The Relationship between Nrf2 and HO-1 with the Severity of COVID-19 Disease

Mihić, Damir; Loinjak, Domagoj; Maričić, Lana; Stoehr, Robert; Šahinović, Ines; Steiner, Kristina L.; Viland, Sven; Šerić, Vatroslav; Duvnjak, Mario

doi:10.3390/medicina58111658

Cited by 6 publications

(7 citation statements)

References 56 publications

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“…The presence of complications such as bacteriemia and sepsis can inhibit Nrf2 activation [47][48][49]. This is in line with research conducted on patients with COVID-19 infection [50][51][52] in which patients with the most severe form of the disease have lower Nrf2 values. When analyzing other exogenous activators of Nrf2, 1,25-dihydroxy vitamin D should be pointed out in COVID-19 infection.…”

Section: Clinical Implications Of Nrf2/ho-1 Pathway In Covid-19 Infec...supporting

confidence: 75%

Anti-Inflammatory and Antioxidant Response in COVID-19 Infection

Maričić

Mihić

Šego

2023

Southeast. Eur. med. j. (Online)

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SARS-CoV-2 virus infection starts with the internalization of the viral particle into the host cells, mainly the upper respiratory system epithelial cells which have the highest expression of the ACE2 receptor which is essential for the internalization process. The pathophysiology of severe forms of COVID-19 disease results not only from direct, cytopathic viral effect but also from immune response dysregulation of the host resulting in hyperinflammatory state and oxidative stress. The nuclear factor erythroid 2-related factor 2 (Nrf2) ability to protect cells and induce a rapid anti-inflammatory and antioxidant response primarily depends on its constitutive cellular expression, which can be affected by numerous endogenous and exogenous factors. The binding of Nrf2 to cellular receptors leads to the transcription of a large number of genes encoding various antioxidant enzymes and other cytoprotective molecules, including heme oxygenase-1(HO-1). Activation of HO-1 results in antioxidant, anti-inflammatory and anti-apoptotic effects. Based on previous studies, the Nrf2/HO-1 pathway provides protection against oxidative stress and inflammatory and immune response which is significant in COVID-19 infection, which is characterized by a strong hyperinflammatory response. This narrative review aims to describe the role of the hyperinflammatory response in the development of COVID-19 infection, with a focus on the NrF2/HO-1 pathway.

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Section: Clinical Implications Of Nrf2/ho-1 Pathway In Covid-19 Infec...supporting

confidence: 75%

Anti-Inflammatory and Antioxidant Response in COVID-19 Infection

Maričić

Mihić

Šego

2023

Southeast. Eur. med. j. (Online)

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“…Nrf2/HO-1 has been reported to play a critical mediator in regulating antioxidative and antiviral immune response ( Loboda et al., 2016 ; Ma et al., 2024 ). Previous studies have shown that Rutin via Nrf2/HO-1signaling pathway relieve oxidative stress ( Mihic et al., 2022 ; Wu et al., 2023 ; Lee et al., 2024 ). In typical physiological conditions, the Nrf2 is primarily located within the cellular cytoplasm and forms a complex with its inhibitory partner, Kelch-like ECH-associated protein 1 (Keap1) ( Bellezza et al., 2018 ; Abdul-Muneer, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Rutin prevents EqHV-8 induced infection and oxidative stress via Nrf2/HO-1 signaling pathway

Chen,

Li,

et al. 2024

Front. Cell. Infect. Microbiol.

