Pregnan X receptor (PXR) is a nuclear receptor that plays an important role in the regulation of the expression enzymes of biotransformation and metabolism. The functioning and possible mechanisms of PXR regulation under conditions of nitrosative stress have not been studied yet and this was the purpose of this study. Nitrosative stress (NS) was modeled in Caco-2 cells, which were incubated in the presence of 1 μM, 10 μM, 50 μM, 100 μM, and 500 μM concentrations of S-nitrosoglutathione (GSNO) for 3 h, 24 h, and 72 h. The amount of PXR was assessed by Western blotting. Incubation of Caco-2 cells with all GSNO concentrations for 3 h led to a decrease in the amount of PXR. Incubation with GSNO (1−50 μM) for 24 h was accompanied by an increase in the amount of PXR, while at a higher concentration (100 μM) this indicator did not significantly differ from the control and at a concentration of 500 μM it was below the control level. Prolonged incubation (for 72 h) enhanced NS and led to a normalization (1 μM GSNO) or a decrease of the PXR level (10−500 μM GSNO). Bityrosine formed during NS induced PXR expression at concentrations of 0.4 mM and 1 mM.
{"title":"Pregnan X Receptor Functioning under Conditions of Nitrosative Stress","authors":"Y. V. Abalenikhina, E. A. Sudakova, A. A. Seidkulieva, A. V. Shchulkin, E. N. Yakusheva","doi":"10.1134/S1990750822020020","DOIUrl":"10.1134/S1990750822020020","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>Pregnan X receptor (PXR) is a nuclear receptor that plays an important role in the regulation of the expression enzymes of biotransformation and metabolism. The functioning and possible mechanisms of PXR regulation under conditions of nitrosative stress have not been studied yet and this was the purpose of this study. Nitrosative stress (NS) was modeled in Caco-2 cells, which were incubated in the presence of 1 μM, 10 μM, 50 μM, 100 μM, and 500 μM concentrations of S-nitrosoglutathione (GSNO) for 3 h, 24 h, and 72 h. The amount of PXR was assessed by Western blotting. Incubation of Caco-2 cells with all GSNO concentrations for 3 h led to a decrease in the amount of PXR. Incubation with GSNO (1−50 μM) for 24 h was accompanied by an increase in the amount of PXR, while at a higher concentration (100 μM) this indicator did not significantly differ from the control and at a concentration of 500 μM it was below the control level. Prolonged incubation (for 72 h) enhanced NS and led to a normalization (1 μM GSNO) or a decrease of the PXR level (10−500 μM GSNO). Bityrosine formed during NS induced PXR expression at concentrations of 0.4 mM and 1 mM.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 2","pages":"140 - 147"},"PeriodicalIF":0.6,"publicationDate":"2022-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4698130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In order to improve the therapeutic properties of the antitumor agent sarcolysin, we have previously developed and characterized a dosage form, representing its ester conjugate with decanol embedded in ultra-small phospholipid nanoparticles less than 30 nm (Sarcolysin-NPh). In this study we have compared the effect of this composition with free substance of sarcolysin in vivo. After the intravenous administration to mice, an improvement in the pharmacokinetic parameters of sarcolysin was associated with a higher (by 22%) initial level in the blood and with prolonged circulation. This was also observed in P388 tumor-bearing mice. At the same time, the amount and duration of the presence of sarcolysin in the tumor tissue were significantly higher (more than two times) when compared with the free substance. In mice with three types of tumors (lymphocytic leukemia P388, lymphocytic leukemia L1210, and mammary adenocarcinoma Ca755), a predominant antitumor effect was shown, which manifested itself in a significantly greater inhibition of tumor growth and an increase in the life span of animals. The maximum inhibition of tumor growth during treatment with Sarcolysin-NPh at a dose of 8.4 mg/kg was noted in the case of lymphocytic leukemia L1210 and mouse mammary adenocarcinoma Ca755 (more than 24% and 17% higher, respectively, in comparison with the substance). At a dose of 10 mg/kg, differences in the life expectancy of animals were higher by 25%, 17.4%, and 11% for lymphocytic leukemia P388, lymphocytic leukemia L1210, and adenocarcinoma Ca755, respectively. Sarcolysin-NPh intravenously to rats, demonstrated significantly lower acute toxicity than commercially available free Sarcolysin (Melphalan and Alkeran): the LD50 value for Sarcolysin-NPh was 2–3 times lower than that for free Sarcolysin. This indicates a lower toxicity of Sarcolysin-NPh.
