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Relationship: 2833

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 Tissue resident cell activation

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Oxidative Stress

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Tissue resident cell activation

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 Leading to Learning and Memory Impairment	adjacent	Moderate	Low	Brendan Ferreri-Hanberry (send email)	Open for citation & comment

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	Low	NCBI
rat	Rattus norvegicus	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	Moderate
Female	Not Specified
Unspecific	Low

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Adult	Moderate
Not Otherwise Specified	Low

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 encompasses an increase in the production of free radicals (e.g., superoxide, hydrogen peroxide and hydroxyl radicals) and a loss of antioxidant mechanisms (e.g., superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT)). This imbalance can lead to damaging by-products that can activate tissue resident cells. Reactive oxygen and nitrogen species (RONS) are examples of free radicals that may promote oxidative injury (Simpson & Oliver, 2020). In addition, excess free radicals can promote a reduced capacity of the cells to maintain redox balance and prevent ongoing oxidative damage (Huang, Zou & Corniola, 2012; Rojo et al., 2014). Depending on the organ/tissue, different resident cell types may become activated by oxidative stress. For example, in the brain, oxidative stress will specifically activate microglial cells and astrocytes (Lee, Cha & Lee, 2021). Microglia cells are macrophages in the brain that respond to tissue injury, provide surveillance to neurons, and maintain synaptic homeostasis (Zhu et al., 2022). Astrocytes are critical regulators of neurogenesis and synaptogenesis, blood brain barrier permeability, and responsible for maintenance of cellular homeostasis (Zhu et al., 2022). Both microglial cells and astrocytes can change from resting to reactive states, termed gliosis, in response to excess RONS (Lee, Cha & Lee, 2021). In response to RONS, Toll like receptors (TLRs) located on microglia become activated to mediate the immune response (Gill et al., 2010; Mehdipour et al., 2021). These receptors then initiate a cascade of signaling pathways that contribute to the production of pro-inflammatory cytokines and free radicals, resulting in neuroinflammation (Heidari et al., 2022).

Reactive microglia cells increase in size and number, display a reduction in the length and density of their processes, and upregulate their macrophagic processes, marked by expression of proteins related to phagocytic activity such as cluster of differentiation 68 (CD68) (Hol & Pekny, 2015). Astrocytes undergoing astrogliosis exhibit cellular hypertrophy and an upregulation of glial fibrillary acidic protein (GFAP), an intermediate filament expressed exclusively in astrocytes that plays a critical role in astroglia cell activation (Hol & Pekny, 2015). Activation of both microglial cells and astrocytes can accelerate neuroinflammatory pathways that can ultimately promote further formation of ROS creating a feedforward loop (Lee, Cha & Lee, 2021; Simpson & Oliver, 2020; Zhu et al., 2022).

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

The strategy for collating the evidence to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Overall Weight of Evidence: Moderate

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

Biological Plausibility is Moderate. RONS can activate some inflammatory and anti-inflammatory pathways (TLR, TGF-β, NF-kB), and RONS are an essential part of multiple inflammatory and anti-inflammatory pathways (TLR4, TNF-a, TGF-β, NF-kB).

RONS activates or is essential to many inflammatory pathways including TGF-β (Barcellos-Hoff and Dix 1996; Jobling, Mott et al. 2006), TNF (Blaser, Dostert et al. 2016), Toll-like receptor (TLR) (Park, Jung et al. 2004; Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006; Miller, Goodson et al. 2017; Cavaillon 2018), and NF-kB signaling (Gloire, Legrand-Poels et al. 2006; Morgan and Liu 2011). These interactions principally involve ROS, but RNS can indirectly activate TLRs and possibly NF-kB. Since inflammatory signaling and activated immune cells can also increase the production of RONS, positive feedback and feedforward loops can occur (Zhao and Robbins 2009; Ratikan, Micewicz et al. 2015; Blaser, Dostert et al. 2016).

