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Oxidative stress and pre-eclampsia
Published in Pankaj Desai, Pre-eclampsia, 2020
Proteins thiol-disulphide oxidoreductases such as thioredoxin, glutaredoxin and protein disulphide isomerase have been found to eliminate ROS. Protein thiol-disulphide oxidoreductases, therefore, have an important role in pre-eclampsia.33 Results from this and similar studies indicate that pre-eclamptic pregnancies were exposed to oxidative stress and the protein thiol-disulphide oxidoreductases were adaptively induced for protection in pre-eclamptic placentae.4
Intracellular Maturation of Acute Phase Proteins
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Erik Fries, E. Mathilda Sjöberg
Nascent polypeptides appear to cross the ER membrane in an essentially unfolded state.39 In most cases, the subsequent folding is completed as soon as the polypeptide has emerged in the lumen of the ER.40 In the simplest situation, the different domains fold as the corresponding sequences appear and the cysteine residues rapidly form disulfide bonds.41,42 In their mature, stable conformation, however, many proteins contain disulfide bonds that are not sequential. Their formation is catalyzed by the enzyme protein disulfide isomerase (PDI), which resides in the lumen of the ER.43 This is, in fact, one of the most abundant proteins in the ER.44
Chemistry and Biochemistry of Vitamin C in Mammalian Systems
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Margreet C.M. Vissers, Juliet M. Pullar, Nicholas Smirnoff
In the previous section, we discussed the regeneration of ascorbate from the ascorbyl radical. Similarly, a number of cellular mechanisms are able to reduce DHA, and this occurs by two-electron reduction [10], with GSH, NADH, and NADPH serving as electron donors (Figure 2.1) [10,19,127]. GSH can react directly with DHA, but this reaction may not be highly favorable at physiologic GSH concentrations [128]. Rather, enzyme-dependent reduction of DHA mediated by glutaredoxin [129], protein disulfide isomerase [130,131], and thioredoxin reductase [33,132–134] is considered to be responsible for most of this activity in vivo. The dependency of the body on GSH to support this activity has been well demonstrated in studies with GSH-deficient animals in which tissue ascorbate levels were lowered, together with an increased DHA:AscH− ratio [135,136]. In addition, GSH was shown to be required for ascorbate recycling in cultured endothelial cells [133], and a NADPH-dependent thioredoxin reductase activity was identified in rat liver cells [132]. These enzymatic systems are considered to be the major pathways for ascorbate regeneration from DHA, but other options may also be available. For example, 3α-hydroxysteroid dehydrogenase, an NADPH-dependent oxidoreductase, could reduce DHA under pathologic conditions when its concentrations are high [137]. Therefore, there are numerous possibilities for the recycling of ascorbate that together will allow for many cycles of ascorbate oxidation and will minimize loss from the body pool.
Orally delivered rutin in lipid-based nano-formulation exerts strong antithrombotic effects by protein disulfide isomerase inhibition
Published in Drug Delivery, 2022
Dan Chen, Yurong Liu, Peiwen Liu, Yang Zhou, Longguang Jiang, Cai Yuan, Mingdong Huang
A flavonoid, quercetin-3-O-rutinoside or rutin, was identified to block thrombus formation in the mouse model and reduce thrombin generation in humans through targeting the extracellular protein disulfide isomerase (PDI) (Jasuja et al., 2012; Stopa et al., 2017; Zwicker et al., 2019). PDI is a thiol isomerase that catalyzes disulfide formation, reduction, and isomerization. The extracellular PDI plays an important role in the initiation of clot formation by regulating the oxidation states of labile disulfide bonds in critical hemostatic proteins, including platelet surface receptors αIIbβ3 and GPIbα, adhesive proteins TSP-1 and vitronectin, and coagulation factors (Versteeg & Ruf, 2007; Cho et al., 2008; Reinhardt et al., 2008; Furie & Flaumenhaft, 2014; Liang et al., 2021). The inhibitory potency of rutin on PDI was shown to be at the micromolar range (Jasuja et al., 2012; Lin et al., 2015a). We have recently identified the molecule binding site of rutin on PDI using combined structural biology and mutagenesis techniques, and demonstrated that residue H256 in PDI is the key mediating the rutin inhibition on PDI (Liao et al., 2022). However, rutin has a low water solubility and limited membrane permeability, leading to incomplete absorption and poor oral bioavailability. Therefore, rutin is often administered in high doses to achieve antithrombotic effects, reducing patient compliance and restricting its clinical translation (Mauludin et al., 2009; Gullon et al., 2017; Pan et al., 2019).
Maternal serum thiol/disulfide homeostasis in pregnancies complicated by fetal hypoxia
Published in Journal of Obstetrics and Gynaecology, 2021
Serhat Ege, Hasan Akduman, Muhammet Hanifi Bademkıran, Nurullah Peker, Selami Erdem, İhsan Bağlı, Erdal Özmen, Ruşen Köçeroğlu, Recep Yıldızhan
Thioredoxin eliminates reactive oxygen radicals of protein thiol/disulphide oxidoreductases, such as glutaredoxin and protein disulphide isomerase, and has regenerated oxidative protein damage. It is also thought that protein thiol/disulphide oxidoreductases could play a protective role against preeclampsia; these proteins were found at rates 2–3 times greater in the placenta of preeclamptic women, to adapt to the oxidative stress caused by the preeclampsia, compared to normal placenta, in an immunohistochemical study (Shibata et al. 2001). In contrast, Sahlin et al. (2000) found that m-RNA level of thioredoxin and glutaredoxin was decreased in preeclamptic placenta, and Llurba et al. (2004) emphasised that the plasma protein thiol levels in preeclamptic women were significantly low.
Untargeted proteomics reveals upregulation of stress response pathways during CHO-based monoclonal antibody manufacturing process leading to disulfide bond reduction
Published in mAbs, 2021
Seo-Young Park, Susan Egan, Anthony J. Cura, Kathryn L. Aron, Xuankuo Xu, Mengyuan Zheng, Michael Borys, Sanchayita Ghose, Zhengjian Li, Kyongbum Lee
Protein folding activity in the ER can itself be a source of ROS generation. Folding and re-folding of unfolded or misfolded proteins within the ER is facilitated by protein disulfide isomerase (PDI), which catalyzes disulfide bond formation and isomerization.55 Oxidative folding by PDI results in the reduction of the isomerase, which needs to be regenerated to its oxidized form by oxidizing enzymes such as ERO1. This, in turn, generates H2O2 as a byproduct (Figure 5, #4). We also found increased abundance of several antioxidant enzymes in the rolled condition, including TRXR1, GSR, and glutathione-S-transferase (Figure 1e, f). In concert with the glutathione (GSH) reductase system, the TRXR system protects against oxidative damage to macromolecules56 by reducing oxidized cysteine and methionine residues (Figure 5, #5).