29 results on '"Akimov MG"'
Search Results
2. The Interaction of the Endocannabinoid Anandamide and Paracannabinoid Lysophosphatidylinositol during Cell Death Induction in Human Breast Cancer Cells.
- Author
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Akimov MG, Gretskaya NM, Gorbacheva EI, Khadour N, Chernavskaya VS, Sherstyanykh GD, Kovaleko TF, Fomina-Ageeva EV, and Bezuglov VV
- Subjects
- Humans, Female, Polyunsaturated Alkamides pharmacology, Cell Death, Receptor, Cannabinoid, CB1, Tumor Microenvironment, Endocannabinoids pharmacology, Breast Neoplasms drug therapy, Arachidonic Acids, Lysophospholipids
- Abstract
Endocannabinoid anandamide (AEA) and paracannabinoid lysophosphatidylinositol (LPI) play a significant role in cancer cell proliferation regulation. While anandamide inhibits the proliferation of cancer cells, LPI is known as a cancer stimulant. Despite the known endocannabinoid receptor crosstalk and simultaneous presence in the cancer microenvironment of both molecules, their combined activity has never been studied. We evaluated the effect of LPI on the AEA activity in six human breast cancer cell lines of different carcinogenicity (MCF-10A, MCF-7, BT-474, BT-20, SK-BR-3, MDA-MB-231) using resazurin and LDH tests after a 72 h incubation. AEA exerted both anti-proliferative and cytotoxic activity with EC
50 in the range from 31 to 80 µM. LPI did not significantly affect the cell viability. Depending on the cell line, the response to the LPI-AEA combination varied from a decrease in AEA cytotoxicity to an increase in it. Based on the inhibitor analysis of the endocannabinoid receptor panel, we showed that for the former effect, an active GPR18 receptor was required and for the latter, an active CB2 receptor. The data obtained for the first time are important for the understanding the manner by which endocannabinoid receptor ligands acting simultaneously can modulate cancer growth at different stages.- Published
- 2024
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3. The Mechanisms of GPR55 Receptor Functional Selectivity during Apoptosis and Proliferation Regulation in Cancer Cells.
- Author
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Akimov MG, Gretskaya NM, Dudina PV, Sherstyanykh GD, Zinchenko GN, Serova OV, Degtyaryova KO, Deyev IE, and Bezuglov VV
- Subjects
- Ligands, Receptors, Cannabinoid metabolism, Signal Transduction, Cell Proliferation, Apoptosis, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2 genetics, Neoplasms genetics
- Abstract
GPR55 is a non-canonical cannabinoid receptor, important for cancer proliferation. Depending on the ligand, it induces either cell proliferation or death. The objective of the study was to establish the mechanisms of this multidirectional signaling. Using the CRISPR-Cas9 system, the GPR55, CB1, CB2, and GPR18 receptor knockouts of the MDA-MB-231 line were obtained. After the CB2 receptor knockout, the pro-apoptotic activity of the pro-apoptotic ligand docosahexaenoyl dopamine (DHA-DA) slightly increased, while the pro-proliferative activity of the most active synthetic ligand of the GPR55 receptor (ML-184) completely disappeared. On the original cell line, the stimulatory effect of ML-184 was removed by the CB2 receptor blocker and by GPR55 receptor knockout. Thus, it can be confidently assumed that when proliferation is stimulated with the participation of the GPR55 receptor, a signal is transmitted from the CB2 receptor to the GPR55 receptor due to the formation of a heterodimer. GPR18 was additionally involved in the implementation of the pro-apoptotic effect of DHA-DA, while the CB1 receptor is not involved. In the implementation of the pro-apoptotic action of DHA-DA, the elimination of Gα
13 led to a decrease in cytotoxicity. The obtained data provide novel details to the mechanism of the pro-proliferative action of GPR55.- Published
- 2023
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4. N -Acyl Dopamines Induce Apoptosis in Endometrial Stromal Cells from Patients with Endometriosis.
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Gamisonia AM, Yushina MN, Fedorova-Gogolina IA, Akimov MG, Eldarov CM, Pavlovich SV, Bezuglov VV, Gretskaya NM, Sukhikh GT, and Bobrov MY
- Subjects
- Caspase 3 metabolism, Caspase 9 metabolism, Cell Survival drug effects, Cells, Cultured, Dopamine pharmacology, Endometriosis pathology, Endometrium drug effects, Female, Humans, Membrane Potential, Mitochondrial drug effects, Reactive Oxygen Species metabolism, Signal Transduction drug effects, Stromal Cells drug effects, Apoptosis drug effects, Arachidonic Acids pharmacology, Dopamine analogs & derivatives, Endometriosis metabolism, Endometrium metabolism, Stromal Cells metabolism
- Abstract
Endometriosis is characterized by the formation and development of endometrial tissues outside the uterus, based on an imbalance between proliferation and cell death, leading to the uncontrolled growth of ectopic foci. The potential target for the regulation of these processes is the endocannabinoid system, which was found to be involved in the migration, proliferation, and survival of tumor cells. In this paper, we investigated the effect of endocannabinoid-like compounds from the N -acyl dopamine (NADA) family on the viability of stromal cells from ectopic and eutopic endometrium of patients with ovarian endometriosis. N -arachidonoyldopamine, N -docosahexaenoyldopamine, and N -oleoyldopamine have been shown to have a five-times-more-selective cytotoxic effect on endometrioid stromal cells. To study the mechanisms of the toxic effect, inhibitory analysis, measurements of caspase-3/9 activity, reactive oxygen species, and the mitochondrial membrane potential were performed. It was found that NADA induced apoptosis via an intrinsic pathway through the CB1 receptor and downstream serine palmitoyltransferase, NO synthase activation, increased ROS production, and mitochondrial dysfunction. The higher selectivity of NADA for endometriotic stromal cells and the current lack of effective drug treatment can be considered positive factors for further research of these compounds as possible therapeutic agents against endometriosis.
