Integrating Network Pharmacology and Experimental Validation to Decipher the Anti-Inflammatory Effects of Magnolol on LPS-induced RAW264.7 Cells


Citar

Texto integral

Resumo

Introduction:Magnolol is beneficial against inflammation-mediated damage. However, the underlying mechanisms by which magnolol exerts anti-inflammatory effects on macrophages remain unclear.

Objective:In this study, network pharmacology and experimental validation were used to assess the effect of magnolol on inflammation caused by lipopolysaccharide (LPS) in RAW264.7 cells.

Materials and Methods:Genes related to magnolol were identified in the PubChem and Swiss Target Prediction databases, and gene information about macrophage polarization was retrieved from the GeneCards, OMIM, and PharmGKB databases. Analysis of protein-protein interactions was performed with STRING, and Cytoscape was used to construct a component-target-disease network. GO and KEGG enrichment analyses were performed to ascertain significant molecular biological processes and signaling pathways. LPS was used to construct the inflammatory cell model. ELISA and qRT‒PCR were used to examine the expression levels of inflammationassociated factors, immunofluorescence was used to examine macrophage markers (CD86 and CD206), and western blotting was used to examine protein expression levels.

Results:The hub target genes of magnolol that act on macrophage polarization were MDM2, MMP9, IL-6, TNF, EGFR, AKT1, and ERBB2. The experimental validation results showed that magnolol treatment decreased the levels of proinflammatory factors (TNF-α, IL-1β, and IL-6). Moreover, the levels of anti-inflammatory factors (IL-10 and IL-4) were increased. In addition, magnolol upregulated the expression of M2 markers (Agr-1, Fizzl, and CD206) and downregulated M1 markers (CD86). The cell experiment results supported the network pharmacological results and demonstrated that magnolol alleviated inflammation by modulating the PI3k-Akt and P62/keap1/Nrf2 signaling pathways.

Conclusion:According to network pharmacology and experimental validation, magnolol attenuated inflammation in LPS-induced RAW264.7 cells mainly by inhibiting M1 polarization and enhancing M2 polarization by activating the PI3K/Akt and P62/keap1/Nrf2 signaling pathways.

Sobre autores

Lei Hao

Department of Surgery Two, First Affiliated Hospital of Guangzhou University of Chinese Medicine

Email: info@benthamscience.net

Xiaoying Zhong

, Guangzhou University of Chinese Medicine,

Email: info@benthamscience.net

Runjia Yu

, Guangzhou University of Chinese

Email: info@benthamscience.net

Jiahui Chen

, Guangzhou University of Chinese Medicine

Email: info@benthamscience.net

Wei Li

, Guangzhou University of Chinese Medicine

Email: info@benthamscience.net

Yuzhong Chen

Department of Surgery Two, First Affiliated Hospital of Guangzhou University of Chinese Medicine

Email: info@benthamscience.net

Weiqi Lu

Department of Surgery Two, the First Affiliated Hospital of Guangzhou University of Chinese

Email: info@benthamscience.net

Jianyu Wu

Department of Surgery Two, First Affiliated Hospital of Guangzhou University of Chinese Medicine

