Development of an epitope-based vaccine inhibiting immune cells rolling and migration against atherosclerosis using in silico approaches

2017 ◽  
Vol 70 ◽  
pp. 156-163 ◽  
Author(s):  
Mehdi Tourani ◽  
Ahmad Karkhah ◽  
Ali Najafi
Keyword(s):  
Immune Cells ◽  
In Silico ◽  
And Migration

scholarly journals The Role of Sphingolipids in Cancer Immunotherapy

2021 ◽  
Vol 22 (12) ◽  
pp. 6492
Author(s):  
Paola Giussani ◽  
Alessandro Prinetti ◽  
Cristina Tringali
Keyword(s):  
Immune System ◽  
Cancer Cells ◽  
Immune Cells ◽  
Plasma Membranes ◽  
Checkpoint Inhibitors ◽  
Surface Receptors ◽  
Car T ◽  
Sphingosine 1 Phosphate ◽  
And Migration ◽  
Lymphocyte Egress

Immunotherapy is now considered an innovative and strong strategy to beat metastatic, drug-resistant, or relapsing tumours. It is based on the manipulation of several mechanisms involved in the complex interplay between cancer cells and immune system that culminates in a form of immune-tolerance of tumour cells, favouring their expansion. Current immunotherapies are devoted enforcing the immune response against cancer cells and are represented by approaches employing vaccines, monoclonal antibodies, interleukins, checkpoint inhibitors, and chimeric antigen receptor (CAR)-T cells. Despite the undoubted potency of these treatments in some malignancies, many issues are being investigated to amplify the potential of application and to avoid side effects. In this review, we discuss how sphingolipids are involved in interactions between cancer cells and the immune system and how knowledge in this topic could be employed to enhance the efficacy of different immunotherapy approaches. In particular, we explore the following aspects: how sphingolipids are pivotal components of plasma membranes and could modulate the functionality of surface receptors expressed also by immune cells and thus their functionality; how sphingolipids are related to the release of bioactive mediators, sphingosine 1-phosphate, and ceramide that could significantly affect lymphocyte egress and migration toward the tumour milieu, in addition regulating key pathways needed to activate immune cells; given the renowned capability of altering sphingolipid expression and metabolism shown by cancer cells, how it is possible to employ sphingolipids as antigen targets.

scholarly journals Distinct microbial and immune niches of the human colon

2019 ◽  
Author(s):  
KR James ◽  
T Gomes ◽  
R Elmentaite ◽  
N Kumar ◽  
EL Gulliver ◽  
...  
Keyword(s):  
Immune Cells ◽  
Cell Activation ◽  
T Regulatory Cells ◽  
Bacterial Species ◽  
Human Colon ◽  
Mesenteric Lymph Nodes ◽  
Gastrointestinal Microbiota ◽  
Regional Specificity ◽  
Transcriptional Adaptation ◽  
And Migration

AbstractGastrointestinal microbiota and immune cells interact closely and display regional specificity, but little is known about how these communities differ with location. Here, we simultaneously assess microbiota and single immune cells across the healthy, adult human colon, with paired characterisation of immune cells in the mesenteric lymph nodes, to delineate colonic immune niches at steady-state. We describe distinct T helper cell activation and migration profiles along the colon and characterise the transcriptional adaptation trajectory of T regulatory cells between lymphoid tissue and colon. Finally, we show increasing B cell accumulation, clonal expansion and mutational frequency from caecum to sigmoid colon, and link this to the increasing number of reactive bacterial species.

scholarly journals Isolation, Characterization, and Agent-Based Modeling of Mesenchymal Stem Cells in a Bio-construct for Myocardial Regeneration Scaffold Design

Data ◽  
2019 ◽  
Vol 4 (2) ◽  
pp. 71 ◽  
Author(s):  
Diana Victoria Ramírez López ◽  
María Isabel Melo Escobar ◽  
Carlos A. Peña-Reyes ◽  
Álvaro J. Rojas Arciniegas ◽  
Paola Andrea Neuta Arciniegas
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
In Silico ◽  
Cardiac Tissue ◽  
Cellular Level ◽  
Cell Behavior ◽  
Agent Based Model ◽  
Agent Based ◽  
And Migration

