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6-Shogaol reduces progression of experimental endometriosis in vivo and in vitro via regulation of VGEF and inhibition of COX-2 and PGE2-mediated inflammatory responses

  • Wang, Dan (Department of Obstetrics and Gynecology, Tongren Hospital of WuHan University (Wuhan Third Hospital)) ;
  • Jiang, Yiling (Department of Obstetrics and Gynecology, Hubei Provincial Hospital of Integrated Chinese and Western Medicine) ;
  • Yang, Xiaoxin (Department of Obstetrics and Gynecology, Tongren Hospital of WuHan University (Wuhan Third Hospital)) ;
  • Wei, Qiong (Department of Obstetrics and Gynecology, Tongren Hospital of WuHan University (Wuhan Third Hospital)) ;
  • Wang, Huimin (Department of Obstetrics and Gynecology, Tongren Hospital of WuHan University (Wuhan Third Hospital))
  • Received : 2017.11.11
  • Accepted : 2018.02.27
  • Published : 2018.11.01

Abstract

Endometriosis (EM) is one of the most common gynaecological disorder affecting women in their reproductive age. Mechanisms involved in the pathogenesis of EM remains poorly understood, however inflammatory responses have been reported to be significantly involved. The efficacy of 6-shogaol on proliferation of endometriotic lesions and inflammatory pathways in experimentally-induced EM model was explored in this study. EM was stimulated in Sprague-Dawley rats by implantation of autologous endometrium onto the peritoneum abdominal wall. Separate groups were treated with 6-shogaol (50, 100 or 150 mg/kg b.wt/day) via oral gavage for one month period. Gestrinone (GTN) group received GTN (0.5 mg/kg/day) as positive control. Five weeks after implantation, the spherical volume of ecto-uterine tissues was determined. Treatment with 6-shogaol significantly reduced the implant size. Histological analysis reported atrophy and regression of the lesions. 6-shogaol administration effectively down-regulated $NF-{\kappa}B$ signaling, VEGF and VEGFR-2 (Flk-1) expression in the endometriotic lesions. Excess production of $IL-1{\beta}$ and IL-6 (pro-inflammatory cytokines), PGE2 and nitric oxide (NO) were reduced. Overall, the results of the study reveal the efficacy of 6-shogaol against endometriosis via effectively suppressing proliferation of the lesions and modulating angiogenesis and $COX-2/NF-{\kappa}B$-mediated inflammatory cascades.

Keywords

References

  1. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 1997;24:235-258. https://doi.org/10.1016/S0889-8545(05)70302-8
  2. Viatour P, Merville MP, Bours V, Chariot A. Phosphorylation of NFkappaB and IkappaB proteins: implications in cancer and inflammation. Trends Biochem Sci. 2005;30:43-52. https://doi.org/10.1016/j.tibs.2004.11.009
  3. Kennedy S, Bergqvist A, Chapron C, D'Hooghe T, Dunselman G, Greb R, Hummelshoj L, Prentice A, Saridogan E; ESHRE Special Interest Group for Endometriosis and Endometrium Guideline Development Group. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20:2698-2704. https://doi.org/10.1093/humrep/dei135
  4. Ruhland B1, Agic A, Krampe J, Diedrich K, Hornung D. Innovations in conservative endometriosis treatment: an updated review. Minerva Ginecol. 2011;63:247-259.
