Skip to main content

Advertisement

SpringerLink
Log in

A new prenylated benzoquinone from Cyathocalyx pruniferus abrogates LPS-induced inflammatory responses associated with PGE2, COX-2 and cytokines biosynthesis in human plasma

  • Original Article
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

In our previous laboratory findings, Cyathocalyx pruniferus extracts exhibited platelet-activating factor inhibition, suggesting their anti-inflammatory potential. Hence, this study was designed with the aim to isolate phyto-constituents from C. pruniferus with potent anti-inflammatory activities. Column and volume liquid chromatography were used for isolation of phyto-constituents. The structure elucidation was carried out using spectroscopic analysis (HRESI-MS, 1H and 13C-NMR) and compared with published literature. For cytotoxicity analysis, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide assay was performed on peripheral blood mononuclear cells. Anti-inflammatory activities were evaluated against the levels of inflammatory cytokines (IL-1β and IL-6), prostaglandin-E2 (PGE2) and cyclooxegenase-2 (COX-2), in lipopolysaccharide (LPS)-induced human plasma using ELISA and radioimmunoassay (RIA). The chromatographic purification of methanol leaves extract afforded 13 (1–13) secondary metabolites. Additionally, cytotoxicity analysis suggested that isolates were non-cytotoxic at 100 μM. In anti-inflammatory evaluation, 2-octaprenyl-1, 4-benzoquinone (5) produced strong (≥ 70%) inhibition of PGE2, COX-2, IL-1β and IL-6 at 50 µM. Moreover, 2-octaprenyl-1,4-benzoquinone (5) exhibited concentration-dependent inhibition with IC50 values (µM) of 11.21, 6.61, 2.20 and 3.56 as compared to controls; indomethacin for PGE2 (11.84) and dexamethasone in COX-2 (5.19), IL-1β (1.83) and IL-6 (3.76) analysis, respectively. In conclusion, two new compounds including 2-octaprenyl-1, 4-benzoquinone (5) and 14-methyloctadec-1-ene (6) are reported for the first time from plant species. Additionally, 2-octaprenyl-1, 4-benzoquinone (5) dose-dependently suppressed the production of pro-inflammatory mediators involved in acute and chronic inflammation at non-cytotoxic concentrations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

COX-2:

Cyclooxygenase- 2

PGE2 :

Prostaglandin E2

IL:

Interleukins

FBS:

Foetal bovine serum

RPMI medium:

Roswell park memorial institute medium

eNOS:

Endothelial nitric oxide synthase

IκB:

Inhibitor of NF-κB

iNOS:

Inducible nitric oxide synthetase

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-phenyltetrazolium bromide

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

PBMC:

Peripheral blood mononuclear cells

NO:

Nitric oxide

NOS:

Nitric oxide synthase

ROS:

Reactive oxygen species

ELISA:

Enzyme-linked immunosorbent assay

LPS:

Lipopolysaccharides

TN F-α:

Tumour necrosis factor-alpha

JNK:

Jun-N-terminal kinase

MAPKs:

Mitogen-activated protein kinase

References

  • Adachi Y, Do ND, Kinjo M, Makisako S, Yamakawa R, Mori K, Ando T (2010) Positions and stereochemistry of methyl branches in the novel sex pheromone components produced by a lichen moth, Lyclene dharma dharma. J Chem Ecol 36:814–823

    CAS  PubMed  Google Scholar 

  • Attiq A, Jalil J, Husain K (2017) Annonaceae: breaking the wall of inflammation. Front Pharmacol 8:752

    PubMed  PubMed Central  Google Scholar 

  • Attiq A, Jalil J, Husain K, Ahmad W (2018) Raging the war against inflammation with natural products. Front Pharmacol 9:976. https://doi.org/10.3389/fphar.2018.00976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baker JK, Myers CW (1991) One-dimensional and two-dimensional 1H-and 13C-nuclear magnetic resonance (NMR) analysis of vitamin E raw materials or analytical reference standards. Pharm Res 8:763–770

    CAS  PubMed  Google Scholar 

  • Bettaieb A, Cremonini E, Kang H, Kang J, Haj FG, Oteiza PI (2016) Anti-inflammatory actions of (−)-epicatechin in the adipose tissue of obese mice. Int J Biochem Cell Biol 81:383–392

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bian L, Cao S, Cheng L, Nakazaki A, Nishikawa T, Qi J (2018) Semi-synthesis and structure-activity relationship of neuritogenic oleanene derivatives. ChemMedChem 13:1972–1977

