Redox Biology
·
2023
·
IF 11.4
Tao Jiang,Tao Qin,Peng Gao,Zhiwen Tao,Xiaowei Wang,Mengyuan Wu,Jun Gu,Bo Chu,Ziyang Zheng,Jiang Yi,Tao Xu,Yifan Huang,Hao Liu,Shujie Zhao,Yongxin Ren,Jian Chen,Guoyong Yin
Disruption of the blood-spinal cord barrier (BSCB) leads to inflammatory cell infiltration and neural cell death, thus, contributing to poor functional recovery after spinal cord injury (SCI). Previous studies have suggested that Sirtuin 1 (SIRT1), an NAD + -dependent class III histone deacetylase, is abundantly expressed in endothelial cells and promotes endothelial homeostasis. However, the role of SIRT1 in BSCB function after SCI remains poorly defined. Here, we report that SIRT1 is highly expressed in spinal cord endothelial cells, and its expression significantly decreases after SCI. Using endothelial cell-specific SIRT1 knockout mice, we observed that endothelial cell-specific knockout of SIRT1 aggravated BSCB disruption, thus, resulting in widespread inflammation, neural cell death and poor functional recovery after SCI. In contrast, activation of SIRT1 by the agonist SRT1720 had beneficial effects. In vitro, knockdown of SIRT1 exacerbated IL-1β-induced endothelial barrier disruption in bEnd.3 cells, whereas overexpression of SIRT1 was protective. Using RNA-seq and IP/MS analysis, we identified p66Shc, a redox protein, as the potential target of SIRT1. Further studies demonstrated that SIRT1 interacts with and deacetylates p66Shc, thereby attenuating oxidative stress and protecting endothelial barrier function. Overall, our results indicate that SIRT1 decreases endothelial ROS production and attenuates BSCB disruption by deacetylating p66Shc after SCI, and suggest that SIRT1 activation has potential as a therapeutic approach to promote functional recovery against BSCB disruption following SCI.
研究领域:
神经科学
·
分子生物学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-26
·
IF 14.7
Zhou Kai,Wei Wei,Yang Dan,Zhang Hui,Yang Wei,Zhang Yunpeng,Nie Yingnan,Hao Mingming,Wang Pengcheng,Ruan Hang,Zhang Ting,Wang Shouyan,Liu Yaobo
The neural signals produced by varying electrical stimulation parameters lead to characteristic neural circuit responses. However, the characteristics of neural circuits reconstructed by electrical signals remain poorly understood, which greatly limits the application of such electrical neuromodulation techniques for the treatment of spinal cord injury. Here, we develop a dual electrical stimulation system that combines epidural electrical and muscle stimulation to mimic feedforward and feedback electrical signals in spinal sensorimotor circuits. We demonstrate that a stimulus frequency of 10−20 Hz under dual stimulation conditions is required for structural and functional reconstruction of spinal sensorimotor circuits, which not only activates genes associated with axonal regeneration of motoneurons, but also improves the excitability of spinal neurons. Overall, the results provide insights into neural signal decoding during spinal sensorimotor circuit reconstruction, suggesting that the combination of epidural electrical and muscle stimulation is a promising method for the treatment of spinal cord injury.
研究领域:
神经科学
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康复医学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
FEBS Open Bio
·
2021
·Vol. 11
·期 8
·2118-2126
·
IF 2.693
Na Wei,Tan Lu,Libin Yang,Yonghan Dong,Xiaotan Liu
Ferroptosis is an iron-dependent programmed cell death, which participates in the pathogenesis of spinal cord injury (SCI). Our previous study has revealed that Lipoxin A4 (LXA4) exerts a protective role in SCI. Here, we investigated whether LXA4 can protect SCI through inhibiting neuronal ferroptosis. We treated primary spinal cord neurons with Erastin (ferroptosis activator) to induce ferroptosis. Erastin treatment reduced cell viability and enhanced cell death of primary spinal cord neurons, which was rescued by ferrostatin-1 (ferroptosis inhibitor). Moreover, Erastin repressed glutathione peroxidase 4 (GPX4) expression and the levels of glutathione and cysteine in primary spinal cord neurons. Erastin also enhanced the expression of ferroptosis biomarkers (PTGS2 and ACSL4) and the levels of reactive oxygen species (ROS) in primary spinal cord neurons. The influence conferred by Erastin was effectively abolished by LXA4 treatment. Furthermore, LXA4 enhanced the protein expression of p-AKT, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and haem-oxygenase-1 (HO-1) in primary spinal cord neurons. LXA4-mediated inhibition of ferroptosis of primary spinal cord neurons was prohibited by LY294002 (AKT inhibitor), brusatol (Nrf2 inhibitor) or zinc protoporphyrin (HO-1 inhibitor). In conclusion, this work demonstrated that LXA4 exerted a neuroprotective effect in Erastin-induced ferroptosis of primary spinal cord neurons by activating the Akt / Nrf2 / HO-1 signaling pathway. Thus, this work provides novel insights into the mechanisms of action of LXA4 in ferroptosis of primary spinal cord neurons and indicates that LXA4 may be a potential therapeutic agent for SCI.
