INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 3
·2126
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IF 5.6
Shouchao Xu,Jiehong Yang,Haitong Wan,Li Yu,Yu He
Promotion of angiogenesis and restoration of the blood flow in the ischemic penumbra is an effective treatment for patients with ischemic stroke (IS). Radix astragali-safflower (AS), a classic herbal pair for accelerating blood circulation and dispersing blood stasis, has been used for thousands of years to treat patients with IS in China. Even so, the mechanism of the treatment of IS by AS is still undecipherable. In the current study, network pharmacology was firstly employed to unveil the mechanism of AS in treating IS, which showed that AS might promote angiogenesis associated with PTGS2 silence. Middle cerebral artery occlusion/reperfusion (MCAO/R) model rats were then used as the experimental animals to verify the prediction result. The experimental results revealed that treatment with AS improved the cerebral infarct volume, neurological damage, and cerebral histopathological damage; inhibited cell apoptosis; increased the contents of PDGF-BB, EPO, and TGF-β1; and reduced the levels of PF4, Ang-2, and TIMP-1 in serum. Immunohistochemical staining demonstrated that the expression of PTGS2 was dramatically increased in the hippocampus and cerebral cortex of rats with MCAO/R, and this trend was reversed by the treatment of AS. Immunofluorescent staining expressed that AS reversed the down-regulation of VEGF and further promoted the expression of CD31, which indicated that AS promoted angiogenesis in MCAO/R rats. The abnormal protein or mRNA expression of PTGS2, PGI2, bFGF, TSP-1, and VEGF in the penumbra were transposed by AS or Celecoxib (an inhibitor of PTGS2). In conclusion, the protective mechanism of AS for IS promoted angiogenesis and was involved with PTGS2 silence.Keywords:Radix astragali and safflower;angiogenesis;ischemic stroke;ischemic penumbra;PTGS2
研究领域:
药理学
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神经科学
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中医药学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2023
·Vol. 60
·期 7
·3824-3838
·
IF 5.1
Deng Ling,Zhang Jiyu,Chen Sha,Wu Yu,Fan Xiaomei,Zuo Tianrui,Hu Qingwen,Jiang Lu,Yang Shaonan,Dong Zhi
Blood-brain barrier (BBB) disruption can induce further hemorrhagic transformation in ischemic stroke (IS). miR-671-5p, a micro-RNA, is abundant in the cortex of mammalian brains. Herein, we investigated the roles and potential mechanisms for the effects of miR-671-5p on BBB permeability in IS. Results showed that miR-671-5p levels were significantly downregulated in the cerebral cortex of middle cerebral artery occlusion/reperfusion (MCAO/R) C57/BL6 mice in vivo . miR-671-5p agomir administration via right intracerebroventricular injection significantly reduced infarct volume, improved neurological deficits, the axon of neurons and nerve fiber, attenuated cell injury and apoptosis, as well as reduced BBB permeability in MCAO/R mice. Treatment with miR-671-5p agomir alleviated tight junction proteins degradation, including claudin, occludin, and ZO-1 in MCAO/R mice, and these effects were reversed following NF-κB overexpression. Bend.3 brain endothelial cells were subjected to oxygen and glucose deprivation/reoxygenation (OGD/R) treatment in vivo , and then miR-671-5p agomir was transfected into the cells. This resulted in reduction of cytotoxicity, improved cell viability, trans-endothelial electrical resistance, reduced fluorescein sodium permeability, and inhibited tight junction degradation in Bend.3 OGD/R cells. However, these effects were reversed following NF-κB overexpression. These results demonstrated that upregulation of miR-671-5p in IS models in vivo and i n vitro alleviated BBB permeability by targeting NF-κB/MMP-9. In summary, miR-671-5p is a potential therapeutic target for protecting BBB permeability in IS to minimize cerebral hemorrhage transformation.