Email: info@benthamscience.net

Peizong Wang

Department of Anesthesiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine,

Autor responsável pela correspondência
Email: info@benthamscience.net

Bibliografia

  1. Yan, J.; Horng, T. Lipid metabolism in regulation of macrophage functions. Trends Cell Biol., 2020, 30(12), 979-989. doi: 10.1016/j.tcb.2020.09.006 PMID: 33036870
  2. Funes, S.C.; Rios, M.; Escobar-Vera, J.; Kalergis, A.M. Implications of macrophage polarization in autoimmunity. Immunology, 2018, 154(2), 186-195. doi: 10.1111/imm.12910 PMID: 29455468
  3. Shanley, L.C.; Mahon, O.R.; Kelly, D.J.; Dunne, A. Harnessing the innate and adaptive immune system for tissue repair and regeneration: Considering more than macrophages. Acta Biomater., 2021, 133, 208-221. doi: 10.1016/j.actbio.2021.02.023 PMID: 33657453
  4. Kim, S.; Chang, H.J.; Volin, M.V.; Umar, S.; Van Raemdonck, K.; Chevalier, A.; Palasiewicz, K.; Christman, J.W.; Volkov, S.; Arami, S.; Maz, M.; Mehta, A.; Zomorrodi, R.K.; Fox, D.A.; Sweiss, N.; Shahrara, S. Macrophages are the primary effector cells in IL-7-induced arthritis. Cell. Mol. Immunol., 2020, 17(7), 728-740. doi: 10.1038/s41423-019-0235-z PMID: 31197255
  5. Shapouri-Moghaddam, A.; Mohammadian, S.; Vazini, H.; Taghadosi, M.; Esmaeili, S.A.; Mardani, F.; Seifi, B.; Mohammadi, A.; Afshari, J.T.; Sahebkar, A. Macrophage plasticity, polarization, and function in health and disease. J. Cell. Physiol., 2018, 233(9), 6425-6440. doi: 10.1002/jcp.26429 PMID: 29319160
  6. Kim, S.Y.; Nair, M.G. Macrophages in wound healing: Activation and plasticity. Immunol. Cell Biol., 2019, 97(3), 258-267. doi: 10.1111/imcb.12236 PMID: 30746824
  7. Li, S.; Qi, D.; Li, J.; Deng, X.; Wang, D. Vagus nerve stimulation enhances the cholinergic anti-inflammatory pathway to reduce lung injury in acute respiratory distress syndrome via STAT3. Cell Death Discov., 2021, 7(1), 63. doi: 10.1038/s41420-021-00431-1 PMID: 33782389
  8. Li, Y.; Dong, M.; Wang, Q.; Kumar, S.; Zhang, R.; Cheng, W.; Xiang, J.; Wang, G.; Ouyang, K.; Zhou, R.; Xie, Y.; Lu, Y.; Yi, J.; Duan, H.; Liu, J. HIMF deletion ameliorates acute myocardial ischemic injury by promoting macrophage transformation to reparative subtype. Basic Res. Cardiol., 2021, 116(1), 30. doi: 10.1007/s00395-021-00867-7 PMID: 33893593
  9. Notarte, K.I.R.; Quimque, M.T.J.; Macaranas, I.T.; Khan, A.; Pastrana, A.M.; Villaflores, O.B.; Arturo, H.C.P.; Pilapil, D.Y.H., IV; Tan, S.M.M.; Wei, D.Q.; Wenzel-Storjohann, A.; Tasdemir, D.; Yen, C.H.; Ji, S.Y.; Kim, G.Y.; Choi, Y.H.; Macabeo, A.P.G. Attenuation of lipopolysaccharide-induced inflammatory responses through inhibition of the NF-κB pathway and the increased NRF2 level by a flavonol-enriched n -butanol fraction from uvaria alba. ACS Omega, 2023, 8(6), 5377-5392. doi: 10.1021/acsomega.2c06451 PMID: 36816691
  10. Quimque, M.T.; Notarte, K.I.; Letada, A.; Fernandez, R.A.; Pilapil, D.Y., IV; Pueblos, K.R.; Agbay, J.C.; Dahse, H.M.; Wenzel-Storjohann, A.; Tasdemir, D.; Khan, A.; Wei, D.Q.; Gose Macabeo, A.P. Potential cancer- and alzheimer’s disease-targeting phosphodiesterase inhibitors from uvaria alba: Insights from in vitro and consensus virtual screening. ACS Omega, 2021, 6(12), 8403-8417. doi: 10.1021/acsomega.1c00137 PMID: 33817501
