Qing-Wu Yang

Third Military Medical University, Ch’ung-ch’ing-shih, Chongqing Shi, China

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Publications (27)90.53 Total impact

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    ABSTRACT: Objective: Inflammatory injury plays a critical role in intracerebral hemorrhage (ICH)-induced secondary brain injury. However, the upstream events that initiate inflammatory responses following ICH remain elusive. Our previous studies suggested that Toll-like receptor 4 (TLR4) may be the upstream signal that triggers inflammatory injury in ICH. In addition, recent clinical findings indicated that both TLR2 and TLR4 may participate in ICH-induced brain injury. However, it is unclear how TLR2 functions in ICH-induced inflammatory injury and how TLR2 interacts with TLR4. Methods: The role of TLR2 and TLR2/TLR4 heterodimerization in ICH-induced inflammatory injury was investigated in both in vivo and in vitro models of ICH. Results: TLR2 mediated ICH-induced inflammatory injury, which forms a heterodimer with TLR4 in both in vivo and in vitro models of ICH. Hemoglobin(Hb), not other blood components, triggered inflammatory injury in ICH via assembly of TLR2/TLR4 heterodimer. Myeloid differentiation primary response gene 88(MyD88), but not toll/IR-1(TIR)-domain-containing adaptor protein inducing interferon-beta(TRIF), was required for ICH-induced TLR2/TLR4 heterodimerization. Mutation the MyD88 Arg196 abolished the TLR2/TLR4 heterodimerization. Interpretation: Our results suggest that a novel TLR2/TLR4 heterodimer induced by Hb initiates inflammatory injury in ICH. Interfering with assembly of TLR2/TLR4 heterodimer maybe a novel target for developing effective treatment of ICH. ANN NEUROL 2014. © 2014 American Neurological Association.
    Annals of Neurology 04/2014; · 11.19 Impact Factor
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    ABSTRACT: Recent reports have shown that preconditioning with the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) protects against cerebral ischemia/reperfusion (I/R) injury. However, it is unclear whether poly(I:C) treatment after cerebral I/R injury is also effective. We used mouse/rat middle cerebral artery occlusion and cell oxygen-glucose deprivation models to evaluate the therapeutic effects and mechanisms of poly(I:C) treatment. Poly(I:C) was i.p. injected 3 h after ischemia (treatment group). Cerebral infarct volumes and brain edemas were significantly reduced, and neurologic scores were significantly increased. TNF-α and IL-1β levels were markedly decreased, whereas IFN-β levels were greatly increased, in the ischemic brain tissues, cerebral spinal fluid, and serum. Injuries to hippocampal neurons and mitochondria were greatly reduced. The numbers of TUNEL-positive and Fluoro-Jade B(+) cells also decreased significantly in the ischemic brain tissues. Poly(I:C) treatment increased the levels of Hsp27, Hsp70, and Bcl2 and decreased the level of Bax in the ischemic brain tissues. Moreover, poly(I:C) treatment attenuated the levels of TNF-α and IL-1β in serum and cerebral spinal fluid of mice stimulated by LPS. However, the protective effects of poly(I:C) against cerebral ischemia were abolished in TLR3(-/-) and TLR4(-/-)mice. Poly(I:C) downregulated TLR4 signaling via TLR3. Poly(I:C) treatment exhibited obvious protective effects 14 d after ischemia and was also effective in the rat permanent middle cerebral artery occlusion model. The results suggest that poly(I:C) exerts therapeutic effects against cerebral I/R injury through the downregulation of TLR4 signaling via TLR3. Poly(I:C) is a promising new drug candidate for the treatment of cerebral infarcts.
    The Journal of Immunology 04/2014; · 5.52 Impact Factor
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    ABSTRACT: Intracerebral hemorrhage (ICH) is a leading cause of morbidity and mortality around the world. Currently, there is no effective medical treatment available to improve functional outcomes in patients with ICH due to its unknown mechanisms of damage. Increasing evidence has shown that the metabolic products of erythrocytes are the key contributor of ICH-induced secondary brain injury. Iron, an important metabolic product that accumulates in the brain parenchyma, has a detrimental effect on secondary injury following ICH. Because the damage mechanism of iron during ICH-induced secondary injury is clear, iron removal therapy research on animal models is effective. Although many animal and clinical studies have been conducted, the exact metabolic pathways of iron and the mechanisms of iron removal treatments are still not clear. This review summarizes recent progress concerning the iron metabolism mechanisms underlying ICH-induced injury. We focus on iron, brain iron metabolism, the role of iron in oxidative injury, and iron removal therapy following ICH, and we suggest that further studies focus on brain iron metabolism after ICH and the mechanism for iron removal therapy.
