Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models,once tauopathy is initiated,by restoring the autophagic flux

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTau^P301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTau^P301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.     

Residual cholesterol synthesis and simvastatin induction of cholesterol synthesis in Smith-Lemli-Opitz syndrome fibroblasts

Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive, malformation syndrome caused by mutations in the 3beta-hydroxysterol delta7-reductase gene (DHCR7). DHCR7 catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. We report the mutation analysis and determination of residual cholesterol synthesis in 47 SLOS patients, and the effects of treatment of SLOS skin fibroblasts with simvastatin. Using deuterium labeling we have quantified the amount of synthesized cholesterol and 7DHC in homozygote, heterozygote, and control fibroblast cell lines. In SLOS fibroblasts, the fraction of synthesized cholesterol to total sterol synthesis ranged from undetectable to over 50%. This establishes that different mutant alleles encode enzymes with varying degrees of residual activity. There was a correlation between increased phenotypic severity and decreased residual cholesterol synthesis (r(2)=0.45, p<0.0001). Simvastatin treatment of SLOS fibroblasts with residual DHCR7 enzymatic activity decreased 7DHC levels and increased cholesterol synthesis. This increase in cholesterol synthesis is due to increased expression of a mutant allele with residual function. Determination of residual enzymatic activity for specific DHCR7 mutant alleles will help in understanding the processes underlying the broad phenotypic spectrum found in this disorder and will be useful in identifying patients who may benefit from simvastatin therapy.     

Microbiologically Pure Cotton Fabrics Treated with Tetrabutylammonium OXONE as Mild Disinfection Agent

The microbiological purity of textiles plays a pivotal role in the use of textiles, especially in hospitals and other medical facilities. Microbiological purity of cotton fabric was achieved by a new disinfection method using tetrabutyloammonium OXONE (TBA-OXONE) before washing. As a result of the disinfection, the cotton fabric became microbiologically pure, despite the markedly decreased washing time with respect to the widely used standard procedure. Shortening of the washing time allowed for significant energy savings. In addition, the effect of the number of disinfection and washing cycles on the tensile properties and tearing force of the fabric was examined. After 120 disinfection and washing cycles the mechanical properties of cotton fabric were only slightly worsened.     

Fatty Acids and Eicosanoids Change during High-Fiber Diet in NAFLD Patients—Randomized Control Trials (RCT)

Background: Non-alcoholic fatty liver disease (NAFLD) is a wide spectrum condition characterized by excessive liver fat accumulation in people who do not abuse alcohol. There is no effective medical treatment for NAFLD; therefore, most important recommendations to reduce liver steatosis are diet and lifestyle, including proper physical activity. The aim of our study was to analyze the fatty acids and eicosanoids changes in the serum of patients who consumed high-fiber rolls for 8 weeks. Materials and Methods: The group of 28 Caucasian participants was randomly divided into two groups, those who received 24 g of fiber/day—from 2 buns of 12 g each (n = 14), and those who received 12 g of fiber/day—from 2 buns of 6 g (n = 14). At the beginning and on the last visit of the 8-week intervention, all patients underwent NAFLD evaluation, biochemical parameter measurements, and fatty acids and eicosanoids evaluation. Results: Patients who received 12 g of fiber had significantly reduced liver steatosis and body mass index. In the group who received 24 g of fiber/day, we observed a trend to liver steatosis reduction (p = 0.07) and significant decrease in aspartate aminotransferase (p = 0.03) and total cholesterol (p = 0.03). All changes in fatty acid and eicosanoids profile were similar. Fatty acids analysis revealed that extra fiber intake was associated with a significant increase in monounsaturated fatty acids and decrease in saturated fatty acids. Moreover, both groups showed increased concentration of gamma linoleic acid and docosahexaenoic acid. We also observed reduction in prostaglandin E₂. Conclusions: Our study revealed that a high amount of fiber in the diet is associated with a reduction in fatty liver, although this effect was more pronounced in patients in the lower fiber group. However, regardless of the amount of fiber consumed, we observed significant changes in the profile of FAs, which may reflect the positive changes in the lipids liver metabolism. Regardless of the amount of fiber consumed, patients decreased the amount of PGE₂, which may indicate the lack of disease progression associated with the development of inflammation.     

