(1): 4190, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519898

RESUMO

The KRAS oncoprotein, a critical driver in 33% of lung adenocarcinoma (LUAD), has remained an elusive clinical target due to its perceived undruggable nature. The identification of dependencies borne through common co-occurring mutations are sought to more effectively target KRAS-mutant lung cancer. Approximately 20% of KRAS-mutant LUAD carry loss-of-function mutations in KEAP1, a negative regulator of the antioxidant response transcription factor NFE2L2/NRF2. We demonstrate that Keap1-deficient KrasG12D lung tumors arise from a bronchiolar cell-of-origin, lacking pro-tumorigenic macrophages observed in tumors originating from alveolar cells. Keap1 loss activates the pentose phosphate pathway, inhibition of which, using 6-AN, abrogated tumor growth. These studies highlight alternative therapeutic approaches to specifically target this unique subset of KRAS-mutant LUAD cancers.


Assuntos
Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/metabolismo , Animais , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Imuno-Histoquímica , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo
3.
Int J Mol Sci ; 20(15)2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31382550

RESUMO

Reactive oxygen species (ROS) are highly reactive signaling molecules that maintain redox homeostasis in mammalian cells. Dysregulation of redox homeostasis under pathological conditions results in excessive generation of ROS, culminating in oxidative stress and the associated oxidative damage of cellular components. ROS and oxidative stress play a vital role in the pathogenesis of acute kidney injury and chronic kidney disease, and it is well documented that increased oxidative stress in patients enhances the progression of renal diseases. Oxidative stress activates autophagy, which facilitates cellular adaptation and diminishes oxidative damage by degrading and recycling intracellular oxidized and damaged macromolecules and dysfunctional organelles. In this review, we report the current understanding of the molecular regulation of autophagy in response to oxidative stress in general and in the pathogenesis of kidney diseases. We summarize how the molecular interactions between ROS and autophagy involve ROS-mediated activation of autophagy and autophagy-mediated reduction of oxidative stress. In particular, we describe how ROS impact various signaling pathways of autophagy, including mTORC1-ULK1, AMPK-mTORC1-ULK1, and Keap1-Nrf2-p62, as well as selective autophagy including mitophagy and pexophagy. Precise elucidation of the molecular mechanisms of interactions between ROS and autophagy in the pathogenesis of renal diseases may identify novel targets for development of drugs for preventing renal injury.


Assuntos
Lesão Renal Aguda/genética , Autofagia/genética , Estresse Oxidativo/genética , Insuficiência Renal Crônica/genética , Lesão Renal Aguda/patologia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Fator 2 Relacionado a NF-E2/genética , Proteínas Quinases/genética , Proteínas de Ligação a RNA/genética , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/patologia
4.
Am J Chin Med ; 47(5): 1113-1131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31352786

RESUMO

Pulmonary fibrosis (PF) is characterized by myofibroblast activation, which can be triggered by oxidative stress. In this study, we investigated the antifibrotic effect of the ethyl acetate extract of Salvia miltiorrhiza (EASM) on PF and examined the underlying molecular mechanism. EASM suppressed myofibroblast activation with reduced extracellular matrix deposition in the lungs of mice subjected to bleomycin (BLM) challenge, demonstrating the inhibitory effects on PF. EASM positively alleviated oxidative stress by upregulating nuclear factor-erythroid 2-related factor 2 (Nrf2) and concomitantly downregulating NADPH oxidase 4 (Nox4) in the lungs of BLM-treated mice. This effect was also observed in an in vitro model of transforming growth factor beta 1 (TGF-ß1)-stimulated fibroblast activation. EASM reduced reactive oxygen species (ROS) generation in fibroblasts by stabilizing Nrf2 protein with promoting kelch-like ECH-associated protein 1 (Keap1) degradation. Nrf2 knockdown in the lungs of BLM-treated mice diminished the inhibitory effects of EASM on fibrosis, providing evidence in vivo to address the unique role of Nrf2. Additionally, EASM inhibited TGF-ß1/Smad3 signaling by downregulating protein kinase C delta (PKC-δ) and Smad3 phosphorylation (p-Smad3), which led to suppression of the TGF-ß1-induced fibrogenic response. These results indicate that EASM exhibits potent antifibrotic activity in vitro and in vivo, which might be associated with activation of Nrf2 pathway and inhibition of TGF-ß1/Smad3 pathway. Our findings support that EASM may act as an effective antifibrotic remedy for PF.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , NADPH Oxidase 4/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Salvia miltiorrhiza/química , Animais , Feminino , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , NADPH Oxidase 4/genética , Fator 2 Relacionado a NF-E2/genética , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo
5.
J Agric Food Chem ; 67(32): 8794-8809, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31345023

