{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T14:35:14Z","timestamp":1771338914715,"version":"3.50.1"},"reference-count":71,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T00:00:00Z","timestamp":1740096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82173731"],"award-info":[{"award-number":["82173731"]}]},{"name":"National Natural Science Foundation of China","award":["21ZR1427300"],"award-info":[{"award-number":["21ZR1427300"]}]},{"name":"National Natural Science Foundation of China","award":["34050002"],"award-info":[{"award-number":["34050002"]}]},{"name":"Natural Science Foundation of Shanghai","award":["82173731"],"award-info":[{"award-number":["82173731"]}]},{"name":"Natural Science Foundation of Shanghai","award":["21ZR1427300"],"award-info":[{"award-number":["21ZR1427300"]}]},{"name":"Natural Science Foundation of Shanghai","award":["34050002"],"award-info":[{"award-number":["34050002"]}]},{"name":"Shanghai Frontiers Research Center of the Hadal Biosphere","award":["82173731"],"award-info":[{"award-number":["82173731"]}]},{"name":"Shanghai Frontiers Research Center of the Hadal Biosphere","award":["21ZR1427300"],"award-info":[{"award-number":["21ZR1427300"]}]},{"name":"Shanghai Frontiers Research Center of the Hadal Biosphere","award":["34050002"],"award-info":[{"award-number":["34050002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In recent years, arginine-rich basic proteins have garnered significant attention due to their essential roles in various biological processes. However, the potential of marine-derived proteins in this domain remains largely unexplored. This study presents, for the first time, the isolation and purification of a 14.3 kDa protamine (SOP) from the mature spermatogonial tissues of Symplectoteuthis oualaniensis. Additionally, we obtained an 18.5 kDa PEGylated derivative, SOP-PEG. The physicochemical properties of both SOP and SOP-PEG were comprehensively characterized using SEM, FTIR, CD, and TGA. PEGylation markedly altered the surface morphology, secondary structure, and thermal stability of SOP. In vitro studies demonstrated that PEGylation significantly enhanced the biocompatibility of SOP, leading to improved proliferation of L-929 fibroblasts. Furthermore, both SOP and its PEGylated derivative (SOP-PEG) regulated the cell cycle, activated the PI3K-Akt signaling pathway, and modulated anti-apoptotic mechanisms, suggesting their potential to support cell survival and facilitate tissue regeneration. Notably, SOP-PEG exhibited superior bioactivity, likely attributable to its enhanced delivery efficiency conferred by PEGylation. Collectively, these findings underscore the promising applications of SOP and SOP-PEG in regenerative medicine and highlight the pivotal role of PEGylation in augmenting the bioactivity of SOP.<\/jats:p>","DOI":"10.3390\/ijms26051869","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T11:08:50Z","timestamp":1740136130000},"page":"1869","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Polyethylene Glycolylation of the Purified Basic Protein (Protamine) of Squid (Symplectoteuthis oualaniensis): Structural Changes and Evaluation of Proliferative Effects on Fibroblast"],"prefix":"10.3390","volume":"26","author":[{"given":"Na","family":"Li","sequence":"first","affiliation":[{"name":"Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiren","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4115-9918","authenticated-orcid":false,"given":"Jeevithan","family":"Elango","sequence":"additional","affiliation":[{"name":"Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"},{"name":"Department of Biomaterials Engineering, Faculty of Health Sciences, UCAM-Universidad Cat\u00f3lica San Antonio de Murcia, Guadalupe, 30107 Murcia, Spain"},{"name":"Center of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600077, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1710-8582","authenticated-orcid":false,"given":"Wenhui","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"},{"name":"Marine Biomedical Science and Technology Innovation Platform of Lin-gang Special Area, Shanghai 201306, China"},{"name":"Putuo Branch of International Combined Research Center for Marine Biological Sciences, Zhoushan 316104, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Khalifa, S., Elias, N., Farag, M., Chen, L., Saeed, A., Hegazy, M.E., Moustafa, M., Abd Elwahed, A., Al-Mousawi, S., and Musharraf, S. (2019). Marine Drugs Marine Natural Products: A Source of Novel Anticancer Drugs. Mar. Drugs, 17.","DOI":"10.3390\/md17090491"},{"key":"ref_2","unstructured":"Verma, A.S., and Singh, A. (2020). Chapter 28\u2014Marine Resources and Animals in Modern Biotechnology. Animal Biotechnology, Academic Press. [2nd ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Li, R., and Li, P. (2023). High-Value Utilization of Marine Biological Resources. Foods, 12.","DOI":"10.3390\/foods12224054"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Nimesh, S. (2013). 