한국산학기술학회논문지 (Journal of the Korea Academia-Industrial cooperation Society)

  • 제22권4호
  • /
  • Pages.483-492
  • /
  • 2021
  • /
  • 1975-4701(pISSN)
  • /
  • 2288-4688(eISSN)
한국산학기술학회 (The Korea Academia-Industrial cooperation Society)
권호 표지
DOI QR코드

DOI QR Code

곽향의 성분 분석 및 주요 성분들의 in silico 항당뇨 타겟 단백질 탐색

Analysis of Chemical Constituents of Agastachis Herba and in silico Investigation on Antidiabetic Target Proteins of its Major Compounds

  • 최종근 (청운대학교 화학공학과)
  • Choi, Jongkeun (Department of Chemical Engineering, Chungwoon University)
  • 투고 : 2021.01.06
  • 심사 : 2021.04.02
  • 발행 : 2021.04.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

곽향은 식욕부진, 메스꺼움 등의 치료에 사용될 뿐만 아니라 최근에는 항당뇨 효능도 알려졌다. 본 연구에서는 곽향의 항산화력과 주요 성분들을 조사한 다음, in-silico 방법론을 적용하여 타겟 단백질들을 예측하였다. 먼저 메탄올 추출물의 DPPH와 ABTS 라디칼 소거능의 EC50 값은 각각 78.6 ㎍/mL과 31.0 ㎍/mL이었다. 이것은 ascorbic acid의 값(9.9 ㎍/mL, 5.2 ㎍/mL)과 비교할 때 항산화력이 뛰어나다고 할 수 있다. HPLC-PDA-MS/MS를 이용하여 성분들을 정성 분석한 결과, 추출물의 주요 화합물로 rosmarinic acid, tilianin, agastachoside 그리고 acacetin을 확인하였다. 이들 성분들의 항당뇨 작용 타겟 단백질을 DIA-DB 서버를 사용하여 구조 유사도와 inverse doking 방법론을 적용하여 예측하였다. 본 가상 탐색 결과, 주요 타겟 단백질들은 PPAR-γ, DPP IV, glucokinase, α-glucosidase, SGLT2, aldose reductase, corticosteroid 11-beta-dehydrogenase로 예측되었다. 그리고 이들 단백질들 중 일부는 이미 실험적으로 검증된 타겟 단백질이었다. 따라서 in silico 검색 방법이 유효하다고 생각할 수 있다. 마지막으로 활성성분들의 최적의 추출 조건을 결정하기 위하여 여러 추출 용매들로 곽향을 추출하였다. 여러 유기 용매들 중에는 메탄올이 그리고 에탄올-물 혼합용매에서는 80% 에탄올이 가장 효과적인 추출 용매로 확인되었다.

Agastachis Herba (AH) to treat anorexia and nausea and its antidiabetic efficacy was recently reported. This study examined the antioxidant activities and chemical constituents of AH and predicted the target proteins of each compound using in silico approaches. The results showed that EC50 values of AH methanol extract for DPPH and ABTS radical scavenging were 78.6 ㎍/mL and 31.0 ㎍/mL, respectively. Compared to the EC50 values of ascorbic acid (9.9 ㎍/mL, 5.2 ㎍/mL), the AH methanol extract possessed excellent antioxidant activities. Rosmarinic acid, tilianin, agastachoside, and acetin were confirmed as the major compounds of extracts by qualitative analysis performed with HPLC-PDA-MS/MS. The antidiabetic target proteins of these compounds were predicted by applying a structural similarity and inverse docking methodology using a DIA-DB server. The resulting target proteins were PPAR-γ, DPP IV, glucokinase, α-glucosidase, SGLT2, aldose reductase, and corticosteroid 11-beta-dehydrogenase, some of which have already been proven experimentally as target proteins. Therefore, the in silico methods can be considered valid. Finally, AH were extracted with various solvents to determine the optimal conditions for the extraction of active components. Methanol among organic solvents and 80% ethanol in ethanol-water mixtures were identified as the most effective solvent for the extraction.

