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Rutaecarpine (RUT), the major bioactive ingredient isolated from the Chinese herb Evodia rutaecarpa, possesses a wide spectrum of biological activities, including anti-inflammation and preventing cardiovascular diseases. However, its high cytotoxicity hampers pharmaceutical development. We designed and synthesized a derivative of RUT, bromo-dimethoxyrutaecarpine (Br-RUT), which showed no cytotoxicity at 20 μM. Br-RUT suppressed nitric oxide (NO) production and tumor necrosis factor-a release in concentration-dependent (0~20 μM) manners in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages; protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 induced by LPS were downregulated. Br-RUT inhibited cell migration and invasion of ovarian carcinoma A2780 cells with 0~48h of treatment. Furthermore, Br-RUT enhanced the expression of transient receptor potential vanilloid type 1 and activated endothelial NOS in human aortic endothelial cells. These results suggest that the synthetic Br-RUT possesses very low cytotoxicity but retains its activities against inflammation and vasodilation that could be beneficial for cardiovascular disease therapeutics. [ABSTRACT FROM AUTHOR]

The major cell wall constituent of Ganoderma lucidum (G. lucidum) is β-1,3-glucan. This study examined the polysaccharide from the residues of alkaline-extracted fruiting bodies using high-performance anion-exchange chromatography (HPAEC), and it employed nuclear magnetic resonance (NMR) andmass spectrometry (MS) to confirmthe structures.We have successfully isolated low-molecular-weight β-1,3-glucan (LMG), in high yields, from the waste residue of extracted fruiting bodies of G. lucidum. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay evaluated the capability of LMG to suppress H2O2- induced cell death in RAW264.7 cells, identifying that LMG protected cells fromH2O2-induced damage. LMGtreatment decreased H2O2-induced intracellular reactive oxygen species (ROS) production. LMG also influenced sphingomyelinase (SMase) activity, stimulated by cell death to induce ceramide formation, and then increase cell ROS production. Estimation of the activities of neutral and acid SMases in vitro showed that LMG suppressed the activities of both neutral and acid SMases in a concentrationdependent manner. These results suggest that LMG, a water-soluble β-1,3-glucan recycled from extracted residue of G. lucidum, possesses antioxidant capability against H2O2-induced cell death by attenuating intracellular ROS and inhibiting SMase activity. [ABSTRACT FROM AUTHOR]

Inactivation of glycogen synthase kinase (GSK)-3 has been implicated in cancer progression. Previously, we showed an abundance of inactive GSK-3 in the human chronic myeloid leukemia (CML) cell line. CML is a hematopoietic malignancy caused by an oncogenic Bcr-Abl tyrosine kinase. In Bcr-Abl signaling, the role of GSK-3 is not well defined. Here, we report that enforced expression of constitutively active GSK-3 reduced proliferation and increased Bcr-Abl inhibition-induced apoptosis by nearly 1-fold. Bcr-Abl inhibition activated GSK-3 and GSK-3-dependent apoptosis. Inactivation of GSK-3 by Bcr-Abl activity is, therefore, confirmed. To reactivate GSK-3, we used glucosylceramide synthase (GCS) inhibitor PDMP to accumulate endogenous ceramide, a tumor-suppressor sphingolipid and a potent GSK-3 activator. We found that either PDMP or silence of GCS increased Bcr-Abl inhibition-induced GSK-3 activation and apoptosis. Furthermore, PDMP sensitized the most clinical problematic drug-resistant CML T315I mutant to Bcr-Abl inhibitor GNF-2-, imatinib-, or nilotinib-induced apoptosis by >5-fold. Combining PDMP and GNF-2 eliminated transplanted-CML-T315I-mutants in vivo and dose dependently sensitized primary cells from CML T315I patients to GNF-2-induced proliferation inhibition and apoptosis. The synergistic efficacy was Bcr-Abl restricted and correlated to increased intracellular ceramide levels and acted through GSK-3-mediated apoptosis. This study suggests a feasible novel anti-CML strategy by accumulating endogenous ceramide to reactivate GSK-3 and abrogate drug resistance. [ABSTRACT FROM AUTHOR]

The aim of the present study was to further characterize potential clinicopathological predictors for urinary bladder recurrence-free survival (UBRFS) in patients with primary urothelial carcinoma of the upper urinary tract (UUT-UC). The present series included 385 cases of surgically treated primary localized UUT-UC without previous or concurrent urothelial carcinoma of the urinary bladder. Among the 374 patients with follow-up information, clinicopathological features and therapeutic information including whether they received a laparoscopy-assisted nephroureterectomy (LNU) and adjuvant chemotherapy were correlated with UBRFS. After a median follow up of 69 months, 86 patients (23%) developed urinary bladder recurrence. The median time to develop urinary bladder recurrence was 12 months. At the univariate level, an increment in histological grade ( P= 0.0321), a prominent papillary configuration ( P= 0.0004), LNU ( P= 0.0397) and male gender ( P= 0.0401) significantly predicted an inferior UBRFS. At the multivariate level, increase of histological grade ( P < 0.0001, relative risk (RR) = 3.776), prominent papillary configuration ( P < 0.0001, RR = 3.244), and male gender ( P= 0.0463, RR = 1.444) independently predicted UBRFS. In conclusion, male patients and those with high-grade and papillary UUT-UC, and who received LNU had higher risks of urinary bladder recurrence. Accordingly, for these patients, more intensive follow up coupled with postoperative intravesical adjuvant therapy to prevent urinary bladder recurrence should also be considered. [ABSTRACT FROM AUTHOR]