Solid-Phase Synthesis of Biaryl Cyclic Peptides Containing a Histidine-Phenylalanine Linkage

The feasibility of the solid-phase intramolecular 4(5)-arylation of a histidine residue to obtain biaryl cyclic peptides bearing a His-Phe linkage was esta     

Antimicrobial and antiviral activities of an actinomycete (Streptomyces sp.) isolated from a Brazilian tropical forest soil

A promising producer of bioactive compounds isolated from a Brazilian tropical soil was tested for its range of antimicrobial activities. Strain 606, classified as Streptomyces sp., could not be identified up to species level, suggesting a possible new taxon. The supernatant and 10 extracts and fractions, obtained by extraction and chromatographic techniques, presented antimicrobial activity using antibiograms. The methanolic fraction was highly active against pathogenic bacteria, phytopathogenic fungi and the human pathogenic yeast Candida albicans. It also possessed high antiviral activity inhibiting the propagation of an acyclovir-resistant herpes simplex virus type 1 strain on HEp-2 cells at non-cytotoxic concentration. The strong cytotoxic effect suggests an antitumour action. This revised version was published online in August 2006 with corrections to the Cover Date.     

The role of nutrition on epigenetic modifications and their implications on health

Nutrition plays a key role in many aspects of health and dietary imbalances are major determinants of chronic diseases including cardiovascular disease, obesity, diabetes and cancer. Adequate nutrition is particularly essential during critical periods in early life (both pre- and postnatal). In this regard, there is extensive epidemiologic and experimental data showing that early sub-optimal nutrition can have health consequences several decades later.     

The effects of insulin on choline kinase activity in cultured rat liver cells

The effect of insulin on phosphatidylcholine biosynthesis in cultured rat liver cells was assessed by measuring changes in the activity of the first enzyme in the choline pathway of phosphatidylcholine biosynthesis, choline kinase (ATP: cholinephosphortransferase, EC 2.7.1.32), in the presence or absence of the hormone. Choline kinase specific activity in liver cells incubated for 18 hours in the presence of 10^?7M insulin increased two-fold from 3.4 ± 0.3 nmoles phosphorylcholine formed/min/mg protein to 7.5 ± 0.6 nmoles/min/mg protein. This effect was dose dependent and reversed by the addition of actinomycin D and cycloheximide. It is concluded that the increase in specific activity is due to synthesis of new enzyme rather than activation of existing enzyme.     

Comparison of dose distribution in IMRT and RapidArc technique in prostate radiotherapy

AimThe aim was to provide a dosimetric comparison between IMRT and RapidArc treatment plans with RPI index with simultaneous comparison of the treatment delivery time.BackgroundIMRT and RapidArc provide highly conformal dose distribution with good sparing of normal tissues. However, a complex spatial dosimetry of IMRT and RapidArc plans hampers the evaluation and comparison between plans calculated for the two modalities. RPI was used in this paper for treatment plan comparisons. The duration of the therapeutic session in RapidArc is reported to be shorter in comparison to therapeutic time of the other dynamic techniques. For this reasons, total treatment delivery time in both techniques was compared and discussed.Materials and methods15 patients with prostate carcinoma were randomly selected for the analysis. Two competitive treatment plans using respectively the IMRT and RapidArc techniques were computed for each patient in Eclipse planning system v. 8.6.15. RPIwin^® application was used for RPI calculations for each treatment plan.Additionally, total treatment time was compared between IMRT and RapidArc plans. Total treatment time was a sum of monitor units (MU) for each treated field.ResultsThe mean values of the RPI indices were insignificantly higher for IMRT plans in comparison to rotational therapy. Comparison of the mean numbers of monitor units confirmed that the use of rotational technique instead of conventional static field IMRT can significantly reduce the treatment time.ConclusionAnalysis presented in this paper, demonstrated that RapidArc can compete with the IMRT technique in the field of treatment plan dosimetry reducing the time required for dose delivery.     

The inhibition of phospholipase A2 by manoalide and manoalide analogues

Manoalide, a natural product from sponge, displays anti-inflammatory activity in vivo. Previous work has shown that manoalide is also a potent covalent inhibitor of the extracellular phospholipase A2 from cobra venom and that the inhibition correlated with a pH-dependent change in manoalide (Lombardo and Dennis (1985) J. Biol. Chem. 260, 7234-7240). Manoalide contains two rings and the opening of either would produce an alpha,beta-unsaturated aldehyde. The cobra venom phospholipase A2 may be able to catalyze the opening or isomerization of one of these rings, raising the possibility that manoalide is acting as a suicide substrate. To ascertain the role of the gamma-lactone ring in the inhibition, we have now investigated a synthetic manoalide analogue, 3(cis,cis-7,10)-hexadecadienyl-4-hydroxy-2-butenolide (HDHB) which contains only the alpha,beta-unsaturated gamma-lactone ring. We have found that the closed and open forms are in rapid equilibrium between pH 4 and 9 with the cyclic form being preferred at acidic pH values and the open cis form preferred at pH 9.5. When the pH is raised above 12, the alpha,beta double bond isomerizes to form trans-HDHB. Once the trans compound is formed, it is stable at all pH values and does not recyclize to the gamma-lactone ring. The observed pKa of 7.7 found for the inhibition of manoalide agrees well with the transition of the closed to the cis form of the gamma-lactone ring. Kinetic experiments with the HDHB compound show that under conditions in which the cis and closed form of the inhibitor are present in equal molar ratios, HDHB is not an irreversible inhibitor, but reversibly competes with substrate. However, the kinetics of this inhibition are complex and do not follow either pure competitive or non-competitive inhibition. The trans-HDHB exhibits similar complex kinetic but is several times more potent. The distinct differences between the behavior of manoalide and HDHB clearly indicate that while the gamma-lactone ring may play an important role in manoalide inhibition, it alone does not produce irreversible inhibition.     

