Chronic exposure to a glyphosate-containing pesticide leads to mitochondrial dysfunction and increased reactive oxygen species production in Caenorhabditis elegans
C. elegans; Glyphosate; Hydrogen peroxide; Mitochondrial inhibition; oxidative stress; Toxicology; Environmental Sciences & Ecology; Pharmacology & Pharmacy; parkinsons-disease; brain; alzheimers-disease; mechanisms; degeneration; species; neurodegenerative diseases; 6-ohda; C. elegans; complex-i; Herbicide; Reactive oxygen
Glyphosate-containing herbicides are among the most widely-used in the world. Although glyphosate itself is relatively non-toxic, growing evidence suggests that commercial herbicide formulations may lead to increased oxidative stress and mitochondrial inhibition. In order to assess these mechanisms in vivo, we chronically (24 h) exposed Caenorhabditis elegans to various concentrations of the glyphosate-containing herbicide TouchDown (TD). Following TD exposure, we evaluated the function of specific mitochondrial electron transport chain complexes. Initial oxygen consumption studies demonstrated inhibition in mid- and high-TD concentration treatment groups compared to controls. Results from tetramethylrhodamine ethyl ester and ATP assays indicated reductions in the proton gradient and ATP levels, respectively. Additional studies were designed to determine whether TD exposure resulted in increased reactive oxygen species (ROS) production. Data from hydrogen peroxide, but not superoxide or hydroxyl radical, assays showed statistically significant increases in this specific ROS. Taken together, these data indicate that exposure of Caenorhabditis elegans to TD leads to mitochondrial inhibition and hydrogen peroxide production.
Bailey D C; Todt C E; Burchfield S L; Pressley A S; Denney R D; Snapp I B; Negga R; Traynor W L; Fitsanakis V A
Environmental Toxicology and Pharmacology
2018
2018-01
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.etap.2017.11.005" target="_blank" rel="noreferrer noopener">10.1016/j.etap.2017.11.005</a>
Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy.
Alzheimer's disease; Animal; Animals; Antigens; Biological; Calcium Binding Proteins – Metabolism; Calcium-Binding Proteins/metabolism; Cells – Drug Effects; Cells – Metabolism; Cells – Pathology; Chemokine CX3CL1/*genetics/metabolism; Cognition Disorders – Etiology; Cognition Disorders/etiology; CX3CL1; CX3CR1; Cytokines; Cytokines – Metabolism; Cytokines/metabolism; Differentiation/genetics/metabolism; Disease Models; Gene Expression Regulation/drug effects/*genetics; Genes; Genes – Drug Effects; Learning; Lipopolysaccharides; Lipopolysaccharides/toxicity; Maze Learning; Mice; Microfilament Proteins – Metabolism; Microfilament Proteins/metabolism; Microglia; Microglia/drug effects/*metabolism/pathology; Models; Mutation; Mutation/genetics; Nerve Tissue Proteins; Nerve Tissue Proteins – Metabolism; Neurodegenerative Diseases; Neurodegenerative Diseases – Complications; Neurodegenerative Diseases – Pathology; Neuroinflammation; Surface; Surface – Metabolism; Tau; tau Proteins/genetics/metabolism; Tauopathies; Tauopathies/complications/genetics/*pathology; Transgenic
BACKGROUND: Fractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function. We have previously shown that Cx3cr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX3CL1 is essential in regulating neuronal tau pathology. METHODS: We used transgenic mice lacking endogenous Cx3cl1 (Cx3cl1(-/-)) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX3CL1 (referred to as Cx3cl1(105Delta) mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy. RESULTS: First, increased basal tau levels accompanied microglial activation in Cx3cl1(105Delta) mice compared to control groups. Second, increased CD45(+) and F4/80(+) neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cx3cl1(-/-), and hTau/Cx3cl1(105Delta) mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX3CR1 was reduced in Cx3cl1(105Delta) mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx3cr1 deletion), which likely contributes to the elevated tau pathology. CONCLUSIONS: Collectively, our data suggest that overexpression of only chemokine domain of CX3CL1 does not protect against tau pathology.
Bemiller Shane M; Maphis Nicole M; Formica Shane V; Wilson Gina N; Miller Crystal M; Xu Guixiang; Kokiko-Cochran Olga N; Kim Ki-Wook; Jung Steffen; Cannon Judy L; Crish Samuel D; Cardona Astrid E; Lamb Bruce T; Bhaskar Kiran
Journal of neuroinflammation
2018
2018-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s12974-018-1310-6" target="_blank" rel="noreferrer noopener">10.1186/s12974-018-1310-6</a>
RNAseq analysis of hippocampal microglia after kainic acid-induced seizures.
Animals; Gene Expression Profiling; Gene Ontology; Hippocampus/*pathology; Immunity; Interferon-beta/metabolism; Kainic Acid; Mice; Microglia/*metabolism/*pathology; RNA/*methods; Seizures/*chemically induced; Sequence Analysis; Signal Transduction/genetics; Up-Regulation/genetics
Microglia have been shown to be of critical importance to the progression of temporal lobe epilepsy. However, the broad transcriptional changes that these cells undergo following seizure induction is not well understood. As such, we utilized RNAseq analysis upon microglia isolated from the hippocampus to determine expression pattern alterations following kainic acid induced seizure. We determined that microglia undergo dramatic changes to their expression patterns, particularly with regard to mitochondrial activity and metabolism. We also observed that microglia initiate immunological activity, specifically increasing interferon beta responsiveness. Our results provide novel insights into microglia transcriptional regulation following acute seizures and suggest potential therapeutic targets specifically in microglia for the treatment of seizures and epilepsy.
Bosco Dale B; Zheng Jiaying; Xu Zhiyan; Peng Jiyun; Eyo Ukpong B; Tang Ke; Yan Cheng; Huang Jun; Feng Lijie; Wu Gongxiong; Richardson Jason R; Wang Hui; Wu Long-Jun
Molecular brain
2018
2018-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s13041-018-0376-5" target="_blank" rel="noreferrer noopener">10.1186/s13041-018-0376-5</a>
Interprofessional education model for geriatric falls risk assessment and prevention.
Background: One in three people over the age of 65 fall every year, with 1/3 sustaining at least moderate injury. Falls risk reduction requires an interprofessional health team approach. The literature is lacking in effective models to teach students how to work collaboratively in interprofessional teams for geriatric falls prevention. The purpose of this paper is to describe the development, administration and outcome measures of an education programme to teach principles of interprofessional care for older adults in the context of falls prevention. Methods: Students from three academic institutions representing 12 health disciplines took part in the education programme over 18 months (n=237). A mixed method one-group pretest and post-test experimental design was implemented to measure the impact of a multistep education model on progression in interprofessional collaboration competencies and satisfaction. Results: Paired t-tests of pre-education to posteducation measures of Interprofessional Socialization and Valuing Scale scores (n=136) demonstrated statistically significant increase in subscales and total scores (p\textless0.001). Qualitative satisfaction results were strongly positive. Discussion: Results of this study indicate that active interprofessional education can result in positive student attitude regarding interprofessional team-based care, and satisfaction with learning. Lessons learnt in a rapid cycle plan-do-study-act approach are shared to guide replication efforts for other educators. Conclusion: Effective models to teach falls prevention interventions and interprofessional practice are not yet established. This education model is easily replicable and can be used to teach interprofessional teamwork competency skills in falls and other geriatric syndromes.
Brown Diane K; Fosnight Sue; Whitford Maureen; Hazelett Susan; McQuown Colleen; Drost Jenifer C; Kropp Denise J; Hovland Cynthia A; Niederriter Joan E; Patton Rikki; Morgan Abigail; Fleming Eileen; Steiner Richard P; Scott Edward Demond; Ortiz Figueroa Fabiana
BMJ open quality
2018
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1136/bmjoq-2018-000417" target="_blank" rel="noreferrer noopener">10.1136/bmjoq-2018-000417</a>
Glycoprotein NMB: an Emerging Role in Neurodegenerative Disease.