  11. Fernandez, R.A.; Quimque, M.T.; Notarte, K.I.; Manzano, J.A.; Pilapil, D.Y., IV; de Leon, V.N.; San Jose, J.J.; Villalobos, O.; Muralidharan, N.H.; Gromiha, M.M.; Brogi, S.; Macabeo, A.P.G. Myxobacterial depsipeptide chondramides interrupt SARS-CoV-2 entry by targeting its broad, cell tropic spike protein. J. Biomol. Struct. Dyn., 2022, 40(22), 12209-12220. doi: 10.1080/07391102.2021.1969281 PMID: 34463219
  12. de Leon, V.N.O.; Manzano, J.A.H.; Pilapil, D.Y.H., IV; Fernandez, R.A.T.; Ching, J.K.A.R.; Quimque, M.T.J.; Agbay, J.C.M.; Notarte, K.I.R.; Macabeo, A.P.G. Anti-HIV reverse transcriptase plant polyphenolic natural products with in silico inhibitory properties on seven non-structural proteins vital in SARS-CoV-2 pathogenesis. J. Genet. Eng. Biotechnol., 2021, 19(1), 104. doi: 10.1186/s43141-021-00206-2 PMID: 34272647
  13. Zhang, J.; Chen, Z.; Huang, X.; Shi, W.; Zhang, R.; Chen, M.; Huang, H.; Wu, L. Insights on the multifunctional activities of magnolol. BioMed Res. Int., 2019, 2019, 1-15. doi: 10.1155/2019/1847130 PMID: 31240205
  14. Sarrica, A.; Kirika, N.; Romeo, M.; Salmona, M.; Diomede, L. Safety and toxicology of magnolol and honokiol. Planta Med., 2018, 84(16), 1151-1164. doi: 10.1055/a-0642-1966 PMID: 29925102
  15. Liu, C.M.; Chen, S.H.; Liao, Y.W.; Yu, C.H.; Yu, C.C.; Hsieh, P.L. Magnolol ameliorates the accumulation of reactive oxidative stress and inflammation in diabetic periodontitis. J. Formos. Med. Assoc., 2021, 120(7), 1452-1458. doi: 10.1016/j.jfma.2021.01.010 PMID: 33581965
  16. Mao, S.H.; Feng, D.D.; Wang, X.; Zhi, Y.H.; Lei, S.; Xing, X.; Jiang, R.L.; Wu, J.N. Magnolol protects against acute gastrointestinal injury in sepsis by down-regulating regulated on activation, normal T-cell expressed and secreted. World J. Clin. Cases, 2021, 9(34), 10451-10463. doi: 10.12998/wjcc.v9.i34.10451 PMID: 35004977
  17. Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E.E. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res., 2021, 49(D1), D1388-D1395. doi: 10.1093/nar/gkaa971 PMID: 33151290
  18. Stelzer, G.; Rosen, N.; Plaschkes, I.; Zimmerman, S.; Twik, M.; Fishilevich, S.; Stein, T.I.; Nudel, R.; Lieder, I.; Mazor, Y. The genecards suite: From gene data mining to disease genome sequence analyses. Curr. Protoc. Bioinformatics., 2016, 54, 1.30.1-1.30.33. doi: 10.1002/cpbi.5
  19. Amberger, JS Hamosh, A Searching Online Mendelian Inheritance in Man (OMIM): A knowledgebase of human genes and genetic phenotypes. Curr. Protoc. Bioinformatics, 2017, 58, 1.2.1-1.2.12. doi: 10.1002/cpbi.27
  20. Barbarino, J.M.; Whirl-Carrillo, M.; Altman, R.B.; Klein, T.E. PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip. Rev. Syst. Biol. Med., 2018, 10(4), e1417. doi: 10.1002/wsbm.1417 PMID: 29474005
  21. Szklarczyk, D.; Morris, J.H.; Cook, H.; Kuhn, M.; Wyder, S.; Simonovic, M.; Santos, A.; Doncheva, N.T.; Roth, A.; Bork, P.; Jensen, L.J.; von Mering, C. The STRING database in 2017: Quality-controlled protein–protein association networks, made broadly accessible. Nucleic Acids Res., 2017, 45(D1), D362-D368. doi: 10.1093/nar/gkw937 PMID: 27924014
  22. Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res., 2003, 13(11), 2498-2504. doi: 10.1101/gr.1239303 PMID: 14597658
