대한한의학방제학회지 (Herbal Formula Science)

  • 제26권3호
  • /
  • Pages.183-193
  • /
  • 2018
  • /
  • 1229-1218(pISSN)
  • /
  • 2288-5641(eISSN)
대한한의학방제학회 (The Korean Medicine Society for the Herbal Formula Study)
권호 표지
DOI QR코드

DOI QR Code

음양곽(淫羊藿) 열수 추출물의 Smad 신호 억제를 통한 간성상세포의 활성 조절

Epimedium koreanum Nakai Water Extract Regulates Hepatic Stellate Cells Activation through Inhibition of Smad Signaling Pathway

  • 정지윤 (대구한의대학교 한의과대학) ;
  • 민병구 (충남대학교 약학대학) ;
  • 박정아 (대구한의대학교 한의과대학) ;
  • 변성희 (대구한의대학교 한의과대학) ;
  • 조일제 (대구한의대학교 한의과대학) ;
  • 김상찬 (대구한의대학교 한의과대학)
  • Jung, Ji Yun (College of Korean Medicine, Daegu Haany University) ;
  • Min, Byung-Gu (College of Pharmacy, Chungnam National University) ;
  • Park, Chung A (College of Korean Medicine, Daegu Haany University) ;
  • Byun, Sung Hui (College of Korean Medicine, Daegu Haany University) ;
  • Cho, Il Je (College of Korean Medicine, Daegu Haany University) ;
  • Kim, Sang Chan (College of Korean Medicine, Daegu Haany University)
  • 투고 : 2018.03.20
  • 심사 : 2018.07.23
  • 발행 : 2018.08.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Objectives : In Traditional Korean Medicine, Epimedium koreanum Nakai has diverse pharmacological activities to treat impotence, forgetfulness, cataract and exophthalmos. Present study investigated anti-fibrogenic effects of E. koreanum water extract (EKE) in hepatic stellate cells (HSCs). Methods : To study anti-fibrogenic effects of EKE, LX-2 cells, a human immortalized HSCs, were pre-treated with $3-300{\mu}g/mL$ of EKE, and then subsequently exposed to 5 ng/mL of transforming growth $factor-{\beta}1$ ($TGF-{\beta}1$). Expression level of ${\alpha}-smooth$ muscle actin was determined by immunoblot analysis. Phosphorylation of Smad, transactivation of Smad, and expression of plasminogen activator inhibitor-1 (PAI-1) were monitored to investigate the effect of EKE on $TGF-{\beta}1-mediated$ signaling pathway. Results : Up to $100{\mu}g/mL$, EKE did not show any cytotoxicity on LX-2 cells. Pre-treatment of EKE ($100{\mu}g/mL$) significantly inhibited ${\alpha}-smooth$ muscle actin expression induced by $TGF-{\beta}1$. In addition, EKE significantly decreased Smad2 and Smad3 phosphorylations, Smad binding element-driven luciferase activity and PAI-1 expression by $TGF-{\beta}1$. Of three flavonoid compounds found in EKE, only quercertin ($30{\mu}M$) attenuated $TGF-{\beta}1-mediated$ PAI-1 expression. Conclusion : These results suggest that EKE has an ability to suppress fibrogenic process in HSCs via inhibition of $TGF-{\beta}1/Smad$ signaling pathway.