Regenerative medicine involves methods to control and modify normal tissue repair processes. Polymer and cell constructs are under research to create tissue that replaces the affected area in cardiac tissue after myocardial infarction (MI). The aim of the present study is to evaluate the behavior of differentiated and undifferentiated mesenchymal stem cells (MSCs) in vitro and in silico and to compare the results that both offer when it comes to the design process of biodevices for the treatment of infarcted myocardium in biomodels. To assess in vitro behavior, MSCs are isolated from rat bone marrow and seeded undifferentiated and differentiated in multiple scaffolds of a gelled biomaterial. Subsequently, cell behavior is evaluated by trypan blue and fluorescence microscopy, which showed that the cells presented high viability and low cell migration in the biomaterial. An agent-based model intended to reproduce as closely as possible the behavior of individual MSCs by simulating cellular-level processes was developed, where the in vitro results are used to identify parameters in the agent-based model that is developed, and which simulates cellular-level processes: Apoptosis, differentiation, proliferation, and migration. Thanks to the results obtained, suggestions for good results in the design and fabrication of the proposed scaffolds and how an agent-based model can be helpful for testing hypothesis are presented in the discussion. It is concluded that assessment of cell behavior through the observation of viability, proliferation, migration, inflammation reduction, and spatial composition in vitro and in silico, represents an appropriate strategy for scaffold engineering.

scholarly journals Identification of HMGCR as the anticancer target of physapubenolide against melanoma cells by in silico target prediction

2021 ◽  
Author(s):  
Hai-yan Wang ◽  
Pian Yu ◽  
Xi-sha Chen ◽  
Hui Wei ◽  
Shi-jie Cao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
In Silico ◽  
Molecular Mechanisms ◽  
Mevalonate Pathway ◽  
Xenograft Model ◽  
Target Prediction ◽  
Quantitative Structure Activity Relationship ◽  
Melanoma Cells ◽  
And Migration ◽  
Coa Reductase

AbstractPhysapubenolide (PB), a withanolide-type compound extracted from the traditional herb Physalis minima L., has been demonstrated to exert remarkable cytotoxicity against cancer cells; however, its molecular mechanisms are still unclear. In this study, we demonstrated that PB inhibited cell proliferation and migration in melanoma cells by inducing cell apoptosis. The anticancer activity of PB was further verified in a melanoma xenograft model. To explore the mechanism underlying the anticancer effects of PB, we carried out an in silico target prediction study, which combined three approaches (chemical similarity searching, quantitative structure-activity relationship (QSAR), and molecular docking) to identify the targets of PB, and found that PB likely targets 3-hydroxy-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, which promotes cancer cell proliferation, migration, and metastasis. We further demonstrated that PB interacted with HMGCR, decreased its protein expression and inhibited the HMGCR/YAP pathway in melanoma cells. In addition, we found that PB could restore vemurafenib sensitivity in vemurafenib-resistant A-375 cells, which was correlated with the downregulation of HMGCR. In conclusion, we demonstrate that PB elicits anticancer action and enhances sensitivity to vemurafenib by targeting HMGCR.

scholarly journals In Silico Assessment of 5-FU Therapy via A Mathematical Model with Fuzzy Uncertain Parameters

2020 ◽  
Author(s):  
Sajad Shafiekhani ◽  
Amir. H. Jafari ◽  
L. Jafarzadeh ◽  
N. Gheibi
Keyword(s):  
Differential Equation ◽  
Immune Cells ◽  
In Silico ◽  
Parametric Uncertainty ◽  
Testable Hypothesis ◽  
Model Parameters ◽  
Ode Model ◽  
Ode Models ◽  
Mathematical Oncology ◽  
Uncertainty Band

Abstract Background: Ordinary differential equation (ODE) models widely have been used in mathematical oncology to capture dynamics of tumor and immune cells and evaluate the efficacy of treatments. However, for dynamic models of tumor-immune system (TIS), some parameters are uncertain due to inaccurate, missing or incomplete data, which has hindered the application of ODEs that require accurate parameters. Methods: We extended an available ODE model of TIS interactions via fuzzy logic to illustrate the fuzzification procedure of an ODE model. Fuzzy ODE (FODE) models, in comparison with the stochastic differential equation (SDE) models, assigns a fuzzy number instead of a random number (from a specific probability density function) to the parameters, to capture parametric uncertainty. We used FODE model to predict tumor and immune cells dynamics and assess the efficacy of 5-FU. The present model is configurable for 5-FU chemotherapy injection timing and propose testable hypothesis in vitro/ in vivo experiments. Result: FODE model was used to explore the uncertainty of cells dynamics resulting from parametric uncertainty in presence and absence of 5-FU therapy. In silico experiments revealed that the frequent 5-FU injection created a beneficial tumor microenvironment that exerted detrimental effects on tumor cells by enhancing the infiltration of CD8+ T cells, and NK cells, and decreasing that of myeloid-derived suppressor (MDSC) cells. We investigate the effect of perturbation on model parameters on dynamics of cells through global sensitivity analysis (GSA) and compute correlation between model parameters and cell dynamics. Conclusion: ODE models with fuzzy uncertain kinetic parameters cope with insufficient experimental data in the field of mathematical oncology and can predict cells dynamics uncertainty band. In silico assessment of treatments considering parameter uncertainty and investigating the effect of the drugs on movement of cells dynamics uncertainty band may be more appropriate than in crisp setting.

