Liquiritin ameliorates acute myocardial infarction via the COX-2/NLRP3 signaling pathway: network pharmacology and experimental validation
Main Article Content
Keywords
acute myocardial infarction, COX-2/NLRP3 signaling pathway, liquiritin, molecular docking, network pharmacology
Abstract
Liquiritin is beneficial to cardiovascular diseases, including myocardial hypoxia/reoxygenation (H/R) injury, myocardial hypertrophy, and acute myocardial infarction (AMI). However, the mechanism of liquiritin on AMI is unknown. This study is of great significance for elucidating the mechanism of liquiritin in preventing and treating AMI and developing cardiovascular protective drugs. Network pharmacology and molecular docking were used to screen the targets of liquiritin. AMI rats were built by coronary left anterior descending ligation. Echocardiography was used to monitor cardiac function; HE staining was used to detect pathological changes, and cardiac enzymes were detected. The expressions of COX-2, NLRP3, Caspase-1, ASC, and GSDMD were detected by RT-PCR and Western Blot. ELISA was used for the detection of IL-1β and IL-18 expression. COX-2 was detected as the most considerable protein in the PPI network. Molecular docking predicted that liquiritin has a high binding affinity with COX-2. AMI model rats showed significantly lower EF and FS (P<0.01) and increased LVIDd and LVIDs (P<0.01), which were improved by liquiritin. Liquiritin significantly reduced cardiac pathological changes and decreased LDH, CK, cTn-I, and BNP levels. Liquiritin reduced the mRNA and protein expressions of COX-2, NLRP3, Caspase-1, ASC, and GSDMD. Liquiritin inhibited IL-1β and IL-18 overexpression. Liquiritin has a better effect against AMI, and its mechanism is related to inhibiting the COX-2/NLRP3 signaling pathway.
References
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Han X., Yang Y., Zhang M., Li L., Xue Y., Jia Q., et al. (2022). Liquiritin protects against cardiac fibrosis after myocardial infarction by inhibiting CCL5 expression and the NF-κB signaling pathway. Drug Design, Development and Therapy, 16, 4111–4125. 10.2147/DDDT.S386805
Lee Y.M., Kim R.B., Lee H.J., Kim K., Shin M.H., Park H.K., et al. (2018). Relationships among medication adherence, lifestyle modification, and health-related quality of life in patients with acute myocardial infarction: a cross-sectional study. Health and Quality of Life Outcomes, 16(1), 100. 10.1186/s12955-018-0921-z
Li W., Yuan G., Pan Y., Wang C., Chen H. (2017). Network pharmacology studies on the bioactive compounds and action mechanisms of natural products for the treatment of diabetes mellitus: a review. Frontiers in Pharmacology, 8, 74. 10.3389/fphar.2017.00074
Liu J., Sun L., Chen D., Huo X., Tian X., Li J., et al. (2022). Prdx6-induced inhibition of ferroptosis in epithelial cells contributes to liquiritin-exerted alleviation of colitis. Food and Function, 13(18), 9470–9480. 10.1039/D2FO00945E
Liu Y., Grimm M., Dai W.T., Hou M.C., Xiao Z.X., Cao Y. (2020). CB-Dock: a web server for cavity detection-guided protein-ligand blind docking. Acta Pharmacologica Sinica, 41(1), 138–144. 10.1038/s41401-019-0228-6
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Thu V.T., Yen N.T.H., Ly N.T.H. (2021). Liquiritin from Radix Glycyrrhizae protects cardiac mitochondria from hypoxia/reoxygenation damage. Journal of Analytical Methods in Chemistry, 2021, 1857464. 10.1155/2021/1857464
Wahab S., Annadurai S., Abullais S.S., Das G., Ahmad W., Ahmad M.F., et al. (2021). Glycyrrhiza glabra (Licorice): A comprehensive review on its phytochemistry, biological activities, clinical evidence and toxicology. Plants, 10(12) 2751. 10.3390/plants10122751
