Anticancer activity of a thymidine quinoxaline conjugate is modulated by cytosolic thymidine pathways

Background High levels of thymidine kinase 1 (TK1) and thymidine phosphorylase (TYMP) are key molecular targets by thymidine therapeutics in cancer treatment. The dual roles of TYMP as a tumor growth factor and a key activation enzyme of anticancer metabolites resulted in a mixed outcome in cancer patients. In this study, we investigated the roles of TK1 and TYMP on a thymidine quinoxaline conjugate to evaluate an alternative to circumvent the contradictive role of TYMP. Methods TK1 and TYMP levels in multiple liver cell lines were assessed along with the cytotoxicity of the thymidine conjugate. Cellular accumulation of the thymidine conjugate was determined with organelle-specific dyes. The impacts of TK1 and TYMP were evaluated with siRNA/shRNA suppression and pseudoviral overexpression. Immunohistochemical analysis was performed on both normal and tumor tissues. In vivo study was carried out with a subcutaneous liver tumor model. Results We found that the thymidine conjugate had varied activities in liver cancer cells with different levels of TK1 and TYMP. The conjugate mainly accumulated at endothelial reticulum and was consistent with cytosolic pathways. TK1 was responsible for the cytotoxicity yet high levels of TYMP counteracted such activities. Levels of TYMP and TK1 in the liver tumor tissues were significantly higher than those of normal liver tissues. Induced TK1 overexpression decreased the selectivity of dT-QX due to the concurring cytotoxicity in normal cells. In contrast, shRNA suppression of TYMP significantly enhanced the selective of the conjugate in vitro and reduced the tumor growth in vivo. Conclusions TK1 was responsible for anticancer activity of dT-QX while levels of TYMP counteracted such an activity. The counteraction by TYMP could be overcome with RNA silencing to significantly enhance the dT-QX selectivity in cancer cells

Crystal Structures of Influenza A Virus Matrix Protein M1: Variations on a Theme

Matrix protein 1 (M1) of the influenza A virus plays multiple roles in virion assembly and infection. Interest in the pH dependence of M1\u27s multiple functions led us to study the effect of subtle pH changes on M1 structure, resulting in the elucidation of a unique low-pH crystal structure of the N1-165-domain of A/WSN/33 (H1N1) M1 that has never been reported. Although the 2.2 Å crystal structure of M1 N-terminus shows a dimer with the two monomers interacting in a face-to-face fashion at low pH as observed earlier, a 44° rotation of the second monomer has led to a significantly different dimer interface that possibly affects dimer stability. More importantly, while one of the monomers is fully defined, the N-terminal half of the second monomer shows considerable disorder that appears inherent in the protein and is potentially physiologically relevant. Such disorder has not been observed in any other previously reported structure at either low or high pH conditions, despite similar crystallization pH conditions. By comparing our novel N1-165-domain structure with other low-pH or neutral-pH M1 structures, it appears that M1 can energetically access different monomer and dimer conformations, as well as oligomeric states, with varying degree of similarities. The study reported here provides further insights into M1 oligomerization that may be essential for viral propagation and infectivity

Antimalarial Activity of a cis-terpenone

Background Malaria is the third most prevalent cause of infectious disease in the world. Resistance of the parasite to classical drugs makes the discovery of new and effective drugs more urgent. The oxidized derivative of hydroxy-cis terpenone (OHCT) is a synthetic molecule that is not toxic to cultured human liver cells at concentrations as high as 60 μM and inhibits activity of cytochrome P450s that metabolize many drugs. Methods OHCT activity against chloroquine-sensitive and -resistant strains of Plasmodium falciparum, and aP. falciparum clone that is partially resistant to artemisinin was assayed in vitro. Results OHCT at nanomolar concentrations was effective against all intraerythrocytic stages of P. falciparum and exhibited activity in vitro against both chloroquine-sensitive and -resistant strains of P. falciparum as well as a P. falciparum clone that is partially resistant to artemisinin. Moreover, OHCT exhibited potent activity against gametocytes, the form that is transmitted by mosquitoes and essential for the spread of malaria. Conclusion OHCT displays strong growth inhibitory activity against all stages of P. falciparum and no evidence of toxicity to human cells in culture. It is easily synthesized and has the potential for inhibiting metabolism of drugs used in combination therapies

Metal-slotted polymer optical waveguide device

Metal-slotted optical waveguides (MSOWs) using an electro-optic polymer material have been experimentally demonstrated. The device consists of a three-layered slab waveguide in that the thin metal (gold) film strips are embedded on top of the lower cladding. The optical mode shapes and effective index of the propagation modes of the proposed waveguide structure were calculated using a simplified effective index method and a simulation tool. The fabrication and the device characteristics of a variable optical attenuator and an optical phase modulator based on MSOWs are discussed.open5

Intestinal Absorption and First-Pass Metabolism of Polyphenol Compounds in Rat and Their Transport Dynamics in Caco-2 Cells

<div><h3>Background</h3><p>Polyphenols, a group of complex naturally occurring compounds, are widely distributed throughout the plant kingdom and are therefore readily consumed by humans. The relationship between their chemical structure and intestinal absorption, transport, and first-pass metabolism remains unresolved, however.</p> <h3>Methods</h3><p>Here, we investigated the intestinal absorption and first-pass metabolism of four polyphenol compounds, apigenin, resveratrol, emodin and chrysophanol, using the <em>in vitro</em> Caco-2 cell monolayer model system and <em>in situ</em> intestinal perfusion and <em>in vivo</em> pharmacokinetic studies in rats, so as to better understand the relationship between the chemical structure and biological fate of the dietary polyphenols.</p> <h3>Conclusion</h3><p>After oral administration, emodin and chrysophanol exhibited different absorptive and metabolic behaviours compared to apigenin and resveratrol. The differences in their chemical structures presumably resulted in differing affinities for drug-metabolizing enzymes, such as glucuronidase and sulphatase, and transporters, such as MRP2, SGLT1, and P-glycoprotein, which are found in intestinal epithelial cells.</p> </div