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1.
J Environ Pathol Toxicol Oncol ; 38(2): 143-152, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679277

RESUMO

The current study evaluated the cardioprotective activity of genistein in cases of doxorubicin-(Dox) induced cardiac toxicity and a probable mechanism underlying this protection, such as an antioxidant pathway in cardiac tissues. Animals used in this study were categorized into four groups. The first group was treated with sodium carboxymethylcellulose (0.3%; CMC-Na) solution. The second group received Dox (3.0 mg/kg, i.p.) on days 6, 12, 18, and 24. The third and fourth groups received Dox (3 mg/kg, i.p.) on days 6, 12, 18, and 24 and received protective doses of genistein (100 [group 3] and 200 [group 4] mg/kg/day, p.o.) for 30 days. Treatment with genistein significantly improved the altered cardiac function markers and oxidative stress markers. This was coupled with significant improvement in cardiac histopathological features. Genistein enhanced the Nrf2 and HO-1 expression, which showed protection against oxidative insult induced by Dox. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed substantial inhibition of apoptosis by genistein in myocardia. The study showed that genistein has a strong reactive oxygen species scavenging property and potentially (P ≤ .001) decreases the lipid peroxidation as well as inhibits DNA damage in cardiac toxicity induced by Dox. In conclusion, the potential antioxidant effect of genistein may be because of its modulatory effect on Nrf2/HO-1 signalling pathway and by this means exhibits cardioprotective effects from Dox-induced oxidative injury.


Assuntos
Cardiotônicos/farmacologia , Cardiotoxinas/toxicidade , Doxorrubicina/toxicidade , Genisteína/farmacologia , Heme Oxigenase-1/genética , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Animais , Cardiotoxicidade/etiologia , Heme Oxigenase-1/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Wistar
2.
Chem Biol Interact ; 314: 108848, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610156

RESUMO

Cardiomyocyte injury induced by acute myocardial infarction contributes to myocardial dysfunction. Accumulating evidence has demonstrated that pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) is a cytoprotective protein that protects against various adverse injuries. However, whether PHLPP2 participates in regulating myocardial-infarction-induced cardiomyocyte injury remains unknown. In the present study, we aimed to investigate the biological role and molecular mechanism of PHLPP2 in regulating hypoxia-induced cardiomyocyte injury. Cardiomyocytes were cultured in an anaerobic chamber for 24 h to induce hypoxic injury in vitro. The expression of PHLPP2 was determined by real-time quantitative PCR and Western blot analysis. Cell viability was measured by MTT assay. Cell apoptosis was assessed by TUNEL and caspase-3 activity assays. Intracellular reactive oxygen species (ROS) levels were measured by DCFH-DA probe. PHLPP2 expression was highly upregulated in hypoxia-injured cardiomyocytes. Inhibition of PHLPP2 by small interfering RNA (siRNA)-mediated gene silencing significantly improved the viability of hypoxia-injured cardiomyocytes and attenuated hypoxia-induced apoptosis and ROS production. In contrast, PHLPP2 overexpression exacerbated hypoxia-induced apoptosis and ROS production in cardiomyocytes. Mechanism research revealed that PHLPP2 silencing increased the phosphorylation of glycogen synthase kinase (GSK)-3ß and promoted the nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, PHLPP2 inhibition promoted Nrf2/antioxidant response element (ARE) transcriptional activity. However, Nrf2 silencing markedly reversed PHLPP2-inhibition-mediated cardioprotection, while GSK-3ß inhibition partially blocked the PHLPP2-overexpression-induced adverse effect. Taken together, these findings demonstrate that PHLPP2 inhibition alleviates hypoxia-induced cardiomyocyte injury by reinforcing Nrf2/ARE antioxidant signaling via inactivating GSK-3ß, a pathway that highlights the importance of the PHLPP2/GSK-3ß/Nrf2/ARE signaling axis in regulation of cardiomyocyte injury. Our study suggests a potential relevance for PHLPP2 in acute myocardial infarction, and this protein may serve as a promising target for cardioprotection.


