{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:34:30Z","timestamp":1791221670820,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T00:00:00Z","timestamp":1720569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sika Deer Industrial Scientific and Technological Innovation\u2014Modern pharmacological connotation, biological mechanism of action and basic research on the traditional core functions of Sika deer medicinal parts","award":["20220304001YY"],"award-info":[{"award-number":["20220304001YY"]}]},{"name":"Sika Deer Industrial Scientific and Technological Innovation\u2014Modern pharmacological connotation, biological mechanism of action and basic research on the traditional core functions of Sika deer medicinal parts","award":["20220304002YY"],"award-info":[{"award-number":["20220304002YY"]}]},{"name":"Sika Deer Industrial Scientific and Technological Innovation\u2014Modern pharmacological connotation, biological mechanism of action and basic research on the traditional core functions of Sika deer medicinal parts","award":["202300801-04"],"award-info":[{"award-number":["202300801-04"]}]},{"name":"Sika Deer Industrial Scientific and Technological Innovation\u2014Modern pharmacological connotation, biological mechanism of action and basic research on the traditional core functions of Sika deer medicinal parts","award":["23JQ08"],"award-info":[{"award-number":["23JQ08"]}]},{"name":"Sika Deer Industrial Scientific and Technological Innovation\u2014Modern pharmacological connotation, biological mechanism of action and basic research on the traditional core functions of Sika deer medicinal parts","award":["20240601086RC"],"award-info":[{"award-number":["20240601086RC"]}]},{"name":"the Jilin Province Major Science and Technology Special Project","award":["20220304001YY"],"award-info":[{"award-number":["20220304001YY"]}]},{"name":"the Jilin Province Major Science and Technology Special Project","award":["20220304002YY"],"award-info":[{"award-number":["20220304002YY"]}]},{"name":"the Jilin Province Major Science and Technology Special Project","award":["202300801-04"],"award-info":[{"award-number":["202300801-04"]}]},{"name":"the Jilin Province Major Science and Technology Special Project","award":["23JQ08"],"award-info":[{"award-number":["23JQ08"]}]},{"name":"the Jilin Province Major Science and Technology Special Project","award":["20240601086RC"],"award-info":[{"award-number":["20240601086RC"]}]},{"name":"the Demonstration and Promotion of Sika Deer Breeding and Reproduction, Disease Prevention, and Control, Product Processing Industry Technology","award":["20220304001YY"],"award-info":[{"award-number":["20220304001YY"]}]},{"name":"the Demonstration and Promotion of Sika Deer Breeding and Reproduction, Disease Prevention, and Control, Product Processing Industry Technology","award":["20220304002YY"],"award-info":[{"award-number":["20220304002YY"]}]},{"name":"the Demonstration and Promotion of Sika Deer Breeding and Reproduction, Disease Prevention, and Control, Product Processing Industry Technology","award":["202300801-04"],"award-info":[{"award-number":["202300801-04"]}]},{"name":"the Demonstration and Promotion of Sika Deer Breeding and Reproduction, Disease Prevention, and Control, Product Processing Industry Technology","award":["23JQ08"],"award-info":[{"award-number":["23JQ08"]}]},{"name":"the Demonstration and Promotion of Sika Deer Breeding and Reproduction, Disease Prevention, and Control, Product Processing Industry Technology","award":["20240601086RC"],"award-info":[{"award-number":["20240601086RC"]}]},{"name":"the study on key technology and industrialization of deer heart peptide product, a special diet that can increase exercise endurance","award":["20220304001YY"],"award-info":[{"award-number":["20220304001YY"]}]},{"name":"the study on key technology and industrialization of deer heart peptide product, a special diet that can increase exercise endurance","award":["20220304002YY"],"award-info":[{"award-number":["20220304002YY"]}]},{"name":"the study on key technology and industrialization of deer heart peptide product, a special diet that can increase exercise endurance","award":["202300801-04"],"award-info":[{"award-number":["202300801-04"]}]},{"name":"the study on key technology and industrialization of deer heart peptide product, a special diet that can increase exercise endurance","award":["23JQ08"],"award-info":[{"award-number":["23JQ08"]}]},{"name":"the study on key technology and industrialization of deer heart peptide product, a special diet that can increase exercise endurance","award":["20240601086RC"],"award-info":[{"award-number":["20240601086RC"]}]},{"name":"the Jilin Province Science and Technology Department Talent Special\u2014deer sinew chelated calcium preparation key technology and industrialization