Search

The Trp53 gene encodes several isoforms of elusive biological significance. Here, we show that mice lacking the Trp53 alternatively spliced (AS) exon, thereby expressing the canonical p53 protein but not isoforms with the AS C-terminus, have unexpectedly lost a male-specific protection against Myc-induced B-cell lymphomas. Lymphomagenesis was delayed in Trp53+/+Eμ-Myc males compared to Trp53ΔAS/ΔAS Eμ-Myc males, but also compared to Trp53+/+Eμ-Myc and Trp53ΔAS/ΔAS Eμ-Myc females. Pre-tumoral splenic cells from Trp53+/+Eμ-Myc males exhibited a higher expression of Ackr4, encoding an atypical chemokine receptor with tumor suppressive effects. We identified Ackr4 as a p53 target gene whose p53-mediated transactivation is inhibited by estrogens, and as a male-specific factor of good prognosis relevant for murine Eμ-Myc-induced and human Burkitt lymphomas. Furthermore, the knockout of ACKR4 increased the chemokine-guided migration of Burkitt lymphoma cells. These data demonstrate the functional relevance of alternatively spliced p53 isoforms and reveal sex disparities in Myc-driven lymphomagenesis.

Reasoning about analogical arguments is known to be subjectto a variety of cognitive biases, and a lack of clarity aboutwhich factors can be considered strengths or weaknesses ofan analogical argument. This can make it difficult both to de-sign empirical experiments to study how people reason aboutanalogical arguments, and to develop scalable tutoring toolsfor teaching how to reason and analyze analogical arguments.To address these concerns, we describe WG-A (Warrant Game— Analogy), a framework for people to analyze analogical ar-guments based on Bartha’s (2010) Articulation Model of ana-logical argumentation. We carry out two experiments designedto probe WG-A’s effectiveness in improving participants’ abil-ity to reason about analogical arguments and argumentation ingeneral, and argue that WG-A is a promising approach, thoughit is in need of further development.

Background: Blackcurrant (Ribes nigrum L.) leaves are valuable sources of bioactive compounds, including phenolic acids, flavonoids, and tannins, which contribute to their potent antioxidant, anti-inflammatory, and antimicrobial properties. Objectives: The overall aim of this study was to investigate the antimicrobial potential of extracts rich in bioactive compounds from blackcurrant leaves prepared in natural deep eutectic solvents (NaDESs). The objectives included the optimization of polyphenols extraction in NaDESs, characterization of the phytochemical composition by liquid chromatography–mass spectrometry (LC-MS), explanation of the chemical interactions between solvent systems and the main bioactive compound (chlorogenic acid) by molecular dynamics simulations, and evaluation of biological efficacy through antimicrobial tests. Methods: Two hydrogen-bond acceptors (HBAs) and three hydrogen-bond donors (HBDs) were tested. The experimental design included variables such as the HBA:HBD molar ratio, water percentage, extraction time, and extraction techniques used, specifically ultrasound-assisted extraction (UAE) and ultra-turrax extraction (UTE). The evaluated responses included the total polyphenol content, total flavonoid content, and total antioxidant activity. Antimicrobial assays were performed on four Gram-positive and three Gram-negative bacterial species, as well as one fungus, Candida albicans. Results: The extracts obtained by UAE showed higher concentrations of polyphenols and increased antioxidant potential. LC-MS analysis revealed the predominant presence of chlorogenic acid. The extracts showed significant activities against Gram-positive bacteria and Candida albicans. Conclusions: This study highlights the antioxidant and antimicrobial potentials of blackcurrant leaves extracts prepared in NaDESs, confirming that this type of solvent enhances polyphenols extraction and offers perspectives for new therapeutic formulations. [ABSTRACT FROM AUTHOR]

