135 results found
Gonzalez Carter DA, Leo BF, Ruenraroengsak P, et al., 2017, Silver nanoparticles reduce brain inflammation and related neurotoxicity through induction of H2S-synthesizing enzymes, Scientific Reports, Vol: 7, ISSN: 2045-2322
Silver nanoparticles (AgNP) are known to penetrate into the brain and cause neuronal death. However, there is a paucity in studies examining the effect of AgNP on the resident immune cells of the brain, microglia. Given microglia are implicated in neurodegenerative disorders such as Parkinson’s disease (PD), it is important to examine how AgNPs affect microglial inflammation to fully assess AgNP neurotoxicity. In addition, understanding AgNP processing by microglia will allow better prediction of their long term bioreactivity. In the present study, the in vitro uptake and intracellular transformation of citrate-capped AgNPs by microglia, as well as their effects on microglial inflammation and related neurotoxicity were examined. Analytical microscopy demonstrated internalization and dissolution of AgNPs within microglia and formation of non-reactive silver sulphide (Ag2S) on the surface of AgNPs. Furthermore, AgNP-treatment up-regulated microglial expression of the hydrogen sulphide (H2S)-synthesizing enzyme cystathionine-γ-lyase (CSE). In addition, AgNPs showed significant anti-inflammatory effects, reducing lipopolysaccharide (LPS)-stimulated ROS, nitric oxide and TNFα production, which translated into reduced microglial toxicity towards dopaminergic neurons. Hence, the present results indicate that intracellular Ag2S formation, resulting from CSE-mediated H2S production in microglia, sequesters Ag+ ions released from AgNPs, significantly limiting their toxicity, concomitantly reducing microglial inflammation and related neurotoxicity.
Hanak C, Benoit J, Fabry L, et al., 2017, Changes in Pro-Inflammatory Markers in Detoxifying Chronic Alcohol Abusers, Divided by Lesch Typology, Reflect Cognitive Dysfunction, ALCOHOL AND ALCOHOLISM, Vol: 52, Pages: 529-534, ISSN: 0735-0414
Jansen IE, Ye H, Heetveld S, et al., 2017, Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing, GENOME BIOLOGY, Vol: 18, ISSN: 1474-760X
Martin-Bastida A, Ward RJ, Newbould R, et al., 2017, Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson's disease, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
Ong ZY, Chen S, Nabavi E, et al., 2017, Multi-Branched Gold Nanoparticles with Intrinsic LAT-1 Targeting Capabilities for Selective Photothermal Therapy of Breast Cancer., ACS Appl Mater Interfaces
Due to the critical role of the large neutral amino acid transporter-1 (LAT-1) in promoting tumor growth and proliferation, it is fast emerging as a highly attractive biomarker for the imaging and treatment of human malignancies, including breast cancer. Whilst multi-branched gold nanoparticles (AuNPs) have emerged as a promising modality in the photothermal therapy (PTT) of cancers, some of the key challenges limiting their clinical translation lies in the need to develop reproducible and cost-effective synthetic methods as well as the selective accumulation of sufficient AuNPs at tumor sites. In this study, we report a simple and direct seed-mediated synthesis of monodispersed multi-branched AuNPs using the catechol-containing LAT-1 ligands, L- and D-dopa, to confer active cancer targeting. This route obviates the need for additional conjugation with targeting moieties such as peptides or antibodies. Nanoflower-like AuNPs (AuNF) with diameters of approximately 46, 70 and 90 nm were obtained and were found to possess excellent colloidal stability and biocompatibility. A significantly higher intracellular accumulation of the L- and D-dopa functionalized AuNFs was observed in a panel of breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-468, and MDA-MB-453) when compared to the non-targeting control AuNFs synthesized with dopamine and 4-ethylcatechol. Importantly, no significant