    Translational Stroke Research 12/2013;
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    ABSTRACT: Intracerebral hemorrhage (ICH) accounts for 10-15% of all strokes and is associated with high mortality and morbidity. Currently, no effective medical treatment is available to improve functional outcomes in patients with ICH. Potential therapies targeting secondary brain injury are arousing a great deal of interest in translational studies. Increasing evidence has shown that inflammation is the key contributor of ICH-induced secondary brain injury. Inflammation progresses in response to various stimuli produced after ICH. Hematoma components initiate inflammatory signaling via activation of microglia, subsequently releasing proinflammatory cytokines and chemokines to attract peripheral inflammatory infiltration. Hemoglobin (Hb), heme, and iron released after red blood cell lysis aggravate ICH-induced inflammatory injury. Danger associated molecular patterns such as high mobility group box 1 protein, released from damaged or dead cells, trigger inflammation in the late stage of ICH. Preclinical studies have identified inflammatory signaling pathways that are involved in microglial activation, leukocyte infiltration, toll-like receptor (TLR) activation, and danger associated molecular pattern regulation in ICH. Recent advances in understanding the pathogenesis of ICH-induced inflammatory injury have facilitated the identification of several novel therapeutic targets for the treatment of ICH. This review summarizes recent progress concerning the mechanisms underlying ICH-induced inflammation. We focus on the inflammatory signaling pathways involved in microglial activation and TLR signaling, and explore potential therapeutic interventions by targeting the removal of hematoma components and inhibition of TLR signaling.
    Progress in Neurobiology 11/2013; · 9.04 Impact Factor
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    ABSTRACT: Carotid artery atherosclerosis may cause increased intima-media thickness (IMT), plaque formation, and vessel stenosis or occlusion. However, the association between carotid artery atherosclerosis and cognitive impairment remains uncertain. This study explored the effects of IMT and carotid artery stenosis on cognitive function in an elderly Chinese non-stroke population. A total of 2015 patients were recruited. The IMT of carotid arteries and the presence of plaques and stenosis in carotid arteries were assessed with B-mode ultrasound examination. Cognitive performance was evaluated with neuropsychological tests. The cross-sectional relationships between cognitive performance and carotid wall characteristics were analyzed. Carotid artery atherosclerosis (IMT>1.0) and stenosis were found in 86% and 51% of patients, respectively. Cognitive impairment was found in 356 (17.7%) patients. After adjustment for possible confounders, IMT (odds ratio [OR]=1.96; 95% confidence interval [CI] 1.23-3.16) and hyperdense plaque (OR=4.72; 95% CI 2.56-11.2) were associated with poor cognitive performance. Patients with severe (⩾70%) carotid artery stenosis had a lower Mini-Mental State Examination score compared with the mild to modest (40-70%) carotid artery stenosis group. Cognitive performance differed between patients with left and right carotid artery stenosis, but no differences were observed between patients with severe left and right carotid artery stenosis. This study indicates that carotid artery atherosclerosis is correlated with cognitive impairment in the elderly Chinese population. A larger sample size across multiple centers and a longitudinal study are required to further explore the impact of carotid artery atherosclerosis on cognition in the elderly population.
