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PubMed: 24563850

Title
Molecular chaperones and proteostasis regulation during redox imbalance.
Journal
Redox biology
Volume
2
Issue
None
Pages
323-32
Date
2014-01-01
Authors
Cheimonidou C | Niforou K | Trougakos IP

Evidence 008ada1417
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Specifically, ROS have been shown to regulate a wide variety of signalling pathways including anti- inflammatory responses and adaptation to hypoxia [77,78], autop- hagy [79], immune cell function [80], cellular differentiation [81], integrins [82], as well as oncogenes signalling [83].

a(CHEBI:"reactive oxygen species") increases bp(GO:"negative regulation of inflammatory response") View Subject | View Object

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a(CHEBI:"reactive oxygen species") regulates bp(GO:"response to hypoxia") View Subject | View Object

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a(CHEBI:"reactive oxygen species") regulates bp(GO:autophagy) View Subject | View Object

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a(CHEBI:"reactive oxygen species") regulates bp(GO:"leukocyte activation") View Subject | View Object

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a(CHEBI:"reactive oxygen species") regulates bp(GO:"cell differentiation") View Subject | View Object

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a(CHEBI:"reactive oxygen species") regulates bp(GO:"integrin activation") View Subject | View Object

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Evidence f87d6ebf01
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Free radicals were originally believed to be harmful, but it has been realized that in physiological concentrations they serve as redox messengers, which are essential in the regulation of intra- cellular signalling and significant cellular processes including meta- bolism, antioxidant defenses and responses to pathogens [1,4].

a(CHEBI:radical) association bp(GO:"detection of redox state") View Subject | View Object

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a(CHEBI:radical) regulates bp(GO:"intracellular receptor signaling pathway") View Subject | View Object

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a(CHEBI:radical) regulates bp(MESH:Metabolism) View Subject | View Object

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a(CHEBI:radical) decreases a(MESH:Antioxidants) View Subject | View Object

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a(CHEBI:radical) association bp(MESH:"Host-Pathogen Interactions") View Subject | View Object

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bp(GO:"detection of redox state") association a(CHEBI:radical) View Subject | View Object

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bp(MESH:"Host-Pathogen Interactions") association a(CHEBI:radical) View Subject | View Object

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Evidence 8bd49fbe95
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Free radicals-derived protein modification can result in either gain- or loss-of-function due to the protein misfolding or unfolding.

a(CHEBI:radical) increases bp(HBP:misfolding) View Subject | View Object

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a(CHEBI:radical) increases bp(HBP:"non-enzymatic protein modification") View Subject | View Object

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Evidence cdc54d7930
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Proteome oxidation and instability has been associated with ageing and the progression of several age-related diseases, including cardiovascular disorders, neu- rodegeneration, and cancer [7,95,96].

a(CHEBI:radical) increases bp(GO:"protein oxidation") View Subject | View Object

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bp(GO:"protein oxidation") association bp(GO:aging) View Subject | View Object

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bp(GO:"protein oxidation") association path(MESH:"Cardiovascular Diseases") View Subject | View Object

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bp(GO:"protein oxidation") association bp(HP:Neurodegeneration) View Subject | View Object

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bp(GO:"protein oxidation") association path(MESH:Neoplasms) View Subject | View Object

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bp(GO:aging) association bp(GO:"protein oxidation") View Subject | View Object

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bp(HP:Neurodegeneration) association bp(GO:"protein oxidation") View Subject | View Object

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path(MESH:"Cardiovascular Diseases") association bp(GO:"protein oxidation") View Subject | View Object

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path(MESH:Neoplasms) association bp(GO:"protein oxidation") View Subject | View Object

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Evidence f535045431
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A frequent oxidative modification of proteins is irreversible carbonylation which can occur by either direct oxidation where oxidants act and leave a functional carbonyl group on amino acid side chains or in the protein backbone, or, indirectly, by protein conjugation with oxidation pro- ducts of polyunsaturated fatty acids and carbohydrates [98].

a(CHEBI:radical) increases bp(MESH:"Protein Carbonylation") View Subject | View Object

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Evidence 826fd31f84
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Notably, free radicals may also arise from exogenous sources including various types of radiations (e.g. UV light, X-rays or gamma rays), atmospheric pollutants and metal-catalyzed reac- tions [1–3].

