Abstract
COVID-19 is caused by the SARS-CoV-2 virus, which enters target cells via interactions with ACE2 and TMPRSS2. Here, we show AKT serine/threonine kinase-dependent epigenetic control of ACE2 and TMPRSS2 expression by high-cannabidiol (CBD) cannabis extracts and their individual components. CBD alone and extracts #1, #5, #7, and #129 downregulated ACE2 and TMPRSS2 in lung fibroblast WI-38 cells through AKT-mediated inhibition. miR-200c-3p and let-7a-5p were two contributing miRNAs in CBD-mediated suppression of ACE2 and TMPRSS2. CBD and terpene PTWT2.2 profoundly inhibited ACE2 and TMPRSS2 expression, both individually and in combination. Extracts #1, #5, #7, and #169 suppressed COX2 expression and remarkably attenuated TNFα/IFNγ-triggered induction of proinflammatory factors IL-6 and IL-8 by AKT pathway. The most abundant molecules present in extracts #1 and #7 modulated the expression of COX2, IL-6, and IL-8 both individually and in combination. These results reveal that high-CBD cannabis extracts attenuated ACE2 and TMPRSS2 expression and the induction of inflammatory mediators COX2, IL-6, and IL-8 via the AKT pathway, highlighting their potential anti-COVID-19 features.
Highlights
As of this writing SARS-CoV-2-induced coronavirus disease (COVID-19) [1, 2] affected over 295 million people, and caused over 5.4 million deaths.Patients with severe COVID-19, who account for 20% of all cases, develop serious complications, including acute respiratory distress symptoms (ARDS), as well as acute cardiac, liver, kidney, and nervous system injuries [1, 3–6]
CBD and cannabis extracts inhibit angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 expression both transcriptionally and/or posttranscriptionally Our previous studies indicated that high-CBD cannabis extracts may inhibit SARS-CoV-2 infection of host cells by downregulating ACE2 and TMPRSS2 [19]
Since the extract-caused suppression of interleukin 6 (IL-6) and interleukin 8 (IL-8) induction triggered by TNFα/IFNγ was found to be negatively correlated with the phosphorylation of AKT1/2/3 (Fig. 5B, D), we looked at the role of the extract-activated AKT pathway in IL-6 and IL-8 transcription
Summary
As of this writing SARS-CoV-2-induced coronavirus disease (COVID-19) [1, 2] affected over 295 million people, and caused over 5.4 million deaths. Accumulating evidence indicates that cannabinoids may have anti-inflammatory and anti-cancer properties mediated by reducing the production of proinflammatory cytokines and attenuating tumor growth [17, 18]. Our previous studies in 3D tissue models have shown that cannabis extracts downregulate the expression of ACE2, IL-6, and TNF-α, the key factors in COVID-19 progression [19, 20]. Using human normal cell lines as a model system, we found that cannabis extracts #1, #5, #98, and #129 inhibit ACE2 and TMPRSS2 expression, and extracts #1, #5, #7, and #169 attenuate the expression of inflammatory mediators cyclooxygenase-2 (COX2), IL-6, and interleukin 8 (IL-8), transcriptionally and/or posttranscriptionally. Our findings highlight the anti-SARS-CoV-2 host entry and anti-cytokine release syndrome properties of selected cannabis extracts, supporting the urgent need for clinical trials
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