Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Loganin Inhibits α-MSH and IBMX-induced Melanogenesis by Suppressing the Expression of Tyrosinase in B16F10 Melanoma Cells

마우스 흑색종 B16F10세포에서 loganin의 티로시나아제 발현 억제를 통한 멜라닌 생성 억제에 대한 기전연구

  • Jung, Hee Jin (Longevity Life Science and Technology Institutes, Pusan National University) ;
  • Bang, EunJin (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Kim, Byeong Moo (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Jeong, Seong Ho (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Lee, Gil Han (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Chung, Hae Young (Longevity Life Science and Technology Institutes, Pusan National University)
  • 정희진 (부산대학교 장수생명과학기술연구원) ;
  • 방은진 (부산대학교 약학대학 약학과) ;
  • 김병무 (부산대학교 약학대학 약학과) ;
  • 정성호 (부산대학교 약학대학 약학과) ;
  • 이길한 (부산대학교 약학대학 약학과) ;
  • 정해영 (부산대학교 장수생명과학기술연구원)
  • Received : 2019.09.27
  • Accepted : 2019.11.14
  • Published : 2019.11.30
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Abstract

Ultraviolet radiation exposure is a major cause of extrinsic skin aging, which leads to skin hyperpigmentation. Loganin, a major iridoid glycoside obtained from Corni fructus, has anti-inflammatory, anti-diabetic, and neuroprotective effects. In this study, we investigated the mechanisms underlying the anti-melanogenic effects of loganin in B16F10 melanocytes treated with ${\alpha}$-melanocyte stimulating hormone (${\alpha}-MSH$) and 3-isobutyl-1-methylxanthine (IBMX). Anti-melanogenic activity was measured by treating cells with loganin at concentrations between 1 and $20{\mu}m$. Cell viability assays confirmed that doses of loganin up to $20{\mu}m$ were not cytotoxic. Loganin significantly and dose-dependently decreased intracellular melanin production. We also investigated potential molecular signaling pathways for the anti-melanogenesis effects of loganin. Western blotting showed that treatment with ${\alpha}-MSH$ and IBMX increased the phosphorylation of cAMP response element-binding protein (CREB) and the gene expressions of microphthalmia-associated transcription factor (MITF) and tyrosinase. Addition of loganin suppressed these increases, while promoting the phosphorylation of extracellular signal regulated kinase (ERK) and the anti-melanogenesis response. Our data therefore indicated that loganin could attenuate the increased melanin synthesis induced by ${\alpha}-MSH$ and IBMX treatment of B16F10 melanocytes. This attenuation appears to occur by downregulation of CREB phosphorylation and MITF and tyrosinase gene expression and upregulation of ERK phosphorylation. These finding suggests that loganin could be a valuable candidate for treatment of skin diseases related to hyperpigmentation.

Loganin은 Corni fructus의 주요 iridoid glycoside이며 항염증, 항당뇨 그리고 뇌신경보호 효과 등이 보고되었다. 본 연구에서는 ${\alpha}-MSH$와 IBMX처리된 B16F10세포에서 loganin의 melanogenesis억제효과의 신호전달 경로를 조사하였다. Loganin의 미백 활성을 확인하기 위해 B16F10세포에서 $1{\mu}m$에서 $20{\mu}m$사이의 농도를 처리하여 세포독성 실험을 수행한 결과 최대 $20{\mu}m$농도에서 독성을 나타내지 않았다. 또한 loganin은 ${\alpha}-MSH$와 IBMX처리된 B16F10세포에서 농도-의존적으로 멜라닌 생성을 감소시키는 것을 확인하였다. 또한 loganin의 멜라닌 생성을 억제하는 신호전달 경로를 Western blotting을 실시하여 조사하였다. Western blot결과에 따르면 loganin은 ${\alpha}-MSH$와 IBMX 처리된 B16F10세포에서 증가된 CREB인산화(Ser133)와 MITF 발현 및 tyrosinase의 유전자 발현을 감소시켰고 ERK의 인산화를 증가시켜 melanin 생성을 억제하였다. 결론적으로 loganin은 ${\alpha}-MSH$와 IBMX에 의해 유도된 과도한 멜라닌 합성을 CREB인산화와 MITF 및 tyrosinase의 유전자 발현을 억제하고 ERK의 활성화를 통해 멜라닌 합성을 감소됨을 확인하였다. 따라서 loganin은 과색소 침착과 관련된 피부질환의 보호제로서 활용될 가능성을 가지는 것으로 사료된다.