  5. Guo SW, Olive DL. Two unsuccessful clinical trials on endometriosis and a few lessons learned. Gynecol Obstet Invest. 2007;64:24-35. https://doi.org/10.1159/000098413
  6. Groothuis PG, Nap AW, Winterhager E, Grummer R. Vascular development in endometriosis. Angiogenesis. 2005;8:147-156. https://doi.org/10.1007/s10456-005-9005-x
  7. Taylor RN, Lebovic DI, Mueller MD. Angiogenic factors in endometriosis. Ann N Y Acad Sci. 2002;955:89-100; discussion 118, 396-406. https://doi.org/10.1111/j.1749-6632.2002.tb02769.x
  8. Bourlev V, Volkov N, Pavlovitch S, Lets N, Larsson A, Olovsson M. The relationship between microvessel density, proliferative activity and expression of vascular endothelial growth factor-A and its receptors in eutopic endometrium and endometriotic lesions. Reproduction. 2006;132:501-509. https://doi.org/10.1530/rep.1.01110
  9. Van Langendonckt A, Casanas-Roux F, Donnez J. Oxidative stress and peritoneal endometriosis. Fertil Steril. 2002;77:861-870. https://doi.org/10.1016/S0015-0282(02)02959-X
  10. Santanam N, Murphy AA, Parthasarathy S. Macrophages, oxidation, and endometriosis. Ann N Y Acad Sci. 2002;955:183-198; discussion 19-200, 396-406. https://doi.org/10.1111/j.1749-6632.2002.tb02779.x
  11. Laschke MW, Elitzsch A, Scheuer C, Vollmar B, Menger MD. Selective cyclo-oxygenase-2 inhibition induces regression of autologous endometrial grafts by down-regulation of vascular endothelial growth factor-mediated angiogenesis and stimulation of caspase-3-dependent apoptosis. Fertil Steril. 2007;87:163-171. https://doi.org/10.1016/j.fertnstert.2006.05.068
  12. Tariverdian N, Theoharides TC, Siedentopf F, Gutierrez G, Jeschke U, Rabinovich GA, Blois SM, Arck PC. Neuroendocrine-immune disequilibrium and endometriosis: an interdisciplinary approach. Semin Immunopathol. 2007;29:193-210. https://doi.org/10.1007/s00281-007-0077-0
  13. Wu MH, Shoji Y, Chuang PC, Tsai SJ. Endometriosis: disease pathophysiology and the role of prostaglandins. Expert Rev Mol Med. 2007;9:1-20.
  14. Perkins ND. Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol. 2007;8:49-62. https://doi.org/10.1038/nrm2083
  15. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364:1789-1799. https://doi.org/10.1016/S0140-6736(04)17403-5
  16. Chishima F, Hayakawa S, Sugita K, Kinukawa N, Aleemuzzaman S, Nemoto N, Yamamoto T, Honda M. Increased expression of cyclooxygenase-2 in local lesions of endometriosis patients. Am J Reprod Immunol. 2002;48:50-56. https://doi.org/10.1034/j.1600-0897.2002.01101.x
  17. Park JY, Pillinger MH, Abramson SB. Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases. Clin Immunol. 2006;119:229-240. https://doi.org/10.1016/j.clim.2006.01.016
  18. Kim YA, Kim JY, Kim MR, Hwang KJ, Chang DY, Jeon MK. Tumor necrosis factor-alpha-induced cyclooxygenase-2 overexpression in eutopic endometrium of women with endometriosis by stromal cell culture through nuclear factor-kappaB activation. J Reprod Med. 2009;54:625-630.
  19. Gonzalez-Ramos R, Van Langendonckt A, Defrere S, Lousse JC, Colette S, Devoto L, Donnez J. Involvement of the nuclear $factor-{\kappa}B$ pathway in the pathogenesis of endometriosis. Fertil Steril. 2010;94:1985-1994. https://doi.org/10.1016/j.fertnstert.2010.01.013
  20. Suekawa M, Ishige A, Yuasa K, Sudo K, Aburada M, Hosoya E. Pharmacological studies on ginger. I. Pharmacological actions of pungent constitutents, (6)-gingerol and (6)-shogaol. J Pharmacobiodyn. 1984;7:836-848. https://doi.org/10.1248/bpb1978.7.836
  21. Park KK, Chun KS, Lee JM, Lee SS, Surh YJ. Inhibitory effects of [6]-gingerol, a major pungent principle of ginger, on phorbol esterinduced inflammation, epidermal ornithine decarboxylase activity and skin tumor promotion in ICR mice. Cancer Lett. 1998;129:139-144. https://doi.org/10.1016/S0304-3835(98)00081-0
  22. Ishiguro K, Ando T, Maeda O, Ohmiya N, Niwa Y, Kadomatsu K, Goto H. Ginger ingredients reduce viability of gastric cancer cells via distinct mechanisms. Biochem Biophys Res Commun. 2007;362:218-223. https://doi.org/10.1016/j.bbrc.2007.08.012
  23. Ali BH, Blunden G, Tanira MO, Nemmar A. Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research. Food Chem Toxicol. 2008;46:409-420. https://doi.org/10.1016/j.fct.2007.09.085
