Liquiritin Exhibits Anti-acute Lung Injury Activities Through Suppressing the JNK/Nur77/c-Jun Pathway

Overview

Journal Chin Med

Publisher Biomed Central

Specialty Biomedical Engineering

Date 2023 Apr 4

PMID 37013552

Authors

Hongling Zhou

Tangjia Yang

Zibin Lu

Xuemei He

Jingyu Quan

Shanhong Liu

Yuyao Chen

Kangtai Wu

Huihui Cao

Junshan Liu

Linzhong Yu

Affiliations

Soon will be listed here.

Abstract

Background: Licorice (Glycyrrhiza uralensis Fisch.), a well-known traditional medicine, is traditionally used for the treatment of respiratory disorders, such as cough, sore throat, asthma and bronchitis. We aim to investigate the effects of liquiritin (LQ), the main bioactive compound in licorice against acute lung injury (ALI) and explore the potential mechanism.

Methods: Lipopolysaccharide (LPS) was used to induce inflammation in RAW264.7 cells and zebrafish. Intratracheal instillation of 3 mg/kg of LPS was used for induction an ALI mice model. The concentrations of IL-6 and TNF-α were tested using the enzyme linked immunosorbent assay. Western blot analysis was used to detect the expression of JNK/Nur77/c-Jun related proteins. Protein levels in bronchoalveolar lavage fluid (BALF) was measured by BCA protein assay. The effect of JNK on Nur77 transcriptional activity was determined by luciferase reporter assay, while electrophoretic mobility shift assay was used to examine the c-Jun DNA binding activity.

Results: LQ has significant anti-inflammatory effects in zebrafish and RAW264.7 cells. LQ inhibited the expression levels of p-JNK (Thr183/Tyr185), p-Nur77 (Ser351) and p-c-Jun (Ser63), while elevated the Nur77 expression level. Inhibition of JNK by a specific inhibitor or small interfering RNA enhanced the regulatory effect of LQ on Nur77/c-Jun, while JNK agonist abrogated LQ-mediated effects. Moreover, Nur77-luciferase reporter activity was suppressed after JNK overexpression. The effects of LQ on the expression level of c-Jun and the binding activity of c-Jun with DNA were attenuated after Nur77 siRNA treatment. LQ significantly ameliorated LPS-induced ALI with the reduction of lung water content and BALF protein content, the downregulation of TNF-α and IL-6 levels in lung BALF and the suppression of JNK/Nur77/c-Jun signaling, which can be reversed by a specific JNK agonist.

Conclusion: Our results indicated that LQ exerts significant protective effects against LPS-induced inflammation both in vivo and in vitro via suppressing the activation of JNK, and consequently inhibiting the Nur77/c-Jun signaling pathway. Our study suggests that LQ may be a potential therapeutic candidate for ALI and inflammatory disorders.

Citing Articles

Modified Xiao-Qing-Long-decoction prevents inflammation and promotes Nur77 expression in mice with acute respiratory distress syndrome by inhibiting HDAC7 expression.

Zhang Q, Liu Y, Jiang L, Yang D Pharm Biol. 2025; 63(1):110-117.

PMID: 39902793 PMC: 11795767. DOI: 10.1080/13880209.2025.2459247.

Dang-Gui-Si-Ni decoction facilitates wound healing in diabetic foot ulcers by regulating expression of AGEs/RAGE/TGF-β/Smad2/3.

Zhang S, Xu Y, Zhang Junior C, Chen X, Zhu J Arch Dermatol Res. 2024; 316(7):338.

PMID: 38847916 DOI: 10.1007/s00403-024-03021-0.

Self-Assembled Nanoparticles from Xie-Bai-San Decoction: Isolation, Characterization and Enhancing Oral Bioavailability.

Nie W, Liu Y, Lan J, Li T, He Y, Li Z Int J Nanomedicine. 2024; 19:3405-3421.

PMID: 38617795 PMC: 11012829. DOI: 10.2147/IJN.S449268.

Liquiritin Carbomer Gel Cold Paste Promotes Healing of Solar Dermatitis in Mice.

Huang Y, Li S, Pan J, Song C, Chen W, Zhang Y Int J Mol Sci. 2024; 25(7).

PMID: 38612578 PMC: 11011678. DOI: 10.3390/ijms25073767.

Effects of Varying Ratios of and Donkey Hide Gelatin Water Extracts on Dinitrochlorobenzene-Induced Atopic Dermatitis in NC/Nga Mice.

Dong L, Lee J, Jo E, Lee J, Kim S, Lee D Nutrients. 2023; 15(9).

PMID: 37432237 PMC: 10181245. DOI: 10.3390/nu15092094.

References

Fan E, Brodie D, Slutsky A . Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment. JAMA. 2018; 319(7):698-710. DOI: 10.1001/jama.2017.21907. View

Hu M, Luo Q, Alitongbieke G, Chong S, Xu C, Xie L . Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy. Mol Cell. 2017; 66(1):141-153.e6. PMC: 5761061. DOI: 10.1016/j.molcel.2017.03.008. View

Hou Z, Sun G . Predictive quality control for compound liquorice tablets by the intelligent mergence fingerprint method combined with the systematic quantitative fingerprint method. Phytochem Anal. 2021; 32(6):1118-1130. DOI: 10.1002/pca.3053. View

Lee S, Gong E, Hong C, Kim K, Han J, Ryu J . ROS inhibit the expression of testicular steroidogenic enzyme genes via the suppression of Nur77 transactivation. Free Radic Biol Med. 2009; 47(11):1591-600. DOI: 10.1016/j.freeradbiomed.2009.09.004. View

