Nrf2 Activator PB125 ® as a Potential Therapeutic Agent Against COVID-19

  1. Joe M. McCord
  2. Brooks M. Hybertson
  3. Adela Cota-Gomez
  4. Bifeng Gao

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Abstract

Nrf2 is a transcription factor that regulates cellular redox balance and the expression of a wide array of genes involved in immunity and inflammation, including antiviral actions. Nrf2 activity declines with age, making the elderly more susceptible to oxidative stress-mediated diseases, which include type 2 diabetes, chronic inflammation, and viral infections. Published evidence suggests that Nrf2 activity may regulate important mechanisms affecting viral susceptibility and replication. We examined gene expression levels by GeneChip microarray and by RNA-seq assays. We found that the potent Nrf2 activating composition PB125® downregulates ACE2 and TMPRSS2 mRNA expression in human liver-derived HepG2 cells. ACE2 is a surface receptor and TMPRSS2 activates the spike protein for SARS-Cov-2 entry into host cells. Furthermore, in endotoxin-stimulated primary human pulmonary artery endothelial cells we report the marked downregulation by PB125 of 36 genes encoding cytokines. These include IL1-beta, IL6, TNF-α, the cell adhesion molecules ICAM1, VCAM1, and E-selectin, and a group of IFN-γ-induced genes. Many of these cytokines have been specifically identified in the “cytokine storm” observed in fatal cases of COVID-19, suggesting that Nrf2 activation may significantly decrease the intensity of the storm.

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  1. Version published to 10.1101/2020.05.16.099788v2 on bioRxiv
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    SciScore for 10.1101/2020.05.16.099788: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    HepG2 and HPAEC cells are suitable models in the present work because they each have a Nrf2 pathway that responds in a normal manner to Nrf2 activators [33,34], and do not have reported mutations in Nrf2/KEAP1.
    HepG2
    suggested: CLS Cat# 300198/p2277_Hep-G2, RRID:CVCL_0027)
    Software and Algorithms
    SentencesResources
    Gene Expression Assays: 2.5.
    Gene Expression Assays
    suggested: None
    One-way ANOVA with Tukey multiple comparisons testing or Student’s t test for unpaired data were performed using Prism software (version 6.0, GraphPad Software, San Diego, CA, USA).
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    A potential limitation of the study is the use of LPS as a surrogate for SARS-CoV-2 to induce the inflammatory response. We propose that one evolutionary driving force for the Nrf2 pathway may have been to provide a failsafe brake for out-of-control inflammatory events. The increase in oxidative stress at the site of an intense inflammatory locus may have been the intended trigger for a system to activate Nrf2, allowing it to end the assault at a point where the invader has likely been vanquished but from which the host may be able to survive. In fact, the cadre of genes induced by Nrf2 have long been referred to as “survival genes” [3].

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  3. Version published to 10.1101/2020.05.16.099788v1 on bioRxiv