DOCSLIB.ORG

Natural Modulators of Amyloid Formation in Alzheimer's Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Natural Modulators of Amyloid Formation in Alzheimer's Disease Natural modulators of amyloid formation in Alzheimer’s disease Sirwan M. Amin Al-Jaf A Thesis Submitted for the degree of Doctors of Philosophy July 2016 University of Sheffield Department of Molecular Biology and Technology For Sirwan’s Family; Mother, father, wife, children, brothers and sisters. Abstract Alzheimer’s disease (AD) is the most common cause of dementia, and the deposition of amyloid β (Aβ) peptide in the AD brains is a hallmark of the disease. Other amyloidogenic proteins like Transthyretin (TTR) and human Cystatin C (hCC) can modulate the aggregation of Aβ. These two proteins are proposed to play a role in the pathophysiology of AD as they are found co-deposited in amyloid deposits in the brains of AD patients, most notably at the cell surface. Animal models and cell line assays showed protective roles for TTR and hCC against Aβ-induced toxicity, and Aβ fibril formation is inhibited through interaction with TTR and hCC. This study investigated the mechanism of in vitro interaction of TTR with Aβ. The ability of WT TTR to inhibit Aβ fibrillisation in the presence of Aβ binding surfaces was higher than in the presence of non-binding surfaces. Then, the interaction between different TTR mutants with different multimeric stabilities and different alloforms of Aβ showed that TTRs with less stable tetramers and unfolded monomers are the best inhibitors of Aβ fibrillisation. Analysing the thioflavin T curves of Aβ aggregation in the presence of TTRs and the interaction of TTRs with different forms of Aβ showed that the interaction between the two proteins occurs mainly through binding to early nucleating species of Aβ rather than to the monomer. The dose-dependent inhibition of Aβ fibrillisation and the promotion of amorphous aggregates by hCC were validated. However, the previous suggestion of simple monomer to monomer interaction between Aβ and hCC was not confirmed. Instead, a proposed hCC binding to oligomeric species of Aβ was supported by the observed hCC interaction with different aggregated species of Aβ. The dimeric form of hCC was found to be a less effective inhibitor compared to WT monomer, indicating that the active site could be the hydrophobic loops involved in dimerisation and protease inhibition. This interpretation was supported, as mutation of hydrophobic residues in the active site significantly reduced the intensity of hCC to inhibit Aβ fibrillisation. We showed that these two proteins are mainly inhibit Aβ fibrillisation through interaction with the early aggregated structures of Aβ (some form of oligomers). As it is known that oligomers are responsible for Aβ toxicity in vivo, the potential of these two proteins to be used as natural modulators is supported by this study. Acknowledgements First and foremost I must thank my supervisor Rosie Staniforth who has been wonderful, both for supervising my PhD in the first place and for all her guidance, support and encouragement throughout the last four years, especially during the painful writing up process. I would also like to thank my advisors Jon Waltho, John Rafferty and Mike Williamson for all their help and guidance. Andrea Hounslow has been amazing, assisting me with the NMR experiments and analysis. Thank you also to Svet Tzokov for all of his help with EM. Thank you also to amyloid group, particularly Abi, Pete, Amy, Liam and Alex. Abi has been simply a great colleauge, she was always around for a help and a part of my research has been based on her work, for which I am very grateful. The NMR group have been great; it would be impossible to name everybody (and I would undoubtedly forget someone), but thank you all so much for the help and advice. Thank you also to the NMR group Nicky, Claire, Luke and Angus. Thanks for all the excellent cakes, I have enjoyed Friday cakes a lot. Outside the lab, I have met many wonderful people since moving to Sheffield, but special thanks must go to Taib, Isam, Salar, and Omed. I’m so glad I met you all, and I definitely wouldn’t have made it through without you all. Outside the university, I would like to thank Sarwat, Sartip and Barzan, especially Sarwat for his help at the early days on arriving to UK and been a great friend all the time. Thank you to my wonderful family, to Mum, Dad and the whole family (brothers and sisters) for all their love and support, it means so much to me and I am truly grateful. Thanks to The Higher Committee for Education Development in Iraq, for sponsoring my PhD. Thanks to my friends and university colleagues back home, they were always happy to help for anything I needed there. Last but not least, thank you to my wonderful wife, Srwa, for companionship, as I made her to live away of her family and friends for 4 years, putting up with me and for always believing in me. I couldn’t have done it without you. Table of contents Contents Pages Chapter 1: Introduction .................................................................................................. 1 Background ............................................................................................................................. 1 1. 1. Classification of Amyloid ................................................................................................ 2 1. 2. Alzheimer’s disease ......................................................................................................... 4 1. 3. The structure of amyloid ................................................................................................ 6 1. 4. Atomic-level structural determination .......................................................................... 