{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:22:01Z","timestamp":1787318521582,"version":"build-2736575974"},"reference-count":53,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Parkinson's disease (PD) is a neurodegenerative disease closely related to neuroinflammation and with obvious age characteristics. Existing therapeutic drugs have problems such as insufficient efficacy and side effects. Cycloastragenol (CAG) is a known natural telomerase activator, and previous studies have found that it has a good improvement effect on PD. As a lead compound, there is significant room for improvement in pharmacological activity. Therefore, we further explore safe and efficient small molecules for PD drug exploration through structural optimization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We introduced carboxylic acid small molecules into the CAG structure and evaluated the pharmacological effects of the derivatives using a PD in\u00a0vitro model and a neuroinflammatory model. The structure\u2013activity relationship analysis was used to screen the derivatives with the best activity for subsequent in\u00a0vivo animal experiments. Utilize metabolomics and subsequent validation experiments to elucidate the potential mechanisms by which the derivatives exert their effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Result<\/jats:title>\n                    <jats:p>We screened and obtained compound R2 from 29 derivatives, which can significantly enhance anti\u2010inflammatory activity and cell protection. In the MPTP induced PD mouse model, R2 can improve motor dysfunction, restore the number of TH positive neurons in the substantia nigra, and reduce inflammation levels in brain tissue and serum. Metabolomics analysis showed that R2 intervenes in PD progression by regulating the tyrosine metabolism pathway, and further validated the mechanism of compound R2 around the TLR4\/NF\u2010\u03baB\/TERT signaling pathway. This study provides a new strategy for the development of anti PD drugs based on CAG, while expanding the potential application of carboxylic acid modification in natural product structure optimization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study focuses on the potential mechanism of CAG derivative R2 in treating PD through \u201cinflammation\u2010aging\u201d research. By inhibiting inflammation and restoring telomerase activity, it breaks the vicious cycle and provides new ideas for the treatment of PD, laying a foundation for the development of drugs using CAG for PD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.70787","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T13:32:31Z","timestamp":1770816751000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cycloastragenol Derivatives Improve Tyrosine Metabolism, Regulate\n                    <scp>TLR4<\/scp>\n                    \/\n                    <scp>NF<\/scp>\n                    \u2010\n                    <scp>\u03baB<\/scp>\n                    \/\n                    <scp>TERT<\/scp>\n                    Signaling Pathways, and Inhibit\n                    <scp>MPTP<\/scp>\n                    Induced Neuroinflammation and\n                    <scp>PD<\/scp>\n                    Symptoms"],"prefix":"10.1002","volume":"32","author":[{"given":"Shengnan","family":"Xiao","sequence":"first","affiliation":[{"name":"Institute of Taihang Materia Medica Shanxi University of Chinese Medicine  Jinzhong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianmei","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Taihang Materia Medica Shanxi University of Chinese Medicine  Jinzhong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Qin","sequence":"additional","affiliation":[{"name":"Institute of Taihang Materia Medica Shanxi University of Chinese Medicine  Jinzhong China"},{"name":"Modern Research Center for Traditional Chinese Medicine of Shanxi University  Taiyuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Taihang Materia Medica Shanxi University of Chinese Medicine  Jinzhong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0655-6942","authenticated-orcid":false,"given":"Zhenyu","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Taihang Materia Medica Shanxi University of Chinese Medicine  Jinzhong China"},{"name":"Modern Research Center for Traditional Chinese Medicine of Shanxi University  Taiyuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7464-5384","authenticated-orcid":false,"given":"Zhi","family":"Chai","sequence":"additional","affiliation":[{"name":"Institute of Taihang Materia Medica Shanxi University of Chinese Medicine  Jinzhong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01419-8"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01478-2"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.29410"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1201\/9781003464648"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01486-5"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.2174\/97816810877261210101"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c01257"},{"key":"e_1_2_13_9_1","volume-title":"Nutritional Neurosciences","author":"Singh A. K.","year":"2025"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.26599\/FSHW.2022.9250035"},{"key":"e_1_2_13_11_1","volume-title":"Medicinal Plants in Parkinson's Therapy","author":"Rai S. N.","year":"2025"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/st9.0000000000000046"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-020-01791-8"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2022.111756"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2025.156645"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2025.156462"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2024.156210"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-020-0386-6"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2025.156502"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.7b00080"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrestox.0c00339"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01660-9"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2021.104864"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2020.104078"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.4c06060"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2CS00889K"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202115805"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-025-00976-1"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.9b03305"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbdv.201900516"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2023.101802"},{"key":"e_1_2_13_32_1","volume-title":"Phytochemicals and Gut Health","author":"Rai S. N.","year":"2025"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00456-5"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1FO02758A"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101968"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.03.020"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-023-01186-7"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1201\/9781032620442"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-44732-2"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.11.001"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2011.00700.x"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.05.048"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom14010131"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2024.156146"},{"key":"e_1_2_13_45_1","volume-title":"Neurobiology of Aging Exploring Cognitive Decline and Neurodegeneration","author":"Rai S. N.","year":"2025"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-021-08909-7"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2013.11.041"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2024.140080"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.2c06560"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202310244"},{"key":"e_1_2_13_51_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-024-03267-5"},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-024-03204-6"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2025.1596728"},{"key":"e_1_2_13_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2012.09.005"}],"container-title":["CNS Neuroscience &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cns.70787","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cns.70787","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cns.70787","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T19:57:52Z","timestamp":1772999872000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cns.70787"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2]]},"references-count":53,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1002\/cns.70787"],"URL":"https:\/\/doi.org\/10.1002\/cns.70787","archive":["Portico"],"relation":{},"ISSN":["1755-5930","1755-5949"],"issn-type":[{"value":"1755-5930","type":"print"},{"value":"1755-5949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2]]},"assertion":[{"value":"2025-10-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70787"}}