Kaempferol-3-O-rutinoside protects myocardial cell injury by inhibiting the TXNIP/NLRP3 pathway
Main Article Content
Keywords
Kaempferol-3-O-rutinoside, molecular docking, myocardial cell injury, TXNIP/NLRP3 pathway
Abstract
Kaempferol-3-O-rutinoside (KR), a compound commonly found in green tea, has demonstrated significant myocardial protective effects. The aim of this study was to reveal the cardioprotective mechanism of KR. In this study, molecular docking was employed to predict the binding affinity of KR to thioredoxin-interacting protein (TXNIP). An injury model of H9c2 cells was established using lipopolysaccharide (LPS) and adenosine triphosphate (ATP). Lactate dehydrogenase (LDH) levels were measured using specific kits, while total superoxide dismutase (T-SOD), malondialdehyde (MDA), glutathione (GSH), and catalase (CAT) activities were assessed with colorimetric assays. The reactive oxygen species (ROS) level was determined using the DCFH-DA fluorescent probe assay. In addition, the expression levels of TXNIP, NLR-family pyrin domain-containing protein 3 (NLRP3), cysteinyl aspartate specific proteinase-1 (Caspase-1), and thioredoxin (TRX) were quantified by reverse transcription polymerase chain reaction (RT-PCR) and Western blot (WB) assays. Levels of interleukin-1β (IL-1β) and IL-18 were determined by ELISA. The results indicated that KR has a specific binding affinity for TXNIP. KR was found to reduce LDH and MDA activities, increase CAT, GSH, T-SOD, and inhibit ROS production. Mechanistically, KR decreased the gene and protein expressions of TXNIP, Caspase-1, and NLRP3, while increasing the gene and protein expression of TRX. Also, KR decreased the levels of IL-1β and IL-18. In conclusion, the protective mechanism of KR against cardiomyocyte injury involves the inhibition of the TXNIP/NLRP3 pathway, providing experimental evidence for its potential clinical application.
References
Bai, W. X., Wang, C., Wang, Y. J., Zheng, W. J., Wang, W., Wan, X. C., et al. (2017). Novel acylated flavonol tetraglycoside with inhibitory effect on lipid accumulation in 3T3-L1 cells from Lu’an GuaPian tea and quantification of flavonoid glycosides in six major processing types of tea. Journal of Agricultural and Food Chemistry, 65, 2999–3005. 10.1021/acs.jafc.7b00239
Bharti, V., Tan, H., Zhou, H., & Wang, J. F. (2019). TXNIP mediates glucocorticoid-activated NLRP3 inflammatory signaling in mouse microglia. Neurochemistry International, 131, 104564. 10.1016/j.neuint.2019.104564
Cheng, Y. C., Chu, L.W., Chen, J. Y., Hsieh, S. L., Chang, Y. C., Dai, Z. K., et al. (2020). Loganin attenuates high glucose-induced Schwann cells pyroptosis by inhibiting ROS generation and NLRP3 inflammasome activation. Cells, 9, 1948. 10.3390/cells9091948
de Torre-Minguela, C., Gómez, A. I., Couillin, I., & Pelegrín, P. (2021). Gasdermins mediate cellular release of mitochondrial DNA during pyroptosis and apoptosis. FASEB Journal, 35, e21757. 10.1096/fj.202100085R
Dubey, R., & Dubey, K. (2021). Molecular docking studies of bioactive nicotiflorin against 6W63 novel coronavirus 2019 (COVID-19). Combinatorial Chemistry & High Throughput Screening, 24, 874–878. 10.2174/1386207323999200820162551
Frangogiannis, N. G. (2014). The inflammatory response in myocardial injury, repair, and remodelling. Nature Reviews Cardiology, 11, 255–265. 10.1038/nrcardio.2014.28
Guedes, I. A., de Magalhães, C. S., & Dardenne L. E. (2014). Receptor-ligand molecular docking. Biophysical Reviews, 6, 75–87. 10.1007/s12551-013-0130-2
