bFGF Protects Against Blood-Brain Barrier Damage Through Junction Protein Regulation via PI3K-Akt-Rac1 Pathway Following Traumatic Brain Injury

Wang, Zhouguang; Cheng, Yi; Yu, Xiang; Ye, Li-Bing; Xia, Qing-Hai; Johnson, Noah R.; Wei, Xiaojie; Chen, Daqing; Cao, Guodong; Fu, Xiaobing; Li, Xiaokun; Zhang, Hongyu; Xiao, Jian

doi:10.1007/s12035-015-9583-6

Cited by 116 publications

(86 citation statements)

References 39 publications

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“…Animal care and all animal experiments conformed to the Guide for the Care and Use of Laboratory Animals provided by U.S. National Institutes of Health and were approved by the Animal Care and Use Committee of Wenzhou Medical College, China. The controlled cortical impact (CCI) mouse traumatic brain injury (TBI) model was constructed by surgical procedures as previously described . Briefly, C57BL/6J (20–25 g) mice were anesthetized with 4% choral hydrate (10 mL kg −1 intraperitoneally [IP]) and surgery was performed under aseptic conditions and mounted in a stereotaxic system (Benchmark Deluxe; MyNeurolab, St Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

“…A dose of 500 µg kg −1 FGF2 C78S/C96S , PEG‐FGF2 C78 , and PEG‐FGF2 C96 was administrated intranasally 1 h before TBI induction in the TBI+FGF2 C78S/C96S , TBI+PEG‐FGF2 C78 , and TBI+PEG‐FGF2 C96 groups, respectively. The dosage and mode of administration were selected based on a previous report …”

Section: Methodsmentioning

confidence: 99%

“…For analysis of cerebrovascular permeability after TBI, Evans blue (EB) extravasation assays were performed 24 h after TBI, as previously described . Briefly, five mice were selected from each group and were injected IP with 250 mL of 2% EB.…”

Section: Methodsmentioning

confidence: 99%

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Structure‐Based Site‐Specific PEGylation of Fibroblast Growth Factor 2 Facilitates Rational Selection of Conjugate Sites

Zhao

et al. 2019

Biotechnology Journal

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Polyethylene glycol modification (PEGylation) can enhance the pharmacokinetic properties of therapeutic proteins by the attachment of polyethylene glycol (PEG) to the surface of a protein to shield the protein surface from proteolytic degradation and limit aggregation. However, current PEGylation strategies often reduce biological activity, potentially as a result of steric hindrance of PEG. Overall, there are no structure-based guidelines for selection of conjugate sites that retain optimal biological activity with improved pharmacokinetic properties. In this study, site-specific PEGylation based on the FGF2-FGFR1-heparin complex structure is performed. The effects of the conjugate sites on protein function are investigated by measuring the receptor/heparin binding affinities of the modified proteins and performing assays to measure cell-based bio-activity and in vivo stability. Comprehensive analysis of these data demonstrates that PEGylation of FGF2 that avoids the binding sites for fibroblast growth factor receptor 1 (FGFR1) and heparin provides optimal pharmacokinetic enhancement with minimal losses to biological activity. Animal experiments demonstrate that PEGylated FGF2 exhibits greater efficacy in protecting against traumatic brain injury-induced brain damage and neurological functions than the non-modified FGF2. This rational structure-based PEGylation strategy for protein modification is expected to have a major impact in the area of protein-based therapeutics.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Structure‐Based Site‐Specific PEGylation of Fibroblast Growth Factor 2 Facilitates Rational Selection of Conjugate Sites

Zhao

et al. 2019

Biotechnology Journal

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“…31 BBB breakdown occurs within hours or days after TBI accompanying with oedema, neuroinflammation and cell death. 33 Dl-NBP is widely used to treat for ischaemic stroke patients. 33 Dl-NBP is widely used to treat for ischaemic stroke patients.…”

