Effects of Arborvitae (Thuja plicata) Essential Oil on Cervical Cancer Cells: Insights into Molecular Mechanisms


Cite item

Full Text

Abstract

Aims:This study aimed to assess the effects of AEO in an in vitro model of cell lines derived from cervical cancer—namely, HeLa and SiHa—by screening for AEO’s cytotoxic properties and examining its influence on the modulation of gene expression.

Background:Cervical cancer stands as a prevalent global health concern, affecting millions of women worldwide. The current treatment modalities encompass surgery, radiation, and chemotherapy, but significant limitations and adverse effects constrain their effectiveness. Therefore, exploring novel treatments that offer enhanced efficacy and reduced side effects is imperative. Arborvitae essential oil, extracted from Thuja Plicata, has garnered attention for its antimicrobial, anti-inflammatory, immunomodulatory, and tissue-remodeling properties; however, its potential in treating cervical cancer remains uncharted.

Objective:The objective of this study was to delve into the molecular mechanisms induced by arborvitae essential oil in order to learn about its anticancer effects on cervical cancer cell lines.

Methods:The methods used in this study were assessments of cell viability using WST-1 and annexin V– propidium iodide, mRNA sequencing, and subsequent bioinformatics analysis.

Results:The findings unveiled a dose-dependent cytotoxic effect of arborvitae essential oil on both HeLa and SiHa cell lines. Minor effects were observed only at very low doses in the HaCaT non-tumorigenic human keratinocyte cells. RNA-Seq bioinformatics analysis revealed the regulatory impact of arborvitae essential oil on genes enriched in the following pathways: proteasome, adherens junctions, nucleocytoplasmic transport, cell cycle, proteoglycans in cancer, protein processing in the endoplasmic reticulum, ribosome, spliceosome, mitophagy, cellular senescence, and viral carcinogenesis, among others, in both cell lines. It is worth noting that the ribosome and spliceosome KEGG pathways are the most significantly enriched pathways in HeLa and SiHa cells.

Conclusion:Arborvitae essential oil shows potential as a cytotoxic and antiproliferative agent against cervical cancer cells, exerting its cytotoxic properties by regulating many KEGG pathways.

About the authors

Ruben Piña-Cruz

Programa de Doctorado en Ciencias en Biología Molecular en Medicina, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara

Email: info@benthamscience.net

Andrea Molina-Pineda

Consejo Nacional de Humanidades, Ciencias y Tecnologías, CONAHCYT

Email: info@benthamscience.net

Marco Aguila-Estrada

División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS)

Email: info@benthamscience.net

María Villaseñor-García

División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS)

Email: info@benthamscience.net

Georgina Hernández-Flores

División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS)

Email: info@benthamscience.net

Luis Jave-Suarez

División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS)

Author for correspondence.
Email: info@benthamscience.net

Adriana Aguilar-Lemarroy

División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS)