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- 2021
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5. N-arachidonoyl dopamine inhibits epithelial-mesenchymal transition of breast cancer cells through ERK signaling and decreasing the cellular cholesterol.
- Author
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Bandyopadhayaya S, Akimov MG, Verma R, Sharma A, Sharma D, Kundu GC, Gretskaya NM, Bezuglov VV, and Mandal CC
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- Breast Neoplasms pathology, Cell Line, Tumor, Female, HEK293 Cells, Humans, Neoplasm Proteins metabolism, Breast Neoplasms metabolism, Cholesterol biosynthesis, Dopamine analogs & derivatives, Dopamine pharmacology, Epithelial-Mesenchymal Transition drug effects, MAP Kinase Signaling System drug effects
- Abstract
N-acyl dopamines (NADAs) are bioactive lipids of the endovanilloid family with known cytotoxicity for the cancer cells; however, the available data on the participation of the endovanilloids in epithelial-mesenchymal transition (EMT) and cancer stemness are controversial. This study unveils the inhibitory role of N-arachidonoyl dopamine (AA-DA), a typical representative of the NADA family, in breast cancer cell migration, EMT, and stemness. AA-DA treatment also led to a decrease in cholesterol biosynthesis gene expressions, and addition of exogenous cholesterol reverted these AA-DA-mediated inhibitory effects. Notably, AA-DA treatment inhibited the key regulatory gene of the cholesterol biosynthesis pathway, sterol regulatory element-binding protein 1 (SREBP1), with concurrent repression of the endoplasmic reticulum kinase 1/2 (ERK1/2) pathway. Furthermore, U0126, an ERK inhibitor, inhibited SREBP1 and decreased cellular cholesterol level, unwinding the molecular mechanism behind AA-DA-mediated anticancer activity. Thus, we, for the first time, revealed that AA-DA counteracts breast cancer EMT via inhibition of ERK signaling and cholesterol content., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
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6. ACTH(6-9)PGP Peptide Protects SH-SY5Y Cells from H 2 O 2 , tert -Butyl Hydroperoxide, and Cyanide Cytotoxicity via Stimulation of Proliferation and Induction of Prosurvival-Related Genes.
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Akimov MG, Fomina-Ageeva EV, Dudina PV, Andreeva LA, Myasoyedov NF, and Bezuglov VV
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- Cell Line, Tumor, Humans, Hydrogen Peroxide toxicity, Neuroprotective Agents pharmacology, Proline pharmacology, Reactive Oxygen Species metabolism, Adrenocorticotropic Hormone pharmacology, Antioxidants pharmacology, Apoptosis drug effects, Cell Proliferation drug effects, Oligopeptides pharmacology, Oxidative Stress drug effects, Proline analogs & derivatives
- Abstract
Stabilized melanocortin analog peptide ACTH(6-9)PGP (HFRWPGP) possesses a wide range of neuroprotective activities. However, its mechanism of action remains poorly understood. In this paper, we present a study of the proproliferative and cytoprotective activity of the adrenocorticotropic hormone fragment 6-9 (HFRW) linked with the peptide prolyine-glycyl-proline on the SH-SY5Y cells in the model of oxidative stress-related toxicity. The peptide dose-dependently protected cells from H
2 O2 , tert -butyl hydroperoxide, and KCN and demonstrated proproliferative activity. The mechanism of its action was the modulation of proliferation-related NF-κB genes and stimulation of prosurvival NRF2 -gene-related pathway, as well as a decrease in apoptosis.- Published
- 2021
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7. GPR55 Receptor Activation by the N -Acyl Dopamine Family Lipids Induces Apoptosis in Cancer Cells via the Nitric Oxide Synthase (nNOS) Over-Stimulation.
- Author
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Akimov MG, Gamisonia AM, Dudina PV, Gretskaya NM, Gaydaryova AA, Kuznetsov AS, Zinchenko GN, and Bezuglov VV
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- Animals, Antineoplastic Agents chemistry, Apoptosis drug effects, Cannabinoid Receptor Agonists chemistry, Cell Line, Tumor, Dopamine chemistry, Dopamine pharmacology, Enzyme Activators chemistry, Fatty Acids chemistry, Fatty Acids pharmacology, Humans, Molecular Docking Simulation, Neoplasms drug therapy, Neoplasms metabolism, PC12 Cells, Rats, Antineoplastic Agents pharmacology, Cannabinoid Receptor Agonists pharmacology, Dopamine analogs & derivatives, Enzyme Activators pharmacology, Nitric Oxide Synthase Type I metabolism, Receptors, Cannabinoid metabolism
- Abstract
GPR55 is a GPCR of the non-CB1/CB2 cannabinoid receptor family, which is activated by lysophosphatidylinositol (LPI) and stimulates the proliferation of cancer cells. Anandamide, a bioactive lipid endocannabinoid, acts as a biased agonist of GPR55 and induces cancer cell death, but is unstable and psychoactive. We hypothesized that other endocannabinoids and structurally similar compounds, which are more hydrolytically stable, could also induce cancer cell death via GPR55 activation. We chemically synthesized and tested a set of fatty acid amides and esters for cell death induction via GPR55 activation. The most active compounds appeared to be N -acyl dopamines, especially N -docosahexaenoyl dopamine (DHA-DA). Using a panel of cancer cell lines and a set of receptor and intracellular signal transduction machinery inhibitors together with cell viability, Ca
2+ , NO, ROS (reactive oxygen species) and gene expression measurement, we showed for the first time that for these compounds, the mechanism of cell death induction differed from that published for anandamide and included neuronal nitric oxide synthase (nNOS) overstimulation with concomitant oxidative stress induction. The combination of DHA-DA with LPI, which normally stimulates cancer proliferation and is increased in cancer setting, had an increased cytotoxicity for the cancer cells indicating a therapeutic potential.- Published
- 2021
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8. In Vivo Targeted Metabolomic Profiling of Prostanit, a Novel Anti-PAD NO-Donating Alprostadil-Based Drug.
