Triterpenoids are used for medicinal purposes in many countries. Some, such as oleanolic and glycyrrhetinic acids, are known to be anti‐inflammatory and anticarcinogenic. However, the biological ...activities of these naturally occurring molecules against their particular targets are weak, so the synthesis of new synthetic analogues with enhanced potency is needed. By combining modifications to both the A and C rings of 18βH‐glycyrrhetinic acid, the novel synthetic derivative methyl 2‐cyano‐3,12‐dioxo‐18βH‐olean‐9(11),1(2)‐dien‐30‐oate was obtained. This derivative displays high antiproliferative activity in cancer cells, including a cell line with a multidrug‐resistance phenotype. It causes cell death by inducing the intrinsic caspase‐dependent apoptotic pathway.
A new killer of cancer: Glycyrrhetinic acid derivatives were screened for their potential as inducers of human cancer cell death. Compound 1 displayed potent single‐agent activity at micromolar concentrations, and induced death in various human cancer cells. Further analysis indicated that cell death was caused by the intrinsic caspase‐dependent apoptosis pathway.
Tumour development is characterised by the increased circulating DNA (cirDNA) concentration and by tumour-related changes in blood plasma DNA. Concentration of cirDNA and methylation of RARbeta2, ...RASSF1A and HIC-1 gene promoters were investigated in cell-free and cell-surface-bound fractions from healthy donors, patients with breast cancer, and patients with breast fibroadenoma. Tumour development was shown to lead to significant changes in the distribution of cirDNA between cell-free and cell-surface-bound fractions. Analysis of RARbeta2 and RASSF1A methylation in the total cirDNA provides 95% diagnostic coverage in breast cancer patients, 60% in patients with benign lesions, and is without false-positive results in healthy women. Results of the study indicate that methylation-specific PCR of RARbeta2 and RASSF1A genes based on the total cirDNA combined with the quantitative analysis of cirDNA distribution between cell-bound and cell-free fractions in blood provide the sensitive and accurate detection and discrimination of malignant and benign breast tumours.
Exosomes represent a sort of extracellular vesicles, which transfer molecular signals in the body and contain markers of the exosome-producing cell. This study was aimed at search of exosomes in the ...tears of healthy humans, validation of their nature and examination of their morphological and molecular-biological characteristics. Samples of the tears individually collected from 24 healthy donors (aged 45–60 years) were centrifuged at 20000 g for 15 min to pellet cell debris. The supernatants were examined in an electron microscope using negative staining and were also used for isolation and purification of exosomes by filtration (100 nm pore-size) and double ultracentrifugation (90 min at 100000 g, 4°C). Resultant pellets were investigated by electron microscopy and immunolabeling, RNA and DNA were isolated and their sizes were determined by capillary electrophoresis, concentration and localization of nucleic acids in the isolated exosomes were studied. DNA sequencing was performed using MiSeq (Illumina, USA), data were analyzed using CLC GW 7.5 (Qiagen, USA). Sequences were mapped on human genome (hg19). Supernatants of the tears contained cell debris, spherical microparticles (20–40 nm), and vesicles; some of the vesicles had morphology and sizes corresponding to exosomes. The pellets obtained after ultracentrifugation of tears contained microparticles (17%), spherical and cup-shaped vesicles (40–100 nm, 83%), which were positive for CD63, CD9, and CD24 receptors (specific markers of exosomes). The study revealed high concentrations of exosomes in human tears; these exosomes contained both RNA (of less than 200 nucleotides in size) and DNA (of 3–9 kb in size). DNA sequencing demonstrated that about 92% of the reads was mapped to human genome.
A vexing difficulty of the RNA world hypothesis is how RNA molecules of significant complexity could ever have evolved given their susceptibility to degradation. One way degradation might have been ...reduced is through low temperature. Here we report that truncated and fragmented derivatives of the hairpin ribozyme can catalyze ligation of a wide variety of RNA molecules to a given sequence in frozen solution despite having little or no activity under standard solution conditions. These results suggest that complex RNAs could have evolved in freezing environments on the early earth and perhaps elsewhere.
The beam-spin asymmetries in the hard exclusive electroproduction of photons on the proton (e p-->epgamma) were measured over a wide kinematic range and with high statistical accuracy. These ...asymmetries result from the interference of the Bethe-Heitler process and of deeply virtual Compton scattering. Over the whole kinematic range (x(B) from 0.11 to 0.58, Q2 from 1 to 4.8 GeV2, -t from 0.09 to 1.8 GeV2), the azimuthal dependence of the asymmetries is compatible with expectations from leading-twist dominance, A approximately a sinphi/(1+c cosphi). This extensive set of data can thus be used to constrain significantly the generalized parton distributions of the nucleon in the valence quark sector.
