Current Computer-Aided Drug DesignCurrent Computer-Aided Drug DesignCurrent Computer-Aided Drug Design1573-40991875-6697Bentham Science64454010.2174/0115734099259071231115072421ChemistryResearch ArticleNetwork Pharmacology and Bioinformatics Analyses Identify the Core Genes and Pyroptosis-Related Mechanisms of Nardostachys Chinensis for Atrial FibrillationXueWeiqiinfo@benthamscience.netLuoYuaninfo@benthamscience.netHeWeifenginfo@benthamscience.netYanMengyuaninfo@benthamscience.netZhaoHuanyiinfo@benthamscience.netQingLijininfo@benthamscience.netFirst School of Clinical Medicine, Guangzhou University of Chinese Medicine, First Affiliated Hospital of Guangzhou University of Chinese Medicine010720242071070108607012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://rjeid.com/1573-4099/article/view/644540

Background:Nardostachys chinensis is an herbal medicine widely used in the treatment of atrial fibrillation (AF), but the mechanism is unclear.

Objective:To explore the molecular mechanism of N. chinensis against AF.

Methods:The TCMSP was used to screen the active N. chinensis compounds and their targets. Differentially expressed genes (DEGs) for AF were identified using open-access databases. Using Venn diagrams, the cross-targets of N. chinensis, pyroptosis, and AF were obtained. The genes underwent molecular docking as well as gene set enrichment analysis (GSEA). A nomogram based on candidate genes was constructed and evaluated with the clinical impact curve. After that, the immune infiltration of the dataset was analyzed by single sample GSEA (ssGSEA). Finally, microRNAs (miRNAs) and transcription factors (TFs) were predicted based on candidate genes.

Results:Tumor necrosis factor (TNF) and caspase-8 (CASP8) were obtained as candidate genes by taking the intersection of DEGs, targets of N. chinensis, and pyroptosis-related genes. Tolllike receptor (TLR) and peroxisome proliferator-activated receptor (PPAR) signaling pathways were linked to candidate genes. Additionally, immune cell infiltration analysis revealed that CASP8 was associated with natural killer T cells, natural killer cells, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSC), macrophages, CD8 T cells, and CD4 T cells. Finally, miR-34a-5p and several TFs were found to regulate the expression of CASP8 and TNF.

Conclusion:CASP8 and TNF are potential targets of N. chinensis intervention in pyroptosisrelated AF, and the TLR/NLRP3 signaling pathway may be associated with this process.

Atrial fibrillationNardostachys chinensispyroptosisbioinformatic analysisnetwork pharmacologyimmune cell infiltration.Chugh, S.S.; Havmoeller, R.; Narayanan, K.; Singh, D.; Rienstra, M.; Benjamin, E.J.; Gillum, R.F.; Kim, Y.H.; McAnulty, J.H., Jr; Zheng, Z.J.; Forouzanfar, M.H.; Naghavi, M.; Mensah, G.A.; Ezzati, M.; Murray, C.J.L. Worldwide epidemiology of atrial fibrillation: A Global Burden of Disease 2010 Study. Circulation, 2014, 129(8), 837-847. doi: 10.1161/CIRCULATIONAHA.113.005119 PMID: 24345399Kirchhof, P.; Benussi, S.; Kotecha, D.; Ahlsson, A.; Atar, D.; Casadei, B.; Castella, M.; Diener, H.C.; Heidbuchel, H.; Hendriks, J.; Hindricks, G.; Manolis, A.S.; Oldgren, J.; Popescu, B.A.; Schotten, U.; Van Putte, B.; Vardas, P.; Agewall, S.; Camm, J.; Baron Esquivias, G.; Budts, W.; Carerj, S.; Casselman, F.; Coca, A.; De Caterina, R.; Deftereos, S.; Dobrev, D.; Ferro, J.M.; Filippatos, G.; Fitzsimons, D.; Gorenek, B.; Guenoun, M.; Hohnloser, S.H.; Kolh, P.; Lip, G.Y.H.; Manolis, A.; McMurray, J.; Ponikowski, P.; Rosenhek, R.; Ruschitzka, F.; Savelieva, I.; Sharma, S.; Suwalski, P.; Tamargo, J.L.; Taylor, C.J.; Van Gelder, I.C.; Voors, A.A.; Windecker, S.; Zamorano, J.L.; Zeppenfeld, K. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace, 2016, 18(11), 1609-1678. doi: 10.1093/europace/euw295 PMID: 27567465Camm, A.J.; Lip, G.Y.H.; De Caterina, R.; Savelieva, I.; Atar, D.; Hohnloser, S.H.; Hindricks, G.; Kirchhof, P.; Bax, J.J.; Baumgartner, H.; Ceconi, C.; Dean, V.; Deaton, C.; Fagard, R.; Funck-Brentano, C.; Hasdai, D.; Hoes, A.; Kirchhof, P.; Knuuti, J.; Kolh, P.; McDonagh, T.; Moulin, C.; Popescu, B.A.; Reiner, Ž.; Sechtem, U.; Sirnes, P.A.; Tendera, M.; Torbicki, A.; Vahanian, A.; Windecker, S.; Vardas, P.; Al-Attar, N.; Alfieri, O.; Angelini, A.; Blömstrom-Lundqvist, C.; Colonna, P.; De Sutter, J.; Ernst, S.; Goette, A.; Gorenek, B.; Hatala, R.; Heidbüchel, H.; Heldal, M.; Kristensen, S.D.; Kolh, P.; Le Heuzey, J-Y.; Mavrakis, H.; Mont, L.; Filardi, P.P.; Ponikowski, P.; Prendergast, B.; Rutten, F.H.; Schotten, U.; Van Gelder, I.C.; Verheugt, F.W.A. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation. Eur. Heart J., 2012, 33(21), 2719-2747. doi: 10.1093/eurheartj/ehs253 PMID: 22922413Trigo, P.; Fischer, G.W. Managing atrial fibrillation in the elderly: Critical appraisal of dronedarone. Clin. Interv. Aging, 2012, 7, 1-13. PMID: 22291468Henry, L.; Ad, N. The surgical treatment for atrial fibrillation: Ablation technology and surgical approaches. Rambam Maimonides ME., 2013, 4(3), 15-19.Katz, E.S.; Tsiamtsiouris, T.; Applebaum, R.M.; Schwartzbard, A.; Tunick, P.A.; Kronzon, I. Surgical left atrial appendage ligation is frequently incomplete: A transesophageal echocardiographic study. J. Am. Coll. Cardiol., 2000, 36(2), 468-471. doi: 10.1016/S0735-1097(00)00765-8 PMID: 10933359Wijesurendra, R.S.; Casadei, B. Mechanisms of atrial fibrillation. Heart, 2019, 105(24), 1860-1867. doi: 10.1136/heartjnl-2018-314267 PMID: 31444267Andrade, J.; Khairy, P.; Dobrev, D.; Nattel, S. The clinical profile and pathophysiology of atrial fibrillation: Relationships among clinical features, epidemiology, and mechanisms. Circ. Res., 2014, 114(9), 1453-1468. doi: 10.1161/CIRCRESAHA.114.303211 PMID: 24763464Khoury, M.K.; Gupta, K.; Franco, S.R.; Liu, B. Necroptosis in the pathophysiology of disease. Am. J. Pathol., 2020, 190(2), 272-285. doi: 10.1016/j.ajpath.2019.10.012 PMID: 31783008Zychlinsky, A.; Prevost, M.C.; Sansonetti, P.J. Shigella flexneri induces apoptosis in infected macrophages. Nature, 1992, 358(6382), 167-169. doi: 10.1038/358167a0 PMID: 1614548D’Souza, C.A.; Heitman, J. Dismantling the cryptococcus coat. Trends Microbiol., 2001, 9(3), 112-113. doi: 10.1016/S0966-842X(00)01945-4 PMID: 11303499Frank, D.; Vince, J.E. Pyroptosis versus necroptosis: Similarities, differences, and crosstalk. Cell Death Differ., 2019, 26(1), 99-114. doi: 10.1038/s41418-018-0212-6 PMID: 30341423Martinon, F.; Burns, K.; Tschopp, J. The inflammasome. Mol. Cell, 2002, 10(2), 417-426. doi: 10.1016/S1097-2765(02)00599-3 PMID: 12191486Xia, S.; Hollingsworth, L.R., IV; Wu, H. Mechanism and regulation of gasdermin-mediated cell death. Cold Spring Harb. Perspect. Biol., 2020, 12(3), a036400. doi: 10.1101/cshperspect.a036400 PMID: 31451512Newton, K.; Wickliffe, K.E.; Maltzman, A.; Dugger, D.L.; Reja, R.; Zhang, Y.; Roose-Girma, M.; Modrusan, Z.; Sagolla, M.S.; Webster, J.D.; Dixit, V.M. Activity of caspase-8 determines plasticity between cell death pathways. Nature, 2019, 575(7784), 679-682. doi: 10.1038/s41586-019-1752-8 PMID: 31723262Moujalled, D.; Strasser, A.; Liddell, J.R. Molecular mechanisms of cell death in neurological diseases. Cell Death Differ., 2021, 28(7), 2029-2044. doi: 10.1038/s41418-021-00814-y PMID: 34099897Sharma, B.R.; Kanneganti, T.D. NLRP3 inflammasome in cancer and metabolic diseases. Nat. Immunol., 2021, 22(5), 550-559. doi: 10.1038/s41590-021-00886-5 PMID: 33707781Shen, H.H.; Yang, Y.X.; Meng, X.; Luo, X.Y.; Li, X.M.; Shuai, Z.W.; Ye, D.Q.; Pan, H.F. NLRP3: A promising therapeutic target for autoimmune diseases. Autoimmun. Rev., 2018, 17(7), 694-702. doi: 10.1016/j.autrev.2018.01.020 PMID: 29729449Zhaolin, Z.; Guohua, L.; Shiyuan, W.; Zuo, W. Role of pyroptosis in cardiovascular disease. Cell Prolif., 2019, 52(2), e12563. doi: 10.1111/cpr.12563 PMID: 30525268Alvarez-Erviti, L.; Couch, Y.; Richardson, J.; Cooper, J.M.; Wood, M.J.A. Alpha-synuclein release by neurons activates the inflammatory response in a microglial cell line. Neurosci. Res., 2011, 69(4), 337-342. doi: 10.1016/j.neures.2010.12.020 PMID: 21255620Singh, P.K.; Muqit, M.M.K. Parkinson’s: A disease of aberrant vesicle trafficking. Annu. Rev. Cell Dev. Biol., 2020, 36(1), 237-264. doi: 10.1146/annurev-cellbio-100818-125512 PMID: 32749865Mao, Z.; Liu, C.; Ji, S.; Yang, Q.; Ye, H.; Han, H.; Xue, Z. The NLRP3 inflammasome is involved in the pathogenesis of Parkinson’s disease in rats. Neurochem. Res., 2017, 42(4), 1104-1115. doi: 10.1007/s11064-017-2185-0 PMID: 28247334Hou, J.; Zhao, R.; Xia, W.; Chang, C.W.; You, Y.; Hsu, J.M.; Nie, L.; Chen, Y.; Wang, Y.C.; Liu, C.; Wang, W.J.; Wu, Y.; Ke, B.; Hsu, J.L.; Huang, K.; Ye, Z.; Yang, Y.; Xia, X.; Li, Y.; Li, C.W.; Shao, B.; Tainer, J.A.; Hung, M.C. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. Nat. Cell Biol., 2020, 22(10), 1264-1275. doi: 10.1038/s41556-020-0575-z PMID: 32929201Wei, Q.; Mu, K.; Li, T.; Zhang, Y.; Yang, Z.; Jia, X.; Zhao, W.; Huai, W.; Guo, P.; Han, L. Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression. Lab. Invest., 2014, 94(1), 52-62. doi: 10.1038/labinvest.2013.126 PMID: 24166187Yu, P; Zhang, X; Liu, N; Tang, L; Peng, C; Chen, X. Pyroptosis: Mechanisms and diseases. Signal Transduct Tar., 2021, 6(1) doi: 10.1038/s41392-021-00507-5Xu, Y.J.; Zheng, L.; Hu, Y.W.; Wang, Q. Pyroptosis and its relationship to atherosclerosis. Clin. Chim. Acta, 2018, 476, 28-37. doi: 10.1016/j.cca.2017.11.005 PMID: 29129476Yang, F.; Qin, Y.; Lv, J.; Wang, Y.; Che, H.; Chen, X.; Jiang, Y.; Li, A.; Sun, X.; Yue, E.; Ren, L.; Li, Y.; Bai, Y.; Wang, L. Silencing long non-coding RNA Kcnq1ot1 alleviates pyroptosis and fibrosis in diabetic cardiomyopathy. Cell Death Dis., 2018, 9(10), 1000. doi: 10.1038/s41419-018-1029-4 PMID: 30250027Hu, Y.F.; Chen, Y.J.; Lin, Y.J.; Chen, S.A. Inflammation and the pathogenesis of atrial fibrillation. Nat. Rev. Cardiol., 2015, 12(4), 230-243. doi: 10.1038/nrcardio.2015.2 PMID: 25622848Zhang, J.; Qiang, C.C.; Li, W.J.; Liu, L.J.; Lin, X.X.; Cheng, Y.J.; Tang, K.; Yao, F.J.; Wu, S.H. Effects of Nardostachys chinensis on spontaneous ventricular arrhythmias in rats with acute myocardial infarction. J. Cardiovasc. Pharmacol., 2014, 64(2), 127-133. doi: 10.1097/FJC.0000000000000096 PMID: 24662492Li, M; Xu, X; Yang, X; Kwong, JSW; Shang, H The cardioprotective and antiarrhythmic effects of Nardostachys chinensis in animal and cell experiments. BMC Complem Altern M., 2017, 17(1) doi: 10.1186/s12906-017-1910-1Abbasi, W.M.; Ahmad, S.; Perveen, S.; Rehman, T. Preliminary phytochemical analysis and in vivo evaluation of antipyretic effects of hydro-methanolic extract of Cleome scaposa leaves. J. Tradit. Complement. Med., 2018, 8(1), 147-149. doi: 10.1016/j.jtcme.2017.05.004 PMID: 29322003Hopkins, A.L. Network pharmacology. Nat. Biotechnol., 2007, 25(10), 1110-1111. doi: 10.1038/nbt1007-1110 PMID: 17921993Liu, H.; Wang, J.; Zhou, W.; Wang, Y.; Yang, L. Systems approaches and polypharmacology for drug discovery from herbal medicines: An example using licorice. J. Ethnopharmacol., 2013, 146(3), 773-793. doi: 10.1016/j.jep.2013.02.004 PMID: 23415946Karki, R.; Kanneganti, T.D. Diverging inflammasome signals in tumorigenesis and potential targeting. Nat. Rev. Cancer, 2019, 19(4), 197-214. doi: 10.1038/s41568-019-0123-y PMID: 30842595Man, S.M.; Kanneganti, T.D. Regulation of inflammasome activation. Immunol. Rev., 2015, 265(1), 6-21. doi: 10.1111/imr.12296 PMID: 25879280Xia, X.; Wang, X.; Cheng, Z.; Qin, W.; Lei, L.; Jiang, J.; Hu, J. The role of pyroptosis in cancer: Pro-cancer or pro-"host"? Cell Death Dis., 2019, 10(9), 650. doi: 10.1038/s41419-019-1883-8 PMID: 31501419Zhou, G.; Soufan, O.; Ewald, J.; Hancock, R.E.W.; Basu, N.; Xia, J. NetworkAnalyst 3.0: A visual analytics platform for comprehensive gene expression profiling and meta-analysis. Nucleic Acids Res., 2019, 47(W1), W234-41.Blaauw, Y.; Van Gelder, I.C.; Crijns, H.J. Treatment of atrial fibrillation. Br. Heart J., 2002, 88(4), 432-437. doi: 10.1136/heart.88.4.432 PMID: 12231613Jiang, X.; Luo, Y.; Wang, X.; Chen, Y.; Wang, T.; He, J.; Xia, Y.; Zhao, J.; Chai, X.; Yao, L.; Liu, C.; Chen, Y. Investigating the efficiency and tolerability of traditional Chinese formulas combined with antiarrhythmic agents for paroxysmal atrial fibrillation: A systematic review and Bayesian network meta-analysis. Phytomedicine, 2022, 94, 153832. doi: 10.1016/j.phymed.2021.153832 PMID: 34781230Kalifa, J.; Avula, U.M.R. The Chinese herb extract Wenxin Keli: Atrial selectivity from the Far East. Heart Rhythm, 2012, 9(1), 132-133. doi: 10.1016/j.hrthm.2011.11.030 PMID: 22116050Liu, Y.; Zhang, Z.; Yang, Y.; Zhang, N.; Li, G.; Liu, T. The Chinese herb extract Wenxin Keli: A promising agent for the management of atrial fibrillation. Int. J. Cardiol., 2016, 203, 614-615. doi: 10.1016/j.ijcard.2015.10.211 PMID: 26580340Ma, J.; Yin, C.; Ma, S.; Qiu, H.; Zheng, C. Chen, Q Shensong Yangxin capsule reduces atrial fibrillation susceptibility by inhibiting atrial fibrosis in rats with post-myocardial infarction heart failure. Drug Des. Devel. Ther., 2018, 12, 3407-3418. doi: 10.2147/DDDT.S182834Yang, H.J.; Kong, B.; Shuai, W.; Zhang, J.; Huang, H. Shensong Yangxin attenuates metabolic syndrome-induced atrial fibrillation via inhibition of ferroportin-mediated intracellular iron overload. Phytomedicine, 2022, 101, 154086. doi: 10.1016/j.phymed.2022.154086 PMID: 35421806Shalini, S.; Dorstyn, L.; Dawar, S.; Kumar, S. Old, new and emerging functions of caspases. Cell Death Differ., 2015, 22(4), 526-539. doi: 10.1038/cdd.2014.216 PMID: 25526085Simpson, C.D.; Anyiwe, K.; Schimmer, A.D. Anoikis resistance and tumor metastasis. Cancer Lett., 2008, 272(2), 177-185. doi: 10.1016/j.canlet.2008.05.029 PMID: 18579285Fritsch, M.; Günther, S.D.; Schwarzer, R.; Albert, M.C.; Schorn, F.; Werthenbach, J.P.; Schiffmann, L.M.; Stair, N.; Stocks, H.; Seeger, J.M.; Lamkanfi, M.; Krönke, M.; Pasparakis, M.; Kashkar, H. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature, 2019, 575(7784), 683-687. doi: 10.1038/s41586-019-1770-6 PMID: 31748744Mandal, R.; Barrón, J.C.; Kostova, I.; Becker, S.; Strebhardt, K. Caspase-8: The double-edged sword. Biochimica et Biophysica Acta (BBA) -. Rev. Can., 2020, 1873(2), 188357.Newton, K.; Wickliffe, K.E.; Dugger, D.L.; Maltzman, A.; Roose-Girma, M.; Dohse, M.; Kőműves, L.; Webster, J.D.; Dixit, V.M. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. Nature, 2019, 574(7778), 428-431. doi: 10.1038/s41586-019-1548-x PMID: 31511692Orning, P.; Weng, D.; Starheim, K.; Ratner, D.; Best, Z.; Lee, B.; Brooks, A.; Xia, S.; Wu, H.; Kelliher, M.A.; Berger, S.B.; Gough, P.J.; Bertin, J.; Proulx, M.M.; Goguen, J.D.; Kayagaki, N.; Fitzgerald, K.A.; Lien, E. Pathogen blockade of TAK1 triggers caspase-8–dependent cleavage of gasdermin D and cell death. Science, 2018, 362(6418), 1064-1069. doi: 10.1126/science.aau2818 PMID: 30361383Charitakis, E.; Karlsson, L.O.; Papageorgiou, J.M.; Walfridsson, U.; Carlhäll, C.J. Echocardiographic and biochemical factors predicting arrhythmia recurrence after catheter ablation of atrial fibrillation-an observational study. Front. Physiol., 2019, 10, 1215. doi: 10.3389/fphys.2019.01215 PMID: 31632285Hiram, R.; Xiong, F.; Naud, P.; Xiao, J.; Sirois, M.; Tanguay, J.F.; Tardif, J.C.; Nattel, S. The inflammation-resolution promoting molecule resolvin-D1 prevents atrial proarrhythmic remodelling in experimental right heart disease. Cardiovasc. Res., 2021, 117(7), 1776-1789. doi: 10.1093/cvr/cvaa186 PMID: 32866246Kalliolias, G.D.; Ivashkiv, L.B. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat. Rev. Rheumatol., 2016, 12(1), 49-62. doi: 10.1038/nrrheum.2015.169 PMID: 26656660Micheau, O.; Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell, 2003, 114(2), 181-190. doi: 10.1016/S0092-8674(03)00521-X PMID: 12887920Liew, R.; Khairunnisa, K.; Gu, Y.; Tee, N.; Yin, N.O.; Naylynn, T.M.; Moe, K.T. Role of tumor necrosis factor-α in the pathogenesis of atrial fibrosis and development of an arrhythmogenic substrate. Circ. J., 2013, 77(5), 1171-1179. doi: 10.1253/circj.CJ-12-1155 PMID: 23370453Ren, M.; Li, X.; Hao, L.; Zhong, J. Role of tumor necrosis factor alpha in the pathogenesis of atrial fibrillation: A novel potential therapeutic target? Ann. Med., 2015, 47(4), 316-324. doi: 10.3109/07853890.2015.1042030 PMID: 25982799Ye, T.; Zhang, C.; Wu, G.; Wan, W.; Liang, J.; Liu, X.; Liu, D.; Yang, B. Pinocembrin attenuates autonomic dysfunction and atrial fibrillation susceptibility via inhibition of the NF-κB/TNF-α pathway in a rat model of myocardial infarction. Int. Immunopharmacol., 2019, 77, 105926. doi: 10.1016/j.intimp.2019.105926 PMID: 31704291Ding, S.; Liu, D.; Wang, L.; Wang, G.; Zhu, Y. Inhibiting MicroRNA-29a protects myocardial ischemia-reperfusion injury by targeting SIRT1 and suppressing oxidative stress and NLRP3-mediated pyroptosis pathway. J. Pharmacol. Exp. Ther., 2020, 372(1), 128-135. doi: 10.1124/jpet.119.256982 PMID: 31481517Li, Z.; Liu, T.; Feng, Y.; Tong, Y.; Jia, Y.; Wang, C. PPARγ alleviates sepsis-induced liver injury by inhibiting hepatocyte pyroptosis via inhibition of the ROS/TXNIP/NLRP3 signaling pathway. Oxid. Med. Cell. Longev., 2022, 2022, 1-15. doi: 10.1155/2022/8999899Wang, N.; Kong, R.; Han, W.; Bao, W.; Shi, Y.; Ye, L.; Lu, J. Honokiol alleviates ulcerative colitis by targeting PPAR-γ–TLR4–NF-κB signaling and suppressing gasdermin-D-mediated pyroptosis in vivo and in vitro. Int. Immunopharmacol., 2022, 111, 109058. doi: 10.1016/j.intimp.2022.109058 PMID: 35901530Pinzi, L.; Rastelli, G. Molecular docking: Shifting paradigms in drug discovery. Int. J. Mol. Sci., 2019, 20(18), 4331. doi: 10.3390/ijms20184331 PMID: 31487867Rehman, T.; Ahmad, S. Nardostachys chinensis Batalin: A review of traditional uses, phytochemistry, and pharmacology. Phytother. Res., 2019, 33(10), 2622-2648. doi: 10.1002/ptr.6447 PMID: 31359527Li, G.R.; Wang, H.B.; Qin, G.W.; Jin, M.W.; Tang, Q.; Sun, H.Y.; Du, X.L.; Deng, X.L.; Zhang, X.H.; Chen, J.B.; Chen, L.; Xu, X.H.; Cheng, L.C.; Chiu, S.W.; Tse, H.F.; Vanhoutte, P.M.; Lau, C.P. Acacetin, a natural flavone, selectively inhibits human atrial repolarization potassium currents and prevents atrial fibrillation in dogs. Circulation, 2008, 117(19), 2449-2457. doi: 10.1161/CIRCULATIONAHA.108.769554 PMID: 18458165Zhu, Y.; Bu, J.; Shi, S.; Wang, H-Q.; Niu, X-S.; Zhao, Z-F.; Wu, W-D.; Zhang, X-L.; Ma, Z.; Zhang, Y.J.; Zhang, H. Acacetin protects against cerebral ischemia-reperfusion injury via the NLRP3 signaling pathway. Neural Regen. Res., 2019, 14(4), 605-612. doi: 10.4103/1673-5374.247465 PMID: 30632500Bak, M.J.; Hong, S.G.; Lee, J.W.; Jeong, W.S. Red ginseng marc oil inhibits iNOS and COX-2 via NFκB and p38 pathways in LPS-stimulated RAW 264.7 macrophages. Molecules, 2012, 17(12), 13769-13786. doi: 10.3390/molecules171213769 PMID: 23174895Li, W.; Cao, T.; Luo, C.; Cai, J.; Zhou, X.; Xiao, X.; Liu, S. Crosstalk between ER stress, NLRP3 inflammasome, and inflammation. Appl. Microbiol. Biotechnol., 2020, 104(14), 6129-6140. doi: 10.1007/s00253-020-10614-y PMID: 32447438Liu, H.; Zhan, X.; Xu, G.; Wang, Z.; Li, R.; Wang, Y.; Qin, Q.; Shi, W.; Hou, X.; Yang, R.; Wang, J.; Xiao, X.; Bai, Z. Cryptotanshinone specifically suppresses NLRP3 inflammasome activation and protects against inflammasome-mediated diseases. Pharmacol. Res., 2021, 164, 105384. doi: 10.1016/j.phrs.2020.105384 PMID: 33352229Han, X.; Wu, Y.C.; Meng, M.; Sun, Q.S.; Gao, S.M.; Sun, H. Linarin prevents LPS induced acute lung injury by suppressing oxidative stress and inflammation via inhibition of TXNIP/NLRP3 and NF κB pathways. Int. J. Mol. Med., 2018, 42(3), 1460-1472. doi: 10.3892/ijmm.2018.3710 PMID: 29845284Coll, R.C.; Schroder, K.; Pelegrín, P. NLRP3 and pyroptosis blockers for treating inflammatory diseases. Trends Pharmacol. Sci., 2022, 43(8), 653-668. doi: 10.1016/j.tips.2022.04.003 PMID: 35513901Ajoolabady, A.; Nattel, S.; Lip, G.Y.H.; Ren, J. Inflammasome signaling in atrial fibrillation. J. Am. Coll. Cardiol., 2022, 79(23), 2349-2366. doi: 10.1016/j.jacc.2022.03.379 PMID: 35680186Yao, C.; Veleva, T.; Scott, L., Jr; Cao, S.; Li, L.; Chen, G.; Jeyabal, P.; Pan, X.; Alsina, K.M.; Abu-Taha, I.; Ghezelbash, S.; Reynolds, C.L.; Shen, Y.H.; LeMaire, S.A.; Schmitz, W.; Müller, F.U.; El-Armouche, A.; Tony Eissa, N.; Beeton, C.; Nattel, S.; Wehrens, X.H.T.; Dobrev, D.; Li, N. Enhanced cardiomyocyte NLRP3 inflammasome signaling promotes atrial fibrillation. Circulation, 2018, 138(20), 2227-2242. doi: 10.1161/CIRCULATIONAHA.118.035202 PMID: 29802206Zhang, Y.; Zhang, S.; Li, B.; Luo, Y.; Gong, Y.; Jin, X.; Zhang, J.; Zhou, Y.; Zhuo, X.; Wang, Z.; Zhao, X.; Han, X.; Gao, Y.; Yu, H.; Liang, D.; Zhao, S.; Sun, D.; Wang, D.; Xu, W.; Qu, G.; Bo, W.; Li, D.; Wu, Y.; Li, Y. Gut microbiota dysbiosis promotes age-related atrial fibrillation by lipopolysaccharide and glucose-induced activation of NLRP3-inflammasome. Cardiovasc. Res., 2022, 118(3), 785-797. doi: 10.1093/cvr/cvab114 PMID: 33757127Lawlor, K.E.; Khan, N.; Mildenhall, A.; Gerlic, M.; Croker, B.A.; D’Cruz, A.A.; Hall, C.; Kaur Spall, S.; Anderton, H.; Masters, S.L.; Rashidi, M.; Wicks, I.P.; Alexander, W.S.; Mitsuuchi, Y.; Benetatos, C.A.; Condon, S.M.; Wong, W.W.L.; Silke, J.; Vaux, D.L.; Vince, J.E. RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat. Commun., 2015, 6(1), 6282. doi: 10.1038/ncomms7282 PMID: 25693118Zhou, R.; Jin, D.; Zhang, Y.; Duan, L.; Zhang, Y.; Duan, Y.; Kang, X.; Lian, F. Investigating the mechanisms of pollen typhae in the treatment of diabetic retinopathy based on network pharmacology and molecular docking. Evid. Based Complement. Alternat. Med., 2022, 2022, 1-14. doi: 10.1155/2022/5728408 PMID: 35024051Chen, H.; Deng, Y.; Gan, X.; Li, Y.; Huang, W.; Lu, L.; Wei, L.; Su, L.; Luo, J.; Zou, B.; Hong, Y.; Cao, Y.; Liu, Y.; Chi, W. NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma. Mol. Neurodegener., 2020, 15(1), 26. doi: 10.1186/s13024-020-00372-w PMID: 32295623Messaoud-Nacer, Y.; Culerier, E.; Rose, S.; Maillet, I.; Rouxel, N.; Briault, S.; Ryffel, B.; Quesniaux, V.F.J.; Togbe, D. STING agonist diABZI induces PANoptosis and DNA mediated acute respiratory distress syndrome (ARDS). Cell Death Dis., 2022, 13(3), 269. doi: 10.1038/s41419-022-04664-5 PMID: 35338116Roy, P.; Orecchioni, M.; Ley, K. How the immune system shapes atherosclerosis: Roles of innate and adaptive immunity. Nat. Rev. Immunol., 2022, 22(4), 251-265. doi: 10.1038/s41577-021-00584-1Poli, A.; Michel, T.; Thérésine, M.; Andrès, E.; Hentges, F.; Zimmer, J. CD56 bright natural killer (NK) cells: An important NK cell subset. Immunology, 2009, 126(4), 458-465. doi: 10.1111/j.1365-2567.2008.03027.x PMID: 19278419Zhang, Z.; Zhang, Y.; Xia, S.; Kong, Q.; Li, S.; Liu, X. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature, 2020, 579(7799), 415-420.Kazem, N.; Sulzgruber, P.; Thaler, B.; Baumgartner, J.; Koller, L.; Laufer, G.; Steinlechner, B.; Hohensinner, P.; Wojta, J.; Niessner, A. CD8+CD28null T lymphocytes are associated with the development of atrial fibrillation after elective cardiac surgery. Thromb. Haemost., 2020, 120(8), 1182-1187. doi: 10.1055/s-0040-1713096 PMID: 32594507Hammer, A.; Niessner, A.; Sulzgruber, P. The impact of CD4+CD28null T lymphocytes on atrial fibrillation: a potential pathophysiological pathway. Inflamm. Res., 2021, 70(10-12), 1011-1014. doi: 10.1007/s00011-021-01502-w PMID: 34536081Jiao, Y.; Zhang, T.; Zhang, C.; Ji, H.; Tong, X.; Xia, R.; Wang, W.; Ma, Z.; Shi, X. Exosomal miR-30d-5p of neutrophils induces M1 macrophage polarization and primes macrophage pyroptosis in sepsis-related acute lung injury. Crit. Care, 2021, 25(1), 356. doi: 10.1186/s13054-021-03775-3 PMID: 34641966Sun, Z.; Zhou, D.; Xie, X.; Wang, S.; Wang, Z.; Zhao, W.; Xu, H.; Zheng, L. Cross-talk between macrophages and atrial myocytes in atrial fibrillation. Basic Res. Cardiol., 2016, 111(6), 63. doi: 10.1007/s00395-016-0584-z PMID: 27660282Zhang, Z.; Zhang, D.; Xie, K.; Wang, C.; Xu, F. Luteolin activates Tregs to promote IL-10 expression and alleviating caspase-11-dependent pyroptosis in sepsis-induced lung injury. Int. Immunopharmacol., 2021, 99, 107914. doi: 10.1016/j.intimp.2021.107914 PMID: 34246059Yan, W.; Zhao, Y.; Xie, K.; Xing, Y.; Xu, F. Aspergillus fumigatus influences gasdermin-d-dependent pyroptosis of the lung via regulating toll-like receptor 2-mediated regulatory T cell differentiation. J. Immunol. Res., 2021, 2021, 1-14. doi: 10.1155/2021/5538612 PMID: 34222495Chen, Y.; Chang, G.; Chen, X.; Li, Y.; Li, H.; Cheng, D.; Tang, Y.; Sang, H. IL-6-miR-210 suppresses regulatory T cell function and promotes atrial fibrosis by targeting foxp3. Mol. Cells, 2020, 43(5), 438-447. PMID: 32345003Zhang, Y.; Sun, D.; Zhao, X.; Luo, Y.; Yu, H.; Zhou, Y.; Gao, Y.; Han, X.; Duan, Y.; Fang, N.; Duan, X.; Li, T.; Zhang, S.; Gong, Y.; Li, Y. Bacteroides fragilis prevents aging-related atrial fibrillation in rats via regulatory T cells-mediated regulation of inflammation. Pharmacol. Res., 2022, 177, 106141. doi: 10.1016/j.phrs.2022.106141 PMID: 35202820Du, Y.; Du, L.; He, Z.; Zhou, J.; Wen, C.; Zhang, Y. Cryptotanshinone ameliorates the pathogenesis of systemic lupus erythematosus by blocking T cell proliferation. Int. Immunopharmacol., 2019, 74, 105677. doi: 10.1016/j.intimp.2019.105677 PMID: 31177018Zhao, N.; Dong, Q.; Fu, X.X.; Du, L.L.; Cheng, X.; Du, Y.M.; Liao, Y.H. Acacetin blocks kv1.3 channels and inhibits human T cell activation. Cell. Physiol. Biochem., 2014, 34(4), 1359-1372. doi: 10.1159/000366343 PMID: 25301362Liu, L.; Yang, J.; Zu, B.; Wang, J.; Sheng, K.; Zhao, L.; Xu, W. Acacetin regulated the reciprocal differentiation of Th17 cells and Treg cells and mitigated the symptoms of collagen‐induced arthritis in mice. Scand. J. Immunol., 2018, 88(4), e12712. doi: 10.1111/sji.12712 PMID: 30176062Chen, X.; Zhang, S.; Xuan, Z.; Ge, D.; Chen, X.; Zhang, J.; Wang, Q.; Wu, Y.; Liu, B. The phenolic fraction of mentha haplocalyx and its constituent linarin ameliorate inflammatory response through inactivation of NF-κB and MAPKs in lipopolysaccharide-induced RAW264.7 cells. Molecules, 2017, 22(5), 811. doi: 10.3390/molecules22050811 PMID: 28509854Ren, J.; Yue, B.; Wang, H.; Zhang, B.; Luo, X.; Yu, Z.; Zhang, J.; Ren, Y.; Mani, S.; Wang, Z.; Dou, W. Acacetin ameliorates experimental colitis in mice via inhibiting macrophage inflammatory response and regulating the composition of gut microbiota. Front. Physiol., 2021, 11, 577237. doi: 10.3389/fphys.2020.577237 PMID: 33536931Chiou, W.F.; Don, M.J. Cryptotanshinone inhibits macrophage migration by impeding F-actin polymerization and filopodia extension. Life Sci., 2007, 81(2), 109-114. doi: 10.1016/j.lfs.2007.04.028 PMID: 17568618Wang, H.; Chen, Y.; Tao, T.; Zhao, X.; Wang, Y.; Luo, J.; Guo, Y. Identification of microRNA biomarkers in serum of patients at different stages of atrial fibrillation. Heart Lung, 2020, 49(6), 902-908. doi: 10.1016/j.hrtlng.2020.03.021 PMID: 32482362Zhu, Y.; Feng, Z.; Cheng, W.; Xiao, Y. MicroRNA 34a mediates atrial fibrillation through regulation of Ankyrin B expression. Mol. Med. Rep., 2018, 17(6), 8457-8465. doi: 10.3892/mmr.2018.8873 PMID: 29658562Zheng, Q.; Lin, R.; Chen, Y.; Lv, Q.; Zhang, J.; Zhai, J.; Xu, W.; Wang, W. SARS-CoV-2 induces "cytokine storm" hyperinflammatory responses in RA patients through pyroptosis. Front. Immunol., 2022, 13, 1058884. doi: 10.3389/fimmu.2022.1058884 PMID: 36532040