Keywords

References

  1. Ah, A. Y., Hwang, J. Y., Lee, J. S. and Kim, Y. C. 2015. Cornus officinalis methanol extract upregulates melanogenesis in melan-a cells. Toxicol. Res. 31,165-172. https://doi.org/10.5487/TR.2015.31.2.165
  2. Akihisa, T., Seino, K., Kaneko, E., Watanabe, K., Tochizawa, S., Fukatsu, M., Banno, N., Metori, K. and Kimura, Y. 2010. Melanogenesis inhibitory activities of iridoid-, hemiterpene-, and fatty acid-glycosides from the fruits of Morinda citrifolia (Noni). J. Oleo. Sci. 59, 49-57. https://doi.org/10.5650/jos.59.49
  3. Ando, H., Kondoh, H., Ichihashi, M. and Hearing, V. J. 2007. Approaches to identify inhibitors of melanin biosynthesis via the quality control of tyrosinase. J. Invest. Dermatol. 127, 751-761. https://doi.org/10.1038/sj.jid.5700683
  4. Bertolotto, C., Abbe, P., Hemesath, T. J., Bille, K., Fisher, D. E., Ortonne, J. P. and Ballotti, R. 1998. Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes. J. Cell Biol. 142, 827-835. https://doi.org/10.1083/jcb.142.3.827
  5. Bertolotto, C., Bille, K., Ortonne, J. P. and Ballotti, R. 1996. Regulation of tyrosinase gene expression by cAMP in B16 melanoma cells involves two CATGTG motifs surrounding the TATA box: implication of the microphthalmia gene product. J. Cell Biol. 134, 747-755. https://doi.org/10.1083/jcb.134.3.747
  6. Bhakta, H. K., Park, C. H., Yokozawa, T., Min, B. S., Jung, H. A. and Choi, J. S. 2016. Kinetics and molecular docking studies of loganin, morroniside and 7-O-galloyl-D-sedoheptulose derived from Corni fructus as cholinesterase and beta-secretase 1 inhibitors. Arch. Pharm. Res. 39, 794-805. https://doi.org/10.1007/s12272-016-0745-5
  7. Bilodeau, M. L., Greulich, J. D., Hullinger, R. L., Bertolotto, C., Ballotti, R. and Andrisani, O. M. 2001. BMP-2 stimulates tyrosinase gene expression and melanogenesis in differentiated melanocytes. Pigment Cell Res. 14, 328-336. https://doi.org/10.1034/j.1600-0749.2001.140504.x
  8. Busca, R. and Ballotti, R. 2000. Cyclic AMP a key messenger in the regulation of skin pigmentation. Pigment Cell Res. 13, 60-69. https://doi.org/10.1034/j.1600-0749.2000.130203.x
  9. Busca, R., Bertolotto, C., Ortonne, J. P. and Ballotti, R. 1996. Inhibition of the phosphatidylinositol 3-kinase/p70(S6)-kinase pathway induces B16 melanoma cell differentiation. J. Biol. Chem. 271, 31824-31830. https://doi.org/10.1074/jbc.271.50.31824
  10. Cai, Z., Wang, C., Zou, L., Liu, X., Chen, J., Tan, M., Mei, Y. and Wei, L. 2019. Comparison of multiple bioactive constituents in the flower and the caulis of Lonicera japonica based on UFLC-QTRAP-MS/MS combined with multivariate statistical analysis. Molecules 24, 1936. https://doi.org/10.3390/molecules24101936
  11. Chang, F. P., Chao, W., Wang, S. Y., Huang, H. C., Sung, P. J., Chen, J. J., Cheng, M. J., Huang, G. J. and Kuo, Y. H. 2018. Three new iridoid derivatives have been isolated from the stems of Neonauclea reticulata (Havil.) Merr. with cytotoxic activity on hepatocellular carcinoma cells. Molecules 23, 2297. https://doi.org/10.3390/molecules23092297
  12. Chang, J. S., Chiang, L. C., Hsu, F. F. and Lin, C. C. 2004. Chemoprevention against hepatocellular carcinoma of Cornus officinalis in vitro. Am. J. Chin. Med. 32, 717-725. https://doi.org/10.1142/S0192415X04002296
  13. Chang, T. S. 2012. Natural melanogenesis inhibitors acting through the down-regulation of tyrosinase activity. Materials 5, 1661-1685. https://doi.org/10.3390/ma5091661
