DOCSLIB.ORG

Topography of a Binding Site for Small Amnestic Peptides Deduced from Structure-Activity Studies: Relation to Amnestic Effect of Amyloid F8 Protein JAMES F

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Topography of a Binding Site for Small Amnestic Peptides Deduced from Structure-Activity Studies: Relation to Amnestic Effect of Amyloid F8 Protein JAMES F Proc. Natl. Acad. Sci. USA Vol. 91, pp. 380-384, January 1994 Neurobiology Topography of a binding site for small amnestic peptides deduced from structure-activity studies: Relation to amnestic effect of amyloid f8 protein JAMES F. FLOOD*, EUGENE ROBERTStt, MARK A. SHERMAN§, BRUCE E. KAPLAN§, AND JOHN E. MORLEY* Geriatric Research Education and Clinical Center (GRECC), Veterans Administration Medical Center, St. Louis, MO 63106, and St. Louis University School of Medicine, Division of Geriatric Medicine, St. Louis, MO 63104; and tDepartment of Neurobiochemistry and §Biology Division, Beckman Research Institute of the City of Hope, Duarte, CA 91010 Contributed by Eugene Roberts, September 7, 1993 ABSTRACT Four peptides homologous to amyloid (B pro- With the exception of commercially purchased peptides tein containng the Val-Phe-Phe (VFF) sequence administered VF and FV, all peptides used in these studies were synthe- intracerebroventricularly after training caused amnesia for sized and analyzed to establish purity by standard methods. footshock active avoidance training in mice. Results with VFF Prior to neutralization and appropriate dilution with saline, and other peptides containing VFF or portions thereof were peptides were dissolved in (i) saline, (ii) dimethyl sulfoxide, used to generate a topographic map for a hypothetical binding (iii) glacial acetic acid, or (iv) NaOH. Upon testing for surface for amnestic peptides, termed Z. Effects on retention of retention of FAAT, groups receiving posttraining icv admin- footshock active avoidance training were rationalized in terms istration of2 1d ofappropriate dilutions ofthe above vehicles of flt to Z, making possible design of potential memory- showed no significant differences among them (ANOVA, F modulating peptidic and nonpeptidic substances. Three pep- < 1). The mean trials to criterion of the most frequently tides that neither improved nor impahred retention blocked the emploved vehicle (vehicle ii above; final concentration of amnestic effects of -(12-28), a peptide homologous to amyloid 13 protein, opening the way to development of substances that dimethyl sulfoxide, 0.001%) were compared to that of mice can antagonize the neurotoxic effects of amyloid (3 protein on receiving test peptides. neural structures and thus attenuate symptoms and progres- With the exception of dose-response curves, the experi- sion of Alzheimer disease. ments reported below tested whether or not peptides im- paired retention at 6.14 nmol per mouse. Although f-(1-28) Intracerebroventricular (icv) administration of a synthetic (1) and (-(12-28) were significantly amnestic at 1.5 nmol per peptide homologous to amyloid 13protein (AP), [Glnl1]13-(1- mouse, the 6.14-nmol dose was chosen so that substances 28) (DAEFRHDSGYQVHHQKLVFFAEDVGSNK), im- with weaker effects might be detected. mediately after training caused amnesia for footshock active avoidance training (FAAT) in mice in a dose-dependent RESULTS fashion. Also amnestic were peptides l3-(12-28), -(18-28), and /3-(12-20) (1). The above amnestic peptides have the Topography of a Binding Site Deduced from a Structure- sequence VFF in common. ,B-(1-11), which does not contain Activity Study of Amnestic Effects. Examination of Corey- VFF, is not amnestic (see below). FAAT experiments were Pauling-Koltun (CPK) models of the peptides tested (Table performed with 28 peptides, 22 of which contained the VFF 1) and