桑叶通过调节代谢组学和 AGEs/RAGE 及 p38MAPK/NF-κB 通路改善糖尿病。
Mulberry leaves ameliorate diabetes via regulating metabolic profiling and AGEs/RAGE and p38 MAPK/NF-κB pathway.
机构信息
Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, And Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, And Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
出版信息
J Ethnopharmacol. 2022 Jan 30;283:114713. doi: 10.1016/j.jep.2021.114713. Epub 2021 Oct 6.
ETHNOPHARMACOLOGICAL RELEVANCE
Mulberry leaves have been used as traditional hypoglycemic medicine-food plant for thousand years in China. According to traditional Chinese medicine theory, type 2 diabetes mellitus (T2DM) belongs to the category of XiaoKe. Presently, the research of mulberry leaf hypoglycemic and lipid-lowering direction is mature, but the curative effects of alkaloids, flavonoids, polysaccharides, and other bioactive ingredients and the related mechanism is still unclear.
AIM OF THE STUDY
This paper aims to study the efficacy and mechanism of alkaloids, flavonoids, polysaccharides, and other bioactive components in mulberry leaves in the treatment of T2DM individually.
MATERIALS AND METHODS
The determination of levels of fasting blood glucose (FBG), triglyceride (TG) and total cholesterol (T-Cho), and pyruvate kinase (PK), hexokinase (HK), and alanine aminotransferase (ALT/GPT) of in plasma of diabetic mice. Urine metabolomics was analyzed by UPLC-QTOF/MS to evaluate differential metabolites from multiple metabolic pathways. The glucose uptake of HepG2 cells and 3T3-L1 cells. Expression of Caspase-3 and caspase-9, inflammatory injury and p38MAPK/NF-κB signaling pathway in GLUTag cells.
RESULTS
Our study revealed alkaloids, flavonoids, and polysaccharides in mulberry leaf could increase the levels of PK, HK, and ALT/GPT, and decrease the levels of TG and T-Cho significantly, and regulate glucose, amino acid, and lipid metabolism. Furthermore, 1-deoxynojirimycin (DNJ) and isoquercitrin (QG) both could increase glucose uptake and promote differentiation of HepG2 cells, increase PPARγ, C/EBPα and SREBP-l expression in 3T3-L1 cells, and inhibit AGEs-induced injury and apoptosis in GLUTag cells, reduce the expression of proteins related to AGEs/RAGE and p38MAPK/NF-κB pathway. Notably, isoquercitrin exhibited more pronounced anti-diabetic efficacy.
CONCLUSIONS
The alkaloids, flavonoids, and polysaccharides from mulberry leaf exhibited hypoglycemic activity through the regulation of glucose, amino acid, and lipid metabolism. 1-DNJ and QG increased glucose uptake and promoted differentiation of HepG2 cells, increased PPARγ, C/EBPα and SREBP-l expression in 3T3-L1 cells, and inhibited AGEs-induced injury and apoptosis in GLUTag cells via the AGEs/RAGE and p38 MAPK/NF-κB pathway.
ETHNOPHARMACOLOGICAL 相关性：桑树叶在中国已被用作传统降血糖药食同源植物已有数千年历史。根据中医理论，2 型糖尿病（T2DM）属于消渴范畴。目前，桑树叶降血糖、调血脂的研究方向已经成熟，但生物碱、黄酮类、多糖等生物活性成分的疗效及其相关机制尚不清楚。
目的
本研究旨在分别研究桑树叶中生物碱、黄酮类、多糖等生物活性成分治疗 T2DM 的疗效及作用机制。
材料与方法
测定糖尿病小鼠血浆中空腹血糖（FBG）、甘油三酯（TG）、总胆固醇（T-Cho）、丙酮酸激酶（PK）、己糖激酶（HK）、丙氨酸氨基转移酶（ALT/GPT）水平。采用 UPLC-QTOF/MS 分析尿液代谢组学，评估来自多个代谢途径的差异代谢物。检测 HepG2 细胞和 3T3-L1 细胞的葡萄糖摄取量。检测 GLUTag 细胞中 Caspase-3 和 caspase-9 的表达、炎症损伤以及 p38MAPK/NF-κB 信号通路。
结果
本研究表明，桑树叶中的生物碱、黄酮类和多糖可显著提高 PK、HK 和 ALT/GPT 的水平，降低 TG 和 T-Cho 的水平，调节糖、氨基酸和脂质代谢。此外，1-脱氧野尻霉素（DNJ）和异槲皮苷（QG）均可增加葡萄糖摄取量，促进 HepG2 细胞分化，增加 3T3-L1 细胞中 PPARγ、C/EBPα 和 SREBP-l 的表达，抑制 GLUTag 细胞中 AGEs 诱导的损伤和凋亡，降低 AGEs/RAGE 和 p38MAPK/NF-κB 通路相关蛋白的表达。值得注意的是，异槲皮苷表现出更显著的抗糖尿病功效。
结论
桑树叶中的生物碱、黄酮类和多糖通过调节糖、氨基酸和脂质代谢发挥降血糖作用。1-DNJ 和 QG 增加葡萄糖摄取量，促进 HepG2 细胞分化，增加 3T3-L1 细胞中 PPARγ、C/EBPα 和 SREBP-l 的表达，抑制 GLUTag 细胞中 AGEs 诱导的损伤和凋亡，通过 AGEs/RAGE 和 p38MAPK/NF-κB 通路。
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