The Potential Application of Starch and Walnut Shells as Biofillers for Natural Rubber (NR) Composites.

The goal of this study was application of corn starch and ground walnut shells in various amounts by weight as biofillers of natural rubber (NR) biocomposites. Additionally, ionic liquid 1-butyl-3-methylimidazolium chloride (BmiCl) and (3-aminopropyl)-triethoxysilane (APTES) were used to increase the activity of biofillers and to improve the curing characteristics of NR composites. The effect of biofillers used and their modification with aminosilane or ionic liquid on the curing characteristics of NR composites and their functional properties, including crosslink density, mechanical properties in static and dynamic conditions, hardness, thermal stability and resistance to thermo-oxidative aging were investigated. Starch and ground walnut shells were classified as inactive fillers, which can be used alternatively to commercial inactive fillers, e.g., chalk. BmiCl and APTES were successfully used to support the vulcanization and to improve the dispersion of biofillers in NR elastomer matrix. Vulcanizates with starch, especially those containing APTES and BmiCl, exhibited improved tensile properties due to the higher crosslink density and homogenous dispersion of starch, which resulted from BmiCl addition. NR filled with ground walnut shells demonstrated improved resistance to thermo-oxidative aging. It resulted from lignin present in walnut shells, the components of which belong to polyphenols, that have an antioxidant activity.

Micro-RNAs in Response to Active Forms of Vitamin D3 in Human Leukemia and Lymphoma Cells.

Non-coding micro-RNA (miRNAs) regulate the protein expression responsible for cell growth and proliferation. miRNAs also play a role in a cancer cells' response to drug treatment. Knowing that leukemia and lymphoma cells show different responses to active forms of vitamin D3, we decided to investigate the role of selected miRNA molecules and regulated proteins, analyzing if there is a correlation between the selected miRNAs and regulated proteins in response to two active forms of vitamin D3, calcitriol and tacalcitol. A total of nine human cell lines were analyzed: five leukemias: MV-4-1, Thp-1, HL-60, K562, and KG-1; and four lymphomas: Raji, Daudi, Jurkat, and U2932. We selected five miRNA molecules-miR-27b, miR-32, miR-125b, miR-181a, and miR-181b-and the proteins regulated by these molecules, namely, CYP24A1, Bak1, Bim, p21, p27, p53, and NF-kB. The results showed that the level of selected miRNAs correlates with the level of proteins, especially p27, Bak1, NFκB, and CYP24A1, and miR-27b and miR-125b could be responsible for the anticancer activity of active forms of vitamin D3 in human leukemia and lymphoma.

The Impact of Exosomes/Microvesicles Derived from Myeloid Dendritic Cells Cultured in the Presence of Calcitriol and Tacalcitol on Acute B-Cell Precursor Cell Lines with MLL Fusion Gene.

Vitamin D analogs (VDAs) may directly inhibit the growth of normal and malignant (derived from acute lymphoblastic leukemia (ALL)) B cells, as both types of cells express vitamin D receptor (VDR). We performed anti-proliferative, morphology tests and phenotyping to evaluate the sensitivity of monocytes and iDCs (immature myeloid-derived dendritic cells) on calcitriol and tacalcitol treatment, phenotyping, morphology, and size distribution measurement to determine the characteristics of microvesicles (MVs) and exosomes (EXs) derived from them and, finally, phenotyping and Elisa test to determine the effects of VDAs on modulation of the phenotype of B cells through extracellular vesicles (EVs) released by iDCs. Our results confirmed that both SC cells and iDCs were sensitive to the VDAs and showed altered surface expression of markers associated with monocyte differentiation, which was resulting in the phenotypic changes in EVs derived from them. We also showed that obtained EVs could change the morphology and phenotype of ALL-B-derived precursor cells in a different way, depending on their origin. The differential effect of VDAs on ALL-B cells, which was associated with increased or decreased expression of CD27, CD24, CD38, and CD23 expression, was observed. Hence, further studies to explain the modulation in the composition of EVs by VDAs are required.

Micro- and Nanosecond Pulses Used in Doxorubicin Electrochemotherapy in Human Breast and Colon Cancer Cells with Drug Resistance.

