RADIATION PROTECTION:

RADIATION TOXICOLOGY.
GLYCOPROTEINS.
DMITRI POPOV MD (RUSSIA), PHD RADIOBIOLOGY.
ADVANCED MEDICAL TECHNOLOGY AND SYSTEMS INC. CANADA.

GLYCOPROTEINS
Research Proposal:
Radiation Protection: Radiation Toxicology. Glycoproteins. Pathway to
biodozimetry and pathway to cancer diagnosis.

Dmitri Popov
Full-text available Research Proposal Aug 2015
Add resources
File name:Radiation Toxicology Glycoproteins.pptx
DOI:10.13140/RG.2.2.13696.64001

GLYCOPROTEINS
Keywords:
ACUTE RADIATION SYNDROMES, BIOLOGICAL RRADIATION
EFFECTS, GAMMA RADIATION, RADIOSENSETIVITY,
BIOLOGICAL EFFECTS.

GLYCOPROTEINS
Glycoproteins play key roles in inflammatory and pathological
processes. The Differential Diagnosis of Acute Radiation Syndromes
can be assessed by quantifying circulating levels of glycoproteins
with ELISA.

Measurements based on the glycan structures of circulating

proteins represent critically important path for improving diagnosis,
prognosis and risk prediction of common inflammatory disorders
after electromagnetic irradiation.

GLYCOPROTEINS
Inflammatory glycoproteins are predominantly synthesized
and secreted by hepatocytes but can be produced by
activated macrophages and neutrophils in the periphery.

C. Gabay, I. Kushner, Acute-phase proteins and other

systemic responses to inflammation,

N. Engl. J. Med. 340 (6) (1999) 448454.

GLYCOPROTEINS
E. Gruys, M.J. Toussaint, T.A. Niewold, S.J. Koopmans, Acute phase
reaction and acute phase proteins, J. Zhejiang Univ. Sci. B 6 (11)
(2005) 10451056.

X.L. Zhang, Roles of glycans and glycopeptides in immune system

and immune-related diseases, Curr. Med. Chem. 13 (10) (2006)
11411147.

J.D.Marth, P.K. Grewal, Mammalian glycosylation in immunity,

Nat. Rev. Immunol. 8 (11) (2008) 874887.

GLYCOPROTEINS
Acute-phase proteinsare a class ofproteinswhoseplasma
concentrations increase (positive acute-phase proteins) or
decrease (negative acute-phase proteins) in response to
inflammation.

This response is called theacute-phase reaction(also called

acute-phase response).

GLYCOPROTEINS
In response to injury, localinflammatorycells (neutrophil
granulocytes,andmacrophages) secrete a number ofcytokinesinto the
bloodstream, most notable of which are theinterleukinsIL1,IL6andIL8,
andTNF. Theliverresponds by producing a large number ofacutephase reactants. At the same time, the production of a number of
other proteins is reduced; these are, therefore, referred to as "negative"
acute-phase reactants. Increased acute phase proteins from the liver
may also contribute to the promotion ofsepsis, or acute radiation
syndromes (after irradiation).

ACUTE PHASE PROTEINS.

Positive acute-phase proteins serve (part of the innate
immune system) different physiological functions for
theimmune system. Some act to destroy or inhibit growth of
microbes, e.g.,C-reactive protein,mannose-binding
protein,complement factors.etc.

GLYCOPROTEINS
Therefore, there are both intracellular and extracellular post-translational
processes that contribute to the overall diversity of glycan structures
that can occur in any one individual. These are also many factors that
can influence glycan complexity including: 1) cell-type specific expression
of glycosyltransferases, glycosidases, 2) availability of the various
monosaccharides, 3) age, 4) gender, 5) epigenetic background, 5) environment
(e.g. health, diet, smoking and alcohol consumption) and 6)
disease processes (e.g. autoimmune diseases, cancer as well as low grade
inflammatory diseases such as CVD and T2DM).

GLYCOPROTEINS
W. Dijk, G. Turner, A. Mackiewicz, Changes in glycosylation of
acute-phase proteins

in health and disease: occurrence, regulation and function,

Glycoconj. J. 1 (1)

(1994) 514.

GLYCOPROTEINS
F. Ceciliani, V. Pocacqua, The acute phase protein alpha1-acid
glycoprotein: a model for altered glycosylation during
diseases, Curr. Protein Pept. Sci. 8 (1) (2007) 91108.

O. Gornik, G. Lauc, Glycosylation of serum proteins in

inflammatory diseases, Dis.

Markers 25 (45) (2008) 267278.

GLYCOPROTEINS.
Besides changes in circulating protein levels, the glycan
structures of acute phase glycoproteins are dynamically
altered by glycosidases, glycosyltransferases and sialyl
transferases in the blood and lymph- circulation.

