EGCG改善D-gal诱导阿尔茨海默病模型大鼠认知障碍机制研究

目的探讨表没食子儿茶素没食子酸酯(EGCG)通过抑制p75NTR介导的凋亡通路相关因子改善D-gal诱导阿尔茨海默病(AD)模型大鼠学习记忆障碍的作用及其机制。方法以Morris水迷宫观察动物行为学变化,TUNEL法检测神经细胞凋亡情况,同时采用免疫组化及Western blot法检测其脑内Cleaved-Caspase-3表达水平,并用Western blot法检测p75NTR介导的凋亡通路相关蛋白表达水平。结果 EGCG明显改善D-gal诱导AD模型大鼠学习记忆障碍,抑制其脑内TUNEL阳性细胞表达,降低凋亡特征性蛋白Cleaved-Caspase-3的表达水平。同时,EGCG可通过抑制p75NTR介导的凋亡相关通路,显著降低p75ICD表达水平及其下游JNK2、c-Jun磷酸化水平,降低下游凋亡相关蛋白p53的表达水平,从而发挥抗凋亡、改善学习记忆障碍的抗AD作用。结论 EGCG可能通过抑制p75NTR介导的JNK/c-Jun/p53凋亡相关信号通路,抑制D-gal诱导AD模型大鼠脑内神经细胞凋亡,从而改善其认知障碍。     

Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multifaceted actions and "fine tuning" modulation

This review summarizes recent developments that have contributed to understand how adenosine receptors, particularly A2A receptors, modulate brain injury in various animal models of neurological disorders, including Parkinson's disease (PD), stroke, Huntington's disease (HD), multiple sclerosis, Alzheimer's disease (AD) and HIV-associated dementia. It is clear that extracellular adenosine acting at adenosine receptors influences the functional outcome in a broad spectrum of brain injuries, indicating that A2A Rs may modulate some general cellular processes to affect neuronal cells death. Pharmacological, neurochemical and molecular/genetic approaches to the complex actions of A2A receptors in different cellular elements suggest that A2A receptor activation can be detrimental or protective after brain insults, depending on the nature of brain injury and associated pathological conditions. An interesting concept that emerges from these studies is A2A R's ability to fine tune neuronal and glial functions to produce neuroprotective effects. While the data presented here clearly highlight the complexity of using adenosinergic agents therapeutically in PD and other neurodegenerative disorders and point out many areas for further inquiry, they also confirm that adenosine receptor ligands, particularly A2A receptor ligands, have many promising characteristics that encourage the pursuit of their therapeutic potential.     

The Influence of In Vivo Metabolic Modifications on ADMET Properties of Green Tea Catechins–In Silico Analysis

The health effects of green tea are associated with catechins: (?)-epigallocatechin-3-O-gallate (EGCG), (?)-epigallocatechin, (?)-epicatechin-3-O-gallate, and (?)-epicatechin. An understanding of compound absorption, distribution, metabolism, excretion, and toxicity characteristics is essential for explaining its biological activities. Herein, absorption, distribution, metabolism, excretion, and toxicity properties of in vivo detected metabolites of green tea catechins (GTCs) have been analyzed in silico. The influence of metabolic transformations on absorption, distribution, metabolism, and excretion profiles of GTCs corresponds to the effects of size, charge, and lipophilicity, as already observed for other small molecules. Mutagenic, carcinogenic, or liver toxic effects were predicted only for a few metabolites. Similar to galloylated GTCs EGCG and (--)-epicatechin-3-O-gallate, the sulfo-conjugates were predicted to bind at the warfarin binding site. The low free plasma concentration of these derivatives may be consequential to their serum albumin binding. The activity cliff detected for methylated conjugates of EGCG indicates that GTCs' pro-oxidative activity in bound state comes primarily from free hydroxyl groups of the pyrogallol ring B.     

开胸手术围术期多模式镇痛的临床研究

目的：探讨围术期多模式镇痛与传统术后镇痛方法用于开胸手术的镇痛效果及副作用.方法：36例择期行开胸肺叶切除术的病人,随机分为2组：A组（多模式镇痛组）于麻醉诱导前10分钟静注曲马多1.5 mg/kg,诱导时开始经静脉舒芬太尼病人自控镇痛（PCIA）,并于切皮前进行一次罗哌卡因肋间神经阻滞;B组于麻醉诱导时静脉注射舒芬太尼0.4 μg/kg,并于术后开始PCIA.分别于术后各时间点观察病人的VAS评分、镇静与舒适状态评分、镇痛药的使用剂量、PCA的按压次数、生命体征及副作用,并记录排气时间、计算PCA按压次数比及舒芬太尼使用量.结果：（1）与B组比较,A组静止及活动状态时的VAS评分、舒芬太尼用量、PCA按压次数明显下降,舒适状态评分明显升高,PCA按压次数比上升（P＜0.05）;（2）两组病人术后生命体征,镇静评分,排气时间,恶心、呕吐、皮肤瘙痒、胸闷等副作用的发生率无明显差异（P＞0.05）.结论：开胸手术围术期多模式镇痛的效果优于传统术后镇痛方法.     

