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Background:The Angiotensin-I converting enzyme (ACE) is one of the most important components of the renin-angiotensin-aldosterone system controlling blood pressure and renal functions. Inhibitors of ACE are first line therapeutics used in the treatment of hypertension and related cardiovascular diseases. Somatic ACE consists of two homologous catalytic domains, the C- and N-domains. Recent findings have shown that although both domains are highly homologous in structure, they may have different physiological functions. The C-domain is primarily involved in the control of blood pressure, in contrast to the N-domain that is engaged in the regulation of hematopoietic stem cell proliferation. The currently available ACE inhibitors have some adverse effects that can be attributed to the non-selective inhibition of both domains. In addition, specific Ndomain inhibitors have emerged as potential antifibrotic drugs. Therefore, ACE is still an important drug target for the development of novel domain-selective drugs not only for the cardiovascular system but also for other systems.Objective:Detailed structural information about interactions in the protein-ligand complex is crucial for rational drug design. This review highlights the structural information available from crystallographic data which is essential for the development of domain selective inhibitors of ACE.Methods:Over eighty crystal complexes of ACE are placed into the Protein Database. An overview of X-ray ACE complexes with various inhibitors in C- and N-domains and an analysis of their binding mode have given mechanistic explanation of the structural determinants of selective ligand binding. In addition, ACE domain selective inhibitors with dual modes of action in complexes with ACE are also discussed.Conclusion:Selectivity of ACE inhibitors for the N- and C-domain is controlled by subtle differences in the amino-acids forming the active site. Reported studies of crystal complexes of inhibitors in the C- and N-domains revealed that most selective inhibitors interact with non-conserved amino-acids between domains and have distinct interactions with the residues in the S2 and S2’ subsites of the ACE catalytic site. Moreover, unusual binding of the second molecule of inhibitors in the binding cavity opens new possibilities of exploiting more distant regions of the catalytic center in structure-based design of novel drugs.

Background: Vertical jump is one of the most prevalent activities performed in volleyball. During adolescence, boys and girls undergo substantial changes in physiological and anthropometric characteristics that influence vertical jump performance. Objective: The purpose of this study was to examine and quantify sex and age-related differences in vertical jump performance assessed as vertical jumps height (VJH) and ground contact time (Tc) during repeated vertical jump tests within the Czech and Slovak population of elite adolescent volleyball players. Further aims were to compare the obtained results to non-athletic adolescent national normative data and investigate the relationship between basic anthropometric measures and VJH. Methods: The cross-sectional study was conducted on 203 females and 180 males from 13 to 19 years old. Statistical analysis of VJH differences between sex and age categories was performed using two-way ANOVA with Tukey's post hoc test. The relationship between basic anthropometric parameters and VJH were examined by Pearson's correlation analysis. Results: ANOVA showed statistically significant differences in VJH between males and females (p < .001) and across the age categories (p < .001). Males performed better than females in each age group and VJH increased along with age. For females VJH reached a plateau at the age of 14 and then stagnated. Male players have lower Tc than females (p < .05), although age did not show significant influence on Tc in either females or males (p > .05). Volleyball players have significantly higher VJH than non-athletes across all age categories and sex differences in volleyball players were smaller than the sex differences among non-athletic adolescents. A correlation analysis revealed only weak sex specific correlations of VJH with body height, body mass and BMI. Conclusions: The presented study showed significant sex differences in VJH between elite male and female volleyball players from the age of 15. VJH increases continually with increasing age in males. In females the effect of age on VJH was insignificant.

The randomized trials showed that the addition of training resistance program to androgen-deprivation therapy (ADT) had many beneficial effects for prostate cancer (PC) patients (significant protective effect on the volume of muscle mass) and the studies have revealed a panel of miRNAs, which are deregulate in PC and may serve as promising biomarkers of PC risk. The primary aim of our present study was to investigate the effect of exercise training to changes in body composition (muscle strength) and the secondary endpoint was to investigate the impact of an exercise training program on plasma levels of selected myogenic microRNAs (miRNAs) (miRNA-1, miRNA-29b, and miRNA-133) in PC patients undergoing the ADT. Effect of ADT and exercise intervention showed significant increase (experimental group vs. control group) the changes in body composition, free testosterone levels, IL-6 and plasma levels of myogenic miRNAs and significant reduced insulin serum levels. In conclusion, resistance training with ADT in the treatment of PC significantly changed the physical and metabolic function and the plasma levels of specific myogenic miRNAs. Our data support with the other publicized results.

