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Cited by 57Advanced Glycation End Products researchGalectins and Cancer BiologyImmune Response and Inflammation

Therapeutic potential of targeting the receptor for advanced glycation end products (RAGE) by small molecule inhibitors

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Singh, Harbinder, Agrawal, Devendra K.·2022·Drug Development Research
DOI 10.1002/ddr.21971PMC PMC9474610
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Abstract

Receptor for advanced glycation end products (RAGE) is a 45 kDa transmembrane receptor of immunoglobulin family that can bind to various endogenous and exogenous ligands and initiate the inflammatory downstream signaling pathways. RAGE is involved in various disorders including cardiovascular and neurodegenerative diseases, cancer, and diabetes. This review summarizes the structural features of RAGE and its various isoforms along with their pathological effects. Mainly, the article emphasized on the translational significance of antagonizing the interactions of RAGE with its ligands using small molecules reported in the last 5 years and discusses future approaches that could be employed to block the interactions in the treatment of chronic inflammatory ailments. The RAGE inhibitors described in this article could prove as a powerful approach in the management of immune-inflammatory diseases. A critical review of the literature suggests that there is a dire need to dive deeper into the molecular mechanism of action to resolve critical issues that must be addressed to understand RAGE-targeting therapy and long-term blockade of RAGE in human diseases.

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  • Multiple small molecules developed to block RAGE signaling have shown potential to inhibit glial cell activation in vitro and in animal models.

    “Multiple small molecules have been developed to block RAGE signaling and have shown potential to inhibit glial cells activation in vitro and in animal models.345”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [345]

    The RAGE INHIBITORS section reports that the small-molecule inhibitor FPS-ZM1 inhibits activation of primary microglia by AGEs. The Conclusion also discusses FPS-ZM1 in cell culture and rodent models, but our copy does not say that multiple molecules inhibited glial-cell activation in both in vitro and animal models. (LLM, conf=0.86)

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  1. Adrover, M., Marino, L., Sanchis, P., Pauwels, K., Kraan, Y., Lebrun, P., & Donoso, J. (2014). Mechanistic insights in glycation‐induced protein aggregation. Biomacromolecules, 15(9), 3449– 3462. 10.1021/bm501077j 25057908 · DOI
  2. Ahmad, S. S., Khan, H., Danish Rizvi, S. M., Ansari, S. A., Ullah, R., Rastrelli, L., & Siddiqui, M. H. (2019). Computational study of natural compounds for the clearance of amyloid‐betaeta: A potential therapeutic management strategy for Alzheimer's disease. Molecules, 24(18). 10.3390/molecules24183233 PMC6767296 31491967 · DOI
  3. Akhter, F., Khan, M. S., & Ahmad, S. (2015). Acquired immunogenicity of calf thymus DNA and LDL modified by d‐ribose: A comparative study. International Journal of Biological Macromolecules, 72, 1222– 1227. 10.1016/j.ijbiomac.2014.10.034 25450543 · DOI
  4. Anisuzzaman, Hatta, T., Miyoshi, T., Matsubayashi, M., Islam, M. K., Alim, M. A., & Tsuji, N. (2014). Longistatin in tick saliva blocks advanced glycation end‐product receptor activation. Journal of Clinical Investigation, 124(10), 4429– 4444. 10.1172/jci74917 25401185 PMC4191044 · DOI
  5. Basta, G. (2008). Receptor for advanced glycation endproducts and atherosclerosis: From basic mechanisms to clinical implications. Atherosclerosis, 196(1), 9– 21. 10.1016/j.atherosclerosis.2007.07.025 17826783 · DOI
  6. Bierhaus, A., Humpert, P. M., Morcos, M., Wendt, T., Chavakis, T., Arnold, B., & Nawroth, P. P. (2005). Understanding RAGE, the receptor for advanced glycation end products. Journal of Molecular Medicine, 83(11), 876– 886. 10.1007/s00109-005-0688-7 16133426 · DOI · Paper page
