The regulatory role of Pin1 in neuronal death

Regulated cell death predominantly involves apoptosis,autophagy,and regulated necrosis.It is vital that we understand how key regulatory signals can control the process of cell death.Pin1 is a cis-trans isomerase that catalyzes the isomerization of phosphorylated serine or threonine-proline motifs of a protein,thereby acting as a crucial molecular switch and regulating the protein functionality and the signaling pathways involved.However,we know very little about how Pin1-associated pathways might play a role in regulated cell death.In this paper,we review the role of Pin1 in regulated cell death and related research progress and summarize Pin1-related pathways in regulated cell death.Aside from the involvement of Pin1 in the apoptosis that accompanies neurodegenerative diseases,accumulating evidence suggests that Pin1 also plays a role in regulated necrosis and autophagy,thereby exhibiting distinct effects,including both neurotoxic and neuroprotective effects.Gaining an enhanced understanding of Pin1 in neuronal death may provide us with new options for the development of therapeutic target for neurodegenerative disorders.

Pre-B-cell colony-enhancing factor as a target for protecting against apoptotic neuronal death and mitochondrial damage in ischemia

Focal ischemic stroke（FIS）results from the lack of blood flow in a particular region of the brain and accounts for about 80%of all human strokes.Although tremendous efforts have been made in translational research,the treatment strategies are still limited.Tissue plasminogen activator is the only FDA-approved drug currently available for acute stroke treatment,

Reactive changes in astrocytes, and delayed neuronal death, in the rat hippocampal CA1 region following cerebral ischemia/reperfusion

BACKGROUND： Blood supply to the hippocampus is not provided by the middle cerebral artery. However, previous studies have shown that delayed neuronal death in the hippocampus may occur following focal cerebral ischemia induced by middle cerebral artery occlusion. OBJECTIVE： To observe the relationship between reactive changes in hippocampal astrocytes and delayed neuronal death in the hippocampal CA1 region following middle cerebral artery occlusion. DESIGN, TIME AND SETTING： The immunohistochemical, randomized, controlled animal study was performed at the Laboratory of Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, from July to November 2007. MATERIALS： Rabbit anti-glial fibrillary acidic protein （GFAP） （Neomarkers, USA）, goat anti-rabbit IgG （Sigma, USA） and ApoAlert apoptosis detection kit （Biosciences Clontech, USA） were used in this study. METHODS： A total of 42 healthy adult male Wistar rats, aged 3–5 months, were randomly divided into a sham operation group （n = 6） and a cerebral ischemia/reperfusion group （n = 36）. In the cerebral ischemia/reperfusion group, cerebral ischemia/reperfusion models were created by middle cerebral artery occlusion. In the sham operation group, the thread was only inserted into the initial region of the internal carotid artery, and middle cerebral artery occlusion was not induced. Rats in the cerebral ischemia/reperfusion group were assigned to a delayed neuronal death （＋） subgroup and a delayed neuronal death （–） subgroup, according to the occurrence of delayed neuronal death in the ischemic side of the hippocampal CA1 region following cerebral ischemia. MAIN OUTCOME MEASURES： Delayed neuronal death in the hippocampal CA1 region was measured by Nissl staining. GFAP expression and delayed neuronal death changes were measured in the rat hippocampal CA1 region at the ischemic hemisphere by double staining for GFAP and TUNEL. RESULTS： After 3 days of ischemia/reperfusion, astrocytes with abnormal morphology were detected in the rat hippocampal CA1 region in the delayed neuronal death （＋） subgroup. No significant difference in GFAP expression was found in the rat hippocampal CA1 region at the ischemic hemisphere in the sham operation group, delayed neuronal death （＋） subgroup and delayed neuronal death （–） subgroup （P 〉 0.05）. After 7 days of ischemia/reperfusion, many GFAP-positive cells, which possessed a large cell body and an increased number of processes, were activated in the rat hippocampal CA1 region at the ischemic hemisphere. GFAP expression in the hippocampal CA1 region was greater in the delayed neuronal death （＋） subgroup and delayed neuronal death （–） subgroup compared with the sham operation group （P 〈 0.01）. Moreover, GFAP expression was significantly greater in the delayed neuronal death （–） subgroup than in the delayed neuronal death （＋） subgroup （P 〈 0.01）. After 30 days of ischemia/reperfusion, GFAP-positive cells were present in scar-like structures in the rat hippocampal CA1 region at the ischemic hemisphere. GFAP expression was significantly greater in the delayed neuronal death （＋） subgroup and delayed neuronal death （–） subgroup compared with the sham operation group （P 〈 0.05）. GFAP expression was significantly lower in the delayed neuronal death （–） subgroup than in the delayed neuronal death （＋） subgroup （P 〈 0.05）. The delayed neuronal death rates were 42% （5/12）, 33% （4/12） and 33% （4/12） at 3, 7 and 30 days, respectively, followingischemia/reperfusion. No significant differences were detected at various time points （χ2 = 0.341, P 〉 0.05）. CONCLUSION： The activation of astrocytes was poor in the hippocampal CA1 region during the early stages of ischemia, which is an important reason for delayed neuronal death. Glial scar formation aggravated delayed neuronal death during the advanced ischemic stage.