Author for correspondence.
Email: info@benthamscience.net

References

  1. Johnson, C.A.; James, D.; Marzan, A.; Armaos, M. Cervical cancer: An overview of pathophysiology and management. Semin. Oncol. Nurs., 2019, 35(2), 166-174. doi: 10.1016/j.soncn.2019.02.003 PMID: 30878194
  2. Bray, F.; Laversanne, M.; Sung, H.; Ferlay, J.; Siegel, R.L.; Soerjomataram, I.; Jemal, A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2024, 74(3), 229-263. doi: 10.3322/caac.21834 PMID: 38572751
  3. Lewandowska, A.; Szubert, S.; Koper, K.; Koper, A.; Cwynar, G.; Wicherek, L. Analysis of long-term outcomes in 44 patients following pelvic exenteration due to cervical cancer. World J. Surg. Oncol., 2020, 18(1), 234. doi: 10.1186/s12957-020-01997-3 PMID: 32878646
  4. Boon, S.S.; Luk, H.Y.; Xiao, C.; Chen, Z.; Chan, P.K.S. Review of the standard and advanced screening, staging systems and treatment modalities for cervical cancer. Cancers (BaseL), 2022, 14(12), 2913. doi: 10.3390/cancers14122913.
  5. Waldman, A.D.; Fritz, J.M.; Lenardo, M.J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat. Rev. Immunol., 2020, 20(11), 651-668. doi: 10.1038/s41577-020-0306-5 PMID: 32433532
  6. Esfahani, K.; Roudaia, L.; Buhlaiga, N.; Del Rincon, S.V.; Papneja, N.; Miller, W.H., Jr A review of cancer immunotherapy: from the past, to the present, to the future. Curr. Oncol., 2020, 27(12), 87-97. doi: 10.3747/co.27.5223 PMID: 32368178
  7. Odiase, O.; Noah-Vermillion, L.; Simone, B.A.; Aridgides, P.D. The incorporation of immunotherapy and targeted therapy into chemoradiation for cervical cancer: A focused review. Front. Oncol., 2021, 11, 663749. doi: 10.3389/fonc.2021.663749 PMID: 34123823
  8. Schmidt, MW.; Battista, MJ.; Schmidt, M.; Garcia, M.; Siepmann, T.; Hasenburg, A.; Anic, K. Efficacy and safety of immunotherapy for cervical cancer-A systematic review of clinical trials. Cancers (Basel), 2022, 14(2), 441. doi: 10.3390/cancers14020441.
  9. Shen, G.; Zheng, F.; Ren, D.; Du, F.; Dong, Q.; Wang, Z.; Zhao, F.; Ahmad, R.; Zhao, J. Anlotinib: A novel multi-targeting tyrosine kinase inhibitor in clinical development. J. Hematol. Oncol., 2018, 11(1), 120. doi: 10.1186/s13045-018-0664-7 PMID: 30231931
  10. Schilder, R.J.; Sill, M.W.; Lee, Y.C.; Mannel, R. A phase II trial of erlotinib in recurrent squamous cell carcinoma of the cervix: A gynecologic oncology group study. Int. J. Gynecol. Cancer, 2009, 19(5), 929-933. doi: 10.1111/IGC.0b013e3181a83467 PMID: 19574787
  11. Goncalves, A.; Fabbro, M.; Lhommé, C.; Gladieff, L.; Extra, J.M.; Floquet, A.; Chaigneau, L.; Carrasco, A.T.; Viens, P. A phase II trial to evaluate gefitinib as second- or third-line treatment in patients with recurring locoregionally advanced or metastatic cervical cancer. Gynecol. Oncol., 2008, 108(1), 42-46. doi: 10.1016/j.ygyno.2007.07.057 PMID: 17980406
  12. Nogueira-Rodrigues, A.; Moralez, G.; Grazziotin, R.; Carmo, C.C.; Small, I.A.; Alves, F.V.G.; Mamede, M.; Erlich, F.; Viegas, C.; Triginelli, S.A.; Ferreira, C.G. Phase 2 trial of erlotinib combined with cisplatin and radiotherapy in patients with locally advanced cervical cancer. Cancer, 2014, 120(8), 1187-1193. doi: 10.1002/cncr.28471 PMID: 24615735
  13. Tewari, K.S.; Sill, M.W.; Long, H.J., III; Penson, R.T.; Huang, H.; Ramondetta, L.M.; Landrum, L.M.; Oaknin, A.; Reid, T.J.; Leitao, M.M.; Michael, H.E.; Monk, B.J. Improved survival with bevacizumab in advanced cervical cancer. N. Engl. J. Med., 2014, 370(8), 734-743. doi: 10.1056/NEJMoa1309748 PMID: 24552320
  14. Tewari, K.S.; Sill, M.W.; Penson, R.T.; Huang, H.; Ramondetta, L.M.; Landrum, L.M.; Oaknin, A.; Reid, T.J.; Leitao, M.M.; Michael, H.E.; DiSaia, P.J.; Copeland, L.J.; Creasman, W.T.; Stehman, F.B.; Brady, M.F.; Burger, R.A.; Thigpen, J.T.; Birrer, M.J.; Waggoner, S.E.; Moore, D.H.; Look, K.Y.; Koh, W.J.; Monk, B.J. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet, 2017, 390(10103), 1654-1663. doi: 10.1016/S0140-6736(17)31607-0 PMID: 28756902
  15. Coleman, R.L.; Lorusso, D.; Gennigens, C.; González-Martín, A.; Randall, L.; Cibula, D.; Lund, B.; Woelber, L.; Pignata, S.; Forget, F.; Redondo, A.; Vindeløv, S.D.; Chen, M.; Harris, J.R.; Smith, M.; Nicacio, L.V.; Teng, M.S.L.; Laenen, A.; Rangwala, R.; Manso, L.; Mirza, M.; Monk, B.J.; Vergote, I.; Raspagliesi, F.; Melichar, B.; Gaba Garcia, L.; Jackson, A.; Henry, S.; Kral, Z.; Harter, P.; De Giorgi, U.; Bjurberg, M.; Gold, M.; O’Malley, D.; Honhon, B.; Vulsteke, C.; De Cuypere, E.; Denys, H.; Baurain, J-F.; Zamagni, C.; Tenney, M.; Gordinier, M.; Bradley, W.; Schlumbrecht, M.; Spirtos, N.; Concin, N.; Mahner, S.; Scambia, G.; Leath, C.; Farias-Eisner, R.; Cohen, J.; Muller, C.; Bhatia, S. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): A multicentre, open-label, single-arm, phase 2 study. Lancet Oncol., 2021, 22(5), 609-619. doi: 10.1016/S1470-2045(21)00056-5 PMID: 33845034