{"title":"The Effect of Lipid Derivative of the Anti-Tumor Drug Sarcolysin Embedded in Phospholipid Nanoparticles in the Experiments in Vivo","authors":"Yu. A. Tereshkina, T. I. Torkhovskaya, M. A. Sanzhakov, L. V. Kostryukova, Yu. Yu. Khudoklinova, E. G. Tikhonova","doi":"10.1134/S1990750822020093","DOIUrl":"10.1134/S1990750822020093","url":null,"abstract":"<p>In order to improve the therapeutic properties of the antitumor agent sarcolysin, we have previously developed and characterized a dosage form, representing its ester conjugate with decanol embedded in ultra-small phospholipid nanoparticles less than 30 nm (Sarcolysin-NPh). In this study we have compared the effect of this composition with free substance of sarcolysin in vivo. After the intravenous administration to mice, an improvement in the pharmacokinetic parameters of sarcolysin was associated with a higher (by 22%) initial level in the blood and with prolonged circulation. This was also observed in P388 tumor-bearing mice. At the same time, the amount and duration of the presence of sarcolysin in the tumor tissue were significantly higher (more than two times) when compared with the free substance. In mice with three types of tumors (lymphocytic leukemia P388, lymphocytic leukemia L1210, and mammary adenocarcinoma Ca755), a predominant antitumor effect was shown, which manifested itself in a significantly greater inhibition of tumor growth and an increase in the life span of animals. The maximum inhibition of tumor growth during treatment with Sarcolysin-NPh at a dose of 8.4 mg/kg was noted in the case of lymphocytic leukemia L1210 and mouse mammary adenocarcinoma Ca755 (more than 24% and 17% higher, respectively, in comparison with the substance). At a dose of 10 mg/kg, differences in the life expectancy of animals were higher by 25%, 17.4%, and 11% for lymphocytic leukemia P388, lymphocytic leukemia L1210, and adenocarcinoma Ca755, respectively. Sarcolysin-NPh intravenously to rats, demonstrated significantly lower acute toxicity than commercially available free Sarcolysin (Melphalan and Alkeran): the LD<sub>50</sub> value for Sarcolysin-NPh was 2–3 times lower than that for free Sarcolysin. This indicates a lower toxicity of Sarcolysin-NPh.</p>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 2","pages":"125 - 133"},"PeriodicalIF":0.6,"publicationDate":"2022-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4693724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Prenatal alcohol exposure (PAE) can lead to developmental disorders of the central nervous system (CNS) and mental retardation. Toll-like receptor (TLR) 4 plays an important role in the development of defects in the nervous system caused by PAE. However, how PAE affects the TLR4 response in the brain remains unclear. Using the model of semi-forced alcoholization of pregnant rats, we have investigated TLR4-mediated signaling on the 30th day of postnatal development in their offspring. Rats exposed to PAE showed a higher expression of proinflammatory cytokines in the prefrontal cortex, but TLR4-mediated signaling in response to lipopolysaccharide (LPS) was weakened. These data suggest that PAE can lead to neuroinflammation and suppression of the TLR4-mediated response to LPS in the prefrontal cortex of young rats. Since innate immunity plays an important role in brain development, PAE-induced suppression of the TLR4-mediated response may be one of the mechanisms for the development of CNS pathology.