  23. Yu, G.; Wang, W.; Wang, X.; Xu, M.; Zhang, L.; Ding, L.; Guo, R.; Shi, Y. Network pharmacology-based strategy to investigate pharmacological mechanisms of Zuojinwan for treatment of gastritis. BMC Complement. Altern. Med., 2018, 18(1), 292. doi: 10.1186/s12906-018-2356-9 PMID: 30382864
  24. Bindea, G.; Mlecnik, B.; Hackl, H.; Charoentong, P.; Tosolini, M.; Kirilovsky, A.; Fridman, W.H.; Pagès, F.; Trajanoski, Z.; Galon, J.; Clue, GO A cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics, 2009, 25(8), 1091-1093. doi: 10.1093/bioinformatics/btp101 PMID: 19237447
  25. Sherman, B.T.; Hao, M.; Qiu, J.; Jiao, X.; Baseler, M.W.; Lane, H.C.; Imamichi, T.; Chang, W. DAVID: A web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res., 2022, 50(W1), W216-W221. doi: 10.1093/nar/gkac194 PMID: 35325185
  26. Rahman, M.M.; Rahaman, M.S.; Islam, M.R.; Rahman, F.; Mithi, F.M.; Alqahtani, T.; Almikhlafi, M.A.; Alghamdi, S.Q.; Alruwaili, A.S.; Hossain, M.S.; Ahmed, M.; Das, R.; Emran, T.B.; Uddin, M.S. Role of phenolic compounds in human disease: Current knowledge and future prospects. Molecules, 2021, 27(1), 233. doi: 10.3390/molecules27010233 PMID: 35011465
  27. Rahman, M.M.; Bibi, S.; Rahaman, M.S.; Rahman, F.; Islam, F.; Khan, M.S.; Hasan, M.M.; Parvez, A.; Hossain, M.A.; Maeesa, S.K. Natural therapeutics and nutraceuticals for lung diseases: Traditional significance, phytochemistry, and pharmacology. Biomed. Pharmacother., 2022, 150, 113041. doi: 10.1016/j.biopha.2022.113041
  28. Rauf, A.; Abu-Izneid, T.; Khalil, A.A.; Imran, M.; Shah, Z.A.; Emran, T.B.; Mitra, S.; Khan, Z.; Alhumaydhi, F.A.; Aljohani, A.S.M.; Khan, I.; Rahman, M.M.; Jeandet, P.; Gondal, T.A. Berberine as a potential anticancer agent: A comprehensive review. Molecules, 2021, 26(23), 7368. doi: 10.3390/molecules26237368 PMID: 34885950
  29. Rahman, M.M.; Islam, F. -Or-Rashid, M.H.; Mamun, A.A.; Rahaman, M.S.; Islam, M.M.; Meem, A.F.K.; Sutradhar, P.R.; Mitra, S.; Mimi, A.A.; Emran, T.B.; Fatimawali; Idroes, R.; Tallei, T.E.; Ahmed, M.; Cavalu, S. The gut microbiota (microbiome) in cardiovascular disease and its therapeutic regulation. Front. Cell. Infect. Microbiol., 2022, 12, 903570. doi: 10.3389/fcimb.2022.903570 PMID: 35795187
  30. Peng, Y.; Chen, B.; Zhao, J.; Peng, Z.; Xu, W.; Yu, G. Effect of intravenous transplantation of hUCB-MSCs on M1/M2 subtype conversion in monocyte/macrophages of AMI mice. Biomed. Pharmacother., 2019, 111, 624-630. doi: 10.1016/j.biopha.2018.12.095
  31. Liu, Y.; Gao, X.; Miao, Y.; Wang, Y.; Wang, H.; Cheng, Z.; Wang, X.; Jing, X.; Jia, L.; Dai, L.; Liu, M.; An, L. NLRP3 regulates macrophage M2 polarization through up-regulation of IL-4 in asthma. Biochem. J., 2018, 475(12), 1995-2008. doi: 10.1042/BCJ20180086 PMID: 29626160
  32. Wang, J.; Sun, Y.; Zhang, L.; Xu, W.; You, J.; Lu, H.; Song, Y.; Wei, J.; Li, L. Magnolol inhibits streptococcus suis-induced inflammation and ROS formation via TLR2/MAPK/NF-κB signaling in RAW264.7 cells. Pol. J. Vet. Sci., 2023, 21(1), 111-118. doi: 10.24425/119028 PMID: 29624001
  33. Xu, L.; Cai, Z.; Yang, F.; Chen, M. Activation-induced upregulation of MMP9 in mast cells is a positive feedback mediator for mast cell activation. Mol. Med. Rep., 2017, 15(4), 1759-1764. doi: 10.3892/mmr.2017.6215 PMID: 28259919
