Dehydro-alpha-lapachone, a plant product with antivascular activity

Antivascular agents have become a standard of treatment for many malignancies. However, most of them target the VEGF pathway and lead to refractoriness. To improve the diversity of options for antivascular therapy, we applied a high-throughput screen for small molecules targeting cell adhesion. We then assayed the resulting antiadhesion hits in a transgenic zebrafish line with endothelial expression of EGFP (Tg(fli1:EGFP)(y1)) to identify nontoxic molecules with antivascular activity selective to neovasculature. This screen identified dehydro-α-lapachone (DAL), a natural plant product. We found that DAL inhibits vessel regeneration, interferes with vessel anastomosis, and limits plexus formation in zebrafish. Furthermore, DAL induces vascular pruning and growth delay in orthotopic mammary tumors in mice. We show that DAL targets cell adhesion by promoting ubiquitination of the Rho-GTPase Rac1, which is frequently up-regulated in many different cancers.     

Potential selective inhibitors against Rv0183 of Mycobacterium tuberculosis targeting host lipid metabolism

Tuberculosis is the second leading infectious killer with 9 million new cases in 2009. Extensive use of pathogen's lipid metabolism especially in utilizing the host lipids and virulence highlights the importance of exported lipid-catabolizing enzymes. Current study aims to emphasize the importance of Rv0183, an exported monoacylglycerol lipase, involved in metabolizing the host cell membrane lipids. Sequence analysis and homology modeling shows Rv0183 is highly conserved throughout mycobacterial species even in Mycobacterium leprae and also significantly divergent from mammalian lipases. Additionally, employing virtual screening using NCI diversity set and ZINC database with criteria of molecules with higher predicted free energy of binding toward Rv0183 than human lipase, potential inhibitors have been identified for Rv0183. A tautomer of ZINC13451138, known inhibitor for HIV-1 integrase is the best hit with difference in free energy of binding of 8.72 kcal/mol. The sequence and structure analysis were helpful in identifying the ligand binding sites and molecular function of the mycobacterial specific monoacylglycerol lipase. Rv0183 represents a suitable and promising drug target and is also a step towards understanding dormancy development and reactivation, thereby addressing pathogen's drug resistance. Experimental studies on the discovered potential inhibitors in this virtual screen should further validate the therapeutic utility of Rv0183.     

Anticancer and apoptotic activity in neuroblastoma SK-N-SH using phospholipid extract from bone of Scomberomorus niphonius

Among various types children's health challenges, neuroblastoma is the most serious solid neoplasm forming outside the cranium. Scomberomorus niphonius is a valuable edible fish that has been widely used for a meal. In this study, we obtained phospholipid extract from the bone of S. niphonius with the supercritical CO₂ extraction method and tested anticancer activity with a cell viability assay. The phospholipid showed anticancer activity on neuroblastoma SK-N-SH cells, and the anticancer activity was presented with an IC₅₀ of 710.25 ± 28.31 μg/ml, but did not show a significant toxicity on HUVEC cell lines. Western blot was used to detect signaling proteins; Bak, caspase-9, caspase-8, caspase-3, Bax, and IκBα were increased, whereas IKKβ and NFκB were downregulated in experimental groups compared to untreated groups. Gene expression was revealed by RT-qPCR, and the fold ratio of Apaf-1, cytochrome-c, caspase-9, caspase-3, and Bax genes' expression was raised in treated groups, implying apoptosis. Gel electrophoresis revealed that the experimental groups had more fragmented DNA than the control group. The study shows that a phospholipid extract from S. niphonius' bone could be used as a biological origin of anticancer activity in neuroblastoma SK-N-SH cells.     

Heart on the left,diaphragm on the right: A case of congenital diaphragmatic eventration

Congenital Diaphragmatic Eventration (DE) requires a prompt diagnosis to avert the potentially life‐threatening complications. Herein, a 5‐month‐old male presented with recurrent respiratory infections due to a right‐sided diaphragmatic eventration. Misdiagnosed from previous medical visits, timely surgical intervention by thoracoscopic plication of the diaphragm was crucial for our patient''s survival.