Role of axon resealing in retrograde neuronal death and regeneration after spinal cord injury

Spinal cord injury leads to persistent behavioral deficits because mammalian central nervous system axons fail to regenerate. A neuron's response to axon injury results from a complex interplay of neuron-intrinsic and environmental factors. The contribution of axotomy to the death of neurons in spinal cord injury is controversial because very remote axotomy is unlikely to result in neuronal death, whereas death of neurons near an injury may reflect environmental factors such as ischemia and inflammation. In lampreys, axotomy due to spinal cord injury results in delayed apoptosis of spinal-projecting neurons in the brain, beyond the extent of these environmental factors. This retrograde apoptosis correlates with delayed resealing of the axon, and can be reversed by inducing rapid membrane resealing with polyethylene glycol. Studies in mammals also suggest that polyethylene glycol may be neuroprotective, although the mechanism(s) remain unclear. This review examines the early, mechanical, responses to axon injury in both mammals and lampreys, and the potential of polyethylene glycol to reduce injury-induced pathology. Identifying the mechanisms underlying a neuron's response to axotomy will potentially reveal new therapeutic targets to enhance regeneration and functional recovery in humans with spinal cord injury.

Role of P2X_7 receptors in neuronal death in the retina

Acknowledgments： I would like to express my appreciation to Professor Puro DG for leading me to this research topic during my stay as a research fellow in his laboratory at the University of Michigan in 2001, and also to Professor Ikeda T forgiving me the opportunity to study abroad and then to continue to investigate this topic in the Department of Ophthalmology at Osaka Medical College, lapan.

Relevance and therapeutic potential of Cyp A targeting to block apoptosis inducing factor-mediated neuronal cell death

Programmed cell death （PCD） signaling pathways are import- ant contributors to acute neurological insults such as hypox- ic-ischemic brain damage, traumatic brain injury, stroke etc. The pathogenesis of all these diseases is closely linked with ab- erration of apoptotic cell death pathways. Mitochondria play a crucial role during PCD, acting as both sensors of death signals, and as initiators of biochemical path- ways, which cause cell death （Bras et al., 2005）. Cytochrome c was the firstly identified apoptogenic factor released from mitochondria into the cytosol, where it induces apoptosome formation through the activation of caspases. Other proteins, such as apoptosis inducing factor （AIF）, have been subsequently identified as mitochondrial released factors. AIF contributes to apoptotic nuclear DNA damage （Bras et al., 2005）. in a caspase-independent way

Clemastine in remyelination and protection of neurons and skeletal muscle after spinal cord injury