    CAS  PubMed  Google Scholar 

  • Bremner P et al (2009) Assessing medicinal plants from South-Eastern Spain for potential anti-inflammatory effects targeting nuclear factor-Kappa B and other pro-inflammatory mediators. J Ethnopharmacol 124:295–305

    CAS  PubMed  Google Scholar 

  • Bruce TJ et al (2005) Response of economically important aphids to components of Hemizygia petiolata essential oil. Pest Manag Sci 61:1115–1121

    CAS  PubMed  Google Scholar 

  • Chan EWC, Lim YY, Omar M (2007) Antioxidant and antibacterial activity of leaves of Etlingera species (Zingiberaceae) in Peninsular Malaysia. Food Chem 104:1586–1593

    CAS  Google Scholar 

  • Chaturvedula VSP, Prakash I (2012) Isolation of stigmasterol and β-sitosterol from the dichloromethane extract of Rubus suavissimus. Int Curr Pharm J 1:239–242

    CAS  Google Scholar 

  • Cho H, Walker A, Williams J, Hasty KA (2015) Study of osteoarthritis treatment with anti-inflammatory drugs: cyclooxygenase-2 inhibitor and steroids. BioMed Res Int 2015

  • Comalada M et al (2006) Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: analysis of the structure–activity relationship. Biochem Pharmacol 72:1010–1021

    CAS  PubMed  Google Scholar 

  • Cronstein BN, Terkeltaub R (2006) The inflammatory process of gout and its treatment. Arthritis Res Ther 8:1–7

  • de Santana Souza MT et al (2014) Structure-activity relationship of terpenes with anti-inflammatory profile–a systematic review. Basic Clin Pharmacol Toxicol 115:244–256

    Google Scholar 

  • Dmitrieva OS, Shilovskiy IP, Khaitov MR, Grivennikov SI (2016) Interleukins 1 and 6 as main mediators of inflammation and cancer. Biochemistry 81:80–90

    CAS  PubMed  Google Scholar 

  • Faure R, Ramanoelina AR, Rakotonirainy O, Bianchini JP, Gaydou EM (1991) Two-dimensional nuclear magnetic resonance of sesquiterpenes. 4—Application to complete assignment of 1H and 13C NMR spectra of some aromadendrane derivatives. Magn Reson Chem 29:969–971

    CAS  Google Scholar 

  • Gil B, Jesús M, Terencio MC, De Giulio A, De Rosa S, Alcaraz MJ, Paya M (1995) Effects of marine 2-polyprenyl-1, 4-hydroquinones on phospholipase A2 activity and some inflammatory responses. Eur J Pharmacol 285:281–288

    CAS  PubMed  Google Scholar 

  • Gomes A, Fernandes E, Lima JL, Mira L, Corvo ML (2008) Molecular mechanisms of anti-inflammatory activity mediated by flavonoids. Curr Med Chem 15:1586–1605

    CAS  PubMed  Google Scholar 

  • Han MH et al (2016) Flavonoids Isolated from Flowers of Lonicera japonica Thunb. Inhibit Inflammatory Responses in BV2 Microglial Cells by Suppressing TNF-α and IL-β Through PI3K/Akt/NF-kb. Signalling pathways. Phytother Res 30:1824–1832

    CAS  PubMed  Google Scholar 

  • Hirao K, Yumoto H, Nakanishi T, Mukai K, Takahashi K, Takegawa D, Matsuo T (2010) Tea catechins reduce inflammatory reactions via mitogen-activated protein kinase pathways in toll-like receptor 2 ligand-stimulated dental pulp cells. Life Sci 86:654–660. https://doi.org/10.1016/j.lfs.2010.02.017

    Article  CAS  PubMed  Google Scholar 

  • Hosseinzadeh H, Zarei H, Taghiabadi E (2011) Antinociceptive, anti-inflammatory and acute toxicity effects of Juglans regia L. leaves in mice. Iran Red Crescent Med J 13:27

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hsieh IN, Chang AS-Y, Teng C-M, Chen C-C, Yang C-R (2011) Aciculatin inhibits lipopolysaccharide-mediated inducible nitric oxide synthase and cyclooxygenase-2 expression via suppressing NF-κB and JNK/p38 MAPK activation pathways. J Biomed Sci 18:28. https://doi.org/10.1186/1423-0127-18-28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang X et al (2013) Identification and characterization of (E)-β-caryophyllene synthase and α/β-pinene synthase potentially involved in constitutive and herbivore-induced terpene formation in cotton. Plant Physiol Biochem 73:302–308

    CAS  PubMed  Google Scholar 

  • IPNI (2020) International Plant Names Index. Published on the Internet http://www.ipni.org, The Royal Botanic Gardens, Kew, Harvard University Herbaria & Libraries and Australian National Botanic Gardens

