Person: Wang, Xiaoying
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Wang
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Xiaoying
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Wang, Xiaoying
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Publication Thrombospondin-1 Gene Deficiency Worsens the Neurological Outcomes of Traumatic Brain Injury in Mice(Ivyspring International Publisher, 2017) Cheng, Chongjie; Yu, Zhanyang; Zhao, Song; Liao, Zhengbu; Xing, Changhong; Jiang, Yinghua; Yang, Yong-Guang; Whalen, Michael; Lo, Eng; Sun, Xiaochuan; Wang, XiaoyingBackground: Thrombospondin-1 (TSP-1) is an extracellular matrix protein that plays multiple physiological and pathophysiological roles in the brain. Experimental reports suggest that TSP-1 may have an adverse role in neuronal function recovery under certain injury conditions. However, the roles of TSP-1 in traumatic brain injury (TBI) have not been elucidated. In this study we for the first time investigated the roles of TSP-1 in a controlled cortical impact (CCI) model of TBI in TSP-1 knockout (TSP-1 KO) and wild type (WT) mice. Methods: We examined blood brain-barrier (BBB) damage using at 1 day post-TBI by measuring Evans Blue leakage, and neurological functional recovery at 3 weeks post-TBI by measuring neurological severity score (NSS), wire gripping, corner test and Morris Water Maze (MWM). Mechanistically, we quantified pro-angiogenic biomarkers including cerebral vessel density, vascular endothelial growth factors (VEGF) and angiopoietin-1 (Ang-1) protein expression, synaptic biomarker synaptophysin, and synaptogenesis marker brain-derived neurotrophic factor (BDNF) protein expression in contralateral and ipsilateral (peri-lesion) cortex at 21 days after TBI using immunohistochemistry and Western Blot. Results: TSP-1 is upregulated at early phase of TBI in WT mice. Compared to WT mice, TSP-1 KO (1) significantly worsened TBI-induced BBB leakage at 1 day after TBI; (2) had similar lesion size as WT mice at 3 weeks after TBI; (3) exhibited a significantly worse neurological deficits in motor and cognitive functions; (4) had no significant difference in cerebral vessel density, but significant increase of VEGF and Ang-1 protein expressions in peri-lesion cortex; (5) significantly increased BDNF but not synaptophysin protein level in peri-lesion cortex compared to sham, but both synaptophysin and BDNF expressions were significantly decreased in contralateral cortex compared to WT. Conclusion: Our results suggest that TSP-1 may be beneficial for maintaining BBB integrity in the early phase and functional recovery in late phase after TBI. The molecular mechanisms of TSP-1 in early BBB pathophysiology, and long-term neurological function recovery after TBI need to be further investigated.Publication Progression of White Matter Hyperintensities Contributes to Lacunar Infarction(JKL International LLC, 2018) Xu, Xin; Gao, Yuanyuan; Liu, Renyuan; Qian, Lai; Chen, Yan; Wang, Xiaoying; Xu, YunBoth white matter hyperintensities (WMHs) and lacunar infarctions (LIs) are magnetic resonance imaging (MRI) markers of cerebral small vessel disease (SVD). However, the association between WMH and LI remains unclear. In this study, we asked whether WMH progression is related to LI occurrence using retrospective data. Overall, 8475 WMH patients with at least two MRI images were screened, and 187 patients were included in the final study; 76 patients had WMH with LI (WL), and 111 patients had WMH without LI (WOL). The 187 patients were divided into three groups according to WMH progression: Group 1 (no progression), Group 2 (0-53.64% WMH progression) and Group 3 (≥53.64% WMH progression). We found that both WMH volumes and Fazekas scores were higher in WL patients compared with those in WOL patients according to the 1st and 2nd MRI images (P<0.001), whereas WMH progression was not significantly different between these two groups (P>0.05). Importantly, we found that the occurrence rates for LI were increased in Groups 2 and 3 compared with those in Group 1. Multiple logistic regression analysis demonstrated that the risk of LI occurrence was significantly increased in Group 2 versus that in Group 1 (odds ratio, 3.36; 95% CI, 1.48 to 7.67; P=0.004) after adjusting for the baseline patient characteristics and the interval between the two MRI scans. Additionally, with a stratification time of less than 24 months, the risk of LI occurrence was higher in Group 2 versus that in Group 1, after adjusting for baseline confounding factors (odds ratio, 3.68; 95% CI, 1.51 to 8.99; P=0.004). In conclusion, we found that WMH progression