a(MESH:"Air Pollution") increases a(CHEBI:radical) View Subject | View Object

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bp(GO:"response to radiation") increases a(CHEBI:radical) View Subject | View Object

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Evidence bf174f3ea2
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HSF1 binds to a consensus heat shock element (HSE) within the promoter regions of HSP genes resulting in the activation of HSPs' gene expression and the control of cellular responses to oxidative and proteotoxic stress [108].

a(MESH:"Heat-Shock Proteins") regulates bp(GO:"response to oxidative stress") View Subject | View Object

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p(HGNC:HSF1) increases a(MESH:"Heat-Shock Proteins") View Subject | View Object

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Evidence 49a7db8a80
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Excessive amounts of free radicals and radical-derived reactive species may also arise from the activity of NAD(P)H oxidases (NOx) and/or xanthine oxidase, as well as from nitric oxide synthase (NOS), P450 metabolism and peroxisomes.

act(a(MESH:Peroxisomes)) increases a(CHEBI:radical) View Subject | View Object

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act(a(MESH:Peroxisomes)) increases a(CHEBI:"reactive oxygen species") View Subject | View Object

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act(a(MESH:Peroxisomes)) increases a(CHEBI:"reactive nitrogen species") View Subject | View Object

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act(p(FPLX:"NADPH_oxidase")) increases a(CHEBI:radical) View Subject | View Object

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act(p(FPLX:"NADPH_oxidase")) increases a(CHEBI:"reactive oxygen species") View Subject | View Object

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act(p(FPLX:"NADPH_oxidase")) increases a(CHEBI:"reactive nitrogen species") View Subject | View Object

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act(p(FPLX:NOS)) increases a(CHEBI:radical) View Subject | View Object

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act(p(FPLX:NOS)) increases a(CHEBI:"reactive oxygen species") View Subject | View Object

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act(p(FPLX:NOS)) increases a(CHEBI:"reactive nitrogen species") View Subject | View Object

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act(p(HGNC:XDH)) increases a(CHEBI:radical) View Subject | View Object

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act(p(HGNC:XDH)) increases a(CHEBI:"reactive oxygen species") View Subject | View Object

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act(p(HGNC:XDH)) increases a(CHEBI:"reactive nitrogen species") View Subject | View Object

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act(p(HGNCGENEFAMILY:"Cytochrome P450 family 1")) increases a(CHEBI:radical) View Subject | View Object

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act(p(HGNCGENEFAMILY:"Cytochrome P450 family 1")) increases a(CHEBI:"reactive oxygen species") View Subject | View Object

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act(p(HGNCGENEFAMILY:"Cytochrome P450 family 1")) increases a(CHEBI:"reactive nitrogen species") View Subject | View Object

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Evidence 6c2a6e47cd
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Moreover, it was shown that the concentration of the extracellular heat shock protein 72 (eHSP72) increases during exercise-heat stress [65].

bp(GO:"cellular response to heat") increases p(HGNC:HSPA1A, loc(MESH:"Extracellular Space")) View Subject | View Object

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Evidence 8aa1e86fb9
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Moreover, HSP22 stimu- lates autophagy-mediated degradation of protein aggregates in an eIF2α-dependent manner [30].

p(HGNC:HSPB8) association p(HGNC:EIF2A) View Subject | View Object

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bp(GO:"chaperone-mediated autophagy") decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

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p(HGNC:EIF2A) association p(HGNC:HSPB8) View Subject | View Object

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p(HGNC:HSPB8) increases bp(GO:"chaperone-mediated autophagy") View Subject | View Object

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Evidence b9624ffa04
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Excessive amounts of ROS may also arise from inflammatory processes [75].

bp(GO:"inflammatory response") increases a(CHEBI:"reactive oxygen species") View Subject | View Object

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Evidence a37ad28518
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sHSPs are tightly regulated by EPMs (e.g. phosphorylation) that enable them to respond upon stress and to perform their chaperone activities [25,26].

bp(GO:"post-translational protein modification") regulates p(HGNCGENEFAMILY:"Small heat shock proteins") View Subject | View Object

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Evidence f8c383a392
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Upon ER proteotoxic stress, GRP78 dissociates from its binding partners, which are then free to trigger the Unfolded Protein Response (UPR) by regulating specific gene responses aiming to restore ER proteome stability.

