Cannabidiol inhibits SARS‐Cov‐2 spike (S) protein‐induced cytotoxicity and inflammation through a PPARγ‐dependent TLR4/NLRP3/Caspase‐1 signaling suppression in Caco‐2 cell line

Abstract

Given the abundancy of angiotensin converting enzyme 2 (ACE-2) receptors density, beyond the lung, the intestine is considered as an alternative site of infection and replication for severe acute respiratory syndrome by coronavirus type 2 (SARS-CoV-2).Cannabidiol (CBD) has recently been proposed in the management of coronavirus disease 2019 (COVID-19) respiratory symptoms because of its anti-inflammatory and immunomodulatory activity exerted in the lung. In this study, we demonstrated the in vitro PPAR-γ-dependent efficacy of CBD (10 À9 -10 À7 M) in preventing epithelial damage and hyperinflammatory response triggered by SARS-CoV-2 spike protein (SP) in a Caco-2 cells. Immunoblot analysis revealed that CBD was able to reduce all the analyzed proinflammatory markers triggered by SP incubation, such as tool-like receptor 4 (TLR-4), ACE-2, family members of Ras homologues A-GTPase (RhoA-GTPase), inflammasome complex (NLRP3), and Caspase-1. CBD caused a parallel inhibition of interleukin 1 beta (IL-1β), IL-6, tumor necrosis factor alpha (TNF-α), and IL-18 by enzyme-linked immunosorbent assay (ELISA) assay. By immunofluorescence analysis, we observed increased expression of tight-junction proteins and restoration of transepithelial electrical resistance (TEER) following CBD treatment, as well as the rescue of fluorescein isothiocyanate (FITC)-dextran permeability induced by SP. Our data indicate, in conclusion, that CBD is a powerful inhibitor of SP protein enterotoxicity in vitro.

Potential benefits of ginseng against COVID-19 by targeting inflammasomes

“…In vitro studies have clearly demonstrated that SARS-CoV-2 infection activates the NLRP3 inflammasome in various cell types. SARS-CoV-2 S protein activates the NLRP3 inflammasome in Cacp-2 cells [ 24 ], and SARS-CoV-2 viroporin encoded by ORF3a triggers the NLRP3 inflammasome pathway in A549 cells [ 25 ]. In vitro studies of SARS-CoV-2-induced NLRP3 inflammasome activation have also been conducted in macrophages, human peripheral blood mononuclear cells (PBMCs), hematopoietic stem/progenitor cells (HSPCs), and endothelial progenitor cells (EPCs).…”

“… Types Roles Activators/inhibitors Models Ref. NLRP3 Activation SARS-CoV-2 spike protein Caco-2 [ 24 ] SARS-CoV-2 viroporin HEK293 & A549 [ 25 ] SARS-CoV-2 single-stranded RNA Macrophages [ 26 ] SARS-CoV-2 envelope protein BMDMs [ 27 ] SARS-CoV-2 nucleocapsid protein BMDMs & THP-1 [ 28 ] SARS-CoV-2 spike protein PBMCs [ 30 ] SARS-CoV-2 spike protein HSPCs & EPCs [ 31 ] SARS-CoV-2 spike protein HSPCs & EPCs [ 34 ] SARS-CoV-2 NSP6 Lung epithelial cells of COVID-19 patients [ 35 ] SARS-CoV-2 Blood cells of COVID-19 patients [ 37 ] SARS-CoV-2 Circulating monocytes of COVID-19 patients [ 38 ] SARS-CoV-2 Circulating monocytes of COVID-19 patients [ 39 ] SARS-CoV-2 spike protein BV-2 [ 42 ] SARS-CoV-2 Cerebral cortical tissues of COVID-19 patients [ 43 ] SARS-CoV-2 Aged COVID-19 patients [ 46 ] Inhibition SARS-CoV-2 NSP1 and NSP13 HEK293 & THP-1 [ 29 ] …”

Cannabidiol and SARS-CoV-2 Infection

“…A recent finding has shown that CBD can reduce both the expression of ACE-2 and RhoA-GTPase/Caspase-1/NLRP3 signaling through its interaction with PPARγ in Caco-2 cells, as intestinal epithelium cells in vitro . This interaction leads to counteract the viral entry and viral replication in SARS-CoV-2 infection ( 33 ). CBD exerts its activity through the interaction with PPARγ in COVID-19 infection ( 4 , 33 ).…”

“…This interaction leads to counteract the viral entry and viral replication in SARS-CoV-2 infection ( 33 ). CBD exerts its activity through the interaction with PPARγ in COVID-19 infection ( 4 , 33 ). PPARγ (peroxisome proliferator-activated receptor gamma) is a ligand-activated transcription factor which binds PPREs (PPAR-response elements).…”

COVID-19-induced immune thrombocytopenic purpura; Immunopathogenesis and clinical implications

“…Recent articles have also highlighted the potential role of NLRP3-inflammasome in COVID-19. For example, studies have investigated the role of non-coding RNAs in the regulation of NLRP3-inflammasome complex in COVID-19, the relationship between NL-RP3-inflammasome and probiotics in COVID-19, the various aspects of inflammasomes as role players in COVID-19, and the potential role of the NLRP3-inflammasomes in COVID-19 [32][33][34][35][36][37][38][39][40][41]. Interestingly, a recent study has shown that specific suppression of the NLRP3-inflammasome represses the immune over-activation and diminishes COVID-19-like pathology in mice [42].…”