Anti-Cancer Effects of Carnosine—A Dipeptide Molecule

Background: Carnosine is a dipeptide molecule (β-alanyl-l-histidine) with anti-inflammatory, antioxidant, anti-glycation, and chelating properties. It is used in exercise physiology as a food supplement to increase performance; however, in vitro evidence suggests that carnosine may exhibit anti-cancer properties. Methods: In this study, we investigated the effect of carnosine on breast, ovarian, colon, and leukemic cancer cell proliferation. We further examined U937 promonocytic, human myeloid leukemia cell phenotype, gene expression, and cytokine secretion to determine if these are linked to carnosine’s anti-proliferative properties. Results: Carnosine (1) inhibits breast, ovarian, colon, and leukemic cancer cell proliferation; (2) upregulates expression of pro-inflammatory molecules; (3) modulates cytokine secretion; and (4) alters U937 differentiation and phenotype. Conclusion: These effects may have implications for a role for carnosine in anti-cancer therapy.     

Improvement of source and wind field input of atmospheric dispersion model by assimilation of concentration measurements: Method and applications in idealized settings

The problem of correcting the pollutant source emission rate and the wind velocity field inputs in a puff atmospheric dispersion model by data assimilation of concentration measurements has been considered. Variational approach to data assimilation has been used, in which the specified cost function is minimized with respect to source strength and/or wind field. The analyzed wind field satisfied the constraints derived from the conditions of mass conservation and linearized flow equations for perturbations from the first guess wind field. ‘Identical twin’ numerical experiments have been performed for the validation of the method. The first guess estimation errors of source emission rate and wind field were set to a factor of up to 10 and up to 6 m/s respectively. The calculations results showed that in most studied cases an improvement of vector wind difference (VWD) error by about 0.7–1 m/s could be achieved. The resulting normalized mean square error (NMSE) of concentration field was also reduced significantly.     

An EEG study of brain connectivity dynamics at the resting state

We investigated the dynamical behavior of resting state functional connectivity using EEG signals. Employing a recently introduced methodology that considers the time variations of phase coupling among signals from different channels, a sequence of functional connectivity graphs (FCGs) was constructed for different frequency bands and analyzed based on graph theoretic tools. In the first stage of analysis, hubs were detected in the FCGs based on local and global efficiency. The probability of each node to be identified as a hub was estimated. This defined a topographic function that showed widespread distribution with prominence over the frontal brain regions for both local and global efficiency. Hubs consistent across time were identified via a summarization technique and found to locate over forehead. In the second stage of analysis, the modular structure of each single FCG was delineated. The derived time-dependent signatures of functional structure were compared in a systematic way revealing fluctuations modulated by frequency. Interestingly, the evolution of functional connectivity can be described via abrupt transitions between states, best described as short-lasting bimodal functional segregations. Based on a distance function that compares clusterings, we discovered that these segregations are recurrent. Entropic measures further revealed that the apparent fluctuations are subject to intrinsic constraints and that order emerges from spatially extended interactions.     

Selection and characterization of DNA aptamers against the steroid testosterone

Anabolic androgenic steroids (AAS) are frequently abused in human and animal sports as performance-enhancing drugs, and consequently their use is controlled by international sports authorities. Testosterone is one of the most frequently used AAS, and therefore the accurate determination of its levels in biological fluids is very important. The authors describe the selection of testosterone-binding aptamers performed using a classic SELEX approach with the target immobilized on magnetic beads. Counter selections with structurally similar steroids were implemented at different stages. Pools from different selection rounds were sequenced with Next Generation Sequencing and ten aptamer candidates were selected for further characterization. Low nanomolar range dissociation constants were calculated by a bead-based PCR assay and verified by microscale thermophoresis. Future work will focus on the development of aptamer-based platforms for the sensitive detection of testosterone in biological samples and the validation of these assays for the rapid screening of suspicious samples.

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Graphical abstract The selection of testosterone-binding aptamers is described via classic SELEX using the target immobilized on magnetic beads combined with Next Generation Sequencing. The process let to the identification of several unique aptamer candidates which were characterized and their binding to testosterone was evaluated.

     

Conformational studies of immunodominant myelin basic protein 1�C11 analogues using NMR and molecular modeling

Τwo dimensional nuclear magnetic resonance studies complimented by molecular dynamics simulations were conducted to investigate the conformation of the immunodominant epitope of acetylated myelin basic protein residues 1-11 (Ac-MBP(1-11)) and its altered peptide ligands, mutated at position 4 to an alanine (Ac-MBP(1-11)[4A]) or a tyrosine residue (Ac-MBP(1-11)[4Y]). Conformational analysis of the three analogues indicated that they adopt an extended conformation in DMSO solution as no long distance NOE connectivities were observed and seem to have a similar conformation when bound to the active site of the major histocompatibility complex (MHC II). The interaction of each peptide with MHC class II I-A(u) was further investigated in order to explore the molecular mechanism of experimental autoimmune encephalomyelitis induction/inhibition in mice. The present findings indicate that the Gln(3) residue, which serves as a T-cell receptor (TCR) contact site in the TCR/peptide/I-A(u) complex, has a different orientation in the mutated analogues especially in the Ac-MBP(1-11)[4A] peptide. In particular the side chain of Gln(3) is not solvent exposed as for the native Ac-MBP(1-11) and it is not available for interaction with the TCR.     

