Tag Archives: inflammation

Common mechanisms of placental dysfunction in preeclampsia, gestational diabetes, and COVID-19 in pregnant women

S. G. Vari1*, O. Shevchuk2, A. Boychuk3, S. Kramar4,
Z. Nebesna4, Y. Yakymchuk5, L. Kobylinska6, V. Chernyshenko7,
D. Korolova7, A. Gaspar-Suranyi8, T. Altorjay8, R. Gaspar9

1International Research and Innovation in Medicine Program, Cedars-Sinai Medical Center, Los Angeles, California, USA;
2Department of Pharmacology and Clinical Pharmacology, I. Horbachevsky Ternopil National Medical University, Ukraine;
3Department of Obstetrics and Gynecology, I. Horbachevsky Ternopil National Medical University, Ukraine;
4Department of Histology and Embryology, I. Horbachevsky Ternopil National Medical University, Ukraine;
5Department of Therapeutics and Family Medicine, I. Horbachevsky Ternopil National Medical University, Ukraine;
6Department of Biochemistry, Danylo Halytsky Lviv National Medical University, Ukraine;
7Department of Protein Structure and Function, Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
8Department of Obstetrics and Gynecology, Albert Szent-Györgyi Medical School, University of Szeged, Hungary;
9Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical School, University of Szeged, Hungary;
*e-mail: sandor.vari@cshs.org

Received: 13 June 2023; Revised: July 2023;
Accepted: July 2023; Available on-line: 11 July 2023

COVID-19 infection, preeclampsia and gestational diabetes mellitus in pregnancy cause similar changes in the placenta and influence development of the fetus between conception and birth in gestation. Proper uterine and placental vascularization is essential for normal fetal development. The transplacental exchange is regulated and maintained by the placental endothelium. During placental implantation, the trophoblast differentiates into two distinct layers, the inner cytotrophoblast and outer syncytiotrophoblast, which are key elements of the human placental barrier. Proinflammatory cytokines exacerbate ischemic events and create an upward spiral of an inflammatory reaction in the placenta. Placental pathology in gestational COVID-19 shows desquamation and damage of trophoblast and chronic histiocytic intervillositis. Similar lesions also occur in gestational diabetes mellitus and preeclampsia. The systemic inflammatory response of the mother, the increased inflammation in the placenta and cytokine production by placental trophoblasts should be monitored throughout pregnancy. Placental angiogenesis can be evaluated by serum vascular endothelial growth factor, Annexin A2, placental growth factor or sclerostin. Tissue damage can be assessed by measuring levels of serum lactate dehydrogenase and myeloperoxidase. Blood flow can be monitored with three-dimensional Doppler and pathological changes can be documented with paraffin-embedded tissue sections stained with hematoxylin and eosin, and electron microscope images as well as immunohistochemistry tests for vascular endothelial growth factor, placental growth factor, sclerostin and Annexin A2. The damage of maternal and fetal vascular perfusion (villitis and fibrin deposition) is a common mechanism of gestational diseases. The placenta lesions liberate anti-endothelial factors that lead to anti-angiogenic conditions and are the common mechanism of maternal placental vascular malperfusion in gestational diseases.

Inflammation is the common mechanism of diseases (CMD) in COVID-19 disease during pregnancy and in gestational diabetes mellitus

Sandor G. Vari

Cedars-Sinai Medical Center, International Research and Innovation in Medicine Program, Los Angeles, California, United States

