{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T15:29:04Z","timestamp":1772033344478,"version":"3.50.1"},"reference-count":39,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: This study evaluated the anti-inflammatory effects of ocotillol, a compound isolated from the ethanol extract of propolis of the Tetragonula iridipennis stingless bee. Through its ability to inhibit NO production in an in vitro model, it investigated the NO inhibition mechanism using network pharmacology combined with molecular docking. Methods: The NO production inhibitory activity was determined by colorimetric assay using Griess reagent. An in silico study was performed using network pharmacology analysis, molecular docking, and molecular dynamics simulations. Results: The in vitro results demonstrated that ocotillol exhibited significant anti-inflammatory effects by effectively inhibiting NO production, with an IC50 value of 20.29 \u00b1 2.1 \u00b5g\/mL. The network pharmacology analysis revealed that ocotillol targets 14 molecular sites related to NO, with TACR1 showing the best binding affinity at \u221210.0 kcal\/mol. Molecular dynamics simulations suggest that TACR1 is a potential target. As indicated by the stable interaction profile, further validation in complex biological membranes is warranted. Conclusions: This study also provides evidence for the correlation between in vitro and in silico models, thus laying the groundwork for in vivo evaluations to confirm the anti-inflammatory mechanism of ocotillol.<\/jats:p>","DOI":"10.3390\/ph19030361","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T13:37:37Z","timestamp":1772026657000},"page":"361","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anti-Inflammatory Activities of Ocotillol Isolated from Tetragonula iridipennis Propolis: A Study on In Vitro and In Silico Models"],"prefix":"10.3390","volume":"19","author":[{"given":"Nguyen Thanh","family":"Cong","sequence":"first","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacognosy and Traditional Medicine, Hanoi University of Pharmacy, Hanoi 11000, Vietnam"},{"name":"Faculty of Pharmacy, Dai Nam University, Hanoi 10000, Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1915-0565","authenticated-orcid":false,"given":"Nguyen Van","family":"Phuong","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacognosy and Traditional Medicine, Hanoi University of Pharmacy, Hanoi 11000, Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Do Van","family":"Hieu","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Dai Nam University, Hanoi 10000, Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nguyen Hoang","family":"Viet","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Dai Nam University, Hanoi 10000, Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8375-4187","authenticated-orcid":false,"given":"Le Nguyen","family":"Thanh","sequence":"additional","affiliation":[{"name":"National Institute of Medicinal Materials (NIMM), Hanoi 11018, Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6557","DOI":"10.1016\/S0040-4020(01)00547-6","article-title":"Preparation and evaluation of new L-canavanine derivatives as nitric oxide synthase inhibitors","volume":"57","author":"Li","year":"2001","journal-title":"Tetrahedron"},{"key":"ref_2","unstructured":"Ignarro, L.J. (2000). Nitric Oxide: Biology and Pathobiology, Academic Press."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"11584","DOI":"10.1073\/pnas.95.20.11584","article-title":"An activity in rat tissues that modifies nitrotyrosine-containing proteins","volume":"95","author":"Kamisaki","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S0031-6997(25)06663-3","article-title":"Nitric oxide: Physiology, pathophysiology and pharmacology","volume":"43","author":"Moncada","year":"1991","journal-title":"Pharmacol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2303259","DOI":"10.1002\/advs.202303259","article-title":"Nitric oxide: Physiological functions, delivery, and biomedical applications","volume":"10","author":"Andrabi","year":"2023","journal-title":"J. Adv. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cimid.2005.11.001","article-title":"Comparative nitric oxide production by LPS-stimulated monocyte-derived macrophages from Ovis canadensis and Ovis aries","volume":"29","author":"Sacco","year":"2006","journal-title":"Comp. Immunol. Microbiol. Infect. Dis."},{"key":"ref_7","first-page":"1934578X231219088","article-title":"Chemical constituents, cytotoxicity, and molecular docking studies of Tetragonula iridipennis propolis","volume":"18","author":"Phuong","year":"2023","journal-title":"Nat. Prod. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroscience.2011.08.002","article-title":"Ginseng derivative ocotillol enhances neuronal activity through increased glutamate release: A possible mechanism underlying increased spontaneous locomotor activity of mice","volume":"195","author":"Wang","year":"2011","journal-title":"Neuroscience"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"116427","DOI":"10.1016\/j.ejmech.2024.116427","article-title":"Discovery of novel ocotillol derivatives modulating glucocorticoid receptor\/NF-\u03baB signaling for the treatment of sepsis","volume":"271","author":"Ma","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"114784","DOI":"10.1016\/j.ejmech.2022.114784","article-title":"Design, synthesis, and biological evaluation of ocotillol derivatives fused with 2-aminothiazole via A-ring as modulators of P-glycoprotein-mediated multidrug resistance","volume":"243","author":"Wang","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_11","first-page":"568","article-title":"Cardioprotective effect of ocotillol, a derivate of pseudoginsenoside F11, on myocardial injury induced by isoproterenol in rats","volume":"57","author":"Yu","year":"2007","journal-title":"Arzneimittelforschung"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2309966","DOI":"10.1002\/advs.202309966","article-title":"Extracellular matrix sulfation in the tumor microenvironment stimulates cancer stemness and invasiveness","volume":"11","author":"Uzun","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Berdiaki, A., Neagu, M., Tzanakakis, P., Spyridaki, I., P\u00e9rez, S., and Nikitovic, D. (2024). Extracellular Matrix Components and Mechanosensing Pathways in Health and Disease. Biomolecules, 14.","DOI":"10.3390\/biom14091186"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7024","DOI":"10.1021\/acs.jafc.5b02183","article-title":"Ocotillol, a majonoside R2 metabolite, ameliorates 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice by restoring the balance of Th17\/Treg cells","volume":"63","author":"Lee","year":"2015","journal-title":"J. Agric. Food Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"189079","DOI":"10.1016\/j.bbcan.2024.189079","article-title":"VEGF signaling: Role in angiogenesis and beyond","volume":"1879","author":"Shaw","year":"2024","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Singh, S., Behl, T., and Kumar, D. (2024). Molecular mechanism of angiogenesis, inflammation, and oxidative stress in Cancer. Targeting Angiogenesis, Inflammation, and Oxidative Stress in Chronic Diseases, Elsevier.","DOI":"10.1016\/B978-0-443-13587-3.00008-4"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1248\/bpb.b21-00504","article-title":"Rap1 small GTPase regulates vascular endothelial-cadherin-mediated endothelial cell\u2013cell junctions and vascular permeability","volume":"44","author":"Yamamoto","year":"2021","journal-title":"Biol. Pharm. Bull."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"90","DOI":"10.20892\/j.issn.2095-3941.2016.0086","article-title":"Roles of Rap1 signaling in tumor cell migration and invasion","volume":"14","author":"Zhang","year":"2017","journal-title":"Cancer Biol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1007\/s00018-015-2112-y","article-title":"FOXO transcription factors in cancer development and therapy","volume":"73","author":"Demoulin","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kim, M.E., Kim, D.H., and Lee, J.S. (2022). FoxO transcription factors: Applicability as a novel immune cell regulators and therapeutic targets in oxidative stress-related diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911877"},{"key":"ref_21","first-page":"2023.08.16.553495","article-title":"Alcohol responsive genes in the neutrophils of acute-on-chronic liver failure reveal modulation of intracellular calcium, ROS, and phagocytosis","volume":"BioRxiv","author":"Saha","year":"2023","journal-title":"BioRxiv"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1196\/annals.1432.001","article-title":"Connection between the striatal neurokinin-1 receptor and nitric oxide formation during methamphetamine exposure","volume":"1133","author":"Wang","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1111\/j.1471-4159.2009.06330.x","article-title":"The neurokinin-1 receptor modulates the methamphetamine-induced striatal apoptosis and nitric oxide formation in mice","volume":"111","author":"Zhu","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_24","first-page":"235604","article-title":"Contrasting effects of the neuropeptides substance P, somatostatin, and neuropeptide Y on the methamphetamine-induced production of striatal nitric oxide in mice","volume":"1","author":"Afanador","year":"2012","journal-title":"J. Drug Addict. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s00280-024-04661-9","article-title":"Gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the neurokinin-1 receptor antagonist-based antiemetic regimens: A candidate-gene association study in breast cancer patients","volume":"94","author":"Ghorbani","year":"2024","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pakai, E., Tekus, V., Zsiboras, C., Rumbus, Z., Olah, E., Keringer, P., Khidhir, N., Matics, R., Deres, L., and Ordog, K. (2018). The neurokinin-1 receptor contributes to the early phase of lipopolysaccharide-induced fever via stimulation of peripheral cyclooxygenase-2 protein expression in mice. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00166"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Marques, R.V., Sestito, S.E., Bourgaud, F., Miguel, S., Cailotto, F., Reboul, P., Jouzeau, J.-Y., Rahuel-Clermont, S., Boschi-Muller, S., and Simonsen, H.T. (2022). Anti-inflammatory activity of bryophytes extracts in LPS-stimulated RAW264.7 murine macrophages. Molecules, 27.","DOI":"10.3390\/molecules27061940"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.foodchem.2006.08.013","article-title":"Comparison of NO-scavenging and NO-suppressing activities of different herbal teas with those of green tea","volume":"103","author":"Tsai","year":"2007","journal-title":"Food Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"429","DOI":"10.3390\/md8030429","article-title":"Inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells by the norsesterterpene peroxide, epimuqubilin A","volume":"8","author":"Cheenpracha","year":"2010","journal-title":"Mar. Drugs"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e202204376","DOI":"10.1002\/slct.202204376","article-title":"Microwave-assisted multicomponent synthesis of new 6-arylated 5-hydroxy-benzo[a]phenazine derivatives and their potential anti-inflammatory activiy","volume":"8","author":"Nguyen","year":"2023","journal-title":"ChemistrySelect"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1479-7364-5-6-709","article-title":"In-silico human genomics with GeneCards","volume":"5","author":"Stelzer","year":"2011","journal-title":"Hum. Genom."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/(SICI)1098-1004(200001)15:1<57::AID-HUMU12>3.0.CO;2-G","article-title":"Online Mendelian inheritance in man (OMIM)","volume":"15","author":"Hamosh","year":"2000","journal-title":"Hum. Mutat."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"W32","DOI":"10.1093\/nar\/gku293","article-title":"SwissTargetPrediction: A web server for target prediction of bioactive small molecules","volume":"42","author":"Gfeller","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"D684","DOI":"10.1093\/nar\/gkm795","article-title":"STITCH: Interaction networks of chemicals and proteins","volume":"36","author":"Kuhn","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1093\/bioinformatics\/btz931","article-title":"ShinyGO: A graphical enrichment tool for animals and plants","volume":"36","author":"Ge","year":"2020","journal-title":"Bioinformatics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1002\/jcc.20504","article-title":"An iterative knowledge-based scoring function to predict protein\u2013ligand interactions: I. Derivation of interaction potentials","volume":"27","author":"Huang","year":"2006","journal-title":"J. Comput. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"044130","DOI":"10.1063\/5.0014475","article-title":"Scalable molecular dynamics on CPU and GPU architectures with NAMD","volume":"153","author":"Phillips","year":"2020","journal-title":"J. Chem. Phys."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"641a","DOI":"10.1016\/j.bpj.2015.11.3431","article-title":"CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM\/OpenMM simulations using the CHARMM36 additive force field","volume":"110","author":"Lee","year":"2016","journal-title":"Biophys. J."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/3\/361\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T13:42:23Z","timestamp":1772026943000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/3\/361"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,25]]},"references-count":39,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ph19030361"],"URL":"https:\/\/doi.org\/10.3390\/ph19030361","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,25]]}}}