雷帕霉素抗神经退行性病研究进展

雷帕霉素作为一种传统的抗真菌药物,具有免疫抑制剂和抗肿瘤的作用。值得注意的是,它通过抑制哺乳动物雷帕霉素靶标蛋白mTOR、受体FKBP、VMP1,促进自噬,抑制了帕金森病、亨廷顿病等神经退行性变的病理过程,从而有望成为一种新的抗神经退行病药物。本文对其新的研究进展予以综述。

神经退行病与神经保护

神经退行病是脑特定区域由于进展性脑神经功能不全或死亡而产生的疾病，这种脑神经恶化在临床症状发作前早已发生，如柏金森氏症(PD)在临床发病时，脑黑质多巴胺神经元已失去80％。神经退行病中最常见的有老年痴呆症(AD)，柏金森氏症(PD)，肌萎缩侧索硬化症(ALS)，亨廷顿氏症(HD)等。

3-磷酸甘油醛脱氢酶与神经元凋亡

综述了 3-磷酸甘油醛脱氢酶 ( glyceraldehyde- 3- phosphate dehydrogenase,GAPDH)的基因表达、酶活性及亚细胞定位等三个方面与神经元凋亡的关系的研究新进展 ,并列举了一些 GAPDH参与神经退行性疾病的临床证据。

The roles of the proteasome pathway in signal transduction and neurodegenerative diseases

There are two degradation systems in mammalian cells, autophagy/lysosomal pathway and ubiquitin-proteasome pathway. Proteasome is consist of multiple protein subunits and plays important roles in degradation of short-lived cellular proteins. Recent studies reveal that proteasomal degradation system is also involved in signal transduction and regulation of various cellular functions. Dysfunction or dysregulation of proteasomal function may thus be an important pathogenic mechanism in certain neurological disorders. This paper reviews the biological functions of proteasome in signal transduction and its potential roles in neurodegenerative diseases.

Neurogenic bowel dysfunction in patients with spinal cord injury, myelomeningocele, multiple sclerosis and Parkinson’s disease

Exciting new features have been described concerning neurogenic bowel dysfunction,including interactions between the central nervous system,the enteric nervous system,axonal injury,neuronal loss,neurotransmission of noxious and non-noxious stimuli,and the fields of gastroenterology and neurology.Patients with spinal cord injury,myelomeningocele,multiple sclerosis and Parkinson's disease present with serious upper and lower bowel dysfunctions characterized by constipation,incontinence,gastrointestinal motor dysfunction and altered visceral sensitivity.Spinal cord injury is associated with severe autonomic dysfunction,and bowel dysfunction is a major physical and psychological burden for these patients.An adult myelomeningocele patient commonly has multiple problems reflecting the multisystemic nature of the disease.Multiple sclerosis is a neurodegenerative disorder in which axonal injury,neuronal loss,and atrophy of the central nervous system can lead to permanent neurological damage and clinical disability.Parkinson's disease is a multisystem disorder involving dopaminergic,noradrenergic,serotoninergic and cholinergic systems,characterizedby motor and non-motor symptoms.Parkinson's disease affects several neuronal structures outside the substantia nigra,among which is the enteric nervous system.Recent reports have shown that the lesions in the enteric nervous system occur in very early stages of the disease,even before the involvement of the central nervous system.This has led to the postulation that the enteric nervous system could be critical in the pathophysiology of Parkinson's disease,as it could represent the point of entry for a putative environmental factor to initiate the pathological process.This review covers the data related to the etiology,epidemiology,clinical expression,pathophysiology,genetic aspects,gastrointestinal motor dysfunction,visceral sensitivity,management,prevention and prognosis of neurogenic bowel dysfunction patients with these neurological diseases.Embryological,morphological and experimental studies on animal models and humans are also taken into account.