The Regional Cooperation for Health, Science and Technology (RECOOP HST) Consortium, led by Cedars-Sinai Medical Center was formed in 2006, was transformed into an Association in 2012 and includes 17 universities and academic organizations from eight countries: seven in Central and Eastern Europe (Croatia, Czech Republic, Hungary, Poland, Romania, Slovakia, Ukraine) and the United States. RECOOP builds multinational, multidisciplinary collaborations, and assists as well as coordinates the research activities of the sixteen research groups that are the Cedars-Sinai Medical Center – RECOOP Research Centers (CRRCs). https://www.cedars-sinai.org/research/administration/recoop.html.
Implementations of RECOOP’s strategic goals enable diverse talents geared towards integration of new knowledge derived from multiple specialties to investigate Common Mechanism of Diseases (CMD). While some may consider RECOOP’s CMD research strategy unorthodox, recent and timely scientific evidence shows that inflammation is the triggering event in the change of vascularization and it is the common mechanism of these two diseases: COVID-19 Disease during pregnancy and gestational diabetes mellitus (GDM).
Binding of the SARS-CoV-2 virus to the ACE2 receptor and its entrance into endothelial cells plays a role in vascular thrombosis but has a lesser effect placental endothelial dysfunction. The latter is induced by inflammation and exacerbated by proinflammatory cytokines, resulting in ischemic events and creating an upward spiral of an inflammatory reaction in pregnant women, accompanied by similar conditions in the placenta that will ultimately affect fetal development. In mild or moderate COVID-19 disease, changes in placental vascularization and blood flow have similarities to comorbidities in pregnancy such as GDM. However, during severe or critical stages of COVID-19 Disease, the changes could be harsher than those observed in GDM.
In COVID-19 Disease and GDM the immune status of pregnant women and consequently the newborn is altered due to inflammation and characterized by changes in levels of C-reactive protein (CRP), immunoglobulins (IgG, IgM, IgA) and proinflammatory cytokines that are detectable in maternal and umbilical cord blood and in mother milk.
To examine changes and monitor placental angiogenesis it is necessary to measure Vascular Endothelial Growth Factor (VEGF), Placental Growth Factor (PLGF), and Umbilical Cord Blood Sclerostin (UCBS) in maternal and umbilical cord blood serum. The angiogenic activity of sclerostin must be validated with the well-known marker VEGF, which is a proven indicator for changes in vascularization. The morphology of the vascular tree and blood flow in the placenta could be evaluated with three-dimensional power Doppler. The proinflammatory and ischemic effects in the placenta should be quantified with histopathology and immunohistochemistry. Changes in blood flow in the placenta and the morphology of the vascular tree in COVID-19 Disease during pregnancy may have similarities to those observed in GDM.
In summary, to improve maternal and fetal outcomes it is imperative to formulate better strategies for managing pregnancies during COVID-19 Disease and comorbidities like GDM. VEGF, PLGF and UCBS could be predictors of placental weight, birth weight, and fetal outcomes. In addition, further studies are needed to investigate the effects, if any, of proinflammatory and anti-inflammatory cytokines on postnatal development.

Freezing influences, the exposure of IgG glycans in sera from multiple sclerosis patients

M. Bozhenko1, M. Boichuk1, G. Bila2, T. Nehrych1*, R. Bilyy2*

1Department of Neurology, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine;
2Department of Histology, Cytology and Embryology, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine;
*e-mail: r.bilyy@gmail.com; tnehrych@gmail.com

Received: 08 January 2020; Accepted: 27 March 2020

N-glycan residues attached to Asn297 of the immunoglobulin IgG molecule are responsible for changing­ its structural conformation and are used as markers of many inflammatory diseases. Freezing stabilizes protein structure, while recent solution NMR data showed greatly altered IgG glycan mobility at different­ temperatures. The aim of the current work was to investigate whether freezing sera samples from multiple sclerosis (MS) patients and normal healthy donors (NHD) influences exposure of IgG glycans. The developed lectin immunosorbent assay was used to evaluate exposure of native IgG glycans with fucose-binding AAL lectin and sialic acid-binding SNA lectin. Sera samples were divided and either immediately frozen at -20 °C or stored at 4 °C. Lectin exposure was compared between 5 MS patient groups (n = 75) vs NHD (n = 23) and in paired samples with and without freezing. A significant increase in the exposure of fucose residues on IgG glycans in MS patients, compared to NHD, was observed. This increase was only observed if sera were frozen before analysis. The exposure of sialic acid was decreased in MS vs NHD samples after freezing sera samples. The exposure of core fucose residues and terminal sialic residues differed significantly in paired sera samples after freezing. Combined parameters of fucose and sialic acid exposure on native IgG glycans using frozen sera samples serve as a discriminative marker between MS and NHD. For AAL exposure, the discrimination of MS was characterized by AUROC of 0.906, sensitivity of 76.7% and specificity of 59.0% (P < 0.0001).