Wang X., Wang Z.Y., Zheng J.H., Li S. (2022). TCM network pharmacology: A new trend towards combining computational, experimental and clinical approaches. Chinese Journal of Natural Medicines, 19(1), 1–11. 10.4236/cm.2022.131001
Xiao L., Liu J., Li G., Zheng Y., Chen M., He S. (2022). Acute myocardial infarction after a local anesthetic procedure in a middle-aged patient. The American Journal of the Medical Sciences, 364(1), 106–110. 10.1016/j.amjms.2022.03.009
Yang H.H., Duan J.X., Liu S.K., Xiong J.B., Guan X.X., Zhong W.J., et al. (2020). A COX-2/sEH dual inhibitor PTUPB alleviates lipopolysaccharide-induced acute lung injury in mice by inhibiting NLRP3 inflammasome activation. Theranostics, 10(11), 4749–4761. 10.7150/thno.43108
Yang H.Y., Liu M.L., Luo P., Yao X.S., Zhou H. (2022). Network pharmacology provides a systematic approach to understanding the treatment of ischemic heart diseases with traditional Chinese medicine. Phytomedicine, 104, 154268. 10.1016/j.phymed.2022.154268
Yang R., Yuan B.C., Ma Y.S., Zhou S., Liu Y. (2017). The anti-inflammatory activity of licorice, a widely used Chinese herb. Pharmaceutical Biology, 55(1), 5–18. 10.1080/13880209.2016.1225775
Zhang L., Fan Y., Su H., Wu L., Huang Y., Zhao L., et al. (2018). Chlorogenic acid methyl ester exerts strong anti-inflammatory effects via inhibiting the COX-2/NLRP3/NF-κB pathway. Food and Function, 9(12), 6155–6164. 10.1039/C8FO01281D
Zhang M., Lei Y.S., Meng X.W., Liu H.Y., Li L.G., Zhang J., et al. (2021). Iguratimod alleviates myocardial ischemia/reperfusion injury through inhibiting inflammatory response induced by cardiac fibroblast pyroptosis via COX2/NLRP3 signaling pathway. Frontiers in Cell and Developmental Biology, 9, 746317. 10.3389/fcell.2021.746317
Zhang Y., Zhang L., Zhang Y., Xu J.J., Sun L.L., Li S.Z. (2016). The protective role of liquiritin in high fructose-induced myocardial fibrosis via inhibiting NF-κB and MAPK signaling pathway. Biomedicine and Pharmacotherapy, 84, 1337–1349. 10.1016/j.biopha.2016.10.036
Zhao L., Zhang H., Li N., Chen J., Xu H., Wang Y., et al. (2023). Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula. Journal of Ethnopharmacology, 309, 116306. 10.1016/j.jep.2023.116306
Zhou J., Liu H., Zhang T., Wang Z., Zhang J., Lu Y., et al. (2023). MORN4 protects cardiomyocytes against ischemic injury via MFN2-mediated mitochondrial dynamics and mitophagy. Free Radical Biology and Medicine, 196, 156–170. 10.1016/j.freeradbiomed.2023.01.016
Zhou P., Shen A.L., Liu P.P., Wang S.S., Wang L. (2022). Molecular docking and in vivo studies of liquiritin against acute myocardial infarction via TLR4/MyD88/NF-κB signaling. Italian Journal of Food Science, 34(2), 1–9. 10.15586/ijfs.v34i2.2188
Zhuang Y., Zhao F., Liang J., Deng X., Zhang Y., Ding G., et al. (2017). Activation of COX-2/mPGES-1/PGE2 cascade via NLRP3 inflammasome contributes to albumin-induced proximal tubule cell injury. Cellular Physiology and Biochemistry, 42(2), 797–807. 10.1159/000478070
Alhouayek M., Muccioli G.G. (2014). COX-2-derived endocannabinoid metabolites as novel inflammatory mediators. Trends in Pharmacological Sciences, 35(6), 284–292. 10.1016/j.tips.2014.03.001
Frantz S., Hundertmark M.J., Schulz-Menger J., Bengel F.M., Bauersachs J. (2022). Left ventricular remodeling post-myocardial infarction: pathophysiology, imaging, and novel therapies. European Heart Journal, 43(27), 2549–2561. 10.1093/eurheartj/ehac223
Gfeller D., Grosdidier A., Wirth M., Daina A., Michielin O., Zoete V. (2014). Swiss Target Prediction: a web server for target prediction of bioactive small molecules. Nucleic Acids Research, 42, W32–38. 10.1093/nar/gku293
Gong F.F., Vaitenas I., Malaisrie S.C., Maganti K. (2021). Mechanical complications of acute myocardial infarction: a review. JAMA Cardiology, 6(3), 341-349. 10.1001/jamacardio.2020.3690