superimposition of appropriate configurations of the sequence or portions thereof. A topographic model for the amnestically active ones led to devisal of a provisional binding site ofamnestic peptides, termed Z, was derived from topographic model ofthe site (Z) to which all ofthe amnestic the structure-activity study of the latter. substances might bind. A more refined hypothetical three- In separate experiments, 3 of 15 nonamnestic peptides dimensional binding surface for the peptides (described be- were found to counteract the amnestic effects of ,B-(12-28). low) then was generated by surrounding with small molecules that mimic the properties of amino acids the peptide Gln- MATERIALS AND METHODS Phe-Phe-y-aminobutyric acid that fit optimally to all of the proposed contact points on the original map. A solvent- The care and handling of test mice, surgical procedures for accessible surface was generated using the algorithm of preparation of mice for icv administration, the testing appa- Connolly (2). Peptides then were docked onto the surface and ratus, training and testing procedures, and methods of sta- energy-minimized to optimize contacts [Dreiding II forcefield tistical treatment of data have been described (1). Immedi- (3)]. Images were created with the BIOGRAF program (Mo- ately after training, groups of mice (10-15 mice per group) lecular Simulations, Waltham, MA). The hypothetical recep- were given icv injections (2 ,ul) of vehicle alone or vehicle tor map thus generated (Z) is presented at the outset. Without containing 6.14 nmol of a peptide. Tests for retention of FAAT were performed 1 week later. Results were expressed a detailed molecular definition of the structure of Z, quanti- as the mean and SEM. Significance of overall effects of tative assessments of binding energies of ligands are not treatment was determined by ANOVA run on trials to reach possible. Qualitative and semiquantitative arguments devel- a footshock avoidance criterion in the retention test (trials to oped with the data at hand were employed to interpret the criterion). Tukey's t test was used to make statistical com- results. Numbering clockwise from the lower left in Fig. 11, parisons among group means. Treatment was judged to be the postulated sites on Z are characterized as: 1, H-bonding; amnestic when the mean of vehicle and a treatment group gave a P value of <0.01. Abbreviations: AA3, amyloid ,B protein; FAAT, footshock active avoidance training; icv, intracerebroventricular; VIP, vasoactive intestinal peptide. The publication costs of this article were defrayed in part by page charge *To whom reprint requests should be addressed at: Department of payment. This article must therefore be hereby marked "advertisement" Neurobiochemistry, Beckman Research Institute of the City of in accordance with 18 U.S.C. §1734 solely to indicate this fact. Hope, Duarte, CA 91010. 380 Downloaded by guest on September 23, 2021 Neurobiology: Flood et al. Proc. Natl. Acad. Sci. USA 91 (1994) 381 Table 1. Effect of 6.14 nmol of icv-administered peptides on amino group, for a total of five groups per molecule. Water retention of T-maze FAAT (15 mice per group) clusters may be organized at those sites, the sizes and shapes Peptide Trials to of which are determined by combinatorial influences of Peptide tested criterion, no. molecular and environmental factors. Unbound Z site is presumed to have water clusters associated with sites 1, 3, 1* VFF 9.67 0.40t and 5 (Fig. 11). VFF (Fig. 14) is posited to orient on Z in such 2* VFFAE 8.73 0.38t a manner that the attractive energy between VFF and Z 3* KLVFF 7.73 0.42 becomes great enough to squeeze out intervening water, in 4* KLVFFAE 6.87 0.27 this way minimizing the energy of the system. The molar 5* FFV 9.07 0.41t amnestic efficacy ofVFF was not significantly