  34. Inoue, H.; Hattori, T.; Zhou, X.; Etling, E.B.; Modena, B.D.; Trudeau, J.B.; Holguin, F.; Wenzel, S.E. Dysfunctional ErbB2, an EGF receptor family member, hinders repair of airway epithelial cells from asthmatic patients. J. Allergy Clin. Immunol., 2019, 143(6), 2075-2085.e10. doi: 10.1016/j.jaci.2018.11.046 PMID: 30639343
  35. London, M.; Gallo, E. Epidermal growth factor receptor (EGFR) involvement in epithelial‐derived cancers and its current antibody‐based immunotherapies. Cell Biol. Int., 2020, 44(6), 1267-1282. doi: 10.1002/cbin.11340 PMID: 32162758
  36. Vergadi, E.; Ieronymaki, E.; Lyroni, K.; Vaporidi, K.; Tsatsanis, C. Akt signaling pathway in macrophage activation and M1/M2 polarization. J. Immunol., 2017, 198(3), 1006-1014. doi: 10.4049/jimmunol.1601515
  37. Arranz, A.; Doxaki, C.; Vergadi, E.; Martinez de la Torre, Y.; Vaporidi, K.; Lagoudaki, E.D.; Ieronymaki, E.; Androulidaki, A.; Venihaki, M.; Margioris, A.N.; Stathopoulos, E.N.; Tsichlis, P.N.; Tsatsanis, C. Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization. Proc. Natl. Acad. Sci., 2012, 109(24), 9517-9522. doi: 10.1073/pnas.1119038109 PMID: 22647600
  38. Lee, J.O.; Choi, E.; Shin, K.K.; Hong, Y.H.; Kim, H.G.; Jeong, D.; Hossain, M.A.; Kim, H.S.; Yi, Y.S.; Kim, D.; Kim, E.; Cho, J.Y. Compound K, a ginsenoside metabolite, plays an antiinflammatory role in macrophages by targeting the AKT1-mediated signaling pathway. J. Ginseng Res., 2019, 43(1), 154-160. doi: 10.1016/j.jgr.2018.10.003 PMID: 30662304
  39. Li, Y.; Zou, L.; Li, T.; Lai, D.; Wu, Y.; Qin, S. Mogroside V inhibits LPS-induced COX-2 expression/ROS production and overexpression of HO-1 by blocking phosphorylation of AKT1 in RAW264.7 cells. Acta Biochim. Biophys. Sin., 2019, 51(4), 365-374. doi: 10.1093/abbs/gmz014 PMID: 30877761
  40. Odkhuu, E.; Mendjargal, A.; Koide, N.; Naiki, Y.; Komatsu, T.; Yokochi, T. Lipopolysaccharide downregulates the expression of p53 through activation of MDM2 and enhances activation of nuclear factor-kappa B. Immunobiology, 2015, 220(1), 136-141. doi: 10.1016/j.imbio.2014.08.010 PMID: 25172547
  41. Kanehisa, M.; Furumichi, M.; Tanabe, M.; Sato, Y.; Morishima, K. KEGG: New perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res., 2017, 45(D1), D353-D361. doi: 10.1093/nar/gkw1092 PMID: 27899662
  42. Sun, X.; Chen, L.; He, Z. PI3K/Akt-Nrf2 and anti-inflammation effect of macrolides in chronic obstructive pulmonary disease. Curr. Drug Metab., 2019, 20(4), 301-304. doi: 10.2174/1389200220666190227224748 PMID: 30827233
  43. Lian, G.; Chen, S.; Ouyang, M.; Li, F.; Chen, L.; Yang, J. Colon cancer cell secretes EGF to promote M2 polarization of TAM through EGFR/PI3K/AKT/mTOR pathway. Technol. Cancer Res. Treat., 2019, 18. doi: 10.1177/1533033819849068 PMID: 31088266
  44. Zhao, S.J.; Kong, F.Q.; Jie, J.; Li, Q.; Liu, H.; Xu, A.D.; Yang, Y.Q.; Jiang, B.; Wang, D.D.; Zhou, Z.Q.; Tang, P.Y.; Chen, J.; Wang, Q.; Zhou, Z.; Chen, Q.; Yin, G.Y.; Zhang, H.W.; Fan, J. Macrophage MSR1 promotes BMSC osteogenic differentiation and M2-like polarization by activating PI3K/AKT/GSK3β/β-catenin pathway. Theranostics, 2020, 10(1), 17-35. doi: 10.7150/thno.36930 PMID: 31903103
