Natural phytochemicals as P2X7 receptor inhibitors for the treatment of inflammation-related diseases

Main Article Content

Qian Niu
Jin-cai Li
Meng Zhang
Peng Zhou

Keywords

autoimmune diseases, baicalin, dihydrotanshinone, molecular docking, P2X7 receptor, phytochemicals

Abstract

P2X7 receptor (P2X7R) inhibition is critical for reducing the overactivation of its downstream signaling pathway in autoimmune diseases. Phytochemicals are a source of medicinal compounds for various diseases and contribute to the development of effective and safe P2X7R-targeted drugs. This review is aimed at identifying and screening novel safe, effective, and economically feasible inhibitors of P2X7R from phytochemicals extracted from food and plants. The results of the docking study revealed that the VINA scores of dihydrotanshinone, baicalin, berberine, genistin, dioscin, resveratrol, apigenin, cannabidiol, esculin, and luteolin were lower than or equal to that of A740003 (P2X7R inhibitor). The VINA scores of dihydrotanshinone and baicalin were lower than or equal to JNJ47965567 (P2X7R inhibitor). Dihydrotanshinone and baicalin can be used as lead compounds for P2X7R inhibition. These active ingredients will contribute to the discovery of lead compounds and the development of innovative P2X7R agents for the treatment of autoimmune diseases.

Abstract 385 | PDF Downloads 595 HTML Downloads 150 XML Downloads 227

References

Adinolfi, E., Giuliani, A.L., De Marchi, E., Pegoraro, A., Orioli, E. and Di Virgilio F., 2018. The P2X7 receptor: a main player in inflammation. Biochemical Pharmacology. 151: 234–244. 10.1016/j.bcp.2017.12.021

Ahn, Y., Seo, J., Lee, E.J., Kim, J.Y., Park, M.Y., Hwang, S., Almurayshid, A., Lim, B.J., Yu, J.W. and Oh, S.H., 2020. ATP-P2X7-induced inflammasome activation contributes to melanocyte death and CD8+ T-cell trafficking to the skin in Vitiligo. The Journal of Investigative Dermatology. 140(9): 1794–1804. 10.1016/j.jid.2019.12.035

Alakurtti, S., Mäkelä, T., Koskimies, S. and Yli-Kauhaluoma, J., 2006. Pharmacological properties of the ubiquitous natural product betulin. European Journal of Pharmaceutical Sciences. 29(1): 1–13. 10.1016/j.ejps.2006.04.006

Allegri, L., Domenis, R., Navarra, M., Celano, M., Russo, D., Capriglione, F., Damante, G. and Baldan F., 2021. Dihydrotanshinone exerts antitumor effects and improves the effects of cisplatin in anaplastic thyroid cancer cells. Oncology Reports. 46(3): 204. 10.3892/or.2021.8155

Atalay, S., Jarocka-Karpowicz, I. and Skrzydlewska, E., 2019., Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants (Basel). 9(1): 21. 10.3390/antiox9010021

Aziz, N., Kim, M.Y. and Cho, J.Y., 2018. Anti-inflammatory effects of luteolin: a review of in vitro, in vivo, and in silico studies. Journal of Ethnopharmacology. 225: 342–358. 10.1016/j.jep.2018.05.019

Babaei, F., Mirzababaei, M. and Nassiri-Asl, M., 2018. Quercetin in food: possible mechanisms of its effect on memory. Journal of Food Science. 83(9): 2280–2287. 10.1111/1750-3841.14317

Bai, J., Zhang, Y., Tang, C., Hou, Y., Ai, X., Chen, X., Zhang, Y., Wang, X. and Meng, X., 2021. Gallic acid: pharmacological activities and molecular mechanisms involved in inflammation--related diseases. Biomedicine Pharmacotherapy. 133: 110985. 10.1016/j.biopha.2020.110985

Burstein, S., 2015. Cannabidiol (CBD) and its analogs: a review of their effects on inflammation. Bioorganic Medicinal Chemistry. 23(7): 1377–1385. 10.1016/j.bmc.2015.01.059

