Testing the Utility of Polygenic Risk Scores for Type 2 Diabetes and Obesity in Predicting Metabolic Changes in a Prediabetic Population: An Observational Study

Prediabetes is an intermediate state of hyperglycemia during which glycemic parameters are above normal levels but below the T2D threshold. T2D and its precursor prediabetes affect 6.28% and 7.3% of the world’s population, respectively. The main objective of this paper was to create and compare two polygenic risk scores (PRSs) versus changes over time (Δ) in metabolic parameters related to prediabetes and metabolic complications. The genetics of 446 prediabetic patients from the Polish Registry of Diabetes cohort were investigated. Seventeen metabolic parameters were measured and compared at baseline and after five years using statistical analysis. Subsequently, genetic polymorphisms present in patients were determined to build a T2D PRS (68 SNPs) and an obesity PRS (21 SNPs). Finally, the association among the two PRSs and the Δ of the metabolic traits was assessed. After a multiple linear regression with adjustment for age, sex, and BMI at a nominal significance of (p < 0.05) and adjustment for multiple testing, the T2D PRS was found to be positively associated with Δ fat mass (FM) (p = 0.025). The obesity PRS was positively associated with Δ FM (p = 0.023) and Δ 2 h glucose (p = 0.034). The comparison of genotype frequencies showed that AA genotype carriers of rs10838738 were significantly higher in Δ 2 h glucose and in Δ 2 h insulin. Our findings suggest that prediabetic individuals with a higher risk of developing T2D experience increased Δ FM, and those with a higher risk of obesity experience increased Δ FM and Δ two-hour postprandial glucose. The associations found in this research could be a powerful tool for identifying prediabetic individuals with an increased risk of developing T2D and obesity.     

Decomposition of methane in the presence of ethanol over activated carbon catalyst

The interest in hydrogen as a potential fuel of the future has stimulated development of new technologies of its production. The main method of hydrogen production is based on the process of steam reforming of methane, but recently increasing attention has been paid to the catalytic decomposition of methane (CDM) whose advantage is its pro-ecological character. This reaction, besides hydrogen, produces also catalytically low-active carbonaceous deposit which settles on the surface of the catalyst and leads to its deactivation. The study reported is an attempt at suppressing the catalyst deactivation by developing a method leading to formation of carbonaceous deposit potentially active in CDM process. For this purpose, it was proposed that the reaction system would contain methane and ethanol. Simultaneous decomposition of these two substances was performed in parallel at three temperatures of 750, 850 or 950 °C. The catalyst was activated carbon obtained from the hazelnut shells. The addition of ethanol was found to have a positive effect on the course of CDM, leading to an increase in the amount of hydrogen produced and to stabilisation of the catalyst activity at a high level.     

Dexamethasone and 1,25-Dihydroxyvitamin D3 Reduce Oxidative Stress-Related DNA Damage in Differentiating Osteoblasts

The process of osteoblast differentiation is regulated by several factors, including RUNX2. Recent reports suggest an involvement of RUNX2 in DNA damage response (DDR), which is important due to association of differentiation with oxidative stress. In the present work we explore the influence of two RUNX2 modifiers, dexamethasone (DEX) and 1,25-dihydroxyvitamin D3 (1,25-D3), in DDR in differentiating MC3T3-E1 preosteoblasts challenged by oxidative stress. The process of differentiation was associated with reactive oxygen species (ROS) production and tert-butyl hydroperoxide (TBH) reduced the rate of differentiation. The activity of alkaline phosphatase (ALP), a marker of the process of osteoblasts differentiation, increased in a time-dependent manner and TBH further increased this activity. This may indicate that additional oxidative stress, induced by TBH, may accelerate the differentiation process. The cells displayed changes in the sensitivity to TBH in the course of differentiation. DEX increased ALP activity, but 1,25-D3 had no effect on it. These results suggest that DEX might stimulate the process of preosteoblasts differentiation. Finally, we observed a protective effect of DEX and 1,25-D3 against DNA damage induced by TBH, except the day 24 of differentiation, when DEX increased the extent of TBH-induced DNA damage. We conclude that oxidative stress is associated with osteoblasts differentiation and induce DDR, which may be modulated by RUNX2-modifiers, DEX and 1,25-D3.     