Animals; GPNMB; Humans; Immune System/metabolism; Membrane Glycoproteins/chemistry/*metabolism; Nerve Degeneration/pathology; Neurodegeneration; Neurodegenerative Diseases/*metabolism/therapy; Neuroinflammation; Neuroprotection
Neurodegeneration is characterized by severe neuronal loss leading to the cognitive and physical impairments that define various neurodegenerative diseases. Neuroinflammation is one hallmark of neurodegenerative diseases and can ultimately contribute to disease progression. Increased inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1beta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha) are associated with Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Unfortunately, current therapeutic options lack ability to stop or effectively slow progression of these diseases and are primarily aimed at alleviating symptoms. Thus, it is crucial to discover novel treatment candidates for neurodegenerative diseases. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type-I transmembrane glycoprotein first identified in a melanoma cell line. GPNMB augments bone mineral deposition by stimulating osteoblast differentiation. Aside from its anabolic function in the bone, emerging evidence suggests that GPNMB has anti-inflammatory and reparative functions. GPNMB has also been demonstrated to be neuroprotective in an animal model of ALS, cerebral ischemia, and other disease models. Given these discoveries, GPNMB should be investigated as a potential therapeutic option for multiple neurodegenerative diseases.
Budge Kevin M; Neal Matthew L; Richardson Jason R; Safadi Fayez F
Molecular neurobiology
2018
2018-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s12035-017-0707-z" target="_blank" rel="noreferrer noopener">10.1007/s12035-017-0707-z</a>
Editorial: Axonopathy in Neurodegenerative Disease.
axon degeneration; chemotherapy induced neuropathy; glaucoma; mitochondrial dysfuncion; neuropathy
Burgess Robert W; Crish Samuel D
Frontiers in neuroscience
2018
1905-7
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3389/fnins.2018.00769" target="_blank" rel="noreferrer noopener">10.3389/fnins.2018.00769</a>
Quantifying ceramide kinetics in vivo using stable isotope tracers and LC-MS/MS.
dyslipidemia; insulin resistance; kinetics; lipid turnover; mass spectrometry
Numerous studies have implicated dyslipidemia as a key factor in mediating insulin resistance. Ceramides have received special attention since their levels are inversely associated with normal insulin signaling and positively associated with factors that are involved in cardiometabolic disease. Despite the growing literature surrounding ceramide biology, there are limited data regarding the activity of ceramide synthesis and turnover in vivo. Herein, we demonstrate the ability to measure ceramide kinetics by coupling the administration of [(2)H]water with LC-MS/MS analyses. As a "proof-of-concept" we determined the effect of a diet-induced alteration on ceramide flux; studies also examined the effect of myriocin (a known inhibitor of serine palmitoyltransferase, the first step in sphingosine biosynthesis). Our data suggest that one can estimate ceramide synthesis and draw conclusions regarding the source of fatty acids; we discuss caveats in regards to method development in this area.
Chen Ying; Berejnaia Olga; Liu Jinqi; Wang Sheng-Ping; Daurio Natalie A; Yin Wu; Mayoral Rafael; Petrov Aleksandr; Kasumov Takhar; Zhang Guo-Fang; Previs Stephen F; Kelley David E; McLaren David G
American journal of physiology. Endocrinology and metabolism
2018
2018-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpendo.00457.2017" target="_blank" rel="noreferrer noopener">10.1152/ajpendo.00457.2017</a>
Ahr And Cyp1a2 Genotypes Both Affect Susceptibility To Motor Deficits Following Gestational And Lactational Exposure To Polychlorinated Biphenyls
Aryl hydrocarbon receptor; Cerebellum; CYP1A2; developmental exposure; dioxin-like compounds; dopamine concentrations; in-utero; Motor function; Neurosciences & Neurology; Nigrostriatal pathways; parkinsons-disease; pcb exposure; perinatal exposure; Pharmacology & Pharmacy; Polychlorinated biphenyls; prenatal exposure; risk assessment; school-age; Toxicology
Colter B T; Garber H F; Fleming S M; Fowler J P; Harding G D; Hooven M K; Howes A A; Infante S K; Lang A L; MacDougall M C; Stegman M; Taylor K R; Curran C P
Neurotoxicology
2018
2018-03
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.neuro.2018.01.008" target="_blank" rel="noreferrer noopener">10.1016/j.neuro.2018.01.008</a>
Anterograde Tract Tracing for Assaying Axonopathy and Transport Deficits in Glaucoma.
*Axonal transport; *Axonopathy; *Neuronal tracing; *Optic nerve; *Superior colliculus; Animal; Animals; Axonal Transport; Axons/metabolism/*pathology/physiology; Cholera Toxin/*metabolism; Confocal; Disease Models; Glaucoma/*diagnostic imaging/metabolism/physiopathology; Humans; Mice; Microscopy; Rats; Visual Pathways
Whether to stage degeneration or investigate early pathology in glaucoma, examination of axonal structure and function is essential. There are a wide variety of methods available to investigators using animal models of glaucoma, with varying utilities depending on the questions asked. Here, we describe the use of anterograde neuronal tract tracing using cholera toxin B (CTB) for the determination of axon transport integrity of the retinofugal projection. This method reveals the structure of the retinal axons as well as the functional integrity of anterograde transport systems.
Crish Samuel D; Schofield Brett R
Methods in molecular biology (Clifton, N.J.)
2018
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/978-1-4939-7407-8_15" target="_blank" rel="noreferrer noopener">10.1007/978-1-4939-7407-8_15</a>
Mitoneet Ligand-1 Alleviates Experimental Alcoholic Steatohepatitis In Mice Through Mitigation Of Ferroptosis
Substance Abuse
Daniels M; Zhou Z; Bonavita G; Ye T J; You M
Alcoholism-Clinical and Experimental Research
2018
2018-08
Journal Article or Conference Abstract Publication
n/a
Evidence of Wnt/beta-catenin alterations in brain and bone of a tauopathy mouse model of Alzheimer's disease.
*Alzheimer's disease; *Beta catenin; *Bone mineral density; *Neurodegeneration; *Tauopathy; *Wnt proteins; *Wnt Signaling Pathway; Alzheimer Disease/*genetics/*metabolism; Animal; Animals; beta Catenin/metabolism; Bone and Bones/*metabolism; Bone Density; Bone Remodeling/genetics; Brain/*metabolism; Disease Models; Female; Gene Expression; Male; Mice; Osteogenesis/genetics; Osteoporosis/etiology/genetics; tau Proteins/*metabolism; Tauopathies/genetics/*metabolism; Wnt Proteins/metabolism
Low bone mineral density (BMD) is a significant comorbidity in Alzheimer's disease (AD) and may reflect systemic regulatory pathway dysfunction. Low BMD has been identified in several AD mouse models selective for amyloid-beta or tau pathology, but these deficits were attributed to diverse mechanisms. In this study, we identified common pathophysiological mechanisms accounting for bone loss and neurodegeneration in the htau mouse, a tauopathy model with an early low BMD phenotype. We investigated the Wnt/beta-catenin pathway-a cellular signaling cascade linked to both bone loss and neuropathology. We showed that low BMD persisted in male htau mice aged from 6 to 14 months, remaining significantly lower than tau-null and C57BL/6J controls. Osteogenic gene expression in female and male htau mice was markedly reduced from controls, indicating impaired bone remodeling. In both the bone and brain, htau mice showed alterations in Wnt/beta-catenin signaling genes suggestive of increased inhibition of this pathway. These findings implicate dysfunctional Wnt signaling as a potential target for addressing bone loss in AD.
Dengler-Crish Christine M; Ball Hope C; Lin Li; Novak Kimberly M; Cooper Lisa Noelle
Neurobiology of aging
2018
2018-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.neurobiolaging.2018.03.021" target="_blank" rel="noreferrer noopener">10.1016/j.neurobiolaging.2018.03.021</a>
Exacerbation of sensorimotor dysfunction in mice deficient in Atp13a2 and overexpressing human wildtype alpha-synuclein.