Damage inflicted by RONS on cells activate TLRs and other receptors to promote release of cytokines (Ratikan, Micewicz et al. 2015). For example, oxidized lipids or oxidative stress-induced heat shock proteins can activate TLR4 (Miller, Goodson et al. 2017; Cavaillon 2018).

ROS is essential to TLR4 activation of downstream signals including NF-kB. Activation of TLR4 promotes the surface expression and movement of TLR4 into signal-promoting lipid rafts (Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006). This signal promotion requires NADPH-oxidase and ROS (Park, Jung et al. 2004; Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006). ROS is also required for the TLR4/TRAF6/ASK-1/p38 dependent activation of inflammatory cytokines (Matsuzawa, Saegusa et al. 2005). ROS therefore amplifies the inflammatory process.

RONS can also fail to activate or actively inhibit inflammatory pathways, and the circumstances determining response to RONS are not well known (Gloire, Legrand-Poels et al. 2006).

Responses to oxidative stress can vary depending on the organ system. In the central nervous system (CNS), biological plausibility supporting the connection between increased oxidative stress to tissue resident cell activation is moderately supported by evidence compiled from studies using animal and in vitro models. Multiple studies have shown that microglial cells and astrocytes are activated in response to RONS, meaning they change from resting to reactive states by secreting pro-inflammatory mediators and initiating antioxidant defenses mediated through TLRs (Simpson & Oliver, 2020; Heidari et al., 2022). Literature reviews describing the role of oxidative stress imbalances and glial cell activation in the context of general oxidative injury (Lee, Cha & Lee, 2021), stroke (Zhu et al., 2022) and neurodegenerative diseases (Reynolds et al., 2007; Simpson & Oliver, 2020) also suggest a relationship between increased oxidative stress and increased tissue resident cell activation in the CNS.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Empirical Evidence is Moderate. Both RONS and inflammation increase in response to agents that increase RONS or inflammation, and antioxidants reduce inflammation. Multiple studies show dose-dependent changes in both RONS and inflammation in response to stressors including ionizing radiation and antioxidants. RONS have been measured at the same or earlier time points as inflammatory markers, but additional studies are needed to characterize the inflammatory response at the earliest time points to support causation. Uncertainties come from the positive feedback from inflammation to RONS potentially interfering with attempts to establish causality, and from the large number of inflammation-related endpoints with differing responses to stressors and experimental variation.

Oxidative activity is required for or promotes the response to multiple inflammatory stressors, including ionizing radiation, UV radiation (particularly UVB), the endotoxin LPS and other pathogen associated immune activators, and hemorrhagic shock (Park, Jung et al. 2004; Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006; Zhao and Robbins 2009; Ha, Chung et al. 2010; Hiramoto, Kobayashi et al. 2012; Straub, New et al. 2015).

Both intracellular concentrations of RONS and a wide range of inflammatory markers increase in response to RONS stressors. This paired increase was observed in vivo in rodents in tissue from multiple internal organs following exposure to whole body or abdominal ionizing radiation (Berruyer, Martin et al. 2004; Ha, Chung et al. 2010; Sinha, Das et al. 2011; Sinha, Das et al. 2012; Das, Manna et al. 2014; Ozyurt, Cevik et al. 2014; Khan, Manna et al. 2015; Zetner, Andersen et al. 2016; Haddadi, Rezaeyan et al. 2017; Ezz, Ibrahim et al. 2018) or following UV skin irradiation (Sharma, Meeran et al. 2007; Hiramoto, Kobayashi et al. 2012; Martinez, Pinho-Ribeiro et al. 2016). In vitro, the relationship has been reported in response to IR and UV in keratinocytes (Park, Ju et al. 2006; Kang, Kim et al. 2007; Martin, Sur et al. 2008; Lee, Jeon et al. 2010; Ren, Shi et al. 2016; Hung, Tang et al. 2017; Zhang, Zhu et al. 2017), immune cells (Matsuzawa, Saegusa et al. 2005; Nakahira, Kim et al. 2006; Manna, Das et al. 2015; Soltani, Ghaemi et al. 2016), as well as corneal and conjunctival epithelia, HEK cells, and vocal cord and foreskin fibroblasts (Narayanan, LaRue et al. 1999; Park, Jung et al. 2004; Saltman, Kraus et al. 2010; Black, Gordon et al. 2011; Han, Min et al. 2015). Direct application of micromolar concentrations of H2O2 in vitro also increases inflammatory markers in immune cells (Matsuzawa, Saegusa et al. 2005; Nakao, Kurokawa et al. 2008) and keratinocytes (Zhang, Zhu et al. 2017).

