scholarly journals Mechanism of Ca2+-Dependent Pro-Apoptotic Action of Selenium Nanoparticles, Mediated by Activation of Cx43 Hemichannels

Biology ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 743
Author(s):  
Egor A. Turovsky ◽  
Elena G. Varlamova
Keyword(s):  
Intracellular Signaling ◽  
Cell Activation ◽  
Selenium Nanoparticles ◽  
Ip3 Receptor ◽  
Glioblastoma Cells ◽  
Vesicular Release ◽  
Induction Of Apoptosis ◽  
Relationship Of ◽  
First Time

To date, there are practically no data on the mechanisms of the selenium nanoparticles action on calcium homeostasis, intracellular signaling in cancer cells, and on the relationship of signaling pathways activated by an increase in Ca2+ in the cytosol with the induction of apoptosis, which is of great importance. The study of these mechanisms is important for understanding the cytotoxic effect of selenium nanoparticles and the role of this microelement in the regulation of carcinogenesis. The work is devoted to the study of the role of selenium nanoparticles obtained by laser ablation in the activation of the calcium signaling system and the induction of apoptosis in human glioblastoma cells (A-172 cell line). In this work, it was shown for the first time that the generation of Ca2+ signals in A-172 cells occurs in response to the application of various concentrations of selenium nanoparticles. The intracellular mechanism responsible for the generation of these Ca2+ signals has also been established. It was found that nanoparticles promote the mobilization of Ca2+ ions from the endoplasmic reticulum through the IP3-receptor. This leads to the activation of vesicular release of ATP through connexin hemichannels (Cx43) and paracrine cell activation through purinergic receptors (mainly P2Y). In addition, it was shown that the activation of this signaling pathway is accompanied by an increase in the expression of pro-apoptotic genes and the induction of apoptosis. For the first time, the role of Cx43 in the regulation of apoptosis caused by selenium nanoparticles in glioblastoma cells has been shown. It was found that inhibition of Cx43 leads to a significant suppression of the induction of apoptosis in these cells after 24 h treatment of cells with selenium nanoparticles at a concentration of 5 µg/mL.

Glioblastoma invasion and NMDA receptors: A novel prospect

2019 ◽  
Vol 106 (3) ◽  
pp. 250-260 ◽  
Author(s):  
DN Nandakumar ◽  
P Ramaswamy ◽  
C Prasad ◽  
D Srinivas ◽  
K Goswami
Keyword(s):  
Glutamate Receptors ◽  
Cell Lines ◽  
Intracellular Signaling ◽  
Transcript Level ◽  
Glioblastoma Cells ◽  
Invasion And Migration ◽  
Matrigel Invasion ◽  
Nmdar Activation ◽  
And Migration

Purpose Glioblastoma cells create glutamate-rich tumor microenvironment, which initiates activation of ion channels and modulates downstream intracellular signaling. N-methyl-D-aspartate receptors (NMDARs; a type of glutamate receptors) have a high affinity for glutamate. The role of NMDAR activation on invasion of glioblastoma cells and the crosstalk with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is yet to be explored. Main methods LN18, U251MG, and patient-derived glioblastoma cells were stimulated with NMDA to activate NMDAR glutamate receptors. The role of NMDAR activation on invasion and migration and its crosstalk with AMPAR were evaluated. Invasion and migration of glioblastoma cells were investigated by in vitro trans-well Matrigel invasion and trans-well migration assays, respectively. Expression of NMDARs and AMPARs at transcript level was evaluated by quantitative real-time polymerase chain reaction. Results We determined that NMDA stimulation leads to enhanced invasion in LN18, U251MG, and patient-derived glioblastoma cells, whereas inhibition of NMDAR using MK-801, a non-competitive antagonist of the NMDAR, significantly decreased the invasive capacity. Concordant with these findings, migration was significantly augmented by NMDAR in both cell lines. Furthermore, NMDA stimulation upregulated the expression of GluN2 and GluA1 subunits at the transcript level. Conclusions This study demonstrated the previously unexplored role of NMDAR in invasion of glioblastoma cells. Furthermore, the expression of the GluN2 subunit of NMDAR and the differential overexpression of the GluA1 subunit of AMPAR in both cell lines provide a plausible rationale of crosstalk between these calcium-permeable subunits in the glutamate-rich microenvironment of glioblastoma.

