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Article ; Online: Agonists or positive allosteric modulators of α7 nicotinic acetylcholine receptor prevent interaction of SARS-Cov-2 receptor-binding domain with astrocytoma cells.

Kalashnyk, Olena / Lykhmus, Olena / Sullivan, Raymond / Komisarenko, Serhiy / Skok, Maryna

Biochemical and biophysical research communications

2024 Volume 709, Page(s) 149825

Abstract: SARS-Cov-2, the virus causing COVID-19, penetrates host target cells via the receptor of angiotensin-converting enzyme 2 (ACE2). Disrupting the virus interaction with ACE2 affords a plausible mechanism for prevention of cell penetration and inhibiting ... ...

Abstract	SARS-Cov-2, the virus causing COVID-19, penetrates host target cells via the receptor of angiotensin-converting enzyme 2 (ACE2). Disrupting the virus interaction with ACE2 affords a plausible mechanism for prevention of cell penetration and inhibiting dissemination of the virus. Our studies demonstrate that ACE2 interaction with the receptor binding domain of SARS-Cov-2 spike protein (RBD) can be impaired by modulating the α7 nicotinic acetylcholine receptor (α7 nAChR) contiguous with ACE2. U373 cells of human astrocytoma origin were shown to bind both ACE2-specific antibody and recombinant RBD in Cell-ELISA. ACE2 was found to interact with α7 nAChR in U373 cell lysates studied by Sandwich ELISA. Our studies demonstrate that inhibition of RBD binding to ACE2-expressing U373 cells were defined with α7 nAChR agonists choline and PNU282987, but not a competitive antagonist methyllicaconitine (MLA). Additionally, the type 2 positive allosteric modulator (PAM2) PNU120596 and hydroxyurea (HU) also inhibited the binding. Our studies demonstrate that activation of α7 AChRs has efficacy in inhibiting the SARS-Cov-2 interaction with the ACE2 receptor and in such a way can prevent virus target cell penetration. These studies also help to clarify the consistent efficacy and positive outcomes for utilizing HU in treating COVID-19.
MeSH term(s)	Humans ; alpha7 Nicotinic Acetylcholine Receptor/metabolism ; Angiotensin-Converting Enzyme 2/metabolism ; COVID-19 ; Protein Binding ; Receptors, Nicotinic/metabolism ; SARS-CoV-2/metabolism ; Spike Glycoprotein, Coronavirus/chemistry
Chemical Substances	alpha7 Nicotinic Acetylcholine Receptor ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Receptors, Nicotinic ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2024-03-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2024.149825
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Article ; Online: Hydroxyurea interaction with α7 nicotinic acetylcholine receptor can underlie its therapeutic efficacy upon COVID-19.

Lykhmus, Olena / Kalashnyk, Olena / Sullivan, Raymond / Skok, Maryna

Journal of neuroimmunology

2023 Volume 385, Page(s) 578244

Abstract: In this paper the authors provide evidence that hydroxyurea (hydroxycarbamide) interacts with α7 nicotinic acetylcholine receptor, exerts anti-inflammatory and pro-survival effect, prevents α7 nicotinic receptor interaction with angiotensin-converting ... ...

Abstract	In this paper the authors provide evidence that hydroxyurea (hydroxycarbamide) interacts with α7 nicotinic acetylcholine receptor, exerts anti-inflammatory and pro-survival effect, prevents α7 nicotinic receptor interaction with angiotensin-converting enzyme-2 and stimulates IgM to IgG class switch upon immunization with SARS spike protein fragment 674-685. Hydroxyurea shifts immunoglobulin glycosylation profile to anti-inflammatory phenotype and prevents the appearance of anti-idiotypic α7(179-190)-specific antibodies, as well as memory impairment. According to these results, interaction with α7 nicotinic acetylcholine receptor may underlie positive therapeutic effects of hydroxyurea upon SARS-Cov-2 infection by interfering with virus penetration into the cell and providing anti-inflammatory and immunomodulatory effects.
MeSH term(s)	Humans ; alpha7 Nicotinic Acetylcholine Receptor/genetics ; COVID-19 ; Hydroxyurea/pharmacology ; Hydroxyurea/therapeutic use ; SARS-CoV-2/metabolism ; Anti-Inflammatory Agents/therapeutic use ; Receptors, Nicotinic
Chemical Substances	alpha7 Nicotinic Acetylcholine Receptor ; Hydroxyurea (X6Q56QN5QC) ; Anti-Inflammatory Agents ; Receptors, Nicotinic
Language	English
Publishing date	2023-11-21
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	8335-5
ISSN	1872-8421 ; 0165-5728
ISSN (online)	1872-8421
ISSN	0165-5728
DOI	10.1016/j.jneuroim.2023.578244
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Article: Corrigendum: Positive Allosteric Modulation of Alpha7 Nicotinic Acetylcholine Receptors Transiently Improves Memory but Aggravates Inflammation in LPS-Treated Mice.

