Synthesis and biological evaluation of N‐acylated tyramine sulfamates containing C–F bonds as steroid sulfatase inhibitors

Steroid sulfatase (STS) is responsible for the hydrolysis of biologically inactive sulfated steroids into their active un‐sulfated forms and promotes the growth of various hormone‐dependent cancers (e.g., breast cancer). Therefore, the STS enzyme is a promising therapeutic target for the treatment of steroid‐sensitive cancers. Herein, we report the synthesis and biological evaluation of sulfamate analogs as potential STS inhibitors based on N‐acylated tyramines that contain C–F bonds. The inhibitory effects of the analogs were tested using STS isolated from human placenta. Of the analogs tested, 4‐(2‐perfluoroundecanoylaminoethyl)‐phenyl sulfamate, 5r , demonstrated the greatest inhibitory effect, with an IC₅₀ value of 2.18 μm (IC₅₀ value of 2.13 μm for coumarin‐7‐O‐sulfamate was used as a reference). These findings were supported by the results our computational analyses performed using molecular docking techniques.     

Longitudinal assessment of renal size and function in extremely low birth weight children at 7 and 11 years of age

Background

There are a lack of studies describing a longitudinal association between preterm delivery and renal complications later in life. We assessed renal size and function in preterm infants born with extremely low birth weight (ELBW) during 4 years of follow-up, comparing these parameters to age-matched children born full term (term controls).

Methods

The results of selected renal laboratory tests [levels of cystatin C, creatinine, blood urea nitrogen (BUN)] and of renal ultrasound evaluations were compared between the ELBW group and the term control group at age 7 and 11 years.

Results

The study population consisted of 64 children born with ELBW (ELBW children) who had been recruited at birth and 36 children born at term (term children) who took part in both follow-up assessments. Renal ultrasound examination revealed a significantly smaller renal volume in the 7- and 11-year-old ELBW children compared to the term controls [right kidney volume: 50.8 vs. 61.2 ml/m², respectively, at 7 years (p <0.01) and 51.4 vs. 58.2 ml/m², respectively, at 11 years (p <0.01); left kidney volume: 51.4 vs. 60.3 ml/m², respectively, at 7 years (p <0.01) and 55.2 vs. 60.7 ml/m², respectively, at 11 years (p?=?0.02)]. Renal function in ELBW children was also affected. Serum cystatin C levels were significantly higher in ELBW children than in the controls at 7 years of age, and this difference remained statistically significant at 11 years of age [0.63 vs. 0.59 mg/l, respectively, at 7 years (p?=?0.02) and 0.72 vs. 0.61 mg/l, respectively, at 11 years (p?=?0.01)]. Six ELBW children also had elevated cystatin C levels (0.97–1.11 mg/l) at 11 years of age. Cystatin C levels were within normal range in the ELBW children at age 7 years and in term children in both follow-up studies. BUN levels were higher in ELBW children at the age of 11 years (4.49 vs. 4.15 mmol/l; p?=?0.028).

Conclusion

Continued follow-up of these patients will reveal whether the observed worsening in renal function will persist into adulthood.

     

Recurrent fetal complex ovarian cysts with rupture followed by simple cyst in the neonatal period with no adverse sequelae

Fetal ovarian cysts are the most frequent type of abdominal tumors in female fetuses with prenatal detection rate of more than 30%. The etiology of fetal ovarian cysts is unclear, but hormonal stimulation as well as presence of maternal diabetes, hypothyroidism, Rh iso-immune hemolytic disease and toxemia has been generally considered responsible for the disease. Complications of fetal ovarian cysts include compression of other viscera, cyst rupture, hemorrhage and, most frequently, ovarian torsion with consequent loss of the ovary. Management is controversial with several options described in the literature, including watchful expectancy, antenatal aspiration of simple cysts to prevent torsion and ovarian loss and finally, resection of all complex cysts in the neonatal period. To date, no case report has described recurrent complex cysts with rupture in the fetal period and recurrence of simple cyst in neonatal period. By presenting this case, we wanted to show that surgical intervention in case of prenatally diagnosed fetal ovarian cyst should be considered postnatally and only in symptomatic or complicated cases.     