Interventions to reduce oxidative activity also reduce inflammation, further implicating RONS in the inflammatory process. Reduction of inflammation by these interventions has been documented in animals in response to IR (Berruyer, Martin et al. 2004; Sinha, Das et al. 2011; Sinha, Das et al. 2012; Das, Manna et al. 2014; Ozyurt, Cevik et al. 2014; Khan, Manna et al. 2015; Zetner, Andersen et al. 2016; Haddadi, Rezaeyan et al. 2017; Ezz, Ibrahim et al. 2018), UV (Sharma, Meeran et al. 2007; Lee, Jeon et al. 2010; Hiramoto, Kobayashi et al. 2012; Han, Min et al. 2015; Martinez, Pinho-Ribeiro et al. 2016; Ren, Shi et al. 2016; Hung, Tang et al. 2017) and hemorrhagic shock (Powers, Szaszi et al. 2006). In vitro, multiple studies in immune cells (Matsuzawa, Saegusa et al. 2005; Nakahira, Kim et al. 2006; Manna, Das et al. 2015; Soltani, Ghaemi et al. 2016)and keratinocytes (Park, Ju et al. 2006; Kang, Kim et al. 2007; Martin, Sur et al. 2008; Lee, Jeon et al. 2010; Ren, Shi et al. 2016; Hung, Tang et al. 2017; Zhang, Zhu et al. 2017) as well as HEK293, fibroblasts, and epithelial cells (Lee, Dimtchev et al. 1998; Narayanan, LaRue et al. 1999; Park, Jung et al. 2004; Han, Min et al. 2015) provide further evidence for reduction in various inflammatory markers with interventions to reduce RONS. Interventions include antioxidants such as propyl gallate, n-acetylcysteine, or naringin, as well as reduction in the function of NADPH oxidases (NOX/DUOX) via DPI or knockdown of gene expression. In studies using multiple doses of antioxidant, inflammation was reduced dose-dependently with the antioxidant dose (Nakahira, Kim et al. 2006; Manna, Das et al. 2015; Ren, Shi et al. 2016). Interventions reducing nitric oxide were not common, but in one study inhibiting iNOS did not reduce activation of NF-kB by IR (Lee, Dimtchev et al. 1998). The treatment to reduce RONS is administered before, or occasionally immediately after the inflammatory stressor, but experiments often continue treatment or don’t explicitly report changing media in vitro, so the exact time point at which RONS are required is difficult to pinpoint.

IR and RONS decrease endogenous antioxidant activity (glutathione, superoxide dismutase, and catalase), and antioxidants rescue this suppression in antioxidant activity (Sharma, Meeran et al. 2007; Das, Manna et al. 2014). Mice with more endogenous glutathione have a lower inflammatory response to IR (Berruyer, Martin et al. 2004), suggesting that IR increases inflammation in part by decreasing antioxidants.

