叶酸与神经变性疾病相关性研究进展

神经变性疾病是一种中老年人常见的神经退行性疾病,与氧化应激、线粒体功能障碍、Ca~(2+)内流、脑血管损伤等因素导致的中枢神经细胞变性凋亡有关。叶酸能够通过参与一碳物质代谢,参与DNA、mtDNA合成,维护线粒体结构和功能,减少细胞的损伤。叶酸片价格低廉,如能作为一种保护神经的治疗手段,将会受众颇广。然而,目前国内外有关叶酸与神经变性疾病关系的研究结论尚存在争议。本文针对叶酸代谢过程,叶酸与神经变性疾病相关性以及补充叶酸治疗等方面的有关研究进展情况作以综述。     

PPARs与神经退行性疾病

过氧化物酶体增殖剂激活受体(peroxisome prolifera-tion-activated receptors,PPARs)是由配体激活的核转录因子,属于核激素受体(nuclear hormone receptors)超家族。PPARs的激活可能对某些细胞的生长、分化甚至凋亡有重要影响。近年来的研究表明,PPARs具有神经保护作用,可减轻神经退行性疾病所致的脑组织损害,PPARs激动药可能用于阿尔采末病、帕金森病、缺血性脑中风及多发性硬化等神经退行性疾病的治疗。本文对PPARs在中枢神经系统的分布及功能、PPARs介导的信号途径及PPARs对阿尔采末病、帕金森病、缺血性脑中风及多发性硬化等神经退行性疾病的作用做一综述。     

细胞骨架与神经退行性疾病

神经退行性疾病(Neurodegenerative disease)是一种以神经元退行性病变为基础的慢性进行性神经系统疾病,其病因十分复杂,其中线粒体功能障碍学说、氧化应激学说、蛋白质发生错误折叠聚集、炎症、免疫功能缺陷,基因突变等已经得到普遍认可。近年来的研究发现,细胞骨架在神经元变性过程中发挥了重要作用。细胞骨架是细胞质内蛋白质丝组成的纤维网架体系,其决定和维持着细胞的形态结构,同时参与细胞运动、分裂、胞浆运输等生命活动,对信号传导具有重要的意义。该文就其在神经退行性疾病方面的研究进行综述。     

Therapeutic strategies against protein misfolding in neurodegenerative diseases

Background: Neurodegenerative diseases are a group of chronic and progressive disorders of the nervous system. A hallmark event in these diseases is the misfolding and accumulation in the brain of protein aggregates. Objective: In this article, we describe the knowledge of the mechanism of protein misfolding and aggregation, its role in neurodegeneration and the diverse therapeutic targets for intervention. We also critically review various strategies under development to discover drugs attacking this process. Conclusion: In spite of the substantial progress on understanding the critical role of protein misfolding and aggregation, drugs effective against this process are still years away from approval.     

Cancer risk in patients with osteoporosis: a population-based cohort study

Background: Osteoporosis has been associated with cancer development. We conducted a nationwide population-based cohort study in Taiwan to evaluate this possible association of osteoporosis with subsequent cancer development.

Methods: A total of 35,979 patients diagnosed with osteoporosis between 2000 and 2010 identified from the National Health Insurance Research Database comprised the osteoporosis cohort, and each patient was randomly frequency matched with one individual from the general population (without osteoporosis) based on age, sex, and year of osteoporosis diagnosis to form the non-osteoporosis (control) cohort. Cox proportional hazard regression analysis was used to calculate adjusted hazard ratios and 95% confidence intervals and determine the effect of osteoporosis on cancer risk.

Results: Patients with osteoporosis showed a significantly higher risk of developing liver and thyroid cancers and lower risk of colorectal cancer than did individuals without osteoporosis. Male patients with osteoporosis had a significantly increased risk for liver cancer, whereas female patients with osteoporosis had a significantly increased risk for thyroid cancer, but a significantly decreased risk for overall and colorectal cancers. In addition, more significant findings were observed when age ≤64 years or the follow-up duration was ≤5 years; however, a significantly lower risk for colorectal cancer was observed when follow-up duration was >5 years. Study limits including lack of data for some health-related behaviors, inclusion criteria of osteoporosis and potential selection bias have been discussed.