8 1.4. 1. X-Ray Fibre Diffraction ............................................................................................. 8 1.4.2. Microscopy Techniques ............................................................................................ 9 1.4.3. Cryo-electron microscopy ....................................................................................... 10 1.4.4. Hydrogen-deuterium exchange (HX) ...................................................................... 12 1.4. 5. Limited proteolysis ................................................................................................. 13 1.4. 6. Solid-state nuclear magnetic resonance spectroscopy ............................................ 14 1. 5. Amyloid probing .......................................................................................................... 15 1. 5. 1. Congo red ................................................................................................................ 15 1. 5. 2. Thioflavin T (ThT) .................................................................................................. 16 1. 6. Definitions of amyloid structures ................................................................................. 16 1. 6. 1. Amyloid fibril ......................................................................................................... 16 1. 6. 2. Protofilament ........................................................................................................... 17 1. 6. 3. Amyloid intermediates ............................................................................................ 17 1. 6. 3. 1. Protofibrils .......................................................................................................... 17 1. 6. 3. 2. Annular aggregates ............................................................................................. 18 1. 6. 3. 3. Oligomers ............................................................................................................ 18 1. 6. 3. 4. Aβ-derived diffusible ligands (ADDLs). ............................................................ 19 1. 6. 4. Amorphous aggregate ............................................................................................. 19 1. 6. 5. Amyloid fibril seed ................................................................................................. 19 1. 7. Transformation to the amyloid-forming competent state ......................................... 20 1. 8. Mechanism of fibril formation ..................................................................................... 22 1. 9. Kinetic models ............................................................................................................... 23 1.10. Alzheimer’s disease and related proteins ....................................................................... 27 1. 10. 1. Transthyretin (TTR) .................................................................................................. 27 1. 10. 1. 1. TTR amyloidosis ............................................................................................... 28 1. 10. 1. 2. TTR and Aβ ...................................................................................................... 29 1. 10. 2. Human Cystatin C ..................................................................................................... 33 1. 10. 2. 1. Cystatin C amyloidosis ..................................................................................... 33 1. 10. 2. 2. Cystatin C and Aβ ............................................................................................. 35 1. 10. 2. 3. Genetic studies .................................................................................................. 36 1. 10. 2. 4. Mechanisms of neuroprotection ........................................................................ 37 1. 10. 3. Neuroserpin
Load more

Recommended publications
  • Effects of Polyols on the Processing and Qualities of Wheat Tortillas'
    BREADMAKING Effects of Polyols on the Processing and Qualities of Wheat Tortillas' E. L. SUHENDRO, 2 R. D. WANISKA,2 L. W. ROONEY, 2 and M. H. GOMEZ 3 ABSTRACT Cereal Chem. 72(l):122-127 Effects of polyols on processing of hot-press wheat tortillas were evalu- Doughs containing 6% polyols, except maltitol, were stickier and less ated. Hot-press wheat tortillas with 0, 2, 4, or 6% glycerol were prepared machinable than control doughs. Tortillas prepared from 10.2% protein from wheat flour of 10.2, 11.0, or 11.5% protein content. Tortillas with flour with or without polyols were less rollable during storage compared 2, 4, or 6% propylene glycol, sorbitol, or maltitol were prepared from to those prepared from higher protein flours. Tortillas containing glycerol the 11.0% protein flour. Farinograph and alveograph values, dough mixing had less moisture, higher liquid content, and improved shelf-stability, characteristics and machinability, rollability over time, sensory evaluation, except when prepared from low protein flour. Water activity decreased water holding capacity, total liquid content, and water activity were deter- with increasing polyol level. Propylene glycol and glycerol were more mined. Low protein (10.2%) flour required less water, shorter mixing effective in decreasing water activity than sorbitol and maltitol. Formulas time, and yielded tortilla doughs that were less machinable compared containing 4% polyols and Ž11.0% protein flour had good machinability to other flours. Water absorption decreased with increasing polyol level. and yielded acceptable tortillas with improved rollability during storage. The increased production of wheat tortillas in the United States Propylene glycol (J.T.