{"title":"Prenatal Exposure to Alcohol Alters TLR4 Mediated Signaling in the Prefrontal Cortex in Rats","authors":"M. I. Airapetov, S. O. Eresko, E. R. Bychkov, A. A. Lebedev, P. D. Shabanov","doi":"10.1134/S1990750822020032","DOIUrl":"10.1134/S1990750822020032","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>Prenatal alcohol exposure (PAE) can lead to developmental disorders of the central nervous system (CNS) and mental retardation. Toll-like receptor (TLR) 4 plays an important role in the development of defects in the nervous system caused by PAE. However, how PAE affects the TLR4 response in the brain remains unclear. Using the model of semi-forced alcoholization of pregnant rats, we have investigated TLR4-mediated signaling on the 30th day of postnatal development in their offspring. Rats exposed to PAE showed a higher expression of proinflammatory cytokines in the prefrontal cortex, but TLR4-mediated signaling in response to lipopolysaccharide (LPS) was weakened. These data suggest that PAE can lead to neuroinflammation and suppression of the TLR4-mediated response to LPS in the prefrontal cortex of young rats. Since innate immunity plays an important role in brain development, PAE-induced suppression of the TLR4-mediated response may be one of the mechanisms for the development of CNS pathology.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 2","pages":"134 - 139"},"PeriodicalIF":0.6,"publicationDate":"2022-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4695430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Methylene blue, a phenothiazine dye, that is widely used in medicine and is under clinical trials as an agent for treatment of Alzheimer’s disease. One of the factors of the unique therapeutic effect of methylene blue is its redox properties, allowing implementation of alternative electron transport: the dye accepts electrons from reducing equivalents in mitochondria and transfer them to other components of the respiratory chain or molecular oxygen. Azure I, an N-dimethylated metabolite of methylene blue, is potentially a more effective compound than methylene blue, but its ability for alternative electron transport has not been studied yet. We have shown that in contrast to methylene blue, azure I is unable to restore the membrane potential in isolated mouse brain mitochondria, inhibited by rotenone and, therefore, is unable to perform bypass of the respiratory chain complex I. Moreover, addition of azure I does not affect the rate of mitochondrial respiration in contrast to methylene blue, which increases the rate of non-phosphorylation respiration. At the same time, both dyes stimulate an increase in H2O2 production. Thus, only methylene blue is capable of alternative electron transport, while azure I does not produce complex I bypass. This limits its therapeutic application only as a mitochondrial-targeted agent, but does not question its antidepressant effects.
{"title":"The Effect of Methylene Blue and Its Metabolite—Azure I—on Bioenergetic Parameters of Intact Mouse Brain Mitochondria","authors":"A. P. Gureev, N. A. Samoylova, D. V. Potanina, V. N. Popov","doi":"10.1134/S1990750822020044","DOIUrl":"10.1134/S1990750822020044","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>Methylene blue, a phenothiazine dye, that is widely used in medicine and is under clinical trials as an agent for treatment of Alzheimer’s disease. One of the factors of the unique therapeutic effect of methylene blue is its redox properties, allowing implementation of alternative electron transport: the dye accepts electrons from reducing equivalents in mitochondria and transfer them to other components of the respiratory chain or molecular oxygen. Azure I, an <i>N</i>-dimethylated metabolite of methylene blue, is potentially a more effective compound than methylene blue, but its ability for alternative electron transport has not been studied yet. We have shown that in contrast to methylene blue, azure I is unable to restore the membrane potential in isolated mouse brain mitochondria, inhibited by rotenone and, therefore, is unable to perform bypass of the respiratory chain complex I. Moreover, addition of azure I does not affect the rate of mitochondrial respiration in contrast to methylene blue, which increases the rate of non-phosphorylation respiration. At the same time, both dyes stimulate an increase in H<sub>2</sub>O<sub>2</sub> production. Thus, only methylene blue is capable of alternative electron transport, while azure I does not produce complex I bypass. This limits its therapeutic application only as a mitochondrial-targeted agent, but does not question its antidepressant effects.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 2","pages":"148 - 153"},"PeriodicalIF":0.6,"publicationDate":"2022-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1134/S1990750822020044.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4695431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The experimental data obtained by Simats, A. et al. (Molecular and Cellular Proteomics, 2020, vol. 19, no. 12, pp. 1921–1936) were analyzed using a bioinformatic aproach. Original experimental results available in the ProteomeXchange database were obtained using a comprehensive multiomics approach to identify potential blood biomarkers in ischemic stroke in mice. The identification of peptides with post-translational modification (PTM) was performed by us using the raw data (accession code PXD016538). Only phosphorylation and deamination were considered as PTMs. Different combinations of data sets (ischemic tissue with intact tissue, ischemic tissue with control taken from mice after sham surgery, etc.) were compared both in terms of the ratio of abundance for the modified peptide to the unmodified variant and in terms of absolute values of abundance. The most probable change in the PTM levels was shown for 27 proteins, which included dynamin, glycogen phosphorylase and 70 kDa heat shock protein.
