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Liu X.,Hebei Medical University | Zhang X.,Hebei Medical University | Zhang X.,Hebei Collaborative Innovation Center for Cardio cerebrovascular Disease | Zhang X.,Hebei Key Laboratory for Neurology | And 15 more authors.
Neuroscience | Year: 2014

Background and object: Apoptosis is a major form of cell death in cerebral ischemia/reperfusion (I/R) pathogenesis and may represent a target for treatment. Diosmin (DM), a micronized purified flavonoid drug, possesses an anti-apoptotic effect in the treatment of varicose veins and renal injury. However, the effect of DM in the acute phase of cerebral I/R is not clear. This study investigated DM's role in cerebral I/R and its potential mechanism. Methods: Male CD-1 mice were subjected to transient middle cerebral artery occlusion (tMCAO). Experiment 1 was used to evaluate the time course expression of Janus tyrosine kinase-2 (JAK2), signal transducer and activator of transcription-3 (STAT3), phosphorylated JAK2 (pJAK2) and phosphorylated STAT3 (pSTAT3) after cerebral I/R, and six time points were included. In experiment 2, DM was given orally at doses of 50. mg/kg or 100. mg/kg for 6 consecutive days before receiving tMCAO. At 24. h after reperfusion, neurological deficit, Nissl staining, brain water content and infarct volume were examined. Bcl-2, Bax, pJAK2, and pSTAT3 were detected by immunohistochemistry, qRT-PCR and Western blot. Confocal microscope was used to observe the location of pSTAT3 in the cerebral cortex. Results: Compared with Vehicle group, the high dose of DM significantly alleviated neurological deficit, brain water content, infarct volume, increased the Nissl-positive cells, upregulated the expression of pJAK2, pSTAT3 and Bcl-2 and downregulated Bax (P<. 0.05). Conclusion: These results showed that DM protected against cerebral I/R injury through activating JAK2/STAT3 signal pathway. © 2014 IBRO.


Yang Y.,Hebei Medical University | Yang Y.,Hebei Collaborative Innovation Center for Cardio cerebrovascular Disease | Yang Y.,Hebei Key Laboratory for Neurology | Zhang X.,Hebei Medical University | And 12 more authors.
Neuroscience Letters | Year: 2014

Apelin has been proved to protect the heart against ischemia/reperfusion (I/R) injury via the activation of phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) signaling pathways. Whether this protective effect applies to brain I/R injury needed to be explored. We therefore investigated the potential neuroprotective role of Apelin-13 and the underlying mechanisms. Focal transient cerebral I/R model in male ICR mice was induced by 60. min of ischemia followed by reperfusion. Apelin-13 intracerebroventricular injection was performed 15. min before reperfusion. Neurological function, infarct volume, brain edema and apoptosis were measured at 24. h after stroke. To further test the mechanism of Apelin-13, PI3K inhibitor LY294002 and ERK1/2 inhibitor PD98059 were injected into the lateral cerebral ventricle 15. min before ischemia. Compared with the Vehicle group, Apelin-13 significantly ameliorated neurological deficit, infarct volume, brain edema and reduced TUNEL-positive cells. Bax, caspase-3 and cleaved caspase-3 were down-regulated and Bcl-2 up-regulated. While, the effect of Apelin-13 on Bax, Bcl-2, caspase-3 and cleaved caspase-3 was attenuated by LY294002 and PD98059. Apelin protected the brain against I/R insult injury, and this effect may be through activation of PI3K/Akt and ERK1/2 signaling pathways. © 2014 Elsevier Ireland Ltd.


