Inhibition of Autophagy Facilitates XY03-EA-Mediated Neuroprotection against the Cerebral Ischemia/Reperfusion Injury in Rats
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Objective. L-3-n-Butylphthalide (NBP) is used to treat moderate and severe acute ischemia stroke. A previous screening study indicates that XY03-EA, a novel derivative of NBP, is more potent than NBP in the oxyradical scavenging capacity. In this study, in vivo and in vitro ischemia/reperfusion (I/R) models were used to test whether the XY03-EA offered therapeutic benefits in the ischemic stroke and explore the underlying mechanism of action. Methods. For this purpose, behavioral scores, cerebral infarct volume, cerebral blood flow, oxidative stress levels, inflammatory factor expression, energy metabolism levels, and autophagy activation were estimated in the rat middle cerebral artery occlusion and reperfusion (MCAO/R) model. The nonhuman primate MCAO/R model was conducted to validate the therapeutic effect of XY03-EA applied for 3 weeks. The neurological deficit score (NDS) progression rate and the infarct volume were continuously recorded on days 3, 7, 14, and 21. The PC-12 cell OGD/R model was used to assess the cell survival rate, reactive oxygen species (ROS) levels, the expression of autophagy execution molecules, and the activation of autophagy-related signaling pathways. Results. XY03-EA decreased the cerebral injuries and NDS by increasing cerebral blood flow, improving brain energy metabolism, accelerating ROS clearance, suppressing inflammatory responses, and inhibiting autophagy in the MCAO/R model rats. In the nonhuman primate MCAO/R model, the treatment of XY03-EA for 3 weeks could significantly inhibit the NDS progression rate and indicate a positive trend to reduce the infarct volume in a dose-dependent way. Mechanistically, XY03-EA inhibited ROS-dependent autophagy activation and thereby protected the PC-12 cells from the autophagic cell death induced by OGD/R. Conclusions. In this study, we found that XY03-EA alleviated the cerebral I/R injuries in rats and nonhuman primates. Our results demonstrated that XY03-EA exerted neuroprotective effects against the ROS-mediated autophagic neurocyte death and had great potential for the treatment of ischemic stroke.Inducer
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macroautophagy 的角色(此后 autophagy ) 在癌症，到临床的干预的生物学和反应是复杂的。autophagy 是在许多肿瘤背景的 dysregulated，是清楚的，在肿瘤开始和前进期间，并且响应治疗。然而，在控制房间行为的 autophagy 的多种的机械学的角色使在一个给定的肿瘤背景预言困难 autophagy 的角色，并且，由扩展，指向 autophagy 的治疗学的结果，力量。在这评论，我们在在癌症支持 pro-tumorigenic 和 anti-tumorigenic 和 autophagy 的治疗学的角色的文学总结证据。这概述在滋养的管理，房间死亡，房间老朽， proteotoxic 应力的规定和细胞的动态平衡包含 autophagy 的角色，在在新陈代谢的变化的肿瘤主人相互作用和参予的规定。在可能的地方，我们也试着理解，为 autophagy 的这些角色的机械学的底。我们明确地阐述在在 vivo.We 使这些问题清楚些的癌症的模型也考虑 autophagy 蛋白质的任何东西或上述所有函数怎么可能是可指向的由的遗传上设计的老鼠的新兴的角色现存或 pharmacologic 代理人的未来类。我们由简短在细胞的过程为关键 autophagy 蛋白质的子集探索不在经典中的角色得出结论，并且这些怎么可能在癌症之上影响。
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Ischemia is defined as cell death caused by insufficient perfusion of the tissue due to reduction in arterial or venous blood flow, depletion of cellular energy storages, and accumulation of toxic metabolites. The positive effects of controlled reperfusion are known and are used clinically. But the positive effects of controlled reperfusion on ovarian tissue have not been seen in the literature yet. The biochemical and histopathological comparative investigation of rat ovaries that were experimentally exposed to ischemia (IG), ischemia-reperfusion (I/R), and ischemia-controlled reperfusion (ICR) was aimed. Forty rats were divided into four groups (10 rats per group). First group: 3 h ischemia by vascular clips on ovarian tissue. Second group: 3 h ischemia + 1 h reperfusion. Third group: 3 h ischemia + 1 h controlled reperfusion (on-off method: controlled reperfusion by opening and closing the clips (on/off) in 10-second intervals, for 5 times for a total of 100 seconds). Fourth group: healthy rats. Biochemical (tGSH, MDA, and DNA damage level and SOD activity) and histopathological analysis were performed. The highest glutathione and superoxide dismutase measurements were found in ischemia/controlled reperfusion group among the ischemia or ischemia/reperfusion groups. Similarly the damage indicators (malondialdehyde, DNA damage level and histopathological damage grade) were the lowest in ischemia/controlled reperfusion group. These results indicate that controlled reperfusion can be helpful in minimizing ischemia-reperfusion injury in ovarian tissue exposed to ischemia for various reasons (ovarian torsion, tumor, etc.).
