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Choline derivatives as natural ligands of mitochondrial nicotinic acetylcholine receptors
O. Lykhmus, M. Izmailov, M. Skok*
Department of Molecular Immunology, Palladin Institute of Biochemistry,
National Academy of Sciences of Ukraine, Kyiv;
*e-mail: skok@biochem.kiev.ua
Received: 16 March 2023; Revised: 28 April 2023;
Accepted: 05 June 2023; Available on-line: 20 June 2023
Nicotinic acetylcholine receptors (nAChRs) regulate mitochondria-driven apoptosis; however, their intracellular ligands are unknown. In the present paper, we show that choline and its derivatives (phosphocholine (PC), L-α-glycerophosphocholine (G-PC) and 1-palmitoyl-sn-glycero-3-phosphocholine (P-GPC)) dose-dependently influence cytochrome c release from isolated mouse liver mitochondria. Choline inhibited Ca2+-stimulated cytochrome c release, while PC attenuated wortmannin-induced cytochrome c release. Small doses of G-PC and P-GPC (up to 0.1 µM) were protective against either Ca2+ or wortmannin, while larger doses (up to 1 µM) stimulated cytochrome c release by themselves. Choline and PC disrupted interaction of VDAC1, Bax and Bcl-2 with mitochondrial α7 nAChRs and favored their interaction with α9 nAChR subunits. It is concluded that choline metabolites can regulate apoptosis by affecting mitochondrial nAChRs.
Immunological mechanisms of increased susceptibility to COVID-19 disease and its severe course in patients with diabetes mellitus type 2 and obesity
K. P. Zak1, M. D. Tronko1, S. V. Komisarenko2*
1V. P. Komisarenko Institute of Endocrinology and Metabolism,
National Academy of Medical Sciences of Ukraine, Kyiv;
2Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
*e-mail: svk@biochem.kiev.ua
Received: 28 April 2023; Revised: 28 May 2023;
Accepted: 05 June 2023; Available on-line: 20 June 2023
In this review, we analyze and summarize literature data and the results of our own research related to the immunity status of patients with type 2 diabetes mellitus (T2D) and those T2D patients who were infected with the SARS-CoV-2 virus. It was shown that in the blood plasma of T2D patients, especially those with elevated BMI, the level and ultrastructure of the main cellular components of natural immunity – neutrophils and monocytes – were affected accompanied by high levels of proinflammatory cytokines (IL-1β, IL-6, IL-17 and TNF-α). It was suggested that the increased susceptibility of T2D patients to SARS-CoV-2 infection is primarily due to a weakening of the innate immune defense against pathogens, whereas in T2D patients who have COVID-19, adaptive T-cell immunity disorders accompanied by a cytokine storm prevail. It was concluded that hyperinflammation in T2D+COVID19 patients is the result of enhancement of already existing before SARS-CoV-2 infection T2D-caused disorders of innate and adaptive immunity, in the mechanism of which cytokines and chemokines play a significant role.
Genome secrets of extinct hominids, or can paleogenomics answer the question: humankind, who we are? Nobel Prize in Physiology or Medicine 2022
S. V. Komisarenko, S. I. Romaniuk
Paladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
e-mail: svk@biochem.kiev.ua
Received: 28 February 2022; Revised: 02 March 2022;
Accepted: 13 April 2023; Available on-line: 27 April 2023
The Nobel Prize in Physiology or Medicine 2022 was awarded to Professor Svante Pääbo, a Swedish paleogenetic researcher, specialist in the field of evolutionary genetics, Director of the Department of Evolutionary Genetics at the Max Planck Institute for Evolutionary Anthropology of Leipzig (Germany), for “discoveries concerning the genomes of extinct hominids and human evolution”. Explaining the significance of S. Pääbo’s work, the Nobel Committee noted that “he pioneered the methods to isolate and analyze DNA from archaic bone remains. In ancient bones, DNA has decayed, been chemically damaged and massively contaminated with DNA from bacteria and contemporary humans who work with the samples. Having utilized modern genetic methods, S. Pääbo created his own methods of sequencing the ancient DNA”.