  24. Bak MJ, Ok S, Jun M, Jeong WS. 6-shogaol-rich extract from ginger up-regulates the antioxidant defense systems in cells and mice. Molecules. 2012;17:8037-8055. https://doi.org/10.3390/molecules17078037
  25. Shukla Y, Singh M. Cancer preventive properties of ginger: a brief review. Food Chem Toxicol. 2007;45:683-690. https://doi.org/10.1016/j.fct.2006.11.002
  26. Ray A, Vasudevan S, Sengupta S. 6-Shogaol inhibits breast cancer cells and stem cell-like spheroids by modulation of notch signaling pathway and induction of autophagic cell death. PLoS One. 2015;10:e0137614. https://doi.org/10.1371/journal.pone.0137614
  27. Seow SLS, Hong SL, Lee GS, Malek SNA, Sabaratnam V. 6-shogaol, a neuroactive compound of ginger (jahe gajah) induced neuritogenic activity via NGF responsive pathways in PC-12 cells. BMC Complement Altern Med. 2017;17:334. https://doi.org/10.1186/s12906-017-1837-6
  28. Park G, Oh DS, Lee MG, Lee CE, Kim YU. 6-Shogaol, an active compound of ginger, alleviates allergic dermatitis-like skin lesions via cytokine inhibition by activating the Nrf2 pathway. Toxicol Appl Pharmacol. 2016;310:51-59. https://doi.org/10.1016/j.taap.2016.08.019
  29. Han Q, Yuan Q, Meng X, Huo J, Bao Y, Xie G. 6-Shogaol attenuates LPS-induced inflammation in BV2 microglia cells by activating $PPAR-{\gamma}$. Oncotarget. 2017;8:42001-42006.
  30. National Research Council, Committee for the update of the guide for the care and use of laboratory animals, Institute for Laboratory Animal Research, Division on Earth and Life Studies. Guide for the care and use of laboratory animals. 8th ed. Washington, D.C.: National Academy Press; 2011.
  31. Vernon MW, Wilson EA. Studies on the surgical induction of endometriosis in the rat. Fertil Steril. 1985;44:684-694. https://doi.org/10.1016/S0015-0282(16)48988-0
  32. Tang Q, Shang F, Wang X, Yang Y, Chen G, Chen Y, Zhang J, Xu X. Combination use of ferulic acid, ligustrazine and tetrahydropalmatine inhibits the growth of ectopic endometrial tissue: a multi-target therapy for endometriosis rats. J Ethnopharmacol. 2014;151:1218-1225. https://doi.org/10.1016/j.jep.2013.12.047
  33. Yildirim G, Attar R, Ozkan F, Kumbak B, Ficicioglu C, Yesildaglar N. The effects of letrozole and melatonin on surgically induced endometriosis in a rat model: a preliminary study. Fertil Steril. 2010;93:1787-1792. https://doi.org/10.1016/j.fertnstert.2009.09.021
  34. Lebovic DI, Kir M, Casey CL. Peroxisome proliferator-activated receptor-gamma induces regression of endometrial explants in a rat model of endometriosis. Fertil Steril. 2004;82 Suppl 3:1008-1013. https://doi.org/10.1016/j.fertnstert.2004.02.148
  35. Gonzalez-Ramos R, Donnez J, Defrere S, Leclercq I, Squifflet J, Lousse JC, Van Langendonckt A. Nuclear factor-kappa B is constitutively activated in peritoneal endometriosis. Mol Hum Reprod. 2007;13:503-509. https://doi.org/10.1093/molehr/gam033
  36. Lousse JC, Van Langendonckt A, Gonzalez-Ramos R, Defrere S, Renkin E, Donnez J. Increased activation of nuclear factor-kappa B (NF-kappaB) in isolated peritoneal macrophages of patients with endometriosis. Fertil Steril. 2008;90:217-220. https://doi.org/10.1016/j.fertnstert.2007.06.015
  37. Tamura M, Sebastian S, Yang S, Gurates B, Ferrer K, Sasano H, Okamura K, Bulun SE. Up-regulation of cyclooxygenase-2 expression and prostaglandin synthesis in endometrial stromal cells by malignant endometrial epithelial cells. A paracrine effect mediated by prostaglandin E2 and nuclear factor-kappa B. J Biol Chem. 2002;277:26208-26216. https://doi.org/10.1074/jbc.M201347200
  38. Han S, Sidell N. RU486-induced growth inhibition of human endometrial cells involves the nuclear factor-kappa B signaling pathway. J Clin Endocrinol Metab. 2003;88:713-719. https://doi.org/10.1210/jc.2002-020876
  39. Hoffmann A, Baltimore D. Circuitry of nuclear factor kappaB signaling. Immunol Rev. 2006;210:171-186. https://doi.org/10.1111/j.0105-2896.2006.00375.x
  40. Farina AR, Tacconelli A, Vacca A, Maroder M, Gulino A, Mackay AR. Transcriptional up-regulation of matrix metalloproteinase-9 expression during spontaneous epithelial to neuroblast phenotype conversion by SK-N-SH neuroblastoma cells, involved in enhanced invasivity, depends upon GT-box and nuclear factor kappaB elements. Cell Growth Differ. 1999;10:353-367.