키워드

참고문헌

  1. Korean Diabetes Association. Diabetes fact sheet in Korea 2016. Available From: http://www.diabetes.or.kr
  2. J. Meece, "Dispelling Myths and Removing BarriersAbout Insulin in Type 2 Diabetes", The Diabetes Educator, Vol.32, No.1, pp.9S-18S, 2006. https://doi.org/10.1177/0145721705285638
  3. American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care. Vol.42, Suppl.1, pp.90S-102S. 2019. DOI: https://doi.org/10.2337/dc19-S009
  4. X.-L. Tong, L. Dong, L. Chen, Z. Zhen. "Treatment of diabetes using traditional Chinese medicine: past, present and future", The American Journal of Chinese Medicine. Vol.40, No.5, pp.877-886, 2010. DOI: https://doi.org/10.1142/S0192415X12500656
  5. M. S. H. Akash, K. Rehman, S. Chen, "Effects of coffee on type 2 diabetes mellitus", Nutrition. Vol.30, No.7-8, pp.755-763, 2014. DOI: https://doi.org/10.1016/j.nut.2013.11.020
  6. P. V. Babu, D. Liu, E. R. Gilbert, "Recent advances in understanding the anti-diabetic actions of dietary flavonoids", J. Nutr. Biochem., Vol.24, No.11 pp.1777-1789, 2013. DOI: https://doi.org/10.1016/j.jnutbio.2013.06.003
  7. Korea Food and Drug Administration. The Korean Herbal Pharmacopoeia. Korea Food and Drug Administration. Cheongju. pp.53, 2014.
  8. S. K. Lee, Agastachis Herba, Research Report, Research Center for Standardization of Herbal Medicines, korea, pp. 8-10. Available From: https://www.nifds.go.kr/brd/m_184/down.do?brd_id=303&seq=5&data_tp=A&file_seq=9
  9. G. Haiyan, H. Lijuan, L. Shaoyu, Z. Chen, M. A. Ashraf, "Antimicrobial, antibiofilm and antitumor activities of essential oil of Agastache rugosa from Xinjiang, China", Saudi J. Biol. Sci., Vol.23 No.4, pp.524-530, Jul. 2016. DOI: https://doi.org/10.1016/j.sjbs.2016.02.020
  10. S. H. Kim, J. H. Hong, W. K. Yang, J. H. Geum, H. R. Kim, S. Y. Choi, Y M. Kang, H. J. An, Y. C. Lee, "Herbal Combinational Medication of Glycyrrhiza glabra, Agastache rugosa Containing Glycyrrhizic Acid, Tilianin Inhibits Neutrophilic Lung Inflammation by Affecting CXCL2, Interleukin-17/STAT3 Signal Pathways in a Murine Model of COPD", Nutrients. Vol.27, No.4, pp.926, Mar. 2020. DOI: https://doi.org/10.3390/nu12040926
  11. M. S. Yun, C. Kim, J. K. Hwang, "Agastache rugosa Kuntze Attenuates UVB-Induced Photoaging in Hairless Mice through the Regulation of MAPK/AP-1 and TGF-β/ Smad Pathways", J. Microbiol. Biotechnol., Vol.29, No.9, pp.1349-1360, Sep. 2019. DOI: https://doi.org/10.4014/jmb.1908.08020
  12. S. M. Shin, J. J. Jeong, D. W. Park, H. Ko, G. T Kim, E.-H. Kim, T. Kim, E.-H. Sohn, J.E. Kwon, E. J. Koo, S. C. Kang, "Screening for Anti-diabetic Effects of Prescribed Korean Traditional Medicines", Korean J. Plant Res., Vol.25, No.6, pp.670-681, 2012. DOI: http://dx.doi.org/10.7732/kjpr.2012.25.6.670
  13. Y.-J. Ji, E. Y. Lee, J. Y. Lee, Y. J. Lee, S. E. Lee, K. H. Seo, H. D. Kim, "Antioxidant and anti-diabetic effects of Agastache rugosa extract", J. East Asian Soc. Diet Life, Vol.30, No.4, pp.297-305, 2020. DOI: http://dx.doi.org/10.17495/easdl.2020.8.30.4.297
  14. Q. Zhang, J. Zhang, J. Shen, A. Silva, D. A. Dennis, C. J. Barrow, "A simple 96-well microplate method for estimation of total polyphenol content in seaweeds", J Appl. Phycol., Vol.18, pp.445-450, 2006. DOI: https://doi.org/10.1007/s10811-006-9048-4