    Journal of Clinical Neuroscience 08/2013; · 1.25 Impact Factor
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    ABSTRACT: Accumulating evidence indicates that inflammatory responses cause secondary injury after intracerebral hemorrhage (ICH). We recently demonstrated the involvement of toll-like receptor 4 (TLR4) signaling in these processes. The purpose of the current study was to investigate the protective effect and mechanism of TAK-242 (Ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1 -carboxylate, Takeda), a TLR4 antagonist, in an ICH mouse model. TAK-242 was intraperitoneally injected 6 hours after ICH once daily for 5 successive days. We assessed neurological deficit scores; changes in brain water content; and levels of inflammatory factors, DNA damage, and neuronal degeneration in perihematomal region 1, 3, and 5 days after ICH. Peripheral inflammatory cell infiltration was determined using flow cytometry; and the expression of TLR4 downstream signaling molecules was assessed by Western blot. TAK-242 significantly reduced brain water content, neurological deficit scores, and levels of inflammatory factors. The levels of DNA damage and neuronal degeneration were also significantly decreased, as was peripheral inflammatory cell infiltration. The expression of TLR4 downstream signaling molecules, including myeloid differentiation primary response gene 88, toll/IR-1(TIR)-domain-containing adaptor protein inducing interferon-beta IκBα, nuclear factor-κBp65, and phosphorylated nuclear factor-κBp65, was significantly downregulated. The results suggest that TLR4 antagonist reduced inflammatory injury and neurological deficits in a mouse model of ICH. The mechanism may involve decreased expression of signaling molecules downstream of TLR4.
    Stroke 07/2013; · 6.16 Impact Factor
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    ABSTRACT: Intracerebral hemorrhage (ICH) is a common type of fatal stroke, accounting for about 15% to 20% of all strokes. Hemorrhagic strokes are associated with high mortality and morbidity, and increasing evidence shows that innate immune responses and inflammatory injury play a critical role in ICH-induced neurological deficits. However, the signaling pathways involved in ICH-induced inflammatory responses remain elusive. Toll-like receptor 4 (TLR4) belongs to a large family of pattern recognition receptors that play a key role in innate immunity and inflammatory responses. In this review, we summarize recent findings concerning the involvement of TLR4 signaling in ICH-induced inflammation and brain injury. We discuss the key mechanisms associated with TLR4 signaling in ICH and explore the potential for therapeutic intervention by targeting TLR4 signaling.
    Journal of Neuroinflammation 02/2013; 10(1):27. · 4.35 Impact Factor
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    ABSTRACT: Epidemiological studies have evaluated the association between apolipoprotein E (ApoE) gene polymorphism and multiple sclerosis (MS) risk. However, the results remain conflicting. Therefore, in order to derive a more precise association of ApoE gene polymorphism with MS risk, we performed this meta-analysis. Systematic searches of electronic databases PubMed, Embase and Web of Science, as well as hand searching of the references of identified articles were performed. Twenty studies were identified, covering a total of 4080 MS cases and 2897 controls. The results showed evidence for significant association between ApoE ε2 mutation and MS risk (for ε2/ε4 versus ε3/ε3: OR=1.74, 95% CI=1.12-2.71, p=0.01; for ε2 allele versus ε3 allele: OR=1.16, 95% CI=1.01-1.35, p=0.04). In the subgroup analysis by ethnicity, the similar results were obtained among Europeans (for ε2/ε4 versus ε3/ε3: OR=1.81, 95% CI=1.14-2.87, p=0.01; for ε2 allele versus ε3 allele: OR=1.19, 95% CI=1.02-1.38, p=0.03). After excluding the outlier studies by observing Galbraith plot, marginal association was found between ApoE ε3/ε4 genotype and the protective factor for MS (for ε3/ε4 versus ε3/ε3: OR=0.86, 95% CI=0.75-0.99, p=0.04). In summary, the present meta-analysis provides evidence that ApoE ε2 mutation is associated with MS risk. In addition, ApoE ε3/ε4 genotype appears to be a protective factor for MS.
    Gene 09/2012; 511(1):12-7. · 2.20 Impact Factor
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    ABSTRACT: The association between estrogen receptor alpha (ESR1) c.454-397T>C and c.454-351A>G polymorphism and ischemic stroke remains controversial. The aim of this study was to perform a meta-analysis to investigate a more authentic association between c.454-397T>C and c.454-351A>G mutation and ischemic stroke. Systematic searches of electronic databases Embase, PubMed, Web of Science as well as hand-searching of the references of identified articles and the meeting abstracts were performed. Study selection, data abstraction and study quality evaluation were independently conducted in duplicate. Statistical analyses were performed using software Stata 11.0. The pooled odds ratios (ORs) with 95 % confidence intervals (95 % CIs) were performed. Different effect models were used according to the difference in heterogeneity. Publication bias was tested by Begg's funnel plot and Egger's regression test. For c.454-397T>C mutation, five studies were combined. Significant association was found in allelic model (OR = 1.12, 95 % CI = 1.01-1.25, p = 0.03), additive model (OR = 1.25, 95 % CI = 1.01-1.54, p = 0.04), and recessive model (OR = 1.23, 95 % CI = 1.02-1.49, p = 0.03), whereas no evidence of association was found for dominant model (OR = 1.10, 95 % CI = 0.85-1.42, p = 0.47). For c.454-351A>G mutation, no evidence of association was found for all genetic models. Our meta-analysis suggests that ESR1 c.454-397T>C mutation is significantly associated with increased risk of ischemic stroke, whereas no evidence of association was found for ESR1 c.454-351A>G mutation.