different from 6t FFVG 8.47 0.33t+ that ofthe APhomologue [Gln11]f-(1-28) (Fig. 2A). Ifbinding 7t DFFV 7.27 0.38 of its VFF segment to Z is key to the amnestic effect of the 8t DFFVG 6.87 0.33 latter, its flanking regions must contribute to strength of 9 KLFFVAE 9.58 0.39t attachment since neither the a-amino group of Val nor the lo§ VF 9.13 0.94t carboxyl group of F-2 is available to contribute to binding ii§ VFT 9.73 0.31t efficacy. Similar considerations apply to other such compar- 12§ AVFT 9.73 ± 0.21t isons, as for AVFT and VIP in Fig. 2B. 13§ AVF 6.80 ± 0.25 If residues with H-bonding side chains that do not bind to 14 VVF 9.27 ± 0.37t Z are added at either end of a peptide that, by itself, binds to 15 VFV 9.07 ± 0.43t Z, water clusters on the nonbinding moieties may become 16 FVF 6.93 ± 0.29 sufficiently large and stable so that resulting physical and 171 FV 9.40 ± 0.46t energetic barriers deter effective attachment ofthe peptide to 1811 SFVG 7.47 ± 0.45 Z. A curvilinearly decremental trend in amnestic potency was 19** QFVG 6.80 ± 0.39 noted with increasing numbers of side-chain H-bonding 20ft FF 7.00 ± 0.42 groups in such peptides related to VFF (Fig. 3A). 21#* QFFG 9.00 ± 0.46t FFV, also amnestic (Table 1 and Fig. 3B), attaches to 22 SFFG 7.33 ± 0.40 aromatic sites 2 and 4 on Z, but the C-terminal carboxyl group 23§H AFIG 6.67 ± 0.26 of Val in FFV is directed to cationic site 3 (Fig. 17). Addition 24§§ AIFT 7.00 ± 0.29 of H-bonding groups to FFV also reduced amnestic potency 25§§ GFMT 6.80 ± 0.34 (Fig. 3B). It is presumed that a water cluster can be mobilized 26§§ NLIT 7.07 ± 0.36 on the amide nitrogen of a peptide bond when Gly is the 27 vv 6.80 ± 0.31 C-terminal residue because, uniquely among the amino acids, 28* DAEFRHDSGYQ 6.93 ± 0.28 the C-terminal Gly offers little side-chain interference to Data for trials to criterion are expressed as the mean t SEM. P water cluster formation. For the latter reason, the number of values were obtained for selected comparisons after obtaining a H-bonding groups assigned to a peptide was increased by one significant F value by ANOVA; F(16,204) = 8.22, P < 0.001. for peptides with a C-terminal Gly (Fig.
Load more

Recommended publications
  • Amylase Release from Rat Parotid Gland Slices C.L
    Br. J. P!harmnic. (1981) 73, 517-523 THE EFFECTS OF SUBSTANCE P AND RELATED PEPTIDES ON a- AMYLASE RELEASE FROM RAT PAROTID GLAND SLICES C.L. BROWN & M.R. HANLEY MRC Neurochemical Pharmacology Unit, Medical Research Council Centre, Medical School, Hills Road, Cambridge CB2 2QH 1 The effects of substance P and related peptides on amylase release from rat parotid gland slices have been investigated. 2 Supramaximal concentrations (1 F.M) of substance P caused enhancement of amylase release over the basal level within 1 min; this lasted for at least 40 min at 30°C. 3 Substance P-stimulated amylase release was partially dependent on extracellular calcium and could be inhibited by 50% upon removal of extracellular calcium. 4 Substance P stimulated amylase release in a dose-dependent manner with an ED50 of 18 nm. 5 All C-terminal fragments of substance P were less potent than substance P in stimulating amylase release. The C-terminal hexapeptide of substance P was the minimum structure for potent activity in this system, having 1/3 to 1/8 the potency of substance P. There was a dramatic drop in potency for the C-terminal pentapeptide of substance P or substance P free acid. Physalaemin was more potent than substance P (ED50 = 7 nM), eledoisin was about equipotent with substance P (ED5o = 17 nM), and kassinin less potent than substance P (ED50 = 150 nM). 6 The structure-activity profile observed is very similar to that for stimulation of salivation in vivo, indicating that the same receptors are involved in mediating these responses.
