scholarly journals Exploiting aneuploidy-imposed stresses and coping mechanisms to battle cancer

Open Biology ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 200148
Author(s):  
Lin Zhou ◽  
Laura J. Jilderda ◽  
Floris Foijer
Keyword(s):  
Cancer Cells ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Metabolic Stress ◽  
Coping Mechanisms ◽  
Immune Cell Activation ◽  
Cycle Arrest ◽  
Biological Responses ◽  
And Coping

Aneuploidy, an irregular number of chromosomes in cells, is a hallmark feature of cancer. Aneuploidy results from chromosomal instability (CIN) and occurs in almost 90% of all tumours. While many cancers display an ongoing CIN phenotype, cells can also be aneuploid without displaying CIN. CIN drives tumour evolution as ongoing chromosomal missegregation will yield a progeny of cells with variable aneuploid karyotypes. The resulting aneuploidy is initially toxic to cells because it leads to proteotoxic and metabolic stress, cell cycle arrest, cell death, immune cell activation and further genomic instability. In order to overcome these aneuploidy-imposed stresses and adopt a malignant fate, aneuploid cancer cells must develop aneuploidy-tolerating mechanisms to cope with CIN. Aneuploidy-coping mechanisms can thus be considered as promising therapeutic targets. However, before such therapies can make it into the clinic, we first need to better understand the molecular mechanisms that are activated upon aneuploidization and the coping mechanisms that are selected for in aneuploid cancer cells. In this review, we discuss the key biological responses to aneuploidization, some of the recently uncovered aneuploidy-coping mechanisms and some strategies to exploit these in cancer therapy.

scholarly journals A bi-directional dialog between vascular cells and monocytes/macrophages regulates tumor progression

2021 ◽  
Author(s):  
Victor Delprat ◽  
Carine Michiels
Keyword(s):  
Tumor Progression ◽  
Cancer Progression ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
The Body ◽  
Vascular Cells ◽  
Tumor Associated Macrophage ◽  
Immune Cell Activation ◽  
The Impact

AbstractCancer progression largely depends on tumor blood vessels as well on immune cell infiltration. In various tumors, vascular cells, namely endothelial cells (ECs) and pericytes, strongly regulate leukocyte infiltration into tumors and immune cell activation, hence the immune response to cancers. Recently, a lot of compelling studies unraveled the molecular mechanisms by which tumor vascular cells regulate monocyte and tumor-associated macrophage (TAM) recruitment and phenotype, and consequently tumor progression. Reciprocally, TAMs and monocytes strongly modulate tumor blood vessel and tumor lymphatic vessel formation by exerting pro-angiogenic and lymphangiogenic effects, respectively. Finally, the interaction between monocytes/TAMs and vascular cells is also impacting several steps of the spread of cancer cells throughout the body, a process called metastasis. In this review, the impact of the bi-directional dialog between blood vascular cells and monocytes/TAMs in the regulation of tumor progression is discussed. All together, these data led to the design of combinations of anti-angiogenic and immunotherapy targeting TAMs/monocyte whose effects are briefly discussed in the last part of this review.

9 METABOLIC UTILIZATION OF PROPANEDIOL BY ADHERENT-INVASIVE E. COLI REGULATES INTESTINAL TISSUE IMMUNITY

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S33-S33
Author(s):  
Monica Viladomiu ◽  
Maeva Metz ◽  
Svetlana Lima ◽  
Chun-Jun Guo ◽  
Kenneth Simpson ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Th17 Cells ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Mononuclear Phagocytes ◽  
Secretion Systems ◽  
E Coli ◽  
Immune Cell Activation

