scholarly journals CSNK1A1 and Gli2 as Novel Targets Identified through an Integrative Analysis of Gene Expression Data, Protein–Protein Interaction and Pathways Networks in Glioblastoma Tumors: Can these Two be Antagonistic Proteins?

2014 ◽  
Vol 13 ◽  
pp. CIN.S18377 ◽  
Author(s):  
Seema Mishra
Keyword(s):  
Signaling Pathways ◽  
Drug Targets ◽  
Active Role ◽  
Integrative Approach ◽  
Significant Differential Expression ◽  
Shh Signaling ◽  
Protein Protein Interaction ◽  
Shh Pathway ◽  
Expression Of Genes ◽  
The Relationship

Glioblastoma (GBM) is the malignant form of glioma, and the interplay of different pathways working in concert in GBM development and progression needs to be fully understood. Wnt signaling and sonic hedgehog (SHH) signaling pathways, having basic similarities, are among the major pathways aberrantly activated in GBM, and hence, need to be targeted. It becomes imperative, therefore, to explore the functioning of these pathways in context of each other in GBM. An integrative approach may help provide new biological insights, as well as solve the problem of identifying common drug targets for simultaneous targeting of these pathways. The beauty of this approach is that it can recapitulate several known facts, as well as decipher new emerging patterns, identifying those targets that could be missed when relying on one type of data at a time. This approach can be easily extended to other systems to discover key patterns in the functioning of signaling molecules. Studies were designed to assess the relationship between significant differential expression of genes of the Wnt (Wnt/β-catenin canonical and Wnt non-canonical) and SHH signaling pathways and their connectivity patterns in interaction and signaling networks. Further, the aim was to decipher underlying mechanistic patterns that may be involved in a more specific way and to generate a ranked list of genes that can be used as markers or drug targets. These studies predict that Wnt pathway plays a relatively more pro-active role than the SHH pathway in GBM. Further, CTNNB1, CSNK1A1, and Gli2 proteins may act as key drug targets common to these pathways. While CTNNB1 is a widely studied molecule in the context of GBM, the likely roles of CSNK1A1 and Gli2 are found to be relatively novel. It is surmised that Gli2 may be antagonistic to CSNK1A1, preventing the phosphorylation of CTNNB1 and SMO proteins in Wnt and SHH signaling pathway, respectively, by CSNK1A1, and thereby, aberrant activation. New insights into the possible behavior of these pathway molecules relative to each other in GBM reveal some key interesting patterns.

scholarly journals Identification of potential therapeutic targets and mechanisms of COVID-19 through network analysis and screening of chemicals and herbal ingredients

2021 ◽  
Author(s):  
Hong Wang ◽  
Jingqing Zhang ◽  
Zhigang Lu ◽  
Weina Dai ◽  
Chuanjiang Ma ◽  
...  
Keyword(s):  
Drug Targets ◽  
Drug Repurposing ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Therapeutic Effects ◽  
Protein Protein Interaction ◽  
Disease Module ◽  
Approved Drugs ◽  
Data Driven Modeling ◽  
The Relationship

Abstract After experiencing the COVID-19 pandemic, it is widely acknowledged that a rapid drug repurposing method is highly needed. A series of useful drug repurposing tools have been developed based on data-driven modeling and network pharmacology. Based on the disease module, we identified several hub proteins that play important roles in the onset and development of the COVID-19, which are potential targets for repositioning approved drugs. Moreover, different network distance metrics were applied to quantify the relationship between drug targets and COVID-19 disease targets in the protein–protein-interaction (PPI) network and predict COVID-19 therapeutic effects of bioactive herbal ingredients and chemicals. Furthermore, the tentative mechanisms of candidates were illustrated through molecular docking and gene enrichment analysis. We obtained 15 chemical and 15 herbal ingredient candidates and found that different drugs may play different roles in the process of virus invasion and the onset and development of the COVID-19 disease. Given pandemic outbreaks, our method has an undeniable immense advantage in the feasibility analysis of drug repurposing or drug screening, especially in the analysis of herbal ingredients.

scholarly journals Overexpression and Activation of αvβ3 Integrin Differentially Affects TGFβ2 Signaling in Human Trabecular Meshwork Cells

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1923
Author(s):  
Mark S. Filla ◽  
Kristy K. Meyer ◽  
Jennifer A. Faralli ◽  
Donna M. Peters
Keyword(s):  
Trabecular Meshwork ◽  
Open Angle Glaucoma ◽  
Integrin Signaling ◽  
Αvβ3 Integrin ◽  
Rna Seq ◽  
Significant Differential Expression ◽  
Protein Protein Interaction ◽  
Trabecular Meshwork Cells ◽  
Expression Of Genes ◽  
Genes Encoding

