180 results on '"Robert A. Yokel"'
Search Results
52. In Vivo Processing of Ceria Nanoparticles inside Liver: Impact on Free-Radical Scavenging Activity and Oxidative Stress
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Alan Dozier, Eric A. Grulke, D. Allan Butterfield, Jason M. Unrine, Sarita S. Hardas, Rukhsana Sultana, Burtron H. Davis, Uschi M. Graham, Michael T. Tseng, Jacek B. Jasinski, and Robert A. Yokel
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Free Radical Scavenging Activity ,Chemistry ,Nanoparticle ,Nanotechnology ,General Chemistry ,medicine.disease_cause ,Redox ,Article ,In vivo ,Biophysics ,medicine ,Solubility ,Cytotoxicity ,Oxidative stress - Abstract
The cytotoxicity of ceria ultimately lies in its electronic structure, which is defined by the crystal structure, composition, and size. Despite previous studies focused on ceria uptake, distribution, biopersistance, and cellular effects, little is known about its chemical and structural stability and solubility once sequestered inside the liver. Mechanisms will be presented that elucidate the in vivo transformation in the liver. In vivo processed ceria reveals a particle-size effect towards the formation of ultrafines, which represent a second generation of ceria. A measurable change in the valence reduction of the second-generation ceria can be linked to an increased free-radical scavenging potential. The in vivo processing of the ceria nanoparticles in the liver occurs in temporal relation to the brain cellular and protein clearance responses that stem from the ceria uptake. This information is critical to establish a possible link between cellular processes and the observed in vivo transformation of ceria. The temporal linkage between the reversal of the pro-oxidant effect (brain) and ceria transformation (liver) suggests a cause-effect relationship.
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- 2015
53. Aluminum
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Robert A. Yokel, Bengt Sjögren, Anders Iregren, and Johan Montelius
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inorganic chemicals ,Gastrointestinal tract ,Inhalation ,business.industry ,Developmental toxicity ,Physiology ,Urine ,Dialysis Encephalopathy ,medicine.disease ,complex mixtures ,Excretion ,Aluminum can ,Pulmonary fibrosis ,medicine ,business - Abstract
Aluminum is ubiquitous in the environment. Its proportion of the Earth’s crust is about 8%. Aluminum can be absorbed from the gastrointestinal tract and from the lungs. Excretion is mainly through the kidneys, probably as aluminum citrate. Aluminum is a well-known neurotoxicant. Significant accumulation in the human body has been related to the presence of aluminum in dialysis fluids and the concomitant intake of aluminum-containing drugs by those with significant renal impairment and to occupational exposure in some industrial settings. Accumulation in patients with renal impairment has resulted in dialysis encephalopathy that was often fatal; this problem is now well recognized and usually avoided. Neurotoxic effects have been observed in welders with aluminum urine concentrations around 100 μg/L. The upper reference limit among nonexposed individuals is 16 μg/L urine. There is no consensus on whether human studies provide sufficient evidence for an association between aluminum and Alzheimer disease. Occupational exposure to aluminum powder has resulted in pulmonary fibrosis. Asthma has been associated with the inhalation of aluminum sulfate, aluminum fluoride, and potassium aluminum tetrafluoride, and exposure to the complex environment in potrooms during electrolytic aluminum production. Cancer and ischemic heart disease have been observed among aluminum production workers. However, it is unlikely that aluminum is the cause of these diseases. Reproductive and developmental toxicity are presented in Chapter 20. Recent reviews on aluminum were written by Krewski et al. (2007), Riihimaki and Aitio (2012), Willhite et al. (2012), DECOS (2010), and NEG (2011).
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- 2015
54. List of Contributors
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Jan Aaseth, Peter Aggett, Antero Aitio, Jan Alexander, Shegufta Ameer, Christian B.I. Andersen, Ole Andersen, Pietro Apostoli, Michael Aschner, Farida Louise Assem, Lars Barregård, David C. Bellinger, Ingvar A. Bergdahl, Maths Berlin, Balázs Berlinger, Alfred Bernard, Carolina Bigert, Poul Bjerregaard, Robyn Blain, Karin Broberg, Jason Brocato, Ronald P. Brown, Esben Budtz-Jørgensen, Samuel W. Caito, Simona Catalani, C.-J. Chen, C.-H. Selene, J. Chou, Max Costa, Todd Davidson, John W. Eaton, Alison Elder, Carl -Gustaf Elinder, Dag G. Ellingsen, Hisham A. El-Masri, Karin Engström, Bengt Fadeel, Obaid M. Faroon, Bruce A. Fowler, Silvia Fustinoni, Lars Gerhardsson, Philippe Grandjean, Per Gustavsson, James S. Holler, Per Hultman, Ivo Iavicoli, Anders Iregren, Marek Jakubowski, Taiyi Jin, Robert L. Jones, Hanna L. Karlsson, George Kazantzis, Qindong Ke, Larry S. Keith, Mirja Kiilunen, Yangho Kim, Catherine Klein, Michael Kleinman, David Kotelchuck, Yukinori Kusaka, Philip J. Landrigan, Sverre Langård, Freda Laulicht, Per E. Leffler, Veruscka Leso, Dominique Lison, Roberto G. Lucchini, Nikki Maples-Reynolds, Daphne B. Moffett, Lisbeth Birk Møller, Johan Montelius, Moiz M. Mumtaz, Koji Nogawa, Gunnar F. Nordberg, Monica Nordberg, Agneta Oskarsson, Elena A. Ostrakhovich, Cezary PałczyŃski, K. Michael Pollard, Prem Ponka, Candace M. Prusiewicz, Patricia Ruiz, Harold H. Sandstead, Tiina Santonen, Marko ŠariĆ, Kazuhiro Sato, Hiroshi Satoh, Mary J. Sexton, Bengt Sjögren, Staffan Skerfving, Donald R. Smith, Dexter W. Sullivan, Jonas Tallkvist, Milton Tenenbein, Muhammet S. Toprak, Carolyn Tylenda, Tomohiro Umemura, Richard P. Wedeen, Robert A. Yokel, and Rudolfs K. Zalups
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- 2015
55. Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration
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Robert A. Yokel
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Organic anion transporter 1 ,Iron ,Calcium pump ,ATP7A ,Blood–brain barrier ,Basement Membrane ,Alzheimer Disease ,medicine ,Humans ,Manganese ,Voltage-dependent calcium channel ,biology ,Chemistry ,General Neuroscience ,Neurodegeneration ,Brain ,Membrane Transport Proteins ,Parkinson Disease ,Transporter ,Mercury ,General Medicine ,medicine.disease ,Zinc ,Psychiatry and Mental health ,Clinical Psychology ,medicine.anatomical_structure ,Biochemistry ,Blood-Brain Barrier ,Nerve Degeneration ,biology.protein ,Biophysics ,Efflux ,Geriatrics and Gerontology ,Copper ,Aluminum - Abstract
The etiology of many neurodegenerative diseases has been only partly attributed to acquired traits, suggesting environmental factors may also contribute. Metal dyshomeostasis causes or has been implicated in many neurodegenerative diseases. Metal flux across the blood-brain barrier (the primary route of brain metal uptake) and the choroid plexuses as well as sensory nerve metal uptake from the nasal cavity are reviewed. Transporters that have been described at the blood-brain barrier are listed to illustrate the extensive possibilities for moving substances into and out of the brain. The controversial role of aluminum in Alzheimer's disease, evidence suggesting brain aluminum uptake by transferrin-receptor mediated endocytosis and of aluminum citrate by system Xc;{-} and an organic anion transporter, and results suggesting transporter-mediated aluminum brain efflux are reviewed. The ability of manganese to produce a parkinsonism-like syndrome, evidence suggesting manganese uptake by transferrin- and non-transferrin-dependent mechanisms which may include store-operated calcium channels, and the lack of transporter-mediated manganese brain efflux, are discussed. The evidence for transferrin-dependent and independent mechanisms of brain iron uptake is presented. The copper transporters, ATP7A and ATP7B, and their roles in Menkes and Wilson's diseases, are summarized. Brain zinc uptake is facilitated by L- and D-histidine, but a transporter, if involved, has not been identified. Brain lead uptake may involve a non-energy-dependent process, store-operated calcium channels, and/or an ATP-dependent calcium pump. Methyl mercury can form a complex with L-cysteine that mimics methionine, enabling its transport by the L system. The putative roles of zinc transporters, ZnT and Zip, in regulating brain zinc are discussed. Although brain uptake mechanisms for some metals have been identified, metal efflux from the brain has received little attention, preventing integration of all processes that contribute to brain metal concentrations.
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- 2006
56. Aluminum bioavailability from the approved food additive leavening agent acidic sodium aluminum phosphate, incorporated into a baked good, is lower than from water
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Rebecca L. Florence and Robert A. Yokel
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Male ,food.ingredient ,Animal feed ,Drinking ,Biological Availability ,chemistry.chemical_element ,Toxicology ,Phosphates ,law.invention ,food ,Pharmacokinetics ,law ,Aluminium ,Animals ,Cooking ,Food science ,Aluminum Compounds ,Salp ,Leavening agent ,Radioisotopes ,biology ,Chemistry ,Spectrophotometry, Atomic ,Food additive ,Water ,Hydrogen-Ion Concentration ,biology.organism_classification ,Animal Feed ,Sodium Compounds ,Rats, Inbred F344 ,Rats ,Bioavailability ,Environmental chemistry ,Food Additives ,Atomic absorption spectroscopy - Abstract
There are estimates of oral aluminum (Al) bioavailability from drinking water, but little information on Al bioavailability from foods. Foods contribute approximately 95% and drinking water 1-2% of the typical human's daily Al intake. The objectives were to estimate oral Al bioavailability from a representative food containing the food additive acidic sodium aluminum phosphate (acidic SALP), a leavening agent in baked goods. Rats were acclimated to a special diet that resulted in no stomach contents 14 h after its withdrawal. They were trained to rapidly consume a biscuit containing 1.5% acidic SALP. Oral Al bioavailability was then determined from a biscuit containing 1% or 2% acidic SALP, synthesized to contain (26)Al. The rats received concurrent (27)Al infusion. Blood was repeatedly withdrawn and serum analyzed for (26)Al by accelerator mass spectrometry. Total Al was determined by atomic absorption spectrometry. Oral (26)Al bioavailability was determined from the area under the (26)Al, compared to (27)Al, serum concentrationxtime curves. Oral Al bioavailability (F) from biscuit containing 1% or 2% acidic (26)Al-SALP averaged approximately 0.11% and 0.13%; significantly less than from water, which was previously shown to be approximately 0.3%. The time to maximum serum (26)Al concentration was 4.2 and 6h after consumption of biscuit containing 1% or 2% (26)Al-acidic SALP, respectively, compared to 1-2h following (26)Al in water. These results of oral Al bioavailability from acidic (26)Al-SALP in a biscuit (F approximately 0.1%) and results from (26)Al in water (F approximately 0.3%) x the contributions of food and drinking water to the typical human's daily Al intake ( approximately 5-10mg from food and 0.1mg from water, respectively) suggest food provides approximately 25-fold more Al to systemic circulation, and potential Al body burden, than does drinking water.
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- 2006
57. The Speciation of Metals in Mammals Influences Their Toxicokinetics and Toxicodynamics and Therefore Human Health Risk Assessment1
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Stephen M. Lasley, David C. Dorman, and Robert A. Yokel
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inorganic chemicals ,Toxicodynamics ,Health, Toxicology and Mutagenesis ,Inorganic chemistry ,chemistry.chemical_element ,Manganese ,Toxicology ,Mercury (element) ,Metal ,Chromium ,chemistry ,Biotransformation ,visual_art ,Environmental chemistry ,visual_art.visual_art_medium ,Toxicokinetics ,Arsenic - Abstract
Chemical form (i.e., species) can influence metal toxicokinetics and toxicodynamics and should be considered to improve human health risk assessment. Factors that influence metal speciation (and examples) include: (1) carrier-mediated processes for specific metal species (arsenic, chromium, lead and manganese), (2) valence state (arsenic, chromium, manganese and mercury), (3) particle size (lead and manganese), (4) the nature of metal binding ligands (aluminum, arsenic, chromium, lead, and manganese), (5) whether the metal is an organic versus inorganic species (arsenic, lead, and mercury), and (6) biotransformation of metal species (aluminum, arsenic, chromium, lead, manganese and mercury). The influence of speciation on metal toxicokinetics and toxicodynamics in mammals, and therefore the adverse effects of metals, is reviewed to illustrate how the physicochemical characteristics of metals and their handling in the body (toxicokinetics) can influence toxicity (toxicodynamics). Generalizing from mercury,...
