gw9662 and dorsomorphin

Airway smooth muscle (ASM) cells have been reported to contribute to the inflammation of asthma. Because the thiazolidinediones (TZDs) exert anti-inflammatory effects, we examined the effects of troglitazone and rosiglitazone on the release of inflammatory moieties from cultured human ASM cells. Troglitazone dose-dependently reduced the IL-1β-induced release of IL-6 and vascular endothelial growth factor, the TNF-α-induced release of eotaxin and regulated on activation, normal T expressed and secreted (RANTES), and the IL-4-induced release of eotaxin. Rosiglitazone also inhibited the TNF-α-stimulated release of RANTES. Although TZDs are known to activate peroxisome proliferator-activated receptor-γ (PPARγ), these anti-inflammatory effects were not affected by a specific PPARγ inhibitor (GW 9662) or by the knockdown of PPARγ using short hairpin RNA. Troglitazone and rosiglitazone each caused the activation of adenosine monophosphate-activated protein kinase (AMPK), as detected by Western blotting using a phospho-AMPK antibody. The anti-inflammatory effects of TZDs were largely mimicked by the AMPK activators, 5-amino-4-imidazolecarboxamide ribose (AICAR) and metformin. However, the AMPK inhibitors, Ara A and Compound C, were not effective in preventing the anti-inflammatory effects of troglitazone or rosiglitzone, suggesting that the effects of these TZDs are likely not mediated through the activation of AMPK. These data indicate that TZDs inhibit the release of a variety of inflammatory mediators from human ASM cells, suggesting that they may be useful in the treatment of asthma, and the data also indicate that the effects of TZDs are not mediated by PPARγ or AMPK.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Anilides; Anti-Inflammatory Agents; Antimetabolites; Asthma; Cells, Cultured; Chromans; Cytokines; Enzyme Activators; Enzyme Inhibitors; Gene Knockdown Techniques; Humans; Hypoglycemic Agents; Inflammation Mediators; Metformin; Myocytes, Smooth Muscle; PPAR gamma; Pyrazoles; Pyrimidines; Respiratory System; Ribonucleotides; Rosiglitazone; Thiazolidinediones; Troglitazone; Vidarabine

Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPAR)-γ agonist, has been demonstrated to possess cardioprotective properties during ischemia-reperfusion. However, this notion remains controversial as recent evidence has suggested an increased risk in cardiac events associated with long-term use of RGZ in patients with type 2 diabetes. In this study, we tested the hypothesis that acute RGZ treatment is beneficial during I/R by modulating cardioprotective signaling pathways in a nondiabetic mouse model. RGZ (1 μg/g) was injected intravenously via the tail vein 5 min before reperfusion. Myocardial infarction was significantly reduced in mice treated with RGZ compared with vehicle controls (8.7% ± 1.1% vs. 20.2% ± 2.5%, P < 0.05). Moreover, isolated hearts were subjected to 20 min of global, no-flow ischemia in an ex vivo heart perfusion system. Postischemic recovery was significantly improved with RGZ treatment administered at the onset of reperfusion compared with vehicle (P < 0.001). Immunoblot analysis data revealed that the levels of both phospho-AMP-activated protein kinase (Thr(172)) and phospho-Akt (Ser(473)) were significantly upregulated when RGZ was administered 5 min before reperfusion compared with vehicle. On the other hand, inflammatory signaling [phospho-JNK (Thr(183)/Tyr(185))] was significantly downregulated as a result of RGZ treatment compared with vehicle (P < 0.05). Intriguingly, pretreatment with the selective PPAR-γ inhibitor GW-9662 (1 μg/g iv) 10 min before reperfusion significantly attenuated these beneficial effects of RGZ on the ischemic heart. Taken together, acute treatment with RGZ can reduce ischemic injury in a nondiabetic mouse heart via modulation of AMP-activated protein kinase, Akt, and JNK signaling pathways, which is dependent on PPAR-γ activation.

Topics: AMP-Activated Protein Kinases; Anilides; Animals; Cardiotonic Agents; Disease Models, Animal; Drug Administration Schedule; Enzyme Activation; Injections, Intravenous; JNK Mitogen-Activated Protein Kinases; Male; Mice; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphorylation; PPAR gamma; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Rosiglitazone; Signal Transduction; Thiazolidinediones; Time Factors; Ventricular Function, Left; Ventricular Pressure

Nesfatin-1 is recently reported as a satiety molecule to suppress food intake via the melanocortin signaling in hypothalamus when injected centrally and peripherally. Here we report that nesfatin-1 is also anti-hyperglycemic. It was found that the intravenous injection of nesfatin-1 significantly reduced blood glucose in hyperglycemic db/db mice. This anti-hyperglycemic effect of nesfatin-1 was time-, dose-, insulin-dependent and peripheral.

Topics: Anilides; Animals; Appetite Depressants; Blood Glucose; Calcium-Binding Proteins; DNA-Binding Proteins; Eating; Hyperglycemia; Hypolipidemic Agents; Insulin; Mice; Mice, Mutant Strains; Nerve Tissue Proteins; Nucleobindins; Peptide Hormones; Pyrazoles; Pyrimidines; Receptors, Leptin; Rosiglitazone; Thiazolidinediones

Hyperglycemia is a risk factor for cardiovascular complications in diabetic state. Hyperglycemia-induced oxidative stress up-regulates intracellular adhesion molecule-1 (ICAM-1) which aggravates endothelial dysfunction, although the underlying mechanisms remain unclear. We hypothesized that carbon monoxide (CO) attenuates ICAM-1 expression induced by high glucose in endothelial cells through activation of AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma (PPAR-gamma) pathway.. Human umbilical vein endothelial cells (HUVEC) were pre-treated with CO releasing molecule-2 (CORM-2) alone or in combination with troglitazone or GW1929, PPAR-gamma agonists or GW9662, PPAR-gamma antagonist and then cells were co-treated with high glucose (25mM) for 48h for detection of ICAM-1 expression by Western blot or luciferase assay. The involvement of AMPK on PPAR-gamma and ICAM-1 expressions was tested using pharmacological inducer or inhibitor, as well as transient transfection with AMPK-DN vector.. CO derived from CORM-2 down-regulated ICAM-1 expression induced by high glucose. CORM-2 induced the activity of PPAR-gamma at 24h, and AMPK from 5min to 3h. PPAR-gamma agonists significantly suppressed ICAM-1 expression, whereas in the presence of antagonist (GW9662) CORM-2 failed to inhibit ICAM-1. Thus inhibition of ICAM-1 was dependent on activation of PPAR-gamma. Transfection with AMPK-DN or AMPK inhibitor resulted in attenuation of inducible effect of CORM-2 on PPAR-gamma and subsequently suppressive effect on ICAM-1 expression.. Our results indicate that PPAR-gamma and AMPK pathways activated by CO are required for attenuation of ICAM-1 expression induced by high glucose. Thus, this study highlights a new property for CO derived from CORM-2 as anti-atherogenic drug for diabetic patients.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Anilides; Anti-Inflammatory Agents; Benzophenones; Carbon Monoxide; Cell Adhesion; Cells, Cultured; Chromans; Dose-Response Relationship, Drug; Endothelial Cells; Enzyme Activation; Enzyme Activators; Glucose; Humans; Hypoglycemic Agents; Intercellular Adhesion Molecule-1; Organometallic Compounds; PPAR gamma; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Ribonucleotides; Signal Transduction; Thiazolidinediones; Time Factors; Transfection; Troglitazone; Tyrosine