{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:56:01Z","timestamp":1792788961406,"version":"4.5.0"},"reference-count":29,"publisher":"IMR Press","issue":"2","license":[{"start":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T00:00:00Z","timestamp":1740009600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health research project of Fuyang Health Commission","award":["FY2023-141"],"award-info":[{"award-number":["FY2023-141"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene, resulting in progressive motor neuron loss and muscle atrophy. The urotensin 2 (UTS2) gene, located on chromosome 9q34.2, plays a significant role in cellular activities such as proliferation, apoptosis, and inflammatory responses. Notably, elevated expression levels of UTS2 have been observed in SMA patients. However, its precise contribution to disease pathogenesis remains unclear. This study aimed to investigate the effects of UTS2, which is overexpressed in SMA patients, in SMA cell models using a UTS2 inhibitor. Methods: We conducted genomic sequencing and bioinformatics analysis on clinical samples to identify proteins highly expressed in association with SMA. Using RNA interference technology, we suppressed SMN1 gene expression in bone marrow mesenchymal stem cells (MSCs) to establish an in vitro cellular model of SMA. To assess the biological consequences of SMN1 gene knockdown, we employed molecular biological techniques such as immunofluorescence, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and western blotting. Furthermore, we treated the SMA cellular model with the urantide UTS2 receptor inhibitor and examined its effects on cell proliferation, apoptosis, and the expression of relevant proteins. Results: UTS2 was successfully identified as a highly expressed protein associated with SMA. A stable MSC model with SMN1 gene knockdown was established. RNA interference (RNAi) technology effectively suppressed SMN1 gene expression, leading to changes in cellular morphology and neuron-specific marker expression. Urantide intervention significantly affected both proliferation and apoptosis in the SMA cell model in a dose-dependent manner. Techniques such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, TUNEL fluorescence staining, and flow cytometry analysis revealed that uride decreased cell viability while increasing the proportion of apoptotic cells. Following urantide intervention, there was a notable increase in caspase-3 messenger ribonucleic acid (mRNA) levels, as well as an increase in caspase-3 protein expression, as demonstrated by immunofluorescence analysis. Conclusion: We elucidated the role of the UTS2 gene in an SMA cell model, emphasizing its dysregulation and identifying potential therapeutic targets. Urantide, a UTS2 inhibitor, had significant biological effects on the SMA cell model, indicating that it is a promising therapeutic strategy for SMA. These findings provide valuable insights for advancing drug development and clinical treatment of SMA.<\/jats:p>","DOI":"10.31083\/fbl28242","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T06:00:03Z","timestamp":1740722403000},"source":"Crossref","is-referenced-by-count":4,"title":["Elucidating the Pathogenic Mechanism of Spinal Muscular Atrophy Through the Investigation of UTS2"],"prefix":"10.31083","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2173-884X","authenticated-orcid":true,"given":"Xu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, The Second Affiliated Hospital of Anhui Medical University, 230601 Hefei, Anhui, China"},{"name":"Department of Pediatrics, Fuyang People\u2019s Hospital, 236000 Fuyang, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5316-4265","authenticated-orcid":true,"given":"Liqi","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, The Second Affiliated Hospital of Anhui Medical University, 230601 Hefei, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2025,2,20]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Ogino S, Leonard DGB, Rennert H, Ewens WJ, Wilson RB. Genetic risk assessment in carrier testing for spinal muscular atrophy. American Journal of Medical Genetics. 2002; 110: 301\u2013307.","DOI":"10.1002\/ajmg.10425."},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Pearn J. Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy. Journal of Medical Genetics. 1978; 15: 409\u2013413.","DOI":"10.1136\/jmg.15.6.409."},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. European Journal of Human Genetics. 2012; 20: 27\u201332.","DOI":"10.1038\/ejhg.2011.134."},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Lefebvre S, B\u00fcrglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995; 80: 155\u2013165.","DOI":"10.1016\/0092-8674(95)90460-3."},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Spinal muscular atrophy. Nature Reviews Disease Primers. 2022; 8: 51.","DOI":"10.1038\/s41572-022-00385-3."},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Kim JK, Jha NN, Awano T, Caine C, Gollapalli K, Welby E, et al. A spinal muscular atrophy modifier implicates the SMN protein in SNARE complex assembly at neuromuscular synapses. Neuron. 2023; 111: 1423\u20131439.e4.","DOI":"10.1016\/j.neuron.2023.02.004."},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Monani UR. Spinal muscular atrophy: a deficiency in a ubiquitous protein; a motor neuron-specific disease. Neuron. 2005; 48: 885\u2013896.","DOI":"10.1016\/j.neuron.2005.12.001."},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. The New England Journal of Medicine. 2017; 377: 1713\u20131722.","DOI":"10.1056\/NEJMoa1706198."},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. The New England Journal of Medicine. 2017; 377: 1723\u20131732.","DOI":"10.1056\/NEJMoa1702752."},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Sivaramakrishnan M, McCarthy KD, Campagne S, Huber S, Meier S, Augustin A, et al. Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers. Nature Communications. 2017; 8: 1476.","DOI":"10.1038\/s41467-017-01559-4."},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Yanfei W, Langping S, Mingzhong S. Prognostic Significance and Functional Mechanism of UTS2 in Glioblastoma Multiforme. Current Cancer Drug Targets. 