DOCSLIB.ORG

Reduced Sulfotransferase SULT2A1 Activity in Patients with Alzheimer´S Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Reduced Sulfotransferase SULT2A1 Activity in Patients with Alzheimer´S Disease Physiol. Res. 64 (Suppl. 2): S265-S273, 2015 https://doi.org/10.33549/physiolres.933160 Reduced Sulfotransferase SULT2A1 Activity in Patients With Alzheimer´s Disease M. VAŇKOVÁ1, M. HILL1, M. VELÍKOVÁ1, J. VČELÁK1, G. VACÍNOVÁ1, P. LUKÁŠOVÁ1, D. VEJRAŽKOVÁ1, K. DVOŘÁKOVÁ1, R. RUSINA2,4, I. HOLMEROVÁ3, E. JAROLÍMOVÁ3, H. VAŇKOVÁ3,5, B. BENDLOVÁ1 1Institute of Endocrinology, Prague, Czech Republic, 2Thomayer Hospital, Prague, Czech Republic, 3Faculty of Humanities, Charles University, Prague, Czech Republic, 4Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, First Faculty of Medicine and General University Hospital in Prague, Czech Republic, 5Third Faculty of Medicine, Charles University in Prague, Czech Republic Received August 2, 2015 Accepted August 18, 2015 Summary Introduction Steroids are important components in the pathophysiology of Alzheimer’s disease (AD). Although their role has been studied, Alzheimer’s disease (AD) represents more than the corresponding metabolomic data is limited. In the present one half of total dementias in seniors. The number of study we evaluate the role of steroid sulfotransferase SULT2A1 in people living with dementia worldwide today is estimated the pathophysiology of AD on the basis of circulating steroids at 44 million, set to almost double by 2030 and more than (measured by GC-MS), in which the sulfation catalyzed by triple by 2050 (Prince et al. 2014). SULT2A1 dominates over glucuronidation (pregnenolone/sulfate, AD is a neurodegenerative disease with DHEA/sulfate, androstenediol/sulfate and 5α-reduced pregnane progressive decline of episodic memory and impairment and androstane catabolites). To estimate a general trend of in other cognitive domains leading to dementia with loss SUL2A1 activity in AD patients we compared the ratios of steroid of autonomy. Definite diagnosis of AD requires conjugates to their unconjugated counterparts (C/U) in controls neuropathological confirmation from autopsy. Current (11 men and 22 women) and AD patients (18 men and diagnostic criteria for AD are mainly based on clinical 16 women) for individual circulating steroids after adjustment for and neuropsychological assessment (McKhann et al. age and BMI using ANCOVA model including the factors AD 2011). status and gender. Decreased C/U ratio for the C19 steroids There is increasing evidence that pathological demonstrate an association between attenuated sulfation of processes in the brain of AD patients may begin even C19 steroids in adrenal zona reticularis and the pathophysiology 10-20 years before the first symptoms appear (Holtzman of AD. et al. 2011), therefore, the need for early diagnosis is important and other biomarkers may be useful. Key words Various factors including altered steroid Alzheimer’s disease • SULT2A1 • GC-MS • Steroids biosynthesis may participate in the pathophysiology of AD. Steroid hormones are effective regulators of many Corresponding author physiological processes, including those in the brain M. Vaňková, Department of Molecular Endocrinology, Institute of (Hampl and Bicikova 2010). Steroid hormones active in Endocrinology, Národní 8, Prague, 116 94, Czech Republic. neural tissue are neuroactive steroids, which arise in the E-mail: [email protected] gonads (in women only in the reproductive period) and in the adrenal glands (the main source of postmenopausal women) and into the central nervous system are PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online) 2015 Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic Fax +420 241 062 164, e-mail: [email protected], www.biomed.cas.cz/physiolres S266 Vaňková et al. Vol. 64 transported across the blood-brain barrier directly or in pregnane steroids may also modulate the permeability of the form of precursors. However, a small portion of various ion channels such as excitatory glutamate steroids, called neurosteroids, are produced directly in receptors on one hand or inhibitory gamma-aminobutyric nervous tissue. The peripheral steroidogenesis may acid (GABA) receptors on the other hand (Bergeron et al. substantially influence neuronal activity in the brain. 