research","award":["20220304001YY"],"award-info":[{"award-number":["20220304001YY"]}]},{"name":"the Jilin Province Science and Technology Department Talent Special\u2014deer sinew chelated calcium preparation key technology and industrialization research","award":["20220304002YY"],"award-info":[{"award-number":["20220304002YY"]}]},{"name":"the Jilin Province Science and Technology Department Talent Special\u2014deer sinew chelated calcium preparation key technology and industrialization research","award":["202300801-04"],"award-info":[{"award-number":["202300801-04"]}]},{"name":"the Jilin Province Science and Technology Department Talent Special\u2014deer sinew chelated calcium preparation key technology and industrialization research","award":["23JQ08"],"award-info":[{"award-number":["23JQ08"]}]},{"name":"the Jilin Province Science and Technology Department Talent Special\u2014deer sinew chelated calcium preparation key technology and industrialization research","award":["20240601086RC"],"award-info":[{"award-number":["20240601086RC"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Depression is one of the most common psychological disorders nowadays. Studies have shown that 20(S)-protopanaxatriol (PPT) can effectively improve depressive symptoms in mice. However, its mechanism needs to be further explored. In this study, we used an integrated approach combining network pharmacology and transcriptomics to explore the potential mechanisms of PPT for depression. First, the potential targets and pathways of PPT treatment of depression were screened through network pharmacology. Secondly, the BMKCloud platform was used to obtain brain tissue transcription data of chronic unpredictable mild stress (CUMS) model mice and screen PPT-altered differential expression genes (DEGs). Gene ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed using network pharmacology and transcriptomics. Finally, the above results were verified by molecular docking, Western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR). In this study, we demonstrated that PPT improved depression-like behavior and brain histopathological changes in CUMS mice, downregulated nitric oxide (NO) and interleukin-6 (IL-6) levels, and elevated serum levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) after PPT treatment compared to the CUMS group. Eighty-seven potential targets and 350 DEGs were identified by network pharmacology and transcriptomics. Comprehensive analysis showed that transthyretin (TTR), klotho (KL), FOS, and the phosphatidylinositol 3-kinase\u2013protein kinase B (PI3K-AKT) signaling pathway were closely associated with the therapeutic effects of PPT. Molecular docking results showed that PPT had a high affinity for PI3K, AKT, TTR, KL, and FOS targets. Gene and protein level results showed that PPT could increase the expression of PI3K, phosphorylation of PI3K (p-PI3K), AKT, phosphorylation of AKT (p-AKT), TTR, and KL and inhibit the expression level of FOS in the brain tissue of depressed mice. Our data suggest that PPT may achieve the treatment of depression by inhibiting the expression of FOS, enhancing the expression of TTR and KL, and modulating the PI3K-AKT signaling pathway.<\/jats:p>","DOI":"10.3390\/ijms25147574","type":"journal-article","created":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T08:47:41Z","timestamp":1720774061000},"page":"7574","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Network Pharmacology and Transcriptomics to Explore the Pharmacological Mechanisms of 20(S)-Protopanaxatriol in the Treatment of Depression"],"prefix":"10.3390","volume":"25","author":[{"given":"Xiangjuan","family":"Guo","sequence":"first","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Su","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiling","family":"Shi","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Sun","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijia","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianan","family":"Geng","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Li","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0730-0519","authenticated-orcid":false,"given":"Ying","family":"Zong","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongmei","family":"He","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Du","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Li, M., Fu, X., Xie, W., Guo, W., Li, B., Cui, R., and Yang, W. (2020). Effect of Early Life Stress on the Epigenetic Profiles in Depression. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00867"},{"key":"ref_2","unstructured":"W.H. Organization (2023, March 31). Depressive Disorder (Depression). Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/depression."