(1) Background: Pulsed electric field (PEF) techniques are commonly used to support the delivery of various molecules. A PEF seems a promising method for low permeability drugs or when cells demonstrate therapy resistance and the cell membrane becomes an impermeable barrier. (2) Methods: In this study, we have used doxorubicin-resistant and sensitive models of human breast cancer (MCF-7/DX, MCF-7/WT) and colon cancer cells (LoVo, LoVoDX). The study aimed to investigate the susceptibility of the cells to doxorubicin (DOX) and electric fields in the 20-900 ns pulse duration range. The viability assay was utilized to evaluate the PEF protocols' efficacy. Cell confluency and reduced glutathione were measured after PEF protocols. (3) Results: The obtained results showed that PEFs significantly supported doxorubicin delivery and cytotoxicity after 48 and 72 h. The 60 kV/cm ultrashort pulses × 20 ns × 400 had the most significant cytotoxic anticancer effect. The increase in DOX concentration provokes a decrease in cell viability, affected cell confluency, and reduced GSSH when combined with the ESOPE (European Standard Operating Procedures of Electrochemotherapy) protocol. Additionally, reactive oxygen species after PEF and PEF-DOX were detected. (4) Conclusions: Ultrashort electric pulses with low DOX content or ESOPE with higher DOX content seem the most promising in colon and breast cancer treatment.

Future Treatment Options in Systemic Sclerosis-Potential Targets and Ongoing Clinical Trials.

Systemic sclerosis is an autoimmune connective tissue disease characterized by vasculopathy and fibrosis of the skin and internal organs. The pathogenesis of systemic sclerosis is very complex. Mediators produced by immune cells are involved in the inflammatory processes occurring in the tissues. The currently available therapeutic options are often insufficient to halt disease progress. This article presents an overview of potential therapeutic targets and the pipeline of possible future therapeutic options. It is based on research of clinical trials involving novel, unestablished methods of treatment. Increasing knowledge of the processes and mediators involved in systemic scleroderma has led to the initiation of drug trials with therapeutic targets of CD28-CD80/86, CD19, CCL24, CD20, CD30, tumor necrosis factor (TNF), transforming growth factor ß (TGF-ß), B-cell activating factor (BAFF), lysophosphatidic acid receptor 1 (LPA1 receptor), soluble guanylate cyclase (sGC), Janus kinases (JAK), interleukin 6 (IL-6), endothelin receptor, and autotaxin. Data from clinical trials on these drugs indicate a significant potential for several new therapeutic options for systemic sclerosis in the upcoming future.

The Synergistic Effect of Dibenzyldithiocarbamate Based Accelerator on the Vulcanization and Performance of the Silica-Filled Styrene-Butadiene Elastomer.

This work focused on studying the effect of dibenzyldithocarbamate vulcanization accelerator on the curing characteristics and performance of styrene-butadiene elastomer (SBR) filled with nanosized silica. A dibenzyldithocarbamate derivative was applied as an additional accelerator to enhance the efficiency and the rate of sulfur vulcanization in the presence of two other accelerators, i.e., N-cyclohexyl-2-benzothiazole sulfenamide (CBS) and/or 1,3-diphenylguanidine (DPG). Furthermore, the possibility of reducing the amount of zinc oxide (ZnO) and the elimination of CBS and DPG from elastomer compounds using dibenzyldithiocarbamate accelerator was tested. Dibenzyldithocarbamate derivative applied with other accelerators (especially CBS) effectively enhances the efficiency of SBR vulcanization by reducing the optimal vulcanization time and increasing the crosslink density of the vulcanizates despite the lower amount of ZnO. Moreover, vulcanizates with dibenzyldithocarbamate demonstrate higher tensile strength while having a smaller content of CBS or DPG compared to the reference SBR composites. Thus, the synergistic effect of dibenzydithiocarbamate derivative on the vulcanization and performance of SBR was confirmed. Furthermore, dibenzyldithocarbamate derivative enables the amount of ZnO to be reduced by 40% without harmful influence on the crosslink density and performance of the vulcanizates. Finally, it is possible to replace CBS with a dibenzyldithiocarbamate derivative without the crosslink density and tensile strength of the vulcanizates being adversely affected, while improving their resistance to thermo-oxidative aging.

Influence of the Silica Specific Surface Area and Ionic Liquids on the Curing Characteristics and Performance of Styrene-Butadiene Rubber Composites.