Sturmian maximizing measures for the piecewise-linear cosine family

Let T be the angle-doubling map on the circle $\mathbb{T}$ , and consider the 1-parameter family of piecewise-linear cosine functions $f_\theta :\mathbb{T} \to \mathbb{R}$ , defined by $f_\theta (x) = 1 - 4d_\mathbb{T} (x,\theta )$ . We identify the maximizing T-invariant measures for this family: for each ?? the f _?? -maximizing measure is unique and Sturmian (i.e. with support contained in some closed semi-circle). For rational p/q, we give an explicit formula for the set of functions in the family whose maximizing measure is the Sturmian measure of rotation number p/q. This allows us to analyse the variation with ?? of the maximum ergodic average for f _?? .     

Inclusion compounds of plant growth regulators in cyclodextrins, part VII: study of the crystal structures of 2-naphthylacetic acid encapsulated in β-cyclodextrin and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin complexes by X-ray crystallography

The crystal structures of the β-naphthylacetic acid (2NAA)/β-cyclodextrin (β-CD) and the 2NAA/heptakis(2,3,6-tri-O-methyl)-β-CD (TMβCD) complexes are reported. The 2NAA/β-CD complex crystallizes in the triclinic system forming a dimer inside the cavity of which two 2NAA molecules disordered over two sites are located. The dimers are stacked along the c axis according to the channel packing mode forming a nanotube which resembles a wireway as it contains guest molecules linked by π–π interactions inside each dimeric cavity and by H-bonds between the adjacent dimers. The 2NAA/TMβCD complex crystallizes in the orthorhombic space group P2₁2₁2₁. Its asymmetric unit contains one host, one guest distributed over two sites and one water molecule having a low occupancy factor. The complexes are packed in a head-to-tail mode forming a screw channel along the b axis. The carboxyl group of the guest protrudes towards the “free” space between the complexes and is H-bonded to the water molecule which in turn is H-bonded to the O5n atom of the host of the subsequent complex. The orientation of the guest molecule in the 2NAA/β-CD complex has been found opposite to that of the guest in the 2NAA/TMβCD complex probably due to the formation of dimers and the π–π interactions between the naphthalene moieties of the encapsulated molecules inside the dimeric cavity.     

A Global Review on Short Peptides: Frontiers and Perspectives

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. Peptide “drugs” initially played only the role of hormone analogs to balance disorders. Nowadays, they achieve numerous biomedical tasks, can cross membranes, or reach intracellular targets. The role of peptides in bio-processes can hardly be mimicked by other chemical substances. The article is divided into independent sections, which are related to either the progress in short peptide-based theranostics or the problems posing challenge to bio-medicine. In particular, the SWOT analysis of short peptides, their relevance in therapies of diverse diseases, improvements in (bio)synthesis platforms, advanced nano-supramolecular technologies, aptamers, altered peptide ligands and in silico methodologies to overcome peptide limitations, modern smart bio-functional materials, vaccines, and drug/gene-targeted delivery systems are discussed.     

HPTLC‐MALDI MS for (glyco)sphingolipid multiplexing in tissues and blood: A promising strategy for biomarker discovery and clinical applications

Sphingolipids have hydrophilic and hydrophobic properties, different saturation and combination of the oligosaccharide chains and mass homology of species located in a narrow m/z region hampering their recognition. To target sphingolipids for diagnostic purposes, standardized methods for lipid extraction, quali‐ and quantitative assessments are required. In this study, HPTLC‐MALDI MS was adopted to establish sphingolipid and glycosphingolipid profiles in muscle, brain and serum to create a database of molecules to be searched in the preclinical and clinical investigations. Specific protocols for lipid extraction were set up based on the characteristics of the tissue or/and fluids; this approach maximizes the HPTLC‐MALDI MS analytical throughput both for lipids extracted in organic and aqueous phase. This study indicates that alkaline hydrolysis is necessary for the detection of low abundant species such as Gb3Cer and ceramides in serum and Gb4Cer, CerP and HexCer in muscle tissue. The high hydrophobicity of ceramides has been overcome by the development of HPTLC plate in chloroform:methanol/50:3.5, which increases the number and the intensity of low abundant Cer species. MS/MS analysis has been conducted directly on HPTLC plate allowing the molecular recognition; furthermore a dataset of spectra was acquired to create a database for future profiling of these molecules.     

Setup for human sera MALDI profiling: the case of rhEPO treatment

The implementation of high-throughput technologies based on qualitative and quantitative methodologies for the characterization of complex protein mixtures is increasingly required in clinical laboratories. MALDI profiling is a robust and sensitive technology although the serum high dynamic range imposes a major limitation hampering the identification of less abundant species decreasing the quality of MALDI profiling. A setup to improve these parameters has been performed for recombinant human erythropoietin (rhEPO) monitoring in serum, analyzing the effects of two commercially available columns (MARS Hu7 and Hu14) for immunodepletion, and two matrices (α-cyano-4-hydroxycinnamic acid and 2',4'-dihydroxyacetophenone) for peak quality improvement. The immunodepletion capability of both columns was determined by 2-D DIGE, which precisely revealed the efficacy of Hu14 in protein removal and the serum dynamic range decrement. In addition, the type of matrix, the sample dilution, and the efficacy of optimized parameters were used for serum profiling of ten healthy subjects before and after rhEPO treatment. The principal component analysis indicates that a combination of Hu14 column and 2',4'-dihydroxyacetophenone matrix increases data quality allowing the discrimination between treated and untreated samples, making serum MALDI profiling suitable for clinical monitoring of rhEPO.