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Shestakova KM, Moskaleva NE, Mesonzhnik NV, Kukharenko AV, Serkov IV, Lyubimov II, Fomina-Ageeva EV, Bezuglov VV, Akimov MG, and Appolonova SA
- Subjects
- Alprostadil blood, Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, Aorta drug effects, Aorta metabolism, Chromatography, Liquid, Humans, Mass Spectrometry, Metabolic Networks and Pathways, Myocytes, Smooth Muscle drug effects, Myocytes, Smooth Muscle metabolism, Nitric Oxide biosynthesis, Peripheral Arterial Disease drug therapy, Rabbits, Alprostadil analogs & derivatives, Alprostadil pharmacokinetics, Anti-Inflammatory Agents, Non-Steroidal pharmacokinetics, Metabolomics methods, Nitric Oxide antagonists & inhibitors
- Abstract
Prostanit is a novel drug developed for the treatment of peripheral arterial diseases. It consists of a prostaglandin E
1 (PGE1 ) moiety with two nitric oxide (NO) donor fragments, which provide a combined vasodilation effect on smooth muscles and vascular spastic reaction. Prostanit pharmacokinetics, however, remains poorly investigated. Thus, the object of this study was to investigate the pharmacokinetics of Prostanit-related and -affected metabolites in rabbit plasma using the liquid chromatography-mass spectrometry (LC-MS) approach. Besides, NO generation from Prostanit in isolated rat aorta and human smooth muscle cells was studied using the Griess method. In plasma, Prostanit was rapidly metabolized to 1,3-dinitroglycerol (1,3-DNG), PGE1 , and 13,14-dihydro-15-keto-PGE1 . Simultaneously, the constant growth of amino acid (proline, 4-hydroxyproline, alanine, phenylalanine, etc.), steroid (androsterone and corticosterone), and purine (adenosine, adenosine-5 monophosphate, and guanosine) levels was observed. Glycine, aspartate, cortisol, and testosterone levels were decreased. Ex vivo Prostanit induced both NO synthase-dependent and -independent NO generation. The observed pharmacokinetic properties suggested some novel beneficial activities (i.e., effect prolongation and anti-inflammation). These properties may provide a basis for future research of the effectiveness and safety of Prostanit, as well as for its characterization from a clinical perspective.- Published
- 2020
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9. Novel bexarotene derivatives: Synthesis and cytotoxicity evaluation for glioma cells in 2D and 3D in vitro models.
- Author
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Gretskaya NM, Gamisonia AM, Dudina PV, Zakharov SS, Sherstyanykh G, Akasov R, Burov S, Serkov IV, Akimov MG, Bezuglov VV, and Markvicheva E
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Apoptosis drug effects, Bexarotene analogs & derivatives, Bexarotene chemical synthesis, Brain Neoplasms metabolism, Brain Neoplasms pathology, Cell Culture Techniques, Cell Line, Tumor, Cell Movement drug effects, Dose-Response Relationship, Drug, Glioma metabolism, Glioma pathology, Humans, Inhibitory Concentration 50, Molecular Structure, Neoplasm Invasiveness, Rats, Spheroids, Cellular, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Bexarotene pharmacology, Brain Neoplasms drug therapy, Glioma drug therapy
- Abstract
Glioblastoma (GBM) is an aggressive and lethal form of brain cancer with a high invasion capacity and a lack of effective chemotherapeutics. Retinoid bexarotene (BXR) inhibits the neurospheroidal colony formation and migration of primary glioblastoma cells but has side effects. To enhance the BXR glioblastoma selectivity and cytotoxicity, we chemically modified it at the carboxyl group with either nitroethanolamine (NEA) bearing a NO-donating group (a well-known bioactivity enhancer; BXR-NEA) or with a dopamine (DA) moiety (to represent the highly toxic for various tumor cells N-acyldopamine family; BXR-DA). These two novel compounds were tested in the 2D (monolayer culture) and 3D (multicellular tumor spheroids) in vitro models. Both BXR-DA and BXR-NEA were found to be more toxic for rat C6 and human U-87MG glioma cells than the initial BXR. After 24 h incubation of the cells (monolayer culture) with the drugs, the IC
50 values were in the range of 28-42, and 122-152 μM for BXR derivatives and BXR, respectively. The cell death occurred via apoptosis according to the annexin staining and caspase activation. The tumor spheroids demonstrated higher resistance to the treatment compared to that one of the monolayer cultures. BXR-DA and BXR-NEA were more specific against tumor cells than the parental drug, in particular the selectivity index was 1.8-2.7 vs. 1.3-1.5, respectively. Moreover, they inhibited cell migration more effectively than parental BXR according to a scratch assay. Cell spreading from the tumor spheroids was also inhibited. Thus, the obtained BXR derivatives could be promising for glioblastoma treatment., (Copyright © 2020 Elsevier B.V. All rights reserved.)- Published
- 2020
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10. The Influence of the Cholesterol Level in Cells on Endovanilloid Cytotoxicity.