研究领域:
神经科学
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分子生物学
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药理学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
Journal of Integrative Neuroscience
·
2024
·Vol. 23
·期 11
·196
·
IF 2.5
Yan Shi,Yufeng Yang,Juntong Liu,Jinling Zheng
Background:
Avicularin (AL), an ingredient of Banxia, has anti-inflammatory properties in cerebral disease and regulates polarization of macrophages, but its effects on ischemic stroke (IS) damage have not been studied.
Methods:
In vivo, AL was administered by oral gavage to middle cerebral artery occlusion/reperfusion (MCAO/R) C57BL/6J mice in doses of 1.25, 2.5, and 5 mg/kg/day for seven days, and, in vitro, AL was added to treat oxygen-glucose deprivation (OGD)-BV2 cells. Modified neurological severity score, Triphenyltetrazolium chloride (TTC) staining, brain-water-content detection, TdT-mediated dUTP nick-end labeling (TUNEL) assay, flow cytometry, immunofluorescence assay, Enzyme linked immunosorbent assay (ELISA), and Western-blot analysis were used to investigate the functions and mechanism of the effect of AL treatment on IS. The exosomes of AL-treated microglia were studied by transmission electron microscope (TEM), nanoparticle tracking analyzer (NTA), and Western-blot analysis.
Results:
AL treatment reduced the neurological severity score, infarct volume, brain-water content, neuronal apoptosis, and the release of inflammatory factors, that were induced by MCAO/R. Notably, M2 microglia polarization was promoted but M1 microglia polarization was inhibited by AL in the ischemic penumbra of MCAO/R mice. Subsequently, anti-inflammatory and polarization-regulating effects of AL were verified in vitro. Suppressed NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation was found in the ischemic penumbra of animal and Oxygen-Glucose Deprivation/Reoxygenation (OGD/R) cells treated with AL, as evidenced by decreasing NLRP3-inflammasome-related protein and downstream factors. After AL treatment, the anti-apoptosis effect of microglial exosomes on OGD/R primary cortical neurons was increased.
Conclusion:
AL reduce inflammatory responses and neuron death of IS-associated models by regulating microglia polarization by the NLRP3 pathway and by affecting microglial exosomes.
研究领域:
神经科学
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药理学
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分子生物学
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细胞生物学
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炎症研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Dan Han,Meihua Wang,Ningyu Dong,Jiaxing Zhang,Dingran Li,Xiaoling Ma,Ying Ma,Siliang Wang,Yun Zhu,Cheng Wang
Lipid nanoparticles (LNPs) hold great promise as carriers for developing drug delivery systems (DDSs) aimed at managing ischemic stroke (IS). Previous research has highlighted the vital role played by the lipid composition and biophysical characteristics of LNPs, influencing their interactions with cells and tissues. This understanding presents an opportunity to engineer LNPs tailored specifically for enhanced IS treatment. We previously introduced the innovative concept of reconstituted lipid nanoparticles (rLNPs), which not only retain the advantages of conventional LNPs but also incorporate lipids from the originating cell or tissue. Brain-derived rLNPs (B-rLNPs) exhibit significantly superior accumulation within the cerebral ischemic region when compared to liver-derived rLNPs (L-rLNPs). The homing effect of B-rLNPs was then employed to construct 3-n-butylphthalide (NBP) loaded DDS (B-rLNPs/NBP) for the treatment of IS. Our results demonstrated that compared with free NBP, B-rLNPs/NBP can significantly reduce infarct volume, neurological deficits, blood-brain barrier (BBB) leakage rate, brain water content, neutrophil infiltration, alleviate pathological structures, and improve the motor function in MCAO/R model. We also proved that B-rLNPs/NBP showed further reinforced protective effects on the same model than free NBP through the regulation of TLR4/MyD88/NF-κB (anti-inflammation) and Bax/Bcl-2 (anti-apoptosis) pathways. This study offers a promising tool towards improved IS treatment.