    [Show full text]
  • A Guide to Transthyretin Amyloidosis
    A Guide to Transthyretin Amyloidosis Authored by Teresa Coelho, Bo-Goran Ericzon, Rodney Falk, Donna Grogan, Shu-ichi Ikeda, Mathew Maurer, Violaine Plante-Bordeneuve, Ole Suhr, Pedro Trigo 2016 Edition Edited by Merrill Benson, Mathew Maurer What is amyloidosis? Amyloidosis is a systemic disorder characterized by extra cellular deposition of a protein-derived material, known as amyloid, in multiple organs. Amyloidosis occurs when native or mutant poly- peptides misfold and aggregate as fibrils. The amyloid deposits cause local damage to the cells around which they are deposited leading to a variety of clinical symptoms. There are at least 23 different proteins associated with the amyloidoses. The most well-known type of amyloidosis is associated with a hematological disorder, in which amyloid fibrils are derived from monoclonal immunoglobulin light-chains (AL amyloidosis). This is associated with a clonal plasma cell disorder, closely related to and not uncommonly co-existing with multiple myeloma. Chronic inflammatory conditions such as rheumatoid arthritis or chronic infections such as bronchiectasis are associated with chronically elevated levels of the inflammatory protein, serum amyloid A, which may misfold and cause AA amyloidosis. The hereditary forms of amyloidosis are autosomal dominant diseases characterized by deposition of variant proteins, in dis- tinctive tissues. The most common hereditary form is transthyretin amyloidosis (ATTR) caused by the misfolding of protein monomers derived from the tetrameric protein transthyretin (TTR). Mutations in the gene for TTR frequently re- sult in instability of TTR and subsequent fibril formation. Closely related is wild-type TTR in which the native TTR protein, particu- larly in the elderly, can destabilize and re-aggregate causing non- familial cases of TTR amyloidosis.
    [Show full text]
  • Frequency of Renal Monitoring – Creatinine and Cystatin C): an Observational Cohort Study of Primary Care Patients with Reduced Egfr
    Accepted Manuscript British Journal of General Practice FORM-2C (Frequency of Renal Monitoring – Creatinine and Cystatin C): An observational cohort study of primary care patients with reduced eGFR Fleming, Susannah; Perera, Rafael; Taylor, Kathryn; Jones, Louise; Hobbs, FD Richard; James, Tim; O’Callaghan, Chris; Shine, Brian; Verbakel, Jan ; Stevens, Richard; Bankhead, Clare DOI: https://doi.org/10.3399/BJGP.2020.0940 To access the most recent version of this article, please click the DOI URL in the line above. Received 19 October 2020 Revised 15 March 2021 Accepted 07 April 2021 © 2021 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License (http://creativecommons.org/licenses/by/4.0/). Published by British Journal of General Practice. For editorial process and policies, see: https://bjgp.org/authors/bjgp-editorial-process-and-policies When citing this article please include the DOI provided above. Author Accepted Manuscript This is an ‘author accepted manuscript’: a manuscript that has been accepted for publication in British Journal of General Practice, but which has not yet undergone subediting, typesetting, or correction. Errors discovered and corrected during this process may materially alter the content of this manuscript, and the latest published version (the Version of Record) should be used in preference to any preceding versions Title page FORM-2C (Frequency of Renal Monitoring – Creatinine and Cystatin C): An observational cohort study of primary care patients
    [Show full text]
