Download PDF
Planta Med
DOI: 10.1055/a-2440-5166
Original Papers

Anti-Inflammatory Activity of Labdane and Norlabdane Diterpenoids from Leonurus sibiricus Related to Modulation of MAPKs Signaling Pathway

Nguyen Minh Trang
1   College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea
,
Le Ba Vinh 
2   Institute of Marine Biochemistry (IMBC), Vietnam Academy of Science and Technology, Hanoi, Vietnam
,
Nguyen Viet Phong 
3   Department of Biology Education, Teachers College and Institute for Phylogenomics and Evolution, Kyungpook National University, Daegu, Republic of Korea
,
Seo Young Yang
3   Department of Biology Education, Teachers College and Institute for Phylogenomics and Evolution, Kyungpook National University, Daegu, Republic of Korea
› Author AffiliationsThis research was supported by the National Research Foundation of Korea (NRF) and funded by the Korea government (MSIT) (No. NRF- 2022R1C1 C1004636). The authors would like to thank the Institute of Chemistry, VAST, for NMR measurement services and the Institute of Marine Biochemistry, VAST, for HR-MS and ECD measurement services.
› Further Information
Also available at
    Permissions and Reprints

Abstract

Leonurus sibiricus, a widely cultivated herbaceous plant in Asian countries, exhibits diverse medicinal applications. Recent studies emphasize its pharmacological properties and efficacy in promoting bone health. In addition to the known compounds and their pharmacological activities, in this study, we isolated and elucidated two new labdane-type diterpenoids, (3R,5R,6S,10S)-3,6-dihydroxy-15-ethoxy-7-oxolabden-8(9),13(14)-dien-15,16-olide (1) and (4R,5R,10S)-18-hydroxy-14,15-bisnorlabda-8-en-7,13-dione (2), a new natural phenolic compound, and a known compound from L. sibiricus using advanced spectroscopic techniques, including circular dichroism spectroscopy, high-resolution mass spectrometry, and 1- and 2-dimensional NMR. Among these, compound 1 demonstrated potent inhibition of nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) mRNA expression levels, followed by compound 2. Whereas compounds 3 and 4 did not exhibit effectiveness in RAW264.7 macrophages. Moreover, compound 1 suppressed pro-inflammatory markers induced by lipopolysaccharide (LPS) stimulation. Compound 1 also suppressed iNOS and cyclooxygenase-2 (COX-2) protein levels and downregulated pro-inflammatory cytokines. Additionally, compound 1 showed inhibition of the phosphorylation of p38, JNK, and ERK, key mediators of the MAPK signaling pathway. These findings indicate that a natural-derived product, compound 1, might be a potential candidate as an anti-inflammation mediator.

Keywords

Leonurus sibiricus - labdane diterpenoid - anti-inflammation - MAPKs

Supporting Information

    NMR and HR-MS spectra of compounds 1–3, uncropped full-length image of Western blot membrane, and the details of primer sequences are available as Supporting Information.

