scholarly journals The First Reconstruction of Intercellular Interaction Network in Mus musculus Immune System

2019 ◽  
Author(s):  
Somayeh Azadian ◽  
Javad Zahiri ◽  
Seyed Shahriar Arab ◽  
Reza Hassan sajedi
Keyword(s):  
Stromal Cells ◽  
Interaction Network ◽  
High Specificity ◽  
Genome Project ◽  
Intercellular Interaction ◽  
Ligand Interaction ◽  
Intercellular Interactions ◽  
Genes Expression ◽  
Ligand Interactions ◽  
Reconstructed Network

AbstractIntercellular interactions play an important role in regulating communications of cells with each other. So far, many studies have been done with both experimental and computational approaches in this field. Therefore, in order to investigate and analyze the intercellular interactions, use of network reconstruction has attracted the attention of many researchers recently. The intercellular interaction network was reconstructed using receptor and ligand interaction dataset and gene expression data of the first phase of the immunological genome project. In the reconstructed network, there are 9271 communications between 162 cells which were created through 460 receptor-ligand interactions. The results indicate that cells of hematopoietic lineages use fewer communication pathways for interacting with each other and the most network communications belong to non-hematopoietic stromal cells and macrophages. The results indicated the importance of the communication of stromal cells with immune cells and also high specificity of genes expression in these cells. The stromal cells have the most autocrine communication, and interactions between the wnt5a with the Ror1/2 and Fzd5a among the stromal lineage cells are abundant.

scholarly journals Elucidating Binding Sites and Affinities of ERα Agonist and Antagonist to Human Alpha-Fetoprotein by in silico Modeling and Point Mutagenesis

2019 ◽  
Author(s):  
Nurbubu T. Moldogazieva ◽  
Daria S. Ostroverkhova ◽  
Nikolai N. Kuzmich ◽  
Vladimir V. Kadochnikov ◽  
Alexander A. Terentiev ◽  
...  
Keyword(s):  
Binding Sites ◽  
In Silico ◽  
Disulfide Bonds ◽  
Electrostatic Interactions ◽  
Molecular Mechanisms ◽  
3D Structure ◽  
Scoring Function ◽  
Alpha Fetoprotein ◽  
Ligand Interaction ◽  
Ligand Interactions

Alpha-fetoprotein (AFP) is a major embryo- and tumor-associated protein capable of binding and transporting variety of hydrophobic ligands including estrogens. AFP has been shown to inhibit estrogen receptor (ER)-positive tumor growth and this can be attributed to its estrogen-binding ability. Despite AFP has long been investigated, its three-dimensional (3D) structure has not been experimentally resolved and molecular mechanisms underlying AFP-ligand interaction remain obscure. In our study we constructed homology-based 3D model of human AFP (HAFP) with the purpose to perform docking of ERα ligands, three agonists (17β-estradiol, estrone and diethylstilbestrol) and three antagonists (tamoxifen, afimoxifene and endoxifen) into the obtained structure. Based on ligand docked scoring function, we identified three putative estrogen- and antiestrogen-binding sites with different ligand binding affinities. Two high-affinity sites were located in (i) a tunnel formed within HAFP subdomains IB and IIA and (ii) opposite side of the molecule in a groove originating from cavity formed between domains I and III, while (iii) the third low-affinity site was found at the bottom of the cavity. 100 ns MD simulation allowed studying their geometries and showed that HAFP-estrogen interactions occur due to van der Waals forces, while both hydrophobic and electrostatic interactions were almost equally involved in HAFP-antiestrogen binding. MM/GBSA rescoring method estimated binding free energies (ΔGbind) and showed that antiestrogens have higher affinities to HAFP as compared to estrogens. We performed in silico point substitutions of amino acid residues to confirm their roles in HAFP-ligand interactions and showed that Thr132, Leu138, His170, Phe172, Ser217, Gln221, His266, His316, Lys453, and Asp478 residues along two disulfide bonds, Cys224-Cys270 and Cys269-Cys277 have key roles in both HAFP-estrogen and HAFP-antiestrogen binding. Data obtained in our study contribute to understanding mechanisms underlying protein-ligand interactions and anti-cancer therapy strategies based on ER-binding ligands.