    Molecular Biology Reports 07/2012; 39(10):9331-8. · 2.51 Impact Factor
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    ABSTRACT: To determine the role of toll like receptor 4 (TLR4) in intimal hyperplasia induced by low shear stress (LSS). TLR4(-/-) mice and control mice C57BL/6J were used. Polyethylene cuff was placed on murine carotid to establishing a LSS model. Cultured vascular endothelial cells under LSS condition were used as an in vitro LSS cell model. Intimal hyperplasia was evaluated pathologically. TLR4 was tested by Western blot and the expression of IL-1β, IL-6 and TNF-α mRNA were detected using RT-PCR. Cell proliferation was determined by detecting DNA synthesis. LSS elicited significant carotid intimal hyperplasia in normal mice but a slight neointima formation in TLR4(-/-) mice (42.67 ± 16.46 vs 7.03 ± 2.95, P < 0.05). LSS upregulated the expression of TLR4 (2.30 ± 0.66 vs 0.16 ± 0.10, P < 0.05), as well as the mRNA of IL-1β (6.52 ± 3.15 vs 1.65 ± 0.45, P < 0.01), IL-6 (16.17 ± 7.49 vs 6.50 ± 1.84, P < 0.01) and TNF-α(9.98 ± 3.77 vs 2.72 ± 1.03, P < 0.01) in normal mice. However, only moderate increases in IL-6 and TNF-α mRNA were observed in TLR4(-/-) mice. LSS induced the proliferation in cultured endothelial cells. And it was further enhanced by TLR4 overexpression (177 ± 33 vs 83 ± 15, P < 0.05) but attenuated by TLR4 silencing (40 ± 8 vs 83 ± 15, P < 0.05). TLR4 plays an important role in LSS-induced intimal hyperplasia. It is likely that LSS induces the proliferation of endothelial cells through TLR4-mediated inflammatory reaction and ultimately promotes intimal hyperplasia.
    Zhonghua yi xue za zhi 03/2012; 92(11):773-7.
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    ABSTRACT: Inflammatory injury plays a critical role in intracerebral hemorrhage (ICH)-induced neurological deficits; however, the signaling pathways are not apparent by which the upstream cellular events trigger innate immune and inflammatory responses that contribute to neurological impairments. Toll-like receptor 4 (TLR4) plays a role in inflammatory damage caused by brain disorders. In this study, we investigate the role of TLR4 signaling in ICH-induced inflammation. In the ICH model, a significant upregulation of TLR4 expression in reactive microglia has been demonstrated using real-time RT-PCR. Activation of microglia was detected by immunohistochemistry, cytokines were measured by ELISA, MyD88, TRIF and NF-κB were measured by Western blot and EMSA, animal behavior was evaluated by animal behavioristics. Compared to WT mice, TLR4(-/-) mice had restrained ICH-induced brain damage showing in reduced cerebral edema and lower neurological deficit scores. Quantification of cytokines including IL-6, TNF-α and IL-1β and assessment of macrophage infiltration in perihematoma tissues from TLR4(-/-), MyD88(-/-) and TRIF(-/-) mice showed attenuated inflammatory damage after ICH. TLR4(-/-) mice also exhibited reduced MyD88 and TRIF expression which was accompanied by decreased NF-κB activity. This suggests that after ICH both MyD88 and TRIF pathways might be involved in TLR4-mediated inflammatory injury possibly via NF-κB activation. Exogenous hemin administration significantly increased TLR4 expression and microglial activation in cultures and also exacerbated brain injury in WT mice but not in TLR4(-/-) mice. Anti-TLR4 antibody administration suppressed hemin-induced microglial activation in cultures and in the mice model of ICH. Our findings suggest that heme potentiates microglial activation via TLR4, in turn inducing NF-κB activation via the MyD88/TRIF signaling pathway, and ultimately increasing cytokine expression and inflammatory injury in ICH. Targeting TLR4 signaling may be a promising therapeutic strategy for ICH.