RESUMO

Oxidative stress may play a critical role in the progression of liver disorders. Increasing interest has been given to the associations among diet, oxidative stress, gut-liver axis, and nonalcoholic fatty liver disease. Here, we investigated the effects of processed meat proteins on biomarkers of lipid homeostasis, hepatic metabolism, antioxidant functions, and gut microbiota composition in glutaredoxin1 deficient (Glrx1-/-) mice. The wild-type (WT) and Glrx1-/- mice were fed a soy protein diet (SPD), a dry-cured pork protein diet (DPD), a braised pork protein diet (BPD), and a cooked pork protein diet (CPD) at a dose of 20% of protein for 3 months. Serum and hepatic total cholesterol, serum endotoxin, hepatic liver droplet %, and antioxidant capacity were significantly increased in the CPD fed WT mice. In addition, CPD fed Glrx1-/- mice significantly increased total cholesterol, triacylglycerol, and pro-inflammatory cytokines which are accompanied by higher steatosis scores, intrahepatic lipid accumulation, and altered gene expression associated with lipid metabolism. Furthermore, hepatic gene expression of Nrf2/keap1 signaling pathway and its downstream signaling targets were determined using RT-qPCR. Glrx1 deficiency increased Nrf2 activity and expression of its target genes (GPx, catalase, SOD1, G6pd, and Bbc3), which was exacerbated by intake of CPD. Metagenomic analyses revealed that Glrx1-/- mice fed meat protein diets had higher abundances of Mucispirillum, Oscillibacter, and Mollicutes but lower abundances of Bacteroidales S24-7 group_norank, Blautia, and Anaerotruncus than their wild-type counterparts. In summary, Glrx1 deficiency induced an increase in serum biomarkers for lipid homeostasis, gut microbiota imbalance, and upregulation of Nrf2/Keap1 and antioxidant defense genes, which was aggravated by cooked meat protein diet.


Assuntos
Glutarredoxinas/genética , Inflamação/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipogênese , Fígado/metabolismo , Produtos da Carne/efeitos adversos , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Colesterol/sangue , Citocinas/metabolismo , Feminino , Microbioma Gastrointestinal , Glutarredoxinas/deficiência , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/microbiologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Carne Vermelha , Transdução de Sinais , Triglicerídeos/sangue
6.
J Med Food ; 22(9): 885-895, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31274380

RESUMO

We have previously demonstrated the hepatoprotective effect of Schisandra chinensis polysaccharides (SCP) against the liver injury induced by alcohol, high-fat diet, and carbon tetrachloride in mice. In this study, we investigated the effect of SCP against the immunological liver injury induced by concanavalin A (Con A) in mice. The results showed that SCP could significantly reduce the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) in the serum of mice with immunological liver injury. SCP could significantly decrease the content of malondialdehyde (MDA) and nitric oxide (NO) and increase the activity of superoxide dismutase (SOD) and glutathione (GSH) in the liver tissue. SCP could significantly increase the number of CD4+ and decrease the number of CD8+ in the peripheral blood, and elevate the ratio of CD4+/CD8+. SCP could significantly downregulate the expression of Kelch-like ECH-associated protein 1 (Keap1) and upregulate the expression of nuclear factor-erythroid 2-related factor2 (Nrf2) and downstream gene heme oxygenase-1 (HO-1), and downregulate the expression of toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), and nuclear factor-kappa B (NF-κB) proteins. This study indicates that SCP can reduce the release of a large number of inflammatory factors to inhibit the oxidative stress in mice with the immunological liver injury induced by Con A, and its mechanism is closely related to the regulation of Nrf2/antioxidant response element and TLR4/NF-κB signaling pathways.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Hepatopatias/prevenção & controle , Fígado/lesões , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Polissacarídeos/administração & dosagem , Substâncias Protetoras/administração & dosagem , Schisandra/química , Receptor 4 Toll-Like/imunologia , Animais , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/imunologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Hepatopatias/genética , Hepatopatias/imunologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Óxido Nítrico/imunologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
7.
Cell Mol Neurobiol ; 39(8): 1177-1186, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31270710