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Objective: To study NF-κB and IL-6 expression in a rat retina that has been inj ured by ischemia-reperfusion and the effect of β-aescin on its expression.Methods: A retinal model of the rat retina for ischemia-reperfusion was establi s hed. 60 SD rats were divided into two groups: one was an ischemia-reperfusion g r oup and the other was an ischemia-reperfussion and β-aescin group. Each group wa s then divided into sub-groups according to the amount of time after ischemia- re perfusion:1 hour,6 hours,12 hours,24 hours,48 hours,and 72 hours. Each sub -group consisted of 5 rats. NF-κB mRNA and IL-6 mRNA in the rat retina was m easured by the ISH method. Each rat was examined by ERG before being sacrificed.Results: NF-κB and IL-6 began to express at 6 hours after ischemia-reperfusio n i n the ischemia-reperfusion group. The highest level of expression occurred 24 h o urs after injury. In the ischemia-reperfusion and β-aescin group,the NF-κB and IL-6 expressed at 12 hours after ischemia-reperfusion injury and reached the hi ghest level at 24 hours. However,its level was lower than the level for the isc hemia-reperfusion group at every stage(P0.05). The b wave of the ERG in the is chemia-reperfusion group was lower than that for the ischemia-reperfusion and β-aescin group at every stage(P0.05).Conclusion: NF-κB may induce IL-6 and play an important role in ischemia-reperfusion inj ury in the rat retina. The β-aescin may suppress NF-κB activity and protect the retina from injury caused by ischemia-reperfusion.
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Background Autophagy is one of the most attractive research fields in recent years. It has been found to be extensively related to myocardial ischemia reperfusion injury. Purpose This article outlines the recent progresses in the research on autophagy. Content To elucidate the classification of autophagy, its character and the detection method, as well as the relationship between autohagy and myocardial reperfusion injury, including the inducement mechanism of it. Trend The further understanding of the relationship between autophagy and reperfusion injury and the underlying mechanism is still to be elucidated,and the extent of benefitial induction of autophagy to protect myocardium from reperfusion injury is still to be decided.
Key words:
Autophagy; Schemia/reperfusion injury
Myocardial Reperfusion Injury
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Autophagy 是导致长寿蛋白质和不正常的细胞器的降级的高度调整的细胞的机制。这个过程处于与神经病学的疾病相关的许多生理、病理学的条件被含有。最近的研究证明在服的局部缺血的 autophagy 的存在，而是没有一致还处于这个条件关于 autophagy 的功能被到达了。这篇文章在服的局部缺血或灌注期间加亮 autophagy 的激活，特别在神经原和星形细胞，以及在 neuronal 或 astrocytic 房间死亡和幸存的 autophagy 的角色。我们建议那 autophagy 的生理的层次，大概引起了由对谦虚组织缺氧或局部缺血温和，看起来保护。然而，严重组织缺氧或局部缺血或灌注引起的 autophagy 的高水平可以引起自我消化和最终的 neuronal 和 astrocytic 房间死亡。我们也讨论那氧化并且 endoplasmic 蜂窝胃(嗯) 在服的组织缺氧或局部缺血或灌注的压力是在神经原和星形细胞的 autophagy 的有势力刺激。另外，我们考察一方面建议在 autophagy 之间的可观的重叠的证据，和 apoptosis，坏死和 necroptosis 在另一方面，在决定结果和损坏神经原和星形细胞的最后的形态学。
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[Objective]To study the IL-6 express in rat's retina which injuried by ischemia-reperfusion and the effect of β-aescin on its expression. The model of rat's retina ischemia-reperfusion was employed. 60 SD rats were devided into two groups, one was ischemia-reperfusion group, the other was ischemia-reperfusion andβ-aescin group. Every group was devided into 1 hour, 6 hour, 12 hour, 24 hour, 48 hour and 72 hour groups. Every group had 5 rats. IL-6 mRNA was measured by ISH method in rat's retina. Every rat was examinated ERG before executed. IL-6 began to express at 6 hours after ischemia-reperfusion in ischemia-reperfusion group. It expressed most at 24 hours after ischemia-reperfusion injury. In ischemia-reperfusion and β-aescin group, IL-6 expressed at 12 hours after ischmia-reperfusion injury and reached the hightest level was lower than ischemia-reperfusion group at every stage (P 0.05). The a wave of ERG of ischemia-reperfusion group was lower than ischemia-reperfusion and β-aescin group at every stage (P 0.05). [Conclusion] IL-6 take important role in rat's retina ischemia-reperfusion injury, the β-aescni may suppress the activity of IL-6 and relieve the retina injury from the ischemia-reperfusion.