Sufentanil induces delayed myocardial preconditioning mediated by HO-1

Purpose. The objective of this study was to examine whether sufentanil also confers delayed cardioprotection and whether this effect is mediated through HO-1.
Methods. Male Sprague-Dawley rats received either delayed ischemic preconditioning （DIPC） or sufentanilinduced preconditioning （SPC; with 3 μg/kg, 15 μg/kg, 30 μg/kg, 60 μg/kg, or 120 μg/kg sufentanil） or an ischemic reperfusion（CON）. After 24 h, all animals were subjected to a 30 min coronary occlusion followed by a 2 h reperfusion. In the group treated with 120 μg/kg sufentanil, the selective HO-1 inhibitor Zinc protoporphyrin IX （Znpp IX） was administered. The infarct size （IS） was determined with 2,3,5-triphenyltetrazolium chloride staining. Western blotting analysis was used to examine HO-1 expression.
Results. The IS/AAR ratios in the animals treated with DIPC （0.33±0.07） or with SPC （0.44±0.08, 0.32±0.10, 0.32±0.06, and 0.28±0.07 for the groups treated with 15 μg/kg, 30 μg/kg, 60 t~g/kg, or 120 μg/kg sufentanil, respectively） were significantly reduced compared with control （CON） group （0.54±0.06; P〈0.05）. The ED50 of sufentanil was found to be 13.83 μg/kg according to the sigmoid equation. Znpp IX abolished the effect of the 120 μg/kg sufentanil treatment （the IS/ AAR values were 0.54±0.04 for the SPC±Znpp IX group and 0.28±0.07 for the group treated with 120μg/kg SPC; P〈0.05）. The 120 μg/kg SPC treatment increased the expression of HO-1 compared with the CON group（P〈0.05）, and this effect was prevented by Znpp IX （P〈0.05）.
Conclusion. These results indicate that sufentanil produces delayed cardioprotection in anaesthetized rats and HO-1 may be involved in it.     

Neutrophil activation in Alzheimer’s disease and mild cognitive impairment: A systematic review and meta-analysis of protein markers in blood and cerebrospinal fluid

Inflammation is involved in the pathophysiology of Alzheimer’s disease (AD), with multiple inflammatory processes implicated in its risk and progression. This review included original peer-reviewed studies measuring the cerebrospinal fluid or peripheral blood concentrations of protein markers specifically related to neutrophil activity in healthy controls (HC) and in patients with AD or mild cognitive impairment (MCI). A total of 35 studies (N_HC = 3095, N_AD = 2596, N_MCI = 1203) were included. Random-effects meta-analyses were used to estimate between-groups standardized mean differences (SMD) and 95 % confidence intervals. In blood, concentrations of myeloperoxidase (MPO; N_AD/N_HC = 271/209, SMD = 0.41 [0.20, 0.62]; I² = 15.7 %) and neutrophil gelatinase associated lipocalin (NGAL; N_AD/N_HC = 273/185, SMD = 0.30 [0.11, 0.49]; I² < 0.005 %) were significantly higher in AD relative to HC. Peripheral blood concentrations of NGAL were also higher in MCI compared to HC (N_MCI/N_HC = 489/145, SMD = 0.39 [0.11, 0.67]; I² = 38.6 %). None of the protein markers exhibited a significant difference between HC, MCI, or AD groups in the cerebrospinal fluid. The evidence suggests that peripheral neutrophil activation, as indicated by blood concentrations of NGAL and MPO, may be a pathological feature of cognitive impairment due to AD, evident at stages of MCI and AD dementia.     

Multinutrient diets improve cerebral perfusion and neuroprotection in a murine model of Alzheimer's disease

Nutritional intervention may retard the development of Alzheimer's disease (AD). In this study we tested the effects of 2 multi-nutrient diets in an AD mouse model (APP_swe/PS1_dE9). One diet contained membrane precursors such as omega-3 fatty acids and uridine monophosphate (DEU), whereas another diet contained cofactors for membrane synthesis as well (Fortasyn); the diets were developed to enhance synaptic membranes synthesis, and contain components that may improve vascular health. We measured cerebral blood flow (CBF) and water diffusivity with ultra-high-field magnetic resonance imaging, as alterations in these parameters correlate with clinical symptoms of the disease. APP_swe/PS1_dE9 mice on control diet showed decreased CBF and changes in brain water diffusion, in accordance with findings of hypoperfusion, axonal disconnection and neuronal loss in patients with AD. Both multinutrient diets were able to increase cortical CBF in APP_swe/PS1_dE9 mice and Fortasyn reduced water diffusivity, particularly in the dentate gyrus and in cortical regions. We suggest that a specific diet intervention has the potential to slow AD progression, by simultaneously improving cerebrovascular health and enhancing neuroprotective mechanisms.     

Neuroimaging in dementia

Over the last few years, advances in neuroimaging have generated biomarkers, which increase diagnostic certainty, provide valuable information about prognosis, and suggest a particular pathology underlying the clinical dementia syndrome. We aim to review the evidence for use of already established imaging modalities, along with selected techniques that have a great potential to guide clinical decisions in the future. We discuss structural, functional and molecular imaging, focusing on the most common dementias: Alzheimer's disease, fronto-temporal dementia, dementia with Lewy bodies and vascular dementia. Finally, we stress the importance of conducting research using representative cohorts and in a naturalistic set up, in order to build a strong evidence base for translating imaging methods for a National Health Service. If we assess a broad range of patients referred to memory clinic with a variety of imaging modalities, we will make a step towards accumulating robust evidence and ultimately closing the gap between the dramatic advances in neurosciences and meaningful clinical applications for the maximum benefit of our patients.