Conclusion: Patients with osteoporosis showed a higher risk for liver and thyroid cancers and a lower risk for colorectal cancer than did control individuals. Stratified analyses by sex, age, and follow-up duration showed various patterns in different cancers.     

Targeting ASK1 in ER stress-related neurodegenerative diseases

The accumulation of malfolded proteins in the endoplasmic reticulum (ER) induces ER stress, leading to the disturbance of ER function. To restore ER function and ER homeostasis, cells possess a highly specific ER quality control system termed the unfolded protein response (UPR), which increases the capacity of protein folding and reduces the amount of malfolded proteins. In case of prolonged ER stress or malfunction of the UPR, apoptosis signaling is activated. ER stress-induced apoptosis has recently been implicated in the pathogenesis of various conformational diseases. Apoptosis signal-regulating kinase 1 (ASK1), a member of the MAPK kinase kinase (MAP3K) family, is activated by ER stress and mediates apoptosis. Recent studies have shown that the ASK1 pathway is involved in ER stress-induced neuronal cell death and contributes to the pathogenesis of neurodegenerative diseases. In this review, we summarize the molecular mechanisms of the UPR and ER stress-induced apoptosis and the possible roles of ASK1 activation in neurodegenerative diseases.     

组蛋白脱乙酰基酶6在聚集小体和神经变性疾病中的作用

组蛋白脱乙酰基酶6(HDAC6)是主要存在于胞浆中的微管脱乙酰基酶,在体内参与多种重要的生物学过程。研究表明,错误折叠和聚集的蛋白质组成的聚集小体是神经变性疾病的主要病理特征,聚集小体在早期通过自吞噬作用,对细胞起着保护性作用,而HDAC6能调节聚集小体的形成并且参与自噬性降解。本文综述了近几年HDAC6参与聚集小体以及神经变性疾病发生发展的研究进展,为神经变性疾病的治疗提供新的研究思路,并为新药研发提供更多的理论依据。     

胱抑素C在神经系统变性疾病中的研究进展

胱抑素C是目前反映早期肾功能损害较敏感的内源性标志物,近年来越来越多的研究发现,胱抑素C通过参与炎症反应、诱导自噬、抑制组织蛋白酶等途径与阿尔茨海默病、帕金森病、肌萎缩侧索硬化、多系统萎缩的发生发展密切相关,本文就胱抑素C与神经系统变性疾病的最新研究进展做一综述。     

Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases

Introduction: Asparagine endopeptidase (AEP) is a pH-dependent endolysosomal cysteine protease that cleaves its substrates after asparagine residues. Our most recent study identifies that it possesses the delta-secretase activity, and that it is implicated in numerous neurological diseases such as Alzheimer’s disease (AD) and stroke. Accumulating evidence supports that the inhibition of AEP exhibits beneficial effects for treating these devastating diseases.

Areas covered: Based on recent evidence, it is clear that AEP cleaves its substrate, such as amyloid precursor protein (APP), tau and SET, and plays a critical role in neuronal cell death in various neurodegenerative diseases and stroke. In this article, the basic biology of AEP, its knockout phenotypes in mouse models, its substrates in neurodegenerative diseases, and its small peptidyl inhibitors and prodrugs are discussed. In addition, we discuss the potential of AEP as a novel therapeutic target for neurodegenerative diseases.

Expert opinion: AEP plays a unique role in numerous biological processes, depending on both pH and context. Most striking is our most recent finding; that AEP is activated in an age-dependent manner and simultaneously cleaves both APP and tau, thereby unifying both major pathological events in AD. Thus, AEP acts as an innovative trigger for neurodegenerative diseases. Inhibition of AEP will provide a disease-modifying treatment for neurodegenerative diseases including AD.     

