Rui Xiong1, Xiu-Ling Wang2, Jian-Ming Wu3, Yong Tang4, Wen-Qiao Qiu5, Xin Shen6, Jin-Feng Teng7, Rong Pan8, Ya Zhao9, Lu Yu10, Jian Liu11, Hai-Xia Chen12, Da-Lian Qin13, Chong-Lin Yu14, An-Guo Wu15. 1. Sichuan Key Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Bioactivity Screening in Traditional Chinese Medicine and Druggability Evalution, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China. Electronic address: rxiong2017@sina.com. 2. Sichuan Key Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Bioactivity Screening in Traditional Chinese Medicine and Druggability Evalution, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Department of Pharmacy, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China. Electronic address: wangxiuling@hospital.cqmu.edu.cn. 3. Sichuan Key Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Bioactivity Screening in Traditional Chinese Medicine and Druggability Evalution, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Institute of Cardiovascular Research, The Key Laboratory of Medical Electrophysiology, Ministry of Education of China, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, China. Electronic address: jianmingwu@swmu.edu.cn. 4. Sichuan Key Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Bioactivity Screening in Traditional Chinese Medicine and Druggability Evalution, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China. Electronic address: tangy1989@yeah.net. 5. Sichuan Key Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Bioactivity Screening in Traditional Chinese Medicine and Druggability Evalution, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China. Electronic address: fanny.qiu@outlook.com. 6. Sichuan Key Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Bioactivity Screening in Traditional Chinese Medicine and Druggability Evalution, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Department of Chinese Materia Medica, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China. Electronic address: shenxin1105@163.com. 7. Sichuan Key Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Bioactivity Screening in Traditional Chinese Medicine and Druggability Evalution, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China. Electronic address: 18883178848@163.com. 8. Sichuan Key Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Bioactivity Screening in Traditional Chinese Medicine and Druggability Evalution, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Department of Human Anatomy, School of Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China. Electronic address: pr18982779805@163.com. 9. Sichuan Key Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Bioactivity Screening in Traditional Chinese Medicine and Druggability Evalution, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China. Electronic address: zhaoya129@126.com. 10. Sichuan Key Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Bioactivity Screening in Traditional Chinese Medicine and Druggability Evalution, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China. Electronic address: yulu863@sina.com. 11. Sichuan Key Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Bioactivity Screening in Traditional Chinese Medicine and Druggability Evalution, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China. Electronic address: belkn@icloud.com. 12. Sichuan Key Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Bioactivity Screening in Traditional Chinese Medicine and Druggability Evalution, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China. Electronic address: dna0805001@163.com. 13. Sichuan Key Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Bioactivity Screening in Traditional Chinese Medicine and Druggability Evalution, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Institute of Cardiovascular Research, The Key Laboratory of Medical Electrophysiology, Ministry of Education of China, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, China. Electronic address: dalianqin@swmu.edu.cn. 14. Department of Human Anatomy, School of Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China. Electronic address: 8056ycl@swmu.edu.cn. 15. Sichuan Key Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Bioactivity Screening in Traditional Chinese Medicine and Druggability Evalution, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Institute of Cardiovascular Research, The Key Laboratory of Medical Electrophysiology, Ministry of Education of China, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, China. Electronic address: wuanguo@swmu.edu.cn.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Lychee seed, the seed of Litchi chinensis Sonn. is one of the commonly used in traditional Chinese medicine (TCM). It possesses many pharmacological effects such as blood glucose and lipid-lowering effects, liver protection, and antioxidation. Our preliminary studies have proven that an active fraction derived from lychee seed (LSF) can significantly decrease the blood glucose level, inhibit amyloid-β (Aβ) fibril formation and Tau hyperphosphorylation, and improve the cognitive function and behavior of Alzheimer's disease (AD) model rats. AIM OF THE STUDY: The aim of this study was to identify the main active components in LSF that can inhibit the hyperphosphorylation of Tau through improving insulin resistance (IR) in dexamethasone (DXM)-induced HepG2 and HT22 cells. MATERIALS AND METHODS: The isolation was guided by the bioactivity evaluation of the improvement effect of IR in HepG2 and HT22 cells. The mRNA and protein expressions of IRS-1, PI3K, Akt, GSK-3β, and Tau were measured by RT-PCR, Western blotting, and immunofluorescence methods, respectively. RESULTS: After extraction, isolation, and elucidation using chromatography and spectrum technologies, three polyphenols including catechin, procyanidin A1 and procyanidin A2 were identified from fractions 3, 5, and 9 derived from LSF. These polyphenols inhibit hyperphosphorylated Tau via the up-regulation of IRS-1/PI3K/Akt and down-regulation of GSK-3β. Molecular docking result further demonstrate that these polyphenols exhibit good binding property with insulin receptor. CONCLUSIONS: catechin, procyanidin A1, and procyanidin A2 are the main components in LSF that inhibit Tau hyperphosphorylation through improving IR via the IRS-1/PI3K/Akt/GSK-3β pathway. Therefore, the findings in the current study provide novel insight into the anti-AD mechanism of the components in LSF derived from lychee seed, which is valuable for the further development of a novel drug or nutrient supplement for the prevention and treatment of AD.
ETHNOPHARMACOLOGICAL RELEVANCE: Lychee seed, the seed of Litchi chinensis Sonn. is one of the commonly used in traditional Chinese medicine (TCM). It possesses many pharmacological effects such as blood glucose and lipid-lowering effects, liver protection, and antioxidation. Our preliminary studies have proven that an active fraction derived from lychee seed (LSF) can significantly decrease the blood glucose level, inhibit amyloid-β (Aβ) fibril formation and Tau hyperphosphorylation, and improve the cognitive function and behavior of Alzheimer's disease (AD) model rats. AIM OF THE STUDY: The aim of this study was to identify the main active components in LSF that can inhibit the hyperphosphorylation of Tau through improving insulin resistance (IR) in dexamethasone (DXM)-induced HepG2 and HT22 cells. MATERIALS AND METHODS: The isolation was guided by the bioactivity evaluation of the improvement effect of IR in HepG2 and HT22 cells. The mRNA and protein expressions of IRS-1, PI3K, Akt, GSK-3β, and Tau were measured by RT-PCR, Western blotting, and immunofluorescence methods, respectively. RESULTS: After extraction, isolation, and elucidation using chromatography and spectrum technologies, three polyphenols including catechin, procyanidin A1 and procyanidin A2 were identified from fractions 3, 5, and 9 derived from LSF. These polyphenols inhibit hyperphosphorylated Tau via the up-regulation of IRS-1/PI3K/Akt and down-regulation of GSK-3β. Molecular docking result further demonstrate that these polyphenols exhibit good binding property with insulin receptor. CONCLUSIONS:catechin, procyanidin A1, and procyanidin A2 are the main components in LSF that inhibit Tau hyperphosphorylation through improving IR via the IRS-1/PI3K/Akt/GSK-3β pathway. Therefore, the findings in the current study provide novel insight into the anti-AD mechanism of the components in LSF derived from lychee seed, which is valuable for the further development of a novel drug or nutrient supplement for the prevention and treatment of AD.