研究领域:
神经科学
·
药理学
·
细胞生物学
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神经病学
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产品关联
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2020
·
IF 5.076
Xing Li,Dan Luo,Yu Hou,Yonghui Hou,Shudong Chen,Jiheng Zhan,Jiyao Luan,Le Wang,Dingkun Lin
Spinal cord microcirculation involves functioning endothelial cells at the blood spinal cord barrier (BSCB) and maintains normal functioning of spinal cord neurons, axons, and glial cells. Protection of both the function and integrity of endothelial cells as well as the prevention of BSCB disruption may be a strong strategy for the treatment of spinal cord injury (SCI) cases. Sodium Tanshinone IIA silate (STS) is used for the treatment of coronary heart disease and improves microcirculation. Whether STS exhibits protective effects for SCI microcirculation is not yet clear. The purpose of this study is to investigate the protective effects of STS on oxygen-glucose deprivation- (OGD-) induced injury of spinal cord endothelial cells (SCMECs) in vitro and to explore effects on BSCB and neurovascular protection in vivo. SCMECs were treated with various concentrations of STS (1 μM, 3 μM, and 10 μM) for 24 h with or without OGD-induction. Cell viability, tube formation, migration, and expression of Notch signaling pathway components were evaluated. Histopathological evaluation (H&E), Nissl staining, BSCB permeability, and the expression levels of von Willebrand Factor (vWF), CD31, NeuN, and Notch signaling pathway components were analyzed. STS was found to improve SCMEC functions and reduce inflammatory mediators after OGD. STS also relieved histopathological damage, increased zonula occludens-1 (ZO-1), inhibited BSCB permeability, rescued microvessels, protected motor neuromas, and improved functional recovery in a SCI model. Moreover, we uncovered that the Notch signaling pathway plays an important role during these processes. These results indicated that STS protects microcirculation in SCI, which may be used as a therapeutic strategy for SCI in the future.
研究领域:
神经科学
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药理学
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细胞生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2023
·
IF 7.5
Bo Xu,Jiaqi Fang,Jianguang Wang,Xuehan Jin,Shengfu Liu,Kaihang Song,Ping Wang,Junjian Liu,Shuhao Liu
The disruption of the blood spinal cord barrier (BSCB) after spinal cord injury (SCI) can trigger secondary tissue damage. Edaravone is likely to protect the BSCB as a free radical scavenger, whereas it has been rarely reported thus far. In this study, the protective effect of edaravone was investigated with the use of compression spinal cord injured rats and human brain microvascular endothelial cells (HBMECs) injury. As indicated by the result of this study, edaravone treatment facilitated functional recovery after rats were subjected to SCI, ameliorated the vascular damage, and up-regulated the expression of BSCB-associated proteins. In vitro results, edaravone improved HBMECs viability, restored intercellular junctions, and promoted cellular angiogenic activities. It is noteworthy that autophagy was activated and RIP1/RIP3/MLKL phosphorylation was notably up-regulated. However, edaravone treatment exhibited the capability of mitigating above-mentioned tendency in vivo and in vitro. Moreover, rapamycin (Rapa) treatment deteriorated the protective effect of edaravone while aggravating the phosphorylation of RIP1/RIP3/MLKL expression. In the model of necrotic activator-induced HBMECs, autophagic expression was increased, whereas edaravone prevented autophagy and phosphorylation of RIP1/RIP3/MLKL. In general, our results suggested that edaravone is capable of reducing the destruction of BSCB and promoting functional recovery after SCI. The possible underlying mechanism is that edaravone is capable of protecting angiogenic activity and improving autophagy and the phosphorylation of RIP1/RIP3/MLKL, as well as their mutual deterioration. Accordingly, edaravone can be a favorable option for the treatment of SCI.
