scholarly journals THE STATE OF THE CELLS OF THE IMMUNE SYSTEM IN EXPERIMENTAL IMMUNE-MEDIATED INFLAMMATION OF VARIOUS GENESIS

2021 ◽  
Vol 17 (2) ◽  
pp. 20-26
Author(s):  
S.I. Pavlovych ◽  
N.G. Grushka ◽  
O.A. Kondratska ◽  
N.O. Krasutska ◽  
R.I. Yanchii
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Membrane Integrity ◽  
Genotoxic Stress ◽  
Pathological Process ◽  
The Body ◽  
Cellular Mechanisms ◽  
Nonspecific Resistance ◽  
Immune Mediated ◽  
Endotoxemia Model

Relevance. Immune-mediated inflammation of various genesis plays a significant pathogenetic role in autoimmune, allergic, inflammatory and infectious diseases. The objective of the work was a comparative study of the functional status and pathways of cell death of natural and adaptive immunity in mice under the conditions of experimental hyperimmunocomplexemia and endotoxemia to identify the features and common cellular mechanisms of these pathologies. Materials and methods. Hyperimmunocomplexemia was simulated by six-fold immunization of female mice with increasing doses of the antigen, bovine serum albumin (BSA), once a week; the endotoxemia model was induced by the administration of lipopolysaccharide (LPS). Results. The use of both BSA and LPS led to a systemic inflammatory process with significant neutrophilia with a shift of the leukogram to the left. There was a significant increase in the functional and metabolic activity of nonspecific resistance cells. Genotoxic stress was observed in thymus cells and lymph nodes with significant DNA damage, decreased viability, and a significant increase in necrotic death. Violation of the plasma membrane integrity of primary alteration and the release of the cellular content outside has a strong pro-inflammatory and immunogenic effect, which can lead to further intensification of the disease and an increase in its duration with a tendency to chronicity of the pathological process. Conclusions. Thus, both models are characterized by the development of immune-inflammatory processes that lead to significant DNA damage and cell death, which can cause a new round of intensification of necrotic, inflammatory and autoimmune reactions in the body.

scholarly journals Gut Microbiome and Organ Fibrosis

Nutrients ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 352
Author(s):  
Carolina F. F. A. Costa ◽  
Benedita Sampaio-Maia ◽  
Ricardo Araujo ◽  
Diana S. Nascimento ◽  
Joana Ferreira-Gomes ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Inflammatory Diseases ◽  
Adaptive Immune System ◽  
Organ Damage ◽  
Pathological Process ◽  
The Body ◽  
Intestinal Fibrosis ◽  
Immune Mediated ◽  
Major Player ◽  
Organ Fibrosis

Fibrosis is a pathological process associated with most chronic inflammatory diseases. It is defined by an excessive deposition of extracellular matrix proteins and can affect nearly every tissue and organ system in the body. Fibroproliferative diseases, such as intestinal fibrosis, liver cirrhosis, progressive kidney disease and cardiovascular disease, often lead to severe organ damage and are a leading cause of morbidity and mortality worldwide, for which there are currently no effective therapies available. In the past decade, a growing body of evidence has highlighted the gut microbiome as a major player in the regulation of the innate and adaptive immune system, with severe implications in the pathogenesis of multiple immune-mediated disorders. Gut microbiota dysbiosis has been associated with the development and progression of fibrotic processes in various organs and is predicted to be a potential therapeutic target for fibrosis management. In this review we summarize the state of the art concerning the crosstalk between intestinal microbiota and organ fibrosis, address the relevance of diet in different fibrotic diseases and discuss gut microbiome-targeted therapeutic approaches that are current being explored.

scholarly journals Anti-Apoptotic Effects of Carotenoids in Neurodegeneration

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3453 ◽  
Author(s):  
Han-A Park ◽  
Mary Margaret Hayden ◽  
Sydni Bannerman ◽  
Joseph Jansen ◽  
Kristi M. Crowe-White
Keyword(s):  
Cell Death ◽  
Neurodegenerative Disease ◽  
Antioxidant Properties ◽  
Membrane Integrity ◽  
Protective Role ◽  
Brain Cell ◽  
Type I ◽  
Cellular Mechanisms ◽  
Apoptotic Pathways ◽  
Apoptotic Effects

