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Objective:To explore the mechanism of gypenoside ⅩⅦ against cerebral ischemia/reperfusion (I/R) through nuclear factor erythroid 2-related factor 2/antioxidant responsive element (Nrf2/ARE) signaling pathway.Methods:Forty SPF Sprague Dawley (SD) rats were randomly divided into sham operated group, I/R model group, 25, 50 and 100 mg/kg gypenoside ⅩⅦ groups ( n = 8). Gypenoside ⅩⅦ groups were administered 25, 50 or 100 mg/kg (0.01 mL/g) gypenoside ⅩⅦ by intragastric administration for 14 days; the other two groups received the same dose of saline. Rat cerebral I/R model was established by modified line bolt method; rats in the sham operated group underwent the same procedure without producing substantial embolization. After 24 hours of reperfusion, the neurological deficit scores of the rats in each group were assessed. Rat abdominal aortic whole blood was collected and the serum reactive oxygen species (ROS), heme oxygenase-1 (HO-1), γ-glutamylcysteine synthase (γ-GCS), superoxide dismutase (SOD), quinone NADH oxidoreductase 1 (NQO1), and malondialdehyde (MDA) were detected. Then whole brain tissue was harvested and penumbra tissue was isolated from cerebral cortex, the general condition of rat brain tissue and the volume of cerebral infarction were evaluated, the histopathological changes in the brain were observed under light microscopy, the mRNA expressions of Nrf2 and Keap1 were measured by real-time fluorescent quantitative polymerase chain reaction (RT-qPCR), the protein expressions of Nrf2 and Keap1 were determined by Western blotting. Results:After 24 hours of reperfusion, compared with the sham operated group, the score of neurological deficit and infarct volume were significantly increased, the NQO1, SOD and γ-GCS levels in serum were significantly decreased, MDA, HO-1 and ROS levels in serum were significantly increased, the Nrf2 and Keap1 mRNA and protein expressions in the ischemic penumbra were significantly increased in rats from I/R model group. Compared with the I/R model group, the neurological deficit scores (1.50±0.53, 1.37±0.52 vs. 2.75±0.46) and brain infarct volume [(19.8±5.1)%, (21.4±6.4)% vs. (42.3±5.8)%] were significantly reduced, serum NQO1, SOD, HO-1 and γ-GCS were significantly increased [NQO1 (ng/L): 186.05±10.38, 220.75±16.22 vs. 131.36±5.95, SOD (kU/L): 63.23±5.30, 72.70±8.62 vs. 36.75±6.55, HO-1 (ng/L): 60.57±7.93, 60.35±4.72 vs. 42.72±4.95, γ-GCS (kU/L): 8.81±0.53, 8.72±0.69 vs. 6.80±0.56], serum MDA and ROS levels were significantly reduced [MDA (μmol/L): 5.94±0.66, 5.61±0.53 vs. 10.88±1.34, ROS (kU/L): 69.11±4.23, 67.12±4.52 vs. 104.43±7.54], the mRNA and protein expressions of Nrf2 and Keap1 in the ischemic penumbra were significantly increased in rats from 50 mg/kg and 100 mg/kg gypenoside ⅩⅦ groups [Nrf2 mRNA (2 -△△Ct): 1.90±0.13, 2.13±0.18 vs. 1.48±0.11, Keap1 mRNA (2 -△△Ct): 1.78±0.11, 1.85±0.10 vs. 1.43±0.10, Nrf2/β-actin: 0.73±0.04, 0.79±0.03 vs. 0.60±0.03, Keap1/β-actin: 0.71±0.01, 0.76±0.03 vs. 0.61±0.01], all the comparative differences were statistically significant (all P < 0.01); 25 mg/kg gypenoside ⅩⅦ had no significant effect. Conclusion:Gypenoside ⅩⅦ (50 mg/kg and 100 mg/kg) may play a role in anti-cerebral I/R injury by regulating NQO1, SOD, HO-1, γ-GCS, ROS and MDA through Nrf2/ARE signaling pathway.
