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Plant lycopene exhibits antioxidant activity in animal tissues. Transient cerebral ischemia/reperfusion in Mongolian gerbils resulted in delayed neuronal death in hippocampal regions. We examined the antioxidant effects of lycopene because we expected lycopene to attenuate ischemia-related neuronal damage by controlling apoptosis at the gene level. The gerbils were divided into two groups: the normal feeding (control) group that received normal market food (MF) and the lycopene group that received MF containing lycopene (5 mg in 100 g MF food). After 1.5–2.0 months (when body weight were 60–65 g), the lycopene level was 38.2 ± 17.6 ng/ml in serum and 11.9 ± 4.0 μg/g-wet weight tissue in the liver. Levels of B cell leukemia-2, an apoptosis-suppressing protein, decreased in control animal brains 1, 3, and 7 days after surgery, whereas the levels increased in lycopene-treated animal brains. Moreover, cysteinyl aspartate-specific protease-3 activity increased gradually after ischemia, but was suppressed in the lycopene-treated animal brains 7 days after surgery. Finally, hippocampal superoxide dismutase (SOD) activity decreased in the control group 3 h after ischemia and, gradually increased thereafter, whereas it was significantly elevated in the lycopene group. Thus, orally administered lycopene is accumulated in the body, and provided protections against ischemia/reperfusion-induced brain injury by inducing an increase in SOD activity and inhibiting apoptosis.  相似文献   

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Focal cerebral ischemia can impair the induction of activity-dependent long-term potentiation (LTP) in the hippocampus. This impairment of hippocampal synaptic plasticity can be caused by excitotoxicity and subsequent perturbation of hippocampal LTP-relevant transmitter systems, which include NR2B and PSD-95. It has been suggested that hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels may play an important role in the control of membrane excitability and rhythmic neuronal activity. Our previous study has indicated that the selective HCN channel blocker ZD7288 can produce a dose-dependent inhibition of the induction of LTP at the Schaffer collateral-CA1 synapse of hippocampus by reducing the amount of glutamate released. It has also been demonstrated that ZD7288 can protect against neuronal injury caused by oxygen glucose deprivation. In the present study, we investigated the effect of ZD7288 on the induction of activity-dependent LTP and the expression of NR2B and PSD-95 after focal cerebral ischemia/reperfusion injury. The results showed that the induction of LTP was significantly impaired and the levels of NR2B and PSD-95 mRNA and protein were markedly decreased in the CA1 region of hippocampus following focal cerebral ischemia/reperfusion injury. Administration of low dose ZD7288 (0.25 μg) at 30 min and 3 h after the onset of ischemia attenuated the impairment of LTP induction and alleviated the NR2B and PSD-95 mRNA and protein down-regulation commonly induced by cerebral ischemia/reperfusion injury. These results suggest that low dose ZD7288 can ameliorate the ischemia/reperfusion-induced impairment of synaptic plasticity in the hippocampal CA1 region.  相似文献   

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ObjectivesTransient receptor potential vanilloid 1 (TRPV1) -positive sensory nerves are widely distributed in the kidney, suggesting that TRPV1-mediated action may participate in the regulation of renal function under pathophysiological conditions. Stimulation of TRPV1 channels protects against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). However, it is unknown whether inhibition of these channels is detrimental in AKI or not. We tested the role of TRPV1 channels in I/R-induced AKI by modulating these channels with capsaicin (TRPV1 agonist), capsazepine (TRPV1 antagonist) and using Trpv1−/− mice.ConclusionsActivation of TRPV1 channels ameliorates I/R-induced AKI, but inhibition of these channels does not affect the outcome of AKI. Our results may have clinical implications for long-term safety of renal denervation to treat resistant hypertension in man, with respect to the function of primary sensory nerves in the response of the kidney to ischemic stimuli.  相似文献   

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Inflammation and apoptosis play critical roles in the acute progression of ischemic injury pathology. Emerging evidence indicates that vagus nerve stimulation (VNS) following focal cerebral ischemia and reperfusion (I/R) may be neuroprotective by limiting infarct size. However, the underlying molecular mechanisms remain unclear. In this study, we investigated whether the protective effects of VNS in acute cerebral I/R injury were associated with anti-inflammatory and anti-apoptotic processes. Male Sprague-Dawley (SD) rats underwent VNS at 30 min after focal cerebral I/R surgery. Twenty-four h after reperfusion, neurological deficit scores, infarct volume, and neuronal apoptosis were evaluated. In addition, the levels of pro-inflammatory cytokines were detected using enzyme-linked immune sorbent assay (ELISA), and immunofluorescence staining for the endogenous “cholinergic anti-inflammatory pathway” was also performed. The protein expression of a7 nicotinic acetylcholine receptor (a7nAchR), phosphorylated Akt (p-Akt), and cleaved caspase 3 in ischemic penumbra were determined with Western blot analysis. I/R rats treated with VNS (I/R+VNS) had significantly better neurological deficit scores, reduced cerebral infarct volume, and decreased number of TdT mediated dUTP nick end labeling (TUNEL) positive cells. Furthermore, in the ischemic penumbra of the I/R+VNS group, the levels of pro-inflammatory cytokines and cleaved caspase 3 protein were significantly decreased, and the levels of a7nAchR and phosphorylated Akt were significantly increased relative to the I/R alone group. These results indicate that VNS is neuroprotective in acute cerebral I/R injury by suppressing inflammation and apoptosis via activation of cholinergic and a7nAchR/Akt pathways.  相似文献   

