{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T22:23:19Z","timestamp":1776205399849,"version":"3.50.1"},"reference-count":80,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,15]],"date-time":"2022-10-15T00:00:00Z","timestamp":1665792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["UIDB\/04567\/2020"],"award-info":[{"award-number":["UIDB\/04567\/2020"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["UIDP\/04567\/2020"],"award-info":[{"award-number":["UIDP\/04567\/2020"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["UI\/BD\/151422\/2021"],"award-info":[{"award-number":["UI\/BD\/151422\/2021"]}]},{"name":"FCT","award":["UIDB\/04567\/2020"],"award-info":[{"award-number":["UIDB\/04567\/2020"]}]},{"name":"FCT","award":["UIDP\/04567\/2020"],"award-info":[{"award-number":["UIDP\/04567\/2020"]}]},{"name":"FCT","award":["UI\/BD\/151422\/2021"],"award-info":[{"award-number":["UI\/BD\/151422\/2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Plectranthus ornatus Codd, the genus Plectranthus of the Lamiaceae family, has been used as traditional medicine in Africa, India and Australia. Pharmacological studies show the use of this plant to treat digestive problems. In turn, leaves were used for their antibiotic properties in some regions of Brazil to treat skin infections. The present study examines the anti-inflammatory, antioxidant and cytotoxic effects of the halimane and labdane diterpenes (11R*,13E)-11-acetoxyhalima-5,13-dien-15-oic acid (HAL) and 1\u03b1,6\u03b2-diacetoxy-8\u03b1,13R*-epoxy-14-labden-11-one (PLEC) and the forskolin-like 1:1 mixture of 1,6-di-O-acetylforskolin and 1,6-di-O-acetyl-9-deoxyforskolin (MRC) isolated from P. ornatus on lung (A549) and leukemia (CCRF-CEM) cancer cell lines, and on normal human retinal pigment epithelial (ARPE-19) cell line in vitro. Additionally, molecular docking and computational approaches were used. ADMET properties were analysed through SwissADME and proTox-II\u2014Prediction. The results indicate that all tested compounds significantly reduced the viability of the cancer cells and demonstrated no cytotoxic effects against the non-neoplastic cell line. The apoptosis indicators showed increased ROS levels for both the tested A549 and CCRF-CEM cancer cell lines after treatment. Furthermore, computational studies found HAL to exhibit moderate antioxidant activity. In addition, selected compounds changed mitochondrial membrane potential (MMP), and increased DNA damage and mitochondrial copy number for the CCRF-CEM cancer cell line; they also demonstrated anti-inflammatory effects on the ARPE-19 normal cell line upon lipopolysaccharide (LPS) treatment, which was associated with the modulation of IL-6, IL-8, TNF-\u03b1 and GM-CSF genes expression. Docking studies gave indication about the lowest binding energy for 1,6-di-O-acetylforskolin docked into IL-6, TNF-\u03b1 and GM-CSF, and 1,6-di-O-acetyl-9-deoxyforskolin docked into IL-8. The ADMET studies showed drug-likeness properties for the studied compounds. Thus, halimane and labdane diterpenes isolated from P. ornatus appear to offer biological potential; however, further research is necessary to understand their interactions and beneficial properties.<\/jats:p>","DOI":"10.3390\/cells11203243","type":"journal-article","created":{"date-parts":[[2022,10,16]],"date-time":"2022-10-16T21:10:10Z","timestamp":1665954610000},"page":"3243","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["An Evaluation of the Novel Biological Properties of Diterpenes Isolated from Plectranthus ornatus Codd. In Vitro and In Silico"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5495-3550","authenticated-orcid":false,"given":"Przemys\u0142aw","family":"Sitarek","sequence":"first","affiliation":[{"name":"Department of Biology and Pharmaceutical Botany, Medical University of Lodz, ul. Muszy\u0144skiego 1, 90-151 Lodz, Poland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4559-5015","authenticated-orcid":false,"given":"Tomasz","family":"Kowalczyk","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-237 Lodz, Poland"}]},{"given":"Ewelina","family":"Synowiec","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9987-4573","authenticated-orcid":false,"given":"Anna","family":"Merecz-Sadowska","sequence":"additional","affiliation":[{"name":"Department of Computer Science in Economics, University of Lodz, 90-214 