Total Synthesis of Two Diastereomers of Megastigmane Glycoside Lauroside B

<p>Lauroside B, a megastigmane sesquiterpene glycoside isolated from <i>L. nobilis</i> leaves, has the potential effect of inducing apoptosis of several highly aggressive malignant melanoma cell lines. To promote the potential development of lauroside B as a possible chemotherapeutic agent to treat human melanoma, the structure and activity relationship studies should be of great importance. In this work, two diastereomers of lauroside B were synthesized through a straightforward approach and the details of the key steps were investigated, which would provide useful information for developing an efficient method toward the synthesis of lauroside B and its structural analogs.</p

Total Synthesis and Biological Evaluation of Apratoxin E and Its C30 Epimer: Configurational Reassignment of the Natural Product

Apratoxin E provided the inspiration for the design of apratoxin A/E hybrids under preclinical development. Through total synthesis using two different strategies, it was determined that the originally proposed configuration of the thiazoline at C30 is opposite from that in apratoxin A, in contrast to previous assumptions on biosynthetic grounds. The epimer and true natural apratoxin E were synthesized, and the biological activities were evaluated

Smart Nanodevice Combined Tumor-Specific Vector with Cellular Microenvironment-Triggered Property for Highly Effective Antiglioma Therapy

Malignant glioma, a highly aggressive tumor, is one of the deadliest types of cancer associated with dismal outcome despite optimal chemotherapeutic regimens. One explanation for this is the failure of most chemotherapeutics to accumulate in the tumors, additionally causing serious side effects in periphery. To solve these problems, we sought to develop a smart therapeutic nanodevice with cooperative dual characteristics of high tumor-targeting ability and selectively controlling drug deposition in tumor cells. This nanodevice was fabricated with a cross-linker, containing disulfide linkage to form an inner cellular microenvironment-responsive “-<i>S</i>-<i>S</i>-” barrier, which could shield the entrapped drug leaking in blood circulation. In addition, dehydro­ascorbic acid (DHA), a novel small molecular tumor-specific vector, was decorated on the nanodevice for tumor-specific recognition <i>via</i> GLUT1, a glucose transporter highly expressed on tumor cells. The drug-loaded nanodevice was supposed to maintain high integrity in the bloodstream and increasingly to specifically bind with tumor cells through the association of DHA with GLUT1. Once within the tumor cells, the drug release was triggered by a high level of intracellular glutathione. When these two features were combined, the smart nanodevice could markedly improve the drug tumor-targeting delivery efficiency, meanwhile decreasing systemic toxicity. Herein, this smart nanodevice showed promising potential as a powerful platform for highly effective antiglioma treatment

Length and tissue mass of <i>Fgl1^+/+</i> and <i>Fgl1^−/−</i> mice.

<p>(n = 5 for both cohorts except for liver (*) where n = 9).</p

Glucose metabolism in the Fgl1 null mouse.

<p>A) <i>Fgl1^−/−</i> mice have fasting hyperglycemia (P = 0.005, n = 10 for <i>Fgl1^+/+</i> and n = 8 for <i>Fgl1^−/−</i>). B) Glucose tolerance tests of fasted 3 month old mouse. The graph represents a plot of plasma glucose versus time after i.p. administration of glucose. The superimposed panel represents plots of average area under the curve (AUC) for each mouse. The baseline was set as the mean pre-glucose administration plasma level. The difference is glucose levels as determined from the AUC is significant (P = 0.002, n = 4 per group). C) Insulin tolerance test on 3 month old fasted mouse shows a similar rate of decline of glucose levels between the <i>Fgl1^+/+</i> and <i>Fgl1^−/−</i> mice. AUC calculations after normalizing for baseline glucose for the first 45 min of the test shows no differences between Fgl1 containing and deficient mice (n = 5 per group). D) Insulin levels are not different between <i>Fgl1^+/+</i> and <i>Fgl1^−/−</i> mice. E) HOMA scores are not different for <i>Fgl1^+/+</i> and <i>Fgl1^−/−</i> (n = 5 for <i>Fgl1^+/+</i> and 4 for <i>Fgl1^−/−</i>). F) Graph of glucose levels following administration of pyruvate to fasted mice. Inset is AUC calculation which shows a difference in glucose levels over the duration of the experiment (P = 0.029, n = 5 per group).</p

Fgl1 in hepatic and brown adipose tissue.

