Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections

A series of thirty-two anilides of 3-(trifluoromethyl)cinnamic acid (series 1) and 4-(trifluoromethyl)cinnamic acid (series 2) was prepared by microwave-assisted synthesis. All the compounds were tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE). All the compounds were evaluated in vitro against Mycobacterium smegmatis ATCC 700084 and M. marinum CAMP 5644. (2E)-3-[3-(Trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)phenyl]prop-2-enamide (1j), (2E)-N-(3,5-dichlorophenyl)-3-[3-(trifluoromethyl)phenyl]prop-2-enamide (1o) and (2E)-N-[3-(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)-phenyl]prop-2-enamide (2i), (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]-prop-2-enamide (2p) showed antistaphylococcal (MICs/MBCs 0.15–5.57 µM) as well as anti-enterococcal (MICs/MBCs 2.34–44.5 µM) activity. The growth of M. marinum was strongly inhibited by compounds 1j and 2p in a MIC range from 0.29 to 2.34 µM, while all the agents of series 1 showed activity against M. smegnatis (MICs ranged from 9.36 to 51.7 µM). The performed docking study demonstrated the ability of the compounds to bind to the active site of the mycobacterial enzyme InhA. The compounds had a significant effect on the inhibition of bacterial respiration, as demonstrated by the MTT assay. The compounds showed not only bacteriostatic activity but also bactericidal activity. Preliminary in vitro cytotoxicity screening was assessed using the human monocytic leukemia cell line THP-1 and, except for compound 2p, all effective agents did show insignificant cytotoxic effect. Compound 2p is an interesting anti-invasive agent with dual (cytotoxic and antibacterial) activity, while compounds 1j and 1o are the most interesting purely antibacterial compounds within the prepared molecules.     

The effects of high altitude on choice reaction time mean and intra-individual variability: Results of the Edinburgh Altitude Research Expedition of 2008.

Objective: This study aimed to investigate the effects of high altitude on reaction time (RT) mean and intra-individual variability. Method: Ten students (6 men, 4 women) took a 4-choice RT test and had their vital signs and Lake Louise (LL) score measured on 21 occasions during the Edinburgh Altitude Research Expedition of 2008 to the Western Himalayas (max. altitude 5,565 m). Results: Linear mixed modeling revealed that mean RT was significantly impaired at altitudes above 4,000 m (p B = 1.97, 95% CI [0.70, 3.23], p B = ?1.50, 95% CI [?2.60, ?0.39], p B = ?2.16, 95% CI [?2.49, ?1.83], p B = 0.01801, 95% CI [0.0049, 0.0311], p B = ?0.00754, 95% CI [?0.0119, ?0.0032], p     

Impaired Innate Immunity in Pediatric Patients Type 1 Diabetes—Focus on Toll-like Receptors Expression

Type 1 diabetes (DM1) is classified as an autoimmune disease. An uncontrolled response of B and T lymphocytes to the body’s own tissues develops in the absence of immune tolerance. The main aim of the study was to evaluate the effect of the duration of type 1 diabetes in children on the expression of TLR receptors and the relationship with the parameters of glycemic control in patients. As a result, we showed significant differences in the level of TLR2, TLR4 and TLR9 expression in patients with DM1 in the early stage of the disease and treated chronically compared to the healthy group. Additionally, in this study, we found that the numbers of CD19+ B cells, CD3+ CD4+, CD3+ CD8+ T cells and NK cells are different for newly diagnosed DM1 individuals, patients receiving chronic treatment and for healthy controls, indicating an important role of these cells in killing pancreatic beta cells. Moreover, higher levels of IL-10 in patients with newly diagnosed DM1 have also been found, confirming the reports found in the literature.     

rs7041 and rs4588 Polymorphisms in Vitamin D Binding Protein Gene (VDBP) and the Risk of Diseases

