Search results for "SHM"

Ensemble-based ADME-Tox profiling and virtual screening for the discovery of new inhibitors of the Leishmania mexicana cysteine protease CPB2.8ΔCTE

2018

Abstract: In an effort to identify novel molecular warheads able to inhibit Leishmania mexicana cysteine protease CPB2.8CTE, fused benzo[b]thiophenes and ,'-triketones emerged as covalent inhibitors binding the active site cysteine residue. Enzymatic screening showed a moderate-to-excellent activity (12%-90% inhibition of the target enzyme at 20m). The most promising compounds were selected for further profiling including in vitro cell-based assays and docking studies. Computational data suggest that benzo[b]thiophenes act immediately as non-covalent inhibitors and then as irreversible covalent inhibitors, whereas a reversible covalent mechanism emerged for the 1,3,3'-triketones with a Y-to…

Triazolopyridyl ketones as a novel class of antileishmanial agents. DNA binding and BSA interaction

2014

A new series of triazolopyridyl pyridyl ketones has been synthetized by regioselective lithiation of the corresponding [1,2,3]triazolo[1,5-a]pyridine at 7 position followed by reaction with different electrophiles. The in vitro antileishmanial activity of these compounds was evaluated against Leishmaniainfantum, Leishmaniabraziliensis, Leishmaniaguyanensis and Leishmaniaamazonensis. Compounds 6 and 7 were found to be the most active leishmanicidal agents. Both of them showed activities at micromolar concentration against cultured promastigotes of Leishmania spp. (IC₅₀=99.8-26.8 μM), without cytotoxicity on J774 macrophage cells. These two compounds were also tested in vivo in a murine model…

Requirements for Th1-dependent immunity against infection with Leishmania major

2004

Protective immunity against cutaneous leishmaniasis is dependent on the induction of Th1/Tc1 immune responses resulting in efficient parasite elimination. In this review, the mechanisms leading to protection are discussed with special focus on the role of Leishmania major-infected dendritic cells (DC) in induction of Th1-dependent immunity. Murine strain-dependent differences between DC derived from Leishmania-susceptible as compared to resistant mice are highlighted.

Research in practice: Different dendritic cell types in skin with various functions - important implications for intradermal vaccines

2011

Summary It was long believed that epidermal Langerhans cells (LC) are responsible for the initiation of cellular immunity. Only recently it has been shown that in skin alone 5 different subtypes of dendritic cells (DC) can be identified. Among these, LC, but also two Langerin-expressing dermal DC populations and two more Langerin-negative DC subtypes exist. Novel findings in the model disease leishmaniasis, as well as evidence from research in contact hypersensitivity, have revealed that activation of LC in skin leads to induction of regulatory, immunosuppressive T cells, whereas the other skin DC subtypes stimulate effector T cells. Thus, when producing vaccines designed for intradermal us…

Venezuela's humanitarian crisis, resurgence of vector-borne diseases, and implications for spillover in the region

2019

In the past 5–10 years, Venezuela has faced a severe economic crisis, precipitated by political instability and declining oil revenue. Public health provision has been affected particularly. In this Review, we assess the impact of Venezuela's health-care crisis on vector-borne diseases, and the spillover into neighbouring countries. Between 2000 and 2015, Venezuela witnessed a 359% increase in malaria cases, followed by a 71% increase in 2017 (411 586 cases) compared with 2016 (240 613). Neighbouring countries, such as Brazil, have reported an escalating trend of imported malaria cases from Venezuela, from 1538 in 2014 to 3129 in 2017. In Venezuela, active Chagas disease transmission has be…

Promising trypanocidal heterocyclic compounds of natural origin and their synthetic analogs

2019

Abstract Diseases caused by members of the order Trypanosomatidae include human African trypanosomiasis (HAT) and Chagas disease, caused by species of Trypanosoma brucei and Trypanosoma cruzi, respectively, as well as leishmaniasis, caused by various species of Leishmania spp. These infections belong to the so-called neglected tropical diseases group, which are a diverse group of communicable diseases that prevail in tropical and subtropical conditions in 149 countries and affect more than one billion people in addition to costing developing economies billions of dollars every year. The available pharmacotherapies for combatting these diseases are limited and associated with strong side eff…

Cytotoxicity and antileishmanial activity of Annona muricata pericarp

2000

Abstract Hexane, ethyl acetate and methanol extracts of Annona muricata pericarp were tested in vitro against Leishmania braziliensis and L. panamensis promastigotes, and against cell line U-937. The ethyl acetate extract was more active than the other extracts and even of Glucantime® used as reference substance. Its fractionation led to the isolation of three acetogenins — annonacin, annonacin A and annomuricin A.

Beliefs in the necessity of corporal punishment of children and public perceptions of child physical abuse as a social problem.

2008

Is It Considered Violence? The Acceptability of Physical Punishment of Children in Europe

2008

This study analyzes correlates of the acceptability of physical punishment of children in Europe. The design was a three-level ordinal logistic regression of 10,812 people nested within 208 localities (cities), nested within 14 countries of the European Union. Results showed that higher levels of acceptability were reported by men, the older, the less educated, and those who perceived that violence against children was less frequent in their own country. At the country level, the existence of laws prohibiting physical punishment of children as well as a lower number of child maltreatment deaths were significantly associated with lower levels of acceptability of physical punishment of childr…

Child-rearing and child abuse antecedents of criminality

1999

A number of studies reviewed here show that those who are exposed to negative child-rearing practices varying from punitive and lax parenting to severe punishment and abuse in childhood tend to be antisocial, aggressive and commit violent crimes later in life. Both the record approach (Widom) studying later outcomes among abused children and the retrospective approach (Lewis) studying violent childhood experiences among offenders provide support for the violence breeds violence hypothesis. It appears clear that punishment in child-rearing increases the risk for maladaptive developmental outcomes but that the mechanism explaining the link between negative parenting and later maladjustment is…