  16. Min, H.Y.; Lee, H.Y. Mechanisms of resistance to chemotherapy in non-small cell lung cancer. Arch. Pharm. Res., 2021, 44(2), 146-164. doi: 10.1007/s12272-021-01312-y PMID: 33608812
  17. Ortiz, M.; Wabel, E.; Mitchell, K.; Horibata, S. Mechanisms of chemotherapy resistance in ovarian cancer. Cancer Drug Resist., 2022, 5(2), 304-316. doi: 10.20517/cdr.2021.147 PMID: 35800369
  18. Eslami, M.; Davarpanah, A.; Rismanbaf, A.H.; Taghizadeh-Hesary, F.; Dorgaleleh, S.; Memar, S.S.; Nayernia, K.; Behnam, B. Molecular mechanisms for targeting metastatic cancer cells and to overcome or prevent chemotherapy resistance. Preprints, 2023. doi: 10.20944/preprints202306.0602.v1.
  19. Kanno, Y.; Chen, C.Y.; Lee, H.L.; Chiou, J.F.; Chen, Y.J. Molecular mechanisms of chemotherapy resistance in head and neck cancers. Front. Oncol., 2021, 11, 640392. doi: 10.3389/fonc.2021.640392 PMID: 34026617
  20. Zahedipour, F.K.; Prashant, K.; Sahebkar, A. Mechanisms of multidrug resistance in cancer. In: Aptamers Engineered Nanocarriers for Cancer Therapy; , 2023; pp. 51-83. doi: 10.1016/B978-0-323-85881-6.00002-6.
  21. George, I.A.C.; Chauhan, R.; Dhawale, R.E.; Iyer, R.; Limaye, S.; Sankaranarayanan, R.; Kumar, P.; Venkataramanan, R. Insights into therapy resistance in cervical cancer. Adv. Cancer Bio. Metasis, 2022, 6(4), 100074. doi: 10.1016/j.adcanc.2022.100074.
  22. Mann, M.; Singh, V.P.; Kumar, L. Cervical cancer: A tale from HPV infection to PARP inhibitors. Genes Dis., 2023, 10(4), 1445-1456. doi: 10.1016/j.gendis.2022.09.014 PMID: 37397551
  23. Lai, J.; Yang, S.; Lin, Z.; Huang, W.; Li, X.; Li, R.; Tan, J.; Wang, W. Update on chemoresistance mechanisms to first-line chemotherapy for gallbladder cancer and potential reversal strategies. Am. J. Clin. Oncol., 2023, 46(4), 131-141. doi: 10.1097/COC.0000000000000989 PMID: 36867653
  24. Fedotcheva, T.A.; Shimanovsky, N.L. Pharmacological strategies for overcoming multidrug resistance to chemotherapy. Pharm. Chem. J., 2023, 56(10), 1307-1313. doi: 10.1007/s11094-023-02790-8 PMID: 36683825
  25. Rose, P.G.; Ali, S.; Watkins, E.; Thigpen, J.T.; Deppe, G.; Clarke-Pearson, D.L.; Insalaco, S. Long-term follow-up of a randomized trial comparing concurrent single agent cisplatin, cisplatin-based combination chemotherapy, or hydroxyurea during pelvic irradiation for locally advanced cervical cancer: A gynecologic oncology group study. J. Clin. Oncol., 2007, 25(19), 2804-2810. doi: 10.1200/JCO.2006.09.4532 PMID: 17502627
  26. Kumar, L.; Gupta, S. Integrating chemotherapy in the management of cervical cancer: A critical appraisal. Oncology, 2016, 91, 8-17. doi: 10.1159/000447576 PMID: 27464068
  27. Katsumata, N.; Yoshikawa, H.; Kobayashi, H.; Saito, T.; Kuzuya, K.; Nakanishi, T.; Yasugi, T.; Yaegashi, N.; Yokota, H.; Kodama, S.; Mizunoe, T.; Hiura, M.; Kasamatsu, T.; Shibata, T.; Kamura, T.; Japan, G. Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: A Japan Clinical Oncology Group trial (JCOG 0102). Br. J. Cancer, 2013, 108(10), 1957-1963. doi: 10.1038/bjc.2013.179 PMID: 23640393
  28. Lin, S.R.; Chang, C.H.; Hsu, C.F.; Tsai, M.J.; Cheng, H.; Leong, M.K.; Sung, P.J.; Chen, J.C.; Weng, C.F. Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence. Br. J. Pharmacol., 2020, 177(6), 1409-1423. doi: 10.1111/bph.14816 PMID: 31368509
  29. Dehelean, C.A.; Marcovici, I.; Soica, C.; Mioc, M.; Coricovac, D.; Iurciuc, S.; Cretu, O.M.; Pinzaru, I. Plant-derived anticancer compounds as new perspectives in drug discovery and alternative therapy. Molecules, 2021, 26(4), 1109. doi: 10.3390/molecules26041109 PMID: 33669817
  30. Andrade, M.A.; Braga, M.A.; Cesar, P.H.S.; Trento, M.V.C.; Espósito, M.A.; Silva, L.F.; Marcussi, S. Anticancer properties of essential oils: An overview. Curr. Cancer Drug Targets, 2018, 18(10), 957-966. doi: 10.2174/1568009618666180102105843 PMID: 29295695
  31. Abd Rashid, N.; Mohamad Najib, N.H.; Abdul Jalil, N.A.; Teoh, S.L. Essential oils in cervical cancer: Narrative review on current insights and future prospects. Antioxidants, 2023, 12(12), 2109. doi: 10.3390/antiox12122109 PMID: 38136228
  32. Singh, T.; Aggarwal, N.; Thakur, K.; Chhokar, A.; Yadav, J.; Tripathi, T.; Jadli, M.; Bhat, A.; Kumar, A.; Narula, R.H.; Gupta, P.; Khurana, A.; Bharti, A.C. Evaluation of therapeutic potential of selected plant-derived homeopathic medicines for their action against cervical cancer. Homeopathy, 2023, 112(4), 262-274. doi: 10.1055/s-0042-1756436 PMID: 36858077
  33. Pal, A.; Das, S.; Basu, S.; Kundu, R. Apoptotic and autophagic death union by Thuja occidentalis homeopathic drug in cervical cancer cells with Thujone as the bioactive principle. J. Integr. Med., 2022, 20(5), 463-472. doi: 10.1016/j.joim.2022.06.004 PMID: 35752587
