{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:35:15Z","timestamp":1760243715589,"version":"build-2065373602"},"reference-count":29,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2012,10,22]],"date-time":"2012-10-22T00:00:00Z","timestamp":1350864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The need for new therapeutics for Ankylosing Spondylitis (AS) is highlighted by the general lack of efficacy for most agents currently available for this disease. Many recent studies have detailed molecular pathways in AS, and several molecule-targeting agents are undergoing evaluation. We aimed to explore the mechanism of AS and identify biologically active small molecules capable of targeting the sub-pathways which were disregulated in the development of AS. By using the GSE25101 microarray data accessible from the Gene Expression Omnibus database, we first identified the differentially expressed genes (DEGs) between AS samples and healthy controls, followed by the sub-pathway enrichment analysis of the DEGs. In addition, we propose the use of an approach based on targeting sub-pathways to identify potential agents for AS. A total of 3,280 genes were identified as being significantly different between patients and controls with p-values &lt; 0.1. Our study showed that neurotrophic signaling pathway and some immune-associated pathways may be involved in the development of AS. Besides, our bioinformatics analysis revealed a total of 15 small molecules which may play a role in perturbing the development of AS. Our study proposes the use of an approach based on targeting sub-pathways to identify potential agents for AS. Candidate agents identified by our approach may provide the groundwork for a combination therapy approach for AS.<\/jats:p>","DOI":"10.3390\/molecules171012460","type":"journal-article","created":{"date-parts":[[2012,10,22]],"date-time":"2012-10-22T11:27:55Z","timestamp":1350905275000},"page":"12460-12468","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Sub-Pathway Based Method to Identify Candidate Agents for Ankylosing Spondylitis"],"prefix":"10.3390","volume":"17","author":[{"given":"Kai","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Changhai Hospital, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingchuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Changhai Hospital, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Changhai Hospital, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuanfeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Changhai Hospital, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziqiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Changhai Hospital, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yushu","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Changhai Hospital, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaodong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Changhai Hospital, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Changhai Hospital, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2012,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1007\/978-1-4419-0298-6_8","article-title":"Bone formation versus bone resorption in Ankylosing Spondylitis","volume":"649","author":"Schett","year":"2009","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3899\/jrheum.100469","article-title":"Whole-blood gene expression profiling in Ankylosing Spondylitis shows upregulation of toll-like receptor 4 and 5","volume":"38","author":"Assassi","year":"2011","journal-title":"J. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.berh.2006.03.004","article-title":"Major histocompatibility genes and Ankylosing Spondylitis","volume":"20","author":"Reveille","year":"2006","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1038\/ng.2007.17","article-title":"Asociation scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants","volume":"39","author":"Burton","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1097\/BOR.0b013e32832b3795","article-title":"Genetics and the pathogenesis of Ankylosing Spondylitis","volume":"21","author":"Brown","year":"2009","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1517\/14656566.4.1.1","article-title":"Recent progress in Ankylosing Spondylitis treatment","volume":"4","author":"Toussirot","year":"2003","journal-title":"Expert. Opin. Pharmacother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1136\/ard.2009.126706","article-title":"Mixed response to tocilizumab for Ankylosing Spondylitis","volume":"69","author":"Henes","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1093\/rheumatology\/ken362","article-title":"The use of rituximab to treat a patient with ankylosing spondylitis and hepatitis B","volume":"47","year":"2008","journal-title":"Rheumatology (Oxford)"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/nar\/gkn923","article-title":"Bioinformatics enrichment tools: Paths toward the comprehensive functional analysis of large gene lists","volume":"37","author":"Huang","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1093\/bioinformatics\/btq714","article-title":"A sub-pathway-based approach for identifying drug response principal network","volume":"27","author":"Chen","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1136\/ard.2003.008052","article-title":"Technical validation of cDNA based microarray as screening technique to identify candidate genes in synovial tissue biopsy specimens from patients with spondyloarthropathy","volume":"63","author":"Rihl","year":"2004","journal-title":"Ann. Rheum. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1136\/ard.2004.032599","article-title":"Involvement of neurotrophins and their receptors in spondyloarthritis synovitis: Relation to inflammation and response to treatment","volume":"64","author":"Rihl","year":"2005","journal-title":"Ann. Rheum. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1146\/annurev.neuro.24.1.677","article-title":"Neurotrophins: Roles in neuronal development and function","volume":"24","author":"Huang","year":"2001","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/0955-0674(95)80073-5","article-title":"Influence of growth factors on neuronal differentiation","volume":"7","author":"Birling","year":"1995","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2174\/156720506775697061","article-title":"Dissecting the diverse actions of pro- and mature neurotrophins","volume":"3","author":"Hempstead","year":"2006","journal-title":"Curr. Alzheimer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1098\/rstb.2006.1894","article-title":"Neurotrophin-regulated signalling pathways","volume":"361","author":"Reichardt","year":"2006","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3226","DOI":"10.1016\/S0021-9258(18)95953-3","article-title":"Inhibitors of protein biosynthesis. II. Mode of action of anisomycin","volume":"242","author":"Grollman","year":"1967","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S0166-4328(02)00045-1","article-title":"Memory for context is impaired by injecting anisomycin into dorsal hippocampus following context exploration","volume":"134","author":"Barrientos","year":"2002","journal-title":"Behav. Brain Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/nbt1272","article-title":"Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug","volume":"25","author":"Marks","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1146\/annurev.pharmtox.45.120403.095825","article-title":"Clinical development of histone deacetylase inhibitors as anticancer agents","volume":"45","author":"Drummond","year":"2005","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_21","unstructured":"GEO Homepage. Available online:http:\/\/www.ncbi.nlm.nih.gov\/geo\/."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/art.1780270401","article-title":"Evaluation of diagnostic criteria for Ankylosing Spondylitis. A proposal for modification of the New York criteria","volume":"27","author":"Valkenburg","year":"1984","journal-title":"Arthritis Rheum."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/0470857897.ch8","article-title":"The KEGG database","volume":"247","author":"Kanehisa","year":"2002","journal-title":"Novartis Found. Symp."},{"key":"ref_24","unstructured":"KEGG Homepage. Available online:http:\/\/www.genome.jp\/kegg\/."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1126\/science.1132939","article-title":"The Connectivity Map: Using gene-expression signatures to connect small molecules, genes, and disease","volume":"313","author":"Lamb","year":"2006","journal-title":"Science"},{"key":"ref_26","unstructured":"(2011). SubpathwayMiner-R-Based Software, R Foundation for Statistical Computing."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1093\/biostatistics\/4.2.249","article-title":"Exploration, normalization, and summaries of high density oligonucleotide array probe level data","volume":"4","author":"Irizarry","year":"2003","journal-title":"Biostatistics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: A practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Series B Stat. Methodol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Li, C., Li, X., Miao, Y., Wang, Q., Jiang, W., Xu, C., Li, J., Han, J., Zhang, F., and Gong, B. (2009). SubpathwayMiner: A software package for flexible identification of pathways. Nucleic Acids Res., e131.","DOI":"10.1093\/nar\/gkp667"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/17\/10\/12460\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:53:00Z","timestamp":1760219580000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/17\/10\/12460"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,10,22]]},"references-count":29,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2012,10]]}},"alternative-id":["molecules171012460"],"URL":"https:\/\/doi.org\/10.3390\/molecules171012460","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2012,10,22]]}}}