The Role of miRNAs in PI3K Signaling Pathway in Blood Malignancies: A Review Article

2021 ◽  
Author(s):  
Haniyeh Gaffari-Nazari ◽  
Samira Karami ◽  
Leila Noorazar ◽  
Sayeh Parkhideh ◽  
Elham Roshandel ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Pi3k Pathway ◽  
Pi3k Signaling ◽  
Laboratory Findings ◽  
A Cell ◽  
Pi3k Signaling Pathway ◽  
Relationship Of

Background: The PI3K/Akt/mTOR signaling pathway is one of the most important intracellular signaling pathways by regulating the cell cycle process. The direct relationship of this pathway with important mechanisms such as cell quiescence, longevity, and proliferation has been established. The overactive PI3K pathway with decreased and increased apoptosis and cell proliferation respectively is involved in pathogenesis of many cancers, including blood malignancies such as leukemia. Methods: Laboratory findings have shown that different factors, such as miRNAs, play a role in regulating PI3K signaling pathway. These molecules can alter the fate of a cell by interfering in suppression/overexpression of mRNA, transcription factors or stimulating the transcription of some genes. In this article, we reviewed the role of miRNAs in regulating the PI3K/Akt/mTOR pathway and its effect on leukemic progression and treatment failure. Conclusion: At present, miRNAs are known to be one of the causes of treatment failure and relapse in cancers.

scholarly journals FcγRIIIa receptor polymorphism influences NK cell mediated ADCC activity against HIV

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Sneha Pramod Talathi ◽  
Nawaj Najir Shaikh ◽  
Sudhanshu Shekhar Pandey ◽  
Vandana Ashish Saxena ◽  
Megha Sunil Mamulwar ◽  
...  
Keyword(s):  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Adcc Activity ◽  
Efficient Treatment ◽  
Activation Assay ◽  
Dependent Cell ◽  
Infected Cells ◽  
First Time

Abstract Background HIV-specific Antibody Dependent Cell Cytotoxicity (ADCC) has shown to be important in HIV control and resistance. The ADCC is mediated primarily by natural killer cell activated through the binding of FcγRIIIa receptor to the Fc portion of antibody bound to the antigen expressed on the infected cells. However, no data is available on the influence of the polymorphism in FcγRIIIa receptor on HIV-specific ADCC response. Methods The Sanger’s method of sequencing was used to sequence the exon of FcγRIIIa receptor while the ADCC activity was determined using NK cell activation assay. The polymorphism in FcγRIIIa receptor was assessed in HIV-infected Indian individuals with or without HIV-specific ADCC antibodies and its influence on the magnitude of HIV-specific ADCC responses was analyzed. Results Two polymorphisms: V176F (rs396991) and Y158H (rs396716) were observed. The Y158H polymorphism is reported for the first time in Indian population. Both, V176F (V/V genotype) (p = 0.004) and Y158H (Y/H genotype) (p = 0.032) were found to be significantly associated with higher magnitude of HIV-specific ADCC response. Conclusion The study underscores the role of polymorphism in the FcγRIIIa receptor on HIV-specific ADCC response and suggests that the screening of the individuals for FcγRIIIa-V176F and Y158H polymorphisms could be useful for prediction of efficient treatment in monoclonal antibody-based therapies aimed at ADCC in HIV infection.

scholarly journals Isoform-Specific Roles of ERK1 and ERK2 in Arteriogenesis

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 38 ◽  
Author(s):  
Nicolas Ricard ◽  
Jiasheng Zhang ◽  
Zhen W. Zhuang ◽  
Michael Simons
Keyword(s):  
Endothelial Cells ◽  
Intracellular Signaling ◽  
Clinical Importance ◽  
Macrophage Infiltration ◽  
Endothelial Cell Proliferation ◽  
Vascular Endothelial ◽  
Ischemic Event ◽  
Intracellular Signaling Pathway ◽  
First Time

Despite the clinical importance of arteriogenesis, this biological process is poorly understood. ERK1 and ERK2 are key components of a major intracellular signaling pathway activated by vascular endothelial growth (VEGF) and FGF2, growth factors critical to arteriogenesis. To investigate the specific role of each ERK isoform in arteriogenesis, we used mice with a global Erk1 knockout as well as Erk1 and Erk2 floxed mice to delete Erk1 or Erk2 in endothelial cells, macrophages, and smooth muscle cells. We found that ERK1 controls macrophage infiltration following an ischemic event. Loss of ERK1 in endothelial cells and macrophages induced an excessive macrophage infiltration leading to an increased but poorly functional arteriogenesis. Loss of ERK2 in endothelial cells leads to a decreased arteriogenesis due to decreased endothelial cell proliferation and a reduced eNOS expression. These findings show for the first time that isoform-specific roles of ERK1 and ERK2 in the control of arteriogenesis.