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Objective:To investigate protective effect of Pinus massoniana needle extract (PMNE) against oxidative stress in human dermal papilla cells (HDPC) , and to explore its mechanisms. Methods:As research objects, some cultured HDPC were treated with H 2O 2 at different concentrations of 0 (control group) , 0.1, 0.2, 0.4, 0.8 and 1.0 mmol/L, in order to establish the optimal condition for in vitro oxidative stress in HDPC; some other HDPC were transfected with nuclear factor-erythroid 2-related factor 2 (Nrf2) specific small interfering RNAs (siRNA1, siRNA2, siRNA3) or a Nrf2-overexpressing plasmid (pCMV6-XL5-Nrf2) , the HDPC transfected with a scrambled-siRNA and an empty plasmid pCMV6-XL5 served as the control siRNA group and control plasmid group respectively, and HDPC subjected to conventional culture served as the blank group; after the above treatment, real-time fluorescence-based quantitative PCR and Western blot analysis were performed to determine Nrf2 mRNA and protein expression, respectively; cell viability and apoptosis were detected in the above transfected cells after the treatment with H 2O 2 at an optimal concentration. In the subsequent experiment, some HDPC were divided into several groups: control group subjected to conventional culture, dihydrotestosterone group treated with 0.03 μg/ml dihydrotestosterone, proanthocyanidin group treated with 0.03 μg/ml dihydrotestosterone and 6.00 μg/ml proanthocyanidin B2, PMNE groups treated with 0.03 μg/ml dihydrotestosterone and PMNE at different concentrations of 1, 5, 25 and 100 μg/ml; after the above treatment, cell viability and apoptosis were detected, relative fluorescence intensity of intracellular reactive oxygen species (ROS) , malondialdehyde (MDA) content, mRNA and protein expression of Nrf2, quinone oxidoreductase 1 (NQO1) , heme oxygenase 1 (HO-1) , Kelch-like ECH-related protein 1 (Keap1) , transforming growth factor (TGF) -β1, Sma- and Mad-related protein 2/3 (Smad2/3) , phosphorylated Smad2/3 (p-Smad2/3) were determined in HDPC. One-way analysis of variance was used for comparisons among multiple groups, and least significant difference- t test for multiple comparisons. Results:The viability of HDPC ranged from 75% to 85% after the treatment with 0.4 mmol/L H 2O 2, which was selected as the optimal condition for in vitro oxidative stress in HDPC. Compared with the blank group and control siRNA group, the Nrf2-siRNA1, Nrf2-siRNA2, Nrf2-siRNA3 groups showed significantly decreased Nrf2 mRNA and protein expression (all P < 0.05) , but significantly increased apoptosis rate (Nrf2-siRNA1, Nrf2-siRNA2, Nrf2-siRNA3 groups, blank group and control group: 12.50% ± 0.05%, 26.07% ± 0.05%, 58.44% ± 1.03%, 10.38% ± 0.64%, 13.05% ± 0.12%, respectively; all P < 0.05) . Nrf2 protein expression was the lowest in the Nrf2-siRNA2 group, so Nrf2-siRNA2 was selected as the optimal interfering fragment for subsequent experiments. Compared with the blank group and control plasmid group, the Nrf2 overexpression group showed significantly increased Nrf2 mRNA and protein expression (both P < 0.05) , but a significantly decreased apoptosis rate (all P < 0.05) . After the treatment with 0.4 mmol/L H 2O 2, the Nrf2 overexpression group showed a significantly decreased apoptosis rate, but significantly increased cell viability compared with the empty vector group ( t = 3.66, 40.40, respectively, both P < 0.001) ; the Nrf2-siRNA2 group showed a significantly increased apoptosis rate, but significantly decreased cell viability compared with the control group ( t = 13.13, 67.37, respectively, both P < 0.001) . In the PMNE treatment experiment, the proanthocyanidin group and PMNE groups showed significantly increased cell viability, but significantly decreased apoptosis rates compared with the dihydrotestosterone group (all P < 0.01) ; proanthocyanidin and PMNE at different concentrations could significantly inhibit dihydrotestosterone-induced overexpression of ROS and MDA in HDPC (all P < 0.01) ; the protein expression of Nrf2, NQO1 and HO-1 was significantly higher in the proanthocyanidin group, 5-, 25- and 100-μg/ml PMNE groups than in the dihydrotestosterone group (all P < 0.05) , while the protein expression of Keap1 and TGF-β1, and the Smad2/3 phosphorylation level were significantly lower in the proanthocyanidin group, 25- and 100-μg/ml PMNE groups than in the dihydrotestosterone group (all P < 0.05) . Conclusion:Nrf2 plays an important role in protecting against oxidative damage in HDPC, and PMNE may exert marked protective effect on HDPC by activating the Nrf2-antioxidant responsive element signaling pathway.