1996, Majewska et al. 1990, Hill et al. 2015, Starka et al. Age-related deficit of sex steroid hormones 2015). increases the risk of dysfunction in hormone-responsive Steroid sulfates having distinct physiological tissues, including brain. Age-dependent hormone role compared with their unconjugated counterparts are depletion in the brain may result in diminished important precursors of further bioactive steroids (Strott neuroprotection, which increases a risk of 2002). The circulating levels of conjugated steroids are neurodegenerative diseases such as AD (Rosario and Pike usually much higher than in their non-conjugated forms. 2008). AD is more prevalent in women, which may be The steroid conjugates are frequently metabolic end- explained by differences in life expectancy in women products with excellent water solubility enabling their compared to men. However, incidence of AD is also uncomplicated excretion into the urine. The conjugation higher in women (Ruitenberg et al. 2001). Nevertheless, generally alters biological activity (Strott 1996) and may the basis of higher vulnerability for females to AD even convert the unconjugated steroids to their biological remains unclear. antagonists (Park-Chung et al. 1997, 1999). Even though From the menopause, dehydroepiandrosterone the sulfotransferase activity in primate brain is low (Kriz (DHEA) remains the exclusive and adrenal tissue-specific et al. 2005), the sulfation of brain neurosteroids might source of sex steroids in women while in (65-75 year-old) participate on the maintenance of brain function. Steroid men, the contribution of adrenal DHEA to the total sulfates are bound to serum proteins such as albumin, androgens is approximately 40 % (Labrie 2010). Sex corticosteroid binding globulin (CBG), and sex hormone steroid hormones derived from DHEA show a similar binding globulin (SHBG), and serve as circulating decline from the age of 30 years in both genders, but reservoir, while non-conjugated forms are more active at there is a continuous supply of testosterone, estrone and the tissue level. estradiol from testes in men. The ovarian estradiol Human SULT2A1 (sulfotransferase family 2A, secretion in women ends at the menopause. dehydroepiandrosterone-preferring, member 1) is enzyme Age-related loss of sex steroid hormones is strongly expressed in fetal zone of the fetal adrenal gland associated with numerous diseases such as tissue atrophy, (Barker et al. 1994), and in the zona reticularis of the bone loss, fat accumulation, type 2 diabetes mellitus, and mature adrenal gland. Besides the primary source of also with cognition problems, memory loss and perhaps steroid sulfotransferase activity in adrenal zona with AD (Labrie 2007). Alterations in steroid reticularis, also the kidneys and small intestine exhibit biosynthesis may contribute to the pathology of AD (Liu significant sulfotransferase activities (Barker et al. 1994, et al. 2013, Napolitano et al. 2014, Schumacher et al. Otterness et al. 1992). SULT2A1 expression is also 2014, Winkler and Fox 2013). detectable in ovary and prostate, in stomach and colon The endogenous sex steroids, estrogens, (Javitt et al. 2001), but these tissues produce the enzyme androgens, and progesterone, have effects on the brain, at a lower levels (Shimada et al. 2001). Besides the especially in perimenopausal and postmenopausal