Liquiritin: A natural flavonoid with potential cardiovascular protection

Main Article Content

Lan Zhou
Jia-zhi Peng
Peng Zhou

Keywords

biosynthesis; cardiovascular diseases; liquiritin; molecular docking; pharmacology

Abstract

Liquiritin is a flavonoid glycoside extracted from traditional Chinese medicine, Radix et Rhizoma Glycyrrhizae. The provide evidence has found that liquiritin has been found to be beneficial to cardiovascular disease. Inflammation and oxidation play key roles in cardiovascular diseases. In this review, the natural sources, biosynthesis, pharmacology and molecular docking of liquiritin were reviewed for the first time. Additionally, we have highlighted the target prediction of liquiritin. Docking results displayed that the three targets with the largest difference in VINA scores were TLR4, Keap-1 and AMPK, which suggested that liquiritin was likely to act on TLR4, Keap-1 and AMPK. Liquiritin will provide theoretical basis for future development and research in cardiovascular diseases. 

Abstract 54 | PDF Downloads 41 XML Downloads 4 HTML Downloads 0

References

Adegbola P., Aderibigbe I., Hammed W. and Omotayo T. 2017. Antioxidant and anti-inflammatory medicinal plants have potential role in the treatment of cardiovascular disease: a review. Am J Cardiovasc Dis. 7(2):19–32.
Aiyasiding X., Liao H.H., Feng H., Zhang N., Lin Z., Ding W., et al. 2022. Liquiritin attenuates pathological cardiac hypertrophy by activating the PKA/LKB1/AMPK pathway. Front Pharmacol. 13: 870699. https://doi.org/10.3389/fphar.2022.870699
Amin M.N., Siddiqui S.A., Ibrahim M., Hakim M.L., Ahammed M.S., Kabir A., et al. 2020. Inflammatory cytokines in the pathogenesis of cardiovascular disease and cancer. SAGE Open Med. 8: 2050312120965752. https://doi.org/10.1177/2050312120965752
Buonfiglio R., Prati F., Bischetti M., Cavarischia C., Furlotti G. and Ombrato R. 2020. Discovery of novel imidazopyridine GSK-3β inhibitors supported by computational approaches. Molecules. 25(9): 2163. https://doi.org/10.3390/molecules25092163
Castrejón-Téllez V., Del Valle-Mondragón L., Pérez-Torres I., Guarner-Lans V., Pastelín-Hernández G., Ruiz-Ramírez A., et al. 2022. TRPV1 contributes to modulate the nitric oxide pathway and oxidative stress in the isolated and perfused rat heart during ischemia and reperfusion. Molecules. 27(3): 1031. https://doi.org/10.3390/molecules27031031
Chen M., Zhang C., Zhang J., Kai G., Lu B., Huang Z., et al. 2019. The involvement of DAMPs-mediated inflammation in cyclophosphamide-induced liver injury and the protection of liquiritigenin and liquiritin. Eur J Pharmacol. 856: 172421. https://doi.org/10.1016/j.ejphar.2019.172421
Deng X., Yang P., Gao T., Liu M. and Li X. 2021. Allicin attenuates myocardial apoptosis, inflammation and mitochondrial injury during hypoxia-reoxygenation: an in vitro study. BMC Cardiovasc Disord. 21(1): 200. https://doi.org/10.1186/s12872-021-01918-6
Dong X., Zhao S.P., Liu Y., Fu G.X., Li K.M. and Li P. 2009. Protective effect of liquiritin on cardiocyte injury of neonate rat induced by aconitin. China J Tradi Chin Med Pharm. 24(2): 163–166.