  15. B. M. Dietz, Y. H. Kang, G. Liu, A. L. Eggler, P. Yao, L. R. Chadwick, G. F. Pauli, N. R. Farnsworth, A. D. Mesecar, R. B. van Breemen, J. L. Bolton, "Xanthohumol isolated from Humulus lupulus Inhibits menadione-induced DNA damage through induction of quinone reductase", Chem. Res. Toxicol., Vol.18, No.8, pp.1296-1305, Aug. 2005. DOI: https://doi.org/10.1021/tx050058x
  16. R. Re, N. Pellegrini, A. Proteggente, A. Pannala, M. Yang, C. Rice-Evans, "Antioxidant activity applying an improved ABTS radical cation decolorization assay", Free Radic. Biol. Med. Vol.26, No.9-10, pp.1231-1237, May 1999. DOI: https://doi.org/10.1016/s0891-5849(98)00315-3
  17. Ministry of Food and Durg Safety. The Korean Herbal Standard Chemical Profile Guidline. Ministry of Food and Durg Safety. Cheongju, pp.7-23, 2017
  18. H. Perez-Sanchez, H. den-Haan, J. Pena-Garcia, J. Lozano-Sanchez, M. E. Martinez Moreno, A. Sanchez-Perez, A. Munoz, P. Ruiz-Espinosa, A. S. P. Pereira, A. Katsikoudi, J. A. Gabaldon Hernandez, I. Stojanovic, A. S. Carretero, A. G. Tzakos. "DIA-DB: A Database and Web Server for the Prediction of Diabetes Drugs", J. Chem. Inf. Model. Vol.28, No.9 pp.4124-4130, Sep. 2020. DOI: https://doi.org/10.1021/acs.jcim.0c00107
  19. D. R. Laybutt, H. Kaneto, W. Hasenkamp, S. Grey, J. C. Jonas, D. C. Sgroi, A. Groff, C. Ferran, S. Bonner-Weir, A. Sharma, G. C. Weir, "Increased expression of antioxidant andantiapoptic genes in is lets that may contribute to β-cellsurvival during chronic hyperglycemia", Diabetes, Vol.51, No.2, pp.:413-456, 2002. DOI: https://doi.org/10.2337/diabetes.51.2.413
  20. M. S. Ola, D. Al-Dosari, A. S. Alhomida, "Role of oxidativestress in diabetic retinopathy and the beneficial effects offlavonoids", Curr. Pharm. Des., Vol.24, No.19, pp.2180-2187, 2018. DOI: https://doi.org/10.2174/1381612824666180515151043
  21. H. Chen, Q. Zhang, X. Wang, J. Yang, Q. Wang, "Qualitative analysis and simultaneous quantification of phenolic compounds in the aerial parts of Salvia miltiorrhiza by HPLC-DAD and ESI/MS(n)", Phytochem. Anal., Vol.22, No.3, pp.247-257, May-Jun 2011. DOI: https://doi.org/10.1002/pca.1272.
  22. L. L. Xu, J. J. Xu, K. R. Zhong, Z. P. Shang, F. Wang, R. F. Wang, L. Zhang, J. Y. Zhang, B. Liu, "Analysis of Non-Volatile Chemical Constituents of Menthae Haplocalycis Herba by Ultra-High Performance Liquid Chromatography-High Resolution Mass Spectrometry", Molecules, Vol.22, No.10, pp.1756, Oct. 2017. DOI: https://doi.org/10.3390/molecules22101756.
  23. J. L. Santos, V. S. Bispo, A. B. Filho, I. F. Pinto, L. S. Dantas, D. F. Vasconcelos, F. F. Abreu, D. A. Melo, I. A. Matos, F. P. Freitas, O. F. Gomes, M. H. Medeiros, H. R. Matos, "Evaluation of chemical constituents and antioxidant activity of coconut water (Cocus nucifera L.) and caffeic acid in cell culture", An. Acad. Bras Cienc., Vol.85, No.4, pp.1235-1247, 2013. DOI: https://doi.org/10.1590/0001-37652013105312
  24. J. H. An, H. J. Yuk, D.-Y. Kim, C. W. Nho, D. Lee, H. W. Ryu, S.-R. Oh, "Evaluation of phytochemicals in Agastache rugosa (Fisch. & C.A.Mey.) Kuntze at different growth stages by UPLC-QTof-MS", Ind. Crops Prod., Vol.112, pp.608-616, 2018. DOI: https://doi.org/10.1016/j.indcrop.2017.12.050
  25. D. Gfeller, A. Grosdidier, M. Wirth, A. Daina, O. Michielin, V. Zoete, "SwissTargetPrediction: a web server for target prediction of bioactive small molecules", Nucleic Acids Res. Vol.42, pp.W32-38, Jul. 2014. DOI: https://doi.org/10.1093/nar/gku293
