Publications by authors named "Paulo J Costa"

Eukaryotic cells possess surveillance mechanisms that detect and degrade defective transcripts. Aberrant transcripts include mRNAs with a premature termination codon (PTC), targeted by the nonsense-mediated decay (NMD) pathway, and mRNAs lacking a termination codon, targeted by the nonstop decay (NSD) pathway. The eukaryotic exosome, a ribonucleolytic complex, plays a crucial role in mRNA processing and turnover through its catalytic subunits PM/Scl100 (Rrp6 in yeast), DIS3 (Rrp44 in yeast), and DIS3L1.

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  • Tuberculosis (TB) is a serious disease affecting vulnerable populations, and researchers have created new compounds called -alkyl nitrobenzamides that show potential against TB by targeting the enzyme DprE1 found in Mycobacterium tuberculosis (Mtb).
  • The study demonstrated that specific derivatives of these compounds, particularly those with certain chemical structures and chain lengths, exhibited strong antitubercular activity, performing similarly to the existing TB treatment, isoniazid.
  • Evidence from docking studies suggests that these compounds likely work by interacting with the DprE1 enzyme, supporting their potential as viable candidates for TB therapy.
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  • Organometallic complexes are gaining interest as potential anticancer therapies, especially to address the limitations of existing platinum-based drugs.
  • Researchers synthesized and characterized four new cobalt(III)-cyclopentadienyl complexes using various analytical techniques.
  • These complexes exhibited significant cytotoxic effects in multiple human cancer cell lines through mechanisms like ROS production and apoptosis, while proving nontoxic to healthy cells in an ex ovo chick embryo model.
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  • The scientists studied new silver compounds that might help fight cancer, especially in cases where other drugs don’t work.
  • They used various techniques to analyze these compounds and understand how they work against different cancer cells.
  • The results showed that one type of silver compound was very effective against a certain cancer type and caused cells to die in a unique way, which could make it a good treatment option for difficult cancers.
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Compounds containing halogens can form halogen bonds (XBs) with biological targets such as proteins and membranes due to their anisotropic electrostatic potential. To accurately describe this anisotropy, off-center point-charge (EP) models are commonly used in force field methods, allowing the description of XBs at the molecular mechanics and molecular dynamics level. Various EP implementations have been documented in the literature, and despite being efficient in reproducing protein-ligand geometries and sampling of XBs, it is unclear how well these EP models predict experimental properties such as hydration free energies (Δ), which are often used to validate force field performance.

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Several factors affect the passive membrane permeation of small molecules, including size, charge, pH, or the presence of specific chemical groups. Understanding these features is paramount to identifying or designing drug candidates with optimal ADMET properties and this can be achieved through experimental/knowledge-based methodologies or using computational approaches. Empirical methods often lack detailed information about the underlying molecular mechanism.

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Pd(II) catalysts, particularly the acetate salt in acetic acid, tended to favor regioselective C-H activation of quinoline N-oxides (QOs) at the C2 position. However, Pd(II)Cl was shown to catalyze their C-H activation at C8 and, in the presence of water, C8-H activation was accompanied by the formation of 2-quinolinones. The aim of the DFT study described in this work was to shed light on the complete mechanism of these competing catalytic reactions, when PdCl reacts with QO and benzaldehyde in dichloroethane.

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Halogen bonds (XBs) have become increasingly popular over the past few years with numerous applications in catalysis, material design, anion recognition, and medicinal chemistry. To avoid a rationalization of XB trends, descriptors can be tentatively employed to predict the interaction energy of potential halogen bonds. These typically comprise the electrostatic potential maximum at the tip of the halogen, , or properties based on the topological analysis of the electronic density.

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DIS3L2 degrades different types of RNAs in an exosome-independent manner including mRNAs and several types of non-coding RNAs. DIS3L2-mediated degradation is preceded by the addition of nontemplated uridines at the 3'end of its targets by the terminal uridylyl transferases 4 and 7. Most of the literature that concerns DIS3L2 characterizes its involvement in several RNA degradation pathways, however, there is some evidence that its dysregulated activity may contribute to cancer development.