The purpose of the study was to investigate the role of vitamin D binding protein (VDBP, DBP) and its polymorphism in the vitamin D pathway and human health. This narrative review shows the latest literature on the most popular diseases that have previously been linked to VDBP. Vitamin D plays a crucial role in human metabolism, controlling phosphorus and calcium homeostasis. Vitamin D binding protein bonds vitamin D and its metabolites and transports them to target tissues. The most common polymorphisms in the VDBP gene are rs4588 and rs7041, which are located in exon 11 in domain III of the VDBP gene. rs4588 and rs7041 may be correlated with differences not only in vitamin D status in serum but also with vitamin D metabolites. This review supports the role of single nucleotide polymorphisms (SNPs) in the VDBP gene and presents the latest data showing correlations between VDBP variants with important human diseases such as obesity, diabetes mellitus, tuberculosis, chronic obstructive pulmonary disease, and others. In this review, we aim to systematize the knowledge regarding the occurrence of diseases and their relationship with vitamin D deficiencies, which may be caused by polymorphisms in the VDBP gene. Further research is required on the possible influence of SNPs, modifications in the structure of the binding protein, and their influence on the organism. It is also important to mention that most studies do not have a specific time of year to measure accurate vitamin D metabolite levels, which can be misleading in conclusions due to the seasonal nature of vitamin D.     

The Influence of Intravaginal Gestagens Treatment on the Morphological Features and Endometrial Steroid Hormone Receptors Content during Anestrus Type II in Dairy Cattle

Background: Gestagens are the most widely used therapy in anestrus type II. The aim of this research is to evaluate the effectiveness of the vaginal progesterone inserts therapy in anestrus type II in cows. Methods: The study was conducted on 33 cows. Progesterone (PR) and estrogen (ER) receptors expression in endometrium was assessed on a molecular level based on mRNA tissue expression. Additionally, blood 17ß-estradiol and progesterone levels were evaluated. Results: A decrease in mRNA expression of A and B PR and ER α was noted in treated and untreated animals. In the treated group, an increase of ERß mRNA expression was observed, while a decreased was found in untreated animals. There was increased PR, ERα and ß expression in endometrial tissue in treated cows, and decreased expression of these factors in untreated cows. In the treated group, recurrence of ovarian cyclicity was noted in 52% of animals and pregnancy was obtained in 34.8% of them, while in the untreated group, recurrence did not occur. In the control group, spontaneous recurrence of ovarian cyclicity was not observed. An increase of PR expression was correlated with increased proliferation of endometrial cells. Conclusions: It seems likely that the endometrium is well developed and ready for placentation after removing the exogenous source of progesterone and preventing the recurrence of cyclicity of ovaries.     

The Influence of Angiotensin Peptides on Survival and Motility of Human High-Grade Serous Ovarian Cancer Cells in Serum Starvation Conditions

High-grade serous ovarian carcinoma (HGSOC) is the most frequent and malignant form of ovarian cancer. A local renin–angiotensin system (RAS) has been found in the ovary, and changes in selected components of this system were observed in pathological states and also in ovarian cancer. In the present study, we examined the effect of three peptides, Ang-(1-7), Ang-(1-9) and Ang-(3-7), on proliferation and motility of the OVPA8 cell line, a new well-defined and preclinical model of HGSOC. We confirmed the presence of mRNA for all angiotensin receptors in the tested cells. Furthermore, our findings indicate that all tested angiotensin peptides increased the metabolic serum in the medium by activation of cell defense mechanisms such as nuclear factor kappaB signaling pathway andapoptosis. Moreover, tested angiotensin peptides intensified serum starvation-induced cell cycle arrest at the G0/G1 phase. In the case of Ang-(3-7), a significant decrease in the number of Ki67 positive cells (Ki67+) and reduced percentage of activated ERK1/2 levels in ovarian cancer cells were additionally reported. The angiotensin-induced effect of the accumulation of cells in the G0/G1 phase was not observed in OVPA8 cells growing on the medium with 10% FBS. Moreover, in the case of Ang-(3-7), the tendency was quite the opposite. Ang-(1-7) but not Ang-(1-9) or Ang-(3-7) increased the mobility of reluctant-to-migrate OVAP8 cells cultured in the serum-free medium. In any cases, the changes in the expression of VIM and HIF1A gene, associated with epithelial–mesenchymal transition (EMT), were not observed. In conclusion, we speculate that the adaptation to starvation in nutrient-deprived tumors can be modulated by peptides from the renin–angiotensin system. The influence of angiotensin peptides on cancer cells is highly dependent on the availability of growth factors and nutrients.     