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IntroductionThe Nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway has been extensively studied for its role in regulating antioxidant and antiviral responses. The Equid herpesvirus type 8 (EqHV-8) poses a significant threat to the equine industry, primarily manifesting as respiratory disease, abortions, and neurological disorders in horses and donkeys. Oxidative stress is considered a key factor associated with pathogenesis of EqHV-8 infection. Unfortunately, there is currently a dearth of therapeutic interventions available for the effective control of EqHV-8. Rutin has been well documented for its antioxidant and antiviral potential. In current study we focused on the evaluation of Rutin as a potential therapeutic agent against EqHV-8 infection.MethodsFor this purpose, we encompassed both in-vitro and in-vivo investigations to assess the effectiveness of Rutin in combatting EqHV-8 infection.Results and DiscussionThe results obtained from in vitro experiments demonstrated that Rutin exerted a pronounced inhibitory effect on EqHV-8 at multiple stages of the viral life cycle. Through meticulous experimentation, we elucidated that Rutin’s antiviral action against EqHV-8 is intricately linked to the Nrf2/HO-1 signaling pathway-mediated antioxidant response. Activation of this pathway by Rutin was found to significantly impede EqHV-8 replication, thereby diminishing the viral load. This mechanistic insight not only enhances our understanding of the antiviral potential of Rutin but also highlights the significance of antioxidant stress responses in combating EqHV-8 infection. To complement our in vitro findings, we conducted in vivo studies employing a mouse model. These experiments revealed that Rutin administration resulted in a substantial reduction in EqHV-8 infection within the lungs of the mice, underscoring the compound’s therapeutic promise in vivo.ConclusionIn summation, our finding showed that Rutin holds promise as a novel and effective therapeutic agent for the prevention and control of EqHV-8 infections.

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“…In contrast, pharmacologic activation of Nrf2 reduces activation of microglia and neuroinflammation, alleviates neurotoxicity, and improves synaptic and mitochondrial function in animals following lipopolysaccharide challenge [ 32 , 33 ]. Recent studies have shown that levels of Nrf2 and its antioxidant target genes in the plasma and tissues are significantly lower in COVID-19 patients than control subjects and that a lower levels of Nrf2 are negatively correlated with the levels of proinflammatory markers [ 23 , 34 , 35 ]. In the present study, we found that mRNA expression of Nrf2 was decreased in the PVN 1 week after completion of S1 protein injection and remained significantly lower 3 weeks later.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Spike Protein S1 Exposure Increases Susceptibility to Angiotensin II-Induced Hypertension in Rats by Promoting Central Neuroinflammation and Oxidative Stress

Sun,

Li,

Jin

et al. 2023

Neurochem Res

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The SARS-CoV-2 spike S1 subunit (S1) can cross the blood–brain barrier and elicit neuroinflammatory response independent of viral infection. Here we examined whether S1 influences blood pressure (BP) and sensitizes the hypertensive response to angiotensin (ANG) II by enhancing neuroinflammation and oxidative stress in hypothalamic paraventricular nucleus (PVN), a key brain cardiovascular regulatory center. Rats received central S1 or vehicle (VEH) injection for 5 days. One week after injection, ANG II or saline (control) was subcutaneously delivered for 2 weeks. S1 injection induced greater increases in BP, PVN neuronal excitation and sympathetic drive in ANG II rats but had no effects in control rats. One week after S1 injection, mRNA for proinflammatory cytokines and oxidative stress marker were higher but mRNA of Nrf2, the master regulator of inducible antioxidant and anti-inflammatory responses, was lower in the PVN in S1-injected rats than in VEH-injected rats. Three weeks after S1 injection, mRNA for proinflammatory cytokines and oxidative stress marker, microglia activation and reactive oxygen species in the PVN were comparable between S1 and VEH treated control rats but were elevated in two groups of ANG II rats. Notably, ANG II-induced elevations in these parameters were exaggerated by S1. Interestingly, ANG II increased PVN Nrf2 mRNA in VEH-treated rats but not in S1-treated rats. These data suggest that S1 exposure has no effect on BP, but post-S1 exposure increases susceptibility to ANG II-induced hypertension by downregulating PVN Nrf2 to promote neuroinflammation and oxidative stress and augment sympathetic excitation.

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The Relationship between Nrf2 and HO-1 with the Severity of COVID-19 Disease

Cited by 6 publications

References 56 publications

Anti-Inflammatory and Antioxidant Response in COVID-19 Infection

Anti-Inflammatory and Antioxidant Response in COVID-19 Infection

Rutin prevents EqHV-8 induced infection and oxidative stress via Nrf2/HO-1 signaling pathway

SARS-CoV-2 Spike Protein S1 Exposure Increases Susceptibility to Angiotensin II-Induced Hypertension in Rats by Promoting Central Neuroinflammation and Oxidative Stress

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