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ObjectiveTo investigate the effects of pentoxifylline (PTX) on oxidative stress in brains of epileptic (EP) rats based on the nuclear factor E2 related factor 2 (Nrf2) antioxidant response element (ARE) signal pathway.MethodsThirty-six healthy and adult male Wistar rats were included in the experiment and were divided into blank control group (peritoneal injection of isotonic saline), EP control group (induced EP episode), and PTX group (induced EP episode ＋ PTX pretreatment) according to a completely random method, then 12 rats in each group. The behavioral changes of rats in each group were monitored, and the EP attack rate and seizure latency were recorded. The rats were sacrificed to collect substantia nigra and hippocampus for testing oxidative stress indicators and expression levels of Nrf2 ARE signaling pathway-related proteins.ResultsNo abnormal reaction was observed in the control group after treatment. The EP attack rate in the EP control group reached 83.33%. The EP attack rate (33.3%) and the attack level ((2.14±0.40) vs (3.09±0.58)) in the PTX group were significantly lower than those in the EP control group, and the seizure latency was significantly longer than that in the EP control group (P0.05) ). The expression of substantia nigra tissue was significantly higher than that of the blank control group (P<0.05).ConclusionPTX can inhibit EP seizure and improve the oxidative stress in the brain of rats at the early stage of EP. The possible mechanism is that PTX can specifically activate Nrf2 ARE signaling pathway.
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OBJECTIVE@#To study the role of Nrf2/ARE signaling pathway in cypermethrin-induced oxidative stress and apoptosis of cerebral cortex neurons in C57BL/6 mice.@*METHODS@#The cortical neurons of C57BL/6 mice were cultured and identified, and a cypermethrin-induced cell injury model was established by treating the cells with 0, 25, 50 and 100 μmol/L of cypermethrin for 48 h. CCK-8 assay was used to analyze the effects of cypermethrin on the cell viability, and the fluorescence probe DCFH-DA was used for detecting intracellular reactive oxygen species (ROS); flow cytometry was performed for determining the apoptosis rate of the cells. The mRNA and protein expression levels of Nrf2 and its downstream genes HO-1 and NQO1 were detected using qPCR and Western blotting.@*RESULTS@#Exposure to cypermethrin at different doses inhibited the viability of the cultured cortical neurons. With the increase of cypermethrin dose, the viability of the neurons decreased progressively, the intracellular ROS and the cell apoptosis rate increased, and the neuronal injury worsened. At the dose of 50 and 100 μmol/L, cypermethrin significantly down-regulated the expressions of HO-1, NQO1 and Nrf2 at both the mRNA and protein levels in the cells ( < 0.01).@*CONCLUSIONS@#Cypermethrin exposure shows a dose-dependent neurotoxicity by inhibiting Nrf2/ARE signaling pathway, down-regulating the expression of Nrf2 and its downstream genes HO-1, NQO1 mRNA and protein, and inducing oxidative damage and apoptosis in primary mouse cortical neurons, .
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Animals , Mice , Carboxylic Ester Hydrolases , Cerebral Cortex , Mice, Inbred C57BL , NF-E2-Related Factor 2 , Neurons , Pyrethrins , Signal TransductionABSTRACT
Aim: To investigate the effect of Nrf2 pathway on the expression of MRP1 in mildly stable COPD mice. Methods: The mild COPD mouse model was established by passive cigarette smoking. The pathological changes of lung tissues were examined by HE staining. Immunohistochemistry and Western blot were used to detect the protein expression of MRP1, Nrf2 and HO-1. Results: Compared with normal group, each lung function index of the mild-moderate COPD model group was significantly lower, but compared with wide type(WT) model group, the reduction was more significant in Nrf2-/- model group. HE results showed diffuse inflammatory reaction and alveolar bronchial structure damage in alveolar of WT and Nrf2-/- model mice, and it was more pronounced in Nrf2-/- mice. Immunohistochemistry and Western blot results showed that the expression of MRP1 in lung tissue of Nrf2-/- normal mice was significantly reduced compared with the normal WT group. After passive cigarette smoking, The expression of MRP1, Nrf2 and HO-1 in WT model group increased significantly, but compared with Nrf2-/- normal mice, there was no significant change in the expression of MRP1 in Nrf2-/- model group. Conclusions: Mildly stable COPD mice may counteract the xenobiotic damage caused by cigarette smoke through up-regulating the expression of MRP1 protein, which may be associated with Nrf2 signaling activation.
