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Scutellariae Radix and Coptidis Rhizoma Improve Glucose and Lipid Metabolism in T2DM Rats via Regulation of the Metabolic Profiling and MAPK/PI3K/Akt Signaling Pathway.
Int J Mol Sci. 2018 Nov 18; 19(11)IJ

Abstract

Aim Scutellariae Radix (SR) and Coptidis Rhizoma (CR) have often been combined to cure type 2 diabetes mellitus (T2DM) in the clinical practice for over thousands of years, but their compatibility mechanism is not clear. Mitogen-activated protein kinase (MAPK) signaling pathway has been suggested to play a critical role during the process of inflammation, insulin resistance, and T2DM. This study was designed to investigate their compatibility effects on T2DM rats and explore the underlying mechanisms by analyzing the metabolic profiling and MAPK/PI3K/Akt signaling pathway. Methods The compatibility effects of SR and CR were evaluated with T2DM rats induced by a high-fat diet (HFD) along with a low dose of streptozocin (STZ). Ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was performed to discover potential biomarkers. The levels of pro-inflammatory cytokines; biochemical indexes in serum, and the activities of key enzymes related to glycometabolism in liver were assessed by ELISA kits. qPCR was applied to examine mRNA levels of key targets in MAPK and insulin signaling pathways. Protein expressions of p65; p-p65; phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K); phosphorylated-PI3K (p-PI3K); protein kinase B (Akt); phosphorylated Akt (p-Akt) and glucose transporter 2 (Glut2) in liver were investigated by Western blot analysis. Results Remarkably, hyperglycaemia, dyslipidemia, inflammation, and insulin resistance in T2DM were ameliorated after oral administration of SR and CR, particularly their combined extracts. The effects of SR, CR, low dose of combined extracts (LSC) and high dose of combined extracts (HSC) on pro-inflammatory cytokine transcription in T2DM rats showed that the MAPK pathway might account for the phenomenon with down-regulation of MAPK (P38 mitogen-activated protein kinases (P38), extracellular regulated protein kinases (ERK), and c-Jun N-terminal kinase (JNK)) mRNA, and protein reduction in p-P65. While mRNA levels of key targets such as insulin receptor substrate 1 (IRS1), PI3K, Akt2, and Glut2 in the insulin signaling pathway were notably up-modulated, phosphorylations of PI3K, Akt, and expression of Glut2 were markedly enhanced. Moreover, the increased activities of phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase (FBPase), glucose 6-phosphatase (G6Pase), and glycogen phosphorylase (GP) were highly reduced and the decreased activities of glucokinase (GK), phosphofructokinase (PFK), pyruvate kinase (PK), and glycogen synthase (GS) in liver were notably increased after treatment. Further investigation indicated that the metabolic profiles of plasma and urine were clearly improved in T2DM rats. Fourteen potential biomarkers (nine in plasma and five in urine) were identified. After intervention, these biomarkers returned to normal level to some extent. Conclusion The results showed that SR, CR, and combined extract groups were normalized. The effects of combined extracts were more remarkable than single herb treatment. Additionally, this study also showed that the metabonomics method is a promising tool to unravel how traditional Chinese medicines work.

Authors+Show Affiliations

Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China. 15951975518@163.com.Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China. qiandw@njucm.edu.cn.Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China. jiangshu2020@126.com.Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China. shex@sina.com.Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China. 18913133908@163.com.Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China. dja@njucm.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30453687

