1.Bioactive Dihydro-β-agarofuran Sesquiterpenoids from the Australian Rainforest Plant Maytenus bilocularis.
Wibowo M1, Levrier C1,2, Sadowski MC2, Nelson CC2, Wang Q3,4, Holst J3,4, Healy PC5, Hofmann A1,6, Davis RA1. J Nat Prod. 2016 Apr 27. [Epub ahead of print]
Chemical investigations of the CH2Cl2 extract obtained from the leaves of the Australian rainforest tree Maytenus bilocularis afforded three new dihydro-β-agarofurans, bilocularins A-C (1-3), and six known congeners, namely, celastrine A (4), 1α,6β,8α-triacetoxy-9α-benzoyloxydihydro-β-agarofuran (5), 1α,6β-diacetoxy-9α-benzoyloxy-8α-hydroxydihydro-β-agarofuran (6), Ejap-10 (11), 1α,6β-diacetoxy-9β-benzoyloxydihydro-β-agarofuran (12), and Ejap-2 (13). The major compound 1 was used in semisynthetic studies to afford four ester derivatives (7-10). The chemical structures of 1-3 were elucidated following analysis of 1D/2D NMR and MS data. The absolute configurations of bilocularins A (1) and B (2) were determined by single-crystal X-ray diffraction analysis. All compounds were evaluated for cytotoxic activity against the human prostate cancer cell line LNCaP; none of the compounds were active. However, several compounds showed similar potency to the drug efflux pump inhibitor verapamil in reversing the drug resistance of the human leukemia CEM/VCR R cell line.
2.Mesothelin's minimal MUC16 binding moiety converts TR3 into a potent cancer therapeutic via hierarchical binding events at the plasma membrane.
Su Y1,2, Tatzel K1, Wang X1, Belt B1, Binder P3, Kuroki L3, Powell MA3,4, Mutch DG3,4, Hawkins WG1,4, Spitzer D1,4. Oncotarget. 2016 Apr 22. doi: 10.18632/oncotarget.8925. [Epub ahead of print]
TRAIL has been extensively explored as a cancer drug based on its tumor-selective activity profile but it is incapable per se of discriminating between death receptors expressed by normal host cells and transformed cancer cells. Furthermore, it is well documented that surface tethering substantially increases its biologic activity. We have previously reported on Meso-TR3, a constitutive TRAIL trimer targeted to the biomarker MUC16 (CA125), in which the entire ectodomain of human mesothelin was genetically fused to the TR3 platform, facilitating attachment to the cancer cells via the MUC16 receptor. Here, we designed a truncation variant, in which the minimal 64 amino acid MUC16 binding domain of mesothelin was incorporated into TR3. It turned out that the dual-domain biologic Meso64-TR3 retained its high MUC16 affinity and bound to the cancer cells quickly, independent of the TR3/death receptor interaction. Furthermore, it was substantially more potent than Meso-TR3 and TR3 in vitro and in a preclinical xenograft model of MUC16-dependent ovarian cancer.
3.Hyaluronic acid-conjugated liposome nanoparticles for targeted delivery to CD44 overexpressing glioblastoma cells.
Hayward SL1, Wilson CL1, Kidambi S1,2,3,4,5. Oncotarget. 2016 Apr 22. doi: 10.18632/oncotarget.8926. [Epub ahead of print]
Glioblastoma Multiforme (GBM) is a highly prevalent and deadly brain malignancy characterized by poor prognosis and restricted disease management potential. Despite the success of nanocarrier systems to improve drug/gene therapy for cancer, active targeting specificity remains a major hurdle for GBM. Additionally, since the brain is a multi-cell type organ, there is a critical need to develop an approach to distinguish between GBM cells and healthy brain cells for safe and successful treatment. In this report, we have incorporated hyaluronic acid (HA) as an active targeting ligand for GBM. To do so, we employed HA conjugated liposomes (HALNPs) to study the uptake pathway in key cells in the brain including primary astrocytes, microglia, and human GBM cells. We observed that the HALNPs specifically target GBM cells over other brain cells due to higher expression of CD44 in tumor cells. Furthermore, CD44 driven HALNP uptake into GBM cells resulted in lysosomal evasion and increased efficacy of Doxorubicin, a model anti-neoplastic agent, while the astrocytes and microglia cells exhibited extensive HALNP-lysosome co-localization and decreased antineoplastic potency.
4.Continuous treatment of flotation collector wastewater using a membrane bioreactor.
Lin W1, Dai Y1, Wu C2, Xu P1, Ren J1, Sun S1, Li B1. Water Sci Technol. 2016 Apr;73(8):1901-1909.
Aniline aerofloat (DDA) is a widely used material in China and has become a main pollutant in floatation wastewater. In this study, a membrane reactor (MBR) was constructed to continuously treat simulated wastewater contaminated with DDA. The study investigated the hydraulic retention time (HRT) and the impact of influent DDA concentration on MBR performance, and analyzed intermediates from the DDA biodegradation pathway and activated sludge transfer pathway. The results showed that a 3 h HRT was an efficient and economical time period for MBR to remove 95 ± 5 mg/L DDA from the simulated wastewater; the chemical oxygen demand reduction rate was 89.9%. DDA concentration negatively impacted MBR performance. MBR performance fluctuated slightly when HRT was 3 h, dissolved oxygen ranged from 4.8 to 5.3 mg/L, pH was between 6.5 and 7.0, and DDA concentrations were at 95 ± 5 mg/L DDA. The transfer pathway in the activated sludge of DDA was through soluble microbial products, loosely bound extracellular polymeric substances, tightly bound extracellular polymeric substances, and finally cell biodegradation.