脑铁代谢和神经变性性疾病

最近关于脑铁代谢研究的新成果,尤其是与脑铁转运、储存、调节相关的某些突变基因的发现,足以得出以下结论,即异常增高的脑铁至少是部份神经变性疾病的起始原因。研究显示,脑铁过量积聚主要是由于遗传性和非遗传性因素所引起的某些服铁代谢蛋白功能异常或表达失控。正是异常增高的脑铁触发一系列病理反应,最终导致神经为性性疾病病人服神经元死亡。本文简要叙述了目前对服铁分布、功能和脑铁代谢蛋白的认识,讨论了内铁转运机制以及服铁和神经变性性疾病之间的关系研究的新进展。     

Urinary Biomarkers of Brain Diseases

Biomarkers are the measurable changes associated with a physiological or pathophysiological process. Unlike blood, urine is not subject to homeostatic mechanisms. Therefore, greater fluctuations could occur in urine than in blood, better reflecting the changes in human body. The roadmap of urine biomarker era was proposed. Although urine analysis has been attempted for clinical diagnosis, and urine has been monitored during the progression of many diseases, particularly urinary system diseases, whether urine can reflect brain disease status remains uncertain. As some biomarkers of brain diseases can be detected in the body fluids such as cerebrospinal fluid and blood,there is a possibility that urine also contain biomarkers of brain diseases. This review summarizes the clues of brain diseases reflected in the urine proteome and metabolome.     

创伤性脑损伤中神经炎症相关细胞的研究进展

创伤性脑损伤(traumatic brain injury, TBI), 亦称颅脑损伤或头部外伤, 专指由外伤引起的脑组织损害。然而,从轻度到重度的TBI,改善TBI患者预后的治疗方法都十分匮乏。神经炎症可引起脑外伤后急性继发性损伤,并与慢性神经退行性疾病有关,因此,系统了解参与TBI后神经炎性反应的细胞显得尤为重要。主要对TBI中参与炎症反应的细胞（如小胶质细胞、星形胶质细胞、少突细胞、中性粒细胞和淋巴细胞）的启动以及相互作用的最新研究进展进行了综述,以期为临床研究提供新的策略。     

多光子显微成像技术在脑部疾病研究中的应用

由于多光子显微技术具有高时空分辨率、低损伤性、可对活体长时间成像等特点,近年来已被广泛应用于生物医学等领域,并且在多种疾病诊断中展现出巨大的应用潜力.尤其是在脑部疾病的研究中,利用多光子成像技术可实现对复杂神经网络的研究,包括对脑部神经细胞、血管、肿瘤等进行实时成像并研究各自之间的相互作用,能进一步揭示脑疾病的发病机制并指导检测治疗方法的开发.本文简要介绍了多光子成像技术的基本原理及特点,总结了其在阿尔茨海默病、脑中风、脑肿瘤等多种脑部疾病中的应用,详细阐述了近年来利用多光子成像技术在脑部疾病研究中所获得的成果,并对多光子成像技术的发展前景进行了展望,预期其在脑部疾病的研究中将发挥更大的作用.     

Ultrasound-Enhanced Drug Transport and Distribution in the Brain

Drug delivery in the brain is limited by slow drug diffusion in the brain tissue. This study tested the hypothesis that ultrasound can safely enhance the permeation of drugs in the brain. In vitro exposure to ultrasound at various frequencies (85 kHz, 174 kHz, and 1 MHz) enhanced the permeation of tritium-labeled molecules with molecular weight up to 70 kDa across porcine brain tissue. A maximum enhancement of 24-fold was observed at 85 kHz and 1,200 J/cm². In vivo exposure to 1-MHz ultrasound further demonstrated the ability of ultrasound to facilitate molecule distribution in the brain of a non-human primate. Finally, ultrasound under conditions similar to those used in vivo was shown to cause no damage to plasmid DNA, siRNA, adeno-associated virus, and fetal rat cortical neurons over a range of conditions. Altogether, these studies demonstrate that ultrasound can increase drug permeation in the brain in vitro and in vivo under conditions that did not cause detectable damage.     

Cellular Basis of Anoxic-Ischemic Brain Injury

Anoxic-ischemic cerebral disease is an important primary cause of morbidity and mortality, and also complicates a number of systemic diseases. Its clinical manifestations, such as hemiparesis and coma, represent cellular injury sustained by the complex, inhomogeneous brain. An understanding of the nature and pattern of anoxic-ischemic cerebral injury, and of the logical basis for avenues of therapy, is necessary to the management of patients with the various anoxic-ischemic disorders.     

