Page last updated: 2024-10-24

cellular response to nitrosative stress

Definition

Target type: biologicalprocess

Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a nitrosative stress stimulus. Nitrosative stress is a state often resulting from exposure to high levels of nitric oxide (NO) or the highly reactive oxidant peroxynitrite, which is produced following interaction of NO with superoxide anions. [GOC:mah]

Nitrosative stress is a cellular condition characterized by an imbalance in the production and detoxification of reactive nitrogen species (RNS), primarily nitric oxide (NO) and its derivatives. RNS can cause a range of damaging effects, including protein modification, DNA damage, and lipid peroxidation. Cells have evolved complex mechanisms to respond to nitrosative stress, aiming to mitigate these harmful effects and maintain cellular homeostasis.

The cellular response to nitrosative stress involves a multi-layered network of signaling pathways and enzymatic activities.

1. **Detection and Signaling:** The initial step involves the sensing of RNS by specific cellular sensors. These sensors include redox-sensitive proteins like thioredoxins, peroxiredoxins, and glutathione S-transferases, which undergo conformational changes upon encountering RNS. This triggers downstream signaling cascades, often involving the activation of transcription factors like Nrf2 and NF-κB.

2. **Antioxidant Defense:** Cells deploy a battery of antioxidant enzymes to neutralize RNS. Superoxide dismutase (SOD) converts superoxide radicals (O2-) into hydrogen peroxide (H2O2), which is further reduced to water by catalase or glutathione peroxidases. Glutathione reductase, in conjunction with NADPH, keeps glutathione in its reduced state, enhancing its antioxidant capacity.

3. **Repair Mechanisms:** Nitrosative stress can induce DNA damage, protein misfolding, and lipid peroxidation. Cells have repair mechanisms in place to deal with these damages. DNA repair pathways, such as base excision repair (BER) and nucleotide excision repair (NER), remove damaged bases and repair DNA breaks. Molecular chaperones like Hsp70 assist in protein refolding, while enzymes like glutathione S-transferases detoxify lipid peroxidation products.

4. **Regulation of Gene Expression:** Transcription factors like Nrf2 and NF-κB play crucial roles in regulating gene expression in response to nitrosative stress. Upon activation, Nrf2 promotes the expression of genes involved in antioxidant defense, detoxification, and cellular repair. NF-κB, on the other hand, regulates genes involved in inflammation, apoptosis, and immune responses.

5. **Apoptosis and Autophagy:** In cases of severe or prolonged nitrosative stress, cells may initiate apoptosis (programmed cell death) to eliminate damaged cells and prevent further damage to the organism. Autophagy, a process of cellular self-eating, can also be triggered to remove damaged organelles and proteins, thereby promoting cellular survival.

The cellular response to nitrosative stress is a complex and dynamic process that involves intricate interplay between signaling pathways, enzymatic activities, and gene expression. The balance between RNS production and detoxification is crucial for maintaining cellular homeostasis. Dysregulation of these processes can contribute to the pathogenesis of various diseases, including cancer, neurodegenerative diseases, and cardiovascular diseases.'
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Proteins (1)

ProteinDefinitionTaxonomy
Serine-protein kinase ATMA serine-protein kinase ATM that is encoded in the genome of human. [PRO:CNA]Homo sapiens (human)

Compounds (20)

CompoundDefinitionClassesRoles
pd 173074aromatic amine;
biaryl;
dimethoxybenzene;
pyridopyrimidine;
tertiary amino compound;
ureas
antineoplastic agent;
EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor;
fibroblast growth factor receptor antagonist
caffeinepurine alkaloid;
trimethylxanthine
adenosine A2A receptor antagonist;
adenosine receptor antagonist;
adjuvant;
central nervous system stimulant;
diuretic;
EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor;
EC 3.1.4.* (phosphoric diester hydrolase) inhibitor;
environmental contaminant;
food additive;
fungal metabolite;
geroprotector;
human blood serum metabolite;
mouse metabolite;
mutagen;
plant metabolite;
psychotropic drug;
ryanodine receptor agonist;
xenobiotic
2-(4-morpholinyl)-8-phenyl-4h-1-benzopyran-4-one2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one: specific inhibitor of phosphatidylinositol 3-kinase; structure in first sourcechromones;
morpholines;
organochlorine compound
autophagy inhibitor;
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor;
geroprotector
schizandrin bschizandrin B: a phytogenic antineoplastic agent with anti-inflammatory activity; isolated from Schisandra plant
thioureathiourea : The simplest member of the thiourea class, consisting of urea with the oxygen atom substituted by sulfur.

Thiourea: A photographic fixative used also in the manufacture of resins. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), this substance may reasonably be anticipated to be a carcinogen (Merck Index, 9th ed). Many of its derivatives are ANTITHYROID AGENTS and/or FREE RADICAL SCAVENGERS.
one-carbon compound;
thioureas;
ureas
antioxidant;
chromophore
ku 559332-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one: specific inhibitor of the ataxia-telangiectasia mutated kinase ATM; structure in first source
cgk 733diarylmethane
nu 70262-(morpholin-4-yl)benzo(h)chromen-4-one: a radiosensitizing agent that inhibits DNA-dependent protein kinase; structure in first sourceorganic heterotricyclic compound;
organooxygen compound
nu 74418-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one: structure in first sourcedibenzothiophenes
ku-0060648dibenzothiophenes
dactolisibdactolisib : An imidazoquinoline that is 3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinoline substituted at position 1 by a 4-(1-cyanoisopropyl)phenyl group and at position 8 by a quinolin-3-yl group. A dual PI3K/mTOR inhibitor used in cancer treatment.

dactolisib: antineoplastic agent that inhibits both phosphatidylinositol 3-kinase and mTOR
imidazoquinoline;
nitrile;
quinolines;
ring assembly;
ureas
antineoplastic agent;
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor;
mTOR inhibitor
ku 60019
cp 466722quinazolines
(3R)-4-[2-(1H-indol-4-yl)-6-(1-methylsulfonylcyclopropyl)-4-pyrimidinyl]-3-methylmorpholineindoles
ve 8213-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide: an antineoplastic agent; structure in first sourcearomatic amide
torin 2torin 2 : A member of the class of pyridoquinolines that is benzo[h][1,6]naphthyridin-2-one carrying additional 3-(trifluoromethyl)phenyl and 6-aminopyridin-3-yl substituents at positions 1 and 9 respectively. It is a potent inhibitor of mTOR and exhibits anti-cancer properties.aminopyridine;
organofluorine compound;
primary amino compound;
pyridoquinoline
antineoplastic agent;
mTOR inhibitor
byl719proline derivative
cc-1151-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino(2,3-b)pyrazin-2(1H)-one: an mTOR kinase inhibitor; structure in first source
vx-970berzosertib: an ATR kinase inhibitorsulfonamide
etp-46464ETP-46464: inhibits ATM and Rad3-related kinase; structure in first source