  41. Tamura M, Sebastian S, Yang S, Gurates B, Fang Z, Bulun SE. Interleukin-1beta elevates cyclooxygenase-2 protein level and enzyme activity via increasing its mRNA stability in human endometrial stromal cells: an effect mediated by extracellularly regulated kinases 1 and 2. J Clin Endocrinol Metab. 2002;87:3263-3273.
  42. Cao WG, Morin M, Metz C, Maheux R, Akoum A. Stimulation of macrophage migration inhibitory factor expression in endometrial stromal cells by interleukin 1, beta involving the nuclear transcription factor NFkappaB. Biol Reprod. 2005;73:565-570. https://doi.org/10.1095/biolreprod.104.038331
  43. Cao WG, Morin M, Sengers V, Metz C, Roger T, Maheux R, Akoum A. Tumour necrosis factor-alpha up-regulates macrophage migration inhibitory factor expression in endometrial stromal cells via the nuclear transcription factor NF-kappaB. Hum Reprod. 2006;21:421-428. https://doi.org/10.1093/humrep/dei315
  44. Chen SU, Lee H, Chang DY, Chou CH, Chang CY, Chao KH, Lin CW, Yang YS. Lysophosphatidic acid mediates interleukin-8 expression in human endometrial stromal cells through its receptor and nuclear factor-kappaB-dependent pathway: a possible role in angiogenesis of endometrium and placenta. Endocrinology. 2008;149:5888-5896. https://doi.org/10.1210/en.2008-0314
  45. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000;18:621-663. https://doi.org/10.1146/annurev.immunol.18.1.621
  46. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2:675-680. https://doi.org/10.1038/90609
  47. Boulanger D, Bureau F, Melotte D, Mainil J, Lekeux P. Increased nuclear factor kappaB activity in milk cells of mastitis-affected cows. J Dairy Sci. 2003;86:1259-1267. https://doi.org/10.3168/jds.S0022-0302(03)73710-2
  48. Chilov D, Kukk E, Taira S, Jeltsch M, Kaukonen J, Palotie A, Joukov V, Alitalo K. Genomic organization of human and mouse genes for vascular endothelial growth factor C. J Biol Chem. 1997;272:25176-25183. https://doi.org/10.1074/jbc.272.40.25176
  49. McLaren J. Vascular endothelial growth factor and endometriotic angiogenesis. Hum Reprod Update. 2000;6:45-55. https://doi.org/10.1093/humupd/6.1.45
  50. Harada T, Iwabe T, Terakawa N. Role of cytokines in endometriosis. Fertil Steril. 2001;76:1-10. https://doi.org/10.1016/S0015-0282(01)01816-7
  51. Wu MH, Sun HS, Lin CC, Hsiao KY, Chuang PC, Pan HA, Tsai SJ. Distinct mechanisms regulate cyclooxygenase-1 and -2 in peritoneal macrophages of women with and without endometriosis. Mol Hum Reprod. 2002;8:1103-1110. https://doi.org/10.1093/molehr/8.12.1103
  52. Wu MY, Chao KH, Yang JH, Lee TH, Yang YS, Ho HN. Nitric oxide synthesis is increased in the endometrial tissue of women with endometriosis. Hum Reprod. 2003;18:2668-2671. https://doi.org/10.1093/humrep/deg484
  53. Kiriakidis S, Andreakos E, Monaco C, Foxwell B, Feldmann M, Paleolog E. VEGF expression in human macrophages is NF-kappaBdependent: studies using adenoviruses expressing the endogenous NF-kappaB inhibitor IkappaBalpha and a kinase-defective form of the IkappaB kinase 2. J Cell Sci. 2003;116:665-674. https://doi.org/10.1242/jcs.00286
  54. Lin YJ, Lai MD, Lei HY, Wing LY. Neutrophils and macrophages promote angiogenesis in the early stage of endometriosis in a mouse model. Endocrinology. 2006;147:1278-1286. https://doi.org/10.1210/en.2005-0790
  55. Becker CM, D'Amato RJ. Angiogenesis and antiangiogenic therapy in endometriosis. Microvasc Res. 2007;74:121-130. https://doi.org/10.1016/j.mvr.2007.04.008
  56. Machado DE, Berardo PT, Palmero CY, Nasciutti LE. Higher expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) and metalloproteinase-9 (MMP-9) in a rat model of peritoneal endometriosis is similar to cancer diseases. J Exp Clin Cancer Res. 2010;29:4. https://doi.org/10.1186/1756-9966-29-4
  57. Wang HB, Lang JH, Leng JH, Zhu L, Liu ZF, Sun DW. Expression of vascular endothelial growth factor receptors in the ectopic and eutopic endometrium of women with endometriosis. Zhonghua Yi Xue Za Zhi. 2005;85:1555-1559.