RESUMO

Oxidative glutamate toxicity plays a vital role in the neurodegeneration diseases, including Alzheimer's diseases (AD). This study set out with the aim to investigate the beneficial effects of fangchinoline (FAN), a natural alkaloid, against glutamate-induced oxidative damage, and to clarify the underlying cellular and biochemical mechanisms. FAN prevented HT22 cells death from oxidative glutamate cytotoxicity in a dose-dependent manner, and significantly attenuated the overproduction of intracellular reactive oxygen species (ROS) and reversed the reduction of superoxide dismutase (SOD) activity induced by glutamate. Further investigations on the underlying mechanisms demonstrated that FAN potently up-regulated the protein level of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase (HO-1), in glutamate-exposed HT22 cells. The protective effects of FAN were almost completely antagonized by inhibitor of Nrf2. Subsequent studies revealed that FAN could down-regulate Kelch-like ECH-associated protein 1 (Keap1) in both mRNA level and protein level. To sum up, our result demonstrated the protective effects of FAN against glutamate-induced oxidative neuronal damage, and for the first time clarified the anti-oxidative mechanisms of FAN involve activating endogenous antioxidant defense system including enhancing SOD activity and regulating Keap1/Nrf-2 antioxidation signaling through modulation of Keap1 expression. Above results shed more light on the molecular mechanisms of FAN's neuroprotective effects, and may provide important clues for the drug development in preventing oxidative stress-associated neurodegenerative diseases.


Assuntos
Alcaloides/farmacologia , Benzilisoquinolinas/farmacologia , Ácido Glutâmico/toxicidade , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Heme Oxigenase-1/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
8.
EBioMedicine ; 45: 25-38, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262713

RESUMO

BACKGROUND: The transcription factor Nrf2 is a master regulator of antioxidant response. While Nrf2 activation may counter increasing oxidative stress in aging, its activation in cancer can promote cancer progression and metastasis, and confer resistance to chemotherapy and radiotherapy. Thus, Nrf2 has been considered as a key pharmacological target. Unfortunately, there are no specific Nrf2 inhibitors for therapeutic application. Moreover, high Nrf2 activity in many tumors without Keap1 or Nrf2 mutations suggests that alternative mechanisms of Nrf2 regulation exist. METHODS: Interaction of FAM129B with Keap1 is demonstrated by immunofluorescence, colocalization, co-immunoprecipitation and mammalian two-hybrid assay. Antioxidative function of FAM129B is analyzed by measuring ROS levels with DCF/flow cytometry, Nrf2 activation using luciferase reporter assay and determination of downstream gene expression by qPCR and wester blotting. Impact of FAM129B on in vivo chemosensitivity is examined in mice bearing breast and colon cancer xenografts. The clinical relevance of FAM129B is assessed by qPCR in breast cancer samples and data mining of publicly available databases. FINDINGS: We have demonstrated that FAM129B in cancer promotes Nrf2 activity by reducing its ubiquitination through competition with Nrf2 for Keap1 binding via its DLG and ETGE motifs. In addition, FAM129B reduces chemosensitivity by augmenting Nrf2 antioxidative signaling and confers poor prognosis in breast and lung cancer. INTERPRETATION: These findings demonstrate the important role of FAM129B in Nrf2 activation and antioxidative response, and identify FMA129B as a potential therapeutic target. FUND: The Chang Gung Medical Foundation (Taiwan) and the Ministry of Science and Technology (Taiwan).


Assuntos
Antioxidantes/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/genética , Fosfoproteínas/genética , Envelhecimento/genética , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Camundongos , Ligação Proteica/genética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Int J Mol Sci ; 20(11)2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31159323

RESUMO

BACKGROUND: The KEAP1/NRF2 pathway is the key regulator of antioxidants and cellular stress responses, and is implicated in neoplastic progression and resistance of tumors to treatment. KEAP1 silencing by promoter methylation is widely reported in solid tumors as part of the complex regulation of the KEAP1/NRF2 axis, but its prognostic role remains to be addressed in lung cancer. METHODS: We performed a detailed methylation density map of 13 CpGs located into the KEAP1 promoter region by analyzing a set of 25 cell lines from different histologies of lung cancer. The methylation status was assessed using quantitative methylation specific PCR (QMSP) and pyrosequencing, and the performance of the two assays was compared. RESULTS: Hypermethylation at the promoter region of the KEAP1 was detected in one third of cell lines and its effect on the modulation KEAP1 mRNA levels was also confirmed by in vitro 5-Azacytidine treatment on lung carcinoid, small lung cancer and adenocarcinoma cell lines. QMSP and pyrosequencing showed a high rate of concordant results, even if pyrosequencing revealed two different promoter CpGs sub-islands (P1a and P1b) with a different methylation density pattern. CONCLUSIONS: Our results confirm the effect of methylation on KEAP1 transcription control across multiple histologies of lung cancer and suggest pyrosequencing as the best approach to investigate the pattern of CpGs methylation in the promoter region of KEAP1. The validation of this approach on lung cancer patient cohorts is mandatory to clarify the prognostic value of the epigenetic deregulation of KEAP1 in lung tumors.


