Pub Date : 2022-08-15DOI: 10.1134/S1990750822030052
A. T. Eprintsev, I. R. Bondareva, N. V. Selivanova
Abstract—
A significant decrease in the activity of liver lactate dehydrogenase (LDH, EC 1.1.1.27) associated with a decrease in the expression of the corresponding genes was found in rats with alloxan-induced diabetes. The decrease in the LDH activity was due to the cytoplasmic isoform of this enzyme. It was found that the level of ldha and ldhb gene transcripts in the liver of healthy rats was higher than in animals with alloxan diabetes. The ldha gene expression demonstrated almost 9-fold decrease, while a decrease in the ldhb gene expression was less pronounced (just 1.25-fold). Our data indicate an important role of LDH in the adaptive response of cellular metabolism in the development of type I diabetes mellitus.
{"title":"Expression Levels and Activity of Rat Liver Lactate Dehydrogenase Isoenzymes in Alloxan Diabetes","authors":"A. T. Eprintsev, I. R. Bondareva, N. V. Selivanova","doi":"10.1134/S1990750822030052","DOIUrl":"10.1134/S1990750822030052","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>A significant decrease in the activity of liver lactate dehydrogenase (LDH, EC 1.1.1.27) associated with a decrease in the expression of the corresponding genes was found in rats with alloxan-induced diabetes. The decrease in the LDH activity was due to the cytoplasmic isoform of this enzyme. It was found that the level of <i>ldha</i> and <i>ldhb</i> gene transcripts in the liver of healthy rats was higher than in animals with alloxan diabetes. The <i>ldha</i> gene expression demonstrated almost 9-fold decrease, while a decrease in the <i>ldhb</i> gene expression was less pronounced (just 1.25-fold). Our data indicate an important role of LDH in the adaptive response of cellular metabolism in the development of type I diabetes mellitus.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 3","pages":"210 - 215"},"PeriodicalIF":0.6,"publicationDate":"2022-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4598373","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}
Pub Date : 2022-08-15DOI: 10.1134/S1990750822030076
A. E. Kostyunin, T. V. Glushkova, D. K. Shishkova, V. E. Markova, E. A. Ovcharenko
Abstract—
Bioprosthetic heart valves (BHVs) have lower thrombogenicity rates and excellent hemodynamic parameters similar to native valves. However, the lifespan of these medical devices is limited to 15 years due to the structural valve degeneration (SVD). One of the mechanisms underlying functional impairment and calcification of BHVs includes proteolytic degradation of biomaterials. However, proteases found in xenogeneic tissue of BHVs remain poorly studied. In this study using the dot blot assay, we have performed a screening analysis of proteolytic enzymes and their inhibitors in the leaflets of five BHVs explanted due to dysfunction. Five aortic valves (AVs) explanted due to calcific aortic valve disease were used as a comparison group. The results of the study have demonstrated the presence of at least 17 proteases and 19 of their inhibitors in BHVs. In the AVs 20 proteases and 21 of their inhibitors were identified. Small quantitative differences were found between proteomic profiles of BHVs and AVs. Matrix metalloproteinases (MMPs) were expressed in BHVs and AVs at comparable levels, but the level of tissue inhibitors of metalloproteinases-1/-2 and reversion-inducing-cysteine-rich protein with Kazal motifs in implant tissues was lower than in native valves. This suggests that excessive activity of MMPs cannot be counterbalanced by their specific inhibitors in BHVs and therefore MMPs initiate the process of degeneration. Moreover, the detection of a wide range of proteolytic enzymes and their inhibitors in the degenerated BHVs suggests the existence of several pathophysiological pathways that can lead to SVD.