*Alpha-synuclein; *ATP13A2; *Mice; *Phenotype; *Sensorimotor; Adenosine Triphosphatases/*deficiency/genetics; alpha-Synuclein/genetics/*metabolism; Animal; Animals; Body Temperature; Body Weight; Disease Models; Female; Gait Disorders; Humans; Inbred C57BL; Male; Membrane Proteins/*deficiency/genetics; Mice; Motor Skills/physiology; Neurologic/*metabolism; Phenotype; Severity of Illness Index; Sex Characteristics; Transgenic
Loss of function mutations in the gene ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis, the former designated as an inherited form of Parkinson's disease (PD). The function of ATP13A2 is unclear but in vitro studies indicate it is a lysosomal protein and may interact with the presynaptic protein alpha-synuclein (aSyn) and certain heavy metals. Accumulation of aSyn is a major component of lewy bodies, the pathological hallmark of PD. Atp13a2-deficient (13a2) mice develop age-dependent sensorimotor deficits, and accumulation of insoluble aSyn in the brain. To better understand the interaction between ATP13A2 and aSyn, double mutant mice with loss of Atp13a2 function combined with overexpression of human wildtype aSyn were generated. Female and male wildtype (WT), 13a2, aSyn, and 13a2-aSyn mice were tested on a battery of sensorimotor tests including adhesive removal, challenging beam traversal, spontaneous activity, gait, locomotor activity, and nest-building at 2, 4, and 6 months of age. Double mutant mice showed an earlier onset and accelerated alterations in sensorimotor function that were age, sex and test-dependent. Female 13a2-aSyn mice showed early and progressive dysfunction on the beam and in locomotor activity. In males, 13a2-aSyn mice showed more severe impairments in spontaneous activity and adhesive removal. Sex differences were also observed in aSyn and 13a2-aSyn mice on the beam, cylinder, and adhesive removal tests. In other tasks, double mutant mice displayed deficits similar to aSyn mice. These results indicate loss of Atp13a2 function exacerbates the sensorimotor phenotype in aSyn mice in an age and sex-dependent manner.
Dirr Emily R; Ekhator Osunde R; Blackwood Rachel; Holden John G; Masliah Eliezer; Schultheis Patrick J; Fleming Sheila M
Behavioural brain research
2018
2018-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bbr.2018.01.029" target="_blank" rel="noreferrer noopener">10.1016/j.bbr.2018.01.029</a>
Preparation of emulsifying wax/glyceryl monooleate nanoparticles and evaluation as a delivery system for repurposing simvastatin in bone regeneration.
Animals; bone; Bone Regeneration/*drug effects/physiology; drug delivery; Drug Delivery Systems/*methods; Drug Evaluation; Drug Repositioning/methods; Emulsifying Agents/administration & dosage/*chemical synthesis; Glycerides/administration & dosage/*chemical synthesis; Mice; nanoemulsions; nanoparticles; Nanoparticles/administration & dosage/*chemistry; osteoblasts; Osteoblasts/drug effects/physiology; Osteoclasts; Preclinical/methods; RAW 264.7 Cells; Simvastatin/administration & dosage/*chemical synthesis; Waxes/chemical synthesis/pharmacology
Simvastatin (Sim) is a widely known drug in the treatment of hyperlipidemia, which has attracted so much attention in bone regeneration due to its potential osteoanabolic effect. However, repurposing of Sim in bone regeneration will require suitable delivery systems that can negate undesirable off-target/side effects. In this study, we have investigated a new lipid nanoparticle (NP) platform that was fabricated using a binary blend of emulsifying wax (Ewax) and glyceryl monooleate (GMO). Using the binary matrix materials, NPs loaded with Sim (0-500 microg/mL) were prepared and showed an average particle size of about 150 nm. NP size stability was dependent on Sim concentration loaded in NPs. The suitability of NPs prepared with the binary matrix materials in Sim delivery for potential application in bone regeneration was supported by biocompatibility in pre-osteoclastic and pre-osteoblastic cells. Additional data demonstrated that biofunctional Sim was released from NPs that facilitated differentiation of osteoblasts (cells that form bones) while inhibiting differentiation of osteoclasts (cells that resorb bones). The overall work demonstrated the preparation of NPs from Ewax/GMO blends and characterization to ascertain potential suitability in Sim delivery for bone regeneration. Additional studies on osteoblast and osteoclast functions are warranted to fully evaluate the efficacy of Sim-loaded Ewax/GMO NPs using in-vitro and in-vivo approaches.
Eskinazi-Budge Aaron; Manickavasagam Dharani; Czech Tori; Novak Kimberly; Kunzler James; Oyewumi Moses O
Drug development and industrial pharmacy
2018
2018-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1080/03639045.2018.1483381" target="_blank" rel="noreferrer noopener">10.1080/03639045.2018.1483381</a>
The effect of manganese exposure in Atp13a2-deficient mice.
*Alpha-synuclein; *Lipofuscin; *Manganese; *Mice; *Parkinson's disease; *Sensorimotor function
Loss of function mutations in the P5-ATPase ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis. While the function of ATP13A2 is unclear, in vitro studies suggest it is a lysosomal protein that interacts with the metals manganese (Mn) and zinc and the presynaptic protein alpha-synuclein. Loss of ATP13A2 function in mice causes sensorimotor deficits, enhanced autofluorescent storage material, and accumulation of alpha-synuclein. The present study sought to determine the effect of Mn administration on these same outcomes in ATP13A2-deficient mice. Wildtype and ATP13A2-deficient mice received saline or Mn at 5-9 or 12-19 months for 45days. Sensorimotor function was assessed starting at day 30. Autofluorescence was quantified in multiple brain regions and alpha-synuclein protein levels were determined in the ventral midbrain. Brain Mn, iron, zinc, and copper concentrations were measured in 5-9 month old mice. The results show Mn enhanced sensorimotor function, increased autofluorescence in the substantia nigra, and increased insoluble alpha-synuclein in the ventral midbrain in older ATP13A2-deficient mice. In addition, the Mn regimen used increased Mn concentration in the brain and levels were higher in Mn-treated mutants than controls. These results indicate loss of ATP13A2 function leads to increased sensitivity to Mn in vivo.
Fleming Sheila M; Santiago Nicholas A; Mullin Elizabeth J; Pamphile Shanta; Karkare Swagata; Lemkuhl Andrew; Ekhator Osunde R; Linn Stephen C; Holden John G; Aga Diana S; Roth Jerome A; Liou Benjamin; Sun Ying; Shull Gary E; Schultheis Patrick J
Neurotoxicology
2018
2018-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.neuro.2017.06.005" target="_blank" rel="noreferrer noopener">10.1016/j.neuro.2017.06.005</a>
The effect of manganese exposure in Atp13a2-deficient mice.
Female; Male; Animals; Mice; *Parkinson's disease; *Alpha-synuclein; Mice; Membrane Proteins/genetics/*metabolism; Motor Activity; *Lipofuscin; *Manganese; *Sensorimotor function; Behavior; Inbred C57BL; Animal; Knockout; Adenosine Triphosphatases/genetics/*metabolism; alpha-Synuclein/metabolism; Brain/*drug effects/*metabolism; Manganese/metabolism/*toxicity
Loss of function mutations in the P5-ATPase ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis. While the function of ATP13A2 is unclear, in vitro studies suggest it is a lysosomal protein that interacts with the metals manganese (Mn) and zinc and the presynaptic protein alpha-synuclein. Loss of ATP13A2 function in mice causes sensorimotor deficits, enhanced autofluorescent storage material, and accumulation of alpha-synuclein. The present study sought to determine the effect of Mn administration on these same outcomes in ATP13A2-deficient mice. Wildtype and ATP13A2-deficient mice received saline or Mn at 5-9 or 12-19 months for 45days. Sensorimotor function was assessed starting at day 30. Autofluorescence was quantified in multiple brain regions and alpha-synuclein protein levels were determined in the ventral midbrain. Brain Mn, iron, zinc, and copper concentrations were measured in 5-9 month old mice. The results show Mn enhanced sensorimotor function, increased autofluorescence in the substantia nigra, and increased insoluble alpha-synuclein in the ventral midbrain in older ATP13A2-deficient mice. In addition, the Mn regimen used increased Mn concentration in the brain and levels were higher in Mn-treated mutants than controls. These results indicate loss of ATP13A2 function leads to increased sensitivity to Mn in vivo.
Fleming Sheila M; Santiago Nicholas A; Mullin Elizabeth J; Pamphile Shanta; Karkare Swagata; Lemkuhl Andrew; Ekhator Osunde R; Linn Stephen C; Holden John G; Aga Diana S; Roth Jerome A; Liou Benjamin; Sun Ying; Shull Gary E; Schultheis Patrick J
Neurotoxicology
2018
2018-01
<a href="http://doi.org/10.1016/j.neuro.2017.06.005" target="_blank" rel="noreferrer noopener">10.1016/j.neuro.2017.06.005</a>
Hyperammonemia Induced Redox Changes In Skeletal Muscle Perturbs Glucose-pyruvate Metabolism And Tissue Bioenergetics
Gastroenterology & Hepatology
Gangadhariah M; Allawy A; Davuluri G; Kumar A; Kant S; Alchirazi K A; Shah R; Sandlers Y; Kasumov T; Mao X; O'Connell T; Harris R; Dasarathy S
Hepatology
2018
2018-10
Journal Article or Conference Abstract Publication
n/a
Evidence of Oropharyngeal Dysfunction in Feeding in the Rat Rotenone Model of Parkinson's Disease.