  7. Bongarzone, S., Savickas, V., Luzi, F., & Gee, A. D. (2017). Targeting the receptor for advanced glycation endproducts (RAGE): A medicinal chemistry perspective. Journal of Medicinal Chemistry, 60(17), 7213– 7232. 10.1021/acs.jmedchem.7b00058 28482155 PMC5601361 · DOI · Paper page
  8. Brett, J., Schmidt, A. M., Yan, S. D., Zou, Y. S., Weidman, E., Pinsky, D., Nowygrod, R., Neeper, M., Przysiecki, C., Shaw, A., Migheli, A., & Stern, D. (1993). Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. American Journal of Pathology, 143(6), 1699– 1712. https://www.ncbi.nlm.nih.gov/pubmed/8256857 8256857 PMC1887265
  9. Burstein, A. H., Grimes, I., Galasko, D. R., Aisen, P. S., Sabbagh, M., & Mjalli, A. M. (2014). Effect of TTP488 in patients with mild to moderate Alzheimer's disease. BMC Neurology, 14, 12. 10.1186/1471-2377-14-12 24423155 PMC4021072 · DOI
  10. Burstein, A. H., Sabbagh, M., Andrews, R., Valcarce, C., Dunn, I., & Altstiel, L. (2018). Development of azeliragon, an oral small molecule antagonist of the receptor for advanced glycation endproducts, for the potential slowing of loss of cognition in mild Alzheimer's disease. Journal of Prevention of Alzheimers Disease, 5(2), 149– 154. 10.14283/jpad.2018.18 29616709 · DOI
  11. Cary, B. P., Brooks, A. F., Fawaz, M. V., Drake, L. R., Desmond, T. J., Sherman, P., & Scott, P. J. (2016). Synthesis and evaluation of [(18)F]RAGER: A first generation small‐molecule PET radioligand targeting the receptor for advanced glycation endproducts. ACS Chemical Neuroscience, 7(3), 391– 398. 10.1021/acschemneuro.5b00319 26771209 PMC5682588 · DOI
  12. Chavakis, T., Bierhaus, A., Al‐Fakhri, N., Schneider, D., Witte, S., Linn, T., & Nawroth, P. P. (2003). The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: A novel pathway for inflammatory cell recruitment. Journal of Experimetnal Medicine, 198(10), 1507– 1515. 10.1084/jem.20030800 PMC2194124 14623906 · DOI
  13. Chen, C., Jiang, P., Xue, H., Peterson, S. E., Tran, H. T., McCann, A. E., & Deng, W. (2020). Author correction: Role of astroglia in down's syndrome revealed by patient‐derived human‐induced pluripotent stem cells. Nature Communications, 11(1), 1070. 10.1038/s41467-020-14865-1 PMC7035289 32081845 · DOI
  14. Cheng, C., Tsuneyama, K., Kominami, R., Shinohara, H., Sakurai, S., Yonekura, H., & Yamamoto, Y. (2005). Expression profiling of endogenous secretory receptor for advanced glycation end products in human organs. Modern Pathology, 18(10), 1385– 1396. 10.1038/modpathol.3800450 15933755 · DOI
  15. Chiou, J. W., Fu, B., Chou, R. H., & Yu, C. (2016). Blocking the interactions between calcium‐bound S100A12 protein and the V domain of RAGE using tranilast. PLoS One, 11(9), e0162000. 10.1371/journal.pone.0162000 27598566 PMC5012620 · DOI
  16. Cho, H. J., Son, S. M., Jin, S. M., Hong, H. S., Shin, D. H., Kim, S. J., & Mook‐Jung, I. (2009). RAGE regulates BACE1 and abeta generation via NFAT1 activation in Alzheimer's disease animal model. FASEB Journal, 23(8), 2639– 2649. 10.1096/fj.08-126383 19332646 · DOI
  17. Choi, K., Lim, K. S., Shin, J., Kim, S. H., Suh, Y. G., Hong, H. S., & Lee, J. (2015). 6‐Phenoxy‐2‐phenylbenzoxazoles, novel inhibitors of receptor for advanced glycation end products (RAGE). Bioorganic and Medicinal Chemistry, 23(15), 4919– 4935. 10.1016/j.bmc.2015.05.022 26051601 · DOI
  18. Chuah, Y. K., Basir, R., Talib, H., Tie, T. H., & Nordin, N. (2013). Receptor for advanced glycation end products and its involvement in inflammatory diseases. International Journal of Inflammation, 2013, 403460. 10.1155/2013/403460 24102034 PMC3786507 · DOI
  19. Dattilo, B. M., Fritz, G., Leclerc, E., Kooi, C. W., Heizmann, C. W., & Chazin, W. J. (2007). The extracellular region of the receptor for advanced glycation end products is composed of two independent structural units. Biochemistry, 46(23), 6957– 6970. 10.1021/bi7003735 17508727 PMC2527459 · DOI
