• MeSH
• Aspirin therapeutic use   MeSH
• Heparin, Low-Molecular-Weight administration & dosage   therapeutic use   MeSH
• Platelet Aggregation Inhibitors therapeutic use   MeSH
• Humans MeSH
• Multiple Myeloma * complications   MeSH
• Antineoplastic Agents adverse effects   therapeutic use   MeSH
• Thromboembolism * etiology   chemically induced   prevention & control   MeSH
• Warfarin therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Practice Guideline MeSH

Aging is an unavoidable process characterized by gradual failure of homeostasis that constitutes a critical risk factor for several age-related disorders. It has been unveiled that manipulation of various key pathways may decelerate the aging progression and the triggering of age-related diseases. As a consequence, the identification of compounds, preferably natural-occurring, administered through diet, with lifespan-extending, anti-aggregation and anti-oxidation properties that in parallel exhibit negligible side-effects is the main goal in the battle against aging. Here we analyze the role of 2,3-dehydrosilybin A/B (DHS A/B), a minor component of silymarin used in a plethora of dietary supplements. This flavonolignan is well-known for its anti-oxidative and neuroprotective properties, among others. We demonstrate that DHS A/B confers oxidative stress resistance not only in human primary cells but also in the context of a multi-cellular aging model, namely Caenorhabditis elegans (C. elegans) where it also promotes lifespan extension. We reveal that these DHS A/B outcomes are FGT-1 and DAF-16 dependent. We additionally demonstrate the anti-aggregation properties of DHS A/B in human cells of nervous origin but also in nematode models of Alzheimer's disease (AD), eventually leading to decelerated progression of AD phenotype. Our results identify DHS A/B as the active component of silymarin extract and propose DHS A/B as a candidate anti-aging and anti-aggregation compound.

• MeSH
• Cell Line MeSH
• Caenorhabditis elegans MeSH
• CHO Cells MeSH
• Cricetulus MeSH
• Longevity drug effects   MeSH
• Cricetinae MeSH
• Humans MeSH
• Protective Agents pharmacology   MeSH
• Oxidative Stress MeSH
• Protein Aggregation, Pathological prevention & control   MeSH
• Drug Evaluation, Preclinical MeSH
• Caenorhabditis elegans Proteins metabolism   MeSH
• Glucose Transport Proteins, Facilitative metabolism   MeSH
• Silymarin pharmacology   MeSH
• Cell Survival drug effects   MeSH
• Animals MeSH
• Check Tag
• Cricetinae MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

• MeSH
• Clinical Medicine MeSH
• Statistics as Topic MeSH
• Publication type
• Abstracts MeSH
• Conference Proceedings MeSH
• Collected Work MeSH
• News MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• statistika, zdravotnická statistika
• lékařství

• MeSH
• Nuclear Medicine MeSH
• Publication type
• Periodical MeSH
• Ephemera MeSH

• Conspectus
• Lékařské vědy. Lékařství
• NML Fields
• radiologie, nukleární medicína a zobrazovací metody

• MeSH
• Cell Aggregation MeSH
• Leukemia complications   pathology   MeSH
• Leukocytes physiology   pathology   MeSH
• Lymphadenitis MeSH
• Lung physiopathology   pathology   MeSH
• Vascular Patency MeSH
• Thrombosis MeSH
• Publication type
• Review MeSH

• MeSH
• Molecular Biology MeSH
• Spectrum Analysis MeSH
• Publication type
• Abstracts MeSH

• Conspectus
• Biochemie. Molekulární biologie. Biofyzika
• NML Fields
• biologie
• radiologie, nukleární medicína a zobrazovací metody

Cultures of three-dimensional aggregates of embryonic stem cells (ESCs) called embryoid bodies (EBs) provide a valuable system for analyzing molecular mechanisms that regulate differentiation of this unique cell type. Cyclin-dependent kinase inhibitor p27Kip1 (p27) becomes elevated during the differentiation of mouse ESCs (mESCs). In this study, various aspects of differentiation of EBs produced from normal and p27-deficient mESCs were analyzed to address the biological significance of this elevation. It was found that EBs lacking p27 grew significantly bigger, but this was not accompanied by detect-able abnormalities in the activities of cyclin-dependent kinases (CDKs). In most EB cells, downregulation of activating cyclins rather than upregulation of inhibiting p27 is probably responsible for lowering the activity of their CDKs. Abnormalities in the development of specific cell lineages were also observed in p27-deficient EBs. These included elimination of cells positive for cytokeratin endo-A (TROMA-I) and increased proliferation and formation of cavities originating from cells positive for Lewis-X. Our data also suggest that although two different pools of Lewis-X-expressing cells, cluster forming (ESC-like) and cavity forming (neural progenitors), normally exist in EBs, the absence of p27 leads to the enhancement of only the neural pool. No failure was found when the neurogenic capacity of p27-deficient mESCs was tested using various protein markers. Together, our data point to a dual role of p27 in mESCs, with one role being in the regulation of proliferation and the other role in establishing some other aspects of a differentiated phenotype.

