{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T15:50:49Z","timestamp":1782402649023,"version":"3.54.5"},"reference-count":118,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008641","name":"Chung Shan Medical University","doi-asserted-by":"publisher","award":["CSMU-CCH-113-04"],"award-info":[{"award-number":["CSMU-CCH-113-04"]}],"id":[{"id":"10.13039\/501100008641","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Plants"],"abstract":"<jats:p>Carnivorous plants have garnered attention as sources of pharmacologically active compounds, yet their floral tissues remain largely underexplored. In this study, we investigated the bioactive properties of Nepenthes miranda flower extracts prepared using water, methanol, ethanol, and acetone. Among these, the ethanol extract exhibited the highest total phenolic content (18.2 mg GAE\/g), flavonoid content (68.9 mg QUE\/g), and antioxidant activity (DPPH IC50 = 66.9 \u03bcg\/mL), along with strong antibacterial effects against Escherichia coli and Staphylococcus aureus. Cosmetically relevant enzyme inhibition assays revealed significant activity against tyrosinase (IC50 = 48.58 \u03bcg\/mL), elastase (IC50 = 1.77 \u03bcg\/mL), and hyaluronidase (IC50 = 7.33 \u03bcg\/mL), supporting its potential as an anti-skin aging agent. For antidiabetic evaluation, the ethanol extract demonstrated potent \u03b1-glucosidase inhibition (IC50 = 24.53 \u03bcg\/mL), outperforming standard inhibitors such as acarbose and quercetin. The extract also displayed marked cytotoxicity against A431 epidermoid carcinoma cells (IC50 = 90.61 \u03bcg\/mL), inducing dose-dependent apoptosis, inhibiting cell migration and colony formation, and causing significant DNA damage as shown by comet assay. Furthermore, the ethanol extract strongly inhibited the activity of purified human dihydroorotase (IC50 = 25.11 \u03bcg\/mL), indicating that disruption of pyrimidine biosynthesis may underlie its anticancer activity. Overall, this study provides the first characterization of N. miranda flower extracts, particularly the ethanol fraction, as a promising source of multifunctional bioactive compounds with possible applications in cosmetics, antidiabetic therapy, and cancer treatment.<\/jats:p>","DOI":"10.3390\/plants14162579","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T15:29:29Z","timestamp":1755617369000},"page":"2579","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Bioactive Potential of Nepenthes miranda Flower Extracts: Antidiabetic, Anti-Skin Aging, Cytotoxic, and Dihydroorotase-Inhibitory Activities"],"prefix":"10.3390","volume":"14","author":[{"given":"Kuan-Ming","family":"Lai","sequence":"first","affiliation":[{"name":"Hemato Oncology Division Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6347-3030","authenticated-orcid":false,"given":"Yen-Hua","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Chung Shan Medical University, Taichung City 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1613-552X","authenticated-orcid":false,"given":"Yi","family":"Lien","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Yang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Chung Shan Medical University, Taichung City 402, Taiwan"},{"name":"Department of Medical Research, Chung Shan Medical University Hospital, Taichung City 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Pavlovi\u010d, A. (New Phytol., 2025). How the diversity in digestion in carnivorous plants may have evolved, New Phytol., Online ahead of print.","DOI":"10.1111\/nph.70229"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1093\/aob\/mcaf024","article-title":"Construction costs and tradeoffs in carnivorous pitcher plant leaves: Towards a pitcher leaf economic spectrum","volume":"135","author":"Gilbert","year":"2025","journal-title":"Ann. Bot."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.jbiotec.2017.11.014","article-title":"Nepenthes: State of the art of an inspiring plant for biotechnologists","volume":"265","author":"Miguel","year":"2018","journal-title":"J. Biotechnol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.pbi.2016.10.010","article-title":"Cells, walls, and endless forms","volume":"34","author":"Monniaux","year":"2016","journal-title":"Curr. Opin. Plant Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1126\/science.1523408","article-title":"Carnivorous plants: Phylogeny and structural evolution","volume":"257","author":"Albert","year":"1992","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lee, C.