Fu D., Zhou J., Xu S., Tu J., Cai Y., Liu J., et al. 2022. Smilax glabra Roxb. flavonoids protect against pathological cardiac hypertrophy by inhibiting the Raf/MEK/ERK pathway: in vivo and in vitro studies. J Ethnopharmacol. 292: 115213. https://doi.org/10.1016/j.jep.2022.115213
Gallo S., Vitacolonna A., Bonzano A., Comoglio P. and Crepaldi T. 2019. ERK: a key player in the pathophysiology of cardiac hypertrophy. Int J Mol Sci. 20(9): 2164. https://doi.org/10.3390/ijms20092164
García N., Zazueta C. and Aguilera-Aguirre L. 2017. Oxidative stress and inflammation in cardiovascular disease. Oxid Med Cell Longev. 2017: 5853238. https://doi.org/10.1155/2017/5853238
Goetz M.E., Judd S.E., Safford M.M., Hartman T.J., McClellan W.M. and Vaccarino V. 2016. Dietary flavonoid intake and incident coronary heart disease: the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Am J Clin Nutr. 104(5): 1236–1244. https://doi.org/10.3945/ajcn.115.129452
Gong C.W., Yuan M.M., Qiu B.Q., Wang L.J., Zou H.X., Hu T., et al. 2022. Identification and validation of ferroptosis-related biomarkers in septic cardiomyopathy via bioinformatics analysis. Front Genet. 13: 827559. https://doi.org/10.3389/fgene.2022.827559
Guo D., Wang Q., Li A., Li S., Wang B., Li Y., et al. 2024. Liquiritin targeting Th17 cells differentiation and abnormal proliferation of keratinocytes alleviates psoriasis via NF-κB and AP-1 pathway. Phytother Res. 38(1): 174–186. https://doi.org/10.1002/ptr.8038
Han J., Shi X., Xu J., Lin W., Chen Y., Han B., et al. 2022. DL-3-n-butylphthalide prevents oxidative stress and atherosclerosis by targeting Keap-1 and inhibiting Keap-1/Nrf-2 interaction. Eur J Pharm Sci. 172: 106164. https://doi.org/10.1016/j.ejps.2022.106164
He S.H., Liu H.G., Zhou Y.F. and Yue Q.F. 2017. Liquiritin (LT) exhibits suppressive effects against the growth of human cervical cancer cells through activating Caspase-3 in vitro and xenograft mice in vivo. Biomed Pharmacother. 92: 215–228. https://doi.org/10.1016/j.biopha.2017.05.026
Hua F., Zhou P., Bao G.H. and Ling T.J. 2022. Flavonoids in Lu'an GuaPian tea as potential inhibitors of TMA-lyase in acute myocardial infarction. J Food Biochem. 14: e14110. https://doi.org/10.1111/jfbc.14110
Itteboina R., Ballu S., Sivan S.K. and Manga V. 2016. Molecular docking, 3D QSAR and dynamics simulation studies of imidazo-pyrrolopyridines as janus kinase 1 (JAK 1) inhibitors. Comput Biol Chem. 64: 33–46. https://doi.org/10.1016/j.compbiolchem.2016.04.009
Jia G., Whaley-Connell A. and Sowers J.R. 2018. Diabetic cardiomyopathy: a hyperglycaemia- and insulin-resistance-induced heart disease. Diabetologia. 61(1): 21–28. https://doi.org/10.1007/s00125-017-4390-4
Jiang W.B., Zhao W., Chen H., Wu Y.Y., Wang Y., Fu G.S., et al. 2018. Baicalin protects H9c2 cardiomyocytes against hypoxia/reoxygenation-induced apoptosis and oxidative stress through activation of mitochondrial aldehyde dehydrogenase 2. Clin Exp Pharmacol Physiol. 45(3): 303–311. https://doi.org/10.1111/1440-1681.12876
Jnoff E., Albrecht C., Barker J.J., Barker O., Beaumont E., Bromidge S., et al. 2014. Binding mode and structure-activity relationships around direct inhibitors of the Nrf2-Keap1 complex. Chem Med Chem. 9(4): 699–705. https://doi.org/10.1002/cmdc.201490011; https://doi.org/10.1002/cmdc.201300525