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Akimov MG, Dudina PV, Gamisonia AM, Gretskaya NM, Zinchenko GN, Mandal CC, and Bezuglov VV
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- Anticholesteremic Agents pharmacology, Apoptosis, Atorvastatin pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Dopamine pharmacology, Female, Humans, Receptors, Cannabinoid metabolism, Tumor Cells, Cultured, Atorvastatin pharmacokinetics, Breast Neoplasms pathology, Cholesterol metabolism, Dopamine analogs & derivatives
- Abstract
The influence of the cellular cholesterol content on the cytotoxicity of endovanilloids acyldopamines was studied in MDA-MB-231 and MCF 10A cells. The activity of acyldopamines depends on the cellular cholesterol content, and a decrease in cholesterol content increases the cytotoxicity of acyldopamines.
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- 2020
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11. Neuroprotective and Antioxidant Activity of Arachidonoyl Choline, Its Bis-Quaternized Analogues and Other Acylcholines.
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Akimov MG, Dudina PV, Fomina-Ageeva EV, Gretskaya NM, Bosaya AA, Rudakova EV, Makhaeva GF, Kagarlitsky GO, Eremin SA, Tsetlin VI, and Bezuglov VV
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- 2-Propanol chemistry, Arachidonic Acid chemistry, Cell Line, Tumor, Chromans chemistry, Docosahexaenoic Acids chemistry, Drug Screening Assays, Antitumor, Fatty Acids, Free Radicals chemistry, Humans, Hydrogen Peroxide chemistry, Linoleic Acid chemistry, Oleic Acid chemistry, Antioxidants chemistry, Arachidonic Acids chemistry, Choline chemistry
- Abstract
The antioxidant activity and protective effect in the toxicity model of H
2 O2 were studied for arachidonic (AA-CHOL), docosahexaenoic (DHA-CHOL), linoleic (Ln-CHOL), and oleic (Ol-CHOL) fatty acids, as well as arachidonoyl dicholine (AA-diCHOL) and O-arachidonoyl bistetramethylaminoisopropanol (ABTAP). AA-CHOL, DHA-CHOL and Ln-CHOL provided a 20% increase in cell survival. AA-CHOL, AA-diCHOL, Ol-CHOL, and ABTAP had a radical-scavenging effect in the ABTS test, approximately equal to the activity of a standard radical scavenger Trolox.- Published
- 2020
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12. Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System.
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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, Dyachenko IA, Kasheverov IE, Tsetlin VI, and Bezuglov VV
- Subjects
- A549 Cells, Acetylcholine metabolism, Acetylcholinesterase metabolism, Animals, Arachidonic Acids metabolism, Butyrylcholinesterase metabolism, Calcium metabolism, Cell Line, Tumor, Cell Proliferation, Cell Survival, Choline metabolism, Erythrocytes enzymology, Female, Horses, Humans, Inhibitory Concentration 50, Kinetics, Lymnaea metabolism, Male, Mice, Mice, Inbred ICR, Molecular Docking Simulation, Oocytes metabolism, Protein Binding, Signal Transduction, Torpedo metabolism, Xenopus, Acetylcholine pharmacology, Arachidonic Acids pharmacology, Choline pharmacology, Cholinesterase Inhibitors pharmacology
- Abstract
Cholines acylated with unsaturated fatty acids are a recently discovered family of endogenous lipids. However, the data on the biological activity of acylcholines remain very limited. We hypothesized that acylcholines containing residues of arachidonic (AA-CHOL), oleic (Ol-CHOL), linoleic (Ln-CHOL), and docosahexaenoic (DHA-CHOL) acids act as modulators of the acetylcholine signaling system. In the radioligand binding assay, acylcholines showed inhibition in the micromolar range of both α7 neuronal nAChR overexpressed in GH4C1 cells and muscle type nAChR from Torpedo californica , as well as Lymnaea stagnalis acetylcholine binding protein. Functional response was checked in two cell lines endogenously expressing α7 nAChR. In SH-SY5Y cells, these compounds did not induce Ca
2+ rise, but inhibited the acetylcholine-evoked Ca2+ rise with IC50 9 to 12 μM. In the A549 lung cancer cells, where α7 nAChR activation stimulates proliferation, Ol-CHOL, Ln-CHOL, and AA-CHOL dose-dependently decreased cell viability by up to 45%. AA-CHOL inhibited human erythrocyte acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BChE) by a mixed type mechanism with Ki = 16.7 ± 1.5 μM and αKi = 51.4 ± 4.1 μM for AChE and Ki = 70.5 ± 6.3 μM and αKi = 214 ± 17 μM for BChE, being a weak substrate of the last enzyme only, agrees with molecular docking results. Thus, long-chain unsaturated acylcholines could be viewed as endogenous modulators of the acetylcholine signaling system., Competing Interests: The authors declare no conflict of interest.- Published
- 2020
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13. 5-alkylvinyl-1,2,4-triazole nucleosides: Synthesis and biological evaluation.