脑铁代谢及调控

随着研究的深入,脑铁代谢相关分子突变引起的疾病越来越多的被人们所认识。脑铁代谢紊乱可能是神经退行性疾病的发病原因之一。对脑铁代谢机理的认识将为预防和治疗脑铁代谢紊乱相关疾病提供重要的理论根据。对脑铁代谢的过程,脑铁代谢的相关分子以及这些分子对脑内铁稳态的调控作用作一介绍。     

Brain repair by endogenous progenitors

Stem cells within the adult brain can be stimulated by injury and growth factor treatment to replace damaged neurons, even neurons that are not normally generated in adults. Coupled with recent insights into the mechanism by which Nogo inhibits axonal regeneration, this discovery may inspire new treatments for central nervous system injuries and neurodegenerative diseases.     

生物标记物对脑损伤患儿早期诊断及监测价值的研究进展

脑损伤是新生儿期危害严重的疾病之一,可导致脑瘫、运动发育迟缓、认知功能障碍及学习困难等后遗症,严重影响了新生儿的健康发育及生活质量的提高。新生儿脑损伤(NBI)是一种由多种原因导致的范围很广的疾病,其临床表现缺乏特异性,临床上在判断其损伤严重程度、持续时间及产前损伤时间等存在较大的困难,受到广大科研者及临床医师的重视。目前,影像学方法是NBI确诊的主要手段,但影像学检查通常存在滞后性和一定的局限性。体液生物标记物水平在脑损伤后会较早发生变化,通过检测其水平变化可早期预测脑损伤情况。近年来,新生儿各种体液中已检测出多种具有敏感性的脑损伤生物标记物,主要包括神经元特异性烯醇化酶(NSE)、泛素羟基末端水解酶L-1(UCH-L1)、S100B蛋白、Tau蛋白、髓鞘碱性蛋白(MBP)、胶质纤维酸性蛋白(GFAP)、激活素A等,本研究对上述常用生物标记物在NBI中的应用情况以及研究进展进行综述,探讨其临床应用前景。     

Connecting Malfunctioning Glial Cells and Brain Degenerative Disorders

The DNA damage response(DDR) is a complex biological system activated by different types of DNA damage.Mutations in certain components of the DDR machinery can lead to genomic instability disorders that culminate in tissue degeneration,premature aging,and various types of cancers.Intriguingly,malfunctioning DDR plays a role in the etiology of late onset brain degenerative disorders such as Parkinson's,Alzheimer's,and Huntington's diseases.For many years,brain degenerative disorders were thought to result from aberrant neural death.Here we discuss the evidence that supports our novel hypothesis that brain degenerative diseases involve dysfunction of glial cells(astrocytes,microglia,and oligodendrocytes).Impairment in the functionality of glial cells results in pathological neuro-glial interactions that,in turn,generate a ‘‘hostile" environment that impairs the functionality of neuronal cells.These events can lead to systematic neural demise on a scale that appears to be proportional to the severity of the neurological deficit.     

脑疾病与游离氨基酸的研究

脑疾病包括肝性脑病 (或肝昏迷 ) ,乙型脑炎 ,儿童智力发育不全 ,脑瘫 ,新生儿缺氧缺血脑病以及脑衰老等。研究结果说明 :( 1 )肝性脑病 (或肝昏迷 )和乙型脑炎患者体液中谷氨酰胺水平升高 ,这种升高可以作为以上两种疾病的早期诊断 ;( 2 )脑瘫 ,智力发育不全以及脑衰老 (动物 )等患者 ,体液中谷氨酸浓度降低而r 氨基酸 (GABA)浓度升高 ,它们可以作为评价大脑损伤程度的指标 ,同时也有早期诊断这些疾病的价值 ;( 3)适当补充必需氨基酸能控制以上各种脑疾病的发展。     

Translation of the Prion Protein mRNA Is Robust in Astrocytes but Does Not Amplify during Reactive Astrocytosis in the Mouse Brain

Prion diseases induce neurodegeneration in specific brain areas for undetermined reasons. A thorough understanding of the localization of the disease-causing molecule, the prion protein (PrP), could inform on this issue but previous studies have generated conflicting conclusions. One of the more intriguing disagreements is whether PrP is synthesized by astrocytes. We developed a knock-in reporter mouse line in which the coding sequence of the PrP expressing gene (Prnp), was replaced with that for green fluorescent protein (GFP). Native GFP fluorescence intensity varied between and within brain regions. GFP was present in astrocytes but did not increase during reactive gliosis induced by scrapie prion infection. Therefore, reactive gliosis associated with prion diseases does not cause an acceleration of local PrP production. In addition to aiding in Prnp gene activity studies, this reporter mouse line will likely prove useful for analysis of chimeric animals produced by stem cell and tissue transplantation experiments.     

