{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T16:41:23Z","timestamp":1777912883702,"version":"3.51.4"},"reference-count":81,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T00:00:00Z","timestamp":1745884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["SFB 1278\/2 PolyTarget- 316213987\u2014D02, C02, Z01"],"award-info":[{"award-number":["SFB 1278\/2 PolyTarget- 316213987\u2014D02, C02, Z01"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Influenza A virus (IAV) infections continue to threaten public health. Current strategies, such as vaccines and antiviral drugs, are limited due to their time-consuming development and drug-resistant strains. Therefore, new effective treatments are needed. Here, virus-supportive cellular factors are promising drug targets, and the encapsulation of candidate substances in poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) is intended to improve their bioavailability. This study investigates the potential of the indirubin derivative 6-bromoindirubin-3\u2032-glycerol-oxime ether (6BIGOE), a glycogen synthase kinase 3 (GSK-3)\u03b2 inhibitor, for its potential to regulate IAV replication in vitro. The effects of 6BIGOE-loaded PLGA NPs on cell metabolism were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays in A549 and Calu-3 cells. Viral replication and spread were monitored in various IAV-infected cell lines in the absence and presence of free and 6BIGOE-loaded PLGA NPs via plaque assays and Western blot analysis. The encapsulation of 6BIGOE in PLGA NPs resulted in reduced negative side effects on cell viability while maintaining antiviral efficacy. Both encapsulated and free 6BIGOE exhibited antiviral activity, potentially through GSK-3\u03b2 inhibition and the disruption of key signaling pathways required for viral replication. The data indicate 6BIGOE, particularly after encapsulation in NPs, as a potential candidate for further investigation and development as an antiviral agent to treat IAV infections.<\/jats:p>","DOI":"10.3390\/ijms26094235","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T09:00:39Z","timestamp":1745917239000},"page":"4235","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Anti-Influenza Activity of 6BIGOE: Improved Pharmacological Profile After Encapsulation in PLGA Nanoparticles"],"prefix":"10.3390","volume":"26","author":[{"given":"Josefine","family":"Schroeder","sequence":"first","affiliation":[{"name":"Section of Experimental Virology, Institute of Medical Microbiology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans Knoell-Str. 2, 07745 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1353-5922","authenticated-orcid":false,"given":"Jan","family":"Westhoff","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Technology and Biopharmacy, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Cauerstr. 4, 91058 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Vilotijevi\u0107","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena, Humboldtstr. 10, 07743 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5064-4379","authenticated-orcid":false,"given":"Oliver","family":"Werz","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, 07743 Jena, Germany"},{"name":"Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5770-5197","authenticated-orcid":false,"given":"Stephanie","family":"Hoeppener","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena, Humboldtstr. 10, 07743 Jena, Germany"},{"name":"Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bettina","family":"L\u00f6ffler","sequence":"additional","affiliation":[{"name":"Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany"},{"name":"Institute of Medical Microbiology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dagmar","family":"Fischer","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Technology and Biopharmacy, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Cauerstr. 4, 91058 Erlangen, Germany"},{"name":"Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany"},{"name":"FAU NeW-Research Center for New Bioactive Compounds, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8879-6087","authenticated-orcid":false,"given":"Christina","family":"Ehrhardt","sequence":"additional","affiliation":[{"name":"Section of Experimental Virology, Institute of Medical Microbiology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans Knoell-Str. 2, 07745 Jena, Germany"},{"name":"Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"ref_1","first-page":"659","article-title":"Influenza update: A review of currently available vaccines","volume":"36","author":"Clayville","year":"2011","journal-title":"Pharm. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1016\/S0140-6736(17)33293-2","article-title":"Estimates of global seasonal influenza-associated respiratory mortality: A modelling study","volume":"391","author":"Iuliano","year":"2018","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1128\/mr.56.1.152-179.1992","article-title":"Evolution and ecology of influenza A viruses","volume":"56","author":"Webster","year":"1992","journal-title":"Microbiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1001\/archinte.1994.00420220037005","article-title":"Prevention of respiratory infections in adults. Influenza and pneumococcal vaccines","volume":"154","author":"Fiebach","year":"1994","journal-title":"Arch. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s00018-025-05611-1","article-title":"Antiviral strategies against influenza virus: An update on approved and innovative therapeutic approaches","volume":"82","author":"Bonomini","year":"2025","journal-title":"Cell Mol. Life Sci."},{"key":"ref_6","first-page":"Doc02","article-title":"Prophylaxis and treatment of influenza: Options, antiviral susceptibility, and existing recommendations","volume":"9","author":"Duwe","year":"2021","journal-title":"GMS Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.coviro.2014.04.009","article-title":"The epidemiology and spread of drug resistant human influenza viruses","volume":"8","author":"Hurt","year":"2014","journal-title":"Curr. Opin. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Meineke, R., Rimmelzwaan, G.F., and Elbahesh, H. (2019). Influenza Virus Infections and Cellular Kinases. Viruses, 11.","DOI":"10.3390\/v11020171"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/978-1-4419-1132-2_15","article-title":"New strategies to overcome the drawbacks of currently available flu vaccines","volume":"655","author":"Fichera","year":"2009","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/nature08699","article-title":"Human host factors required for influenza virus replication","volume":"463","author":"Konig","year":"2010","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.semcancer.2017.12.010","article-title":"Glycogen synthase kinases: Moonlighting proteins with theranostic potential in cancer","volume":"56","author":"Nagini","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.jbior.2017.06.003","article-title":"GSK3 and its interactions with the PI3K\/AKT\/mTOR signalling network","volume":"65","author":"Hermida","year":"2017","journal-title":"Adv. Biol. Regul."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4629495","DOI":"10.1155\/2017\/4629495","article-title":"Multifaceted Roles of GSK-3 in Cancer and Autophagy-Related Diseases","volume":"2017","author":"Mancinelli","year":"2017","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lin, J., Song, T., Li, C., and Mao, W. (2020). GSK-3beta in DNA repair, apoptosis, and resistance of chemotherapy, radiotherapy of cancer. Biochim. Biophys. Acta Mol. Cell Res., 1867.","DOI":"10.1016\/j.bbamcr.2020.118659"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1080\/01616412.2019.1709744","article-title":"Anvirzel(TM)regulates cell death through inhibiting GSK-3 activity in human U87 glioma cells","volume":"42","author":"Nalli","year":"2020","journal-title":"Neurol. Res."},{"key":"ref_16","first-page":"381029","article-title":"Small-Molecule Inhibitors of GSK-3: Structural Insights and Their Application to Alzheimer\u2019s Disease Models","volume":"2012","author":"Kramer","year":"2012","journal-title":"Int. J. Alzheimers Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1055\/s-0044-100186","article-title":"GSK-3 Inhibitors: A Double-Edged Sword?\u2014An Update on Tideglusib","volume":"68","author":"Mathuram","year":"2018","journal-title":"Drug Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"588","DOI":"10.2337\/diabetes.52.3.588","article-title":"Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo","volume":"52","author":"Ring","year":"2003","journal-title":"Diabetes"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Hoffmeister, L., Diekmann, M., Brand, K., and Huber, R. (2020). GSK3: A Kinase Balancing Promotion and Resolution of Inflammation. Cells, 9.","DOI":"10.3390\/cells9040820"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Alfhili, M.A., Alsughayyir, J., McCubrey, J.A., and Akula, S.M. (2020). GSK-3-associated signaling is crucial to virus infection of cells. Biochim. Biophys. Acta Mol. Cell Res., 1867.","DOI":"10.1016\/j.bbamcr.2020.118767"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1128\/JVI.01940-13","article-title":"Novel neuroprotective GSK-3beta inhibitor restricts Tat-mediated HIV-1 replication","volume":"88","author":"Guendel","year":"2014","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.bbrc.2016.09.135","article-title":"Melittin ameliorates CVB3-induced myocarditis via activation of the HDAC2-mediated GSK-3beta\/Nrf2\/ARE signaling pathway","volume":"480","author":"Wang","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1038\/sj.cdd.4401652","article-title":"Inhibition of glycogen synthase kinase 3beta suppresses coxsackievirus-induced cytopathic effect and apoptosis via stabilization of beta-catenin","volume":"12","author":"Yuan","year":"2005","journal-title":"Cell Death Differ."