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- 2006
58. Manganese distribution across the blood–brain barrierIV. Evidence for brain influx through store-operated calcium channels
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Janelle S Crossgrove and Robert A. Yokel
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Male ,Thapsigargin ,chemistry.chemical_element ,Cell Separation ,In Vitro Techniques ,Calcium ,Toxicology ,Blood–brain barrier ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,medicine ,Animals ,Calcium metabolism ,Manganese ,Voltage-dependent calcium channel ,General Neuroscience ,Sodium ,Temperature ,Brain ,Endothelial Cells ,Proteins ,Anatomy ,Calcium Channel Blockers ,Capillaries ,Rats ,Amiloride ,medicine.anatomical_structure ,chemistry ,Blood-Brain Barrier ,Metals ,Biophysics ,Verapamil ,Cattle ,Calcium Channels ,Cyclopiazonic acid ,medicine.drug - Abstract
Manganese (Mn) is a required co-factor for many ubiquitous enzymes; however, chronic Mn overexposure can cause manganism, a parkinsonian-like syndrome. Previous studies showed Mn influx into brain is carrier-mediated, though the putative carrier(s) were not established. Studies conducted with cultured bovine brain microvascular endothelial cells (bBMECs), which comprise the blood-brain barrier, revealed (54)Mn (II) uptake positively correlated with pH, was temperature-dependent, and was sodium- and energy-independent. Brain (54)Mn uptake correlated inversely with calcium (Ca) concentration, but (45)Ca uptake was unaltered by high Mn concentration. Lanthanum (La), a non-selective inhibitor of several Ca channel types, as well as verapamil and amiloride, inhibitors of voltage-operated Ca channels, failed to inhibit Mn uptake into cells. Nickel (Ni), another non-selective inhibitor of several Ca channel types, inhibited Mn and Ca uptake into cells by 88 and 85%, respectively. Cyclopiazonic acid (CPA) and thapsigargin, which activate store-operated calcium channels (SOCCs), increased (54)Mn and (45)Ca uptake into cultured bBMECs. In situ brain perfusion studies were conducted in adult, male Sprague-Dawley rats to verify the cell culture results. Both nickel and verapamil produced a non-significant decrease in Mn and Ca influx. Lanthanum significantly increased Mn influx to 675 and 450% of control in parietal cortex and caudate, respectively, while producing no significant effect on Ca influx. Vanadate, which inhibits Ca-ATPase, inhibited Mn uptake into cultured blood-brain barrier cells, but not into perfused rat brain. Overall these results suggest that both Ca-dependent and Ca-independent mechanisms play a role in brain Mn influx. This work provides evidence that store-operated Ca channels, as well as another mechanism at the blood-brain barrier, likely play a role in carrier-mediated Mn influx into the brain.
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- 2005
59. 26Al-containing acidic and basic sodium aluminum phosphate preparation and use in studies of oral aluminum bioavailability from foods utilizing 26Al as an aluminum tracer
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Robert A. Lodder, Robert A. Yokel, John P. Selegue, Aaron Urbas, and Rebecca L. Florence
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Absorption (pharmacology) ,Nuclear and High Energy Physics ,biology ,Chemistry ,Sodium ,chemistry.chemical_element ,biology.organism_classification ,Bioavailability ,Aluminium ,TRACER ,Organic chemistry ,Sample preparation ,Instrumentation ,Nuclear chemistry ,Leavening agent ,Salp - Abstract
We synthesized 26 Al-containing acidic and basic (alkaline) sodium aluminum phosphates (SALPs) which are FDAapproved leavening and emulsifying agents, respectively, and used them to determine the oral bioavailability of aluminum incorporated in selected foods. We selected applicable methods from published syntheses (patents) and scaled them down (3000- and 850-fold) to prepare 300–400 mg of each SALP. The 26 Al was incorporated at the beginning of the syntheses to maximize 26 Al and 27 Al equilibration and incorporate the 26 Al in the naturally-occurring Al-containing chemical species of the products. Near infrared spectroscopy (NIR) and X-ray powder diffraction (XRD) were used to characterize the two SALP samples and some intermediate samples. Multi-elemental analysis (MEA) was used to determine Na, Al and P content. Commercial products were included for comparison. Satisfactory XRD analyses, near infrared spectra and MEA results confirmed that we synthesized acidic and basic SALP, as well as some of the syntheses intermediates. The 26 Al-containing acidic and basic SALPs were incorporated into a biscuit material and a processed cheese, respectively. These were used in oral bioavailability studies conducted in rats in which the 26 Al present in blood after its oral absorption was quantified by accelerator mass spectrometry. The results showed oral Al bioavailability from acidic SALP in biscuit was 0.02% and from basic SALP in cheese 0.05%, lower than our previous determination of Al bioavailability from drinking water, 0.3%. Both food and water can appreciably contribute to the Al absorbed from typical human Al intake. 2005 Elsevier B.V. All rights reserved.
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- 2005
60. Manganese Distribution Across the Blood–Brain Barrier III The Divalent Metal Transporter-1 is not the Major Mechanism Mediating Brain Manganese Uptake
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Janelle S Crossgrove and Robert A. Yokel
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Male ,Perfusion scanning ,Toxicology ,Blood–brain barrier ,Species Specificity ,Iron-Binding Proteins ,Extracellular fluid ,medicine ,Animals ,Rats, Wistar ,Cation Transport Proteins ,chemistry.chemical_classification ,Manganese ,Chemistry ,General Neuroscience ,Brain ,Endothelial Cells ,Iron-binding proteins ,Transporter ,Rats ,Endothelial stem cell ,medicine.anatomical_structure ,Blood-Brain Barrier ,Transferrin ,Biophysics ,Female ,Neuroscience ,Perfusion - Abstract
Manganese (Mn) is essential for and toxic to the brain. Brain Mn uptake utilizes both diffusion and transporter-mediated pathways. The divalent metal transporter-1 (DMT-1) has been suggested to mediate brain Mn uptake. The b/b Belgrade rat does not express significant amounts of functional DMT-1. In the present work, brain influx transfer coefficients of (54) Mn ion and (54) Mn transferrin (Mn Tf) were determined in b/b and +/b Belgrade and Wistar rats using the in situ brain perfusion technique. Brain Mn uptake was not significantly different among the three rat strains for either Mn species. We hypothesized that Mn may enter brain endothelial cells by a DMT-1-independent process but not be able to distribute across those cells into brain tissue due to the absence of DMT-1 activity. To test this hypothesis the brain capillary endothelial cells were isolated from b/b and +/b Belgrade rats and Wistar rats after in situ brain perfusion. Some animals received cerebrovascular washout after in situ brain perfusion to ascertain any affect of genotype on (54) Mn adsorption to the endothelial cell luminal surface. Less than 30% of the brain (54) Mn after (54) Mn ion or (54) Mn Tf perfusion remained associated with endothelial cells, suggesting the majority had distributed into brain extracellular fluid (ECF) and/or brain cells. Mn appears to distribute across the rat blood-brain barrier (BBB) into the brain by one or more carrier-mediated processes other than the DMT-1.
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- 2004
61. Aluminum
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Robert A. Yokel
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Chemistry ,Environmental chemistry ,Relevance (information retrieval) - Published
- 2004
62. Manganese Distribution Across the Blood–Brain Barrier
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Bonny L. Bukaveckas, Robert A. Yokel, and Janelle S Crossgrove
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General Neuroscience ,Analytical chemistry ,chemistry.chemical_element ,Manganese ,Membrane transport ,Toxicology ,Phosphate ,Blood–brain barrier ,chemistry.chemical_compound ,medicine.anatomical_structure ,Dextran ,chemistry ,Extracellular fluid ,medicine ,Biophysics ,Toxicokinetics ,Citric acid - Abstract
There is concern about manganese (Mn) neurotoxicity. Mn can enter the brain by carrier-mediated influx. There have been no previous reports of investigation of Mn efflux from the brain. We used an established method that determines the rate of efflux out of the brain across the blood-brain barrier (BBB) from the product of the brain distribution volume (Vbrain) and the apparent elimination rate constant (Kel). Vbrain is determined as 54Mn uptake into rat parietal brain slices versus time. Kel is determined from the percentage of 54Mn remaining in the brain at various times after its discrete injection into the parietal cortex, compared to a reference compound which is expected to very slowly diffuse out of the brain. The Mn ion, Mn citrate and Mn transferrin (Mn Tf) were studied. 14C-sucrose and 14C-dextran were used as reference compounds. The volume of distribution of the Mn species in brain slices was approximately 3-5 ml/g, indicating concentrative uptake. Mn, as the Mn ion or Mn citrate, was injected into the brain with sucrose or dextran to determine Kel. Based on the rapid exchange rate of Mn with ligands and on thermodynamic calculations, injection of Mn ion or Mn citrate into the brain would be expected to result in rapid formation of the same Mn species, predominantly the Mn ion, Mn citrates and Mn phosphate, in brain extracellular fluid. After injection into the brain Mn did not efflux from the brain more rapidly than sucrose or dextran, which diffuse across the BBB. Brain capillary diffusion of the Mn ion and Mn citrate would be expected to be slower than sucrose or dextran. The rate of Mn efflux from the brain is consistent with diffusion.
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- 2003
63. Evaluation of 3,4-Hydroxypyridinecarboxylic Acids as Possible Bidentate Chelating Agents for Aluminium(III): Synthesis and Metal−Ligand Solution Chemistry
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Andrea Tapparo, Valerio Di Marco, Maria Grazia Ferlin, Robert A. Yokel, and G. Giorgio Bombi
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Denticity ,Chemistry ,Ligand ,chemistry.chemical_element ,Solution chemistry ,Combinatorial chemistry ,Inorganic Chemistry ,Metal ,Aluminium ,visual_art ,visual_art.visual_art_medium ,Organic chemistry ,Chelation ,Chelation therapy - Published
- 2002
64. Aluminum chelation principles and recent advances
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Robert A. Yokel
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Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Toxicity ,Inorganic chemistry ,Materials Chemistry ,Chelation ,Physical and Theoretical Chemistry ,Pharmacology ,Deferiprone - Abstract
Acute Al toxicity is not common. Toxicity from prolonged Al exposure has become much less common, but still occurs occasionally. The potential contribution of Al to Alzheimer's disease and related disorders is not resolved. Diagnosis of Al accumulation and treatment of Al toxicity can be achieved with chelators. The biology and chemistry of Al relevant to its chelation are reviewed. The approaches that have been used to assess potential Al chelators are summarized. The chemistry of desferrioxamine and the hydroxypyridinones in relation to Al chelation and the results of the more recent studies with these agents are reviewed. There is very little clinical experience with the hydroxypyridinones as Al chelators. The results of chemical and animal studies suggest they have potential to replace desferrioxamine, as orally effective Al chelators. However, adverse effects associated with the use of 1,2-dimethyl-3,4-hydroxypyridinone (deferiprone) dampen enthusiasm for the hydroxypyridinones as Al chelators. The uses of Al chelators to enhance Al removal, concentration, detection and speciation are reviewed. The role of Al chelators in the environment and their production by plants to reduce Al toxicity is summarized.