The solubilisation of poorly soluble antineoplastic drug camptothecin by nonionic surfactants (polysorbates and octylphenol ethoxylates) and alkyldimethylamine oxide surfactants with the alkyl chain length 8 to 16 carbon atoms was investigated. The hydrophobicity of the solubilising agent turned out to be the primary structural parameter controlling the solubility efficiency of camptothecin in an aqueous solution. The quantitative parameter of solubilisation (drug loading coefficient) provided values in the range of 0.1–1.2% and 0.1–1.0% for alkyldimethylamine oxides and nonionic surfactants, respectively. The decreasing number of oxyethylene units and the extension of the hydrophobic part of nonionic surfactant molecule resulted in the increase of camptothecin solubility. From the dynamic light scattering measurements, the hydrodynamic diameter values of camptothecin-loaded alkyldimethylamine oxide and nonionic micelles were found in the range of 4–42 nm and 5–120 nm, respectively. The experimental values confirmed the increase in micellar size with the increasing alkyl chain length. The values of the packing parameter of camptothecin-loaded dodecyldimethylamine oxide micelles indicate their spherical shape at all the investigated surfactant concentrations. A simple computer model of camptothecin-loaded dodecyldimethylamine oxide micelle provided the diameter of the structure cross section which is consistent with the experimental values.

Systematic physical activity increases physical fitness and exercise capacity that lead to the improvement of health status and athletic performance. Considerable effort is devoted to identifying new biomarkers capable of evaluating exercise performance capacity and progress in training, early detection of overtraining, and monitoring health-related adaptation changes. Recent advances in OMICS technologies have opened new opportunities in the detection of genetic, epigenetic and transcriptomic biomarkers. Very promising are mainly small non-coding microRNAs (miRNAs). miRNAs post-transcriptionally regulate gene expression by binding to mRNA and causing its degradation or inhibiting translation. A growing body of evidence suggests that miRNAs affect many processes and play a crucial role not only in cell differentiation, proliferation and apoptosis, but also affect extracellular matrix composition and maintaining processes of homeostasis. A number of studies have shown changes in distribution profiles of circulating miRNAs (c-miRNAs) associated with various diseases and disorders as well as in samples taken under physiological conditions such as pregnancy or physical exercise. This overview aims to summarize the current knowledge related to the response of blood c-miRNAs profiles to different modes of exercise and to highlight their potential application as a novel class of biomarkers of physical performance capacity and training adaptation.

Interfacial area per surfactant molecule values at the air/liquid interface for heterocyclic and dipropylamino derivatives of zwitterionic hexadecylphosphocholine and cationic cetyltrimethylammonium bromide derivatives were calculated from surface tension measurements in NaBr and salt-free aqueous solutions. The interfacial area values were found to be in the range of 0.45–0.86 nm 2 for both zwitterionic and cationic derivatives. The interfacial area data were correlated with the structure and arrangement of surfactants molecules at the interface. In NaBr solutions, cationic cetyltrimethylammonium bromide derivatives acquire denser packing in the interfacial layer due to the repulsion reduction between cationic headgroups by bromide ions which resulted in smaller interfacial area values. In salt-free aqueous solutions, interfacial area of cetyltrimethylammonium bromide derivatives increased above the level of that of hexadecylphosphocholine derivatives due to the repulsion between positively charged headgroups of adjacent cationic surfactant molecules. The arrangement of hexadecylphosphocholine derivative molecules in the interfacial layer is tighter due to the absence of repulsive electrostatic interactions between neighboring ammonium and phosphate groups. The introduction of electrolyte ions in the hexadecylphosphocholine derivative surfactant aqueous solution results in electrostatic disruption of tight arrangement of its molecules and hence, in the interfacial area increase. The comparison of the experimentally obtained interfacial area values with the surfaces of minimum energy conformers representing the surfactants headgroup parts obtained from molecular models indicates that the arrangement of molecules of hexadecylphosphocholine derivatives in the interfacial layer can be affected more by inter- and intramolecular interactions than the arrangement of cetyltrimethylammonium bromide derivatives.

