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https://www.readbyqxmd.com/read/28535263/gene-expression-variability-and-the-analysis-of-large-scale-rna-seq-studies-with-the-mdseq
#1
Di Ran, Z John Daye
Rapidly decreasing cost of next-generation sequencing has led to the recent availability of large-scale RNA-seq data, that empowers the analysis of gene expression variability, in addition to gene expression means. In this paper, we present the MDSeq, based on the coefficient of dispersion, to provide robust and computationally efficient analysis of both gene expression means and variability on RNA-seq counts. The MDSeq utilizes a novel reparametrization of the negative binomial to provide flexible generalized linear models (GLMs) on both the mean and dispersion...
May 23, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28534925/osmotin-loaded-magnetic-nanoparticles-with-electromagnetic-guidance-for-the-treatment-of-alzheimer-s-disease
#2
Faiz Ul Amin, Ali Kafash Hoshiar, Ton Duc Do, Yeongil Noh, Shahid Ali Shah, Muhammad Sohail Khan, Jungwon Yoon, Myeong Ok Kim
Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disease, pathologically characterized by the accumulation of aggregated amyloid beta (Aβ) in the brain. Here, we describe for the first time the development of a new, pioneering nanotechnology-based drug delivery approach for potential therapies for neurodegenerative diseases, particularly AD. We demonstrated the delivery of fluorescent carboxyl magnetic Nile Red particles (FMNPs) to the brains of normal mice using a functionalized magnetic field (FMF) composed of positive- and negative-pulsed magnetic fields generated by electromagnetic coils...
May 23, 2017: Nanoscale
https://www.readbyqxmd.com/read/28534273/tauroursodeoxycholic-acid-enhances-mitochondrial-biogenesis-neural-stem-cell-pool-and-early-neurogenesis-in-adult-rats
#3
Rita Soares, Filipa F Ribeiro, Sara Xapelli, Tânia Genebra, Maria F Ribeiro, Ana M Sebastião, Cecília M P Rodrigues, Susana Solá
Although neurogenesis occurs in restricted regions of the adult mammalian brain, neural stem cells (NSCs) produce very few neurons during ageing or after injury. We have recently discovered that the endogenous bile acid tauroursodeoxycholic acid (TUDCA), a strong inhibitor of mitochondrial apoptosis and a neuroprotective in animal models of neurodegenerative disorders, also enhances NSC proliferation, self-renewal, and neuronal conversion by improving mitochondrial integrity and function of NSCs. In the present study, we explore the effect of TUDCA on regulation of NSC fate in neurogenic niches, the subventricular zone (SVZ) of the lateral ventricles and the hippocampal dentate gyrus (DG), using rat postnatal neurospheres and adult rats exposed to the bile acid...
May 22, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28534246/microglia-housekeeper-of-the-central-nervous-system
#4
REVIEW
John Alimamy Kabba, Yazhou Xu, Handson Christian, Wenchen Ruan, Kitchen Chenai, Yun Xiang, Luyong Zhang, Juan M Saavedra, Tao Pang
Microglia, of myeloid origin, play fundamental roles in the control of immune responses and the maintenance of central nervous system homeostasis. These cells, just like peripheral macrophages, may be activated into M1 pro-inflammatory or M2 anti-inflammatory phenotypes by appropriate stimuli. Microglia do not respond in isolation, but form part of complex networks of cells influencing each other. This review addresses the complex interaction of microglia with each cell type in the brain: neurons, astrocytes, cerebrovascular endothelial cells, and oligodendrocytes...
May 22, 2017: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/28534084/the-emerging-link-between-o-glcnacylation-and-neurological-disorders
#5
REVIEW
Xiaofeng Ma, He Li, Yating He, Junwei Hao
O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is involved in the regulation of many cellular cascades and neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. In the brain, the expression of O-GlcNAcylation is notably heightened, as is that of O-linked N-acetylglucosaminyltransferase (OGT) and β-N-acetylglucosaminidase (OGA), the presence of which is prominent in many regions of neurological importance. Most importantly, O-GlcNAcylation is believed to contribute to the normal functioning of neurons; conversely, its dysregulation participates in the pathogenesis of neurological disorders...