Hua, F., Zhou, P., Liu, P. P., & Bao, G. H. (2021). Rat plasma protein binding of kaempferol-3-O-rutinoside from Lu’an GuaPian tea and its anti-inflammatory mechanism for cardiovascular protection. Journal of Food Biochemistry, 45, e13749. 10.1111/jfbc.13749
Hua, F., Zhou, P., Wu, H. Y., Chu, G. X., Xie, Z. W., & Bao, G. H. (2018). Inhibition of α-glucosidase and α-amylase by flavonoid glycosides from Lu’an GuaPian tea: Molecular docking and interaction mechanism. Food & Function, 9, 4173–4183. 10.1039/C8FO00562A
Hua, F., Li, J. Y., Zhang, M., Zhou, P., Wang, L., Ling, T. J., et al. (2022). Kaempferol-3-O-rutinoside exerts cardioprotective effects through NF-κB/NLRP3/Caspase-1 pathway in ventricular remodeling after acute myocardial infarction. Journal of Food Biochemistry, 46, e14305. 10.1111/jfbc.14305
Imre, G. (2024). Pyroptosis in health and disease. American Journal of Physiology-Cell Physiology, 326, C784–C794. 10.1152/ajpcell.00503.2023
Kawaguchi, M., Takahashi, M., Hata, T., Kashima, Y., Usui, F., Morimoto, H., et al. (2011). Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation, 123, 594–604. 10.1161/CIRCULATIONAHA.110.982777
Li, H., Guan, Y., Liang, B., Ding, P., Hou, X., & Wei, W. (2022). Therapeutic potential of MCC950, a specific inhibitor of NLRP3 inflammasome. European Journal of Pharmacology, 928, 175091. 10.1016/j.ejphar.2022.175091
Liang, F., Zhang, F., Zhang, L., & Wei, W. (2020). The advances in pyroptosis initiated by inflammasome in inflammatory and immune diseases. Inflammation Research, 69, 159–166. 10.1007/s00011-020-01315-3
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, 138–144. 10.11648/j.cb.20200802.13
Luo, T., Zhou, X., Qin, M., Lin, Y., Lin, J., Chen G., et al. (2022). Corilagin restrains NLRP3 inflammasome activation and pyroptosis through the ROS/TXNIP/NLRP3 pathway to prevent inflammation. Oxidative Medicine and Cellular Longevity, 2022, 1652244. 10.1155/2022/1652244
Mezzaroma, E., Told,o S., Farkas, D., Seropian, I. M., Van Tassell, B. W., Salloum, F. N., et al. (2011). The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proceedings of the National Academy of Sciences USA, 108, 1972–-19730. 10.1073/pnas.1108586108
Palasubramaniam, J., Wang, X., & Peter, K. (2019). Myocardial infarction–From atherosclerosis to thrombosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 39, e176–e185. 10.1161/ATVBAHA.119.312578
Petpiroon, N., Suktap, C., Pongsamart, S., Chanvorachote, P., & Sukrong, S. (2015). Kaempferol-3-O-rutinoside from Afgekia mahidoliae promotes keratinocyte migration through FAK and Rac1 activation. Journal of Natural Medicines, 69, 340–348. 10.1007/s11418-015-0899-3
Polekhina, G., Ascher, D. B., Kok, S. F., Beckham, S., Wilce, M., & Waltham, M. (2013). Structure of the N-terminal domain of human thioredoxin-interacting protein. Acta Crystallographica. Section D, Biological Crystallography, 69, 333–344. 10.1107/S0907444912047099
Qiu, Z., He, Y., Ming, H., Lei, S., Leng, Y., & Xia, Z. Y. (2019). Lipopolysaccharide (LPS) aggravates high glucose-and hypoxia/reoxygenation-induced injury through activating ROS-dependent NLRP3 inflammasome-mediated pyroptosis in H9C2 cardiomyocytes. Journal of Diabetes Research, 2019, 8151836. 10.1155/2019/8151836
Sukhanov, S., Higashi, Y., Yoshida, T., Mummidi, S., Aroor, A. R., Jeffrey Russell, J., et al. (2021). The SGLT2 inhibitor empagliflozin attenuates interleukin-17A-induced human aortic smooth muscle cell proliferation and migration by targeting TRAF3IP2/ROS/NLRP3/Caspase-1-dependent IL-1β and IL-18 secretion. Cell Signalling, 77, 109825. 10.1016/j.cellsig.2020.109825
Toldo, S., & Abbate, A. (2024). The role of the NLRP3 inflammasome and pyroptosis in cardiovascular diseases. Nature Reviews Cardiology, 21, 219–237. 10.1038/s41569-023-00946-3
Wang, D. S., Yan, L. Y., Yang, D. Z., Lyu, Y., Fang, L. H., Wang, S. B., et al. (2020). Formononetin ameliorates myocardial ischemia/reperfusion injury in rats by suppressing the ROS-TXNIP-NLRP3 pathway. Biochemical and Biophysical Research Communications, 525, 759–766. 10.1016/j.bbrc.2020.02.147
Wang, Y., Tang, C., & Zhang, H. (2015). Hepatoprotective effects of kaempferol 3-O-rutinoside and kaempferol 3-O-glucoside from Carthamus tinctorius L. on CCl4-induced oxidative liver injury in mice. Journal of Food and Drug Analysis, 23, 310–317. 10.1016/j.jfda.2014.10.002
Xi, X., Zhang, R., Chi, Y., Zhu, Z., Sun, R., & Gong, W. (2024). TXNIP regulates NLRP3 inflammasome-induced pyroptosis related to aging via cAMP/PKA and PI3K/Akt signaling pathways. Molecular Neurobiology, doi: 10.1007/s12035-024-04089-5 [Online ahead of print]. 10.1007/s12035-024-04089-5
Yang, Y. L., Zhao, C. Z., Zhao, C. C., Wen, Z. Y., Ma, Y. Y., & Zhao, X. N. (2024). Ling-Gui-Zhu-Gan decoction protects against doxorubicin-induced myocardial injury by downregulating ferroptosis. Journal of Pharmacy and Pharmacology, 76, 405–415. 10.1093/jpp/rgae005
Yoshihara, E., Matsuo, Y., Masaki, S., Chen, Z., Tian, H., Masutani, H., et al. (2024). Redoxisome update: TRX and TXNIP/TBP2-dependent regulation of NLRP-1/NLRP-3 inflammasome. Antioxidants & Redox Signaling, 40, 595–597. 10.1089/ars.2024.0549
Zhang, Y., Zhao, H., Fu, X., Wang, K., Yang, J., Zhang, X., et al. (2024). The role of hydrogen sulfide regulation of pyroptosis in different pathological processes. European Journal of Medicinal Chemistry, 268, 116254. 10.1016/j.ejmech.2024.116254
Zhao, H., Lin, X., Chen, Q., Wang, X., Wu, Y., & Zhao, X. (2023). Quercetin inhibits the NOX2/ROS-mediated NF-κB/TXNIP signaling pathway to ameliorate pyroptosis of cardiomyocytes to relieve sepsis-induced cardiomyopathy. Toxicology and Applied Pharmacology, 477, 116672. 10.1016/j.taap.2023.116672
Zheng, Z., Lei, C., Liu, H., Jiang, M., Zhou, Z., Zhao, Y., et al. (2022). A ROS-responsive liposomal composite hydrogel integrating improved mitochondrial function and pro-angiogenesis for efficient treatment of myocardial infarction. Advanced Healthcare Materials, 11, e2200990. 10.1002/adhm.202200990
Zhou, P., Ma, Y. Y., Zhao, X. N., & Hua F. (2023). Phytochemicals as potential target on thioredoxin-interacting protein (TXNIP) for the treatment of cardiovascular diseases. Inflammopharmacology, 31, 207–220. 10.1007/s10787-022-01130-8
Zhu, L., Yang, Y. M., Huang, Y., Xie, H. K., Luo, Y., Li, C., et al. (2024). Shexiang Tongxin dropping pills protect against ischemic stroke-induced cerebral microvascular dysfunction via suppressing TXNIP/NLRP3 signaling pathway. Journal of Ethnopharmacology, 322, 117567. 10.1016/j.jep.2023.117567
Article Sidebar
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Copyright Agreement with Authors
Before publication, after the acceptance of the manuscript, Authors have to sign a Publication Agreement with "Italian Journal of Food Science", granting and assigning to "Italian Journal of Food Science" the perpetual right to distribute the work free of charge by any means and in any parts of the world, including the communication to the public through the journal website.
License for Published Contents
http://creativecommons.org/licenses/by-nc-nd/4.0/