THE USE OF MANDAMUS TO COMPEL EDUCATIONAL INSTITUTIONS TO CONFER DEGREES

Hispolon is an active phenolic compound of <i>Phellinus igniarius</i>, a mushroom that was recently shown to have antioxidant and anticancer activities in various solid tumors. Here, the molecular mechanisms by which hispolon exerts anticancer effects in acute myeloid leukemia (AML) cells was investigated. The results showed that hispolon suppressed cell proliferation in the various AML cell lines. Furthermore, hispolon effectively induced apoptosis of HL-60 AML cells through caspases-8, -9, and -3 activations and PARP cleavage. Moreover, treatment of HL-60 cells with hispolon induced sustained activation of JNK1/2, and inhibition of JNK by JNK1/2 inhibitor or JNK1/2-specific siRNA significantly abolished the hispolon-induced activation of the caspase-8/-9/-3. In vivo, hispolon significantly reduced tumor growth in mice with HL-60 tumor xenografts. In hispolon-treated tumors, activation of caspase-3 and a decrease in Ki67-positive cells were observed. Our results indicated that hispolon may have the potential to serve as a therapeutic tool to treat AML

The distributions of demographical characteristics in 561 controls and 595 patients with oral cancer.

<p>Mann-Whitney U test or Fisher's exact test was used between healthy controls and patients with oral cancer.</p>*<p><i>p</i> value<0.05 as statistically significant.</p

Adjusted odds ratio (AOR) and 95% confidence interval (CI) of oral cancer associated with <i>ICAM-1</i> genotypic frequencies and betel nut chewing among 727 smokers.

<p>The odds ratios (ORs) with their 95% confidence intervals were estimated by logistic regression models.</p><p>The adjusted odds ratios (AORs) with their 95% confidence intervals were estimated by multiple logistic regression models after controlling for age, gender and alcohol consumption.</p>a<p>Individual with wild genotype but without betel nut chewing.</p>b<p>Individual with either at least one mutated genotype or betel nut chewing.</p>c<p>Individual with both at least one mutated genotype and betel nut chewing.</p

Clinical status and <i>ICAM-1</i> genotypic frequencies in 595 oral cancer patients.

<p>T2: tumor size >2 cm in the greatest dimension.</p>*<p>P value<0.05 as statistically significant.</p

Distribution frequency of <i>ICAM-1</i> genotypes in 561 healthy controls and 595 oral cancer patients.

<p>The odds ratios (ORs) and with their 95% confidence intervals (CIs) were estimated by logistic regression models. The adjusted odds ratios (AORs) with their 95% confidence intervals (CIs) were estimated by multiple logistic regression models after controlling for age, gender, betel nut chewing, tobacco and alcohol consumption.</p>*<p><i>P</i> value<0.05 as statistically significant.</p

TaqMan primer sets for <i>ICAM-1</i> genotyped SNPs.

<p>TaqMan primer sets for <i>ICAM-1</i> genotyped SNPs.</p

Pterostilbene Simultaneously Induced G0/G1-Phase Arrest and MAPK-Mediated Mitochondrial-Derived Apoptosis in Human Acute Myeloid Leukemia Cell Lines

<div><p>Background</p><p>Pterostilbene (PTER) is a dimethylated analog of the phenolic phytoalexin, resveratrol, with higher anticancer activity in various tumors. Herein, the molecular mechanisms by which PTER exerts its anticancer effects against acute myeloid leukemia (AML) cells were investigated.</p><p>Methodology and Principal Findings</p><p>Results showed that PTER suppressed cell proliferation in various AML cell lines. PTER-induced G0/G1-phase arrest occurred when expressions of cyclin D3 and cyclin-dependent kinase (CDK)2/6 were inhibited. PTER-induced cell apoptosis occurred through activation of caspases-8-9/-3, and a mitochondrial membrane permeabilization (MMP)-dependent pathway. Moreover, treatment of HL-60 cells with PTER induced sustained activation of extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK)1/2, and inhibition of both MAPKs by their specific inhibitors significantly abolished the PTER-induced activation of caspases-8/-9/-3. Of note, PTER-induced cell growth inhibition was only partially reversed by the caspase-3-specific inhibitor, Z-DEVE-FMK, suggesting that this compound may also act through a caspase-independent pathway. Interestingly, we also found that PTER promoted disruption of lysosomal membrane permeabilization (LMP) and release of activated cathepsin B.</p><p>Conclusion</p><p>Taken together, our results suggest that PTER induced HL-60 cell death via MAPKs-mediated mitochondria apoptosis pathway and loss of LMP might be another cause for cell apoptosis induced by PTER.</p></div

Effect of pterostilbene (PTER) on lysosomal membrane alterations in HL-60 cells.