  26. J. Zhou, Q. Wang, Z. Xiang, Q. Tong, J. Pan, L. Wan, J. Chen, "Network Pharmacology Analysis of Traditional Chinese Medicine Formula Xiao Ke Yin Shui Treating Type 2 Diabetes Mellitus", Evid. Based Complement. Alternat. Med., Vol.2019, pp.4202563, Sep. 2019. DOI: https://doi.org/10.1155/2019/4202563
  27. A. Daina, O. Michielin, V. Zoete, "SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules:, Nucleic Acids Res. Vol.47, No.W1, pp.W357-W364, Jul. 2019. DOI: https://doi.org/10.1093/nar/gkz382
  28. A. S. P. Pereira, H. den Haan, J. Pena-Garcia, M. M. Moreno, H. Perez-Sanchez, Z. Apostolides, "Exploring African Medicinal Plants for Potential Anti-Diabetic Compounds with the DIA-DB Inverse Virtual Screening Web Server", Molecules. Vol.24, No.10, pp.2002, May, 2019, DOI: https://doi.org/10.3390/molecules24102002
  29. H. Perez-Sanchez, H. den-Haan, J. Pena-Garcia, J. Lozano-Sanchez, M. E. Martinez Moreno, A. Sanchez-Perez, A. Munoz, P. Ruiz-Espinosa, A. S. P. Pereira, A. Katsikoudi, J. A. Gabaldon Hernandez, I. Stojanovic, A. S. Carretero, A. G. Tzakos, "DIA-DB: A Database and Web Server for the Prediction of Diabetes Drugs", J. Chem. Inf. Model., Vol.60, No.9, pp.4124-4130, Sep. 2020. DOI: https://doi.org/10.1021/acs.jcim.0c00107
  30. M. R. Al-Sereiti, K. M. Abu-Amer, P. Sen, "Pharmacology of rosemary (Rosmarinus officinalis Linn.) and its therapeutic potentials", Indian J. Exp. Biol., Vol.37, pp.124-130, 1999.
  31. K. A. Scheckel, S. C. Degner, D. F. Romagnolo, "Rosmarinic acid antagonizes activator protein-1-dependent activation of cyclooxygenase-2 expression in human cancer and nonmalignant cell lines", J. Nutr., Vol.138, pp.2098-2105, 2008. DOI: https://doi.org/10.3945/jn.108.090431.
  32. N. A. Al-Dhabi, M. V. Arasu, C. H. Park, S. U. Park, "Recent studies on rosmarinic acid and its biological and pharmacological activities", EXCLI J. Vol.13, pp.1192-1195, 2014.
  33. C. Lu, Y. Zou, Y. Liu, Y. Niu, "Rosmarinic acid counteracts activation of hepatic stellate cells via inhibiting the ROS-dependent MMP-2 activity: Involvement of Nrf2 antioxidant system", Toxicol. Appl. Pharmacol. Vol.318, pp.69-18, Mar. 2017. DOI: https://doi.org/10.1016/j.taap.2017.01.008
  34. J. Lee, E. Jung, Y. Kim, J. Lee, J. Park, S. Hong, C. G. Hyun, D. Park, Y. S. Kim, "Rosmarinic acid as a downstream inhibitor of IKK-beta in TNF-alpha-induced upregulation of CCL11 and CCR3", Br. J. Pharmacol., Vol.148, No.3, pp.366-375, Jun. 2006. DOI: https://doi.org/10.1038/sj.bjp.0706728
  35. X. Zhang, Z. G. Ma, Y. P. Yuan, S. C. Xu, W. Y. Wei, P. Song, C. Y. Kong, W. Deng, Q. Z. Tang, "Rosmarinic acid attenuates cardiac fibrosis following long-term pressure overload via AMPKα/Smad3 signaling", Cell Death Dis. Vol.9, No.2, pp.102, Jan. 2018. DOI: https://doi.org/10.1038/s41419-017-0123-3
  36. J. Kang, Y. Tang, Q. Liu, N. Guo, J. Zhang, Z. Xiao, R. Chen, Z. Shen, "Isolation, modification, and aldose reductase inhibitory activity of rosmarinic acid derivatives from the roots of Salvia grandifolia", Fitoterapia, Vol.112, pp.197-204, Jul. 2016. DOI: https://doi.org/10.1016/j.fitote.2016.05.011
