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Relationship: 2771

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Oxidative Stress leads to Increased, Altered Signaling

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Deposition of energy leads to vascular remodeling adjacent Vinita Chauhan (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens Low NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI
Pig Pig Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male High
Female Low
Unspecific Low

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adult Moderate
Juvenile Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Oxidative stress occurs when the production of free radicals exceeds the capacity of cellular antioxidant defenses (Cabrera & Chihuailaf, 2011). Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are both free radicals that can contribute to oxidative stress (Ping et al., 2020), however, ROS are more commonly studied (Nagane et al., 2021). ROS can mediate oxidative damage to biomacromolecules as they react with DNA, proteins and lipids, resulting in functional changes to these molecules (Ping et al., 2020). For example, ROS acting on lipids creates lipid peroxidation (Cabrera & Chihuailaf, 2011).

Many signaling pathways control and maintain physiological balance within a living organism, and these can be impacted by oxidative stress. Excessive reactive oxygen and nitrogen species (RONS) during oxidative stress can modify biological molecules and directly cause DNA damage, which can lead to altered signal transduction pathways (Hughson, Helm & Durante, 2018; Nagane et al., 2021; Ping et al., 2020; Ramadan et al., 2021; Schmidt-Ullrich et al., 2000; Soloviev & Kizub, 2019; Wang, Boerma & Zhou, 2016; Venkatesulu et al., 2018; Zhang et al., 2016). Different cell types have distinct functional roles within the body and therefore, can express distinct cellular pathways. Different signaling pathways respond differently to an increase in oxidative stress. For example, oxidative stress in endothelial cells has been shown to inhibit the insulin-like growth factor 1 receptor (IGF-1R) and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathway and to activate the mitogen-activated protein kinase (MAPK) pathway, which can then have downstream detrimental effects (Ping et al., 2020). In contrast, oxidative stress in bone cells can lead to increased expression of the receptor activator of nuclear factor kappa B ligand (RANKL) and Nrf2 activation (Tahimic & Globus, 2017; Tian et al., 2017). Following activation, Nrf2 then interferes with the activation of runt-related transcription factor 2 (Runx2), and depending on the level of oxidative stress, this may result in altered bone cell function (Kook et al., 2015)

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Many reviews describe the role of oxidative stress in altered signaling. The mechanisms through which oxidative stress can contribute to changes in various signaling pathways are well-described. For example, oxidative stress can directly alter signaling pathways through protein oxidation (Ping et al., 2020; Schmidt-Ullrich et al., 2000; Valerie et al., 2007). Oxidation of cysteine and methionine residues, which are particularly sensitive to oxidation, can cause conformational change, protein expansion, and degradation, leading to changes in the protein levels of signaling pathways (Ping et al., 2020). Furthermore, oxidation of key residues in signaling proteins can alter their function, resulting in altered signaling. For example, oxidation of methionine 281 and 282 in the Ca2+/calmodulin binding domain of Ca2+/calmodulin-dependent protein kinase II leads to constitutive activation of its kinase activity and subsequent downstream alterations in signaling pathways (Ping et al., 2020). Similarly, during oxidative stress, tyrosine phosphatases can be inhibited by oxidation of a catalytic cysteine residue, resulting in increased phosphorylation of proteins in various signaling pathways (Schmidt-Ullrich et al., 2000; Valerie et al., 2007). Particularly relevant to this are the MAPK pathways. For example, the extracellular signal-regulated kinase (ERK) pathway is activated by upstream tyrosine kinases and relies on tyrosine phosphatases for deactivation (Valerie et al., 2007).

