Mangiferin Upregulates Glyoxalase 1 Through Activation of Nrf2/ARE Signaling in Central Neurons Cultured with High Glucose.
Mangiferin, a natural C-glucoside xanthone, has anti-inflammatory, anti-oxidative, neuroprotective actions. Our previous study showed that mangiferin could attenuate diabetes-associated cognitive impairment of rats by enhancing the function of glyoxalase 1 (Glo-1) in brain. The aim of this study was to investigate whether Glo-1 upregulation by mangiferin in central neurons exposed to chronic high glucose may be related to activation of Nrf2/ARE pathway. Compared with normal glucose (25 mmol/L) culture, Glo-1 protein, mRNA, and activity levels were markedly decreased in primary hippocampal and cerebral cortical neurons cultured with high glucose (50 mmol/L) for 72 h, accompanied by the declined Nrf2 nuclear translocation and protein expression of Nrf2 in cell nucleus, as well as protein expression and mRNA level of γ-glutamylcysteine synthetase (γ-GCS) and superoxide dismutase activity, target genes of Nrf2/ARE signaling. Nonetheless, high glucose cotreating with mangiferin or sulforaphane, a typical inducer of Nrf2 activation, attenuated the above changes in both central neurons. In addition, mangiferin and sulforaphane significantly prevented the formation of advanced glycation end-products (AGEs) reflecting Glo-1 activity, while elevated the level of glutathione, a cofactor of Glo-1 activity and production of γ-GCS, in high glucose cultured central neurons. These findings demonstrated that Glo-1 was greatly downregulated in central neurons exposed to chronic high glucose, which is expected to lead the formation of AGEs and oxidative stress damages. We also proved that mangiferin enhanced the function of Glo-1 under high glucose condition by inducing activation of Nrf2/ARE signaling pathway.
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.|Department of Pharmacology, School of Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
Yao-Wu
YW
Liu
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.|Department of Pharmacy, Taizhaou People's Hospital, Taizhou, 225300, Jiangsu, China.
Ya-Qin
YQ
Cheng
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
Xiao-Li
XL
Liu
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
Yun-Chao
YC
Hao
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
Yu
Y
Li
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
Xia
X
Zhu
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
Fan
F
Zhang
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China. yinxx@xzmc.edu.cn.
Xiao-Xing
XX
Yin
D000818:Animals; D061745:Antioxidant Response Elements / Q000235:genetics*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D005947:Glucose / Q000633:toxicity*; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007791:Lactoylglutathione Lyase / Q000235:genetics* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009997:Osmotic Pressure; D011312:Pressure; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D012997:Solvents; D013482:Superoxide Dismutase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D044004:Xanthones / Q000494:pharmacology*
D017127:Glycation End Products, Advanced; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D012997:Solvents; D044004:Xanthones; C013592:mangiferin; D013482:Superoxide Dismutase; D007791:Lactoylglutathione Lyase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D005947:Glucose
Advanced glycation end-products; Glyoxalase 1; High glucose; Hippocampal and cortical neurons; Nrf2/ARE pathway; Oxidative stress