{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:34:37Z","timestamp":1760060077281,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T00:00:00Z","timestamp":1754092800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82274166"],"award-info":[{"award-number":["82274166"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Acute mountain sickness (AMS) is a prevalent and potentially life-threatening condition caused by rapid exposure to high-altitude hypoxia, affecting pulmonary and neurological functions. Tongqiao Jiuxin Oil (TQ), a traditional Chinese medicine formula composed of aromatic and resinous ingredients such as sandalwood, agarwood, frankincense, borneol, and musk, has been widely used in the treatment of cardiovascular and cerebrovascular disorders. Clinical observations suggest its potential efficacy against AMS, yet its pharmacological mechanisms remain poorly understood. Methods: The chemical profile of TQ was characterized using UHPLC-Q-Exactive Orbitrap HRMS. Network pharmacology was applied to predict the potential targets and pathways involved in AMS. A rat model of AMS was established by exposing animals to hypobaric hypoxia (~10% oxygen), simulating an altitude of approximately 5500 m. TQ was administered at varying doses. Physiological indices, oxidative stress markers (MDA, SOD, GSH), histopathological changes, and the expression of hypoxia- and apoptosis-related proteins (HIF-1\u03b1, VEGFA, EPO, Bax, Bcl-2, Caspase-3) in lung and brain tissues were assessed. Results: A total of 774 chemical constituents were identified from TQ. Network pharmacology predicted the involvement of multiple targets and pathways. TQ significantly improved arterial oxygenation and reduced histopathological damage in both lung and brain tissues. It enhanced antioxidant activity by elevating SOD and GSH levels and reducing MDA content. Mechanistically, TQ downregulated the expression of HIF-1\u03b1, VEGFA, EPO, and pro-apoptotic markers (Bax\/Bcl-2 ratio, Caspase-3), while upregulated Bcl-2, the anti-apoptotic protein expression. Conclusions: TQ exerts protective effects against AMS-induced tissue injury by improving oxygen homeostasis, alleviating oxidative stress, and modulating hypoxia-related and apoptotic signaling pathways. This study provides pharmacological evidence supporting the potential of TQ as a promising candidate for AMS intervention, as well as the modern research method for multi-component traditional Chinese medicine.<\/jats:p>","DOI":"10.3390\/ph18081153","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T09:41:17Z","timestamp":1754300477000},"page":"1153","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological Investigation of Tongqiao Jiuxin Oil Against High-Altitude Hypoxia: Integrating Chemical Profiling, Network Pharmacology, and Experimental Validation"],"prefix":"10.3390","volume":"18","author":[{"given":"Jiamei","family":"Xie","sequence":"first","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhang","family":"Du","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohua","family":"Su","sequence":"additional","affiliation":[{"name":"Guangzhou Baiyunshan Xingqun Pharmaceutical Co., Ltd., Guangzhou 510288, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yige","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongcheng","family":"An","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8873-2120","authenticated-orcid":false,"given":"Xin","family":"Mao","sequence":"additional","affiliation":[{"name":"Guangzhou Baiyunshan Xingqun Pharmaceutical Co., Ltd., Guangzhou 510288, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Menglu","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyi","family":"Shan","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiyun","family":"Huang","sequence":"additional","affiliation":[{"name":"Guangzhou Baiyunshan Xingqun Pharmaceutical Co., Ltd., Guangzhou 510288, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuchang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baosheng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.pcad.2010.02.003","article-title":"Acute Mountain Sickness: Pathophysiology, Prevention, and Treatment","volume":"52","author":"Imray","year":"2010","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1016\/S0140-6736(03)13591-X","article-title":"High-Altitude Illness","volume":"361","author":"Basnyat","year":"2003","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1056\/NEJM200107123450206","article-title":"High-Altitude Illness","volume":"345","author":"Hackett","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/S2213-2600(14)70238-3","article-title":"High-Altitude Medicine","volume":"3","author":"West","year":"2015","journal-title":"Lancet Respir. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1056\/NEJMcp1214870","article-title":"Clinical Practice: Acute High-Altitude Illnesses","volume":"368","author":"Swenson","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.cell.2012.01.021","article-title":"Hypoxia-Inducible Factors in Physiology and Medicine","volume":"148","author":"Semenza","year":"2012","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.blre.2012.12.003","article-title":"Regulation of Erythropoiesis by Hypoxia-Inducible Factors","volume":"27","author":"Haase","year":"2013","journal-title":"Blood Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1172\/JCI5912","article-title":"Impaired Physiological Responses to Chronic Hypoxia in Mice Partially Deficient for Hypoxia-Inducible Factor 1\u03b1","volume":"103","author":"Yu","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s10555-007-9063-1","article-title":"Hypoxia, Gene Expression, and Metastasis","volume":"26","author":"Chan","year":"2007","journal-title":"Cancer Metastasis Rev."},{"key":"ref_10","first-page":"1983","article-title":"Effects of sublingual administration of Tongqiao Jiuxin Oil on the quality of life in unstable angina pectoris patients with qi stagnation and blood stasis syndrome","volume":"22","author":"Zhuang","year":"2019","journal-title":"Chin. Gen. Pract."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.neuroscience.2010.11.029","article-title":"Protection by Borneol on Cortical Neurons against Oxygen-Glucose Deprivation\/Reperfusion: Involvement of Anti-Oxidation and Anti-Inflammation through Nuclear Transcription Factor \u03baappaB Signaling Pathway","volume":"176","author":"Liu","year":"2011","journal-title":"Neuroscience"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3892\/mmr.2021.12565","article-title":"Oxidative Stress and Expression of Inflammatory Factors in Lung Tissue of Acute Mountain Sickness Rats","volume":"25","author":"Pu","year":"2022","journal-title":"Mol. Med. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.redox.2017.02.014","article-title":"Oxidative Stress and Apoptosis after Acute Respiratory Hypoxia and Reoxygenation in Rat Brain","volume":"12","author":"Alva","year":"2017","journal-title":"Redox Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1080\/13880209.2021.1992449","article-title":"Salidroside Orchestrates Metabolic Reprogramming by Regulating the HIF-1\u03b1 Signalling Pathway in Acute Mountain Sickness","volume":"59","author":"Yan","year":"2021","journal-title":"Pharm. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Pena, E., El Alam, S., Siques, P., and Brito, J. (2022). Oxidative Stress and Diseases Associated with High-Altitude Exposure. Antioxidants, 11.","DOI":"10.3390\/antiox11020267"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.3181\/0712-RM-337","article-title":"Role of Oxidative Stress and NFkB in Hypoxia-Induced Pulmonary Edema","volume":"233","author":"Sarada","year":"2008","journal-title":"Exp. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"tay075","DOI":"10.1093\/jtm\/tay075","article-title":"Association between Decreased Osteopontin and Acute Mountain Sickness upon Rapid Ascent to 3500 m among Young Chinese Men","volume":"25","author":"Tang","year":"2018","journal-title":"J. Travel. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1089\/ham.2016.0119","article-title":"Oxidative Stress in Acute Hypobaric Hypoxia","volume":"18","author":"Allard","year":"2017","journal-title":"High. Alt. Med. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Calvani, M., Comito, G., Giannoni, E., and Chiarugi, P. (2012). Time-Dependent Stabilization of Hypoxia Inducible Factor-1\u03b1 by Different Intracellular Sources of Reactive Oxygen Species. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038388"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Li, Y., Ren, M., Wang, J., Ma, R., Chen, H., Xie, Q., Li, H., Li, J., and Wang, J. (2021). Progress in Borneol Intervention for Ischemic Stroke: A Systematic Review. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.606682"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"104704","DOI":"10.1016\/j.cellimm.2023.104704","article-title":"Muscone Promotes Functional Recovery by Facilitating Microglia Polarization into M2 Phenotype through PPAR-\u03b3 Pathway after Ischemic Stroke","volume":"386","author":"Liu","year":"2023","journal-title":"Cell. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1080\/01926230701320337","article-title":"Apoptosis: A Review of Programmed Cell Death","volume":"35","author":"Elmore","year":"2007","journal-title":"Toxicol. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e402225","DOI":"10.1590\/acb402225","article-title":"Effects of Borneol on Apoptosis of Hypoxia\/Reoxygenation H9c2 Cells and Myocardial Ischemia-Reperfusion Injury Rats","volume":"40","author":"Zhang","year":"2025","journal-title":"Acta Cir. Bras."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4166","DOI":"10.1002\/ptr.7878","article-title":"L-Borneol Promotes Neurovascular Unit Protection in the Subacute Phase of Transient Middle Cerebral Artery Occlusion Rats: P38-MAPK Pathway Activation, Anti-Inflammatory, and Anti-Apoptotic Effect","volume":"37","author":"Xie","year":"2023","journal-title":"Phytother. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.cell.2007.06.009","article-title":"AKT\/PKB Signaling: Navigating Downstream","volume":"129","author":"Manning","year":"2007","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroscience.2020.02.031","article-title":"Musk Ketone Induces Neural Stem Cell Proliferation and Differentiation in Cerebral Ischemia via Activation of the PI3K\/Akt Signaling Pathway","volume":"435","author":"Zhou","year":"2020","journal-title":"Neuroscience"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"gaab045","DOI":"10.1093\/molehr\/gaab045","article-title":"Acetylcholine Ameliorated Hypoxia-Induced Oxidative Stress and Apoptosis in Trophoblast Cells via P38 MAPK\/NF-\u03baB Pathway","volume":"27","author":"Wang","year":"2021","journal-title":"Mol. Hum. Reprod."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1080\/10717544.2018.1486471","article-title":"Borneol, a Messenger Agent, Improves Central Nervous System Drug Delivery through Enhancing Blood-Brain Barrier Permeability: A Preclinical Systematic Review and Meta-Analysis","volume":"25","author":"Zheng","year":"2018","journal-title":"Drug Deliv."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Nischang, V., Witt, F.M., B\u00f6rner, F., Gomez, M., Jordan, P.M., and Werz, O. (2024). Frankincense Preparation Promotes Formation of Inflammation-Resolving Lipid Mediators by Manipulating Lipoxygenases in Human Innate Immune Cells. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1332628"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Loeser, K., Seemann, S., K\u00f6nig, S., Lenhardt, I., Abdel-Tawab, M., Koeberle, A., Werz, O., and Lupp, A. (2018). Protective Effect of Casperome\u00ae, an Orally Bioavailable Frankincense Extract, on Lipopolysaccharide- Induced Systemic Inflammation in Mice. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.00387"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Xu, Z., Lu, D., Yuan, J., Ren, M., Ma, R., Xie, Q., Li, Y., Li, J., and Wang, J. (2021). Storax, A Promising Botanical Medicine for Treating Cardio-Cerebrovascular Diseases: A Review. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.785598"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13020-021-00565-5","article-title":"Qingwei San Treats Oral Ulcer Subjected to Stomach Heat Syndrome in Db\/Db Mice by Targeting TLR4\/MyD88\/NF-\u03baB Pathway","volume":"17","author":"Shi","year":"2022","journal-title":"Chin. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Shan, Z., Zhang, H., He, C., An, Y., Huang, Y., Fu, W., Wang, M., Du, Y., Xie, J., and Yang, Y. (2024). High-Protein Mulberry Leaves Improve Glucose and Lipid Metabolism via Activation of the PI3K\/Akt\/PPAR\u03b1\/CPT-1 Pathway. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25168726"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/8\/1153\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:21:56Z","timestamp":1760034116000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/8\/1153"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,2]]},"references-count":33,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ph18081153"],"URL":"https:\/\/doi.org\/10.3390\/ph18081153","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2025,8,2]]}}}