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Aim: To study the induction of apoptotic effect of sodium selenite on human lung cancer A549 cells and its mechanisms. Methods: A549 cells were exposed to different concentrations of sodium selenite for 24 h. MTT assay was applied to determine A549 cell proliferation. Inverted fluorescence microscope was used to investigate the morphological changes in A549 cells. Flow cytometry analysis was applied to assess the apoptotic rates of A549 cells. Laser confocal microscope was employed to measure the reactive oxygen species (ROS) fluorescence intensity. A multi-detection reader was used to determine the antioxidant parameter. Western blot was utilized to detect the expression of Keapl, Nrf2, HO-1 and Nrf2 in cytoplasm and nucleus. Results: MTT results showed that sodium selenite inhibited the proliferation of A549 cells in a concentration-dependent manner. After treatment with sodium selenite for 24 h, the apoptotic rate of A549 cells was markedly increased through Hoechst 33342 staining and flow cytometry measurement. Sodium selenite significantly up-regulated ROS and malondialdehyde (MDA) content and down-regulated the levels of superoxide dismutase (SOD) and glutathione (GSH). Meanwhile, sodium selenite treatment also reduced the expressions of Keapl, Nrf2 and HO-1 at protein levels and inhibited Nrf2 protein nuclear translocation in A549 cells. Conclusions: Treatment with sodium selenite induces A549 cells apoptosis, which may contribute to the anti-proliferation activity, induction of apoptosis and regulation of oxidative stress reaction and Keapl/Nrf2/ARE antioxidative signaling pathway expression.
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Aim: To establish ARE dual-luciferase reporter assay system and used it to identify the antioxidant substance of Scutellaria baicalensis Georgi. Methods: 293T cells were transiently co-transfected with ARE luciferase reporter plasmid PGL 4. 37 and sea kidney luciferase reporter plasmid PRL-TK. Three major active ingredients of Scutellaria baicalensis Georgi such as scutellarin, baicalein, baicalin and/or estrogen receptor (ER) specific inhibitor were added to Nrf2-ARE luciferase reporter assay system to detect whether they exerted antioxidant effect through the estrogen receptor affecting the Nrf2-ARE signaling pathway. Results: Baicalin (100 μmol · L-1) could obviously activate Nrf2-ARE pathway in 293T cells, and the induced expression was(1. 56 ±0. 01) times that of blank group (P < 0. 01). After pre-administration of ER specific inhibitor, the induced expression decreased to (1. 02 ±0. 23) times, and the antioxidant effect disappeared. After pre-administration of ER and Nrf2-ARE pathway specific inhibitor respectively, ROS in HaCaT cells injured by UVB significantly increased and and SOD was markedly down-regulated by baicalin. Conclusion Baicalin plays antioxidant activity through mediating Nrf2-ARE signaling pathway based on estrogen receptor.
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The chemical constituents from methanol extract of Dichroa hirsuta were separated by silica gel and Sephadex LH-20 column chromatography,high pressure preparative liquid chromatography( HPLC) and recrystallization. Their structures were elucidated by NMR and MS. Nine compounds were obtained and their structures were identified as 3β,21α-O-diacetyl-lup-9( 11)-en-7β-ol( 1),( Z)-methyl p-hydroxycinnamate( 2),cis-p-coumaric acid ethyl ester( 3),( E)-methyl p-hydroxycinnamate( 4),trans-p-coumaric acid ethyl ester( 5),4( 3 H)-quinazolinone( 6),7-hydroxycoumarin( 7),hydrangenol( 8) and thunberginol C( 9). Compound 1 is a new lupane-type triterpenoid,and compounds 1-5,8-9 were firstly isolated from this plant. Dual reporter assay results showed that compounds 2-5 could activate the Nrf2-ARE signaling pathway.