    [Show full text]
  • Identification of a Novel Vasodilatory Octapeptide from the Skin Secretion
    molecules Article Identification of a Novel Vasodilatory Octapeptide from the Skin Secretion of the African Hyperoliid Frog, Kassina senegalensis Qiang Du 1,†, Hui Wang 1,*,†, Chengbang Ma 2, Yue Wu 2, Xinping Xi 2,*, Mei Zhou 2 ID , Tianbao Chen 2 ID , Chris Shaw 2 and Lei Wang 2 1 School of Pharmacy, China Medical University, Shenyang 110001, Liaoning, China; [email protected] 2 Natural Drug Discovery Group, School of Pharmacy, Queen’s University, Belfast BT9 7BL, Northern Ireland, UK; [email protected] (C.M.); [email protected] (Y.W.); [email protected] (M.Z.); [email protected] (T.C.); [email protected] (C.S.); [email protected] (L.W.) * Correspondence: [email protected] (H.W.); [email protected] (X.X.); Tel.: +86-24-2325-6666 (H.W.); +44-28-9097-2200 (X.X.); Fax: +86-2325-5471 (H.W.); +44-28-9094-7794 (X.X.) † These authors contributed equally to this work. Received: 5 July 2017; Accepted: 19 July 2017; Published: 19 July 2017 Abstract: The defensive skin secretions of amphibians continue to be an excellent source of novel biologically-active peptides. Here we report the identification and pharmacological activity of a novel C-terminally amided myotropic octapeptide from the skin secretion of the African hyperoliid frog, Kassina senegalensis. The 8-amino acid peptide has the following primary structure: WMSLGWSL-amide and has a molecular mass of 978 Da. The primary structure and organisation of the biosynthetic precursor of WL-8 amide was successfully deduced from cloned skin secretion-derived cDNA.
    [Show full text]
  • Peptide Chemistry up to Its Present State
    Appendix In this Appendix biographical sketches are compiled of many scientists who have made notable contributions to the development of peptide chemistry up to its present state. We have tried to consider names mainly connected with important events during the earlier periods of peptide history, but could not include all authors mentioned in the text of this book. This is particularly true for the more recent decades when the number of peptide chemists and biologists increased to such an extent that their enumeration would have gone beyond the scope of this Appendix. 250 Appendix Plate 8. Emil Abderhalden (1877-1950), Photo Plate 9. S. Akabori Leopoldina, Halle J Plate 10. Ernst Bayer Plate 11. Karel Blaha (1926-1988) Appendix 251 Plate 12. Max Brenner Plate 13. Hans Brockmann (1903-1988) Plate 14. Victor Bruckner (1900- 1980) Plate 15. Pehr V. Edman (1916- 1977) 252 Appendix Plate 16. Lyman C. Craig (1906-1974) Plate 17. Vittorio Erspamer Plate 18. Joseph S. Fruton, Biochemist and Historian Appendix 253 Plate 19. Rolf Geiger (1923-1988) Plate 20. Wolfgang Konig Plate 21. Dorothy Hodgkins Plate. 22. Franz Hofmeister (1850-1922), (Fischer, biograph. Lexikon) 254 Appendix Plate 23. The picture shows the late Professor 1.E. Jorpes (r.j and Professor V. Mutt during their favorite pastime in the archipelago on the Baltic near Stockholm Plate 24. Ephraim Katchalski (Katzir) Plate 25. Abraham Patchornik Appendix 255 Plate 26. P.G. Katsoyannis Plate 27. George W. Kenner (1922-1978) Plate 28. Edger Lederer (1908- 1988) Plate 29. Hennann Leuchs (1879-1945) 256 Appendix Plate 30. Choh Hao Li (1913-1987) Plate 31.
