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

While peripheral immune access to the central nervous system (CNS) is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults. Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS. This acute neuroinflammatory response includes activation of the resident immune cells (microglia) resulting in a phagocytic phenotype and the release of inflammatory mediators such as cytokines and chemokines. While an acute insult may trigger oxidative and nitrosative stress, it is typically short-lived and unlikely to be detrimental to long-term neuronal survival. In contrast, chronic neuroinflammation is a long-standing and often self-perpetuating neuroinflammatory response that persists long after an initial injury or insult. Chronic neuroinflammation includes not only long-standing activation of microglia and subsequent sustained release of inflammatory mediators, but also the resulting increased oxidative and nitrosative stress. The sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors. Neurodegenerative CNS disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), tauopathies, and age-related macular degeneration (ARMD), are associated with chronic neuroinflammation and elevated levels of several cytokines. Here we review the hallmarks of acute and chronic inflammatory responses in the CNS, the reasons why microglial activation represents a convergence point for diverse stimuli that may promote or compromise neuronal survival, and the epidemiologic, pharmacologic and genetic evidence implicating neuroinflammation in the pathophysiology of several neurodegenerative diseases.
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PMID:Does neuroinflammation fan the flame in neurodegenerative diseases? 1991 31

Retinitis pigmentosa, age-related macular degeneration, and Parkinson's disease remain major problems in the field of medicine. Some of the strategies being explored for treatment include replacement of damaged tissue by transplantation of healthy tissues or progenitor cells and delivery of neurotrophins to rescue degenerating tissue. One of the neurotrophins with promise is the ciliary neurotrophic factor (CNTF). In this study, we report the role played by CNTF in retinal cell differentiation and survival in retinal progenitors. We found that CNTF is a survival factor for multipotential human retinal cells and increased cell survival by 50%, over a 7-d period, under serum-free conditions, as determined by apoptotic assays (immunohistochemistry and flow cytometry). This effect is dose dependent with a maximum survival at a CNTF concentration of 20 ng/ml. We also report that CNTF might be a cell commitment factor, directing the differentiation mainly toward large multipolar cells with ganglionic and amacrine phenotype. These cells express tyrosine hydroxylase (amacrine cells) as well as, thy 1.1 and neuron-specific enolase (ganglionic cells). Additionally, there was also an increase in protein kinase C alpha, a protein expressed in rod and cone bipolars as well as cone photoreceptors and calbindin, a protein expressed in cone photoreceptors and horizontal cells. In our studies, CNTF doubled the number of cells with ganglionic phenotypes, and basic fibroblast growth factor doubled the number of cells with photoreceptor phenotype. Additionally, CNTF induced a subset of progenitors to undergo multiple rounds of cell division before acquiring the large multipolar ganglionic phenotype. Our conclusion is that CNTF could be an agent that has therapeutic potential and possibly induces differentiation of large multipolar ganglionic phenotype in a subset of progenitors.
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PMID:Ciliary neurotrophic factor: a survival and differentiation inducer in human retinal progenitors. 2042 61

In contrast to the tremendous amount of research data from the central nervous system, relatively little is known about microglial homeostasis in the retina. This may be explained by a strong research bias towards important brain pathologies including Alzheimer's disease, Parkinson's disease, and Multiple Sclerosis. In addition, there are specific technical limitations which hampered the analysis of retinal microglia, including their relatively small number in ocular tissue. The lack of experimental tools also prevented direct visualization and molecular analysis of this specialized neuronal macrophage population. Over the last few years, this situation has changed considerably as more and more retinal disorders have come into focus. Many rare monogenic forms as well as more prevalent complex disorders, in particular the age-related macular degeneration involves innate immune mechanisms. As a consequence, new genetic and experimental mouse models have been developed that mimic various forms of human retinal degeneration. In conjunction with these disease models, novel macrophage/microglia-specific reporter mice were established that allow the monitoring of retinal microglia in situ and in vivo. This review summarizes recent findings from these mouse models and thereby provides an overview of microglial homeostasis in the healthy and degenerating retina. Based on this knowledge, microglia-targeted therapies are envisioned which could delay or attenuate degenerative retinal disease.
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PMID:Microglia in the healthy and degenerating retina: insights from novel mouse models. 2057 18