Impact of miRNAs on cardiovascular aging

Aging is a multidimensional process that leads to an increased risk of developing severe diseases, such as cancer and cardiovascular, neurodegenerative, and immunological diseases. Recently, small non-coding RNAs known as microRNAs （miRNAs） have been shown to regulate gene expression, which contributes to many physiological and pathophysiological processes in humans. Increasing evidence suggests that changes in miRNA expression profiles contribute to cellular senescence, aging and aging-related diseases. However, only a few miRNAs whose functions have been elucidated have been associated with aging and/or aging-related diseases. This article reviews the currently available findings regarding the roles of aging-related miRNAs, with a focus on cardiac and cardiovascular aging.

A panel of monoclonal antibodies against the prion protein proves that there is no prion protein in human pancreatic ductal epithelial cells

Prion diseases are a group of neurodegenerative diseases that are fatal. The study of these unique diseases in China is hampered by a lack of resources. Amongst the most important resources for biological study are monoclonal antibodies. Here, we characterize a panel of monoclonal antibodies specific for cellular prion protein by enzyme-linked immunosorbent assay(ELISA), immunofluorescent staining, flow cytometry, and western blotting. We identify several antibodies that can be used for specific applications and we demonstrate that there is no prion protein expression in human pancreatic ductal epithelial cells(HPDC).

Targeting voltage-gated sodium channels for treatment for chronic visceral pain

Voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability,and their abnormal activity is related to several pathological processes,including cardiac arrhythmias,epilepsy,neurodegenerative diseases,spasticity and chronic pain.In particular,chronic visceral pain,the central symptom of functional gastrointestinal disorders such as irritable bowel syndrome,is a serious clinical problem that affects a high percentage of the world population.In spite of intense research efforts and after the dedicated decade of pain control and research,there are not many options to treat chronic pain conditions.However,there is a wealth of evidence emerging to give hope that a more refined approach may be achievable.By using electronic databases,available data on structural and functional properties of VGSCs in chronic pain,particularly functional gastrointestinal hypersensitivity,were reviewed.We summarize the involvement and molecular bases of action of VGSCs in the pathophysiology of several organic and functionalgastrointestinal disorders.We also describe the efficacy of VGSC blockers in the treatment of these neurological diseases,and outline future developments that may extend the therapeutic use of compounds that target VGSCs.Overall,clinical and experimental data indicate that isoform-specific blockers of these channels or targeting of their modulators may provide effective and novel approaches for visceral pain therapy.

The complex role of physical exercise and reactive oxygen species on brain

Reactive oxygen species （ROS） are continuously generated during aerobic metabolism and at moderate level. They play a role in redox signaling, but in significant concentration they cause oxidative damage and neurodegeneration. Because of the enhanced sensitivity of brain to ROS, it is especially important to maintain the normal redox state in different types of neuron cells. In last decade it became clear that regular exercise beneficially affects brain function, and can play an important preventive and therapeutic role in stroke, Alzheimer, and Parkinson diseases. The effects of exercise appear to be very complex and could include neurogenesis via neurotrophic factors, increased capillariszation, decreased oxidative damage, and increased proteolyfic degradation by proteasome and neprilysin. Data from our and other laboratories indicate that exercise-induced modulation of ROS levels plays a role in the protein content and expression of brain-derived neurotrophic factor, tyrosinerelated kinase B （TrkB）, and cAMP response element binding protein, resulting in better function and increased neurogenesis. Therefore, it appears that exercise-induced modulation of the redox state is an important means, by which exercise benefits brain function, increases the resistance against oxidative stress, facilitates recovery from oxidative stress, and attenuates age-associated decline in cognition.

Polyglutamine toxicity in non-neuronal cells

The neurodegenerative polyglutamine diseases are caused various disease proteins. Although these mutant proteins are by an expansion of unstable polyglutamine repeats in expressed ubiquitously in neuronal and non-neuronal cells, they cause selective degeneration of specific neuronal populations. Recently, increasing evidence shows that polyglutamine disease proteins also affect non-neuronal cells. However, it remains unclear how the expression of polyglutamine proteins in non-neuronal cells contributes to the course of the polyglutamine diseases. Here, we discuss recent findings about the expression of mutant polyglutamine proteins in non-neuronal cells and their influence on neurological symptoms. Understanding the contribution of non-neuronal polyglutamine proteins to disease progres- sion will help elucidate disease mechanisms and also help in the development of new treatment options.

