{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T20:54:00Z","timestamp":1789592040244,"version":"build-2803163510"},"reference-count":51,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,6]],"date-time":"2025-07-06T00:00:00Z","timestamp":1751760000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Science Foundation of Jilin Province, China","award":["20250601064R"],"award-info":[{"award-number":["20250601064R"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Paeoniflorin (PF), a monomeric compound extracted from the dry roots of Paeonia lactiflora, has been widely used in the treatment of nervous system diseases, marking it as a critical formula in Parkinson\u2019s disease (PD). However, the action of PF against PD and its molecular mechanism are still unclear. In this study, tandem mass tags quantitative proteomics was performed to systematically clarify the underlying mechanism of action of PF against PD and to confirm it using in vivo and in vitro studies. The results showed that PF notably enhanced the viability of PC12 cells and mitigated MPP+-induced mitochondrial dysfunction, oxidative stress, and apoptosis. Tandem mass tag-based quantitative proteome analysis revealed the identification of 6405 proteins, of which 92 were downregulated and 190 were upregulated. Among them, the levels of PI3K, AKT, CREB, and BDNF in the MPP+-induced PC12 cell and MPTP mice were considerably lower than in the control group, indicating the role of the BDNF\/CREB pathway in the pathogenesis of neuroprotection. The related DEP (PI3K, AKT, CREB, and BDNF) expression levels were verified by Western blot. PF effectively restored the altered expression of the four DEPs induced by MPP+ and MPTP. Summarily, PF exerted remarkable neuroprotective effects in MPP+-induced PC12 cell and MPTP-induced mice. Further, our research may provide proteomics insights that contribute to the further exploration of PF as a potential treatment for PD.<\/jats:p>","DOI":"10.3390\/ijms26136498","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T08:58:23Z","timestamp":1751878703000},"page":"6498","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Tandem Mass Tags Quantitative Proteomics Reveal the Mechanism by Which Paeoniflorin Regulates the PI3K\/AKT and BDNF\/CREB Signaling Pathways to Inhibit Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1445-0591","authenticated-orcid":false,"given":"Zhen","family":"Feng","sequence":"first","affiliation":[{"name":"College of Life Sciences, Changchun Normal University, Changchun 130032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Jin","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Changchun Normal University, Changchun 130032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Changchun Normal University, Changchun 130032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7858-8656","authenticated-orcid":false,"given":"Huiming","family":"Xue","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Changchun Normal University, Changchun 130032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5212-3609","authenticated-orcid":false,"given":"Yongxing","family":"Ai","sequence":"additional","affiliation":[{"name":"College of Animal Science, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Technical Innovation Laboratory for Research and Development of Economic Plants and Edible and Medicinal Fungi in Cold Regions of Jilin Province, Changchun Normal University, Changchun 130032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meizhu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Central Laboratory, Changchun Normal University, Changchun 130032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongfang","family":"Shi","sequence":"additional","affiliation":[{"name":"Central Laboratory, Changchun Normal University, Changchun 130032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/S1474-4422(21)00030-2","article-title":"Challenges in the diagnosis of Parkinson\u2019s disease","volume":"20","author":"Tolosa","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_2","first-page":"S257","article-title":"Defining Parkinson\u2019s Disease: Past and Future","volume":"14","author":"Kulcsarova","year":"2024","journal-title":"J. Park. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1093\/bmb\/ldad035","article-title":"Genetics in Parkinson\u2019s disease, state-of-the-art and future perspectives","volume":"149","author":"Trevisan","year":"2024","journal-title":"Br. Med. Bull."