Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human B lymphocytes and derived lines from a spectrum of B cell malignancy were studied for expression of dopaminergic pathway components and for their cytostatic response to the catecholamine and related, potentially therapeutic compounds. Proliferating normal lymphocytes and dividing malignant clones rapidly arrested on exposure to dopamine in the low (</=10 muM) micromolar range. The antiparkinsonian drugs l-DOPA and apomorphine (particularly) were similarly antiproliferative. With the exception of D4, dopamine receptors D1-D5 were variably expressed among normal and neoplastic B cell populations, as was the dopamine transporter. Transcripts for D1 and D2 were frequently found, whereas D3 and D5 revealed restricted expression; dopamine transporter was detected in most cases. Nevertheless, pharmacological analysis disclosed that dopamine targeted cycling B cells independent of these structures. Rather, oxidative stress constituted the primary mechanism: the catecholamine's actions being mimicked by hydrogen peroxide and reversed by exogenous catalase, and evidence for the intracellular redox protein thioredoxin contributing protection. Among proliferating clones, growth arrest was accompanied by cell death in populations deplete in antiapoptotic Bcl-2: resting lymphocytes escaping low micromolar dopamine toxicity. Dysregulated bcl-2 expression, although preventing oxidative-induced caspase-dependent apoptosis, by itself conferred only minor protection against dopamine cytostasis. The selective impact of dopamine on lymphocytes that are in active cycle indicates an axis for therapeutic intervention not only in B cell neoplasia but also in lymphoproliferative disturbances generally. Rational tailoring of drug delivery systems already in development for Parkinson's disease could provide ideal vehicles for carrying the oxidative hit directly to the target populations.
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PMID:Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin's lymphoma. 1693 64

We describe a method of generating an enriched population of NCAM-positive cells from a human teratocarcinoma cell line (NTera2/D1) and their differentiation into midbrain dopaminergic neurons in the absence of the caudalizing factor retinoic acid (RA). NTera2 cells were induced to form embryoid bodies and then to generate nestin-positive cells on treatment with serum-free defined medium supplemented with neurotrophic factors. We enriched the neuroprogenitor population by magnetic sorting of the nestin-positive cells using the antibody to neural cell adhesion molecule (NCAM). These cells were expanded by exposing them to the signaling molecule sonic hedgehog (SHH) in conjunction with fibroblast growth factor-8 (FGF-8). The predifferentiated cells when analyzed by RT-PCR showed expression of dopaminergic markers such as Nurr1, Engrailed-1, aromatic amino decarboxylase (AADC), VMAT2, tyrosine hydroxylase (TH), and dopamine transporter (DAT). These cells also stained positively for protein markers such as nestin, NCAM, MAP-2, and TH. We further demonstrated that when transplanted into the brain of Parkinsonian rats, these neuroprogenitor cells did not form tumors but differentiated into dopaminergic neurons, as revealed by TH immunolabeling. The origin of transplanted cells were further confirmed by positive immunolabeling with anti-human nuclei. Our results suggest that enriching the neuroprogenitor population by magnetic sorting prevents tumor formation and is a prerequisite before cell replacement therapy for Parkinson's disease.
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PMID:Enriched NCAM-positive cells form functional dopaminergic neurons in the rat model of Parkinson's disease. 1697 60

DJ-1/PARK7, a cancer- and Parkinson's disease (PD)-associated protein, protects cells from toxic stresses. However, the functional basis of this protection has remained elusive. We found that loss of DJ-1 leads to deficits in NQO1 [NAD(P)H quinone oxidoreductase 1], a detoxification enzyme. This deficit is attributed to a loss of Nrf2 (nuclear factor erythroid 2-related factor), a master regulator of antioxidant transcriptional responses. DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2's subsequent ubiquitination. Without intact DJ-1, Nrf2 protein is unstable, and transcriptional responses are thereby decreased both basally and after induction. This effect of DJ-1 on Nrf2 is present in both transformed lines and primary cells across human and mouse species. DJ-1's effect on Nrf2 and subsequent effects on antioxidant responses may explain how DJ-1 affects the etiology of both cancer and PD, which are seemingly disparate disorders. Furthermore, this DJ-1/Nrf2 functional axis presents a therapeutic target in cancer treatment and justifies DJ-1 as a tumor biomarker.
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PMID:DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. 1701 34

