{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T21:32:08Z","timestamp":1785879128374,"version":"3.56.0"},"reference-count":43,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Korean government (MSIT)","award":["NRF 2018R1A6A1A03025124"],"award-info":[{"award-number":["NRF 2018R1A6A1A03025124"]}]},{"name":"Korean government (MSIT)","award":["NRF 2022R1A2C1091779"],"award-info":[{"award-number":["NRF 2022R1A2C1091779"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Facial nerve injury can lead to significant functional impairment, emotional impacts, and difficulties in social and economic activities. Although peripheral nerves have the potential for recovery, incomplete regeneration can pose challenges. Suppressor of Mothers Against Decapentaplegic Homolog (SMAD) proteins are crucial in the nerve-regeneration process. The study aimed to investigate the changes in SMAD protein expression involved in peripheral nerve regeneration following facial nerve injury induced by compression or axotomy in a pre-clinical study conducted on Sprague Dawley rats. Facial nerve recovery was assessed at 1, 2, 3, 4, 8, and 12 weeks post-facial nerve compression and axotomy using behavioral tests, including whisker movement and eyelid blink-reflex tests. Additionally, the role of SMAD proteins in the nerve regeneration process was evaluated by analyzing the expression of SMAD1\u20138 proteins at 2 and 12 weeks post-injury. Behavioral tests revealed significant impairment in facial nerve function in both the Compression and Axotomy groups compared with the Sham group at early time points. Recovery was observed in the Compression group by 2 weeks, whereas the Axotomy group exhibited prolonged impairment through 12 weeks. SMAD protein analyses showed increased expression of SMAD2, SMAD7, and SMAD8 following compression injury, whereas axotomy led to more extensive increases in expression that included SMAD1, SMAD2, SMAD3, SMAD4, SMAD6, SMAD7, and SMAD8. These findings suggest that SMAD proteins play differential roles in nerve regeneration following facial nerve injuries caused by compression versus axotomy. The distinct expression patterns of SMAD proteins highlight their potential as therapeutic targets for enhancing nerve regeneration and functional recovery in peripheral nerve injuries.<\/jats:p>","DOI":"10.3390\/ijms26052291","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T13:31:31Z","timestamp":1741095091000},"page":"2291","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Expression Patterns of SMAD1\u20138 in the Peripheral Facial Nerve Following Compressive Nerve Injury or Axotomy"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7546-9765","authenticated-orcid":false,"given":"Jae Min","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology\u2013Head and Neck Surgery, College of Medicine, Kyung Hee University Medical Center, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1628-9948","authenticated-orcid":false,"given":"Dong Keon","family":"Yon","sequence":"additional","affiliation":[{"name":"Center for Digital Health, Medical Science Research Institute, Kyung Hee University School of Medicine, Kyung Hee University Medical Center, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6817-7668","authenticated-orcid":false,"given":"Sung Soo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8021-1024","authenticated-orcid":false,"given":"Seung Geun","family":"Yeo","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\u2013Head and Neck Surgery, College of Medicine, Kyung Hee University Medical Center, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Department of Convergence Medicine, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,4]]},"reference":[{"key":"ref_1","first-page":"S1","article-title":"Clinical Practice Guideline: Bell\u2019s Palsy","volume":"149","author":"Baugh","year":"2013","journal-title":"Otolaryngol. Head. Neck Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1007\/s00405-008-0646-4","article-title":"Management of Peripheral Facial Nerve Palsy","volume":"265","author":"Finsterer","year":"2008","journal-title":"Eur. Arch. Oto-Rhino-Laryngol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.autrev.2012.05.008","article-title":"Bell\u2019s Palsy and Autoimmunity","volume":"12","author":"Greco","year":"2012","journal-title":"Autoimmun. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"dev170316","DOI":"10.1242\/dev.170316","article-title":"The Regulation of the Homeostasis and Regeneration of Peripheral Nerve Is Distinct from the CNS and Independent of a Stem Cell Population","volume":"145","author":"Stierli","year":"2018","journal-title":"Development"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.hcl.2013.04.002","article-title":"Nerve Physiology","volume":"29","author":"Menorca","year":"2013","journal-title":"Hand Clin."