Synthesis and evaluation of peptidic metal chelators for neuroprotection in neurodegenerative diseases

Abstract: A series of novel derivatives of neuropeptides with a metal‐chelating moiety was synthesized and examined for various properties related to iron (Fe) chelation and neuroprotective action. All derivatives chelated Fe to form stable Fe complexes in water. Some strongly inhibited Fe‐induced lipid peroxidation with an IC₅₀ value of about 12 μm . In PC12 cell culture, several compounds, at concentrations as low as 1 μm , attenuated serum‐free stimulated cell death and improved cell survival by 20–35%. At this concentration, these analogs also protected against 6‐hydroxydopamine (6‐OHDA)‐induced cell death, increasing cell viability by 20–30%. Electron paramagnetic resonance (EPR) studies indicated that besides being good Fe chelators, these analogs act as radical scavengers to directly scavenge hydroxyl radicals. Together, the data indicate that some of the analogs could be further developed as possible neuroprotective agents for treatment of neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's diseases, Friedreich's atxia, amyotrophic, and lateral sclerosis where Fe misregulation has been reported.     

ATM蛋白在神经退行性病变中的作用及机制研究进展

ATM蛋白缺失是运动失调性毛细血管扩张症(ataxia telangiectasia,AT),是这种罕见的常染色体隐性遗传病的发病基础,其病变的一个重要特征就是神经退行性病变.本文主要从氧化应激、DNA损伤及修复和细胞自噬等角度对ATM蛋白在神经退行性病变中的作用及相关机制做一综述,以此阐明ATM蛋白作为神经退行性病变治疗药物靶点的可能性.     

黄酮类化合物在防治神经退行性疾病中作用的研究进展

帕金森病、阿尔茨海默病及亨廷顿病等一系列神经退行性疾病的发病因素很多,其中包括神经炎症、内源性抗氧化剂缺失、谷氨酸兴奋性神经毒性损伤以及铁离子代谢异常等。研究表明,黄酮类化合物对神经退行性疾病的临床防治具有一定的疗效。黄酮类化合物可抑制神经炎症、抗氧化应激、抗细胞凋亡、抗谷氨酸神经毒性并调节铁代谢平衡,从而减缓神经细胞损伤并改善学习记忆和脑血管功能。     

Patented therapeutic RNAi strategies for neurodegenerative diseases of the CNS

Background: Owing to its biological properties, RNA interference (RNAi) holds the greatest promise as a therapeutic agent for the treatment of a wide range of diseases. The following review is based on the most recent discoveries of RNAi biological mechanisms, highlighting their efficacy, safety, in vivo delivery and use in future clinical trials. Objectives: This review highlights recent advances in RNAi research and focuses on RNAi therapeutic patents for neurodegenerative diseases of the CNS. Method: We used online database free patent resources to summarize RNAi discoveries with particular attention to those regarding the CNS application. We attempted to include the major contributions in the field, and the list of patents reviewed should be considered exhaustive. Conclusion: Patents cover a wide range of RNAi-related fields: molecular findings for understanding RNAi mechanisms, delivery systems and RNAi-based therapeutic applications for neurodegenerative diseases of the CNS.     

The discovery and development of new potential antioxidant agents for the treatment of neurodegenerative diseases

Introduction: Several neurodegenerative disorders (NDs) including Alzheimer’s and Huntington’s diseases have had associations with the oxidative process and free radical damage. Consequently, in past decades, several natural and synthetic antioxidants have been assessed as therapeutic agents but have shown limitations in bioavailability, metabolic susceptibility and permeability to the blood brain barrier. Given these issues, medicinal chemists are hard at work to modify/improve the chemical structures of these antioxidants, thereby improving their efficacy.