scholarly journals The Mechanisms Underlying the Protective Action of Selenium Nanoparticles against Ischemia/Reoxygenation Are Mediated by the Activation of the Ca2+ Signaling System of Astrocytes and Reactive Astrogliosis

2021 ◽  
Vol 22 (23) ◽  
pp. 12825
Author(s):  
Elena G. Varlamova ◽  
Egor A. Turovsky ◽  
Valentina A. Babenko ◽  
Egor Y. Plotnikov
Keyword(s):  
Cerebral Cortex ◽  
Protective Action ◽  
Selenium Nanoparticles ◽  
Ip3 Receptor ◽  
Extracellular Medium ◽  
Phosphoinositide Signaling ◽  
Anticancer Effects ◽  
Paracrine Activation ◽  
First Time ◽  
The Brain

In recent years, much attention has been paid to the study of the therapeutic effect of the microelement selenium, its compounds, especially selenium nanoparticles, with a large number of works devoted to their anticancer effects. Studies proving the neuroprotective properties of selenium nanoparticles in various neurodegenerative diseases began to appear only in the last 5 years. Nevertheless, the mechanisms of the neuroprotective action of selenium nanoparticles under conditions of ischemia and reoxygenation remain unexplored, especially for intracellular Ca2+ signaling and neuroglial interactions. This work is devoted to the study of the cytoprotective mechanisms of selenium nanoparticles in the neuroglial networks of the cerebral cortex under conditions of ischemia/reoxygenation. It was shown for the first time that selenium nanoparticles dose-dependently induce the generation of Ca2+ signals selectively in astrocytes obtained from different parts of the brain. The generation of these Ca2+ signals by astrocytes occurs through the release of Ca2+ ions from the endoplasmic reticulum through the IP3 receptor upon activation of the phosphoinositide signaling pathway. An increase in the concentration of cytosolic Ca2+ in astrocytes leads to the opening of connexin Cx43 hemichannels and the release of ATP and lactate into the extracellular medium, which trigger paracrine activation of the astrocytic network through purinergic receptors. Incubation of cerebral cortex cells with selenium nanoparticles suppresses ischemia-induced increase in cytosolic Ca2+ and necrotic cell death. Activation of A2 reactive astrocytes exclusively after ischemia/reoxygenation, a decrease in the expression level of a number of proapoptotic and proinflammatory genes, an increase in lactate release by astrocytes, and suppression of the hyperexcitation of neuronal networks formed the basis of the cytoprotective effect of selenium nanoparticles in our studies.

scholarly journals Using the Biology of Chronic Lymphocytic Leukemia to Choose Treatment

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 104-109 ◽  
Author(s):  
Peter Hillmen
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Intracellular Signaling ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Signaling Mechanisms ◽  
The Individual ◽  
First Time ◽  
Targeted Approach

AbstractIn recent years, our understanding of the pathophysiology of chronic lymphocytic leukemia (CLL) has advanced significantly. It is now clear that CLL is a relatively proliferative disorder that requires the help of its microenvironment to be maintained and to progress. The stimulation of the CLL cell occurs in most, if not all, patients through antigen stimulation via the BCR. In addition, there is now a clearer appreciation of the role of the p53 pathway leading to chemoresistance. These insights are allowing a more targeted approach with the use of p53-independent drugs such as mAbs and high-dose steroids to overcome genetically poor-risk CLL. The elucidation of the molecular and intracellular signaling mechanisms of disease is just beginning to facilitate the development of several targeted small molecules that promise to revolutionize the treatment of CLL. The measurement of the level of minimal residual disease (MRD) in CLL is becoming more available, facilitating approaches in which the aim of therapy is the eradication of detectable MRD. This also promises to improve personalization of therapy to the individual. Recently, the addition of rituximab to fludarabine plus cyclophosphamide (FCR) has improved overall survival in CLL for the first time, and it appears that this will only be the first small step on the path to much more effective therapies and, hopefully, less toxic targeted therapies.

scholarly journals Interpersonal dependence and differential types of reflection in students – boys and girls