摘要:Simats, A. et al. (Molecular and Cellular Proteomics, 2020, vol. 19, no. 5)获得的实验数据。12, pp. 1921-1936)使用生物信息学方法进行分析。ProteomeXchange数据库中的原始实验结果是使用综合多组学方法鉴定小鼠缺血性中风中潜在的血液生物标志物获得的。我们使用原始数据(登录码PXD016538)进行翻译后修饰肽的鉴定。只有磷酸化和脱氨作用被认为是PTMs。不同的数据集组合(缺血组织与完整组织、缺血组织与假手术后小鼠的对照等)在修饰肽与未修饰变体的丰度比率以及丰度绝对值方面进行了比较。27种蛋白的PTM水平最有可能发生变化，其中包括动力蛋白、糖原磷酸化酶和70 kDa热休克蛋白。
{"title":"The Bioinformatic Identification of Proteins with Varying Levels of Post-Translational Modifications in Experimental Ischemic Stroke in Mice","authors":"V. S. Skvortsov, Ya. O. Ivanova, A. I. Voronina","doi":"10.1134/S199075082202007X","DOIUrl":"10.1134/S199075082202007X","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>The experimental data obtained by Simats, A. et al. (<i>Molecular and Cellular Proteomics</i>, 2020, vol. 19, no. 12, pp. 1921–1936) were analyzed using a bioinformatic aproach. Original experimental results available in the ProteomeXchange database were obtained using a comprehensive multiomics approach to identify potential blood biomarkers in ischemic stroke in mice. The identification of peptides with post-translational modification (PTM) was performed by us using the raw data (accession code PXD016538). Only phosphorylation and deamination were considered as PTMs. Different combinations of data sets (ischemic tissue with intact tissue, ischemic tissue with control taken from mice after sham surgery, etc.) were compared both in terms of the ratio of abundance for the modified peptide to the unmodified variant and in terms of absolute values of abundance. The most probable change in the PTM levels was shown for 27 proteins, which included dynamin, glycogen phosphorylase and 70 kDa heat shock protein.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 2","pages":"113 - 124"},"PeriodicalIF":0.6,"publicationDate":"2022-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4698129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Non-small cell lung cancer (NSCLC) dominates in the morbidity of lung cancer. In stage I, only 60–70% patients overcome the 5-year survival barrier, and in stage II 5-year survival rate is declining to 35–40%. The reason for such a high mortality is relapse of the disease. The main histological forms of NSCLC are adenocarcinoma (AС) and squamous cell carcinoma (SCC). They differ in course, protocols and effectiveness of treatment. Comparative survival data for AC and SCC are controversial, and reliable biomarkers for determining the risk of tumor progression still have not been found. In order to determine the risk of disease progression we have investigated the possibility of using laboratory parameters characterizing the level of some blood proteins involved in carcinogenesis in patients with early stages of AС and SCC. We retrospectively analyzed the duration of relapse-free period after surgical treatment for one year in 1250 patients (816 with stages I and II AC, G1-3 and 434 with early stages of SCC, G1-3). In 81 AC patients and 36 SCC patients (stages I−II, G1-3) we determined the level of CYFRA 21-1 and SCC, TPA, chemokines CXCL5, CXCL8, pyruvate kinase M2, HIF-1α, hyaluronic acid and receptors CXCR1, CXCR2, CD44v6. Using the Kaplan−Meier graphical analysis, groups of low (stage I G1-2 + stage II G1) and high (stage I G3 + stage II G2-3) risk of tumor progression were identified. The one-year survival rate of AС patients was higher than in SCC patients. AС patients with high risk of tumor recurrence had higher levels of CYFRA 21-1, the mean intensity of fluorescence (MFI) of CXCR1 receptor in granulocytes, and the relative content of CXCR2 receptor in lymphocytes than patients with low risk. In the case of rapid disease progression in SCC patients, the relative content of CXCR2 receptor in lymphocytes, the proportion of monocytes supplied with CD44v6 receptor, and SCC level were higher than in patients with slow progression. Regression equations, including combinations of the above parameters (threshold value for AC—0.512, for SCC—0.409, sensitivity—91.9% and 90.0%, specificity—90.0% and 87.5%, respectively), allow to predict the probability of tumor recurrence.
