军事医学科学院药物毒理学研究30年回顾

军事医学科学院的药物毒理学研究源远流长、与时俱进,经过近30年的积累与发展,已建立一整套服务于新药发现、临床前开发、临床实验及上市后监督再评价等完整研发链条的药物毒理学研究体系和学科群,涵盖新药早期发现毒理学、非临床安全性评价以及药物毒性作用机制研究等内容,通过与新药研发体系中其他学科互动与协作,为军事医学科学院乃至全国的新药研发提供了良好的非临床安全性评价的技术平台和保障.     

交感皮肤反应在糖尿病周围神经病变诊断中的应用

糖尿病周围神经病变（Diabetic Peripheral Neuropathy,DPN）是糖尿病最常见的并发症之一。由于目前DPN发病机制不清楚、治疗效果不理想,故早诊断、早治疗显得至关重要。有研究指出交感神经皮肤反应（Sympathetic Skin Response,SSR）可作为评价2型糖尿病患者早期周围植物神经功能状态的指标。本文对SSR应用于DPN临床诊断中的检测技术、观测参数进行综述,发现多数研究中指出,在临床应用中SSR波形、波幅以及潜伏期指标的异常率常受到多种因素的影响、会发生很大波动,而电位曲线下面积减少值相对稳定。据此笔者建议在DPN早期临床诊断中以SSR电位曲线下面积减少作为关键参数,辅助参考SSR波形、波幅以及潜伏期指标进行诊断。     

8-OHdG在医学领域的应用与研究进展

氧化应激带来的氧化损伤是造成人体多种损伤和病变的重要因素。8-羟基脱氧鸟苷(8-hydroxy-2’-deoxyguanosine,8-OHdG)作为DNA氧化损伤产物是广泛用于研究疾病中氧化损伤机制的关键标志物。国内外大量研究已普遍应用8-OHdG作为分析指标,该文着眼于近年来研究动向,就8-OHdG的作用机理与检测方法,以及职业与环境暴露的危害评价、辅助疾病早期诊断、治疗和新药研发等方面的应用作一综述。     

Gamma节律：认知障碍疾病的潜在诊断靶点

神经精神类疾病是威胁人类健康的重大疾病,具有高患病率的特点,且患者通常伴随有认知障碍.长期以来,临床针对神经精神疾病的诊断主要是根据患者的临床表现,缺乏统一的客观标准,治疗手段也具有一定的难度且会产生副作用.因此开发高效客观的诊疗方式是神经精神疾病研究和临床实践的重难点.脑电图是反映脑功能变化的一种临床检查方式,其特征性节律的检测可作为大脑损伤的指标. Gamma节律(γ节律)作为与认知相关的一个重要神经节律,在大脑高级功能中扮演重要角色.众多研究发现神经精神类疾病的患者和动物模型伴随有γ节律的紊乱,这预示着基于认知核心脑区γ节律的神经检测与调控可能实现精准诊疗.本文综述了面向神经退行性疾病和精神类疾病开展的γ节律研究进展,通过梳理以往研究中γ节律在调节认知、学习记忆时的特征规律和相关分子基础,提出γ节律可能成为未来临床检测神经精神疾病无创高效的客观靶标,并在此基础上对未来的研究进行了展望.     

非人灵长类动物模型睡眠研究在神经精神疾病的早期诊断和药效评价中的作用

清醒-睡眠的周期性调节需要众多单胺类神经递质(5-HT、NE、DA等)、乙酰胆碱等兴奋性神经递质以及GABA等抑制性神经递质的参与。这些递质系统的异常不仅会导致睡眠周期紊乱,还与一系列的精神性和神经退行性疾病相关。睡眠异常被认为是抑郁症、帕金森氏病等神经系统疾病发生的早期预警信号。相比起低等哺乳动物,非人灵长类动物的睡眠与人类的睡眠具有更好的可比性。近来,利用非人灵长类动物来建立神经精神疾病模型的研究已取得明显进展。在建模的同时监测动物的睡眠状况,有助于我们进一步了解睡眠在这些疾病早期诊断和发展过程中的作用,为疾病的早期诊断、治疗和药效评价提供更好的客观依据。     

用于立体视检测的微机软件包的设计

为了快速、方便、准确地检测人的立体视功能,根据双眼视差原理,设计了用于立体视检测的微机软件包称为立体视检测(SVT).利用该软件可在彩色屏幕(VGA)上产生静态等视差图(图中各部分的视差不随空间位置的变化而改变)、变视差图、以及在深度上的正弦波状起伏图形.叙述了设计原理和程序框图;报导了用SVT软件包对视力正常和异常儿童的立体视检测结果并讨论了其临床应用价值．     