Background/Objectives: Fluoroquinolones (FQs) are topoisomerase II inhibitors with antibacterial activity, repositioned recently as anti-cancer agents. Glutamic acid (GLA) is an amino acid that affects human metabolism. Since an anti-cancer mechanism of FQs is human topoisomerase II inhibition, it is expected that FQ-GLA hybrids can act similarly. Methods: We designed 27 hypothetical hybrids of 6 FQs and GLA through amide bonds at the 3- and 7-position groups of FQs or via ethylenediamine/ethanolamine linkers at the carboxyl group of the FQ. Hydroxamic acid derivatives were also theoretically formulated. Computational methods were used to predict their physicochemical, pharmacokinetic, or toxicological properties and their anti-cancer activity. For comparison, etoposide was used as an anti-cancer agent inhibiting topoisomerase II. Molecular docking assessed whether the hybrids could interact with the human topoisomerase II beta in the same binding site and interaction sites as etoposide. Results: All the hybrids acted as potential topoisomerase II inhibitors, demonstrating possible anti-cancer activity on several cancer cell lines. Among all the proposed hybrids, MF-7-GLA would be the ideal candidate as a lead compound. The hybrid OF-3-EDA-GLA and the hydroxamic acid derivatives also stood out. Conclusions: Both FQs and GLA have advantageous structures for obtaining hybrids with favourable properties. Improvements in the hybrids' structure could lead to promising results. [ABSTRACT FROM AUTHOR]

Steroidal 5α-reductase type 2 (S5αR2) is a key enzyme involved in the conversion of testosterone (TST) to dihydrotestosterone (DHT), a crucial process in the development of benign prostatic hyperplasia (BPH). Phytosterols (PSs), natural plant-derived compounds, have been proposed as potential inhibitors of S5αR2, but studies on their efficacy are limited. This study evaluates the inhibitory effects of three PSs (β-sitosterol, stigmasterol, and campesterol) on S5αR2 activity using a combined in vitro and in silico approach. The inhibitory activity of the respective PSs was assessed in vitro, by measuring TST and DHT, while molecular docking and dynamics explored PS interactions with S5αR2's active site. The in vitro tests indicated significantly higher IC50 values (β-sitosterol, 3.24 ± 0.32 µM; stigmasterol, 31.89 ± 4.26 µM; and campesterol, 15.75 ± 5.56 µM) for PSs compared to dutasteride (4.88 × 10−3 ± 0.33 µM), suggesting a lower efficiency in inhibiting S5αR2. The in silico studies confirmed these observations, explained by the lower binding affinity identified for PSs to the enzyme's active site in the molecular docking studies and the reduced stability of the interactions with the active site of the enzyme during the molecular dynamics simulations compared to dutasteride. The results suggest that PSs exhibit low-to-negligible inhibitory activity against S5αR2 (µM range) compared to the synthetic inhibitor dutasteride (nM range). Among the three PSs studied, β-sitosterol showed the highest inhibitory activity and the best stability in its interaction with S5αR2, when compared with stigmasterol and campesterol. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance poses a major threat to global health as the number of efficient antimicrobials decreases and the number of resistant pathogens rises. Our research group has been actively involved in the design of novel antimicrobial drugs. The blueprints of these compounds were azolic heterocycles, particularly thiazole. Starting with oxadiazolines, our research group explored, one by one, the other five-membered heterocycles, developing more or less potent compounds. An overview of this research activity conducted by our research group allowed us to observe an evolution in the methodology used (from inhibition zone diameters to minimal inhibitory concentrations and antibiofilm potential determination) correlated with the design of azole compounds based on results obtained from molecular modeling. The purpose of this review is to present the development of in-house azole compounds with antimicrobial activity, designed over the years by this research group from the departments of Pharmaceutical and Therapeutical Chemistry in Cluj-Napoca. [ABSTRACT FROM AUTHOR]

A series of thiazolyl–catechol compounds with antioxidant and cytotoxic activities were synthesized by a Hantzsch heterocyclization, using diverse thioamides as the thiocarbonyl component and 4-chloroacetyl-catechol as haloketone. These compounds were characterized by MS, IR spectroscopy, and NMR. Their antioxidant potential was evaluated by antiradical, electron transfer, and ferrous ion chelation assays using ascorbic acid, Trolox, and EDTA-Na2 as references. The cytotoxicity of the synthesized compounds was evaluated on two different cell types, normal human foreskin fibroblasts (BJ) and human pulmonary malignant cells (A549), using gefitinib as a reference anticancer drug. The results obtained from the tests highlighted compounds 3g and 3h with significant antioxidant activities. The highest cytotoxic potency against A549 cells was exhibited by compounds 3i and 3j, while compound 3g demonstrated exceptional selectivity on malignant cells compared to gefitinib. These promising results encourage further investigation into targeted modifications on position 2 of the thiazole ring, in order to develop novel therapeutic agents. [ABSTRACT FROM AUTHOR]