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- 2002
65. Aluminum citrate uptake by immortalized brain endothelial cells: implications for its blood–brain barrier transport
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Robert A. Yokel, Marieangela C. Wilson, Wesley R. Harris, and Andrew P. Halestrap
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Erythrocytes ,Organic anion transporter 1 ,Blotting, Western ,Carboxylic Acids ,Biological Transport, Active ,Transferrin receptor ,Oxidative phosphorylation ,Blood–brain barrier ,Citric Acid ,Ouabain ,Receptors, Transferrin ,medicine ,Animals ,Molecular Biology ,Cell Line, Transformed ,Monocarboxylate transporter ,Microscopy, Confocal ,biology ,Chemistry ,General Neuroscience ,Brain ,Citrate transport ,Rats ,medicine.anatomical_structure ,Biochemistry ,Blood-Brain Barrier ,biology.protein ,Endothelium, Vascular ,Neurology (clinical) ,Carrier Proteins ,Aluminum ,Developmental Biology ,medicine.drug ,Organic anion - Abstract
The objective was to further test the hypothesis that aluminum (Al) citrate transport across the blood-brain barrier is mediated by a monocarboxylate transporter (MCT). Speciation calculations showed that Al citrates were the predominant Al species under the conditions employed. Al citrate did not inhibit lactate uptake and was not taken up by the rat erythrocyte, suggesting it does not serve as an effective substrate for either MCT1 or the anion exchanger. Studies were conducted with b.End5 cells derived from mouse brain endothelial cells to identify the properties of the carrier(s) mediating Al citrate transport. Western blot analysis of b.End5 cells showed expression of the transferrin receptor and MCT1, but not MCT2 or MCT4. Uptake of Al citrate was approximately 70% faster than citrate. Citrate and Al citrate uptake were sodium independent. Citrate uptake increased at pH 6.9 compared to 7.4, whereas Al citrate uptake did not. Al citrate uptake was reduced by inhibitors of mitochondrial respiration and oxidative phosphorylation, suggesting ATP dependence, but not by ouabain, suggesting no role for Na/K-ATPase. Uptake was not affected by alpha-ketoglutarate or malonate, substrates for the dicarboxylate carrier. Many substrates and inhibitors of MCT1 and organic anion transporters reduced Al citrate uptake into b.End5 cells. BSP and fluorescein, organic anion transporter substrates/inhibitors, inhibited Al citrate uptake. We conclude that Al citrate transport across the blood-brain barrier is carrier-mediated, involving either an uncharacterized MCT isoform expressed in the brain such as MCT7 or MCT8 and/or one of the many members of the organic anion transporting protein family, some of which are known to be expressed at the blood-brain barrier.
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- 2002
66. Entry, Half-Life, and Desferrioxamine-Accelerated Clearance of Brain Aluminum after a Single 26Al Exposure
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Susan S. Rhineheimer, Pankaj Sharma, Patrick J. McNamara, Robert A. Yokel, and David Elmore
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Male ,medicine.medical_specialty ,medicine.medical_treatment ,Central nervous system ,Deferoxamine ,Dialysis Encephalopathy ,Toxicology ,Mass Spectrometry ,Internal medicine ,medicine ,Animals ,Humans ,Toxicokinetics ,Antidote ,Saline ,Chelating Agents ,Radioisotopes ,business.industry ,Transferrin ,Brain ,Half-life ,Al-transferrin ,Rats ,medicine.anatomical_structure ,Endocrinology ,Anesthesia ,business ,Aluminum ,Half-Life ,medicine.drug - Abstract
The objectives of our study were to estimate the percentage of aluminum (Al) that enters the brain, the half-life of brain Al, and the ability of an Al chelator to reduce brain Al. Rats received an iv infusion of Al transferrin, the primary Al species in plasma, or Al citrate, the predominant small molecular weight Al species in plasma. The infusion contained approximately 0.2-0.3 nCi (0.4-0.6 nmol) (26)Al, enabling the study of Al distribution into and retention by the brain at physiological Al concentrations. Some Al transferrin-infused rats received ip injections of the Al chelator desferrioxamine (DFO), 0.15 mmol/kg, three times weekly. The others received saline injections. The rats were euthanized from 4 hr to 4 days (Al citrate) or 256 days (Al transferrin) later. Brain (26)Al was determined by accelerator mass spectrometry. Peak brain (26)Al concentration was approximately 0.005% of the (26)Al dose in each gram of brain, irrespective of Al species administered. In the absence of DFO treatments, brain (26)Al concentration decreased with a half-life of approximately 150 days. The brain Al half-life in the DFO-treated rats was approximately 55 days. The results show a small fraction of Al in blood enters the brain, where it persists for a long time. The ability of repeated DFO treatments to modestly accelerate the reduction of brain Al is consistent with the necessity of prolonged DFO therapy to significantly reduce Al-induced dialysis encephalopathy.
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- 2001
67. Aluminum bioavailability from drinking water is very low and is not appreciably influenced by stomach contents or water hardness
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Pankaj Sharma, Patrick J. McNamara, David Elmore, Russell D. Brauer, Susan S. Rhineheimer, and Robert A. Yokel
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Male ,Absorption (pharmacology) ,Drinking ,Administration, Oral ,Biological Availability ,chemistry.chemical_element ,Calcium ,Toxicology ,Animal science ,Pharmacokinetics ,medicine ,Animals ,Toxicokinetics ,Magnesium ion ,Chemistry ,Spectrophotometry, Atomic ,Stomach ,Hard water ,Water ,Rats, Inbred F344 ,Rats ,Bioavailability ,medicine.anatomical_structure ,Biochemistry ,Food ,Gastric Mucosa ,Area Under Curve ,Aluminum - Abstract
The objectives were to estimate aluminum (Al) oral bioavailability under conditions that model its consumption in drinking water, and to test the hypotheses that stomach contents and co-administration of the major components of hard water affect Al absorption. Rats received intragastric 26Al in the absence and presence of food in the stomach and with or without concomitant calcium (Ca) and magnesium (Mg) at concentrations found in hard drinking water. The use of 26Al enables the study of Al pharmacokinetics at physiological Al concentrations without interference from 27Al in the environment or the subject. 27Al was intravenously administered throughout the study. Repeated blood withdrawal enabled determination of oral 26Al bioavailability from the area under its serum concentrationxtime curve compared to serum 27Al concentration in relation to its infusion rate. Oral Al bioavailability averaged 0.28%. The presence of food in the stomach and Ca and Mg in the water that contained the orally dosed 26Al appeared to delay but not significantly alter the extent of 26Al absorption. The present and published results suggest oral bioavailability of Al from drinking water is very low, about 0.3%. The present results suggest it is independent of stomach contents and water hardness.
- Published
- 2001
68. Persistent hepatic structural alterations following nanoceria vascular infusion in the rat
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Zhongbin Deng, Michael T. Tseng, Uschi M. Graham, Qiang Fu, Robert A. Yokel, Khoua Lor, D. Allan Butterfield, Eric A. Grulke, and G. Rafael Fernandez-Botran
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Male ,Pathology ,medicine.medical_specialty ,CD3 Complex ,Kupffer Cells ,Aqueous dispersion ,Apoptosis ,Lymphocyte proliferation ,Pharmacology ,Toxicology ,Pathology and Forensic Medicine ,Rats, Sprague-Dawley ,Sprague dawley rats ,medicine ,In Situ Nick-End Labeling ,Animals ,Secretion ,Molecular Biology ,Cell Proliferation ,Cluster of differentiation ,Chemistry ,Cell Biology ,Metabolism ,Cerium ,Immunohistochemistry ,Rats ,Liver ,Toxicity - Abstract
Understanding the long-term effects and possible toxicity of nanoceria, a widely utilized commercial metal oxide, is of particular importance as it is poised for development as a therapeutic agent based on its autocatalytic redox behavior. We show here evidence of acute and subacute adverse hepatic responses, after a single infusion of an aqueous dispersion of 85 mg/kg, 30 nm nanoceria into Sprague Dawley rats. Light and electron microscopic evidence of avid uptake of nanoceria by Kupffer cells was detected as early as 1 hr after infusion. Biopersistent nanoceria stimulated cluster of differentiation 3+ lymphocyte proliferation that intermingled with nanoceria-containing Kupffer cells to form granulomata that were observed between days 30 and 90. Ultrastructural tracking of ceria nanoparticles revealed aggregated nanoceria in phagolysosomes. An increased formation of small nanoceria over time observed in the latter suggests possible dissolution and precipitation of nanoceria. However, the pathway for nanoceria metabolism/secretion remains unclear. Although frank hepatic necrosis was not observed, the retention of nanoceria increased hepatic apoptosis acutely, this persisted to day 90. These findings, together with our earlier reports of 5-nm ceria-induced liver toxicity, provide additional guidance for nanoceria development as a therapeutic agent and for its risk assessment.
- Published
- 2013
69. Binding, Transcytosis and Biodistribution of Anti-PECAM-1 Iron Oxide Nanoparticles for Brain-Targeted Delivery
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Robert A. Yokel, David B. Cochran, Thomas D. Dziubla, and Mo Dan
- Subjects
Male ,Biodistribution ,lcsh:Medicine ,Metal Nanoparticles ,02 engineering and technology ,Blood–brain barrier ,Ferric Compounds ,Immunoglobulin G ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,In vivo ,medicine ,Animals ,Humans ,Tissue Distribution ,lcsh:Science ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,biology ,Cell adhesion molecule ,lcsh:R ,Antibodies, Monoclonal ,Brain ,Endothelial Cells ,021001 nanoscience & nanotechnology ,In vitro ,Rats ,Platelet Endothelial Cell Adhesion Molecule-1 ,medicine.anatomical_structure ,Transcytosis ,chemistry ,Blood-Brain Barrier ,Immunology ,embryonic structures ,Biophysics ,biology.protein ,cardiovascular system ,lcsh:Q ,0210 nano-technology ,Iron oxide nanoparticles ,Research Article ,Protein Binding - Abstract
Objective: Characterize the flux of platelet-endothelial cell adhesion molecule (PECAM-1) antibody-coated superparamagnetic iron oxide nanoparticles (IONPs) across the blood-brain barrier (BBB) and its biodistribution in vitro and in vivo. Methods: Anti-PECAM-1 IONPs and IgG IONPs were prepared and characterized in house. The binding affinity of these nanoparticles was investigated using human cortical microvascular endothelial cells (hCMEC/D3). Flux assays were performed using a hCMEC/D3 BBB model. To test their immunospecificity index and biodistribution, nanoparticles were given to Sprague Dawley rats by intra-carotid infusion. The capillary depletion method was used to elucidate their distribution between the BBB and brain parenchyma. Results: Anti-PECAM-1 IONPs were ,130 nm. The extent of nanoparticle antibody surface coverage was 63.668.4%. Only 6.3961.22% of labeled antibody dissociated from IONPs in heparin-treated whole blood over 4 h. The binding affinity of PECAM-1 antibody (KD) was 32 nM with a maximal binding (Bmax )o f 17610 5 antibody molecules/cell. Anti-PECAM-1 IONP flux across a hCMEC/D3 monolayer was significantly higher than IgG IONP’s with 31% of anti-PECAM-1 IONPs in the receiving chamber after 6 h. Anti-PECAM-1 IONPs showed higher concentrations in lung and brain, but not liver or spleen, than IgG IONPs after infusion. The capillary depletion method showed that 17612% of the anti-PECAM-1 IONPs crossed the BBB into the brain ten minutes after infusion. Conclusions: PECAM-1 antibody coating significantly increased IONP flux across the hCMEC/D3 monolayer. In vivo results showed that the PECAM-1 antibody enhanced BBB association and brain parenchymal accumulation of IONPs compared to IgG. This research demonstrates the benefit of anti-PECAM-1 IONPs for association and flux across the BBB into the brain in relation to its biodistribution in peripheral organs. The results provide insight into potential application and toxicity concerns of anti-PECAM-1 IONPs in the central nervous system.
- Published
- 2013
70. Glomerular lesions in male rabbits treated with aluminium lactate: with special reference to microaneurysm formation
- Author
-
Mark A. Lovell, Robert A. Yokel, C.B. Hong, Andrea M. Fredenburg, and Kenneth M. Dickey
- Subjects
Male ,Cytoplasm ,Pathology ,medicine.medical_specialty ,Necrosis ,Kidney Glomerulus ,urologic and male genital diseases ,Toxicology ,Pathology and Forensic Medicine ,Fibrosis ,medicine ,Animals ,Aluminum Compounds ,Microaneurysm ,Lagomorpha ,biology ,urogenital system ,business.industry ,Glomerular mesangium ,Calcinosis ,Glomerulonephritis ,Cell Biology ,General Medicine ,medicine.disease ,biology.organism_classification ,Aneurysm ,female genital diseases and pregnancy complications ,Glomerular Mesangium ,Mesangiolysis ,Lactates ,Kidney Diseases ,Rabbits ,medicine.symptom ,business ,Aluminum ,Calcification - Abstract
Novel glomerular lesions were seen in male rabbits after intravenous administration of aluminum lactate. Eight rabbits in the treated group were given 0.1 mmol/kg of aluminum lactate 5 days a week for 4 weeks. The control group of 8 rabbits was given 0.3 mmol/kg of sodium lactate by the same injection protocol. In the treated group, the mesangial cells in the glomerular tufts in 6 of 8 rabbits were distended with grayish blue granular material, which was identified by laser microprobe mass spectrometry and acid solochrome azurine stain as an aluminum compound. Other consistent findings in the glomeruli included microaneurysm in 6 of 8 rabbits and segmental sclerosis in 6 of 8 rabbits. Less frequently observed glomerular changes included crescent formation, necrosis with calcification, fibrosis of the Bowman's capsule, cystic dilation of the Bowman's space, and exudation of erythrocytes into the Bowman's space. The mechanism by which aluminum lactate induces the glomerular changes is not certain. However, the pathogenesis may involve the deposition of aluminum in the mesangial cells, resulting in mesangiolysis which in turn causes microaneurysm. The sclerotic change is interpreted as a sequela of microaneurysm. The findings suggest that aluminum induces glomerular lesions in rabbits. This may serve as a good animal model to study mesangiolysis and microaneurysm formation.
