scholarly journals Integrated analyses of early responses to radiation in glioblastoma identify new alterations in RNA processing and candidate targets to improve treatment outcomes

2020 ◽  
Author(s):  
Saket Choudhary ◽  
Suzanne Burns ◽  
Hoda Mirsafian ◽  
Whenzheng LI ◽  
Dat Vo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Early Response ◽  
Radiation Sensitivity ◽  
Integrated Analysis ◽  
High Dose ◽  
Transcriptional Level ◽  
Altered Expression ◽  
Improve Treatment ◽  
Expression Of Genes ◽  
Main Component

Abstract BackgroundHigh-dose radiation is the main component of glioblastoma therapy. Unfortunately, radio-resistance is a common problem and a major contributor to tumor relapse. Understanding the molecular mechanisms driving response to radiation is critical for identifying regulatory routes that could be targeted to improve treatment response. Methods: We conducted an integrated analysis in the U251 and U343 glioblastoma cell lines to map early alterations in the expression of genes at three levels: transcription, splicing, and translation in response to ionizing radiation. ResultsChanges at the transcriptional level were the most prevalent response. Downregulated genes are strongly associated with cell cycle and DNA replication and linked to a coordinated module of expression. Alterations in this group are likely driven by decreased expression of the transcription factor FOXM1 and members of the E2F family. Genes involved in RNA regulatory mechanisms were affected at the mRNA, splicing, and translation levels, highlighting their importance in radiation-response. We identified a number of oncogenic factors, with an increased expression upon radiation exposure, including BCL6, RRM2B, IDO1, FTH1, APIP, and LRIG2 and lncRNAs NEAT1 and FTX. Several of these targets have been previously implicated in radio- resistance. Therefore, antagonizing their effects post-radiation could increase therapeutic efficacy. ConclusionsOur integrated analysis provides a comprehensive view of early response to radiation in glioblastoma. We identify new biological processes involved in altered expression of various oncogenic factors and suggest new target options to increase radiation sensitivity and prevent relapse.

scholarly journals Genomic analyses of early responses to radiation in glioblastoma reveal new alterations at transcription, splicing, and translation levels

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Saket Choudhary ◽  
Suzanne C. Burns ◽  
Hoda Mirsafian ◽  
Wenzheng Li ◽  
Dat T. Vo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Early Response ◽  
Radiation Sensitivity ◽  
Integrated Analysis ◽  
High Dose ◽  
Transcriptional Level ◽  
Altered Expression ◽  
Expression Of Genes ◽  
Post Radiation ◽  
Main Component

Abstract High-dose radiation is the main component of glioblastoma therapy. Unfortunately, radio-resistance is a common problem and a major contributor to tumor relapse. Understanding the molecular mechanisms driving response to radiation is critical for identifying regulatory routes that could be targeted to improve treatment response. We conducted an integrated analysis in the U251 and U343 glioblastoma cell lines to map early alterations in the expression of genes at three levels: transcription, splicing, and translation in response to ionizing radiation. Changes at the transcriptional level were the most prevalent response. Downregulated genes are strongly associated with cell cycle and DNA replication and linked to a coordinated module of expression. Alterations in this group are likely driven by decreased expression of the transcription factor FOXM1 and members of the E2F family. Genes involved in RNA regulatory mechanisms were affected at the mRNA, splicing, and translation levels, highlighting their importance in radiation-response. We identified a number of oncogenic factors, with an increased expression upon radiation exposure, including BCL6, RRM2B, IDO1, FTH1, APIP, and LRIG2 and lncRNAs NEAT1 and FTX. Several of these targets have been previously implicated in radio-resistance. Therefore, antagonizing their effects post-radiation could increase therapeutic efficacy. Our integrated analysis provides a comprehensive view of early response to radiation in glioblastoma. We identify new biological processes involved in altered expression of various oncogenic factors and suggest new target options to increase radiation sensitivity and prevent relapse.

scholarly journals Integrated analyses of early responses to radiation in glioblastoma identify new alterations in RNA processing and candidate target genes to improve treatment outcomes

2019 ◽  
Author(s):  
Saket Choudhary ◽  
Suzanne C. Burns ◽  
Hoda Mirsafian ◽  
Wenzheng Li ◽  
Dat T. Vo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Early Response ◽  
Radiation Sensitivity ◽  
Integrated Analysis ◽  
High Dose ◽  
Transcriptional Level ◽  
Altered Expression ◽  
Improve Treatment ◽  
Main Component