Zhang N.,Hebei Medical University | Zhang X.,Hebei Medical University | Zhang X.,Hebei Collaborative Innovation Center for Cardio Cerebrovascular Disease | Zhang X.,Hebei Key Laboratory for Neurology | And 6 more authors.
Mediators of Inflammation | Year: 2014

The most effective way to contain cerebral ischemic injury is reperfusion; however, reperfusion itself may result in tissue injury, for which inflammatory damage is one of the main causative factors. NALP3 inflammasome is a multiprotein complex. It consists of NALP3, ASC, and caspase-1, whose function is to switch on the inflammatory process. Chrysophanol is an extract from plants of Rheum genus and it possesses many pharmacological effects including its anti-inflammation activity. In this study, the effects of chrysophanol in cerebral ischemia/reperfusion and the potential mechanisms were investigated. Male CD1 mice were subject to transient middle cerebral artery occlusion (tMCAO). The NALP3 inflammasome activation status and its dynamic expression during the natural inflammatory response induced by tMCAO were first profiled. The neuroprotective effects of chrysophanol were then assessed and the potential mechanisms mediating the observed neuroprotection were then explored. Physical parameters including neurological deficit, infarct size, brain edema, and BBB permeability were measured at 24 h after tMCAO. Confocal microscopy, Western blotting, immunohistochemistry, and qRT-PCR techniques were utilized to analyze the expression of NALP3 inflammasome and IL-1β. Our results indicated that the brain tissue damage during cerebral ischemia/reperfusion is accompanied by NALP3 inflammasome activation. Chrysophanol could inhibit the activation of NALP3 inflammasome and protect cerebral ischemic stroke. © 2014 Nan Zhang et al.


Bai X.,Hebei Medical University | Zhang X.,Hebei Medical University | Zhang X.,Hebei Collaborative Innovation Center for Cardio Cerebrovascular Disease | Zhang X.,Hebei Key Laboratory for Neurology | And 6 more authors.
Neurochemical Research | Year: 2014

Inflammatory damage plays a pivotal, mainly detrimental role in cerebral ischemic pathogenesis and may represent a promising target for treatment. Naringenin (NG) has gained growing appreciation for its beneficial biological effects through its anti-inflammatory property. Whether this protective effect applies to cerebral ischemic injury, we therefore investigate the potential neuroprotective role of NG and the underlying mechanisms. Focal cerebral ischemia in male Sprague-Dawley rats was induced by permanent middle cerebral artery occlusion (pMCAO) and NG was pre-administered intragastrically once daily for four consecutive days before surgery. Neurological deficit, brain water content and infarct volume were measured at 24 h after stroke. Immunohistochemistry, Western blot and RT-qPCR were used to explore the anti-inflammatory potential of NG in the regulation of NOD2, RIP2 and NF-κB in ischemic cerebral cortex. Additionally, the activities of MMP-9 and claudin-5 were analyzed to detect NG's influence on blood-brain barrier. Compared with pMCAO and Vehicle groups, NG noticeably improved neurological deficit, decreased infarct volume and edema at 24 h after ischemic insult. Consistent with these results, our data also indicated that NG significantly downregulated the expression of NOD2, RIP2, NF-κB and MMP-9, and upregulated the expression of claudin-5 (P < 0.05). The results provided a neuroprotective profile of NG in cerebral ischemia, this effect was likely exerted by down-regulated NOD2, RIP2, NF-κB, MMP-9 and up-regulated claudin-5 expression. © 2014 Springer Science+Business Media.


Zhao T.,Hebei Medical University | Zhang X.,Hebei Medical University | Zhang X.,Hebei Collaborative Innovation Center for Cardio cerebrovascular Disease | Zhang X.,Hebei Key Laboratory for Neurology | And 8 more authors.
Neurochemical Research | Year: 2014

Inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Evodiamine (Evo) has been proved to elicit a variety of biological effects through its anti-inflammatory property in the treatment of infectious disease, Alzheimer's disease and hypoxia-induced inflammatory response. Whether this protective effect applies to cerebral ischemic injury, we therefore investigated the potential neuroprotective role of Evo and the underlying mechanisms. Male Institute of Cancer Research (ICR) mice were subjected to permanent middle cerebral artery occlusion (pMCAO) and randomly divided into five groups: Sham (sham-operated + 1 % DMSO + 0.5 % tween80), pMCAO (pMCAO + 0.9 % saline), Vehicle (pMCAO + 1 % DMSO + 0.5 % tween80), Evo-L (Vehicle + Evo 50 mg/kg) and Evo-H (Vehicle + Evo 100 mg/kg) groups. Evo was administered intragastrically twice daily for 3 days, and once again 30 min before mouse brain ischemia was induced by pMCAO. Neurological deficit, brain water content and infarct size were measured at 24 h after stroke. The expression of pAkt, pGSK3β, NF-κB and claudin-5 in ischemic cerebral cortex was analyzed by western blot and qRT-PCR. Compared with Vehicle group, Evo significantly ameliorated neurological deficit, brain water content and infarct size, upregulated the expression of pAkt, pGSK3β and claudin-5, and downregulated the nuclear accumulation of NF-κB (P < 0.05). Evo protected the brain from ischemic damage caused by pMCAO; this effect may be through upregulation of pAkt, pGSK3β and claudin-5, and downregulation of NF-κB expression. © 2014 Springer Science+Business Media.


Wen Y.,Hebei Medical University | Wen Y.,Hebei Key Laboratory for Neurology | Wen Y.,Hebei Collaborative Innovation Center for Cardio cerebrovascular Disease | Zhang X.,Hebei Medical University | And 11 more authors.
Molecular Medicine | Year: 2015

Inflammatory responses play a critical role in ischemic brain injury. MicroRNA-155 (miR-155) induces the expression of inflammatory cytokines, and acety lbritannilactone (ABL) exerts potent anti inflammatory actions by inhibiting expression of inflammation-related genes. However, the functions of miR-155 and the actual relationship between ABL and miR-155 in ischemia-induced cerebral inflammation remain unclear. In this study, cerebral ischemia of wild-type (WT) and miR-155-/- mice was induced by permanent middle cerebral artery occlusion (MCAO). pAd-miR-155 was injected into the lateral cerebral ventricle 24 h before MCAO to in- duce miR-155 over expression. MCAO mice and oxygen-glucose deprivation (OGD)-treated BV2 cells were used to examine the effects of ABL and miR-155 over expression or deletion on the expression of pro inflammatory cytokines. We demonstrated that ABL treatment significantly reduced neurological deficits and cerebral infarct volume by inhibiting tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) expression in ischemic cerebral tissue and OGD-treated BV2 cells. Mechanistic studies suggested that the ob- served decrease in TNF-α and IL-1β expression was attributable to the ABL-induced suppression of the expression of nuclear factor- kappa B (NF-κB) and Toll-like receptor 4 (TLR4). We further found that miR-155 promoted TNF-α and IL-1β expression by up regulating TLR4 and down regulating the expression of suppressor of cytokine signaling 1 (SOCS1) and myeloid differentiation primary response gene 88 (MyD88), while ABL exerted an inhibitory effect on miR-155-mediated gene expression. In conclusion, miR-155 mediates in- flammatory responses in ischemic cerebral tissue by modulating TLR4/MyD88 and SOCS1 expression, and ABL exerts its anti inflammatory action by suppressing miR-155 expression, suggesting a novel miR-155-based therapy for ischemic stroke. © 2015, Uninversity of Michigan. All rights reserved.