Assuntos
Metilação de DNA , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Neoplasias Pulmonares/genética , Alelos , Sequência de Bases , Linhagem Celular Tumoral , Ilhas de CpG , Humanos , Neoplasias Pulmonares/patologia , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas , Análise de Sequência de DNA
10.
Biochimie ; 163: 163-170, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201843

RESUMO

Acute myocardial infarction causes irreversible myocardial damage and is a leading cause of death and disability worldwide. Casein kinase 2 interacting protein-1 (CKIP-1) has been suggested to confer cytoprotection against various pathologic injuries. However, it remains unclear whether CKIP-1 regulates myocardial infarction-induced cardiomyocyte injury. This study aimed to explore the potential role of CKIP-1 in regulating hypoxia-induced cardiomyocyte injury and reveal the underlying mechanism. The results demonstrated that hypoxia-exposed cardiomyocytes showed lower CKIP-1 expression. CKIP-1 restoration by transfecting a CKIP-1 expression vector significantly improved viability and reduced apoptosis in hypoxia-treated cardiomyocytes. Moreover, CKIP-1 overexpression suppressed hypoxia-induced oxidative stress in cardiomyocytes. Mechanism research revealed that CKIP-1 overexpression reduced the expression of kelch-like ECH-associated protein 1 (Keap1) and increased the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2), actions which resulted in an increase in the transcription of Nrf2 target genes. However, Keap1 overexpression partially reversed CKIP-1-mediated Nrf2 promotion and cardioprotection. Notably, the blockade of Nrf2 signaling also significantly abolished CKIP-1-mediated cardioprotection. Overall, our findings demonstrate that CKIP-1 alleviates hypoxia-induced cardiomyocyte injury through the up-regulation of Nrf2 antioxidant signaling via the down-regulation of Keap1, suggesting a potential role for CKIP-1 in myocardial infarction.


Assuntos
Apoptose , Proteínas de Transporte/metabolismo , Hipóxia/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Animais , Células Cultivadas , Regulação da Expressão Gênica , Hipóxia/genética , Hipóxia/fisiopatologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/fisiologia , Fator 2 Relacionado a NF-E2/metabolismo , Ratos
11.
J Sci Food Agric ; 99(13): 6097-6107, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31250448

RESUMO

BACKGROUND: Reactive oxygen species (ROS) can cause DNA damage. Rice protein (RP) inhibits ROS accumulation. However, a link between the reduction of ROS-derived DNA damage and the intake of RP is far from clear. The main objective of this study is to elucidate the effects of RPs on the reduction of DNA damage in growing and adult rats. RESULTS: An intake of RP for 2 weeks significantly reduced the hepatic accumulation of ROS and 8-hydroxydeoxyguanosine (8-OHdG) in growing and adult rats, whereas the hepatic p53 content was markedly increased by RPs. After 2 weeks' feeding, the mRNA levels and protein expressions of p53, ataxia-telangiectasia mutated (ATM), and Checkpoint kinase 2 (Chk2) were up-regulated by RPs, whereas Murine Double Minute 2 (MDM2) expressions were markedly inhibited by RPs, resulting in more p53 being translocated into the nucleus. Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) was activated by RP by reducing Kelch-like ECH-associated protein 1 (Keap1), resulting in the up-regulation of antioxidant expressions of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in RP groups. CONCLUSION: Rice protein can exert an endogenous antioxidant activity to reduce ROS-derived DNA damage by activating the Nrf2-Keap1 pathway. This study suggests that the activation of the ATM-Chk2-p53 pathway might be one of the mechanisms exerted by RP for reducing DNA damage in growing and adult rats. © 2019 Society of Chemical Industry.