Spinal cord injuries affect nearly five to ten individuals per million every year. Spinal cord injury causes damage to the nerves, muscles, and the tissue surrounding the spinal cord. Depending on the severity, spinal injuries are linked to degeneration of axons and myelin, resulting in neuronal impairment and skeletal muscle weakness and atrophy. The protection of neurons and promotion of myelin regeneration during spinal cord injury is important for recovery of function following spinal cord injury. Current treatments have little to no effect on spinal cord injury and neurogenic muscle loss. Clemastine, an Food and Drug Administration-approved antihistamine drug, reduces inflammation, protects cells, promotes remyelination, and preserves myelin integrity. Recent clinical evidence suggests that clemastine can decrease the loss of axons after spinal cord injury, stimulating the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes that are capable of myelination. While clemastine can aid not only in the remyelination and preservation of myelin sheath integrity, it also protects neurons. However, its role in neurogenic muscle loss remains unclear. This review discusses the pathophysiology of spinal cord injury, and the role of clemastine in the protection of neurons, myelin, and axons as well as attenuation of skeletal muscle loss following spinal cord injury.

Added after Anoxia-Reoxigenation Stress, Genistein Rescues from Death the Rat Embryo Cortical Neurons

Estrogens and phytoestrogens have neuroprotective effect against neuronal damage induced by cerebral ischemia /reperfusion (I/R) injury. In preceding studies, the phytoestrogen effects have been assessed by administration previous to the ischemic period, conditions which are unusual to apply to the treatment of human stroke. Here we present a study on neuroprotection afforded by genistein on rat embryo cortical neurons subjected to oxygen and glucose deprivation (OGD) followed by re-oxigenation, when added after the stress stimulus. At 1 and 2 h of OGD times and after 24 h of reperfusion, cell viability, necrotic, apoptotic and autophagic cell death and different parameters related to oxidative stress and mitochondrial dysfunction were measured in the absence and presence of 1 μM genisteine. We found an in-creasing loss of neuronal viability after 1-5 h of OGD which was only reversed in part by 24 h of reperfusion. These changes were preceded by increases in ROS generation, caspase-3 activation, LDH release and increase in LC3B lipi-dation, indicative of autophagia. Treatment with 1 μM genistein during the 24 h reperfusion significantly attenuated neuronal necrosis and autophagia induced by 1 and 2 h of OGD exposure. Genistein also decreased ROS generation and lipid-peroxidation induced by 2 h of OGD. These results suggest an important neuroprotective effect of genistein against transient post-ischemic-like

Delayed hippocampal neuronal death in young gerbil following transient global cerebral ischemia is related to higher and longer-term expression of p63 in the ischemic hippocampus

The tumor suppressor p63 is one of p53 family members and plays a vital role as a regulator of neuronal apoptosis in the development of the nervous system. However, the role of p63 in mature neuronal death has not been addressed yet. In this study, we first compared ischemia-induced effects on p63 expression in the hippocampal regions （CA1-3） between the young and adult gerbils subjected to 5 minutes of transient global cerebral ischemia. Neuronal death in the hippocampal CA1 region of young gerbils was significantly slow compared with that in the adult gerbils after transient global cerebral ischemia, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons in the sham-operated young group was significantly low compared with that in the sham-operated adult group, p63 immunoreactivity was apparently changed in ischemic hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. In the ischemia-operated adult groups, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons was significantly decreased at 4 days post-ischemia; however, p63 immunoreactivity in the ischemia-operated young group was significantly higher than that in the ischemia-operated adult group. At 7 days post-ischemia, p63 immunoreactivity was decreased in the hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. Change patterns of p63 level in the hippocampal CA1 region of adult and young gerbils after ischemic damage were similar to those observed in the immunohistochemical results. These findings indicate that higher and longer-term expression of p63 in the hippocampal CA1 region of the young gerbils after ischemia/reperfusion may be related to more delayed neuronal death compared to that in the adults.