Han X., Yang Y., Zhang M., Li L., Xue Y., Jia Q., et al. (2022). Liquiritin protects against cardiac fibrosis after myocardial infarction by inhibiting CCL5 expression and the NF-κB signaling pathway. Drug Design, Development and Therapy, 16, 4111–4125. 10.2147/DDDT.S386805
Lee Y.M., Kim R.B., Lee H.J., Kim K., Shin M.H., Park H.K., et al. (2018). Relationships among medication adherence, lifestyle modification, and health-related quality of life in patients with acute myocardial infarction: a cross-sectional study. Health and Quality of Life Outcomes, 16(1), 100. 10.1186/s12955-018-0921-z
Li W., Yuan G., Pan Y., Wang C., Chen H. (2017). Network pharmacology studies on the bioactive compounds and action mechanisms of natural products for the treatment of diabetes mellitus: a review. Frontiers in Pharmacology, 8, 74. 10.3389/fphar.2017.00074
Liu J., Sun L., Chen D., Huo X., Tian X., Li J., et al. (2022). Prdx6-induced inhibition of ferroptosis in epithelial cells contributes to liquiritin-exerted alleviation of colitis. Food and Function, 13(18), 9470–9480. 10.1039/D2FO00945E
Liu Y., Grimm M., Dai W.T., Hou M.C., Xiao Z.X., Cao Y. (2020). CB-Dock: a web server for cavity detection-guided protein-ligand blind docking. Acta Pharmacologica Sinica, 41(1), 138–144. 10.1038/s41401-019-0228-6
Mo J., Zhou P., Chu Z., Zhao Y., Wang X. (2022). Liquiritin attenuates angiotensin II-induced cardiomyocyte hypertrophy via ATE1/TAK1-JNK1/2 pathway. Evidence-Based Complementary and Alternative Medicine, 2022, 7861338. 10.1155/2022/7861338
Mou S.Q., Zhou Z.Y., Feng H., Zhang N., Lin Z., Aiyasiding X., et al. (2021). Liquiritin attenuates lipopolysaccharides-induced cardiomyocyte injury via an AMP-activated protein kinase-dependent signaling pathway. Frontiers in Pharmacology, 12, 648688. 10.3389/fphar.2021.648688
Orlando B.J., Malkowski M.G. (2016). Crystal structure of rofecoxib bound to human cyclooxygenase-2. Acta Crystallographica Section F Structural Biology Communications, 72(10), 772–776. 10.1107/S2053230X16014230
Pilz P.M., Lang M., Hamza O., Szabo P.L., Inci M., Kramer A.M., et al. (2020). Semi-minimal invasive method to induce myocardial infarction in rats and the assessment of cardiac function by an isolated working heart system. Journal of Visualized Experiments, 2020, 160. 10.3791/61033
Pinzi L., Rastelli G. (2019). Molecular docking: Shifting paradigms in drug discovery. International Journal of Molecular Sciences, 20(18), 4331. 10.3390/ijms20184331
Qin J., Chen J., Peng F., Sun C., Lei Y., Chen G., et al. (2022). Pharmacological activities and pharmacokinetics of liquiritin: a review. Journal of Ethnopharmacology, 293, 115257. 10.1016/j.jep.2022.115257
Rao T., Tan Z., Peng J., Guo Y., Chen Y., Zhou H., et al. (2019). The pharmacogenetics of natural products: A pharmacokinetic and pharmacodynamic perspective. Pharmacological Research, 146, 104283. 10.1016/j.phrs.2019.104283
Rubinfeld G.D., Berger J.S., Smilowitz N.R. (2022). Acute myocardial infarction following hospitalization for gastrointestinal bleeding: Incidence, predictors, management, and outcomes. The American Journal of Medicine, 135(8), e263–e278. 10.1016/j.amjmed.2022.03.030
Stelzer G., Rosen N., Plaschkes I., Zimmerman S., Twik M., Fishilevich S., et al. (2016). The GeneCards suite: from gene data mining to disease genome sequence analyses. Current Protocols in Bioinformatics, 54, 1–30. 10.1002/cpbi.5
Thu V.T., Yen N.T.H., Ly N.T.H. (2021). Liquiritin from Radix Glycyrrhizae protects cardiac mitochondria from hypoxia/reoxygenation damage. Journal of Analytical Methods in Chemistry, 2021, 1857464. 10.1155/2021/1857464
Wahab S., Annadurai S., Abullais S.S., Das G., Ahmad W., Ahmad M.F., et al. (2021). Glycyrrhiza glabra (Licorice): A comprehensive review on its phytochemistry, biological activities, clinical evidence and toxicology. Plants, 10(12) 2751. 10.3390/plants10122751
