Investigation of the Antiproliferative Properties of Natural Sesquiterpenes from Artemisia asiatica and Onopordum acanthium on HL-60 Cells in Vitro

Plants and plant extracts play a crucial role in the research into novel antineoplastic agents. Four sesquiterpene lactones, artecanin (1), 3β-chloro-4α,10α-dihydroxy-1α,2α-epoxy-5α,7αH-guaia-11(13)-en-12,6α-olide (2), iso-seco-tanapartholide 3-O-methyl ether (3) and 4β,15-dihydro-3-dehydrozaluzanin C (4), were isolated from two traditionally used Asteraceae species (Onopordum acanthium and Artemisia asiatica). When tested for antiproliferative action on HL-60 leukemia cells, these compounds exhibited reasonable IC₅₀ values in the range 3.6–13.5 μM. Treatment with the tested compounds resulted in a cell cycle disturbance characterized by increases in the G1 and G2/M populations, while there was a decrease in the S phase. Additionally, 1–3 elicited increases in the hypodiploid (subG1) population. The compounds elicited concentration-dependent chromatin condensation and disruption of the membrane integrity, as revealed by Hoechst 33258–propidium staining. Treatment for 24 h resulted in significant increases in activity of caspases-3 and -9, indicating that the tested sesquiterpenes induced the mitochondrial pathway of apoptosis. The proapoptotic properties of the sesquiterpene lactones were additionally demonstrated withannexin V staining. Compounds 1 and 2 increased the Bax/Bcl-2 expression and decreased the expressions of CDK1 and cyclin B2, as determined at the mRNA level by means of RT-PCR. These experimental results indicate that sesquiterpene lactones may be regarded as potential starting structures for the development of novel anticancer agents.     

The Effect of Electroporation of a Lyotroic Liquid Crystal Genistein-Based Formulation in the Recovery of Murine Melanoma Lesions

A lamellar lyotropic liquid crystal genistein-based formulation (LLC-Gen) was prepared in order to increase the aqueous solubility of the lipophilic phytocompound genistein. The formulation was applied locally, in a murine model of melanoma, with or without electroporation. The results demonstrated that, when the formulation was applied by electroporation, the tumors appeared later. During the 21 days of the experiment, the LLC-Gen formulation decreased the tumor volume, the amount of melanin and the degree of erythema, but when electroporation was applied, all these parameters indicated a better prognosis even (lower tumor volume, amount of melanin and degree of erythema). Although hematoxylin–eosin (HE) staining confirmed the above events, application of the LLC-Gen formulation by electroporation did not lead to a significant effect in terms of the serum concentrations of the protein S100B and serum neuron specific enolase (NSE), or the tissue expression of the platelet-derived growth factor receptor β (PDGFRβ) antibody.     

How to assess the limits of ion-selective electrodes: method for the determination of the ultimate span, response range, and selectivity coefficients of neutral carrier-based cation selective electrodes

The span and range of an ion-selective electrode (ISE) has been identified by IUPAC as a potential or activity difference between the upper and lower detection limits of the electrode. Once the span is known, the ultimately attainable detection limit of the ISE can be calculated using its theoretical response slope. In this paper, we propose an original method for the determination of the ultimate span and response range of ISEs. The simple measurement of span is recommended to aid the fast screening of novel ionophores and help to focus optimization processes to the most promising candidates. The measurement of span is combined with a generally applicable procedure for the determination of the three seminal parameters of ISEs: the response slope, the ultimate selectivity coefficients, and detection limit. In the proposed procedure, following the span measurement, two subsequent exponential dilution experiments are completed in which the responses of the electrode for the primary and the interfering ions are tested using a solution of a discriminated ion and deionized water as diluting electrolytes in consecution. The advantages and the practical usefulness of the proposed methods and procedures are demonstrated through the evaluation of the performance characteristics of novel and well-characterized ionophore-based potassium and calcium sensors.     

Empirical Investigation of the Convergence Speed of Inclusion Functions in a Global Optimization Context

This paper deals with the empirical convergence speed of inclusion functions applied in interval methods for global optimization. According to our experience the natural interval extension of a given function can be as good as a usual quadratically convergent inclusion function, and although centered forms are in general only of second-order, they can perform as one of larger convergence order. These facts indicate that the theoretical convergence order should not be the only indicator of the quality of an inclusion function, it would be better to know which inclusion function can be used most efficiently in concrete instances. For this reason we have investigated the empirical convergence speed of the usual inclusion functions on some test functions.This work has been supported by the Grants OTKA T 034350 and T 032118, OMFB D–30/2000, and OMFB E–24/2001.The authors are grateful for the anonymous referees for their suggestions.     