Assuntos
Antioxidantes/metabolismo , Dano ao DNA , Oryza/metabolismo , Proteínas de Plantas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Catalase/genética , Catalase/metabolismo , Quinase do Ponto de Checagem 2/genética , Quinase do Ponto de Checagem 2/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fígado/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Proteína Supressora de Tumor p53/genética
12.
Anim Sci J ; 90(8): 990-998, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31251457

RESUMO

The study was conducted to investigate the effects of dietary leucine on antioxidant activity and expression of antioxidant- and mitochondrial-related genes in longissimus dorsi muscle and liver of piglets. Three diets were formulated with different levels of supplemented leucine (0%, 0.25%, 0.5%). Results showed that supplementation of 0.25% leucine significantly increased antisuperoxide anion (ASA) and antihydroxyl radical (AHR) levels and activities of total superoxide dismutade (T-SOD), glutathione peroxidase (GPx), glutathione S-transferase (GST), and total antioxidant capacity (T-AOC) in serum, longissimus dorsi muscle and liver of piglets as compared with the control group. The SOD2, catalase (CAT), GPx, GST, glutathione reductase (GR), and nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA levels in longissimus dorsi muscle and liver were significantly increased by 0.25% leucine supplementation. However, the malondialdehyde (MDA) content and the mRNA level of Kelch-like ECH-associated protein 1 (Keap1) exhibited an opposite tendency. Additionally, supplementation of 0.25% leucine significantly increased the mRNA levels of mitochondrial-related genes in longissimus dorsi muscle and liver of piglets. Results suggested that supplementation of 0.25% leucine improved antioxidant activity and mitochondrial biogenesis and function of piglets, which was related to the increase in antioxidant enzymes activities and upregulation of expression of antioxidant- and mitochondrial-related genes.


Assuntos
Antioxidantes/metabolismo , Dieta/veterinária , Suplementos Nutricionais , Expressão Gênica/efeitos dos fármacos , Leucina/administração & dosagem , Leucina/farmacologia , Fígado/metabolismo , Mitocôndrias/genética , Músculo Esquelético/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Suínos/genética , Suínos/metabolismo , Animais , Catalase/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Malondialdeído/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo
13.
Fish Shellfish Immunol ; 92: 489-499, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31220575

RESUMO

In this study, we cloned the full-length cDNA of the Kelch-like ECH-associated protein 1 (Keap1) from the scallops Chlamys farreri (C. farreri). Sequences alignment and phylogenetic analysis showed that CfKeap1 was highly specific in the scallops, and the amino acid sequence identity value is closer to that in zebrafish Keap1b and Nothobranchius furzeri Keap1b than Keap1a. The highest transcription level of CfKeap1 expression was detected in the digestive glands. The gene expressions of CfKeap1, NF-E2-related nuclear factor 2 (Nrf2), Superoxide Dismutase (SOD), Catalase (CAT) and Glutathione Peroxidase (GPx) in digestive glands were evaluated by quantitative real-time PCR (qRT-PCR) after being exposed to benzo(a)pyrene (BaP) (0.25, 1and 4 µg/L) for 15 days, which indicated that the activation of Nrf2 and Keap1 expression can be significantly induced under BaP exposure. RNA interference (RNAi) experiments were conducted to examine the expression profiles of CfKeap1, Nrf2, antioxidant genes (Cu/Zn-SOD, CAT and GPx), mitogen-activated protein kinase (MAPKs) and protein kinase C (PKC) signaling pathways key genes in digestive glands and gills when exposed to BaP. Results showed that the mRNA level of CfKeap1 was significantly decreased by 60.69% and59.485%. The changes of CfKeap1 and Nrf2 suggested that the enhancement of Keap1 expression stimulating Nrf2 degradation. Furthermore, the expression of antioxidant genes were consistent with the Nrf2 gene, which suggesting that Nrf2-Keap1 signaling pathway is required for the induction of antioxidant genes. Besides, the changes of PKC, c-Jun N-terminal kinase (JNK) and p38 genes expression suggested that PKC and MAPKs signaling pathways played a synergistic role with Nrf2-Keap1 signaling pathway in the anti-oxidative defense system of bivalve molluscs. In conclusion, these data demonstrated that Keap1 can sense nucleophilic or oxidative stress factors to regulate the Nrf2 signaling pathway together with Cul3-based E3 Ubiquitin Ligase (E3), and the Nrf2-Keap1 signaling pathway played an important role in modulating gene expression of antioxidant enzymes in bivalve mollusks.


Assuntos
Benzo(a)pireno/efeitos adversos , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/imunologia , Pectinidae/efeitos dos fármacos , Poluentes Químicos da Água/efeitos adversos , Sequência de Aminoácidos , Animais , Perfilação da Expressão Gênica , Proteína 1 Associada a ECH Semelhante a Kelch/química , Fator 2 Relacionado a NF-E2/química , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , Pectinidae/genética , Pectinidae/imunologia , Filogenia , Alinhamento de Sequência , Transdução de Sinais
14.
PLoS One ; 14(5): e0216668, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31107893