    Journal of Neuroinflammation 03/2012; 9:46. · 4.35 Impact Factor
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    ABSTRACT: It remains controversial regarding the association between Apolipoprotein E (ApoE) gene polymorphism and the risk of vascular dementia (VaD). The present meta-analysis was performed to derive a more precise estimation of the relationship. The meta-analysis was performed by searching PubMed, Embase and Web of Science databases. A total of 29 studies included 1763 VaD cases and 4534 controls were identified. The results showed evidence for significant association between ApoE ɛ4 mutation and VaD risk (for ɛ3/ɛ4 vs. ɛ3/ɛ3: OR=1.65, 95% CI=1.40-1.94, p-value<0.00001; for ɛ4/ɛ4 vs. ɛ3/ɛ3: OR=3.17, 95% CI=2.09-4.80, p-value<0.00001; for ɛ4 allele vs. ɛ3 allele: OR=1.72, 95% CI=1.40-2.12, p-value<0.00001). The similar results were obtained in the subgroup analysis based on ethnicity. In summary, the present meta-analysis suggests an association between ApoE ɛ4 mutation and increased risk of VaD. However, due to the small sample size in most of the included studies and the selection bias existed in some studies, the results should be interpreted with caution.
    Neuroscience Letters 02/2012; 514(1):6-11. · 2.03 Impact Factor
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    ABSTRACT: Meta-analysis in European population found no association between rs12425791/rs11833579 and ischemic stroke. Several studies focused on East Asians have evaluated the association between this two SNPs and risk of ischemic stroke, but the results have been inconsistent. The aim of this study was to perform a meta-analysis to investigate a more authentic association between rs12425791 and rs11833579 G>A mutation and ischemic stroke in East Asian population, as well as in Chinese Han population. Systematic searches of electronic databases Embase, PubMed, Web of Science, and CBM as well as hand searching of the references of identified articles and the meeting abstracts were performed. Study selection, data abstraction and study quality evaluation were independently conducted in duplicate. Statistical analyses were performed using software Stata 11.0. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were performed. Different effects models were used according to the difference in heterogeneity. Publication bias was tested by Begg's funnel plot and Egger's regression test. A total of 4 publications including 7 studies were involved. For rs12425791, significant association was found in allelic model (OR=1.06, 95%CI=1.00-1.11) and dominant model (OR=1.10, 95%CI=1.03-1.18), whereas no evidence of association was found for additive model (OR=1.04, 95%CI=0.93-1.17) and for recessive model (OR=0.99, 95%CI=0.88-1.10). For rs11833579, no evidence of association was found for all genetic models. In the analysis of Chinese Han population, there is lack of evidence for association of ischemic stroke for both SNPs. In summary, our meta-analysis suggests that rs12425791 is significantly associated with ischemic stroke in East Asian population but not Chinese Han population, of which A alleles increase the risk of ischemic stroke, whereas no evidence of association was found for rs11833579 in East Asian population as well as Chinese Han population.
    Journal of the neurological sciences 01/2012; 316(1-2):116-21. · 2.32 Impact Factor
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    ABSTRACT: Epidemiological studies have evaluated the association between paraoxonase 2 (PON2) Ser311Cys polymorphism and ischemic stroke risk which developed inconsistent conclusions. The aim of this study was to perform a meta-analysis to investigate a more authentic association between PON2 Ser311Cys polymorphism and ischemic stroke. Systematic searches in PUBMED, EMBASE, CBM, and CNKI databases were performed. Data analyses were carried out by Review Manager 5.1.2 and Stata 11.0. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used for additive model (Cys/Cys vs. Ser/Ser), dominant model (Ser/Cys+Cys/Cys vs. Ser/Ser), recessive model (Cys/Cys vs. Ser/Cys+Ser/Ser), and allelic model (Cys allele vs. Ser allele), respectively. Publication bias was analyzed by Begg's funnel plot and Egger's test. A total of 7 studies including 2,046 cases and 2,962 controls were involved. Overall, no significant association was found between PON2 Ser311Cys polymorphism and ischemic stroke risk when all studies were pooled into the meta-analysis (for additive model: OR = 0.87, 95% CI = 0.67-1.14; for dominant model: OR = 1.05, 95% CI = 0.91-1.22; for recessive model: OR = 0.90, 95% CI = 0.77-1.05; and for allelic model: OR = 1.17, 95% CI = 0.86-1.59). In the subgroup analysis by ethnicity, significant association was found among Europeans (for recessive model: OR = 0.83, 95% CI = 0.69-0.99). However, due to the small number of studies included in subgroup analysis, the result for European population should be interpreted cautiously.
