3''R,4''R-二取代角型吡喃香豆素的不对称合成

目的:寻找具有钙离子拮抗作用和乙酰胆碱酯酶抑制活性双重作用机制的早老性痴呆(Alzheimer′s Disease,AD)新型抑制剂.方法:间二苯酚为底物,AD-mix-β作不对称双羟基化试剂进行凯林内酯类香豆素的全合成;所有产物进行乙酰胆碱酯酶(AchE)抑制活性测试.结论:立体选择性地合成cis-3′R,4′R-二取代角型二氢吡喃香豆素,但AchE 抑制活性明显低于cis-3′R,4′R-二取代线型二氢吡喃香豆素.     

3′R,4′R-二取代角型吡喃香豆素的不对称合成(英文)

目的:寻找具有钙离子拮抗作用和乙酰胆碱酯酶抑制活性双重作用机制的早老性痴呆(Alzheimer′sDisease,AD)新型抑制剂。方法:间二苯酚为底物,AD-mix-β作不对称双羟基化试剂进行凯林内酯类香豆素的全合成;所有产物进行乙酰胆碱酯酶(AchE)抑制活性测试。结论:立体选择性地合成cis3′-R,4′R-二取代角型二氢吡喃香豆素,但AchE抑制活性明显低于cis3′-R,4′R-二取代线型二氢吡喃香豆素。     

3，4-二取代香豆素类衍生物的合成及其对HIV-1逆转录酶的抑制活性

苯并六元杂环类化合物是重要的逆转录酶抑制剂,目前报道的活性较好的化合物在结构上都有一个疏水的苯环和与苯环相连的酰胺部分。通过对酰胺部分进行结构改造,探索其对HIV-1逆转录酶活性的影响。合成了一系列未见文献报道的3,4-二取代香豆素类化合物,其结构经IR,1H NMR,MS及元素分析确证。初步的药理活性实验表明,23个化合物中有7个化合物具有一定的HIV-1逆转录酶抑制活性。     

酵母发酵液催化不对称还原反应合成(S)-4-氯-3-羟基-丁酸乙酯的条件优化

目的:优化酵母发酵液直接催化4-氯乙酰乙酸乙酯(COBE)合成(S)-4-氯-3-羟基-丁酸乙酯((S)-CHBE)的反应条件. 方法:考察酵母发酵液催化该反应过程中基质变化的规律,研究底物和能源供体对反应的影响,并通过正交实验设计法优化反应条件. 结果:在酵母发酵液催化COBE不对称还原反应的过程中,底物和还原糖消耗、产物合成相对集中在反应的前期;反复分批式添加底物和蔗糖有利于反应效率的提高;正交实验优化反应条件的结果表明:酵母发酵液直接催化COBE不对称还原反应合成(S)-CHBE的最佳反应条件为:蔗糖添加方式Ⅱ(反应开始2 h后添加5 g/120 mL),底物添加方式Ⅳ[0.5(3)],缓冲剂添加量2 g/120 mL,β-环糊精添加量为2 g/120 mL,反应后测定产物的产率达96%,ee(对映体过量值)达100%. 结论:通过反应条件优化提高了酵母发酵液的催化效果.     

3-(4′-苯甲酰基氨基-苯基)-香豆素衍生物的合成及体外降血糖活性

首先以对氨基苯乙酸和水杨醛类化合物为原料,通过Perkin缩合反应,再经盐酸酸化合成了3个3-芳基香豆素类化合物4a~4c;再与取代苯甲酰氯6a~6h通过酰胺化反应合成得到了10个3-(4′-苯甲酰基氨基-苯基)香豆素类化合物7a~7j。所有目标化合物的结构均经过¹H NMR,¹³C NMR,ESI-MS进行了确证。通过测定α-葡萄糖苷酶抑制活性和晚期糖基化终产物(AGEs)形成抑制活性评价了目标化合物的体外降血糖活性。结果表明化合物7f(IC₅₀=10.84±0.36 μmol/L)表现出较好的α-葡萄糖苷酶的抑制活性;化合物7g(IC₅₀=5.01±0.55 μmol/L)对AGEs形成抑制活性远高于阳性药氨基胍盐酸盐(AG,IC₅₀=290.31±7.32 μmol/L),这些结果为抗糖尿病药物的进一步研究提供了理论基础。     

脑脊液中补体3水平与老年痴呆相关性Meta分析

目的采用Meta分析对阿尔茨海默症(AD)与脑脊液（CSF）中补体3（C3）水平的关联性进行评价,探讨CSF中C3水平变化对于AD的临床意义。方法计算机检索Pubmed、Embase、中国期刊网(CNKI)、万方数据库(WANFANGDATA)、中国科技期刊数据库(VIP),并辅以文献追溯等方法收集2017年8月以前国内外公开发表的关于AD患者CSF中C3水平的研究文献,采用Revman4.2软件进行Meta分析。结果共纳入4篇合格文献,累计241例患者和362例健康对照组。AD患者CSF中C3水平高于对照组,其合并标准化均数差（SMD）值为0.39及其95%CI：(0.02~0.77)。结论CSF中C3水平是早期诊断AD的一个潜在生物标记分子,但其病因关联性仍有待于在人群中开展大样本、前瞻性对照研究。     