Animal Studies; Deglutition – Drug Effects; Deglutition Disorders; Eating – Drug Effects; Feeding Methods; Isoflavones – Administration and Dosage; Isoflavones – Pharmacodynamics; Mastication; Oropharynx – Pathology; Parkinson Disease; Phenotype; Rats
Swallowing disorders in Parkinson's disease are not responsive to dopamine depletion therapy and contribute to morbidity. They are poorly understood owing to a lack of adequate models. We present the first evidence of oropharyngeal changes in a rotenone toxicity model of Parkinson's disease. Rats were recorded while feeding before and after daily rotenone injections at two different doses (2.75 mg/kg and 3 mg/kg). The higher dose had a much more severe parkinsonian phenotype than the low dose. Timing and amplitude of chewing changed, as did the coordination of chewing and swallowing. Dose-dependent effects were evident. These preliminary results indicate that future research in toxicological models of Parkinson's disease should incorporate the study of oropharyngeal dysfunction. A better understanding of nongenetic models of Parkinson's disease in feeding may open new avenues for research into the neurological and behavioral bases for swallowing dysfunction in Parkinson's disease.
Gould Francois D H; Gross Andrew; German Rebecca Z; Richardson Jason R
Parkinson's disease
2018
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1155/2018/6537072" target="_blank" rel="noreferrer noopener">10.1155/2018/6537072</a>
Reduced AMPK activation and increased HCAR activation drive anti-inflammatory response and neuroprotection in glaucoma.
AMP-activated protein kinase; AMP-Activated Protein Kinases/*metabolism; Animal; Animals; Biological; Calcium Binding Proteins – Metabolism; Calcium-Binding Proteins/metabolism; Cells – Drug Effects; Cells – Pathology; Diet; Disease Models; Eye Proteins/genetics; Female; G-Protein-Coupled – Metabolism; G-Protein-Coupled/*metabolism; Glaucoma; Glaucoma – Complications; Glaucoma – Pathology; Glaucoma/*complications/pathology; Impact of Events Scale; Inbred DBA; Inflammation – Etiology; Inflammation – Prevention and Control; Inflammation hydroxycarboxylic acid receptor; Inflammation/*etiology/*prevention & control; Ketogenic diet; Ketogenic/methods; Male; Membrane Glycoproteins; Membrane Glycoproteins/genetics; Mice; Microfilament Proteins – Metabolism; Microfilament Proteins/metabolism; Microglia/drug effects/pathology; Models; Mutation; Mutation/genetics; Neuroprotection/drug effects/*physiology; NLR Family; Optic Nerve – Pathology; Optic Nerve/pathology; Phosphotransferases – Metabolism; Proteins; Pyrin Domain-Containing 3 Protein/genetics/metabolism; Receptors; Retina – Drug Effects; Retina – Pathology; Retinal Ganglion Cells/drug effects/*pathology; Transgenic
BACKGROUND: Glaucoma is a chronic degenerative disease for which inflammation is considered to play a pivotal role in the pathogenesis and progression. In this study, we examined the impact of a ketogenic diet on the inflammation evident in glaucoma as a follow-up to a recent set of experiments in which we determined that a ketogenic diet protected retinal ganglion cell structure and function. METHODS: Both sexes of DBA/2J (D2) mice were placed on a ketogenic diet (keto) or standard rodent chow (untreated) for 8 weeks beginning at 9 months of age. DBA/2J-Gpnmb(+) (D2G) mice were also used as a non-pathological genetic control for the D2 mice. Retina and optic nerve (ON) tissues were micro-dissected and used for the analysis of microglia activation, expression of pro- and anti-inflammatory molecules, and lactate- or ketone-mediated anti-inflammatory signaling. Data were analyzed by immunohistochemistry, quantitative RT-PCR, ELISA, western blot, and capillary tube-based electrophoresis techniques. RESULTS: Microglia activation was observed in D2 retina and ON as documented by intense microglial-specific Iba1 immunolabeling of rounded-up and enlarged microglia. Ketogenic diet treatment reduced Iba1 expression and the activated microglial phenotype. We detected low energy-induced AMP-activated protein kinase (AMPK) phosphorylation in D2 retina and ON that triggered NF-kappaB p65 signaling through its nuclear translocation. NF-kappaB induced pro-inflammatory TNF-alpha,
Harun-Or-Rashid Mohammad; Inman Denise M
Journal of neuroinflammation
2018
2018-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s12974-018-1346-7" target="_blank" rel="noreferrer noopener">10.1186/s12974-018-1346-7</a>
Structural and Functional Rescue of Chronic Metabolically Stressed Optic Nerves through Respiration.
b-hydroxybutyrate; ketogenic diet; neural-glial interaction; optic nerve
Axon degeneration can arise from metabolic stress, potentially a result of mitochondrial dysfunction or lack of appropriate substrate input. In this study, we investigated whether the metabolic vulnerability observed during optic neuropathy in the DBA/2J (D2) model of glaucoma is due to dysfunctional mitochondria or impaired substrate delivery to axons, the latter based on our observation of significantly decreased glucose and monocarboxylate transporters in D2 optic nerve (ON), human ON, and mice subjected to acute glaucoma injury. We placed both sexes of D2 mice destined to develop glaucoma and mice of a control strain, the DBA/2J-Gpnmb(+), on a ketogenic diet to encourage mitochondrial function. Eight weeks of the diet generated mitochondria, improved energy availability by reversing monocarboxylate transporter decline, reduced glial hypertrophy, protected retinal ganglion cells and their axons from degeneration, and maintained physiological signaling to the brain. A robust antioxidant response also accompanied the response to the diet. These results suggest that energy compromise and subsequent axon degeneration in the D2 is due to low substrate availability secondary to transporter downregulation.SIGNIFICANCE STATEMENT We show axons in glaucomatous optic nerve are energy depleted and exhibit chronic metabolic stress. Underlying the metabolic stress are low levels of glucose and monocarboxylate transporters that compromise axon metabolism by limiting substrate availability. Axonal metabolic decline was reversed by upregulating monocarboxylate transporters as a result of placing the animals on a ketogenic diet. Optic nerve mitochondria responded capably to the oxidative phosphorylation necessitated by the diet and showed increased number. These findings indicate that the source of metabolic challenge can occur upstream of mitochondrial dysfunction. Importantly, the intervention was successful despite the animals being on the cusp of significant glaucoma progression.
Harun-Or-Rashid Mohammad; Pappenhagen Nate; Palmer Peter G; Smith Matthew A; Gevorgyan Victoria; Wilson Gina N; Crish Samuel D; Inman Denise M
The Journal of neuroscience : the official journal of the Society for Neuroscience
2018
2018-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1523/JNEUROSCI.3652-17.2018" target="_blank" rel="noreferrer noopener">10.1523/JNEUROSCI.3652-17.2018</a>
The anti-parkinsonian drug zonisamide reduces neuroinflammation: Role of microglial Nav 1.6.
*gp91(phox); *Microglia; *MPTP; *Na(v)1.6; *Neuroinflammation; *Parkinson's disease; *TNF-alpha; *Voltage-gated sodium channels; *Zonisamide
Parkinson's disease (PD), the second most common age-related progressive neurodegenerative disorder, is characterized by dopamine depletion and the loss of dopaminergic (DA) neurons with accompanying neuroinflammation. Zonisamide is an-anti-convulsant drug that has recently been shown to improve clinical symptoms of PD through its inhibition of monoamine oxidase B (MAO-B). However, zonisamide has additional targets, including voltage-gated sodium channels (Nav), which may contribute to its reported neuroprotective role in preclinical models of PD. Here, we report that Nav1.6 is highly expressed in microglia of post-mortem PD brain and of mice treated with the parkinsonism-inducing neurotoxin MPTP. Administration of zonisamide (20mg/kg, i.p. every 4hx3) following a single injection of MPTP (12.5mg/kg, s.c.) reduced microglial Nav 1.6 and microglial activation in the striatum, as indicated by Iba-1 staining and mRNA expression of F4/80. MPTP increased the levels of the pro-inflammatory cytokine TNF-alpha and gp91(phox), and this was significantly reduced by zonisamide. Together, these findings suggest that zonisamide may reduce neuroinflammation through the down-regulation of microglial Nav 1.6. Thus, in addition to its effects on parkinsonian symptoms through inhibition of MAO-B, zonisamide may have disease modifying potential through the inhibition of Nav 1.6 and neuroinflammation.