Apoptosis, programmed cell death type I, is a critical part of neurodegeneration in cerebral ischemia, Parkinson’s, and Alzheimer’s disease. Apoptosis begins with activation of pro-death proteins Bax and Bak, release of cytochrome c and activation of caspases, loss of membrane integrity of intracellular organelles, and ultimately cell death. Approaches that block apoptotic pathways may prevent or delay neurodegenerative processes. Carotenoids are a group of pigments found in fruits, vegetables, and seaweeds that possess antioxidant properties. Over the last several decades, an increasing number of studies have demonstrated a protective role of carotenoids in neurodegenerative disease. In this review, we describe functions of commonly consumed carotenoids including lycopene, β-carotene, lutein, astaxanthin, and fucoxanthin and their roles in neurodegenerative disease models. We also discuss the underlying cellular mechanisms of carotenoid-mediated neuroprotection, including their antioxidant properties, role as signaling molecules, and as gene regulators that alleviate apoptosis-associated brain cell death.

scholarly journals Internalization of Titanium Dioxide Nanoparticles Is Cytotoxic for H9c2 Rat Cardiomyoblasts

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 1955 ◽  
Author(s):  
Elizabeth Huerta-García ◽  
Iván Zepeda-Quiroz ◽  
Helen Sánchez-Barrera ◽  
Zaira Colín-Val ◽  
Ernesto Alfaro-Moreno ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Death ◽  
Titanium Dioxide ◽  
Titanium Dioxide Nanoparticles ◽  
Membrane Integrity ◽  
The Body ◽  
Potential Health ◽  
Tio2 Nps

Titanium dioxide nanoparticles (TiO2 NPs) are widely used in industry and daily life. TiO2 NPs can penetrate into the body, translocate from the lungs into the circulation and come into contact with cardiac cells. In this work, we evaluated the toxicity of TiO2 NPs on H9c2 rat cardiomyoblasts. Internalization of TiO2 NPs and their effect on cell proliferation, viability, oxidative stress and cell death were assessed, as well as cell cycle alterations. Cellular uptake of TiO2 NPs reduced metabolic activity and cell proliferation and increased oxidative stress by 19-fold measured as H2DCFDA oxidation. TiO2 NPs disrupted the plasmatic membrane integrity and decreased the mitochondrial membrane potential. These cytotoxic effects were related with changes in the distribution of cell cycle phases resulting in necrotic death and autophagy. These findings suggest that TiO2 NPs exposure represents a potential health risk, particularly in the development of cardiovascular diseases via oxidative stress and cell death.

Effects of chloride channel inhibitors on H2O2-induced renal epithelial cell injury

2000 ◽  
Vol 278 (1) ◽  
pp. F83-F90 ◽  
Author(s):  
Xianmin Meng ◽  
W. Brian Reeves
Keyword(s):  
Lipid Peroxidation ◽  
Dna Damage ◽  
Cell Death ◽  
Epithelial Cell ◽  
Small Molecules ◽  
Cell Injury ◽  
Membrane Integrity ◽  
Atp Depletion ◽  
Renal Epithelial Cell ◽  
Epithelial Cell Injury

Oxidative stress contributes to renal epithelial cell injury in certain settings. Chloride influx has also been proposed as an important component of acute renal epithelial cell injury. The present studies examined the role of Cl− in H2O2-induced injury to LLC-PK1 renal epithelial cells. Exposure of LLC-PK1 cells to 1 mM H2O2 resulted in the following: depletion of intracellular ATP content; DNA damage; lipid peroxidation; and a loss of membrane integrity to both small molecules, e.g., trypan blue, and macromolecules, e.g., lactate dehydrogenase (LDH), and cell death. Substitution of Cl− by isethionate or the inclusion of certain Cl− channel blockers, e.g., diphenylamine-2-carboxylate (DPC), 5-nitro-2-(3-phenylpropylamino)· benzoate (NPPB), and niflumic acid, prevented the H2O2-induced loss of membrane integrity to LDH. In addition, the H2O2-induced loss of membrane integrity was prevented by raising the osmolality of the extracellular solutions, by depletion of cell ATP, and by inhibitors of volume-sensitive Cl− channels. However, these maneuvers did not prevent the H2O2-induced permeability to small molecules or H2O2-induced ATP depletion, DNA damage, lipid peroxidation, or cell death. These results support the view that volume-sensitive Cl− channels play a role in the progressive loss of cell membrane integrity during injury.