Citation

Cui, Xiang, et al. "Scutellariae Radix and Coptidis Rhizoma Improve Glucose and Lipid Metabolism in T2DM Rats Via Regulation of the Metabolic Profiling and MAPK/PI3K/Akt Signaling Pathway." International Journal of Molecular Sciences, vol. 19, no. 11, 2018.
Cui X, Qian DW, Jiang S, et al. Scutellariae Radix and Coptidis Rhizoma Improve Glucose and Lipid Metabolism in T2DM Rats via Regulation of the Metabolic Profiling and MAPK/PI3K/Akt Signaling Pathway. Int J Mol Sci. 2018;19(11).
Cui, X., Qian, D. W., Jiang, S., Shang, E. X., Zhu, Z. H., & Duan, J. A. (2018). Scutellariae Radix and Coptidis Rhizoma Improve Glucose and Lipid Metabolism in T2DM Rats via Regulation of the Metabolic Profiling and MAPK/PI3K/Akt Signaling Pathway. International Journal of Molecular Sciences, 19(11). https://doi.org/10.3390/ijms19113634
Cui X, et al. Scutellariae Radix and Coptidis Rhizoma Improve Glucose and Lipid Metabolism in T2DM Rats Via Regulation of the Metabolic Profiling and MAPK/PI3K/Akt Signaling Pathway. Int J Mol Sci. 2018 Nov 18;19(11) PubMed PMID: 30453687.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Scutellariae Radix and Coptidis Rhizoma Improve Glucose and Lipid Metabolism in T2DM Rats via Regulation of the Metabolic Profiling and MAPK/PI3K/Akt Signaling Pathway. AU - Cui,Xiang, AU - Qian,Da-Wei, AU - Jiang,Shu, AU - Shang,Er-Xin, AU - Zhu,Zhen-Hua, AU - Duan,Jin-Ao, Y1 - 2018/11/18/ PY - 2018/10/11/received PY - 2018/11/12/revised PY - 2018/11/12/accepted PY - 2018/11/21/entrez PY - 2018/11/21/pubmed PY - 2019/2/20/medline KW - CR KW - Compatibility KW - MAPK/PI3K/Akt signaling pathway KW - SR KW - T2DM KW - metabolic profiling JF - International journal of molecular sciences JO - Int J Mol Sci VL - 19 IS - 11 N2 - Aim Scutellariae Radix (SR) and Coptidis Rhizoma (CR) have often been combined to cure type 2 diabetes mellitus (T2DM) in the clinical practice for over thousands of years, but their compatibility mechanism is not clear. Mitogen-activated protein kinase (MAPK) signaling pathway has been suggested to play a critical role during the process of inflammation, insulin resistance, and T2DM. This study was designed to investigate their compatibility effects on T2DM rats and explore the underlying mechanisms by analyzing the metabolic profiling and MAPK/PI3K/Akt signaling pathway. Methods The compatibility effects of SR and CR were evaluated with T2DM rats induced by a high-fat diet (HFD) along with a low dose of streptozocin (STZ). Ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was performed to discover potential biomarkers. The levels of pro-inflammatory cytokines; biochemical indexes in serum, and the activities of key enzymes related to glycometabolism in liver were assessed by ELISA kits. qPCR was applied to examine mRNA levels of key targets in MAPK and insulin signaling pathways. Protein expressions of p65; p-p65; phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K); phosphorylated-PI3K (p-PI3K); protein kinase B (Akt); phosphorylated Akt (p-Akt) and glucose transporter 2 (Glut2) in liver were investigated by Western blot analysis. Results Remarkably, hyperglycaemia, dyslipidemia, inflammation, and insulin resistance in T2DM were ameliorated after oral administration of SR and CR, particularly their combined extracts. The effects of SR, CR, low dose of combined extracts (LSC) and high dose of combined extracts (HSC) on pro-inflammatory cytokine transcription in T2DM rats showed that the MAPK pathway might account for the phenomenon with down-regulation of MAPK (P38 mitogen-activated protein kinases (P38), extracellular regulated protein kinases (ERK), and c-Jun N-terminal kinase (JNK)) mRNA, and protein reduction in p-P65. While mRNA levels of key targets such as insulin receptor substrate 1 (IRS1), PI3K, Akt2, and Glut2 in the insulin signaling pathway were notably up-modulated, phosphorylations of PI3K, Akt, and expression of Glut2 were markedly enhanced. Moreover, the increased activities of phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase (FBPase), glucose 6-phosphatase (G6Pase), and glycogen phosphorylase (GP) were highly reduced and the decreased activities of glucokinase (GK), phosphofructokinase (PFK), pyruvate kinase (PK), and glycogen synthase (GS) in liver were notably increased after treatment. Further investigation indicated that the metabolic profiles of plasma and urine were clearly improved in T2DM rats. Fourteen potential biomarkers (nine in plasma and five in urine) were identified. After intervention, these biomarkers returned to normal level to some extent. Conclusion The results showed that SR, CR, and combined extract groups were normalized. The effects of combined extracts were more remarkable than single herb treatment. Additionally, this study also showed that the metabonomics method is a promising tool to unravel how traditional Chinese medicines work. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/30453687/Scutellariae_Radix_and_Coptidis_Rhizoma_Improve_Glucose_and_Lipid_Metabolism_in_T2DM_Rats_via_Regulation_of_the_Metabolic_Profiling_and_MAPK/PI3K/Akt_Signaling_Pathway_ L2 - https://www.mdpi.com/resolver?pii=ijms19113634 DB - PRIME DP - Unbound Medicine ER -