difference in uptake between the targeting and non-targeting AuNFs was observed in a non-tumorigenic MCF-10A breast epithelial cell line, hence demonstrating tumor selectivity. For PTT of breast cancer, Ag(+) was introduced during synthesis to obtain L-dopa functionalized nanourchin-like AuNPs (AuNUs) with strong near infrared (NIR) absorbance. The L-dopa functionalized AuNUs mediated selective photothermal ablation of the triple negative MDA-MB-231 breast cancer cell line and sensitized the cells to the anticancer drugs cisplatin and docetaxel. This work brings forward an effective strategy
Sharma P, Wells L, Coello C, et al., 2017, Chemogenetic modulation of the pedunculopontine nucleus coupled with C-11-PHNO uptake reveals striatal dopamine release accompanies profound motor recovery in a rodent model of Parkinson's disease, 28th International Symposium on Cerebral Blood Flow, Metabolism and Function / 13th International Conference on Quantification of Brain Function with PET, Publisher: SAGE PUBLICATIONS INC, Pages: 88-89, ISSN: 0271-678X
Sundriyal S, Moniot S, Mahmud Z, et al., 2017, Thienopyrimidinone Based Sirtuin-2 (SIRT2)-Selective Inhibitors Bind in the Ligand Induced Selectivity Pocket., J Med Chem, Vol: 60, Pages: 1928-1945
Sirtuins (SIRTs) are NAD-dependent deacylases, known to be involved in a variety of pathophysiological processes and thus remain promising therapeutic targets for further validation. Previously, we reported a novel thienopyrimidinone SIRT2 inhibitor with good potency and excellent selectivity for SIRT2. Herein, we report an extensive SAR study of this chemical series and identify the key pharmacophoric elements and physiochemical properties that underpin the excellent activity observed. New analogues have been identified with submicromolar SIRT2 inhibtory activity and good to excellent SIRT2 subtype-selectivity. Importantly, we report a cocrystal structure of one of our compounds (29c) bound to SIRT2. This reveals our series to induce the formation of a previously reported selectivity pocket but to bind in an inverted fashion to what might be intuitively expected. We believe these findings will contribute significantly to an understanding of the mechanism of action of SIRT2 inhibitors and to the identification of refined, second generation inhibitors.
Sundriyal S, Moniot S, Mahmud Z, et al., 2017, Thienopyrimidinone Based Sirtuin-2 (SIRT2)-Selective Inhibitors Bind in the Ligand Induced Selectivity Pocket, JOURNAL OF MEDICINAL CHEMISTRY, Vol: 60, Pages: 1928-1945, ISSN: 0022-2623
Ward RJ, Dexter DT, Crichton RR, 2017, Treatment of Neurodegenerative Diseases by Chelators, RSC Metallobiology, Pages: 153-182
© The Royal Society of Chemistry 2017. Changes in metal ion homeostasis occur with aging which may precipitate the development of neurodegenerative diseases in susceptible individuals. Slight increases in iron content of specific brain regions, sometimes as little as two-fold, may have a devastating effect on brain function. In this current review we shall initially discuss changes that occ ur in brain iron homeostasis during healthy aging and longevity, and how alterations of its concentration and distribution may expedite various neurodegenerative diseases. Changes in metal ion homeostasis of other metal ions, namely copper and zinc, also occur in neurodegenerative diseases and will be discussed. Over the past five years the use of iron chelators to slow the progression of the disease and even improve clinical symptoms in some neurodegenerative diseases has been reported; clinical trials have confirmed their efficacy in specific neurodegenerative diseases, namely Friederich's ataxia and Parkinson's disease. The development of new chelators which are able to target specific regions of the brain, combined with drugs which are able to modulate the inflammatory processes, will further advance hope for the eradication of these debilitating neurodegenerative diseases.