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The synthesis and biological evaluation of novel guanidino sugars as isonucleoside analogs is described. 5-Guanidino xylofuranoses containing 3-O-saturated/unsaturated hydrocarbon or aromatic-containing moieties were accessed from 5-azido xylofuranoses via reduction followed by guanidinylation with N,N'-bis(tert-butoxycarbonyl)-N''-triflylguanidine. Molecules comprising novel types of isonucleosidic structures including 5-guanidino 3-O-methyl-branched N-benzyltriazole isonucleosides and a guanidinomethyltriazole 3'-O-dodecyl xylofuranos-5'-yl isonucleoside were accessed.

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Tau proteins are known to be mainly involved in regulation of microtubule dynamics. Besides this function, which is critical for axonal transport and signal transduction, tau proteins also have other roles in neurons. Moreover, tau proteins are turned into aggregates and consequently trigger many neurodegenerative diseases termed tauopathies, of which Alzheimer's disease (AD) is the figurehead.

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The objective of this work was to analyze the flow behavior of a commonly used filler (pregelatinised starch) and the effect of two of the most used lubricants (talc and colloidal silicon dioxide). The studies were carried out according to the conventional methods (Angle of Repose, Bulk and Tapped densities and from these the Compressibility Index) and shear cell methods (Brookfield Powder Flow Tester apparatus) described in European Pharmacopeia (Ph. Eur.

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The reaction of [{(ArNCMe)CH}Al] (Ar = 2,6-di-iso-propylphenyl) with aryl methyl ethers proceeded with alumination of the sp C-O bond. The selectivity of this reaction could be switched by inclusion of a catalyst. In the presence of [Pd(PCy)], chemoselective sp C-O bond functionalisation was observed.

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Synthetic anion transporters are promising therapeutic agents designed to emulate the specialized role of certain transmembrane proteins that maintain the ion concentration in cells. In the last few years, besides hydrogen bonds and ion pairs, halogen bonds have also been explored to promote the association between the synthetic molecule and the anion and their subsequent transport. This interaction is due to an anisotropic charge distribution on the halogen, and therefore, modeling halogen bonds is not a trivial task using classical force field methods that typically rely on point-charge models.

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In force-field methods, the usage of off-center point charges, also called extra points (EPs), is a common strategy to tackle the anisotropy of the electrostatic potential of covalently bonded halogens (X), thus allowing the description of halogen bonds (XBs) at the molecular mechanics/molecular dynamics (MM/MD) level. Diverse EP implementations exist in the literature differing on the charge sets and/or the X-EP distances. Poisson-Boltzmann and surface area (PBSA) calculations can be used to obtain solvation free energies (Δ) of small molecules, often to compute binding free energies (Δ) at the MM-PBSA level.

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The interaction between human serum transferrin (hTf) and three promising organometallic Ru (II)- (η-CH) derived complexes, that have already shown strong in vitro cytotoxicity towards human cancer cell lines, has been investigated using fluorescence spectroscopic techniques. The results suggested that the formation of Ru-hTf systems involves a dynamic collision. The binding process occurs spontaneously (ΔG < 0), mainly driven by hydrophobic interactions.

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Non-catalysed and catalysed reactions of aluminium reagents with furans, dihydrofurans and dihydropyrans were investigated and lead to ring-expanded products due to the insertion of the aluminium reagent into a C-O bond of the heterocycle. Specifically, the reaction of [{(ArNCMe)CH}Al] (Ar = 2,6-di-iso-propylphenyl, ) with furans proceeded between 25 and 80 °C leading to dearomatised products due to the net transformation of a sp C-O bond into a sp C-Al bond. The kinetics of the reaction of with furan were found to be 1st order with respect to with activation parameters Δ = +19.