Lykhmus, Olena / Kalashnyk, Olena / Uspenska, Kateryna / Skok, Maryna

Frontiers in aging neuroscience

2020 Volume 12, Page(s) 18

Abstract: This corrects the article DOI: 10.3389/fnagi.2019.00359.]. ...

Abstract	[This corrects the article DOI: 10.3389/fnagi.2019.00359.].
Language	English
Publishing date	2020-02-06
Publishing country	Switzerland
Document type	Published Erratum
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2020.00018
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Article: Immunization with 674–685 fragment of SARS-Cov-2 spike protein induces neuroinflammation and impairs episodic memory of mice

Lykhmus, Olena / Kalashnyk, Olena / Koval, Lyudmyla / Krynina, Olga / Komisarenko, Serhiy / Skok, Maryna

Biochemical and biophysical research communications. 2022 Sept. 24, v. 622

2022

Abstract: COVID-19 is accompanied by strong inflammatory reaction and is often followed by long-term cognitive disorders. The fragment 674–685 of SARS-Cov-2 spike protein was shown to interact with α7 nicotinic acetylcholine receptor involved in regulating both ... ...

Abstract	COVID-19 is accompanied by strong inflammatory reaction and is often followed by long-term cognitive disorders. The fragment 674–685 of SARS-Cov-2 spike protein was shown to interact with α7 nicotinic acetylcholine receptor involved in regulating both inflammatory reactions and cognitive functions. Here we show that mice immunized with the peptide corresponding to 674–685 fragment of SARS-Cov-2 spike protein conjugated to hemocyanin (KLH-674-685) demonstrate decreased level of α7 nicotinic acetylcholine receptors, increased levels of IL-1β and TNFα in the brain and impairment of episodic memory. Choline injections prevented α7 nicotinic receptor decline and memory loss. Mice injected with immunoglobulins obtained from the blood of (KLH-674-685)-immunized mice also demonstrated episodic memory decline. These data allow suggesting that post-COVID memory impairment in humans is related to SARS-Cov-2 spike protein-specific immune reaction. The mechanisms of such effect are being discussed.
Keywords	COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; acetylcholine ; blood ; brain ; choline ; cognition ; decline ; hemocyanin ; immune response ; immunization ; immunoglobulins ; memory ; memory disorders ; nicotinic receptors ; research
Language	English
Dates of publication	2022-0924
Size	p. 57-63.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2022.07.016
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Article: Positive Allosteric Modulation of Alpha7 Nicotinic Acetylcholine Receptors Transiently Improves Memory but Aggravates Inflammation in LPS-Treated Mice.

Lykhmus, Olena / Kalashnyk, Olena / Uspenska, Kateryna / Skok, Maryna

Frontiers in aging neuroscience

2020 Volume 11, Page(s) 359

Abstract: Neuroinflammation accompanies or even precedes the development of cognitive changes in many brain pathologies, including Alzheimer's disease. Therefore, dampening inflammatory reactions within the brain is a promising strategy for supporting cognitive ... ...

Abstract	Neuroinflammation accompanies or even precedes the development of cognitive changes in many brain pathologies, including Alzheimer's disease. Therefore, dampening inflammatory reactions within the brain is a promising strategy for supporting cognitive functions in elderly people and for preventing the development of neurodegenerative disorders. Nicotinic acetylcholine receptors containing α7 subunits (α7 nAChRs) are involved in regulating cell survival, inflammation, and memory. The aim of our study was to evaluate the efficiency of α7-specific therapy at different stages of inflammation and to compare the effects of orthosteric agonist PNU282987 and type 2 positive allosteric modulator (PAM) PNU120596 in mice after a single injection of lipopolysaccharide (LPS). The data presented demonstrate that PNU282987 protected mice from LPS-induced impairment of episodic memory by decreasing IL-6 levels in the blood, stabilizing the brain mitochondria and up-regulating the brain α7-, α3-, and α4-containing nAChRs. Such treatment was efficient when given simultaneously with LPS or a week after LPS injection and was not efficient if LPS had been injected 2 months before. PNU120596 also decreased IL-6, stabilized mitochondria and up-regulated the brain nAChRs. However, its memory-improving effect was transient and disappeared after the end of the injection cycle. Moreover, cessation of PNU120596 treatment resulted in a sharp increase in IL-1β and IL-6 levels in the blood. It is concluded that activating α7 nAChRs protects the mouse brain from the pathogenic effect of LPS in the early stages of inflammation but is not efficient when irreversible changes have already occurred. The use of a PAM does not improve the effect of the agonist, possibly potentiates the effect of endogenous agonists, and results in undesirable effects after treatment cessation.
Language	English
Publishing date	2020-01-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2019.00359
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Article ; Online: Immunization with 674-685 fragment of SARS-Cov-2 spike protein induces neuroinflammation and impairs episodic memory of mice.