Wang X., Wang Z.Y., Zheng J.H., Li S. (2022). TCM network pharmacology: A new trend towards combining computational, experimental and clinical approaches. Chinese Journal of Natural Medicines, 19(1), 1–11. 10.4236/cm.2022.131001
Xiao L., Liu J., Li G., Zheng Y., Chen M., He S. (2022). Acute myocardial infarction after a local anesthetic procedure in a middle-aged patient. The American Journal of the Medical Sciences, 364(1), 106–110. 10.1016/j.amjms.2022.03.009
Yang H.H., Duan J.X., Liu S.K., Xiong J.B., Guan X.X., Zhong W.J., et al. (2020). A COX-2/sEH dual inhibitor PTUPB alleviates lipopolysaccharide-induced acute lung injury in mice by inhibiting NLRP3 inflammasome activation. Theranostics, 10(11), 4749–4761. 10.7150/thno.43108
Yang H.Y., Liu M.L., Luo P., Yao X.S., Zhou H. (2022). Network pharmacology provides a systematic approach to understanding the treatment of ischemic heart diseases with traditional Chinese medicine. Phytomedicine, 104, 154268. 10.1016/j.phymed.2022.154268
Yang R., Yuan B.C., Ma Y.S., Zhou S., Liu Y. (2017). The anti-inflammatory activity of licorice, a widely used Chinese herb. Pharmaceutical Biology, 55(1), 5–18. 10.1080/13880209.2016.1225775
Zhang L., Fan Y., Su H., Wu L., Huang Y., Zhao L., et al. (2018). Chlorogenic acid methyl ester exerts strong anti-inflammatory effects via inhibiting the COX-2/NLRP3/NF-κB pathway. Food and Function, 9(12), 6155–6164. 10.1039/C8FO01281D
Zhang M., Lei Y.S., Meng X.W., Liu H.Y., Li L.G., Zhang J., et al. (2021). Iguratimod alleviates myocardial ischemia/reperfusion injury through inhibiting inflammatory response induced by cardiac fibroblast pyroptosis via COX2/NLRP3 signaling pathway. Frontiers in Cell and Developmental Biology, 9, 746317. 10.3389/fcell.2021.746317
Zhang Y., Zhang L., Zhang Y., Xu J.J., Sun L.L., Li S.Z. (2016). The protective role of liquiritin in high fructose-induced myocardial fibrosis via inhibiting NF-κB and MAPK signaling pathway. Biomedicine and Pharmacotherapy, 84, 1337–1349. 10.1016/j.biopha.2016.10.036
Zhao L., Zhang H., Li N., Chen J., Xu H., Wang Y., et al. (2023). Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula. Journal of Ethnopharmacology, 309, 116306. 10.1016/j.jep.2023.116306
Zhou J., Liu H., Zhang T., Wang Z., Zhang J., Lu Y., et al. (2023). MORN4 protects cardiomyocytes against ischemic injury via MFN2-mediated mitochondrial dynamics and mitophagy. Free Radical Biology and Medicine, 196, 156–170. 10.1016/j.freeradbiomed.2023.01.016
Zhou P., Shen A.L., Liu P.P., Wang S.S., Wang L. (2022). Molecular docking and in vivo studies of liquiritin against acute myocardial infarction via TLR4/MyD88/NF-κB signaling. Italian Journal of Food Science, 34(2), 1–9. 10.15586/ijfs.v34i2.2188
Zhuang Y., Zhao F., Liang J., Deng X., Zhang Y., Ding G., et al. (2017). Activation of COX-2/mPGES-1/PGE2 cascade via NLRP3 inflammasome contributes to albumin-induced proximal tubule cell injury. Cellular Physiology and Biochemistry, 42(2), 797–807. 10.1159/000478070
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Apr 1, 2024
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Zhou, L., Ding, H.- min, Du, Y.- qin, Hu, Z.- qing, Li, J.- ya, Wang, L., & Zhou, P. (2024). Liquiritin ameliorates acute myocardial infarction via the COX-2/NLRP3 signaling pathway: network pharmacology and experimental validation. Italian Journal of Food Science, 36(2), 61-73. https://doi.org/10.15586/ijfs.v36i2.2523
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How to Cite
Zhou, L., Ding, H.- min, Du, Y.- qin, Hu, Z.- qing, Li, J.- ya, Wang, L., & Zhou, P. (2024). Liquiritin ameliorates acute myocardial infarction via the COX-2/NLRP3 signaling pathway: network pharmacology and experimental validation. Italian Journal of Food Science, 36(2), 61-73. https://doi.org/10.15586/ijfs.v36i2.2523