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fibroblast-like synovial cells, inflammation, MAPK-signaling pathway, Orientin, rheumatoid arthritis
Background: Natural compounds are found to play an essential role in diverse inflammatory diseases, including rheumatoid arthritis (RA). Orientin, a flavonoid compound, is closely related to diverse pathological processes. Nevertheless, the role of orientin in RA is still unknown.
Methods: The cell viability was tested through cell counting kit 8 (CCK-8) assay, and the number of cell colonies was calculated via colony formation assay. In addition, flow cytometry assay was employed to detect apoptosis rate in human RA fibroblast-like synoviocytes (RA-FLS). Besides, Transwell assay was introduced to determine cell migratory and invasive abilities. Moreover, the level of cytokines (IL-8, IL-1β, and IL-6) was estimated with quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent serologic assay. Furthermore, western blotting analysis was used to test the protein levels of cleaved-caspase-3, Bax, BCL-2, matrix metalloproteinase (MMP)-2, MMP-9, phosphorylated c-Jun N-terminal kinase, p-P38, and phospho-extracellular signal-related kinase.
Results: Orientin inhibited cell viability, migration as well as invasion in a concentration- dependent manner in human RA-FLS. Additionally, treatment of orientin facilitated apoptosis and decreased the secretion of cytokines induced by tumor necrosis factor alpha (TNF-α) in human RA-FLS. Moreover, orientin inactivated mitogen-activated protein kinase (MAPK)-related signaling pathway, notably in human RA-FLS.
Conclusion: These findings confirmed that orientin inhibited human RA-FLS development and decreased TNF-α-induced inflammatory factors, at least partly, by modulating MAPK-signaling pathway, which implied that orientin might be an effective agent for treating RA.
2. Du H, Zhang X, Zeng Y, Huang X, Chen H, Wang S, et al. A novel phytochemical, DIM, inhibits proliferation, migration, invasion and TNF-alpha induced inflammatory cytokine production of synovial fibroblasts from rheumatoid arthritis patients by targeting MAPK and AKT/mTOR signal pathway. Front Immunol. 2019;10:1620. 10.3389/fimmu.2019.01620
3. Huber LC, Distler O, Tarner I, Gay RE, Gay S, Pap T. Synovial fibroblasts: Key players in rheumatoid arthritis. Rheumatology (Oxford). 2006;45(6):669–75. 10.1093/rheumatology/kel065
4. Liu Y, Pan YF, Xue YQ, Fang LK, Guo XH, Guo X, et al. uPAR promotes tumor-like biologic behaviors of fibroblast-like synoviocytes through PI3K/Akt signaling pathway in patients with rheumatoid arthritis. Cell Mol Immunol. 2018;15(2):171–81. 10.1038/cmi.2016.60
5. Ma JD, Jing J, Wang JW, Yan T, Li QH, Mo YQ, et al. A novel function of artesunate on inhibiting migration and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients. Arthritis Res Ther. 2019;21(1):153. 10.1186/s13075-019-1935-6
6. Kong ZL, Che K, Hu JX, Chen Y, Wang YY, Wang X, et al. Orientin protects podocytes from high glucose induced apoptosis through mitophagy. Chem Biodivers. 2020;17(3):e1900647. 10.1002/cbdv.201900647
7. Yuan L, Wu Y, Ren X, Liu Q, Wang J, Liu X. Isoorientin attenuates lipopolysaccharide-induced pro-inflammatory responses through down-regulation of ROS-related MAPK/NF-kappaB signaling pathway in BV-2 microglia. Mol Cell Biochem. 2014;386(1–2):153–65. 10.1007/s11010-013-1854-9
8. Yu L, Wang S, Chen X, Yang H, Li X, Xu Y, et al. Orientin alleviates cognitive deficits and oxidative stress in Abeta1-42-induced mouse model of Alzheimer’s disease. Life Sci. 2015;121:104–9. 10.1016/j.lfs.2014.11.021
9. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: Dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008;8(5):349–61. 10.1038/nri2294
10. Li F, Zong J, Zhang H, Zhang P, Xu L, Liang K, et al. Orientin reduces myocardial infarction size via eNOS/NO signaling and thus mitigates adverse cardiac remodeling. Front Pharmacol. 2017;8:926. 10.3389/fphar.2017.00926
11. Li C, Cai C, Zheng X, Sun J, Ye L. Orientin suppresses oxidized low-density lipoproteins induced inflammation and oxidative stress of macrophages in atherosclerosis. Biosci Biotechnol Biochem. 2020;84(4):774–9. 10.1080/09168451.2019.1702871
12. Kim SJ, Pham TH, Bak Y, Ryu HW, Oh SR, Yoon DY. Orientin inhibits invasion by suppressing MMP-9 and IL-8 expression via the PKCalpha/ ERK/AP-1/STAT3-mediated signaling pathways in TPA-treated MCF-7 breast cancer cells. Phytomedicine. 2018;50:35–42. 10.1016/j.phymed.2018.09.172
13. Pan J-X. LncRNA H19 promotes atherosclerosis by regulating MAPK and NF-kB signaling pathway. Eur Rev Med Pharmacol Sci. 2017;21(2):322–8.
