Role of HMOX1 Promoter Genetic Variants in Chemoresistance and Chemotherapy Induced Neutropenia in Children with Acute Lymphoblastic Leukemia

Whilst the survival rates of childhood acute lymphoblastic leukemia (ALL) have increased remarkably over the last decades, the therapy resistance and toxicity are still the major causes of treatment failure. It was shown that overexpression of heme oxygenase-1 (HO-1) promotes proliferation and chemoresistance of cancer cells. In humans, the HO-1 gene (HMOX1) expression is modulated by two polymorphisms in the promoter region: (GT)n-length polymorphism and single-nucleotide polymorphism (SNP) A(−413)T, with short GT repeat sequences and 413-A variants linked to an increased HO-1 inducibility. We found that the short alleles are significantly more frequent in ALL patients in comparison to the control group, and that their presence may be associated with a higher risk of treatment failure, reflecting the role of HO-1 in chemoresistance. We also observed that the presence of short alleles may predispose to develop chemotherapy-induced neutropenia. In case of SNP, the 413-T variant co-segregated with short or long alleles, while 413-A almost selectively co-segregated with long alleles, hence it is not possible to determine if SNPs are actually of phenotypic significance. Our results suggest that HO-1 can be a potential target to overcome the treatment failure in ALL patients.     

Myopathy-Sensitive G-Actin Segment 227-235 Is Involved in Salt-Induced Stabilization of Contacts within the Actin Filament

Formation of stable actin filaments, critically important for actin functions, is determined by the ionic strength of the solution. However, not much is known about the elements of the actin fold involved in ionic-strength-dependent filament stabilization. In this work, F-actin was destabilized by Cu²⁺ binding to Cys374, and the effects of solvent conditions on the dynamic properties of F-actin were correlated with the involvement of Segment 227-235 in filament stabilization. The results of our work show that the presence of Mg²⁺ at the high-affinity cation binding site of Cu-modified actin polymerized with MgCl₂ strongly enhances the rate of filament subunit exchange and promotes the filament instability. In the presence of 0.1 M KCl, the filament subunit exchange was 2–3-fold lower than that in the MgCl₂-polymerized F-actin. This effect correlates with the reduced accessibility of the D-loop and Segment 227-235 on opposite filament strands, consistent with an ionic-strength-dependent conformational change that modulates involvement of Segment 227-235 in stabilization of the intermonomer interface. KCl may restrict the mobility of the α-helix encompassing part of Segment 227-235 and/or be bound to Asp236 at the boundary of Segment 227-235. These results provide experimental evidence for the involvement of Segment 227-235 in salt-induced stabilization of contacts within the actin filament and suggest that they can be weakened by mutations characteristic of actin-associated myopathies.     

Computer-Aided Search for 5-Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1-Based Multidrug Resistance

ABCB1 modulation is an interesting strategy in the search for new anticancer agents that can overcome multidrug resistance (MDR). Hence, 17 new 5-arylideneimidazolones containing an amine moiety, as potential ABCB1 inhibitors, were designed, synthesized, and investigated. The series was tested in both parental (PAR) and multidrug-resistant (MDR) ABCB1-overexpressing T-lymphoma cancer cells using cytotoxicity assays. The ABCB1-modulating activity was examined in rhodamine 123 accumulation tests, followed by Pgp-Glo™ Assay to determine the influence of the most active compounds on ATPase activity. Lipophilic properties were assessed both, in silico and experimentally (RP-TLC). Pharmacophore-based molecular modelling toward ABCB1 modulation was performed. The studies allowed the identification of anticancer agents (p-fluorobenzylidene derivatives) more potent than doxorubicin, with highly selective action on MDR T-lymphoma cells (selectivity index >40). Most of the investigated compounds showed ABCB1-modulating action; in particular, two 5-benzyloxybenzylidene derivatives displayed activity nearly as strong as that of tariquidar.     