scholarly journals Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia

2021 ◽  
Vol 22 (22) ◽  
pp. 12167
Author(s):  
Somayeh S. Tarighat ◽  
Fei Fei ◽  
Eun Ji Joo ◽  
Hisham Abdel-Azim ◽  
Lu Yang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Stromal Cells ◽  
Lymphoblastic Leukemia ◽  
High Specificity ◽  
Leukemia Cells ◽  
Cell Precursor ◽  
Cell Responses ◽  
Galectin 3 ◽  
Dose Dependent

Environmentally-mediated drug resistance in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) significantly contributes to relapse. Stromal cells in the bone marrow environment protect leukemia cells by secretion of chemokines as cues for BCP-ALL migration towards, and adhesion to, stroma. Stromal cells and BCP-ALL cells communicate through stromal galectin-3. Here, we investigated the significance of stromal galectin-3 to BCP-ALL cells. We used CRISPR/Cas9 genome editing to ablate galectin-3 in stromal cells and found that galectin-3 is dispensable for steady-state BCP-ALL proliferation and viability. However, efficient leukemia migration and adhesion to stromal cells are significantly dependent on stromal galectin-3. Importantly, the loss of stromal galectin-3 production sensitized BCP-ALL cells to conventional chemotherapy. We therefore tested novel carbohydrate-based small molecule compounds (Cpd14 and Cpd17) with high specificity for galectin-3. Consistent with results obtained using galectin-3-knockout stromal cells, treatment of stromal-BCP-ALL co-cultures inhibited BCP-ALL migration and adhesion. Moreover, these compounds induced anti-leukemic responses in BCP-ALL cells, including a dose-dependent reduction of viability and proliferation, the induction of apoptosis and, importantly, the inhibition of drug resistance. Collectively, these findings indicate galectin-3 regulates BCP-ALL cell responses to chemotherapy through the interactions between leukemia cells and the stroma, and show that a combination of galectin-3 inhibition with conventional drugs can sensitize the leukemia cells to chemotherapy.

scholarly journals Reconstruction of Protein-Protein Interaction Network of Insulin Signaling inHomo Sapiens

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Saliha Durmuş Tekir ◽  
Pelin Ümit ◽  
Aysun Eren Toku ◽  
Kutlu Ö. Ülgen
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Signaling ◽  
Homo Sapiens ◽  
Interaction Network ◽  
Protein Protein Interaction ◽  
Signaling Mechanisms ◽  
Reconstructed Network ◽  
Protein Protein Interaction Network

Diabetes is one of the most prevalent diseases in the world. Type 1 diabetes is characterized by the failure of synthesizing and secreting of insulin because of destroyed pancreaticβ-cells. Type 2 diabetes, on the other hand, is described by the decreased synthesis and secretion of insulin because of the defect in pancreaticβ-cells as well as by the failure of responding to insulin because of malfunctioning of insulin signaling. In order to understand the signaling mechanisms of responding to insulin, it is necessary to identify all components in the insulin signaling network. Here, an interaction network consisting of proteins that have statistically high probability of being biologically related to insulin signaling inHomo sapienswas reconstructed by integrating Gene Ontology (GO) annotations and interactome data. Furthermore, within this reconstructed network, interacting proteins which mediate the signal from insulin hormone to glucose transportation were identified using linear paths. The identification of key components functioning in insulin action on glucose metabolism is crucial for the efforts of preventing and treating type 2 diabetes mellitus.

scholarly journals Elucidating Binding Sites and Affinities of ERα Agonists and Antagonists to Human Alpha-Fetoprotein by In Silico Modeling and Point Mutagenesis

2020 ◽  
Vol 21 (3) ◽  
pp. 893 ◽  
Author(s):  
Nurbubu T. Moldogazieva ◽  
Daria S. Ostroverkhova ◽  
Nikolai N. Kuzmich ◽  
Vladimir V. Kadochnikov ◽  
Alexander A. Terentiev ◽  
...  
Keyword(s):  
Binding Sites ◽  
In Silico ◽  
Electrostatic Interactions ◽  
Molecular Mechanisms ◽  
3D Structure ◽  
Alpha Fetoprotein ◽  
Affinity Binding ◽  
Scoring Functions ◽  
Ligand Interaction ◽  
Ligand Interactions