    Molecular Biology Reports 12/2011; 39(5):5623-30. · 2.51 Impact Factor
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    ABSTRACT: To investigate the carotid angioplasty and stenting (CAS)-induced hemodynamic depression (HD) and its impact on postprocedural complications so as to identify its risk factors. The incidence, onset time, duration and severity of HD were observed in 196 CAS patients. The influences of clinical baseline and vascular angiographic characteristics on HD were recorded and the relationship between HD and postprocedural complications was analyzed. Logistic regression analysis was used to identify the independent risk factors of HD. The incidence of HD was 53.1%. Most cases of HD (67.3%) developed within 1 - 16 hours postprocedural. And 55.8% HD lasted for over 24 hours and became relieved within 3 - 16 days post-operation. And 78.9% HD patients required medications for the controls of blood pressure and heart rate. Diabetes, hypertension, smoking, plaque involving carotid bulb, ulcerated plaque and calcified plaque were shown to be associated with HD. Further analysis of logistic regression suggested that diabetes and smoking were two protective factors for HD while plaque involving carotid bulb and calcified plaque two independent risk factors for HD. The HD patients were at an increased risk of neurological and cardiopulmonary complications. With a high post-CAS incidence after CAS, HD is associated with postprocedural complications. Lesions involving carotid bulb and calcified plaque are two independent risk factors for HD.
    Zhonghua yi xue za zhi 05/2011; 91(19):1308-13.
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    ABSTRACT: High-mobility group protein box-1 (HMGB1) has recently been recognized as a novel candidate in a specific upstream pathway promoting inflammation after brain ischemia. However, its downstream pathway and underlying mechanism have yet to be elucidated. The HMGB1 level in the acute cerebral infarct (ACI) group was significantly increased compared with that of control group, and correlated with the severity of neurologic impairment of ACI patients. Further, recombinant human HMGB1 (rhHMGB1) had no effect on microglia derived from mice lacking the Toll-like receptor 4 (TLR4(-/-)). Intracerebroventricular injection of rhHMGB1 in TLR4(+/+) mice cause significantly more injury after cerebral ischemia-reperfusion than control group. But, TLR4(-/-) mice administered with rhHMGB1 showed moderate impairment after ischemia-reperfusion than TLR4(+/+) mice. To determine the potential downstream signaling of HMGB1/TLR4 in cerebral ischemic injury, we used the ischemic-reperfusion model with Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon-β knockout mice (TRIF(-/-)) and evaluated the activity and expression of TRIF pathway-related kinases. The results suggest that the TRIF pathway is not likely to be involved in TLR4-mediated ischemia brain injury. Finally, we found that TLR4 expressed by immigrant macrophages was involved in the development of ischemic brain damage. These results suggest that HMBG1 mediates ischemia-reperfusion injury by TRIF-adaptor independent Toll-like receptor 4 signaling. The TLR4 expressed by immigrant macrophages may be involved in the development of ischemic brain damage.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 02/2011; 31(2):593-605. · 5.46 Impact Factor
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    Yan-Chun Wang, Sen Lin, Qing-Wu Yang
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    ABSTRACT: Cerebral ischemia triggers acute inflammation, which has been associated with an increase in brain damage. The mechanisms that regulate the inflammatory response after cerebral ischemia are multifaceted. An important component of this response is the activation of the innate immune system. However, details of the role of the innate immune system within the complex array of mechanisms in cerebral ischemia remain unclear. There have been recent great strides in our understanding of the innate immune system, particularly in regard to the signaling mechanisms of Toll-like receptors (TLRs), whose primary role is the initial activation of immune cell responses. So far, few studies have examined the role of TLRs in cerebral ischemia. However, work with experimental models of ischemia suggests that TLRs are involved in the enhancement of cell damage following ischemia, and their absence is associated with lower infarct volumes. It may be possible that therapeutic targets could be designed to modulate activities of the innate immune system that would attenuate cerebral brain damage. Ischemic tolerance is a protective mechanism induced by a variety of preconditioning stimuli. Interpreting the molecular mechanism of ischemic tolerance will open investigative avenues into the treatment of cerebral ischemia. In this review, we discuss the critical role of TLRs in mediating cerebral ischemic injury. We also summarize evidence demonstrating that cerebral preconditioning downregulates pro-inflammatory TLR signaling, thus reducing the inflammation that exacerbates ischemic brain injury.
