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  • In the previous study concerning HO mediated

    2021-09-18

    In the previous study concerning HO-1-mediated inhibtion of HCV replication, the mechanism underlying IFN-α/β indcuction by HO-1 involved in HO-1-catalyzed heme metabolic product, biliverdin (Zhu et al., 2010; Lehmann et al., 2010). However, in the present study SnPP, an inhibitor of HO-1 enzymatic activity, did not reverse antiviral activities of CoPP, and mutant construct GFP-HO-1 (H25A) did not inhibit ISGs production compared to GFP-HO-1 treatment. Hence, HO-1 enzymatic activity and metabolic product might be not necessary for HO-1 anti-influenza viruses. Instead, it might work through direct regulation of HO-1 on the signal pathway involved in the production of IFN-α/β. IRF3 is known to be essential for IFN-α/β production in response to viral infection (Suthar et al., 2013). We therefore speculated that IRF3 was important for HO-1-mediatd WAY-100635 IFN-α/β production. As expected, we observed p-IRF3 was accumulated in the nucleus after 6 h of CoPP treatment. Furthermore, we showed that HO-1 interacted directly with IRF3 through GST pulldown and Co-IP assay. These results were consistent with the previous study showing that HO-1 was essential for IFN-β induction in responses to WAY-100635 infection via interaction with IRF3 (Tzima et al., 2009). Thus, these findings suggest that IFN-α/β generation by HO-1 is associated with interaction between IRF3 and HO-1 which promotes p-IRF3 accumulation in the nucleus.
    Acknowledgments This work was supported by the National Science and Technology Major Project of theMinistry of Science and Technology of China, China [grant number 2018ZX09711003-005-004]; Science Fund for Creative Research Groups of the National Natural Science Foundation of China, China (grant number 81621064); CAMS Initiative for Innovative Medicine, CAMS, China [grant number 2017-I2M-3-010]; Shanghai Municipal Education Commission-Plateau Disciplinary Program for Medical Technology of SUMHS, Shanghai Municipal Education Commission, China, 2018-2020.
    Introduction Preeclampsia (PE) is a pregnancy related syndrome that causes major maternal and fetal morbidity and mortality worldwide [1]. It is estimated that PE causes up to 75,000 maternal and 500,000 fetal deaths worldwide each year, but especially in low and middle income countries [2]. The International Society for the Study of Hypertension in Pregnancy (ISSHP) defines PE by its clinical findings: de novo hypertension and proteinuria [7], [8]. The pathogenesis underlying PE is still not fully understood but the two-stage model is up to date the most accepted way to describe how the syndrome progresses [3], [4]. Early onset PE, defined by onset before 34 gestational weeks, is in general the more severe form of PE characterized by placental involvement and often intra-uterine growth restriction (IUGR). In early onset PE the first stage is initiated by impaired remodeling of the maternal spiral arteries, which induces oxidative stress in the placenta due to uneven blood flow [5]. Several placental factors have been suggested to leak over into the maternal blood circulation where inflammation causes vascular damage and vasoconstriction. The second stage of early onset PE is characterized by the maternal symptoms, hypertension and proteinuria [6]. In late onset PE, maternal constitutional risk factors such as body mass index (BMI) and other diseases, play an important role in the etiology. Also in late onset PE, in the second phase a diseased placenta produces factors into the maternal circulation inducing vascular damage and vasoconstriction. Increased synthesis and accumulation of cell free fetal hemoglobin (HbF) has been demonstrated in PE placentas [9]. The free HbF causes placental tissue damage and oxidative stress, which consequently leads to leakage of free HbF over the blood-placenta barrier into the maternal circulation [10], [11]. In fact, increased concentrations of HbF have been shown in maternal plasma/serum in both early-[12], [13] and late onset PE suggesting it to be an important etiological factor linking stage one and two of the two-stage model [11], [14].