7 results on '"Soon, Cynthia P. W."'
Search Results
2. Diacetylbis(N(4)-methylthiosemicarbazonato) Copper(II) (CuII(atsm)) Protects against Peroxynitrite-induced Nitrosative Damage and Prolongs Survival in Amyotrophic Lateral Sclerosis Mouse Model.
- Author
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Soon, Cynthia P. W., Donnelly, Paul S., Turner, Bradley J., Hung, Lin W., Crouch, Peter J., Sherratt, Nicki A., Tan, Jiang-Li, Lim, Nastasia K.-H., Lam, Linh, Bica, Laura, SinChun Lim, Hickey, James L., Morizzi, Julia, Powell, Andrew, Finkelstein, David I., Culvenor, Janetta G., Masters, Colin L., Duce, James, White, Anthony R., and Barnham, Kevin J.
- Subjects
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AMYOTROPHIC lateral sclerosis , *PEROXYNITRITE , *LABORATORY mice , *COPPER , *ANIMAL models in research , *CARBONYLATION kinetics - Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive paralyzing disease characterized by tissue oxidative damage and motor neuron degeneration. This study investigated the in vivo effect of diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)), which is an orally bioavailable, blood-brain barrier-permeable complex. In vitro the compound inhibits the action of peroxynitrite on Cu,Zn-superoxide dismutase (SOD1) and subsequent nitration of cellular proteins. Oral treatment of transgenic SOD1G93A mice with CuII(atsm) at presymptomatic and symptomatic ages was performed. The mice were examined for improvement in lifespan and motor function, as well as histological and biochemical changes to key disease markers. Systemic treatment of SOD1G93A mice significantly delayed onset of paralysis and prolonged lifespan, even when administered to symptomatic animals. Consistent with the properties of this compound, treated mice had reduced protein nitration and carbonylation, as well as increased antioxidant activity in spinal cord. Treatment also significantly preserved motor neurons and attenuated astrocyte and microglial activation in mice. Furthermore, CuII(atsm) prevented the accumulation of abnormally phosphorylated and fragmented TAR DNA-binding protein-43 (TDP-43) in spinal cord, a protein pivotal to the development of ALS. CuII(atsm) therefore represents a potential new class of neuroprotective agents targeting multiple major disease pathways of motor neurons with therapeutic potential for ALS. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
3. Investigation of matrix metalloproteinases, MMP-2 and MMP-9, in plasma reveals a decrease of MMP-2 in Alzheimer's disease.
- Author
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Lim NK, Villemagne VL, Soon CP, Laughton KM, Rowe CC, McLean CA, Masters CL, Evin G, Li QX, Lim, Nastasia K-H, Villemagne, Victor L, Soon, Cynthia P W, Laughton, Katrina M, Rowe, Christopher C, McLean, Catriona A, Masters, Colin L, Evin, Genevieve, and Li, Qiao-Xin
- Subjects
ALZHEIMER'S disease ,AMINES ,BIOMARKERS ,COGNITION disorders ,ENZYME-linked immunosorbent assay ,LONGITUDINAL method ,NEUROPSYCHOLOGICAL tests ,PEPTIDES ,PROTEOLYTIC enzymes ,QUESTIONNAIRES ,THIAZOLES - Abstract
Pathological changes in the Alzheimer's disease (AD) brain include amyoid-β (Aβ) plaques, and neurofibrillary tangles, as well as neuronal death and synaptic loss. Matrix metalloproteinases MMP-2 and MMP-9 are known to degrade Aβ, and their expressions are increased in the AD brain, in particular in the astrocytes surrounding amyloid plaque. To investigate a possible association between plasma metalloproteinases and AD, we quantified MMP-2 and MMP-9 activities in the plasma of healthy controls (HC, n = 56), cases with mild cognitive impairment (MCI, n = 45), and AD (n = 50). All cases had previously been imaged with Pittsburgh compound B (PiB) and had a Mini-Mental Status Examination (MMSE) assessment. MMP-2 and MMP-9 activity was determined using gelatine-zymography. There was a significant 1.5-fold decrease in MMP-2 activity in the AD group compared to HC (p < 0.001) and a 1.4-fold decrease compared to MCI (p < 0.01). There was no difference in MMP-9 levels between the three groups. A positive correlation was identified between MMP-2 plasma activity and MMSE score (r = 0.16, p < 0.05), but there was no association with PiB. This is the first report of a change in MMP-2 activity in AD plasma and these findings may provide some insight into AD pathogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
4. Diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)) protects against peroxynitrite-induced nitrosative damage and prolongs survival in amyotrophic lateral sclerosis mouse model.