  14. Costin, G. E. and Hearing, V. J. 2007. Human skin pigmentation: melanocytes modulate skin color in response to stress. FASEB J. 21, 976-994. https://doi.org/10.1096/fj.06-6649rev
  15. Cui, Y., Wang, Y., Zhao, D., Feng, X., Zhang, L. and Liu, C. 2018. Loganin prevents BV-2 microglia cells from $A{\beta}_{1-42}$-induced inflammation via regulating TLR4/TRAF6/NF-kappaB axis. Cell Biol. Int. 42, 1632-1642. https://doi.org/10.1002/cbin.11060
  16. Du, J., Miller, A. J., Widlund, H. R., Horstmann, M. A., Ramaswamy, S. and Fisher, D. E. 2003. MLANA/MART1 and SILV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma. Am. J. Pathol. 163, 333-343. https://doi.org/10.1016/S0002-9440(10)63657-7
  17. Englaro, W., Bertolotto, C., Busca, R., Brunet, A., Pages, G., Ortonne, J. P. and Ballotti, R. 1998. Inhibition of the mitogen-activated protein kinase pathway triggers B16 melanoma cell differentiation. J. Biol. Chem. 273, 9966-9970. https://doi.org/10.1074/jbc.273.16.9966
  18. Gilchrest, B. A., Park, H. Y., Eller, M. S. and Yaar, M. 1996. Mechanisms of ultraviolet light-induced pigmentation. Photochem. Photobiol. 63, 1-10. https://doi.org/10.1111/j.1751-1097.1996.tb02988.x
  19. Goding, C. R. 2000. Mitf from neural crest to melanoma: signal transduction and transcription in the melanocyte lineage. Genes Dev. 14, 1712-1728.
  20. Guo, R., Wang, T., Zhou, G., Xu, M., Yu, X., Zhang, X., Sui, F., Li, C., Tang, L. and Wang, Z. 2018. Botany, phytochemistry, pharmacology and toxicity of strychnos nux-vomica L.: A review. Am. J. Chin. Med. 46, 1-23. https://doi.org/10.1142/S0192415X18500015
  21. Habib, A., Creminon, C., Frobert, Y., Grassi, J., Pradelles, P. and Maclouf, J. 1993. Demonstration of an inducible cyclooxygenase in human endothelial cells using antibodies raised against the carboxyl-terminal region of the cyclooxygenase-2. J. Biol. Chem. 268, 23448-23454. https://doi.org/10.1016/S0021-9258(19)49483-0
  22. Halaban, R., Pomerantz, S. H., Marshall, S. and Lerner, A. B. 1984. Tyrosinase activity and abundance in Cloudman melanoma cells. Arch. Biochem. Biophys. 230, 383-387. https://doi.org/10.1016/0003-9861(84)90121-8
  23. Hoh, J. F., Rossmanith, G. H. and Hamilton, A. M. 1991. Effects of dibutyryl cyclic AMP, ouabain, and xanthine derivatives on crossbridge kinetics in rat cardiac muscle. Circ. Res. 68, 702-713. https://doi.org/10.1161/01.RES.68.3.702
  24. Hwang, E. S., Kim, H. B., Lee, S., Kim, M. J., Lee, S. O., Han, S. M., Maeng, S. and Park, J. H. 2017. Loganin enhances long-term potentiation and recovers scopolamine-induced learning and memory impairments. Physiol. Behav. 171, 243-248. https://doi.org/10.1016/j.physbeh.2016.12.043
  25. Jang, J. Y., Lee, J. H., Kang, B. W., Chung, K. T., Choi, Y. H. and Choi, B. T. 2009. Dichloromethane fraction of Cimicifuga heracleifolia decreases the level of melanin synthesis by activating the ERK or AKT signaling pathway in B16F10 cells. Exp. Dermatol. 18, 232-237. https://doi.org/10.1111/j.1600-0625.2008.00794.x
  26. Jiang, W. L., Zhang, S. P., Hou, J. and Zhu, H. B. 2012. Effect of loganin on experimental diabetic nephropathy. Phytomedicine 19, 217-222. https://doi.org/10.1016/j.phymed.2011.08.064
  27. Jung, H. J., Lee, A. K., Park, Y. J, Lee, S., Kang, D., Jung, Y. S., Chung, H. Y. and Moon, H. R. 2018. (2E,5E)-2,5-bis(3-hydroxy-4-methoxybenzylidene) cyclopentanone exerts anti-melanogenesis and anti-wrinkle activities in B16F10 melanoma and Hs27 fibroblast cells. Molecules 23, 1415. https://doi.org/10.3390/molecules23061415
