Memory loss and dementia are major public health concerns with a substantial economic burden.Oxidative stress has been shown to play a crucial role in the pathophysiology of hippocampal damage-induced memory impairmen...Memory loss and dementia are major public health concerns with a substantial economic burden.Oxidative stress has been shown to play a crucial role in the pathophysiology of hippocampal damage-induced memory impairment.To investigate whether the antioxidant and anti-inflammatory compound vanillyla cetone(zingerone) can protect against hippocampal damage and memory loss induced by cadmium chloride(CdCl_(2)) administration in rats,we explo red the potential involvement of the nuclear factor erythroid 2-related factor 2(Nrf2) signaling pathway,which is known to modulate oxidative stress and inflammation.Sixty healt hy male Wistar rats were divided into five groups:vehicle-treated(control),vanillylacetone,CdCl_(2),vanillylacetone+ CdCl_(2),vanillylacetone+ CdCl_(2)+ brusatol(a selective pharmacological N rf2inhibitor) groups.Vanillylacetone effectively attenuated CdCl_(2)-induced damage in the dental gyrus of the hippocampus and improved the memory function assessed by the Morris Water Maze test.Additionally,vanillylacetone markedly decreased the hippocampal tissue levels of inflammatory biomarkers(interleukin-6,tumor necrosis factor-α,intracellular cell adhesive molecules) and apoptosis biomarkers(Bax and cleaved caspase-3).The control and CdCl_(2)-treated groups treated with va nillylacetone showed reduced generation of reactive oxygen species,decreased malondialdehyde levels,and increased superoxide dismutase and glutathione activities,along with significant elevation of nuclear Nrf2 mRNA and protein expression in hippocampal tissue.All the protective effects of vanillylacetone we re substantially blocked by the co-administration of brusatol(a selective N rf2 inhibitor).Va nillylacetone mitigated hippocampal damage and memory loss induced by CdCl_(2),at least in part, by activating the nuclear transcription factor Nrf2.Additionally,vanillylacetone exerted its potent antioxidant and antiinflammatory actions.展开更多
BACKGROUND： The KEAP1-Nrf2 antioxidant signaling pathway is important in protecting liver from various insults. However,little is known about the expression of Nrf2-related genes in human liver in different diseases....BACKGROUND： The KEAP1-Nrf2 antioxidant signaling pathway is important in protecting liver from various insults. However,little is known about the expression of Nrf2-related genes in human liver in different diseases.METHODS： This study utilized normal donor liver tissues（n=35）, samples from patients with hepatocellular carcinoma（HCC, n=24）, HBV-related cirrhosis（n=27）, alcoholic cirrhosis（n=5） and end-stage liver disease（n=13）. All of the liver tissues were from the Oriental Liver Transplant Center, Beijing,China. The expressions of Nrf2 and Nrf2-related genes, including its negative regulator Kelch-like ECH-associated protein 1（KEAP1）, its targeted gene NAD（P）H-quinone oxidoreductase 1（NQO1）, glutamate-cysteine ligase catalytic subunit（GCLC） and modified subunit（GCLM）, heme oxygenase 1（HO-1） and peroxiredoxin-1（PRDX1） were evaluated. RESULTS： The expression of Nrf2 was decreased in HCC, increased in alcoholic cirrhosis and end-stage liver disease. The expression of KEAP1 was increased in all of the liver samples.The most notable finding was the increased expression of NQO1 in HCC（18-fold）, alcoholic cirrhosis（6-fold）, endstage liver disease（5-fold） and HBV-related cirrhosis（3-fold）.Peri-HCC also had 4-fold higher NQO1 m RNA as compared to the normal livers. GCLC m RNA levels were lower only in HCC, as compared to the normal livers and peri-HCC tissues.GCLM m RNA levels were higher in HBV-related cirrhosis and end-stage liver disease. HO-1 m RNA levels were increased in all liver tissues except for HCC. Peri-HCC had higher PRDX1 m RNA levels compared with HCC and normal livers.CONCLUSION： Nrf2 and Nrf2-related genes are aberrantly expressed in the liver in different diseases and the increase of NQO1 was the most notable finding, especially in HCC.展开更多