In response to inflammatory stressors, RONS has been measured at the same (Nakao, Kurokawa et al. 2008; Ha, Chung et al. 2010; Saltman, Kraus et al. 2010; Azimzadeh, Scherthan et al. 2011; Ameziane-El-Hassani, Talbot et al. 2015; Azimzadeh, Sievert et al. 2015; Zhang, Zhu et al. 2017) or earlier time points as inflammatory markers (Nakahira, Kim et al. 2006; Black, Gordon et al. 2011), This suggests that RONS precedes the generation of inflammatory markers, consistent with a role for RONS in promoting inflammation. However, inflammatory markers are not typically measured at the earliest time points, and a more comprehensive survey of the appearance of these events at early time points would help to clarify the timeline and confirm the temporal evidence for causation.

A relatively small number of studies in a variety of cell types have examined both RONS and inflammatory markers across multiple doses. Three of these report dose-dependent increases in both RONS and inflammatory markers; one in which the key events are evaluated immediately after H2O2 application (Nakao, Kurokawa et al. 2008), and two others evaluating them 24 hours or 8-16 weeks after IR (Ha, Chung et al. 2010; Azimzadeh, Sievert et al. 2015). A fourth study reports a dose-dependent reduction in inflammation in response to treatment with antioxidants (Nakahira, Kim et al. 2006). In three other studies, some or all markers of inflammation increase at lower doses but decrease at higher doses (Saltman, Kraus et al. 2010; Black, Gordon et al. 2011; Zhang, Zhu et al. 2017). In two of these studies, RONS is also not consistently increasing with dose (Saltman, Kraus et al. 2010; Zhang, Zhu et al. 2017), however, this finding is consistent with findings from other studies about lack of dose-dependence of ROS measured at intermediate time points after IR. Similarly, 30 minutes after low dose, IR IL8 increases with dose while ROS does not (Narayanan, LaRue et al. 1999). The mixed inflammatory response at higher doses suggests that additional factors such as negative and positive feedback and crosstalk between pathways are also involved in the relationship between RONS and IR.

Dose Concordance

Evidence to support this relationship in the brain is derived from studies using gamma rays (Schnegg et al., 2012), 6-OHDA (Wang et al., 2017), or H2O2 (Daverey & Agrawal, 2016) as the stressor. Oxidative stress and tissue resident cell activation was then assessed within the brain or glial cell cultures (Davery & Agrawal, 2016; Schnegg et al., 2012; Wang, 2017; Daverey & Agrawal, 2016; Schnegg et al., 2012; Wang et al., 2017). Few studies show that oxidative stress occurs at lower or the same dose of a stressor than tissue-resident cell activation. Treatment with 4 µg/µL of the neurotoxin 6-hydroxydopamine caused decreased antioxidant levels as well as increased glial fibrillary acidic protein (GFAP) levels in rats (Wang et al., 2017). In another study, astrocyte activation showed a slight linear increase in response to 50 µM, 100 µM and 200 µM of H2O2 (Daverey & Agrawal, 2016).

Time Concordance

Few studies show that oxidative stress occurs before or at the same time as tissue-resident cell activation in a time course. BV-2 microglia irradiated with 10 Gy gamma rays showed an increase in ROS 1h post-irradiation, while an increase in NF-κB and AP-1 DNA binding was also observed 1h post-irradiation (Schnegg et al., 2012). Treatment of human glioblastoma astrocytes (A172 cell) with 50 µM of H2O2 for various times, showed a small linear increase in GFAP levels from 2h to 24h of treatment (Daverey & Agrawal, 2016).

Incidence Concordance

Schnegg et al. (2012) irradiated BV-2 microglia with gamma rays and showed increased ROS as well as increased NF-κB and AP-1 DNA binding, indicating activated glial cells, at the same dose of 10 Gy.

