Alcohol abuse has recently become a serious health concern worldwide,and the incidence of alcoholic liver disease(ALD)is rapidly increasing with high morbidity and mortality.Ferroptosis is a newly recognized form of r...Alcohol abuse has recently become a serious health concern worldwide,and the incidence of alcoholic liver disease(ALD)is rapidly increasing with high morbidity and mortality.Ferroptosis is a newly recognized form of regulated cell death caused by the iron-dependent accumulation of lipid peroxidation.Here we showed that the circadian clock protein brain and muscle arnt-like protein-1(BMAL1)in hepatocytes is both necessary and sufficient to protect against ALD by mitigating ferroptosis.U pon exposure to alcohol(5%Lieber-DeCarli liquid alcohol diet for 10 days before binged alcohol with 5 g/kg body weight in vivo,300 mmol/L for 12 h in vitro,respectively),the content of iron,reactive oxygen species(ROS)and malondialdehyde(MDA)was boosted signifi cantly while glutathione(GSH)was decreased that mainly based on the downregulated protein expression of ferritin heavy chain(FTH),ferroportin(FPN),heme oxygenase1(HO-1)and anti-cystine/glutamate antiporter(SLC7A11),while these changes could be abolished by ferroptosis inhibitor Ferrostatin-1[Fer-1(5 mg/kg body weight for 10 days in vivo,10μmol/L for 2 h in vitro,respectively)].Further study indicated that the alcohol could activate the protein expression of BMAL1 which exerts a protective effect against ferroptosis through promoting nuclear factor erythroid 2-related factor 2(Nrf2)translocation into nuclear and subsequently stimulating its downstream proteins FTH,FPN,glutathione peroxidase 4 activity(GPX4),HO-1,SLC7A11,while knockdown of BMAL1 and Nrf2 by RNA interference further downregulated the expression of these protein and thus promoting ferroptosis in response to alcohol.Collectively,our results unveiled that the protective action of BMAL1 during alcohol challenge depends on its ability to activate Nrf2-ARE antiferroptosis pathway and targeting hepatic BMAL1 to dampen hepatic ferroptosis signaling may have therapeutic potential for ALD.展开更多
A large body of literature suggests that bone metabolism is susceptible to the ill effects of reactive species that accumulate in the body and cause cellular dysfunction. One of the body＇s front lines in defense agai...A large body of literature suggests that bone metabolism is susceptible to the ill effects of reactive species that accumulate in the body and cause cellular dysfunction. One of the body＇s front lines in defense against such damage is the transcription factor, Nrf2. This transcription factor regulates a plethora of antioxidant and cellular defense pathways to protect cells from such damage. Despite the breadth of knowledge of both the function of Nrf2 and the effects of reactive species in bone metabolism, the direct role of Nrf2 in skeletal biology has yet to be thoroughly examined. Thus, in the current study, we have examined the role of Nrf2 in postnatal bone metabolism in mice. Mice lacking Nrf2 （Nrf2-/-） exhibited a marked deficit in postnatal bone acquisition, which was most severe at 3 weeks of age when osteoblast numbers were 12-fold less than observed in control animals. While primary osteoblasts from Nrf2-/- mice functioned normally in vitro, the colony forming capacity of bone marrow stromal cells （BMSCs） from these mice was significantly reduced compared to controls. This defect could be rescued through treatment with the radical scavenger N-acetyl cysteine （NAC）, suggesting that increased reactive species stress might impair early osteoblastogenesis in BMSCs and lead to the failure of bone acquisition observed in Nrf2-/- animals. Taken together, these studies suggest Nrf2 represents a key pathway in regulating bone metabolism, which may provide future therapeutic targets to treat osteoporosis.展开更多