RESUMO

Oxidative stress has been shown to play a crucial role in the pathophysiology of the neurodegenerative disease Ataxia Telangiectasia. We have recently demonstrated that Dexamethasone treatment is able to counteract the oxidative state by promoting nuclear factor erythroid 2-related factor 2 (NRF2) nuclear accumulation. However, substantial gaps remain in our knowledge of the underlying molecular mechanism(s) according to which Dexamethasone acts as an NRF2 inducer. Herein we investigate the possible effects of the drug on the main NRF2 activation pathways by initially focusing on key kinases known to differently affect NRF2 activation. Neither AKT nor ERK1/2, known to be NRF2-activating kinases, were found to be activated upon Dexamethasone treatment, thus excluding their involvement in the transcription factor nuclear shift. Likewise, GSK3 inactivating kinase was not inhibited, thus ruling out its role in NRF2 activation. On the other hand, p38 MAPK, another NRF2-inhibitory kinase, was indeed switched-off in Ataxia Telangiectasia cells by Dexamethasone-mediated induction of DUSP1 phosphatase, and therefore it appeared that it might account for NRF2 triggering. However, this mechanism was excluded by the use of a selective p38 inhibitor, which failed to cause a significant NRF2 nuclear shift and target gene induction. Finally, dexamethasone effects on the classical oxidative pathway orchestrated by KEAP1 were addressed. Dexamethasone was found to decrease the expression of the inhibitor KEAP1 at both mRNA and protein levels and to induce the shift from the reduced to the oxidized form of KEAP1, thus favouring NRF2 translocation into the nucleus. Furthermore, preliminary data revealed very low levels of the negative regulator Fyn in Ataxia Telangiectasia cells, which might account for the prolonged NRF2-activated gene expression.


Assuntos
Ataxia Telangiectasia/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/metabolismo , Ataxia Telangiectasia/genética , Linhagem Celular , Dexametasona/farmacologia , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/antagonistas & inibidores , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/genética , Doenças Neurodegenerativas/genética , Oxirredução , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia
15.
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
16.
Int J Mol Sci ; 20(10)2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31126053

RESUMO

BACKGROUND: The KEAP1/NRF2 pathway has been widely investigated in tumors since it was implicated in cancer cells survival and therapies resistance. In lung tumors the deregulation of this pathway is mainly related to point mutations of KEAP1 and NFE2L2 genes and KEAP1 promoter hypermethylation, but these two genes have been rarely investigated in low/intermediate grade neuroendocrine tumors of the lung. METHODS: The effects of KEAP1 silencing on NRF2 activity was investigated in H720 and H727 carcinoid cell lines and results were compared with those obtained by molecular profiling of KEAP1 and NFE2L2 in a collection of 47 lung carcinoids. The correlation between methylation and transcript levels was assessed by 5-aza-dC treatment. RESULTS: We demonstrated that in carcinoid cell lines, the KEAP1 silencing induces an upregulation of NRF2 and some of its targets and that there is a direct correlation between KEAP1 methylation and its mRNA levels. A KEAP1 hypermethylation and Loss of Heterozygosity at KEAP1 gene locus was also observed in nearly half of lung carcinoids. CONCLUSIONS: This is the first study that has described the effects of KEAP1 silencing on the regulation of NRF2 activity in lung carcinoids cells. The epigenetic deregulation of the KEAP1/NRF2 by a KEAP1 promoter hypermethylation system appears to be a frequent event in lung carcinoids.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Neoplasias Pulmonares/genética , Fator 2 Relacionado a NF-E2/genética , Tumores Neuroendócrinos/genética , Adulto , Linhagem Celular Tumoral , Metilação de DNA , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Adulto Jovem
17.
PLoS Pathog ; 15(4): e1007541, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31017975