May 22, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28533744/pin1-modulates-huntingtin-levels-and-aggregate-accumulation-an-in-vitro-model
#6
Alisia Carnemolla, Silvia Michelazzi, Elena Agostoni
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a polyglutamine expansion within the N-terminal region of huntingtin protein (HTT). Cellular mechanisms promoting mutant huntingtin (mHTT) clearance are of great interest in HD pathology as they can lower the level of the mutant protein and its toxic aggregated species, thus affecting disease onset and progression. We have previously shown that the prolyl-isomerase PIN1 represents a promising negative regulator of mHTT aggregate accumulation using a genetically precise HD mouse model, namely Hdh(Q111) mice...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28533741/adulthood-exposure-to-lipopolysaccharide-exacerbates-the-neurotoxic-and-inflammatory-effects-of-rotenone-in-the-substantia-nigra
#7
Chun Huang, Li Zhu, Huan Li, Fu-Guo Shi, Guo-Qing Wang, Yi-Zheng Wei, Jie Liu, Feng Zhang
Parkinson's disease (PD) is the second most neurodegenerative disorder with a regional decrease of dopamine (DA) neurons in the substantia nigra (SN). Despite intense exploration, the etiology of PD progressive process remains unclear. This study was to investigate the synergistic effects of systemic inflammation of lipopolysaccharide (LPS) and neurotoxicity of rotenone (ROT) on exacerbating DA neuron lesion. Male SD adulthood rats received a single intraperitoneal injection of LPS. Seven months later, rats were subcutaneously given ROT five times a week for consecutive 4 weeks...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28533388/selective-lowering-of-synapsins-induced-by-oligomeric-%C3%AE-synuclein-exacerbates-memory-deficits
#8
Megan E Larson, Susan J Greimel, Fatou Amar, Michael LaCroix, Gabriel Boyle, Mathew A Sherman, Hallie Schley, Camille Miel, Julie A Schneider, Rakez Kayed, Fabio Benfenati, Michael K Lee, David A Bennett, Sylvain E Lesné
Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-β (Aβ), tau, or α-synuclein (αSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric αSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of αSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression...
May 22, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28533113/a-novel-serine-racemase-inhibitor-suppresses-neuronal-over-activation-in-vivo
#9
Hisashi Mori, Ryogo Wada, Satoyuki Takahara, Yoshikazu Horino, Hironori Izumi, Tetsuya Ishimoto, Tomoyuki Yoshida, Mineyuki Mizuguchi, Takayuki Obita, Hiroaki Gouda, Shuichi Hirono, Naoki Toyooka
Serine racemase (SRR) is an enzyme that produces d-serine from l-serine. d-Serine acts as an endogenous coagonist of NMDA-type glutamate receptors (NMDARs), which regulate many physiological functions. Over-activation of NMDARs induces excitotoxicity, which is observed in many neurodegenerative disorders and epilepsy states. In our previous works on the generation of SRR gene knockout (Srr-KO) mice and its protective effects against NMDA- and Aβ peptide-induced neurodegeneration, we hypothesized that the regulation of NMDARs' over-activation by inhibition of SRR activity is one such therapeutic strategy to combat these disease states...
May 11, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28531300/anosmia-a-clinical-review
#10
Sanne Boesveldt, Elbrich M Postma, Duncan Boak, Antje Welge-Luessen, Veronika Schöpf, Joel D Mainland, Jeffrey Martens, John Ngai, Valerie B Duffy
Anosmia and hyposmia, the inability or decreased ability to smell, is estimated to afflict 3-20% of the population. Risk of olfactory dysfunction increases with old age and may also result from chronic sinonasal diseases, severe head trauma, and upper respiratory infections, or neurodegenerative diseases. These disorders impair the ability to sense warning odors in foods and the environment, as well as hinder the quality of life related to social interactions, eating, and feelings of well-being. This article reports and extends on a clinical update commencing at the 2016 Association for Chemoreception Sciences annual meeting...