The Associations between Metalloestrogens,GSTP1, and SLC11A2 Polymorphism and the Risk of Endometrial Cancer

Background: The incidence of endometrial cancer (EC) is still rising. Numerous risk factors including patient characteristics and molecular instability have been identified for EC. The presence of specific molecular markers allows specific diagnostic and prognostic approaches. Several single nucleotide polymorphisms (SNPs) have been identified to influence endometrial cancer risk. Metalloestrogens are metal ions which can mimic estrogen activity; however, their role in uterine pathologies remains unknown. This study aimed to investigate total blood trace elements levels and evaluate the distribution of selected genotypes in GSTP1 and SLC11A2 genes. Methods: This retrospective case-control analysis was carried out in peripheral blood samples of 110 women with endometrial cancer (EC; n = 21), uterine fibroma (n = 25), endometrial polyp (n = 48), and normal endometrium (n = 16). Analysis included measurement of metals and phosphor in serum, and of genetic polymorphisms in GST (rs1695) and SLC11A2 (rs224589) in DNA from white blood cells. Serum trace elements were measured using ICP-OES spectrometry. SNPs were identified using Taq Man real-time PCR genotyping assays. Results: The study confirmed higher age (OR 2.19, 95% CI 1.69–2.24), post-menopausal status (OR 1.89, 95% CI 1.36–1.94), and diabetes type 2 (OR 1.54; 95% CI 0.97–1.72) as independent risk factors for EC. We also found a high level of Cd (OR 1.49; 95% CI 1.31–1.63) and a low level of Co (OR 0.76; 95% CI 0.53–0.59) to be independent risk factors of EC. None of the tested polymorphisms of GSTP1 and SLC11A2 were associated with EC risk. However, high Cd (OR 1.21, 95% CI 1.15–1.29) and Ni (OR 1.07, 95% CI 1.05–1.18) serum levels were significantly associated with a SLC1A2 TG genotype, and high Cd levels with GSTP1 (OR 1.05, 95% CI 1.01–1.13).     

Oxazoline scaffold in synthesis of benzosiloxaboroles and related ring-expanded heterocycles: diverse reactivity,structural peculiarities and antimicrobial activity

Two isomeric benzosiloxaborole derivatives 3a and 5a bearing fluorine and 4,4-dimethyl-2-oxazolin-2-yl substituents attached to the aromatic rings were obtained. Both compounds were prone to hydrolytic cleavage of the oxazoline ring after initial protonation or methylation of the nitrogen atom. The derivative 3c featuring N-methylammoniumalkyl ester functionality was successfully subjected to N-sulfonylation and N-acylation reactions to give respective derivatives which demonstrates its potential for modular synthesis of structurally extended benzosiloxaboroles. Compound 5c bearing N-ammoniumalkyl ester underwent conversion to a unique macrocyclic dimer due to siloxaborole ring opening. Furthermore, an unexpected 4-electron reduction of the oxazoline ring occurred during an attempted synthesis of 5a. The reaction gave rise to an unprecedented 7-membered heterocyclic system 4a comprising a relatively stable B–O–B–O–Si linkage and stabilized by an intramolecular N–B coordination. It could be cleaved to derivative 4c bearing BOH and SiMe₂OH groups which acts as a pseudo-diol as demonstrated by formation of an adduct with Tavaborole. Apart from the multinuclear NMR spectroscopy characterization, crystal structures of the obtained products were determined in many cases by X-ray diffraction. Investigation of biological activity of the obtained compounds revealed that derivatives 3e and 3f with pendant N-methyl arylsulfonamide groups exhibit high activity against Gram-positive cocci such as methicillin-sensitive Staphylococcus aureus ATCC 6538P, methicillin-resistant S. aureus (MRSA) ATCC 43300 as well as the MRSA clinical strains, with MIC values in the range of 3.12–6.25 mg L⁻¹. These two compounds also showed activity against Enterococcus faecalis ATCC 29212 and Enterococcus faecium ATCC 6057 (with MICs of 25–50 mg L⁻¹). The results of the antimicrobial activity and cytotoxicity studies indicate that 3e and 3f can be considered as potential antibacterial agents, especially against S. aureus MRSA.

Transformations of oxazoline–benzosiloxaborole conjugates gave rise to novel boracyclic systems as well as functionalized derivatives featuring antibacterial activity.     

The Influence of Intensive Nutritional Education on the Iron Status in Infants

Iron is an essential nutrient for a child’s proper development at every growth stage. It is crucial for the production of red blood and muscle cells, DNA replication, and the development of the brain, nervous and immune systems. Iron deficiency is the most common micronutrient deficiency in children worldwide. Despite widespread access to nutritional information for children, parents continue to make many feeding mistakes. This study aimed to assess whether any nutritional intervention would affect the iron status in children. The parents of 203 children were randomly assigned to one of two groups: the study group received intensive mobile nutritional education for a year, while the control group received no intervention. Blood tests were performed on both groups at the beginning of the study and one year later. The educational intervention resulted in statistically significantly higher levels of RBC (red blood cells; p = 0.020), HGB (haemoglobin; p = 0.039), HCT (haematocrit; p = 0.036), MCV (mean cell volume; p = 0.018) parameters and iron dietary intake (p ≤ 0.001). Even a non-targeted dietary intervention improves the iron status in children. As iron management is insufficient in most children, an iron-targeted nutritional intervention appears necessary.     