AbstractBackgroundHigh-dose radiation is the main component of glioblastoma therapy. Unfortunately, radio-resistance is a common problem and a major contributor to tumor relapse. Understanding the molecular mechanisms driving response to radiation is critical for identifying regulatory routes that could be targeted to improve treatment response.MethodsWe conducted an integrated analysis in the U251 and U343 glioblastoma cell lines to map early alterations in the expression of genes at three levels: transcription, splicing, and translation in response to ionizing radiation.ResultsChanges at the transcriptional level were the most prevalent response. Downregulated genes are strongly associated with cell cycle and DNA replication and linked to a coordinated module of expression. Alterations in this group are likely driven by decreased expression of the transcription factor FOXM1 and members of the E2F family. Genes involved in RNA regulatory mechanisms were affected at the mRNA, splicing, and translation levels, highlighting their importance in radiation-response. We identified a number of oncogenic factors, with an increased expression upon radiation exposure, including BCL6, RRM2B, IDO1, FTH1, APIP, and LRIG2 and lncRNAs NEAT1 and FTX. Several of these targets have been previously implicated in radio-resistance. Therefore, antagonizing their effects post-radiation could increase therapeutic efficacy.ConclusionsOur integrated analysis provides a comprehensive view of early response to radiation in glioblastoma. We identify new biological processes involved in altered expression of various oncogenic factors and suggest new target options to increase radiation sensitivity and prevent relapse.

Herpesvirus-Associated Proliferative Skin Disease in Frogs and Toads: Proposed Pathogenesis

2021 ◽  
pp. 030098582110063
Author(s):  
Francesco C. Origgi ◽  
Patricia Otten ◽  
Petra Lohmann ◽  
Ursula Sattler ◽  
Thomas Wahli ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Rana Temporaria ◽  
Skin Lesions ◽  
Bufo Bufo ◽  
Careful Examination ◽  
Altered Expression ◽  
Expression Of Genes ◽  
Cell Remodeling ◽  
Tissue Changes

A comparative study was carried out on common and agile frogs ( Rana temporaria and R. dalmatina) naturally infected with ranid herpesvirus 3 (RaHV3) and common toads ( Bufo bufo) naturally infected with bufonid herpesvirus 1 (BfHV1) to investigate common pathogenetic pathways and molecular mechanisms based on macroscopic, microscopic, and ultrastructural pathology as well as evaluation of gene expression. Careful examination of the tissue changes, supported by in situ hybridization, at different stages of development in 6 frogs and 14 toads revealed that the skin lesions are likely transient, and part of a tissue cycle necessary for viral replication in the infected hosts. Transcriptomic analysis, carried out on 2 naturally infected and 2 naïve common frogs ( Rana temporaria) and 2 naturally infected and 2 naïve common toads ( Bufo bufo), revealed altered expression of genes involved in signaling and cell remodeling in diseased animals. Finally, virus transcriptomics revealed that both RaHV3 and BfHV1 had relatively high expression of a putative immunomodulating gene predicted to encode a decoy receptor for tumor necrosis factor in the skin of the infected hosts. Thus, the comparable lesions in infected frogs and toads appear to reflect a concerted epidermal and viral cycle, with presumptive involvement of signaling and gene remodeling host and immunomodulatory viral genes.

Drugs used to treat bipolar disorder act via microRNAs to regulate expression of genes involved in neurite outgrowth

2020 ◽  
Vol 34 (3) ◽  
pp. 370-379 ◽  
Author(s):  
Srisaiyini Kidnapillai ◽  
Ben Wade ◽  
Chiara C Bortolasci ◽  
Bruna Panizzutti ◽  
Briana Spolding ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Neurite Outgrowth ◽  
Neural Plasticity ◽  
Drug Combination ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Drug Effects ◽  
Differentially Expressed ◽  
Transcriptional Level ◽  
Expression Of Genes

