The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular an...The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.展开更多
OBJECTIVE To investigates the effects of imperatorin on the oxidative stress in the cerebral cortex and hippocampus after focal cerebral ischemia/reperfusion injury.METHODS Transient focal cerebral ischemia/reperfusio...OBJECTIVE To investigates the effects of imperatorin on the oxidative stress in the cerebral cortex and hippocampus after focal cerebral ischemia/reperfusion injury.METHODS Transient focal cerebral ischemia/reperfusion model in male Sprague-Dawley rats was induced by 2 h middle cerebral artery occlusion followed by 24 h reperfusion.Imperatorin(1.25 and 2.5 mg·kg-1)or vehicle were administered intraperitoneally at 1,5 and 9 h after the onset of ischemia.At 24 h after reperfusion,the biomarkers of oxidative stress such as the levels of reactive oxygen species(ROS),lipid peroxidation products malondialdehyde(MDA),nitric oxide(NO)and total antioxidant capacity(T-AOC),the activities of inducible nitric oxide synthase(iN OS),superoxide dismutase(SOD)and catalase(CAT)in the cerebral cortex and hippocampus were observed.We also assessed the nuclear factor erythroid 2-related factor 2(Nrf2),heme oxygenase-1(HO-1),and the NAD(P)H-quinone oxidoreductase 1(NQO-1)protein expression by Western blot.RESULTS As compared to vehicle-treated animals,imperatorin treatment significantly reduced the ROS,MDA,NO levels and i NOS activity,increased T-AOC and the activities of SOD and CAT.Furthermore,imperatorin treatment also significantly induced the nuclear translocation of Nrf2,enhanced the protein expression of HO-1 and NQO-1 in the cerebral cortex and hippocampus.CONCLUSION Our findings indicate that imperatorin can protect the brain against the excessive oxidative stress induced by cerebral ischemia/reperfusion through activation of Nrf2 signaling pathway.展开更多
目的应用成年斑马鱼放射脑损伤模型研究莱菔硫烷对放射性脑损伤的保护作用。方法成年斑马鱼90条按随机数表法分为正常组、照射组、照射+莱菔硫烷组(SFN组),每组30条,放射后48 h检测各组斑马鱼氧化应激相关因子活性氧簇(ROS)、丙二醛(MDA...目的应用成年斑马鱼放射脑损伤模型研究莱菔硫烷对放射性脑损伤的保护作用。方法成年斑马鱼90条按随机数表法分为正常组、照射组、照射+莱菔硫烷组(SFN组),每组30条,放射后48 h检测各组斑马鱼氧化应激相关因子活性氧簇(ROS)、丙二醛(MDA)和超氧歧化酶(SOD)活力的变化。利用聚合酶链反应和免疫蛋白印迹的方法检测斑马鱼脑组织中核因子E2相关因子2 (Nrf2)和血红素加氧合酶1 (HO-1)的基因和蛋白表达情况。结果与照射组相比,SFN组减少了ROS [相对倍数改变:(1.56±0.17) vs (2.13±0.24)]和MDA [相对倍数改变:(1.77±0.13) vs (3.28±0.25)]的产生,差异均有统计学意义(P<0.05);与照射组相比,SFN组提高了SOD [相对倍数改变:(1.83±0.22) vs (0.65±0.14)]的水平,差异有统计学意义(P<0.05);SFN组提高了Nrf2的核内蛋白水平[相对倍数改变:(2.07±0.38) vs (1.2±0.34)],提高了HO-1基因[相对倍数改变:(2.41±0.25) vs (1.19±0.14)]和蛋白表达水平[相对倍数改变:(2.36±0.43) vs (1.40±0.18)],差异均有统计学意义(P<0.05)。结论在斑马鱼放射性脑损伤模型中,SFN通过激活Nrf2/HO-1通路起到减缓放射性脑损伤的作用。展开更多
Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma.However,its clinical applications have been hindered due to low efficacy and bioavailability,and particularly frequent emergence of reactive...Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma.However,its clinical applications have been hindered due to low efficacy and bioavailability,and particularly frequent emergence of reactive oxygen species(ROS)-decrease induced drug resistance.The transcription factor NF-E2-related factor 2(Nrf2)is increased in cancer patients and induces poor outcome in osteosarcoma treatment,making it a novel target to improve the efficacy of chemotherapy.Herein,a hyaluronidase-responsive multi-layer liposome(HLCN)for co-delivery of cisplatin and Nrf2 siRNA(siNrf2)is developed.It is composed of Vpr52-96 modified liposome covered with hyaluronic acid(HA).HLCN selectively accumulates in osteosarcoma by targeting tumor-specific CD44,and can be degraded by endosomal hyaluronidase to generate cationic liposome,which promotes the endosomal escape of Vpr52-96,cisplatin and siNrf2.HLCN can effectively decrease Nrf2 level,promote ROS generation,activate itochondrial apoptotic pathway,and consequently enhance anticancer efficacy of cisplatin.Particularly,HLCN shows high cytotoxicity to osteosarcoma cells with an IC50 value of about 1µM,which is four-fold lower than liposomal cisplatin(IC504µM),indicating that Nrf2 silence can significantly improve cisplatin sensitivity in cancer cells.Importantly,HLCN can remarkably inhibit tumor growth in the xenograft osteosarcoma mice with minimal systemic adverse effects.Therefore,this novel stimuli-responsive combination therapy of cisplatin and siNrf2 provides a promising strategy for the treatment of osteosarcoma.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82271327 (to ZW),82072535 (to ZW),81873768 (to ZW),and 82001253 (to TL)。
文摘The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.