Adaptive Synthesis of Functional Amphiphilic Dendrons as a Novel Approach to Artificial Supramolecular Objects

Supramolecular structures, such as micelles, liposomes, polymerosomes or dendrimerosomes, are widely studied and used as drug delivery systems. The behavior of amphiphilic building blocks strongly depends on their spatial distribution and shape of polar and nonpolar component. This report is focused on the development of new versatile synthetic protocols for amphiphilic carbosilane dendrons (amp-CS-DDNs) capable of self-assembly to regular micelles and other supramolecular objects. The presented strategy enables the fine modification of amphiphilic structure in several ways and also enables the facile connection of a desired functionality. DLS experiments demonstrated correlations between structural parameters of amp-CS-DDNs and the size of formed nanoparticles. For detailed information about the organization and spatial distribution of amp-CS-DDNs assemblies, computer simulation models were studied by using molecular dynamics in explicit water.     

Study of Biological Activities and ADMET-Related Properties of Novel Chlorinated N-arylcinnamamides

A series of eighteen 4-chlorocinnamanilides and eighteen 3,4-dichlorocinnamanilides were designed, prepared and characterized. All compounds were evaluated for their activity against gram-positive bacteria and against two mycobacterial strains. Viability on both cancer and primary mammalian cell lines was also assessed. The lipophilicity of the compounds was experimentally determined and correlated together with other physicochemical properties of the prepared derivatives with biological activity. 3,4-Dichlorocinnamanilides showed a broader spectrum of action and higher antibacterial efficacy than 4-chlorocinnamanilides; however, all compounds were more effective or comparable to clinically used drugs (ampicillin, isoniazid, rifampicin). Of the thirty-six compounds, six derivatives showed submicromolar activity against Staphylococcus aureus and clinical isolates of methicillin-resistant S. aureus (MRSA). (2E)-N-[3,5-bis(trifluoromethyl)phenyl]- 3-(4-chlorophenyl)prop-2-enamide was the most potent in series 1. (2E)-N-[3,5-bis(Trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-enamide, (2E)-3-(3,4-dichlorophenyl)-N-[3-(trifluoromethyl)phenyl]prop-2-enamide, (2E)-3-(3,4-dichloro- phenyl)-N-[4-(trifluoromethyl)phenyl]prop-2-enamide and (2E)-3-(3,4-dichlorophenyl)- N-[4-(trifluoromethoxy)phenyl]prop-2-enamide were the most active in series 2 and in addition to activity against S. aureus and MRSA were highly active against Enterococcus faecalis and vancomycin-resistant E. faecalis isolates and against fast-growing Mycobacterium smegmatis and against slow-growing M. marinum, M. tuberculosis non-hazardous test models. In addition, the last three compounds of the above-mentioned showed insignificant cytotoxicity to primary porcine monocyte-derived macrophages.     

Multimodal Spectroscopic Imaging of Pea Root Nodules to Assess the Nitrogen Fixation in the Presence of Biofertilizer Based on Nod-Factors

Multimodal spectroscopic imaging methods such as Matrix Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI MSI), Fourier Transform Infrared spectroscopy (FT-IR) and Raman spectroscopy were used to monitor the changes in distribution and to determine semi quantitatively selected metabolites involved in nitrogen fixation in pea root nodules. These approaches were used to evaluate the effectiveness of nitrogen fixation by pea plants treated with biofertilizer preparations containing Nod factors. To assess the effectiveness of biofertilizer, the fresh and dry masses of plants were determined. The biofertilizer was shown to be effective in enhancing the growth of the pea plants. In case of metabolic changes, the biofertilizer caused a change in the apparent distribution of the leghaemoglobin from the edges of the nodule to its centre (the active zone of nodule). Moreover, the enhanced nitrogen fixation and presumably the accelerated maturation form of the nodules were observed with the use of a biofertilizer.     

Upgrading biogas produced at dairy farms into renewable natural gas by methanation

Renewable natural gas can be produced from raw biogas, a product of the anaerobic decomposition of organic material, by upgrading its CO₂ content (25‐50%) via thermocatalytic hydrogenation (CO₂ methanation). The H₂ needed for this reaction can be generated by water electrolysis powered by carbon emission‐free energy sources such as renewable or nuclear power, or using surplus electricity. Herein, after briefly outlining some aspects of biogas production at dairy farms and highlighting recent developments in the design of methanation systems, a case study on the renewable natural gas generation is presented. The performance of a system for renewable natural gas generation from a 2000‐head dairy farm livestock manure is evaluated and assessed for its economic potential. The project is predicted to generate revenue through the sale of energy and carbon credits with the payback period of 5 years, with a subsidized energy price.