  20. Deane, R., Singh, I., Sagare, A. P., Bell, R. D., Ross, N. T., LaRue, B., & Zlokovic, B. V. (2012). A multimodal RAGE‐specific inhibitor reduces amyloid beta‐mediated brain disorder in a mouse model of Alzheimer disease. Journal of Clinical Investigation, 122(4), 1377– 1392. 10.1172/JCI58642 22406537 PMC3314449 · DOI · Paper page
  21. Egana‐Gorrono, L., Lopez‐Diez, R., Yepuri, G., Ramirez, L. S., Reverdatto, S., Gugger, P. F., & Schmidt, A. M. (2020). Receptor for advanced glycation end products (RAGE) and mechanisms and therapeutic opportunities in diabetes and cardiovascular disease: Insights from human subjects and animal models. Frontiers in Cardiovascular Medicine, 7, 37. 10.3389/fcvm.2020.00037 32211423 PMC7076074 · DOI
  22. El‐Far, A., Munesue, S., Harashima, A., Sato, A., Shindo, M., Nakajima, S., & Yamamoto, Y. (2018). In vitro anticancer effects of a RAGE inhibitor discovered using a structure‐based drug design system. Oncology Letters, 15(4), 4627– 4634. 10.3892/ol.2018.7902 29541234 PMC5835888 · DOI
  23. Emanuele, E., D'Angelo, A., Tomaino, C., Binetti, G., Ghidoni, R., Politi, P., & Geroldi, D. (2005). Circulating levels of soluble receptor for advanced glycation end products in Alzheimer disease and vascular dementia. Archives of Neurology, 62(11), 1734– 1736. 10.1001/archneur.62.11.1734 16286548 · DOI
  24. Esposito, G., Imitola, J., Lu, J., De Filippis, D., Scuderi, C., Ganesh, V. S., & Sheen, V. (2008). Genomic and functional profiling of human Down syndrome neural progenitors implicates S100B and aquaporin 4 in cell injury. Human Molecular Genetics, 17(3), 440– 457. 10.1093/hmg/ddm322 17984171 · DOI · Paper page
  25. Falcone, C., Emanuele, E., D'Angelo, A., Buzzi, M. P., Belvito, C., Cuccia, M., & Geroldi, D. (2005). Plasma levels of soluble receptor for advanced glycation end products and coronary artery disease in nondiabetic men. Arteriosclerosis, Thrombosis, and Vascular Biology, 25(5), 1032– 1037. 10.1161/01.ATV.0000160342.20342.00 15731496 · DOI
  26. Filipek, A., & Lesniak, W. (2020). S100A6 and its brain ligands in neurodegenerative disorders. International Journal of Molecular Sciences, 21(11). 10.3390/ijms21113979 PMC7313082 32492924 · DOI
  27. Fritz, G. (2011). RAGE: A single receptor fits multiple ligands. Trends in Biochemical Sciences, 36(12), 625– 632. 10.1016/j.tibs.2011.08.008 22019011 · DOI
  28. Gao, H., Li, H., Li, W., Shen, X., & Di, B. (2017). Pioglitazone attenuates atherosclerosis in diabetic mice by inhibition of receptor for advanced glycation end‐product (RAGE) signaling. Medical Science Monitor, 23, 6121– 6131. 10.12659/msm.907401 29278639 PMC5749137 · DOI
  29. Geroldi, D., Falcone, C., & Emanuele, E. (2006). Soluble receptor for advanced glycation end products: From disease marker to potential therapeutic target. Current Medicinal Chemistry, 13(17), 1971– 1978. 10.2174/092986706777585013 16842191 · DOI
  30. Han, Y. T., Choi, G. I., Son, D., Kim, N. J., Yun, H., Lee, S., & Suh, Y. G. (2012). Ligand‐based design, synthesis, and biological evaluation of 2‐aminopyrimidines, a novel series of receptor for advanced glycation end products (RAGE) inhibitors. Journal of Medicinal Chemistry, 55(21), 9120– 9135. 10.1021/jm300172z 22742537 · DOI
  31. He, M., Kubo, H., Morimoto, K., Fujino, N., Suzuki, T., Takahasi, T., & Yamamoto, H. (2011). Receptor for advanced glycation end products binds to phosphatidylserine and assists in the clearance of apoptotic cells. EMBO Reports, 12(4), 358– 364. 10.1038/embor.2011.28 21399623 PMC3077249 · DOI
  32. Heier, M., Margeirsdottir, H. D., Torjesen, P. A., Seljeflot, I., Stensaeth, K. H., Gaarder, M., & Dahl‐Jorgensen, K. (2015). The advanced glycation end product methylglyoxal‐derived hydroimidazolone‐1 and early signs of atherosclerosis in childhood diabetes. Diabetes & Vascular Disease Research, 12(2), 139– 145. 10.1177/1479164114560910 25616705 · DOI
  33. Hofmann, M. A., Drury, S., Fu, C., Qu, W., Taguchi, A., Lu, Y., & Schmidt, A. M. (1999). RAGE mediates a novel proinflammatory axis: A central cell surface receptor for S100/calgranulin polypeptides. Cell, 97(7), 889– 901. 10.1016/s0092-8674(00)80801-6 10399917 · DOI · Paper page
