Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry最新文献

{"title":"The Influence of Pantogam and Atomoxetine on Attention Stability and Distribution of Dopamine D2 and GABAB Receptors in the Attention Deficit Mouse Model","authors":"G. I. Kovalev,&nbsp;N. A. Sukhorukova,&nbsp;E. V. Vasileva,&nbsp;E. A. Kondrakhin,&nbsp;R. M. Salimov","doi":"10.1134/S1990750822010048","DOIUrl":"10.1134/S1990750822010048","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>The closed enriched cross maze test was employed as a novel experimental model of the attention deficit disorder (ADD) for evaluation of the behavioral and neurochemical effects of the nootropic drug pantogam (100 mg/kg, intraperitoneally) and atomoxetine hydrochloride (3 mg/kg, intraperitoneally) administered subchronically to CD-1 outbred mice. Two subpopulations of rodents spontaneously diverging in attention to enriched compartments (ED-Low and ED-High), were estimated on the basis of time spent by the mice in the empty or enriched compartments. The ED-Low and ED-High mice did not differ in parameters associated with anxiety, exploratory efficacy, and locomotor activity. Subchronic administration of both drugs in selected doses produced a corrective effect on animal behavior manifested as selective increase in the ED-ratio values in the ED-Low subpopulation (<i>p</i> &lt; 0.05). The radioligand binding assays revealed differences in the distribution of dopamine D₂ and GABA_B receptors (<i>B</i>_max) in prefrontal cortex of control ED-Low and ED-High mice. In prefrontal cortex of ED-Low mice treatment with atomoxetine produced a decrease in the <i>B</i>_max values of D₂ receptors by 14%, while pantogam decreased the <i>B</i>_max values of D₂ receptors by 22% (<i>p</i> &lt; 0.05) and increased the <i>B</i>_max values for GABA_B receptor binding by 44%. Thus, subchronic administration of pantogam had a selective corrective effect on the behavior parameters and the density of the studied receptor subtypes in animals having had severe attention deficit in the test.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 1","pages":"30 - 37"},"PeriodicalIF":0.6,"publicationDate":"2022-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4863067","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}

{"title":"Antifungal Macrocycle Antibiotic Amphotericin B—Its Present and Future. Multidisciplinary Perspective for the Use in the Medical Practice","authors":"A. A. Baghirova,&nbsp;Kh. M. Kasumov","doi":"10.1134/S1990750822010024","DOIUrl":"10.1134/S1990750822010024","url":null,"abstract":"<div><div><h3>\u0000 <b>Abstract</b>—</h3><p>This review is devoted to a broad analysis of the results of studies of the effect of macrocyclic antifungal polyene antibiotic amphotericin B on cell membranes. A detailed study of polyenes has shown that some of them can have not only antifungal, but also antiviral and antitumor effects. Under conditions of global pandemic fungal pathology develops especially quickly and in this case leads to invasive aspergillosis, which contributes to the complication of coronavirus infection in the lungs and even secondary infection with invasive aspergillosis. The treatment of an invasive form of bronchopulmonary aspergillosis is directly related to the immunomodulatory and immunostimulating properties of the macrocyclic polyene drug amphotericin B. The article presents experimental data on the study of the biological activity and membrane properties of amphotericin B and the effect of its chemically modified derivatives, as well as liposomal forms of amphotericin B on viral, bacterial and fungal infections. The mechanism of action of amphotericin B and its analogues is based on their interaction with cellular and lipid membranes, followed by formation of ion channels of molecular size in the membranes. The importance of these studies is that polyenes are sensitive to membranes that contain sterols of a certain structure. The analysis showed that pathogenic fungal cells containing ergosterol were 10−100 times more sensitive to polyene antibiotics than host cell membranes containing cholesterol. The high sterol selectivity of the action of polyenes opens broad prospects for the use of polyene antifungal drugs in practical medicine and pharmacology in the treatment of invasive mycoses and the prevention of atherosclerosis. In this context, it should be noted that polyene antibiotics are the main tool in the study of the biochemical mechanism of changes in the permeability of cell membranes for energy-dependent substrates. Chemical and genetic engineering transformation of the structure of polyene antibiotic molecules opens prospects for the identification and creation of new biologically active forms of the antibiotic that have a high selectivity of action in the treatment of pathogenic infections.</p></div></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 1","pages":"1 - 12"},"PeriodicalIF":0.6,"publicationDate":"2022-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1134/S1990750822010024.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4567151","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}