{"title":"Screening Analysis of Proteolytic Enzymes and Their Inhibitors in the Leaflets of Epoxy-Treated Bioprosthetic Heart Valves Explanted due to Dysfunction","authors":"A. E. Kostyunin, T. V. Glushkova, D. K. Shishkova, V. E. Markova, E. A. Ovcharenko","doi":"10.1134/S1990750822030076","DOIUrl":"10.1134/S1990750822030076","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>Bioprosthetic heart valves (BHVs) have lower thrombogenicity rates and excellent hemodynamic parameters similar to native valves. However, the lifespan of these medical devices is limited to 15 years due to the structural valve degeneration (SVD). One of the mechanisms underlying functional impairment and calcification of BHVs includes proteolytic degradation of biomaterials. However, proteases found in xenogeneic tissue of BHVs remain poorly studied. In this study using the dot blot assay, we have performed a screening analysis of proteolytic enzymes and their inhibitors in the leaflets of five BHVs explanted due to dysfunction. Five aortic valves (AVs) explanted due to calcific aortic valve disease were used as a comparison group. The results of the study have demonstrated the presence of at least 17 proteases and 19 of their inhibitors in BHVs. In the AVs 20 proteases and 21 of their inhibitors were identified. Small quantitative differences were found between proteomic profiles of BHVs and AVs. Matrix metalloproteinases (MMPs) were expressed in BHVs and AVs at comparable levels, but the level of tissue inhibitors of metalloproteinases-1/-2 and reversion-inducing-cysteine-rich protein with Kazal motifs in implant tissues was lower than in native valves. This suggests that excessive activity of MMPs cannot be counterbalanced by their specific inhibitors in BHVs and therefore MMPs initiate the process of degeneration. Moreover, the detection of a wide range of proteolytic enzymes and their inhibitors in the degenerated BHVs suggests the existence of several pathophysiological pathways that can lead to SVD.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 3","pages":"264 - 270"},"PeriodicalIF":0.6,"publicationDate":"2022-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4599395","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}
Pub Date : 2022-08-15DOI: 10.1134/S199075082203009X
J. U. Panada, V. A. Klopava, T. A. Kulahava, Y. V. Faletrov, N. S. Frolova, S. V. Koran, E. G. Fomina, V. M. Shkumatov
Abstract—
The effect of the synthesized N-alkynyl-17-aminosteroids and N-alkynyl-20-aminosteroids (based on dehydroepiandrosterone and pregnenolone, respectively) on C6 rat glioma cell functions has been investigated. At 10 μM, the compounds had an insignificant effect on C6 glioma mitochondrial membrane potential, but increased cell autophagy by 70–90%; this effect was comparable to the known autophagy inducer dexamethasone. Docking simulations predict a potential high-affinity interaction between N-alkynylaminosteroids and Keap1 and the Hedgehog pathway protein, Smoothened, which are involved in autophagy regulation. The possible mechanisms of observed processes are discussed.
{"title":"Influence of N-Alkynylaminosteroids on Mitochondrial Functioning and Autophagy in Glioma Cells","authors":"J. U. Panada, V. A. Klopava, T. A. Kulahava, Y. V. Faletrov, N. S. Frolova, S. V. Koran, E. G. Fomina, V. M. Shkumatov","doi":"10.1134/S199075082203009X","DOIUrl":"10.1134/S199075082203009X","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>The effect of the synthesized <i>N</i>-alkynyl-17-aminosteroids and <i>N</i>-alkynyl-20-aminosteroids (based on dehydroepiandrosterone and pregnenolone, respectively) on C6 rat glioma cell functions has been investigated. At 10 μM, the compounds had an insignificant effect on C6 glioma mitochondrial membrane potential, but increased cell autophagy by 70–90%; this effect was comparable to the known autophagy inducer dexamethasone. Docking simulations predict a potential high-affinity interaction between <i>N</i>-alkynylaminosteroids and Keap1 and the Hedgehog pathway protein, Smoothened, which are involved in autophagy regulation. The possible mechanisms of observed processes are discussed.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 3","pages":"246 - 252"},"PeriodicalIF":0.6,"publicationDate":"2022-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4598376","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}
Pub Date : 2022-08-15DOI: 10.1134/S1990750822030039
V. G. Blinova, Y. A. Gladilina, D. D. Eliseeva, T. A. Lobaeva, D. D. Zhdanov
Abstract—
Regulatory T cells CD4+CD25+FoxP3+СD127low (Tregs) play a key role in the maintenance of tolerance to autoantigens, inhibit the function of effector T and B lymphocytes, and provide a balance between effector and regulatory arms of immunity. Patients with autoimmune diseases are characterized by decreased Treg numbers and impaired suppressive activity. Replacement therapy with autologous Tregs transformed ex vivo could restore the destroyed balance of the immune system. We developed a method for the cultivation of Treg precursor cells. Using this method, we were able to grow up to 300−400 million Treg cells from 50 mL of peripheral blood during a week. In this study, we demonstrated that 90−95% of ex vivo-transformed Tregs had the phenotype CD4+CD25+FoxP3+СD127low and increased the transcription of the FoxP3 and Helios genes. Ex vivo-transformed Tregs were characterized by increased demethylation of the FoxP3 promoter and activation of the proliferation gene markers cyclin B1, Ki67 and LGALS 1. Ex vivo-transformed Tregs had increased suppressive activity, and up to 80–90% of these cells secreted the cytokines TNFα and IFNγ. Our data suggest that ex vivo-transformed autologous Tregs have genetic, immunophenotypic and functional characteristics of regulatory T cells. In the future, they can be used for adoptive immunotherapy of autoimmune diseases and inhibition of transplantation immunity.