Proteasome alteration and delayed neuronal death in hippocampal CA1 and dentate gyrus regions following transient cerebral ischemia

BACKGROUND： Proteasome dysfunction has been reported to induce abnormal protein aggregation and cell death. OBJECTIVE： To investigate the effect of proteasome changes on delayed neuronal death in CA1 and dentate gyrus （DG） regions of the rat hippocampus following transient cerebral ischemia. DESIGN, TIME AND SETTING： A randomized, controlled animal experiment. The study was performed at the Department of Biochemistry and Molecular Biology, Norman Bethune Medical College of Jilin University, from September 2006 to May 2008. MATERIALS： Rabbit anti-19S S10B polyclonal antibody was purchased from Bioreagents, USA; propidium iodide and fluorescently-labeled goat anti-rabbit IgG were purchased from Jackson Immunoresearch, USA; hematoxylin and eosin staining solution was purchased from Sigma, USA; LSM 510 confocal microscope was purchased from Zeiss, Germany. METHODS： A total of 40 healthy Wistar rats, male, 4 months old, were randomly divided into sham surgery group （n = 8） and model group （n = 32）. Ischemic models were established in the model group by transient clamping of the bilateral carotid arteries and decreased blood pressure. After 20 minutes of global ischemia, the clamp was removed to allow blood flow for 30 minutes, 4, 24 and 72 hours, respectively, with 8 rats at each time point. The bilateral carotid arteries were not ligated in the sham surgery group. MAIN OUTCOME MEASURES： Neuronal death in the CA1 and DG regions was observed by hematoxylin-eosin staining. Proteasome expression in CA1 and DG region neurons was detected by immunohistochemistry. RESULTS： Hematoxylin-eosin staining showed neuronal death in the CA1 region alone at 72 hours of reperfusion following ischemia. In comparison to the sham surgery group, a significant decrease in proteasome expression was observed, by immunohistochemistry, in the CA1 and DG regions in the model group, following 30 minutes, 4, 24, and 72 hours of reperfusion （P 〈 0.01）. After 72 hours of reperfusion following ischemia, proteasome expression had almost completely disappeared in the CA1 region. In contrast, neurons of the DG region showed minimized proteasome expression at 24 hours, with a slight increase at 72 hours （P 〈 0.01）. CONCLUSION： The alteration of proteasome following ischemia/reperfusion in the neurons of hippocampal CA1 and DG regions reduces the ability of cells to degrade abnormal protein, which may be an important factor resulting in delayed neuronal death following transient cerebral ischemia.

Responses of CDKs and p53 in Delayed Ischemic Neuronal Death

Stroke is a debilitating disease that affects millions each year. While in many cases cerebral ischemic injury can be limited by effective resuscitation or thrombolytic treatment, the injured neurons wither in a process known as delayed neuronal death (DND). Mounting evidence indicates that DND is not simply necrosis played out in slow motion but apoptosis is triggered. Of particular interest are two groups of signal proteins that participate in apoptosis cyclin dependent kinases (CDKs) and p53 among a myriad of signaling events after an ischemic insult. Recent investigations have shown that CDKs, a family of enzymes initially known for their role in cell cycle regulation, are activated in injured neurons in DND. As for p53, new reports suggest that its up regulation may represent a failed attempt to rescue injured neurons, although its up regulation was previously considered an indication of apoptosis. These observations thus rekindle an old quest to identify new neuroprotective targets to minimize the stroke damage. In this review, the author will examine the evidence that indicates the participation of CDKs and p53 in DND and then introduce pre clinical data to explore CDK inhibition as a potential neuroprotective target. Finally, using CDK inhibition as an example, this paper will discuss the pertinent criteria for a viable neuroprotective strategy for ischemic injury.