{"title":"The Study of the Cerebrospinal Fluid Cytokine Profile in Children with Acute Lymphocytic Leukemia and Neurotoxic Side Effects of Chemotherapy","authors":"V. V. Bazarnyi,&nbsp;O. P. Kovtun,&nbsp;O. V. Koryakina,&nbsp;L. G. Polushina,&nbsp;A. Yu. Maksimova","doi":"10.1134/S1990750822010036","DOIUrl":"10.1134/S1990750822010036","url":null,"abstract":"<p>In some cases standard chemotherapy of acute lymphocytic leukemia (ALL) leads to neurotoxicity; its mechanisms, methods of prognosis, and prevention are being actively studied. The aim of this study was to assess the cerebrospinal fluid (CSF) cytokine profile in children with ALL and neurotoxic side effects of chemotherapy. This prospective study included 24 children with ALL aged from 3 to 17 years. Patients were further subdivided into ALL patients with (the main group) and without neurological complications (the comparison group). The level of CSF cytokines was measured by the Xmap technology (Luminex) using Invitrogen test systems (eBioscience) and the Luminex 200 system. The comparative analysis of the cytokine profile in the group of children with chemotherapy-induced neurotoxic complications revealed elevated levels of chemokine CXCL12 (SDF-1α) and stem cell factor (SCF). The increased level of these cytokines in CSF suggested a relatively risk for development of the toxic peripheral neuropathy.</p>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 1","pages":"74 - 77"},"PeriodicalIF":0.6,"publicationDate":"2022-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4569502","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}

{"title":"PCR Analysis of the Expression of Chromosome 18 Genes in Human Liver Tissue: Interindividual Variability","authors":"O. S. Timoshenko,&nbsp;S. A. Khmeleva,&nbsp;E. V. Poverennaya,&nbsp;Y. Y. Kiseleva,&nbsp;L. K. Kurbatov,&nbsp;S. P. Radko,&nbsp;I. V. Buromski,&nbsp;S. S. Markin,&nbsp;A. V. Lisitsa,&nbsp;A. I. Archakov,&nbsp;E. A. Ponomarenko","doi":"10.1134/S1990750822010097","DOIUrl":"10.1134/S1990750822010097","url":null,"abstract":"<p>Using human chromosome 18 (Ch18) genes as an example, a PCR analysis of the interindividual variability of expression of 244 genes was performed in the liver tissue. Although the quantitative profiles of the Ch18 transcriptome, expressed as the number of cDNA copies per single cell, showed a high degree of correlation between donors (Pearson correlation coefficient <i>r</i>_p ranged from 0.963 to 0.966), the expression of the significant number of genes (from 13% to 19%, depending on the method of experimental data normalization) varied by more than 4-fold when comparing donors pairwise. At the same time, the proportion of differentially expressed genes increased with a decrease in the level of their expression. It is shown that the higher quantitative variability of low-abundance transcripts has mainly biological rather than technical nature. Bioinformatic analysis of the interindividual variability of the differential expression of Ch18 genes in the human liver tissue did not reveal any statistically significant groups of genes related to certain biological processes. This obviously indicates a rather transient nature of the interindividual variability of Ch18 gene expression, probably reflecting the response of cells of an individual to specific external stimuli.</p>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"16 1","pages":"13 - 21"},"PeriodicalIF":0.6,"publicationDate":"2022-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4567759","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}