<p>A) mRNA levels of Fgl1 in the liver at baseline (0 h) and at 24 h and 48 h after PH. Note the increased expression after PH. P = 0.002 between 0 h and 24 h and less than 0.0001 between 0 h and 48 h after PH. The difference between levels at 24 h and 48 h is not significant. B) mRNA levels of Fgl1 in brown adipose tissue (BAT) at baseline and at 24 h and 48 h after partial hepatectomy. Fgl1 is detectable in BAT prior to injury but expression is enhanced after PH. P = 0.026 between 0 and 24 h and P = 0.013 between 0 and 48 h after PH. The difference between levels at 24 h and 48 h is not significant. n = 3 for samples in 1A and B. C) Gel electrophoresis of amplified cDNA from BAT at baseline and at 24 h and 48 h after PH. Cyclophilin A is the loading control. D) Comparison of BAT Fgl1 levels pre and post PH with hepatic Fgl1 levels at baseline. Samples are normalized to hepatic Fgl1 at 100%. Fgl1 in BAT is 0.4%, 2.6% and 3.4% of hepatic levels at baseline and at 24 h and 48 h after PH (P<0.0001).</p

Food intake and indirect calorimetry.

<p>Scatter plot of average food intake versus average weight for individually housed <i>Fgl1^+/+</i> (blue squares, n = 4) and <i>Fgl1^−/−</i>(red circles, n = 8) taken daily over an 18 day period. Note that <i>Fgl1^−/−</i> remain larger that wild types for the duration of the experiment. B and C) Indirect calorimetric values for VO₂ and VCO₂ respectively and D) RER. The RER is significant irrespective of day and night cycles (P = 0.04 and 0.016 respectively) and over the entire 24 h (P = 0.019). E) Heat generation is not significantly different and F) activity is not different between the Fgl1 containing and deficient mice. n = 6 for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058084#pone-0058084-g006" target="_blank">Figures 6B to 6F</a>.</p

Plasma lipid, cholesterol and free fatty acid levels in the Fgl1 null mouse.

<p>A) There is no significant difference in steady state plasma TG levels of <i>Fgl1^+/+</i> and <i>Fgl1^−/−</i> mice. B) Free fatty acid levels are decreased in the Fgl1 null mouse (P = 0.001). C and D) Plasma cholesterol levels are levels are lower as determined by total cholesterol (P = 0.003) and FPLC analysis. n = 5 per group.</p

Structure, content and activity of adipose tissues in the Fgl1 null mouse.

<p>A) Representative H&E stains (40× magnification) of brown adipose tissue. Lipid droplets are larger in <i>Fgl1^−/−</i> mice. B) Quantitation of lipid droplet size show significant difference between <i>Fgl1^+/+</i> and <i>Fgl1^−/−</i> mice (P = 0.011, n = 5 per group). C) Expression of brown adipose genes. Note the paradoxical up regulation of DiO2 and UCP1 (P = 0.002 and 0.0001 respectively. n = 11 per group except for Perilipin and HSL where n = 5 and 6 respectively). D) ¹⁸FDG incorporation into BAT. The % uptake represents the uptake of injected dose per gram of tissue. Note the marked decrease in radioisotope uptake in BAT (P = 0.05, n = 5 per group). E). Representative H&E stains (40× magnification) of white adipose tissue. Lipid droplets are larger in <i>Fgl1^−/−</i> mice. F) Quantitation of number of cells per HPF shows smaller number of white adipose cells in <i>Fgl1^−/−</i> (P = 0.005, n = 5). G) Expression of white adipose genes. Glut4, leptin and perilipin are significantly down regulated (*) with a P<0.04 for each. P for ATGL (#) is 0.06. n = 4–6 mice per group.</p