    [Show full text]
  • Neuropeptide Proctolin (H-Arg-Tyr-Leu-Pro-Thr-OH)
    Proc. NatL Acad. Sci. USA Vol. 78, No. 9, pp. 5899-5902, September 1981 Neurobiology Neuropeptide proctolin (H-Arg-Tyr-Leu-Pro-Thr-OH): Immunological detection and neuronal localization in insect central nervous system (peptide neurotransmitter/identified neurons) CYNTHIA A. BISHOP, MICHAEL O'SHEA*, AND RICHARD J. MILLER The Department of Pharmacological and Physiological Sciences, The University of Chicago, 947 E. 58th Street, Chicago, Illinois 60637 Communicated by Solomon H. Snyder, June 19, 1981 ABSTRACT Proctolin (H-Arg-Tyr-Leu-Pro-Thr-OH) is a pen- vestigation ofneuropeptide action in a relatively simple nervous tapeptide first extracted from cockroaches. It is known to have system. many neurohormonal effects and has been associated with spe- cific, identified cockroach neurons. We have produced proctolin MATERIALS AND METHODS antisera and report here on their application in detecting proc- tolin-like immunoreactivity (PLI) in the cockroach central nervous Adult specimens, both male and female, of the large American system. Radioimmunoassay, capable ofdetecting 50 fmol ofproc- cockroach (Periplaneta americana; Carolina Biological Supply, tolin, was used to quantify the distribution of PLI. Highest con- Burlington, NC) were used. Authentic proctolin for immuni- centrations were detected in the genital ganglia and lowest in the zation was obtained from Sigma. Enkephalins were.a gift of S. cerebral ganglia. Immunohistochemistry on the cockroach central Wilkinson, Wellcome Research Laboratories (Beckenham, nervous system demonstrated that PLI is localized to neurons. Kent, England). Gut bombesin was a gift of J. Rivier, Salk In- Neurons stained by using immunohistochemistry were widespread stitute (La Jolla, CA). Other peptides were obtained from in the ganglia.
    [Show full text]
  • A 0.70% E 0.80% Is 0.90%
    US 20080317666A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0317666 A1 Fattal et al. (43) Pub. Date: Dec. 25, 2008 (54) COLONIC DELIVERY OF ACTIVE AGENTS Publication Classification (51) Int. Cl. (76) Inventors: Elias Fattal, Paris (FR); Antoine A6IR 9/00 (2006.01) Andremont, Malakoff (FR); A61R 49/00 (2006.01) Patrick Couvreur, A6II 5L/12 (2006.01) Villebon-sur-Yvette (FR); Sandrine A6IPI/00 (2006.01) Bourgeois, Lyon (FR) (52) U.S. Cl. .......................... 424/1.11; 424/423; 424/9.1 (57) ABSTRACT Correspondence Address: Drug delivery devices that are orally administered, and that David S. Bradlin release active ingredients in the colon, are disclosed. In one Womble Carlyle Sandridge & Rice embodiment, the active ingredients are those that inactivate P.O.BOX 7037 antibiotics, such as macrollides, quinolones and beta-lactam Atlanta, GA 30359-0037 (US) containing antibiotics. One example of a Suitable active agent is an enzyme Such as beta-lactamases. In another embodi ment, the active agents are those that specifically treat colonic (21) Appl. No.: 11/628,832 disorders, such as Chrohn's Disease, irritable bowel syn drome, ulcerative colitis, colorectal cancer or constipation. (22) PCT Filed: Feb. 9, 2006 The drug delivery devices are in the form of beads of pectin, crosslinked with calcium and reticulated with polyethylene imine. The high crosslink density of the polyethyleneimine is (86). PCT No.: PCT/GBO6/OO448 believed to stabilize the pectin beads for a sufficient amount of time such that a Substantial amount of the active ingredi S371 (c)(1), ents can be administered directly to the colon.