12\u2014Protamine Nanoparticles. Gene Therapy, Woodhead Publishing.","DOI":"10.1533\/9781908818645"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"116256","DOI":"10.1016\/j.lwt.2024.116256","article-title":"Ultrasound-Assisted Acid Extraction of Coregonus peled Protamine: Extraction, Physicochemical and Functional Properties","volume":"201","author":"Wang","year":"2024","journal-title":"LWT"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1016\/j.procbio.2006.04.001","article-title":"Purification and Analysis of Protamine","volume":"41","author":"Gill","year":"2006","journal-title":"Process Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/978-1-62703-038-0_38","article-title":"Protamine Extraction and Analysis of Human Sperm Protamine 1\/Protamine 2 Ratio Using Acid Gel Electrophoresis","volume":"927","author":"Liu","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Gupta, S., Tiwari, N., and Munde, M. (2019). A Comprehensive Biophysical Analysis of the Effect of DNA Binding Drugs on Protamine-Induced DNA Condensation. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-41975-8"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Jarzebska, N.T., Mellett, M., Frei, J., K\u00fcndig, T.M., and Pascolo, S. (2021). Protamine-Based Strategies for RNA Transfection. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13060877"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Nemeno, J.G.E., Lee, S., Yang, W., Lee, K.M., and Lee, J.I. (2014). Applications and Implications of Heparin and Protamine in Tissue Engineering and Regenerative Medicine. Biomed. Res. Int., 2014.","DOI":"10.1155\/2014\/936196"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/s11671-015-0845-z","article-title":"Protamine Nanoparticles for Improving shRNA-Mediated Anti-Cancer Effects","volume":"10","author":"Liu","year":"2015","journal-title":"Nanoscale Res. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1007\/s40496-024-00385-0","article-title":"Protamine: Current Insights and Evolving Applications in Medical and Dental Perspectives","volume":"11","author":"Alshargabi","year":"2024","journal-title":"Curr. Oral Health Rep."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wei, M., Jeevithan, L., Li, N., Liu, L., Xu, J., Wu, W., and Elango, J. (2024). Stem-Cell-Regenerative and Protective Effects of Squid (Symplectoteuthis oualaniensis) Skin Collagen Peptides Against H2O2-Induced Fibroblast Injury. Mar. Drugs, 22.","DOI":"10.3390\/md22060255"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/0092-1157(88)90012-1","article-title":"The Establishment and Characterization of Mouse L-929 Cells in Protein-Free Eagle\u2019s Minimal Essential Medium","volume":"16","author":"Cinatl","year":"1988","journal-title":"J. Biol. Stand."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Schmitz, W., Koderer, C., El-Mesery, M., Gubik, S., Sampers, R., Straub, A., K\u00fcbler, A.C., and Seher, A. (2021). Metabolic Fingerprinting of Murine L929 Fibroblasts as a Cell-Based Tumour Suppressor Model System for Methionine Restriction. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063039"},{"key":"ref_16","first-page":"863","article-title":"Mouse Fibroblast L929 Cell Line as a Useful Tool for Replication and Adaptation of Infectious Bursal Disease Virus","volume":"78","author":"Torabi","year":"2023","journal-title":"Arch. Razi Inst."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2801","DOI":"10.1016\/j.bbamem.2012.06.019","article-title":"Comparative Studies of Polyethylene Glycol-Modified Liposomes Prepared Using Different PEG-Modification Methods","volume":"1818","author":"Nakamura","year":"2012","journal-title":"Biochim. Biophys. Acta (BBA) Biomembr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2300105","DOI":"10.1002\/adhm.202300105","article-title":"Poly Ethylene Glycol (PEG)-Based Hydrogels for Drug Delivery in Cancer Therapy: A Comprehensive Review","volume":"12","author":"Wang","year":"2023","journal-title":"Adv. Healthc. Mater."},{"key":"ref_19","unstructured":"Parambath, A. (2018). 14\u2014PEGylation and Its Alternatives: A Summary. Engineering of Biomaterials for Drug Delivery Systems, Woodhead Publishing."