Cinnamaldehyde inhibits cytokine storms induced by the ORF3a protein of SARS‐CoV‐2 via ROS‐elimination in activated T cells

Abstract

Cytokine storms are the cause of complications in patients with severe COVID‐19, and it becomes the target of therapy. Several natural compounds were selected to screen the inhibitory effect on T‐cell proliferation by Fluorescence‐Activated Cell Sorting (FACS) and cytokine production by enzyme‐linked immunosorbent assay (ELISA). Open reading frame 3a (ORF3a) of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) stimulates the specific T‐cell activation model in vivo and in vitro. The coculture system included the macrophage cell line RAW264.7 and splenocytes. Reactive oxygen species (ROS) levels and glycolysis in T cells were evaluated. Cinnamaldehyde effectively inhibits cytokine storms both in vitro and in vivo. It decreased inflammatory cytokine (such as IFN‐γ, TNF‐α, IL‐6, and IL‐2) production by murine peripheral blood cells upon direct stimulation with ConA, after immunization with the MHV‐A59 virus or ORF3a peptide from SARS‐CoV‐2. Cinnamaldehyde restored the percentage of T cells, which was originally decreased in the peripheral blood and splenocytes of ORF3a‐immunized mice. In a coculture system, cinnamaldehyde reduced the secretion of inflammatory cytokines from macrophages in a T‐cell dependent manner. Furthermore, cinnamaldehyde decreased the ROS level in activated T cells, which in turn reduced glycolysis and the activation of T cells. Cinnamaldehyde can be used as a candidate molecule for COVID‐19.

SARS-CoV-2 ORF3a Protein as a Therapeutic Target against COVID-19 and Long-Term Post-Infection Effects

“…Additionally, FDA-approved drugs like doxycycline, metformin, and ibrutinib also exhibit inhibitory effects on ORF3a-mediated inflammasome activation [51]. Cinnamaldehyde, a natural compound acting as an NLRP3 inflammasome inhibitor, has demonstrated efficacy in vitro and in vivo by reducing inflammatory cytokine and ROS production in activated T-cells [123]. Other drugs targeting the NLRP3 pathway have been investigated in clinical trials or considered for repurposing to manage cytokine storms in COVID-19.…”

“…During acute infection, anti-NLRP3 inflammasome drugs could mitigate cytokine storms, especially important in older individuals [51,123]. A direct ORF3a inhibitor capable of addressing acute and chronic effects would be ideal, although no such inhibitor is known currently.…”

The role and mechanism of cinnamaldehyde in cancer

“…CA scavenges free radicals and enhances the activity of endogenous antioxidant enzymes [ 112 ], for example, Ismail found that CA enhances cardiac antioxidant activity through the reduction of malondialdehyde (MDA) levels and the increase in activities of glutathione S-transferase (GST), superoxide dismutase (SOD), catalase, reduced glutathione (GSH), and glutathione peroxidase (Gpx) [ 113 ], which play crucial roles in cellular defense against oxidative damage [ 114 ]. Recently, Ma et al performed fluorescence-activated cell sorting (FACS) and cytokine production through enzyme-linked immunosorbent assay (ELISA) and found that CA inhibited the cytokine storm induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) open reading frame 3a (ORF3a) protein by eliminating ROS in activated T cells [ 115 ]. The primary antioxidant mechanism of TCA involves the inhibition of ROS production and the activation of crucial oxidative stress defense systems, including Nrf2 and the thioredoxin signaling pathways [ 116 ].…”