Xuxu Zheng

Geniposide, a novel agonist for GLP-1 receptor, prevents PC12 cells from oxidative damage via MAP kinase pathway

Alzheimers disease (AD) is the most common form of dementia. Glucagon-like peptide-1 (GLP-1) gives a new genre in therapeutic targets for intervention in AD with its neurotrophic and neuroprotective functions. In previous work, we identified that geniposide is a novel agonist for GLP-1 receptor, which shows neurotrophic characteristics to induce the neuronal differentiation of PC12 cells. The aim of this study is to determine whether geniposide prevents neurons from oxidative damage, and to explore its signaling pathways. The results demonstrated that geniposide increased the expression of anti-apoptotic proteins, including Bcl-2 and heme oxygenase-1 (HO-1), to antagonize the oxidative damage in PC12 cells induced by hydrogen peroxide. LY294002 (a PI3K inhibitor) inhibited the effect of geniposide increasing of Bcl-2 level by activation of MAPK, MEK and c-Raf phosphorylation in hydrogen peroxide treated PC12 cells. U0126 (a selective inhibitor of MEK) also attenuated the enhancement of geniposide on Bcl-2 level by inhibiting the phosphorylation of p90RSK in the hydrogen peroxide treated PC12 cells. All these data demonstrate that geniposide, an agonist for GLP-1 receptor, regulates expression of anti-oxidative proteins including HO-1 and Bcl-2 by activating the transcriptor of p90RSK via MAPK signaling pathway in PC12 cells.

Neurotrophic property of geniposide for inducing the neuronal differentiation of PC12 cells.

The emerging data show that the insulinotrophic hormone glucagon‐like peptide‐1(GLP‐1) and its agonist extendin‐4 have neurotrophic function to inducing neuronal differentiation of PC12 cells and prevent neurons damage challenged by oxidative stress. Here, with the model of high throughput screen for GLP‐1 receptor agonists, we screen and identify that geniposide is a novel agonist for GLP‐1 receptor. Furthermore, geniposide induces the neuronal differentiation of PC12 cells with resulting neurites outgrowth; we also observe an increase in expression of growth‐associated protein‐43. U0126, a selective MEK inhibitor, prevents neurites out growth and phosphorylation of mitogen‐activated kinase proteins in PC12 cells induced by geniposide. All these results show that activation of GLP‐1 receptor by geniposide to induce the neuronal differentiation of PC12 cells involves in MAPK signaling cascade.

GLP-1 receptor plays a critical role in geniposide-induced expression of heme oxygenase-1 in PC12 cells

AbstractAim:To explore the role of activation of glucagon-like peptide 1 receptor (GLP-1R) and its relative cell signaling pathway in the cytoprotection of geniposide.Methods:Cell viability was determined by MTT assay. Knockdown of the Glp-1r gene was carried out with shRNA. The levels of HO-1 protein and cAMP response element binding protein (CREB) phosphorylation were measured by Western blotting.Results:Geniposide protected PC12 cells from oxidative damage induced by 3-morpholinosydnonimine hydrochloride (SIN-1) by enhancing the expression of heme oxygenase 1 (HO-1) via the cAMP-PKA-CREB signal pathway. After transfecting PC12 cells with the AB1 enhancer from the HO-1 gene, luciferase activity induced by geniposide increased in a dose-dependent manner, but not in the PC12 cells whose Glp-1r gene was disrupted. Additionally, inhibition of HO-1 activity by Sn-protoporphyrin IX (SnPP) or shRNA-mediated knockdown of Glp-1r decreased the neuroprotection of geniposide in PC12 cells.Conclusion:GLP-1R plays a critical role in geniposide-induced HO-1 expression to attenuate oxidative insults in PC12 cells.

Geniposide Suppresses Hepatic Glucose Production via AMPK in HepG2 Cells.

Geniposide is one of the main compounds in Gardenia jasminoides ELLIS and has many pharmacological activities, but its anti-hyperglycemic activity has not yet been fully explored. This study was designed to determine, for the first time, how geniposide from G. jasminoides regulates hepatic glucose production, and the underlying mechanisms. During in vitro study, we found the inhibitory effect of geniposide on the hepatic glucose production is partly through AMP-activated protein kinase (AMPK) activation in HepG2 cells. Geniposide significantly inhibited hepatic glucose production in a dose-dependent manner. AMPK, acetyl coenzyme A synthetase (ACC) and forkhead box class O1 (FoxO1) phosphorylation were stimulated by different concentrations of geniposide. In addition, the enzyme activities of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) were all significantly suppressed. What is important is that these effects were partly reversed by (1) inhibition of AMPK activity by compound C, a selective AMPK inhibitor, and by (2) suppression of AMPKα expression by small interfering RNA (siRNA). In summary, geniposide potentially ameliorates hyperglycemia through inhibition of hepatic gluconeogenesis by modulation of the AMPK-FoxO1 signaling pathway. Geniposide or geniposide-containing medicinal plants could represent a promising therapeutic agent to prevent type 2 diabetes on gluconeogenesis.

Geniposide improves insulin production and reduces apoptosis in high glucose-induced glucotoxic insulinoma cells

Abstract Our previous work revealed that in the pancreatic &bgr; cell line, geniposide modulated ATP production and glucose‐stimulated insulin secretion (GSIS) induced by the acute stimulation of high glucose concentration. However, the effects of geniposide on functional impairment and the mass of &bgr;‐cells exposed to elevated levels of glucose remains unknown. In the present study, impaired GSIS and restrained proliferation were observed in the prolonged culture of insulinoma INS‐1 cells with 33 mM of glucose (high glucose). Our results indicate that the glucose‐induced impairment of insulin release was significantly reverted by the inclusion of 1 or 10 &mgr;M of geniposide. Moreover, induction of the phosphorylation of AMP‐activated protein kinase (AMPK) was observed, which promoted the utilization of nutrient stores for energy production. AMPK phosphorylation was enhanced by an increased number of INS‐1 cells, and the increased expression of AMPK downstream target heme oxygenase 1 (HO‐1), under high glucose concentration. Furthermore, geniposide protected rat insulinoma cells from apoptosis in high‐glucose concentrations. We have shown that these effects were associated with an increased apoptosis‐related Bcl‐2/BAX protein ratio. In conclusion, geniposide dose dependently improves &bgr;‐cell function and increases the proliferation of &bgr;‐cells exposed to prolonged hyperglycemia. Graphical abstract Figure. No Caption available.

A Study on the Production Process Control of Zanthoxylum bungeanum Maxim Seed Kernel Oil without Trans-Fatty Acids

The process control of the production of Zanthoxylum bungeanum Maxim seed kernel oil (ZSKO) with no trans-fatty acids (TFAs) was investigated. Results revealed that drying temperature and time had a small effect on TFA formation in ZSKO. And high concentrations of sodium hydroxide solution had some effect on TFA formation in ZKSO, but there were no TFAs when the concentration of the sodium hydroxide solution was lower than 20% and even at boiling temperature for one hour. The roasting temperature and duration for Zanthoxylum bungeanum Maxim seed (ZS) should be properly controlled at 100°C for six hours or 150°C for two hours. ZS, which has a moisture content of 18%, was pressed four times (two hours) at less than 60°C, and ZSKO was obtained by collection through centrifuge separation. This contained 90.84% unsaturated fatty acids, which mainly include 32.49%  α-linolenic acid, 29.88% linoleic acid, and 27.52% oleic acids; and there was no TFA. Its acidic value and peroxide value conformed to China standards for edible oil. Therefore, ZKSO could be used as a healthy food for further development.