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
·
药学
·
生物技术
·
纳米技术
✓ 已验证
DOI
PubMed
高影响因子
NEUROSCIENCE
·
2024
·
IF 2.9
Tao Ye,Ning Zhang,Yunting He,Chunyan Chen,Qiqi Zha,Anbang Zhang,Xiuqi Sun,Xuemei Wu
Cerebral ischemia–reperfusion injury is frequently associated with neuroinflammation. The modulation of microglial polarization presents a promising approach for addressing cerebral ischemia–reperfusion injury. While electroacupuncture preconditioning has demonstrated efficacy in the management of ischemic stroke, the underlying therapeutic mechanisms remain inadequately understood. The investigation focused on elucidating the relationship between alterations in the TLR4/NF-κB/TXNIP/NLRP3 signaling pathway and microglial polarization subsequent to EA pretreatment. Established a middle cerebral artery occlusion (MCAO) rat model following electroacupuncture (EA) treatment at the Baihui (GV 20) acupoint. Male Sprague-Dawley rats were randomly assigned to the sham, Ischemia/Reperfusion (I/R), I/R + EA groups (n = 6). The results of Nissl Staining and TUNEL Stainingl showed that the number of curative neurons increased significantly after pretreatment, indicating an improvement in neuron formation and an increase in the number of austenite. The level of apoptosis in brain tissue in the I/R group was significantly higher than that in the sham operation group. Electroacupuncture pretreatment can effectively inhibit apoptosis occurrence. In addition, electric acupuncture pretreatment protects rat blood–brain barrier integrity and mitochondrial function. After treatment, the number of M1-type microglia decreased, while the number of M2-type microglia increased. These results suggest that EA preconditioning may alleviate neurological deficits and neuronal apoptosis caused by cerebral I/R injury, while maintaining the integrity of the blood–brain barrier and promoting microglial polarization through the TLR4/NF-κB/TXNIP/NLRP3 signaling pathway. Our findings establish a new molecular mechanism and theoretical foundation for electroacupuncture therapy of ischemic stroke.
研究领域:
神经科学
·
免疫学
·
药理学
·
中医
✓ 已验证
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
·
分子生物学
·
针灸
·
中风研究
✓ 已验证
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
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2021
·
IF 4.932
Difan Zhang,Yi Feng,Hanbo Pan,Zhenquan Xuan,Sicheng Yan,Yuechun Mao,Xiao Xiao,Xinghan Huang,Hui Zhang,Fei Zhou,Bojun Chen,Xiaowei Chen,Hao Liu,Xiaojun Yan,Hongze Liang,Wei Cui
Objectives This study was aimed to investigate the neuroprotective effects of 9-methylfascaplysin, a novel marine derivative derived from sponge, against middle cerebral artery occlusion/reperfusion (MCAO)-induced motor impairments, neuroinflammation and oxidative stress in rats. Methods Neurological and behavioral tests were used to evaluate behavioral changes. The 2, 3, 5-triphenyltetrazolium chloride staining was used to determine infarct size and edema extent. Activated microglia/macrophage was analyzed by immunohistochemical staining of Iba-1. RT-PCR and ELISA were used to measure the expression of inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1β, CD16 and CD206. Western blotting analysis was performed to explore the activation of nuclear factor-κB (NF-κB) and NLRP3. The levels of oxidative stress were studied by evaluating the activities of superoxide dismutase, catalase and glutathione peroxidase. Results Post-occlusion intracerebroventricular injection of 9-methylfascaplysin significantly attenuated motor impairments and infarct size in MCAO rats. Moreover, 9-methylfascaplysin reduced the activation of microglia/macrophage in ischemic penumbra as evidenced by the decreased Iba-1-positive area and the reduced expression of pro-inflammatory factors. Furthermore, 9-methylfascaplysin inhibited MCAO-induced oxidative stress and activation of NF-κB and NLRP3 inflammasome. Conclusion All the results suggested that 9-methylfascaplysin might produce neuroprotective effects against MCAO via the reduction of oxidative stress and neuroinflammation, simultaneously, possibly via the inhibition of NF-κB and NLRP3 inflammasome.