- Published
- 2000
71. The Hexadentate Hydroxypyridinonate TREN‐(Me‐3,2‐HOPO) is a More Orally Active Iron Chelator Than Its Bidentate Analogue
- Author
-
Patricia W. Durbin, Jide Xu, Mary Kay Rayens, Kenneth N. Raymond, Robert A. Yokel, and Andrea M. Fredenburg
- Subjects
Excretion ,Iron Chelator ,Orally active ,Denticity ,Chemistry ,Oral administration ,Inorganic chemistry ,Pharmaceutical Science ,Chelation ,IV injection ,Volume concentration ,Nuclear chemistry - Abstract
Bidentate hydroxypyridinone chelators effectively complex and facilitate excretion of trivalent iron. To test the hypothesis that hexadentate chelators are more effective than bidentate chelators at low concentrations, urinary and biliary Fe excretions were determined in Fe‐loaded rats before and after administration of a bidentate chelator, Pr‐(Me‐3,2‐HOPO), or its hexadentate analogue, TREN‐(Me‐3,2‐HOPO). The bidentate chelator slightly increased biliary Fe excretion in Fe‐loaded rats after IV (90 μmol/kg) and PO (90 or 270 μmol/kg) administration, but chelation efficiency did not exceed 1%. The hexadentate chelator markedly increased biliary Fe excretion, achieving overall chelation efficiencies of 14% after IV administration of 30 μmol/kg and 8 or 3% after PO (30 or 90 μmol/kg) administration. The hexadentate chelator was significantly more effective than the bidentate chelator after IV injection and oral dosing. In chelator‐treated Fe‐loaded or saline‐injected rats, >90% of the excreted Fe was in the bile. Oral TREN‐(Me‐3,2‐HOPO), given to non‐Fe‐loaded rats, did not appreciably change Fe output, indicating that there was little Fe depletion in the absence of Fe overload. These results support the hypothesis that greater Fe chelation efficiency can be achieved with hexadentate than with bidentate chelators at lower, and presumably safer, concentrations. The results also demonstrate that TREN‐(Me‐3,2‐HOPO) is a promising, orally effective, Fe chelator. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 545–555, 2000
- Published
- 2000
72. The distribution of aluminum into and out of the brain
- Author
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Robert A. Yokel, David D. Allen, and David C Ackley
- Subjects
Monocarboxylate transporter ,medicine.medical_specialty ,Microdialysis ,biology ,Chemistry ,Brain ,Blood–brain barrier ,Endocytosis ,Biochemistry ,Rats ,Inorganic Chemistry ,medicine.anatomical_structure ,Endocrinology ,Blood-Brain Barrier ,Internal medicine ,Blood plasma ,Extracellular fluid ,medicine ,Extracellular ,biology.protein ,Animals ,Efflux ,Aluminum - Abstract
The extent, rate and possible mechanism(s) by which aluminum enters and is removed from the brain are presented. Introduction of Al into systemic circulation as Al.transferrin, the predominant Al species in plasma, resulted in about 7 x 10(-5) of the dose in the brain 1 day after injection. This brain Al entry could be mediated by transferrin-receptor-mediated endocytosis (TfR-ME). When Al.citrate, the predominant small molecular weight Al species in blood plasma, is introduced systemically, Al rapidly enters the brain. The rate of Al.citrate brain influx suggests a more rapid process than mediated by diffusion or TfR-ME. The question has been raised: "Is the brain a 'one-way sink' for aluminum?". Clinical observations are a basis for this suggestion. Rat brain 26Al concentrations decreased only slightly from 1 to 35 days after systemic 26Al injection, in the absence or presence of the aluminum chelator desferrioxamine, suggesting prolonged brain Al retention. However, studies of brain and blood extracellular Al at steady state, using microdialysis, suggest brain Al efflux exceeds influx, suggesting carrier-mediated brain Al efflux. The predominant brain extracellular fluid Al species is probably Al.citrate. The hypothesis that brain Al efflux, presumably of Al.citrate, is mediated by the monocarboxylate transporter was tested and supported. Although some Al that enters the brain is rapidly effluxed, it is suggested that a fraction enters brain compartments within 24 h from which it is only very slowly eliminated.
- Published
- 1999
73. Postmortem elevation in extracellular glutamate in the rat hippocampus when brain temperature is maintained at physiological levels: implications for the use of human brain autopsy tissues
- Author
-
Nada G Chang, Robert A. Yokel, Joseph P. McGillis, David C Ackley, James W. Geddes, and Natalie S Soultanian
- Subjects
Male ,medicine.medical_specialty ,Microdialysis ,Taurine ,Glutamic Acid ,Biology ,Hippocampal formation ,Hippocampus ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Quinoxalines ,Internal medicine ,medicine ,Extracellular ,Animals ,Humans ,Molecular Biology ,Chromatography, High Pressure Liquid ,gamma-Aminobutyric Acid ,General Neuroscience ,Glutamate receptor ,Brain ,Human brain ,Rats ,Dizocilpine ,Endocrinology ,medicine.anatomical_structure ,Biochemistry ,chemistry ,Postmortem Changes ,NBQX ,Autopsy ,Neurology (clinical) ,Dizocilpine Maleate ,Excitatory Amino Acid Antagonists ,Body Temperature Regulation ,Developmental Biology ,medicine.drug - Abstract
Postmortem alterations in the neuronal cytoskeleton resemble some aspects of the cytoskeletal disruption associated with neurodegenerative disorders, and are also similar to those observed following ischemia and produced by excitotoxins in vivo and in vitro. This suggests the involvement of excitotoxic mechanisms during the postmortem interval. The purpose of this study was to determine if extracellular levels of glutamate are elevated postmortem. Extracellular levels of GABA and taurine were also monitored using in vivo microdialysis. These three amino acids were analyzed using high-performance liquid chromatography. When postmortem rat brain temperature cooled rapidly to near room temperature, dialysate concentrations of glutamate were not increased in the hippocampal CA1 region during a 2-h postmortem interval, although increased extracellular levels of GABA and taurine were observed. In contrast, maintenance of brain temperature at 37 degrees C resulted in a 12-to-40 fold elevation in extracellular glutamate levels 20-120 min postmortem. In addition, the elevation in dialysate taurine concentration was greater than that observed in rats in which postmortem brain temperature was not maintained. Excitatory amino acid antagonists, NBQX (2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline) and MK-801 (dizocilpine, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cylohepten-5, 10-imine hydrogen maleate blocked the additional elevation in taurine associated with maintaining brain at 37 degrees C, but had less robust effects against glutamate and GABA release. The results indicate that extracellular concentrations of glutamate, taurine and GABA increase in postmortem rat brain when physiologic temperatures are maintained, but that these increases are blunted when brain temperature decreases. After death, the human brain cools much more slowly than does the rat brain. Therefore, extracellular glutamate levels are likely to increase in the postmortem human brain and may contribute to excitotoxic neuronal damage occurring in the interval between death and autopsy.
- Published
- 1999
74. Aluminum and phosphorus separation: application to preparation of target from brain tissue for 26Al determination by accelerator mass spectrometry
- Author
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J. David Robertson, Pankaj Sharma, Robert A. Yokel, and Russell D. Brauer
- Subjects
Nuclear and High Energy Physics ,Chromatography ,Elution ,Phosphorus ,Radiochemistry ,Crucible ,chemistry.chemical_element ,Phosphate ,chemistry.chemical_compound ,Hydrofluoric acid ,chemistry ,Ashing ,Ion-exchange resin ,Instrumentation ,Accelerator mass spectrometry - Abstract
Acid digested brain containing 4 mg added 27 Al was ashed at 1000°C to prepare an Al 2 O 3 target for accelerator mass spectrometry (AMS) analysis of 26 Al. A glass-like material usually resulted which was thought to be aluminum (Al) oxyphosphate. The separation of Al and phosphate was investigated. Al, but not phosphate, was bound by a cation exchange resin (AG 50-X8). Hydrofluoric acid eluted the Al from the resin. Removal of phosphate from acid digested brain by this method produced an amorphous material after ashing that was easier to recover from the porcelain crucible and had a higher AMS beam current. This procedure to separate Al from phosphate may have utility in other applications.
- Published
- 1999
75. Aluminum transport out of brain extracellular fluid is proton dependent and inhibited by mersalyl acid, suggesting mediation by the monocarboxylate transporter (MCT1)
- Author
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David C Ackley and Robert A. Yokel
- Subjects
Male ,Monocarboxylic Acid Transporters ,Microdialysis ,Ionophore ,Mersalyl Acid ,Mersalyl ,Toxicology ,Blood–brain barrier ,Rats, Sprague-Dawley ,Extracellular fluid ,medicine ,Extracellular ,Animals ,Enzyme Inhibitors ,Monocarboxylate transporter ,biology ,Chemistry ,Membrane Proteins ,Transporter ,Hydrogen-Ion Concentration ,Frontal Lobe ,Rats ,medicine.anatomical_structure ,Biochemistry ,Blood-Brain Barrier ,biology.protein ,Protons ,Carrier Proteins ,Extracellular Space ,Aluminum - Abstract
Blood–brain barrier transport of aluminum citrate was assessed in rats by microdialysis of the jugular vein as well as the right and left frontal cortices. Previous studies (Allen et al., 1995. Evidence for energy-dependent transport of aluminum out of brain extracellular fluid. Toxicology 92, 193–202; Ackley and Yokel, 1997. Aluminum citrate is transported from brain into blood via the monocarboxylic acid transporter located at the blood–brain barrier. Toxicology 120, 89–97), and the current study, demonstrated that the steady-state brain-to-blood ratio of the unbound extracellular aluminum immediately surrounding the microdialysis probe is less than 1, suggesting the presence of a process other than diffusion across the blood–brain barrier. It was speculated that a monocarboxylate transporter at the blood–brain barrier was maintaining this ratio at less than 1 (Ackley and Yokel, 1997). Monocarboxylate transporters are proton co-transporters. Decreasing extracellular pH (increasing proton availability) increases monocarboxylate transport. After alkalinizing the dialysate perfusing a brain microdialysis probe (to pH=10.2), the steady-state aluminum brain-to-blood ratio increased from 0.35 to 0.80. The addition of the proton ionophore, p -(trifluoromethoxy)phenylhydrazone (FCCP) (1 mM), to brain dialysate increased this ratio from 0.21 to 0.61. These increased ratios suggest that a proton-dependent process is removing Al from brain extracellular fluid. The monocarboxylate transporter is the only known proton-dependent transporter at the blood–brain barrier. There are two known isoforms of this transporter in the rodent, MCT1 and MCT2. Organomercurial thiol reagents, such as mersalyl acid, inhibit MCT1 but not MCT2. Mersalyl acid (50 mM) addition to brain dialysate increased the steady-state aluminum brain-to-blood ratio from 0.19 to 0.87, suggesting that MCT1 is at least partially mediating the efflux of aluminum from brain extracellular fluid.
