Laboratory of oxylipins

Department of molecular bases of neurosignalization

Head: Vladimir Bezuglov, D.Sc, professor
vvbez@oxylipin.ibch.ru+7(495)330-65-92

oxylipin.ibch.ru

oxylipins; endocannabinoids; endovanilloids; biochemistry; lipids; neurochemistry; cell biology; neurodegeneration; cancer; stroke

The research of the Laboratory is aimed at revealing the role of lipids as molecules that transmit information in the body regulation system. One of the directions is the study of signaling pathways that mediate the lipids ability to enhance proliferation or induce apoptosis, protect cells of the nervous system from the effects of damaging factors, induce cell differentiation and morphogenesis. Lipids are important regulators of a wide range of normal and pathological processes in the body, so the search for lipid molecules with more selective action is also at the center of the Laboratory's attention.

The main object of the Laboratory's research is natural oxylipins (prostaglandins, etc.), natural neurolypes (conjugates of fatty acids with biogenic amines, neurotransmitters and amino acids) and their synthetic analogues.

Earlier, the Laboratory staff (Bezuglov et al., 1995) suggested that the acylated derivatives of endogenous neurotransmitters can be a new family of bioregulators combining the properties of neuroactive lipids (anandamide) and classical neurotransmitters (dopamine, serotonin, etc.). Acyl-dopamines and derivatives of fatty acids with various amino acids were then found in the nervous and peripheral tissues of various organisms, including mammals. It turned out that these compounds have a wide range of biological effects that continue to be studied at the Laboratory.

The Laboratory discovered new ways of metabolizing acyl-dopamines and clarified some aspects of their biosynthesis. Also, the team showed that acyl-dopamines  has a neuroprotective effect and it is able to induce apoptosis of the oncotransformed cells of various tissue origin in vitro, which indicates the large pharmacological potential of these substances. Now the researchers are investigating the mechanism of their toxic and differentiating effects on cancer cells, and also seek to increase the effectiveness of existing antitumor drugs.

To fight neurodegenerative diseases, an important socially significant problem, the Laboratory developed a strategy for searching for new neuroprotectors and protecting neurons from irreversible changes under the influence of stress. This approach is based on the use of the natural neuroactive lipids, peptides and other low-molecular bioregulators potential. Researchers managed to show that some modified acyl-dopamine are promising candidates for treatment of stroke consequences. In addition, the Laboratory is developing methods of directional delivery compounds to neurons capable to slowing down and reversing the neurodegenerative process.

Researchers of the Laboratory actively use modern methods of cell and molecular biology, fine organic synthesis, analytical chemistry and biochemistry.

The Laboratory cooperates with the Institute departments, as well as the Institute of Molecular Genetics of the Russian Academy of Sciences (RAS), the Mendeleev Russian Chemistry and Technology University, the Zakusov Institute of Pharmacology RAS, the Institute of Physiologically Active Substances RAS, the Koltsov Institute of Developmental Biology RAS, the Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus, the Central University of Rajasthan (India), the Max Mousseron Institute of Biomolecules (France) etc.

The Laboratory was founded in 1990 on the basis of the Group of Prostaglandins and Leukotrienes.