women DHEA, the SULT2A1 catalyzes the sulfation of further (Yaffe et al. 2000). DHEA, which may be converted to androgens, their 5α/β-reduced catabolites, pregnenolone, estrogens locally in the brain, have been shown to 5α/β-reduced pregnanolone isomers and pregnanediols, enhance memory and learning functions (Vallee et al. and also the bile acids. Whereas the lower ratio of 2001). Similarly, DHEA sulfate (DHEAS) influences circulating sulfates to unconjugated form of steroids may brain function and affects memory capacity (Hunt et al. indicate the lower overall SULT2A1 activity, we 2000). DHEA acting in the brain is either of peripheral attempted to investigate whether the reduced ratios of origin, or may be synthesized directly in the brain and steroid sulfates to their unconjugated counterparts are may be also converted into estrogens or androgens in consistently lower in the AD and if so, whether these brain tissues. Various brain areas express nuclear ratios may be used as markers of AD. receptors for estrogens, androgens and progesterone. Besides the nuclear receptors, both androstane and 2015 Reduced SULT2A1 Activity in Alzheimer´s Disease S267 Materials and Methods Cognitive Assessment, and Geriatric Depression Scale), biochemical examination of cerebrospinal fluid Subjects (β-amyloid peptides, total and phosphorylated τ-proteins) A total of 34 patients with AD (16 women and and magnetic resonance imaging of the brain. In our 18 men) fulfilling NINCDS-ADRDA criteria (National cohort of patients, 25 patients had AD, 3 patients had Institute of Neurological Communicative Disorders and possible dementia with Lewy bodies in comorbidity and Stroke – Alzheimer's disease and Related Disorders 6 patients had AD and significant subcortical ischemic Association) for probable Alzheimer´s disease and white matter lesions consistent with the diagnosis of 33 controls of similar age as the patients (22 women and mixed dementia. Controls were examined with the
Load more

Recommended publications
  • Hormonal Regulation During Initial Berry Development in Grapevine
    1 Année 2013 Thèse N° 2064 THESE pour le DOCTORAT DE L’UNIVERSITE BORDEAUX 2 Ecole Doctorale des Sciences de la Vie et de la Santé de l’Université Bordeaux-Segalen Spécialité: Biologie Végétale Hormonal regulation during initial berry development in grapevine par María Francisca Godoy Santin Née le 20 Février 1985 à Santiago, Chili Soutenue publiquement le 15 Novembre, à Pontificia Universidad Católica de Chile, Santiago, Chili Membres du Jury : Pr. Alexis KALERGIS, Universidad Católica de Chile Pr. Michael HANDFORD, University of Chile Rapporteur Pr. Claudia STANGE, University of Chile Rapportrice Pr. Loreto HOLUIGUE, Universidad Católica de Chile Examinatrice Pr. Serge DELROT, Université Victor Ségalen Bordeaux2 Examinateur Pr. Patricio ARCE-JONHSON, Universidad Católica de Chile Co-Directeur de thèse Dr. Virginie LAUVERGEAT, Université Bordeaux1 Co-Directrice de thèse 2 Acknowledgements I would like to thank my advisors Dr Patricio Arce and Dr Virginie Lauvergeat for their guidance, patience and help at every step of the way. I also want to specially acknowledge to all my labmates for their ideas, support, laughs and much more: Jenn, Xime, Amparo, Mindy, Anita, Felipe, Tomás, Susan, Mónica, Jessy, Claudia, Dani H, and everyone else who made the working place the best one ever. Special thanks to Consuelo, who guided me from the first day, and to Anibal, who has been an amazing help during these lasts years. I want to thank Nathalie Kühn for all her ideas, discussion, company and help during these experiments, where she played a fundamental part. Also, I am very grateful to my other lab across the sea, in INRA, for receiving me there: Mariam, María José, Julien, Eric, Pierre, Le, Huan, Messa, David, Fatma and all the staff for all their help.