  • Polyols Have a Variety of Functional Properties That Make Them Useful Alternatives to Sugars in Applications Including Baked Goods
    Polyols have a variety of functional properties that make them useful alternatives to sugars in applications including baked goods. Photo © iStockphoto.com/Synergee pg 22 09.12 • www.ift.org BY LYN NABORS and THERESA HEDRICK SUGAR REDUCTION WITH Polyols Polyols are in a unique position to assist with reduced-sugar or sugar-free reformulations since they can reduce calories and complement sugar’s functionality. ugar reduction will be an important goal over the of the product’s original characteristics may still be main- next few years as consumers, government, and in- tained with the replacement of those sugars by polyols. Sdustry alike have expressed interest in lower-calorie In addition, excellent, good-tasting sugar-free products and lower-sugar foods. The 2010 Dietary Guidelines for can be developed by using polyols. Polyols are in a unique Americans put a strong emphasis on consuming fewer position to assist with reduced-sugar or sugar-free refor- calories and reducing intake of added sugars. The In- mulations; since they are only partially digested and ab- stitute of Medicine (IOM) held a public workshop in sorbed, they can reduce calories and complement sugar’s November 2010 to discuss ways the food industry can functionality. Polyols provide the same bulk as sugars and use contemporary and innovative food processing tech- other carbohydrates. Additionally, polyols have a clean, nologies to reduce calorie intake in an effort to reduce sweet taste, which is important since consumers are not and prevent obesity, and in October 2011 recommended likely to sacrifice taste for perceived health benefits. Poly- front-of-package labeling that includes rating the product ols have a host of other functional properties that make based on added sugars content.
    [Show full text]
  • Sweet Sensations by Judie Bizzozero | Senior Editor
    [Confections] July 2015 Sweet Sensations By Judie Bizzozero | Senior Editor By R.J. Foster, Contributing Editor For many, terms like “reduced-sugar” or “sugar-free” do not go with the word “candy.” And yet, the confectionery industry is facing growing demand for treats that offer the taste people have grown to love without the adverse health effects they’re looking to avoid. Thankfully, there is a growing palette of ingredients from which candy makers can paint a new picture of sweetness that will be appreciated by the even most discerning of confectionery critics. SUGAR ALCOHOLS Also referred to as polyols, sugar alcohols are a common ingredient in reduced-sugar and sugar-free applications, especially confections. Funny thing, they’re not sugars or alcohols. Carbohydrate chains composed of monomeric, dimeric and polymeric units, polyols resemble both sugars and alcohols, but do not contain an ethanol molecule. All but two sugar alcohols are less sweet than sugar. Being only partially digestible, though, replacing a portion of a formulation’s sugar with a sugar alcohol reduces total calories without losing bulk (which can occur when replacing sugar with high-intensity sweeteners). Unique flavoring, texturizing and moisture-controlling effects also make polyols well-suited for confectionery products. Two very common and very similar monomeric polyols are sorbitol and mannitol. Present in a variety of fruits and vegetables, both are derived from products of cornstarch hydrolysis. Sorbitol is made via hydrogenation of glucose, which is why sorbitol is sometimes referred to as glucitol. Mannitol is created when fructose hydrogenation converts fructose into mannose, for which the final product, mannitol, is named.
