sirolimus and geniposide

Geniposide (GP), extracted from a traditional Chinese herb Gardenia jasminoides, has extensive pharmacological effects. But the effects and the potential mechanisms of GP on myocardial ischemia/reperfusion (I/R) injury are poorly understood. In present study, we investigated the effect of GP on myocardial I/R injury in vivo and hypoxia/reoxygenation (H/R) in vitro respectively, and its mechanism. The results showed that GP reduced myocardial infarct size, alleviated acute myocardial injury, improved cardiac function, regulated apoptosis-related proteins and inhibited apoptosis. In vitro experiments revealed that GP enhanced the cell viability, regulated apoptosis-related proteins and prevented cell apoptosis during H/R in H9c2 cells. GP inhibited the expression of autophagy-related proteins and autophagosome accumulation both in vivo and in vitro. The effects of GP were blocked by rapamycin (RAPA) administration. In summary, our results showed that GP protected against myocardial I/R injury and involved inhibition of autophagy, which might be through activating AKT/mTOR signaling pathways.

Topics: Animals; Apoptosis; Autophagosomes; Autophagy; Cardiotonic Agents; Cell Line; Cell Survival; Heart; Iridoids; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Insulin resistance (IR) is known to be an important factor, which can lead to the onset of type 2 diabetes. Autophagy is a cellular process, which sequesters senescent or damaged proteins in autophagosomes for recycling of their products. Insulin and intracellular molecules, including mammalian target of rapamycin (mTOR), are well‑known inhibitors of autophagy. In patients with type 2 diabetes, the expression levels of glucose transporter 4 (GLUT‑4) in skeletal muscles are significantly decreased, indicating decreased glucose‑processing ability. Geniposide is an iridoid compound isolated from Gardenia jasminoides Ellis. Previously, it was reported that geniposide significantly promoted glucose uptake. In the present study, a HepG2 cell model of IR was constructed to determine whether geniposide can promote autophagy to inhibit insulin resistance in HepG2 cells via P62/nuclear factor (NF)‑κB/GLUT‑4. Cell proliferation was analyzed by performing an MTT assay, and the mRNA expression levels of NF‑κB and GLUT‑4 were assessed using semi‑quantitative polymerase chain reaction and immunohistochemical staining. In addition, the protein levels of GLUT‑4, P62 and phosphorylated‑P65 were assessed by western blotting. The expression of GLUT‑4 was initially increased following geniposide treatment, decreasing in time to its lowest level at 8 h. The expression levels of NF‑κB and GLUT‑4 in the IR cells treated with and without geniposide were significantly different, compared with those in the control group. Geniposide promoted autophagy in the IR HepG2 cells and significantly improved IR in the HepG2 cells, which may be associated with the dynamic regulation of the P62/NF‑κB/GLUT‑4 pathway.

Topics: Autophagy; Glucose Transporter Type 4; Hep G2 Cells; Humans; Insulin Resistance; Iridoids; Microscopy, Confocal; Microscopy, Electron, Transmission; Microtubule-Associated Proteins; Models, Biological; NF-kappa B; Sequestosome-1 Protein; Signal Transduction; Sirolimus