scholarly journals Influence of Individual Radiosensitivity on the Adaptive Response Phenomenon: Toward a Mechanistic Explanation Based on the Nucleo-Shuttling of ATM Protein

Dose-Response ◽  
2018 ◽  
Vol 16 (3) ◽  
pp. 155932581878983 ◽  
Author(s):  
Clément Devic ◽  
Mélanie L. Ferlazzo ◽  
Nicolas Foray
Keyword(s):  
Adaptive Response ◽  
Molecular Mechanisms ◽  
Low Dose ◽  
Mechanistic Model ◽  
Mechanistic Explanation ◽  
Human Cells ◽  
Cellular Models ◽  
Individual Radiosensitivity ◽  
Challenging Dose ◽  
Atm Protein

The adaptive response (AR) phenomenon generally describes a protective effect caused by a “priming” low dose ( dAR) delivered after a period of time (Δ tAR) before a higher “challenging” dose ( DAR). The AR is currently observed in human cells if dAR, Δ tAR, and DAR belong to (0.001-0.5 Gy), (2-24 hours), (0.1-5 Gy), respectively. In order to investigate the molecular mechanisms specific to AR in human cells, we have systematically reviewed the experimental AR protocols, the cellular models, and the biological endpoints used from the 1980s. The AR appears to be preferentially observed in radiosensitive cells and is strongly dependent on individual radiosensitivity. To date, the model of the nucleo-shuttling of the ATM protein provides a relevant mechanistic explanation of the AR molecular and cellular events. Indeed, the priming dose dAR may result in the diffusion of a significant amount of active ATM monomers in the nucleus. These ATM monomers, added to those induced directly by the challenging dose DAR, may increase the efficiency of the response to DAR by a better ATM-dependent DNA damage recognition. Such mechanistic model would also explain why AR is not observed in radioresistant or hyperradiosensitive cells. Further investigations at low dose are needed to consolidate our hypotheses.

scholarly journals Influence of Individual Radiosensitivity on the Hormesis Phenomenon: Toward a Mechanistic Explanation Based on the Nucleoshuttling of ATM Protein

Dose-Response ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. 155932582091378
Author(s):  
Clément Devic ◽  
Mélanie L. Ferlazzo ◽  
Elise Berthel ◽  
Nicolas Foray
Keyword(s):  
Low Dose ◽  
Molecular Model ◽  
Dose Range ◽  
Mechanistic Explanation ◽  
Dna Double Strand Breaks ◽  
Dna Breaks ◽  
Cellular Models ◽  
Individual Radiosensitivity ◽  
Biological Interpretation ◽  
Atm Protein

Hormesis is a low-dose phenomenon that has been reported to occur, to different extents, in animals, plants, and microorganisms. However, a review of the literature shows that only a few reports describe it in humans. Also, the diversity of experimental protocols and cellular models used makes deciphering the mechanisms of hormesis difficult. In humans, hormesis mostly appears in the 20 to 75 mGy dose range and in nontransformed, radioresistant cells. In a previous paper by Devic et al, a biological interpretation of the adaptive response (AR) phenomenon was proposed using our model that is based on the radiation-induced nucleoshuttling of the ATM protein (the RIANS model). Here, we showed that the 20 to 75 mGy dose range corresponds to a maximum amount of ATM monomers diffusing into the nucleus, while no DNA double-strand breaks is produced by radiation. These ATM monomers are suggested to help in recognizing and repairing spontaneous DNA breaks accumulated in cells and contribute to reductions in genomic instability and aging. The RIANS model also permitted the biological interpretation of hypersensitivity to low doses (HRS)—another low-dose phenomenon. Hence, for the first time to our knowledge, hormesis, AR, and HRS can be explained using the same unified molecular model.

scholarly journals Cellular Adaptive Response and Regulation of HIF after Low Dose Gamma-radiation Exposure

2018 ◽  
Author(s):  
Nitin Motilal Gandhi
Keyword(s):  
Radiation Exposure ◽  
Adaptive Response ◽  
Low Dose ◽  
Lower Amount ◽  
Induced Response ◽  
Priming Dose ◽  
Γ Radiation ◽  
Radiation Induced ◽  
Challenging Dose