2024.  (in press)","DOI":"10.2174\/0115680096275291231226081320."},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Kwok T, Huerta-White T, Briegel K, Singh A, Yeguvapalli S, Chitrala KN. Bioinformatics analysis of the potential biomarkers of Multiple Sclerosis and Guillain\u2012-Barr\u00e9 syndrome. 2024. bioRxiv.  (preprint)","DOI":"10.1101\/2024.05.29.595759."},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"de Miguel-G\u00f3mez L, Sebasti\u00e1n-Le\u00f3n P, Romeu M, Pellicer N, Faus A, Pellicer A, et al. Endometrial gene expression differences in women with coronavirus disease 2019. Fertility and Sterility. 2022; 118: 1159\u20131169.","DOI":"10.1016\/j.fertnstert.2022.09.013."},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Deng Z, Liu J, He S, Gao W. The Pyroptosis-Related Signature Predicts Diagnosis and Indicates Immune Characteristic in Major Depressive Disorder. Frontiers in Pharmacology. 2022; 13: 848939.","DOI":"10.3389\/fphar.2022.848939."},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Quan FB, Gaillard AL, Alejevski F, P\u00e9zeron G, Tostivint H. Urotensin II-related peptide (Urp) is expressed in motoneurons in zebrafish, but is dispensable for locomotion in larva. Peptides. 2021; 146: 170675.","DOI":"10.1016\/j.peptides.2021.170675."},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Bearce EA, Irons ZH, O\u2019Hara-Smith JR, Kuhns CJ, Fisher SI, Crow WE, et al. Urotensin II-related peptides, Urp1 and Urp2, control zebrafish spine morphology. 2022; 11: e83883.","DOI":"10.7554\/eLife.83883."},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Dubessy C, Cartier D, Lectez B, Bucharles C, Chartrel N, Montero-Hadjadje M, et al. Characterization of urotensin II, distribution of urotensin II, urotensin II-related peptide and UT receptor mRNAs in mouse: evidence of urotensin II at the neuromuscular junction. Journal of Neurochemistry. 2008; 107: 361\u2013374.","DOI":"10.1111\/j.1471-4159.2008.05624.x."},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Vaudry H, Do Rego J-C, Le Mevel J-C, Chatenet D, Tostivint H, Fournier A, et al. Urotensin II, from fish to human. Annals of the New York Academy of Sciences. 2010; 1200: 53\u201366.","DOI":"10.1111\/j.1749-6632.2010.05514.x."},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Zeng W, Kong X, Alamana C, Liu Y, Guzman J, Pang PD, et al. Generation of two induced pluripotent stem cell lines from spinal muscular atrophy type 1 patients carrying no functional copies of SMN1 gene. Stem Cell Research. 2023; 69: 103095.","DOI":"10.1016\/j.scr.2023.103095."},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Vaudry H, Leprince J, Chatenet D, Fournier A, Lambert DG, Le M\u00e9vel JC, et al. International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, urotensin II-related peptide, and their receptor: from structure to function. Pharmacological Reviews. 2015; 67: 214\u2013258.","DOI":"10.1124\/pr.114.009480."},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Fraser DR. Emerging roles of urotensin-II in cardiovascular disease. Pharmacology & Therapeutics. 2004; 103: 223\u2013243.","DOI":"10.1016\/j.pharmthera.2004.07.004."},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Ogbonmide T, Rathore R, Rangrej SB, Hutchinson S, Lewis M, Ojilere S, et al. Gene Therapy for Spinal Muscular Atrophy (SMA): A Review of Current Challenges and Safety Considerations for Onasemnogene Abeparvovec (Zolgensma). Cureus. 2023; 15: e36197.","DOI":"10.7759\/cureus.36197."},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Pereira-Castro J, Br\u00e1s-Silva C, Fontes-Sousa AP. Novel insights into the role of urotensin II in cardiovascular disease. Drug Discovery Today. 2019; 24: 2170\u20132180.","DOI":"10.1016\/j.drudis.2019.08.005."},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Sun S, Liu L. Urotensin II: an inflammatory cytokine. Journal of Endocrinology. 2019; 204: R107\u2013R117.","DOI":"10.1530\/joe-18-0505."},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Svistunov AA, Tarasov VV, Shakhmardanova SA, Sologova SS, Bagaturiya ET, Chubarev VN, et al. Urotensin II: molecular mechanisms of biological activity. Current Protein and Peptide Science. 2018; 19: 924\u2013934.","DOI":"10.2174\/1389203718666170829162335."},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Yumrutas O, Oztuzcu S, B\u00fcy\u00fckhatipoglu H, Bozgeyik I, Bozgeyik E, Igci YZ, et al. The role of the UTS2 gene polymorphisms and plasma Urotensin-II levels in breast cancer. Tumor Biology. 2015; 36: 4427\u20134432.","DOI":"10.1007\/s13277-015-3082-2."},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Hirose T, Takahashi K, Mori N, Nakayama T, Kikuya M, Ohkubo T, et al. Increased expression of urotensin II, urotensin II-related peptide and urotensin II receptor mRNAs in the cardiovascular organs of hypertensive rats: comparison with endothelin-1. Peptides. 2009; 30: 1124\u20131129.","DOI":"10.1016\/j.peptides.2009.02.009."},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Jarry M, Diallo M, Lecointre C, Desrues L, Tokay T, Chatenet D, et al. The vasoactive peptides urotensin II and urotensin II-related peptide regulate astrocyte activity through common and distinct mechanisms: involvement in cell proliferation. The Biochemical Journal. 2010; 428: 113\u2013124.","DOI":"10.1042\/BJ20090867."},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"Langham RG, Kelly DJ. Urotensin II and the kidney. Current Opinion in Nephrology and Hypertension. 2013; 22: 107\u2013112.","DOI":"10.1097\/MNH.0b013e32835b6d57"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/30\/2\/10.31083\/FBL28242","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T06:12:54Z","timestamp":1740723174000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/30\/2\/10.31083\/FBL28242"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,20]]},"references-count":29,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025]]}},"alternative-id":["S2768-6701(24)01615-0"],"URL":"https:\/\/doi.org\/10.31083\/fbl28242","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,20]]},"article-number":"28242"}}