ERα36–GPER1 Collaboration Inhibits TLR4/NFκB-Induced Pro-Inflammatory Activity in Breast Cancer Cells

Inflammation is important for the initiation and progression of breast cancer. We have previously reported that in monocytes, estrogen regulates TLR4/NFκB-mediated inflammation via the interaction of the Erα isoform ERα36 with GPER1. We therefore investigated whether a similar mechanism is present in breast cancer epithelial cells, and the effect of ERα36 expression on the classic 66 kD ERα isoform (ERα66) functions. We report that estrogen inhibits LPS-induced NFκB activity and the expression of downstream molecules TNFα and IL-6. In the absence of ERα66, ERα36 and GPER1 are both indispensable for this effect. In the presence of ERα66, ERα36 or GPER1 knock-down partially inhibits NFκB-mediated inflammation. In both cases, ERα36 overexpression enhances the inhibitory effect of estrogen on inflammation. We also verify that ERα36 and GPER1 physically interact, especially after LPS treatment, and that GPER1 interacts directly with NFκB. When both ERα66 and ERα36 are expressed, the latter acts as an inhibitor of ERα66 via its binding to estrogen response elements. We also report that the activation of ERα36 leads to the inhibition of breast cancer cell proliferation. Our data support that ERα36 is an inhibitory estrogen receptor that, in collaboration with GPER1, inhibits NFκB-mediated inflammation and ERα66 actions in breast cancer cells.     

Development of Specific LC-ESI-MS/MS Methods to Determine Bifenthrin, Lufenuron, and Iprodione Residue Levels in Green Beans, Peas, and Chili Peppers Under Egyptian Field Conditions

The dissipation of bifenthrin, lufenuron, and iprodione was studied in green beans, peas, and chilli peppers under Egyptian field conditions. For this purpose, three specific and one multi-analyte liquid chromatography-electrospray ionization-tandem mass spectrometry methods were developed and validated according to SANCO guidelines for the determination of bifenthrin, iprodione, and lufenuron residues in the selected commodities. Sample preparation was carried out by the QuEChERs approach, and determination was performed in positive ionization mode for iprodione and bifenthrin and in negative mode for lufenuron. Optimization of the ionization parameters and the chromatographic conditions was performed for each method developed. All methods showed satisfactory performance criteria. Linear dynamic range, limits of detection (LOD) and quantification (LOQ), precision, recovery, and matrix effects were estimated, and the calculated LODs were in the micrograms-per-kilogram range, namely 0.14, 0.61, and 1.4 μg/kg for bifenthrin, lufenuron, and iprodione, respectively. Field trials were carried out in one of the biggest farms in Egypt (Blue Nile) that exports significant quantities of vegetables to the European Union (EU) countries. All the examined pesticides showed high degradation rates. The t _1/2 values for bifenthrin were 3.3, 2.1, and 9.6 days in green beans, peas, and chili peppers, respectively. For iprodione, they reached 2.4 and 14.4 days in green beans and peppers. Furthermore, the calculated pre-harvest interval (PHI) values, according to the maximum residue limits set by EU, were 0, 4, and 0 days for bifenthrin in green beans, peas, and peppers, respectively, and for iprodione, 2 days in green beans and 0 days in peppers. In case of lufenuron, no t _1/2 and PHI were estimated as no residues were found in all pea samples.     

Quiescent and shear-induced non-isothermal crystallization of isotactic polypropylene-based nanocomposites

The paper reports a study of the effect of the addition of clay nanoparticles on melt rheology, phase structure, and non-isothermal crystallization process of isotactic polypropylene/hydrogenated oligocyclopentadiene (iPP/HOCP) system in quiescent conditions by DSC and under shear applied at different temperatures by SAXS. For both crystallization conditions, the addition of clay and/or HOCP shifts always the crystallization onset to lower values with respect to iPP. These results can be attributed to the diluent effect of HOCP that causes a decrease in the rate of nucleation and grow of the crystals, to the presence of segregated non-crystallizable phases/particles which hinder the transport of macromolecules chains toward the growing nuclei, and to the formation of beta iPP crystals and in the case of shear-induced crystallization to the presence of HPS which seems to reduce, mainly at low T _s, the amount of oriented polymer crystals, which are nuclei for the crystallization. At a given composition, the crystallization temperatures related at the crystallization under shear are always higher that those obtained by quiescent crystallization supporting the idea that the presence of extended chains in these samples act as nucleating agents favoring the crystallization process of iPP.     