Background: The drugs commonly used to treat bipolar disorder have limited efficacy and drug discovery is hampered by the paucity of knowledge of the pathophysiology of this disease. This study aims to explore the role of microRNAs in bipolar disorder and understand the molecular mechanisms of action of commonly used bipolar disorder drugs. Methods: The transcriptional effects of bipolar disorder drug combination (lithium, valproate, lamotrigine and quetiapine) in cultured human neuronal cells were studied using next generation sequencing. Differential expression of genes ( n=20) and microRNAs ( n=6) was assessed and the differentially expressed microRNAs were confirmed with TaqMan MicroRNA Assays. The expression of the differentially expressed microRNAs were inhibited to determine bipolar disorder drug effects on their target genes ( n=8). Independent samples t-test was used for normally distributed data and Kruskal-Wallis/Mann-Whitney U test was used for data not distributed normally. Significance levels were set at p<0.05. Results: We found that bipolar disorder drugs tended to increase the expression of miR-128 and miR-378 ( p<0.05). Putative target genes of these microRNAs targeted pathways including those identified as “neuron projection development” and “axonogenesis”. Many of the target genes are inhibitors of neurite outgrowth and neurogenesis and were downregulated following bipolar disorder drug combination treatment (all p<0.05). The bipolar disorder drug combination tended to decrease the expression of the target genes ( NOVA1, GRIN3A, and VIM), however this effect could be reversed by the application of microRNA inhibitors. Conclusions: We conclude that at a transcriptional level, bipolar disorder drugs affect several genes in concert that would increase neurite outgrowth and neurogenesis and hence neural plasticity, and that this effect is mediated (at least in part) by modulation of the expression of these two key microRNAs.

scholarly journals MicroRNAs as Potential Biomarkers in Atherosclerosis

2019 ◽  
Vol 20 (22) ◽  
pp. 5547 ◽  
Author(s):  
Alexey Churov ◽  
Volha Summerhill ◽  
Andrey Grechko ◽  
Varvara Orekhova ◽  
Alexander Orekhov
Keyword(s):  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Inflammatory Cells ◽  
Cellular Protein ◽  
Cholesterol Homeostasis ◽  
Transcriptional Level ◽  
High Morbidity ◽  
Industrialized Countries ◽  
Rna Molecules ◽  
Expression Of Genes

Atherosclerosis is a complex multifactorial disease that, despite advances in lifestyle management and drug therapy, remains to be the major cause of high morbidity and mortality rates from cardiovascular diseases (CVDs) in industrialized countries. Therefore, there is a great need in reliable diagnostic/prognostic biomarkers and effective treatment alternatives to reduce its burden. It was established that microRNAs (miRNAs/miRs), a class of non-coding single-stranded RNA molecules, can regulate the expression of genes at the post-transcriptional level and, accordingly, coordinate the cellular protein expression. Thus, they are involved not only in cell-specific physiological functions but also in the cellular and molecular mechanisms of human pathologies, including atherosclerosis. MiRNAs may be significant in the dysregulation that affects endothelial integrity, the function of vascular smooth muscle and inflammatory cells, and cellular cholesterol homeostasis that drives the initiation and growth of an atherosclerotic plaque. Besides, distinct expression patterns of several miRNAs are attributed to atherosclerotic and cardiovascular patients. In this article, the evidence indicating the multiple critical roles of miRNAs and their relevant molecular mechanisms related to atherosclerosis development and progression was reviewed. Moreover, the effects of miRNAs on atherosclerosis enabled to exploit them as novel diagnostic biomarkers and therapeutic targets that may lead to better management of atherosclerosis and CVDs.

scholarly journals 3,5-T2 alters murine genes relevant for xenobiotic, steroid, and thyroid hormone metabolism

2016 ◽  
Vol 56 (4) ◽  
pp. 311-323 ◽  
Author(s):  
Julika Lietzow ◽  
Janine Golchert ◽  
Georg Homuth ◽  
Uwe Völker ◽  
Wenke Jonas ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Phase Iii ◽  
Whole Body ◽  
High Dose ◽  
Thyroid Hormone Metabolism ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Novel Target