Areas covered: In this review, the authors critically analyze several biological mechanisms involved in the generation of free radicals. Additionally, they analyze free radicals’ role in the generation of oxidative stress and in the progression of many NDs. Further, the authors review a collection of natural and synthetic antioxidants, their role as free radical scavengers along with their mechanisms of action and their potential for preventing neurodegenerative diseases.

Expert opinion: So far, preclinical studies on several antioxidants have shown promise for treating NDs, despite their limitations. The authors do highlight the lack of the adequate animal models for preclinical assessment and this does hinder further progression into clinical trials. Further studies are necessary to fully investigate the potential of these antioxidants as ND therapeutic options.     

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

A pivotal role for excitotoxicity in neurodegenerative diseases is gaining increasingly more acceptance, but the underlying mechanisms through which it participates in neurodegeneration still need further investigation. Excessive activation of glu- tamate receptors by excitatory amino acids leads to a number of deleterious consequences, including impairment of calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition and secondary excitotoxic- ity. Recent studies implicate excitotoxicity in a variety of neuropathological conditions, suggesting that neurodegenerative diseases with distinct genetic etiologies may share excitotoxicity as a common pathogenic pathway. Thus, understanding the pathways involved in excitotoxicity is of critical importance for the future clinical treatment of many neurodegenerative diseases. This review discusses the current understanding of excitotoxic mechanisms and how they are involved in the pathogenesis of neurodegenerative diseases.     

Multiple regulation and targeting effects of borneol in the neurovascular unit in neurodegenerative diseases

Efficient delivery of brain-targeted drugs is highly important for the success of therapies in neurodegenerative diseases. Borneol has several biological activities, such as anti-inflammatory and cell penetration enhancing effect, and can regulate processes in the neurovascular unit (NVU), such as protein toxic stress, autophagosome/lysosomal system, oxidative stress, programmed cell death and neuroinflammation. However, the influence of borneol on NVU in neurodegenerative diseases has not been fully explained. This study searched the keywords ‘borneol’, ‘neurovascular unit’, ‘endothelial cell’, ‘astrocyte’, ‘neuron’, ‘blood–brain barrier’, ‘neurodegenerative diseases’ and ‘brain disease’ in PubMed, BioMed Central, China National Knowledge Infrastructure (CNKI) and Bing search engines to explore the influence of borneol on NVU. In addition to the principle and mechanism of penetration of borneol in the brain, this study also showed its multiple regulation effects on NVU. Borneol was able to penetrate the blood–brain barrier (BBB), affecting the signal transmission between BBB and the microenvironment of the brain, downregulating the expression of inflammatory and oxidative stress proteins in NVU, especially in microglia and astrocytes. In summary, borneol is a potential drug delivery agent for drugs against neurodegenerative diseases.     

脑缺血、葡萄糖/能量代谢障碍与神经退行性疾病

葡萄糖 /能量代谢障碍是引起缺血性脑损伤的主要原因 ,也是神经退行性疾病的综合征之一。由于脑缺血致能量耗竭的过程可分为 3个阶段 ,即缺血开始、完全性能量耗竭和能量恢复阶段。该文通过提供大量科学研究资料 ,如神经化学、细胞学和分子生物学以及病理生理学研究资料来证明葡萄糖 /能量代谢障碍在神经退行性疾病过程中所起的作用 ,对抗脑缺血药的研究进展及其评价作了介绍。     

RNAi在神经退行性疾病发病机制及防治研究中的应用

RNA干扰（RNA interference，RNAi）技术能特异性降解mRNA，沉默靶基因，在转录后水平抑制基因的表达，从而可用来进行基因功能的分析和药物靶标的研究。RNAi技术日趋成熟，已被广泛应用于生命科学的各个领域。在神经科学上，尤其是在神经退行性疾病，如阿尔茨海默病、帕金森病、亨廷顿病、脊髓小脑性共济失调、肌萎缩性侧索硬化症、朊病毒病等的研究中取得了显著进展，RNAi的应用为神经退行性疾病发病机制的揭示和治疗另辟了蹊径。