研究领域:
神经科学
·
药理学
·
神经病学
·
炎症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-15
·
IF 10.435
Guo Lin,Huang Zhixuan,Huang Lijuan,Liang Jia,Wang Peng,Zhao Liang,Shi Yijie
Background The incidence of ischemic stroke in the context of vascular disease is high, and the expression of growth-associated protein-43 (GAP43) increases when neurons are damaged or stimulated, especially in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). Experimental design We bioengineered neuron-targeting exosomes (Exo) conjugated to a monoclonal antibody against GAP43 (mAb GAP43) to promote the targeted delivery of quercetin (Que) to ischemic neurons with high GAP43 expression and investigated the ability of Exo to treat cerebral ischemia by scavenging reactive oxygen species (ROS). Results Our results suggested that Que loaded mAb GAP43 conjugated exosomes (Que/mAb GAP43-Exo) can specifically target damaged neurons through the interaction between Exo-delivered mAb GAP43 and GAP43 expressed in damaged neurons and improve survival of neurons by inhibiting ROS production through the activation of the Nrf2/HO-1 pathway. The brain infarct volume is smaller, and neurological recovery is more markedly improved following Que/mAb GAP43-Exo treatment than following free Que or Que-carrying exosome (Que-Exo) treatment in a rat induced by MCAO/R. Conclusions Que/mAb GAP43-Exo may serve a promising dual targeting and therapeutic drug delivery system for alleviating cerebral ischemia/reperfusion injury.
研究领域:
神经科学
·
药理学
·
分子生物学
·
生物医学工程
✓ 已验证
DOI
高影响因子
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
·
2025
·
IF 5
Yue-Xin Ning,Ji-Ru Cai,Ting-Ting Wang,Yi-Han Wang,Yu Cui,Hui-Sheng Chen
Background Endovascular treatment (EVT) alone was not demonstrated to be non-inferior to intravenous alteplase bridging EVT in acute large vessel occlusion (LVO) stroke. Using cerebral ischemia/reperfusion (I/R) injury model, intravenous tenecteplase (TNK) was administrated after ischemia followed by reperfusion at various time points. Objectives To investigate whether intravenous TNK bridging EVT vs EVT alone could improve I/R injury, and this effect may be associated with the time from TNK to reperfusion. Methods Rats received intravenous TNK (1.4 mg/kg) or vehicle (sterile water) 1.0 hour after middle cerebral artery occlusion (MCAO), followed by reperfusion after 0.5 or 1.0 hour following TNK. Neurological deficit scores, infarct volume, and brain edema were measured at 24 hours after MCAO. Microthrombi were determined by immunofluorescence staining for CD31 + /fibrinogen + and CD31 + /thrombocyte + . Inflammatory cell infiltration in the ischemic brain region was determined by flow cytometry. Results Compared with vehicle, TNK significantly reduced neurological deficit scores, brain infarction, neuro-inflammation, and blood-brain barrier (BBB) disruption, and significantly reduced intravascular fibrin and platelet deposition, and brain inflammatory cell infiltration in penumbra of I/R rats. Furthermore, a better beneficial trend was found in TNK bridging reperfusion at 0.5 hour after TNK compared with TNK bridging reperfusion at 1.0 hour after TNK. Conclusions Our results demonstrate that intravenous TNK bridging reperfusion produced neuroprotective action through dissolving microvascular thrombus and alleviating inflammatory cell infiltration to improve microcirculation, with the result of maintaining BBB integrity and inhibiting neuroinflammation, and the neuroprotective benefit may be associated with the time from TNK to reperfusion.
研究领域:
神经科学
·
药理学
·
实验性卒中研究
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2019
·
IF 3.845
Zhong Zhi-feng,Han Jing,Zhang Ji-Zhou,Xiao Qing,Chen Jing-yan,Zhang Kai,Hu Juan,Chen Li-dian
Salidroside, a phenylpropanoid glycoside, is the main bioactive component of Rhodiola rosea L. Salidroside has prominent anti-stroke effects in cerebral ischemia/reperfusion models. However, the underlying mechanisms of its actions are poorly understood. This study examined the anti-stroke effects of salidroside in middle cerebral artery occlusion (MCAO)-induced rat model of stroke and its potential mechanisms involving the dopaminergic system. Salidroside administration increased the levels of dopamine (DA), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) in the ipsilateral striatum after induction of transient ischemia, which were assessed using microdialysis with high-performance liquid chromatography coupled with electrochemical detection (HPLC-ECD). Furthermore, treatment with salidroside ameliorated neurobehavioral impairment, assessed with the modified neurological severity scores (mNSS), the balance beam test, and the foot fault test. Moreover, enzyme-linked immunosorbent assay (ELISA) suggested that MCAO-induced reduction in monoamine oxidase (MAO) was inhibited by salidroside. Immunohistochemical and immunofluorescence analyses revealed high level of tyrosine hydroxylase (TH) in the ipsilateral striatal caudate putamen (CPu) after cerebral ischemia/reperfusion, which could be further elevated by salidroside. In addition, salidroside could reverse the decreased immunoreactivity of TH in the substantia nigra pars compacta (SNpc). These results suggest that the anti-stroke effects of salidroside in MCAO-induced cerebral ischemia/reperfusion may involve the modulation of monoamine metabolism in the striatum and SNpc, which may be related to the function of the dopaminergic system in the rat brain.