Relation of phospholipase A2-Ⅴ and indoxam to hippocampal neuronal death

BACKGROUND: Ⅴ secretory phospholipase A2 (sPLA2-Ⅴ) is abundant in many mammal tissues. However, it remains unknown whether sPLA2-Ⅴ causes biological or pathological response in central nervous system. OBJECTIVE: To observe the effect of phospholipase A2-Ⅴ (PLA2-Ⅴ) and its inhibitor (indoxam) on hippocampal neuron survival. DESIGN: A repetitive measurement. SETTING: The Animal Center of South Carolina University. MATERIALS: Sprague-Dawley pregnancy day-7, 14, 21 female rats were selected; Reagents: sPLA2- Ⅴ and indoxam were obtained from the Dennis Research Laboratories METHODS: The experiment was finished at the animal center in South Carolina University from January to December, 2004. 0, 12.5, 25, 50 and 100 μg/L sPLA2-Ⅴ were added to neuron with none-MgCl2 Eagle’s medium at 37 ℃, then changed to normal neuron culture medium after 3 hours. 1, 2.5, 5 and 10 μmol/L indoxam was added at 6 hours after 100 μg/L sPLA2-Ⅴwas put to Day-21 SD rat hippocampal embryonic neurons with none-MgCl2 Eagle’s medium at 37 ℃. After 3 hours in the inhibition experiment, it was changed to normal neuron culture medium. The embryonic hippocampal neurons were primarily cultured, and the neuron survival ratio was detected with morphological method. MAIN OUTCOME MEASURES: Survival ratio of hippocampal neurons. RESULTS: ① Effects of sPLA2-Ⅴon neuron survival: When sPLA2-Ⅴ was 0, 12.5, 25, 50 and 100 μg/L, the neuron survival ratios in embryonic neurons of day-7 SD rats were (95.3±1.1)%, (81.4±3.1)%, (74.2±2.2)%, (62.4±1.7)% and (48.9±1.6)%, those in embryonic neurons of day-14 rats were (93.2±1.4)%, (74.3±1.9)%, (68.1±1.7)%, (56.1±1.4)% and (42.5±1.1)%, and those in embryonic neurons of day-21 rats were (91.2±1.2)%, (69.4±2.1)%, (60.3±2.2)%, (49.1±1.2)% and (35.5±1.9)%. There were significant differences among different concentrations (P < 0.05). ② Effects of indoxam on neuron survival: In case of sPLA2-Ⅴ 100 μg/L, the neuron survival ratios were (58.65±1.4)%, (69.34±1.1)%, (82.11±1.2)% and (95.28±0.9)% when indoxam was 1, 2.5, 5 and 10 μmol/L, respectively. There were significant differences among different concentrations (P < 0.05). CONCLUSION: ① The of neuronal death ratio is in a concentration-dependent manner with sPLA2-Ⅴ, and increases as the embryonic aging. ② Indoxam inhibits the proapoptotic effect of sPLA2-Ⅴ.

针刺调节神经元程序性细胞死亡的机制研究进展

神经系统疾病的发生和发展过程中常伴随着异常的神经元程序性细胞死亡。针刺作为神经系统疾病的常用防治手段,其调控失衡的神经元程序性细胞死亡的作用值得深入探讨。针刺主要可通过调控神经元凋亡、焦亡、自噬、铁死亡来治疗脑缺血、脑出血、颅脑外伤、脊髓损伤、阿尔茨海默病等疾病。故本文就针刺之于神经元程序性细胞死亡的作用机制进行综述,以期挖掘针刺在多种神经系统疾病治疗过程中的共同生物学机制,为深入开展相关研究提供新思路。