was significantly associated with LI occurrence, particularly within the first two years, and that this progression could serve as an independent indicator of LI development.Publication TNFAIP1 contributes to the neurotoxicity induced by Aβ25–35 in Neuro2a cells(BioMed Central, 2016) Liu, Ning; Yu, Zhanyang; Xun, Yu; Li, Miaomiao; Peng, Xiaoning; Xiao, Ye; Hu, Xiang; Sun, Yi; Yang, Manjun; Gan, Shiquan; Yuan, Shishan; Wang, Xiaoying; Xiang, Shuanglin; Zhang, JianBackground: Amyloid-beta (Aβ) accumulation is a hallmark of Alzheimer’s disease (AD) that can lead to neuronal dysfunction and apoptosis. Tumor necrosis factor, alpha-induced protein 1 (TNFAIP1) is an apoptotic protein that was robustly induced in the transgenic C. elegans AD brains. However, the roles of TNFAIP1 in AD have not been investigated. Results: We found TNFAIP1 protein and mRNA levels were dramatically elevated in primary mouse cortical neurons and Neuro2a (N2a) cells exposed to Aβ25–35. Knockdown and overexpression of TNFAIP1 significantly attenuated and exacerbated Aβ25–35-induced neurotoxicity in N2a cells, respectively. Further studies showed that TNFAIP1 knockdown significantly blocked Aβ25–35-induced cleaved caspase 3, whereas TNFAIP1 overexpression enhanced Aβ25–35-induced cleaved caspase 3, suggesting that TNFAIP1 plays an important role in Aβ25–35-induced neuronal apoptosis. Moreover, we observed that TNFAIP1 was capable of inhibiting the levels of phosphorylated Akt and CREB, and also anti-apoptotic protein Bcl-2. TNFAIP1 overexpression enhanced the inhibitory effect of Aβ25–35 on the levels of p-CREB and Bcl-2, while TNFAIP1 knockdown reversed Aβ25–35-induced attenuation in the levels of p-CREB and Bcl-2. Conclusion: These results suggested that TNFAIP1 contributes to Aβ25–35-induced neurotoxicity by attenuating Akt/CREB signaling pathway, and Bcl-2 expression.Publication Reduced Microvascular Volume and Hemispherically Deficient Vasoreactivity to Hypercapnia in Acute Ischemia: MRI Study using Perm(Nature Publishing Group, 2015-02-18) Kim, Young; Suh, Ji-Yeon; Shim, Woo Hyun; Fan, Xiang; Kwon, Sean Joo; Kim, JJ; Dai, George; Wang, Xiaoying; Cho, Gyunggoo; Wang, XiaoyingVasoreactivity to hypercapnia has been used for assessing cerebrovascular tone and control altered by ischemic stroke. Despite the high prognostic potential, traits of hypercapnia-induced hemodynamic changes have not been fully characterized in relation with baseline vascular states and brain tissue damage. To monitor cerebrovascular responses, T2- and T2*-weighted MRI images were acquired alternatively using spin- and gradient-echo EPI (GESE EPI) sequence with 5% CO2 gas inhalation in normal (n=5) and acute stroke rats (n=10). Dynamic relative changes in cerebrovascular volume (CBV), microvascular volume (MVV) and vascular size index (VSI) were assessed from regions of interest (ROIs) delineated by the percent decrease of apparent diffusion coefficient (ADC). The baseline CBV was not affected by MCAO whereas the baseline MVV in ischemic areas were significantly lower than that in the rest of the brain and correlated with ADC. Vasoreactivity to hypercapnic challenge was considerably attenuated in the entire ipsilesional hemisphere including normal ADC regions, in which unsolicited, spreading depression-associated increases of CBV and MVV were observed. The lesion-dependent inhomogeneity in baseline MVV indicates the effective perfusion reserve for accurately delineating the true ischemic damage while the cascade of 4 neuronal depolarization is probably responsible for the hemispherically lateralized changes in overall neurovascular physiologyPublication Association of increased Treg and Th17 with pathogenesis of moyamoya disease(Nature Publishing Group UK, 2017) Weng, Leihua; Cao, Xiang; Han, Lijuan; Zhao, Haoran; Qiu, Shuwei; Yan, Yaping; Wang, Xiaoying; Chen, Xiangyan; Zheng, Weihong; Xu, Xin; Gao, Yuanyuan; Chen, Yan; Li, Jie; Yang, Yongbo; Xu, YunImmuno-inflammation has been shown to play a pivotal role in the pathogenesis of moyamoya disease (MMD). However, how did circulating Treg/Th17 cells involve in MMD patients remains unclear. 