  58. Celik O, Hascalik S, Elter K, Tagluk ME, Gurates B, Aydin NE. Combating endometriosis by blocking proteasome and nuclear factor-kappaB pathways. Hum Reprod. 2008;23:2458-2465. https://doi.org/10.1093/humrep/den246
  59. Ebert AD, Bartley J, David M. Aromatase inhibitors and cyclooxygenase- 2 (COX-2) inhibitors in endometriosis: new questions--old answers? Eur J Obstet Gynecol Reprod Biol. 2005;122:144-150. https://doi.org/10.1016/j.ejogrb.2005.04.017
  60. Olivares C, Bilotas M, Buquet R, Borghi M, Sueldo C, Tesone M, Meresman G. Effects of a selective cyclooxygenase-2 inhibitor on endometrial epithelial cells from patients with endometriosis. Hum Reprod. 2008;23:2701-2708. https://doi.org/10.1093/humrep/den315
  61. Machado DE, Berardo PT, Landgraf RG, Fernandes PD, Palmero C, Alves LM, Abrao MS, Nasciutti LE. A selective cyclooxygenase-2 inhibitor suppresses the growth of endometriosis with an antiangiogenic effect in a rat model. Fertil Steril. 2010;93:2674-2679. https://doi.org/10.1016/j.fertnstert.2009.11.037
  62. Machado DE, Rodrigues-Baptista KC, Alessandra-Perini J, Soares de Moura R, Santos TA, Pereira KG, Marinho da Silva Y, Souza PJ, Nasciutti LE, Perini JA. Euterpe oleracea extract (Acai) is a promising novel pharmacological therapeutic treatment for experimental endometriosis. PLoS One. 2016;11:e0166059. https://doi.org/10.1371/journal.pone.0166059
  63. Bruner KL, Matrisian LM, Rodgers WH, Gorstein F, Osteen KG. Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice. J Clin Invest. 1997;99:2851-2857. https://doi.org/10.1172/JCI119478
  64. Falconer H, Mwenda JM, Chai DC, Wagner C, Song XY, Mihalyi A, Simsa P, Kyama C, Cornillie FJ, Bergqvist A, Fried G, D'Hooghe TM. Treatment with anti-TNF monoclonal antibody (c5N) reduces the extent of induced endometriosis in the baboon. Hum Reprod. 2006;21:1856-1862. https://doi.org/10.1093/humrep/del044
  65. Mihalyi A, Simsa P, Mutinda KC, Meuleman C, Mwenda JM, D'Hooghe TM. Emerging drugs in endometriosis. Expert Opin Emerg Drugs. 2006;11:503-524. https://doi.org/10.1517/14728214.11.3.503
  66. Ergenoglu AM, Yeniel AO, Erbas O, Aktug H, Yildirim N, Ulukus M, Taskiran D. Regression of endometrial implants by resveratrol in an experimentally induced endometriosis model in rats. Reprod Sci. 2013;20:1230-1236. https://doi.org/10.1177/1933719113483014
  67. Zhang Y, Cao H, Hu YY, Wang H, Zhang CJ. Inhibitory effect of curcumin on angiogenesis in ectopic endometrium of rats with experimental endometriosis. Int J Mol Med. 2011;27:87-94.

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