Assuntos
Elementos de Resposta Antioxidante/genética , Hipóxia Celular , Fator 2 Relacionado a NF-E2/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular , Regulação para Baixo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosfoproteínas Fosfatases/genética , Fosforilação , Pirimidinas/farmacologia , Pirróis/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Life Sci ; 236: 116867, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31520598

RESUMO

AIM: Cyclophosphamide (CP) is a potent anticancer and immunosuppressant drug. Studies have shown significant oxidative stress and cognitive impairment but neuroinflammatory and histological aberrations with its administration is underexplored. Nerolidol (NER) is a lipophilic bioactive molecule with antioxidant and anti-inflammatory properties but it has not been explored for neuroprotective potential in CP-induced neurotoxic manifestations. Therefore, in the present study, we aimed to evaluate the neuroprotective potential of NER in CP-induced neuroinflammation and associated comorbid conditions like depression and cognitive dysfunctions. MATERIALS AND METHOD: In-silico study using Schrödinger software was used to assess the binding affinity of NER with Nrf2. In the In vivo study, NER 200 and 400 mg/kg p.o. were given from 1st day to 14th day. CP 200 mg/kg, i.p., was administered on the 7th day. After 24 h of the last dosing, neurobehavioral tests like spontaneous body alternation, passive avoidance and forced swim test were performed. On completion of study, mice were sacrificed, hippocampus and cortex were removed for biochemical estimations, histopathology and immunohistochemistry of p65 NF- κB and Nrf2. KEY FINDINGS: In-silico study showed significant binding of NER into the pocket domain of Nrf2. In-vivo study showed protective effect of NER against CP-induced neuroinflammation, oxidative stress, cognitive impairment and structural abnormalities in the hippocampus and cortex regions. SIGNIFICANCE: Findings of the study suggested that NER is a potential therapeutic molecule which can mitigate CP-induced neurotoxic manifestations via Nrf2 and NF-κB pathway. However, more detailed studies are needed to explicate the mechanism underlying its neuroprotective effect.


Assuntos
Disfunção Cognitiva/prevenção & controle , Ciclofosfamida/toxicidade , Inflamação/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Síndromes Neurotóxicas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Regulação da Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imunossupressores/toxicidade , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Fármacos Neuroprotetores , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Transdução de Sinais
4.
J Agric Food Chem ; 67(40): 11089-11098, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31509411

RESUMO

Reactive oxygen species and subsequent oxidative stress are reported to play important roles in chronic metabolic diseases. Plant-derived polyphenols, especially food-derived phenolics, have attracted a lot of attention due to their potential usage against oxidative stress-related diseases. The leaf of Psidium guajava (known as guava) is regarded as a good resource of polyphenols and its products are commercially available in Japan as functional foods against multiple chronic metabolism disorders. In the course of finding novel polyphenols with antioxidative activities from guava leaf, 11 acylated phenolic glycosides (1-11), including 5 new oleuropeic acid-conjugated phenolic glycosides, named guajanosides A-E (1, 2, and 5-7), along with 17 known meroterpenoides (12-28), were isolated and identified. Their structures were determined by spectroscopic data analysis, chemical degradation, and acid hydrolysis. Compounds 1, 2, and 5-11 displayed potent reactive oxygen species-scavenging activity in lipopolysaccharide-stimulated RAW 264.7 macrophage cells. Western blot revealed that compound 6 markedly increased the expression levels of nuclear factor-erythroid 2-related factor 2 (Nrf2), NAD(P)H quinone dehydrogenase 1 (NQO1), and the glutamate-cysteine ligase catalytic subunit. The current study revealed the presence of oleuropeic acid-derived phenolic glycosides in guava leaf and highlighted the potential usage of this type of phenolics against oxidative stress-related metabolic diseases via activation of the Nrf2 signaling pathway.