Furthermore, oxidative stress can indirectly influence signaling pathways through oxidative DNA damage which can lead to mutations or changes in the gene expression of proteins in signaling pathways (Ping et al., 2020; Schmidt-Ullrich et al., 2000; Valerie et al., 2007). In addition, DNA damage surveillance proteins like ataxia telangiectasia mutated (ATM) kinase and ATM/Rad3-related (ATR) protein kinase phosphorylate over 700 proteins, leading to changes in downstream signaling (Nagane et al., 2021; Schmidt-Ullrich et al., 2000; Valerie et al., 2007). For example, ATM phosphorylates many proteins in the ERK, p38, and Jun N-terminal kinase (JNK) MAPK pathways, leading to various downstream effects (Nagane et al., 2021; Schmidt-Ullrich et al., 2000).

The relationship between oxidative stress and signaling pathways has been extensively studied in both vascular tissue and bone tissue. In endothelial cells, oxidative stress can induce changes in signaling in the acidic sphingomyelinase (ASMase)/ceramide pathway, the PI3K/Akt pathway, the MAPK pathways, the p53/p21 pathway, and the signaling proteins p16 and p27 (Hughson, Helm & Durante, 2018; Nagane et al., 2021; Ping et al., 2020; Ramadan et al., 2021; Soloviev & Kizub, 2019; Wang, Boerma & Zhou, 2016). In bone cells, oxidative stress can induce signaling changes in the Wnt/β-catenin pathway, the RANK/RANKL pathway, the Nrf2/HO-1 pathway, and the MAPK pathways (Domazetovic et al., 2017; Manolagas & Almeida, 2007; Tian et al., 2017). The mechanisms of oxidative stress leading to altered signaling may be different for each pathway. For example, although both the PI3K/Akt and MAPK pathways can be regulated by insulin-like growth factor (IGF)-1, ROS results in selective inhibition of the IGF-1R/PI3K/Akt pathway by inhibiting the IGF-1 receptor (IGF-1R) activation of IRS1 (Ping et al., 2020). In another mechanism, ROS competitively inhibit the Wnt/β-catenin pathway through the activation of forkhead box O (FoxO), which are involved in the antioxidant response and require binding of β-catenin for transcriptional activity (Tian et al., 2017).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help
  • MAPK pathways can exhibit varied responses after exposure to oxidative stress. The expected response is an increase in the activity of the ERK, JNK, and p38 pathways as protein phosphatases, involved in the inactivation of MAPK pathways, are deactivated by oxidative stress (Valerie et al., 2007). Although some studies observe this (Azimzadeh et al., 2021; Sakata et al., 2015), others show a decrease (Fan et al., 2017; Yoo, Han & Kim, 2016) or varying changes (Azimzadeh et al., 2015) in the MAPK pathways.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Modulating factor

Details

Effects on the KER

References

Drug

Fenofibrate (PPARα activator, PPARα is a transcription factor that can activate antioxidant response)

Treatment of mice with 100 mg/kg of body weight daily for 2 weeks before and 2 weeks after radiation restored SOD activity, returned the level of phosphorylated MAPK proteins and increased Nrf2 levels.

Azimzadeh et al., 2021

Drug

L-carnitine (antioxidant)

L-carnitine injections (100 mg/kg) following irradiation resulted in decreased DHE staining, indicating ROS, and increased p-p38/p38 and p-Nrf2/Nrf2.

Fan et al., 2017

Drug

N-acetyl cysteine (antioxidant)

Treatment of osteoblast-like cells with 5 mM restored ROS levels, SOD activity, and the level of proteins in the Nrf2/HO-1 pathway.

Kook et al., 2015

Drug

Curcumin (antioxidant)

Treatment of osteoblast-like cells with 4 µM reduced ROS levels and the RANKL/OPG ratio. Treatment of rats with 40 mg/kg of body weight reduced oxidative stress and the RANKL/OPG ratio.

Xin et al., 2015

Drug

Bradykinin potentiating factor (BFP)

(antioxidant)

Treatment with BFP (1ug/g) after irradiation showed decreased AngII and aldosterone levels compared to irradiation alone.

Hasan, Radwan & Galal, 2020

Media

Hydrogen-rich

(antioxidant)

Osteoblasts in a medium consisting of 75% H2, 20% O2, and 5% CO2 (vol/vol/vol) showed a reduction in ROS production and restoration of normal signaling.