Brain Iron Toxicity: Differential Responses of Astrocytes,Neurons, and Endothelial Cells

Iron accumulation or iron overload in brain is commonly associated with neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases, and also plays a role in cellular damage following hemorrhagic stroke and traumatic brain injury. Despite the brain’s highly regulated system for iron utilization and metabolism, these disorders often present following disruptions within iron metabolic pathways. Such dysregulation allows saturation of proteins involved in iron transport and storage, and may cause an increase in free ferrous iron within brain leading to oxidative damage. Not only do astrocytes, neurons, and brain endothelial cells serve unique purposes within the brain, but their individual cell types are equipped with distinct protective mechanisms against iron-induced injury. This review evaluates iron metabolism within the brain under homeostatic and pathological conditions and focuses on the mechanism(s) of brain cellular iron toxicity and differential responses of astrocytes, neurons, and brain vascular endothelial cells to excessive free iron. Special issue dedicated to Dr. Moussa Youdim. An erratum to this article can be found at     

Brain Tumor Stem Cells

Primary malignant brain cancer, one of the most deadly diseases, has a high rate of recurrence after treatment. Studies in the past several years have led to the hypothesis that the root of the recurrence may be brain tumor stem cells (BTSCs), stem-like subpopulation of cells that are responsible for propagating the tumor. Current treatments combining surgery and chemoradiotherapy could not eliminate BTSCs because these cells are highly infiltrative and possess several properties that can reduce the damages caused by radiation or anti-cancer drugs. BTSCs are similar to NSCs in molecular marker expression and multi-lineage differentiation potential. Genetic analyses of Drosophila CNS neoplasia, mouse glioma models, and human glioma tissues have revealed a link between increased NSC self-renewal and brain tumorigenesis. Furthermore, data from various rodent models of malignant brain tumors have provided compelling evidence that multipotent NSCs and lineage-restricted neural progenitor cells (NPCs) could be the cell origin of brain tumors. Thus, the first event of brain tumorigenesis might be the occurrence of oncogenic mutations in the stem cell self-renewal pathway in an NSC or NPC. These mutations convert the NSC or NPC to a BTSC, which then initiates and sustains the growth of the tumor. The self-renewal of BTSCs is controlled by several evolutionarily conserved signaling pathways and requires an intact vascular niche. Targeting these pathways and the vascular niche could be a principle in novel brain tumor therapies aimed to eliminate BTSCs.     

Brain functional network modeling and analysis based on fMRI: a systematic review

In recent years, the number of patients with neurodegenerative diseases (i.e., Alzheimer’s disease, Parkinson’s disease, mild cognitive impairment) and mental disorders (i.e., depression, anxiety and schizophrenia) have increased dramatically. Researchers have found that complex network analysis can reveal the topology of brain functional networks, such as small-world, scale-free, etc. In the study of brain diseases, it has been found that these topologies have undergoed abnormal changes in different degrees. Therefore, the research of brain functional networks can not only provide a new perspective for understanding the pathological mechanism of neurological and psychiatric diseases, but also provide assistance for the early diagnosis. Focusing on the study of human brain functional networks, this paper reviews the research results in recent years. First, this paper introduces the background of the study of brain functional networks under complex network theory and the important role of topological properties in the study of brain diseases. Second, the paper describes how to construct a brain functional network using neural image data. Third, the common methods of functional network analysis, including network structure analysis and disease classification, are introduced. Fourth, the role of brain functional networks in pathological study, analysis and diagnosis of brain functional diseases is studied. Finally, the paper summarizes the existing studies of brain functional networks and points out the problems and future research directions.     

Molecular Cytogenetics and Cytogenomics of Brain Diseases

Molecular cytogenetics is a promising field of biomedical research that has recently revolutionized our thinking on genome structure and behavior. This is in part due to discoveries of human genomic variations and their contribution to biodiversity and disease. Since these studies were primarily targeted at variation of the genome structure, it appears apposite to cover them by molecular cytogenomics. Human brain diseases, which encompass pathogenic conditions from severe neurodegenerative diseases and major psychiatric disorders to brain tumors, are a heavy burden for the patients and their relatives. It has been suggested that most of them, if not all, are of genetic nature and several recent studies have supported the hypothesis assuming them to be associated with genomic instabilities (i.e. single-gene mutations, gross and subtle chromosome imbalances, aneuploidy). The present review is focused on the intriguing relationship between genomic instability and human brain diseases. Looking through the data, we were able to conclude that both interindividual and intercellular genomic variations could be pathogenic representing, therefore, a possible mechanism for human brain malfunctioning. Nevertheless, there are still numerous gaps in our knowledge concerning the link between genomic variations and brain diseases, which, hopefully, will be filled by forthcoming studies. In this light, the present review considers perspectives of this dynamically developing field of neurogenetics and genomics.     