Abstract While the molecular mechanisms by which the microbiome modulates mucosal immunity in Crohn’s disease (CD) are still largely unknown, recent data highlight the involvement of specific diet- and bacterial-derived metabolites in the regulation of intestinal immune cell activation and differentiation. We have recently shown that Adherent-Invasive E.coli (AIEC), which are enriched in CD patients, are sufficient to induce intestinal Th17 cells. Although AIEC lack pathogenic factors including type III secretion systems, many CD-derived isolates express virulence-associated metabolic enzymes including propanediol dehydratase (PduC), which enables AIEC to use fucose-derived propanediol as an alternate carbon source in the gut. We found that pduC is enriched in the microbiome and among E. coli genomes in CD patients compared to healthy controls. With fucosylated oligosaccharides on the surface of intestinal epithelial cells, we hypothesized that this propanediol utilization pathway provides AIEC a competitive advantage for epithelial cell adherence and intestinal immune cell activation. To evaluate the physiologic contribution of pduC to mucosal Th17 induction, we generated a pduC-deficient (ΔpduC) mutant of a CD-derived, AIEC isolate. Deletion of pduC resulted in reduced inflammatory Th17 cells and attenuated weight loss following T cell transfer colitis. Using genetic mouse models, we found that CX3CR1+ mononuclear phagocytes are required for this AIEC-mediated Th17 induction and IL-10 is required to restrain pduC-dependent dextran sodium sulfate (DSS)-induced colitis. Using a catalytically-inactive mutant, we determined that PduC metabolic activity was required for this immune phenotype. Cell-free supernatants from WT AIEC (but not the isogenic, pduC-deficient clone) promoted ex vivo Th17 cell polarization and metabolomics analysis (LC-MS) of these supernatants defined PduC-dependent metabolites capable of promoting Th17 polarization. These studies reveal a link between AIEC microbial metabolism and inflammatory Th17 cells with the potential to serve as a therapeutic target in the treatment of Crohn’s disease.

scholarly journals Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice

Blood ◽  
2011 ◽  
Vol 117 (24) ◽  
pp. 6582-6588 ◽  
Author(s):  
Philippe Krebs ◽  
Karine Crozat ◽  
Daniel Popkin ◽  
Michael B. Oldstone ◽  
Bruce Beutler
Keyword(s):  
T Cells ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Elevated Serum ◽  
Cytokine Signaling ◽  
Cell Contact ◽  
Inflammatory Disorder ◽  
Immune Cell Activation

AbstractHemophagocytic lymphohistiocytosis (HLH) is a rare inflammatory disorder with a poor prognosis for affected individuals. To find a means of suppressing the clinical phenotype, we investigated the cellular and molecular mechanisms leading to HLH in Unc13djinx/jinx mice, in which cytolytic function of NK and CD8+ T cells is impaired. Unc13djinx/jinx mutants infected with lymphochoriomeningitis virus (LCMV) present typical clinical features of HLH, including splenomegaly, elevated serum IFNγ, and anemia. Proteins mediating cell-cell contact, cytokine signaling or Toll-like receptor (TLR) signaling were analyzed. We show that neither the integrin CD18, which is involved in adhesion between antigen-presenting cells and effector T cells, nor tumor necrosis factor (TNF) made nonredundant contributions to the disease phenotype. Disruption of IFNγ signaling reduced immune cell activation in Unc13djinx/jinx mice, but also resulted in uncontrolled viral proliferation and exaggerated release of inflammatory cytokines. Abrogating the function of myeloid differentiation primary response gene 88 (MyD88) in Unc13djinx/jinx mice suppressed immune cell activation and controlled cytokine production in an IL-1 receptor 1 (IL-1R1)–independent way. Our findings implicate MyD88 as the key initiator of myeloid and lymphoid proliferation in HLH, and suggest that blockade of this signaling molecule may reduce immunopathology in patients.

scholarly journals Neuroinflammatory Basis of Depression: Learning From Experimental Models

2021 ◽  
Vol 15 ◽  
Author(s):  
Ruqayya Afridi ◽  
Kyoungho Suk
Keyword(s):  
Cell Activation ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Brain Regions ◽  
Experimental Models ◽  
Sterile Inflammation ◽  
Immune Cell Activation ◽  
Glial Cell Activation ◽  
Intensive Investigation