Interaction of 4 allotropic modifications of carbon nanoparticles with living tissues

S. Ya. Paryzhak1, T. I. Dumych1, S. M. Peshkova1,2,
E. E. Bila2, A. D. Lutsyk1, A. Barras3,
R. Boukherroub3, S. Szunerits3, R. O. Bilyy1

1Danylo Halytsky Lviv National Medical University, Ukraine;
2Ivan Franko Lviv National University, Ukraine;
3Univ. Lille, CNRS, Centrale Lille, ISEN, Univ. Valenciennes, France;
e-mail: r.bilyy@gmail.com

Received: 19 January 2019; Accepted: 20 March 2019

Environmental pollution and technological progress lead to carbon nanoparticles that pose a serious health risk. They are present in soot, dust, and printing toner and can also be formed during grinding and cutting. Human neutrophils are able to sequester foreign material by formation of neutrophil extracellular traps (NETs), a process that can cause a strong inflammatory response. In the current work we compared proinflammatory properties of different carbon-based nanostructures: nanodiamonds, graphene oxide, fullere­nes C60 and carbon dots. We tested adjuvant properties of carbon nanoparticles in a murine immunization model by investigating humoral (specific IgG and IgM antibodies) and cellular (delayed type hypersensitivity) immune responses. The ability of NETs to sequester nanoparticles was analyzed in a mouse air pouch model and neutrophil activation was verified by in vivo tracking of near-infrared labeled nanodiamonds and ex vivo fluorescent assays using human blood-derived neutrophils. All carbon nanoparticles exhibited proinflammatory adjuvant-like properties by stimulating production of specific IgG but not IgM antibodies (humoral immune response). The adjuvant-like response decreased in this order: from nanodiamonds, graphene oxide, fullerenes C60 to carbon dots. None of the studied carbon nanoparticles triggered a delayed type hypersensitivity reaction (cellular immune response). Nanodiamonds and fullerenes C60 were sequestrated in the body by NETs, as confirmed in the air pouch model and by in vivo fluorescent tracking of near-infrared labeled nanodiamonds.

Blood coagulation and aortic wall integrity in rats with obesity-induced insulin resistance

O. S. Dziuba1, V. O. Chernyshenko1, Ie. A. Hudz1, L. O. Kasatkina1, T. M. Chernyshenko1,
P. P. Klymenko2, H. V. Kosiakova1, T. M. Platonova1, N. M. Hula1, E. V. Lugovskoy1

1Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
e-mail: oksana.dziuba86@gmail.com;
2State Institute of Gerontology of AMS of Ukraine, Kyiv

Obesity is an important factor in pathogenesis of disorders caused by chronic inflammation. Diet-induced obesity leads to dyslipidemia and insulin resistance (IR) that in turn provoke the development of type 2 diabetes and cardiovascular diseases. Thus, the aim of this work was to investigate the possible pro-atherogenic effects in the blood coagulation system and aortic wall of rats with obesity-induced IR. The experimental model was induced by a 6-month high-fat diet (HFD) in white rats. Blood samples were collected from 7 control and 14 obese IR rats. Prothrombin time (PT) and partial activated thromboplastin time (APTT) were performed by standard methods using Coagulometer Solar СТ 2410. Fibrinogen concentration in the blood plasma was determined by the modified spectrophotometric method. Levels of protein C (PC), prothrombin and factor X were measured using specific chromogenic substrates and activa­ting enzymes from snake venoms. Platelet aggregation was measured and their count determined using Aggregometer Solar AP2110. The aorta samples were stained by hematoxylin and eosin according to Ehrlich. Aortic wall thickness was measured using morphometric program Image J. Statistical analysis was performed using Mann-Whitney U Test. The haemostasis system was characterized by estimation of the levels of individual coagulation factors, anticoagulant system involvement and platelet reactivity. PT and APTT demonstrated that blood coagulation time strongly tended to decrease in obese IR rats in comparison to the control group. It was also detec­ted that 30% of studied obese IR rats had decreased factor X level, 40% had decreased level of prothrombin whereas fibrinogen concentration was slightly increased up to 3 mg/ml in 37% of obese IR rats. A prominent decrease of anticoagulant PC in blood plasma of obese rats was detected. Obese IR rats also had increased platelet count and higher rate of platelet aggregation in comparison to control animals. Histological analysis identified the disruption of aorta endothelium and tendency for the thickening of the aorta wall in the group with obesity-induced IR compared to the group of control rats. Changes of individual coagulation factors were assumed as the evidence of imbalance in the blood coagulation system. Increase of fibrinogen level, drop in PC concentration and pathological platelet reactivity were taken to corroborate the development of low-grade inflammation in obese IR rats. Instant generation of small amounts of thrombin in their blood plasma is expected. Since the aorta morphology assay detected the trend of its wall to thicken and the emergence of disruptions, we assumed there were initial stages of atherosclerosis and the danger of developing atherothrombosis. We detected an increase of blood coagulability and changes in aorta morphology in rats with obesity-induced IR which we assume indicate early development of atherosclerosis.