Chemokines are small secreted proteins belonging to the cytokine family which were initially discovered for their chemoattractant properties for immune cells. Recently it was shown that chemokines and their G-protein-coupled receptors can be constitutively expressed or induced in several organs and different cell types. Thus chemokines have been shown to regulate immune functions involving infection and inflammation, stem cell migration during development, to be implicated in oncogenic, neovascularization and atherosclerosis processes, to modulate neuronal excitability regulating neurotransmitter release, and to play a key role in the pathogenesis of various neurodegenerative diseases such as Parkinson's disease or age-related-macular degeneration and in pain. Some of these recent advances concerning chemokine functions will be highlighted in this broad appeal symposium which aims to introduce this emerging field. This introductory chapter will examine the basic properties of the various chemokine systems and their receptors.
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PMID:[New prospects for chemokines]. 2121 43

Many forms of neurodegenerative disease, for instance Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, Hallervorden Spatz syndrome and macular degeneration, are associated with elevated levels of redox active metals in the brain and eye. A logical therapeutic approach therefore, is to remove the toxic levels of these metals, copper and iron in particular, by selective chelation. The increased number of iron-selective chelators now available for clinical use has enhanced interest in this type of therapy. This review summarises the recent developments in the design of chelators for treatment of neurodegenerative disease, identifies some of the essential properties for such molecules and suggests some future strategies.
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PMID:The potential application of iron chelators for the treatment of neurodegenerative diseases. 2134 71

Essential polyunsaturated fatty acids (PUFAs) are critical nutritional lipids that must be obtained from the diet to sustain homeostasis. Omega-3 and -6 PUFAs are key components of biomembranes and play important roles in cell integrity, development, maintenance, and function. The essential omega-3 fatty acid family member docosahexaenoic acid (DHA) is avidly retained and uniquely concentrated in the nervous system, particularly in photoreceptors and synaptic membranes. DHA plays a key role in vision, neuroprotection, successful aging, memory, and other functions. In addition, DHA displays anti-inflammatory and inflammatory resolving properties in contrast to the proinflammatory actions of several members of the omega-6 PUFAs family. This review discusses DHA signalolipidomics, comprising the cellular/tissue organization of DHA uptake, its distribution among cellular compartments, the organization and function of membrane domains rich in DHA-containing phospholipids, and the cellular and molecular events revealed by the uncovering of signaling pathways regulated by DHA and docosanoids, the DHA-derived bioactive lipids, which include neuroprotectin D1 (NPD1), a novel DHA-derived stereoselective mediator. NPD1 synthesis agonists include neurotrophins and oxidative stress; NPD1 elicits potent anti-inflammatory actions and prohomeostatic bioactivity, is anti-angiogenic, promotes corneal nerve regeneration, and induces cell survival. In the context of DHA signalolipidomics, this review highlights aging and the evolving studies on the significance of DHA in Alzheimer's disease, macular degeneration, Parkinson's disease, and other brain disorders. DHA signalolipidomics in the nervous system offers emerging targets for pharmaceutical intervention and clinical translation.
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PMID:Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer's, and other neurodegenerative diseases. 2175 34

Neurological syndromes, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis, and lysosomal storage disorders, such as Battens disease, are devastating because they result in increasing loss of cognitive and physical function. Sadly, no drugs are currently available to halt their progression. The relative paucity of curative approaches for these and other conditions of the nervous system have led to a widespread evaluation of alternative treatment modalities including cell-based interventions. Several cell types have been tested successfully in animal models where safety and efficacy have been demonstrated. Early clinical trials have also been initiated in humans, and some have shown a degree of success albeit on a more limited scale than in animal experiments. Recent demonstrations that pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, can differentiate into a variety of specific neural phenotypes has stimulated worldwide enthusiasm for developing cell-based intervention of neurological disease. Indeed, several groups are preparing investigational new drug applications to treat disorders as diverse as macular degeneration, lysosomal storage diseases, and Parkinson's disease. It is noteworthy that cell replacement therapies for neurological conditions face key challenges, some of which are unique, because of the development and organization of the nervous system, its metabolism, and connectivity. Choice of the cell (or cells), the process of manufacturing them, defining the delivery pathway, developing and testing in an appropriate preclinical model, selecting a patient population, and visualizing and following or monitoring patients all pose specific issues as related to the central and peripheral nervous systems. In this review, we address a myriad of challenges that are solvable, but require careful planning and attention to the special demands of the human nervous system.
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PMID:Cell-based therapy for neural disorders--anticipating challenges. 2190 85