26 MMD, 21 atherothrombotic stroke, and 32 healthy controls were enrolled in this study. MMD patients have a significantly higher percentage of circulating Treg and Th17 cells as well as their dominantly secreting cytokines than other groups (P < 0.0001), whereas no difference was found in the ratio of Treg/Th17 between patients in MMD and atherothrombotic stroke group or control subjects (P = 0.244). However, the increased Treg in MMD patients which were enriched with FrIII Treg cells had deficient suppressive functions (P = 0.0017) compared to healthy volunteers. There was a positive correlation between Treg or TGF-β and MMD Suzuki’s stage. And the level of circulating Treg was as an independent factor associated with MMD stage. Besides, TGF-β was also correlated with the increased expression of VEGF in MMD patients. Our findings indicated an important involvement of circulating Treg in the pathogenic development of MMD and TGF-β in Treg induced VEGF.Publication Characteristics of primary rat microglia isolated from mixed cultures using two different methods(BioMed Central, 2017) Lin, Li; Desai, Rakhi; Wang, Xiaoying; Lo, Eng; Xing, ChanghongBackground: Microglial cultures comprise a critically important model system for investigating inflammatory mechanisms in almost all CNS disorders. Mild trypsinization and shaking are the two most commonly used methods to isolate primary microglia from mixed glial cultures. In this study, we characterized and compared microglia obtained using these two methods. Methods: Primary rat microglia cultures were prepared from cerebral cortices of 1–2-day-old neonatal Sprague-Dawley rats. After achieving confluency at about 14 days in vitro, microglia were isolated from mixed glial cultures via either mild trypsinization or shaking. The purity of microglia was estimated by flow cytometry. Quantitative real-time PCR was used to measure mRNA expression. TNFα, IL-1β, IL-10, and IGF-1 in cell culture supernatant were measured using ELISA kits. Phagocytic function was assessed using fluorescein-labeled Escherichia coli K-12 BioParticles. Results: Mild trypsinization generated a higher yield and purity than shaking. Microglia isolated by mild trypsinization appeared to be in a quiescent state with ramified morphology. Microglia isolated by shaking showed a more heterogenous morphology, including cells with rounded shapes suggestive of activation. Compared with shaking, microglia isolated by trypsinization also had lower baseline phenotype markers (iNOS, CD86, CD206, and arginase 1) and lower levels of cytokines (TNFα, IL-1β, IL-10, and IGF-1) as well as reduced phagocytic capability. Both methods yielded microglia that were responsive to various stimuli such as IL-4, lipopolysaccharide (LPS), or interferon-γ (IFNγ). Although stimulated patterns of gene expression and cytokine release were generally similar, there were also significant differences in terms of absolute response. LPS treatment induced significantly higher levels of TNFα and IL-10 in microglia isolated by mild trypsinization versus shaking. IFNγ induced a lower response in TNFα in microglia obtained by mild trypsinization versus shaking. Conclusions: Our results suggest that isolating microglia with the shaking method may induce slight activation even at baseline, and this may affect stimulus responses in subsequent experiments. Caution and attention should be warranted when choosing isolation protocols for primary microglia cultures.Publication Combination Low-Dose Tissue-Type Plasminogen Activator Plus Annexin A2 for Improving Thrombolytic Stroke Therapy(Frontiers Media S.A., 2015) Jiang, Yinghua; Fan, Xiang; Yu, Zhanyang; Liao, Zhengbu; Wang, Xiao-Shu; van Leyen, Klaus; Sun, Xiaochuan; Lo, Eng; Wang, XiaoyingRisk of hemorrhagic transformation, incomplete reperfusion, neurotoxicity, and a short treatment time window comprises major challenges for tissue plasminogen activator (tPA) thrombolytic stroke therapy. Improving tPA therapy has become one of the highest priorities in the stroke field. This mini review article focuses on our recent efforts aimed at evaluating a novel combination approach of low-dose tPA plus recombinant annexin A2 (rA2, a tPA, and plasminogen co-receptor), which might enhance tPA thrombolytic efficacy, while reducing its associated complications related to intracerebral hemorrhagic transformation. Results of our experimental studies using a focal embolic stroke model in rats support the feasibility of the combination approach and suggest the potential for successful clinical translation.Publication Intravenous tPA Therapy Does Not Worsen Acute Intracerebral Hemorrhage in Mice(Public Library of Science, 2013) Foerch, Christian; Rosidi, Nathanael L.; Schlunk, Frieder; Lauer, Arne; Cianchetti, Flor A.; Mandeville, Emiri; Arai, Ken; Yigitkanli, Kazim; Fan, Xiang; Wang, Xiaoying; van Leyen, Klaus; Steinmetz, Helmuth; Schaffer, Chris B.; Lo, EngTissue plasminogen activator (tPA) is the only FDA-approved treatment for reperfusing ischemic strokes. But widespread use of tPA is still limited by fears of inadvertently administering tPA in patients with intracerebral