Lykhmus, Olena / Kalashnyk, Olena / Koval, Lyudmyla / Krynina, Olga / Komisarenko, Serhiy / Skok, Maryna

Biochemical and biophysical research communications

2022 Volume 622, Page(s) 57–63

Abstract: COVID-19 is accompanied by strong inflammatory reaction and is often followed by long-term cognitive disorders. The fragment 674-685 of SARS-Cov-2 spike protein was shown to interact with α7 nicotinic acetylcholine receptor involved in regulating both ... ...

Abstract	COVID-19 is accompanied by strong inflammatory reaction and is often followed by long-term cognitive disorders. The fragment 674-685 of SARS-Cov-2 spike protein was shown to interact with α7 nicotinic acetylcholine receptor involved in regulating both inflammatory reactions and cognitive functions. Here we show that mice immunized with the peptide corresponding to 674-685 fragment of SARS-Cov-2 spike protein conjugated to hemocyanin (KLH-674-685) demonstrate decreased level of α7 nicotinic acetylcholine receptors, increased levels of IL-1β and TNFα in the brain and impairment of episodic memory. Choline injections prevented α7 nicotinic receptor decline and memory loss. Mice injected with immunoglobulins obtained from the blood of (KLH-674-685)-immunized mice also demonstrated episodic memory decline. These data allow suggesting that post-COVID memory impairment in humans is related to SARS-Cov-2 spike protein-specific immune reaction. The mechanisms of such effect are being discussed.
MeSH term(s)	Animals ; COVID-19 ; Humans ; Immunization ; Inflammation ; Memory Disorders/etiology ; Memory Disorders/metabolism ; Memory, Episodic ; Mice ; Neuroinflammatory Diseases ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/adverse effects ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/metabolism ; alpha7 Nicotinic Acetylcholine Receptor/metabolism
Chemical Substances	Spike Glycoprotein, Coronavirus ; alpha7 Nicotinic Acetylcholine Receptor ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2022.07.016
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Zs.A 116: Show issues

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Article ; Online: α7 Nicotinic acetylcholine receptors regulate translocation of HIF-1α to the cell nucleus and mitochondria upon hypoxia.

Kalashnyk, Olena / Lykhmus, Olena / Koval, Lyudmyla / Uspenska, Kateryna / Obolenskaya, Maria / Chernyshov, Volodymyr / Komisarenko, Serhiy / Skok, Maryna

Biochemical and biophysical research communications

2023 Volume 657, Page(s) 35–42

Abstract: Nicotinic acetylcholine receptors (nAChRs), initially characterized as ligand-gated ion channels mediating fast synaptic transmission, are now found in many non-excitable cells and mitochondria where they function in ion-independent manner and regulate ... ...

Abstract	Nicotinic acetylcholine receptors (nAChRs), initially characterized as ligand-gated ion channels mediating fast synaptic transmission, are now found in many non-excitable cells and mitochondria where they function in ion-independent manner and regulate vital cellular processes like apoptosis, proliferation, cytokine secretion. Here we show that the nAChRs of α7 subtype are present in the nuclei of liver cells and astrocytoma U373 cell line. As shown by lectin ELISA, the nuclear α7 nAChRs are mature glycoproteins that follow the standard rout of post-translational modifications in Golgi; however, their glycosylation profile is non-identical to that of mitochondrial nAChRs. They are exposed on the outer nuclear membrane and are found in combination with lamin B1. The nuclear α7 nAChRs are up-regulated in liver within 1 h after partial hepatectomy and in H
MeSH term(s)	Humans ; alpha7 Nicotinic Acetylcholine Receptor/metabolism ; Cell Nucleus/metabolism ; Hydrogen Peroxide/metabolism ; Hypoxia/metabolism ; Mitochondria/metabolism ; Hypoxia-Inducible Factor 1/metabolism
Chemical Substances	alpha7 Nicotinic Acetylcholine Receptor ; Hydrogen Peroxide (BBX060AN9V) ; Chrna7 protein, human ; HIF1A protein, human ; Hypoxia-Inducible Factor 1
Language	English
Publishing date	2023-03-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2023.03.021
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Article ; Online: Corrigendum to "α7 nicotinic acetylcholine receptors are involved in suppression of the antibody immune response" [J Neuroimmunol Vol 318. (2018) 8-14].