中国特有植物明党参化学成分和药理研究进展

本文报道中国特有名贵中药明党参ＣｈａｎｇｉｕｍｓｍｙｒｎｉｏｉｄｅｓＷｏｌｆ根的化学成分与药理研究的最新进展及应用历史概况,阐明了该药物治病物质基础,发现了新的活性成分和药效,提出了合理、科学、先进的质量检测指标和方法。为开发防治老年病的新药提供了实验基础。对明党参道地性研究亦具有重要意义。     

震动感觉阈值检查对老年糖尿病周围神经病变的诊断价值

目的:糖尿病周围神经病变(DPN)是糖尿病最常见的慢性并发症之一,危害严重,而大部分患者早期无症状,以致延误了早期诊断,失去了早期治疗的机会.目前DPN的筛查方法众多,但尚无确定有效的筛查方法.震动感觉阈值检查(VPT)在发达国家已广泛应用于糖尿病神经病变的临床筛查,但目前国内很少应用.本文旨在探讨VPT对老年糖尿病周围神经病变的临床应用价值.方法:采用数字震动感觉阈值检查仪、128 Hz音叉检测40例老年2型糖尿病患者(DM组)和36例非糖尿病老年人(对照组)的VPT和音叉震动觉,与神经传导速度(NCV)进行对比分析.结果:40例DM组中有周围神经病症状18 人(45％),音叉震动觉减弱17例(42.5％),VPT异常21例(52.5％),NCV异常24例(60％).以NCV检查结果作为诊断金标准,评价VPT的敏感性79.2％,特异性87.5％.结论:VPT检查是一种特异、敏感、有效、简便的DPN早期筛查方法,能及早发现严重并发症的高风险人群,适合常规的门诊筛查.VPT检测结合临床症状、体征,能更方便、可靠地诊断老年糖尿病周围神经病变,对于DPN的疾病风险、早期干预、评价预后非常重要.     

脂肪肝的临床生化检测指标及与其发生、发展的关系研究

目的:研究临床生化指标与脂肪肝发生发展之间的关系。方法:收集我院收治的脂肪肝患者作为病例组,选择同期健康体检者作为对照组,检测其生化指标,分析生化指标变化对于脂肪肝的影响。结果:病例组的血清酶活性、TC、TG、BILT以及BILD含量较均较对照组显著提高(P0.05);不同程度脂肪肝患者的血清酶活性、TC以及TG水平无明显差异(P0.05),但CHE、BILT及BILD差异显著(P0.05)。结论:血清酶活性以及血脂含量均与脂肪肝的发生及发展具有密切关系,检测患者的临床生化指标对于早期诊断脂肪肝具有重要价值。     

超声在糖尿病肾病诊断中的应用价值

由于快速变化的生活方式,我国糖尿病的患病率呈逐年上升趋势。糖尿病肾病(diabetic nephropathy,DN)是糖尿病最常见、最严重的微血管病变并发症之一,并且已经成为全球终末期肾病的最常见病因。因此,早期诊断、早期治疗是延缓DN进展的重点。超声是临床评价肾脏形态、功能常用的检查方法,与血、尿实验室检查相比,具有方便、快捷、无创、经济的优势。随着科学技术的发展,越来越多的超声新技术应用于临床,极大的丰富了诊断信息。本文就各项超声检查技术在检测DN患者肾脏体积、实质回声、血流动力学改变中的应用价值作一综述。得出结论:在DN早期血、尿实验室检查正常时超声已经可以发现肾脏体积、血流动力学发生了变化。因此,超声在DN的早期诊断、动态监测病程进展方面所发挥的作用是其他检查方法所不可替代的。三维超声技术和超声弹性成像在DN患者肾脏功能评价方面有着广泛研究空间及临床应用前景。     

A decade of modeling Alzheimer's disease in transgenic mice

It has been over a decade since the first Alzheimer's disease (AD) transgenic mouse models were reported. These models have enabled dramatic advances in our understanding of the pathogenic mechanism in AD and of potential therapeutic approaches to tackling the inexorable clinical progression of the disease. In this article, we discuss the current status of AD mouse models and focus on recent work that has examined the development of the neuropathological lesions observed in AD (plaques and tangles). The relationship between these lesions, neurodegeneration and development of the clinical syndrome will be explored.     