GLYCOPROTEINS
Glycoproteinsareproteinsthat
containoligosaccharidechains (glycans)covalentlyattached
topolypeptideside-chains.
The carbohydrate is
attached to the protein in aco-translationalorposttranslational modification.
This process is known
asglycosylation.
Secreted
extracellular proteinsare often glycosylated.

GLYCOPROTEINS
Glycoproteins are also often importantintegral membrane proteins,
where they play a role in cellcell interactions. It is important to
distinguish endoplasmic reticulum-based glycosylation of the
secretory system without of reversible cytosolic/nuclear glycosylation.
Glycoprotein of thecytosoland nucleus can be modified through the
reversible addition of a single GlcNAc residues that is consider
reciprocal to phosphorylation and the functions of these are likely to
be additional regulatory mechanism that controls phosphorylationbased signalling

GLYCOPROTEINS
One example of glycoproteins found in the body ismucins, which are secreted in the
mucus of the respiratory and digestive tracts. The sugars when attached to mucins
give them considerable water-holding capacity and also make them resistant
toproteolysis by digestive enzymes.

Glycoproteins are important forwhite blood cell recognition, especially

inmammals.Examples of glycoproteins in theimmune systemare:

molecules such asantibodies(immunoglobulins), which interact directly

withantigens.

molecules of themajor histocompatibility complex(or MHC), which are expressed on

the surface of cells and interact withT cellsas part of the adaptive immune
response.

sialyl Lewis X antigen on the surface of leukocytes.

GLYCOPROTEINS
Sialyl LewisX, also known assialyl LeXandSLeX, is a tetra
saccharidecarbohydratethat is usually attached to Oglycanson the surface of cells. It is known to play a vital role
in cell-to-cell recognition processes.

GLYCOPROTEINS
Sialyl LewisXis also one of the most important blood group antigens
and is displayed on the terminus of glycolipids that are present on the
cell surface. TheSialyl LewisXdeterminant, E-selectinligand
carbohydrate structure, is constitutively expressed on
granulocytesandmonocytesand mediates inflammatory
extravasation of these cells. Resting T and Blymphocyteslack its
expression and are induced to strongly expresssialyl LewisXupon
activation. TheSialyl LewisXdeterminant is expressed preferentially
on activatedTh1 cellsbut not on Th2 cells.

GLYCOPROTEINS
Defective synthesis of the sialyl LewisXantigen results in immunodeficiency (leukocyte adhesion
deficiencytype 2). Defective synthesis can be caused by the loss of fucosyltransferase, impairing the
glycosylation of the glycosphingolipid.

Sialyl Lewis x is being used in studies to fight tumors and cancer cell growth. It has been shown that
there is frequent overexpression of sialyl Lewis x on cancer cells and is found on both N-glycan and Oglycans. Sialyl Lewis x is being researched with CD markers to find new ways to create biosensors for
cancer cells. Also, it is being used in new ways to target cancer cells specifically for cancer treatment.

It plays a key role in the inflammatory response and may be used to increase the leukocyte response to
infections.

Sialyl Lewis x is an inflammation-associated antigen on liver cells. It becomes over expressed on

diseased liver cells and can be used as a way to detect liver disease in a patient.

Sialyl Lewis x is also being researched for detection and treatment of immune disorders because of its
presence on leukocytes. There is congenital disorder where there is an inclination to recurring severe
infections. This stems from an absence of sialyl Lewis x attached to E-selectin ligands on their
neutrophils. https://en.wikipedia.org/wiki/Sialyl-Lewis_X

GLYCOPROTEINS
Leukocyte homing and cancer metastasis
Sialyl-Lewisxisimportantinleukocytetetheringandrolling.Leukocytesmovethroughthebloodstreamand
thentetherthemselvestotheendothelialwallandrollalongtheendothelialtissuetodetermineiftheywant
toleavethebloodstreamtogettonecessarytissue.

Sialyl-Lewisxisanecessarypartnerforthethreeselectinsthatbindtheleukocyteandendothelialcells.
Whensialyl-LewisxispartofanO-glycanandattachedtoCD34itcanthenbindtoL-selectin.Forthebinding
toL-selectintooccursialyl-Lewis xmustundergosulfation.

Forsialyl-LewisxtoattachtoP-selectinitmustbindtoP-SelectinGlycoproteinLigand-1(PSGL-1)firstwhich
isthensulfatedallowingsialyl-Lewis xtoattachtoP-selectin.Forsialyl-Lewis xtobindtoE-selectinitneedsto
bepartofanN-glycanandthenbindtoCD44orpossiblyglycolipidswhichhavealsobeenimplicatedto
assistinbinding.

Thisbindingallowstheleukocytestosticktoandbereleasedfromtheendothelialcellsasneededtoreach
theirdestination.

