PMID- 30424024 OWN - NLM STAT- MEDLINE DCOM- 20190123 LR - 20190123 IS - 1420-3049 (Electronic) IS - 1420-3049 (Linking) VI - 23 IP - 11 DP - 2018 Nov 9 TI - Ethanolic Extract of Folium Sennae Mediates the Glucose Uptake of L6 Cells by GLUT4 and Ca(2). LID - 10.3390/molecules23112934 [doi] LID - 2934 AB - In today's world, diabetes mellitus (DM) is on the rise, especially type 2 diabetes mellitus (T2DM), which is characterized by insulin resistance. T2DM has high morbidity, and therapies with natural products have attracted much attention in the recent past. In this paper, we aimed to study the hypoglycemic effect and the mechanism of an ethanolic extract of Folium Sennae (FSE) on L6 cells. The glucose uptake of L6 cells was investigated using a glucose assay kit. We studied glucose transporter 4 (GLUT4) expression and AMP-activated protein kinase (AMPK), protein kinase B (PKB/Akt), and protein kinase C (PKC) phosphorylation levels using western blot analysis. GLUT4 trafficking and intracellular Ca(2+) levels were monitored by laser confocal microscopy in L6 cells stably expressing IRAP-mOrange. GLUT4 fusion with plasma membrane (PM) was observed by myc-GLUT4-mOrange. FSE stimulated glucose uptake; GLUT4 expression and translocation; PM fusion; intracellular Ca(2+) elevation; and the phosphorylation of AMPK, Akt, and PKC in L6 cells. GLUT4 translocation was weakened by the AMPK inhibitor compound C, PI3K inhibitor Wortmannin, PKC inhibitor Go6983, G protein inhibitor PTX/Gallein, and PLC inhibitor U73122. Similarly, in addition to PTX/Gallein and U73122, the IP3R inhibitor 2-APB and a 0 mM Ca(2+)-EGTA solution partially inhibited the elevation of intracellular Ca(2+) levels. BAPTA-AM had a significant inhibitory effect on FSE-mediated GLUT4 activities. In summary, FSE regulates GLUT4 expression and translocation by activating the AMPK, PI3K/Akt, and G protein(-)PLC(-)PKC pathways. FSE causes increasing Ca(2+) concentration to complete the fusion of GLUT4 vesicles with PM, allowing glucose uptake. Therefore, FSE may be a potential drug for improving T2DM. FAU - Zhao, Ping AU - Zhao P AD - Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in the Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China. p.zhao@scuec.edu.cn. AD - National Demonstration Center for Experimental Ethnopharmacology Education, South-Central University for Nationalities, Wuhan 430074, China. p.zhao@scuec.edu.cn. FAU - Ming, Qian AU - Ming Q AD - Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in the Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China. 18062196191@163.com. FAU - Qiu, Junying AU - Qiu J AD - Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in the Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China. qiu927633@163.com. FAU - Tian, Di AU - Tian D AD - Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in the Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China. tiandi_2983@126.com. FAU - Liu, Jia AU - Liu J AD - Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in the Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China. 13512566172@163.com. FAU - Shen, Jinhua AU - Shen J AD - Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in the Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China. shenjinhua2013@163.com. FAU - Liu, Qing-Hua AU - Liu QH AD - Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in the Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China. qinghualiu95@163.com. FAU - Yang, Xinzhou AU - Yang X AD - National Demonstration Center for Experimental Ethnopharmacology Education, South-Central University for Nationalities, Wuhan 430074, China. xzyang@mail.scuec.edu.cn. AD - School of Pharmaceutical Sciences, South-Central University for Nationalities, 182 Min-Zu Road, Wuhan 430074, China. xzyang@mail.scuec.edu.cn. LA - eng GR - 31070744/National Natural Science Foundation of China grants/ GR - 81573561/National Natural Science Foundation of China grants/ GR - 81774000/National Natural Science Foundation of China grants/ GR - CZR18003/Fundamental Research Funds for the Central Universities, South-Central University for Nationalities/ GR - CZP17060/Fundamental Research Funds for the Central Universities, South-Central University for Nationalities/ GR - CZP17048/Fundamental Research Funds for the Central Universities, South-Central University for Nationalities/ GR - 2017060201010217/Wuhan Applied Basic Research Program of Science and Technology/ PT - Journal Article DEP - 20181109 PL - Switzerland TA - Molecules JT - Molecules (Basel, Switzerland) JID - 100964009 RN - 0 (Biomarkers) RN - 0 (Glucose Transporter Type 4) RN - 0 (Plant Extracts) RN - IY9XDZ35W2 (Glucose) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Biological Transport MH - Biomarkers MH - Calcium/*metabolism MH - Cassia/*chemistry MH - Cell Line MH - Gene Expression MH - Glucose/*metabolism MH - Glucose Transporter Type 4/genetics/*metabolism MH - Plant Extracts/chemistry/*pharmacology MH - Signal Transduction/drug effects PMC - PMC6278344 OTO - NOTNLM OT - Ca2+ OT - FSE OT - GLUT4 OT - L6 cell OT - T2DM COIS- The authors declare no conflict of interest. EDAT- 2018/11/15 06:00 MHDA- 2019/01/24 06:00 PMCR- 2018/11/09 CRDT- 2018/11/15 06:00 PHST- 2018/09/29 00:00 [received] PHST- 2018/11/02 00:00 [revised] PHST- 2018/11/08 00:00 [accepted] PHST- 2018/11/15 06:00 [entrez] PHST- 2018/11/15 06:00 [pubmed] PHST- 2019/01/24 06:00 [medline] PHST- 2018/11/09 00:00 [pmc-release] AID - molecules23112934 [pii] AID - molecules-23-02934 [pii] AID - 10.3390/molecules23112934 [doi] PST - epublish SO - Molecules. 2018 Nov 9;23(11):2934. doi: 10.3390/molecules23112934.