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1177\/1054773816634912","article-title":"Nursing Research in Parkinson\u2019s Disease From 2006 to 2015: A Systematic Review","volume":"26","author":"Shin","year":"2017","journal-title":"Clin. Nurs. Res."},{"key":"ref_5","first-page":"237","article-title":"BDNF function and intracellular signaling in neurons","volume":"25","author":"Numakawa","year":"2010","journal-title":"Histol. Histopathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.jad.2023.01.107","article-title":"Serum BDNF levels are involved in the diagnosis and treatment response in patients with PD","volume":"327","author":"Li","year":"2023","journal-title":"J. Affect. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1096\/fasebj.8.10.8050673","article-title":"Role of neurotrophins in mouse neuronal development","volume":"8","author":"Klein","year":"1994","journal-title":"FASEB J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s11011-022-00946-1","article-title":"Expression of BDNF-Associated lncRNAs in Parkinson\u2019s disease","volume":"37","author":"Akbari","year":"2022","journal-title":"Metab. Brain Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"113091","DOI":"10.1016\/j.fct.2022.113091","article-title":"Curcumin can improve Parkinson\u2019s disease via activating BDNF\/PI3k\/Akt signaling pathways","volume":"164","author":"Jin","year":"2022","journal-title":"Food Chem. Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"111207","DOI":"10.1016\/j.intimp.2023.111207","article-title":"Formoterol attenuated mitochondrial dysfunction in rotenone-induced Parkinson\u2019s disease in a rat model: Role of PINK-1\/PARKIN and PI3K\/Akt\/CREB\/BDNF\/TrKB axis","volume":"125","author":"Khidr","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1007\/s13311-022-01248-1","article-title":"Treating Parkinson\u2019s Disease via Activation of BDNF\/TrkB Signaling Pathways and Inhibition of Delta-Secretase","volume":"19","author":"Kang","year":"2022","journal-title":"Neurotherapeutics"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s41420-022-01063-9","article-title":"Regulation of BDNF transcription by Nrf2 and MeCP2 ameliorates MPTP-induced neurotoxicity","volume":"8","author":"Cao","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Tan, Y.Q., Chen, H.W., Li, J., and Wu, Q.J. (2020). Efficacy, Chemical Constituents, and Pharmacological Actions of Radix Paeoniae Rubra and Radix Paeoniae Alba. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.01054"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.biopha.2018.12.090","article-title":"Paeoniflorin improves pressure overload-induced cardiac remodeling by modulating the MAPK signaling pathway in spontaneously hypertensive rats","volume":"111","author":"Liu","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"107452","DOI":"10.1016\/j.pharmthera.2019.107452","article-title":"Anti-inflammatory and immunoregulatory effects of paeoniflorin and total glucosides of paeony","volume":"207","author":"Zhang","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Li, X., Sun, C., Zhang, J., Hu, L., Yu, Z., Zhang, X., Wang, Z., Chen, J., Wu, M., and Liu, L. (2023). Protective effects of paeoniflorin on cardiovascular diseases: A pharmacological and mechanistic overview. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1122969"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"20220905","DOI":"10.1515\/biol-2022-0905","article-title":"The analgesic effect of paeoniflorin: A focused review","volume":"19","author":"Li","year":"2024","journal-title":"Open Life Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1097\/FJC.0000000000001021","article-title":"Recent Insights Into the Protective Mechanisms of Paeoniflorin in Neurological, Cardiovascular, and Renal Diseases","volume":"77","author":"Jiao","year":"2021","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1080\/17425247.2023.2253146","article-title":"Continuous subcutaneous levodopa-carbidopa for the treatment of advanced Parkinson\u2019s disease: Is it an improvement on other delivery?","volume":"20","author":"Doggrell","year":"2023","journal-title":"Expert Opin Drug Deliv."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s40035-018-0119-7","article-title":"Adjunct rasagiline to treat Parkinson\u2019s disease with motor fluctuations: A randomized, double-blind study in China","volume":"7","author":"Zhang","year":"2018","journal-title":"Transl. Neurodegener."