研究领域:
神经科学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Bioengineering & Translational Medicine
·
2023
·
IF 7.4
Jiawei Shu,Chenggui Wang,Yiqing Tao,Shaoke Wang,Feng Cheng,Yuang Zhang,Kesi Shi,Kaishun Xia,Ronghao Wang,Jingkai Wang,Chao Yu,Jiangjie Chen,Xianpeng Huang,Haibin Xu,Xiaopeng Zhou,Haobo Wu,Chengzhen Liang,Qixin Chen,Shigui Yan,Fangcai Li
Spinal cord injury (SCI) causes blood-spinal cord barrier (BSCB) disruption, leading to secondary damage, such as hemorrhagic infiltration, inflammatory response, and neuronal cell death. It is of great significance to rebuild the BSCB at the early stage of SCI to alleviate the secondary injury for better prognosis. Yet, current research involved in the reconstruction of BSCB is insufficient. Accordingly, we provide a thermosensitive hydrogel-based G protein-coupled receptor 124 (GPR124) delivery strategy for rebuilding BSCB. Herein, we firstly found that the expression of GPR124 decreased post-SCI and demonstrated that treatment with recombinant GPR124 could partially alleviate the disruption of BSCB post-SCI by restoring tight junctions (TJs) and promoting migration and tube formation of endothelial cells. Interestingly, GPR124 could also boost the energy metabolism of endothelial cells. However, the absence of physicochemical stability restricted the wide usage of GPR124. Hence, we fabricated a thermosensitive heparin-poloxamer (HP) hydrogel that demonstrated sustained GPR124 production and maintained the bioactivity of GPR124 (HP@124) for rebuilding the BSCB and eventually enhancing functional motor recovery post-SCI. HP@124 hydrogel can encapsulate GPR124 at the lesion site by injection, providing prolonged release, preserving wounded tissues, and filling injured tissue cavities. Consequently, it induces synergistically efficient integrated regulation by blocking BSCB rupture, decreasing fibrotic scar formation, minimizing inflammatory response, boosting remyelination, and regenerating axons. Mechanistically, giving GPR124 activates energy metabolism via elevating the expression of phosphoenolpyruvate carboxykinase 2 (PCK2), and eventually restores the poor state of endothelial cells. This research demonstrated that early intervention by combining GPR124 with bioactive multifunctional hydrogel may have tremendous promise for restoring locomotor recovery in patients with central nervous system disorders, in addition to a translational approach for the medical therapy of SCI.
研究领域:
神经科学
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生物医学工程
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药学
·
再生医学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2023
·
IF 4.6
Yingqiao Li,Zhiru Zou,Jinyu An,Xiaoyao Liu,Qian Wu,Junpeng Sun,Xiaobang Liu,Jiaqun Du,Ying Xiong,Chao Wu,Xifan Mei,He Tian
Spinal cord injury (SCI) is a central system disease with a high rate of disability. Pathological changes such as ischemia and hypoxia of local tissues, oxidative stress and apoptosis could lead to limb pain, paralysis and even life-threatening. It was reported that catalase (CAT) was the main antioxidant in organisms, which could remove reactive oxygen species (ROS) and release oxygen (O 2 ). However, the efficacy of the drug is largely limited due to its poor stability, low bioavailability and inability to cross the blood spinal cord barrier (BSCB). Therefore, in this study, we prepared folic acid-functionalized chitosan nanoparticles to deliver CAT (FA-CSN CAT) for solving this problem. In vivo small animal imaging results showed that FA-CSN could carry CAT across the BSCB and target to the inflammatory site. In addition, Immunofluorescence, ROS assay and JC-1 probe were used to detect the therapeutic effect of FA-CSN CAT in vitro and in vivo. The results showed that FA-CSN CAT could alleviate the hypoxic environment at the injured site and remove ROS, thereby inhibiting oxidative stress and protecting neurons, which may provide a new idea for clinical medication of SCI.