  34. Hong, Y., Shen, C., Yin, Q., Sun, M., Ma, Y., & Liu, X. (2016). Effects of RAGE‐Specific inhibitor FPS‐ZM1 on amyloid‐beta metabolism and AGEs‐induced inflammation and oxidative stress in rat hippocampus. Neurochemical Research, 41(5), 1192– 1199. 10.1007/s11064-015-1814-8 26738988 · DOI
  35. Hori, O., Brett, J., Slattery, T., Cao, R., Zhang, J., Chen, J. X., Nagashima, M., Lundh, E. R., Vijay, S., Nitecki, D., Morser, J., Stern, D., & Schmidt, A. M. (1995). The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co‐expression of rage and amphoterin in the developing nervous system. Journal of Biological Chemistry, 270(43), 25752– 25761. 10.1074/jbc.270.43.25752 7592757 · DOI · Paper page
  36. Huang, Y. K., Chou, R. H., & Yu, C. (2016). Tranilast blocks the interaction between the protein S100A11 and receptor for advanced glycation end products (RAGE) V domain and inhibits cell proliferation. Journal of Biological Chemistry, 291(27), 14300– 14310. 10.1074/jbc.M116.722215 27226584 PMC4933184 · DOI
  37. Hudson, B. I., & Lippman, M. E. (2018). Targeting RAGE signaling in inflammatory disease. Annual Review of Medicine, 69, 349– 364. 10.1146/annurev-med-041316-085215 29106804 · DOI
  38. Hudson, B. I., Kalea, A. Z., Del Mar Arriero, M., Harja, E., Boulanger, E., D'Agati, V., & Schmidt, A. M. (2008). Interaction of the RAGE cytoplasmic domain with diaphanous‐1 is required for ligand‐stimulated cellular migration through activation of Rac1 and Cdc42. Journal of Biological Chemistry, 283(49), 34457– 34468. 10.1074/jbc.M801465200 18922799 PMC2590709 · DOI
  39. Jabir, N. R., Ahmad, S., & Tabrez, S. (2018). An insight on the association of glycation with hepatocellular carcinoma. Seminars in Cancer Biolog, 49, 56– 63. 10.1016/j.semcancer.2017.06.005 28634055 · DOI
  40. Jahan, H., & Choudhary, M. I. (2021). Gliclazide alters macrophages polarization state in diabetic atherosclerosis in vitro via blocking AGE‐RAGE/TLR4‐reactive oxygen species‐activated NF‐kbeta nexus. European Journal of Pharmacology, 894, 173874. 10.1016/j.ejphar.2021.173874 33460615 · DOI
  41. Jules, J., Maiguel, D., & Hudson, B. I. (2013). Alternative splicing of the RAGE cytoplasmic domain regulates cell signaling and function. PLoS One, 8(11), e78267. 10.1371/journal.pone.0078267 24260107 PMC3832623 · DOI
  42. Kalea, A. Z., Schmidt, A. M., & Hudson, B. I. (2009). RAGE: A novel biological and genetic marker for vascular disease. Clin Sci (Lond), 116(8), 621– 637. 10.1042/CS20080494 19275767 · DOI
  43. Katsuoka, F., Kawakami, Y., Arai, T., Imuta, H., Fujiwara, M., Kanma, H., & Yamashita, K. (1997). Type II alveolar epithelial cells in lung express receptor for advanced glycation end products (RAGE) gene. Biochemical and Biophysical Research Communications, 238(2), 512– 516. 10.1006/bbrc.1997.7263 9299542 · DOI
  44. Kierdorf, K., & Fritz, G. (2013). RAGE regulation and signaling in inflammation and beyond. Journal of Leukocyte Biology, 94(1), 55– 68. 10.1189/jlb.1012519 23543766 · DOI
  45. Koch, M., Chitayat, S., Dattilo, B. M., Schiefner, A., Diez, J., Chazin, W. J., & Fritz, G. (2010). Structural basis for ligand recognition and activation of RAGE. Structure, 18(10), 1342– 1352. 10.1016/j.str.2010.05.017 20947022 PMC4250094 · DOI
  46. Kosaka, T., Fukui, R., Matsui, M., Kurosaka, Y., Nishimura, H., Tanabe, M., & Fujita, T. (2014). RAGE, receptor of advanced glycation endoproducts, negatively regulates chondrocytes differentiation. PLoS One, 9(9), e108819. 10.1371/journal.pone.0108819 25275461 PMC4183532 · DOI
  47. Kozlyuk, N., Gilston, B. A., Salay, L. E., Gogliotti, R. D., Christov, P. P., Kim, K., & Chazin, W. J. (2021). A fragment‐based approach to discovery of receptor for advanced glycation end products inhibitors. Proteins, 89(11), 1399– 1412. 10.1002/prot.26162 34156100 PMC8492516 · DOI
  48. Leclerc, E., Fritz, G., Weibel, M., Heizmann, C. W., & Galichet, A. (2007). S100B and S100A6 differentially modulate cell survival by interacting with distinct RAGE (receptor for advanced glycation end products) immunoglobulin domains. Journal of Biological Chemistry, 282(43), 31317– 31331. 10.1074/jbc.M703951200 17726019 · DOI