{"title":"Increased Suppressor Activity of Ex Vivo Transformed Regulatory T Cells in Comparison with Unstimulated Cells of the Same Donor","authors":"V. G. Blinova, Y. A. Gladilina, D. D. Eliseeva, T. A. Lobaeva, D. D. Zhdanov","doi":"10.1134/S1990750822030039","DOIUrl":"10.1134/S1990750822030039","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>Regulatory T cells CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup>СD127<sup>low</sup> (Tregs) play a key role in the maintenance of tolerance to autoantigens, inhibit the function of effector T and B lymphocytes, and provide a balance between effector and regulatory arms of immunity. Patients with autoimmune diseases are characterized by decreased Treg numbers and impaired suppressive activity. Replacement therapy with autologous Tregs transformed ex vivo could restore the destroyed balance of the immune system. We developed a method for the cultivation of Treg precursor cells. Using this method, we were able to grow up to 300−400 million Treg cells from 50 mL of peripheral blood during a week. In this study, we demonstrated that 90−95% of ex vivo-transformed Tregs had the phenotype CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup>СD127<sup>low</sup> and increased the transcription of the <i>FoxP3</i> and <i>Helios</i> genes. Ex vivo-transformed Tregs were characterized by increased demethylation of the <i>FoxP3</i> promoter and activation of the proliferation gene markers cyclin B1, Ki67 and LGALS 1. Ex vivo-transformed Tregs had increased suppressive activity, and up to 80–90% of these cells secreted the cytokines TNFα and IFNγ. Our data suggest that ex vivo-transformed autologous Tregs have genetic, immunophenotypic and functional characteristics of regulatory T cells. In the future, they can be used for adoptive immunotherapy of autoimmune diseases and inhibition of transplantation immunity.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 3","pages":"225 - 237"},"PeriodicalIF":0.6,"publicationDate":"2022-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4600437","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}
Pub Date : 2022-08-15DOI: 10.1134/S1990750822030088
G. E. Morozevich, N. I. Kozlova, N. M. Gevorkian, A. E. Berman
Abstract—
Using a model of the human SK-Mel-147 melanoma cell line, it was shown that blocking the expression of integrin α3β1 by transduction of cells with α3-specific shRNA did not affect their proliferation, but sharply increased the proportion of SA-β-Gal-positive cells, a phenotypic feature of cell senescence. These changes were accompanied by a significant increase in the activity of the Akt and mTOR protein kinases and the expression of p53 and p21 oncosupressors. The pharmacological inhibition of mTORC1 reduced the number SA-β-Gal-positive cells in the SK-Mel-147 cell population depleted of α3β1. Based on our recent data on a non-canonical function of Akt isoforms in the regulation of SK-Mel-147 cell senescence caused by α2β1 receptor deficiency, we have investigated the role of Akt isoforms in senescence induced by the α3β1 knockdown. It appeared that in the cell population with downregulated α3β1, inhibition of Akt1 reduced the number SA-β-Gal positive cells to the level of control cell population, while inhibition of Akt2 had no visible effect. Our results demonstrate that: (i) the laminin-specific integrin α3β1, like the collagen-specific receptor α2β1, is involved in tumor cell protection from senescence; (ii) senescence induced by α3β1 suppression is based on a signaling mechanism employing a non-canonical function of the Akt1 isoform.