Nuclear factor erythroid-derived 2-like 2(Nrf2)is the master regulator of antioxidant defenses.High-intensity interval training(HIIT)has been proposed as a time-efficient training program and has become a substantial ...Nuclear factor erythroid-derived 2-like 2(Nrf2)is the master regulator of antioxidant defenses.High-intensity interval training(HIIT)has been proposed as a time-efficient training program and has become a substantial component of modern training program In the present study,we evaluated the effects of sulforaphane(SFN),a dietary isothiocyanate derived from cruciferous vegetables and a potent Nrf2 activator,on Nrf2-mediated antioxidant defense responses of skeletal muscle induced by exhaustive exercise in HIIT mice.Male C57 BL/6 J mice were randomly allocated into control group,HIIT group,and HIIT pretreated with SFN(HIIT+SFN)group.On the third day after completion of a 6-weeks HIIT protocol,an exhaustive treadmill test was conducted in all mice.Mice were intraperitoneally injected with SFN(HIIT+SFN group)or PBS(HIIT and control mice)4 times in 3 days prior to the exhaustive treadmill test.The results indicated that the 6-weeks HIIT protocol did not increase the antioxidative capacity of skeletal muscle during exhaustive exercise.Importantly,SFN treatment improved anti oxidative capacity of skeletal muscle in response to the acute exhaustive exercise by increasing mRNA and nucleoprotein expression of Nrf2 and these genes involved in antioxidant generation and decreasing blood creatine kinase(CK)and 4-hydroxy-2-nonenal(4-HNE)-modified protein levels in the HIIT mice.展开更多
Nuclear factor erythroid 2-related factor 2 （Nrf2） controls the expression of a wide array of antioxidant response element （ARE）-driven genes, which are involved in stress response and metabolism regulation. The r...Nuclear factor erythroid 2-related factor 2 （Nrf2） controls the expression of a wide array of antioxidant response element （ARE）-driven genes, which are involved in stress response and metabolism regulation. The role of Nrf2/ARE signaling in resistances of cancer cells to radiotherapy and chemotherapy has been widely accepted. However, much less is known about the relevance of Nrf2 to chemotherapy-associated toxicities, such as hepatotoxicity. In the present study, nine chemotherapeutic agents were firstly tested in embryonic fibroblasts （MEFs） and hepatocytes isolated from Nrf2 deficient or wild-type mice. The results indicate that the cytotoxicity of oxaliplatin in hepatocytes was significantly higher than that in MEFs and enhanced by Nrf2 deficiency. Furthermore, oxaliplatin treatment caused more pronounced steatosis and severer liver injury in Nrf2-/- mice compared with wild-type counterparts, as evidenced by dramatically elevated serum transaminase and bilirubin, increased accumulation of fat, inflammatory infiltration and blood congestion. The increased hepatotoxicity in Nrf2 deficient mice was possibly caused by decreased expression of antioxidant genes and glutathione depletion. Our results demonstrated that oxaliplatin-induced hepatotoxicity was significantly impacted by Nrf2 status, therefore Nrf2 could potentially serve as a biomarker to predict or a target to prevent hepatotoxicity of oxaliplatin.展开更多
文摘Alcohol abuse has recently become a serious health concern worldwide,and the incidence of alcoholic liver disease(ALD)is rapidly increasing with high morbidity and mortality.Ferroptosis is a newly recognized form of regulated cell death caused by the iron-dependent accumulation of lipid peroxidation.Here we showed that the circadian clock protein brain and muscle arnt-like protein-1(BMAL1)in hepatocytes is both necessary and sufficient to protect against ALD by mitigating ferroptosis.U pon exposure to alcohol(5%Lieber-DeCarli liquid alcohol diet for 10 days before binged alcohol with 5 g/kg body weight in vivo,300 mmol/L for 12 h in vitro,respectively),the content of iron,reactive oxygen species(ROS)and malondialdehyde(MDA)was boosted signifi cantly while glutathione(GSH)was decreased that mainly based on the downregulated protein expression of ferritin heavy chain(FTH),ferroportin(FPN),heme oxygenase1(HO-1)and anti-cystine/glutamate antiporter(SLC7A11),while these changes could be abolished by ferroptosis inhibitor Ferrostatin-1[Fer-1(5 mg/kg body weight for 10 days in vivo,10μmol/L for 2 h in vitro,respectively)].Further study indicated that the alcohol could activate the protein expression of BMAL1 which exerts a protective effect against ferroptosis through promoting nuclear factor erythroid 2-related factor 2(Nrf2)translocation into nuclear and subsequently stimulating its downstream proteins FTH,FPN,glutathione peroxidase 4 activity(GPX4),HO-1,SLC7A11,while knockdown of BMAL1 and Nrf2 by RNA interference further downregulated the expression of these protein and thus promoting ferroptosis in response to alcohol.Collectively,our results unveiled that the protective action of BMAL1 during alcohol challenge depends on its ability to activate Nrf2-ARE antiferroptosis pathway and targeting hepatic BMAL1 to dampen hepatic ferroptosis signaling may have therapeutic potential for ALD.