Sun et al., 2013

Drug

Melatonin

(antioxidant)

Treatment with 200nM melatonin reversed the effect of microgravity on Cu/Zn-SOD and Mn-SOD to control levels.

Yoo, Han & Kim, 2016

Drug

Polyphenol S3

Polyphenol S3 treatment reverses the effect of microgravity on CAT, SOD and MDA, returning the levels to near control values when S3 is used at high dose (60mg/kg/d). Runx2 mRNA levels and  β-catenin/ β-actin levels increased following treatment and simulated microgravity.

Diao et al., 2018

Drug

Sildenafil

Sildenafil (5uM) inhibits O2- production and attenuates intracelular peroxynitrite in BAECs after 10 Gy irradiation. As well, ASMase activity and ceramide generation was inhibited.

Wortel et al., 2019

Drug

DPI

(NOX-inhibitor)

Inhibits O2-  production and intracellular H2O2 in BAECs after 10 Gy irradiation.

Wortel et al., 2019

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Reference

Experiment Description

Result

Azimzadeh et al., 2017

In-vitro. HCAECs were irradiated with 0.5 Gy of X-rays (0.5 Gy/min). Protein carbonylation and Glutathione S-transferase omega-1 (GSTO1) antioxidant level were measured with a carbonylation assay and immunoblotting, respectively. Proteins from various signaling pathways including RhoGDI, p16, and p21 were measured with immunoblotting.

After 0.5 Gy, carbonyl content increased a maximum of 1.2-fold and GSTO1 decreased a maximum of 0.78-fold. After 0.5 Gy, p-RhoGDI decreased a maximum of 0.7-fold, p16 increased a maximum of 1.5-fold, and p21 increased a maximum of 1.2-fold.

Kenchegowda et al., 2018

In-vivo. Male 3- to 5-month-old Gottingen minipigs and Sinclair minipigs were whole-body irradiated with 1.7-2.3 Gy of gamma rays (0.6 Gy/min). Both survivors (n=23) and euthanized moribund animals (n=17) had measurements taken for oxidative stress and altered signaling taken from the heart. SOD, CAT, and p67 (subunit of NADPH oxidase/NOX, involved in producing superoxide) levels were determined with western blot. ELISA and western blot were used to measure altered signaling in the IGF/PI3K/Akt pathway.

Compared to survivors, radiation induced a 2.1-fold increase in p67, 0.87-fold decrease in SOD, and a 0.83-fold decrease in CAT (non-significant, ns) in the deceased group. Compared to survivors, the ratio of activated (phosphorylated) to total IGF-1R and the ratio of activated (phosphorylated) to total Akt both decreased 0.5-fold in the deceased group.

Kook et al., 2015

In-vitro. MC3T3-E1 osteoblast-like cells were irradiated with 2, 4, and 8 Gy of X-rays (1.5 Gy/min). ROS were measured with a fluorescent probe, and SOD, CAT, and GSH antioxidant activities were determined with assay kits. Protein levels in the Nrf2/HO-1 signaling pathway were determined by either western blot or RT-PCR.

ROS increased linearly at 2 and 4 Gy up to 1.4-fold at 8 Gy (significant changes at 4 Gy and 8 Gy). GSH and SOD were decreased 0.7-fold at 4 Gy and 0.5-fold at 8 Gy (insignificant increases at 2 Gy). CAT was also decreased but not significantly. HO-1 increased 3.3-fold after 4 Gy and 4.9-fold after 8 Gy (insignificant increase at 2 Gy). Nrf2 increased 2.3-fold after 8 Gy. Runx2 mRNA was decreased 0.5-fold after 8 Gy.

Bai et al., 2020

In-vitro. Rat-derived bone marrow-derived mesenchymal stem cells (BMSCs) were irradiated with 2, 5, and 10 Gy of gamma rays. Mitochondrial and cellular ROS levels were determined with fluorescent probes. RT-qPCR was performed to measure antioxidant enzyme expression. Protein expression in various signaling pathways was measured by western blot.