{"title":"The Integrin α3β1 Signaling in the Regulation of the SK-Mel-147 Melanoma Cell Senescence","authors":"G. E. Morozevich, N. I. Kozlova, N. M. Gevorkian, A. E. Berman","doi":"10.1134/S1990750822030088","DOIUrl":"10.1134/S1990750822030088","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>Using a model of the human SK-Mel-147 melanoma cell line, it was shown that blocking the expression of integrin α3β1 by transduction of cells with α3-specific shRNA did not affect their proliferation, but sharply increased the proportion of SA-β-Gal-positive cells, a phenotypic feature of cell senescence. These changes were accompanied by a significant increase in the activity of the Akt and mTOR protein kinases and the expression of p53 and p21 oncosupressors. The pharmacological inhibition of mTORC1 reduced the number SA-β-Gal-positive cells in the SK-Mel-147 cell population depleted of α3β1. Based on our recent data on a non-canonical function of Akt isoforms in the regulation of SK-Mel-147 cell senescence caused by α2β1 receptor deficiency, we have investigated the role of Akt isoforms in senescence induced by the α3β1 knockdown. It appeared that in the cell population with downregulated α3β1, inhibition of Akt1 reduced the number SA-β-Gal positive cells to the level of control cell population, while inhibition of Akt2 had no visible effect. Our results demonstrate that: (i) the laminin-specific integrin α3β1, like the collagen-specific receptor α2β1, is involved in tumor cell protection from senescence; (ii) senescence induced by α3β1 suppression is based on a signaling mechanism employing a non-canonical function of the Akt1 isoform.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 3","pages":"187 - 194"},"PeriodicalIF":0.6,"publicationDate":"2022-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4890434","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}
Pub Date : 2022-05-17DOI: 10.1134/S1990750822020056
T. A. Gureeva, O. S. Timoshenko, E. V. Kugaevskaya, N. I. Solovyova
Abstract—
Cysteine cathepsins (Cts) also known as thiol proteinases belong to the superfamily of cysteine proteinases. Most Cts are endopeptidases; some of them exhibit exopeptidase activity. All Cts are synthesized as zymogens and activation of most of them occurs autocatalytically. Ct activity depends on pH and it is regulated by endogenous inhibitors. Although the major role of Cts consists in lysosomal degradation of cell proteins these enzymes are also detected in the nucleus, cytoplasm, plasma membrane, and in the extracellular medium. The latter is especially important in the case of certain pathological including cancer. Extracellular Cts not only hydrolyze extracellular matrix (ECM) proteins, but also contribute to ECM remodeling via specific processing of various proteins including cytokines, chemokines, cell adhesion molecules. Normally, expression and activity of Cts are very low and these enzymes are mainly detected inside cells. In cancer, the expression and activity of Cts sharply increase both in cell lysosomes and in the intercellular space and this promotes neoplastic transformation, invasion, metastasis and leads to further tumor progression. It has been shown that Cts expression depends on the cells type, and therefore, their role in the tumor development differs in dependence of their cellular origin. However, the mechanism of Cts action is not limited only by their proteolytic degradation of ECM proteins. Cts play an important role in processing of proteins involved in oncogenic cell signaling. For example, Cts participation in processing of growth factors is mediated through receptor tyrosine kinases (RTK) and various signaling mitogen-activated protein kinases (MAPK), which are involved in regulation of such cell processes as gene transcription, apoptosis, proliferation, and cell migration capacity. In addition, Cts also promote the epithelial-mesenchymal transition (EMT) by activating TGF-β signaling, which is considered as one of the key signaling pathways in this process.
{"title":"Cysteine Cathepsins: Structure, Physiological Functions, and the Role in Carcinogenesis","authors":"T. A. Gureeva, O. S. Timoshenko, E. V. Kugaevskaya, N. I. Solovyova","doi":"10.1134/S1990750822020056","DOIUrl":"10.1134/S1990750822020056","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>Cysteine cathepsins (Cts) also known as thiol proteinases belong to the superfamily of cysteine proteinases. Most Cts are endopeptidases; some of them exhibit exopeptidase activity. All Cts are synthesized as zymogens and activation of most of them occurs autocatalytically. Ct activity depends on pH and it is regulated by endogenous inhibitors. Although the major role of Cts consists in lysosomal degradation of cell proteins these enzymes are also detected in the nucleus, cytoplasm, plasma membrane, and in the extracellular medium. The latter is especially important in the case of certain pathological including cancer. Extracellular Cts not only hydrolyze extracellular matrix (ECM) proteins, but also contribute to ECM remodeling via specific processing of various proteins including cytokines, chemokines, cell adhesion molecules. Normally, expression and activity of Cts are very low and these enzymes are mainly detected inside cells. In cancer, the expression and activity of Cts sharply increase both in cell lysosomes and in the intercellular space and this promotes neoplastic transformation, invasion, metastasis and leads to further tumor progression. It has been shown that Cts expression depends on the cells type, and therefore, their role in the tumor development differs in dependence of their cellular origin. However, the mechanism of Cts action is not limited only by their proteolytic degradation of ECM proteins. Cts play an important role in processing of proteins involved in oncogenic cell signaling. For example, Cts participation in processing of growth factors is mediated through receptor tyrosine kinases (RTK) and various signaling mitogen-activated protein kinases (MAPK), which are involved in regulation of such cell processes as gene transcription, apoptosis, proliferation, and cell migration capacity. In addition, Cts also promote the epithelial-mesenchymal transition (EMT) by activating TGF-β signaling, which is considered as one of the key signaling pathways in this process.