异泽兰黄素改善蛛网膜下腔出血模型大鼠学习记忆能力的机制

背景:异泽兰黄素是一种源自青蒿属的黄酮类活性成分,可缓解蛛网膜下腔出血大鼠的炎症反应,改善神经学评分,但其在学习记忆方面的作用和机制仍不清楚。目的:探究异泽兰黄素对蛛网膜下腔出血模型大鼠学习记忆能力及P38有丝分裂素激活蛋白激酶(p38 MAPK)/信号传导和转录活化因子3(STAT3)通路蛋白的影响。方法:采用随机数字表法将50只SD大鼠随机分为假手术组、模型组、异泽兰黄素组、橙皮素组、异泽兰黄素+橙皮素组,每组10只。除假手术组外,其余4组通过血管内穿孔构建蛛网膜下腔出血模型,造模成功2 h后,异泽兰黄素组尾静脉注射10 mg/kg异泽兰黄素,橙皮素组尾静脉注射50 mg/kg橙皮素(p38 MAPK/STAT3信号通路激活剂),异泽兰黄素+橙皮素组尾静脉注射10 mg/kg异泽兰黄素+50 mg/kg橙皮素,假手术组与模型组尾静脉注射10 mL/kg生理盐水。药物治疗24 h后,采用神经功能评分及Morris水迷宫实验检测大鼠神经功能及学习记忆能力,苏木精-伊红染色检测海马组织病理学变化,TUNEL法检测神经细胞凋亡,免疫荧光染色检测海马组织双皮质素阳性细胞数,Western blot检测海马组织p38 MAPK/STAT3蛋白表达。结果与结论:①与假手术组比较,模型组大鼠神经功能评分、学习记忆能力、双皮质素阳性细胞数均降低(P<0.05),神经细胞凋亡率及p-p38 MAPK/p38 MAPK、p-STAT3/STAT3蛋白表达均升高(P<0.05);②与模型组比较,异泽兰黄素组大鼠神经功能评分、学习记忆能力、双皮质素阳性细胞数均升高(P<0.05),神经细胞凋亡率及p-p38 MAPK/p38 MAPK、p-STAT3/STAT3蛋白表达均降低(P<0.05);橙皮素组大鼠神经功能评分、学习记忆能力、双皮质素阳性细胞数均降低(P<0.05),神经细胞凋亡率及p-p38 MAPK/p38 MAPK、p-STAT3/STAT3蛋白表达均升高(P<0.05);③与异泽兰黄素组比较,异泽兰黄素+橙皮素组大鼠神经功能评分、学习记忆能力、双皮质素阳性细胞数均降低(P<0.05),神经细胞凋亡率及p-p38 MAPK/p38 MAPK、p-STAT3/STAT3蛋白表达均升高(P<0.05);④苏木精-伊红染色显示,相较于模型组,异泽兰黄素组神经细胞排列较为整齐,橙皮素组神经细胞排列紊乱,异泽兰黄素+橙皮素组神经细胞排列与模型组相似;⑤结果表明,异泽兰黄素可能通过抑制p38 MAPK/STAT3信号通路改善蛛网膜下腔出血模型大鼠的学习记忆能力。

基于严重痫样发作行为的小鼠匹罗卡品颞叶癫痫模型构建

目的探讨C57BL/6J亚系小鼠经腹腔注射匹罗卡品建立颞叶癫痫模型的方法,总结可用于预测造模成功的癫痫发作急性期行为学表现,为癫痫研究提供可行的造模方案。方法选择30只C57BL/6J亚系小鼠(主要研究对象)和40只C57BL/6N亚系小鼠(对照),通过单次腹腔注射匹罗卡品的方法诱导小鼠癫痫发作从而建立颞叶癫痫模型。两种亚系的小鼠各分为3组,分别经腹腔注射300 mg/kg、330 mg/kg或360 mg/kg的匹罗卡品,观察并比较两种亚系小鼠的运动性癫痫发作的行为学表现,并在造模后第7天开始连续监测小鼠的自发性癫痫发作(spontaneous recurrent seizures,SRS)行为。造模后28 d,处死小鼠并观察其海马的病理改变情况。结果注射匹罗卡品后,C57BL/6N亚系小鼠表现出典型的运动性癫痫发作,而后进入癫痫持续状态(status epilepticus,SE);C57BL/6J小鼠较少观察到典型的运动性癫痫发作及后续的SE,而更多表现为单侧肢体抽搐后持续数秒至数十秒的全身颤抖,本研究将此行为学表现定义为严重痫样发作(severe seizure,SS)。腹腔注射330 mg/kg和360 mg/kg匹罗卡品后,在癫痫急性期出现过SS的C57BL/6J小鼠,经过潜伏期后可出现SRS,C57BL/6J亚系小鼠造模后SRS的比例(70%)和经历过SE后出现SRS的C57BL/6N亚系小鼠(75%)相近。造模后28 d,C57BL/6J小鼠海马出现颞叶癫痫的特征性病理改变,包括苔藓纤维出芽和神经元丢失。结论C57BL/6J亚系小鼠经腹腔注射匹罗卡品诱导癫痫模型时,造模成功的行为学标准可以是SE的发生,也可以是SS的出现。

