2,6-Dipeptidyl-anthraquinones are a promising class of nucleic acid-binding compounds that act as NC inhibitors in vitro. We designed, synthesized, and tested new series of 2,6-disubstituted-anthraquinones, which are able to bind viral nucleic acid substrates of NC. We demonstrate here that these novel derivatives interact preferentially with noncanonical structures of TAR and cTAR, stabilize their dynamics, and interfere with NC chaperone activity.
There was not enough evidence to support the routine use of omega-3 supplementation during pregnancy. Given the 73% significant decrease in perinatal death in the singleton gestations who started omega-3 supplementation ≤ 20 weeks, further research is needed. Large RCTs in multiple gestations and longer follow-up are also required.
Abstract:The present research has been focused on the evaluation of seasonal changes in mass concentrations and compositions of heavy metals in Particular Matters (PM) 10 collected from a typical urban-industrial site in Acerra, a city located in an area called "triangle of death". No significant (p < 0.05) seasonal variation was evidenced for the PM 10 concentration, but in all the seasons (except for autumn) exceedances of daily concentrations (50 µg m −3 ) were observed. Airborne PM was analyzed for these heavy metals: Al, As, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Sb, V and Zn, which represented about 8% of the PM 10 concentrations. None of the metals classified by IARC as carcinogenic in humans (group 1) exceeded on average the annual EU's and Italy's limit. For the mentioned heavy metals the enrichment factors (EnFs) were analyzed and highlighted high enrichment for Cd, Sb, Pb, As, Cu and Zn. Principal component analysis (PCA) for the heavy metals in PM 10 identified oil combustion, vehicle and industrial emissions as major sources. To assess the health risk related to the inhalation to airborne PM 10 metals, we applied the Cancer Risk (CR) and Target Hazard Quotient (THQ). The results showed that the CR was similar for a child and an adult, while the THQ proved to be higher for a child than for an adult. The low PM metals risk in the urban industrial site was in agreement with the ongoing lowering trend of metals in Italy and Europe.
The HIV-1 nucleocapsid (NC) protein represents an excellent molecular target for the development of anti-retrovirals by virtue of its well-characterized chaperone activities, which play pivotal roles in essential steps of the viral life cycle. Our ongoing search for candidates able to impair NC binding/annealing activities led to the identification of peptidyl-anthraquinones as a promising class of nucleic acid ligands. Seeking to elucidate the inhibition determinants and increase the potency of this class of compounds, we have now explored the effects of chirality in the linker connecting the planar nucleus to the basic side chains. We show here that the non-natural linker configuration imparted unexpected TAR RNA targeting properties to the 2,6-peptidyl-anthraquinones and significantly enhanced their potency. Even if the new compounds were able to interact directly with the NC protein, they manifested a consistently higher affinity for the TAR RNA substrate and their TAR-binding properties mirrored their ability to interfere with NC-TAR interactions. Based on these findings, we propose that the viral Tat protein, sharing the same RNA substrate but acting in distinct phases of the viral life cycle, constitutes an additional druggable target for this class of peptidyl-anthraquinones. The inhibition of Tat-TAR interaction for the test compounds correlated again with their TAR-binding properties, while simultaneously failing to demonstrate any direct Tat-binding capabilities. These considerations highlighted the importance of TAR RNA in the elucidation of their inhibition mechanism, rather than direct protein inhibition. We have therefore identified anti-TAR compounds with dual in vitro inhibitory activity on different viral proteins, demonstrating that it is possible to develop multitarget compounds capable of interfering with processes mediated by the interactions of this essential RNA domain of HIV-1 genome with NC and Tat proteins.
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