Witoelar A, Jansen IE, Wang Y, et al., 2017, Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases., JAMA Neurol, Vol: 74, Pages: 780-792
Importance: Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. Objectives: To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. Design, Setting, and Participants: Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. Main Outcomes and Measures: The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases. Results: Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in met
Bastida A, Ward R, Piccini P, et al., 2016, SYSTEMIC INFLAMMATION INFLUENCES THE ABILITY OF DEFERIPRONE TO CHELATE IRON FROM SPECIFIC BRAIN REGIONS IN PARKINSON'S DISEASE PATIENTS, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 91, Pages: E232-E232, ISSN: 0361-8609
Gonzalez-Carter D, Goode AE, Fiammengo R, et al., 2016, Inhibition of Leptin-ObR Interaction Does not Prevent Leptin Translocation Across a Human Blood-Brain Barrier Model, JOURNAL OF NEUROENDOCRINOLOGY, Vol: 28, ISSN: 0953-8194
Harrison IF, Anis HK, Dexter DT, 2016, Associated degeneration of ventral tegmental area dopaminergic neurons in the rat nigrostriatal lactacystin model of parkinsonism and their neuroprotection by valproate, NEUROSCIENCE LETTERS, Vol: 614, Pages: 16-23, ISSN: 0304-3940
Ruffmann C, Calboli FCF, Bravi I, et al., 2016, Cortical Lewy bodies and Ab burden are associated with prevalence and timing of dementia in Lewy body diseases, NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, Vol: 42, Pages: 436-450, ISSN: 0305-1846
Srai SK, Kallo V, Ward R, et al., 2016, THE EFFECT OF NEUROINFLAMMATION ON IRON REGULATION IN CELLS OF THE CENTRAL NERVOUS SYSTEM, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 91, Pages: E165-E165, ISSN: 0361-8609
Brauer R, Bhaskaran K, Chaturvedi N, et al., 2015, Glitazone Treatment and Incidence of Parkinson's Disease among People with Diabetes: A Retrospective Cohort Study, PLOS MEDICINE, Vol: 12, ISSN: 1549-1676
Di Fruscia P, Zacharioudakis E, Liu C, et al., 2015, The Discovery of a Highly Selective 5,6,7,8-Tetrahydrobenzo[4,5]thieno[ 2,3-d] pyrimidin-4(3H)-one SIRT2 Inhibitor that is Neuroprotective in an in vitro Parkinson's Disease Model, CHEMMEDCHEM, Vol: 10, Pages: 69-82, ISSN: 1860-7179
Durrenberger PF, Fernando FS, Kashefi SN, et al., 2015, Common mechanisms in neurodegeneration and neuroinflammation: a BrainNet Europe gene expression microarray study, JOURNAL OF NEURAL TRANSMISSION, Vol: 122, Pages: 1055-1068, ISSN: 0300-9564
Goode AE, Carter DAG, Motskin M, et al., 2015, High resolution and dynamic imaging of biopersistence and bioreactivity of extra and intracellular MWNTs exposed to microglial cells, BIOMATERIALS, Vol: 70, Pages: 57-70, ISSN: 0142-9612
Harrison IF, Crum WR, Vernon AC, et al., 2015, Neurorestoration induced by the HDAC inhibitor sodium valproate in the lactacystin model of Parkinson's is associated with histone acetylation and up-regulation of neurotrophic factors, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 172, Pages: 4200-4215, ISSN: 0007-1188
Hurley MJ, Durrenberger PF, Gentleman SM, et al., 2015, Altered Expression of Brain Proteinase-Activated Receptor-2, Trypsin-2 and Serpin Proteinase Inhibitors in Parkinson's Disease, JOURNAL OF MOLECULAR NEUROSCIENCE, Vol: 57, Pages: 48-62, ISSN: 0895-8696
Hurley MJ, Gentleman SM, Dexter DT, 2015, Calcium CaV1 Channel Subtype mRNA Expression in Parkinson's Disease Examined by In Situ Hybridization, Journal of Molecular Neuroscience, Vol: 55, Pages: 715-724, ISSN: 0895-8696
The factors which make some neurons vulnerable to neurodegeneration in Parkinson's disease while others remain resistant are not fully understood. Studies in animal models of Parkinson's disease suggest that preferential use of CaV1.3 subtypes by neurons may contribute to the neurodegenerative process by increasing mitochondrial oxidant stress. This study quantified the level of mRNA for the CaV1 subtypes found in the brain by in situ hybridization using CaV1 subtype-specific [35S]-radiolabelled oligonucleotide probes. In normal brain, the greatest amount of messenger RNA (mRNA) for each CaV1 subtype was found in the midbrain (substantia nigra), with a moderate level in the pons (locus coeruleus) and lower quantities in cerebral cortex (cingulate and primary motor). In Parkinson's disease, the level of CaV1 subtype mRNA was maintained in the midbrain and pons, despite cell loss in these areas. In cingulate cortex, CaV1.2 and CaV1.3 mRNA increased in cases with late-stage Parkinson's disease. In primary motor cortex, the level of CaV1.2 mRNA increased in late-stage Parkinson's disease. The level of CaV1.3 mRNA increased in primary motor cortex of cases with early-stage Parkinson's disease and normalized to near the control level in cases from late-stage Parkinson's disease. The finding of elevated CaV1 subtype expression in cortical brain regions supports the view that disturbed calcium homeostasis is a feature of Parkinson's disease throughout brain and not only a compensatory consequence to the neurodegenerative process in areas of cell loss. © 2014 Springer Science+Business Media New York.