  • Supporting Information


Publication History

Received: 16 May 2024

Accepted after revision: 12 October 2024

Accepted Manuscript online:
12 October 2024

Article published online:
04 November 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Megha KB, Joseph X, Akhil V, Mohanan PV. Cascade of immune mechanism and consequences of inflammatory disorders. Phytomedicine 2021; 91: 153712
    CrossrefPubMedGoogle Scholar
  • 2 Viet Phong N, Thi Nguyet Anh D, Yeong Chae H, Young Yang S, Jeong Kwon M, Sun Min B, Ah Kim J. Anti-inflammatory activity and cytotoxicity against ovarian cancer cell lines by amide alkaloids and piperic esters isolated from Piper longum fruits: In vitro assessments and molecular docking simulation. Bioorg Chem 2022; 128: 106072
    CrossrefPubMedGoogle Scholar
  • 3 Ba Vinh L, Jang HJ, Viet Phong N, Dan G, Won Cho K, Ho Kim Y, Young Yang S. Bioactive triterpene glycosides from the fruit of Stauntonia hexaphylla and insights into the molecular mechanism of its inflammatory effects. Bioorg Med Chem Lett 2019; 29: 2085-2089
    CrossrefPubMedGoogle Scholar
  • 4 Wang S, Lei B, Zhang E, Gong P, Gu J, He L, Han L, Yuan Z. Targeted therapy for inflammatory diseases with mesenchymal stem cells and their derived exosomes: From basic to clinics. Int J Nanomedicine 2022; 17: 1757-1781
    CrossrefPubMedGoogle Scholar
  • 5 Zhang Y, Zhao W, Ruan J, Wichai N, Li Z, Han L, Zhang Y, Wang T. Anti-inflammatory canthin-6-one alkaloids from the roots of Thailand Eurycoma longifolia Jack. J Nat Med 2020; 74: 804-810
    CrossrefPubMedGoogle Scholar
  • 6 Zhang H, Wang M, Xu Y. Understanding the mechanisms underlying obesity in remodeling the breast tumor immune microenvironment: from the perspective of inflammation. Cancer Biol Med 2023; 20: 268-286
    CrossrefPubMedGoogle Scholar
  • 7 Seo S, Lee KG, Shin JS, Chung EK, Lee JY, Kim HJ, Lee KT. 6′-O-Caffeoyldihydrosyringin isolated from Aster glehni suppresses lipopolysaccharide-induced iNOS, COX-2, TNF-α, IL-1β and IL-6 expression via NF-κB and AP-1 inactivation in RAW 264.7 macrophages. Bioorg Med Chem Lett 2016; 26: 4592-4598
    CrossrefPubMedGoogle Scholar
  • 8 Serhan CN. Treating inflammation and infection in the 21st century: New hints from decoding resolution mediators and mechanisms. FASEB J 2017; 31: 1273-1288
    CrossrefPubMedGoogle Scholar
  • 9 Vendrame S, Klimis-Zacas D. Anti-inflammatory effect of anthocyanins via modulation of nuclear factor-κB and mitogen-activated protein kinase signaling cascades. Nutr Rev 2015; 73: 348-358
    CrossrefPubMedGoogle Scholar
  • 10 Park J, Min JS, Kim B, Chae UB, Yun JW, Choi MS, Kong IK, Chang KT, Lee DS. Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways. Neurosci Lett 2015; 584: 191-196
    CrossrefPubMedGoogle Scholar
  • 11 Qiao Y, Yan W, He J, Liu X, Zhang Q, Wang X. Identification, evolution and expression analyses of mapk gene family in Japanese flounder (Paralichthys olivaceus) provide insight into its divergent functions on biotic and abiotic stresses response. Aquat Toxicol 2021; 241: 106005
    CrossrefPubMedGoogle Scholar
  • 12 Bahar ME, Kim HJ, Kim DR. Targeting the RAS/RAF/MAPK pathway for cancer therapy: From mechanism to clinical studies. Signal Transduct Target Ther 2023; 8: 455
    CrossrefPubMedGoogle Scholar
  • 13 Kim HK. Role of ERK/MAPK signalling pathway in anti-inflammatory effects of Ecklonia cava in activated human mast cell line-1 cells. Asian Pac J Trop Med 2014; 7: 703-708
    CrossrefPubMedGoogle Scholar
  • 14 Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, Li Y. Inflammation and tumor progression: Signaling pathways and targeted intervention. Signal Transduct Target Ther 2021; 6: 263
    CrossrefPubMedGoogle Scholar
  • 15 Behl T, Upadhyay T, Singh S, Chigurupati S, Alsubayiel AM, Mani V, Vargas-De-La-Cruz C, Uivarosan D, Bustea C, Sava C, Stoicescu M, Radu AF, Bungau SG. Polyphenols targeting MAPK mediated oxidative stress and inflammation in rheumatoid arthritis. Molecules 2021; 26: 6570
    CrossrefPubMedGoogle Scholar
  • 16 Sitarek P, Skała E, Toma M, Wielanek M, Szemraj J, Nieborowska-Skorska M, Kolasa M, Skorski T, Wysokińska H, Śliwiński T. A preliminary study of apoptosis induction in glioma cells via alteration of the Bax/Bcl-2-p 53 axis by transformed and non-transformed root extracts of Leonurus sibiricus L. Tumor Biol 2016; 37: 8753-8764
    CrossrefPubMedGoogle Scholar
  • 17 Narukawa Y, Niimura A, Noguchi H, Tamura H, Kiuchi F. New diterpenoids with estrogen sulfotransferase inhibitory activity from Leonurus sibiricus L. J Nat Med 2014; 68: 125-131
    CrossrefPubMedGoogle Scholar
  • 18 Pitschmann A, Waschulin C, Sykora C, Purevsuren S, Glasl S. Microscopic and phytochemical comparison of the three Leonurus species L. cardiaca, L. japonicus, and L. sibiricus . Planta Med 2017; 83: 1233-1241