4-Thiazolidinone-based derivatives rescue TNAα-inhibited osteoblast differentiation in mouse mesenchymal precursor cells

Kh. V. Malysheva1,2,3, N. S. Finiuk1, O. K. Pavlenko4, D. Ya. Havrylyuk5,
R. B. Lesyk5, R. S. Stoika1, O. G. Korchynskyi1,3

1Institute of Cell Biology, NAS of Ukraine, Lviv;
2Insitute of Animal Biology, NAAS of Ukraine, Lviv;
3Centre for Innovative Research in Medical and Natural Sciences,
Rzeszow University and Medical Faculty, Poland;
4Ivan Franko National University of Lviv, Ukraine;
5Danylo Halytsky Lviv National Medical University, Ukraine;
e-mail: olexkor@hotmail.com

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease of yet unknown etiology. Tumor necrosis factor α (TNFα) is recognized as a regulatory substance that plays a central role in RA development and progression. On the other side, the bone morphogenetic protein (BMP) and Wnt signaling pathways are key mechanisms that induce and support cartilage and bone formation and maintenance. Previous studies showed that the pro-inflammatory cytokines TNFα and interleukin 1β (IL-1β) are central players in the inhibition of activity of skeletogenesis. The aim of this study was to evaluate the anti-inflammatory activity of novel 4-thiazolidinone-based derivatives towards TNFα–induced pro-inflammatory effects during bone formation. We performed in vitro evaluation of functional effects of 4-thiazolidinones denoted as Les-4368, Les-4370, Les-3882 and Les-3288 that were used in different doses (0.02, 0.1, 0.3 and 1.0 μM) on the TNFα-mediated inhibition of the BMP-induced osteoblast differentiation in mouse mesenchymal precursor (stem) cells of C2C12 line. Treatment of these cells with TNFα completely inhibited their myogenic differentiation, as well as strongly inhibited the BMP-induced osteogenesis. Strikingly, the treatment of C2C12 cells with Les-4368 and Les-3882 rescued the osteoblast differentiation from negative control of TNFα, and, moreover, converted this cytokine from the inhibitor of osteogenesis into its stimulator. Western-blot analysis of Inhibitory κBα (I-κBα) degradation was used to elucidate a mechanism of the anti-inflammatory effects. Les-3882 was more active, and it stimulated osteoblast differentiation at low dose (0.1 μM), presumably, via modulation of the NF-κB signaling pathway.

Effect of hydrogen sulfide-releasing aspirin on esophageal and gastric mucosa compromised by stress injury

O. S. Zayachkivska1, N. S. Bula1, Ya. I. Pavlovskiy1, I. O. Pshyk-Titko1,
E. M. Gavriluk1, O. I. Grushka1, J. L. Wallace2,3

1Danylo Halytsky Lviv National Medical University, Ukraine;
2University of Calgary, Canada;
3University of Toronto, Canada;
e-mail: ozayachkivska@gmail.com