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Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is the main cause to poor outcomes of SAH patients, and early inflammation plays an important role in the acute pathophysiological events. It has been demonstrated that ethyl pyruvate (EP) has anti-inflammatory and neuroprotective effects in various critical diseases, however, the role of EP on EBI following SAH remains to be elucidated. Our study aimed to evaluate the effects of EP on EBI following SAH in the endovascular perforation rabbit model. All rabbits were randomly divided into three groups: sham, SAH?+?Vehicle (equal volume) and SAH?+?EP (30?mg/kg/day). MRI was performed to estimate the reliability of the EBI at 24 and 72?h after SAH. Neurological scores were recorded to evaluate the neurological deficit, ELISA kit was used to measure the level of tumor necrosis factor-α (TNF-α), and western blot was used to detect the expression of TNF-α, tJNK, pJNK, bax and bcl-2 at 24 and 72?h after SAH. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Fluoro-jade B (FJB) staining were used to detect neuronal apoptosis and neurodegeneration respectively, meanwhile hematoxylin and eosin (H&E) staining was used to assess the degree of vasospasm. Our results demonstrated that EP alleviated brain tissue injury (characterized by diffusion weighted imaging and T2 sequence in MRI scan), and significantly improved neurological scores at 72?h after SAH. EP decreased the level of TNF-α and downregulated pJNK/tJNK and bax/bcl-2 in cerebral cortex and hippocampus effectively both at 24 and 72?h after SAH. Furthermore, EP reduced TUNEL and FJB positive cells significantly. In conclusion, the present study supported that EP afforded neuroprotective effects possibly via reducing TNF-α expression and inhibition of the JNK signaling pathway. Therefore, EP may be a potent therapeutic agent to attenuate EBI following SAH.  相似文献   

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D Yang  P Xie  Z Liu 《PloS one》2012,7(7):e42076
Mitogen-activated protein kinase phosphatases (MKPs) are a family of dual-specificity phosphatases. Endothelial cells express multiple MKP family members, such as MKP-3. However, the effects of MKP-3 on endothelial biological processes have not yet been fully elucidated. Here, we address the association between MKP-3 and endothelial Nitric oxide (NO) formation under ischemia/reperfusion (IS/RP) condition. Human umbilical vein endothelial cells (HUVECs) were subjected to IS/RP treatment. The MKP-3 expression and NO formation were examined. IS/RP induced endothelial MKP-3 expression and inhibited eNOS expression and NO formation, accompanied by an increase of endothelial apoptosis. The siRNA experiments showed that MKP-3 was an important mediator in impairing eNOS expression and NO production in endothelial cells. Transfection of HUVECs with constitutively active ERK plasmids suggested that the above mentioned effect of MKP-3 was via inactivation of ERK1/2 pathway. Furthermore, impairment of eNOS expression was restored by treatment of histone deacetylase (HDAC) inhibitor and related to histone deacetylation and recruitment of HDAC1 to the eNOS promoter. Finally, Salvianolic acid A (SalA) markedly attenuated induction of MKP-3 and inhibition of eNOS expression and NO formation under endothelial IS/RP condition. Overall, these results for the first time demonstrated that IS/RP inhibited eNOS expression by inactivation of ERK1/2 and recruitment of HDAC1 to the gene promoter, leading to decreased NO formation through a MKP-3-dependent mechanism in endothelial cells, and SalA has therapeutic significance in protecting endothelial cells from impaired NO formation in response to IS/RP.  相似文献   