- Author
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Prutkov AN, Chudinov MV, Matveev AV, Grebenkina LE, Akimov MG, and Berezovskaya YV
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- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Hepacivirus drug effects, Humans, Influenza A virus drug effects, Microbial Sensitivity Tests, Molecular Structure, Nucleosides chemical synthesis, Nucleosides chemistry, Structure-Activity Relationship, Triazoles chemical synthesis, Triazoles chemistry, Vinyl Compounds chemical synthesis, Vinyl Compounds chemistry, Antineoplastic Agents pharmacology, Antiviral Agents pharmacology, Nucleosides pharmacology, Triazoles pharmacology, Vinyl Compounds pharmacology
- Abstract
Some 5-substituted ribavirin analogues have a high antiviral and anticancer activity, but their mechanisms of action are obviously not the same as their parent compound. The SAR studies performed on 3 (5)-substituted 1,2,4-triazole nucleosides have shown a high dependency between the structure of the 3 (5)-substituent and the level of antiviral/anticancer activity. The most active substances of the row contain coplanar with the 1,2,4-triazole ring aromatic substituent which is connected by a rigid ethynyl bond. However, the compounds with the trans-vinyl linker also had antiviral activity. We decided to study the antitumor activity of ribavirin analogues with alkyl/aryl vinyl substituents in the 5th position of the 1,2,4-triazole ring. Protected nucleoside analogues with various 5-alkylvinyl substituents were obtained by Horner-Wadsworth-Emmons reaction from the common precursor and converted to the nucleosides. Arylvinyl nucleosides were synthesised according the reported procedures. All compounds did not show significant antiproliferative activity on several tumour cell lines. Coplanar aromatic motif in the 5-substituent for the anticancer activity manifestation was confirmed.
- Published
- 2020
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14. Neuroprotective Action of Amidic Neurolipins in Models of Neurotoxicity on the Culture of Human Neural-Like Cells SH-SY5Y.
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Akimov MG, Ashba AM, Fomina-Ageeva EV, Gretskaya NM, Myasoedov NF, and Bezuglov VV
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- Cell Line, Humans, Neurodegenerative Diseases chemically induced, Neurodegenerative Diseases prevention & control, Amides chemistry, Amides pharmacology, Fatty Acids chemistry, Fatty Acids pharmacology, Neurodegenerative Diseases metabolism, Neuroprotective Agents chemistry, Neuroprotective Agents pharmacology, Signal Transduction drug effects
- Abstract
It was established that in neurodegeneration models in the human neuron-like cell line SH-SY5Y, amide derivatives of arachidonic and docosahexaenoic acids were inactive in experiments with MPP
+ and CoCl2 but protected from H2 O2 . The protective activity of neurolipins decreased in the series DHA-DA > AA-SER ≥ AA-GLY > AA-GABA ≥ AA-EA and was manifested starting from a concentration of 0.5 nM.- Published
- 2019
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15. Synthesis of N-acyl derivatives of Pro-Gly-Pro-Leu peptide: Proteolytic stability in vitro and effects on mouse macrophage cells RAW264.7.
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Shevchenko KV, Bezuglov VV, Akimov MG, Nagaev IY, Shevchenko VP, and Myasoedov NF
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- Animals, Anti-Inflammatory Agents, Non-Steroidal metabolism, Chemistry Techniques, Synthetic, Dose-Response Relationship, Drug, Mice, Oligopeptides metabolism, Protein Stability, RAW 264.7 Cells, Anti-Inflammatory Agents, Non-Steroidal chemical synthesis, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Macrophages drug effects, Oligopeptides chemical synthesis, Oligopeptides pharmacology, Proteolysis
- Abstract
Acetyl, oleoyl, arachidonoyl, and docosahexaenoyl derivatives of the Pro-Gly-Pro-Leu peptide with a chemical purity of 99.8% were synthesized. The degradation kinetics of the Pro-Gly-Pro-Leu derivatives under the action of leucine aminopeptidase, nasal mucus, and microsomal fraction of the brain and blood of rats was studied. It was shown that the N-acyl derivatives of Pro-Gly-Pro-Leu proved to be more resistant to the action of leucine aminopeptidase and other enzyme systems. The study of the cytotoxic and anti-inflammatory activity of preparations on the mouse macrophage cell line RAW264.7 showed that acylation with oleic and arachidonic acid makes the peptide cytotoxic with LC50 in the range of 70-15 μM and gives it anti-inflammatory properties with EC50 of 32 and 36 μM, respectively.
- Published
- 2017
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16. N-acyl dopamines induce apoptosis in PC12 cell line via the GPR55 receptor activation.
- Author
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Akimov MG, Ashba AM, Gretskaya NM, and Bezuglov VV
- Subjects
- Animals, Kinetics, PC12 Cells, Rats, Apoptosis drug effects, Dopamine chemistry, Dopamine pharmacology, Receptors, Cannabinoid metabolism, Receptors, G-Protein-Coupled metabolism
- Abstract
Dopamine amides of arachidonic, docosahexaenoic, and oleic acids were found to induce apoptosis in PC12 cells, which was blocked exclusively by antagonists and preincubation agonists of the receptor GPR55, belonging to the group of non-CB1/CB2 receptors.
- Published
- 2017
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17. N-acyl dopamines induce cell death in PC12 cell line via induction of nitric oxide generation and oxidative stress.
