Apigenin C-glycosides of Microcos paniculata protects lipopolysaccharide induced apoptosis and inflammation in acute lung injury through TLR4 signaling pathway

Li, K. et al. (2018) Apigenin C-glycosides of Microcos paniculata protects lipopolysaccharide induced apoptosis and inflammation in acute lung injury through TLR4 signaling pathway. Free Radical Biology and Medicine, 124, pp. 163-175. (doi:10.1016/j.freeradbiomed.2018.06.009) (PMID:29890216)

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Abstract

Acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are life-threatening conditions with high morbility and mortality, underscoring the urgent need for novel treatments. Leaves of the medicinal herb Microcos paniculata have been traditionally used for treating upper airway infections, by virtue of its content of flavonoids such as apigenin C-glycosides (ACGs). C-glycosides have been shown to exert strong anti-inflammatory properties, although their mechanism of action remains unknown. Herein, hypothesizing that ACGs from M. paniculata inhibit progression of ALI, we used the experimental model of lipopolysaccharide (LPS)-induced ALI in BALB/c mice to evaluate the therapeutic potential of purified ACGs. Our results showed that M. paniculata ACGs inhibited lung inflammation in animals undergoing ALI. The protective effects of ACGs were assessed by determination of cytokine levels and in situ analysis of lung inflammation. ACGs reduced the pulmonary edema and microvascular permeability, demonstrating a dose-dependent down-regulation of LPS-induced TNF-α, IL-6 and IL-1β expression in lung tissue and bronchoalveolar lavage fluid, along with reduced apoptosis. Moreover, metabolic profiling of mice serum and subsequent Ingenuity Pathway Analysis suggested that ACGs activated protective protein networks and pathways involving inflammatory regulators and apoptosis-related factors, such as JNK, ERK1/2 and caspase-3/7, suggesting that ACGs-dependent effects were related to MAPKs and mitochondrial apoptosis pathways. These results were further supported by evaluation of protein expression, showing that ACGs blocked LPS-activated phosphorylation of p38, ERK1/2 and JNK on the MAPKs signaling, and significantly upregulated the expression of Bcl-2 whilst down-regulated Bax and cleaved caspase-3. Remarkably, ACGs inhibited the LPS-dependent TLR4 and TRPC6 upregulation observed during ALI. Our study shows for the first time that ACGs inhibit acute inflammation and apoptosis by suppressing activation of TLR4/TRPC6 signaling pathway in a murine model of ALI. Our findings provide new evidence for better understanding the anti-inflammatory effects of ACGs. In this regard, ACGs could be exploited in the development of novel therapeutics for ALI and ARDS.

Item Type:Articles
Additional Information:The work was supported in part by the National Natural Science Foundation of China [Grant no. 31300273], the Science and Technology Planning Project of Guangdong Province, China [Grant no. 2015A030302082], the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, China [Grant no. 20151098], the International Science and Technology Cooperation Project of Guangdong Province, China [Grant nos. 2015A050502050, 2016B050501003].
Keywords:Acute lung injury, apigenin C-glycosides, GC-MS, ingenuity pathway analysis, MAPKs, metabolic profiling, microcos paniculata, TLR4, TRPC6.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Pineda, Dr Miguel
Authors: Li, K., He, Z., Wang, X., Pineda, M., Chen, R., Liu, H., Ma, K., Shen, H., Wu, C., Huang, N., Pan, T., Liu, Y., and Guo, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Free Radical Biology and Medicine
Publisher:Elsevier
ISSN:0891-5849
ISSN (Online):1873-4596
Published Online:08 June 2018
Copyright Holders:Copyright © 2018 Elsevier Inc.
First Published:First published in Free Radical Biology and Medicine 124: 163-175
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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