},{"key":"ref_6","first-page":"100","article-title":"Neurobiology of Peripheral Nerve Injury, Regeneration, and Functional Recovery: From Bench Top Research to Bedside Application","volume":"13","author":"Sulaiman","year":"2013","journal-title":"Ochsner J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3521","DOI":"10.1113\/JP270874","article-title":"The Repair Schwann Cell and Its Function in Regenerating Nerves","volume":"594","author":"Jessen","year":"2016","journal-title":"J. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/j.1750-3639.1999.tb00229.x","article-title":"Nerve Injury, Axonal Degeneration and Neural Regeneration: Basic Insights","volume":"9","author":"Stoll","year":"1999","journal-title":"Brain Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1074\/mcp.R115.053751","article-title":"Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury","volume":"15","author":"Tuszynski","year":"2016","journal-title":"Mol. Cell. Proteom."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lopes, B., Sousa, P., Alvites, R., Branquinho, M., Sousa, A.C., Mendon\u00e7a, C., Atayde, L.M., Lu\u00eds, A.L., Varej\u00e3o, A.S.P., and Maur\u00edcio, A.C. (2022). Peripheral Nerve Injury Treatments and Advances: One Health Perspective. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020918"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.mce.2010.04.005","article-title":"The Anti-Inflammatory and Immunosuppressive Effects of Glucocorticoids, Recent Developments and Mechanistic Insights","volume":"335","author":"Coutinho","year":"2011","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"698256","DOI":"10.1155\/2014\/698256","article-title":"Peripheral Nerve Reconstruction after Injury: A Review of Clinical and Experimental Therapies","volume":"2014","author":"Grinsell","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wei, C., Guo, Y., Ci, Z., Li, M., Zhang, Y., and Zhou, Y. (2024). Advances of Schwann Cells in Peripheral Nerve Regeneration: From Mechanism to Cell Therapy. Biomed. Pharmacother., 175.","DOI":"10.1016\/j.biopha.2024.116645"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7769","DOI":"10.3390\/cimb46070460","article-title":"Roles of SMAD and SMAD-Associated Signaling Pathways in Nerve Regeneration Following Peripheral Nerve Injury: A Narrative Literature Review","volume":"46","author":"Lee","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Alexander, P.B., and Wang, X.-F. (2017). TGF-\u03b2 Family Signaling in the Control of Cell Proliferation and Survival. Cold Spring Harb. Perspect. Biol., 9.","DOI":"10.1101\/cshperspect.a022145"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.pneurobio.2013.07.002","article-title":"BMP-Smad 1\/5\/8 Signalling in the Development of the Nervous System","volume":"109","author":"Hegarty","year":"2013","journal-title":"Prog. Neurobiol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Lee, J.M., Yoo, M.C., Kim, Y.J., Kim, S.S., and Yeo, S.G. (2024). Expression of ChAT, Iba-1, and NNOS in the Central Nervous System Following Facial Nerve Injury. Antioxidants, 13.","DOI":"10.3390\/antiox13050595"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kim, I., Kim, Y., Kang, D., Jung, J., Kim, S., Rim, H., Kim, S., and Yeo, S.-G. (2021). Neuropeptides Involved in Facial Nerve Regeneration. Biomedicines, 9.","DOI":"10.3390\/biomedicines9111575"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Hata, A., and Chen, Y.-G. (2016). TGF-\u03b2 Signaling from Receptors to Smads. Cold Spring Harb. Perspect. Biol., 8.","DOI":"10.1101\/cshperspect.a022061"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"44","DOI":"10.2106\/00004623-200300003-00009","article-title":"Initiation of Smad-Dependent and Smad-Independent Signaling via Distinct BMP-Receptor Complexes","volume":"85","author":"Hassel","year":"2003","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7116","DOI":"10.1523\/JNEUROSCI.5397-08.2009","article-title":"Axotomy-Induced Smad1 Activation Promotes Axonal Growth in Adult Sensory Neurons","volume":"29","author":"Zou","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6807","DOI":"10.1007\/s12035-019-1555-9","article-title":"BMP4\/Smad1 Signalling Promotes Spinal Dorsal Column Axon Regeneration and Functional Recovery After Injury","volume":"56","author":"Farrukh","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1167\/iovs.18-26449","article-title":"Activation of the BMP4\/Smad1 Pathway Promotes Retinal Ganglion Cell Survival and Axon Regeneration","volume":"60","author":"Thompson","year":"2019","journal-title":"Investig. Opthalmology Vis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S0092-8674(03)00432-X","article-title":"Mechanisms of TGF-\u03b2 Signaling from Cell Membrane to the Nucleus","volume":"113","author":"Shi","year":"2003","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Liu, L., Liu, X., Ren, X., Tian, Y., Chen, Z., Xu, X., Du, Y., Jiang, C., Fang, Y., and Liu, Z. (2016). Smad2 and Smad3 Have Differential Sensitivity in Relaying TGF\u03b2 Signaling and Inversely Regulate Early Lineage Specification. Sci. Rep., 