Multiple sclerosis (MS) is a severe neurodegenerative disease of polygenic etiology affecting the central nervous system. In addition to genetic factors, epigenetic mechanisms, primarily DNA ...methylation, which regulate gene expression, play an important role in MS development and progression. In this study, we have performed the first whole-genome DNA methylation profiling of peripheral blood mononuclear cells in relapsing-remitting MS (RRMS) and primary-progressive MS (PPMS) patients and compared them to those of healthy individuals in order to identify the differentially methylated CpG-sites (DMSs) associated with these common clinical disease courses. In addition, we have performed a pairwise comparison of DNA methylation profiles in RRMS and PPMS patients. All three pairwise comparisons showed significant differences in methylation profiles. Hierarchical clustering of the identified DMS methylation levels and principal component analysis for data visualization demonstrated a clearly defined aggregation of DNA samples of the compared groups into separate clusters. Compared with the control, more DMSs were identified in PPMS patients than in RRMS patients (67 and 30, respectively). More than half of DMSs are located in genes, exceeding the expected number for random distribution of DMSs between probes. RRMS patients mostly have hypomethylated DMSs, while in PPMS patients DMSs are mostly hypermethylated. CpG-islands and CpG-shores contain 60% of DMSs, identified by pairwise comparison of RRMS and control groups, and 79% of those identified by pairwise comparison of PPMS and control groups. Pairwise comparison of patients with two clinical MS courses revealed 51 DMSs, 82% of which are hypermethylated in PPMS. Overall, it was demonstrated that there are more changes in the DNA methylation profiles in PPMS than in RRMS. The data confirm the role of DNA methylation in MS development. We have shown, for the first time, that DNA methylation as an epigenetic mechanism is involved in the formation of two distinct clinical courses of MS: namely, RRMS and PPMS.
Background. Extracellular vesicles (EVs) play an essential role in the communication between cells and transport of diagnostically significant molecules. A wide diversity of approaches utilizing ...different biochemical properties of EVs and a lack of accepted protocols make data interpretation very challenging. Scope of Review. This review consolidates the data on the classical and state-of-the-art methods for isolation of EVs, including exosomes, highlighting the advantages and disadvantages of each method. Various characteristics of individual methods, including isolation efficiency, EV yield, properties of isolated EVs, and labor consumption are compared. Major Conclusions. A mixed population of vesicles is obtained in most studies of EVs for all used isolation methods. The properties of an analyzed sample should be taken into account when planning an experiment aimed at studying and using these vesicles. The problem of adequate EVs isolation methods still remains; it might not be possible to develop a universal EV isolation method but the available protocols can be used towards solving particular types of problems. General Significance. With the wide use of EVs for diagnosis and therapy of various diseases the evaluation of existing methods for EV isolation is one of the key problems in modern biology and medicine.
In an exclusive measurement of the reaction gammad-->K(+)K(-)pn, a narrow peak that can be attributed to an exotic baryon with strangeness S=+1 is seen in the K(+)n invariant mass spectrum. The peak ...is at 1.542+/-0.005 GeV/c(2) with a measured width of 0.021 GeV/c(2) FWHM, which is largely determined by experimental mass resolution. The statistical significance of the peak is (5.2+/-0.6)sigma. The mass and width of the observed peak are consistent with recent reports of a narrow S=+1 baryon by other experimental groups.
The atomic nucleus is composed of two different kinds of fermions: protons and neutrons. If the protons and neutrons did not interact, the Pauli exclusion principle would force the majority of ...fermions (usually neutrons) to have a higher average momentum. Our high-energy electron-scattering measurements using 12C, 27Al, 56Fe, and 208Pb targets show that even in heavy, neutron-rich nuclei, short-range interactions between the fermions form correlated high-momentum neutron-proton pairs. Thus, in neutron-rich nuclei, protons have a greater probability than neutrons to have momentum greater than the Fermi momentum. This finding has implications ranging from nuclear few-body systems to neutron stars and may also be observable experimentally in two-spin–state, ultracold atomic gas systems.
In this study, we measured the ratios of electroproduction cross sections from a proton target for three exclusive meson-baryon final states: ΛK+, pπ0, and nπ+, with the CLAS detector at Jefferson ...Lab. Using a simple model of quark hadronization, we extract qq¯ creation probabilities for the first time in exclusive two-body production, in which only a single qq¯ pair is created. We observe a sizable suppression of strange quark-antiquark pairs compared to nonstrange pairs, similar to that seen in high-energy production.
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