2018 ◽  
Vol 71 (4) ◽  
pp. 111-117
Author(s):  
O. V. Myloslavska
Keyword(s):  
Personal Autonomy ◽  
Rank Correlation ◽  
Necessary Condition ◽  
Positive Role ◽  
Self Confidence ◽  
National University ◽  
The Individual ◽  
Relationship Of ◽  
First Time

The article presents results of the study of interpersonal dependence in the context of reflection as a necessary condition for personal autonomy and the mechanism of constructing and organizing a life perspective in adolescence. The psychological content of the phenomenon of interpersonal dependence is revealed, its destructive influence on the personality is emphasized, the positive role of reflection as a factor of actualization of the autonomy of the individual and the neutralization of interpersonal dependence is substantiated. The purpose of the study was to identify the relationship of interpersonal dependence and differential types of reflection in students – boys and girls. The scientific novelty of the research is determined by the fact that in the work for the first time the peculiarities of the functioning of interpersonal dependence and differential types of reflection on the students were determined, differences in the structure of the interrelationship between these phenomena in students – boys and girls were analyzed. The Interpersonal Dependency Inventory by R. M. A. Hirschfeld, Relationship Profile Test by R. F. Bornstein (both – in an adaptation by O. P. Makushina) and Differential Test of Reflexivity by D. A. Leontiev and E. M. Osin were applied to solve empirical problems. The sample consisted of 96 students of V. N. Karazin Kharkiv National University. The first group included of 45 boys, the second – 51 girls. For the mathematical processing of data the Spearman rank correlation coefficient was used. It has been established that in both groups an increase in the propensity to unproductive types of reflection is a potential for the development of manifestations of interpersonal dependence. Both boys and girls, with increased introspection, there is an aggravation of destructive overdependence. It was also found that in young men the increase in such manifestations of interpersonal dependence, such as the need for emotional reliance on others, lack of self-confidence, and dependence in general, occurs along with the actualization of the tendency to introspection, while in girls – with the actualization of the tendency to quasi-reflection, together with than in these subjects, destructive overdependence grows. It should be noted that healthy dependence is involved in relationships with the differential types of reflection only in the group of girls, in which its severity increases with increasing ability to systemic reflection and inhibition of quasi-reflection. Results can be used for gender specification of psychological programs for the prevention and correction of interpersonal dependence in the students age. It is noted that the prospect of further research is to study the psychological characteristics that may act as inhibitors of interpersonal dependence in adolescence.

scholarly journals DESIGNING EFFECTIVE ONLINE ADVERTISEMENTS FOR A PREVENTION CAMPAIGN: MISTRUST AND OTHER BARRIERS

2019 ◽  
Vol 2019 ◽  
Author(s):  
Claire Henry
Keyword(s):  
Behavioral Change ◽  
Online Advertising ◽  
Effective Media ◽  
Prevention Campaign ◽  
Online Advertisements ◽  
Seeking Help ◽  
The One ◽  
Relationship Of ◽  
First Time

This paper reports on the preliminary findings of a research project that is investigating the potential for online advertisements to reduce the incidence of Child Sexual Abuse Material (CSAM) consumption on the internet. First time or novice offenders often use search engines to look for CSAM, which presents an opportunity to use display advertisements (for a 24-hour sexual harm helpline) on search results for early intervention. This approach—currently being piloted in New Zealand—aims to decrease the number of potential/novice offenders accessing CSAM, and increase the number seeking help and self-referring for treatment. However, achieving these outcomes crucially depends upon the use of effective images and advertisements, and yet limited research has been undertaken on the characteristics of effective media-based interventions in this context. These outcomes also crucially depend on a two-way relationship of trust: on the one hand, the advertiser’s trust in primary prevention as a strategy, in the potential of online advertising to encourage behavioral change, and in the users’ likelihood of users self-referring contacting the helpline; and on the other hand, the users’ trust—or overcoming of mistrust—in both display advertising targeted at them and in the advertisers themselves (when engagement with both may involve overcoming fears about privacy, surveillance, prosecution, or stigmatization). This paper discusses the pivotal role of trust in informing the development of CSAM prevention display advertisements, arguing that facilitating this two-way relationship of trust is core to the success of a prevention campaign and must be embedded into its design.

scholarly journals MOTIFS TRANSFORMATION OF M. DESBORDES-VALMORE LYRICS IN THE WORKS OF MARINA TSVETAEVA

2021 ◽  
Vol 7 (1) ◽  
pp. 128-143
Author(s):  
Ekaterina M. BELAVINA
Keyword(s):  
French Literature ◽  
Poetic Voice ◽  
European Culture ◽  
French Writer ◽  
Marina Tsvetaeva ◽  
History Of ◽  
The Moment ◽  
Relationship Of ◽  
First Time