Hossain Muhammad M; Weig Blair; Reuhl Kenneth; Gearing Marla; Wu Long-Jun; Richardson Jason R
Experimental neurology
2018
2018-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.expneurol.2018.07.005" target="_blank" rel="noreferrer noopener">10.1016/j.expneurol.2018.07.005</a>
Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR.
Humans; Male; Animals; Mice; *Atherosclerosis; *Farnesoid X receptor; *NAFLD; *Obesity; *TGR5; Diet; Hep G2 Cells; Receptors; Inbred C57BL; High-Fat/adverse effects; Cytoplasmic and Nuclear/*agonists; Bile Acids and Salts/pharmacology/*therapeutic use; Hypercholesterolemia/*drug therapy/etiology/metabolism; Non-alcoholic Fatty Liver Disease/*drug therapy/etiology/metabolism; Obesity/*drug therapy/etiology/metabolism; G-Protein-Coupled/*agonists
OBJECTIVES: Activation of the bile acid (BA) receptors farnesoid X receptor (FXR) or G protein-coupled bile acid receptor (GPBAR1; TGR5) improves metabolic homeostasis. In this study, we aim to determine the impact of pharmacological activation of bile acid receptors by INT-767 on reversal of diet-induced metabolic disorders, and the relative contribution of FXR vs. TGR5 to INT-767's effects on metabolic parameters. METHODS: Wild-type (WT), Tgr5(-/-), Fxr(-/-), Apoe(-/-) and Shp(-/-) mice were used to investigate whether and how BA receptor activation by INT-767, a semisynthetic agonist for both FXR and TGR5, could reverse diet-induced metabolic disorders. RESULTS: INT-767 reversed HFD-induced obesity dependent on activation of both TGR5 and FXR and also reversed the development of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Mechanistically, INT-767 improved hypercholesterolemia by activation of FXR and induced thermogenic genes via activation of TGR5 and/or FXR. Furthermore, INT-767 inhibited several lipogenic genes and de novo lipogenesis in the liver via activation of FXR. We identified peroxisome proliferation-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (CEBPalpha) as novel
Jadhav Kavita; Xu Yang; Xu Yanyong; Li Yuanyuan; Xu Jiesi; Zhu Yingdong; Adorini Luciano; Lee Yoon Kwang; Kasumov Takhar; Yin Liya; Zhang Yanqiao
Molecular metabolism
2018
2018-03
<a href="http://doi.org/10.1016/j.molmet.2018.01.005" target="_blank" rel="noreferrer noopener">10.1016/j.molmet.2018.01.005</a>
Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR.
*Atherosclerosis; *Farnesoid X receptor; *NAFLD; *Obesity; *TGR5
OBJECTIVES: Activation of the bile acid (BA) receptors farnesoid X receptor (FXR) or G protein-coupled bile acid receptor (GPBAR1; TGR5) improves metabolic homeostasis. In this study, we aim to determine the impact of pharmacological activation of bile acid receptors by INT-767 on reversal of diet-induced metabolic disorders, and the relative contribution of FXR vs. TGR5 to INT-767's effects on metabolic parameters. METHODS: Wild-type (WT), Tgr5(-/-), Fxr(-/-), Apoe(-/-) and Shp(-/-) mice were used to investigate whether and how BA receptor activation by INT-767, a semisynthetic agonist for both FXR and TGR5, could reverse diet-induced metabolic disorders. RESULTS: INT-767 reversed HFD-induced obesity dependent on activation of both TGR5 and FXR and also reversed the development of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Mechanistically, INT-767 improved hypercholesterolemia by activation of FXR and induced thermogenic genes via activation of TGR5 and/or FXR. Furthermore, INT-767 inhibited several lipogenic genes and de novo lipogenesis in the liver via activation of FXR. We identified peroxisome proliferation-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (CEBPalpha) as novel
Jadhav Kavita; Xu Yang; Xu Yanyong; Li Yuanyuan; Xu Jiesi; Zhu Yingdong; Adorini Luciano; Lee Yoon-Kwang; Kasumov Takhar; Yin Liya; Zhang Yanqiao
Molecular metabolism
2018
2018-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.molmet.2018.01.005" target="_blank" rel="noreferrer noopener">10.1016/j.molmet.2018.01.005</a>
Mineralocorticoid Receptor Antagonist Utilization in a Nationally Representative Heart Failure With Reduced Ejection Fraction Outpatient Population: A Cross-Sectional Study.
BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) improve survival among patients with heart failure with reduced ejection fraction (HFrEF); however, studies have identified low utilization rates. No study has evaluated the prevalence and predictors of MRA prescribing in a nationally representative outpatient cohort. STUDY QUESTION: What is the prevalence and predictors of MRA prescribing among outpatients with HFrEF in the United States? STUDY DESIGN: A national cross-sectional secondary analysis of the National Ambulatory Medical Care Survey from 2007 to 2014 including all office visits for HFrEF in patients aged \textgreater55 years. Office visits involving patients with any history of chronic renal failure and hyperkalemia were excluded. MEASURES AND OUTCOMES: The primary end point was the MRA prescribing rate. Multivariable logistic regression models were created to identify predictors of use. RESULTS: In total, 1259 visits were eligible for inclusion, representing more than 30 million visits when weighted. MRAs were initiated or continued in 11.1% of HFrEF visits (95% confidence interval [CI] 8.8-13.8). In the full model, predictors included diabetes mellitus (OR 2.27; 95% CI 1.12-4.61), Northeast region (OR 0.20; 95% CI 0.05-0.74), and \textgreater/=4 chronic conditions (OR 0.26; 95% CI 0.10-0.71). Among symptomatic patients, predictors included non-Hispanic black patients (OR 4.55; 95% CI 1.81-11.43), patients aged 65-74 years (OR 3.38; 95% CI 1.53-7.44), and office systolic blood pressure \textgreater130 mm Hg (OR 0.31; 95% CI 0.16-0.60). Physician specialty, visit year, patient sex, and payor type were not significant predictors of MRA utilization. CONCLUSIONS: Although significant data support the use of MRA in HFrEF, utilization is lower than previously estimated.
Joyner Kayla Rena; Soric Mate Michael; Boyle Jaclyn Ann; Moorman John Michael; Fredrickson Mary Elizabeth; Turosky Jodie Zlotnik; Kleven Casondra Lee
American Journal of Therapeutics
2018
2018-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1097/MJT.0000000000000823" target="_blank" rel="noreferrer noopener">10.1097/MJT.0000000000000823</a>
Glycation Reduces the Stability of ApoAI and Increases HDL Dysfunction in Diet-Controlled Type 2 Diabetes.