scholarly journals Helicobacter pylori-Induced Heparanase Promotes H. pylori Colonization and Gastritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Li Tang ◽  
Bo Tang ◽  
Yuanyuan Lei ◽  
Min Yang ◽  
Sumin Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Heparan Sulfate ◽  
Chronic Gastritis ◽  
Immune Cells ◽  
Mapk Signaling ◽  
Inflammatory Conditions ◽  
Cytokines And Chemokines ◽  
And Migration ◽  
H Pylori

Chronic gastritis caused by Helicobacter pylori (H. pylori) infection has been widely recognized as the most important risk factor for gastric cancer. Analysis of the interaction between the key participants in gastric mucosal immunity and H. pylori infection is expected to provide important insights for the treatment of chronic gastritis and the prevention of gastric cancer. Heparanase is an endoglycosidase that degrades heparan sulfate, resulting in remodeling of the extracellular matrix thereby facilitating the extravasation and migration of immune cells towards sites of inflammation. Heparanase also releases heparan sulfate-bound cytokines and chemokines that further promote directed motility and recruitment of immune cells. Heparanase is highly expressed in a variety of inflammatory conditions and diseases, but its role in chronic gastritis has not been sufficiently explored. In this study, we report that H. pylori infection promotes up-regulation of heparanase in gastritis, which in turn facilitates the colonization of H. pylori in the gastric mucosa, thereby aggravating gastritis. By sustaining continuous activation, polarization and recruitment of macrophages that supply pro-inflammatory and pro-tumorigenic cytokines (i.e., IL-1, IL-6, IL-1β, TNF-α, MIP-2, iNOS), heparanase participates in the generation of a vicious circle, driven by enhanced NFκB and p38-MAPK signaling, that supports the development and progression of gastric cancer. These results suggest that inhibition of heparanase may block this self-sustaining cycle, and thereby reduce the risk of gastritis and gastric cancer.

scholarly journals Differential MMP-14 Targeting by Lumican-Derived Peptides Unraveled by In Silico Approach

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4930
Author(s):  
Jonathan Dauvé ◽  
Nicolas Belloy ◽  
Romain Rivet ◽  
Nicolas Etique ◽  
Pierre Nizet ◽  
...  
Keyword(s):  
Amino Acids ◽  
In Silico ◽  
Primary Melanoma ◽  
Direct Interaction ◽  
Inhibitory Effect ◽  
Melanoma Tumor ◽  
And Migration ◽  
Key Residues

Lumican, a small leucine-rich proteoglycan (SLRP) of the extracellular matrix (ECM), displays anti-tumor properties through its direct interaction with MMP-14. Lumican-derived peptides, such as lumcorin (17 amino acids) or L9M (10 amino acids), are able to inhibit the proteolytic activity of MMP-14 and melanoma progression. This work aimed to visualize the interactions of lumican-derived peptides and MMP-14. Molecular modeling was used to characterize the interactions between lumican-derived peptides, such as lumcorin, L9M, and cyclic L9M (L9Mc, 12 amino acids), and MMP-14. The interaction of L9Mc with MMP-14 was preferential with the MT-Loop domain while lumcorin interacted more with the catalytic site. Key residues in the MMP-14 amino acid sequence were highlighted for the interaction between the inhibitory SLRP-derived peptides and MMP-14. In order to validate the in silico data, MMP-14 activity and migration assays were performed using murine B16F1 and human HT-144 melanoma cells. In contrast to the HT-144 melanoma cell line, L9Mc significantly inhibited the migration of B16F1 cells and the activity of MMP-14 but with less efficacy than lumican and lumcorin. L9Mc significantly inhibited the proliferation of B16F1 but not of HT-144 cells in vitro and primary melanoma tumor growth in vivo. Thus, the site of interaction between the domains of MMP-14 and lumcorin or L9Mc were different, which might explain the differences in the inhibitory effect of MMP-14 activity. Altogether, the biological assays validated the prediction of the in silico study. Possible and feasible improvements include molecular dynamics results.

scholarly journals Loss of Hem1 disrupts macrophage function and impacts on migration, phagocytosis and integrin-mediated adhesion

2020 ◽  
Author(s):  
Stephanie Stahnke ◽  
Hermann Döring ◽  
Charly Kusch ◽  
David J.J. de Gorter ◽  
Sebastian Dütting ◽  
...  
Keyword(s):  
Immune Cells ◽  
Focal Adhesions ◽  
Specific Protein ◽  
Macrophage Function ◽  
Actin Networks ◽  
Motile Cells ◽  
Regulatory Complex ◽  
And Migration ◽  
Dependent Processes ◽  
Essential Subunit