Alpha-fetoprotein (AFP) is a major embryo- and tumor-associated protein capable of binding and transporting a variety of hydrophobic ligands, including estrogens. AFP has been shown to inhibit estrogen receptor (ER)-positive tumor growth, which can be attributed to its estrogen-binding ability. Despite AFP having long been investigated, its three-dimensional (3D) structure has not been experimentally resolved and molecular mechanisms underlying AFP–ligand interaction remains obscure. In our study, we constructed a homology-based 3D model of human AFP (HAFP) with the purpose of molecular docking of ERα ligands, three agonists (17β-estradiol, estrone and diethylstilbestrol), and three antagonists (tamoxifen, afimoxifene and endoxifen) into the obtained structure. Based on the ligand-docked scoring functions, we identified three putative estrogen- and antiestrogen-binding sites with different ligand binding affinities. Two high-affinity binding sites were located (i) in a tunnel formed within HAFP subdomains IB and IIA and (ii) on the opposite side of the molecule in a groove originating from a cavity formed between domains I and III, while (iii) the third low-affinity binding site was found at the bottom of the cavity. Here, 100 ns molecular dynamics (MD) simulation allowed us to study their geometries and showed that HAFP–estrogen interactions were caused by van der Waals forces, while both hydrophobic and electrostatic interactions were almost equally involved in HAFP–antiestrogen binding. Molecular mechanics/Generalized Born surface area (MM/GBSA) rescoring method exploited for estimation of binding free energies (ΔGbind) showed that antiestrogens have higher affinities to HAFP as compared to estrogens. We performed in silico point substitutions of amino acid residues to confirm their roles in HAFP–ligand interactions and showed that Thr132, Leu138, His170, Phe172, Ser217, Gln221, His266, His316, Lys453, and Asp478 residues, along with two disulfide bonds (Cys224–Cys270 and Cys269–Cys277), have key roles in both HAFP–estrogen and HAFP–antiestrogen binding. Data obtained in our study contribute to understanding mechanisms underlying protein–ligand interactions and anticancer therapy strategies based on ERα-binding ligands.

scholarly journals Prediction of Protein–Ligand Interaction Based on the Positional Similarity Scores Derived from Amino Acid Sequences

2019 ◽  
Vol 21 (1) ◽  
pp. 24 ◽  
Author(s):  
Dmitry Karasev ◽  
Boris Sobolev ◽  
Alexey Lagunin ◽  
Dmitry Filimonov ◽  
Vladimir Poroikov
Keyword(s):  
Prediction Accuracy ◽  
Sequence Similarity ◽  
Amino Acid Sequences ◽  
Protein Families ◽  
Pairwise Sequence Alignment ◽  
Ligand Interaction ◽  
Protein Ligand Interactions ◽  
General Chemical ◽  
Local Sequence ◽  
Ligand Interactions

The affinity of different drug-like ligands to multiple protein targets reflects general chemical–biological interactions. Computational methods estimating such interactions analyze the available information about the structure of the targets, ligands, or both. Prediction of protein–ligand interactions based on pairwise sequence alignment provides reasonable accuracy if the ligands’ specificity well coincides with the phylogenic taxonomy of the proteins. Methods using multiple alignment require an accurate match of functionally significant residues. Such conditions may not be met in the case of diverged protein families. To overcome these limitations, we propose an approach based on the analysis of local sequence similarity within the set of analyzed proteins. The positional scores, calculated by sequence fragment comparisons, are used as input data for the Bayesian classifier. Our approach provides a prediction accuracy comparable or exceeding those of other methods. It was demonstrated on the popular Gold Standard test sets, presenting different sequence heterogeneity and varying from the group, including different protein families to the more specific groups. A reasonable prediction accuracy was also found for protein kinases, displaying weak relationships between sequence phylogeny and inhibitor specificity. Thus, our method can be applied to the broad area of protein–ligand interactions.