- Published
- 1998
76. Introduction to the themed collection on nanoceria research
- Author
-
Robert A. Yokel
- Subjects
Engineering ,business.industry ,Materials Science (miscellaneous) ,Nanotechnology ,business ,General Environmental Science - Published
- 2014
77. Aluminum citrate is transported from brain into blood via the monocar☐ylic acid transporter located at the blood-brain barrier
- Author
-
Robert A. Yokel and David C Ackley
- Subjects
Male ,Microdialysis ,Biological Transport, Active ,Toxicology ,Blood–brain barrier ,Citric Acid ,Diffusion ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,In vivo ,Dialysis Solutions ,Pyruvic Acid ,medicine ,Animals ,Toxicokinetics ,Chromatography, High Pressure Liquid ,Chromatography ,Valproic Acid ,Transporter ,Light metal ,Rats ,Quaternary Ammonium Compounds ,medicine.anatomical_structure ,Membrane ,Biochemistry ,chemistry ,Blood-Brain Barrier ,Pyruvic acid ,Jugular Veins ,2,4-Dinitrophenol ,Antipyrine ,Aluminum - Abstract
Aluminum citrate transport across the blood-brain barrier was assessed in rats by in vivo microdialysis. Microdialysis probes were implanted in the jugular vein as well as the left and right frontal cortex. It was demonstrated previously (Allen et al., 1995), in this study, that the steady-state aluminum citrate brain-to-blood-ratio (BBr) is less than 1, suggesting the presence of a process other than diffusion. The addition of 2,4-dinitrophenol (10 microM) to the dialysate perfusing a microdialysis probe in the brain increased the steady-state aluminum citrate brain-to-blood-ratio to a value (1.14) not significantly different from 1, suggesting the presence of an active transporter that is blocked by the metabolic inhibitor. The addition of valproic and pyruvic acid, as putative and known substrates for the monocarboxylic acid transporter, respectively, to brain dialysate (10 and 100 mM) had different outcomes. Valproic acid was ineffective at either concentration, whereas pyruvic acid (100 mM) significantly increased the aluminum citrate brain-to-blood-ratio from 0.19 to 0.31. Pyruvic acid (1 M in the dialysate) increased the aluminum citrate brain-to-blood-ratio to a value not different from unity, suggesting competition between aluminum citrate and pyruvic acid for transport. The only energy-dependent, pyruvic acid-inhibitable transporter is the monocarboxylic acid transporter. Theoretical, pharmacokinetic modeling suggests that the transporter producing an aluminum citrate brain-to-blood-ratio less than 1 is predominantly located at the blood-brain barrier, rather than at neuronal or glial cell membranes. We propose that the monocarboxylic acid transporter at the blood-brain barrier maintains a steady-state aluminum citrate brain-to-blood-ratio much less than 1.
- Published
- 1997
78. Hippocampal Acetylcholine Increases During Eyeblink Conditioning in the Rabbit
- Author
-
David D. Allen, Robert A. Yokel, and Jerome J. Meyer
- Subjects
Male ,Microdialysis ,medicine.medical_specialty ,Magnetic Resonance Spectroscopy ,Conditioning, Classical ,Experimental and Cognitive Psychology ,Hippocampal formation ,Hippocampus ,Behavioral Neuroscience ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Neurotransmitter ,Chromatography, High Pressure Liquid ,Blinking ,Chemistry ,Anti-Inflammatory Agents, Non-Steroidal ,Classical conditioning ,Acetylcholine ,Endocrinology ,Eyeblink conditioning ,Cholinergic ,Rabbits ,Nictitating membrane ,Extracellular Space ,Neuroscience ,Antipyrine ,Aluminum ,medicine.drug - Abstract
The classically conditioned rabbit nictitating membrane reflex (NMR) is modulated by the septohippocampal cholinergic system. Disruption of this system retards NMR acquisition. Aluminium (Al) is a neurotoxin that interferes with hippocampal acetylcholine (ACh) synthesis and release. Using microdialysis, this study tested the hypothesis that NMR acquisition in the rabbit is associated with hippocampal ACh release. This was conducted by measuring ACh release in control and A1-intoxicated rabbits during NMR training. NMR training consisted of four sessions of 100 conditioning trials/session in a delay paradigm. The percentage of conditioned responses (CRs) increased with each conditioning session for both groups, although percent CRs was significantly greater in the control group. Acetylcholine release in the ventral hippocampus increased significantly over baseline in the control group during the second and third conditioning sessions. In the Al-intoxicated group, ACh release did not increase significantly during any conditioning session. A separate group of rabbits was pseudoconditioned, receiving the same conditioning stimuli, although explicitly unpaired. This group did not acquire the CR. Acetylcholine release did not significantly increase during any conditioning session, suggesting that the increase in ACh release observed in the control group was not merely a product of conditioning stimuli presentation. The lack of increased ACh release in the Al-intoxicated rabbits was associated with a CR acquisition deficit. The results of this study are consistent with a role of hippocampal cholinergic function in NMR acquisition in the rabbit.
- Published
- 1996
79. PREVENTION AND TREATMENT OF ALUMINUM TOXICITY INCLUDING CHELATION THERAPY: STATUS AND RESEARCH NEEDS
- Author
-
J. P. Day, J Savory, Trond Peder Flaten, Robert A. Yokel, E Burgess, José L. Domingo, and P Ackrill
- Subjects
Pathology ,medicine.medical_specialty ,Chemotherapy ,Chemistry ,medicine.medical_treatment ,Pharmacology ,Toxicology ,Pollution ,Transplantation ,Deferoxamine ,Oral administration ,Toxicity ,medicine ,Chelation ,Chelation therapy ,Antidote ,medicine.drug - Abstract
The prevention and treatment of aluminum (Al) accumulation and toxicity are reviewed. Recommendations to further our understanding of desferrioxamine (deferoxamine, DFO) treatment and to develop more effective chelation approaches are provided. Reduction of Al accumulation and toxicity may benefit end-stage renal disease (ESRD) patients and perhaps those suffering from specific neurodegenerative disorders as well as workers with Al-induced neurocognitive disorders. The clearance of Al may be increased by extracorporeal chelation, renal transplantation, perhaps complexation with simple ligands such as silicon (Si), and systemic chelation therapy. The abilities of extracorporeal chelation and Si to reduce Al accumulation require further evaluation. Although it may not be possible to design Al-specific chelators, chelators with greater Al selectivity are desired. Aluminum-selective chelation might be achieved by targeted chelator distribution or by the use of adjuvants with the chelator. The ability of carboxylic acids to facilitate Al elimination, under specific conditions, warrants further study. Desferrioxamine does not produce significant biliary Al excretion. A chelator with this property may be useful in ESRD patients. The necessity for an Al chelator to distribute extravascularly to be effective is unknown and should be determined to guide the selection of alternatives to DFO. The lack of oral efficacy and occasional side effects of DFO encourage identification of orally effective, safer Al chelators. The bidentate 3-hydroxypyridin-4-ones are currently the most encouraging alternatives to DFO. They have been shown to increase urinary Al excretion in rats and rabbits, but to have toxicity comparable to, or greater than, DFO. Their toxicity may relate to incomplete metal complexation. The ability of orally effective chelators to increase absorption of chelated metal from the gastrointestinal (Gl) tract needs to be evaluated. Orally effective, safe Al chelators would be of benefit to peritoneal dialysis patients and those with neurodegenerative disorders, if Al chelation therapy is indicated. The reduction of Alzheimer's disease (AD) progression and the reversal of Al-induced behavioral deficits and neurofibrillary tangles by DFO encourage further study of Al chelation therapy for selected neurodegenerative disorders.
- Published
- 1996
80. Aluminum chelation by 3-hydroxypyridin-4-ones in the rat demonstrated by microdialysis
- Author
-
Robert A. Yokel
- Subjects
Male ,medicine.medical_specialty ,Microdialysis ,Frontal cortex ,Pyridones ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Biochemistry ,Rats, Sprague-Dawley ,Inorganic Chemistry ,Jugular vein ,Internal medicine ,medicine ,Animals ,Distribution (pharmacology) ,Tissue Distribution ,Chelation ,Chelating Agents ,Chemistry ,Biochemistry (medical) ,General Medicine ,Rats ,Orally active ,Endocrinology ,Lipophilicity ,Body Burden ,Aluminum - Abstract
The ability and site of the metal-chelating 3-hydroxypyridin-4-ones (HPs) to mobilize aluminum (Al) was assessed in Al-loaded rats using microdialysis. Four HPs with greatly varying lipophilicity were studied. One week after Al loading, microdialysis probes were implanted in the liver, a jugular vein, and the frontal cortex. An HP was given iv followed by continuous microdialysis for 5 h. Al concentrations in dialysates from the liver increased rapidly and were consistently greater than from blood, suggesting that liver was a primary site of Al chelation. Brain dialysate Al concentrations remained low, suggesting little Al chelation in the brain and little distribution of the Al HP complex into the brain. Al concentrations were determined in the main organs/tissues of a separate group of Al-loaded rats, and the percentage of the total Al body burden in each organ/tissue was calculated. The skeletal system and liver had 57 and 28% of the Al body burden, consistent with the liver as a primary site of Al chelation. The HPs chelate extravascular Al and have been shown by others to be orally active. They warrant further investigation as Al chelators.
- Published
- 1996
81. Delayed elevation of platelet activating factor in ischemic hippocampus
- Author
-
Hsin-Hsiung Tai, Susan D. Craddock, L. Creed Pettigrew, Steven M. Butler, Robert A. Yokel, and Jerome J. Meyer
- Subjects
Male ,medicine.medical_specialty ,Microdialysis ,Thromboxane ,Ischemia ,Hippocampus ,Pilot Projects ,Thromboxane A2 ,chemistry.chemical_compound ,Internal medicine ,Reaction Time ,medicine ,Extracellular ,Animals ,Platelet Activating Factor ,Rats, Wistar ,Molecular Biology ,Analysis of Variance ,Platelet-activating factor ,business.industry ,General Neuroscience ,medicine.disease ,Rats ,Thromboxane B2 ,Endocrinology ,Eicosanoid ,chemistry ,Ischemic Attack, Transient ,Reperfusion ,lipids (amino acids, peptides, and proteins) ,Neurology (clinical) ,business ,Developmental Biology - Abstract
We used in vivo microdialysis to define the chronological relationship between release of thromboxane and platelet activating factor (PAF) into the extracellular space of ischemic hippocampus. The thromboxane level peaked after 20 min of postischemic reperfusion, followed by a delayed PAF response 120 min later. We conclude that cerebral ischemia causes delayed elevation of PAF in the extracellular space, long after the immediate synthesis and release of thromboxane metabolites.
- Published
- 1995
82. Selective adherence of a sucralfate—tetracycline complex to gastric ulcers: Implications for the treatment ofHelicobacter pylori
- Author
-
Robert A. Yokel, Arthur H. Goldberg, and Kenneth M. Dickey
- Subjects
Male ,medicine.medical_specialty ,Tetracycline ,medicine.drug_class ,Sucralfate ,Antibiotics ,Pharmaceutical Science ,Gastroenterology ,Helicobacter Infections ,Drug Delivery Systems ,Internal medicine ,medicine ,Animals ,Pharmacology (medical) ,Stomach Ulcer ,Dosing ,Antrum ,Antibacterial agent ,Pharmacology ,Helicobacter pylori ,biology ,business.industry ,Stomach ,digestive, oral, and skin physiology ,General Medicine ,Anti-Ulcer Agents ,biology.organism_classification ,digestive system diseases ,Anti-Bacterial Agents ,Drug Combinations ,medicine.anatomical_structure ,Rabbits ,business ,Aluminum ,medicine.drug - Abstract
The adherence of a sucralfate-tetracycline complex to gastric ulcers and to nearby non-ulcer sites was determined in the rabbit antrum. Persistent gastric ulcers were produced by a previously described method. The presence of the complex was assessed 1 and 4 h after dosing. Drug adherence was determined by quantitation of aluminum in stomach wall biopsies. Significantly more aluminum adhered to ulcer sites than to nearby non-ulcer sites. Adherence of the complex did not significantly decrease from 1 to 4 h. The complexation of tetracycline to sucralfate did not alter the selective adherence of sucralfate to gastric ulcers, providing a mechanism of ulcer site-selective drug delivery in the treatment of Helicobacter pylori gastric ulcer disease.
- Published
- 1995
83. Evidence for energy-dependent transport of aluminum out of brain extracellular fluid
- Author
-
Robert A. Yokel, David D. Allen, and Chris Orvig
- Subjects
Male ,inorganic chemicals ,medicine.medical_specialty ,Microdialysis ,Biological Transport, Active ,Toxicology ,Blood–brain barrier ,complex mixtures ,Rats, Sprague-Dawley ,Extracellular fluid ,medicine ,Animals ,Toxicokinetics ,Analysis of Variance ,Chemistry ,Permeation ,Light metal ,Rats ,Surgery ,medicine.anatomical_structure ,Blood-Brain Barrier ,Permeability (electromagnetism) ,Toxicity ,Biophysics ,Extracellular Space ,Aluminum - Abstract
Aluminum (Al) can cause CNS toxicity. The mechanism of its blood-brain barrier (BBB) permeation is poorly understood. In this study, microdialysis was used to determine extracellular fluid (ECF) unbound aluminum distribution between frontal cortex (FC) and blood during steady-state aluminum concentrations. The brain/blood aluminum ratio was determined. Over a 16-fold range of aluminum concentrations (dosed as aluminum citrate), brain/blood aluminum ratios were 0.10-0.15, consistently and significantly1. Aluminum diffusion cannot account for these results, suggesting the presence of a carrier that moves aluminum out of brain extracellular fluid. These aluminum brain/blood ratios (BBRs) were not significantly different over the range of concentrations studied, suggesting an inability to saturate the carrier. Brain/blood aluminum ratios obtained with four aluminum-hydroxypyridinones were also significantly1 (0.1-0.3), and were generally significantly different among themselves and from the aluminum citrate BBR. Movement of a BBB permeability marker from blood into brain extracellular fluid suggested partial BBB opening. The aluminum BBRs obtained (all1), in the presence of a partially opened BBR, suggest an efficient carrier moving aluminum out of brain ECF. Addition of cyanide to the brain microdialysis probe solution significantly increased the Al (citrate) BBR to 1. These results suggest the presence of an efficient, energy-dependent carrier that removes aluminum from brain ECF, either into brain cells or blood.