14. Drosten M, Barbacid M. Targeting the MAPK pathway in KRAS-driven tumors. Cancer Cell. 2020;37(4):543–50. 10.1016/j.ccell.2020.03.013
15. Li Y, Zhang L, Gong J. Naringin attenuated acute lung injury in rat model with acute pancreatitis in pregnancy through inactivation of p38 MAPK pathway. Signa Vitae. 2020;16(2):189–94. 10.22514/sv.2020.16.0079
16. Yong H-Y, Koh MS, Moon A. The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Expert Opin Investig Drugs. 2009;8(12):1893–905. 10.1517/13543780903321490
17. Yang G, Chang CC, Yang Y, Yuan L, Xu L, Ho CT, et al. Resveratrol alleviates rheumatoid arthritis via reducing ROS and inflammation, inhibiting MAPK signaling pathways, and suppressing angiogenesis. J Agric Food Chem. 2018;66(49):12953–60. 10.1021/acs.jafc.8b05047
18. Qi S, Feng Z, Li Q, Qi Z, Zhang Y. Inhibition of ROS-mediated activation Src-MAPK/AKT signaling by orientin alleviates H2O2-induced apoptosis in PC12 cells. Drug Des Devel Ther. 2018;12:3973–84. 10.2147/DDDT.S178217
19. Yang Y, Yang X, Wu Y, Fu M. METTL3 promotes inflammation and cell apoptosis in a pediatric pneumonia model by regulating EZH2. Allergol Immunopathol (Madr). 2021;49(5):49–56. 10.15586/aei.v49i5.445
20. Chen J, Xiao X, He S, Qiao Y, Ma S. Altered circular RNA expression profiles in an ovalbumin-induced murine model of allergic rhinitis. Allergol Immunopathol (Madr). 2021;49(2):94–103. 10.15586/aei.v49i2.33
21. Bastani A, Asghary A, Heidari MH, Karimi-Busheri F. Evaluation of the sensitivity and specificity of serum level of prostasin, CA125, LDH, AFP, and hCG+β in epithelial ovarian cancer patients. Eur J Gynaecol Oncol. 2017;38(3):418–24.
22. Regidor PA, Regidor M, Callies R, Schindler AE. Detection of p53 auto-antibodies in the sera of breast cancer patients with a new recurrence using an ELISA assay. Does a correlation with the recurrence free interval exist? Eur J Gynaecol Oncol. 1996;17(3):192–9.