bp(GO:"response to endoplasmic reticulum stress") increases act(p(HGNC:HSPA5)) View Subject | View Object

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Evidence c0f58f948a
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The three sensors of ER proteotoxic stress facilitate contra- dictory responses since they either promote cell survival by decreasing the misfolded protein and/or oxidative load, or, if UPR fails, they promote the activation of apoptotic pathways that eventually result in cell death [57].

bp(GO:"response to endoplasmic reticulum stress") decreases bp(HBP:misfolding) View Subject | View Object

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bp(GO:"response to endoplasmic reticulum stress") decreases bp(GO:"cell death") View Subject | View Object

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bp(GO:"response to endoplasmic reticulum stress") increases bp(GO:"cell death") View Subject | View Object

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bp(GO:"response to endoplasmic reticulum stress") increases bp(GO:"apoptotic process") View Subject | View Object

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Evidence 6ad0cd6ab2
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Oxidative stress abrogates the Keap1-mediated degradation of Nrf2 which in turn accumulates in the nucleus where it heterodimerizes with a small musculoapo- neurotic fibrosarcoma (Maf) protein on antioxidant response elements (AREs) to stimulate the expression of a wide arrays of phase II and antioxidant enzymes including NAD(P)H quinone oxidoreductase 1 (Nqo1), heme oxygenase 1 (Hmox1), glutamane- cysteine ligase (GCL) and glutathione S transferases (GSTs) [84,85,87,88].

bp(GO:"response to oxidative stress") decreases act(p(HGNC:KEAP1)) View Subject | View Object

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bp(GO:"response to oxidative stress") increases p(HGNC:NFE2L2) View Subject | View Object

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complex(p(HGNC:MAF), p(HGNC:NFE2L2)) increases p(HGNC:NQO1) View Subject | View Object

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complex(p(HGNC:MAF), p(HGNC:NFE2L2)) increases p(HGNC:HMOX1) View Subject | View Object

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complex(p(HGNC:MAF), p(HGNC:NFE2L2)) increases p(HGNC:GCLC) View Subject | View Object

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complex(p(HGNC:MAF), p(HGNC:NFE2L2)) increases p(FPLX:GST) View Subject | View Object

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act(p(HGNC:KEAP1)) increases deg(p(HGNC:NFE2L2)) View Subject | View Object

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Evidence f94104694c
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Additional studies in mammalian peroxiredoxins showed that over-oxidation induces the formation of high molecular weight oligomers which function as potent chaperones and prevent protein aggregation [128,129];

bp(GO:"response to oxidative stress") increases act(p(FPLX:PRDX)) View Subject | View Object

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act(p(FPLX:PRDX)) decreases a(MESH:"Protein Aggregates") View Subject | View Object

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Evidence 97ac348a42
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sHSPs are overexpressed upon many different types of stress as they are key components of the PN and PDR.

bp(GO:"response to stress") increases p(HGNCGENEFAMILY:"Small heat shock proteins") View Subject | View Object

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Evidence faedae9937
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During elevated stress the chaperones within the repressive HSF1-containing multi-chaperone complexes bind the unfolded proteins and thus the liberated monomeric HSF1s undergo phosphorylation, trimerization and nuclear localization with increased transcriptional activity [109].

bp(GO:"response to stress") increases p(HGNC:HSF1, pmod(Ph)) View Subject | View Object

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bp(GO:"response to stress") increases p(HGNC:HSF1, loc(MESH:"Cell Nucleus")) View Subject | View Object

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bp(GO:"response to stress") increases act(p(HGNC:HSF1), ma(tscript)) View Subject | View Object

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Evidence d6af580ffb
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Proteome is modified post-translationally by either numerous highly regulated enzymatic protein modifications (EPMs) (e.g. phosphorylation, acetylation, ubiquitination, methylation, etc.) or by non-enzymatic protein modifications (NEPMs), which are mostly stochastic and increase with ageing or in age-related diseases (Fig. 1).

bp(GO:aging) positiveCorrelation bp(HBP:"non-enzymatic protein modification") View Subject | View Object

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bp(HBP:"non-enzymatic protein modification") positiveCorrelation bp(GO:aging) View Subject | View Object