{"title":"Determination of the Risk of Tumor Progression in Patients with Early Stages of Adenocarcinoma and Squamous Cell Lung Carcinoma Based on Laboratory Parameters","authors":"A. D. Tahanovich, N. N. Kauhanka, V. I. Prohorova, D. I. Murashka, O. V. Gotko","doi":"10.1134/S1990750822020081","DOIUrl":"10.1134/S1990750822020081","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>Non-small cell lung cancer (NSCLC) dominates in the morbidity of lung cancer. In stage I, only 60–70% patients overcome the 5-year survival barrier, and in stage II 5-year survival rate is declining to 35–40%. The reason for such a high mortality is relapse of the disease. The main histological forms of NSCLC are adenocarcinoma (AС) and squamous cell carcinoma (SCC). They differ in course, protocols and effectiveness of treatment. Comparative survival data for AC and SCC are controversial, and reliable biomarkers for determining the risk of tumor progression still have not been found. In order to determine the risk of disease progression we have investigated the possibility of using laboratory parameters characterizing the level of some blood proteins involved in carcinogenesis in patients with early stages of AС and SCC. We retrospectively analyzed the duration of relapse-free period after surgical treatment for one year in 1250 patients (816 with stages I and II AC, G1-3 and 434 with early stages of SCC, G1-3). In 81 AC patients and 36 SCC patients (stages I−II, G1-3) we determined the level of CYFRA 21-1 and SCC, TPA, chemokines CXCL5, CXCL8, pyruvate kinase M2, HIF-1α, hyaluronic acid and receptors CXCR1, CXCR2, CD44v6. Using the Kaplan−Meier graphical analysis, groups of low (stage I G1-2 + stage II G1) and high (stage I G3 + stage II G2-3) risk of tumor progression were identified. The one-year survival rate of AС patients was higher than in SCC patients. AС patients with high risk of tumor recurrence had higher levels of CYFRA 21-1, the mean intensity of fluorescence (MFI) of CXCR1 receptor in granulocytes, and the relative content of CXCR2 receptor in lymphocytes than patients with low risk. In the case of rapid disease progression in SCC patients, the relative content of CXCR2 receptor in lymphocytes, the proportion of monocytes supplied with CD44v6 receptor, and SCC level were higher than in patients with slow progression. Regression equations, including combinations of the above parameters (threshold value for AC—0.512, for SCC—0.409, sensitivity—91.9% and 90.0%, specificity—90.0% and 87.5%, respectively), allow to predict the probability of tumor recurrence.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 2","pages":"154 - 163"},"PeriodicalIF":0.6,"publicationDate":"2022-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4696699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Extracellular vesicles (EVs) are spherical functionally important structures of cell membrane origin ranging in size from 40 nm to 5000 nm. They are involved in the horizontal transfer of mainly proteins and microRNAs. The mechanisms of EV internalization include clathrin-dependent endocytosis, caveolin-dependent endocytosis, raft-mediated endocytosis, and macropinocytosis. Type 2 diabetes mellitus (T2DM) is a common group of metabolic disorders in adults; the incidence and prevalence of T2DM increase in parallel with the obesity epidemic. Since adipose tissue plays a key role in the development of insulin resistance, EVs secreted by adipose tissue may be considered as an information transmitter in this process. EVs of the adipocyte origin are predominantly captured up by tissue macrophages, adipocytes themselves, hepatocytes, and skeletal muscles. The EV uptake promotes M1 polarization of macrophages, a decrease in glucose uptake by hepatocytes and myocytes due to the transfer of functionally active microRNAs influencing carbohydrate and lipid metabolism. Patients with T2DM and impaired glucose tolerance, have a significantly higher level of CD235a-positive (erythrocyte) EVs and a trend to the increase in CD68-positive (leukocyte) and CD62p-positive (platelet/endothelial cells) EVs. The levels of CD31+/CD146-positive EVs (endothelial cells) were comparable between diabetic and euglycemic patients. EVs from diabetic patients were preferentially internalized by monocytes (predominantly classical and transitional, and to a lesser extent nonclassical monocyte fractions) and B cells as compared to euglycemic patients. Internalization of EVs from patients with T2DM by monocytes led to a decrease in their apoptosis, changes in differentiation, and suppression of monocyte reactions controlling oxidative stress. Thus, insulin resistance increases the secretion of EVs, which are preferentially internalized by monocytes and alter their function. EVs are considered as sources of promising clinical markers of insulin resistance, complications of diabetes mellitus (endothelial dysfunction, retinopathy, nephropathy, neuropathy), and EV markers can also be used to monitor the effectiveness of therapy for these complications.
