Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge

Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.     

Epigenetic profiling of multidrug-resistant human MCF-7 breast adenocarcinoma cells reveals novel hyper- and hypomethylated targets

The successful treatment of cancer requires a clear understanding of multiple interacting factors involved in the development of drug resistance. Presently, two hypotheses, genetic and epigenetic, have been proposed to explain mechanisms of acquired cancer drug resistance. In the present study, we examined the alterations in epigenetic mechanisms in the drug-resistant MCF-7 human breast cancer cells induced by doxorubicin (DOX) and cisplatin (cisDDP), two chemotherapeutic drugs with different modes of action. Despite this difference, both of the drug-resistant cell lines displayed similar pronounced changes in the global epigenetic landscape showing loss of global DNA methylation, loss of histone H4 lysine 20 trimethylation, increased phosporylation of histone H3 serine 10, and diminished expression of Suv4-20h2 histone methyltransferase compared with parental MCF-7 cells. In addition to global epigenetic changes, the MCF-7/DOX and MCF-7/cisDDP drug-resistant cells are characterized by extensive alterations in region-specific DNA methylation, as indicated by the appearance of the number of differentially methylated DNA genes. A detailed analysis of hypo- and hypermethylated DNA sequences revealed that the acquisition of drug-resistant phenotype of MCF-7 cells to DOX and cisDDP, in addition to specific alterations induced by a particular drug only, was characterized by three major common mechanisms: dysfunction of genes involved in estrogen metabolism (sulfatase 2 and estrogen receptor alpha), apoptosis (p73, alpha-tubulin, BCL2-antagonist of cell death, tissue transglutaminase 2 and forkhead box protein K1), and cell-cell contact (leptin, stromal cell-derived factor receptor 1, activin A receptor E-cadherin) and showed that two opposing hypo- and hypermethylation processes may enhance and complement each other in the disruption of these pathways. These results provided evidence that epigenetic changes are an important feature of cancer cells with acquired drug-resistant phenotype and may be a crucial contributing factor to its development. Finally, deregulation of similar pathways may explain the existence and provide mechanism of cross-resistance of cancer cells to different types of chemotherapeutic agents.     

Enhancement of Y5−xPrxSb3−yMy (M = Sn,Pb) Electrodes for Lithium- and Sodium-Ion Batteries by Structure Disordering and CNTs Additives

The maximally disordered (MD) phases with the general formula Y_5−xPr_xSb_3−yM_y (M = Sn, Pb) are formed with partial substitution of Y by Pr and Sb by Sn or Pb in the binary Y₅Sb₃ compound. During the electrochemical lithiation and sodiation, the formation of Y_5-xPr_xSb_3-yM_yLi_z and Y_5−xPr_xSb_3−yM_yNa_z maximally disordered–high entropy intermetallic phases (MD-HEIP), as the result of insertion of Li/Na into octahedral voids, were observed. Carbon nanotubes (CNT) are an effective additive to improve the cycle stability of the Y_5−xPr_xSb_3−yM_y (M = Sn, Pb) anodes for lithium-ion (LIBs) and sodium-ion batteries (SIBs). Modification of Y_5−xPr_xSb_3−ySn_y alloys by carbon nanotubes allowed us to significantly increase the discharge capacity of both types of batteries, which reaches 280 mAh · g⁻¹ (for LIBs) and 160 mAh · g⁻¹ (for SIBs), respectively. For Y_5−xPrxSb_3−yPb_y alloys in which antimony is replaced by lead, these capacities are slightly smaller and are 270 mAh · g⁻¹ (for LIBs) and 155 mAh · g⁻¹ (for SIBs), respectively. Results show that structure disordering and CNT additives could increase the electrode capacities up to 30% for LIBs and up to 25% for SIBs.     

Sodium channels amplify spine potentials

Dendritic spines mediate most excitatory synapses in the brain. Past theoretical work and recent experimental evidence have suggested that spines could contain sodium channels. We tested this by measuring the effect of the sodium channel blocker tetrodotoxin (TTX) on depolarizations generated by two-photon uncaging of glutamate on spines from mouse neocortical pyramidal neurons. In practically all spines examined, uncaging potentials were significantly reduced by TTX. This effect was postsynaptic and spatially localized to the spine and occurred with uncaging potentials of different amplitudes and in spines of different neck lengths. Our data confirm that spines from neocortical pyramidal neurons are electrically isolated from the dendrite and indicate that they have sodium channels and are therefore excitable structures. Spine sodium channels could boost synaptic potentials and facilitate action potential backpropagation.     

Characterization of Polyelectrolyte Complexes Based on Maleic Anhydride Alternating Copolymers by Static and Dynamic Light Scattering

The influence of the hydrophobicity of oppositely charged polyelectrolytes based on maleic anhydride alternating copolymers on the complex formation has been investigated by means of DLS and SLS. The change of hydrophobicity of the stock polyions was provided by variation of the comonomer (ethylene, isobutylene and styrene) in the polymer backbone. The particle size and the polydispersity at certain mixing ratios increase with increasing hydrophobicity of the used polyelectrolytes. Below the isoelectric point (1:1 interaction stoichiometry) an increase in the mixing ratio n^?/n⁺ leads to an increasing molar mass and density of the PECs within separate series while the polydispersity is decreasing. The radius of gyration and the hydrodynamic radius are less affected by the mixing ratio in this range. Above the isoelectric point, size and molar mass of the PECs increase strongly and depend on the amount and stabilizing efficiency of the added stabilizing polyelectrolyte. All studied PECs are found to be of spherical shape with different internal structure depending on the used polymers and the mixing ratio.