The endogenous thyroid hormone (TH) metabolite 3,5-diiodo-l-thyronine (3,5-T2) acts as a metabolically active substance affecting whole-body energy metabolism and hepatic lipid handling in a desirable manner. Considering possible adverse effects regarding thyromimetic action of 3,5-T2 treatment in rodents, the current literature remains largely controversial. To obtain further insights into molecular mechanisms and to identify novel target genes of 3,5-T2 in liver, we performed a microarray-based liver tissue transcriptome analysis of male lean and diet-induced obese euthyroid mice treated for 4 weeks with a dose of 2.5 µg/g bw 3,5-T2. Our results revealed that 3,5-T2 modulates the expression of genes encoding Phase I and Phase II enzymes as well as Phase III transporters, which play central roles in metabolism and detoxification of xenobiotics. Additionally, 3,5-T2 changes the expression of TH responsive genes, suggesting a thyromimetic action of 3,5-T2 in mouse liver. Interestingly, 3,5-T2 in obese but not in lean mice influences the expression of genes relevant for cholesterol and steroid biosynthesis, suggesting a novel role of 3,5-T2 in steroid metabolism of obese mice. We concluded that treatment with 3,5-T2 in lean and diet-induced obese male mice alters the expression of genes encoding hepatic xenobiotic-metabolizing enzymes that play a substantial role in catabolism and inactivation of xenobiotics and TH and are also involved in hepatic steroid and lipid metabolism. The administration of this high dose of 3,5-T2 might exert adverse hepatic effects. Accordingly, the conceivable use of 3,5-T2 as pharmacological hypolipidemic agent should be considered with caution.

Novel nuclear target for thrombin: activation of the Elk1 transcription factor leads to chemokine gene expression

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3696-3706 ◽  
Author(s):  
Qi-Jing Li ◽  
Sucheta Vaingankar ◽  
Frances M. Sladek ◽  
Manuela Martins-Green
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Gene Activation ◽  
Tumor Development ◽  
Growth Factor Receptor ◽  
Early Response ◽  
Transcriptional Level ◽  
Binding Domains ◽  
Thrombin Activation

Thrombin is primarily known for its role in homeostasis and thrombosis. However, this enzyme also plays important roles in wound healing and pathologic situations such as inflammation and tumorigenesis. Among the molecules stimulated by thrombin in these latter processes are the stress response proteins, chemokines. Chemokines are also known for their roles in inflammatory responses and tumor development. These correlative observations strongly suggest that chemokines may be mediators of some of thrombin's functions in these processes. Elucidation of the molecular mechanisms of stimulation of chemokines by thrombin may help to unravel the ways in which their expression can be modulated. Up-regulation of the chemokine 9E3/cCAF by thrombin occurs via its proteolytically activated receptor with subsequent transactivation of the epidermal growth factor receptor tyrosine kinase. This study shows that stimulation by thrombin very rapidly activates this chemokine at the transcriptional level, that 2 Elk1 binding elements located between −534 and −483 bp of the promoter are major thrombin response elements, that activation occurs via the Elk1 transcription factor, and that the latter is directly activated by MEK1/ERK2. The common occurrence of Elk1 binding domains in the promoters of immediate early response genes suggests that it may be characteristically involved in gene activation by stress-inducing agents.

scholarly journals Markers of Adipogenesis, but Not Inflammation, in Adipose Tissue Are Independently Related to Insulin Sensitivity

2017 ◽  
Vol 102 (8) ◽  
pp. 3040-3049 ◽  
Author(s):  
Natalia Matulewicz ◽  
Magdalena Stefanowicz ◽  
Agnieszka Nikołajuk ◽  
Monika Karczewska-Kupczewska
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Immune Cells ◽  
Insulin Signaling ◽  
Transcriptional Level ◽  
Altered Expression ◽  
Ecm Remodeling ◽  
Expression Of Genes ◽  
Obese Subjects

