In silico investigation of PARP-1 catalytic domains in holo and apo states for the design of high-affinity PARP-1 inhibitors

The rational design of high-affinity inhibitors of poly-ADP-ribose polymerase-1 (PARP-1) is at the heart of modern anti-cancer drug design. While relevance of enzyme to DNA repair processes in cellular environment is firmly established, the structural and functional understanding of the main determinants for high-affinity ligands controlling PARP-1 activity is still lacking. The conserved active site of PARP-1 represents an ideal target for inhibitors and may offer a novel target at the treatment of breast cancer. To fill the gap in the structural knowledge, we report on the combination of molecular dynamics (MD) simulations, principal component analysis (PCA), and conformational analysis that analyzes in great details novel binding mode for a number of inhibitors at the PARP-1. While optimization of the binding affinity for original target is an important goal in the drug design, many of the promising molecules for treatment of the breast cancer are plagued by significant cardiotoxicity. One of the most common side-effects reported for a number of polymerase inhibitors is its off-target interactions with cardiac ion channels and hERG1 channel, in particular. Thus, selected candidate PARP-1 inhibitors were also screened in silico at the central cavities of hERG1 potassium ion channel.     

Utilizing peanut husk (Arachis hypogaea L.) in the manufacture of medium-density fiberboards

The main objective of this study was to investigate the potential of peanut husk (Arachis hypogaea L.) as a fiber–peanut mixture to produce fiberboards for general purposes. For panel production, the addition of peanut husk at various percentages to the wood fiber was the only variable. Panels produced utilizing peanut husk were compared to panels produced using 100% wood fiber. The chemical properties of peanut husk; holocellulose and lignin content, alcohol–benzene, hot and cold water, and dilute alkali (1% NaOH) solubility, were also determined. Results indicated that panels could be produced utilizing up to 30% peanut husk without affecting the usability of the panels. It was not possible to meet the minimum IB strength standards when peanut husk was added to the mixture. Higher additions resulted in panels having lower elastic and rupture moduli than the minimum requirements according to TS-EN standards.     

Developmental exposure to noninherited maternal antigens induces CD4+ T regulatory cells: relevance to mechanism of heart allograft tolerance

We hypothesize that developmental exposure to noninherited maternal Ags (NIMA) results in alloantigen-specific natural and adaptive T regulatory (T(R)) cells. We compared offspring exposed to maternal H-2(d) (NIMA(d)) with nonexposed controls. In vitro assays did not reveal any differences in T cell responses pretransplant. Adoptive transfer assays revealed lower lymphoproliferation and greater cell surface TGF-beta expression on CD4(+) T cells of NIMA(d)-exposed vs control splenocytes. NIMA(d)-exposed splenocytes exhibited bystander suppression of tetanus-specific delayed-type hypersensitivity responses, which was reversed with Abs to TGF-beta and IL-10. Allospecific T effector cells were induced in all mice upon i.v. challenge with B6D2F1 splenocytes or a DBA/2 heart transplant, but were controlled in NIMA(d)-exposed mice by T(R) cells to varying degrees. Some (40%) NIMA(d)-exposed mice accepted a DBA/2 allograft while others (60%) rejected in delayed fashion. Rejector and acceptor NIMA(d)-exposed mice had reduced T effector responses and increased Foxp3(+) T(R) cells (CD4(+)CD25(+)Foxp3(+) T(R)) in spleen and lymph nodes compared with controls. The key features distinguishing NIMA(d)-exposed acceptors from all other mice were: 1) higher frequency of IL-10- and TGF-beta-producing cells primarily in the CD4(+)CD25(+) T cell subset within lymph nodes and allografts, 2) a suppressed delayed-type hypersensitivity response to B6D2F1 Ags, and 3) allografts enriched in LAP(+), Foxp3(+), and CD4(+) T cells, with few CD8(+) T cells. We conclude that the beneficial NIMA effect is due to induction of NIMA-specific T(R) cells during ontogeny. Their persistence in the adult, and the ability of the host to mobilize them to the graft, may determine whether NIMA-specific tolerance is achieved.     