Assuntos
Depuradores de Radicais Livres/farmacologia , Glicosídeos/farmacologia , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Psidium/química , Espécies Reativas de Oxigênio/metabolismo , Animais , Depuradores de Radicais Livres/química , Glicosídeos/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fenóis/química , Extratos Vegetais/química , Folhas de Planta/química , Células RAW 264.7
5.
J Agric Food Chem ; 67(37): 10342-10351, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31461273

RESUMO

Maltol, a maillard reaction product from ginseng (Panax ginseng C. A. Meyer), has been confirmed to inhibit oxidative stress in several animal models. Its beneficial effect on oxidative stress related brain aging is still unclear. In this study, the mouse model of d-galactose (d-Gal)-induced brain aging was employed to investigate the therapeutic effects and potential mechanisms of maltol. Maltol treatment significantly restored memory impairment in mice as determined by the Morris water maze tests. Long-term d-Gal treatment reduced expression of cholinergic regulators, i.e., the cholineacetyltransferase (ChAT) (0.456 ± 0.10 vs 0.211 ± 0.03 U/mg prot), the acetylcholinesterase (AChE) (36.4 ± 5.21 vs 66.5 ± 9.96 U/g). Maltol treatment prevented the reduction of ChAT and AChE in the hippocampus. Maltol decreased oxidative stress levels by reducing levels of reactive oxygen species (ROS) and malondialdehyde (MDA) production in the brain and by elevating antioxidative enzymes. Furthermore, maltol treatment minimized oxidative stress by increasing the phosphorylation levels of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), nuclear factor-erythroid 2-related factor 2 (Nrf2), and hemeoxygenase-1 (HO-1). The above results clearly indicate that supplementation of maltol diminishes d-Gal-induced behavioral dysfunction and neurological deficits via activation of the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway in brain. Maltol might become a potential drug to slow the brain aging process and stimulate endogenous antioxidant defense capacity. This study provides the novel evidence that maltol may slow age-associated brain aging.


Assuntos
Envelhecimento/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Galactose/efeitos adversos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/administração & dosagem , Pironas/administração & dosagem , Envelhecimento/metabolismo , Animais , Heme Oxigenase-1/genética , Humanos , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Panax/química , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo
6.
J Agric Food Chem ; 67(36): 10059-10068, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31431007

RESUMO

Torularhodin is a natural product extracted from Sporidiobolus pararoseus and has a similar chemical structure to ß-carotene. The antioxidative effects of torularhodin were investigated using DPPH, ABTS, a cell oxidative damage model in vitro, and a d-galactose-induced liver-injured mouse model in vivo. Cell experiments demonstrated that torularhodin had a powerful effect on oxidative damage caused by H2O2 to AML12 cells. Torularhodin significantly reduced inflammatory cytokines and increased the activity of antioxidant enzymes both in mouse serum and the liver. The inhibition of d-galactose-induced oxidative damage in the liver was correlated with the torularhodin-mediated effects on improving the activity of Nrf2/HO-1, reducing the expression of Bax and NF-κB p65 by western blot analysis. RT-PCR results demonstrated torularhodin upregulated the antioxidative mRNA expression of Nrf2, NQO1, and HO-1 in the liver. In summary, torularhodin significantly scavenged free radicals and prevented oxidative damage in vitro and reduced d-galactose-induced liver oxidation via promotion of the Nrf2/HO-1 pathways in vivo.


Assuntos
Antioxidantes/administração & dosagem , Basidiomycota/química , Carotenoides/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Galactose/efeitos adversos , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos ICR , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(7): 862-866, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31441411