In this work, we present the effect of silica's specific surface area (180 m2·g-1 and 380 m2·g-1, respectively) on the crosslinking of styrene-butadiene rubber (SBR) composites, as well as their crosslink density and functional properties, such as thermal stability, damping behavior, resistance to thermo-oxidative aging, and tensile properties. Ionic liquids (ILs) with a bromide anion and different cations, i.e., 1-butyl-3-methylimidazolium (Bmi), 1-butyl-3-methylpyrrolidinium (Bmpyr), and 1-butyl-3-methylpiperidinium (Bmpip), were used to enhance the cure characteristics of SBR compounds and the functional properties of SBR vulcanizates. It was proven that apart from the silica's specific surface area, the filler-polymer and filler-filler physical interactions have a significant impact on the vulcanization kinetics of silica-filled SBR composites. Additionally, the performed studies have shown that ILs positively affected the dispersion of silica's particles and reduced their ability to form agglomerates in the elastomer matrix, which enhanced the functional properties of the SBR vulcanizates.

Effects of high-frequency nanosecond pulses on prostate cancer cells.

Electroporation with pulsed electric fields show a potential to be applied as an experimental focal therapy of tumors. Sub-microsecond regime of electric pulses displays unique electrophysical features operative in cells and membranes. Recently, MHz compression of nanosecond pulses electric fields (nsPEFs) bursts proved to enhance the effectiveness of the therapy. High morbidity of prostate cancer (PCa) and risk of overtreatment associated with this malignancy call for new minimal-invasive treatment alternative. Herein we present the in vitro study for developing applications based on this new technology. In this study, we used flow cytometric analysis, cell viability assay, caspase activity analysis, wound healing assay, confocal microscopy study, and immunofluorescence to investigate the biological effect of high-frequency nsPEFs on PCa cells. Our results show that high-frequency nsPEFs induces the permeabilization and cell death of PCa cells. The cytotoxicity is significantly enhanced in MHz compression of pulses and with the presence of extracellular Ca2+. High-frequency nsPEFs trigger changes in PCa cells' cytoskeleton and their mobility. The presented data show a therapeutic potential of high-frequency nsPEFs in a PCa setting. The sub-microsecond regime of pulses can potentially be applied in nanosecond electroporation protocols for PCa treatment.

Zinc Complexes with 1,3-Diketones as Activators for Sulfur Vulcanization of Styrene-Butadiene Elastomer Filled with Carbon Black.

Zinc oxide nanoparticles (N-ZnO) and zinc complexes with 1,3-diketones of different structures were applied instead of microsized zinc oxide (M-ZnO) to activate the sulfur vulcanization of styrene-butadiene rubber (SBR). The influence of vulcanization activators on the cure characteristics of rubber compounds, as well as crosslink density and functional properties of SBR vulcanizates, such as tensile properties, hardness, damping behavior, thermal stability and resistance to thermo-oxidative aging was explored. Applying N-ZnO allowed to reduce the content of zinc by 40% compared to M-ZnO without detrimental influence on the cure characteristic and performance of SBR composites. The activity of zinc complexes in vulcanization seems to strongly depend on their structure, i.e., availability of zinc to react with curatives. The lower the steric hindrance of the substituents and thus the better the availability of zinc ions, the greater was the activity of the zinc complex and consequently the higher the crosslink density of the vulcanizates. Zinc complexes had no detrimental effect on the time and temperature of SBR vulcanization. Despite lower crosslink density, most vulcanizates with zinc complexes demonstrated similar or improved functional properties in comparison with SBR containing M-ZnO. Most importantly, zinc complexes allowed the content of zinc in SBR compounds to be reduced by approximately 90% compared to M-ZnO.

Task-Specific Ionic Liquids with Lactate Anion Applied to Improve ZnO Dispersibility in the Ethylene-Propylene-Diene Elastomer.

Task-specific ionic liquids (TSILs) are ionic liquids with structures and, consequently, properties and behaviors designed for particular applications. In this work, task-specific ILs with alkylammonium or benzalkonium cations and carboxyl groups in the form of lactate anions were used to promote the homogeneous dispersion of the curatives in the elastomer matrix. The reaction of carboxyl groups of TSILs with zinc oxide, which acts as a vulcanization activator, was confirmed. This interaction improved the solubility and dispersibility of zinc oxide particles in the ethylene-propylene-diene (EPDM) monomer matrix, which consequently affected the curing characteristics of rubber compounds. Most importantly, TSILs increased the efficiency of vulcanization by shortening the time, lowering the temperature and increasing the enthalpy of this process, while maintaining safe processing of elastomer composites. EPDM vulcanizates containing TSILs with lactate anion were characterized by satisfactory functional properties.

