Network pharmacology-based strategy to investigate harmacological mechanisms of Isodon serra (Maxim.) Hara for treatment of inflammatory

doi:10.5246/jcps.2022.04.022

Abstract

Abstract:

Widely distributed in plants, ent-kaurane diterpenoids could reduce the incidence of inflammatory. The most important active ingredient of Isodon serra (Maxim.) Hara is ent-kaurane diterpenoids, which contribute to the anti-inflammatory pharmacological effects of Isodon serra. However, the ingredients, the active compounds, drug targets, inflammatory targets and exact molecular mechanism of Isodon serra in treating inflammatory are still unclear. The purpose of this study was to use the method of network pharmacological analysis to find the active compounds in Isodon serra. These active compounds match the library of ent-kaurane diterpenoids compounds we established, and we find all the eligible ent-kaurane diterpenoids compounds. Isodon serra related and anti-inflammatory targets were found and then combined to get intersection, which represented potential anti-inflammatory targets of active compounds in Isodon serra. Moreover, anti-inflammatory targets and active compounds targets protein-protein interaction network were merged to get the protein-protein interaction network intersection and core genes in anti-inflammatory target protein-protein interaction network. For the anti-inflammatory targets of Isodon serra, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were executed to confirm gene functions of Isodon serra in antagonizing inflammation. Finally, TCMSP analysis identified 10 active compounds out of 48 ent-kaurane. The pathway analysis showed enrichment for different pathways like AGE-RAGE signaling pathway in diabetic complications, small cell lung cancer and human cytomegalovirus infection, which were all connected to inflammatory. On the whole, the proposed method clearly identified the ent-kaurane diterpenoids of Isodon serra and the results gave the active compounds of Isodon serra for the first time. The combining use of the qualitative analysis of traditional Chinese medicine (TCM) and network pharmacological methods could discover potential drug targets and reveal the biological process of TCM, which would open up a new approach in the study of TCM in future.

Key words: Isodon serra (Maxim.) Hara, Network pharmacology, Active compounds, ent-Kaurane diterpenoids, Inflammatory targets

Supporting:

Weiwei Xie, Xuqing Wen, Dedong Zhang, Yuqian Zhang, Zhiqing Zhang, Yiran Jin, Yingfeng Du. Network pharmacology-based strategy to investigate harmacological mechanisms of Isodon serra (Maxim.) Hara for treatment of inflammatory[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(4): 250-263.