Klioueva NM, Rademaker MC, Dexter DT, et al., 2015, BrainNet Europe's Code of Conduct for brain banking, JOURNAL OF NEURAL TRANSMISSION, Vol: 122, Pages: 937-940, ISSN: 0300-9564
Pienaar IS, Gartside SE, Sharma P, et al., 2015, Pharmacogenetic stimulation of cholinergic pedunculopontine neurons reverses motor deficits in a rat model of Parkinson's disease, MOLECULAR NEURODEGENERATION, Vol: 10, ISSN: 1750-1326
Pienaar IS, Harrison IF, Elson JL, et al., 2015, An animal model mimicking pedunculopontine nucleus cholinergic degeneration in Parkinson's disease, BRAIN STRUCTURE & FUNCTION, Vol: 220, Pages: 479-500, ISSN: 1863-2653
Pienaar IS, Lee CH, Elson JL, et al., 2015, Deep-brain stimulation associates with improved microvascular integrity in the subthalamic nucleus in Parkinson's disease, NEUROBIOLOGY OF DISEASE, Vol: 74, Pages: 392-405, ISSN: 0969-9961
Ward RJ, Dexter DT, Crichton RR, 2015, Neurodegenerative diseases and therapeutic strategies using iron chelators, Journal of Trace Elements in Medicine and Biology, Vol: 31, Pages: 267-273, ISSN: 0946-672X
This review will summarise the current state of our knowledge concerning the involvement of iron in various neurological diseases and the potential of therapy with iron chelators to retard the progression of the disease. We first discuss briefly the role of metal ions in brain function before outlining the way by which transition metal ions, such as iron and copper, can initiate neurodegeneration through the generation of reactive oxygen and nitrogen species. This results in protein misfolding, amyloid production and formation of insoluble protein aggregates which are contained within inclusion bodies. This will activate microglia leading to neuroinflammation. Neuroinflammation plays an important role in the progression of the neurodegenerative diseases, with activated microglia releasing pro-inflammatory cytokines leading to cellular cell loss. The evidence for metal involvement in Parkinson's and Alzheimer's disease as well as Friedreich's ataxia and multiple sclerosis will be presented. Preliminary results from trials of iron chelation therapy in these neurodegenerative diseases will be reviewed.
Ward RJ, Dexter DT, Crichton RR, 2015, Ageing, neuroinflammation and neurodegeneration., Front Biosci (Schol Ed), Vol: 7, Pages: 189-204
During ageing, different iron complexes accumulate in specific brain regions which are associated with motor and cognitive dysfunction. In neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, changes in local iron homoeostasis result in altered cellular iron distribution and accumulation, ultimately inducing neurotoxicity. The use of iron chelators which are able to penetrate the blood brain barrier and reduce excessive iron accumulation in specific brain regions have been shown to reduce disease progression in both Parkinson's disease and Friedreich's Ataxia. Neuroinflammation often occurs in neurodegenerative diseases, which is mainly sustained by activated microglia exhibiting the M1 phenotype. Such inflammation contributes to the disease progression. Therapeutic agents which reduce such inflammation, e.g. taurine compounds, may ameliorate the inflammatory process by switching the microglia from a M1 to a M2 phenotype.
Ward RJ, Dexter DT, Crichton RR, 2015, Ageing, neuroinflammation and neurodegeneration, Frontiers in Bioscience - Scholar, Vol: 7S, Pages: 189-204, ISSN: 1945-0516
© 2015, Frontiers in Bioscience. All rights reserved. During ageing, different iron complexes accumulate in specific brain regions which are associated with motor and cognitive dysfunction. In neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, changes in local iron homoeostasis result in altered cellular iron distribution and accumulation, ultimately inducing neurotoxicity. The use of iron chelators which are able to penetrate the blood brain barrier and reduce excessive iron accumulation in specific brain regions have been shown to reduce disease progression in both Parkinson's disease and Friedreich's Ataxia. Neuroinflammation often occurs in neurodegenerative diseases, which is mainly sustained by activated microglia exhibiting the M1 phenotype. Such inflammation contributes to the disease progression. Therapeutic agents which reduce such inflammation, e.g. taurine compounds, may ameliorate the inflammatory process by switching the microglia from a M1 to a M2 phenotype.
Beilina A, Rudenko IN, Kaganovich A, et al., 2014, Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease, Proceedings of the National Academy of Sciences, Vol: 111, Pages: 2626-2631, ISSN: 0027-8424
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