The role and therapeutic potential of connexins,pannexins and their channels in Parkinson's disease

Lack of effective medication for slowing down progression of Parkinson's disease (PD) as a highly prevalent neurodegenerative disorder requires novel avenues of scientific investigation to elucidate the underlying molecular and cellular mechanisms. Studying connexins, pannexins and their channels has uncovered their potential role in mediating communication and signaling pathways that drive neurodegenerative diseases, including PD. Indeed, given their critical role in tissue homeostasis, it is not surprising that connexins, pannexins and their channels are frequently involved in pathological processes. For this reason, pharmacological tools to further clarify their functions and to validate connexins, pannexins and their channels as drug targets for the development of novel therapies for PD treatment are urgently needed. In this paper, a state-of-the-art overview is provided of current neuropathological and molecular understanding of PD. Focus is put on the roles of connexins, pannexins and their channels, in particular in the development of potential innovative disease-modifying therapies for PD treatment.     

Huntingtin-protein interactions and the pathogenesis of Huntington's disease

At least nine inherited neurodegenerative diseases share a polyglutamine expansion in their respective disease proteins. These diseases show distinct neuropathological changes, suggesting that protein environment and protein-protein interactions play an important role in the specific neuropathology. A gain of toxic function as a result of an expanded polyglutamine tract can cause the protein huntingtin to interact abnormally with a variety of proteins, resulting in the complex of neuropathological changes seen in Huntington's disease. Recent studies have identified several huntingtin-interacting proteins that might be associated with the normal function of huntingtin and/or involved in the pathology of Huntington's disease. In this article, we focus on the potential roles of huntingtin-protein interactions in the pathogenesis of Huntington's disease.     

Predementia Alzheimer's disease. Benefits of early diagnosis

Given population aging and the rise in the number of persons with Alzheimer's disease, measures that aim not only to delay but also to prevent the development of this disease are increasingly required. Advances in the diagnosis of Alzheimer's disease support the need for a review of current clinical standards for mild cognitive impairment and provide new goals in the early treatment of this disease. The current diagnostic process should be refocussed toward the pathological substrate of this disease rather than symptoms in order to initiate therapeutic measures as soon as possible without waiting for clinical manifestations to appear. Such an approach is essential in patients with greater cognitive reserve, in whom the lesions are usually more severe at diagnosis and treatment is less effective. To identify disease-modifying therapies to delay the onset of the clinical symptoms of Alzheimer's disease in cognitively intact persons at high risk, biomarkers for this disease must be validated. A single biomarker is unlikely to provide the required diagnostic accuracy and therefore a multimodal approach, incorporating biochemical, neuropathological and anatomical and metabolic neuroimaging methods, should be employed. To optimize the results of drugs under investigation, a combination of biomarkers should be used to select appropriate participants in the earliest phases of the disease, and disease progression should be followed-up. Early diagnosis might clarify essential questions in the care of patients with Alzheimer's disease, such as the possibility of distinguishing among various subtypes, thus encouraging the development of optimal treatments for each. The ultimate goal is to develop disease-modifying treatments that could be initiated early, while patients are asymptomatic or only minimally symptomatic, to maintain their quality of life.     

Neuroimaging Alzheimer's disease: early diagnosis, monitoring, and mechanism understanding

Neuroimaging offers a promising tool for the priority goals of current researches in Alzheimer's disease (AD) including early diagnosis, monitoring the progression of the disease and understanding the underlying mechanisms. The brain profiles of atrophy and hypometabolism associated with AD are well known and they can be used as support for early diagnosis, although the accuracy of each of these biomarkers on its own is not sufficient. An increasing number of studies highlights the relevance of disconnection processes in the development and progression of AD. The recent development of PET tracers such as the Pittsburg compound (PiB) allowing to visualize in vivo one of the neuropathological lesions characterizing AD (i.e. beta-amyloid depositions) offers a unique opportunity to better understand the mechanisms underlying this multifaceted disease.     