scholarly journals Plasmodium falciparum Replication factor C subunit 1 is involved in genotoxic stress response

2020 ◽  
Author(s):  
O Sheriff ◽  
Y Aniweh ◽  
Soak-Kuan Lai ◽  
HL Loo ◽  
S. K Sze ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Dna Repair ◽  
Plasmodium Falciparum ◽  
Stress Response ◽  
Programmed Cell Death ◽  
Genotoxic Stress ◽  
Antimalarial Drugs ◽  
Protein Levels ◽  
Factor C

AbstractAbout half the world’s population is at risk of malaria, with Plasmodium falciparum malaria being responsible for the most malaria related deaths globally. Antimalarial drugs such as chloroquine and artemisinin are directed towards the proliferating intra-erythrocytic stages of the parasite, which is responsible for all the clinical symptoms of the disease. These antimalarial drugs have been reported to function via multiple pathways, one of which induces DNA damage via the generation of free radicals and reactive oxygen species. An urgent need to understand the mechanistic details of drug response and resistance is highlighted by the decreasing clinical efficacy of the front line drug, Artemisinin.The replication factor C subunit 1 protein is an important component of the DNA replication machinery and DNA damage response mechanism. Here we show the translocation of PfRFC1 from an intranuclear localization to the nuclear periphery indicating an orchestrated progression of distinct patterns of replication in the developing parasites. PfRFC1 responds to genotoxic stress via elevated protein levels in soluble and chromatin bound fractions.Reduction of PfRFC1 protein levels upon treatment with antimalarials suggests an interplay of replication and DNA repair pathways leading to cell death. Additionally, mislocalization of the endogenously tagged protein confirmed its essential role in parasites’ replication and DNA repair. This study provides key insights into DNA replication, DNA damage response and cell death in plasmodium falciparum.ImportanceFrontline drugs have been found to induce DNA damage in the human malaria parasite Plasmodium falciparum. The genotoxic stress response in Plasmodium and the interplay between DNA damage repair, replication and activation of programmed cell death pathways remains largely undescribed. This study shows a distinct pattern of localization of PfRFC1 during replication and DNA repair. PfRFC1 responds to genotoxic stress with an increase in protein expression. Interfering with the RFC complex formation or mislocalization of PfRFC1 is associated with disrupted genotoxic stress response. Additionally, a reduction of PfRFC1 protein levels is observed upon treatment with antimalarial drugs or under apoptosis like conditions, highlighting the role of DEVD/G like motif in mediating programmed cell death in these parasites. This study sheds light on the role of PfRFC1 in differentially responding to replication, genotoxic stress and programmed cell death in Plasmodium parasites.

scholarly journals Cell cycle checkpoints cooperate to suppress DNA and RNA associated molecular pattern recognition and anti-tumor immune responses

2020 ◽  
Author(s):  
Jie Chen ◽  
Shane M Harding ◽  
Ramakrishnan Natesan ◽  
Lei Tian ◽  
Joseph L Benci ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pattern Recognition ◽  
Dna Damage ◽  
Immune Responses ◽  
Genotoxic Stress ◽  
Cell Cycle Checkpoints ◽  
Dependent Manner ◽  
Dna And Rna ◽  
Molecular Pattern ◽  
Immune Mediated

SummaryThe DNA dependent pattern recognition receptor, cGAS mediates communication between genotoxic stress and the immune system. Mitotic chromosome missegregation is an established stimulator of cGAS activity, however, it is unclear if progression through mitosis is required for cancer cell intrinsic activation of immune mediated anti-tumor responses. Moreover, it is unknown if disruption of cell cycle checkpoints can restore responses in cancer cells that are recalcitrant to DNA damage induced inflammation. Here we demonstrate that prolonged cell cycle arrest at the G2-mitosis boundary from either CDK1 inhibition or excessive DNA damage prevents inflammatory stimulated gene expression and immune mediated destruction of distal tumors. Remarkably, DNA damage induced inflammatory signaling is restored in a cGAS-and RIG-I-dependent manner upon concomitant disruption of p53 and the G2 checkpoint. These findings link aberrant cell progression and p53 loss to an expanded spectrum of damage associated molecular pattern recognition and have implications for the design of rational approaches to augment antitumor immune responses.