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The ability of some hydrogels to exhibit a phase transition or change their structure in response to stimuli has been extensively explored for drug depot formation and controlled drug release. Taking advantage of the unique features of the tumor microenvironment (TME) or externally applied triggers, several injectable stimuli-responsive hydrogels have been described as promising candidates for intratumoral drug delivery. In this review, we provide a brief overview of the TME and highlight the advantages of intratumoral administration, followed by a summary of the reported strategies to endow hydrogels with responsiveness to physical (temperature and light), chemical (pH and redox potential), or biological (enzyme) stimuli.

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Halogen bonds (XBs) are noncovalent interactions where halogen atoms act as electrophilic species interacting with Lewis bases. These interactions are relevant in biochemical systems being increasingly explored in drug discovery, mainly to modulate protein-ligand interactions, but are also found in engineered protein or nucleic acid systems. In this work, we report direct evidence for the existence of XBs in the context of biological membrane systems, thus expanding the scope of application of these interactions.

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Oromucosal films and tablets were developed as multifunctional biomaterials for the treatment of oral mucositis. These are intended to function as a hybrid, performing as a controlled drug delivery system and as a wound-dressing device. The dosage forms are precursors for in loco hydrogels that are activated by the saliva.

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The synthesis of stable and potentially bioactive xylofuranosyl nucleoside analogues and potential sugar diphosphate or nucleotide mimetics comprising a 1,2,3-triazole moiety is reported. 3'-O-Methyl-branched N-benzyltriazole isonucleosides were accessed in 5-7 steps and 42-54 % overall yields using a Cu(I)-catalyzed cycloaddition of 3-O-propargyl-1,2-O-isopropylidene-α-D-xylofuranose with benzyl azide as key step. Related isonucleotides were obtained by 5-O-phosphorylation of acetonide-protected 3-O-propargyl xylofuranose and further "click" cycloaddition or by Staudinger-phosphite reaction of a 5-azido N-benzyltriazole isonucleoside.

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A family of compounds with the general formula [Fe(η-CH)(CO)(PPh)(NCR)] has been synthesized (NCR = benzonitrile (); 4-hydroxybenzonitrile (); 4-hydroxymethylbenzonitrile (); 4-aminobenzonitrile (); 4-bromobenzonitrile (); and, 4-chlorocinnamonitrile ()). All of the compounds were obtained in good yields and were completely characterized by standard spectroscopic and analytical techniques. Compounds , , and crystallize in the monoclinc P21/c space group and packing is determined by short contacts between the phosphane phenyl rings and cyclopentadienyl (compounds and ) or π-π lateral interactions between the benzonitrile molecules (complex ).

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In this article, we present supportive data related to the research article "A role for DIS3L2 over natural nonsense-mediated mRNA decay targets in human cells" [1], where interpretation of the data presented here is available. Indeed, here we analyze the impact of the DIS3L2 exoribonuclease over nonsense-mediated mRNA decay (NMD)-targets. Specifically, we present data on: a) the expression of various reporter human β-globin mRNAs, monitored by Northern blot and RT-qPCR, before and after altering DIS3L2 levels in HeLa cells, and b) the gene expression levels of deregulated transcripts generated by re-analyzing publicly available data from UPF1-depleted HeLa cells that were further cross-referenced with a dataset of transcripts upregulated in DIS3L2-depleted cells.

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Article Synopsis
  • The nonsense-mediated decay (NMD) pathway helps get rid of faulty mRNAs that tell the cell to stop making proteins too early and also helps control normal mRNAs that make full-length proteins.
  • In humans, NMD works by cutting and breaking down these faulty mRNAs, involving some complicated processes and a specific group of enzymes.
  • The study found that a protein called DIS3L2 is important for this process in human cells, and it works together with other proteins to help get rid of the unwanted mRNAs.
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RNA degradation is considered a critical posttranscriptional regulatory checkpoint, maintaining the correct functioning of organisms. When a specific RNA transcript is no longer required in the cell, it is signaled for degradation through a number of highly regulated steps. Ribonucleases (or simply RNases) are key enzymes involved in the control of RNA stability.

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