TP53inp1 Gene Is Implicated in Early Radiation Response in Human Fibroblast Cells

Tumor protein 53-induced nuclear protein-1 (TP53inp1) is expressed by activation via p53 and p73. The purpose of our study was to investigate the role of TP53inp1 in response of fibroblasts to ionizing radiation. γ-Ray radiation dose-dependently induces the expression of TP53inp1 in human immortalized fibroblast (F11hT) cells. Stable silencing of TP53inp1 was done via lentiviral transfection of shRNA in F11hT cells. After irradiation the clonogenic survival of TP53inp1 knockdown (F11hT-shTP) cells was compared to cells transfected with non-targeting (NT) shRNA. Radiation-induced senescence was measured by SA-β-Gal staining and autophagy was detected by Acridine Orange dye and microtubule-associated protein-1 light chain 3 (LC3B) immunostaining. The expression of TP53inp1, GDF-15, and CDKN1A and alterations in radiation induced mitochondrial DNA deletions were evaluated by qPCR. TP53inp1 was required for radiation (IR) induced maximal elevation of CDKN1A and GDF-15 expressions. Mitochondrial DNA deletions were increased and autophagy was deregulated following irradiation in the absence of TP53inp1. Finally, we showed that silencing of TP53inp1 enhances the radiation sensitivity of fibroblast cells. These data suggest functional roles for TP53inp1 in radiation-induced autophagy and survival. Taken together, we suppose that silencing of TP53inp1 leads radiation induced autophagy impairment and induces accumulation of damaged mitochondria in primary human fibroblasts.     

Early social deprivation induces disturbed social communication and violent aggression in adulthood.

Disturbed social relations during childhood (e.g., social neglect) often lead to aggression-related psychopathologies in adulthood. Social isolation also increased aggressiveness in laboratory animals. Here the authors show in rats, that social isolation from weaning not only increases the level of aggressiveness, but results in abnormal attack patterns and deficits in social communication. In socially deprived rats, the share of attacks aimed at vulnerable body parts of opponents (head, throat, and belly) dramatically increased and the attack/threat ratio was shifted toward attacks, suggesting a decrease in intention signaling. Moreover, a Multiple Regression Analysis showed that the nonassociation of attacks with offensive threats predicted the occurrence of vulnerable attacks with 81.1% accuracy. The authors suggest that the social deprivation-induced abnormal aggression models the aggression-related problems resulting from early social neglect in humans, and studies on its brain mechanisms may increase our understanding of the mechanisms underlying psychopathologies resulting from early social problems. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Planar Location and Design of a New Facility with Inner and Outer Competition: An Interval Lexicographical-like Solution Procedure

A chain has to decide the location and design for a single new facility in a region where a set of facilities already exists offering the same type of product. Some of the existing facilities belong to the chain and the others are competitors. Since competition comes from outside the chain, the maximization of the profit is the main objective of the chain’s owner. Customers are supposed to patronize all the facilities, the old and the new, proportionally to the attraction they feel for them. The entrance of the new facility may thus also have a detrimental effect on the market shares of the existing chain-owned facilities, and this cannibalization should be minimized as a secondary objective. This problem is formulated as a biobjective optimization problem, and a variant of the lexicographic method is proposed to generate certain efficient solutions. This requires solving two related optimization problems, both neither convex nor concave, for which a unified interval branch and bound method is developed. Computational experiments on randomly generated problems show the feasibility of the approach, while an application of the model with real data demonstrates its use for economical analysis. This paper has been supported by the Ministry of Education and Science of Spain under the research project SEJ2005-06273/ECON, in part financed by the European Regional Development Fund (ERDF). Boglárka Tóth, on leave from the Research Group on Artificial Intelligence of the Hungarian Academy of Sciences and the University of Szeged, H-6720 Szeged, Aradi vértanúk tere 1., Hungary.     

On the impact of spatial pattern,aggregation, and model parameters in planar Huff-type competitive location and design problems

A chain wants to set up a single new facility in a planar market where similar facilities of competitors, and possibly of its own chain, are already present. Fixed demand points split their demand probabilistically over all facilities in the market proportionally with their attraction to each facility, determined by the different perceived qualities of the facilities and the distances to them, through a gravitational or logit type model. Both the location and the quality (design) of the new facility are to be found so as to maximize the profit obtained for the chain. Several types of constraints and costs are considered. Applying an interval analysis based global optimization method on several spatial patterns in a quasi-real-world environment, the behaviour of optimal solutions is investigated when changes are made in the basic model parameters. The study yields valuable insight for modellers into the impact of spatial pattern and various model parameters of the model on the resulting location and design decision. Spatial patterns differ in distribution of demand, of own and/or competing facilities, and of facility qualities. Studied model parameters include push force effects, investment restrictions and aggregation of demand. An extended version of this paper including additional studies on model parameters and the exact data used in the computational experiments is available at Optimization Online (see Tóth et al. (2008)). This work has been supported by grants from the Ministry of Science and Innovation of Spain (TIN2008-01117, SEJ2005-06273/ECON and ECO2008-00667/ECON), Junta de Andalucía (P08-TIC-3518), and in part by the European Regional Development Fund (ERDF).