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高CBD含量大麻提取物抗COVID-19作用的新的依赖AKT的机制

New AKT-dependent mechanisms of anti-COVID-19 action of high-CBD Cannabis sativa extracts.

作者信息

Wang Bo, Li Dongping, Fiselier Anna, Kovalchuk Igor, Kovalchuk Olga

机构信息

Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, T1K 3M4, Canada.

Pathway Rx Inc., Lethbridge, AB, T1K 3M4, Canada.

出版信息

Cell Death Discov. 2022 Mar 11;8(1):110. doi: 10.1038/s41420-022-00876-y.

DOI:10.1038/s41420-022-00876-y
PMID:35277472
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8913855/
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.

摘要

新型冠状病毒肺炎（COVID-19）由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起，该病毒通过与血管紧张素转换酶2（ACE2）和跨膜丝氨酸蛋白酶2（TMPRSS2）相互作用进入靶细胞。在此，我们展示了高含量大麻二酚（CBD）的大麻提取物及其单一成分对ACE2和TMPRSS2表达的AKT丝氨酸/苏氨酸激酶依赖性表观遗传控制。单独的CBD以及提取物#1、#5、#7和#129通过AKT介导的抑制作用下调了肺成纤维细胞WI-38中的ACE2和TMPRSS2。miR-200c-3p和let-7a-5p是CBD介导的ACE2和TMPRSS2抑制作用中的两种起作用的微小RNA（miRNA）。CBD和萜类化合物PTWT2.2单独或联合使用时均能显著抑制ACE2和TMPRSS2的表达。提取物#1、#5、#7和#169通过AKT途径抑制环氧化酶2（COX2）的表达，并显著减弱肿瘤坏死因子α/干扰素γ触发的促炎因子白细胞介素6（IL-6）和白细胞介素8（IL-8）的诱导。提取物#1和#7中含量最丰富的分子单独或联合使用时均能调节COX2、IL-6和IL-8的表达。这些结果表明，高含量CBD的大麻提取物通过AKT途径减弱了ACE2和TMPRSS2的表达以及炎症介质COX2、IL-6和IL-8的诱导，突出了它们潜在的抗新型冠状病毒肺炎的特性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e96/8917229/1ed1b2506ced/41420_2022_876_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e96/8917229/548c8a693701/41420_2022_876_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e96/8917229/89d1297f284b/41420_2022_876_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e96/8917229/0afcdbfba0d5/41420_2022_876_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e96/8917229/1ed1b2506ced/41420_2022_876_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e96/8917229/548c8a693701/41420_2022_876_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e96/8917229/4f4363a5a205/41420_2022_876_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e96/8917229/e5b6da778a7a/41420_2022_876_Fig3_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e96/8917229/89d1297f284b/41420_2022_876_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e96/8917229/0afcdbfba0d5/41420_2022_876_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e96/8917229/1ed1b2506ced/41420_2022_876_Fig7_HTML.jpg

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