GATA4在心肌肥厚中的作用

新近观点认为,病理性心肌肥厚是心肌细胞与冠脉血管不平衡生长的结果,即冠脉系统的生长不能够赶上心肌生长,从而导致心肌收缩障碍和心力衰竭。GATA4是其中一个重要转录调控因子,传统认为它与心肌收缩障碍和心力衰竭密切相关;现在研究发现GATA4是鼠类心脏血管生成的关键调控因子,在各种疾病导致的心肌肥厚中,冠脉血管生成有利于持续的心脏功能代偿,延缓心衰发生。由此看来,在心肌肥厚发病过程中,GATA4既是一个破坏者,也是一个保护者。     

对热休克反应的哲学思考

生物细胞在受到各种有害因素刺激后,会发生一种应激反应,其间细胞内的正常蛋白质合成受抑,而合成一些新的蛋白质,这种现象及所合成的蛋白质被称之为热休克反应和热休克蛋白。研究发现,热休克反应是生物细胞对环境因素的适应性反应,并广泛存在于从原核到真核生物的生物体内。对人类而言,其功能是多样的,利弊共存,形成了相互联系相互转化的对立统一关系     

DGAVP易化记忆巩固过程与脑内蛋白质合成关系的探讨

本实验研究了脱甘氨酰胺精氨酸加压素(DGAVP)易化记忆巩固过程的作用,证明DGAVP能够防止蛋白质合成抑制剂茴香霉素(ANI)对记忆的破坏作用,并从突触体水平上探讨了DGAVP的作用与蛋白质合成的关系。 实验结果表明:(1)在复杂迷宫趋食反应中,DGAVP能够增强小鼠对觅食路径的记忆。(2)ANI破坏小鼠的记忆,而预先给予DGAVP则能防止ANI的破坏作用;在一次性被动回避反应中ANI和DGAVP的作用与迷宫实验的结果一致。(3)ANI抑制究触体对蛋白质合成前体亮氨酸的摄取,作用非常显著。DGAVP能够改善ANI的抑制效应,体外和体内的实验结果完全一致。实验结果提示DGAVP的作用机制与蛋白质合成有一定关系。     

查美尼克在分子生物学方面的贡献

查美尼克是分子生物学的奠基人之一,第一个开发了无细胞蛋白质合成体系,发现了蛋白质合成中氨基酸ATP活化机制,发现了tRNA及其在基因表达中的作用,特别是发明的反义技术创造了一个新的生物技术原理。通过查美尼克的成就我们可以对分子生物学历史面貌有一个了解从而对生命科学的发展有一个新的视点。     

从炎症在心力衰竭进展中的作用谈心力衰竭治疗策略的制订

心力衰竭是一个以免疫激活和低程度的慢性炎症为特点的疾病.一些炎症因子能通过促进心肌细胞肥厚、恶化心肌收缩功能以及诱导凋亡,在心衰的发展过程中具有重要作用.炎症因子能成为心衰治疗的重要目标.但炎症因子还有心脏代偿和保护作用.制订新的心衰治疗策略时需要进一步了解心衰中炎症反应激活的机制.     

查美尼克在分子生物学方面的贡献

查美尼克是分子生物学的奠基人之一,第一个开发了无细胞蛋白质合成体系,发现了蛋白质合成中氨基酸ATP活化机制,发现了tRNA及其在基因表达中的作用,特别是发明的反义技术创造了一个新的生物技术原理.通过查美尼克的成就我们可以对分子生物学历史面貌有一个了解从而对生命科学的发展有一个新的视点.     

从炎症在心力衰竭进展中的作用谈心力衰竭治疗策略的制订

心力衰竭是一个以免疫激活和低程度的慢性炎症为特点的疾病。一些炎症因子能通过促进心肌细胞肥厚、恶化心肌收缩功能以及诱导凋亡,在心衰的发展过程中具有重要作用。炎症因子能成为心衰治疗的重要目标。但炎症因子还有心脏代偿和保护作用。制订新的心衰治疗策略时需要进一步了解心衰中炎症反应激活的机制。     

端粒,端粒酶：人类长寿及肿瘤治疗的新策略

端粒是真核生物染色体末端由许多简单重复序列和相关蛋白质组成的复合结构,具有维持染色体结构的完整性及解决末端复制难题的作用,端业酶是一种逆转录酶,由ＲＮＡ和蛋白质组成,它以自身ＲＮＡ为模块,合成端粒重复序列,加至新合成ＤＮＡ链末端,端粒及闰酶在细胞衰老及肿瘤形成过程中起重要作用,针对端粒栈瓣肿瘤治疗有可能成为肿瘤治疗新途径。     