研究领域:
神经科学
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纳米技术
·
药学
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL NEUROLOGY
·
2023
·
IF 5.3
Qian Wang,Jiang Yi,Hao Liu,Mingran Luo,Guoyong Yin,Zhenfei Huang
Destruction of the blood-spinal cord barrier (BSCB) after spinal cord injury (SCI) is an important factor promoting the progression of the injury. This study addressed how to repair the BSCB in order to promote the repair of injured spinal cords. Iguratimod (IGU), an anti-rheumatic drug, has been approved for clinical use. A spinal cord injury mouse model and TNF-α-stimulated bEnd.3 cells were used to investigate the effect and mechanism of IGU on injured BSCB. An intracerebroventricular osmotic pump was used to administer drugs to the SCI mouse model. The results showed that the SCI mice in the treatment group had better recovery of neurological function than the control group. Examination of the tissue revealed better repair of the BSCB in injured spinal cords after medication. According to the results from the cell model, IGU promoted the expression of tight junction proteins and reduced cell permeability. Further research found that IGU repaired the barrier function by regulating glycolysis levels in the injured endothelial cells. In studying the mechanism, IGU was found to regulate HIF-1α expression through the NF-κB pathway, thereby regulating the expression of the glycolytic enzymes related to endothelial injury. In summary, IGU promoted functional recovery in vivo by repairing the BSCB. In vitro, IGU regulated the level of glycolysis in the damaged endothelium through the NF-κB pathway, thereby repairing the tight junctions between the endothelium. Therefore, IGU may become a potential drug for treating spinal cord injury.
研究领域:
神经科学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
·
2022
·
IF 6.819
Yingqiao Li,Zhiru Zou,Jinyu An,Qian Wu,Le Tong,Xifan Mei,He Tian,Chao Wu
Spinal cord injury (SCI) is a serious central nervous system disease, and secondary injury, including oxidative stress, the inflammatory response and accompanying neuronal apoptosis, will aggravate the condition. Due to the existence of the blood–spinal cord barrier (BSCB), the existing drugs for SCI treatment are difficulty to reach the injury site and thus their efficacy is limited. In this study, we designed chitosan-modified hollow manganese dioxide nanoparticles (CM) for the delivery of resveratrol to help it pass through the BSCB. Resveratrol (Res), a poorly soluble drug, was adsorbed into CM with a particle size of approximately 130 nm via the adsorption method, and the drug loading reached 21.39 ± 2.53%. In vitro dissolution experiment, the Res release of the loaded sample (CMR) showed slowly release behavior and reached about 87% at 36 h. In vitro at the cellular level and in vivo at the animal level experiments demonstrated that CMR could alleviate significantly oxidative stress by reducing level of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and increasing glutathione peroxidase (GSH) level. Additionally, immunofluorescence (iNOS, IL-1β, and Cl caspase-3) and western blot (iNOS, cox-2, IL-1β, IL-10, Cl caspase-3, bax, and bcl-2) were used to detect the expression of related factors, which verified that CMR could also reduce inflammation and neuronal apoptosis. These results indicated that CM, as a potential central nervous system drug delivery material, was suitable for SCI treatment.
研究领域:
纳米医学
·
神经科学
·
药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Toxicology Research
·
2025
·Vol. 14
·期 2
·
IF 2.1
Fu Dan,Li Ziyou,Feng Huafeng,Fan Fangling,Zhang Wang,He Liang
Spinal cord injury (SCI)-induced ischemic delayed paralysis is one of the most serious side effects of aneurysms surgeries. Recent studies prove that the activation of autophagy, including macroautophagy and micro-autophagy pathways, occur during SCI-induced brain neuron damage. However, the role of chaperone mediated autophagy (CMA) during SCI remains to be unveiled. In the present work, rat model of delayed paralysis after aneurysms operation and adenovrius induced LAMP2A knockdown in microglia cells were applied in the present work to investigate the involvement of LAMP2A-mediated CMA in the aneurysm operation related SCI and delayed paralysis. The results showed that LAMP2A was upregulated in the SCI procedure, and contributed to neuron death and pro-inflammation perturbation via inducing iNOS+ polarization in microgila. We additionally observed that knockdown of LAMP2A resulted in the shift of microglia from iNOS+ to ARG1+ phenotype, as well as alleviated neuron damage during SCI. Furthermore, the analysis of BBB score, the result of immunohistological staining, and protein detection confirmed the activation of LAMP2A-mediated CMA activation and its interaction with NF-κB signaling, which leads to neuron death and motor function loss. These results prove that LAMP2A-mediated CMA contributes to the upregulation of pro-inflammatory cytokines and results in cell death in neurons during ischemic delayed paralysis via activating NF-κB signaling. Inhibition of LAMP2A promotes neurons survival during ischemic delayed paralysis.