Potential of Silver Nanoparticles in Overcoming the Intrinsic Resistance of Pseudomonas aeruginosa to Secondary Metabolites from Carnivorous Plants

Carnivorous plants are exemplary natural sources of secondary metabolites with biological activity. However, the therapeutic antimicrobial potential of these compounds is limited due to intrinsic resistance of selected bacterial pathogens, among which Pseudomonas aeruginosa represents an extreme example. The objective of the study was to overcome the intrinsic resistance of P. aeruginosa by combining silver nanoparticles (AgNPs) with secondary metabolites from selected carnivorous plant species. We employed the broth microdilution method, the checkerboard titration technique and comprehensive phytochemical analyses to define interactions between nanoparticles and active compounds from carnivorous plants. It has been confirmed that P. aeruginosa is resistant to a broad range of secondary metabolites from carnivorous plants, i.e., naphthoquinones, flavonoids, phenolic acids (MBC = 512 µg mL⁻¹) and only weakly sensitive to their mixtures, i.e., extracts and extracts’ fractions. However, it was shown that the antimicrobial activity of extracts and fractions with a significant level of naphthoquinone (plumbagin) was significantly enhanced by AgNPs. Our studies clearly demonstrated a crucial role of naphthoquinones in AgNPs and extract interaction, as well as depicted the potential of AgNPs to restore the bactericidal activity of naphthoquinones towards P. aeruginosa. Our findings indicate the significant potential of nanoparticles to modulate the activity of selected secondary metabolites and revisit their antimicrobial potential towards human pathogenic bacteria.     

Anti-Inflammatory Activity of Oat Beta-Glucans in a Crohn’s Disease Model: Time- and Molar Mass-Dependent Effects

Background: The incidence of Crohn’s disease (CD) is increasing worldwide, and it has currently become a serious public health issue in society. The treatment of CD continues throughout a patient’s lifetime, and therefore, it is necessary to develop new, effective treatment methods, including dietotherapy. The present study aimed to determine the effects of consumption of oat beta-glucans with different molar mass on colon inflammation (colitis) in the early stages of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced CD in an animal model. Methods: Sprague–Dawley rats (control and TNBS-induced CD) were divided into three dietary groups and fed for 3 days (reflecting acute inflammation) or 7 days (reflecting remission) with a feed containing 1% low (βGl) or high (βGh) molar mass oat beta-glucan or a feed without this polysaccharide. The level of colon inflammatory markers and the expression of cytokines and their receptor genes were measured by ELISA and RT-PCR methods, respectively. Results: Acute inflammation or remission (3 or 7 days after TNBS administration, respectively) stages of experimentally induced CD were characterized by an increase in the level of inflammatory markers (IL-1, IL-6, IL-10, IL-12, TNF-α, CRP, MPO, COX, and PGE2) and the disruption of some cytokine signaling pathways as well as macro- and microscopic changes of colon tissue. The consumption of oat beta-glucans reduced the level of inflammatory markers and recovered the signaling pathways and histological changes, with stronger effects of βGl after 7 days of colitis. Conclusions: Dietary oat beta-glucans can reduce colitis at the molecular and organ level and accelerate CD remission.     

The Co-Culture of Staphylococcal Biofilm and Fibroblast Cell Line: The Correlation of Biological Phenomena with Metabolic NMR1 Footprint

Staphylococcus aureus is one of the most prevalent pathogens associated with several types of biofilm-based infections, including infections of chronic wounds. Mature staphylococcal biofilm is extremely hard to eradicate from a wound and displays a high tendency to induce recurring infections. Therefore, in the present study, we aimed to investigate in vitro the interaction between S. aureus biofilm and fibroblast cells searching for metabolites that could be considered as potential biomarkers of critical colonization and infection. Utilizing advanced microscopy and microbiological methods to examine biofilm formation and the staphylococcal infection process, we were able to distinguish 4 phases of biofilm development. The analysis of staphylococcal biofilm influence on the viability of fibroblasts allowed us to pinpoint the moment of critical colonization—12 h post contamination. Based on the obtained model we performed a metabolomics analysis by ¹H NMR spectroscopy to provide new insights into the pathophysiology of infection. We identified a set of metabolites related to the switch to anaerobic metabolism that was characteristic for staphylococcal biofilm co-cultured with fibroblast cells. The data presented in this study may be thus considered a noteworthy but preliminary step in the direction of developing a new, NMR-based tool for rapid diagnosing of infection in a chronic wound.     