Oxidative stress plays crucial role in the pathogenesis of neurodegenerative diseases. However, the precise mechanism for an increased production of reactive oxygen species (ROS) under pathological conditions is not yet fully understood. We have recently demonstrated an implication of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a tumor suppressor, in ROS generation and neuronal apoptosis induced by staurosporine. These findings raised further interest whether PTEN functions as a common mediator of oxidative stress in neurodegenerative processes. To address this issue, neural cells were exposed to oxygen-glucose deprivation (OGD) and to the neurotoxin 1-methyl-4-phenylpyridinium iodide (MPP(+)), which mimic cerebral ischemia and Parkinson's disease, respectively. OGD for 4 h followed by 16 h of reoxygenation or incubation with MPP(+) (250 microM) for 48 h induced 33% and 45% neuronal death in rat hippocampal and in human dopaminergic SH-SY5Y neurons, respectively, accompanied by a gradual increase in the intracellular level of ROS. The increase in ROS by OGD and by MPP(+) did not cause oxidative inactivation of PTEN and thus, PTEN remains constitutively active. In support, the protein level of PTEN was not reduced in both cell cultures after challenging with OGD or MPP(+). Importantly, the elevated intracellular ROS levels and the neuronal death caused by OGD or by MPP(+) toxicity were significantly inhibited when PTEN was downregulated by a specific antisense oligonucleotide or by siRNA. Because SOD2 protein level is not altered either by knockdown of PTEN nor by an inhibition of the PI3K/Akt signalling, we suggest that SOD2 do not contribute to the pathomechanism of oxidative stress induced by PTEN or by inhibiting the related Akt signalling. The present study highlights PTEN as a crucial and common mediator of ROS generation and neuronal death and suggests that PTEN could become a potential therapeutic target for interfering with neurodegeneration.
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PMID:Implication of PTEN in production of reactive oxygen species and neuronal death in in vitro models of stroke and Parkinson's disease. 1716 62

Because a limited study previously showed that alpha-synuclein (alpha-syn), the major pathogenic protein for Parkinson disease, was expressed in differentiating brain tumors as well as various peripheral cancers, the main objective of the present study was to determine whether alpha-syn might be involved in the regulation of tumor differentiation. For this purpose, alpha-syn and its non-amyloidogenic homologue beta-syn were stably transfected to human osteosarcoma MG63 cell line. Compared with beta-syn-overexpressing and vector-transfected cells, alpha-syn-overexpressing cells exhibited distinct features of differentiated osteoblastic phenotype, as shown by up-regulation of alkaline phosphatase and osteocalcin as well as inductive matrix mineralization. Further studies revealed that proteasome activity was significantly decreased in alpha-syn-overexpressing cells compared with other cell types, consistent with the fact that proteasome inhibitors stimulate differentiation of various osteoblastic cells. In alpha-syn-overexpressing cells, protein kinase C (PKC) activity was significantly decreased, and reactivation of PKC by phorbol ester significantly restored the proteasome activity and abrogated cellular differentiation. Moreover, activity of lysosome was up-regulated in alpha-syn-overexpressing cells, and treatment of these cells with autophagy-lysosomal inhibitors resulted in a decrease of proteasome activity associated with up-regulation of alpha-syn expression, leading to enhance cellular differentiation. Taken together, these results suggest that the stimulatory effect of alpha-syn on tumor differentiation may be attributed to down-regulation of proteasome, which is further modulated by alterations of various factors, such as protein kinase C signaling pathway and a autophagy-lysosomal degradation system. Thus, the mechanism of alpha-syn regulation of tumor differentiation and neuropathological effects of alpha-syn may considerably overlap with each other.
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PMID:alpha-Synuclein stimulates differentiation of osteosarcoma cells: relevance to down-regulation of proteasome activity. 1718 70

Neural stem cells (NSCs)of the central nervous system (CNS) have recently received a great deal of attention and interest for their therapeutic potential for neurological disorders. NSCs are defined as CNS progenitor cells that have the capacity for self-renewal and multipotent potential to become neurons or glial cells. Recent studies have shown that NSCs isolated from mammalian CNS including human can be propagated in vitro and then implanted into the brain of animal models of human neurological disorders. Recently, we have generated clonally derived immortalized human NSC cell lines via a retroviral vector encoded with v-myc oncogene. One of the human NSC lines, HB1.F3, was utilized in stem-cell based therapy in animal models of human neurological disorders. When F3 human NSCs were implanted into the brain of murine models of lysosomal storage diseases, stroke, Parkinson disease, Huntington disease or stroke, implanted F3 NSCs were found to migrate to the lesion sites, differentiate into neurons and glial cells, and restore functional deficits found in these neurological disorders. In animal models of brain tumors, F3 NSCs could deliver a bioactive therapeutically relevant molecules to effect a significant anti-tumor response intracranial tumor mass. Since these genetically engineered human NSCs are immortalized and continuously multiplying, there would be limitless supply of human neurons for treatment for patients suffering from neurological disorders including stroke, Parkinson disease, Huntington disease, ALS, multiple sclerosis and spinal cord injury. The promising field of stem cell research as it applies to regenerative medicine is still in infancy, but its potential appears limitless, and we are blessed to be involved in this exciting realm of research.
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PMID:Genetically engineered human neural stem cells for brain repair in neurological diseases. 1730 60