Essentiality

Studies examining the use of antioxidants to inhibit free radicals demonstrate the essentiality of oxidative stress and tissue resident cell activation. This has been observed in microglial cells using multiple types of inhibitors. In BV-2 microglia, activation of PPARδ (involved in anti-inflammatory responses) with the agonist L-16504, reduced formation of reactive oxygen species and microglial activation (Schnegg et al., 2012). Treatment with multiple doses of an antioxidant Kukoamine A (KuA) elicited a dose-dependent partial attenuation of radiation-induced markers of microglial cell activation in rats (Zhang et al. 2017). After administration of another antioxidant, curcumin, levels of SOD and GSH-Px were restored and GFAP levels were decreased (Daverey & Agrawal, 2016; Wang et al., 2017). Furthermore, a knockout model of mitochondrial SOD (SOD2) resulted in an increase in reactivity of microglial cells post-irradiation (Fishman et. al 2009).

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

Although ROS can activate NF-KB (Gloire, Legrand-Poels et al. 2006), not all studies consistently show NF-kB activation after RONs stressor IR. It is possible that the link between ROS and NF-kB depends on the local environmental context, with different studies not adequately controlling all influential variables. One study offers a possible explanation based on temporal response: in macrophages, NF-kB was activated by shorter exposures to H2O2 (30 min), but the response disappeared with longer exposures (Nakao, Kurokawa et al. 2008).

While many models in vivo and in vitro showed a decreased inflammatory response to RONS stressors IR in combination with antioxidants, in endothelial cells in culture the increase in IL6 and IL8 after IR was not reduced by antioxidants, although a synergistic increase in those cytokines occurring with combined TNF-a and IR treatment was reduced by antioxidants (Meeren, Bertho et al. 1997). This is a reminder that multiple mechanisms can increase inflammation, that inflammatory factors participate in positive feedback loops, and that responses to stimuli vary between cells.

Many studies do not report direct measures of RONS. As RONS are quickly scavenged, the quantitative understanding of this relationship can be inconsistent, due to varied response of antioxidant enzymes across experimental conditions and time measurements.

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	KuA (antioxidant)	After 30 Gy X-ray whole-brain irradiation of rats, activated microglia increased to over 320% of control. KuA at 5 mg/kg decreased this to 240%, at 10 mg/kg decreased it to 180% and at 20 mg/kg decreased it to 170%.	Zhang et al., 2017
Drug	L-16504 (PPARδ agonist, involved in anti-inflammatory responses)	Treatment prevented the increase in ROS and reduced NF-κB and AP-1 DNA binding.	Schnegg et al., 2012
Drug	Curcumin (antioxidant)	Treatment increased SOD and GSH-Px levels and decreased the number of GFAP-positive cells.	Wang et al., 2017; Daverey & Agrawal, 2016
Age	Increased age	Increased age can cause susceptibility to ROS accumulation and tissue-resident cell activation.	Liguori et al., 2018; Hanslik, Marino & Ulland, 2021
Diet	High antioxidant diet	Increased antioxidants in diet can lead to reduced oxidative stress.	Ávila-Escalante et al., 2020
Diet	Hypocaloric diet	Caloric restriction has been shown to lead to reduced markers of oxidative stress.	Ávila-Escalante et al., 2020
Smoking	Active smokers	Active smokers show reduced GSH-Px activity compared to non-smokers (measured in patients with coronary artery disease).	Kamceva et al., 2016
Prior Disease	Neurodegenerative diseases like Alzheimer’s and Parkinson’s	These diseases can generate an environment of increased oxidative stress and promotes the activation of glial cells.	Hanslik, Marino & Ulland, 2021
Genotype	SOD knockout mice	SOD2 knockout mice experienced increased microglia activation following irradiation, indicating an impact of genotype on tissue resident cell activation.	Fishman et al., 2009

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

The table below provides some representative examples of quantitative linkages between the two key events. It was difficult to identify a general trend across all the studies due to differences in experimental design and reporting of the data. All data is statistically significant unless otherwise stated.