Studies from our laboratory have suggested that activation of αvβ3 integrin-mediated signaling could contribute to the fibrotic-like changes observed in primary open angle glaucoma (POAG) and glucocorticoid-induced glaucoma. To determine how αvβ3 integrin signaling could be involved in this process, RNA-Seq analysis was used to analyze the transcriptomes of immortalized trabecular meshwork (TM) cell lines overexpressing either a control vector or a wild type (WT) or a constitutively active (CA) αvβ3 integrin. Compared to control cells, hierarchical clustering, PANTHER pathway and protein-protein interaction (PPI) analysis of cells overexpressing WT-αvβ3 integrin or CA-αvβ3 integrin resulted in a significant differential expression of genes encoding for transcription factors, adhesion and cytoskeleton proteins, extracellular matrix (ECM) proteins, cytokines and GTPases. Cells overexpressing a CA-αvβ3 integrin also demonstrated an enrichment for genes encoding proteins found in TGFβ2, Wnt and cadherin signaling pathways all of which have been implicated in POAG pathogenesis. These changes were not observed in cells overexpressing WT-αvβ3 integrin. Our results suggest that activation of αvβ3 integrin signaling in TM cells could have significant impacts on TM function and POAG pathogenesis.

scholarly journals Systems Biomedicine of Rabies Delineates the Affected Signaling pathways

2016 ◽  
Author(s):  
Sadegh Azimzadeh Jamalkandi ◽  
Hamid Gholami Pourbadie ◽  
Mehdi Mirzaie ◽  
Sayed Hamid Reza Mozhgani ◽  
Farsheed Noorbakhsh ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Rabies Virus ◽  
Drug Targets ◽  
Psychological Symptoms ◽  
Interaction Network ◽  
Signal Propagation ◽  
Protein Protein Interaction ◽  
Infected Cells ◽  
Microarray Datasets ◽  
Whole Transcriptome

AbstractThe prototypical neurotropic virus, rabies, is a member of the Rhabdoviridae family that causes lethal encephalomyelitis. Although there have been a plethora of studies investigating the etiological mechanism of the rabies virus and many precautionary methods have been implemented to avert the disease outbreak over the last century, the disease has surprisingly no definite remedy at its late stages. The psychological symptoms and the underlying etiology, as well as the rare survival rate from rabies encephalitis, has still remained a mystery. We, therefore, undertook a systems biomedicine approach to identify the network of gene products implicated in rabies. This was done by meta-analyzing whole-transcriptome microarray datasets of the CNS infected by strain CVS-11, and integrating them with interactome data using computational and statistical methods. We first determined the differentially expressed genes (DEGs) in each study and horizontally integrated the results at the mRNA and microRNA levels separately. A total of 61 seed genes involved in signal propagation system were obtained by means of unifying mRNA and microRNA detected integrated DEGs. We then reconstructed a refined protein-protein interaction network (PPIN) of infected cells to elucidate biological signaling transduction pathways affected by rabies virus. To validate our findings, we confirmed differential expression of randomly selected genes in the network using Real-time PCR. In conclusion, the identification of seed genes and their network neighborhood within the refined PPIN can be useful for demonstrating signaling pathways including interferon circumvent, toward proliferation and survival, and neuropathological clue, explaining the intricate underlying molecular neuropathology of rabies infection and thus rendered a molecular framework for predicting potential drug targets.

scholarly journals Lhx2 is a progenitor-intrinsic modulator of Sonic Hedgehog signaling during early retinal neurogenesis

2021 ◽  
Author(s):  
Xiaodong Li ◽  
Patrick J Gordon ◽  
John A Gaynes ◽  
Alexandra W Fuller ◽  
Randy Ringuette ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathways ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling ◽  
Downstream Targets ◽  
Shh Pathway ◽  
Pathway Activation ◽  
Retinal Neurogenesis

An important question in organogenesis is how tissue-specific transcription factors interact with signaling pathways. In some cases, transcription factors define the context for how signaling pathways elicit tissue- or cell-specific responses, and in others, they influence signaling through transcriptional regulation of signaling components or accessory factors. We previously showed that during optic vesicle patterning, the Lim-homeodomain transcription factor Lhx2 has a contextual role by linking the Sonic Hedgehog (Shh) pathway to downstream targets without regulating the pathway itself. Here, we show that during early retinal neurogenesis, Lhx2 is a multilevel regulator of Shh signaling. Specifically, Lhx2 acts cell autonomously to control the expression of pathway genes required for efficient activation and maintenance of signaling in retinal progenitor cells. The Shh co-receptors Cdon and Gas1 are candidate direct targets of Lhx2 that mediate pathway activation, whereas Lhx2 directly or indirectly promotes the expression of other pathway components important for activation and sustained signaling. We also provide genetic evidence suggesting that Lhx2 has a contextual role by linking the Shh pathway to downstream targets. Through these interactions, Lhx2 establishes the competence for Shh signaling in retinal progenitors and the context for the pathway to promote early retinal neurogenesis. The temporally distinct interactions between Lhx2 and the Shh pathway in retinal development illustrate how transcription factors and signaling pathways adapt to meet stage-dependent requirements of tissue formation.