  28. Kawano, M., Matsuyama, K., Miyamae, Y., Shinmoto, H., Kchouk, M. E., Morio, T., Shigemori, H. and Isoda, H. 2007. Antimelanogenesis effect of Tunisian herb Thymelaea hirsuta extract on B16 murine melanoma cells. Exp. Dermatol. 16, 977-984. https://doi.org/10.1111/j.1600-0625.2007.00618.x
  29. Khaled, M., Larribere, L., Bille, K., Ortonne, J. P., Ballotti, R. and Bertolotto, C. 2003. Microphthalmia associated transcription factor is a target of the phosphatidylinositol-3-kinase pathway. J. Invest. Dermatol. 121, 831-836. https://doi.org/10.1046/j.1523-1747.2003.12420.x
  30. Kim, D. S., Park, S. H., Kwon, S. B., Park, E. S., Huh, C. H., Youn, S. W. and Park, K. C. 2006. Sphingosylphosphorylcholine-induced ERK activation inhibits melanin synthesis in human melanocytes. Pigment Cell Res. 19, 146-153. https://doi.org/10.1111/j.1600-0749.2005.00287.x
  31. Kim, H., Youn, K., Ahn, M. R., Kim, O. Y., Jeong, W. S., Ho, C. T. and Jun, M. 2015. Neuroprotective effect of loganin against $A{\beta}_{25-35}$-induced injury via the $NF-{\kappa}B$-dependent signaling pathway in PC12 cells. Food Funct. 6, 1108-1116. https://doi.org/10.1039/C5FO00055F
  32. Kim, M. J., Bae, G. S., Jo, I. J., Choi, S. B., Kim, D. G., Shin, J. Y., Lee, S. K., Kim, M. J., Shin, S., Song, H. J. and Park, S. J. 2015. Loganin protects against pancreatitis by inhibiting $NF-{\kappa}B$ activation. Eur. J. Pharmacol. 765, 541-550. https://doi.org/10.1016/j.ejphar.2015.09.019
  33. Kwon, S. H., Kim, J. A., Hong, S. I., Jung, Y. H., Kim, H. C., Lee, S. Y. and Jang, C. G. 2011. Loganin protects against hydrogen peroxide-induced apoptosis by inhibiting phosphorylation of JNK, p38, and ERK 1/2 MAPKs in SH-SY5Y cells. Neurochem. Int. 58, 533-541. https://doi.org/10.1016/j.neuint.2011.01.012
  34. Lee, A., Kim, J. Y., Heo, J., Cho, D. H., Kim, H. S., An, I. S., An, S. and Bae, S. 2018. The inhibition of melanogenesis via the PKA and ERK signaling pathways by chlamydomonas reinhardtii extract in B16F10 melanoma cells and artificial Human Skin Equivalents. J. Microbiol. Biotechnol. 28, 2121-2132. https://doi.org/10.4014/jmb.1810.10008
  35. Lee, C. M., Jung, H. A., Oh, S. H., Park, C. H., Tanaka, T., Yokozawa, T. and Choi, J. S. 2015. Kinetic and molecular docking studies of loganin and 7-O-galloyl-D-sedoheptulose from Corni fructus as therapeutic agents for diabetic complications through inhibition of aldose reductase. Arch. Pharm. Res. 38, 1090-1098. https://doi.org/10.1007/s12272-014-0493-3
  36. Lee, C. S., Jang, W. H., Park, M., Jung, K., Baek, H. S., Joo, Y. H., Park, Y. H. and Lim, K. M. 2013. A novel adamantyl benzylbenzamide derivative, AP736, suppresses melanogenesis through the inhibition of cAMP-PKA-CREB-activated microphthalmia-associated transcription factor and tyrosinase expression. Exp. Dermatol. 22, 762-764. https://doi.org/10.1111/exd.12248
  37. Lee, J., Jung, K., Kim, Y. S. and Park, D. 2007. Diosgenin inhibits melanogenesis through the activation of phosphatidylinositol-3-kinase pathway (PI3K) signaling. Life Sci. 81, 249-254. https://doi.org/10.1016/j.lfs.2007.05.009
  38. Lee, W. J., Bang, S., Chung, B. Y., Jung, H., Oh, E. S. and Chang, S. E. 2016. Inhibitory effects of N,N,N-trimethyl phytosphingosine-iodide on melanogenesis via ERK activation-mediated MITF degradation. Biosci. Biotechnol. Biochem. 80, 121-127. https://doi.org/10.1080/09168451.2015.1072459
  39. Li, Y., Li, Z., Shi, L., Zhao, C., Shen, B., Tian, Y. and Feng, H. 2016. Loganin inhibits the inflammatory response in mouse 3T3L1 adipocytes and mouse model. Int. Immunopharmacol. 36, 173-179. https://doi.org/10.1016/j.intimp.2016.04.026
