Protective effect of α-mangostin derivatives on hypoxia/reoxygenation-induced apoptosis in H9C2 cells and their mechanism |
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| Institution: | 1. College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China;2. College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China;3. Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China;1. Institute of Marine Biochemistry (IMBC), Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam;2. Faculty of Natural Resources and Environment, Vietnam National University of Agriculture, Trau Quy, Gia Lam, Hanoi, Viet Nam;3. Institut de Chimie des Substances Naturelles, CNRS-ICSN, UPR 2301, Université Paris-Saclay, 91198, Gif-sur-Yvette, France;4. School of Chemical Engineering, Hanoi University of Science and Technology, 1 Dai Co Viet, Hai Ba Trung, Hanoi, Viet Nam;5. Graduate University of Science and Technology, VAST, 18 Hoang Quoc Viet, Caugiay, Hanoi, Viet Nam;1. Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand;2. Department of Biology, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand;3. Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand;4. Natural Products Research Unit, Department of Chemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand;5. Department of Nutritional Science, Faculty of Health and Welfare Science, Okayama Prefectural University, Okayama 719-1197, Japan;6. The Graduate School of Environmental and Life Science, Okayama University, Okayama 700-8530, Japan;1. Escuela de Química, Universidad Autónoma de Santo Domingo (UASD), Facultad de Ciencias, Ciudad Universitaria, Santo Domingo, D.N., Dominican Republic;2. Instituto de Química, Universidad Autónoma de Santo Domingo (UASD), Facultad de Ciencias, Ciudad Universitaria, Santo Domingo, D.N., Dominican Republic;3. BioLab, Instituto Universitario de Bio-Orgánica Antonio González (IUBO-AG), Universidad de La Laguna, 38206 La Laguna, Spain;4. Biointerfaces Institute, McMaster University, Engineering Technology Building, Room 413, 1280 Main Street West, Hamilton, ON L8S 0A3, Canada;1. Gilson Purification, 22 rue Bourseul, ZI du Poteau, 56890, Saint Ave, France;2. AsterBioChem Research Team, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café s/n, Ribeirão Preto, SP, 14040-903, Brazil;1. College of Chinese Medicine Material, Jilin Agricultural University, Changchun 130118, China;2. Xinjiang Institute of Chinese and Ethnic Medicine, Urumqi 830002, China;3. Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China;1. Department of Pharmaceutical Engineering, Shanxi Pharmaceutical Vocational College, Taiyuan, 030031, People’s Republic of China;2. School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People’s Republic of China;3. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, People’s Republic of China |
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| Abstract: | In this study, 17 α-mangostin Boc amino acid/organic acid ester derivatives 1–17 were synthesized and subjected to cytotoxicity and cell viability screening assays. A hypoxia/reoxygenation model of cardiomyocyte injury was selected and compound 5 was found to have a better protective effect against hypoxia/reoxygenation-induced myocardial injury by prophylactic administration screening. The levels of LDH and CK-MB in extracellular fluid were detected by ELISA; apoptosis was detected by Hoechst3358/PI double staining, Annexin V-FITC/PI double staining and mitochondrial membrane potential; the expression of key proteins in PI3K/Akt signaling pathway was detected by western blot. The result showed that compound 5 was non-toxic and has a significant cytoprotection effect at concentrations of 1 μM and 10 μM, and reduced the levels of LDH and CK-MB in the extracellular fluid. Hoechst 33,258/PI double staining results showed that compound 5 treatment significantly reduced bright blue cell nuclei and had anti-apoptotic effects; flow cytometry results showed that compound 5 improved hypoxia/reoxygenation-induced mitochondrial membrane potential and thus apoptosis. The western blot results showed that compound 5 upregulated the levels of p-PI3K and p-Akt, decreased the expression of cleaved caspase-3, cleaved caspase-9 and increased the Bcl-2/Bax ratio in a concentration-dependent manner. In addition, compound 5 reversed the effect of the LY294002 inhibitor. The present study suggests that compound 5 may serve as a potential PI3K activator and a safe and effective lead compound for the treatment of cardiovascular disease. |
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| Keywords: | α-mangostin Derivatives H9C2 cells Apoptosis PI3K/Akt |
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