A Note on the Publication History of John Polidori's The Vampyre

2020 ◽  
Vol 22 (3) ◽  
pp. 330-343
Author(s):  
Fabio Camilletti
Keyword(s):  
Textual Criticism ◽  
Active Role ◽  
Publication History ◽  
History Of ◽  
The Relationship ◽  
Opening Up

It is generally assumed that The Vampyre was published against John Polidori's will. This article brings evidence to support that he played, in fact, an active role in the publication of his tale, perhaps as a response to Frankenstein. In particular, by making use of the tools of textual criticism, it demonstrates how the ‘Extract of a Letter from Geneva’ accompanying The Vampyre in The New Monthly Magazine and in volume editions could not be written without having access to Polidori's Diary. Furthermore, it hypothesizes that the composition of The Vampyre, traditionally located in Geneva in the course of summer 1816, can be postdated to 1818, opening up new possibilities for reading the tale in the context of the relationship between Polidori, Byron, and the Shelleys.

THE GENDER IMPLEMENTATION OF THE “POWER” FRAME IN SHAKESPEARE’S TRAGEDY “MACBETH”

2020 ◽  
Vol 6 (2) ◽  
pp. 19-36
Author(s):  
Ekaterina A. LOBANOVA
Keyword(s):  
Main Idea ◽  
Point Of View ◽  
Integrative Approach ◽  
Discursive Analysis ◽  
Historical Text ◽  
Gender Characteristics ◽  
And Gender ◽  
Linguistic Methods ◽  
Relationship Of ◽  
The Relationship

This article studies the cognitive features of the “power” frame and its gender implementation in the historical tragedy by W. Shakespeare “Macbeth”. Here, the author examines the concepts of “frame” and “gender” in linguistics, studying different approaches to their definition. The relevance of this work is determined by the close attention of the contemporary linguistics to these concepts, as well as their place in the contemporary academic paradigm. The academic affirmation of the “frame” and “gender” concepts designates a new step in understanding the ways and peculiarities of the language interaction, consciousness, and culture, and, consequently, it shows new aspects of the relationship of linguistics with other sciences. Nevertheless, the problems of both frame and gender are not yet fully understood. This study allows describing in detail the essence of the frame “power” and showing its meaning, use, and ways of its gender implementation in fiction, which explains the novelty of this article. The study’s methodology is based on the cognitive-discursive analysis of the text, as well as on an integrative approach to the discourse study, which combines methods of both cognitive and gender linguistics, as well as the discourse analysis. Common research methods were used along with private linguistic methods. The application of cognitive-discursive analysis has significantly increased the depth of understanding of the “power” frame that dominates Shakespeare’s historical tragedy. This historical text presents the central theme of political tragedy: the overthrow of the rightful ruler and the usurpation of power. The motive for the seizure of power forms a thematic core and is presented from the usurpers’ point of view. In this article, the author observes the gender shift and duality of the female and male beginnings: Shakespeare puts the female protagonist, hungry for power, among men, thus the images of Lady Macbeth and her husband come into conflict with the gender characteristics attributed to them. The play clearly traces the main idea of Machiavellianism: the goal justifies the means. The results conclude that the “power” frame is the leading one in Lady Macbeth’s monologue, thus setting one of the main themes of this tragedy.

scholarly journals Development of a Novel High-Throughput Screen and Identification of Small-Molecule Inhibitors of the Gα–RGS17 Protein–Protein Interaction Using AlphaScreen

2011 ◽  
Vol 16 (8) ◽  
pp. 869-877 ◽  
Author(s):  
Duncan I. Mackie ◽  
David L. Roman
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
Protein Interaction ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Screening Method ◽  
Fold Increase ◽  
Rgs Proteins ◽  
High Throughput Screen ◽  
Protein Protein Interaction

In this study, the authors used AlphaScreen technology to develop a high-throughput screening method for interrogating small-molecule libraries for inhibitors of the Gαo–RGS17 interaction. RGS17 is implicated in the growth, proliferation, metastasis, and the migration of prostate and lung cancers. RGS17 is upregulated in lung and prostate tumors up to a 13-fold increase over patient-matched normal tissues. Studies show RGS17 knockdown inhibits colony formation and decreases tumorigenesis in nude mice. The screen in this study uses a measurement of the Gαo–RGS17 protein–protein interaction, with an excellent Z score exceeding 0.73, a signal-to-noise ratio >70, and a screening time of 1100 compounds per hour. The authors screened the NCI Diversity Set II and determined 35 initial hits, of which 16 were confirmed after screening against controls. The 16 compounds exhibited IC50 <10 µM in dose–response experiments. Four exhibited IC50 values <6 µM while inhibiting the Gαo–RGS17 interaction >50% when compared to a biotinylated glutathione-S-transferase control. This report describes the first high-throughput screen for RGS17 inhibitors, as well as a novel paradigm adaptable to many other RGS proteins, which are emerging as attractive drug targets for modulating G-protein-coupled receptor signaling.