RESUMO

OBJECTIVE: To investigate the key role of nuclear factor E2-related factor 2 (Nrf2) in the treatment of lung injury in sepsis mice by regulating Nrf2/heme oxygenase-1 (HO-1)/high mobility group protein B1 (HMGB1) pathway. METHODS: 120 male wild type (WT) and 120 Nrf2 knockout (Nrf2-KO) ICR mice were randomly divided into Sham group, H2 control group (Sham+H2 group), cecal ligation and puncture (CLP) induced sepsis model group (CLP group) and H2 intervention group (CLP+H2 group), with 30 mice in each group. The sepsis model was reproduced by CLP. The same operation was done in Sham group and Sham+H2 group except CLP. The mice in Sham+H2 group and CLP+H2 group were challenged by 2% H2 for 1 hour at 1 hour and 6 hours after operation respectively, while the mice in Sham group and CLP group only inhaled air. Twenty mice in each group were collected to observe the 7-day survival. The other mice were sacrificed at 24 hours after the reproduction of model, and the lung tissues were harvested. The activities of superoxide dismutase (SOD) and catalase (CAT) and malondialdehyde (MDA) contents were determined by enzyme-linked immunosorbent assay (ELISA). The expressions of HO-1 and HMGB1 were determined by Western Blot, and the positive expression of HO-1 was also detected by immunofluorescence. RESULTS: Compared with Sham groups, the 7-day survival rates of WT and Nrf2-KO mice in CLP groups were significantly lowered [WT: 0% (0/20) vs. 100% (20/20), Nrf2-KO: 0% (0/20) vs. 100% (0/20), both P < 0.05]; the 7-day survival rates of CLP+H2 group in WT mice were significantly higher than those of CLP group [40% (8/20) vs. 0% (0/20), P < 0.05], but there was no significant difference between CLP+H2 group and CLP group in Nrf2-KO mice [0% (0/20) vs. 0% (0/200), P > 0.05]. In WT mice, compared with Sham group, the activities of SOD and CAT in lung tissue of CLP group were decreased significantly [SOD (kU/g): 131.30±28.21 vs. 251.00±22.84, CAT (kU/g): 13.43±1.52 vs. 20.76±1.63, both P < 0.01], the MDA content, the expressions of HO-1 and HMGB1 were increased significantly [MDA (µmol/g): 6.26±1.18 vs. 4.16±0.58, HO-1/ß-actin: 0.160±0.045 vs. 0.023±0.005, HMGB1/ß-actin: 0.656±0.055 vs. 0.005±0.001, all P < 0.05]. Compared with CLP group, the activities of SOD, CAT and HO-1 expression in lung tissue of CLP+H2 group were significantly increased [SOD (kU/g): 220.32±35.06 vs. 131.30±28.21, CAT (kU/g): 18.95±2.49 vs. 13.43±1.52, HO-1/ß-actin: 0.376±0.025 vs. 0.160±0.045, all P < 0.01], while the MDA contents and HMGB1 expressions were significantly decreased [MDA (µmol/g): 4.26±0.75 vs. 6.26±1.18, HMGB1/ß-actin: 0.343±0.040 vs. 0.656±0.055, both P < 0.05]. In Nrf2-KO mice, compared with Sham group, the activity of CAT in CLP group was significantly lowered (kU/g: 12.28±1.49 vs. 19.11±1.53, P < 0.01), MDA contents and the expressions of HO-1 and HMGB1 were significantly increased [MDA (µmol/g): 6.85±0.54 vs. 4.59±0.50, HO-1/ß-actin: 0.063±0.005 vs. 0.021±0.003, HMGB1/ß-actin: 0.713±0.035 vs. 0.005±0.001, all P < 0.01], while there was no significant difference in SOD activity (kU/g: 114.19±9.94 vs. 135.75±28.10, P > 0.05). There was no significant difference in above parameters between CLP+H2 group and CLP group. CONCLUSIONS: H2 inhibits lung injury in septic mice through Nrf2/HO-1/HMGB1 pathway. Nrf2 plays a major role in the treatment of septic lung injury by H2.


Assuntos
Hidrogênio , Lesão Pulmonar , Fator 2 Relacionado a NF-E2/genética , Sepse , Animais , Técnicas de Inativação de Genes , Proteína HMGB1/metabolismo , Heme Oxigenase-1/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Knockout
8.
J Agric Food Chem ; 67(35): 9782-9788, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31390859

RESUMO

Sulforaphane, a potent antioxidant compound, is unstable at ambient temperature, whereas its precursor glucoraphanin is stable and metabolized to sulforaphane. Thus, we hypothesized that glucoraphanin-rich diet could effectively induce antioxidant enzyme activities and investigated the protective effects of long-term intake of a glucoraphanin-enriched kale (GEK) diet on skin aging in senescence-accelerated mouse prone 1 (SAMP1) mice. The senescence grading score was significantly lower after treatment with GEK for 39 weeks than that of the control mice. GEK also suppressed the thinning of the dorsal skin layer. Moreover, the GEK treatment enhanced the collagen production and increased the nuclear translocation of Nrf2 and HO-1 expression level in the skin tissue. TßRII and Smad3 expressions were clearly higher in the GEK-treated group than in the control group. Thus, GEK suppressed senescence in SAMP1 mice by enhancing the antioxidant activity and collagen production via the TßRII/Smad3 pathway, suggesting its practical applications for protection against skin aging.