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.cellsig.2006.07.003","article-title":"Varicella-zoster virus requires a functional PI3K\/Akt\/GSK-3alpha\/beta signaling cascade for efficient replication","volume":"19","author":"Rahaus","year":"2007","journal-title":"Cell Signal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5229","DOI":"10.1074\/jbc.M805747200","article-title":"Glycogen synthase kinase-3 regulates the phosphorylation of severe acute respiratory syndrome coronavirus nucleocapsid protein and viral replication","volume":"284","author":"Wu","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/j.bbrc.2014.06.077","article-title":"Inhibition of Akt kinase activity suppresses entry and replication of influenza virus","volume":"450","author":"Hirata","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: Progress, challenges and recommendations","volume":"18","author":"Pushpakom","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1517\/13543776.2015.1019865","article-title":"Indirubin derivatives: A patent review (2010-present)","volume":"25","author":"Vougogiannopoulou","year":"2015","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1074\/jbc.M002466200","article-title":"Indirubins inhibit glycogen synthase kinase-3 beta and CDK5\/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer\u2019s disease. A property common to most cyclin-dependent kinase inhibitors?","volume":"276","author":"Leclerc","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wang, J., Yang, C., Liang, Z., Sun, J., Zhang, M., Qiu, S., Du, X., He, X., Pang, X., and Ma, X. (2024). Indirubin-3\u2032-monoxime exhibits potent antiviral and anti-inflammatory effects against human adenoviruses in vitro and in vivo. Biomed. Pharmacother., 174.","DOI":"10.1016\/j.biopha.2024.116558"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.antiviral.2014.03.019","article-title":"Anti-inflammatory and antiviral effects of indirubin derivatives in influenza A (H5N1) virus infected primary human peripheral blood-derived macrophages and alveolar epithelial cells","volume":"106","author":"Mok","year":"2014","journal-title":"Antiviral Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1097\/01.aids.0000194805.74293.11","article-title":"Indirubin-3\u2032-monoxime, a derivative of a Chinese antileukemia medicine, inhibits P-TEFb function and HIV-1 replication","volume":"19","author":"Heredia","year":"2005","journal-title":"AIDS"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.jep.2009.02.028","article-title":"The cytotoxicity to leukemia cells and antiviral effects of Isatis indigotica extracts on pseudorabies virus","volume":"123","author":"Hsuan","year":"2009","journal-title":"J. Ethnopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"925830","DOI":"10.1155\/2012\/925830","article-title":"Antiviral Activity of Isatis indigotica Extract and Its Derived Indirubin against Japanese Encephalitis Virus","volume":"2012","author":"Chang","year":"2012","journal-title":"Evid. Based Complement. Alternat Med."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Czapka, A., Konig, S., Pergola, C., Grune, C., Vougogiannopoulou, K., Skaltsounis, A.L., Fischer, D., and Werz, O. (2020). The indirubin derivative 6-bromoindirubin-3\u2032-glycerol-oxime ether (6BIGOE) potently modulates inflammatory cytokine and prostaglandin release from human monocytes through GSK-3 interference. Biochem. Pharmacol., 180.","DOI":"10.1016\/j.bcp.2020.114170"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Dan, N.T., Quang, H.D., Van Truong, V., Huu Nghi, D., Cuong, N.M., Cuong, T.D., Toan, T.Q., Bach, L.G., Anh, N.H.T., and Mai, N.T. (2020). Design, synthesis, structure, in vitro cytotoxic activity evaluation and docking studies on target enzyme GSK-3beta of new indirubin-3\u2032-oxime derivatives. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-68134-8"},{"key":"ref_37","first-page":"195727","article-title":"Drug solubility: Importance and enhancement techniques","volume":"2012","author":"Savjani","year":"2012","journal-title":"ISRN Pharm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1080\/10717544.2021.1938756","article-title":"PLGA-based biodegradable microspheres in drug delivery: Recent advances in research and application","volume":"28","author":"Su","year":"2021","journal-title":"Drug Deliv."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1208\/s12249-023-02502-1","article-title":"Application of PLGA as a Biodegradable and Biocompatible Polymer for Pulmonary Delivery of Drugs","volume":"24","author":"Mahar","year":"2023","journal-title":"AAPS PharmSciTech"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"474","DOI":"10.2174\/13816128113199990400","article-title":"Nanotechnology versus other techniques in improving drug dissolution","volume":"20","author":"Kwok","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"560","DOI":"10.2174\/1389450116666150202163022","article-title":"Multiscale Imaging of Nanoparticle Drug Delivery","volume":"16","author":"Dobrucki","year":"2015","journal-title":"Curr. Drug Targets"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.3390\/polym3031377","article-title":"Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier","volume":"3","author":"Makadia","year":"2011","journal-title":"Polymers"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.jconrel.2012.01.043","article-title":"PLGA-based nanoparticles: An overview of biomedical applications","volume":"161","author":"Danhier","year":"2012","journal-title":"J. Control