  • Isman MB, Seffrin R (2014) Natural insecticides from the Annonaceae: a unique example for developing biopesticides. In: Advan Plant Biopesti Springer, pp 21–33

  • Izzi V, Masuelli L, Tresoldi I, Sacchetti P, Modesti A, Galvano F, Bei R (2012) The effects of dietary flavonoids on the regulation of redox inflammatory networks. Front Biosci (Landmark Ed) 17:2396–2418

    Google Scholar 

  • Jalil J et al (2015) Inhibitory effect of triterpenoids from Dillenia serrata (Dilleniaceae) on prostaglandin E2 production and quantitative HPLC analysis of its koetjapic acid and betulinic acid. Molecules 20:3206–3220

    PubMed  PubMed Central  Google Scholar 

  • Jalil J, Attiq A, Hui CC, Yao LJ, Zakaria NA (2020) Modulation of inflammatory pathways, medicinal uses and toxicities of Uvaria species: potential role in the prevention and treatment of inflammation. Inflammopharmacology 28:1195–1218. https://doi.org/10.1007/s10787-020-00734-2

    Article  CAS  PubMed  Google Scholar 

  • Jantan I, Rafi I, Jalil J (2005) Platelet-activating factor (PAF) receptor-binding antagonist activity of Malaysian medicinal plants. Phytomedicine 12:88–92

    CAS  PubMed  Google Scholar 

  • Kasperska-Zajac A, Brzoza Z, Rogala B (2008) Platelet activating factor as a mediator and therapeutic approach in bronchial asthma. Inflammation 31:112–120

    CAS  PubMed  Google Scholar 

  • Kato M, Mori K (1985) Synthesis of the enantiomers of 14-methyl-1-octadecene, the sex pheromone of the peach leafminer moth. Agri Bio Chem 49:2479–2480

    CAS  Google Scholar 

  • Kim EY, Moudgil KD (2017) Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines. Cytokine 98:87–96

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim HP, Park H, Son KH, Chang HW, Kang SS (2008) Biochemical pharmacology of biflavonoids: implications for anti-inflammatory action. Arch Pharm Res 31:265

    CAS  PubMed  Google Scholar 

  • Lingappan K (2018) NF-κB in oxidative stress. Curr Opin Toxicol 7:81–86

    PubMed  Google Scholar 

  • Liu M, Lu S (2016) Plastoquinone and ubiquinone in plants: biosynthesis, physiological function and metabolic engineering. Front Plant Sci 7:1898

    PubMed  PubMed Central  Google Scholar 

  • Liu H et al (2010) Flavonoids from Halostachys caspica and their antimicrobial and antioxidant activities. Molecules 15:7933–7945

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu X, Lin R, Zhao B, Guan R, Li T, Jin R (2016) Correlation between oxidative stress and the NF-κB signaling pathway in the pulmonary tissues of obese asthmatic mice. Mol Med Rep 13:1127–1134. https://doi.org/10.3892/mmr.2015.4663

    Article  CAS  PubMed  Google Scholar 

  • Mihopoulos N, Vagias C, Chinou I, Roussakis C, Scoullos M, Harvala C, Roussis V (1999) Antibacterial and cytotoxic natural and synthesized hydroquinones from sponge Ircinia spinosula. Z Naturforsch C 54:417–423

    CAS  PubMed  Google Scholar 

  • Moharam BA, Jantan I, Jalil J, Shaari K (2010) Inhibitory effects of phylligenin and quebrachitol isolated from Mitrephora vulpina on platelet activating factor receptor binding and platelet aggregation. Molecules 15:7840–7848

    CAS  PubMed  PubMed Central  Google Scholar 

  • Moharam BA, Jantan I, Jalil J, Ahmad F (2012) Inhibitory effect of compounds from Goniothalamus tapis Miq. and Goniothalamus uvaroides king on platelet-activating factor receptor binding. Phytother Res 26:687–691

    CAS  PubMed  Google Scholar 

  • Molaae N, Mosayebi G, Pishdadian A, Ejtehadifar M, Ganji A (2017) Evaluating the proliferation of human peripheral blood mononuclear cells using MTT assay. IJBSM 2:25–28

    Google Scholar 

  • Nordin N, Jalil J, Jantan I, Murad S (2012) Platelet-activating factor (PAF) receptor binding activity of the roots of Enicosanthellum pulchrum. Pharm Biol 50:284–290