  • Neuroactive lipids and their role in normal and pathological processes.
  • Mechanisms of lipid signals perception and intracellular transmission.
  • The development of novel molecular instruments based of bioactive lipids (including fluorescent, biotynilated and isotope-labeled compounds).
  • The development of new types of drugs, based on the conception of Information multifunctional compound molecules.
  • The characterization of biosynthetic and catabolic pathways of N-acyl dopamines in rat liver, brain and spinal cord, as well as in freshwater hydra homogenate. The alternate pathways of N-acyl dopamines (sulfation, glucuronidation and catechol group oxidation) were identified for the first time.
  • The identification of N-docosahexaenoyl dopamine in Hydra magnipapillata and H. Attenuate. The morphogenetic effect of acyl-dopamines and their ability to regulate regeneration processes in hydra were shown.
  • It was shown for the first time that neurolypes from the group of N-acyl dopamine interfere in the death of neurons, save their functional properties in models of neurodegenerative processes, reduce the volume of neural tissue damage in focal ischemia, and increase survival in acute hypoxia and contribute to the preservation of cognitive functions in the posthypoxic period in experimental animals.
  • The mechanism of signal transmission during the induction of apoptosis by N-acyl dopamine is established, the main proteins participating in this process are identified, including the cytoplasmic receptor, intracellular regulatory proteins, kinases and transcription factors.
  • The ability of acyl-dopamine to induce the differentiation of oncotransformed cells was detected, new cell lines with increased resistance to acyl dopamine were obtained.
  • A test system was developed to assess the hydrolytic stability of peptides and other compounds when administered orally on the basis of the rat gastrointestinal tract fragments.
  • A new class of hybrid molecules peptolipins was synthesized, combining fragments of bioactive lipids, peptides and biogenic amines, which possess neuroprotective, vasoactive and anti-inflammatory effects.
  • The development of a novel conception for pharmacological drug action prolongation using non-covalent complexes of protein with natural polysialic acid (size <=100 nm). A technology for the manufacturing of such nanocomplexes with genetical engineered interferons α2b and β1b, insulin and human G-CSF was developed, which is quite simple and productive. The experiments with cell cultures and animals confirmed the prolonged activity of the proteins inside nanocomplexes.
NamePositionContacts
Vladimir Bezuglov, D.Sc, professorHead of lab.vvbez@oxylipin.ibch.ru+7(495)330-65-92
Mikhail Akimov, Ph.D.s. r. f.akimovmike@yandex.ru+7(495)330-65-92
Natal'ja Greckaja, Ph.D.s. r. f.natalia.gretskaya@gmail.com+7(495)330-65-92
Elena Fomina-Ageeva, Ph.D.r. f.+7(495)330-65-92
Galina Zinchenkoj. r. f.zgn55@yandex.ru+7(495)330-65-92
Alina GamisoniaPhD stud.alyafonya@mail.ru+7(495)330-65-92
Alina LavrovaPhD stud.alinalavrova1@gmail.com

Former members:

Mihail Bobrov, Ph.D.s. r. f.

All publications (show selected)

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Vladimir Bezuglov

Endovaniloids acyldopamines - regulators of cholesterol biosynthesis and inhibitors of cell migration in breast cancer

It was established for the first time that the level of cholesterol in cancer cells is an important parameter that determines their sensitivity to the cytotoxic action of endovanilloids acyldopamines. A decrease in the content of cholesterol in cells and, first of all, in the cytoplasmic membrane, leads to an increase in the cytotoxicity of acyldopamines, presumably as a result of the destruction of rafts. It was also shown for the first time that acyldopamines in breast cancer cells inhibit their migration, epithelial-mesynchymal transition, and stemness. In addition, acyl dopamines inhibit key genes for cholesterol biosynthesis in cancer cells. This result is important for the development of new therapeutic strategies for combating cancer, based on the use of endogenous anticancer compounds and small molecules synthesized on the template of their structures.

Publications

  1. Akimov MG, Dudina PV, Gamisonia AM, Gretskaya NM, Zinchenko GN, Mandal CC, Bezuglov VV (2020). The Influence of the Cholesterol Level in Cells on Endovanilloid Cytotoxicity. Dokl Biochem Biophys 493 (1), 167–170

New endogenous modulators of the acetylcholine system and selective agonists acting on cancer and immune cells

In collaboration with Laboratory of molecular toxinology,  Laboratory of ligand-receptor interactions,  Department of molecular bases of neurosignalization

It was established for the first time that endogenous analogs of acetylcholine, in which unsaturated fatty acids replace the acetyl group, are modulators of the acetylcholine system capable of inhibiting muscle and neuronal alpha7 nicotinic acetylcholine receptors (nAChR), as well as acetylcholinesterase. Arachidonoylcholine has been found to exhibit antioxidant activity in in vitro and ex vivo models. In A549 cancer cells, whose growth is enhanced by the activation of alpha7 nAChR, these compounds dose-dependently inhibited their growth by 50%. Using PNU 282,987, a selective alpha7 nAChR agonist, we investigated the effect of activation of these receptors on cytokine expression and, for the first time, on the expression of membrane macrophage markers. It was found that the expression of HLA-DR, CD54, and CD11b increases, while the expression of the CD14 receptor decreases. At the same time, along with the previously known decrease in the expression of TNF-α, a significant decrease in the expression of the cytokine IL-10 was noted, which may be of great importance for the fight against sepsis and immunosuppression in the "cytokine storm".