Chronic antidepressant-like effect of EMD386088, a partial 5-HT6 receptor agonist,in olfactory bulbectomy model may be connected with BDNF and/or CREB signalling pathway

Background

The removal of the olfactory bulbs has been attributed to behavioral changes and neuroplasticity manifesting themselves among others like increases in brain neurotrophin expression and neurogenesis. Earlier data presented that EMD386088, a 5-HT₆ receptor partial agonist, exerts antidepressant-like properties after chronic administration in olfactory bulbectomy (OB) model as was it compared with amitriptyline (AMI). The aim of this study was to compare acute and chronic biochemical effects of EMD386088, administered in its antidepressant active (2.5 mg/kg) and non-active (1.25 mg/kg) doses, found in the open field test in OB rats, with those of AMI (10 mg/kg). The levels of 5-HT₆ receptor protein and selected neurotrophins in prefrontal cortex (PFC) and hippocampus (Hp) of rats have been examined.

Assessment of metabolic changes within normal appearing gray and white matter in children with growth hormone deficiency: Magnetic resonance spectroscopy and hormonal correlation

Objective: The pathogenesis of idiopathic growth hormone deficiency (GHD) in children, including possible cerebral metabolic alterations, remains unclear. The aim of the study was to evaluate metabolic changes within the normal appearing brain in children with GHD using MR spectroscopy (MRS) and to correlate MRS measurements with hormonal concentrations and with pituitary gland size. Methods: Seventy children with GHD (mean age 7.8 yrs) and 11 healthy controls (mean age 8.4 yrs) were enrolled in the study. The MRS examinations were performed on a 1.5T scanner. Voxels were located in the posterior cingulate gyrus (PCG) and the left parietal white matter (PWM). The NAA/Cr, Cho/Cr and mI/Cr ratios were analyzed. The metabolite ratios, pituitary gland size and hormonal concentrations: growth hormone (GH) in two stimulation tests and GH during the night, as well as IGF-1 (insulin-like growth factor) and IGFBP3 (insulin-like growth factor-binding protein) levels were also correlated. Results: There was a significant (p < 0.05) decrease of the NAA/Cr ratios in PCG and PWM in children with GHD compared to the normal subjects. Other metabolite ratios showed no significant differences. We also found significant positive correlations between NAA/Cr ratio in PWM and IGFBP3 level, as well as with GH concentration in a stimulation test with glucagon. Conclusions: The reduction of NAA/Cr ratios may suggest loss of neuronal activity within normal appearing gray and white matters in children with GHD. MRS could be a sensitive marker of cerebral metabolic disturbances associated with GHD and maybe used as an additional indicator for therapy with recombinant GH.     

Hydrophobic sodium fluoride‐based nanocrystals doped with lanthanide ions: assessment of in vitro toxicity to human blood lymphocytes and phagocytes

In vitro immunotoxicity of hydrophobic sodium fluoride‐based nanocrystals (NCs) doped with lanthanide ions was examined in this study. Although there is already a significant amount of optical and structural data on NaYF₄ NCs, data on safety assessment are missing. Therefore, peripheral whole blood from human volunteers was used to evaluate the effect of 25 and 30 nm hydrophobic NaYF₄ NCs dissolved in cyclohexane (CH) on lymphocytes, and of 10 nm NaYF₄ NCs on phagocytes. In the concentration range 0.12–75 µg cm^?2 (0.17–106 µg ml^?1), both 25 and 30nm NaYF₄ NCs did not induce cytotoxicity when measured as incorporation of [³H]‐thymidine into DNA. Assessment of lymphocyte function showed significant suppression of the proliferative activity of T‐lymphocytes and T‐dependent B‐cell response in peripheral blood cultures (n = 7) stimulated in vitro with mitogens phytohemagglutinin (PHA) and pokeweed (PWM) (PHA > PWM). No clear dose–response effect was observed. Phagocytic activity and respiratory burst of leukocytes (n = 5–8) were generally less affected. A dose‐dependent suppression of phagocytic activity of granulocytes in cultures treated with 25 nm NCs was observed (vs. medium control). A decrease in phagocytic activity of monocytes was found in cells exposed to higher doses of 10 and 30 nm NCs. The respiratory burst of phagocytes was significantly decreased by exposure to the middle dose of 30 nm NCs only. In conclusion, our results demonstrate immunotoxic effects of hydrophobic NaYF₄ NCs doped with lanthanide ions to lymphocytes and to lesser extent to phagocytes. Further research needs to be done, particularly faze transfer of hydrophobic NCs to hydrophilic ones, to eliminate the solvent effect. Copyright © 2014 John Wiley & Sons, Ltd.     

