D-Limonene Is a Potential Monoterpene to Inhibit PI3K/Akt/IKK-α/NF-κB p65 Signaling Pathway in Coronavirus Disease 2019 Pulmonary Fibrosis

Abstract

At the time of the prevalence of coronavirus disease 2019 (COVID-19), pulmonary fibrosis (PF) related to COVID-19 has become the main sequela. However, the mechanism of PF related to COVID (COVID-PF) is unknown. This study aimed to explore the key targets in the development of COVID-PF and the mechanism of d-limonene in the COVID-PF treatment. The differentially expressed genes of COVID-PF were downloaded from the GeneCards database, and their pathways were analyzed. d-Limonene was molecularly docked with related proteins to screen its pharmacological targets, and a rat lung fibrosis model was established to verify d-limonene's effect on COVID-PF-related targets. The results showed that the imbalance between collagen breakdown and metabolism, inflammatory response, and angiogenesis are the core processes of COVID-PF; and PI3K/AKT signaling pathways are the key targets of the treatment of COVID-PF. The ability of d-limonene to protect against PF induced by bleomycin in rats was reported. The mechanism is related to the binding of PI3K and NF-κB p65, and the inhibition of PI3K/Akt/IKK-α/NF-κB p65 signaling pathway expression and phosphorylation. These results confirmed the relationship between the PI3K–Akt signaling pathway and COVID-PF, showing that d-limonene has a potential therapeutic value for COVID-PF.

PI3K/Akt/mTOR pathway: a potential target for anti-SARS-CoV-2 therapy

“…The inflammation caused by the host immune system during COVID-19 can lead to pathological injuries, including acute respiratory distress syndrome (ARDS) and eventual death. High percentages of Th17 and low percentages of Treg have been reported in COVID-19 patients [ 1 ]. Previous studies have shown that mTORC1 plays a role in inducing Th17 and Th1 differentiation during viral infections, and mTORC2 can enhance Th2 differentiation, while both complexes reduce Treg differentiation [ 11 ].…”

“…Once the virus enters, the activation of eukaryotic translation initiation factor 4E-binding protein1 (4-E-BP1) and ribosomal protein S6 kinase beta 1 (S6K1) (downstream mTOR compounds) leads to increased synthesis of ribosomes and proteins (including viral proteins) [ 9 ]. SARS-CoV-2 infection can lead to hyperactivation of mTOR in vitro, and since the unregulated activation of the mTOR pathway plays a decisive role in COVID-19-induced pathogenesis, inhibiting this pathway can prevent the progression of infection [ 1 ]. Thus, drug inhibitors of the mTOR or microRNAs that interact with 3-UTR of mTOR could be a proper candidate for treating COVID-19 patients [ 9 ].…”

“…SARS-CoV-2 has emerged since December 2019, a single-stranded RNA virus from a β-Coronaviridae family that causes acute clinical manifestations. An extremely contagious viral infection that soon turned into a global nightmare [ 1 ]. COVID-19, with high mortality rates and severe clinical manifestations, has become the world’s greatest challenge since 2019.…”

Targeting the PI3K/Akt/mTOR pathway: A therapeutic strategy in COVID-19 patients

“…In addition to thrombosis, one of the outcomes of COVID-19 is pulmonary fibrosis. Interestingly, the PI3K/Akt pathway was identified as a therapeutic target for COVID-19 associated pulmonary fibrosis and, in a bleomycin-induced lung fibrosis rat model, targeting the pathway using D -Limonene was protective against fibrosis [47] .…”

Characterization, Antioxidant and Anti-Inflammation Capacities of Fermented Flammulina velutipes Polyphenols

“…NF-κB p65 is usually bound to the cytoplasm in an inactive form with the IKB inhibitory factor. When bacteria, viruses, or cytokines stimulate the cells, IKB and NF-κB p65 are degraded by activated IKK; thus, the latter is activated in the nucleus to perform its functions [ 15 ]. One of the most important antioxidant signaling pathways in the body is the NLRP3 signaling pathway [ 16 ].…”