Planta Med 2024; 90(13): 976-991
DOI: 10.1055/a-2401-6049
Biological and Pharmacological Activity
Reviews

Cnicus benedictus: Folk Medicinal Uses, Biological Activities, and In Silico Screening of Main Phytochemical Constituents

Katarzyna Ziętal
1   Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, Warszawa, Poland
,
Dagmara Mirowska-Guzel
1   Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, Warszawa, Poland
,
Alicja Nowaczyk
2   Department of Organic Chemistry, Faculty of Pharmacy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
,
Kamilla Blecharz-Klin
1   Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, Warszawa, Poland
› Author Affiliations
The authors declare no competing interests. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The project was implemented with CePT infrastructure financed by the EU: the European Regional Development Fund within the Operational Programme “Innovative economy” for 2007 – 2013.

Abstract

Traditional medicine has long recognized the therapeutic potential of Cnicus benedictus, and recent scientific research has shed light on the pharmacological properties of this plant. The bioactive compounds that can be extracted from it, such as the sesquiterpene lactones arctigenin, arctiin, and cnicin, are very interesting to researchers.

In this article, based on available data from pre-clinical in vitro and in vivo studies, we delve into the pharmacology of the active constituents of this plant to explore its potential therapeutic applications and underlying mechanisms of action. In addition, we present a computer analysis designed to reveal the pharmacokinetic and toxicological properties of the main phytochemicals that are active in C. benedictus through new in silico techniques and predictive tools such as SwissADME and PubChem.

The data from the in silico study presented here support the traditional use of C. benedictus, as well as its promise as a source of new therapeutic chemical compounds.



Publication History

Received: 09 April 2024

Accepted after revision: 21 August 2024

Article published online:
12 September 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Tiwana G, Fua J, Lu L, Cheesman MJ, Cock IE. A review of the traditional uses, medicinal properties and phytochemistry of Centaurea benedicta L. Pharmacogn J 2021; 13: 798-812
  • 2 Ulbricht C, Basch E, Dacey C, Dith S, Hammerness P, Hashmi S, Seamon E, Vora M, Weissner W. An evidence-based systematic review of blessed thistle (Cnicus benedictus) by the natural standard research collaboration. J Diet Suppl 2008; 5: 422
  • 3 Al-Snafi E. The constituents and pharmacology of Cnicus Benedictus–A review. Pharm Chem J 2016; 3: 129-135
  • 4 Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001; 46(1 – 3): 3-26
  • 5 Ertl P, Rohde B, Selzer P. Fast calculation of molecular polar surface area as a sum of fragment based contributions and its application to the prediction of drug transport properties. J Med Chem 2000; 43: 3714-3717
  • 6 Rai M, Singh AV, Paudel N, Kanase A, Falletta E, Kerkar P, Heyda J, Barghash RF, Pratap Singh S, Soos M. Herbal concoction unveiled: A computational analysis of phytochemicalsʼ pharmacokinetic and toxicological profiles using novel approach methodologies (NAMs). Curr Res Toxicol 2023; 5: 100118
  • 7 Bero S, Muda A, Choo Y, Muda N, Pratama S. Similarity measure for molecular structure: A brief review. J Phys Conf Ser 2017; 892 (01) 012015
  • 8 Yu R, Liu Z, Yu R, Zhang H, Shao Y, Mei L, Tao Y. A simple method for isolation and structural identification of arctigenin from Saussurea medusa Maxim. by preparation chromatography and single crystal X-ray diffraction. J Med Plant Res 2021; 5: 979-983