蛋白质化学与分子生物学携手前进

蛋白质化学的发展历经了几次重大的转变,分析仪器的商品化使蛋白质从实验室走向市场;一级结构信息促进了多肽的合成与改造;分子生物学技术的成熟使人们从设计改造功能蛋白转向设计基因,并尝试进行基因治疗和ＤＮＡ免疫。这些转变,使蛋白质化学技术与分子生物学技术成为人们手中的工具,为人们研究生命拓宽了思路。     

卡托普利异氟醚联合预处理对心脏瓣膜置换术患者的心肌保护作用

探讨卡托普利与畀氟醚联合预处理对心肌缺血再灌注损伤的保护作用。选择100例瓣膜置换术患者分为五组,分别给以不同的药物预处理。观察各组心肌酶、心肌蛋白、炎症因子的变化,以及心脏复跳率和血管活性药物使用。结果显示,卡托普利与异氟醚联合处理组的心肌酶、心肌蛋白、炎症因子以及心脏复跳率和血管活性药物用量与其他三组相比有显著性差异（P〈0．05）。认为卡托普利延迟相或早期相复合异氟醚预处理对心脏瓣膜置换术患者的心肌缺血再灌注损伤均具有更强保护作用,并以卡托普利延迟相组为优。     

Synaptic plasticity and translation initiation

It is widely accepted that protein synthesis, including local protein synthesis at synapses, is required for several forms of synaptic plasticity. Local protein synthesis enables synapses to control synaptic strength independent of the cell body via rapid protein production from pre-existing mRNA. Therefore, regulation of translation initiation is likely to be intimately involved in modulating synaptic strength. Our understanding of the translation-initiation process has expanded greatly in recent years. In this review, we discuss various aspects of translation initiation, as well as signaling pathways that might be involved in coupling neurotransmitter and neurotrophin receptors to the translation machinery during various forms of synaptic plasticity.     

The anaphase promoting complex is required for memory function in mice

Learning and memory processes critically involve the orchestrated regulation of de novo protein synthesis. On the other hand it has become clear that regulated protein degradation also plays a major role in neuronal plasticity and learning behavior. One of the key pathways mediating protein degradation is proteosomal protein destruction. The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets proteins for proteosomal degradation by the 26S proteasome. While the APC/C is essential for cell cycle progression it is also expressed in postmitotic neurons where it has been implicated with axonal outgrowth and neuronal survival. In this study we addressed the role of APC/C in learning and memory function by generating mice that lack the essential subunit APC2 from excitatory neurons of the adult forebrain. Those animals are viable but exhibit a severe impairment in the ability to extinct fear memories, a process critical for the treatment of anxiety diseases such as phobia or post-traumatic stress disorder. Since deregulated protein degradation and APC/C activity has been implicated with neurodegeneration we also analyzed the effect of Apc2 deletion in a mouse model for Alzheimer's disease. In our experimental setting loss of APC2 form principle forebrain neurons did not affect the course of pathology in an Alzheimer's disease mouse model. In conclusion, our data provides genetic evidence that APC/C activity in the adult forebrain is required for cognitive function.     

BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory?

It is generally believed that late-phase long-term potentiation (L-LTP) and long-term memory (LTM) require new protein synthesis. Although the full complement of proteins mediating the long-lasting changes in synaptic efficacy have yet to be identified, several lines of evidence point to a crucial role for activity-induced brain-derived neurotrophic factor (BDNF) expression in generating sustained structural and functional changes at hippocampal synapses thought to underlie some forms of LTM. In particular, BDNF is sufficient to induce the transformation of early to late-phase LTP in the presence of protein synthesis inhibitors, and inhibition of BDNF signaling impairs LTM. Despite solid evidence for a critical role of BDNF in L-LTP and LTM, many issues are not resolved. Given that BDNF needs to be processed in Golgi outposts localized at the branch point of one or few dendrites, a conceptually challenging problem is how locally synthesized BDNF in dendrites could ensure synapse-specific modulation of L-LTP. An interesting alternative is that BDNF-TrkB signaling is involved in synaptic tagging, a prominent hypothesis that explains how soma-derived protein could selectively modulate the tetanized (tagged) synapse. Finally, specific roles of BDNF in the acquisition, retention or extinction of LTM remain to be established.     