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2470547020971232","DOI":"10.1177\/2470547020971232","article-title":"Role of Spirituality in the Management of Major Depression and Stress-Related Disorders","volume":"5","author":"Varghese","year":"2021","journal-title":"Chronic Stress"},{"key":"ref_4","first-page":"1791","article-title":"Progress in study of antidepressants metabolism in vivo","volume":"12","author":"Zhang","year":"2017","journal-title":"Acta Pharm. Sin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5537","DOI":"10.1039\/D2FO03484K","article-title":"Ginsenosides can target brain-derived neurotrophic factor to improve Parkinson\u2019s disease","volume":"14","author":"Ding","year":"2023","journal-title":"Food Funct."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.jgr.2021.07.007","article-title":"Effects of Panax ginseng and ginsenosides on oxidative stress and cardiovascular diseases: Pharmacological and therapeutic roles","volume":"46","author":"Hyun","year":"2022","journal-title":"J. Ginseng Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1093\/jpp\/rgab048","article-title":"A review of anti-tumour effects of ginsenoside in gastrointestinal cancer","volume":"73","author":"Xu","year":"2021","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Fu, B., Ma, R., Liu, F., Chen, X., Teng, X., Yang, P., Liu, J., Zhao, D., and Sun, L. (2022). Ginsenosides improve reproductive capability of aged female Drosophila through mechanism dependent on ecdysteroid receptor (ECR) and steroid signaling pathway. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.964069"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ding, L., Qi, H., Wang, Y., Zhang, Z., Liu, Q., Guo, C., Liu, J., Chen, Z., Li, J., and Chen, J. (2023). Recent advances in ginsenosides against respiratory diseases: Therapeutic targets and potential mechanisms. Biomed. Pharmacother., 158.","DOI":"10.1016\/j.biopha.2022.114096"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10376","DOI":"10.1021\/acs.jafc.4c00415","article-title":"20(S)-Protopanaxadiol Exerts Antidepressive Effects in Chronic Corticosterone-Induced Rodent Animal Models as an Activator of Brain-Type Creatine Kinase","volume":"72","author":"Zhu","year":"2024","journal-title":"J. Agric. Food Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.1002\/ptr.7779","article-title":"20(S)-protopanaxatriol inhibited D-galactose-induced brain aging in mice via promoting mitochondrial autophagy flow","volume":"37","author":"Zhang","year":"2023","journal-title":"Phytother. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.tips.2021.11.004","article-title":"Network pharmacology: Curing causal mechanisms instead of treating symptoms","volume":"43","author":"Nogales","year":"2022","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Yuan, H., Ma, Q., Cui, H., Liu, G., Zhao, X., Li, W., and Piao, G. (2017). How Can Synergism of Traditional Medicines Benefit from Network Pharmacology?. Molecules, 22.","DOI":"10.3390\/molecules22071135"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Yang, X., Kui, L., Tang, M., Li, D., Wei, K., Chen, W., Miao, J., and Dong, Y. (2020). High-Throughput Transcriptome Profiling in Drug and Biomarker Discovery. Front. Genet., 11.","DOI":"10.3389\/fgene.2020.00019"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1186\/s12931-021-01781-1","article-title":"Mechanism of protective effect of xuan-bai-cheng-qi decoction on LPS-induced acute lung injury based on an integrated network pharmacology and RNA-sequencing approach","volume":"22","author":"Zhu","year":"2021","journal-title":"Respir. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"116873","DOI":"10.1016\/j.jep.2023.116873","article-title":"Network pharmacology and transcriptomics to determine Danggui Yifei Decoction mechanism of action for the treatment of chronic lung injury","volume":"318","author":"Guo","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1002\/ptr.6044","article-title":"Neuroprotective effects of 20(S)-protopanaxatriol (PPT) on scopolamine-induced cognitive deficits in mice","volume":"32","author":"Lu","year":"2018","journal-title":"Phytother. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.jep.2017.11.037","article-title":"Regulation of the kynurenine metabolism pathway by Xiaoyao San and the underlying effect in the hippocampus of the depressed rat","volume":"214","author":"Wang","year":"2018","journal-title":"J. Ethnopharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"109417","DOI":"10.1016\/j.intimp.2022.109417","article-title":"Fluoxetine shows neuroprotective effects against LPS-induced neuroinflammation via the Notch signaling pathway","volume":"113","author":"Zhang","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"D1373","DOI":"10.1093\/nar\/gkac956","article-title":"PubChem 2023 