-Y., Chen, Y.-C., Huang, Y.-H., Lien, Y., and Huang, C.-Y. (2024). Cytotoxicity and Multi-Enzyme Inhibition of Nepenthes miranda Stem Extract on H838 Human Non-Small Cell Lung Cancer Cells and RPA32, Elastase, Tyrosinase, and Hyaluronidase Proteins. Plants, 13.","DOI":"10.3390\/plants13060797"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"W\u00f3jciak, M., Feldo, M., Stolarczyk, P., and P\u0142achno, B.J. (2023). Biological Potential of Carnivorous Plants from Nepenthales. Molecules, 28.","DOI":"10.3390\/molecules28083639"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"W\u00f3jciak, M., Feldo, M., Stolarczyk, P., and P\u0142achno, B.J. (2023). Carnivorous Plants from Nepenthaceae and Droseraceae as a Source of Secondary Metabolites. Molecules, 28.","DOI":"10.3390\/molecules28052155"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Miclea, I. (2022). Secondary Metabolites with Biomedical Applications from Plants of the Sarraceniaceae Family. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179877"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Guan, H.-H., Huang, Y.-H., Lin, E.-S., Chen, C.-J., and Huang, C.-Y. (2021). Plumbagin, a Natural Product with Potent Anticancer Activities, Binds to and Inhibits Dihydroorotase, a Key Enzyme in Pyrimidine Biosynthesis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22136861"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.fct.2018.11.040","article-title":"Plumbagin from a tropical pitcher plant (Nepenthes alata Blanco) induces apoptotic cell death via a p53-dependent pathway in MCF-7 human breast cancer cells","volume":"123","author":"De","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wang, L., and Zhou, Q. (2016). Surface hydrophobicity of slippery zones in the pitchers of two Nepenthes species and a hybrid. Sci. Rep., 6.","DOI":"10.1038\/srep19907"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"143714","DOI":"10.1016\/j.foodchem.2025.143714","article-title":"Cleavage specificity of the pitcher fluid proteases from Nepenthes \u00d7 miranda and their reduction on allergenicity of cow\u2019s milk proteins","volume":"478","author":"Li","year":"2025","journal-title":"Food Chem."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lin, E.S., and Huang, C.Y. (2022). Cytotoxic activities and the allantoinase inhibitory effect of the leaf extract of the carnivorous pitcher plant Nepenthes miranda. Plants, 11.","DOI":"10.3390\/plants11172265"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.biochi.2020.03.005","article-title":"Identification and characterization of dihydropyrimidinase inhibited by plumbagin isolated from Nepenthes miranda extract","volume":"171\u2013172","author":"Huang","year":"2020","journal-title":"Biochimie"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lin, E.S., Huang, Y.H., Chung, J.C., Su, H.H., and Huang, C.Y. (2023). The Inhibitory effects and cytotoxic activities of the stem extract of Nepenthes miranda against single-stranded DNA-binding protein and oral carcinoma cells. Plants, 12.","DOI":"10.3390\/plants12112188"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Su, H.H., Lin, E.S., Huang, Y.H., Lien, Y., and Huang, C.Y. (2024). Inhibition of SARS-CoV-2 Nsp9 ssDNA-binding activity and cytotoxic effects on H838, H1975, and A549 human non-small cell lung cancer cells: Exploring the potential of Nepenthes miranda leaf extract for pulmonary disease treatment. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25116120"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Seyyedi-Mansour, S., Donn, P., Barciela, P., Perez-Vazquez, A., Nogueira-Marques, R., Chamorro, F., Carpena, M., and Prieto, M.A. (2025). Citrus aurantium Flowers: Overview of Chemistry, Functionality, and Technological Applications. Molecules, 30.","DOI":"10.3390\/molecules30040930"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Safir, W., Malik, A., Saadia, H., Zahid, A., and Li, J. (2025). Extraction, GC-MS analysis, cytotoxic, anti-inflammatory and anticancer potential of Cannabis sativa female flower; in vitro, in vivo and in silico. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1546062"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ksi\u0105\u017ckiewicz, M., Karczewska, M., Nawrot, F., Korybalska, K., and Studzi\u0144ska-Sroka, E. (2025). Traditionally Used Edible Flowers as a Source of Neuroactive, Antioxidant, and Anti-Inflammatory Extracts and Bioactive Compounds: A Narrative Review. Molecules, 30.","DOI":"10.3390\/molecules30030677"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chen, C.-Y., Wang, G.-H., Chang, Y.-C., Liu, S., Lin, Y.-T., Lai, Y.-L., and Chung, Y.-C. (2025). Cosmeceutical application of extracts from the flowers, stems, and leaves of Buddleja davidii grown at different altitudes. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1551134"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Cetinkaya, A., Yayla, S., Hurkul, M.M., and Ozkan, S.A. (2025). The Sample Preparation Techniques and Their Application in the Extraction of Bioactive Compounds from Medicinal Plants. Crit. Rev. Anal. Chem., 1\u201336.","DOI":"10.1080\/10408347.2025.2503437"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41574-024-01047-y","article-title":"Inflammation and resolution in obesity","volume":"21","author":"Clark","year":"2025","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/s41574-025-01114-y","article-title":"Insulin resistance in type 2 diabetes mellitus","volume":"21","author":"Accili","year":"2025","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3455","DOI":"10.1038\/s41591-024-03373-0","article-title":"Lifestyle interventions for cardiometabolic health","volume":"30","author":"Rutters","year":"2024","journal-title":"Nat. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1080\/07388551.2024.2423153","article-title":"A comprehensive review on influence of millet processing on carbohydrate-digesting enzyme inhibitors and implications for diabetes management","volume":"45","author":"Bhujle","year":"2025","journal-title":"Crit. Rev. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.det.2023.07.005","article-title":"Clinical Assessment, Diagnosis, and Management of Infraorbital Wrinkles and Pigmentation","volume":"42","author":"Rathore","year":"2024","journal-title":"Dermatol. Clin."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Goh, C.F. (2024). Diversity of Asian skin: A review on skin biophysical properties. Exp. Dermatol., 33.","DOI":"10.1111\/exd.14959"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Da\u0144czak-Pazdrowska, A., Gornowicz-Porowska, J., Pola\u0144ska, A., Krajka-Ku\u017aniak, V., Stawny, M., Gosty\u0144ska, A., Rubi\u015b, B., Nourredine, S., Ashiqueali, S., and Schneider, A. (2023). Cellular senescence in skin-related research: Targeted signaling pathways and naturally occurring therapeutic agents. Aging Cell, 22.","DOI":"10.1111\/acel.13845"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1177\/0963689717725755","article-title":"Fighting against Skin Aging: The Way from Bench to Bedside","volume":"27","author":"Zhang","year":"2018","journal-title":"Cell Transplant."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/S0047-6374(01)00425-0","article-title":"Molecular mechanisms of skin ageing","volume":"123","author":"Jenkins","year":"2002","journal-title":"Mech. Ageing Dev."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Michalak, M. (2023). Plant Extracts as Skin Care and Therapeutic Agents. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242015444"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Zolghadri, S., Beygi, M., Mohammad, T.F., Alijanianzadeh, M., Pillaiyar, T., Garcia-Molina, P., Garcia-Canovas, F., Munoz-Munoz, J., and Saboury, A.A. (2023). Targeting tyrosinase in hyperpigmentation: Current status, limitations and future promises. Biochem. Pharmacol., 212.","DOI":"10.1016\/j.bcp.2023.115574"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Logesh, R., Prasad, S.R., Chipurupalli, S., Robinson, N., and Mohankumar, S.K. (2023). Natural tyrosinase enzyme inhibitors: A path from melanin to melanoma and its reported pharmacological activities. Biochim. Biophys. Acta Rev. Cancer, 1878.","DOI":"10.1016\/j.bbcan.2023.188968"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Baber, M.A., Crist, C.M., Devolve, N.L., and Patrone, J.D. (2023). Tyrosinase Inhibitors: A Perspective. Molecules, 28.","DOI":"10.3390\/molecules28155762"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1080\/14756366.2021.2014832","article-title":"Flavonoids as tyrosinase inhibitors in in silico and in vitro models: Basic framework of SAR using a statistical modelling approach","volume":"37","author":"Jakimiuk","year":"2022","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Song, S.Y., Lee, S.H., Bae, M.S., Park, D.H., and Cho, S.S. (2023). Strong inhibition of xanthine oxidase and elastase of Baccharis trimera (Less.) DC stem extract and analysis of biologically active constituents. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1160330"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Papaemmanouil, C.D., Pe\u00f1a-Garc\u00eda, J., Banegas-Luna, A.J., Kostagianni, A.D., Gerothanassis, I.P., P\u00e9rez-S\u00e1nchez, H., and Tzakos, A.G. (2022). ANTIAGE-DB: A Database and Server for the Prediction of Anti-Aging Compounds Targeting Elastase, Hyaluronidase, and Tyrosinase. Antioxidants, 11.","DOI":"10.3390\/antiox11112268"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.jep.2018.07.002","article-title":"Anti-Deinagkistrodon acutus venom properties of ethanolic root extract from Cynanchum paniculatum (Bunge) kitag and its GC-MS analysis","volume":"225","author":"Xiong","year":"2018","journal-title":"J. Ethnopharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1038\/s43587-025-00901-6","article-title":"Skin health and biological aging","volume":"5","author":"Furman","year":"2025","journal-title":"Nat. Aging"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1038\/s43587-025-00827-z","article-title":"The complex interplay between aging and cancer","volume":"5","author":"Trastus","year":"2025","journal-title":"Nat. Aging"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/s41576-025-00825-2","article-title":"Integrating model systems and genomic insights to decipher mechanisms of cancer metastasis","volume":"26","author":"Leung","year":"2025","journal-title":"Nat. Rev. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/s41568-024-00788-2","article-title":"Defining a \u2018cells to society\u2019 research framework for appendiceal tumours","volume":"25","author":"Holowatyj","year":"2025","journal-title":"Nat. Rev. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s41573-024-01060-w","article-title":"DNA damage response inhibitors in cancer therapy: Lessons from the past, current status and future implications","volume":"24","author":"Drew","year":"2025","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/s41573-025-01147-y","article-title":"Tumour-agnostic kinase inhibitors","volume":"24","author":"Adashek","year":"2025","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/s41571-023-00853-z","article-title":"Optimizing the FDA\u2019s Project Optimus: Opportunities and challenges","volume":"21","author":"Rodney","year":"2023","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/s41568-023-00648-5","article-title":"Decoding the basis of histological variation in human cancer","volume":"24","author":"Fujii","year":"2023","journal-title":"Nat. Rev. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/s41573-023-00709-2","article-title":"Antibody-drug conjugates come of age in oncology","volume":"22","author":"Dumontet","year":"2023","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/s41556-024-01574-w","article-title":"Metabolic rewiring in skin epidermis drives tolerance to oncogenic mutations","volume":"27","author":"Hemalatha","year":"2025","journal-title":"Nat. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/s41580-024-00821-0","article-title":"Shaping epithelial tissues by stem cell mechanics in development and cancer","volume":"26","author":"Fiore","year":"2025","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1038\/s43018-024-00794-1","article-title":"Determinants of resistance and response to melanoma therapy","volume":"5","author":"Robertson","year":"2024","journal-title":"Nat. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jdin.2020.10.013","article-title":"The global burden of skin cancer: A longitudinal analysis from the Global Burden of Disease Study, 1990-2017","volume":"2","author":"Urban","year":"2021","journal-title":"JAAD Int."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Ci\u0105\u017cy\u0144ska, M., Kami\u0144ska-Winciorek, G., Lange, D., Lewandowski, B., Reich, A., S\u0142awi\u0144ska, M., Pabianek, M., Szczepaniak, K., Hankiewicz, A., and U\u0142a\u0144ska, M. (2021). The incidence and clinical analysis of non-melanoma skin cancer. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-94435-7"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"62","DOI":"10.7861\/clinmedicine.16-1-62","article-title":"Non-melanoma skin cancer","volume":"16","author":"Griffin","year":"2016","journal-title":"Clin. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"107788","DOI":"10.1016\/j.phrs.2025.107788","article-title":"Targeting tumor-associated macrophage polarization with traditional Chinese medicine active ingredients: Dual reversal of chemoresistance and immunosuppression in tumor microenvironment","volume":"216","author":"Qi","year":"2025","journal-title":"Pharmacol. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"119969","DOI":"10.1016\/j.jep.2025.119969","article-title":"Whether traditional Chinese medicine injection can reduce adverse events in patients with cancer? A meta-analysis of randomized controlled trials","volume":"349","author":"Long","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2595","DOI":"10.7150\/jca.109420","article-title":"Development of Traditional Chinese Medicine in combination with EGFR Inhibitors against Cancer","volume":"16","author":"Chen","year":"2025","journal-title":"J. Cancer"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"An, S., An, J., Lee, D., Kang, H.N., Kang, S., Ahn, C.H., Syahputra, R.A., Ribeiro, R., and Kim, B. (2025). Natural Products for Melanoma Therapy: From Traditional Medicine to Modern Drug Discovery. Plants, 14.","DOI":"10.3390\/plants14060951"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural Products as Sources of New Drugs over the Nearly Four Decades from 01\/1981 to 09\/2019","volume":"83","author":"Newman","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1021\/acs.jnatprod.5b01055","article-title":"Natural Products as Sources of New Drugs from 1981 to 2014","volume":"79","author":"Newman","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"11489","DOI":"10.1016\/S0021-9258(18)33787-6","article-title":"Synthesis, turnover, and down-regulation of epidermal growth factor receptors in human A431 epidermoid carcinoma cells and skin fibroblasts","volume":"257","author":"Krupp","year":"1982","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Huang, C.Y. (2025). The Loop-In Binding Mode of Dihydroorotase: Implications for Ligand Binding and Therapeutic Targeting. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26031359"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Li, G., Li, D., Wang, T., and He, S. (2021). Pyrimidine Biosynthetic Enzyme CAD: Its Function, Regulation, and Diagnostic Potential. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910253"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1093\/nar\/gkz1162","article-title":"Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites","volume":"48","author":"Basbous","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.bbrc.2019.08.153","article-title":"Crystal structure of dihydropyrimidinase in complex with anticancer drug 5-fluorouracil","volume":"519","author":"Huang","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Huang, C.Y. (2015). Inhibition of a putative dihydropyrimidinase from Pseudomonas aeruginosa PAO1 by flavonoids and substrates of cyclic amidohydrolases. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0127634"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Huang, Y.H., Yang, P.C., Lin, E.S., Ho, Y.Y., Peng, W.F., Lu, H.P., Huang, C.C., and Huang, C.Y. (2023). Crystal Structure of Allantoinase from Escherichia coli BL21: A Molecular Insight into a Role of the Active Site Loops in Catalysis. Molecules, 28.","DOI":"10.3390\/molecules28020827"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.biochi.2014.01.001","article-title":"Allantoinase and dihydroorotase binding and inhibition by flavonols and the substrates of cyclic amidohydrolases","volume":"101","author":"Peng","year":"2014","journal-title":"Biochimie"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1007\/s00726-012-1451-3","article-title":"Chemical rescue of the post-translationally carboxylated lysine mutant of allantoinase and dihydroorotase by metal ions and short-chain carboxylic acids","volume":"44","author":"Ho","year":"2013","journal-title":"Amino