  49. Li, J., Liu, D., Sun, L., Lu, Y., & Zhang, Z. (2012). Advanced glycation end products and neurodegenerative diseases: Mechanisms and perspective. Journal of the Neurological Sciences, 317(1‐2), 1– 5. 10.1016/j.jns.2012.02.018 22410257 · DOI
  50. Lin, L., Park, S., & Lakatta, E. G. (2009). RAGE signaling in inflammation and arterial aging. Frontiers of Bioscience (Landmark Ed), 14(4), 1403– 1413. 10.2741/3315 PMC2661616 19273137 · DOI
  51. Lin, M., Fang, Y., Li, Z., Li, Y., Feng, X., Zhan, Y., & Deng, H. (2021). S100P contributes to promoter demethylation and transcriptional activation of SLC2A5 to promote metastasis in colorectal cancer. British Journal of Cancer, 125(5), 734– 747. 10.1038/s41416-021-01306-z 34188196 PMC8405647 · DOI
  52. Liu, Y., Shen, W., Chen, Q., Cao, Q., Di, W., Lan, R., & Xu, W. (2020). Inhibition of RAGE by FPS‐ZM1 alleviates renal injury in spontaneously hypertensive rats. European Journal of Pharmacology, 882, 173228. 10.1016/j.ejphar.2020.173228 32502492 · DOI
  53. Logsdon, C. D., Fuentes, M. K., Huang, E. H., & Arumugam, T. (2007). RAGE and RAGE ligands in cancer. Current Molecular Medicine, 7(8), 777– 789. 10.2174/156652407783220697 18331236 · DOI · Paper page
  54. Ma, W., Rai, V., Hudson, B. I., Song, F., Schmidt, A. M., & Barile, G. R. (2012). RAGE binds C1q and enhances C1q‐mediated phagocytosis. Cellular Immunology, 274(1‐2), 72– 82. 10.1016/j.cellimm.2012.02.001 22386596 · DOI
  55. Manigrasso, M. B., Pan, J., Rai, V., Zhang, J., Reverdatto, S., Quadri, N., & Schmidt, A. M. (2016). Small molecule inhibition of ligand‐stimulated RAGE‐DIAPH1 signal transduction. Scientific Reports, 6, 22450. 10.1038/srep22450 26936329 PMC4776135 · DOI
  56. Nabi, R., Alvi, S. S., Shah, A., Chaturvedi, C. P., Iqbal, D., Ahmad, S., & Khan, M. S. (2019). Modulatory role of HMG‐CoA reductase inhibitors and ezetimibe on LDL‐AGEs‐induced ROS generation and RAGE‐associated signalling in HEK‐293 cells. Life Sciences, 235, 116823. 10.1016/j.lfs.2019.116823 31476307 · DOI
  57. Nasser, M. W., Wani, N. A., Ahirwar, D. K., Powell, C. A., Ravi, J., Elbaz, M., & Ganju, R. K. (2015). RAGE mediates S100A7‐induced breast cancer growth and metastasis by modulating the tumor microenvironment. Cancer Research, 75(6), 974– 985. 10.1158/0008-5472.CAN-14-2161 25572331 PMC4359968 · DOI
  58. Neeper, M., Schmidt, A. M., Brett, J., Yan, S. D., Wang, F., Pan, Y. C., & Shaw, A. (1992). Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. Journal of Biological Chemistry, 267(21), 14998– 15004. https://www.ncbi.nlm.nih.gov/pubmed/1378843 1378843
  59. Nenna, A., Spadaccio, C., Lusini, M., Ulianich, L., Chello, M., & Nappi, F. (2015). Basic and clinical research against advanced glycation end products (AGEs): New compounds to tackle cardiovascular disease and diabetic complications. Recent Advances in Cardiovascular Drug Discovery, 10(1), 10– 33. 10.2174/1574890110666151104120039 26530458 · DOI
  60. Oczypok, E. A., Perkins, T. N., & Oury, T. D. (2017). All the “RAGE” in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses. Paediatric Respiratory Reviews, 23, 40– 49. 10.1016/j.prrv.2017.03.012 28416135 PMC5509466 · DOI
  61. Orlova, V. V., Choi, E. Y., Xie, C., Chavakis, E., Bierhaus, A., Ihanus, E., & Chavakis, T. (2007). A novel pathway of HMGB1‐mediated inflammatory cell recruitment that requires Mac‐1‐integrin. EMBO Journal, 26(4), 1129– 1139. 10.1038/sj.emboj.7601552 17268551 PMC1852832 · DOI
  62. Penumutchu, S. R., Chou, R. H., & Yu, C. (2014). Structural insights into calcium‐bound S100P and the V domain of the RAGE complex. PLoS One, 9(8), e103947. 10.1371/journal.pone.0103947 25084534 PMC4118983 · DOI
  63. Rai, V., Maldonado, A. Y., Burz, D. S., Reverdatto, S., Yan, S. F., Schmidt, A. M., & Shekhtman, A. (2012). Signal transduction in receptor for advanced glycation end products (RAGE): Solution structure of C‐terminal rage (ctRAGE) and its binding to mDia1. Journal of Biological Chemistry, 287(7), 5133– 5144. 10.1074/jbc.M111.277731 22194616 PMC3281598 · DOI