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脊髓损伤后胶质瘢痕的形成是阻碍神经恢复的关键原因之一。碱性成纤维细胞生长因子(basic fibroblast growth factor,bFGF)具有良好的神经保护及促进脊髓损伤的修复作用,然而其对于胶质瘢痕的影响及其机制仍不清楚。本研究通过采用血管动脉夹(30 g)夹闭雌性SD大鼠脊髓2 min造成急性脊髓损伤模型并予以每天皮下注射bFGF(80 μg/kg),探讨bFGF促进脊髓损伤的恢复作用是否涉及到胶质瘢痕调控和Nogo-A/NgR信号的相关机制。通过检测损伤后28 d,各组BBB评分和斜板试验,发现bFGF显著促进脊髓损伤后大鼠运动功能的恢复。HE及尼氏染色显示,bFGF处理组相对于生理盐水处理组,其神经元明显增多,空洞面积减少。同时,星形胶质细胞标记物GFAP免疫荧光结果表明,bFGF减少胶质瘢痕形成,抑制星形胶质细胞过度激活。同样,通过Western 印迹检测发现,bFGF处理后,胶质瘢痕相关蛋白(如GFAP, neurocan)以及神经突生长抑制蛋白(Nogo-A)信号通路相关蛋白质表达量下降。上述结果表明,bFGF可能通过抑制Nogo-A信号蛋白的表达,从而抑制胶质瘢痕的形成,促进脊髓损伤的恢复。此机制研究为脊髓损伤的治疗和恢复提供全新的思路和药物靶点。  相似文献   

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目的:观察罗布麻叶提取物(apocynum venetum leaf extract AVLE)预处理对心肌缺血再灌注(MI/R)损伤的影响。方法:采用SD大鼠MI/R模型,随机分为sham(假手术)组、MI/R组、AVLE预处理+MI/R组,检测血流动力学,采用氯化三苯基四氮唑和伊文思蓝双染法检测心梗面积、以血浆肌酸激酶(CK)和乳酸脱氢酶(LDH)活性检测心肌损伤情况、以超氧化物、丙二醛(MAD)和超氧化物歧化酶(SOD)含量检测心肌氧化应激以及Western blot方法检测gp91phox的表达。结果:与MI/R组相比,AVLE预处理组左室压上升、下降最大速率(±LVdp/dtmax)升高(P0.05),心肌梗死面积减少,两组分别为41.5±4.5%和32.0±3.5%(P0.05),血浆CK和LDH活性分别降低到1653±62 U/L和2461±152 U/L(P0.05),减少了心肌组织超氧化物的含量(P0.05)。AVLE治疗显着降低gp91phox的表达(P0.05),使SOD活性增加(P0.05),MDA水平显著降低(P0.05)。结论:AVLE通过抑制I/R心肌的氧化应激发挥心脏保护作用。  相似文献   

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In this study, we investigated the neuroprotective effect of Ro25-6981 against cerebral ischemia/reperfusion injury. Ro25-6981 alone or in combination with rapamycin was intracerebroventricularly administered to rats which suffered transient forebrain ischemia inducing by 4-vessel occlusion and reperfusion. Nissl staining was used to determine the survival of CA1 pyramidal cells of the hippocampus, while immunohistochemistry was performed to measure neuron-specific enolase (NSE) expression. The expression of autophagy-related proteins, such as microtubule-associated protein l light chain 3 (LC3), Beclin 1, and sequestosome 1 (p62), was assessed by immunoblotting. Nissl staining showed that neuronal damage was reduced in the hippocampal CA1 pyramidal layer in rats that received Ro25-6981. The protective effect of Ro25-6981 was dose-dependent, with a significant effect in the middle-dose range. The expression of NSE increased after Ro25-6981 treatment. Ro25-6981 significantly decreased LC3II (which is membrane bound) and Beclin 1, and increased p62. In addition, Ro25-6981 decreased rapamycin-induced neuronal damage and excessive activation of autophagy after I/R. Taken together, the results suggest that Ro25-6981 could suppress ischemic brain injury by regulating autophagy-related proteins during ischemia/reperfusion.  相似文献   

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Our previous data indicated that hypoxic preconditioning (HPC) ameliorates transient global cerebral ischemia (tGCI)-induced neuronal death in hippocampal CA1 subregion of adult rats. However, the possible molecular mechanisms for neuroprotection of this kind are largely unknown. This study was performed to investigate the role of the mitogen-activated protein kinase/extra-cellular signal-regulated kinase kinase (MEK)/extra-cellular signal-regulated kinase (ERK) pathway in HPC-induced neuroprotection. tGCI was induced by applying the four-vessel occlusion method. Pretreatment with 30 min of hypoxia applied 1 day before 10 min tGCI significantly decreased the level of MEK1/2 and ERK1/2 phosphorylation in ischemic hippocampal CA1 subregion. Also, HPC decreased the expression of phosphorylated ERK1/2 in degenerating neurons and astrocytes. However, the administration of U0126, a MEK kinase inhibitor, partly blocked MEK1/2 and ERK1/2 phosphorylation induced by tGCI. Meanwhile, neuronal survival was improved, and glial cell activation was significantly reduced. Collectively, these data indicated that the MEK/ERK signaling pathway might be involved in HPC-induced neuroprotection following tGCI. Also, HPC resulted in a reduction of glial activation.  相似文献   