update","volume":"51","author":"Kim","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"W357","DOI":"10.1093\/nar\/gkz382","article-title":"Swiss Target Prediction: Updated data and new features for efficient prediction of protein targets of small molecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"W356","DOI":"10.1093\/nar\/gkx374","article-title":"PharmMapper 2017 update: A web server for potential drug target identification with a comprehensive target pharmacophore database","volume":"45","author":"Wang","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"D976","DOI":"10.1093\/nar\/gky987","article-title":"ETCM: An encyclopaedia of traditional Chinese medicine","volume":"47","author":"Xu","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"baw030","DOI":"10.1093\/database\/baw030","article-title":"Genic insights from integrated human proteomics in GeneCards","volume":"2016","author":"Fishilevich","year":"2016","journal-title":"Database"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1093\/nar\/30.1.52","article-title":"Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders","volume":"30","author":"Hamosh","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2960","DOI":"10.1016\/j.csbj.2021.05.015","article-title":"The DisGeNET cytoscape app: Exploring and visualizing disease genomics data","volume":"19","author":"Sanz","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Bardou, P., Mariette, J., Escudi\u00e9, F., Djemiel, C., and Klopp, C. (2014). jvenn: An interactive Venn diagram viewer. BMC Bioinform., 15.","DOI":"10.1186\/1471-2105-15-293"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3442","DOI":"10.1093\/nar\/28.18.3442","article-title":"STRING: A web-server to retrieve and display the repeatedly occurring neighbourhood of a gene","volume":"28","author":"Snel","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"W216","DOI":"10.1093\/nar\/gkac194","article-title":"DAVID: A web server for functional enrichment analysis and functional annotation of gene lists (2021 update)","volume":"50","author":"Sherman","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Zhu, Y., Zhang, J., Wang, C., Zheng, T., Di, S., Wang, Y., Fei, W., Liang, W., and Wang, L. (2023). Ameliorative Effect of Ethanolic Echinacea purpurea against Hyperthyroidism-Induced Oxidative Stress via AMRK and PPAR Signal Pathway Using Transcriptomics and Network Pharmacology Analysis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010187"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Tang, D., Chen, M., Huang, X., Zhang, G., Zeng, L., Zhang, G., Wu, S., and Wang, Y. (2023). SRplot: A free online platform for data visualization and graphing. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0294236"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Berman, H., Henrick, K., and Nakamura, H. (2003). Announcing the worldwide Protein Data Bank. Nat. Struct. Mol. Biol., 10.","DOI":"10.1038\/nsb1203-980"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Schoch, C.L., Ciufo, S., Domrachev, M., Hotton, C.L., Kannan, S., Khovanskaya, R., Leipe, D., McVeigh, R., O\u2018Neill, K., and Robbertse, B. (2020). NCBI Taxonomy: A comprehensive update on curation, resources and tools. Database J. Biol. Databases Curation, 2020.","DOI":"10.1093\/database\/baaa062"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"106837","DOI":"10.1016\/j.phrs.2023.106837","article-title":"Molecular mechanisms of rapid-acting antidepressants: New perspectives for developing antidepressants","volume":"194","author":"Chen","year":"2023","journal-title":"Pharmacol. Res."},{"key":"ref_35","first-page":"1934578X221093916","article-title":"Antidepressant-Like Effect of Essential Oils From Citrus reticulata in Reserpine-Induced Depressive Mouse","volume":"17","author":"Tang","year":"2022","journal-title":"Nat. Prod. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1248\/bpb.b14-00669","article-title":"Anti-stress Effects of 20(S)-Protopanaxadiol and 20(S)-Protopanaxatriol in Immobilized Mice","volume":"38","author":"Oh","year":"2015","journal-title":"Biol. Pharm. Bull."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nchembio.118","article-title":"Network pharmacology: The next paradigm in drug discovery","volume":"4","author":"Hopkins","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Yan, Z.-Y., Jiao, H.-Y., Chen, J.-B., Zhang, K.-W., Wang, X.-H., Jiang, Y.-M., Liu, Y.-Y., Xue, Z., Ma, Q.-Y., and Li, X.-J. (2021). Antidepressant Mechanism of Traditional Chinese Medicine Formula Xiaoyaosan in CUMS-Induced Depressed Mouse Model via RIPK1-RIPK3-MLKL Mediated Necroptosis Based on Network Pharmacology Analysis. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.773562"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.eurpsy.2013.10.005","article-title":"Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex","volume":"29","author":"Zhou","year":"2014","journal-title":"Eur. Psychiatry J. Assoc. Eur. Psychiatr."