Liu Z, Wang P, Lu S, Guo R, Gao W, Tong H . Liquiritin, a novel inhibitor of TRPV1 and TRPA1, protects against LPS-induced acute lung injury. Cell Calcium. 2020; 88:102198. DOI: 10.1016/j.ceca.2020.102198. View

Xu H, Ye P, Wu C, Ding X, Chen S, Zhang H . Trametinib alleviates lipopolysaccharide-induced acute lung injury by inhibiting the MEK-ERK-Egr-1 pathway. Int Immunopharmacol. 2020; 80:106152. DOI: 10.1016/j.intimp.2019.106152. View

Zhou X, Liao Y . Gut-Lung Crosstalk in Sepsis-Induced Acute Lung Injury. Front Microbiol. 2022; 12:779620. PMC: 8733643. DOI: 10.3389/fmicb.2021.779620. View

Hanna R, Shaked I, Hubbeling H, Punt J, Wu R, Herrley E . NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis. Circ Res. 2011; 110(3):416-27. PMC: 3309661. DOI: 10.1161/CIRCRESAHA.111.253377. View

Lu Z, Xie P, Zhang D, Sun P, Yang H, Ye J . 3-Dehydroandrographolide protects against lipopolysaccharide-induced inflammation through the cholinergic anti-inflammatory pathway. Biochem Pharmacol. 2018; 158:305-317. DOI: 10.1016/j.bcp.2018.10.034. View

10.

Bosma K, Lewis J . Emerging therapies for treatment of acute lung injury and acute respiratory distress syndrome. Expert Opin Emerg Drugs. 2007; 12(3):461-77. DOI: 10.1517/14728214.12.3.461. View

11.

Xiong L, Tan Y, Ma H, Dai P, Qin Y, Yang R . Administration of SB239063, a potent p38 MAPK inhibitor, alleviates acute lung injury induced by intestinal ischemia reperfusion in rats associated with AQP4 downregulation. Int Immunopharmacol. 2016; 38:54-60. DOI: 10.1016/j.intimp.2016.03.036. View

12.

Liu Z, Zhong J, Zhang M, Chen Z, Wang J, Chen H . The Alexipharmic Mechanisms of Five Licorice Ingredients Involved in CYP450 and Nrf2 Pathways in Paraquat-Induced Mice Acute Lung Injury. Oxid Med Cell Longev. 2019; 2019:7283104. PMC: 6512064. DOI: 10.1155/2019/7283104. View

13.

Zhai K, Duan H, Cui C, Cao Y, Si J, Yang H . Liquiritin from Glycyrrhiza uralensis Attenuating Rheumatoid Arthritis via Reducing Inflammation, Suppressing Angiogenesis, and Inhibiting MAPK Signaling Pathway. J Agric Food Chem. 2019; 67(10):2856-2864. DOI: 10.1021/acs.jafc.9b00185. View

14.

Novoszel P, Holcmann M, Stulnig G, De Sa Fernandes C, Zyulina V, Borek I . Psoriatic skin inflammation is promoted by c-Jun/AP-1-dependent CCL2 and IL-23 expression in dendritic cells. EMBO Mol Med. 2021; 13(4):e12409. PMC: 8033525. DOI: 10.15252/emmm.202012409. View

15.

Qin Q, Chen M, Yi B, You X, Yang P, Sun J . Orphan nuclear receptor Nur77 is a novel negative regulator of endothelin-1 expression in vascular endothelial cells. J Mol Cell Cardiol. 2014; 77:20-8. PMC: 4312239. DOI: 10.1016/j.yjmcc.2014.09.027. View

16.

Pintha K, Chaiwangyen W, Yodkeeree S, Suttajit M, Tantipaiboonwong P . Suppressive Effects of Rosmarinic Acid Rich Fraction from Perilla on Oxidative Stress, Inflammation and Metastasis Ability in A549 Cells Exposed to PM via C-Jun, P-65-Nf-Κb and Akt Signaling Pathways. Biomolecules. 2021; 11(8). PMC: 8392772. DOI: 10.3390/biom11081090. View

17.

Zhang Q, Huang H, Qiu M, Wu Z, Xin Z, Cai X . Traditional Uses, Pharmacological Effects, and Molecular Mechanisms of Licorice in Potential Therapy of COVID-19. Front Pharmacol. 2021; 12:719758. PMC: 8661450. DOI: 10.3389/fphar.2021.719758. View

18.

Brito R, Canedo A, Farias D, Rocha T . Transgenic zebrafish (Danio rerio) as an emerging model system in ecotoxicology and toxicology: Historical review, recent advances, and trends. Sci Total Environ. 2022; 848:157665. DOI: 10.1016/j.scitotenv.2022.157665. View

19.

Lee J, Ko H, Woo E, Lee S, Moon B, Lee C . Moracin M inhibits airway inflammation by interrupting the JNK/c-Jun and NF-κB pathways in vitro and in vivo. Eur J Pharmacol. 2016; 783:64-72. DOI: 10.1016/j.ejphar.2016.04.055. View

20.

Luh S, Chiang C . Acute lung injury/acute respiratory distress syndrome (ALI/ARDS): the mechanism, present strategies and future perspectives of therapies. J Zhejiang Univ Sci B. 2006; 8(1):60-9. PMC: 1764923. DOI: 10.1631/jzus.2007.B0060. View