研究领域:
神经科学
·
药理学
·
神经病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CURRENT NEUROVASCULAR RESEARCH
·
2023
·Vol. 20
·期 4
·480-492
·
IF 2.1
Li Xuejing,Wang Ying,Zhou Xiang,Wang Hui,Xu Jiang
Background: Increasing evidence shows that electroacupuncture pretreatment (EP) plays a crucial role in cerebral ischemia-reperfusion (I/R) injury, and cerebral I/R injury is the most serious complication of ischemic stroke treatment. The role of miR-155-5p in cerebral I/R injury has
been studied, but the regulation of EP on miR-155-5p has not been reported.Methods: The middle cerebral artery occlusion (MCAO) mice were used to investigate the role of EP in cerebral I/R injury. Longa and modified neurological severity scores (mNSS) were used to evaluate neurological
impairment. HE staining and TUNEL staining were used to evaluate brain injury. The expressions of miR-155-5p, Yin Yang 1 (YY1) and p53 were detected by qRT-PCR. The expressions of related proteins were detected by western blot. The binding of YY1 to miR- 155-5p was verified by dual-luciferase
reporter assay and chromatin immunoprecipitation (ChIP) assay. Mice brain microvascular endothelial cells (BMECs) were isolated and cultured for in vitro experiments. Oxygen-glucose deprivation/reoxygenation (OGD/R) was used to verify the role of YY1, p53 and miR-155-5p in cerebral I/R injury
in vitro.Results: MCAO modeling induced brain injury, apoptosis, and increased levels of miR-155-5p, YY1, and p53. EP markedly alleviated brain injury and reduced levels of miR-155-5p, p53, and YY1. miR-155 agomir markedly increased the expression of miR-155-5p and p53. miR-155 antagomir
decreased the levels of miR-155-5p and p53. Dual-luciferase reporter and ChIP assay verified that YY1 regulated miR-155-5p expression. YY1 shNRA greatly decreased miR-155-5p and p53. Inhibition of p53 decreased miR-155-5p expression. Both miR-155-5p inhibitor and YY1 shRNA promoted proliferation,
inhibited apoptosis, and decreased levels of ICAM-1 and Eselectin of OGD/R-treated BMECs. Inhibition of p53 strengthened the effect of miR-155-5p inhibitor and YY1 shNRA on BMECs.Conclusion: Electroacupuncture pretreatment alleviates cerebral ischemia-reperfusion injury by regulating the
YY1/p53/miR-155-5p axis.
研究领域:
神经科学
·
分子生物学
·
针灸
·
脑血管疾病
✓ 已验证
DOI
PubMed
高影响因子
Journal of Integrative Neuroscience
·
2024
·Vol. 23
·期 8
·145
·
IF 2.5
Yuan Xu,Yushi Yang,Jie Yang,Junshuan Cui,Jian Yan,Jiannan Jiang,Zhangwei Yan,Hua Yang
Background: Ischemic stroke is mainly caused by cerebral artery thrombosis. This study investigated the role of glycine receptor beta subunit (GlyR-β) in the recovery from cerebral ischemia stroke/reperfusion. Methods: The oxygen glucose deprivation and recovery (OGD/R) bEnd3 cell model and the middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model were used in this study. Results: Expression of both the GlyR-β gene and vascular endothelial growth factor (Vegf), cell proliferation, and tube formation ability was decreased in bEnd3 cells after OGD/R, and was reversed by overexpression of GlyR-β. Neurological function, asindicated by Zea Longa scores, area of cerebral ischemia, and pathological changes were increased in mice after MCAO/R, and were ameliorated by overexpression of the glycine receptor beta (Glrb) gene at 24 h and 7 d after MCAO/R. Expression of GlyR-β and Gap-43 was decreased, and the expression of CD34, Vegf, and Bdnf, and cell growth as determined by a bromodeoxyuridine (BrdU) assay, increased in the affected brain tissue of MCAO/R mice in a time-dependent manner. GlyR-β overexpression resulted in enhanced expression of CD34, Vegf, Growth association protein 43 (Gap-43), and brain-derived neurotrophic factor (Bdnf) and cell growth in affected brain tissue of MCAO/R mice in a time-dependent manner. Conclusions: GlyR-β promoted potential angiogenesis and neurological regeneration in affected brain tissue, thus promoting recovery from cerebral ischemia stroke/reperfusion.
研究领域:
神经科学
·
分子生物学
·
药理学
·
病理生理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）