4-取代氨基甲酰胺基-4-脱氧-4′-去甲基表鬼臼毒素衍生物的合成及其抗肿瘤活性

根据鬼臼毒素类化合物C_4位氮取代衍生物构效原理,设计并合成了11个4-取代氨基或烃氧甲酰胺基表鬼臼毒素类似物。从鬼臼毒素出发,经溴代、水解、叠氮化、还原以及酰化等六步反应合成标题化合物。体外抗肿瘤活性试验表明这类化合物具有较为显著的生物活性,多数化合物对L1210白血病肿瘤细胞与KB细胞生长抑制活性超过临床用药依托泊甙。     

阿魏酸衍生物的合成及其抗胆碱酯酶活性

阿魏酸(ferulic acid,FA)是一种含酚羟基的苯丙素类天然产物,药理活性广泛,对于阿尔茨海默病(Alzheimer′s disease,AD)具有一定疗效。以FA为原料,通过甲酯化对羧基进行保护,拼接氨基甲酸酯活性官能团,水解反应以及酰胺缩合等4步反应首次合成一系列阿魏酸氨基甲酸酯苯胺衍生物,采用Ellman法对FA衍生物进行体外抑制胆碱酯酶活性评价。共设计合成15个新颖的FA衍生物,结构经¹H NMR、¹³C NMR、ESI-MS确证;体外胆碱酯酶活性测试显示,化合物5c,5f,5j,5g,5m5个化合物对乙酰胆碱酯酶具有抑制作用,除化合物5l,5m以外,几乎所有化合物都对丁酰胆碱酯酶具有抑制活性,且远高于乙酰胆碱酯酶抑制活性。化合物5c,5f,5j,5g可以作为潜在的靶向胆碱酯酶的AD治疗药物。     

Mechanisms of Electroacupuncture on Alzheimer's Disease: A Review of Animal Studies

Alzheimer's disease(AD) is the main type of dementia affecting elderly people. The medicines used for treating AD have limits in their ability to alleviate cognitive and functional decline. Electroacupuncture(EA), an economical alternative and complementary therapeutic measure used in Chinese medicine, has strong clinical applicability, and its treatment effects are more reliable as its stimulation factors can be standardized. EA has been effectively used for ameliorating spatial learning and memory impairment in AD patients and rodent AD models. Here, we summarized the mechanisms of EA on rodent AD models, aiming to provide a theoretical basis for identifying new targets and research directions, and exploring appropriate EA stimulation parameters, then provide a detailed methodology to optimize the effects of EA, ultimately reducing the heavy burden of treating AD patients on families and countries. Our review showed that 8 acupoints were used when treating AD animals; Baihui(GV 20) was the most frequently used. Four mechanisms of EA were studied:(1) protection of cerebral neurons from oxidative stress, apoptosis, neuroinflammation, synaptic plasticity and hormone levels;(2) regulation of metabolism, including glucose metabolism and plasma metabolism;(3) regulation of brainderived neurotrophic factor; and(4) regulation of β-amyloid peptide protein deposition.     

Sequential Therapy Based on Evolvement of Patterns: A New Model for Treatment of Alzheimer’s Disease

In order to solve the problem of long-term (>9 months) efficacy in the treatment of Alzheimer''s disease (AD) by conventional therapy (CT), a staged and multiply-targeted sequential therapy based on the evolvement of patterns (STEP) was developed. Its main innovations include: (1) the time order of evolution of patterns defined by Chinese medicine (CM) in AD was found, that is, "the orderly pattern evolution starting from Shen (Kidney) deficiency, progressing to phlegm, stasis and fire, and worsening to severe toxin as well as functional collapse"; (2) the cascade hypothesis of Shen deficiency in AD and its sequential therapy based on Shen-reinforcing was proposed, that is, "reinforcing Shen in the early stage and throughout the whole process, resolving phlegm, activating blood and purging fire in the middle stage, detoxifying and replenishing vitality to stop the collapse in the advanced stage", and through meta-analysis, clinical drug use was optimized, thus the leap from "inferential selection" to "evidence-based selection" was realized; (3) the STEP regimen combined with CT maintained cognitive and behavioral stability in AD patients for at least 12 months, with cognitive enhancement and behavioral synergy after 9 months, and cognitive benefit was superior to CT at 9, 12, 15, 18, 21, and 24 months, respectively. The 2-year cognitive improvement rate was increased by 25.64% (P=0.020) and the cognitive deterioration rate was decreased by 48.71% (P=0.000). Among them, the cognitive and functional benefits of Shen-reinforcing therapy for very early AD (350 cases) for 1 year were better than the placebo (P<0.001), and the dementia conversion rate was reduced by 8.85% (P=0.002). The behavioral symptomatic relief of patients with vascular dementia received fire-purging therapy (540 cases) was superior to those received CT (P=0.016). These data suggested that the STEP regimen has synergistic effects on CTs at least in terms of cognitive benefit, and the earlier the use, the greater the benefit will have. Therefore, the STEP regimen should be considered as one of the clinical options, particularly for the dearth of effective pharmaceutical or immunological interventions that are currently available for AD.     

