DNA甲基化与高血压的相关性研究进展

高血压是缺血性卒中最常见的可调节危险因素之一,作为一种多病因、高度异质性的疾病,环境、遗传因素在高血压的发生、发展过程中发挥着重要作用。基因与环境之间的相互作用,也就是表观遗传修饰可能介导遗传因素、环境因素和缺血性卒中之间的关系,但具体机制仍不明确。表观遗传修饰包括DNA甲基化、组蛋白修饰、染色质重塑等,其中DNA甲基化是表观遗传的重要组成部分,也是研究相对成熟的机制。DNA甲基化可以调节基因的表达,同时也受环境因素的影响。本文介绍了DNA甲基化在高血压相关病理生理机制、危险因素及环境因素等方面的研究进展,探讨了与高血压相关的DNA甲基化影响卒中风险的潜在机制,提出DNA甲基化用于高血压诊断、治疗及预防缺血性卒中的新靶点和新思路。     

缺血性卒中早期超氧化物歧化酶的变化特点

目的 研究缺血性卒中患者血液超氧化物歧化酶在缺血性卒中不同时点的变化特点。方法 对28例缺血性卒中发作不超过6h的住院病人，在发病后6h、24h、3d、7d采血，通过光谱仪法测定血浆超氧化物歧化酶及红细胞内超氧化物歧化酶的活性，对照组病人选用年龄和性别匹配的正常对照。结果 缺血性卒中病人平均抗氧化酶活性低于对照组，但随着时间的延长有上升趋势。结论 急性缺血性卒中后抗氧化酶水平下降可能是氧化应激增高的结果。     

DNA甲基化/去甲基化调控缺血性卒中的研究进展

卒中是我国首位的致死致残原因,其中急性缺血性卒中（ischemic stroke, IS）约占全部卒中的80%,是一种具有遗传背景的复杂疾病。脱氧核糖核酸（deoxyribonucleic acid,DNA）甲基化/去甲基化是表观遗传的重要方式之一,近年研究发现其在IS的发病和复发中发挥重要作用,预示着DNA甲基化/去甲基化分子有望成为IS新的诊断标志物和药物治疗靶点。现将DNA甲基化/去甲基化在缺血性卒中的研究进展进行综述。     

氧化应激与缺血性卒中急性事件

动脉粥样硬化(AS)是导致缺血性卒中的最主要原因。近年来对动脉粥样硬化发病机制的研究有了长足的发展,如动脉粥样硬化的氧化学说,并逐步建立了氧化应激重要标志物-氧化低密度脂蛋白(ox—LDL)在AS形成和斑块破裂中的关键地位。糖尿病、代谢综合征、血脂异常、吸烟、高血压等因素增加缺血性卒中的风险,但单纯从以上因素的角度并不能完全解释所增加的血管风险;而其他的重要风险因素如氧化应激/炎症则发挥了更重要的作用。控制血脂等因素后剩留血管风险的出现,提示我们在缺血性卒中的治疗中还有被忽略的重要靶点-氧化应激。在现有调脂、抗栓等常规治疗的基础上,加强对氧化应激的风险管理,正日益显示出广阔的临床治疗前景。抗氧化治疗逐渐成为缺血性心卒中综合管理策略中的重要组成部分。毕齐     

缺血性卒中早期超氧化物歧化酶的变化特点

目的研究缺血性卒中患者血液超氧化物歧化酶在缺血性卒中不同时点的变化特点.方法对28例缺血性卒中发作不超过6h的住院病人,在发病后6h、24h、3d、7d采血,通过光谱仪法测定血浆超氧化物歧化酶及红细胞内超氧化物歧化酶的活性,对照组病人选用年龄和性别匹配的正常对照.结果缺血性卒中病人平均抗氧化酶活性低于对照组,但随着时间的延长有上升趋势.结论急性缺血性卒中后抗氧化酶水平下降可能是氧化应激增高的结果.     

