DIMP53-1:A novel small-molecule dual inhibitor of p53-MDM2/X interactions with multifunctional p53-dependent anticancer properties

The transcription factor p53 plays a crucial role in cancer development and dissemination, and thus, p53-targeted therapies are among the most encouraging anticancer strategies. In human cancers with wild-type (wt) p53, its inactivation by interaction with murine double minute (MDM)2 and MDMX is a common event. Simultaneous inhibition of the p53 interaction with both MDMs is crucial to restore the tumor suppressor activity of p53. Here, we describe the synthesis of the new tryptophanol-derived oxazoloisoindolinone DIMP53-1 and identify its activity as a dual inhibitor of the p53-MDM2/X interactions using a yeast-based assay. DIMP53-1 caused growth inhibition, mediated by p53 stabilization and upregulation of p53 transcriptional targets involved in cell cycle arrest and apoptosis, in wt p53-expressing tumor cells, including MDM2- or MDMX-overexpressing cells. Importantly, DIMP53-1 inhibits the p53-MDM2/X interactions by potentially binding to p53, in human colon adenocarcinoma HCT116 cells. DIMP53-1 also inhibited the migration and invasion of HCT116 cells, and the migration and tube formation of HMVEC-D endothelial cells. Notably, in human tumor xenograft mice models, DIMP53-1 showed a p53-dependent antitumor activity through induction of apoptosis and inhibition of proliferation and angiogenesis. Finally, no genotoxicity or undesirable toxic effects were observed with DIMP53-1. In conclusion, DIMP53-1 is a novel p53 activator, which potentially binds to p53 inhibiting its interaction with MDM2 and MDMX. Although target-directed, DIMP53-1 has a multifunctional activity, targeting major hallmarks of cancer through its antiproliferative, proapoptotic, antiangiogenic, anti-invasive, and antimigratory properties. DIMP53-1 is a promising anticancer drug candidate and an encouraging starting point to develop improved derivatives for clinical application

Effects of gamma radiation on chemical and antioxidant properties, anti-hepatocellular carcinoma activity and hepatotoxicity of borututu

Borututu is a well-known medicinal plant in Angola for the treatment of liver diseases and for the prophylaxis of malaria. Our research group reported, in a recent study, that its infusion, pills and syrups display significant antioxidant and anti-hepatocellular carcinoma activities. However, during the processing and storage, it can be easily exposed to contamination that can lead to a microbial deterioration or insect infestation compromising its quality, shelf life, and efficiency. Herein, we investigated the effect of gamma irradiation, one of the most promising decontamination methods for many foodstuffs and plant materials, at different doses (1 and 10 kGy) on borututu regarding its nutritional value, lipophilic (fatty acids and tocopherols) and hydrophilic (free sugars and organic acids) compounds, antioxidant and anti-hepatocellular carcinoma activities. In general, the irradiation treatment did not appreciably affect the nutritional value of the studied plant, but the highest energetic contribution (383.83 kcal/100 g), total sugars (8.63 g/100 g), organic acids (3.31 g/100 g dw), total tocopherols (336.72 mg/100 g dw), and PUFA (32.75%) contents were found in the sample irradiated at 10 kGy. Furthermore, this sample presented also the highest levels of total phenolics and flavonoids and, in general, the highest antioxidant activity (EC50 values of 0.04 to 0.24 mg/mL for the methanolic extract and 0.03 to 1.34 mg/mL for the infusion). Irradiated samples kept the anti-hepatocellular carcinoma activity, but a decrease was observed in the methanolic extract prepared from sample irradiated at 10 kGy (GI50 = 188.97 μg/mL). Overall, gamma irradiation proved to be a suitable technique of preservation of dried herbs without affecting the bioactive compounds

Recent results in relativistic heavy ion collisions: from ``a new state of matter'' to "the perfect fluid"