- Published
- 1995
84. Block copolymer cross-linked nanoassemblies improve particle stability and biocompatibility of superparamagnetic iron oxide nanoparticles
- Author
-
Robert J. Wydra, Peter A. Hardy, Mo Dan, J. Zach Hilt, Robert A. Yokel, Daniel Scott, and Younsoo Bae
- Subjects
Materials science ,Hot Temperature ,Biocompatibility ,Superparamagnetic iron oxide nanoparticles ,Cell Survival ,Particle stability ,Pharmaceutical Science ,Nanoparticle ,Nanotechnology ,Biocompatible Materials ,Article ,Cell Line ,Polyethylene Glycols ,Mice ,Copolymer ,Animals ,Chemical Precipitation ,Pharmacology (medical) ,Citrates ,Particle Size ,Magnetite Nanoparticles ,Cell survival ,Pharmacology ,Organic Chemistry ,Brain ,Biocompatible material ,Magnetic Resonance Imaging ,Cross-Linking Reagents ,Magnetic Fields ,Molecular Medicine ,Particle size ,Peptides ,Biotechnology - Abstract
To develop cross-linked nanoassemblies (CNAs) as carriers for superparamagnetic iron oxide nanoparticles (IONPs).Ferric and ferrous ions were co-precipitated inside core-shell type nanoparticles prepared by cross-linking poly(ethylene glycol)-poly(aspartate) block copolymers to prepare CNAs entrapping Fe(3)O(4) IONPs (CNA-IONPs). Particle stability and biocompatibility of CNA-IONPs were characterized in comparison to citrate-coated Fe(3)O(4) IONPs (Citrate-IONPs).CNA-IONPs, approximately 30 nm in diameter, showed no precipitation in water, PBS, or a cell culture medium after 3 or 30 h, at 22, 37, and 43°C, and 1, 2.5, and 5 mg/mL, whereas Citrate-IONPs agglomerated rapidly (400 nm) in all aqueous media tested. No cytotoxicity was observed in a mouse brain endothelial-derived cell line (bEnd.3) exposed to CNA-IONPs up to 10 mg/mL for 30 h. Citrate-IONPs (0.05 mg/mL) reduced cell viability after 3 h. CNA-IONPs retained the superparamagnetic properties of entrapped IONPs, enhancing T2-weighted magnetic resonance images (MRI) at 0.02 mg/mL, and generating heat at a mild hyperthermic level (40 ~ 42°C) with an alternating magnetic field (AMF).Compared to citric acid coating, CNAs with a cross-linked anionic core improved particle stability and biocompatibility of IONPs, which would be beneficial for future MRI and AMF-induced remote hyperthermia applications.
- Published
- 2012
85. Nanoceria distribution, biotransformation, and safety/toxicity in the rat
- Author
-
Rukhsana Sultana, Michael T. Tseng, Peng Wu, Uschi M. Graham, Robert A. Yokel, Robert C. MacPhail, Eric A. Grulke, D. Allan Butterfield, Jason M. Unrine, Mo Dan, and Sarita S. Hardas
- Subjects
Biotransformation ,Chemistry ,Environmental chemistry ,Toxicity ,Genetics ,Distribution (pharmacology) ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2012
86. Distribution, elimination, and biopersistence to 90 days of a systemically introduced 30 nm ceria-engineered nanomaterial in rats
- Author
-
Eric A. Grulke, Michael T. Tseng, Uschi M. Graham, Peng Wu, Jason M. Unrine, Robert A. Yokel, D. Allan Butterfield, Michael C. Goodman, Tu C. Au, Mo Dan, Sarita S. Hardas, Hamed Haghnazar, Rukhsana Sultana, and Robert C. MacPhail
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Antioxidant ,Metabolic Clearance Rate ,medicine.medical_treatment ,Spleen ,Toxicology ,medicine.disease_cause ,Weight Gain ,Excretion ,Rats, Sprague-Dawley ,Microscopy, Electron, Transmission ,Bone Marrow ,Internal medicine ,medicine ,Animals ,Particle Size ,Infusions, Intravenous ,Granuloma ,Chemistry ,Histology ,Mononuclear phagocyte system ,Cerium ,Organ Size ,Nanostructures ,Rats ,Oxidative Stress ,medicine.anatomical_structure ,Endocrinology ,Liver ,Bone marrow ,medicine.symptom ,Weight gain ,Oxidative stress - Abstract
Nanoceria is used as a catalyst in diesel fuel, as an abrasive in printed circuit manufacture, and is being pursued as an antioxidant therapeutic. Our objective is to extend previous findings showing that there were no reductions of cerium in organs of the mononuclear phagocyte (reticuloendothelial) system up to 30 days after a single nanoscale ceria administration. An ~5% aqueous dispersion of citrate-stabilized 30 nm ceria, synthesized and characterized in-house, or vehicle, was iv infused into rats terminated 1, 7, 30, or 90 days later. Cageside observations were obtained daily, body weight weekly. Daily urinary and fecal cerium outputs were quantified for 2 weeks. Nine organs were weighed and samples collected from 14 tissues/organs/systems, blood and cerebrospinal fluid for cerium determination. Histology and oxidative stress were assessed. Less than 1% of the nanoceria was excreted in the first 2 weeks, 98% in feces. Body weight gain was initially impaired. Spleen weight was significantly increased in some ceria-treated groups, associated with abnormalities. Ceria was primarily retained in the spleen, liver, and bone marrow. There was little decrease of ceria in any tissue over the 90 days. Granulomas were observed in the liver. Time-dependent oxidative stress changes were seen in the liver and spleen. Nanoscale ceria was persistently retained by organs of the mononuclear phagocyte system, associated with adverse changes. The results support concern about the long-term fate and adverse effects of inert nanoscale metal oxides that distribute throughout the body, are persistently retained, and produce adverse changes.
- Published
- 2012
87. Aluminum in Food – The Nature and Contribution of Food Additives
- Author
-
Robert A. Yokel
- Subjects
Allergy injections ,food.ingredient ,food ,Minimal risk ,Daily intake ,Food additive ,Dietary intake ,digestive, oral, and skin physiology ,Environmental science ,Food science - Abstract
Aluminum (Al) is distributed throughout the environment because of its presence as the third most abundant element on earth. Concern about Al toxicity to humans, including from food sources, has persisted since the demonstration that it has the potential to be a neurotoxicant (Wiley 1928, 1929; Schaeffer et al. 1928; Dollken 1898; Gies 1911; Anon. 1913; Yokel and Golub 1997; WHO 1997; Krewski et al. 2007; ATSDR 2008). Exposure of humans to Al is mainly from food, water, airborne dust, antiperspirants, immunizations, allergy injections and antacids (Table 1). Foods and beverages are the single largest contributor of Al intake for the typical human, providing ~ 3.5 to 10 mg/day. Food additives provide a significant percentage of the daily intake. Among the food additives, sodium aluminum phosphates (SALPs) are the main contributors. Drinking water provides ~ 0.1 mg. Other sources for some humans, their daily exposures and intakes, estimated percentage absorbed, and amount of Al that enters the blood are summarized in Table 1. The history of the use and regulation of Al food additives in the US, approved Al-containing food additives in the US and some other countries, primary food types contributing Al to the diet, typical daily dietary Al intake, dietary intake in relation to established tolerable intake and minimal risk levels, and some discussion of Al absorption, distribution, excretion, and toxicity are presented in this chapter.
- Published
- 2012
88. Rat brain pro-oxidant effects of peripherally administered 5 nm ceria 30 days after exposure
- Author
-
Eric A. Grulke, Michael T. Tseng, Uschi M. Graham, Peng Wu, D. Allan Butterfield, Jason M. Unrine, Robert A. Yokel, Govind Warrier, Mo Dan, Rebecca L. Florence, Rukhsana Sultana, and Sarita S. Hardas
- Subjects
Male ,medicine.medical_specialty ,Glutathione reductase ,Nitric Oxide Synthase Type II ,Spectroscopy, Electron Energy-Loss ,Toxicology ,medicine.disease_cause ,Antioxidants ,Mass Spectrometry ,Nitric oxide ,Superoxide dismutase ,Protein Carbonylation ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,HSP70 Heat-Shock Proteins ,chemistry.chemical_classification ,Aldehydes ,Glutathione Peroxidase ,biology ,Dose-Response Relationship, Drug ,Superoxide Dismutase ,General Neuroscience ,Glutathione peroxidase ,Brain ,Glutathione ,Cerium ,Nanostructures ,Rats ,Dose–response relationship ,Microscopy, Electron ,Endocrinology ,Glutathione Reductase ,chemistry ,Biochemistry ,Catalase ,biology.protein ,Tyrosine ,Oxidative stress - Abstract
The objective of this study was to determine the residual pro-or anti-oxidant effects in rat brain 30 days after systemic administration of a 5 nm citrate-stabilized ceria dispersion. A ∼4% aqueous ceria dispersion was iv-infused (0 or 85 mg/kg) into rats which were terminated 30 days later. Ceria concentration, localization, and chemical speciation in the brain was assessed by inductively coupled plasma mass spectrometry (ICP-MS), light and electron microscopy (EM), and electron energy loss spectroscopy (EELS), respectively. Pro- or anti-oxidant effects were evaluated by measuring levels of protein carbonyls (PC), 3-nitrotyrosine (3NT), and protein-bound-4-hydroxy-2-trans-nonenal (HNE) in the hippocampus, cortex, and cerebellum. Glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase levels and activity were measured in addition to levels of inducible nitric oxide (iNOS), and heat shock protein-70 (Hsp70). The blood brain barrier (BBB) was visibly intact and no ceria was seen in the brain cells. Ceria elevated PC and Hsp70 levels in hippocampus and cerebellum, while 3NT and iNOS levels were elevated in the cortex. Whereas glutathione peroxidase and catalase activity were decreased in the hippocampus, GR levels were decreased in the cortex, and GPx and catalase levels were decreased in the cerebellum. The GSH:GSSG ratio, an index of cellular redox status, was decreased in the hippocampus and cerebellum. The results are in accordance with the observation that this nanoscale material remains in this mammal model up to 30 days after its administration and the hypothesis that it exerts pro-oxidant effects on the brain without crossing the BBB. These results have important implications on the potential use of ceria ENM as therapeutic agents.
- Published
- 2012
89. Pharmacokinetics of aluminum 3-hydroxypyridin-4-one complexes: implications for aluminum redistribution subsequent to chelation therapy
- Author
-
Robert A. Yokel, Chris Orvig, and David D. Allen
- Subjects
Male ,Volume of distribution ,Chemotherapy ,Pyridones ,Chemistry ,Stereochemistry ,medicine.medical_treatment ,3-hydroxypyridin-4-one ,Pharmacology ,Toxicology ,Models, Biological ,Rats ,Rats, Sprague-Dawley ,Bolus (medicine) ,Pharmacokinetics ,Toxicity ,medicine ,Animals ,Regression Analysis ,Chelation ,Chelation therapy ,Aluminum ,Chelating Agents - Abstract
The pharmacokinetics of selected aluminum-hydroxypyridinone (Al-HP complexes were determined in rats to better understand the relationship between their disposition and elimination parameters and the safety of HPs in the chelation therapy of Al intoxication. Five complexes were administered as i.v. bolus doses of Al-HP (0.25 mmol/kg Al-0.75 mmol/kg HP). The Al-HP steady state volumes of distribution ranged from 220 to 871 ml/kg, suggesting that each complex distributed out of the vascular compartment (which should have been approximately 65 ml/kg). Systemic clearances ranged from 189 to 906 ml/h per kg. Elimination half-lives (t1/2) and mean residence times ranged from 0.36 to 0.84 and 0.52 to 1.20 h, respectively. The Al-CP20 complex had a short t1/2 and a midrange volume of distribution. It demonstrated no apparent toxicity, whereas myoclonic seizures were observed after Al-CP22, Al-CP24 and Al-CP94 administration. The most appropriate choice for Al chelation among the HPs tested may be CP20. Characterization of the distribution and elimination of Al-HP complexes improves the understanding of potential toxicity that may be associated with HP therapy of Al intoxication.