Extracellular vesicle–based drug delivery system boosts phytochemicals’therapeutic effect for neurodegenerative diseases

Neurodegenerative diseases(NDs)are a major threat to the elderly,and efficient therapy is rarely available.A group of phytochemicals has been shown to ameliorate NDs;however,poor stability,low bioavailability,and reduced drug accumulation in brain tissue limit their application in NDs.Therefore,a targeted drug delivery system is a feasible treatment strategy for NDs.Extracellular vesicles(EVs)possess many favorable bioactivities and are excellent carriers for targeting brain tissue.This review summarizes EVs as novel phytochemical carriers in ND therapy.First,we discuss the current challenges of ND therapy and the therapeutic effects of phytochemicals for NDs.Second,we highlight the ability of EVs to cross the blood-brain barrier and act as drug carriers to enhance the therapeutic efficacy of drugs for NDs.Finally,encapsulation strategies for phytochemicals in EVs are particularly reviewed,as they are critical for obtaining high loading efficacy and stable drug delivery systems.This review provides new insights into EV-based drug delivery systems for improving the therapeutic effect of phytochemicals for ND treatment.Therefore,the release rate and pharmacokinetics of phytochemicals should be well controlled to ensure the therapeutic efficacy of phytochemical-loaded EVs in the brain.

Development of a Zebrafish Model for Rapid Drug Screening against Alzheimer＇s Disease

Alzheimer＇s disease, the leading cause of dementia in the elderly, is a complex neurodegenerative disorder which leads to a progressive decline in cognitive functions. A rapid screening model is highly demanded for identification and evaluation of novel anti-Alzheimer＇s disease drugs from a large numbers of compounds. Until now, numerous studies utilized zebrafish model for drug discovery. Since aluminum can induce a similar biological activity in zebrafish as in Alzheimer patients, in this study, we developed a novel animal model using 3 to 5 day post-fertilization larval zebrafish by optimizing the doses and duration of aluminum chloride exposure. Six anti-Alzheimer＇s disease drugs with a variety of mechanisms were tested to validate the newly developed zebrafish model. Importantly, Rivastigmine, ThT, Flurbiprofen and AM-117 could increase the value of Dyskinesia Recovery Rate by 53.4-64%, 169.4-200%, 54.5-96% and 70.9-121%, respectively. Rivastigmine, Memantine, ThT, Flurbiprofen, Rosiglitazone and AM-117 improved the value of Response Efficiency by 86.6-175.1%, 28.2-66.6%, 127.2-236.5%, 118.3-323.7%, 26.6-140.8% and 70.2-161.4%, respectively. Our results suggest that the zebrafish model developed in this study could be a useful tool for high throughput screening of potential novel anti-Alzheimer＇s disease leading compounds targeting acetylcholinesterase, N-methyl-D-aspartic acid receptor, γ-secretase, peroxisome proliferator-activated receptor-γand amyloid-β.

PrP 106-126 Altered PrP mRNA Gene Expression in Mouse Microglia BV-2 Cells

Prion diseases are infectious and fatal neurodegenerative diseases.The pathogenic agent is an abnormal prion protein aggregate.Microglial activation in the centre nervous system is a characteristic feature of prion disease.In this study,we examined the effect of PrP 106-126 on PrP mRNA gene expression in Mouse microglia cells BV-2 by real-time quantitative PCR.PrP mRNA expression level was found to be significantly increased after 18 h exposure of BV-2 cells to PrP 106-126,with 3-fold increase after 18 h and 4.5-fold increase after 24 h and BV-2 cells proliferating occurred correspondingly.Our results provide the first in vitro evidence of the increase of PrP mRNA levels in microglial cells exposed to PrP 106-126,and indicate that microglial cells might play a critical role in prion pathogenesis.