- Author
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Ashba AM, Akimov MG, Gretskaya NM, and Bezuglov VV
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- Animals, Cell Death physiology, Cell Survival drug effects, Cell Survival physiology, Dopamine toxicity, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, NG-Nitroarginine Methyl Ester pharmacology, Nitric Oxide Synthase antagonists & inhibitors, Nitric Oxide Synthase metabolism, Oxidative Stress physiology, PC12 Cells, Rats, Reactive Oxygen Species metabolism, Cell Death drug effects, Dopamine analogs & derivatives, Fatty Acids, Unsaturated toxicity, Nitric Oxide metabolism, Oxidative Stress drug effects
- Abstract
It was shown that dopamine amides of arachidonic, oleic, and docosahexaenoic acids exhibit toxicity with respect to PC12 pheochromocytoma cell line. The mechanism of realization of the cytotoxic effect of acyl dopamines is the induction of oxidative stress. This event is preceded by triggering the synthesis of nitric oxide.
- Published
- 2016
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18. Cytotoxicity of Endogenous Lipids N-acyl Dopamines and their Possible Metabolic Derivatives for Human Cancer Cell Lines of Different Histological Origin.
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Akimov MG, Gretskaya NM, Zinchenko GN, and Bezuglov VV
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- Animals, Dopamine analogs & derivatives, Fatty Acids metabolism, Glioblastoma pathology, HEK293 Cells, Humans, MCF-7 Cells, Neoplasms pathology, Structure-Activity Relationship, Dopamine metabolism, Glioblastoma metabolism, Lipids, Neoplasms metabolism
- Abstract
Background/aim: Dopamine amides of long chain fatty acids are a family of endogenous mammalian lipids with an unknown function; they are anti-proliferative for the C6 glioblastoma cell line. To assess their possible anti-cancer activity we evaluated their cytotoxicity for a set of cancer cell lines., Materials and Methods: Anti-proliferative and cytotoxic actions of these substances were evaluated in HOS, IMR-32, MCF-7, Namalwa, K-562 and HEK 293 cell lines (18 h incubation time) using MTT and lactate dehydrogenase (LDH) tests, accordingly., Results: All N-acyl dopamines (NADA) induced cell death in all cell lines tested with a 50% lethal dose (LD50) in the range of 0.5-80 μM, except for HEK-293. For HEK-293 only N-arachidonoyl epinephrine demonstrated an LD50 below 100 μM., Conclusion: According to the structure-activity relationship, N-acyl dopamines with an intact catechol group and a non-modified hydrophobic fatty acid residue are cytotoxic to cancer cell lines of various histological origins., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)
- Published
- 2015
19. Synthesis of a new fluorescent analogue of proglyprol and study of the mechanisms of its transport into the cultured rat pheochromocytoma cells.
- Author
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Akimov MG, Gretskaya NM, Sinitsyna IA, Efremova AS, Andreeva LA, Shram SI, Bezuglov VV, and Myasoedov NF
- Subjects
- Animals, Fluorescent Dyes chemistry, Fluorescent Dyes pharmacokinetics, Fluorometry, Microscopy, Confocal, Molecular Structure, PC12 Cells, Pheochromocytoma metabolism, Photomicrography, Porphobilinogen analogs & derivatives, Porphobilinogen chemical synthesis, Porphobilinogen chemistry, Porphobilinogen pharmacokinetics, Proline chemistry, Rats, Spectrum Analysis, Fluorescent Dyes chemical synthesis, Oligopeptides chemistry, Proline analogs & derivatives
- Published
- 2015
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20. [The optimization of the nitric oxide quantitative analysis for its determination in the cultural medium of mammalian cell culture].
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Akimov MG, Fomina-Ageeva EV, and Bezuglov VV
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- Animals, Cell Line, Tumor, Oxidation-Reduction, Rats, Cadmium chemistry, Nitrates chemistry, Nitric Oxide analysis
- Abstract
The protocol for the quantitative analysis of nitric oxide as nitrite-ion suitable for determination of its production by a mammalian cell culture was developed. The optimal results were obtained using microvolume-adjusted Griess method after the preliminary reduction of NO3- to NO2- with non-activated cadmium. The protocol was verified on a rat glioma C6 cell culture. The developed method may be used for the nitric oxide determination in 96-well and 48-well microplates; the detection limit is 2.1 ± 0.1 μM for NO2- and 2.9 ± 0.1 μM for NO3-.
- Published
- 2015
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21. [The influence of docosahexaenoic acid moiety on cytotoxic activity of 1,2,4-thiadiazole derivatives].
- Author
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Akimov MG, Gretskaia NM, Karnoukhova VA, Serkov IV, Proshin AN, Shtratnikova VIu, and Bezuglov VV
- Subjects
- Amides chemical synthesis, Animals, Antineoplastic Agents chemical synthesis, Cell Line, Tumor, Cytotoxins chemical synthesis, Drug Design, Inhibitory Concentration 50, Neuroglia pathology, Rats, Structure-Activity Relationship, Thiadiazoles chemical synthesis, Amides pharmacology, Antineoplastic Agents pharmacology, Cytotoxins pharmacology, Docosahexaenoic Acids chemistry, Neuroglia drug effects, Thiadiazoles pharmacology
- Abstract
Among 3-(2-aminopropyl)-1,2,4-thiadiazole derivatives contatining substitution-ready secondary amino group and exhibiting cytotoxic towards rat C 6 glioma cells three compounds with LD 50 values ranged from 6 to 48 мM were chosen. For these compounds amides with docosahexaenoic acid were synthetised and their cytotoxic activity was studied. It was shown that, although docosahexaenoic acid itself was not toxic for C 6 glioma cells, its addition to the amino derivatives of 1,2,4-thiadiazole increased or decreased resultant cytotoxicity. The effect depended on the structure of 1,2,4-thiadiazole substituents. The obtained data show that the acylation of cytotoxic compounds with docosahexaenoic acid does not necessarily lead to the increase of their activity, but sometimes can inactivate a compound. This fact should be taken into account, especially in the case of anti-cancer drug development.