PubMed | Hebei Collaborative Innovation Center for Cardio cerebrovascular Disease and Hebei Medical University
Type: | Journal: Neuroscience | Year: 2016

Silent mating type information regulation 2 homolog 1 (SIRT1) is a class III histone deacetylase and activates peroxisome proliferator-activated receptor- co-activator-1 (PGC-1) which attenuates oxidative damage. Alpha-lipoic acid (ALA) has been proven to protect the rat brain against cerebral ischemia injury by reducing oxidative stress. However, the underlying mechanisms are poorly understood. In this study, we investigated the potential neuroprotection and the possible role of ALA in SIRT1 pathway.Male CD-1 mice were randomly assigned to three groups: Sham, permanent middle cerebral artery occlusion (pMCAO) and ALA group (ALA, 50mg/kg). ALA was administered intraperitoneally 30min prior to ischemia in the ALA group. Neurological deficit, infarct volume, and brain edema were detected at 24h after cerebral ischemia. Immunohistochemistry, western blot and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect the expression of SIRT1 and PGC-1. Activities of superoxide dismutase (SOD) were measured by assay kits.Compared with the pMCAO group, the ALA group significantly ameliorated neurological deficit, lessened infarct volume and brain edema, increased the expression of SIRT1, PGC-1 and activities of SOD (P<0.05).ALA protected the mouse brain against ischemic damage, and this protection may be through up-regulating SIRT1-dependent PGC-1 expression.


PubMed | Hebei Collaborative Innovation Center for Cardio cerebrovascular Disease and Hebei Medical University
Type: Journal Article | Journal: Neurochemical research | Year: 2016

Aliskiren (ALK), a pharmacological renin inhibitor, is an effective antihypertensive drug and has potent anti-apoptotic activity, but it is currently unknown whether ALK is able to attenuate brain damage caused by acute cerebral ischemia independent of its blood pressure-lowering effects. This study aimed to investigate the role of ALK and its potential mechanism in cerebral ischemia. C57/BL6 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and treated for 5days with Vehicle or ALK (10 or 25mg/kg per day via intragastric administration), whereas Sham-operated animals served as controls. Treatment with ALK significantly improved neurological deficits, infarct volume, brain water content and Nissl bodies after stroke (P<0.05), which did not affect systemic blood pressure. Furthermore, the protection of ALK was also related to decreased levels of apoptosis in mice by enhanced activation of phosphatidylinositol 3-kinase (PI3K)/AKT pathway, increased level of Bcl-2 and reduced Bax expression (P<0.05). In addition, ALKs effects were reversed by PI3K inhibitors LY294002 (P<0.05). Our data indicated that ALK protected the brain from reperfusion injuries without affecting blood pressure, and this effect may be through PI3K/AKT signaling pathway.


PubMed | Hebei Collaborative Innovation Center for Cardio cerebrovascular Disease and Hebei Medical University
Type: | Journal: Brain research bulletin | Year: 2014

Oxidative damage plays a detrimental role in the pathophysiology of cerebral ischemia and may represent a therapeutic target. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) controls the coordinated expression of the important antioxidant and detoxification genes through a promotor sequence termed the antioxidant response element. Bicyclol has been proved to elicit a variety of biological effects through its antioxidant and anti-inflammatory properties. But the underlying mechanisms are poorly understood. In this study, the role of bicyclol in cerebral ischemia and its potential mechanism were investigated.Male Sprague-Dawley rats were randomly assigned to five groups: MCAO (middle cerebral artery occlusion), Vehicle (MCAO+0.5% sodium carboxymethylcellulose), By-L (Vehicle+bicyclol 50mg/kg), By-H (Vehicle+bicyclol 100mg/kg) and Sham operated groups. Bicyclol was administered intragastrically once a day for 3 consecutive days; after 1h of bicyclol pretreatment on the third day, rat ischemic stroke was induced by MCAO. Neurological deficit, infarct volume, and brain edema were detected at 24h after stroke. Western blot and RT-qPCR were used to measure the expression of Nrf2, HO-1 and SOD1. MDA was detected by the spectrophotometer.Compared with MCAO group, By-H group significantly ameliorated neurological deficit, lessened the infarct volume and brain edema, increased the expression of Nrf2, HO-1 and SOD1 (P<0.05), and decreased the content of MDA (P<0.05).Bicyclol protected the rat brain from ischemic damage caused by MCAO, and this effect may be through the upregulation of the transcription factor Nrf2 expression.

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