The neuroinflammatory basis of depression encompasses the detrimental role of otherwise supportive non-neuronal cells and neuroinflammation in hampering neuronal function, leading to depressive behavior. Animals subjected to different stress paradigms show glial cell activation and a surge in proinflammatory cytokines in various brain regions. The concept of sterile inflammation observed in animal models of depression has intrigued many researchers to determine the possible triggers of central immune cell activation. Notably, microglial activation and subsequent phenotypic polarization in depression have been strongly advocated by the wealth of recent preclinical studies; however, findings from human studies have shown contradictory results. Despite intensive investigation, many research gaps still exist to elucidate the molecular mechanisms of neuroinflammatory cascades underlying the pathophysiology of depression. In this mini-review, recent progress in understanding neuroinflammatory mechanisms in light of experimental models of depression will be thoroughly discussed. The challenges of mirroring depression in animal and in vitro models will also be highlighted. Furthermore, prospects of targeting neuroinflammation to treat depressive disorder will be covered.

Oxidized Haemoglobin–Driven Endothelial Dysfunction and Immune Cell Activation: Novel Therapeutic Targets for Atherosclerosis

2013 ◽  
Vol 20 (37) ◽  
pp. 4806-4814 ◽  
Author(s):  
Brigitta Buttari ◽  
Elisabetta Profumo ◽  
Rita Businaro ◽  
Luciano Saso ◽  
Raffaele Capoano ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Cell Activation ◽  
Immune Cell ◽  
Therapeutic Targets ◽  
Immune Cell Activation ◽  
Novel Therapeutic

scholarly journals Neuronal guidance proteins in cardiovascular inflammation

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Marius Keller ◽  
Valbona Mirakaj ◽  
Michael Koeppen ◽  
Peter Rosenberger
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Vascular Endothelial ◽  
Therapeutic Approaches ◽  
Immune Cell Activation ◽  
Cytokines And Chemokines ◽  
The Future ◽  
Cardiovascular Pathologies ◽  
Neuronal Guidance

AbstractCardiovascular pathologies are often induced by inflammation. The associated changes in the inflammatory response influence vascular endothelial biology; they complicate the extent of ischaemia and reperfusion injury, direct the migration of immune competent cells and activate platelets. The initiation and progression of inflammation is regulated by the classical paradigm through the system of cytokines and chemokines. Therapeutic approaches have previously used this knowledge to control the extent of cardiovascular changes with varying degrees of success. Neuronal guidance proteins (NGPs) have emerged in recent years and have been shown to be significantly involved in the control of tissue inflammation and the mechanisms of immune cell activation. Therefore, proteins of this class might be used in the future as targets to control the extent of inflammation in the cardiovascular system. In this review, we describe the role of NGPs during cardiovascular inflammation and highlight potential therapeutic options that could be explored in the future.

scholarly journals Oxidative stress and immune cell activation quantification in sepsis and non-sepsis critical care patients by neopterin/7,8-dihydroneopterin analysis

Pteridines ◽  
2020 ◽  
Vol 31 (1) ◽  
pp. 68-82
Author(s):  
Gregory Baxter-Parker ◽  
Ravinder Reddy Gaddam ◽  
Elena Moltchanova ◽  
Anitra Carr ◽  
Geoff Shaw ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Function ◽  
Cell Activation ◽  
Immune Cell ◽  
Intensive Care Patients ◽  
Immune Cell Activation ◽  
Immune System Activation ◽  
System Activation ◽  
Urinary Neopterin ◽  
Critical Care Patients

AbstractIntroduction: Neopterin and 7,8-dihydroneopterin are used as biomarkers of oxidative stress and inflammation, but the effect of kidney function on these measurements has not been extensively explored. We examine the levels of oxidative stress, inflammation and kidney function in intensive patients and compare them to equivalent patients without sepsis.Methods: 34 Intensive care patients were selected for the study, 14 without sepsis and 20 with. Both groups had equivalent levels of trauma, assessed by SAPS II, SOFA, and APACHE II and III scores. Plasma and urinary neopterin and total neopterin (neopterin + 7,8-dihydroneopterin) values were measured.Results: Neopterin and total neopterin were significantly elevated in urine and plasma for multiple days in sepsis versus non-sepsis patients. Plasma neopterin and total neopterin have decreasing relationships with increased eGFR (p<0.008 and p<0.001, respectively). Plasma/urinary neopterin and total neopterin ratios demonstrate that total neopterin flux is more influenced by eGFR than neopterin, with significantce of p<0.02 and p<0.0002 respectively.Conclusion: Sepsis patients present with greater levels of oxidative stress and immune system activation than non-sepsis patients of equal levels of trauma, as measured by neopterin and total neopterin. eGFR may need to be taken into account when accessing the level of inflammation from urinary neopterin measurements.