    Journal of Neuroinflammation 01/2011; 8:134. · 4.35 Impact Factor
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    ABSTRACT: One of the hallmark pathologies of Alzheimer's disease (AD) is amyloid plaque deposition in the brain. Although the advent of new therapeutic strategies aimed at reducing beta-amyloid burden in the brain is to potentially delay cognitive loss, improved methods for amyloid visualization have become more imperative. Studies so far have shown that positron emission tomography (PET) has produced the greatest strides toward accomplishing this ambitious goal. Several PET amyloid imaging ligands have recently been developed and tested in AD patients. High amyloid content can be detected in vivo by PET in prodromal AD preceding the impairment of functional activity. Hopefully, amyloid imaging may help in the early detection of the disease and can be used for evaluating new drug therapies in AD. This study provides an overview of recent advances in the development of amyloid imaging agents and includes a summary of the clinical significance of amyloid imaging.
    Nuclear Medicine Communications 01/2010; 31(1):4-11. · 1.38 Impact Factor
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    ABSTRACT: High-mobility group protein box-1 (HMGB1) is a proinflammatory involved in many inflammatory diseases. However, its roles in intracerebral hemorrhage (ICH) remain unknown. The purpose of this study was to examine the correlation between changes in serum levels of HMGB1 following acute ICH and the severity of stroke as well as the underlying mechanism. Changes in serum levels of HMGB1 in 60 consecutive patients with primary hemispheric ICH within 12 hours of onset of symptoms were determined. The correlation of HMGB1 with disease severity, IL-6, and TNF-α was analyzed. Changes in HMGB1 levels were detected with ELISA and Western blot. Compared with normal controls, patients with ICH had markedly elevated levels of HMGB1, which was significantly correlated with the levels of IL-6 and TNF-α, NIHSS score at the 10th day, and mRS score at 3 months. In comparison with the control group, the levels of HMGB1 in the perihematomal tissue in mice with ICH increased dramatically, peaked at 72 hours, and decreased at 5 days. Meanwhile, heme could stimulate cultured microglia to release large amounts of HMGB1 whereas Fe(2+/3+) ions failed to stimulate HMGB1 production from microglia. Our findings suggest that HMGB1 may play an essential role in the ICH-caused inflammatory injury.
    Mediators of Inflammation 01/2010; 2010. · 3.88 Impact Factor
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    ABSTRACT: HMGB1 is a ubiquitous, highly conserved DNA-binding protein with well-established functions in the maintenance of nuclear homeostasis. Much of the recent work about its signaling functions in the brain has focused on its proinflammatory properties and relationship to known inflammatory receptors such as toll-like receptor 4 (TLR4). HMGB1 is massively released into the extracellular space immediately after ischemic insult and that it subsequently induces neuroinflammation in the postischemic brain, indicating that HMGB1 acts as a novel mediator in cerebral ischemic injury. Consistently, numerous reports point to TLR4 as a pivotal player in the ischemic brain. The use of HMGB1 and TLR4 ligand as preconditioning stimulus may be benefit of the outcome of cerebral ischemia. Therefore, this review presents the latest findings supporting the involvement of HMGB1 and TLR4 in cerebral ischemia. Targeting HMGB1/TLR4 signaling may provide a novel therapeutic approach for clinical prevention of cerebral ischemic injury.
    Frontiers in bioscience (Scholar edition) 01/2010; 2:1081-91.