Section: Discussionmentioning

confidence: 99%

Dl‐3n‐butylphthalide improves traumatic brain injury recovery via inhibiting autophagy‐induced blood‐brain barrier disruption and cell apoptosis

et al. 2019

J Cellular Molecular Medi

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Blood-brain barrier (BBB) disruption and neuronal apoptosis are important pathophysiological processes after traumatic brain injury (TBI). In clinical stroke, Dl-3nbutylphthalide (Dl-NBP) has a neuroprotective effect with anti-inflammatory, anti-oxidative, anti-apoptotic and mitochondrion-protective functions. However, the effect and molecular mechanism of Dl-NBP for TBI need to be further investigated.Here, we had used an animal model of TBI and SH-SY5Y/human brain microvascular endothelial cells to explore it. We found that Dl-NBP administration exerts a neuroprotective effect in TBI/OGD and BBB disorder, which up-regulates the expression of tight junction proteins and promotes neuronal survival via inhibiting mitochondrial apoptosis. The expressions of autophagy-related proteins, including ATG7, Beclin1 and LC3II, were significantly increased after TBI/OGD, and which were reversed by Dl-NBP treatment both in vivo and in vitro. Moreover, rapamycin treatment had abolished the effect of Dl-NBP for TBI recovery. Collectively, our current studies indicate that Dl-NBP treatment improved locomotor functional recovery after TBI by inhibiting the activation of autophagy and consequently blocking the junction protein loss and neuronal apoptosis. Dl-NBP, as an anti-inflammatory and anti-oxidative drug, may act as an effective strategy for TBI recovery.Fangfang Wu and Ke Xu contributed equally to this work. | 1221WU et al.

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“…One common component in several shear-mediated signaling pathways involves the activation of small GTPases8, 15. One small GTPase in particular, RhoA, is also implicated as a regulator of BBB integrity16- 19. Previous studies have demonstrated that increased RhoA activity leads to a disassembly of the complexes within cell-cell junctions and subsequent barrier disruption8, 20, 21. Another small GTPase, Rac1, has been associated with stabilization of the BBB22, 23, and recent studies have also identified Rac1 activation as a downstream response to fluid shear stress12. Therefore, this study investigates the effect of shear stress on the activity of both RhoA and Rac1 to gain insight into their role in shear-mediated barrier integrity.…”

Section: Introductionmentioning

confidence: 99%

CD44 regulates blood-brain barrier integrity in response to fluid shear stress

Fan

et al. 2020

Preprint

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Fluid shear stress is an important mediator of vascular permeability, yet the molecular mechanisms underlying the response of the blood-brain barrier to shear have yet to be studied in cerebral vasculature despite its importance for brain homeostasis. The goal of this study is to probe components of shear mechanotransduction within the blood-brain barrier to gain a better understanding of pathologies associated with changes in cerebral blood flow including ischemic stroke.Interrogating the effects of shear stress in vivo is complicated by the complexity of factors in the brain parenchyma and the difficulty associated with modulating blood flow regimes.Recent advances in the ability to mimic the in vivo microenvironment using three-dimensional in vitro models provide a controlled setting to study the response of the blood-brain barrier to shear stress. The in vitro model used in this study is compatible with real-time measurement of barrier function using transendothelial electrical resistance as well as immunocytochemistry and dextran permeability assays. These experiments reveal that there is a threshold level of shear stress required for barrier formation and that the composition of the extracellular matrix, specifically the presence of hyaluronan, dictates the flow response. Gene editing to modulate the expression of CD44, a receptor for hyaluronan that previous studies have identified to be mechanosensitive, demonstrates that the receptor is required for the endothelial response to shear stress.Manipulation of small GTPase activity reveals CD44 activates Rac1 while inhibiting RhoA activation. Additionally, adducin-γ localizes to tight junctions in response to shear stress and RhoA inhibition and is required to maintain the barrier. This study identifies specific components of the mechanosensing complex associated with the blood-brain barrier response to fluid shear stress, and therefore illuminates potential targets for barrier manipulation in vivo.

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bFGF Protects Against Blood-Brain Barrier Damage Through Junction Protein Regulation via PI3K-Akt-Rac1 Pathway Following Traumatic Brain Injury

Cited by 116 publications

References 39 publications

Structure‐Based Site‐Specific PEGylation of Fibroblast Growth Factor 2 Facilitates Rational Selection of Conjugate Sites

Structure‐Based Site‐Specific PEGylation of Fibroblast Growth Factor 2 Facilitates Rational Selection of Conjugate Sites

Dl‐3n‐butylphthalide improves traumatic brain injury recovery via inhibiting autophagy‐induced blood‐brain barrier disruption and cell apoptosis

CD44 regulates blood-brain barrier integrity in response to fluid shear stress

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