Two new neoflavonoids and C-glycosylflavones from Passiflora serratodigitata

The aerial parts of Passiflora serratodigitata yielded 5,7-dihydroxy-4-phenylcoumarin, its 7-β-glucoside and the known C-glycosylflavones 2″-xylosylvitexin, 2″-xylosylisovitexin, vitexin, isovitexin, a vicenin, and orientin. The known flavone chrysin was also isolated. This is the first report of neoflavonoids in the family Passifloraceae.     

Sesquiterpene lactones from Smyrnium cordifolium

In addition to previously obtained furanosesquiterpenes, two new eudesmanolides and a new glechomanolide were isolated from the fruits of Smyrnium cordifolium, while the roots gave two new eudesmanolides. The new compounds from the fruits were 1β-acetoxy-eudesman-4(15), 7(11)-dien-8,12-olide, 1β-acetoxy-8β-hydroxy-eudesman-4(15),7(11)-dien-8,12-olide, 1β,10α;4α,5β-diepoxy-8-hydroxy-glechomanolide, those obtained from the roots were smyrnicordiolide and the corresponding 8β-hydroxy derivative belonging to a new type of oxepine derivative.     

<Emphasis Type="Italic">R-spondin1</Emphasis> and <Emphasis Type="Italic">FOXL2</Emphasis>act into two distinct cellular types during goat ovarian differentiation

Background  

Up to now, two loci have been involved in XX sex-reversal in mammals following loss-of-function mutations, PIS (Polled Intersex Syndrome) in goats and R-spondin1 (RSPO1) in humans. Here, we analyze the possible interaction between these two factors during goat gonad development. Furthermore, since functional redundancy between different R-spondins may influence gonad development, we also studied the expression patterns of RSPO2, 3 and 4.     

Trace Elements in Obese Turkish Children

The quality of the diet of obese children is poor. Eating habits may alter micronutrient status in obese patients. In this study, we determined the serum levels of selenium, zinc, vanadium, molybdenum, iron, copper, beryllium, boron, chromium, manganese, cobalt, silver, barium, aluminum, nickel, cadmium, mercury, and lead in obese Turkish children. Thirty-four obese and 33 healthy control subjects were enrolled in the study. Serum vanadium and cobalt levels of obese children were significantly lower than those of the control group (0.244 ± 0.0179 vs. 0.261 ± 0.012 μg/l, p < 0.001, and 0.14 ± 0.13 vs. 0.24 ± 0.15 μg/l, p = 0.011, respectively). There was no significant difference between groups regarding the other serum trace element levels. In conclusion, there may be alterations in the serum levels of trace elements in obese children and these alterations may have a role in the pathogenesis of obesity.     

Comparative investigation of the use of various commercial microcarriers as a substrate for culturing mammalian cells

Microcarriers provide large adhesion area allowing high cell densities in bioreactor systems. This study focused on the investigation of cell adhesion and cell growth characteristics of both anchorage-dependent CHO-K1 and anchorage-independent Ag8 myeloma cell lines cultivated on four different microcarriers (Biosilon®, Microhex®, Cytodex 3®, Cytoline 2®) by considering the cell kinetics and physiological data. Experiments were performed in both static and agitated cell culture systems by using 24-well tissue culture plates and then 50-ml spinner flasks. In agitated cultures, the highest specific growth rates (0.026 h for CHO-K1 and 0.061 h for Ag8 cell line) were obtained with Cytodex 3® and Cytoline 2® microcarriers for CHO-K1 and Ag8 cell line, respectively. Metabolic characteristics showed some variation among the cultures with the four microcarriers. The most significant being the higher production of lactate with microcarriers with CHO-K1 cells relative to the Ag8 cells. SEM analyses revealed the differences in the morphology of the cells along with microcarriers. On Cytodex 3® and Cytoline 2®, CHO-K1 cells attached to the substratum through long, slender filopodia, whereas the cells showed a flat morphology by covering the substratum on the Biosilon® and Microhex®. Ag8 cells maintained their spherical shapes throughout the culture for all types of microcarriers. In an attempt to scale-up, productions were carried out in 50-ml spinner flasks. Cytodex 3® (for CHO-K1 cells) and Cytoline 2® (for Ag8 cells) were evaluated. The results demonstrate that high yield of biomass could be achieved through the immobilization of the cells in each culture system. And cell cultures on microcarriers, especially on Cytodex 3® and Cytoline 2®, represented a good potential as microcarriers for larger scale cultures of CHO-K1 and Ag8, respectively. Moreover, owing to the fact that the cell lines and culture media are specific, outcomes will be applicable for other clones derived from the same host cell lines.     