    [Show full text]
  • Sugar Alcohols a Sugar Alcohol Is a Kind of Alcohol Prepared from Sugars
    Sweeteners, Good, Bad, or Something even Worse. (Part 8) These are Low calorie sweeteners - not non-calorie sweeteners Sugar Alcohols A sugar alcohol is a kind of alcohol prepared from sugars. These organic compounds are a class of polyols, also called polyhydric alcohol, polyalcohol, or glycitol. They are white, water-soluble solids that occur naturally and are used widely in the food industry as thickeners and sweeteners. In commercial foodstuffs, sugar alcohols are commonly used in place of table sugar (sucrose), often in combination with high intensity artificial sweeteners to counter the low sweetness of the sugar alcohols. Unlike sugars, sugar alcohols do not contribute to the formation of tooth cavities. Common Sugar Alcohols Arabitol, Erythritol, Ethylene glycol, Fucitol, Galactitol, Glycerol, Hydrogenated Starch – Hydrolysate (HSH), Iditol, Inositol, Isomalt, Lactitol, Maltitol, Maltotetraitol, Maltotriitol, Mannitol, Methanol, Polyglycitol, Polydextrose, Ribitol, Sorbitol, Threitol, Volemitol, Xylitol, Of these, xylitol is perhaps the most popular due to its similarity to sucrose in visual appearance and sweetness. Sugar alcohols do not contribute to tooth decay. However, consumption of sugar alcohols does affect blood sugar levels, although less than that of "regular" sugar (sucrose). Sugar alcohols may also cause bloating and diarrhea when consumed in excessive amounts. Erythritol Also labeled as: Sugar alcohol Zerose ZSweet Erythritol is a sugar alcohol (or polyol) that has been approved for use as a food additive in the United States and throughout much of the world. It was discovered in 1848 by British chemist John Stenhouse. It occurs naturally in some fruits and fermented foods. At the industrial level, it is produced from glucose by fermentation with a yeast, Moniliella pollinis.
    [Show full text]
  • Distinct Human Prolactin (Hprl) and Growth Hormone (Hgh)
    Available online at www.sciencedirect.com Journal of Biotechnology 133 (2008) 27–35 Distinct human prolactin (hPRL) and growth hormone (hGH) behavior under bacteriophage lambda PL promoter control: Temperature plays a major role in protein yields C.R.J. Soares ∗, E.K.M. Ueda, T.L. Oliveira, F.I.C. Gomide, S.R. Heller, P. Bartolini Biotechnology Department, IPEN-CNEN, Av. Lineu Prestes, 2242 Cidade Universit´aria, 05508-900 S˜ao Paulo, Brazil Received 6 February 2007; received in revised form 21 August 2007; accepted 24 August 2007 Abstract When producing recombinant protein for therapy, it is desirable not only to obtain substantial amounts of the protein, but also to make sure that potential contaminants such as inducing agents are not present in the final product. To prevent this, one can use expression systems in which the promoter (␭PL) is activated by a temperature shift that denatures a repressor (e.g., cIts). In this manner, hGH was successfully expressed and ␮ −1 −1 ◦ secreted in Escherichia coli periplasm, with specific yields well above 1 gml A600, after a temperature shift from 30 to 42 C. However, attempts ␮ −1 −1 to express a related hormone, human prolactin, employing the same protocol were unsuccessful, providing 0.03 gml A600 at the most. A process is described in which this labile protein is obtained from a cIts− strain under optimized temperature condition (37 ◦C). The highest periplasmic ± ␮ −1 −1 ∼ secretions of prolactin ever reported were thus obtained: 0.92 0.10 gml A600 at an optical density of 3A600 units in shake flask cultures and ∼ ␮ −1 −1 1 gml A600,atanODof35A600 units, via a rapid and flexible batch feed process in laboratory bioreactor.
    [Show full text]
  • Cystatin C: a Potential Target for Alzheimers Treatment
    Editorial Cystatin C: a potential target for Alzheimer’s treatment Expert Rev. Neurotherapeutics 8(5), 687–689 (2008) Efrat Levy “…cystatin C binds soluble Aβ and inhibits Aβ oligomerization Departments of and amyloidogenesis, protecting the brain against Psychiatry & Pharmacology, amyloid-induced toxicity.” New York University School of Medicine, Alzheimer's disease is one of the most in familial Alzheimer’s disease in the Nathan S. Kline prevalent chronic diseases of the aging brains of mice results in amyloid plaque Institute, 140 Old population. Neuropathologically, the deposition. Some proteins associated Orangeburg Road, Orangeburg, disease is characterized by neurodegener- with amyloid lesions may have a role in NY 10962, USA ation and the presence of two patho- the pathological processes leading to Tel.: +1 845 398 5540 logical features, amyloid plaques and amyloidogenesis and neuronal degenera- Fax: +1 845 398 5422 neurofibrillary tangles. Amyloid-β (Aβ) tion, and others may bind secondarily to [email protected] is the major constituent of the amyloid amyloid deposits. It was demonstrated plaques. It is a ubiquitously expressed that cystatin C binds to the Aβ region soluble peptide that can form aggregates, within full-length amyloid precursor pro- either oligomeric or fibrillar, that are tein and that this association does not neurotoxic. Extensive research focuses on affect Aβ generation either in vitro [10] or prevention of Aβ aggregation as a possi- in vivo [11]. The association of cystatin C ble therapy for the disease. Recent stud- with the amyloid precursor protein was ies have shown that the endogenous pro- recently confirmed by in vivo mapping of tein cystatin C binds soluble Aβ and protein interactions in intact mouse inhibits Aβ oligomerization and amyloido- tissue [12].