  45. Liu, L.; Zhu, X.; Zhao, T.; Yu, Y.; Xue, Y.; Zou, H. Sirt1 ameliorates monosodium urate crystal–induced inflammation by altering macrophage polarization via the PI3K/Akt/STAT6 pathway. Rheumatology, 2019, 58(9), 1674-1683. doi: 10.1093/rheumatology/kez165 PMID: 31106362
  46. Wang, L.; He, C. Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis. Front. Immunol., 2022, 13, 967193. doi: 10.3389/fimmu.2022.967193 PMID: 36032081
  47. Aki, T.; Funakoshi, T.; Noritake, K.; Unuma, K.; Uemura, K. Extracellular glucose is crucially involved in the fate decision of LPS-stimulated RAW264.7 murine macrophage cells. Sci. Rep., 2020, 10(1), 10581. doi: 10.1038/s41598-020-67396-6 PMID: 32601294
  48. Kiani, A.A.; Elyasi, H.; Ghoreyshi, S.; Nouri, N.; Safarzadeh, A.; Nafari, A. Study on hypoxia-inducible factor and its roles in immune system. Immunol. Med., 2021, 44(4), 223-236. doi: 10.1080/25785826.2021.1910187 PMID: 33896415
  49. Orecchioni, M.; Ghosheh, Y.; Pramod, A.B.; Ley, K. Macrophage polarization: Different gene signatures in M1(LPS+) vs. classically and M2(LPS–) vs. Alternatively activated macrophages. Front. Immunol., 2019, 10, 1084. doi: 10.3389/fimmu.2019.01084 PMID: 31178859
  50. Li, S.; Dai, Q.; Zhang, S.; Liu, Y.; Yu, Q.; Tan, F.; Lu, S.; Wang, Q.; Chen, J.; Huang, H.; Liu, P.; Li, M. Ulinastatin attenuates LPS-induced inflammation in mouse macrophage RAW264.7 cells by inhibiting the JNK/NF-κB signaling pathway and activating the PI3K/Akt/Nrf2 pathway. Acta Pharmacol. Sin., 2018, 39(8), 1294-1304. doi: 10.1038/aps.2017.143 PMID: 29323338
  51. Mata, A.; Cadenas, S. The antioxidant transcription factor Nrf2 in cardiac ischemia-reperfusion injury. Int. J. Mol. Sci., 2021, 22(21), 11939. doi: 10.3390/ijms222111939 PMID: 34769371
  52. Kobayashi, E.H.; Suzuki, T.; Funayama, R.; Nagashima, T.; Hayashi, M.; Sekine, H.; Tanaka, N.; Moriguchi, T.; Motohashi, H.; Nakayama, K.; Yamamoto, M. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun., 2016, 7(1), 11624. doi: 10.1038/ncomms11624 PMID: 27211851
  53. Zhuang, Y.; Wu, H.; Wang, X.; He, J.; He, S.; Yin, Y. Resveratrol attenuates oxidative stress-induced intestinal barrier injury through PI3K/Akt-mediated Nrf2 signaling pathway. Oxid. Med. Cell. Longev., 2019, 2019, 1-14. doi: 10.1155/2019/7591840 PMID: 31885814
  54. Linton, M.F.; Moslehi, J.J.; Babaev, V.R. Akt signaling in macrophage polarization, survival, and atherosclerosis. Int. J. Mol. Sci., 2019, 20(11), 2703. doi: 10.3390/ijms20112703 PMID: 31159424
  55. Zhang, W.; Feng, C.; Jiang, H. Novel target for treating Alzheimer’s Diseases: Crosstalk between the Nrf2 pathway and autophagy. Ageing Res. Rev., 2021, 65, 101207. doi: 10.1016/j.arr.2020.101207 PMID: 33144123
  56. Ichimura, Y.; Komatsu, M. Activation of p62/SQSTM1-Keap1-nuclear factor erythroid 2-related factor 2 pathway in cancer. Front. Oncol., 2018, 8, 210. doi: 10.3389/fonc.2018.00210 PMID: 29930914
  57. Tsai, T.F.; Chen, P.C.; Lin, Y.C.; Chou, K.Y.; Chen, H.E.; Ho, C.Y.; Lin, J.F.; Hwang, T.I.S. Miconazole contributes to NRF2 activation by noncanonical P62-KEAP1 pathway in bladder cancer cells. Drug Des. Devel. Ther., 2020, 14, 1209-1218. doi: 10.2147/DDDT.S227892 PMID: 32273683

Arquivos suplementares

Arquivos suplementares
Ação
1. JATS XML
Baixar

Declaração de direitos autorais © Bentham Science Publishers, 2024