Targeting poly(ADP-ribose) polymerase activity for cancer therapy

Poly(ADP-ribosyl)ation is a ubiquitous protein modification found in mammalian cells that modulates many cellular responses, including DNA repair. The poly(ADP-ribose) polymerase (PARP) family catalyze the formation and addition onto proteins of negatively charged ADP-ribose polymers synthesized from NAD+. The absence of PARP-1 and PARP-2, both of which are activated by DNA damage, results in hypersensitivity to ionizing radiation and alkylating agents. PARP inhibitors that compete with NAD+ at the enzyme’s activity site are effective chemo- and radiopotentiation agents and, in BRCA-deficient tumors, can be used as single-agent therapies acting through the principle of synthetic lethality. Through extensive drug-development programs, third-generation inhibitors have now entered clinical trials and are showing great promise. However, both PARP-1 and PARP-2 are not only involved in DNA repair but also in transcription regulation, chromatin modification, and cellular homeostasis. The impact on these processes of PARP inhibition on long-term therapeutic responses needs to be investigated

Uniaxially stretched poly(ethylene naphthalene 2,6-dicarboxylate) films studied by broadband dielectric spectroscopy

International audienc

Identification and measurement of veterinary drug residues in beehive products

There is an increasing concern about the negative impacts of veterinary drugs in beehive compartments. This study evaluates the presence and distribution of chemical residues in beeswax, bee bread and honey and determinates in what extension honeybees are exposed to them. Samples were analyzed by LC-MS/MS and GC–MS/MS with a wide scope of 322 chemical residues. Samples were collected from apiaries located in rural and forest areas, showing no difference in contamination of phytosanitary applications. Residues of acaricides used for sanitary treatments, coumaphos and two transformation products of amitraz (DMF and DMPF), were quantified at higher levels in wax and bee bread than in honey in most cases. Coumaphos, DMF and DMPF were detected in honey in the range 6–36 µg.kg−1; 45–541 µg.kg−1; 15–107 µg.kg−1, respectively. All, except one sample, were below the EU MRLs, 396/2005 Regulation. Other pesticide residues were detected in beeswax and bee bread at various levels

Non-target evaluation of contaminants in honey bees and pollen samples by gas chromatography time-of-flight mass spectrometry

This work presents a non-targeted screening approach for the detection and quantitation of contaminants in bees and pollen, collected from the same hive, by GC-EI-ToF-MS. It consists of a spectral library datasets search using a compound database followed by a manual investigation and analytical standard confirmation together with semi-quantitation purposes. Over 20% of the compounds found automatically by the library search could not be confirmed manually. This number of false positive detections was mainly a consequence of an inadequate ion ratio criterion (±30%), not considered in the automatic searching procedure. Eight compounds were detected in bees and pollen. They include insecticides/acaricides (chlorpyrifos, coumaphos, fluvalinate-tau, chlorfenvinphos, pyridaben, and propyl cresol) at a concentration range of 1–1207 μg kg−1, herbicides (oxyfluorfen) at a concentration range of 212–1773 μg kg−1 and a growth regulator hormone (methoprene). Some compounds were detected only in pollen; such as herbicides (clomazone), insecticides/acaricides and fungicides used to control Varroa mites as benzylbenzoate, bufencarb, allethrin, permethrin, eugenol and cyprodinil. Additional compounds were detected only in bees flamprop-methyl, 2-methylphenol (2–49 μg kg−1) and naphthalene (1–23 μg kg−1). The proposed method presents important advantages as it can avoid the use of an unachievable number of analytical standards considered target compounds “a priori” but not present in the analyzed samples. © 2017 Elsevier Lt

ZAPS is a potent stimulator of signaling mediated by the RNA helicase RIG-I during antiviral responses

The poly(ADP-ribose) polymerases (PARPs) participate in various processes. Here, we report that the PARP-13/ZAP shorter isoform (hereafter called ZAPS), rather than the full length protein, is selectively induced by 3pRNA, and functions as a potent stimulator of retinoic acid-inducible gene-I (RIG-I)-mediated interferon (IFN) responses in human cells. ZAPS associates with RIG-I to promote the oligomerization and ATPase activity of RIG-I, leading to robust activation of IRF3 and NF-κB pathways. Disruption of the PARP-13/ZAP gene, ZC3HAV1, severely abrogated the induction of IFN-α, IFN-β and other cytokines upon viral infection. These results indicate that ZAPS is a key regulator of RIG-I signaling during the innate antiviral immune response, suggesting its possible use as a therapeutic target for viral control

Thermotropic Phase Behavior of Trialkyl Cyclohexanetriamides

The thermotropic phase behavior of symmetric cyclohexanetriamides carrying various linear and branched alkyl chains was investigated using calorimetry, microscopy, solid-state NMR, dielectric relaxation spectroscopy, and X-ray scattering techniques. Cyclohexanetriamides carrying C6 or longer linear alkyl chains formed columnar plastic phases with a pseudocentered rectangular lattice. Those with C8 or longer alkyl chain also showed a nematic liquid crystalline phase. Cyclohexanetriamides carrying branched octyl chains displayed columnar phases with rectangular lattices, except for the triamide with the highly branched tetramethylbutyl group. The occurrence of less symmetrical columnar phases is ascribed to the mode of stacking of cyclohexanetriamides which leads to noncylindrical columns. Dielectric relaxation spectra also featured highly cooperative relaxation processes related to reorientation of the macrodipolar columns in the mesophase, showing the potential of these molecules as building blocks in responsive materials