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Exercise Redox Signalling
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Ruy A. Louzada, Jessica Bouviere, Rodrigo S. Fortunato, Denise P. Carvalho
The NADPH oxidase enzymes (NOXs) are unique proteins specialized in ROS production and are composed of seven members: NOX1 to NOX5 and DUOX1 and 2. Most of the NOXs have been reported to be present in skeletal muscle in vivo (Hori et al., 2011; Loureiro et al., 2016) (Figure 3.1). NOX2 is constitutively associated with the protein p22phox in the biological membrane. Activation of the NOX2-p22phox complex requires the translocation of cytosolic factors such as p47phox, p67phox, and p40phox to the membrane (Figure 3.1) (Henriquez-Olguin et al., 2020; Henríquez-Olguín et al., 2019a). NOX4 activity seems to be mainly dependent on its expression level, as well as the partial oxygen pressure (Ambasta et al., 2004; Ameziane-El-Hassani et al., 2016; Sun et al., 2011). Moreover, ATP can directly bind and negatively regulate NOX4 activity in the inner mitochondrial membrane, suggesting that subcellular redistribution of ATP levels from the mitochondria might act as an allosteric switch to activate NOX4 (Shanmugasundaram et al., 2017). While NOX2 and 4 produce , DUOX1/2 require maturation factors (DUOXA1/A2) to be targeted at the plasma membrane and generate H2O2 (Ameziane-El-Hassani et al., 2016; Carré et al., 2015; Louzada et al., 2018).
Microglial Voltage-Gated Proton Channel Hv1 in Neurological Disorders
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Madhuvika Murugan, Long-Jun Wu
Proton currents were proposed to function cooperatively with NOX activities during respiratory burst, which is associated with both intracellular acidosis and membrane depolarization (DeCoursey 2003): (1) NOX activation induces electron transfer across the membrane, which depolarizes the membrane, with an estimated membrane potential of +58 mV during the respiratory burst. The depolarization could reach up to +190 mV within 20 ms in the absence of a charge compensatory mechanism (DeCoursey, Morgan, and Cherny 2003); (2) during NOX activation, protons are accumulated when electrons are transported across the cell membrane. Consistently, NOX activation induces a dramatic decrease in cytoplasmic pH in human neutrophils during phagocytosis (Morgan et al. 2009). Hence, the combined effect of membrane depolarization and intracellular acidosis during NOX activation is sufficient to open Hv1. On the other hand, NOX activity is inhibited by membrane depolarization or intracellular acidosis (DeCoursey 2003). Therefore, under constant NOX activation such as respiratory oxidation, there must be mechanisms to compensate for the charge transfer and to relieve intracellular acidosis. Hv1 is ideally suited for the dual functions in cooperation with NOX. Consistent with this idea, studies have shown that Hv1 is coupled to NOX-dependent pH regulation, membrane depolarization, and ROS production in neutrophils (El Chemaly et al. 2010), B cells (Capasso et al. 2010), and eosinophils (Zhu, Mose, and Zimmermann 2013).
Regulation of Skeletal Muscle Reactive Oxygen Species During Exercise
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Catherine A. Bellissimo, Christopher G.R. Perry
NOX-derived superoxide is elevated following contraction and exercise: NOXs are highly abundant, exist in multiple isoforms, and are tightly coupled to specific cell functions regulated by redox signalling. For example, sarcolemmal-bound NOXs are thought to be activated by extracellular hormonal ligands (33, 40, 41, 89, 114, 121). NOX bound to the sarcoplasmic reticulum and t-tubules are also thought to contribute to exercise-induced ROS, given they are activated in response to muscle fibre stretch or contraction (74, 119). Intriguingly, microtubule-bound NOX are activated under mechanical stretch, suggesting that contraction may increase NOX activity through mechanotransduction (74, 119). NOX are also expressed in other cellular compartments, including mitochondria and nuclei (45, 47, 130, 136, 142), but their potential responses to exercise are unknown.