缺血性脑卒中的氧化应激相关因子研究进展

近年来,氧化应激(oxidative stress)等非传统风险因素已成为缺血性卒中(ischemic stroke,IS)研究的焦点,因为从血管内皮细胞损伤到动脉粥样硬化斑块形成,从斑块破裂到卒中事件的发生,一直到卒中后缺血再灌注损伤,乃至介入术后血管再狭窄,氧化应激贯穿始终.故寻找有效的氧化损伤标志物来了解缺血性脑卒中的病因机制、氧化损伤程度、治疗疗效及评估预后显得尤为重要.     

血小板反应蛋白1与缺血性卒中

正新生血管是导致动脉粥样硬化斑块破裂的重要原因,斑块破裂后出血,血小板聚集到病变处形成血栓,加重脑血管狭窄;此外,大动脉粥样硬化病变脱落的栓子可堵塞远端脑血管。脑组织对缺血性卒中的急性反应是复杂的。首先,活性氧(reactive oxygen species,ROS)增加引起氧化应激,氧化应激在缺血性卒中及脑缺血再灌注损伤的发病机制中起着至关重要的作用,     

急性缺血性卒中血压调控研究进展

高血压是缺血性卒中的独立危险因素,缺血性卒中患者血压的管理直接影响患者的预后,但目前缺血性卒中急性期的血压管理存在许多争议。本文主要介绍血压管理对缺血性卒中的影响及急性期血压调控的争论,重点探讨国际国内相关研究的结论及今后的研究方向,明确缺血性卒中急性期血压调控对临床的指导意义。     

缺血性卒中后血管新生的细胞和分子调节机制

卒中是由脑供血异常引起的急性神经功能缺损,其中缺血性卒中占60%～80%。脑组织对缺血缺氧十分敏感,卒中后缺血中心区脑细胞迅速大量死亡,及时抢救缺血半暗带区脑细胞可减轻脑损伤,卒中后期血管新生亦在为神经再生和脑组织修复创建良好环境中发挥重要作用,如何调控卒中后血管新生是目前缺血性卒中治疗探索热点之一,而目前其调节机制仍处于研究之中,因此本文就缺血性卒中后     

动脉粥样硬化相关基因与缺血性卒中的相关性研究进展

动脉粥样硬化发病机制主要涉及炎症、脂质浸润、氧化应激。不稳定斑块破损是动脉粥样硬化性脑梗死的主要发病机制,目前研究动脉粥样硬化相关基因,揭示其与缺血性卒中亚型尤其是动脉粥样硬化性脑梗死的遗传易感性,并结合其他危险因子评估,对于指导选择最优干预措施及筛选药物作用靶点有积极意义。本文对内皮功能相关基因、白细胞介素基因、载脂蛋白E基因、同型半胱氨酸相关基因、缝隙连接蛋白基因与缺血性卒中亚型相关性进行了综述。     

Hes1 Knockdown Exacerbates Ischemic Stroke Following tMCAO by Increasing ER Stress-Dependent Apoptosis via the PERK/ eIF2a/ATF4/CHOP Signaling Pathway

Apoptosis induced by endoplasmic reticulum(ER)stress plays a crucial role in mediating brain damage after ischemic stroke.Recently,Hes1(hairy and enhancer of split 1)has been implicated in the regulation of ER stress,but whether it plays a functional role after ischemic stroke and the underlying mechanism remain unclear.In this study,using a mouse model of ischemic stroke via transient middle cerebral artery occlusion(tMCAO),we found that Hes1 was induced following brain injury,and that siRNA-mediated knockdown of Hes1 increased the cerebral infarction and worsened the neurological outcome,suggesting that Hes1 knockdown exacerbates ischemic stroke.In addition,mechanistically,Hes1 knockdown promoted apoptosis and activated the PERK/eIF2a/ATF4/CHOP signaling pathway after tMCAO.These results suggest that Hes1 knockdown promotes ER stress-induced apoptosis.Furthermore,inhibition of PERK with the specific inhibitor GSK2606414 markedly attenuated the Hes1 knockdown-induced apoptosis and the increased cerebral infarction as well as the worsened neurological outcome following tMCAO,implying that the protection of Hes1 against ischemic stroke is associated with the amelioration of ER stress via modulating the PERK/eIF2a/ATF4/CHOP signaling pathway.Taken together,these results unveil the detrimental role of Hes1 knockdown after ischemic stroke and further relate it to the regulation of ER stress-induced apoptosis,thus highlighting the importance of targeting ER stress in the treatment of ischemic stroke.     