- Published
- 2014
- Full Text
- View/download PDF
22. [A new fluorescent analogue for the investigation of anandamide transport in cell cultures].
- Author
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Gretskaia NM, Akimov MG, and Bezuglov VV
- Subjects
- Animals, Arachidonic Acid chemistry, Arachidonic Acids chemistry, Arachidonic Acids metabolism, Cell Tracking methods, Endocannabinoids chemistry, Endocannabinoids metabolism, Glioma chemistry, Polyunsaturated Alkamides chemistry, Polyunsaturated Alkamides metabolism, Rats, Arachidonic Acids isolation & purification, Endocannabinoids isolation & purification, Fluorescent Dyes chemistry, Glioma metabolism, In Vitro Techniques methods, Polyunsaturated Alkamides isolation & purification
- Abstract
For the first time a new fluorescent analogue of anadamide incorporating BODIPY®-FL-fluorophore, attached to arachidonic acid via 2,2'-(ethylenedioxy)-bis(ethylenediamine), was prepared. Using rat glioma C6 cells it was demonstrated that the fluorescent analogue is a substrate of the cellular anandamide uptake system (Km 4.5 ± 0.9 µM, Vmax 20 ± 1 amol/(min x cell)).
- Published
- 2014
23. [The study of peptide stability during hydrolysis by rat gastroenteric tract fragments].
- Author
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Akimov MG, Nazimov IV, Gretskaia NM, Deĭgin VI, and Bezuglov VV
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Aspirin pharmacokinetics, Aspirin pharmacology, Enkephalin, Leucine-2-Alanine pharmacokinetics, Enkephalin, Leucine-2-Alanine pharmacology, Hydrolysis, Ibuprofen pharmacokinetics, Ibuprofen pharmacology, Oligopeptides pharmacology, Peptides, Peptides, Cyclic pharmacology, Rats, Rats, Wistar, Anti-Inflammatory Agents, Non-Steroidal pharmacokinetics, Enkephalin, Leucine-2-Alanine analogs & derivatives, Gastrointestinal Tract enzymology, Oligopeptides pharmacokinetics, Peptide Hydrolases metabolism, Peptides, Cyclic pharmacokinetics
- Abstract
The hydrolytic stability of therapeutic peptides such as dalargin, stemokin and some others, including cyclic tripeptides modified by ibuprofen and aspirin, was studied. Two experimental systems were used, one containing purified enzymes pepsin, trypsin and chymotrypsin and other based on fragments of rat stomach and ileum. It was found that linear peptides without D-aminoacids are hydrolyzed by fragments of stomach and ileum but resistant to hydrolysis with purified enzymes. The peptides with D-aminoacids and cyclic peptides are stable in all experimental conditions used, however, peptides modified with aspirin lost acetyl moiety of aspirin residue in acidic medium, the process is accelerated in presence of pepsin.
- Published
- 2010
- Full Text
- View/download PDF
24. [Docosahexaenoyl dopamine in freshwater hydra: effects on regeneration and metabolic changes].
- Author
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Ostroumova TV, Markova LN, Akimov MG, Gretskaia NM, and Bezuglov VV
- Subjects
- Animals, Dopamine analogs & derivatives, Regeneration physiology, Docosahexaenoic Acids pharmacology, Dopamine pharmacology, Dopamine Agents pharmacology, Hydra physiology, Regeneration drug effects
- Abstract
The effects of docosahexaenoyl dopamine and docosahexaenoic acid on the regeneration of hydra gastric and basal fragments are studied. Docosahexaenoyl dopamine induced morphogenetic abnormalities such as single ectopic tentacles in the gastric region and projections in the gastric and basal regions. Docosahexaenoic acid had no effect on the morphogenesis except for a mild slowing of the regeneration rate. Since no hydrolysis of docosahexaenoyl dopamine was detected in hydra extract, it was assumed that the morphogenetic effect could be associated with the dopamine component of this complex.
- Published
- 2010
25. Sulfation of N-acyl dopamines in rat tissues.
- Author
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Akimov MG, Nazimov IV, Gretskaya NM, Zinchenko GN, and Bezuglov VV
- Subjects
- Animals, Arachidonic Acids metabolism, Cytosol enzymology, Kinetics, Rats, Rats, Wistar, Spectrometry, Mass, Electrospray Ionization, Spectrophotometry, Stearates metabolism, Substrate Specificity, Arylsulfotransferase metabolism, Brain metabolism, Dopamine analogs & derivatives, Dopamine metabolism, Fatty Acids metabolism, Liver metabolism, Spinal Cord metabolism
- Abstract
Sulfation of N-acyl dopamines has been shown for the first time in cytosolic fractions of rat liver and nervous system. Sulfation of dopamine amides of docosahexaenoic and oleic acids occurred in all tissues studied, N-arachidonoyl dopamine was sulfated in the liver and spinal cord, and N-stearoyl dopamine was sulfated only in the liver. Depending on the substrate and tissue, the sulfation activity varied from 0.5 to 3.5 nmol/min per mg total protein. Kinetic parameters of N-docosahexaenoyl dopamine sulfation in the brain were determined. The findings characterize the sulfation system as the most productive metabolic pathway of N-acyl dopamines, but the role of this system in the body is unclear because of high K(m) value.