Recent data of study H2S in gastrointestinal tract has proven its potent cytoprotection on mucosal defense among acid-related diseases in the gut. The aim was to evaluate the effects of H2S-releasing aspirin derivative (ATB-340) on esophageal and gastric mucosa compromised by stress injury. Rats were treated with vehicle (control), aspirin (10 mg/kg), ATB-340 (17.5 mg/kg) single or 9 days duration, with or without induction of stress injury. Esophageal mucosa, gastric mucosa were estimated by histopathological damage scoring. Serological levels of VCAM-1, IL-6 by ELISA. ATB-340 treatment resulted in protective effect and lower grade of damage score in esophageal mucosa and gastric mucosa lesions vs effect of aspirin in single or 9 days applications. The serum levels of VCAM, IL-6 in rats who were aspirin-treated and subjected to stress-injury were higher than those in control animals. Treatment with ATB-340 produced an anti-inflammatory effect by decreasing VCAM and IL-6 vs aspirin. Cytoprotective effect of ATB-340 on esophageal mucosa and gastric mucosa was modulated by inhibi­ting inflammation and improving endothelial functions.

Role of plasminogen/plasmin in functional activity of blood cells

D. D. Zhernossekov, E. I. Yusova, T. V. Grinenko

Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;

The article deals with the data concerning structural peculiarities of plasminogen/plasmin molecule, which define the specificity of intermolecular interactions and provide the variety of its biological functions. The main principles of the modern classification of plasminogen receptors and factors, which modulate their expression, have been presented. We have considered the mechanisms regulating both plasmin formation and activity on the surface of cells, fibrin and proteins of extracellular matrix. The data of previous investigators and our own results, concerning the influence of plasminogen/plasmin on platelet aggregation induced by different agonists, have been summarized. The participation of plasminogen/plasmin in atherogenesis and angiogenesis mediated­ by endotheliocyte receptors has been discussed. Special attention was given to plasminogen/plasmin pro-inflammatory function, which is realized by regulatory processes of activation, secretion, migration and apoptosis of monocytes and macrophages.

Use of vitamins for correction of the functional state of cytochrome P450 systems at experimental allergic encephalomyelitis

E. P. Pasichna1, G. V. Donchenko1, A. P. Burlaka2, V. S. Nedzvetskiy3,
E. P. Sidorik2, I. I.Ganusevich2, N. V. Delemenchuk1

1Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
2Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Kyiv;
3Honchar National University, Dnipropetrovsk, Ukraine;
e-mail: ellapasich@gmail.com

It is known that inflammatory cytokines, which level is significantly increased in the pathogenesis of multiple sclerosis (MS), as well as interferon-β, which is used to treat autoimmune diseases, can inhibit cytochrome P450-dependent processes of detoxification and biotransformation. The uncontrolled decrease of the activity of these processes may have a negative affect on the state of patients, so it is urgent to study the functional state of the cytochrome P450 system and to develop effective means for its regulation in these conditions. The effect of vitamin D3 and efficiency of its composition with vitamins B1, B2, B6, PP, E, α-lipoic, α-linolenoic acid and mineral substances (Mg, Zn, Se) in prevention of a functional state changes of cytochrome P450- and b5-dependent systems of the rat brain and liver endoplasmic reticulum at EAE are investigated. It has been shown that the essential decrease of the level of these cytochromes is observed both in the brain and liver. In addition the level of activity of NADH-and NADPH-oxidoreductases, which are part of microsomal electron transport chain components and coupled with monooxigenases, was reduced. These changes confirm the disturbances of a redox state and functional activity of detoxication and biotransformation systems in the studied animal tissues. Supplement of vitamin D3 as well as the composition of biologically active substances, which we developed earlier, effectively eliminated the decrease of the level of cytochromes and activities of NADH-oxidoreductase in immunised rat tissues. Normalization of these disturbances can be explained by antioxidant and membrane-stabilizing properties of applied substances, and also by the ability to reduce the activity of inflammatory reactions by regulation of the level of inflammatory cytokines in rat organism at EAE. Thus the studied vitamin-mineral composition appeared to be more effective to normalize the found disturbances and it can be useful for prevention of exacerbations and for improvement of a status of patients with multiple sclerosis and other diseases, which are accompanied with hyperactivation of immune system.