Campagno, K.E., Lu, W., Jassim, A.H., Albalawi, F., Cenaj, A., Tso, H.Y., Clark, S.P., Sripinun, P., Gómez, N.M. and Mitchell, C.H., 2021. Rapid morphologic changes to microglial cells and upregulation of mixed microglial activation state markers induced by P2X7 receptor stimulation and increased intraocular pressure. Journal of Neuroinflammation. 18(1): 217. 10.1186/s12974-021-02251-7

Chai, Y., Cai, Y., Fu, Y., Wang, Y., Zhang, Y., Zhang, X., Zhu, L., Miao, M. and Yan, T., 2022. Salidroside ameliorates depression by suppressing NLRP3-mediated pyroptosis via P2X7/NF-κB/NLRP3 signaling pathway. Frontiers in Pharmacology. 13: 812362. 10.3389/fphar.2022.812362

Chang, X., He, H., Zhu, L., Gao, J., Wei, T., Ma, Z. and Yan, T., 2015. Protective effect of apigenin on Freund's complete adjuvant--induced arthritis in rats via inhibiting P2X7/NF-κB pathway. Chemico-Biological Interactions. 236: 41–46. 10.1016/j.cbi.2015.04.021

Chen, X., Yu, J., Zhong, B., Lu, J., Lu, J.J., Li, S. and Lu, Y., 2019. Pharmacological activities of dihydrotanshinone I, a-natural product from Salvia miltiorrhiza Bunge. Pharmacological Research. 145: 104254. 10.1016/j.phrs.2019.104254

Cheng, L., Chen, Q., Pi, R. and Chen, J., 2021. A research update on the therapeutic potential of rhein and its derivatives. European Journal of Pharmacology. 899: 173908. 10.1016/j.ejphar.2021.173908

Choi, Y.R., Shim, J. and Kim, M.J., 2020. Genistin: a novel potent anti-adipogenic and anti-lipogenic agent. Molecules. 25(9): 2042. 10.3390/molecules25092042

Cicero, A.F. and Baggioni, A., 2016. Berberine and its role in chronic disease. Advances in Experimental Medicine and Biology. 928: 27–45. 10.1007/978-3-319-41334-1_2

Deng, Y., Zhao, X.T., Zhou, M.T., Xue, X.Y., Liao, L., Wang, J. and Li, Y.X., 2022. Phillygenin mitigates LPS/ATP-induced L02 cell inflammation by regulation of P2X7R/NF-κB/NLRP3 inflammasome signaling pathway. Chinese Journal Expermental Traditional Medicine Formulae. 10.13422/j.cnki.syfjx.20220808

Di Virgilio, F., Dal Ben, D., Sarti, A.C., Giuliani, A.L. and Falzoni, S., 2017. The P2X7 receptor in infection and inflammation. Immunity. 47(1): 15–31. 10.1016/j.immuni.2017.06.020

Ding, X., Lu, D. and Fan, J., 2021. A natural product phillygenin suppresses osteosarcoma growth and metastasis by regulating the SHP-1/JAK2/STAT3 signaling. Bioscience, Biotechnology, and Biochemistry. 85(2): 307–314. 10.1093/bbb/zbaa007

Dong, X., Fu, J., Yin, X., Cao, S., Li, X., Lin, L.; Huyiligeqi; Ni, J., 2016. Emodin: a review of its pharmacology, toxicity and pharmacokinetics. Phytotherapy Research. 30(8): 1207–1218. 10.1002/ptr.5631

Dou, J.Y., Jiang, Y.C., Hu, Z.H., Yao, K.C., Yuan, M.H., Bao, X.X., Zhou, M.J., Liu, Y., Li, Z.X., Lian, L.H., Nan, J.X. and Wu, Y.L., 2022. Betulin targets lipin1/2-meidated P2X7 receptor as a therapeutic approach to attenuate lipid accumulation and metaflammation. Biomolecules Therapeutics. 30(3): 246–256. 10.4062/biomolther.2021.136

Faria, R.X., de Jesus Hiller, N., Salles, J.P., Resende, J.A.L.C., Diogo, R.T., von Ranke, N.L., Bello, M.L., Rodrigues, C.R., Castro, H.C. and de Luna Martins, D., 2019. Arylboronic acids inhibit P2X7 receptor function and the acute inflammatory response. Journal of Bioenergetics and Biomembranes. 51(4): 277–290. 10.1007/s10863-019-09802-x

Fresta, C.G., Caruso, G., Fidilio, A., Platania, C.B.M., Musso, N., Caraci, F., Drago, F. and Bucolo, C., 2020. Dihydrotanshinone, a natural diterpenoid, preserves blood-retinal barrier integrity via P2X7 receptor. International Journal of Molecular Sciences. 21(23): 9305. 10.3390/ijms21239305

Ge, H., Sun, M., Wei, X., Zhang, M., Tu, H., Hao, Y., Chen, R., Ye, M. and Gao, Y., 2020. Protective effects of dihydromyricetin on primary hippocampal astrocytes from cytotoxicity induced by comorbid diabetic neuropathic pain and depression. Purinergic Signalling. 16(4): 585–599. 10.1007/s11302-020-09752-9

Ginwala, R., Bhavsar, R., Chigbu, D.I., Jain, P. and Khan, Z.K., 2019. Potential role of flavonoids in treating chronic inflammatory diseases with a special focus on the anti-inflammatory activity of apigenin. Antioxidants (Basel). 8(2): 35. 10.3390/antiox8020035

Gu, M., Zheng, A.B., Jin, J., Cui, Y., Zhang, N., Che, Z.P., Wang, Y., Zhan, J. and Tu, W.J., 2016. Cardioprotective effects of genistin in rat myocardial ischemia-reperfusion injury studies by regulation of P2X7/NF-κB pathway. Evidence-Based Complementary and Alternative Medicine. 2016: 5381290. 10.1155/2016/5381290

Guan, S., Shen, Y., Ge, H., Xiong, W., He, L., Liu, L., Yin, C., Wei, X. and Gao, Y., 2019. Dihydromyricetin alleviates diabetic neuropathic pain and depression comorbidity symptoms by inhibiting P2X7 receptor. Frontiers in Psychiatry. 10: 770. 10.3389/fpsyt.2019.00770

Haanes, K.A., Schwab, A. and Novak, I., 2012. The P2X7 receptor supports both life and death in fibrogenic pancreatic stellate cells. PLoS One. 7(12): e51164. 10.1371/journal.pone.0051164

Hao, H., Cao, L., Jiang, C., Che, Y., Zhang, S., Takahashi, S., Wang, G. and Gonzalez, FJ., 2017. Farnesoid X receptor regulation of the NLRP3 inflammasome underlies cholestasis-associated sepsis. Cell Metabolism. 25(4): 856–867. 10.1016/j.cmet.2017.03.007

He, F. and Yao, G., 2021. Ginsenoside Rg1 as a potential regulator of hematopoietic stem/progenitor cells. Stem Cells International. 2021: 4633270. 10.1155/2021/4633270

He, X., Zhang, Y., Xu, Y., Xie, L., Yu, Z. and Zheng, J., 2021. Function of the P2X7 receptor in hematopoiesis and leukemogenesis. Experimental Hematology. 104: 40–47. 10.1016/j.exphem.2021.10.001

Hou, L., Jiang, F., Huang, B., Zheng, W., Jiang, Y., Cai, G., Liu, D., Hu, C.Y. and Wang, C., 2021. Dihydromyricetin ameliorates inflammation-induced insulin resistance via phospholipase C-CaMKK-AMPK signal pathway. Oxidative Medicine and Cellular Longevity. 2021: 8542809. 10.21203/rs.3.rs-184435/v1

Hu, F., Xing, F., Zhu, G., Xu, G., Li, C., Qu, J., Lee, I. and Pan, L., 2015. Rhein antagonizes P2X7 receptor in rat peritoneal macrophages. Scientific Reports. 5: 14012. 10.1038/srep14012

Huang, T., Liu, Y. and Zhang, C., 2019. Pharmacokinetics and bioavailability enhancement of baicalin: a review. European Journal of Drug Metabolism and Pharmacokinetics. 44(2): 159–168. 10.1007/s13318-018-0509-3

Huang, Z., Xie, N., Illes, P., Di Virgilio, F., Ulrich, H., Semyanov, A., Verkhratsky, A., Sperlagh, B., Yu, S.G., Huang, C. and Tang, Y., 2021. From purines to purinergic signalling: molecular functions and human diseases. Signal Transduction and Targeted Therapy. 6(1): 162. 10.1038/s41392-021-00553-z

Illes, P., Müller, C.E., Jacobson, K.A., Grutter, T., Nicke, A., Fountain, S.J., Kennedy, C., Schmalzing, G., Jarvis, M.F., Stojilkovic, S.S., King, B.F. and Di Virgilio, F., 2021. Update of P2X receptor properties and their pharmacology: IUPHAR Review 30. British Journal of Pharmacology. 178(3): 489–514. 10.1111/bph.15299

Islam, A., Islam, M.S., Uddin, M.N., Hasan, M.M.I. and Akanda, M.R., 2020. The potential health benefits of the isoflavone glycoside genistin. Archives of Pharmacal Research. 43(4): 395–408. 10.1007/s12272-020-01233-2

Karasawa, A. and Kawate, T., 2016. Structural basis for subtype--specific inhibition of the P2X7 receptor. Elife. 5: e22153. 10.7554/eLife.22153

Kashyap, P., Shikha, D., Thakur, M. and Aneja, A., 2022. Functionality of apigenin as a potent antioxidant with emphasis on bioavailability, metabolism, action mechanism and in vitro and in vivo studies: a review. Journal of Food Biochemistry. 46(4): e13950. 10.1111/jfbc.13950

Kotha, R.R. and Luthria, DL., 2019. Curcumin: biological, pharmaceutical, nutraceutical, and analytical aspects. Molecules. 24(16): 2930. 10.3390/molecules24162930

Li, G.M., Chen, J.R., Zhang, H.Q., Cao, X.Y., Sun, C., Peng, F., Yin, Y.P., Lin, Z., Yu, L., Chen, Y., Tang, Y.L., Xie, X.F. and Peng, C., 2021. Update on pharmacological activities, security, and pharmacokinetics of rhein. Evidence-Based Complementary and Alternative Medicine. 2021: 4582412. 10.1155/2021/4582412

Liu, C., Ma, H., Slitt, A.L. and Seeram, N.P., 2020a. Inhibitory effect of cannabidiol on the activation of NLRP3 inflammasome is associated with its modulation of the P2X7 receptor in human monocytes. Journal of Natural Products. 83(6): 2025–2029. 10.1021/acs.jnatprod.0c00138

Liu, J., Yong, H., Liu, Y. and Bai, R., 2020b. Recent advances in the preparation, structural characteristics, biological properties and applications of gallic acid grafted polysaccharides. International Journal of Biological Macromolecules. 156: 1539–1555. 10.1016/j.ijbiomac.2019.11.202

Liu, Y., Grimm, M., Dai, W.T., Hou, M.C., Xiao, Z.X. and Cao, Y., 2020c. CB-Dock: a web server for cavity detection-guided protein--ligand blind docking. Acta Pharmacologica Sinica. 41: 138–144. 10.1038/s41401-019-0228-6

Liu, Z., Pan, H., Zhang, Y., Zheng, Z., Xiao, W., Hong, X., Chen, F., Peng, X., Pei, Y., Rong, J., He, J., Zou, L., Wang, J., Zhong, J., Han, X. and Cao, Y., 2022. Ginsenoside-Rg1 attenuates sepsis--induced cardiac dysfunction by modulating mitochondrial damage via the P2X7 receptor-mediated Akt/GSK-3β signaling pathway. Journal of Biochemical and Molecular Toxicology. 36(1): e22885. 10.1002/jbt.22885

Lu, L., Huang, J., Xue, X., Wang, T., Huang, Z. and Li, J., 2021a. Berberine regulated miR150-5p to inhibit P2X7 receptor, EMMPRIN and MMP-9 expression in oxLDL induced macrophages. Frontiers in Pharmacology. 12: 639558. 10.3389/fphar.2021.639558

Lu, Z., Yao, Y., Wang, J. and Peng, J.Y., 2021b. Dioscin ameliorates diabetes cognitive dysfunction via adjusting P2X7R/NLRP3-signal. International Immunopharmacology. 101: 108314. 10.1016/j.intimp.2021.108314

Nevoral, J., Zalmanova, T., Hoskova, K., Stiavnicka, M., Hosek, P., Petelak, A. and Petr, J., 2018. Involvement of K+ATP and Ca2+ channels in hydrogen sulfide-suppressed ageing of porcine oocytes. Biological Research. 51(1): 38. 10.1186/s40659-018-0187-2

Parsons, C., Jahanafroozi, M. and Kathariou, S., 2019. Requirement of lmo1930, a gene in the menaquinone biosynthesis operon, for esculin hydrolysis and lithium chloride tolerance in Listeria monocytogenes. Microorganisms. 7(11): 539. 10.3390/microorganisms7110539

Patel, R.V., Mistry, B.M., Shinde, S.K., Syed, R., Singh, V. and Shin, H.S., 2018. Therapeutic potential of quercetin as a cardiovascular agent. European Journal of Medicinal Chemistry. 155: 889–904. 10.1016/j.ejmech.2018.06.053

Pelegrin, P., 2021. P2X7 receptor and the NLRP3 inflammasome: partners in crime. Biochemical Pharmacology. 187: 114385. 10.1016/j.bcp.2020.114385

Prateeksha., Yusuf, M.A., Singh, B.N., Sudheer, S., Kharwar, R.N., Siddiqui, S., Abdel-Azeem, A.M., Fernandes Fraceto, L., Dashora, K. and Gupta, V.K., 2019. Chrysophanol: a natural anthraquinone with multifaceted biotherapeutic potential. Biomolecules. 9(2): 68. 10.3390/biom9020068

Roman, S., Cusdin, F.S., Fonfria, E., Goodwin, J.A., Reeves, J., Lappin, S.C., Chambers, L., Walter, D.S., Clay, W.C. and Michel, A.D., 2009. Cloning and pharmacological characterization of the dog P2X7 receptor. British Journal of Pharmacology. 158(6): 1513–1526. 10.1111/j.1476-5381.2009.00425.x

Semwal, R.B., Semwal, D.K., Combrinck, S. and Viljoen, A., 2021. Emodin—a natural anthraquinone derivative with diverse pharmacological activities. Phytochemistry. 190: 112854. 10.1016/j.phytochem.2021.112854

Serralha, R.S., Rodrigues, I.F., Bertolini, A., Lima, D.Y., Nascimento, M., Mouro, M.G., Punaro, G.R., Visoná, I., Rodrigues, A.M. and Higa, E.M.S., 2020. Esculin reduces P2X7 and reverses mitochondrial dysfunction in the renal cortex of diabetic rats. Life Sciences. 254: 117787. 10.1016/j.lfs.2020.117787

Sharma, B.R. and Kanneganti, T.D., 2021. NLRP3 inflammasome in cancer and metabolic diseases. Nature Immunology 22(5): 550–559. 10.1038/s41590-021-00886-5

Shen, C.Y., Jiang, J.G., Yang, L., Wang, D.W. and Zhu, W., 2017. Anti-ageing active ingredients from herbs and nutraceuticals used in traditional Chinese medicine: pharmacological mechanisms and implications for drug discovery. British Journal of Pharmacology. 174(11): 1395–1425. 10.1111/bph.13631

Shi, X.X., Zheng, K.C., Shan, P.R., Zhang, L., Wu, S.J. and Huang, Z.Q., 2021. Elevated circulating level of P2X7 receptor is related to severity of coronary artery stenosis and prognosis of acute myocardial infarction. Cardiology Journal. 28(3): 453–459. 10.5603/CJ.a2020.0074

Skaper, S.D., Debetto, P. and Giusti, P., 2010. The P2X7 purinergic receptor: from physiology to neurological disorders. FASEB Journal. 24(2): 337–345. 10.1096/fj.09-138883

Song, Y., Wang, X., Qin, S., Zhou, S., Li, J. and Gao, Y., 2018. Esculin ameliorates cognitive impairment in experimental diabetic nephropathy and induces anti-oxidative stress and anti-inflammatory effects via the MAPK pathway. Molecular Medicine Reports. 17(5): 7395–7402. 10.3892/mmr.2018.8727

Sun, S., Tuo, Q., Li, D., Wang, X., Li, X., Zhang, Y., Zhao, G. and Lin, F., 2020. Antioxidant effects of salidroside in the cardiovascular system. Evidence-Based Complementary and Alternative Medicine. 2020: 9568647. 10.1155/2020/9568647

Taheri, Y., Sharifi-Rad, J., Antika, G., Yılmaz, Y.B., Tumer, T.B., Abuhamdah, S., Chandra, S., Saklani, S., Kılıç, C.S., Sestito, S., Daştan, S.D., Kumar, M., Alshehri, M.M., Rapposelli, S., Cruz-Martins, N. and Cho, W.C., 2021. Paving luteolin therapeutic potentialities and agro-food-pharma applications: emphasis on in vivo pharmacological effects and bioavailability traits. Oxidative Medicine and Cellular Longevity. 2021: 1987588. 10.1155/2021/1987588

Tang, D., Chen, K., Huang, L. and Li, J., 2017. Pharmacokinetic properties and drug interactions of apigenin, a natural flavone. Expert Opinion on Drug Metabolism Toxicology. 13(3): 323–330. 10.1080/17425255.2017.1251903

Tao, X., Yin, L., Xu, L. and Peng, J., 2018. Dioscin: a diverse acting natural compound with therapeutic potential in metabolic diseases, cancer, inflammation and infections. Pharmacological Research. 137: 259–269. 10.1016/j.phrs.2018.09.022

Tew, X.N., Xin Lau, N.J., Chellappan, D.K., Madheswaran, T., Zeeshan, F., Tambuwala, M.M., Aljabali, A.A., Balusamy, S.R., Perumalsamy, H., Gupta, G., Oliver, B.G., Hsu, A., Wark, P., Reddy, K., Wadhwa, R., Hansbro, P.M. and Dua, K., 2020. Immunological axis of berberine in managing inflammation underlying chronic respiratory inflammatory diseases. Chemico-Biological Interactions. 317: 108947. 10.1016/j.cbi.2020.108947

Thawkar, B.S. and Kaur, G., 2019. Inhibitors of NF-κB and P2X7/NLRP3/Caspase 1 pathway in microglia: novel therapeutic opportunities in neuroinflammation induced early-stage Alzheimer’s disease. Journal of Neuroimmunology. 326: 62–74. 10.1016/j.jneuroim.2018.11.010

Tuli, H.S., Sak, K., Gupta, D.S., Kaur, G., Aggarwal, D., Chaturvedi Parashar, N., Choudhary, R., Yerer, M.B., Kaur, J., Kumar, M., Garg, V.K. and Sethi, G., 2021. Anti-inflammatory and anticancer properties of birch bark-derived betulin: recent developments. Plants (Basel). 10(12): 2663. 10.3390/plants10122663

Vivoli, E., Cappon, A., Milani, S., Piombanti, B., Provenzano, A., Novo, E., Masi, A., Navari, N., Narducci, R., Mannaioni, G., Moneti G., Oliveira, C.P., Parola, M. and Marra, F., 2016. NLRP3 inflammasome as a target of berberine in experimental murine liver injury: interference with P2X7 signalling. Clinical Science (London). 130(20): 1793–1806. 10.1042/CS20160400

Wang, D., Wang, H., Gao, H., Zhang, H., Zhang, H., Wang, Q. and Sun, Z., 2020a. P2X7 receptor mediates NLRP3 inflammasome activation in depression and diabetes. Cell Bioscience. 10: 28. 10.1186/s13578-020-00388-1

Wang, Z., Ren, W., Zhao, F., Han, Y., Liu, C. and Jia, K., 2020b. Curcumin amends Ca2+ dysregulation in microglia by suppressing the activation of P2X7 receptor. Molecular and Cellular Biochemistry. 465(1–2): 65–73. 10.1007/s11010-019-03668-8

Xin, L., Gao, J., Lin, H., Qu, Y., Shang, C., Wang, Y., Lu, Y. and Cui, X., 2020. Regulatory mechanisms of baicalin in cardiovascular diseases: a review. Frontiers in Pharmacology. 11: 583200. 10.3389/fphar.2020.583200

Xin, Q., Yuan, R., Shi, W., Zhu, Z., Wang, Y. and Cong, W., 2019. A review for the anti-inflammatory effects of paeoniflorin in inflammatory disorders. Life Sciences. 237: 116925. 10.1016/j.lfs.2019.116925

Xu, H., Xiong, C., He, L., Wu, B., Peng, L., Cheng, Y., Jiang, F., Tan, L., Tang, L., Tu, Y., Yang, Y., Liu, C., Gao, Y., Li, G., Zhang, C., Liu, S., Xu, C., Wu, H., Li, G. and Liang, S., 2015. Trans-resveratrol attenuates high fatty acid-induced P2X7 receptor expression and IL-6 release in PC12 cells: possible role of P38 MAPK pathway. Inflammation. 38(1): 327–337. 10.1007/s10753-014-0036-6

Xu, Z., Chen, Z.M., Wu, X., Zhang, L., Cao, Y. and Zhou, P., 2020. Distinct molecular mechanisms underlying potassium efflux for NLRP3 inflammasome activation. Frontiers in Immunology. 11: 609441. 10.3389/fimmu.2020.609441

Yang, L., Ren, S., Xu, F., Ma, Z., Liu, X. and Wang, L., 2019. Recent advances in the pharmacological activities of dioscin. BioMed Research International. 2019: 5763602. 10.1155/2019/5763602

Yang, R., Li, Z., Zou, Y., Yang, J., Li, L., Xu, X., Schmalzing, G., Nie, H., Li, G., Liu, S., Liang, S. and Xu, C., 2021. Gallic acid alleviates neuropathic pain behaviors in rats by inhibiting P2X7 receptor-mediated NF-κB/STAT3 signaling pathway. Frontiers in Pharmacology. 12: 680139. 10.3389/fphar.2021.680139

Ye, T., Li, X., Zhou, P., Ye, S., Gao, H., Hua, R., Ma, J., Wang, Y. and Cai, B., 2020. Chrysophanol improves memory ability of-d-galactose and Aβ25-35 treated rat correlating with inhibiting tau hyperphosphorylation and the CaM-CaMKIV signal pathway in hippocampus. 3 Biotech 10(3): 111. 10.1007/s13205-020-2103-z

Yu, D., Tang, Z., Li, B., Yu, J., Li, W., Liu, Z. and Tian, C., 2021. Resveratrol against cardiac fibrosis: research progress in-experimental animal models. Molecules. 26(22): 6860. 10.3390/molecules26226860

Yu, J., Chen, Y., Li, M., Gao, Q., Peng, Y., Gong, Q., Zhang, Z. and Wu, X., 2015. Paeoniflorin down-regulates ATP-induced inflammatory cytokine production and P2X7R expression on peripheral blood mononuclear cells from patients with primary Sjögren’s syndrome. International Immunopharmacology. 28(1): 115–120. 10.1016/j.intimp.2015.05.023

Zhang, J., Chen, Y., Luo, H., Sun, L., Xu, M., Yu, J., Zhou, Q., Meng, G. and Yang, S., 2018. Recent update on the pharmacological effects and mechanisms of dihydromyricetin. Frontiers in Pharmacology. 9: 1204. 10.3389/fphar.2018.01204

Zhang, K., Liu, J., You, X., Kong, P., Song, Y., Cao, L., Yang, S., Wang, W., Fu, Q. and Ma, Z., 2016. P2X7 as a new target for chrysophanol to treat lipopolysaccharide-induced depression in mice. Neuroscience Letters. 613: 60–65. 10.1016/j.neulet.2015.12.043

Zhang, L.X., Li, C.X., Kakar, M.U., Khan, M.S., Wu, P.F., Amir, R.M., Dai, D.F., Naveed, M., Li, Q.Y., Saeed, M., Shen, J.Q., Rajput, S.A. and Li, J.H., 2021a. Resveratrol (RV): a pharmacological review and call for further research. Biomedicine Pharmacotherapy. 143: 112164. 10.1016/j.biopha.2021.112164

Zhang, W.Y., Guo, Y.J., Han, W.X., Yang, M.Q., Wen, L.P., Wang, K.Y. and Jiang, P., 2019. Curcumin relieves depressive-like behaviors via inhibition of the NLRP3 inflammasome and kynurenine pathway in rats suffering from chronic unpredictable mild stress. International Immunopharmacology. 67: 138–144. 10.1016/j.intimp.2018.12.012

Zhang, Z.H., Yang, H.X., Jin, Q., Wu, Y.L., Cui, Z.Y., Shang, Y., Liu, J., Zhan, Z.Y., Lian, L.H. and Nan, J.X., 2021b. Luteolin attenuates hepatic injury in septic mice by regulating P2X7R-based HMGB1 release. Food Function. 12(21): 10714–10727. 10.1039/D1FO01746B

Zhao, C.C., Wu, X.Y., Yi, H., Chen, R. and Fan, G., 2021a. The therapeutic effects and mechanisms of salidroside on cardiovascular and metabolic diseases: an updated review. Chemistry Biodiversity. 18(7): e2100033. 10.1002/cbdv.202100033

Zhao, X., Gong, L., Wang, C., Liu, M., Hu, N., Dai, X., Peng, C. and Li, Y., 2021b. Quercetin mitigates ethanol-induced hepatic steatosis in zebrafish via P2X7R-mediated PI3K/ Keap1/Nrf2 signaling pathway. Journal of Ethnopharmacology. 268: 113569. 10.1016/j.jep.2020.113569

Zhao, Y., Chen, X., Lyu, S., Ding, Z., Wu, Y., Gao, Y. and Du, J., 2021c. Identification of novel P2X7R antagonists by using structure--based virtual screening and cell-based assays. Chemical Biology Drug Design. 98(1): 192–205. 10.1111/cbdd.13867

Zhou, M., Tang, Y., Liao, L., Liu, M., Deng, Y., Zhao, X. and Li, Y., 2021. Phillygenin inhibited LPS-induced RAW 264.7 cell inflammation by NF-κB pathway. European Journal of Pharmacology. 899: 174043. 10.1016/j.ejphar.2021.174043

Zhou, Y.X., Gong, X.H. and Zhang, H., Peng, C., 2020. A review on the pharmacokinetics of paeoniflorin and its anti-inflammatory and immunomodulatory effects. Biomedicine Pharmacotherapy. 130: 110505. 10.1016/j.biopha.2020.110505

Zhu, F., Du, B. and Xu, B., 2018. Anti-inflammatory effects of phytochemicals from fruits, vegetables, and food legumes: a review. Critical Reviews in Food Science and Nutrition. 58(8): 1260–1270. 10.1080/10408398.2016.1251390

Zhu, S., Wang, Y., Wang, X., Li, J. and Hu, F., 2014. Emodin inhibits ATP-induced IL-1β secretion, ROS production and-phagocytosis attenuation in rat peritoneal macrophages via antagonizing P2X7 receptor. Pharmaceutical Biology. 52(1): 51–67. 10.3109/13880209.2013.810648