Synthesis and Antibacterial Activity of New N-Alkylammonium and Carbonate-Triazole Derivatives within Desosamine of 14- and 15-Membered Lactone Macrolides

Desosamines of azithromycin (AZM) and clarithromycin (CLA) were modified by N-alkylation or nucleophilic substitution at the carbonyl/CuAAC sequence. Biological studies revealed a higher antibacterial potency of quaternary N-alkylammonium bromides of CLA as compared to AZM. SAR studies of CLA salts, including biological, conformation and molecular-docking analysis, enriched by physicochemical parameters, showed the importance of less bulky and unsaturated substituent for an efficient docking mode at the ribosomal tunnel and good antibacterial potency against clinical and standard Streptococcus pneumoniae and Streptococcus pyogenes strains (MICs 0.25 or 0.5 μg/mL). These CLA salts also have an at least threefold lower cytotoxicity than reference antibiotics at comparable antibacterial activity against the S. pneumoniae clinical strain. Differences in antibacterial effects noted for AZM and CLA salts bearing less bulky N-substituents can be better understood when their binding modes in the ribosomal tunnel are considered rather than their common low lipophilicity and excellent water solubility.     

Modification of microporous polyurethane elastomers with different types of ash—morphological,mechanical, and thermal studies

Incorporation of wood ash particles from wood gasification into microporous polyurethane elastomers has been investigated and compared to addition of commercially available microspheres resulting from coal burning. Samples were modified with 3 and 6 wt% of fillers. Structure, mechanical, and thermal properties of obtained elastomers were investigated. Incorporation of both types of ash particles decreased the density of polyurethanes simultaneously increasing their tensile strength and elongation at break. Addition of microspheres caused changes in segment structure of polyurethane, which had negative impact on thermal stability. Although the use of ash from wood pyrolysis enhanced thermal stability of elastomers, causing “labyrinth effect,”, which inhibited significantly thermal degradation of material. Results of research show that wood ash can be successfully used as a modifier of mechanical and thermal properties in polyurethane elastomers. POLYM. COMPOS., 37:881–889, 2016. © 2014 Society of Plastics Engineers     

Influence of Complexation of Thiosemicarbazone Derivatives with Cu (II) Ions on Their Antitumor Activity against Melanoma Cells

A series of thiosemicarbazone derivatives was prepared and their anti-tumor activity in vitro was tested. The X-ray investigation performed for compounds T2, T3 and T5 confirmed the synthesis pathway and assumed molecular structures of analyzed thiosemicarbazones. The conformational preferences of the thiosemicarbazone system were characterized using theoretical calculations by AM1 method. Selected compounds were converted into complexes of Cu (II) ions. The effect of complexing on anti-tumor activity has been investigated. The copper(II) complexes, with Schiff bases T1, T10, T12, T13, and T16 have been synthesized and characterized by chemical and elemental analysis, FTIR spectroscopy and TGA method. Thermal properties of coordination compounds were studied using TG-DTG techniques under dry air atmosphere. G361, A375, and SK-MEL-28 human melanoma cells and BJ human normal fibroblast cells were treated with tested compounds and their cytotoxicity was evaluated with MTT test. The compounds with the most promising anti-tumour activity were then selected and their cytotoxicity was verified with cell cycle analysis and apoptosis/necrosis detection. Additionally, DNA damages in the form of a basic sites presence and the expression of oxidative stress and DNA damage response genes were evaluated. The obtained results indicate that complexation of thiosemicarbazone derivatives with Cu (II) ions improves their antitumor activity against melanoma cells. The observed cytotoxic effect is associated with DNA damage and G2/M phase of cell cycle arrest as well as disorders of the antioxidant enzymes expression.     

KIT Expression Is Regulated by DNA Methylation in Uveal Melanoma Tumors

Uveal melanoma (UM) is an ocular tumor with a dismal prognosis. Despite the availability of precise molecular and cytogenetic techniques, clinicopathologic features with limited accuracy are widely used to predict metastatic potential. In 51 UM tissues, we assessed a correlation between the expression of nine proteins evaluated by immunohistochemistry (IHC) (Melan-A, S100, HMB45, Cyclin D1, Ki-67, p53, KIT, BCL2, and AIFM1) and the presence of UM-specific chromosomal rearrangements measured by multiplex ligation-dependent probe amplification (MLPA), to find IHC markers with increased prognostic information. Furthermore, mRNA expression and DNA methylation values were extracted from the whole-genome data, achieved by analyzing 22 fresh frozen UM tissues. KIT positivity was associated with monosomy 3, increasing the risk of poor prognosis more than 17-fold (95% CI 1.53–198.69, p = 0.021). A strong negative correlation was identified between mRNA expression and DNA methylation values for 12 of 20 analyzed positions, five located in regulatory regions of the KIT gene (r = −0.658, p = 0.001; r = −0.662, p = 0.001; r = −0.816; p < 0.001; r = −0.689, p = 0.001; r = −0.809, p < 0.001, respectively). DNA methylation β values were also inversely associated with KIT protein expression (p = 0.001; p = 0.001; p = 0.015; p = 0.025; p = 0.002). Our findings, showing epigenetic deregulation of KIT expression, may contribute to understanding the past failure to therapeutically target KIT in UM.     