Noninvasive and Targeted Gene Delivery into the Brain Using Microbubble-Facilitated Focused Ultrasound

Recombinant adeno-associated viral (rAAV) vectors are potentially powerful tools for gene therapy of CNS diseases, but their penetration into brain parenchyma is severely limited by the blood-brain barrier (BBB) and current delivery relies on invasive stereotactic injection. Here we evaluate the local, targeted delivery of rAAV vectors into the brains of mice by noninvasive, reversible, microbubble-facilitated focused ultrasound (FUS), resulting in BBB opening that can be monitored and controlled by magnetic resonance imaging (MRI). Using this method, we found that IV-administered AAV2-GFP (green fluorescence protein) with a low viral vector titer (1×10⁹ vg/g) can successfully penetrate the BBB-opened brain regions to express GFP. We show that MRI monitoring of BBB-opening could serve as an indicator of the scale and distribution of AAV transduction. Transduction peaked at 3 weeks and neurons and astrocytes were affected. This novel, noninvasive delivery approach could significantly broaden the application of AAV-viral-vector-based genes for treatment of CNS diseases.     

Neuronal Mitochondrial Toxicity of Malondialdehyde: Inhibitory Effects on Respiratory Function and Enzyme Activities in Rat Brain Mitochondria

Malondialdehyde (MDA) is a product of oxidative damage to lipids, amino acids and DNA, and accumulates with aging and diseases. MDA can possibly react with amines so as to modify proteins and inactivate enzymes; it can also modify nucleosides so as to cause mutagenicity. Brain mitochondrial dysfunction is a major contributor to aging and neurodegenerative diseases. We hypothesize that MDA accumulated during aging targets mitochondrial enzymes so as to cause further mitochondrial dysfunction and additional contributions to aging and neurodegeneration. Herein, we investigated the neuronal mitochondrial toxic effects of MDA on mitochondrial respiration and activities of enzymes (mitochondrial complexes I–V, α-ketoglutarate dehydrogenase (KGDH) and pyruvate dehydrogenase (PDH)), in isolated rat brain mitochondria. MDA depressed mitochondrial membrane potential, and also showed a dose-dependent inhibition of mitochondrial complex I- and complex II-linked respiration. Complex I and II, and PDH activities were depressed by MDA at ≥0.2 μmol/mg; KGDH and complex V were inhibited by ≥0.4 and ≥1.6 μmol MDA/mg, respectively. However, MDA did not have any toxic effects on complex III and IV activities over the range 0–2 μmol/mg. MDA significantly elevated mitochondrial reactive oxygen species (ROS) and protein carbonyls at 0.2 and 0.002 μmol/mg, respectively. As for the antioxidant defense system, a high dose of MDA slightly decreased mitochondrial GSH and superoxide dismutase. These results demonstrate that MDA causes neuronal mitochondrial dysfunction by directly promoting generation of ROS and modifying mitochondrial proteins. The results suggest that MDA-induced neuronal mitochondrial toxicity may be an important contributing factor to brain aging and neurodegenerative diseases. Special issue article in honor of Dr. Akitane Mori.     

脑死亡诱发肺损伤机制及治疗进展

肺移植是终末期肺疾病的最终治疗方案.供体短缺是肺移植所面临的主要问题.目前,脑死亡供体是肺移植供体的重要来源.然而,脑死亡过程会诱发急性肺损伤并且加重肺缺血再灌注损伤.脑死亡肺损伤机制主要包括三个方面:血流动力学的剧烈改变、全身炎症改变、神经内分泌的改变.其肺损伤表现于肺间质水肿、血浆外漏和肺泡出血,造成肺水肿等.深入探索脑死亡肺损伤的机制,将对治疗及实施肺保护提供有力的依据.     

Nicotinamide Phosphoribosyltransferase May Be Involved in Age-Related Brain Diseases

Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme for nicotinamide adenine dinucleotide (NAD) biosynthesis, and can be found either intracellularly (iNAMPT) or extracellularly (eNAMPT). Studies have shown that both iNAMPT and eNAMPT are implicated in aging and age-related diseases/disorders in the peripheral system. However, their functional roles in aged brain remain to be established. Here we showed that upon aging, NAMPT level increased in serum but decreased in brain, decreased in cortex and hippocampus but remained unchanged in cerebellum and striatum in brain, and increased in microglia but likely decreased in neuron. Accordingly, total NAD (tNAD) level significantly decreased in hippocampus, cerebellum and striatum in aged brain. Application of recombinant NAMPT, mimicking the elevated serum NAMPT level, enhanced the susceptibility of cerebral endothelial cells to ischemic injury, while inhibition of iNAMPT by FK866, a specific inhibitor, reduced intracellular NAD level and induced neuronal death. Taken together, we have revealed a region- and cell-specific change of NAMPT level in brain and serum upon aging, deduced its potential consequences, which suggests that NAMPT is a regulatory factor in aging and age-related brain diseases.