Oxidative stress increases levels of endogenous amyloid-beta peptides secreted from primary chick brain neurons

Oxidative damage is associated with Alzheimer's disease and mild cognitive impairment, but its relationship to the development of neuropathological lesions involving accumulation of amyloid-beta (Abeta) peptides and hyperphosphorylated tau protein remains poorly understood. We show that inducing oxidative stress in primary chick brain neurons by exposure to sublethal doses of H(2)O(2 )increases levels of total secreted endogenous Abeta by 2.4-fold after 20 h. This occurs in the absence of changes to intracellular amyloid precursor protein or tau protein levels, while heat-shock protein 90 is elevated 2.5-fold. These results are consistent with the hypothesis that aging-associated oxidative stress contributes to increasing Abeta generation and up-regulation of molecular chaperones in Alzheimer's disease.     

La enfermedad de Alzheimer antes de la demencia. Beneficios del diagnóstico precoz

Given population aging and the rise in the number of persons with Alzheimer's disease, measures that aim not only to delay but also to prevent the development of this disease are increasingly required. Advances in the diagnosis of Alzheimer's disease support the need for a review of current clinical standards for mildcognitive impairment and provide new goals in the early treatment of this disease. The current diagnostic process should be refocussed toward the pathological substrate of this disease rather than symptoms in order to initiate therapeutic measures as soon as possible without waiting for clinical manifestations to appear. Such an approach is essential in patients with greater cognitive reserve, in whom the lesions are usually more severe at diagnosis and treatment is less effective.To identify disease-modifying therapies to delay the onset of the clinical symptoms of Alzheimer's disease in cognitively intact persons at high risk, biomarkers for this disease must be validated. A single biomarker is unlikely to provide the required diagnostic accuracy and therefore a multimodal approach, incorporating biochemical, neuropathological and anatomical and metabolic neuroimaging methods, should be employed. To optimize the results of drugs under investigation, a combination of biomarkers should be used to select appropriate participants in the earliest phases of the disease, and disease progression should be followedup.Early diagnosis might clarify essential questions in the care of patients with Alzheimer's disease, such as the possibility of distinguishing among various subtypes, thus encouraging the development of optimal treatments for each.The ultimate goal is to develop disease-modifying treatments that could be initiated early, while patients are asymptomatic or only minimally symptomatic, to maintain their quality of life.     

Tau蛋白高度磷酸化致阿尔茨海默病动物模型研究进展

阿尔茨海默病（Alzheimer＇sdisease,AD）是老年人中最常见的神经退行性疾病,以过度磷酸化tau蛋白为核心形成的神经原纤维缠结为AD的主要病理特征之一。近年来对tau蛋白磷酸化的研究备受关注。在AD的实验研究中,探索理想的AD动物模型对于明确AD的病因、发病机制及药物的研发等方面起关键作用。本文对Tau蛋白磷酸化致AD主要动物模型的研究进展进行了综述,包括Tau转基因动物模型、激酶和磷酸化酶系统失衡致Tau蛋白过度磷酸化损伤模型、降低Tau蛋白糖基化致Tau过度磷酸化模型等。     

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that typically develops as a result of acute liver failure or chronic liver disease. Brain edema is a common feature associated with HE. In acute liver failure, brain edema contributes to an increase in intracranial pressure, which can fatally lead to brain stem herniation. In chronic liver disease, intracranial hypertension is rarely observed, even though brain edema may be present. This discrepancy in the development of intracranial hypertension in acute liver failure versus chronic liver disease suggests that brain edema plays a different role in relation to the onset of HE. Furthermore, the pathophysiological mechanisms involved in the development of brain edema in acute liver failure and chronic liver disease are dissimilar. This review explores the types of brain edema, the cells, and pathogenic factors involved in its development, while emphasizing the differences in acute liver failure versus chronic liver disease. The implications of brain edema developing as a neuropathological consequence of HE, or as a cause of HE, are also discussed.     

Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome

Amyloid-beta (Abeta) plaques and neurofibrillary tangles are the hallmark neuropathological lesions of Alzheimer's disease (AD). Using a triple transgenic model (3xTg-AD) that develops both lesions in AD-relevant brain regions, we determined the consequence of Abeta clearance on the development of tau pathology. Here we show that Abeta immunotherapy reduces not only extracellular Abeta plaques but also intracellular Abeta accumulation and most notably leads to the clearance of early tau pathology. We find that Abeta deposits are cleared first and subsequently reemerge prior to the tau pathology, indicative of a hierarchical and direct relationship between Abeta and tau. The clearance of the tau pathology is mediated by the proteasome and is dependent on the phosphorylation state of tau, as hyperphosphorylated tau aggregates are unaffected by the Abeta antibody treatment. These findings indicate that Abeta immunization may be useful for clearing both hallmark lesions of AD, provided that intervention occurs early in the disease course.