  64. Rajpoot, S., Wary, K. K., Ibbott, R., Liu, D., Saqib, U., Thurston, T. L. M., & Baig, M. S. (2021). TIRAP in the mechanism of inflammation. Frontiers in Immunology, 12, 697588. 10.3389/fimmu.2021.697588 34305934 PMC8297548 · DOI · Paper page
  65. Ramasamy, R., Vannucci, S. J., Yan, S. S., Herold, K., Yan, S. F., & Schmidt, A. M. (2005). Advanced glycation end products and RAGE: A common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology, 15(7), 16R– 28R. 10.1093/glycob/cwi053 15764591 · DOI · Paper page
  66. Ray, R., Juranek, J. K., & Rai, V. (2016). RAGE axis in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis. Neuroscience and Biobehavioral Reviews, 62, 48– 55. 10.1016/j.neubiorev.2015.12.006 26724598 · DOI
  67. Riehl, A., Nemeth, J., Angel, P., & Hess, J. (2009). The receptor RAGE: Bridging inflammation and cancer. Cell Communication and Signaling, 7, 12. 10.1186/1478-811X-7-12 19426472 PMC2690588 · DOI
  68. Rodriguez Gonzalez‐Moro, J. M., de Lucas Ramos, P., Izquierdo Alonso, J. L., Lopez‐Muniz Ballesteros, B., Anton Diaz, E., Ribera, X., & Martin, A. (2009). Impact of COPD severity on physical disability and daily living activities: EDIP‐EPOC I and EDIP‐EPOC II studies. International Journal of Clinical Practice, 63(5), 742– 750. 10.1111/j.1742-1241.2009.02040.x 19392924 · DOI
  69. Rong, L. L., Gooch, C., Szabolcs, M., Herold, K. C., Lalla, E., Hays, A. P., & Schmidt, A. M. (2005). RAGE: A journey from the complications of diabetes to disorders of the nervous system ‐ striking a fine balance between injury and repair. Restorative Neurology and Neurosciences, 23(5‐6), 355– 365. https://www.ncbi.nlm.nih.gov/pubmed/16477098 16477098
  70. Sabbagh, M. N., Agro, A., Bell, J., Aisen, P. S., Schweizer, E., & Galasko, D. (2011). PF‐04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease. Alzheimer Disease and Associated Disorders, 25(3), 206– 212. 10.1097/WAD.0b013e318204b550 21192237 PMC3346183 · DOI
  71. Saito, T., Hojo, Y., Ogoyama, Y., Hirose, M., Ikemoto, T., Katsuki, T., & Kario, K. (2012). S100A12 as a marker to predict cardiovascular events in patients with chronic coronary artery disease. Circulation Journal, 76(11), 2647– 2652. 10.1253/circj.cj-12-0093 22786469 · DOI
  72. Sajithlal, G. B., Chithra, P., & Chandrakasan, G. (1998). Advanced glycation end products induce crosslinking of collagen in vitro. Biochimica et Biophysica Acta/General Subjects, 1407(3), 215– 224. 10.1016/s0925-4439(98)00043-x 9748585 · DOI
  73. Santilli, F., Vazzana, N., Bucciarelli, L. G., & Davi, G. (2009). Soluble forms of RAGE in human diseases: Clinical and therapeutical implications. Current Medicinal Chemistry, 16(8), 940– 952. 10.2174/092986709787581888 19275604 · DOI
  74. Scavello, F., Zeni, F., Milano, G., Macri, F., Castiglione, S., Zuccolo, E., & Raucci, A. (2021). Soluble receptor for advanced glycation end‐products regulates age‐associated cardiac fibrosis. International Journal of Biological Sciences, 17(10), 2399– 2416. 10.7150/ijbs.56379 34326683 PMC8315019 · DOI
  75. Schmidt, A. M., Yan, S. D., Wautier, J. L., & Stern, D. (1999). Activation of receptor for advanced glycation end products: A mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circulation Research, 84(5), 489– 497. 10.1161/01.res.84.5.489 10082470 · DOI
  76. Schmidt, A. M., Yan, S. D., Yan, S. F., & Stern, D. M. (2000). The biology of the receptor for advanced glycation end products and its ligands. Biochimica et Biophysica Acta/General Subjects, 1498(2‐3), 99– 111. 10.1016/s0167-4889(00)00087-2 11108954 · DOI
  77. Schmidt, A. M., Yan, S. D., Yan, S. F., & Stern, D. M. (2001). The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. Journal of Clinical Investigation, 108(7), 949– 955. 10.1172/JCI14002 11581294 PMC200958 · DOI
  78. Serratos, I. N., Castellanos, P., Pastor, N., Millan‐Pacheco, C., Rembao, D., Perez‐Montfort, R., & Santamaria, A. (2015). Modeling the interaction between quinolinate and the receptor for advanced glycation end products (RAGE): Relevance for early neuropathological processes. PLoS One, 10(3), e0120221. 10.1371/journal.pone.0120221 25757085 PMC4354912 · DOI