Dose Concordance

Reference	Experiment description	Result
Wang, 2017	In vivo. Adult male Sprague-Dawley rats were treated with 4 µg/µL of the neurotoxin 6-hydroxydopamine. Oxidative stress was measured by SOD and GSH-Px levels through a bicinchoninic acid protein assay kit. GFAP was used as a marker of astrocytes and was detected using immunohistochemistry.	SOD decreased 0.64-fold and GSH-Px decreased 0.34-fold. GFAP increased 1.7-fold.
Daverey & Agrawal, 2016	In vitro. Human A172 (glioblastoma astrocytes) and HA-sp (spinal cord astrocytes) cell lines were treated with H2O2. GFAP expression was detected through immunofluorescence.	After 50 µM of H2O2, both cell types showed increased GFAP expression about 1.5-fold. GFAP was also increased 1.5- to 2-fold after 100 and 200 µM of H2O2.

Time Concordance

Reference	Experiment description	Result
Schnegg et al., 2012	In vitro. BV-2 immortalized microglia were irradiated with 10 Gy of 137Cs gamma raysat 3.56 Gy/min. Measured 1h after irradiation, intracellular ROS generation was measured by the fluorescent DCFH-DA probe, and activation of NF-κB and AP-1 was determined by immunoblotting as a measure of cell activation.	Both measured 1h after irradiation, ROS increased about 7-fold while NF-κB and AP-1 DNA binding was increased 2.5- and 2-fold, respectively.
Daverey & Agrawal, 2016	In vitro. Human A172 (glioblastoma astrocytes) and HA-sp (spinal cord astrocytes) cell lines were treated with 50 µM of the ROS H2O2. GFAP expression was detected through immunofluorescence after various durations of H2O2 treatment.	Both cell types showed increased GFAP about 1.5-fold, measured after treatment with H2O2. H2O2 administered for 2, 6 and 12h showed slight increases at each timepoint, while after 24h of H2O2 treatment, GFAP was only increased in A172 cells.

Incidence Concordance

Reference	Experimental description	Result
Schnegg et al., 2012	In vitro. BV-2 immortalized microglia were irradiated with 10 Gy of 137Cs gamma rays at 3.56 Gy/min. Intracellular ROS generation was measured by the fluorescent DCFH-DA probe, and activation of NF-κB and AP-1 was determined by immunoblotting as a measure of cell activation.	ROS increased about 7-fold while NF-κB and AP-1 DNA binding was increased 2.5- and 2-fold, respectively.

Response-response Relationship

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

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

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

Since inflammatory signaling and activated immune cells can also increase the production of RONS, positive feedback and feedforward loops can occur (Zhao and Robbins 2009; Ratikan, Micewicz et al. 2015; Blaser, Dostert et al. 2016). Similarly, positive feedforward and feedback loops regarding RONS, cellular activation, and inflammation also occur in the CNS. Both RONS and microglial cell activation can accelerate neuroinflammatory pathways that can ultimately promote further formation of RONS (Lee, Cha & Lee, 2021; Simpson & Oliver, 2020; Zhu et al., 2022).

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

Evidence for this relationship comes from in vitro human- and mouse-derived models, as well as in vivo rat models. Most of the evidence are in male adult and male models, although sex and age are not always specified.

References

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

Ávila‐Escalante, M. L. et al. (2020), "The effect of diet on oxidative stress and metabolic diseases—Clinically controlled trials", Journal of Food Biochemistry, Vol. 44/5, https://doi.org/10.1111/jfbc.13191.

Daverey, A. and S. K. Agrawal. (2016), "Curcumin alleviates oxidative stress and mitochondrial dysfunction in astrocytes", Neuroscience, Vol. 333, https://doi.org/10.1016/j.neuroscience.2016.07.012.

Fishman, K. et al. (2009), "Radiation-induced reductions in neurogenesis are ameliorated in mice deficient in CuZnSOD or MnSOD", Free Radical Biology and Medicine, Vol. 47/10, https://doi.org/10.1016/j.freeradbiomed.2009.08.016.