Cathepsin inhibitors as potent inhibitors against SARS-CoV-2 main protease. In silico molecular screening and toxicity prediction
O. Sekiou1*, W. Kherfane2, M. Boumendjel3,
H. Cheniti4, A. Benselhoub1*, S. Bellucci5
1Environmental Research Center, Annaba, Algeria;
2Laboratory of Geodynamics and Natural Resources, Department of Hydraulics,
Badji Mokhtar Annaba University, Annaba, Algeria;
3Laboratory of Biochemistry and Environmental Toxicology,
Badji Mokhtar Annaba University, Algeria;
4National High School of Technology and Engineering (ESTI), Annaba, Algeria;
5INFN Frascati National Laboratories, Rome, Italy;
*e-mail: aissabenselhoub@cre.dz; sekiouomar@yahoo.fr
Received: 05 March 2023; Revised: 28 March 2023;
Accepted: 13 April 2023; Available on-line: 27 April 2023
Since the emergence of the newly identified Coronavirus SARS-CoV-2, no targeted therapeutic agents for COVID-19 treatment are available, and effective treatment options remain very limited. Successful crystallization of the SARS-CoV-2 main protease (Mpro, PDB-ID 6LU7) made possible the research on finding its potential inhibitors for the prevention of virus replication. To conduct molecular docking, we selected ten representatives of the Cathepsin inhibitors family as possible ligands with a high potential of binding the active site of SARS-CoV-2 main protease as a potential target. The results of molecular docking studies revealed that Ligand1 and Ligand2, with vina scores -8.8 and -8.7 kcal/mol for Mpro, respectively, were the most effective in binding. In silico prediction of physicochemical and toxicological behavior of assessed ligands approved the possibility of their use in clinical essays against SARS-COVID-19.
Fatty acids composition of actinobacteria isolated from mussels Mytilus galloprovincialis of the Black Sea Odesa Bay
N. V. Korotaeva*, K. S. Potapenko, Z. Yu. Sergieieva,
N. Yu. Vasylieva, V. O. Ivanytsia
Odesa National I. I. Mechnykov University, Odesa, Ukraine;
*e-mail: korotaeva.n@onu.edu.ua
Received: 11 December 2022; Revised: 16 March 2023;
Accepted: 13 April 2023; Available on-line: 27 April 2023
Analysis of the fatty acid composition of total cellular lipids is important chemotaxonomic characteristic that is used to identify microorganisms, in particular actinobacteria, with the help of fatty acid spectra libraries. Actinobacteria are well known as producers of secondary metabolites, which are of pharmacological and commercial interest. A significant number of actinomycetes is associated with various marine benthic communities. The aim of this study was determination of the fatty acid composition and preliminary identification of actinobacteria isolated from mussels Mytilus galloprovincialis of the Black Sea Odesa Bay. Actinobacteria of 12 isolated strains were grown in a liquid medium at 28° C for 72 h. Methyl esters of fatty acids were determined on a gas chromatograph Agilent. The MIDI Sherlock microorganisms identification system was used to identify the studied strains. It was found that the fatty acids methyl esters profiles of studied actinobacteria strains were characterized by the predominance of 12-17 saturated branched-chain fatty acids with high content of 12-methyltridecanoic, 12-methyltetradecanoic, 14-methylpentadecanoic and 14-methylhexadecanoic fatty acids. All 12 actinobacteria strains isolated from mussels (Mytilus galloprovincialis) of Odesa Bay were identified as members of the Streptomyces genus.
Indices of antioxidant and osmoprotective systems in seedlings of winter wheat cultivars with different frost resistance
T. O. Yastreb1, Yu. E. Kolupaev1,2*, A. I. Kokorev1, B. E. Маkaova2,
N. I. Ryabchun1, O. A. Zmiievska1, G. D. Pospielova2
1Yuriev Plant Production Institute, National Academy of Agrarian Sciences of Ukraine, Kharkiv;
2Poltava State Agrarian University, Ukraine;
*e-mail: plant_biology@ukr.net
Received: 02 January 2023; Revised: 27 January 2023;
Accepted: 13 April 2023; Available on-line: 27 April 2023
The functioning of the stress-protective systems of wheat under the action of cold at the early stages of plant development remains poorly studied. The aim of this work was a comparative study of antioxidant activity and the content of sugars and proline as indicators of osmoprotective activity during cold adaptation of seedlings of seven winter bread wheat (Triticum aestivum L.) cultivars that differ significantly in frost resistance. The 3-day-old etiolated seedlings were hardened at 2°C for 6 days and then frozen for 5 h at -6 or -9°C. Two days after freezing, the survival of seedlings was assessed by their ability to grow. A decrease in ROS content, an increase in the activity of antioxidant enzymes catalase and guaiacol peroxidase and accumulation of sugars in the shoots of high-frost-resistant cultivars during hardening were detected. The absolute values of catalase and guaiacol peroxidase activity correlated positively with the frost resistance of seedlings. The negative correlation between the frost tolerance of the cultivars and the accumulation of proline in the seedlings during hardening was recorded. The possibility of using the studied biochemical indices for frost resistance screening of winter wheat varieties at the seedling stage was stated.