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 2","pages":"91 - 103"},"PeriodicalIF":0.6,"publicationDate":"2022-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4696598","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}
Pub Date : 2022-05-17DOI: 10.1134/S1990750822020068
V. V. Salmin, A. V. Morgun, R. Ya. Olovyannikova, V. A. Kutyakov, E. V. Lychkovskaya, E. B. Brusina, A. B. Salmina
Abstract—
The review summarizes literature data on molecular and biochemical mechanisms of nonspecific protection of respiratory epithelium. The special attention is paid to comprehensive analysis of up-to-date data on the activity of the lactoperoxidase system expressed on the surface of the respiratory epithelium which provides the generation of hypothiocyanate and hypoiodite in the presence of locally produced or inhaled hydrogen peroxide. Molecular mechanisms of production of active compounds with antiviral and antibacterial effects, expression profiles of enzymes, transporters and ion channels involved in the generation of hypothiocyanite and hypoiodite in the mucous membrane of the respiratory system in physiological and pathological conditions (inflammation) are discussed. A hypothesis about the effect of atmospheric air composition on the efficiency of hypothiocyanate and hypoiodite generation in the respiratory epithelium in the context of its antibacterial and antiviral protection is presented. The causes and consequences of insufficiency of the lactoperoxidase system caused by the action of atmospheric factors are discussed in the context of controlling the sensitivity of the epithelium to the action of bacterial agents and viruses. Good evidence exists that restoration of the lactoperoxidase system activity can be achieved by application of pharmacological agents aimed to compensate for the deficit of halides in tissues, and by the control of chemical composition of the inhaled air.
{"title":"Atmospheric Reactive Oxygen Species and Some Aspects of the Antiviral Protection at the Respiratory Epithelium","authors":"V. V. Salmin, A. V. Morgun, R. Ya. Olovyannikova, V. A. Kutyakov, E. V. Lychkovskaya, E. B. Brusina, A. B. Salmina","doi":"10.1134/S1990750822020068","DOIUrl":"10.1134/S1990750822020068","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>The review summarizes literature data on molecular and biochemical mechanisms of nonspecific protection of respiratory epithelium. The special attention is paid to comprehensive analysis of up-to-date data on the activity of the lactoperoxidase system expressed on the surface of the respiratory epithelium which provides the generation of hypothiocyanate and hypoiodite in the presence of locally produced or inhaled hydrogen peroxide. Molecular mechanisms of production of active compounds with antiviral and antibacterial effects, expression profiles of enzymes, transporters and ion channels involved in the generation of hypothiocyanite and hypoiodite in the mucous membrane of the respiratory system in physiological and pathological conditions (inflammation) are discussed. A hypothesis about the effect of atmospheric air composition on the efficiency of hypothiocyanate and hypoiodite generation in the respiratory epithelium in the context of its antibacterial and antiviral protection is presented. The causes and consequences of insufficiency of the lactoperoxidase system caused by the action of atmospheric factors are discussed in the context of controlling the sensitivity of the epithelium to the action of bacterial agents and viruses. Good evidence exists that restoration of the lactoperoxidase system activity can be achieved by application of pharmacological agents aimed to compensate for the deficit of halides in tissues, and by the control of chemical composition of the inhaled air.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 2","pages":"79 - 90"},"PeriodicalIF":0.6,"publicationDate":"2022-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1134/S1990750822020068.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4693756","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}
Pub Date : 2022-05-17DOI: 10.1134/S1990750822020020
Y. V. Abalenikhina, E. A. Sudakova, A. A. Seidkulieva, A. V. Shchulkin, E. N. Yakusheva
Abstract—
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}
Pub Date : 2022-05-17DOI: 10.1134/S1990750822020093
Yu. A. Tereshkina, T. I. Torkhovskaya, M. A. Sanzhakov, L. V. Kostryukova, Yu. Yu. Khudoklinova, E. G. Tikhonova
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}
Pub Date : 2022-05-17DOI: 10.1134/S1990750822020032
M. I. Airapetov, S. O. Eresko, E. R. Bychkov, A. A. Lebedev, P. D. Shabanov
Abstract—
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}
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