May 22, 2017: Chemical Senses
https://www.readbyqxmd.com/read/28531191/exogenous-expression-of-drp1-plays-neuroprotective-roles-in-the-alzheimer-s-disease-in-the-a%C3%AE-42-transgenic-drosophila-model
#11
Fengshou Lv, Xiaopeng Yang, Chuanju Cui, Chunhe Su
BACKGROUND: Alzheimer's disease (AD) is one of the most common neurodegenerative disorders. Recent studies have shown that mitochondrial dysfunction is a causative factor of AD. Drp1 (Dynamin-related protein 1), a regulator of mitochondrial fission, shows neuroprotective effects on Parkinson's disease. In this study, we investigate the effect and mechanism of Drp1 on Aβ42 transgenic Drosophila. METHODS: Elav-gal4/UAS>Aβ42 transgenic Drosophila model was constructed using Elav-gal4 promoter...
2017: PloS One
https://www.readbyqxmd.com/read/28531131/the-role-of-interleukin-18-oxidative-stress-and-metabolic-syndrome-in-alzheimer-s-disease
#12
REVIEW
Johanna O Ojala, Elina M Sutinen
The role of interleukins (ILs) and oxidative stress (OS) in precipitating neurodegenerative diseases including sporadic Alzheimer's disease (AD), requires further clarification. In addition to neuropathological hallmarks-extracellular neuritic amyloid-β (Aβ) plaques, neurofibrillary tangles (NFT) containing hyperphosphorylated tau and neuronal loss-chronic inflammation, as well as oxidative and excitotoxic damage, are present in the AD brain. The pathological sequelae and the interaction of these events during the course of AD need further investigation...
May 21, 2017: Journal of Clinical Medicine
https://www.readbyqxmd.com/read/28530802/discovery-of-n-5-fluoropyridin-2-yl-6-methyl-4-pyrimidin-5-yloxy-picolinamide-vu0424238-a-novel-negative-allosteric-modulator-of-metabotropic-glutamate-receptor-subtype-5-selected-for-clinical-evaluation
#13
Andrew S Felts, Alice L Rodriguez, Anna L Blobaum, Ryan D Morrison, Brittney S Bates, Analisa Thompson Gray, Jerri M Rook, Mohammed N Tantawy, Frank W Byers, Sichen Chang, Daryl F Venable, Vincent B Luscombe, Gilles D Tamagnan, Colleen M Niswender, J Scott Daniels, Carrie K Jones, P Jeffrey Conn, Craig W Lindsley, Kyle A Emmitte
Preclinical evidence in support of the potential utility of mGlu5 NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu5 NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu5 versus the other mGlu receptors, and binding studies established a Ki value of 4...
May 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28529829/connecting-ca-2-and-lysosomes-to-parkinson-disease
#14
Bethan S Kilpatrick
The neurodegenerative movement disorder Parkinson disease (PD) is prevalent in the aged population. However, the underlying mechanisms that trigger disease are unclear. Increasing work implicates both impaired Ca(2+) signalling and lysosomal dysfunction in neuronal demise. Here I aim to connect these distinct processes by exploring the evidence that lysosomal Ca(2+) signalling is disrupted in PD. In particular, I highlight defects in lysosomal Ca(2+) content and signalling through NAADP-regulated two-pore channels in patient fibroblasts harbouring mutations in the PD-linked genes, GBA1 and LRRK2...