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The protective role of etanercept in myocardial ischemia/reperfusion is not well understood. The aim of this study was to investigate whether etanercept modulates neutrophil accumulation, TNF-α induction and oxidative stress in an ischemia/reperfusion injured rat heart model. Rats were randomly exposed to sham operation, myocardial ischemia/reperfusion (MI/R) alone, MI/R+ etanercept. The results demonstrated that compared to MI/R, etanercept reduced myocardial infarction area, myocardial myeloperoxidase (MPO) levels, serum creatinine kinase (CK) and lactate dehydrogenase (LDH) levels, and both serum and myocardial TNF-α production. Etanercept also markedly enhanced the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), and reduced the level of malondialdehyde (MDA) in MI/R rats. In summary, our data suggested that etanercept has protective effects against MI/R injury in rats, which may be attributed to attenuating inflammation and oxidative stress.  相似文献   

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Background

Luteolin (LUT), a kind of flavonoid which is extracted from a variety of diets, has been reported to convey protective effects of various diseases. Recent researches have suggested that LUT can carry out cardioprotective effects during ischemia/reperfusion (I/R). However, there have no reports on whether LUT can exert protective effects against myocardial I/R injury through the actions of specific microRNAs (miRs). The purpose of this study was to determine which miRs and target genes LUT exerted such function through.

Methods

Expression of various miRs in perfused rat hearts was detected using a gene chip. Target genes were predicted with TargetScan, MiRDB and MiRanda. Anoxia/reoxygenation was used to simulate I/R. Cells were transfected by miR-208b-3p mimic, inhibitor and small interfering RNA of Ets1 (avian erythroblastosis virus E26 (v ets) oncogene homolog 1). MiR-208b-3p and Ets1 mRNA were quantified by real-time quantitative polymerase chain reaction. The percentage of apoptotic cells was detected by annexin V-fluorescein isothiocyanate/propidium iodide dyeing and flow cytometry. The protein expression levels of cleaved caspase-3, Bcl-2, Bax, and Ets1 were examined by western blot analysis. A luciferase reporter assay was used to verify the combination between miR-208b-3p and the 3’-untranslated region of Ets1.

Results

LUT pretreatment reduced miR-208b-3p expression in myocardial tissue, as compared to the I/R group. And LUT decreased miR-208b-3p expression and apoptosis caused by I/R. However, overexpression of miR-208b-3p further aggravated the changes caused by I/R and blocked all the effects of LUT. Knockdown of miR-208b-3p expression also attenuated apoptosis, while knockdown of Ets1 promoted apoptosis. Further, the luciferase reporter assay showed that miR-208b-3p could inhibit Ets1 expression.

Conclusion

LUT pretreatment conveys anti-apoptotic effects after myocardial I/R injury by decreasing miR-208b-3p and increasing Ets1 expression levels.  相似文献   

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This study was designed to investigate whether Resveratrol (Res) could be a prophylactic factor in the prevention of I/R injury and to shed light on its underlying mechanism. Primary culture of neonatal rat cardiomyocytes were randomly distributed into three groups: the normal group (cultured cardiomyocytes were in normal conditions), the I/R group (cultured cardiomyocytes were subjected to 2 h simulated ischemia followed by 4 h reperfusion), and the Res+I/R group (100 µmol/L Res was administered before cardiomyocytes were subjected to 2 h simulated ischemia followed by 4 h reperfusion). To test the extent of cardiomyocyte injury, several indices were detected including cell viability, LDH activity, Na+-K+-ATPase and Ca2+-ATPase activity. To test apoptotic cell death, caspase-3 activity and the expression of Bcl-2/Bax were detected. To explore the underlying mechanism, several inhibitors, intracellular calcium, SOD activity and MDA content were used to identify some key molecules involved. Res increased cell viability, Na+-K+-ATPase and Ca2+-ATPase activity, Bcl-2 expression, and SOD level. While LDH activity, capase-3 activity, Bax expression, intracellular calcium and MDA content were decreased by Res. And the effect of Res was blocked completely by either L-NAME (an eNOS inhibitor) or MB (a cGMP inhibitor), and partly by either DS (a PKC inhibitor) or Glybenclamide (a KATP inhibitor). Our results suggest that Res attenuates I/R injury in cardiomyocytes by preventing cell apoptosis, decreasing LDH release and increasing ATPase activity. NO, cGMP, PKC and KATP may play an important role in the protective role of Res. Moreover, Res enhances the capacity of anti-oxygen free radical and alleviates intracellular calcium overload in cardiomyocytes.  相似文献   

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