  34. Tsiri, D.; Graikou, K.; Pobłocka-Olech, L.; Krauze-Baranowska, M.; Spyropoulos, C.; Chinou, I. Chemosystematic value of the essential oil composition of Thuja species cultivated in Poland-antimicrobial activity. Molecules, 2009, 14(11), 4707-4715. doi: 10.3390/molecules14114707 PMID: 19935470
  35. Yatagai, M.; Sato, T.; Takahashi, T. Terpenes of leaf oils from Cupressaceae. Biochem. Syst. Ecol., 1985, 13(4), 377-385. doi: 10.1016/0305-1978(85)90081-X
  36. Svajdlenka, E.; Pavol, M.; Grancai, D.; Tomasko, I. Essential oil composition of Thuja occidentalis L. samples from Slovakia. J. Essent. Oil Res., 2011, 11, 532-536. doi: 10.1080/10412905.1999.9701208
  37. Buben, I.; Karmazín, M.; Trojánková, J.; Nova, D. Seasonal variability in the contents and composition of essential oil in various Thuja species occurring in Czechoslovakia. Acta Hortic., 1992, (1), 200-203. doi: 10.17660/ActaHortic.1992.306.21
  38. Kéïta, S.M.; Vincent, C.; Schmidt, J.P.; Arnason, J.T. Insecticidal effects of Thuja occidentalis (Cupressaceae) essential oil on Callosobruchus maculatus . Can. J. Plant Sci., 2000, 81, 173-177. doi: 10.4141/P00-059
  39. Von Rudloff, E.; Lapp Martin, S.; Yeh Francis, C. Chemosystematic study of Thuja plicata : Multivariate analysis of leaf oil terpene composition. Biochem. Syst. Ecol., 1988, 16, 199-125. doi: 10.1016/0305-1978(88)90083-X.
  40. von Rudloff, E. Gas—liquid chromatography of terpenes VI. The volatile oil of Thuja plicata Donn. Phytochemistry, 1962, 1(3), 195-202. doi: 10.1016/S0031-9422(00)82822-8
  41. Naser, B.; Bodinet, C.; Tegtmeier, M.; Lindequist, U. Thuja occidentalis (Arbor vitae): A review of its pharmaceutical, pharmacological and clinical properties. Evid. Based Complement. Alternat. Med., 2005, 2(1), 69-78. doi: 10.1093/ecam/neh065 PMID: 15841280
  42. Caruntu, S.; Ciceu, A.; Olah, N.K.; Don, I.; Hermenean, A.; Cotoraci, C. Thuja occidentalis L. (Cupressaceae): Ethnobotany, phytochemistry and biological activity. Molecules, 2020, 25(22), 5416. doi: 10.3390/molecules25225416 PMID: 33228192
  43. Lee, J.Y.; Park, H.; Lim, W.; Song, G. Therapeutic potential of α,β‐thujone through metabolic reprogramming and caspase‐dependent apoptosis in ovarian cancer cells. J. Cell. Physiol., 2021, 236(2), 1545-1558. doi: 10.1002/jcp.30086 PMID: 33000501
  44. Lee, J.Y.; Park, H.; Lim, W.; Song, G. α,β-Thujone suppresses human placental choriocarcinoma cells via metabolic disruption. Reproduction, 2020, 159(6), 745-756. doi: 10.1530/REP-20-0018 PMID: 32240978
  45. Torres, A.; Vargas, Y.; Uribe, D.; Carrasco, C.; Torres, C.; Rocha, R.; Oyarzún, C.; San Martín, R.; Quezada, C. Pro-apoptotic and anti-angiogenic properties of the α /β-thujone fraction from Thuja occidentalis on glioblastoma cells. J. Neurooncol., 2016, 128(1), 9-19. doi: 10.1007/s11060-016-2076-2 PMID: 26900077
  46. Antos, J.A.; Filipescu, C.N.; Negrave, R.W. Ecology of western redcedar (Thuja plicata ): Implications for management of a high-value multiple-use resource. For. Ecol. Manage., 2016, 375, 211-222. doi: 10.1016/j.foreco.2016.05.043
  47. Western Redcedar. 1990. Available from: https://www.srs.fs.usda.gov/pubs/misc/ag_654/volume_1/thuja/plicata.htm
  48. Han, X.; Parker, T.L. Arborvitae ( Thuja plicata ) essential oil significantly inhibited critical inflammation- and tissue remodeling-related proteins and genes in human dermal fibroblasts. Biochim. Open, 2017, 4, 56-60. doi: 10.1016/j.biopen.2017.02.003 PMID: 29450142
  49. Hudson, J.; Kuo, M.; Vimalanathan, S. The antimicrobial properties of cedar leaf (Thuja plicata ) oil; A safe and efficient decontamination agent for buildings. Int. J. Environ. Res. Public Health, 2011, 8(12), 4477-4487. doi: 10.3390/ijerph8124477 PMID: 22408584
  50. Vimalanathan, S.; Huson, J. The activity of cedar leaf oil vapor against respiratory viruses: Practical applications. J. Appl. Pharm. Sci., 2013, 3, 11-15. doi: 10.7324/JAPS.2013.31103.
  51. Sebaugh, J.L. Guidelines for accurate EC50/IC50 estimation. Pharm. Stat., 2011, 10(2), 128-134. doi: 10.1002/pst.426 PMID: 22328315
  52. Liao, Y.; Smyth, G.K.; Shi, W. The R package Rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads. Nucleic Acids Res., 2019, 47(8), e47. doi: 10.1093/nar/gkz114 PMID: 30783653
  53. Ulgen, E.; Ozisik, O.; Sezerman, O.U. pathfindR: An R package for comprehensive identification of enriched pathways in omics data through active subnetworks. Front. Genet., 2019, 10, 858. doi: 10.3389/fgene.2019.00858 PMID: 31608109
  54. Huang, M.; Lu, J.J.; Ding, J. Natural products in cancer therapy: Past, present and future. Nat. Prod. Bioprospect., 2021, 11(1), 5-13. doi: 10.1007/s13659-020-00293-7 PMID: 33389713
  55. Biswas, R.; Mandal, S.K.; Dutta, S.; Bhattacharyya, S.S.; Boujedaini, N.; Khuda-Bukhsh, A.R. Thujone‐rich fraction of Thuja occidentalis demonstrates major anti‐cancer potentials: Evidences from in vitro studies on A375 cells. Evid. Based Complement. Alternat. Med., 2011, 2011(1), 568148. doi: 10.1093/ecam/neq042 PMID: 21647317