    [Show full text]
  • 251-Bolton-Hunter- Labeled Substance P Binding Sites in Rat Spinal Cord’
    0270.6474/65/0505-1293$02.00/O The Journal of Neuroscience Copyright 0 Society for Neuroscience Vol. 5, No. 5, pp. 1293-1299 Printed in U.S.A. May 1985 Characterization and Segmental Distribution of ‘251-Bolton-Hunter- labeled Substance P Binding Sites in Rat Spinal Cord’ CLIVEL G. CHARLTON’ AND CINDA J. HELKE Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814 Abstract al., 1982) are two sources for SP in the ventral horn. The nucleus interfascicularis hypoglossi also supplies SP-containing nerve termi- Substance P (SP) is widely distributed in the spinal cord nals to the IML cells of origin for autonomic preganglion fibers (Helke and has been implicated as a neurotransmitter in several et al., 1982). spinal cord neuronal systems. To investigate SP receptors in Functional studies support the concept of a neurotransmOitter role the spinal cord, 1251-Bolton-Hunter-SP (‘*‘I-BH-SP) was used for SP in the spinal cord. Nociception (Piercey et al., 1981; Akerman to identify and characterize spinal cord binding sites for the et al., 1982; Fasmer and Post, 1983) motor control (Otsuka and peptide. The binding of ‘*%BH-SP had the following charac- Konishi, 1977; Yanagisawa et al., 1982) and certain autonomic teristics: high affinity; time, temperature, and membrane con- functions (Loewy and Sawyer, 1982; Keeler and Helke, 1984) are centration dependent; reversible; and saturable. The KS0 of modulated by spinal cord SP. In addition, SP receptors in the spinal SP in whole spinal cord was 0.46 nM as compared with 0.95, cord have been demonstrated by iontophoretic studies in which SP 60, and 150 nM for physalaemin, eledoisin, and kassinin.
    [Show full text]
  • Tachykinins in Endocrine Tumors and the Carcinoid Syndrome
    European Journal of Endocrinology (2008) 159 275–282 ISSN 0804-4643 CLINICAL STUDY Tachykinins in endocrine tumors and the carcinoid syndrome Janet L Cunningham1, Eva T Janson1, Smriti Agarwal1, Lars Grimelius2 and Mats Stridsberg1 Departments of 1Medical Sciences and 2Genetics and Pathology, University Hospital, SE 751 85 Uppsala, Sweden (Correspondence should be addressed to J Cunningham who is now at Section of Endocrine Oncology, Department of Medical Sciences, Lab 14, Research Department 2, Uppsala University Hospital, Uppsala University, SE 751 85 Uppsala, Sweden; Email: [email protected]) Abstract Objective: A new antibody, active against the common tachykinin (TK) C-terminal, was used to study TK expression in patients with endocrine tumors and a possible association between plasma-TK levels and symptoms of diarrhea and flush in patients with metastasizing ileocecal serotonin-producing carcinoid tumors (MSPCs). Method: TK, serotonin and chromogranin A (CgA) immunoreactivity (IR) was studied by immunohistochemistry in tissue samples from 33 midgut carcinoids and 72 other endocrine tumors. Circulating TK (P-TK) and urinary-5 hydroxyindoleacetic acid (U-5HIAA) concentrations were measured in 42 patients with MSPCs before treatment and related to symptoms in patients with the carcinoid syndrome. Circulating CgA concentrations were also measured in 39 out of the 42 patients. Results: All MSPCs displayed serotonin and strong TK expression. TK-IR was also seen in all serotonin- producing lung and appendix carcinoids. None of the other tumors examined contained TK-IR cells. Concentrations of P-TK, P-CgA, and U-5HIAA were elevated in patients experiencing daily episodes of either flush or diarrhea, when compared with patients experiencing occasional or none of these symptoms.
    [Show full text]
  • Identification of Substance P Precursor Forms in Human Brain Tissue
    Proc. Nati. Acad. Sci. USA Vol. 82, pp. 3921-3924, June 1985 Neurobiology Identification of substance P precursor forms in human brain tissue (prohormones/tachykinins/hypothalamus/substantia nigra/caudate nucleus) FRED NYBERG, PIERRE LE GREvls, AND LARS TERENIUS Department of Pharmacology, University of Uppsala, S-751 24 Uppsala, Sweden Communicated by Tomas Hokfelt, January 28, 1985 ABSTRACT Substance P prohormones were identified in glycine (19). Enzymes involved in the processing of the the caudate nucleus, hypothalamus, and substantia nigra of precursors are incompletely known. human brain. A polypeptide fraction of acidic brain extracts The present paper reports the identification of substance P was fractionated on Sephadex G-50. The Iyophilized fractions precursors in human brain. The strategy for the experimental were sequentially treated with trypsin and a substance P- approach is based on the enzymatic generation in vitro of a degrading enzyme with strong preference toward the Phe7- unique peptide fragment (20, 21). Trypsin treatment of any Phe' and Phe8-Gly9 bonds. The released substance P(1-7) product of the preprotachykinins containing the substance P fragment was isolated by ion-exchange chromatography and sequence generates a fragment with the NH2-terminal region quantitated by a specific radioimmunoassay. Confirmation of identical with that of the native peptide. Further conversion the structure of the isolated radioimmunoassay-active frag- of this fragment with an endopeptidase capable of hydrolyz- ment was achieved by electrophoresis and HPLC. By using this ing substance P at the Phe7-Phe8 bond releases the substance enzymatic/radioimmunoassay procedure, two polypeptide P(1-7) sequence as a fragment that can be recovered by fractions of apparent M, 5000 and 15,000, respectively, were ion-exchange chromatography and quantitated by a specific identified.