Molecular and Functional Characterization of MobK Protein—A Novel-Type Relaxase Involved in Mobilization for Conjugational Transfer of Klebsiella pneumoniae Plasmid pIGRK

Conjugation, besides transformation and transduction, is one of the main mechanisms of horizontal transmission of genetic information among bacteria. Conjugational transfer, due to its essential role in shaping bacterial genomes and spreading of antibiotics resistance genes, has been widely studied for more than 70 years. However, new and intriguing facts concerning the molecular basis of this process are still being revealed. Most recently, a novel family of conjugative relaxases (Mob proteins) was distinguished. The characteristic feature of these proteins is that they are not related to any of Mobs described so far. Instead of this, they share significant similarity to tyrosine recombinases. In this study MobK—a tyrosine recombinase-like Mob protein, encoded by pIGRK cryptic plasmid from the Klebsiella pneumoniae clinical strain, was characterized. This study revealed that MobK is a site-specific nuclease and its relaxase activity is dependent on both a conserved catalytic tyrosine residue (Y¹⁷⁹) that is characteristic of tyrosine recombinases and the presence of Mg²⁺ divalent cations. The pIGRK minimal origin of transfer sequence (oriT) was also characterized. This is one of the first reports presenting tyrosine recombinase-like conjugative relaxase protein. It also demonstrates that MobK is a convenient model for studying this new protein family.     

Effect of Vitamin C/Hydrocortisone Immobilization within Curdlan-Based Wound Dressings on In Vitro Cellular Response in Context of the Management of Chronic and Burn Wounds

Bioactive dressings are usually produced using natural or synthetic polymers. Recently, special attention has been paid to β-glucans that act as immunomodulators and have pro-healing properties. The aim of this research was to use β-1,3-glucan (curdlan) as a base for the production of bioactive dressing materials (curdlan/agarose and curdlan/chitosan) that were additionally enriched with vitamin C and/or hydrocortisone to improve healing of chronic and burn wounds. The secondary goal of the study was to compressively evaluate biological properties of the biomaterials. In this work, it was shown that vitamin C/hydrocortisone-enriched biomaterials exhibited faster vitamin C release profile than hydrocortisone. Consecutive release of the drugs is a desired phenomenon since it protects wounds against accumulation of high and toxic concentrations of the bioactive molecules. Moreover, biomaterials showed gradual release of low doses of the hydrocortisone, which is beneficial during management of burn wounds with hypergranulation tissue. Among all tested variants of biomaterials, dressing materials enriched with hydrocortisone and a mixture of vitamin C/hydrocortisone showed the best therapeutic potential since they had the ability to significantly reduce MMP-2 synthesis by macrophages and increase TGF-β1 release by skin cells. Moreover, materials containing hydrocortisone and its blend with vitamin C stimulated type I collagen deposition by fibroblasts and positively affected their migration and proliferation. Results of the experiments clearly showed that the developed biomaterials enriched with bioactive agents may be promising dressings for the management of non-healing chronic and burn wounds.     

Interactions between effects of environmental chemicals and natural stressors: A review

Ecotoxicological effect studies often expose test organisms under optimal environmental conditions. However, organisms in their natural settings rarely experience optimal conditions. On the contrary, during most of their lifetime they are forced to cope with sub-optimal conditions and occasionally with severe environmental stress. Interactions between the effects of a natural stressor and a toxicant can sometimes result in greater effects than expected from either of the stress types alone. The aim of the present review is to provide a synthesis of existing knowledge on the interactions between effects of “natural” and chemical (anthropogenic) stressors. More than 150 studies were evaluated covering stressors including heat, cold, desiccation, oxygen depletion, pathogens and immunomodulatory factors combined with a variety of environmental pollutants. This evaluation revealed that synergistic interactions between the effects of various natural stressors and toxicants are not uncommon phenomena. Thus, synergistic interactions were reported in more than 50% of the available studies on these interactions. Antagonistic interactions were also detected, but in fewer cases. Interestingly, about 70% of the tested chemicals were found to compromise the immune system of humans as judged from studies on human cell lines. The challenge for future studies will therefore be to include aspects of combined stressors in effect and risk assessment of chemicals in the environment.