scholarly journals An Investigation of Small GTPases in relation to Liver Tumorigenesis Using Traditional Chinese Medicine

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Tzu-Chieh Hung ◽  
Wen-Yuan Lee ◽  
Kuen-Bao Chen ◽  
Yueh-Chiu Chan ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Molecular Dynamics ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Hydrophobic Interactions ◽  
Small Gtpases ◽  
Ligand Interaction ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Protein Ligand Interaction ◽  
Better Than

Recently, an important topic of liver tumorigenesis had been published in 2013. In this report, Ras and Rho had defined the relation of liver tumorigenesis. The traditional Chinese medicine (TCM) database has been screened for molecular compounds by simulating molecular docking and molecular dynamics to regulate Ras and liver tumorigenesis. Saussureamine C, S-allylmercaptocysteine, and Tryptophan are selected based on the highest docking score than other TCM compounds. The molecular dynamics are helpful in the analysis and detection of protein-ligand interactions. Based on the docking poses, hydrophobic interactions, and hydrogen bond variations, this research surmises are the main regions of important amino acids in Ras. In addition to the detection of TCM compound efficacy, we suggest Saussureamine C is better than the others for protein-ligand interaction.

scholarly journals Adverse effects of nicotine on endometrium receptivity markers: and protective effect of caffeic acid phenyl ester

2020 ◽  
Author(s):  
AMIN NAMDARI ◽  
FARIDEH MOHAMMADIAN ◽  
Fatemeh KHAJEH ◽  
SOUDABEH KAVOUSIPOUR ◽  
behnoosh miladpour
Keyword(s):  
Protective Effect ◽  
Caffeic Acid ◽  
Stromal Cells ◽  
Reproductive System ◽  
Quantitative Polymerase Chain Reaction ◽  
Protective Effects ◽  
Uterine Receptivity ◽  
Endometrial Stromal Cells ◽  
Genes Expression ◽  
Endometrium Receptivity

Abstract Background nicotine adversely affects the female reproductive system and changes the methylation pattern of some genes in the placenta. In contrast, caffeic acid phenylethyl ester) CAPE (, as a potent antioxidant, has protective effects against the harmful effects of oxygen free radical molecules, methotrexate, and pesticides on the reproductive system. To find the effect of nicotine on the endometrium, we investigated three markers of endometrium receptivity including fibroblast growth factor 2, vascular endothelial growth factors A, and C-X-C motif chemokine ligand 12 and also changes in methylation levels of CXCL-12 gene promoter. In addition, we evaluated the protective effect of CAPE against nicotine. Methods the appropriate treatment dose was selected based on the literature, the endometrial stromal cells were divided into 4 groups, including control, treated with nicotine, CAPE, and nicotine followed by CAPE. Finally, the quantitative polymerase chain reaction and Methylation-Specific PCR were carried out. Results The results showed that treatment of endometrial stromal cells with nicotine (10− 6 µM) for 24 h significantly reduced expression of CXCL-12, FGF, and VEGFA genes. However, a decrease in CXCL-12 expression was not associated with increased methylation levels in the studied promoter region. In contrast, endometrial stromal cells treated with CAPE (4 µg/ml) for 24 h adverse significantly nicotine-induced reduction of CXCL-12, FGF, and VEGFA genes expression. Conclusion Exposure to nicotine has negative effects on uterine receptivity, implantation, and fertility, via reducing the expression of VEGFA, CXCL-12, and FGF2 genes. In contrast, CAPE has a protective effects and improves these genes expression.

scholarly journals Anti-leukemic activity of phosphoproteins from Sesamin via induction of nuclear antigen H731and CLIP-associating protein 2 isoform X25 mediated apoptosis

2017 ◽  
Vol 9 (2) ◽  
Author(s):  
Pattharin Wannapruk ◽  
Atchara Paemanee ◽  
Sittiruk Roytrakul ◽  
Dalina I Tanyong
Keyword(s):  
Cancer Cells ◽  
Sesame Seed ◽  
Interaction Network ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Nuclear Antigen ◽  
Therapeutic Drug ◽  
Ligand Interaction ◽  
Biological Regulation ◽  
Leukemic Cell Lines