RESUMO

DNA damage response (DDR) and selective autophagy both can be activated by reactive oxygen/nitrogen species (ROS/RNS), and both are of paramount importance in cancer development. The selective autophagy receptor and ubiquitin (Ub) sensor p62 plays a key role in their crosstalk. ROS production has been well documented in latent infection of oncogenic viruses including Epstein-Barr Virus (EBV). However, p62-mediated selective autophagy and its interplay with DDR have not been investigated in these settings. In this study, we provide evidence that considerable levels of p62-mediated selective autophagy are spontaneously induced, and correlate with ROS-Keap1-NRF2 pathway activity, in virus-transformed cells. Inhibition of autophagy results in p62 accumulation in the nucleus, and promotes ROS-induced DNA damage and cell death, as well as downregulates the DNA repair proteins CHK1 and RAD51. In contrast, MG132-mediated proteasome inhibition, which induces rigorous autophagy, promotes p62 degradation but accumulation of the DNA repair proteins CHK1 and RAD51. However, pretreatment with an autophagy inhibitor offsets the effects of MG132 on CHK1 and RAD51 levels. These findings imply that p62 accumulation in the nucleus in response to autophagy inhibition promotes proteasome-mediated CHK1 and RAD51 protein instability. This claim is further supported by the findings that transient expression of a p62 mutant, which is constitutively localized in the nucleus, in B cell lines with low endogenous p62 levels recaptures the effects of autophagy inhibition on CHK1 and RAD51 protein stability. These results indicate that proteasomal degradation of RAD51 and CHK1 is dependent on p62 accumulation in the nucleus. However, small hairpin RNA (shRNA)-mediated p62 depletion in EBV-transformed lymphoblastic cell lines (LCLs) had no apparent effects on the protein levels of CHK1 and RAD51, likely due to the constitutive localization of p62 in the cytoplasm and incomplete knockdown is insufficient to manifest its nuclear effects on these proteins. Rather, shRNA-mediated p62 depletion in EBV-transformed LCLs results in significant increases of endogenous RNF168-γH2AX damage foci and chromatin ubiquitination, indicative of activation of RNF168-mediated DNA repair mechanisms. Our results have unveiled a pivotal role for p62-mediated selective autophagy that governs DDR in the setting of oncogenic virus latent infection, and provide a novel insight into virus-mediated oncogenesis.


Assuntos
Autofagia , Transformação Celular Viral , Dano ao DNA , Infecções por Vírus Epstein-Barr/patologia , Estresse Oxidativo , Proteínas de Ligação a RNA/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Linfoma de Burkitt/genética , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patologia , Linfoma de Burkitt/virologia , Cromatina , Reparo do DNA , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/fisiologia , Humanos , 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 , Complexo de Endopeptidases do Proteassoma , Proteínas de Ligação a RNA/genética , Transdução de Sinais , Ubiquitina/metabolismo , Latência Viral
18.
J Dairy Sci ; 102(6): 5530-5541, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30954259

RESUMO

Enhancing the supply of rumen-protected Met (RPM) during the peripartum period alleviates inflammation and oxidative stress status in dairy cows. We tested the hypothesis that RPM could increase abundance of genes and proteins related to glutathione (GSH) metabolism and the antioxidant transcription factor nuclear factor erythroid 2-like 2 (NFE2L2) in subcutaneous adipose tissue. Multiparous Holstein cows were fed a basal diet [control prepartum diet = 1.47 Mcal/kg of dry matter (DM) and 15.3% crude protein; control postpartum diet = 1.67 Mcal/kg of DM and 17.7% crude protein] or the control plus ethyl-cellulose RPM at a rate of 0.09 and 0.10% of DM intake before expected calving and after calving, respectively. Sixty cows were assigned to treatments based on parity, previous 305-d milk yield, and body condition score at 28 d from parturition. Diets were fed from -28 to 30 d. Biopsies of subcutaneous adipose tissue collected on d -10, 10, and 30 relative to parturition from 7 cows in each group were used for measuring concentrations of GSH, reactive oxygen species, superoxide dismutase, malondialdehyde, and mRNA and protein abundance (Western blotting). A repeated-measures ANOVA was used for statistics. The statistical model included the random effect of block and fixed effects of treatment, time, and its interaction. There was a diet × time effect for reactive oxygen species due to lower concentrations in Met versus control cows specifically at d -10. Cows fed Met also had lower concentrations of malondialdehyde in subcutaneous adipose tissue. Compared with controls, overall mRNA abundance of the GSH metabolism-related genes cystathionine-ß-synthase (CBS), glutamate-cysteine ligase modifier subunit (GCLM), glutathione reductase (GSR), and glutathione peroxidase 1 (GPX1) was greater in cows fed Met. Furthermore, supply of Met resulted in an overall upregulation of protein abundance of glutathione peroxidase (GPX) 1, GPX3, glutathione S-transferase mu 1 (GSTM1), and glutathione S-transferase α 4 (GSTA4), all related to GSH metabolism. There was a diet × time effect for protein abundance of NFE2L2 and its repressor Kelch-like ECH associated protein 1 (KEAP1) due to lower values at 30 d in cows fed Met versus controls. The abundance of phosphorylated NFE2L2 was lower at 30 d in response to Met. Overall, the data suggest that exogenous Met may play a role in activating GSH metabolism and the antioxidant NFE2L2 pathways in subcutaneous adipose tissue.