Aquaporin 4 (AQP4) is a predominant water channel protein in mammalian brains, which is localized in the astrocyte plasma membrane. AQP4 has gained much attraction due to its involvement in the physiopathology of cerebral disorders including stroke, tumor, infection, hydrocephalus, epilepsy, and traumatic brain injury. But there is almost no evidence whether abnormal AQP4 levels are associated with degenerative diseases, such as Parkinson's disease (PD). In our studies, we established PD animal models by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to test the hypothesis that abnormal AQP4 expression is involved in the pathophysiology of this disease. We show that mutant mice lacking AQP4 were significantly more prone to MPTP-induced neurotoxicity than their wild-type littermates. Furthermore, after administration of MPTP, astroglial proliferation and GDNF protein synthesis were inhibited by AQP4 deficiency. This study demonstrates that AQP4 is important in the MPTP neurotoxic process and indicates that the therapeutic strategy targeted to astrocytic modulation with AQP4 may offer a great potential for the development of new treatment for PD.
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PMID:Hypersensitivity of aquaporin 4-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine and astrocytic modulation. 1735 68

Recently, the introduction of 3 tesla (3T) magnetic resonance (MR) system for more sophisticated clinical applications has yielded in important benefits, especially in neuroradiology. The aim of this article is to illustrate the practical scientific applications of the 3T system in the neuroradiological filed. From the clinical point of view, we focused on the usefulness of 3T system for the diagnosis of several neurological disorders, such as brain tumors, vascular lesions, hemorrhagic lesions, acute cerebral infarcts and degenerative diseases. The greatest advantage of high-field MR system is a higher signal to noise ratio. This higher spatial resolution can provide precise anatomical information for brain tumor itself and its surrounding structures. Diffusion weighted imaging (DWI) also benefits from the higher signal to noise ratio and offers useful information for tumor characteristics. Navigation system with diffusion tensor tractgraphy is also available for surgical operation of brain tumors. Parallel imaging enables to improve the quality of tractgraphy by reducing susceptibility artifacts. 3T TOF (time-of-flight) MR angiography (MRA) demonstrates superior depiction of intracranial aneurysms compared with that of 1.5T TOF MRA. 3T TOF MRA is also useful for the evaluation and follow-up of stenoocclusive diseases including moyamoya disease. Susceptibility weighted imaging (SWI) is a BOLD (blood oxygenation level dependent)-sensitive method for visualizing anatomical features such as small cerebral veins in high detail. Therefore, 3T system has advantages for obtaining detailed, high spatial resolution images of the venous network. SWI is useful for detection of hemorrhagic lesions and early diagnosis of acute hemorrhagic infarcts. SWI also can detect embolus and evaluate functional changes showing dilatation of medullary veins in the area of acute cerebral infarcts. Neuromelanin imaging using 3T system can directly demonstrate the locus ceruleus and substantia nigra by the neuromelanin content and have the potential to become a powerful tool in Parkinson's disease and other neurodegenerative disorders with Parkinsonism. Hyperintense putaminal rim can be often observed in clinically normal subjects on fast spin echo T2-weighted images at 3T system. This finding should not be mistaken for multiple system atrophy. 3T MR system indeed offers new potential because of a substantial increase in signal intensity provided by the higher magnetic field. Routine neuroradiologic imaging would benefit from higher magnetic field. However, It is required that extended knowledge of clinical data in comparison with 1.5T system to elucidate the efficacy of 3T system in the neuroradiology.
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PMID:[Clinical applications of 3.0 T magnetic resonance system in the neuroradiological field]. 1753 73

Positron emission tomography has enabled us to measure various fundamental parameters of human brain physiology and chemistry, such as cerebral blood flow, metabolism and synaptic functions. Blood flow and oxygen metabolism is important for the understanding of cerebro-vascular disease. Glucose metabolism is tightly coupled with brain function and FDG-PET is useful for the determination of epileptic foci and for the evaluation of tumor malignancy. Imaging analysis of functional neuroanatomy of these parameters is very promising for the early diagnosis of dementia, such as Alzheimer's disease. Measurement of pre- and post-synaptic function is applicable to the differential diagnosis of parkinsonism. In early stage of Parkinson's disease, only presynaptic dopaminergic function is impaired, while in multiple system atrophy with striato-nigral degeneration type, both pre-and post dopaminergic function is reduced. Development of new radiotracers is expected for detection of early specific pathological changes and more previous changes underlying the deterioration of neurochemistry, such as genetic abnormalities.
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PMID:[Positron emission tomography with FDG and newly developed tracers for the assessment of brain metabolism and synaptic function in neurological disorders]. 1753 75

The aim of stem cell therapy for Parkinson's disease is to reconstruct nigro-striatal neuronal pathways using endogenous neural stem/precursor cells or grafted dopaminergic neurons. As an alternative, transplantation of stem cell-derived dopaminergic neurons into the striatum has been attempted, with the aim of stimulating local synapse formation and/or release of dopamine and cytokines from grafted cells. Candidate stem cells include neural stem/precursor cells, embryonic stem cells and other stem/precursor cells. Among these, embryonic stem cells are pluripotent cells that proliferate extensively, making them a good potential donor source for transplantation. However, tumor formation and ethical issues present major problems for embryonic stem cell therapy. This review describes the current status of stem cell therapy for Parkinson's disease, as well as future research approaches from a clinical perspective.
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PMID:Stem cell therapy for Parkinson's disease. 1756 50


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