 

1. Akimov MG, Kudryavtsev DS, Kryukova EV, Fomina-Ageeva EV, Zakharov SS, Gretskaya NM, Zinchenko GN, Serkov IV, Makhaeva GF, Boltneva NP, Kovaleva NV, Serebryakova OG, Lushchekina SV, Palikov VA, Palikova Y, Dyhenko IA, Kasheverov IE, Tsetlin VI, Bezuglov VV. Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System. Biomolecules. 2020 Feb 12; 10 (2): 283.
2. Akimov MG, Dudina PV, Fomina-Ageeva EV, Gretskaya NM, Bosaya AA, Rudakova EV, Makhaeva GF, Kagarlitsky GO, Eremin SA, Tsetlin VI, Bezuglov VV. Neuroprotective and Antioxidant Activity of Arachidonoyl Choline, Its Bis-Quaternized Analogues and Other Acylcholines. Dokl Biochem Biophys. 2020 Mar; 491 (1): 93-97.
3. Siniavin AE, Streltsova MA, Kudryavtsev DS, Shelukhina IV, Utkin YN, Tsetlin VI. Activation of α7 Nicotinic Acetylcholine Receptor Upregulates HLA-DR and Macrophage Receptors: Potential Role in Adaptive Immunity and in Preventing Immunosuppression. Biomolecules. 2020 Mar 27; 10 (4): 507.

Targeted drug delivery to dopaminergic neurons by the functionalized derivative of the dopamine transporter inhibitor GBR12909: a proof of concept.

A structure has been created that is capable of selectively delivering active molecules to dopaminergic neurons. The relevance of creating such drugs is due to the need to protect dopaminergic neurons, which progressively die in Parkinson's disease. The dopamine transporter inhibitor (DAT) GBR12909, which differs from other known inhibitors by its high selectivity and affinity for DAT, is selected as the address part of the prototype drug design being created. To test the applicability of this design for targeted delivery of pharmacologically active substances to dopaminergic neurons, a fluorescent analog of functionalized GBR12909 with BODIPY-FL-fluorophore was synthesized. By experiments on cells containing active DAT, it was shown that the fluorescent analog penetrates the PC12 pheochromocytoma cells and rat brain dopaminergic neurons through selective transport using DAT. Thus, it was found that the fluorescent analog of GB12909 is a ligand of the dopamine transporter and the DAT system can be used for targeted delivery of active compounds to dopaminergic neurons.

A.V. Lavrova, N.M. Gretskaya, M.G. Akimov and V.V. Bezuglov A Novel Fluorescent Analog of the Dopamine Reuptake Inhibitor GBR12909 // Russian J. Bioorgan. Chem. —2019. — Vol. 45. — No 5. — P. 416–424.

New fluorescent analogues of acyldopamines with the preserved the address moiety

New fluorescent analogues of natural acyldopamines mimicking residues of palmitic and oleic acids carrying the reporter BODIPY group at the distal end of molecule were synthesized. The specific uptake of mentioned compounds in rat pheochromocytoma PC12 cells was demonstrated and characteristics of this process were measured. Uptake rate of oleic analogue was more than three times as palmitic one. Synthesized compounds are ready to be used for investigation of acyldopamine transport in various cells of human or animal origin.

Modified peptides based on proglyprol structure with increased effectiveness

Hybrid compounds based on proglyprol (PGP) peptide carrying residues of docosahexaenoic acid and (or) dopamine were synthesized for the first time. Prepared compounds possess advanced neuroprotectory  and anti-inflammatory activity and may consider as prototypes of novel pharmaceuticals.