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Chromatography, High Pressure Liquid , Drugs, Chinese Herbal , Hydrangea , Chemistry , Phytochemicals , Pharmacology , Triterpenes , PharmacologyABSTRACT
Objective To investigate the protective effect of 5-aminosalicylic acid (5-ASA) on renal injury poisoned by paraquat (PQ) in rats and its mechanism. Methods Twenty-four healthy clean male Sprague-Dawley (SD) rats were randomly divided into four groups: normal saline (NS) control group, 5-ASA control group, PQ model group and 5-ASA treatment group, with 6 rats in each group. The rat model of PQ poisoning was reproduced by intraperitoneal injection of 2% PQ solution 20 mg/kg, and the same volume of NS was given in NS control group and 5-ASA control group. Two hours later, the rats in 5-ASA control group and 5-ASA treatment group were intragastrically administered with 1 mL 5-ASA (75 mg/kg) for one time after NS or PQ administration, and those in NS control group and PQ model group were administered with 1 mL double distilled water. Behavioral changes were observed in rats. Then the rats were sacrificed at 24 hours after starting of the experiment for cardiac blood harvest which could be used to detect the biomarkers of renal injury and oxidative stress parameters. The kidney tissue was collected, and the hematein-eosin (HE) staining was conducted for observation of pathological changes in renal tissue, and protein expressions of Nrf 2 and heme oxygenase-1 (HO-1) were determined by Western Blot. Results At 30 minutes after PQ poisoning, rats appeared obvious poisoning symptoms and signs. Twenty-four hours after PQ poisoned, hemocoel of glomerular capillary, swelling of renal tubular epithelial cell and serious micronecrosis appeared under the light microscope. Compared with NS control group, blood urea nitrogen (BUN), serum creatinine (SCr), superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT) and glutathione (GSH) levels were significantly abnormal in PQ model group, and Nrf 2 and HO-1 protein expressions in renal tissue were increased. After administration of 5-ASA, the morphological changes and pathological damage were mitigated as compared with those of PQ model group, the levels of BUN, SCr and MDA were decreased significantly [BUN (mmol/L): 11.98±1.81 vs. 18.56±2.32, SCr (μmol/L): 30.67±2.31 vs. 43.67±9.02, MDA (μmol/L):5.28±0.43 vs. 6.81±1.00], and the SOD activity, CAT and GSH contents were significantly increased [SOD (kU/L):125.49±7.63 vs. 106.76±7.94, CAT (ng/L): 30.68±3.51 vs. 23.05±1.55, GSH (μmol/L): 3.81±0.44 vs. 3.14±0.17], while the protein expressions of Nrf 2 and HO-1 were further increased [Nrf 2 protein (gray value): 0.76±0.04 vs. 0.52±0.03, HO-1 protein (gray value): 0.56±0.02 vs. 0.31±0.02, all P < 0.05]. Only 5-ASA intervention had no significant effect on behavior, pathology, renal injury markers and oxidative stress parameters, but it could induce the expressions of Nrf 2 and HO-1 protein in renal tissue, which were significantly higher than those of NS control group [Nrf 2 protein (gray value): 0.78±0.02 vs. 0.41±0.04, HO-1 protein (gray value): 0.51±0.03 vs. 0.23±0.01, both P < 0.01]. Conclusion 5-ASA attenuates the damage of acute renal injury (AKI) caused by PQ, which mechanism may be related with the activation of Nrf 2-antioxidant response element (ARE) signaling pathway.