  37. A. M. Bower, L. M. Real Hernandez, M. A. Berhow, E. G. de Mejia, "Bioactive compounds from culinary herbs inhibit a molecular target for type 2 diabetes management, dipeptidyl peptidase IV", J. Agric. Food Chem., Vol.62, No.26, pp.6147-6158, Jul. 2014. DOI: https://doi.org/10.1021/jf500639f
  38. M. R. Akanda, M. N. Uddin, I. S. Kim, D. Ahn, H. J. Tae, B. Y. Park, "The biological and pharmacological roles of polyphenol flavonoid tilianin", Eur. J. Pharmacol., Vol.842, pp.291-297, Jan. 2019. DOI: https://doi.org/10.1016/j.ejphar.2018.10.044
  39. H. M. Oh, Y. J. Kang, Y. S. Lee, M. K. Park, S. H. Kim, H. J. Kim, H. G. Seo, J. H. Lee, K. C. Chang, "Protein kinase G-dependent heme oxygenase-1 induction by Agastache rugosa leaf extract protects RAW264.7 cells from hydrogen peroxide-induced injury", J. Ethnopharmacol., Vol.103, No.2, pp.229-235, Jan. 2006. DOI: https://doi.org/10.1016/j.jep.2005.08.030
  40. K. H. Nam, J. H. Choi, Y. J. Seo, Y. M. Lee, Y. S. Won, M. R. Lee, M. N. Lee, J. G. Park, Y. M. Kim, H. C. Kim, C. H. Lee, H. K. Lee, S. R. Oh, G. T. Oh, "Inhibitory effects of tilianin on the expression of inducible nitric oxide synthase in low density lipoprotein receptor deficiency mice", Exp. Mol. Med. Vol.38, No.4, pp.445-452, Aug. 2006. DOI: https://doi.org/10.1038/emm.2006.52
  41. M. E. Gonzalez-Trujano, H. Ponce-Munoz, S. Hidalgo-Figueroa, G. Navarrete-Vazquez, S. Estrada-Soto, "Depressant effects of Agastache mexicana methanol extract and one of major metabolites tilianin" Asian Pac. J. Trop. Med. Vol.8, No.3, pp.185-190, Mar. 2015. DOI: https://doi.org/10.1016/S1995-7645(14)60312-6
  42. J. A. Garcia-Diaz, G. Navarrete-Vazquez, S. Garcia-Jimenez, S. Hidalgo-Figueroa, J. c. Almanza-Perez, F. J. Alarcon-Aguilar, J. Gomez-Zamudio, M. Cruz, M. Ibarra-Barajas, S. Estrada-Soto. "Antidiabetic, antihyperlipidemic and anti-inflammatory effects of tilianin in streptozotocin-nicotinamide diabetic rats", Biomed. Pharmacother., Vol.83, pp.667-675, Oct. 2016. DOI: https://doi.org/10.1016/j.biopha.2016.07.023
  43. S. Jo, H. Kim, S. Kim, D. H. Shin, M. S. Kim, "Characteristics of flavonoids as potent MERS-CoV 3C-like protease inhibitors", Chem. Biol. Drug Des., Vol.94, No.6, pp.2023-2030, Dec. 2019. DOI: https://doi.org/10.1111/cbdd.13604
  44. S. Singh, P. Gupta, A. Meena, S. Luqman, "Acacetin, a flavone with diverse therapeutic potential in cancer, inflammation, infections and other metabolic disorders", Food Chem. Toxicol. Vol.145, pp.111708, Nov. 2020. DOI: https://doi.org/10.1016/j.fct.2020.111708
  45. Y. Wei, P. Yuan, Q. Zhang, Y. Fu, Y. Hou, L. Gao, X. Zheng, W. Feng, "Acacetin improves endothelial dysfunction and aortic fibrosis in insulin-resistant SHR rats by estrogen receptors", Mol. Biol. Rep., Vol.47, No.9, pp.6899-6918, Sep. 2020. DOI: https://doi.org/10.1007/s11033-020-05746-3
  46. J. Wang, J. Xu, T. J. Zhang, "Optimization of hydrolysis process of linarin using response surface methodology and research about ARI activity of glycosylation-acacetin", Zhongguo Zhong Yao Za Zhi. Vol.39, No.11, pp.2060-2064, Jun. 2014. DOI: https://doi.org/10.4268/cjcmm20141123
  47. E. B. Kwon, M. J. Kang, H. W. Ryu, S. Lee, J. W. Lee, M. K. Lee, H. S. Lee, S. U. Lee, S. R. Oh, M. O. Kim, "Acacetin enhances glucose uptake through insulin-independent GLUT4 translocation in L6 myotubes", Phytomedicine, Vol.68, pp.153178, Mar. 2020. DOI: https://doi.org/10.1016/j.phymed.2020.153178