    [Show full text]
  • Regulation of Sulfotransferase Enzymes by Prototypical Microsomal Enzyme Inducers in Mice
    JPET Fast Forward. Published on November 9, 2007 as DOI: 10.1124/jpet.107.129650 JPET FastThis Forward.article has not Published been copyedited on and November formatted. The 9, final 2007 version as DOI:10.1124/jpet.107.129650may differ from this version. JPET # 129650 Regulation of Sulfotransferase enzymes by Prototypical Microsomal Enzyme Inducers in Mice Yazen Alnouti and Curtis D Klaassen (YA): Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Downloaded from Medical Center, Kansas City, KS 66160 (CDK): Department of Pharmacology, Toxicology and Therapeutics, University of jpet.aspetjournals.org Kansas Medical Center, Kansas City, KS 66160 at ASPET Journals on October 2, 2021 1 Copyright 2007 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on November 9, 2007 as DOI: 10.1124/jpet.107.129650 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 129650 Short Title: Regulation of Sults Expression in Male and Female Mice Corresponding Author: Curtis Klaassen, Ph.D. Department of Pharmacology, Toxicology, and Therapeutics University of Kansas Medical Center Downloaded from 3901 Rainbow Blvd., Kansas City, KS 66160-7417, USA. Phone: (913)588-7714 jpet.aspetjournals.org Fax: (913) 588-7501; E-mail: [email protected] at ASPET Journals on October 2, 2021 Number of text pages: 23 pages Number of tables: 4 tables Number of figures: 10 figures Number of references: 59 Number of words in abstract: 235 Number of words in introduction: 685 (including references in the text) Number of words in discussion: 2671 (including references in the text) Abbreviations: Sult: Sulfotransferase, bDNA: branched DNA signal amplification assay, PAPS: 3'-phosphoadenosine 5'phosphosulfate, RLU: relative light unit(s), AhR: hydrocarbon receptor, CAR: constitutive androstane receptor, PXR: pregnane X receptor, PPARα: peroxisome proliferator activated receptor α, and Nrf2: NF-E2 related factor 2.
    [Show full text]
  • Supplementary Table 3: Genes Only Influenced By
    Supplementary Table 3: Genes only influenced by X10 Illumina ID Gene ID Entrez Gene Name Fold change compared to vehicle 1810058M03RIK -1.104 2210008F06RIK 1.090 2310005E10RIK -1.175 2610016F04RIK 1.081 2610029K11RIK 1.130 381484 Gm5150 predicted gene 5150 -1.230 4833425P12RIK -1.127 4933412E12RIK -1.333 6030458P06RIK -1.131 6430550H21RIK 1.073 6530401D06RIK 1.229 9030607L17RIK -1.122 A330043C08RIK 1.113 A330043L12 1.054 A530092L01RIK -1.069 A630054D14 1.072 A630097D09RIK -1.102 AA409316 FAM83H family with sequence similarity 83, member H 1.142 AAAS AAAS achalasia, adrenocortical insufficiency, alacrimia 1.144 ACADL ACADL acyl-CoA dehydrogenase, long chain -1.135 ACOT1 ACOT1 acyl-CoA thioesterase 1 -1.191 ADAMTSL5 ADAMTSL5 ADAMTS-like 5 1.210 AFG3L2 AFG3L2 AFG3 ATPase family gene 3-like 2 (S. cerevisiae) 1.212 AI256775 RFESD Rieske (Fe-S) domain containing 1.134 Lipo1 (includes AI747699 others) lipase, member O2 -1.083 AKAP8L AKAP8L A kinase (PRKA) anchor protein 8-like -1.263 AKR7A5 -1.225 AMBP AMBP alpha-1-microglobulin/bikunin precursor 1.074 ANAPC2 ANAPC2 anaphase promoting complex subunit 2 -1.134 ANKRD1 ANKRD1 ankyrin repeat domain 1 (cardiac muscle) 1.314 APOA1 APOA1 apolipoprotein A-I -1.086 ARHGAP26 ARHGAP26 Rho GTPase activating protein 26 -1.083 ARL5A ARL5A ADP-ribosylation factor-like 5A -1.212 ARMC3 ARMC3 armadillo repeat containing 3 -1.077 ARPC5 ARPC5 actin related protein 2/3 complex, subunit 5, 16kDa -1.190 activating transcription factor 4 (tax-responsive enhancer element ATF4 ATF4 B67) 1.481 AU014645 NCBP1 nuclear cap
    [Show full text]
  • Decreased Phenol Sulfotransferase Activities Associated With