Vitamin D Compounds PRI-2191 and PRI-2205 Enhance Anastrozole Activity in Human Breast Cancer Models.

1,25-Dihydroxycholecalciferol, the hormonally active vitamin D3 metabolite, is known to exhibit therapeutic effects against breast cancer, mainly by lowering the expression of estrogen receptors and aromatase activity. Previously, the safety of the vitamin D active metabolite (24R)-1,24-dihydroxycholecalciferol (PRI-2191) and 1,25(OH)2D3 analog PRI-2205 was tested, and the in vitro activity of these analogs against different cancer cell lines was studied. We determined the effect of the two vitamin D compounds on anastrozole (An) activity against breast cancer based on antiproliferative activity, ELISA, flow cytometry, enzyme inhibition potency, PCR, and xenograft study. Both the vitamin D active metabolite and synthetic analog regulated the growth of not only estrogen receptor-positive cells (T47D and MCF-7, in vitro and in vivo), but also hormone-independent cancer cells such as SKBR-3 (HER-2-positive) and MDA-MB-231 (triple-negative), despite their relatively low VDR expression. Combined with An, PRI-2191 and PRI-2205 significantly inhibited the tumor growth of MCF-7 cells. Potentiation of the antitumor activity in combined treatment of MCF-7 tumor-bearing mice is related to the reduced activity of aromatase by both An (enzyme inhibition) and vitamin D compounds (switched off/decreased aromatase gene expression, decreased expression of other genes related to estrogen signaling) and by regulation of the expression of the estrogen receptor ERα and VDR.

Manganese and Nickel Acetylacetonates as Curatives for Chloroprene Rubber Based on Heck's Reaction.

The commonly used curing system for chloroprene rubber (CR) is a combination of two metal oxides, such as magnesium oxide (MgO) and zinc oxide (ZnO). Application of MgO and ZnO enables to obtain a good balance between processability of rubber compounds and mechanical properties of the vulcanizates. Despite high activity in crosslinking reactions, ZnO is classified as ecotoxic to aquatic organisms, thus environmental legislation requires its quantity in technology to be limited. In our studies more environmentally friendly curing systems were applied, which enabled eliminating ZnO from CR compounds. These curing systems consisted of manganese acetylacetonate (Mn(acac)) or nickel acetylacetonate (Ni(acac)) and triethanolamine (TEOA) used as a base necessary to perform Heck's reaction. Both metal acetylacetonates exhibited high activity in crosslinking reactions, which was confirmed by a great torque increment during rheometric measurements and high degree of elastomer crosslinking. The type of metal acetylacetonate and the amount of TEOA seemed to have less influence on the efficiency of the curing system than the filler used. Rubber compounds filled with carbon black (CB) were characterized by definitely shorter optimal vulcanization times and higher degree of crosslinking compared to CR composites filled with nanosized SiO2. Moreover, application of the proposed curing systems allowed to obtain CR vulcanizates with mechanical properties comparable with the benchmarks cured with metal oxides.

All That Glitters Is Not Silver-A New Look at Microbiological and Medical Applications of Silver Nanoparticles.

Silver and its nanoparticles (AgNPs) have different faces, providing different applications. In recent years, the number of positive nanosilver applications has increased substantially. It has been proven that AgNPs inhibit the growth and survival of bacteria, including human and animal pathogens, as well as fungi, protozoa and arthropods. Silver nanoparticles are known from their antiviral and anti-cancer properties; however, they are also very popular in medical and pharmaceutical nanoengineering as carriers for precise delivery of therapeutic compounds, in the diagnostics of different diseases and in optics and chemistry, where they act as sensors, conductors and substrates for various syntheses. The activity of AgNPs has not been fully discovered; therefore, we need interdisciplinary research to fulfil this knowledge. New forms of products with silver will certainly find application in the future treatment of many complicated and difficult to treat diseases. There is still a lack of appropriate and precise legal condition regarding the circulation of nanomaterials and the rules governing their safety use. The relatively low toxicity, relative biocompatibility and selectivity of nanoparticle interaction combined with the unusual biological properties allow their use in animal production as well as in bioengineering and medicine. Despite a quite big knowledge on this topic, there is still a need to organize the data on AgNPs in relation to specific microorganisms such as bacteria, viruses or fungi. We decided to put this knowledge together and try to show positive and negative effects on prokaryotic and eukaryotic cells.

