Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidati...Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.展开更多
The study aimed to explore the efficacy and potential mechanisms of a naturally aromatic cyanogenic compound amygdalin(AMY)in treating glucocorticoid(GC)-associated necrosis of the femoral head(GANFH).We demonstrated ...The study aimed to explore the efficacy and potential mechanisms of a naturally aromatic cyanogenic compound amygdalin(AMY)in treating glucocorticoid(GC)-associated necrosis of the femoral head(GANFH).We demonstrated that GC exacerbates the oxidative stress(OS)microenvironment via promoting nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4)expression in human,rat,and mesenchymal stem cells(MSCs)samples,thus generating excessive reactive oxygen species(ROS),leading to increased apoptosis and unbalanced osteolipogenic differentiation.Furthermore,computational docking results revealed that AMY could bind specifically to the predicted binding sites of NOX4.Additionally,AMY ameliorated the OS microenvironment of MSCs via decreasing NOX4 expression and inhibiting NOX4/ROS/p38MAPK signaling,thereby reversing the GC-induced apoptosis and imbalanced osteolipogenic differentiation,and ultimately alleviating GANFH.In summary,we demonstrated for the first time that AMY attenuated apoptosis and maintained osteolipogenic differentiation balance in MSCs via specifically targeting NOX4,inhibiting NOX4/ROS/p38MAPK signaling,thereby treating GANFH.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82271444(to JP),82271268(to BZ),and 82001346(to YL)the National Key Research and Development Program of China,No.2022YFE0210100(to BZ)。
文摘Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.
基金supported by the Natural Science Foundation of China(81873325)the State Administration of Traditional Chinese Medicine of Zhejiang Province(2021ZZ014).
文摘The study aimed to explore the efficacy and potential mechanisms of a naturally aromatic cyanogenic compound amygdalin(AMY)in treating glucocorticoid(GC)-associated necrosis of the femoral head(GANFH).We demonstrated that GC exacerbates the oxidative stress(OS)microenvironment via promoting nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4)expression in human,rat,and mesenchymal stem cells(MSCs)samples,thus generating excessive reactive oxygen species(ROS),leading to increased apoptosis and unbalanced osteolipogenic differentiation.Furthermore,computational docking results revealed that AMY could bind specifically to the predicted binding sites of NOX4.Additionally,AMY ameliorated the OS microenvironment of MSCs via decreasing NOX4 expression and inhibiting NOX4/ROS/p38MAPK signaling,thereby reversing the GC-induced apoptosis and imbalanced osteolipogenic differentiation,and ultimately alleviating GANFH.In summary,we demonstrated for the first time that AMY attenuated apoptosis and maintained osteolipogenic differentiation balance in MSCs via specifically targeting NOX4,inhibiting NOX4/ROS/p38MAPK signaling,thereby treating GANFH.