    [Show full text]
  • Bradykinin in Carcinoid Syndrome
    Gut: first published as 10.1136/gut.28.11.1417 on 1 November 1987. Downloaded from Gut, 1987, 28, 1417-1419 Alimentary tract and pancreas Bradykinin in carcinoid syndrome J,GUSTAFSEN. S BOESBY, F NIELSEN, AND J GIESE Froti th(1 Department of .Surgical Gastroenterology C, Rigshospitalet, Copenhagen 0 and Department of (Clinical Physiology, Glostriup Hospital, Glostriup, Denmark SUMMARY Bradykinin concentrations in peripheral venous blood were measured in seven patients with carcinoid syndrome. The diagnosis was based on typical symptoms and raised urinary excretion of 5-hydroxy-3-indole acetic acid; the carcinoid tumour was verified histologically. Two patients were flushing constantly and the other patients had flushing attacks two to 10 times daily. Several blood samples were taken at weekly intervals from six of seven patients. During 30 sampling procedures the patients were flushing during sampling in 12 instances. Bradykinin was measured by a sensitive solid phase radioimmunoassay technique. Blood bradykinin concentration was normal in all patients. Bradykinin is unlikely to be the vasoactive mediator of flushing. The symptoms in carcinoid syndrome may be symptoms of cardiac failure. The diagnosis was caused by the release of several different biologically confirmed histologically and the carcinoid tumour active substances into the bloodstream or activation wais located in the terminal part of the ileum in of vasoiactive substances in the bloodstream.'' aill. The patients presented with metastases at Bradykinin, which is formed in the blood, has laparotomy, six had liver metastases and one http://gut.bmj.com/ traiditionailly been considered to be one of these mesenteric metastases. The median urinary excre- substances and perhaps the most important.' We tion of 5-hydroxy-3-indole acetic acid was 500 have measured bradykinin in peripheral venous mmol/24 h (range 75-1666 mmol/24 h); normal blood in a group of patients with carcinoid syndrome <50 mmol/24 h.
    [Show full text]
  • Tachykinins in Endocrine Tumors and the Carcinoid Syndrome
    European Journal of Endocrinology (2008) 159 275–282 ISSN 0804-4643 CLINICAL STUDY Tachykinins in endocrine tumors and the carcinoid syndrome Janet L Cunningham1, Eva T Janson1, Smriti Agarwal1, Lars Grimelius2 and Mats Stridsberg1 Departments of 1Medical Sciences and 2Genetics and Pathology, University Hospital, SE 751 85 Uppsala, Sweden (Correspondence should be addressed to J Cunningham who is now at Section of Endocrine Oncology, Department of Medical Sciences, Lab 14, Research Department 2, Uppsala University Hospital, Uppsala University, SE 751 85 Uppsala, Sweden; Email: [email protected]) Abstract Objective: A new antibody, active against the common tachykinin (TK) C-terminal, was used to study TK expression in patients with endocrine tumors and a possible association between plasma-TK levels and symptoms of diarrhea and flush in patients with metastasizing ileocecal serotonin-producing carcinoid tumors (MSPCs). Method: TK, serotonin and chromogranin A (CgA) immunoreactivity (IR) was studied by immunohistochemistry in tissue samples from 33 midgut carcinoids and 72 other endocrine tumors. Circulating TK (P-TK) and urinary-5 hydroxyindoleacetic acid (U-5HIAA) concentrations were measured in 42 patients with MSPCs before treatment and related to symptoms in patients with the carcinoid syndrome. Circulating CgA concentrations were also measured in 39 out of the 42 patients. Results: All MSPCs displayed serotonin and strong TK expression. TK-IR was also seen in all serotonin- producing lung and appendix carcinoids. None of the other tumors examined contained TK-IR cells. Concentrations of P-TK, P-CgA, and U-5HIAA were elevated in patients experiencing daily episodes of either flush or diarrhea, when compared with patients experiencing occasional or none of these symptoms.