Time-course pattern of neuronal loss and gliosis in gerbil hippocampi following mild, severe, or lethal transient global cerebral ischemia

Transient ischemia in the whole brain leads to neuronal loss/death in vulnerable brain regions. The striatum, neocortex and hippocampus selectively loose specific neurons after transient ischemia. Just 5 minutes of transient ischemia can cause pyramidal neuronal death in the hippocampal cornu ammonis (CA) 1 field at 4 days after transient ischemia. In this study, we investigated the effects of 5-minute (mild), 15-minute (severe), and 20-minute (lethal) transient ischemia by bilateral common carotid artery occlusion (BCCAO) on behavioral change and neuronal death and gliosis (astrocytosis and microgliosis) in gerbil hippocampal subregions (CA1-3 region and dentate gyrus). We performed spontaneous motor activity test to evaluate gerbil locomotor activity, cresyl violet staining to detect cellular distribution, neuronal nuclei immunohistochemistry to detect neuronal distribution, and Fluoro-Jade B histofluorescence to evaluate neuronal death. We also conducted immunohistochemical staining for glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 (Ibal) to evaluate astrocytosis and microgliosis, respectively. Animals subjected to 20-minute BCCAO died in at least 2 days. BCCAO for 15 minutes led to pyramidal cell death in hippocampal CA1-3 region 2 days later and granule cell death in hippocampal de匚tate gyrus 5 days later. Similar results were not found in animals subjected to 5-minute BCCAO. Gliosis was much more rapidly and severely progressed in animals subjected to 15-minute BCCAO than in those subjected to 5- minute BCCAO. Our results indicate that neuronal loss in the hippocampal formation following transient ischemia is significantly different according to regions and severity of transient ischemia. The experimental protocol was approved by Institutional Animal Care and Use Committee (AICUC) of Kangwon National University (approval No. KW-180124-1) on May 22, 2018.

Regulation of neuronal survival by DNA methyltransferases

The limited regenerative capacity of neuronal cells requires tight orchestration of cell death and survival regulation in the context of longevity, age-associated diseases as well as during the development of the nervous system. Subordinate to genetic networks epigenetic mechanisms like DNA methylation and histone modifications are involved in the regulation of neuronal development, function and aging. DNA methylation by DNA methyltransferases （DNMTs）, mostly correlated with gene silencing, is a dynamic and reversible process. In addition to their canonical actions performing cytosine methylation, DNMTs influence gene expression by interactions with histone modifying enzymes or complexes increasing the complexity of epigenetic transcriptional networks. DNMTs are expressed in neuronal progenitors, post-mi- totic as well as adult neurons. In this review, we discuss the role and mode of actions of DNMTs including downstream networks in the regulation of neuronal survival in the developing and aging nervous system and its relevance for associated disorders.