    Pagan et al. Translational Psychiatry (2021) 11:23 https://doi.org/10.1038/s41398-020-01125-5 Translational Psychiatry ARTICLE Open Access Decreased phenol sulfotransferase activities associated with hyperserotonemia in autism spectrum disorders Cécile Pagan1,2,3,4,8,MarionBenabou3, Claire Leblond3, Freddy Cliquet 3, Alexandre Mathieu 3, Nathalie Lemière3, Hany Goubran-Botros3, Richard Delorme2,3,5, Marion Leboyer2,6,7, Jacques Callebert1,4, Thomas Bourgeron 2,3 and Jean-Marie Launay 1,2,4 Abstract Hyperserotonemia is the most replicated biochemical abnormality associated with autism spectrum disorders (ASD). However, previous studies of serotonin synthesis, catabolism, and transport have not elucidated the mechanisms underlying this hyperserotonemia. Here we investigated serotonin sulfation by phenol sulfotransferases (PST) in blood samples from 97 individuals with ASD and their first-degree relatives (138 parents and 56 siblings), compared with 106 controls. We report a deficient activity of both PST isoforms (M and P) in platelets from individuals with ASD (35% and 78% of patients, respectively), confirmed in autoptic tissues (9 pineal gland samples from individuals with ASD—an important source of serotonin). Platelet PST-M deficiency was strongly associated with hyperserotonemia in individuals with ASD. We then explore genetic or pharmacologic modulation of PST activities in mice: variations of PST activities were associated with marked variations of blood serotonin, demonstrating the influence of the sulfation pathway on serotonemia. We also conducted in 1645 individuals an extensive study of SULT1A genes, encoding PST and mapping 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; at highly polymorphic 16p11.2 locus, which did not reveal an association between copy number or single nucleotide variations and PST activity, blood serotonin or the risk of ASD.
    [Show full text]
  • The Steroid Alcohol and Estrogen Sulfotransferases in Rodent and Human Mammary Tumors1
    [CANCER RESEARCH 35,1791-1798, July 1975] The Steroid Alcohol and Estrogen Sulfotransferases in Rodent and Human Mammary Tumors1 Viviane C. Godefroi, Elizabeth R. Locke,2 Dharm V. Singh,3 and S. C. Brooks Michigan Cancer Foundation (V. C. G., E. R. L.. D. V. S.. S. C. B.} and Department of Biochemistry, Wayne State University School of Medicine (S C a.], Detroit. Michigan 48201 SUMMARY products as intermediates (21, 23). Several studies also indicate that sulfate conjugation may play an essential role Rodent and human mammary tumor systems were in the metabolism of estrogens, particularly in hepatic tissue investigated to relate the steroid alcohol and estrogen (7, 10, 27). Furthermore, it has been demonstrated that sulfotransferase activities to the hormonal dependency of breast carcinoma, unlike normal breast tissue, is active in the tumor as determined by estrogen receptor content. sulfating 3j8-hydroxy-A5-steroids and the 3-phenolic group Unlike the normal mammary gland or the hyperplastic of estrogens (I, 12). If, in fact, sulfate conjugates are in alveolar nodule, rodent mammary neoplasms displayed volved in steroid biosynthesis and metabolism, sulfation by significant levels of these two sulfotransferases. In the breast tumor extracts may reflect the 1st stage of a meta hormone-independent mouse tumors produced from out bolic sequence leading to more profound changes in the growth lines D!, D2, and D8, high dehydroepiandrosterone steroid moiety. Indeed, Adams and Wong (3) have shown sulfotransferase activity was characteristic of the rapidity breast carcinomas to exhibit a "paraendocrine" behavior with which hyperplastic alveolar nodules developed into a that is normally confined to endocrine glands in their neoplasm (Vmax = 52.8 versus 1.8 fmoles/min/mg protein) capacity to produce changes in steroid structure.