Abstract Context In obesity, adipose tissue (AT) undergoes dynamic remodeling, including an alternation in adipogenesis, AT-resident cell content, angiogenesis, and turnover of extracellular matrix (ECM) components. Studies of AT in humans have been carried out mostly in people with severe metabolic abnormalities, like type 2 diabetes or morbid obesity. Objective The purpose of this study was to investigate subcutaneous AT gene expression of markers of adipogenesis, ECM remodeling, and inflammation in young, healthy, overweight or obese subjects. Design The study group comprised 83 normal-weight, 48 overweight, and 19 obese subjects. Euglycemic hyperinsulinemic clamp, biopsy of subcutaneous AT, and isolation of peripheral blood mononuclear cells (PBMCs) were performed. Gene expression was measured with real-time polymerase chain reaction. Results Overweight/obese subjects had lower AT expression of markers of adipogenesis, insulin signaling, and angiogenesis; higher expression of markers of ECM remodeling; altered expression of genes of the nuclear factor-κ-B (NFκB), but not c-Jun NH2-terminal kinase, pathway; and higher expression of macrophage markers but not markers of other immune cells. In multiple regression analysis, the expression of CEBPA, ADIPOQ, IRS1, IRS2, SLC2A4, and MMP9 was associated with insulin sensitivity independently of body mass index. No differences were found in inflammatory-gene PBMC expression. Conclusion Overweight/obesity is associated with altered expression of genes of adipogenesis, insulin signaling, ECM remodeling, and inflammation. NFκB seems to be the earliest inflammatory pathway altered at the transcriptional level in AT. Macrophages seem to be the first immune cells to infiltrate AT. Adipogenesis and ECM remodeling are the initial processes in AT that are independently associated with insulin sensitivity.

scholarly journals Endometritis and pyometra in bitches: a review

2013 ◽  
Vol 58 (No. 6) ◽  
pp. 289-297 ◽  
Author(s):  
B. Kempisty ◽  
D. Bukowska ◽  
M. Wozna ◽  
H. Piotrowska ◽  
M. Jackowska ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Reproductive Tract ◽  
Molecular Level ◽  
Altered Expression ◽  
Expression Of Genes ◽  
Clinical Stages ◽  
Compound Process ◽  
Immunological Changes

Endometritis-pyometra is the most frequent and complex pathology in domestic bitches. This process involves several immunological changes as well as molecular mechanisms responsible for inflammation in the female uterus. The various clinical stages of pyometra are associated with various symptoms. In this review, several aspects are described, including physiological and pathological mechanisms as well as molecular changes which take place during induction of endometritis-pyometra. The authors also highlight the important role of growth factors and their receptors in this process. It is well known that pyometra is a compound process which mainly involves immunological changes during inflammation. However, this review presents a new overview of this process, which includes changes at the molecular level, e.g., the altered expression of genes crucial for the development of this disease. Although pyometra is the most frequent disease of the reproductive tract in bitches, the molecular basis of this process is still not entirely understood. &nbsp;

scholarly journals Genome-wide expression and network analyses of mutants in key brassinosteroid signaling genes

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Razgar Seyed Rahmani ◽  
Tao Shi ◽  
Dongzhi Zhang ◽  
Xiaoping Gou ◽  
Jing Yi ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Differential Expression Analysis ◽  
Transcriptional Level ◽  
Partial Recovery ◽  
Hormone Signaling ◽  
Loss Of Function ◽  
Altered Expression ◽  
Network Analyses

Abstract Background Brassinosteroid (BR) signaling regulates plant growth and development in concert with other signaling pathways. Although many genes have been identified that play a role in BR signaling, the biological and functional consequences of disrupting those key BR genes still require detailed investigation. Results Here we performed phenotypic and transcriptomic comparisons of A. thaliana lines carrying a loss-of-function mutation in BRI1 gene, bri1–5, that exhibits a dwarf phenotype and its three activation-tag suppressor lines that were able to partially revert the bri1–5 mutant phenotype to a WS2 phenotype, namely bri1–5/bri1–1D, bri1–5/brs1–1D, and bri1–5/bak1–1D. From the three investigated bri1–5 suppressors, bri1–5/bak1–1D was the most effective suppressor at the transcriptional level. All three bri1–5 suppressors showed altered expression of the genes in the abscisic acid (ABA signaling) pathway, indicating that ABA likely contributes to the partial recovery of the wild-type phenotype in these bri1–5 suppressors. Network analysis revealed crosstalk between BR and other phytohormone signaling pathways, suggesting that interference with one hormone signaling pathway affects other hormone signaling pathways. In addition, differential expression analysis suggested the existence of a strong negative feedback from BR signaling on BR biosynthesis and also predicted that BRS1, rather than being directly involved in signaling, might be responsible for providing an optimal environment for the interaction between BRI1 and its ligand. Conclusions Our study provides insights into the molecular mechanisms and functions of key brassinosteroid (BR) signaling genes, especially BRS1.

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