Koval, Lyudmyla / Kalashnyk, Olena / Lykhmus, Olena / Skok, Maryna

Journal of neuroimmunology

2018 Volume 319, Page(s) 149

Language	English
Publishing date	2018-05-08
Publishing country	Netherlands
Document type	Published Erratum
ZDB-ID	8335-5
ISSN	1872-8421 ; 0165-5728
ISSN (online)	1872-8421
ISSN	0165-5728
DOI	10.1016/j.jneuroim.2018.04.013
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Article ; Online: Mesenchymal stem cell application for treatment of neuroinflammation-induced cognitive impairment in mice.

Skok, Maryna / Deryabina, Olena / Lykhmus, Olena / Kalashnyk, Olena / Uspenska, Kateryna / Shuvalova, Nadia / Pokholenko, Ianina / Lushnikova, Iryna / Smozhanyk, Kateryna / Skibo, Galyna / Kordyum, Vitalii

Regenerative medicine

2022 Volume 17, Issue 8, Page(s) 533–546

Abstract: Background: ...

Abstract	Background:
MeSH term(s)	Animals ; Cognitive Dysfunction/therapy ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells ; Mice ; Neuroinflammatory Diseases ; Umbilical Cord
Language	English
Publishing date	2022-05-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2274500-2
ISSN	1746-076X ; 1746-0751
ISSN (online)	1746-076X
ISSN	1746-0751
DOI	10.2217/rme-2021-0168
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Article ; Online: α7 Nicotinic acetylcholine receptors regulate translocation of HIF-1α to the cell nucleus and mitochondria upon hypoxia

Kalashnyk, Olena / Lykhmus, Olena / Koval, Lyudmyla / Uspenska, Kateryna / Obolenskaya, Maria / Chernyshov, Volodymyr / Komisarenko, S. V. / Skok, Maryna

Biochemical and Biophysical Research Communications. 2023 May, v. 657 p.35-42

2023

Abstract	Nicotinic acetylcholine receptors (nAChRs), initially characterized as ligand-gated ion channels mediating fast synaptic transmission, are now found in many non-excitable cells and mitochondria where they function in ion-independent manner and regulate vital cellular processes like apoptosis, proliferation, cytokine secretion. Here we show that the nAChRs of α7 subtype are present in the nuclei of liver cells and astrocytoma U373 cell line. As shown by lectin ELISA, the nuclear α7 nAChRs are mature glycoproteins that follow the standard rout of post-translational modifications in Golgi; however, their glycosylation profile is non-identical to that of mitochondrial nAChRs. They are exposed on the outer nuclear membrane and are found in combination with lamin B1. The nuclear α7 nAChRs are up-regulated in liver within 1 h after partial hepatectomy and in H₂O₂-treated U373 cells. As shown both in silico and experimentally, the α7 nAChR interacts with hypoxia-inducible factor HIF-1α and this interaction is impaired by α7-selective agonists PNU282987 and choline or type 2 positive allosteric modulator PNU120596, which prevent HIF-1α accumulation in the nuclei. Similarly, HIF-1α interacts with mitochondrial α7 nAChRs in U373 cells treated with dimethyloxalylglycine. It is concluded that functional α7 nAChRs influence HIF-1α translocation into the nucleus and mitochondria upon hypoxia.
Keywords	acetylcholine ; apoptosis ; astrocytoma ; cell lines ; choline ; computer simulation ; cytokines ; glycoproteins ; glycosylation ; hepatectomy ; hypoxia ; lectins ; liver ; mitochondria ; nuclear membrane ; research ; secretion ; synaptic transmission ; α7 nicotinic acetylcholine receptor ; Cell nucleus ; HIF-1α ; nAChR ; PHE
Language	English
Dates of publication	2023-05
Size	p. 35-42.
Publishing place	Elsevier Inc.
Document type	Article ; Online
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2023.03.021
Database	NAL-Catalogue (AGRICOLA)

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