Acids"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/bs.apcsb.2020.05.002","article-title":"Structure, catalytic mechanism, posttranslational lysine carbamylation, and inhibition of dihydropyrimidinases","volume":"122","author":"Huang","year":"2020","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s00775-008-0428-x","article-title":"Effect of metal binding and posttranslational lysine carboxylation on the activity of recombinant hydantoinase","volume":"14","author":"Huang","year":"2009","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1126\/science.1079237","article-title":"Dispelling the myths--biocatalysis in industrial synthesis","volume":"299","author":"Schoemaker","year":"2003","journal-title":"Science"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1007\/s00239-013-9580-1","article-title":"Evolution of cyclic amidohydrolases: A highly diversified superfamily","volume":"77","author":"Barba","year":"2013","journal-title":"J. Mol. Evol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.bbapap.2008.01.005","article-title":"Amidohydrolases of the reductive pyrimidine catabolic pathway purification, characterization, structure, reaction mechanisms and enzyme deficiency","volume":"1784","author":"Schnackerz","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"6383","DOI":"10.1021\/bi047326v","article-title":"Structural and catalytic diversity within the amidohydrolase superfamily","volume":"44","author":"Seibert","year":"2005","journal-title":"Biochemistry"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1146\/annurev.biochem.70.1.209","article-title":"Divergent evolution of enzymatic function: Mechanistically diverse superfamilies and functionally distinct suprafamilies","volume":"70","author":"Gerlt","year":"2001","journal-title":"Annu. Rev. Biochem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1002\/pro.4158","article-title":"Deciphering CAD: Structure and function of a mega-enzymatic pyrimidine factory in health and disease","volume":"30","year":"2021","journal-title":"Protein Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"33035","DOI":"10.1074\/jbc.R400007200","article-title":"Mammalian pyrimidine biosynthesis: Fresh insights into an ancient pathway","volume":"279","author":"Evans","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1038\/s41467-024-45852-5","article-title":"Hijacking of nucleotide biosynthesis and deamidation-mediated glycolysis by an oncogenic herpesvirus","volume":"15","author":"Wan","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1038\/s41556-023-01146-4","article-title":"De novo pyrimidine biosynthetic complexes support cancer cell proliferation and ferroptosis defence","volume":"25","author":"Yang","year":"2023","journal-title":"Nat. Cell Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1016\/j.cell.2018.07.019","article-title":"Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures","volume":"174","author":"Lee","year":"2018","journal-title":"Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.1038\/s41467-024-45594-4","article-title":"Comprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants","volume":"15","author":"Hayes","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3270","DOI":"10.1158\/0008-5472.CAN-20-3436","article-title":"Afatinib Exerts Immunomodulatory Effects by Targeting the Pyrimidine Biosynthesis Enzyme CAD","volume":"81","author":"Tu","year":"2021","journal-title":"Cancer Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/S0076-6879(99)99017-1","article-title":"Analysis of total phenols and other oxidation substrates and antioxidants by means of folin-ciocalteu reagent","volume":"299","author":"Singleton","year":"1999","journal-title":"Methods Enzymol."},{"key":"ref_85","first-page":"178","article-title":"Estimation of total flavonoid content in propolis by two complementary colorimetric methods","volume":"10","author":"Chang","year":"2002","journal-title":"J. Food Drug Anal."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Lin, E.S., Huang, Y.H., Yang, P.C., Peng, W.F., and Huang, C.Y. (2023). Complexed Crystal Structure of the Dihydroorotase Domain of Human CAD Protein with the Anticancer Drug 5-Fluorouracil. Biomolecules, 13.","DOI":"10.3390\/biom13010149"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1093\/aob\/mcs287","article-title":"Secreted pitfall-trap fluid of carnivorous Nepenthes plants is unsuitable for microbial growth","volume":"111","author":"Buch","year":"2013","journal-title":"Ann. Bot."