Dipeptide glycyl-L-proline (gly-pro) is degradation product of collagen. This degradation product is further cleaved by prolidase and proline can be recycled in to the new collagen or other peptide. Gly-pro labeled by technetium [99mTc] may potentially allow the in vivo visualization of synthesis and degradation of collagen. The aim of our work is conformational study of potential technetium complexes with gly-pro prepared in the acid reaction medium using AMBER and ZINDO/1 molecular modeling methods. In this reaction medium technetium creates two types of complexes with schematic formula ML2 and ML3. Existence of these complexes was proved by HPLC, electrophoresis on the paper and thin layer chromatography (Silufol© UV254). Gly-pro (ligand) in these two complexes can have cis and trans configuration. This configuration depends on the torsion angle between glycine and proline in the peptide bond. ML2 and ML3 complexes are created with TcO2+ as the result of reduction of TcO4− with SnCl2. Bonds presented in ML2 complex are between technetium, two amino groups and two oxygen atoms. These four atoms and central atom form square planar configuration. The most optimal ML2 complex is axial symmetric and both ligands have cis configuration. In ML3 complex TcO2+ creates three bonds with amino groups and three bonds with oxygen atoms. The most optimal ML3 complex has two ligands with cis and one ligand with trans configuration.

Values of the area per surfactant molecule of various single chain and gemini quaternary ammonium surfactants containing biodegradable amide and ester groups are obtained from the surface tension measurements and they are mutually compared. It was found that surfactant molecules with the ester group in their structure occupy smaller area at the air/water interface than the corresponding molecules with the amide group, mainly due to the higher conformational flexibility of ester groups. In decreasing the area per surfactant molecule value, hydrogen bonding (both inter- and intramolecular) plays a significant role when amide groups are present in the spacer of a gemini molecule. They must be separated by a polymethylene chain or a flexible group such as cyclohexane which is short enough to allow intramolecular hydrogen bonds. The flexible cyclohexane group with the amide group in single chain surfactants may lead to the formation of intermolecular hydrogen bonds among surfactant molecules which also results in the reduction of the area per surfactant molecule.

Aggregation properties of biodegradable ammonium surfactants containing amide and ester groups in the bulk and at the air-water interface were investigated as a function of surfactant tail length m using dynamic light scattering and surface tension experimental methods. The results indicate that surfactants containing an ester group in the structure display higher aggregation ability in the volume and form more densely packed layer of molecules at the air-water interface than those with an amide group. The results of physical measurements were correlated with 3D models of respective surfactant molecules. As the results indicate, a surfactant molecule headgroup containing an ester group shows higher flexibility than that with an amide group in its structure, which is documented by somewhat smaller headgroup size and denser packing at the air-water interface.

Background Postembryonic development, including metamorphosis, of many animals is under control of hormones. In Drosophila and other insects these developmental transitions are regulated by the coordinate action of two principal hormones, the steroid ecdysone and the sesquiterpenoid juvenile hormone (JH). While the mode of ecdysone action is relatively well understood, the molecular mode of JH action remains elusive. Methodology/Principal Findings To gain more insights into the molecular mechanism of JH action, we have tested the biological activity of 86 structurally diverse JH agonists in Drosophila melanogaster. The results were evaluated using 3D QSAR analyses involving CoMFA and CoMSIA procedures. Using this approach we have generated both computer-aided and species-specific pharmacophore fingerprints of JH and its agonists, which revealed that the most active compounds must possess an electronegative atom (oxygen or nitrogen) at both ends of the molecule. When either of these electronegative atoms are replaced by carbon or the distance between them is shorter than 11.5 Å or longer than 13.5 Å, their biological activity is dramatically decreased. The presence of an electron-deficient moiety in the middle of the JH agonist is also essential for high activity. Conclusions/Significance The information from 3D QSAR provides guidelines and mechanistic scope for identification of steric and electrostatic properties as well as donor and acceptor hydrogen-bonding that are important features of the ligand-binding cavity of a JH target protein. In order to refine the pharmacophore analysis and evaluate the outcomes of the CoMFA and CoMSIA study we used pseudoreceptor modeling software PrGen to generate a putative binding site surrogate that is composed of eight amino acid residues corresponding to the defined molecular interactions.