  • 9 Cho MK, Jang YP, Kim YC, Kim SG. Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan, inhibits MAP kinases and AP-1 activation via potent MKK inhibition: the role in TNF-alpha inhibition. Int Immunopharmacol 2004; 4: 1419-1429
  • 10 Koech PK, Jócsák G, Boldizsár I, Moldován K, Borbély S, Világi I, Dobolyi A, Varró P. Anti-glutamatergic effects of three lignan compounds: Arctigenin, matairesinol and trachelogenin – An ex vivo study on rat brain slices. Planta Med 2023; 89: 879-889
  • 11 Xiao Y, Shao K, Zhou J, Wang L, Ma X, Wu D, Yang Y, Chen J, Feng J, Qiu S, Lv Z, Zhang L, Zhang P, Chen W. Structure-based engineering of substrate specificity for pinoresinol-lariciresinol reductases. Nat Commun 2021; 12: 2828
  • 12 TargetMol, a drug screening expert. Accessed on March 10, 2024 at: https://www.targetmol.com/compound/trachelogenin?utm_source=Bing&utm_medium+=CPC&utm_term=Trachelogenin&msclkid=5292e987eb6b1afceac88c3c9dcb28c6
  • 13 Moujir L, Callies O, Sousa PMC, Sharopov F, Seca AML. Applications of sesquiterpene lactones: A review of some potential success cases. Applied Sciences 2020; 10: 3001
  • 14 Bosco A, Golsteyn RM. Emerging anti-mitotic activities and other bioactivities of sesquiterpene compounds upon human cells. Molecules 2017; 22: 459
  • 15 Ulubelen A, Berkan T. Triterpenic and steroidal compounds of Cnicus benedictus . Planta Med 1977; 31: 375-377
  • 16 Rezig K, Benkaci-Ali F, Foucaunier ML, Laurent S, Umar HI, Alex OD, Tata S. HPLC/ESI-MS characterization of phenolic compounds from Cnicus benedictus L. roots: A study of antioxidant, antibacterial, anti-inflammatory, and anti-alzheimerʼs activity. Chem Biodivers 2024; 21: e202300724
  • 17 Avula B, Katragunta K, Wang YH, Ali Z, Khan IA. Simultaneous determination and characterization of flavonoids, sesquiterpene lactone, and other phenolics from Centaurea benedicta and dietary supplements using UHPLC-PDA-MS and LC-DAD-QToF. J Pharm Biomed Anal 2022; 216: 114806
  • 18 Bradley PR. (editor) British Herbal Compendium. Vol 1. Bournemouth: British Herbal Medicine Association; 1992: 126-127
  • 19 Schneider G, Lachner I. Beitrag zur Analytik und Wirkung von Cnicin [Analysis and action of cnicin]. Planta Med 1987; 53: 247-251
  • 20 Vanhaelen-Fastre R. Présence du Saloniténolide dans Cnicus benedictus . Planta Med 1974; 26: 375-379
  • 21 Rosselli S, Maggio A, Raccuglia RA, Bruno M. Rearrangement of germacranolides. Synthesis and absolute configuration of elemane and heliangolane derivatives from cnicin. European J Org Chem 2003; 14: 2690-2694
  • 22 Saleem A, Walshe-Roussel B, Harris C, Asim M, Tamayo C, Sit S, Arnason JT. Characterisation of phenolics in Flor-Essence – a compound herbal product and its contributing herbs. Phytochem Anal 2009; 20: 395-401
  • 23 Ivancheva S, Stantcheva B. Ethnobotanical inventory of medicinal plants in Bulgaria. J Ethnopharmacol 2000; 69: 165-172
  • 24 El-Hilaly J, Hmammouchi M, Lyoussi B. Ethnobotanical studies and economic evaluation of medicinal plants in Taounate province (Northern Morocco). J Ethnopharmacol 2003; 86: 149-158
  • 25 Leporatti ML, Ivancheva S. Preliminary comparative analysis of medicinal plants used in the traditional medicine of Bulgaria and Italy. J Ethnopharmacol 2003; 87: 123-142
  • 26 European Medicines Agency (EMA). Accessed on 10 August 2024 at: https://www.ema.europa.eu/en/medicines/herbal/cnici-benedicti-herba
  • 27 Tamayo C, Richardson MA, Diamond S, Skoda I. The chemistry and biological activity of herbs used in Flor-Essence herbal tonic and Essiac. Phytother Res 2000; 14: 1-14
  • 28 Nice FJ. Common herbs and foods used as galactogogues. ICAN 011; 3: 129 – 132.