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/s41581-025-00938-1","article-title":"Endoplasmic reticulum stress as a driver and therapeutic target for kidney disease","volume":"21","author":"Byun","year":"2025","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/s41581-024-00837-x","article-title":"Post-translational modifications in kidney diseases and associated cardiovascular risk","volume":"20","author":"Noels","year":"2024","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/s41585-022-00621-1","article-title":"Potential role of oxidative stress in the pathogenesis of diabetic bladder dysfunction","volume":"19","author":"Song","year":"2022","journal-title":"Nat. Rev. Urol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"511","DOI":"10.2147\/CCID.S500255","article-title":"Progress in the Application of Molecular Hydrogen in Medical Skin Cosmetology","volume":"18","author":"Guo","year":"2025","journal-title":"Clin. Cosmet. Investig. Dermatol."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Choi, J.Y., Ha, N.G., Lee, W.J., and Boo, Y.C. (2025). Synthetic and Natural Agents Targeting Advanced Glycation End-Products for Skin Anti-Aging: A Comprehensive Review of Experimental and Clinical Studies. Antioxidants, 14.","DOI":"10.3390\/antiox14040498"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Zheng, X.Q., Zhang, X.H., Gao, H.Q., Huang, L.Y., Ye, J.J., Ye, J.H., Lu, J.L., Ma, S.C., and Liang, Y.R. (2024). Green Tea Catechins and Skin Health. Antioxidants, 13.","DOI":"10.3390\/antiox13121506"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Ricci, A., Stefanuto, L., Gasperi, T., Bruni, F., and Tofani, D. (2024). Lipid Nanovesicles for Antioxidant Delivery in Skin: Liposomes, Ufasomes, Ethosomes, and Niosomes. Antioxidants, 13.","DOI":"10.3390\/antiox13121516"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"425","DOI":"10.2174\/1568026622666220117104709","article-title":"A Comprehensive Review on Current Perspectives of Flavonoids as Antimicrobial Agent","volume":"22","author":"Gupta","year":"2022","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2456","DOI":"10.2174\/1568026615666150619141702","article-title":"Anti-inflammatory glycosylated flavonoids as therapeutic agents for treatment of diabetes-impaired wounds","volume":"15","year":"2015","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.2174\/1568026622666220221110506","article-title":"The Antibacterial Activity of Natural-derived Flavonoids","volume":"22","author":"Tan","year":"2022","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s12964-023-01451-3","article-title":"Exosomes in skin photoaging: Biological functions and therapeutic opportunity","volume":"22","author":"Soheilifar","year":"2024","journal-title":"Cell Commun. Signal."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/j.1365-2362.1994.tb02253.x","article-title":"alpha-Glucosidase inhibitors in diabetes: Efficacy in NIDDM subjects","volume":"24","author":"Toeller","year":"1994","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"8825","DOI":"10.1002\/fsn3.4555","article-title":"Effects of Resveratrol on Nonmelanoma Skin Cancer (NMSC): A Comprehensive Review","volume":"12","author":"Zamanian","year":"2024","journal-title":"Food Sci. Nutr."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Alghuthaymi, M.A., Patil, S., Rajkuberan, C., Krishnan, M., Krishnan, U., and Abd-Elsalam, K.A. (2023). Polianthes tuberosa-Mediated Silver Nanoparticles from Flower Extract and Assessment of Their Antibacterial and Anticancer Potential: An In Vitro Approach. Plants, 12.","DOI":"10.3390\/plants12061261"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1111\/exd.14621","article-title":"UVB-induced SFRP1 methylation potentiates skin damage by promoting cell apoptosis and DNA damage","volume":"31","author":"Liang","year":"2022","journal-title":"Exp. Dermatol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3892\/ol.2020.12321","article-title":"Antitumor effects of dioscin in A431 cells via adjusting ATM\/p53-mediated cell apoptosis, DNA damage and migration","volume":"21","author":"Wang","year":"2021","journal-title":"Oncol. Lett."