Mitochondrial ROS increased 1.6-fold at 2 Gy (non-significant), 2-fold at 5 Gy, and 2.3-fold at 10 Gy. Cellular ROS increased 1.2-fold at 2 Gy, 1.5-fold at 5 Gy, and 2.1-fold at 10 Gy. Antioxidants SOD1, SOD2, and CAT all decreased about 0.9-fold (ns for SOD2) after 2 Gy, 0.8- to 0.7-fold at 5 Gy, and 0.7- to 0.4-fold at 10 Gy. Runx2 decreased 0.9-fold at 2 and 5 Gy and 0.6-fold at 10 Gy. p21 increased 1.6-fold at 5 Gy and 2.5-fold at 10 Gy. p53 increased 1.6-fold at 5 Gy and 1.7-fold at 10 Gy. p16 remained unchanged.

Fan et al., 2017

In-vivo. 10-week old male C57Bl/6j mice were irradiated with Gamma rays at 3Gy/day for 5 days. Left ventricular cardiac tissue was harvested for analysis. ROS was detected by dihydroethidium (DHE) staining. MAPK and Nrf2 signaling molecules were measured by Western blot

Following irradiation, ROS production increased by 3.6-fold.

p-p38/p38 decreased by 0.36-fold and p-Nrf2/Nrf2 decreased by 0.14-fold.

Hasan, Radwan & Galal, 2020

In-vivo. 6-week old male Wistar rats were irradiated with 6 Gy Gamma rays. Oxidative stress was measured by MDA and GSH in heart tissue. Angiotensin II (AngII) and aldosterone, key molecules in the RAAS pathway, were measured with ELISA kits in serum.

Following irradiation, MDA levels increased by 1.5-fold and GSH levels decreased by 0.5-fold. AngII and aldosterone increased 1.4-fold compared to control.

 

Azimzadeh et al., 2015

In-vivo. Male 10-week-old  C57Bl/6 mice were irradiated with 8 and 16 Gy of X-rays. SOD, MDA, and protein carbonylation levels were determined with immunoblotting, lipid peroxidation, and protein carbonylation assays, respectively, in heart tissue. Proteins in various signaling pathways were measured with immunoblotting in heart tissue.

SOD decreased 0.7-fold at both 8 and 16 Gy and MDA increased 1.4-fold after 8 Gy and 2.1-fold after 16 Gy. Protein carbonylation increased 1.4-fold after 16 Gy. Levels and activity of proteins in the PI3K/Akt pathway were decreased between 0.5- and 0.1-fold at both 8 and 16 Gy. The ERK/MAPK pathway was found decreased 0.5-fold at 16 Gy and the p38/MAPK pathway was found increased 1.3-fold at 16 Gy. p16 was increased 1.6-fold at both 8 and 16 Gy. p21 was increased 2.4-fold at both 8 and 16 Gy.

Sakata et al., 2015

In-vitro. HUVECs were irradiated with 10 Gy X-rays at a dose rate of 5 Gy/min. Measurements were performed 0-72 h post-irradiation.

ROS was detected by fluorescence microscopy. MAPK, Akt, p-p38, JNK and ERK1/2 signaling molecules were measured by Western blot.

Following 10 Gy irradiation, the intensity representing ROS generation increased 20- and 30-fold at the 24 and 72 h timepoints, respectively.

MAPK, p38 and JNK remained unchanged for the 72 h measured following 10 Gy irradiation.

p-Akt/Akt in HUVECs after 10 Gy irradiation showed an initial decrease at 5 min and a delayed decrease of 0.5-fold at 6-24 h. p-ERK1/2 decreased at 5 min then increased to a maximum 1.75-fold change.

