Anti-influenza A Virus Effects and Mechanisms of Emodin and Its Analogs via Regulating PPARα/γ-AMPK-SIRT1 Pathway and Fatty Acid Metabolism

Abstract

The peroxisome proliferator-activated receptor (PPAR) α/γ-adenosine 5 ′ -monophosphate- (AMP-) activated protein kinase- (AMPK-) sirtuin-1 (SIRT1) pathway and fatty acid metabolism are reported to be involved in influenza A virus (IAV) replication and IAV-pneumonia. Through a cell-based peroxisome proliferator responsive element- (PPRE-) driven luciferase bioassay, we have investigated 145 examples of traditional Chinese medicines (TCMs). Several TCMs, such as Polygonum cuspidatum, Rheum officinale Baillon, and Aloe vera var. Chinensis (Haw.) Berg., were found to possess high activity. We have further detected the anti-IAV activities of emodin (EMO) and its analogs, a group of common important compounds of these TCMs. The results showed that emodin and its several analogs possess excellent anti-IAV activities. The pharmacological tests showed that emodin significantly activated PPARα/γ and AMPK, decreased fatty acid biosynthesis, and increased intracellular ATP levels. Pharmaceutical inhibitors, siRNAs for PPARα/γ and AMPKα1, and exogenous palmitate impaired the inhibition of emodin. The in vivo test also showed that emodin significantly protected mice from IAV infection and pneumonia. Pharmacological inhibitors for PPARα/γ and AMPK signal and exogenous palmitate could partially counteract the effects of emodin in vivo. In conclusion, emodin and its analogs are a group of promising anti-IAV drug precursors, and the pharmacological mechanism of emodin is linked to its ability to regulate the PPARα/γ-AMPK pathway and fatty acid metabolism.

Network Pharmacology, Molecular Docking and Molecular Dynamics Simulation Studies of the Molecular Targets and Mechanisms of ChuanKeZhi in the Treatment of COVID-19

“…In a study of influenza A virus (IAV) -pneumonia, the activation of AMPK inhibited fatty acid biosynthesis and suppressed inflammatory progression and viral replication. 55 In the progression of SARS-COV-2 infection, phosphorylated and active forms of AMPK, AMPK substrates, and AMPK downregulated targets were suppressed. 56 Our pharmacology network-based study demonstrated a number of potential pharmacological targets, functions, and signalling pathways of CKZI in COVID-19 treatment.…”

Promising Role of Emodin as Therapeutics to Against Viral Infections

“…For IAV (PR8), the mechanism of the anti-viral effect of emodin in A549 cells was to activate PPARα/γ and AMPK, decrease fatty acid biosynthesis, and increase intracellular ATP levels. In order to further prove that PPARα/γ and AMPK are the key proteins that inhibit PR8 replication, inhibitors were used, and it was found that the inhibitors of PPARα/γ and AMPK weakened the antiviral effect of emodin ( Bei et al, 2021 ). For H1N1, inhibiting the expression of hemagglutinin and neuraminidase, increasing the expression of interferon beta (IFN-β) through Toll-like receptor 9 (TLR9) are the key ways to inhibit the replication of it ( Lin CJ et al, 2015 ).…”

“…For H1N1, inhibiting the expression of hemagglutinin and neuraminidase, increasing the expression of interferon beta (IFN-β) through Toll-like receptor 9 (TLR9) are the key ways to inhibit the replication of it ( Lin CJ et al, 2015 ). In vivo studies, emodin also significantly protected mice from IAV infection and pneumonia ( Bei et al, 2021 ). Meanwhile, though experiments on A549 cells and C57BL/6J mice, DAI et al comprehensively explored the mechanism of emodin’s antiviral effect to H1N1.…”

“…Virus-infection diseases pose a significant treatment burden owing to their characteristics of recurrency and resulting complications. For example, seasonal influenza A virus (IAV) infection of patients with metabolic diseases may lead to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) ( Bei et al, 2021 ), and HSV causes lifelong infections by establishing latency in neurons which promote recurrent disease and new infections when the immune system is weak ( Ma et al, 2021 ). All of these features present difficulties for antiviral treatment, and we all know that the development of vaccines against many viruses is still in progress.…”

Antiviral potential of anthraquinones from Polygonaceae, Rubiaceae and Asphodelaceae: Potent candidates in the treatment of SARS-COVID-19, A comprehensive review

“…Rheum officinale Baillon, Aloe vera and Polygonum cuspidatum have been demonstrated to display high inhibitory effects against IAV and their activity has been assigned to their phytoconstituents, including anthraquinones. Naturally occurring anthraquinones like emodin, aloe-emodin-8-O-β-D-glucopyranoside, chrysophanol-8-O-glucoside and emodin-1-O-β-D-glucopyranoside have been shown to significantly suppress IAV replication even at the lowest concentration of 3.125 μg/mL ( Bei et al, 2021 ). Aloe vera extract and its constituents, including aloe-emodin have been also reported to inhibit IAV.…”