- Published
- 2009
- Full Text
- View/download PDF
26. [Nanocomplexes of recombinant proteins and polysialic acid: preparation, characteristics, and biological activity].
- Author
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Bezuglov VV, Gretskaya NM, Klinov DV, Bobrov MIu, Shibanova ED, Akimov MG, Fomina-Ageeva EV, Zinchenko GN, Bairamashvili DI, and Miroshnikov AI
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Electrophoresis, Polyacrylamide Gel, Granulocyte Colony-Stimulating Factor pharmacology, Humans, Hypoglycemic Agents chemistry, Hypoglycemic Agents pharmacology, Insulin pharmacology, Interferon alpha-2, Interferon beta-1b, Interferon-alpha pharmacology, Interferon-beta pharmacology, Mice, Microscopy, Atomic Force, Rabbits, Recombinant Proteins chemistry, Recombinant Proteins pharmacology, Sialic Acids pharmacology, Granulocyte Colony-Stimulating Factor chemistry, Insulin chemistry, Interferon-alpha chemistry, Interferon-beta chemistry, Nanostructures, Sialic Acids chemistry
- Abstract
A preparation of nanocomplexes containing recombinant proteins (interferons alpha2b and beta1b, insulin, and human granulocyte colony stimulating factor) and natural polysialic acid (PSA) has been described. The incorporation of protein into the complex changes its electrophoretic mobility. Atomic force microscopy reveals the average size of 23-kD insulin complexes with PSA of 10-20 nm and demonstrates that more than 60% of glycopolymer molecules carry a single protein molecule. Experiments with cultured cells show that cytokines bound to polysialic acid retain their ability to regulate cell proliferation. Insulin bound to PSA has a prolonged hypoglycemic effect in vivo.
- Published
- 2009
- Full Text
- View/download PDF
27. [Modification of recombinant proteins by covalent polysialation illustrated with the example of human insulin].
- Author
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Bezuglov VV, Gretskaia NM, Bobrov MIu, Akimov MG, Fomina-Ageeva EV, Zinchenko GN, Bairamashvili DI, and Miroshnikov AI
- Subjects
- Humans, Recombinant Proteins chemistry, Insulin chemistry, Sialic Acids chemistry
- Abstract
Methods of selective and nonselective covalent immobilization of genetically engineered proteins on molecules of natural polysialic acid are described by the example of human insulin. Such modification increases insulin lifetime in vivo.
- Published
- 2009
- Full Text
- View/download PDF
28. [N-arachidonoyl dopamine is a possible factor of the rate of tentacle formation in freshwater hydra].
- Author
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Markova LN, Ostroumova TV, Akimov MG, and Bezuglov VV
- Subjects
- Animal Structures cytology, Animals, Arachidonic Acids pharmacology, Dopamine metabolism, Dopamine pharmacology, Dopamine Antagonists pharmacology, Haloperidol pharmacology, Hydra cytology, Regeneration drug effects, Animal Structures physiology, Arachidonic Acids metabolism, Dopamine analogs & derivatives, Hydra physiology, Regeneration physiology
- Abstract
The effect of N-arachidonoyl dopamine, haloperidol, and their mixture on the rate of tentacle formation was studied during regeneration of the gastral and basal fragments of freshwater hydra. Some concentrations of haloperidol inhibited the tentacle formation, which was more pronounced in the basal fragment. N-arachidonoyl dopamine accelerated the tentacle formation in both fragments, particularly, in the basal one (an inversion of the natural difference in the rate of tentacle formation between the gastral and basal fragments). After the exposure to the mixture of these drugs, the effects of each of them were observed. Mass spectrometry assay has demonstrated endogenous N-arachidonoyl dopamine in the intact hydra homogenate. The possible involvement of this acyl-neurotransmitter in the regulation of the rate of tentacle formation in regenerating hydra is discussed.
- Published
- 2008
29. [New aspects of biosynthesis and metabolism of N-acyldopamines in rat tissues].
- Author
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Akimov MG, Gretskaia NM, Shevchenko KV, Shevchenko VP, Miasoedov NF, Bobrov MIu, and Bezuglov VV
- Subjects
- Animals, Decarboxylation, Dopamine biosynthesis, Oxidation-Reduction, Rats, Arachidonic Acid metabolism, Dopamine metabolism
- Abstract
Possible biosynthetic pathways of N-acyldopamines in rat tissues were compared. It was shown that an insignificant amount of the conjugation products was formed during the incubation of arachidonic acid and dopamine, whereas the substitution of tyrosine for dopamine resulted in the productive biosynthesis of N-arachidonoyldopamine. The biosynthesis presumably involves several closely conjugated enzymatic stages, and free fatty acids rather than their CoA esters served as the starting substrates. The decarboxylation stage probably precedes the stage of catechol system formation, because N-acetyltyramine (a probable intermediate) was easily oxidized by monophenol monooxygenase to N-acyldopamine, whereas N-acyltyrosine is hydrolyzed under these conditions. Biosynthesis of N-acyldopamines in a cell-free medium was accompanied by their methylation. The possibility of oxidative metabolism of N-acyldopamines, which could serve as co-substrates or inhibitors of different oxidoreductases, was shown for the first time.
- Published
- 2007
- Full Text
- View/download PDF
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