Sialyl-Lewisxalsoplaysacriticalroleincancermetastasis,facilitatingtheextravasationofcancercellsoutof
thebloodstreamwhiletheyaremovingthroughthebody.

https://en.wikipedia.org/wiki/Sialyl-Lewis_X

GLYCOPROTEINS
H antigen of the ABO blood compatibility antigens. Other
examples of glycoproteins include:

glycoprotein IIb/IIIa, an integrin found onplateletsthat is

required for normal platelet aggregation and adherence to
theendothelium.

components of thezona pellucida, which surrounds

theoocyte, and is important forsperm-egg interaction.

GLYCOPROTEINS AND LYMPHOCYTES.

Antigen-specific receptors and functionally related molecules
Recognition of substances foreign to an organism is the basis
of immune response. The recognition is accomplished by
soluble recognition molecules, i.e. immunoglobulins, and by
membrane-bound antigen specific receptors. There are
basically two kinds of these receptors: membrane
immunoglobulins of B lymphocytes and so called T cell
antigen receptors of T lymphocytes.

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Most, if not all, external proteins of mammalian cells are
glycoproteins.
These comprise both various receptors and antigenic
determinants.

GLYCOPROTEIN (EBOLA VIRUS EXAMPLE)

Ebola virus infection causes a highly lethal hemorrhagic fever
syndrome associated with profound immunosuppression
through its ability to induce widespread inflammation and
cellular damage. Though GP, the viral envelope glycoprotein,
mediates many of these effects, the molecular events that
underlie Ebola virus cytopathicity are poorly understood.
Here, we define a cellular mechanism responsible for Ebola
virus GP cytotoxicity. GP selectively decreased the expression
of cell surface molecules that are essential for cell adhesion
and immune function

GLYCOPROTEINS (EBOLA VIRUS EXAMPLE)

GP dramatically reduced levels of V3 without affecting the levels of
21 or cadherin, leading to cell detachment and death. This effect
was inhibited in vitro and in vivo by brefeldin A and was dependent on
dynamin, the GTP ase. GP also decreased cell surface expression of
major histocompatibility complex class I molecules, which alters
recognition by immune cells, and this effect was also dependent on
the mucin domain previously implicated in GP cytotoxicity. By altering
the trafficking of select cellular proteins, Ebola virus GP inflicts cell
damage and may facilitate immune escape by the virus

GLYCOPROTEINS
Thehuman leukocyte antigen(HLA) system is agene
complexencoding themajor histocompatibility complex(MHC)
proteins in humans. Thesecell-surface proteinsare responsible
for the regulation of theimmune system in humans. The HLA
gene complex resides on a 3Mbpstretch withinchromosome
6p 21. HLA genes are highlypolymorphic, which means that
they have many different alleles, allowing them to fine-tune
theadaptive immune system. The proteins encoded by certain
genes are also known asantigens, as a result of theirhistoric
discoveryas factors in organ transplants.

GLYCOPROTEINS.
Inflammatory glycoproteins in cardio-metabolic disorders, autoimmune diseases
and cancer.

Margery A. Connelly a, Eke G. Gruppen b,c, James D. Otvos a, Robin P.F. Dullaart
b,

a LipoScience, Laboratory Corporation of America Holdings, Raleigh, NC, USA

b Department of Endocrinology, University Medical Center Groningen, University
of Groningen, Groningen, The Netherlands

c Department of Nephrology, University Medical Center Groningen, University of

Groningen, Groningen, The Netherlands

GLYCOPROTEINS
Knowledge of the membrane glycoprotein patterns on the
surface of normal leukocytes and encoded with the human
leukocyte antigen(HLA) system, and membrane
glycoprotein patterns on surface classes of themajor
histocompatibility complex(MHC) for other vertebrates is
fundamental for the discovery of possible molecular defects
and development of toxic effects associated with Acute
Radiation Syndromes.

GLYCOPROTEINS
Currently, concentrations of individual inflammatory glycoproteins
are determined using immunochemical methods such as enzyme linked
Immuno-sorbent assays (ELISAs), electro-chemiluminescence immuno assay
(ECLIA), luminex based assays, radioimmunoassays (RIA)
and nephelometric assays that quantify the amount of protein present
in biological samples.
Method of Differential Diagnosis of Acute Radiation Diseases was elaborated in All
Union Institute of vet. Medicine. Kazan. Tatarstan. 1990 yy. Authors: Popov D.N.,
Kirshin V.A.

GLYCOPROTEINS.
1. Glycoproteins playing important role in the development
clinical picture and biological sequela after different types of
radiation.

2. Method ELISA effective for Differential Diagnosis of Acute

Radiation Syndromes and effective for monitoring possible cancer
transformation after irradiation.

3. Specific Auto antibodies to several glycoproteins can be

effective Antidote.