Interplay between Coumarin Accumulation,Iron Deficiency and Plant Resistance to Dickeya spp.

Coumarins belong to a group of secondary metabolites well known for their high biological activities including antibacterial and antifungal properties. Recently, an important role of coumarins in plant resistance to pathogens and their release into the rhizosphere upon pathogen infection was discovered. It is also well documented that coumarins play a crucial role in the Arabidopsis thaliana growth under Fe-limited conditions. However, the mechanisms underlying interplay between plant resistance, accumulation of coumarins and Fe status, remain largely unknown. In this work, we investigated the effect of both mentioned factors on the disease severity using the model system of Arabidopsis/Dickeya spp. molecular interactions. We evaluated the disease symptoms in Arabidopsis plants, wild-type Col-0 and its mutants defective in coumarin accumulation, grown in hydroponic cultures with contrasting Fe regimes and in soil mixes. Under all tested conditions, Arabidopsis plants inoculated with Dickeya solani IFB0099 strain developed more severe disease symptoms compared to lines inoculated with Dickeya dadantii 3937. We also showed that the expression of genes encoding plant stress markers were strongly affected by D. solani IFB0099 infection. Interestingly, the response of plants to D. dadantii 3937 infection was genotype-dependent in Fe-deficient hydroponic solution.     

Effect of Ca2+ and Mg2+ ions on the sintering and spectroscopic properties of cr-doped yttrium aluminum garnet ceramics

In this work, we investigated the effects of Ca²⁺ and Mg²⁺ ions and annealing temperature on the spectroscopic parameters of chromium-doped yttrium aluminum garnet ceramics (Cr:YAG). Samples were obtained with either a separate or a simultaneous addition of calcium and magnesium oxides. To achieve this, aqueous suspensions were prepared using Y₂O₃, Al₂O₃, Cr₂O₃, MgO, and CaO high-purity powders as raw materials. The obtained suspensions were freeze-granulated, pressed into pellets, debinded, and subjected to reactive sintering in vacuum at 1715°C for 6 h. Each material was annealed in air with temperatures between 1300 and 1700°C. Samples were also compared to Cr:YAG ceramics with the addition of silica as a sintering aid. All the materials obtained were then exposed to 445 nm excitation, and emission spectra in the visible and infrared wavelengths were recorded. The results showed that the emission spectra of Cr:YAG ceramics varied according to the annealing conditions: as-sintered samples exhibited strong emissions of around 680 nm and, after air annealing, of around 1400 nm. This phenomenon is attributed to the Cr³⁺→Cr⁴⁺ transition. Samples doped solely with MgO exhibited the highest emission intensity in the infrared region. Thus, Mg²⁺ ions provided the best conversion efficiency of chromium ions.     

Stability of nonlinear 2D systems described by the continuous-time Roesser model

This paper considers systems with two-dimensional dynamics (2D systems) described by the continuous-time nonlinear state-space Roesser model. The sufficient conditions of exponential stability in terms of vector Lyapunov functions are established. These conditions are then applied to analysis of the absolute stability of a certain class of systems comprising a linear continuous-time plant in the form of the Roesser model with a nonlinear characteristic in the feedback loop, which satisfies quadratic constraints. The absolute stability conditions are reduced to computable expressions in the form of linear matrix inequalities. The obtained results are extended to the class of continuous-time systems governed by the Roesser model with Markovian switching. The problems of absolute stability and stabilization via state- and output-feedback are solved for linear systems of the above class. The solution procedures for these problems are in the form of algorithms based on linear matrix inequalities.     

Comments on “Necessary and sufficient stability condition of fractional-order interval linear systems” [Automatica 44 (2008), 2985–2988]

This paper shows that the main thesis of the article “Necessary and sufficient stability condition of fractional-order interval linear systems” by Ahn and Chen (Automatica, vol. 44, pp. 2985–2988) is only a sufficient (and not a necessary) condition for the robust stability of fractional-order linear systems.