Aromatic Guanylhydrazones for the Control of Heme-Induced Antibody Polyreactivity

In a healthy immune repertoire, there exists a fraction of polyreactive antibodies that can bind to a variety of unrelated self- and foreign antigens. Apart from naturally polyreactive antibodies, in every healthy individual, there is a fraction of antibody that can gain polyreactivity upon exposure to porphyrin cofactor heme. Molecular mechanisms and biological significance of the appearance of cryptic polyreactivity are not well understood. It is believed that heme acts as an interfacial cofactor between the antibody and the newly recognized antigens. To further test this claim and gain insight into the types of interactions involved in heme binding, we herein investigated the influence of a group of aromatic guanylhydrazone molecules on the heme-induced antibody polyreactivity. From the analysis of SAR and the results of UV-vis absorbance spectroscopy, it was concluded that the most probable mechanism by which the studied molecules inhibit heme-mediated polyreactivity of the antibody is the direct binding to heme, thus preventing heme from binding to antibody and/or antigen. The inhibitory capacity of the most potent compounds was substantially higher than that of chloroquine, a well-known heme binder. Some of the guanylhydrazone molecules were able to induce polyreactivity of the studied antibody themselves, possibly by a mechanism similar to heme. Results described here point to the conclusion that heme indeed must bind to an antibody to induce its polyreactivity, and that both pi-stacking interactions and iron coordination contribute to the binding affinity, while certain structures, such as guanylhydrazones, can interfere with these processes

Supplementary data for article: Božinović, N.; Ajdačić, V.; Lazic, J.; Lecerf, M.; Daventure, V.; Nikodinovic-Runic, J.; Opsenica, I. M.; Dimitrov, J. D. Aromatic Guanylhydrazones for the Control of Heme-Induced Antibody Polyreactivity. ACS Omega 2019, 4 (24), 20450–20458. https://doi.org/10.1021/acsomega.9b01548

Supporting information for: [https://doi.org/10.1021/acsomega.9b01548]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/3793

Supplementary data for article: Božinović, N.; Ajdačić, V.; Lazic, J.; Lecerf, M.; Daventure, V.; Nikodinovic-Runic, J.; Opsenica, I. M.; Dimitrov, J. D. Aromatic Guanylhydrazones for the Control of Heme-Induced Antibody Polyreactivity. ACS Omega 2019, 4 (24), 20450–20458. https://doi.org/10.1021/acsomega.9b01548

Supporting information for: [https://doi.org/10.1021/acsomega.9b01548]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/3793

ATM inhibition blocks glucose metabolism and amplifies the sensitivity of resistant lung cancer cell lines to oncogene driver inhibitors

Background: ATM is a multifunctional serine/threonine kinase that in addition to its well-established role in DNA repair mechanisms is involved in a number of signaling pathways including regulation of oxidative stress response and metabolic diversion of glucose through the pentose phosphate pathway. Oncogene-driven tumorigenesis often implies the metabolic switch from oxidative phosphorylation to glycolysis which provides metabolic intermediates to sustain cell proliferation. The aim of our study is to elucidate the role of ATM in the regulation of glucose metabolism in oncogene-driven cancer cells and to test whether ATM may be a suitable target for anticancer therapy. Methods: Two oncogene-driven NSCLC cell lines, namely H1975 and H1993 cells, were treated with ATM inhibitor, KU55933, alone or in combination with oncogene driver inhibitors, WZ4002 or crizotinib. Key glycolytic enzymes, mitochondrial complex subunits (OXPHOS), cyclin D1, and apoptotic markers were analyzed by Western blotting. Drug-induced toxicity was assessed by MTS assay using stand-alone or combined treatment with KU55933 and driver inhibitors. Glucose consumption, pyruvate, citrate, and succinate levels were also analyzed in response to KU55933 treatment. Both cell lines were transfected with ATM-targeted siRNA or non-targeting siRNA and then exposed to treatment with driver inhibitors. Results: ATM inhibition deregulates and inhibits glucose metabolism by reducing HKII, p-PKM2Tyr105, p-PKM2Ser37, E1α subunit of pyruvate dehydrogenase complex, and all subunits of mitochondrial complexes except ATP synthase. Accordingly, glucose uptake and pyruvate concentrations were reduced in response to ATM inhibition, whereas citrate and succinate levels were increased in both cell lines indicating the supply of alternative metabolic substrates. Silencing of ATM resulted in similar changes in glycolytic cascade and OXPHOS levels. Furthermore, the driver inhibitors amplified the effects of ATM downregulation on glucose metabolism, and the combined treatment with ATM inhibitors enhanced the cytotoxic effect of driver inhibitors alone by increasing the apoptotic response. Conclusions: Inhibition of ATM reduced both glycolytic enzymes and OXPHOS levels in oncogene-driven cancer cells and enhanced apoptosis induced by driver inhibitors thus highlighting the possibility to use ATM and the driver inhibitors in combined regimens of anticancer therapy in vivo