AbstractPurposeCellular damage due to low dose of γ-radiation (≤0.1 Gy) is generally extrapolated from observing the effects at higher doses. These estimations are not accurate. This has led to uncertainties while assessing the radiation risk factors at low doses. Although there are reports on the radiation induced adaptive response, the mechanism of action is not fully elucidated, leading to the uncertainties. One of the outcomes of low dose radiation exposure is believed to be adaptive response. The mechanism of adaptive response is not fully understood. Therefore, the study was undertaken to understand the role of hypoxia inducible factor (HIF) on radiation induced adaptive response.Materials and methodsMCF-7 cells pre-exposed to low dose γ-radiation (0.1 Gy; Priming dose) were exposed to 2 Gy (challenging dose) 8 hrs after the priming dose and studied for the adaptive response. Cell death was measured by MTT assay, and apoptosis was measured by FACS analysis. DNA damage was measures by alkaline comet assay. HIF transcription activity was assayed using transiently transfected plasmid having HIF consensus sequence and luciferase as the reporter gene.ResultsCells when exposed to 0.1 Gy priming dose 8 hrs prior to the higher dose (2 Gy; Challenging dose) results in lower amount of radiation induced damages compared to the cells exposed to 2 Gy alone. Cobalt chloride treatment in place of priming dose also results in the protection to cells when exposed to challenging dose. There was up-regulation of HIF activity when cells were exposed to priming dose, indicating the role of HIF in radiation induced response.ConclusionResults indicate the γ-radiation induced adaptive response. One of the mechanism proposed is up-regulation of HIF after low dose exposure, which protects the cells from damages when they are exposed to challenging dose of 2 Gy radiation dose.

scholarly journals Modeling of Molecular Mechanisms of Radiation Adaptive Response Formation

2021 ◽  
Keyword(s):  
Adaptive Response ◽  
Molecular Mechanisms ◽  
Low Dose ◽  
Low Doses ◽  
Radiation Hormesis ◽  
Biological Objects ◽  
Mechanisms Of Formation ◽  
Radiation Induced ◽  
High Doses ◽  
Lnt Model

The phenomenon of adaptive response is expressed in the increase of resistance of a biological object to high doses of mutagens under the conditions of previous exposure to these (or other) mutagens in low doses. Low doses of mutagen activate a number of protective mechanisms in a living object, which are called hormetic. Thus, the adaptive response and hormesis are links in the same chain. Radiation hormesis refers to the generally positive effect of low doses of low LET radiation on biological objects. The phenomenology of radiation-induced adaptive response and radiation hormesis for biological objects of different levels of organization is considered; the review of existing theories describing the dose-effect relationship has been reviewed. The hypothesis proposing one of the mechanisms of formation of radiation adaptive response of cells taking into account the conformational structure of chromatin has been submitted. The analysis of modern concepts of the phenomenon of hormesis on the basis of modeling of molecular mechanisms of formation of hormetic reactions to low-dose low LET radiation has been carried out. The parameters that can be used for quantitative and graphical evaluation of the phenomenon of hormesis was considered, and a formula for calculating the coefficient of radiation-induced adaptive response has been proposed. A review of mathematical models describing the radiation relative risk of gene mutations and neoplastic transformations at low-dose irradiation of cohorts has been performed. The following conclusions have been made: radiation hormesis and adaptive response are generally recognized as real and reproducible biological phenomena, which should be considered as very important phenomena of evolutionarily formed biological protection of living organisms from ionizing radiation. The hormesis model of dose-response relationship makes much more accurate predictions of a living object's response to radiation (or other stressors) in the low-dose range than the linear threshold (LNT) model does. The LNT model can adequately describe reactions only in the region of high doses of radiation, and, therefore, extrapolation modeling of biological object’s reactions from the zone of high doses to low doses is not correct.

scholarly journals TEAD4 modulated LncRNA MNX1-AS1 contributes to gastric cancer progression partly through suppressing BTG2 and activating BCL2

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
You Shuai ◽  
Zhonghua Ma ◽  
Weitao Liu ◽  
Tao Yu ◽  
Changsheng Yan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Mechanistic Model ◽  
Ectopic Expression ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Tissue Samples ◽  
Reporter Assays