    [Show full text]
  • Glyphosate's Suppression of Cytochrome P450 Enzymes
    Entropy 2013, 15, 1416-1463; doi:10.3390/e15041416 OPEN ACCESS entropy ISSN 1099-4300 www.mdpi.com/journal/entropy Review Glyphosate’s Suppression of Cytochrome P450 Enzymes and Amino Acid Biosynthesis by the Gut Microbiome: Pathways to Modern Diseases Anthony Samsel 1 and Stephanie Seneff 2,* 1 Independent Scientist and Consultant, Deerfield, NH 03037, USA; E-Mail: [email protected] 2 Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA 02139, USA * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-617-253-0451; Fax: +1-617-258-8642. Received: 15 January 2013; in revised form: 10 April 2013 / Accepted: 10 April 2013 / Published: 18 April 2013 Abstract: Glyphosate, the active ingredient in Roundup®, is the most popular herbicide used worldwide. The industry asserts it is minimally toxic to humans, but here we argue otherwise. Residues are found in the main foods of the Western diet, comprised primarily of sugar, corn, soy and wheat. Glyphosate's inhibition of cytochrome P450 (CYP) enzymes is an overlooked component of its toxicity to mammals. CYP enzymes play crucial roles in biology, one of which is to detoxify xenobiotics. Thus, glyphosate enhances the damaging effects of other food borne chemical residues and environmental toxins. Negative impact on the body is insidious and manifests slowly over time as inflammation damages cellular systems throughout the body. Here, we show how interference with CYP enzymes acts synergistically with disruption of the biosynthesis of aromatic amino acids by gut bacteria, as well as impairment in serum sulfate transport. Consequences are most of the diseases and conditions associated with a Western diet, which include gastrointestinal disorders, obesity, diabetes, heart disease, depression, autism, infertility, cancer and Alzheimer’s disease.
    [Show full text]
  • REVIEW 5A-Reduced Glucocorticoids: a Story of Natural Selection
    111 REVIEW 5a-Reduced glucocorticoids: a story of natural selection Mark Nixon, Rita Upreti and Ruth Andrew Endocrinology, Queen’s Medical Research Institute, University/British Heart Foundation Centre for Cardiovascular Science, Edinburgh EH16 4TJ, UK (Correspondence should be addressed to R Andrew; Email: [email protected]) Abstract 5a-Reduced glucocorticoids (GCs) are formed when one of recently the abilities of 5a-reduced GCs to suppress the two isozymes of 5a-reductase reduces the D4–5 double inflammation have been demonstrated in vitro and in vivo. bond in the A-ring of GCs. These steroids are largely viewed Thus, the balance of parent GC and its 5a-reduced inert, despite the acceptance that other 5a-dihydro steroids, metabolite may critically affect the profile of GR signalling. e.g. 5a-dihydrotestosterone, retain or have increased activity 5a-Reduction of GCs is up-regulated in liver in metabolic at their cognate receptors. However, recent findings suggest disease and may represent a pathway that protects from both that 5a-reduced metabolites of corticosterone have dis- GC-induced fuel dyshomeostasis and concomitant inflam- sociated actions on GC receptors (GRs) in vivo and in vitro matory insult. Therefore, 5a-reduced steroids provide hope and are thus potential candidates for safer anti-inflammatory for drug development, but may also act as biomarkers of the steroids. 5a-Dihydro- and 5a-tetrahydro-corticosterone can inflammatory status of the liver in metabolic disease. With bind with GRs, but interest in these compounds had been these proposals in mind, careful attention must be paid to the limited, since they only weakly activated metabolic gene possible adverse metabolic effects of 5a-reductase inhibitors, transcription.
    [Show full text]
  • The Metabolism of Androstenone and Other Steroid Hormone Conjugates in Relation to Boar Taint
    The Metabolism of Androstenone and Other Steroid Hormone Conjugates in Relation to Boar Taint by Heidi M. Laderoute A Thesis presented to The University of Guelph In partial fulfillment of requirements for the degree of Master of Science in Animal and Poultry Science with Toxicology Guelph, Ontario, Canada © Heidi M. Laderoute, April, 2015 ABSTRACT THE METABOLISM OF ANDROSTENONE AND OTHER STEROID HORMONE CONJUGATES IN RELATION TO BOAR TAINT Heidi M. Laderoute Advisor: University of Guelph, 2015 Dr. E.J. Squires Increased public interest in the welfare of pigs reared for pork production has led to an increased effort in finding new approaches for controlling the unpleasant odour and flavour from heated pork products known as boar taint. Therefore, this study investigated the metabolism of androstenone and the enzymes involved in its sulfoconjugation in order to further understand the pathways and genes involved in the development of this meat quality defect. Leydig cells that were incubated with androstenone produced 3-keto- sulfoxy-androstenone, providing direct evidence, for the first time, that sulfoconjugation of this steroid does occur in the boar. In addition, human embryonic kidney cells that were overexpressed with porcine sulfotransferase (SULT) enzymes showed that SULT2A1, but not SULT2B1, was responsible for sulfoconjugating androstenone. These findings emphasize the importance of conjugation in steroid metabolism and its relevance to boar taint is discussed. ACKNOWLEDGEMENTS I would like to gratefully and sincerely thank my advisor, Dr. E. James Squires, for providing me with the opportunity to be a graduate student and for introducing me to the world of boar taint. This project would not have been possible without your guidance, encouragement, and patience over the last few years.