  • 29 McBride GM, Stevenson R, Zizzo G, Rumbold AR, Amir LH, Keir AK, Grzeskowiak LE. Use and experiences of galactagogues while breastfeeding among Australian women. PLoS One 2021; 16: e0254049
  • 30 Bela Z. Blessed thistle – Panacea of the 16th century Europe. Panacea 2005; 1: 38-42
  • 31 Chabane D, Assani A, Mouhoub F, Bourakba C, Nazeli N. Anatomical, phytochemical and pharmacological studies of roots of Cnicus benedictus L. Int J Med Plant Res 2013; 2: 204-208
  • 32 Fabbri CN. Treating medieval plague: The wonderful virtues of theriac. Early Sci Med 2007; 12: 247-283
  • 33 Zhang J, Shen S, Zhu S, Jia F, Li J, Sun Y. Cnicus benedictus extract-loaded electrospun gelatin wound dressing for treating diabetic wounds: An in vitro and in vivo study. J Appl Biomater Funct Mater 2024; 22
  • 34 Steenkamp V, Gouws M. Cytotoxicity of six South African medicinal plant extracts used in the treatment of cancer. S Afr J Bot 2006; 72: 630-633
  • 35 Vanhaelen-Fastre R. Constitution et propietes anti- bacteriennes de lʼhuile essentielle de Cnicus benedictus . Planta Med 1973; 24: 165-175
  • 36 Bach SM, Fortuna MA, Attarian R, de Trimarco JT, Catalán CA, Av-Gay Y, Bach H. Antibacterial and cytotoxic activities of the sesquiterpene lactones cnicin and onopordopicrin. Nat Prod Commun 2011; 6: 163-166
  • 37 Vanhaelen-Fastre R. Constituents polyacetyleniques de Cnicus benedictus L. Planta Med 1974; 25: 47-59
  • 38 Vanhaelen-Fastre R, Vanhaelen M. Activite antibiotique et cytotoxique de la cnicine et de sesproduits dʼhydrolyse. Relation structure chimique – Activite biologique. Planta Med 1976; 29: 179-189
  • 39 Szabó I, Pallag A, Blidar CF. The antimicrobial activity of the Cnicus benedictus L. extracts. Analele Universitatii din Oradea, Fascicula Biologie 2009, Tom. XVI/1, 126–128. https://www.semanticscholar.org/paper/The-antimicrobial-activity-of-the-Cnicus-benedictus-Szab%25C3%25B3-Pallag/5723d742035dda2b6a361f941fd24838ed5de90b%23citing-papers
  • 40 Yasin Y, Ibrahem EJ. Antibacterial activity of ethanolic extract of roots of the goo (Cnicus benedictus L.). Cihan Univ Sci J 2017; 2017: 298-310
  • 41 Raina D, Kumar C, Kumar V, Khan IA, Saran S. Potential inhibitors targeting Escherichia coli UDP-N-acetylglucosamine enolpyruvyl transferase (MurA): An overview. Indian J Microbiol 2022; 62: 11-22
  • 42 Bachelier A, Mayer R, Klein CD. Sesquiterpene lactones are potent and irreversible inhibitors of the antibacterial target enzyme MurA. Bioorg Med Chem Lett 2006; 16: 5605-5609
  • 43 Monsalve LN, Rosselli S, Bruno M, Baldessari A. Lipase-catalysed preparation of acyl derivatives of the germacranolide cnicin. J Mol Catal B Enzym 2009; 57: 40-47
  • 44 Skarzynski T, Mistry A, Wonacott A, Hutchinson SE, Kelly VA, Duncan K. Structure of UDP-N-acetylglucosamine enolpyruvyl transferase, an enzyme essential for the synthesis of bacterial peptidoglycan, complexed with substrate UDP-N-acetylglucosamine and the drug fosfomycin. Structure 1996; 4: 1465-1474
  • 45 Steinbach A, Skarzynski T, Scheidig AJ, Klein CD. The Antibacterial Target Enzyme Mura Synthesizes its Own Non-Covalent Suicide Inhibitor from the Natural Product Cnicin. Available online: https://wwwrcsborg/structure/2Z2C.%20Accessed%20on%2010%20August%202024
  • 46 Shigetomi K, Shoji K, Mitsuhashi S, Ubukata M. The antibacterial properties of 6-tuliposide B. Synthesis of 6-tuliposide B analogues and structure-activity relationship. Phytochemistry 2010; 71: 312-324
  • 47 Barrero AF, Oltra JE, Alvarez M, Raslan DS, Saúde DA, Akssira M. New sources and antifungal activity of sesquiterpene lactones. Fitoterapia 2000; 71: 60-64
  • 48 Barrero AF, Oltra JE, Raslan DS, Saude DA. Microbial transformation of sesquiterpene lactones by the fungi cunninghamella echinulata and rhizopus oryzae. J Nat Prod 1999; 62: 726-729
  • 49 Minoda K, Nagaoka Y, Uesato S, Hayashi K, Hayashi T. Synergistic effect of oseltamivir and arctigenin from seeds (Goboshi) of Arctium lappal on Anti-influenza A Virus Activity. Symposium on the chemistry of natural products. 2006; P-206.
