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.
Highlights
Pathogenic influenza A virus (IAV) infection or seasonal IAV infection of patients with basal metabolic diseases usually leads to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)
Transfection of siRNAs for PPARα, PPARγ, and AMPKα1 significantly counteracted the inhibition of emodin on IAV replication (Figure 3(c)) and on IAV-induced injury of cell viability (Figure 3(d)). These results indicated that the PPARα/γAMPK pathway was involved in the inhibition of emodin on IAV replication and IAV-induced cell injury
In the past more than ten years, we have always engaged in the screening and classification of traditional Chinese medicines (TCMs) and their active compounds by different cell-based luciferase bioassays according to different pathogenic mechanisms of IAV
Summary
Pathogenic influenza A virus (IAV) infection or seasonal IAV infection of patients with basal metabolic diseases usually leads to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). There is no specific medicine available for the treatment of ALI/ARDS. Classical anti-IAV drugs, such as M2 channel and neuraminidase inhibitors, are limited in use by their side effects or the resistant viral strains [1]. The development of novel anti-IAV drugs is still an urgent need. To research the synergistic effects of traditional Chinese medicines (TCMs) and their active compounds, we have engaged in the classification of TCMs according to the different IAV pathogenic mechanisms for many years. The peroxisome proliferator-activated receptor (PPAR) α/γ signaling pathway has been shown to be an antiviral innate immune signal that can protect against lethal IAV attacks in mice [2, 3]. It has been reported that PPARα agonist gemfibrozil can increase the survival of IAV
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