{"title":"Oxytocin Receptor Expression is Associated with Estrogen Receptor Status in Breast Tumors","authors":"T. S. Kalinina,&nbsp;V. V. Kononchuk,&nbsp;S. V. Sidorov,&nbsp;D. A. Obukhova,&nbsp;G. R. Abdullin,&nbsp;L. F. Gulyaeva","doi":"10.1134/S1990750821040065","DOIUrl":"10.1134/S1990750821040065","url":null,"abstract":"<div><p>The oxytocin receptor (OXTR) plays an important role in childbirth, breastfeeding, and social interactions. Increasing evidence exists that OXTR is associated with the breast cancer (BC) initiation and progression. However, the mechanisms leading to its altered expression, the diagnostic or prognostic values of this receptor in BC are currently poorly understood. Here, we have evaluated the relative level of OXTR expression in BC samples (<i>n</i> = 107), and also investigated the effect of estradiol on its expression in MCF-7 and MDA-MB-231 cells. The level of OXTR expression was significantly lower in breast tumor tissue than in normal tissue obtained from the same patient. The OXTR expression depended on the status and expression of the estrogen receptor (ER): the level of OXTR mRNA was significantly lower in ER-negative BC samples compared to ER-positive BC samples. OXTR expression was also lower in samples from patients with luminal subtype with a low value of ER expression (0–5 score according to the IHC assay, Allred scoring) compared with samples with high ER expression (6–8 score). In luminal BC, OXTR expression was associated with the HER2 expression level: the OXTR mRNA level was higher in tumors with the HER2 IHC score of 1+ as compared to cases with the HER2 expression score of 2+, 3+. We also showed that estradiol increased the level of OXTR mRNA in MCF-7 cells, but not in ER-negative MDA-MB-231 cells. The data obtained indicate that changes in OXTR expression in BC tissues can be induced by increased ER expression. We found no association between OXTR and T or N stages and progesterone receptor expression.</p></div>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"15 4","pages":"320 - 325"},"PeriodicalIF":0.6,"publicationDate":"2021-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4100855","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}

{"title":"Carnitine Chloride Reduces the Severity of Experimental Hyperhomocysteinemia and Promotes Lactate Utilization by the Mitochondrial Fraction of the Rat Epididymis","authors":"V. I. Zvyagina,&nbsp;E. S. Belskikh","doi":"10.1134/S1990750821040119","DOIUrl":"10.1134/S1990750821040119","url":null,"abstract":"<p>Hyperhomocysteinemia is a risk factor for many diseases, including reproductive disorders in men. L-carnitine is used in medical practice to correct impaired bioenergetic conditions; in patients with idiopathic forms of infertility its effects are associated with improvement of the sperm parameters. However, the effect of exogenous L-carnitine on the level of homocysteine in the gonadal tissues, as a risk factor for impaired fertility, has not been investigated yet. The aim of this study was to investigate activity of bioenergetic enzymes in the epididymal mitochondrial fraction, the dynamics of changes in the cytoplasmic and mitochondrial lactate levels and LDH activity, the total carnitine content, as well as the oxidative status of these cells under conditions of oxidative stress caused by hyperhomocysteinemia, and to assess the effect of carnitine chloride on these parameters under conditions of methionine administration to male Wistar rats. Methionine administration to animals for three weeks at a dose of 3 g/kg, resulted in development of the severe form of hyperhomocysteinemia with serum homocysteine concentrations exceeding 100 μmol/L. This was accompanied by a decrease in the activity of enzymes involved in the bioenergetic processes of the cell: tissue respiration (succinate dehydrogenase) and oxidative phosphorylation (H⁺-ATPase) in the epididymal head and tail. The change in lactate metabolism included an increase in its level in both the mitochondrial and cytoplasmic fractions of the epididymal head and mitochondria of the epididymal tail, and also simultaneous statistically significant decrease in LDH activity in the mitochondria and cytoplasm of the epididymal head. In male rats with severe hyperhomocysteinemia, an increase in the activity of mitochondrial SOD accompanied by an increase in the carbonylation of mitochondrial proteins in the head and tail of the epididymis was noted. Modeling of hyperhomocysteinemia under conditions of carnitine chloride administration led to different reactions of the cells of the studied tissues assayed in the epididymal head and tail homogenate. In the epididymal head, carnitine chloride promoted an increase in the mitochondrial lactate concentration and a decrease in the cytoplasmic lactate concentration, as well as an increase in the LDH activity associated with the mitochondrial fraction. These changes were accompanied by an increase in the activity of H⁺-ATPase in the epididymal, thus suggesting that carnitine chloride stimulated lactate transport into the mitochondria and its use as an energy substrate under conditions of oxidative stress caused by hyperhomocysteinemia. In the tail tissues, the changes were protective in nature and were associated with a decrease in the formation of oxidatively modified proteins.</p>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"15 4","pages":"326 - 336"},"PeriodicalIF":0.6,"publicationDate":"2021-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4099171","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}