Different Binding Modes of Small and Large Binders of GAT1

Well‐known inhibitors of the γ‐aminobutyric acid (GABA) transporter GAT1 share a common scaffold of a small cyclic amino acid linked by an alkyl chain to a moiety with two aromatic rings. Tiagabine, the only FDA‐approved GAT1 inhibitor, is a typical example. Some small amino acids such as (R)‐nipecotic acid are medium‐to‐strong binders of GAT1, but similar compounds, such as proline, are very weak binders. When substituted with 4,4‐diphenylbut‐3‐en‐1‐yl (DPB) or 4,4‐bis(3‐methylthiophen‐2‐yl)but‐3‐en‐1‐yl (BTB) groups, the resulting compounds have similar pK_i and pIC₅₀ values, even though the pure amino acids have very different values. To investigate if small amino acids and their substituted counterparts share a similar binding mode, we synthesized butyl‐, DPB‐, and BTB‐substituted derivatives of small amino acids. Supported by the results of docking studies, we propose different binding modes not only for unsubstituted und substituted, but also for strong‐ and weak‐binding amino acids. These data lead to the conclusion that following a fragment‐based approach, not pure but N‐butyl‐substituted amino acids should be used as starting points, giving a better estimate of the activity when a BTB or DPB substituent is added.     

Structure‐Based Design of Microsomal Prostaglandin E2 Synthase‐1 (mPGES‐1) Inhibitors using a Virtual Fragment Growing Optimization Scheme

A small library of 2,3‐dihydroxybenzamide‐ and N‐(2,3‐dihydroxyphenyl)‐4‐sulfonamide‐based microsomal prostaglandin E₂ synthase‐1 (mPGES‐1) inhibitors was identified following a step‐by‐step optimization of small aromatic fragments selected to interact in focused regions in the active site of mPGES‐1. During the virtual optimization process, the 2,3‐dihydroxybenzamide moiety was first selected as a backbone of the proposed new chemical entities; the identified compounds were then synthesized and biologically evaluated, identifying derivatives with very promising inhibitory activities in the micromolar range. Subsequent structure‐guided replacement of the 2,3‐dihydroxybenzamide by the N‐(2,3‐dihydroxyphenyl)sulfonamide moiety led to the identification of N‐(2,3‐dihydroxyphenyl)‐4‐biphenylsulfonamide ( 6 ), the most potent small molecule of the series (IC₅₀=0.53±0.04 μm ). The simple synthetic procedure and the possibility of enhancing the potency of this class of inhibitors through additional structural modifications pave the way for further development of new molecules with mPGES‐1‐inhibitory activity, with potential application as anti‐inflammatory and anticancer agents.     

Fuzzy maps: A new tool for mobile robot perception and planning

An essential component of an autonomous mobile robot is the exteroceptive sensory system. Sensing capabilities should be integrated with a method for extracting a representation of the environment from uncertain sensor data and with an appropriate planning algorithm. In this article, fuzzy logic concepts are used to introduce a tool useful for robot perception as well as for planning collision-free motions. In particular, a map of the environment is defined as the fuzzy set of unsafe points, whose membership function quantifies the possibility for each point to belong to an obstacle. The computation of this set is based on a specific sensor model and makes use of intermediate sets generated from range measures and aggregated by means of fuzzy set operators. This general approach is applied to a robot with ultrasonic rangefinders. The resulting map building algorithm performs well, as confirmed by a comparison with stochastic methods. The planning problem on fuzzy maps can be solved by defining various path cost functions, corresponding to different strategies, and by searching the map for optimal paths. To this end, proper instances of the A* algorithm are devised. Experimental results for a Nomad 200™ robot moving in a real-world environment are presented. © 1997 John Wiley & Sons, Inc.     

The Other Side of the Coin: May Androgens Have a Role in Breast Cancer Risk?

Breast cancer prevention is a major challenge worldwide. During the last few years, efforts have been made to identify molecular breast tissue factors that could be linked to an increased risk of developing the disease in healthy women. In this concern, steroid hormones and their receptors are key players since they are deeply involved in the growth, development and lifetime changes of the mammary gland and play a crucial role in breast cancer development and progression. In particular, androgens, by binding their own receptor, seem to exert a dichotomous effect, as they reduce cell proliferation in estrogen receptor α positive (ERα+) breast cancers while promoting tumour growth in the ERα negative ones. Despite this intricate role in cancer, very little is known about the impact of androgen receptor (AR)-mediated signalling on normal breast tissue and its correlation to breast cancer risk factors. Through an accurate collection of experimental and epidemiological studies, this review aims to elucidate whether androgens might influence the susceptibility for breast cancer. Moreover, the possibility to exploit the AR as a useful marker to predict the disease will be also evaluated.