Signaling Mechanisms Mediating BDNF Modulation of Synaptic Plasticity in the Hippocampus

Although recent studies indicate that brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal synaptic plasticity, the underlying signaling mechanisms remain largely unknown. Here, we have characterized the signaling events that mediate the BDNF modulation of high-frequency synaptic transmission. Mitogen-associated protein kinase (MAPK), phosphotidylinositol-3 kinase (PI3K), and phospholipase C-γ (PLC-γ) are the three signaling pathways known to mediate neurotrophin signaling in other systems. In neonatal hippocampal slices, application of BDNF rapidly activated MAPK and PI3K but not PLC-γ. BDNF greatly attenuated synaptic fatigue at CA1 synapses induced by a train of high-frequency, tetanic stimulation (HFS). Inhibition of the MAPK and PI3K, but not PLC-γ, prevented the BDNF modulation of high-frequency synaptic transmission. Neurotrophin-3 (NT-3), a close relative of BDNF, did not activate MAPK or PI3K and had no effect on synaptic fatigue in the neonatal hippocampus. Neither forskolin, which activated MAPK but not PI3 kinase, nor ciliary neurotrophic factor (CNTF), which activated PI3K but not MAPK, affected HFS-induced synaptic fatigue. Treatment of the slices with forskolin together with CNTF still had no effect on synaptic fatigue. Thus, although the activation of MAPK and PI3K is required, the two together are not sufficient to mediate the BDNF effect. Inhibition of new protein synthesis by anisomycin or cycloheximide did not prevent the BDNF effect. These data suggest that BDNF modulation of high-frequency transmission is independent of protein synthesis but requires MAPK and PI3K and yet another signaling pathway to act together in the hippocampus.     

Insulin receptor signaling in long-term memory consolidation following spatial learning

Evidence has shown that the insulin and insulin receptor (IR) play a role in cognitive function. However, the detailed mechanisms underlying insulin's action on learning and memory are not yet understood. Here we investigated changes in long-term memory-associated expression of the IR and downstream molecules in the rat hippocampus. After long-term memory consolidation following a water maze learning experience, gene expression of IR showed an up-regulation in the CA1, but a down-regulation in the CA3 region. These were correlated with a significant reduction in hippocampal IR protein levels. Learning-specific increases in levels of downstream molecules such as IRS-1 and Akt were detected in the synaptic membrane accompanied by decreases in Akt phosphorylation. Translocation of Shc protein to the synaptic membrane and activation of Erk1/2 were also observed after long-term memory formation. Despite the clear memory-correlated alterations in IR signaling pathways, insulin deficits in experimental diabetes mellitus (DM) rats induced by intraperitoneal injections of streptozotocin resulted in only minor memory impairments. This may be due to higher glucose levels in the DM brain, and to compensatory mechanisms from other signaling pathways such as the insulin-like growth factor-1 receptor (IGF-1R) system. Our results suggest that insulin/IR signaling plays a modulatory role in learning and memory processing, which may be compensated for by alternative pathways in the brain when an insulin deficit occurs.     

Lidocaine attenuates anisomycin-induced amnesia and release of norepinephrine in the amygdala

When administered near the time of training, protein synthesis inhibitors such as anisomycin impair later memory. A common interpretation of these findings is that memory consolidation requires new protein synthesis initiated by training. However, recent findings support an alternative interpretation that abnormally large increases in neurotransmitter release after injections of anisomycin may be responsible for producing amnesia. In the present study, a local anesthetic was administered prior to anisomycin injections in an attempt to mitigate neurotransmitter actions and thereby attenuate the resulting amnesia. Rats received lidocaine and anisomycin injections into the amygdala 130 and 120 min, respectively, prior to inhibitory avoidance training. Memory tests 48 h later revealed that lidocaine attenuated anisomycin-induced amnesia. In other rats, in vivo microdialysis was performed at the site of amygdala infusion of lidocaine and anisomycin. As seen previously, anisomycin injections produced large increases in release of norepinephrine in the amygdala. Lidocaine attenuated the anisomycin-induced increase in release of norepinephrine but did not reverse anisomycin inhibition of protein synthesis, as assessed by c-Fos immunohistochemistry. These findings are consistent with past evidence suggesting that anisomycin causes amnesia by initiating abnormal release of neurotransmitters in response to the inhibition of protein synthesis.