基于超声联合生物标志物的重症脑损伤患者早期死亡风险预测模型建立与验证

目的构建重症脑损伤患者早期(发病30 d内)死亡风险预测模型。方法本研究为前瞻性观察性研究,收集2022年6月至2023年5月重庆市红十字会医院收治的139例重症脑损伤患者的相关资料为训练集,采用Logistic回归建立死亡预测模型,并评价模型区分度、校准度、临床适用度,最终以列线图展示模型结果。另收集2023年6月至2023年10月收治的31例重症脑损伤患者为验证集,用于对模型进行外部验证。结果139例重症脑损伤患者住院期间死亡50例,病死率为35.97%。单因素分析显示,入院时气管插管状态、对光反射状态、脑疝形成、凝血障碍、GCS评分、平均动脉压、急性生理学和慢性健康状况评价Ⅱ(APACHEⅡ)评分、血小板计数、神经元特异性烯醇化酶(neuron-specific enolase,NSE)、搏动指数(pulsatility index,PI)及视神经鞘直径(optic nerve sheath diameter,ONSD)是重症脑损伤患者早期死亡的危险因素。多因素Logistic回归分析得到死亡风险预测概率公式为:Logit(P)=-14.266+0.14×(APACHEⅡ评分)+0.047×(NSE)+1.57×(PI)+0.908×(ONSD)+2.375×(凝血状态),本风险模型预测重症脑损伤患者早期死亡发生的ROC曲线下面积(AUC)为0.886(P<0.01),敏感度和特异度分别为76.00%和91.00%。外部验证结果显示,预测模型AUC为0.810,敏感度为75.00%,特异度为87.00%。结论由APACHEⅡ评分、NES、PI、ONSD和凝血功能异常构建的风险预测模型对重症脑损伤患者早期死亡具有较高的评估效能。

Heterogeneity in the regenerative abilities of central nervous system axons within species: why do some neurons regenerate better than others?

Some neurons,especially in mammalian peripheral nervous system or in lower vertebrate or in vertebrate central nervous system(CNS)regenerate after axotomy,while most mammalian CNS neurons fail to regenerate.There is an emerging consensus that neurons have different intrinsic regenerative capabilities,which theoretically could be manipulated therapeutically to improve regeneration.Population-based comparisons between"good regenerating"and"bad regenerating"neurons in the CNS and peripheral nervous system of most vertebrates yield results that are inconclusive or difficult to interpret.At least in part,this reflects the great diversity of cells in the mammalian CNS.Using mammalian nervous system imposes several methodical limitations.First,the small sizes and large numbers of neurons in the CNS make it very difficult to distinguish regenerating neurons from non-regenerating ones.Second,the lack of identifiable neurons makes it impossible to correlate biochemical changes in a neuron with axonal damage of the same neuron,and therefore,to dissect the molecular mechanisms of regeneration on the level of single neurons.This review will survey the reported responses to axon injury and the determinants of axon regeneration,emphasizing non-mammalian model organisms,which are often under-utilized,but in which the data are especially easy to interpret.

Transglutaminase inhibition:A therapy to protect cells from death in neurodegeneration?

Transglutaminases(TGs;E.C.2.3.2.13)are ubiquitous enzymes which catalyze post-translational modifications of proteins.TGs and TG-catalyzed post-translational modifications of proteins have been shown to be involved in the molecular mechanisms responsible for several human diseases.In particular,TG activity has been hypothesized to also be involved also in the molecular mechanisms responsible for human neurodegenerative diseases.In support of this hypothesis,Basso et al recently demonstrated that the TG inhibition protects against oxidative stress-induced neuronal death,suggesting that multiple TG isoforms participate in oxidative stress-induced cell death and that nonselective TG isoform inhibitors will be most effective in fighting oxidative death in neurological disorders.In this commentary,we discuss the possible molecular mechanisms by which TG activity could be involved in the pathogenesis of neurological diseases,with particular reference to neurodegenerative diseases,and the possible involvement of multiple TG isoforms expressed simultaneously in the nervous system in these diseases.Moreover,therapeutic strategies based on the use of selective or nonselective TG inhibitors for the amelioration of thesymptoms of patients with neurological diseases,characterized by aberrant TG activity,are also discussed.