23. Orgaz JL, Pandya P, Dalmeida R, Karagiannis P, Sanchez-Laorden B, Viros A, et al. Diverse matrix metalloproteinase functions regulate cancer amoeboid migration. Nat Commun. 2014;5:4255. 10.1038/ncomms5255
24. Chabottaux V, Noel A. Breast cancer progression: Insights into multifaceted matrix metalloproteinases. Clin Exp Metastasis. 2007;24(8):647–56. 10.1007/s10585-007-9113-7
25. Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, et al. Rheumatoid arthritis. Nat Rev Dis Primers. 2018;4:18001. 10.1038/nrdp.2018.1
26. Chen W, Wang J, Xu Z, Huang F, Qian W, Ma J, et al. Apremilast ameliorates experimental arthritis via suppression of Th1 and Th17 cells and enhancement of CD4(+) Foxp3(+) regulatory T cells differentiation. Front Immunol. 2018;9:1662. 10.3389/fimmu.2018.01662
27. Chen Z, Bozec A, Ramming A, Schett G. Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis. Nat Rev Rheumatol. 2019;15(1):9–17. 10.1038/s41584-018-0109-2
28. Bartok B, Firestein GS. Fibroblast-like synoviocytes: Key effector cells in rheumatoid arthritis. Immunol Rev. 2010;233(1):233–55. 10.1111/j.0105-2896.2009.00859.x
29. Raju J, Gupta D, Rao AR, Yadava PK, Baquer NZ. Trigonellafoenum graecum (fenugreek) seed powder improves glucose homeostasis in alloxan diabetic rat tissues by reversing the altered glycolytic, gluconeogenic and lipogenic enzymes. Mol Cell Biochem. 2001;224(1–2):45–51. 10.1023/a:1011974630828
30. Gao F, Du W, Zafar MI, Shafqat RA, Jian L, Cai Q, et al. 4-Hydroxyisoleucine ameliorates an insulin resistant-like state in 3T3-L1 adipocytes by regulating TACE/TIMP3 expression. Drug Des Devel Ther. 2015;9:5727–36. 10.2147/DDDT.S92355
31. Shabana Shabbeer MS, Anchoori RK, Kachhap S, Hidalgo M, Jimeno A, Davidson N, et al. Fenugreek: A naturally occurring edible spice as an anticancer agent. Cancer Biol Ther. 2009;8(3):272–8. 10.4161/cbt.8.3.7443
32. Gautam S, Ishrat N, Yadav P, Singh R, Narender T, Srivastava AK. 4-Hydroxyisoleucine attenuates the inflammation-mediated insulin resistance by the activation of AMPK and suppression of SOCS-3 co-immunoprecipitation with both the IR-beta subunit as well as IRS-1. Mol Cell Biochem. 2016;414(1–2):95–104. 10.1007/s11010-016-2662-9
33. Lam KY, Ling AP, Koh RY, Wong YP, Say YH. A review on medicinal properties of orientin. Adv Pharmacol Sci. 2016;2016:4104595. 10.1155/2016/4104595
34. Yang F, Zhou S, Wang C, Huang Y, Li H, Wang Y, et al. Epigenetic modifications of interleukin-6 in synovial fibroblasts from osteoarthritis patients. Sci Rep. 2017;7:43592. 10.1038/srep43592
35. An F, Wang S, Tian Q, Zhu D. Effects of orientin and vitexin from Trollius chinensis on the growth and apoptosis of esophageal cancer EC-109 cells. Oncol Lett. 2015;10(4):2627–33. 10.3892/ol.2015.3618
36. Czemplik M, Mierziak J, Szopa J, Kulma A. Flavonoid C-glucosides derived from flax straw extracts reduce human breast cancer cell growth in vitro and induce apoptosis. Front Pharmacol. 2016;7:282. 10.3389/fphar.2016.00282
37. Zhao L, Liu Y, Tong D, Qin Y, Yang J, Xue M, et al. MeCP2 promotes gastric cancer progression through regulating FOXF1/ Wnt5a/β-Catenin and MYOD1/Caspase-3 signaling pathways. EBio Med. 2017;16:87–100. 10.1016/j.ebiom.2017.01.021
38. Li X, Bao C, Ma Z, Xu B, Ying X, Liu X, et al. Perfluorooctanoic acid stimulates ovarian cancer cell migration, invasion via ERK/NF-kappaB/MMP-2/-9 pathway. Toxicol Lett. 2018;294:44–50. 10.1016/j.toxlet.2018.05.009
39. Zhang J, Wang R, Cheng L, Xu H. Celastrol inhibit the proliferation, invasion and migration of human cervical HeLa cancer cells through down-regulation of MMP-2 and MMP-9. J Cell Mol Med. 2021;25(11):5335–8. 10.1111/jcmm.16488
40. Liu H, Yang J, Yang W, Hu S, Wu Y, Zhao B, et al. Focus on notoginsenoside R1 in metabolism and prevention against human diseases. Drug Design Dev Ther. 2020;14:551–65. 10.2147/DDDT.S240511
41. Thiel MJ, Schaefer CJ, Lesch ME, Mobley JL, Dudley DT, Tecle H, et al. Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: Potential proinflammatory mechanisms. Arthritis Rheum. 2007;56(10):3347–57.
42. Morel J, Audo R, Hahne M, Combe B. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt. J Biol Chem. 2005;280(16):15709–18. 10.1074/jbc.M414469200
43. Lowin T, Straub RH, Neumann E, Bosserhoff A, Vogel C, Moissl C, et al. Glucocorticoids increase alpha5 integrin expression and adhesion of synovial fibroblasts but inhibit ERK signaling, migration, and cartilage invasion. Arthritis Rheum. 2009;60(12):3623–32. 10.1002/art.24985