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Guan, H.H., Huang, Y.H., Lin, E.S., Chen, C.J., and Huang, C.Y. (2021). Structural Analysis of Saccharomyces cerevisiae Dihydroorotase Reveals Molecular Insights into the Tetramerization Mechanism. Molecules, 26.","DOI":"10.3390\/molecules26237249"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Guan, H.H., Huang, Y.H., Lin, E.S., Chen, C.J., and Huang, C.Y. (2021). Complexed Crystal Structure of Saccharomyces cerevisiae Dihydroorotase with Inhibitor 5-Fluoroorotate Reveals a New Binding Mode. Bioinorg. Chem. Appl., 2021.","DOI":"10.1155\/2021\/2572844"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.bbrc.2021.03.001","article-title":"Structural basis for the interaction modes of dihydroorotase with the anticancer drugs 5-fluorouracil and 5-aminouracil","volume":"551","author":"Guan","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.2174\/0929866522666151008151145","article-title":"Creation of a putative third metal binding site in type II dihydroorotases significantly enhances enzyme activity","volume":"22","author":"Huang","year":"2015","journal-title":"Protein Pept. Lett."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0023-6438(95)80008-5","article-title":"Use of a free radical method to evaluate antioxidant activity","volume":"28","author":"Cuvelier","year":"1995","journal-title":"LWT Food Sci. Technol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.jpha.2015.11.005","article-title":"Methods for in vitro evaluating antimicrobial activity: A review","volume":"6","author":"Balouiri","year":"2016","journal-title":"J. Pharm. Anal."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s10930-010-9272-2","article-title":"Identification and characterization of a putative dihydroorotase, KPN01074, from Klebsiella pneumoniae","volume":"29","author":"Wang","year":"2010","journal-title":"Protein J."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.bbrc.2004.05.163","article-title":"Inhibition effects of (+)-catechin-aldehyde polycondensates on proteinases causing proteolytic degradation of extracellular matrix","volume":"320","author":"Kim","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1055\/s-2006-957470","article-title":"The inhibitory components from Artocarpus incisus on melanin biosynthesis","volume":"64","author":"Shimizu","year":"1998","journal-title":"Planta Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"16723","DOI":"10.3390\/molecules200916723","article-title":"Anti-Oxidant, Anti-Aging, and Anti-Melanogenic Properties of the Essential Oils from Two Varieties of Alpinia zerumbet","volume":"20","author":"Tu","year":"2015","journal-title":"Molecules"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"},{"key":"ref_115","first-page":"1111","article-title":"A rapid fluorometric method for semiautomated determination of cytotoxicity and cellular proliferation of human tumor cell lines in microculture","volume":"9","author":"Larsson","year":"1989","journal-title":"Anticancer. Res."},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Chen, M.H., Yang, W.L., Lin, K.T., Liu, C.H., Liu, Y.W., Huang, K.W., Chang, P.M., Lai, J.M., Hsu, C.N., and Chao, K.M. (2011). Gene expression-based chemical genomics identifies potential therapeutic drugs in hepatocellular carcinoma. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027186"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nprot.2007.30","article-title":"In vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro","volume":"2","author":"Liang","year":"2007","journal-title":"Nat. Protoc."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1385\/1-59259-973-7:275","article-title":"The comet assay: A sensitive genotoxicity test for the detection of DNA damage and repair","volume":"314","author":"Speit","year":"2006","journal-title":"Methods Mol. Biol."}],"container-title":["Plants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2223-7747\/14\/16\/2579\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:31:17Z","timestamp":1760034677000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2223-7747\/14\/16\/2579"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,19]]},"references-count":118,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["plants14162579"],"URL":"https:\/\/doi.org\/10.3390\/plants14162579","relation":{},"ISSN":["2223-7747"],"issn-type":[{"value":"2223-7747","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,19]]}}}