  79. Shen, C., Ma, Y., Zeng, Z., Yin, Q., Hong, Y., Hou, X., & Liu, X. (2017). RAGE‐Specific inhibitor FPS‐ZM1 attenuates AGEs‐induced neuroinflammation and oxidative stress in rat primary microglia. Neurochemical Research, 42(10), 2902– 2911. 10.1007/s11064-017-2321-x 28664403 · DOI
  80. Sims, G. P., Rowe, D. C., Rietdijk, S. T., Herbst, R., & Coyle, A. J. (2010). HMGB1 and RAGE in inflammation and cancer. Annual Review of Immunology, 28, 367– 388. 10.1146/annurev.immunol.021908.132603 20192808 · DOI · Paper page
  81. Sirois, C. M., Jin, T., Miller, A. L., Bertheloot, D., Nakamura, H., Horvath, G. L., & Latz, E. (2013). RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA. Journal of Experimetnal Medicine, 210(11), 2447– 2463. 10.1084/jem.20120201 PMC3804942 24081950 · DOI
  82. Sparvero, L. J., Asafu‐Adjei, D., Kang, R., Tang, D., Amin, N., Im, J., & Lotze, M. T. (2009). RAGE (receptor for advanced glycation endproducts), RAGE ligands, and their role in cancer and inflammation. Journal of Translational Medicine, 7, 17. 10.1186/1479-5876-7-17 19292913 PMC2666642 · DOI
  83. Sturchler, E., Galichet, A., Weibel, M., Leclerc, E., & Heizmann, C. W. (2008). Site‐specific blockade of RAGE‐Vd prevents amyloid‐beta oligomer neurotoxicity. Journal of Neuroscience, 28(20), 5149– 5158. 10.1523/JNEUROSCI.4878-07.2008 18480271 PMC6670634 · DOI · Paper page
  84. Tabrez, S., Al‐Shali, K. Z., & Ahmad, S. (2015). Lycopene powers the inhibition of glycation‐induced diabetic nephropathy: A novel approach to halt the AGE‐RAGE axis menace. Biofactors, 41(5), 372– 381. 10.1002/biof.1238 26453295 · DOI
  85. Takeuchi, A., Yamamoto, Y., Munesue, S., Harashima, A., Watanabe, T., Yonekura, H., & Tsuchiya, H. (2013). Low molecular weight heparin suppresses receptor for advanced glycation end products‐mediated expression of malignant phenotype in human fibrosarcoma cells. Cancer Prevention Research, 104(6), 740– 749. 10.1111/cas.12133 PMC7657155 23421467 · DOI
  86. Tanji, N., Markowitz, G. S., Fu, C., Kislinger, T., Taguchi, A., Pischetsrieder, M., & D'Agati, V. D. (2000). Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. Journal of the American Society of Nephrology, 11(9), 1656– 1666. 10.1681/ASN.V1191656 10966490 · DOI
  87. Tian, J., Huang, K., Krishnan, S., Svabek, C., Rowe, D. C., Brewah, Y., & Sims, G. P. (2013). RAGE inhibits human respiratory syncytial virus syncytium formation by interfering with F‐protein function. Journal of General Virology, 94(Pt 8), 1691– 1700. 10.1099/vir.0.049254-0 23559480 PMC3749528 · DOI
  88. Wang, X., Sun, Z., Tian, W., Piao, C., Xie, X., Zang, J., & Wang, Y. (2020). S100A12 is a promising biomarker in papillary thyroid cancer. Scientific Reports, 10(1), 1724. 10.1038/s41598-020-58534-1 32015423 PMC6997206 · DOI
  89. Wetzels, S., Vanmierlo, T., Scheijen, J., van Horssen, J., Amor, S., Somers, V., & Wouters, K. (2019). Methylglyoxal‐derived advanced glycation endproducts accumulate in multiple sclerosis lesions. Frontiers in Immunology, 10, 855. 10.3389/fimmu.2019.00855 31068938 PMC6491451 · DOI · Paper page
  90. Xie, J., Burz, D. S., He, W., Bronstein, I. B., Lednev, I., & Shekhtman, A. (2007). Hexameric calgranulin C (S100A12) binds to the receptor for advanced glycated end products (RAGE) using symmetric hydrophobic target‐binding patches. Journal of Biological Chemistry, 282(6), 4218– 4231. 10.1074/jbc.M608888200 17158877 · DOI
  91. Xie, J., Xu, H., Wu, X., Xie, Y., Lu, X., & Wang, L. (2021). Design, synthesis and anti‐TNBC activity of azeliragon triazole analogues. Bioorganic & Medicinal Chemistry Letters, 54, 128444. 10.1016/j.bmcl.2021.128444 34763082 · DOI
  92. Xu, D., Young, J. H., Krahn, J. M., Song, D., Corbett, K. D., Chazin, W. J., & Esko, J. D. (2013). Stable RAGE‐heparan sulfate complexes are essential for signal transduction. ACS Chemical Biology, 8(7), 1611– 1620. 10.1021/cb4001553 23679870 PMC3806902 · DOI