    [Show full text]
  • Erythritol As Sweetener—Wherefrom and Whereto?
    Applied Microbiology and Biotechnology (2018) 102:587–595 https://doi.org/10.1007/s00253-017-8654-1 MINI-REVIEW Erythritol as sweetener—wherefrom and whereto? K. Regnat1 & R. L. Mach1 & A. R. Mach-Aigner1 Received: 1 September 2017 /Revised: 12 November 2017 /Accepted: 13 November 2017 /Published online: 1 December 2017 # The Author(s) 2017. This article is an open access publication Abstract Erythritol is a naturally abundant sweetener gaining more and more importance especially within the food industry. It is widely used as sweetener in calorie-reduced food, candies, or bakery products. In research focusing on sugar alternatives, erythritol is a key issue due to its, compared to other polyols, challenging production. It cannot be chemically synthesized in a commercially worthwhile way resulting in a switch to biotechnological production. In this area, research efforts have been made to improve concentration, productivity, and yield. This mini review will give an overview on the attempts to improve erythritol production as well as their development over time. Keywords Erythritol . Sugar alcohols . Polyols . Sweetener . Sugar . Sugar alternatives Introduction the range of optimization parameters. The other research di- rection focused on metabolic pathway engineering or genetic Because of today’s lifestyle, the number of people suffering engineering to improve yield and productivity as well as to from diabetes mellitus and obesity is increasing. The desire of allow the use of inexpensive and abundant substrates. This the customers to regain their health created a whole market of review will present the history of erythritol production- non-sugar and non-caloric or non-nutrient foods. An impor- related research from a more commercial viewpoint moving tant part of this market is the production of sugar alcohols, the towards sustainability and fundamental research.
    [Show full text]
  • Higher Plasma Cystatin C Is Associated with Mortality After Acute
    Hendrickson et al. Critical Care (2020) 24:416 https://doi.org/10.1186/s13054-020-03111-1 RESEARCH Open Access Higher plasma cystatin C is associated with mortality after acute respiratory distress syndrome: findings from a Fluid and Catheter Treatment Trial (FACTT) substudy Carolyn M. Hendrickson1* , Yuenting D. Kwong2, Annika G. Belzer3, Michael G. Shlipak4,5, Michael A. Matthay6,7 and Kathleen D. Liu6,7 Abstract Background: Cystatin C is a well-validated marker of glomerular filtration rate in chronic kidney disease. Higher plasma concentrations of cystatin C are associated with worse clinical outcomes in heterogenous populations of critically ill patients and may be superior to creatinine in identifying kidney injury in critically ill patients. We hypothesized that elevated levels of plasma cystatin C in patients with acute respiratory distress syndrome (ARDS) would be associated with mortality risk. Methods: In a retrospective study, cystatin C was measured by nephelometry on plasma obtained at enrollment from 919 patients in the Fluid and Catheter Treatment Trial. Multivariable logistic regression was performed testing the association between quartiles of cystatin C and 60-day mortality. Analyses were stratified by acute kidney injury (AKI) status identified in the first 7 days after enrollment by Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Results: Cystatin C was significantly higher among those patients who died compared to those who survived to 60 days [1.2 (0.9–1.9) mg/L vs. 0.8 (0.6–1.2) mg/L, p < 0.001]. Compared to the lower three quartiles, subjects in the highest quartile of cystatin C had a significantly higher odds of death at 60 days [OR 1.8 (1.2–2.6), p = 0.003 in adjusted analyses]; the odds of death incrementally rose in higher cystatin C quartiles compared to the lowest quartile (OR 1.1, 1.8, and 2.5).