scholarly journals Network Analysis Identifies Drug Targets and Small Molecules to Modulate Apoptosis Resistant Cancers

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 851
Author(s):  
Samreen Fathima ◽  
Swati Sinha ◽  
Sainitin Donakonda
Keyword(s):  
Cell Death ◽  
Small Molecules ◽  
Drug Targets ◽  
Apoptotic Cell ◽  
Colon Adenocarcinoma ◽  
Interaction Networks ◽  
Small Cell Lung ◽  
Protein Protein Interaction ◽  
Cell Death Genes ◽  
Death Genes

Programed cell death or apoptosis fails to induce cell death in many recalcitrant cancers. Thus, there is an emerging need to activate the alternate cell death pathways in such cancers. In this study, we analyzed the apoptosis-resistant colon adenocarcinoma, glioblastoma multiforme, and small cell lung cancers transcriptome profiles. We extracted clusters of non-apoptotic cell death genes from each cancer to understand functional networks affected by these genes and their role in the induction of cell death when apoptosis fails. We identified transcription factors regulating cell death genes and protein–protein interaction networks to understand their role in regulating cell death mechanisms. Topological analysis of networks yielded FANCD2 (ferroptosis, negative regulator, down), NCOA4 (ferroptosis, up), IKBKB (alkaliptosis, down), and RHOA (entotic cell death, down) as potential drug targets in colon adenocarcinoma, glioblastoma multiforme, small cell lung cancer phenotypes respectively. We also assessed the miRNA association with the drug targets. We identified tumor growth-related interacting partners based on the pathway information of drug-target interaction networks. The protein–protein interaction binding site between the drug targets and their interacting proteins provided an opportunity to identify small molecules that can modulate the activity of functional cell death interactions in each cancer. Overall, our systematic screening of non-apoptotic cell death-related genes uncovered targets helpful for cancer therapy.

scholarly journals In silico characterization and structural modeling of bacterial metalloprotease of family M4

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Rajnee Hasan ◽  
Md. Nazmul Haq Rony ◽  
Rasel Ahmed
Keyword(s):  
Drug Targets ◽  
Active Sites ◽  
Pathogenic Bacteria ◽  
Tertiary Structure ◽  
Transmembrane Helix ◽  
Confidence Score ◽  
Potential Drug ◽  
Protein Protein Interaction ◽  
Industrial Level ◽  
Potential Drug Targets

Abstract Background The M4 family of metalloproteases is comprised of a large number of zinc-containing metalloproteases. A large number of these enzymes are important virulence factors of pathogenic bacteria and therefore potential drug targets. Whereas some enzymes have potential for biotechnological applications, the M4 family of metalloproteases is known almost exclusively from bacteria. The aim of the study was to identify the structure and properties of M4 metalloprotease proteins. Results A total of 31 protein sequences of M4 metalloprotease retrieved from UniProt representing different species of bacteria have been characterized for various physiochemical properties. They were thermostable, hydrophillic protein of a molecular mass ranging from 38 to 66 KDa. Correlation on the basis of both enzymes and respective genes has also been studied by phylogenetic tree. B. cereus M4 metalloprotease (PDB ID: 1NPC) was selected as a representative species for secondary and tertiary structures among the M4 metalloprotease proteins. The secondary structure displaying 11 helices (H1-H11) is involved in 15 helix-helix interactions, while 4 β-sheet motifs composed of 15 β-strands in PDBsum. Possible disulfide bridges were absent in most of the cases. The tertiary structure of B. cereus M4 metalloprotease was validated by QMEAN4 and SAVES server (Ramachandran plot, verify 3D, and ERRAT) which proved the stability, reliability, and consistency of the tertiary structure of the protein. Functional analysis was done in terms of membrane protein topology, disease-causing region prediction, proteolytic cleavage sites prediction, and network generation. Transmembrane helix prediction showed absence of transmembrane helix in protein. Protein-protein interaction networks demonstrated that bacillolysin of B. cereus interacted with ten other proteins in a high confidence score. Five disorder regions were identified. Active sites analysis showed the zinc-binding residues—His-143, His-147, and Glu-167, with Glu-144 acting as the catalytic residues. Conclusion Moreover, this theoretical overview will help researchers to get a details idea about the protein structure and it may also help to design enzymes with desirable characteristics for exploiting them at industrial level or potential drug targets.

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