Chemical and Structural Characterization of Amorphous and Crystalline Alumina Obtained by Alternative Sol–Gel Preparation Routes

Aluminum oxide is one of the most commonly used materials in the industry. It is used in the field of catalysis, refractories, and optics. Despite the fact that there are many techniques available, there is still a great challenge in obtaining a material with desired and designed properties. Nevertheless, there is a great flexibility in making customized alumina materials with desired physicochemical properties synthesized by sol–gel methods. This work consists in characterizing the physicochemical properties of sol–gel synthesized aluminum oxide using different sol–gel preparation routes. Three different sols were obtained by using organic precursors and underwent thermal treatment. The structure (Middle Infrared Spectroscopy, Diffused Reflectance Infrared Spectroscopy, X-ray Diffraction, Magic Angle Spinning Nuclear Magnetic Resonance) and microstructure (Scanning Electron Microscopy with Electron Dispersive Spectroscopy) tests of the materials were carried out. The specific surface area was determined by using the Brunauer–Emmett–Teller (BET) method. Thermal analysis was performed for all the powders, in order to analyze the specific temperature of materials transformation.     

New Acceptor–Donor–Acceptor Systems Based on Bis-(Imino-1,8-Naphthalimide)

In this paper, six novel symmetrical bis-(imino-1,8-naphthalimides) differing in core and N-substituent structure were synthesized, and their thermal (TGA, DSC), optical (UV-Vis, PL), electrochemical (DPV, CV) properties were evaluated. The compounds were stable to 280 °C and could be transferred into amorphous materials. Electrochemical investigations showed their ability to occur reductions and oxidations processes. They exhibited deep LUMO levels of about −3.22 eV and HOMO levels above −5.80 eV. The optical investigations were carried out in the solutions (polar and non-polar) and in films and blends with PVK:PBD. Bis-(imino-1,8-naphthalimides) absorbed electromagnetic radiation in the range of 243–415 nm and emitted light from blue to yellow. Their capacity for light emission under voltage was preliminarily tested in devices with an active layer consisting of a neat compound and a blend with PVK:PBD. The diodes emitted green or red light.     

Mechanical and Combustion Properties of Agglomerates of Wood of Popular Eastern European Species

The objective of the reported project was to produce wood agglomerates from popular East European species to determine their strength and combustion properties. Closed-die pellets were produced from sawdust of six types of wood common on the East European market: pine, willow, oak, poplar, birch, and beech. The properties of pellets, determined by the type of wood, were influenced by the compaction pressure and the moisture content of the sawdust. The highest average pellet density was obtained for oak sawdust, while the lowest density was obtained for poplar pellets. Expansion of pellets after removing from the die was found to be dependent on the wood species, and as expected, on compaction pressure. The pellet expansion increased after 2 h of conditioning in the laboratory and with an increase in moisture content. The highest and the smallest strength were obtained for oak pellets and for birch sawdust, respectively. The strength of the pellets increased by more than 100% with an increase in the compaction pressure from 60 MPa to 120 MPa. The average strength decreased by 65% with increasing moisture content. For all tested materials, drop resistance remained at a high level, acceptable in industrial practice. The highest calorific value of 18.97 MJ/kg was obtained for pine pellets. The highest ash value of 1.52% was obtained for willow pellets and the lowest value of 0.32% for pine pellets.     

Effects of the Water-Based Foaming Process on the Basic and Rheological Properties of Bitumen 70/100

The process of water-based foaming of bitumen produces binders that can be incorporated in cold recycled asphalt mixes and pavement upper structural layers made of half-warm mix asphalt prepared at 100–130 °C. During the foaming process, cold water and air act on hot bitumen (160–170 °C), which results in the explosive vaporization of water leading to changes in the binder structure. The impact of foaming on the properties of bitumen 70/100 was evaluated by investigating the binder characteristics before and after foaming. Determination of two foaming parameters, maximum expansion and half-life, was followed by measurements of penetration at 25 °C, softening point, Fraass breaking point, and dynamic viscosity at 60, 90, and 135 °C. Rheological and low-temperature tests were also performed before and after foaming bitumen 70/100. The Bending Beam Rheometer method was applied to determine the low temperature stiffness modulus. A DHR-2 rheometer was used to determine the dynamic modulus and phase angle of the tested binder. The Black and master curves before and after foaming were plotted in the 2S2P1D model and the model parameters were analysed. Analysis of the test results confirmed the effects of the foaming process on the basic, low-temperature, and rheological characteristics of the bitumen.