Effects of nutrition on zinc, folic acid, and vitamin B12 levels during pregnancy

In this article, we report the results of a case control study carried out on 290 Turkish pregnant women at 5–24 wk of gestation to determine their zinc, folic acid, and vitamin B₁₂ levels in relation to their nutritional and socioconomic status. The women were divided into two groups (n=145 each), depending on the stage of gestation. Group I consisted of women in the first trimester of gestation; those in the second trimester were allocated into group II. Twenty-five age-matched, healthy nonpregnant women were selected as controls. The nutritional status of the subjects was determined by means of a survey. Based on this, the women were subdivided into three subgroups: malnourished (PN), moderately nourished (MN), and well nourished (WN). Also from the survey, the socioeconomic status was classified as good (G) or bad (B). A statistically significant decrease on zinc and folic acid was observed in group I women, as their socioeconomic status worsened. In group II, zinc decreased only in the PN and MN subgroups, p<0.001. The folic acid and vitamin B₁₂ levels did not change significantly during the second trimester of gestation in all subgroups. Regarding zinc, nutrition, or dietary habits are more relevant than socioeconomic status, but poor nutrition affects folic acid levels only during the first trimester of gestation.     

Elevated homocysteine levels in patients with slow coronary flow: relationship with Helicobacter pylori infection

BACKGROUND AND OBJECTIVE: Elevation of plasma homocysteine (Hcy) level has been implicated in the pathogenesis of slow coronary flow (SCF) as it can severely disturb vascular endothelial function. Helicobacter pylori chronically infect the human stomach and causes malabsorption of vitamin B(12) and folate in food, leading ultimately to an increase in circulating Hcy levels. METHODS: Forty-three patients with angiographically proven SCF (group I) were enrolled in this study; 43 cases with normal coronary flow pattern (group II) served as controls. Fasting plasma levels of Hcy, vitamin B(12), and folate were measured in all subjects. Presence of H. pylori infection was defined as positive 14 C urea breath test. Coronary flow patterns for each major epicardial coronary artery were determined with the Thrombolysis in Myocardial Infarction (TIMI) frame count method. RESULTS: Mean TIMI frame count was 46.3 +/- 8.7 in group I and 24.3 +/- 2.9 in Group II (p = .0001). Vitamin B(12) levels were similar, whereas folate levels were dramatically reduced in group I compared to group II (13.2 +/- 4.3 vs. 17.1 +/- 5.2, p = .0001). Plasma Hcy levels were significantly higher in group I compared to group II (13.4 +/- 5.6 vs. 7.9 +/- 2.5, p = .0001) as was the prevalence of H. pylori infection (90.7% in group I vs. 58.1% in group II, p = .001). Hcy levels were elevated (11.7 +/- 5.3 vs. 7.5 +/- 2.7, p = .0001) and folate levels were reduced (13.9 +/- 4.7 vs. 18.6 +/- 4.9, p = .0001) in patients with H. pylori infection, while vitamin B(12) levels were similar in patients with and without H. pylori infection. Correlation analysis revealed a significant negative correlation between plasma folate and Hcy levels and also between folate levels and mean TIMI frame counts (r = -.33, p = .002 vs. r = -.33, p = .003). Moreover, there was a significant positive correlation between plasma Hcy levels and mean TIMI frame counts (r = .66, p = .0001). In addition, the folate level was the only significant determinant of the variance of Hcy in multiple regression analysis (r = -.21, p = .03). CONCLUSION: Our data showed that plasma folate levels were decreased and plasma Hcy levels were increased in patients with SCF compared to controls. Also, the prevalence of H. pylori infection was increased in patients with SCF. These findings suggest that elevated levels of plasma Hcy, possibly caused by H. pylori infection, and/or a possible disturbance in its metabolism may play a role in the pathogenesis of SCF.