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Objective:The retina ischemia-reperfusion injury is caused by many factors. A lot of cell factors take part in it. Many researches suggest MCP-1 has special effect on leukocyte and lymphocyte.The research try to study the effect of MCP-1 in rat's retina ischemia-reperfusion injury.Methods:To employ the rat's retina ischemia-reperfusion model and use SABC method to test the expression of MCP-1 on retina.Results:There was no MCP-1 expressed in retina after ischemia-reperfusion injury for one hour. MCP-1 began to express in retina after ischemia-reperfusion injury for six hours, and expressed at most after ischemia-reperfusion injury for 24 hours. Then it began to decrease in 48 hours after ischemia-reperfusion injury, but it still expressed in retina in seventy-two hours after ischemia-reperfusion injury.Conclusions:MCP-1 plays an important role in rat's retina ischemia-reperfusion injury.
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Objective To investigate the effect of palm oil(PO) on the volume of the infarction,the expression of Bcl-2 and Bax protein following focal cerebral ischemia/reperfusion in rats,and explore the protective effect of PO on focal cerebral ischemia/reperfusion and the underlying mechanism.Methods The acute focal cerebral ischemia/reperfusion models were established with suture emboli.Healthy male Sprague-Dawley rats were randomly divided into four groups: normal control group,sham group,IR group and PO group.There were 12 rats in each of the normal control group and the sham group.The IR group and PO group were further subdivided into subgroups and sacrificed 2 h,6 h,12 h,24 h,72 h and 7 d after ischemia/reperfusion(n=12).The volume of the infarction was observed by the TTC method;and the expression of Bcl-2 and Bax was determined by Western blotting to observe the protective effect of PO.Results ① TTC staining: there was no region of ischemia/reperfusion injury in the normal control group and the sham group.There was no region of ischemia/reperfusion injury in IR group and PO group 2 h after ischemia/reperfusion.At the time points of 6 h,12 h,24 h,72 h and 7 d after ischemia/reperfusion,there were statistical differences in mass percentage of the infracted regions between the PO group and the IR group(P0.05),and mass percentage of the infracted cerebral regions in the PO group was reduced as compared to the IR group.② Western-blotting: From the time point of 6h after reperfusion,in both PO group and IR group,the expression of Bcl-2 and Bax increased with time in the ischemia penumbra with peak expression at 12 h,and then decreased.The expression of Bax reached the peak at 24 h,and then decreased.Western-blotting analysis showed a gradual increase in Bcl-2 expression(P0.05) and a gradual decrease in Bax expression(P0.05) in PO group at each time point(6 h,12 h,24 h and 72 h after ischemia/reperfusion),compared with IR group.Conclusions ① PO can reduce the region of ischemia injury following focal cerebral ischemia/reperfusion injury;② PO can protect nerve cells by increasing the expression of Bcl-2 and decreasing the expression of Bax,following the cerebral ischemia/reperfusion injury.
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