Abstract Background Gastric cancer (GC) is the third leading cause of cancer-related mortality globally. Long noncoding RNAs (lncRNAs) are dysregulated in obvious malignancies including GC and exploring the regulatory mechanisms underlying their expression is an attractive research area. However, these molecular mechanisms require further clarification, especially upstream mechanisms. Methods LncRNA MNX1-AS1 expression in GC tissue samples was investigated via microarray analysis and further determined in a cohort of GC tissues via quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Cell proliferation and flow cytometry assays were performed to confirm the roles of MNX1-AS1 in GC proliferation, cell cycle regulation, and apoptosis. The influence of MNX1-AS1 on GC cell migration and invasion was explored with Transwell assays. A xenograft tumour model was established to verify the effects of MNX1-AS1 on in vivo tumourigenesis. The TEAD4-involved upstream regulatory mechanism of MNX1-AS1 was explored through ChIP and luciferase reporter assays. The mechanistic model of MNX1-AS1 in regulating gene expression was further detected by subcellular fractionation, FISH, RIP, ChIP and luciferase reporter assays. Results It was found that MNX1-AS1 displayed obvious upregulation in GC tissue samples and cell lines, and ectopic expression of MNX1-AS1 predicted poor clinical outcomes for patients with GC. Overexpressed MNX1-AS1 expression promoted proliferation, migration and invasion of GC cells markedly, whereas decreased MNX1-AS1 expression elicited the opposite effects. Consistent with the in vitro results, MNX1-AS1 depletion effectively inhibited the growth of xenograft tumour in vivo. Mechanistically, TEAD4 directly bound the promoter region of MNX1-AS1 and stimulated the transcription of MNX1-AS1. Furthermore, MNX1-AS1 can sponge miR-6785-5p to upregulate the expression of BCL2 in GC cells. Meanwhile, MNX1-AS1 suppressed the transcription of BTG2 by recruiting polycomb repressive complex 2 to BTG2 promoter regions. Conclusions Our findings demonstrate that MNX1-AS1 may be able to serve as a prognostic indicator in GC patients and that TEAD4-activatd MNX1-AS1 can promote GC progression through EZH2/BTG2 and miR-6785-5p/BCL2 axes, implicating it as a novel and potent target for the treatment of GC.

Molecular mechanisms involved in the adaptive response to cadmium-induced apoptosis in human myelomonocytic lymphoma U937 cells

2011 ◽  
Vol 25 (8) ◽  
pp. 1687-1693 ◽  
Author(s):  
Zheng-Guo Cui ◽  
Ryohei Ogawa ◽  
Jin-Lan Piao ◽  
Kei Hamazaki ◽  
Loreto B. Feril ◽  
...  
Keyword(s):  
Adaptive Response ◽  
Molecular Mechanisms ◽  
U937 Cells ◽  
Induced Apoptosis

scholarly journals Ionizing Radiation and Translation Control: A Link to Radiation Hormesis?

2020 ◽  
Vol 21 (18) ◽  
pp. 6650
Author(s):  
Usha Kabilan ◽  
Tyson E. Graber ◽  
Tommy Alain ◽  
Dmitry Klokov
Keyword(s):  
Protein Synthesis ◽  
Ionizing Radiation ◽  
Molecular Mechanisms ◽  
Low Dose ◽  
Mrna Translation ◽  
Cellular Responses ◽  
Translation Control ◽  
Cis Acting ◽  
Radiation Hormesis ◽  
Downstream Signaling

Protein synthesis, or mRNA translation, is one of the most energy-consuming functions in cells. Translation of mRNA into proteins is thus highly regulated by and integrated with upstream and downstream signaling pathways, dependent on various transacting proteins and cis-acting elements within the substrate mRNAs. Under conditions of stress, such as exposure to ionizing radiation, regulatory mechanisms reprogram protein synthesis to translate mRNAs encoding proteins that ensure proper cellular responses. Interestingly, beneficial responses to low-dose radiation exposure, known as radiation hormesis, have been described in several models, but the molecular mechanisms behind this phenomenon are largely unknown. In this review, we explore how differences in cellular responses to high- vs. low-dose ionizing radiation are realized through the modulation of molecular pathways with a particular emphasis on the regulation of mRNA translation control.

scholarly journals Ecological mechanisms in cognitive science

2019 ◽  
Vol 29 (5) ◽  
pp. 676-696 ◽  
Author(s):  
Sabrina Golonka ◽  
Andrew D. Wilson
Keyword(s):  
Simple Model ◽  
Circadian Rhythms ◽  
Cognitive Science ◽  
Real Time ◽  
Mechanistic Model ◽  
Mechanistic Explanation ◽  
Perceptual Information ◽  
Proof Of Concept ◽  
Time Interaction ◽  
Ecological Mechanisms

In 2010, Bechtel and Abrahamsen defined and described what it means to be a dynamic causal mechanistic explanatory model. They discussed the development of a mechanistic explanation of circadian rhythms as an exemplar of the process and challenged cognitive science to follow this example. This article takes on that challenge. A mechanistic model is one that accurately represents the real parts and operations of the mechanism being studied. These real components must be identified by an empirical programme that decomposes the system at the correct scale and localises the components in space and time. Psychological behaviour emerges from the nature of our real-time interaction with our environments—here we show that the correct scale to guide decomposition is picked out by the ecological perceptual information that enables that interaction. As proof of concept, we show that a simple model of coordinated rhythmic movement, grounded in information, is a genuine dynamical mechanistic explanation of many key coordination phenomena.

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