Adult; Aged; Animal Studies; Animals; Apolipoprotein A-I/blood/*metabolism; Apolipoproteins – Blood; Apolipoproteins – Metabolism; Biochemical Phenomena; Case Control Studies; Case-Control Studies; Cells; Comparative Studies; Cultured; Diabetes Mellitus; Diet; Dyslipidemias/complications/diet therapy/*metabolism; Evaluation Research; Female; Funding Source; Glycosylation; HDL – Metabolism; HDL/*metabolism; Human; Humans; Hyperglycemia – Complications; Hyperglycemia – Diet Therapy; Hyperglycemia – Metabolism; Hyperglycemia/complications/diet therapy/*metabolism; Hyperlipidemia – Complications; Hyperlipidemia – Diet Therapy; Hyperlipidemia – Metabolism; Lipoproteins; Male; Mice; Middle Age; Middle Aged; Multicenter Studies; Protein Stability; Type 2 – Complications; Type 2 – Diet Therapy; Type 2 – Metabolism; Type 2/complications/*diet therapy/metabolism; Validation Studies
Context: Hyperglycemia plays a key role in the pathogenesis of cardiovascular complications of diabetes. Type 2 diabetes mellitus (T2DM) is associated with high-density lipoprotein (HDL) dysfunction and increased degradation of apolipoprotein I (ApoAI). The mechanism(s) of these changes is largely unknown. Objective: To study the role of hyperglycemia-induced glycation on ApoAI kinetics and stability in patients with diet-controlled T2DM. Design: 2H2O-metabolic labeling approach was used to study ApoAI turnover in patients with diet-controlled T2DM [n = 9 (5 F); 59.3 +/- 8.5 years] and matched healthy controls [n = 8 (4 F); 50.7 +/- 11.6 years]. The effect of Amadori glycation on in vivo ApoAI stability and the antioxidant and cholesterol efflux properties of HDL were assessed using a proteomics approach and in vitro assays. Results: Patients with T2DM had increased turnover of ApoAI and impaired cholesterol efflux and antioxidant properties of HDL. Glycated hemoglobin was negatively correlated with the half-life of ApoAI and cholesterol efflux function of HDL. Proteomics analysis identified several nonenzymatic early (Amadori) glycations of ApoAI at lysine sites. The kinetics analysis of glycated and native ApoAI peptides in patients with T2DM revealed that glycation resulted in a threefold shorter ApoAI half-life. Conclusions: The 2H2O method allowed the detection of early in vivo impairments in HDL metabolism and function that were related to hyperglycemia-induced glycation of ApoAI in T2DM.
Kashyap Sangeeta R; Osme Abdullah; Ilchenko Serguei; Golizeh Makan; Lee Kwangwon; Wang Shuhui; Bena James; Previs Stephen F; Smith Jonathan D; Kasumov Takhar
The Journal of clinical endocrinology and metabolism
2018
2018-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1210/jc.2017-01551" target="_blank" rel="noreferrer noopener">10.1210/jc.2017-01551</a>
Management of Phenobarbital and Apixaban Interaction in Recurrent Cardioembolic Stroke.
King Philip K; Stump Trevor A; Walkama Allyn M; Ash Benjamin M; Bowling Susana M
Annals of Pharmacotherapy
2018
2018-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1177/1060028018759938" target="_blank" rel="noreferrer noopener">10.1177/1060028018759938</a>
Hepatic Mitochondrial Defects in a Nonalcoholic Fatty Liver Disease Mouse Model Are Associated with Increased Degradation of Oxidative Phosphorylation Subunits.
Energy metabolism; heavy water; Mass Spectrometry; metabolic labeling; Mitochondria function or biology; oxidative phosphorylation; Oxidative stress; Protein Degradation; Protein Turnover
Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic mitochondrial dysfunction characterized by reduced ATP synthesis. We applied the (2)H2O-metabolic labeling approach to test the hypothesis that the reduced stability of oxidative phosphorylation proteins contributes to mitochondrial dysfunction in a diet-induced mouse model of NAFLD. A high fat diet containing cholesterol (a so-called Western diet (WD)) led to hepatic oxidative stress, steatosis, inflammation and mild fibrosis, all markers of NAFLD, in low density cholesterol (LDL) receptor deficient (LDLR(-/-)) mice. In addition, compared with controls (LDLR(-/-) mice on normal diet), livers from NAFLD mice had reduced citrate synthase activity and ATP content, suggesting mitochondrial impairment. Proteome dynamics study revealed that mitochondrial defects are associated with reduced average half-lives of mitochondrial proteins in NAFLD mice (5.41 +/- 0.46 versus 5.15 +/- 0.49 day, p \textless 0.05). In particular, the WD reduced stability of oxidative phosphorylation subunits, including cytochrome b-c1 complex subunit 1 (5.9 +/- 0.1 versus 3.4 +/- 0.8 day), ATP synthase subunit alpha (6.3 +/- 0.4 versus 5.5 +/- 0.4 day) and ATP synthase F(0) complex subunit B1 of complex V (8.5 +/- 0.6 versus 6.5 +/- 0.2 day) (p \textless 0.05). These changes were associated with impaired complex III and F0F1-ATP synthase activities. Markers of mitophagy were increased, but proteasomal degradation activity were reduced in NAFLD mice liver, suggesting that ATP deficiency because of reduced stability of oxidative phosphorylation complex subunits contributed to inhibition of ubiquitin-proteasome and activation of mitophagy. In conclusion, the (2)H2O-metabolic labeling approach shows that increased degradation of hepatic oxidative phosphorylation subunits contributed to mitochondrial impairment in NAFLD mice.
Lee Kwangwon; Haddad Andrew; Osme Abdullah; Kim Chunki; Borzou Ahmad; Ilchenko Sergei; Allende Daniela; Dasarathy Srinivasan; McCullough Arthur; Sadygov Rovshan G; Kasumov Takhar
Molecular & cellular proteomics : MCP
2018
2018-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1074/mcp.RA118.000961" target="_blank" rel="noreferrer noopener">10.1074/mcp.RA118.000961</a>
Dyslipidemia Alters HDL Metabolism and Function in NAFLD
Gastroenterology & Hepatology
McCullough A J; Kim C; Osme A; Lee K; Dasarathy J; Dasarathy S; Kasumov T
Hepatology
2018
2018-10
Journal Article or Conference Abstract Publication
n/a
Stable isotope-based flux studies in nonalcoholic fatty liver disease.
*Citric acid cycle; *Fatty acid oxidation; *Fibrosis; *NAFLD; *Oxidative stress; *Stable isotopes; Animals; Humans; Isotopes/metabolism; Mass Spectrometry/*methods; Non-alcoholic Fatty Liver Disease/*metabolism
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with the worldwide epidemics of obesity, diabetes and cardiovascular diseases. NAFLD ranges from benign fat accumulation in the liver (steatosis) to non-alcoholic steatohepatitis (NASH), and cirrhosis which can progress to hepatocellular carcinoma and liver failure. Mass spectrometry and magnetic resonance spectroscopy-coupled stable isotope-based flux studies provide new insights into the understanding of NAFLD pathogenesis and the disease progression. This review focuses mainly on the utilization of mass spectrometry-based methods for the understanding of metabolic abnormalities in the different stages of NAFLD. For example, stable isotope-based flux studies demonstrated multi-organ insulin resistance, dysregulated glucose, lipids and lipoprotein metabolism in patients with NAFLD. We also review recent developments in the stable isotope-based technologies for the study of mitochondrial dysfunction, oxidative stress and fibrogenesis in NAFLD. We highlight the limitations of current methodologies, discuss the emerging areas of research in this field, and future directions for the applications of stable isotopes to study NAFLD and its complications.
McCullough Arthur; Previs Stephen; Kasumov Takhar
Pharmacology & therapeutics
2018
2018-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.pharmthera.2017.07.008" target="_blank" rel="noreferrer noopener">10.1016/j.pharmthera.2017.07.008</a>
Transport of a manganese/zinc ethylene-bis-dithiocarbamate fungicide may involve pre-synaptic dopaminergic transporters
C. elegans; Toxicology; Neurosciences & Neurology; parkinsons-disease; exposure; degeneration; costa-rica; pregnant-women; antidepressant; caenorhabditis-elegans; infants environmental-health; leads; Mancozeb; Mancozeb; Manzate; Mn/Zn ethylene-bis-dithiocarbamate; Neurotransmitter transporters; Neurotransmitters
Mancozeb (MZ), an organic-metal fungicide used predominantly on vegetables and fruits, has been linked to neurodegeneration and behavioral disruptions in a variety of organisms, including humans. Both gamma-aminobutyric acid and dopamine neurons appear to be more vulnerable to MZ exposure than other neuronal populations. Based on these observations, we hypothesized that MZ may be differentially transported into these cells through their presynaptic neurotransmitter transporters. To test this, we pretreated Caenorhabditis elegans with transporter antagonists followed by exposure to various concentrations of MZ. Potential neuroprotection was monitored via green fluorescence associated with various neuron populations in transgenic worm strains. Neurodegeneration associated with subacute MZ treatment (30 min) was not altered by transporter antagonist pretreatment. On the other hand, pretreatment with a dopamine transporter antagonist (GBR12909) appeared to protect dopaminergic neurons from chronic (24 h) MZ treatment. These results are consistent with other reports that dopamine transporter levels or activity may modulate toxicity for neurotoxicants.