<p>Leukemia is an uncontrolled proliferation hematopoietic cancer cells that commonly treats with conventional therapies such as chemotherapy. However, many side effects were reported. Alternative medicines have been developed by using natural or herb compounds as therapeutic drug. Sesamin, a class of phytoestrogen isolated from sesame seed displaying potent anticancer activity in <em>vitro</em> and in <em>vivo</em>.However, the mechanism by which <em>sesamin</em> mediates <em>anticancer</em> effects on leukemic cells are notfully understood. In thisstudy, the effects of sesamin on cell viability, cell apoptosis and expression of phosphoproteins in Molt-4 and NB4 leukemic cell lines were investigated using MTT assay, flow cytometry and immobilized metal affinity chromatography (IMAC) phosphoprotein enrichment and LC-MS, respectively. The results showed that sesamin reduced viability and induced apoptosis in leukemic cells. In addition, 79 phosphoproteins were identified from LC-MS within three main clusters including biological regulation, cellular processand metabolic process. Interestingly, nuclear antigen H731 (PDCD4) and CLIP-associating protein 2 isoform X25 (CLASP2) showed increased in sesamin treated cells and associated protein-ligand interaction network with allicin, capsaicin, cucurbitacin B, and rapamycin which are known to activate <em>apoptosis</em> in <em>cancer cells</em>.Then, sesamin could be developed as candidate of alternative leukemia treatment  in the future.</p>

scholarly journals Bis(monoacylglycerol) phosphate in rat uterine stromal cells: structural characterization and specific esterification of docosahexaenoic acid

2000 ◽  
Vol 351 (3) ◽  
pp. 795-804 ◽  
Author(s):  
Céline LUQUAIN ◽  
René DOLMAZON ◽  
Jean-Marie ENDERLIN ◽  
Christian LAUGIER ◽  
Michel LAGARDE ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Docosahexaenoic Acid ◽  
Polyunsaturated Fatty Acids ◽  
Stromal Cells ◽  
Total Phospholipid ◽  
Acyl Chain ◽  
Primary Alcohol ◽  
High Specificity ◽  
Acyl Chains ◽  
Two Peaks

In rat uterine stromal cells (UIII cells), docosahexaenoic acid (DHA) was esterified extensively in alkenylacyl-glycerophosphoethanolamine and in an unknown phospholipid accounting for only 0.7% of the total phospholipid. The latter was identified as a bis(monoacylglycerol) phosphate (BMP) using MS. Incorporation studies using C18:3n-3 and C20:5n-3 demonstrated that BMP had a high specificity to incorporate DHA and C22 polyunsaturated fatty acids of the (n-3) series. By contrast, polyunsaturated fatty acids of the (n-6) series were never incorporated into BMP. Incubation of UIII cells with 5µM DHA for 24h increased the DHA content of BMP from 36 to 71% of the total acyl chains. [3H]DHA-labelled BMP purified as a single TLC spot was resolved into three peaks using HPLC. These peaks were also observed when cells were labelled with [3H]phosphatidylglycerol, an exogenous BMP precursor, and with [33P]Pi. Electrospray MS of BMP from control cells showed that the first two peaks contained the same molecular species (mainly C22:6n-3/C22:6n-3 and C18:1n-9/C22:6n-3) while the third peak mainly contained the C18:1n-9/C18:1n-9 species. The stereoconfiguration analysis of the compounds revealed an sn-glycero-3-phospho-1′-sn-glycerol configuration for the first peak and sn-glycero-1-phospho-1′-sn-glycerol configurations for the other two. BMP from rat testis was used to establish the positions of the acyl groups. More than 70% of its acyl chains were C22:5n-6. It was separated on HPLC into three peaks that co-migrated with the three peaks of BMP from UIII cells. Lipase activity and NMR analysis of the second peak showed that fatty acids esterified the primary alcohol group on each glycerol moiety. We conclude that the three peaks are stereoisomeric compounds with different acyl-chain locations and may be the result of different metabolic fates depending on subcellular localization.

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