<p>(A) PTER enhanced lysosome permeability. HL-60 cells were treated with 100 µM PTER for 12 h, then stained with acridine orange (5 µg/ml) for 15 min, and examined under a fluorescence microscope (×200 magnification). Representative images of three independent experiments are shown. (B) PTER concentration-dependently induced translocation of cathepsin B from lysosomes to the cytosol. Cytosolic cathepsin B levels were assessed by a Western blot analysis after treatment with various concentrations of PTER (0∼100 µM) for 24 h. Protein levels of both the 37-kDa pro-cathepsin and 25-kDa activated cathepsin B are shown. β-actin and C23 were respectively used as positive and negative cytosolic internal controls. (C) HL-60 cells were treated with 100 µM PTER for 1 h and stained with H₂DCFDA; then total ROS level was analyzed by FACS, and data are presented as the mean multiples of increase in fluorescence compared to the control ± SE. *<i>p</i><0.05, compared to the control. (D and E) The reactive oxygen species (ROS) scavenger, N-acetyl cysteine (NAC; 10 mM) was added 1 h prior to the addition of 100 µM PTER. Lysosome permeability (D) and cathepsin B cytosolic translocation (E) were analyzed 24 h later. (F) The cathepsin B inhibitor, CA074-Me (50 and 100 µM), was added 1 h prior to the addition of 100 µM PTER. Cell proliferation was determined by an MTS assay. Values are presented as the mean ± SE of three independent experiments. Data were analyzed using a one-way ANOVA with Tukey’s post-hoc tests at 95% confidence intervals; Different letters represent significantly different, <i>p</i><0.05.</p

Proposed signal transduction pathways by which pterostilbene (PTER) inhibits the growth of HL-60 cells.

<p>‘Bold solid lines’ indicate pathways affected by PTER. ‘Bold dashed lines’ indicate hypothetical pathways which might be affected by PTER. LMP, lysosomal membrane permeabilization; MMP, mitochondrial membrane permeabilization; cyto C, cytochrome C.</p

Effect of pterostilbene (PTER) on alterations of cell-cycle regulatory proteins in HL-60 cells.

<p>Proteins were extracted from cultured HL-60 cells at 24 h after PTER treatment and probed with proper dilutions of specific antibodies. (A and B) PTER at a concentration of 100 µM induced significant decreases in protein levels of cyclin D3, CDK2, and CDK6. Upper panels: Representative results of cyclins and cyclin-dependent kinase (CDK) protein levels as determined by a Western blot analysis. Lower panels: Quantitative results of cyclin and CDK protein levels, which were adjusted to the β-actin protein level and expressed as multiples of induction beyond its own control. Values are presented as the mean ± SE of three independent experiments. *<i>p</i><0.05, compared to the vehicle control group. (C) There were no significant differences in protein levels of p15 INK4B, p21 Cip1, or p27 Kip1 between control and PTER-treated HL-60 cells. Upper panel: Representative results of p15, p21, and p27 protein levels as determined by a Western blot analysis. Lower panel: Quantitative results of p15, p21, and p27 protein levels, which were adjusted with the β-actin protein level and expressed as multiples of induction beyond its own control. (D) Cyclin D3, CDK2, and CDK6 peotein expression were downregulated in a concentration-dependent fashion after PTER treatment in HL-60 cells. Left panel: Representative results of cyclin D3, CDK2, and CDK6 protein levels as determined by a Western blot analysis. Right panel: Quantitative results of cyclin D3, CDK2, and CDK6 protein levels, which were adjusted with the β-actin protein level and expressed as multiples of induction beyond its own control. *<i>p</i><0.05, compared to the vehicle control group.</p