The complement system is a critical component of innate immunity that requires regulation to avoid inappropriate activation. This regulation is provided by many proteins, including complement factor H (CFH), a critical regulator of the alternative pathway of complement activation. Given its regulatory function, mutations in CFH have been implicated in diseases such as age-related macular degeneration and membranoproliferative glomerulonephritis, and central nervous system diseases such as Alzheimer's disease, Parkinson's disease, and a demyelinating murine model, experimental autoimmune encephalomyelitis (EAE). There have been few investigations on the transcriptional regulation of CFH in the brain and CNS. Our studies show that CFH mRNA is present in several CNS cell types. The murine CFH (mCFH) promoter was cloned and examined through truncation constructs and we show that specific regions throughout the promoter contain enhancers and repressors that are positively regulated by inflammatory cytokines in astrocytes. Database mining of these regions indicated transcription factor binding sites conserved between different species, which led to the investigation of specific transcription factor binding interactions in a 241 base pair (bp) region at -416 bp to -175 bp that showed the strongest activity. Through supershift analysis, it was determined that c-Jun and c-Fos interact with the CFH promoter in astrocytes in this region. These results suggest a relationship between cell cycle and complement regulation, and how these transcription factors and CFH affect disease will be a valuable area of investigation.
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PMID:c-Jun and c-Fos regulate the complement factor H promoter in murine astrocytes. 2192 Jun 6

Age-related neurodegeneration in the brain and retina is complicated. It comprises a series of events encompassing different modes of degeneration in neurons, as well as inflammation mediated by glial cells. Systemic inflammation and risk factors can contribute to disease progression. Age-related conditions such as Alzheimer's disease (AD), Parkinson's disease (PD) and Age-related Macular Degeneration (AMD) affect patients for 5 to 20 years and are highly associated with risk factors such as hyperhomocysteinaemia, hypercholesterolaemia, hypertension, and symptoms of mood disorder. The long duration of the degeneration and the wide array of systemic factors provide the opportunity for nutraceutical intervention to prevent or delay disease progression. Small molecules such as phenolic compounds are candidates for neuroprotection because they have anti-oxidant activities and can modulate intracellular signaling pathways. Bigger entities such as oligosaccharides and polysaccharides have often been neglected because of their complex structure. However, certain big molecules can provide neuroprotective effects. They may also have a wide spectrum of action against risk factors. In this review we use an integrative approach to the potential uses of nutraceutical products to prevent age-related neurodegeneration. These include direct effects of phenolic compounds and polysaccharides on neurons to antagonize various neurodegenerative mechanisms in AD, PD and AMD, and indirect effects of these compounds on peripheral disease-related risk factors.
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PMID:From small to big molecules: how do we prevent and delay the progression of age-related neurodegeneration? 2221 81

Human induced pluripotent stem cells (hiPSCs) are expected to be used in various life science areas, ranging from basic research to medical applications. This article describes perspectives regarding the potential use of hiPSCs, especially in Japan, for manufacturing products related to regenerative medicine as well as for establishing cell-based assay/screening systems that can be used for effective and efficient assessment of candidates for new drugs. The applications of hiPSCs include the following: hiPSC-derived retinal pigment epithelial cells for treating age-related macular degeneration; potential corneal reconstruction by using a combination of various relevant hiPSC-derived differentiated cells; potential treatment of Parkinson's disease by using dopaminergic neurons generated from hiPSCs; potential treatment of spinal cord injury by using neural stem/progenitor cells generated from hiPSCs; potential treatment of chronic heart failure by using hiPSC-derived functional cardiomyocytes; and development of cell-based drug toxicity screening and drug effect assay systems involving cells such as cardiomyocytes, hepatocytes, and neural cells that are differentiated from hiPSCs and can be used in the early phase of new drug development. The current situation regarding the development of guidelines for ensuring the quality and safety of hiPSC-derived medicinal products has also been described.
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PMID:[Perspectives regarding the potential use of human induced pluripotent stem cells for the development of and research on medicinal products]. 2222 1


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