Experimental Physics with Relativistic Heavy Ions dates from 1992 when a beam of 197Au of energy greater than 10A GeV/c first became available at the Alternating Gradient Synchrotron (AGS) at Brookhaven National Laboratory (BNL) soon followed in 1994 by a 208Pb beam of 158A GeV/c at the Super Proton Synchrotron (SPS) at CERN (European Center for Nuclear Research). Previous pioneering measurements at the Berkeley Bevalac in the late 1970's and early 1980's were at much lower bombarding energies (~ 1 A GeV/c) where nuclear breakup rather than particle production is the dominant inelastic process in A+A collisions. More recently, starting in 2000, the Relativistic Heavy Ion Collider (RHIC) at BNL has produced head-on collisions of two 100A GeV beams of fully stripped Au ions, corresponding to nucleon-nucleon center-of-mass energy, sqrt(sNN)=200 GeV, total c.m. energy 200A GeV. The objective of this research program is to produce nuclear matter with extreme density and temperature, possibly resulting in a state of matter where the quarks and gluons normally confined inside individual nucleons (r < 1 fm) are free to act over distances an order of magnitude larger. Progress from the period 1992 to the present will be reviewed, with reference to previous results from light ion and proton-proton collisions where appropriate. Emphasis will be placed on the measurements which formed the basis for the announcements by the two major laboratories: "A new state of matter", by CERN on Feb 10, 2000 and "The perfect fluid", by BNL on April 19, 2005.Comment: 62 pages, 39 figures. Review article published in Reports on Progress in Physics on June 23, 2006. In this published version, mistakes, typographical errors, and citations have been corrected and a subsection has been adde

Characterization of a genomic signature of pregnancy identified in the breast.

The objective of this study was to comprehensively compare the genomic profiles in the breast of parous and nulliparous postmenopausal women to identify genes that permanently change their expression following pregnancy. The study was designed as a two-phase approach. In the discovery phase, we compared breast genomic profiles of 37 parous with 18 nulliparous postmenopausal women. In the validation phase, confirmation of the genomic patterns observed in the discovery phase was sought in an independent set of 30 parous and 22 nulliparous postmenopausal women. RNA was hybridized to Affymetrix HG_U133 Plus 2.0 oligonucleotide arrays containing probes to 54,675 transcripts, scanned and the images analyzed using Affymetrix GCOS software. Surrogate variable analysis, logistic regression, and significance analysis of microarrays were used to identify statistically significant differences in expression of genes. The false discovery rate (FDR) approach was used to control for multiple comparisons. We found that 208 genes (305 probe sets) were differentially expressed between parous and nulliparous women in both discovery and validation phases of the study at an FDR of 10% and with at least a 1.25-fold change. These genes are involved in regulation of transcription, centrosome organization, RNA splicing, cell-cycle control, adhesion, and differentiation. The results provide initial evidence that full-term pregnancy induces long-term genomic changes in the breast. The genomic signature of pregnancy could be used as an intermediate marker to assess potential chemopreventive interventions with hormones mimicking the effects of pregnancy for prevention of breast cancer

Characterization of a genomic signature of pregnancy identified in the breast.

The objective of this study was to comprehensively compare the genomic profiles in the breast of parous and nulliparous postmenopausal women to identify genes that permanently change their expression following pregnancy. The study was designed as a two-phase approach. In the discovery phase, we compared breast genomic profiles of 37 parous with 18 nulliparous postmenopausal women. In the validation phase, confirmation of the genomic patterns observed in the discovery phase was sought in an independent set of 30 parous and 22 nulliparous postmenopausal women. RNA was hybridized to Affymetrix HG_U133 Plus 2.0 oligonucleotide arrays containing probes to 54,675 transcripts, scanned and the images analyzed using Affymetrix GCOS software. Surrogate variable analysis, logistic regression, and significance analysis of microarrays were used to identify statistically significant differences in expression of genes. The false discovery rate (FDR) approach was used to control for multiple comparisons. We found that 208 genes (305 probe sets) were differentially expressed between parous and nulliparous women in both discovery and validation phases of the study at an FDR of 10% and with at least a 1.25-fold change. These genes are involved in regulation of transcription, centrosome organization, RNA splicing, cell-cycle control, adhesion, and differentiation. The results provide initial evidence that full-term pregnancy induces long-term genomic changes in the breast. The genomic signature of pregnancy could be used as an intermediate marker to assess potential chemopreventive interventions with hormones mimicking the effects of pregnancy for prevention of breast cancer

A sustainable multi-function biomorphic material for pollution remediation or UV absorption: aerosol assisted preparation of highly porous ZnO-based materials from cork templates