{"title":"Peptide Inhibitors of the Interaction of the SARS-CoV-2 Receptor-Binding Domain with the ACE2 Cell Receptor","authors":"R. Sh. Bibilashvili,&nbsp;M. V. Sidorova,&nbsp;U. S. Dudkina,&nbsp;M. E. Palkeeva,&nbsp;A. S. Molokoedov,&nbsp;L. I. Kozlovskaya,&nbsp;A. M. Egorov,&nbsp;A. A. Ishmukhametov,&nbsp;E.V. Parfyonova","doi":"10.1134/S199075082104003X","DOIUrl":"10.1134/S199075082104003X","url":null,"abstract":"<p>Computer simulation has been used to identify peptides that mimic the natural target of the SARS-CoV-2 coronavirus spike (S) protein, the angiotensin-converting enzyme type 2 (ACE2) cell receptor. Based on the structure of the complex of the protein S receptor-binding domain (RBD) and ACE2, the design of chimeric molecules consisting of two 22–23-mer peptides linked to each other by disulfide bonds was carried out. The chimeric molecule X1 was a disulfide dimer, in which terminal cysteine residues in the precursor molecules h1 and h2 were connected by the S-S bond. In the chimeric molecule X2, the disulfide bond was located in the middle of each precursor peptide molecule. The precursors h1 and h2 mimic amino acid sequences of α1- and α2-helices of the ACE2 extracellular peptidase domain, respectively, keeping intact most of the amino acid residues involved in the interaction with RBD. The aim of the work was to evaluate the binding efficiency of chimeric molecules and their constituent peptides with RBD (particularly in dependence of the middle and terminal methods of fixing the initial peptides h1 and h2). The proposed polypeptides and chimeric molecules were synthesized by chemical methods, purified to 95–97% purity, and characterized by HPLC and MALDI-TOF mass spectrometry. Binding of these peptides to the SARS-CoV-2 RBD was evaluated by microthermophoresis with recombinant domains corresponding in sequence to the original Chinese (GenBank ID NC_045512.2) and the British (B. 1.1.7, GISAID EPI_ISL_683466) variants. The original RBD of the Chinese variant bound to three synthesized peptides: linear h2 and both chimeric variants. Chimeric peptides were also bound to the RBD of the British variant. The antiviral activity of the proposed peptides was evaluated in Vero cell line.</p>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"15 4","pages":"274 - 280"},"PeriodicalIF":0.6,"publicationDate":"2021-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1134/S199075082104003X.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4100554","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}

{"title":"TLR3 Induction During Long-Term Alcoholization Increases the Content of Rat Brain Interferons by TRAIL Signaling","authors":"M. I. Airapetov,&nbsp;S. O. Eresko,&nbsp;A. K. Vasiliev,&nbsp;V. Y. Vasilieva,&nbsp;E. R. Bychkov,&nbsp;A. A. Lebedev,&nbsp;P. D. Shabanov","doi":"10.1134/S1990750821040028","DOIUrl":"10.1134/S1990750821040028","url":null,"abstract":"<p>The pathogenetic mechanisms associated with alcohol use include dysregulation of the innate immune system mechanisms in the brain. Increased TLR3 expression was found in the postmortem material of the prefrontal cortex of humans. An increase in the TLR3 signaling activity leads to the induction of interferons (IFNs). IFNs are associated with depressive symptoms and, therefore, may play a role in the pathogenesis of alcoholism; however, the exact mechanisms of the ethanol effects on intracellular signaling pathways are not fully elucidated and their study was the purpose of this work. The experimental results showed that ethanol and the TLR3 agonist Poly (I:C) increased the content of TLR3, IFNβ, and IFNγ mRNA in the prefrontal cortex. In addition, expression of the <i>TRAIL</i> encoding gene also increased, and this increase positively correlated with the mRNA content of TLR3, IFNβ and IFNγ both under alcoholization conditions and after injections of the TLR3 agonist. The data obtained may indicate that alcoholization is able to activate TLR3-TRAIL-IFN-signaling in the medial prefrontal cortex (mPFC) of the rat brain.</p>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"15 4","pages":"306 - 312"},"PeriodicalIF":0.6,"publicationDate":"2021-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4099791","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}