研究领域:
神经科学
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药学
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生物技术
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纳米技术
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DOI
PubMed
高影响因子
NEUROCHEMISTRY INTERNATIONAL
·
2024
·
IF 4.4
Hong Guo,Yuanwei Dong,Danqing Luo,Meng Gong,Jianfeng Sun,Zhipeng Wu,Zhixiang Liu,Lei Zhong,Song Jin
Neuronal death is the key cause of ischemic stroke. Acupuncture (Acu) is a recognized method for the treatment and amelioration of cerebral ischemia. However, the molecular mechanism of Acu for treating ischemic stroke has not yet been detailedly elucidated. Based our microarray analysis results, mitochondrial ribosomal protein L41 (MRPL41), which is related to apoptosis, was identified as the target of Acu. MRPL41 expression was increased in middle cerebral artery occlusion/reperfusion (MCAO/R) model and reduced after Acu treatment. Following, MCAO/R model and oxygen and glucose deprivation/reoxygenation (OGD/R) model were established to explore the effect of MRPL41. Knockdown of MRPL41 increased cell viability and ani-apoptotic protein (Bcl-2) expression, and reduced apoptosis intensity and pro-apoptotic protein (Bax and Cleaved caspase-3) of OGD/R neurons. In vivo , MRPL41 silencing decreased neurological severity score, shrank infarct area, reduced encephaledema and neuron apoptosis. In addition, reduction of MRPL41 caused loss of p53. Our data uncover that Acu targets MRPL41, following with inhibiting neuron apoptosis via p53 pathway, thereby ameliorating ischemic stroke.
研究领域:
神经科学
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分子生物学
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针灸
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中风研究
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产品关联
DOI
PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2024
·
IF 3.1
Wei Liangli,Yuan Yuqi,Yang Ziteng,Li Yuqing,Wang Tingting,Hu Shenglin,Cai Biao,Wang Guangyun
The neuroprotective function of ginsenoside Rb1 (GRb1) in cerebral ischemia–reperfusion (I/R) was lately emphasized. However, whether GRb1 plays a regulatory role on endoplasmic reticulum (ER) stress-associated pathway in cerebral I/R damage is still unclear. The aim of this study is to explore the function of GRb1 in cerebral ischemia-induced ER stress and the underlying mechanism related to IRE1/TRAF2/JNK pathway. Longa method, cerebral infarct volume, and HE staining were used to evaluate the efficacy of GRb1 in mice with a mouse model of middle cerebral artery occlusion reperfusion (MCAO/R). We also investigated the effect and mechanism of GRb1 against ischemic stroke using in vitro oxygen–glucose deprivation reperfusion (OGD/R) model. We found that GRb1 could improve neurological scores, infarct volume, and histological injury in ischemic mice. Ischemic attack also activated neuronal apoptosis and ER stress, and this effect was attenuated by GRb1. In addition, GRb1 significantly reduced I/R-induced IRE1-TRAF2 interaction, IRE1, and JNK phosphorylation. The present study also confirmed that GRb1 significantly improved OGD/R-induced PC12 cells injury. GRb1 could decrease ER stress in OGD/R-injured PC12 cells, which was reflected by the decreased expression of GRP78 and CHOP. The ER stress inducer tunicamycin partially prevented the effects of GRb1 on cell viability, ER stress, and apoptosis after OGD/R, whereas the ER stress inhibitor 4-PBA exerted the opposite effect. Moreover, GRb1 markedly decreased IRE1-TRAF2 interaction, IRE1, and JNK phosphorylation in the presence of OGD/R insult. Furthermore, JNK inhibitor SP600125 and IRE1 inhibitor DBSA pretreatment further promoted the inhibition of GRb1 on ER stress induction and cell damage induced by OGD/R. Molecular docking further elucidated that the mechanism by which GRb1 improves cerebral ischemia maybe related to its direct binding to the kinase domain of IRE1, which in turn inhibited the phosphorylation of IRE1. Collectively, these results demonstrated that GRb1 reduced ischemic stroke-induced apoptosis through the ER stress-associated IRE1/TRAF2/JNK pathway and GRb1 has the potential as a protective drug for the treatment of cerebral ischemia.
研究领域:
神经科学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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