研究领域:
神经科学
·
分子生物学
·
医学
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2021
·
IF 7.348
Xue Jiang,Xiaoyao Liu,Qi Yu,Wenwen Shen,Xifan Mei,He Tian,Chao Wu
Spinal cord injury (SCI) causes secondary injury, accompanied by pathological changes such as oxidative stress, inflammation and neuronal apoptosis. This leads to permanent disabilities such as paralysis and loss of movement or sensation. Due to the ineffectiveness of drugs passing through the blood spinal cord barrier (BSCB), there is currently no effective treatment for SCI. The aim of this experiment was to design plasma complex component functionalized manganese-doped silica nanoparticles (PMMSN) with a redox response as a targeted drug carrier for resveratrol (RES), which effectively transports insoluble drugs to cross the BSCB. RES was adsorbed into PMMSN with a particle size of approximately 110 nm by the adsorption method, and the drug loading reached 32.61 ± 3.38%. The RES release results for the loaded sample (PMMSN-RES) showed that the PMMSN-RES exhibited a release slowly effect. In vitro and vivo experiments demonstrated that PMMSN-RES decreased reactive oxygen species (ROS) and malondialdehyde (MDA), increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, reduced the expression of inflammatory (TNF-α, IL-1β and IL-6) and apoptotic cytokines (cleaved caspase-3) in spinal cord tissue after SCI. In summary, PMMSN-RES may be a potential pharmaceutical preparation for the treatment of SCI by reducing neuronal apoptosis and inhibiting inflammation caused by reducing oxidative stress to promote the recovery of mouse motor function.
研究领域:
纳米技术
·
神经科学
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2023
·
IF 9.7
Wang Xin,Zhang Baokun,Chen Zhiheng,Shi Qiang,Yang Erzhu,Xu Jianguang,Lian Xiaofeng
After spinal cord injury (SCI), blood–spinal cord barrier (BSCB) disruption and hemorrhage lead to blood cell infiltration and progressive secondary injuries. Therefore, early restoration of the BSCB represents a key step in the treatment of SCI. Bazedoxifene (BZA), a third-generation estrogen receptor modulator, has recently been reported to inhibit inflammation and alleviate blood–brain barrier disruption caused by traumatic brain injury, attracting great interest in the field of central nervous system injury and repair. However, whether BZA can attenuate BSCB disruption and contribute to SCI repair remains unknown. Here, we developed a new type of biomaterial carrier and constructed a BZA-loaded HSPT (hyaluronic acid (HA), sodium alginate (SA), polyvinyl alcohol (PVA), tetramethylpropane (TPA) material construction) ( [email protected] ) system to effectively deliver BZA to the site of SCI. We found that [email protected] could significantly reduce inflammation in the spinal cord in SCI rats and attenuate BSCB disruption by providing covering scaffold, inhibiting oxidative stress , and upregulating tight junction proteins, which was mediated by regulation of the NF-κB/MMP signaling pathway . Importantly, functional assessment showed the evident improvement of behavioral functions in the [email protected] SCI rats. These results indicated that [email protected] can attenuate BSCB disruption via the NF-κB pathway after SCI, shedding light on its potential therapeutic benefit for SCI. Statement of significance After spinal cord injury, blood–spinal cord barrier disruption and hemorrhage lead to blood cell infiltration and progressive secondary injuries. Bazedoxifene has recently been reported to inhibit inflammation and alleviate blood–brain barrier disruption caused by traumatic brain injury. However, whether BZA can attenuate BSCB disruption and contribute to SCI repair remains unknown. In this study, we developed a new type of biomaterial carrier and constructed a bazedoxifene-loaded HSPT ( [email protected] ) system to efficiently treat SCI. [email protected] could provide protective coverage, inhibit oxidative stress, and upregulate tight junction proteins through NF-κB/MMP pathway both in vivo and in vitro , therefore attenuating BSCB disruption. Our study fills the application gap of biomaterials in BSCB restoration.
研究领域:
神经科学
·
药理学
·
生物材料
·
创伤医学
✓ 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）