Wortel et al., 2019

In-vitro. BAECs were irradiated with 10 Gy 137Cs gamma rays at a rate of 1.66 Gy/min. Extracellular H2O2 was measured by Amplex Red Assay, intracellular H2O2 levels were determined by HyPer sensor and peroxynitrite was quantified by chemiluminescence assay. The activation of the ASMase enzyme and the levels of ceramide were quantified by radioenzymatic assay to deter mine the changes on the ASMase/ceramide pathway.

Following 10 Gy irradiation, intracellular H2O2 increased to a maximum 1.35-fold. Extracellular H2O2 increased by 1.75-fold (ns). Peroxynitrite increased by 2.86-fold after 10 Gy (Fig 5). ASMase activity increased to a maximum 5.6-fold at 5 min after irradiation, then decreased and remained unchanged until the 30 min time-point. Ceramide increased from -500 to over 3000 pmol/106.

Azimzadeh et al., 2021

In-vivo. Male C57BL/6J mice 8 weeks of age were irradiated with 16 Gy of X-rays to the heart. SOD antioxidant activity and MDA were determined with an assay kit and lipid peroxidation assay, respectively, in heart tissue. The level of proteins in MAPK pathways were determined by ELISA in heart tissue.

After 16 Gy, SOD decreased 0.8-fold and MDA increased 1.3-fold. Lipid peroxidation increased by 1.3-fold. After 16 Gy, p-ERK increased 1.5-fold, p-p38 increased 1.3-fold, and p-JNK increased 1.3-fold.

Xin et al., 2015

In-vitro and in-vivo.

In-vitro. MC3T3-E1 osteoblast-like cells were exposed to microgravity for 96 hours. ROS were determined with a fluorescent probe and the RANK/RANKL pathway was measured using RANKL and OPG assay kits.

In-vivo. Male 8-week-old Sprague-Dawley rats were exposed to hind-limb suspension for 6 weeks. Femur and plasma MDA and femur sulfhydryl levels were measured with assay kits and the RANK/RANKL pathway was measured in the femur using RANKL and OPG assay kits.

In-vitro. ROS increased 1.5-fold and the RANKL/OPG ratio increased 1.6-fold.

In-vivo. Serum and femur MDA increased 1.4-fold and femur sulfhydryl decreased 0.6-fold. The RANKL/OPG ratio increased 3.5-fold.

Sun et al., 2013

In-vitro. MC3T3-E1 osteoblast-like cells were exposed to microgravity (10-2 G) for 96 hours. ROS production was measured by a fluorescent probe. The RANKL/OPG ratio was determined by assay kit and Runx2 mRNA expression was determined by RT-qPCR

ROS increased 1.5-fold. The RANKL/OPG ratio increased 1.6-fold. Runx2 expression decreased 0.4-fold.

Yoo, Han & Kim, 2016

In-vitro. Preosteoblast MC3T3-E1 cells were exposed to microgravity conditions by a 3D clinostat at a speed from 1-10 rpm. Oxidative stress was measured by Cu/Zn-SOD, Mn-SOD and catalase activity. Signaling molecules, p-Akt, phosphorylation of the mechanistic target of rapamycin p-(mTOR), and p-ERK were measured by Western blot. 

Following microgravity exposure, Cu/Zn-SOD and Mn-SOD levels decreased by 0.24 and 0.65-fold, respectively. CAT increased by 1.25-fold. Signaling molecules p-Akt decreased by 0.36-fold. p-mTOR and p-ERK decreased by 0.58-fold.

Diao et al., 2018

In-vivo. The left femur of rats were studied after exposure to simulated microgravity. Oxidative stress was measured by MDA, SOD, and CAT levels. RANK/RANKL signaling pathway was measured in rat femur by enzyme-linked immunoassay detection of OPG/RANKL molecules. Signaling molecule, Runx2, mRNA levels were measured by quantitative real time PCR. The Wnt//β-catenin pathway was measured by Western blot for β-catenin protein levels.