  56. Elansary, H.O.; Abdelgaleil, S.A.M.; Mahmoud, E.A.; Yessoufou, K.; Elhindi, K.; El-Hendawy, S. Effective antioxidant, antimicrobial and anticancer activities of essential oils of horticultural aromatic crops in northern Egypt. BMC Complement. Altern. Med., 2018, 18(1), 214. doi: 10.1186/s12906-018-2262-1 PMID: 30005652
  57. R, E.B.; Jesubatham, P.D.; v M, Belin, G.V.M.; Vismanathan, S.; Srividya, S. Non-toxic and non teratogenic extract of Thuja orientalis L. inhibited angiogenesis in zebra fish and suppressed the growth of human lung cancer cell line. Biomed. Pharmacother., 2018, 106, 699-706. doi: 10.1016/j.biopha.2018.07.010 PMID: 29990861
  58. Saha, S.; Bhattacharjee, P.; Mukherjee, S.; Mazumdar, M.; Chakraborty, S.; Khurana, A.; Nayak, D.; Manchanda, R.; Chakrabarty, R.; Das, T.; Sa, G. Contribution of the ROS-p53 feedback loop in thuja-induced apoptosis of mammary epithelial carcinoma cells. Oncol. Rep., 2014, 31(4), 1589-1598. doi: 10.3892/or.2014.2993 PMID: 24482097
  59. Siveen, K.S.; Kuttan, G. Thujone inhibits lung metastasis induced by B16F-10 melanoma cells in C57BL/6 mice. Can. J. Physiol. Pharmacol., 2011, 89(10), 691-703. doi: 10.1139/y11-067 PMID: 21905822
  60. Swor, K.; Satyal, P.; Poudel, A.; Setzer, W.N. Gymnosperms of Idaho: Chemical compositions and enantiomeric distributions of essential oils of Abies lasiocarpa, Picea engelmannii, Pinus contorta, Pseudotsuga menziesii, and Thuja plicata. Molecules, 2023, 28(6), 2477. doi: 10.3390/molecules28062477 PMID: 36985451
  61. Pudełek, M.; Catapano, J.; Kochanowski, P.; Mrowiec, K.; Janik-Olchawa, N.; Czyż, J.; Ryszawy, D. Therapeutic potential of monoterpene α-thujone, the main compound of Thuja occidentalis L. essential oil, against malignant glioblastoma multiforme cells in vitro . Fitoterapia, 2019, 134, 172-181. doi: 10.1016/j.fitote.2019.02.020 PMID: 30825580
  62. Kozics, K.; Buckova, M.; Puskarova, A.; Kalaszova, V.; Cabicarova, T.; Pangallo, D. The effect of ten essential oils on several cutaneous drug-resistant microorganisms and their cyto/genotoxic and antioxidant properties. Molecules, 2019, 24(24), 4570. doi: 10.3390/molecules24244570.
  63. Liu, Q.; Li, A.; Tian, Y.; Wu, J.D.; Liu, Y.; Li, T.; Chen, Y.; Han, X.; Wu, K. The CXCL8-CXCR1/2 pathways in cancer. Cytokine Growth Factor Rev., 2016, 31, 61-71. doi: 10.1016/j.cytogfr.2016.08.002 PMID: 27578214
  64. Waugh, D.J.J.; Wilson, C. The interleukin-8 pathway in cancer. Clin. Cancer Res., 2008, 14(21), 6735-6741. doi: 10.1158/1078-0432.CCR-07-4843 PMID: 18980965
  65. Knall, C.; Worthen, G.S.; Johnson, G.L. Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils independent of extracellular signal-regulated kinase and p38 mitogen-activated protein kinases. Proc. Natl. Acad. Sci. USA, 1997, 94(7), 3052-3057. doi: 10.1073/pnas.94.7.3052 PMID: 9096344
  66. Fernandez-Avila, L.; Castro-Amaya, A.M.; Molina-Pineda, A.; Hernández-Gutiérrez, R.; Jave-Suarez, L.F.; Aguilar-Lemarroy, A. The Value of CXCL1, CXCL2, CXCL3, and CXCL8 as potential prognosis markers in cervical cancer: Evidence of E6/E7 from HPV16 and 18 in chemokines regulation. Biomedicines, 2023, 11(10), 2655. doi: 10.3390/biomedicines11102655 PMID: 37893029
  67. Xiong, X.; Liao, X.; Qiu, S.; Xu, H.; Zhang, S.; Wang, S.; Ai, J.; Yang, L. CXCL8 in tumor biology and its implications for clinical translation. Front. Mol. Biosci., 2022, 9, 723846. doi: 10.3389/fmolb.2022.723846 PMID: 35372515
  68. Chen, X.; Gu, X.; Shan, Y.; Tang, W.; Yuan, J.; Zhong, Z.; Wang, Y.; Huang, W.; Wan, B.; Yu, L. Identification of a novel human lactate dehydrogenase gene LDHAL6A, which activates transcriptional activities of AP1(PMA). Mol. Biol. Rep., 2009, 36(4), 669-676. doi: 10.1007/s11033-008-9227-2 PMID: 18351441
  69. Eferl, R.; Wagner, E.F. AP-1: A double-edged sword in tumorigenesis. Nat. Rev. Cancer, 2003, 3(11), 859-868. doi: 10.1038/nrc1209 PMID: 14668816
  70. Ran, L.; Mou, X.; Peng, Z.; Li, X.; Li, M.; Xu, D.; Yang, Z.; Sun, X.; Yin, T. ADORA2A promotes proliferation and inhibits apoptosis through PI3K/AKT pathway activation in colorectal carcinoma. Sci. Rep., 2023, 13(1), 19477. doi: 10.1038/s41598-023-46521-1 PMID: 37945707
  71. Jing, N.; Zhang, K.; Chen, X.; Liu, K.; Wang, J.; Xiao, L.; Zhang, W.; Ma, P.; Xu, P.; Cheng, C.; Wang, D.; Zhao, H.; He, Y.; Ji, Z.; Xin, Z.; Sun, Y.; Zhang, Y.; Bao, W.; Gong, Y.; Fan, L.; Ji, Y.; Zhuang, G.; Wang, Q.; Dong, B.; Zhang, P.; Xue, W.; Gao, W.Q.; Zhu, H.H. ADORA2A-driven proline synthesis triggers epigenetic reprogramming in neuroendocrine prostate and lung cancers. J. Clin. Invest., 2023, 133(24), e168670. doi: 10.1172/JCI168670 PMID: 38099497