- Published
- 1994
90. Ceria-engineered nanomaterial distribution in, and clearance from, blood: size matters
- Author
-
Peng Wu, Jason M. Unrine, Uschi M. Graham, Robert A. Yokel, Mo Dan, and Eric A. Grulke
- Subjects
Male ,Serum ,Materials science ,Metabolic Clearance Rate ,Pharmacokinetic modeling ,Biomedical Engineering ,Medicine (miscellaneous) ,chemistry.chemical_element ,Bioengineering ,Nanotechnology ,Development ,Nanomaterials ,Rats, Sprague-Dawley ,Hydroxides ,Distribution (pharmacology) ,Animals ,General Materials Science ,Particle Size ,Blood Coagulation ,Whole blood ,Ions ,Nanotubes ,Half-life ,Cerium ,Pharmacokinetic analysis ,Rats ,Kinetics ,chemistry ,Nanoparticles ,Clearance ,Nuclear chemistry ,Half-Life - Abstract
Aims: Characterize different sized ceria-engineered nanomaterial (ENM) distribution in, and clearance from, blood (compared to the cerium ion) following intravenous infusion. Materials & Methods: Cerium (Ce) was quantified in whole blood, serum and clot (the formed elements) up to 720 h. Results: Traditional pharmacokinetic modeling showed best fit for 5 nm ceria ENM and the cerium ion. Ceria ENMs larger than 5 nm were rapidly cleared from blood. After initially declining, whole blood 15 and 30 nm ceria increased (results that have not been well-described by traditional pharmacokinetic modeling). The cerium ion and 5 and 55 nm ceria did not preferentially distribute into serum or clot, a mixture of cubic and rod shaped ceria was predominantly in the clot, and 15 and 30 nm ceria migrated into the clot over 4 h. Conclusion: Reticuloendothelial organs may not readily recognize five nm ceria. Increased ceria distribution into the clot over time may be due to opsonization. Traditional pharmacokinetic analysis was not very informative. Ceria ENM pharmacokinetics are quite different from the cerium ion.
- Published
- 2011
91. Alteration of hepatic structure and oxidative stress induced by intravenous nanoceria
- Author
-
Eric A. Grulke, Michael T. Tseng, D. Allan Butterfield, Robert A. Yokel, Uschi M. Graham, Peng Wu, Jason M. Unrine, Xiaoqin Lu, Xiaoxian Duan, Rukhsana Sultana, and Sarita S. Hardas
- Subjects
Male ,Biodistribution ,Pathology ,medicine.medical_specialty ,Antioxidant ,Liver cytology ,Kupffer Cells ,medicine.medical_treatment ,Apoptosis ,Pharmacology ,Toxicology ,medicine.disease_cause ,Protein Carbonylation ,Rats, Sprague-Dawley ,Microscopy, Electron, Transmission ,medicine ,In Situ Nick-End Labeling ,Animals ,HSP70 Heat-Shock Proteins ,Aspartate Aminotransferases ,TUNEL assay ,Granuloma ,Chemistry ,Superoxide Dismutase ,Kupffer cell ,Cerium ,Catalase ,Immunohistochemistry ,Rats ,Oxidative Stress ,medicine.anatomical_structure ,Glutathione Reductase ,Liver ,Heme Oxygenase (Decyclizing) ,Hepatic stellate cell ,Hepatocytes ,Nanoparticles ,Tyrosine ,Oxidative stress - Abstract
Beyond the traditional use of ceria as an abrasive, the scope of nanoceria applications now extends into fuel cell manufacturing, diesel fuel additives, and for therapeutic intervention as a putative antioxidant. However, the biological effects of nanoceria exposure have yet to be fully defined, which gave us the impetus to examine its systemic biodistribution and biological responses. An extensively characterized nanoceria (5 nm) dispersion was vascularly infused into rats, which were terminated 1 h, 20 h or 30 days later. Light and electron microscopic tissue characterization was conducted and hepatic oxidative stress parameters determined. We observed acute ceria nanoparticle sequestration by Kupffer cells with subsequent bioretention in parenchymal cells as well. The internalized ceria nanoparticles appeared as spherical agglomerates of varying dimension without specific organelle penetration. In hepatocytes, the agglomerated nanoceria frequently localized to the plasma membrane facing bile canaliculi. Hepatic stellate cells also sequestered nanoceria. Within the sinusoids, sustained nanoceria bioretention was associated with granuloma formations comprised of Kupffer cells and intermingling CD3⁺ T cells. A statistically significant elevation of serum aspartate aminotransferase (AST) level was seen at 1 and 20 h, but subsided by 30 days after ceria administration. Further, elevated apoptosis was observed on day 30. These findings, together with increased hepatic protein carbonyl levels on day 30, indicate ceria-induced hepatic injury and oxidative stress, respectively. Such observations suggest a single vascular infusion of nanoceria can lead to persistent hepatic retention of particles with possible implications for occupational and therapeutic exposures.
- Published
- 2011
92. The neurotoxic potential of engineered nanomaterials
- Author
-
Chunying Chen, William K. Boyes, Rui Chen, and Robert A. Yokel
- Subjects
business.industry ,Potential risk ,General Neuroscience ,Engineered nanomaterials ,Systemic absorption ,Brain ,Nanotechnology ,Environmental Exposure ,Toxicology ,Risk Assessment ,Retina ,Nanostructures ,Viscera ,Risk Factors ,Medicine ,Humans ,Environmental Pollutants ,Neurotoxicity Syndromes ,Tissue Distribution ,Tissue distribution ,business ,Biotransformation - Abstract
The expanding development and production of engineered nanomaterials (ENMs) have diverse and far-reaching potential benefits in consumer products, food, drugs, medical devices and for enhancing environmental cleanup and remediation. The knowledge of potential implications of ENMs, including the potential for inadvertent exposures and adverse neurotoxic consequences, is lagging behind their development. A potential risk for neurotoxicity arises if exposure leads to systemic absorption and distribution to the nervous system. This paper is the summary of a symposium entitled Neurotoxicity Potential of Engineered Nanomaterials presented at the 2011 Xi'an International Neurotoxicology Conference held June 5-9 in Xi'an China. The following topics were featured in the symposium: the toxicokinetics of engineered nanomaterials; differential uptake of nanoceria in brain and peripheral organs; translocation into the brain and potential damage following nanoparticle exposure; and the retina as a potential site of nanomaterial phototoxicity. Each of these topics is discussed fully in sections of the manuscript. The promising benefits of ENM technology can be best realized if the potential risks are first understood and then minimized in product and system designs.
- Published
- 2011
93. Evaluation of 4-hydroxy-6-methyl-3-pyridinecarboxylic acid and 2,6-dimethyl-4-hydroxy-3-pyridinecarboxylic acid as chelating agents for iron and aluminium
- Author
-
Ignazio Castagliuolo, Maria Grazia Ferlin, Paola Brun, Annalisa Dean, Valerio Di Marco, Robert A. Yokel, G. Giorgio Bombi, and Alfonso Venzo
- Subjects
Octanol ,Aqueous solution ,medicine.diagnostic_test ,Ligand ,Potentiometric titration ,Inorganic chemistry ,chemistry.chemical_element ,Inorganic Chemistry ,Metal ,chemistry.chemical_compound ,chemistry ,Aluminium ,Spectrophotometry ,visual_art ,Materials Chemistry ,medicine ,visual_art.visual_art_medium ,Chelation ,Physical and Theoretical Chemistry ,Nuclear chemistry - Abstract
4-Hydroxy-6-methyl-3-pyridinecarboxylic acid (DQ6) and the new compound 2,6-dimethyl-4-hydroxy-3-pyridinecarboxylic acid (DQ726) were evaluated for possible application for iron (Fe) and aluminium (Al) chelation therapy. Metal/ligand solution chemistry, cytotoxicity, octanol/water partitioning (Do/w), and chelation efficiency were studied. The solution chemistry of the two ligands with Fe(III) and Al(III) was investigated in aqueous 0.6 m (Na)Cl at 25 °C by means of potentiometric titrations, UV–Vis spectrophotometry, and 1H NMR spectroscopy. DQ6 exhibited a high coordination efficiency towards Al(III). Fe(III)/DQ6, Al(III)/DQ726, and Fe(III)/DQ726 complexes were less stable. These results were confirmed by chelation efficiency measurements performed in an octanol/aqueous solution. Accordingly, the effects of the substitution at various ring positions of 4-hydroxy-3-pyridinecarboxylic acid were rationalised. Partitioning experiments at pH 7.4 showed both DQ6 and DQ726, and their Fe(III) and Al(III) complexes, to be hydrophilic. The toxicity of DQ6 and of DQ726 was investigated with human cancer cell lines and normal human primary cells: no cytotoxic effects were observed up to 0.1 mM, following a 3 days exposure. According to our results, DQ6 has the favourable properties to be a chelating agent for Al.
- Published
- 2011
94. Brain distribution and toxicological evaluation of a systemically delivered engineered nanoscale ceria
- Author
-
Rebecca L. Florence, Mo Dan, Jason M. Unrine, Sarita S. Hardas, Robert A. Yokel, Rukhsana Sultana, Peng Wu, Eric A. Grulke, Uschi M. Graham, David Allan Butterfield, and Michael T. Tseng
- Subjects
Male ,Antioxidant ,medicine.medical_treatment ,Glutathione reductase ,Toxicology ,Blood–brain barrier ,medicine.disease_cause ,Horseradish peroxidase ,Rats, Sprague-Dawley ,medicine ,Animals ,chemistry.chemical_classification ,biology ,Chemistry ,Glutathione peroxidase ,Neurotoxicity ,Brain ,Cerium ,Hydrogen-Ion Concentration ,medicine.disease ,Catalase ,Nanostructures ,Rats ,Oxidative Stress ,medicine.anatomical_structure ,Biochemistry ,Blood-Brain Barrier ,biology.protein ,Biophysics ,Oxidative stress - Abstract
Engineered nanoscale ceria is used as a diesel fuel catalyst. Little is known about its mammalian central nervous system effects. The objective of this paper is to characterize the biodistribution of a 5-nm citrate-stabilized ceria dispersion from blood into brain and its pro- or antioxidant effects. An approximately 4% aqueous ceria dispersion was iv infused into rats (0, 100, and up to 250 mg/kg), which were terminated after 1 or 20 h. Ceria concentration, localization, and chemical speciation in the brain were assessed by inductively coupled plasma mass spectrometry, light and electron microscopy (EM), and electron energy loss spectroscopy (EELS). Pro- or antioxidative stress effects were assessed as protein carbonyls, 3-nitrotyrosine, and protein-bound 4-hydroxy-2-trans-nonenal in hippocampus, cortex, and cerebellum. Glutathione reductase, glutathione peroxidase, manganese superoxide dismutase, and catalase levels and activities were measured in hippocampus. Catalase levels and activities were also measured in cortex and cerebellum. Na fluorescein and horseradish peroxidase (HRP) were given iv as blood-brain barrier (BBB) integrity markers. Mortality was seen after administration of 175-250 mg ceria/kg. Twenty hours after infusion of 100 mg ceria/kg, brain HRP was marginally elevated. EM and EELS revealed mixed Ce(III) and Ce(IV) valence in the freshly synthesized ceria in vitro and in ceria agglomerates in the brain vascular compartment. Ceria was not seen in microvascular endothelial or brain cells. Ceria elevated catalase levels at 1 h and increased catalase activity at 20 h in hippocampus and decreased catalase activity at 1 h in cerebellum. Compared with a previously studied approximately 30-nm ceria, this ceria was more toxic, was not seen in the brain, and produced little oxidative stress effect to the hippocampus and cerebellum. The results are contrary to the hypothesis that a smaller engineered nanomaterial would more readily permeate the BBB.