  • 50 Hayashi K, Narutaki K, Nagaoka Y, Hayashi T, Uesato S. Therapeutic effect of arctiin and arctigenin in immunocompetent and immunocompromised mice infected with influenza A virus. Biol Pharm Bull 2010; 33: 1199-1205
  • 51 So J, Kim JH, Lee S, Kim C, Park R, Park J. Arctigenin from Forsythia viridissima fruit inhibits the replication of human coronavirus. Int J Mol Sci 2024; 25: 7363
  • 52 Alhadrami HA, Sayed AM, Hassan HM, Youssif KA, Gaber Y, Moatasim Y, Kutkat O, Mostafa A, Ali MA, Rateb ME, Abdelmohsen UR, Gamaleldin NM. Cnicin as an anti-SARS-CoV-2: An integrated in silico and in vitro approach for the rapid identification of potential COVID-19 therapeutics. Antibiotics (Basel) 2021; 10: 542
  • 53 Queiroz LS, Ferreira EA, Mengarda AC, Almeida ADC, Pinto PF, Coimbra ES, de Moraes J, Denadai ÂML, Da Silva Filho AA. In vitro and in vivo evaluation of cnicin from blessed thistle (Centaurea benedicta) and its inclusion complexes with cyclodextrins against Schistosoma mansoni . Parasitol Res 2021; 120: 1321-1333
  • 54 Ahmadimoghaddam D, Sadeghian R, Ranjbar A, Izadidastenaei Z, Mohammadi S. Antinociceptive activity of Cnicus benedictus L. leaf extract: A mechanistic evaluation. Res Pharm Sci 2020; 15: 463-472
  • 55 De Sousa OV, Gonçalves GC, Queiroz LS, Ferreira EA, Santos BCS, Silva Filho AA, Taranto AG. Cnicin from Centaurea benedicta L. is an active compound against skin inflammation in a mouse model. 2021 doi:10.21203/rs.3.rs-1124507/v1
  • 56 Demiroz T, Albayrak G, Nalbantsoy A, Gocmen B, Baykan S. Anti-inflammatory properties of Centaurea calolepis Boiss and cnicin against Macrovipera lebetina obtusa (Dwigubsky, 1832) and Montivipera xanthina (Gray, 1849) venoms in rat. Toxicon 2018; 152: 37-42
  • 57 Gobrecht P, Gebel J, Leibinger M, Zeitler C, Chen Z, Gründemann D, Fischer D. Cnicin promotes functional nerve regeneration. Phytomedicine 2024; 129: 155641
  • 58 Li H, Zuo J, Tang W. Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases. Front Pharmacol 2018; 9: 1048
  • 59 Li H, Li J, Zhang X, Feng C, Fan C, Yang X, Zhang R, Zhu F, Zhou Y, Xu Y, Liu H, Tang W. DC591017, a phosphodiesterase-4 (PDE4) inhibitor with robust anti-inflammation through regulating PKA-CREB signaling. Biochem Pharmacol 2020; 177: 113958
  • 60 Li H, Zhang X, Xiang C, Feng C, Fan C, Liu M, Lu H, Su H, Zhou Y, Qi Q, Xu Y, Tang W. Identification of phosphodiesterase-4 as the therapeutic target of arctigenin in alleviating psoriatic skin inflammation. J Adv Res 2021; 33: 241-251
  • 61 Nose M, Fujimoto T, Nishibe S, Ogihara Y. Structural transformation of lignan compounds in rat gastrointestinal tract; II. Serum concentration of lignans and their metabolites. Planta Med 1993; 59: 131-134
  • 62 Mascolo N, Autore G, Capasso F, Menghini A, Fasulo MP. Biological screening of Italian medicinal plants for antiinflammatory activity. Phytother Res 1987; 1: 28-31
  • 63 Durdun C, Papuc C, Crivineanu M, Nicorescu V. Antioxidant potential of Lycopodium clavatum and Cnicus benedictus hydroethanolic extracts on stressed mice. Sci Works. C Series. Vet Med 2011; 57: 61-68
