Search results for "ISM [radio lines]"
showing 10 items of 1018 documents
Lack of a peroxiredoxin suppresses the lethality of cells devoid of electron donors by channelling electrons to oxidized ribonucleotide reductase
2017
The thioredoxin and glutaredoxin pathways are responsible of recycling several enzymes which undergo intramolecular disulfide bond formation as part of their catalytic cycles such as the peroxide scavengers peroxiredoxins or the enzyme ribonucleotide reductase (RNR). RNR, the rate-limiting enzyme of deoxyribonucleotide synthesis, is an essential enzyme relying on these electron flow cascades for recycling. RNR is tightly regulated in a cell cycle-dependent manner at different levels, but little is known about the participation of electron donors in such regulation. Here, we show that cytosolic thioredoxins Trx1 and Trx3 are the primary electron donors for RNR in fission yeast. Unexpectedly,…
RBFOX1, encoding a splicing regulator, is a candidate gene for aggressive behavior
2020
The RBFOX1 gene (or A2BP1) encodes a splicing factor important for neuronal development that has been related to autism spectrum disorder and other neurodevelopmental phenotypes. Evidence from complementary sources suggests that this gene contributes to aggressive behavior. Suggestive associations with RBFOX1 have been identified in genome-wide association studies (GWAS) of anger, conduct disorder, and aggressive behavior. Nominal association signals in RBFOX1 were also found in an epigenome-wide association study (EWAS) of aggressive behavior. Also, variants in this gene affect temporal lobe volume, a brain area that is altered in several aggression-related phenotypes. In animals, this gen…
Study of novel anticancer 4-thiazolidinone derivatives
2016
Abstract 4-Thiazolidinones are a known class of prospective drug-like molecules, especially in the design of new anticancer agents. Two of the most prominent subtypes of these compounds are 5-ene-2-amino(amino)-4-thiazolidinones and thiopyrano[2,3-d]thiazoles. The latter are considered to be cyclic mimetics of biologically active 5-ene-4-thiazolidinones with similar pharmacological profiles. Therefore, the aim of this study was to evaluate the impact of 4-thiazolidinone-based compounds on cytotoxicity, the apoptotic process, and metabolism in the human squamous carcinoma (SCC-15) cell line. The SCC-15 cells were cultured in phenol red-free DMEM/F12 medium supplemented with 10% FBS, hydrocor…
New insights into the mechanism of action of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives endowed with anticancer potential
2018
Due to the scarce biological profile, the pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one scaffold (PBT) has been recently explored as promising core for potential anticancer candidates. Several suitably decorated derivatives (PBTs) exhibited antiproliferative activity in the low-micromolar range associated with apoptosis induction and cell cycle arrest on S phase. Herein, we selected the most active derivatives and submitted them to further biological explorations to deepen the mechanism of action. At first, a DNA targeting is approached by means of flow Linear Dichroism experiments so as to evaluate how small planar molecules might interact with DNA, including the interference with the catal…
Specific and highly efficient condensation of GC and IC DNA by polyaza pyridinophane derivatives
2018
Abstract Two bis-polyaza pyridinophane derivatives and their monomeric reference compounds revealed strong interactions with ds-DNA and RNA. The bis-derivatives show a specific condensation of GC- and IC-DNA, which is almost two orders of magnitude more efficient than the well-known condensation agent spermine. The type of condensed DNA was identified as ψ-DNA, characterized by the exceptionally strong CD signals. At variance to the almost silent AT(U) polynucleotides, these strong CD signals allow the determination of GC-condensates at nanomolar nucleobase concentrations. Detailed thermodynamic characterisation by ITC reveals significant differences between the DNA binding of the bis-deriv…
Abstract C097: Pyrrolo[2′,3′:3,4]cyclohepta[1,2-d][1,2]oxazoles: A new class of antimitotic agents
2019
Abstract Tubulin-binding molecules constitute an important class of antineoplastic agents, with broad activity in both solid and hematologic malignancies. Oxazoles represent the core structure of many drug candidates with multiple targets, providing an attractive scaffold in medicinal chemistry. Diaryl[1,2]oxazoles have emerged as potent analogues of the antitubulin compound combretastatin A-4 (CA-4). Naphtylcombretastin and its derivatives incorporating the isoxazole moiety displayed potent cytotoxic effects and inhibition of tubulin polymerization. In particular, 5-(naphthalen-2-yl)-4-(TMP)-1,2-oxazole and 4-(naphthalen-2-yl)-5-(TMP)-1,2-oxazole showed the same inhibitory potency as napht…
Alterations in Tau Protein Level and Phosphorylation State in the Brain of the Autistic-Like Rats Induced by Prenatal Exposure to Valproic Acid
2021
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficient social interaction and communication besides repetitive, stereotyped behaviours. A characteristic feature of ASD is altered dendritic spine density and morphology associated with synaptic plasticity disturbances. Since microtubules (MTs) regulate dendritic spine morphology and play an important role in spine development and plasticity the aim of the present study was to investigate the alterations in the content of neuronal α/β-tubulin and Tau protein level as well as phosphorylation state in the valproic acid (VPA)-induced rat model of autism. Our results indicated that maternal exposure to VPA indu…
Fishing anti-inflammatories from known drugs: In silico repurposing, design, synthesis and biological evaluation of bisacodyl analogues
2017
Herein is described in silico repositioning, design, synthesis, biological evaluation and structure-activity relationship (SAR) of an original class of anti-inflammatory agents based on a polyaromatic pharmacophore structurally related to bisacodyl (BSL) drug used in therapeutic as laxative. We describe the potential of TOMOCOMD-CARDD methods to find out new anti-inflammatory drug-like agents from a diverse series of compounds using the total and local atom based bilinear indices as molecular descriptors. The models obtained were validated by biological studies, identifying BSL as the first anti-inflammatory lead-like using in silico repurposing from commercially available drugs. Several bi…
Kinase Inhibitors in Multitargeted Cancer Therapy
2017
The old-fashioned anticancer approaches, aiming in arresting cancer cell proliferation interfering with non-specific targets (e.g. DNA), have been replaced, in the last decades, by more specific target oriented ones. Nonetheless, single-target approaches have not always led to optimal outcomes because, for its complexity, cancer needs to be tackled at various levels by modulation of several targets. Although at present, combinations of individual single-target drugs represent the most clinically practiced therapeutic approaches, the modulation of multiple proteins by a single drug, in accordance with the polypharmacological strategy, has become more and more appealing. In the perspective of…
Cardiovascular toxicity of abacavir: a clinical controversy in need of a pharmacological explanation.
2017
: There is a long-lasting controversy surrounding an association between abacavir (ABC) and an increased risk of cardiovascular disease in HIV-positive patients. Although differing in their specifics, a number of published cohort studies and clinical trials support such an association, usually relating it to recent exposure to the drug, independently of traditional predisposing factors. However, other clinical trials have failed to reveal such a relation and have pointed to methodological differences to explain discrepancies. Significantly, the controversy has been fueled by the lack of a credible mechanism of action to justify the putative detrimental actions of ABC. There is a myriad of c…