scholarly journals LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells

Blood ◽  
2020 ◽  
Vol 136 (6) ◽  
pp. 684-697 ◽  
Author(s):  
Tomoyasu Jo ◽  
Momoko Nishikori ◽  
Yasunori Kogure ◽  
Hiroshi Arima ◽  
Katsuhiro Sasaki ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
B Cells ◽  
B Cell ◽  
Gene Mutations ◽  
B Cell Lymphoma ◽  
Genotoxic Stress ◽  
Nucleotide Polymorphisms ◽  
Ubiquitin Chain

Abstract The linear ubiquitin chain assembly complex (LUBAC) is a key regulator of NF-κB signaling. Activating single-nucleotide polymorphisms of HOIP, the catalytic subunit of LUBAC, are enriched in patients with activated B-cell–like (ABC) diffuse large B-cell lymphoma (DLBCL), and expression of HOIP, which parallels LUBAC activity, is elevated in ABC-DLBCL samples. Thus, to clarify the precise roles of LUBAC in lymphomagenesis, we generated a mouse model with augmented expression of HOIP in B cells. Interestingly, augmented HOIP expression facilitated DLBCL-like B-cell lymphomagenesis driven by MYD88-activating mutation. The developed lymphoma cells partly shared somatic gene mutations with human DLBCLs, with increased frequency of a typical AID mutation pattern. In vitro analysis revealed that HOIP overexpression protected B cells from DNA damage-induced cell death through NF-κB activation, and analysis of the human DLBCL database showed that expression of HOIP positively correlated with gene signatures representing regulation of apoptosis signaling, as well as NF-κB signaling. These results indicate that HOIP facilitates lymphomagenesis by preventing cell death and augmenting NF-κB signaling, leading to accumulation of AID-mediated mutations. Furthermore, a natural compound that specifically inhibits LUBAC was shown to suppress the tumor growth in a mouse transplantation model. Collectively, our data indicate that LUBAC is crucially involved in B-cell lymphomagenesis through protection against DNA damage–induced cell death and is a suitable therapeutic target for B-cell lymphomas.

scholarly journals A Review and Rationale for the Use of Genetically Engineered Animals in the Study of Traumatic Brain Injury

2001 ◽  
Vol 21 (11) ◽  
pp. 1241-1258 ◽  
Author(s):  
Luca Longhi ◽  
Kathryn E. Saatman ◽  
Ramesh Raghupathi ◽  
Helmut L. Laurer ◽  
Philipp M. Lenzlinger ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Dna Damage ◽  
Cell Death ◽  
Brain Injury ◽  
Human Head ◽  
Genetically Engineered ◽  
Cellular Mechanisms ◽  
Cell Dysfunction ◽  
Damage Repair ◽  
Genetically Engineered Mice

The mechanisms underlying secondary cell death after traumatic brain injury (TBI) are poorly understood. Animal models of TBI recapitulate many clinical and pathologic aspects of human head injury, and the development of genetically engineered animals has offered the opportunity to investigate the specific molecular and cellular mechanisms associated with cell dysfunction and death after TBI, allowing for the evaluation of specific cause-effect relations and mechanistic hypotheses. This article represents a compendium of the current literature using genetically engineered mice in studies designed to better understand the posttraumatic inflammatory response, the mechanisms underlying DNA damage, repair, and cell death, and the link between TBI and neurodegenerative diseases.

scholarly journals 310 T cell intrinsic DNA damage and repair response as a novel marker associated with clinical response to PD-1 blockade

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A335-A335
Author(s):  
Yuki Muroyama ◽  
Sasikanth Manne ◽  
Allison Greenplate ◽  
Divij Mathew ◽  
Derek Oldridge ◽  
...  
Keyword(s):  
Dna Damage ◽  
T Cells ◽  
Cell Death ◽  
Cell Differentiation ◽  
T Cell ◽  
Clinical Response ◽  
Cd8 T Cells ◽  
Uterine Cancer ◽  
Genotoxic Stress ◽  
T Cell Differentiation