    CAS  PubMed  Google Scholar 

  • Nowicka B, Kruk J (2010) Occurrence, biosynthesis and function of isoprenoid quinones. Biochim Biophys Acta 1797:1587–1605. https://doi.org/10.1016/j.bbabio.2010.06.007

    Article  CAS  PubMed  Google Scholar 

  • Pałgan K, Bartuzi Z (2015) Platelet activating factor in allergies. Int J Immunopathol Pharmacol 28:584–589

    PubMed  Google Scholar 

  • Rahmi EP, Kumolosasi E, Jalil J, Husain K, Buang F, Jamal JA (2020) Anti-hyperuricemic and anti-inflammatory effects of Marantodes pumilum as potential treatment for gout. Front Pharmacol 11:289

  • Rios MY, Delgado G (1992) Polyprenols and acylphloroglucinols from Esenbeckia nesiotica. Phytochemistry 31:3491–3494

    CAS  Google Scholar 

  • Saadawi S, Jalil J, Jasamai M, Jantan I (2012) Inhibitory effects of acetylmelodorinol, chrysin and polycarpol from mitrella kentii on prostaglandin E2 and thromboxane B2 production and platelet activating factor receptor binding. Molecules 17:4824–4835

    CAS  PubMed  PubMed Central  Google Scholar 

  • Saidana D et al (2008) Chemical composition and antimicrobial activity of volatile compounds of Tamarix boveana (Tamaricaceae). Microbiol Res 163:445–455

    CAS  PubMed  Google Scholar 

  • Salleh WMNHW, Khamis S, Nadri MH, Kassim H, Tawang A (2020) Chemical composition and acetylcholinesterase inhibition of the essential oil of Cyathocalyx pruniferus (Maingay ex Hook. f. & Thomson). J Sinclair Nat Volat Essent Oils 7:8–13

    CAS  Google Scholar 

  • Sazali SNM, Jalil J, Arriffin NM, Abdullah SA, Jamil S (2017) In vitro inhibitory effects of flavonoids from the extracts of Artocarpus species on prostaglandin E2 (PGE2) production in human plasma. J Innov Pharma Biol Sci 11:181–190

    Google Scholar 

  • Silva F, Koolen H, Barisson A, Souza A, Pinheiro M (2012) Steroids and triterpene from the bark of Unonopsis guatterioids RE FR. (Annonaceae). Int J Pharm Pharm Sci 4:522–523

    Google Scholar 

  • Smith WL, Murphy RC (2016) The eicosanoids: cyclooxygenase, lipoxygenase and epoxygenase pathways. In: Biochemistry of lipids, lipoproteins and membranes. Elsevier, pp 259–296

  • Stranden M, Borg-Karlson A-K, Mustaparta H (2002) Receptor neuron discrimination of the germacrene D enantiomers in the moth Helicoverpa armigera. Chem Senses 27:143–152

    CAS  PubMed  Google Scholar 

  • Sunassee SN, Davies-Coleman MT (2012) Cytotoxic and antioxidant marine prenylated quinones and hydroquinones. Nat Prod Rep 29:513–535

    CAS  PubMed  Google Scholar 

  • Taguri T, Yamakawa R, Adachi Y, Mori K, Ando T (2010) Improved synthesis of three methyl-branched pheromone components produced by the female lichen moth. Biosci Biotech Biochem 74:119–124

    CAS  Google Scholar 

  • Terencio MC et al (1998) Suppression of leukotriene B4 and tumour necrosis factor α release in acute inflammatory responses by novel prenylated hydroquinone derivatives. Naunyn Schmiedebergs Arch Pharmacol 357:565–572

    CAS  PubMed  Google Scholar 

  • Tillman JA, Seybold SJ, Jurenka RA, Blomquist GJ (1999) Insect pheromones—an overview of biosynthesis and endocrine regulation. Insect Biochem Mol Biol 29:481–514

    CAS  PubMed  Google Scholar 

  • Tunon M, Garcia-Mediavilla M, Sanchez-Campos S, Gonzalez-Gallego J (2009) Potential of flavonoids as anti-inflammatory agents: modulation of pro-inflammatory gene expression and signal transduction pathways. Curr Drug Metab 10:256–271

    CAS  PubMed  Google Scholar 

  • Usman A, Thoss V, Nur-e-Alam M (2016) Isolation of (-)-Epicatechin from Trichilia emetica Whole Seeds. Am J Org Chem 6:81–85

    CAS  Google Scholar 

  • Vieira IJC, de Aquino AO, de Souza JJ, Braz-Filho R, dos Santos GM, de Araújo MF (2013) Hirtinone, a novel cycloartane-type triterpene and other compounds from Trichilia hirta L. (Meliaceae). Molecules 18:2589–2597