Assuntos
Brassica/metabolismo , Glucosinolatos/metabolismo , Imidoésteres/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Envelhecimento da Pele/fisiologia , Proteína Smad3/metabolismo , Animais , Antioxidantes/metabolismo , Brassica/química , Colágeno/metabolismo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Fator 2 Relacionado a NF-E2/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Transdução de Sinais , Envelhecimento da Pele/genética , Proteína Smad3/genética , Fatores de Tempo
9.
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
10.
Diabetes Res Clin Pract ; 155: 107801, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31356832

RESUMO

AIM: A growing body of evidence supports the impact of intermittent fasting on normalizing body metabolism and lowering oxidative stress and inflammation. Mounting evidence confirms that oxidative stress and chronic inflammation trigger the way for the development of metabolic diseases, such as diabetes. This research was conducted to evaluate the impact of Ramadan intermittent fasting (RIF) on the expression of cellular metabolism (SIRT1 and SIRT3) and antioxidant genes (TFAM, SOD2, and Nrf2). METHODS: Fifty-six (34 males and 22 females) overweight and obese subjects and six healthy body weight controls were recruited and monitored before and after Ramadan. RESULTS: Results showed that the relative gene expressions in obese subjects in comparison to counterpart expressions of controls for the antioxidant genes (TFAM, SOD2, and Nrf2) were significantly increased at the end of Ramadan, with percent increments of 90.5%, 54.1% and 411.5% for the three genes, respectively. However, the metabolism-controlling gene (SIRT3) showed a highly significant (P < 0.001) downregulation accompanied with a trend for reduction in SIRT1 gene at the end of Ramadan month, with percent decrements of 61.8% and 10.4%, respectively. Binary regression analysis revealed significant positive correlation (P < 0.05) between high energy intake (>2000 Kcal/day vs. <2000 Kcal/day) and expressions of SOD2 and TFAM (r = 0.84 and r = 0.9, respectively). CONCLUSION: Results suggest that RIF ameliorates the genetic expression of antioxidant and anti-inflammatory, and metabolic regulatory genes. Thus, RIF presumably may entail a protective impact against oxidative stress and its adverse metabolic-related derangements in non-diabetic obese patients.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Jejum/fisiologia , Proteínas Mitocondriais/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Obesidade/fisiopatologia , Sobrepeso/fisiopatologia , Sirtuína 1/metabolismo , Sirtuína 3/metabolismo , Superóxido Dismutase/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Estudos de Casos e Controles , Proteínas de Ligação a DNA/genética , Feminino , Regulação da Expressão Gênica , Humanos , Islamismo , Masculino , Proteínas Mitocondriais/genética , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Estudos Prospectivos , Sirtuína 1/genética , Sirtuína 3/genética , Superóxido Dismutase/genética , Fatores de Transcrição/genética
11.
J Agric Food Chem ; 67(29): 8227-8234, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31299148

RESUMO

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


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ácido Tióctico/análogos & derivados , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Células PC12 , Ratos , Transdução de Sinais/efeitos dos fármacos , Ácido Tióctico/farmacologia
13.
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
14.
Aquat Toxicol ; 213: 105219, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31195325

RESUMO

Nrf2 is a crucial transcription factor that regulates the expression of cytoprotective enzymes and controls cellular redox homeostasis. Both arsenic and fluoride are potent toxicants that are known to induce Nrf2. They are reported to coexist in many areas of the world leading to complex mixture effects in exposed organisms. The present study investigated the expression of Nrf2 and related xenobiotic metabolizing enzymes along with other stress markers such as histopathological alterations, catalase activity, reduced glutathione content and lipid peroxidation in zebrafish liver as a function of combined exposure to environmentally relevant concentrations of arsenic (37.87 µgL-1 or 5.05 × 10-7 M) and fluoride (6.8 mg L-1 or 3.57 × 10-4 M) for 60 days. The decrease in the total reduced glutathione level was evident in all treatment conditions. Hyperactivity of catalase along with conspicuous elevation in reactive oxygen species, malondialdehyde content and histo-architectural anomalies signified the presence of oxidative stress in the treatment groups. Nrf2 was seen to be induced at both transcriptional and translational levels in case of both individual and co-exposure. The same pattern was observed in case of its nuclear translocation also. From the results of qRT-PCR it was evident that at each time point co-exposure to arsenic and fluoride seemed to alter the gene expression of Cu/Zn Sod, Mn Sod, Gpx and Nqo1 just like their individual exposure but at a very low magnitude. In conclusion, this study demonstrates for the first time the differential expression and activity of Nrf2 and other stress response genes in the zebrafish liver following individual and combined exposure to arsenic and fluoride.