Jubaidi F.F., Zainalabidin S., Taib I.S., Hamid Z.A. and Budin S.B. 2021. The potential role of flavonoids in ameliorating diabetic cardiomyopathy via alleviation of cardiac oxidative stress, inflammation and apoptosis. Int J Mol Sci. 22(10): 5094. https://doi.org/10.3390/ijms22105094
Jung K.T., Bapat A., Kim Y.K., Hucker W.J. and Lee K. 2022. Therapeutic hypothermia for acute myocardial infarction: a narrative review of evidence from animal and clinical studies. Korean J Anesthesiol. 75(3): 216–230. https://doi.org/10.4097/kja.22156
Langendorf C.G., Ngoei K.R.W., Scott J.W., Ling N.X.Y., Issa S.M.A.V., Gorman M.A., et al. 2016. Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding. Nat Commun. 7: 10912. https://doi.org/10.1038/ncomms10912
Li Y., Xia C., Yao G., Zhang X., Zhao J., Gao X., et al. 2021. Protective effects of liquiritin on UVB-induced skin damage in SD rats. Int Immunopharmacol. 97: 107614. https://doi.org/10.1016/j.intimp.2021.107614
Liu C., Yuan D., Zhang C., Tao Y., Meng Y., Jin M., et al. 2022. Liquiritin alleviates depression-like behavior in CUMS mice by inhibiting oxidative stress and NLRP3 inflammasome in hippocampus. Evid Based Complement Alternat Med. 2022: 7558825. https://doi.org/10.1155/2022/7558825
Liu Y., Grimm M., Dai W.T., Hou M.C., Xiao Z.X. and Cao Y. 2020. CB-Dock: a web server for cavity detection-guided protein-ligand blind docking. Acta Pharmacol Sin. 41(1): 138–144. https://doi.org/10.1038/s41401-019-0228-6
Liu Z., Wang P., Lu S., Guo R., Gao W., Tong H., et al. 2020. Liquiritin, a novel inhibitor of TRPV1 and TRPA1, protects against LPS-induced acute lung injury. Cell Calcium. 88: 102198. https://doi.org/10.1016/j.ceca.2020.102198
Liu Y., Zhao S.P., Dong X., Xiao C., Tang G.Y., Li P., et al. 2008. Effects of liquiritin and ginsenoside on aconitine-induced changes of ion channel mRNA expression in myocardial cells. J Basic Chin Med. 14(5): 359–361.
Mo J., Zhou P., Chu Z., Zhao Y. and Wang X. 2022. Liquiritin attenuates angiotensin II-induced cardiomyocyte hypertrophy via ATE1/TAK1-JNK1/2 pathway. Evid Based Complement Alternat Med. 2022: 7861338. https://doi.org/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. Front Pharmacol. 12: 648688. https://doi.org/10.3389/fphar.2021.648688
Munck J.M., Berdini V., Bevan L., Brothwood J.L., Castro J., Courtin A., et al. 2021. ASTX029, a novel dual-mechanism ERK inhibitor, modulates both the phosphorylation and catalytic activity of ERK. Mol Cancer Ther. 20(10): 1757–1768. https://doi.org/10.1158/1535-7163.MCT-20-0909
Nadezhdin K.D., Neuberger A., Nikolaev Y.A., Murphy L.A., Gracheva E.O., Bagriantsev S.N., et al. 2021. Extracellular cap domain is an essential component of the TRPV1 gating mechanism. Nat Commun. 12(1): 2154. https://doi.org/10.1038/s41467-021-22507-3
Nakatani Y., Kobe A., Kuriya M., Hiroki Y., Yahagi T., Sakakibara I., et al. 2017. Neuroprotective effect of liquiritin as an antioxidant via an increase in glucose-6-phosphate dehydrogenase expression on B65 neuroblastoma cells. Eur J Pharmacol. 815: 381–390. https://doi.org/10.1016/j.ejphar.2017.09.040
