{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:34:08Z","timestamp":1791945248480,"version":"4.3.4"},"reference-count":46,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2017,5,12]],"date-time":"2017-05-12T00:00:00Z","timestamp":1494547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001868","name":"National Science Council","doi-asserted-by":"publisher","award":["104-2320-B-259-001-MY3"],"award-info":[{"award-number":["104-2320-B-259-001-MY3"]}],"id":[{"id":"10.13039\/501100001868","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nanomaterials"],"abstract":"<jats:p>Natural supplements comprise good efficacy with less adverse effects as against diabetic therapy, but their advancement as anti-diabetic agents is unsatisfactory with regard to the delivery system. Dipeptidyl peptidase-4 (DPP4)\/CD26) can degrade glucagon-like pepetide-1 (GLP-1) which renders a decrease of blood glucose levels. 16-hydroxycleroda-3,13-dine-16,15-olide (HCD) extracted from Polyalthia longifolia, exhibits numerous medicinal potentials including hypoglycemic potential. On consideration of HCD application, the bioavailability is affected by low solubility. Extended experiments of anti-diabetic efficacy confirmed HCD biocompatible with mesoporous silica nanoparticles (MSNs) encapsulation resulted in a sustained release property in delivering HCD for the inhibition of DPP4 via the activity and protein levels of DPP4 analysis. In the enzymatic activity assay, MSN-HCD directly changed DPP4 activity. Moreover, MSN-HCD nanoparticles were treated with Caco-2 cells and the protein levels of DPP4 determined within the cells. The results revealed that MSN-HCD caused reduction of DPP4 activity in a time- and dose-dependent fashion. Orally administered MSN-HCD in diet-induced diabetic mice alleviated blood glucose via an oral glucose tolerance test. In addition, administration of MSN-HCD for five weeks revealed that the biochemical cues such as pyruvate transaminase (GPT), glutamate oxaloacetate transaminase (GOT), triglycerides (TG), cholesterol (CHO), and glycated hemoglobin (HbA1c) in mice were commendable as further confirmation of MSN-HCD efficacy and less adverse effects in down-regulation of hyperglycemia. Furthermore, this formulation effectively controlled blood glucose and significantly decreased the body weight of mice, suggesting that MSN-HCD exerts natural DPP4 inhibitor as a potential clinical drug for the treatment of diabetes.<\/jats:p>","DOI":"10.3390\/nano7050112","type":"journal-article","created":{"date-parts":[[2017,5,12]],"date-time":"2017-05-12T11:03:53Z","timestamp":1494587033000},"page":"112","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Encapsulation of 16-Hydroxycleroda-3,13-Dine-16,15-Olide in Mesoporous Silica Nanoparticles as a Natural Dipeptidyl Peptidase-4 Inhibitor Potentiated Hypoglycemia in Diabetic Mice"],"prefix":"10.3390","volume":"7","author":[{"given":"Po-Kai","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Xiang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May-Jywan","family":"Tsai","sequence":"additional","affiliation":[{"name":"Neural Regeneration Laboratory, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6927-1517","authenticated-orcid":false,"given":"Max","family":"Leong","sequence":"additional","affiliation":[{"name":"Department of Chemistry, National Dong Hwa University, Hualien 97401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4160-2361","authenticated-orcid":false,"given":"Shian-Ren","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjith","family":"Kankala","sequence":"additional","affiliation":[{"name":"College of Chemical Engineering, Huaqiao University, Xiamen 361021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Hung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Feng","family":"Weng","sequence":"additional","affiliation":[{"name":"Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3495","DOI":"10.1021\/bm500364a","article-title":"Bio-inspired synthetic nanovesicles for glucose-responsive release of insulin","volume":"15","author":"Tai","year":"2014","journal-title":"Biomacromolecules"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/adfm.201001762","article-title":"Nanotechnology-enabled closed loop insulin delivery device: In vitro and in vivo evaluation of glucose-regulated insulin release for diabetes control","volume":"21","author":"Gordijo","year":"2011","journal-title":"Adv. Funct. Mater."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1172\/JCI112855","article-title":"Insulinotropin: Glucagon-like peptide i (7\u201337) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas","volume":"79","author":"Mojsov","year":"1987","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S0014-2999(02)01434-6","article-title":"Glucagon-like peptide 1 as a regulator of food intake and body weight: Therapeutic perspectives","volume":"440","author":"Meier","year":"2002","journal-title":"Eur. J. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/BF01316798","article-title":"Truncated-1 (proglucagon 78\u2013107-amide) inhibits gastric and pancreatic functions in man","volume":"38","author":"Wettergren","year":"1993","journal-title":"Dig. Dis. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1017\/S0007114599000483","article-title":"Glucagon-like peptide-1, satiety and appetite control","volume":"81","author":"Blundell","year":"1999","journal-title":"Br. J. Nutr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"251","DOI":"10.2165\/00063030-200822040-00004","article-title":"Long-acting GLP-1 analogs for the treatment of type 2 diabetes mellitus","volume":"22","author":"Vilsboll","year":"2008","journal-title":"BioDrugs"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"E199","DOI":"10.1152\/ajpendo.00545.2003","article-title":"Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans","volume":"287","author":"Holst","year":"2004","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1007\/s001250051444","article-title":"Twenty-four-hour insulin secretion rates, circulating concentrations of fuel substrates and gut incretin hormones in healthy offspring of type ii (non-insulin-dependent) diabetic parents: Evidence of several aberrations","volume":"42","author":"Nyholm","year":"1999","journal-title":"Diabetologia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3717","DOI":"10.1210\/jcem.86.8.7750","article-title":"Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients","volume":"86","author":"Damholt","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1055\/s-2004-826163","article-title":"Beta- and alpha-cell dysfunction in type 2 diabetes","volume":"36","author":"Marchetti","year":"2004","journal-title":"Horm. Metab. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.1016\/j.biomaterials.2012.12.043","article-title":"The absorption, distribution, excretion and toxicity of mesoporous silica nanoparticles in mice following different exposure routes","volume":"34","author":"Fu","year":"2013","journal-title":"Biomaterials"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.nano.2014.09.014","article-title":"Mesoporous silica nanoparticles in drug delivery and biomedical applications","volume":"11","author":"Wang","year":"2015","journal-title":"Nanomedicine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.nantod.2009.02.001","article-title":"Mesoporous materials for encapsulating enzymes","volume":"4","author":"Lee","year":"2009","journal-title":"Nano Today"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1158\/1535-7163.MCT-10-0884","article-title":"Enhanced chemotherapy of cancer using ph-sensitive mesoporous silica nanoparticles to antagonize P-glycoprotein-mediated drug resistance","volume":"10","author":"Huang","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8214","DOI":"10.1002\/anie.201002639","article-title":"Intracellular pH-responsive mesoporous silica nanoparticles for the controlled release of anticancer chemotherapeutics","volume":"49","author":"Lee","year":"2010","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"86072","DOI":"10.1039\/C5RA16023E","article-title":"Killing cancer cells by delivering a nanoreactor for inhibition of catalase and catalytically enhancing intracellular levels of ros","volume":"5","author":"Kankala","year":"2015","journal-title":"RSC Adv."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.ijpharm.2012.03.026","article-title":"Mesoporous silica nanoparticles for the improved anticancer efficacy of cis-platin","volume":"429","author":"Lin","year":"2012","journal-title":"Int. J. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.3390\/nano5042169","article-title":"Utilization of enzyme-immobilized mesoporous silica nanocontainers (IBN-4) in prodrug-activated cancer theranostics","volume":"5","author":"Hung","year":"2015","journal-title":"Nanomaterials"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3255","DOI":"10.2147\/IJN.S104604","article-title":"Controlled release hydrogen sulfide delivery system based on mesoporous silica nanoparticles protects graft endothelium from ischemia-reperfusion injury","volume":"11","author":"Wang","year":"2016","journal-title":"Int. J. Nanomed."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.colsurfb.2016.03.076","article-title":"Colloidal mesoporous silica nanoparticles enhance the biological activity of resveratrol","volume":"144","author":"Summerlin","year":"2016","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.jcis.2016.05.002","article-title":"Membrane interactions of mesoporous silica nanoparticles as carriers of antimicrobial peptides","volume":"475","author":"Braun","year":"2016","journal-title":"J. Colloid Interface Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.biomaterials.2016.03.019","article-title":"Mesoporous silica nanoparticles with organo-bridged silsesquioxane framework as innovative platforms for bioimaging and therapeutic agent delivery","volume":"91","author":"Du","year":"2016","journal-title":"Biomaterials"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1093\/jnci\/djr400","article-title":"Nano dot technology enters clinical trials","volume":"103","author":"Friedman","year":"2011","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"225102","DOI":"10.1088\/0957-4484\/27\/22\/225102","article-title":"Biodegradable mesoporous bioactive glass nanospheres for drug delivery and bone tissue regeneration","volume":"27","author":"Xiaojian","year":"2016","journal-title":"Nanotechnology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"013003","DOI":"10.1088\/1468-6996\/13\/1\/013003","article-title":"Recent progress in mesoporous titania materials: Adjusting morphology for innovative applications","volume":"13","author":"Chiang","year":"2012","journal-title":"Sci. Technol. Adv. Mater."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5232","DOI":"10.1039\/c1cc10659g","article-title":"Biocompatible, surface functionalized mesoporous titania nanoparticles for intracellular imaging and anticancer drug delivery","volume":"47","author":"Wu","year":"2011","journal-title":"Chem. Commun."},{"key":"ref_28","first-page":"1507","article-title":"Overcoming multidrug resistance through co-delivery of ros-generating nano-machinery in cancer therapeutics","volume":"5","author":"Kankala","year":"2017","journal-title":"J. Mater. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5151","DOI":"10.1039\/c2cc31708g","article-title":"Highly biocompatible, hollow coordination polymer nanoparticles as cisplatin carriers for efficient intracellular drug delivery","volume":"48","author":"Lian","year":"2012","journal-title":"Chem. Commun."},{"key":"ref_30","first-page":"2447","article-title":"Hollow mesoporous hydroxyapatite nanoparticles (hmHANPs) with enhanced drug loading and pH-responsive release properties for intracellular drug delivery","volume":"1","author":"Yang","year":"2013","journal-title":"J. Mater. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1002\/asia.201300072","article-title":"Inorganic-organic hybrid nanoparticles with biocompatible calcium phosphate thin shells for fluorescence enhancement","volume":"8","author":"Bastakoti","year":"2013","journal-title":"Chem. Asian J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1246\/cl.131174","article-title":"Mof-derived nanoporous carbon as intracellular drug delivery carriers","volume":"43","author":"Torad","year":"2014","journal-title":"Chem. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3852","DOI":"10.1021\/jp400442x","article-title":"A pH gated, glucose-sensitive nanoparticle based on worm-like mesoporous silica for controlled insulin release","volume":"117","author":"Sun","year":"2013","journal-title":"J. Phys. Chem. B"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8358","DOI":"10.1021\/acsami.5b12576","article-title":"Alizarin complexone functionalized mesoporous silica nanoparticles: A smart system integrating glucose-responsive double-drugs release and real-time monitoring capabilities","volume":"8","author":"Zou","year":"2016","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1021\/np000176e","article-title":"Cytotoxic constituents of polyalthia longifolia var. Pendula","volume":"63","author":"Chen","year":"2000","journal-title":"J. Nat. Prod."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1055\/s-2006-951691","article-title":"Anti-inflammatory and cytotoxic diterpenes from formosan Polyalthia longifolia var. Pendula","volume":"72","author":"Chang","year":"2006","journal-title":"Planta Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.tox.2011.04.004","article-title":"16-hydroxycleroda-3,13-dien-15,16-olide deregulates PI3K and aurora B activities that involve in cancer cell apoptosis","volume":"285","author":"Lin","year":"2011","journal-title":"Toxicology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.lfs.2011.09.011","article-title":"16-hydroxycleroda-3,13-dien-15,16-olide regulates the expression of histone-modifying enzymes PRC2 complex and induces apoptosis in CML k562 cells","volume":"89","author":"Lin","year":"2011","journal-title":"Life Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S1056-8719(00)00107-6","article-title":"Drug-like properties and the causes of poor solubility and poor permeability","volume":"44","author":"Lipinski","year":"2000","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1177\/0192623307310946","article-title":"Drug nanoparticles: Formulating poorly water-soluble compounds","volume":"36","author":"Liversidge","year":"2008","journal-title":"Toxicol. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.colsurfb.2016.01.038","article-title":"A focal adhesion kinase inhibitor 16-hydroxy-cleroda-3,13-dien-16,15-olide incorporated into enteric-coated nanoparticles for controlled anti-glioma drug delivery","volume":"141","author":"Thiyagarajan","year":"2016","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3283","DOI":"10.1002\/adfm.200800521","article-title":"Synthesis and characterization of positive-charge functionalized mesoporous silica nanoparticles for oral drug delivery of an anti-inflammatory drug","volume":"18","author":"Lee","year":"2008","journal-title":"Adv. Funct. Mater."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/s12951-015-0136-y","article-title":"Nanoparticle based insulin delivery system: The next generation efficient therapy for type 1 diabetes","volume":"13","author":"Sharma","year":"2015","journal-title":"J. Nanobiotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2017493","DOI":"10.1155\/2017\/2017493","article-title":"Electrospun nanofibers loaded with quercetin promote the recovery of focal entrapment neuropathy in a rat model of streptozotocin-induced diabetes","volume":"2017","author":"Thipkaew","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s13346-011-0023-5","article-title":"Chitosan-coated solid lipid nanoparticles enhance the oral absorption of insulin","volume":"1","author":"Fonte","year":"2011","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Sun, S.P., Liang, N., Gong, X.F., An, W.W., Kawashima, Y., Cui, F.D., and Yan, P.F. (2016). Multifunctional composite microcapsules for oral delivery of insulin. Int. J. Mol. Sci., 18, Available online: http:\/\/www.mdpi.com\/1422-0067\/18\/1\/54\/htm.","DOI":"10.3390\/ijms18010054"}],"container-title":["Nanomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-4991\/7\/5\/112\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:35:41Z","timestamp":1760207741000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-4991\/7\/5\/112"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,12]]},"references-count":46,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2017,5]]}},"alternative-id":["nano7050112"],"URL":"https:\/\/doi.org\/10.3390\/nano7050112","relation":{},"ISSN":["2079-4991"],"issn-type":[{"value":"2079-4991","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,12]]}}}