基金supported by a Johns Hopkins Musculoskeletal Research Pilot and Feasibility Grant (RKT) and NIH R01 AR062074 (DJD)
文摘A large body of literature suggests that bone metabolism is susceptible to the ill effects of reactive species that accumulate in the body and cause cellular dysfunction. One of the body＇s front lines in defense against such damage is the transcription factor, Nrf2. This transcription factor regulates a plethora of antioxidant and cellular defense pathways to protect cells from such damage. Despite the breadth of knowledge of both the function of Nrf2 and the effects of reactive species in bone metabolism, the direct role of Nrf2 in skeletal biology has yet to be thoroughly examined. Thus, in the current study, we have examined the role of Nrf2 in postnatal bone metabolism in mice. Mice lacking Nrf2 （Nrf2-/-） exhibited a marked deficit in postnatal bone acquisition, which was most severe at 3 weeks of age when osteoblast numbers were 12-fold less than observed in control animals. While primary osteoblasts from Nrf2-/- mice functioned normally in vitro, the colony forming capacity of bone marrow stromal cells （BMSCs） from these mice was significantly reduced compared to controls. This defect could be rescued through treatment with the radical scavenger N-acetyl cysteine （NAC）, suggesting that increased reactive species stress might impair early osteoblastogenesis in BMSCs and lead to the failure of bone acquisition observed in Nrf2-/- animals. Taken together, these studies suggest Nrf2 represents a key pathway in regulating bone metabolism, which may provide future therapeutic targets to treat osteoporosis.
基金supported by Winter Sports Nutrition Research Center in Beijing Sport University supported by Herbalife Nutrition~(TM)Scientific Research Program Funded by Shaanxi Provincial Education Department(20JK0993 to Y.X.)Exercise and Physical Fitness,the Key Laboratory of Ministry of Education in Beijing Sport University。
文摘Nuclear factor erythroid-derived 2-like 2(Nrf2)is the master regulator of antioxidant defenses.High-intensity interval training(HIIT)has been proposed as a time-efficient training program and has become a substantial component of modern training program In the present study,we evaluated the effects of sulforaphane(SFN),a dietary isothiocyanate derived from cruciferous vegetables and a potent Nrf2 activator,on Nrf2-mediated antioxidant defense responses of skeletal muscle induced by exhaustive exercise in HIIT mice.Male C57 BL/6 J mice were randomly allocated into control group,HIIT group,and HIIT pretreated with SFN(HIIT+SFN)group.On the third day after completion of a 6-weeks HIIT protocol,an exhaustive treadmill test was conducted in all mice.Mice were intraperitoneally injected with SFN(HIIT+SFN group)or PBS(HIIT and control mice)4 times in 3 days prior to the exhaustive treadmill test.The results indicated that the 6-weeks HIIT protocol did not increase the antioxidative capacity of skeletal muscle during exhaustive exercise.Importantly,SFN treatment improved anti oxidative capacity of skeletal muscle in response to the acute exhaustive exercise by increasing mRNA and nucleoprotein expression of Nrf2 and these genes involved in antioxidant generation and decreasing blood creatine kinase(CK)and 4-hydroxy-2-nonenal(4-HNE)-modified protein levels in the HIIT mice.
基金National Natural Science Foundation of China(Grant No.81272468,81372266,91429305 and 21001011)WU JIEPING Medical Foundation(Grant No.320.6750.12196)
文摘Nuclear factor erythroid 2-related factor 2 （Nrf2） controls the expression of a wide array of antioxidant response element （ARE）-driven genes, which are involved in stress response and metabolism regulation. The role of Nrf2/ARE signaling in resistances of cancer cells to radiotherapy and chemotherapy has been widely accepted. However, much less is known about the relevance of Nrf2 to chemotherapy-associated toxicities, such as hepatotoxicity. In the present study, nine chemotherapeutic agents were firstly tested in embryonic fibroblasts （MEFs） and hepatocytes isolated from Nrf2 deficient or wild-type mice. The results indicate that the cytotoxicity of oxaliplatin in hepatocytes was significantly higher than that in MEFs and enhanced by Nrf2 deficiency. Furthermore, oxaliplatin treatment caused more pronounced steatosis and severer liver injury in Nrf2-/- mice compared with wild-type counterparts, as evidenced by dramatically elevated serum transaminase and bilirubin, increased accumulation of fat, inflammatory infiltration and blood congestion. The increased hepatotoxicity in Nrf2 deficient mice was possibly caused by decreased expression of antioxidant genes and glutathione depletion. Our results demonstrated that oxaliplatin-induced hepatotoxicity was significantly impacted by Nrf2 status, therefore Nrf2 could potentially serve as a biomarker to predict or a target to prevent hepatotoxicity of oxaliplatin.