Release"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Czapka, A., Grune, C., Schadel, P., Bachmann, V., Scheuer, K., Dirauf, M., Weber, C., Skaltsounis, A.L., Jandt, K.D., and Schubert, U.S. (2022). Drug delivery of 6-bromoindirubin-3\u2032-glycerol-oxime ether employing poly(D,L-lactide-co-glycolide)-based nanoencapsulation techniques with sustainable solvents. J. Nanobiotechnol., 20.","DOI":"10.1186\/s12951-021-01179-7"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Bachmann, V., Schadel, P., Westhoff, J., Peric, M., Schomberg, F., Skaltsounis, A.L., Hoppener, S., Pantsar, T., Fischer, D., and Vilotijevic, I. (2024). Bromo-substituted indirubins for inhibition of protein kinase-mediated signalling involved in inflammatory mediator release in human monocytes. Bioorg Chem., 149.","DOI":"10.1016\/j.bioorg.2024.107470"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6421","DOI":"10.1021\/jm800648y","article-title":"Soluble 3\u2032,6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase -3 alter circadian period","volume":"51","author":"Vougogiannopoulou","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.ejps.2013.08.021","article-title":"Physicochemical characterization and in vitro permeation of an indirubin derivative","volume":"50","author":"Heshmati","year":"2013","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.jpba.2018.10.039","article-title":"Preliminary pharmacokinetic study of the anticancer 6BIO in mice using an UHPLC-MS\/MS approach","volume":"164","author":"Tchoumtchoua","year":"2019","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Wiese-Rischke, C., Murkar, R.S., and Walles, H. (2021). Biological Models of the Lower Human Airways-Challenges and Special Requirements of Human 3D Barrier Models for Biomedical Research. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13122115"},{"key":"ref_50","first-page":"L493","article-title":"Calu-3: A human airway epithelial cell line that shows cAMP-dependent Cl- secretion","volume":"266","author":"Shen","year":"1994","journal-title":"Am. J. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1002\/ijc.2910170110","article-title":"A continuous tumor-cell line from a human lung carcinoma with properties of type II alveolar epithelial cells","volume":"17","author":"Lieber","year":"1976","journal-title":"Int. J. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3792","DOI":"10.1002\/jps.23696","article-title":"Enhancement of oral bioavailability of E804 by self-nanoemulsifying drug delivery system (SNEDDS) in rats","volume":"102","author":"Heshmati","year":"2013","journal-title":"J. Pharm. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Guo, X., Zuo, X., Zhou, Z., Gu, Y., Zheng, H., Wang, X., Wang, G., Xu, C., and Wang, F. (2023). PLGA-Based Micro\/Nanoparticles: An Overview of Their Applications in Respiratory Diseases. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054333"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Mundekkad, D., and Cho, W.C. (2022). Nanoparticles in Clinical Translation for Cancer Therapy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031685"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"413","DOI":"10.2174\/0929867043455909","article-title":"Nanoparticles of biodegradable polymers for clinical administration of paclitaxel","volume":"11","author":"Feng","year":"2004","journal-title":"Curr. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2790","DOI":"10.1016\/j.biomaterials.2009.01.057","article-title":"The uptake and intracellular fate of PLGA nanoparticles in epithelial cells","volume":"30","author":"Cartiera","year":"2009","journal-title":"Biomaterials"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Vij, N., Min, T., Marasigan, R., Belcher, C.N., Mazur, S., Ding, H., Yong, K.T., and Roy, I. (2010). Development of PEGylated PLGA nanoparticle for controlled and sustained drug delivery in cystic fibrosis. J. Nanobiotechnol., 8.","DOI":"10.1186\/1477-3155-8-22"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1021\/mp900138a","article-title":"Partial correction of cystic fibrosis defects with PLGA nanoparticles encapsulating curcumin","volume":"7","author":"Cartiera","year":"2010","journal-title":"Mol. Pharm."},{"key":"ref_59","first-page":"4553","article-title":"Effects of Caryota mitis profilin-loaded PLGA nanoparticles in a murine model of allergic asthma","volume":"8","author":"Xiao","year":"2013","journal-title":"Int. J. Nanomed."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1016\/j.ejpb.2014.09.012","article-title":"Synergistic co-delivery of doxorubicin and paclitaxel by porous PLGA microspheres for pulmonary inhalation treatment","volume":"88","author":"Feng","year":"2014","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Kwok, H.H., Poon, P.Y., Fok, S.P., Ying-Kit Yue, P., Mak, N.K., Chan, M.C., Peiris, J.S., and Wong, R.N. (2016). Anti-inflammatory effects of indirubin derivatives on influenza A virus-infected human pulmonary microvascular endothelial cells. Sci. Rep., 6.","DOI":"10.1038\/srep18941"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1111\/j.1462-5822.2009.01309.x","article-title":"A new player in a deadly game: Influenza viruses and the PI3K\/Akt signalling pathway","volume":"11","author":"Ehrhardt","year":"2009","journal-title":"Cell Microbiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3058","DOI":"10.1128\/JVI.02082-06","article-title":"Influenza A virus NS1 protein activates the PI3K\/Akt pathway to mediate antiapoptotic signaling responses","volume":"81","author":"Ehrhardt","year":"2007","journal-title":"J. Virol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Srinivasan, S., Burckhardt, C.J., Bhave, M., Chen, Z., Chen, P.H., Wang, X., Danuser, G., and Schmid, S.L. (2018). A noncanonical role for dynamin-1 in regulating early stages of clathrin-mediated endocytosis in non-neuronal cells. PLoS Biol., 16.","DOI":"10.1101\/251983"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nn.2571","article-title":"Dynamin I phosphorylation by GSK3 controls activity-dependent bulk endocytosis of synaptic vesicles","volume":"13","author":"Clayton","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2132","DOI":"10.15252\/embj.201591518","article-title":"Crosstalk between Akt\/GSK3beta signaling and dynamin-1 regulates clathrin-mediated endocytosis","volume":"34","author":"Reis","year":"2015","journal-title":"EMBO J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.1128\/AAC.02798-13","article-title":"Akt inhibitor MK2206 prevents influenza pH1N1 virus infection in vitro","volume":"58","author":"Denisova","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/j.jep.2011.01.005","article-title":"Mechanism of action of the suppression of influenza virus replication by Ko-Ken Tang through inhibition of the phosphatidylinositol 3-kinase\/Akt signaling pathway and viral RNP nuclear export","volume":"134","author":"Wu","year":"2011","journal-title":"J. Ethnopharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"10189","DOI":"10.1074\/jbc.M210837200","article-title":"Identification of a proline-rich Akt substrate as a 14-3-3 binding partner","volume":"278","author":"Kovacina","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.cellsig.2010.02.002","article-title":"Phosphorylation of PRAS40 on Thr246 by PKB\/AKT facilitates efficient phosphorylation of Ser183 by mTORC1","volume":"22","author":"Nascimento","year":"2010","journal-title":"Cell Signal"},{"key":"ref_71","first-page":"3625","article-title":"Phosphorylation of PRAS40 contributes to the activation of the PI3K\/AKT\/mTOR signaling pathway and the inhibition of autophagy following status epilepticus in rats","volume":"20","author":"Lin","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"E1453","DOI":"10.1152\/ajpendo.00660.2011","article-title":"Role of PRAS40 in Akt and mTOR signaling in health and disease","volume":"302","author":"Wiza","year":"2012","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"69076","DOI":"10.18632\/oncotarget.17299","article-title":"PRAS40 signaling in tumor","volume":"8","author":"Lv","year":"2017","journal-title":"Oncotarget"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1080\/1061186X.2021.1882470","article-title":"Targeting PRAS40: A novel therapeutic strategy for human diseases","volume":"29","author":"Zhou","year":"2021","journal-title":"J. Drug Target."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1038\/nchembio.645","article-title":"Chemical inhibition of RNA viruses reveals REDD1 as a host defense factor","volume":"7","author":"Mata","year":"2011","journal-title":"Nat. Chem. Biol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Kuss-Duerkop, S.K., Wang, J., Mena, I., White, K., Metreveli, G., Sakthivel, R., Mata, M.A., Munoz-Moreno, R., Chen, X., and Krammer, F. (2017). Influenza virus differentially activates mTORC1 and mTORC2 signaling to maximize late stage replication. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006635"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"372","DOI":"10.3109\/07853890.2014.912836","article-title":"PI3K\/AKT signaling pathway and cancer: An updated review","volume":"46","author":"Martini","year":"2014","journal-title":"Ann. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1097\/01.cad.0000173476.67239.3b","article-title":"PI3K\/Akt\/mTOR pathway as a target for cancer therapy","volume":"16","author":"Morgensztern","year":"2005","journal-title":"Anticancer. Drugs"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s12964-018-0287-1","article-title":"WNK pathways in cancer signaling networks","volume":"16","author":"Karra","year":"2018","journal-title":"Cell Commun. Signal"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1161\/HYPERTENSIONAHA.112.201509","article-title":"Phosphatidylinositol 3-kinase\/Akt signaling pathway activates the WNK-OSR1\/SPAK-NCC phosphorylation cascade in hyperinsulinemic db\/db mice","volume":"60","author":"Nishida","year":"2012","journal-title":"Hypertension"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4235\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:24:14Z","timestamp":1760030654000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4235"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,29]]},"references-count":81,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26094235"],"URL":"https:\/\/doi.org\/10.3390\/ijms26094235","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,29]]}}}