Gill, R., A. Tsung and T. Billiar. (2010), "Linking oxidative stress to inflammation: Toll-like receptors", Free Radical Biology and Medicine, Vol. 48/9, https://doi.org/10.1016/j.freeradbiomed.2010.01.006.

Hanslik, K. L., K. M. Marino and T. K. Ulland. (2021), "Modulation of Glial Function in Health, Aging, and Neurodegenerative Disease", Frontiers in Cellular Neuroscience, Vol. 15, https://doi.org/10.3389/fncel.2021.718324.

Heidari, A., N. Yazdanpanah and N. Rezaei. (2022), "The role of Toll-like receptors and neuroinflammation in Parkinson’s disease", Journal of Neuroinflammation, Vol. 19/1, https://doi.org/10.1186/s12974-022-02496-w.

Hol, E. M. and M. Pekny. (2015), "Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system", Current Opinion in Cell Biology, Vol. 32, https://doi.org/10.1016/j.ceb.2015.02.004.

Huang, T. T., Y. Zou and R. Corniola. (2012), "Oxidative stress and adult neurogenesis—Effects of radiation and superoxide dismutase deficiency", Seminars in Cell & Developmental Biology, Vol. 23/7, https://doi.org/10.1016/j.semcdb.2012.04.003.

Kamceva, G. et al. (2016), "Cigarette Smoking and Oxidative Stress in Patients with Coronary Artery Disease", Open Access Macedonian Journal of Medical Sciences, Vol. 4/4, https://doi.org/10.3889/oamjms.2016.117.

Lee, K. H., M. Cha and B. H. Lee. (2021), "Crosstalk between Neuron and Glial Cells in Oxidative Injury and Neuroprotection", International Journal of Molecular Sciences, Vol. 22/24, https://doi.org/10.3390/ijms222413315.

Liguori, I. et al. (2018), "Oxidative stress, aging, and diseases", Clinical Interventions in Aging, Vol.13, https://doi.org/10.2147/CIA.S158513.

Mehdipour, A. et al. (2021), "Ionizing radiation and toll like receptors: A systematic review article", Human Immunology, Vol. 82/6, https://doi.org/10.1016/j.humimm.2021.03.008.

Reynolds, A. et al. (2007), "Oxidative Stress and the Pathogenesis of Neurodegenerative Disorders", International Review of Neurobiology, Vol. 82, https://doi.org/10.1016/S0074-7742(07)82016-2.

Rojo, A. I. et al. (2014), "Redox Control of Microglial Function: Molecular Mechanisms and Functional Significance", Antioxidants & Redox Signaling, Vol. 21/12, https://doi.org/10.1089/ars.2013.5745.

Schnegg, C. I. et al. (2012), "PPARδ prevents radiation-induced proinflammatory responses in microglia via transrepression of NF-κB and inhibition of the PKCα/MEK1/2/ERK1/2/AP-1 pathway", Free Radical Biology and Medicine, Vol. 52/9, Pergamon, https://doi.org/10.1016/J.FREERADBIOMED.2012.02.032.

Simpson, D. S. A. and P. L. Oliver. (2020), "ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease", Antioxidants, Vol. 9/8, https://doi.org/10.3390/antiox9080743.

Wang, Y. L. et al. (2017), "Protective Effect of Curcumin Against Oxidative Stress-Induced Injury in Rats with Parkinson’s Disease Through the Wnt/ β-Catenin Signaling Pathway", Cellular Physiology and Biochemistry, Vol. 43/6, https://doi.org/10.1159/000484302.

Zhang, Y. et al. (2017), "Kukoamine A Prevents Radiation-Induced Neuroinflammation and Preserves Hippocampal Neurogenesis in Rats by Inhibiting Activation of NF-κB and AP-1", Neurotoxicity Research, Vol. 31/2, https://doi.org/10.1007/s12640-016-9679-4.

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