Abstract Long noncoding (lnc)RNAs modulate gene expression alongside presenting unexpected source of neoantigens. Despite their immense interest, their ability to be transferred and control adjacent cells is unknown. Extracellular Vesicles (EVs) offer a protective environment for nucleic acids, with pro and antitumourigenic functions by controlling the immune response. In contrast to extracellular nonvesicular RNA, few studies have addressed the full RNA content within human fluids’ EVs and have compared them with their tissue of origin. Here, we performed Total RNA‐Sequencing on six Formalin‐Fixed‐Paraffin‐Embedded (FFPE) prostate cancer (PCa) tumour tissues and their paired urinary (u)EVs to provide the first whole transcriptome comparison from the same patients. UEVs contain simplified transcriptome with intron‐free cytoplasmic transcripts and enriched lnc/circular (circ)RNAs, strikingly common to an independent 20 patients’ urinary cohort. Our full cellular and EVs transcriptome comparison within three PCa cell lines identified a set of overlapping 14 uEV‐circRNAs characterized as essential for prostate cell proliferation in vitro and 28 uEV‐lncRNAs belonging to the cancer‐related lncRNA census (CLC2). In addition, we found 15 uEV‐lncRNAs, predicted to encode 768 high‐affinity neoantigens, and for which three of the encoded‐ORF produced detectable unmodified peptides by mass spectrometry. Our dual analysis of EVs‐lnc/circRNAs both in urines’ and in vitro’s EVs provides a fundamental resource for future uEV‐lnc/circRNAs phenotypic characterization involved in PCa.

Copyright of Farmacia is the property of Societatea de Stiinte Farmaceutice Romania and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Amides containing methyl esters of γ-aminobutyric acid (GABA), L-proline and L-tyrosine, and esters containing 3-(pyridin-3-yl)propan-1-ol were synthesized by conjugation with 3,5-di-tert-butyl-4-hydroxybenzoic, an NSAID (tolfenamic acid), or 3-phenylacrylic (cinnamic, (E)-3-(3,4-dimethoxyphenyl)acrylic and caffeic) acids. The rationale for the conjugation of such moieties was based on the design of structures with two or more molecular characteristics. The novel compounds were tested for their antioxidant, anti-inflammatory and hypolipidemic properties. Several compounds were potent antioxidants, comparable to the well-known antioxidant, Trolox. In addition, the radical scavenging activity of compound 6 reached levels that were slightly better than that of Trolox. All the tested compounds demonstrated remarkable activity in the reduction in carrageenan-induced rat paw edema, up to 59% (compound 2, a dual antioxidant and anti-inflammatory molecule, with almost 2.5-times higher activity in this experiment than the parent NSAID). Additionally, the compounds caused a significant decrease in the plasma lipidemic indices in Triton-induced hyperlipidemic rats. Compound 2 decreased total cholesterol by 75.1% and compound 3 decreased triglycerides by 79.3% at 150 μmol/kg (i.p.). The hypocholesterolemic effect of the compounds was comparable to that of simvastatin, a well-known hypocholesterolemic drug. Additionally, all compounds lowered blood triglycerides. The synthesized compounds with multiple activities, as designed, may be useful as potential candidates for conditions involving inflammation, lipidemic deregulation and oxygen toxicity. [ABSTRACT FROM AUTHOR]