• MeSH
• Lewis X Antigen metabolism   MeSH
• Cell Differentiation MeSH
• Cell Cycle MeSH
• Time Factors MeSH
• Down-Regulation MeSH
• Embryo, Mammalian physiology   MeSH
• Phenotype MeSH
• Financing, Organized MeSH
• Microscopy, Fluorescence MeSH
• Immunohistochemistry MeSH
• Immunoprecipitation MeSH
• Cyclin-Dependent Kinase Inhibitor p27 MeSH
• Stem Cells metabolism   MeSH
• Mice MeSH
• Tumor Suppressor Proteins physiology   genetics   MeSH
• Neurons metabolism   MeSH
• Cell Proliferation MeSH
• Cell Cycle Proteins physiology   genetics   MeSH
• Flow Cytometry MeSH
• Up-Regulation MeSH
• Cell Survival MeSH
• Blotting, Western MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH

The potential for gene exchange across ploidy levels has long been recognized, but only a few studies have explored the rate of gene flow among different cytotypes. In addition, most of the existing knowledge comes from contact zones between diploids and tetraploids. The purpose of this paper was to investigate relationships between diploid and hexaploid individuals within the Aster amellus aggregate. A. amellus is known to occur in diploid and hexaploid cytotypes in Europe, with a complex contact zone in central Europe. Patterns of genetic diversity were investigated using seven microsatellite loci at three different spatial scales: (1) in the single known mixed-ploidy population; (2) in populations at the contact zone and (3) in a wider range of populations across Europe. The results show clear separation of the cytotypes at all three spatial scales. In addition, analysis of molecular variance strongly supported a model predicting a single origin of the hexaploids, with no or very limited gene flow between the cytotypes. Some hexaploid individuals found in the mixed-ploidy population, however, fell into the diploid cluster. This could suggest recurrent polyploid formation or occasional cross-pollination between cytotypes; however, there are strong post-zygotic breeding barriers between the two cytotypes, making the latter less plausible. Overall, the results suggest that the cytotypes could represent two cryptic species. Nevertheless, their formal separation is difficult as they cannot be distinguished morphologically, occupy very similar habitat conditions and have largely overlapping distribution ranges. These results show that polyploid complexes must be treated with caution as they can hide biological diversity and can have different adaptation potentials, evolving independently.

• MeSH
• Principal Component Analysis MeSH
• Aster Plant genetics   MeSH
• Bayes Theorem MeSH
• Diploidy * MeSH
• Phylogeography MeSH
• Genetic Variation MeSH
• Microsatellite Repeats MeSH
• Models, Genetic MeSH
• Polyploidy * MeSH
• Genes, Plant MeSH
• Gene Flow * MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Europe MeSH

• MeSH
• Medicine MeSH
• Publication type
• Periodical MeSH

• Conspectus
• Lékařské vědy. Lékařství
• NML Fields
• lékařství

Drug repurposing is a versatile strategy to improve current therapies. Disulfiram has long been used in the treatment of alcohol dependency and multiple clinical trials to evaluate its clinical value in oncology are ongoing. We have recently reported that the disulfiram metabolite diethyldithiocarbamate, when combined with copper (CuET), targets the NPL4 adapter of the p97VCP segregase to suppress the growth of a spectrum of cancer cell lines and xenograft models in vivo. CuET induces proteotoxic stress and genotoxic effects, however important issues concerning the full range of the CuET-evoked tumor cell phenotypes, their temporal order, and mechanistic basis have remained largely unexplored. Here, we have addressed these outstanding questions and show that in diverse human cancer cell models, CuET causes a very early translational arrest through the integrated stress response (ISR), later followed by features of nucleolar stress. Furthermore, we report that CuET entraps p53 in NPL4-rich aggregates leading to elevated p53 protein and its functional inhibition, consistent with the possibility of CuET-triggered cell death being p53-independent. Our transcriptomics profiling revealed activation of pro-survival adaptive pathways of ribosomal biogenesis (RiBi) and autophagy upon prolonged exposure to CuET, indicating potential feedback responses to CuET treatment. The latter concept was validated here by simultaneous pharmacological inhibition of RiBi and/or autophagy that further enhanced CuET's tumor cytotoxicity, using both cell culture and zebrafish in vivo preclinical models. Overall, these findings expand the mechanistic repertoire of CuET's anti-cancer activity, inform about the temporal order of responses and identify an unorthodox new mechanism of targeting p53. Our results are discussed in light of cancer-associated endogenous stresses as exploitable tumor vulnerabilities and may inspire future clinical applications of CuET in oncology, including combinatorial treatments and focus on potential advantages of using certain validated drug metabolites, rather than old, approved drugs with their, often complex, metabolic profiles.

• MeSH
• Zebrafish metabolism   MeSH
• Disulfiram * metabolism   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• Neoplasms * metabolism   MeSH
• Ribosomes metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH