The prospect and underlying mechanisms of Chinese medicine in treating periodontitis

Abstract

Inflammation represents a critical immune response triggered by cellular activities and inflammatory mediators following tissue damage. It plays a central role in the pathological progression of diverse diseases, including psychiatric disorders, cancer, and immunological conditions, rendering it an essential target for therapeutic intervention. Periodontitis, a prevalent oral inflammatory disease, is a leading cause of tooth loss and poses significant health challenges globally. Traditionally, inflammatory diseases such as periodontitis have been treated with systemic administration of synthetic chemicals. However, recent years have witnessed challenges, including drug resistance and microbial dysbiosis associated with these treatments. In contrast, natural products derived from Chinese medicine offer numerous benefits, such as high safety profiles, minimal side effects, innovative pharmacological mechanisms, ease of extraction, and multiple targets, rendering them viable alternatives to conventional antibiotics for treating inflammatory conditions. Numerous effective anti-inflammatory natural products have been identified in traditional Chinese medicine (TCM), including alkaloids, flavonoids, terpenoids, lignans, and other natural products that exhibit inhibitory effects on inflammation and are potential therapeutic agents. Several studies have confirmed the substantial anti-inflammatory and immunomodulatory properties of these compounds. This comprehensive review examines the literature on the anti-inflammatory effects of TCM-derived natural products from databases such as PubMed, Web of Science, and CNKI, focusing on terms like "inflammation", "periodontitis", "pharmacology", and "traditional Chinese medicine". The analysis systematically summarizes the molecular pharmacology, chemical composition, and biological activities of these compounds in inflammatory responses, alongside their mechanisms of action. This research seeks to deepen understanding of the mechanisms and biological activities of herbal extracts in managing inflammatory diseases, potentially leading to the development of promising new anti-inflammatory drug candidates. Future applications could extend to the treatment of various inflammatory conditions, including periodontitis.

Keywords

Anti-inflammatory / Chinese medicines / Natural products / Cytokines / Inflammatory signaling pathway / Periodontitis

References

[1] Tasneem S, Liu B, Li B, et al. Molecular pharmacology of inflammation: Medicinal plants as anti-inflammatory agents. Pharmacol Res. 2019; 139:126-140. https://doi.org/10.1016/j.phrs.2018.11.001.

[2] Wolf D, Ley K.Immunity and inflammation in atherosclerosis. Circ Res. 2019; 124(2):315-327. https://doi.org/10.1161/CIRCRESAHA.118.313591.

[3] Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med. 2020; 383(23):2255-2273. https://doi.org/10.1056/NEJMra2026131.

[4] Graves D. Cytokines that promote periodontal tissue destruction. J Periodontol. 2008; 79(8):1585-1591. https://doi.org/10.1902/jop.2008.080183.

[5] Preshaw PM. Host response modulation in periodontics. Periodontol 2000. 2008; 48:92-110. https://doi.org/10.1111/j.1600-0757.2008.00252.x.

[6] Fragoulis GE, McInnes IB, Siebert S. JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis. Rheumatology. 2019; 58:43-54. https://doi.org/10.1093/rheumatology/key276.

[7] Rekvig OP, Van der Vlag J. The pathogenesis and diagnosis of systemic lupus erythematosus: still not resolved. Semin Immunopathol. 2014; 36(3):301-311. https://doi.org/10.1007/s00281-014-0428-6.

[8] Dispenza MC.Classification of hypersensitivity reactions. Allergy Asthma Proc. 2019; 40(6):470-473. https://doi.org/10.2500/aap.2019.40.4274.

[9] Venkatesan A, Murphy OC. Viral Encephalitis. Neurol Clin. 2018; 36(4):705-724. https://doi.org/10.1016/j.ncl.2018.07.001.

[10] Okazaki K, Nakamura S, Koyano K, et al. Neonatal asphyxia as an inflammatory disease: reactive oxygen species and cytokines. Front Pediatr. 2023;11:1070743. https://doi.org/10.3389/fped.2023.1070743.

[11] Quinn R, Moulson N, Wang J, et al. Sports-related dudden cardiac death attributable to myocarditis: a systematic review and meta-analysis. Can J Cardiol. 2022; 38(11):1684-1692. https://doi.org/10.1016/j.cjca.2022.07.006.

[12] Zhang ZH, Zheng YH, Chen N, et al. San Huang Xiao Yan recipe modulates the HMGB1-mediated abnormal inflammatory microenvironment and ameliorates diabetic foot by activating the AMPK/Nrf2 signalling pathway. Phytomedicine. 2023;118:154931. https://doi.org/10.1016/j.phymed.2023.154931.

[13] Zeng HR, Zhao B, Zhang D, et al. Viola yedoensis Makino formula alleviates DNCB-induced atopic dermatitis by activating JAK2/STAT3 signaling pathway and promoting M2 macrophages polarization. Phytomedicine. 2022;103:154228. https://doi.org/10.1016/j.phymed.2022.154228.

[14] Zhao B, Hui XD, Zeng HR, et al. Sophoridine inhibits the tumour growth of non-small lung cancer by inducing macrophages M1 polarisation via MAPK-mediated inflammatory pathway. Front Oncol. 2021;11:634851. https://doi.org/10.3389/fonc.2021.634851.

[15] Deng YY, Chu XY, Li Q, et al. Xanthohumol ameliorates drug-induced hepatic ferroptosis via activating Nrf2/xCT/GPX4 signaling pathway. Phytomedicine. 2024;126:155458. https://doi.org/10.1016/j.phymed.2024.155458.

[16] Karygianni L, Al-Ahmad A, Argyropoulou A, et al. Natural antimicrobials and oral microorganisms: a systematic review on herbal interventions for the eradication of multispecies oral biofilms. Front Microbiol. 2016;6:1529. https://doi.org/10.3389/fmicb.2015.01529.

[17] Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol. 2015; 15(1):30-44. https://doi.org/10.1038/nri3785.

[18] Hajishengallis G, Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat Rev Immunol. 2021; 21(7):426-440. https://doi.org/10.1038/s41577-020-00488-6.

[19] Abdulkhaleq LA, Assi MA, Abdullah R, et al. The crucial roles of inflammatory mediators in inflammation: a review. Vet World. 2018; 11(5):627-635. https://doi.org/10.14202/vetworld.2018.627-635.

[20] Neuhöfer P, Liang S, Einwächter H, et al. Deletion of IκBα activates RelA to reduce acute pancreatitis in mice through up-regulation of Spi2A. Gastroenterology. 2013; 144(1):192-201. https://doi.org/10.1053/j.gastro.2012.09.058.

[21] Shen J, Cheng JZ, Zhu SG, et al. Regulating effect of baicalin on IKK/IKB/NF-κB signaling pathway and apoptosis-related proteins in rats with ulcerative colitis. Int Immunopharmacol. 2019; 73:193-200. https://doi.org/10.1016/j.intimp.2019.04.052.

[22] Senegas A, Gautheron J, Maurin AGD, et al. IKK-related genetic diseases: probing NF-κB functions in humans and other matters. Cell Mol Life Sci. 2015; 72(7):1275-1287. https://doi.org/10.1007/s00018-014-1793-y.

[23] Yu H, Lin LB, Zhang ZQ, et al. Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduct Target Ther. 2020; 5(1):209. https://doi.org/10.1038/s41392-020-00312-6.

[24] Nikzad-Langerodi R, Ortmann S, Pferschy-Wenzig EM, et al. Assessment of anti-inflammatory properties of extracts from Honeysuckle (Lonicera sp. L., Caprifoliaceae) by ATR-FTIR spectroscopy[J]. Talanta. 2017; 175: 264-272. https://doi.org/10.1016/j.talanta.2017.07.045.

[25] Chen SB, Ye JF, Chen XR, et al.Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-κB pathway dependent of HDAC3. J Neuroinflammation. 2018; 15(1):150. https://doi.org/10.1186/s12974-018-1193-6.

[26] Venugopal P, Koshy T, Lavu V, et al. Differential expression of microRNAs let-7a, miR-125b, miR-100, and miR-21 and interaction with NF-κB pathway genes in periodontitis pathogenesis. J Cell Physiol. 2018; 233(8):5877-5884. https://doi.org/10.1002/jcp.26391.

[27] de Araújo AA, de Morais HB, de Medeiros C, et al. Gliclazide reduced oxidative stress, inflammation, and bone loss in an experimental periodontal disease model. J Appl Oral Sci. 2019;27:e20180211. https://doi.org/10.1590/1678-7757-2018-0211.

[28] de Oliveira RR, Novaes AB, Garlet GP, et al. The effect of a single episode of antimicrobial photodynamic therapy in the treatment of experimental periodontitis. Microbiological profile and cytokine pattern in the dog mandible. Lasers Med Sci. 2011; 26(3):359-367. https://doi.org/10.1007/s10103-010-0864-z.

[29] Wang CY, Chen SS, Guo HY, et al. Forsythoside A mitigates Alzheimer’s-like pathology by inhibiting ferroptosis-mediated neuroinflammation via Nrf2/GPX4 axis activation. Int J Biol Sci. 2022; 18(5):2075-2090. https://doi.org/10.7150/ijbs.69714.

[30] Wu D, Jin LL, Huang X, et al. Arctigenin: pharmacology, total synthesis, and progress in structure modification. J Enzyme Inhib Med Chem. 2022; 37(1):2452-2477. https://doi.org/10.1080/14756366.2022.2115035.

[31] Hyam SR, Lee IA, Gu W, et al. Arctigenin ameliorates inflammation in vitro and in vivo by inhibiting the PI3K/AKT pathway and polarizing M1 macrophages to M2-like macrophages. Eur J Pharmacol. 2013; 708(1-3):21-29. https://doi.org/10.1016/j.ejphar.2013.01.014.

[32] Shi XB, Sun HZ, Zhou D, et al. Arctigenin attenuates lipopolysaccharide-induced acute lung injury in rats. Inflammation. 2015; 38(2):623-631. https://doi.org/10.1007/s10753-014-9969-z.

[33] Zhang WZ, Jiang ZK, He BX, et al. Arctigenin protects against lipopolysaccharide-induced pulmonary oxidative stress and inflammation in a mouse model via suppression of MAPK, HO-1, and iNOS signaling. Inflammation. 2015; 38(4):1406-1414. https://doi.org/10.1007/s10753-015-0115-3.

[34] Zhang ZS.Association betweenCOX2-765 G/C polymorphism and periodontitis in Chinese population: a meta-analysis. BMC Oral Health. 2018; 18(1):32. https://doi.org/10.1186/s12903-018-0483-9.

[35] Morkmued S, Clauss F, Schuhbaur B, et al. Deficiency of the SMOC2 matricellular protein impairs bone healing and produces age-dependent bone loss. Sci Rep. 2020; 10(1):14817. https://doi.org/10.1038/s41598-020-71749-6.

[36] Cao YZ, Shi H, Sung ZG, et al.Protective effects of magnesium glycyrrhizinate on methotrexate-induced hepatotoxicity and intestinal toxicity may be by reducing COX-2. Front Pharmacol. 2019;10:11. https://doi.org/10.3389/fphar.2019.00119.

[37] Hu XY, Li J, Fu MR, et al. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021; 6(1):402. https://doi.org/10.1038/s41392-021-00791-1.

[38] Xin P, Xu XY, Deng CJ, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol. 2020;80:106210. https://doi.org/10.1016/j.intimp.2020.106210.

[39] Boyle DL, Soma K, Hodge J, et al. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann Rheum Dis. 2015; 74(6):1311-1316. https://doi.org/10.1136/annrheumdis-2014-206028.

[40] Cooney RN. Suppressors of cytokine signaling (SOCS): inhibitors of the JAK/STAT pathway. Shock. 2002; 17(2):83-90. https://doi.org/10.1097/00024382-200202000-00001.

[41] Krebs DL, Hilton DJ. SOCS: physiological suppressors of cytokine signaling. J Cell Sci. 2000; 113(16):2813-2819. https://doi.org/10.1242/jcs.113.16.2813.

[42] de Souza JAC, Nogueira AVB, de Souza PPC, et al. Suppressor of cytokine signaling 1 expression during LPS-induced inflammation and bone loss in rats. Braz Oral Res. 2017;31:e75. https://doi.org/10.1590/1807-3107BOR-2017.vol31.0075.

[43] Duncan SA, Baganizi DR, Sahu R, et al. SOCS proteins as regulators of inflammatory responses induced by bacterial infections: a review. Front Microbiol. 2017;8:2431. https://doi.org/10.3389/fmicb.2017.02431.

[44] Ghafouri-Fard S, Gholami L, Sadeghpour S, et al. Altered expression of SOCS genes periodontitis. BMC Oral Health. 2022; 22(1):551. https://doi.org/10.1186/s12903-022-02602-7.

[45] Pacios S, Kang J, Galicia J, et al. Diabetes aggravates periodontitis by limiting repair through enhanced inflammation. FASEB J. 2012; 26(4):1423-1430. https://doi.org/10.1096/fj.11-196279.

[46] Sun WL, Chen LL, Zhang SZ, et al. Inflammatory cytokines, adiponectin, insulin resistance and metabolic control after periodontal intervention in patients with type 2 diabetes and chronic periodontitis. Intern Med. 2011; 50(15):1569-1574. https://doi.org/10.2169/internalmedicine.50.5166.

[47] Wang Q, Li H, Xie HH, et al. 25-Hydroxyvitamin D3 attenuates experimental periodontitis through downregulation of TLR4 and JAK1/STAT3 signaling in diabetic mice. J Steroid Biochem Mol Biol. 2013; 135:43-50. https://doi.org/10.1016/j.jsbmb.2013.01.008.

[48] Qiao SM, Lv CJ, Tao Y, et al. Arctigenin disrupts NLRP3 inflammasome assembly in colonic macrophages via downregulating fatty acid oxidation to prevent colitis-associated cancer. Cancer Lett. 2020; 491:162-179. https://doi.org/10.1016/j.canlet.2020.08.033.

[49] Kou XJ, Qi SM, Dai WX, et al. Arctigenin inhibits lipopolysaccharide-induced iNOS expression in RAW264.7 cells through suppressing JAK-STAT signal pathway. Int Immunopharmacol. 2011; 11(8):1095-1102. https://doi.org/10.1016/j.intimp.2011.03.005.

[50] Li YL, Jiao JJ, Qi YZ, et al. Curcumin: a review of experimental studies and mechanisms related to periodontitis treatment. J Periodontal Res. 2021; 56(5):837-847. https://doi.org/10.1111/jre.12914.

[51] Dong C, Davis RJ, Flavell RA. MAP kinases in the immune response. Annu Rev Immunol. 2002; 20:55-72. https://doi.org/10.1146/annurev.immunol.20.091301.131133.

[52] Rajput SA, Wang XQ, Yan HC. Morin hydrate: a comprehensive review on novel natural dietary bioactive compound with versatile biological and pharmacological potential. Biomed Pharmacother. 2021;138:11511. https://doi.org/10.1016/j.biopha.2021.111511.

[53] Kumar A, Mahendra J, Mahendra L, et al. Synergistic effect of biphasic calcium phosphate and platelet-rich fibrin attenuate markers for inflammation and osteoclast differentiation by suppressing NF-κB/MAPK signaling pathway in chronic periodontitis. Molecules. 2021; 26(21):6578. https://doi.org/10.3390/molecules26216578.

[54] Xia ZX, Li Q, Tang ZY. Network pharmacology, molecular docking, and experimental pharmacology explored Ermiao Wan protected against periodontitis via the PI3K/AKT and NF-κB/MAPK signal pathways. J Ethnopharmacol. 2023;303:115900. https://doi.org/10.1016/j.jep.2022.115900.

[55] Wang LP, Zheng J, Pathak JL, et al. SLIT2 overexpression in periodontitis intensifies inflammation and alveolar bone loss, possibly via the activation of MAPK pathway. Front Cell Dev Biol. 2020;8:593. https://doi.org/10.3389/fcell.2020.00593.

[56] Wang LY, Wu F, Song Y, et al. Erythropoietin induces the osteogenesis of periodontal mesenchymal stem cells from healthy and periodontitis sources via activation of the p38 MAPK pathway. Int J Mol Med. 2018; 41(2):829-835. https://doi.org/10.3892/ijmm.2017.3294.

[57] Nonaka K, Kajiura Y, Bando M, et al. Advanced glycation end-products increase IL-6 and ICAM-1 expression via RAGE, MAPK and NF-κB pathways in human gingival fibroblasts. J Periodontal Res. 2018; 53(3):334-344. https://doi.org/10.1111/jre.12518.

[58] Yao XY, Li GL, Bai Q, et al. Taraxerol inhibits LPS-induced inflammatory responses through suppression of TAK1 and Akt activation. Int Immunopharmacol. 2013; 15(2):316-324. https://doi.org/10.1016/j.intimp.2012.12.032.

[59] Xu KH, He RZ, Zhang Y, et al. Forsythiaside inhibited titanium particle-induced inflammation via the NF-κB signaling pathway and RANKL-induced osteoclastogenesis and titanium particle-induced periprosthetic osteolysis via JNK, p38, and ERK signaling pathways. RSC Adv. 2019; 9(22):12384-12393. https://doi.org/10.1039/c8ra10007a.

[60] Acosta-Martinez M, Cabail MZ. The PI3K/Akt pathway in meta-inflammation. Int J Mol Sci. 2022; 23(23):15330. https://doi.org/10.3390/ijms232315330.

[61] He XG, Li Y, Deng B, et al. The PI3K/AKT signalling pathway in inflammation, cell death and glial scar formation after traumatic spinal cord injury: mechanisms and therapeutic opportunities. Cell Prolif. 2022; 55(9):e13275. https://doi.org/10.1111/cpr.13275.

[62] Vara JAF, Casado E, de Castro J, et al. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004; 30(2):193-204. https://doi.org/10.1016/j.ctrv.2003.07.007.

[63] Sun K, Luo J, Guo J, et al. The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthritis Cartilage. 2020; 28(4):400-409. https://doi.org/10.1016/j.joca.2020.02.027.

[64] Sun XJ, Chen L, He ZY. PI3K/Akt-Nrf2 and anti-inflammation effect of macrolides in chronic obstructive pulmonary disease. Curr Drug Metab. 2019; 20(4):301-304. https://doi.org/10.2174/1389200220666190227224748.

[65] Wang LN, Dong M, Shi DM, et al. Role of PI3K in the bone resorption of apical periodontitis. BMC Oral Health. 2022; 22(1):345. https://doi.org/10.1186/s12903-022-02364-2.

[66] Kuo CH, Zhang BH, Huang SE, et al. Xanthine derivative KMUP-1 attenuates experimental periodontitis by reducing osteoclast differentiation and inflammation. Front Pharmacol. 2022;13:821492. https://doi.org/10.3389/fphar.2022.821492.

[67] Zhou MJ, Xu XH, Li J, et al. C-reactive protein perturbs alveolar bone homeostasis: an experimental study of periodontitis and diabetes in the rat. J Clin Periodontol. 2022; 49(10):1052-1066. https://doi.org/10.1111/jcpe.13667.

[68] Ying YK, Luo J. Salidroside promotes human periodontal ligament cell proliferation and osteocalcin secretion via ERK1/2 and PI3K/Akt signaling pathways. Exp Ther Med. 2018; 15(6):5041-5045. https://doi.org/10.3892/etm.2018.6006.

[69] Zhang LL, Wei W. Anti-inflammatory and immunoregulatory effects of paeoniflorin and total glucosides of paeony. Pharmacol Ther. 2020;207:107452. https://doi.org/10.1016/j.pharmthera.2019.107452.

[70] Zheng SH, Xue TY, Wang B, et al. Chinese medicine in the treatment of ulcerative colitis: the mechanisms of signaling pathway regulations. Am J Chin Med. 2022; 50(07):1781-1798. https://doi.org/10.1142/S0192415X22500756.

[71] Gu CY, Zhang QK, Li YJ, et al. The PI3K/AKT pathway-the potential key mechanisms of traditional Chinese medicine for stroke. Front Med. 2022;9:900809. https://doi.org/10.3389/fmed.2022.900809.

[72] Jeong JH, Lee DH, Song J. HMGB1 signaling pathway in diabetes-related dementia: blood-brain barrier breakdown, brain insulin resistance, and Aβ accumulation. Biomed Pharmacother. 2022;150:112933. https://doi.org/10.1016/j.biopha.2022.112933.

[73] Kang R, Chen RC, Zhang QH, et al. HMGB1 in health and disease. Mol Aspects Med. 2014; 40:1-116. https://doi.org/10.1016/j.mam.2014.05.001.

[74] Zhang P, Yang MR, Chen CH, et al. Toll-like receptor 4 (TLR4)/opioid receptor pathway crosstalk and impact on opioid analgesia, immune function, and gastrointestinal motility. Front Immunol. 2020;11:1455. https://doi.org/10.3389/fimmu.2020.01455.

[75] Sims GP, Rowe DC, Rietdijk ST, et al. HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol. 2010, 28:367-388. https://doi.org/10.1146/annurev.immunol.021908.132603.

[76] Luo L, Xie P, Gong P, et al. Expression of HMGB1 and HMGN2 in gingival tissues, GCF and PICF of periodontitis patients and peri-implantitis. Arch Oral Biol. 2011; 56(10):1106-1111. https://doi.org/10.1016/j.archoralbio.2011.03.020.

[77] Morimoto Y, Kawahara KI, Tancharoen S, et al.Tumor necrosis factor-alpha stimulates gingival epithelial cells to release high mobility-group box 1. J Periodontal Res. 2008; 43(1):76-83. https://doi.org/10.1111/j.1600-0765.2007.00996.x.

[78] Ebe N, Hara-Yokoyama M, Iwasaki K, et al. Pocket epithelium in the pathological setting for HMGB1 release. J Dent Res. 2011; 90(2):235-240. https://doi.org/10.1177/0022034510385688.

[79] Nogueira AVB, de Souza JAC, de Molon RS, et al. HMGB1 localization during experimental periodontitis. Mediators Inflamm. 2014;2014:816320. https://doi.org/10.1155/2014/816320.

[80] Yoshihara-Hirata C, Yamashiro K, Yamamoto T, et al. Anti-HMGB1 neutralizing antibody attenuates periodontal inflammation and bone resorption in a murine periodontitis model. Infect Immun. 2018; 86(5):e00111-e00118. https://doi.org/10.1128/IAI.00111-18.

[81] Ning WC, Acharya A, Li SM, et al. Identification of key pyroptosis-related genes and distinct pyroptosis-related clusters in periodontitis. Front Immunol. 2022;13:862049. https://doi.org/10.3389/fimmu.2022.862049.

[82] Bell RF, Moreira VM, Kalso EA, et al. Liquorice for pain?. Ther Adv Psychopharmacol. 2021;11:20451253211024873. https://doi.org/10.1177/20451253211024873.

[83] Huan CC, Xu Y, Zhang W, et al. Research progress on the antiviral activity of glycyrrhizin and its derivatives in liquorice. Front Pharmacol. 2021; 12:680674. https://doi.org/10.3389/fphar.2021.680674.

[84] Ichimura Y, Waguri S, Sou Y, et al. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell. 2013; 51(5):618-631. https://doi.org/10.1016/j.molcel.2013.08.003.

[85] Tu WJ, Wang H, Li S, et al. The anti-inflammatory and anti-oxidant mechanisms of the Keap1/Nrf2/ARE signaling pathway in chronic diseases. Aging Dis. 2019; 10(3):637-651. https://doi.org/10.14336/AD.2018.0513.

[86] Stefanson AL, Bakovic M. Dietary regulation of Keap1/Nrf2/ARE pathway: focus on plant-derived compounds and trace minerals. Nutrients. 2014; 6(9):3777-3801. https://doi.org/10.3390/nu6093777.

[87] Xiang MJ, Namani A, Wu SJ, et al. Nrf2: bane or blessing in cancer?. J Cancer Res Clin Oncol. 2014; 140(8):1251-1259. https://doi.org/10.1007/s00432-014-1627-1.

[88] Bai XP, Chen YB, Hou XY, et al. Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters. Drug Metab Rev. 2016; 48(4):541-567. https://doi.org/10.1080/03602532.2016.1197239.

[89] Bellezza I, Giambanco I, Minelli A, et al. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res. 2018; 1865(5):721-733. https://doi.org/10.1016/j.bbamcr.2018.02.010.

[90] Ahmed SMU, Luo L, Namani A, et al. Nrf2 signaling pathway: Pivotal roles in inflammation. Biochim Biophys Acta Mol Basis Dis. 2017; 1863(2):585-597. https://doi.org/10.1016/j.bbadis.2016.11.005.

[91] Liu XC, Hou YB, Yang MX, et al. N-acetyl-L-cysteine-derived carbonized polymer dots with ROS scavenging via Keap1-Nrf2 pathway regulate alveolar bone homeostasis in periodontitis. Adv Healthc Mater. 2023; 12(26):e2300890. https://doi.org/10.1002/adhm.202300890.

[92] Gou HQ, Chen X, Zhu XM, et al. Sequestered SQSTM1/p62 crosstalk with Keap1/NRF2 axis in hPDLCs promotes oxidative stress injury induced by periodontitis. Free Radic Biol Med. 2022; 190:62-74. https://doi.org/10.1016/j.freeradbiomed.2022.08.001.

[93] Liu M, Chen R, Xu YX, et al. Exosomal miR-141-3p from PDLSCs alleviates high glucose-induced senescence of PDLSCs by activating the KEAP1-NRF2 signaling pathway. Stem Cells Int. 2023;2023:7136819. https://doi.org/10.1155/2023/7136819.

[94] Huang J, Zhu Y, Li ST, et al. Licochalcone B confers protective effects against LPS-induced acute lung injury in cells and mice through the Keap1/Nrf2 pathway. Redox Rep. 2023; 28(1):2243423. https://doi.org/10.1080/13510002.2023.2243423.

[95] Liu WJ, Chen WW, Chen JY, et al. Baicalin attenuated metabolic dysfunction-associated fatty liver disease by suppressing oxidative stress and inflammation via the p62-Keap1-Nrf2 signalling pathway in db/db mice[J]. Phytother Res. 2023: 11. https://doi.org/10.1002/ptr.8010.

[96] Hu JK, Ding Y, Liu W, et al. When AHR signaling pathways meet viral infections. Cell Commun Signal. 2023; 21(1):42. https://doi.org/10.1186/s12964-023-01058-8.

[97] Bersten DC, Sullivan AE, Peet DJ, et al.bHLH-PAS proteins in cancer. Nat Rev Cancer. 2013; 13(12):827-841. https://doi.org/10.1038/nrc3621.

[98] Baba T, Mimura J, Gradin K, et al. Structure and expression of the Ah receptor repressor gene. J Biol Chem. 2001; 276(35):33101-33110. https://doi.org/10.1074/jbc.M011497200.

[99] Hahn ME, Allan LL, Sherr DH. Regulation of constitutive and inducible AHR signaling: complex interactions involving the AHR repressor. Biochem Pharmacol. 2009; 77(4):485-497. https://doi.org/10.1016/j.bcp.2008.09.016.

[100] Larigot L, Juricek L, Dairou J, et al. AhR signaling pathways and regulatory functions. Biochim Open. 2018; 7:1-9. https://doi.org/10.1016/j.biopen.2018.05.001.

[101] Tomkiewicz C, Herry L, Bui LC, et al. The aryl hydrocarbon receptor regulates focal adhesion sites through a non-genomic FAK/Src pathway. Oncogene. 2013; 32(14):1811-1820. https://doi.org/10.1038/onc.2012.197.

[102] Diry M, Tomkiewicz C, Koehle C, et al. Activation of the dioxin/aryl hydrocarbon receptor (AhR) modulates cell plasticity through a JNK-dependent mechanism. Oncogene. 2006; 25(40):5570-5574. https://doi.org/10.1038/sj.onc.1209553.

[103] Matsumura F. The significance of the nongenomic pathway in mediating inflammatory signaling of the dioxin-activated Ah receptor to cause toxic effects. Biochem Pharmacol. 2009; 77(4):608-626. https://doi.org/10.1016/j.bcp.2008.10.013.

[104] Li H, Zhong XH, Li W, et al. Effects of 1,25-dihydroxyvitamin D3 on experimental periodontitis and AhR/NF-κB/NLRP3 inflammasome pathway in a mouse model. J Appl Oral Sci. 2019;27:e20180713. https://doi.org/10.1590/1678-7757-2018-0713.

[105] Hao T, Zhang R, Zhao T, et al. Porphyromonas gingivalis infection promotes inflammation via inhibition of the AhR signalling pathway in periodontitis. Cell Prolif. 2023; 56(2):e13364. https://doi.org/10.1111/cpr.13364.

[106] Huang J, Cai XJ, Ou YJ, et al. Protective roles of FICZ and aryl hydrocarbon receptor axis on alveolar bone loss and inflammation in experimental periodontitis. J Clin Periodontol. 2019; 46(9):882-893. https://doi.org/10.1111/jcpe.13166.

[107] Li YY, Wang XJ, Su YL, et al. Baicalein ameliorates ulcerative colitis by improving intestinal epithelial barrier via AhR/IL-22 pathway in ILC3s. Acta Pharmacol Sin. 2022; 43(6):1495-1507. https://doi.org/10.1038/s41401-021-00781-7.

[108] Jing WH, Dong SJ, Luo XL, et al. Berberine improves colitis by triggering AhR activation by microbial tryptophan catabolites. Pharmacol Res. 2021;164:105358. DOI: 10.1016/j.phrs.2020.105358. https://doi.org/10.1016/j.phrs.2020.105358.

[109] Wang Y, Zhou XQ, Zhao D, et al. Berberine inhibits free fatty acid and LPS-induced inflammation via modulating ER stress response in macrophages and hepatocytes. PLoS One. 2020; 15(5):e0232630. https://doi.org/10.1371/journal.pone.0232630.

[110] Izadparast F, Riahi-Zajani B, Yarmohammadi F, et al. Protective effect of berberine against LPS-induced injury in the intestine: a review. Cell Cycle. 2022; 21(22):2365-2378. https://doi.org/10.1080/15384101.2022.2100682.

[111] Habtemariam S. Berberine pharmacology and the gut microbiota: A hidden therapeutic link. Pharmacol Res. 2020;155:104722. https://doi.org/10.1016/j.phrs.2020.104722.

[112] Bai F, Tao H, Wang P, et al. Berberine hydrochloride inhibits inflammation and fibrosis after canalicular laceration repair in rabbits. Life Sci. 2020;261:118479. https://doi.org/10.1016/j.lfs.2020.118479.

[113] Li CL, Ai GX, Wang YF, et al. Oxyberberine, a novel gut microbiota-mediated metabolite of berberine, possesses superior anti-colitis effect: Impact on intestinal epithelial barrier, gut microbiota profile and TLR4-MyD88-NF-κB pathway. Pharmacol Res. 2020;152:104603. https://doi.org/10.1016/j.phrs.2019.104603.

[114] Dong YL, Fan H, Zhang Z, et al. Berberine ameliorates DSS-induced intestinal mucosal barrier dysfunction through microbiota-dependence and Wnt/β-catenin pathway. Int J Biol Sci. 2022; 18(4):1381-1397. https://doi.org/10.7150/ijbs.65476.

[115] Han Y, Guo SJ, Li YP, et al. Berberine ameliorate inflammation and apoptosis via modulating PI3K/AKT/NF-κB and MAPK pathway on dry eye. Phytomedicine. 2023;121:155081. https://doi.org/10.1016/j.phymed.2023.155081.

[116] Chen AM, Fang DF, Ren Y, et al. Matrine protects colon mucosal epithelial cells against inflammation and apoptosis via the Janus kinase 2 /signal transducer and activator of transcription 3 pathway. Bioengineered. 2022; 13(3):6490-6499. https://doi.org/10.1080/21655979.2022.2031676.

[117] Zheng SH, Chen YY, Wang ZW, et al. Combination of matrine and tacrolimus alleviates acute rejection in murine heart transplantation by inhibiting DCs maturation through ROS/ERK/NF-κB pathway. Int Immunopharmacol. 2021;101:108218. https://doi.org/10.1016/j.intimp.2021.108218.

[118] Jin HZ, Zhao KL, Li JJ, et al. Matrine alleviates oxidative stress and ferroptosis in severe acute pancreatitis-induced acute lung injury by activating the UCP2/SIRT3/PGC1α pathway. Int Immunopharmacol. 2023;117:109981. https://doi.org/10.1016/j.intimp.2023.109981.

[119] Li X, Tang ZW, Wen L, et al. Matrine: A review of its pharmacology, pharmacokinetics, toxicity, clinical application and preparation researches. J Ethnopharmacol. 2021;269:113682. https://doi.org/10.1016/j.jep.2020.113682.

[120] Xiao YH, Yu Y, Hu LL, et al. Matrine alleviates sepsis-induced myocardial injury by inhibiting ferroptosis and apoptosis. Inflammation. 2023; 46(5):1684-1696. https://doi.org/10.1007/s10753-023-01833-2.

[121] Lin YD, He FM, Wu L, et al. Matrine exerts pharmacological effects through multiple signaling pathways: a comprehensive review. Drug Des Devel Ther. 2022; 16:533-569. https://doi.org/10.2147/DDDT.S349678.

[122] Xu YX, Lin HZ, Zheng WJ, et al. Matrine ameliorates adriamycin-induced nephropathy in rats by enhancing renal function and modulating Th17/Treg balance. Eur J Pharmacol. 2016; 791:491-501. https://doi.org/10.1016/j.ejphar.2016.09.022.

[123] Zhang RH, Liu ZK, Yang DS, et al. Phytochemistry and pharmacology of the genus Leonurus: The herb to benefit the mothers and more. Phytochemistry. 2018; 147:167-183. https://doi.org/10.1016/j.phytochem.2017.12.016.

[124] Yin WH and Lei Y. Leonurine inhibits IL-1β induced inflammation in murine chondrocytes and ameliorates murine osteoarthritis. Int Immunopharmacol. 2018; 65:50-59. https://doi.org/10.1016/j.intimp.2018.08.035.

[125] Liu XH, Pan LL, Wang XL, et al. Leonurine protects against tumor necrosis factor-α-mediated inflammation in human umbilical vein endothelial cells. Atherosclerosis. 2012; 222(1):34-42. https://doi.org/10.1016/j.atherosclerosis.2011.04.027.

[126] Shen SY, Wu GJ, Luo W, et al. Leonurine attenuates angiotensin II-induced cardiac injury and dysfunction via inhibiting MAPK and NF-κB pathway. Phytomedicine. 2023;108:154519. https://doi.org/10.1016/j.phymed.2022.154519.

[127] Yan K, Hu JQ, Hou TH, et al. Leonurine inhibits the TXNIP/NLRP3 and NF-κB pathways via Nrf2 activation to alleviate carrageenan-induced pleurisy in mice. Phytother Res. 2022; 36(5):2161-2172. https://doi.org/10.1002/ptr.7437.

[128] Ma XN, Feng W, Li N, et al. Leonurine alleviates rheumatoid arthritis by regulating the Hippo signaling pathway. Phytomedicine. 2024;123:155243. https://doi.org/10.1016/j.phymed.2023.155243.

[129] Bhagya N, Chandrashekar KR. Autophagy and cancer: can tetrandrine be a potent anticancer drug in the near future?. Biomed Pharmacother. 2022;148:112727. https://doi.org/10.1016/j.biopha.2022.112727.

[130] Wang Y, Cheng B, Lin YJ, et al. Preliminary study on the effect and molecular mechanism of tetrandrine in alleviating pulmonary inflammation and fibrosis induced by silicon dioxide. Toxics. 2023; 11(9):765. https://doi.org/10.3390/toxics11090765.

[131] Laurindo LF, Santos AROD, Carvalho ACA, et al. Phytochemicals and regulation of NF-κB in inflammatory Bowel diseases: an overview of in vitro and in vivo effect. Metabolites. 2023; 13(1):96. https://doi.org/10.3390/metabo13010096.

[132] Liu H, He SQ, Li C, et al. Tetrandrine alleviates inflammation and neuron apoptosis in experimental traumatic brain injury by regulating the IRE1α/JNK/CHOP signal pathway. Brain Behav. 2022; 12(12):e2786. https://doi.org/10.1002/brb3.2786.

[133] Li WX, Huang ZQ, Luo Y, et al. Tetrandrine alleviates atherosclerosis via inhibition of STING-TBK1 pathway and inflammation in macrophages. Int Immunopharmacol. 2023;119:110139. https://doi.org/10.1016/j.intimp.2023.110139.

[134] Xu J, Liu DB, Yin Q, et al. Tetrandrine suppresses β-glucan-induced macrophage activation via inhibiting NF-κB, ERK and STAT3 signaling pathways. Mol Med Rep. 2016; 13(6):5177-5184. https://doi.org/10.3892/mmr.2016.5187.

[135] Ranjbar Bushehri M, Babaei N, et al.Esmaeili Gouvarchin Ghaleh H, Anti-inflammatory activity of peiminine in acetic acid-induced ulcerative colitis model. Inflammopharmacolog. 2024; 32(1):657-665. https://doi.org/10.1007/s10787-023-01360-4.

[136] Zhang YS, Sreekrishna K, Lin YK, et al. Modulation of transient receptor potential (TRP) channels by Chinese herbal extracts. Phytother Res. 2011; 25(11):1666-1670. https://doi.org/10.1002/ptr.3427.

[137] Yu L, Chen YX, Yuan SH, et al. Peiminine Induces G₀/G₁-phase arrest, apoptosis, and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells in vitro and in vivo. Front Pharmacol. 2021;12:770846. https://doi.org/10.3389/fphar.2021.770846.

[138] Ruan X, Yang L, Cui WX, et al. Optimization of supercritical fluid extraction of total alkaloids, peimisine, peimine and peiminine from the bulb of Fritillaria thunbergii Miq, and evaluation of antioxidant activities of the extracts. Materials. 2016; 9(7):524. https://doi.org/10.3390/ma9070524.

[139] Liu CY, Zhen D, Du HH, et al. Synergistic anti-inflammatory effects of peimine, peiminine, and forsythoside a combination on LPS-induced acute lung injury by inhibition of the IL-17-NF-κB/MAPK pathway activation. J Ethnopharmacol. 2022;295:115343. https://doi.org/10.1016/j.jep.2022.115343.

[140] Li JS, Ma JD, Tian YG, et al. Effective-component compatibility of Bufei Yishen formula II inhibits mucus hypersecretion of chronic obstructive pulmonary disease rats by regulating EGFR/PI3K/mTOR signaling. J Ethnopharmacol. 2020;257:112796. https://doi.org/10.1016/j.jep.2020.112796.

[141] Gong Q, Li YW, Ma H, et al. Peiminine protects against lipopolysaccharide-induced mastitis by inhibiting the AKT/NF-κB, ERK1/2 and p38 signaling pathways. Int J Mol Sci. 2018; 19(9):2637. https://doi.org/10.3390/ijms19092637.

[142] Zhu M, Xu W, Jiang J, et al. Peiminine suppresses RANKL-induced osteoclastogenesis by inhibiting the NFATc1, ERK, and NF-κB signaling pathways. Front Endocrinol (Lausanne). 2021;12:736863. https://doi.org/10.3389/fendo.2021.736863.

[143] Shen N, Wang T, Gan Q, et al. Plant flavonoids: classification, distribution, biosynthesis, and antioxidant activity. Food Chem. 2022;383:132531. https://doi.org/10.1016/j.foodchem.2022.132531.

[144] Serafini M, Peluso I, Raguzzini A.Flavonoids as anti-inflammatory agents. Proc Nutr Soc. 2010; 69(3):273-278. https://doi.org/10.1017/S002966511000162X.

[145] Wen KM, Fang XC, Yang JL, et al. Recent Research on Flavonoids and their Biomedical Applications. Curr Med Chem. 2021; 28(5):1042-1066. https://doi.org/10.2174/0929867327666200713184138.

[146] Pastorino G, Cornara L, Soares S, et al. Liquorice (Glycyrrhiza glabra): a phytochemical and pharmacological review. Phytother Res. 2018; 32(12):2323-2339. https://doi.org/10.1002/ptr.6178.

[147] Jiang RH, Xu JJ, Zhu DC, et al. Glycyrrhizin inhibits osteoarthritis development through suppressing the PI3K/AKT/NF-κB signaling pathway in vivo and in vitro. Food Funct. 2020; 11(3):2126-2136. https://doi.org/10.1039/c9fo02241d.

[148] Luo YY, Li J, Wang B, et al. Protective effect of glycyrrhizin on osteoarthritis cartilage degeneration and inflammation response in a rat model. J Bioenerg Biomembr. 2021; 53(3):285-293. https://doi.org/10.1007/s10863-021-09889-1.

[149] Hu ZH, Xiao M, Cai HX, et al. Glycyrrhizin regulates rat TMJOA progression by inhibiting the HMGB1-RAGE/TLR4-NF-κB/AKT pathway. J Cell Mol Med. 2022; 26(3):925-936. https://doi.org/10.1111/jcmm.17149.

[150] Shen CH, Ma ZY, Li JH, et al. Glycyrrhizin improves inflammation and apoptosis via suppressing HMGB1 and PI3K/mTOR pathway in lipopolysaccharide-induced acute liver injury. Eur Rev Med Pharmacol Sci. 2020; 24(12):7122-7130. https://doi.org/10.26355/eurrev_202006_21706.

[151] Ye SJ, Zhu Y, Ming YZ, et al. Glycyrrhizin protects mice against renal ischemia-reperfusion injury through inhibition of apoptosis and inflammation by downregulating p38 mitogen-activated protein kinase signaling. Exp Ther Med. 2014; 7(5):1247-1252. https://doi.org/10.3892/etm.2014.1570.

[152] Kotha RR, Luthria DL. Curcumin: biological, pharmaceutical, nutraceutical, and analytical aspects. Molecules. 2019; 24(16):2930. https://doi.org/10.3390/molecules24162930.

[153] He Y, Yue Y, Zheng X, et al. Curcumin, inflammation, and chronic diseases: how are they linked?. Molecules. 2015; 20(5):9183-9213. https://doi.org/10.3390/molecules20059183.

[154] Peng Y, Ao MY, Dong BH, et al. Anti-inflammatory effects of curcumin in the inflammatory diseases: status, limitations and countermeasures. Drug Des Devel Ther. 2021; 15:4503-4525. https://doi.org/10.2147/DDDT.S327378.

[155] Uddin SJ, Hasan MF, Afroz M, et al. Curcumin and its multi-target function against pain and inflammation: an update of pre-clinical data. Curr Drug Targets. 2021; 22(6):656-671. https://doi.org/10.2174/1389450121666200925150022.

[156] Wang ZH, Chen Z, Li BS, et al. Curcumin attenuates renal interstitial fibrosis of obstructive nephropathy by suppressing epithelial-mesenchymal transition through inhibition of the TLR4/NF-κB and PI3K/AKT signalling pathways. Pharm Biol. 2020; 58(1):828-837. https://doi.org/10.1080/13880209.2020.1809462.

[157] Wang MX, Jin LM, Zhang QH, et al. Curcumin analog JM-2 alleviates diabetic cardiomyopathy inflammation and remodeling by inhibiting the NF-κB pathway. Biomed Pharmacother. 2022;154:113590. https://doi.org/10.1016/j.biopha.2022.113590.

[158] Zhou JX, Wu NS and Lin LY. Curcumin suppresses apoptosis and inflammation in hypoxia/reperfusion-exposed neurons via Wnt signaling pathway. Med Sci Monit. 2020;26:e920445. https://doi.org/10.12659/MSM.920445.

[159] Wu Q, Wu XX, Wang M, et al. Therapeutic mechanism of baicalin in experimental colitis analyzed using network pharmacology and metabolomics. Drug Des Devel Ther. 2023; 17:1007-1024. https://doi.org/10.2147/DDDT.S399290.

[160] Ma LY, Wu F, Shao QQ, et al. Baicalin alleviates oxidative stress and inflammation in diabetic nephropathy via Nrf2 and MAPK signaling pathway. Drug Des Devel Ther. 2021; 15:3207-3221. https://doi.org/10.2147/DDDT.S319260.

[161] Shen BY, Zhang HQ, Zhu ZJ, et al. Baicalin relieves LPS-induced lung inflammation via the NF-κB and MAPK pathways. Molecules. 2023; 28(4):1873. https://doi.org/10.3390/molecules28041873.

[162] Zhang L, Sun Y, Xu W, et al. Baicalin inhibits Salmonella typhimurium-induced inflammation and mediates autophagy through TLR4/MAPK/NF-κB signalling pathway. Basic Clin Pharmacol Toxicol. 2021; 128(2):241-255. https://doi.org/10.1111/bcpt.13497.

[163] Zhao H, Li CD, Li LN, et al. Baicalin alleviates bleomycin-induced pulmonary fibrosis and fibroblast proliferation in rats via the PI3K/AKT signaling pathway. Mol Med Rep. 2020; 21(6):2321-2334. https://doi.org/10.3892/mmr.2020.11046.

[164] Xu M, Li X, Song LC. Baicalin regulates macrophages polarization and alleviates myocardial ischaemia/reperfusion injury via inhibiting JAK/STAT pathway. Pharm Biol. 2020; 58(1):655-663. https://doi.org/10.1080/13880209.2020.1779318.

[165] Fu YJ, Xu B, Huang SW, et al.Baicalin prevents LPS-induced activation of TLR4/NF-κB p 65 pathway and inflammation in mice via inhibiting the expression of CD14. Acta Pharmacol Sin. 2021; 42(1):88-96. https://doi.org/10.1038/s41401-020-0411-9.

[166] Ishfaq M, Wu ZY, Wang J, et al. Baicalin alleviates Mycoplasma gallisepticum-induced oxidative stress and inflammation via modulating NLRP3 inflammasome-autophagy pathway. Int Immunopharmacol. 2021;101:108250. https://doi.org/10.1016/j.intimp.2021.108250.

[167] Hosseini A, Razavi BM, Banach M, et al. Quercetin and metabolic syndrome: a review. Phytother Res. 2021; 35(10):5352-5364. https://doi.org/10.1002/ptr.7144.

[168] Li Y, Yao JY, Han CY, et al.Quercetin, inflammation and immunity. Nutrients. 2016; 8(3):167. https://doi.org/10.3390/nu8030167.

[169] Saccon TD, Nagpal R, Yadav H, et al. Senolytic combination of dasatinib and quercetin alleviates intestinal senescence and inflammation and modulates the gut microbiome in aged mice. J Gerontol A Biol Sci Med Sci. 2021; 76(11):1895-1905. https://doi.org/10.1093/gerona/glab002.

[170] Islam MT, Tuday E, Allen S, et al. Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age. Aging Cell. 2023; 22(2):e13767. https://doi.org/10.1111/acel.13767.

[171] Luo X, Bao XY, Weng XZ, et al. The protective effect of quercetin on macrophage pyroptosis via TLR2/Myd88/NF-κB and ROS/AMPK pathway. Life Sci. 2022;291:120064. https://doi.org/10.1016/j.lfs.2021.120064.

[172] Fang YN, Jin WW, Guo Z, et al. Quercetin alleviates asthma-induced airway inflammation and remodeling through downregulating periostin via blocking TGF-β1/Smad pathway. Pharmacology. 2023; 108(5):432-443. https://doi.org/10.1159/000530703.

[173] Zhu W, Li YH, Zhao JJ, et al. The mechanism of triptolide in the treatment of connective tissue disease-related interstitial lung disease based on network pharmacology and molecular docking. Ann Med. 2022; 54(1):541-552. https://doi.org/10.1080/07853890.2022.2034931.

[174] Piao XM, Zhou JR, Xue L. Triptolide decreases rheumatoid arthritis fibroblast-like synoviocyte proliferation, invasion, inflammation and presents a therapeutic effect in collagen-induced arthritis rats via inactivating lncRNA RP11-83 J16.1 mediated URI1 and β-catenin signaling. Int Immunopharmacol. 2021;99:108010. https://doi.org/10.1016/j.intimp.2021.108010.

[175] Huang RS, Guo F, Li YP, et al. Activation of AMPK by triptolide alleviates nonalcoholic fatty liver disease by improving hepatic lipid metabolism, inflammation and fibrosis. Phytomedicine. 2021;92:153739. https://doi.org/10.1016/j.phymed.2021.153739.

[176] Zhao L, Lan ZX, Peng L, et al. Triptolide promotes autophagy to inhibit mesangial cell proliferation in IgA nephropathy via the CARD9/p38 MAPK pathway. Cell Prolif. 2022; 55(9):e13278. https://doi.org/10.1111/cpr.13278.

[177] Zheng Z, Yan GR, Xi NY, et al. Triptolide induces apoptosis and autophagy in cutaneous squamous cell carcinoma via Akt/mTOR pathway. Anticancer Agents Med Chem. 2023; 23(13):1596-1604. https://doi.org/10.2174/1871520623666230413130417.

[178] Chen Q, Lei YQ, Liu JF, et al. Triptolide improves neurobehavioral functions, inflammation, and oxidative stress in rats under deep hypothermic circulatory arrest. Aging. 2021; 13(2):3031-3044. https://doi.org/10.18632/aging.202460.

[179] Wang ZP, Jin HF, Xu RD, et al. Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression. Exp Mol Med. 2009; 41(10):717-727. https://doi.org/10.3858/emm.2009.41.10.078.

[180] Fan M, Zhang X, Song HP, et al. Dandelion (Taraxacum genus): a review of chemical constituents and pharmacological effects. Molecules. 2023; 28(13):5022. https://doi.org/10.3390/molecules28135022.

[181] Chen JF, Wu WB, Zhang MM, et al. Taraxasterol suppresses inflammation in IL-1β-induced rheumatoid arthritis fibroblast-like synoviocytes and rheumatoid arthritis progression in mice. Int Immunopharmacol. 2019; 70:274-283. https://doi.org/10.1016/j.intimp.2019.02.029.

[182] Wang SS, Wang Y, Liu XY, et al. Anti-inflammatory and anti-arthritic effects of taraxasterol on adjuvant-induced arthritis in rats. J Ethnopharmacol. 2016; 187:42-48. https://doi.org/10.1016/j.jep.2016.04.031.

[183] Zhang XM, Xiong HZ, Li HY, et al. Protective effect of taraxasterol against LPS-induced endotoxic shock by modulating inflammatory responses in mice. Immunopharmacol Immunotoxicol. 2014; 36(1):11-16. https://doi.org/10.3109/08923973.2013.861482.

[184] Sang R, Yu YF, Ge BJ, et al. Taraxasterol from Taraxacum prevents concanavalin A-induced acute hepatic injury in mice via modulating TLRs/NF-κB and Bax/Bc1-2 signalling pathways. Artif Cells Nanomed Biotechnol. 2019; 47(1):3929-3937. https://doi.org/10.1080/21691401.2019.1671433.

[185] Yang JQ, Xin CL, Yin GF, et al. Taraxasterol suppresses the proliferation and tumor growth of androgen-independent prostate cancer cells through the FGFR2-PI3K/AKT signaling pathway. Sci Rep. 2023; 13(1):13072. https://doi.org/10.1038/s41598-023-40344-w.

[186] Yang F, Ye XJ, Chen MY, et al. Inhibition of NLRP3 inflammasome activation and pyroptosis in macrophages by taraxasterol is associated with its regulation on mTOR signaling. Front Immunol. 2021;12:632606. https://doi.org/10.3389/fimmu.2021.632606.

[187] Zeng B, Wei AL, Zhou Q, et al. Andrographolide: a review of its pharmacology, pharmacokinetics, toxicity and clinical trials and pharmaceutical researches. Phytother Res. 2022; 36(1):336-364. https://doi.org/10.1002/ptr.7324.

[188] Duan MX, Zhou H, Wu QQ, et al. Andrographolide protects against HG-induced inflammation, apoptosis, migration, and impairment of angiogenesis via PI3K/AKT-eNOS signalling in HUVECs. Mediators Inflamm. 2019;2019:6168340. https://doi.org/10.1155/2019/6168340.

[189] Burgos RA, Alarcón P, Quiroga J, et al. Andrographolide, an anti-inflammatory multitarget drug: all roads lead to cellular metabolism. Molecules. 2021; 26(1):5. https://doi.org/10.3390/molecules26010005.

[190] Luo RL, Wang YJ, Guo Q, et al. Andrographolide attenuates Mycoplasma gallisepticum-induced inflammation and apoptosis by the JAK/PI3K/AKT signal pathway in the chicken lungs and primary alveolar type II epithelial cells. Int Immunopharmacol. 2022;109:108819. https://doi.org/10.1016/j.intimp.2022.108819.

[191] Xie SY, Deng W, Chen JJ, et al. Andrographolide protects against adverse cardiac remodeling after myocardial infarction through enhancing Nrf2 signaling pathway. Int J Biol Sci. 2020; 16(1):12-26. https://doi.org/10.7150/ijbs.37269.

[192] Yin XL, Zhuang XQ, Luo WT, et al. Andrographolide promote the growth and immunity of Litopenaeus vannamei, and protects shrimps against Vibrio alginolyticus by regulating inflammation and apoptosis via a ROS-JNK dependent pathway. Front Immunol. 2022;13:990297. https://doi.org/10.3389/fimmu.2022.990297.

[193] Efferth T. Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Curr Drug Targets. 2006; 7(4):407-421. https://doi.org/10.2174/138945006776359412.

[194] Salehi N, Nourbakhsh M, Noori S, et al. Tehranolid and artemisinin effects on ameliorating experimental autoimmune encephalomyelitis by modulating inflammation and remyelination. Mol Neurobiol. 2023; 60(10):5975-5986. https://doi.org/10.1007/s12035-023-03449-x.

[195] Yuan X, Li J, Li YF, et al. Artemisinin, a potential option to inhibit inflammation and angiogenesis in rosacea. Biomed Pharmacother. 2019;117:109181. https://doi.org/10.1016/j.biopha.2019.109181.

[196] Jiang Y, Du HJ, Liu X, et al. Artemisinin alleviates atherosclerotic lesion by reducing macrophage inflammation via regulation of AMPK/NF-κB/NLRP3 inflammasomes pathway. J Drug Target. 2020; 28(1):70-79. https://doi.org/10.1080/1061186X.2019.1616296.

[197] You XL, Jiang XY, Zhang CM, et al. Dihydroartemisinin attenuates pulmonary inflammation and fibrosis in rats by suppressing JAK2/STAT3 signaling. Aging. 2022; 14(3):1110-1127. https://doi.org/10.18632/aging.203874.

[198] Feng FB, Qiu HY. Effects of Artesunate on chondrocyte proliferation, apoptosis and autophagy through the PI3K/AKT/mTOR signaling pathway in rat models with rheumatoid arthritis. Biomed Pharmacother. 2018; 102:1209-1220. https://doi.org/10.1016/j.biopha.2018.03.142.

[199] Jiang L, Deng Y, Li W, et al. Arctigenin suppresses fibroblast activity and extracellular matrix deposition in hypertrophic scarring by reducing inflammation and oxidative stress. Mol Med Rep. 2020; 22(6):4783-4791. https://doi.org/10.3892/mmr.2020.11539.

[200] Shabgah AG, Suksatan W, Achmad MH, et al. Arctigenin an anti-tumor agent; a cutting-edge topic and up-to-the-minute approach in cancer treatment. Eur J Pharmacol. 2021;909:174419. https://doi.org/10.1016/j.ejphar.2021.174419.

[201] Lu YN, Zhao XD, Xu X, et al. Arctigenin exhibits hepatoprotective activity in Toxoplasma gondii-infected host through HMGB1/TLR4/NF-κB pathway. Int Immunopharmacol. 2020;84:106539. https://doi.org/10.1016/j.intimp.2020.106539.

[202] Li W, Zhang ZH, Zhang K, et al. Arctigenin suppress Th17 cells and ameliorates experimental autoimmune encephalomyelitis through AMPK and PPAR-γ/ROR-γt signaling. Mol Neurobiol. 2016; 53(8):5356-5366. https://doi.org/10.1007/s12035-015-9462-1.

[203] Lin YP, Li YK, Zeng YL, et al. Pharmacology, toxicity, bioavailability, and formulation of magnolol: an update. Front Pharmacol. 2021;12:632767. https://doi.org/10.3389/fphar.2021.632767.

[204] Tao WW, Hu YW, Chen ZY, et al. Magnolol attenuates depressive-like behaviors by polarizing microglia towards the M2 phenotype through the regulation of Nrf2/HO-1/NLRP3 signaling pathway. Phytomedicine. 2021;91:153692. https://doi.org/10.1016/j.phymed.2021.153692.

[205] Zeng MY, Xie ZY, Zhang JH, et al. Arctigenin attenuates vascular inflammation induced by high salt through TMEM16A/ESM1/VCAM-1 pathway. Biomedicines. 2022; 10(11):2760. https://doi.org/10.3390/biomedicines10112760.

[206] Chen HC, Fu WY, Chen HY, et al. Magnolol attenuates the inflammation and enhances phagocytosis through the activation of MAPK, NF-κB signal pathways in vitro and in vivo. Mol Immunol. 2019; 105:96-106. https://doi.org/10.1016/j.molimm.2018.11.008.

[207] Kuo DH, Lai YS, Lo CY, et al. Inhibitory effect of magnolol on TPA-induced skin inflammation and tumor promotion in mice. J Agric Food Chem. 2010; 58(9):5777-5783. https://doi.org/10.1021/jf100601r.

[208] Zhang L, Wang J, Xu W, et al. Magnolol inhibits Streptococcus suis-induced inflammation and ROS formation via TLR2/MAPK/NF-κB signaling in RAW264.7 cells. Pol J Vet Sci. 2018; 21(1):111-118. https://doi.org/10.24425/119028.

[209] Xu Y, Liu Z, Sun J, et al. Schisandrin B prevents doxorubicin-induced chronic cardiotoxicity and enhances its anticancer activity in vivo. PLoS One. 2011; 6(12):e28335. https://doi.org/10.1371/journal.pone.0028335.

[210] Luo W, Lin K, Hua JY, et al. Schisandrin B attenuates diabetic cardiomyopathy by targeting MyD88 and inhibiting MyD88-dependent inflammation. Adv Sci. 2022; 9(31):e2202590. https://doi.org/10.1002/advs.202202590.

[211] Ran JS, Ma CY, Xu K, et al. Schisandrin B ameliorated chondrocytes inflammation and osteoarthritis via suppression of NF-κB and MAPK signal pathways. Drug Des Devel Ther. 2018; 12:1195-1204. https://doi.org/10.2147/DDDT.S162014.

[212] Duan HXY, Zhang Q, Liu J, et al. Suppression of apoptosis in vascular endothelial cell, the promising way for natural medicines to treat atherosclerosis. Pharmacol Res. 2021;168:105599. https://doi.org/10.1016/j.phrs.2021.105599.

[213] Zhang WW, Wang WS, Shen CZ, et al. Network pharmacology for systematic understanding of Schisandrin B reduces the epithelial cells injury of colitis through regulating pyroptosis by AMPK/Nrf2/NLRP3 inflammasome. Aging. 2021; 13(19):23193-23209. https://doi.org/10.18632/aging.203611.

[214] Chen S, Ding YH, Shi SS, et al. Schisandrin B inhibits NLRP3 inflammasome pathway and attenuates early brain injury in rats of subarachnoid hemorrhage. Chin J Integr Med. 2022; 28(7):594-602. https://doi.org/10.1007/s11655-021-3348-z.

[215] Wang ZY, Xia Q, Liu X, et al. Phytochemistry,pharmacology, quality control and future research of Forsythia suspensa (Thunb.) Vahl: a review. J Ethnopharmacol. 2018; 210:318-339. https://doi.org/10.1016/j.jep.2017.08.040.

[216] Quan XH, Liu HH, Ye DM, et al. Forsythoside A alleviates high glucose-induced oxidative stress and inflammation in podocytes by inactivating MAPK signaling via MMP12 inhibition. Diabetes Metab Syndr Obes. 2021; 14:1885-1895. https://doi.org/10.2147/DMSO.S305092.

[217] Zhang XT, Ding Y, Kang P, et al. Forsythoside A modulates zymosan-induced peritonitis in mice. Molecules. 2018; 23(3):593. https://doi.org/10.3390/molecules23030593.

[218] Zhang X, Zhang HQ, Gao YK, et al. Forsythoside A regulates autophagy and apoptosis through the AMPK/mTOR/ULK1 pathway and alleviates inflammatory damage in MAC-T cells. Int Immunopharmacol. 2023;118:110053. https://doi.org/10.1016/j.intimp.2023.110053.

[219] Gong LH, Wang C, Zhou HL, et al. A review of pharmacological and pharmacokinetic properties of Forsythiaside A. Pharmacol Res. 2021;169:105690. https://doi.org/10.1016/j.phrs.2021.105690.

[220] Wang J, Xue X, Zhao X, et al. Forsythiaside A alleviates acute lung injury by inhibiting inflammation and epithelial barrier damages in lung and colon through PPAR-γ/RXR-α complex. J Adv Res. 2024, 60:183-200. https://doi.org/10.1016/j.jare.2023.08.006.

[221] Zafar S, Sarfraz I, Rasul A, et al. Osthole: a multifunctional natural compound with potential anticancer, antioxidant and anti-inflammatory activities. Mini Rev Med Chem. 2021; 21(18):2747-2763. https://doi.org/10.2174/1389557520666200709175948.

[222] Yao L, Lu P, Li YM, et al. Osthole relaxes pulmonary arteries through endothelial phosphatidylinositol 3-kinase/Akt-eNOS-NO signaling pathway in rats. Eur J Pharmacol. 2013; 699(1-3):23-32. https://doi.org/10.1016/j.ejphar.2012.11.056.

[223] Bae H, Lee JY, Song J, et al. Osthole interacts with an ER-mitochondria axis and facilitates tumor suppression in ovarian cancer. J Cell Physiol. 2021; 236(2):1025-1042. https://doi.org/10.1002/jcp.29913.

[224] Kordulewska NK, Topa J, Rozmus D, et al. Effects of osthole on inflammatory gene expression and cytokine secretion in histamine-induced inflammation in the Caco-2 cell line. Int J Mol Sci. 2021; 22(24):13634. https://doi.org/10.3390/ijms222413634.

[225] Xu RG, Liu Z, Hou JD, et al. Osthole improves collagen-induced arthritis in a rat model through inhibiting inflammation and cellular stress. Cell Mol Biol Lett. 2018;23:19. https://doi.org/10.1186/s11658-018-0086-0.

[226] Singh G, Bhatti R, Mannan R, et al. Osthole ameliorates neurogenic and inflammatory hyperalgesia by modulation of iNOS, COX-2, and inflammatory cytokines in mice. Inflammopharmacology. 2019; 27(5):949-960. https://doi.org/10.1007/s10787-018-0486-9.

[227] Li YQ, Wang JY, Qian ZQ, et al. Osthole inhibits intimal hyperplasia by regulating the NF-κB and TGF-β1/Smad2 signalling pathways in the rat carotid artery after balloon injury. Eur J Pharmacol. 2017; 811:232-239. https://doi.org/10.1016/j.ejphar.2017.06.025.

[228] Dai Q, Xie DQ, Zhang CL, et al. Osthole blocks HMGB1 release from the nucleus and confers protective effects against renal ischemia-reperfusion injury. Front Physiol. 2021;12:735425. https://doi.org/10.3389/fphys.2021.735425.

[229] Hua KF, Yang SM, Kao TY, et al. Osthole mitigates progressive IgA nephropathy by inhibiting reactive oxygen species generation and NF-κB/NLRP3 pathway. PLoS One. 2013; 8(10):e77794. https://doi.org/10.1371/journal.pone.0077794.

[230] Ma T, Wang XP, Qu WJ, et al. Osteoarthritis development by enhancing autophagy activated via the AMPK/ULK1 pathway. Molecules. 2022; 27(23):8624. https://doi.org/10.3390/molecules27238624.

[231] Tsai CY, Tang CY, Tan TS, et al. Subgingival microbiota in individuals with severe chronic periodontitis. J Microbiol Immunol Infect. 2018; 51(2):226-234. https://doi.org/10.1016/j.jmii.2016.04.007.

[232] Sufaru IG, Teslaru S, Pasarin L, et al. Host response modulation therapy in the diabetes mellitus-periodontitis conjuncture: a narrative review. Pharmaceutics. 2022; 14(8):1728. https://doi.org/10.3390/pharmaceutics14081728.

[233] Ceruelos AH, Romero-Quezada LC, Ledezma JCR, et al. Therapeutic uses of metronidazole and its side effects: an update. Eur Rev Med Pharmacol Sci. 2019; 23(1):397-401. https://doi.org/10.26355/eurrev_201901_16788.

[234] Sukumaran SK, Vadakkekuttical RJ, Kanakath H. Comparative evaluation of the effect of curcumin and chlorhexidine on human fibroblast viability and migration: An in vitro study. J Indian Soc Periodontol. 2020; 24(2):109-116. https://doi.org/10.4103/jisp.jisp_173_19.

[235] Meng Y, Jiang ZT, Yan GJ, et al. Mechanism of Qingwei Powder in treatment of periodontitis based on UPLC-Q-TOF-MS, GC-MS, network pharmacology and molecular docking. China J Chin Mater Med. 2022; 47(10):2778-2787. https://doi.org/10.19540/j.cnki.cjcmm.20211027.403.

[236] Liu JR, Huang Y, Lou XZ, et al. Effect of Pudilan Keyanning antibacterial mouthwash on dental plaque and gingival inflammation in patients during periodontal maintenance phase: study protocol for double-blind, randomised clinical trial. BMJ Open. 2021; 11(11):e048992. https://doi.org/10.1136/bmjopen-2021-048992.

[237] Cheng L, Liu W, Zhang T, et al. Evaluation of the effect of a toothpaste containing Pudilan extract on inhibiting plaques and reducing chronic gingivitis: a randomized, double-blinded, parallel controlled clinical trial. J Ethnopharmacol. 2019;240:111870. https://doi.org/10.1016/j.jep.2019.111870.

[238] Sun JY, Li DL, Dong Y, et al. Baicalin inhibits toll-like receptor 2/4 expression and downstream signaling in rat experimental periodontitis. Int Immunopharmacol. 2016; 36:86-93. https://doi.org/10.1016/j.intimp.2016.04.012.

[239] Gu LP, Ke YY, Gan JC, et al. Berberine suppresses bone loss and inflammation in ligature-induced periodontitis through promotion of the G protein-coupled estrogen receptor-mediated inactivation of the p38MAPK/NF-κB pathway. Arch Oral Biol. 2021;122:104992. https://doi.org/10.1016/j.archoralbio.2020.104992.

[240] Sun YR, Zhao BH, Li ZB, et al. Beneficial effects of glycyrrhizin in chronic periodontitis through the inhibition of inflammatory response. Dose-Response. 2020; 18(3):1559325820952660. https://doi.org/10.1177/1559325820952660.

[241] Wei Y, Fu JY, Wu WJ, et al. Quercetin prevents oxidative stress-Induced injury of periodontal ligament cells and alveolar bone loss in periodontitis. Drug Des Devel Ther. 2021; 15:3509-3522. https://doi.org/10.2147/DDDT.S315249.