{"title":"A Possible Mechanism of the Antioxidant Action of Dinitrosyl Iron Complexes","authors":"K. B. Shumaev,&nbsp;O. V. Kosmachevskaya,&nbsp;D. I. Grachev,&nbsp;A. A. Timoshin,&nbsp;A. F. Topunov,&nbsp;V. Z. Lankin,&nbsp;E. K. Ruuge","doi":"10.1134/S1990750821040090","DOIUrl":"10.1134/S1990750821040090","url":null,"abstract":"<p>The antioxidant effect of dinitrosyl iron complexes (DNICs) was studied in various model systems. DNICs with glutathione ligand (DNIC-GS) effectively inhibited Cu²⁺-induced peroxidation of low density lipoproteins (LDL). The antioxidant effect of DNICs with phosphate ligands and free reduced glutathione (GSH) was less pronounced. In addition, DNIC-GS suppressed reactive oxygen species (ROS) formation during co-oxidation of lecithin liposomes and glucose. Free radical oxidation in this system was induced with a lipophilic azo initiator (AIBN) and evaluated by luminol-dependent chemiluminescence. NO sharply stimulated chemiluminescence during co-oxidation of glucose and liposomes, thus suggesting the formation of potent oxidants under these conditions. DNIC-GS scavenged the superoxide radical anion generated in the xanthine-xanthine oxidase system. Superoxide production was assessed by lucigenin-dependent chemiluminescence and electron paramagnetic resonance (EPR) spectroscopy. Chemiluminescence revealed the dose-dependent mode of the antiradical effect DNIC-GS; moreover, these complexes were more efficient than GSH. EPR spectra of adducts of the DEPMPO spin trap with free radicals suggest that the interaction of DNIC-GS and superoxide does not result in the formation of the thiyl radical of glutathione. Here we propose a mechanism of the antioxidant action of DNIC-GS, suggesting that unstable intermediate complexes are formed upon their interaction with superoxide or lipid radicals. After subsequent intramolecular rearrangement, these intermediates decompose without the free radical formation as the by-products.</p>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"15 4","pages":"313 - 319"},"PeriodicalIF":0.6,"publicationDate":"2021-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4100861","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}

{"title":"Master Regulators Associated with Poor Prognosis in Glioblastoma Multiforme","authors":"M. Kalya,&nbsp;T. Beißbarth,&nbsp;A. E. Kel","doi":"10.1134/S1990750821040077","DOIUrl":"10.1134/S1990750821040077","url":null,"abstract":"<p>Glioblastoma multiforme is a highly malignant brain tumor with average survival time of 15 months. Less than 2% of the patients survive beyond 36 months. To understand the molecular mechanism responsible for poor prognosis, we analyzed GBM samples of TCGA microarray (<i>n</i> = 560) data. We identified 720 genes that have a significant impact upon survival based on univariate cox regression. We applied the Genome Enhancer pipeline to analyze potential mechanisms of regulation of activity of these genes and to build gene regulatory networks. We identified 12 transcription factors enriched in the promoters of these genes including the key molecule of GBM<i>—STAT3</i>. We found that <i>STAT3</i> has significant differential expression across extreme survivor groups (short-term survivors– survival &lt; 12 months and long-term survivors—survival &gt; 36 months) and also has significant impact on survival. In the next step, we identified master regulators in the signal transduction network that regulate the activity of these transcription factors. Master regulators are filtered based on their differential expression across extreme survivor groups and impact on survival. This work validates our earlier report on master regulators <i>IGFBP2</i>, <i>PDGFA</i>, <i>OSMR</i> and <i>AEBP1</i> driving short survival. Additionally, we propose <i>CD14</i>, <i>CD44</i>, <i>DUSP6</i>, <i>GRB10</i>, <i>IL1RAP</i>, <i>FGFR3</i> and <i>POSTN</i> as master regulators driving poor survival. These master regulators are proposed as promising therapeutic targets to counter poor prognosis in GBM. Finally, the algorithm has prioritized several drugs for the further study as potential remedies to conquer the aggressive forms of GBM and to extend survival of the patients.</p>","PeriodicalId":485,"journal":{"name":"Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry","volume":"15 4","pages":"263 - 273"},"PeriodicalIF":0.6,"publicationDate":"2021-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4100878","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}