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  • Title: The effect of reactive oxygen species on the synthesis of prostanoids from arachidonic acid.
    Author: Korbecki J, Baranowska-Bosiacka I, Gutowska I, Chlubek D.
    Journal: J Physiol Pharmacol; 2013 Aug; 64(4):409-21. PubMed ID: 24101387.
    Abstract:
    Reactive oxygen species (ROS), such as hydrogen peroxide, superoxide anion radical or hydroxyl radical, play an important role in inflammation processes as well as in transduction of signals from receptors to interleukin -1β (IL-1β), tumor necrosis factor α (TNF-α) or lipopolysaccharides (LPS). NADPH oxidase increases the ROS levels, leading to inactivation of protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A) and protein tyrosine phosphatase (PTP): MAPK phosphatase 1 (MKP-1). Inactivation of phosphatases results in activation of mitogen-activated protein kinase (MAPK) cascades: c-Jun N-terminal kinase (JNK), p38 and extracellular signal-regulated kinase (Erk), which, in turn, activate cytosolic phospholipase A₂ (cPLA₂). ROS cause cytoplasmic calcium influx by activation of phospholipase C (PLC) and phosphorylation of IP₃-sensitive calcium channels. ROS activate nuclear factor κB (NF-κB) via IκB kinase (IKK) through phosphoinositide 3-kinase (PI3K), tumor suppressor phosphatase and tensin homolog (PTEN) and protein kinase B (Akt/PKB) or NF-κB-inducing kinase (NIK). IKK phosphorylates NF-κB α subunit (IκBα) at Ser³². Oxidative stress inactivates NIK and IκB kinase γ subunit/NF-κB essential modulator (IKKγ/NEMO), which might cause activation of NF-κB that is independent on IKK and inhibitor of IκBα degradation, including phosphorylation of Tyr⁴² at IκBα by c-Src and spleen tyrosine kinase (Syk), phosphorylation of the domain rich in proline, glutamic acid, serine and threonine (PEST) sequence by casein kinase II and inactivation of protein tyrosine phosphatase 1B (PTP1B). NF-κB and MAPK cascades-activated transcription factor activator protein 1 (AP-1) and CREB-binding protein (CBP/p300) lead to expression of cytosolic phospholipase A₂ (cPLA₂), cyclooxygenase-2 (COX-2) and membrane-bound prostaglandin E synthase 1 (mPGES-1), and thus to increased release of arachidonic acid and production of prostaglandins, particularly prostaglandin E₂ (PGE₂). ROS increase the activity of hematopoietic-type PGD synthase (H-PGDS), and, as a result, the production of prostaglandin D₂ (PGD₂). However, the superoxide radical reacts with nitric oxide forming peroxynitrite that inactivates prostaglandin I synthase (PGIS), suppressing the production of prostaglandin I₂ (PGI₂). ROS do not affect thromboxane synthesis in a direct manner; this is achieved by an increase in cPLA₂ activity and COX-2 expression. The aim of this review was to summarize knowledge of influence of ROS on the synthesis of prostanoids from arachidonic acid.
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