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Scutellarin acts on the AR-NOX axis to remediate oxidative stress injury in a mouse model of cerebral ischemia/reperfusion injury

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机构: [1]Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China [2]State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China [3]Department of Second Institute of Clinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China [4]Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou, China [5]Department of Anatomy, Sun Yat-Sen School of Medicine, Sun Yat-Sen University, Shenzhen, China [6]Faculty of Medicine, Macau University of Science and Technology, Macau, China
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关键词: Scutellarin Aldose reductase NADPH oxidase Ischemia-reperfusion Quantitative proteomic analysis

摘要:
Background: Oxidative stress plays an important role in the pathology of ischemic stroke. Studies have confirmedthat scutellarin has antioxidant effects against ischemic injury, and we also reported that the involvement of Aldose reductase (AR) in oxidative stress and cerebral ischemic injury, in this study we furtherly explicit whether the antioxidant effect of scutellarin on cerebral ischemia injury is related to AR gene regulation and its specific mechanism. Methods: C57BL/6N mice (Wild-type, WT) and AR knockout (AR(-/-)) mice suffered from transient middle cerebral artery occlusion (tMCAO) injury (1 h occlusion followed by 3 days reperfusion), and scutellarin was administered from 2 h before surgery to 3 days after surgery. Subsequently, neurological function was assessed by the modified Longa score method, the histopathological morphology observed with 2,3,5-triphenyltetrazolium chloride (TTC) and hematoxylin-eosin (HE) staining. Enzyme-linked immunosorbent assay (Elisa) was used to detect the levels of ROS, 4-hydroxynonenal (4-HNE), 8-hydroxydeoxyguanosine (8-OHDG), Neurotrophin-3 (NT-3), poly ADP-ribose polymerase-1 (PARP1) and 3-nitrotyrosine (3-NT) in the ischemic penumbra regions. Quantitative proteomics profiling using quantitative nano-HPLC-MS/MS were performed to compare the protein expression difference between AR(-/- )and WT mice with or without tMCAO injury. The expression of AR, nicotinamide adenine dinucleotide phosphate oxidases (NOX1, NOX2 and NOX4) in the ipsilateral side of ischemic brain were detected by qRT-PCR, Western blot and immunofluorescence co-staining with NeuN. Results: Scutellarin treatment alleviated brain damage in tMCAO stroke model such as improved neurological function deficit, brain infarct area and neuronal injury and reduced the expression of oxidation-related products, moreover, also down-regulated tMCAO induced AR mRNA and protein expression. In addition, the therapeutic effect of scutellarin on the reduction of cerebral infarction area and neurological function deficits abolished in AR- /- miceunder ischemia cerebral injury, which indicated that the effect of scutellarin treatment on tMCAO injury is through regulating AR gene. Proteomic analysis of AR(-/-)and WT mice indicated AR knockout would affect oxidation reaction even as NADPH related process and activity in mice under cerebral ischemia conditions. Moreover, NOX isoforms (NOX1, NOX2 and NOX4) mRNA and protein expression were significant decreased in neurons of penumbra region in AR(-/- )mice compared with that in WT mice at 3d after tMCAO injury, which indicated that AR should be the upstream protein regulating NOX after cerebral ischemia. Conclusions: We first reported that AR directly regulates NOX subtypes (not only NOX2 but also NOX1 and NOX4) after cerebral ischaemic injury. Scutellarin specifically targets the AR-NOX axis and has antioxidant effects in mice with cerebral ischaemic injury, providing a theoretical basis and accurate molecular targets for the clinical application of scutellarin.

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出版当年[2021]版:
大类 | 2 区 医学
小类 | 1 区 植物科学 1 区 全科医学与补充医学 1 区 药学 2 区 药物化学
最新[2025]版:
大类 | 1 区 医学
小类 | 1 区 药物化学 1 区 全科医学与补充医学 1 区 药学 1 区 植物科学
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出版当年[2020]版:
Q1 PHARMACOLOGY & PHARMACY Q1 PLANT SCIENCES Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE Q1 CHEMISTRY, MEDICINAL
最新[2023]版:
Q1 CHEMISTRY, MEDICINAL Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE Q1 PHARMACOLOGY & PHARMACY Q1 PLANT SCIENCES

影响因子: 最新[2023版] 最新五年平均 出版当年[2020版] 出版当年五年平均 出版前一年[2019版] 出版后一年[2021版]

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第一作者机构: [1]Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China [3]Department of Second Institute of Clinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
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通讯机构: [1]Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China [2]State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China [3]Department of Second Institute of Clinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China [4]Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou, China [*1]Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, 111 Dade Road, Guangzhou, 510120, China.
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