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.addr.2015.09.012","article-title":"PEGylation as a Strategy for Improving Nanoparticle-Based Drug and Gene Delivery","volume":"99","author":"Suk","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"105","DOI":"10.2174\/138920012798356934","article-title":"PEGylation of Proteins and Liposomes: A Powerful and Flexible Strategy to Improve the Drug Delivery","volume":"13","author":"Milla","year":"2012","journal-title":"Curr. Drug Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.cbpa.2016.08.006","article-title":"How PEGylation Influences Protein Conformational Stability","volume":"34","author":"Lawrence","year":"2016","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"106808","DOI":"10.1016\/j.elecom.2020.106808","article-title":"A Highly Selective Electrochemical Assay Based on the Sakaguchi Reaction for the Detection of Protein Arginine Methylation State","volume":"118","author":"He","year":"2020","journal-title":"Electrochem. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"110776","DOI":"10.1016\/j.mehy.2022.110776","article-title":"Low Molecular Weight Protamine-Corticosteroid Conjugate for Topical Treatment of Psoriasis: A Hypothesis","volume":"160","author":"Cheng","year":"2022","journal-title":"Med. Hypotheses"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0049-3848(98)00201-1","article-title":"Low Molecular Weight Protamine: A Potential Nontoxic Heparin Antagonist","volume":"94","author":"Byun","year":"1999","journal-title":"Thromb. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Balhorn, R. (2007). The Protamine Family of Sperm Nuclear Proteins. Genome Biol., 8.","DOI":"10.1186\/gb-2007-8-9-227"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ookubo, M., Tashiro, Y., Asano, K., Kamei, Y., Tanaka, Y., Honda, T., Yokoyama, T., and Honda, M. (2024). \u201cRich Arginine and Strong Positive Charge\u201d Antimicrobial Protein Protamine: From Its Action on Cell Membranes to Inhibition of Bacterial Vital Functions. Biochim. Biophys. Acta (BBA)Biomembr., 1866.","DOI":"10.1016\/j.bbamem.2024.184323"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4947","DOI":"10.21037\/tcr-21-1582","article-title":"The Expression, Function, and Utilization of Protamine1: A Literature Review","volume":"10","author":"Ren","year":"2021","journal-title":"Transl. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"42083","DOI":"10.1021\/acsomega.2c04227","article-title":"Exploring Structures and Dynamics of Protamine Molecules Through Molecular Dynamics Simulations","volume":"7","author":"Shadman","year":"2022","journal-title":"ACS Omega"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2860","DOI":"10.1093\/nar\/29.13.2860","article-title":"Amino Acid\u2013Base Interactions: A Three-Dimensional Analysis of Protein\u2013DNA Interactions at an Atomic Level","volume":"29","author":"Luscombe","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.ijbiomac.2015.03.054","article-title":"The Interaction of Amino Acids, Peptides, and Proteins with DNA","volume":"78","author":"Solovyev","year":"2015","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1021\/acs.chemrev.7b00305","article-title":"Electrostatic Interactions in Protein Structure, Folding, Binding, and Condensation","volume":"118","author":"Zhou","year":"2018","journal-title":"Chem. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1126\/science.1110525","article-title":"Membrane Protein Insertion and Stability","volume":"307","author":"MacKinnon","year":"2005","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e24075","DOI":"10.1002\/pep2.24075","article-title":"Relative Role(S) of Leucine Versus Isoleucine in the Folding of Membrane Proteins","volume":"111","author":"Deber","year":"2017","journal-title":"Pept. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0079-6603(08)60825-9","article-title":"RNA and Protein Interactions Modulated by Protein Arginine Methylation","volume":"61","author":"Gary","year":"1998","journal-title":"Prog. Nucleic Acid Res. Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Gupta, M.N., and Uversky, V.N. (2024). Biological Importance of Arginine: A Comprehensive Review of the Roles in Structure, Disorder, and Functionality of Peptides and Proteins. Int. J. Biol. Macromol., 257.","DOI":"10.1016\/j.ijbiomac.2023.128646"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.chembiol.2018.01.011","article-title":"N-Acetyl Cysteine Functions as a Fast-Acting Antioxidant by Triggering Intracellular H2S and Sulfane Sulfur Production","volume":"25","author":"Takano","year":"2018","journal-title":"Cell Chem. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Chen, L., Wang, L., Ma, L., Wang, C., Qin, X., Wang, M., Zhang, X., Yang, R., Fang, B., and An, J. (2024). Synergistic Antioxidant Effects of Cysteine Derivative and Sm-Cluster for Food Applications. Antioxidants, 13.","DOI":"10.3390\/antiox13080910"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Liu, S., Zhang, Y., Chen, Y., Su, Y., Chen, B., Wang, Y., Xu, M., Qiao, K., Li, S., and Liu, Z. (2024). Isolation and Purification of Protamine from the Cultured Takifugu Flavidus and Its Physicochemical Properties. Molecules, 29.","DOI":"10.3390\/molecules29010263"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.1021\/bi101926u","article-title":"How PEGylation Enhances the Stability and Potency of Insulin: A Molecular Dynamics Simulation","volume":"50","author":"Yang","year":"2011","journal-title":"Biochemistry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1021\/acschembio.9b00432","article-title":"Influence of PEGylation on the Strength of Protein Surface Salt Bridges","volume":"14","author":"Xiao","year":"2019","journal-title":"ACS Chem. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.ijbiomac.2021.01.217","article-title":"Protein Morphology Drives the Structure and Catalytic Activity of Bio-Inorganic Hybrids","volume":"176","author":"Kaur","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/s41580-024-00718-y","article-title":"Opportunities and Challenges in Design and Optimization of Protein Function","volume":"25","author":"Listov","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1007\/s10529-020-02867-4","article-title":"PEG Modification Enhances the In Vivo Stability of Bioactive Proteins Immobilized on Magnetic Nanoparticles","volume":"42","author":"Xu","year":"2020","journal-title":"Biotechnol. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1093\/bbb\/zbae059","article-title":"PEG Modification Increases Thermostability and Inhibitor Resistance of Bst DNA Polymerase","volume":"88","author":"Yang","year":"2024","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Liu, Y., Bai, X., Wang, H., Wang, J., Li, S., Zhang, H., Wang, F., and Hong, Z. (2025). PEG-Modification Enhances the Targeted Photothermal Therapy of Affibody-Conjugated Indocyanine Green for Precision Cancer Treatment. Biochem. Biophys. Res. Commun., 742.","DOI":"10.1016\/j.bbrc.2024.151155"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1006\/abio.2000.4880","article-title":"Estimation of Protein Secondary Structure from Circular Dichroism Spectra: Comparison of CONTIN, SELCON, and CDSSTR Methods with an Expanded Reference Set","volume":"287","author":"Sreerama","year":"2000","journal-title":"Anal. Biochem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0167-4781(01)00204-4","article-title":"Checking out the G2\/M Transition","volume":"1519","author":"Smits","year":"2001","journal-title":"Biochim. Biophys. Acta (BBA) Gene Struct. Expr."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1046\/j.1365-2184.2003.00266.x","article-title":"The Cell Cycle: A Review of Regulation, Deregulation and Therapeutic Targets in Cancer","volume":"36","author":"Vermeulen","year":"2003","journal-title":"Cell Prolif."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.semcancer.2024.02.002","article-title":"The Cell Cycle Revisited: DNA Replication Past S Phase Preserves Genome Integrity","volume":"99","author":"Bournaka","year":"2024","journal-title":"Semin. Cancer Biol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Iliaki, S., Beyaert, R., and Afonina, I.S. (2021). Polo-like Kinase 1 (PLK1) Signaling in Cancer and Beyond. Biochem. Pharmacol., 193.","DOI":"10.1016\/j.bcp.2021.114747"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1038\/s41416-023-02468-8","article-title":"The Cyclin-Dependent Kinase 1: More than a Cell Cycle Regulator","volume":"129","author":"Massacci","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Mouery, R.D., Hsu, C., Bonacci, T., Bolhuis, D.L., Wang, X., Mills, C.A., Toomer, E.D., Canterbury, O.G., Robertson, K.C., and Branigan, T.B. (2023). Proteomic Analysis Reveals a PLK1-Dependent G2\/M Degradation Program and Links PKA-AKAP2 to Cell Cycle Control. bioRxiv.","DOI":"10.1101\/2023.10.11.561963"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3050","DOI":"10.1242\/dev.137075","article-title":"Proliferation, Survival and Metabolism: The Role of PI3K\/AKT\/mTOR Signalling in Pluripotency and Cell Fate Determination","volume":"143","author":"Yu","year":"2016","journal-title":"Development"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/s41392-021-00828-5","article-title":"Targeting PI3K\/Akt Signal Transduction for Cancer Therapy","volume":"6","author":"He","year":"2021","journal-title":"Sig. Transduct. Target. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1186\/s12943-023-01827-6","article-title":"PI3K\/AKT\/mTOR Signaling Transduction Pathway and Targeted Therapies in Cancer","volume":"22","author":"Glaviano","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.biopha.2018.04.072","article-title":"Inhibition of PI3K\/Akt\/mTOR Pathway by Apigenin Induces Apoptosis and Autophagy in Hepatocellular Carcinoma Cells","volume":"103","author":"Yang","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1038\/s41419-020-02998-6","article-title":"PI3K\/AKT Pathway as a Key Link Modulates the Multidrug Resistance of Cancers","volume":"11","author":"Liu","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"104787","DOI":"10.1016\/j.yexmp.2022.104787","article-title":"The PI3K\/AKT Signaling Pathway in Cancer: Molecular Mechanisms and Possible Therapeutic Interventions","volume":"127","author":"Khezri","year":"2022","journal-title":"Exp. Mol. Pathol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Zhao, C., Shen, C., Bakun, A., Yan, Y., and Kang, B. (2021). Purpleback Flying Squid Sthenoteuthis oualaniensis in the South China Sea: Growth, Resources and Association with the Environment. Water, 13.","DOI":"10.3390\/w13010065"},{"key":"ref_61","first-page":"165","article-title":"Enzyme-Responsive and Enzyme Immobilized Nanoplatforms for Therapeutic Delivery: An Overview of Research Innovations and Biomedical Applications","volume":"Volume 3","author":"Yata","year":"2020","journal-title":"Nanopharmaceuticals: Principles and Applications"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Li, C., Li, T., Tian, X., An, W., Wang, Z., Han, B., Tao, H., Wang, J., and Wang, X. (2024). Research Progress on the PEGylation of Therapeutic Proteins and Peptides (TPPs). Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1353626"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Batra, J., Robinson, J., Mehner, C., Hockla, A., Miller, E., Radisky, D.C., and Radisky, E.S. (2012). PEGylation Extends Circulation Half-Life While Preserving In Vitro and In Vivo Activity of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1). PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050028"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.intimp.2012.12.012","article-title":"The Impact of PEGylation on Protein Immunogenicity","volume":"15","author":"Gefen","year":"2013","journal-title":"Int. Immunopharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Zuma, L.K., Gasa, N.L., Makhoba, X.H., and Pooe, O.J. (2022). Protein PEGylation: Navigating Recombinant Protein Stability, Aggregation, and Bioactivity. Biomed. Res. Int., 2022.","DOI":"10.1155\/2022\/8929715"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S0168-3659(98)00192-8","article-title":"Robert Langer FTIR Characterization of the Secondary Structure of Proteins Encapsulated Within PLGA Microspheres1","volume":"58","author":"Fu","year":"1999","journal-title":"J. Control. Release"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.ijbiomac.2019.06.042","article-title":"A Strategic Approach of Enzyme Engineering by Attribute Ranking and Enzyme Immobilization on Zinc Oxide Nanoparticles to Attain Thermostability in Mesophilic Bacillus subtilis Lipase for Detergent Formulation","volume":"136","author":"Khan","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/0022-2836(68)90293-3","article-title":"On the Structure and Stability of DNA-Protamine and DNA-Polypeptide Complexes","volume":"33","author":"Olins","year":"1968","journal-title":"J. Mol. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1097\/01.ASW.0000579700.20404.56","article-title":"Effectiveness of Arginine Supplementation on Wound Healing in Older Adults in Acute and Chronic Settings: A Systematic Review","volume":"32","author":"Schneider","year":"2019","journal-title":"Adv Ski. Wound Care"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1038\/227680a0","article-title":"Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4","volume":"227","author":"Laemmli","year":"1970","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Hou, C., Lei, Y., Li, N., Wei, M., Wang, S., Rahman, S.U., Bao, C., Bao, B., Elango, J., and Wu, W. (2023). Collagen from Iris Squid Grafted with Polyethylene Glycol and Collagen Peptides Promote the Proliferation of Fibroblast Through PI3K\/AKT and Ras\/RAF\/MAPK Signaling Pathways. Int. J. Biol. Macromol., 247.","DOI":"10.1016\/j.ijbiomac.2023.125772"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/1869\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:40:09Z","timestamp":1760028009000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/1869"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,21]]},"references-count":71,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ijms26051869"],"URL":"https:\/\/doi.org\/10.3390\/ijms26051869","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,21]]}}}