Objective:To explore the expression of Nrf2/ARE pathway in hindbrain tissue after the traumatic brain injury（TBI） and its anli-oxidative stress effect in the secondary nerve injury.Methods: The mice with Nrf2 gene k...Objective:To explore the expression of Nrf2/ARE pathway in hindbrain tissue after the traumatic brain injury（TBI） and its anli-oxidative stress effect in the secondary nerve injury.Methods: The mice with Nrf2 gene knockout were used for the establishment of brain injury model.The experimental animals were divided into four groups:(Nrf2<sup>+/+</sup>) sham-operation group,(Nrf2<sup>+/+</sup>) brain injury group,（Nrf2T） sham-operation group and(Nrf2<sup>-/-</sup>) brain injury group.The specimen 24 h after cerebral trauma was selected.Then RT-PCR method was adopted to detect the expression of Nrf2 mRNA in brain;Western blotting method was adopted to detect the levels of Nrf2,HO-1 and NQO1 proteins in brain;EUSA method was adopted to detect the oxidative stress indicators: protein carbonyls,4-hydroxy-2-nonenal（4-HNE） and 8-hydroxy-2’-deoxyguanosine（8-OHdG）. ResuHs:The Nrf2 mRNA and protein of Nrf2<sup>-/-</sup> mice were not expressed,and the diflerence of the relative amount of Nrf2 mRNA between Nrf2<sup>+/+</sup> TBI group and Nrf2<sup>+/+</sup> sham-operation group was not statistically significant（P】0.05）;the level of Nrf2 protein in Nrf2<sup>+/+</sup> TBI group increased significantly compared with the Nrf2<sup>+/+</sup> sham-operation group（P【0.01）;in the sham-operation groups,the levels of HO-1 and NQO1 proteins of Nrf2<sup>-/-</sup> mice decreased obviously compared with the Nrf2<sup>+/+</sup> mice（P【0.01）;after brain injury,the levels of HO-1 and NQO1 proteins of Nrf2<sup>+/+</sup> mice increased obviously compared with the corresponding sham-operation group（P【0.01）;the levels of HO-1 and NQOl proteins of Nrf2<sup>-/-</sup> mice in TBI group had no obvious change compared with the corresponding sham-operation group（P】0.05）;there was only a little amount of expression of protein carbonyls,4-HNE and 8-OHdG proteins in brain tissues in the Nrf2<sup>-/+</sup> and Nrf2<sup>-/-</sup> shamoperation groups,and the difference was not statistically significant（P】0.05）;after brain injury, the three oxidative stress indicators were significantly up-regulated in the Nrf2<sup>+/+</sup> and Nrf2<sup>-/-</sup> groups,and the up-regulation of the latter group was more significant（P【0.01）.Conclusions: After TBI the Nrf2/ARE pathway is activated and the activity of Nrf2 transcription regulation increases.However,the regulation dose not occur in the gene transcription level and only could increase the Nrf2 protein level,while the mRNA expression level has no obvious change.The nerve cell protective effect of Nrf2/ARE pathway in TBI achieves through inhibiting the oxidative stress injuries.展开更多
基金funded by the Research Deanship of King Khalid University,No.GRP-215-43 (to FHA)Princess Nourah bint Abdulrohman University Researchers Supporting Project,No.PNURSP2023R110 (to AFD)。
文摘Memory loss and dementia are major public health concerns with a substantial economic burden.Oxidative stress has been shown to play a crucial role in the pathophysiology of hippocampal damage-induced memory impairment.To investigate whether the antioxidant and anti-inflammatory compound vanillyla cetone(zingerone) can protect against hippocampal damage and memory loss induced by cadmium chloride(CdCl_(2)) administration in rats,we explo red the potential involvement of the nuclear factor erythroid 2-related factor 2(Nrf2) signaling pathway,which is known to modulate oxidative stress and inflammation.Sixty healt hy male Wistar rats were divided into five groups:vehicle-treated(control),vanillylacetone,CdCl_(2),vanillylacetone+ CdCl_(2),vanillylacetone+ CdCl_(2)+ brusatol(a selective pharmacological N rf2inhibitor) groups.Vanillylacetone effectively attenuated CdCl_(2)-induced damage in the dental gyrus of the hippocampus and improved the memory function assessed by the Morris Water Maze test.Additionally,vanillylacetone markedly decreased the hippocampal tissue levels of inflammatory biomarkers(interleukin-6,tumor necrosis factor-α,intracellular cell adhesive molecules) and apoptosis biomarkers(Bax and cleaved caspase-3).The control and CdCl_(2)-treated groups treated with va nillylacetone showed reduced generation of reactive oxygen species,decreased malondialdehyde levels,and increased superoxide dismutase and glutathione activities,along with significant elevation of nuclear Nrf2 mRNA and protein expression in hippocampal tissue.All the protective effects of vanillylacetone we re substantially blocked by the co-administration of brusatol(a selective N rf2 inhibitor).Va nillylacetone mitigated hippocampal damage and memory loss induced by CdCl_(2),at least in part, by activating the nuclear transcription factor Nrf2.Additionally,vanillylacetone exerted its potent antioxidant and antiinflammatory actions.