    [Show full text]
  • Loss of Chondroitin 6-O-Sulfotransferase-1 Function Results in Severe Human Chondrodysplasia with Progressive Spinal Involvement
    Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement Holger Thiele*†, Masahiro Sakano‡, Hiroshi Kitagawa‡, Kazuyuki Sugahara‡, Anna Rajab§, Wolfgang Ho¨ hne¶, Heide Ritter*†, Gundula Leschik*, Peter Nu¨ rnberg*†, and Stefan Mundlos*ʈ** *Institute of Medical Genetics and ¶Institute of Biochemistry, Charite´University Hospital, Humboldt University, Berlin 13353, Germany; †Gene Mapping Center, Max Delbru¨ck Center for Molecular Medicine, Berlin 13092, Germany; ‡Department of Biochemistry, Kobe Pharmaceutical University, Higashinada, Kobe 658-8558, Japan; §Genetic Unit, Directorate General of Health Affairs, Ministry of Health, 138 Muscat, Sultanate of Oman; and ʈMax Planck Institute for Molecular Genetics, 14195 Berlin, Germany Edited by Victor A. McKusick, Johns Hopkins University School of Medicine, Baltimore, MD, and approved May 17, 2004 (received for review January 15, 2004) We studied two large consanguineous families from Oman with a Pakistani type and the mouse mutant ‘‘brachymorphic’’ also show distinct form of spondyloepiphyseal dysplasia (SED Omani type). By undersulfation of CS chains (7) and are caused by defects in the using a genome-wide linkage approach, we were able to map the ATPSK2 gene (OMIM 603005), which is necessary for sulfate underlying gene to a 4.5-centimorgan interval on chromosome 10q23. activation (8). Defects in both DTDST and ATPSK2 most likely We sequenced candidate genes from the region and identified a result in lowering the intracellular PAPS concentration, which likely missense mutation in the chondroitin 6-O-sulfotransferase (C6ST-1) causes broad nonspecific undersulfation of CS chains present gene (CHST3) changing an arginine into a glutamine (R304Q) in the abundantly in the skeletal structure.
    [Show full text]
  • Intratumoral Estrogen Sulfotransferase Induction Contributes to the Anti-Breast Cancer Effects of the Dithiocarbamate Derivative TM208
    npg Acta Pharmacologica Sinica (2015) 36: 1246–1255 © 2015 CPS and SIMM All rights reserved 1671-4083/15 www.nature.com/aps Original Article Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208 Xi-wei JI 1, 2, Guang-ping CHEN4, Yan SONG5, Ming HUA1, Li-jie WANG1, Liang LI1, Yin YUAN1, Si-yuan WANG1, Tian-yan ZHOU1, 3, *, Wei LU1, 3 1Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; 2Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100191, China; 3State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China; 4Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA; 5Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China Aim: Sulfotransferase-catalyzed sulfation is the most important pathway for inactivating estrogens. Thus, activation of estrogen sulfotransferase (EST) may be an alternative approach for the treatment of estrogen-dependent breast cancer. In this study we investigated the involvement of EST in anti-breast cancer effects of the dithiocarbamate derivative TM208 in vitro and in vivo. Methods: The viability of human breast cancer MCF-7 cells was determined using a SBB assay. Nude mice bearing MCF-7 cells were orally administered TM208 (50 and 150 mg·kg-1·d-1) for 18 days. The xenograft tumors and uteri were collected. The mRNA expression of EST was examined with real-time PCR. EST protein was detected with Western blot, ELISA or immunohistochemical staining assays. A radioactive assay was used to measure the EST activity.