- Author
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Soon CPW, Donnelly PS, Turner BJ, Hung LW, Crouch PJ, Sherratt NA, Tan JL, Lim NK, Lam L, Bica L, Lim S, Hickey JL, Morizzi J, Powell A, Finkelstein DI, Culvenor JG, Masters CL, Duce J, White AR, Barnham KJ, and Li QX
- Subjects
- Animals, Antioxidants chemistry, Astrocytes cytology, Coordination Complexes, Copper chemistry, DNA-Binding Proteins pharmacology, Disease Models, Animal, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microglia cytology, Neurodegenerative Diseases embryology, Neurons metabolism, Oxidative Stress, Oxygen chemistry, Spinal Cord pathology, Superoxide Dismutase-1, Transgenes, Amyotrophic Lateral Sclerosis metabolism, Organometallic Compounds chemistry, Peroxynitrous Acid metabolism, Superoxide Dismutase genetics, Thiosemicarbazones chemistry
- Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive paralyzing disease characterized by tissue oxidative damage and motor neuron degeneration. This study investigated the in vivo effect of diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)), which is an orally bioavailable, blood-brain barrier-permeable complex. In vitro the compound inhibits the action of peroxynitrite on Cu,Zn-superoxide dismutase (SOD1) and subsequent nitration of cellular proteins. Oral treatment of transgenic SOD1G93A mice with CuII(atsm) at presymptomatic and symptomatic ages was performed. The mice were examined for improvement in lifespan and motor function, as well as histological and biochemical changes to key disease markers. Systemic treatment of SOD1G93A mice significantly delayed onset of paralysis and prolonged lifespan, even when administered to symptomatic animals. Consistent with the properties of this compound, treated mice had reduced protein nitration and carbonylation, as well as increased antioxidant activity in spinal cord. Treatment also significantly preserved motor neurons and attenuated astrocyte and microglial activation in mice. Furthermore, CuII(atsm) prevented the accumulation of abnormally phosphorylated and fragmented TAR DNA-binding protein-43 (TDP-43) in spinal cord, a protein pivotal to the development of ALS. CuII(atsm) therefore represents a potential new class of neuroprotective agents targeting multiple major disease pathways of motor neurons with therapeutic potential for ALS.
- Published
- 2011
- Full Text
- View/download PDF
5. Zinc induces depletion and aggregation of endogenous TDP-43.
- Author
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Caragounis A, Price KA, Soon CP, Filiz G, Masters CL, Li QX, Crouch PJ, and White AR
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- Animals, Blotting, Western, Cell Line, Cell Survival drug effects, Fluorescent Antibody Technique, Humans, Inclusion Bodies metabolism, Inclusion Bodies pathology, Neurodegenerative Diseases metabolism, Neurodegenerative Diseases pathology, Neurodegenerative Diseases physiopathology, Neurons metabolism, Neurons pathology, Oxidative Stress drug effects, Oxidative Stress physiology, Rats, Chlorides toxicity, DNA-Binding Proteins drug effects, DNA-Binding Proteins metabolism, Inclusion Bodies drug effects, Neurons drug effects, Zinc Compounds toxicity
- Abstract
Ubiquitinated neuronal aggregates containing TDP-43 are pathological hallmarks in the spectrum of frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS). In affected neurons, TDP-43 undergoes C-terminal fragmentation, phosphorylation, and ubiquitination and forms aggregates in the cytoplasm or nucleus. Although in vitro studies have been able to recapitulate these features using transfected cell culture models, little is known about the biochemical mechanisms that underlie pathological changes to endogenous TDP-43. As altered metal ion homeostasis and increased oxidative stress are central features of neurodegeneration, including FTLD and ALS, we sought to determine the affects of these factors on endogenous TDP-43 metabolism in mammalian cells. Treatment of SY5Y neuronal-like cells expressing endogenous TDP-43 with zinc (Zn) induced depletion of TDP-43 expression and formation of inclusions that were TDP-43 positive. TDP-43 was also detected in the cytosol of Zn-affected cells but this was not aggregated. No evidence of C-terminal fragmentation, phosphorylation, or ubiquitination was observed. The depletion and aggregation of TDP-43 were associated with the specific action of Zn but were not seen with copper, iron, or H(2)O(2). These studies describe for the first time specific induction of endogenous TDP-43 aggregation in neuronal-like cells and suggest that specific Zn-associated processes could affect TDP-43 metabolism in neurodegenerative diseases., ((c) 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
6. Serum matrix metalloproteinase-9 activity is dysregulated with disease progression in the mutant SOD1 transgenic mice.