Ohto U., Fukase K., Miyake K. and Shimizu T. 2012. Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2. Proc Natl Acad Sci USA. 109(19): 7421–7426. https://doi.org/10.1073/pnas.1201193109
Qin W., Cao L. and Massey I.Y. 2021. Role of PI3K/Akt signaling pathway in cardiac fibrosis. Mol Cell Biochem. 476(11): 4045–4059. https://doi.org/10.1007/s11010-021-04219-w
Qin J., Chen J., Peng F., Sun C., Lei Y., Chen G., et al. 2022. Pharmacological activities and pharmacokinetics of liquiritin: a review. J Ethnopharmacol. 293: 115257. https://doi.org/10.1016/j.jep.2022.115257
Qiu M., Cheng L., Xu J., Jin M., Yuan W., Ge Q., et al. 2024. Liquiritin reduces chondrocyte apoptosis through P53/PUMA signaling pathway to alleviate osteoarthritis. Life Sci. 343: 122536. https://doi.org/10.1016/j.lfs.2024.122536
Sharif H., Wang L., Wang W.L., Magupalli V.G., Andreeva L., Qiao Q., et al. 2019. Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome. Nature. 570(7761): 338–343. https://doi.org/10.1038/s41586-019-1295-z
Shaya G.E., Leucker T.M., Jones S.R., Martin S.S. and Toth P.P. 2022. Coronary heart disease risk: low-density lipoprotein and beyond. Trends Cardiovasc Med. 32(4): 181–194. https://doi.org/10.1016/j.tcm.2021.04.002
Shen M., Xu Z., Xu W., Jiang K., Zhang F., Ding Q., et al. 2019. Inhibition of ATM reverses EMT and decreases metastatic potential of cisplatin-resistant lung cancer cells through JAK/STAT3/PD-L1 pathway. J Exp Clin Cancer Res. 38(1): 149. https://doi.org/10.1186/s13046-019-1161-8
Simard J.R., Getlik M., Grütter C., Pawar V., Wulfert S., Rabiller M., et al. 2009. Development of a fluorescent-tagged kinase assay system for the detection and characterization of allosteric kinase inhibitors. J Am Chem Soc. 131(37): 13286–13296. https://doi.org/10.1021/ja902010p
Tang K., Zhong B., Luo Q., Liu Q., Chen X., Cao D., et al. 2022. Phillyrin attenuates norepinephrine-induced cardiac hypertrophy and inflammatory response by suppressing p38/ERK1/2 MAPK and AKT/NF-kappaB pathways. Eur J Pharmacol. 927: 175022. https://doi.org/10.1016/j.ejphar.2022.175022
Tham Y.K., Bernardo B.C., Ooi J.Y., Weeks K.L. and McMullen J.R. 2015. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Arch Toxicol. 89(9): 1401–1438. https://doi.org/10.1007/s00204-015-1477-x
Thu V.T., Yen N.T.H. and Ly N.T.H. 2021. Liquiritin from Radix Glycyrrhizae protects cardiac mitochondria from hypoxia/reoxygenation damage. J Anal Methods Chem. 2021: 1857464. https://doi.org/10.1155/2021/1857464
Walker E.H., Pacold M.E., Perisic O., Stephens L., Hawkins P.T., Wymann M.P., et al. 2000. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell. 6(4): 909–919. https://doi.org/10.1016/S1097-2765(05)00089-4
Wang Y., Liu X., Shi H., Yu Y., Yu Y., Li M., et al. 2020. NLRP3 inflammasome, an immune-inflammatory target in pathogenesis and treatment of cardiovascular diseases. Clin Transl Med. 10(1): 91–106. https://doi.org/10.1002/ctm2.13
Wei J., Fan S., Yu H., Shu L. and Li Y. 2021. A new strategy for the rapid identification and validation of the direct targets of aconitine-induced cardiotoxicity. Drug Des Devel Ther. 15: 4649–4664. https://doi.org/10.2147/DDDT.S335461