Oxidative stress: apoptosis in neuronal injury

Apoptosis has been well documented to play a significant role in cell loss during neurodegenerative disorders, such as stroke, Parkinson disease, and Alzheimer's disease. In addition, reactive oxygen species (ROS) has been implicated in the cellular damage during these neurodegenerative disorders. These ROS can react with cellular macromolecular through oxidation and cause the cells undergo necrosis or apoptosis. The control of the redox environment of the cell provides addition regulation in the signal transduction pathways which are redox sensitive. Recently, many researches focus on the relationship between apoptosis and oxidative stress. However, till now, there is no clear and defined mechanisms that how oxidative stress could contribute to the apoptosis. This review hopes to make clear that generation of ROS during brain injury, particularly in ischemic stroke and Alzheimer's Disease, and the fact that oxidative state plays a key role in the regulation and control of the cell survival and cell death through its interaction with cellular macromolecules and signal transduction pathway, and ultimately helps in developing an unique therapy for the treatment of these neurodegenerative disorders.     

Time‐dependent change of in vivo optical imaging of oxidative stress in a mouse stroke model

Nuclear factor erythroid 2‐related factor 2 (Nrf2) plays a pivotal role in cellular defense against oxidative stress damage after ischemic stroke. In the present study, we examined the time‐dependent change of in vivo optical imaging of oxidative stress after stroke with Keap1‐dependent oxidative stress detector (OKD) mice. OKD mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 45 min, and in vivo optical signals were detected during the pre‐operative period, 12 h, 1 d, 3 d, and 7 d after tMCAO. Ex vivo imaging was performed immediately after obtaining in vivo optical signals at 1 d after tMCAO. Immunohistochemical analyses and infarct volume were also examined after in vivo imaging at each period. The in vivo signals showed a peak at 1 d after tMCAO that was slightly correlated to infarct volume. The strong ex vivo signals, which were detected in the peri‐ischemic area, corresponded to endogenous Nrf2 expression. Moreover, endogenous Nrf2 expression was detected mainly in neurons followed by oligodendrocytes and pericytes, but only slightly in astrocytes, microglia, endothelial cells. The present study successfully demonstrated the temporal change of in vivo imaging of oxidative stress after tMCAO, which is consistent with strong expression of endogenous Nrf2 in the peri‐ischemic area with a similar time course. © 2017 Wiley Periodicals, Inc.     

Oxidative stress in acute ischemic stroke.

Oxidative stress plays an important role in acute ischemic stroke pathogenesis. Free radical formation and subsequent oxidative damage may be a factor in stroke severity. Serum levels of nitric oxide (NO), malondialdehyde (MDA) and glutathione (GSH) were measured within the first 48 h of stroke in 70 patients. The levels were also correlated with the clinical outcomes using Canadian Neurological Scale (CNS) scores. The results were compared with a control group consisting of 70 volunteers with similar stroke risk factors. Serum NO, MDA and GSH levels were significantly elevated in acute stroke patients. CNS score was negatively correlated with both MDA and NO levels. However, no statistically significant correlation between GSH levels and CNS scores was detected. Our results suggest deleterious effects of oxidative stress on clinical outcome in acute ischemic stroke. The elevation of GSH levels may be an adaptive mechanism during this period.     

Preconditioning to mild oxidative stress mediates astroglial neuroprotection in an IL-10-dependent manner