Assuntos
Arsênico/toxicidade , Fluoretos/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Fator 2 Relacionado a NF-E2/genética , Xenobióticos/metabolismo , Peixe-Zebra/metabolismo , Animais , Catalase/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
15.
Ann Hematol ; 98(9): 2045-2052, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31243572

RESUMO

Thalassemia has a high prevalence in Thailand. Oxidative damage to erythroid cells is known to be one of the major etiologies in thalassemia pathophysiology. Oxidative stress status of thalassemia is potentiated by the heme, nonheme iron, and free iron resulting from imbalanced globin synthesis. In addition, levels of antioxidant proteins are reduced in α-thalassemia and ß-thalassemia erythrocytes. However, the primary molecular mechanism for this phenotype remains unknown. Our study showed a high expression of miR-144 in ß- and α-thalassemia. An increased miR-144 expression leads to decreased expression of nuclear factor erythroid 2-related factor 2 (NRF2) target, especially in α-thalassemia. In α-thalassemia, miR-144 and NRF2 target are associated with glutathione level and anemia severity. To study the effect of miR-144 expression, the gain-loss of miR-144 expression was performed by miR inhibitor and mimic transfection in the erythroblastic cell line. This study reveals that miR-144 expression was upregulated, whereas NRF2 expression and glutathione levels were decreased in comparison with the untreated condition after miR mimic transfection, while the reduction of miR-144 expression contributed to the increased NRF2 expression and glutathione level compared with the untreated condition after miR inhibitor transfection. Moreover, miR-144 overexpression leads to significantly increased sensitivity to oxidative stress at indicated concentrations of hydrogen peroxide (H2O2) and rescued by miR-144 inhibitor. Taken together, our findings suggest that dysregulation of miR-144 may play a role in the reduced ability of erythrocyte to deal with oxidative stress and increased RBC hemolysis susceptibility especially in thalassemia.


Assuntos
Eritrócitos/metabolismo , MicroRNAs/biossíntese , Fator 2 Relacionado a NF-E2/biossíntese , Estresse Oxidativo , Regulação para Cima , Talassemia alfa/metabolismo , Talassemia beta/metabolismo , Eritrócitos/patologia , Feminino , Glutationa/biossíntese , Glutationa/genética , Hemólise , Humanos , Peróxido de Hidrogênio/metabolismo , Células K562 , Masculino , MicroRNAs/genética , Fator 2 Relacionado a NF-E2/genética , Talassemia alfa/genética , Talassemia alfa/patologia , Talassemia beta/genética , Talassemia beta/patologia
16.
J Cancer Res Clin Oncol ; 145(8): 2045-2050, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31250159

RESUMO

BACKGROUND: RRx-001, a minimally toxic next-generation checkpoint inhibitor that targets myeloid suppressor cells in the tumor microenvironment, has also been shown to protect normal tissues from the cytotoxic effects of chemotherapy and radiation. The following experiments were carried out to determine whether the cytoprotective functions of RRx-001 in normal cells were operative in tumor cells. DESIGN: The effects of RRx-001 on normal cells, and ovarian cancer A2780 and UWB1 cells were evaluated with a colony-forming assay. Western blot densitometry was used to measure Nrf2 nuclear translocation in Caco2 cells after exposure to RRx-001. Following incubation with RRx-001, levels of the antioxidant, NQO1, were determined in Caco2 cells by measuring absorbance over 300 min at 440 nm. RRx-001-mediated cytotoxicity in HCT-116 colorectal cancer cells was evaluated with an MTT assay. In addition, the effect of RRx-001 incubation on the protein expression of Nrf2, PARP, cleaved PARP, procaspases 3, 8, and 9, Bcl-2, and Bax in HCT-116 colorectal cells was determined by western blot analysis. RESULTS: RRx-001 is demonstrated to induce Nrf2 in normal tissues, mediating protection, and to downregulate the Nrf2-controlled antiapoptotic target gene, B-cell lymphoma 2 (Bcl-2) in tumors, mediating cytotoxicity. CONCLUSION: Through Nrf2 induction in normal cells and inhibition of Bcl-2 in tumor cells, RRx-001 selectively protects normal cells against lethality in normal cells, but induces apoptosis in tumor cells.