Figures/Tables 7

References 40

[1]	The Pharmacopeia Commission of People’s Republic of China, Pharmacopoeia of the People’s Republic of China, Chinese Medical Science and Technology Press, Beijing, 2010. Appendix III 26.
[2]	Wan, J.; Liu, M.; Jiang, H.Y.; Yang, J.; Du, X.; Li, X.N.; Wang, W.G.; Li, Y.; Pu, J.X.; Sun, H.D. Bioactive ent-kaurane diterpenoids from Isodon serra. Phytochemistry. 2016, 130, 244–251.
[3]	Wang, W.Q.; Xuan, L.J. Ent-6,7-Secokaurane diterpenoids from Rabdosia serra and their cytotoxic activities. Phytochemistry. 2016, 122, 119–125.
[4]	Tang, H.M.; Chen, J.N.; Zhang, Y.; Lai, X.P.; Huang, S. Simultaneous determination of eight water-soluble compositions in Isodon serra from different origins by HPLC. Chin. J. Pharm. Anal. 2015, 35, 228–234.
[5]	Sun, H.D.; Huang, S.X.; Han, Q.B. Diterpenoids from Isodon species and their biological activities. Nat. Prod. Rep. 2006, 23, 673–698.
[6]	Liu, P.W.; Du, Y.F.; Zhang, X.W.; Sheng, X.N.; Shi, X.W.; Zhao, C.C.; Zhu, H.; Wang, N.; Wang, Q.; Zhang, L.T. Rapid analysis of 27 components of isodon serra by LC-ESI-MS-MS. Chromatographia. 2010, 72, 265–273.
[7]	Yang, Y.S.; Sun, H.D.; Zhou, Y.P.; Ji, S.Y.; Li, M.L. Effects of three diterpenoids on tumor cell proliferation and telomerase activity. Nat. Prod. Res. 2009, 23, 1007–1012.
[8]	Jin, Y.R.; Du, Y.F.; Shi, X.W.; Liu, P.W. Simultaneous quantification of 19 diterpenoids in Isodon amethystoides by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry. J. Pharm. Biomed. Anal. 2010, 53, 403–411.
[9]	Huang, W.H.; Liang, Y.Y.; Wang, J.J.; Li, G.Q.; Wang, G.C.; Li, Y.L.; Chung, H.Y. Anti-angiogenic activity and mechanism of kaurane diterpenoids from Wedelia chinensis. Phytomedicine. 2016, 23, 283–292.
[10]	Yang, L.; Zhang, Y.B.; Chen, L.F.; Chen, N.H.; Wu, Z.N.; Jiang, S.Q.; Jiang, L.; Li, G.Q.; Li, Y.L.; Wang, G.C. New labdane diterpenoids from Croton laui and their anti-inflammatory activities. Bioorg. Med. Chem. Lett. 2016, 26, 4687–4691.
[11]	Niu, C.S.; Li, Y.; Liu, Y.B.; Ma, S.G.; Li, L.; Qu, J.; Yu, S.S. Analgesic diterpenoids from the twigs of Pieris Formosa. Tetrahedron. 2016, 72, 44–49.
[12]	Liu, Z.G.; Li, Z.L.; Li, D.H.; Li, N.; Bai, J.; Zhao, F.; Meng, D.L.; Hua, H.M. Ent-Abietane-type diterpenoids from the roots of Euphorbia ebracteolata with their inhibitory activities on LPS-induced NO production in RAW 264.7 macrophages. Bioorg. Med. Chem. Lett. 2016, 26, 1–5.
[13]	Tiwari, N.; Thakur, J.; Saikia, D.; Gupta, M.M. Antitubercular diterpenoids from Vitex trifolia. Phytomedicine. 2013, 20, 605–610.
[14]	Chen, S.J.; Cui, M.C. Systematic understanding of the mechanism of salvianolic acid A via computational target fishing. Molecules. 2017, 22, 644.
[15]	Zhai, L.; Ning, Z.W.; Huang, T.; Wen, B.; Liao, C.H.; Lin, C.Y.; Zhao, L.; Xiao, H.T.; Bian, Z.X. Cyclocarya paliurus leaves tea improves dyslipidemia in diabetic mice: a lipidomics-based network pharmacology study. Front. Pharmacol. 2018, 9, 973.
[16]	Hutchinson, L.; Kirk, R. High drug attrition rates—where are we going wrong? Nat. Rev. Clin. Oncol. 2011, 8, 189–190.
[17]	Hopkins, A.L. Network pharmacology. Nat. Biotechnol. 2007, 25, 1110–1111.
[18]	Li, S.; Zhang, B.; Zhang, N. Network target for screening synergistic drug combinations with application to traditional Chinese medicine. BMC Syst. Biol. 2011, 5, S10.
[19]	Li, S.; Zhang, B. Traditional Chinese medicine network pharmacology: theory, methodology and application. Chin. J. Nat. Med. 2013, 11, 110–120.
[20]	Vitali, F.; Mulas, F.; Marini, P.; Bellazzi, R. Network-based target ranking for polypharmacological therapies. J. Biomed. Inform. 2013, 46, 876–881.
[21]	Kibble, M.; Saarinen, N.; Tang, J.; Wennerberg, K.; Mäkelä, S.; Aittokallio, T. Network pharmacology applications to map the unexplored target space and therapeutic potential of natural products. Nat. Prod. Rep. 2015, 32, 1249–1266.
[22]	Musyoka, T.; Bishop, Ö.T. South African abietane diterpenoids and their analogs as potential antimalarials: novel insights from hybrid computational approaches. Molecules. 2019, 24, 4036.