  40. Liou, S. S., Liu, I. M., Hsu, S. F. and Cheng, J. T. 2004. Corni fructus as the major herb of Die-Huang-Wan for lowering plasma glucose in Wistar rats. J. Pharm. Pharmacol. 56, 1443-1447. https://doi.org/10.1211/0022357044670
  41. Liu, F., Singh, A., Yang, Z., Garcia, A., Kong, Y. and Meyskens, F. L. Jr. 2010. MiTF links Erk1/2 kinase and p21 CIP1/WAF1 activation after UVC radiation in normal human melanocytes and melanoma cells. Mol. Cancer 9, 214. https://doi.org/10.1186/1476-4598-9-214
  42. Liu, K., Xu, H., Lv, G., Liu, B., Lee, M. K., Lu, C., Lv, X. and Wu, Y. 2015. Loganin attenuates diabetic nephropathy in C57BL/6J mice with diabetes induced by streptozotocin and fed with diets containing high level of advanced glycation end products. Life Sci. 123, 78-85. https://doi.org/10.1016/j.lfs.2014.12.028
  43. Nawa, Y., Endo, J. and Ohta, T. 2007. The inhibitory effect of the components of Cornus officinalis on melanogenesis. J. Cosmet. Sci. 58, 505-517.
  44. Nestle, F. O., Di Meglio, P., Qin, J. Z. and Nickoloff, B. J. 2009. Skin immune sentinels in health and disease. Nat. Rev. Immunol. 9, 679-691. https://doi.org/10.1038/nri2622
  45. Oka, M., Nagai, H., Ando, H., Fukunaga, M., Matsumura, M., Araki, K., Ogawa, W., Miki, T., Sakaue, M., Tsukamoto, K., Konishi, H., Kikkawa, U. and Ichihashi, M. 2000. Regulation of melanogenesis through phosphatidylinositol 3-kinase-Akt pathway in human G361 melanoma cells. J. Invest. Dermatol. 115, 699-703. https://doi.org/10.1046/j.1523-1747.2000.00095.x
  46. Park, C. H., Tanaka, T., Kim, J. H., Cho, E. J., Park, J. Shibahara, C. N. and Yokozawa, T. 2011. Hepato-protective effects of loganin, iridoid glycoside from Corni Fructus, against hyperglycemia-activated signaling pathway in liver of type 2 diabetic db/db mice. Toxicology 290, 14-21. https://doi.org/10.1016/j.tox.2011.08.004
  47. Park, H. Y., Wu, C., Yonemoto, L., Murphy-Smith, M., Wu, H., Stachur, C. M. and Gilchrest, B. A. 2006. MITF mediates cAMP-induced protein kinase C-beta expression in human melanocytes. Biochem. J. 395, 571-578. https://doi.org/10.1042/BJ20051388
  48. Phacharapiyangkul, N., Thirapanmethee, K., Sa-Ngiamsuntorn, K., Panich, U., Lee, C. H. and Chomnawang, M. T. 2019. Effect of sucrier banana peel extracts on inhibition of melanogenesis through the ERK signaling pathway. Int. J. Med. Sci. 16, 602-606. https://doi.org/10.7150/ijms.32137
  49. Schiaffino, M. V. 2010. Signaling pathways in melanosome biogenesis and pathology. Int. J. Biochem. Cell Biol. 42, 1094-1104. https://doi.org/10.1016/j.biocel.2010.03.023
  50. Sim, M. O., Ham, J. R. and Lee, M. K. 2017. Young leaves of reed (Phragmites communis) suppress melanogenesis and oxidative stress in B16F10 melanoma cells. Biomed. Pharmacother. 93, 165-171. https://doi.org/10.1016/j.biopha.2017.06.037
  51. Son, Y. O., Lee, S. A., Kim, S. S., Jang, Y. S., Chun, J. C. and Lee, J. C. 2011. Acteoside inhibits melanogenesis in B16F10 cells through ERK activation and tyrosinase down-regulation. J. Pharm. Pharmacol. 63, 1309-1319. https://doi.org/10.1111/j.2042-7158.2011.01335.x
  52. Tseng, Y. T., Lin, W. J., Chang, W. H. and Lo, Y. C. 2019. The novel protective effects of loganin against 1-methyl-4-phenylpyridinium-induced neurotoxicity: Enhancement of neurotrophic signaling, activation of IGF-1R/GLP-1R, and inhibition of RhoA/ROCK pathway. Phytother. Res. 33, 690-701.