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Majd, M., Saunders, E.F.H., and Engeland, C.G. (2020). Inflammation and the dimensions of depression: A review. Front. Neuroendocrinol., 56.","DOI":"10.1016\/j.yfrne.2019.100800"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12974-021-02100-7","article-title":"On inflammatory hypothesis of depression: What is the role of IL-6 in the middle of the chaos?","volume":"18","author":"Roohi","year":"2021","journal-title":"J. Neuroinflammation"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/s41583-019-0260-z","article-title":"Dentate gyrus circuits for encoding, retrieval and discrimination of episodic memories","volume":"21","author":"Hainmueller","year":"2020","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Jeong, N., and Singer, A.C. (2022). Learning from inhibition: Functional roles of hippocampal CA1 inhibition in spatial learning and memory. Curr. Opin. Neurobiol., 76.","DOI":"10.1016\/j.conb.2022.102604"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2901","DOI":"10.1038\/s41467-020-16698-4","article-title":"The lateralization of left hippocampal CA3 during the retrieval of spatial working memory","volume":"11","author":"Song","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1177\/0284185120975182","article-title":"Evaluation of the effect of myelotomy on nerve function in rats with spinal cord injury by diffusion tensor imaging","volume":"62","author":"Liu","year":"2021","journal-title":"Acta Radiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4547","DOI":"10.1074\/jbc.M115.698761","article-title":"Insulin Receptor Substrate 1, the Hub Linking Follicle-stimulating Hormone to Phosphatidylinositol 3-Kinase Activation","volume":"291","author":"Law","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"107367","DOI":"10.1016\/j.jstrokecerebrovasdis.2023.107367","article-title":"VEGF-A ameliorates ischemia hippocampal neural injury via regulating autophagy and Akt\/CREB signaling in a rat model of chronic cerebral hypoperfusion","volume":"32","author":"Kang","year":"2023","journal-title":"J. Stroke Cerebrovasc. Dis. Off. J. Natl. Stroke Assoc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.bbr.2016.04.039","article-title":"Liquiritigenin reverses depression-like behavior in unpredictable chronic mild stress-induced mice by regulating PI3K\/Akt\/mTOR mediated BDNF\/TrkB pathway","volume":"308","author":"Tao","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Matsuda, S., Ikeda, Y., Murakami, M., Nakagawa, Y., Tsuji, A., and Kitagishi, Y.J.D. (2019). Roles of PI3K\/AKT\/GSK3 Pathway Involved in Psychiatric Illnesses. Diseases, 7.","DOI":"10.3390\/diseases7010022"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1111\/bcp.12845","article-title":"New perspectives on the involvement of mTOR in depression as well as in the action of antidepressant drugs","volume":"82","author":"Arent","year":"2016","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"He, W., Wang, Y., Yang, R., Ma, H., Qin, X., Yan, M., Rong, Y., Xie, Y., Li, L., and Si, J. (2022). Molecular Mechanism of Naringenin Against High-Glucose-Induced Vascular Smooth Muscle Cells Proliferation and Migration Based on Network Pharmacology and Transcriptomic Analyses. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.862709"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e689","DOI":"10.1038\/tp.2015.185","article-title":"Feasibility of investigating differential proteomic expression in depression: Implications for biomarker development in mood disorders","volume":"5","author":"Frye","year":"2015","journal-title":"Transl. Psychiatry"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1002\/ar.24740","article-title":"Antidepressant effect of electroacupuncture on modulating the expression of c-Fos\/AP-1 through the JNK signaling pathway","volume":"304","author":"Li","year":"2021","journal-title":"Anat. Rec."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Woo, H.G., Chang, Y., Ryu, D.R., and Song, T.J. (2019). Plasma Klotho concentration is associated with the presence, burden and progression of cerebral small vessel disease in patients with acute ischaemic stroke. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0220796"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7574\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:12:52Z","timestamp":1760109172000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7574"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,10]]},"references-count":54,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["ijms25147574"],"URL":"https:\/\/doi.org\/10.3390\/ijms25147574","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,10]]}}}