    [Show full text]
  • Lansoprazole Delayed Release Orally Disintegrating Tablets,116 15 Mg
    45 14 5 Proposed Draft Labeling 4188168 ID: Reference NDA 208025 Lansoprazole Delayed Release Orally Disintegrating Tablets,116 15 mg 14 Tablets (Inner Carton) 14.5 sorbitol, sucralose, sugar spheres, talc, titanium dioxide, triethyl citrate triethyl dioxide, titanium talc, spheres, sugar sucralose, sorbitol, you develop a rash or joint pain joint or rash a develop you diarrhea get you I I polysorbate 80, propylene glycol, silicon dioxide, sodium stearyl fumarate, fumarate, stearyl sodium dioxide, silicon glycol, propylene 80, polysorbate you need to take more than 1 course of treatment every 4 months 4 every treatment of course 1 than more take to need you I 8U174 00 V5 EXP Batch No. maize maltodextrin, maltitol, mannitol, meglumine, microcrystalline cellulose, cellulose, microcrystalline meglumine, mannitol, maltitol, maltodextrin, maize you need to take this product for more than 14 days 14 than more for product this take to need you I copovidone, crospovidone, flavor, hypromellose, hypromellose phthalate, phthalate, hypromellose hypromellose, flavor, crospovidone, copovidone, Stop use and ask a doctor if doctor a ask and use Stop your heartburn continues or worsens or continues heartburn your I Inactive ingredients Inactive ascorbic acid, cetyl alcohol, colloidal silicon dioxide, dioxide, silicon colloidal alcohol, cetyl acid, ascorbic methotrexate (arthritis medicine) (arthritis methotrexate I I atazanavir (medicine for HIV infection) HIV for (medicine atazanavir I protect product from moisture from product protect I tacrolimus or mycophenolate mofetil (immune system medicines) system (immune mofetil mycophenolate or tacrolimus I keep product out of high heat and humidity and heat high of out product keep (68-77°F) 20-25°C at store I I theophylline (asthma medicine) (asthma theophylline I keep the carton and package insert.
    [Show full text]
  • Valorization Studies on Ice-Cream Wastewater and Whey Permeate
    South Dakota State University Open PRAIRIE: Open Public Research Access Institutional Repository and Information Exchange Electronic Theses and Dissertations 2020 Valorization Studies on Ice-Cream Wastewater and Whey Permeate Maryam Enteshari South Dakota State University Follow this and additional works at: https://openprairie.sdstate.edu/etd Part of the Dairy Science Commons, and the Food Chemistry Commons Recommended Citation Enteshari, Maryam, "Valorization Studies on Ice-Cream Wastewater and Whey Permeate" (2020). Electronic Theses and Dissertations. 4189. https://openprairie.sdstate.edu/etd/4189 This Dissertation - Open Access is brought to you for free and open access by Open PRAIRIE: Open Public Research Access Institutional Repository and Information Exchange. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of Open PRAIRIE: Open Public Research Access Institutional Repository and Information Exchange. For more information, please contact [email protected]. VALORIZATION STUDIES ON ICE-CREAM WASTEWATER AND WHEY PERMEATE BY MARYAM ENTESHARI A dissertation submitted in partial fulfillment of the requirements for the Doctor of Philosophy Major in Biological Sciences Specialization in Dairy Science South Dakota State University 2020 ii DISSERTATION ACCEPTANCE PAGE Maryam Enteshari This dissertation is approved as a creditable and independent investigation by a candidate for the Doctor of Philosophy degree and is acceptable for meeting the dissertation requirements for this degree. Acceptance of this does not imply that the conclusions reached by the candidate are necessarily the conclusions of the major department. Sergio Martinez-Monteagudo Advisor Date Vikram Mistry Department Head Date Dean, Graduate School Date iii This dissertation is dedicated to my amazing mother who sacrificed her entire life for my success and encouraged me to pursue my dreams and finish Ph.D.
    [Show full text]