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Sayed MA, Alam MA, Islam MS, Ali MT, Ullah ME, Shibly AZ, Ali MA, Hasan-Olive MM. Leonurus sibiricus L. (honeyweed): A review of its phytochemistry and pharmacology. Asian Pac J Trop Biomed 2016; 6: 1076-1080
    CrossrefPubMedGoogle Scholar
  • 20 Krishnan V, Subramaniam S, Chia-Chuan C, Venkatachalam B, Thomas Cheeran A, Chi-Ying FH. Anticancer activity of Leonurus sibiricus L.: Possible involvement of intrinsic apoptotic pathway. Nutr Cancer 2022; 74: 225-236
    CrossrefPubMedGoogle Scholar
  • 21 Kim JH, Kim M, Jung HS, Sohn Y. Leonurus sibiricus L. ethanol extract promotes osteoblast differentiation and inhibits osteoclast formation. Int J Mol Med 2019; 44: 913-926
    PubMedGoogle Scholar
  • 22 Li J, Niu L, Huang H, Li Q, Xie C, Yang C. Anti-inflammatory labdane diterpenoids from the aerial parts of Leonurus sibiricus. Phytochemistry 2024; 217: 113927
    CrossrefPubMedGoogle Scholar
  • 23 Pitschmann A, Zehl M, Heiss E, Purevsuren S, Urban E, Dirsch VM, Glasl S. Quantitation of phenylpropanoids and iridoids in insulin-sensitising extracts of Leonurus sibiricus L. (Lamiaceae). Phytochem Anal 2016; 27: 23-31
    CrossrefPubMedGoogle Scholar
  • 24 Merecz-Sadowska A, Sitarek P, Kowalczyk T, Palusiak M, Hoelm M, Zajdel K, Zajdel R. In vitro evaluation and in silico calculations of the antioxidant and anti-inflammatory properties of secondary metabolites from Leonurus sibiricus L. root extracts. Molecules 2023; 28: 6550
    CrossrefPubMedGoogle Scholar
  • 25 Yang L, Liu G, Zhu X, Luo Y, Shang Y, Gu XL. The anti-inflammatory and antioxidant effects of leonurine hydrochloride after lipopolysaccharide challenge in broiler chicks. Poult Sci 2019; 98: 1648-1657
    CrossrefPubMedGoogle Scholar
  • 26 Kuo HT, Peng CF, Huang HY, Lin CH, Chen IS, Tsai IL. Chemical constituents and antitubercular activity of Formosan Pisonia umbellifera . Planta Med 2011; 77: 736-741
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Zhang RH, Liu ZK, Yang DS, Zhang XJ, Sun HD, Xiao WL. Phytochemistry and pharmacology of the genus Leonurus: The herb to benefit the mothers and more. Phytochemistry 2018; 147: 167-183
    CrossrefPubMedGoogle Scholar
  • 28 Wang C, Tian J, Liu C, He Y, Li J, Zhang Q, Xiao T, Xie C, Yang C. Labdane and ent-halimane diterpenoids with STAT3-inhibitory activity from Leonurus sibiricus . Phytochemistry 2023; 214: 113802
    CrossrefPubMedGoogle Scholar
  • 29 Zhang XJ, Zhong WM, Liu RX, Wang YM, Luo T, Zou Y, Qin HY, Li XL, Zhang R, Xiao WL. Structurally diverse labdane diterpenoids from Leonurus japonicus and their anti-inflammatory properties in LPS-induced RAW264.7 cells. J Nat Prod 2020; 83: 2545-2558
    CrossrefPubMedGoogle Scholar
  • 30 Huong PTM, Phong NV, Huong NT, Trang DT, Thao DT, Cuong NX, Nam NH, Van Thanh N. Aplydactylonins A–C, three new sesquiterpenes from the Vietnamese sea hare Aplysia dactylomela and their cytotoxicity. J Nat Med 2022; 76: 210-219
    CrossrefPubMedGoogle Scholar
  • 31 Wahlberg I, Eklund AM, Nordfors K, Vogt C, Enzell CR, Berg JE. Tobacco Chemistry. 69. Five new labdanic compounds. Acta Chem Scand 1988; 42: 708-716
    CrossrefPubMedGoogle Scholar
  • 32 Nguyen LTT, Vo HKT, Dang SV, Le TH, Ha LD, Nguyen LTT, Nguyen LHD. Labdane and norlabdane diterpenoids from the aerial parts of Leonurus japonicus . Phytochem Lett 2017; 22: 174-178
    CrossrefPubMedGoogle Scholar
  • 33 Hwu JR, Varadaraju TG, Abd-Elazem IS, Huang RCC. First total syntheses of oresbiusins A and B, their antipodes, and racemates: Configuration revision and anti-HIV activity. Eur J Org Chem 2012; 2012: 4684-4688
    CrossrefPubMedGoogle Scholar
  • 34 Wang HMD, Fu L, Cheng CC, Gao R, Lin MY, Su HL, Belinda NE, Nguyen TH, Lin WH, Lee PC, Hsieh LP. Inhibition of LPS-induced oxidative damages and potential anti-inflammatory effects of Phyllanthus emblica extract via down-regulating NF-κB, COX-2, and iNOS in RAW 264.7 cells. Antioxidants 2019; 8: 270
    CrossrefPubMedGoogle Scholar
  • 35 Trang NM, Kim EN, Pham TH, Jeong GS. Citropten ameliorates osteoclastogenesis related to MAPK and PLCγ/Ca2+ signaling pathways through the regulation of amyloid beta. J Agric Food Chem 2023; 71: 10037-10049
    CrossrefPubMedGoogle Scholar
  • 36 Trang NM, Kim EN, Lee HS, Jeong GS. Effect on osteoclast differentiation and ER stress downregulation by amygdalin and RANKL binding interaction. Biomolecules 2022; 12: 256
    CrossrefPubMedGoogle Scholar
  • 37 Bruggisser R, von Daeniken K, Jundt G, Schaffner W, Tullberg-Reinert H. Interference of plant extracts, phytoestrogens and antioxidants with the MTT tetrazolium assay. Planta Med 2002; 68: 445-448
    Article in Thieme ConnectPubMedGoogle Scholar