  • 64 Jang YP, Kim SR, Choi YH, Kim J, Kim SG, Markelonis GJ, Oh TH, Kim YC. Arctigenin protects cultured cortical neurons from glutamate-induced neurodegeneration by binding to kainate receptor. J Neurosci Res 2002; 68: 233-240
  • 65 Kang HS, Lee JY, Kim CJ. Anti-inflammatory activity of arctigenin from Forsythiae Fructus. J Ethnopharmacol 2008; 116: 305-312
  • 66 Zhao F, Wang L, Liu K. In vitro anti-inflammatory effects of arctigenin, a lignan from Arctium lappa L., through inhibition on iNOS pathway. J Ethnopharmacol 2009; 122: 457-462
  • 67 Zhang W, Jiang Z, He B, Liu X. Arctigenin protects against lipopolysaccharide-induced pulmonary oxidative stress and inflammation in a mouse model via suppression of MAPK, HO-1, and inos. signaling, Inflammation 2015; 38: 1406-1414
  • 68 Erel SB, Karaalp C, Bedir E, Kaehlig H, Glasl S, Khan S, Krenn L. Secondary metabolites of Centaurea calolepis and evaluation of cnicin for anti-inflammatory, antioxidant, and cytotoxic activities. Pharm Biol 2011; 49: 840-849
  • 69 Qi Y, Dou DQ, Jiang H, Zhang BB, Qin WY, Kang K, Zhang N, Jia D. Arctigenin attenuates learning and memory deficits through PI3 k/Akt/GSK-3β pathway reducing tau hyperphosphorylation in Aβ-induced AD mice. Planta Med 2017; 83: 51-56
  • 70 Shri SR, Manandhar S, Nayak Y, Pai KSR. Role of GSK-3β inhibitors: New promises and opportunities for alzheimerʼs disease. Adv Pharm Bull 2023; 13: 688-700
  • 71 Kim JY, Hwang JH, Cha MR, Yoon MY, Son ES, Tomida A, Ko B, Song SW, Shin-ya K, Hwang Y. Arctigenin blocks the unfolded protein response and shows therapeutic antitumor activity. J Cell Physiol 2010; 224: 33-40
  • 72 Awale S, Lu J, Kalauni SK, Kurashima Y, Tezuka Y, Kadota S, Esumi H. Identification of arctigenin as an antitumor agent having the ability to eliminate the tolerance of cancer cells to nutrient starvation. Cancer Res 2006; 66: 1751-1757
  • 73 Takasaki M, Konoshima T, Komatsu K, Tokuda H, Nishino H. Anti-tumor-promoting activity of lignans from the aerial part of Saussurea medusa . Cancer Lett 2000; 158: 53-59
  • 74 Hirose M, Yamaguchi T, Lin C, Kimoto N, Futakuchi M, Kono T, Nishibe S, Shirai T. Effects of arctiin on PhIP-induced mammary, colon and pancreatic carcinogenesis in female Sprague-Dawley rats and MeIQx-induced hepatocarcinogenesis in male F344 rats. Cancer Lett 2000; 155: 79-88
  • 75 Sen A, Ozbas Turan S, Bitis L. Bioactivity-guided isolation of anti-proliferative compounds from endemic Centaurea kilaea . Pharm Biol 2017; 55: 541-546
  • 76 Jöhrer K, Obkircher M, Neureiter D, Parteli J, Zelle-Rieser C, Maizner E, Kern J, Hermann M, Hamacher F, Merkel O. Antimyeloma activity of the sesquiterpene lactone cnicin: Impact on Pim-2 kinase as a novel therapeutic target. J Mol Med (Berl) 2012; 90: 681-693
  • 77 Barrero AF, Oltra JE, Morales V, Alvarez M, Rodríguez-García I. Biomimetic cyclization of cnicin to malacitanolide, a cytotoxic eudesmanolide from Centaurea malacitana . J Nat Prod 1997; 60: 1034-1035
  • 78 Matsuzaki Y, Koyama M, Hitomi T, Yokota T, Kawanaka M, Nishikawa A, Germain D, Sakai T. Arctiin induces cell growth inhibition through the down-regulation of cyclin D1 expression. Oncol Rep 2008; 19: 721-727
  • 79 Hirano T, Gotoh M, Oka K. Natural flavonoids and lignans are potent cytostatic agents against human leukemic HL-60 cells. Life Sci 1994; 55: 1061-1069