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Objective To observe the effects of melatonin (MT) on the expression of heme oxygenase-1 (HO-1),phosphorylated adenine dinucleotide quinone oxidoreductase-1 (NQO-1) and nuclear factor erythroid-2-related factor 2 (Nrf2),so as to explore the mechanism of MT's action in the Nrf2-ARE signaling pathway.Methods A total of 72 Sprague-Dawley rats were randomly divided into a control group,an injury group and a melatonin group,each of 24.T11-T12 acute SCI was induced in the injury and melatonin groups using the modified Allen's method.Ten minutes after the injury,equal amounts of absolute ethyl alcohol and melatonin were intraperitoneally injected into the rats in the injury and melatonin groups.For the control group,the vertebral plate was cut to expose the T11-T12 spinal cord without any injury of the nerves.Six rats from each group were randomly selected for sacrifice at 6,12 and 24 hours after the operation,and T11-T12 spinal cord specimens were collected.The spinal cord injury and inflammatory response were observed using haematoxylin eosin staining.The expression of HO-1,NQO-1 and Nrf2 was examined using immunofluorescence,while the expression of HO-1,NQO-1 and Nrf2 protein and mRNA were detected using RT-PCRs.Results The neuronal cells in the spinal cords of the control rats were of normal shape,without edema,necrosis or obvious hemorrhagic foci.Hemorrhagic foci,significantly more inflammatory cells and some spinal cord neurons with edema and necrosis were observed in the injury group.However,significantly fewer hemorrhagic spots and cells with edema were found in the melatonin group compared with the injury group.The average expression of HO-1,NQO-1 and Nrf2 protein and mRNA was significantly higher in the melatonin group than in the other two groups.The levels in the injury group were also significantly higher than in the control group 12 and 24 hours after the experiments.Immunofluorescence showed that the greatest number of cells with HO-1,NQO-1 and Nrf2 was found in the melatonin group,followed by the injury group and then the control group,with significant differences among all 3 groups.Conclusion Melatonin can promote the expression of HO-1,NQO-1 and Nrf2 in rats with acute spinal cord injury,which might be related with its activating the Nrf2-ARE signaling pathway.
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[Objective]To investigate the pharmacological mechanism of montelukast in the inhibition of inflammation.[Meth-ods]Respiratory syncytial virus-infected human bronchial epithelial cell(16HBEC)inflammatory cell model was established,and mRNA and protein expressions of Nuclear factor NF-E2 related factor(Nrf2),heme oxygenase(HO-1),quinone oxidoreductase (NQO-1),and glutathione transferase (GST) were determined by qPCR and Western-blot ,and production of cellular reactive oxygen species(ROS)was measured by DCFH-DA fluorescent probe method. Nrf2 siRNA was further synthesized to reduce the expression of Nrf2 ,to investigate the chang of inflammatory index.[Results]Montelukast significantly reduced the expressions of inflammatory cytokines IL-6,TNF-α,and IL-1β(P<0.05)on respiratory syncytial virus-infected 16HBEC,and the ROS level in inflammatory cell model was decreased(P<0.05),increased the mRNA and protein expressions of Nrf2,HO-1,NQO-1 and GST (P < 0.05),with a more significant effect at higher dose. After the down-regulation of Nrf2,the expressions of inflammatory cyto-kines IL-6,TNF-α,and IL-1βwere increased(P<0.05),and ROS level was significantly increased(P<0.05),mRNA and pro-tein expressions of Nrf2,HO-1,NQO-1 and GST were decreased(P<0.05).[Conclusion]Montelukast inhibits the inflammation of human bronchial epithelial cells infected by respiratory syncytial virus (RSV),and the potential mechanism may involve its ef-fect on the Nrf2/ARE signaling pathway.
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Nuclear factor erythroid-2 related factor 2 ( Nrf2 ) is an important nuclear transcription factor which protects cells a-gainst oxidative stress injury. Upon exposure to reactive oxygen species ( ROS) or electrophilic stress, Nrf2 can translocate into the nucleus, and then bind to the antioxidant response element ( ARE) , regulating the expression of several antioxidant enzymes and phase Ⅱ detoxifying enzymes which aimed at the detoxifica-tion and elimination of harmful exogenous chemicals, resulting in the facilitation of hepatoprotection. Oxidative stress is the com-mon pathogenesis of many liver diseases, while the Nrf2-ARE signaling pathway is extremely important in the prevention and progression of many liver diseases. Nrf2 has more recently been implicated as a new therapeutic target in treating liver diseases. Here, we focus on the most common liver diseases and the devel-opment of these conditions where activation of Nrf2 may alleviate disease progression, so as to provide reference for related re-search in the future.
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Chemoprevention of cancers is still very important since we have not got effective treatments for them.Many natural products(e.g.extracts from plants) or chemical synthetic substances(e.g.additives in foods) were used as chemoprevention regents.Some of them fight the carcinogens or other toxins through induction of the phase 2 antioxidant enzymes.Recently,it is wildly believed that the mechanism of this induction is the activation of Keap1-Nrf2-ARE signaling pathway.Thus understanding of this signaling pathway will widen the field of the cancer research and chemoprevention.