Considering the pivotal role of angiogenesis in solid tumor progression, we developed a novel series of quinazoline–thiazole hybrids (SA01–SA07) as antiproliferative and anti-angiogenic agents. Four out of the seven compounds displayed superior antiproliferative activity (IC50 =1.83-4.24 µM) on HepG2 cells compared to sorafenib (IC50 = 6.28 µM). The affinity towards the VEGFR2 kinase domain was assessed through in silico prediction by molecular docking, molecular dynamics studies, and MM-PBSA. The series displayed a high degree of similarity to sorafenib regarding the binding pose within the active site of VEGFR2, with a different orientation of the 4-substituted-thiazole moieties in the allosteric pocket. Molecular dynamics and MM-PBSA evaluations identified SA05 as the hybrid forming the most stable complex with VEGFR2 compared to sorafenib. The impact of the compounds on vascular cell proliferation was assessed on EA.hy926 cells. Six compounds (SA01–SA05, SA07) displayed superior anti-proliferative activity (IC50 = 0.79–5.85 µM) compared to sorafenib (IC50 = 6.62 µM). The toxicity was evaluated on BJ cells. Further studies of the anti-angiogenic effect of the most promising compounds, SA04 and SA05, through the assessment of impact on EA.hy296 motility using a wound healing assay and in ovo potential in a CAM assay compared to sorafenib, led to the confirmation of the anti-angiogenic potential. [ABSTRACT FROM AUTHOR]

Abstract We introduce a k-mer-based computational protocol, DE-kupl, for capturing local RNA variation in a set of RNA-seq libraries, independently of a reference genome or transcriptome. DE-kupl extracts all k-mers with differential abundance directly from the raw data files. This enables the retrieval of virtually all variation present in an RNA-seq data set. This variation is subsequently assigned to biological events or entities such as differential long non-coding RNAs, splice and polyadenylation variants, introns, repeats, editing or mutation events, and exogenous RNA. Applying DE-kupl to human RNA-seq data sets identified multiple types of novel events, reproducibly across independent RNA-seq experiments.

Herein, we report the synthesis of four new hybrid molecules between ketoprofen or 2-(3-benzoylphenyl)propanoic acid and N-containing heterocyclic compounds, such as piperidine, pyrrolidine, 1,2,3,4-tetrahydroquinoline, and 1,2,3,4-tetrahydroisoquinoline. The obtained hybrid compounds were fully characterized using 1H- and 13C-NMR, UV-Vis, and HRMS spectra. Detailed HRMS analysis is provided for all novel hybrid molecules. The compounds were assessed for their in vitro anti-inflammatory and antioxidant activity. The lipophilicity of the hybrids was determined, both theoretically (cLogP) and experimentally (RM). The affinity of the compounds to the human serum albumin was assessed in silico by molecular docking study using two software, and the stability of the predicted complexes was evaluated by molecular dynamics study. All novel hybrids have shown very good HPSA activity, statistically close when compared to the reference—quercetin. The molecular docking confirmed the obtained in vitro results. Tetrahydroquinoline derivative 3c and tetrahydroisoquinoline derivative 3d have the highest affinity for albumin. They show stronger anti-inflammatory action than their predecessor, ketoprofen and the regularly used ibuprofen. [ABSTRACT FROM AUTHOR]

Copyright of Farmacia is the property of Societatea de Stiinte Farmaceutice Romania and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The development of hybrid molecules with significant human therapeutic properties is one of the main approaches of pharmaceutical research. One of the most important pharmacophores is the quinazolin-4(3H)-one heterocycle moiety, due to its wide range of biological activities. By its derivatization with polyphenolic compounds, in our previous research, it proved to possess a good antiradical activity of ortho-diphenolic derivatives of quinazolin-4(3H)-one. In this study, we developed two new series of compounds, with an additional phenolic group or with a methyl group on the thioacetohydrazone fragment. The methods used to evaluate the activity of the compounds were radical scavenging, reduction of oxidizing reagents and transition metals' ions chelation assays. Quantum descriptors were also calculated in order to evaluate the influence of substituents and their position on the activity of the compounds. The cytotoxic activity was evaluated using normal human foreskin fibroblast cells (BJ) and two cancerous cell lines, lung adenocarcinoma cells (A549) and prostate carcinoma cells (LNCaP). The results obtained for the pyrogallol derivatives showed a high antioxidant activity compared to ascorbic acid and Trolox. All the synthesized compounds displayed a higher cytotoxicity against the cancerous cell types and a high cytocompatibility with the normal cells. The antioxidant activity was deeply influenced by the addition of the third phenolic group in the synthesized molecules. [ABSTRACT FROM AUTHOR]