  93. Xue, J., Rai, V., Singer, D., Chabierski, S., Xie, J., Reverdatto, S., & Shekhtman, A. (2011). Advanced glycation end product recognition by the receptor for AGEs. Structure, 19(5), 722– 732. 10.1016/j.str.2011.02.013 21565706 PMC3150472 · DOI
  94. Yamagishi, S. (2011). Role of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) in vascular damage in diabetes. Experimental Gerontology, 46(4), 217– 224. 10.1016/j.exger.2010.11.007 21111800 · DOI
  95. Yamagishi, S. I. (2019). Role of advanced glycation endproduct (AGE)‐Receptor for advanced glycation endproduct (RAGE) axis in cardiovascular disease and its therapeutic intervention. Circulation Journal, 83(9), 1822– 1828. 10.1253/circj.CJ-19-0618 31366777 · DOI
  96. Yamamoto, K., Murata, H., Putranto, E. W., Kataoka, K., Motoyama, A., Hibino, T., & Huh, N. H. (2013). DOCK7 is a critical regulator of the RAGE‐Cdc42 signaling axis that induces formation of dendritic pseudopodia in human cancer cells. Oncology Reports, 29(3), 1073– 1079. 10.3892/or.2012.2191 23254359 · DOI
  97. Yatime, L., & Andersen, G. R. (2013). Structural insights into the oligomerization mode of the human receptor for advanced glycation end‐products. FEBS Journal, 280(24), 6556– 6568. 10.1111/febs.12556 24119142 · DOI
  98. Yoshizawa, K., Takeuchi, K., Nakamura, T., Ukai, S., Takahashi, Y., Sato, A., & Tanuma, S. I. (2021). Antinociceptive activity of the novel RAGE inhibitor, papaverine, in a mouse model of chronic inflammatory pain. Synapse, 75(3), e22188. 10.1002/syn.22188 32979223 · DOI
  99. Zhang, L., Zhu, T., Miao, H., & Liang, B. (2021). The calcium binding protein S100A11 and its roles in diseases. Frontiers in Cell and Developmental Biology, 9, 693262. 10.3389/fcell.2021.693262 34179021 PMC8226020 · DOI
  100. Zhang, L., Bukulin, M., Kojro, E., Roth, A., Metz, V. V., Fahrenholz, F., & Postina, R. (2008). Receptor for advanced glycation end products is subjected to protein ectodomain shedding by metalloproteinases. Journal of Biological Chemistry, 283(51), 35507– 35516. 10.1074/jbc.M806948200 18952609 · DOI
  101. Zong, H., Madden, A., Ward, M., Mooney, M. H., Elliott, C. T., & Stitt, A. W. (2010). Homodimerization is essential for the receptor for advanced glycation end products (RAGE)‐mediated signal transduction. Journal of Biological Chemistry, 285(30), 23137– 23146. 10.1074/jbc.M110.133827 20504772 PMC2906307 · DOI

Cited by

Sorted by citations

  • Role of neuroinflammation in neurodegeneration development

    Zhang, W., Xiao, D., Mao, Q., & Xia, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01486-5 · Cited by 1,668 · see citing works

    “Multiple small molecules have been developed to block RAGE signaling and have shown potential to inhibit glial cells activation in vitro and in animal models.(345) But they still need further pre-clinical and clinical studies to justify whether it could be useful in the treatment of neurological disorders.”
    Background

Authors
Singh, H., & Agrawal, D. K.
Affiliations
Western University of Health Sciences (US)
Corresponding author
Agrawal, Devendra K.
ORCID
Venue
Drug Development Research
Publisher
Wiley
Published
2022-07-04
Volume
83
Issue
6
Pages
1257-1269
ISSN
  • 0272-4391 (ISSN-L)
  • 1098-2299
DOI
10.1002/ddr.21971
PMC
PMC9474610
OpenAlex
W4283791224
Cited by
57
References
9
Citations by year
2026: 6 · 2025: 15 · 2024: 17 · 2023: 15 · 2022: 4
FWCI
1.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Drug Development Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (R01 HL144125, R01 HL147662)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Life Sciences › Immunology and Microbiology › Immunology › Galectins and Cancer Biology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
receptor for advanced glycation end products, RAGE, RAGE inhibitors, small molecule inhibitors, chronic inflammation, neurodegenerative diseases, cardiovascular disease, diabetes mellitus, cancer, immunoglobulin superfamily receptors
MeSH terms
Receptor for Advanced Glycation End Products, Diabetes Mellitus, Humans, Ligands, Signal Transduction, Glycation End Products, Advanced

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