Combined administration of D-galactose and aluminium induces Alzheimer-like lesions in brain

Objective It has been reported that D-galactose （D-gal） can model subacute aging, and aluminum （AI） acts as a neurotoxin, but combined effects of them have not been reported. The present work aimed to reveal the effect of combined administration of D-gal and A1 in mice and compare the effect of D-gal treatment with that of A1 treatment. Meth- ods A1 was intragastricaHy administered and D-gal was subcutaneously injected into Kunming mice for 10 consecutive weeks. Learning and memory, eholinergic systems, as well as protein levels of amyloid β （Aβ） and hyperphosphorylated tau were determined using Morri water maze test, biochemical assays and immunohistochemical staining, respectively. Results The mice with combined treatment had obvious learning and memory deficits, and showed decreases in brain ace- tylcholine （ACh） level and in activities of choline acetyltransferase （CHAT） and acetyleholinesterase （ACHE）. Formation of senile plaque （SP）-like and neurofibrillary tangle （NFT）-like structures was also observed. The behavioral and pathologi- cal changes persisted for at least 6 weeks after withdrawal of D-gal and A1. Conclusion Combined use of D-gal and A1 is an effective way to establish the non-transgenic Alzheimer＇s disease （AD） animal model, and is useful for studies of AD pathogenesis and therapeutic evaluation.

Current understanding on the pathogenesis of polyglutamine diseases

Polyglutamine （polyQ） diseases are a family of neurodegenerative disorders including Huntington’s disease, spinobulbar muscular atrophy,dentatorubral-pallidoluysian atrophy and several spinocerebellar ataxias.polyQ diseases are caused by abnormal expansion of CAG repeats in certain genes.The expanded CAG repeats are then translated into a series of abnormally expanded polyQ tracts.Such polyQ tracts may induce misfolding of the disease-causing proteins.The present review mainly focuses on the common characteristics of the pathogenesis of these polyQ diseases,including conformational transition of proteins and its influence on the function of these proteins,the correlation between decreased ability of proteoly-sis and late-onset polyQ diseases,and the relationship between wide expression of disease-causing proteins and selective neuronal death.

Neuroprotective effect of fucoxanthin on β-amyloid-induced cell death

Alzheimer＇s disease （AD） is one of the most common cognitive disorders of the elderly. Fucoxanthin is a carotenoid that is found in common edible seaweed, and it is considered as a major active compound of marine algae with cancer-preventing, antioxidant and anti-inflammatory properties. In this study, we investigated the ability of fucoxanthin to protect against the β-amyloid protein （Aβ）-induced neurotoxicity in primary cortical cultured neurons and PC12 cells. Neuroprotective effects of fucoxanthin were determined by measuring cell viability and nuclei double-staining with Hoechst 33342 and propidium iodide following Aβ treatment with or without fucoxanthin. Moreover, we also evaluated its potential mechanism on antioxidation by detecting the total antioxidant capacity （T-AOC）, level of lipid peroxidation malondialdehyde （MDA） and activity of superoxide dismutase （SOD）. We found that exposure of cortical cultured neurons or PC12 cells to Aβ resulted in neuronal cell death, whereas pre-treatment with fucoxanthin reduced Aβ-induced cell death. The data on the T-AOC, MDA level and SOD activity showed that Aβ treatment resulted in decreases in T-AOC and SOD activity and an increase in MDA level. After fucoxanthin administration, the results of T-AOC, MDA level and SOD activity showed an opposite trend, indicating that T-AOC was increased and MDA level was reduced. These results suggested that fucoxanthin prevented Aβ-induced neurotoxicity through attenuating oxidative stress induced by Aβ. Therefore, fucoxanthin might be useful as a potential preventive or theraoeutic agent for AD.