scholarly journals RhoA Signaling in Immune Cell Response and Cardiac Disease

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1681
Author(s):  
Lucia Sophie Kilian ◽  
Derk Frank ◽  
Ashraf Yusuf Rangrez
Keyword(s):  
Cardiac Disease ◽  
Cell Response ◽  
Cell Activation ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Heart Diseases ◽  
Small Gtpase ◽  
Cardiac Inflammation ◽  
Immune Cell Activation ◽  
Immune Cell Response

Chronic inflammation, the activation of immune cells and their cross-talk with cardiomyocytes in the pathogenesis and progression of heart diseases has long been overlooked. However, with the latest research developments, it is increasingly accepted that a vicious cycle exists where cardiomyocytes release cardiocrine signaling molecules that spiral down to immune cell activation and chronic state of low-level inflammation. For example, cardiocrine molecules released from injured or stressed cardiomyocytes can stimulate macrophages, dendritic cells, neutrophils and even T-cells, which then subsequently increase cardiac inflammation by co-stimulation and positive feedback loops. One of the key proteins involved in stress-mediated cardiomyocyte signal transduction is a small GTPase RhoA. Importantly, the regulation of RhoA activation is critical for effective immune cell response and is being considered as one of the potential therapeutic targets in many immune-cell-mediated inflammatory diseases. In this review we provide an update on the role of RhoA at the juncture of immune cell activation, inflammation and cardiac disease.

scholarly journals Hybrid Nanoassemblies from Viruses and DNA Nanostructures

Nanomaterials ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1413
Author(s):  
Sofia Ojasalo ◽  
Petteri Piskunen ◽  
Boxuan Shen ◽  
Mauri A. Kostiainen ◽  
Veikko Linko
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Dna Nanotechnology ◽  
Biological Properties ◽  
Dna Nanostructures ◽  
Dna Structures ◽  
Nanoscale Structures ◽  
Immune Cell Activation ◽  
Wide Range ◽  
Structural Dna Nanotechnology

Viruses are among the most intriguing nanostructures found in nature. Their atomically precise shapes and unique biological properties, especially in protecting and transferring genetic information, have enabled a plethora of biomedical applications. On the other hand, structural DNA nanotechnology has recently emerged as a highly useful tool to create programmable nanoscale structures. They can be extended to user defined devices to exhibit a wide range of static, as well as dynamic functions. In this review, we feature the recent development of virus-DNA hybrid materials. Such structures exhibit the best features of both worlds by combining the biological properties of viruses with the highly controlled assembly properties of DNA. We present how the DNA shapes can act as “structured” genomic material and direct the formation of virus capsid proteins or be encapsulated inside symmetrical capsids. Tobacco mosaic virus-DNA hybrids are discussed as the examples of dynamic systems and directed formation of conjugates. Finally, we highlight virus-mimicking approaches based on lipid- and protein-coated DNA structures that may elicit enhanced stability, immunocompatibility and delivery properties. This development also paves the way for DNA-based vaccines as the programmable nano-objects can be used for controlling immune cell activation.

scholarly journals Antibody Conjugation of Fluorescent Nanodiamonds for Targeted Innate Immune Cell Activation

2021 ◽  
Author(s):  
Lorena P. Suarez-Kelly ◽  
Steven H. Sun ◽  
Casey Ren ◽  
Isaac V. Rampersaud ◽  
David Albertson ◽  
...  
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Innate Immune ◽  
Innate Immune Cell ◽  
Immune Cell Activation ◽  
Antibody Conjugation ◽  
Fluorescent Nanodiamonds
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