Montgomery K; Corona C; Frye R; Barnett R; Bailey A; Fitsanakis V A
Neurotoxicology and Teratology
2018
2018-07
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.ntt.2018.05.004" target="_blank" rel="noreferrer noopener">10.1016/j.ntt.2018.05.004</a>
Novel compounds that target lipoprotein lipase and mediate growth arrest in acute lymphoblastic leukemia.
*Acute lymphoblastic leukemia; *Cancer; *Co-culture model; *Lipids; *Lipoprotein lipase; *Metabolism; Amides/chemistry/metabolism/pharmacology; Antineoplastic Agents/*chemistry/metabolism/pharmacology; Binding Sites; Cell Line; Cell Proliferation/drug effects; Coculture Techniques; Dyslipidemias/complications/metabolism/pathology; Humans; Lipoprotein Lipase/antagonists & inhibitors/*metabolism; Mesenchymal Stem Cells/cytology/metabolism; Molecular Docking Simulation; Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications/metabolism/pathology; Protein Binding; Protein Structure; Serum Albumin/chemistry/metabolism; Tertiary; Tumor
Over the past decade, the therapeutic strategies employed to treat B-precursor acute lymphoblastic leukemia (ALL) have been progressively successful in treating the disease. Unfortunately, the treatment associated dyslipidemia, either acute or chronic, is very prevalent and a cause for decreased quality of life in the surviving patients. To overcome this hurdle, we tested a series of cylopropanecarboxamides, a family demonstrated to target lipid metabolism, for their anti-leukemic activity in ALL. Several of the compounds tested showed anti-proliferative activity, with one, compound 22, inhibiting both Philadelphia chromosome negative REH and Philadelphia chromosome positive SupB15 ALL cell division. The novel advantage of these compounds is the potential synergy with standard chemotherapeutic agents, while concomitantly blunting the emergence of dyslipidemia. Thus, the cylopropanecarboxamides represent a novel class of compounds that can be potentially used in combination with the present standard-of-care to limit treatment associated dyslipidemia in ALL patients.
Nair Rajesh R; Geldenhuys Werner J; Piktel Debbie; Sadana Prabodh; Gibson Laura F
Bioorganic & medicinal chemistry letters
2018
2018-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2018.03.061" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2018.03.061</a>
The glycoprotein GPNMB attenuates astrocyte inflammatory responses through the CD44 receptor.
Astrocyte; CD44; GPNMB; Neuroinflammation; Parkinson's disease
BACKGROUND: Neuroinflammation is one of the hallmarks of neurodegenerative diseases, such as Parkinson's disease (PD). Activation of glial cells, including microglia and astrocytes, is a characteristic of the inflammatory response. Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane glycoprotein that releases a soluble signaling peptide when cleaved by ADAM10 or other extracellular proteases. GPNMB has demonstrated a neuroprotective role in animal models of ALS and ischemia. However, the mechanism of this protection has not been well established. CD44 is a receptor expressed on astrocytes that can bind GPNMB, and CD44 activation has been demonstrated to reduce NFkappaB activation and subsequent inflammatory responses in macrophages. GPNMB signaling has not been investigated in models of PD or specifically in astrocytes. More recently, genetic studies have linked polymorphisms in GPNMB with risk for PD. Therefore, it is important to understand the role this signaling protein plays in PD. METHODS: We used data mining techniques to evaluate mRNA expression of GPNMB and its receptor CD44 in the substantia nigra of PD and control brains. Immunofluorescence and qPCR techniques were used to assess GPNMB and CD44 levels in mice treated with MPTP. In vitro experiments utilized the immortalized mouse astrocyte cell line IMA2.1 and purified primary mouse astrocytes. The effects of recombinant GPNMB on cytokine-induced astrocyte activation was determined by qPCR, immunofluorescence, and measurement of nitric oxide and reactive oxygen production. RESULTS: Increased GPNMB and CD44 expression was observed in the substantia nigra of human PD brains and in GFAP-positive astrocytes in an animal model of PD. GPNMB treatment attenuated cytokine-induced levels of inducible nitric oxide synthase, nitric oxide, reactive oxygen species, and the inflammatory cytokine IL-6 in an astrocyte cell line and primary mouse astrocytes. Using primary mouse astrocytes from CD44 knockout mice, we found that the anti-inflammatory effects of GPNMB are CD44-mediated. CONCLUSIONS: These results demonstrate that GPNMB may exert its neuroprotective effect through reducing astrocyte-mediated neuroinflammation in a CD44-dependent manner, providing novel mechanistic insight into the neuroprotective properties of GPNMB.
Neal Matthew L; Boyle Alexa M; Budge Kevin M; Safadi Fayez F; Richardson Jason R
Journal of neuroinflammation
2018
2018-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s12974-018-1100-1" target="_blank" rel="noreferrer noopener">10.1186/s12974-018-1100-1</a>
Epigenetic regulation of astrocyte function in neuroinflammation and neurodegeneration.
*Astrocyte; *DNA methylation; *Epigenesis; *Epigenetic; *Histone; *Neurodegeneration; *Neuroinflammation; Acetylation; Alzheimer Disease/genetics/pathology; Animals; Astrocytes/*cytology/immunology; Cell Differentiation; DNA Methylation; Genetic; Histones/metabolism; Humans; Inflammation/*pathology; Methylation; MicroRNAs/metabolism; Neurodegenerative Diseases/genetics/*pathology; Neuroglia/metabolism; Neurons/immunology; Parkinson Disease/genetics/pathology
Epigenetic mechanisms control various functions throughout the body, from cell fate determination in development to immune responses and inflammation. Neuroinflammation is one of the prime contributors to the initiation and progression of neurodegeneration in a variety of diseases, including Alzheimer's and Parkinson's diseases. Because astrocytes are the largest population of glial cells, they represent an important regulator of CNS function, both in health and disease. Only recently have studies begun to identify the epigenetic mechanisms regulating astrocyte responses in neurodegenerative diseases. These epigenetic mechanisms, along with the epigenetic marks involved in astrocyte development, could elucidate novel pathways to potentially modulate astrocyte-mediated neuroinflammation and neurotoxicity. This review examines the known epigenetic mechanisms involved in regulation of astrocyte function, from development to neurodegeneration, and links these mechanisms to potential astrocyte-specific roles in neurodegenerative disease with a focus on potential opportunities for therapeutic intervention.
Neal Matthew; Richardson Jason R
Biochimica et biophysica acta. Molecular basis of disease
2018
2018-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bbadis.2017.11.004" target="_blank" rel="noreferrer noopener">10.1016/j.bbadis.2017.11.004</a>
Time to get Personal: A Framework for Personalized Targeting of Oxidative Stress in Neurotoxicity and Neurodegenerative Disease.
The annual cost for neurological disorders in the United States was $789 billion in 2014, and with an aging population these numbers are expected to significantly increase in the next 50 years [1]. Neurodegenerative diseases make up a significant portion of these costs. Neurodegenerative diseases are characterized by the loss of neuronal populations in specific regions of the brain. Although the cause is still unknown for most of these diseases, both genetic and environmental factors are thought to play important roles. There are multiple convergent mechanisms underlying the unique susceptibility of neurons to degeneration, including aging, inflammation, mitochondrial dysfunction, and oxidative stress. Oxidative stress (OS) is of particular importance because evidence indicates that the neuronal populations lost in neurodegenerative diseases are particular susceptible to OS. OS is a complex neurotoxic mechanism that arises from excessive generation of free radicals such as reactive oxygen species (ROS), reduction in anti-oxidant factors, or a combination of the two. A complex interplay between the endogenous susceptibility of the brain, genetic factors, and environmental exposures leads to the harmful generation of OS in the brain and contributes significantly to the initiation and/or progression of neurodegeneration. Unfortunately, therapeutics for neurodegenerative diseases have consistently failed in clinical trials. Thus, a better understanding of the interplay between genetic susceptibility and common molecular mechanisms of environmental contributors to OS generation could aid in elucidation of novel therapeutic strategies for neurodegenerative diseases. This review will explore the current picture of oxidative stress in the brain as it relates to neurotoxicity, specifically exploring common mechanisms behind the endogenous susceptibility of the brain to OS, genetic susceptibility and environmental exposures leading to neurotoxicity, to identify precision/personalized medicine approaches for improving therapeutic outcome.