MDA increased by 1.4-fold. SOD and CAT levels decreased by 0.4-fold. OPG/RANKL decreased by 0.6-fold. Runx2 mRNA levels decreased 0.04-fold (Fig 8d). β-catenin decreased 0.6-fold.

Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Reference

Experiment Description

Result

Azimzadeh et al., 2017

In-vitro. HCAECs were irradiated with 0.5 Gy of X-rays (0.5 Gy/min). Protein carbonylation and Glutathione S-transferase omega-1 (GSTO1) antioxidant level were measured with a carbonylation assay and immunoblotting, respectively. Proteins from various signaling pathways including RhoGDI, p16 and p21 were measured with immunoblotting. Measurements were taken at 1, 7, and 14 days after irradiation

After 7 and 14 days, carbonyl content increased 1.2-fold (insignificant increase at 1 day post-irradiation). After 1-14 days, GSTO1 decreased 0.78-fold (significant increases at all timepoints). After 1 and 7 days, p-RhoGDI decreased 0.7-fold (insignificant decrease at 14 days post-irradiation). p16 increased 1.2-fold after 7 days and 1.5-fold after 14 days (insignificant increase at 1 day post-irradiation). p21 increased 1.2-fold after 7 and 14 days (insignificant increase at 1 day post-irradiation).

Kook et al., 2015

In-vitro. MC3T3-E1 osteoblast-like cells were irradiated with X-rays (1.5 Gy/min). ROS were measured with a fluorescent probe, and SOD, CAT, and GSH antioxidant activities were determined with assay kits. Protein levels in the Nrf2/HO-1 signaling pathway were determined by either western blot or RT-PCR.

After 1 day and 8 Gy, ROS increased 1.4-fold, GSH decreased 0.5-fold, and SOD decreased 0.5-fold. CAT was also decreased but not significantly. After 1 day and 8 Gy, Nrf2 increased 2.3-fold. After 2 days and 8 Gy, HO-1 increased 4.9-fold. After 3 days and 8 Gy, Runx2 mRNA was decreased 0.5-fold.

Azimzadeh et al., 2015

In-vivo. Male 10-week-old  C57Bl/6 mice were irradiated with various doses of X-rays. SOD, MDA, and protein carbonylation levels were determined with immunoblotting, lipid peroxidation, and protein carbonylation assays, respectively. Proteins in various signaling pathways were measured with immunoblotting.

At 16 Gy and 16 weeks post-irradiation, SOD decreased 0.7-fold, MDA increased 2.1-fold, protein carbonylation increased 1.4-fold, levels and activity of proteins in the PI3K/Akt pathway were decreased between 0.5- and 0.1-fold, the ERK/MAPK pathway was decreased 0.5-fold, the p38/MAPK pathway was increased 1.3-fold, p16 was increased 1.6-fold, and p21 was increased 2.4-fold.

Wortel et al., 2019

In-vitro. BAECs were irradiated with 10 Gy 137Cs gamma rays at a rate of 1.66 Gy/min. Extracellular H2O2 was measured by Amplex Red Assay, and intracellular H2O2 levels were determined by the HyPer sensor. The activation of the ASMase enzyme and the levels of ceramide were quantified by radioenzymatic assay to determine the changes on the ASMase/ceramide pathway.

Following 10 Gy irradiation, intracellular H2O2 increased by 1.24-fold immediately after irradiation and continued to increase to a maximum 1.35-fold at 30 min time-point. Extracellular H2O2 increased by 1.75-fold (n.s.). ASMase activity increased to a maximum 5.6-fold at 5 min after irradiation, then decreased and remained unchanged until the 30 min time-point. Ceramide increased from -500 to over 3000 pmol/106 cells at 300 sec.

Park et al., 2016

In-vitro. Human aortic endothelial cells (HAECs) were exposed to viral overexpression of GDF15. The level of ROS was assessed with a fluorescent probe, p16 expression was assessed by RT-PCR, and p-ERK was assessed by western blot.