The influence of French culture on the poetry of M. Tsvetaeva was noted by her contemporaries (B. Pasternak, S. Bobrov), and also became the subject of scientific research (for example, N. Strelnikova). However, the relationship of her poetry with the French writer work of the romanticism era, M. Desbordes-Valmore (1786-1859), which is almost forgotten in our days, is analyzed for the first time, which seems relevant in light of the growing interest in the role of women in European culture. The article uses a biographical method, with the involvement of the poetics of the rhythm of H. Meshonnik. The article examines the mentions of M. Desbordes-Valmore in M. Tsvetaeva’s poetry and in correspondence with B. Pasternak, provides a brief comparison of biographies in terms of their influence on the formation of a poetic voice. Their tragic fates have a lot in common: both survived revolutions, as a consequence the ruin of the family nest, extreme poverty, the loss of loved ones. The main similarity between M. Tsvetaeva and M. Desbordes-Valmore lies in the auditory imagination, in intonational rhythmic expressiveness and in vivid metaphor. Both M. Desbordes-Valmore and M. Tsvetaeva left evidence of a moment preceding the moment of writing, “music” preceding verbal expression. They often rely on the song as a precedent text (O. Revzina), a precedent rhythm. The autobiographical nature of the lyrics and the musicality bring together so dissimilar authors at first glance. M. Tsvetaeva read M. Desbordes-Valmore in the original, probably having become acquainted with her work at the summer courses in the history of French literature at the Sorbonne. The analysis of the transformations of M. Desbordes-Valmore’s poems motifs in M. Tsvetaeva’s lyrics clearly show not only a deep knowledge and understanding of the French romantic tradition, but also the innovation of her own poetic language.

scholarly journals Endothelial Cell Activation by Interleukin-1 and Extracellular Matrix Laminin-10 Occurs via the Yap Signalling Pathway

2021 ◽  
Author(s):  
Hannah Thurgur ◽  
Jeffrey Penny ◽  
Emmanuel Pinteaux
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cell ◽  
Cell Activation ◽  
Interleukin 1 ◽  
Tube Formation ◽  
Signalling Pathway ◽  
Endothelial Cell Activation ◽  
First Time

Abstract Background: The extracellular matrix (ECM) plays an important role for normal brain functions and homeostasis, and contributes to the inflammatory response and mechanisms of brain repair after acute brain injury. We have previously reported that the ECM laminin-10 (LM-10) is a key regulator of blood-brain barrier (BBB) integrity, and is involved in BBB repair after hypoxic injury and interleukin-1 (IL-1)-induced inflammation in vitro. To further investigate the role of LM-10 in BBB inflammation and repair, we investigated for the first time the signalling mechanisms regulated by LM-10 in brain endothelial cells in response to IL-1β-induced inflammation in vitro. Methods: Human brain endothelial cell line hCMEC/D3 cultured on Matrigel- or LM-10-coated tissue culture plates were left untreated or were treated with human recombinant IL-1β at various concentrations and/or for various periods of time. In vitro hallmarks of angiogenesis were assessed using a scratch injury model and tube formation assay. Expression of cell adhesion molecules ICAM-1 and VCAM-1, as well as IL-8 was measured using ELISA. Activation of signalling pathways ERK1/2, p38, NF-κB and YAP was assessed by quantitative ELISA or Western blot. Activation of genes downstream of YAP signalling was assessed by quantitative polymerase chain reaction.Results: LM-10 promoted endothelial proliferation and subsequent repair of an endothelial monolayer after scratch injury, induced tube formation, and upregulated IL-1β-induced ICAM-1 and VCAM-1 expression in vitro. Classical IL-1β-induced signalling pathway ERK1/2 and p38 were not modulated by LM-10, whilst LM-10 upregulated IL-1β-induced NF-κB activation. Importantly, we demonstrate for the first time a role of the YAP signalling pathway in endothelial cell activation, in that LM-10 significantly downregulates p-YAP (S397) activation without affecting phosphorylation of YAP (S127), leading to differential expression of YAP target genes, ctgf and serpine-1 involved in endothelial cell activation. Conclusion: Our study provides for the first time evidence that the YAP signalling pathway is an important regulator of endothelial cell activation, and could be a new therapeutic target for the treatment of cerebrovascular inflammatory diseases. 

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