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang H, Cao Z (2014) Anti-inflammatory effects of (-)-epicatechin in lipopolysaccharide-stimulated raw 264.7 macrophages. Trop J Pharm Res 13:1415–1419

    CAS  Google Scholar 

  • Wang RJ, Saunders RM (2006) The genus Cyathocalyx (Annonaceae) in the Philippines. Syst Bot 31:285–297

    Google Scholar 

  • Wijeratne EMK, De Silva LB, Kikuchi T, Tezuka Y, Gunatilaka AAL, Kingston DGI (1995) Cyathocaline, an Azafluorenone Alkaloid from Cyathocalyx zeylanica. J Nat Prod 58:459–462. https://doi.org/10.1021/np50117a020

    Article  CAS  Google Scholar 

  • Xiao C, Zhou J, He Y, Jia H, Zhao L, Zhao N, Lu A (2009) Effects of triptolide from Radix Tripterygium wilfordii (Leigongteng) on cartilage cytokines and transcription factor NF-kappaB: a study on induced arthritis in rats. Chin Med 4:13–13. https://doi.org/10.1186/1749-8546-4-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ying X, Chen X, Cheng S, Shen Y, Peng L, zi Xu H (2013) Piperine inhibits IL-β induced expression of inflammatory mediators in human osteoarthritis chondrocyte Int Immunopharmacol 17:293–299

  • Yu T, Lao X, Zheng H (2016) Influencing COX-2 activity by COX related pathways in inflammation and cancer. Mini Rev Med Chem 16:1230–1243

    CAS  PubMed  Google Scholar 

  • Zhang W-y, Liu H-q, Xie K-q, Yin L-l, Li Y, Kwik-Uribe CL (2006) Procyanidin dimer B2 [epicatechin-(4β-8)-epicatechin] suppresses the expression of cyclooxygenase-2 in endotoxin-treated monocytic cells. Biochem Biophysical Res Comm 345:508–515

    CAS  Google Scholar 

  • Zhang T, Ma W-L, Li T-R, Wu J, Wang J-R, Du Z-T (2013) A Facile Asymmetric Synthesis of (S)-14-Methyl-1-Octadecene, the Sex Pheromone of the Peach Leafminer Moth. Molecules 18:5201–5208

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhong Y, Chiou Y-S, Pan M-H, Shahidi F (2012) Anti-inflammatory activity of lipophilic epigallocatechin gallate (EGCG) derivatives in LPS-stimulated murine macrophages. Food Chem 134:742–748

    CAS  PubMed  Google Scholar 

  • Ziebell JM, Morganti-Kossmann MC (2010) Involvement of pro-and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics 7:22–30

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The authors would like to thank the Universiti Kebangsaan Malaysia (UKM) for the financial support under grant number GGP-2017–005 and the Ministry of Agriculture and Agro-based Industry (MOA) Malaysia, under grant number NH1014D028.

Author information

Authors and Affiliations

  1. Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300, Kuala Lumpur, Malaysia

    Ali Attiq, Juriyati Jalil, Khairana Husain, Jamia Azdina Jamal & Elysha Nur Ismail

  2. Faculty of Pharmacy, MAHSA University, Bandar Saujana Putra, 42610, Jenjarom, Selangor, Malaysia

    Ali Attiq

  3. Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Sardang, Selangor, Malaysia

    Elysha Nur Ismail

Authors
  1. Ali Attiq
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juriyati Jalil
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Khairana Husain
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jamia Azdina Jamal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elysha Nur Ismail
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AA and ENI carried out the experiments and data interpretation. AA wrote the manuscript, performed statistical analysis. JJ as the principal investigator and study supervisor was responsible for the design of the study, editing and proof reading of the manuscript. JJ and JAJ obtained funding for the research project. KH participated in the study design and spectroscopic analysis. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Juriyati Jalil.

Ethics declarations

Conflict of interest

Authors report no conflict of interest for the present paper.

Ethics approval

Human blood use for bioassays was permitted by the Human Ethics Committee, Universiti Kebangsaan Malaysia, under approval number NF-052–15.

Consent for publication

All authors have approved the present study for publication purpose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 102 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Attiq, A., Jalil, J., Husain, K. et al. A new prenylated benzoquinone from Cyathocalyx pruniferus abrogates LPS-induced inflammatory responses associated with PGE2, COX-2 and cytokines biosynthesis in human plasma. Inflammopharmacol 29, 841–854 (2021). https://doi.org/10.1007/s10787-021-00807-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-021-00807-w

Keywords

Search

Navigation