Neal Matthew; Richardson Jason R
Current opinion in toxicology
2018
2018-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.cotox.2018.02.003" target="_blank" rel="noreferrer noopener">10.1016/j.cotox.2018.02.003</a>
Overcoming missed opportunities in diabetes management to improve outcomes for hospitalized patients with diabetes.
Aged; Blood Glucose/*metabolism; Cohort Studies; Diabetes Mellitus; Female; Glycated Hemoglobin A/*metabolism; Hospitalization; Humans; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Type 2/*drug therapy
AIMS: The purpose of this study is to assess the impact of hospitalization on
Oravec Michael; Salem James; Kunz Jason; Cudnik Michelle L; Clough Lynn; Woods Robert; Elavsky Megan
Diabetes research and clinical practice
2018
2018-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.diabres.2018.04.020" target="_blank" rel="noreferrer noopener">10.1016/j.diabres.2018.04.020</a>
Changes in ganglioside GM1 expression in glaucomic retina.
Pappenhagen Nate; Inman Denise M
Journal of neuroscience research
2018
2018-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/jnr.24273" target="_blank" rel="noreferrer noopener">10.1002/jnr.24273</a>
Retinal amyloid pathology requires CD36 receptors
Ophthalmology
Plyler E; Smith M A; Richardson J R; Dengler-Crish C M; Crish S D
Investigative Ophthalmology & Visual Science
2018
2018-07
Journal Article
n/a
Assessment of a structured longitudinal professional identity development curriculum for pharmacy students.
Professional development; Professional identity; Student pharmacist development
BACKGROUND AND PURPOSE: To describe and assess a longitudinal Professional Identity Development (PID) curriculum at Northeast Ohio Medical Universities (NEOMED) College of Pharmacy. EDUCATIONAL ACTIVITY AND SETTING: Northeast Ohio Medical University, a four-year professional program, has assimilated its career development and advising program into the curriculum as a primary element of the Pharmacist Patient Care Experience (PPCE) course. The concept of PID focuses on student pharmacist career development. The goals for the PID module include guided self-assessment and goal-setting related to career choice with attention to work-life balance, community engagement and leadership. Students also work in small groups, called Professional Development Advising Teams (PDAT), led by a PDAT clinical advisor who is a practicing pharmacist. These meetings provide a forum to debrief self-assessment work and clinical experiences and make connections between the two. FINDINGS: A voluntary survey was administered to six classes of NEOMED alumni (2011-2016) to evaluate the longitudinal PID curriculum. Respondents found many aspects of the PID curriculum to be beneficial in the development of their professional identity and career planning journey. Most felt that PID sessions enabled them to effectively prepare for a career in pharmacy, with goal setting, Curriculum Vitae (CV) review, and career exploration most helpful in planning for their future careers. DISCUSSION: PID curricula are resource-intensive and require a firm commitment from administration and the faculty. Elements of the program can be adapted and utilized in a variety of different ways, making this model accessible to all pharmacy schools.
Pokorny Anita; Boyle Jaclyn; Hoffman Alexander; Coffey Cory P; Schneider Stacey
Currents in pharmacy teaching & learning
2018
2018-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.cptl.2018.08.007" target="_blank" rel="noreferrer noopener">10.1016/j.cptl.2018.08.007</a>
d2ome, Software for in Vivo Protein Turnover Analysis Using Heavy Water Labeling and LC-MS, Reveals Alterations of Hepatic Proteome Dynamics in a Mouse Model of NAFLD
40S ribosomal proteins; algorithm; amino-acids; Biochemistry & Molecular Biology; dna; in vivo protein turnover; isotopomer; Mass spectrometry; metabolic labeling; NAFLD; nonlinear least-squares modeling; peak detection and integration; proliferation; protein half-life; proteome dynamics; proteostasis; quantification; rates; respiratory-chain; steatosis; UPR
Metabolic labeling with heavy water followed by LC-MS is a high throughput approach to study proteostasis in vivo. Advances in mass spectrometry and sample processing have allowed consistent detection of thousands of proteins at multiple time points. However, freely available automated bioinformatics tools to analyze and extract protein decay rate constants are lacking. Here, we describe d2ome-a robust, automated software solution for in vivo protein turnover analysis. d2ome is highly scalable, uses innovative approaches to nonlinear fitting, implements Grubbs' outlier detection and removal, uses weighted-averaging of replicates, applies a data dependent elution time windowing, and uses mass accuracy in peak detection. Here, we discuss the application of d2ome in a comparative study of protein turnover in the livers of normal vs Western diet-fed LDLR-/- mice (mouse model of nonalcoholic fatty liver disease), which contained 256 LC-MS experiments. The study revealed reduced stability of 40S ribosomal protein subunits in the Western diet-fed mice.
Sadygov R G; Avva J; Rahman M; Lee K; Ilchenko S; Kasumov T; Borzou A
Journal of Proteome Research
2018
2018-11
Journal Article
<a href="http://doi.org/10.1021/acs.jproteorne.8b00417" target="_blank" rel="noreferrer noopener">10.1021/acs.jproteorne.8b00417</a>
d2ome, Software for in Vivo Protein Turnover Analysis Using Heavy Water Labeling and LC-MS, Reveals Alterations of Hepatic Proteome Dynamics in a Mouse Model of NAFLD.
40S ribosomal proteins; in vivo protein turnover; isotopomer quantification; metabolic labeling; NAFLD; nonlinear least-squares modeling; peak detection and integration; protein half-life; proteome dynamics; UPR
Metabolic labeling with heavy water followed by LC-MS is a high throughput approach to study proteostasis in vivo. Advances in mass spectrometry and sample processing have allowed consistent detection of thousands of proteins at multiple time points. However, freely available automated bioinformatics tools to analyze and extract protein decay rate constants are lacking. Here, we describe d2ome-a robust, automated software solution for in vivo protein turnover analysis. d2ome is highly scalable, uses innovative approaches to nonlinear fitting, implements Grubbs' outlier detection and removal, uses weighted-averaging of replicates, applies a data dependent elution time windowing, and uses mass accuracy in peak detection. Here, we discuss the application of d2ome in a comparative study of protein turnover in the livers of normal vs Western diet-fed LDLR(-/-) mice (mouse model of nonalcoholic fatty liver disease), which contained 256 LC-MS experiments. The study revealed reduced stability of 40S ribosomal protein subunits in the Western diet-fed mice.
Sadygov Rovshan G; Avva Jayant; Rahman Mahbubur; Lee Kwangwon; Ilchenko Sergei; Kasumov Takhar; Borzou Ahmad
Journal of proteome research
2018
2018-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1021/acs.jproteome.8b00417" target="_blank" rel="noreferrer noopener">10.1021/acs.jproteome.8b00417</a>
Detection of single mRNAs in individual cells of the auditory system.
Cochlea; Immunohistochemistry; Inner hair cell; Outer hair cell; Single-molecule fluorescence in situ hybridization; Spiral ganglion neuron
Gene expression analysis is essential for understanding the rich repertoire of cellular functions. With the development of sensitive molecular tools such as single-cell RNA sequencing, extensive gene expression data can be obtained and analyzed from various tissues. Single-molecule fluorescence in situ hybridization (smFISH) has emerged as a powerful complementary tool for single-cell genomics studies because of its ability to map and quantify the spatial distributions of single mRNAs at the subcellular level in their native tissue. Here, we present a detailed method to study the copy numbers and spatial localizations of single mRNAs in the cochlea and inferior colliculus. First, we demonstrate that smFISH can be performed successfully in adult cochlear tissue after decalcification. Second, we show that the smFISH signals can be detected with high specificity. Third, we adapt an automated transcript analysis pipeline to quantify and identify single mRNAs in a cell-specific manner. Lastly, we show that our method can be used to study possible correlations between transcriptional and translational activities of single genes. Thus, we have developed a detailed smFISH protocol that can be used to study the expression of single mRNAs in specific cell types of the peripheral and central auditory systems.
Salehi Pezhman; Nelson Charlie N; Chen Yingying; Lei Debin; Crish Samuel D; Nelson Jovitha; Zuo Hongyan; Bao Jianxin
Hearing research
2018
2018-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.heares.2018.07.008" target="_blank" rel="noreferrer noopener">10.1016/j.heares.2018.07.008</a>