    [Show full text]
  • Custom Peptide Synthesis 2
    Biologically Active Peptides Catalogue 2013-2014 The Companies of the ChinaPeptides Laboratories Group 1 Custom Peptide Synthesis 2 Catalogue Peptides 3 Technical Details 3 Confidentiality, Quoting, Sequence, Counterion, Quantity Purity, Lead time, Cost, Certification of Analysis, Peptide Purity Peptide Content, Additional Analysis, Reconstitution Storage, Shipment, Ordering Prices List for Custom Peptide Synthesis 7 Modification Prices for Custom Peptide Synthesis 8 Contact Addresses 8 Overview of Catalogue Peptides 9 Biologically Functional Peptides 11 Glossary 67 Appendix 69 Sample Certification of Analysis 2 The Companies of the ChinaPeptides Laboratories Group The ChinaPeptides Laboratories Group is a Further information can be obtained from our privately-owned network of companies located web site http://www.chinapeptides.com or by in Zhangjiang High-Tech Park, Shanghai contacting us directly. ChinaPeptides China, specializing in the manufacture of Laboratories is committed to close customer peptides for basic research and for contact. We believe that every project is a therapeutic applications. The companies of partnership and that valuable time and money the Group are specifically equipped to can be saved by discussing the chemistry and complement each other both in terms of scale biology of the project before starting the and focus, allowing ChinaPeptides synthesis. We are dedicated to serving our Laboratories to keep pace with peptide customers. peptide needs and would welcome projects as quantity, synthetic strategy and your input for new products, your comments regulatory requirements change. We can on our products and services, or simply an respond quickly, competently and cost exchange of views on topics related to effectively to customers. needs whether these peptides.
    [Show full text]
  • Food Intake in Birds: Hypothalamic Mechanisms Betty R. Mcconn
    Food intake in birds: hypothalamic mechanisms Betty R. McConn Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Animal and Poultry Sciences Mark A. Cline, Chair Elizabeth R. Gilbert Paul B. Siegel D. Michael Denbow Wayne J. Kuenzel April 16, 2018 Blacksburg, VA Keywords: hypothalamus, food intake, chicken, Japanese quail Copyright 2018, Betty R. McConn Food intake in birds: hypothalamic mechanisms Betty R. McConn ABSTRACT (Academic) Feeding behavior is a complex trait that is regulated by various hypothalamic neuropeptides and neuronal populations (nuclei). Understanding the physiological regulation of food intake is important for improving nutrient utilization efficiency in agricultural species and for understanding and treating eating disorders. Knowledge about appetite in birds has agricultural and biomedical relevance and provides evolutionary perspective. I thus investigated hypothalamic molecular mechanisms associated with appetite in broilers, layers, chicken lines selected for low (LWS) or high (HWS) body weight, and Japanese quail, which provide a unique perspective to understanding appetite. Broiler-type chicks have been genetically selected for rapid growth and consume much more feed than do layer-type chicks which have been selected for egg production. Long-term selection has caused the LWS chicks to have different severities of anorexia while the HWS chicks become obese, thus making these lines a valuable model for metabolic disorders. Lastly, the Japanese quail have not undergone as extensive artificial selection as the chicken, thus this model may provide insights on how human intervention has changed the mechanisms that regulate feeding behavior in birds.
    [Show full text]