- Author
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Soon CP, Crouch PJ, Turner BJ, McLean CA, Laughton KM, Atkin JD, Masters CL, White AR, and Li QX
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- Amyotrophic Lateral Sclerosis diagnosis, Animals, Biomarkers analysis, Biomarkers blood, Disease Models, Animal, Disease Progression, Gene Dosage genetics, Gene Expression Regulation, Enzymologic genetics, Genetic Predisposition to Disease, Matrix Metalloproteinase 2 analysis, Matrix Metalloproteinase 2 blood, Matrix Metalloproteinase 9 analysis, Mice, Mice, Transgenic, Motor Neurons pathology, Mutation genetics, Neuroglia enzymology, Spinal Cord pathology, Spinal Cord physiopathology, Superoxide Dismutase genetics, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis blood, Amyotrophic Lateral Sclerosis enzymology, Matrix Metalloproteinase 9 blood, Motor Neurons enzymology, Spinal Cord enzymology
- Abstract
Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal neurodegenerative disorder characterized by progressive deterioration of motor neurons in the spinal cord, brainstem, and cerebral cortex. Matrix metalloproteinase-9 (MMP-9) is proposed to be a biomarker for ALS due to a potential pathological role in the disease. However, despite numerous studies, it is still unclear whether there is a direct correlation between MMP-9 expression in serum and progression of disease. Therefore, we used a TgSOD1(G93A) mouse with a low transgene copy number. This model shows slow disease progression analogous to human ALS and provides a useful model to study biomarker expression at different stages of disease. Using zymography, we found that serum MMP-9 activity was significantly elevated in animals showing early signs of disease when compared to the younger, pre-symptomatic animals. This was followed by a decrease in MMP-9 activity in TgSOD1(G93A) mice with end-stage disease. These results were confirmed in serum of a high copy number strain of TgSOD1(G93A) mice with rapid progression. MMP-9 expression was changed accordingly in spinal motor neurons, glia and neuropil, suggesting a spinal cord contribution to blood MMP-9 activity. Serum MMP-2 activity followed a similar profile as the MMP-9 in these two models. These data indicate that circulating MMP-9 is altered throughout the course of disease progression in mice. Further studies in human ALS may validate the suitability of serum MMP-9 activity as a biomarker for early stage disease., (Copyright 2009 Elsevier B.V. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
7. Restored degradation of the Alzheimer's amyloid-beta peptide by targeting amyloid formation.
- Author
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Crouch PJ, Tew DJ, Du T, Nguyen DN, Caragounis A, Filiz G, Blake RE, Trounce IA, Soon CP, Laughton K, Perez KA, Li QX, Cherny RA, Masters CL, Barnham KJ, and White AR
- Subjects
- Amyloid drug effects, Amyloid beta-Peptides drug effects, Amyloid beta-Peptides genetics, Clioquinol pharmacology, Dose-Response Relationship, Drug, Enzyme-Linked Immunosorbent Assay methods, Glutamic Acid genetics, Glutamine genetics, Humans, Insulysin pharmacology, Matrix Metalloproteinase 2 metabolism, Microscopy, Electron, Transmission methods, Mutation, Neprilysin pharmacology, Peptide Fragments drug effects, Peptide Fragments genetics, Peptide Fragments metabolism, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization methods, Time Factors, Zinc pharmacology, Amyloid metabolism, Amyloid beta-Peptides metabolism
- Abstract
Accumulation of neurotoxic amyloid-beta (Abeta) is central to the pathology of Alzheimer's disease (AD). Elucidating the mechanisms of Abeta accumulation will therefore expedite the development of Abeta-targeting AD therapeutics. We examined activity of an Abeta-degrading protease (matrix metalloprotease 2) to investigate whether biochemical factors consistent with conditions in the AD brain contribute to Abeta accumulation by altering Abeta sensitivity to proteolytic degradation. An Abeta amino acid mutation found in familial AD, Abeta interactions with zinc (Zn), and increased Abeta hydrophobicity all strongly prevented Abeta degradation. Consistent to all of these factors is the promotion of specific Abeta aggregates where the protease cleavage site, confirmed by mass spectrometry, is inaccessible within an amyloid structure. These data indicate decreased degradation due to amyloid formation initiates Abeta accumulation by preventing normal protease activity. Zn also prevented Abeta degradation by the proteases neprilysin and insulin degrading enzyme. Treating Zn-induced Abeta amyloid with the metal-protein attenuating compound clioquinol reversed amyloid formation and restored the peptide's sensitivity to degradation by matrix metalloprotease 2. This provides new data indicating that therapeutic compounds designed to modulate Abeta-metal interactions can inhibit Abeta accumulation by restoring the catalytic potential of Abeta-degrading proteases.
- Published
- 2009
- Full Text
- View/download PDF
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