June 1, 2016: Messenger
https://www.readbyqxmd.com/read/28529827/deviant-lysosomal-ca-2-signalling-in-neurodegeneration-an-introduction
#15
Sandip Patel
Lysosomes are key acidic Ca(2+) stores. The principle Ca(2+)-permeable channels of the lysosome are TRP mucolipins (TRPMLs) and NAADP-regulated two-pore channels (TPCs). Recent studies, reviewed in this collection, have linked numerous neurodegenerative diseases to both gain and loss of function of TRPMLs/TPCs, as well as to defects in acidic Ca(2+) store content. These diseases span rare lysosomal storage disorders such as Mucolipidosis Type IV and Niemann-Pick disease, type C, through to more common ones such as Alzheimer and Parkinson disease...
June 1, 2016: Messenger
https://www.readbyqxmd.com/read/28529475/fragile-x-associated-tremor-ataxia-syndrome-from-molecular-pathogenesis-to-development-of-therapeutics
#16
REVIEW
Ha Eun Kong, Juan Zhao, Shunliang Xu, Peng Jin, Yan Jin
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a premutation CGG repeat expansion (55-200 repeats) within the 5' UTR of the fragile X gene (FMR1). FXTAS is characterized by intension tremor, cerebellar ataxia, progressive neurodegeneration, parkinsonism and cognitive decline. The development of transgenic mouse and Drosophila melanogaster models carrying an expanded CGG repeat has yielded valuable insight into the pathophysiology of FXTAS. To date, we know of two main molecular mechanisms of this disorder: (1) a toxic gain of function of the expanded CGG-repeat FMR1 mRNA, which results in the binding/sequestration of the CGG-binding proteins; and (2) CGG repeat-associated non-AUG-initiated (RAN) translation, which generates a polyglycine peptide toxic to cells...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28529318/neurodegenerative-disorders-ataxin-2-reduction-rescues-motor-defects
#17
Sarah Crunkhorn
No abstract text is available yet for this article.
May 19, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28529068/adverse-outcome-pathways-application-to-enhance-mechanistic-understanding-of-neurotoxicity
#18
REVIEW
Anna Bal-Price, M E Meek
Recent developments have prompted the transition of empirically based testing of late stage toxicity in animals for a range of different endpoints including neurotoxicity to more efficient and predictive mechanistically based approaches with greater emphasis on measurable key events early in the progression of disease. The adverse outcome pathway (AOP) has been proposed as a simplified organizational construct to contribute to this transition by linking molecular initiating events and earlier (more predictive) key events at lower levels of biological organization to disease outcomes...
May 18, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28528956/brain-interference-revisiting-the-role-of-ifn%C3%AE-in-the-central-nervous-system
#19
REVIEW
S Monteiro, S Roque, F Marques, M Correia-Neves, J J Cerqueira
Interferon gamma (IFNγ) is a pro-inflammatory cytokine, first described as a secreted molecule capable of interfering with viral replication. Since then, numerous other important actions in the context of the immune response to invading pathogens (including those invading the brain) have been ascribed to this pleiotropic cytokine. Nevertheless, the precise role of IFNγ in neuropsychiatric and neurodegenerative disorders, and its possible contribution to the regulation of normal brain function, remains enigmatic...
May 18, 2017: Progress in Neurobiology
https://www.readbyqxmd.com/read/28528298/emerging-role-of-monoamine-oxidase-as-a-therapeutic-target-for-cardiovascular-disease
#20
REVIEW
Soni Deshwal, Moises Di Sante, Fabio Di Lisa, Nina Kaludercic
In the past decade, accumulating evidence highlighted the role of monoamine oxidases (MAOs) in cardiovascular disease (CVD). MAOs are flavoenzymes located in the outer mitochondrial membrane, responsible for the degradation of neurotransmitters and biogenic amines. During this process they generate hydrogen peroxide, aldehydes and ammonia, species that can target mitochondria and induce mitochondrial dysfunction and cardiomyocyte death. Indeed, MAO inhibition affords cardioprotection in several models of CVD, such as ischemia/reperfusion, heart failure and diabetes...
May 18, 2017: Current Opinion in Pharmacology
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