For the first time, highly porous ZnO-based biomorphic materials were synthesised using cork as a natural sustainable template. In the first step, waste cork powder was pyrolysed and converted into inorganic carbon. This template was then infiltrated using a novel approach employing an aerosol of zinc-containing solutions. The infiltrated powders were calcined to convert the precursors into zinc oxide. Depending on temperature, these could form either a ZnO-graphite composite material, or pure ZnO. Their morphology, porosity, microstructure and composition were characterised; their optical band gap energies, ability to adsorb and photodegrade organic pollutants and UV absorption were also assessed. When heated to 350 °C they maintained the 3D porous cork structure, producing a graphite-containing composite material, with both physical adsorption and photocatalytic activity (Eg = 3.19 eV), suitable for environmental remediation. When heated to 700 °C, the powders were pure ZnO (no graphite), and they absorbed in the UV region, hence suitable for use as sunscreen. Doped ZnO ecoceramics were also produced, using silver and aluminium. An addition of 1 mol% Ag improved photocatalysis under solar light. Conversely, adding 2 mol% Al and calcining at 700 °C deactivated photocatalysis, but maintained strong UV absorption, producing a safer sunscreen material (no generation of free radicals). This is the first time that photocatalytic or UV absorption properties of any wood-derived biomorphic material or ecoceramic have been reported.This work wasfinancially supported by the projects HApECOrk,funded by "Fondazione Con il Sud”(project 2015-0243), and“FutureInResearch”APQ Ricerca Regione Puglia. This work was de-veloped within the scope of the project CICECO-Aveiro Institute ofMaterials, FCT (Fundação para a Ciência e a Tecnologia, Portugal) Ref.UID/CTM/50011/2019,financed by national funds through the FCT/MCTES. The authors wish to thank Ms. Stefania D’Amone for the helpwith SEM microscopy. R.C. Pullar thanks FCT grant IF/00681/2015 forsupporting this work, and R.M. Novais wishes to thank FCT projectH2CORK (PTDC/CTM-ENE/6762/2014). The authors also acknowledge Amorim Cork Composites for providing the cork samples.publishe

Evolution of the endomembrane systems of trypanosomatids:conservation and specialisation

Parasite surfaces support multiple functions required for survival within their hosts, and maintenance and functionality of the surface depends on membrane trafficking. To understand the evolutionary history of trypanosomatid trafficking, where multiple lifestyles and mechanisms of host interactions are known, we examined protein families central to defining intracellular compartments and mediating transport, namely Rabs, SNAREs and RabGAPs, across all available Euglenozoa genomes. Bodonids possess a large trafficking repertoire, which is mainly retained by the Trypanosoma cruzi group, with extensive losses in other lineages, particularly African trypanosomes and phytomonads. There are no large-scale expansions or contractions from an inferred ancestor, excluding direct associations between parasitism or host range. However, we observe stepwise secondary losses within Rab and SNARE cohorts (but not RabGAPs). Major changes are associated with endosomal and late exocytic pathways, consistent with the diversity in surface proteomes between trypanosomatids and mechanisms of interaction with the host. Along with the conserved core family proteins, several lineage-specific members of the Rab (but not SNARE) family were found. Significantly, testing predictions of SNARE complex composition by proteomics confirms generalised retention of function across eukaryotes

Effect of Training on the Reliability of Satiety Evaluation and Use of Trained Panellists to Determine the Satiety Effect of Dietary Fibre: A Randomised Controlled Trial

Background: The assessment of satiety effects on foods is commonly performed by untrained volunteers marking their perceived hunger or fullness on line scales, marked with pre-set descriptors. The lack of reproducibility of satiety measurement using this approach however results in the tool being unable to distinguish between foods that have small, but possibly important, differences in their satiety effects. An alternate approach is used in sensory evaluation; panellists can be trained in the correct use of the assessment line-scale and brought to consensus on the meanings of descriptors used for food quality attributes to improve the panel reliability. The effect of training on the reliability of a satiety panel has not previously been reported. Method: In a randomised controlled parallel intervention, the effect of training in the correct use of a satiety labelled magnitude scale (LMS) was assessed versus no-training. The test-retest precision and reliability of two hour postprandial satiety evaluation after consumption of a standard breakfast was compared. The trained panel then compared the satiety effect of two breakfast meals containing either a viscous or a non-viscous dietary fibre in a crossover trial.Results: A subgroup of the 23 panellists (n = 5) improved their test re-test precision after training. Panel satiety area under the curve, “after the training” intervention was significantly different to “before training” (p < 0.001). Reliability of the panel determined by intraclass correlation (ICC) of test and retest showed improved strength of the correlation from 0.70 pre-intervention to 0.95 post intervention. The trained “satiety expert panel” determined that a standard breakfast with 5g of viscous fibre gave significantly higher satiety than with 5g non-viscous fibre (area under curve (AUC) of 478.2, 334.4 respectively) (p ≤ 0.002). Conclusion: Training reduced between panellist variability. The improved strength of test-retest ICC as a result of the training intervention suggests that training satiety panellists can improve the discriminating power of satiety evaluation