P2Y6 receptor and immunoinflammation

The immunocytes microglia in the central nervous system （CNS） were reported to play a crucial role in neurodegeneration. As a member of P2 receptors family, purinoceptor P2Y6 has attracted much attention recently. Previous studies showed that purinoceptor P2Y6 mainly contributed to microglia activation and their later phagocytosis in CNS, while in immune system, it participated in the secretion of interleukin （IL）-8 from monocytes and macrocytes. So there raises a question： whether purinoceptor P2Y6 also takes part in neuroinflammation？ Thus, this review mainly concerns about the properties and roles of purinoceptor P2Y6, including （1） structure of purinoceptor P2Y6; （2） distribution and properties of purinoceptor P2Y6; （3） relationships between purinoceptor P2Y6 and microglia; （4） relationships between purinoceptor P2Y6 and immunoinflammation. It＇s proposed that purinoceptor P2Y6 may play a role in neuroinflammation in CNS, although further research is still required.

Protective effects of 20-hydroxyecdysone on H_2 O_2-induced cytotoxicity in human neuroblastoma SH-SY5Y cells

The aim of this study was to investigate the possible protective effects and mechanisms of 20-hydroxyecdysone, an insect steroid hormone, on HEO2-induced cytotoxicity in human neuroblastoma SH-SYSY cells. Pretreatment with 20-hydroxyecdysone significantly elevated the cell viability and decreased LDH leakage in H2O2-treated SH-SY5Y cells. 20-Hydroxyecdysone also dramatically reduced malondialdehyde （MDA） contents and enhanced the superoxide dismutase （SOD） activities under oxidative stress conditions. Furthermore, 20-hydroxyecdysone pretreatment inhibited apoptosis by decreasing the Bax/Bcl-2 ratio and attenuating the activation of caspase-3. These results suggest that 20-hydroxyecdysone can protect SH-SYSY cells against H2O2-induced cytotoxicity and might potentially be used to treat neurodegenerative diseases induced by oxidative stress and anontosis.

Induced pluripotent stem cells and neurodegenerative diseases

Neurodegenerative diseases,including Parkinson＇s disease,Alzheimer＇s disease and Amyotrophic Lateral Sclerosis,are characterized by idiopathic neuron loss in different regions of the central nervous system,which contributes to the relevant dysfunctions in the patients.The application of cell replacement therapy using human embryonic stem（hES） cells,though having attracted much attention,has been hampered by the intrinsic ethical problems.It has been demonstrated that adult somatic cells can be reprogrammed into the embryonic state,called induced pluripotent stem（iPS） cells.It is soon realized that iPS cells may be an alternative source for cell replacement therapy,because it raises no ethical problems and using patient-specific iPS cells for autologous transplantation will not lead to immunological rejection.What＇s more,certain types of neurons derived from patient-specific iPS cells may display disease-relevant phenotypes.Thus,patientspecific iPS cells can provide a unique opportunity to directly investigate the pathological properties of relevant neural cells in individual patient,and to study the vulnerability of neural cells to pathogenic factors in vitro,which may help reveal the pathogenesis of many neurodegenerative diseases.In this review,the recent development in cellular treatment of neurodegenerative diseases using iPS cells was summarized,and the potential value of iPS cells in the modeling of neurodegenerative disease was discussed.

MicroRNAs in neural cell development and brain diseases

MicroRNAs play important roles in post-transcriptional regulation of gene expression by inhibiting protein translation and/or promoting mRNA degradation.Importantly,biogenesis of microRNAs displays specific temporal and spatial profiles in distinct cell and tissue types and hence affects a broad spectrum of biological functions in normal cell growth and tumor development.Recent discoveries have revealed sophisticated mechanisms that control microRNA production and homeostasis in response to developmental and extracellular signals.Moreover,a link between dysregulation of microRNAs and human brain disorders has become increasingly evident.In this review,we focus on recent advances in understanding the regulation of microRNA biogenesis and function in neuronal and glial development in the mammalian brain,and dysregulation of the microRNA pathway in neurodevelopmental and neurodegenerative diseases.