All after 24h, ROS increased 1.6-fold, p16 increased 3.4-fold, and p-ERK also increased.

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Based on the prioritized studies presented here, the evidence of taxonomic applicability is low for humans despite there being strong plausibility as the evidence only includes in-vitro human cell-derived models. The taxonomic applicability for mice and rats is considered high as there is much available data using in-vivo rodent models that demonstrate the concordance of the relationship. The taxonomic applicability was determined to be moderate for pigs as only one in-vivo study provided meaningful support to the relationship. In terms of sex applicability, all in-vivo studies that indicated the sex of the animals used male animals, therefore, the evidence for males is high and females is considered to be low for this KER. The majority of studies used adolescent animals, with a few using adult animals. Preadolescent animals were not used to support the KER, however, the relationship in preadolescent animals is still plausible.

References

List of the literature that was cited for this KER description. More help

Arfin, S. et al. (2021), “Oxidative Stress in Cancer Cell Metabolism”, Antioxidants 2021, Vol. 10/5, MDPI, Basel, https://doi.org/10.3390/ANTIOX10050642

Azimzadeh, O. et al. (2015), "Integrative proteomics and targeted transcriptomics analyses in cardiac endothelial cells unravel mechanisms of long-term radiation-induced vascular dysfunction", Journal of Proteome Research, Vol. 14/2, American Chemical Society, Washington, https://doi.org/10.1021/pr501141b

Azimzadeh, O. et al. (2021), "Activation of pparα by fenofibrate attenuates the effect of local heart high dose irradiation on the mouse cardiac proteome", Biomedicines, Vol. 9/12, MDPI, Basel, https://doi.org/10.3390/biomedicines9121845

Azimzadeh, O. et al. (2017), "Proteome analysis of irradiated endothelial cells reveals persistent alteration in protein degradation and the RhoGDI and NO signalling pathways", International Journal of Radiation Biology, Vol. 93/9, Informa, London, https://doi.org/10.1080/09553002.2017.1339332

Bai, J. et al. (2020), "Irradiation-induced senescence of bone marrow mesenchymal stem cells aggravates osteogenic differentiation dysfunction via paracrine signaling", American Journal of Physiology - Cell Physiology, Vol. 318/5, American Physiological Society, https://doi.org/10.1152/ajpcell.00520.2019

Boyce, B. F. and L. Xing. (2007), "The RANKL/RANK/OPG pathway", Current Osteoporosis Reports, Vol. 5/3, https://doi.org/10.1007/s11914-007-0024-y

Cabrera, M. P. and R. H. Chihuailaf. (2011), "Antioxidants and the Integrity of Ocular Tissues", Veterinary Medicine International, Vol. 2011, Hindawi, London, https://doi.org/10.4061/2011/905153

Diao, Y. et al. (2018), "Polyphenols (S3) Isolated from Cone Scales of Pinus koraiensis Alleviate Decreased Bone Formation in Rat under Simulated Microgravity", Scientific Reports, Vol. 8/1, Nature, https://doi.org/10.1038/s41598-018-30992-8

Domazetovic, V. et al. (2017), "Oxidative stress in bone remodeling: role of antioxidants", Clinical cases in mineral and bone metabolism, Vol. 14/2, pp. 209-216

Fan, Z. et al. (2017), "L-carnitine preserves cardiac function by activating p38 MAPK/Nrf2 signalling in hearts exposed to irradiation", European Journal of Pharmacology, Vol. 804, Elsevier, Amsterdam, https://doi.org/10.1016/j.ejphar.2017.04.003

Hasan, H. F., R. R. Radwan and S. M. Galal. (2020), "Bradykinin‐potentiating factor isolated from Leiurus quinquestriatus scorpion venom alleviates cardiomyopathy in irradiated rats via remodelling of the RAAS pathway", Clinical and Experimental Pharmacology and Physiology, Vol. 47/2, Wiley, https://doi.org/10.1111/1440-1681.13202

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