Spatial and seasonal variability of the mass concentration and chemical composition of PM2.5 in Poland

The seasonal changes in ambient mass concentrations and chemical composition of fine particulate matter (PM_2.5) were investigated in three locations in Poland. The analyses included PM_2.5-bound hazardous benzo(a)pyrene (BaP), As, Ni, Cd, and Pb. The samples of PM_2.5 were collected daily in Katowice (southern Poland, urban background site), Gdańsk, and Diabla Góra (northern Poland, urban and regional background sites, respectively) during 1-year-long campaign in 2010. Based on monthly ambient concentrations of PM_2.5-bound carbon (organic and elemental), water-soluble ions (Na⁺, NH₄ ⁺, K⁺, Mg²⁺, Ca²⁺, Cl^?, NO₃ ^?, SO₄ ^2?), and elements As, Ni, Cd, Pb, Ti, Al, Fe, the chemical mass closure of PM_2.5 was checked for each of the four seasons of the year and for the heating and non-heating periods at each site. Also, the annual concentrations of PM_2.5 were determined and the annual PM_2.5 mass closure checked. At each measuring point, the PM_2.5 concentrations were high compared to its Polish yearly permissible value, 25 μg/m³, and its concentrations elsewhere in Europe. The highest annual PM_2.5 concentration, 43 μg/m³, occurred in Katowice; it was twice the annual PM_2.5 concentration in Gdańsk, and thrice the one in Diabla Góra. The high annual averages were due to very high monthly concentrations in the heating period, which were highest in the winter. PM_2.5 consisted mainly of carbonaceous matter (elemental carbon (EC) + organic matter (OM), the sum of elemental carbon, EC, and organic matter, OM; its annual mass contributions to PM_2.5 were 43, 31, and 33 % in Katowice, Gdansk, and Diabla Góra, respectively), secondary inorganic aerosol (SIA), the Na_Cl group, and crustal matter (CM)—in the decreasing order of their yearly mass contributions to PM_2.5. OM, EC, SIA, Na_Cl, and CM accounted for almost 81 % of the PM_2.5 mass in Katowice, 74 % in Gdańsk, and 90 % in Diabla Góra. The annual average toxic metal contribution to the PM_2.5 mass was not greater than 0.2 % at each site. In Katowice and Gdańsk, the yearly ambient BaP concentrations were high (15.4 and 3.2 ng/m³, respectively); in rural Diabla Góra, the concentrations of BaP were almost equal to 1 ng/m³, the Polish BaP annual limit. The great seasonal fluctuations of the shares of the component groups in PM_2.5 and of the concentrations of PM_2.5 and its components are due to the seasonal fluctuations of the emissions of PM and its precursors from hard and brown coal combustion for energy production, growing in a heating season, reaching maximum in winter, and decreasing in a non-heating period. In Gdańsk, northern Poland, especially in the spring and autumn, sea spray might have affected the chemical composition of PM_2.5. The greatest hazard from PM_2.5 occurs in Katowice, southern Poland, in winter, when very high concentrations of PM_2.5 and PM_2.5-related carbonaceous matter, including BaP, are maintained by poor natural ventilation in cities, weather conditions, and the highest level of industrialization in Poland. In less industrialized northern Poland, where the aeration in cities is better and rather gaseous than solid fuels are used, the health hazard from ambient PM_2.5 is much lower.     

The chicken chorioallantoic membrane model in biology,medicine and bioengineering

The chicken chorioallantoic membrane (CAM) is a simple, highly vascularized extraembryonic membrane, which performs multiple functions during embryonic development, including but not restricted to gas exchange. Over the last two decades, interest in the CAM as a robust experimental platform to study blood vessels has been shared by specialists working in bioengineering, development, morphology, biochemistry, transplant biology, cancer research and drug development. The tissue composition and accessibility of the CAM for experimental manipulation, makes it an attractive preclinical in vivo model for drug screening and/or for studies of vascular growth. In this article we provide a detailed review of the use of the CAM to study vascular biology and response of blood vessels to a variety of agonists. We also present distinct cultivation protocols discussing their advantages and limitations and provide a summarized update on the use of the CAM in vascular imaging, drug delivery, pharmacokinetics and toxicology.