  • 80 Zeller W, de Gols M, Hausen BM. The sensitizing capacity of Compositae plants. VI. Guinea pig sensitization experiments with ornamental plants and weeds using different methods. Arch Dermatol Res 1985; 277: 28-35
  • 81 Blessed Thistle. 2022 Feb 20. In: Drugs and Lactation Database (LactMed®) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; 2006. PMID: 30000834
  • 82 OECD Guidelines for the Testing of Chemicals, Section 4. Accessed on 10 August 2024 at: https://wwwoecd-ilibraryorg/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788
  • 83 Maharjan RS, Singh AV, Hanif J, Rosenkranz D, Haidar R, Shelar A, Singh SP, Dey A, Patil R, Zamboni P, Laux P, Luch A. Investigation of the associations between a nanomaterialʼs microrheology and toxicology. ACS Omega 2022; 7: 13985-13997
  • 84 Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017; 7: 42717
  • 85 Cheng T, Zhao Y, Li X, Lin F, Xu Y, Zhang X, Li Y, Wang R, Lai L. Computation of octanol water partition coefficients by guiding an additive model with knowledge. J Chem Inf Model 2007; 47: 2140-2148
  • 86 Wildman SA, Crippen GM. Prediction of physicochemical parameters by atomic contributions. J Chem Inf Model 1999; 39: 868-873
  • 87 Moriguchi I, Shuichi H, Liu Q, Nakagome I, Matsushita Y. Simple method of calculating octanol/water partition coefficient. Chem Pharm Bull 1992; 40: 127-130
  • 88 Moriguchi I, Shuichi H, Nakagome I, Hirano H. Comparison of reliability of log P values for drugs calculated by several methods. Chem Pharm Bull 1994; 42: 976-978
  • 89 Daina A, Zoete V. A BOILED-Egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem 2016; 11: 1117-1121
  • 90 Suenderhauf C, Hammann F, Huwyler J. Computational prediction of blood-brain barrier permeability using decision tree induction. Molecules 2012; 17: 10429-10445
  • 91 Singh AV, Chandrasekar V, Laux P, Luch A, Dakua SP, Zamboni P, Shelar A, Yang Y, Pandit V, Tisato V, Gemmati D. Micropatterned neurovascular interface to mimic the blood-brain barrierʼs neurophysiology and micromechanical function: A BBB-on-CHIP model. Cells 2022; 11: 2801
  • 92 Nabeka H. Prosaposin, a neurotrophic factor, protects neurons against kainic acid-induced neurotoxicity. Anat Sci Int 2021; 96: 359-369
  • 93 Daina A, Michielin O, Zoete V. SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res 2019; 47: W357-W364
  • 94 Gfeller D, Michielin O, Zoete V. Shaping the interaction landscape of bioactive molecules. Bioinformatics 2013; 29: 3073-3079
  • 95 Wu D, Jin L, Huang X, Deng H, Shen QK, Quan ZS, Zhang C, Guo HY. Arctigenin: Pharmacology, total synthesis, and progress in structure modification. J Enzyme Inhib Med Chem 2022; 37: 2452-2477
  • 96 Mizuno S, Ikegami M, Koyama T, Sunami K, Ogata D, Kage H, Yanagaki M, Ikeuchi H, Ueno T, Tanikawa M, Oda K, Osuga Y, Mano H, Kohsaka S. High-throughput functional evaluation of MAP2K1 variants in cancer. Mol Cancer Ther 2023; 22: 227-239
  • 97 Xie LH, Ahn EM, Akao T, Abdel-Hafez AA, Nakamura N, Hattori M. Transformation of arctiin to estrogenic and antiestrogenic substances by human intestinal bacteria. Chem Pharm Bull (Tokyo) 2003; 51: 378-384