Lodz, Poland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2545-1812","authenticated-orcid":false,"given":"Gabrielle","family":"Bangay","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Lus\u00f3fona University\u2019s Research Center for Biosciences and Health Technologies, 1749-024 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3440-8373","authenticated-orcid":false,"given":"Salvatore","family":"Princiotto","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Lus\u00f3fona University\u2019s Research Center for Biosciences and Health Technologies, 1749-024 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8385-7744","authenticated-orcid":false,"given":"Tomasz","family":"\u015aliwi\u0144ski","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7992-8343","authenticated-orcid":false,"given":"Patricia","family":"Rijo","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-237 Lodz, Poland"},{"name":"CBIOS\u2014Lus\u00f3fona University\u2019s Research Center for Biosciences and Health Technologies, 1749-024 Lisbon, Portugal"},{"name":"Instituto de Investiga\u00e7\u00e3o do Medicamento (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,15]]},"reference":[{"key":"ref_1","first-page":"210","article-title":"The Role and Place of Medicinal Plants in the Strategies for Disease Prevention","volume":"10","author":"Sofowora","year":"2013","journal-title":"Afr. J. Tradit. Complement. Altern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Yuan, H., Ma, Q., Ye, L., and Piao, G. (2016). The Traditional Medicine and Modern Medicine from Natural Products. Molecules, 21.","DOI":"10.3390\/molecules21050559"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Krause, J., and Tobin, G. (2013). Discovery, Development, and Regulation of Natural Products. Using Old Solutions to New Problems\u2014Natural Drug Discovery in the 21st Century, IntechOpen.","DOI":"10.5772\/56424"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.3389\/fpls.2021.691462","article-title":"Utilizing Plant Synthetic Biology to Improve Human Health and Wellness","volume":"12","author":"Barnum","year":"2021","journal-title":"Front. Plant Sci."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kowalczyk, T., Merecz-Sadowska, A., Rijo, P., Mori, M., Hatziantoniou, S., G\u00f3rski, K., Szemraj, J., Piekarski, J., \u015aliwi\u0144ski, T., and Bijak, M. (2022). Hidden in Plants\u2014A Review of the Anticancer Potential of the Solanaceae Family in In Vitro and In Vivo Studies. Cancers, 14.","DOI":"10.3390\/cancers14061455"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.2174\/1389201023666220304095225","article-title":"In Vitro and In Silico Studies on Leonotis Nepetifolia (L.) R. Br. Root Extract against Cancer Cells","volume":"23","author":"Sitarek","year":"2022","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kowalczyk, T., Merecz-Sadowska, A., Rijo, P., Isca, V.M.S., Picot, L., Wielanek, M., \u015aliwi\u0144ski, T., and Sitarek, P. (2021). Preliminary Phytochemical Analysis and Evaluation of the Biological Activity of Leonotis Nepetifolia (L.) R. Br Transformed Roots Extracts Obtained through Rhizobium Rhizogenes-Mediated Transformation. Cells, 10.","DOI":"10.3390\/cells10051242"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kowalczyk, T., Sitarek, P., Merecz-Sadowska, A., Szyposzy\u0144ska, M., Sp\u0142awska, A., Gorniak, L., Bijak, M., and \u015aliwi\u0144ski, T. (2021). Methyl Jasmonate Effect on Betulinic Acid Content and Biological Properties of Extract from Senna Obtusifolia Transgenic Hairy Roots. Molecules, 26.","DOI":"10.3390\/molecules26206208"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"\u015aliwi\u0144ski, T., Sitarek, P., Ska\u0142a, E., Isca, V.M.S., Synowiec, E., Kowalczyk, T., Bijak, M., and Rijo, P. (2020). Diterpenoids from Plectranthus Spp. as Potential Chemotherapeutic Agents via Apoptosis. Pharmaceuticals, 13.","DOI":"10.3390\/ph13060123"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sitarek, P., Toma, M., Ntungwe, E., Kowalczyk, T., Ska\u0142a, E., Wieczfinska, J., \u015aliwi\u0144ski, T., and Rijo, P. (2020). Insight the Biological Activities of Selected Abietane Diterpenes Isolated from Plectranthus spp.. Biomolecules, 10.","DOI":"10.3390\/biom10020194"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.sajb.2011.07.001","article-title":"Plectranthus: A Plant for the Future?","volume":"77","author":"Rice","year":"2011","journal-title":"South Afr. J. Bot."