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"723","DOI":"10.2165\/00023210-200519090-00001","article-title":"Treatment of Parkinson\u2019s disease: What\u2019s on the horizon?","volume":"19","author":"Wu","year":"2005","journal-title":"CNS Drugs"},{"key":"ref_22","first-page":"183","article-title":"Progression of Cognitive Decline in Parkinson\u2019s Disease","volume":"8","author":"Roheger","year":"2018","journal-title":"J. Park. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"411","DOI":"10.5604\/12321966.1232774","article-title":"Motor assessment in Parkinson\u2019s disease","volume":"24","author":"Opara","year":"2017","journal-title":"Ann. Agric. Environ. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"113249","DOI":"10.1016\/j.jep.2020.113249","article-title":"The signaling pathways and targets of traditional Chinese medicine and natural medicine in triple-negative breast cancer","volume":"264","author":"Yang","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Deng, C., Chen, H., Meng, Z., and Meng, S. (2022). Roles of traditional Chinese medicine regulating neuroendocrinology on AD treatment. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.955618"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.3390\/v6041861","article-title":"Characterization of the Anti-Influenza Activity of the Chinese Herbal Plant Paeonia Lactiflora","volume":"6","author":"Ho","year":"2014","journal-title":"Viruses"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"116539","DOI":"10.1016\/j.jep.2023.116539","article-title":"Preliminary exploration of method for screening efficacy markers compatibility in TCM prescriptions based on Q-markers: Anti-inflammatory activity of Dachaihu decoction as an example","volume":"312","author":"Bi","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"112182","DOI":"10.1016\/j.jep.2019.112182","article-title":"Total glucosides of paeony (TGP) extracted from Radix Paeoniae Alba exerts neuroprotective effects in MPTP-induced experimental parkinsonism by regulating the cAMP\/PKA\/CREB signaling pathway","volume":"245","author":"Zheng","year":"2019","journal-title":"J. Ethnopharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"117319","DOI":"10.1016\/j.jep.2023.117319","article-title":"Total Glucosides of White Paeony Capsule ameliorates Parkinson\u2019s disease-like behavior in MPTP-induced mice model by regulating LRRK2\/alpha-synuclein signaling","volume":"319","author":"Li","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.jep.2013.05.026","article-title":"Protective effects of aqueous extract from Acanthopanax senticosus against corticosterone-induced neurotoxicity in PC12 cells","volume":"148","author":"Wu","year":"2013","journal-title":"J. Ethnopharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.prp.2010.09.006","article-title":"Parathyroid hormone(1-34)-induced apoptosis in neuronal rat PC12 cells: Implications for neurotoxicity","volume":"206","author":"An","year":"2010","journal-title":"Pathol. Res. Pract."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1007\/s10571-015-0194-6","article-title":"Attenuation of Cisplatin-Induced Neurotoxicity by Cyanidin, a Natural Inhibitor of ROS-Mediated Apoptosis in PC12 Cells","volume":"35","author":"Li","year":"2015","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Msibi, Z.N.P., and Mabandla, M.V. (2019). Oleanolic Acid Mitigates 6-Hydroxydopamine Neurotoxicity by Attenuating Intracellular ROS in PC12 Cells and Striatal Microglial Activation in Rat Brains. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.01059"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.neulet.2019.01.055","article-title":"The primary neuronal cells are more resistant than PC12 cells to \u03b1-synuclein toxic aggregates","volume":"701","author":"Heravi","year":"2019","journal-title":"Neurosci. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1038\/s41467-024-46485-4","article-title":"AlphaPept: A modern and open framework for MS-based proteomics","volume":"15","author":"Strauss","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e2200432","DOI":"10.1002\/pmic.202200432","article-title":"Global profiling of protein lysine lactylation and potential target modified protein analysis in hepatocellular carcinoma","volume":"23","author":"Hong","year":"2023","journal-title":"Proteomics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4725","DOI":"10.1523\/JNEUROSCI.2273-21.2022","article-title":"Voluntary Exercise Boosts Striatal Dopamine Release: Evidence for the Necessary and Sufficient Role of BDNF","volume":"42","author":"Bastioli","year":"2022","journal-title":"J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.parkreldis.2022.08.020","article-title":"Altered BDNF levels are associated with cognitive impairment in Parkinson?s disease patients with depression","volume":"103","author":"Wang","year":"2022","journal-title":"Park. Relat. Disord."