Effects of Acupuncture on Alzheimer’s Disease: Evidence from Neuroimaging Studies

As the worldwide population ages, the prevalence of Alzheimer''s disease (AD) increases. However, the results of promising medications have been unsatisfactory. Chinese acupuncture has a long history of treating dementia, but lack of evidence from well-designed randomized controlled trials that validate its efficacy and safety, as well as its lack of clear underlying mechanisms, contribute to its limited application in clinical practice. In recent years, brain imaging technologies, such as functional magnetic resonance imaging and positron emission tomography, have been used to assess brain responses to acupuncture in a dynamic, visual, and objective way. These techniques are frequently used to explore neurological mechanisms of responses to acupuncture in AD and provide neuroimaging evidence as well as starting points to elucidate the possible mechanisms. This review summarizes the existing brain imaging evidence that explains the effects of acupuncture for AD and analyzes brain responses to acupuncture at cognitive-related acupoints [Baihui (GV 20), Shenmen (HT 7), Zusanli (ST 36), Neiguan (PC 6), and Taixi (KI 3)] from perspectives of acupoint specificity and acupoint combinations. Key issues and directions to consider in future studies are also put forward. This review should deepen our understanding of how brain imaging studies can be used to explore the underlying mechanisms of acupuncture in AD.     

阿尔茨海默病样三重转基因小鼠血小板的功能改变及机制探讨

目的探讨常见的阿尔茨海默病(AD)小鼠模型APP/PS-1/tau(3xTg)小鼠血小板功能变化情况及机制分析。方法实验小鼠分为3xTg-AD组和WT组;采用流式细胞术和粘附试验等方法评价3xTg-AD和WT小鼠血小板的功能;并采用Western blotting方法对其机制进行探讨。结果老年3xTg-AD小鼠血小板计数和糖蛋白表达与对照WT小鼠差异无统计学意义(P0.05)。但是与对照WT小鼠相比,3xTg-AD小鼠血小板与纤维蛋白原的粘附能力增强(P0.05)。此外,与纤维蛋白原粘附功能增强的3xTg-AD小鼠血小板信号蛋白的磷酸化也增加,包括PI3激酶Akt和p38MAP激酶(P0.05)。然而,两组小鼠中由激动剂诱导的活化血小板无统计学差异(P0.05)。结论 3xTg-AD小鼠循环血液中血小板粘附功能增加,可能与AD疾病的进展相关。     

Frequency-specific Alterations of Large-scale Functional Brain Networks in Patients with Alzheimer's Disease

Background:

Previous studies have indicated that the cognitive deficits in patients with Alzheimer''s disease (AD) may be due to topological deteriorations of the brain network. However, whether the selection of a specific frequency band could impact the topological properties is still not clear. Our hypothesis is that the topological properties of AD patients are also frequency-specific.

Methods:

Resting state functional magnetic resonance imaging data from 10 right-handed moderate AD patients (mean age: 64.3 years; mean mini mental state examination [MMSE]: 18.0) and 10 age and gender-matched healthy controls (mean age: 63.6 years; mean MMSE: 28.2) were enrolled in this study. The global efficiency, the clustering coefficient (CC), the characteristic path length (CpL), and “small-world” property were calculated in a wide range of thresholds and averaged within each group, at three different frequency bands (0.01–0.06 Hz, 0.06–0.11 Hz, and 0.11–0.25 Hz).

Results:

At lower-frequency bands (0.01–0.06 Hz, 0.06–0.11 Hz), the global efficiency, the CC and the “small-world” properties of AD patients decreased compared to controls. While at higher-frequency bands (0.11–0.25 Hz), the CpL was much longer, and the “small-world” property was disrupted in AD, particularly at a higher threshold. The topological properties changed with different frequency bands, suggesting the existence of disrupted global and local functional organization associated with AD.

Conclusions:

This study demonstrates that the topological alterations of large-scale functional brain networks in AD patients are frequency dependent, thus providing fundamental support for optimal frequency selection in future related research.