hemorrhage (ICH). Surprisingly, however, the assumption that tPA will worsen ICH has never been biologically tested. Here, we assessed the effects of tPA in two models of ICH. In a mouse model of collagenase-induced ICH, hemorrhage volumes and neurological deficits after 24 hrs were similar in saline controls and tPA-treated mice, whereas heparin-treated mice had 3-fold larger hematomas. In a model of laser-induced vessel rupture, tPA also did not worsen hemorrhage volumes, while heparin did. tPA is known to worsen neurovascular injury by amplifying matrix metalloproteinases during cerebral ischemia. In contrast, tPA did not upregulate matrix metalloproteinases in our mouse ICH models. In summary, our experimental data do not support the assumption that intravenous tPA has a deleterious effect in acute ICH. However, due to potential species differences and the inability of models to fully capture the dynamics of human ICH, caution is warranted when considering the implications of these findings for human therapy.Publication Neuroglobin, a Novel Target for Endogenous Neuroprotection against Stroke and Neurodegenerative Disorders(Molecular Diversity Preservation International (MDPI), 2012) Liu, Ning; Liu, Jianxiang; Yang, Kevin; Yu, Zhanyang; Wang, XiaoyingBrain neurons and tissues respond to sublethal injury by activating endogenous protective pathways. Recently, following the failure of a large number of clinical trials for protective strategies against stroke that aim to inhibit a specific ischemia response pathway, endogenous neuroprotection has emerged as a more promising and hopeful strategy for development of therapeutics against stroke and neurodegenerative disorders. Neuroglobin (Ngb) is an oxygen-binding globin protein that is highly and specifically expressed in brain neurons. Accumulating evidence have clearly demonstrated that Ngb is an endogenous neuroprotective molecule against hypoxic/ischemic and oxidative stress-related insults in cultured neurons and animals, as well as neurodegenerative disorders such as Alzheimer’s disease, thus any pharmacological strategy that can up-regulate endogenous Ngb expression may lead to novel therapeutics against these brain disorders. In this review, we summarize recent studies about the biological function, regulation of gene expression, and neuroprotective mechanisms of Ngb. Furthermore, strategies for identification of chemical compounds that can up-regulate endogenous Ngb expression for neuroprotection against stroke and neurodegenerative disorders are discussed.Publication Decreased Cerebrovascular Brain-Derived Neurotrophic Factor–Mediated Neuroprotection in the Diabetic Brain(American Diabetes Association, 2011) Navaratna, Deepti; Guo, Shu-Zhen; Hayakawa, Kazhuhide; Wang, Xiaoying; Gerhardinger, Chiara; Lo, EngObjective: Diabetes is an independent risk factor for stroke. However, the underlying mechanism of how diabetes confers that this risk is not fully understood. We hypothesize that secretion of neurotrophic factors by the cerebral endothelium, such as brain-derived neurotrophic factor (BDNF), is suppressed in diabetes. Consequently, such accrued neuroprotective deficits make neurons more vulnerable to injury. Research Design and Methods: We examined BDNF protein levels in a streptozotocin-induced rat model of diabetes by Western blotting and immunohistochemistry. Levels of total and secreted BDNF protein were quantified in human brain microvascular endothelial cells after exposure to advanced glycation end product (AGE)-BSA by enzyme-linked immunosorbent assay and immunocytochemistry. In media transfer experiments, the neuroprotective efficacy of conditioned media from normal healthy endothelial cells was compared with AGE-treated endothelial cells in an in vitro hypoxic injury model. Results: Cerebrovascular BDNF protein was reduced in the cortical endothelium in 6-month diabetic rats. Immunohistochemical analysis of 6-week diabetic brain sections showed that the reduction of BDNF occurs early after induction of diabetes. Treatment of brain microvascular endothelial cells with AGE caused a similar reduction in BDNF protein and secretion in an extracellular signal–related kinase-dependent manner. In media transfer experiments, conditioned media from AGE-treated endothelial cells were less neuroprotective against hypoxic injury because of a decrease in secreted BDNF. Conclusions: Taken together, our findings suggest that a progressive depletion of microvascular neuroprotection in diabetes elevates the risk of neuronal injury for a variety of central nervous system diseases, including stroke and neurodegeneration.