scholarly journals The Syngeneic BT4C Rat Malignant Glioma is a Valuable Model to study Myelomonocytic cells in Tumors

2012 ◽  
Vol 5 ◽  
pp. CGM.S9314 ◽  
Author(s):  
Thomas Wirth ◽  
Farizan Ahmad ◽  
Agnieszka Pacholska ◽  
Haritha Samaranayake ◽  
Seppo Ylä-Herttuala
Keyword(s):  
Malignant Glioma ◽  
Malignant Gliomas ◽  
Immunohistochemical Analysis ◽  
Infiltration Rate ◽  
Cell Types ◽  
Myelomonocytic Cells ◽  
Glioma Model ◽  
The Impact ◽  
High Infiltration

Background The impact of infiltrating macrophages on tumor progression in malignant gliomas has been studied extensively. However, there is a lack of animal models for studying the role of infiltrating macrophages in malignant gliomas. Material and methods: The BT4C rat malignant glioma model was characterized by immunohistochemical analysis of inflammatory cell types associated with the tumors. Results BT4C malignant gliomas are highly vascularized tumors with an infiltrative behavior. BT4C gliomas demonstrated a high infiltration rate of macrophages. Particularly, a CD68/VEGFR-1 positive subtype of macrophages was detected at the edges of malignant gliomas. Also, CD133 positive cells were located mainly at the infiltrative edges of gliomas, whereas VEGFR-2 was highly expressed throughout the malignant glioma. Conclusion The immunocompetent BT4C rat malignant glioma model shows features similar to its human counterpart, which makes it a valuable model to study the impact of tumor associated macrophages in the pathology of malignant gliomas.

scholarly journals Optimizing expression quantitative trait locus mapping workflows for single-cell studies

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Anna S. E. Cuomo ◽  
Giordano Alvari ◽  
Christina B. Azodi ◽  
Davis J. McCarthy ◽  
Marc Jan Bonder ◽  
...  
Keyword(s):  
Gene Expression ◽  
Quantitative Trait Locus ◽  
Single Cell ◽  
Quantitative Trait ◽  
Cell Types ◽  
Expression Quantitative Trait Locus ◽  
Eqtl Mapping ◽  
Trait Locus ◽  
The Impact

Abstract Background Single-cell RNA sequencing (scRNA-seq) has enabled the unbiased, high-throughput quantification of gene expression specific to cell types and states. With the cost of scRNA-seq decreasing and techniques for sample multiplexing improving, population-scale scRNA-seq, and thus single-cell expression quantitative trait locus (sc-eQTL) mapping, is increasingly feasible. Mapping of sc-eQTL provides additional resolution to study the regulatory role of common genetic variants on gene expression across a plethora of cell types and states and promises to improve our understanding of genetic regulation across tissues in both health and disease. Results While previously established methods for bulk eQTL mapping can, in principle, be applied to sc-eQTL mapping, there are a number of open questions about how best to process scRNA-seq data and adapt bulk methods to optimize sc-eQTL mapping. Here, we evaluate the role of different normalization and aggregation strategies, covariate adjustment techniques, and multiple testing correction methods to establish best practice guidelines. We use both real and simulated datasets across single-cell technologies to systematically assess the impact of these different statistical approaches. Conclusion We provide recommendations for future single-cell eQTL studies that can yield up to twice as many eQTL discoveries as default approaches ported from bulk studies.

scholarly journals Nano-Biomimetic Drug Delivery Vehicles: Potential Approaches for COVID-19 Treatment

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5952
Author(s):  
Bwalya A. Witika ◽  
Pedzisai A. Makoni ◽  
Larry L. Mweetwa ◽  
Pascal V. Ntemi ◽  
Melissa T. R. Chikukwa ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Targeted Delivery ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Charge Composition ◽  
Drug Delivery Vehicles ◽  
Therapeutic Outcomes ◽  
Delivery Vehicles ◽  
The Impact

The current COVID-19 pandemic has tested the resolve of the global community with more than 35 million infections worldwide and numbers increasing with no cure or vaccine available to date. Nanomedicines have an advantage of providing enhanced permeability and retention and have been extensively studied as targeted drug delivery strategies for the treatment of different disease. The role of monocytes, erythrocytes, thrombocytes, and macrophages in diseases, including infectious and inflammatory diseases, cancer, and atherosclerosis, are better understood and have resulted in improved strategies for targeting and in some instances mimicking these cell types to improve therapeutic outcomes. Consequently, these primary cell types can be exploited for the purposes of serving as a “Trojan horse” for targeted delivery to identified organs and sites of inflammation. State of the art and potential utilization of nanocarriers such as nanospheres/nanocapsules, nanocrystals, liposomes, solid lipid nanoparticles/nano-structured lipid carriers, dendrimers, and nanosponges for biomimicry and/or targeted delivery of bioactives to cells are reported herein and their potential use in the treatment of COVID-19 infections discussed. Physicochemical properties, viz., hydrophilicity, particle shape, surface charge, composition, concentration, the use of different target-specific ligands on the surface of carriers, and the impact on carrier efficacy and specificity are also discussed.