Oxidative stress plays an important role in the pathogenesis of various brain insults, including stroke. Astroglia are the main glial cells that play a fundamental role in maintaining the homeostasis of the CNS. They are important for protection from injury and aid the brain in functional recovery after injuries. It has been shown that the brain can be prepared to withstand an oxidative stress insult by a process known as preconditioning. We used primary astroglial cell culture to investigate whether preconditioning to mild oxidative stress and glucose deprivation (OSGD) can increase both astroglia survival and neuroprotective features. We found that preconditioning astroglia to mild OSGD increases astroglial survival of a second insult through activation of the NF-E2-related factor-2 (Nrf-2) pathway. Moreover, we found that Nrf-2 is highly expressed in adult brain astroglia and that preconditioning to OSGD in vivo, such as in a murine model of ischemic stroke, leads to a significant increase in astroglial Nrf-2 expression. Furthermore, we discovered an increase in neuroprotection, as measured by increased neuronal cell survival, following OSGD in the presence of medium from astroglia exposed to a mild OSGD condition. Interestingly, we discovered a significant increase in astroglial secretion of the anti-inflammatory cytokine IL-10 vs. the pro-inflammatory cytokine IL-1β in mild vs. severe oxidative stress, respectively. We demonstrated that preconditioning astroglia to mild oxidative stress increases neuroprotection in an IL-10-dependent manner. By using tert-butylhydroquinone (tBHQ), a known specific activator of Nrf-2, we found that Nrf-2 can enhance IL-10 expression. Further studies of Nrf-2-mediated cellular pathways in astroglia through IL-10 may provide useful insights into the development of therapeutic interventions following oxidative stress insults such as ischemic stroke.     

Mitochondrial quality control in acute ischemic stroke

Mitochondria play a central role in the pathophysiological processes of acute ischemic stroke. Disruption of the cerebral blood flow during acute ischemic stroke interrupts oxygen and glucose delivery, leading to the dysfunction of mitochondrial oxidative phosphorylation and cellular bioenergetic stress. Cells can respond to such stress by activating mitochondrial quality control mechanisms, including the mitochondrial unfolded protein response, mitochondrial fission and fusion, mitophagy, mitochondrial biogenesis, and intercellular mitochondrial transfer. Collectively, these adaptive response strategies contribute to retaining the integrity and function of the mitochondrial network, thereby helping to recover the homeostasis of the neurovascular unit. In this review, we focus on mitochondrial quality control mechanisms occurring in acute ischemic stroke. A better understanding of how these regulatory pathways work in maintaining mitochondrial homeostasis will provide a rationale for developing innovative neuroprotectants when these mechanisms fail in acute ischemic stroke.     

Microglia-associated neuroinflammation is a potential therapeutic target for ischemic stroke

Microglia-associated neuroinflammation plays an important role in the pathophysiology of ischemic stroke. Microglial activation and polarization, and the inflammatory response mediated by these cells play important roles in the development, progression and outcome of brain injury after ischemic stroke. Currently, there is no effective strategy for treating ischemic stroke in clinical practice. Therefore, it is clinically important to study the role and regulation of microglia in stroke. In this review, we discuss the involvement of microglia in the neuroinflammatory process in ischemic stroke, with the aim of providing a better understanding of the relationship between ischemic stroke and microglia.     

Involvement of oxidative stress and caspase-3 in cortical infarction after photothrombotic ischemia in mice.

Apoptosis-related cell death is linked to oxidative stress and caspases in experimental cerebral ischemia. However, the role of oxidative stress in caspase activation and subsequent apoptotic cell death after cerebral ischemia is unknown. The authors evaluated the role of oxidative stress in ischemic cerebral infarction after photothrombosis and the relation between oxidative stress and caspase-related cell death 6 and 24 hours after ischemia with and without U-74389G, a potent free radical scavenger (10 mg/kg, 30 minutes before and after ischemia induction). Reactive oxygen species, detected by hydroethidine oxidation, and cytosolic cytochrome c were detected in early ischemic lesions. Western blot analysis showed the cleaved form and the increased level of the proform of caspase-3 in the ischemic lesion 24 hours after ischemia. Decreased caspase-3 immunoreactivity was detected in the antioxidant-treated group after ischemia. Decreased DNA fragmentation and laddering were detected and the lesion was smaller in the treated group after ischemia compared with the untreated group. Oxidative stress and cytochrome c release occur in the ischemic lesion after photothrombotic ischemia. The free radical scavenger attenuated caspase-3 up-regulation, DNA fragmentation, and the final lesion. The authors concluded that oxidative stress may mediate caspase-related apoptotic cell death and subsequent cortical infarction after photothrombotic ischemia.