Activity of respiratory chain cytochrome complexes and cytochromes content in the rat kidney mitochondria under different nutrients content in a diet
H. P. Kopylchuk, O. M. Voloshchuk*
Educational and Scientific Institute of Biology, Chemistry and Natural Resources,
Yuriy Fedkovych Chernivtsi National University, Chernivtsi, Ukraine;
*e-mail: o.voloschuk@chnu.edu.ua
Received: 07 February 2023; Revised: 17 March 2023;
Accepted: 13 April 2023; Available on-line: 27 April 2023
An important role in ensuring the functioning of the respiratory chain belongs to the cytochrome part, which includes complexes III (ubiquinol-cytochrome c oxidoreductase) and IV (cytochrome c oxidase). The key components of these enzymatic complexes are heme-containing cytochromes, the number of which depends on the balance of heme synthesis and catabolism. δ-Aminolevulinate synthase catalyzes the first step of the heme biosynthetic pathway, while heme oxygenase is the key enzyme of heme degradation. It is known that nutritional imbalances drive many risk factors for chronic kidney disease. That is why our research aimed to study the activity of ubiquinol-cytochrome c oxidoreductase and cytochrome oxidase complexes, the level of cytochromes a+a3, b, c, and c1, and the activity of key enzymes of heme metabolism in the mitochondria of rat kidneys under conditions of different content of protein and sucrose in animal diet. The obtained results showed a decreased activity of ubiquinol-cytochrome c oxidoreductase and cytochrome oxidase complexes and reduced levels of mitochondria cytochromes a+a3, b, c, and c1 in the kidney mitochondria under the conditions of nutrient imbalance, with the most pronounced changes found in animals kept on a low-protein/high-sucrose diet. A decrease in δ-aminolevulinate synthase activity with a simultaneous 2-fold increase in heme oxygenase activity was found in kidney mitochondria of animals kept on a low-protein/high-sucrose diet compared to those kept on full-value diet indicating an intensification of heme catabolism along with inhibition of its synthesis. The obtained results testify the energy imbalance under the conditions of low-protein/high-sucrose which in turn can lead to the progression of kidney injury.
Potential circulating biomarkers of atherosclerotic plaque vulnerability in patients in the early recovery period of atherothrombotic stroke
O. Ya. Mykhalojko, I. Ya. Mykhalojko
Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine;
e-mail: myhalojko@i.ua
Received: 30 November 2022; Revised: 02 February 2023;
Accepted: 13 April 2023; Available on-line: 27 April 2023
Despite the informative value of ultrasound examination of atherosclerotic vascular lesions, predicting the plaque vulnerability remains difficult. Circulating blood biomarkers could provide additional criteria that would allow better determination of the risk of recurrent stroke. The aim of our study was to estimate the level of C-reactive protein (CRP), low-density lipoproteins (LDL) and lipoprotein-associated phospholipase A2 (Lp-PLA2) in the blood of patients in the early recovery period of atherothrombotic stroke depending on the density of atherosclerotic plaque according to duplex scanning of cerebral vessels. Clinical and laboratory analysis of 69 men and 61 women aged (60.42 ± 7.40) years in the early recovery period of atherothrombotic stroke was conducted. Depending on the structure of the atherosclerotic plaque the examinees were divided into two groups with stable (n = 80) and unstable (n = 50) atherosclerotic layers. The blood lipid spectrum was examined on a biochemical analyzer Screen master, the level of CRP was determined with a diagnostic kit and that of Lp-PLA2 by ELISA. Significantly higher levels of LDL, CRP and Lp-PLA2 were observed in patients with unstable atherosclerotic plaque compared to patients with stable atherosclerotic plaque in the early recovery period of atherothrombotic stroke. The increased level of LDL, CRP, and Lp-PLA2 in patients with cerebral atherosclerosis can be considered as an indicator of the vulnerability of atherosclerotic plaques, prone to rupture, and as a prognostic marker of repeated acute ischemic events.