    [Show full text]
  • (Sult1e1) Expression and Function in Mcf10a-Series Breast Epithelial Cells
    Wayne State University Wayne State University Dissertations 1-1-2011 Estrogen sulfotransferase (sult1e1) expression and function in mcf10a-series breast epithelial cells: role as a modifier of breast carcinogenesis and regulation by proliferation state Jiaqi Fu Wayne State University, Follow this and additional works at: http://digitalcommons.wayne.edu/oa_dissertations Part of the Pathology Commons, and the Toxicology Commons Recommended Citation Fu, Jiaqi, "Estrogen sulfotransferase (sult1e1) expression and function in mcf10a-series breast epithelial cells: role as a modifier of breast carcinogenesis and regulation by proliferation state" (2011). Wayne State University Dissertations. Paper 308. This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. ESTROGEN SULFOTRANSFERASE (SULT1E1) EXPRESSION AND FUNCTION IN MCF10A-SERIES BREAST EPITHELIAL CELLS: ROLE AS A MODIFIER OF BREAST CARCINOGENESIS AND REGULATION BY PROLIFERATION STATE by JIAQI FU DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2011 MAJOR: MOLECULAR AND CELLULAR TOXICOLOGY Approved by: Advisor Date DEDICATION I dedicate this work to my parents for all the sacrifices they have made on my behalf. To Luan, for his love and support during the preparation of this work. ii ACKNOWLEDGEMENTS I owe my deepest gratitude to Dr. Melissa Runge-Morris and Dr. Thomas A. Kocarek, for the encouragement and support throughout all these years of study. Their guidance helped me in all the time of research and writing of this thesis.
    [Show full text]
  • The Role of Estrogen Sulfotransferase in Ischemic Acute Kidney Injury
    Title Page The role of estrogen sulfotransferase in ischemic acute kidney injury By Anne Caroline Silva Barbosa Bachelor of Pharmacy, UFRN, 2015 Submitted to the Graduate Faculty of the School of Pharmacy in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2020 i Committee Membership Page UNIVERSITY OF PITTSBURGH SCHOOL OF PHARMACY This dissertation was presented By Anne Caroline Silva Barbosa It was defended on July 17, 2020 And approved by Christian Fernandez, PhD, Assistant Professor, Pharmaceutical Sciences Robert B. Gibbs, PhD, Professor, Pharmaceutical Sciences Youhua Liu, MD, PhD, Professor, Pathology Thomas D. Nolin, PhD, Associate Professor, Pharmacy & Therapeutics Dissertation Advisor: Wen Xie, MD, PhD, Professor, Pharmaceutical Sciences ii Copyright © by Anne Caroline Silva Barbosa 2020 iii Abstract The role of estrogen sulfotransferase in ischemic acute kidney injury Anne Caroline Silva Barbosa, PhD University of Pittsburgh, 2020 Acute kidney injury (AKI) is a sudden impairment of kidney function. It has been suggested that estrogens may protect mice from AKI. Estrogen sulfotransferase (SULT1E1/EST) plays an important role in estrogen homeostasis by sulfonating and deactivating estrogens, but the role of SULT1E1 in AKI has not been previously reported. In this dissertation, Wild-type (WT) mice, Sult1e1 knockout (Sult1e1 KO) mice, and Sult1e1 KO mice with hepatic reconstitution of Sult1e1 were subjected to a bilateral kidney ischemia-reperfusion model of AKI, in the absence or presence of gonadectomy. Kidney injury was assessed at biochemical, histological and gene expression levels. WT mice treated with the Sult1e1 inhibitor triclosan were also used to determine the effect of pharmacological inhibition of Sult1e1 on AKI.
    [Show full text]