ABSTRACTThe hematopoietic-specific protein 1 (Hem1) comprises an essential subunit of the WAVE Regulatory Complex (WRC) in immune cells. WRC has a fundamental role in Arp2/3 complex activation and the protrusion of branched actin networks in motile cells.Hem1 deficiency leads to suppression of the entire WRC in immune cells. Defective WRC function in macrophages results in loss of lamellipodia and migration defects. Moreover, phagocytosis, commonly accompanied by lamellipodium protrusion during cup formation, is altered in Hem1 null cells concerning frequency and efficacy. When analyzing cell spreading, adhesion and podosome formation, we found that Hem1 null cells are capable, in principle, of podosome formation and consequently, do not show any quantitative differences in extracellular matrix degradation. Their adhesive behavior, however, was significantly altered. Specifically, adhesion as well as de-adhesion of Hem1 null cells was strongly compromised, likely contributing to the observed reduced efficiency of phagocytosis. In line with this, phosphorylation of the prominent adhesion component paxillin was diminished. Non-hematopoietic somatic cells disrupted in expression for both Hem1 and its ubiquitous orthologue Nck-associated protein 1 (Nap1) or the essential WRC components Sra-1/PIR121 did not only confirm defective paxillin phosphorylation, but also revealed that paxillin turnover in focal adhesions is accelerated in the absence of WRC. Finally, adhesion assays using platelets lacking functional WRC as model system unmasked radically decreased αIIbβ3 integrin activation.Our results thus demonstrate that WRC-driven actin networks impact on integrin-dependent processes controlling formation and dismantling of different types of cell-substratum adhesion.One sentence summaryInterference of Hem1 function in mice and cells uncovers a hitherto unrecognized role in integrin-mediated cell adhesion that is crucial for macrophage function and connects to recently discovered immunodeficiencies in patients carrying Hem1 mutations.

SHMT2 is Associated with Tumor Purity, CD8+ T Immune Cells Infiltration, and a Novel Therapeutic Target in Four Different Human Cancers

2022 ◽  
Vol 22 ◽  
Author(s):  
Muhammad Usman ◽  
Yasir Hameed ◽  
Mukhtiar Ahmad ◽  
Muhammad Junaid Iqbal ◽  
Aghna Maryam ◽  
...  
Keyword(s):  
Immune Cells ◽  
Promoter Methylation ◽  
In Silico ◽  
Human Cancer ◽  
Enrichment Analysis ◽  
Genetic Alterations ◽  
Pathway Enrichment Analysis ◽  
Human Cancers ◽  
Tumor Purity

Aims: This study was launched to identify the SHMT2 associated Human Cancer subtypes. Background: Cancer is the 2nd leading cause of death worldwide. Previous reports revealed the limited involvement of SHMT2 in human cancer. In the current study, we comprehensively analyzed the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a few subtypes that are mainly associated with SHMT2. Objective:: We aim to comprehensively analyze the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a few subtypes that are mainly associated with SHMT2. Earlier, limited knowledge exists in the medical literature regarding the involvement of Serine Hydroxymethyltransferase 2 (SHMT2) in human cancer. Methods: In the current study, we comprehensively analyzed the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a few subtypes that are mainly associated with SHMT2. Pan-cancer transcriptional expression profiling of SHMT2 was done using UALCAN while further validation was performed using GENT2. For translational profiling of SHMT2, we utilized Human Protein Atlas (HPA) platform. Promoter methylation, genetic alteration, and copy number variations (CNVs) profiles were analyzed through MEXPRESS and cBioPortal. Survival analysis was carried out through Kaplan–Meier (KM) plotter platform. Pathway enrichment analysis of SHMT2 was performed using DAVID, while the gene-drug network was drawn through CTD and Cytoscape. Furthermore, in the tumor microenvironment, a correlation between tumor purity, CD8+ T immune cells infiltration, and SHMT2 expression was accessed using TIMER. Results: SHMT2 was found overexpressed in 24 different subtypes of human cancers and its overexpression was significantly associated with the reduced Overall survival (OS) and Relapse-free survival durations of Breast cancer (BRCA), Kidney renal papillary cell carcinoma (KIRP), Liver hepatocellular carcinoma (LIHC), and Lung adenocarcinoma (LUAD) patients. This implies that SHMT2 plays a significant role in the development and progression of these cancers. We further noticed that SHMT2 was also up-regulated in BRCA, KIRP, LIHC, and LUAD patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of SHMT2 enriched genes in five diverse pathways. Furthermore, we also explored some interesting correlations between SHMT2 expression and promoter methylation, genetic alterations, CNVs, tumor purity, and CD8+ T immune cell infiltrates. Conclusion: Our results suggested that overexpressed SHMT2 is correlated with the reduced OS and RFS of the BRCA, KIRP, LIHC, and LUAD patients and can be a potential diagnostic and prognostic biomarker for these cancers.

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