Assuntos
Antineoplásicos/farmacologia , Azetidinas/farmacologia , Citoproteção/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Neoplasias/patologia , Nitrocompostos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Apoptose/efeitos dos fármacos , Células CACO-2 , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
17.
Chem Biol Interact ; 309: 108701, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31181187

RESUMO

Pelargonidin, a well-known natural anthocyanidin found in berries strawberries, blueberries, red radishes and other natural foods, has been found to possess health beneficial effects including anti-cancer effect. Herein, we investigated the effect of pelargonidin on cellular transformation in mouse skin epidermal JB6 (JB6 P+) cells induced by tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Pelargonidin treatment significantly decreased colony formation and suppressed cell viability of JB6 P+ cells. Pelargonidin also induced the anti-oxidant response element (ARE)-luciferase activation in HepG2-C8 cells overexpressing the ARE-luciferase reporter. Knockdown of nuclear factor E2-related factor 2 (Nrf2) in shNrf2 JB6 P+ cells enhanced TPA-induced colony formation and attenuated pelargonidin's blocking effect. Pelargonidin reduced the protein levels of genes encoding methyltransferases (DNMTs) and histone deacetylases (HDACs). Importantly, pelargonidin decreased the DNA methylation in the Nrf2 promoter region of JB6 P+ cells and increased Nrf2 downstream target genes expression, such as NAD(P)H/quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1), involved in cellular protection. In summary, our results showed that pelargonidin blocks TPA-induced cell transformation. The possible molecular mechanisms of its potential anti-cancer effects against neoplastic transformation may be attributed to its activation of Nrf2-ARE signaling pathway and its cytoprotective effect.


Assuntos
Antocianinas/farmacologia , Desmetilação do DNA/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Antocianinas/química , Elementos de Resposta Antioxidante/genética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , DNA-Citosina Metilases/metabolismo , Células Epidérmicas/citologia , Células Epidérmicas/efeitos dos fármacos , Células Epidérmicas/metabolismo , Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Histona Desacetilases/metabolismo , Humanos , Camundongos , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Acetato de Tetradecanoilforbol/farmacologia
18.
Chem Biol Interact ; 309: 108689, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31173751

RESUMO

Diabetes mellitus is an independent risk factor for renal impairment in patients exposed to contrast media. It doubles the risk and decreases survival rate of contrast induced nephropathy (CIN). Sulforaphane has antioxidant properties via Nrf2 activation. The interaction of diabetes and/or sulforaphane with contrast media on Nrf2 regulation is not yet understood. Herein, diabetes was induced by a single intra-peritoneal injection of streptozotocin. Animals were then divided into five groups; control non-diabetic group; diabetic group; diabetic/sulforaphane group; diabetic/CIN group; diabetic/CIN/sulforaphane group. Animals were assessed 24 h after CIN induction. Sulforaphane improved the impaired nephrotoxicity parameters, histopathological features, and oxidative stress markers induced by contrast media (meglumine diatrizoate) in diabetic rats. Immunofluorescence detection revealed increased Nrf2 expression in kidney sections after sulforaphane pretreatment. Moreover, gene expression of Nrf2 and HO-1 were up-regulated, while IL-6 and caspase3 were down-regulated in kidney tissues of animals pretreated with sulforaphane. In NRK-52E cells, sulforaphane pretreatment significantly ameliorated the cytotoxicity of meglumine diatrizoate. However, silencing Nrf2 using small interfering RNA (siRNA) abolished the cytoprotective effects of sulforaphane. Collectively, the results of this study suggest that Nrf2/HO-1 pathway has a protective role against CIN and support the clinical implication of Nrf2 activators, such as sulforaphane, in CIN particularly in diabetic patients.