基金supported by grants from the Chinese 863 Project(2012AA022409)Guizhou Science and Technology Foundation(2009-70019)
文摘BACKGROUND： The KEAP1-Nrf2 antioxidant signaling pathway is important in protecting liver from various insults. However,little is known about the expression of Nrf2-related genes in human liver in different diseases.METHODS： This study utilized normal donor liver tissues（n=35）, samples from patients with hepatocellular carcinoma（HCC, n=24）, HBV-related cirrhosis（n=27）, alcoholic cirrhosis（n=5） and end-stage liver disease（n=13）. All of the liver tissues were from the Oriental Liver Transplant Center, Beijing,China. The expressions of Nrf2 and Nrf2-related genes, including its negative regulator Kelch-like ECH-associated protein 1（KEAP1）, its targeted gene NAD（P）H-quinone oxidoreductase 1（NQO1）, glutamate-cysteine ligase catalytic subunit（GCLC） and modified subunit（GCLM）, heme oxygenase 1（HO-1） and peroxiredoxin-1（PRDX1） were evaluated. RESULTS： The expression of Nrf2 was decreased in HCC, increased in alcoholic cirrhosis and end-stage liver disease. The expression of KEAP1 was increased in all of the liver samples.The most notable finding was the increased expression of NQO1 in HCC（18-fold）, alcoholic cirrhosis（6-fold）, endstage liver disease（5-fold） and HBV-related cirrhosis（3-fold）.Peri-HCC also had 4-fold higher NQO1 m RNA as compared to the normal livers. GCLC m RNA levels were lower only in HCC, as compared to the normal livers and peri-HCC tissues.GCLM m RNA levels were higher in HBV-related cirrhosis and end-stage liver disease. HO-1 m RNA levels were increased in all liver tissues except for HCC. Peri-HCC had higher PRDX1 m RNA levels compared with HCC and normal livers.CONCLUSION： Nrf2 and Nrf2-related genes are aberrantly expressed in the liver in different diseases and the increase of NQO1 was the most notable finding, especially in HCC.
文摘Objective:To explore the expression of Nrf2/ARE pathway in hindbrain tissue after the traumatic brain injury（TBI） and its anli-oxidative stress effect in the secondary nerve injury.Methods: The mice with Nrf2 gene knockout were used for the establishment of brain injury model.The experimental animals were divided into four groups:(Nrf2<sup>+/+</sup>) sham-operation group,(Nrf2<sup>+/+</sup>) brain injury group,（Nrf2T） sham-operation group and(Nrf2<sup>-/-</sup>) brain injury group.The specimen 24 h after cerebral trauma was selected.Then RT-PCR method was adopted to detect the expression of Nrf2 mRNA in brain;Western blotting method was adopted to detect the levels of Nrf2,HO-1 and NQO1 proteins in brain;EUSA method was adopted to detect the oxidative stress indicators: protein carbonyls,4-hydroxy-2-nonenal（4-HNE） and 8-hydroxy-2’-deoxyguanosine（8-OHdG）. ResuHs:The Nrf2 mRNA and protein of Nrf2<sup>-/-</sup> mice were not expressed,and the diflerence of the relative amount of Nrf2 mRNA between Nrf2<sup>+/+</sup> TBI group and Nrf2<sup>+/+</sup> sham-operation group was not statistically significant（P】0.05）;the level of Nrf2 protein in Nrf2<sup>+/+</sup> TBI group increased significantly compared with the Nrf2<sup>+/+</sup> sham-operation group（P【0.01）;in the sham-operation groups,the levels of HO-1 and NQO1 proteins of Nrf2<sup>-/-</sup> mice decreased obviously compared with the Nrf2<sup>+/+</sup> mice（P【0.01）;after brain injury,the levels of HO-1 and NQO1 proteins of Nrf2<sup>+/+</sup> mice increased obviously compared with the corresponding sham-operation group（P【0.01）;the levels of HO-1 and NQOl proteins of Nrf2<sup>-/-</sup> mice in TBI group had no obvious change compared with the corresponding sham-operation group（P】0.05）;there was only a little amount of expression of protein carbonyls,4-HNE and 8-OHdG proteins in brain tissues in the Nrf2<sup>-/+</sup> and Nrf2<sup>-/-</sup> shamoperation groups,and the difference was not statistically significant（P】0.05）;after brain injury, the three oxidative stress indicators were significantly up-regulated in the Nrf2<sup>+/+</sup> and Nrf2<sup>-/-</sup> groups,and the up-regulation of the latter group was more significant（P【0.01）.Conclusions: After TBI the Nrf2/ARE pathway is activated and the activity of Nrf2 transcription regulation increases.However,the regulation dose not occur in the gene transcription level and only could increase the Nrf2 protein level,while the mRNA expression level has no obvious change.The nerve cell protective effect of Nrf2/ARE pathway in TBI achieves through inhibiting the oxidative stress injuries.