  72. Zhang, Y.; Gu, J.; Wang, L.; Zhao, Z.; Pan, Y.; Chen, Y. Ablation of PPP1R3G reduces glycogen deposition and mitigates high-fat diet induced obesity. Mol. Cell. Endocrinol., 2017, 439, 133-140. doi: 10.1016/j.mce.2016.10.036 PMID: 27815211
  73. Saigusa, H.; Mimura, I.; Kurata, Y.; Tanaka, T.; Nangaku, M. Hypoxia‐inducible lncRNA MIR210HG promotes HIF1α expression by inhibiting miR‐93‐5p in renal tubular cells. FEBS J., 2023, 290(16), 4040-4056. doi: 10.1111/febs.16794 PMID: 37029581
  74. Li, Z.Y.; Xie, Y.; Deng, M.; Zhu, L.; Wu, X.; Li, G.; Shi, N.X.; Wen, C.; Huang, W.; Duan, Y.; Yin, Z.; Lin, X.J. c-Myc-activated intronic miR-210 and lncRNA MIR210HG synergistically promote the metastasis of gastric cancer. Cancer Lett., 2022, 526, 322-334. doi: 10.1016/j.canlet.2021.11.006 PMID: 34767926
  75. Wang, A.H.; Jin, C.H.; Cui, G.Y.; Li, H.Y.; Wang, Y.; Yu, J.J.; Wang, R.F.; Tian, X.Y. MIR210HG promotes cell proliferation and invasion by regulating miR-503-5p/TRAF4 axis in cervical cancer. Aging (Albany NY), 2020, 12(4), 3205-3217. doi: 10.18632/aging.102799 PMID: 32087604
  76. Yu, T.; Li, G.; Wang, C.; Gong, G.; Wang, L.; Li, C.; Chen, Y.; Wang, X. MIR210HG regulates glycolysis, cell proliferation, and metastasis of pancreatic cancer cells through miR-125b-5p/HK2/PKM2 axis. RNA Biol., 2021, 18(12), 2513-2530. doi: 10.1080/15476286.2021.1930755 PMID: 34110962
  77. Bedard, K.; Jaquet, V.; Krause, K.H. NOX5: From basic biology to signaling and disease. Free Radic. Biol. Med., 2012, 52(4), 725-734. doi: 10.1016/j.freeradbiomed.2011.11.023 PMID: 22182486
  78. Salcher, S.; Hermann, M.; Kiechl-Kohlendorfer, U.; Ausserlechner, M.J.; Obexer, P. C10ORF10/DEPP-mediated ROS accumulation is a critical modulator of FOXO3-induced autophagy. Mol. Cancer, 2017, 16(1), 95. doi: 10.1186/s12943-017-0661-4 PMID: 28545464
  79. Tong, S.; Xia, T.; Fan, K.; Jiang, K.; Zhai, W.; Li, J-S.; Wang, S-H.; Wang, J-J. Loss of Par3 promotes lung adenocarcinoma metastasis through 14-3-3ζ protein. Oncotarget, 2016, 7(39), 64260-64273. doi: 10.18632/oncotarget.11728 PMID: 27588399
  80. Zhou, P.J.; Wang, X.; An, N.; Wei, L.; Zhang, L.; Huang, X.; Zhu, H.H.; Fang, Y.X.; Gao, W.Q. Loss of Par3 promotes prostatic tumorigenesis by enhancing cell growth and changing cell division modes. Oncogene, 2019, 38(12), 2192-2205. doi: 10.1038/s41388-018-0580-x PMID: 30467379
  81. Stacker, S.; Achen, M. Emerging roles for VEGF-D in human disease. Biomolecules, 2018, 8(1), 1. doi: 10.3390/biom8010001 PMID: 29300337
  82. Zhang, Q.; Zheng, L.; Bai, Y.; Su, C.; Che, Y.; Xu, J.; Sun, K.; Ni, J.; Huang, L.; Shen, Y.; Jia, L.; Xu, L.; Yin, R.; Li, M.; Hu, J. ITPR1-AS1 promotes small cell lung cancer metastasis by facilitating P21 splicing and stabilizing DDX3X to activate the cRaf-MEK-ERK cascade. Cancer Lett., 2023, 577, 216426. doi: 10.1016/j.canlet.2023.216426 PMID: 37820992
  83. Wu, D.; Li, D.; Liu, Z.; Liu, X.; Zhou, S.; Duan, H. Role and underlying mechanism of SPATA12 in oxidative damage. Oncol. Lett., 2018, 15(3), 3676-3684. doi: 10.3892/ol.2018.7749 PMID: 29467887
  84. Dan, L.; Lifang, Y.; Guangxiu, L. Expression and possible functions of a novel gene SPATA12 in human testis. J. Androl., 2007, 28(4), 502-512. doi: 10.2164/jandrol.106.001560 PMID: 17251597
  85. Zhang, Y.; Yang, L.; Lin, Y.; Rong, Z.; Liu, X.; Li, D. SPATA12 and its possible role in DNA damage induced by ultraviolet-C. PLoS One, 2013, 8(10), e78201. doi: 10.1371/journal.pone.0078201 PMID: 24205157
  86. Aguilar-Rojas, A.; Huerta-Reyes, M.; Maya-Núñez, G.; Arechavaleta-Velásco, F.; Conn, P.M.; Ulloa-Aguirre, A.; Valdés, J. Gonadotropin-releasing hormone receptor activates GTPase RhoA and inhibits cell invasion in the breast cancer cell line MDA-MB-231. BMC Cancer, 2012, 12(1), 550. doi: 10.1186/1471-2407-12-550 PMID: 23176180
  87. Dondi, D.; Festuccia, C.; Piccolella, M.; Bologna, M.; Motta, M. GnRH agonists and antagonists decrease the metastatic progression of human prostate cancer cell lines by inhibiting the plasminogen activator system. Oncol. Rep., 2006, 15(2), 393-400. doi: 10.3892/or.15.2.393 PMID: 16391860
  88. Emons, G.; Müller, V.; Ortmann, O.; Schulz, K.D. Effects of LHRH-analogues on mitogenic signal transduction in cancer cells. J. Steroid Biochem. Mol. Biol., 1998, 65(1-6), 199-206. doi: 10.1016/S0960-0760(97)00189-1 PMID: 9699874
  89. Fister, S.; Günthert, A.R.; Emons, G.; Gründker, C. Gonadotropin-releasing hormone type II antagonists induce apoptotic cell death in human endometrial and ovarian cancer cells in vitro and in vivo . Cancer Res., 2007, 67(4), 1750-1756. doi: 10.1158/0008-5472.CAN-06-3222 PMID: 17308117
  90. Suo, L.; Chang, X.; Xu, N.; Ji, H. The anti-proliferative activity of GnRH through downregulation of the Akt/ERK Pathways in pancreatic cancer. Front. Endocrinol. (Lausanne), 2019, 10, 370. doi: 10.3389/fendo.2019.00370 PMID: 31263453