scholarly journals Optimising expression quantitative trait locus mapping workflows for single-cell studies

2021 ◽  
Author(s):  
Anna S.E. Cuomo ◽  
Giordano Alvari ◽  
Christina B. Azodi ◽  
Davis J. McCarthy ◽  
Marc Jan Bonder ◽  
...  
Keyword(s):  
Gene Expression ◽  
Quantitative Trait Locus ◽  
Single Cell ◽  
Quantitative Trait ◽  
Cell Types ◽  
Expression Quantitative Trait Locus ◽  
Eqtl Mapping ◽  
Trait Locus ◽  
The Impact

AbstractSingle-cell RNA-sequencing (scRNA-seq) has enabled the unbiased, high-throughput quantification of gene expression specific to cell types and states. With the cost of scRNA-seq decreasing and techniques for sample multiplexing improving, population-scale scRNA-seq, and thus single-cell expression quantitative trait locus (sc-eQTL) mapping, is increasingly feasible. Mapping of sc-eQTL provides additional resolution to study the regulatory role of common genetic variants on gene expression across a plethora of cell types and states, and promises to improve our understanding of genetic regulation across tissues in both health and disease. While previously established methods for bulk eQTL mapping can, in principle, be applied to sc-eQTL mapping, there are a number of open questions about how best to process scRNA-seq data and adapt bulk methods to optimise sc-eQTL mapping. Here, we evaluate the role of different normalisation and aggregation strategies, covariate adjustment techniques, and multiple testing correction methods to establish best practice guidelines. We use both real and simulated datasets across single-cell technologies to systematically assess the impact of these different statistical approaches and provide recommendations for future single-cell eQTL studies that can yield up to twice as many eQTL discoveries as default approaches ported from bulk studies.

scholarly journals Inhibition of FABP6 Reduces Tumor Cell Invasion and Angiogenesis through the Decrease in MMP-2 and VEGF in Human Glioblastoma Cells

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2782
Author(s):  
Feng-Cheng Pai ◽  
Hsiang-Wei Huang ◽  
Yu-Ling Tsai ◽  
Wen-Chiuan Tsai ◽  
Yu-Chen Cheng ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Malignant Gliomas ◽  
Matrix Metalloproteinase 2 ◽  
Migration And Invasion ◽  
Rapid Progression ◽  
Normal Brain ◽  
Mouse Tumor ◽  
Vegf Receptor ◽  
Fatty Acid Binding ◽  
The Impact

Malignant glioma is one of the most lethal cancers with rapid progression, high recurrence, and poor prognosis in the central nervous system. Fatty acid-binding protein 6 (FABP6) is a bile acid carrier protein that is overexpressed in colorectal cancer. This study aimed to assess the involvement of FABP6 expression in the progression of malignant glioma. Immunohistochemical analysis revealed that FABP6 expression was higher in glioma than in normal brain tissue. After the knockdown of FABP6, a decrease in the migration and invasion abilities of glioma cells was observed. The phosphorylation of the myosin light chain was inhibited, which may be associated with migration ability. Moreover, expression levels of invasion-related proteins, matrix metalloproteinase-2 (MMP-2) and cathepsin B, were reduced. Furthermore, tube formation was inhibited in the human umbilical vein endothelial cells with a decreased concentration of vascular endothelial growth factor (VEGF) in the conditioned medium after the knockdown of FABP6. The phosphorylation of the extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p65 were also decreased after FABP6 reduction. Finally, the bioluminescent images and immunostaining of MMP-2, cluster of differentiation 31 (CD31), and the VEGF receptor 1 (VEGFR1) revealed attenuated tumor progression in the combination of the FABP6-knocked-down and temozolomide (TMZ)-treated group in an orthotopic xenograft mouse tumor model. This is the first study that revealed the impact of FABP6 on the invasion, angiogenesis, and progression of glioma. The results of this study show that FABP6 may be a potential therapeutic target combined with TMZ for malignant gliomas.

scholarly journals Downregulation of the CCL2/CCR2 and CXCL10/CXCR3 axes contributes to antitumor effects in a mouse model of malignant glioma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kenji Shono ◽  
Izumi Yamaguchi ◽  
Yoshifumi Mizobuchi ◽  
Hiroshi Kagusa ◽  
Akiko Sumi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Malignant Glioma ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Paracrine Signaling ◽  
Therapeutic Approaches ◽  
Antitumor Effects ◽  
Glioma Model ◽  
Dose Dependent