Assuntos
Bovinos/fisiologia , Suplementos Nutricionais , Glutationa/metabolismo , Inflamação/veterinária , Metionina/administração & dosagem , Fator 2 Relacionado a NF-E2/metabolismo , Tecido Adiposo/metabolismo , Animais , Antioxidantes/metabolismo , Celulose/análogos & derivados , Celulose/química , Dieta/veterinária , Feminino , Inflamação/prevenção & controle , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Metionina/química , Leite/metabolismo , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Período Periparto , Fosforilação , Período Pós-Parto/efeitos dos fármacos , Gravidez , Espécies Reativas de Oxigênio/metabolismo , Rúmen/metabolismo
19.
Mol Biol Rep ; 46(3): 3213-3224, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30941643

RESUMO

Influence of Glutathione S-transferase Mu1 (GSTM1) has long been studied in breast cancer and GSTM1 null genotype was correlated with breast cancer risk. Nuclear factor-erythroid 2-related factor-2 (NRF2) is a transcription factor that forms a complex with Kelch-like ECH-associated protein-1 (KEAP1). Recent studies have demonstrated that expression of these proteins is deregulated in several malignancies. Thus, in the present study we aim to distinguish GSTM1 heterozygous from wild type genotype in breast cancer patients and evaluate the presence and clinical significance of NRF2 and KEAP1 polymorphisms, alone or in association, with breast cancer prognosis, in cases confirmed to have GSTM1-present genotype. Study population consisted in 52 patients with breast cancer. Genomic DNA was extracted, GSTM1 was genotyped through multiplex PCR and gene dose was evaluated through real-time PCR. All cases were sequenced, through Sanger sequencing, for specific regions of NRF2 and KEAP1. Genotyping and clinicopathological data were correlated and statistical analysis was performed. GSTM1 wild type was identified in 1 case and 26 cases were identified as heterozygous, these data were correlated with Human Epidermal growth factor Receptor 2 (HER2) status (p value = 0.017). We also verified that most cancers diagnosed at younger ages had the presence of KEAP1 and/or NRF2 polymorphisms. The association of GSTM1 heterozygous genotype with rs1048290 and rs35652124 seems to be associated with HER2+ (p < 0.05). Our results suggest that GSTM1 * 1/0 genotype and the cumulative presence of at least one allele mutated in KEAP1 and/or NRF2 polymorphisms might be associated with worse prognosis for breast cancer patients.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Glutationa Transferase/genética , Hormônios/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/genética , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Análise Mutacional de DNA , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico
20.
J Agric Food Chem ; 67(19): 5521-5529, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31012578

RESUMO

The purpose of this study was to compare the hepatoprotective effects of Oxy (oxyresveratrol), Res (resveratrol), and MulA (mulberroside A) (80 mg/kg body weight/d, i.g.) on acute liver injury (ALI) induced by lipopolysaccharide (LPS)/d-galactosamine (d-GalN) in mice. After 7 h of LPS (50 µg/kg body weight, i.p.) and d-GalN (500 mg/kg body weight, i.p.) exposure, the activities of serum transaminases and antioxidant enzymes were determined. The expressions of the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signal pathway, the nuclear factor-kappa B (NF-κB) signal pathway, and the mitogen-activated protein kinase (MAPK) signal pathway related proteins were evaluated by Western blot assays. Histopathological analysis was performed by hematoxylin-eosin (H&E) staining on the separated livers of mice. The results showed that treatment with Oxy, Res, and MulA could significantly decreases the levels of alanine transaminase (ALT) and aspartate transaminase (AST) ( P < 0.01). MulA was the most effective ingredient among the three, and the ALT and AST levels were reduced at 90.3 ± 1.3% and 93.9 ± 1.1% compared with the LPS/D-GalN treated group ( P < 0.01). Meanwhile, the stilbenes curbed the expression of inflammatory factors, NF-κB pathway activation, and MAPKs phosphorylation and upregulated antioxidant enzymes, Nrf2, NAD (P) H:quinone oxidoreductase (NQO1), and heme oxygenase-1 (HO-1) expression levels. Stilbenes might protect the ALI caused by LPS/d-GalN through inhibiting the negative effectiveness of oxidation stress and inflammation. The protective performance of MulA was better than those of Oxy and Res, and we hypothesize that it might be due to the mediation of the specific metabolic pathway of the MulA in vivo. All of these results implied that stilbenes in mulberry twigs might be promising as natural additives.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Morus/química , Extratos Vegetais/administração & dosagem , Substâncias Protetoras/administração & dosagem , Estilbenos/administração & dosagem , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Extratos Vegetais/química , Caules de Planta/química , Substâncias Protetoras/química , Estilbenos/química
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