The Influence of Curing Systems on the Cure Characteristics and Physical Properties of Styrene-Butadiene Elastomer.

The goal of this work is to study the influence of different curing systems on the cure characteristics and performance of styrene-butadiene elastomer (SBR) filled with carbon black or nanosized silica. A multifunctional additive for rubber compounds, namely Activ8, was applied as an additional activator and accelerator to increase the efficiency of sulfur vulcanization and to reduce the content of zinc oxide elastomers cured in the presence of 2-mercaptobenzothizole or 1,3-diphenylguanidine as a primary accelerator. The influence of the curing system composition on the crosslink density and physical properties of SBR vulcanizates, such as mechanical properties, thermal stability, and resistance to thermo-oxidative aging, is also reported. Activ8 effectively supports the vulcanization of SBR compounds, especially filled with nanosized silica. It reduces the optimal vulcanization time of SBR compounds and increases the crosslink density of the vulcanizates. Moreover, vulcanizates with Activ8 exhibit higher tensile strength and better damping properties than elastomer with zinc oxide. Activ8 allows the amount of ZnO to be reduced by 40% without detrimental effects on the crosslink density and mechanical performance compared to the vulcanizates conventionally crosslinked with ZnO. This is an important ecological goal since ZnO is classified as being toxic to aquatic species.

Heterogeneity of telomerase reverse transcriptase mutation and expression, telomerase activity and telomere length across human cancer cell lines cultured in vitro.

Promoter region of the telomerase reverse transcriptase gene (TERTp) constitutes a regulatory element capable to affect TERT expression (TE), telomerase activity (TA) and telomere length (TL). TERTp mutation status, TL, TA and TE were assessed in 27 in vitro cultured human cell lines, including 11 solid tumour, 13 haematological and 3 normal cell lines. C228T and C250T TERTp mutations were detected in 5 solid tumour and none of haematological cell lines (p = 0.0100). As compared to other solid tumour cell lines, those with the presence of somatic mutations were characterized by: shorter TL, lower TA and TE. Furthermore, cell lines carrying TERTp mutations showed a linear correlation between TE and TA (R = 0.9708, p = 0.0021). Moreover, haematological cell lines exhibited higher TE compared to solid tumour cell lines (p = 0.0007). TL and TA were correlated in both solid tumour (R = 0.4875, p = 0.0169) and haematological (R = 0.4719, p = 0.0095) cell lines. Our results based on the in vitro model suggest that oncogenic processes may differ between solid tumours and haematological malignancies with regard to their TERT gene regulation mechanisms.

Ionic Liquids and Calcium Oxide Grafted with Allylmalonic Acid Applied to Support the Peroxide Crosslinking of an Ethylene-Propylene Copolymer.

Nanosized calcium oxide (CaO) featuring a surface grafted with allylmalonic acid (ALA) was used to increase the efficiency of the peroxide crosslinking of an ethylene-propylene copolymer (EPM) filled with silica nanoparticles. In this study, 1-butyl-3-methylimidazolium ionic liquids (ILs) with different anions were applied to improve the dispersion of CaO/ALA and silica nanoparticles in the EPM copolymer, as well as to catalyze the interfacial crosslinking reactions. In this article, we discuss the effects of CaO/ALA and ILs on the curing characteristics, vulcanization temperature, crosslink density, mechanical properties, and thermal stability of EPM, as well as the resistance of EPM to weather aging. The CaO/ALA with ILs reduced the vulcanization time of the rubber compounds without a significant effect on the vulcanization temperature. Their application resulted in an increased vulcanizate crosslink density, as well as improved tensile strength compared to the pure peroxide system. The influence of 1-butyl-3-methylimidazolium ILs on EPM vulcanization and performance depends on the anion present in the molecules of the ionic liquid. The most active IL seems to be that with the tetrafluoroborate anion.

Octahydroquinoxalin-2(1H)-One-Based Aminophosphonic Acids and Their Derivatives-Biological Activity Towards Cancer Cells.

In the search for new antitumor agents, aminophosphonic acids and their derivatives based on octahydroquinoxalin-2(1H)-one scaffold were obtained and their cytotoxic properties and a mechanism of action were evaluated. Phosphonic acid and phosphonate moieties increased the antiproliferative activity in comparison to phenolic Mannich bases previously reported. Most of the obtained compounds revealed a strong antiproliferative effect against leukemia cell line (MV-4-11) with simultaneous low cytotoxicity against normal cell line (mouse fibroblasts-BALB/3T3). The most active compound was diphenyl-[(1R,6R)-3-oxo-2,5-diazabicyclo[4.4.0]dec-4-yl]phosphonate. Preliminary evaluation of the mechanism of action showed the proapoptotic effect associated with caspase 3/7 induction.

Effect of SILPs on the Vulcanization and Properties of Ethylene-Propylene-Diene Elastomer.

Ionic liquids (ILs) are increasingly used in elastomer technology due to unique physico-chemical properties, which are stable at the temperature of preparation and during processing of rubber compounds. The latest IL application concept is supported ionic liquid-phase (SILP) materials, where an IL film is immobilized on the solid phase. The main aim of this work was studying the influence of IL immobilized on the surface of solid supports, such as silica and carbon black, on the vulcanization process, mechanical properties, and thermal behavior of ethylene-propylene-diene (EPDM) elastomer. Application of the SILP materials enabled the control of EPDM vulcanization without deterioration of the crosslink density, damping properties, thermal stability, and resistance of the vulcanizates to thermo-oxidative aging. Slight improvements in the tensile strength and hardness of the vulcanizates were observed.

Divergent Effect of Tacalcitol (PRI-2191) on Th17 Cells in 4T1 Tumor Bearing Young and Old Ovariectomized Mice.

Vitamin D and its analogs are known for their role in the development of breast cancer and in immunomodulation. Our previous studies have shown the pro-metastatic effect of calcitriol and tacalcitol (PRI-2191) in young mice bearing 4T1 breast cancer and the anti-metastatic effect in aged ovariectomized (OVX) mice. Therefore, the aim of our work was to characterize Th17 cell population in young and aged OVX mice bearing 4T1 tumors treated with calcitriol and PRI-2191. The expression of genes typical for Th17 cells was examined in splenocytes, as well as splenocytes differentiated with IL-6 and TGF-ß to Th17 cells (iTh17). Expression of genes encoding vitamin D receptor (Vdr) and osteopontin (Spp1) as well as the secretion of IL-17A were evaluated in iTh17 cells. PRI-2191 treatment increased the expression of Rora and Rorc transcription factors, Il17a, Il17re and Il21 in iTh17 cells from young mice. In aged OVX mice this effect was not observed. Increased expression was observed in the case of Vdr and Spp1 genes in iTh17 cells from young mice treated with PRI-2191. What is more, in young mice treated with PRI-2191 the secretion of IL-17A to the culture media by iTh17 cells was increased, whereas in aged OVX mice a significant decrease was noted. Increased expression of Spp1 in young mice treated with PRI-2191 may enhance the differentiation of Th17 cells.

Organic Zinc Salts as Pro-Ecological Activators for Sulfur Vulcanization of Styrene-Butadiene Rubber.

Organic zinc salts and complexes were applied as activators for sulfur vulcanization of styrene-butadiene elastomer (SBR) in order to reduce the content of zinc ions in rubber compounds as compared with conventionally used zinc oxide. In this article, the effects of different organic zinc activators on the curing characteristics, crosslink densities, and mechanical properties of SBR as well as the aging resistance and thermal behavior of vulcanizates are discussed. Organic zinc salts seem to be good substitutes for zinc oxide as activators for sulfur vulcanization of SBR rubber, without detrimental effects to the vulcanization time and temperature. Moreover, vulcanizates containing organic zinc salts exhibit higher tensile strength and better damping properties than vulcanizate crosslinked with zinc oxide. The application of organic zinc activators allows the amount of zinc ions in SBR compounds to be reduced by 70-90 wt % compared to vulcanizate with zinc oxide. This is very important for ecological reasons, since zinc oxide is classified as being toxic to aquatic species.