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jep.2005.09.011","article-title":"Plectranthus: A Review of Ethnobotanical Uses","volume":"103","author":"Lukhoba","year":"2006","journal-title":"J. Ethnopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3390\/70200271","article-title":"Chemistry of the Genus Plectranthus","volume":"7","author":"Albar","year":"2002","journal-title":"Molecules"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1002\/cbdv.201000048","article-title":"The Genus Plectranthus in India and Its Chemistry","volume":"8","author":"Waldia","year":"2011","journal-title":"Chem. Biodivers."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1590\/0001-3765201720170068","article-title":"Antibiotic Activity of Plectranthus Ornatus Codd., a Traditional Medicinal Plant","volume":"89","author":"Nascimento","year":"2017","journal-title":"An. Acad. Bras. Ci\u00eancias"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1006\/anbo.1999.0937","article-title":"Glandular Trichomes on the Leaves and Flowers of Plectranthus Ornatus: Morphology, Distribution and Histochemistry","volume":"84","author":"Mota","year":"1999","journal-title":"Ann. Bot."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10320","DOI":"10.3390\/molecules180910320","article-title":"Volatile Organic Compounds Obtained by in Vitro Callus Cultivation of Plectranthus Ornatus Codd. (Lamiaceae)","volume":"18","author":"Meira","year":"2013","journal-title":"Molecules"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1021\/np020203w","article-title":"Neoclerodane and Labdane Diterpenoids from Plectranthus Ornatus","volume":"65","author":"Rijo","year":"2002","journal-title":"J. Nat. Prod."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.bse.2006.10.011","article-title":"Further Diterpenoids from Plectranthus Ornatus and P. Grandidentatus","volume":"35","author":"Rijo","year":"2007","journal-title":"Biochem. Syst. Ecol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/mrc.1600","article-title":"Structural and Spectral Assignment of Three Forskolin-like Diterpenoids Isolated from Plectranthus Ornatus","volume":"43","author":"Rijo","year":"2005","journal-title":"Magn. Reson. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Sitarek, P., Synowiec, E., Kowalczyk, T., Bangay, G., \u015aliwi\u0144ski, T., Picot, L., Princiotto, S., and Rijo, P. (2022). Anticancer Properties of Plectranthus ornatus-Derived Phytochemicals Inducing Apoptosis via Mitochondrial Pathway. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911653"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Reiniers, M.J., de Haan, L.R., Reeskamp, L.F., Broekgaarden, M., van Golen, R.F., and Heger, M. (2021). Analysis and Optimization of Conditions for the Use of 2\u2032,7\u2032-Dichlorofluorescein Diacetate in Cultured Hepatocytes. Antioxidants, 10.","DOI":"10.3390\/antiox10050674"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e3128","DOI":"10.21769\/BioProtoc.3128","article-title":"Analysis of the Mitochondrial Membrane Potential Using the Cationic JC-1 Dye as a Sensitive Fluorescent Probe","volume":"9","author":"Sivandzade","year":"2019","journal-title":"Bio-Protocol"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Bijak, M., Synowiec, E., Sitarek, P., Sliwi\u0144ski, T., and Saluk-Bijak, J. (2017). Evaluation of the Cytotoxicity and Genotoxicity of Flavonolignans in Different Cellular Models. Nutrients, 9.","DOI":"10.3390\/nu9121356"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ceremuga, M., Stela, M., Janik, E., Gorniak, L., Synowiec, E., Sliwinski, T., Sitarek, P., Saluk-Bijak, J., and Bijak, M. (2020). Melittin\u2014A Natural Peptide from Bee Venom Which Induces Apoptosis in Human Leukaemia Cells. Biomolecules, 10.","DOI":"10.3390\/biom10020247"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Sitarek, P., Synowiec, E., Kowalczyk, T., \u015aliwi\u0144ski, T., and Ska\u0142a, E. (2018). An In Vitro Estimation of the Cytotoxicity and Genotoxicity of Root Extract from Leonurus Sibiricus L. Overexpressing AtPAP1 against Different Cancer Cell Lines. Molecules, 23.","DOI":"10.3390\/molecules23082049"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/0014-4827(88)90265-0","article-title":"A Simple Technique for Quantitation of Low Levels of DNA Damage in Individual Cells","volume":"175","author":"Singh","year":"1988","journal-title":"Exp. Cell Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/0921-8777(95)00063-1","article-title":"The Comet Assay: Mechanisms and Technical Considerations","volume":"363","author":"Klaude","year":"1996","journal-title":"Mutat. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1093\/mutage\/gel019","article-title":"HOGG1 Recognizes Oxidative Damage Using the Comet Assay with Greater Specificity than FPG or ENDOIII","volume":"21","author":"Smith","year":"2006","journal-title":"Mutagenesis"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing Real-Time PCR Data by the Comparative CT Method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1021\/acs.jchemed.0c00959","article-title":"Computational Chemistry Activities with Avogadro and ORCA","volume":"98","author":"Snyder","year":"2021","journal-title":"J. Chem. Educ."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1021\/ed074p905","article-title":"ACD\/ChemSketch 1.0 (Freeware); ACD\/ChemSketch 2.0 and Its Tautomers, Dictionary, and 3D Plug-Ins; ACD\/HNMR 2.0; ACD\/CNMR 2.0","volume":"74","author":"Hunter","year":"1997","journal-title":"J. Chem. Educ."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An Open Chemical Toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1002\/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B","article-title":"Automated Docking Using a Lamarckian Genetic Algorithm and an Empirical Binding Free Energy Function","volume":"19","author":"Morris","year":"1998","journal-title":"J. Comput. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1039\/D0RA09995C","article-title":"The Importance of Intramolecular Hydrogen Bonds on the Translocation of the Small Drug Piracetam through a Lipid Bilayer","volume":"11","author":"Coimbra","year":"2021","journal-title":"RSC Adv."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-likeness and Medicinal Chemistry Friendliness of Small Molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"576559","DOI":"10.3389\/fonc.2020.576559","article-title":"P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers","volume":"10","author":"Seelig","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2007.10.024","article-title":"Cytochrome P450s in the development of target-based anticancer drugs","volume":"259","author":"Purnapatre","year":"2008","journal-title":"Cancer Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"200","DOI":"10.4103\/2231-4040.104709","article-title":"Natural Products Derived from Plants as a Source of Drugs","volume":"3","author":"Veeresham","year":"2012","journal-title":"J. Adv. Pharm. Technol. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"397","DOI":"10.3389\/fphar.2020.00397","article-title":"Unraveling Plant Natural Chemical Diversity for Drug Discovery Purposes","volume":"11","author":"Russo","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1016\/j.biotechadv.2015.08.001","article-title":"Discovery and Resupply of Pharmacologically Active Plant-Derived Natural Products: A Review","volume":"33","author":"Atanasov","year":"2015","journal-title":"Biotechnol. Adv."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1002\/ppp3.10138","article-title":"Molecules from Nature: Reconciling Biodiversity Conservation and Global Healthcare Imperatives for Sustainable Use of Medicinal Plants and Fungi","volume":"2","author":"Howes","year":"2020","journal-title":"Plants People Planet"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"627375","DOI":"10.1155\/2013\/627375","article-title":"New Perspectives on How to Discover Drugs from Herbal Medicines: CAM\u2019s Outstanding Contribution to Modern Therapeutics","volume":"2013","author":"Pan","year":"2013","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Bhat, S.G. (2021). Medicinal Plants and Its Pharmacological Values. Natural Medicinal Plants, IntechOpen.","DOI":"10.4018\/978-1-7998-2094-9.ch004"},{"key":"ref_46","unstructured":"St\u00e9phane, F.F.Y., Jules, B.K.J., Batiha, G.E.-S., Ali, I., and Bruno, L.N. (2021). Extraction of Bioactive Compounds from Medicinal Plants and Herbs. Natural Medicinal Plants, IntechOpen."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S1572-5995(01)80009-0","article-title":"Labdane-Type Diterpenes: Chemistry and Biological Activity","volume":"25","author":"Demetzos","year":"2001","journal-title":"Stud. Nat. Prod. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Mani, V., Park, S., Kim, J.A., Lee, S.I., and Lee, K. (2021). Metabolic Perturbation and Synthetic Biology Strategies for Plant Terpenoid Production\u2014An Updated Overview. Plants, 10.","DOI":"10.3390\/plants10102179"},{"key":"ref_49","first-page":"497","article-title":"Diterpene Lactones with Labdane, Halimane and Clerodane Frameworks","volume":"6","author":"Silva","year":"2011","journal-title":"Nat. Prod. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1039\/C8NP00016F","article-title":"Halimane Diterpenoids: Sources, Structures, Nomenclature and Biological Activities","volume":"35","author":"Roncero","year":"2018","journal-title":"Nat. Prod. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"12450","DOI":"10.1002\/slct.202002836","article-title":"Diterpenoids: Natural Distribution, Semisynthesis at Room Temperature and Pharmacological Aspects\u2014A Decade Update","volume":"5","author":"Majhi","year":"2020","journal-title":"ChemistrySelect"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"820312","DOI":"10.3389\/fphar.2021.820312","article-title":"Antimicrobial Diterpenes: Recent Development From Natural Sources","volume":"12","author":"Saha","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Seaman, F., Bohlmann, F., Zdero, C., and Mabry, T.J. (1990). Biological Activity of Diterpenes. Diterpenes Flower. Plants, Springer.","DOI":"10.1007\/978-1-4612-3274-2"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1016\/j.phytochem.2010.04.019","article-title":"Cytotoxic Terpenoids from Nardophyllum Bryoides","volume":"71","author":"Mazzuca","year":"2010","journal-title":"Phytochemistry"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1002\/cbdv.201500071","article-title":"Structure Elucidation, Antimicrobial and Cytotoxic Activities of a Halimane Isolated from Vellozia Kolbekii Alves (Velloziaceae)","volume":"12","author":"Silva","year":"2015","journal-title":"Chem. Biodivers."},{"key":"ref_56","first-page":"11","article-title":"Isolation and Absolute Configuration of Ent-Halimane Diterpenoids from Hymenaea Courbaril from the Suriname Rain Forest1","volume":"65","author":"Berger","year":"2001","journal-title":"J. Nat. Prod."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.ab.2017.07.009","article-title":"Mitochondrial Membrane Potential","volume":"552","author":"Zorova","year":"2018","journal-title":"Anal. Biochem."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"K\u00fchlbrandt, W. (2015). Structure and Function of Mitochondrial Membrane Protein Complexes. BMC Biol., 13.","DOI":"10.1186\/s12915-015-0201-x"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1146\/annurev-genet-102108-134850","article-title":"The Role of Mitochondria in Apoptosis*","volume":"43","author":"Wang","year":"2009","journal-title":"Annu. Rev. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.trecan.2017.10.006","article-title":"Mitochondria, Bioenergetics and Apoptosis in Cancer","volume":"3","author":"Burke","year":"2017","journal-title":"Trends Cancer"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"35895","DOI":"10.1038\/srep35859","article-title":"Altered Mitochondrial DNA Copy Number Contributes to Human Cancer Risk: Evidence from an Updated Meta-Analysis","volume":"6","author":"Hu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.molmed.2006.07.007","article-title":"DNA Damage-Induced Cell Death by Apoptosis","volume":"12","author":"Roos","year":"2006","journal-title":"Trends Mol. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1021\/acs.jcim.2c00104","article-title":"Current Trends in Computational Quantum Chemistry Studies on Antioxidant Radical Scavenging Activity","volume":"2022","author":"Spiegel","year":"2022","journal-title":"J. Chem. Inf. Model."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1055\/s-2007-990230","article-title":"Andrographolide Inhibits Human Hepatoma-Derived Hep3B Cell Growth through the Activation of c-Jun N-Terminal Kinase","volume":"73","author":"Ji","year":"2007","journal-title":"Planta Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.fitote.2017.06.006","article-title":"Diterpenoids with Diverse Scaffolds from Vitex Trifolia as Potential Topoisomerase I Inhibitor","volume":"120","author":"Luo","year":"2017","journal-title":"Fitoterapia"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"7204","DOI":"10.18632\/oncotarget.23208","article-title":"Inflammatory Responses and Inflammation-Associated Diseases in