Abstract Glioblastoma multiforme involves glioma stem cells (GSCs) that are resistant to various therapeutic approaches. Here, we studied the importance of paracrine signaling in the glioma microenvironment by focusing on the celecoxib-mediated role of chemokines C–C motif ligand 2 (CCL2), C-X-C ligand 10 (CXCL10), and their receptors, CCR2 and CXCR3, in GSCs and a GSC-bearing malignant glioma model. C57BL/6 mice were injected with orthotopic GSCs intracranially and divided into groups administered either 10 or 30 mg/kg celecoxib, or saline to examine the antitumor effects associated with chemokine expression. In GSCs, we analyzed cell viability and expression of chemokines and their receptors in the presence/absence of celecoxib. In the malignant glioma model, celecoxib exhibited antitumor effects in a dose dependent manner and decreased protein and mRNA levels of Ccl2 and CxcL10 and Cxcr3 but not of Ccr2. CCL2 and CXCL10 co-localized with Nestin+ stem cells, CD16+ or CD163+ macrophages and Iba-1+ microglia. In GSCs, celecoxib inhibited Ccl2 and Cxcr3 expression in a nuclear factor-kappa B-dependent manner but not Ccr2 and CxcL10. Moreover, Ccl2 silencing resulted in decreased GSC viability. These results suggest that celecoxib-mediated regulation of the CCL2/CCR2 and CXCL10/ CXCR3 axes may partially contribute to glioma-specific antitumor effects.

scholarly journals The Endocannabinoid System in Glial Cells and Their Profitable Interactions to Treat Epilepsy: Evidence from Animal Models

2021 ◽  
Vol 22 (24) ◽  
pp. 13231
Author(s):  
Jon Egaña-Huguet ◽  
Edgar Soria-Gómez ◽  
Pedro Grandes
Keyword(s):  
Glial Cells ◽  
Endocannabinoid System ◽  
Cell Types ◽  
Specific Cell ◽  
Neuronal Viability ◽  
Wide Range ◽  
Novel Target ◽  
Different Cell Types ◽  
The Impact

Epilepsy is one of the most common neurological conditions. Yearly, five million people are diagnosed with epileptic-related disorders. The neuroprotective and therapeutic effect of (endo)cannabinoid compounds has been extensively investigated in several models of epilepsy. Therefore, the study of specific cell-type-dependent mechanisms underlying cannabinoid effects is crucial to understanding epileptic disorders. It is estimated that about 100 billion neurons and a roughly equal number of glial cells co-exist in the human brain. The glial population is in charge of neuronal viability, and therefore, their participation in brain pathophysiology is crucial. Furthermore, glial malfunctioning occurs in a wide range of neurological disorders. However, little is known about the impact of the endocannabinoid system (ECS) regulation over glial cells, even less in pathological conditions such as epilepsy. In this review, we aim to compile the existing knowledge on the role of the ECS in different cell types, with a particular emphasis on glial cells and their impact on epilepsy. Thus, we propose that glial cells could be a novel target for cannabinoid agents for treating the etiology of epilepsy and managing seizure-like disorders.

scholarly journals The role of hub neurons in modulating cortical dynamics

2021 ◽  
Author(s):  
Eyal Gal ◽  
Oren Amsalem ◽  
Alon Schindel ◽  
Michael London ◽  
Felix Schuermann ◽  
...  
Keyword(s):  
Network Science ◽  
Structural Integrity ◽  
Cell Types ◽  
Brain Regions ◽  
Cortical Layers ◽  
Disease Manifestation ◽  
Cortical Dynamics ◽  
The Impact ◽  
Specific Neuron

Many neurodegenerative diseases are associated with the death of specific neuron types in particular brain regions. What makes the death of specific neuron types particularly harmful for the integrity and dynamics of the respective network is not well understood. To start addressing this question we used the most up-to-date biologically-realistic dense neocortical microcircuit (NMC) of rodent, which has reconstructed a volume of 0.3 mm3 and containing 31,000 neurons, 36 million synapses, and 55 morphological cell types arranged in 6 cortical layers. Using modern network science tools, we identified ״hub-neurons״ in the NMC, that are connected synaptically to a large number of their neighbors and systematically examined the impact of abolishing these cells. In general, the structural integrity of the network is robust to cellsֿ' attack; yet, attacking hub neurons strongly impacted the ״small worldness״ topology of the network, whereas similar attacks on random neurons have a negligible effect. Such hub-specific attacks are also impactful on the network dynamics, both when the network is at its spontaneous synchronous state and when it was presented with synchronized thalamo-cortical visual-like input. We found that attacking layer 5 hub neurons are most harmful to the structural and functional integrity of the NMC. The significance of our results for understanding the role of specific neuron types and cortical layers for disease manifestation is discussed.