Assuntos
Apoptose/efeitos dos fármacos , Meios de Contraste/toxicidade , Dano ao DNA/efeitos dos fármacos , Diabetes Mellitus Experimental/patologia , Diatrizoato de Meglumina/toxicidade , Isotiocianatos/química , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Antioxidantes/química , Linhagem Celular , Meios de Contraste/química , Diabetes Mellitus Experimental/induzido quimicamente , Diatrizoato de Meglumina/química , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Nefrite/induzido quimicamente , Nefrite/metabolismo , Nefrite/patologia , Interferência de RNA , RNA Interferente Pequeno , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
19.
Chem Biol Interact ; 309: 108706, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31194955

RESUMO

Oxidative-stress-induced osteoblast dysfunction plays an important role in the development and progression of osteoporosis. BTB and CNC homology 1 (Bach1) has been suggested as a critical regulator of oxidative stress; however, whether Bach1 plays a role in regulating oxidative-stress-induced osteoblast dysfunction remains unknown. Thus, we investigated the potential role and mechanism of Bach1 in regulating oxidative-stress-induced osteoblast dysfunction. Osteoblasts were treated with hydrogen peroxide (H2O2) to mimic a pathological environment for osteoporosis in vitro. H2O2 exposure induced Bach1 expression in osteoblasts. Functional experiments demonstrated that Bach1 silencing improved cell viability and reduced cell apoptosis and reactive oxygen species (ROS) production in H2O2-treated cells, while Bach1 overexpression produced the opposite effects. Notably, Bach1 inhibition upregulated alkaline phosphatase activity and osteoblast mineralization. Mechanism research revealed that Bach1 inhibition increased the activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling and upregulated heme oxygenase 1 and NAD(P)H:quinone oxidoreductase 1 mRNA expression. The Bach1 inhibition-mediated protective effect was partially reversed by silencing Nrf2 in H2O2-exposed osteoblasts. Taken together, these results demonstrate that Bach1 inhibition alleviates oxidative-stress-induced osteoblast apoptosis and dysfunction by enhancing Nrf2/ARE signaling activation, findings that suggest a critical role for the Bach1/Nrf2/ARE regulation axis in osteoporosis progression. Our study suggests that Bach1 may serve as a potential therapeutic target for treating osteoporosis.


Assuntos
Elementos de Resposta Antioxidante/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Peróxido de Hidrogênio/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina Básica/antagonistas & inibidores , Fatores de Transcrição de Zíper de Leucina Básica/genética , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Camundongos , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Osteoblastos/citologia , Osteoblastos/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo
20.
Biotechnol Appl Biochem ; 66(5): 738-743, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31210367

RESUMO

Astroglia support neuron by providing substrates for neuronal metabolism, glutamate clearance, and antioxidative protection. Nuclear factor erythroid 2-related factor 2 (Nrf2) participates in the antioxidative defense response. Also, Nrf2 signaling is recognized to activate the neurotrophic pathway to replace/protect damaged organelles. Ellagic acid (EA), an extraction component of fruits and nuts, presents many pharmacological activities such as anti-inflammation, antioxidation, and neuroprotection. However, few studies have been focused on the neurotrophic properties of EA. Our study investigated whether EA could increase neuronal survival and the target cells. Thus, primary neuron-enriched cultures and primary astroglia-enriched cultures were applied to detect whether EA-elicited neurotrophic effects were mediated by astroglia Nrf2. This study indicated that EA promoted neuronal survival. Further, astroglia Nrf2 participate in EA-elicited neuronal survival with the following scenarios. First, EA elicited astroglia proliferation, glial cell line-derived neurotrophic factor (GDNF) release, and Nrf2 activation. Second, after silencing astroglia Nrf2, EA-induced astrogliosis, GDNF release, and neuronal survival disappeared. Thus, EA-mediated astroglia Nrf2 activation is important to enhance neurotrophic effects on neurons, which might provide new insights for neurodegenerative disease.


Assuntos
Ácido Elágico/farmacologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Animais , Células Cultivadas , Inativação Gênica/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/metabolismo , Ratos , Reação em Cadeia da Polimerase em Tempo Real
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