RhoGDIα is an inhibitor of RhoGDP dissociation that involves in Aβ metabolism and NFTs production in Alzheimer's disease (AD) by regulating of RhoGTP enzyme activity. Our previous research revealed that RhoGDIα, as the target of Polygala saponin (Sen), might alleviate apoptosis of the nerve cells caused by hypoxia/reoxygenation (H/R). To further clarify the role of RhoGDIα in the generation of NFTs, we explored the relationship between RhoGDIα and Tau. We found out that RhoGDIα and Tau can bind with each other and interact by using coimmunoprecipitation (Co-IP) and GST pulldown methods in vitro. This RhoGDIα-Tau partnership was further verified by using immunofluorescence colocalization and fluorescence resonance energy transfer (FRET) approaches in PC12 cells. Using the RNA interference (RNAi) technique, we found that the RhoGDIα may be involved in an upstream signaling pathway for Tau. Subsequently, in Aβ25-35- and H/R-induced PC12 cells, forced expression of RhoGDIα via cDNA plasmid transfection was found to reduce the hyperphosphorylation of Tau, augment the expression of bcl-2 protein, and inhibit the expression of Bax protein (reducing the Bax/bcl-2 ratio) and the activity of caspase-3. In mouse AD and VaD models, forced expression of RhoGDIα via injection of a viral vector (pAAV-EGFP-RhoGDIα) into the lateral ventricle of the brain alleviated the pathological symptoms of AD and VaD. Finally, GST pulldown confirmed that the binding sites on RhoGDIα for Tau were located in the range of the ΔC33 fragment (aa 1–33). These results indicate that RhoGDIα is involved in the phosphorylation of Tau and apoptosis in AD and VaD. Overexpression of RhoGDIα can inhibit the generation of NFTs and delay the progress of these two types of dementia.

Myocardial dysfunction accompanied by severe sepsis could significantly increase the mortality rate of septic patients. This study investigated the effects and the potential mechanisms of sevoflurane preconditioning on septic myocardial dysfunction, which was induced by lipopolysaccharide (LPS; from Escherichia coli O55:B5; 18 mg/kg) in mice. Results indicated that 1 hour after the administration, LPS induced a significant increase in cell-surface Toll-like receptor 4 (TLR4), cytoplasmic IKKα protein expression, and nuclear translocation of nuclear factor kappa-B (NF-κB) protein (P < 0.05), which was attenuated by preconditioning with sevoflurane. Two hours after the administration, inhalation of sevoflurane significantly reduced the serum levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-10 (P < 0.05). Twelve hours after administration, LPS caused pathological damage to the heart and elevated the serum levels of lactate dehydrogenase (LDH) and creatine kinase-MB (P < 0.05). Echocardiography indicated that sevoflurane preconditioning significantly improved systolic and diastolic function. The inhalation of sevoflurane inhibited increases in myeloperoxidase (MPO), macrophage inflammatory protein-2 (MIP-2), TNF-α, and IL-1β levels (P < 0.05) induced by endotoxemia, whereas IL-6 release was facilitated. Sevoflurane attenuated the myocardial levels of nitric oxide (P < 0.05) without an apparent influence on malondialdehyde (MDA) or superoxide dismutase (P > 0.05). In conclusion, our study indicates that exposure to 2% sevoflurane before LPS challenge is protective against myocardial dysfunction. Sevoflurane preconditioning may attenuate neutrophil infiltration and the release of inflammatory mediators during endotoxemia.

目的：初步探讨缺氧／复氧（ hypoxia／reoxygenation，H／R）诱导PC12细胞凋亡模型中tau蛋白及其磷酸化水平、凋亡相关蛋白Bax、Bcl－2的表达情况。方法：类神经元PC12细胞体外培养并传至第三代，进行相应处理，实验分组为正常对照组（ control组）、模型组（ H／R组）。 Annexin V－PI双染流式细胞术分别检测各组凋亡率以确定模型是否成功；造模成功后，使用RIPA裂解液提取蛋白；Western blotting技术检测各组tau蛋白及其磷酸化、Bax和Bcl－2的表达变化。结果：与control组相比，H／R组细胞凋亡率显著升高（ P＜0．05），提示模型构建成功；Westem blotting结果显示，与control组相比，H／R组中tau蛋白表达显著减少（P＜0．05），且tau蛋白Ser202位点的磷酸化水平显著升高（P＜0．05），Bax／Bcl－2显著升高（P＜0．05）。结论：Tau蛋白可能参与了缺氧／复氧诱导的神经细胞凋亡，其机制有待深入研究。

可溶性β淀粉样蛋白（β-amyloid， Aβ）寡聚物可以削弱突触的可塑性，导致与阿尔茨海默病（Alzheimer disease， AD）相关的突触数量减少。 Kim等的研究发现，鼠成对免疫球蛋白样受体B蛋白（ paired immunoglobulin-like receptor B ， PirB）及其人直系同源物（ortholog）--白细胞免疫球蛋白样受体B2（leukocyte immunoglobulin-like receptor B2， LilrB2；表达于人脑中）都是Aβ寡聚物的受体，且亲和力可达纳摩尔级。PirB和LilrB2的前2个胞外免疫球蛋白（ Ig）结构域介导了受体与Aβ的相互作用，从而导致丝切蛋白（ cofilin）信号的增强；在AD病人大脑中也可看到这一现象。在小鼠中，Aβ寡聚物对海马长时程增强效应的损害需要PirB的参与。在AD转基因模型中，PirB不仅导致了成年小鼠的记忆缺失，同时也介导了幼年小鼠视觉皮层中突触可塑性的降低。这些发现提示LilrB2可能在人AD的神经病理学机制中具有重要作用，阻断LilrB2的功能有助于治疗AD。

Neuronal apoptosis is an important event in hypoxia/reoxygenation (H/R)-induced neuronal injury. Senegenin (Sen), the predominant and most active component in Radix Polygalae root extracts, displays anti-apoptotic and anti-oxidative properties. Sen protects against H/R-induced neuronal apoptosis of highly differentiated PC12 cells and primary cortical neurons. Sen has also been investigated as a source of potential therapeutic targets. In this study, a proteomic approach was used to identify Sen-regulated proteins in PC12 cells. We found that Sen protected against H/R-induced neuronal apoptosis by upregulating RhoGDIα protein expression. The regulatory functions of RhoGDIα were investigated by knocking down RhoGDIα expression in PC12 cells using small interfering RNA (siRNA), followed by quantification of apoptosis and then altering the expression levels of apoptosis-related proteins. Our data show that after silencing RhoGDIα, the neuroprotective effects of Sen on H/R-induced PC12 cell apoptosis were absent. Furthermore, RhoGDIα silencing alleviated the Sen-mediated inhibition of the JNK pathway. Therefore, these findings indicated that Sen attenuates H/R-induced neuronal apoptosis by upregulating RhoGDIα expression and inhibiting the JNK pathway. In addition to the mechanism underlying neuroprotective effects of Sen, RhoGDIα was identified as a putative target of Sen based on a primary rat cortical neuron model of H/R-induced injury.