Organs","volume":"9","author":"Chen","year":"2017","journal-title":"Oncotarget"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Das, U.N. (2011). Inflammation. Molecular Basis of Health and Disease, Springer.","DOI":"10.1007\/978-94-007-0495-4"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Kany, S., Vollrath, J.T., and Relja, B. (2019). Cytokines in Inflammatory Disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20236008"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1615\/CritRevEukarGeneExpr.v20.i2.10","article-title":"Tumor Necrosis Factor-\u03b1 Signaling in Macrophages","volume":"20","author":"Parameswaran","year":"2010","journal-title":"Crit. Rev. Eukaryot. Gene Expr."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1084\/jem.194.7.873","article-title":"Granulocyte Macrophage Colony-Stimulating Factor: A New Putative Therapeutic Target in Multiple Sclerosis","volume":"194","author":"McQualter","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1038\/cr.2008.310","article-title":"The Role of Granulocyte Macrophage-Colony-Stimulating Factor in Acute Intestinal Inflammation","volume":"18","author":"Xu","year":"2008","journal-title":"Cell Res."},{"key":"ref_72","unstructured":"(2022, July 09). Reposit\u00f3rio Da Universidade de Lisboa: Phytochemical Study and Biological Activities of Diterpenes and Derivatives from Plectranthus Species. Available online: https:\/\/repositorio.ul.pt\/handle\/10451\/2833."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1431789","DOI":"10.1155\/2016\/1431789","article-title":"Forskolin Inhibits Lipopolysaccharide-Induced Modulation of MCP-1 and GPR120 in 3T3-L1 Adipocytes through an Inhibition of NF\u03ba B","volume":"2016","author":"Chiadak","year":"2016","journal-title":"Mediators Inflamm."},{"key":"ref_74","first-page":"377","article-title":"Evaluation of Anti-Inflammatory and Antioxidant Properties of Crude Extract and Forskolin from Solena Amplexicaulis Leaf","volume":"78","author":"Karthika","year":"2016","journal-title":"Indian J. Pharm. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"112280","DOI":"10.1016\/j.phytochem.2020.112280","article-title":"Halimane and Labdane Diterpenoids from Leonurus Japonicus and Their Anti-Inflammatory Activity","volume":"172","author":"Li","year":"2020","journal-title":"Phytochemistry"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"11779322211021430","DOI":"10.1177\/11779322211021430","article-title":"Inhibitory Potential of Phytochemicals on Interleukin-6-Mediated T-Cell Reduction in COVID-19 Patients: A Computational Approach","volume":"15","author":"Malik","year":"2021","journal-title":"Bioinform. Biol. Insights"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"363","DOI":"10.6026\/97320630017348","article-title":"Molecular docking analysis of stachydrine and sakuranetin with IL-6 and TNF-\u03b1 in the context of inflammation","volume":"17","author":"Prathap","year":"2021","journal-title":"Bioinformation"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"6471400","DOI":"10.1155\/2021\/6471400","article-title":"Molecular Mechanism of Jinchan Oral Liquid in the Treatment of Children with Respiratory Syncytial Virus Pneumonia Based on Network Pharmacology and Molecular Docking Technology","volume":"2021","author":"Shen","year":"2021","journal-title":"Biomed Res. Int."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Alzahrani, A.A. (2022). New Investigation into the Molecular Mechanism of Andrographolide towards Reducing Cytokine Storm. Molecules, 27.","DOI":"10.3390\/molecules27144555"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"5196302","DOI":"10.1155\/2020\/5196302","article-title":"A Systems Pharmacology Approach for Identifying the Multiple Mechanisms of Action for the Rougui-Fuzi Herb Pair in the Treatment of Cardiocerebral Vascular Diseases","volume":"2020","author":"Li","year":"2020","journal-title":"Evid. Based Complement. Altern. Med."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/20\/3243\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:54:56Z","timestamp":1760144096000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/20\/3243"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,15]]},"references-count":80,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["cells11203243"],"URL":"https:\/\/doi.org\/10.3390\/cells11203243","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,15]]}}}