- Published
- 2010
95. 4-trimethylammonium antipyrine: A quaternary ammonium nonradionuclide marker for blood-brain barrier integrity during in vivo microdialysis
- Author
-
Peter A. Crooks, David D. Allen, and Robert A. Yokel
- Subjects
Male ,Microdialysis ,Frontal cortex ,Pharmacology ,Toxicology ,Blood–brain barrier ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Cerebrospinal fluid ,In vivo ,Extracellular fluid ,medicine ,Animals ,Ammonium ,Chromatography, High Pressure Liquid ,Brain ,Permeation ,Rats ,Quaternary Ammonium Compounds ,medicine.anatomical_structure ,nervous system ,Biochemistry ,chemistry ,Blood-Brain Barrier ,cardiovascular system ,Dialysis ,Antipyrine ,Evans Blue - Abstract
The well-controlled microdialysis (MD) study of substance permeation into brain extracellular fluid (ECF) and cerebrospinal fluid requires consideration of blood-brain barrier (BBB) integrity, which might be compromised by microdialysis probe implantation. Others have assessed BBB integrity with radionuclide markers. A nonradionuclide marker may be desirable in many studies. A charged antipyrine analogue may be useful to determine BBB integrity with concomitant antipyrine characterization of probe efficiency (Yokel et al., 1992, J Pharmacol Toxicol Methods 27: 135–142), and may not require another analytical technique. We synthesized, validated, and evaluated 4-trimethylammonium antipyrine (4TMA-AP) as a BBB integrity marker. BBB permeation was determined by calculation of a BBB integrity percentage (P i ) from brain/blood concentrations. The P i s of Evan's blue, which does not permeate the intact BBB, and 4TMA-AP were not significantly different in rats without known BBB disruption, suggesting a lack of 4TMA-AP permeation through the intact BBB. When MD probes were slowly implanted into the frontal cortex, 4TMA-AP P i s were usually zero. Intracarotid oleic acid injection to open the BBB significantly increased 4TMA-AP P i s, suggesting that 4TMA-AP entered brain ECF when the BBB was compromised. Rapid probe implantation produced increased 4TMA-AP P i s, suggesting BBB disruption. The predicted appearance of 4TMA-AP in brain ECF suggests that it is a BBB integrity marker.
- Published
- 1992
96. Dissimilar Aluminum and Gallium Permeation of the Blood-Brain Barrier Demonstrated by In Vivo Microdialysis
- Author
-
Robert A. Yokel and David D. Allen
- Subjects
Male ,Microdialysis ,Time Factors ,Femoral vein ,Gallium ,Vascular permeability ,Blood–brain barrier ,Biochemistry ,Capillary Permeability ,Cellular and Molecular Neuroscience ,Jugular vein ,medicine ,Animals ,Tissue Distribution ,Chemistry ,Osmolar Concentration ,Area under the curve ,Brain ,Rats, Inbred Strains ,Anatomy ,Permeation ,Rats ,medicine.anatomical_structure ,Blood-Brain Barrier ,Ventricle ,Biophysics ,Dialysis ,Aluminum - Abstract
Aluminum (Al) and gallium (Ga) permeations of the blood-brain barrier (BBB) were assessed in rats. Unbound extracellular Al and Ga concentrations were ascertained at the two potential sites of BBB permeation, cerebral capillaries and choroid plexuses, by implantation of microdialysis probes in the frontal cortex and lateral ventricle, respectively. A microdialysis probe implanted in the jugular vein revealed unbound blood Al or Ga concentrations. Al or 67Ga citrate was administered via the femoral vein. Peak Al and Ga concentrations were seen within the first 10 min at all three sites. Area under the curve (concentration vs. time to final sample) values were calculated using RSTRIP. Within-rat overall frontal cortical/blood and lateral ventricular/blood ratios [brain/blood ratios (oBBRs)] were calculated from area under the curve values. Aluminum frontal cortical oBBRs were significantly higher than those for the lateral ventricle. Ga oBBRs were not significantly different between the two sites. Al and Ga oBBRs were significantly different in the lateral ventricle. These results suggest that the primary site of A1 permeation across the BBB is at cerebral capillaries, whereas Ga permeation across the BBB does not significantly differ between cerebral capillaries and choroid plexuses. The use of Ga as a model to study Al pharmacokinetics may not be appropriate in the elucidation of the site or mechanism of Al entry into the brain.
- Published
- 1992
97. Intranasal drug delivery of didanosine-loaded chitosan nanoparticles for brain targeting; an attractive route against infections caused by AIDS viruses
- Author
-
Ahmad H. Malkawi, Abeer M. Al-Ghananeem, Robert A. Yokel, Rebecca L. Florence, and Hayder Saeed
- Subjects
Drug ,Male ,media_common.quotation_subject ,Pharmaceutical Science ,HIV Infections ,Pharmacology ,Mass Spectrometry ,Chitosan ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Drug Delivery Systems ,Pharmacokinetics ,Microscopy, Electron, Transmission ,medicine ,Animals ,Microparticle ,Didanosine ,Administration, Intranasal ,media_common ,Drug Carriers ,biology ,virus diseases ,Brain ,Rats ,Disease Models, Animal ,chemistry ,Biochemistry ,Enzyme inhibitor ,biology.protein ,Nanoparticles ,Reverse Transcriptase Inhibitors ,Nasal administration ,Drug carrier ,medicine.drug ,Chromatography, Liquid - Abstract
The primary aim of this study was to investigate intranasal (i.n.) administration as a potential route to enhance systemic and brain delivery of didanosine (ddI). A further aim was to investigate the potential use of chitosan nanoparticles as a delivery system to enhance the systemic and brain targeting efficiency of ddI following i.n. administration. Didanosine-loaded chitosan nanoparticles, were prepared through ionotropic gelation of chitosan with tripolyphosphonate anions, and characterized in terms of their size, drug loading, and in vitro release. The nanoparticles were administered i.n. to rats, compared to i.n. and intravenous (i.v.) administration of ddI in solution. The concentrations of ddI in blood, CSF, and brain tissues were analyzed by ultra performance liquid chromatography mass spectroscopy (UPLC/MS). The brain/plasma, olfactory bulb/plasma and CSF/plasma concentration ratios were significantly higher (P0.05) after i.n. administration of ddI nanoparticles or solution than those after i.v. administration of didanosine aqueous solution. The ratio of ddI concentration values of the nanoparticles to the solution at 180 min post-i.n. dosing was 2.1 and 1.9 in CSF and brain, respectively. Thus, both the i.n. route of administration and formulation of ddI in chitosan nanoparticles increased delivery of ddI to CSF and brain.
- Published
- 2009
98. Mucosal Injury and γ-Irradiation Produce Persistent Gastric Ulcers in the Rabbit
- Author
-
Kenneth M. Dickey and Robert A. Yokel
- Subjects
Pathology ,medicine.medical_specialty ,Gastrointestinal tract ,Muscularis mucosae ,Hepatology ,biology ,Antiulcer drug ,Stomach ,digestive, oral, and skin physiology ,Gastroenterology ,digestive system diseases ,Fibrin ,Sucralfate ,medicine.anatomical_structure ,Submucosa ,biology.protein ,medicine ,Antrum ,medicine.drug - Abstract
A method producing persistent gastric ulcers in the rhesus monkey by combined mucosal injury and γ-irradiation was modified and evaluated in the rabbit. γ-Irradiation (800–1000 cGy) immediately after removal of 2-mm-diameter sections of antral mucosa resulted in ulcer craters 5–7 days later. Ulcer sites were characterized by loss of the mucosa, muscularis mucosa, and much of the submucosa. The exposed submucosa was coated with fibrin and necrotic debris infiltrated with heterophils, the rabbit equivalent of neutrophils. These ulcers strongly resemble human chronic gastric ulcers. Binding of Carafate (sucralfate; Marion Laboratories, Inc., Kansas City, MO) and Maalox (magnesia-alumina oral suspension; Wm. H. Rorer, Inc., Ft. Washington, PA) to ulcer and nearby nonulcer sites in the antrum was assessed 1 hour after drug dosing. Drug binding was determined by aluminum quantitation of stomach wall punch biopsies at necropsy. Both drugs significantly increased aluminum bound to the stomach wall compared with vehicle treatment. Significantly more antiulcer drug was bound to ulcer sites than to nearby nonulcer sites only after sucralfate administration. This model of persistent gastric ulcer should be useful to further study gastric ulcer pathogenesis and treatment.
- Published
- 1991
99. Aluminum mobilization by desferrioxamine assessed by microdialysis of the blood, liver and brain☆☆☆
- Author
-
Urban Ungerstedt, Vitauts Lidums, and Robert A. Yokel
- Subjects
Male ,medicine.medical_specialty ,Microdialysis ,medicine.medical_treatment ,Encephalopathy ,Deferoxamine ,Toxicology ,Internal medicine ,medicine ,Extracellular ,Animals ,Chelation therapy ,Antidote ,Dialysis ,Brain Chemistry ,Chemotherapy ,Chemistry ,Spectrophotometry, Atomic ,Brain ,Rats, Inbred Strains ,medicine.disease ,Chelation Therapy ,Rats ,Kinetics ,Endocrinology ,Liver ,Injections, Intraperitoneal ,Aluminum ,medicine.drug - Abstract
Aluminum (Al) mobilization by i.v. desferrioxamine (DFO) into blood and into brain and liver extracellular space was followed in the Al-loaded rat using microdialysis probes. Dialyzable extracellular liver Al peaked at an estimated 1360 microgram/l whereas dialyzable blood and extracellular brain Al peaked at 860 and 155-175 microgram/l, respectively. Estimated Al concentrations were derived from dialysate Al from microdialysis probes which was corrected for probe efficiency. Liver Al after DFO was generally greater than blood Al. Both declined over time. The rapid increase in extracellular liver Al above blood Al suggests the ability of DFO to rapidly distribute out of the vascular compartment to mobilize Al from hepatocytes. Presumably an Al-DFO complex was formed and released into blood, from which it was eliminated. Extracellular brain Al and DFO was less than blood Al and did not decline during 5 h. After an i.v. Al-DFO injection to non-Al-loaded rats, blood Al was greater than liver much greater than brain Al, suggesting Al-DFO diffusion down a concentration gradient and demonstrating the ability of Al-DFO to permeate vascular membranes and the blood-brain barrier. The lack of decline of brain extracellular Al after DFO was presumably due to its inability to diffuse into the blood against the concentration gradient. The DFO-induced mobilization of Al in the brain may explain the reports of sudden onset or worsening of encephalopathy associated with DFO treatment of Al-loaded humans.
- Published
- 1991
100. Aluminum distribution into brain and liver of rats and rabbits following intravenous aluminum lactate or citrate: A microdialysis study*1, *2
- Author
-
Urban Ungerstedt, Robert A. Yokel, Vitauts Lidums, and Patrick J. McNamara
- Subjects
Pharmacology ,medicine.medical_specialty ,Microdialysis ,Lagomorpha ,biology ,Chemistry ,Toxicology ,biology.organism_classification ,Dialysis tubing ,Endocrinology ,Biochemistry ,In vivo ,Internal medicine ,Blood plasma ,Extracellular fluid ,medicine ,Extracellular ,Toxicokinetics - Abstract
Microdialysis probes were utilized to follow the appearance and disappearance of dialyzable aluminum (Al) in rat and rabbit brain and liver extracellular fluid compared to blood after iv Al lactate or Al citrate injection. Dialyzable Al was assumed to be the fraction not protein bound or self-associated into complexes > the molecular weight cutoff of the dialysis membrane. Aluminum concentrations peaked in brain frontal cortex and ventral hippocampus and in the liver in the first 20-min dialysis sample, indicating rapid Al penetration into the extracellular space of these organs. In vitro recovery experiments conducted with microdialysis probes at room temperature revealed an average dialysis efficiency of about 10% for both Al lactate and citrate. At 37°C Al recovery increased for both Al lactate and citrate. In vivo Al recovery from rabbit blood averaged 5.15% for Al lactate and 3.25% for Al citrate. These observations are consistent with results from recovery studies of other substances showing an increased recovery with increased temperature but an overestimate of recovery by in vitro methods. Tissue/blood Al ratios (TBR; representing dialyzable extracellular tissue Al ÷ dialyzable blood plasma Al) for liver were ≈1, suggesting unhindered diffusion of Al between blood and liver. In contrast, brain TBR were TBR for Al citrate, suggesting that Al citrate did not preferentially penetrate the blood-brain barrier. Higher TBR were seen in the rabbit than the rat, perhaps contributing to the greater susceptibility of the rabbit to Al-induced neurobehavioral toxicity. Metals can be repetitively sampled in the extracellular space using microdialysis, enabling metal toxicokinetic determinations in these compartments.
- Published
- 1991
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