  53. Vareed, S. K., Reddy, M. K., Schutzki, R. E. and Nair, M. G. 2006. Anthocyanins in Cornus alternifolia, Cornus controversa, Cornus kousa and Cornus florida fruits with health benefits. Life Sci. 78, 777-784. https://doi.org/10.1016/j.lfs.2005.05.094
  54. Videira, I. F., Moura, D. F. and Magina, S. 2013. Mechanisms regulating melanogenesis. An. Bras. Dermatol. 88, 76-83. https://doi.org/10.1590/S0365-05962013000100009
  55. Widlund, H. R. and Fisher, D. E. 2003. Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival. Oncogene 22, 3035-3041. https://doi.org/10.1038/sj.onc.1206443
  56. Xu, Y. D., Cui, C., Sun, M. F., Zhu, Y. L., Chu, M., Shi, Y. W., Lin, S. L., Yang, X. S. and Shen, Y. Q. 2017. Neuroprotective effects of loganin on MPTP-induced Parkinson's disease mice: neurochemistry, glial reaction and autophagy studies. J. Cell Biochem. 118, 3495-3510. https://doi.org/10.1002/jcb.26010
  57. Yamabe, N., Kang, K. S., Matsuo, Y., Tanaka, T. and Yokozawa, T. 2007. Identification of antidiabetic effect of iridoid glycosides and low molecular weight polyphenol fractions of Corni fructus, a constituent of Hachimi-jio-gan, in streptozotocin-induced diabetic rats. Biol. Pharm. Bull. 30, 1289-1296. https://doi.org/10.1248/bpb.30.1289
  58. Yamabe, N., Kang, K. S., Park, C. H., Tanaka, T. and Yokozawa, T. 2009. 7-O-galloyl-D-sedoheptulose is a novel therapeutic agent against oxidative stress and advanced glycation endproducts in the diabetic kidney. Biol. Pharm. Bull. 32, 657-664. https://doi.org/10.1248/bpb.32.657
  59. Yamabe, N., Noh, J. S., Park, C. H., Kang, K. S., Shibahara, N., Tanaka, T. and Yokozawa, T. 2010. Evaluation of loganin, iridoid glycoside from Corni fructus, on hepatic and renal glucolipotoxicity and inflammation in type 2 diabetic db/db mice. Eur. J. Pharmacol. 648, 179-187. https://doi.org/10.1016/j.ejphar.2010.08.044
  60. Yanase, H., Ando, H., Horikawa, M., Watanabe, M., Mori, T. and Matsuda, N. 2001. Possible involvement of ERK 1/2 in UVA-induced melanogenesis in cultured normal human epidermal melanocytes. Pigment Cell Res. 14, 103-109. https://doi.org/10.1034/j.1600-0749.2001.140205.x
  61. Yao, L., Peng, S. X., Xu, Y. D., Lin, S. L., Li, Y. H., Liu, C. J., Zhao, H. D., Wang, L. F. and Shen, Y. Q. 2017. Unexpected neuroprotective effects of loganin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity and cell death in zebrafish. J. Cell Biochem. 118, 615-628. https://doi.org/10.1002/jcb.25749
  62. Yokozawa, T., Kang, K. S., Park, C. H., Noh, J. S., Yamabe, N., Shibahara, N. and Tanaka, T. 2010. Bioactive constituents of Corni fructus: The therapeutic use of morroniside, loganin, and 7-O-galloyl-D-sedoheptulose as renoprotective agents in type 2 diabetes. Drug Discov. Ther. 4, 223-234.
  63. Youn, K., Jeong, W. S. and Jun, M. 2013. $\beta$-Secretase (BACE1) inhibitory property of loganin isolated from Corni fructus. Nat. Prod. Res. 27, 1471-1474. https://doi.org/10.1080/14786419.2012.718774