scholarly journals The Role of Platelets in Cancer Pathophysiology: Focus on Malignant Glioma

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 569 ◽  
Author(s):  
Sascha Marx ◽  
Yong Xiao ◽  
Marcel Baschin ◽  
Maximilian Splittstöhser ◽  
Robert Altmann ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Immune Cells ◽  
Potential Role ◽  
Immune Cell ◽  
Malignant Gliomas ◽  
Cell Communication ◽  
Distant Metastases ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System

The link between thrombocytosis and malignancy has been well known for many years and its associations with worse outcomes have been reported mainly for solid tumors. Besides measuring platelet count, it has become popular to assess platelet function in the context of malignant diseases during the last decade. Malignant gliomas differ tremendously from malignancies outside the central nervous system because they virtually never form distant metastases. This review summarizes the current understanding of the platelet–immune cell communication and its potential role in glioma resistance and progression. Particularly, we focus on platelet-derived proinflammatory modulators, such as sphingosine-1-phosphate (S1P). The multifaceted interaction with immune cells puts the platelet into an interesting perspective regarding the recent advances in immunotherapeutic approaches in malignant glioma.

scholarly journals Mechanistic paradigms of cell death - revisited

2021 ◽  
Vol 42 (4) ◽  
pp. 903-917
Author(s):  
S.V.S. Rana ◽  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Human Health Risk ◽  
Cell Types ◽  
Enzymatic Antioxidants ◽  
Cellular Targets ◽  
A Cell ◽  
The Impact ◽  
Made In

Present review is the description of a journey that originates from Virchows' cell theory and terminates with the role of molecular switches in cell death recently proposed by Orrenius. Landmark discoveries made, in between, to characterize regulated as well as accidental cell death have also been documented. It embraces the studies that were made in early nineties to understand cellular homeostasis in health and disease. Furthermore, the effects of foreign chemicals on different cell types witnessed in late nineties have been classified into necrosis, apoptosis, autophagy etc. Since it is important to know how a cell dies, studies made in our own and other laboratories on the role of reactive oxygen species, oxidative stress, intracellular Ca2+ homeostasis, redox imbalance, mitochondrial and ER stress in cell death have also been reviewed. Possibility of a cross talk amongst these mechanisms has also been examined. It discusses the impact of wonder molecules like CYP450, GSH, metallothionein and melatonin together with enzymatic and non-enzymatic antioxidants on cell death. Understanding the cellular targets and molecular mechanisms activated by a variety of environmental xenobiotics is fundamental for human health risk assessment. It is expected that the contents of this article will answer the fundamental question- why and how cells die.

scholarly journals Role of RAGE and Its Ligands on Inflammatory Responses to Brain Tumors

2021 ◽  
Vol 15 ◽  
Author(s):  
Griffith Kyle Otazu ◽  
Mojtaba Dayyani ◽  
Behnam Badie
Keyword(s):  
Cancer Progression ◽  
Inflammatory Responses ◽  
Checkpoint Inhibitors ◽  
Malignant Gliomas ◽  
Low Grade ◽  
Molecular Pattern ◽  
The Impact

Gliomas, the most common form of brain cancer, can range from relatively slow-growing low-grade to highly aggressive glioblastoma that has a median overall survival of only 15 months despite multimodal standard therapy. Although immunotherapy with checkpoint inhibitors has significantly improved patient survival for some cancers, to date, these agents have not shown consistent efficacy against malignant gliomas. Therefore, there is a pressing need to better understand the impact of host inflammatory responses on the efficacy of emerging immunotherapy approaches for these resistant tumors. RAGE is a multi-ligand pattern recognition receptor that is activated in various inflammatory states such as diabetes, Alzheimer’s disease, cystic fibrosis, and cancer. Low levels of RAGE can be found under normal physiological conditions in neurons, immune cells, activated endothelial, and vascular smooth muscle cells, but it is over-expressed under chronic inflammation due to the accumulation of its ligands. RAGE binds to a range of damage-associated molecular pattern molecules (DAMPs) including AGEs, HMGB1, S100s, and DNA which mediate downstream cellular responses that promote tumor growth, angiogenesis, and invasion. Both in vitro and in vivo studies have shown that inhibition of RAGE signaling can disrupt inflammation and cancer progression and metastasis. Here, we will review our current understanding of the role of RAGE pathway on glioma progression and how it could be exploited to improve the efficacy of immunotherapy approaches.

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