  91. von Alten, J.; Fister, S.; Schulz, H.; Viereck, V.; Frosch, K.H.; Emons, G.; Gründker, C. GnRH analogs reduce invasiveness of human breast cancer cells. Breast Cancer Res. Treat., 2006, 100(1), 13-21. doi: 10.1007/s10549-006-9222-z PMID: 16758121
  92. Du, J.; Xiang, Y.; Liu, H.; Liu, S.; Kumar, A.; Xing, C.; Wang, Z. RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis. Nat. Commun., 2021, 12(1), 7067. doi: 10.1038/s41467-021-27367-5 PMID: 34862394
  93. Zhuo, X.; Chen, L.; Lai, Z.; Liu, J.; Li, S.; Hu, A.; Lin, Y. Protein phosphatase 1 regulatory subunit 3G (PPP1R3G) correlates with poor prognosis and immune infiltration in lung adenocarcinoma. Bioengineered, 2021, 12(1), 8336-8346. doi: 10.1080/21655979.2021.1985817 PMID: 34592886
  94. Niedernberg, A.; Tunaru, S.; Blaukat, A.; Ardati, A.; Kostenis, E. Sphingosine 1-phosphate and dioleoylphosphatidic acid are low affinity agonists for the orphan receptor GPR63. Cell. Signal., 2003, 15(4), 435-446. doi: 10.1016/S0898-6568(02)00119-5 PMID: 12618218
  95. Zeng, S.; Liang, Y.; Hu, H.; Wang, F.; Liang, L. Endothelial cell-derived S1P promotes migration and stemness by binding with GPR63 in colorectal cancer. Pathol. Res. Pract., 2022, 240, 154197. doi: 10.1016/j.prp.2022.154197 PMID: 36371997
  96. Diao, L.; Wang, S.; Sun, Z. Long noncoding RNA GAPLINC promotes gastric cancer cell proliferation by acting as a molecular sponge of miR-378 to modulate MAPK1 expression. OncoTargets Ther., 2018, 11, 2797-2804. doi: 10.2147/OTT.S165147 PMID: 29785127
  97. Hu, Y.; Wang, J.; Qian, J.; Kong, X.; Tang, J.; Wang, Y.; Chen, H.; Hong, J.; Zou, W.; Chen, Y.; Xu, J.; Fang, J.Y. Long noncoding RNA GAPLINC regulates CD44-dependent cell invasiveness and associates with poor prognosis of gastric cancer. Cancer Res., 2014, 74(23), 6890-6902. doi: 10.1158/0008-5472.CAN-14-0686 PMID: 25277524
  98. Luo, Y.; Ouyang, J.; Zhou, D.; Zhong, S.; Wen, M.; Ou, W.; Yu, H.; Jia, L.; Huang, Y.; Long Noncoding, R.N.A. Long noncoding RNA GAPLINC promotes cells migration and invasion in colorectal cancer cell by regulating miR-34a/c-MET signal pathway. Dig. Dis. Sci., 2018, 63(4), 890-899. doi: 10.1007/s10620-018-4915-9 PMID: 29427222
  99. Wang, S.; Pang, L.; Liu, Z.; Meng, X. SERPINE1 associated with remodeling of the tumor microenvironment in colon cancer progression: A novel therapeutic target. BMC Cancer, 2021, 21(1), 767. doi: 10.1186/s12885-021-08536-7 PMID: 34215248
  100. Sheng, Y.H.; He, Y.; Hasnain, S.Z.; Wang, R.; Tong, H.; Clarke, D.T.; Lourie, R.; Oancea, I.; Wong, K.Y.; Lumley, J.W.; Florin, T.H.; Sutton, P.; Hooper, J.D.; McMillan, N.A.; McGuckin, M.A. MUC13 protects colorectal cancer cells from death by activating the NF-κB pathway and is a potential therapeutic target. Oncogene, 2017, 36(5), 700-713. doi: 10.1038/onc.2016.241 PMID: 27399336
  101. Sheng, Y.; Wong, K.Y.; Seim, I.; Wang, R.; He, Y.; Wu, A.; Patrick, M.; Lourie, R.; Schreiber, V.; Giri, R.; Ng, C.P.; Popat, A.; Hooper, J.; Kijanka, G.; Florin, T.H.; Begun, J.; Radford, K.J.; Hasnain, S.; McGuckin, M.A. MUC13 promotes the development of colitis-associated colorectal tumors via β-catenin activity. Oncogene, 2019, 38(48), 7294-7310. doi: 10.1038/s41388-019-0951-y PMID: 31427737
  102. Chen, C.I.; Li, W.S.; Chen, H.P.; Liu, K.W.; Tsai, C.J.; Hung, W.J.; Yang, C.C. High expression of folate receptor alpha (FOLR1) is Associated with aggressive tumor behavior, poor response to chemoradiotherapy, and worse survival in rectal cancer. Technol. Cancer Res. Treat., 2022, 21, 15330338221141795. doi: 10.1177/15330338221141795 PMID: 36426547
  103. Nawaz, F.Z.; Kipreos, E.T. Emerging roles for folate receptor FOLR1 in signaling and cancer. Trends Endocrinol. Metab., 2022, 33(3), 159-174. doi: 10.1016/j.tem.2021.12.003 PMID: 35094917
  104. Bouchard, D.; Morisset, D.; Bourbonnais, Y.; Tremblay, G.M. Proteins with whey-acidic-protein motifs and cancer. Lancet Oncol., 2006, 7(2), 167-174. doi: 10.1016/S1470-2045(06)70579-4 PMID: 16455481
  105. Madar, S.; Brosh, R.; Buganim, Y.; Ezra, O.; Goldstein, I.; Solomon, H.; Kogan, I.; Goldfinger, N.; Klocker, H.; Rotter, V. Modulated expression of WFDC1 during carcinogenesis and cellular senescence. Carcinogenesis, 2009, 30(1), 20-27. doi: 10.1093/carcin/bgn232 PMID: 18842679
  106. Liang, R.J.; Taylor, S.; Nahiyaan, N.; Song, J.; Murphy, C.J.; Dantas, E.; Cheng, S.; Hsu, T.W.; Ramsamooj, S.; Grover, R.; Hwang, S.K.; Ngo, B.; Cantley, L.C.; Rhee, K.Y.; Goncalves, M.D. GLUT5 (SLC2A5) enables fructose-mediated proliferation independent of ketohexokinase. Cancer Metab., 2021, 9(1), 12. doi: 10.1186/s40170-021-00246-9 PMID: 33762003
  107. Weng, Y.; Fan, X.; Bai, Y.; Wang, S.; Huang, H.; Yang, H.; Zhu, J.; Zhang, F. SLC2A5 promotes lung adenocarcinoma cell growth and metastasis by enhancing fructose utilization. Cell Death Discov., 2018, 4(1), 38. doi: 10.1038/s41420-018-0038-5 PMID: 29531835