PRDX6 alleviates lipopolysaccharide-induced inflammation and ferroptosis in periodontitis
Published in Acta Odontologica Scandinavica, 2022
Wen-Ying Yang, Xiang Meng, Yue-Rong Wang, Qing-Qing Wang, Xin He, Xiao-Yu Sun, Nan Cheng, Lei Zhang
PRDX6 is unique because it has peroxidase in antioxidant functions and aiPLA2 activity in oxidant generation. It has been reported that blocking the aiPLA2 activity of PRDX6 by MJ33 enhanced ferroptosis in cancer cell lines [34]. While in a mouse model of ALI, blocking PRDX6-aiPLA2 activity could attenuate lungs damage, presumably by inhibiting oxidative stress and preventing the amplification of lungs inflammation [42]. Inhibiting PRDX6-aiPLA2 activity downregulated the production of LPS-induced LOOH and inflammatory cytokines. The potential mechanism for MJ33 to alleviate the inflammation and ferroptosis state could be through the inhibition of the aiPLA2 activity to block NOX2 activation. NOX2 is the enzyme responsible for ROS generation associated with inflammation [42]. It has been reported that enhanced NOX2 activity is most likely one of the ROS sources in periodontal tissues [43]. Although the aiPLA2 also has enzyme activity in reducing phospholipid hydroperoxides and repairing peroxidized cell membranes, its protective role is less than that of PL hydroperoxide GPx (PHGPx) activity and LPCAT activity in PRDX6. Therefore, inhibition of aiPLA2 activity could alleviate the LPS-induced inflammation and ferroptotic injury in HGFs.
Neutrophil extracellular trap-associated molecules: a review on their immunophysiological and inflammatory roles
Published in International Reviews of Immunology, 2022
Abraham U. Morales-Primo, Ingeborg Becker, Jaime Zamora-Chimal
On the other hand, NOX independent-NETosis is instigated by stimuli such as the ionophores A23187 and nigericin, or physiological agents like the granulocyte-macrophage colony-stimulating factor (GM-CSF).21,22 Besides the absence of NOX activity, this process also lacks both NE and MPO proteins for chromatin loosing.21 Instead, this task is performed by PAD4, a peptidyl-arginine deaminase that is activated by binding with calcium ions due to the stimuli-induced calcium influx.23 Once PAD4 gets activated, it translocates inside the nucleus. It will interact with the arginine residues of H3 and H4 histones, converting them into citrulline, neutralizing positive charges in a process called citrullination, consequently decondensing the chromatin.24 Along with this process, kinases such as JNK, PYK2, AKT, p38, and SRC, will trigger their cascades by activating transcription factors, initiating transcription at specific promoters, aiding for chromatin relaxing.25 Interestingly, promoter sites are found citrullinated, showing the synergistic labor of PAD4 and kinases in the formation of NETs.25 Another important step for NOX independent-NETosis exerted by the stimuli-induced calcium influx is the activation of the small-conductance calcium-activated potassium channel 3 (SK3).26 SK3 channels bind Ca+2 to its calmodulin subunit, causing conformational changes and opening the channel.27 Finally, mitochondrial ROS is also necessary for the NET formation and is linked to SK3 activation.26
Thrombosis in Covid-19 and non-Covid-19 pneumonia: role of platelets
Published in Platelets, 2021
Francesco Violi, Vittoria Cammisotto, Pasquale Pignatelli
Recent studies provided further support to this report as Zhao et al. and Choudhury et al. [46,47] showed that Covid-19 uses TLR4 to activate cells implicated in the thrombotic process such as monocytes and leucocytes. Covid-19 binding to TLRs may have deleterious effect for its implication in thrombotic process via up-regulation of Nox2, the most important cellular producer of reactive oxidant species (ROS), resulting in endosomal hydrogen peroxide generation [26,48]. Nox2 is a key enzyme of the innate immune system, which, intriguingly, is also localized in endothelial cells and platelets [49,50]. Investigation of patients with chronic granulomatous disease, a rare disease characterized by hereditary deficiency of Nox2, demonstrated that Nox2 is a powerful vasoconstrictive molecule likely via inactivation of nitric oxide(NO) [51] and favors platelet activation via production of F2-isoprostanes and inactivating NO [50]; recent studies confirmed a role for Nox2-mediated platelet activation in an experimental model of thrombosis [52]. Analysis of circulating levels of soluble Nox2, which is a marker of Nox2 activation by blood cells including platelet and leucocytes [50], revealed that Nox2 activation occurs not only in CAP but also in Covid-19 [53,54].