6.","DOI":"10.1038\/srep21602"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15955","DOI":"10.1073\/pnas.1920829117","article-title":"The Stem Cell Marker Prom1 Promotes Axon Regeneration by down-Regulating Cholesterol Synthesis via Smad Signaling","volume":"117","author":"Lee","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4211","DOI":"10.1038\/sj.emboj.7600437","article-title":"Essential Role of Smad3 in the Inhibition of Inflammation-Induced PPAR\u03b2\/\u03b4 Expression","volume":"23","author":"Tan","year":"2004","journal-title":"EMBO J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.expneurol.2013.10.008","article-title":"Smad3 Deficiency Increases Cortical and Hippocampal Neuronal Loss Following Traumatic Brain Injury","volume":"250","author":"Villapol","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.3892\/etm.2020.8832","article-title":"Role of Smad3 Inhibitor and the Pyroptosis Pathway in Spinal Cord Injury","volume":"20","author":"Zhu","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S1359-6101(99)00027-1","article-title":"The Smads: Transcriptional Regulation and Mouse Models","volume":"11","author":"Datto","year":"2000","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S0925-4773(01)00367-7","article-title":"Smad5 Is Required for Mouse Primordial Germ Cell Development","volume":"104","author":"Chang","year":"2001","journal-title":"Mech. Dev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.brainres.2006.11.019","article-title":"Altered Expression of Smad Family Members in Injured Motor Neurons of Rat","volume":"1132","author":"Okuyama","year":"2007","journal-title":"Brain Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Miyazawa, K., and Miyazono, K. (2017). Regulation of TGF-\u03b2 Family Signaling by Inhibitory Smads. Cold Spring Harb. Perspect. Biol., 9.","DOI":"10.1101\/cshperspect.a022095"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1101\/gad.12.2.186","article-title":"Smad6 Inhibits BMP\/Smad1 Signaling by Specifically Competing with the Smad4 Tumor\u2009Suppressor","volume":"12","author":"Hata","year":"1998","journal-title":"Genes. Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1186\/s12964-023-01273-3","article-title":"The Long Non-Coding RNA LINC00707 Interacts with Smad Proteins to Regulate TGF\u03b2 Signaling and Cancer Cell Invasion","volume":"21","author":"Papoutsoglou","year":"2023","journal-title":"Cell Commun. Signal."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1007\/s00109-021-02083-1","article-title":"Expression and Function of Smad7 in Autoimmune and Inflammatory Diseases","volume":"99","author":"Hu","year":"2021","journal-title":"J. Mol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1172\/JCI12821","article-title":"Blocking Smad7 Restores TGF-\u03921 Signaling in Chronic Inflammatory Bowel Disease","volume":"108","author":"Monteleone","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e14538","DOI":"10.1111\/and.14538","article-title":"Co-Overexpression of VEGF and Smad7 Improved the Therapeutic Effects of Adipose-Derived Stem Cells on Neurogenic Erectile Dysfunction in the Rat Model","volume":"54","author":"He","year":"2022","journal-title":"Andrologia"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12938","DOI":"10.1073\/pnas.94.24.12938","article-title":"Smad8 Mediates the Signaling of the Receptor Serine\u2009Kinase","volume":"94","author":"Chen","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Lopez, M.A., Si, Y., Hu, X., Williams, V., Qushair, F., Carlyle, J., Alesce, L., Conklin, M., Gilbert, S., and Bamman, M.M. (2022). Smad8 Is Increased in Duchenne Muscular Dystrophy and Suppresses MiR-1, MiR-133a, and MiR-133b. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147515"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1002\/hep.30780","article-title":"Ablation of Hepatocyte Smad1, Smad5, and Smad8 Causes Severe Tissue Iron Loading and Liver Fibrosis in Mice","volume":"70","author":"Wang","year":"2019","journal-title":"Hepatology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1002\/acn3.117","article-title":"Smads as Muscle Biomarkers in Amyotrophic Lateral Sclerosis","volume":"1","author":"Si","year":"2014","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2309499018812953","DOI":"10.1177\/2309499018812953","article-title":"BMP-7\/Smad Expression in Dedifferentiated Schwann Cells during Axonal Regeneration and Upregulation of Endogenous BMP-7 Following Administration of PTH (1\u201334)","volume":"26","author":"Kokubu","year":"2018","journal-title":"J. Orthop. Surg."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/2291\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:47:11Z","timestamp":1760028431000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/2291"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,4]]},"references-count":43,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ijms26052291"],"URL":"https:\/\/doi.org\/10.3390\/ijms26052291","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,4]]}}}