9 research outputs found
11β-HSD1 content in visceral fat is attenuated with RU486 treatment but not with C113176 or C108297 treatment.
<p>No changes were found in lipolytic protein levels with treatment of antagonists. 11β-HSD1 content was measured in epididymal fat pads to represent visceral adipose tissue and expressed relative to α-tubulin content (A). CD36 protein levels were measured from epididymal fat pads (B) as well as adipose triglyceride lipase (ATGL) (C) and hormone-sensitive lipase (HSL) (D) protein levels as markers of lipolytic adipose tissue activity and expressed relative to loading control. Bars that do not share similar letters denote statistical significance, p<0.05 one-way ANOVA using Tukey's post-hoc test. n = 5–6. All values are means ± SE.</p
Glucose stimulated insulin secretion (GSIS) was normalized with RU486 and C113176 treatment.
<p>GSIS in isolated islets was measured in low (2.8 mM) and high (16.7 mM) glucose media for 1-hour incubations expressed as ng/ml/islet/hour. Bars that do not share similar letters denote statistical significance, p<0.05 one-way ANOVA using student's unpaired t-test. n = 3–7. All values are means ± SE.</p
C113176 treatment maintains body mass while RU486 increases body mass with ROD treatment.
<p>Animal body mass (g) were recorded every two days for 10 days as a measure of fold change from day 0, pellet surgery (A). Animal body mass on day 10 was measured as a percent change of body mass from day 0 (B). The dotted line (100%) represents no change in body mass from day 0. Arrow indicates that 2 days after pellet surgeries respective antagonists or vehicle were administered at 80 mg/kg/day to each treatment group. Bars that do not share similar letters denote statistical significance, p<0.05, one-way ANOVA using Tukey's post-hoc test. n = 7–10. All values are means ± SE.</p
Glucose intolerance and acute insulin response (AIR) is improved with RU486 and C113176 treatment.
<p>Fasting (basal, 0 minutes) and stimulated blood glucose levels (mM) were measured at 5, 15, 30, 60, 90 and 120 minutes post oral glucose gavage (A). Glucose area under the curve (AUC) was calculated based on fasting blood glucose of individual animals (A′). Fasting (basal, 0 minutes) and glucose-stimulated insulin levels (ng/ml) were measured at 15, 30, 60, and 120 minutes post oral glucose gavage (B). Insulin area under the curve (AUC) was calculated based on fasting individual insulin levels within each group (B′). To measure insulin capacity acute insulin response (AIR) was measured by the difference in insulin levels between fasting insulin and 15 minutes post glucose gavage (C). Negative values represent a decrease in insulin response, indicating impairment in insulin secretion. Bars that do not share similar letters denote statistical significance, p<0.05, one-way ANOVA using Tukey's post-hoc. A student's unpaired t-test was performed between controls and ROD, C108297 and C113176 groups (C). n = 7–10. All values are means ± SE.</p
Fat accumulation is normalized with RU486 in skeletal muscle and liver cross sections.
<p>To determine fat content in skeletal muscle, tibialis anterior muscle was dissected and stained with a neutral lipid stain (Oil Red O) (A–E). Cross sections of liver were also stained with Oil Red O to measure lipid content (F–J).</p
Corticosterone concentrations, absolute and relative food intake.
<p>Note: BM = Body Mass. Different letters denote statistical significance, p<0.05, n = 6–10. The * indicates that a significant difference was performed by a student's unpaired t-test. All values are mean ± SE.</p
Anthropometric data for epididymal fat pad, liver, heart, epitrochlearis, soleus and tibialis anterior mass (g/kg of body mass).
<p>Note: Different letters denote statistical significance, p<0.05, n = 6–10. All values are means ± SE.</p
Fed and fasting glucose, insulin, and non-esterified fatty acids (NEFAs) levels on day 12.
<p>Note: Different letters denote statistical significance, p<0.05, n = 6–10. All values are means ± SE.</p
Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1
Checkpoint
kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating
cell-cycle arrest to provide sufficient time for lesion repair. This
leads to the hypothesis that inhibition of ChK1 might enhance the
effectiveness of DNA-damaging therapies in the treatment of cancer.
Lead compound <b>1</b> (GNE-783), the prototype of the 1,7-diazacarbazole
class of ChK1 inhibitors, was found to be a highly potent inhibitor
of acetylcholine esterase (AChE) and unsuitable for development. A
campaign of analogue synthesis established SAR delineating ChK1 and
AChE activities and allowing identification of new leads with improved
profiles. In silico docking using a model of AChE permitted rationalization
of the observed SAR. Compounds <b>19</b> (GNE-900) and <b>30</b> (GNE-145) were identified as selective, orally bioavailable
ChK1 inhibitors offering excellent in vitro potency with significantly
reduced AChE activity. In combination with gemcitabine, these compounds
demonstrate an in vivo pharmacodynamic effect and are efficacious
in a mouse p53 mutant xenograft model