基金supported by National Natural Science Foundation of China(81060269 and81360492)Natural Science Foundation of Jiangxi Province of China(20122BAB205036)
文摘OBJECTIVE To investigates the effects of imperatorin on the oxidative stress in the cerebral cortex and hippocampus after focal cerebral ischemia/reperfusion injury.METHODS Transient focal cerebral ischemia/reperfusion model in male Sprague-Dawley rats was induced by 2 h middle cerebral artery occlusion followed by 24 h reperfusion.Imperatorin(1.25 and 2.5 mg·kg-1)or vehicle were administered intraperitoneally at 1,5 and 9 h after the onset of ischemia.At 24 h after reperfusion,the biomarkers of oxidative stress such as the levels of reactive oxygen species(ROS),lipid peroxidation products malondialdehyde(MDA),nitric oxide(NO)and total antioxidant capacity(T-AOC),the activities of inducible nitric oxide synthase(iN OS),superoxide dismutase(SOD)and catalase(CAT)in the cerebral cortex and hippocampus were observed.We also assessed the nuclear factor erythroid 2-related factor 2(Nrf2),heme oxygenase-1(HO-1),and the NAD(P)H-quinone oxidoreductase 1(NQO-1)protein expression by Western blot.RESULTS As compared to vehicle-treated animals,imperatorin treatment significantly reduced the ROS,MDA,NO levels and i NOS activity,increased T-AOC and the activities of SOD and CAT.Furthermore,imperatorin treatment also significantly induced the nuclear translocation of Nrf2,enhanced the protein expression of HO-1 and NQO-1 in the cerebral cortex and hippocampus.CONCLUSION Our findings indicate that imperatorin can protect the brain against the excessive oxidative stress induced by cerebral ischemia/reperfusion through activation of Nrf2 signaling pathway.
文摘目的应用成年斑马鱼放射脑损伤模型研究莱菔硫烷对放射性脑损伤的保护作用。方法成年斑马鱼90条按随机数表法分为正常组、照射组、照射+莱菔硫烷组(SFN组),每组30条,放射后48 h检测各组斑马鱼氧化应激相关因子活性氧簇(ROS)、丙二醛(MDA)和超氧歧化酶(SOD)活力的变化。利用聚合酶链反应和免疫蛋白印迹的方法检测斑马鱼脑组织中核因子E2相关因子2 (Nrf2)和血红素加氧合酶1 (HO-1)的基因和蛋白表达情况。结果与照射组相比,SFN组减少了ROS [相对倍数改变:(1.56±0.17) vs (2.13±0.24)]和MDA [相对倍数改变:(1.77±0.13) vs (3.28±0.25)]的产生,差异均有统计学意义(P<0.05);与照射组相比,SFN组提高了SOD [相对倍数改变:(1.83±0.22) vs (0.65±0.14)]的水平,差异有统计学意义(P<0.05);SFN组提高了Nrf2的核内蛋白水平[相对倍数改变:(2.07±0.38) vs (1.2±0.34)],提高了HO-1基因[相对倍数改变:(2.41±0.25) vs (1.19±0.14)]和蛋白表达水平[相对倍数改变:(2.36±0.43) vs (1.40±0.18)],差异均有统计学意义(P<0.05)。结论在斑马鱼放射性脑损伤模型中,SFN通过激活Nrf2/HO-1通路起到减缓放射性脑损伤的作用。
基金This work was supported by the National Key Research and Development Program of China(No.2019YFA0802800)the Key Research and Development Program of Jiangsu Provincial Department of Science and Technology of China(No.BE2019002)+5 种基金the Medical Key Young Talents Programs of Jiangsu Province(No.QNRC2016915)the“The Six Top Talents”of Jiangsu Province(No.WSW-112)the Fundamental Research Funds for the Central Universities(No.021314380120)the National Key Research and Development Program of China(No.2018YFB1105400)National Natural Science Foundation of China(No.21708019)Natural Science Foundation of Jiangsu(No.BK20170987).
文摘Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma.However,its clinical applications have been hindered due to low efficacy and bioavailability,and particularly frequent emergence of reactive oxygen species(ROS)-decrease induced drug resistance.The transcription factor NF-E2-related factor 2(Nrf2)is increased in cancer patients and induces poor outcome in osteosarcoma treatment,making it a novel target to improve the efficacy of chemotherapy.Herein,a hyaluronidase-responsive multi-layer liposome(HLCN)for co-delivery of cisplatin and Nrf2 siRNA(siNrf2)is developed.It is composed of Vpr52-96 modified liposome covered with hyaluronic acid(HA).HLCN selectively accumulates in osteosarcoma by targeting tumor-specific CD44,and can be degraded by endosomal hyaluronidase to generate cationic liposome,which promotes the endosomal escape of Vpr52-96,cisplatin and siNrf2.HLCN can effectively decrease Nrf2 level,promote ROS generation,activate itochondrial apoptotic pathway,and consequently enhance anticancer efficacy of cisplatin.Particularly,HLCN shows high cytotoxicity to osteosarcoma cells with an IC50 value of about 1µM,which is four-fold lower than liposomal cisplatin(IC504µM),indicating that Nrf2 silence can significantly improve cisplatin sensitivity in cancer cells.Importantly,HLCN can remarkably inhibit tumor growth in the xenograft osteosarcoma mice with minimal systemic adverse effects.Therefore,this novel stimuli-responsive combination therapy of cisplatin and siNrf2 provides a promising strategy for the treatment of osteosarcoma.