Antioxidant enzymes expression in lymphocytes of patients undergoing carotid endarterectomy

To remedy carotid artery stenosis and prevent stroke surgical intervention is commonly used, and the gold standard being carotid endarterectomy (CEA). During CEA cerebrovascular hemoglobin oxygen saturation decreases and when this decrease reaches critical levels it leads to cerebral hypoxia that causes neuronal damage. One of the proposed mechanism that affects changes during CEA and contribute to acute brain ischemia (ABI) is oxidative stress. The increased production of reactive oxygen species and reactive nitrogen species during ABI may cause an unregulated inflammatory response and further lead to structural and functional injury of neurons. Antioxidant activity are involved in the protection against neuronal damage after cerebral ischemia. We hypothesized that neuronal injury and poor outcomes in patients undergoing CEA may be results of oxidative stress that disturbed function of antioxidant enzymes and contributed to the DNA damage in lymphocytes

Measurement of differential cross sections for top quark pair production using the lepton plus jets final state in proton-proton collisions at 13 TeV

National Science Foundation (U.S.

Identification of heavy-flavour jets with the CMS detector in pp collisions at 13 TeV

Many measurements and searches for physics beyond the standard model at the LHC rely on the efficient identification of heavy-flavour jets, i.e. jets originating from bottom or charm quarks. In this paper, the discriminating variables and the algorithms used for heavy-flavour jet identification during the first years of operation of the CMS experiment in proton-proton collisions at a centre-of-mass energy of 13 TeV, are presented. Heavy-flavour jet identification algorithms have been improved compared to those used previously at centre-of-mass energies of 7 and 8 TeV. For jets with transverse momenta in the range expected in simulated $\mathrm{t}\overline{\mathrm{t}}$ events, these new developments result in an efficiency of 68% for the correct identification of a b jet for a probability of 1% of misidentifying a light-flavour jet. The improvement in relative efficiency at this misidentification probability is about 15%, compared to previous CMS algorithms. In addition, for the first time algorithms have been developed to identify jets containing two b hadrons in Lorentz-boosted event topologies, as well as to tag c jets. The large data sample recorded in 2016 at a centre-of-mass energy of 13 TeV has also allowed the development of new methods to measure the efficiency and misidentification probability of heavy-flavour jet identification algorithms. The heavy-flavour jet identification efficiency is measured with a precision of a few per cent at moderate jet transverse momenta (between 30 and 300 GeV) and about 5% at the highest jet transverse momenta (between 500 and 1000 GeV)

Particle-flow reconstruction and global event description with the CMS detector

The CMS apparatus was identified, a few years before the start of the LHC operation at CERN, to feature properties well suited to particle-flow (PF) reconstruction: a highly-segmented tracker, a fine-grained electromagnetic calorimeter, a hermetic hadron calorimeter, a strong magnetic field, and an excellent muon spectrometer. A fully-fledged PF reconstruction algorithm tuned to the CMS detector was therefore developed and has been consistently used in physics analyses for the first time at a hadron collider. For each collision, the comprehensive list of final-state particles identified and reconstructed by the algorithm provides a global event description that leads to unprecedented CMS performance for jet and hadronic tau decay reconstruction, missing transverse momentum determination, and electron and muon identification. This approach also allows particles from pileup interactions to be identified and enables efficient pileup mitigation methods. The data collected by CMS at a centre-of-mass energy of 8 TeV show excellent agreement with the simulation and confirm the superior PF performance at least up to an average of 20 pileup interactions

Search for heavy resonances decaying to a top quark and a bottom quark in the lepton+jets final state in proton–proton collisions at 13 TeV

info:eu-repo/semantics/publishe

Evidence for the Higgs boson decay to a bottom quark–antiquark pair

info:eu-repo/semantics/publishe