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Long, H.Z., Cheng, Y., Zhou, Z.W., Luo, H.Y., Wen, D.D., and Gao, L.C. (2021). PI3K\/AKT Signal Pathway: A Target of Natural Products in the Prevention and Treatment of Alzheimer\u2019s Disease and Parkinson\u2019s Disease. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.648636"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Singh, R., Zahra, W., Singh, S.S., Birla, H., Rathore, A.S., Keshri, P.K., Dilnashin, H., Singh, S., and Singh, S.P. (2023). Oleuropein confers neuroprotection against rotenone-induced model of Parkinson\u2019s disease via BDNF\/CREB\/Akt pathway. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-29287-4"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"112692","DOI":"10.1016\/j.bbr.2020.112692","article-title":"Neuroprotective action of agmatine in rotenone-induced model of Parkinson\u2019s disease: Role of BDNF\/cREB and ERK pathway","volume":"392","author":"Bilge","year":"2020","journal-title":"Behav. Brain Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Yang, L., Wang, H., Liu, L., and Xie, A. (2018). The Role of Insulin\/IGF-1\/PI3K\/Akt\/GSK3\u03b2 Signaling in Parkinson\u2019s Disease Dementia. Front. Neurosci., 12.","DOI":"10.3389\/fnins.2018.00073"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3075","DOI":"10.1158\/0008-5472.CAN-17-3024","article-title":"Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells","volume":"78","author":"Rahmani","year":"2018","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"253","DOI":"10.3892\/ijmm.2016.2833","article-title":"PI3K\/AKT signaling mediated by G protein-coupled receptors is involved in neurodegenerative Parkinson\u2019s disease (Review)","volume":"39","author":"Nakano","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2400","DOI":"10.2741\/3386","article-title":"Regulation of neutrophil apoptosis by modulation of PKB\/Akt activation","volume":"14","author":"Rane","year":"2009","journal-title":"Front. Biosci. (Landmark Ed.)"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1007\/s10787-023-01305-x","article-title":"PI3K\/AKT signaling activation by roflumilast ameliorates rotenone-induced Parkinson\u2019s disease in rats","volume":"32","author":"Farid","year":"2024","journal-title":"Inflammopharmacology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.neuro.2021.10.003","article-title":"Baicalein Protects against Mpp+\/Mptp-Induced Neurotoxicity by Ameliorating Oxidative Stress in SH-SY5Y Cells and Mouse Model of Parkinson\u2019s Disease","volume":"87","author":"Song","year":"2021","journal-title":"Neurotoxicology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7769355","DOI":"10.1155\/2022\/7769355","article-title":"Quercetin Protects against MPP+\/MPTP-Induced Dopaminergic Neuron Death in Parkinson\u2019s Disease by Inhibiting Ferroptosis","volume":"2022","author":"Lin","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"307","DOI":"10.31083\/j.jin2002030","article-title":"Behavioral characterization in MPTP\/p mouse model of Parkinson\u2019s disease","volume":"20","author":"Wada","year":"2021","journal-title":"J. Integr. Neurosci."},{"key":"ref_50","first-page":"529","article-title":"Neuroprotective Effects of a GLP-2 Analogue in the MPTP Parkinson\u2019s Disease Mouse Model","volume":"11","author":"Zhang","year":"2021","journal-title":"J. Park. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"154","DOI":"10.5582\/ddt.2022.01026","article-title":"Effects of eugenol on the behavioral and pathological progression in the MPTP-induced Parkinson\u2019s disease mouse model","volume":"16","author":"Vora","year":"2022","journal-title":"Drug Discov. Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6498\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:05:18Z","timestamp":1760033118000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6498"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,6]]},"references-count":51,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26136498"],"URL":"https:\/\/doi.org\/10.3390\/ijms26136498","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,6]]}}}