키워드

참고문헌

  1. Moreira RK. Hepatic stellate cells and liver fibrosis. Arch Pathol Lab Med. 2007;131:1728-34.
  2. Kisseleva T, Brenner DA. Hepatic stellate cells and the reversal of fibrosis. J Gastroenterol Hepatol. 2006;21:S84-7. https://doi.org/10.1111/j.1440-1746.2006.04584.x
  3. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209-18. https://doi.org/10.1172/JCI24282
  4. Yoshida K, Murata M, Yamaguchi T, Matsuzaki K, Okazaki K. Reversible Human TGF-${\beta}$ signal shifting between tumor suppression and fibro-carcinogenesis: implications of smad phospho-Isoforms for hepatic epithelialmesenchymal transitions. J Clin Med. 2016;5:7. https://doi.org/10.3390/jcm5010007
  5. Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S, Gauthier JM. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J. 1998;17:3091-100. https://doi.org/10.1093/emboj/17.11.3091
  6. Choi DY, Kim JG, Yeom YH. New Comprehension on Jingyue Herbal Formulation. 1st Ed. Seoul:Bubin publisher. 2004:445.
  7. Gong TX. Shoushibaoyuan. 1st Ed. Beijing: Zhongguozhongyiyao publisher. 1993:445.
  8. Yu B. Yixuezhengchaun. 1st Ed. Seoul:Seongbosa. 1986:234.
  9. Heo J. Dongeuibogam. 1st Ed. Seoul:Namsandang. 1966:367, 667.
  10. Lee SI. Herbology. Seoul:Suseowon. 1981:71-72.
  11. Jung JY, Park SM, Ko HL, Lee JR, Park CA, Byun SH, Ku SK, Cho IJ, Kim SC. Epimedium koreanum Nakai water extract ameliorates oxidative stress-mediated liver injury by activating nuclear factor erythroid 2-related factor 2. Am J Chin Med. 2018;46:469-88. https://doi.org/10.1142/S0192415X18500246
  12. Jung JY, Byun SH, Park CA, Cho IJ, Kim SC. Anti-inflammatory effects of Epimedium koreanum Nakai water extract through inhibition of nuclear factor-kB in RAW 264.7 cells. Kor J Herbol. 2018;33:19-28.
  13. Cho IJ, Kim SH, Kim SG. Inhibition of $TGF{\beta}1$-mediated PAI-1 induction by oltipraz through selective interruption of Smad 3 activation. Cytokine. 2006;35:284-94. https://doi.org/10.1016/j.cyto.2006.10.001
  14. Kim JK, Lee JE, Jung EH, Jung JY, Jung DH, Ku SK, Cho IJ, Kim SC. Hemistepsin A ameliorates acute inflammation in macrophages via inhibition of nuclear factor-${\kappa}B$ and activation of nuclear factor erythroid 2-related factor 2. Food Chem Toxicol. 2018;111:176-88. https://doi.org/10.1016/j.fct.2017.11.014
  15. Choi SS, Omenetti A, Witek RP, Moylan CA, Syn WK, Jung Y, Yang L, Sudan DL, Sicklick JK, Michelotti GA, Rojkind M, Diehl AM. Hedgehog pathway activation and epithelial-tomesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis. Am J Physiol Gastrointest Liver Physiol. 2009;297:G1093-106. https://doi.org/10.1152/ajpgi.00292.2009
  16. Lee W, Nam JH, Cho HJ, Lee JY, Cho WK, Kim Y, We YM, Ma JY, Hoe HS. Epimedium koreanum Nakai inhibits PMA-induced cancer cell migration and invasion by modulating NF-${\kappa}B$/MMP-9 signaling in monomorphic malignant human glioma cells. Oncol Rep. 2017;38:3619-31.
  17. Song J, Feng L, Zhong R, Xia Z, Zhang L, Cui L, Yan H, Jia X, Zhang Z. Icariside II inhibits the EMT of NSCLC cells in inflammatory microenvironment via down-regulation of Akt/NF-${\kappa}B$ signaling pathway. Mol Carcinog. 2017;56:36-48. https://doi.org/10.1002/mc.22471
  18. Kim B, Park B. Baohuoside I suppresses invasion of cervical and breast cancer cells through the downregulation of CXCR4 chemokine receptor expression. Biochemistry. 2014;53:7562-9. https://doi.org/10.1021/bi5011927
  19. Verrecchia F, Chu ML, Mauviel A. Identification of novel TGF-beta /Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem. 2001;276:17058-62. https://doi.org/10.1074/jbc.M100754200
  20. Chen SJ, Yuan W, Mori Y, Levenson A, Trojanowska M, Varga J. Stimulation of type I collagen transcription in human skin fibroblasts by TGF-beta: involvement of Smad 3. J Invest Dermatol. 1999;112:49-57. https://doi.org/10.1046/j.1523-1747.1999.00477.x
  21. Ghosh AK, Vaughan DE. PAI-1 in tissue fibrosis. J Cell Physiol. 2012;227:493-507. https://doi.org/10.1002/jcp.22783
  22. Matsuo S, Lopez-Guisa JM, Cai X, Okamura DM, Alpers CE, Bumgarner RE, Peters MA, Zhang G, Eddy AA. Multifunctionality of PAI-1 in fibrogenesis: evidence from obstructive nephropathy in PAI-1-overexpressing mice. Kidney Int. 2005;67:2221-38. https://doi.org/10.1111/j.1523-1755.2005.00327.x
  23. Wang H, Zhang Y, Heuckeroth RO. PAI-1 deficiency reduces liver fibrosis after bile duct ligation in mice through activation of tPA. FEBS Lett. 2007;581:3098-104. https://doi.org/10.1016/j.febslet.2007.05.049
  24. Hu PF, Zhu YW, Zhong W, Chen YX, Lin Y, Zhang X, Yin C, Yue HY, Xie WF. Inhibition of plasminogen activator inhibitor-1 expression by siRNA in rat hepatic stellate cells. J Gastroenterol Hepatol. 2008;23:1917-25. https://doi.org/10.1111/j.1440-1746.2008.05485.x
  25. Wu L, Zhang Q, Mo W, Feng J, Li S, Li J, Liu T, Xu S, Wang W, Lu X, Yu Q, Chen K, Xia Y, Lu J, Xu L, Zhou Y, Fan X, Guo C. Quercetin prevents hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing autophagy via the TGF-${\beta}1$/Smads and PI3K/Akt pathways. Sci Rep. 2017;7:9289. https://doi.org/10.1038/s41598-017-09673-5
  26. Wang R, Zhang H, Wang Y, Song F, Yuan Y. Inhibitory effects of quercetin on the progression of liver fibrosis through the regulation of NF-${\kappa}B$/$I{\kappa}B{\alpha}$, p38 MAPK, and Bcl-2/Bax signaling. Int Immunopharmacol. 2017;47:126-33. https://doi.org/10.1016/j.intimp.2017.03.029
  27. Li X, Jin Q, Yao Q, Xu B, Li Z, Tu C. Quercetin attenuates the activation of hepatic stellate cells and liver fibrosis in mice through modulation of HMGB1-TLR2/4-NF-${\kappa}B$ signaling pathways. Toxicol Lett. 2016;261:1-12. https://doi.org/10.1016/j.toxlet.2016.09.002
  28. Algandaby MM, Breikaa RM, Eid BG, Neamatallah TA, Abdel-Naim AB, Ashour OM. Icariin protects against thioacetamide-induced liver fibrosis in rats: Implication of anti-angiogenic and anti-autophagic properties. Pharmacol Rep. 2017;69:616-24. https://doi.org/10.1016/j.pharep.2017.02.016
  29. Li J, Liu P, Zhang R, Cao L, Qian H, Liao J, Xu W, Wu M, Yin Z. Icaritin induces cell death in activated hepatic stellate cells through mitochondrial activated apoptosis and ameliorates the development of liver fibrosis in rats. J Ethnopharmacol. 2011;137:714-23. https://doi.org/10.1016/j.jep.2011.06.030