The influence of hypomagnesemia on erythrocyte antioxidant enzyme defence system in mice

The effect of magnesium deficiency on antioxidant defence system was studied in RBC of mice suffering from hypomagnesemia. The animals were kept for 8, 15 and 22 days on magnesium-deficient diet with consequent reduction of magnesium level in plasma by 38% at the first 8 days and by 64% after 22 days of experiment. The activities of the most important antioxidant enzymes, catalase, glutathione peroxidase, superoxide dismutase, glutathione reductase, glutahione S-transferase were assayed in hemolysates. The level of reduced glutathione in erythrocytes was measured as well. Apart from catalase, the activities of antioxidant enzymes were decreasing. The activity of superoxide dismutase decreased gradually during the experiment and on the 15th and 22nd day of experiment was significantly (P<0,05) lowered by 30 and 32% respectively. The catalase activity was increased on each point of the experiment with the peak value up to 149% on 15th day, and by 32% on 22nd day. Glutathione peroxidase activity was insignificantly reduced. The reduction of Glutatione reductase and Glutathione S-transferase activities by 24 and 21%, respectively, were observed after 8 days of the experiment with a further downward tendency. The reduced glutathione was significantly depleted after 8 days by 33% and was kept on that level in the course of the study. These findings support previous reports on the hypomagnesemia – induced alteration in endogenous enzyme antioxidant defences and glutathione redox cycle of mice.     

Plasma Biomarkers Discriminate Clinical Forms of Multiple Sclerosis

Multiple sclerosis, the most common cause of neurological disability in young population after trauma, represents a significant public health burden. Current challenges associated with management of multiple sclerosis (MS) patients stem from the lack of biomarkers that might enable stratification of the different clinical forms of MS and thus prompt treatment for those patients with progressive MS, for whom there is currently no therapy available. In the present work we analyzed a set of thirty different plasma cytokines, chemokines and growth factors present in circulation of 129 MS patients with different clinical forms (relapsing remitting, secondary progressive and primary progressive MS) and 53 healthy controls, across two independent cohorts. The set of plasma analytes was quantified with Luminex xMAP technology and their predictive power regarding clinical outcome was evaluated both individually using ROC curves and in combination using logistic regression analysis. Our results from two independent cohorts of MS patients demonstrate that the divergent clinical and histology-based MS forms are associated with distinct profiles of circulating plasma protein biomarkers, with distinct signatures being composed of chemokines and growth/angiogenic factors. With this work, we propose that an evaluation of a set of 4 circulating biomarkers (HGF, Eotaxin/CCL11, EGF and MIP-1β/CCL4) in MS patients might serve as an effective tool in the diagnosis and more personalized therapeutic targeting of MS patients.     

Ail Proteins of Yersinia pestis and Y. pseudotuberculosis Have Different Cell Binding and Invasion Activities

The Yersinia pestis adhesin Ail mediates host cell binding and facilitates delivery of cytotoxic Yop proteins. Ail from Y. pestis and Y. pseudotuberculosis is identical except for one or two amino acids at positions 43 and 126 depending on the Y. pseudotuberculosis strain. Ail from Y. pseudotuberculosis strain YPIII has been reported to lack host cell binding ability, thus we sought to determine which amino acid difference(s) are responsible for the difference in cell adhesion. Y. pseudotuberculosis YPIII Ail expressed in Escherichia coli bound host cells, albeit at ∼50% the capacity of Y. pestis Ail. Y. pestis Ail single mutants, Ail-E43D and Ail-F126V, both have decreased adhesion and invasion in E. coli when compared to wild-type Y. pestis Ail. Y. pseudotuberculosis YPIII Ail also had decreased binding to the Ail substrate fibronectin, relative to Y. pestis Ail in E. coli. When expressed in Y. pestis, there was a 30–50% decrease in adhesion and invasion depending on the substitution. Ail-mediated Yop delivery by both Y. pestis Ail and Y. pseudotuberculosis Ail were similar when expressed in Y. pestis, with only Ail-F126V giving a statistically significant reduction in Yop delivery of 25%. In contrast to results in E. coli and Y. pestis, expression of Ail in Y. pseudotuberculosis led to no measurable adhesion or invasion, suggesting the longer LPS of Y. pseudotuberculosis interferes with Ail cell-binding activity. Thus, host context affects the binding activities of Ail and both Y. pestis and Y. pseudotuberculosis Ail can mediate cell binding, cell invasion and facilitate Yop delivery.