{"title":"Production and Internalization of Extracellular Vesicles in Norm and under Conditions of Hyperglycemia and Insulin Resistance","authors":"N. V. Yunusova, E. E. Dandarova, D. A. Svarovsky, N. S. Denisov, D. N. Kostromitsky, M. R. Patysheva, O. V. Cheremisina, L. V. Spirina","doi":"10.1134/S199075082202010X","DOIUrl":"10.1134/S199075082202010X","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>Extracellular vesicles (EVs) are spherical functionally important structures of cell membrane origin ranging in size from 40 nm to 5000 nm. They are involved in the horizontal transfer of mainly proteins and microRNAs. The mechanisms of EV internalization include clathrin-dependent endocytosis, caveolin-dependent endocytosis, raft-mediated endocytosis, and macropinocytosis. Type 2 diabetes mellitus (T2DM) is a common group of metabolic disorders in adults; the incidence and prevalence of T2DM increase in parallel with the obesity epidemic. Since adipose tissue plays a key role in the development of insulin resistance, EVs secreted by adipose tissue may be considered as an information transmitter in this process. EVs of the adipocyte origin are predominantly captured up by tissue macrophages, adipocytes themselves, hepatocytes, and skeletal muscles. The EV uptake promotes M1 polarization of macrophages, a decrease in glucose uptake by hepatocytes and myocytes due to the transfer of functionally active microRNAs influencing carbohydrate and lipid metabolism. Patients with T2DM and impaired glucose tolerance, have a significantly higher level of CD235a-positive (erythrocyte) EVs and a trend to the increase in CD68-positive (leukocyte) and CD62p-positive (platelet/endothelial cells) EVs. The levels of CD31+/CD146-positive EVs (endothelial cells) were comparable between diabetic and euglycemic patients. EVs from diabetic patients were preferentially internalized by monocytes (predominantly classical and transitional, and to a lesser extent nonclassical monocyte fractions) and B cells as compared to euglycemic patients. Internalization of EVs from patients with T2DM by monocytes led to a decrease in their apoptosis, changes in differentiation, and suppression of monocyte reactions controlling oxidative stress. Thus, insulin resistance increases the secretion of EVs, which are preferentially internalized by monocytes and alter their function. EVs are considered as sources of promising clinical markers of insulin resistance, complications of diabetes mellitus (endothelial dysfunction, retinopathy, nephropathy, neuropathy), and EV markers can also be used to monitor the effectiveness of therapy for these complications.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 2","pages":"104 - 112"},"PeriodicalIF":0.6,"publicationDate":"2022-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4697679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Despite the fact that acetylsalicylic acid (ASA) is the “gold” standard for the prevention of cardiovascular complications in patients with coronary heart disease (CAD), some patients still have risks of atherothrombosis. In the present study, the antithrombotic effect of ASA in patients with CAD was assessed using integral hemostasis tests: the T-TAS system (Total Thrombus-formation Analysis System) and the thrombin generation test (TGT) in platelet-rich plasma (PRP). The study involved 34 patients with stable CAD (11 women, 23 men) and 33 people (15 women, 18 men) in the control group. Evaluation of the activity of thrombus formation by means of the T-TAS system revealed a significant decrease in the area under the curve (AUC10) in the group of CAD patients as compared with the control (135.6 [88.0–222.3] and 260.5 [217.3–301.9], p < 0.05). The TGT analysis in PRP has shown that in CAD patients, there was a decrease in the peak concentration of thrombin (PTh) and the rate of thrombin (VI) formation (100.5 [78.3–127.7] and 125.7 [118.7–161.5], nmol; 7.2 [4.7–11.1] and 14.9 [11.6–18.1], nmol/min, p < 0.01, respectively), and an increase in time parameters of the test. The number of patients with high platelet reactivity detected by T-TAS was higher than those detected by TGT (38.2% (n = 13) and 20.8% (n = 7), respectively). In the group of CAD patients correlation analysis revealed a relationship between an increase in VI with an increase in AUC10 according to T-TAS data (r = 0.37; p = 0.03). Thus, the study, T-TAS and TGT in PRP have shown their effectiveness in assessing the antithrombotic properties of ASA in CAD patients.
{"title":"Integral Tests of the Hemostasis System in Assessing the Efficiency of Acetylsalicylic Acid in Patients with Ischemic Heart Disease","authors":"O. S. Melnichnikova, I. A. Nazarova, O. V. Sirotkina, A. V. Panov, I. T. Abesadze, M. Z. Alugishvili, N. L. Lokhovinina, T. V. Vavilova","doi":"10.1134/S199075082201005X","DOIUrl":"10.1134/S199075082201005X","url":null,"abstract":"<p>Despite the fact that acetylsalicylic acid (ASA) is the “gold” standard for the prevention of cardiovascular complications in patients with coronary heart disease (CAD), some patients still have risks of atherothrombosis. In the present study, the antithrombotic effect of ASA in patients with CAD was assessed using integral hemostasis tests: the T-TAS system (Total Thrombus-formation Analysis System) and the thrombin generation test (TGT) in platelet-rich plasma (PRP). The study involved 34 patients with stable CAD (11 women, 23 men) and 33 people (15 women, 18 men) in the control group. Evaluation of the activity of thrombus formation by means of the T-TAS system revealed a significant decrease in the area under the curve (AUC10) in the group of CAD patients as compared with the control (135.6 [88.0–222.3] and 260.5 [217.3–301.9], <i>p</i> < 0.05). The TGT analysis in PRP has shown that in CAD patients, there was a decrease in the peak concentration of thrombin (PTh) and the rate of thrombin (VI) formation (100.5 [78.3–127.7] and 125.7 [118.7–161.5], nmol; 7.2 [4.7–11.1] and 14.9 [11.6–18.1], nmol/min, <i>p</i> < 0.01, respectively), and an increase in time parameters of the test. The number of patients with high platelet reactivity detected by T-TAS was higher than those detected by TGT (38.2% (<i>n</i> = 13) and 20.8% (<i>n</i> = 7), respectively). In the group of CAD patients correlation analysis revealed a relationship between an increase in VI with an increase in AUC10 according to T-TAS data (<i>r</i> = 0.37; <i>p</i> = 0.03). Thus, the study, T-TAS and TGT in PRP have shown their effectiveness in assessing the antithrombotic properties of ASA in CAD patients.</p>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 1","pages":"60 - 65"},"PeriodicalIF":0.6,"publicationDate":"2022-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4863059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Orexin and its receptors (OXR) are involved in the mechanisms of pathological craving for alcohol and psychoactive drugs. The orexin system is also involved in the mechanisms of non-chemical forms of addiction: binge eating and gambling. The aim of this study was to investigate the level of orexin receptor mRNA in the hypothalamus, hippocampus, and prefrontal cortex of rats prone to impulsivity in behavior in a model for studying the elements of gambling addiction (a variant of the Iowa Gambling Task test). Brain structures were isolated on the 22nd day of the experiment. The OX1R gene expression was higher in the hypothalamus by 122% and in the hippocampus—by 149% in rats preferring to receive a high reward, but with a low probability as compared with a group of animals that preferred a low level of reinforcement, but with a 100% probability. On the contrary, no significant changes were observed in the level of OX1R mRNA in the prefrontal cortex. The level of OX2R mRNA insignificantly changed in the hypothalamus, hippocampus, and prefrontal cortex of rats prone to impulsivity in behavior. The data obtained suggest involvement of OX1R in the hypothalamus and hippocampus in the mechanisms mediating impulsive behavior and the choice of the significance of positive reinforcement in terms of its varying strength and probability.
{"title":"Increase in the Level of Orexin Receptor 1 (OX1R) mRNA in the Brain Structures of Rats Prone to Impulsivity in Behavior","authors":"E. A. Sekste, A. A. Lebedev, E. R. Bychkov, M. I. Airapetov, K. E. Gramota, I. Yu. Tissen, P. D. Shabanov","doi":"10.1134/S1990750822010085","DOIUrl":"10.1134/S1990750822010085","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>Orexin and its receptors (OXR) are involved in the mechanisms of pathological craving for alcohol and psychoactive drugs. The orexin system is also involved in the mechanisms of non-chemical forms of addiction: binge eating and gambling. The aim of this study was to investigate the level of orexin receptor mRNA in the hypothalamus, hippocampus, and prefrontal cortex of rats prone to impulsivity in behavior in a model for studying the elements of gambling addiction (a variant of the Iowa Gambling Task test). Brain structures were isolated on the 22nd day of the experiment. The <i>OX1R</i> gene expression was higher in the hypothalamus by 122% and in the hippocampus—by 149% in rats preferring to receive a high reward, but with a low probability as compared with a group of animals that preferred a low level of reinforcement, but with a 100% probability. On the contrary, no significant changes were observed in the level of <i>OX1R</i> mRNA in the prefrontal cortex. The level of <i>OX2R</i> mRNA insignificantly changed in the hypothalamus, hippocampus, and prefrontal cortex of rats prone to impulsivity in behavior. The data obtained suggest involvement of <i>OX1R</i> in the hypothalamus and hippocampus in the mechanisms mediating impulsive behavior and the choice of the significance of positive reinforcement in terms of its varying strength and probability.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 1","pages":"38 - 44"},"PeriodicalIF":0.6,"publicationDate":"2022-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4863073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The content of amino acids, the sources of gasotransmitters and activities of enzymes involved in their metabolism have been studied in the placenta and amniotic fluid in full-term and complicated by preterm birth. Determination of amino acids was performed using an automatic analyzer and enzyme activities were assayed by means of specific spectrophotometric methods. The development of preterm birth was accompanied by notable changes in metabolism amino acids already in the second trimester of pregnancy. Differently directed correlations were found between the level of amino acids and the activity of the corresponding enzymes. The imbalance of amino acids in the fetoplacental system in preterm birth was accompanied by changes in the production of their low molecular weight derivatives—gasotransmitters (NO, CO, H2S), playing an important role in the regulation of numerous metabolic processes.
{"title":"Impairments in Metabolism of Amino Acids—Precursors of Gasotransmitters—in the Premature Birth","authors":"A. A. Mikhelson, T. N. Pogorelova, V. O. Gunko, A. A. Nikashina, N. V. Palieva","doi":"10.1134/S1990750822010061","DOIUrl":"10.1134/S1990750822010061","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>The content of amino acids, the sources of gasotransmitters and activities of enzymes involved in their metabolism have been studied in the placenta and amniotic fluid in full-term and complicated by preterm birth. Determination of amino acids was performed using an automatic analyzer and enzyme activities were assayed by means of specific spectrophotometric methods. The development of preterm birth was accompanied by notable changes in metabolism amino acids already in the second trimester of pregnancy. Differently directed correlations were found between the level of amino acids and the activity of the corresponding enzymes. The imbalance of amino acids in the fetoplacental system in preterm birth was accompanied by changes in the production of their low molecular weight derivatives—gasotransmitters (NO, CO, H<sub>2</sub>S), playing an important role in the regulation of numerous metabolic processes.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 1","pages":"54 - 59"},"PeriodicalIF":0.6,"publicationDate":"2022-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4567147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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