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Evidence f6e7a277a2
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EPMs alter the targeted proteins, which however remain fully functional, while NEPMs may induce protein unfolding or misfolding resulting in increased proteome instability.

bp(HBP:"non-enzymatic protein modification") increases bp(HBP:misfolding) View Subject | View Object

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Evidence d4215c4d71
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In those organismal states (e.g. ageing or diseases) where the chaperone network becomes deregulated, the accumulating non-native, misfolded or unfolded proteins can form (among others) fibrils, amyloids or large amorphous aggregates [15].

bp(HBP:misfolding) increases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

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Evidence eedb1f423a
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Heavily carbonylated proteins tend to form aggregates that are resistant to degradation and accumulate as unfolded or damaged proteins [101].

bp(MESH:"Protein Carbonylation") increases a(MESH:"Protein Aggregates") View Subject | View Object

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Evidence 8f5232f379
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Moreover, Nrf2 contributes to cellular proteostasis by regulating the expression of molecular chaperones [89], as well as of additional players of proteome stability and maintenance, namely the proteasome subunits [90–92].

p(HGNC:NFE2L2) increases bp(HBP:Proteostasis) View Subject | View Object

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Evidence baa8870624
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n general, HSP90s are more specialized than other chaperones and are essential for survival in eukaryotic cells as they also are capable of binding non-native polypeptides (at the late stages of their folding) and preventing their aggregation [14].

p(FPLX:HSP90) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

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Evidence 5698fd75ca
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HSP70 chaperones have a diverse array of cellular functions but their major role is to ensure correct folding of newly synthesized proteins and to perform the refolding of proteins that are misfolded and/or aggregated.

p(FPLX:HSPA) increases bp(GO:"'de novo' protein folding") View Subject | View Object

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p(FPLX:HSPA) increases bp(GO:"protein folding") View Subject | View Object

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p(FPLX:HSPA) decreases bp(HBP:misfolding) View Subject | View Object

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p(FPLX:HSPA) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

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Evidence c78eab3c07
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Primary cellular defensive mechanisms include enzymes like the superoxide dismutases, SOD1 (Cu–Zn SOD) and SOD2 (MnSOD) that convert superoxide to H 2 O 2 and catalase or glutathione peroxidase that convert H 2 O 2 to H 2 O;

p(HGNC:CAT) increases rxn(reactants(a(CHEBI:"hydrogen peroxide")), products(a(CHEBI:dioxygen), a(CHEBI:water))) View Subject | View Object

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p(HGNC:GPX1) increases rxn(reactants(a(CHEBI:"hydrogen peroxide")), products(a(CHEBI:water))) View Subject | View Object

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p(HGNC:SOD1) increases rxn(reactants(a(CHEBI:superoxide)), products(a(CHEBI:"hydrogen peroxide"), a(CHEBI:dioxygen))) View Subject | View Object

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p(HGNC:SOD2) increases rxn(reactants(a(CHEBI:superoxide)), products(a(CHEBI:"hydrogen peroxide"), a(CHEBI:dioxygen))) View Subject | View Object

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Evidence df83d57569
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PDI is a redox sensitive chaperone that acts not only as a sensor but also as a protein involved in the processing of oxidized proteins and in preventing misfolding and/or aggregation of proteins.

p(HGNCGENEFAMILY:"Protein disulfide isomerases") decreases bp(GO:"protein oxidation") View Subject | View Object

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Annotations
MeSH
Endoplasmic Reticulum

p(HGNCGENEFAMILY:"Protein disulfide isomerases") decreases bp(HBP:misfolding) View Subject | View Object

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Annotations
MeSH
Endoplasmic Reticulum

p(HGNCGENEFAMILY:"Protein disulfide isomerases") decreases a(MESH:"Protein Aggregates") View Subject | View Object

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Annotations
MeSH
Endoplasmic Reticulum

Evidence 44794f16bb
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These chaperones provide high-affinity binding platforms for unfolded proteins and prevent protein aggregation specifically during stress conditions.

p(HGNCGENEFAMILY:"Small heat shock proteins") decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

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Evidence a069273225
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Specifically, they have been found overexpressed in many different diseases including various types of cancer where they contribute in reducing proteotoxic stress [7].

path(MESH:Neoplasms) increases p(HGNCGENEFAMILY:"Small heat shock proteins") View Subject | View Object

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