  108. Luo, W.; Gangwal, K.; Sankar, S.; Boucher, K.M.; Thomas, D.; Lessnick, S.L. GSTM4 is a microsatellite-containing EWS/FLI target involved in Ewing’s sarcoma oncogenesis and therapeutic resistance. Oncogene, 2009, 28(46), 4126-4132. doi: 10.1038/onc.2009.262 PMID: 19718047
  109. Hemming, M.L.; Coy, S.; Lin, J.R.; Andersen, J.L.; Przybyl, J.; Mazzola, E.; Abdelhamid Ahmed, A.H.; van de Rijn, M.; Sorger, P.K.; Armstrong, S.A.; Demetri, G.D.; Santagata, S. HAND1 and BARX1 act as transcriptional and anatomic determinants of malignancy in gastrointestinal stromal tumor. Clin. Cancer Res., 2021, 27(6), 1706-1719. doi: 10.1158/1078-0432.CCR-20-3538 PMID: 33451979
  110. Hemming, M.L.; Lawlor, M.A.; Zeid, R.; Lesluyes, T.; Fletcher, J.A.; Raut, C.P.; Sicinska, E.T.; Chibon, F.; Armstrong, S.A.; Demetri, G.D.; Bradner, J.E. Gastrointestinal stromal tumor enhancers support a transcription factor network predictive of clinical outcome. Proc. Natl. Acad. Sci. USA, 2018, 115(25), E5746-E5755. doi: 10.1073/pnas.1802079115 PMID: 29866822
  111. Huang, X.; Wang, Z.; Zhang, J.; Ni, X.; Bai, G.; Cao, J.; Zhang, C.; Han, Z.; Liu, T. BARX1 promotes osteosarcoma cell proliferation and invasion by regulating HSPA6 expression. J. Orthop. Surg. Res., 2023, 18(1), 211. doi: 10.1186/s13018-023-03690-z PMID: 36927457
  112. Sun, G.; Ge, Y.; Zhang, Y.; Yan, L.; Wu, X.; Ouyang, W.; Wang, Z.; Ding, B.; Zhang, Y.; Long, G.; Liu, M.; Shi, R.; Zhou, H.; Chen, Z.; Ye, Z. Transcription factors BARX1 and DLX4 contribute to progression of clear cell renal cell carcinoma via promoting proliferation and epithelial–mesenchymal transition. Front. Mol. Biosci., 2021, 8, 626328. doi: 10.3389/fmolb.2021.626328 PMID: 34124141
  113. Zhang, T.; Qiu, L.; Cao, J.; Li, Q.; Zhang, L.; An, G.; Ni, J.; Jia, H.; Li, S.; Li, K. ZFP36 loss-mediated BARX1 stabilization promotes malignant phenotypes by transactivating master oncogenes in NSCLC. Cell Death Dis., 2023, 14(8), 527. doi: 10.1038/s41419-023-06044-z PMID: 37587140
  114. Kumar, D.; Asthana, S. Autophagy and metabolism: Potential target for cancer therapy; Academic Press: London, United Kingdom; San Diego, CA, 2022.
  115. Boese, A.C.; Kang, S. Mitochondrial metabolism-mediated redox regulation in cancer progression. Redox Biol., 2021, 42, 101870. doi: 10.1016/j.redox.2021.101870 PMID: 33509708
  116. Shi, T.; Polderman, P.E.; Pagès-Gallego, M.; van Es, R.M.; Vos, H.R.; Burgering, B.M.T.; Dansen, T.B. p53 forms redox-dependent protein–protein interactions through cysteine 277. Antioxidants, 2021, 10(10), 1578. doi: 10.3390/antiox10101578 PMID: 34679713
  117. He, Z.; Simon, H.U. A novel link between p53 and ROS. Cell Cycle, 2013, 12(2), 201-202. doi: 10.4161/cc.23418 PMID: 23287470
  118. Montero, J.; Dutta, C.; van Bodegom, D.; Weinstock, D.; Letai, A. p53 regulates a non-apoptotic death induced by ROS. Cell Death Differ., 2013, 20(11), 1465-1474. doi: 10.1038/cdd.2013.52 PMID: 23703322
  119. Santos, P.A.S.R.; Avanço, G.B.; Nerilo, S.B.; Marcelino, R.I.A.; Janeiro, V.; Valadares, M.C.; Machinski, M. Assessment of cytotoxic activity of rosemary ( Rosmarinus officinalis L.), turmeric ( Curcuma longa L.), and ginger ( Zingiber officinale R.) essential oils in cervical cancer cells (HeLa). ScientificWorldJournal, 2016, 2016, 1-8. doi: 10.1155/2016/9273078 PMID: 28042599
  120. Rezaieseresht, H.; Shobeiri, S.S.; Kaskani, A. Chenopodium botrys essential oil as a source of sesquiterpenes to induce apoptosis and G1 cell cycle arrest in cervical cancer cells. Iran. J. Pharm. Res., 2020, 19(2), 341-351. PMID: 33224241
  121. Nikakhtar, Z.; Hasanzadeh, M.; Hamedi, S.S.; Najafi, M.N.; Tavassoli, A.P.; Feyzabadi, Z.; Meshkat, Z.; Saki, A. The efficacy of vaginal suppository based on myrtle in patients with cervicovaginal human papillomavirus infection: A randomized, double‐blind, placebo trial. Phytother. Res., 2018, 32(10), 2002-2008. doi: 10.1002/ptr.6131 PMID: 29943384
  122. Puškárová, A.; Bučková, M.; Kraková, L.; Pangallo, D.; Kozics, K. The antibacterial and antifungal activity of six essential oils and their cyto/genotoxicity to human HEL 12469 cells. Sci. Rep., 2017, 7(1), 8211. doi: 10.1038/s41598-017-08673-9 PMID: 28811611
  123. McGregor, R.C.; Parker, K.A.; Hornby, J.M.; Latta, L.C., IV Microbial population dynamics under microdoses of the essential oil arborvitae. BMC Complement. Altern. Med., 2019, 19(1), 247. doi: 10.1186/s12906-019-2666-6 PMID: 31488126
  124. Reis, D.; Jones, T. Aromatherapy: Using essential oils as a supportive therapy. Clin. J. Oncol. Nurs., 2017, 21(1), 16-19. doi: 10.1188/17.CJON.16-19 PMID: 28107335

Supplementary files

Supplementary Files
Action
1. JATS XML

Copyright (c) 2024 Bentham Science Publishers