Cardioprotective effect of Ginger in a rat model of myocardial damage and its possible intervention in PERK-ATF4-CHOP-PUMA apoptotic pathway
M. M. Mohammed1*, N. A. A. Osman2, F. M. Mourad3, M. F. Abedelbaky1
1Department of Biochemistry, Faculty of Medicine, Minia University, El-Minia, Egypt;
2Department of Pathology, Faculty of Medicine, Minia University, El-Minia, Egypt;
3BS Pharm, Faculty of Pharmacy, Deraya University, El-Minia, Egypt;
*e-mail: mostafa.mohamed@mu.edu.eg
Received: 11 March 2023; Revised: 27 March 2023;
Accepted: 13 April 2023; Available on-line: 27 April 2023
For today the exact mechanisms of myocardial infarction and ischemia/reperfusion injury are still not fully understood. ER stress and integrated stress response pathways are thought to play an essential role in myocardial damage. This includes activation of endoplasmic reticulum kinase (PERK), induction of activating transcription factor 4 (ATF4), expression of pro-apoptotic transcription factor (CHOP) and P53 up-regulated modulator of apoptosis (PUMA) involved in apoptosis control. We used a rat model of isoproterenol-induced myocardial damage to elucidate the possible cardioprotective effect of Ginger through the influence on ER stress-induced apoptotic pathway. We also compared its effect with Captopril, inhibitor of angiotensin-converting enzyme. Male albino Wistar rats received 1.0 or 2.0 ml of Zingiber officinale (Ginger) powder suspension (200 mg/ml) daily by intra-gastric intubation for 28 days. Isoproterenol at a dose of 85 mg/kg was IP injected on the 27th and 28th days. Serum aspartate transaminase (AST) level was measured using kinetic kit. Heart tissue was used for RNA extraction, evaluation of gene expression by Q-RT-PCR, immuno-histochemical determination of caspase-3 expression and histopathological studies. Our results showed that Isoproterenol administration increased CHOP-mRNA expression 4 folds in cardiac muscle tissue compared to normal control. Ginger pretreatment significantly decreased both CHOP and ATF4, and PUMA mRNA expression compared to Isoproterenol-treated groups. A significant reduction in ATF4 mRNA expression in a group pretreated with Captopril and Ginger compared to normal control group was observed. The results showed that Ginger reduced AST serum levels which correlated with results of histopathological studies of heart tissue. Our findings suggest that the protective effects of Ginger against myocardium damage induced by Isoproterenol may be mediated by reducing the endoplasmic reticulum stress by affecting the ATF4-CHOP-PUMA pathway.
Novel putative ligands of cannabinoid receptors: synthesis and effects on cell signaling and neuronal functions
J. Senkiv1, A. Kryshchyshyn-Dylevych2*, D. Khylyuk3,
M. Wujec3, R. Stoika1*, A. J. Irving4, R. Lesyk2,5
1Department of Regulation Cell Proliferation and Apoptosis, Institute of Cell Biology,
National Academy of Sciences of Ukraine, Lviv;
2Department of Pharmaceutical, Organic and Bioorganic Chemistry,
Danylo Halytsky Lviv National Medical University, Lviv, Ukraine;
3Department of Organic Chemistry, Faculty of Pharmacy with Medical Analytics Division,
Medical University of Lublin, Lublin, Poland;
4School of Biomedical and Biomolecular Science, University College of Dublin, Dublin, Ireland;
5Department of Biotechnology and Cell Biology, Medical College,
University of Information Technology and Management in Rzeszow, Rzeszow, Poland;
*e-mail: stoika.rostyslav@gmail.com; kryshchyshyn.a@gmail.com
Received: 01 December 2022; Revised: 28 February 2023;
Accepted: 13 April 2023; Available on-line: 27 April 2023
Cannabinoid ligands are known to possess neuroprotective actions and may have utility in the treatment of neurodegeneration. The major targets for cannabinoids include the classical CB1 cannabinoid receptor, as well as the novel cannabinoid receptor GPR55 which binds to many synthetic cannabinoid ligands. In this study, novel thiopyranothiazoles 1, 3, 4, 6, and 7 were synthesized and their pharmacological activity as potential cannabinoid-like ligands was evaluated in glioblastoma cells, cultured cortical neurons, and cells of HEK293 line expressing GPR55. Stimulation of protein kinase ERK1/2, MAP-kinases and cAMP response element binding protein (CREB) was evaluated using Western-blot analysis. CREB activation was additionally monitored by means of confocal imaging of nuclear phospho-CREB labeling. Docking simulation confirmed the good affinity of the synthesized compounds to CB1 and CB2 receptors. Striking effects of the chromeno[4′,3′:4,5]thiopyrano[2,3-d][1,3]thiazol with ethylacetate moiety (3) and isothiochromeno[4a,4-d]thiazole with phenazone fragment (7) on pCREB activation as the indicator of stimulation of the pathway beneficial for neurons survival were observed.