Weng W., Wang Q., Wei C., Adu-Frimpong M., Toreniyazov E., Ji H., et al. 2021. Mixed micelles for enhanced oral bioavailability and hypolipidemic effect of liquiritin: preparation, in vitro and in vivo evaluation. Drug Dev Ind Pharm. 47(2): 308–318. https://doi.org/10.1080/03639045.2021.1879839
Wu S. and Zou M.H. 2020. AMPK, mitochondrial function, and cardiovascular fisease. Int J Mol Sci. 21(14): 4987. https://doi.org/10.3390/ijms21144987
Yang Z., Liu Y., Li Z., Feng S., Lin S., Ge Z., et al. 2023 Aug. Coronary microvascular dysfunction and cardiovascular disease: pathogenesis, associations and treatment strategies. Biomed Pharmacother. 164:115011. https://doi.org/10.1016/j.biopha.2023.115011
Yin Y., Li Y., Jiang D., Zhang X., Gao W. and Liu C. 2020. De novo biosynthesis of liquiritin in Saccharomyces cerevisiae. Acta Pharm Sin B. 10(4): 711–721. https://doi.org/10.1016/j.apsb.2019.07.005
Yuan L., Wang D. and Wu C. 2022. Protective effect of liquiritin on coronary heart disease through regulating the proliferation of human vascular smooth muscle cells via upregulation of sirtuin1. Bioengineered. 13(2): 2840–2850. https://doi.org/10.1080/21655979.2021.2024687
Zeng Z., Wang Q., Yang X., Ren Y., Jiao S., Zhu Q., et al. 2019. Qishen granule attenuates cardiac fibrosis by regulating TGF-β /Smad3 and GSK-3β pathway. Phytomedicine. 62: 152949. https://doi.org/10.1016/j.phymed.2019.152949
Zhai K.F., Duan H., Cui C.Y., Cao Y.Y., Si J.L., Yang H.J., et al. 2019. Liquiritin from glycyrrhiza uralensis attenuating rheumatoid arthritis via reducing inflammation, suppressing angiogenesis, and inhibiting MAPK signaling pathway. J Agric Food Chem. 67(10): 2856–2864. https://doi.org/10.1021/acs.jafc.9b00185
Zhang H. and Dhalla N.S. 2024. The role of pro-Inflammatory cytokines in the pathogenesis of cardiovascular disease. Int J Mol Sci. 25(2): 1082. https://doi.org/10.3390/ijms25021082
Zhang Q.H., Huang H.Z., Qiu M., Wu Z.F., Xin Z.C., Cai X.F., et al. 2021. Traditional uses, pharmacological effects, and molecular mechanisms of licorice in potential therapy of COVID-19. Front Pharmacol. 12: 719758. https://doi.org/10.3389/fphar.2021.719758
Zhang X., Song Y., Han X., Feng L., Wang R., Zhang M., et al. 2013. Liquiritin attenuates advanced glycation end products-induced endothelial dysfunction via RAGE/NF-κB pathway in human umbilical vein endothelial cells. Mol Cell Biochem. 374(1–2): 191–201. https://doi.org/10.1007/s11010-012-1519-0
Zhang Q., Wang L., Wang S., Cheng H., Xu L., Pei G., et al. 2022. Signaling pathways and targeted therapy for myocardial infarction. Signal Transduct Target Ther. 7(1): 78. https://doi.org/10.1038/s41392-022-00925-z
Zhang Y., Zhang L., Zhang Y., Xu J.J., Sun L.L. and Li S.Z. 2016. The protective role of liquiritin in high fructose-induced myocardial fibrosis via inhibiting NF-κB and MAPK signaling pathway. Biomed Pharmacother. 84: 1337–1349. https://doi.org/10.1016/j.biopha.2016.10.036
Zhou P., Shen A.L., Liu P.P., Wang S.S. and Wang L. 2022. Molecular docking and in vivo studies of liquiritin against acute myocardial infarction via TLR4/MyD88/NF-κB signaling. Italian J Food Sci. 34(2): 1–9. https://doi.org/10.15586/ijfs.v34i2.2188