[23]	Shaker, S.; Sang, J.; Yan, X.L.; Fan, R.Z.; Tang, G.H.; Xu, Y.K.; Yin, S. Diterpenoids from Euphorbia royleana reverse P-glycoprotein-mediated multidrug resistance in cancer cells. Phytochemistry. 2020, 176, 112395.
[24]	Isca, V.M.S.; Ferreira, R.J.; Garcia, C.; Monteiro, C.M.; Dinic, J.; Holmstedt, S.; André, V.; Pesic, M.; dos Santos, D.J.V.A.; Candeias, N.R.; Afonso, C.A.M.; Rijo, P. Molecular docking studies of royleanone diterpenoids from plectranthus spp. as P-glycoprotein inhibitors. ACS Med. Chem. Lett. 2020, 11, 839–845.
[25]	Bai, N.; He, K.; Zhou, Z.; Tsai, M.L.; Zhang, L.; Quan, Z.; Shao, X.; Pan, M.H.; Ho, C.T. Ent-kaurane diterpenoids from Rabdosia rubescens and their cytotoxic effects on human cancer cell lines. Planta Med. 2010, 76, 140–145.
[26]	Musyoka, T.; Bishop, Ö.T. South African abietane diterpenoids and their analogs as potential antimalarials: novel insights from hybrid computational approaches. Molecules. 2019, 24, 4036.
[27]	Shaker, S.; Sang, J.; Yan, X.L.; Fan, R.Z.; Tang, G.H.; Xu, Y.K.; Yin, S. Diterpenoids from Euphorbia royleana reverse P-glycoprotein-mediated multidrug resistance in cancer cells. Phytochemistry. 2020, 176, 112395.
[28]	Reyes-Gordillo, K.; Shah, R.; Arellanes-Robledo, J.; Cheng, Y.; Ibrahim, J.; Tuma, P.L. Akt1 and Akt2 isoforms play distinct roles in regulating the development of inflammation and fibrosis associated with alcoholic liver disease. Cells. 2019, 8. 1337.
[29]	Huang, X.F.; Cheng, W.B.; Jiang, Y.; Liu, Q.; Liu, X.H.; Xu, W.F.; Huang, H.T. A network pharmacology-based strategy for predicting anti-inflammatory targets of ephedra in treating asthma. Int. Immunopharmacol. 2020, 83, 106423.
[30]	Mussard, E.; Jousselin, S.; Cesaro, A.; Legrain, B.; Lespessailles, E.; Esteve, E.; Berteina-Raboin, S.; Toumi, H. Andrographis paniculata and its bioactive diterpenoids protect dermal fibroblasts against inflammation and oxidative stress. Antioxidants. 2020, 9, 432.
[31]	Lossi, L.; Cocito, C.; Alasia, S.; Merighi, A. Ex vivo imaging of active caspase 3 by a FRET-based molecular probe demonstrates the cellular dynamics and localization of the protease in cerebellar granule cells and its regulation by the apoptosis-inhibiting protein survivin. Mol. Neurodegener. 2016, 11, 34.
[32]	Kozłowska, A.; Kozera, P.; Majewski, M.; Godlewski, J. Co-expression of caspase-3 or caspase-8 with galanin in the human stomach section affected by carcinoma. Apoptosis. 2018, 23, 484–491.
[33]	Kunzmann, A.T.; Murray, L.J.; Cardwell, C.R.; McShane, C.M.; McMenamin, U.C.; Cantwell, M.M. PTGS2 (Cyclooxygenase-2) expression and survival among colorectal cancer patients: a systematic review. Cancer Epidemiol. Biomark. Prev. 2013, 22, 1490–1497.
[34]	Körber, H.; Goericke-Pesch, S. Expression of PTGS2, PGFS and PTGFR during downregulation and restart of spermatogenesis following GnRH agonist treatment in the dog. Cell Tissue Res. 2019, 375, 531–541.
[35]	Chen, X.; Vodanovic-Jankovic, S.; Johnson, B.; Keller, M.; Komorowski, R.; Drobyski, W.R. Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease. Blood. 2007, 110, 3804–3813.
[36]	Yin, X.W.; Liu, B.; Wei, H.X.; Wu, S.S.; Guo, L.J.; Xu, F.R.; Liu, T.T.; Bi, H.S.; Guo, D.D. Activation of the Notch signaling pathway disturbs the CD4⁺/CD8⁺, Th17/Treg balance in rats with experimental autoimmune uveitis. Inflamm. Res. 2019, 68, 761–774.
[37]	Montfort, A.; Colacios, C.; Levade, T.; Andrieu-Abadie, N.; Meyer, N.; Ségui, B. The TNF paradox in cancer progression and immunotherapy. Front. Immunol. 2019, 10, 1818.
[38]	Wu, H.Y.; Wang, W.G.; Jiang, H.Y.; Du, X.; Li, X.N.; Pu, J.X.; Sun, H.D. Cytotoxic and anti-inflammatory ent-kaurane diterpenoids from Isodon wikstroemioides. Fitoterapia. 2014, 98, 192–198.
[39]	Jiang, S.; Du, J.; Kong, Q.; Li, C.; Li, Y.; Sun, H.; Pu, J.; Mao, B. A group of ent-kaurane diterpenoids inhibit hedgehog signaling and induce cilia elongation. PLoS One. 2015, 10, e0139830.
[40]	Sarwar, M.S.; Xia, Y.X.; Liang, Z.M.; Tsang, S.W.; Zhang, H.J. Mechanistic pathways and molecular targets of plant-derived anticancer ent-kaurane diterpenes. Biomolecules. 2020, 10, 144.