BackgroundDespite the success of immune checkpoint blockade (ICB), many patients still fail to achieve durable clinical benefit. Previous studies have shown that CD8 T cells are reinvigorated by ICB. However, not all patients with this immunological response experience an effective clinical response, suggesting additional parameters may be relevant.DNA damage and repair (DDR) has been extensively studied in the context of inducing cell death of highly-proliferating tumor cells. However, whether T cell-intrinsic DDR impacts T cell differentiation and function, and how the coordination of DDR affects immunological and clinical response to proliferation-inducing ICBs have been largely unexplored. We hypothesized that the T celI-intrinsic DDR responses to proliferative and genotoxic stress might contribute to the disparity between immunological and clinical response.MethodsTo understand the impact of cell-intrinsic DDR on T cell differentiation and responses to cancer therapies, we developed a novel high-dimensional cytometry platform. This DDR-Immune platform enables simultaneous analysis of T cell differentiation state and multiple DDR pathways at single cell resolution. We then investigated immune reinvigoration and its association with DDR, in a cohort of chemotherapy-resistant hypermutated or microsatellite instability-high (MSI-H) uterine cancer patients treated with nivolumab. Peripheral blood samples were examined every 2–4 weeks after initiating anti-PD-1 treatment (N = 21).ResultsThe DDR-Immune platform revealed consistent T cell subset specific patterns of DDR, as well as specific DDR pathways induced by different types of DNA damage, such as γ-irradiation (IR), UV irradiation (UV) or proliferative stress (i.e. anti-CD3/CD28 stimulation). For example, terminally differentiated effector cells had higher DNA damage accumulation and cell death. In contrast, stem cell memory (TSCM) and regulatory T cells (Treg) displayed high DDR with less cell death, suggesting better cell-intrinsic DDR against genotoxic stress for survival advantage. In hypermutated MSI-H uterine cancer patients, CD8 T cells underwent rapid pharmacodynamic proliferation 2–4 weeks after starting PD-1 blockade, which did not correlate with clinical response. Application of the DDR-Immune platform to this cohort revealed, however, that in clinical responders but not clinical non-responders, Ki67+ CD8 T cells responding to PD-1 blockade had rapid induction of DDR represented as a spike increase of phosphorylated-ATM, presumably adapting T cell ‘fitness’ in response to proliferative stress induced by PD-1 blockade.ConclusionsCollectively, the new platform reveals previously unrecognized roles for T cell-intrinsic DDR as a novel determinant of immune responsiveness and clinical outcome to ICB and have potential application to other cancer therapies including chemotherapy and radiotherapy.Ethics ApprovalThe study was approved by MSKCC Ethics Board, approval number 17–180 (NCT03241745).

scholarly journals Contribution of GADD45 Family Members to Cell Death Suppression by Cellular Bcl-xL and Cytomegalovirus vMIA

2005 ◽  
Vol 79 (23) ◽  
pp. 14923-14932 ◽  
Author(s):  
Geoffrey B. Smith ◽  
Edward S. Mocarski
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Mammalian Cells ◽  
Regulatory Protein ◽  
Family Members ◽  
Genotoxic Stress ◽  
Cell Cycle Regulatory Protein ◽  
Protein Levels ◽  
A Cell ◽  
Interfering Rna

ABSTRACT Mammalian cells and viruses encode inhibitors of programmed cell death that localize to mitochondria and suppress apoptosis initiated by a wide variety of inducers. Mutagenesis was used to probe the role of a predicted α-helical region within the hydrophobic antiapoptotic domain (AAD) of cytomegalovirus vMIA, the UL37x1 gene product. This region was found to be essential for cell death suppression activity. A screen for proteins that interacted with the AAD of functional vMIA but that failed to interact with mutants identified growth arrest and DNA damage 45 (GADD45α), a cell cycle regulatory protein activated by genotoxic stress, as a candidate cellular binding partner. GADD45α interaction required the AAD α-helical character that also dictated GADD45α-mediated enhancement of death suppression. vMIA mutants that failed to interact with GADD45α were completely nonfunctional in cell death suppression, and any of the three GADD45 family members (GADD45α, GADD45β/MyD118, or GADD45γ/OIG37/CR6/GRP17) was able to cooperate with vMIA; however, none influenced cell death when introduced into cells alone. GADD45α was found to increase vMIA protein levels comparably to treatment with protease inhibitors MG132 and ALLN. Targeted short interfering RNA knockdown of all three GADD45 family members maximally reduced vMIA activity, and this reduction was abrogated by additional GADD45α. Interestingly, GADD45 family members were also able to bind and enhance cell death suppression by Bcl-xL, a member of the Bcl-2 family of cell death suppressors, suggesting a direct cooperative link between apoptosis and the proteins that regulate the DNA damage response.

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